Non-cleavable polymer conjugated with αVβ3 integrin thyroid antagonists

• US 10,201,616 B2
• Filed: 06/07/2017
• Issued: 02/12/2019
• 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:
  US15/616,637
• Publication Number:
  US 20170348425A1
• Time in Patent Office: 615 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 composition comprising:

a general formula;

2. The composition of claim 1, wherein n₁ is 0, 1 or 2.

3. The composition of claim 1, wherein Y=

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

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin, alginic acid, chitosan and hyaluronic acid.

5. The composition of claim 1, wherein at least one of R¹, R², R³ or R⁴ is selected from the group consisting an isopropyl group, a tert-butyl group and a combination thereof.

6. The composition of claim 1, wherein the composition has a chemical formula of:

16. The composition of claim 1, wherein the composition have an anti-angiogenesis utility for the treatment of pathological angiogenesis associated disorders.

17. The composition of claim 16, wherein the pathological angiogenesis associated disorders include Cancer.

18. The composition of claim 17, where Cancer includes solid tumors and liquid cancer in humans or mammals.

19. The composition of claim 18, where solid tumors include Glioblastoma, pancreatic, ovarian, breast, prostate, bladder, lung, liver.

20. The composition of claim 18, where liquid cancer include acute myeloid leukemia, multiple myeloma, Lymphoma and chronic lymphocytic leukemia.

21. The composition of claim 16, wherein pathological angiogenesis associated disorders include Ocular vascular disorders, diabetic retinopathy, and age-Related Macular Degeneration.

22. The composition of claim 16, wherein pathological angiogenesis associated disorders include skin vascular disorders selected from the group consisting of Rosacea, Poikiloderma and Psoriasis.

23. The composition of claim 16, wherein pathological angiogenesis associated disorders include skin cancer.

7. A composition comprising:

a general formula;

8. The composition of claim 7, wherein at least one of R¹, R², R³ or R⁴ is selected from the group consisting an isopropyl group, a tert-butyl group and a combination thereof.

9. The composition of claim 7, wherein the composition has a chemical formula of:

10. A composition comprising:

A thyroid antagonist;

a non-biodegradable polymer; and

a linker covalently bound to the thyroid antagonist and the non-biodegradable polymer via a non-cleavable covalent bond, wherein the linker comprises one of the following;

11. The composition of claim 10, wherein the thyroid antagonist is selected from the group consisting of tetraiodothyroacetic acid (tetrac), triiodothyroacetic acid (triac) and derivatives thereof.

12. The composition of claim 10, wherein the non-biodegradable polymer is selected from the group consisting of polyethylene glycol (PEG), α

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin, chitosan, alginic acid, hyaluronic acid and a combination thereof.

13. The composition of claim 10, wherein the composition is selected from the group consisting of PEG-diamino tetrac (P-DAT), PEG-monoamino tetrac (P-MAT), PEG-triazole tetrac (P-TAT), cyclodextrin bound diamino tetrac (C-DAT), cyclodextrin bound monoamino tetrac (C-MAT), cyclodextrin bound triazole tetrac (C-TAT), cyclodextrin bound P-DAT, cyclodextrin bound P-MAT, cyclodextrin bound P-TAT, chitosan bound diamino tetrac, chitosan bound monoamino tetrac, chitosan bound triazole tetrac, alginic acid-monoamino tetrac (A-MAT), alginic acid-diamino tetrac (A-DAT), alginic acid-triazole tetrac (A-TAT), hyaluronic acid-monoamino tetrac (H-MAT), hyaluronic acid-diamino tetrac (H-DAT) and hyaluronic acid-triazole tetrac (H-TAT).

14. The composition of claim 12 where the PEG is bi-functional or tetra-functional.

15. The composition of claim 14, wherein the composition is selected from the group consisting of PEG-bi-monoamino tetrac or triac (P-bi-MAT), PEG-bi-diamino tetrac or triac (P-bi-DAT), PEG-bi-triazole tetrac or triac (P-bi-TAT), PEG-tetra-monoamino tetrac (P-tetra-MAT), PEG-tetra-diamino tetrac or triac (P-tetra-DAT), PEG-tetra-triazole tetrac or triac (P-tetra-TAT) and derivatives thereof.