BRPI0717874A2 - USE OF ORGANIC COMPOUNDS - Google Patents

Description

Patent Descriptive Report for "USE OF ORGANIC COMPOUNDS". Use of Organic Compounds

The present invention relates to a method of treatment wherein a dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor) or a pharmaceutically acceptable salt thereof is administered to a patient to prevent, retard progress or reduce the occurrence. edema, for example peripheral edema or drug-induced edema.

Treated patients are preferably suffering from hypertension, hyperglycemia such as diabetes mellitus, preferably non-insulin dependent diabetes mellitus or Impaired Glucose Metabolism (IGM), preferably Impaired Glucose Tolerance (IGT).

Diabetes mellitus is a relatively common disorder (estimated at about 1% prevalence in the general population) that is characterized by hyperglycemia. There are three basic types of diabetes mellitus, type I or insulin-dependent diabetes mellitus (IDDM), type II or non-insulin dependent diabetes mellitus (NIDDM), and type A insulin resistance. Type I or Type II may become insensitive to the effects of exogenous ("insulin resistant") insulin through a variety of mechanisms. Insulin resistance of type A results in either mutations in the insulin receptor gene or in post-receptor sites of critical action for glucose metabolism.

Impaired Glucose Metabolism (IGM) is defined by blood glucose levels that are above the normal range but are not high enough to meet the diagnostic criteria for type 2 diabetes mellitus. The incidence of IGM varies from country to country, but It usually occurs 2 to 3 times more often than visible diabetes. Among subjects with IGM, about 58% have Impaired Glucose Tolerance (IGT), another 29% have Impaired Fasting Glucose (IFG), and 13% have both abnormalities (IFG / IGT). IGT is characterized by elevated postprandial (post-meal) hyperglycemia while IFG was defined based on fasting glycemic values. Type 2 diabetes is a progressive disease, and although monotherapy may initially control blood glucose in some patients, it is associated with a high rate of secondary insufficiency. This high incidence of therapeutic failure is a major contributor to the high rate of complications associated with long-term hyperglycemia in patients with type 2 diabetes.

Thiazolidinediones are effective and commonly administered drugs to control plasma glucose concentrations in patients with type 2 diabetes mellitus. Thiazolidinedione are commonly used oral antidiabetic agents. However thiazolidinediones have significant safety / tolerability results that limit their use or safe use.

Indeed, it is well known that the main safety outcome of thiazolidinediones is to increase the occurrence of edema in treated patients. Fluid retention occurs in 5% to 15% of patients taking thiazolidinediones. In some of these patients, use of thiazolidinediones appears to be a cause of macular edema, and drug cessation appears to result in rapid resolution of both peripheral and macular edema. Fluid retention associated with thiazolidinedion use should be considered when evaluating treatment options for patients with diabetic macular edema (MSD), especially those with concomitant peripheral edema. In large clinical trials with rosiglitazone and pioglitazone, the frequency of weaning in patients treated with thiazolidinedione was about 3 to 4 times higher than in patients treated with placebo. In addition to peripheral edema, reports have reported pulmonary edema associated with thiazolidinedione therapy. Options for thiazolidinedione-associated edema control include dose reduction, drug discontinuation, and symptomatic diuretic therapy. However, this is not an appropriate solution for diabetic patients depending on thiazolidinedion treatment.

We have surprisingly found that DPP-IV inhibitors especially vildagliptin, or a pharmaceutically acceptable salt thereof, can reduce the occurrence of edema in patients.

In particular, the applicant surprisingly found that especially vildagliptin DPP-IV inhibitors, or a pharmaceutically acceptable salt thereof, can be used in combination with thiazolidinediones, for example one or two thiazolidinediones, or a pharmaceutically salt. acceptable to reduce the occurrence of thiazolidinedione-associated edema. Thus long-term treatment with such a combination has significantly less inconvenient edema side effects than other combinations.

Antidiabetic thiazolidinedione (i.e. glitazone) is, for example, (SH (3,4-dihydro-2- (phenylmethyl) -2H-1-benzopyran-6-yl) methylcyrazolidine-2,4-dione (englitazone), 5 - {[4- (3- (5-methyl-2-phenyl-4-oxazolyl) -1-oxopropyl) phenyl] methyl} thiazolidine-2,4-dione (darglitazone) , 5 - {[4- (1-methyl-cyclohexyl) methoxy) -phenyl] methyl} -thiazolidine-2,4-dione (ciglitazone), 5 - {[4- (2- (1-indolyl) ethoxy ) phenyl] methyl} thiazolidine-2,4-dione (DRF2189), 5- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy)] benzyl} thiazolidine -2,4-dione (BM-13.1246), 5- (2-naphthylsulfonyl) thiazolidine-2,4-dione (AY-31637), bis {4 - [(2,4-dioxo-5-thiazolidinyl) - methyl] phenyl} methane (YM268), 5- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-hydroxyethoxy] -benzyl} -thiazolidine-2,4-dione (AD-5075 ), 5- [4- (1-phenyl-1-cyclopropanecarbonylamino) -benzyl] -thiazolidine-2,4-dione (DN-108) 5 - {[4- (2- (2,3-dihydroindol-1- yl) ethoxy) phenylmethyl} -thiazolidine-2,4-dione, 5- [3- (4-chlorophenyl]) -2-propynyl] -5-phenylsulfonyl) thiazolidine-2,4-dione, 5- [3- (4-chlorophenyl]) - 2-pr opinyl] -5- (4-fluorophenyl sulfonyl) thiazolidine-2,4-dione, 5 - {[4- (2- (methyl-2-pyridinyl-amino) ethoxy) phenyl] methyl} -thiazolidin-2-one 2,4-dione (rosiglitazone), 5 - {[4- (2- (5-ethyl-2-pyridyl) ethoxy) phenyl] methyl} thiazolidine-2,4-dione (pioglitazone), 5 - {[4 - ((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy) -phenyl] -methyl} -thiazolidine-2,4-one dione (troglitazone), 5- [6- (2-fluoro-benzyloxy) naphthalen-2-ylmethyl] -thiazolidine-2,4-dione (MCC555), 5 - {[2- (2-naphthyl) -benzoxazol-5 -yl] methyl} thiazolidine-2,4-dione (T-174) and 5- (2,4-dioxothiazolidin-5-ylmethyl) -2-methoxy-N- (4-trifluoromethyl-benzyl) benzamide (KRP297).

Specific glyitazone such as "pioglitazone", "rosiglitazone" is also intended to comprise any pharmaceutically acceptable salt thereof, crystal form, hydrate, solvate, diastereoisomer or enantiomer thereof.

For administration of a thiazolidinedione ANTIDIABETIC, especially a glitazone to an adult diabetic patient (body weight: 50 kg), for example, the dose per day is generally 0.01 to 1000 mg, preferably 0.1 to 500 mg. . This dose may be administered once to several times a day. Especially, when pioglitazone hydrochloride is employed as the insulin sensitizer, the dose of pioglitazone hydrochloride per day is generally 7.5 to 60 mg, preferably 15 to 45 mg. When troglitazone is employed as the insulin sensitizer, the dose of troglitazone per day is generally 100 to 1000 mg, preferably 200 to 600 mg. When rosiglitazone (or its maleate) is used as the insulin sensitizer, the dose of rosiglitazone per day is usually 1 to 12 mg, preferably 2 to 12 mg.

Thiazolidinedione (glitazone) is preferably pioglitazone, pioglitazone hydrochloride, troglitazone or rosiglitazone (or its maleate salt), especially preferably pioglitazone hydrochloride or rosiglitazone maleate.

The dose of ACTOS® (pioglitazone HCI) should not exceed 45 mg once daily alone or in combination with sulfonylurea, metformin, or insulin. ACTS in combination with metformin may be started at 15 mg or 30 mg once daily. The current metformin dose may be continued at initiation of ACTOS therapy. It is unlikely that the metformin dose will require adjustment due to hypoglycaemia during combination therapy with ACTOS. ACTOS is available in 15 mg, 30 mg, and 45 mg tablets.

AVANDIA® (rosiglitazone maleate) may be administered either in a starting dose of 4 mg as a single or divided daily dose and administered in the morning and evening. For patients who respond inappropriately following 8 to 12 weeks of treatment as determined by reduction in PGF, the dose may be increased to 8 mg daily as monotherapy or in combination with metformin. The dose of AVANDIA should not exceed 8 mg daily as a single or divided twice daily dose. AVANDIA is available in 2 mg, 4 mg, and 8 mg tablets. Marketed combinations comprising metformin and a thiazolidinedione derivative may also be used in accordance with the present invention. In particular it may be possible to administer rosiglitazone in combination with metformin as it is marketed, for example, under the trademark AVANDAMET®. The dosage of anti-diabetic therapy with AVANDAMET should be individualized based on efficacy and tolerability while not exceeding the maximum recommended daily dose of 8 mg / 2,000 mg. AVANDAMET® provides different types of tablets. Each tablet contains rosiglitazone such as maleate and metformin hydrochloride as follows: 1 mg / 500 mg, 2 mg / 500 mg, 4 mg / 500 mg, 2 mg / 1,000 mg, 4 mg / 1,000 mg.

In the present context the term "thiazolidinedione" also means any salt or crystal form thereof, for example, the rosiglitazone maleate salt. Metformin has been widely prescribed for glucose lowering.

in patients with NIDDM and is marketed at intensities of 500, 750, 850 and 1000 mg. However, because it is a short-acting drug, metformin requires dosing twice daily or three times daily (comp. 500 to 850 mg 2 to 3 / day or 1000 mg twice daily with meals). The biguanide metformin antihyperglycemic agent described in United States Patent No. 3,174,901 is currently marketed in the United States as its hydrochloride salt (Glucophagen ™), Bristol-Myers Squibb Company). The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is a prior art condition and was first described by Emil A. Werner and James Bell, J. Chem. Sound. 121, 1922, 1790-1794. Metformin, may be administered, for example, in the form as marketed under the trademark GLUCOPHAGE®.

Metformin increases insulin sensitivity in host peripheral tissues. Metformin is also involved in inhibiting intestinal glucose absorption, suppressing hepatic gluconeogenesis, and inhibiting fatty acid oxidation. Suitable metformin dosage regimens include unit doses of 500 mg two to three times daily and may further be set at five times daily or 850 mg once or twice daily. (Martindale, The Complete Drug Reference).

The term "metformin" as used herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, metformin fumarate salt (2: 1), and metformin succinate salt ( 2: 1) as described in United States Serial Application No. 09 / 262,526 filed March 4, 1999, the hydrobromide salt, p-chlorophenoxy acetate or embonate, and other known metformin salts. mono- and dibasic carboxylic acid acids including those described in U.S. Patent No. 3,174,901, all of whose salts are collectively referred to as metformin. It is preferred that the metformin employed herein is the metformin hydrochloride salt, i.e. that marketed as GLUCOPHAGE-D or GLUCOPHAGE XR (trademark of Bristol-Myers Squibb Company). The term "DPP-IV inhibitor" is intended to indicate a molecule

exhibiting inhibition of enzymatic activity of DPP-IV and functionally related enzymes, such as 1 to 100% inhibition, and especially preserving the action of substrate molecules, including but not limited to peptide-1. glucagon type, gastric inhibitor polypeptide, peptide histidine methionine, substance P, neuropeptide Y, and other molecules typically containing alanine or proline residues at the second amino terminal position. Treatment with DPP-IV inhibitors prolongs the duration of action of peptide substrates and increases levels of their intact undegraded forms, resulting in a spectrum of biological activities relevant to the invention described.

DPP-IV can be used to control glucose metabolism because its substrates include Glucagon-like peptide-1 (GLP-1) insulinotropic hormones and gastric inhibitor peptide (GIP). GLP-1 and GIP are active only in their intact form; Removal of their two N-terminal amino acids inactivates them. In vivo administration of synthetic DPP-IV inhibitors prevents N-terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance. For this purpose, chemical compounds are tested for their ability to inhibit purified CD26 / DPP-IV enzyme activity. Briefly, CD26 / DPP-IV activity is measured in vitro by its ability to cleave the synthetic Gly-Pro-p-nitroanilide substrate (Gly-Pro-pNA). Cleavage of Gly-Pro-pNA by DPP-IV releases the p-nitroanilide (pNA) product, whose rate of onset is directly proportional to enzyme activity. Inhibition of enzyme activity by specific enzyme inhibitors slows down the generation of pNA. Stronger interaction between an inhibitor and the enzyme results in a slower rate of pNA generation. Thus, the degree of inhibition of pNA accumulation rate is a direct measure of enzyme inhibition intensity. PNA accumulation is measured with a spectrophotometer. The inhibition constant, Ki, for each compound is determined by incubating fixed amounts of enzyme with several different concentrations of inhibitor and substrate.

In the present context "a DPP-IV inhibitor" is also intended to comprise active metabolites and prodrugs thereof, such as active metabolites and DPP-IV inhibitor prodrugs. A "metabolite" is an active derivative of a DPP-IV inhibitor produced when the DPP-IV inhibitor is metabolised. A "prodrug" is a compound that is either metabolized to a DPP-IV inhibitor or metabolized to the same metabolite (s) as a DPP-IV inhibitor. In the present context the term "a DPP-IV inhibitor" is also intended to comprise pharmaceutical salts thereof.

DPP-IV inhibitors are known in the art. In the following,

Reference is made to representative DPP-IV inhibitors:

Preferred DPP-IV inhibitors are described in the following patent applications; WO 02053548 especially compounds 1001 to 1293 and examples 1 to 124, WO 02067918 especially compounds 1000 to 1278 and 2001 to 2159, WO 02066627 especially the described examples, WO 02/068420 especially all compounds specifically listed in examples I to LXIII and the like Preferred compounds, further preferred compounds are 2 (28), 2 (88), 2 (119), 2 (136) described in the table relating to IC50, WO 02083128 as in claims 1 to 5 especially compound described in the examples. 1 to 13 and claims 6 to 10, US 2003096846 especially the specifically described compounds, WO 2004/037181 especially examples 1 to 33, WO 0168603 especially compounds of examples 1 to 109, especially compounds of examples 1 to 60, especially WO 0181337 examples 1 to 118, WO 02083109 especially examples 1A to 1D, WO 030003250 especially compounds of examples 1 to 166, more preferably 1 to 8, WO 03035067 especially the compounds described in examples, WO 03/035057, especially the compounds described in the examples, US2003216450 especially examples 1 to 450, WO 99/46272 especially compounds of claims 12, 14, 15 and 17, WO 0197808 especially compounds of claims. claim 2, WO 03002553 especially compounds of examples 1 to 33, WO 01/34594 especially compounds described in examples 1 to 4, WO 02051836 especially examples 1 to 712, EP1245568 especially examples 1 to 7, EP1258476 especially examples 1 to 32, US 2003087950 especially the examples described, WO 02/076450 especially examples 1 to 128, WO 03000180 especially examples 1 to 162, WO 03000181 especially examples 1 to 66, WO 03004498 especially examples 1 to 33, WO 0302942 especially examples 1 to 68, US 6482844 especially the examples described, WO 0155105 especially the compounds listed in examples 1 and 2, WO 0202560 especially examples 1 to 166, WO 03004496 especially examples 1 to 103, WO 03/024965 and especially examples 1 to 54, WO 0303727 especially examples 1 to 209, WO 0368757 especially examples 1 to 88, WO 03074500 especially examples 1 to 72, examples 4.1 to 4.23, examples 5.1 to 5.10, examples 6.1 to 6.30, examples 7.1 to 7.23, Examples 8.1 to 8.10, Examples 9.1 to 9.30, WO 02038541 especially Examples 1 to 53, WO 02062764 especially Examples 1 to 293, preferably Example 95 (2 - {{3- (Aminomethyl) -4-butoxy-hydrochloride) 2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl} oxide} acetamide), WO 02308090 especially examples 1-1 to 1-109, examples 2-1 to 2-9, example 3 , examples 4-1 to 4-19, examples 5-1 to 5-39, examples 6-1 to 6-4, examples 7-1 to 7-10, examples 8-1 to 8-8, examples 7 -1 to 7-7 page 90, examples 8-1 to 8-59 of pages 91 to 95, examples 9-1 to 9-33, examples 10-1 to 10-20, US 2003225102 especially compounds 1 to 115, compounds of examples 1 to 121, preferably compounds a) az), aa) to az), ba) to bz), ca) to cz) and da) to dk), WO 0214271 especially examples 1 to 320, US 2003096857, United States Serial Application 09 / 788,173 filed February 16, 2001 (Attorney LA50 file) especially the described examples, W099 / 38501 especially the described examples, W099 / 46272 especially the examples described and DE19616 486 A1 especially val-pyr, val-thiazolidide, iso-leucyl-thiazolidide, isoleucyl-pyrrolidide, and fumare salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.

Other preferred DPP-IV inhibitors include the specific examples described in United States Patent Nos. 6124305 and US 6107317, International Patent Applications, Publication Numbers WO 9819998, WO 95153 09 and WO 9818763; such as 1 [2 - [(5-eianopyridin-2-yl) aminoethylamino] acetyl-2-cyano- (S) -pyrrolidine and (2S) -1 - [(2S) -2-amino-3,3-dimethylbutanoyl ] -2-pyrrolidinecarbonitrile. In a further preferred embodiment, the DPP-IV inhibitor is

an N-peptidyl-O-aroyl hydroxylamine or a pharmaceutically acceptable salt thereof. The peptidyl moiety preferably comprises two α-amino acids, for example glycine, alanine, leucine, phenylalanine, lysine or proline, of which the one directly attached to the hydroxylamine nitrogen atom is preferably proline.

In each particular case in the compound claims and the end products of the exemplary preparations, the subject matter of the end products, the pharmaceutical preparations and the claims are hereby incorporated by reference to these publications. WO 9819998 describes N- (N'-substituted glycyl) -2-cyano pyrrolidines,

in particular 1- [2- [5-cyanopyridin-2-yl] amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine. Preferred compounds described in W003 / 002553 are listed on pages 9 to 11 and are incorporated herein by reference.

DE19616 486 A1 describes val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and fuming salts of isoleucyl-thiazolidide and iso-leucyl-pyrrolidide.

WO 0034241 and US 6110949 describe N-substituted adamantyl aminoacetyl-2-cyano pyrrolidines and W (substituted glycyl) -4-cyano pyrrolidines respectively. DPP-IV inhibitors of interest are especially those cited in claims 1 to 4.

WO 9515309 describes amino acid 2-cyanopyrrolidine amides as DPP-IV inhibitors and WO 9529691 describes peptidyl derivatives of alpha-aminoalkylphosphonic acid diesters, particularly those with proline or related structures. DPP-IV inhibitors of interest are especially those cited in Tables 1 to 8.

WO 01/72290 DPP-IV inhibitors of interest are especially those cited in example 1 and claims 1, 4, and 6.

W001 / 52825 especially describes (S) -1- {2- [5-cyanopyridin-2yl) amino] ethyl-aminoacetyl) -2-cyano-pyrrolidine or (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine (LAF237).

WO 9310127 describes proline boronic esters useful as DPP-IV inhibitors. DPP-IV inhibitors of interest are especially those cited in examples 1 to 19.

Published patent application WO 9925719 describes sulfostin, a DPP-IV inhibitor prepared by culturing a Streptomyces microorganism.

WO 9938501 describes N-substituted 4- to 8-membered heterocyclic rings. DPP-IV inhibitors of interest are especially those cited in claims 15 to 20. WO 9946272 describes phosphoric compounds as inhibitors of

DPP-IV. DPP-IV inhibitors of interest are especially those cited in claims 1 to 23. Other preferred DPP-IV inhibitors are the compounds of formula I, II or III described in WO 03/057200 on pages 14 More preferred DPP-IV inhibitors are the compounds specifically described on pages 28 and 29.

Published patent applications WO 9967278 and WO 9967279 describe DPP-IV prodrugs and inhibitors of form A-B-C where C is either a stable or unstable DPP-IV inhibitor.

Preferably, N-peptidyl-O-aroyl hydroxylamine is a compound of formula V11.

Re1

H O

<VI «>

on what

j is 0, 1 or 2;

Rei represents the side chain of a natural amino acid; and R 2 represents lower alkoxy, lower alkyl, halogen or nitro; or a pharmaceutically acceptable salt thereof. In a most preferred embodiment of the invention, hydroxylamino

N-peptidyl-O-aroyl is a compound of formula VIIIa

H ° (Villa)

or a pharmaceutically acceptable salt thereof.

N-peptidyl-O-aroyl hydroxylamines, for example of formula VII or Vila, and their preparation are described by H.U. Demuth et al. In J. Enzyme Inhibition 1988, Vol. 2, pages 129-142, especially on pages 130-132.

Preferred DPP-IV inhibitors are those described by Mona Patel et al. (Expert Opinion Investig Drugs. 2003 Apr; 12 (4): 623-33) in paragraph 5, especially P32 / 98, K-364, FE-999011 , BDPX, NVP-DDP-728 and others, the publication of which is hereby incorporated by reference especially the DPP-IV inhibitors described.

Another preferred DPP-IV inhibitor is N-815541 (T 6666) of

Tanabe

Preferred DPP-IV inhibitors are also described in WO 02/083128, especially the compounds described in examples 1 to 13, US 6,395,767 examples 1 to 109 and WO 03/033671 all specifically described compounds, for example. for example compounds 1 to 393, compounds of pages 67-70.

FE-999011 is described in WO 95/15309 page 14 as compound No. 18.

Another preferred inhibitor is compound BMS-477118 described in WO 2001068603 or United States Patent No. 6,395,767 (example compound 60) also known as (1S, 3S, 5S) -2 - [(2S) -2-amino -2- (3-hydroxytricyclo [3.3.1.13,7] dec-1-yl) -1-oxoethyl] -2-azabicyclo [3.1.0] hexane-3-carbonitrile benzoate (1: 1) such as as described in Formula M of patent application WO 2004/052850 on page 2, and the corresponding free base, (1S, 3S, 5S) -2 - [(2S) -2-amino-2- (3-hydroxy -cyclo [3.3.1.13'7] dec-1-yl) -1-oxoethyl] -2-azabicyclo [3.1.0] hexane-3-carbonitrile (M ') and its monohydrate (M ") as described in Formula M from WO 2004/052850 on page 3. Compound BMS-477118 is also known as saxagliptin.

Another preferred inhibitor is compound GSK23A described in WO 03/002531 (example 9) also known as (2S, 4S) -1 - ((2R) -2-amino-3 - [(4-methoxybenzyl) sulfonyl] - hydrochloride 3-methylbutanoyl) -4-fluoropyrrolidine-2-carbonitrile.

P32 / 98 (CAS number 251572-86-8) also known as

3 - [(2S, 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine may be used as a mixture of 3 - [(2S, 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine and (2E) -2-butenedioate (2: 1) and is described in WO 99/61431 and the formula below, is described in WO 99/61431 and also in Diabetes 1998, 47, 1253-1258, in the name of Probiodrug as well as compound P93 / 01 described by the same company.

Other most preferred DPP-IV inhibitors are the compounds described in WO 02/083128 as in claims 1 to 5. More preferred DPP-IV inhibitors are the compounds specifically described by examples 1 to 13 and claims. 6 to 10.

Other most preferred DPP-IV inhibitors are the compounds described by Bristol-Myers Squibb such as saxagliptin (BMS477118). Other very preferred DPP-IV inhibitors of the invention are

International Patent Application WO 02/076450 (especially Examples 1 to 128) and by Wallace T. Ashton (Bioorganic & Medicinal Chemistry Letters 14 (2004) 859-863) especially compound 1 and the compounds listed in tables 1 and 2. The preferred compound is compound 21 e (table 1) of formula:

Other preferred DPP-IV inhibitors are described in patent applications WO 2004/037169 especially those described in examples 1 to 48 and WO 02/062764 especially the examples described 1 to 293, still preferred are compounds 3- ( aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2 - {[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1 , 2-dihydro-6-isoquinolyl] oxy} acetamide described on page 7 and also in patent application WO2004 / 024184 especially in reference examples 1 to 4.

Other preferred DPP-IV inhibitors are described in patent application WO 03/004498 especially examples 1 to 33 and more preferably the compound of formula ΜΚ-Μ91.

described by example 7 and also known as MK-0431 or Sitagliptin. Preferred daily administration of sitagliptin is between 25 and 100 mg.

In each particular case in the compound claims and the end products of the preparation examples, the subject matter of the end products, the pharmaceutical preparations and the claims are hereby incorporated herein by reference to these publications.

Preferred DPP-IV inhibitors are also described in patent application WO 2004/037181 especially examples 1 to 33 and more preferably the compounds described in claims 3 to 5. Preferred DPP-IV inhibitors are adamantyl pyrrolidines.

N-substituted N-substituted aminoacetyl-2-cyano, N (substituted glycyl) -4-cyano pyrrolidines, N- (N'-substituted glycyl) -2-cyano pyrrolidines, N-aminoacyl thiazolidines, N-pyrrolidines aminoacyl, L-allo-isoleucyl thiazolidine, L-threo-isoleucyl pyrrolidine, and L-allo-isoleucyl pyrrolidine, 1- [2 - [(5-cyanopyridin-2-yl) amino] ethylamino] acetyl 2-cyano- (S) -pyrrolidine, Sitagliptin and pharmaceutical salts thereof.

More preferred DPP-IV inhibitors are selected from [S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidine carbonitrile monohydrochloride, (S) -1 - [( L-threo-isoleucyl 3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine and thiazolidine (compound code according to Probiodrug: P32 / 98 as described above), sitagliptin, 3- ( aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2 - {[3- (amino-methyl) -2-isobutyl-4-phenyl-1-oxo -1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally pharmaceutical salts thereof. [S] -1- [2- (5-cyano-2-pyridinyl) carbonitrile monohydrochloride

mino) ethylamino] acetyl-2-pyrrolidine and (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine are specifically described in Example 3 of WO 98/19998 and Example 1 of WO 00/34241, respectively. DPP-IV inhibitor P32 / 98 (see above) is specifically described in Diabetes 1998, 47, 1253-1258. Carbonitrile [S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidine monohydrochloride and (S) -1 - [(3-hydroxy-1-adamantyl) amino] ace Til-2-cyano-pyrrolidine may be formulated as described on WO 98/19998 or WO 00/34241.

ethylamino} acetyl-2- (S) -cyano-pyrrolidine (also called carbonitrile [S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidine carbonitrile monohydrochloride) of formula:

especially the dihydrochloride and monohydrochloride form thereof, pyrrolidine, 1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-, (S) (also called (S) -1 - [(3 -hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine, LAF237 or villadagliptin) of formula

and L-threo-isoleucyl thiazolidine (compound code according to Probiodrug: P32 / 98 as described above), Sitagliptin, GSK23A, saxagliptin, 3- (aminomethyl) -2-isobutyl-1-oxo-4- phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2 - {[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally in any case pharmaceutical salts thereof.

WO 98/19998 and Example 1 of WO 00/34241, respectively. DPP-IV inhibitor P32 / 98 (see above) is specifically described in Diabetes 1998, 47, 1253-1258. DPP728 and LAF237 may be formulated as described on page 20 of WO 98/19998 or WO 00/34241, or in Application

Especially preferred are 1- {2 - [(5-cyanopyridin-2-yl) amino]

N

DPP728 and LAF237 are specifically described in Example 3 of International Patent No. EP2005 / 000400 (application number).

Any of the substances described in the aforementioned patent documents or scientific publications, hereby incorporated by reference, are considered potentially useful as DPP-IV inhibitors to be used in carrying out the present invention.

DPP-IV inhibitor to be used alone according to the present invention may be used in combination with a vehicle.

A carrier in the present context is a tool (natural, synthetic, peptide, non-peptide), for example, a protein that transports specific substances across the cell membrane in which it is embedded and in the cell. Different vehicles (natural, synthetic, peptide, non-peptide) are required to carry different substances, as each is designed to recognize only one similar substance or group of substances. Any means of detection known to the skilled person

It can be used in the art to detect the association of DPP-IV with a vehicle, for example through vehicle labeling.

The DPP-IV inhibitor may be a peptide or preferably a non-peptide.

Most preferred are orally active DPP-IV inhibitors and

pharmaceutical salts thereof.

The class of Calcium Channel Blockers (CCBs) essentially comprises dihydropyridines (DHPs) and non-DHPs such as diltiazem-type and verapamil-type CCBs. It is well known that the primary safety outcome of CCBs is to increase the occurrence of edema in treated patients.

The CCB is preferably a representative DHP selected from the group consisting of amlodipine, felodipine, riosidine, isradipine, iacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably non-DHP. representative representative of the group consisting of flunarizine, prenylamine, diltiazem, phenyline, galopamil, mibefradil, anipamyl, thiapamil and verapamil, and in each case a pharmaceutically acceptable salt or prodrug thereof. All of these CCBs are therapeutically used, for example, as antihypertensive, antiangina pectoris or antiarrhythmic drugs.

Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, for example, dependent on specific CCB, a pharmaceutically acceptable salt or prodrug thereof. Especially preferred as DHP is amlodipine or a pharmaceutically acceptable salt, especially besylate thereof. An especially preferred representative of non-DHPs is

rapamyl or a pharmaceutically acceptable salt, especially the hydrochloride thereof. The CCB is preferably amlodipine or a pharmaceutically acceptable salt, especially besylate thereof. CBBs are preferably administered from about 1 mg to about 100 mg daily, preferably from about 1 to 10 mg daily.

In case of amlodipine, preferred unit dosage forms

They are, for example, tablets or capsules comprising, for example, from about 1 mg to about 40 mg, preferably 2.5 to 20 mg daily when administered orally. Particularly preferred are doses of 2.5, 5 and 10 mg, in particular 5 mg daily.

The active ingredients (eg thiazolidinediones,

calcium channel inhibitors or DPP-IV inhibitors) or pharmaceutically acceptable salts thereof according to the present invention may also be used in the form of a solvate, such as a hydrate or including other solvents, used for crystallization. .

It has now been surprisingly found that inhibitors

Especially vildagliptin or pharmaceutically acceptable salt thereof, DPP-IV may be used to prevent, retard progress or reduce the occurrence of edema, especially drug-associated edema, for example, thiazolidinedione-associated edema.

Thus in a first embodiment, this invention provided

A method for preventing, slowing progress or reducing the occurrence of thiazolidinedione-associated edema comprising administering a therapeutically effective amount of a thiazolidinedione, for example one or two thiazolidinedione, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a DPP-IV inhibitor, preferably vildagliptin, or pharmaceutically acceptable salt thereof, to a patient in need thereof.

This invention also provides a method for preventing, retarding progress or reducing the occurrence of edema, comprising administering a therapeutically effective amount of a DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof. , to a patient in need of this.

The invention further relates to the use of thiazolidinediones, for example one or two thiazolidinediones, in combination with a DPP-IV inhibitor, or in any case or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing, slow progress or reduce the occurrence of thiazolidinedione-associated edema.

The invention further relates to the use of a DPP-IV inhibitor or pharmaceutically acceptable salt thereof for the manufacture of a medicament to prevent, retard progress or reduce the occurrence of edema.

Method or use as described herein above, wherein the edema is

preferably thiazolidinedione-associated edema, i.e. subsequent to treatment with thiazolidinedione, i.e. edema in patients treated with thiazolidinedione, for example one or two thiazolidinedione.

A method or use as described hereinabove, wherein the edema is preferably drug-associated edema, ie subsequent to treatment with a drug (pharmacological active agent), that is, edema in drug-treated patients. (pharmacological active agent). Drug-associated edema may for example result from treatment with one or two drugs such as antidiabetic agents (e.g. thiazolidinediones, metformin or insulin), antihypertensive agents (eg calcium channel antagonists, renin aliskiren, angiotensin II receptor antagonists such as valsartan, angiotensin converting enzyme inhibitors such as benazepril, alpha adrenergic receptor blocker such as doxazosin, calcium channel blockers such as amlodipine or diltiazem).

A method or use as described hereinabove, wherein the edema is preferably antihypertensive agent-induced edema, ie subsequent to treatment with antihypertensive agents, ie edema in patients treated with antihypertensive agents. for example one or two antihypertensive agents such as valsartan, aliskiren or amlodipine.

A method or use as described hereinabove, wherein the edema is preferably peripheral edema, diabetic macular edema (MSD) or pulmonary edema, preferably thiazolidinedione-associated edema or edema associated with calcium channel blockers.

A method or use as described hereinabove, wherein the DPP-4 inhibitor is administered in combination with one, two or three additional compounds selected from antidiabetic agents and antihypertensive agents, preferably selected from sulfonylureas, thiazolidinediones, metformin. , insulin, and calcium channel blockers.

A method or use as described hereinabove, wherein the DPP-4 inhibitor is administered in combination with a thiazolidinedione and metformin.

Preferably the patient treated in the methods or uses claimed herein is selected from one thiazolidinediones, the treated patient (e.g. one or two thiazolidinediones) suffering from side effects of thiazolidinedion-induced edema. Preferably the patient treated in the methods or uses herein

claimed is selected from a patient treated with one or two drugs selected from antihypertensive agents, preferably suffering from side effects of edema induced by antihypertensive agents or edema induced by calcium channel blockers. Preferably the DPP-IV inhibitor is (S) -1 - [(3-hydroxy-1-ada).

mannyl) amino] acetyl-2-cyano-pyrrolidine (LAF237 or vildagliptin) or pharmaceutically acceptable salt thereof. In the present context the terms "(S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine" or "LAF237" or "vildagliptin" also include any salt or form of crystal of it.

Preferably thiazolidinedione is selected from pioglitazone or rosiglitazone, or in any case or pharmaceutically acceptable salt thereof.

Preferably the treated patient is suffering from hyperglycemia or hypertension. More preferably the patient is suffering from a selected disease of hypertension, diabetes mellitus, type I or insulin-dependent diabetes mellitus (IDDM), type II or non-insulin dependent diabetes mellitus (NIDDM). type A, IGM1 IFG or IGT. In a preferred embodiment the patient is suffering from type II or IGT diabetes.

In a more preferred embodiment the DPP-IV inhibitor is added to the treatment of standard diabetes in patients whose disease has not been adequately controlled on portiazolidinedione alone.

The present methods or uses are particularly useful for preventing or delaying the progression of conditions associated with type II or IGT diabetes, particularly cardiovascular and microvascular conditions.

The term "reducing the occurrence of edema" means reducing the frequency or severity of edema.

Edema is defined as a clinically apparent increase in interstitial fluid volume, which may expand by several liters before the abnormality is evident. Anasarca refers to generalized massive edema. Ascites and hydrothorax refer to the accumulation of excess fluid in the peritoneal and pleural cavities, respectively, and are considered to be special forms of edema. Localized edema due to venous or lymphatic obstruction may be caused by thrombophlebitis, chronic Iinfangitis, resection of regional lymph nodes, filariasis, etc. The vast majority of patients with generalized edema suffer from advanced cardiac, renal, hepatic, or nutritional disorders. Depending on its cause and mechanism, edema may be localized or have a widespread distribution; It is recognized in its generalized form by swelling of the face, which is most easily apparent in the periorbital areas, and by persistent indentation of the skin following pressure; this is known as locker edema. In its most subtle form, edema can be detected by noting that after the stethoscope is removed from the chest wall, the bell leaves an indentation on the chest skin for a few minutes. When the ring fits harder than before or when a patient complains of difficulty placing shoes, particularly at night, edema may be present.

The term "edema" includes but is not limited to localized edema, generalized edema, peripheral edema, diabetic macular edema (MSD), pulmonary edema, drug-associated edema, thiazolidinedione-associated edema (such as thiazolidinedione-associated edema). diabetic macular thiazolidinedione-associated edema), antihypertensive agent-associated edema such as calcium channel blocker-induced edema.

Further as used herein, "one daily dose" means the dose given within a 24 hour period.

The term "prevention" means prophylactic administration of the combination to healthy patients to prevent the eruption of the conditions mentioned herein. Moreover, the term "prevention" means prophylactic administration of such a combination to patients being in a pre-stage of the conditions to be treated.

The term "progression delay" used herein means administration of the combination, such as a combined preparation or pharmaceutical composition, to patients in a pre-stage of the condition to be treated in whose patients a corresponding preform. condition is diagnosed.

By the term "treatment" is meant the control and care of a patient for the purpose of combating the disease, condition, or disorder. As used herein, the term "patient" refers to an animal suffering from a disease or disorder, preferably hypertension, hyperglycemia or diabetes or IGM. The preferred animal is a mammal, such as dogs, cats, horses, cows and humans. It is preferred that the patient be a human.

The term "whose disease has not been adequately controlled by thiazolidinedione alone" used herein preferably means a hyperglycemia-related disease such as diabetes, type 2 diabetes, IGT or IGM.

In this field the age of the preferred patient population is

45 years forward, more preferred 65 years forward.

The person skilled in the relevant art is fully capable of selecting a relevant test model and protocols to prove the beneficial effects of the invention.

The invention also relates to a treatment regimen in accordance with

what,

(i) 50 mg, 100 mg or 150 mg of vildagliptin or a pharmaceutically acceptable salt thereof should be administered in combination with a thiazolidinedione or a pharmaceutically acceptable salt thereof.

preferably 15 to 45 mg of pioglitazone or 2-8 mg of rosiglitazone, or in any case a pharmaceutically acceptable salt thereof daily to a patient in need thereof;

ii) the treated patient is selected from a patient suffering from thiazolidinedione-associated edema.

The invention also relates to a treatment regimen,

on what,

(i) 50 mg, 100 mg or 150 mg of vildagliptin or a pharmaceutically acceptable salt thereof should be administered in combination with a thiazolidinedione or a pharmaceutically acceptable salt thereof.

preferably 15 to 45 mg pioglitazone or 2 to 8 mg rosiglitazone, or in any case a pharmaceutically acceptable salt thereof, daily to a patient in need thereof, ii) the treated patient is a patient whose disease was not adequately controlled by a thiazolidinedione alone, and

iii) the treated patient is selected from a patient suffering from thiazolidinedione-associated edema.

Treatment regimen as described herein wherein thiazolidinedione is substituted by another drug such as a calcium channel blocker, for example amlodipine or a salt thereof.

Treatment regimen as described herein wherein the patient is also under treatment with one or two additional active agents such as CBBs1 insulin, sulfonylurea or metformin.

A treatment regimen, treatment method or use as described herein, wherein between 250 mg and 3000 mg of metformin or a salt thereof is administered daily to the treated patient.

When vildagliptin 100 mg or a pharmaceutically acceptable salt thereof is administered daily, they may be in the form of a once daily administration of vildagliptin 100 mg (OD - once daily), or a twice daily administration. daily 50 mg (ie twice daily) of vildagliptin.

In the treatment regime described above, the term "daily" applies to (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine or a pharmaceutically acceptable salt thereof ( vildagliptin) and to the additional drug such as thiazolidinedione or calcium channel blocker.

Preferably the patient treated in the methods or uses or treatment regimens described above is suffering from hyperglycemia or hypertension. More preferably the patient suffering from hyperglycemia, is suffering from a selected disease of diabetes mellitus, type I or insulin dependent diabetes mellitus (IDDM), type II or non-insulin dependent diabetes mellitus (NIDDM), insulin resistance. type A, IGM, IFG or IGT. In a preferred embodiment the patient is suffering from type II or IGT diabetes. In another preferred embodiment the treated patient is a patient whose disease has not been adequately controlled by thiazolidinedione or metformin alone. The structure of active agents identified by code names, generic or trade names may be taken from the current edition of the standard index index compendium or from databases such as international patents (eg world publications). IMS). The corresponding content thereof is hereby incorporated by reference. Anyone skilled in the art is fully skilled in identifying active agents and, based on these references, likewise skilled in manufacturing and testing pharmaceutical indications and properties in standard test models, both in vitro and in vivo.

The pharmaceutical preparations described herein are for enteral, as well as oral, but also rectal or parenteral administration to homeotherms, with preparations comprising the active pharmacological compound either alone or together with customary pharmaceutical auxiliaries. For example, pharmaceutical preparations consist of from about 0.1% to 90%, preferably from about 1% to about 80%, of the active compound. Pharmaceutical preparations for enteral or parenteral as well as ocular administration are, for example, in unit dosage forms such as coated tablets, tablets, capsules or suppositories as well as ampoules. These are prepared in a manner which is known per se, for example using conventional mixing, granulating, coating, solubilizing or lyophilizing processes. Accordingly, pharmaceutical preparations for oral use may be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulating into tablets or tablet cores. coated after having suitable auxiliary substances added.

The dosage of active compound may depend on a variety of factors, such as mode of administration, homeothermic species, age and / or individual condition.

Preferred dosages, for those commercially available active ingredients of the pharmaceutical combination according to the present invention, are especially therapeutically effective commercially available dosages.

The dosage of active compound may depend on a variety of factors, such as mode of administration, homeothermic species, age and / or individual condition.

The corresponding active ingredient or a pharmaceutically acceptable salt thereof may also be used as a hydrate or include other solvents used for crystallization.

The exact dosage will certainly vary depending on the compound employed, mode of administration and desired treatment. The compound may be administered by any conventional, non-oral or preferably oral routine.

For larger mammals, an indicated total daily dosage is in the range of about 0.01 to 100 mg / kg of the compound, conveniently administered in divided doses 2-4 times daily in unit dosage form containing for example about from 0.1 to about 50 mg of the sustained release compound.

Preferably for the especially villil-gliptin DPP-IV inhibitor, a total daily dosage indicated is in the range of 1 to 500 mg, preferably 10 to 200 mg of active ingredient.

Another preferred DPP-IV inhibitor especially vildagliptin oral dosage daily is between 1 and 100 mg, preferably between 10 and 100 mg, for example 10 mg, more preferably between 25 and 100 mg, for example 25 mg or 30 or 40 or 50, 61, 70, 90, 100 mg. The most preferred daily oral dosage of vildagliptin is between 50 and 150 mg.

Unit doses suitable for oral administration contain for example about 25 to about 150 mg DPP-IV inhibitor especially vildagliptin, such as preferably 25, 50, 100 or 150 mg. Suitable doses for parenteral administration contain, for example, from about 1 to about 150 mg of the compound, for example from 10 to 50 mg.

The DPP-IV inhibitor may also be given every day (for example twice a day or once a day), or only every other day, or twice a week.

The compounds may be administered similarly to known standards for use in these utilities. The proper daily dosage for a particular compound will depend on a number of factors such as its relative potency of activity. A person skilled in the art is fully skilled in determining the therapeutically effective dosage.

For example, the doses of aliskiren to be administered to warm-blooded animals, including man, of approximately 75 kg body weight, especially those effective for inhibiting renin activity, for example in decreasing blood pressure, are about 3 mg to about 3 g, preferably from about 10 mg to about 1 g, for example from 20 to 200 mg / person / day, preferably divided into 1 to 4 single doses which may, for example. , be the same size. Generally, children receive about half of the adult dose. The dose required for each individual can be monitored, for example, by measuring the serum concentration of the active ingredient, and adjusted to an optimal level. Single doses comprise, for example, 75 mg, 150 mg or 300 mg per adult patient.

Angiotensin II receptor blockers, for example, val-

sartan, are provided in the form of a suitable dosage unit form, for example a capsule or tablet, and comprising a therapeutically effective amount of an angiosterin II receptor blocker, for example from about 20 to about 320 mg valsartan, which can be applied to patients. Application of the active ingredient may occur up to three times daily starting, for example, with a daily dose of 20 mg or 40 mg of an angiotensin II receptor blocker, eg valsartan, increasing by 80 mg. daily and also to 160 mg daily, and finally up to 320 mg daily. Preferably, an angiotensin II receptor blocker, for example, valsartan is applied once daily or twice daily at a dose of 80 mg or 160 mg, respectively, each. Corresponding doses may be taken, for example, in the morning, noon or evening.

The compound of the invention may be administered in free base to or as a pharmaceutically acceptable acid addition salt or quaternary ammonium. Such salts may be prepared conventionally and exhibit the same order of activity as free forms. If these compounds have, for example, at least one basic center, they may form acid addition salts. Corresponding acid addition salts may also be formed having, if desired, an additionally present basic center. Compounds having an acid group (e.g. COOH) may also form salts with bases. For example, the compounds to be combined may be present as a sodium salt, as a maleate or as a dihydrochloride. The active ingredient or a pharmaceutically acceptable salt thereof may also be used as a hydrate or include other solvents used for crystallization. The present invention relates to a combination comprising

a DPP-IV inhibitor in free or pharmaceutically acceptable salt form, and an additional drug, for example a thiazolidinedione or calcium channel blocker, or the pharmaceutically acceptable salt thereof and optionally at least one pharmaceutically acceptable carrier. vel; wherein the active ingredients may be administered simultaneously or sequentially in any order, separately or in a fixed combination (same galenic formulation).

A combined preparation comprising a free form or pharmaceutically acceptable salt DPP-IV inhibitor and an additional drug, for example a thiazolidinedione or a calcium channel blocker, and optionally at least one, i.e. one or more, for example, two, pharmaceutically acceptable carrier for simultaneous, separate or sequential use is especially a "kit of parts" in the sense that the components, a free-form or pharmaceutically acceptable salt DPP-IV inhibitor and an additional drug , for example, a thiazolidinedione or calcium channel blocker, may be dosed independently or by use of different fixed combinations with different amounts of the components, i.e. at different times or simultaneously. The parts of the parts kit can then, for example, be administered simultaneously or chronologically, that is, at different times and at the same or different time intervals for any part of the parts kit. Preferably, the time intervals are chosen such that the effect on the disease or condition treated in the combined use of the parts is greater than the effect that would be obtained by using only any of the components.

A therapeutically effective amount of each of the combination components of the present invention may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination. For example, the method of treatment of the invention may comprise (i) administering a free-form DPP-IV inhibitor or pharmaceutically acceptable salt and (ii) administering an additional drug, for example a thiazolidinedione or a calcium channel blocker, simultaneously or sequentially in any order, in therapeutically effective amounts together, preferably in synergistically effective amounts, for example, in dosages daily corresponding to the ratios described herein. The pharmaceutical compositions according to the invention may

may be prepared in a manner known per se and are those suitable for enteral administration, such as oral or rectal administration, and parenteral to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound alone. or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.

To further illustrate the invention, but not by way of limitation, the following clinical study is provided. Additional experimental protocols are described in WO 01/52825 describing combinations comprising a DPP-IV inhibitor and an antidiabetic agent, for example thiazolidinedione. The invention has been described above by reference to preferred embodiments, but when those skilled in the art appreciate, many additions, omissions, and modifications are all possible within the scope of the claims below.

All patents and literature references cited in this study

Specification are hereby incorporated by reference in their entirety. In case of inconsistencies, the present description, including definitions and interpretations, shall prevail. EXAMPLE: CLINICAL STUDY Materials and methods:

The study is a randomized, double-blind, parallel-group, controlled, multicenter trial to compare the effects of 24-week treatment with vildagliptin 100 mg combined with pioglitazone 30 mg and a lower dose combination (50 mg vildagliptin + 15 mg pioglitazone) to component monotherapies in T2DM (type 2 diabetes) patients who had never used the drug. All drugs were given as dose amounts. He was conducted in 145 centers in the United States (90), Korea (15), United Kingdom (10), Italy (8), Taiwan (7), Slovakia (6), Czech Republic (5) and India (4). Investigational and reference therapy:

Patients are assigned to double-blind treatment with combination treatment with vildagliptin 100 mg and pioglitazone 30 mg, vildagliptin 100 mg monotherapy, pioglitazone 30 mg monotherapy, or tra - combination treatment with 50 mg vildagliptin and 15 mg pioglitazone in a 1: 1: 1: 1 ratio using a double dummy technique. List of Abbreviations

ADA American Diabetes Association

AE adverse event

ALT alanine aminotransferase / glutamic pyruvic transaminase

transaminase / GPT

ANCOVA Covariance Analysis

AST aspartate aminotransferase / glutamic oxaloacetic transaminase / GOT

AUC Area under plasma concentration time curve

bid bis in diem / twice daily

BMI Body Mass Index

bpm Beats per minute

BUN Blood Urea Nitrogen

CFR Code of Federal Regulations

CPO Country Pharma Organization

CRD Clinical Research and Development

DPP-4 Dipeptidyl peptidase IV

ECG ECG

EDC Electronic Data Capture

FDA Food and Drug Administration

FPG Fasting Plasma Glucose

GLP-1 Glucagon-like peptide 1

HbAic HemogIobinaAIC

HDL High Density Lipoprotein

HPLC High Pressure Liquid Chromatography

IB Researcher's Notebook

IEC Independent Ethics Committee

IRB Institutional Inspection Panel

ITT Purpose to treat

IUD Intrauterine Contraceptive Device

LC-MS / MS Liquid chromatography / serial mass spectrometry

LDL Low Density Lipoprotein LOCF Employed By Last Observation

M1 Myocardial infarction

Pharmacodynamic PD

PK Pharmacokinetics

PP By protocol

When's what 's said?

RAN Randomized

SAE Serious Adverse Event

SAF Security

ULN Upper Normal Limit

VLDL Very Low Density Lipoprotein

WHO World Health Organization

Glossary of Terms

Evaluation

A procedure used to generate data required by the study.

Control; control drug

Record

A study drug used as a comparator to reduce trial bias, preserve investigational drug blindness, assess internal study validity, and / or evaluate comparative effects of the investigational drug.

Point / time of patient entry into the study; the point at which informed consent is to be obtained (ie prior to the initiation of any of the procedures described in the protocol).

Investigational drug

The study drug whose properties

1 :

are being tested in the study; This definition is consistent with Section 312.3 of US CFR 21 and is synonymous with "new investigational drug". Medication Number A unique identifier on the label of each medication package in studies dispensing medication using an IVR system. Patient Number A unique identifier assigned to each patient who enrolls in the study. Phase A major subdivision of the study time line; begins and ends with major study marks such as registration, randomization, completion of treatment, etc. Period A smaller subdivision of the study timeline; splits phases into smaller functional segments. Premature patient withdrawal Point / time when the patient leaves the study prior to the planned completion of all study drug administrations and evaluations; At this time, all study drug administration is discontinued and no further evaluation is planned. Randomization Number A unique identifier assigned to each randomized patient, corresponding to a specific treatment group choice. Study drug Any drug administered to the patient as part of the required study procedures; includes investigational drug and any control drugs. Study drug discontinuation Point / time when patient permanently stops taking study drug for any reason; may or may not also be the point / time of premature patient withdrawal. Variable Information used in data analysis;

derived directly or indirectly from data collected using specified assessments at specified times.

Study plan:

This is a randomized, double-blind, multicenter controlled asset study. Patients who had never used the type 2 diabetes drug (7.5 to 11% HbA1c) are also randomized to vildagliptin 100 mg monotherapy, pioglitazone 30 mg monotherapy, combination treatment with 50 mg vildagliptin and 15 mg pioglitazone, or combination treatment with 100 mg vildagliptin and 30 mg pioglitazone. Each patient attends an analysis visit (Week -2) where the inclusion / exclusion criteria are evaluated. Eligible patients are then randomized to visit 2 (Reference, Day 1) and 4 complete additional visits over a 24-week treatment period. Inclusion / Exclusion Criteria Inclusion

- Non-fertile males and females (females of potential pregnancy

using a medically approved non-hormonal delivery control method) with T2DM who were treated without Oral Antidiabetic Drug (OAD) for at least 12 weeks prior to Visit 1 and who had never received an OAD for> 3 consecutive months at any time in the past

- 18 to 80 years old, 22 to 45 kg / m2 BMI, 7.5 to 11% HbA1c, <15 mmol / L FPG Exclusion

- History of acute metabolic complications of T1DM within the last 6 months,

- History of serious CVD, liver disease, congestive heart failure

- ALT, AST> 2.5 χ ULN, direct bilirubin> 1.3 χ ULN, serum creatinine> 2.5 mg / dL, fasting TG> 700 mg / dL

Study Evaluations

- Primary efficacy assessment - HbAic measured with

HPLC Logo

- Secondary efficacy assessments - FPG, fasting lipids (TG, total cholesterol, HDL, calculated LDL, calculated VLDL and non-HDL cholesterol) and body weight

- Adverse events assessed according to severity and

possible relationship to study medication

- Hypoglycaemia defined as symptoms confirmed by SMBG <3.1 mmol / L plasma equivalent glucose. Severe hypoglycaemia defined as any episode requiring assistance from someone else

Statistical analysis

- Change of reference to week 24 or full stop at

ITT population with LOCF

- ANCOVA models with treatment and predefined united center as measurement of classification variables and reference as covariate.

- Primary comparison in studies is pioglitone monotherapy

tazona

- The safety assessment is based primarily on the frequency of treatment emergent adverse events, the number of post-reference laboratory values falling outside predetermined ranges.

and in the frequency and severity of hypoglycemic events during the double-blind randomized treatment period. Treatment groups are specifically compared using Fisher's exact test with respect to the rate of peripheral edema event. Results:

- Within the study the group is well balanced in reference.

- Study participants 1 are predominantly Asian or Caucasian1 with a mean age of 51.5 years, BMI <30 kg / m2, disease duration of 2.1 years and HbA1c of 8.7% while not receiving any. OAD

- Approximately 1/3 of participants are in the high reference HbA1c group (> 9.0%).

- Each treatment produced significant improvements in

glycemic control, but the decreases in HbA1c with each initial combination regimen are significantly greater than with pioglitazone monotherapy (30 mg daily).

- The difference between treatment in the adjusted mean change (AMA) in HbA1c with 100 mg vildagliptin combined with 30 mg

pioglitazone is -0.6% (95% Cl: [-0.8, -0.3%], P <0.001).

- Of note, initial combination with the combination of vildaglipetin (50 mg) and pioglitazone (15 mg) lower dose decreases HbA1c by 1.7 ± 0.1% which is significantly greater reduction compared to monotherapy of

30 mg pioglitazone.

- Vildagliptin combined with pioglitazone produces a dose-related increase in the percentage of patients achieving the HbAic ADA recommended therapeutic target <7.0%.

- Initial combination treatment with vildagliptin 100 mg + pioglitazone 30 mg has been found to allow 65% of patients to achieve target HbA1c levels. Safety and Tolerability

Number (%) of patients reporting common Adverse Events (AEs) (> 5% in any group)

Initial Combination

100 mg of Vil- 50 mg of Vilda 100 mg of 30 mg of

vildagliptin Pioglitazone

da + +

Pio mg 15 mg Pio amount Daily amount Daily

daily daily

Any AE

Increased weight

N = 148

75 (50.7)

N = 144

66 (45.8)

N = 153

N = 161

11 (7.4)

3 (2.1)

78 (51.0) 1 (0.7)

83 (51.6) 8 (5.0)

Headache

9 (6.1)

Peripheral edema 9 (6,1) Dizziness 7 (4,7)

5 (3.5)

5 (3.5) 3 (2.1)

(3.3)

8 (5.2) 9 (5.9)

5 (3.1)

The applicant surprisingly found that vildagliptin reduces edema occurrence especially thiazolidinedione-associated edema.

Claims (24)

A method for preventing, retarding progress or reducing the occurrence of edema, comprising administering a therapeutically effective amount of a DPP-IV inhibitor, or pharmaceutically acceptable salt thereof, to a patient in need thereof. A method for preventing, retarding progress or reducing the occurrence of thiazolidinedione-associated edema, comprising administering a therapeutically effective amount of a thiazolidinedione, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically acceptable amount. of a DPP-IV inhibitor, or pharmaceutically acceptable salt thereof, to a patient in need thereof. 3. Use of a DPP-IV inhibitor or pharmaceutically acceptable salt thereof for the manufacture of a medicament to prevent, retard progress or reduce the occurrence of edema. 4. Use of a thiazolidinedione or pharmaceutically acceptable salt thereof, in combination with a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to prevent, retard progress or reduce the occurrence of edema associated with thiazolidinedione. A method according to claim 1 or a use according to claim 3, wherein the edema is a drug associated edema. A method according to claim 5 or a use according to claim 5 wherein the drug-associated edema is antihypertensive agent-associated edema or anti-diabetic agent-associated edema. A method according to claim 5 or a use according to claim 5 wherein the edema is thiazolidinedione-associated edema or calcium channel antagonist-associated edema. A method according to claim 5 or a use according to claim 5 wherein the drug is selected from pioglitazone, rosiglitazone and amlodipine, or in any case a pharmaceutically acceptable salt thereof. A method or use according to any preceding claim, wherein the edema is peripheral edema, diabetic macular edema or pulmonary edema. A method or use according to any preceding claim, wherein the DPP-4 inhibitor is administered in combination with one, two or three additional compounds selected from antidiabetic agents and antihypertensive agents or in any case a salt. pharmacist of the same. The method or use according to claim 10, wherein the additional compound is selected from sulfonylureas, thiazolidinediones, metformin, insulin, and calcium channel blockers. A method or use according to any preceding claim, wherein the treated patient is selected from a patient suffering from antihypertensive agent-induced edema or calcium channel blocker-induced edema. A method or use according to any preceding claim, wherein the DPP-IV inhibitor is selected from 1- {2 - [(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2- ( S) -cyano-pyrrolidine (also called carbonitrile monohydrochloride [S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidine), Vildagliptin, L-threo isoleucyl P32 / thiazolidine 98, Sytagliptin, GSK23A, saxagliptin, 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2 - {[3- (aminomethyl) - 2-Isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally in any case pharmaceutical salts thereof. A method or use according to any preceding claim, wherein the DPP-IV inhibitor is vildagliptin or a pharmaceutical salt thereof. A method or use according to any preceding claim, wherein between 50 and 150 mg vildagliptin or pharmaceutical salts thereof is administered daily. A method or use according to any preceding claim, wherein thiazolidinedione is selected from pioglitazone or rosiglitazone or optionally pharmaceutical salts thereof. 17. Treatment regimen wherein i) 50 mg, 100 mg or 150 mg vildagliptin or a pharmaceutically acceptable salt thereof must be administered in combination with a thiazolidinedione or a pharmaceutically acceptable salt thereof daily. , to a patient in need thereof, ii) the treated patient is selected from a patient suffering from thiazolidinedione-associated edema. 18. Treatment regimen wherein i) 50 mg, 100 mg or 150 mg vildagliptin or a pharmaceutically acceptable salt thereof should be administered in combination with a thiazolidinedione or a pharmaceutically acceptable salt thereof daily. to a patient in need thereof, ii) the treated patient is a patient whose disease has not been adequately controlled by a thiazolidinedione alone, and iii) the treated patient is selected from a patient suffering from thiazolidinedione-associated edema. Treatment regimen according to either claim 17 or 18, wherein; - 15 to 45 mg of pioglitazone or a pharmaceutically acceptable salt thereof, or - 2 to 8 mg of rosiglitazone or a pharmaceutically acceptable salt thereof are administered daily to said patient. A treatment regimen according to any one of claims 17 to 19, wherein the patient is also under treatment with an additional active agent such as insulin, sulfonylurea or metformin. A treatment regimen according to any one of claims 17 to 20, wherein thiazolidinedione is selected from pioglitazone or rosiglitazone or optionally a pharmaceutical salt thereof. Use, method or treatment regimen according to any of the preceding claims, wherein the treated patient is suffering from hypertension, diabetes mellitus, type I or insulin dependent diabetes mellitus (IDDM), type II diabetes mellitus. or non-insulin dependent (NIDDM), insulin resistance type A, IGM, IFG or IGT. Use, method or treatment regimen according to any of the preceding claims, wherein between 250 mg and 3000 mg of metformin or a salt thereof is administered daily to the treated patient. Use, method or treatment regimen according to any preceding claim, wherein; - 15 to 45 mg of pioglitazone or a pharmaceutically acceptable salt thereof, - 2 to 8 mg of rosiglitazone or a pharmaceutically acceptable salt thereof, or - 1 to 10 mg of a CBB or a pharmaceutically acceptable salt thereof. is given daily to that patient.