IDO inhibitors and methods of use
Compounds, compositions and methods for the treatment of malignancy are disclosed.
1. A compound having indoleamine 2,3 dioxygenase (IDO) inhibitory activity, said compound having the:
wherein R 1 is H or lower alkyl; R 2 and R 3 are joined together and represent part of a ring which is fused to the pyrrole moiety of formula (I) and which is selected from the group of:
(ii) wherein R E is a hydrocarbyl or alkyl-Q, Q representing a substituent of the formula:
the compound of formula (I) being a brassilexin derivative when R 2 and R 3 joined together represent (i), and an N-substituted brassilexin derivative when R 2 and R 3 joined together represent (ii); X, Y, and Z may be the same or different and are selected from the group consisting of H, halogen, NO 2 , and hydrocarbyl; or Y may also be isothiocyanate.
2. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier medium.
3. A pharmaceutical composition comprising an effective amount of at least one indoleamine 2,3-dioxygenase (IDO) inhibitor and at least one signal transduction inhibitor (STI) in a pharmaceutically acceptable carrier medium, wherein said at least one IDO inhibitor is compounds having the formula:
wherein R 1 is H or lower alkyl; R 2 and R 3 are joined together and represent part of a ring which is fused to the pyrrole moiety of formula (I) and which is selected from the group of:
wherein R E is a hydrocarbyl or alkyl-Q, Q representing a substituent of the formula:
the compound of formula (I) being a brassilexin derivative when R 2 and R 3 joined together represent (i) and an N-substituted brassilexin derivative when R 2 and R 3 joined together represent (ii); X, Y, and Z may be the same or different and are selected from the group consisting of H, halogen, NO 2 , and hydrocarbyl; or Y may also be isothiocyanate.
4. The pharmaceutical composition of claim 3 , wherein said at least one STI is selected from the group consisting of ber/abi kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, her-2/neu receptor inhibitors, farnesyl transferase inhibitors (FTIs), inhibitors of Akt family kinases or the Akt pathway, and cell cycle kinase inhibitors.
5. The pharmaceutical composition of claim 4 , wherein said at least one STI is selected from the group consisting of STI 571, 551-774, C225, ABX-EGF, trastuzumab, L-744,832, rapamycin, LY294002, flavopiridal, and UNC-01.
6. The pharmaceutical composition of claim 5 , wherein said at least one STI is L-744,832.
7. A pharmaceutical composition comprising an effective amount of at least one indoleamine 2,3-dioxygenase (IDO) inhibitor and at least one chemotherapeutic agent in a pharmaceutically acceptable carrier medium, wherein said at least one IDO inhibitor is selected from the group of compounds having the formula:
wherein R 1 is H or lower alkyl; R 2 and R 3 are joined together and represent part of a ring which is fused to the pyrrole moiety of formula (I) and which is selected from the group of:
wherein R E is a hydrocarbyl or alkyl-Q, Q representing a substituent of the formula:
the compound of formula (I) being a brassilexin derivative when R 2 and R 3 joined together represent (i), and an N-substituted brassilexin derivative when R 2 and R 3 joined together represent (ii); X, Y, and Z may be the same or different and are selected from the group consisting of H, halogen, NO 2 , and hydrocarbyl; or Y may also be isothiocyanate.
8. The pharmaceutical composition of claim 7 , wherein said at least one chemotherapeutic agent is selected from the group consisting of paclitaxel TAXOL®, cisplatin, docetaxol, carboplatin, vincristine, vinbiastine, methotrexate, cyclophosphamide, CPT-11, 5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, adriamycin (doxorubicin), etoposide, arsenic trioxide, irinotecan, and epothilone derivatives.
9. The pharmaceutical composition of claim 4 , wherein said at least one chemotherapeutic agent is paclitaxel.