Compounds and methods for inhibiting phosphate transport

Patent metadata

Field	Value
Publication number	US-9278102-B2
Application number	US-201414337032-A
Country	US
Kind code	B2
Filing date	Jul 21, 2014
Priority date	Jul 7, 2010
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I):

including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein X, Y, R 1 and R 2 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

First claim

What is claimed is:

1. A pharmaceutical composition comprising:
a compound of structure (I):

or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
X is substituted aryl or substituted heteroaryl;
Y is halogen, optionally substituted alkylamino, optionally substituted alkoxy, optionally substituted thioalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, —O(optionally substituted cycloalkyl), —O(optionally substituted heterocyclyl) or —O(optionally substituted aryl);
each R 1 is, independently, hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl; and
R 2 is hydrogen or optionally substituted C 1-6 alkyl; and

a pharmaceutically acceptable carrier, diluent, or excipient.

2. A pharmaceutical composition of claim 1 wherein Y is halogen.

3. A pharmaceutical composition of claim 2 wherein Y is chloro.

4. A pharmaceutical composition of claim 1 wherein Y is alkylamino.

5. A pharmaceutical composition of claim 4 wherein Y is diethylamino.

6. A pharmaceutical composition of claim 1 wherein Y is alkoxy.

7. A pharmaceutical composition of claim 1 wherein Y is heterocyclyl.

8. A pharmaceutical composition of claim 7 wherein Y is 1-piperidinyl and the compound has the structure:

9. A pharmaceutical composition of claim 1 wherein Y is —O(cycloalkyl).

10. A pharmaceutical composition of claim 1 wherein X is —ZR 3 , and wherein Z is aryl or heteroaryl and R 3 is a non-hydrogen substituent.

11. A pharmaceutical composition of claim 10 wherein Z is aryl.

12. A pharmaceutical composition of claim 11 wherein Z is phenyl.

13. A pharmaceutical composition of claim 12 wherein the compound has the structure:

14. A pharmaceutical composition of claim 10 wherein Z is heteroaryl.

15. A pharmaceutical composition of claim 14 wherein Z is pyridinyl.

16. A pharmaceutical composition of claim 15 wherein the compound has the structure:

17. A pharmaceutical composition of claim 1 wherein R 3 is:
(a) —CH 2 S(O) 0-2 (optionally substituted C 1-6 alkyl)C(═O)NR 7 R 4 ,
(b) —CH 2 S(O) 0-2 (optionally substituted C 1-6 alkyl)NR 7 R 4 ,
(c) —CH 2 S(O) 0-2 (optionally substituted C 1-6 alkyl)C(═O)OR 5 ,
(d) —CH 2 S(O) 0-2 (optionally substituted C 1-6 alkyl)OR 5 ,
(e) —CH 2 S(O) 0-2 (optionally substituted C 1-6 alkyl)R 6 ,
(f) —CH 2 S(O) 0-2 R 6 ,
(g) —CH 2 S(O) 0-2 NR 7 R 4 ,
(h) —CH 2 S(O) 0-2 (CH 2 CH 2 O) x R 5 ,
(i) —CH 2 NR 7 (CH 2 CH 2 O) x R 5 ,
(j) —C(═O)NR 7 (optionally substituted C 1-6 alkyl)C(═O)NR 7 R 4 ,
(k) —C(═O)NR 7 (optionally substituted C 1-6 alkyl)NR 7 R 4 ,
(l) —C(═O)NR 7 (optionally substituted C 1-6 alkyl)C(═O)OR 5 ,
(m) —C(═O)NR 7 (optionally substituted C 1-6 alkyl)OR 5 ,
(n) —C(═O)NR 7 (optionally substituted C 1-6 alkyl)R 6 , or
(o) —C(═O)NR 7 (CH 2 CH 2 O) x R 5 ,
wherein
R 4 is hydrogen, hydroxyl, alkoxy, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted heteroaryl;
R 5 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted heteroaryl;
R 6 is optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted heteroaryl;
R 7 is hydrogen or optionally substituted C 1-6 alkyl; and
x is an integer from 2 to 10.

18. A pharmaceutical composition of claim 1 wherein each R 1 is hydrogen.

19. A pharmaceutical composition of claim 1 wherein R 2 is hydrogen.

20. A pharmaceutical composition of claim 1 wherein R 2 is an optionally substituted C 1-6 alkyl.

21. A pharmaceutical composition of claim 20 wherein R 2 is trifluoromethyl.

22. The pharmaceutical composition of claim 1 , further comprising one or more additional biologically active agents.

23. The pharmaceutical composition of claim 22 , wherein the additional biologically active agent is selected from vitamin D 2 , vitamin D 3 , active vitamin D and active vitamin D analogs.

24. The pharmaceutical composition of claim 22 , wherein the additional biologically active agent is a phosphate binder, and the compound does not interfere with the phosphate binder.

25. The pharmaceutical composition of claim 24 , wherein the phosphate binder is selected from the group consisting of sevelamer carbonate, sevelamer hydrochloride, lanthanum carbonate, calcium carbonate, calcium acetate, MCI-196, ferric citrate, iron magnesium hydroxy carbonate, APS1585, SBR-759 and PA-21.

26. The pharmaceutical composition of claim 1 , wherein the compound is substantially active as an inhibitor of Na/phosphate co-transport and the Na/phosphate co-transport is mediated by NaPi2b.

27. A pharmaceutical composition of claim 1 wherein the compound is present in the composition in an amount from 0.2 mg to 2 g per daily dosage.

28. A pharmaceutical composition of claim 27 wherein the compound is present in an amount from 10 mg to 250 mg per daily dosage.

29. A pharmaceutical composition of claim 1 wherein the pharmaceutical composition is a powder, granule, pill, tablet, capsule, liquid, syrup, suspension, emulsion, or aqueous injection solution.

Assignees

• Ardelyx Inc

Inventors

• Lewis Jason G
• Jacobs Jeffrey W
• Reich Nicholas
• Leadbetter Michael R
• Bell Noah
• Chang Han-Ting
• Chen Tao
• Navre Marc
• Charmot Dominique
• Carreras Christopher
• Labonte Eric

Classifications

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P5/20

  for decreasing, blocking or antagonising the activity of PTH · CPC title

• A61P5/16

  for decreasing, blocking or antagonising the activity of the thyroid hormones · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/08

  Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04) · CPC title