Oridonin analogs, compositions, and methods related thereto

Patent metadata

Field	Value
Publication number	US-10072022-B2
Application number	US-201715635454-A
Country	US
Kind code	B2
Filing date	Jun 28, 2017
Priority date	Apr 5, 2013
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

Certain embodiments are directed to oridonin analogs or derivatives. In certain aspects, the derivatives are used as anticancer or anti-inflammatory agents.

First claim

The invention claimed is:

1. An oridonin derivative compound having the general formula of Formula Ia or a salt thereof:

where X is CH, C or N;
Y is (CH) n and n is 0, 1, 2, 3, 4, or 5; and
R 1 and R 2 are independently hydrogen, oxo, nitro, halo, mercapto, cyano, azido, amino, imino, azo, —C(NH)(NH 2 ), sulfonyl, sulfinyl, sulfo, thioyl, methyl, ethyl, C2-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 carboxylate, C1-C6 carboxyl, C3-C5 alkenyl, C2-C4 carbonyl, C2-C4 aldehyde, C2-C8 heteroalkyl, C1-C6 alkylsulfonyl, C1C6 alkylhalide, substituted or unsubstituted 3 to 8 membered cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R 1 and R 2 can form a substituted or unsubstituted 5 to 9 membered heterocyle or cycloalkyl.

2. The compound of claim 1 , wherein X is N, R 1 is hydrogen, and n is 0.

3. The compound of claim 2 , wherein R 2 is C1-C4 alkyl, C2-C4aldehyde, or C3-C7 cycloalkyl.

4. The compound of claim 1 , wherein the compound is
(6S,7S,7aR,10R,12bR,15R)-6,7,15-trihydroxy-2,5,5-trimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-19);
(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-amino-6,7,15-trihydroxy-5,5-dimethyl-9- methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-5-41);
(5aR ,6S,7S,7aR,10S,12aS,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-2-(methylamino)-9-methylene-5,5a,6,7,10, 11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7, 8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-5-54);
(6S,7S,7aR, 10R,12bR,15R)-2-(cyclohexylamino)-6, 7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7, 8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-17-2);
(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-(allylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one (CTD-6-18);
(6S,7S,7aR, 10R,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-2-((2-(piperidin-1-yl)ethyl)amino)-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b(epoxymethano)-7a,10-methanocyclohepta[7, 8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-21);
N-((6S,7S,7aR,10R,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-8-oxo-5,5a,6,7,8,9,10,11,12,12a-decahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-2-yl)acetamide (CYD-6-21);
(6S,7S,7aR,10R,12bR,15R)-2-(azepan-l-yl)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7, 8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-26-2);
(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-(butylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7, 8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-28);
1-((5aR,6S,7S,7aR,10S,12aS,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-8-oxo-5,5a,6,7,8,9,10,11,12,12a-decahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7, 8]naphtho[1,2-d]thiazol-2-yl)guanidine (CYD-6-29); or
(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-6,7,15-trihydroxy-2-(isopropylamino)-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-30).

5. The compound of claim 1 , wherein the compound is (6S,7S,7aR,10R,12bR,15R)-2-(cyclohexylamino)-6,7,15 -trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-17-2).

6. The compound of claim 1 , wherein the compound is (5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-(allylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-18).

7. The compound of claim 1 , wherein the compound is (5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-(butylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one (CYD-6-28).

8. A method of treating cancer comprising administering an effective amount of a compound of claim 1 to patient in need thereof.

Assignees

• Univ Texas

Inventors

• Zhou Jia
• Ding Chunyong
• Shen Qiang

Classifications

• C07D513/08

  Bridged systems · CPC title

• C07D493/18 Primary

  Bridged systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D491/08

  Bridged systems · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title