WO2008057337A2

WO2008057337A2 - Use of dipeptidyl peptidase iv inhibitors for preventing, delaying or reducing the occurance of edema

Info

Publication number: WO2008057337A2
Application number: PCT/US2007/022902
Authority: WO
Inventors: Börk BALKAN; David Grenville Holmes; Thomas Edward Hughes; Edwin Bernard Villhauer
Original assignee: Novartis Ag
Priority date: 2006-11-01
Filing date: 2007-10-30
Publication date: 2008-05-15
Also published as: KR20090075747A; BRPI0717874A2; JP2010508348A; CN101557811A; EP2079469A2; CA2668162A1; WO2008057337A3; MX2009004627A; AU2007318059A1

Abstract

A method to prevent, delay the progression or reduce, 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.

Description

Use of Organic compounds

The 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, delay the progression or reduce, the occurrence of edema e.g. peripheral edema or drug induced edema.

The 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) which is characterized by hyperglycemia. There are three basic types of diabetes mellitus, type I or insulin-dependent diabetes mellitus (IDDM), type Il or non-insulin- dependent diabetes mellitus (NIDDM), and type A insulin resistance. Patients with either type I or type Il diabetes can become insensitive to the effects of exogenous insulin ("insulin resistant") through a variety of mechanisms. Type A insulin resistance results from either mutations in the insulin receptor gene or defects in post-receptor sites of action critical 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 usually occurs 2-3 times more frequently than overt 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 has been defined on the basis of 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 secondary failure rate. This high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycemia-associated complications in patients with type 2 diabetes.

Thiazolidinediones are effective and commonly administered drugs for controlling plasma glucose concentrations in patients with type 2 diabetes mellitus. Thiazolidinedione are commonly used oral antidiabetic agents. However thiazolidinediones have significant safety/tolerability issues that limit their use or safe use. Indeed, it is well known that thiazolidinediones' main safety issue is to increase the occurrence of edema in the treated patients. Fluid retention occurs in 5% to 15% of patients taking thiazolidinediones. In some of these patients, thiazolidinediones use 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 thiazolidinediones use should be considered when assessing treatment options for patients with diabetic macular edema (DME), especially those with concomitant peripheral edema. In large clinical trials with rosiglitazone and pioglitazone, the frequency of edema in thiazolidinedione-treated patients was about 3 to 4 times higher than in placebo-treated patients. In addition to peripheral edema, reports have described pulmonary edema associated with thiazolidinedione therapy. Options for management thiazolidinedione-associated edema include dose reduction, drug discontinuation, and symptomatic therapy with diuretics. However, this is not an appropriate solution for diabetic patients depending on thiazolidinediones treatment.

The applicant has surprisingly discovered that DPP-IV inhibitors especially vildagliptin, or a pharmaceutically acceptable salt thereof, can reduce the occurrence of edema in patients.

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

The antidiabetic thiazolidinedione ( i.e. glitazone) is, for example, (S)-((3,4-dihydro-2- (phenyl-methyl)-2H-1 -benzopyran-6-yl)methyl-thiazolidine-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-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4- dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5- {[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-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-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 glitazone like "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 instance, the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. This dose can 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 usually 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 usually 100 to 1000 mg, preferably 200 to 600 mg. When rosiglitazone (or its maleate) is employed as the insulin sensitizer, the dose of rosiglitazone per day is usually 1 to 12 mg, preferably 2 to 12 mg.

The 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 in monotherapy or in combination with sulfonylurea, metformin, or insulin. ACTOS in combination with metformin may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with ACTOS. ACTOS is available in 15 mg, 30 mg, and 45 mg tablets

AVANDIA® (rosiglitazone maleate) may be administered either at a starting dose of 4 mg as a single daily dose or divided and administered in the morning and evening. For patients who respond inadequately following 8 to 12 weeks of treatment, as determined by reduction in FPG, 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 dose or divided twice daily. AVANDIA is available in 2 mg, 4 mg, and 8 mg tablets Marketed combinations comprising metformin and a thiazolidinedione derivative can also be used according to the present invention. In particular it can be possible to administer rosiglitazone in combination with metformin in the form as it is marketed e.g. under the trademark AVANDAMET®. The dosage of antidiabetic therapy with AVANDAMET should be individualized on the basis of effectiveness and tolerability while not exceeding the maximum recommended daily dose of 8 mg/2,000 mg. AVANDAMET® provides different kind of tablets. Each tablet contains rosiglitazone as the 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" is also intended to comprise any salt or crystal form thereof, e.g the rosiglitazone maleate salt.

Metformin has been widely prescribed for lowering blood glucose in patients with NIDDM and is marketed in 500, 750, 850 and 1000 mg strengths. However, because it is a short acting drug, metformin requires twice-daily or three-times-daily dosing (500 - 850 mg tab 2-3/day or 1000 mg bid with meals). The biguanide antihyperglycemic agent metformin disclosed in U.S. Patent No. 3,174,901 is currently marketed in the U.S. in the form of its hydrochloride salt (Glucophage@), Bristol-Myers Squibb Company). The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by Emil A. Werner and James Bell, J. Chem. Soc. 121 , 1922, 1790-1794. Metformin, can be administered e.g. in the form as marketed under the trademarks GLUCOPHAGE™.

Mefformin, increases the sensitivity to insulin in peripheral tissues of the hosts. Mefformin is also involved in inhibition of glucose absorption from the intestine, suppression of hepatic gluconeogenesis, and inhibition of fatty acid oxidation. Suitable dosage regimens of Mefformin include unit doses of 500 mg two to three time's daily and can even be build up to five times daily or 850 mg once or twice daily. [Martindale, The Complete Drug Reference.

The term "metformin" as employed herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2:1) fumarate salt, and the metformin (2:1) succinate salt as disclosed in U.S. application Serial No. 09/262,526 filed March 4, 1999, the hydrobromide salt, the p-chlorophenoxy acetate or the embonate, and other known metformin salts of mono and dibasic carboxylic acids including those disclosed in U.S. Patent No. 3, 174,901 , all of which salts are collectively referred to as metformin. It is preferred that the metformin employed herein be the metformin hydrochloride salt, namely, 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 that exhibits inhibition of the enzymatic activity of DPP-IV and functionally related enzymes, such as from 1-100% inhibition, and specially preserves the action of substrate molecules, including but not limited to glucagon-like peptide-1 , gastric inhibitory polypeptide, peptide histidine methionine, substance P, neuropeptide Y, and other molecules typically containing alanine or proline residues in the second aminoterminal position. Treatment with DPP-IV inhibitors prolongs the duration of action of peptide substrates and increases levels of their intact, undegraded forms leading to a spectrum of biological activities relevant to the disclosed invention.

DPP-IV can be used in the control of glucose metabolism because its substrates include the insulinotropic hormones Glucagon like peptide- 1 (GLP-1) and Gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; removal of their two N-terminal amino acids inactivates them. In vivo administration of synthetic inhibitors of DPP-IV 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 that purpose, chemical compounds are tested for their ability to inhibit the enzyme activity of purified CD26/DPP-IV. Briefly, the activity of CD26/DPP-IV is measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (GIy- Pro-pNA). Cleavage of Gly-Pro-pNA by DPP-IV liberates the product p-nitroanilide (pNA), whose rate of appearance is directly proportional to the enzyme activity. Inhibition of the 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 generation of pNA. Thus, the degree of inhibition of the rate of accumulation of pNA is a direct measure of the strength of enzyme inhibition. The accumulation of pNA 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 prodrugs of DPP-IV inhibitors. 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 metabolised to a DPP-IV inhibitor or is metabolised 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 representatives of 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 the compounds specifically listed in the examples I to LXIII and the described corresponding analogues, even preferred compounds are 2(28), 2(88), 2(119), 2(136) described in the table reporting IC50, WO 02083128 such as in the claims 1 to 5 especially compounds described in examples 1 to 13 and the 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, EP1258480 especially compounds of examples 1 to 60, WO 0181337 especially examples 1 to 118, WO 02083109 especially examples 1A to 1 D, WO 030003250 especially compounds of examples 1 to 166, most preferably 1 to 8, WO 03035067 especially the compounds described in the 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 claim 2, WO 03002553 especially compounds of examples 1 to 33, WO 01/34594 especially the compounds described in the 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 described examples, 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 described examples, WO 0155105 especially the compounds listed in the examples 1 and 2, WO 0202560 especially examples 1 to 166, WO 03004496 especially examples 1 to 103, WO 03/024965 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 the compound of example 95 (2-{{3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1 ,2 dihydro-6- isoquinolinyl}oxy}acetamide hydrochloride), 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 of 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) to z), aa) to az), ba) to bz), ca) to cz) and da) to dk), WO 0214271 especially examples 1 to 320, US 2003096857, U.S. application Serial No. 09/788,173 filed February 16, 2001 (attorney file LA50) especially the described examples, WO99/38501 especially the described examples, W099/46272 especially the described examples and DE19616 486 A1 especally val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and fumar salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.

Further preferred DPP-IV inhibitors include the specific examples disclosed in United States Patent Numbers 6124305 and US 6107317, International Patent Applications, Publication Numbers WO 9819998, WO 95153 09 and WO 9818763; such as 1[2- [(5 eyanopyridin-2- yl)aminoethylamino]acetyl-2-cyano-(S)-pyrrolidine and (2S)- l-[(2S)-2 amino-3,3- dimethylbutanoyl]-2-pyrrolidinecarbonitrile.

In a further preferred embodiment, the DPP-IV inhibitor is a N-peptidyl-O-aroyl hydroxylamine or a pharmaceutically acceptable salt thereof. The peptidyl moiety comprises preferably two α-amino acids, e.g. glycine, alanine, leucine, phenylalanine, lysine or proline, of which the one attached directly to the hydroxylamine nitrogen atom is preferably proline.

In each case in particular in the compound claims and the final products of the working examples, the subject matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.

WO 9819998 discloses 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 WO03/002553 are listed on pages 9 to 11 and are incorporated into the present application by reference.

DE19616 486 A1 discloses val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl- pyrrolidide, and fumar salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.

WO 0034241 and US 6110949 disclose N-substituted adamantyl-amino-acetyl-2-cyano pyrrolidines and W (substituted glycyl)-4-cyano pyrrolidines respectively. DPP-IV inhibitors of interest are specially those cited in claims 1 to 4. WO 9515309 discloses amino acid 2- cyanopyrrolidine amides as inhibitors of DPP-IV and WO 9529691 discloses peptidyl derivates of diesters of alpha-aminoalkylphosphonic acids, particularly those with proline or related structures. DPP-IV inhibitors of interest are specially those cited in Table 1 to 8.

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

WO01/52825 specially discloses (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 discloses proline boronic esters useful as DPP-IV inhibitors. DPP-IV inhibitors of interest are specially those cited in examples 1 to 19.

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

WO 9938501 discloses N-substituted 4- to 8-membered heterocyclic rings. DPP-IV inhibitors of interest are specially those cited in claims 15 to 20.

WO 9946272 discloses phosphoric compounds as inhibitors of DPP-IV. DPP-IV inhibitors of interest are specially those cited in claims 1 to 23.

Other preferred DPP-IV inhibitors are the compounds of formula I, Il or III disclosed in the patent application WO 03/057200 on page 14 to 27. Most preferred DPP-IV inhibitors are the compounds specifically described on pages 28 and 29.

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

Preferably, the N-peptidyl-O-aroyl hydroxylamine is a compound of formula VII

wherein j is 0, 1 or 2;

Re₁ represents the side chain of a natural amino acid; and

Re₂ represents lower alkoxy, lower alkyl, halogen or nitro; or a pharmaceutically acceptable salt thereof.

In a very preferred embodiment of the invention, the N-peptidyl-O-aroyl hydroxylamine is a compound of formula Vila

or a pharmaceutically acceptable salt thereof.

N-Peptidyl-O-aroyl hydroxylamines, e.g. 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 and col. (Expert Opinion

Investig Drugs. 2003 Apr;12(4):623-33) on the paragraph 5, especially P32/98, K-364, FE-

999011 , BDPX, NVP-DDP-728 and others, which publication is hereby incorporated by reference especially the described DPP-IV inhibitors.

Another preferred DPP-IV inhibitor is the No.815541 (T 6666) from Tanabe.

Preferred DPP-IV inhibitors are also described in the patent applications WO 02/083128, especially the compounds described in the examples 1 to 13, US 6,395,767 examples 1 to 109 and WO 03/033671 all the specifically described compounds e.g. 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 the compound BMS-477118 disclosed in WO 2001068603 or U.S. Patent No. 6,395,767 (compound of example 60) also known as is (1S,3S,5S)-2-[(2S)- 2-amino-2-(3-hydroxytricyclo[3.3.1.1^3|7]dec-1 -yl)-1 -oxoethyl]-2-azabicyclo[3.1.0]hexane-3- carbonitrile, benzoate (1 :1) as depicted in Formula M of the patent application WO 2004/052850 on page 2, and the corresponding free base, (IS,3S,5S)-2-[(2S)-2-amino-2- (3- hydroxy-tricyclo[3.3.1.1³'⁷]dec-1 -yl)-1 -oxoethyl]-2-azabicyclo-[3.1.0]hexane-3-carbonitrile (M') and its monohydrate (M") as depicted in Formula M of the patent application WO 2004/052850 on page 3. The compound BMS-477118 is also known as saxagliptin. Another preferred inhibitor is the compound GSK23A disclosed in WO 03/002531 (example 9) also known as (2S.4S)- 1- ((2R)-2-Amino-3-[(4-methoxybenzyl)sulfonyl]-3- methylbutanoyl)-4-fluoropyrrolidine-2-carbonitrile hydrochloride.

P32/98 (CAS number: 251572-86-8) also known as 3-[(2S,3S)-2-amino-3-methyl-1- oxopentyl]thiazolidine can be used as 3-[(2S,3S)-2-amino-3-methyl-1-oxopentyl]thiazolidine and (2E)-2-butenedioate (2:1) mixture and is described in WO 99/61431 and the below formula,

is described in WO 99/61431 and also in Diabetes 1998, 47, 1253-1258, in the name of Probiodrug, as well as the compound P93/01 described by the same company.

Other very preferred DPP-IV inhibitors are the compounds disclosed in the patent application WO 02/083128 such as in the claims 1 to 5. Most preferred DPP-IV inhibitors are the compounds specifically described by the examples 1 to 13 and the claims 6 to 10.

Other very preferred DPP-IV inhibitors are the compounds disclosed By Bristol-Myers Squibb such as Saxagliptin (BMS477118).

Other very preferred DPP-IV inhibitors of the invention are described in the International patent application WO 02/076450 (especially the examples 1 to 128) and by Wallace T. Ashton (Bioorganic & Medicinal Chemistry Letters 14 (2004) 859-863 ) especially the compound 1 and the compounds listed in the tables 1 and 2. The preferred compound is the compound 21 e (table 1) of formula :

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

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

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

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

5.

Preferred DPP-IV inhibitors are N-substituted adamantyl-amino- acetyl-2-cyano pyrrolidines,

N (substituted glycyl)-4-cyano pyrrolidines, N- (N'-substituted glycyl)-2-cyanopyrrolidines, N- aminoacyl thiazolidines, N-aminoacyl pyrrolidines, 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.

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

[SH-^δ-cyano^-pyridinylaminoJethylaminolacetyl^-pyrolidine carbonitrile monohydrochloride and (SJ-i-KS-hydroxy-i-adamantyOaminolacetyl^-cyano-pyrrolidine are specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241 , respectively. The DPP-IV inhibitor P32/98 (see above) is specifically described in Diabetes 1998, 47, 1253-1258. [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrolidine carbonitrile monohydrochloride and (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano- pyrrolidine can be formulated as described on page 20 of WO 98/19998 or in WO 00/34241.

Especially preferred are 1-{2-[(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2-(S)-cyano- pyrrolidine (also named [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrolidine carbonitrile monohydrochloride), of formula :

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

and L-threo-isoleucyl thiazolidine (compound code according to Probiodrug: P32/98 as described above), Sitagliptin, GSK23A, saxagliptin, 3-(aminomethyl)-2-isobuthyl-1-oxo-4- phenyl-1 ,2-dihydro-6-isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2-isobuthyl-4-phenyl- 1-0X0-1 ,2-dihydro-6-isoquinolyl]oxy}acetamide and optionally in any case pharmaceutical salts thereof.

DPP728 and LAF237 are specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241 , respectively. The DPP-IV inhibitor P32/98 (see above) is specifically described in Diabetes 1998, 47, 1253-1258. DPP728 and LAF237 can be formulated as described on page 20 of WO 98/19998 or in WO 00/34241 , or in the International Patent Application No. EP2005/000400 (application number). .

Any of the substances disclosed in the above mentioned patent documents or scientific publications, hereby included 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 can be used in association with a carrier.

A carrier in the instant context is a tool (natural, synthetic, peptidic, non-peptidic) for example a protein which transports specific substances through the cell membrane in which it is embedded and into the cell. Different carriers (natural, synthetic, peptidic, non-peptidic) are required to transport different substances, as each one is designed to recognize only one substance, or group of similar substances.

Any means of detection known by the person skilled in the art can be used to detect the association of the DPP-IV with a carrier, for example, by labelling the carrier.

The DPP-IV inhibitor can be a peptidic or, preferably, non-peptidic one.

Most preferred are orally active DPP-IV inhibitors and pharmaceutical salts thereof.

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

The CCB is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, a pharmaceutically acceptable salt or prodrug thereof. All these CCBs are therapeutically used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs.

Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt or prodrug thereof. Especially preferred as DHP is amlodipine or a pharmaceutically acceptable salt, especially the besylate, thereof. An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof. The CCB is preferably amlodipine or a pharmaceutically acceptable salt, especially the besylate, thereof. CBBs are preferably administered from about 1 mg to about 100 mg daily, preferably between about 1 to 10 mg daily.

In case of amlodipine, preferred dosage unit forms are, for example, tablets or capsules comprising e.g. 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 (e.g. thiazolidinediones, calcium channel blockers or DPP-IV inhibitors) or pharmaceutically acceptable salts thereof according to the present invention may also be used in form of a solvate, such as a hydrate or including other solvents, used for crystallization.

It has now been surprisingly found that DPP-IV inhibitors especially vildagliptin or pharmaceutically acceptable salt thereof, can be used to prevent, delay the progression or reduce, the occurrence of edema, especially drug-associated edema e.g. thiazolidinedione- associated edema.

Thus in a first embodiment, this invention provides a method to prevent, delay the progression or reduce, the occurrence of thiazolidinedione-associated edema, comprising administering a therapeutically effective amount of a thiazolidinedione e.g. one or two thiazolidinediones, or 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 to prevent, delay the progression or reduce, the occurrence of edema, comprising administering a therapeutically effective amount of a DPP- IV inhibitor, preferably vildagliptin, or pharmaceutically acceptable salt thereof, to a patient in need thereof.

The invention furthermore relates to the use of thiazolidinediones e.g. 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 to prevent, delay the progression or reduce, the occurrence of thiazolidinedione-associated edema. The invention furthermore relates to the use of a DPP-IV inhibitor or pharmaceutically acceptable salt thereof, for the manufacture of a medicament to prevent, delay the progression 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 thiazolidinediones i.e. edema in the patients treated with thiazolidinediones e.g. one or two thiazolidinediones.

Method or use as described herein above, wherein the edema is preferably drug-associated edema i.e. subsequent to treatment with a drug (pharmacological active agent) i.e. edema in patients treated with a drug (pharmacological active agent). Drug-associated edema can for instance result from treatment with one or two drugs such as antidiabetic agents (e.g. thiazolidinediones, metformin or insulin), antihypertensive agents (e.g. calcium channel antagonists, renin inhibitors such as aliskiren, angiotensin Il 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).

Method or use as described herein above, wherein the edema is preferably edema induced by antihypertensive agents i.e. subsequent to treatment with antihypertensive agents i.e. edema in patients treated with antihypertensive agents e.g. one or two antihypertensive agents such as valsartan, aliskiren or amlodipine.

Method or use as described herein above, wherein the edema is preferably peripheral edema, diabetic macular edema (DME) or pulmonary edema, preferably thiazolidinedione associated edema or calcium channel blockers-associated edema.

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

Method or use as described herein above, wherein the DPP-4 inhibitor is administered in combination with a thiazolidinedione and metformin.

Preferably the treated patient in the herein claimed methods or uses, is selected from a thiazolidinediones, treated patient (e.g. one or two thiazolidinediones) suffering from thiazolidinediones-induced edema side effects. Preferably the treated patient in the herein claimed methods or uses, is selected from a patient treated by one or two drugs selected from antihypertensive agents, preferably suffering from antihypertensive agents-induced edema side effects or calcium channel blockers-induced edema.

Preferably the DPP-IV inhibitor is (S)-1-[(3-hydroxy-1-adamantyl) 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" is also intended to comprise any salt or crystal form thereof.

Preferably the 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. Most preferably the patient is suffering from a disease selected from hypertension, diabetes mellitus, type I or insulin-dependent diabetes mellitus (IDDM), type Il or non-insulin- dependent diabetes mellitus (NIDDM), type A insulin resistance, IGM, IFG or IGT. In a preferred embodiment the patient is suffering from type Il diabetes or IGT.

In a most preferred embodiment the DPP-IV inhibitor is added to the standard diabetes treatment in patients whose disease was not adequately controlled by thiazolidinediones alone.

The present methods or uses are particularly useful for the prevention or delay of progression of conditions associated with type Il diabetes or IGT, particularly cardiovascular and microvascular conditions.

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

Edema is defined as a clinically apparent increase in the interstitial fluid volume, which may expand by several liters before the abnormality is evident. Anasarca refers to gross, generalized edema. Ascites and hydrothorax refer to 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 lymphangitis, resection of regional lymph nodes, filariasis, etc. The great 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 generalized distribution; it is recognized in its generalized form by puffiness of the face, which is most readily apparent in the periorbital areas, and by the persistence of an indentation of the skin following pressure; this is known as "pitting" edema. In its more subtle form, edema may be detected by noting that after the stethoscope is removed from the chest wall, the rim of the bell leaves an indentation on the skin of the chest for a few minutes. When the ring on a finger fits more snugly than in the past or when a patient complains of difficulty in putting on shoes, particularly in the evening, edema may be present.

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

Furthermore as used herein, "a 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 outbreak of the conditions mentioned herein. Moreover, the term "prevention" means prophylactic administration of such combination to patients being in a pre-stage of the conditions, to be treated.

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

By the term "treatment" is understood the management 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 who is 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 is a human.

The term "whose disease was not adequately controlled by thiazolidinedione alone" used herein means preferably a hyperglycemia related disease such as diabetes, type 2 diabetes, IGT or IGM. In this field the preferred patient population age is from 45 years onwards, most preferred from 65 years onwards.

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

The invention also relates to a treatment regimen, wherein, i) 50 mg, 100 mg or 150 mg of vildagliptin or a pharmaceutically acceptable salt thereof, is to be administered in combination to a thiazolidinedione or a pharmaceutically acceptable salt thereof, preferably 15 to 45 mg of pioglitazone or 2 to 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, wherein, i) 50 mg, 100 mg or 150 mg of vildagliptin or a pharmaceutically acceptable salt thereof, is to be administered in combination to a thiazolidinedione or a pharmaceutically acceptable salt thereof, preferably 15 to 45 mg of pioglitazone or 2 to 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 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 herein described wherein thiazolidinedione is replaced by another drug such as a calcium channel blocker e.g. amlodipine or a salt thereof.

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

A treatment regimen, a method of treatment or a use as herein described, wherein between 250 mg and 3000 mg of metformin or a salt thereof is administered daily to the treated patient. When 100 mg of vildagliptin or a pharmaceutically acceptable salt thereof, is administered daily, it can be in the form of a once a day administration of 100 mg of vildagliptin (OD - once a day), or a twice daily administration of 50 mg (i.e. bid) of vildagliptin.

In the above described treatment regimen, 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 further drug such as the thiazolidinedione or the calcium channel blocker .

Preferably the treated patient in the above described methods or uses or treatment regimens, is suffering from hyperglycemia or hypertension,. Most preferably the patient suffering from hyperglycemia, is suffering from a disease selected from diabetes mellitus, type I or insulin-dependent diabetes mellitus (IDDM), type Il or non-insulin-dependent diabetes mellitus (NIDDM), type A insulin resistance, IGM, IFG or IGT. In a preferred embodiment the patient is suffering from type Il diabetes or IGT. In another preferred embodiment the treated patient is a patient whose disease was not adequately controlled by thiazolidinedione or metformin alone.

The structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.

The herein described pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances. For example, the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compound. Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilising processes. Thus, pharmaceutical preparations for oral use can 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 granulate into tablets or coated tablet cores after having added suitable auxiliary substances.

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

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

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

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

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

Preferably for the DPP-IV inhibitor especially vildagliptin an indicated total daily dosage is in the range from between 1 and 500 mg, preferably between 10 and 200 mg of active ingredient.

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

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

The DPP-IV inhibitor can also be administered every day (e.g. twice a day (BiD) or once a day (OD)), or only every two days, or twice a week. The compounds may be administered in similar manner to known standards for uses in these utilities. The suitable 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 pertinent art is fully enabled to determine 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 the doses effective for the inhibition of renin activity, e.g., in lowering blood pressure, are from about 3 mg to about 3 g, preferably from about 10 mg to about 1 g, e.g., from 20 to 200 mg/person/day, divided preferably into 1 to 4 single doses which may, e.g., be of the same size. Usually, children receive about half of the adult dose. The dose necessary for each individual can be monitored, e.g., by measuring the serum concentration of the active ingredient, and adjusted to an optimum level. Single doses comprise, e.g., 75 mg, 150 mg or 300 mg per adult patient.

Angiotensin Il receptor blockers, e.g., valsartan, are supplied in the form of a suitable dosage unit form, e.g., a capsule or tablet, and comprising a therapeutically effective amount of an angiotensin Il receptor blocker, e.g., from about 20 to about 320 mg of valsartan, which may be applied to patients. The application of the active ingredient may occur up to three times a day, starting, e.g., with a daily dose of 20 mg or 40 mg of an angiotensin Il receptor blocker, e.g., valsartan, increasing via 80 mg daily and further to 160 mg daily, and finally up to 320 mg daily. Preferably, an angiotensin Il receptor blocker, e.g., valsartan is applied once a day or twice a day with a dose of 80 mg or 160 mg, respectively, each. Corresponding doses may be taken, e.g., in the morning, at mid-day or in the evening.

The compound of the invention may be administered in free base for or as a pharmaceutically acceptable acid addition or quaternary ammonium salt. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free forms. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having an acid group (for example COOH) can also form salts with bases. For example, the compounds to be combined can 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 in form of a hydrate or include other solvents used for crystallization. The present invention refers to a combination which comprises a DPP-IV inhibitor in free or pharmaceutically acceptable salt form, and a further drug e.g. a thiazolidinedione or a calcium channel blocker, or the pharmaceutically acceptable salt thereof and optionally at least one pharmaceutically acceptable carrier; wherein the active ingredients can be administered simultaneously or sequentially in any order, separately or in a fixed combination (same galenic formulation).

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

A therapeutically effective amount of each of the components of the combination 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) administration of a DPP-IV inhibitor in free or pharmaceutically acceptable salt form and (ii) administration of a further drug e.g. a thiazolidinedione or a calcium channel blocker, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the ratios described herein.

The pharmaceutical compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration 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 carries, especially suitable for enteral or parenteral application. To further illustrate the invention, but not by way of limitation, the following clinical study is provided. Further experimental protocols are described in the patent application WO 01/52825 describing combinations comprising a DPP-IV inhibitor and an antidiabetic agent e.g. thiazolidinedione.

The invention has been described above by reference to preferred embodiments but, as those skilled in the art will appreciate, many additions, omissions and modifications are possible all within the scope of the claims below.

All patents and literature references cited in this specification are hereby incorporated by reference in their entirety. In case of inconsistencies, the present description, including the definitions and interpretations, will prevail.

Example:

CLINICAL STUDY

Materials and methods:

The study is a multicenter, double-blind, randomized, parallel-group, active-controlled study to compare the effects of 24-week treatment with vildagliptin 100 mg combined with pioglitazone 30 mg and a lower-dose combination (vildagliptin 50 mg + pioglitazone 15 mg) to the component monotherapies in drug-naϊve patients with T2DM (type 2 diabetes). All drugs were given as qd doses. It was conducted at 145 centers in the US (90), Korea (15), UK (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 qd and pioglitazone 30 mg qd, vildagliptin 100 mg qd monotherapy, pioglitazone 30 mg qd monotherapy, or combination treatment with vildagliptin 50 mg qd and pioglitazone 15 mg qd, in a ratio of 1 :1 :1 :1 using a double dummy technique.

List of abbreviations

ADA American Diabetes Association

AE adverse event

ALT alanine aminotransferase/glutamic pyruvic transaminase/GPT

ANCOVA Analysis of co variance

AST aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT

AUC Area under the plasma-concentration time curve bid bis in diem/twice a day

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 Electrocardiogram

EDC Electronic Data capture

FDA Food and Drug Administration

FPG Fasting Plasma Glucose

GLP-I Glucagon-like peptide 1

HbA,c Hemoglobin AlC

HDL High density lipoprotein

HPLC High pressure liquid chromatography

IB Investigator Brochure

IEC Independent Ethics Committee

IRB Institutional Review Board

ITT Intent to treat

IUD Intrauterine contraceptive device

LC-MS/MS Liquid chromatography/tandem mass spectrometry

LDL Low density lipoprotein

LOCF Last Observation Carried Forward

MI Myocardial infarction

PD Pharmacodynamics

PK Pharmacokinetics

PP Per Protocol qd Qua 'que di 'el every day

RAN Randomized

SAE Serious adverse event

SAF Safety

ULN Upper limit of normal

VLDL Very low density lipoprotein

WHO World Health Organization Glossary of terms

Assessment A procedure used to generate data required by the study Control; control drug A study drug used as a comparator to reduce assessment bias, preserve blinding of investigational drug, assess internal study validity, and/or evaluate comparative effects of the investigational drug

Enrollment Point/time of patient entry into the study; the point at which informed consent must be obtained (i.e., prior to starting any of the procedures described in the protocol) Investigational drug The study drug whose properties are being tested in the study; this definition is consistent with US CFR 21 Section 312.3 and is synonymous with "investigational new drug."

Medication number A unique identifier on the label of each medication package in studies that dispense 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 timeline; begins and ends with major study milestones such as enrollment, randomization, completion of treatment, etc.

Period A minor subdivision of the study timeline; divides phases into smaller functional segments

Premature patient withdrawal Point/time when the patient exits from the study prior to the planned completion of all study drug administration and assessments; at this time all study drug administration is discontinued and no further assessments are planned

Randomization number A unique identifier assigned to each randomized patient, corresponding to a specific treatment group assignment

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 the data analysis; derived directly or indirectly from data collected using specified assessments at specified timepoints

Study design:

This is a multicenter, randomized, double-blind, active controlled study. Drug naϊve patients with type 2 diabetes (HbAIc 7.5-11%) are randomized equally to vildagliptin 100 mg qd monotherapy, pioglitazone 30 mg qd monotherapy, combination treatment with vildagliptin 50 mg qd and pioglitazone 15 mg qd, or combination treatment with vildagliptin 100 mg qd and pioglitazone 30 mg qd. Each patient attends one screening visit (Week -2) where the inclusion/exclusion criteria are assessed. Eligible patients are then randomized at visit 2 (Baseline, Day 1) and complete 4 additional visits over a period of 24 weeks of treatment.

Inclusion/Exclusion Criteria Inclusion - Male and non-fertile females (females of childbearing potential using a non-hormonal medically approved birth control method) with T2DM who have been treated with no Oral Anti-diabetic Drug (OAD) for at least 12 weeks prior to Visit 1 and who had never received an OAD for >3 consecutive months any time in the past

- Age 18 - 80 years, BMI 22 - 45 kg/m², HbA_1c 7.5 - 11%, FPG <15 mmol/L Exclusion

- History of T1 DM, acute metabolic complications within past 6 months,

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

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

Study Assessments

- Primary efficacy assessment - HbA₁₀ measured with HPLC methodology

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

- Adverse events assessed as to severity and possible relationship to study medication

- Hypoglycemia defined as symptoms confirmed by SMBG <3.1 mmol/L plasma glucose equivalent. Severe hypoglycemia defined as any episode requiring assistance of another party

Statistical analysis

- Change from baseline to Week 24 or endpoint in the ITT population with LOCF

- ANCOVA models with treatment and pre-defined pooled center as classification variables and baseline measure as covariate

- Primary comparison in studies is to pioglitazone monotherapy

- The assessment of safety is based mainly on the frequency of treatment emergent adverse events, on the number of post baseline laboratory values that fall outside of predetermined ranges and on the frequency and severity of hypoglycemic events during the double-blind, randomized treatment period. The treatment groups are specifically compared using Fisher's exact test with respect to the event rate of peripheral edema.

Results:

- Within the study the group is well-balanced at baseline.

- Participants in Study 1 are predominantly Asian or Caucasian, with a mean age of 51.5 years, BMI <30 kg/m², disease duration of 2.1 years and HbAi₀ of 8.7% while receiving no OAD.

- Approximately 1/3 of participants are in the high baseline HbA₁₀ group (>9.0%). - Each treatment produced meaningful improvements in glycemic control, but the decreases in HbA_1c with either initial combination regimen is significantly greater than with pioglitazone (30 mg daily) monotherapy.

- The between-treatment difference in the adjusted mean change (AMΔ) in HbA₁₀ with vildagliptin 100 mg combined with pioglitazone 30 mg is -0.6% (95% Cl: [-0.8, -0.3%], P<0.001).

- Of note, initial combination with the lower dose vildagliptin (50 mg) and pioglitazone (15 mg) combination decrease HbA_1c by 1.7 ± 0.1% which is significantly greater reduction compared to pioglitazone 30 mg monotherapy.

- Vildagliptin combined with pioglitazone produce dose-related increases in the percentage of patients achieving the ADA-recommended therapeutic goal of HbA_1c <7.0%.

- It is found that initial combination treatment with vildagliptin 100 mg + pioglitazone 30 mg allowed 65% of patients to achieve target HbA_1c levels.

Safety and Tolerability

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

The applicant has surprisingly discovered that vildagliptin does reduce the occurrence of edema especially the thiazolidinedione associated edema.

Claims

What is claimed is:

1) A method to prevent, delay the progression or reduce, 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.

2) A method, to prevent, delay the progression or reduce, the occurrence of thiazolidinedione-associated edema, comprising administering a therapeutically effective amount of a thiazolidinedione, or pharmaceutically acceptable salt thereof, in combination with a therapeutically effective 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, delay the progression or reduce, the occurrence of edema.

4) Use of a thiazolidinedione or pharmaceutically acceptable salt thereof, in combination with a DPP-IV inhibitor or pharmaceutically acceptable salt thereof, for the manufacture of a medicament to prevent, delay the progression or reduce, the occurrence of thiazolidinedione-associated edema.

5) A method according to claim 1 or a use according to claim 3, wherein the edema is a drug-associated edema.

6) A method according to claim 5 or a use according to claim 5, wherein the drug- associated edema is antihypertensive agents associated edema or anti-diabetic agents associated edema.

7) 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.

8) 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.

9) Method or use according to any of the previous claims, wherein the edema is peripheral edema, diabetic macular edema or pulmonary edema. 10) Method or use according to any of the previous claims, wherein the DPP-4 inhibitor is administered in combination with one two or three further compounds selected from antidiabetic agents and antihypertensive agents or in any case a pharmaceutical salts thereof.

11) Method or use according to claim 10, wherein the further compound is selected from sulfonylureas, thiazolidinediones, metformin, insulin, and calcium channel blockers.

12) Method or use according to any of the previous claims, wherein the treated patient is selected from a patient suffering from antihypertensive agents-induced edema or calcium channel blockers-induced edema.

13) Method or use according to any of the previous claims, wherein the DPP-IV inhibitor is selected from 1-{2-[(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2-(S)-cyano-pyrrolidine (also named [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrolidine carbonitrile monohydrochloride), Vildagliptin, L-threo-isoleucyl thiazolidine P32/98, Sitagliptin, GSK23A, saxagliptin, 3-(aminomethyl)-2-isobuthyl-1 -oxo-4-phenyl-1 ,2-dihydro-6- isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2-isobuthyl-4-phenyl-1 -oxo-1 ,2-dihydro-6- isoquinolyl]oxy}acetamide and optionally in any case pharmaceutical salts thereof.

14) Method or use according to any of the previous claims, wherein the DPP-IV inhibitor is vildagliptin or a pharmaceutical salts thereof.

15) Method or use according to any of the previous claims, wherein between 50 and 150 mg of vildagliptin or a pharmaceutical salts thereof is administered daily.

16) Method or use according to any of the previous claims, wherein the thiazolidinedione is selected from pioglitazone or rosiglitazone or optionally a pharmaceutical salts thereof.

17) A treatment regimen, wherein, i) 50 mg, 100 mg or 150 mg of vildagliptin or a pharmaceutically acceptable salt thereof, is to be administered in combination to 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) A treatment regimen, wherein, i) 50 mg, 100 mg or 150 mg of vildagliptin or a pharmaceutically acceptable salt thereof, is to be administered in combination to a thiazolidinedione or 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.

19) A treatment regimen according to any of claims 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.

20) A treatment regimen according to any of claims 17 to 19, wherein the patient is also under treatment with a further active agent such as insulin, sulfonylurea or metformin.

21) A treatment regimen according to any of claims 17 to 20, wherein the thiazolidinedione is selected from pioglitazone or rosiglitazone or optionally a pharmaceutical salts thereof.

22) Use, method or treatment regimen according to any of the previous claims, wherein the treated patient is suffering from hypertension, diabetes mellitus, type I or insulin- dependent diabetes mellitus (IDDM), type Il or non-insulin-dependent diabetes mellitus (NIDDM), type A insulin resistance, IGM, IFG or IGT.

23) Use, method or treatment regimen according to any of the previous claims, wherein between 250 mg and 3000 mg of metformin or a salt thereof is administered daily to the treated patient.

24) Use, method or treatment regimen according to any of the previous claims, 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 administered daily to said patient.