TREATMENT FOR DIABETES IN PATIENTS INAPPROPRIATE FOR METFORMIN THERAPY

• US 20140274890A1
• Filed: 06/03/2014
• Published: 09/18/2014
• Est. Priority Date: 08/06/2008
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: DUGI, Klaus, WOERLE, Hans-Juergen, GRAEFE-MODY, Eva Ulrike, HARPER, Ruth
• Granted Patent: US 9,486,526 B2
• Time in Patent Office: Days
• US Class Current: 514/6.5
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• 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

Abstract

The present invention relates to the finding that certain DPP-4 inhibitors are particularly suitable for treating and/or preventing metabolic diseases, particularly diabetes, in patients for whom metformin therapy is inappropriate due to intolerability or contraindication against metformin.

Claims

1. A method for treating and/or preventing type 2 diabetes mellitus in a patient for whom metformin therapy is inappropriate due to intolerability or contraindication against metformin comprising orally administering to the patient a DPP-4 inhibitor, which is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine or a pharmaceutically acceptable salt thereof, wherein said DPP-4 inhibitor is administered in an oral dose of 5 mg per day to said patient.

2. The method according to claim 1 wherein the patient is ineligible for metformin therapy due to intolerability or contraindication against metformin.

3. The method according to claim 1 wherein the patient is in need of reduced dose metformin therapy due to reduced tolerability, intolerability or contraindication against metformin.

4. The method according to claim 1 wherein the patient has at least one contraindication selected from the group consisting of renal disease, renal impairment or renal dysfunction, dehydration, unstable or acute congestive heart failure, acute or chromic metabolic acidosis, and hereditary galactose intolerance.

5. The method according to claim 4 wherein the contraindication is renal disease, renal impairment or renal dysfunction.

6. The method according to claim 1 wherein the contraindication is renal disease, renal impairment or renal dysfunction, wherein said DPP-4 inhibitor is used for said patient in the same dose as for a patient with normal renal function.

7. The method according to claim 1, characterized in that said DPP-4 inhibitor and its major active metabolite(s) have a relatively wide therapeutic window and/or are primarily eliminated via hepatic metabolism or biliary excretion.

8. The method according to claim 1, wherein said DPP-4 inhibitor is excreted mainly via the liver.

9. The method according to claim 1, wherein for said DPP-4 inhibitor excretion via the kidney represents a minor elimination pathway.

10. The method according to claim 1, wherein said DPP-4 inhibitor is excreted mainly unchanged.

11. The method according to claim 1, wherein for said DPP-4 inhibitor elimination via metabolism represents a minor elimination pathway.

12. The method according to claim 1, wherein said DPP-4 inhibitor has placebo-like safety/tolerability and/or is eliminated primarily as the parent drug via the liver.

13. The method according to claim 1, wherein the main metabolite of said DPP-4 inhibitor is pharmacologically inactive or has a relatively wide therapeutic window.

14. The method according to claim 1 wherein the contraindication is mild, moderate or severe renal impairment or end-stage renal disease.

15. The method according to claim 1 further comprising the use of the DPP-4 inhibitor in combination with one or more further active substances selected from the group consisting of antidiabetics, active substances that lower the blood sugar level, active substances that lower the lipid level in the blood, active substances that raise the HDL level in the blood, active substances that lower the blood pressure, active substances that are indicated in the treatment of atherosclerosis, and active substances that are indicated in the treatment of obesity.

16. The method according to claim 1 further comprising the use of the DPP-4 inhibitor in combination with one or more further active substances selected from the group consisting of sulphonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues.

17. The method according to claim 1 further comprising the use of the DPP-4 inhibitor in combination with one or more further active substances selected from the group consisting of repaglinide, pioglitazone, and insulin and insulin analogues.

18. The method according to claim 1 further comprising the use of the DPP-4 inhibitor in combination with pioglitazone.

19. The method according to claim 1 wherein the intolerability is at least one gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhoea, intestinal gas, and severe abdominal discomfort.

20. A method for treating type 2 diabetes mellitus in a patient with renal disease, renal impairment or renal dysfunction, comprising orally administering to the patient a DPP-4 inhibitor which is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in a dose of 5 mg.

21. The method according to claim 20, wherein the patient has mild, moderate or severe renal impairment or end-stage renal disease.

22. A method for treating type 2 diabetes mellitus in a patient with renal disease, renal impairment or renal dysfunction, comprising orally administering to the patient a DPP-4 inhibitor which is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in a dose of 5 mg, wherein said DPP-4 inhibitor is used for said patient in the same dose as for a patient with normal renal function.

23. The method according to claim 22, wherein the patient has mild, moderate or severe renal impairment or end-stage renal disease

24. A method for treating type 2 diabetes mellitus in a patient having chronic renal insufficiency or impairment of moderate, severe or terminal stage, comprising orally administering to the patient a DPP-4 inhibitor which is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in a dose of 5 mg once daily.

25. The method according to claim 24, wherein the DPP-4 inhibitor is administered to the patient in combination with one or more further active substances selected from the group consisting of repaglinide, pioglitazone, and insulin or insulin analogues.