Novel harringtonines salts in the crystalline state, their use for the purification of the corresponding drug substance and as chemotherapeutic agents given alone or combined with radiotherapy or as immunomodulating agents

Abstract

The invention also relates to a process for preparing and purifying these salts and their use as chemostherapeutic drugs, alone or combined with radiotherapy, or as immunomodulating agents.

1 . A harringtonines salt in the crystalline state exhibiting a protonated nitrogen seen in solid state analysis and having formula 1, 
       
         
           
           
               
               
           
         
         comprising solvate, made by reacting a cephalotaxine ester having formula 2, 
       
       
         
           
           
               
               
           
         
         in which R 1  is, but not limited to, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl, and R 2  is, independently, but not limited to H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl, with an acid having general formula  AH  in a crystallization solvent, wherein the said salt has a water or alkohol solubility ranged approximately from 5 mg/mL to approximately 100 mg/Ml. 
       
     
     
         2 . The salt of  claim 1  wherein the cephalotaxine ester reactant is homoharringtonine (=omacetaxine) having formula 2 in which R 2  is hydrogen and R1 have below formula 3. 
       
         
           
           
               
               
           
         
       
     
     
         3 . The salts of  claim 1  wherein the acid is an organic acid but not limited to, selected among the following list: fumaric, maleic, citramalic, malic, tartaric, tartronic, succinic, itaconic, citric acid or salicylic acid. 
     
     
         4 . The salts of  claim 1 , having below formula 
       
         
           
           
               
               
           
         
       
       in which the malic acid is of configuration 2S having formula 
       
         
           
           
               
               
           
         
       
     
     
         5 . The salts of  claim 4 , wherein the malic acid is of configuration 2R having formula 
       
         
           
           
               
               
           
         
       
     
     
         6 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine hydrogen (R)-malate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtone hydrogen succinate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine hydrogen (2′″S,3′″S)-tartrate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine hydrogen (2′″R,3′″R)-tartrate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine hydrogen itaconate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine hydrogen fumarate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine hydrogen tartronate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine hydrogen malonate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine dihydrogen citrate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The salt of  claim 1 , named (3S,4S,5R,2′R)-homoharringtonine salicate exhibiting the below formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The salt of  claim 1  as crystalline form comprising solvate and co-crystal. 
     
     
         17 . The cation (3S,4S,5R,2′R)-homoharringtoninium as described in  FIGS. 2.3 . 1 ,  2 . 4 . 1 ,  2 . 5 . 1 ,  2 . 6 . 1 ,  2 . 8 . 1 ,  2 . 9 . 1 ,  2 . 11 . 1 , and  2 . 12 . 1 , exhibiting the below formula 
       
         
           
           
               
               
           
         
       
     
     
         18 . The process of preparation and purification of salts of  claim 1  comprising contacting a natural, hemi-synthetic or synthetic harringtonine or its semi-synthetic analog with a weak acid in suspension or in solution in a suitable non-aqueous solvent, preferably an alcohol or mixed at the solid state either at the amorphous state or at the crystalline state then recrystallized said salt in a suitable non aqueous solvent, preferably an alcohol, the said process being also when repeated a method of purification including enantiomeric (fractional crystallization). 
     
     
         19 . The process of  claim 18  wherein the harringtonine is homoharringtonine having formula represented in  claim 2 . 
     
     
         20 . The process of  claim 18  wherein the harringtonine is an harringtonine analog having general formula: 
       
         
           
           
               
               
           
         
         in which R 1  is, but not limited to, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl, and R 2  is, independently, but not limited to H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl. 
       
     
     
         21 . The process of  claim 18 , wherein the acid is, but not limited to, selected among the following list: fumaric, maleic, citramalic, malic, tartaric, tartronic, succinic, itaconic, salicylic or citric acid. 
     
     
         22 . A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a mineral or organic salt or solvate or co-crystal of  claim 1 . 
     
     
         23 . A method of treatment comprising administering a therapeutically effective amount of a pharmaceutical dosage form of  claim 22  to a patient or an animal suffering from cancer including their metastasis, leukemia, lymphoma, parasitic disease, ocular proliferation and/or immune disorder and/or from viral disease. 
     
     
         24 . A method of treating cancer, leukemia and/or lymphoma, comprising administering to a patient or an animal in need thereof the pharmaceutical dosage of  claim 22 , said pharmaceutical dosage being administered alone or in combination with at least another chemotherapeutic agents, eventually combined with radiotherapy. 
     
     
         25 . The method of  claim 24 , wherein the leukemia is acute myelod leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelosclerosis, and
 wherein the lymphoma is a multiple myeloma, a Hodgkin disease or a Burkitt lymphoma, and   wherein the cancer is a breast cancer, a brain cancer or a lung cancer.   
     
     
         26 . The method of  claim 25 , wherein the breast cancer is a triple negative breast cancer (TNBC). 
     
     
         27 . The method of  claim 25  wherein the brain cancer is a neuroblastoma. 
     
     
         28 . The method of  claim 25 , wherein the lung cancer is a non small cell lung cancer (NSCLC). 
     
     
         29 . A method for treating autoimmune disorder, comprising administering to a patient or an animal in need thereof the pharmaceutical dosage of  claim 22 , said pharmaceutical dosage being administered alone or in combination with at least another chemotherapeutic agent. 
     
     
         30 . The method of  claim 29 , wherein the autoimmune disorder is a systemic lupus erythematosus (SLE), a dermatomyositis, a psoriasis or a lichen planopilaris (LPP). 
     
     
         31 . The method of  claim 30 , wherein the lichen planopilaris (LPP) is a frontal fibrosis alopecia (FFA).