Dihydroisoindolones As Allosteric Modulators Of Glucokinase

• US 20070099936A1
• Filed: 10/30/2006
• Published: 05/03/2007
• Est. Priority Date: 11/01/2005
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Zhang, Yongzheng, Rybczynski, Philip, Bian, Hiayan, Dudash, Joseph, Patel, Mona
• Granted Patent: US 7,531,671 B2
• Time in Patent Office: Days
• US Class Current: 514/255.05
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present invention relates to compounds of Formula (I), methods for preparing these compounds, compositions, intermediates and derivatives thereof and for treating glucokinase mediated disorders. More particularly, the compounds of the present invention are glucokinase modulators useful for treating disorders including, but not limited to, type II diabetes.

Claims

1. A compound of Formula (I)

2. The compound of claim 1 wherein

R₁ is C_1-6alkyl optionally substituted with optionally substituted C₆aryl or C₁₀aryl,

R₂ is 0-2 members independently selected from halo;

A is C₆aryl or C₁₀aryl;

B is heteroaryl or heterocyclyl, said heteroaryl being connected to N(1) through a ring carbon atom adjacent to a ring nitrogen, said heterocyclyl being connected to N(1) through a carbon atom that is double-bonded to a ring nitrogen, and additionally said heteroaryl and heterocyclyl having having an additional 0 to 2 heteroatoms selected from S and N, wherein one or more ring nitrogen atoms in said heteroaryl or heterocyclyl can be optionally in an N-oxide form, and said heteroaryl or heterocyclyl being further optionally substituted with 1 or 2 members selected from optionally substituted C_1-4alkyl, optionally substituted C_2-4alkenyl, halo, —

CN, optionally substituted C_6-10aryl, —

C(O)OH, —

C(O)O—

C_1-4alkyl, —

OR₄, —

SR₄, —

C(O)R₄, —

C(O)—

N(R₄)(R₅), —

S(O)₂—

R₄, and —

S(O)₂—

N(R₄)(R₅), wherein R₄ and R₅ are independently selected from H, C_1-6alkyl, aryl, heteroaryl, and heterocyclyl; and

X is optionally substituted C_1-4 alkylene;

or an optical isomer, enantiomer, diastereomer, racemate, prodrug or pharmaceutically acceptable salt thereof.

3. The compound of claim 2 wherein R₁ is methyl substituted with phenyl, said phenyl being optionally substituted with halo, methoxy, dimethoxy, or pyrrolyl.

4. The compound of claim 1 wherein R₂ is 0-2 members independently selected from F and Cl.

5. The compound of claim 1 wherein A is phenyl.

6. The compound of claim 1 wherein B is an optionally substituted member selected

7. The compound of claim 6 wherein B is substituted with 0-2 members selected from halo, C_1-4alkyl, substituted C_1-4alkyl, aryl, substituted aryl, —

C(O)OH, —

C(O)R₄, —

C(O)O—

C_1-4alkyl, and —

S(O)₂—

N(R₄)(R₅).

8. The compound of claim 6 wherein B is substituted with 0-2 members selected from F, Br, —

CH₃, —

CF₃, —

CH₂—

C(O)OH, —

C(O)—

CH₃, —

CH₂—

O—

CH₂—

O—

CH₃, unsubstituted phenyl, halo substituted aryl, —

C(O)OH, —

C(O)O—

CH₃, —

C(O)O—

CH₂—

CH₃, and —

S(O)₂—

NH₂.

9. The compound of claim 1 wherein X is unsubstituted C_1-4 alkylene.

10. The compound of claim 9 wherein X is methylene or ethylene.

11. The compound of claim 1 wherein Y is S.

12. The compound of claim 1 wherein Y is S(O) or S(O)₂.

13. The compound of claim 1 wherein Y is N(H).

14. The compound of claim 1 wherein Y is O.

15. The compound of claim 1 selected from

2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-thiazol-2-yl-acetamide;

2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyrimidin-2-yl-acetamide;

6-[2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-acetyamino]-nicotinic acid;

2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yloxy)-N-pyridin-2-yl-acetamide;

2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylamine)-N-pyridin-2-yl-acetamide;

2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yloxy)-N-thiazol-2-yl-acetamide;

2-[2-(4-Methoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-thiazol-2-yl-acetamide;

2-[2-(4-Chlorobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-thiazol-2-yl-acetamide;

2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyrazin-2-yl-acetamide;

2-(2-Furan-2-ylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-thiazol-2-yl-acetamide;

2-[2-(4-Dimethylaminobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-thiazol-2-yl-acetamide;

6-[2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-acetylamino]-nicotinic acid methyl ester;

6-[2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-acetylamino]-nicotinic acid methyl ester;

{2-[2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-acetylamino]-thiazol-4-yl}-acetic acid ethyl ester;

6-[2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yloxy)-acetylamino]-nicotinic acid methyl ester;

2-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[3-Oxo-2-(3,4,5-trimethoxy-benzyl)-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-{3-Oxo-2-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-2,3-dihydro-1H-isoindol-1-ylsulfanyl}-N-pyridin-2-yl-acetamide;

2-(2-Benzo[1,3]dioxol-5-ylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyridin-2-yl-acetamide;

2-[2-(3,4-Dimethoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-(2-Naphthalen-1-ylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyridin-2-yl-acetamide;

2-(2-Benzo[b]thiophen-5-ylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyridin-2-yl-acetamide;

2-[2-(2,3-Dimethyl-1H-indol-5-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[3-Oxo-2-(4-pyrrol-1-yl-benzyl )-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[3-Oxo-2-(4-pyrazol-1-yl-benzyl)-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

6-{2-[2-(3,4-Dimethoxybenzyl)-4,7-difluoro-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-acetylamino}-nicotinic acid;

2-[3-Oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[2-(4-Methoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[2-(3,4-Dimethoxy-benzyl)-4,7-difluoro-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[2-(4-Dimethylaminobenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[2-(3,4-Dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-(2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yloxy)-N-thiazol-2-yl-acetamide;

6-{2-[2-(4-Fluorobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-acetylamino}-nicotinic acid;

6-{2-[2-(4-Methoxybenzyl)-3-oxo-2,3-dihyd ro-1H-isoindol-1-ylsulfanyl]-acetylamino}-nicotinic acid; and

6-{2-[2-(3,4-Dimethoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-acetylamino}-nicotinic acid.

16. The compound of claim 1 wherein B is N-containing heteroaryl wherein a ring nitrogen in ring B may optionally be in an N-oxide form.

17. The compound of claim 16 wherein B is

18. The compound of claim 1, wherein

R₁ is methyl substituted with phenyl, said phenyl being optionally substituted with halo, methoxy, dimethylamino, or pyrrolyl;

R₂ is 0-2 members independently selected from F and Cl;

A is phenyl;

B is an optionally substituted member selected from

X is methylene or ethylene.

19. The compound of claim 18 wherein B is substituted with 0-2 members selected from halo, C_1-4alkyl, substituted C_1-4alkyl, aryl, substituted aryl, —

C(O)OH, —

C(O)R₄, —

C(O)O—

C_1-4alkyl, and —

S(O)₂—

N(R₄)(R₅).

20. The compound of claim 19 wherein B is substituted with 0-2 members selected from F, Br, —

CH₃, —

CF₃, —

CH₂—

C(O)OH, —

C(O)—

CH₃, —

CH₂—

O—

CH₂—

O—

CH₃, unsubstituted phenyl, halo substituted aryl, —

C(O)OH, —

C(O)O—

CH₃, —

C(O)O—

CH₂—

CH₃, and —

S(O)₂—

NH₂.

21. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.

22. A pharmaceutical composition of claim 21, further comprising at least one additional agent, drug, medicament, antibody and/or inhibitor for treating, ameliorating or preventing a glucokinase mediated disease.

23. The pharmaceutical composition of claim 21 comprising at least one compound selected from

2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-thiazol-2-yl-acetamide;

2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyrimidin-2-yl-acetamide;

6-[2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-acetyamino]-nicotinic acid;

2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yloxy)-N-pyridin-2-yl-acetamide;

2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylamine)-N-pyridin-2-yl-acetamide;

2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yloxy)-N-thiazol-2-yl-acetamide;

2-[2-(4-Methoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-thiazol-2-yl-acetamide;

2-[2-(4-Chlorobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-thiazol-2-yl-acetamide;

2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyrazin-2-yl-acetamide;

2-(2-Furan-2-ylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-thiazol-2-yl-acetamide;

2-[2-(4-Dimethylaminobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-thiazol-2-yl-acetamide;

6-[2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-acetylamino]-nicotinic acid methyl ester;

6-[2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-acetylamino]-nicotinic acid methyl ester;

{2-[2-(3-Oxo-2-thiophen-2-ylmethyl-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-acetylamino]-thiazol-4-yl}-acetic acid ethyl ester;

6-[2-(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yloxy)-acetylamino]-nicotinic acid methyl ester;

2-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[3-Oxo-2-(3,4,5-trimethoxy-benzyl)-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-{3-Oxo-2-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-2,3-dihydro-1H-isoindol-1-ylsulfanyl}-N-pyridin-2-yl-acetamide;

2-(2-Benzo[1,3]dioxol-5-ylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyridin-2-yl-acetamide;

2-[2-(3,4-Dimethoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-(2-Naphthalen-1-ylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyridin-2-yl-acetamide;

2-(2-Benzo[b]thiophen-5-ylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl)-N-pyridin-2-yl-acetamide;

2-[2-(2,3-Dimethyl-1H-indol-5-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[3-Oxo-2-(4-pyrrol-1-yl-benzyl )-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[3-Oxo-2-(4-pyrazol-1-yl-benzyl)-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

6-{2-[2-(3,4-Dimethoxybenzyl)-4,7-difluoro-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-acetylamino}-nicotinic acid;

2-[3-Oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[2-(4-Methoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[2-(3,4-Dimethoxy-benzyl)-4,7-difluoro-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[2-(4-Dimethylaminobenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-[2-(3,4-Dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-N-pyridin-2-yl-acetamide;

2-(2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yloxy)-N-thiazol-2-yl-acetamide;

6-{2-[2-(4-Fluorobenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-acetylamino}-nicotinic acid;

6-{2-[2-(4-Methoxybenzyl)-3-oxo-2,3-dihyd ro-1H-isoindol-1-ylsulfanyl]-acetylamino}-nicotinic acid; and

6-{2-[2-(3,4-Dimethoxybenzyl)-3-oxo-2,3-dihydro-1H-isoindol-1-ylsulfanyl]-acetylamino}-nicotinic acid.

24. The pharmaceutical composition of claim 21 comprising at least one compound of Formula (I) wherein Y is S.

25. A method for treating or ameliorating a glucokinase-mediated condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of claim 1.

26. The method of claim 25 wherein the glucokinase-mediated condition is selected from diabetes, obesity, and associated symptoms or complications thereof.

27. The method of claim 25 wherein the glucokinase mediated condition is selected from obesity, IDDM, NIDDM, IGT, IFG, Syndrome X, hyperglycemia, elevated blood glucose level, and insulin resistance.

28. The method of claim 26 or 27 comprising admistering to the subject a therapeutically effective amount of (a) at least one compound of claim 1;

and (b) at least one adittional agent selected from a glucokinase modulator, an anti-diabetic agent, a lipid lowering agent, an anti-thrombotic agent, direct thrombin inhibitor, and a blood pressure lowering agent, said administration being in any order.

29. The method of claim 28 wherein the additional agent is a glucokinase modulator.

30. A method for preventing or inhibiting the onset of a glucokinase-mediated condition in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of at least one compound according to claim 1.

31. The method of claim 30 wherein the glucokinase-mediated condition is selected from diabetes, obesity, and associated symptoms or complications thereof.

32. The method of claim 30 wherein the glucokinase mediated condition is selected from obesity, IDDM, NIDDM, IGT, IFG, Syndrome X, hyperglycemia, elevated blood glucose level, and insulin resistance.

33. The method of claim 31 or 32 comprising administering to said subject a therapeutically effective amount of (a) at least one compound according to claim 1;

and (b) at least one additional agent selected from the group consisting of a glucokinase modulator, an anti-diabetic agent, a lipid lowering agent, an anti-thrombotic agent, direct thrombin inhibitor, and a blood pressure lowering agent, said co-administration being in any order and the combined amounts providing the desired prophylactic effect.

34. The method of claim 33 wherein the additional agent is a glucokinase modulator.

35. A process for making a pharmaceutical composition comprising admixing any of the compounds according to claim 1 and a pharmaceutically acceptable carrier.

36. The method of claim 25 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 10 mg/kg/day.

37. The method of claim 30 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 10 mg/kg/day.