Induction of apoptosis in cancer cells

• US 7,053,071 B2
• Filed: 12/02/2002
• Issued: 05/30/2006
• Est. Priority Date: 11/30/2001
• Status: Expired

• Current Assignee: Korea Medicine Research Institute, Oregon State University (Oregon University System), Sanford-Burnham Medical Research Institute (Sanford Burnham Prebys Medical Discovery Institute), SRI International, Inc., United States of Government As Represented By The Department of Veterans Affairs, Wayne State University
• Original Assignee: The Burnham Institute
• Inventors: Jong, Ling, Dawson, Marcia, Fontana, Joseph A., Zhang, Xiao-kun, Leid, Mark, Hobbs, Peter D.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Tucker, Zachary C.
• Application Number:
  US10/308,241
• Publication Number:
  US 20030176506A1
• Time in Patent Office: 1,275 Days
• Field of Search: 560/100, 560/104, 560/59, 560/62, 562/467, 562/478, 562/23, 562/25, 562/41, 562/74, 562/83, 562/87, 562/88, 562/466, 562/474, 562/475, 562/492, 564/170, 564/171, 564/176, 558/44, 558/51, 558/58, 558/177, 548/183, 548/252
• US Class Current: 514/92
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 235/08 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 235/52 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 255/57 containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 59/54 containing six-membered aromatic rings and other rings
• CPC Class Codes: C07C 59/56 containing halogen
• CPC Class Codes: C07C 59/72 containing six-membered aromatic rings and other rings
• CPC Class Codes: C07C 59/76 containing keto groups
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 311/66 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 311/74 Benzo[b]pyrans, hydrogenated in the carbocyclic ring
• CPC Class Codes: C07D 311/82 Xanthenes

Abstract

The present invention provides compounds that are inducers or inhibitors of apoptosis or apoptosis preceded by cell-cycle arrest. In addition, the present invention provides pharmaceutical compositions and methods for treating mammals with leukemia or other forms of cancer or for treating disease conditions caused by apoptosis of cells.

Claims

1. A compound having formula (I):

2. The compound of claim 1 wherein R¹ adamantyl.

3. The compound of claim 1 wherein R² is hydroxy, —

COOR¹⁴, —

C(═

O)CH₃, or —

SH.

4. The compound of claim 3 wherein R² is hydroxy.

5. The compound of claim 1 wherein R³ is hydrogen, methyl, ethyl, chloro, bromo, fluoro, or —

CF₃.

6. The compound of claim 5 wherein R³ is hydrogen, or methyl.

7. The compound of claim 1 wherein R⁴ is

8. The compound of claim 7 wherein R⁵ and R⁶ are independently hydrogen, methyl, ethyl, methoxy, ethoxy, chloro, bromo, fluoro, —

CF₃, —

O—

(CH₂)₃—

NH₂, or —

O—

(CH₂)₃—

NH—

C(═

O)CH₃.

9. The compound of claim 8 wherein R⁵ and R⁶ are independently hydrogen, methyl, methoxy, ethoxy, chloro, bromo, fluoro, —

CF₃, —

O—

(CH₂)₃—

NH₂ or —

O—

(CH₂)₃—

NH—

C(═

O)CH₃.

10. The compound of claim 9 wherein R⁵ and R⁶ are independently hydrogen, methyl, chloro, bromo, or fluoro, —

CF₃, —

O—

(CH₂)₃—

NH₂ or —

O—

(CH₂)₃—

NH—

C(═

O)CH₃.

11. The compound of claim 10 wherein one of R⁵ and R⁶ is hydrogen and the other is methyl, chloro, bromo, —

CF₃, —

O—

(CH₂)₃—

NH₂, or —

O—

(CH₂)₃—

NH—

C(═

O)CH₃.

12. The compound of claim 1 wherein R⁹ is —

COOR¹⁴, —

P(O)(OR¹⁴)₂, —

S(O)₂OR¹⁴, or —

C(O)—

NHOR¹⁴.

13. The compound of claim 12 wherein R⁹ is —

COOR¹⁴.

14. The compound of claim 1 wherein R¹² is —

C(H)═

C(H)(R⁹), or aryl-R⁹.

15. The compound of claim 1 wherein having the formula (II):

16. The compound of claim 15 wherein R¹² is the E-isomer.

17. The compound of claim 1 wherein R³ is —

CF₃.

18. The compound of claim 15 having the formula:

19. The compound of claim 15 having the formula:

20. The compound of claim 15 having the formula:

21. The compound of claim 15 having the formula:

22. A method of treating cancer in a mammal comprising contacting the cancer cells with a compound of claim 1, effective to reduce the viability of the cancerous cells, wherein the cancer is lung cancer, breast cancer, prostate cancer, or leukemia.

23. The method of claim 22 wherein the leukemia is acute lymphocytic leukemia, acute myelogenous leukemia, or chronic myelogenous leukemia.

24. A method for inducing apoptosis, inducing caspase activity, or inducing cell death in a mammal comprising contacting target cells with a compound of claim 1, effective to induce apoptosis, induce caspase activity, or induce cell death the target cells, wherein the target cells are lung cancer, breast cancer, prostate cancer, or leukemia cells.