Piperidinone Derivatives as MDM2 Inhibitors for the Treatment of Cancer

Abstract

The present invention provides MDM2 inhibitor compounds of Formula I, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

1 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising a compound of 2-(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The pharmaceutical composition of  claim 31 , further comprising microcrystalline cellulose. 
     
     
         33 . The pharmaceutical composition of  claim 31 , further comprising lactose. 
     
     
         34 . The pharmaceutical composition of  claim 31 , further comprising carboxymethylcellulose. 
     
     
         35 . The pharmaceutical composition of  claim 31 , further comprising magnesium stearate. 
     
     
         36 . The pharmaceutical composition of  claim 31 , in a dosage form formulated for topical administration. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the dosage form is an ointment. 
     
     
         38 . The pharmaceutical composition of  claim 36 , wherein the dosage form is spray. 
     
     
         39 . The pharmaceutical composition of  claim 36 , wherein the dosage form is inhalants. 
     
     
         40 . The pharmaceutical composition of  claim 31  is in a dosage form for oral administration. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the dosage form is tablets. 
     
     
         42 . The pharmaceutical composition of  claim 40 , wherein the dosage form is capsules. 
     
     
         43 . The pharmaceutical composition of  claim 31 , further comprising a pharmaceutically active agent selected from the group consisting of dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, and a pharmaceutically acceptable salt thereof. 
     
     
         44 . A method of treating nausea in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 43 . 
     
     
         45 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim  1 , wherein the cancer is selected from
 (a) Carcinomas, which comprise cancer of the bladder, breast, colon, rectum, kidney, liver, lung, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin;   (b) hematopoietic tumors of lymphoid lineage, which comprise leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma;   (c) hematopoietic tumors of myeloid lineage, which comprise acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;   (d) tumors of mesenchymal origin, which comprise fibrosarcoma and rhabdomyosarcoma, and other sarcomas, which comprise soft tissue sarcomas and bone sarcomas;   (e) tumors of the central and peripheral nervous system, which comprise astrocytoma, neuroblastoma, glioma and schwannomas; or   (f) other tumors, which comprise melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer, Kaposi's sarcoma, endometrial cancer, head and neck cancer, glioblastoma, malignant ascites, and hematopoietic cancers.