Method of inhibiting angiogenesis

• US 20060030597A1
• Filed: 03/22/2005
• Published: 02/09/2006
• Est. Priority Date: 11/20/1998
• Status: Abandoned Application

• Current Assignee: Mary E. Gerritsen, Xiaohua Xin
• Original Assignee: Mary E. Gerritsen, Xiaohua Xin
• Inventors: Gerritsen, Mary E., Xin, Xiaohua
• Application Number:
  US11/085,982
• Publication Number:
  US 20060030597A1
• Time in Patent Office: Days
• US Class Current: 514/340
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/37 involving peptidase or proteinase
• CPC Class Codes: G01N 2333/515 Angiogenesic factors; Angiogenin
• CPC Class Codes: G01N 2333/96486 Metalloendopeptidases (3.4.24)
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity

Abstract

Angiogenesis is inhibited and the growth of tumors is treated by administering an effective amount of a PPAR gamma ligand/agonist, optionally with an RXR receptor ligand.

Claims

1. A method of inhibiting angiogenesis comprising:

(a) identifying a patient in need of an angiogenesis inhibitor; and

(b) administering to the patient a therapeutically effective amount of a PPAR gamma ligand, wherein angiogenesis is inhibited in the patient.

2. The method of claim 1, wherein the patient is a mammal.

3. The method of claim 2, wherein the mammal is human.

4. The method of claim 1, wherein the therapeutically effective amount of a PPAR gamma ligand is an angiogenesis inhibiting amount.

5. The method of claim 1, further comprising administering a therapeutically effective amount of an RXR receptor ligand.

6. The method of claim 1, wherein the PPAR gamma ligand is selected from the group consisting of (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy] phenyl]methyl]-2,4-thiazolidinedione:

(troglitazone);

5-[4-[2-(5-ethylpyridin-2-yl) ethoxyl]benzyl]thiadiazolidine-2,4-dione;

(pioglitazone);

5-[4-[(1-methylcyclohexyl) methoxy]benzyl]thiadiazolidine-2,4-dione;

(ciglitazone);

4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide;

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino] ethoxy]benzyl]-5-methylthiazolidine-2,4-dione;

5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl) ethoxy]benzyl]thiazolidine-2,4-dione;

5-[4-[2[N-methyl-N-(phenoxycarbonyl)amino] ethoxy] benzyl]thiazolidine-2,4-dione;

5-[4-[2-phenoxyethoxy) benzyl]thiazolidine-2,4-dione;

5-[4-[2-(4-chlorophenyl) ethylsulfonyl]benzyl]thiazolidine-2,4-dione;

5-[4-[3-(5-methyl-2-phenyloxazol-4-yl) propionyl]benzyl]thiazolidine-2,4-dione;

5-[[4-(3-hydroxy-1-methylcyclohexyl) methoxy]benzyl]thiadiazolidine-2,4-dione;

5-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxyl]benzyl]thiadiazolidione-2,4-dione;

5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiadiazoline-2,4-dione;

(englitazone);

5-[[2-(2-naphthylmethyl) benzoxazol]-5-ylmethyl] thiadiazoline-2,4-dione;

5-[4-[2-(3-phenylureido)ethoxyl] benzyl]thiadiazoline-2,4-dione;

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzy]thiadiazoline-2,4-dione;

5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiadiazoline-2,4-dione;

5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl)benzofuran-5-ylmethyl]-oxazolidine-, 4-dione;

5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione (BRL 49653); and

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino] ethoxy]benzyl]-oxazolidine-2,4-dione.

7. The method of claim 1, wherein the PPAR gamma ligand is selected from the group consisting of PGA₁, PGA₂, PGB₁, PGB₂, PGD₁, PGD₂, PDJ₂, 15-deoxy-12,14-delta-PGJ₂, and 12-delta-PGJ₂.

8. The method of claim 1, wherein the PPAR gamma ligand is a fatty acid containing about 10 to about 26 carbon atom and zero to about 6 carbon-carbon double bonds or carbon-carbon triple bonds.

9. The method of claim 1, wherein the patient has a disease or disorder characterized by undesirable excessive neovascularization.

10. The method of claim 9, wherein the disease or disorder is selected from the group consisting of a neoplasm, rheumatoid arthritis, psoriasis, atherosclerosis, diabetic and other retinopathy, endometriosis, retrolental fibroplasia, age-related macular degeneration, neovascular glaucoma, thyroid hyperplasia, tissue transplantation, lung inflammation, obesity, and chronic inflammation.

11. The method of claim 10, wherein the neoplasm is a solid malignant tumor.

12. A method of inhibiting angiogenesis in a patient, comprising:

(a) identifying a patient with a disease or disorder selected from the group consisting of a neoplasm, rheumatoid arthritis, psoriasis, atherosclerosis, thyroid hyperplasia, endometriosis, lung inflammation, obesity, and chronic inflammation; and

(b) administering an angiogenesis inhibiting amount of a PPAR gamma ligand, wherein angiogenesis is inhibited in the patient.

13. The method of claim 12, wherein the patient is a mammal.

14. The method of claim 13, wherein the mammal is a human

15. The method of claim 12, further comprising administering a therapeutically effective amount of an RXR receptor ligand.

16. The method of claim 12, wherein the PPAR gamma ligand is selected from the group consisting of (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy] phenyl]methyl]-2,4-thiazolidinedione:

(troglitazone);

5-[4-[2-(5-ethylpyridin-2-yl) ethoxyl]benzyl]thiadiazolidine-2,4-dione;

(pioglitazone);

5-[4-[(1-methylcyclohexyl) methoxy]benzyl]thiadiazolidine-2,4-dione;

(ciglitazone);

4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide;

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino] ethoxy]benzyl]-5-methylthiazolidine-2,4-dione;

5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl) ethoxy]benzyl]thiazolidine-2,4-dione;

5-[4-[2[N-methyl-N-(phenoxycarbonyl)amino) ethoxy] benzyl]thiazolidine-2,4-dione;

5-[4-[2-phenoxyethoxy) benzyl]thiazolidine-2,4-dione;

5-[4-[2-(4-chlorophenyl)ethylsulfonyl]benzyl]thiazolidine-2,4-dione;

5-[4-[3-(5-methyl-2-phenyloxazo[4 yl) propionyl]benzyl]thiazolidine-2,4-dione;

5-[[4-(3-hydroxy-1-methylcyclohexyl) methoxy]benzyl]thiadiazolidine-2,4-dione;

5-[4-[2-(5-methyl-2-phenyloxazolyl)ethoxyl]benzyl]thiadiazolidione-2,4-dione;

5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiadiazoline-2,4-dione;

(englitazone);

5-[[2-(2-naphthylmethyl)benzoxazol]-5-ylmethyl] thiadiazoline-2,4-dione;

5-[4-[2-(3-phenylureido)ethoxyl] benzyl]thiadiazoline-2,4-dione;

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzy]thiadiazoline-2,4-dione;

5-[4-[3-(5-methyl-2-phenyloxazol-4-yl) propionyl]benzyl]thiadiazoline-2,4-dione;

5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl) benzofuran-5-ylmethyl]-oxazolidine-, 4-dione;

5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione (BRL

     49653); and

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino] ethoxy]benzyl]-oxazolidine-2,4-dione.

17. The method of claim 12, wherein the PPAR gamma ligand is selected from the group consisting of PGA₁, PGA₂, PGB₁, PGB₂, PGD₁, PGD₂, PDJ₂, 15-deoxy-12,14-delta-PGJ₂, and 12-delta-PGJ₂.

18. The method of claim 12, wherein the PPAR gamma ligand is a fatty acid containing about 10 to about 26 carbon atoms and zero to about 6 carbon-carbon double bonds or carbon-carbon triple bonds.

19. A method of providing an article of manufacture for inhibiting angiogenesis in a patient, comprising the step of providing:

(a) a container comprising a composition having a therapeutically effective amount of a PPAR gamma ligand therein; and

(b) an indication that the composition can be used to inhibit angiogenesis.

20. The method of claim 19, wherein the patient is a mammal.

21. The method of claim 20, wherein the mammal is human.

22. The method of claim 19, wherein the therapeutically effective amount of a PPAR gamma ligand is an angiogenesis inhibiting amount.

23. The method of claim 19, further comprising the step of providing a composition comprising a therapeutically effective amount of an RXR receptor ligand.

24. The method of claim 19, wherein the PPAR gamma ligand is selected from the group consisting of (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy] phenyl]methyl]-2,4-thiazolidinedione:

(troglitazone);

5-[4-[2-(5-ethylpyridin-2-yl) ethoxyl]benzyl]thiadiazolidine-2,4-dione;

(pioglitazone);

5-[4-[(1-methylcyclohexyl) methoxy]benzyl]thiadiazolidine-2,4-dione;

(ciglitazone);

4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide;

5-[4-[2-N-(benzoxazol-2-yl)-N-methylamino] ethoxy]benzyl]-5-methylthiazolidine-2,4-dione;

5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl) ethoxy]benzyl]thiazolidine-2,4-dione;

5-[4-[2[N-methyl-N-(phenoxycarbonyl)amino] ethoxy] benzyl]thiazolidine-2,4-dione;

5-[4-[2-phenoxyethoxy) benzyl]thiazolidine-2,4-dione;

5-[4-[2-(4-chlorophenyl) ethylsulfonyl]benzyl]thiazolidine-2,4-dione;

5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione;

5-[[4-(3-hydroxy-1-methylcyclohexyl) methoxy]benzyl]thiadiazolidine-2,4-dione;

5-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxyl]benzyl]thiadiazolidione-2,4-dione;

5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiadiazoline-2,4-dione;

(englitazone);

5-[[2-(2-naphthylmethyl) benzoxazol]-5-ylmethyl] thiadiazoline-2,4-dione;

5-[4-[2-(3-phenylureido)ethoxyl] benzyl]thiadiazoline-2,4-dione;

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzy]thiadiazoline-2,4-dione;

5-[4-[3-(5-methyl-2-phenyloxazol-4-yl) propionyl]benzyl]thiadiazoline-2,4-dione;

5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl)benzofuran-5-ylmethyl-oxazolidine-, 4-dione;

5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione (BRL 49653); and

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino] ethoxy]benzyl]-oxazolidine-2,4-dione.

25. The method of claim 19, wherein the PPAR gamma ligand is selected from the group consisting of PGA₁, PGA₂, PGB₁, PGB₂, PGD₁, PGD₂, PDJ₂, 15-deoxy-12,14-delta-PGJ₂, and 12-delta-PGJ₂.

26. The method of claim 19, wherein the PPAR gamma ligand is a fatty acid containing about 10 to about 26 carbon atoms and zero to about 6 carbon-carbon double bonds or carbon-carbon triple bonds.

27. The method of claim 19, wherein a label provides the indication.

28. An article of manufacture for inhibiting angiogenesis prepared by the method of claim 19.

29. An article of manufacture for inhibiting angiogenesis comprising:

(a) a container;

(b) a composition within the container comprising a therapeutically effective amount of a PPAR gamma ligand; and

(c) an indication that the composition can be used to inhibit angiogenesis.