Pyrazoloanthrone and derivatives thereof for the treatment of cancers expressing MISRII

Patent metadata

Field	Value
Publication number	US-9260759-B2
Application number	US-201113328387-A
Country	US
Kind code	B2
Filing date	Dec 16, 2011
Priority date	Mar 22, 2007
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

Provided herein are pyrazoloanthrones or functional derivatives or analogs thereof to activate MIS receptor-mediated downstream effects in a cell. In particular, methods are provided 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 analog thereof. Also provided herein are 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 analog thereof. Also provided are methods to decrease the dose of a chemotherapeutic agent by administering the chemotherapeutic agent with a pyrazoloanthrone or a functional derivative or analog thereof that lowers the effective dose of the chemotherapeutic agent.

First claim

The invention claimed is:

1. A method of decreasing the dose of a chemotherapeutic agent for the treatment of cancer expressing Mullerian Inhibiting Substance Receptor II (MISRII), the method comprising administering to the subject a therapeutically effective amount of a pyrazoloanthrone compound and at least one or a combination of chemotherapeutic agents selected from the group consisting of: paclitaxel, cisplatin, doxorubicin, rapamycin, Mullerian Inhibiting Substance (MIS) or recombinant human MIS (rhMIS), wherein the therapeutically effective dose of the chemotherapeutic agent for an apoptotic effect on a cancer cell expressing MISRII in the presence of the pyrazoloanthrone compound is lower as compared to the therapeutically effective dose of the chemotherapeutic agent for the same apoptotic effect on a cancer cell expressing MISRII in the absence of the pyrazoloanthrone compound.

2. The method of claim 1 , wherein the pyrazoloanthrone compound is anthrapyrazol-6(2H)-one or derivative or analogue of anthrapyrazol-6(2H)-one which has the structure of formula (I) and which activates MISRII signaling or interacts with the MISRII receptor, 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.

3. The method of claim 1 , wherein the Mullerian Inhibiting Substance (MIS) or rhMIS is a MIS molecule having at least 95% sequence identity to SEQ ID NO: 2, and has substantially the same biological activity as the MIS protein encoded by SEQ ID NO:2.

4. The method of claim 1 , wherein the pyrazoloanthrone compound is administered at the same time, or prior to, or following administration of a chemotherapeutic agent.

5. The method of claim 1 , wherein the cancer is ovarian cancer or prostate cancer.

6. The method of claim 1 , wherein the pyrazoloanthrone compound is administered in a pharmaceutically acceptable carrier.

7. The method of claim 6 , wherein the pharmaceutically acceptable carrier comprises an emulsifying agent.

Assignees

• Teixeira Jose
• Donahoe Patricia K
• Gen Hospital Corp

Inventors

• Teixeira Jose
• Donahoe Patricia K

Classifications

• A61K38/22

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35) · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/416 Primary

  condensed with carbocyclic ring systems, e.g. indazole · CPC title