Amino acid complexes of C-aryl glucosides for treatment of diabetes and method

• US 6,774,112 B2
• Filed: 04/08/2002
• Issued: 08/10/2004
• Est. Priority Date: 04/11/2001
• Status: Expired due to Term

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Gougoutas, Jack Z.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Khare, Devesh
• Application Number:
  US10/117,914
• Publication Number:
  US 20030064935A1
• Time in Patent Office: 855 Days
• Field of Search: 514/4, 514/23, 514/866, 536/1.11, 536/17.4, 536/17.6, 536/18.4
• US Class Current: 514/23
• 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 31/351 not condensed with another ring
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 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: C07H 15/203 Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Abstract

Crystalline complexes are obtained from a 1:1 or 2:1 mixtures of either the (D) or (L) enantiomer of natural amino acids and compounds of formula

wherein

R¹, R² and R^2a are independently hydrogen, OH, OR⁵, alkyl, —OCHF₂, —OCF₃, —SR^5a or halogen;

R³ and R⁴ are independently hydrogen, OH, OR^5b, alkyl, cycloalkyl, CF₃, —OCHF₂, —OCF₃, halogen, —CONR⁶R^6a, —CO₂R^5c, —CO₂H, —COR^6b, —CH(OH)R^6c, —CH(OR^5d)R^6d, —CN, —NHCOR^5e, —NHSO₂R^5f, —NHSO₂Aryl, —SR^5g, —SOR^5h, —SO₂R⁵ⁱ, 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 method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above complex alone or in combination with another antidiabetic agent or other therapeutic agent.

Claims

1. Crystalline complexes between either (D) or (L) enantiomers of natural amino acids and compounds of formula I

wherein

R¹, R² and R^2a are independently hydrogen, OH, OR⁵, alkyl, —

OCHF₂, —

OCF₃, —

SR^5a or halogen;

R³ and R⁴ are independently hydrogen, OH, OR^5b, alkyl, cycloalkyl, CF₃, —

OCHF₂, —

OCF₃, halogen, —

CONR⁶R^6a, —

CO₂R^5c, —

CO₂H, —

COR^6b, —

CH(OH)R^6c, —

CH(OR^5d)R^6d, —

CN, —

NHCOR^5e, —

NHSO₂R^5f, —

NHSO₂Aryl, —

SR^5g, —

SOR^5h, —

SO₂R⁵ⁱ, 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, 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^d 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.

2. Complexes of either the (D) or (L) enantiomer of natural amino acids with compounds as defined in claim 1 where R¹ is hydrogen, alkoxy, halogen or lower alkyl;

and R⁴ is lower alkyl, R^5aO, —

OCHF₂, —

SR^5e, —

S(O)R^5e, or —

S(O₂)R^5e.

3. Crystalline 1:

1 or 2;

1 complexes of L-phenylalanine or L-proline or D-phenylalanine with compounds as defined in claim 2 wherein R¹ is hydrogen or methyl and R⁴ is 4-C₂H₅, —

OCHF₂, or —

SMe.

4. Complexes of either the (D) or (L) enantiomer of natural amino acids with with compounds as defined in claim 2 having the structure

5. Crystalline 1:

1 or 2;

1 complexes of L-phenylalanine or L-proline or D-phenylalanine with compounds as defined in claim 1 having the structure

where R¹ is hydrogen, alkoxy, halogen or lower alkyl; and

R⁴ is lower alkyl, R^5aO, —

OCHF₂, —

SR^5e, —

S(O)R^5e, or —

S(O₂) R^5e.

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

7. A pharmaceutical combination comprising a complex of either the (D) or (L) enantiomer of natural amino acids with a 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 lipid-lowering agent.

8. The pharmaceutical combination as defined in claim 7 comprising said compound complexed with either the (D) or (L) enantiomer of natural amino acids and an antidiabetic agent.

9. The combination as defined in claim 8 wherein the complexes of either the (D) or (L) enantiomer of natural amino acids with a compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 300:

1.

10. The combination as defined in claim 7 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a thyroid receptor beta compound, and/or an anorectic agent.

11. The combination as defined in claim 10 wherein the anti-obesity agent is orlistat, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol.

12. The combination as defined in claim 7 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.

13. The combination as defined in claim 12 wherein the lipid lowering agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, atavastatin, rosuvastatin, fenofibrate, gemfibrozil, clofibrate, or avasimibe.

14. The combination as defined in claim 12 wherein the complexes are present in a weight ratio to the lipid-lowering agent within the range from about 0.01 to about 300:

1.

15. The combination as defined in claim 8 wherein the antidiabetic agent is selected from 1, 2, 3 or more of the group 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-l (GLP-l), insulin, a meglitinide, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, a glucoser-6-phosphatase inhibitor.

16. The combination as defined in claim 15 wherein the antidiabetic agent is selected from 1, 2, 3 or more of the group of:

metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, and isaglitazone, repaglinide, nateglinide.

17. 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 natural amino acid complex as defined in claim 1.

18. The method as defined in claim 17 where compounds of Formula (I) have the structure

19. A method for treating type II diabetes which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a complex 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 a hypolipidemic agent.