Dual-action EP4 agonist—bisphosphonate conjugates and uses thereof

Patent metadata

Field	Value
Publication number	US-9650414-B1
Application number	US-201514726020-A
Country	US
Kind code	B1
Filing date	May 29, 2015
Priority date	May 30, 2014
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The invention provides in part, compounds according to Formula I:

and uses thereof.

First claim

What is claimed is:

1. A compound according to Formula II or a pharmaceutically acceptable salt thereof:

wherein:
X is —CH 2 —, —S—, —O—, or —NH—;
Y is optionally substituted tetrazole, —C(O)OR′, or —C(O)NHSO 2 V;
R′ is H or lower alkyl;
V is optionally substituted lower alkyl, optionally substituted aryl or optionally substituted heteroalkyl;
Z is H or OH;
n is 1, 2 or 3;
m is 0, 1, 2, 3, 4, 5, or 6;
q is 0, 1, 2 or 3;
R 1 is each independently —H or halo, or lower alkyl;
Ar is aryl or substituted aryl; and

R 2 and R 3 are each independently radicals selected from the radicals of: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine.

2. The compound of claim 1 wherein R 2 is the radical of isoleucine, leucine, phenylalanine, or proline.

3. The compound of claim 1 wherein R 3 is the radical of arginine.

4. The compound of claim 1 wherein the compound is (4-((((4-((S)-2-((S)-2-((((4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)-5-oxopyrrolidin-2-yl)-1,1-difluoro-1-phenylbut-3-en-2-yl)oxy)-2-oxoethyl)benzyl)oxy)carbonyl)amino)-4-methylpentanamido)-5-guanidinopentanamido)benzyl)oxy)carbonyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid) or (4-((((4-((S)-2-((S)-2-((((4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)-5-oxopyrrolidin-2-yl)-1,1-difluoro-1-(4-iodophenyl)but-3-en-2-yl)oxy)-2-oxoethyl)benzyl)oxy)carbonyl)amino)-4-methylpentanamido)-5-guanidinopentanamido)benzyl)oxy)carbonyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid).

5. A composition comprising the compound of claim 1 in combination with a carrier.

6. The composition of claim 5 wherein the carrier is a pharmaceutically acceptable carrier.

7. A method of selectively delivering the compound of claim 1 or a salt thereof to a bone or an associated site, the method comprising administering the compound of claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

8. The method of claim 7 , wherein the associated site comprises a site adjacent to the bone.

9. The method of claim 7 wherein the bone in need of treatment is a green stick fracture, a compound fracture, a lateral fracture, a pathologic fracture resulting from an invasive tumor, a compression fracture, or a fracture requiring a surgical procedure for realignment of a bone.

10. The method of claim 7 wherein the compound is (4-((((4-((S)-2-((S)-2-((((4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)-5-oxopyrrolidin-2-yl)-1,1-difluoro-1-phenylbut-3-en-2-yl)oxy)-2-oxoethyl)benzyl)oxy)carbonyl)amino)-4-methylpentanamido)-5-guanidinopentanamido)benzyl)oxy)carbonyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid) or (4-((((4-((S)-2-((S)-2-((((4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)-5-oxopyrrolidin-2-yl)-1,1-difluoro-1-(4-iodophenyl)but-3-en-2-yl)oxy)-2-oxoethyl)benzyl)oxy)carbonyl)amino)-4-methylpentanamido)-5-guanidinopentanamido)benzyl)oxy)carbonyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid).

11. The method of claim 7 , wherein the subject is a human.

12. A method of treating a condition associated with excessive bone loss comprising administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

13. The method of claim 12 , wherein the condition is osteoporosis, Paget's disease, abnormally increased bone turnover, bone graft, periodontal disease, alveolar bone loss, tooth loss, bone fracture, periprostheticosteolysis, osteogenesis imperfecta, or metastatic bone disease.

14. The method of claim 13 , wherein the osteoporosis is glucocorticoid-induced osteoporosis.

15. The method of claim 12 , wherein the compound is (4-((((4-((S)-2-((S)-2-((((4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)-5-oxopyrrolidin-2-yl)-1,1-difluoro-1-phenylbut-3-en-2-yl)oxy)-2-oxoethyl)benzyl)oxy)carbonyl)amino)-4-methylpentanamido)-5-guanidinopentanamido)benzyl)oxy)carbonyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid) or (4-((((4-((S)-2-((S)-2-((((4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)-5-oxopyrrolidin-2-yl)-1,1-difluoro-1-(4-iodophenyl)but-3-en-2-yl)oxy)-2-oxoethyl)benzyl)oxy)carbonyl)amino)-4-methylpentanamido)-5-guanidinopentanamido)benzyl)oxy)carbonyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid).

16. The method of claim 12 , wherein the subject is a human.

17. The method of claim 7 wherein the compound stimulates bone growth or inhibits bone resorption.

Assignees

• Univ Fraser Simon

Inventors

• Young Robert N
• Chen Gang
• Xie Haibo

Classifications

• C07K5/06043 Primary

  Leu-amino acid · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K47/548 Primary

  Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544) · CPC title