Dechloromaytansinoids, their pharmaceutical compositions and method of use

A pharmaceutical composition suitable for inhibiting the growth of tumor cells and prolonging the survival time of a tumor-bearing warm blooded animal, which comprises as an active ingredient an effective amount of a compound of the formula:

• ##STR11## wherein R is H, acyl of the formula --COR.sup.2 or acylamino of the formula ##STR12## wherein R.sup.2 is H or a member of the class consisting of C.sub.1-18 alkyl, C.sub.2-10 alkenyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkenyl, phenyl, naphthyl or a group of the class consisting of azetidinyl, pyridyl, 1,2,3,4-tetrahydropyridyl, piperidyl, quinolyl, 1,2-dihydroquinolyl, 3-or 4-isoquinolyl, 1,2-dihydroisoquinolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, indolyl, furyl, pyranyl, dihydropyranyl, benzofuryl, benzopyranyl, thienyl, benzothienyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidyl, pyridazinyl, 2-imidazolinyl, imidazolidinyl, benzimidazolyl, indazolyl, quinoxalyl, quinazolinyl, cinnolinyl, 1,4-dioxanyl, 1,4-benzodioxanyl, 1,2- or 1,3-dithiolanyl, 1,3-dithianyl, isoxazolyl, oxazolyl, morpholinyl, benzisoxazolyl, benzoxazolyl, isothiazolyl, thiazolyl, benzisothiazolyl, benzothiazolyl, benzothiazinyl, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-thiadiazolyl, 1,2,3-, 1,2,5- or 1,3,4-triazolyl, 1,3,5-triazinyl, benzotriazolyl and 1,2,3,4-tetrazolyl,
• any of said R.sup.2 groups being unsubstituted or substituted by C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.2-4 alkanoyl, C.sub.2-4 alkanoyloxy, C.sub.2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C.sub.1-4 alkylamino, C.sub.1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C.sub.1-4 alkanoylamido, and
• said cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclic groups being attached directly or through a C.sub.1-4 alkylene group to the carbonyl group in the acyl radical R;
• wherein R.sup.3 is H, C.sub.1-18 alkyl, C.sub.3-10 cycloalkyl, phenyl, naphthyl, indolyl or imidazolyl, R.sup.4 is H, C.sub.1-18 alkyl, C.sub.3-10 cycloalkyl, phenyl or naphthyl, and R.sup.5 is H, C.sub.1-18 alkyl, C.sub.2-10 alkenyl, C.sub.3-10 cycloalkyl, phenyl, naphthyl or a heterocyclic group of the class consisting of azetidiny, pyridyl, 1,2,3,4-tetrahydropyridyl, piperidyl, quinolyl, 1,2-dihydroquinolyl, 3- or 4-isoquinolyl, 1,2-dihydroisoquinolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, indolyl, furyl, pyranyl, dihydropyranyl, benzofuryl, benzopyranyl, thienyl, benzothienyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidyl, pyridazinyl, 2-imidazolinyl, imidazolidinyl, benzimidazolyl, indazolyl, quinoxalyl, quinazolinyl, cinnolinyl, 1,4-dioxanyl, 1,4-benzodioxanyl, 1,2- or 1,3-dithiolanyl, 1,3-dithianyl, isoxazolyl, oxazolyl, morpholinyl, benzisoxazolyl, benzoxazolyl, isothiazolyl, thiazolyl, benzisothiazolyl, benzothiazolyl, benzothiazinyl, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-thiadiazolyl, 1,2,3-, 1,2,5- or 1,3,4-triazolyl, 1,3,5-triazinyl, benzotriazolyl and 1,2,3,4-tetrazolyl,
• any of said groups in R.sup.3, R.sup.4 and R.sup.5 being unsubstituted or substituted by C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.2-4 alkanoyl, C.sub.2-4 alkanoyloxy, C.sub.2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C.sub.1-4 alkylamino, C.sub.1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C.sub.1-4 alkanoylamido, and
• said cycloalkyl, cycloalkenyl, phenyl, naphthyl, indolyl, imidazolyl and heterocyclic groups when representing R.sup.3, R.sup.4 and R.sup.5 being attached directly or through C.sub.1-4 alkylene, to the carbon between -CO- and N of acylaminoacyl in the case of R.sup.3, to the nitrogen in acylaminoacyl in the case of R.sup.4, and to the carbonyl of the amido group in acylaminoacyl in the case of R.sup.5, and a pharmaceutically acceptable carrier or diluent therefor.

A method for inhibiting the growth of tumor cells and prolonging the survival time of a tumor-bearing warm blooded animal, which comprises administering to said animal an effective amount of a compound of the formula:

• ##STR13## wherein R is H, acyl of the formula --COR.sup.2 or acylaminoacyl of the formula ##STR14## wherein R.sup.2 is H or a member of the class consisting of C.sub.1-18 alkyl, C.sub.2-10 alkenyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkenyl, phenyl, naphthyl or a group of the class consisting of azetidinyl, pyridyl, 1,2,3,4-tetrahydropyridyl, piperidyl, quinolyl, 1,2-dihydroquinolyl, 3- or 4-isoquinolyl, 1,2-dihydroisoquinolyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, indolyl, furyl, pyranyl, dihydropyranyl, benzofuryl, benzopyranyl, thienyl, benzothienyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidyl, pyridazinyl, 2-imidazolinyl, imidazolidinyl, benzimidazolyl, indazolyl, quinoxalyl, quinazolinyl, cinnolinyl, 1,4-dioxanyl, 1,4-benzodioxanyl, 1,2- or 1,3-dithiolanyl, 1,3-dithianyl, isoxazolyl, oxazolyl, morpholinyl, benzisoxazolyl, benzoxazolyl, isothiazolyl, thiazolyl, benzisothiazolyl, benzothiazolyl, benzothiazinyl, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-thiadiazolyl, 1,2,3-, 1,2,5- or 1,3,4-triazolyl, 1,3,5-triazinyl, benzotriazolyl and 1,2,3,4-tetrazolyl,
• any of said R.sup.2 groups being unsubstituted or substituted by C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.2-4 alkanoyl, C.sub.2-4 alkanoyloxy, C.sub.2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C.sub.1-4 alkylamino, C.sub.1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C.sub.1-4 alkanoylamido, and
• said cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclic groups being attached directly or through a C.sub.1-4 alkylene group to the carbonyl group in the acyl radical R;
• wherein R.sup.3 is H, C.sub.1-18 alkyl, C.sub.3-10 cycloalkyl, phenyl, naphthyl, indolyl or imidazolyl, R.sup.4 is H, C.sub.1-18 alkyl, C.sub.3-10 cycloalkyl, phenyl or naphthyl, and R.sup.5 is H, C.sub.1-18 alkyl, C.sub.2-10 alkenyl, C.sub.3-10 cycloalkyl, phenyl, naphthyl or a heterocyclic group of the class consisting of azetidinyl, pyridyl, 1,2,3,4-tetrahydropyridyl, piperidyl, quinolyl, 1,2-dihydroquinolyl, 3- or 4-isoquinolyl, 1,2-dihyroisoquinolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, indolyl, furyl, pyranyl, dihydropyranyl, benzofuryl, benzopyranyl, thienyl, benzothienyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidyl, pyridazinyl, 2-imidazolinyl, imidazolidinyl, benzimidazolyl, indazolyl, quinoxalyl, quinazolinyl, cinnolinyl, 1,4-dioxanyl, 1,4-benzodioxanyl, 1,2- or 1,3-dithiolanyl, 1,3-dithianyl, isoxazolyl, oxazolyl, morpholinyl, benzisoxazolyl, benzoxazolyl, isothiazolyl, thiazolyl, benzisothiazolyl, benzothiazolyl, benzothiazinyl, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-thiadiazolyl, 1,2,3-, 1,2,5- or 1,3,4-triazolyl, 1,3,5-triazinyl, benzotriazolyl and 1,2,3,4-tetrazolyl,
• any of said groups in R.sup.3, R.sup.4 and R.sup.5 being unsubstituted or substituted by C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.2-4 alkanoyl, C.sub.2-4 alkanoyloxy, C.sub.2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C.sub.1-4 alkylamino, C.sub.1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C.sub.1-4 alkanoylamido, and
• said cycloalkyl, cycloalkenyl, phenyl, naphthyl, indolyl, imidazolyl and heterocyclic groups when representing R.sup.3, R.sup.4 and R.sup.5 being attached directly or throuch C.sub.1-4 alkylene, to the carbon between -CO- and N of acylaminoacyl in the case of R.sup.3, to the nitrogen in acylaminoacyl in the case of R.sup.4, and to the carbonyl of the amido group in acylaminoacyl in the case of R.sup.5.