Chemical conjugates of Evans Blue derivatives and their use in the production of long-acting therapeutics

Patent metadata

Field	Value
Publication number	US-10709790-B2
Application number	US-201615735687-A
Country	US
Kind code	B2
Filing date	Jun 21, 2016
Priority date	Jun 22, 2015
Publication date	Jul 14, 2020
Grant date	Jul 14, 2020

Abstract

The present invention is directed to a compound of Formula I or Formula II or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt: Formula I Formula II The compounds of Formula I may be covalently bonded to a therapeutic compound or fragment thereof to provide a compound of Formula II and thereby extend the half-life of the therapeutic compound. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use in the diagnosis or treatment of diseases.

First claim

What is claimed is:

1. A compound of Formula I or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester, amide, or salt,

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are chosen independently from hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; and
L 1 is —(CH 2 ) m — wherein m is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)NH—, providing no two adjacent CH 2 groups are replaced, and wherein L 1 is optionally substituted with 1 substituent -A-B—X, wherein A is a bond, —NH—, —NH(CO)—, —(CO)NH—, B is C 0-12 alkyl, or phenylC 0-12 alkyl, and X is a hydrogen, halogen or an Sn derivative, and wherein when m is 0, the compound additionally comprises a radionuclide.

2. The compound of claim 1 , wherein -A-B—X is

and q is an integer from 0 to 12.

3. The compound of claim 1 , wherein L 1 is —[(CH 2 ) n (CO)NH] p — wherein p is an integer from 0 to 4, and n is an integer from 1 to 3.

4. The compound of claim 3 , wherein m is 0.

5. The compound of claim 1 , wherein R 1 and R 4 are chosen independently from halogen, hydroxyl, cyano, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.

6. The compound of claim 1 , wherein R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen.

7. The compound of claim 3 , wherein R 1 and R 4 are chosen independently from C 1 -C 6 alkyl.

8. The compound of claim 5 , wherein R 1 and R 4 are each methyl.

9. The compound of claim 1 , wherein the compound of Formula I is:

10. The compound of claim 1 , wherein -A-B—X additionally comprises a radionuclide.

11. The compound of claim 1 , wherein the radionuclide is 18 F, 76 Br, 124 I, 125 I, or 131 I, or 117m Sn.

12. A compound of Formula II or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt,

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are chosen independently from hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
L 1 is —(CH 2 ) m — wherein m is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)NH—, providing no two adjacent CH 2 groups are replaced, and wherein L 1 is optionally substituted with 1 substituent which is -A-B—X, wherein A is a bond, —NH—, —NH(CO)—, —(CO)NH—, B is C 0-12 alkyl, or phenylC 0-12 alkyl, and X is a hydrogen, halogen or an Sn derivative;
L 2 is —(CH 2 ) r — wherein r is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)NH—, providing no two adjacent CH 2 groups are replaced; and
R is a therapeutic compound.

13. The compound of claim 12 , wherein -A-B—X is

and q is an integer from 0 to 12.

14. The compound of claim 12 , wherein L 1 is —[(CH 2 ) n (CO)NH] p — wherein p is an integer from 0 to 4, and n is an integer from 1 to 3.

15. The compound of claim 12 , wherein m is 0.

16. The compound of claim 12 wherein m is 0, r is 0, R 1 and R 4 are each methyl, and R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen.

17. The compound of claim 12 , wherein R is a therapeutic protein or peptide.

18. The compound of claim 17 , wherein R is selected from insulin, GLP-1, Exendin-4, exendin (9-39), octreotide, bombesin, RGD peptide (arginylglycylaspartic acid), vascular endothelial growth factor (VEGF), interferon (IFN), tumor necrosis factor (TNF), asparaginase, adenosine deaminase, and the like, or a therapeutic fragment thereof.

19. The compound of claim 12 , wherein R is selected from doxorubicin, paclitaxel, gemcitabine, camptothecin, and temozolomide.

20. The compound of claim 12 wherein R treats or diagnoses diabetes or cancer.

21. The compound of claim 20 wherein R treats or diagnoses diabetes.

22. The compound of claim 12 , wherein the compound is

23. The compound of claim 12 , wherein the compound is

24. The compound of claim 12 , wherein the compound is

25. The compound of claim 12 , additionally comprising a radionuclide.

26. The compound of claim 12 , wherein either -A-B—X or R additionally comprises a radionuclide.

27. The compound of claim 25 , wherein the radionuclide is 18 F, 76 Br, 124 I, 125 I, or 131 I, or 117m Sn.

28. The compound of claim 26 , wherein the compound is

29. The compound of claim 26 , wherein the compound is a compound of Formula III

wherein X is 18 F, 76 Br, 124 I, 125 I, 131 I, or a derivative of 117m Sn.

30. A pharmaceutical composition comprising the compound of Formula II together with a pharmaceutically acceptable carrier.

31. The composition of claim 30 , wherein the pharmaceutically acceptable carrier is selected from binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents, and combinations thereof.

32. A method of treating or diagnosing diabetes in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula II as defined in claim 12 , optionally in combination with one or more additional active ingredients.

33. The method of claim 32 , wherein the one or more additional active ingredients are selected from insulin, exenatide, dipeptidyl peptidase-4 inhibitors, neuropilin, epidermal growth factor, islet neogenesis associated protein, alpha-1 antitrypsin, anti-inflammatory agents, glulisine, glucagons, local cytokines, modulators of cytokines, anti-apoptotic molecules, aptamers, asparaginase, adenosine deaminase, interferon α2a, interferon α2b, granulocyte colony stimulating factor, growth hormone receptor antagonists, and combinations thereof.

Assignees

• Us Health

Inventors

• Chen Xiaoyuan
• Lang Lixin
• Niu Gang

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D207/24

  Oxygen or sulfur atoms · CPC title

• A61K47/643

  Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL] · CPC title

• C09B29/30

  Amino naphtholsulfonic acid · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title