TREATMENT FOR DIABETES IN PATIENTS INAPPROPRIATE FOR METFORMIN THERAPY

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 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.

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, and hereditary galactose intolerance.

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 DPP-IV inhibitor is either, in a first embodiment (embodiment A), of formula (I) ##STR00026## or of formula (II) ##STR00027## or of formula (III) ##STR00028## or of formula (IV) ##STR00029## wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl and R2 denotes 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-propyl)-methylamino, or its pharmaceutically acceptable salt; or, in a second embodiment (embodiment B), selected from the group consisting of sitagliptin, vildagliptin, 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, and 6-[(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 its pharmaceutically acceptable salt.

7. The method according to claim 1, wherein said DPP-4 inhibitor is selected from the group consisting of 1-[(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 and 1-[(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, and 6-[(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, wherein 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 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, and severe 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.

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.

Description

EXAMPLES

[0210] The usability of a DPP-4 inhibitor according to this invention for the purpose of the present invention can be tested using clinical trials:

[0211] For example, in a randomised, double-blind, parallel group trial, the safety and efficacy of a DPP-4 inhibitor according to the invention (e.g. 5 mg of BI 1356 administered orally once daily) is compared with placebo over a treatment period of 18 weeks, followed by a 34 week double-blind extension period (placebo switched to glimepiride) in patients with type 2 diabetes and insufficient glycemic control (e.g. HbA1c 7% to 10%) who are ineligible for metformin therapy due to intolerability or contraindications against metformin.

[0212] Patients ineligible for metformin therapy defined as:

contraindications against metformin therapy according to label, for example: [0213] renal disease or renal dysfunction (e.g., as specified by product information of locally approved metformin), [0214] dehydration by clinical judgement of the investigator, [0215] unstable or acute congestive heart failure, [0216] acute or chronic metabolic acidosis (present condition in patient history), [0217] hereditary galactose intolerance;
or documented intolerable side effects attributed to metformin, for example: [0218] nausea, [0219] vomiting, [0220] diarrhoea, [0221] intestinal gas, [0222] severe abdominal discomfort.

[0223] In this study the efficacy a DPP-4 inhibitor according to this invention in this patient population is investigated over the shorter term treatment period of 18 weeks and safety/tolerability over the longer term treatment period for a maximum of 52 weeks in comparison to a sulfonylurea drug (glimepiride).

[0224] The success of the treatment is tested by determining the HbA1c value, by comparison with the initial value and/or with the value of the placebo group. A significant change in the HbA1c value compared with the initial value and/or the placebo value demonstrates the efficacy of the DPP-4 inhibitor for the treatment. The success of the treatment can be also tested by determining the fasting plasma glucose values, by comparison with the initial values and/or with the values of the placebo group. A significant drop in the fasting glucose levels demonstrates the efficacy of the treatment. Also, the occurrence of a treat to target response (i.e. an HbA1c under treatment <7% or <6.5%) demonstrates the efficacy of the treatment.

[0225] The safety and tolerability of the treatment is investigated by assessing patient's condition and relevant changes from baseline, e.g. incidence and intensity of adverse events (such as e.g. renal adverse events, hypoglycemic episodes or the like) or weight gain under glimepiride therapy compared to DPP-4 inhibitor treatment.

[0226] For other example, in a randomised, double-blind, parallel group trial, the safety, efficacy and tolerability of a DPP-4 inhibitor according to the invention (e.g. 5 mg of BI 1356) is compared with placebo over a treatment period of 52 weeks in type 2 diabetic male and female patients with severe chronic renal impairment (GFR<30 ml/min, who are not on chronic dialysis), including patients on insulin and/or sulfonylurea background medication.

[0227] The safety and tolerability of the treatment is investigated by assessing patient's condition. The efficacy can be investigated by change from baseline in HbA1c after 12 weeks treatment, by change in fasting plasma glucose parameters, or by change in insulin and/or sulfonylurea dosage at 52 weeks compared to baseline and over time.

[0228] Metabolism and elimination properties of a DPP-4 inhibitor for the purpose of this invention:

[0229] The excretion pathways, mass balance and metabolism of a DPP-4 inhibitor according to this invention in a human subject can be investigated using a radiolabelled (e.g. [140]-labelled) DPP-4 inhibitor for oral administration, such as e.g. as follows for a compound determined to be suitable for the purpose of the present invention:

[0230] Following oral administration of 10 mg [14C]BI 1356/subject (e.g. healthy male volunteer), the total radioactivity is primarily eliminated via the feces with a mean of 83.8% of the administered dose excreted within 16 days. Renal excretion accounts for 6.6% of the administered dose after 9 days post dose. Recovery of total radioactivity ranges from 86.1%-95.1% (mean: 90.4%) of the administered dose.

[0231] After oral administration of [14C]BI 1356, the parent compound is the most abundant radioactive species in all matrices investigated. In plasma, the parent compound [14C]BI 1356 accounts for a mean of 74% of sample radioactivity (sample pool: 1.5+3+6 h) after oral administration. The inactive main metabolite is identified in plasma with 16.9% of sample radioactivity in pooled samples. The parent compound [14C]BI 1356 is excreted unchanged in urine and feces with a mean of 90% of excreted radioactivity after oral dosing. Metabolites, including the main metabolite, account individually for <10% in the excreta.