Therapeutic combinations of antihypertensive and antiangiogenics agents

• US 20030144298A1
• Filed: 10/01/2002
• Published: 07/31/2003
• Est. Priority Date: 04/05/2000
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Curwen, Jon Owen, Ogilvie, Donald James
• Granted Patent: US 7,829,573 B2
• Time in Patent Office: Days
• US Class Current: 514/252.17
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 38/556 Angiotensin converting enzyme inhibitors
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The invention concerns the use of a combination of an anti-angiogenic agent and an anti-hypertensive agent for use in the manufacture of a medicament for the treatment of a disease state associated with angiogenesis in a warm-blooded mammal, such as a human being. The invention also relates to pharmaceutical compositions comprising an anti-angiogenic agent and an anti-hypertensive agent, to kits thereof and to a method of treatment of a disease state associated with angiogenesis which comprises the administration of an effective amount of a combination of an anti-angiogenic agent and an anti-hypertensive agent to a warm-blooded animal, such as a human being.

Claims

1. Use of a combination of an anti-angiogenic agent and an anti-hypertensive agent for use in the manufacture of a medicament for the treatment of a disease state associated with angiogenesis in a warm-blooded mammal, such as a human being.

2. Use according to claim 1 wherein the anti-angiogenic agent affects the level of nitric oxide.

3. Use according to claim 1 wherein the anti-angiogenic agent is a VEGF receptor tyrosine kinase inhibitor.

4. Use according to claim 3 wherein the anti-angiogenic agent is selected from:

6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,

4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,

(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline, and

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline;

or a pharmaceutically acceptable salt thereof.

5. Use according to claim 3 wherein the anti-angiogenic agent is a compound of the formula II:

6. Use according to any one of claims 1, 2, 3 and 5 wherein the anti-angiogenic agent is 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4ylmethoxy)quinazoline or a pharmaceutically acceptable salt thereof.

7. Use according to claim 1 wherein the anti-angiogenic agent is a vascular targeting agent.

8. Use according to claim 7 wherein the anti-angiogenic agent is N-acetylcolchinol-O-phosphate.

9. Use according to any one of the preceding claims wherein the anti-hypertensive agent is a calcium channel blocker, an A-II antagonists an ACE inhibitor or a β

-blocker.

10. Use according to any one of the preceding claims wherein the anti-hypertensive agent is an ACE inhibitor.

11. Use according to claim 10 wherein the anti-hypertensive agent is lisinopril or captopril.

12. A pharmaceutical composition, comprising:

a) an anti-angiogenic agent or a pharmaceutically acceptable salt, solvate or pro-drug thereof;

b) an anti-hypertensive agent or a pharmaceutically acceptable salt, solvate or pro-drug thereof; and

optionally

c) a pharmaceutically acceptable carrier or diluent.

13. A kit, for use in producing an anti-angiogenic effect and/or vascular permeability reducing effect in a warm-blooded animal such as a human being, comprising:

a) an anti-angiogenic agent or a pharmaceutically acceptable salt, solvate or pro-drug thereof or a pharmaceutical composition thereof;

b) an anti-hypertensive or a pharmaceutically acceptable salt, solvate or pro-drug thereof or a pharmaceutical composition thereof; and

c) a container means for containing said agents.

14. A method of treatment of a disease state associated with angiogenesis which comprises the administration of an effective amount of a combination of an anti-angiogenic agent and an anti-hypertensive agent to a warm-blooded animal, such as a human being.