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

Abstract

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.

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 a prostaglandin D 2  that is suitable to cause an increase in platelet production by megakaryocytes.   
     
     
         2 . The method according to  claim 1  wherein the prostaglandin D2 is present in a pharmaceutical preparation. 
     
     
         3 . 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. 
     
     
         4 . The method according to  claim 1  further comprising:
 administering to the patient an effective amount of an agent that increases megakaryocyte production. 
 
     
     
         5 . The method according to  claim 4  wherein the agent that increase 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-CSF) 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 (Amgen AMG 531), and any combinations thereof. 
     
     
         6 . The method according to  claim 4  wherein said administering the prostaglandin D 2  and said administering the agent that increases megakaryocyte production are carried out at the same time. 
     
     
         7 . The method according to  claim 4  wherein said administering the prostaglandin D 2  and said administering the agent that increases megakaryocyte production are carried out at different times. 
     
     
         8 . 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, a chemotherapy cancer patient that receives a chemotherapeutic agent that is not an electrophilic tri-terpenoid, or an individual exposed to ionizing radiation or a chemical in doses that cause platelet loss. 
     
     
         9 . 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 one or more electrophilic compounds selected from the group of (i) pentacyclic tri-terpenoid derivatives of betulin or betulinic acid and (ii) tri-cyclic bis-enones, where said administering causes an increase in platelet production by megakaryocytes.   
     
     
         10 . The method according to  claim 9 , wherein the electrophilic pentacyclic tri-terpenoid derivative of betulin or betulinic acid is a compound according to formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein,
 X 11  is C═O, C═NOR 11a , CHOR 11a , CHOCOR 11a , CHOC(O)OR 21 , CHOC(O)OR 11a , CHOC(O)OR 22 , or CHOCOY-Hal; 
 X 14  is CH 2 , CH-Hal, C═O, CHOR 11b , CHOCOR 11b , or CHOC(O)OR 21 ; 
 X 15  is CH 2 , CH-Hal, C═O, CHOR 11b , CHOCOR 11b , or CHOC(O)OR 21 ; 
 R 11-15  are H or lower alkyl; 
 R 17  is COOR 11c , COOR 22 , CO-Hal, C(O)OC(O)R 11c , COOYOCOR 11c , CH 2 OR 11c , CH 2 OCOR 11c , or CH 2 OC(O)OR 21 ; 
 R 19  is R 11d , OR 11d , CH 2 -Hal, CH 2 OR 11d , CH 2 OC(O)OR 21 , or ═CHR 11d ; 
 R 20  is R 11e , CH═NOR 11e , CN, COOR 11 , COR 11e , CH 2 -Hal, CH 2 OR 11e , CH 2 OCOR 11e , CH 2 OC(O)OR 21 , CH 2 OSO 2 CH 3 , or CH 2 OSO 2 C 6 H 4 CH 3 ; 
 R 21  is an OH-substituted alkyl group, an ether group or a cyclic ether; 
 R 22  is lower alkyl substituted by Hal; 
 b is a double bond or a single bond; 
 Y═(CH 2 ) n  with n being 0 to 5; 
 R 11a-11e  are the same or different groups of R 11 ; and 
 Hal is Cl, Br, I, or F. 
 
     
     
         11 . The method according to  claim 10  wherein the compound according to formula (IV) is:
 (3aS,5aR,5bR,9S, 11aR)-methyl 9-acetoxy-3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,1 1 a, 11b,12,13,13a-octadecahydro-l-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3-dioxo-2H-cyclopenta[a]chrysene-3a-carboxylate; 
 (3aS,5aR,5bR,9S,11aR)-methyl 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13, 13a-octadecahydro-9-hydroxy-l-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3-dioxo-2H-cyclopenta[a]chrysene-3a-carboxylate; or 
 (1R,3aS,5aR,5bR,9S,11aR)-1-(1-formylvinyl)-icosahydro-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1H-cyclopenta[a]chrysene-3a-carboxylic acid. 
 
     
     
         12 . The method according to  claim 9  wherein the electrophilic tri-cyclic bis-enone is a compound according to formula (I): 
       
         
           
           
               
               
           
         
       
       wherein,
 R 1  is cyano or substituted or unsubstituted versions of C 1 -C 15 -alkyl, C 2 -C 15 -alkenyl, C 2 -C 15 -alkynyl, C 7 -C 15 -aralkyl, C 2 -C 15 -heteroaralkyl, or C 1 -C 15 -acyl, and R 2 , R 3 , R 4 , and R 5  are each independently hydrogen, hydroxy, amino, cyano, halo, or substituted or unsubstituted versions of C 1 -C 15 -alkyl, C 2 -C 15 -alkenyl, C 2 -C 15 -alkynyl, C 6 -C 15 -aryl, C 7 -C 15 -aralkyl, C 1 -C 15 -heteroaryl, C 2 -C 15 -heteroaralkyl, C 1 -C 15 -acyl, C 1 -C 15 -alkoxy, C 2 -C 15 -alkenyloxy, C 2 -C 15 -alkynyloxy, C 6 -C 15 -aryloxy, C 7 -C 15 -aralkoxy, C 1 -C 15 -heteroaryloxy, C 2 -C 15 -heteroaralkoxy, C 1 -C 15 -acyloxy, C 1 -C 15 -alkylamino, C 2 -C 15 -alkenylamino, C 2 -C 15 -alkynylamino, C 6 -C 15 -arylamino, C 7 -C 15 -aralkylamino, C 1 -C 15 -heteroarylamino, C 2 -C 15 -heteroaralkylamino, or C 2 -C 15 -amido; 
 X is selected from the group consisting of —H and ═O; 
 A, B, and C each independently signifies a single- or double-bond, provided that (i) when C is a double-bond, R 4  is absent, (ii) when B is a double bond, X is ═O, (iii) when B is a single bond, X is —H; 
 any ketone group shown in the formula (I) may replaced by its enol tautomer, and pharmaceutically acceptable salts, and optical isomers thereof. 
 
     
     
         13 . The method according to  claim 12  wherein the compound according to formula (I) is
 (4bS,8aR,10aR)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxo-10a-(prop-1-ynyl)phenanthrene-2,6-dicarbonitrile; 
 (4b S,8aR,10aR)-10a-(but-l-ynyl)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile; 
 (4bS,8aR,10aR)-10a-(buta-1,3-diynyl)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile; 
 (4bS,8aR,10aR)-3,4b,7,8,8a,9,10,10a-octahydro-10a-(3-hydroxyprop-1-ynyl)-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile; 
 (4bS,8aR,10aR)-3,4b,7,8,8a,9,10,10a-octahydro-10a-(3-alkoxyprop-1-ynyl)-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile, where the alkoxy is methyl or ethyl; 
 (4bS,8aR,10aR)-10a-(2-haloethynyl)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile, where the halo is bromo, chloro, or fluoro; 
 (4bS,8aR,10aR)-10a-(2-cyanoethynyl)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile; 
 (4b S,8aR,10aR)-10a-(4-aminobut-l-ynyl)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile and its hydrochloride salt; 
 3-((4aS,8aR,10aR)-3,7-dicyano-1,2,4a,6,8a,9,10,10a-octahydro-1,1,4a-trimethyl-2,6-dioxophenanthren-8a-yl)propiolic acid; 
 alkyl 3-((4aS,8aR,10aR)-3,7-dicyano-1,2,4a,6,8a,9,10,10a-octahydro-1,1,4a-trimethyl-2,6-dioxophenanthren-8a-yl)propiolate, where the alkyl ester is methyl, ethyl, or propyl; 
 3-((4aS,8aR,10aR)-3,7-dicyano-1,2,4a,6,8a,9,10,10a-octahydro-1,1,4a-trimethyl-2,6-dioxophenanthren-8a-yl)propiolamide; 
 3-((4aS,8aR,10aR)-3,7-dicyano-1,2,4a,6,8a,9,10,10a-octahydro-1,1,4a-trimethyl-2,6-dioxophenanthren-8a-yl)-N-alkylpropiolamide, where the alkyl is methyl, ethyl, or 2,2,2-trifluoroethyl; 
 (4bS,8aR,10aR)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxo-10a-(3-oxobut-l-ynyl)phenanthrene-2,6-dicarbonitrile; 
 (4bS,8aR,10aR)-10a-(2-formylethynyl)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile; 
 (4bS,8aR,10aR)-3,4b,7,8,8a,9,10,10a-octahydro-10a-(3-methoxyprop-1-ynyl)-4b,8,8-trimethyl-3,7-dioxophenanthrene-2,6-dicarbonitrile; or 
 (4bS,8aR,10aR)-3,4b,7,8,8a,9,10,10a-octahydro-4b,8,8-trimethyl-3,7-dioxo-10a-(3-phenoxyprop-1-ynyl)phenanthrene-2,6-dicarbonitrile. 
 
     
     
         14 . The method according to  claim 9  wherein the one or more electrophilic compounds is present in a pharmaceutical preparation. 
     
     
         15 . The method according to  claim 9  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. 
     
     
         16 . The method according to  claim 9  further comprising:
 administering to the patient an effective amount of an agent that increases megakaryocyte production. 
 
     
     
         17 . The method according to  claim 16  wherein the agent that increase 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-CSF) 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 (Amgen AMG 531), and any combinations thereof. 
     
     
         18 . The method according to  claim 16  wherein said administering the one or more electrophilic compounds and said administering the agent that increases megakaryocyte production are carried out at the same time. 
     
     
         19 . The method according to  claim 16  wherein said administering the one or more electrophilic compounds and said administering the agent that increases megakaryocyte production are carried out at different times. 
     
     
         20 . The method according to  claim 9  wherein the patient is a radiation therapy cancer patient, a patient having an autoimmunity disorder characterized by low platelet level, a chemotherapy cancer patient that receives a chemotherapeutic agent that is not an electrophilic tri-terpenoid, or an individual exposed to ionizing radiation or a chemical in doses that cause platelet loss. 
     
     
         21 . A pharmaceutical composition or therapeutic system comprising an agent that increases megakaryocyte production and one or more electrophilic compounds selected from the group consisting of (i) an electrophilic prostaglandin, (ii) a pentacyclic tri-terpenoid derivative of betulin or betulinic acid, and (iii) a tri-cyclic bis-enone.