US5064823A
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Pentacyclic triterpenoid compounds as topoisomerase inhibitors or cell differentiation inducers
Assignee: RTI International
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Filing: 1990-05-01
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Granted: 1991-11-12
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Expires: 2010-05-01
Abstract
Abstract Pentacyclic triterpenoid compounds such as alpha boswelic acid and its acetate, beta -boswellic acid and its acetate, which have an inhibitory effect on topoisomerase I and topoisomerase II, are disclosed. Compositions based on the pentacyclic triterpenoid compounds which can be used to treat various cancers in mammals are also disclosed.
Inventors
- 👤 Yue-Wei Lee
- 👤 Qi-Cheng Fang
- 👤 Zhen-Guo Wang
- 👤 De-Hua Li
- 👤 C. E. Cook
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-27 10:18
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/70; A61K31/7004; A61K31/185; A61K31/19; A61K31/21; A61K31/215; C; C07; C07C; C07C62/00; C07C62/02; C07C62/06; C07C69/00; C07H; C07H15/00; C07H15/20; C07H15/24; C07H15/256; C07C2603/00
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
285 words
A method for inhibiting topoisomerase I, which comprises contacting topoisomerase I in vitro or in vivo with an inhibitory effective amount of a compound selected from the group consisting of those having the following formulas: ##STR3## wherein R 1 is -COOR 4 , is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6 -C 8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, or R 1 is -CONH 2 ; -CONHR 5 ; or -CONR 2 5 , where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; or C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR4## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR5## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof.
Claim 2
Independent Claim
285 words
A method for inhibiting topoisomerase I, which comprises contacting topoisomerase I in vitro or in vivo with an inhibitory effective amount of a compound selected from the group consisting of those having the following formulas: ##STR3## wherein R 1 is -COOR 4 , is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6 -C 8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, or R 1 is -CONH 2 ; -CONHR 5 ; or -CONR 2 5 , where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; or C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR4## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR5## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof.
Claim 3
Dependent Claim
25 words
The method according to claim 1, wherein R 1 is -COOR 4 , wherein R 4 is -H, C 1-4 alkyl, or NH 2 .
Claim 4
Dependent Claim
24 words
The method according to claim 1, wherein R 3 is -H and R 2 is -H, -OH, -OAc, -OCOC 2 H 5 or -NHAc.
Claim 5
Dependent Claim
20 words
The method of claim 1, wherein R 6 =R 7 =R 3 =H, R 2 =OH, and R 1 =COOH.
Claim 6
Dependent Claim
22 words
The method of claim 1, wherein R 6 =R 7 =R 3 =H, R 2 =OCOCH 3 , and R 1 =COOH.
Claim 7
Dependent Claim
20 words
The method of claim 1, wherein R 6 =R 7 =R 3 =H, R 2 =OH, and R 1 =COOH.
Claim 8
Independent Claim
287 words
A method for inhibiting topoisomerase II, which comprises contacting topoisomerase II in vitro or in vivo with an inhibitory effective amount of a compound selected from the group consisting of those having the following formulas: ##STR6## wherein R 1 is -COOR 4 , where R 4 is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6 -C 8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or diacetylamino, C 1-4 alkyl, C 2-4 alkenyl, or R 1 is -CONH 2 ; -CONHR 5 ; or -CONR 2 5 , where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR7## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR8## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof.
Claim 9
Independent Claim
287 words
A method for inhibiting topoisomerase II, which comprises contacting topoisomerase II in vitro or in vivo with an inhibitory effective amount of a compound selected from the group consisting of those having the following formulas: ##STR6## wherein R 1 is -COOR 4 , where R 4 is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6 -C 8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or diacetylamino, C 1-4 alkyl, C 2-4 alkenyl, or R 1 is -CONH 2 ; -CONHR 5 ; or -CONR 2 5 , where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR7## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR8## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof.
Claim 10
Dependent Claim
25 words
The method according to claim 7, wherein R 1 is -COOR 4 , wherein R 4 is -H, C 1-4 alkyl, or NH 2 .
Claim 11
Dependent Claim
24 words
The method according to claim 7, wherein R 3 is -H, and R 2 is -H, -OH, -OAc, -OCOC 2 H 5 or -NHAc.
Claim 12
Dependent Claim
20 words
The method of claim 7, wherein R 6 =R 7 =R 3 =H, R 2 =OH, and R 1 =COOH.
Claim 13
Dependent Claim
22 words
The method of claim 7, wherein R 6 =R 7 =R 3 =H, R 2 =OCOCH 3 , and R 1 =COOH.
Claim 14
Dependent Claim
329 words
A composition for treatment of a mammal suffering from a cancer selected from the group consisting of small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, central nervous system cancer, liver cancer and prostate cancer, which comprises: a compound selected from the group consisting of those having the following formulas: ##STR9## wherein R 1 is -COOR 4 , where R 4 is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6 -C 8 aryl-which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or diacetylamino, C 1-4 alkyl, or C 2-4 alkenyl, or R 1 is -CONH 2 ; -CONHR 5 ; or -CONR 2 5 where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; or C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR10## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR11## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof, in combination with an agent for targeting said compound to the site where said cancer is localized in said mammal.
Claim 15
Dependent Claim
329 words
A composition for treatment of a mammal suffering from a cancer selected from the group consisting of small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, central nervous system cancer, liver cancer and prostate cancer, which comprises: a compound selected from the group consisting of those having the following formulas: ##STR9## wherein R 1 is -COOR 4 , where R 4 is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6 -C 8 aryl-which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or diacetylamino, C 1-4 alkyl, or C 2-4 alkenyl, or R 1 is -CONH 2 ; -CONHR 5 ; or -CONR 2 5 where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; or C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR10## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR11## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof, in combination with an agent for targeting said compound to the site where said cancer is localized in said mammal.
Claim 16
Independent Claim
278 words
A method for inducing cellular differentiation, which comprises contacting a cancerous cell with an effective amount of a compound selected from the group consisting of those having the following formulas: ##STR12## wherein Rhu 1 is -COOR 4 , where R 4 is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or diacetylamino, C 1-4 alkyl, C 2-4 alkenyl, or R 1 is -CONH 2 ; -CONHR 5 ; or -CONR 2 5 , where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; or C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 2 5 , ##STR13## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR14## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof.
Claim 17
Independent Claim
278 words
A method for inducing cellular differentiation, which comprises contacting a cancerous cell with an effective amount of a compound selected from the group consisting of those having the following formulas: ##STR12## wherein Rhu 1 is -COOR 4 , where R 4 is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or diacetylamino, C 1-4 alkyl, C 2-4 alkenyl, or R 1 is -CONH 2 ; -CONHR 5 ; or -CONR 2 5 , where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; or C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 2 5 , ##STR13## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR14## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof.
Claim 18
Independent Claim
323 words
A method of treating a cancer selected from the group consisting of small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, central nervous system cancer, liver cancer and prostate cancer, which comprises administering to a mammal in need thereof an effective amount of a composition containing as the active ingredient therein a compound selected from the group consisting of those having the following formulas: ##STR15## wherein Rhu 1 is -COOR 4 , where R 4 is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6 -C 8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or diacetylamino, C 1-4 alkyl, C 2-4 alkenyl, or R 1 -CONH 2 ; -CONR 5 ; or -CONR 2 5 , where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; or C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR16## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR17## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof.
Claim 19
Independent Claim
323 words
A method of treating a cancer selected from the group consisting of small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, central nervous system cancer, liver cancer and prostate cancer, which comprises administering to a mammal in need thereof an effective amount of a composition containing as the active ingredient therein a compound selected from the group consisting of those having the following formulas: ##STR15## wherein Rhu 1 is -COOR 4 , where R 4 is a -H; C 1-4 alkyl; C 2-4 alkenyl; C 3-4 alkynyl; C 6 -C 8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or diacetylamino, C 1-4 alkyl, C 2-4 alkenyl, or R 1 -CONH 2 ; -CONR 5 ; or -CONR 2 5 , where R 5 is a -CH 3 ; -CH 2 COOH; -CH 2 CH 2 COOH; C 2-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl; or C 6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C 1-4 -alkyl-amino, mono- or di-acetylamino, C 1-4 alkyl, C 2-4 alkenyl, and R 2 and R 3 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR16## wherein R 4 and R 5 are as defined above, or R 2 and R 3 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and R 6 and R 7 may be combinations of hydrogen or R 5 , with -H, -OR 4 , -NH 2 , -NHR 5 , -NHR 2 5 , ##STR17## wherein R 4 and R 5 are as defined above, or R 6 and R 7 together may be =O or =N-OR 4 , wherein R 4 is as defined above, and pharmaceutically acceptable salts thereof.
References Cited (Backward Citations)
US4501734A
Cited
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