Substituted isoindoles as glucokinase activators

• US 8,394,843 B2
• Filed: 07/18/2011
• Issued: 03/12/2013
• Est. Priority Date: 05/31/2006
• Status: Expired due to Fees

• Current Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda California, Inc.
• Inventors: Feng, Jun, Gwaltney, Stephen L., Skene, Robert J., Tang, Mingnam, Cao, Sheldon X., Stafford, Jeffrey A., Hossfield, David J.
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US13/185,166
• Publication Number:
  US 20110275665A1
• Time in Patent Office: 603 Days
• Field of Search: 548/181, 514/365, 514/365.371
• US Class Current: 514/371
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Compounds are provided which have the formula:

wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture which contain such compounds, methods and intermediates useful for making the compounds, and methods of using the compounds to activate glucokinase.

Claims

1. A compound of the formula:

2. The compound according to claim 1 having the formula:

3. The compound according to claim 1 having the formula:

4. The compound according to claim 1 which is selected from the following compounds:

3-cyclohexyl-2-(1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(1-imino-6-(methylsulfonyl)isoindolin-2-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(1-imino-6-(N-methylsulfamoyl)isoindolin-2-yl)-N-(thiazol-2-yl)propanamide; and

a pharmaceutically acceptable salt of any one of the aforementioned compounds.

5. The compound according to claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt.

6. The compound of claim 1, wherein p is 1.

7. The compound of claim 1, wherein U is CH₂.

8. The compound of claim 1, wherein V is CH.

9. The compound of claim 1, wherein W is selected from the group consisting of CH, C(NO₂) and C(SO₂CH₃).

10. The compound of claim 1, wherein X is selected from the group consisting of CH, CF, C(OCH₃), C(OH), C(SO₂CH₃) and C(SO₂NHCH₃).

11. The compound of claim 1, wherein Y is CH.

12. The compound of claim 1, wherein R₁ is a substituted or unsubstituted hetero(C_3-12)cycloalkyl.

13. The compound of claim 1, wherein R₁ is a substituted or unsubstituted heteroaryl.

14. The compound of claim 1, wherein R₁ is selected from the group consisting of furanyl, thiophenyl, 2H-pyrrolyl, 1,3-dioxoianyl, oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, pyridinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, 3-H-indolyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinuclidinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl, each substituted or unsubstituted.

15. The compound of claim 1, wherein R₃′

is selected from the group consisting of hydrogen, halo, and substituted or unsubstituted (C_1-3)alkyl.

16. The compound of claim 1, wherein R₃ is selected from the group consisting of (C_1-10)alkyl, cycloalkyl(C_1-5)alkyl, heterocycloalkyl(C_1-5)alkyl, aryl(C_1-5)alkyl, and heteroaryl(C_1-5)alkyl, each substituted or unsubstituted.

17. The compound of claim 1, wherein at least one R₄ is selected from the group consisting of hydrogen, halo, hydroxy, amino, nitro, (C_1-3)alkoxy, (C_1-3)alkylsulfonyl, aminosulfonyl and (C_1-10)alkyl, each substituted or unsubstituted.

18. The compound of claim 1, wherein at least one R₅ is selected from the group consisting of hydrogen, halogen and (C_1-3)alkylsulfonyl, each substituted or unsubstituted.

19. The compound of claim 1, wherein at least one R₆ is selected from the group consisting of hydrogen, (C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, aryl(C_1-10)alkyl, heteroaryl(C_1-10)alkyl, (C_9-12)bicycloaryl, hetero(C_8-12)bicycloaryl, each substituted or unsubstituted.

20. A pharmaceutical composition comprising a compound as defined in claim 1;

and one or more pharmaceutically acceptable excipients.