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20-O-Acylmaytansinoids

  • US 4,294,757 A
  • Filed: 01/15/1980
  • Issued: 10/13/1981
  • Est. Priority Date: 01/31/1979
  • Status: Expired due to Term
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Assignment
First Claim
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1. A compound of the formula:

  • ##STR23## wherein X is chlorine or hydrogen, R1 is hydrogen or acyl;

    R2 is acyl;

    said acyl being represented by the formula;

    

    space="preserve" listing-type="equation">--CO--R.sub.3                                              (a)wherein R3 is hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocyclic group selected from the group consisting of azetidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2,3,4-tetrahydropyridyl, piperidyl, quinolyl, 1,2-dihydroquinolyl, 3-isoquinolyl, 4-isoquinolyl, 1,2-dihydroisoquinolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, indolyl, furyl, pyranyl, dihydropyranyl, benzofuryl, benzopyranyl, thienyl, benzothienyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 2-imidazolyl, imidazolidinyl, benzoimidazolyl, indazolyl, quinoxalyl, quinazolinyl, cinnolinyl, 1,4-dioxanyl 1,4-benzodioxanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,3-dithianyl, isooxazolyl, oxazolyl, morpholinyl, benzoisoxazolyl benzoxazolyl, isothiazolyl, thiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiazinyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,3,5-triadinyl, benzotriazolyl and 1,2,3,4-tetrazolyl, said cycloalkyl, cycloalkenyl, phenyl or heterocyclic group being attached directly to the carbonyl carbon or through a C1-4 alkylene chain, said alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl or heterocyclic group being unsubstituted or substituted by C1-4 alkoxy, C2-4 alkanoyl, C2-4 alkanoyloxy, C2-4 alkanoyl, C2-4 alkanoyloxy, C2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C1-4 -alkylamino, C1-4 alkylthio methylsulfinyl, methylsulfonyl, oxo, thioxo, C1-4 alkanoylamido or carboxy group of the formula -COOR12 wherein R12 is hydrogen, C1-6 alkyl, phenyl or benzyl, and said cycloalkyl, cycloalkenyl, phenyl or heterocyclic group being unsubstituted or substituted by C1-4 alkyl;

     ##STR24## wherein R4 is hydrogen, C1-18 alkyl, C3-10 cycloalkyl, phenyl, indolyl or imidazolyl group, said cycloalkyl, phenyl, indolyl or imidazolyl groups being attached directly to the alpha-carbon atom or, through a C1-4 alkylene chain, said alkyl, cycloalkyl, phenyl, indolyl or imidazolyl being unsubstituted or substituted by C1-4 alkoxy, C2-4 alkanoyl, C2-4 alkanoyloxy, C2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C1-4 -alkylamino, C1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C1-4 alkanoylamido, and said cycloalkyl, phenyl, indolyl or imidazolyl being unsubstituted or substituted by C1-4 alkyl;

     R5 is hydrogen, C1-18 alkyl, C3-10 cycloalkyl, C4-14 cycloalkylalkyl, phenyl or benzyl group, said alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl group being unsubstituted or substituted by C1-4 alkoxy, C2-4 alkanoyl, C2-4 alkanoyloxy, C2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C1-4 -alkylamino, C1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C1-4 alkanoylamido, and said cycloalkyl cycloalkylalkyl, phenyl or benzyl group being unsubstituted or substituted by C1-4 alkyl;

     R6 is hydrogen, C1-7 alkoxy, bornyloxy, isobornyloxy, benzyloxy, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, phenyl or heterocyclic group selected from the group consisting of azetidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2,3,4-tetrahydropyridyl, piperidyl, quinolyl, 1,2-dihydroquinolyl, 3-isoquinolyl, 4-isoquinolyl, 1,2-dihydroisoquinolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, indolyl, furyl, pyranyl, dihydropyranyl, benzofuryl, benzopyranyl, thienyl, benzothienyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 2-imidazolyl, imidazolidinyl, benzoimidazolyl, indazolyl, quinoxalyl, quinazolinyl, cinnolinyl, 1,4-dioxanyl, 1,4-benzodioxanyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,3-dithianyl, isooxazolyl, oxazolyl, morpholinyl, benzoisoxazolyl, benzoxazolyl, isothiazolyl, thiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiazinyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,3,5-triadinyl, benzotriazolyl and 1,2,3,4-tetrazolyl, said cycloalkyl, cycloalkenyl, phenyl or heterocyclic groups being attached directly to the carbonyl carbon atom adjacent the nitrogen atom or through a C1-4 alkylene chain, said alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl or heterocyclic group being unsubstituted or substituted by C1-4 alkoxy, C.sub. 2-4 alkanoyl, C2-4 alkanoyloxy, C2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C1-4 -alkylamino, C1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C1-4 alkanoylamido, and said cycloalkyl, cycloalkenyl, phenyl or heterocyclic group being unsubstituted or substituted by C1-4 alkyl;

     ##STR25## wherein R7 and R8 may be the same or different and each is hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C4-14 cycloalkylalkyl, C4-10 cycloalkenylalky phenyl, phenyl-C1-4 -alkyl, phenyl-C3-10 -cycloalkyl, C3-10 cycloalkylphenyl, biphenyl or heterocyclic group selected from the group consisting of azetidinyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, quinazolyl, quinoxalyl, indolyl, benzofuranyl and benzothienyl, and wherein R7 and R8 together may form a heterocyclic group of azetidinyl, pyrrolidinyl, piperadinyl or morpholinyl taken together with the adjacent nitrogen atom, these groups being unsubstituted or substituted by C1-4 alkoxy, C1-4 alkylthio, phenoxy, phenylthio, cyclohexyloxy, halogen, cyano, C2-5 alkoxycarbonyl, benzyloxycarbonyl, nitro, aminosulfonyl or di-C1-4 -alkylamino, and said cyclic moiety or heterocyclic group being unsubstituted or substituted by C1-4 alkyl;

     or
    

    space="preserve" listing-type="equation">--CO--O--R.sub.9                                           (d)wherein R9 is C1-18 alkyl, C3-10 cycloalkyl, phenyl or phenyl-C1-4 -alkyl, said groups being unsubstituted or substituted by C1-4 alkoxy, phenoxy, benzyloxy, halogen or cyano, and said cyclic moiety being unsubstituted or substituted by C1-4 alkyl.

      

    

  

  
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