C-aryl glucoside SGLT2 inhibitors and method

• US 6,414,126 B1
• Filed: 10/04/2000
• Issued: 07/02/2002
• Est. Priority Date: 10/12/1999
• Status: Expired due to Term

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Washburn, William N., Meng, Wei, Wu, Gang, Sher, Philip M., Ellsworth, Bruce
• Primary Examiner(s): Gitomer, Ralph
• Assistant Examiner(s): Khare, Devesh
• Application Number:
  US09/679,027
• Time in Patent Office: 636 Days
• Field of Search: 536/1.11, 536/17.2, 536/17.3, 536/17.4, 536/17.5, 536/18.4, 514/866, 514/25
• US Class Current: 536/17.2
• 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 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7034 attached to a carbocyclic compound, e.g. phloridzin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07C 43/225 containing halogen
• CPC Class Codes: C07C 45/46 Friedel-Crafts reactions
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07H 15/203 Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Abstract

SGLT2 inhibiting compounds are provided having the formula

where

R¹, R², and R^2a are independently hydrogen, OH, OR⁵, lower alkyl, CF₃, OCHF₂, OCF₃, SR⁵ⁱ or halogen, or two of R¹, R² and R^2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle;

R³ and R⁴ are independently hydrogen, OH, OR^5a, OAryl, OCH₂Aryl, lower alkyl, cycloalkyl, CF₃, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^5b, —CO₂H, —COR^6b, —CH(OH)R^6c, —CH(OR^5h)R^6d, —CONR⁶R^6a, —NHCOR^5c, —NHSO₂R^5d, —NHSO₂Aryl, Aryl, —SR^5e, —SOR^5f, —SO₂R^5g, —SO₂Aryl, or a five, six or seven membered heterocycle, or R³ and R⁴ together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle;

R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g, R^5h and R⁵ⁱ are independently lower alkyl;

R⁶, R^6a, R^6b, R^6c and R^6d are independently hydrogen, alkyl,aryl, alkylaryl or cycloalkyl, or R⁶ and R^6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle;

A is O, S, NH, or (CH₂)_n where n is 0-3.

A method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above compound alone or in combination with another antidiabetic agent or other therapeutic agent.

Claims

1. A compound having the structure

wherein

R¹, R² and R^2a are independently hydrogen, OH, OR⁵, alkyl, CF₃, OCHF₂, OCF₃, SR⁵ⁱ or halogen, or two of R¹, R² and R^2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

R³ and R⁴ are independently hydrogen, OH, OR^5a, OAryl, OCH₂Aryl, alkyl, cycloalkyl, CF₃, —

OCHF₂, —

OCF₃, halogen, —

CN, —

CO₂R^5b, —

CO₂H, COR^6b, —

CH(OH)R^6c, —

CH (OR^5h)R^6d, —

CONR⁶R^6a, —

NHCOR^5c, —

NHSO₂R^5d, —

NHSO₂Aryl, Aryl, —

SR^5e, —

SOR^5f, —

SO₂R^5g, —

SO₂Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³ and R⁴ together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g, R^5h and R⁵ⁱ are independently alkyl;

R⁶, R^6a, R^6b, R^6c, and R^6d are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R⁶ and R^6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

A is O, S, NH, or (CH₂)_n, where n is 0-3, or a pharmaceutically acceptable salt, stereoisomer, or prodrug ester thereof;

with the proviso that where A is (CH₂)_n where n is 0,1,2, or 3 or A is O, and at least one of R¹, R², and R^2a is OH or OR⁵, then at least one of R¹, R², and R^2a is CF₃, OCF₃, or OCHF₂ and/or at least one of R³ and R⁴ is CF₃, —

OCHF₂, —

OCF₃, —

CN, —

CO₂R^5b, CH(OR^5h)R^6d, CH(OH)R^6c, COR^6b, —

NHCOR^5c, —

NHSO₂R^5d, —

NHSO₂Aryl, Aryl, —

SR^5e, —

SOR^5f, —

SO₂R^5g or —

SO₂Aryl.

2. The compound as defined in claim 1 with the proviso that where A is (CH₂)_n where n is 0,1,2, or 3 or A is O, and at least one of R¹, R², R^2a, R³ and R⁴ is OH or OR⁵, then at least one of R¹, R², and R^2a is CF₃, OCF₃, or OCHF₂ and/or at least one of R³ and R⁴ is CF₃, —

OCHF₂, —

OCF₃, —

CN, —

CO₂R^5b, CH(OR^5h)R^6d, —

NHCOR^5c, —

NHSO₂R^5d, —

NHSO₂Aryl, Aryl, —

SR^5e, —

SOR^5f, —

SO₂R^5g, —

SO₂Aryl or halogen.

3. The compound as defined in claim 1 having the structure

4. The compound as defined in claim 1 wherein A is (CH₂)_n.

5. The compound as defined in claim 3 wherein A is CH₂ or O or S.

6. The compound as defined in claim 1 wherein A is CH₂ or O or S;

R¹, R² and R^2a are independently selected from H, lower alkyl, halogen, OR⁵, or OCHF₂, or two of R¹, R² and R^2a are H and the other is lower alkyl, halogen, OR⁵, or OCHF₂;

R³ and R⁴ are independently selected from lower alkyl, OR^5a, —

OCHF₂, —

SR^5e, OH, CO₂R^5b, -3,4-(O—

CH₂—

O)—

, —

COR^6b, —

CH(OH)R^6c, —

CH(OR^5h)R^6d, CF₃,

 

—

SOR^5f, —

SO₂R^5g, Aryl, —

NHSO₂Aryl, —

NHSO₂R^5d, CO₂H, thiadizole, tetrazole, OCH₂Aryl, —

OCF₃, OAryl, or H.

7. The compound as defined in claim 6 wherein A is CH₂;

R¹ is hydrogen, halogen or lower alkyl;

R² and R^2a are each H;

R³ is H;

R⁴ is lower alkyl, —

COR^6b, —

CH(OH)R^6c, —

CH(OR^5h)R^6d, R^5aO, —

OCHF₂, —

OCF₃ or —

SR^5e.

8. The compound as defined in claim 7 where A is CH₂;

R¹ is hydrogen, halogen or lower alkyl; and

R⁴ is lower alkyl, R^5aO, —

OCHF₂, or —

SR^5e.

9. The compound as defined in claim 7 wherein R⁴ is 4-C₂H₅.

10. The compound as defined in claim 3 having the structure

11. The compound as defined in claim 1 having the structure set out as follows:

where A is CH₂ and meta to the glucoside, R¹, R² and R^2a are each H, and R³ is as follows;

4-Me, 4-OH, 3-Me, H, 3-OMe, 4-CO₂Me, 3,4-(OCH₂O), 4-CF₃, 4-NHAc, 4-SO₂Me, 4-Ph, 4-NHSO₂Ph-4′

-Me, 4-NHSO₂Me, 4-CO₂H, 4-Thiadiazole, 4-Tetrazole, 4-OCH₂Ph-4′

-CN, 4-OCHF₂, 4-isopropyl, 2-isopropyl, 4-O-n-propyl, 4-Tetrazole-2′

-Me, 4-Tetrazole-1′

-Me, 4-OPh, 4-n-propyl, 4-n-butyl, 4-SO₂Et, 4-SO₂-n-propyl, 4-SO₂Ph or 4-SOMe.

12. The compound as defined in claim 1 having the structure:

13. The compound as defined in claim 1 having the structure:

where

14. The compound as defined in claim 1 having the structure

15. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

16. A pharmaceutical combination comprising an SGLT2 inhibitor compound as defined in claim 1 and an antidiabetic agent other than an SGLT2 inhibitor, an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic agent, and/or a lipid-lowering agent.

17. The pharmaceutical combination as defined in claim 16 comprising said SGLT2 inhibitor compound and an antidiabetic agent.

18. The combination as defined in claim 17 wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a PPAR α

/γ

dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin, a meglitinide, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, and/or a glucos-6-phosphatase inhibitor.

19. The combination as defined in claim 18 wherein the antidiabetic agent is 1, 2, 3 or more 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/or NVP-DPP-728A.

20. The combination as defined in claim 17 wherein the SGLT2 inhibitor compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 300:

1.

21. The combination as defined in claim 16 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, and/or an anorectic agent.

22. The combination as defined in claim 21 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol.

23. The combination as defined in claim 16 wherein the lipid lowering agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.

24. The combination as defined in claim 23 wherein the lipid lowering agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, atavastatin, rosuvastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, and/or LY295427.

25. The combination as defined in claim 23 wherein the SGLT2 inhibitor is present in a weight ratio to the lipid-lowering agent within the range from about 0.01 to about 300:

1.

26. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

27. The method as defined in claim 26 where the SGLT2 inhibitor compound has the structure

28. A method for treating type II diabetes which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1 alone or in combination with another antidiabetic agent, an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an anti-atherosclerotic agent and/or a hypolipidemic agent.

29. A compound having the structure

wherein

R¹ R² and R^2a are independently hydrogen, OH, OR⁵, lower alkyl, CF₃, OCHF₂, OCF₃, SR⁵ⁱ or halogen, or two of R¹, R² and R^2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

R³ and R⁴ are independently hydrogen, OH, OR^5a, OAryl, OCH₂Aryl, lower alkyl, cycloalkyl, CF₃, —

OCHF₂, —

OCF₃, halogen, —

CN, —

CO₂R^5b, —

CO₂H, —

CONR⁶R^6a, —

NHCOR^5c, —

NHSO₂R^5d, —

NHSO₂Aryl, Aryl, —

SR^5e, —

SOR^5f, —

SO₂R^5g, —

SO₂Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³ and R⁴ together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g and R⁵ⁱ are independently lower alkyl;

R⁶ and R^6a are independently hydrogen, alkyl,aryl, alkylaryl, cycloalkyl, or R⁶ and R^6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

A is O, S, NH, or (CH₂)_n where n is 0-3, or a pharmaceutically acceptable salt thereof, all steroisomers thereof, and a prodrug ester thereof with the proviso that where A is (CH₂)_n where n is 0,1,2, or 3 or A is O, and at least one of R¹, R², R^2a, R³ and R⁴ is OH or OR⁵, then at least one of R¹, R², and R^2a is CF₃, OCF₃, or OCHF₂ and/or at least one of R³ and R⁴ is CF₃, —

OCHF₂, —

OCF₃, —

CN, —

CO₂R^5b, CH(OR^5h)R^6d, CH(OH)R^6c, COR^6b, —

NHCO^5c, —

NHSO₂R^5d, —

NHSO₂Aryl, Aryl, —

SR^5e, —

SOR^5f, —

SO₂R^5g, —

SO₂Aryl or halogen;

or a compound of the structure

wherein

R¹, R² and R^2a are independently hydrogen, OH, OR⁵, lower alkyl, CF₃, OCHF₂, OCF₃, SR⁵ⁱ or halogen, or two of R¹, R² and R^2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

R³ and R⁴ are independently hydrogen, OH, OR^5a, OAryl, OCH₂Aryl, lower alkyl, cycloalkyl, CF₃, —

OCHF₂, —

OCF₃, halogen, —

CN, —

CO₂R^5b, —

CO₂H, —

CONR⁶R^6a, —

NHCOR^5c, —

NHSO₂R^5d, —

NHSO₂Aryl, Aryl, —

SR^5e, —

SOR^5f, —

SO₂R^5g, —

SO₂Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³ and R⁴ together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g and R⁵ⁱ are independently lower alkyl;

R⁶ and R^6a are independently hydrogen, alkyl,aryl, alkylaryl, cycloalkyl, or R⁶ and R^6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

A is O, S, NH, or (CH₂)_n where n is 0-3, or a pharmaceutically acceptable salt thereof, all steroisomers thereof, and a prodrug ester thereof.

30. A compound having the structure