RU2712097C1 - Dipeptidyl peptidase-4 inhibitor for treating type 2 diabetes mellitus, compounds (versions) - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to organic chemistry and specifically to novel compounds which are amides of beta-amino acids of stereoisomers of 3-azabicyclo[2.2.1]heptene-2-carbonitrile of formula (I), or pharmaceutically acceptable salts thereof, where R=H is hydrogen; C– alkyl; R=H is hydrogen; C– alkyl; benzyl (CH-CH), substituted with one, two or three halogen atoms (F); R=H is hydrogen; adamantyl, in which each carbon can have a substitute selected from: hydroxy (OH-); benzyl (CH-CH), in which there can be substitutes: hydroxy- (OH-) and one halogen (F). Invention also relates to amide of beta-amino acids of stereoisomers of 3-(3-azabicyclo[2.2.1]heptane-2-yl)-1,2,4-oxadiazole of formula II and amide of beta-amino acids of stereoisomers 5-(3-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-oxadiazole of formula III, dipeptidyl peptidase-4 inhibitor based on said compounds.,I,EFFECT: development of inhibitors of dipeptidyl peptidase-4 for treating patients with type 2 diabetes mellitus.8 cl, 99 ex, 2 tbl

Description

FIELD OF THE INVENTION

The invention relates to medicine, namely to substances that are dipeptidyl peptidase-4 inhibitors from the group of beta-amino acid amides - N-acyl derivatives of 3- (3-azabicyclo [2.2.1] heptan-2-yl) -1,2,4 -oxadiazole and 3-azabicyclo [2.2.1] heptene-2-carbonitrile for the treatment of diabetes mellitus.

State of the art

Diabetes mellitus is one of the most serious medical and social problems due to its high prevalence, rapid increase in morbidity, high incidence of disability and persistent high mortality due to the development of complications of this disease. There are two forms of diabetes. Type 1 diabetes mellitus or insulin-dependent, in which insulin is a hormone that regulates glucose utilization, is not formed or is formed in small quantities. Insulin-independent type 2 diabetes is characterized by the fact that its blood level is the same or slightly higher than that of people without diabetes, however, there is resistance to the stimulating effect of insulin on glucose metabolism in insulin-sensitive tissues. The reason is not a decrease in the number of insulin receptors, but the defect following the binding of insulin to the receptor, which leads to insufficient activation of insulin utilization in glucose tissues and inadequate suppression of lipolysis by insulin in adipose tissue.

According to the WHO, type 2 diabetes mellitus (DM-2), in turn, was detected in ~ 90% of all patients with diabetes mellitus. Throughout the world, the number of previously rare cases of children with type 2 diabetes has increased significantly. According to WHO forecasts, diabetes will be the seventh leading cause of death in 2030.

Currently, the pharmaceutical market has a number of drugs for correcting the condition of persons suffering from type 2 diabetes.

Biguanides, the hypoglycemic effect of which is due to mechanisms of action not associated with the secretion of insulin by β-cells. Sulfonylurea (SM) preparations - the main mechanism of action of SM drugs is to stimulate insulin secretion. Prandial regulators (glinides) are short-acting drugs that realize their sugar-lowering properties by sharply stimulating insulin secretion after eating. Α-glucosidase inhibitors - this group of drugs includes drugs that compete with dietary carbohydrates for the binding centers of gastrointestinal enzymes involved in the breakdown and absorption of carbohydrates. Dipeptidyl peptidase-4 inhibitors and incretin mimetics - the mechanism of action of these drugs is closely related to the main biological effects of the hormones of the gastrointestinal tract and consists in enhancing the glucose-dependent insulin response and simultaneously suppressing glucose-dependent secretion of glucagon against the background of an increase in blood glucose. Glitazones - PPAR gamma agonists - drugs of this group belong to a new class of oral hypoglycemic agents, acting at the level of receptors activated by peroxisome proliferation (PPARγ).

Dipeptidyl peptidase-4 inhibitors are one of the popular approaches for treating symptoms of diabetes mellitus.

The mechanism of action of these drugs, as well as the effect of incretin mimetics, is closely related to the main biological effects of hormones of the gastrointestinal tract and consists in enhancing the glucose-dependent insulin response and at the same time suppressing glucose-dependent secretion of glucagon against the background of an increase in blood glucose.

Since taking most drugs is accompanied by serious side effects in the form of hypoglycemia, lactic acidosis, hepatotoxicity, nausea, diarrhea, heart failure, puffiness, osteoporosis, etc., which significantly worsens the quality of life of patients, the development of new, more effective, pathogenetically substantiated approaches to therapy for this disease.

One of the links in the pathogenesis of type 2 diabetes is a violation of the function of incretins - hormones of the gastrointestinal tract, produced in response to food and causing stimulation of insulin secretion (incretin - from the English INCRETIN - INtestine seCRETion of INsulin). Two main incretins are known in the human body: a glucose-dependent insulinotropic polypeptide, also known as a gastroinhibitory peptide (HIP) or a gastric inhibitory peptide (GIP) produced by K cells of the duodenum and jejunum, as well as glucagon-like peptide-1 (GLP-1) secreted by enteroendocrine L cells. That is, both hormones are produced by endocrine cells located in the epithelium of the small intestine, and their release is regulated in a similar way by other hormones of the gastrointestinal tract. An increase in the concentration of the substance in the lumen of the gastrointestinal tract (in this case, glucose) acts as a trigger for hormone secretion. Studies showing that in patients with type 2 diabetes, not only the quantitative content of incretins is disturbed, but also the mechanism of their action, allowed us to think about creating a group of drugs that affect the level of incretins. The presence of such agents could improve glycemic control by affecting other pathogenetic links of this disease, in contrast to existing groups of antidiabetic drugs.

The decrease in the effect of incretins in the bloodstream is a consequence of their rapid destruction and excretion from the body. The reason for the degradation of incretins and the loss of their function lies in their structure - the presence of an alanine (Ala) residue in the 2nd position from the N-terminus. Similar amino acid sequences are substrates for the serine protease - dipeptidyl peptidase-4 (DPP-4).

The disclosure of the role of DPP-4 in the metabolism of incretins was a key point in the development of drugs that increase the duration of action of endogenous HIP and GLP-1. Such drugs are DPP-4 inhibitors. The results of experiments on animal models have demonstrated the maintenance of the incretin concentration in the blood under the influence of DPP-4 inhibitors. Measurement of the concentration of endogenous incretins in blood plasma among patients with type 2 diabetes, in whom the use of DPP-4 inhibitors reduced the level of glycemia, confirmed the previously obtained results.

Thus, the development of new drugs that are antagonists of DPP-4 is of great importance and the prospect of obtaining highly selective inhibitors of dipeptidyl peptidase-4.

Known inhibitors of dipeptidyl peptidase-4, RF patents No. 2180901, No. 2251544 "N-substituted 2-cyanopyrrolidines", application US 20130204012.

Known RF patent No. 2286986 "Inhibitors of dipeptidyl peptidase-4 based on condensed cyclopropylpyrrolidines and the method of their use."

Known RF patent for the invention No. 2443687, "New inhibitors of dipeptidyl peptidase IV, methods for their preparation and pharmaceutical compositions containing them."

Known RF patent 2483716.

The invention relates to medicine and the pharmaceutical industry and relates to a pharmaceutical composition comprising a dipeptidyl peptidase-4 inhibitor, preferably vildagliptin from 1.5 to 20% and metformin from 80 to 98.5%. In this case, the active ingredients make up from 60 to 98% of the composition. As a binder, cellulose or its derivatives are used in an amount of 1 to 20%.

A new amino derivative of pyrrolidine was synthesized as a dipeptidyl peptidase-4 inhibitor.

The invention is known according to the application US No. 201330023671 A1, in which the claimed method for the production of saxagliptin - a dipeptidyl peptidase-4 inhibitor, which is a derivative of pyrrolidine.

Saxagliptin is a selective reversible competitive dipeptidyl peptidase-4 inhibitor (DPP-4). In patients with type 2 diabetes mellitus, the administration of saxagliptin leads to a suppression of the activity of the enzyme DPP-4 within 24 hours.

After oral administration, inhibition of DPP-4 leads to a 2-3-fold increase in the concentration of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (HIP), a decrease in the concentration of glucagon, and an increase in the glucose-dependent beta-cell response, which leads to an increase in the concentration of insulin and C-peptide and, accordingly, to reduce fasting and postprandial glycemia.

As dipeptidyl peptidase-4 inhibitors, the pharmaceutical market includes: sitagliptin, vildagliptin, saxagliptin, linagliptin, which have slightly different properties.

A known patent, RU 2628573, in which a dipeptidyl peptidase-4 inhibitor from the group of N-acyl derivatives of aminoacyl-2-cyanopyrrolidine, is a substance:

(R / S) -3-amino-1 - [(S) -5-phenyl- [1,2,4] oxadiazol-3-yl) pyrrolidin-1-yl] -3- (4-fluorophenyl) - propan-1-one corresponding to the structural formula:

effective for the treatment of type 2 diabetes mellitus; along with high efficiency, it also has high stability (Prototype)

Despite the presence on the market of commercial antidiabetic agents - DPP-4 inhibitors, there is a need to create new dipeptidyl peptidase-4 inhibitors that retain their chemical and spatial structure in the natural environment of the human body. Moreover, the compound should be primarily stable, even if its activity is not very high as an inhibitor.

Disclosure of invention

Currently, there remains a need to create new dipeptidyl peptidase-4 inhibitors to expand the line of known dipeptidyl peptidase-4 inhibitors in order to satisfy the need for this drug.

The objective of the invention is the creation of inhibitors of dipeptidyl peptidase-4, resistant to intramolecular cyclization, for the treatment of patients with type 2 diabetes and expanding the range of known inhibitors of dipeptidyl peptidase-4.

This problem is solved due to the fact that

Compounds of the general formula (I) have been created — beta-amino acid amides of 3-azabicyclo [2.2.1] heptene-2-carbonitrile (I) or their pharmaceutically acceptable salts.

Where:

R ¹ = H is hydrogen; C _1-5 is alkyl in which each carbon may independently have one or two substituents; aryl, in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,);

R ² = H is hydrogen; C _1-5 is alkyl in which each carbon may independently have one or two substituents; adamantyl, in which each carbon together or independently may have a substituent selected from: hydroxy (OH-), halogen (F, Cl, Br,); phenyl- (C ₆ H ₅ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,); benzyl- (C ₆ H ₅ -CH ₂ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,);

R ³ = H is hydrogen, C _1-5 is alkyl, in which each carbon independently may have one or two substituents; benzyl- (C ₆ H ₅ —CH ₂ -), in which each carbon of the aromatic ring can have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,) (option I).

At the same time, compounds were synthesized where:

R ¹ = H, R ² = H, R ³ = hydroxyadamantyl-exo-3- [3 - [(3-hydroxy-1-adamantyl) amino] propanoyl] -3-azabicyclo [2.2.1] heptene-2-carbonitrile (12a), or

R ¹ = H, R ² = H, R ³ = hydroxyadamantyl-exo-3- [3 - [(3-hydroxy-1-adamantyl) amino] propanoyl] -3-azabicyclo [2.2.1] heptene-2-carbonitrile (12b), or

R ¹ = H, R ² = H, R ³ = hydroxyadamantyl-endo-3- [3 - [(3-hydroxy-1-adamantyl) amino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (13a), or

R ¹ = H, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl endo-3- [3 - [(3-hydroxy-1-adamantyl) amino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (13b), or

R ¹ = methyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl-exo-3- [3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] propanoyl] -3-azabicyclo [2.2 .1] heptane-2-carbonitrile (20a), or

R ¹ = methyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl-exo-3 - [(3R) -3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] butanoyl] -3 -azabicyclo [2.2.1] heptane-2-carbonitrile (20b), or

R ¹ = methyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl-exo-3 - [(3S) -3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] butanoyl] -3 -azabicyclo [2.2.1] heptane-2-carbonitrile (20c), or

R ¹ = methyl, R ² = methyl, R ³ = 4-fluoro-3-hydroxybenzyl-exo-3- [3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] -3-methyl-butanoyl] - 3-azabicyclo [2.2.1] heptane-2-carbonitrile (20g), or

R ¹ = isopropyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl-exo-3 - [(3S) -3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] -4-methyl -pentanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20e), or

R ¹ = isopropyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl-exo-3 - [(3R) -3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] -4-methyl -pentanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20e), or

R ¹ = H, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl-endo-3- [3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] propanoyl] -3-azabicyclo [2.2 .1] heptane-2-carbonitrile (20g), or

R ¹ = methyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl-endo-3 - [(3R) -3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] butanoyl] -3 -azabicyclo [2.2.1] heptane-2-carbonitrile (20h), or

R ¹ = methyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl

endo-3 - [(3S) -3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20i), or

R ¹ = methyl, R ² = methyl, R ³ = 4-fluoro-3-hydroxybenzyl-endo-3- [3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] -3-methyl-butanoyl] - 3-azabicyclo [2.2.1] heptane-2-carbonitrile (20k), or

R ¹ = methyl, R ² = H, R ³ = 4-fluorobenzyl-exo-3 - [(3R) -3 - [(4-fluorophenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2 -carbonitrile (20 L), or

R ¹ = methyl, R ² = H, R ³ = 4-fluorobenzyl-endo-3 - [(3R) -3 - [(4-fluorophenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2 -carbonitrile (20m), or

R ¹ = methyl, R ² = H, R ³ = 4-fluorobenzyl-endo-3 - [(3S) -3 - [(4-fluorophenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2 -carbonitrile (20n), or

R ¹ = methyl, R ² = H, R ³ = 4-fluorobenzyl-exo-3 - [(3S) -3 - [(4-fluorophenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2 -carbonitrile (20 °), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H-exo-3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- azabicyclo [2.2.1] heptane-2-carbonitrile (17g), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H-endo-3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- azabicyclo [2.2.1] heptane-2-carbonitrile (18g), or

R ¹ = H, R ² = 4-fluorobenzyl, R ³ = H-exo-3 - [(3R) -3-amino-4- (4-fluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane- 2-carbonitrile (173), or

R ¹ = H, R ² = 4-fluorobenzyl, R ³ = H-endo-3 - [(3R) -3-amino-4- (4-fluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane- 2-carbonitrile (18h), or

R ¹ = H, R ² = 3,5-difluorobenzyl, R ³ = H,

exo-3 - [(3R) -3-amino-4- (3,5-difluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17i), or

R ¹ = H, R ² = 3,5-difluorobenzyl, R ³ = H-endo-3 - [(3R) -3-amino-4- (3,5-difluorophenyl) butanoyl] -3-azabicyclo [2.2. 1] heptane-2-carbonitrile (18i), or

R ¹ = H, R ² = H, R ³ = 2,4,5-trifluorobenzyl-exo 3- [3 - [(2,4,5-trifluorophenyl) methylamino] propanoyl] -3-azabicyclo [2.2.1 ] heptane-2-carbonitrile (17k), or

R ¹ = H, R ² = H, R ³ = 2,4,5-trifluorobenzyl-endo-3- [3 - [(2,4,5-trifluorophenyl) methylamino] propanoyl] -3-azabicyclo [2.2.1 ] heptane-2-carbonitrile (18k), or

enantiomerically pure compounds:

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H-exo (2S) -3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl ] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17g-1), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H-exo (2R) -3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl ] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17g-2), or

R ¹ = H, R ² = 4-fluorobenzyl, R ³ = H-exo (2S) -3 - [(3R) -3-amino-4- (4-fluorophenyl) butanoyl] -3-azabicyclo [2.2. 1] heptane-2-carbonitrile (17z-1), or

R ¹ = H, R ² = 3,5-difluorobenzyl, R ³ = H-exo (2S) -3 - [(3R) -3-amino-4- (3,5-difluorophenyl) butanoyl] -3- azabicyclo [2.2.1] heptane-2-carbonitrile (17i-1), or

R ¹ = H, R ² = H, R ³ = 2,4,5-trifluorobenzyl

exo (2S) -3- [3 - [(2,4,5-trifluorophenyl) methylamino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17k-1).

Compounds of the general formula (II) are also created - beta-amino acid amides of 3- (3-azabicyclo [2.2.1] heptan-2-yl) -1,2,4-oxadiazole, or their pharmaceutically acceptable salts.

Where:

R ¹ = H is hydrogen; C _1-5 is alkyl in which each carbon may independently have one or two substituents; aryl, in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, C1, Br,);

R ² = H is hydrogen; C _1-5 is alkyl in which each carbon may independently have one or two substituents; adamantyl, in which each carbon together or independently may have a substituent selected from: hydroxy (OH-), halogen (F, O, Br,); phenyl- (C ₆ H ₅ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, C1, Br,); benzyl- (C ₆ H ₅ -CH ₂ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,);

R ³ = H is hydrogen, C _1-5 is alkyl, in which each carbon independently may have one or two substituents; benzyl- (C ₆ H ₅ -CH ₂ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,);

R ⁴ = H is hydrogen, C _1-5 is alkyl, cyclopropyl, isopropyl in which each carbon may independently have one or two substituents; benzyl- (C ₆ H ₅ -CH ₂ -), in which each carbon of the aromatic ring can have a substituent together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,), hetaryl (C ₅ H ₄ N-CH ₂ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,) (option 2).

At the same time, compounds were synthesized where:

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ -phenyl-exo (3R) -3-amino-1 - [(2S (R)) - 2- (5 -phenyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26a) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = trifluoromethyl-exo (3R) -3-amino-1 - [(2S (R)) - 2- [5 - (trifluoromethyl) -1,2,4-oxadiazol-3-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one ( 26b), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = cyclopropyl-exo (3R) -3-amino-1 - [(2S (R)) - 2- (5 -cyclopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26c) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = fluoropropyl-exo (3R) -3-amino-1 - [(2S (R)) - 2- [5 - (1-fluoro-1-methyl-ethyl) -1,2,4-oxadiazol-3-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5- trifluorophenyl) butan-1-one (26g), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = isopropyl-exo (3R) -3-amino-1 - [(2S (R)) - 2- (5 -isopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26e) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = phenyl-endo (3R) -3-amino-1 - [(2S (R)) - 2- (5 -phenyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27a) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = trifluoromethyl-endo (3R) -3-amino-1 - [(2S (R)) - 2- [5 - (trifluoromethyl) -1,2,4-oxadiazol-3-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one ( 27b), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = cyclopropyl-endo (3R) -3-amino-1 - [(2S (R)) - 2- (5 -cyclopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27c) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = 2-fluoropropyl-endo (3R) -3-amino-1 - [(2S (R)) - 2- [5- (1-fluoro-1-methyl-ethyl) -1,2,4-oxadiazol-3-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4, 5-trifluorophenyl) butan-1-one (27g), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = isopropyl-endo (3R) -3-amino-1 - [(2S (R)) - 2- (5 -isopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27e) , or

enantiomerically pure compounds, where:

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = phenyl-exo (3R) -3-amino-1 - [(2S) -2- (5-phenyl- 1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26a-1), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = cyclopropyl-exo (3R) -3-amino-1 - [(2S) -2- (5-cyclopropyl- 1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26c-1), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = 2-fluoropropyl-exo (3R) -3-amino-1 - [(2S) -2- [5- (1-fluoro-1-methyl-ethyl) -1,2,4-oxadiazol-3-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl ) butan-1-one (27g-1), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = 2-fluoropropyl-exo (3R) -3-amino-1 - [(2S) -2- (5- isopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27g-1 ), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = isopropyl-endo (3R) -3-amino-1 - [(2S) -2- (5-isopropyl- 1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27d-1).

Compounds of the general formula (III), beta-amino acid amides of 5- (3-azabicyclo [2.2.1] heptan-2-yl) -1,2,4-oxadiazole or their pharmaceutically acceptable salts, have also been created.

Where:

R ¹ = H is hydrogen; C _1-5 is alkyl in which each carbon may independently have one or two substituents; aryl, in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,);

R ² = H is hydrogen; C _1-5 is alkyl in which each carbon may independently have one or two substituents; adamantyl, in which each carbon together or independently may have a substituent selected from: hydroxy (OH-), halogen (F, Cl, Br,); phenyl- (C ₆ H ₅ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,); benzyl- (C ₆ H ₅ -CH ₂ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,);

R ³ = H is hydrogen, C _1-5 is alkyl, in which each carbon independently may have one or two substituents; benzyl- (C ₆ H ₅ -CH ₂ -), in which each carbon of the aromatic ring may have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,);

R ⁴ = H is hydrogen, C _1-5 is alkyl, cyclopropyl, isopropyl in which each carbon may independently have one or two substituents; benzyl- (C ₆ H ₅ -CH ₂ -), in which each carbon of the aromatic ring can have a substituent together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,), hetaryl (C ₅ H ₄ N-CH ₂ -), in which each carbon of the aromatic ring can have a substituent, together or independently, selected from: hydroxy- (OH-), halogen (F, Cl, Br,) (option 3).

At the same time, compounds were synthesized where:

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = phenyl-exo (3R) -3-amino-1 - [(2S (R)) - 2- (3 -phenyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36a) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = 3,5-difluoro-2-pyridyl-exo (3R) -3-amino-1 - [(2S ( R)) - 2- [3- (3,5-difluoro-2-pyridyl) -1,2,4-oxadiazol-5-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4 - (2,4,5-trifluorophenyl) butan-1-one (36b), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = isopropyl-exo (3R) -3-amino-1 - [(2S (R)) - 2- (3 -isopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36c) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = 3,5-cyclopropyl-exo (3R) -3-amino-1 - [(2S (R)) - 2- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1- he (36g), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = phenyl-endo (3R) -3-amino-1 - [(2S (R)) - 2- (3 -phenyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (37a) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = 3,5-difluoro-2-pyridyl

endo (3R) -3-amino-1 - [(2S (R)) - 2- [3- (3,5-difluoro-2-pyridyl) -1,2,4-oxadiazol-5-yl] - 3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (37b), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = isopropyl-endo (3R) -3-amino-1 - [(2S (R)) - 2- (3 -isopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (37c) , or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = cyclopropyl-endo (3R) -3-amino-1 - [(2S (R)) - 2- (3 -cyclopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (37 g) , or

enantiomerically pure compounds, where:

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = phenyl-exo (3R) -3-amino-1 - [(2S) -2- (3-phenyl- 1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36a-1), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = phenyl-exo (3R) -3-amino-1 - [(2R) -2- (3-phenyl- 1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36a-2), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = 3,5-difluoro-2-pyridyl-exo (3R) -3-amino-1 - [(2S) -2- [3- (3,5-difluoro-2-pyridyl) -1,2,4-oxadiazol-5-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2 , 4,5-trifluorophenyl) butan-1-one (36b-1), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = isopropyl-exo (3R) -3-amino-1 - [(2S) -2- (3-isopropyl- 1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36B-1), or

R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H, R ⁴ = 3,5-cyclopropyl-exo (3R) -3-amino-1 - [(2S) -2- ( 3-cyclopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36 g -1).

Compounds selected from pharmaceutically acceptable salts of the compounds of the foregoing are also provided.

Moreover, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus or metabolic syndrome is selected from compounds of the general formula I, or II, or III, or from their pharmaceutically acceptable salts.

The implementation of the invention

It is known that in patients with type 2 diabetes, not only the quantitative content of incretins (GLP-1 and HIP) is violated, but also the mechanism of their action, therefore, the need to create a group of drugs that affect the level of incretins is obvious. The presence of such drugs improves glycemic control by affecting other pathogenetic links of this disease, unlike other existing groups of antidiabetic drugs.

The effect of dipeptidyl peptidase-4. The decrease in the effect of incretins in the bloodstream is a consequence of their rapid destruction and excretion from the body. The reason for the degradation of incretins and the loss of their function lies in their structure - the presence of an alanine (Ala) residue in the 2nd position from the N-terminus. Similar amino acid sequences are substrates for the serine protease - dipeptidyl peptidase-4 (DPP-4).

The incretins GLP-1 and HIP are peptide hormones, the mature forms of which are the result of the cleavage of precursors in K- and L-cells of the small intestine. HIP consists of 42 amino acids and is formed as a result of post-translational modification of pro-HIP by the PC1 / 3 prohormone protease in enteroendocrine K cells. The form of GUI is the only known active form of GUI in humans, rats, mice, pigs and cattle. GLP-1 is the result of post-translational cleavage by the prohormone protease PC1 / 3 of the proglucagon gene product in enteroendocrine L cells. GLP-1 is the main form of biologically active circulating GLP-1 in the human body. As a result of proteolytic treatment of GLP-1 and HIP in the 2nd N-terminal position of their sequences, an alanine residue appears. The resulting structures are substrates for dipeptidyl peptidase-4, which cleaves N-terminal dipeptides from the polypeptide chain containing Pro or Ala residues in the 2nd from the N-terminal position.

Another evidence of the role of dipeptidyl peptidase-4 in the pathogenesis of type 2 diabetes is the effect of the function of genes that regulate the expression of the DPP-4 gene. The genes that reduce the expression of this gene are the hepatic nuclear transcription factors 1-α and 1-β members of the family of homeodomain proteins. The presence of mutations that reduce the function of any of these genes and, accordingly, increase the level of expression of DPP-4, leads to the development of diabetes mellitus.

Understanding the role of DPP-4 in the metabolism of incretins has given rise to the creation of drugs that increase the duration of the action of endogenous HIP and GLP-1 - DPP-4 inhibitors. The results of experiments on animal models have demonstrated the maintenance of the incretin concentration in the blood under the influence of DPP-4 inhibitors.

DPP-4 inhibitors have another advantage over currently used hypoglycemic drugs. Since incretin-mediated effects on the biosynthesis and release of insulin are glucose-dependent, with the use of DPP-4 inhibitors the risk of hypoglycemia is significantly lower than with insulin, sulfonylurea or meglitinides. In addition, unlike these drugs, DPP-4 inhibitors do not cause an increase in body weight. Due to the peculiarities of their action, DPP-4 inhibitors are of particular interest in their use in the early stages of type 2 diabetes, both as monotherapy and in combination with other drugs, since they can contribute to the protection of β-cells.

The exopeptidase catalytic activity of dipeptidyl peptidase-4, which cleaves certain N-terminal dipeptides containing Pro or Ala residues from the polypeptide chain in the 2nd and N-terminal positions, is determined by the structure of its active center.

GLP-1 and ISU provide from 60 to 70% of the total 1, 3 insulin response after a meal (incretin effect) in healthy people. In clinical studies of patients with type 2 diabetes mellitus, the effect of incretin was present, but was significantly reduced compared with healthy people. In such patients, after oral administration of glucose, the insulin response was not only delayed in time, but also decreased.

Medicines that inhibit the catalytic activity of DPP-4 (DPP-4 inhibitors) and interact with its active center must meet the following criteria:

- the substructures formed by the Ser630 residue in the catalytic center of the enzyme and neighboring amino acids, as a rule, bind hydrophobic ring groups, such as the tri-fluorobenzyl group of sitagliptin or benzonitrile alogliptin;

- obligatory stabilization of two acid residues - Glu205 and Glu206 - in the binding site of DPP-4 by the amino group of the inhibitor;

- in addition to these mandatory interactions, potential inhibitors may contain various functional groups in order to enhance binding to DPP-4.

According to the above criteria, effective compounds of DPP-4 can be compounds, N-acylated alpha-amino acids derivatives of cyanopyrrolidine. However, this group of substances in aqueous solutions at pH 7.4 is capable of intramolecular cyclization. This phenomenon leads in vivo to the functional inactivation of drugs - N-acylated alpha-amino acids of cyanopyrrolidine derivatives. The cyclization process of such cyanopyrrolidines is reflected below.

Most of the described drugs of the cyanopyrrolidine class are highly effective due to the covalent binding of the cyano fragment to the Ser630 hydroxy group to form the corresponding imidate. However, the presence of an α-amino acid fragment in the inhibitor molecule creates the likelihood of intramolecular cyclization to produce the corresponding diketopiperazine and, as a result, a loss of activity.

The following is the intramolecular cyclization from the cis form of N-acylcyanopyrrolidine.

The process of intramolecular cyclization of N-acylcyanopyrrolidine under physiological conditions suggests that in order to preserve the chemical structure of a potential drug, it is necessary to prevent this property of similar derivatives of cyanopyrrolidine. For example, to include spatially bulky groups in the acyl part of cyanopyrrolidine that impede rapid cyclization or to combine the presence of bulky groups with an increase in the aliphatic chain linking cyanopyrrolidine with the amino function involved in binding in the ligand binding domain so that cyclization is thermodynamically difficult.

The structures of candidate compounds were selected, first of all, for steric correspondence of structures providing interactions with the dipeptyl peptidase-4 molecule, with the assumption of two key assumptions: (i) in the presence of a cyano group, covalent binding to Ser630 is expected and (ii) oxygen at double ligand bonds must form hydrogen bonds with protein atoms in the immediate vicinity of the ligand binding domain.

The key solution was the possibility of the formation of a covalent bond between carbon with a triple bond per nitrogen atom and oxygen Ser630 (as occurs when binding of vildagliptin, as well as the spatial arrangement of the N- (C = O) -C ligand group with carbonyl oxygen involved into hydrogen bonds upon binding to DPP-4. For all the proposed ligands, the geometry of the sequence of bonds (C≡N) -CN- (C = O) -C corresponds to this sequence in the vildagliptin molecule.

The present invention is the development of a number of beta-amino acid amide dipeptidyl peptidase-4 inhibitors, N-acyl derivatives of 3-azabicyclo [2.2.1] heptene-2-carbonitrile (I), 5- (3-azabicyclo [2.2.1] heptane -2-yl) -1,2,4-oxadiazole (II) and 3- (3-azabicyclo [2.2.1] heptan-2-yl) -1,2,4-oxadiazole (III), combined by the general formulas:

Example 1

The synthesis of the key starting reagents of exo- and endo-2-aza-bicyclo [2.2.1] heptane-3-carbonitriles 7a, b was carried out according to the developed synthetic scheme below. Exo and endo-3-azabicyclo [2.2.1] heptane-2-carbonitriles 7a, b were obtained as racemic mixtures.

The procedure for the synthesis of 2-aza-bicyclo [2.2.1] heptane-3-carbonitrile 7a, b.

Exo / endo-ethyl-2-azabicyclo [2.2.1] hept-5-en-3-carboxylate (1a, b).

To a mixture of a saturated solution of ammonium chloride (39.3 g) and a toluene solution of ethyl glyoxylate (50%, 150 g) at a temperature of 19-20 ° C, freshly distilled cyclopentadiene 64.7 g was added portionwise. The reaction mixture was stirred for 12 hours at room temperature, then subjected to extraction with MTBE mixture: PE 1: 3, alkalized to pH 8-9 with NaOH solution (50%), extracted with MTBE, dried over anhydrous. Na ₂ SO ₄ . After distillation of the solvent, 67 g (53%) of the product, mixture 1a, b, were obtained as a yellow thick oil.

(R / S) -Exo-2-tert-butyl-3-ethyl-2-azabicyclo [2.2.1] hept-5-en-2,3-dicarboxylate (2a) and

(R / S) -endo-2-tert-butyl-3-ethyl-2-azabicyclo [2.2.1] hept-5-en-2,3-dicarboxylate (2b).

To a solution of ethyl 2-azabicyclo [2.2.1] hept-5-en-3-carboxylate 1a, b (38 g) in THF (200 ml) under ice-cooling was added dropwise a solution of BOC anhydride (55 g) in THF ( 200 ml). The reaction mixture was left overnight with stirring (room temperature), then the residue was evaporated, the residue was dissolved in a mixture of PE: EtOAc 1: 1 and washed with water. The organic layer was dried over sodium sulfate and the exo and endo isomers were separated on a column. Eluent - PE → PE: EtOAc 30%. After separation of 20 g of pure endo-isomer 2b and 65g of a mixture of exo and endo, the latter was further separated and 17 g of exo-isomer 2a were isolated. The total yield of the mixture of isomers is 77%.

(R / S) -Exo-2-tert-butyl-3-ethyl-2-azabicyclo [2.2.1] heptane-2,3-dicarboxylate (3a)

17 g of the starting carboxylate 2a were hydrogenated for 1.5 h at 55-60 ° C and a pressure of 45 PSI in ethanol in the presence of 0.8 g of 10% Pd / C. The resulting reaction mixture was filtered through celite to separate 10% Pd / C, and the solvent was evaporated under reduced pressure on a rotary solvent. Received 3A (14.8 g, 86%) as a yellow oil.

(R / S) -endo-2-tert-butyl-3-ethyl-2-azabicyclo [2.2.1] heptane-2,3-dicarboxylate (3b)

Hydrogenated 26 g of the original carboxylate 2b at a temperature of 55-60 ° C for 1.5 hours in a solution of ethyl acetate and a pressure of 45-50 PSI, 0.5 g of Pd / C. The resulting reaction mixture was filtered through celite to separate 10% Pd / C, and the solvent was evaporated under reduced pressure on a rotary solvent. Received 3b (23 g, 87%) as a yellow oil.

(R / S) -Exo-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane-3-carboxylic acid (4a)

The methanol-water emulsion of starting ester 3a (14.8 g) was mixed with lithium alkali (monohydrate, 6.58 g). Stirred overnight at room temperature, TLC reaction was not complete. A further 1.5 equivalents of lithium alkali was added and the reaction was heated for 2 hours at 40-50 ° C. Then methanol was distilled off, the reaction mixture was diluted with water, extracted with ethyl acetate, then the aqueous layer was acidified with citric acid to pH = 4, and extracted with methylene chloride. After drying with sodium sulfate and removing the solvent, 11.9 g (89%) of the desired acid 4a were obtained.

(R / S) -endo-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane-3-carboxylic acid (4b)

The water-methanol emulsion of Boc-amino ester 3b (15.7 g) was mixed with lithium alkali (7 g) at the boil for 3 hours. Processed similarly to exo-isomer 4a. Received 12.6 g of endo acid 4b (89%).

(R / S) -Exo-tert-butyl-3-carbamoyl-2-azabicyclo [2.2.1] heptane-2-carboxylate (5a)

Triethylamine (6.54 ml, 4.75 g) was added to a solution of the starting acid 4a (10.3 g) in dry THF upon cooling to -20 ° C in an argon atmosphere. Ethyl chloroformate (5.10 g) was then added dropwise over 10 minutes. The reaction mixture was kept under cooling for 40 minutes and aqueous ammonia (8.36 g) was added dropwise under cooling. After 1 h, THF was evaporated, the residue was treated with a solution of citric acid to pH = 4, extracted with ethyl acetate, the ethyl acetate extracts were washed with a solution of soda and dried with sodium sulfate and concentrated. Received 10 g of a colorless crystalline residue 5A. The output is quantitative.

(R / S) -endo-tert-butyl-3-carbamoyl-2-azabicyclo [2.2.1] heptane-2-carboxylate (5b)

TEA (8 ml) was added to a solution of the initial endo acid 4b (12.3 g) in dry THF upon cooling to -20 ° C and ethyl chloroformate (6.1 g) was added dropwise. After cooling for an hour, it was treated with aqueous ammonia (10 g). The reaction was carried out and treated analogously to exo-isomer 5a. Received 11.8 g of a colorless crystalline substance 5b. The output is quantitative.

(R / S) -Exo-tert-butyl-3-cyano-2-azabicyclo [2.2.1] heptane-2-carboxylate (6a)

To a suspension of the starting amide 5a (10.3 g) in dry THF, at a temperature not exceeding 4 ° C, trifluoroacetic acid anhydride (14.4 g) was added over 10 minutes. The original was present by TLC, another 9 g of trifluoroacetic anhydride was added. The reaction mixture was kept under cooling for 3 hours, then ammonium hydrogen carbonate (45 g) was added portionwise to the reaction mixture under cooling. The reaction mixture was applied to silica gel and separated on a chromatographic column. The eluent is a mixture of PE: EtOAc 4: 1. Received 8.3 g (87%) of the target nitrile 6A in the form of a pale yellow thick oily substance.

(R / S) -endo-tert-butyl-3-cyano-2-azabicyclo [2.2.1] heptane-2-carboxylate (6b)

The reaction was carried out similarly to exo-isomer 6a. The starting amide 5b (11.8 g), trifluoroacetic anhydride (16.5 g + 10.7 g), ammonium bicarbonate 51 g. After purification on a chromatographic column, 6 g (54%) of nitrile 6b in the form of a light yellow oil.

(R / S) -Exo-2-azabicyclo [2.2.1] heptane-3-carbonitrile (7a)

To the original BOC nitrile 6a (7 g) in 30 ml of acetonitrile was added 12 g (twofold excess) of p-toluenesulfonic acid (p-TSC) and allowed to stir overnight. Acetonitrile was distilled off, the residue was triturated with diethyl ether (3-4 decantation treatments). The ether was evaporated, the residue was dissolved in methylene chloride and saturated with ammonia from a balloon. The precipitated ammonium salt of p-TSC was filtered. The filtrate was evaporated and the residue was chromatographed. The eluent was methylene chloride after extraction of aqueous ammonia in a ratio of 1:10 (100 ml of DCM was extracted with 10 ml of aqueous ammonia). The desired product 7a (4.2 g) was obtained after the column as a yellowish oil.

(R / S) -endo-2-azabicyclo [2.2.1] heptane-3-carbonitrile (7b)

Received similarly to the exo-isomer 7a from BOC-nitrile 6b (6 g), p-TSC (10.3 g). After chromatography, 3.4 g of the desired amine (7b) was obtained as a yellowish oil.

For the synthesis of the target compounds, β-amino acids 11a, b, modified at the amino group, were previously synthesized.

Examples:

Synthesis of 3- (3-hydroxy-adamantan-1-ylamino) -propionic acids.

The procedure for the synthesis of 3- (3-hydroxy-adamantan-1-ylamino) -propionic acid 11a.

57 g (0.5 mol) of ethyl acrylate in 100 ml of dioxane was added to 3-amino-adamantane -1-ol 8a in the form of a free base of 16.7 g (0.1 mol). The mixture was heated at 50 ° C for 24 hours. At the end of heating, the mixture was evaporated to dryness, dioxane was again added in a volume of 100 ml, and the mixture was again evaporated to dryness in vacuo on a rotary evaporator. The resulting residue was dissolved in a 1: 1 water / methanol mixture (150 ml). Sodium hydroxide 6 g (0.15 mol) was added to the solution, and the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated to a volume of 75 ml and neutralized with a titrated solution containing 0.15 mol of HCl in water. Yield of 3- (3-hydroxy-adamantan-1-ylamino) -propionic acid 11a 16.1 g (67%).

The synthesis of acid 11b (10 g, 55%) was carried out from 8b similarly to the procedure described for 11a.

The synthesis of the target compounds 12a, b and 13a, b was carried out from racemic exo and endo isomers of 3-azabicyclo [2.2.1] heptane-2-carbonitriles 7a and 7b, according to the scheme shown below.

The synthesis procedure of the target products. 12a, b and 13a, b.

To acid 11a 0.239 g (1 mmol) in 10 ml of dichloromethane was added BOP (0.534 g, 1.2 mmol) and racemic amine 7a (0.122 g, 1 mmol). The mixture was stirred at room temperature overnight. Washed with 10% potash solution, water, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The resulting residue was purified by 4: 1 ethyl acetate-hexane column chromatography. Yield 12a-0.123 g (36%).

Synthesis of 12b (0.085 g, 25%) was carried out from 11b and 7a similarly to the procedure given for 12a.

Synthesis of 13a (0.154 g, 45 %%) was carried out from 11a and 7b similarly to the procedure described for 12a.

Synthesis of 13b (0.188 g, 55%) was carried out from 11b and 7b similarly to the procedure given for 12a.

For simplicity of perception, hereinafter, in all cases of the use of racemic mixtures 7a and 7b, only one enantiomer of the initial reagent and one corresponding stereoisomeric product at each stage will be presented in the schemes.

The synthesis of the target compounds 20a-o was carried out from racemic exo- and endo-isomers of 3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a, b according to the scheme shown below.

The synthesis of the target compounds 17.18g-k was carried out from the racemic exo- and endo-isomers of 3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a, b, according to the schemes depicted below.

The synthesis of the target compounds 26,27a-d and 36,37a-g was carried out from racemic mixtures of exo- and endo-isomers of 3-azabicyclo [2.2.1] heptane-2-carbonitriles 7a, b, according to the schemes shown below.

The synthesis procedure of the target products 17,18zh-k and 20a-o.

To acid 14a, 0.19 g (1 mmol) in DCM (20 ml) was added DIPEA (0.13 g, 1 mmol), BOP (0.44 g, 1 mmol) and racemic amine 7a (0.12 g, 1 mmol). The mixture was stirred at room temperature overnight. Washed with 5% aqueous citric acid solution (3 × 10 ml) and 10% aqueous NaHCO ₃ solution (3 × 10 ml). The organic layer was dried over anhydrous. Na ₂ SO ₄ . The solvent was evaporated to dryness on a rotary evaporator. The residue was dissolved in CHCl ₃ and purified by column chromatography on silica gel (eluent 1-5% MeOH / CHCl ₃ ). Yield 15- 0.21 g (65%).

Synthesis of 15b (0.18 g, 60%) was carried out from 14b and 7a similarly to the procedure given for 15a.

The synthesis of 15c (0.19 g, 62%) was carried out from 14c and 7a similarly to the procedure given for 15a.

The synthesis of 15 g (0.22 g, 70%) was carried out from 14 g and 7a similarly to the procedure described for 15a.

Synthesis of 15e (0.19 g, 58%) was carried out from 14e and 7a, similarly to the procedure described for 15a.

The synthesis of 15e (0.18 g, 55%) was carried out from 14e and 7a similarly to the procedure described for 15a.

Synthesis of 15g (0.30 g, 70%) was carried out from 14g and 7a similarly to the procedure described for 15a.

Synthesis of 15c (0.30 g, 75%) was carried out from 14c and 7a similarly to the procedure given for 15a.

The synthesis of 15i (0.28 g, 68%) was carried out from 14i and 7a similarly to the procedure described for 15a.

The synthesis of 15k (0.34 g, 80%) was carried out from 14i and 7a similarly to the procedure described for 15a.

Synthesis of 16a (0.17 g, 57%) was carried out from 14a and 7b similarly to the procedure given for 15a.

Synthesis of 16b (0.17 g, 48%) was carried out from 14b and 7b similarly to the procedure given for 15a.

Synthesis of 16c (0.18 g, 59%) was carried out from 14c and 7b similarly to the procedure given for 15a.

Synthesis of 16 g (0.19 g, 60%) was carried out from 14 g and 7b in the same manner as in 15a.

Synthesis of 16e (0.19 g, 57%) was carried out from 14e and 7b similarly to the procedure described for 15a.

Synthesis of 16e (0.18 g, 55%) was carried out from 14e and 7b similarly to the procedure described for 15a.

Synthesis of 16g (0.26 g, 60%) was carried out from 14g and 7b similarly to the procedure described for 15a.

The synthesis of 16s (0.25 g, 62%) was carried out from 14s and 7b similarly to the procedure described for 15a.

Synthesis of 16i (0.24 g, 60%) was carried out from 14i and 7b similarly to the procedure described for 15a.

The synthesis of 16k (0.32 g, 75%) was carried out from 14k and 7b similarly to the procedure described for 15a.

Method A.

Compound 15a (0.21 g, 0.65 mmol) was dissolved in DCM (20 ml) and TFA (0.5 ml) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness on a rotary evaporator. Et ₂ O (20 ml) was added to the residue. The precipitate was filtered off and dried in vacuo. Yield 17a as a TFA salt — 0.18 g (90%).

Synthesis of 17b (0.16 g, 85%) was carried out from 156 similarly to the procedure given for 17a.

Synthesis of 17c (0.18 g, 90%) was carried out from 15c in the same manner as in 17a.

Synthesis of 17 g (0.18 g, 80%) was carried out from 15 g similarly to the procedure described for 17a.

Synthesis of 17e (0.18 g, 90%) was carried out from 15e by analogy with the procedure described for 17a.

The synthesis of 17e (0.18 g, 91%) was carried out from 15e similarly to the procedure described for 17a.

Synthesis of 18a (0.16 g, 84%) was carried out from 16a similarly to the procedure given for 17a.

Synthesis of 18b (0.15 g, 81%) was carried out from 16b similarly to the procedure given for 17a.

Synthesis of 18c (0.18 g, 90%) was carried out from 16c in the same manner as in 17a.

Synthesis of 18 g (0.18 g, 80%) was carried out from 16 g similarly to the procedure described for 17a.

Synthesis of 18e (0.18 g, 90%) was carried out from 16e in the same manner as in 17a.

The synthesis of 18e (0.18 g, 91%) was carried out from 16e similarly to the procedure described for 17a.

Method B.

Compound 15g (0.30 g, 0.69 mmol) was dissolved in acetonitrile (20 ml) and para-toluenesulfonic acid (2 equiv.) Was added. The mixture was stirred at room temperature overnight. The precipitate was filtered off, washed with Et ₂ O and dried in vacuo. Yield 17g in the form of p-TSC salt - 0.30 g (85%).

Synthesis of 17c (0.23 g, 65%) was carried out from 15c in the same manner as in 17a.

The synthesis of 17i (0.22 g, 67%) was carried out from 15i and similarly to the procedure described for 17a.

The synthesis of 17k (0.21 g, 53%) was carried out from 15k similarly to the procedure described for 17a.

Synthesis of 18g (0.25 g, 82%) was carried out from 16g similarly to the procedure described for 17a.

Synthesis of 18c (0.22 g, 74%) was carried out from 16c in the same manner as in 17a.

Synthesis of 18i (0.19 g, 67%) was carried out from 16i and similarly to the procedure described for 17a.

Synthesis of 18k (0.24 g, 64%) was carried out from 16k similarly to the procedure described for 17a.

To a solution of 17a 0.18 g (0.58 mmol) in DCM (20 ml) was added aldehyde 19a (2 eq.) And STAB (5 eq.). The mixture was stirred at room temperature overnight, evaporated on a rotary evaporator to ~ 3-4 ml of volume and applied to a column of silica gel. Purification was carried out by column chromatography (eluent 10-50% MeOH / CHCl ₃ ). Yield 20a - 0.06 g (30%).

Synthesis of 20b (0.056 g, 30%) was carried out from 17b and 19a similarly to the procedure given for 20a.

Synthesis of 20b (0.05 g, 29%) was carried out from 17b and 19a similarly to the procedure given for 20a.

The synthesis of 20c (0.06 g, 31%) was carried out from 17c and 19a similarly to the procedure given for 20a.

The synthesis of 20 g (0.05 g, 28%) was carried out from 17 g and 19a similarly to the procedure described for 20a.

The synthesis of 20e (0.05 g, 25%) was carried out from 17e and 19a similarly to the procedure given for 20a.

The synthesis of 20e (0.06 g, 31%) was carried out from 17e and 19a similarly to the procedure described for 20a.

Synthesis of 20g (0.06 g, 29%) was carried out from 18a and 19a similarly to the procedure given for 20a.

Synthesis of 203 (0.05 g, 25%) was carried out from 18b and 19a similarly to the procedure given for 20a.

The synthesis of 20i (0.06 g, 30%) was carried out from 18c and 19a similarly to the procedure given for 20a.

The synthesis of 20k (0.06 g, 31%) was carried out from 18g and 19a similarly to the procedure given for 20a.

The synthesis of 20 l (0.06 g, 30%) was carried out from 17b and 19b similarly to the procedure described for 20a.

The synthesis of 20 m (0.05 g, 26%) was carried out from 18b and 19b similarly to the procedure given for 20a.

The synthesis of 20n (0.06 g, 31%) was carried out from 18c and 19b similarly to the procedure described for 20a.

The synthesis of 20 ° (0.06 g, 31%) was carried out from 17c and 19b similarly to the procedure given for 20a.

The synthesis procedure of the target products 26-27a-d.

To nitrile 15g (0.43 g, 1 mmol) in EtOH (20 ml) was added NH ₂ OH × HCl (0.5 g, 7 mmol) and K ₂ CO ₃ (0.7 g, 5 mmol). The mixture was stirred at a temperature of 65-70 ° C overnight. Cooled to room temperature. DCM (50 ml) was added. The precipitate was filtered off. The mother liquor was evaporated to dryness on a rotary evaporator. The residue (21) was used further without purification.

DIC (0.26 g, 2.5 equiv) was added to acid 23a (0.13 g, 1.1 mmol) in DCM (20 ml). The mixture was stirred at room temperature for 1 hour. Compound 21 was added. Stirring was continued for another 1 hour. The solvent was evaporated on a rotary evaporator. Pyridine (25 ml) was added to the residue. The mixture was stirred at 110 ° C. overnight. Cooled to room temperature. The solvent was evaporated to dryness on a rotary evaporator. DCM (30 ml) was added to the residue. Washed with 5% aqueous citric acid solution (3 × 10 ml) and 10% aqueous NaHCO ₃ solution (3 × 10 ml). The organic layer was dried over anhydrous. Na ₂ SO ₄ . The solvent was evaporated on a rotary evaporator. The residue was dissolved in DCM and purified by column chromatography on silica gel (eluent 0-20% Et ₂ O / DCM). Yield 24a - 0.2 g (37% at 3 stages).

Synthesis of 24b (0.11 g, 20%) was carried out from 15g and 23b similarly to the procedure given for 24a.

Synthesis of 24c (0.21 g, 40%) was carried out from 15g and 23b similarly to the procedure given for 24a.

Synthesis of 24 g (0.15 g, 27%) was carried out from 15 g and 23 g similarly to the procedure described for 24a.

The synthesis of 24d (0.16 g, 30%) was carried out from 15g and 23d similarly to the procedure given for 24a.

Synthesis of 25a (0.19 g, 35%) was carried out from 16g and 23a similarly to the procedure given for 24a.

Synthesis of 25b (0.10 g, 18%) was carried out from 16g and 23b similarly to the procedure given for 24a.

Synthesis of 25c (0.19 g, 36%) was carried out from 16g and 23b in the same manner as in 24a.

Synthesis of 25 g (0.13 g, 23%) was carried out from 16g and 23g similarly to the procedure given for 24a.

The synthesis of 25d (0.14 g, 26%) was carried out from 15g and 23d similarly to the procedure given for 24a.

Method B.

To compound 24a (0.2 g, 0.36 mmol) was added 4M HCl in dioxane (15 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness on a rotary evaporator. Et ₂ O (20 ml) was added to the residue. The precipitate was filtered off and dried in vacuo. Yield 26a as an HCl salt — 0.16 g (93%).

Synthesis of 26b (0.09 g, 93%) was carried out from 24b similarly to the procedure given for 26a.

Synthesis of 26c (0.17 g, 92%) was carried out from 24c in the same manner as in 26a.

Synthesis of 26 g (0.12 g, 94%) was carried out from 24 g similarly to the procedure described for 26a.

Synthesis of 26d (0.12 g, 90%) was carried out from 24d similarly to the procedure described for 26a.

Synthesis of 27a (0.15 g, 91%) was carried out from 25a in the same manner as in 26a.

Synthesis of 27b (0.08 g, 93%) was carried out from 25b similarly to the procedure given for 26a.

Synthesis of 27c (0.15 g, 90%) was carried out from 25c in the same manner as in 26a.

Synthesis of 27 g (0.10 g, 91%) was carried out from 25 g similarly to the procedure described for 26a.

Synthesis of 27e (0.11 g, 93%) was carried out from 25e similarly to the procedure described for 26a.

The synthesis procedure of the target products 36-37a-d.

To nitrile 28a (0.5 g, 5 mmol) in EtOH (20 ml) was added NH ₂ OH × HCl (1.38 g, 20 mmol) and K ₂ CO ₃ (2.05 g, 15 mmol). The mixture was stirred at a temperature of 65-70 ° C overnight. Cooled to room temperature. DCM (50 ml) was added. The precipitate was filtered off. The mother liquor was evaporated to dryness on a rotary evaporator. The residue (29a) was used further without purification.

DIC (1.17 g, 2.5 equiv) was added to acid 4a (0.9 g, 4 mmol) in DCM (50 ml). The mixture was stirred at room temperature for 1 hour. Compound 29a was added. Stirring was continued for another 1 hour. The solvent was evaporated on a rotary evaporator. Pyridine (40 ml) was added to the residue. The mixture was stirred at 110 ° C. overnight. Cooled to room temperature. The solvent was evaporated to dryness on a rotary evaporator. DCM (30 ml) was added to the residue. Washed with 5% aqueous citric acid solution (3 × 10 ml) and 10% aqueous NaHCO ₃ solution (3 × 10 ml). The organic layer was dried over anhydrous. Na ₂ SO ₄ . The solvent was evaporated on a rotary evaporator. The residue was dissolved in CHCl ₃ and purified by column chromatography on silica gel (eluent — CHCl ₃ ). Yield 30a - 0.7 g (55% at 3 stages).

Synthesis of 30b (0.5 g, 35%) was carried out from 28b and 4a, similarly to the procedure described for 20a, with minor modifications. Acid activation and acylation of intermediate 29b were carried out in pyridine (40 ml). The mixture was stirred at room temperature for 2 hours. Then it was heated to a temperature of 110 ° C and stirring was continued overnight. Cooled to room temperature. The solvent was evaporated to dryness on a rotary evaporator. DCM (5 ml) was added to the residue. The residue was dissolved in CHCl ₃ and purified by column chromatography on silica gel (eluent — 0-5% EtOH / CHCl ₃ ).

Synthesis of 30c (0.7 g, 61%) was carried out from 28c and 4a in the same manner as in 30a.

Synthesis of 30 g (0.74 g, 66%) was carried out from 28 g and 4a in the same manner as in 30a.

Synthesis of 31a (0.6 g, 47%) was carried out from 28a and 4b similarly to the procedure described for 30a.

Synthesis of 31b (0.4 g, 28%) was carried out from 28b and 4b similarly to the procedure described for 30b.

Synthesis of 31c (0.6 g, 52%) was carried out from 28c and 4b similarly to the procedure described for 30a.

Synthesis of 31 g (0.65 g, 57%) was carried out from 28 g and 4 g similarly to the procedure described for 30a.

Synthesis of 32a (0.55 g, 96%) was carried out from 30a similarly to the procedure (Method B) described for 26a.

Synthesis of 32b (0.40 g, 86%) was carried out from 30b similarly to the procedure (Method B) described for 26a. The product was obtained as dihydrochloride (× 2HCl).

Synthesis of 32c (0.48 g, 86%) was carried out from 30c in the same manner as in Method B) for 26a.

Synthesis of 32 g (0.52 g, 89%) was carried out from 30 g similarly to the procedure (Method B) described for 26a.

Synthesis of 33a (0.41 g, 84%) was carried out from 31a by the same procedure as (Method B) described for 26a.

Synthesis of 33b (0.31 g, 83%) was carried out from 31b similarly to the procedure (Method B) described for 26a. The product was obtained as dihydrochloride (× 2HCl).

Synthesis of 33c (0.44 g, 92%) was carried out from 31c in the same manner as in Method B) for 26a.

Synthesis of 33 g (0.46 g, 89%) was carried out from 31 g similarly to the procedure described for 26a.

Synthesis of 34a (0.8 g, 73%) was carried out from 32a and 14g similarly to the procedure described for 15a. Purification by column chromatography was carried out in an eluent of 0-20% Et ₂ O / DCM.

Synthesis of 34b (0.40 g, 59%) was carried out from 32b and 14g similarly to the procedure described for 15a, excluding the washing of the reaction mixture with citric acid solution.

Synthesis of 34c (0.69 g, 67%) was carried out from 32c and 14g similarly to the procedure described for 15a. Purification by column chromatography was carried out in an eluent of 0-20% Et ₂ O / DCM.

Synthesis of 34 g (0.71 g, 63%) was carried out from 32 g and 14 g similarly to the procedure described for 15a. Purification by column chromatography was carried out in an eluent of 0-20% Et ₂ O / DCM.

Synthesis of 35a (0.51 g, 61%) was carried out from 33a and 14g similarly to the procedure described for 15a. Purification by column chromatography was carried out in an eluent of 0-20% Et ₂ O / DCM.

Synthesis of 35b (0.26 g, 50%) was carried out from 33b and 14g similarly to the procedure described for 15a, excluding the washing of the reaction mixture with a solution of citric acid.

Synthesis of 35c (0.51 g, 55%) was carried out from 33c and 14g similarly to the procedure described for 15a. Purification by column chromatography was carried out in an eluent of 0-20% Et ₂ O / DCM.

Synthesis of 35 g (0.57 g, 58%) was carried out from 33 g and 14 g similarly to the procedure described for 15a. Purification by column chromatography was carried out in an eluent of 0-20% Et ₂ O / DCM.

Table 1 presents the structures of the obtained compounds, their names, analytical characteristics and indicators of DPP-4 inhibitory activity (IC ₅₀ ) of the target products.

Analysis conditions: column - Onix C18 50 × 4.6 mm; eluent 1 - 0.1% TFA in water; eluent 2 - 0.1% TFA in acetonitrile, gradient - eluent 1 - 2.9 min, eluent 2 - 0.2 min, eluent 1 - washing, flow rate - 3.75 ml / min, detection - UV (254 nm) and mass spectrometry.

Methods have also been developed to produce the individual diastereomers of the target compounds.

Method D (crystallization).

Individual diastereomers 15zh-1 and 15zh-2 were obtained from the isomer mixture 15zh by sequential 5-fold crystallization from a mixture of DCM / Et ₂ O. Removal of the protective group (method B) in 15zh-1 and 15zh-2 led to the target diastereomerically pure products 17zh -1 and 17g-2 (structure in table 2).

Method D (column chromatography on silica gel).

The individual diastereomers 34a-1 and 34a-2 were obtained from the isomeric mixture 34a by column chromatography on silica gel in the eluent 1: 1-> 2: 1 Et ₂ O / n-hexane. Removal of the protective group (method B) in 34a-1 and 34a-2 led to the desired diastereomerically pure products 36a-1 and 36a-2 (structure in table 2).

Method E (stereospecific synthesis of enantiomerically pure exo-3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a-1.

The synthesis of enantiomerically pure (S) -exo-3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a-1 was carried out according to the scheme:

The synthesis procedure of (S) -exo-3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a-1.

Ethyl (2S, 3S) -3- (1-phenylethyl) -3-azabicyclo [2.2.1] hept-5-en-2-carboxylate (39)

A 50% solution of ethyl glyoxylate in toluene (19.6 ml, 0.096 mol), toluene (300 ml) and benzylamine 38 (10.3 ml, 0.08 mol) were placed in a 1-liter flask, stirred for 2 hours until water was separated, then the water was removed using sodium sulfate and the solvent was evaporated. The resulting residue was dissolved in dimethylformamide (100 ml), a solution of trifluoroacetic acid (6.12 ml, 0.08 mol) in dimethylformamide was added while cooling in an ice bath. The reaction mixture was stirred at room temperature for 1 hour. Then, while cooling in an ice bath, freshly distilled cyclopentadiene (10.6 g, 0.16 mol) was added in one portion. The reaction mixture was aged for 24 hours at room temperature.

After 24 hours, the reaction mixture was diluted with 400 ml of a 10% solution of potash while cooling in an ice bath, extracted with ethyl acetate 3 times in 100 ml, the organic layer was dried with sodium sulfate and evaporated at a bath temperature not exceeding 30 ° C. Column chromatography on silica gel in an ethyl acetate: petroleum firm 1:10 system gave 8.1 g (0.0299 mol) of the pure fraction of exo-isomer 39. Yield 37.3%.

(2S) -3-tert-butoxycarbonyl-3-azabicyclo [2.2.1] heptene-2-carboxylic acid ethyl ester (3a-1).

Exo-isomer 39 (8.1 g, 0.0299 mol) was dissolved in 200 ml of benzene, and tris (triphenylphosphine) rhodium chloride (0.405 g, 5% mass) was added. It was hydrogenated on a Parr apparatus at 20psi until hydrogen uptake ceased (about 4 hours). According to LCMS, the completeness of the hydrogenation was monitored. After the completion of the reaction, the solution was passed through a layer of silica gel, washing off the product with the ethyl acetate: petroleum ether 1: 4 system. The resulting solution was evaporated, 200 ml of ethanol, 5% Pd on charcoal (0.8 g) and Bock anhydride (6.9 g, 0.0316 mol) were added. It was then hydrogenated at 20psi on a Parr apparatus. The completeness of the reaction was monitored by LCMS. The resulting reaction mixture was used in the next step.

(2S) -3-tert-butoxycarbonyl-3-azabicyclo [2.2.1] heptene-2-carboxylic acid (4a-1)

The ethanol solution of Bock ester of exo-isomer 3a-1 from the previous stage, after completion of hydrogenation, was filtered off from the catalyst and 50 ml (0.075 mol) of an aqueous solution of sodium hydroxide was added to it. The resulting solution was heated for 1 hour at 60 ° C. After complete ether conversion (TLC control), ethanol was evaporated, the residue was dissolved in water, the solution was acidified with 2M hydrochloric acid to pH 3, the product was extracted with ethyl acetate, the organic extracts were washed with water, dried with sodium sulfate and evaporated. The product was recrystallized from hexane. 5.42 g (0.022 mol) of exo acid 4a-1 were obtained. The yield was 90%. Further, this product was used without further purification.

(2S) -Exo-tert-butyl-3-carbamoyl-2-azabicyclo [2.2.1] heptane-2-carboxylate (5a-1)

Triethylamine 3.45 ml (2.5 g) was added to a solution of the starting acid 4a-1 (5.42 g) in dry THF under cooling to -20 ° С in an argon atmosphere, then ethyl chloroformate (2.68 g, 0.0247 mol) was added dropwise over 10 min. The reaction mixture was kept under cooling for 40 minutes. Then ammonia was passed from the cylinder for 1 h. THF was evaporated, the residue was treated with a solution of citric acid to pH 4, extracted with ethyl acetate, the ethyl acetate extracts were washed with a solution of soda, dried with sodium sulfate and concentrated. Received 5.29 g of a colorless crystalline residue 5A-1. The output is quantitative.

(2S) -Exo-tert-butyl-3-cyano-2-azabicyclo [2.2.1] heptane-2-carboxylate (6a-1)

To a suspension of the starting amide 5a-1 (5.29 g) in dry THF, at a temperature not exceeding 4 ° С, 2 equivalents of triethylamine (6.13 ml, 4.45 g), trifluoroacetic anhydride (6.93 g, 0.033 mol) were added over 10 minutes, each TLC monitored the extent of the reaction. The reaction mixture was allowed to cool for 3 hours. The reaction mixture was evaporated, applied to silica gel and separated on a chromatographic column. The eluent is a mixture of petroleum ether: ethyl acetate 4: 1. Received 4.29 g (87%) of the target nitrile 6a-1 in the form of a pale yellow thick oily substance.

(2S) -Exo-2-azabicyclo [2.2.1] heptane-3-carbonitrile (7a-1)

To the initial BOC nitrile 6a-1 (4.29 g, 0.019 mol) in 30 ml of acetonitrile was added a twofold excess of n-tolylsulfonic acid (PTSK) (6.54 g, 0.038 mol) and allowed to mix overnight. Acetonitrile was distilled off, the residue was triturated with diethyl ether (3-4 decantation treatments). The ether was evaporated. Received 4.58 g of crystalline target substance 7a-1.

tert-butyl-N - [(1R) -3 - [(2S) -2-cyano-3-azabicyclo [2.2.1] heptan-3-yl] -3-oxo-1 - [(2,4,5 trifluorophenyl) methyl] propyl] carbamate (15g-1) (obtained from the enantiomerically pure (S) -exo isomer of 3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a-1, similar to 7a.

To a solution of acid 14g (5.19 g, 0.0156 mol) in 60 ml of dichloromethane were added BOP (8.27 g, 0.0187 mol) and triethylamine (4.74 ml, 0.0468 mol, 3 equiv.). After 15 minutes, amine tosylate 7a-1 (4.57 g, 0.0156 mol) was added at room temperature. After 2 hours, LCMS showed complete conversion. Dichloromethane was evaporated, the residue was dissolved in ethyl acetate and washed with 10% potash solution, then with water, dried with sodium sulfate and evaporated. A small amount of petroleum ether was added to the residue, and the crystallized product was filtered. Received 5.08 g of crystals 15zh-1. Yield 75%

(2S) -3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptene-2-carbonitrile (17zh-1)

For debocking, the side derivative 15zh-1 (5.08 g) was suspended in 100 ml of acetonitrile and a twofold excess of toluenesulfonic acid hydrate (4.02 g, 0.0234 mol) was added. Stirred overnight at room temperature. The precipitate was filtered off and washed with a small amount of acetonitrile. Received 5.18 g of tosylate product 17zh-1. Yield 87%

The synthesis of the following diastereomerically (or enantiomerically) pure target compounds (structures in table 2) was carried out similarly to 17g-1:

17g-1, 17z-1, 17i-1 - from the enantiomerically pure (S) -exo isomer of 3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a-1.

17k-1 - from the enantiomerically pure (S) -exo isomer of 3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a-1.

17g-2 - from the enantiomerically pure (R) -exo isomer of 3-azabicyclo [2.2.1] heptane-2-carbonitrile 7a-2.

26a-1, 26v-1, 26g-1 and 26d-1 - from diastereomerically pure 15zh-1.

36a-1, 36b-1, 36b-1 and 36g-1 are from enantiomerically pure acid 4a-1.

Table 2 presents the structures of the obtained compounds, names, analytical characteristics and indicators of DPP-4 inhibitory activity (IC ₅₀ ) of the target products — individual diastereomers or enantiomers.

Analysis conditions: column - Onix C18 50 × 4.6 mm; eluent 1 - 0.1% TFA in water; eluent 2-0.1% TFA in acetonitrile, gradient - eluent 1 - 2.9 min, eluent 2 - 0.2 min, eluent 1 - washing, flow rate - 3.75 ml / min, detection - UV (254 nm) and mass spectrometry.

The structural element of the molecules of all the obtained DPP-4 inhibitors is the weakly basic functional amino group of the amino acid fragment. A mid-level specialist understands that all substances can be obtained both in the form of salt-free forms (free bases) and salt forms with counterions of an acidic nature - such as:

acetate, aspartate, benzyl sulfonate, benzoate, bicarbonate, tartrate, glutamate, glycolate, saccharinate, hexanoate, hexylresorcinate, mucate, napsilate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate / dihydrogen phosphate, ischlorate, camsylate, propionate, citrate, hydrochloride, lactate, salicylate, stearate, malate, decanoate, maleate, mesylate, sulfate, fumarate, maleate, tosylate, methyl sulfate, gluconate, etc.

Salt-free forms can be obtained by isolating the free base after neutralizing the salt forms resulting from the removal of the BOC-protecting group.

Salt forms can be obtained as a result of:

- removal of the BOC-protecting group:

- n-toluenesulfonic acid in organic solvents,

- hydrochloric acid in alcoholic or aqueous media,

- a solution of hydrogen chloride (HCl) in dioxane,

- trifluoroacetic acid in organic solvents;

- additions to the free bases (salt-free forms) of the acids listed above;

- salt metabolism of the acids listed above.

The study of DPP-4-inhibitory activity of the synthesized compounds.

The inhibitory activity of the synthesized samples against DPP-4 was performed by comparing the activity in the absence and presence in the system of the analyzed sample (substrate). Evaluation was carried out by a fluorescence method using a certified reagent kit (Kit) “Dipeptidyl peptidase IV Inhibitor Screening Assay Kit (ab 133081)”. All manipulations were carried out in full accordance with the instructions for the set. Each substance was analyzed in the concentration range from 10 ^-4 to 10 ^-11 M, in the fluorescence range of 450-465 nm.

The task of the claimed invention is the creation of dipeptidyl peptidase-4 inhibitors resistant to intramolecular cyclization for the treatment of patients with type 2 diabetes mellitus and the expansion of the line of known dipeptidyl peptidase-4 inhibitors is solved by creating a number of dipeptidyl peptidase-4 inhibitors resistant to intramolecular cyclization introducing into the pyrrolidine fragment a steric factor that prevents cyclization, and introducing substituents in which cyclization is impossible.

The problem is solved by synthesis and research of the compounds listed in tables 1 and 2. As a result of studies, it was found that all compounds exhibit an inhibitory effect against DPP-4, while the most active were compounds: exo (2S) -3 - [(3R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17zh-1), exo (3R) -3-amino-1 - [(2S) -2- (5-phenyl- 1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26a-1), and exo (3R) -3-amino-1 - [(2S) -2- (3-phenyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptane-3- yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36a-1).

Industrial applicability is proved and confirmed by examples of synthesis and analysis of the obtained substances.

List of abbreviations.

Diabetes mellitus

CM - sulfonylurea

DPP-4 - dipeptidyl peptidase-4

ISU - gastroinhibitory peptide

GIP - gastric inhibitory peptide

GLP-1 - glucagon-like peptide-1

Ala - Alanine

STAB - Sodium Triacetoxyborohydride

DCM - Dichloromethane (methylene chloride)

MeOH - methanol

EtOH - Ethanol

CHCl - chloroform

p-TSC - para-toluenesulfonic acid

NH ₂ OH × HCl - Hydroxylamine Hydrochloride

K ₂ CO ₃ - potassium carbonate (potash)

HCl - hydrogen chloride

MTBE - methyl tert-butyl ether

NaOH - sodium hydroxide

PE - petroleum ether

EtOAc - Ethyl Acetate

THF - tetrahydrofuran

TEA - triethylamine

Pd / C - Palladium on carbon

DIC - diisopropylcarbodiimide

Et ₂ O - diethyl ether

TFA - trifluoroacetic acid

NaHCO ₃ - sodium bicarbonate

DIPEA - Diisopropylethylamine

Na ₂ SO ₄ - sodium sulfate

BOP - benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate

TLC - thin layer chromatography

LC / MS - High Performance Liquid Chromatography with Mass Detection

NMR - nuclear magnetic resonance

DMSO - Dimethyl Sulfoxide

Mr - molecular weight

IC ₅₀ - inhibitor concentration at which the corresponding biological process in vitro is inhibited by 50%

shir - wide

s - singlet

d - doublet

m - multiplet

Claims (144)

1. Compounds of general formula (I) - beta-amino acid amides of stereoisomers of 3-azabicyclo [2.2.1] hepten-2-carbonitrile (I), or their pharmaceutically acceptable salts,

Where: R ¹ = H is hydrogen; C _1-5 is alkyl; R ² = H is hydrogen; C _1-5 is alkyl; benzyl (C ₆ H ₅ -CH ₂ ) substituted with one, two or three halogen atoms (F); R ³ = H is hydrogen; adamantyl, in which each carbon may have a substituent selected from: hydroxy (OH-); benzyl (C ₆ H ₅ -CH ₂ ), in which there may be substituents: hydroxy- (OH-) and one halogen (F). 2. The compound of claim 1, wherein: R ¹ = H, R ² = H, R ³ = hydroxyadamantyl- exo-3- [3 - [(3-hydroxy-1-adamantyl) amino] propanoyl] -3-azabicyclo [2.2.1] heptene-2-carbonitrile (12a), or R ¹ = H, R ² = H, R ³ = hydroxyadamantyl- exo-3- [3 - [(10-hydroxy-1-adamantyl) amino] propanoyl] -3-azabicyclo [2.2.1] heptene-2-carbonitrile (12b), or R ¹ = H, R ² = H, R ³ = hydroxyadamantyl- endo-3- [3 - [(3-hydroxy-1-adamantyl) amino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (13a), or R ¹ = H, R ² = H, R ³ = hydroxyadamantyl- endo-3- [3 - [(10-hydroxy-1-adamantyl) amino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (13b), or R ¹ = H, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl- exo-3- [3 - [(4-fluoro-3-hydroxyphenyl) methylamino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20a), or R ¹ = methyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl- exo-3 - [(3R) -3 - [(4-fluoro-3-hydroxyphenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20b), or R ¹ = H, R ² = methyl, R ³ = 4-fluoro-3-hydroxybenzyl- exo-3 - [(3S) -3 - [(4-fluoro-3-hydroxyphenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20c), or R ¹ = methyl, R ² = methyl, R ³ = 4-fluoro-3-hydroxybenzyl- exo-3- [3 - [(4-fluoro-3-hydroxyphenyl) methylamino] -3-methyl-butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20 g), or R ¹ = isopropyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl- exo-3 - [(3S) -3 - [(4-fluoro-3-hydroxy-phenyl) methylamino] -4-methyl-pentanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20e), or R ¹ = H, R ² = isopropyl, R ³ = 4-fluoro-3-hydroxybenzyl- exo-3 - [(3R) -3 - [(4-fluoro-3-hydroxyphenyl) methylamino] -4-methyl-pentanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20e), or R ¹ = H, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl- endo-3- [3 - [(4-fluoro-3-hydroxyphenyl) methylamino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20g), or R ¹ = methyl, R ² = H, R ³ = 4-fluoro-3-hydroxybenzyl- endo-3 - [(3R) -3 - [(4-fluoro-3-hydroxyphenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20h), or R ¹ = H, R ² = methyl, R ³ = 4-fluoro-3-hydroxybenzyl endo-3 - [(3S) -3 - [(4-fluoro-3-hydroxyphenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20i), or R ¹ = methyl, R ² = methyl, R ³ = 4-fluoro-3-hydroxybenzyl- endo-3- [3 - [(4-fluoro-3-hydroxyphenyl) methylamino] -3-methyl-butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20K), or R ¹ = methyl, R ² = H, R ³ = 4-fluorobenzyl- exo-3 - [(3R) -3 - [(4-fluorophenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20 L), or R ¹ = methyl, R ² = H, R ³ = 4-fluorobenzyl- endo-3 - [(3R) -3 - [(4-fluorophenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20m), or R ¹ = H, R ² = methyl, R ³ = 4-fluorobenzyl- endo-3 - [(3S) -3 - [(4-fluorophenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20n), or R ¹ = H, R ² = methyl, R ³ = 4-fluorobenzyl- exo-3 - [(3S) -3 - [(4-fluorophenyl) methylamino] butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (20 °), or R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H- zcco-3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17g), or R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H- endo-3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (18g), or R ¹ = H, R ² = 4-fluorobenzyl, R ³ = H- exo-3 - [(3R) -3-amino-4- (4-fluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17h), or R ¹ = H, R ² = 4-fluorobenzyl, R ³ = H- endo-3 - [(3R) -3-amino-4- (4-fluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (18h), or R ¹ = H, R ² = 3,5-difluorobenzyl, R ³ = H, exo-3 - [(3R) -3-amino-4- (3,5-difluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17i), or R ¹ = H, R ² = 3,5-difluorobenzyl, R ³ = H- endo-3 - [(3R) -3-amino-4- (3,5-difluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (18i), or R ¹ = H, R ² = H, R ³ = 2,4,5-trifluorobenzyl- exo-3- [3 - [(2,4,5-trifluorophenyl) methylamino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17k), or R ¹ = H, R ² = H, R ³ = 2,4,5-trifluorobenzyl- endo-3- [3 - [(2,4,5-trifluorophenyl) methylamino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (18k), or enantiomerically pure compounds: R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H- exo (2S) -3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17zh-1), or R ¹ = H, R ² = 2,4,5-trifluorobenzyl, R ³ = H- exo (2R) -3 - [(3R) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17zh-2), or R ¹ = H, R ² = 4-fluorobenzyl, R ³ = H- exo (2S) -3 - [(3R) -3-amino-4- (4-fluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17z-1), or R ¹ = H, R ² = 3,5-difluorobenzyl, R ³ = H- exo (2S) -3 - [(3R) -3-amino-4- (3,5-difluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17i-1), or R ¹ = H, R ² = H, R ³ = 2,4,5-trifluorobenzyl exo (2S) -3- [3 - [(2,4,5-trifluorophenyl) methylamino] propanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile (17k-1). 3. The compounds of general formula (II) are the beta-amino acid amides of the stereoisomers of 3- (3-azabicyclo [2.2.1] heptan-2-yl) -1,2,4-oxadiazole, or their pharmaceutically acceptable salts,

Where: R ¹ = H is hydrogen; R ² = phenyl - (C ₆ H ₅ -) substituted with three halogen atoms (F); R ³ = H is hydrogen; R ⁴ = methyl, in which there may be three substituents selected from halogen (F); cyclopropyl, isopropyl, in which each carbon independently may have one halogen substituent (F); phenyl (C ₆ H ₅ -). 4. The compound of claim 3, wherein: R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = phenyl exo (3R) -3-amino-1 - [(2S (R)) - 2- (5-phenyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26a), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = trifluoromethyl- exo (3R) -3-amino-1 - [(2S (R)) - 2- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26b), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = cyclopropyl- exo (3R) -3-amino-1 - [(2S (R)) - 2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26c), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = 2-fluoro-isopropyl- exo (3R) -3-amino-1 - [(2S (R)) - 2- [5- (1-fluoro-1-methyl-ethyl) -1,2,4-oxadiazol-3-yl] - 3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26g), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = isopropyl- exo (3R) -3-amino-1 - [(2S (R)) - 2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26d), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = phenyl endo (3R) -3-amino-1 - [(2S (R)) - 2- (5-phenyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27a), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = trifluoromethyl- endo (3R) -3-amino-1 - [(2S (R)) - 2- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27b), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = cyclopropyl- endo (3R) -3-amino-1 - [(2S (R)) - 2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27c), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = 2-fluoro-isopropyl- endo (3R) -3-amino-1 - [(2S (R)) - 2- [5- (1-fluoro-1-methyl-ethyl) -1,2,4-oxadiazol-3-yl] - 3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27 g), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = isopropyl- endo (3R) -3-amino-1 - [(2S (R)) - 2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (27e), or enantiomerically pure compounds, where: R ¹ = H, R ² = 2,4,5-trifluorophenyl. R ³ = H, R ⁴ = phenyl exo (3R) -3-amino-1 - [(2S) -2- (5-phenyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl ] -4- (2,4,5-trifluorophenyl) butan-1-one (26a-1), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = cyclopropyl- exo (3R) -3-amino-1 - [(2S) -2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl ] -4- (2,4,5-trifluorophenyl) butan-1-one (26c-1), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = 2-fluoro-isopropyl- exo (3R) -3-amino-1 - [(2S) -2- [5- (1-fluoro-1-methyl-ethyl) -1,2,4-oxadiazol-3-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (26g-1), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = isopropyl- exo (3R) -3-amino-1 - [(2S) -2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -3-azabicyclo [2.2.1] heptan-3-yl ] -4- (2,4,5-trifluorophenyl) butan-1-one (26d-1). 5. The compounds of general formula (III) are the beta-amino acid amides of the stereoisomers of 5- (3-azabicyclo [2.2.1] heptan-2-yl) -1,2,4-oxadiazole, or their pharmaceutically acceptable salts,

Where: R ¹ = H is hydrogen; R ² = phenyl- (C ₆ H ₅ -) substituted with three halogen atoms (F); R ³ = H is hydrogen; R ⁴ = cyclopropyl, isopropyl, phenyl, hetaryl (C ₅ H ₄ N-) substituted with two halogen atoms (F). 6. The compound of claim 5, wherein: R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = phenyl exo (3R) -3-amino-1 - [(2S (R)) - 2- (3-phenyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36a), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = 3,5-difluoro-2-pyridyl- exo (3R) -3-amino-1 - [(2S (R)) - 2- [3- (3,5-difluoro-2-pyridyl) -1,2,4-oxadiazol-5-yl] - 3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36b), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = isopropyl- exo (3R) -3-amino-1 - [(2S (R)) - 2- (3-isopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36c), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = cyclopropyl- exo (3R) -3-amino-1 - [(2S (R)) - 2- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36 g), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = phenyl endo (3R) -3-amino-1 - [(2S (R)) - 2- (3-phenyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (37a), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = 3,5-difluoro-2-pyridyl endo (3R) -3-amino-1 - [(2S (R)) - 2- [3- (3,5-difluoro-2-pyridyl) -1,2,4-oxadiazol-5-yl] - 3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (37b), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = isopropyl- endo (3R) -3-amino-1 - [(2S (R)) - 2- (3-isopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (37c), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = cyclopropyl- endo (3R) -3-amino-1 - [(2S (R)) - 2- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptane- 3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (37 g), or enantiomerically pure compounds, where: R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = phenyl exo (3R) -3-amino-1 - [(2S) -2- (3-phenyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl ] -4- (2,4,5-trifluorophenyl) butan-1-one (36a-1), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = phenyl exo (3R) -3-amino-1 - [(2R) -2- (3-phenyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl ] -4- (2,4,5-trifluorophenyl) butan-1-one (36a-2), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = 3,5-difluoro-2-pyridyl- exo (3R) -3-amino-1 - [(2S) -2- [3- (3,5-difluoro-2-pyridyl) -1,2,4-oxadiazol-5-yl] -3-azabicyclo [2.2.1] heptan-3-yl] -4- (2,4,5-trifluorophenyl) butan-1-one (36b-1), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = isopropyl- exo (3R) -3-amino-1 - [(2S) -2- (3-isopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl ] -4- (2,4,5-trifluorophenyl) butan-1-one (36B-1), or R ¹ = H, R ² = 2,4,5-trifluorophenyl, R ³ = H, R ⁴ = 3,5-cyclopropyl- exo (3R) -3-amino-1 - [(2S) -2- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -3-azabicyclo [2.2.1] heptan-3-yl ] -4- (2,4,5-trifluorophenyl) butan-1-one (36g-1). 7. The compound selected according to any one of the preceding paragraphs, and its pharmaceutically acceptable salt forms. 8. An inhibitor of dipeptidyl peptidase-4 for the treatment of type 2 diabetes mellitus or metabolic syndrome according to claims 1-7, selected from compounds of the general formula I, or II, or III, or from their pharmaceutically acceptable salts.