Triterpenoids and compositions containing the same

Patent metadata

Field	Value
Publication number	US-9539287-B2
Application number	US-201414496488-A
Country	US
Kind code	B2
Filing date	Sep 25, 2014
Priority date	May 8, 2012
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

The present invention provides triterpenoids produced from natural compounds such as oleanolic acid, ursolic acid, betulinic acid, and hederagenin.

First claim

What is claimed is:

1. A compound having the sdstructure of Formula II:

wherein,
at least one of X 1 and X 2 is OR a , NR a R b , or SR a , and the other of X 1 and X 2 is hydrogen, OR a , NR a R b , or SR a , wherein
R a is a hydrogen, cyano, —CF 3 , nitro, amino, or substituted or unsubstituted heteroaryl group;
R b is hydrogen, hydroxyl, alkyl, aryl, aralkyl, acyl, alkoxy, aryloxy, acyloxy, alkylamino, arylamino, amido, or a substituted version of any of these groups;
provided that R a is absent when the atom to which it is bound is part of a double bond, further provided that when R a is absent the atom to which it is bound is part of a double bond;

Y is CH 2 or CH 2 —CH 2 ;
Z is a covalent bond, —C(═O)—, alkanediyl, alkenediyl, alkynediyl, or a substituted version of any of these groups;
the dashed bonds can be independently present or absent;
R 1 , R 2 , R 3 and R 4 are each independently a hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy or substituted alkoxy group;
at least one of R 5 , R 6 , R 8 , R 9 or R 10 is independently —OMs, —CH 2 OMs, —C(═O)C≡CR a , —C≡CCO 2 R a , —C≡CSO 2 R a , —C≡CC(═O)R a or —SO 2 R a , or
R 5 and R 6 , or R 9 and R 10 are together ═CR c R d , wherein
R c is hydrogen or alkylthiyl, and
R d is hydrogen, halo, alkylthiyl, or substituted or unsubstituted alkylsulfonyl or alkylsulfonyl-O—;

the remainder of R 5 , R 6 , R 8 , R 9 and R 10 are independently hydrogen, hydroxyl, halo, cyano, ═O, —C≡CR a , —CO 2 R a , —COR a , alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, alkoxy, aryloxy, acyloxy, alkylamino, arylamino, nitro, amino, amido, —C(O)R e or a substituted version of any of these groups, wherein
R e is hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; or C 1 -C 15 -alkyl, C 2 -C 15 -alkenyl, C 2 -C 15 -alkynyl, C 6 -C 15 -aryl, C 7 -C 15 -aralkyl, C 1 -C 15 -heteroaryl, C 2 -C 15 -heteroaralkyl, C 1 -C 15 -acyl, C 1 -C 15 -alkoxy, C 2 -C 15 -alkenyloxy, C 2 -C 15 -alkynyloxy, C 6 -C 15 -aryloxy, C 7 -C 15 -aralkyloxy, C 1 -C 15 -heteroaryloxy, C 2 -C 15 -heteroaralkyloxy, C 1 -C 15 -acyloxy, C 1 -C 15 -alkylamino, C 2 -C 15 -dialkylamino, C 1 -C 15 -alkoxyamino, C 2 -C 15 -alkenylamino, C 2 -C 15 -alkynylamino, C 6 -C 15 -arylamino, C 7 -C 15 -aralkylamino, C 1 -C 15 -heteroarylamino, C 2 -C 15 -heteroaralkylamino, C 1 -C 15 -alkylsulfonylamino, C 1 -C 15 -amido, C 1 -C 15 -alkylsilyloxy, or substituted versions of any of these groups;

R 11 and R 12 are each independently hydrogen, hydroxyl, halo, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, alkoxy, aryloxy, aralkoxy, heteroaryloxy, hetero-aralkoxy, acyloxy, alkylamino, dialkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, amido, or a substituted version of any of these groups, or
R 11 and R 12 are taken together and are alkanediyl, alkenediyl, arenediyl, alkoxydiyl, alkenyloxydiyl, alkylaminodiyl, alkenylaminodiyl, or alkenylaminooxydiyl;
R 13 is hydrogen, hydroxy or oxo;
R 14 is hydrogen or hydroxyl; and
R 15 is
a hydrogen, hydroxyl, —NR f R g , cyano, halo, azido, phosphate, 1,3-dioxoisoindolin-2-yl, mercapto, silyl or —COOH group,
substituted or unsubstituted versions of C 1 -C 15 -alkyl, C 2 -C 15 -alkenyl, C 2 -C 15 -alkynyl, C 6 -C 15 -aryl, C 7 -C 15 -aralkyl, C 1 -C 15 -heteroaryl, C 2 -C 15 -heteroaralkyl, C 1 -C 15 -acyl, C 1 -C 15 -alkoxy, C 2 -C 15 -alkenyloxy, C 2 -C 15 -alkynyloxy, C 6 -C 15 -aryloxy, C 7 -C 15 -aralkyloxy, C 1 -C 15 -heteroaryloxy, C 2 -C 15 -heteroaralkyloxy, C 1 -C 15 -acyloxy, C 1 -C 15 -alkylamino, C 2 -C 15 -alkenylamino, C 2 -C 15 -alkynylamino, C 6 -C 15 -arylamino, C 7 -C 15 -aralkylamino, C 1 -C 15 -heteroarylamino, C 2 -C 15 -heteroaralkylamino, C 1 -C 15 -amido, C 1 -C 15 -alkylthio, C 2 -C 15 -alkenylthio, C 2 -C 15 -alkynylthio, C 6 -C 15 -arylthio, C 7 -C 15 -aralkylthio, C 1 -C 15 -heteroarylthio, C 2 -C 15 -heteroaralkylthio, C 1 -C 15 -acylthio, C 1 -C 12 -thioacyl, C 1 -C 12 -alkylsulfonyl, C 2 -C 12 -alkenylsulfonyl, C 2 -C 12 -alkynylsulfonyl, C 6 -C 12 -arylsulfonyl, C 7 -C 12 -aralkylsulfonyl, C 1 -C 12 -heteroarylsulfonyl, C 1 -C 12 -heteroaralkylsulfonyl, C 1 -C 12 -alkylsulfinyl, C 2 -C 12 -alkenylsulfinyl, C 2 -C 12 -alkynylsulfinyl, C 6 -C 12 -aryl sulfinyl, C 7 -C 12 -aralkylsulfinyl, C 1 -C 12 -heteroarylsulfinyl, C 1 -C 12 -heteroaralkylsulfinyl, C 1 -C 12 -alkylphosphonyl, C 1 -C 12 -alkylphosphate, C 2 -C 12 -dialkylphosphate, C 1 -C 12 -alkylammonium, C 1 -C 12 -alkylsulfonium, C 1 -C 15 -alkylsilyl, or a substituted version of any of these groups,
a —CO 2 Me, carbonyl imidazole, —CO-D-Glu(OAc) 4 , —CONH 2 , —CONHNH 2 , —CONHCH 2 CF 3 , or —C(═O)-heteroaryl group, or
Z and R 15 form a three to seven-membered ring, wherein
R f and R g are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, thioacyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, or heteroaralkylsulfonyl, or a substituted version of any of these groups;

L is —C(═O)—, —C≡C—, —C≡C—N(—R)—, —C(═O)—N(—R)—, or —C≡C—C(═O)—, wherein
R is hydrogen, or an alkyl, aryl, alkenyl, or alkynyl group, or

L is —C≡C—R—C≡C—, wherein
R is an alkyl, aryl, alkenyl, or alkynyl group.

2. A pharmaceutical composition comprising the compound of claim 1 in admixture with a pharmaceutically acceptable carrier.

Assignees

• Dartmouth College

Inventors

• Gribble Gordon W
• Fu Liangfeng
• Sporn Michael B
• Liby Karen T

Classifications

• A61K35/12

  Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells (vaccines or medicinal preparations containing antigens or antibodies A61K39/00) · CPC title

• C07C323/55

  the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings · CPC title

• A61K35/44 Primary

  Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells · CPC title

• C07C61/29

  having a carboxyl group bound to a condensed ring system · CPC title

• C07C235/78

  the carbon skeleton containing rings · CPC title