MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-kB ACTIVITY AND USE THEREOF
申请人:Yang Bingwei Vera
公开号:US20100063051A1
公开(公告)日:2010-03-11
Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity including inflammatory and immune diseases, obesity and diabetes having the structure of formula (I) an enantiomer, diastereomer, tautomer, solvate (e.g. a hydrate), or a pharmaceutically-acceptable salt, thereof, wherein: M is selected from alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, and heteroaryl, provided that if M is alkyl then R
6
and R
7
taken together with the carbon atom to which they are both attached are selected from a group other than cycloalkyl; Q is selected from (i) hydrogen, C
1
-C
4
alkyl, and substituted C
1
-C
4
alkyl; or (ii) Q and R
6
are combined with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl; or (iii) Q and M
a
M are combined with the carbon atom(s) to which they are attached to form a 3- to 7-membered ring containing 1-2 heteroatoms which are independently selected from the group consisting of O, S, SO
2
, and N which ring may be optionally substituted with 0-2 R
5
groups or carbonyl; Z is selected from cycloalkyl, heterocyclo, aryl, or heteroaryl; and M
a
, Z
a
, R
1
, R
2
, R
3
, R
4
, R
6
, R
7
, and R
22
are as defined herein. Also provided are pharmaceutical compositions and methods of treating metabolic and inflammatory- or immune-associated diseases or disorders using said compounds.
提供了一些新型非类固醇化合物,其在治疗与糖皮质激素受体、AP-1和/或NF-κB活性调节相关的疾病中非常有用,包括炎症和免疫性疾病、肥胖症和糖尿病,具有以下结构公式(I)的对映体、顺反异构体、互变异构体、溶剂化物(例如水合物)或其医药上可接受的盐,其中:M选自烷基、取代烷基、环烷基、芳基、杂环烷基和杂芳基,但如果M是烷基,则R6和R7与它们都连接的碳原子一起选自环烷基之外的一组;Q选自(i)氢、C1-C4烷基和取代的C1-C4烷基;或(ii)Q和R6与它们连接的碳原子结合形成3-到6-成员的环烷基;或(iii)Q和MaM与它们连接的碳原子结合形成1-2个杂原子(独立于O、S、SO2和N组成)的3-到7-成员的环,该环可以选择性地用0-2个R5基团或羰基取代;Z选自环烷基、杂环烷基、芳基或杂芳基;而Ma、Za、R1、R2、R3、R4、R6、R7和R22如本文所定义。还提供了制药组合物和使用所述化合物治疗代谢和炎症或免疫相关疾病或紊乱的方法。