Dechloromaytansinoids, their pharmaceutical compositions and method of use

• US 4,256,746 A
• Filed: 11/09/1979
• Issued: 03/17/1981
• Est. Priority Date: 11/14/1978
• Status: Expired due to Term

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Akimoto, Hiroshi, Miyashita, Osamu
• Primary Examiner(s): Jiles, Henry R.
• Assistant Examiner(s): Bond, Robert T.
• Application Number:
  US06/092,954
• Time in Patent Office: 494 Days
• Field of Search: 260/239.3 P, 424/248.54
• US Class Current: 514/210.18
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

Novel dechloromaytansinoids of the formula: ##STR1## wherein R is H or acyl having 1 to 20 carbon atoms, have antimitotic, antitumor and antimicrobial activities.

Claims

1. A compound of the formula:

##STR8## wherein R is H, acyl of the formula --COR² or acylaminoacyl of the formula ##STR9## wherein R² is H or a member of the class consisting of C_1-18 alkyl, C_2-10 alkenyl, C_3-10 cycloalkyl, C_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 R² groups being unsubstituted or substituted by C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C_1-4 alkanoylamido, and

said cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclic groups being attached directly or through a C_1-4 alkenylene group to the carbonyl group in the acyl radical R;

wherein R³ is H, C_1-18 alkyl, C_3-10 cycloalkyl, phenyl, naphthyl, indolyl or imidazolyl, R⁴ is H, C_1-18 alkyl, C_3-10 cycloalkyl, phenyl or naphthyl, and R⁵ is H, C_1-18 alkyl, C_2-10 alkenyl, C_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-dihdyroquinolyl, 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 R³, R⁴ and R⁵ being unsubstituted or substituted by C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C_1-4 alkanoylamido, and

said cycloalkyl, cycloalkenyl, phenyl, naphthyl, indolyl, imidazolyl and heterocyclic groups when representing R³, R⁴ and R⁵ being attached directly or through C_1-4 alkylene, to the carbon between -CO- and N of acylaminoacyl in the case of R³, to the nitrogen in acylaminoacyl in the case of R⁴, and to the carbonyl of the amido group in acylaminoalcyl in the case of R⁵.

2. A compound according to claim 1, wherein R is acyl of the formula:

space="preserve" listing-type="equation">--COR.sup.2

wherein R² is H or a member of the class consisting of C_1-18 alkyl, C_2-10 alkenyl, C_3-10 cycloalkyl, C_3-10 cycloalkenyl, 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-dihydroisoquinolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, iodolyl, furyl, pyranyl, dihydropyranyl, benzofuryl, benzopyranyl, thienyl, benzothienyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidyl, pyridazinyl, 2-imidazolyl, 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 R² groups being unsubstituted or substituted by C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylamino, C_1-4 alkylthio, methlsulfinyl, methylsulfonyl, oxo, thioxo or C_1-4 alkanoylamido, and

said cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclic groups being attached, directly or through a C_1-4 alkylene group, to the carbonyl group in the acyl radical R.

3. A compound according to claim 1, wherein R is acylaminoacyl of the formula:

##STR10## wherein R³ is H, C_1-18 alkyl, C_3-10 cycloalkyl, phenyl, naphthyl, indolyl or imidazolyl, R⁴ is H, C_1-18 alkyl, C_3-10 cycloalkyl, phenyl or naphthyl, and R⁵ is H, C_1-18 alkyl, C_2-10 alkenyl, C_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-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 R³, R⁴ and R⁵ being unsubstituted or substituted by C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C_1-4 alkanoylamido, and

said cycloalkyl, cycloalkenyl, phenyl, naphthyl, indolyl, imidazolyl and heterocyclic groups representing R³, R⁴ and R⁵ being attached directly or through C_1-4 alkylene, to the carbon between -CO- and N of acylaminoacyl in the case of R³, to the nitrogen in acylaminoacyl in the case of R⁴ and to the carbonyl or the amido group in acylaminoacyl in the case of R⁴.

4. A compound according to claim 2, wherein R² is C_1-6 alkyl, C_3-7 cycloalkyl, phenyl or pyridyl,

said alkyl, being unsubstituted or substituted by halogen, and

said cycloalkyl, phenyl and pyridyl being attached, directly or through C_1-4 alkylene, to the carbonyl group in the acyl R.

5. A compound according to claim 3, wherein R³, R⁴ and R⁵ are C_1-6 alkyl.

6. The compound according to claim 1, which is dechloromaytansinol.

7. The compound according to claim 1, which is dechloromaytansine.

8. The compound according to claim 1, which is D-dechloromaytansine.

9. The compound according to claim 1, which is dechloromaytansinol 3-isobutyrate.

10. The compound according to claim 1, which is dechloromaytansinol 3-nicotinate.

11. The compound to claim 1, which is dechloromaytansinol 3-cyclohexanecarboxylate.

12. The compound according to claim 1, which is dechloromaytansinol 3-phenylacetate.

13. The compound according to claim 1, which is dechloromaytansinol 3-chloroacetate.

14. 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 --COR² or acylamino of the formula ##STR12## wherein R² is H or a member of the class consisting of C_1-18 alkyl, C_2-10 alkenyl, C_3-10 cycloalkyl, C_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 R² groups being unsubstituted or substituted by C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C_1-4 alkanoylamido, and

said cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclic groups being attached directly or through a C_1-4 alkylene group to the carbonyl group in the acyl radical R;

wherein R³ is H, C_1-18 alkyl, C_3-10 cycloalkyl, phenyl, naphthyl, indolyl or imidazolyl, R⁴ is H, C_1-18 alkyl, C_3-10 cycloalkyl, phenyl or naphthyl, and R⁵ is H, C_1-18 alkyl, C_2-10 alkenyl, C_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 R³, R⁴ and R⁵ being unsubstituted or substituted by C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C_1-4 alkanoylamido, and

said cycloalkyl, cycloalkenyl, phenyl, naphthyl, indolyl, imidazolyl and heterocyclic groups when representing R³, R⁴ and R⁵ being attached directly or through C_1-4 alkylene, to the carbon between -CO- and N of acylaminoacyl in the case of R³, to the nitrogen in acylaminoacyl in the case of R⁴, and to the carbonyl of the amido group in acylaminoacyl in the case of R⁵, and a pharmaceutically acceptable carrier or diluent therefor.

15. 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 --COR² or acylaminoacyl of the formula ##STR14## wherein R² is H or a member of the class consisting of C_1-18 alkyl, C_2-10 alkenyl, C_3-10 cycloalkyl, C_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 R² groups being unsubstituted or substituted by C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C_1-4 alkanoylamido, and

said cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclic groups being attached directly or through a C_1-4 alkylene group to the carbonyl group in the acyl radical R;

wherein R³ is H, C_1-18 alkyl, C_3-10 cycloalkyl, phenyl, naphthyl, indolyl or imidazolyl, R⁴ is H, C_1-18 alkyl, C_3-10 cycloalkyl, phenyl or naphthyl, and R⁵ is H, C_1-18 alkyl, C_2-10 alkenyl, C_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 R³, R⁴ and R⁵ being unsubstituted or substituted by C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo or C_1-4 alkanoylamido, and

said cycloalkyl, cycloalkenyl, phenyl, naphthyl, indolyl, imidazolyl and heterocyclic groups when representing R³, R⁴ and R⁵ being attached directly or throuch C_1-4 alkylene, to the carbon between -CO- and N of acylaminoacyl in the case of R³, to the nitrogen in acylaminoacyl in the case of R⁴, and to the carbonyl of the amido group in acylaminoacyl in the case of R⁵.