RU2385723C2 - Application of dipeptidylpeptidase iv inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered application of dipeptidylpeptidase IV inhibitor (DPP-IV inhibitor), preferentially (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidine or its pharmaceutically acceptable salt, for treatment of cardiovascular diseases or injures, renal diseases or damages, cardiac insufficiency or related diseases, related method and pharmaceutical composition of the same purpose.

EFFECT: compound reduces both hypertrophy of blood vessel wall and aortic ventricle, causes endothelium mediated increase of vasorelaxation, and risk of hypostasis in prolonged application in comparison with other DPPs-IV.

26 cl, 4 ex

Description

The present invention relates to the use of a dipeptidyl peptidase IV inhibitor (DPP-IV) or a pharmaceutically acceptable salt thereof for the treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure, to a method for treating warm-blooded animals, including the number of people suffering from cardiovascular diseases or injuries, diseases or injuries to the kidneys, heart failure or diseases related to heart failure NOSTA which comprises administering to said animal in need of such treatment an effective dose of at least one inhibitor or a pharmaceutically acceptable salt thereof.

The up-regulated renin-angiotensin system (ASD) is a well-studied contribution to the pathogenesis of cardiovascular disease and one of the hormonal mechanisms involved in the regulation of pressure / volume of a homeostat and in the expression of hypertension. The renin-angiotensin system also plays an important role in the development of kidney damage.

Continuing research in this area, it was unexpectedly found that dipeptidyl peptidase IV inhibitors (DPP-IV inhibitor) attenuate cardiovascular disease or damage, kidney disease or damage, heart failure or heart failure related diseases. Inhibitors of DPP-IV to a high degree reduce the thickening of the cardiovascular system, bedding matrix, cardiovascular hypertrophy and hypertrophic correction in animals. Secondly, the improvement in the state of these trophic effects was not dependent on changes in systemic blood pressure. The advantage of an effect independent of blood pressure is that in clinical practice it is difficult to achieve the recommended goals. This usually requires 2-3 medicines. In addition, there is no threshold for blood pressure or for cardiovascular and renal diseases or injuries, so protection independent of blood pressure can be very beneficial.

The terms "congestive heart failure (CHF)" or "heart failure (CH)" are used to describe any condition in which the heart cannot properly pump blood in the body / or cannot prevent blood from stagnating in the lungs. These conditions cause, for example, symptoms in the form of frequent breathing (dyspnea), fatigue, weakness and swelling (swelling) of the legs and, sometimes, the abdomen.

Congestive heart failure, regardless of its etiology, is characterized by weakness of the myocardial tissue of the left and / or right ventricle of the heart and, as a result, difficulty in systemic pumping and circulation of blood and / or pumping and circulation in the pulmonary system. Myocardial tissue weakness is usually associated with changes in the circulatory system and the neurohumoral system, which are expressed in insufficient supply of blood and oxygen to peripheral tissues and organs. Some emerging changes include increased pulmonary and systemic pressure, decreased cardiac output, increased vascular resistance, and peripheral and pulmonary edema. Congestive heart failure can also be expressed in the form of rapid breathing, breathing with effort, nocturnal dyspnea at rest, or in the form of seizures. Without treatment, congestive heart failure can lead to death.

Heart failure can be described as systolic or diastolic, high blood pressure or low blood pressure, acute or chronic, right-sided or left-sided, as well as translational and recurrent. Such identification is often used in clinical practice, especially in the early stages of the disease, and at later stages the differences between them often become insignificant.

Difference between systolic and diastolic insufficiency: the difference between these two forms of heart failure is based on a violation of the ventricle’s ability to contract normally and throw out enough blood (systolic insufficiency) or the ability to relax and / or fill up normally with blood (diastolic insufficiency).

The difference between high blood flow and low blood flow in heart failure: it is useful to classify patients with heart failure as those who have low cardiac output, i.e. HF with low blood flow, and those who have an increased cardiac output, i.e. High blood pressure heart failure.

The difference between acute and chronic heart failure: the prototype of acute heart failure is the sudden development of an extensive myocardial infarction or rupture of a heart valve in a patient who was previously completely healthy. Chronic heart failure is usually observed in patients with dilated cardiomyopathy or combined heart disease, which develops or progresses slowly. Acute HF is usually systolic and a sudden decrease in cardiac output per minute often leads to systemic hypotension without peripheral edema. In chronic heart failure, blood pressure is usually well maintained until the late stage of the disease, but swelling often develops.

The difference between right-sided and left-sided heart failure: many clinical manifestations of heart failure are the result of accumulation of excess fluid in one or two ventricles. This fluid usually accumulates upstream of the blood stream, behind the initially affected ventricle.

The difference between translational and recurrent heart failure: for many years, conflicting versions have been raised around the question of the mechanism of clinical manifestations that are a consequence of HF. A clear difference between translational and recurrent heart failure (as well as a clear difference between right-sided and left-sided heart failure) is artificial, since both mechanisms act on varying volumes in most patients with heart failure.

Treatment of heart failure can be divided into four components: (1) removal of the cause of precipitation, (2) correction of the underlying cause, (3) prevention of worsening cardiac function, and (4) monitoring of congestive heart failure.

Typically, a wide range of drugs are used to treat heart failure, including alpha adrenergic agonists, beta adrenergic agonists, calcium channel antagonists, cardiac glycosides, diuretics, nitrates, phosphodiesterase inhibitors, prazosin and various vasodilators.

However, all of the listed drugs have undesirable side effects. For example, the use of alpha-adrenergic agonists leads to the occurrence of edema of peripheral tissues. The prolonged use of beta-adrenergic agents leads to the progressive development of desensitization with respect to the drug. Cardiac glycosides cause toxic side effects in the central nervous system (CNS), as well as in the gastrointestinal and respiratory systems. They also cause proarrhythmic effects. Treatment with diuretics can lead to a variety of side effects, for example, hyponatremia, hypokalemia, hyperchloremic metabolic alkalosis.

The prolonged use of calcium channel antagonists, such as verapamil, diltiazem and nefedipine, makes them ineffective. In addition, calcium channel antagonists have been shown to increase the mortality rate in patients treated with these drugs, since these compounds cause increased oxygen consumption, which additionally leads to a burden on a diseased heart.

Thus, there is a need to create new non-toxic compounds for treating heart failure, improving left ventricular function without increasing myocardial oxygen consumption. It is also preferable that the drugs do not directly affect cardiac contractility and do not cause side effects, such as changes in blood pressure and / or heart rate, which are associated with increased mortality in patients with heart failure.

Continued research in this area has unexpectedly led to the discovery that DPP-IV inhibitors may be useful in preventing, delaying the progression or treatment of heart failure (HF) or diseases associated with heart failure.

The present invention accordingly relates to the use of a dipeptidyl peptidase IV inhibitor (DPP-IV) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure .

The term "DPP-IV inhibitor" is intended to define a molecule that inhibits the enzymatic activity of DPP-IV and functionally linked enzymes by 1-100% inhibition and specifically protects the action of substrate molecules, including, but not limited to, glucagon-like peptide-1, gastric inhibitory polypeptide, histidino-methionine peptide, substance P, neuropeptide Y and other molecules, usually containing alanine or proline residues in the second terminal position of the amino acid. Treatment with DPP-IV inhibitors prolongs the duration of the action of peptide substrates and increases their integrity, indestructible forms, leading to a spectrum of biological activities essential for the present invention.

DPP-IV can be used to control glucose metabolism, since its substrates include insulinotropic hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (IPI). GLP-1 and ZhIP act only when in a holistic form; removal of two N-terminal amino acids leads to their inactivation. In vivo, the administration of synthetic DPP-IV inhibitors prevents the N-terminal destruction of GLP-1 and GIP, which leads to an increase in the content of these hormones in plasma, increased insulin secretion and, therefore, increased glucose resistance. For this, chemical compounds are tested in order to determine their ability to inhibit the enzymatic activity of the purified preparation CD26 / DPP-IV. Briefly, the activity of CD26 / DPP-IV is determined in vitro based on its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNA with DPP-IV enzyme releases the product p-nitroanilide (pNA), whose rate of formation is directly proportional to the activity of the enzyme. Suppression of enzyme activity by specific enzyme inhibitors reduces the percentage of pNA degradation. Hard interaction of the inhibitor and the enzyme leads to a decrease in the rate of destruction of pNA. Thus, the degree of inhibition of pNA accumulation rate is a direct measure of enzyme inhibition. The accumulation of pNA is measured spectrophotometrically. The inhibition constant, Ki, for each compound is determined by incubating mixed amounts of the enzyme and several different concentrations of substrate inhibitor.

In the context of the present invention, the term "DPP-IV inhibitor" also extends to active metabolites and their prodrugs, for example active metabolites and prodrugs of DPP-IV inhibitors. The term "metabolite" means an active derivative of a DPP-IV inhibitor, which is formed during the metabolism of a DPP-IV inhibitor. The term “prodrug” refers to a compound that is either metabolized to form a DPP-IV inhibitor, or the metabolite forms the same metabolite (s) as in the metabolism of a DPP-IV inhibitor.

DPP-IV inhibitors are known in the art. For example, DPP-IV inhibitors in each case, in general and in detail, are described, for example, in WO 98/19998, DE 19616486 A1, WO 00/34241, WO 95/15309, WO 01/72290, WO 01/52825, WO 9310127, WO 9925719, WO 9938501, WO 9946272, WO 9967278 and WO 9967279.

Preferred DPP-IV inhibitors are described in the following patent applications: WO 02053548, especially compounds 1001-1293 and examples 1-124, WO 02067918, especially compounds 1000-1278 and 2001-2159, WO 02066627, especially examples described, WO 02/068420, especially all compounds specifically listed in examples I-LXIII and the corresponding analogs described, as well as preferred are compounds 2 (28), 2 (88), 2 (119), 2 (136) described in the table in which the values are presented IC50, WO 02083128, especially examples 1-13, US 2003096846, particularly specifically described compounds, WO 2004/037181, especially examples 1-33, WO 0168603, particular Especially the compounds of examples 1-109, EP 1258480, especially the compounds of examples 1-60, WO 0181337, especially examples 1-118, WO 02083109, especially examples 1A-1D, WO 030003250, especially the compounds of examples 1-166, the most preferred compounds of examples 1 -8, WO 03035067, especially the compounds described in the examples, WO 03/035057, especially the compounds described in the examples, US2003216450, especially examples 1-450, WO 99/46272, especially the compounds of claims 12, 14, 15 and 17, WO 0197808, especially the compounds of claims 2, WO 03002553, especially the compounds of Examples 1-33, WO 01/34594, especially the compounds described as described in examples 1-4, WO 02051836, especially examples 1-712, EP 1245568, especially examples 1-7, EP 1258476, especially examples 1-32, US 2003087950, especially examples described, WO 02/076450, especially examples 1- 128, WO 03000180, especially examples 1-162, WO 03000181, especially examples 1-66, WO 03004498, especially examples 1-33, WO 0302942, especially examples 1-68, US 6482844, especially examples described, WO 0155105, especially compounds listed in examples 1 and 2, WO 02022560, especially examples 1-166, WO 03004496, especially examples 1-103, WO 03/024965, especially examples 1-54, WO 0303727, especially examples 1-209, WO 0368757, especially examples 1-88, WO 03074500, especially examples 1-72, 4.1-4.23 , 5.1-5.10, 6.1-6.30, 7.1-7.23, 8.1-8.10, 9.1-9.30, WO 02038541, especially examples 1-53, WO 02062764, especially examples 1-293, preferably from example 95, the compound (2 - {{3 - (aminomethyl) -4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl} oxy} acetamide hydrochloride), WO 02308090, especially examples 1-1 to 1-109, examples 2- 1 to 2-9, examples 3, from 4-1 to 4-19, from 5-1 to 5-39, from 6-1 to 6-4, from 7-1 to 7-10, from 8-1 to 8-8, from 7-1 to 7-7 on p. 90, from 8-1 to 8-59 on p. 91-95, examples 9-1 to 9-33, 10-1 to 10-20 US 2003225102, especially compounds 1-115, compounds of examples 1-121, preferably compounds a) to z), aa) to az), ba) to bz), ca) to cz) and da) to dk), WO 0214271, especially p examples 1-320, and US 2003096857, WO 2004/052850, particularly specifically described compounds, for example examples 1-42, and compounds of claims 1, DE 10256 264 A1, especially described compounds, for example, in examples 1-181 and compounds Claim 5, WO 04/076433, especially the compounds specifically described, for example, listed in Table A, preferably the compounds listed in Table B, preferably compounds I-XXXXVII, or the compounds of claims 6-49, WO 04/071454, especially specifically described compounds, for example compounds 1-53, or compounds from Tables Ia-If, or compounds of claims 2-55, WO 02/068420, especially compounds specifically described, for example, compounds I-LXIII, or Beispiele I and analogues 1-140, or Beispiele 2 and analogues 1-174 or Beispiele 3 and analogue 1, or Beispiele 4-5, or Beispiele 6 and analogues 1-5, or Beispiele 7 and analogues 1-3, or Beispiele 8 and analog 1, or Beispiele 9, or Beispiele 10 and analogues 1- 531, also preferred are compounds of claim 13, WO 03/000250, especially compounds specifically described, for example compounds 1-166, preferably compounds of Examples 1-9, WO 03/024942, especially a compound compounds specifically described, for example compounds 1-59, compounds from table 1 (1-68), compounds of claims 6, 7, 8, 9, WO 03024965024942, especially compounds specifically described, for example compounds 1-54, WO 03002593 especially compounds specifically described, for example compounds from table 1 or from claims 2-15, WO 03037327, especially compounds specifically described, for example compounds of examples 1-209, WO 03/000250, especially compounds specifically described, for example 1-166, preferably the compounds of examples 1-9, WO 03/024942, especially the compound compounds specifically described, for example compounds 1-59, compounds of table 1 (1-68), compounds of claims 6, 7, 8, 9, WO 03024965024942, especially compounds specifically described, for example compounds 1-54, WO 03002593, especially compounds specifically described, for example the compounds of table 1 or claims 2-15, WO 03037327, especially compounds specifically described, for example the compounds of examples 1-209, WO 0238541, WO 0230890.

WO 03/000250, especially compounds specifically described, for example compounds 1-166, preferably compounds of examples 1-9, WO 03/024942, especially compounds specifically described, for example compounds 1-59, compounds of table 1 (1-68), compounds of claims 6, 7, 8, 9, WO 03024965024942, especially compounds specifically described, for example compounds 1-54, WO 03002593, especially compounds specifically described, for example compounds of table 1 or claims 2-15, WO 03037327 , especially compounds specifically described, for example, compounds of examples 1-209, WO 0238541, about Especially the compounds specifically described, for example the compounds of examples 1-53, WO 03/002531, especially the compounds specifically described, preferably the compounds listed on pp. 9-13, most preferably the compounds of examples 1-46, as well as the preferred compound of example 9, US patent 6395767, preferably the compounds of examples 1-109, most preferably the compound of example 60.

In each case, in particular the compounds in the claims and the final products in the working examples, the essence of the final products, pharmaceuticals and claims is mentioned in the present invention by reference to their publications.

WO 9819998 describes N- (N'-substituted glycyl) -2-cyanopyrrolidines, in particular 1- [2- [5-cyanopyridin-2-yl] amino] ethylamino] acetyl-2-cyano- (S) pyrrolidine .

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

DE 1961486 A1 describes val-pyr, val-thiazolidine, isoleucyl-thiazolidine, isoleucyl-pyrrolidine and the fumar salts of isoleucyl-thiazolidine and isoleucyl-pyrrolidine.

Published patent application WO 0034241 and published patent US 6,110,949 describe N-substituted adamantylaminoacetyl-2-cyanopyrrolidines and N- (substituted glycyl) -4-cyanopyrrolidines, respectively. DPP-IV inhibitors of interest are specifically mentioned in claims 1-4. In particular, these materials describe the compound 1 - [[(3-hydroxy-1-adamantyl) amino] acetyl] -2-cyano-3-pyrrolidine (also known as LAF237).

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

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

WO 01/52825 describes (S) -1- {2 - [(5-cyanopyridin-2-yl) amino] ethylaminoacetyl) -2-cyanopyrrolidine and (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (LAF237).

WO 9310127 describes esters of proline and boronic acids useful as DPP-IV inhibitors. DPP-IV inhibitors of interest are especially those mentioned in Examples 1-19.

Published patent application WO 9925719 describes a DPP-IV inhibitor sulfostin obtained by culturing a microorganism of the genus Streptomyces.

WO 9938501 describes N-substituted 4-8 membered heterocycle rings. DPP-IV inhibitors of interest are especially those described in claims 15-20.

WO 9946272 describes phosphorus-containing compounds as DPP-IV inhibitors. DPP-IV inhibitors of interest are especially those set forth in claims 1-23.

Other preferred DPP-IV inhibitors are compounds of the formulas I, II or III described in patent application WO 03/057200 on pp. 14-27. The most preferred DPP-IV inhibitors are the compounds described on pages 28 and 29.

The published patent applications WO 9967278 and WO 9967279 describe prodrugs and DPP-IV inhibitors of forms ABC, where C is either a stable or unstable DPP-IV inhibitor. Preferably, N-peptidyl-O-aroyl hydroxylamine is a compound of formula VII

Where

j is 0, 1 or 2;

R _ε1 represents a side chain of a natural amino acid; and

R _ε2 represents a lower alkoxyl group, a lower alkyl group, a halogen or a nitro group;

or a pharmaceutically acceptable salt thereof.

In a highly preferred embodiment of the present invention, N-peptidyl-O-aroylhydroxylamine is a compound of formula VIIa

or a pharmaceutically acceptable salt thereof.

N-peptidyl-O-aroylhydroxylamines, for example of formula VII or VIIa, and their preparation are described by H.U. Demuth et al. In J. Enzyme Inhibition 2, 1988, pp. 129-142, specifically on pp. 130-132.

Preferred are the DPP-IV inhibitors described by Mona Patel et al. (Expert Opinion Investig Drugs. 12, 2003, pp. 623-633) in paragraph 5, specifically inhibitors P32 / 98, K-364, FE-999011, BDPX, NVP -DDP-728 and others, this publication is referred to in the present invention by reference, namely the described DPP-IV inhibitors.

Compound FE-999011 is described in patent application WO 95/15309, p. 14, under the number 18.

Another preferred inhibitor is compound BMS-477118 described in US Pat. No. 6,395,767 (compound in Example 60), also known as (1S, 3S, 5S) -2 - [(2S) -2-amino-2- (3-hydroxytricyclo [3.3.1.1 ^3,7 ] dec-1-yl) -1-oxoethyl] -2-azabicyclo [3.1.0] hexane-3-carbonitrile, benzoate (1: 1), which is shown in formula M of patent application WO 2004/052850 on p.2, and the corresponding free base, (1S, 3S, 5S) -2 - [(2S) -2-amino-2- (3-hydroxytricyclo [3.3.1.1 ^3,7 ] dec-1- il) -1-oxoethyl] -2-azabicyclo- [3.1.0] hexane-3-carbonitrile (M '), as well as its monohydrate (M''), which are shown in formula M of patent application WO 2004/0528 50 on p. 3.

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

Other highly preferred DPP-IV inhibitors of the present invention are described in international patent application WO 02/076450 (especially examples 1-128), as well as Wallace, T. Ashton (Bioorganic & Medicinal Chemistry Letters 14, 2004, pp. 899-863 ), especially compound 1 and the compounds listed in tables 1 and 2. The preferred compound is compound 21e (table 1) of the formula

.

.

Compounds P32 / 98 or P3298 (CAS number: 251572-86-8), also known as a mixture of 3 - [(2S, 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine and (2E) -2 -butenedioate (2: 1) shown below

\tab

\ tab

and are described in WO 99/61431 under the name Probiodrug as compound P 93/01.

Other preferred DPP-IV inhibitors are the compounds described in patent application WO 02/083128, for example, in claims 1-5. Most preferred DPP-IV inhibitors are represented by the compounds specifically described in Examples 1-13 and Claims 6-10.

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

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

described in example 7, and also known under the designation MK-0431.

Preferred DPP-IV inhibitors are also described in patent application WO 2004/037181, especially in examples 1-33, the compounds described in paragraphs 3-5 are most preferred.

Preferred DPP-IV inhibitors are N-substituted adamantilaminoatsetil-2-cyano pyrrolidines, N (substituted glycyl) -4-cyano pyrrolidines, N- (N'-substituted glycyl) -2-cyanopyrrolidines, N-aminoacyl thiazolidines, N-aminoatsilpirrolidiny, L-alloizoleytsiltiazolidin , L-threoisolecylpyrrolidine and L-alloisolecylpyrrolidine, 1- [2 - [(5-cyanopyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine and their pharmaceutically acceptable salts.

Particularly preferred are 1- {2 - [(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2- (S) -cyanopyrrolidinedihydrochloride (DPP728) of the formula

especially its dihydrochloride,

and (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (LAF237) of the formula

,

,

as well as L-threoisolecylthiazolidine (designation of the compound according to Probiodrug: P32 / 98, which is given above), MK-0431, GSK23A, BMS-477118, 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1, 2-dihydro-6-isoquinolinecarboxamide and 2 - {[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally in each case their pharmaceutically acceptable salts.

DPP728 and LAF237 are highly preferred compounds and are specifically described in Example 3 of WO 98/19998 and in Example 1 of WO 00/34241, respectively. The DPP-IV P32 / 98 inhibitor (see above) is specifically described in Diabetes 47, 1998, pp. 1253-1258. Compounds DPP728 and LAF237 can be expressed as a composition as described on page 20 of WO 98/19998 or WO 00/34241. Preferred compositions for administering LAF237 are described in provisional patent application US 60/604274.

Oral DPP-IV inhibitors are particularly preferred. In yet another embodiment of the present invention, preferred DPP-IV inhibitors are preferably non-dipeptide compounds and derivatives thereof.

Any compounds described in the aforementioned patent documents and incorporated by reference into the present invention are considered as potentially useful DPP-IV inhibitors useful in the practice of the present invention.

A DPP-IV inhibitor, typically used alone, in accordance with the present invention can be used with a carrier.

A carrier in the context of the present invention is an instrument (natural, synthetic, peptide, non-peptide in nature), for example a protein, which transfers specific substances into the cell through the cell membrane into which it is immersed. Different carriers (natural, synthetic, peptide, non-peptide nature) are required for the transport of different substances, each carrier is intended only for the transfer of one substance or group of related substances.

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

The DPP-IV inhibitor may be a peptide or, preferably, not of a peptide nature.

Most preferred are oral DPP-IV inhibitors and their pharmaceutically acceptable salts.

The active ingredients or their pharmaceutically acceptable salts of the present invention can also be used in the form of a solvate, for example a hydrate, or include other solvents used for crystallization.

Surprisingly, DPP-IV inhibitors have been found to be useful in preventing, delaying the progression or treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure.

The present invention also relates to the use of a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing, delaying the progression or treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure.

In particular, the present invention relates to a new use of (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (LAF237) of the formula

,

,

or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing, delaying the progression or treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure.

The present invention also relates to a method for preventing, from progressing or treating, cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure, which is to administer to a warm-blooded animal, including a person in need thereof, therapeutically effective amounts of a DPP-IV inhibitor, preferably (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (LAF237) of formula (I).

In yet another embodiment, the present invention relates to a pharmaceutical composition of a therapeutically effective amount of a DPP-IV inhibitor in combination with one or more pharmaceutically acceptable carriers for the treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure .

In addition, it was unexpectedly discovered that the compositions described in the present invention have no drawbacks when compared with currently known compounds. It was found that the compounds of the present invention show a therapeutic effect due to the partial oxidation of fatty acids (pFox) of the inhibitory property and due to the oxidation of glucose activating properties and that they are useful for the treatment of cardiovascular diseases or damage, diseases or injuries of the kidneys, heart failure or diseases related to heart failure.

In particular, the compounds of the present invention switch substrate intake in the heart from fatty acids to glucose / lactates, improving the functioning of the left ventricle, but without causing side effects, such as changes in blood pressure and / or heart rate, and not directly affecting contractility heart, all these changes could be expected from calcium channel blockers.

It was also unexpectedly discovered that DPP-IV inhibitors, in particular, are able to slow down or stop the progression of myocardial correction, improve endothelial function, improve endothelial dependent vasodilator function, lower the progression of atherosclerosis, significantly improve endothelial dependent vasodilator function of acetylcholine, improve vasodilating ability, which is known to be greatly weakened in patients with CHF, to reduce levels of apoptosis and necrosis.

Surprisingly, DPP-IV inhibitors have been found to improve left ventricular function without increasing myocardial oxygen demand. In addition, DPP-IV inhibitors do not directly act to stimulate contractility of the heart and do not cause side effects, such as changes in blood pressure and / or heart rate, which are associated with increased mortality in patients with heart failure.

Unexpectedly, it was found that DPP-IV inhibitors are practically safe (non-toxic) and suitable for long-term use, since they cause less side effects, are well absorbed in the body when administered orally, and have a long-lasting effect.

The method or application of the present invention includes the long-term administration to patients of a daily dose of a DPP-IV inhibitor effective in treating heart failure.

Most preferred according to the present invention are cardiovascular diseases or injuries selected from heart hypertrophy, correction of the heart after myocardial infarction, stagnation of blood in the lungs and fibrosis of the heart during dilated or hypertrophic cardiomyopathy, cardiomyopathy, for example dilated cardiomyopathy, or hypertrophic cardiomyopathy, or diabetic hypertrophy of the left or right ventricle, diabetic myopathy, prevention of stroke with congestive heart failure atherosclerosis, hypertrophic thickening of the middle membrane of arteries and / or large vessels, hypertrophy of the vascular network of the mesentery or atherosclerosis.

Other possible cardiovascular and renal diseases and injuries are selected from diabetic retinal inflammation, diabetic neuropathy, diabetic retinopathy, myocardial infarction, peripheral artery disease, endothelial dysfunction with pro-inflammatory and prooxidant status, endothelial dysfunction, recurrent stenosis, limb ischemia, stroke, nephropathate diabetic nephropathy or coronary disease.

In another embodiment of the present invention, prevention, delays in the progression of cardiovascular disease or destruction are associated with the use of DPP-IV inhibitors to improve left ventricular function.

According to the present invention, it is most preferred that kidney diseases or injuries are selected from renal hyperfiltration, for example, after portal renal ablation, proteinuria in chronic kidney disease, renal arteriopathy resulting from hypertension, nephrosclerosis, hypertensive nephrosclerosis, or mesangial hypertrophy.

In another embodiment of the present invention, the vascular disease is damage to blood vessels in the kidneys, most preferably in an animal or person suffering from hypertension or diabetes.

In yet another embodiment of the present invention, the vascular disease or damage is selected from hypertrophic thickening of the middle membrane in arteries and / or large vessels, hypertrophy of the mesenteric vasculature or atherosclerosis, most preferably in an animal or person suffering from hypertension or diabetes.

In another embodiment of the present invention, the vascular disease or damage is selected from atherosclerosis, preferably coronary, cerebral and peripheral atherosclerosis, most preferably in an animal or person suffering from hypertension or diabetes.

In yet another embodiment of the present invention, cardiovascular and renal diseases or injuries are selected from cardiac hypertrophy, e.g. left ventricular hypertrophy, pulmonary stagnation or cardiomyopathy, e.g. dilated cardiomyopathy, or hypertrophic cardiomyopathy, or diabetic cardiomyopathy, or mesanglial hypertrophy.

In another preferred embodiment of the present invention, a vascular disease or damage is associated with diseases characterized by hypertrophy or hypertrophic correction in the cardiovascular system and / or in the kidneys. Preferably, diseases characterized by hypertrophy or hypertrophic correction in the cardiovascular system are selected from hypertrophic cardiomyopathy, left ventricular hypertrophy or hypertrophic thickening of the middle membrane in arteries and / or large vessels,

In another embodiment of the present invention, a cardiovascular disease or damage, a disease or damage to the kidneys, heart failure or diseases related to heart failure are preferably selected from hypertension-induced cardiovascular diseases or damage, diseases or injuries to the kidneys, heart failure or diseases, associated with heart failure.

In another embodiment of the present invention, a cardiovascular disease or damage, a disease or damage to the kidneys, heart failure or diseases related to heart failure, is preferably selected from diabetes induced by cardiovascular disease or damage, disease or damage to the kidneys, heart failure or diseases associated with heart failure.

The term “heart failure diseases” in the context of the present invention refers to one or more conditions underlying the heart failure being treated, including, but not limited to, decreased cardiac contractility, decreased ventricular pressure, for example, systolic pressure in the left ventricle, impaired heart compliance during diastole, decreased stroke volume of the heart, infection of the heart valves and / or the heart muscle itself (endocarditis and / or myocarditis) and decreased cardiac output, as well as m nimiziruyuschie or attenuating the harmful effects commonly associated with prolonged administration of compounds known in the prior art, such as "oxygen-consuming effects", arrhythmias, and exacerbation of angina pectoris. In the present invention, the term “oxygen-consuming effects” below refers, without limitation, the symptoms and signs of stagnation due to increased pressure during filling of the ventricles and fatigue associated with low cardiac output.

In the present invention, the term “continuous administration” means administration for at least three weeks.

In the present invention, the term “cardiovascular disease or damage” means heart and / or vascular disease and cardiac and / or vascular damage.

The term "endothelial dysfunction with pro-inflammatory and prooxidant status", as used in the present invention, refers, but is not limited to chronic endothelial damage, in which Ang II is highly involved.

The term “hypertension-induced cardiovascular disease or damage, kidney disease or damage, heart failure or heart failure disease” as used in the present invention refers to cardiovascular disease or damage, kidney disease or damage, heart failure or disease, associated with heart failure in animals or people with hypertension. Hypertension-induced cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure are preferably vascular injuries of the vision system, kidneys, heart, general circulatory system and brain.

The term “diabetes-induced cardiovascular disease or damage, kidney disease or damage, heart failure or heart failure disease” as used in the present invention refers to cardiovascular disease or kidney damage or disease or damage in animals or humans diabetes, for example, type 2 diabetes, namely atherosclerosis, hypertrophic cardiomyopathy, stroke prevention in congestive heart failure, heart th failure, left ventricular hypertrophy or vascular injuries vision system, kidneys, heart, the overall circulatory system and brain, for example, preferably atherosclerosis.

Hypertrophy or hypertrophic correction of the heart, blood vessels or kidneys is characterized by an increase in the mass of the heart, arteries, large vessels or kidneys.

Hypertension-induced cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure. Hypertension is a condition of high blood pressure that occurs in a significant part of community members. The consequences of persistent hypertension are damage to the vessels of the visual, renal, cardiac and cerebral systems, and the risk of complications increases with increasing blood pressure. The damage associated with hypertension according to the present invention is preferably associated with, but not limited to, cardiac hypertrophy; they are mainly represented by right or left ventricular hypertrophy (LVH) in patients with hypertension, renal arteriopathy, and vascular diseases.

Endothelial dysfunction at an early stage of the disease is characterized by impaired vasomotor response / tone, prothrombotic status, pro-inflammatory status and / or proliferation of arterial walls. It is assumed that the development of endothelial dysfunction is one of the factors that can affect the pathogenesis of atherosclerosis and other cardiovascular diseases.

Hypertrophy of the heart or hypertrophy of myocytes of the heart is an adaptive process that occurs in the heart and is aimed at reducing wall tension when a load of increased pressure is applied to the myocardium. It has been postulated that activation of the renin-angiotensin system plays an important role in the pathophysiology of heart hypertrophy and heart failure. In vivo studies have shown that angiotensin II increases the mass of the left ventricle and affects phenotypic modulations of the heart, regardless of the effect on blood pressure. In vitro studies have shown that angiotensin II causes cardiac myocyte hypertrophy and corrects interstitial fibrosis.

Adverse cardiac correction after myocardial infarction: loss of tissue capable of contraction as a result of myocardial infarction (MI) is partially compensated by hypertrophy of the remaining viable myocardium. Larger transmural infarcts tend to increase in volume and expansion of the entire ventricle. Adaptation to the increased load of residual myocardium includes hardening of the myocardium due to increased collagen deposition. The whole process is called heart correction (cardiac correction) and occurs under the control of mechanical and humoral factors. It is important that the correction includes macroscopic morphological, histological, cellular and molecular changes in heart attack and scarring, as well as residual myocardium. Progressive expansion is accompanied by progression of left ventricular dysfunction (LV) and electrical instability of the heart. Patients who have had acute myocardial infarction are at risk of recurring ischemia, arrhythmia, and correction even in the absence of symptoms. When assessing patients who have undergone myocardial infarction, it is important to represent the degree of risk of correction and apply secondary preventive therapy, which consists in interrupting or delaying the correction process.

Blood congestion in the lungs and fibrosis of the heart with dilated cardiomyopathy or hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death from a heart attack at a young age, is characterized by cardiac hypertrophy, myocyte dispersion, and interstitial fibrosis.

Stroke prevention in congestive heart failure. Atherosclerosis is a systemic vascular wall disease that is present in the carotid arteries, aorta, coronary arteries, and other peripheral arteries. The main components of atherosclerotic plaques are (1) the extracellular matrix of connective tissue, including collagen, proteoglycans, and fibronectin elastic fibers; (2) cells, for example, macrophage derivative monocytes, T lymphocytes and smooth muscle cells; and (3) crystalline cholesterol, cholesterol esters and phospholipids. During the progression of atherosclerosis, a significant correction of the vessels occurs, leading to an increase in blood vessels and, accordingly, to concentric or eccentric stenotic destruction.

Among the visualization techniques for assessing atherosclerotic plaques in humans, the high-resolution magnetic resonance technique, which allows characterization of plaques in vivo, has become a leading one.

The pathogenesis of left ventricular hypertrophy (LVH) or left ventricular hypertrophy (LVH) involves mechanical, hormonal, and neutral factors. The mass and wall thickness of the left ventricle increases to counteract the load from increasing pressure. Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular disease and death, such as myocardial hypertrophy, heart failure, heart failure associated with hypertension, and other cardiovascular complications that are independent of blood pressure (CD). An individual LVH prognosis can be determined using echocardiography.

Nephrosclerosis or hypertensive nephrosclerosis is characterized by interstitial accumulation of type I, III, IV, V and VI collagen, which is a component of the extracellular matrix, and fibronectin (correction). Such matrix changes are accompanied by progressive infiltration of mononuclear cells in cortical interstitium, confirming that macrophages and T-lymphocytes are involved in the development of fibrogenesis.

Renal arteriopathy resulting from hypertension. This disease leads to a thickening of the arterial wall, accompanied by a violation of elasticity, hypertrophy of smooth muscle cells and collagen cords.

Proteinuria in chronic kidney disease. Intraperitoneal hypertension stimulates proteinuria, which then activates the renin-angiotensin system (RAS).

Hyperfiltration in the kidneys, for example, after portal renal ablation. Partial ablation of the mass of the kidney initiates a cycle of progressive glomerular damage in the remainder. This process is associated with glomerular hypertrophy, hyperfiltration, and systemic hypertension.

Diabetic nephropathy is characterized by persistent albuminuria (> 300 mg / 24 h or 200 μg / min), this disease can be diagnosed clinically provided that the following additional criteria are present: the presence of diabetic retinopathy in the absence of clinical or laboratory confirmation of kidney or urinary tract disease in addition to diabetic glomerulosclerosis . Diabetic nephropathy is the most common cause of the final stage of renal failure in Western society.

Diabetic retinopathy (DR) and diabetic macular edema of the retina (PCA) are common vascular complications in patients with diabetes and can have a sudden and debilitating effect on visual acuity (OZ), ultimately leading to blindness. Advanced stages of the development of DR are characterized by abnormal growth of the blood vessels of the retina, this process is a consequence of ischemia. These blood vessels grow in an effort to provide oxygen-rich blood to the retina of the eye, which suffers from a lack of oxygen. During the progression of DR, at any time in patients with diabetes, DLC may develop, with a retinal thickening in the macula. DZHP develops after the destruction of the retinal blood vessel barrier due to leakage from dilated capillaries with increased permeability and microaneurysms.

Diabetic neuropathy is the least studied vascular complication caused by diabetes, which is expressed in morphological and metabolic changes in the peripheral nerves.

In the present description, the term “treatment” includes both prophylaxis or preventive treatment, and healing or suppressing disease treatment, including treatment of patients at risk of developing a disease or suspected of developing a disease, as well as sick patients. This concept also includes treatment to delay the progression of the disease.

The term "healing" as used in the present invention means the effectiveness of the treatment of currently occurring cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure.

The term "warning" in the context of the present invention means the prophylactic administration of a combination to healthy patients to prevent the development of the conditions mentioned in the context of the present invention. In addition, the term “warning” means the prophylactic administration of such combinations to patients in the stage preceding the initial stage of the condition to be treated.

The term “prophylaxis” means the prevention of the onset or relapse of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure.

The term "delay of progression" in the context of the present invention means the administration of the active compound to patients who are at a preliminary or initial stage of a disease being treated, for which, for example, a preliminary stage of a corresponding disease has been established or who are in a state, for example, during medical treatment or a condition arising from an accident, as a result of which the corresponding disease may occur.

In yet another embodiment of the present invention, it is an object of the present invention to administer a dose of a DPP-IV inhibitor for treating the underlying conditions of heart failure, including, but not limited to, decreased cardiac contractility, abnormal diastolic extensibility, decreased stroke volume, heart valve infection and / or cardiac muscle (endocarditis and / or myocarditis) and decreased cardiac output, along with which minimization, weakening or reduction of harmful effects, usually associated associated with the long-term administration of other compounds known in the prior art, for example, oxygen depletion, arrhythmias, and exacerbation of angina pectoris. Preferably, the dose of the DPP-IV inhibitor is such that the deleterious effects typically associated with the long-term administration of other compounds of the prior art disappear.

Most preferably, the HF condition being treated is secondary to dilated cardiomyopathy (DCMP) and / or coronary ischemic disease (coronary artery disease - LHC).

Most preferably, the treatable heart failure is heart failure associated with diabetes, such as type 2 diabetes, or heart failure associated with hypertension.

In a most preferred embodiment, the present invention relates to the treatment or prevention of heart failure or diseases associated with heart failure in people with diabetes, for example type 2 diabetes, or hypertension.

Another object of the present invention is the use of a pharmaceutical composition comprising, as active ingredients, a DPP-IV inhibitor in free form or in the form of its pharmaceutically acceptable salt, with the aim of preparing a pharmaceutical composition for preventing, delaying the progression or treatment of cardiovascular diseases or injuries, diseases or kidney damage, heart failure, or diseases associated with heart failure.

The invention also relates to a pharmaceutical composition comprising, as active ingredients, a DPP-IV inhibitor in free form or in the form of a pharmaceutically acceptable salt thereof.

Another object of the present invention is the use of a pharmaceutical composition comprising, as active ingredients, a DPP-IV inhibitor in free form or in the form of its pharmaceutically acceptable salt, with the aim of preparing a pharmaceutical composition for preventing, delaying the progression or treatment of cardiovascular diseases or injuries, diseases or kidney damage, heart failure, or diseases associated with heart failure.

The present invention also relates to a method for preventing, delaying the progression or treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure, the method comprising administering to a warm-blooded animal, including a person in need thereof, together therapeutically effective amounts of a pharmaceutical composition comprising, as active ingredients, a DPP-IV inhibitor in free form or in the form thereof rmatsevticheski acceptable salt thereof.

According to the present invention, pharmaceutical compositions can be prepared by a method known in the art and are suitable for oral administration, for example, oral or rectal, as well as parenteral administration to mammals (warm-blooded animals), including humans, the compositions contain a therapeutically effective amount of a pharmacological action compound, one or in combination with one or more pharmaceutically acceptable carriers, and are especially intended for oral administration or for a pair teralnogo application.

These pharmaceutical preparations are intended for oral administration, for example, oral as well as rectal, or for parenteral administration to warm-blooded animals together with preparations comprising a pharmacological action compound, alone or in combination with conventional pharmaceutical substances. For example, pharmaceutical preparations contain from about 0.1 to 90%, preferably from about 1% to about 80%, of the active compound. Pharmaceutical preparations for enteral or parenteral as well as intraocular administration are, for example, unit dosage forms, for example, coated tablets, tablets, capsules or suppositories, as well as ampoules. These preparations are prepared by a method whose essence is known, for example, using traditional methods of mixing, granulating, coating, dissolving or lyophilizing. Thus, pharmaceutical preparations for oral administration can be obtained by combining the active compound with solid excipients, if desired, by granulating the resulting mixture and, if desired or necessary, processing the mixture or granulate into tablets or coated tablets after adding suitable additional substances .

Dosages of the active compound may depend on various factors, for example, on the route of administration, the type of warm-blooded animal, age and / or individual condition.

In the community, heart failure primarily affects people aged 50 years and older, most often aged 65 years and older.

Preferably, the patients, people or animals for whom the use and methods of the present invention are intended are people and animals suffering from hypertension or diabetes.

Preferred doses for these active ingredients in the pharmaceutical combination of the present invention are commercially available, especially therapeutic effective commercially available doses.

The dose of the active compound may depend on various factors, for example, on the route of administration, the type of warm-blooded animal, age and / or individual condition.

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

For the indicated indications, the exact assigned dose of the course of treatment varies depending on the compound used, the route of administration and the treatment desired. The compound may be administered by any conventional route, preferably by the oral or other route.

In general terms, satisfactory results are obtained when a daily dose of about 0.01 to 100 mg / kg is administered, more preferably in a dose range of 0.1-50 mg / kg.

For larger mammals, the indicated total daily dose of the compound is in the range of about 0.01 to 100 mg / kg and is usually administered divided into 2-4 doses per day in a unit dosage form containing, for example, from about 10 to about 100 mg compounds in the form of a sustained release.

Another preferred daily oral dose is from 1 to 500 mg, preferably from 10 to 100 mg, for example 10 mg, more preferably 25-100 mg or 25-50 mg, for example 25 mg, or 40 mg, or 50 mg, or 70 mg , or 100 mg.

The prescribed unit doses for oral administration contain, for example, from about 10 to about 100 mg of the compounds. Suitable doses for parenteral administration include, for example, from about 10 to about 50 mg, or from 25 to about 100 mg of the compound, for example, 25 mg, 50 mg, 75 mg or 100 mg.

The compounds may be administered in a manner similar to known standard methods for applications with the indicated applications. An acceptable daily dose for an individual compound may depend on a number of factors, for example, on the relative strength of the activity shown. Those skilled in the art are able to determine a therapeutically effective dose.

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

Pharmaceutical compositions according to the present invention, which can be prepared by a method known in the art, and are suitable for oral administration, for example, oral or rectal, as well as parenteral administration to mammals (warm-blooded animals), including humans, containing a therapeutically effective amount of a pharmacological compound actions, alone or in combination with one or more pharmaceutically acceptable carriers, and especially suitable for oral administration or for couples oral administration.

It has also been found that a particular regimen improves the treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure. It has surprisingly been found that a DPP-IV inhibitor can be administered with food, preferably shortly before a meal or at the start of a meal, optionally during a meal or even shortly after a meal. The food administration regimen of the present invention results in an unexpected reduction in cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure, especially in patients with diabetes, for example type II diabetes, or with hypertension.

The food administration regimen of the present invention results in an unexpected reduction in atherosclerosis in patients with diabetes, for example, type 2 diabetes.

Another object of the present invention relates to the use of a DPP-IV inhibitor, preferably (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (LAF237) of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing, delaying the progression or treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure in which a DPP-IV inhibitor is administered with food.

The present invention also relates to a method for preventing delayed progression or treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure, comprising administering to a warm-blooded animal, including a human in need thereof, a therapeutically effective amount of a DPP inhibitor -IV, preferably (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (LAF237) of formula (I), a DPP-IV inhibitor is administered I'm with food.

The use or method described above for treating a patient with diabetes, in particular type II diabetes, is most preferred for treating or preventing atherosclerosis.

The use or method described above for treating a patient with diabetes, in particular type II diabetes, or hypertension, most preferably for treating or preventing heart failure or diseases associated with heart failure.

The use or method described above for treating a patient with diabetes, in particular type 2 diabetes, most preferably for treating or preventing diabetic retinal inflammation, diabetic neuropathy, diabetic retinopathy, myocardial infarction, peripheral artery disease, endothelial dysfunction with pro-inflammatory and prooxidant status endothelial dysfunction, repeated stenosis, nephropathy, stroke, diabetic nephropathy or coronary disease.

The term “nutrition” as used in the present invention refers to breakfast, lunch, dinner or midnight meal.

The use of the term “food-related” in the present invention is associated with the administration of a DPP-IV inhibitor and preferably means that the DPP-IV inhibitor is administered shortly before or at the start of a meal. However, the introduction also, obviously, can be carried out during a meal or even shortly after a meal, which is not a departure from the present invention. Thus, the term “food-related” preferably means the administration of a DPP-IV inhibitor about 30 minutes before a meal, preferably 10 minutes before a meal, or about 10 minutes after a meal, more preferably about 5 minutes before the start of the meal and before the end of the meal, most preferably with the start of the meal.

Pharmaceutical activities caused by the administration of representatives of the class of DPP-IV inhibitors that are used according to the present invention can be shown, for example, by using appropriate pharmacological models known in the art. Specialists in the art are quite capable of selecting the relevant animal model to confirm the therapeutic indications and therapeutic effects described in the present invention.

The experimental protocols, which are by no means restrictive and are intended to prove the pharmacological activity of the compounds and compositions of the present invention in cardiovascular or renal diseases, are described below (see also references):

- Evaluation of therapeutic effects in cardiovascular diseases, especially diabetes, from the use of DPP-IV inhibitors can be performed using models such as, for example, Zucker fat rats described in Nawano et al., Metabolism 48, 1999, pp. 1248-1255. In addition, studies using rats with spontaneous hypertension are described in Sato et al., Metabolism 45, 1996, pp. 457-462, Models of rats, for example, a rat rat strain of diabetic hypertension Cohen-Rosenthal (Rosenthal et al. Hypertension, 29, 1997, pp. 1260-1264), can also be used to simultaneously evaluate the effects of a DPP-IV inhibitor on blood pressure and cardiovascular disease.

- Evaluation of therapeutic effects in cardiovascular diseases, especially with left ventricular hypertrophy, can be performed according to the description given by Gaudio C. et al. In J Cardiovasc Pharmacol 42, 2003, pp. 622-628.

- Evaluation of the therapeutic effects of atherosclerosis from the use of DPP-IV inhibitors can be performed using protocols, for example, described in the publication Prescott MF and others in Ann N Y Acad Sci 30, 1999, pp. 179-190.

- Evaluation of the therapeutic effects of the use of DPP-IV inhibitors, manifested in hypertrophy of the left ventricle, can be performed using protocols, for example, described in the publication Arnfried U and others in Am J Med 41, 2003, pp. 41-46.

The experimental protocols, which are by no means restrictive and are intended to prove the pharmacological activity of the compounds and compositions of the present invention in heart failure and diseases associated with heart failure, are described below (see also references):

An assessment that the DPP-IV inhibitors of the present invention can be used to treat heart failure can be carried out, for example, by the methods described by SmithHJ, Nuttalll A in Cardiovasc Res 19, 1985, pp. 181-186. Molecular approaches, for example, transgenic methods, are also described, for example, by Luft et al. In Hypertension, 33, 1999, pp. 212-218. In addition, rat models with hypertension and heart failure described by Doggrell SA, Brown L (Cardiovasc Res 39, 1998, cc 89-105) can be used to pharmacologically evaluate DPP-IV inhibitors. Evaluation of the therapeutic effects on cardiovascular diseases, especially in diabetes, from the use of agents individually or in combination, can be performed using models such as, for example, Zucker fat rats described in the publication Nawano et al., Metabolism 48, 1999, pp. 1248-1255.

- In addition, the experimental protocols are described in patents US 6087360 (in this patent, agricultural pigs were used as a model of heart failure) and US 20030045469.

A useful clinical study of heart failure is described by Stephan Schmidt-Schweda and Christian Holubarsch (Clinical Science, 99, 2000, pp. 27-35).

- Clinical studies of Jay N. Cohn and Gianni Tognoni (A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure, 345, 2001, cc. 1667-1675) and in US patent 5998458 (example 1) are also described.

The structure of active agents, denoted by generic or trade names, can be obtained from the modern edition of the standard reference book “The Merck Index” or from databases, for example Patents International (for example, IMS World Publications). Relevant information is provided in the present invention by reference. Any specialist in this field is able to identify active agents and, based on these sources, can also obtain and test pharmaceutical indications and properties using standard test models both in vitro and in vivo.

A pharmaceutical effect, for example, can be shown in clinical trials or through experiments, the essence of which is described in the present invention and is understood by specialists working in this field.

Preferred DPP-IV inhibitors for the applications and methods of the present invention are 1- {2 - [(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2 (S) -cyanopyrrolidine dihydrochloride (DPP728), especially its dihydrochloride, (S ) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (LA237), L-threoisolecylthiazolidine (Probiodrug code number: P32 / 98 above), MK-0431, GSK23A, BMS-477118 , 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2 - {[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo -1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally in each case ae their pharmaceutically acceptable salts.

experimental part

The following examples can be performed using DPP-IV inhibitors in order to show their activity as claimed in the claims.

Example 1

Animals: Forty-eight male 8-week-old Sprague Dawley rats are anesthetized using enflurane (Abbott Australasia, Kurnal, NSW, Australia) and an osmotic mini pump (Alzet Model 2002, Alzet Corporation, Palo Alto) inserted into the interscapular region . The rats are randomized to administer, using mini-pumps, an excipient (0.15 M NaCl, 1 mmol / L acetic acid) containing or not containing angiotensin II (58 ng / min) as previously described (Cao Z et al. In Kidney Int 58, 2000, pp. 2447-2451). Then the animals are further randomized and either not treated, or DPP-IV inhibitors are administered at a dose of 60 mg / kg per day, and after 12 days the rats are sacrificed. During the study, rats have unlimited access to water and standard rat food. Systolic blood pressure (SKD) is measured by plethysmography (indirect tail-cuff method) in pre-warmed, non-anesthetized animals as previously described (Bunag RD in Journal of Applied Physiology 34, 1973, pp. 279-282). In each group there are 16 animals, 8 are used for histological studies, and the other 8 rats are used to study gene expression. In the last group of animals, they are killed by decapitation, after which the mesenteric vessels are removed and the surrounding fat, connective tissue and veins are exposed to obtain the superior mesenteric arterial tree as described previously (Rumble J et al. In J Hypertension 14, 1996, pp. 601-607) . The vessels are weighed, immediately frozen in liquid nitrogen and then stored at -80 ° C.

Histochemistry and immunohistochemistry: histological studies of vascular architecture are carried out in a subgroup of animals (n = 8 / group). Animals in this subgroup are anesthetized with sodium pentobarbital (product Nembutal, Bomac Laboratories, Asquith, Australia) and the vessels are filled at 10% with neutral buffered formalin through a catheter inserted into the aorta. The tissues are then dissected as previously described (Cooper ME et al. In Diabetes 43, 1994, pp. 1221-1228). Briefly, the mesenteric vessels are placed in ice-cold phosphate buffer, which also contains fat, connective tissue and veins removed by direct excision. The resulting vascular preparations are then immersed in paraffin. Sections are then stained with histochemical or immunohistochemical stains. Histochemical staining involves the use of either hematoxylin and eosin or Masson trichrome (Masson P in J Tech Methods 2, 1929, pp. 75-90) to evaluate the extracellular matrix. Smooth muscles are stained using an anti-smooth muscle α-actin polyclonal antibody (Biogenes, San Ramon, California, USA) as an immuno-dye, and an immunohistochemical study is also carried out using an indirect method using the Avidin-Biotin complex as described previously (Rumble JR et al. in J Clin Invest 99, 1997, pp. 1016-1027).

Quantification of histopathology: the portion of the vessel wall occupied by the middle sheath of the blood vessel is identified using an immunoassay for smooth muscle α-actin, and the wall: lumen ratio is calculated using a video imaging system (Video Pro 32, Leading Edge, Bedford Park, South Australia, Australia) connected to a light microscope (Zeiss, Oberkocken, Germany) with a photographic attachment (Axiophot, Zeiss, Oberkocken, Germany). Using this device, the middle membrane of the walls of blood vessels (areas stained with an antibody to actin) and the corresponding lumen regions on average in 20 vessels (range 10-35) in each animal are determined and expressed as the wall: lumen ratio, as described previously on other models vascular hypertrophy (Kakinuma Y et al. in Kidney Int 42, 1992, pp. 46-55).

ECM is quantified on trichrome stained sections by counting the areas occupied by the ECM using the computer imaging analysis previously described (Lehr HA et al. In J Histochem Cytochem 45, 1997, pp. 1559-1565). Briefly, the ranges of staining the matrix (blue on slices stained with trichrome), smooth muscles of the middle membrane of the wall of blood vessels (red on slices stained with trichrome) are selected and visualized using the chromogen separation method (Lehr HA, etc.). The entire slice was examined using light microscopy (Olympus BX-50 microscope, Olympus Optical, Tokyo, Japan) and recorded using a digital camera (Fujix HC-2000, Fujifilm, Tokyo, Japan). All images are obtained using a 20x zoom lens. Digital images are then downloaded to a Power Macintosh G3 computer (Apple Computer Inc., Cupertino, California, USA) equipped with an integrated graphics card and evaluated using analytical computer software (Analytical Imaging Software, Ontario).

Statistics: All results are shown as mean ± SE unless otherwise indicated. The data obtained are analyzed using ANOVA analysis of variance using the StatView IV program (Brainpower, Calabasas, California, USA) on a Macintosh G3 computer. The comparison between the average values for the groups is carried out by the method of least significant Fisher differences. When the p value is less than 0.05, the result is evaluated as statistically significant.

Results:

Animal data: angiotensin II infusion is associated with increased systolic blood pressure (SKD) compared with animals that received only vehicle (141 ± 2 mmHg when vehicle was used compared to 202 ± 7 mmHg when angiotensin II was used, p <0.001) . The mass of mesenteric vessels is also increased in rats that were injected with angiotensin II (52 mg, p <0.001) by infusion, compared with control animals that received vehicle (32 mg, p <0.001). DPP-IV inhibitors do not significantly affect systolic blood pressure (205 ± 10 mmHg), but significantly reduce mesenteric mass in animals receiving angiotensin II (42 mg, p <0.001).

Histology and immunohistochemistry: histomorphometric analysis shows a significant increase in the ratio of the wall of the middle lining of the blood vessels: the lumen in rats that were injected with angiotensin II by infusion (when the excipient was administered to rats,> 0.39; when infused into rats, angiotensin II was> 0.52, p < 0.001). Treatment with a DPP-IV inhibitor can, for example, significantly lower the wall: lumen ratio in both groups to levels close to the levels of control animals. Sections stained with trichrome show both hypertrophy of the middle wall of the blood vessel membrane and expansion of the collagen ECM in the vessels of the mesentery of animals, which were injected with angiotensin II by infusion. Studies have shown that treatment with a DPP-IV inhibitor can reduce both hypertrophy of the wall of the middle lining of blood vessels and ECM expansion in animals that were injected with angiotensin II by infusion.

Example 2

Nephropathy: antiproteinuric effect in non-insulin-dependent diabetes (NID) rats (Wistar mast rat line) [protocol described by H. Ikeda et al., Diabetes 30, 1981, p. 1045, or using a model of focal glomerulosclerosis; T.W. Meyer and H. G. Renake, Am. J. Physiol. 254, 1988, p. F856 or in WO 01/64200].

An unexpectedly established range of properties means that DPP-IV inhibitors are particularly interesting for the manufacture of medicaments for the treatment of the diseases described in the present invention, especially hypertrophy or hypertrophic correction of the cardiovascular system and / or kidneys and related diseases described in the present invention.

This effect can be especially clinically significant for patients with injuries due to hypertension, for example, described in the present invention.

Experiment 3: effects on cardiac hypertrophy.

Materials and methods: use groups of male Wistar rats weighing 100-120 g, which contain 5 animals per cage (cage size: 425 mm × 266 mm × 180 mm with litter from sawdust) at a temperature of 21 ± 10 ° C and humidity 50 ± 15% with a cycle of day and night 12/12 hours and a 15-20-fold change in air volume / h. The animals are given LP ALTROMIN (REIPER) food and spring water as desired.

Induction of cardiac hypertrophy: left ventricular hypertrophy is induced in rats anesthetized with Nembutal sodium, by narrowing the abdominal aorta with a clamp (0.8 mm diameter) placed on the abdominal aorta between the diaphragm and renal branches; animals in one group, which is then used as a control group, are subjected to the same procedure, but do not produce aortic narrowing (imitation).

Then animals are randomly distributed into the following groups:

Simulated animals: operate without aortic forceps (n = 8)

Control animals: operate with aortic forceps (n = 8)

CLO: operate with aortic forceps and treat for 12 weeks, starting from the day after surgery, with DPP-IV inhibitors that are added to the feed (60-100 mg / kg / day (n = 11).

Assessment of heart function: at the end of treatment, the function of the heart in animals anesthetized with Nembutal sodium salt is evaluated using a polyethylene catheter inserted into the left ventricle through the carotid artery and connected to a pressure transducer (Statham p23 XL) with an amplifier (Biomedica Magnoni bm 61).

The recorded parameters are: heart rate, ventricular blood pressure at the systole stage and at the end of diastole, as well as positive and negative derivatives of ventricular pressure, which are recorded on a personal computer using a data recording system (IDAS). Measurements are taken over 30 minutes.

Macroscopic evaluation: at the end of the experiments, animals are killed with a lethal dose of Nembutal, the abdominal cavity is opened, organs are brought to the surface of the body to verify the exact location of the aortic clamp, then the heart, lungs and liver are removed, thoroughly dried and weighed after an external examination to identify which Any deviations from the norm.

Statistical analysis: The data obtained are expressed as mean ± standard deviation and compared using Student's t test for independent data. Differences with P <0.05 are evaluated as statistically significant.

results

Mass parameters: mass parameters are determined at the end of the experiment;

animal body weight does not change significantly either as a result of aortic narrowing, or as a result of treatment. Aortic narrowing causes significant ventricular hypertrophy; it was found that the heart mass in animals with clamp increases by about 35% compared with animals with imitation (P <0.05); treatment by administering the drug does not modify body weight compared to untreated controls. The values of the mass of the liver and lungs do not change either as a result of narrowing of the aorta, or as a result of treatment by administration of the drug.

Assessment of heart function: aortic narrowing induces a significant increase in both systolic pressure in the left ventricle and pressure at the end of the diastole; with developed pressure, both positive and negative variations in pressure in the ventricle do not show statistically significant changes in absolute values in animals with aortic narrowing compared with animals with imitation.

If the pressure is normalized relative to the mass of the ventricle, a statistically significant decrease in this parameter can be observed in animals with narrowing of the aorta; likewise, a positive derivative of ventricular pressure can be significantly reduced if it is normalized for ventricular systolic pressure.

Treatment of animals with aortic narrowing normalizes the pressure at the end of the diastole, and the pressure develops in accordance with the mass of the ventricle, with a significant improvement in both positive and negative derivatives of ventricular pressure.

Treatment with DPP-IV inhibitors can induce, for example, a further increase in systolic pressure in the left ventricle and normalization of pressure at the end of diastole in animals with aortic narrowing.

Pressure develops in accordance with the mass of the ventricle, and both positive and negative derivatives of ventricular pressure can be significantly improved by treatment with DPP-IV inhibitors.

Experiment 4. Effect on endothelial function (heart failure).

This example describes a study that is conducted to determine the effect of the treatment carried out according to the present invention on the endothelial function in Watanabe rabbits, which are known to develop a complex of atherosclerotic lesions during the first year of life. It was previously mentioned that endothelial dysfunction is associated with the pathophysiology of heart failure.

Rabbits are used at the beginning of the study at the age of 7-8 months, they are randomized into three groups; animals from the first group are killed immediately to obtain initial measurements, animals from the second group (n = 10) receive a DPP-IV inhibitor, and animals in the third group receive an imitation of treatment (placebo; control animals).

Treatment consists of daily administration of a DPP-IV inhibitor for 10 weeks.

All animals are killed at the age of 11 months. Ring preparations are taken from the ileal arteries of animals and evaluated to quantify relaxation caused by acetylcholine (an epithelial dependent vasodilator) after starting treatment with phenylephedrine (as a vasoconstrictor).

Evaluation of ring preparations, for example, shows a significant increase in endothelium-mediated vasorelaxation in treated animals compared to control animals.

Relaxation is not observed if the endothelium is removed from the ring preparations, further confirming the endothelium-specific effect of the treatment described in the present invention. DPP-IV inhibitors can restore attenuated epithelial-dependent relaxation.

The present invention has been described above by reference to preferred embodiments thereof, but those skilled in the art will recognize that many additions, gaps, and modifications are possible within the scope of the claims that follow.

Claims (26)

1. A method for preventing, delaying the progression or treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure, comprising prolonged administration to a warm-blooded animal, including a person in need thereof, of a therapeutically effective amount of a DPP inhibitor -IV (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine, a pharmaceutically acceptable salt thereof, wherein continuous administration includes administration a daily dose of a DPP-IV inhibitor for a period of 3 weeks or more. 2. The method according to claim 1, wherein the cardiovascular disease or damage is selected from cardiac hypertrophy, heart correction after myocardial infarction, pulmonary stasis and cardiac fibrosis during dilated or hypertrophic cardiomyopathy, cardiomyopathy, for example dilated cardiomyopathy, or hypertrophic cardiomyopathy, or diabetic cardiomyopathy, left or right ventricular hypertrophy, diabetic myopathy, stroke prevention in congestive heart failure, hypertrophic thickening of the middle her shell in arteries and / or large vessels, hypertrophy of the vascular network of the mesentery or atherosclerosis. 3. The method according to claim 1, wherein the kidney disease or damage is selected from renal hyperfiltration, for example after portal renal ablation, proteinuria in chronic kidney disease, renal arteriopathy resulting from hypertension, nephrosclerosis, hypertensive nephrosclerosis or mesangial hypertrophy. 4. The method according to claim 1, wherein the cardiovascular and renal diseases or injuries are selected from cardiac hypertrophy, for example left ventricular hypertrophy, pulmonary stagnation or cardiomyopathy, for example dilated cardiomyopathy, or hypertrophic cardiomyopathy, or mesangial hypertrophy. 5. The method according to claim 1, wherein the vascular disease or damage is selected from hypertrophic thickening of the middle membrane in arteries and / or large vessels, hypertrophy of the vascular network of the mesentery or atherosclerosis in an animal or person suffering from hypertension or diabetes. 6. The method according to claim 5, wherein the vascular disease or damage is atherosclerosis. 7. The method according to claim 1 for improving the function of the left ventricle. 8. The method according to claim 1 for the treatment of cardiovascular disease or associated with heart failure. 9. The method according to claim 1, wherein the treated state of heart failure is secondary to idiopathic dilated cardiomyopathy and / or coronary ischemic disease. 10. The method according to claim 4, in which the treated animal or person is suffering from hypertension or diabetes. 11. The method according to claims 2-10, wherein the daily oral dose of the inhibitor is 1-100 mg. 12. The method according to claim 11, wherein the daily oral dose of the inhibitor is 25-100 mg. 13. The use of a DPP-IV (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine inhibitor, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prolonged administration to a warm-blooded animal, including humans, for delay the progression or treatment of cardiovascular disease or damage, disease or damage to the kidneys, heart failure or diseases associated with heart failure. 14. The use of claim 13, wherein the DPP-IV inhibitor is (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine, wherein the DPP-IV inhibitor is administered with food. 15. The use according to claim 13, wherein the cardiovascular disease or injury is selected from cardiac hypertrophy, heart correction after myocardial infarction, pulmonary stasis and cardiac fibrosis during dilated or hypertrophic cardiomyopathy, cardiomyopathy, for example dilated cardiomyopathy, or hypertrophic cardiomyopathy, or diabetic cardiomyopathy, left or right ventricular hypertrophy, diabetic myopathy, stroke prevention in congestive heart failure, hypertrophic thickening with the outer membrane in arteries and / or large vessels, hypertrophy of the vascular network of the mesentery or atherosclerosis. 16. The use according to claim 13, wherein the kidney disease or damage is selected from renal hyperfiltration, for example after portal renal ablation, proteinuria in chronic kidney disease, renal arteriopathy resulting from hypertension, nephrosclerosis, hypertensive nephrosclerosis or mesangial hypertrophy. 17. The use according to claim 13, wherein the cardiovascular and renal diseases or injuries are selected from cardiac hypertrophy, for example left ventricular hypertrophy, pulmonary blood stasis or cardiomyopathy, such as dilated cardiomyopathy, or hypertrophic cardiomyopathy, or mesangial hypertrophy. 18. The use of claim 13, wherein the vascular disease or damage is selected from hypertrophic thickening of the middle membrane in arteries and / or large vessels, hypertrophy of the vascular network of the mesentery, or atherosclerosis in an animal or person suffering from hypertension or diabetes. 19. The use according to claim 18, wherein the vascular disease or damage is atherosclerosis. 20. The application of item 13 to improve the function of the left ventricle. 21. The use according to item 13 for the treatment of cardiovascular disease or associated with heart failure. 22. The use according to claim 13, wherein the treated state of heart failure is secondary to idiopathic dilated cardiomyopathy and / or coronary ischemic disease. 23. The use according to claim 13, wherein the animal or person being treated has hypertension or diabetes. 24. The use according to claims 14-23, wherein the daily oral dose of the inhibitor is 1-100 mg. 25. The application of paragraph 24, wherein the daily oral dose of the inhibitor is 25-100 mg. 26. A pharmaceutical composition comprising a therapeutically effective amount of (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers, which is used for prolonged treatment of cardiovascular diseases or injuries, diseases or injuries of the kidneys, heart failure or diseases associated with heart failure.