Deuterated compounds and uses thereof

Abstract

An anthraquinone compound of formula I (such as the compounds of formulae II to X) and processes for making the same are provided. Pharmaceutical compositions for use in the treatment of cancer, optionally in combination with an agent capable of reducing the level of oxygenation of a tumor, are also provided. Additionally, an option for combination with chemotherapeutic and radiotherapeutic modalities to enhance overall tumor cell kill is provided. Methods for the detection of cellular hypoxia, both in vivo and in vitro, are additionally provided.

The invention claimed is: 
     
       1. A compound having one of Formula III or V: 
       
         
           
           
               
               
           
         
         wherein each Y is independently selected from the group consisting of hydrogen, hydroxy, halogeno, amino, C 1-4  alkoxy and C 2-8  alkanoyloxy. 
       
     
     
       2. The compound according to  claim 1 , wherein the compound is of Formula VII or IX: 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound according to  claim 1  wherein each Y is independently selected from the group consisting of hydrogen, hydroxy and halogeno. 
     
     
       4. The pharmaceutical composition comprising the compound according to  claim 1  together with a pharmaceutically acceptable buffer, diluent, carrier, adjuvant or excipient. 
     
     
       5. A kit for detecting the oxygenation level of cells comprising the compound according to  claim 1 . 
     
     
       6. The kit according to  claim 5  further comprising a non-deuterated form of a compound of Formula V. 
     
     
       7. A method of treating a pancreatic cancer tumour in a patient comprising administering to the patient a therapeutically effective amount of the compound according to  claim 1 . 
     
     
       8. The method according to  claim 7 , wherein administering the therapeutically effective amount treats metastases or reduces metastatic spread. 
     
     
       9. The method according to  claim 7  further comprising administering to the patient one or more of a chemotherapeutic agent and a radiotherapeutic agent in combination with the therapeutically effective amount of the compound. 
     
     
       10. The method according to  claim 9  wherein the one or more of the chemotherapeutic agent and the radiotherapeutic agent is/are selected from the group consisting of anti-androgens (steroidal and non-steroidal), vascular disrupting agents, anti-angiogenic agents, anti-VEGFR agents, IL8 inhibitors, NO synthase inhibitors, vasoconstricting agents, vasodilating agents, and radiotherapeutic modalities. 
     
     
       11. The method according to  claim 10  wherein the one or more of the chemotherapeutic agent and the radiotherapeutic agent is at least one anti-androgen. 
     
     
       12. The method according to  claim 11  wherein the at least one anti-androgen is selected from the group consisting of flutamide, nilutamide, bicalutamide, finasteride, dutasteride, bexlosteride, izonsteride, turosteride, epristeride, abiraterone and combinations thereof. 
     
     
       13. The method according to  claim 12  wherein the at least one anti-androgen is bicalutamide. 
     
     
       14. The method according to  claim 9  wherein the one or more of the chemotherapeutic agent and the radiotherapeutic agent decreases tumour oxygenation in vivo. 
     
     
       15. The method according to  claim 14  wherein the one or more of the chemotherapeutic agent and the radiotherapeutic agent lowers the median oxygen level of the tumour to below 3%. 
     
     
       16. A method of treating a prostate cancer tumour in a patient comprising administering to the patient a therapeutically effective amount of the compound according to  claim 1 . 
     
     
       17. The method according to  claim 16 , wherein administering the therapeutically effective amount treats metastases or reduces metastatic spread. 
     
     
       18. The method according to  claim 16  further comprising administering to the patient one or more of a chemotherapeutic agent and a radiotherapeutic agent in combination with the therapeutically effective amount of the compound. 
     
     
       19. The method according to  claim 18  wherein the one or more of the chemotherapeutic agent and the radiotherapeutic agent is/are selected from the group consisting of anti-androgens (steroidal and non-steroidal), vascular disrupting agents, anti-angiogenic agents, anti-VEGFR agents, IL8 inhibitors, NO synthase inhibitors, vasoconstricting agents, vasodilating agents, and radiotherapeutic modalities. 
     
     
       20. The method according to  claim 19  wherein the one or more of the chemotherapeutic agent and the radiotherapeutic agent is at least one anti-androgen. 
     
     
       21. The method according to  claim 20  wherein the at least one anti-androgen is selected from the group consisting of flutamide, nilutamide, bicalutamide, finasteride, dutasteride, bexlosteride, izonsteride, turosteride, epristeride, abiraterone and combinations thereof. 
     
     
       22. The method according to  claim 21  wherein the at least one anti-androgen is bicalutamide. 
     
     
       23. The method according to  claim 18  wherein the one or more of the chemotherapeutic agent and the radiotherapeutic agent decreases tumour oxygenation in vivo. 
     
     
       24. The method according to  claim 23  wherein the one or more of the chemotherapeutic agent and the radiotherapeutic agent lowers the median oxygen level of the tumour to below 3%. 
     
     
       25. A process for making the compound according to  claim 1  comprising reacting an anthracene-9,10-dione with a deuterated alkylenediamine under conditions suitable for the production of an alkylaminoalkyl-aminoanthraquinone. 
     
     
       26. The process according to  claim 25  further comprising the step of reacting the alkylaminoalkylaminoanthraquinone with a monoperoxyphthalate under conditions suitable for the production of an N-oxide derivative of the alkylaminoalkylaminoanthraquinone. 
     
     
       27. The process according to  claim 25  comprising reacting 1,4-difluoro-5,8-dihydroxyanthracene-9,10-dione, with deuterated N,N-dimethylethylenediamine under conditions suitable for the production of 1,4-bis-{[2-(deuterated-d6-dimethylamino)ethyl]amino)-5,8-dihydroxyanthracene-9,10-dione. 
     
     
       28. The process according to  claim 27  further comprising the step of reacting the 1,4-bis-{[2-(deuterated-d6-dimethylamino)ethyl]amino)-5,8-dihydroxyanthracene-9,10-dione with magnesium monoperoxyphthalate under conditions suitable for the production of 1,4-bis-{[2-(deuterated-d6-dimethylamino-N-oxide)ethyl]amino)-5,8-dihydroxy-anthracene-9,10-dione. 
     
     
       29. A method of detecting hypoxic cells in vitro or in vivo in a group of cells, the method comprising:
 exposing a compound of Formula V: 
 
       
         
           
           
               
               
           
         
         wherein each Y is independently selected from the group consisting of hydrogen, hydroxy, halogeno, amino, C 1-4  alkoxy and C 2-8  alkanoyloxy, 
         to the group of cells; 
         analyzing the cells for the presence of a corresponding reduced compound of Formula III: 
       
       
         
           
           
               
               
           
         
         determining the hypoxic cells based on the presence of the corresponding reduced compound. 
       
     
     
       30. The method according to  claim 29  in vitro. 
     
     
       31. The method according to  claim 29  in vivo. 
     
     
       32. The method according to  claim 31 , further comprising:
 surgically excising cells identified as being hypoxic. 
 
     
     
       33. The method according to  claim 29  wherein the compound is used in combination with a non-deuterated form of a compound of Formula V. 
     
     
       34. The method according to  claim 29  wherein the compound is detected using a method selected from the group consisting of mass spectrometry, nuclear magnetic resonance, infrared spectroscopy, colorimetrically, Raman spectroscopy, nuclear magnetic resonance, affinity capture methods, immunohistochemistry, flow cytometry, microscopy and antibody-based detection methods.