Pyrazoloanthrone and derivatives thereof for treatment of cancers expressing missrii

Abstract

The present invention relates to pyrazoloanthrones or functional derivatives or functional analogues thereof to activate MIS receptor-mediated downstream effects in a cell. In particular, the present invention relates to method to prevent and treat cancer that expresses MIS receptor type II (MISRII) by administering to a subject at least one pyrazoloanthrone or a functional derivative or a functional analogue thereof. Another aspect of the present invention relates to methods to lower plasma androgen levels in a subject, and/or for the treatment of a subject with a disease characterized by excess androgen, whereby the subject is administered at least one pyrazoloanthrone or a functional derivative or a functional analogue thereof. Another aspect provides pharmaceutical compositions comprising at least one pyrazoloanthrone or functional a derivative or a functional analogue thereof, and optionally with one or more additional agents such as chemotherapeutic agents. Another aspect of the present invention relates to methods to decrease the dose of a chemotherapeutic agent by administering the chemotherapeutic agent with a pyrazoloanthrone or a functional derivative or a functional analogue thereof that lowers the effective dose of the chemotherapeutic agent, such as for example, paclitaxel.

1 .- 46 . (canceled) 
     
     
         47 . A pharmaceutical composition for the treatment of a cancer expressing the Mullerian Inhibiting Substance Receptor II (MISRII), comprising a pyrazoloanthrone compound and at least one of: paclitaxel, cisplatin, doxorubicin, rapamycin, Mullerian Inhibiting Substance (MIS) or recombinant human MIS (hMIS) and a pharmaceutical acceptable carrier. 
     
     
         48 . (canceled) 
     
     
         49 . The pharmaceutical composition of  claim 47 , wherein the pyrazoloanthrone compound is anthra[1,9-cd]pyrazol-6(2H)-one or a functional derivative or functional analogue of anthra[1,9-cd]pyrazol-6(2H)-one having the structure of formula (I), wherein formula (I) is as follows: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are optional substituents that are the same or different and independently represent alkyl, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c) or (d): 
 
       
         
           
           
               
               
           
         
         
           R 3  and R 4  taken together represent alkylidene or a heteroatom-containing alkylidene, or R 3  and R 4  are the same or different and independently represent hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di-alkylamino); and 
           R 5  represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, or cycloalkylalkylamino. 
         
       
     
     
         50 .- 78 . (canceled) 
     
     
         79 . The pharmaceutical composition of  claim 47 , wherein the Mullerian Inhibiting Substance (MIS) or recombinant human MIS (hMIS) is a MIS molecule having at least 85% sequence identity to SEQ ID NO: 2 or has substantially the same biological activity as the MIS protein of SEQ ID NO: 2. 
     
     
         80 . The pharmaceutical composition of  claim 47 , further comprising an emulsifying agent. 
     
     
         81 . A kit comprising;
 at least one pyrazoloanthrone compound;   at least one chemotherapeutic agent selected from: paclitaxel, cisplatin, doxorubicin, rapamycin, Mullerian Inhibiting Substance (MIS) or recombinant human MIS (hMIS);   packaging material, wherein the packaging material comprises a label which indicates the pharmaceutical composition may be administered, for a sufficient term at an effective dose, for treating a subject with a cancer which expresses a Mullerian Inhibiting Substance receptor II (MISRII).   
     
     
         82 . The kit of  claim 81 , wherein the cancer is selected from the group consisting of: breast cancer, lung cancer, head and neck cancer, bladder cancer, stomach cancer, cancer of the nervous system, bone cancer, bone marrow cancer, brain cancer, colon cancer, esophageal cancer, endometrial cancer, gastrointestinal cancer, gum cancer, kidney cancer, liver cancer, nasopharynx cancer, ovarian cancer, prostate cancer, skin cancer, stomach cancer, testis cancer, tongue cancer, cervical cancer or uterine cancer. 
     
     
         83 . The kit of  claim 81 , wherein the cancer comprises at least one of: an ovarian cancer cell, vulvar epidermal carcinoma cell, cervical carcinoma cell, endometrial edenocarinaoma cell or ovarian adenocarcinoma cell. 
     
     
         84 . The kit of  claim 81 , wherein the pyrazoloanthrone compound is anthra[1,9-cd]pyrazol-6(2H)-one or a functional derivative or functional analogue of anthra[1,9-cd]pyrazol-6(2H)-one having the structure of formula (I), wherein formula (I) is as follows: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are optional substituents that are the same or different and independently represent alkyl, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c) or (d): 
 
       
         
           
           
               
               
           
         
         R 3  and R 4  taken together represent alkylidene or a heteroatom-containing alkylidene, or R 3  and R 4  are the same or different and independently represent hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di-alkylamino); and 
         R 5  represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, or cycloalkylalkylamino. 
       
     
     
         85 . The kit of  claim 81 , wherein the Mullerian Inhibiting Substance (MIS) or recombinant human MIS (hMIS) is a MIS molecule having at least 85% sequence identity to SEQ ID NO: 2 or has substantially the same biological activity as the MIS protein of SEQ ID NO: 2. 
     
     
         86 . The kit of  claim 81 , further comprising an emulsifying agent.