Dipeptide and tripeptide hemiasterlin analogs

摘要

The compound of formula (I) is useful as an antimitotic agent. In the compound of formula I: R1, R2, R3 and R4 are independently H, R or ArR-, or R1 and R2 and/or R3 and R4 are joined to form a 3-7 membered non-aromatic ring, the ring being within the definition of R; R5 is H, R, ArR- or Ar; R6, R7 and R8 are H, R or ArR-; R9 is Z-C(=O)-Y-; R is a saturated or unsaturated moiety having a linear, branched or non-aromatic cyclic skeleton containing one to ten carbon atoms, zero to four nitrogen atoms, zero to four oxygen atoms, and zero to four sulfur atoms, and the carbon atoms are optionally substituted with: =O, =S, -OH, OR10, O2CR10, -SH, -SR10, -SOCR10, -NH2, -NHR10, -N(R10)2, -NHCOR10, -NR10COR10, I, Br, Cl, F, CN, -CO2H, -CO2R10, -CHO, -COR10, -CONH2, -CONHR10, -CON(R10)2, -COSH, COSR10, -NO2, -SO3H, -SOR10, SO2R10, where R10 is a linear, branched or cyclic, one to ten carbon saturated or unsaturated alkyl group; X is -OH, -OR, =O, =S, -O2CR, -SH, -SR, -SOCR, -NH2, -NHR, -N(R)2, -NHCOR, -NRCOR, -I, -Br, -Cl, -F, -CN, -CO2H, -CO2R, -CHO, -COR, -CONH2, -CONHR, -CON(R)2, -COSH, -COSR, -NO2, -SO3H, -SOR, or -SO2R; Ar is an aromatic ring selected from phenyl, naphthyl, anthracyl, phenanthryl, furyl, pyrrolyl, thiophenyl, benzofuryl, benzothiophenyl, quinolinyl, isoquinolinyl, imidazolyl, thiazolyl, oxazolyl, and pyridinyl all optionally substituted with R or X; Y is a linear, saturated or unsaturated, one to six carbon alkyl group, optionally substituted with R, ArR-, or X; and, Z is -OH, -OR; -SH; -SR; -NH2; -NHR; -N(R)2; -NHCH(R11)COOH; and -NRCH(R11)COOH, where R11 is a moiety having the formula: R, or -(CH2)nNR12R13, where n=1-4 and R12 and R13 are independently H; R; or -C(NH) (NH2). The compound of formula (I) is also described, but the following provisos apply: If R8 is H and Y is optionally substituted one carbon alkyl group, R1 and R2 are not joined to form imidazolidine, and If R8 is H, Y may only be substituted with RÆ or ArÆRÆ (where RÆ is a saturated linear, branched, or cyclic skeleton containing one to ten carbon atoms; and ArÆ is phenyl, naphthyl, anthracycl or phenanthryl, optionally substituted with RÆ). Also described is a dipeptide intermediate of the formula (II), where R3-R7 are as defined for the compound of formula (I); Q and T are R1 or R2 as defined for the compound of formula (I) or Q and/or T is a protecting group, where at least one of Q and T is a protecting group.