Macromolecules for treating atherosclerosis

Patent metadata

Field	Value
Publication number	US-9434681-B2
Application number	US-201314407403-A
Country	US
Kind code	B2
Filing date	Jun 17, 2013
Priority date	Jun 15, 2012
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

Abstract

The invention includes compounds of the formula I and formula II and salts thereof, as well as methods for using the compounds of formula I and formula II for treating atherosclerosis. The invention also includes compounds of formula III and (2l) and salts thereof, as well as methods of using the compounds of formula III and (2l) for treating atherosclerosis. The invention also includes methods of encapsulating molecules using the compounds of the invention.

First claim

What is claimed is:

1. A compound of formula II:
A-(CH(OC(═O)R 3 )) n —W—W 1 —R 2    II

wherein;
A is selected from carboxy, —SO 3 H and —PO 3 H;
n is independently 2, 3, 4, 5 or 6;
W is —C(═O)—, —C(═S)—, or is absent;
W 1 is O, S or NH;
each R 1 is independently a hydrophobic chain;
R 2 is a polyether, wherein the polyether has the following structure:
R 5 —(R 6 —O—) a —R 6 —

wherein R 5 is a 1 to 20 carbon straight-chain or branched alkyl group, —OH, —OR 7 , —NH 2 , —NHR 7 , —NHR 7 R 8 , —CO 2 H, —SO 3 H (sulfo), —CH 2 —OH, —CH 2 —OR 7 , —CH 2 —O—CH 2 —R 7 , —CH 2 —NH 2 , —CH 2 —NHR 7 , —CH 2 —NR 7 R 8 , —CH 2 CO 2 H, —CH 2 SO 3 H, or —O—C(═O)—CH 2 —CH 2 —C(═O)—O—;
R 6 is a 1 to 10 carbon straight-chain or branched divalent alkylene group;
each R 7 and R 8 is independently a 1 to 6 carbon straight-chain or branched alkylene group; and
a is an integer from 2 to 150, inclusive; and

each R 3 is independently (C 1 -C 8 )alkyl wherein each (C 1 -C 8 )alkyl is independently substituted with one or more —O(C═O)R 1 groups;
or a salt thereof.

2. The compound of claim 1 wherein the compound of formula II is a compound of formula IIa:

wherein:
n is 2, 3, 4, 5 or 6;
each R 1 is independently a hydrophobic chain;
R 2 is a polyether, wherein the polyether has the following structure:
R 5 —(R 6 —O—) a —R 6 —

wherein R 5 is a 1 to 20 carbon straight-chain or branched alkyl group, —OH, —OR 7 , —NH 2 , —NHR 7 , —NHR 7 R 8 , —CO 2 H, —SO 3 H (sulfo), —CH 2 —OH, —CH 2 —OR 7 , —CH 2 —O—CH 2 —R 7 , —CH 2 —NH 2 , —CH 2 —NHR 7 , —CH 2 —NR 7 R 8 , —CH 2 CO 2 H, —CH 2 SO 3 H, or —O—C(═O)—CH 2 —CH 2 —C(═O)—O—;
R 6 is a 1 to 10 carbon straight-chain or branched divalent alkylene group;
each R 7 and R 8 is independently a 1 to 6 carbon straight-chain or branched alkylene group; and
a is an integer from 2 to 150, inclusive; and

each R 3 is independently (C 1 -C 8 )alkyl wherein each (C 1 -C 8 )alkyl is independently substituted with one or more —O(C═O)R′ groups;
or a salt thereof.

3. The compound of claim 1 wherein the polyether is a poly(alkylene oxide) having between about 2 and about 150 repeating units.

4. The compound of claim 3 , wherein each alkylene oxide unit comprises straight or branched (C 2 -C 4 ) alkylene oxide.

5. The compound of claim 1 wherein the polyether is a poly(ethylene oxide) having between about 2 and about 150 repeating units.

6. The compound of claim 1 , wherein the polyether comprises an alkoxy-terminal group.

7. The compound of claim 1 wherein the each R 1 is independently (C 1 -C 24 )alkyl, (C 2 -C 24 )alkene or (C 2 -C 24 )alkyne.

8. The compound of claim 1 wherein each R 1 is independently a fatty acid, wherein the fatty acid is caprylic, capric, lauric, myristic, myristoleic, palmitic, palmitoleic, stearic, oleic, linoleic, arachidic, behenic, or erucic acid, or a mixture thereof.

9. The compound of claim 1 wherein the each R 1 is independently a (C 6 -C 18 )alkyl.

10. The compound of claim 1 wherein n is independently 2 or 4.

11. The compound of claim 2 wherein each R 3 is independently a (C 3 -C 6 )alkyl.

12. The compound of claim 1 selected from:

and salts thereof.

13. A pharmaceutical composition comprising a compound of formula II as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method for preventing the uptake of LDL by a cell comprising contacting the cell with a compound of formula II as described in claim 1 .

15. A method for inhibiting atherosclerosis or atherosclerotic development in a mammal, comprising administering an anti-atherosclerosis or anti-atherosclerotic development amount of a compound of formula II as described in claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal.

16. The compound of claim 1 , wherein A is carboxy.

17. The compound of claim 1 , wherein W is —C(═O)—.

18. The compound of claim 1 , wherein W 1 is O.

19. The compound of claim 1 , wherein the polyether is a methoxy-terminated poly(ethylene oxide) having between about 2 and about 150 repeating units.

20. The compound of claim 1 , wherein each R 3 is independently (C 1 -C 8 )alkyl wherein each (C 1 -C 8 )alkyl is independently substituted with two or more —O(C═O)R 1 groups.

Assignees

• Univ Rutgers

Inventors

• Uhrich Kathryn E
• Poree Dawanne E
• Moghe Prabhas

Classifications

• C07C235/10 Primary

  having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups · CPC title

• C07C69/708

  Ethers · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title