6,7-modified paclitaxels

• US 5,380,751 A
• Filed: 09/28/1993
• Issued: 01/10/1995
• Est. Priority Date: 12/04/1992
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Chen, Shu-Hui, Farina, Vittorio, Roth, Gregory, Kadow, John
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Peabody, John
• Application Number:
  US08/128,619
• Time in Patent Office: 469 Days
• Field of Search: 549/510, 514/449
• US Class Current: 514/449
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The present invention provides paclitaxel derivatives of formula I ##STR1## in which R¹ is --COR^z in which R^Z is RO-- or R;

R² is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, or a radical of the formula --W--R^x in which W is a bond, C_2-6 alkenediyl, or --(CH₂)_t --, in which t is one to six; and R^x is naphthyl, phenyl, or heteroaryl, and furthermore R^x can be optionally substituted with one to three same or different C_1-6 alkyl, C_1-6 alkoxy, halogen or --CF₃ groups;

R^a is --OCOR, H, OH, --OR, --OSO₂ R, --OCONR^o R, --OCONHR, --OCOO(CH₂)_t R, or --OCOOR;

R^b and R^c are both hydroxy or together form a bond with the carbon atoms to which they are attached; and

R and R^o are independently C_1-6 alkyl, C_2-6 alkenyl, C_3-6 cycloalkyl, C_2-6 alkynyl, or phenyl, optionally substituted with one to three same or different C_1-6 alkyl, C_1-6 alkoxy, halogen or --CF₃ groups.

Also provided by this invention are pharmaceutical formulations (compositions) and a method of treating mammalian tumors with a compound of formula I.

Claims

1. A compound of formula I ##STR30## in which R¹ is --COR^z in which R^z is RO-- or R;

R² is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, or a radical of the formula --W--R^x in which W is a bond, C_2-6 alkenediyl, or --(CH₂)_t --, in which t is one to six; and

R^x is naphthyl, or phenyl, and furthermore R^x can be optionally substituted with one to three same or different C_1-6 alkyl, C_1-6 alkoxy, halogen or --CF₃ groups;

R^a is --OCOR, H, OH, --OR, --OSO₂ R, --OCONR^o R, --OCONHR, --OCOO(CH₂)_t R, or --OCOOR;

R^b and R^c are both hydroxy or together form a bond with the carbon atoms to which they are attached; and

R and R^o are independently C_1-6 alkyl, C_2-6 alkenyl, C_3-6 cycloalkyl, C_2-6 alkynyl, or phenyl, optionally substituted with one to three same or different C_1-6 alkyl, C_1-6 alkoxy, halogen or --CF₃ groups.

2. A compound of claim 1 in which R¹ is benzoyl or t-butoxycarbonyl;

R² is phenyl;

R^a is acetyloxy; and

R^b and R^c together form a bond with the carbon atoms to which they are attached.

3. The compound of claim 2 that is 6,7-dehydropaclitaxel.

4. A compound of claim 1 in which R¹ is benzoyl or t-butoxycarbonyl;

R² is phenyl;

R^a is acetyloxy; and

R^b and R^c are hydroxy.

5. The compound of claim 4 that is 6α

-hydroxy-7α

-hydroxypaclitaxel.

6. A pharmaceutical formulation which comprises as an active ingredient a compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, associated with one or more pharmaceutically acceptable carriers, excipients or diluents therefor.

7. A method for treating mammalian tumors which comprises administering to a mammal a tumor sensitive amount of a compound as claimed in any one of claims 1 to 5.