Isolation, structural elucidation and synthesis of novel antineoplastic substances denominated "combretastatins"

• US 5,409,953 A
• Filed: 02/10/1992
• Issued: 04/25/1995
• Est. Priority Date: 01/06/1987
• Status: Expired due to Term

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Pettit, George R., Singh, Sheo B.
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): LAMBKIN, DEBORAH C
• Application Number:
  US07/832,998
• Time in Patent Office: 1,170 Days
• Field of Search: 549/438, 549/434, 549/437, 561/646, 561/641, 561/631, 514/464, 514/465, 514/718, 514/720, 514/721, 514/909, 514/733
• US Class Current: 514/464
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07D 317/64 Oxygen atoms

Abstract

New antineoplastic substances have been isolated, structurally elucidated and synthesized having a general structural formula of: ##STR1## wherein: R₁ is OH or OCH₃ ;

R₂ is H or OCH₃ ; or R₁ R₂ is --OCH₂ O--;

R₃ is H or OH;

R₄ is OH or OCH₃.

These substances have been denominated "combretastatin A-1, -A-2, -A-3, -B-1, -B-2, -B-3 and -B-4". Pharmaceutical preparation containing the substances and methods of treating a host inflicted with a neoplastic growth with the preparation is described.

Claims

1. The method of treating a mammalian host afflicted with lymphocytic leukemia comprising administering to said host a pharmaceutical preparation containing as its essential active ingredient an effective amount of a substance having the structural formula of either:

##STR6## wherein;

R₁ is OH or OCH₃ and R₂ is H or OCH₃ or R₁ R₂ is --OCH₂ O--, R₃ is H or OH, and R₄ is OH or OCH₃, with the proviso that when structure (I) is selected and R₁ is OCH₃, R₂ is OCH₃, R₃ is OH and R₄ is OCH₃ ; and

that when structure (I) is selected and R₁ R₂ is --OCH₂ O--, R₃ is H and R₄ is OCH₃ ; and

that when structure (I) is selected and R₁ is OH, R₂ is OCH₃, R₃ is H and R₄ is OCH₃ ; and

that when structure (II) is selected and R₁ is OCH₃ and R₂ is H or OH, R₃ is H and R₄ is OH; and

that when structure (II) is selected and R₁ ═

R₂ ═

OCH.sub. 3, R₃ is OH and R₄ is OCH₃ ; and

that when structure (II) is selected and R₁ is OH, R₂ is OCH₃, R₃ is H and R₄ is OCH₃.

2. A method according to claim 1 in which said substance is denominated combretastatin A-1 and has structural formula I wherein:

R₁ is OCH₃ ;

R₂ is OCH₃ ;

R₃ is OH and R₄ is OCH₃.

3. A method according to claim 1 in which said substance is denominated combretastatin A-2 and has structural formula I wherein:

R₁ R₂ is --OCH₂ O--;

R₃ is H and R₄ is OCH₃.

4. A method according to claim 1 in which said substance is denominated combretastatin A-3 and has structural formula I wherein:

R₁ is OH;

R₂ is OCH₃ ;

R₃ is H and R₄ is OCH₃.

5. A method according to claim 1 in which said substance is denominated combretastatin B-1 and has structural formula II wherein:

R₁ is OCH₃ ;

R₂ is OCH₃ ;

R₃ is OH and R₄ is OCH₃.

6. A method according to claim 1 in which said substance is denominated combretastatin B-2 and has structural formula II wherein:

R₁ is OH;

R₂ is OCH₃ ;

R₃ is H and R₄ is OCH₃.

7. A method according to claim 1 in which said substance has structural formula II wherein R₁ is OCH₃ ;

R₂ is OCH₃ ;

R₃ is H and R₄ is OH and is denominated combretastatin B-3 when R₂ is OCH₃ and is denominated combretastatin B-4 when R₂ is H.