Maytansinoids, pharmaceutical compositions thereof and method of use thereof

• US 4,308,268 A
• Filed: 05/28/1980
• Issued: 12/29/1981
• Est. Priority Date: 06/11/1979
• 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): Bond, Robert T.
• Application Number:
  US06/153,905
• Time in Patent Office: 580 Days
• Field of Search: 260/239.3 P, 424/248.54
• US Class Current: 514/229.5
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

Novel maytansinoids of the formula: ##STR1## wherein X is H or Cl, and Y is Cl, OH, SH, CN, NO₂, --OR or --S(O)_n R wherein R is slkyl, aryl, aralkyl or azaheterocyclic group which may be substituted, and n is 0, 1 or 2, have antimitotic, antitumor and antimicrobial activities.

Claims

1. A compound of the formula:

##STR4## wherein X is H or Cl, and Y is Cl, OH, SH, CN, NO₂, --OR or --S(O)_n R,

wherein n is 0, 1 or 2, and

R is C_1-8 alkyl, phenyl, naphthyl, phenyl-C_1-4 alkyl, 2- or 4-pyridyl, 2- or 4(6)-pyrimidyl, 3(6)-pyridazinyl, 2- or 3-pyrazinyl, 2-s-triazinyl, 2-(1,3,4-triazinyl), 2- or 4(5)-imidazolyl, 3(5)-pyrazolyl, 2-(1,3,4-triazolyl), 5-tetrazolyl, 2-piperazinyl, 2-pyrrolidinyl, 2-oxazolyl, 2-thiazolyl, 2- or 5-oxadiazolyl, 2- or 5-thiadiazolyl, 2-(2-thiazolinyl), 2-benzimidazolyl, 2-benzoxazolyl or 2-benzothiazolyl,

said R group 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, hydroxyl, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, sulfamoyl, mono- or di-C_1-4 alkylsulfamoyl, oxo, thioxo, C_1-4 alkanoylamino, C_1-4 alkylsulfonylamino or --O(CH₂ CH₂ O)_m R¹ wherein R¹ is methyl or ethyl and m is an integer 1 to 4 inclusive.

2. A compound according to claim 1, wherein X is Cl.

3. A compound according to claim 1, wherein the 5- or 6-membered azaheterocyclic group having one to four of N is 2-oxazolyl, 2-thiazolyl, 2- or 4-pyridyl, 2-pyrimidyl or 2-benzimidazolyl.

4. A compound according to claim 1 or 2, wherein Y is Cl, Cn, --OR or --S(O)_n R, wherein n is 0, 1 or 2, and R is C_1-8 alkyl, phenyl, phenyl-C_1-4 alkyl or pyridyl, said R group being unsubstituted or substituted by C_1-4 alkoxy, halogen, nitro and --O(CH₂ CH₂ O)_m R¹ wherein R¹ is methyl or ethyl and m is an integer 1 to 4 inclusive.

5. A compound according to claim 4, wherein Y is Cl, --OR or --S(O)_n R, wherein n is 0, 1 or 2, and R is C_1-8 alkyl, phenyl, benzyl, phenylethyl or pyridyl, said R group being unsubstituted or substituted by C_1-4 alkoxy or halogen.

6. A compound according to claim 5, wherein Y is --OR or --SR, wherein R is phenyl or benzyl, said R group being unsubstituted or substituted by C_1-4 alkoxy or halogen.

7. The compound according to claim 1, which is maytansinol 3-chloroacetate.

8. The compound according to claim 1, which is maytansinol 3-phenoxyacetate.

9. The compound according to claim 1, which is maytansinol 3-o-chlorophenoxyacetate.

10. The compound according to claim 1, which is maytansinol 3-o-methoxyphenoxyacetate.

11. The compound according to claim 1, which is maytansinol 3-p-methoxyphenoxyacetate.

12. The compound according to claim 1, which is maytansinol 3-phenylthioacetate.

13. An antitumor composition which comprises as an active ingredient an effective amount of a compound of the formula:

##STR5## wherein X is H or Cl, and Y is Cl, OH, SH, CN, NO₂, --OR or --S(O)_n R,

wherein n is 0, 1 or 2, and

R is C_1-8 alkyl, phenyl, naphthyl, phenyl-C_1-4 alkyl, 2- or 4-pyridyl, 2- or 4(6)-pyrimidyl, 3(6)-pyridazinyl, 2- or 3-pyrazinyl, 2-s-triazinyl, 2-(1,3,4-triazinyl), 2- or 4(5)-imidazolyl, 3(5)-pyrazolyl, 2-(1,3,4-triazolyl), 5-tetrazolyl, 2-piperzinyl, 2-pyrrolidinyl, 2-oxazolyl, 2-thiazolyl, 2- or 5-oxadiazolyl, 2- or 5-thiadiazolyl, 2-(2-thiazolinyl), 2-benzimidazolyl, 2-benzoxazolyl or 2-benzothiazolyl,

said R group 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, hydroxyl, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, sulfamoyl, mono- or di-C_1-4 alkylsulfamoyl, oxo, thioxo, C_1-4 alkanoylamino, C_1-4 alkylsulfonylamino or --O(CH₂ CH₂ O)_m R¹ wherein R¹ is methyl or ethyl and m is an integer 1 to 4 inclusive,

and a pharmaceutically acceptable carrier or diluent therefor.

14. 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:

##STR6## wherein X is H or Cl, and Y is Cl, OH, SH, CN, NO₂, --OR or --S(O)_n R,

wherein n is 0, 1 or 2, and

R is C_1-8 alkyl, phenyl, naphthyl, phenyl-C_1-4 alkyl, 2- or 4-pyridyl, 2- or 4(6)-pyrimidyl, 3(6)-pyridazinyl, 2- or 3-pyrazinyl, 2-s-triazinyl, 2-(1,3,4-triazinyl), 2- or 4(5)-imidazolyl, 3(5)-pyrazolyl, 2-(1,3,4-triazolyl), 5-tetrazolyl, 2-piperazinyl, 2-pyrrolidinyl, 2-oxazolyl, 2-thiazolyl, 2- or 5-oxadiazolyl, 2- or 5-thiadiazolyl, 2-(2-thiazolinyl, 2-benzimidazolyl, 2-benzoxazolyl or 2-benzothiazolyl,

said R group 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, hydroxyl, nitro, cyano, trifluoromethyl, di-C_1-4 alkylamino, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, sulfamoyl, mono- or di-C_1-4 alkylsulfamoyl, oxo, thioxo, C_1-4 alkanoylamino, C_1-4 alkylsulfonylamino or --O(CH₂ CH₂ O)_m R¹ wherein R¹ is methyl or ethyl and m is an integer 1 to 4 inclusive.