3-3-DI-SUBSTITUTED-OXINDOLES AS INHIBITORS OF TRANSLATION INITIATION

• US 20090299058A1
• Filed: 02/10/2009
• Published: 12/03/2009
• Est. Priority Date: 02/13/2004
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Natarajan, Amarnath, Aktas, Huseyin, Fan, Yun-Hua, Chen, Han, Halperin, Jose A.
• Granted Patent: US 7,846,962 B2
• Time in Patent Office: Days
• US Class Current: 540/456
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• 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 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 209/36 in position 3, e.g. adrenochrome
• CPC Class Codes: C07D 403/02 containing two hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/10 linked by a carbon chain containing aromatic rings

Abstract

Compositions and methods for inhibiting translation using 3-(5-tert-Butyl-2-Hydroxy-phenyl)-3-phenyl-1,3-dihydro-indol-2-one and/or its derivatives are provided. Compositions, methods and kits for treating (1) cellular proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections, using 3-(5-tert-butyl-2-hydroxy-phenyl)-3-phenyl-1,3-dihydro-indol-2-one and/or its derivatives are described.

Claims

1. A compound of formula I:

wherein A is selected from the group consisting of carbocyclic aromatic ring, heterocyclic ring and heteroaromatic ring;

R₁ is selected from the group consisting of (halo)alky, (un)substituted (alkyl)aryl, halogen, CN, COOH, alkenyl, alkynyl, alkoxy and cycloalkoxy;

R₂ is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (un)substituted heteroaromatic, Ar—

NHSO₂Ar and Ar—

NHCOAr;

R₃ is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (un)substituted heteroaromatic, Ar—

NHSO₂Ar and Ar—

NHCOAr;

R₄ is selected from the group consisting of (un)substituted aryl, (un)substituted heterocyclic, (un)substituted heteroaromatic, Ar—

NHSO₂Ar and Ar—

NHCOAr;

X is selected from the group consisting of unsubstituted or substituted nitrogen, oxygen, sulfur and carbon;

Y is selected from the group consisting of unsubstituted or substituted nitrogen, oxygen and sulfur and carbon; and

n=0-4.

2. A compound of formula II:

wherein R₁ is selected from the group consisting of H, 5-bromo, 5-chloro, 7-bromo, 5-iodo, 5-OCF₃, 5-sulfonic acid, 5-nitro, 4-bromo, 6-bromo, 5-ethyl, 7-ethyl, 4-ethyl, 6-ethyl, 7-iodo, 5-fluoro, 7-COOH, 7-COOMe and 4-Cl; and

R₂ is selected from the group consisting of 7-formamide-N-[2-(4-amino-phenyl)-ethyl], 7-CO₂H, 7-CH₂OH, 7-CH₂-N-imidazole and H with the proviso that R₁ and R₂ cannot both be H, and with the further proviso that when R₂ is H, R₁ cannot be 5-chloro, 5-nitro or 5-fluoro.

3. A compound of formula III:

wherein X is selected from the group consisting of oxygen, NH and CH₂; and

R is selected from the group consisting of 3′

-CH₂CH(CO₂Me)NH₂, 3′

-CH₂CH(CO₂Me)NHFmoc, 3′

-t-Bu, 3′

-OH, 3′

-O(CH₂)₃CHCH₂, 3′

-O(CH₂)₄Br, 3′

-O(CH₂)₄NMe₂, 3′

-O(CH₂)₄N₃,

3′

-O(CH₂)₄NH₂, 3′

-CF₃, 3′

-CH₃, 3′

-n-heptyl, 3′

-n-nonyl, 3′

-i-Bu, 3′

-1-propyl, 3′

-n-propyl, 3′

-n-octyl, 3′

-Et, 3′

-n-pentyl, 3′

-n-Bu, 3′

-n-hexyl, 3′

-n-cyclopentyl, 3′

-n-cyclohexyl, 4-NHSO₂(4-tBu)Ph and 3′

-NHSO₂(4-tBu)Ph.

4. A compound of formula IV:

wherein R is selected from the group consisting of 4-F, 4-O(CH₂)₃CHCH₂, 3-Cl, 3-F, 3-Me, 2-Me and 2-OMe.

5. A compound of formula V:

wherein R is selected from the group consisting of —

SO₂-Camphor, —

CO(CH₂)₆CO₂H, —

CO(CH₂)₃CONHOH, —

CH₂CH₂NHBoc, —

CO(CH₂)₃CO₂H, —

CH₂CO₂H, —

CH₂CO-Leu-Phe-CH₂OH and —

CH₂CO₂Me.

6. A compound of formula VI:

wherein R₁ is selected from the group consisting of 7-Br, 4-Cl, 5-Br, 5-NO₂, 5-I, 5-OMe, 5-Cl, 7-CF₃, 5-NH₂, 4-Br, 6-Br, H, 7-OMe, 7-1,5-Et, 7-Et, 4-Et, 6-Et, 5-F, 5-N₃, 7-COOH, 7-CO₂H, 4-Cl, 6-Cl and 5-NHSO₂-1-napthyl; and

R₂ is H or 7-CO₂H.

7. A compound of formula VII:

wherein R₁ is selected from the group consisting of H, 2-OH, 3-O(CH₂)₄NMe₂, 3-O(CH₂)₄N₃, 3-t-Bu, 2-OMe, 3-OMe, 4-OH, 4-OPh, 4-Ph, 4-NMe2, 4-n-propyl, 4-i-Bu, 4-n-Bu, 4-O(CH₂)₂OH, 4-OMe, 2-CH₂CO₂H and 4-t-Bu; and

R₂ is selected from the group consisting of 2-OH, 4-OH, 4-t-Bu and H with the proviso that R₁ and R₂ cannot both be H.

8. A compound of formula VIII:

wherein R₁ is selected from the group consisting of H and 7-CO₂H;

R₂ is selected from the group consisting of H, 2-Me, 3′

-Me, 3-F and 3-CF₃; and

R₃ is selected from the group consisting of H, 2-NHFmoc, 2-NHSO₂CH₂Ph, 2-NHSO₂CH₃, 2-NHSO₂(4-tBu)Ph, 2-NHSO₂(4-NHAc)Ph, 2-NHSO₂(3-CF₃)Ph, 2-NHSO₂(4-NO₂)Ph, 2-NHSO₂(4-OMe)Ph, 2-NHSO₂(4-Br)Ph, 2-NHSO₂(4-I)Ph, 2-NHSO₂(4-Ph)Ph, 2-NHSO₂(4-OPh)Ph, 2-NHAc, 2-NHCO(4-tBu)Ph and 3′

-NHSO₂(4-tBu)Ph.

9. A compound of formula IX:

wherein R is selected from the group consisting of —

CH₂-(4-Cl)Ph, —

CH₂CHCH₂, —

CH₂OH, —

CH₂CO₂H, —

CH₂OCH₂CHCH₂, —

SO₂(4-O-n-Bu)Ph, —

SO₂(4-O-Ph)Ph, —

SO₂(4-NHAc)Ph, —

SO₂(4-CH₂CH₂CO₂Me)Ph, —

SO₂(4-OMe)Ph and —

SO₂(4-t-Bu)Ph.

10. A compound of formula X:

11. A compound of formula XI:

12. A compound of formula XII:

13. A compound of formula XIII:

wherein R is selected from the group consisting of 2-Thiophene, —

(CH₂)₁₁CH₃, —

CH₂Ph, —

CCH, -cyclohexyl and —

C₆F₅.

14. A compound of formula XIV:

wherein R is selected from the group consisting of H, 3-Cl, 3-F, 3-Me and 3-t-Bu.

15. A compound for inhibiting translation, wherein said compound is selected from formulae I-XIV above.