New norcantharidin derivatives e.g. used for treating cancer, neurodegenerative diseases, restenosis, diabetes, asthma and bacterial and fungal infections

摘要

Norcantharidin derivatives (I) are new. Norcantharidin derivatives of formula (I) and their salts are new. [Image] a, b, c, d, e, f : 0 or 1; a + b, c + d : 1 or 2; Ta : (CH2)n, (CH2)mCONH, CMe2, CH2CMe2 or CHR1(CH2)p; n : 1-12; m : 1-3; p : 0 or 1; R1COOH, Me, CH2OH, iBu, COOMe, Pa-phenyl-Pb, CH2-imidazole, CH2-indole or CH2-(N-methylindole); Pa : CH2 or absent; Pb : OH, Me, halo or OCONH-phenyl-R2 or absent; R2NO2, phenylthio or phenoxy or absent; Tb : optionally substituted ring of 5-6 C and/or N atoms, CR3, CR3-NR4-(CH2)q, R3-CR3-NR4-phenyl-R5 or R6-(CH2)o; R3O or S; R4H or Me; R5phenoxy, phenylthio or absent; q : 0-3; R6O, S, phenylene or absent; o : 0-3, but not 0 when R6 is absent; Tc : R3-CR3, NR4-CR3, CR3-NR4, NR4-CR3-R3, R3-CR3-NR4, NR4-CR3-NR4, CR3-piperazyl, NR4-R7 or R3-CR3-NR4-R7; R7S, SO or SO2; Na : R8, A or A-R8; A : 1-6C alkylene; R8O, S, SO, CS or SO2; Nb : halo, 1-6C alkyl, R3-CMe3 or optionally substituted mono-, bi- or tricyclic system of 3-15 C, O, N and/or S atoms; Ra : CH2, SO2NH, SO, SO2, NH, R3, CR3 or R3-CH2, and Rb : optionally substituted mono- or bicyclic system of 5-10 C, O, N and/or S atoms. An independent claim is also included for a pharmaceutical composition comprising at least one compound (I) and optionally other antiproliferative agents, protein phosphatase inhibitors or antimicrobial agents. ACTIVITY : Cytostatic; Neuroprotective; Antiparkinsonian; Nootropic; Antidepressant; Vasotropic; Antidiabetic; Antiasthmatic; Antibacterial; Fungicide. In a test, 2-(3,5-dioxo-10-oxa-4-azatricyclo[5.2.1.02.6>]decan-4-yl)ethyl-4-phenoxyphenylcarbamate had an IC50 value of 39.79 mu M for inhibiting proliferation of HT29 tumor cells in vitro. MECHANISM OF ACTION : None given.