Treatment for diabetes in patients inappropriate for metformin therapy

US 20110263493A1
Filed: 08/05/2009
Published: 10/27/2011
Est. Priority Date: 08/06/2008
Status: Active Grant

First Claim

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1. A method of treating and/or preventing metabolic diseases in a patient for whom metformin therapy is inappropriate due to intolerability or contraindication against metformin comprising orally administering to the patient a DPP-IV inhibitor.

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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.

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27 Claims

1. A method of treating and/or preventing metabolic diseases in a patient for whom metformin therapy is inappropriate due to intolerability or contraindication against metformin comprising orally administering to the patient a DPP-IV inhibitor.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)
- - 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 metabolic disease is type 2 diabetes mellitus and wherein the patient has at least one contraindication selected from:
    - renal disease, renal impairment or renal dysfunction,dehydration,unstable or acute congestive heart failure,acute or chromic metabolic acidosis, andhereditary 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 DPP-IV inhibitor iseither, in a first embodiment (embodiment A),
  - 7. The method according to claim 1, wherein said DPP-4 inhibitor is selected from the group consisting of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine,1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine,1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine and1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,or a pharmaceutically acceptable salt thereof.
  - 8. The method according to claim 7, wherein said DPP-4 inhibitor is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.
  - 9. The method according to claim 1, wherein said DPP-4 inhibitor is selected from the group consisting of saxagliptin, alogliptin,(2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,(2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,(S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,(3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,(1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile,(R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile,5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide,3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,[(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid,(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile, and6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione,or a pharmaceutically acceptable salt thereof.
  - 10. 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 DPP-4 inhibitor is used for said patient in the same dose as for a patient with normal renal function.
  - 11. 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.
  - 12. The method according to claim 1, wherein said DPP-4 inhibitor is excreted mainly via the liver.
  - 13. The method according to claim 1, for which excretion via the kidney represents a minor elimination pathway.
  - 14. The method according to claim 1, wherein said DPP-4 inhibitor is excreted mainly unchanged.
  - 15. The method according to claim 1, for which elimination via metabolism represents a minor elimination pathway.
  - 16. 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.
  - 17. 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.
  - 18. The method according to claim 1 wherein the contraindication is mild, moderate or severe renal impairment or end-stage renal disease.
  - 19. The method according to claim 1 further comprising the use of the DPP-IV inhibitor 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.
  - 20. The method according to claim 1 further comprising the use of the DPP-IV inhibitor 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.
  - 21. The method according to claim 1 further comprising the use of the DPP-IV inhibitor in combination with one or more further active substances selected from repaglinide, pioglitazone, and insulin and insulin analogues.
  - 22. The method according to claim 1 further comprising the use of the DPP-IV inhibitor in combination with pioglitazone.
  - 23. The method according to claim 1 wherein the metabolic disorder is type 2 diabetes mellitus and the intolerability is at least one gastrointestinal side effect selected from:
    - nausea,vomiting,diarrhoea,intestinal gas, andsevere abdominal discomfort.

24. A method of using a DPP-4 inhibitor to treat diabetes in a patient comprising orally administering said DPP-IV inhibitor to said patient, characterized in that <
- 10% of the administered oral dose is excreted via the kidneys.
- View Dependent Claims (25, 26, 27)
- - 25. The method according to claim 24 characterized in that the DPP-IV inhibitor is primarily excreted unchanged via the bile.
  - 26. The method according to claim 24 characterized in that >
    - 80% of the administered oral dose is excreted unchanged as parent drug.
  - 27. The method according to claim 24 characterized in that its main metabolite is pharmacologically inactive.

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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
Harper, Ruth, Graefe-Mody, Eva Ulrike, Woerle, Hans-Juergen, Dugi, Klaus

Granted Patent

US 8,853,156 B2
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Days
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US Class Current

514/5.9
CPC Class Codes

A61K 2300/00   Mixtures or combinations of...

A61K 31/40   having five-membered rings ...

A61K 31/4025   not condensed and containin...

A61K 31/403   condensed with carbocyclic ...

A61K 31/422   not condensed and containin...

A61K 31/427   not condensed and containin...

A61K 31/4375   the heterocyclic ring syste...

A61K 31/4439   containing a five-membered ...

A61K 31/496   Non-condensed piperazines c...

A61K 31/4985   Pyrazines or piperazines or...

A61K 31/5025   ortho- or peri-condensed wi...

A61K 31/506   not condensed and containin...

A61K 31/513   having oxo groups directly ...

A61K 31/522   having oxo groups directly ...

A61K 38/26   Glucagons

A61K 38/28   Insulins

A61K 45/06   Mixtures of active ingredie...

A61K 9/0053   Mouth and digestive tract, ...

A61P 3/10   for hyperglycaemia, e.g. an...

Treatment for diabetes in patients inappropriate for metformin therapy

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Treatment for diabetes in patients inappropriate for metformin therapy

First Claim

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Specification

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