Non-cleavable polymer conjugated with alpha V beta 3 integrin thyroid antagonists

• US 10,695,436 B2
• Filed: 12/18/2018
• Issued: 06/30/2020
• Est. Priority Date: 06/07/2016
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Mousa, Shaker A., Rajabi, Mehdi
• Primary Examiner(s): Berry, Layla D
• Application Number:
  US16/223,176
• Publication Number:
  US 20190111145A1
• Time in Patent Office: 560 Days
• Field of Search: None
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6957 the form being a device or a kit, e.g. stents or microdevices
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Chemical compositions and methods of synthesis thereof. The compositions disclosed and described herein are directed toward and classified as anti-angiogenic thyrointegrin antagonists, which may be capable of reacting with one or more cell surface receptors of the integrin αvβ3 receptor family. Anti-angiogenic thyrointegrin antagonists or derivatives thereof are conjugated via a non-cleavable linker having an amine, diamine or triazole linkage to polymers of Polyethylene Glycol, cyclodextrin, chitosan, alginic acid or hyaluronic acid, forming a single chemical entity. Utility of the compositions disclosed may treat angiogenesis-mediated disorders such as Cancer (Solid tumors and Liquid tumors), ocular disorders (Diabetic Retinopathy and Age-related Macular Degeneration), inflammatory disorders (arthritis, osteoarthritis), atherosclerosis, lesions, and dermatology (Rosacea, Psoriasis, skin cancer) and diseases mediated or dependent upon the generation of new blood cells via angiogenesis to persist and the treatment thereof or dependent on antagonizing the formation of new blood vessels to slow or eliminate angiogenic pathways.

Claims

1. A method of synthesizing a composition, the method comprising:

conjugating a non-biodegradable polymer to a thyroid antagonist using a linker;

wherein the linker is covalently bound to the thyroid antagonist and the non-biodegradable polymer via a non-cleavable bond,

wherein the linker comprises one of the following;

2. The method of claim 1, wherein the thyroid antagonist is selected from the group consisting of tetraiodothyroacetic acid (tetrac), triiodothyroacetic acid (triac) and derivatives thereof.

3. The method of claim 1, wherein the non-biodegradable polymer is selected from the group consisting of polyethylene glycol (PEG), α

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin, alginic acid, chitosan and hyaluronic acid.

4. The method of claim 1, wherein the composition is bi-functional and has two non-cleavable covalent bonds.

5. The method of claim 1, wherein the composition is tetra-functional and has two non-cleavable covalent bonds.

6. A method of synthesizing a thyroid antagonist composition having a non-cleavable covalent bond, the method comprising:

providing a polymer;

tosylating the polymer to form tosylated-polymer;

reacting the tosylated-polymer with thyroid antagonist to form the thyroid antagonist composition having the non-cleavable covalent bond.

7. The method of claim 6, wherein the thyroid antagonist composition having the non-cleavable covalent bond is bi-functional and has two non-cleavable covalent bonds;

wherein the polymer is tosylated to form bi-tosylate-polymer; and

wherein the bi-tosylated-polymer is reacted with thyroid antagonist to form the bi-functional thyroid antagonist composition having two non-cleavable covalent bonds.

8. The method of claim 6, wherein the thyroid antagonist composition having the non-cleavable covalent bond is tetra-functional and has four non-cleavable covalent bonds;

wherein the polymer is a tetra-polymer;

wherein the tetra-polymer is tosylated to form tetra-tosylated-polymer;

wherein the tetra-tosylated-polymer is reacted with thyroid antagonist to form the tetra-functional thyroid antagonist composition having four non-cleavable covalent bonds.

9. The method of claim 6, wherein the thyroid antagonist is one of monoamino tetrac, a monoamino tetrac derivative, diamino tetrac, and a diamino tetrac derivative.

10. The method of claim 6, wherein the thyroid antagonist is one of propargyl tetrac and a propargyl tetrac derivative,

further wherein the step of reacting the tosylated-polymer with the thyroid antagonist comprises first reacting the tosylated-polymer with azide containing compound to form an azido-polymer compound and then reacting the azido-polymer compound with thyroid antagonist to form the thyroid antagonist composition having the non-cleavable bond.

11. The method of claim 6, wherein the polymer is PEG and the method comprises:

providing PEG;

tosylating the PEG to form tosylated PEG;

reacting the tosylated PEG with thyroid antagonist to form the thyroid antagonist composition having the non-cleavable covalent bond.

12. The method of claim 11,

wherein the provided PEG is a monomethoxy PEG;

wherein the monomethoxy PEG is tosylated to form a monotosylated PEG; and

wherein the monotosylated PEG is reacted with thyroid antagonist to form the thyroid antagonist composition having the non-cleavable covalent bond.

13. The method of claim 12, wherein the polymer is PEG;

wherein the thyroid antagonist is one of propargyl tetrac and a propargyl tetrac derivative;

further wherein the step of reacting the tosylated-PEG with the thyroid antagonist comprises first reacting the tosylated-PEG with azide containing compound to form an azido-PEG compound and then reacting the azido-PEG compound with thyroid antagonist to form the thyroid antagonist composition having the non-cleavable bond.

14. The method of claim 7, wherein the polymer is PEG;

wherein the PEG is tosylated to form bi-tosylated PEG; and

wherein the bi-tosylated PEG is reacted with thyroid antagonist to form the bi-functional thyroid antagonist composition having two non-cleavable covalent bonds.

15. The method of claim 14,

wherein the thyroid antagonist is one of propargyl tetrac and a propargyl tetrac derivative;

further wherein the step of reacting the bi-tosylated PEG with the thyroid antagonist comprises first reacting the bi-tosylated PEG with azide containing compound to form a bi-azido-PEG compound and then reacting the bi-azido-PEG compound with thyroid antagonist to form the bi-functional thyroid antagonist composition having two non-cleavable covalent bonds.

16. The method of claim 8, wherein the polymer is PEG;

wherein the provided PEG is a tetra-PEG;

wherein the tetra-PEG is tosylated to form tetra-tosylated PEG;

wherein the tetra-tosylated PEG is reacted with thyroid antagonist to form the tetra-functional thyroid antagonist composition having four non-cleavable covalent bonds.

17. The method of claim 16,

wherein the thyroid antagonist is one of propargyl tetrac and a propargyl tetrac derivative;

further wherein the step of reacting the tetra-tosylated PEG with the thyroid antagonist comprises first reacting the tetra-tosylated PEG with azide containing compound to form a tetra-azido-PEG compound and then reacting the tetra-azido-PEG compound with thyroid antagonist to form the tetra-functional thyroid antagonist composition having four non-cleavable covalent bonds.

18. The method of claim 6, wherein the polymer is cyclodextrin, and the method comprises:

providing a cyclodextrin polymer;

tosylating the cyclodextrin polymer to form tosylated-cyclodextrin;

reacting the tosylated-cyclodextrin with thyroid antagonist to form the thyroid antagonist composition having the non-cleavable covalent bond.

19. The method of claim 6, wherein the polymer is cyclodextrin, and

wherein the thyroid antagonist composition having the non-cleavable covalent bond is one of:

a) bi-functional and has two non-cleavable covalent bonds; and

b) tetra-functional and has four non-cleavable covalent bonds.