CARBOLINE DERIVATIVES USEFUL IN THE INHIBITION OF ANGIOGENESIS

• US 20100125065A1
• Filed: 07/21/2009
• Published: 05/20/2010
• Est. Priority Date: 03/15/2004
• Status: Active Grant

• Current Assignee: Donald Thomas Corson, Hongyan Qi, Liangxian Cao, Nadarajan Tamilarasu, Seongwoo Hwang, Soongyu Choi, William Joseph Lennox, Young-Choon Moon
• Original Assignee: Donald Thomas Corson, Hongyan Qi, Liangxian Cao, Nadarajan Tamilarasu, Seongwoo Hwang, Soongyu Choi, William Joseph Lennox, Young-Choon Moon
• Inventors: Moon, Young-Choon, Choi, Soongyu, Hwang, Seongwoo, Qi, Hongyan, Cao, Liangxian, Corson, Donald Thomas, Lennox, William Joseph, Tamilarasu, Nadarajan
• Granted Patent: US 8,367,694 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5355 Non-condensed oxazines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/04 Anorexiants; Antiobesity agents
• 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: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

In accordance with the present invention, compounds that inhibit the expression of VEGF post-transcriptionally have been identified, and methods for their use provided. In one aspect of the invention, compounds useful in the inhibition of VEGF production, in the inhibition of angiogenesis, and/or in the treatment of cancer, diabetic retinopathy or exudative macular degeneration are provided. In another aspect of the invention, methods are provided for the inhibition of VEGF production, the inhibition of angiogenesis, and/or the treatment of cancer, diabetic retinopathy or exudative macular degeneration using the compounds of the invention.

Claims

1. A compound having the formula:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R_o is halogen, substituted or unsubstituted C₁ to C₈ alkyl or OR_a;

R_a is H or C₁ to C₈ alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

R_d is phenyl substituted with one or more alkoxy or halogen substituents.

2. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R_o is OR_a;

R_a is H or C₁ to C₈ alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

R_d is phenyl substituted with one or more alkoxy or halogen substituents.

3. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R_a is H or C₁ to C₈ alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

R_d is phenyl substituted with one or more halogen substituents.

4. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R_a is C₁ to C₈ alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

R_d is phenyl substituted at the para position with a halogen substituent.

5. The compound of claim 4, or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein X is chloro.

6. The compound of claim 5, or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein R_d is phenyl substituted at the para position with chloro.

7. The compound of claim 6, or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein R_a is unsubstituted C₁ to C₈ alkyl.

8. The compound of claim 6, or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein R_a is C₁ to C₈ alkyl substituted with one or more hydroxyl substituents.

9. A pharmaceutical composition comprising a compound having the formula:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R_o is halogen, substituted or unsubstituted C₁ to C₈ alkyl or OR_a;

R_a is H or C₁ to C₈ alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

R_d is phenyl substituted with one or more alkoxy or halogen substituents, and a pharmaceutically acceptable excipient.

10. The pharmaceutical composition of claim 9, wherein the compound has the formula:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R_a is OR_a;

R_a is H or C₁ to C₈ alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

R_d is phenyl substituted with one or more alkoxy or halogen substituents.

11. The pharmaceutical composition of claim 10, wherein the compound has the formula:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R_a is H or C₁ to C₈ alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

R_d is phenyl substituted with one or more halogen substituents.

12. The pharmaceutical composition of claim 11, wherein the compound has the formula:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R_a is C₁ to C₈ alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

R_d is phenyl substituted at the para position with a halogen substituent.

13. The pharmaceutical composition of claim 12, wherein X is chloro.

14. The pharmaceutical composition of claim 13, wherein R_d is phenyl substituted at the para position with chloro.

15. The pharmaceutical composition of claim 14, wherein R_a is unsubstituted C₁ to C₈ alkyl.

16. The pharmaceutical composition of claim 14, wherein R_a is C₁ to C₈ alkyl substituted with one or more hydroxyl substituents.