# US 2013/0158068 A1 · Dicarboximide derivatives of berbamine, the preparation and use thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2013/0158068 A1 - Document ID: US20130158068A1 - Status: Published application - Kind: A1 - Application number: 13/819,111 - Filed: 2011-08-25 - Published: 2013-06-20 - Earliest claimed: 2010-08-27 - Assignees: Hangzhou Bensheng Pharmaceutical Co., Ltd. - Inventors: Rongzhen Xu; Frank Rong; Fuwen Xie; Hongxi Lai - Web page: https://patentgrep.com/patent/US20130158068A1 ## CPC - C07D 471/04: Ortho-condensed systems - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - C07D 401/14: containing three or more hetero rings - C07D 491/16: Peri-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to a novel dicarboximide derivative of berbamine represented by formula I, including, but not limited to, a phthalimide derivative of berbamine and an aromatic heterocyclic dicarboximide derivative of berbamine, or a pharmaceutically acceptable salt thereof, to a process for preparation of the same, to a pharmaceutical composition comprising said compound and to use thereof in manufacture of an antitumor medicament. ## Claims ### Claim 1 A dicarboximide derivative of berbamine of formula (I): wherein, R1 is selected from H, halogen, amino, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C3-C7 cycloalkyl; A is selected from a linear or branched, substituted or unsubstituted alkylene —(CH2)n—, optionally being interrupted by a heteroatom selected from the group consisting of O, N, S, wherein n is an integer from 1 to 15; W, X, Y and Z are selected from substituted or unsubstituted methine CH, methylene CH2 and a heteroatom selected from the group consisting of O, N and S, wherein at least two of W, X, Y and Z are CH or CH2; wherein “substituted” means a substitution by a sub stituent selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl and mercapto; or a pharmaceutically acceptable salt thereof. ### Claim 2 (depends on 1) A phthalimide derivative of berbamine of formula (I-a): wherein n is an integer of 1-15, and R1 and B are defined same as in formula (I) of claim 1, or a pharmaceutically acceptable salt thereof. ### Claim 3 (depends on 1) An aromatic heterocyclic dicarboximide derivative of berbamine of formula (I-b): wherein the aromatic heterocyclic group (Het) contains one or two heteroatoms selected from the group consisting of O, N and S, and R1, n and B are defined same as in formula (I) of claim 1, or a pharmaceutically acceptable salt thereof. ### Claim 4 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is an integer of 1-10. ### Claim 5 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is an integer of 1-8. ### Claim 6 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is an integer of 1-7. ### Claim 7 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is H, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkyl, C3-C7 cycloalkyl, halogen, nitro, cyano or amino optionally substituted with one or two C1-C6 alkyl. ### Claim 8 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is H, C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl or halogen. ### Claim 9 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is H, C1-C3 alkoxy, C1-C3 alkyl, or C5-C6 cycloalkyl. ### Claim 10 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is H, methoxy, or methyl. ### Claim 11 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is H. ### Claim 12 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1, selected from the following compounds or a pharmaceutically acceptable salt thereof: ### Claim 13 (depends on 1) A process for preparation of a compound of formula (I), comprising reacting the compound of formula (III) and the compound of formula (II) to produce a compound of formula (I), wherein A, B, W, X, Y, Z, R1 and n in the compounds of formula (I), (II) and (III) are defined same as in claim 1, and LG is a leaving group. ### Claim 14 (depends on 13) The process according to claim 13, wherein the leaving group LG is a halogen atom or sulfonate group. ### Claim 15 (depends on 1) A pharmaceutical composition comprising the dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1 and optionally a pharmaceutically acceptable excipient. ### Claim 16 (depends on 1) Use of the dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1 in manufacture of an antitumor medicament. ### Claim 17 (depends on 1) A method for treating a patient suffering from tumor, comprising administrating to the patient in need thereof an therapeutically effective amount of the dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1. ### Claim 18 (depends on 1) The dicarboximide derivative of berbamine or a pharmaceutically acceptable salt thereof according to claim 1 as an antitumor agent. ### Claim 19 (depends on 17) The method according to claim 17, wherein the tumor is selected from leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocellular carcinoma, pancreatic cancer, lung cancer, carcinoma of large intestine, osteosarcoma, human cervical cancer, glioma, nasopharyngeal carcinoma, laryngeal carcinoma, esophageal cancer, middle ear tumor, melanoma and prostate cancer.