Di-aryl ethers and their derivatives as anti-cancer agents

• US 6,169,104 B1
• Filed: 03/25/1998
• Issued: 01/02/2001
• Est. Priority Date: 03/26/1997
• Status: Expired due to Term

• Current Assignee: BiPar Sciences, Inc. (Sanofi ), SRI International, Inc.
• Original Assignee: Large Scale Biology Corporation, SRI International, Inc.
• Inventors: Olsen, Cris M., Laderoute, Keith, Waleh, Nahid, Knapp, A. Merrill, Tuse, Daniel, Chen, Xiaoying, Hiebert, Charles K.
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/047,945
• Time in Patent Office: 1,014 Days
• Field of Search: 514/405
• US Class Current: 514/405
• CPC Class Codes: A61K 31/085 having an ether linkage to aromatic ring nuclear carbon
• CPC Class Codes: A61K 31/09 having two or more such linkages
• CPC Class Codes: A61K 31/095 Sulfur, selenium, or tellurium compounds, e.g. thiols
• CPC Class Codes: A61K 31/10 Sulfides; Sulfoxides; Sulfones
• CPC Class Codes: A61K 31/11 Aldehydes
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 205/59 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 45/29 of hydroxy groups
• CPC Class Codes: C07C 47/575 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 65/24 polycyclic
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates, inter alia, to compounds that bind tubulin and exhibit anti-mitotic properties and to methods of using such compounds to inhibit abnormal cell mitosis and, in particular, to inhibit tumor cell growth. In addition, methods are presented of treating mammalian diseases associated with undesired and uncontrolled angiogenesis.

Claims

1. A method of inhibiting the growth of a tumor cell, said method comprising contacting said tumor cell with a compound having the structure:

or a pharmaceutically acceptable salt thereof;

wherein;

X, if present, is a member selected from the group consisting of

A, together with the carbons to which it is bound, forms an optionally substituted 3, 4, 5 or 6 membered carbocylic or heterocyclic ring;

R⁹ and R¹⁰ are members independently selected from the group consisting of hydrogen, alkyl and halogen;

Y is a member selected from the group consisting of H, alkyl and alkoxy;

Z is a member selected from the group consisting of

Q is a member selected from the group consisting of H, alkyl and S-alkyl;

R¹, R², R³ and R⁴ are members independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, halogen, nitro and amino; and

R⁵, R⁶, R⁷ and R⁸ are members independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy and halogen;

with the proviso that if Z is

and Q is methyl, then Y is other than methoxy and ethoxy.

2. The method in accordance with claim 1 wherein

X is — O—

;

Y is methoxy;

Z is

Q is methyl;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

3. The method in accordance with claim 1 wherein

X is —

O—

;

Y is hydrogen;

Z is

Q is methyl;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

4. The method in accordance with claim 1 wherein

X is —

O—

;

Y is alkyl;

Z is

Q is methyl;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

5. The method in accordance with claim 1 wherein

X is —

O—

;

Y is methoxy;

Z is

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R7 and R⁸ are all hydrogen.

6. The method in accordance with claim 1 wherein

X is —

O—

;

Y is methoxy;

Z is —

CH₂OQ;

Q is hydrogen;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

7. The method in accordance with claim 1 wherein

X is —

O—

;

Y is methoxy;

Z is —

CH₂OQ;

Q is methyl;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

8. The method in accordance with claim 1 wherein said compound is selected from the group consisting of

9. The method in accordance with claim 1 wherein said tumor cell is selected from the group consisting of lung, colon, breast, ovarian, prostate and hepatic cells.

10. The method in accordance with claim 1 wherein said tumor cell is in a mammalian subject.

11. The method in accordance with claim 1 wherein said tumor cell is a squamous cell carcinoma.

12. The method in accordance with claim 1 wherein said compound is formulated in a pharmaceutically acceptable form with an excipient or carrier.

13. The method in accordance with claim 1 wherein said compound is formulated in a liposome.

14. The method in accordance with claim 1 wherein said compound is administered orally.

15. The method in accordance with claim 1 further comprising the step of observing for a reduction in the growth of said tumor cell.

16. A method of inhibiting the growth of a tumor cell in a mammalian subject, said method comprising administering to said subject a therapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof;

wherein;

X, if present, is a member selected from the group consisting of

A, together with the carbons to which it is bound, forms an optionally substituted 3, 4, 5 or 6 membered carbocylic or heterocyclic ring;

R⁹ and R¹⁰ are members independently selected from the group consisting of hydrogen, alkyl and halogen;

Y is a member selected from the group consisting of H, alkyl and alkoxy;

Z is a member selected from the group consisting of

Q is a member selected from the group consisting of H, alkyl and S-alkyl;

R¹, R², R³ and R⁴ are members independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, halogen, nitro and amino; and

R⁵, R⁶, R⁷ and R⁸ are members independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy and halogen;

with the proviso that if Z is

and Q is methyl,

then Y is other than methoxy and ethoxy.

17. A method of inhibiting the growth of a tumor cell in accordance with claim 16 wherein said administration is carded out in combination with immunotherapy.

18. A method of inhibiting the growth of a tumor cell in accordance with claim 17, further comprising the step of administering to said mammal a tumor vaccine.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:

or a pharmaceutically acceptable salt thereof;

wherein;

X, if present, is a member selected from the group consisting of

A, together with the carbons to which it is bound, forms an optionally substituted 3, 4, 5 or 6 membered carbocylic or heterocyclic ring;

R⁹ and R¹⁰ are members independently selected from the group consisting of hydrogen, alkyl and halogen;

Y is a member selected from the group consisting of H, alkyl and alkoxy;

Z is a member selected from the group consisting of

Q is a member selected from the group consisting of H, alkyl and S-alkyl;

R¹, R², R³ and R⁴ are members independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, halogen, nitro and amino; and

R⁵, R⁶, R⁷ and ⁸ are members independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy and halogen;

with the proviso that if Z is

and Q is methyl,

then Y is other than methoxy and ethoxy.

20. The pharmaceutical composition in accordance with claim 19 wherein

X is — O—

;

Y is methoxy;

Z is

Q is methyl;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

21. The pharmaceutical composition in accordance with claim 19 wherein

X is —

O—

;

Y is hydrogen;

Z is

Q is methyl;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

22. The pharmaceutical composition in accordance with claim 19 wherein

X is —

O—

;

Y is alkyl;

Z is

Q is methyl;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

23. The pharmaceutical composition in accordance with claim 19 wherein

X is —

O—

;

Y is methoxy;

Z is

R¹ and R⁴ are both hydrogen;

R² and I³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

24. The pharmaceutical composition in accordance with claim 19 wherein

X is —

O—

;

Y is methoxy;

Z is —

CH₂OQ;

Q is hydrogen;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

25. The pharmaceutical composition in accordance with claim 19 wherein

X is —

O—

;

Y is methoxy;

Z is —

CH₂OQ;

Q is methyl;

R¹ and R⁴ are both hydrogen;

R² and R³ are both iodo; and

R⁵, R⁶, R⁷ and R⁸ are all hydrogen.

26. The pharmaceutical composition in accordance with claim 19 wherein said compound is selected from the group consisting of