Cyclic amide-containing pyridyl xanthines as A2B antagonists
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Publication Number
US-11814387-B2
Publication Date
2023-11-14
Expiration Date
Abstract
Described herein are cyclic amide-containing pyridyl-xanthines of formula I and pharmaceutical compositions thereof that are useful as antagonists of A2B adenosine receptors.
Core Innovation
The invention relates to compounds of formula I, including stereoisomers and pharmaceutically acceptable salts thereof, defined by selections of n, Ring A, and substituents R1 through R7, with alternative Ring A replacement and alternative (CH2)n-R3 definitions under a condition on at least one of R1 and R2. Ring A is selected from phenyl, naphthyl, and a 5-10 membered heteroaryl, and the (CH2)n group is substituted with 0-1 groups selected from C1-6 alkyl, C3-6 cycloalkyl, and —C1-3 alkylene-C3-6 cycloalkyl.
The compound definition provides structured options for R1, R2, and R3, including amide-containing groups and 4-10 membered cyclic amide motifs, and enumerated options for R4 and R5 that include halogens, alkyl and cycloalkyl groups, OR6/SR6, —CN, NR6R7 variants, CF3, OCF3, and multiple carbonyl, ester, amidic, and sulfonamido options. The disclosure also includes alternatives in which R4 and R5 are absent and Ring A is replaced by selected alkyl, CF3, cycloalkyl, and ether-linked phenyl or pyridyl groups, or in which —(CH2)n—R3 is selected from specified groups.
The document presents specific compound structures as embedded images and associated CDX/MOL files, including enumerated examples and table entries. Representative compounds are described as xanthine-based compounds and as cyclic amide-containing pyridyl-xanthines, with substituted heteroaryl rings and peripheral carbonyl/amide-containing groups and halogen substituents.
The disclosure also states that representative compounds are tested as A2B adenosine receptor antagonists using an HEK293 cAMP-coupled assay, with percent inhibition values reported against NECA, and includes compounds marked Not Tested. The patent further discloses pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, and states use in treating A2B-receptor implicated conditions including asthma and chronic obstructive pulmonary disorder (COPD).
Claims Coverage
The claim coverage defines a restricted compound class of formula I through detailed selections for Ring A, n, and substituents R1-R7, including alternative branches and table-listed embodiments, and also includes a pharmaceutical composition combining the compound with a pharmaceutically acceptable carrier.
Formula I compound definition with restricted substituent selection
A compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is selected from 1-10; the (CH2)n group is substituted with 0-1 groups selected from C1-6 alkyl, C3-6 cycloalkyl, and —C1-3 alkylene-C3-6 cycloalkyl; Ring A is selected from phenyl, naphthyl, and a 5-10 membered heteroaryl; and R1, R2, R3, R4, R5, R6, R7, and p are selected according to the specified lists and ranges, including alternative Ring A replacement and an alternative (CH2)n—R3 definition provided that at least one of R1 and R2 is an amide-containing group independently selected from —(CH2)2—NH(C(O)CH3 and —C1-6 alkylene-4-10 membered cyclic amide.
Compounds listed in table 2 and table 4
The compound defined by the claims is limited by dependent references to compounds listed in Table 2 and Table 4, encompassing depicted chemical structures shown as embedded images and associated CDX/MOL files, including stereoisomers and pharmaceutically acceptable salts.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition made from the compound of claim 1, or one of its stereoisomers or pharmaceutically acceptable salts, together with a pharmaceutically acceptable carrier.
The claim coverage defines a restricted compound class of formula I through detailed selections for Ring A, n, and substituents R1-R7, including alternative branches and table-listed embodiments, and also includes a pharmaceutical composition combining the compound with a pharmaceutically acceptable carrier.
Stated Advantages
Tested as A2B adenosine receptor antagonists using an HEK293 cAMP-coupled assay, with percent inhibition reported versus NECA.
Documented Applications
A2B adenosine receptor antagonist evaluation using an HEK293 cAMP-coupled assay for cyclic AMP generation, reporting percent inhibition against NECA (5′-N-ethylcarboxamidoadenosine).
Treating A2B-receptor implicated conditions including asthma and chronic obstructive pulmonary disorder (COPD).
Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the disclosed compound(s).
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