Polycyclic compounds as lysophosphatidic acid receptor antagonists
Inventors
Clark, Ryan • Stearns, Brian Andrew • Scott, Jill Melissa • Coate, Heather Renee • ZHAO, Lucy • Seiders, Thomas J. • VOLKOTS, Deborah • Arruda, Jeannie • STOCK, Nicholas Simon • Truong, Yen Pham • Zalatan, David Nathan
Assignees
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Publication Number
US-8664220-B2
Publication Date
2014-03-04
Expiration Date
Abstract
Described herein are compounds that are antagonists of lysophosphatidic receptor(s). Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such antagonists, alone and in combination with other compounds, for treating LPA-dependent or LPA-mediated conditions or diseases.
Core Innovation
The disclosure provides a set of compounds, or pharmaceutically acceptable salts thereof, selected from enumerated chemical structures built on an isoxazole-biphenyl framework and a cyclopropanecarboxylic acid, acetic acid, or propionic acid scaffold. The compounds vary by substituents on the isoxazole framework and on the aromatic portions, including heterocycle-containing and amino-linked side chains, as well as substituted phenyl and pyridyl-derived substituents.
The examples and named compounds include oxazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, piperidinyl, pyrrolidinyl, piperazine carbonyl, and phenylamino or pyridylamino variants, together with biphenyl-4-yl and 3-methyl-isoxazol-5-yl motifs. The disclosure also includes enantiomer-defined members, with (R) and (S) designations and Enantiomer A and Enantiomer B described for particular compounds.
The material further presents ethyl ester intermediates and corresponding carboxylic acid products, including conversions from ester forms to the free acid. Across the enumerated examples, the compound family is defined by structural variation within the same isoxazole-linked biphenyl-cyclopropanecarboxylic acid chemical space, with related acetic acid and propionic acid analogs also included in the disclosed set.
Claims Coverage
The independent claim coverage is directed to an enumerated group of compounds, or pharmaceutically acceptable salts thereof, defined by specific isoxazole-linked biphenyl and cyclopropanecarboxylic acid structures. The inventive features are the structural scaffold itself, the specified substituent patterns on the isoxazole and aromatic portions, and the inclusion of stereochemically defined members and related acid analogs. Dependent claims in the provided material add a pharmaceutical composition and a method of treating fibrosis, including lung, renal, hepatic, or cutaneous fibrosis.
Enumerated isoxazole-biphenyl-cyclopropanecarboxylic acid compounds
A compound, or pharmaceutically acceptable salt thereof, selected from an enumerated group of specific chemical structures based on an isoxazole-biphenyl scaffold linked to a cyclopropanecarboxylic acid framework.
Substituted heterocycle and amino side chains
The enumerated compounds include substituents such as oxazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, piperidinyl, pyrrolidinyl, piperazine carbonyl, pyridylamino, and phenylamino groups.
Acetic acid and propionic acid analogs
The compound group further includes related acetic acid and propionic acid forms in addition to cyclopropanecarboxylic acid derivatives.
Defined stereochemistry in selected members
Selected compounds are defined with (R) and (S) stereochemistry, including Enantiomer A and Enantiomer B members.
Pharmaceutical composition comprising the enumerated compound
A pharmaceutical composition comprising the compound according to the independent claim, or a pharmaceutically acceptable salt thereof.
Method of treating fibrosis by administering the enumerated compound
A method for treating fibrosis in a mammal by administering a therapeutically effective amount of the compound according to the independent claim, or a pharmaceutically acceptable salt thereof.
Fibrosis indication narrowed to lung, renal, hepatic, or cutaneous fibrosis
The fibrosis being treated is selected from lung fibrosis, renal fibrosis, hepatic fibrosis, or cutaneous fibrosis.
Overall, claim coverage centers on an enumerated family of substituted isoxazole-biphenyl-cyclopropanecarboxylic acid compounds, including related acetic and propionic acid analogs and stereochemically defined members. The dependent claims extend this chemical coverage to a pharmaceutical composition and to fibrosis treatment methods with specific fibrosis types.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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