Phosphono-carboxylate compounds for treating amyloidosis

• US 6,440,952 B2
• Filed: 05/17/2001
• Issued: 08/27/2002
• Est. Priority Date: 04/10/1998
• Status: Expired due to Fees

• Current Assignee: Bellus Health (Interational) Limited
• Original Assignee: Queen's University At Kingston
• Inventors: Kong, Xianqi, Szarek, Walter A., Gorine, Boris, Thatcher, Gregory R. J.
• Primary Examiner(s): Reamer, James H.
• Application Number:
  US09/860,255
• Publication Number:
  US 20010027186A1
• Time in Patent Office: 467 Days
• Field of Search: 514/120, 558/110, 558/70
• US Class Current: 514/120
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

Therapeutic compounds and methods for modulating amyloid deposition in a subject, whatever its clinical setting, are described. Amyloid deposition is modulated by the administration to a subject of an effective amount of a therapeutic compound comprising a phosphonate group and a carboxylate group, a congener thereof, or a pharmaceutically acceptable salt or ester thereof. In preferred embodiments, an interaction between an amyloidogenic protein and a basement membrane constituent is modulated.

Claims

1. A method for preparing a compound represented by the formula:

in which R is alkyl or aryl, and R′

is hydrogen, alkyl, or aryl;

the method comprising;

reacting an ester of a carbonylphosphono diacid halide with a disilylether of a vicinal diol, under conditions such that a compound of said formula is prepared.

3. The method of claim 1, wherein R′

is a substituted alkyl group, such that the compound of said formula is prepared.

11. The method of claim 1 wherein said carbonylphosphono diacid halide is a phosphonodichloridate.

13. The method of claim 11 wherein G is hydrogen, or an alkyl, aryl, halogen, or amino group.

14. The method of claim 11 wherein L is a hydroxy substituted lower alkyl group.

2. A compound represented by the formula:

wherein G is hydrogen or one of more substituents on the aryl ring and the L is a substituted alkyl group.

4. The compound of claim 2 wherein G is hydrogen, or an alkyl, aryl, halogen, or amino group.

5. The compound of claim 2 wherein L is a substituted lower alkyl group or an alkyl group substituted with a nucleoside base.

6. The compound of claim 2 wherein L is a hydroxy substituted alkyl group.

7. The A compound of claim 2 wherein G is an electron withdrawing group in the meta position.

8. The compound of claim 7 wherein G is a fluoro, chloro, bromo, iodo, nitro, or cyano group.

9. The compound of claim 2 wherein G is an electron donating group in the ortho, meta, or para position.

10. The compound of claim 2 wherein L is selected from the following

20. A therapeutic composition comprising a compound of claim 2 and a pharmaceutically acceptable salt.

12. A method of synthesizing a compound represented by the formula

wherein

G is hydrogen or one or more substituents on the aryl ring and the L is a hydroxy substituted alkyl group;

the method comprising reacting an ester of a carbonylphosphono diacid halide with a disilylether of a vicinal diol, under conditions such that the compound of said formula is prepared.

15. The method of claim 12 wherein G is an electron withdrawing group in the meta position.

16. The method of claim 15 wherein G is a fluoro, chloro, bromo, iodo, nitro, or cyano group.

17. The method of claim 12 wherein G is an electron donating group in the ortho, meta, or para position.

18. The method of claim 12 wherein L is selected from the following

19. The method of claim 12 wherein said carbonylphosphono diacid halide is a phosphonodichloridate.