Use of electrophilic compounds for inducing platelet production or maintaining platelet function

9,012,439

12/738949

October 29, 2008

The present invention is directed to a method of inducing platelet production that includes contacting a megakaryocyte with an electrophilic compound under conditions effective to induce platelet production by the contacting megakaryocyte. Methods of treating a patient for low platelet levels, increasing the circulating half-life of platelets, and improving the quality (activity) of platelets are also disclosed herein, which involve administering the electrophilic compound to a patient an effective amount to achieve the desired effect. Pharmaceutical compositions and therapeutic systems are also disclosed for carrying out these therapeutic treatments.

Phipps, Richard P. (Pittsford, NY, US); O'Brien, Jamie (Fairport, NY, US)

University of Rochester (Rochester, NY, US)

1. A method of treating a patient for low platelet levels, the method comprising: administering to a patient having a low platelet level an effective amount of an electrophilic compound that is suitable to cause an increase in platelet production by megakaryocytes, wherein the electrophilic compound is a compound according to formula (II) or formula (III): [chemical expression included] wherein R 2 is CN and R 7 is CN; [chemical expression included] wherein Y is hydroxy, an unsubstituted C 1 -C 14 -alkoxy, an unsubstituted C 1 -C 14 -alkylamino, [chemical expression included] -D-Glu(OMe) 4 , -D-Glu(OAc) 4 , -L-Ara(OAc) 3 , or -D-Gal-(OAc) 4 ; or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 further comprising administering an electrophilic prostaglandin selected from the group of (PG)D 2 , PGJ 2 , 15d-PGJ 2 , and combinations thereof.

3. The method according to claim 1 wherein the electrophilic compound is a compound according to formula (II): [chemical expression included] wherein R 2 is cyano and R 7 is cyano.

4. The method according to claim 1 wherein the electrophilic compound is a compound according to formula (III): [chemical expression included] wherein Y is hydroxy, unsubstituted C 1 -C 14 -alkoxy, unsubstituted C 1 -C 14 -alkylamino, [chemical expression included]  -D-Glu(OMe) 4 , -D-Glu(OAc) 4 , -L-Ara(OAc) 3 , or -D-Gal-(OAc) 4 ; or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 wherein Y is hydroxy, methoxy, ethyl-amino, or [chemical expression included]

6. The method according to claim 1 wherein the electrophilic compound is present in a pharmaceutical preparation.

7. The method according to claim 1 wherein said administering is carried out orally, rectally, vaginally, parenterally, intramuscularly, intraperitoneally, intraarterially, intrathecally, intrabronchially, subcutaneously, intradermally or transdermally, intravenously, or via nasal, buccal or sublingual routes.

8. The method according to claim 1 further comprising: administering to the patient an effective amount of an agent that increases megakaryocyte production.

9. The method according to claim 8 wherein the agent that increases megakaryocyte production is selected from the group of thrombopoietin, megakaryocyte growth and development factor (MGDF), a combination of granulocyte colony stimulating factor (G-CSF) with either interleukin-3 or granulocyte-macrophage colony stimulating factor (GM-C SF) and optionally interleukin-6, a combination of GM-CSF and interleukin-5, pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a small molecule c-Mpl activator, ITP-suitable peptibody, and any combinations thereof.

10. The method according to claim 8 wherein said administering the electrophilic compound and said administering the agent that increases megakaryocyte production are carried out at the same time.

11. The method according to claim 8 wherein said administering the electrophilic compound and said administering the agent that increases megakaryocyte production are carried out at different times.

12. The method according to claim 11 wherein said administering the agent that increases megakaryocyte production is carried out first, followed by said administering the electrophilic compound after a delay.

13. The method according to claim 1 wherein the patient is a radiation therapy cancer patient, a patient having an autoimmunity disorder characterized by low platelet level, or an individual exposed to ionizing radiation or a chemical in doses that cause platelet loss.

14. The method according to claim 1 wherein the patient is a chemotherapy cancer patient that receives a chemotherapeutic agent that is not an electrophilic tri-terpenoid.

15. A pharmaceutical composition or therapeutic system comprising an agent that increases megakaryocyte production and an electrophilic compound capable of inducing platelet production by megakaryocytes, wherein the electrophilic compound is a compound according to formula (II) or formula (III): [chemical expression included] wherein R 2 is CN and R 7 is CN; [chemical expression included] wherein Y is hydroxy, an unsubstituted C 1 -C 14 -alkoxy, an unsubstituted C 1 -C 14 -alkylamino, [chemical expression included]  -D-Glu(OMe) 4 , -D-Glu(OAc) 4 , -L-Ara(OAc) 3 , or -D-Gal-(OAc) 4 ; or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition or therapeutic system according to claim 15 further comprising a pharmaceutically acceptable carrier.

17. The pharmaceutical composition or therapeutic system according to claim 15 in a form suitable for delivery orally, rectally, vaginally, parenterally, intramuscularly, intraperitoneally, intraarterially, intrathecally, intrabronchially, subcutaneously, intradermally or transdermally, intravenously, or via nasal, buccal or sublingual routes.

18. The pharmaceutical composition or therapeutic system according to claim 15 further comprising an electrophilic prostaglandin selected from the group of (PG)D 2 , PGJ 2 , 15d-PGJ 2 , and combinations thereof.

19. The pharmaceutical composition or therapeutic system according to claim 15 wherein the electrophilic compound is a compound according to formula (II): [chemical expression included] wherein R 2 is cyano and R 7 is cyano.

20. The pharmaceutical composition or therapeutic system according to claim 15 wherein the electrophilic compound is a compound according to formula (III): [chemical expression included] wherein Y is hydroxy, unsubstituted C 1 C 14 -alkoxy, unsubstituted C 1 -C 14 -alkylamino, [chemical expression included]  -D-Glu(OMe) 4 , -D-Glu(OAc) 4 , -L-Ara(OAc) 3 , or -D-Gal-(OAc) 4 ; or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition or therapeutic system according to claim 20 wherein Y is hydroxy, methoxy, ethyl-amino, or [chemical expression included]

22. The pharmaceutical composition or therapeutic system according to claim 15 wherein the agent that increases megakaryocyte production is selected from the group of thrombopoietin, megakaryocyte growth and development factor (MGDF), a combination of granulocyte colony stimulating factor (G-CSF) with either interleukin-3 or granulocyte-macrophage colony stimulating factor (GM-C SF) and optionally interleukin-6, a combination of GM-CSF and interleukin-5, pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a small molecule c-Mpl activator, ITP-suitable peptibody, and any combinations thereof.

23. The pharmaceutical composition or therapeutic system according to claim 15 , wherein one or both of the agent that increases megakaryocyte production and the electrophilic compound are present in a polymeric delivery vehicle.

24. A method of treating a patient for low platelet levels, the method comprising: administering to a patient having a low platelet level an effective amount of an electrophilic compound that is suitable to cause an increase in platelet production by megakaryocytes, wherein the electrophilic compound is selected from the group consisting of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), 2-cyano-3,12-dioxooleana-1,9-dien-28-oic imidazolide (CDDO-Im), methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me), and 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid ethyl amide (CDDO-Ea), and a combination of any two or more thereof.

25. A pharmaceutical composition or therapeutic system comprising an agent that increases megakaryocyte production and an electrophilic compound capable of inducing platelet production by megakaryocytes, wherein the electrophilic compound is selected from the group consisting of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), 2-cyano-3,12-dioxooleana-1,9-dien-28-oic imidazolide (CDDO-Im), methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me), and 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid ethyl amide (CDDO-Ea), and a combination of any two or more thereof.

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