Liver targeted conjugates

Patent metadata

Field	Value
Publication number	US-9585964-B2
Application number	US-201313869917-A
Country	US
Kind code	B2
Filing date	Apr 24, 2013
Priority date	Jul 5, 2005
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

Therapeutic conjugates containing a statin or a modified statin (collectively “statin”) linked to a therapeutic agent (also referred to as a drug herein) are targeted to the liver by the statin or modified statin and thereby deliver the therapeutic agent to liver cells.

First claim

The invention claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof; wherein:
R is a therapeutic agent selected from the group consisting of niacin, diclofenac, etodolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen, indoprofen, indomethacin, ketoprofen, ketorolac, lomoxicam, morazone, naproxen, perisoxal, pirprofen, pranoprofen, suprofen, suxibuzone, tropesin, ximoprofen, zaltoprofen, zileuton, zomepirac, salicylate, bleomycin, capecitabine, carubicin, chlorozotocin, a chromomycin, cladribine, colchicine, cytarabine, daunorubicin, demecolcine, denopterin, docetaxel, doxyifluridine, doxorubicin, dromostanolone, edatrexate, enocitabine, epirubicin, epitiostanol, estramustine, etoposide, floxuridine, fludarabine, formestane, gemcitabine, irinotecan, lentinan, lonidamine, melengestrol, melphalan, menogaril, mitolactol, nogalamycin, nordihydroguaiaretic acid, an olivomycin, paclitaxel, pentostatin, pirarubicin, plicamycin, porfiromycin, prednimustine, puromycin, ranimustine, a ristocetin, temozolamide, teniposide, tomudex, topotecan, tubercidin, ubenimax, valrubicin, vinorelbine, vinblastine, vindesine, vinorelbine, and zorubicin;
n is 1, 2, 3, 4, 5, or 6;
X is S, O or NH;
R 3 and R 4 are independently selected from the group consisting of —CH 3 , —OH, H, —CH 2 CH 3 , cyclopropyl, and halogens;
R 1 and R 5 are independently selected from the group consisting of —CH 3 and H; and
R 2 is selected from the group consisting of:

2. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is of Formula (10a):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or medium.

6. The compound of claim 1 or 2 , wherein X is S.

7. The compound of claim 1 or 2 , wherein X is O.

8. The compound of claim 1 or 2 , wherein X is NH.

9. The compound of claim 1 or 2 , wherein R 3 and R 4 are methyl.

10. The compound of claim 1 or 2 , wherein R 3 is methyl and R 4 is H.

11. The compound of claim 1 or 2 , wherein R is of the formula:

12. The compound of claim 1 wherein R 2 is of the formula:

13. The compound of claim 1 wherein R 2 is of the formula:

14. The compound of claim 1 wherein R 2 is of the formula:

15. The compound of claim 1 wherein R 2 is of the formula:

16. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

Assignees

• Harvard College

Inventors

• Verdine Gregory L
• Norimine Yoshihiko
• Gude-Rodriguez Lourdes

Classifications

• C07D209/28

  1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof · CPC title

• C07D309/30

  Oxygen atoms, e.g. delta-lactones · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title