Lactam glycogen phosphorylase inhibitors and method of use

• US 20040002495A1
• Filed: 05/19/2003
• Published: 01/01/2004
• Est. Priority Date: 05/20/2002
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Wu, Gang, Stouch, Terry, Sher, Philip, Ellsworth, Bruce
• Granted Patent: US 7,057,046 B2
• Time in Patent Office: Days
• US Class Current: 514/228.2
• 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 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 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 513/04 Ortho-condensed systems

Abstract

A compound of formula I

wherein

W is a bicyclic hetroaryl of the structure

X is —O—, —S—, —SO₂—, —CHR⁵—, —CHR⁵O—, —CHR⁵S—, —CHR⁵SO₂—, —CHR⁵CO— or —CH₂CHR⁵—;

Y is a bond or —CHR⁶—;

Z is an aryl or heteroaryl group of the following structure:

A is —CH— or —N—;

B is —O— or —S—; and

R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as described herein.

Further provided is a method for treating diabetes and related diseases employing a glycogen phosphorylase inhibiting amount of the above compound, either alone or in combination with another therapeutic agent.

Claims

1. A compound of the formula I

2. The compound as defined in claim 1 wherein Z is an aryl or heteroaryl group of the structure

3. A compound as defined in claim 1 wherein said hydrogen bonding group is selected from the group consisting of OR^9A, OCO₂R¹⁰, OCONR^9AR^9B, CN, NO₂, CN₄R^9A (tetrazole), COCF₃, COR^9A, CO₂R^9A, CONR^9AR^9B, CONR^9AOR^9B, C(NR^9A)NR^9BR^9C, CONR^9ASO₂R^9B, SOR¹⁰, SO₂R¹⁰, SO₃H, SO₂NR^9AR^9B, SO₂NR^9ACOR^9B, SO₂NR^9ACONR^9BR^9C, POR^9AR^9B, PO₂R^9AR^9B, PO₃R^9AR^9B, PO₂R^9ANR^9BR^9C, NR^9AR^9B, NR^9ACOR^9B, NR^9AC(NR^9B)R^9C, NR^9ACO₂R^9B, NR^9ACONR^9BR^9C, NR^9AC(NR^9B) NR^9CR^9D, NR^9ASO₂R^9B, NR^9ACONR^9B SO₂R^9C, NR^9ASO₂NR^9BR^9C, NR^9APOR^9BR^9C, NR^9APO₂R^9BR^9C, NR^9APO₃R^9BR^9C and NR^9APO₂R^9BNR^9CR^9D;

wherein

R^9C and R^9D are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and

R¹⁰ is independently alkyl, arylalkyl, heteroarylalkyl, or aryl;

wherein R^9A, R^9B, R^9C, R^9D or R¹⁰ may further be substituted with one to three additional hydrogen bonding groups;

and wherein

two of R^9A, R^9B, R^9C or R^9D within the same hydrogen bonding group may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups.

4. A pharmaceutical composition that inhibits the enzyme glycogen phosphorylase comprising a compound of formula I

5. The pharmaceutical composition of claim 4 wherein

z is an aryl or heteroaryl group of the structure

6. The pharmaceutical composition of claim 4 wherein said hydrogen bonding group is selected from the group consisting of OR^9A, OCO₂R¹⁰, OCONR^9AR^9B, CN, NO₂, CN₄R^9A (tetrazole), COCF₃, COR^9A, CO₂R^9A, CONR^9AR^9B, CONR^9AOR^9B, C(NR^9A)NR^9BR^9C, CONR^9ASO₂R^9B, SOR¹⁰, SO₂R¹⁰, SO₃H, SO₂NR^9AR^9B, SO₂NR^9ACOR^9B, SO₂NR^9ACONR^9BR^9C, POR^9AR^9B, PO₂R^9AR^9B, PO₃R^9AR^9B, PO₂R^9ANR^9BR^9C, NR^9AR^9B, NR^9ACOR^9B, NR^9AC(NR^9B)R^9C, NR^9ACO₂R^9B, NR^9ACONR^9BR^9C, NR^9AC(NR^9B) NR^9CR^9D, NRSO₂R^9B, NR^9ACONR^9BSO₂R^9C, NR^9ASO₂NR^9BR^9C, NR^9APOR^9BR^9C, NR^9APO₂R^9BR^9C, NR^9APO₃R^9BR^9C and NR^9APO₂R^9BNR^9CR⁹D;

wherein

R^9C and R^9D are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and

R¹⁰ is independently alkyl, arylalkyl, heteroarylalkyl, or aryl;

wherein R^9A, R^9B, R^9C, R^9D or R¹⁰ may further be substituted with one to three additional hydrogen bonding groups;

and wherein

two of R^9A, R^9B, R^9C or R^9D within the same hydrogen bonding group may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups.

7. The pharmaceutical composition of claim 4 wherein

R¹ is hydrogen;

Z is

 

and

W is

8. The pharmaceutical composition of claim 4 wherein

Z is

9. The pharmaceutical composition of claim 4 wherein W is 5-chloroindol-2-yl.

10. The pharmaceutical composition of claim 4 wherein

X is —

CHR⁵—

, —

CHR⁵O—

, —

CHR⁵S—

, —

CHR⁵SO₂—

, —

CHR⁵CO—

or —

CH₂CHR⁵—

;

Y is —

CHR⁶—

; and

R⁵ or R⁶ are CO₂H.

11. The pharmaceutical composition of claim 4 wherein the compound of formula I has the structure:

3-(5-chloroindole-2-carbonylamino)-5-methoxy-3,4-dihydrocarbostyril;

3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (R)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-1-(2-hydroxyethyl)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-1-aminocarbonylmethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-1-aminocarbonylmethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-3-(5-chloroindole-2-carbonylamino)-1-methyl-3,4-dihydrocarbostyril;

(S)-3-(5-chloroindole-2-carbonylamino)-1-methyl-3,4-dihydrocarbostyril;

(S)-1-allyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-3-(5-chloroindole-2-carbonylamino)-1-cyanomethyl-3,4-dihydrocarbostyril;

(R)-3-(5-chloroindole-2-carbonylamino)-1-cyanomethyl-3,4-dihydrocarbostyril;

3-(5-chloroindole-2-carbonylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one;

(S)-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(R)-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(2S,3S)-3-(5-chloroindole-2-carbonylamino)-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(2S,3R)-3-(5-chloroindole-2-carbonylamino)-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzthiazepin-4(5H)-one;

3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzthiazepin-4(5H)-one S,S-dioxide;

(S)-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzthiazepin-4(5H)-one;

(S)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one;

(R)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one;

1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzthiazepin-4(5H)-one;

1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzthiazepin-4(5H)-one S,S-dioxide;

(S)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(R)-4-(5-chloroindole-2-carbonylamino)-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one;

(S)-4-(5-chloroindole-2-carbonylamino)-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one;

(S)-9-aza-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(S)-7-aza-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

3-(indole-2-carbonylamino)-3,4-dihydrocarbostyril;

(3R*,4S*)-4-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(3R*,4R*)-4-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(3R*,4S*)-4-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(3R*,4S*)-4-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

4-benzylaminocarbonylmethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril.

12. The pharmaceutical composition of claim 4 further comprising a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 4 further comprising at least one additional therapeutic agent selected from the group consisting of other compounds of formula I, anti-diabetic agents, anti-obesity agents, anti-hypertensive agents, anti-atherosclerotic agents, anti-ischemic agents, anti-infective agents, anti-cancer agents and lipid-lowering agents.

14. The pharmaceutical composition of claim 13 comprising a compound of formula I and at least one anti-diabetic agent.

15. The pharmaceutical composition of claim 14 wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR alpha/gamma dual agonist, an aP2 inhibitor, an SGLT2 inhibitor, a dipeptidyl peptidase-IV inhibitor, an insulin sensitizer, a thiazolidinedione, a glucagon-like peptide-1 (GLP-1), an aldose reductase inhibitor, a sorbitol dehydrogenase inhibitor, insulin and a meglitinide.

16. The pharmaceutical composition of claim 14 wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902 and NVP-DPP-728A.

17. The pharmaceutical composition of claim 13 wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound and an anorectic agent.

18. The pharmaceutical composition of claim 13 wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

19. The pharmaceutical composition of claim 13 wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, a cholesterol absorption inhibitor, an ileal Na+/bile cotransporter inhibitor, a bile acid sequestrant, a nicotinic acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor and an ACAT inhibitor.

20. The pharmaceutical composition of claim 13 wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, CP-529414, and/or LY295427.

21. The pharmaceutical composition of claim 13 comprising a compound of formula I and at least one anti-hypertensive agent.

22. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, dislipidemia, obesity, hypertriglyceridemia, atherosclerosis, glucose intolerance,

ischemia, hypertension, cancer or infection, which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of the pharmaceutical composition as defined in claim 4.

23. The method according to claim 22 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of other compounds of formula I, anti-diabetic agents, anti-obesity agents, anti-hypertensive agents, anti-atherosclerotic agents, anti-ischemic agents, anti-infective agents, anti-cancer agents and lipid-lowering agents.

24. A method of inhibiting the enzyme glycogen phosphorylase which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of compound of formula I

25. The method of claim 24 wherein

Z is an aryl or heteroaryl group of the structure

26. The method of claim 24 wherein said hydrogen bonding group is selected from the group consisting of OR^9A, OCO₂R¹⁰, OCONR^9AR^9B, CN, NO₂, CN₄R^9A (tetrazole), COCF₃, COR^9A, CO₂R^9A, CONR^9AR^9B, CONR^9AOR^9B, C(NR^9A) NR^9BR^9C, CONR^9ASO₂R^9B, SOR¹⁰, SO₂R¹⁰, SO₃H, SO₂NR^9AR^9B, SO₂NR^9ACOR^9B, SO₂NR^9ACONR^9BR^9C, POR^9AR^9B, PO₂R^9AR^9B, PO₃R^9AR^9B, PO₂R^9ANR^9BR^9C, NR^9AR^9B, NR^9A COR^9B, NR^9AC(NR^9B) R^9C, NR^9ACO₂R^9B, NR^9ACONR^9BR^9C, NR^9AC(NR^9B) NR^9CR^9D, NR^9ASO₂R^9B, NR^9ACONR^9BSO₂R^9C, NR^9ASO₂NR^9BR^9C, NR^9APOR^9BR^9C, NR^9APO₂R^9BR^9C, NR^9APO₃R^9BR^9C and NR^9APO₂R^9BNR^9CR^9D;

wherein

R^9C and R^9D are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and

R¹⁰ is independently alkyl, arylalkyl, heteroarylalkyl, or aryl;

wherein R^9A, R^9B, R^9C R^9D or R¹⁰ may further be substituted with one to three additional hydrogen bonding groups;

and wherein

two of R^9A, R^9B, R^9C or R^9D within the same hydrogen bonding group may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups.