Treatment for diabetes in patients inappropriate for metformin therapy

• US 10,034,877 B2
• Filed: 10/06/2016
• Issued: 07/31/2018
• 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, Graefe-Mody, Eva Ulrike, Harper, Ruth, Woerle, Hans-Juergen
• Primary Examiner(s): Cordero Garcia, Marcela M
• Application Number:
  US15/287,228
• Publication Number:
  US 20170020868A1
• Time in Patent Office: 663 Days
• 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 of treating metabolic diseases in a patient for whom metformin therapy is inappropriate due to at least one contraindication against metformin comprising orally administering to the patient 5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine per day wherein the contraindication is selected from the group consisting of:

renal disease, renal impairment or renal dysfunction, unstable or acute congestive heart failure, acute or chronic metabolic acidosis, and hereditary galactose intolerance,

wherein no adjustment of the daily dose is required for 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in a patient with mild, moderate or severe renal impairment or end-stage renal disease.

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

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

4. The method according to claim 1 wherein the metabolic disease is type 2 diabetes mellitus.

5. The method according to claim 1 wherein the contraindication is renal disease, renal impairment or renal dysfunction.

6. The method according to claim 1 wherein the metabolic disorder is type 2 diabetes mellitus and wherein the contraindication is renal disease, renal impairment or renal dysfunction, and wherein said 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is used for said patient in the same dose as for a patient with normal renal function.

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

8. The method according to claim 1 further comprising administering the 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in combination with one or more further active substances selected from 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.

9. The method according to claim 1 further comprising administering the 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in combination with one or more further active substances selected from sulphonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues.

10. The method according to claim 1 further comprising administering the 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in combination with one or more further active substances selected from repaglinide, pioglitazone, and insulin and insulin analogues.

11. The method according to claim 1 further comprising administering the 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in combination with pioglitazone.

12. A method of treating 2 diabetes mellitus in a patient for whom metformin therapy is inappropriate due to at least one contraindication against metformin comprising orally administering to the patient 5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine per day,

wherein the contraindication is selected from the group consisting of:

renal disease, renal impairment or renal dysfunction, and acute or chronic metabolic acidosis,

wherein no adjustment of the daily dose is required in patients with mild, moderate, or severe renal impairment or end-stage renal disease.

14. The method according to claim 12, wherein the contraindication is severe renal impairment, acute metabolic acidosis, or chronic metabolic acidosis.

13. A method of treating 2 diabetes mellitus in a patient for whom metformin therapy is inappropriate due to at least one contraindication against metformin comprising orally administering to the patient 5 mg of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine per day,

wherein the contraindication is selected from the group consisting of severe renal impairment or end-stage renal disease,

wherein no adjustment of the daily dose is required in patients with severe renal impairment or end-stage renal disease.

15. A method of treating 2 diabetes mellitus in a patient having renal impairment and for whom metformin therapy is contraindicated for renal impairment, comprising orally administering to the patient 5 mg of 1-[(4-methyl-quinazolin-2-yl)-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine per day, wherein the daily dose of 1-[(4-methyl-quinazolin-2-yl)-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine administered to the renally-impaired patient is the same as the daily dose of 1-[(4-methyl-quinazolin-2-yl)-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine administered to a patient with normal renal function.

16. The method according to claim 15, wherein the renal impairment is severe renal impairment.

17. The method according to claim 15 or 16, wherein the patient is ineligible for metformin therapy.