Pentacyclic triterpenoid compounds as topoisomerase inhibitors or cell differentiation inducers

• US 5,064,823 A
• Filed: 05/01/1990
• Issued: 11/12/1991
• Est. Priority Date: 08/24/1988
• Status: Expired due to Term

• Current Assignee: Research Triangle Institute
• Original Assignee: Research Triangle Institute
• Inventors: Lee, Yue-Wei, Wang, Zhen-Guo, Fang, Qi-Cheng, Li, De-Hua, Cook, C. E.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US07/517,176
• Time in Patent Office: 560 Days
• Field of Search: 514/198, 424/180, 424/195.1
• US Class Current: 514/198
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7004 Monosaccharides having only carbon, hydrogen and oxygen atoms
• CPC Class Codes: C07C 2603/00 Systems containing at least three condensed rings
• CPC Class Codes: C07C 62/06 polycyclic
• CPC Class Codes: C07C 69/00 Esters of carboxylic acids; Esters of carbonic or haloformic acids ortho esters, see the relevant groups, e.g. C07C43/32
• CPC Class Codes: C07H 15/256 Polyterpene radicals

Abstract

Pentacyclic triterpenoid compounds such as α boswelic acid and its acetate, β-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.

Claims

1. 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 R¹ is -COOR⁴, is a -H;

C_1-4 alkyl;

C_2-4 alkenyl;

C_3-4 alkynyl;

C₆ -C₈ 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

R¹ is -CONH₂ ;

-CONHR⁵ ;

or -CONR₂⁵, where R⁵ is a -CH₃ ;

-CH₂ COOH;

-CH₂ CH₂ 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

R² and R³ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR4## wherein R⁴ and R⁵ are as defined above, or R² and R³ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

R⁶ and R⁷ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR5## wherein R⁴ and R⁵ are as defined above, or R⁶ and R⁷ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

pharmaceutically acceptable salts thereof.

2. The method according to claim 1, wherein R¹ is -COOR⁴, wherein R⁴ is -H, C_1-4 alkyl, or NH₂.

3. The method according to claim 1, wherein R³ is -H and R² is -H, -OH, -OAc, -OCOC₂ H₅ or -NHAc.

4. The method of claim 1, wherein R⁶ =R⁷ =R³ =H, R² =OH, and R¹ =COOH.

5. The method of claim 1, wherein R⁶ =R⁷ =R³ =H, R² =OCOCH₃, and R¹ =COOH.

6. The method of claim 1, wherein R⁶ =R⁷ =R³ =H, R² =OH, and R¹ =COOH.

7. 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 R¹ is -COOR⁴, where R⁴ is a -H;

C_1-4 alkyl;

C_2-4 alkenyl;

C_3-4 alkynyl;

C₆ -C₈ 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

R¹ is -CONH₂ ;

-CONHR⁵ ;

or -CONR₂⁵, where R⁵ is a -CH₃ ;

-CH₂ COOH;

-CH₂ CH₂ 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

R² and R³ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR7## wherein R⁴ and R⁵ are as defined above, or R² and R³ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

R⁶ and R⁷ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR8## wherein R⁴ and R⁵ are as defined above, or R⁶ and R⁷ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

pharmaceutically acceptable salts thereof.

8. The method according to claim 7, wherein R¹ is -COOR⁴, wherein R⁴ is -H, C_1-4 alkyl, or NH₂.

9. The method according to claim 7, wherein R³ is -H, and R² is -H, -OH, -OAc, -OCOC₂ H₅ or -NHAc.

10. The method of claim 7, wherein R⁶ =R⁷ =R³ =H, R² =OH, and R¹ =COOH.

11. The method of claim 7, wherein R⁶ =R⁷ =R³ =H, R² =OCOCH₃, and R¹ =COOH.

12. 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 R¹ is -COOR⁴, where R⁴ is a -H;

C_1-4 alkyl;

C_2-4 alkenyl;

C_3-4 alkynyl;

C₆ -C₈ 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

R¹ is -CONH₂ ;

-CONHR₅ ;

or -CONR₂ ⁵ where R⁵ is a -CH₃ ;

-CH₂ COOH;

-CH₂ CH₂ 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

R² and R³ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR10## wherein R⁴ and R⁵ are as defined above, or R² and R³ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

R⁶ and R⁷ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR11## wherein R⁴ and R⁵ are as defined above, or R⁶ and R⁷ together may be =O or =N-OR⁴, wherein R⁴ 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.

13. 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 -COOR⁴, where R⁴ 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

R¹ is -CONH₂ ;

-CONHR⁵ ;

or -CONR₂⁵, where R⁵ is a -CH₃ ;

-CH₂ COOH;

-CH₂ CH₂ 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

R² and R³ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR₂⁵, ##STR13## wherein R⁴ and R⁵ are as defined above, or R² and R³ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

R⁶ and R⁷ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR14## wherein R⁴ and R⁵ are as defined above, or R⁶ and R⁷ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

pharmaceutically acceptable salts thereof.

14. 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 -COOR⁴, where R⁴ is a -H;

C_1-4 alkyl;

C_2-4 alkenyl;

C_3-4 alkynyl;

C₆ -C₈ 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

R¹ -CONH₂ ;

-CONR⁵ ;

or -CONR₂ ⁵, where R⁵ is a -CH₃ ;

-CH₂ COOH;

-CH₂ CH₂ 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

R² and R³ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR16## wherein R⁴ and R⁵ are as defined above, or R² and R³ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

R⁶ and R⁷ may be combinations of hydrogen or R⁵, with -H, -OR⁴, -NH₂, -NHR⁵, -NHR₂⁵, ##STR17## wherein R⁴ and R⁵ are as defined above, or R⁶ and R⁷ together may be =O or =N-OR⁴, wherein R⁴ is as defined above, and

pharmaceutically acceptable salts thereof.