Application of dpp-iv inhibitor for reduction of glycemia acute exacerbation

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology and can be used for reduction of hypoglycemia acute exacerbation or severe hypoglycemia exacerbation in patients with type II diabetes after treatment with insulin. For this purpose vildagliptin or its salt is introduces to patient in combination with insulin.

EFFECT: invention ensures reduction of risk of hypoglycemia development, as well as necessity to apply several antihyperglycemic medications.

12 cl, 1 tbl, 1 ex

 

The invention relates to a method of reducing the amount of bouts of hypoglycemia, especially severe episodes of hypoglycemia due to treatment antidiabetic compounds, especially insulin, wherein the patient is administered an inhibitor of dipeptidylpeptidase IV (inhibitor of DPP-IV) or its pharmaceutically acceptable salt.

Patients preferred suffer from hyperglycemia such as diabetes, preferably non-insulin dependent diabetes mellitus or impaired glucose metabolism (IGM), preferably impaired glucose tolerance (IGT).

Diabetes is a fairly common disorder (affecting approximately 1% of the total population), which is characterized by hyperglycemia. There are three main types of diabetes, type I or insulin-dependent diabetes mellitus (IDDM), type II or non-insulin-dependent diabetes mellitus (NIDDM) and the type And or insulin resistance. Patients diagnosed with diabetes type I or type II develops a tolerance to the action of exogenous insulin (“insulin resistance”) by many mechanisms. Insulin resistance type And is caused either by mutations in the gene for the insulin receptor or defects in the post-receptor sites, which play a crucial role in glucose metabolism. Diabetes is usually treated by introduction of exogenous Ann is Lina (primarily patients diagnosed with diabetes type II), when using a special diet and exercise (especially patients diagnosed with diabetes type II), or use both types of treatment.

Impaired glucose metabolism (IGM) mean glucose levels in the blood, which exceed the normal level, but are not high enough to meet the diagnostic criteria of diabetes mellitus type 2. The incidence of IGM varies in different countries, but usually 2-3 times higher than the incidence of overt diabetes. Until recently, the subjects with IGM was seen as predisposed to diabetes, but data from several epidemiological studies indicate that subjects with IGM heterogeneous in relation to risk of diabetes and risk of morbidity and mortality from cardiovascular disease. The data obtained indicate that in subjects with IGM, especially IGT, not always develop diabetes, but regardless of this they are at high risk of morbidity and mortality from cardiovascular disease. Among the subjects with IGM approximately 58% have impaired glucose tolerance (IGT), and 29% impaired fasting glucose (IFG), and 13% are observed in both disorders (IFG/IGT). IGT is characterized by increased afternoon (after a meal) hyperglycemia, whereas IFG is defined in accordance with the tvii with data from the American Association of diabetes (ADA, see the table below) based on the analysis of fasting glucose levels.

Category normal glucose tolerance (NGT), IGM and diabetes type 2 are defined in table ADA in 1997

Due to the fact that IGT is an independent risk factor for adiabatic, as well as in diabetics, this factor is included as a new indication, regardless of diabetes for the prevention and reduction of morbidity and mortality from cardiovascular disease and cancer. In addition, the phase between normoglycemia and diabetes, primarily glycemic stage, becomes of great interest, and there is an urgent need for a way to suppress or slow down the progression of the disease to diabetes type 2 and cardiovascular and microvascular conditions and diseases, and cancer, which are associated with IGM and especially IFG and/or IGT.

Type 2 diabetes is a progressive disease, and although monotherapy allows, first, to regulate the level of blood glucose in some patients, diabetes is associated with a high level of unsuccessful treatment of secondary diseases. This high level of unsuccessful medical treatment is the main cause of frequent complications associated with prolonged hyperglycemia in patients with type 2 diabetes. Limitations of monotherapy to support the Jania glycemic regulation can be overcome, at least some patients and for a limited time, due to a combination of several oral medications to lower glucose levels, which cannot be achieved with long-term therapy with one agent. Available data confirm the conclusion that for most patients with type 2 diabetes oral monotherapy is insufficient and will require treatment with multiple drugs.

However, because type 2 diabetes is a progressive disease, even in patients with a positive initial response to combination therapy, will eventually need to increase the dose or even the treatment of insulin as a stable glucose level is usually not possible to maintain for a long time.

Although combination therapy is an effective way to improve glycemic regulation, such therapy is not without drawbacks. Many results indicate that when combined therapy increases the risk of hypoglycemia and the need to use multiple drugs may also the degree of agreement of patients with treatment. In addition, receiving several antihyperglycemics drugs increases the possibility of pharmacokinetic interactions with other Lakers the governmental funds, which the patient is taking.

The appropriate use of oral combination therapy may temporarily suspend the need for multiple injections of insulin, temporarily to help maintain low glucose or low level of glycosylated hemoglobin (HbA1c) and temporarily prevent vascular complications.

The author unexpectedly found that to reduce severe hypoglycemic episodes in the treatment of antidiabetic compounds, especially insulin, in combination with antidiabetic compounds, especially in combination with insulin can be used inhibitors of DPP-IV, especially LAF237. In addition, prolonged treatment of this combination causes less side effects on sravneiyu with other combinations, for example, insulin in combination with glitazones.

Insulin is a known compound, approved by Management under the control over food and drugs (USA) for the treatment of diabetes.

It is understood that in the present context, the term “insulin” includes any form of insulin or any derivative, as described in patent US 6620780.

In the human insulin contains three primary amino groups: N-terminal group of a-chain and b-chain and the ε-amino group LysB29. In the field of technology is not known is how many derivatives of insulin, zameshannye one or more of the specified amino groups. So, in the US 3528960 (firm Eli Lilly) described N-carboxymethyllysine, in which one, two or three primary amino groups in the molecule of insulin containing group carboxyethyl. In the patent are not described NεB29-substituted insulin.

According to GB 1492997 (firm Nat. Res. Dev. Corp.) it is established that the insulin containing Nε29-carbamylate have improved profile hypoglycemic action.

In published application JP 1-254699 (firm Kodama Co., Ltd.) described insulin, in which the fatty acid is attached to the amino group of PheB1or to the ε-amino group of LysB29or to both groups. The purpose of this modification is to obtain pharmacologically acceptable stable insulin product.

Insulin, which in the position WE contain the amino acid, comprising at least five carbon atoms, which is optionally encoded by a triplet of nucleotides that are described in published application JP 57-067548 (company Shionogi). Stated that insulin analogues can be used for the treatment of diabetes, especially in patients who insulinresistant due to production of antibodies to bovine and porcine insulin.

In the US 5359030 (firm Ekwuribe, Protein Delivery, Inc.) described stabilized by conjugation of the polypeptide composition for oral or parenteral administration, including poly is epted, covalently associated with the polymer comprising a linear fragment of polyalkylene and lipophilic fragment, and these fragments are located relative to each other such that the polypeptide has an increased resistance to degradation by enzymes in vivo.

In EP 511600 A2 described protein derivative of the formula [protein] [Z]nwhere [protein] means a protein containing n amino acid residues, and [Z] stands for a group of the formula-CO-W-COOH, where W means the divalent hydrocarbon group with a long chain, which may also contain several heteroatoms, and n means the average number of amide bonds between [Z] and [protein]. It should be noted that the derived protein according to the invention have a very long half-life in the blood compared to the original protein and do not possess antigenic properties. It should also be noted that one of the proteins that can be modified in this way is insulin, but in EP 511600 not described any specific derivatives of insulin, and there are no instructions on preferred [Z] or (a) preferred provision (s)for which you want to attach [Z] in order to obtain the necessary derivatives of insulin.

It is understood that in the description of the application the term insulin in the plural or in the General sense includes natural insulins and analogues, and p is osvitnye. Derived insulin” means a polypeptide that is similar in structure to human insulin, including disulfide bond between CysA7and CysB7and between CysA20and CysB19and interchain disulfide bonds between CysA6and CysA11and which has the activity of insulin.

Preferably, the insulin is in the form of a pharmaceutical composition which is a solution containing from about 30 nmol/ml to about 3000 nmol/ml or 120 nmol/ml to 1200 nmol/ml, about 600 nmol/ml of insulin.

Examples of insulin include:

NovoLog® (insulin aspart injection, recombinant) is an analogue of human insulin, which is a fast-acting parenteral agent that reduces the level of glucose in the blood. Dosage NovoLog should be selected individually in accordance with the recommendations of the attending physician and the needs of the patient. The total daily dose of insulin in accordance with the individual requirements of typically 0.5 to 1.0 units/kg/day. If the course of treatment, including subcutaneous injection simultaneously with the meal, Novolog allows you to provide your body with 50-70% of the total need for insulin, and the remaining amount is provided by insulin intermediate and prolonged action.

APIDRA™ (insulin-glul the zine, recombinant) is an analogue of human insulin, which is a fast-acting parenteral agent that reduces the level of glucose in the blood. Insulin-glulisine get by recombinant DNA technology using non-pathogenic laboratory strain of Escherichia coli (K12). Insulin-glulisine differs from human insulin in that instead of asparagine at position B3 contains lysine, and at position B instead of lysine contains glutamic acid, i.e. chemically means 3B-Lys-29B-Glu-human insulin with the empirical formula C258H384N64O78S6and molecular weight 5823. The drug APIDRA (100 units/ml, U-100) is available in the following packaging: vials NDC 0088-2500-33 capacity 10 ml Dose APIDRA should be selected individually in accordance with the recommendations of the attending physician and the needs of the patient. APIDRA should generally be used in courses of treatment, which includes long-acting insulin or similar primary insulin.

Humalog (insulin-lispro, recombinant) is an analogue of human insulin, which is a fast-acting parenteral agent that reduces the level of glucose in the blood. Chemically, it is a Lys(B28), Pro(V)human insulin, which is formed when the amino acids at positions 28 and 29 of the b-chain insulin is to swap it with.

LANTUS® (insulin glargine injection, recombinant) is a sterile solution of insulin-glargine; for injection. Insulin glargine is a recombinant analog of human insulin, which has a prolonged action (up to 24 hours inclusive) and reduces the level of glucose in the blood, parenteral (see CLINICAL PHARMACOLOGY). LANTUS get by recombinant DNA technology using non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glargine differs from human insulin in that it instead of asparagine at position A21 contains glycine and C-terminal fragment of the b-chain contains two additional arginine residue. When a clinical trial involving patients with a diagnosis of type 2 diabetes, not subjected to the action of insulin, but previously treated with oral antidiabetic drugs, drug LANTUS started typing at an average dose of 10 Honey. once per day, and gradually brought in line with the needs of the patient's total daily dose of from 2 to 100 Honey.

Exubera® is a short-acting insulin product for inhalation is indicated for the treatment of type 1 diabetes and type 2 manufactured by Pfizer (human insulin, recombinant powder for inhalation). Exubera® is a high-performance powdered human insulin, which is injected ing is the transmission through the oral cavity into the lungs before eating using manual inhaler Exubera®.

It is implied that the term “inhibitor DPP-IV” means a compound that inhibits the enzymatic activity of DPP-IV and the close functional relationship of enzymes, for example, 1-100%, and primarily protects the enzyme from the substrate, including, without limitation, glucagon-like peptide-1, gastric inhibitory polypeptide, peptide histidinemia, substance P, neuropeptide Y, and other compounds, usually containing residues of alanine or Proline in the second position of the N-terminal fragment. Treatment with inhibitors of DPP-IV prolong the duration of action of peptide substrates and increases the level of intact non-degraded form, having a range of biological effects, is included in the scope of the present invention.

DPP-IV can be used for regulation of glucose metabolism because its substrates include insulinotropic hormones, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms and the removal of the two N-terminal amino acid residues leads to their inactivation. Introduction in vivo synthetic inhibitors of DPP-IV prevents cleavage of N-terminal amino acid in GLP-1 and GIP, resulting in higher concentrations of these hormones in the blood plasma, insulin secretion and, consequently, increased the Oh of glucose tolerance. For these purposes, chemical compounds were tested for their ability to inhibit the activity of purified CD26/DPP-IV. The activity of CD26/DPP-IV has been evaluated in vitro for their ability to cleave the synthetic substrate Gly-Pro-para-nitroanilide (Gly-Pro-pNA). The cleavage of Gly-Pro-pNA by the enzyme DPP-IV is the release of the product para-nitroanilide (pNA), and the reaction rate is directly proportional to the activity of the enzyme. Inhibition of specific enzyme inhibitors suppresses the release of pNA. Stronger binding of the inhibitor to the enzyme leads to a decrease in the rate of formation of pNA. Thus, the degree of decrease in the rate of formation of pNA directly reflects the degree of inhibition of the enzyme. The formation of pNA was measured on the spectrophotometer. The inhibition constant Ki for each compound was determined in the incubation of a fixed amount of the enzyme with various concentrations of inhibitor and substrate.

It is understood that in the present context, the term “inhibitor of DPP-IV also includes active metabolites and prodrugs of inhibitors of DPP-IV. The term “metabolite” means active derived inhibitor of DPP-IV, formed by the metabolism of the inhibitor of DPP-IV. “Prodrug” means a compound that is metabolized education inhibitor of DPP-IV or metabolized with the formation of metabolites (metabolites), anal is the same metabolite (metabolite) inhibitor DPP-IV. In this context, the term “inhibitor of DPP-IV also includes its pharmaceutically acceptable salt.

Inhibitors of DPP-IV are known in the art. Typical inhibitors of DPP-IV are described in the following sources.

Inhibitors of DPP-IV are described in each case in General and specifically, for example, in WO 98/19998, DE 19616486 Al, WO 00/34241, WO 95/15309, WO 01/72290, WO 01/52825, WO 03/002553, WO 9310127, WO 99/61431, WO 9925719, WO 9938501, WO 9946272, WO 9967278 and WO 9967279.

Preferred inhibitors of DPP-IV are described in the following patent applications: WO 02053548, primarily compounds 1001-1293 and examples 1-124, WO 02067918, primarily compounds 1000-1278 and 2001-2159, WO 02066627 primarily examples, WO 02/068420, first of all compounds specifically listed in examples I-LXIII, and describes the corresponding analogues, more preferred compounds are compounds 2(28), 2(88), 2(119), 2(136), described in the table indicating the values of the IC50WO 02083128, such as connections, referred to in paragraphs 1-5 above all examples 1-13 and paragraphs 6-10, US 2003096846 primarily specifically listed compounds, WO 2004/037181 primarily examples 1-33, WO 0168603 primarily examples 1-109, EP 1258480 primarily example 1-60, WO 0181337 primarily examples 1-118, WO 02083109 primarily examples 1A-1D, WO 030003250 primarily examples 1-166, most preferably compounds 1-8, WO 03035067, primarily compounds described in the examples, WO 03/035057, first of all compounds described in the example is, US 2003216450 primarily examples 1-450, WO 99/46272, primarily paragraphs 12, 14, 15 and 17, WO 0197808, primarily compounds according to paragraph 2, WO 03002553, primarily compounds described in examples 1-33, WO 01/34594 primarily examples 1-4, WO 02051836 primarily examples 1-712, EP 1245568 primarily examples 1-7, ER primarily examples 1-32, US 2003087950, primarily compounds described in the examples, WO 02/076450 primarily examples 1-128, WO 03000180 primarily examples 1-162, WO 03000181 primarily examples 1-66, WO 03004498 primarily examples 1-33, WO 0302942 primarily examples 1-68, US 6482844, primarily compounds described in the examples, WO 0155105, especially examples 1 and 2, WO 0202560 primarily examples 1-166, WO 03004496 primarily examples 1-103, WO 03/024965 primarily examples 1-54, WO 0303727 primarily examples 1-209, WO 0368757 primarily examples 1-88, WO 03074500 primarily examples 1-72, examples 4.1-4.23, examples 5.1-5.10, examples 6.1-6.30, examples 7.1-7.23, examples 8.1 - 8.10, examples 9.1-9.30, WO 02038541 primarily examples 1-53, WO 02062764 primarily examples 1-293, it is preferable example 95 (hydrochloride, 2-{{3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2 dihydro-6-ethenolysis}oxy}ndimethylacetamide), WO 02308090 primarily examples 1-1-1-109, examples 2-1-2-9, example 3, examples 4-1-4-19, examples 5-1-5-39, examples 6-1-6-4, examples 7-1-7-10, examples 8-1-8-8, examples 7-1-7-7 (p.90), examples 8-1-8-59 (p.91-95), examples 9-1-9-33, examples 10-1-10-20, US 2003225102 primarily examples 1-115, examples 1-121, preferably the compounds (a)-z), aa)-az), ba)-bz), ca)-cz) and da-dk), WO 0214271, primarily compounds described in the examples 1-320, US 2003096857, in the application US 09/788173 (registered 16 February 2001, file LA50), especially the compounds described in the examples, WO 99/38501, primarily compounds described in the examples, WO 099/46272, primarily compounds described in the examples, and DE 19616486 A1, first of all per-peer, per-thiazolidin, isoleucyl-thiazolidin, isoleucyl-pyrrolidide and fumarate isoleucyl-thiazolidine, isoleucyl-pyrrolidide.

Other preferred inhibitors of DPP-IV include specific examples described in US 6124305 and US 6107317, international applications WO 9819998, WO 9515309 and WO 9818763, such as 1[2-[(5-cyano-2-yl)aminoethylamino]acetyl-2-cyano-(8)-pyrrolidine and (2S)-I-[(2S)-2-amino-3,3-dimethylbutanol]-2-pyrrolidinecarbonyl.

In another preferred embodiment, the inhibitor of DPP-IV means N-peptidyl-O-aroylhydrazines or its pharmaceutically acceptable salt. For example, aroyl means afterburner or benzoyl, unsubstituted or mono - or disubstituted, for example, groups (ness.)alkoxy, (ness.)alkyl, halogen or preferably nitro. Peptidyl preferably includes two α-amino acids, e.g. glycine, alanine, leucine, phenylalanine, lysine, or Proline, and group attached directly to the nitrogen atom of the hydroxylamine, preferably means Proline.

In each case mentioned, p is IDE just points related compounds and final products in the examples of the preparation of the compounds object of the invention in the form of the final products, the pharmaceutical preparations and the actual items included in the description of the present application by reference.

In WO 9819998 described N-(N'-substituted glycyl)-2-cyanopyrrolidine, especially 1-[2-[5-cyanopyridine-2-yl]amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidin.

The preferred compounds described in WO 03/002553 are listed on page 9-11 and included in the description of the present application by reference.

In DE 19616486 A1 describes a per-peer, per-thiazolidin, isoleucyl-thiazolidin, isoleucyl-pyrrolidide and fumarate isoleucyl-thiazolidine, isoleucyl-pyrrolidide.

In WO 00/34241 and US 6110949 described N-substituted adamantylamine-2-cyanopyrrolidine and (substituted glycyl)-4-cyanopyrrolidine respectively. Interest inhibitors of DPP-IV specifically listed in paragraphs 1-4.

In WO 9515309 as inhibitors of DPP-IV described 2-cyanopyrrolidine amino acids, and in WO 9529691 described peptidyl derived diesters of α-aminoalkylphosphonic acids, primarily containing Proline or similar structural fragments. Interest inhibitors of DPP-IV specifically listed in tables 1-8.

In WO 01/72290 interest inhibitors of DPP-IV specifically listed in example 1 and paragraphs 1, 4 and 6.

In WO 01/52825 detail (S)-1-{2-[5-inoperation-2-yl)amino]acylaminoacyl)-2-cyanopyrrolidine or (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (LAF237).

In WO 9310127 described prolinnova esters that can be used as inhibitors of DPP-IV. Interest inhibitors of DPP-IV specifically listed in paragraphs 1-19.

In published application WO 9925719 described surfactin, an inhibitor of DPP-IV, obtained from the culture of streptomycete.

In WO 9938501 described N-substituted 4-8 membered heterocyclic system. Interest inhibitors of DPP-IV specifically listed in paragraphs 15-20.

In WO 9946272 as inhibitors of DPP-IV described phosphorus-containing compounds. Interest inhibitors of DPP-IV specifically listed in paragraphs 1-23.

Other preferred inhibitors of DPP-IV are compounds of formula I, II or III described in patent application WO 03/057200 on p.14-27. The most preferred inhibitors of DPP-IV are compounds specifically described on page 28 and 29.

In the published patent applications WO 9967278 and WO 9967279 described prodrugs and inhibitors of DPP-IV in the form a-b-C, where C means a stable or unstable inhibitor of DPP-IV.

Preferably N-peptidyl-O-aroylhydrazines mean compound of formula VII

where

j is 0, 1 or 2,

1means a side chain of natural amino acids, and

2means (ness.)alkoxy, (ness.)alkyl, halogen or nitro,

or its pharmaceutically acceptable salt.

More is predpochtitelno embodiment of the invention N-peptidyl-O-aroylhydrazines mean compound of formula VIIa

or its pharmaceutically acceptable salt.

N-Peptidyl-O-aroylhydrazines, for example, of formula VII or VIIa and obtaining them are described in the article H.U.Demuth and others, J.Enzyme Inhibition, 2, 129-142 (1988), primarily in str-132.

Preferred inhibitors of DPP-IV described in section Mona Patel and others, Expert Opinion Investig. Drugs, 12(4), 623-633, 5 paragraph (April, 2003), primarily compounds R/98, 364, FE-999011, BDPX, NVP-DDP-728 and others, this publication also included in the description of the application as references, primarily described inhibitors of DPP-IV.

Another preferred inhibitor of DPP-IV is the connection # 815541 (T 6666, firm Tanabe).

Preferred inhibitors of DPP-IV is also described in patent applications WO 02/083128, primarily compounds described in examples 1-13, US 6395767, the compounds described in the examples 1-109, and WO 03/033671, all specifically described compounds, for example, compounds 1-393 and connections described on p.67-70.

Connection FE-999011 described in patent application WO 95/15309 (compound No. 18, p.14).

Another preferred inhibitor is a compound BMS-477118, described in WO 2001068603 or US 6395767 (compound described in example 60), also known as (benzoate 1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytriazine[3.3.1.13,7]Oct-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (1:1), i.e. the compound of formula M in the patent application WO 2004/052850 on page 2, and suitable the e free base 1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytriazine[3.3.1.1 3,7]Oct-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (M') and the monohydrate (M), i.e. the compound of formula M in the patent application WO 2004/052850 on page 3. The compound BMS-477118 also known as saxagliptin.

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

In WO 99/61431 described connection R/98 (cat no.251572-86-8), also known as 3-[(2S,3S)-2-amino-3-methyl-1-oxobutyl]thiazolidin that can be used in the form of a mixture of 3-[(2S,3S)-2-amino-3-methyl-1-oxobutyl]thiazolidine and (2E)-2-butenedioate (2:1)and the following formula

described in WO 99/61431, as well as in the journal Diabetes, 47, 1253-1258 (1998), under the name of Probiodrug, as well as connection R/01, described this firm.

Other preferred inhibitors of DPP-IV are compounds described in patent application WO 02/083128, such as connections, referred to in paragraphs 1-5. The most preferred inhibitors of DPP-IV are compounds specifically described in examples 1-13 and in paragraphs 6-10.

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

Other more preferred Inga is itory DPP-IV according to the invention described in international patent application WO 02/076450 (primarily in the examples 1-128) and article Wallace T. Ashton, Bioorganic & Medicinal Chemistry Letters, 14, 859-863 (2004), especially compound 1 and compounds listed in tables 1 and 2. Preferred is a compound a (table 1) formula

Other preferred inhibitors of DPP-IV are described in patent applications WO 2004/037169 primarily examples 1-48, and WO 02/062764 primarily examples 1-293, more preferred are 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}acetamide", she described on page 7, as well as in patent application WO 2004/024184 primarily examples 1-4.

Other preferred inhibitors of DPP-IV is described in patent application WO 03/004498 primarily examples 1-33, and most preferred is a compound of the formula

described in example 7 and is known as the connection MK-0431 or sitagliptin. The preferred daily dose of sitagliptin is 25 to 100 mg

In each case, references, primarily in the paragraphs relating to the compounds and final products in the examples of the preparation of the compounds object of the invention in the form of the final products, the pharmaceutical preparations and the actual items included in the description of the present application by reference.

Preferred inhibitors of DPP-IV is also described in patent application WO 2004/037181, preid the only examples 1-33, the most preferable compounds described in paragraphs 3-5.

Preferred inhibitors of DPP-IV are N-substituted adamantylamine-2-cyanopyrrolidines, N-(substituted glycyl)-4-cyanopyrrolidine, N-(N'-substituted glycyl)-2-cyanopyrrolidines, N-aminoethylethanolamine, N-AMINOETHYLPIPERAZINE, L-ALLO-solicitation, L-threo-isolatin1encoding and L-ALLO-isolatin1encoding, 1-[2-[(5-cyano-2-yl)amino]ethylamino]acetyl-2-cyano-(8)-pyrrolidin, the connection MK-431 and their pharmaceutically acceptable salts.

The most preferred inhibitors of DPP-IV are selected from the group including monohydrochloride [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrrolidinecarbonyl, (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine and L-threo-solicitation (Probiodrug R/98, described above), the connection MK-0431, 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}ndimethylacetamide and not necessarily their pharmaceutically acceptable salts.

Monohydrochloride [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrrolidinecarbonyl, (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine described in detail in WO 98/19998 (example 3) and in WO 00/34241 (example 1), respectively. Inhibitor of DPP-IV R/98 (see above) is described in detail in Diabetes, 47, 1253-1258 (1998). Monohedral the reed [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrrolidinecarbonyl and (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine can be processed into formulations as described in WO 98/19998 (p.20) or in WO 00/34241.

Preferred primarily 1-{2-[(5-cyano-2-yl)amino]ethylamino}acetyl-2-(S)-cyanopyrrolidine (also called monohydrochloride [S]-1-[2-(5-cyano-2-pyridinylamino)ethylamino]acetyl-2-pyrrolidin of carbonitrile) formula

first of all its dihydrochloride and monohydrochloride, (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (also known as (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyano-pyrrolidin, LAF237 or vildagliptin) formula

,

and L-threo-solicitation (Prodrug R/98, described above), sitagliptin, the connection GSK23A, saxagliptin, 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}ndimethylacetamide and optional in each case, their pharmaceutically acceptable salts.

Connection DPP728 and LAF237 is described in detail in WO 98/19998 (example 3) and in WO 00/34241 (example 1), respectively. Inhibitor of DPP-IV R/98 (see above) is described in detail in Diabetes, 47, 1253-1258 (1998). Connection DPP728 and LAF237 can be converted into the compounds as described in WO 98/19998 (p.20) or in WO 00/34241, or in international patent application EP 2005/000400 (application number).

Any of the compounds described in the above patent documents or in scientific publications included in the description in the form of ssy is OK and can be used as inhibitors of DPP-IV in the methods of the present invention.

Inhibitors of DPP-IV, which can be used according to the present invention separately, can also be used in mixture with a carrier.

In this context, the carrier connection means (natural, synthetic, peptide or ones of nature), for example, a protein that carries specific compounds through the cell membrane in which the protein is embedded in the cell. To transfer different connections and different media (natural, synthetic, peptide or ones of nature), because each of them is able to recognize only one connection or group of kindred connection properties.

To determine the Association of an inhibitor of DPP-IV with the media, you can use any known methods, for example, the introduction of media labels.

As an inhibitor of DPP-IV can be used compounds of the peptide or ones of nature.

The most preferred inhibitors of DPP-IV for oral administration and their pharmaceutically acceptable salts.

Active ingredients (inhibitors of DPP-IV) or their pharmaceutically acceptable salts according to the present invention can also be used in the form of MES, such as a hydrate, or MES with other solvents used for crystallization.

Now unexpectedly found that inhibitors of DPP-IV or its salt, especially LAF27, can be used in combination with at least one antidiabetic compound (for example, with one or two antidiabetic compounds), primarily insulin to reduce severe episodes of hypoglycemia due to treatment antidiabetic compounds, primarily to reduce severe episodes of hypoglycemia during treatment with insulin. Thus, in one embodiment, the invention features a method of reducing severe episodes of hypoglycemia, including the introduction of a therapeutically effective amount of an inhibitor of DPP-IV or its salt to a patient who received treatment for at least one antidiabetic compound (for example, one or two antidiabetic compounds), especially the patient, previous treatment with insulin

or a way to reduce episodes of hypoglycemia or severe episodes of hypoglycemia due to treatment with at least one antidiabetic compound (i.e. one or two antidiabetic compounds), primarily due to insulin treatment, including the introduction of a therapeutically effective amount of an inhibitor of DPP-IV or its salt to a patient who underwent treatment antidiabetic drugs, primarily for the patient, previous treatment with insulin

or the use of an inhibitor of DPP-IV or its salts in combination on m is Nisha least one antidiabetic compound (for example, one or two antidiabetic compounds), primarily insulin for obtaining a medicinal product intended to reduce episodes of hypoglycemia or severe episodes of hypoglycemia,

or the use of an inhibitor of DPP-IV or its salt to obtain a medicinal product intended to reduce episodes of hypoglycemia or severe episodes of hypoglycemia in a patient who underwent treatment at least one antidiabetic compound (i.e. one or two antidiabetic compounds), especially in a patient who has attended a course of insulin treatment.

The application, as indicated above, where bouts of hypoglycemia or severe episodes of hypoglycemia are the result of insulin treatment, i.e. the side effect of insulin treatment.

The application, as indicated above, where bouts of hypoglycemia or severe episodes of hypoglycemia are the result of the treatment, i.e. the side effects of treatment, antidiabetic compounds, for example, one, two or three compounds selected from the group comprising Metformin, nateglinide, glitazone (preferably pioglitazone or rosiglitazone), sulfonylureas, GLP-1 or analogues of GLP-1 (preferably on the basis 4), antagonists of receptor-1 cannabinoid receptor-1 (SW) (preferably rimonaban) and insulin. If PAC is enta treated with two antidiabetic compounds, you can use the following combinations: Metformin+sulfonylurea, Metformin+glitazone, Metformin+analogue of GLP-1 Metformin+antagonist SW, glitazone+sulfonylurea, Metformin+insulin, glitazone+insulin, an analogue of GLP-1+sulfonylurea, a sulfonylurea+insulin or an analogue of GLP-1+insulin.

The term “attack of hypoglycemia are known to the person skilled in the art. Hypoglycemia means symptoms indicating a low level of glucose in the blood, as evidenced by the value of SMBG <3.1 mmole/l, equivalent to glucose in the plasma. Severe hypoglycemia refers to any attack that requires intervention (low glucose <3.1 mmole/l, if the severity of the attack does not prevent the determination of glucose). Therefore, according to the present invention, the term “severe hypoglycemia” preferably means an attack of low blood glucose <3.8 mmole/l, preferably <3.1 mmole/L.

Preferably the inhibitor of DPP-IV mean (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (LAF237 or vildagliptin) of the formula (I)

,

or its pharmaceutically acceptable salt.

It is understood that in the present context, the term “(S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine”, or “LAF237 or vildagliptin” also include any salt or crystalline form.

Antidiabetic compounds preferably are selected from the group including modulators of signaling pathways of insulin, such as inhibitors patientinitiated (Ptpase), high-molecular compounds-mimetics and inhibitors of glutaminase-6-phosphate amidotransferase (GFAT), compounds stimulating the impaired production of glucose in the liver, such as inhibitors of glucose-6-phosphatase (G6P), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BP), inhibitors of glycogen phosphorylase (GP), antagonise glucagon receptor and inhibitors phosphoenolpyruvate-carboxykinase (NERSC), inhibitory kinase piruvatdegidrogenazy (PDHK), amplifiers insulin sensitivity, amplifiers insulin secretion inhibitors of α-glucosidase inhibitors of gastric emptying, insulin and α2-adrenergic antagonists or antagonists of the cannabinoid receptors SW.

The term “amplifier insulin sensitivity”used in the description of the application, means any and all pharmacologically active compounds that enhance the tissue sensitivity to insulin. Amplifiers insulin sensitivity include, for example, inhibitors of GSK-3, agonists X of the retinoid receptor (RXR)agonists β-3 AR agonists, UCP antidiabetic preparations of thiazolidinediones (glitazones), negetative PPAR agonistsγ, dual PPAR agonistsγ/PPARαprotevtion the political vanadium-containing compounds and biguanides, for example, Metformin.

The amplifier sensitivity to insulin, preferably selected from the group including antidiabetic preparations of thiazolidinediones, antidiabetic vanadium containing compounds and Metformin.

In one preferred embodiment, the amplifier insulin sensitivity means the Metformin.

Metformin is widely used to reduce blood glucose levels in patients with NIDDM and produced in tablets containing 500, 750, 850 and 1000 mg of the drug. However, because of the short-acting drugs Metformin should be entered twice or three times a day (2-3 tablets containing 500-850 mg of active agent/day or 1000 mg two times per day with meals). Antihyperglycemic agent Metformin (biguanide) described in US 3174901 and currently available in the US in the form of hydrochloride (Glucophage™, Bristol-Myers Squibb Company). Receiving Metformin (dimethylbiguanide) and its hydrochloride is known in the prior art and first described in article Emil A.Werner and James Bell, J. Chem. Soc. 121, 1790-1794 (1922). Metformin can be entered, for example, in the form produced under the trade name GLUCOPHAGE™.

Metformin increases insulin sensitivity in peripheral tissues of the host organism. In addition, Metformin is involved in the inhibition of the absorption of glucose in the intestine, suppression of hepatic gluconeogenesis and inhibition ocil is deposits of fatty acids. Suitable courses of treatment with Metformin include receiving a standard dose of 500 mg two to three times a day and even up to five times per day or 800 mg once or twice per day (Martindale, The Complete Drug Reference).

Some compositions with controlled or delayed release, which include antihyperglycemics drugs, such as Metformin hydrochloride, is limited by the application of a pore-forming or gelling agent, which is used to regulate the release of drugs from dosage forms. These forms are described in WO 96/08243 and in the instructions for use of product GLUCOPHAGE XR, which is a commercial drug Metformin with adjustable release (company Bristol-Myers Squibb).

GLUCOPHAGE (tablets of Metformin hydrochloride) should be entered divided doses with food, while GLUCOPHAGE XR (tablets of Metformin hydrochloride extended-release) is usually injected once a day with evening meal. Metformin preferably used in the form of Metformin hydrochloride.

The term “Metformin”used in the description of the application means of Metformin or its pharmaceutically acceptable salt, such as hydrochloride, fumarate Metformin (2:1) and succinate Metformin (2:1), as described in the application US 09/262526, registered on March 4, 1999, the hydrobromide, the pair-chlorophenoxyacetic is or embonate and other known salts of Metformin and mono - and dibasic carboxylic acids, including salts described in US 3174901, each of which is designated by the term Metformin. Preferably Metformin is used in the form of hydrochloride, sold under the trade name GLUCOPHAGE-D or GLUCOPHAGE XR (Bristol-Myers Squibb Company).

It is also understood that in the present context, the terms “inhibitor of DPP-IV”, “Metformin”, “glitazone” or any other variants glitazone, such as pioglitazone, rosiglitazone include any pharmaceutically acceptable salt, crystalline form, hydrate, MES, diastereoisomer or enantiomer.

Antidiabetics thiazolidinedione (glitazone) means, for example, (S)-((3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl)methylthiazolidine-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-methylcyclohexyl)methoxy)phenyl]methyl}thiazolidin-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 (VM-13.1246), 5-(2-naphthylmethyl)thiazolidin-2,4-dione (AY-31637), bis{4-[(2,4-dioxo-5-thiazolidine)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-cyclopropanecarbonyl)benzyl]thiazolidin-2,4-dione (DN-108) 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl}thiazolidin-2,4-dione, 5-[3-(4-chloro who enyl])-2-PROPYNYL]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-PROPYNYL]-5-(4-perpenicular)thiazolidin-2,4-dione, 5-{[4-(2-(methyl-2-pyridinylamino)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)naphthalene-2-ylmethyl]thiazolidine-2,4-dione (MSS), 5-{[2-(2-naphthyl)benzoxazol-5-yl]methyl}thiazolidine-2,4-dione (T-174) and 5-(2,4-dioxothiazolidine-5-ylmethyl)-2-methoxy-]-N-(4-trifloromethyl)benzamide (KRP297).

Assume that a particular glitazone, such as pioglitazone, rosiglitazone,” includes any pharmaceutically acceptable salt, crystalline form, hydrate, MES, diastereoisomer or enantiomer.

With the introduction of antidiabetic PPAR, primarily glitazone adult patient (body weight 50 kg), suffering from diabetes, the daily dose is usually from 0.01 to 1000 mg, preferably from 0.1 to 500 mg of the Indicated dose can be administered once or several times per day. If the insulin sensitizer is pioglitazone hydrochloride daily dose of pioglitazone hydrochloride is usually from 7.5 to 60 mg, preferably from 15 to 45 mg If the insulin sensitizer is used troglitazone, daily dose of tropicasa is and typically ranges from 100 to 1000 mg, preferably from 200 to 600 mg. If the insulin sensitizer is used rosiglitazone or its maleate), a daily dose of rosiglitazone is usually from 1 to 12 mg, preferably from 2 to 12 mg.

Glitazone means preferably pioglitazone, pioglitazone hydrochloride, troglitazone or rosiglitazone or its maleate), especially preferred hydrochloride pioglitazone.

The dose of the drug ACTOS® (pioglitazone) should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, Metformin or insulin. ACTOS in combination with Metformin, you can start with a dose of 15 mg or 30 mg once a day. The recommended dose of Metformin can continue to enter after the initial introduction of ACTOS. It is unlikely that the dose of Metformin will have to adjust because of hypoglycemia in combination therapy with ACTOS. ACTOS is in the form of tablets containing 15 mg, 30 mg and 45 mg of active agent.

AVANDIA® (rosiglitazone) can be injected in a dose of 4 mg as a single daily dose or divided doses, morning and evening. In the case of patients who have an inadequate response after 8-12 weeks of treatment, which is appreciated for reducing FPG, the dose can be increased to 8 mg daily in monotherapy or in combination with Metformin. The dose of AVANDIA should not exceed 8 mg per day as single dose or once Alannah doses twice a day. The drug AVANDIA is in the form of tablets containing 2 mg, 4 mg and 8 mg of active agent.

According to the present invention can also use a commercial combination comprising Metformin and a derivative thiazolidinedione. Rosiglitazone can be introduced in combination with Metformin dosage forms manufactured under the trade name AVANDAMET®. When antidiabetic drug therapy AVANDAMET dose picked individually on the basis of efficacy and tolerability by the patient without exceeding the maximum recommended daily dose of 8 mg/2000 .AVANDAMET® is manufactured in the form of tablets of various types. Each tablet contains maleate of rosiglitazone and Metformin hydrochloride: 1 mg/500 mg, 2 mg/500 mg, 4 mg/500 mg, 2 mg/1000 mg, 4 mg/1000 mg

Negetative PPAR agonistsγfirst and foremost are the analogues of N-(2-benzoylphenyl)-E-tyrosine, for example, GI-262570 and JTT501.

Amplifiers insulin secretion are pharmacologically active compounds that have the ability to stimulate insulin secretion from β-cells of the pancreas. Examples of enhancers of insulin secretion include antagonists of glucagon receptor (see above), derivatives, sulfonylureas, incretin, especially glucagon-like peptide-1 (GLP-1) or agonists of GLP-1 antagonists of the imidazoline receptor β-cells and high-speed tools, rivushie insulin secretion, such as antidiabetic derivative of phenylacetic acid, derived antidiabetic D-phenylalanine and connection BTS 67582 described in article I. Page and others, Br. J. Pharmacol., 122, 1464-1468 (1997).

Derived sulfonylureas means, for example, glisoxepide, gliburid, glibenclamide, acetohexamide, hlorpropamid, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, glikvidon, glyhexamide, fenbutatin or tolciclate, preferably glimepiride or gliclazide. Tolbutamide, glibenclamide, gliclazide, glibornuride, glikvidon, glisoxepide and glimepiride can be entered, for example, in the forms known under the trade names RASTINON HOECHST™, AZUGLUCON™, DIAMICRON™, GLUBORID™, GLURENORM™, PRO-DIABAN™ and AMARYL™, respectively.

GLP-1 is insulinotropic protein described, for example, article W.E.Schmidt and others, Diabetologia, 28, 704-707 (1985) and in the US 5705483. The term “agonists of GLP-1”used in the description of the application, means variants and analogues of GLP-1(7-36)NH2described primarily in the US 5120712, US 5118666, US 5512549, WO 91/11457 and article .Orskov etc., J. Biol. Chem., 264, 12826 (1989). The term “agonists of GLP-1 includes primarily compounds similar to GLP-1(7-37), which have in the molecule GLP-1(7-36)NH2C-terminal amide Arg36replaced by Gly37and their analogues, including GLN9-GLP-l(7-37), D-GLN9-GLP-1(7-37), acetyl-LYS9-GLP-1(7-37), LYS18-GLP-1(7-37) and especially GLP-1 (7-37), HE, VAL8-GLP-1(7-37), GLY -GLP-1(7-37), THR8-GLP-1(7-37), MET8-GLP-1(7-37) and 4-imidazolidinyl-DER-1. More preferred are also similar agonist GLP, on the basis of 4, described in the article Greig and others, Diabetologia, 42, 45-50 (1999). BYETTA (basis 4) is the first representative of a new class of drugs for the treatment of type 2 diabetes, the so-called mimic incretin, and which in many properties similar to incretin person (like peptide-1 (GLP-1)). The specified agent stated in US 5424286. BYETTA is a dosage form for self-administration in the form of a fixed dose for subcutaneous injection before the morning or evening meal. BYETTA is in the form of a filled syringe "pencil" type containing a dose of 5 mcg and 10 mcg.

Antagonist of cannabinoid receptor SW is a compound that binds to a receptor, but almost unable to activate it. Thanks antagonist prevents or reduces functional activation or employment receptor agonist, such as anandamide, if such agonist is present. In some embodiments, the antagonist has the value of the IC50from approximately 1 μm to approximately 1 nm. In other embodiments, the antagonist has the value of the IC50from approximately 0.1 μm to 0.01 μm, from 1.0 μm to 0.1 μm, or from 0.01 μm to 1 nm. In some embodiments, antagon the article competes with the agonist for interaction with the binding site on the receptor.

One group of suitable antagonists of cannabinoid receptor SW are derivatives of pyrazole. In patent applications EP-A-576357 and EP-658546 describes the typical pyrazole derivatives, which have affinity to the cannabinoid receptors. For example, in EP-A-656354 describes the typical derivatives of pyrazole and claimed N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide connection or SR 141716 and its pharmaceutically acceptable salts, which has a very high affinity to the major cannabinoid receptors. Other typical antagonists of cannabinoid receptor SW described in US 5596106, where it is reported that the compounds of ailment[b]thiophene and benzo[b]furan both block or inhibit cannabinoid receptors in mammals. Preferably such antagonist cannabinoid selective in respect of the receptor SW and is characterized by the value of the IC50when inhibition of the receptor SW, which is ¼ or less compared with IC50characteristic of receptor SW, more preferably 1/10 or less compared with IC50characteristic of receptor SW, or most preferably IC50for receptor SW is 1/100 of the value characteristic of the receptor SW. Each of the above publications are included in the description of the application as references in full.

Other examples select the main antagonists CB 1used in the context of the present invention include, without limitation, the following connections:

1) Connection diarylpyrazole described Sanofi as selective antagonists of the receptor CB1for example, as typical examples of the compounds SR-141716A, SR-147778, SR-140098 and rimonabant and related compounds described, for example, in EP 0969835 or EP 1150961 (Perio, A., Rinaldi-Carmona M., "Central mediation of the cannabinoid chemistry cue: activity of and selective CBj antagonist, SR A", Maruani J. Behavioural Pharmacology, 7(1), 65-71(1996)), the connection WIN-54461 described Sanofi-Winthrop (Pertwee R.G., "cannabinoid chemistry receptor ligands: Clinical and neuropharmacological considerations relevant to future drug discovery and development)), Expert Opinion on Investigational Drugs, 5(10), 1245-1253 (1996)). N-Piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR 141616, cat no.168273-06-1), its pharmaceutically acceptable salt and solvate described to obtain drugs intended for use in the treatment of disorders of appetite. SR 141616 (pINN: rimonabant) is characterized by the formula

Rimonabant is described in detail in EP-B-656354 or article M. Rinaldi-Carmona and others, FEBS Lett., 350, 240-244 (1994). In EP 1446384 A1 describes the new polymorphic modification of rimonabant, a composition comprising rimonabant described in WO 2003082256, and the use of rimonabant for violations of appetite is described in WO 99/00119.

2) Aminoalkylindole described as and the of taganito receptor CB 1for example, a typical example is the connection iodopovidone (AM-630).

3) Aralaraitnerry benzofuran described by the company Eli Lilly as selective antagonists of the receptor CB1for example, LY-320135 ((Pertwee R.G., "cannabinoid chemistry receptor ligands: Clinical and neuropharmacological considerations relevant to future drug discovery and development)), Expert Opinion on Investigational Drugs, 5(10), 1245-1253 (1996)).

4) the Compound described by the Merck & Co., for example, AM 251 and AM 281 (Conference: 31st Annual Meeting of the Society for Neuroscience, San Diego, USA (10-15.11.2001)), and replaced imidazolyl-derivatives described, for example, in US 2003-114495 or WO 03/007887.

5) Derivatives of azetidine described by the firm Aventis Pharma for example, in WO 02/28346 or EP 1328269.

6) Connection CP-55940 from Pfizer Inc. (Felder S., Joyce KE, Briley EM, Mansouri j, Mackie K, Blond o, Lai y, Ma A.L., R.L. Mitchell, "Comparison of the pharmacology and signal transduction of the human cannabinoid chemistry CB1 and CB2 receptorps", Molecular Pharmacology, 48(3), 443 (1995)).

6') of the Compound from Pfizer, described in patent applications EP 1622876, EP 1622902, EP 1622903, EP 162290, EP 1622909, EP 1638570, EP 1594872, EP 1592691, EP 1558615, EP 1556373, EP 1572662, primarily concrete examples, especially the connection CP-945598.

7) Diarylpyrazole company Astra Zeneca, described for example in WO 03/051851.

8) Join ASRA and the ACEA firm Med. Coll. Wisconsin (Univ. Aberdeen, “Effects of AM 251 & AM 281, cannabinoid chemistry CB1 antagonists, on palatable food intake in lewis rats”, J.Pharmacol. Exp.Ther., 289, No. 3, 1427-1433 (1999)).

9) pyrazole Derivatives, described the University of Conneticut, for example, in WO 01/29007.

10) Connection of HU-210 (international Association for the Study of Pain, - Ninth World Congress (Part II) Vienna, Austria, A.H. Dickenson, K. Carpenter, R. Suzuki, IDDB MEETING REPORT (22-27 August, 1999) and the compound HU-243 (Barth F, "cannabinoid chemistry receptor agonists and antagonists", Current Opinion in Therapeutic Patents, 8(3), 301-313 (1998), the company Yissum R&D Co Hebrew Univ., Jerusalem).

11) Connection O-823 firm Organix Inc. (Drug development pipeline: O-585, 0-823, 0-689, O - 1072, nonamins, Organix, Altropane Organix Inc., Company Communication (August 10, 1999), database IDDb) and connection O-2093 company Consiglio Nazionale delle Ricerche (Marzo DV, Griffin G., Petrocellis L., Brandi I., Bisogno T. “A structure/activity relationship study on arvanil, endocannabinoid and vanilloid hybrid.”, Journal of Pharmacology and Experimental Therapeutics, 300(3), 984-991 (2002)).

12) 3-Alkyl-5,5'-diphenylimidazole described as ligands of cannabinoid receptor.

13) Antagonists CB1, currently under development by Bayer AG (database IDDb (28 February 2002).

14) receptor Antagonists SW, which are derivatives of pyrazole of the formula (I)described in US 6028084 included in the description by reference.

15) In the US 6017919 described another group of suitable antagonists of cannabinoid receptor SW for use according to the invention. These antagonists are characterized by the following General formula

where the substituents described in US 6017919, which is included in the description by reference.

16) Antagonist of cannabinoid receptor SV, which is a derivative of 4,5-dihydro-1H-pyrazole with antagonistically activity against the AI SW, described in US 5747524 and in the patent application US 2001/0053788 A1, published December 20, 2001

17) Antagonist of cannabinoid receptor SV, which is a derivative of 4,5-dihydro-1H-pyrazole with antagonistically activity against SV described in patent application US 2001/0053788 A1 and characterized by the formula (I). Patent application US 2001/0053788 A1 published on 20 December 2001 and included in the description by reference.

18) receptor Antagonists SW described in WO 2005049615, primarily compounds described in examples 1-8.

19) receptor Antagonist SB described in WO 2005047285, primarily compounds described in the examples 1-99.

20) receptor Antagonist SB, (4R)-3-(4-chlorophenyl)-4,5-dihydro-N-methyl-4-phenyl-N'-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-pyrazole-1-carboxamidine (connection SLV 326, 34thNeuroscience, Abstr (October 4, 2004)

company Solvay (WO 0170700 Al).

Antagonists of the receptor SW company Solvay SW described in examples of patent applications WO 2005040130 A1, WO 2005028456 A1, WO 2005020988 A1, WO 2004026301 A1, WO 2003078413 A1, WO 2003027076 A2, WO 2003026648 A1, WO 2003026647 A1, WO 2002076949 A1, WO 0170700 A1.

Daily dose of rimonabant, required for implementation of the method according to the present invention may vary, for example, depending on the method of administration and the severity of the patient to be treated. Daily dose of the active agent in oral BB is Denia is from about 1 to about 100 mg, for example, from 5 to 50 mg, or from 5 to 20 mg, usually in the form of a single dose or divided doses.

Preferably, the patient in need of treatment according to the invention, is suffering from hyperglycemia.

Most preferably, the patient suffers from a disease selected from the group comprising diabetes type I, or insulin-dependent diabetes mellitus (IDDM) type II or non-insulin dependent diabetes mellitus (NIDDM), insulinozavisimoy type And impaired glucose metabolism (IGM), impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). In a preferred embodiment, the patient suffers from type II diabetes or IGT.

In the most preferred embodiment, the inhibitor of DPP-IV or its salt include in the standard treatment of diabetes in patients whose treatment of diseases, i.e. diabetes, is inefficient when using one insulin or one, two or three antidiabetic compounds. Criteria for evaluating the effectiveness of treatment known to the person skilled in the art and described in the annual publications of the American Association of diabetes Diabet Care (((Standards of Medical Care, Diabetes, 29, S4-42S (2006)).

Current methods or applications are primarily used to prevent or slow the development conditions associated with type II diabetes or IGT, primarily cardiovascular and microvascular on the of Oseni.

In addition, the invention relates to the use of an inhibitor of DPP-IV or its salt to obtain a medicinal product intended to reduce episodes of hypoglycemia or severe episodes of hypoglycemia in a patient who underwent treatment at least one antidiabetic compound (for example, one or two antidiabetic compounds), or in a patient who underwent treatment with insulin, especially in a patient (e.g. a patient with diabetes type II) after a failed treatment with at least one antidiabetic compound (for example, one or two antidiabetic compounds) or one insulin, i.e. whose disease diabetes or glucose inefficiently suppress at least one antidiabetic compound or one insulin.

Preferably the invention relates to the use of an inhibitor of DPP-IV or its salts in combination with at least one antidiabetic compound (one, two or three antidiabetic compounds) or insulin for obtaining a medicinal product intended to reduce episodes of hypoglycemia or severe episodes of hypoglycemia in a patient (e.g. a patient with diabetes type II) after a failed treatment with one or more antidiabetic compounds or the ne inulin, i.e. whose disease diabetes or glucose inefficiently suppress at least one antidiabetic compound (one, two or three antidiabetic compounds) or one insulin.

The method or use according to the invention, according to which the patient is injected from 25 to 150 mg, preferably 50 mg or 100 mg vildagliptin or its salts, preferably once a day (daily dose).

The term "daily dose"used in the description of the application, means the dose that is administered once within 24 hours

The term “prevention” means prophylactic administration of the combination to healthy patients to prevent the development of this condition. In addition, the term “prevention” means prophylactic administration of this combination in patients who are at an early stage conditions subject to treatment.

The term “slow development”used in the description of the application, means the introduction of combination, such as a combined preparation or pharmaceutical composition, to a patient who is at a preliminary stage of the condition to be treated, in which patients are diagnosed primary form of the corresponding state.

The term “treatment” means monitoring of disease progression and patient care to suppress disease, comprising the Oia or disturbance.

The term “patient”used in the description of the application, means an animal that is suffering from hyperglycemia, or diabetes, or IGM. Preferred animal means a mammal, such as dogs, cats, horses, cattle and people. Preferably the patient is a man.

In this regard, the preferred age of the population is 45 years old or more, preferably from 60 years and over.

Specialist in the art can choose the appropriate model tests and protocols to ensure a favorable therapeutic effect according to the invention.

Methods of monitoring glycemic status held by patients and medical staff, known in this field, for example, described in the guide to diabetes “Tests of Glycemia in Diabetes - American Diabetes Association”, 26, 106-108 (2003), and described below. This publication is included in the description of the application as references in full.

Further information is given in a special survey of American Association for diabetes (e.g., Goldstein D.E., R.R. Little, R.A. Lorenz, Malone J.I., Nathan D., S.M. Peterson, Tests of glycemia in diabetes (Technical Review). Diabetes Care, 18, 896-909 (1995)).

Within only a few years of self-control the level of blood glucose (SMBG) by the patients has considerably improved the effectiveness of the treatment of diabetes. Through the use of methods SMBG patients to the will trainout the degree of glycemia and provide timely treatment.

Methods SMBG is discussed in detail in the conferences of the American Association for diabetes, according to results published an exhaustive review (American Diabetes Association: Self-monitoring of blood glucose (Consensus Statement)", Diabetes Care, 17, 81-86 (1994) and American Diabetes Association: Self-monitoring of blood glucose (Consensus Statement))), Diabetes Care, 10, 93-99 (1987))

Currently SMBG method was replaced by the analysis of glucose in the urine of most patients. Analysis of glucose in urine by patients at home is a semi-quantitative analysis of samples obtained at a single mocheispuskanii, or, more rarely, samples, taken from the “material”collected within 4-24 hours In the latter case, the content of glucose in the urine reflects the average glucose level in the blood during the urine collection.

Analysis of glucose in blood and urine and analysis of ketone in urine provide valuable information for daily management of diabetes.

However, these analyses do not provide the patient and medical staff quantitative and reliable data on blood glucose over a long period of time. Measurement level picolinafen proteins, especially hemoglobin and serum proteins, makes a new contribution to the assessment of glycemia. Thanks to one dimension of each of these tests allows to determine the average glycemia over several weeks or months, thereby complementing insurgents the day control.

Analysis glycopyranose hemoglobin (GHb)

GHb, also known as glycosylated hemoglobin, glycosylated hemoglobin, HbA1Cor HbA1that is the term used to describe a series of stable minor component of hemoglobin, which slowly and without the involvement of enzymes are formed from hemoglobin and glucose. The rate of formation of GHb is directly proportional to glucose concentration. Because the red blood cells permeable to glucose, the level of GHb in blood sample reflects the development of glycemia over the past 120 days, the average period of existence of the erythrocyte. GHb is most accurately reflects glycemia over the preceding 2-3 months.

In the routine clinical laboratory, using a variety of methods for the analysis of different types of GHb, for example, the content of HbA1Ccan be measured by the method GHUR using ion-exchange chromatography analyzer Bio-Rad Diamat. Affinity chromatography is used in the case when the analysis method GHUR observed variants of hemoglobin or peaks, indicating the degradation of hemoglobin.

The methods of analysis vary significantly depending on the analyzed glycosylated components of impurity components and adiabaticheskogo status. Glycosylated hemoglobin is often called hemoglobin A1C. HbA1Cis the preferred standard is m for glycemic control. When you refer to the analysis in the description of the application uses the term “analysis A1C”.

Analysis of A1C should be regularly all patients with diabetes, primarily to check blood glucose levels at initial assessment, and then during the course of treatment. Because the analysis A1C reflects the average blood glucose level over the past 2-3 months, the measurement should be carried out every three months to assess the patient's level of metabolic control and its stability within the specified range.

It is established that the A1C analysis allows to predict the risk of developing many chronic complications of diabetes, like analysis of cholesterol for predicting the risk of cardiovascular disease.

Glycated serum proteins (GSP)

Since the update serum albumin human is much shorter (biochemical half-life is 14-20 days)than the update of hemoglobin (the half-life of red blood cells is 120 days), the glycosylation of serum proteins (primarily albumin) reflects the blood glucose level within a shorter time than the glycosylation of hemoglobin. Measurements of the total GSP and glycosylated serum albumin (GSA) strictly correlated with each other and with the level of glycated hemoglobin (A1C analysis). The EU and the analysis of A1C is impossible or cannot be used (for example, hemolytic anemia), to assess the effectiveness of treatment can be analysed GSP. The literature describes several methods of quantitative determination of GSP or shared GSA. One of the most widely used methods is the analysis of fructosamine. Values GSP change depending on the change rate of the synthesis or clearance, which can be observed in acute systemic diseases or liver diseases. In addition, the debate continues regarding whether the analysis fructosamine and concentration of whey protein or serum albumin.

One dimension GSP reflects the level of glycemic status in the past 1-2 weeks, while one analysis A1C reflects the level of glycemic status over a significantly longer period of time, for example, over the last 2-3 months.

Measurement GSP, regardless of the specific method of analysis cannot be viewed as equivalent analysis A1C, because these data reflect the level of glycemia only for a short time. Therefore, analyses GSP should be done monthly in order to obtain information similar to the data in the analysis of A1C 3-4 times a year. In contrast to the analysis of A1C is not yet established that the level of GSP is associated with the risk of development or progression of chronic complications of diabetes.

Con is the role of the progression of glucose (for example, analysis of the GSP, A1C, insulin) well-known physicians and are described in the prior art, for example, the American diabetes Association.

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which:

1. choose the patient was treated with insulin and ineffectively treated one insulin

2. the specified patient is injected from 25 mg to 150 mg, preferably 50 mg or 100 mg of (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2 - cyanopyrrolidine or its salts in combination with insulin.

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1. select a patient who had been treated with at least one antidiabetic compound (e.g. one, two or three) and were not effectively treated by one insulin

2. the indicated patient once a day injected from 25 mg to 150 mg, preferably 50 mg or 100 mg of (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine or its salts in combination with insulin.

In the above treatment, the term “daily” refers to insulin and (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (vildagliptin) or (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (vildagliptin), for example, if the patient is implanted delivery system daily dose of insulin or any similar device.

Izaberete is s also applies to the treatment of diabetes, for example, type 2 diabetes, according to which

1) select the patient was treated with insulin and who experience bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the indicated patient once a day injected from 25 mg to 150 mg, preferably 50 mg or 100 mg of (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine or its salts in combination with insulin.

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1) select the patient who had been treated with at least one antidiabetic compound (e.g. one, two or three) and who experience bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the indicated patient once a day injected from 25 mg to 150 mg, preferably 50 mg or 100 mg of (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine or its salts in combination with insulin.

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1) select the patient was treated with insulin and who experience bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the specified patient is daily administered inhibitor of DPP-4 or its salt in combination with insulin.

The invention also relates to the treatment of diabetes, e.g. the measures type 2 diabetes, according to which

1) select the patient who had been treated with at least one antidiabetic compound (e.g. one, two or three) and who experience bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the indicated patient once per day administered inhibitor of DPP-4 or its salt in combination with at least one antidiabetic agent is 1).

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1) select the patient who had been treated with at least one antidiabetic compound and which are observed bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the indicated patient once per day administered inhibitor of DPP-4 or its salt in combination with at least one antidiabetic compound 1),

3) the dose or daily dose of at least one antidiabetic compound 1) is gradually decreased to achieve the desired glucose level.

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1) select the patient was treated with insulin and who experience bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the indicated patient once a day injected from 25 mg to 150 is g, preferably 50 mg or 100 mg of (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine or its salts in combination with insulin,

3) the dose or daily dose of insulin gradually reduced to achieve the required level of glucose, i.e. glucose, for example, according to the analysis of level HbA1cblood.

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1) select the patient who had been treated with at least one antidiabetic compound and which are observed bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the indicated patient once a day injected from 25 mg to 150 mg, preferably 50 mg or 100 mg of (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine or its salts in combination with at least one antidiabetic compound 1),

3) the dose or daily dose of at least one antidiabetic compound 1) is gradually decreased to achieve the desired glucose level, i.e. the level of glucose, for example, according to the analysis of level HbA1cblood.

Depending on the form of delivery of insulin can be entered, for example, regularly during the day, twice a day, once a day, every two or three days.

“At least one antidiabetic compound” according to the invention can be entered, for example, the reg is Jarno during the day, twice a day, once a day, every two or three days.

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1) select the patient was treated with insulin and who experience bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the specified patient is daily administered from 25 mg to 150 mg, preferably 50 mg or 100 mg of (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine or its salts in combination with a reduced dose of insulin.

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1) select the patient who had been treated with at least one antidiabetic compound and which are observed bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) the indicated patient once per day administered inhibitor of DPP-4 or its salt in combination with a reduced dose of at least one antidiabetic compound 1).

The invention also relates to the treatment of diabetes, such as type 2 diabetes, according to which

1) select the patient who had been treated with at least one antidiabetic compound (e.g. one, two or three) and who experience bouts of hypoglycemia, preferably heavy bouts of hypoglycemia,

2) of the criminal code is anomo the patient once a day injected from 25 mg to 150 mg, preferably 50 mg or 100 mg of (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine or its salts in combination with a reduced dose of at least one protivodiabeticheskih connection 1).

The treatment described in this context, according to which (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine replace any other inhibitor of DPP-4, primarily on one described in the application, and dose change depending on specific inhibitor of DPP-4.

The course of treatment, method or use described in this context, according to which the patient once a day injected from 25 mg to 200 mg of inhibitor of DPP-4 or its salts. The preferred daily dose of sitagliptin ranges from 25 mg to 100 mg

The course of treatment, method or use described in this context, according to which the inhibitor DPP-4 can be introduced in combination with other antidiabetic compound, such as Metformin, glitazone (e.g., pioglitazone or rosiglitazone or sulfonylurea.

The course of treatment, method or use described in this context, according to which the patient is suffering from insulin-dependent diabetes mellitus (IDDM), non-insulin dependent diabetes mellitus (NIDDM) or insulin resistance of type A.

The course of treatment, method or use described in this context, according to which the inhibitor DPP-4 introduces the in combination with insulin and/or other antidiabetic compound, such as one, two or three antidiabetic compounds selected from the group comprising Metformin, nateglinide, glitazone (preferably pioglitazone or rosiglitazone), sulfonylureas, GLP-1 or analogues of GLP-1 (preferably on the basis 4), antagonists of cannabinoid receptor-1 (SW) (preferably rimonaban) and insulin. If the patient is given two antidiabetic compounds, we used the following combinations: Metformin+sulfonylurea, Metformin+glitazone, Metformin+analogue of GLP-1 Metformin+antagonist CB1, glitazone+sulfonylurea, Metformin+insulin, glitazone+insulin, an analogue of GLP-1+sulfonylurea, a sulfonylurea+insulin.

Preferably in the above-described methods, or applications of a patient suffering from hyperglycemia and bouts of hypoglycemia, for example, severe episodes of hypoglycemia after insulin treatment. Most preferably, the patient suffering from hyperglycemia, diagnosed diseases, selected from the group comprising diabetes type I or insulin-dependent diabetes mellitus (IDDM) type II or non-insulin dependent diabetes mellitus (NIDDM), insulinorezistentnost type A, IGM, IFG or IGT. In a preferred embodiment, the patient suffers from type II diabetes or IGT. In another preferred embodiment, the patient means a patient, a disease which, for example, wipe the glycemia or glucose, ineffectively suppressed one insulin. In another preferred embodiment, the patient means a patient, a disease which, for example, hyperglycemia or glucose, ineffectively suppressed at least one antidiabetic compound.

The term “at least one antidiabetic compound” of the present invention does not include DPP-4 inhibitors.

The structure of the active agents identified by catalog numbers, common and trade names can be found in the latest edition of the standard reference book “The Merck Index” or " ordinary databases, for example, in the International patents (e.g. IMS World Publications). The content of these sources of information included in the description by reference. Any person skilled in the art can identify active agents and on the basis of these documents to synthesize them and to experience their pharmaceutical properties of the standard models in vitro and in vivo.

The application describes pharmaceutical preparations for enteral administration, such as oral, and also rectal or parenteral administration of warm-blooded animals, in the form of medicines, including pharmacologically active compound alone or in a mixture with conventional pharmaceutical excipients. For example, pharmaceutical preparations in luchot from about 0.1% to 90%, preferably from about 1% to about 80% active compound. Pharmaceutical preparations for enteral or parenteral and ophthalmic injection represents, for example, a standard dosage forms, such as coated tablets, tablets, capsules or suppositories, and also ampoules. These dosage forms get by known methods, for example using conventional mixing, granulating, coating, solubilization, or lyophilization. Thus, pharmaceutical preparations for oral administration obtained by mixing the active compounds with solid excipients, optionally granulating the resulting mixture and, if necessary, processing the mixture or granules into tablets or cores of coated tablets after the addition of suitable auxiliary connections.

The dose of the active compound depends on many factors such as route of administration, the warm-blooded species, age and/or specific condition.

The preferred dose of the active ingredients of the pharmaceutical combinations of the present invention, which are commercial preparations primarily represent a therapeutically effective dose, which are commercial products.

The dose of the active compound depends on many is esta factors such as way of introduction, warm-blooded species, age and/or specific condition.

Corresponding active ingredient or its pharmaceutically acceptable salt can also be used in the form of a hydrate or of MES, including solvents used for crystallization.

The exact dose depends on the type of the used compound, the route of administration and the desired treatment. Connection, you can enter any normal way, neuroretinal or preferably by oral method.

In General satisfactory results are obtained with the introduction of an inhibitor of DPP-IV, especially LAF237, in a daily dose of from about 0.01 to 50 mg/kg, more preferably from 0.1 to 50 mg/kg

Treatment with insulin or at least one antidiabetic compound is described in detail in the prior art.

For large mammals, the total daily dose is from about 0.01 to 100 mg/kg compound usually introduced divided doses 2-4 times per day as a standard dosage forms, containing, for example, from about 0.1 to about 50 mg of the compound in the form for slow release.

Preferably the inhibitor of DPP-IV, especially LAF237, the daily dose ranges from 1 mg to 500 mg, preferably 10 mg to 200 mg of active ingredient.

Another preferred inhibitor of DP-IV, first of all, LAF237, is administered in a daily oral dose of from 1 mg to 100 mg, preferably from 10 mg to 100 mg, for example 10 mg, most preferably from 25 mg to 100 mg, for example, 25 mg, or 30 mg, or 40 mg, or 50, 61, 70, 90, 100, 150 mg Most preferably daily oral dose of LAF237 50 mg to 100 mg

Suitable standard doses for oral administration include, for example, from about 25 mg to about 200 mg, or from about 25 mg to about 100 mg of inhibitor of DPP-IV, especially LAF237, for example, preferably 25, 50 or 100 mg of Suitable doses for parenteral administration include, for example, from about 1 mg to about 100 mg of the compound, for example, from 10 mg to 50 mg

Inhibitor of DPP-IV can also enter every day, or only once every two days, or twice a week.

Connections can be entered similarly to known standards for use in these cases. Suitable daily dose of a particular compound depends on a number of factors, such as the relative effectiveness of actions. A therapeutically effective dose is determined by a specialist in this field.

The connection according to the invention can be introduced in the form of free base or in the form of its pharmaceutically acceptable acid additive salts, or salts of Quaternary ammonium bases. Such salts can be obtained normal the way, and they have the activity of the same order as the free base.

If these compounds contain, for example, at least one main group, they can form acid additive salt. The corresponding acid additive salts may be formed when the molecule additional main group. Compounds containing an acid group (for example COOH)can also form salts of the bases. For example, the compounds may be present in the form of sodium salt, maleate or dihydrochloride. The active ingredient or its pharmaceutically acceptable salt can also be used in the form of a hydrate or of MES, including solvents used for crystallization.

Combined preparation, which comprises an inhibitor of DPP-IV in free form or in the form of pharmaceutically acceptable salts and insulin or at least one antidiabetic compound (one, two, or three) and optionally at least one, i.e. one or more, for example, two pharmaceutically acceptable carrier, for simultaneous, separate or sequential use, means primarily “component set” in the sense that the components, an inhibitor of DPP-IV in free form or in the form of pharmaceutically acceptable salts and insulin or at least one antidiabetic compound, m is should be entered independently or with the use of various drugs, containing different numbers of components, i.e. at different times or simultaneously. The components of the kit can, for example, be administered simultaneously or alternately, i.e. at different times with the same or different time intervals for any of the components of the set. Preferably, the spacing is chosen so that the effect on treatable disease or condition on the combined use of kit components exceeded the action of any of the components separately.

A therapeutically effective amount of each of the components of the combination according to the present invention can be administered simultaneously or sequentially and in any order, and the components can be entered separately or as a fixed combination.

The pharmaceutical compositions according to the invention can be obtained in a known manner and such compositions suitable for enteral administration, such as oral or rectal route of administration, or parenteral administration mammals (warm-blooded animals), including man, in the form of medicines, including a therapeutically effective amount of pharmacologically active compounds, separately or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.

The invention illa is trebuetsya the following examples, not limiting its scope.

Although the invention is described with reference to preferred options for its implementation, to a person skilled in the art it is evident that within the essence and scope of the invention, there are various additions, changes and modifications are defined in the claims.

All patents and publications cited in the description included in the text of the application as references in full. In case of discrepancy is preferable for the present invention, including definitions and interpretations.

Example 1

Clinical trials

Insulin is used as a typical antidiabetic compounds that induce bouts of hypoglycemia. To demonstrate the unexpected claimed benefits of DPP-4 inhibitors, similar tests can be performed using other antidiabetic compounds (e.g., one, two or three connections).

The test Protocol

The name of the test

Conducted randomized trial double blind and the method of parallel groups in several medical centers additional therapy connection LAF237 (with the introduction of 50 mg twice a day for 24 weeks compared with placebo) patients diagnosed with type 2 diabetes who had been treated with insulin.

Objective tests

The real test was conducted to demonstrate the effectiveness and safety of adjunctive therapy connection LAF237 (50 mg twice a day) in patients with type 2 diabetes who were treated with insulin. The specified test confirmed the General stabilizing effect LAF237 during combination therapy with insulin in the treatment of type 2 diabetes.

The test parameters

First option: to demonstrate the efficacy of adjunctive therapy connection LAF237 patients with type 2 diabetes who were treated with insulin in order to check the hypothesis that reducing HbA1cwith the introduction of 50 mg connection LAF237 twice a day is the advantage compared to the introduction of a placebo after a test period of 24 weeks.

Secondary parameters

1. To demonstrate the effectiveness of adjunctive therapy connection LAF237 patients with type 2 diabetes who were treated with insulin in order to check the hypothesis that the decrease of fasting glucose (FPG) with the introduction of 50 mg connection LAF237 twice a day is the advantage compared to the introduction of a placebo after a test period of 24 weeks.

2. To demonstrate the security of the connection LAF237 for patients with type 2 diabetes who were treated with insulin, when data is received that additional therapy with the introduction of 50 mg connection LAF237 twice in su is accompanied by a similar profile of adverse effects when compared with placebo after treatment for 2 weeks.

3. To demonstrate the effectiveness of adjunctive therapy connection LAF237 patients with type 2 diabetes who were treated with insulin, by providing evidence that the average reduction in daily insulin dose and the average reduction in the number of daily insulin injections in combination with administration of a 50 mg connection LAF237 (twice a day) is more effective compared to the placebo after treatment for 24 weeks.

4. To demonstrate the effectiveness of adjunctive therapy connection LAF237 patients with type 2 diabetes who were treated with insulin, due to receipt of data indicating that the degree of response is higher with the introduction of 50 mg connection LAF237 (twice a day) compared with the degree of response with the introduction of placebo after treatment for 24 weeks.

5. To demonstrate the effectiveness of adjunctive therapy connection LAF237 patients with type 2 diabetes who were treated with insulin, in the subgroup with baseline HbA1, to assess therapeutic efficacy LAF237 (in terms of reducing levels of HbA1Cwith the introduction of 50 mg 2 times per day compared to placebo) in patients with high baseline HbA1C(>9%) compared with patients with lower baseline HbA1C(<9%) after treatment for 24 weeks.

The analyzed variables

1. To investigate the mechanism of action of LAF237 in to anitelea therapy for patients with type 2 diabetes, which was treated with insulin, when testing the hypothesis that administration of a 50 mg connection LAF237 (2 times per day) improves the function of β-cells (results reduce the concentration of proinsulin on an empty stomach, reducing the ratio of proinsulin/insulin and NOMA) and reduces insulin resistance (according to the results of reducing the concentration of fasting insulin and NOMA IR fasting) compared with placebo after treatment for 24 weeks.

2. To explore additional clinical benefits additional therapy connection LAF237 in patients with type 2 diabetes who were treated with insulin, when testing the hypothesis that the introduction of LAF237 50 mg (2 times a day) has a favorable effect on lipid profiles in plasma glucose and no effect on body weight compared to placebo after treatment for 24 weeks.

3. To explore additional benefits additional therapy connection LAF237 in patients with type 2 diabetes, when receiving the data indicating that the introduction of LAF237 50 mg (2 times a day) has a beneficial effect on quality of life, mood and health of the patient compared with placebo after treatment for 24 weeks.

Population

In these trials used patients diagnosed with type 2 diabetes, which was not effectively treated with insulin and condition which can be improved due to the intensification of the course of treatment, the Oia insulin or due to additional oral antidiabetic agent. In these trials included patients who for at least 4 weeks prior to first visit to the doctor was administered to 30 units of insulin per day.

The population included in the quality of men and women (nefertiri or sterile for medical reasons) aged 18 to 80 years, with the level of HbA1c 7.5-11%.

The test was an outpatient test, which was conducted approximately 80 medical centers in the U.S. and Europe. Pre-selected 384 the patient in order to randomize 192 of the patient.

Criteria for inclusion/exclusion

Inclusion criteria: men and women (neverthele or sterile for medical reasons) with a diagnosis of type 2 diabetes, which was previously treated with insulin for at least 3 months, age 18-80 years, the ratio of body weight 22-45 kg/m2, HbA1cof 7.5-11%, FPG 270 mg/DL (15 mmol/l), gave consent to treatment prior diet and exercise.

Exclusion criteria: pregnant or lactating women, history of illness: type 1 diabetes mellitus, which is the result of damage to the pancreas, or secondary forms of diabetes, acute metabolic diabetic complications within the last 6 months, symptoms of significant diabetic complications, acute infections that may affect the glucose level in the last 4 weeks, bidirectional fusiform ventricular tachycardia, paroxysmal ventricular tachycardia, ventricular fibrillation, percutaneous coronary intervention within the last 3 months, myocardial infarction, coronary bypass surgery or unstable angina within the past 6 months, congestive heart failure NYHA class III or IV, second degree atrioventricular blockade (Mobitz 1 and 2), third degree atrioventricular blockade, the elongation complex QT on ECG, malignancies, including leukemia and rimforsa in the last 5 years, liver disease, acromegaly, or treatment with growth hormone treatment with any oral antidiabetic agent within the last 3 months, treatment with an insulin pump, continuous oral or parenteral treatment with corticosteroids within the last 8 weeks, treatment with antiarrhythmic agents class Ia, Ib, Ic, or III, significant deviations in the results of outpatient tests.

Research and monitoring therapy

In addition to insulin treatment patients were treated with double-blind method with the introduction of LAF237 50 mg (2 times a day) or placebo in a 1:1 ratio.

Plan testing

Conducted a randomized double-blind trial method in several medical centers. In IP is taniah participated patients diagnosed with type 2 diabetes (HbA1c 7.5-11%), which for at least 3 months were treated with insulin. Suitable patients randomized (lapradelle into equal groups) for injection of 50 mg of compound LAF237 (2 times per day) or placebo during treatment with insulin. The insulin dose can be reduced according to clinical indications, but not more than 25% of the original dose.

Each patient underwent one survey (week-4)which assessed inclusion criteria/exclusion (in testing). Then suitable patients randomized during the second visit (baseline, day 1), and then within 24 weeks of combination treatment with compound LAF237 or placebo in combination with insulin patients inflicted another 4 visit to the doctor (5 visits).

Evaluation of effectiveness

The evaluation of the primary efficacy: HbA1cthe assessment of the secondary effectiveness: the level of glucose in the blood plasma of fasting, fasting lipid levels (triglycerides, total cholesterol, calculated LDL, HDL, calculated non-HDL, calculated VLDL), body weight, the function of β-cells (the level of fasting proinsulin, the ratio of proinsulin/insulin on an empty stomach, NOMA), insulin resistance (fasting insulin levels, NOMA IR), average daily insulin dose, the average number of insulin injections and the degree of response of patients with type 2 diabetes, which heal and insulin for at least 3 months.

Other assessments

Safety assessment includes registration of side effects, the main indicators of body condition, results of outpatient tests (Hematology, biochemistry and urinalysis), and electrocardiogram. Other assessments include surveys of quality of life.

The results of the analysis

An assessment of the advantages of injection of 50 mg of compound LAF237 (2 times per day) compared with placebo, connection LAF237 and placebo in combination with insulin, the effect on the reduction of HbA1c levels were checked on the value of N0: δLAF 50 mg (twice a day)placebocompared with the value: δLAF 50 mgthat differs from δplacebowhere δ denotes the average change from baseline in the group specified in the subscript index. The analysis of covariance model (ANCOVA) was performed, including the parameters of treatment, baseline HbA1c and the region. The lowest root-mean-square (adjusted mean) deviation from baseline for each group, the difference in the lowest average quadratic deviations between the two treated groups (LAF237 50 mg (2 times a day) - placebo) and two-sided 95% confidence interval for differences by p-values for comparison of treatment was calculated on the basis of the primary analysis model. Secondary variables efficiency was estimated using the analogue of the offered model.

Patients are encouraged to conduct an independent measurement of glucose (SMBG) in any case of suspected hypoglycemia and before Breakfast at least 3 times a week. Hypoglycemia was defined by symptoms of low glucose levels and largest SMBG <3.1 mmole/l, equivalent glucose levels. Severe hypoglycemia was defined by any attack that requires outside intervention (glucose <3.1 mmole/l, if the severity of the disease does not prevent the determination of glucose).

Therefore, according to the present invention, the term “severe hypoglycemia” preferably means an attack of low blood glucose levels <3.8 mmole/l, preferably <3.1 mmole/L.

All laboratory analyses were performed in Central laboratories. The level of HbA1cwas determined by the method GHUR when compared with standard DCCT in the laboratory level 1 (Bioanalytical Research Corporation [BARC]-EU, Ghent, Belgium, or Covance-US, Indianapolis, IN), certified by the National program of the national glycohemoglobin standardization (NGSP), or in the NGSP laboratory network (Diabetes Diagnostic Laboratory, Columbia, MO). All other laboratory tests performed at BARC-US (Lake Success, NY) or BARC-EU. Analyses were performed on standardized and approved methods in accordance with GLP.

Results

The data obtained confirm that LAF237 is associated with less severe episodes of hypoglycemia, if it is used in isout in combination with insulin. Patients who were treated only with insulin, there are significantly more frequent bouts of hypoglycemia, especially severe episodes of hypoglycemia (1). Patients who were treated with insulin and LAF237, there is no severe episodes of hypoglycemia (1).

(1) the Attacks of hypoglycemia 2 degrees: glucose <3,1 and symptoms of hypoglycemia.

It is established that vildagliptin (LAF237) has a protective effect against insulin-induced hypoglycemia.

Table 1 shows the number of patients who have experienced one or more episodes (panel A), the total number of attacks (panel b) and the number of severe episodes of hypoglycemia (panel C) in patients included in randomized trials, which were administered 2 times per day 50 mg vildagliptin or placebo in combination with insulin. In the group of patients who entered vildagliptin, 33 patients were informed about 113 attacks, none of which were related to severe attacks, i.e. attacks requiring medical attention. In the placebo group, 45 patients were informed about 185 attacks, 6 of which were severe attacks. The number of attacks both types of hypoglycemia was statistically significantly lower in the group of patients who entered vildagliptin (P<0.001 and P=0,032 respectively, on the basis of Pearson criterion with a correction for continuity on Yates).

Table 1
PanelVildagliptin+insulin
The number of patients
Placebo+insulin
The number of patients
And3345
In113185
06

The number of patients reporting any attack of hypoglycemia (panel A), the total number of bouts of hypoglycemia (panel b) and the number of severe episodes of hypoglycemia (panel C) in the treatment for 24 weeks with the introduction of 50 mg vildagliptin 2 times per day (n=144) or placebo (n=152).P<0,05,∗∗∗P<0,001 relative to placebo.

In addition, patients who were treated with compound LAF237, it is possible to reduce the dose of insulin.

1. The use of an inhibitor of DPP-IV or its salt to obtain a medicinal product intended to reduce episodes of hypoglycemia or severe episodes of hypoglycemia or severe episodes of hypoglycemia in patients with diabetes after treatment with insulin, where the inhibitor of DPP-IV is vildagliptin or its salt.

2. The use according to claim 1, in which
i) select a patient to the th was treated with insulin and who experience episodes of hypoglycemia, preferably severe episodes of hypoglycemia,
ii) the specified patient daily enter vildagliptin or its salt in combination with insulin.

3. The use according to any one of the preceding paragraphs, in which
i) select the patient was treated with insulin and who experience episodes of hypoglycemia, preferably heavy bouts of hypoglycemia,
ii) the specified patient daily enter vildagliptin or its salt in combination with insulin, and in which
iii) the total daily insulin dose is gradually decreased to achieve the desired glucose level.

4. The use according to claim 1, in which
i) select the patient was treated with insulin and who experience episodes of hypoglycemia, preferably heavy bouts of hypoglycemia,
ii) the specified patient daily enter vildagliptin or its salt in combination with insulin to reduce the daily dose of insulin.

5. The use according to claim 2, in which
i) select the patient was treated with insulin and who experience episodes of hypoglycemia, preferably heavy bouts of hypoglycemia,
ii) the specified patient is daily administered from 25 mg to 150 mg, preferably 50 mg or 100 mg vildagliptin in combination with insulin.

6. The use according to claim 3, in which
i) select the patient was treated with insulin and who experience episodes of hypoglycemia, pre is respectfully severe episodes of hypoglycemia,
ii) the specified patient is daily administered from 25 mg to 150 mg, preferably 50 mg or 100 mg vildagliptin in combination with insulin,
iii) the indicated patient daily enter vildagliptin or its salt in combination with insulin to achieve the desired glucose level.

7. The use according to claim 4, in which
i) select the patient was treated with insulin and who experience episodes of hypoglycemia, preferably heavy bouts of hypoglycemia,
ii) the specified patient is daily administered from 25 mg to 150 mg, preferably 50 mg or 100 mg vildagliptin in combination with insulin to reduce the daily dose of insulin.

8. The use according to claim 1, where the attack of hypoglycemia means an attack of severe hypoglycemia.

9. The use according to claim 2, in which the patient means a patient whose illness or glucose inefficiently suppress at least one antidiabetic compound or one insulin.

10. The use according to claim 2, wherein vildagliptin or its salt is injected daily at a dose of 25 mg to 150 mg

11. The use of claim 10, wherein vildagliptin or its salt are introduced daily dose from 50 mg to 100 mg vildagliptin or its salts.



 

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FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns an osmotic delivery system promoting Exenatid release at a constant speed varying within approximately 5 mcg/day to approximately 160 mcg/day. The present invention also concerns a method of treating Insulin-independent diabetes in a subject and a method of treating obesity in a subject.

EFFECT: invention provides improved therapeutic consistency, higher clinical effectiveness, improved quality of life for the subjects recovered (in comparison with the injection therapy), and enabled immediate treatment interruption by removing the osmotic delivery system.

15 cl, 5 ex, 5 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of medicine and deals with medication for per oral treatment of diabetes mellitus and other diseases, accompanied by disturbance of tolerance to glucose, and method of obtaining such medication. Medication contains antibodies to beta-subunit of insulin receptor in activated form, obtained by multiple successive dilution and external impact in accordance with homeopathic technology. Method of obtaining hard drug form for per oral treatment of diabetes mellitus and other diseases, accompanied by disturbance of tolerance to glucose, includes mixing efficient amount of carrier, irrigated in pseudo-liquefied layer with water-alcohol dilution of antibodies in activated form to beta-subunit of insulin receptor, prepared by combination of multiple successive dilution - reduction of antibodies concentration and external impact according to homeopathic technology, and dried at temperature not higher than 35°C, with pharmaceutically acceptable additives and further tabletting of mixture by direct dry compressing.

EFFECT: medication can be used for efficient treatment and prevention of diabetes mellitus and other diseases, accompanied by disturbance of tolerance to glucose.

5 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to therapy and endocrinology, and concerns blood pressure reduction in metabolic syndrome and pre-hypertension. That is ensured by introduction of a composition containing an effective amount of a polyphenolic grape extract, containing 2 wt % and more of polyphenols having end links of epicatechin-gallate.

EFFECT: grape extract composition containing low concentrations of polyphenol having end links of epicatechin-gallate, and high concentration of mono- and oligomeric compounds, provides effective treatment of said pathology ensured by blood pressure reduction and lipid exchange normalisation.

38 cl, 7 ex, 4 dwg, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely to therapy and deals with application of organic compound -rennin inhibitor aliskiren for treatment and prevention of type 2 diabetes and kidney disease. For this purpose aliskiren is introduced in efficient amount as monotherapy.

EFFECT: invention ensures efficient treatment and prevention of said diseases due to aliskiren ability to increase sensitivity of tissues to insulin and reduce proteinuria.

5 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of biologically active substance for production of medication for treatment of syndrome of resistance to insulin, diabetes, including type I diabetes and type II diabetes, syndrome of ovary polycystosis, treatment or reduction of probability of atheroslerosis development, arterioslerosis, obesity, hypertension, hyperlipidemia, fatty infiltration of liver, nephropathy, neuropathy or retinopathy, feet ulceration or cataracts associated with diabetes, where medication represents compound of formula , as well as corresponding treatment method, pharmaceutical composition and biologically active substance of the same purpose.

EFFECT: increase of compound activity: 75% reduction of glucose level with loading in contrast to 10% reduction for analogues known before, as well as reduction of level of triglycerides in blood serum.

17 cl, 1 dwg, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood microvesicle level in impaired glucose tolerance. That is ensured by graduated physical activity, and administration of metformin 500 mg twice a day. The therapeutic course is at least 5 weeks.

EFFECT: offered combination of therapeutic modalities enables normalising the blood microvesicle level in a relatively short time that promotes prevention of thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gerontology, endocrinology, and can be used for pathologically raised biological age reduction in the patients with abdominal obesity. That is ensured by prescription of efficient graduated static and dynamic physical activity, daily swimming in a pool for not less than 30 minutes a day, and also administration of metformin in dosage 850 mg twice a day. The therapeutic course is 7 weeks.

EFFECT: offered combination of the modalities enables to adjust the biological and chronological ages that improves quality of life in the case patients.

2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, and can be used for normalisation of adenosine diphosphate and adenosine triphosphate thrombocyte secretion activity in the patients with arterial hypertension and impaired glucose tolerance. That is ensured by graduated physical activities, daily swimming in a pool for at least 20 minutes a day, and also prescribed metformin 500 mg twice a day and lisinopril 10 mg once a day in the morning.

EFFECT: combination of therapeutic modalities enables rapid normalisation of adenosine diphosphate and adenosine triphosphate thrombocyte secretion activity that promotes prevention of thrombotic complications in the case patients.

9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood α2 antiplasmin concentration in arterial hypertension and impaired glucose tolerance. That is ensured by graduated physical activities, daily swimming in a pool for at least 20 minutes a day, and also prescribed metformin 500 mg twice a day and lisinopril 10 mg once a day at regular hours in the morning. The therapeutic course is 1 months.

EFFECT: offered combination of therapeutic modalities enables normalising the blood α2 antiplasmin level in a relatively short time that promotes prevention of thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood plasminogen activator inhibitor concentration in arterial hypertension and impaired glucose tolerance. That is ensured by graduated physical activities, daily swimming in a pool for at least 20 minutes a day, and also prescribed metformin 500 mg twice a day and lisinopril 10 mg once a day in the morning. The therapeutic course is 1 months.

EFFECT: offered combination of therapeutic modalities enables normalising the blood plasminogen activator inhibitor in a relatively short time that promotes prevention thrombotic complications in the case patients.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula in which R1 denotes a) adamantyl, hydroxyadamantyl or trifluoromethylphenyl; R2 denotes hydrogen, methyl, ethyl or cyclopropyl; one of R3 and R4 denotes alkyl, cycloalkyl, haloalkyl or is absent, and the other denotes a) hydrogen, alkyl, pyridinyl, cycloalkyl, cycloalkylalkyl or haloalkyl; b) phenyl or phenyl substituted with one to three substitutes independently selected from fluorine, chlorine, bromine, haloalkyl and alkoxy group; c) phenylalkyl, where the phenylalkyl is optionally substituted with one to three halogens; e) naphthyl or tetrahydronaphthyl; f) phenylalkoxyalkyl; g) hydroxyalkyl; or h) pyridinyloxyalkyl or pyridinyloxyalkyl substituted with an cyano group; or R3 and R4 together with a carbon atom with which they are bonded form a cycloalkane or piperdine, where the cycloalkyl and piperidine are optionally substituted with one to three substitutes independently selected from aryl and arylalkyl; one of R5 and R6 denotes hydrogen, isopropyl, isobutyl or haloalkyl, and the other denotes hydrogen or is absent; and to pharmaceutically acceptable salts thereof, under the condition that 1,3-dihydro-4-phenyl-1-(3-(trifluoromethyl)phenyl)-2H-imidazol-2-one is excluded, and if one of R3 and R4 denotes methyl, ethyl, n-propyl or n-butyl, and the other denotes hydrogen or is absent, then R2 denote hydrogen or methyl. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 11-beta-hydroxysteroid dehydrogenase 1 (11-beta-HSDI) inhibiting activity.

15 cl, 257 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics and medicine, and concerns a pancreas protector which contains a combination of a blood glucose decreasing drug not stimulating insulin secretion and a compound presented by formula (1), where the compound of formula (1) represents 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile or 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrile exhibiting higher efficacy.

EFFECT: improved efficacy of the preparation.

15 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and can be applied for treatment of type 2 diabetes mellitus. Composition containa as active substances N-(β-oxyethyl)-4,6-dimethyldihydropyrimedone-2 (xymedon) and inulin in ratio (2.5-5):(1-3). Composition can additionally contain magnesium, zinc, chromium asparaginates and can be made in form of capsules or pills.

EFFECT: effect from application of pharmaceutical composition for treatment of type 2 diabetes mellitus consists in continuous reduction of glucose level in blood and normalisation of lipid metabolism parameters.

13 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to method of suppressing increase of glucose level in blood with glucose load, reduction of glucose blood level, improvement of insulin-resistance. Method of suppressing glucose level in blood under glucose loading, reduction of glucose blood level, improvement of patient's insulin-resistance, including introduction to patient of efficient quantity of composition, which contains oligosaccharides in defined concentration, where oligosaccharides are β-1,4-manooligosaccharides with degree of polymerisation 2-10.

EFFECT: method described above efficiently suppresses increasing of glucose blood level under glucose loading, reduces blood glucose level, improves insulin-resistance of patient.

6 cl, 2 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: claimed is application of vardenafil or its salt, hydrate or salt hydrate for preparation of pharmaceutical composition for treatment of disease from group of diseases, that includes syndrome of infravesical obstruction (SIVO), genitourinary disorders, which include syndrome of neurogenic urinary bladder (NUB), urinary incontinence (UI), such as mixed, acute, stress or incontinence caused by overfill, pain in pelvis, benign and malignant diseases of organs constituting genitourinary system in men and women, kidney diseases, such as acute and chronic renal failure, immunologically induced kidney diseases such as renal transplant rejection, lupus nephritis, kidney diseases caused by immune complexes, glomerulonephritis, nephritis, toxic nephropathy, and obstructive uropathies in mammals, as well as for treatment of neurogenic urinary bladder, superactive urinary bladder and intersticial cystitis and corresponding pharmaceutical compositions.

EFFECT: demonstrated is relaxation of smooth muscles of urinary bladder and increase of urination interval under effect of vardenafil.

4 cl, 6 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where X denotes S; R1 and R2 taken together with atoms to which they are bonded form a 5-member carbocycle, substituted with up to two substitutes selected from alkyl and CF3; R3 is selected from a group consisting of a hydrogen atom and C1-8-alkyl; R3a denotes a hydrogen atom; R4 denotes a hydrogen atom; R4a denotes a hydrogen atom; R5 denotes a hydrogen atom; R5a denotes a hydrogen atom; R6 denotes a hydrogen atom; R6a denotes a hydrogen atom; R7 denotes a hydrogen atom; or pharmaceutically acceptable salts thereof. The invention also relates to compounds of the given formula, compounds selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which modulate serotonin receptor activity.

6 cl, 19 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to C-phenyl-1-thioglucitols of formula (I), [formula I] , where X is a hydrogen atom or a C1-6alkyl group, Y is a C1-6alkylene group or -O-(CH2)n- (where n equals a integer from 1 to 5), and Z is -CONHRA or -NHCONHRB (provided that when Z is -NHCONHRB, n is not equal to 1), where RA is a C1-6alkyl group substituted with 1-3 substitutes selected from a group consisting of a hydroxyl group and -CONH2, and RB denotes a hydrogen atom or a C1-6alkyl group substituted with 1-3 substitutes selected from a group consisting of a hydroxyl group and -CONH2, and pharmaceutically acceptable salts thereof or hydrates thereof. The invention also relates to a sodium-dependent glucose transporter 1 (SGLT1) activity inhibitor, a sodium-dependent glucose transporter 1 (SGLT1) and sodium-dependent glucose transporter 2 (SGLT2) activity inhibitor, as well as a prophylactic or therapeutic agent against diabetes.

EFFECT: obtaining novel biologically active compounds which are sodium-dependent glucose transporter 1 and sodium-dependent glucose transporter 2 activity inhibitors.

5 cl, 11 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).

35 cl, 565 ex, 10 tbl

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