On December 13, 2018, Bartberger, Michael D.; Beck, Hilary Plake; Degraffenreid, Michael R.; Fox, Brian M.; Gonzalez Lopez De Turiso, Felix; Julian, Lisa D.; Kayser, Frank; Medina, Julio C.; Olson, Steven H.; Rew, Yosup; Roveto, Philip M.; Sun, Daqing; Yan, Xuelei published a patent.Electric Literature of 70931-59-8 The title of the patent was Preparation of cis-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer. And the patent contained the following:
The invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor. The title compounds [I; X = O or S(O)2; R1 = H, C1-6alkyl, (CReRe)nC6-8aryl, (CReRe)nC3-8cycloalkyl, (CReRe)n-3-8 membered heterocycloalkyl, S(O)2C3-8cycloalkyl, C(O)C3-8cycloalkyl, or CRfRa(CReRe)n-Q; Q = (CReRe)nC6-8aryl, (CReRe)n-3-8 membered heterocycloalkyl, (CReRe)n-5-8 membered heteroaryl, (CReRe)nC3-8cycloalkyl, cyano, (CReRe)nOH, CO2H, NReRe, etc.; R2 = H, C1-6alkyl, (CReRe)nC(O)ORe, (CReRe)nNReRe, (CReRe)nC(O)NReRe, (CReRe)nOH, (CReRe)nC(O)H, (CReRe)nC6-8aryl, (CReRe)n-3-8 membered heterocycloalkyl, (CReRe)n-5-8 membered heteroaryl, (CReRe)nCN, -(CReRe)nC(O)5-8 membered heterocycloalkyl, etc.; any heteroaryl or heterocycloalkyl group has one or more heteroatoms independently selected from O, N or S; any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted; R3 = H or C1-6alkyl; R4 = C6-8 aryl or 5-9 membered heteroaryl; R5 = C6-8 aryl or 5-9 membered heteroaryl; R6, R7 = H or C1-6alkyl; Ra = independently H, C1-6alkyl, C2-6alkenyl, (CReRe)nC3-8cycloalkyl, or (CReRe)nC6-8aryl, wherein any cycloalkyl or aryl group can be unsubstituted or substituted; Re, Rf = independently H, C1-6alkyl , or OH; n, m = independently 0-4; provided that R2 and R3 are not both H] or pharmaceutically acceptable salts thereof were prepared These compounds including morpholinone and 2,5,6,8-tetrahydro-3H-imidazo[2,1-c][1,4]oxazine derivatives are inhibitors of MDM2 (oncoprotein) and are useful as therapeutic agents, particularly for the treatment of cancers. Thus, cyclocondensation of rel-(1R,2S)-1,2-bis(4-bromophenyl)-2-(methylamino)ethanol with 2-chloroacetyl chloride gave rel-(5R,6S)-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one which was treated with sodium bis(trimethylsilyl)amide followed by benzylation with benzyl bromide yo give rel-(2S,5R,6S)-2-benzyl-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one (II). II and 2-[rel-(2S,5R,6S)-4-benzyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl]acetic acid (III) showed IC50 of 1.96 and 0.0399 渭M, resp., for inhibiting the interaction of GST-hMDM2 and biotinylated-p53 in an homogeneous time-resolved fluorescence assay (HTRF1 assay). The experimental process involved the reaction of 1-(Bromomethyl)-4-fluoro-2-iodobenzene(cas: 70931-59-8).Electric Literature of 70931-59-8
The Article related to mdm2 oncoprotein inhibitor morpholinone tetrahydroimidazooxazine, morpholinone tetrahydroimidazooxazine preparation treatment cancer, Heterocyclic Compounds (More Than One Hetero Atom): Pyrazines and Quinoxalines (Including Piperazines) and other aspects.Electric Literature of 70931-59-8
Referemce:
Iodide – Wikipedia,
Iodide – an overview | ScienceDirect Topics – ScienceDirect.com