Anti-mitotic agents which inhibit tubulin polymerization

• US 6,162,930 A
• Filed: 12/03/1999
• Issued: 12/19/2000
• Est. Priority Date: 03/06/1998
• Status: Expired due to Term

• Current Assignee: Baylor University
• Original Assignee: Baylor University
• Inventors: Mocharla, Vani P., Pinney, Kevin G., Pettit, George R., Shirali, Anupama, Mejia, Maria del Pilar
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US09/380,429
• Time in Patent Office: 382 Days
• Field of Search: 549/57, 549/58, 549/49, 514/443, 568/632, 568/633, 568/327, 568/328
• US Class Current: 549/57
• CPC Class Codes: C07C 205/37 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 217/84 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 247/16 with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 45/30 with halogen containing compounds, e.g. hypohalogenation
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 307/80 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 333/56 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 333/64 Oxygen atoms

Abstract

Methoxy and ethoxy substituted 3-aroyl-2-arylbenzo[b]thiophenes and benzo[b]thiophene analogues are described for use in inhibiting tubulin polymerization. The compounds'"'"' use for treating tumor cells is also described.

Claims

1. A compound of the structure:

##STR9## wherein X is S,

R₁ -R₄ are independently chosen from the group consisting of H, OH and C₁ -C₅ alkoxy,

Z is chosen from the group consisting of C═

O, CH₂, C₂ H₂, CHOH, and CHOCH₃,

Y is chosen from the group consisting of a covalent bond, CH₂, and CH₂ CH₂,

and Ar and Ar'"'"' are aryl moieties chosen from the group consisting of phenyl and napthyl, further substituted with at least one C₁ -C₅, alkoxy group, at least one of which has at least two C₁ -C₅ alkoxy groups,

wherein when Ar is 3,4,5-trimethoxyphenyl, Z is C═

O, Y is a covalent bond, R₃ is methoxy, R₁, R₂ and R₄ are H, and Ar is substituted with a methoxy group.

2. The compound of claim 1, wherein Z is C═

O.

3. The compound of claim 1 wherein Ar'"'"' is chosen from the group consisting of 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4 diethoxyphenyl and 3,4,5-triethoxyphenyl.

4. The compound of claim 1 wherein Ar is 4-methoxyphenyl.

5. The compound of claim 1 wherein R₃ is OCH₃.

6. A compound of the structure:

##STR10## wherein R₁ -R₄ are independently chosen from the group consisting of H, OH and C₁ -C₅ alkoxy,

Z is C═

O,

Y is chosen from the group consisting of a covalent bond, CH₂, and CH₂ CH₂,

Ar is a phenyl group with at least one C₁ -C₅ alkoxy group and Ar'"'"' is a phenyl group with at least two C₁ -C₅ alkoxy groups, wherein when Ar'"'"' is 3,4,5-trimethoxyphenyl Z is C═

O, Y is a covalent bond, R₃ is methoxy and R₁, R₂ and R₄ are H, and Ar is substituted with a methoxy group.

7. The compound of claim 6 wherein Ar'"'"' is chosen from the group consisting of 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4 diethoxyphenyl and 3,4,5-triethoxyphenyl.

8. The compound of claim 6 wherein Y is a covalent bond.

9. The compound of claim 6 wherein Ar is 4-methoxyphenyl.

10. The compound of claim 6 selected from the group containing 3-(3'"'"',4'"'"'-dimethoxybenzoyl)-2-(4'"'"'-methoxyphenyl)-6-methoxybenzol[b]-thiophene, and 3-[3'"'"',4'"'"',5'"'"'-triethoxy-benzoyl)-2-(4'"'"'-methoxyphenyl)-6-methoxybenzo[b]-thiophene, and 3-[3'"'"'-(3",4",5"-trimethoxyphenyl)propanoyl]-2-(4'"'"'methoxyphenyl)-6-methoxybenzo[b] thiophene.

11. A compound of the structure ##STR11## where R₁ is H or CH₃ O;

R₂ is H, CH₃ O or C₂ H₅ O;

R₃ is CH₃ O of C₂ H₅ O;

R₄, R₅, R₇ and R₈ are independently H, CH₃ O, C₂ H₅ O, or F;

R₆ is H, CH₃ O, C₂ H₅ O, OH, F or N(CH₃)₂ ;

wherein at least one of R₄, R₅, R₆, R₇ or R₈ is F or N(CH₃)₂ ;

and X is ##STR12##

12. A compound of the structure where X is S or S═

O.

13. A compound of the structure ##STR13## where X is CHOH or C═

O.