JP2010508348A - Use of dipeptidyl peptidase IV inhibitors to prevent, delay or alleviate edema - Google Patents

Abstract

  A method for preventing, delaying or reducing the development of edema, comprising administering a therapeutically effective amount of a DPP-IV inhibitor, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment.

Description

  The present invention provides a dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor) or a pharmaceutically acceptable salt thereof for preventing, delaying or reducing the development of edema such as peripheral edema or drug-induced edema. The present invention relates to a method of treatment administered to a patient.

  The treated patient preferably has 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 to have a prevalence of about 1% in the general population) and 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. Any patient with type I or type II diabetes can become insensitive to foreign insulin (“insulin resistance”) through various mechanisms. Type A insulin resistance is caused by either a mutation in the insulin receptor gene or a defect in the post-receptor site of action essential for glucose metabolism.

  Impaired glucose metabolism (IGM) is characterized by blood glucose levels that are above normal but 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. In IGM subjects, approximately 58% have impaired glucose tolerance (IGT), the other 29% have fasting hyperglycemia (IFG), and 13% have both abnormalities (IFG / IGT). IGT is characterized by elevated postprandial (postprandial) hyperglycemia, while IFG is defined based on fasting blood glucose levels.

  Type 2 diabetes is a progressive disease that, in some patients, can initially manage blood glucose with monotherapy, but leads to a high secondary failure rate. This high incidence of treatment failure is a major contributor to the high incidence of long-term hyperglycemia-related complications in patients with type 2 diabetes.

  Thiazolidinediones are effective as pharmaceuticals for controlling plasma glucose concentration in patients with type 2 diabetes mellitus and are generally administered. Thiazolidinedione is a routinely used oral antidiabetic agent. However, thiazolidinediones have significant safety / tolerability issues that limit their use or safety.

  In fact, it is well known that the main safety problem with thiazolidinediones is an increased incidence of edema in treated patients. Fluid retention occurs in 5% to 15% of patients taking thiazolidinediones. In some of these patients, thiazolidinediones use appears to be responsible for macular edema, and it has been observed that dosing cessation results in rapid resolution of peripheral and macular edema. Fluid retention associated with the use of thiazolidinediones must be considered when assessing treatment options, especially for diabetic macular edema (DME) patients associated with peripheral edema. In large clinical trials with rosiglitazone and pioglitazone, the frequency of edema in thiazolidinedione-treated patients was about 3-4 times higher than in placebo-treated patients. In addition to peripheral edema, the report also described pulmonary edema associated with thiazolidinedione treatment. Options for management of thiazolidinedione-related edema include dose reduction, withdrawal, and symptomatic treatment with diuretics. However, this is not a suitable solution for diabetic patients who rely on thiazolidinediones treatment.

  Applicants have discovered that DPP-IV inhibitors, particularly vildagliptin, or a pharmaceutically acceptable salt thereof, can reduce the incidence of edema in patients.

  In particular, surprisingly, applicants have determined that DPP-IV inhibitors, particularly vildagliptin, or a pharmaceutically acceptable salt thereof, can reduce thiazolidinedione-related edema development, such as thiazolidinediones, such as one species. Or it has been discovered that it can be used in combination with two thiazolidinediones, or pharmaceutically acceptable salts thereof. That is, long-term treatment with such combinations has significantly fewer adverse edema side effects than other combinations.

  Anti-diabetic thiazolidinediones (ie glitazones) are 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 ( Dalglitazone), 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-fur Olophenyl-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) Preliminary 5- (2,4-dioxothiazolidin-5-ylmethyl) -2-methoxy -N- (4- trifluoromethyl-benzyl) - benzamide (KRP297).

  Certain glitazones such as “pioglitazone”, “rosiglitazone” also include any of their pharmaceutically acceptable salts, crystalline forms, hydrates, solvates, diastereoisomers or enantiomers. Intended.

  For administration of a thiazolidinedione antidiabetic agent, particularly glitazone, to an adult diabetic patient (body weight: 50 kg), for example, the daily dose is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. This dose can be administered once to several times a day. In particular, when pioglitazone hydrochloride is used as an insulin sensitizer, the dose of pioglitazone hydrochloride per day is usually 7.5 to 60 mg, preferably 15 to 45 mg. When troglitazone is used as an insulin sensitizer, the daily troglitazone dose is usually 100 to 1000 mg, preferably 200 to 600 mg. When rosiglitazone (or its maleate) is used as an insulin sensitizer, the daily dose of rosiglitazone 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), particularly preferably pioglitazone hydrochloride or rosiglitazone maleate.

  The dose of Actos® (pioglitazone HCl) should not exceed 45 mg once a day in monotherapy or in combination with sulfonylurea, metformin, or insulin. Actos in combination with metformin may start at 15 mg or 30 mg once daily. The ongoing metformin dose may be maintained at the start of Actos treatment. There is little need to adjust the metformin dose due to the hypoglycemia that occurs during combination therapy with Actos. Actos is available in 15 mg, 30 mg, and 45 mg tablets.

  AVANDIA® (rosiglitazone maleate) can be administered at a starting dose of 4 mg, either once daily or divided in the morning or evening. For patients with an inadequate response as assessed by a decrease in FPG after 8-12 weeks of treatment, the dosage 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 as divided doses twice daily. AVANDIA is available in 2 mg, 4 mg, and 8 mg tablets.

  Commercial combinations including metformin and thiazolidinedione derivatives can also be used according to the present invention. It is also possible in particular to administer rosiglitazone in combination with metformin, eg in the form as it is marketed, eg under the trade name AVANDAMET®. The dosage of anti-diabetic treatment with AVANDAMET should be determined individually based on efficacy and tolerability without exceeding the maximum recommended daily dosage of 8 mg / 2,000 mg. AVANDAMET® is provided in various tablets. Each tablet contains rosiglitazone 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” is also intended to include all salts or crystalline forms thereof, eg rosiglitazone maleate.

Metformin has been extensively prescribed to lower 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 needs to be administered twice daily or three times daily (500-850 mg tablets 2-3 times / day or 1000 mg twice daily with meals). The biguanide antihyperglycemic agent metformin disclosed in US Pat. No. 3,174,901 is currently marketed in the United States in the form of its hydrochloride salt ((Glucophage @), Bristol-Myers Squibb Company). A process for the preparation of metformin (dimethyldiguanide) and its hydrochloride constitutes the state of the art and was first disclosed in Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794. Metformin, eg in the form as it is marketed under the trade name GLUCOPHAGE ^TM.

  Metformin increases sensitivity to insulin in the host terminal tissue. Metformin is also involved in inhibiting glucose absorption from the intestine, inhibiting gluconeogenesis in the liver, and inhibiting fatty acid oxidation. A suitable regimen for metformin includes a 500 mg unit dose 2 or 3 times a day, and may be increased even up to 5 times a day, or 850 mg once or twice a day. [Martindale, The Complete Drug Reference].

  As used herein, the term “metformin” refers to metformin or a pharmaceutically acceptable salt thereof, such as the hydrochloride salt metformin (2: 2) disclosed in US application Ser. No. 09 / 262,526, filed Mar. 4, 1999. 1) Fumarate, and other known forms, including metformin (2: 1) succinate, hydrobromide, p-chlorophenoxyacetate or carbonate, and those disclosed in US Pat. No. 3,174,901 Means the metformin salts of mono- and dibasic carboxylic acids, and all these salts are collectively referred to as metformin. The metformin used here is preferably metformin hydrochloride, that is, commercially available as GLUCOPHAGE-D or GLUCOPHAGE XR (trademark of Bristol-Myers Squibb Company).

  The term “DPP-IV inhibitor” refers to 1-100% inhibition of the enzymatic activity of DPP-IV and functionally related enzymes, and in particular glucagon-like peptide-1, gastric inhibitory polypeptide, peptide histidine methionine. , Substance P, neuropeptide Y, and other molecules that typically contain an alanine or proline residue at the second amino terminal position, and are intended to indicate molecules that conserve action on substrate molecules . Treatment with a DPP-IV inhibitor prolongs the action time of the peptide substrate, increases the concentration of its intact, undegraded form, and forms a spectrum of biological activity according to the disclosure herein.

  DPP-IV can be used to control glucose metabolism because its substrates include the insulinotropic hormone glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are only active in their intact form; removal of their two N-terminal amino acids renders them inactive. In vivo administration of DPP-IV synthesis inhibitors prevents N-terminal degradation of GLP-1 and GIP, leading to high plasma concentrations of these hormones, increased insulin secretion, and hence improved glucose tolerance. For this purpose, chemicals are tested for their ability to inhibit the enzymatic activity of purified CD26 / DPP-IV. Briefly, the activity of CD26 / DPP-IV is measured for its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA) in vitro. Cleavage of Gly-Pro-pNA by DPP-IV liberates the product p-nitroanilide (pNA) whose appearance rate is directly proportional to enzyme activity. Inhibition of enzyme activity by specific enzyme inhibitors delays the production of pNA. The stronger the interaction between the inhibitor and the enzyme, the slower the pNA production rate. Therefore, the degree to which the rate of pNA accumulation is inhibited is a direct indicator of the strength of enzyme inhibition. pNA accumulation is measured with a spectrophotometer. The inhibition constant, Ki, for each compound is determined by incubating a fixed amount of enzyme with several different concentrations of inhibitor and substrate.

  In this context, “DPP-IV inhibitor” is also intended to include its active metabolites and prodrugs, eg, active metabolites and prodrugs of DPP-IV inhibitors. A “metabolite” is an active derivative of a DPP-IV inhibitor that is produced when the DPP-IV inhibitor is metabolized. A “prodrug” is any compound that is metabolized to a DPP-IV inhibitor or is metabolized to the same metabolite (s) as the DPP-IV inhibitor. In the present context, the term “DPP-IV inhibitor” is also intended to include the pharmaceutical salts thereof.

DPP-IV inhibitors are known in the art. The following describes representative DPP-IV inhibitors:
Preferred DPP-IV inhibitors are described in the following patent applications; WO02053548 (especially compounds 1001-1293 and examples 1-124), WO02067918 (especially compounds 1000-1278 and 2001-2159), WO02066627 (specifically described implementations). Example), WO 02/068420 (especially all compounds specifically listed in Examples I to LXIII and the corresponding analogs described, further preferred compounds are listed in Table 2 (28), reporting IC ₅₀ , 2 (88), 2 (119), 2 (136)), WO02083128 (for example, the compounds described in claims 1 to 5, especially Examples 1 to 13 and claims 6 to 10), US 2003096846 (particularly specifically Described compounds), WO2004 / 037181 (especially Examples 1-33), WO0168603 (especially Examples -109), EP1258480 (especially compounds of Examples 1-60), WO01881337 (especially Examples 1-118), WO02083109 (especially Examples 1A-1D), WO030003250 (especially Examples 1-166, most preferably 1 to 8), WO03035067 (especially the compounds described in the examples), WO03 / 035057 (especially the compounds described in the examples), US2003216450 (especially examples 1 to 450), WO99 / 46272 (particularly claimed) 12, 14, 15 and 17), WO0197808 (especially the compound of claim 2), WO03002553 (especially the compounds of Examples 1-33), WO01 / 34594 (especially the compounds described in Examples 1-4), WO02051836 (especially examples 1 to 712), EP1245568 (especially examples) 1-7), EP1258476 (especially Examples 1-32), US20030887950 (especially described examples), WO02 / 076450 (especially examples 1-128), WO03000180 (especially examples 1-162), WO03000181 (especially implementations) Examples 1-66), WO03004498 (especially examples 1-33), WO0302942 (especially examples 1-68), US6482844 (especially described examples), WO0155105 (especially compounds described in examples 1 and 2), WO0202560 (especially Examples 1 to 166), WO03004496 (especially Examples 1 to 103), WO03 / 024965 (especially Examples 1 to 54), WO0303727 (especially Examples 1 to 209), WO0368757 (especially Examples 1 to 88) ), WO03074500 (especially Examples 1-72, Examples 4.1-4.2) 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 ), WO02038541 (especially Examples 1 to 53), WO02062764 (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)), WO02308090 (especially Examples 1-1 to 1-109, Examples 2-1 to 2-9, Example 3 and Example 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, page 90 Examples 7-1 to 7-7, Examples 8-1 to 8-59 on pages 91 to 95, Examples 9-1 to 9-33, Example 10 1-10-20), US2003225102 (especially compounds 1-115, compounds of Examples 1-121, preferably compounds a) -z), aa) -az), ba) -bz), ca) -cz) and da) -dk)), WO0214271 (especially Examples 1-320), US2003096857, US application Ser. No. 09 / 788,173 (attorney file number LA50) filed on Feb. 16, 2001 (especially described examples), WO99 / 38501 (specially described examples), W099 / 46272 (specially described examples) and DE19616486A1 (especially val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and isoleucyl-thiazolidide and isoleucyl-pyrrolide). Fumarate).

  Further preferred DPP-IV inhibitors are specific examples disclosed in US Pat. Nos. 6,124,305 and 6,107,317, international patent applications, publication numbers WO9819998, WO9515309 and WO9818763; for example 1 [2-[(5-cyano (eyano) pyridine- 2-yl) aminoethylamino] acetyl-2-cyano- (S) -pyrrolidine and (2S) -I-[(2S) -2-anilino-3,3-dimethylbutanoyl] -2-pyrrolidine Contains carbonitrile.

  In a further preferred embodiment, the DPP-IV inhibitor is N-peptidyl-O-aroylhydroxylamine or a pharmaceutically acceptable salt thereof. The peptidyl moiety preferably comprises two α-amino acids such as glycine, alanine, leucine, phenylalanine, lysine or proline, in which it is preferably proline that is directly attached to the hydroxylamine nitrogen atom .

  In each case, particularly in the claimed compounds and the final product of the working examples, the final product, the pharmaceutical formulation and the claimed subject matter are hereby incorporated by reference into these publications.

  WO9819998 describes N- (N′-substituted glycyl) -2-cyanopyrrolidines, especially 1- [2- [5-cyanopyridin-2-yl] amino] -ethylamino] acetyl-2-cyano- (S). Disclose pyrrolidine.

  Preferred compounds described in WO 03/002553 are listed on pages 9-11 and are incorporated herein by reference.

  DE 196 16 486 A1 discloses val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide and the fumarate of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.

  WO0034241 and US6110949 disclose N-substituted adamantyl-amino-acetyl-2-cyanopyrrolidines and W (substituted glycyl) -4-cyanopyrrolidines, respectively. The intended DPP-IV inhibitors are those mentioned in particular in claims 1-4.

  WO9515309 discloses amino acid 2-cyanopyrrolidine amides as DPP-IV inhibitors, and WO9529691 discloses peptidyl derivatives of diesters of alpha-aminoalkylphosphonic acids, particularly those having proline or related structures. Target DPP-IV inhibitors are those specifically mentioned in Tables 1-8.

  In WO 01/72290, the desired DPP-IV inhibitors are those mentioned in particular in Example 1 and claims 1, 4 and 6.

  WO 01/52825 describes (S) -1- {2- [5-cyanopyridine-2yl) amino] ethyl-aminoacetyl) -2-cyano-pyrrolidine or (S) -1-[(3-hydroxy-1- Adamantyl) amino] acetyl-2-cyano-pyrrolidine (LAF237) is disclosed.

  WO9310127 discloses proline boronic esters useful as DPP-IV inhibitors. The intended DPP-IV inhibitors are those specifically mentioned in Examples 1-19.

  Published patent application WO9925719 discloses sulfostin, a DPP-IV inhibitor produced by culturing Streptomyces microorganisms.

  WO9938501 discloses N-substituted 4-8 membered heterocyclic rings. The DPP-IV inhibitors of interest are those specifically mentioned in claims 15-20.

  WO 9946272 discloses phosphorus compounds as DPP-IV inhibitors. The intended DPP-IV inhibitors are those mentioned in particular in claims 1 to 23.

  Other preferred DPP-IV inhibitors are compounds of formula I, II or III disclosed on pages 14-27 of patent application WO 03/057200. The 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 in the form of ABC (where C is either a stable or unstable DPP-IV inhibitor).

〔式中、
ｊは０、１または２であり；
Ｒε_１は、天然アミノ酸の側鎖であり；そして
Ｒε_２は、低級アルコキシ、低級アルキル、ハロゲンまたはニトロである。〕
の化合物、またはその薬学的に許容される塩である。 Preferably, N-peptidyl-O-aroylhydroxylamine is of formula VII

[Where,
j is 0, 1 or 2;
Rε ₁ is the side chain of the natural amino acid; and Rε ₂ is lower alkoxy, lower alkyl, halogen or nitro. ]
Or a pharmaceutically acceptable salt thereof.

の化合物、またはその薬学的に許容される塩である。 In a highly preferred embodiment of the invention, N-peptidyl-O-aroylhydroxylamine is of formula VIIa

Or a pharmaceutically acceptable salt thereof.

  For example, N-peptidyl-O-aroylhydroxylamines of formula VII or VIIa and methods for their preparation are described in HU Demuth et al. In J. Enzyme Inhibition 1988, Vol. 2, pages 129-142, in particular 130- 132.

Preferred DPP-IV inhibitors are those described in paragraph 5 of Mona Patel and colleagues (Expert Opinion Investig Drugs. 2003 Apr; 12 (4): 623-33), in particular P32 / 98, K-364, FE-999011. , BDPX, NVP-DDP-728 and others, the publications, particularly the described DPP-IV inhibitors, are hereby incorporated by reference.
Another preferred DPP-IV inhibitor is Tanabe No. 815541 (T 6666).

Preferred DPP-IV inhibitors are patent applications 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 such as compounds 1 to 393, compounds on pages 67 to 70).
FE-999011 is described as Compound No. 18 on page 14 of WO95 / 15309.

Another preferred inhibitor is the compound BMS-477118 disclosed in WO20010860603 or US Pat. No. 6,395,767 (the compound of Example 60) and is also represented by formula M on page 2 of patent application WO2004 / 052850. (1S, 3S, 5S) -2 - [(2S) -2- amino-2- (3-hydroxy-tricyclo [3.3.1.1 ^{3, 7]} dec-1-yl) -1-oxoethyl] 2-azabicyclo [3.1.0] hexane-3-carbonitrile, benzoate (1: 1) and the corresponding free base described in Formula M on page 3 of patent application WO2004 / 052850, (1S, 3S , 5S) -2 - [(2S) -2-amino-2- (3-hydroxy - tricyclo [3.3.1.1 ^{3, 7]} dec-1-yl) -1-oxoethyl] -2-azabicyclo -[3.1.0] Hexane-3-carbonitrile (M ') And it is also known as its monohydrate (M "). Compound BMS-477118 is also known as saxagliptin.

  Another preferred inhibitor is the compound GSK23A disclosed in WO03 / 002531 (Example 9), (2S, 4S) -1-((2R) -2-amino-3-[(4-methoxybenzyl) Also known as sulfonyl] -3-methylbutanoyl) -4-fluoropyrrolidine-2-carbonitrile hydrochloride.

はＷＯ９９／６１４３１に開示され、またProbiodrug名でDiabetes 1998, 47, 1253-1258にも記載され、化合物Ｐ９３／０１は同社により記載されている。 P32 / 98 (CAS number: 251572-86-8), also known as 3-[(2S, 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine, is 3-[(2S, 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine and (2E) -2-butenedioate (2: 1) mixture, disclosed in WO 99/61431,

Is disclosed in WO 99/61431 and also described in Diabetes 1998, 47, 1253-1258 under the Probiodrug name, and the compound P93 / 01 is described by the company.

  Other highly preferred DPP-IV inhibitors are the compounds disclosed in patent application WO 02/083128, for example in claims 1-5. The most preferred DPP-IV inhibitors are the compounds specifically described in Examples 1-13 and claims 6-10.

  Another highly preferred DPP-IV inhibitor is the compound disclosed by Bristol-Myers Squibb such as saxagliptin (BMS477118).

の化合物２１ｅ(表１)である。 Other highly preferred inventive DPP-IV inhibitors are described by International Patent Application WO 02/076450 (especially Examples 1-128) and Wallace T. Ashton (Bioorganic & Medicinal Chemistry Letters 14 (2004) 859-863). In particular, compounds 1 and the compounds described in Tables 1 and 2. Preferred compounds have the formula:

Compound 21e (Table 1).

  Other preferred DPP-IV inhibitors are described in patent applications WO2004 / 037169 (especially those described in Examples 1-48) and WO02 / 062764 (especially described Examples 1-293), more preferably The compounds 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[described in page 7 of the patent application WO2004 / 024184 3- (Aminomethyl) -2-isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and also those specifically described in Reference Examples 1-4 It is.

の化合物である。シタグリプチンの好ましい１日投与量は２５〜１００mgである。 Other preferred DPP-IV inhibitors are of the formula described in patent application WO 03/004498, in particular in Examples 1-33 and most preferably in Example 7, also known as MK-0431 or sitagliptin.

It is a compound of this. A preferred daily dose of sitagliptin is 25-100 mg.

  In each case, particularly in the claimed compounds and in the final products of the examples, the final product, pharmaceutical formulation and claimed subject matter are hereby incorporated by reference into these publications.

  Preferred DPP-IV inhibitors are the compounds disclosed in patent application WO2004 / 037181, in particular Examples 1-33, most preferably as claimed in claims 3-5.

  Preferred DPP-IV inhibitors are N-substituted adamantyl-amino-acetyl-2-cyanopyrrolidines, N (substituted glycyl) -4-cyanopyrrolidines, N- (N′-substituted glycyl) -2-cyanopyrrolidines. N-aminoacyl thiazolidines, N-aminoacyl pyrrolidines, L-allo-isoleucil thiazolidine, L-threo-isoleucil pyrrolidine, and L-allo-isoleucil pyrrolidine, 1- [2-[(5- Cyanopyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine, sitagliptin and pharmaceutical salts thereof.

  The most preferred DPP-IV inhibitor is [S] -1- [2- (5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidinecarbonitrile monohydrochloride, (S) -1-[(3 -Hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine and L-threo-isoleuylthiazolidine (compound code according to Probiodrug: P32 / 98 as above), sitagliptin, 3- (aminomethyl) -2- Isobuthyl-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 a pharmaceutical salt thereof.

  [S] -1- [2- (5-Cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidinecarbonitrile monohydrochloride and (S) -1-[(3-hydroxy-1-adamantyl) amino] Acetyl-2-cyano-pyrrolidine is specifically described 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-pyrrolidinecarbonitrile monohydrochloride and (S) -1-[(3-hydroxy-1-adamantyl) amino] Acetyl-2-cyano-pyrrolidine can be formulated as described on page 98 of WO 98/19998 or WO 00/34241.

の１−{２−[(５−シアノピリジン−２−イル)アミノ]エチルアミノ}アセチル−２−(Ｓ)−シアノ−ピロリジン(別名[Ｓ]−１−[２−(５−シアノ−２−ピリジニルアミノ)エチルアミノ]アセチル−２−ピロリジンカルボニトリル一塩酸塩)、特にその二塩酸塩および一塩酸塩形態、
式

のピロリジン、１−[(３−ヒドロキシ−１−アダマンチル)アミノ]アセチル−２−シアノ−、(Ｓ)(別名(Ｓ)−１−[(３−ヒドロキシ−１−アダマンチル)アミノ]アセチル−２−シアノ−ピロリジン、ＬＡＦ２３７またはビルダグリプチン)、および
Ｌ−ｔｈｒｅｏ−イソロイシルチアゾリジン(Probiodrugに従う化合物コード：上記の通りＰ３２／９８)、シタグリプチン、ＧＳＫ２３Ａ、サクサグリプチン、３−(アミノメチル)−２−イソブチル(isobuthyl)−１−オキソ−４−フェニル−１,２−ジヒドロ−６−イソキノリンカルボキサミドおよび２−{[３−(アミノメチル)−２−イソブチル(isobuthyl)−４−フェニル−１−オキソ−１,２−ジヒドロ−６−イソキノリル]オキシ}アセトアミドおよび所望によりいずれの場合もその薬学的塩である。 Particularly preferred is the formula:

1- {2-[(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2- (S) -cyano-pyrrolidine (also known as [S] -1- [2- (5-cyano-2) -Pyridinylamino) ethylamino] acetyl-2-pyrrolidinecarbonitrile monohydrochloride), in particular its dihydrochloride and monohydrochloride forms,
formula

Pyrrolidine, 1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-, (S) (also known as (S) -1-[(3-hydroxy-1-adamantyl) amino] acetyl-2 -Cyano-pyrrolidine, LAF237 or vildagliptin), and L-threo-isoleucil thiazolidine (compound code according to Probiodrug: P32 / 98 as above), sitagliptin, GSK23A, saxagliptin, 3- (aminomethyl) -2-isobutyl ( isobuthyl) -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 its pharmaceutical salt.

  DPP728 and LAF237 are specifically disclosed in Example 3 of WO98 / 19998 and Example 1 of WO00 / 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 in WO98 / 19998, page 20 or WO00 / 34241, or international patent application number EP2005 / 000400 (application number).

  Any of the materials disclosed in the above patent documents or scientific publications, incorporated herein by reference, are considered to be DPP-IV inhibitors that may be useful for use in the practice of the present invention.

  A DPP-IV inhibitor used alone according to the present invention may be used with a carrier.

  The carrier in this context is a tool (natural, synthetic, peptidic, non-peptidic), eg a protein, that transports the embedded specific substance across the cell membrane and into the cell. Since each is designed to recognize only one substance or a group of similar substances, different carriers (natural, synthetic, peptidic, non-peptidic) are required to transport different substances.

  Any detection means known by those skilled in the art can be used to detect the binding of DPP-IV to the carrier, for example by labeling the carrier.

The DPP-IV inhibitor may be peptidic or preferably non-peptidic.
Most preferred are orally active DPP-IV inhibitors and pharmaceutical salts thereof.

  The class of CCB (calcium channel blockers) essentially includes dihydropyridines (DHP) and non-DHPs such as diltiazem and verapamil CCBs. A major safety problem with CCB is known to be an increase in edema in treated patients.

  The CCB is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, rasidipine, nicardipine, nifedipine, nigurdipine, nildipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and preferably flunarizine , Prenylamine, diltiazem, fendiline, galopamil, mibefradil, anipamyl, thiapamil and verapamil, and in each case a pharmaceutically acceptable salt or prodrug thereof. All these CCBs are used therapeutically, for example as antihypertensive, anti-anginal or antiarrhythmic agents.

  Preferred CCBs include murodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or pharmaceutically acceptable salts or prodrugs thereof, such as by specific CCB. Particularly preferred as DHP is amlodipine or a pharmaceutically acceptable salt thereof, especially besylate. A particularly preferred representative of non-DHP is verapamil or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt. The CCB is preferably amlodipine or a pharmaceutically acceptable salt thereof, particularly besylate. CBB is preferably administered from about 1 mg to about 100 mg per day, preferably about 1 to 10 mg per day.

  In the case of amlodipine, a preferred dosage form is, for example, a tablet or capsule containing about 1 mg to about 40 mg, preferably 2.5 to 20 mg per day when administered orally, for example. Particularly preferred are 2.5, 5 and 10 mg, especially 5 mg per day.

  Active ingredients according to the present invention (e.g. thiazolidinediones, calcium channel blockers or DPP-IV inhibitors) or pharmaceutically acceptable salts thereof include, for example, hydrates or other solvents used for crystallization, Solvates may also be used.

  It is surprising according to the invention that DPP-IV inhibitors, in particular vildagliptin or pharmaceutically acceptable salts thereof, can be used for the prevention, delay of progression or alleviation of the development of edema, in particular drug-related edema such as thiazolidinedione-related edema Turned out to be.

  Thus, in a first aspect, the present invention provides a patient in need of treatment with a therapeutically effective amount of a thiazolidinedione, such as one or two thiazolidinediones, or a pharmaceutically acceptable salt thereof. A method for preventing, delaying or reducing the development of thiazolidinedione-related edema, comprising administering in combination with a therapeutically effective amount of a DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof. provide.

  The present invention also prevents the development of edema, comprising administering to a patient in need of treatment a therapeutically effective amount of a DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof, Provide a way to delay or mitigate progress.

  The invention further relates to DPP-IV in combination with thiazolidinediones, for example one or two thiazolidinediones, for the manufacture of a medicament for preventing, delaying or reducing the development of thiazolidinedione-related edema. It relates to the use of inhibitors, or in any case their pharmaceutically acceptable salts.

  The present invention further relates to the use of a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing, delaying or reducing the development of edema.

  Method as described above, wherein the edema is preferably thiazolidinedione-related edema, ie edema in a patient secondary to treatment with thiazolidinediones, ie treated with thiazolidinediones, eg one or two thiazolidinediones Or use.

The method or use as described above, wherein the edema is preferably drug-related edema, ie edema in a patient secondary to treatment with a drug (pharmacologically active agent), ie treated with a drug (pharmacologically active agent) . Drug-related edema includes, for example, antidiabetic agents (e.g. thiazolidinediones, metformin or insulin), antihypertensive agents (e.g. calcium channel antagonists, renin inhibitors such as aliskiren, angiotensin II receptor antagonists such as valsartan, angiotensin converting enzyme inhibitors) For example, benazepril, alpha ₁ adrenergic receptor blockers such as doxazosin, calcium channel blockers such as amlodipine or diltiazem).

  Edema is preferably secondary to edema induced by antihypertensive agents, ie treatment with antihypertensive agents, ie treated with antihypertensive agents such as one or two antihypertensive agents such as valsartan, aliskiren or amlodipine The method or use as described above, which is edema in a patient.

  The method or use as described above, wherein the edema is preferably peripheral edema, diabetic macular edema (DME) or pulmonary edema, preferably thiazolidinedione-related edema or calcium channel blocker-related edema.

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

  The method or use above, wherein the DPP-4 inhibitor is administered in combination with thiazolidinedione and metformin.

  Preferably, the patient to be treated in the claimed method or use is selected from thiazolidinedione-treated patients (eg, one or two thiazolidinediones) suffering from thiazolidinediones-induced edema side effects.

  Preferably, the patient to be treated in the claimed method or use is being treated with one or two agents selected from antihypertensive agents, preferably antihypertensive agent induced edema side effects or calcium channel blocker induced edema. Choose from suffering patients.

  Preferably, the DPP-IV inhibitor is (S) -1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine (LAF237 or vildagliptin) or a pharmaceutically acceptable salt thereof. .

  In this context, the term “(S) -1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine” or “LAF237” or “virdagliptin” also includes all salts or crystal forms thereof. Is also intended to be included.

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

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

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

  This method or use is particularly useful for the prevention or delay of progression of conditions associated with type II diabetes or IGT, particularly cardiovascular and microvascular conditions.

The term “reduced incidence of edema” means a decrease in the frequency or severity of edema.
Edema is defined as a clinically apparent increase in interstitial fluid volume that can increase several liters before the abnormality becomes apparent. Anasarca describes holistic, systemic edema. Ascites and hydrothorax describe excessive fluid accumulation in the abdominal cavity and pleural sinus, respectively, and are considered to be a specific form of edema. Localized edema due to venous or lymphatic obstruction may be due to venous thrombosis, chronic lymphangitis, local lymphadenectomy, filariasis and the like. The majority of patients with systemic edema have advanced heart, kidney, liver, or nutritional disorders.

  Depending on its cause and mechanism, the edema may be local or have a systemic distribution; the swollenness of the face that appears most rapidly in the periorbital region and known as “indentation” edema It is recognized in its whole body form by the subsequent persistence of the skin dent. In its more subtle form, edema can be detected by showing that after removing the stethoscope from the chest wall, a dent at the edge of the bell-shaped head remains on the skin of the chest for several minutes. Edema may be present when the ring fits better than before, or when the patient complains that it is difficult to wear shoes, especially at night.

  The term “edema” refers to localized edema, systemic edema, peripheral edema, diabetic macular edema (DME), pulmonary edema, drug-related edema, thiazolidinedione-related edema (eg, thiazolidinedione-related peripheral edema or thiazolidinedione-related) Diabetic macular edema), antihypertensive agent-related edema such as, but not limited to, calcium channel blocker induced edema.

Further, “daily dose” as used herein refers to a dose administered within a 24-hour period.
The term “prevention” means prophylactic administration of the combination to healthy patients to prevent the development of the conditions described herein. Furthermore, the term “prophylaxis” means the prophylactic administration of such a combination to a patient in a pre-stage of the condition to be treated.

  As used herein, the term “delayed progression” refers to a patient that is in a pre-stage of a condition to be treated, such as a pharmaceutical formulation or pharmaceutical composition to a patient whose pre-form of the corresponding condition has been diagnosed Means a combination administration.

The term “treatment” is understood as the management and treatment of a patient for the purpose of combating a disease, condition or disorder.
The term “patient” as used herein refers to an animal having a disease or disorder, preferably hypertension, hyperglycemia or diabetes or IGM. Preferred animals are mammals such as dogs, cats, horses, cows and humans. It is preferred that the patient is a human.

  The term “disease was not properly controlled by thiazolidinedione alone” as used herein preferably means a hyperglycemia related disease such as diabetes, type 2 diabetes, IGT or IGM.

In this field, the preferred patient population age is 45 years old or later, most preferably 65 years old or later.
Those skilled in the relevant arts are well able to select relevant test models and protocols to confirm the beneficial effects of the present invention.

The present invention also provides i) 50 mg, 100 mg or 150 mg vildagliptin or a pharmaceutically acceptable salt thereof with thiazolidinedione or a pharmaceutically acceptable salt thereof, preferably 15-45 mg pioglitazone or 2-8 mg rosiglitazone, Or in any case combined with its pharmaceutically acceptable salt and administered daily to patients in need thereof,
ii) select from patients suffering from treatment-affected thiazolidinedione-related edema,
Also related to treatment regimens.

The present invention also provides
i) 50 mg, 100 mg or 150 mg vildagliptin or a pharmaceutically acceptable salt thereof, thiazolidinedione or a pharmaceutically acceptable salt thereof, preferably 15 to 45 mg pioglitazone or 2 to 8 mg rosiglitazone, or any In combination with its pharmaceutically acceptable salt, administered daily to patients in need thereof,
ii) the treated patient is a patient whose disease was not properly controlled by thiazolidinedione alone; and
ii) Also related to a treatment regimen selected from patients suffering from treatment-affected thiazolidinedione-related edema.

A treatment regimen as described herein, wherein thiazolidinedione is replaced with another agent such as a calcium channel blocker, such as amlodipine or a salt thereof.
A treatment regimen as described herein, wherein the patient is also under the treatment of one or two additional active agents such as CBB, insulin, sulfonylurea or metformin.

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

  When 100 mg vildagliptin or a pharmaceutically acceptable salt thereof is administered daily, 100 mg vildagliptin (OD—once daily) or 50 mg bildagliptin twice daily (ie bid) Can be administered.

  In the above treatment regimen, the term “daily” refers to (S) -1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine or a pharmaceutically acceptable salt thereof (virdagliptin) and thiazolidine. Applies to additional drugs such as diones or calcium channel blockers.

  Preferably, the treated patient in the above method or use or treatment regimen has hyperglycemia or hypertension. Most preferably, the patient with hyperglycemia is from diabetes mellitus, type I or insulin dependent diabetes mellitus (IDDM), type II or non-insulin dependent diabetes mellitus (NIDDM), type A insulin resistance, IGM, IFG or IGT Have the disease selected. In a preferred embodiment, the patient has type II diabetes or IGT. In other preferred embodiments, the treated patient is a patient whose disease was not properly controlled by thiazolidinedione or metformin alone.

  Active agents identified by code number, generic name or trade name may be taken from the current edition of the standard introduction “The Merck Index” or from databases such as Patents International (eg IMS World Publications). The corresponding content is hereby incorporated by reference. All those skilled in the art are well capable of identifying active agents based on these references, as well as manufacturing and testing pharmaceutical indications and properties both in vitro and in vivo in standard test models. Can do.

  The pharmaceutical preparations described here are for enteral, eg enteral, and also rectal or parenteral administration to homeothermic animals, the preparations containing pharmacologically active compounds alone or with conventional pharmaceutical aids. Contains with substances. For example, the pharmaceutical preparations contain from about 0.1% to 90%, preferably from about 1% to about 80% active compound. Pharmaceutical preparations for enteral or parenteral administration and also for ocular administration are, for example, unit dosage forms such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner known per se, for example using conventional mixing, granulating, coating, dissolving or lyophilizing processes. Therefore, pharmaceutical formulations for oral use can be prepared by combining the active compound with solid excipients and, if desired, granulating the resulting mixture and adding appropriate auxiliary substances as required or desired. It can be obtained by processing the granules into tablets or coated tablet cores.

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 doses for the active ingredients of the pharmaceutical combination of the present invention that are commercially available are particularly therapeutically effective commercial doses.

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

  The exact dosage will, of course, vary depending on the compound used, the mode of administration and the treatment desired. The compounds can be administered by any conventional route, parenterally or preferably orally.

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

Preferably for DPP-IV inhibitors, especially vildagliptin, the total daily dose indicated is in the range of 1 to 500 mg, preferably 10 to 200 mg of active ingredient.
Other preferred DPP-IV inhibitors, especially vildagliptin daily oral doses are 1-100 mg, preferably 10-100 mg, such as 10 mg, most preferably 25-100 mg, such as 25 mg or 30 or 40 or 50, 61, 70, 90, 100 mg. A highly preferred daily oral dose of vildagliptin is 50-150 mg.

Suitable unit dosages for oral administration include for example about 25 to about 150 mg of DPP-IV inhibitor, especially vildagliptin, for example preferably 25, 50, 100 or 150 mg. Suitable dosages for parenteral administration include, for example, from about 1 to about 150 mg, eg 10-50 mg of the compound.
The DPP-IV inhibitor can also be administered daily (eg, twice a day (BiD) or once a day (OD)), or every two days, or even once every two weeks.

  The compounds can be administered in a manner similar to known standards for use in these applications. The appropriate daily dosage for a particular compound depends on a number of factors such as its relative activity effects. Those skilled in the relevant art are well capable of determining a therapeutically effective amount.

  For example, the dosage of aliskiren to be administered to warm-blooded animals, including humans weighing about 75 kg, in particular, for example, in blood pressure, the effective dosage of renin activity inhibition may preferably be, for example, the same size 1- From about 3 mg to about 3 g, preferably from about 10 mg to about 1 g, for example 20-200 mg / human / day, divided into four single doses. Children are usually given about half of the adult dose. The required dosage for each individual can be monitored, for example, by measuring the serum concentration of the active ingredient and adjusting to an optimal level. A single dose includes, for example, 75 mg, 150 mg or 300 mg / adult patient.

  Angiotensin II receptor blockers, such as valsartan, are supplied in suitable dosage unit forms, such as capsules or tablets, and are therapeutically effective amounts of angiotensin II receptor blockers, such as about 20 to Contains about 320 mg valsartan. Application of the active ingredient is up to 3 times a day, eg starting with a daily dose of 20 mg or 40 mg angiotensin II receptor blocker, eg valsartan, from 80 mg daily to 160 mg daily and finally Can be increased to 320 mg per day. Preferably, an angiotensin II receptor blocker, such as valsartan, is applied once or twice daily at a dose of 80 mg or 160 mg, respectively. Corresponding doses may be taken, for example in the morning, noon or evening.

  The compounds of the present invention may be administered in free base form or as a pharmaceutically acceptable acid addition salt or quaternary ammonium salt. Such salts can be prepared by conventional methods and exhibit activity comparable to the free form. 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 with further basic centers if desired. Compounds having acid groups (eg COOH) can also form salts with bases. For example, the compounds to be combined can be present as sodium salt, as maleate or as dihydrochloride. The active ingredient or a pharmaceutically acceptable salt thereof can also be used in the form of a hydrate or including other solvents used for crystallization.

  The present invention relates to a free or pharmaceutically acceptable salt form of a DPP-IV inhibitor, and additional agents such as thiazolidinediones or calcium channel blockers, or pharmaceutically acceptable salts thereof and optionally at least one pharmaceutical agent. Refers to a combination comprising a pharmaceutically acceptable carrier; where multiple active ingredients can be administered simultaneously or sequentially in any order, separately or in a fixed combination (same galenical formulation).

  Free or pharmaceutically acceptable salt forms of DPP-IV inhibitors and additional agents, such as thiazolidinediones or calcium channel blockers, and optionally at least one, ie one or more, for example two, simultaneously, A combination formulation comprising a pharmaceutically acceptable carrier for separate or sequential use comprises a component, a free or pharmaceutically acceptable salt form of a DPP-IV inhibitor and an additional agent such as a thiazolidinedione or a calcium channel blocker. Particularly “multi-part kits” in that they can be administered independently or by using different fixed combinations of different amounts of the components, ie at different times or simultaneously. The parts of the multi-part kit can then be administered, for example, simultaneously or offset in time, i.e. at different times, at equal or different time intervals with any part of the multi-part kit. Preferably, the time interval is selected such that the effect on the treatment disease or condition in the combined use of the parts is greater than the effect that would be obtained by the use of any one of the components.

  The therapeutically effective amount of each component of the combination of the present invention may be administered simultaneously, sequentially in any order, and multiple components may be administered separately or as a fixed combination. For example, the methods of treatment of the present invention can be combined with a therapeutically effective amount, preferably a synergistically effective amount, such as a daily dose corresponding to a ratio described herein, (i) free or pharmaceutical Administration of an acceptable salt form of a DPP-IV inhibitor and (ii) administration of additional agents, such as thiazolidinediones or calcium channel blockers, either simultaneously or sequentially in any order.

  The pharmaceutical composition of the present invention can be produced by a method known per se, suitable for enteral administration to mammals including humans (warm-blooded animals), for example, oral or enteral, and parenteral administration, and has a therapeutically effective amount. A pharmacologically active compound of the invention, alone or in combination with one or more pharmaceutically acceptable carriers, particularly suitable for enteral or parenteral application.

  To further illustrate the present invention, but not for the purpose of limitation, the following clinical trials are provided. A further experimental protocol is described in patent application WO 01/52825 which describes a combination comprising a DPP-IV inhibitor and an antidiabetic agent, eg thiazolidinedione.

  The present invention has been described above with reference to preferred embodiments, but it will be appreciated that many additions, deletions, and modifications are possible within the scope of the appended claims, as will be appreciated by those skilled in the art. .

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

Clinical trials Materials and methods:
This study is intended to compare 24-week treatment of vildagliptin 100 mg combined with 30 mg of pioglitazone and low-dose combination (virdagliptin 50 mg + pioglitazone 15 mg) in drug-naive patients with T2DM (type 2 diabetes) with the component monotherapy A multicenter, double-blind, randomized, parallel group, active-control study. All drugs were administered once a day (qd) dose. It was conducted at 145 institutions in the United States (90), South Korea (15), United Kingdom (10), Italy (8), Taiwan (7), Slovakia (6), Czech Republic (5) and India (4).

Study drug and reference treatment:
Patients were treated with bildagliptin 100 mg qd and pioglitazone 30 mg qd, vildagliptin 100 mg qd monotherapy, pioglitazone 30 mg qd monotherapy, or vildagliptin 50 mg qd and pioglitazone 15 mg qd using double dummy techniques. Assign to 1: 1: 1: 1 ratio for double blind treatment.

Glossary

Study Setup This is a multicenter, randomized, double-blind, active control study. Drug naïve patients with type 2 diabetes (HbA1c 7.5-11%) were treated with vildagliptin 100 mg qd monotherapy, pioglitazone 30 mg qd monotherapy, vildagliptin 50 mg qd and pioglitazone 15 mg qd, or vildagliptin 100 mg qd and pioglitazone. Randomize equally to 30 mg qd combination treatment. Each patient participates in screening visit 1 (-2 weeks) where the inclusion / exclusion criteria are evaluated. Eligible patients will then be randomized at Visit 2 (Baseline, Day 1) and will perform four more visits during the entire 24 week treatment period.

Inclusion / exclusion criteria inclusion-T2DM not treated with oral antidiabetic drug (OAD) for at least 12 weeks prior to Visit 1 and not receiving OAD for more than 3 consecutive months at any time in the past Men and non-breeding age women (possible women giving birth using non-hormonal approved contraceptives)
- 18-80 years of _{^{age, BMI 22-45kg / m 2, HbA}} 1c 7.5-11%, FPG <15mmol / L
Exclusion-T1DM, history of acute metabolic complications within the past 6 months,
-History of severe CVD, liver disease, congestive heart failure-ALT, AST> 2.5 × ULN, direct bilirubin> 1.3 × ULN, serum creatinine> 2.5 mg / dL, fasting TG> 700 mg / dL

Test Assessment-Primary Effect Assessment-HbA _1c measured by HPLC method
-Secondary effects assessment-FPG, fasting lipids (TG, total cholesterol, HDL, calculated LDL, calculated VLDL and non-HDL cholesterol) and body weight-Adverse events assessed in relation to severity and study drug relationship-SMBG <3.1 mmol / L Hypoglycemia defined as symptoms confirmed by plasma glucose equivalents. Severe hypoglycemic statistical analysis defined as any event that requires the help of others-Changes in LOCF from baseline to 24 weeks or endpoint in ITT population-Classification variables and baselines measured as covariates As an ANCOVA model including treatment and a given pooled center-Primary comparison in this study is for pioglitazone monotherapy-Safety assessment is mainly double-blind, randomized Based on the number of adverse events that occurred during treatment, post-baseline laboratory values that go outside the planned range, and the frequency and severity of hypoglycemic events. Treatment groups are specifically compared using Fisher's exact test for the incidence of peripheral edema.

result:
-Groups are well balanced at baseline during the study.
-Study 1 participants are primarily Asian or Caucasian with an average age of 51.5 years, BMI <30 kg / m ² , 2.1 year disease duration and 8.7% HbA _1c , but OAD Not being dosed.
-About one third of the participants are in the high baseline HbA _1c group (> 9.0%).
-Each treatment resulted in a meaningful improvement in glycemic control, but the HbA _1c reduction with either initial combination regimen was significantly greater than pioglitazone (30 mg daily) monotherapy.
The adjusted mean change (AMΔ) between-treatment difference in HbA _{1c at} 100 mg vildagliptin in combination with 30 mg pioglitazone is −0.6% (95% CI: [−0. 8, -0.3%], P <0.001).
-Of note, the first combination with the low dose vildagliptin (50 mg) and pioglitazone (15 mg) combination reduced HbA _1c by 1.7 ± 0.1% compared to pioglitazone 30 mg monotherapy. This is a significant reduction.
-Vildagliptin in combination with pioglitazone produces a dose-related increase in the proportion of patients achieving the ADA recommended treatment goal of HbA _1c <7.0%.
-Initial combination treatment with 100 mg vildagliptin + 30 mg pioglitazone was found to achieve the target HbA _1c level in 65% of patients.

Safety and tolerability

  Applicants have surprisingly discovered that vildagliptin reduces the incidence of edema, particularly thiazolidinedione-related edema.

Claims (24)

  A method for preventing, delaying or reducing the development of edema, comprising administering to a patient in need thereof a therapeutically effective amount of a DPP-IV inhibitor, or a pharmaceutically acceptable salt thereof.   A therapeutically effective amount of thiazolidinedione, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a DPP-IV inhibitor, or a pharmaceutically acceptable salt thereof, for a patient in need thereof A method of preventing, delaying or reducing the development of thiazolidinedione-related edema, comprising administering.   Use of a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing, delaying or reducing the development of edema.   Thiazolidinedione or a pharmaceutically acceptable salt thereof in combination with a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing, delaying or reducing the development of thiazolidinedione-related edema Use of salt.   4. The method according to claim 1 or the use according to claim 3, wherein the edema is drug-related edema.   6. The method according to claim 5 or the use according to claim 5, wherein the drug-related edema is antihypertensive agent-related edema or antidiabetic agent-related edema.   6. The method of claim 5 or the use of claim 5, wherein the edema is thiazolidinedione-related edema or calcium channel antagonist-related edema.   6. The method according to claim 5 or the use according to claim 5, wherein the medicament is selected from pioglitazone, rosiglitazone and amlodipine, or in each case a pharmaceutically acceptable salt thereof.   The method or use according to any of claims 1 to 8, wherein the edema is peripheral edema, diabetic macular edema or pulmonary edema.   A DPP-4 inhibitor is administered in combination with two or three additional compounds selected from antidiabetic and antihypertensive agents or in any case pharmaceutical salts thereof. The method or use as described.   11. A method or use according to claim 10, wherein the further compound is selected from sulfonylureas, thiazolidinediones, metformin, insulin, and calcium channel blockers.   12. The method or use according to any of claims 1 to 11, wherein the treated patient is selected from a patient suffering from antihypertensive agent induced edema or calcium channel blocker induced edema.   The DPP-IV inhibitor is 1- {2-[(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2- (S) -cyano-pyrrolidine (also known as [S] -1- [2- ( 5-cyano-2-pyridinylamino) ethylamino] acetyl-2-pyrrolidinecarbonitrile monohydrochloride), vildagliptin, L-threo-isoleucilthiazolidine P32 / 98, sitagliptin, GSK23A, saxagliptin, 3- (aminomethyl)- 2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2-{[3- (aminomethyl) -2-isobuthyl-4-phenyl-1- 13. Oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally in each case selected from its pharmaceutical salts The method or use according to any one.   The method or use according to any one of claims 1 to 13, wherein the DPP-IV inhibitor is vildagliptin or a pharmaceutical salt thereof.   15. The method or use according to any of claims 1 to 14, wherein 50 to 150 mg vildagliptin or a pharmaceutical salt thereof is administered daily.   16. A method or use according to any of claims 1 to 15, wherein the thiazolidinedione is selected from pioglitazone or rosiglitazone or optionally a pharmaceutical salt thereof. i) administering 50 mg, 100 mg or 150 mg vildagliptin or a pharmaceutically acceptable salt thereof to a patient in need thereof daily in combination with thiazolidinedione or a pharmaceutically acceptable salt thereof;
ii) select from patients suffering from treatment-affected thiazolidinedione-related edema,
Treatment regimen. i) administering 50 mg, 100 mg or 150 mg vildagliptin or a pharmaceutically acceptable salt thereof to a patient in need thereof daily in combination with thiazolidinedione or a pharmaceutically acceptable salt thereof;
ii) the treated patient is a patient whose disease was not properly controlled by thiazolidinedione alone; and
ii) select from patients suffering from a treated patient thiazolidinedione-related edema,
Treatment regimen. 19. 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 is administered to the patient daily. Treatment regimen.   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 salt thereof.   2. The treated patient has hypertension, diabetes mellitus, type I or insulin dependent diabetes mellitus (IDDM), type II or non-insulin dependent diabetes mellitus (NIDDM), type A insulin resistance, IGM, IFG or IGT. Use, method or treatment regimen according to any of -21.   23. Use, method or treatment regimen according to any of claims 1-22, wherein 250 mg to 3000 mg of metformin or a salt thereof is administered daily to a treated patient. -15-45 mg of pioglitazone or a pharmaceutically acceptable salt thereof,
24. 2-8 mg rosiglitazone or a pharmaceutically acceptable salt thereof, or 1-10 mg CBB or a pharmaceutically acceptable salt thereof, administered daily to the patient. Use, method or treatment regimen as described.