Maytansinoids, pharmaceutical compositions thereof and methods of use thereof

• US 4,260,608 A
• Filed: 11/09/1979
• Issued: 04/07/1981
• 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): Bond, Robert T.
• Application Number:
  US06/092,953
• Time in Patent Office: 515 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 R¹ is hydrogen atom, an alkyl group which may optionally be substituted or a group of the formula: --A¹ --Y¹ wherein A¹ is an alkylene group or a bond, and Y¹ is a cycloalkyl, phenyl, indolyl or imidazolyl group which may optionally be substituted,

R² is hydrogen atom, an alkyl, cycloalkyl or benzyl group,

R³ is hydrogen atom, an alkyl group which may optionally be substituted, alkoxy, bornyloxy, isobornyloxy, benzyloxy group or a group of the formula: --A² --Y² wherein A² is an alkylene group or a bond, and Y² is an alicyclic hydrocarbon, phenyl or heterocyclic group which may optionally be substituted,

provided that R³ is not an unsubstituted C_1-4 alkyl group when both R¹ and R² are methyl groups, have antimicrobial antimitotic and antitumor activities.

Claims

1. A compound of the formula:

##STR5## wherein R¹ hydrogen, C_1-7 alkyl, or --A¹ --Y¹ ;

A¹ is C_1-4 alkylene or a single covalent bond;

Y¹ is a C_3-7 cycloalkyl, phenyl, indolyl or imidazolyl group,

R² is hydrogen, C_1-7 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4 alkyl or benzyl;

R³ is C_1-4 alkoxy, bornyloxy, isobornyloxy, benzyloxy or --A² --Y² ;

A² is C_1-4 alkylene or a single covalent bond; and

Y² is C_3-7 alicyclic hydrocarbon or phenyl.

8. A pharmaceutical composition for inhibiting the growth of tumor cells and prolonging the survival time or a tumor-bearing warm-blooded animal which comprises as an active ingredient an effective amount of a compound of claim 4, 5, 6, 7, 1, 2 or 3.

9. A method for inhibiting the growth of tumor cells in a warm-blooded animal which comprises administering to said warm-blooded animal an effective amount of a compound of claim 4, 5, 6, 7, 1, 2, or 3.

10. A method for prolonging the survival time of a tumor-bearing warm-blooded animal which comprises administering to said warm-blooded animal an effective amount of a compound of claim 4, 5, 6, 7, 1, 2 or 3.

2. A compound of the formula:

##STR6## wherein A¹ is C_1-4 alkylene or a single covalent bond;

Y¹ is C_3-7 cycloalkyl, phenyl, indolyl or imidazolyl;

R² is hydrogen, C_1-7 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4 alkyl or benzyl;

R³ is hydrogen, C_1-7 alkyl, C_1-4 alkoxy, bornyloxy, isobornyloxy, benzyloxy group or -A² -Y² ;

A² is a C_1-4 alkylene group or a single covalent bond; and

Y² is a C_3-7 alicyclic hydrocarbon or phenyl.

4. A compound according to claim 2 or 3, wherein R³ is a C_1-4 alkyl, C_1-4 alkoxy or phenyl group.

3. A compound of the formula:

##STR7## wherein R¹ is C_4-7 alkyl;

R² is hydrogen, C_1-7 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4 alkyl or benzyl;

R³ is hydrogen, C_1-7 alkyl, C_1-4 alkoxy, bornyloxy, isobornyloxy, benzyloxy group or -A² -Y² ;

A² is C_1-4 alkylene or a single covalent bond; and

Y² is C_3-7 alicyclic hydrocarbon or phenyl.

5. Maytansinol 3-(N-acetyl-N-methyl)leucine ester.

6. Maytansinol 3-(N-acetyl-N-methyl)phenylalanine ester.

7. Maytansinol 3-(N-tert-butoxycarbonyl-N-methyl)alanine ester.