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Demethyl maytansinoids

  • US 4,307,016 A
  • Filed: 05/27/1980
  • Issued: 12/22/1981
  • Est. Priority Date: 03/24/1978
  • Status: Expired due to Term
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First Claim
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1. A demethylmaytansinoid compound of the formula:

  • ##STR22## wherein X is Cl or H;

    R1 is H or an acyl group, the acyl group being represented by one of the formulae;

    

    space="preserve" listing-type="equation">--CO--R.sub.2                                              (a)wherein R2 is hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, phenyl, a heterocyclic group selected from the class 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, quinoxalkyl, 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-triazinyl, 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 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;

     ##STR23## wherein R3 is hydrogen, C1-8 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 alkanyloxy, C2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C1-4 alkylamino, C1-4 alkylthio, methyl- sulfinyl, methylsulfonyl, oxo, thioxo or C1-4 alkanoylamido, and said cycloalkyl, phenyl, indolyl or imidazolyl being unsubstituted or substituted by C1-4 alkyl;

    R4 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;

    R5 is hydrogen, C1-7 alkoxy, bornyloxy, isobornyloxy, benzyloxy, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, phenyl or a heterocyclic group selected from the class 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, quinozolinyl, 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-triazinyl, 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, 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, cycloalkenyl, phenyl or heterocyclic group being unsubstituted or substituted by C1-4 alkyl;

     ##STR24##  wherein R6 and R7 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 cycloalkenylalkyl, phenyl, phenyl-C1-14 alkyl, phenyl-C3-10 cycloalkyl, C3-10 cycloalkylphenyl, biphenyl or heterocyclic group selected from the class consisting of azetidinyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, quinazolyl, quinoxalyl, indolyl, benzofuranyl and benzothienyl, and wherein R6 and R7 together may form a heterocyclic group of azetidinyl, pyrrolidinyl, piperidinyl 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.8                                           (d) wherein R8 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, C3-10 -cycloalkyl, C3-10 -cycloalkenyl or phenyl.

      

    

  

  
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