Novel dipeptidyl peptidase iv inhibitors, synthesis methods thereof and pharmaceutical compositions containing said inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

 

The present application claims the priority based on the application of India No. 610/DREAMS/2006, filed April 3, 2006, and provisional application U.S. No. 60/801437, filed may 18, 2006, which is given here by reference.

The scope of the invention

The present invention relates to new compounds represented by formula I, their derivatives, analogs, tautomeric forms, stereoisomers, bioisosterism, diastereomers, polymorphs, pharmaceutically acceptable salts, solvate containing their pharmaceutically acceptable compositions, which are used in the treatment of type II diabetes and diabetic complications, as well as for the treatment of dyslipidemia, hypercholesterolemia, obesity and hyperglycemia.

More specifically, the present invention relates to compounds of the formula I which are inhibitors of semipretioase, particularly inhibitors dipeptidylpeptidase, more specifically inhibitors dipeptidylpeptidase IV, as well as their derivatives, analogs, tautomeric forms, stereoisomers, bioisosterism, diastereomers, polymorphs, pharmaceutically acceptable salts and solvate. In addition, the present invention relates to pharmaceutically acceptable compositions containing the above compounds.

Compounds of the present invention represented by formula I

its derivatives, analogs, tautomeric forms, stereoisomers, bioisostere, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvate, where

X represents CH2, CHF, CF2, CHCl, CHOH, CHOCH3, NH, NCOCH3, CHPh, O or S,

Y represents CN,

R1and R5selected from hydrogen, C1-C4of alkyl and hydroxy,

R2selected from hydrogen, C1-C4of alkyl, substituted alkyl, C1-4alkoxyl1-4of alkyl, C1-4hydroxyalkyl, R5NHC1-4the alkyl and R5NHC(NH)NHC1-4of alkyl,

R3selected from hydrogen and C1-C4of alkyl,

R4selected from hydrogen, C1-C4of alkyl, substituted alkyl, C1-C4alkoxy, C1-C4alkanoyloxy, hydroxy, amino, nitro, C2-C6alkenyl, acyl and halogen-free,

n represents 1 or 2,

m represents 0, 1 or 2,

R is a R11, R12or R13where

R11includes at least one of the groups selected from the following a), b) or C), where optionally substituted cycloalkyl, heterocyclyl and heteroaryl groups are linked with noradrenaline part, either directly or through adjacent methylene or ethylene, or C-C bond or C-N bond.

The) cycloalkyl group, which is optionally substituted C1-C4the alkyl, dialkyl or oxo, preferably4-C7ring system, more preferably5-C6ring system which may optionally be functionalized or substituted with a high degree of substitution. Examples of possible cycloalkyl groups are cyclopentane, cyclohexane, cyclopentadiene, cyclohexadiene and optional substituents include1-C4alkyl, dialkyl and oxo.

b) Optionally substituted heteroaryl group, preferably 5-to 10-membered ring system in which the heteroaryl ring is a monocyclic, aromatic ring system or a bicyclic aromatic ring system comprising one, two or more heteroatoms selected from nitrogen, sulfur and oxygen. Possible heteroaryl groups include, but are not limited to the above, tetrazole, triazole, pyrazole, imidazole, oxadiazole, pyridine, pyrimidine, indole, furan, benzofuran, benzimidazole, indazole, thiophene and benzothiophene, and heteroaryl substituents in the ring, which may be the same or different, selected from R6and R7where R6represents hydrogen, C1-C4alkyl, C2-C4alkenyl, hydroxy, hydroxyalkyl, alkylamino, g is loginall, amino, acyl, R9or R9and R7selected from the group consisting of hydrogen, hydroxy, halogen, amino, nitro, C1-C8of alkyl, C2-C4alkenyl, R9, CONR8R9, COR9, NHCOOR8NHS(O)2R8NHS(O)R8NHS(O)2Other8, NR8COOR9, NR8COR9, NR8S(O)2R9, NR8CONR8R9, NR8C(S)NR8R9, NHC(O)NH(S)(O)2R8, OSO2R8, OCONR8R9,SO2R8, SOR8, SR8, SO2NR8R9and S(O)3OR8. When there are R6and R7at the adjacent carbon atoms of the ring system, they may together form a six-membered aromatic ring, such as phenyl, or a heterocyclic ring such as pyridine, with additional substituents, such as amino, hydroxy, alkyl, alkylsulfonyl, alkylthio, alkylsulfonyl, carboxy or oxo.

(C) Heterocyclic group, optionally substituted C1-C3the alkyl, dialkyl or exography, where the heterocyclic ring system is a 4-10 membered mono - or bicyclic ring system with one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, where the heteroatoms may also be present as a functional group, such as N-is xidi, the sulfoxidov and sulfadoxine, where the heterocyclic ring system may contain one or two double bonds, and where a monocyclic heterocyclic ring may be optionally condensed with heteroaryl, aryl or cycloalkyl ring, optionally substituted C1-C5by alkyl, halogen, hydroxy, amino, nitro, halogenation, alkylamino, carboxy, NH(CO)R8NHS(O)2R8, NHC(O)other9, NHSOR8NHS(O)2Other8, NR8COOR9, NR8COR9, NR8S(O)2R9, NR8CONR8R9, NR8C(S)NR8R9or NHC(O)NHS(O)2R8. Examples of such heterocyclic ring radicals include, but are not limited to the above, imidazolidine, isothiazoline-1,1-dioxide, pyrrolidine, pyrrolidinone, oxopyrrolidin, isoxazolidine, isoindoline, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, thiophene-1,1-dioxide, thiazolidinedione, piperidine, piperazine, tetrahydropyrimidine, [1,2]-diazinon-1,1-dioxide, tetrahydrothiophene-1,1-dioxide, piperidine and tetrahydrothiopyran-1,1-dioxide.

R12selected from hydrogen, halogen, halogenoalkane, hydroxy, carboxy, nitro, amino, cyano, alkylsulfonyl, alkylsulfonyl, alkylthio, amidine, alkoxy, alkoxycarbonyl, ureido, touraid, alkanoyl, alkanoyloxy, alkanoyl is about, carbamoyl, guanidino, optionally substituted C1-C8the alkyl or C2-C6alkenyl.

R13represents an optionally substituted aryl, where the substituents may be the same or different and include at least one group selected from the

a) hydrogen;

(b) (C1-C8of alkyl, C2-C6alkenyl, halogen, alkylhalogenide, alkoxy, alkylsulfonyl, alkylsulfonyl, alkoxy, alkanoyl, alkanoyloxy, acylamino, carbylamine, guanidino, nitro, amino, R9, R8NHC(O)R9, COR9, CONR8R9, NHC(O)OR8, NHC(O)R8, NHC(O)NR8R9, NHC(O)NR8R9NHS(O)2R8NHS(O)R8NHS(O)2Other8NHS(O)2NHC(O)R8, NR8COOR9, NR8COR9, NR8S(O)2R9, NR8CONR8R9, NR8C(S)NR8R9, NHC(O)NHS(O)2R8, S(O)2R8, SOR8, SR8, S(O)2NR8R9, OCF3, OS(O)2R8or OCONR8R9;

c) a saturated, partially saturated or unsaturated mono - or bicyclic heterocyclic ring system, optionally substituted by one or more groups selected from C1-C3of alkyl, C2-C6alkenyl, dialkyl and oxo, where the heterocyclic ring system is with the battle 4-10-membered ring with one or more heteroatoms, selected from the group consisting of nitrogen, sulfur and oxygen, where the heteroatoms may also be present as functional groups, such as N-oxides, sulfoxidov and sulfadoxine. Examples of such heterocyclic ring radicals include, but are not limited to the above, pyridine, pyrimidine, imidazolidine, imidazolidinyl, indazole, indole, isoindole, hinzelin, quinoline, isoquinoline, cinnamon, isothiazoline-1,1-dioxide, pyrrolidino, 2-piperidine, tetrahydropyrimidine, azetidine and teasan-1,1-dioxide.

R8, R9and R10groups, which are optionally substituted by halogen, hydroxy, alkoxy, cyano, nitro, alkyl, acyl, acylase, hydroxyalkyl, amino, alkylthio or tolkienite groups, which may be the same or different, are selected from hydrogen, optionally substituted C1-C8of alkyl, aryl, arylalkyl, alkoxycarbonyl and arylalkanolamine. When R8and R9are present together at the nitrogen atom, they may form a 5 - or 6-membered, partially unsaturated or unsaturated cyclic system containing carbon atoms, at least one nitrogen atom and optionally one or more other heteroatoms selected from oxygen, sulfur and nitrogen.

The present invention also relates the I to methods of preparing compounds of the formula I, their derivatives, analogs, tautomeric forms, stereoisomers, bioisosteres, diastereomers, polymorphs, pharmaceutically acceptable salt, solvate.

The present invention also relates to novel intermediate compounds, methods for their preparation, their use for obtaining compounds of formula I and their derivatives, analogs, tautomeric forms, stereoisomers, bioisosteres, diastereomers, polymorphs, pharmaceutically acceptable salts and solvate.

The prior art inventions

Diabetes is characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral test tolerance of glucose. There are two types of diabetes. Type 1 diabetes, usually diagnosed in children and young people, was previously known as juvenile diabetes. When type 1 diabetes the body does not produce insulin. Type 2 diabetes is the most common form of diabetes. When type 2 diabetes, the body either does not produce enough insulin or the cells ignore the insulin. Patients with type 2 diabetes are at increased risk of macrovascular and microvascular complications, including coronary artery disease, stroke, hypertension, nephropathy, peripheral vascular disease, neuropathy, and retinopathy.

Significant, quickly took iwaasa part of the population of people affected by type 2 diabetes, a disease characterized by elevated levels of glucose in the blood and relative insulin deficiency. Recent studies have found that the activity of two potent stimulators of insulin secretion, GLP-1 and GIP quickly Annuls serendipidity by dipeptidyl peptidase IV (DPP-IV). DPP-IV is a member of the family serendipidous. CD26 or GPPIV is a membrane-associated peptidase of 766 amino acids, which are widely distributed in many tissues. DPP-4 also exists as a soluble form circulating in the plasma, and a significant activity that is similar to the DPP-4 detected in plasma from humans and rodents. The main biological activity of CD26 (DPP-IV) is its enzymatic function. DPP-IV prefers substrates with aminocentesis with Proline or alanine in position 2, but can also cleave substrates with non-preferred amino acids in position 2. The structure of GIP, GLP-1 and GLP-2 reveals a high degree saved alanine in position 2, making these peptides in an ideal prospective substrates for amino peptidases of dipeptidylpeptidase 4 (DPP-4). Eur. J. Biochem. 1993, 214(3), 829-35.

Looking at the available courses of treatment of type 2 diabetes, which essentially do not change for many years, it becomes clear that they all have their own limitations. There are many pharmacological strategy is s to achieve these goals. The first of these series are inhibitors of alpha-glucosidase, such as acarbose and miglitol that act by creating obstacles when exposed to alpha-glucosidase present in the brush border of the small intestine. The result of this inhibition is to reduce the digestion and subsequent absorption of glucose in the systemic circulation. Reducing the absorption of glucose allows pancreatic beta-cells more effectively regulate insulin secretion. The advantage of the use of alpha-glucosidase inhibitors is that they operate locally in the gut and don't have large systemic effects. Hypoglycemia usually does not occur when using alpha-glucosidase inhibitors, but they are effective for reducing levels of glucose in plasma (FPG) and levels of glycosylated hemoglobin (HbAIc). Common adverse side effects of these inhibitors are abdominal bloating and discomfort, diarrhea and flatulence.

Sulfonylurea drugs and classes meglitinides oral hypoglycemic drugs are called endogenous stimulators of insulin secretion, because they induce the release from the pancreas of endogenous insulin. Due to the fact that these drugs can ind the trigger distinct hypoglycemia, treatment initiate the lowest possible dose, carefully controlled to obtain the dose in FPG 110-140 mg/decilitre. Sulfonylurea drugs act by binding and inhibition of ATP-dependent potassium channel of the pancreatic gland, which is usually involved in mediated glucose insulin secretion. Sulfanilamide have an insignificant impact on the circulation of triglycerides, lipoproteins or cholesterol. Desulfomicrobium stimulants of insulin secretion are as fast and short acting. However, meglitinide (desulfomicrobium stimulants of insulin secretion) have an impact on the potassium conductance. Like sulfanilamides meglitinide not have a direct impact on the levels of circulating lipids in the plasma.

Biguanides reduce glucose levels in serum increase mediated by the insulin suppression of the production of glucose in the liver and increase insulin-stimulated uptake of glucose by skeletal muscle. Metformin is a member of this class and usually the most widely recommended insulin-sensitizing drug in clinical application. Introduction Metformin does not increase the release of insulin from the pancreas and as such the risk of hipoglicemia which is minimal. Due to the fact that the main site of action of Metformin is the liver, its use may be contraindicated in patients with liver dysfunction. In the case of young women with type 2 diabetes, Metformin highly recommended to reduce the incidence and features of the polycystic ovary syndrome. However, two biguanide, phenformin and Metformin can cause lactic acidosis and nausea/diarrhea.

The family of nuclear receptors activated by proliferation peroxisome (R), were subjected to particularly careful research in diabetes and this resulted in the preparations of thiazolidinediones as a class of therapeutic agents. The first generation of preparations of thiazolidinediones were agonists of PPAR gamma and was able to reduce insulin resistance. However, one adverse effect associated with gamma agonists of PPAR, is the increase of body weight. The newly created molecules that activate PPAR alpha. This class is able to reduce the levels of triglycerides and can also increase sensitivity to insulin and the result is a dual agonists, PPAR alpha/gamma PPAR with offer useful actions higher than the existing preferred gamma and PPAR alpha drugs in the treatment of type 2 diabetes. But security problems slow down the introduction of these drugs among the STV.

One of interest to develop classes of agents are agonists of GLP-1. The primary metabolic response to the release of GLP-1 from enteroendocrine L-cells of the intestine are the inhibition of secretion of glucagon and strengthening dependent glucose release of insulin from the pancreas, both effects lead to a decrease glycemic movement. But the hormonal action of GLP-1 is quickly exhausted as the result of enzymatic degradation of DPP IV. Recent clinical data have shown that infusion of GLP-1 or inhibition of DPP IV may lead to dramatic reductions in the concentrations of plasma glucose, lowering of HbAIcand improves the function of beta cells in the pancreas. Therefore, both presents a possible target for prevention of hyperglycemia associated with diabetes and impaired insulin function. There are both benefits and useless effects in modern therapeutic methods targeting the actions of GLP-1 in patients with diabetes. Modern use of mimetics GLP-1 and/or agonists (GLP-1R) receptor GLP-1 focused on peptides or modified peptides and their need to enter the injection, which leads to problems with patient compliance.

For another, a new mechanism for the treatment of type 2 diabetes are inhibitors dipeptidyl duty-IV. The dipeptidyl peptidase IV is a multifunctional protein involved in the cleavage of the hormone internal secretion, therefore, serves for the regulation of glucose homeostasis and, consequently, considered as a target for control in type 2 diabetes. The beneficial effect of dipeptidylpeptidase IV in the treatment of type 2 diabetes based on the fact that the dipeptidyl peptidase IVin vivoeasily inactivates GLP-1 and GIP. They are incretin that are produced when food consumption. These incretin stimulate the production of insulin. Inhibition of dipeptidylpeptidase IV leads to decreased inactivation of incretins, and, in turn, increased the efficiency of incretins in stimulating the production of insulin by the pancreas. Therefore, inhibition of dipeptidylpeptidase IV leads to increased levels of serum insulin. An interesting observation is that incretin are produced only when there is food consumption. So do not assume that the inhibition of dipeptidylpeptidase IV will increase the level of insulin between meals, which can lead to hypoglycemia. Therefore, suggest that the inhibition of dipeptidylpeptidase will increase insulin levels without increasing the risk of hypoglycemia. The investigated inhibitors di is aticipated IV have an advantage over other new therapeutic methods, because they can be administered orally. The compliance of patients is higher when orally delivered drugs than shipping, which requires injections. Therefore, inhibitors dipeptidylpeptidase IV represent a promising new approaches for the treatment of type 2 diabetes, which function, at least partially, as an indirect stimulators of insulin secretion. Mechanism and application of DPPIV inhibitors in various diseases is well explained in the patents of the prior art, such WO 2005/033106 and introduced here by reference in its entirety.

Prior art

In international patent application WO 00/34241 described compounds of General formula

where R represents a substituted substituted.

In international patent application WO 03/04498 described compounds of General formula

In the application US US 2005/038020 described compounds of General formula

where a represents an optionally substituted adamantly group.

In international patent application WO 2006/090244 described compounds of the formula

where n represents 0, 1, 2, or 3.

R2represents a substituted alkyl, substituted or not alseny of alkenyl, substituted or unsubstituted quinil, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted geterotsiklicheskikh, substituted or unsubstituted heteroaromatic, -NR3R4, -NH-S(O)m-R3, -NH-CR3R4C(O)-R5, -C(O)O-R3,

-C(O)NR3R4, -S(O)m-, NR3R4, nitro, cyano, formyl, acetyl, halogen, -SRaor a protective group.

In international patent application WO 2005/021536 described compounds of the formula

where one of the possible substituents In is adamantylamine.

One of the representative examples is a

In international patent application WO 2006/012395 described compounds of the formula

as inhibitors of peptidases. One of the representative examples is a

In international patent application WO 2005095339 described compounds of the formula

in the operation of DPPIV inhibitors.

In the US 20050215784 as DPPIV inhibitors are described compounds of the formula

Although there is a bit of DPPIV inhibitors in various stages of clinical trials, such as in the examples above (LAF-237, MK-0431, BMS-477118, GSK23A), there is still a need for new compounds in this area and the purpose of the present invention to provide a new nonadministrative compounds represented by formula I, which have activity of DPPIV inhibitors, and methods for their preparation.

The invention

The purpose of the present invention constitutes an offer to new compounds of formula I have activity as inhibitors of semipretioase specific activity as inhibitors of dipeptidylpeptidase IV, to reduce the levels of blood glucose, lipid levels, cholesterol levels and reduction of weight of the body against type 2 diabetes and diabetic complications. Therefore, the main aim of the present invention to provide a new nonadministrative compounds represented by formula I, their derivatives, analogs, tautomeric forms, stereoisomers, bioisosteres, diastereomers, polymorphs, pharmaceutically acceptable salts, solvate containing pharmaceutically acceptable compositions.

According to another aspect of the present invention pre is a false way of getting nonadministrative compounds of the formula I, their derivatives, analogs, tautomeric forms, stereoisomers, bioisosteres, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvate.

According to another aspect of the present invention proposed new intermediate compounds, methods for their preparation and the use of such intermediate compounds in the methods of obtaining these nonadministrative compounds represented by formula I and their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, bioisosteres, diastereomers, pharmaceutically acceptable salts and solvate.

According to another aspect of the present invention proposed pharmaceutical compositions containing the compounds of the present invention represented by formula I, their derivatives, analogs, tautomeric forms, stereoisomers, bioisostere, diastereomers, polymorphs, salts, solvate or their mixtures in combination with suitable carriers, solvents, diluents and other media normally used in obtaining such compositions.

Detailed description of the invention

The present invention provides compounds represented by formula I,

their derivatives, analogs, tautomeric forms, stereoisomers, bioisostere, diastereomers, polymorphs, pharmaceutically acceptable with the Lee and their pharmaceutically acceptable solvate, where

X represents CH2, CHF, CF2, CHCl, CHOH, CHOCH3, NH, NCOCH3, CHPh, O or S,

Y represents CN,

R1and R5selected from hydrogen, C1-C4of alkyl and hydroxy,

R2selected from hydrogen, C1-C4of alkyl, substituted alkyl, C1-4alkoxyl1-4of alkyl, C1-4hydroxyalkyl, R5NHC1-4the alkyl and R5NHC(NH)NHC1-4of alkyl,

R3selected from hydrogen and C1-C4of alkyl,

R4selected from hydrogen, C1-4of alkyl, substituted alkyl, C1-4alkoxy, C1-4alkanoyloxy, hydroxy, amino, nitro, C2-C6alkenyl, acyl and halogen-free,

n represents 1 or 2,

m represents 0, 1 or 2,

R is a R11, R12or R13where

R11includes at least one of groups selected from a), b) or C), where optionally substituted cycloalkyl, heterocyclyl and heteroaryl groups are linked with noradrenaline part, either directly or via an adjacent methylene or ethylene, or communication, or communication C.

a) Cycloalkyl group, which is optionally substituted C1-C4the alkyl, dialkyl or oxo, preferably4-C7ring system, more preferably5-C6ring system, which may be up to omnitele functionalized or substituted with a high degree of substitution. Examples of possible cycloalkyl groups are cyclopentane, cyclohexane, cyclopentadiene, cyclohexadiene and possible substituents include1-C4alkyl, dialkyl and oxo.

b) Optionally substituted heteroaryl group, preferably 5-to 10-membered ring system in which the heteroaryl ring is a monocyclic aromatic ring system or a bicyclic aromatic ring system comprising one, two or more heteroatoms selected from nitrogen, sulfur and oxygen. Possible heteroaryl groups include, but are not limited to the above, tetrazole, triazole, pyrazole, imidazole, oxadiazole, pyridine, pyrimidine, indole, furan, benzofuran, benzimidazole, indazole, thiophene and benzothiophene, and the substituents at heteroaryl ring, which may be the same or different, selected from R6and R7where R6represents hydrogen, C1-C4alkyl, C2-C4alkenyl, hydroxy, hydroxyalkyl, alkylamino, halogenated, amino, acyl, R9or COR9and R7selected from the group consisting of hydrogen, hydroxy, halogen, amino, nitro, C1-C8of alkyl, C2-C4alkenyl, R9, CONR8R9, COR9, NHCOOR8NHS(O)2R8NHS(O)R8NHS(O)2Other 8, NR8COOR9, NR8COR9, NR8S(O)2R9, NR8CONR8R9, NR8C(S)NR8R9, NHC(O)NHS(O)2R8, OSO2R8, OCONR8R9, SO2R8, SOR8, SR8, SO2NR8R9and S(O)2OR8. When R6and R7present at the adjacent carbon atoms of the ring system, together they can form a six-membered aromatic ring, such as phenyl, or a heterocyclic ring such as pyridine, with additional substituents, such as amino, hydroxy, alkyl, alkylsulfonyl, alkylthio, alkylsulfonyl, carboxy or oxo.

More preferred heteroaryl groups include

these examples do not limit the present invention.

(C) Heterocyclic group optionally substituted C1-C3alkyl, dialkylamino and exography, where the heterocyclic ring system is a 4-10 membered mono - or bicyclic ring system with one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, where the heteroatoms may also be present as a functional group, such as N-oxides, sulfoxidov and sulfadoxine, where the heterocyclic ring system may contain one or two DVO the data connection and where a monocyclic heterocyclic ring may be optionally condensed with heteroaryl, aryl or cycloalkyl ring, optionally substituted C1-C5by alkyl, halogen, hydroxy, amino, nitro, halogenation, alkylamino, carboxy, NH(CO)R8NHS(O)2R8, NHC(O)other9, NHSOR8NHS(O)2Other8, NR8COOR9, NR8COR9, NR8S(O)2R9, NR8CONR8R9, NR8C(S)NR8R9or NHC(O)NHS(O)2R8. Optional substituents of the heterocyclic ring systems include1-C3alkyl, disciline and the carbonyl group. Examples of such heterocyclic radicals include, but are not limited to the above, imidazolidine, isothiazoline-1,1-dioxide, pyrrolidine, pyrrolidinone, oxopyrrolidin, isoxazolidine, isoindoline, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, thiophene-1,1-dioxide, thiazolidinedione, piperidine, piperazine, tetrahydropyrimidine, [1,2]-diazinon-1,1-dioxide, tetrahydrothiophene-1,1-dioxide, piperidine and tetrahydrothiopyran-1,1-dioxide.

Additional preferred heterocyclic groups include :

where R7represents, as stated above, and Z represents CH2, O, S, SO2, NH, NR6or SN(OH). These examples do not limit the present invention.

R12selected from hydrogen, halogen of halogenoalkane, hydroxy, carboxy, nitro, amino, cyano, alkylsulfonyl, alkylsulfonyl, alkylthio, amidine, alkoxy, alkoxycarbonyl, ureido, touraid, alkanoyl, alkanoyloxy, alkanolamine, carbamoyl, guanidino, optionally substituted C1-C8the alkyl and C2-C6alkenyl.

R13represents an optionally substituted aryl, where the substituents may be the same or different and include at least one group selected from the

a) hydrogen;

(b) (C1-C8of alkyl, C2-C6alkenyl, halogen, alkylhalogenide, alkoxy, alkylsulfonyl, alkylsulfonyl, alkoxy, alkanoyl, alkanoyloxy, acylamino, carbylamine, guanidino, nitro, amino, R9, R8NHC(O)R9, COR9, CONR8R9, NHC(O)OR8, NHC(O)R8, NHC(O)NR8R9, NHC(O)NR8R9NHS(O)2R8NHS(O)R8NHS(O)2Other8NHS(O)2NHC(O)R8, NR8COOR9, NR8COR9, NR8S(O)2R9, NR8CONR8R9, NR8C(S)NR8R9, NHC(O)NHS(O)2R8, S(O)2R8, SOR8, SR8, S(O)2NR8R9, OCF3, OS(O)2R8or OC(O)NR8R9;

c) a saturated, partially saturated or unsaturated mono - or bicyclic heterocyclic ring system, neobyazatel is substituted by one or more groups, selected from C1-C3of alkyl, C2-C6alkenyl, dialkyl and oxo, where the heterocyclic ring system is a 4-10-membered ring with one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, where the heteroatoms may also be present as functional groups, such as N-oxides, sulfoxidov, sulfadoxine. Examples of such heterocyclic ring radicals include, but are not organicists listed, pyridine, pyrimidine, imidazolidine, imidazolidinyl, indazole, indole, isoindole, hinzelin, quinoline, isoquinoline, cinnamon, isothiazoline-1,1-dioxide, pyrrolidino, 2-piperidine, tetrahydropyrimidine, azetidine and teasan-1,1-dioxide.

Additionally preferred heterocyclic groups include :

these examples do not limit the present invention.

Group R8, R9and R10that is not necessarily replaced by groups of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, acyl, acyloxy, hydroxyalkyl, amino, alkylthio, or thioalkyl, may be the same or different and individually selected from hydrogen, optionally substituted C1-C8of alkyl, aryl, arylalkyl, alkoxycarbonyl and arylalkanolamine. When R8and R9presence is Tvout together at the nitrogen atom, they may form a 5 - or 6-membered saturated, partially unsaturated or unsaturated cyclic system containing carbon atoms, at least one nitrogen atom and optionally one or more other heteroatoms selected from oxygen, sulfur and nitrogen.

In the compounds of the invention were obtained either in free form or in the form of their salts, if present soleobrazutaya group. Compounds of the present invention can be converted into pharmaceutically acceptable salts by their interaction with the appropriate acids or bases.

Some compounds of formula I of the present invention may contain one or more chiral centers and the present invention includes the selected stereoisomers, their mixtures, as well as the corresponding racemates.

The enumeration of the terms in the list below is a designation of the various terms used to describe this invention.

The term "alkyl" refers to saturated with normal or branched aliphatic hydrocarbon structure of the chain, which optionally may be substituted with a high degree of substitution. Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and isobutyl. The substituents can be selected from halog the new, hydroxy, alkoxy, acyl, amino and nitro. Unless otherwise noted, for example, the expression "Cx-Cyalkyl"refers to alkyl group with a specific number of carbon atoms in the full specification, the term "alkyl group" refers to C1-C8-group. Similar terminology is also applied to other preferred groups.

The term "alkenyl"used here, either separately or in combination with other radicals, denotes with normal or branched structure With a2-C6aliphatic hydrocarbon chain containing one or more carbon-carbon double bonds, which may be optionally substituted with a high degree of substitution. The term "alkenyl" includes dieny and triene having chains of normal and branched structure, and includes groups such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl and 6-heptenyl.

The term "acyl" refers to-C(O)Ragroup, where Rarepresents a normal or branched structure With a1-C4alkyl or aryl.

Used herein, the term "acylamino" is represented by-NHC(O)Ragroup, where Ramatter, as described above, and examples of p is establet a CH 3CONH, C2H5CONH, C3H7CONH, C6H5CONH.

The term "alkanoyloxy" refers to-OC(O)Ragroup, where Rarepresents a C1-C4alkyl, normal or branched structure, as described above; examples are the atomic charges and propenyloxy.

The term "alkanoyl" refers to-C(O)Ragroup, where Rarepresents a C1-C4alkyl, normal or branched structure, as described above; examples are acetyl or propanol.

The term "alkanolamine" refers to-NH-C(O)Ragroup, where Rarepresents a C1-C4alkyl, normal or branched structure, as described above; examples are CH3NH and C2H5CONH-.

The term "alkoxy" refers to-ORagroup, where Rarepresents an alkyl, as defined here. Representative examples include, but are not limited to, methoxy, ethoxy.

The term "alkoxycarbonyl" refers to-C(O)ORagroup, where Rarepresents an alkyl, as defined here.

The term "alkoxycarbonyl" refers to-NHC(O)or SIGagroup, where Rarepresents an alkyl, as defined here.

The term "alkylamino" refers to-N(Ra)2group, where ODI is R ais an alkyl and the other Rarepresents independently H or alkyl, as defined here.

The term "alkylsulfonyl" refers to-S(O)Ragroup, where Rarepresents an alkyl, as defined here.

The term "alkylsulfonyl" refers to-S(O)2Ragroup, where Rarepresents an alkyl, as defined here.

The term "alkylthio" refers to-SRagroup, where Rarepresents an alkyl, as defined here. Representative examples include, but are not limited to, -S-CH3, -S-CH2CH3.

The term "alkylhalides" refers to RaX group, where Rarepresents an alkyl, as defined above, and X represents a halogen atom selected from fluorine, chlorine, bromine and iodine.

The term "halogen" refers to fluorine atom, chlorine, bromine or iodine.

The term "hydroxyalkyl" refers to RaOH-group, where Rarepresents an alkyl, as defined herein, and representative examples include, but are not limited to, hydroxymethyl, hydroxyethyl and hydroxypropyl.

The term "aryl" refers to aromatic ring system with five-to ten carbon atoms, which may be monocyclic or bicyclic unsaturated or partially saturated, and one or more atoms angle of the ode can be optionally substituted by one or more heteroatoms, selected from N, O and S. the Term "aryl" includes ring(a), optionally substituted with a high degree of substitution, and the substituents may include alkyl, alkylen, dialkyl and oxo.

The term "arylalkyl" refers to Ar-Ragroup, where Ar and Rahave the meanings as indicated above.

The term "arylethoxysilanes" refers to-C(O)or SIGaAr group, where Ar and Rahave the meanings as indicated above.

The term "heteroaryl" refers to monocyclic aromatic ring system or condensed bicyclic aromatic ring system comprising two or more aromatic rings, preferably two rings. These heteroaryl rings contain one or more heteroatoms, such as nitrogen, sulfur and oxygen, where the functional group, such as N-oxides, sulfoxidov and dioxins, is acceptable as replacement heteroatoms. The term "heteroaryl" includes optionally substituted ring system. Examples of heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazol, oxadiazole, thiadiazole, isothiazol, pyridine, pyridazine, pyrazin, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole and their substituted versions.

The term "heterocyclyl" refers to a 3 to 15-membered ring, to the which is either saturated, or has one or more double bonds. Such heterocyclic rings contain one or more heteroatoms, such as nitrogen atoms, sulfur and/or oxygen, where the functional group, such as N-oxides, sulfoxidov and dioxins, are a valid replacement heteroatoms. Such a ring may be optionally condensed with one or more other heterocyclic rings (ring), aryl ring (ring) or cycloalkenyl rings (ring).

The term "stereoisomers" refers to certain described herein, compounds that contain one or more chiral centers, or otherwise, may be able to exist in the form of several stereoisomers. Scope of the present invention includes a pure stereoisomers, mixtures of stereoisomers such as purified enantiomers/diastereomers or a mixture enriched enantiomers/diastereomers, and racemates.

The term "bioisostere" refers to compounds or groups that have similar molecular configurations and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties, such as hydrophobicity. Bioisostere connections are similar biochemically associated systems as agonists or antagonists, and thus give rise to b the ideological properties, which are close to each other.

The term "pharmaceutically acceptable salt" includes salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al and Mn, salts of organic bases, such as N,N-diacetylethylenediamine, 2-dimethylaminoethanol, Isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, Tripropylamine, tromethamine, adamantylamine, diethanolamine, Ethylenediamine, N,N-benzylpenicillin, choline hydroxide, dicyclohexylamine, Metformin, benzylamine, phenylethylamine, dialkylamino, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, and spermidine, chiral bases like alkylenediamine, glycine and phenylglycine, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cysteine, cystine, methionine, Proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, and phenylalanine, non-natural amino acids such as D-isomers or substituted amino acids, salts with an acid group amino acids such as aspartic acid and glutamic acid, guanidine, substituted guanidine where the substituents are selected from nitro, amino, alkyl, alkenyl, quinil, ammonium or substituted ammonium salts. Salt can include an additive salts with an acid, such as sulfates, n is waste, phosphates, perchlorates, borates, hydrogenogenic selected from HCl, HBr, HI, acetates, tartratami, maleate, citrates, succinate, palmoate, methansulfonate, benzoate, salicylates, hydroxynaphthoate, bansilalpet, ascorbate, glycerophosphate and Ketoglutarate.

The term "pharmaceutically acceptable solvate" refers adducts and cocrystalline, such as a hydrate or a solvate, which include other solvents, for example alcohols.

The term "compounds of the invention" or "present invention" refers to compounds of the present invention represented by formula I, as described here, their derivatives, analogs, tautomeric forms, stereoisomers, bioisosterism, diastereomers, polymorphs, their pharmaceutically acceptable salts and solvate.

The term "suitable pharmaceutically acceptable carriers include solid fillers or diluents, sterile aqueous or organic solutions. The active ingredient will be present in such pharmaceutical compositions in amounts sufficient to provide the desired action as described above. Therefore, for oral administration the compounds can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, etc. Pharmaceutical HDMI is tion may contain additional components, such as corrigentov, sweeteners and excipients.

Preferred compounds of the present invention represented by formula Ia and the General structure shown below. In addition, preferred embodiments of presents their derivatives, analogs, tautomeric forms, stereoisomers, bioisostere, diastereomers, polymorphs, pharmaceutically acceptable salts and their pharmaceutically acceptable solvate.

where n represents 1 or 2

m represents 0, 1 or 2

X represents CH2, CHF or S

Y represents CN

R3independently selected from hydrogen and C1-C4the alkyl

R4represents hydrogen, C1-C4alkyl, substituted alkyl, C1-C4alkoxy, C1-C4alkanoyloxy, hydroxy, amino, nitro, C2-C6alkenyl, acyl or halogen

R is a R11, R12or R13and R11, R12, R13have the meanings as indicated above.

Preferred compounds of the present invention include the following compounds:

(2S)-1-[1H-1,2,4-triazole-1-ylmethyl(tricyclo[3,3,1,03,7]non-3-ylamino)acetyl]pyrrolidin-2-carbonitrile

(2S,4S)-4-fluoro-1-{N-[2-(1H-1,2,4-triazole-1-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}PI is Raiden-2-carbonitril

(2S,4R)-4-fluoro-1-{N-[2-(1H-1,2,4-triazole-1-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(4R)-3-{N-[2-(1H-1,2,4-triazole-1-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-1,3-thiazolidin-4-carbonitrile

(2S)-1-{N-[2-(1H-tetrazol-1-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

hydrochloric salt of (2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-(thiomorpholine-4-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

hydrochloric salt of (2S)-1-{N-[2-(thiomorpholine-4-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-[(1,1-dioxothiazolidine-2-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-[(2,4-dioxo-1,3-thiazolidin-3-yl)methyl]hexahydro-2,5-methamphetamin-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

((2S)-1-{N-[2-(1,2,4-oxadiazol-3-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-yl)acetonitrile

(2S)-1-{N-[2-[4-(1,1-dioxothiazolidine-2-yl)phenyl]Gex the hydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S,4S)-1-{N-[2-[4-(1,1-dioxothiazolidine-2-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-4-ftorpirimidinu-2-carbonitril

(2S,4R)-1-{N-[2-[4-(1,1-dioxothiazolidine-2-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-4-ftorpirimidinu-2-carbonitril

(4R)-3-{N-[2-[4-(1,1-dioxothiazolidine-2-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-1,3-thiazolidin-4-carbonitrile

(2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S,4S)-4-fluoro-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(4R)-3-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-1,3-thiazolidin-4-carbonitrile

(2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-[4-(2-Oxymetazoline-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

((2S)-1-{N-[2-[4-(3-methyl-2-Oxymetazoline-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-yl)acetonitrile

(2S)-1-[(tricyclo[3,3,1,03,7]non-3-ylamino)acetyl]pyrrolidin-2-carbonitrile

hydrochloric salt of (2S)-1-[(tricyclo[3,3,1,03,7]non-3-ylamino)acetyl]pyrrolidin-2-carbonitrile

(2S)-1-{[(1-hydroxytriazine[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-Carboni who Rhyl

hydrochloric salt of (2S)-1-{[(1-hydroxytriazine[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile

(2S)-1-{[(1-methoxytrityl[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile

hydrochloric salt of (2S)-1-{[(1-methoxytrityl[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile

(2S)-1-{[(1-amoxicilina[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile

hydrochloric salt of (2S)-1-{[(1-amoxicilina[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile

hydrochloric salt of (2S)-1-{[(1-aminotriazole[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile

(2S)-1-[N-(2-targetsaver-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile

hydrochloric salt of (2S)-1-[N-(2-targetsaver-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

hydrochloric salt of (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-(1,1-dioxothiazolidine-2-yl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

hydrochloric salt of (2S)-1-{N-[2-(1,1-dioxothiazolidine-2-yl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile

(2S)-1-[N-(2-dryer is hexahydro-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile

hydrochloric salt of (2S)-1-[N-(2-phenylhexane-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-(4-nitrophenyl)hexahydro-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile

(2S)-1-{N-[2-(4-AMINOPHENYL)hexahydro-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile

According to another aspect of the present invention the methods of obtaining described above for the compounds of General formula I.

Scheme I

Where

R represents H or a protective group,

L represents a group to delete selected from the group consisting of halogen atoms, tozilaty, mesylates and triflates

R, R1, R2, R3, R4, n, m, X and Y have the meanings as indicated above.

The compounds of formula I get the following stages, including:

A. The interaction of one equivalent of the compound of formula III with about 1-5 equivalents of amine compounds of formula II in free form or in salt form or in the form of compounds, where the amine is protected, in the presence of one or more bases, such as (but not limited to the above) hydrides of alkali metals like NaH and KH; organolithium compounds such as CH3Li and BuLi; alkoxides, such NaOMe, NaOEt, KOtBu; tertiary amines such as triethylamine and DBU; CT the courses, like potassium carbonate, potassium bicarbonate, sodium carbonate and cesium carbonate.

b. This interaction is carried out at a temperature in the range from about -5 º C to 120 ºC in an inert solvent, such as dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, DMSO, etc.

C. this interaction is carried out for from 0.5 to 72 hours, preferably for from 0.5 to 60 hours.

d. The allocation of the formed compounds of formula I.

The compounds of formula III can be obtained by the methods provided in the present level of technology (WO 2003/002553, WO 00/034241, WO 98/19998, US 2005/0038020, Bioorganic and Medicinal Chemistry Letters 1996, 6,1163-66, Journal of Medicinal Chemistry 2003, 46, 2774-2789).

The intermediate compound II can be obtained by sequential reactions are summarized in scheme II and III.

Scheme II

Scheme II describes the following stages, including:

1A. The interaction of benzene and 5-hydroxyadamantane by the reaction of the Friedel-in the presence of triflates acid over a period of about 1-4 hours at the boiling temperature under reflux to obtain 5-fenilalanina.

1b. Constriction rings of adamantanone to nordmanniana occurred in 2 stages, first was the conversion of 2-methyl-5-phenylalamine-2-ol by the Grignard reaction, where Reagan the Grignard reagent selected from the group includes methylmethanamine similar to the CH3MgCl, CH3MgBr, CH3MgI with subsequent narrowing of the rings in the presence of an oxidizing agent in a solvent, like water, THF, benzene, or a combination of these solvents, followed by treatment with a base in the proton solvent such as water, alcohols, with the formation of Ib. Preferred alcohols are1-C4alcohols and a base selected from NaOH and KOH. The oxidizing agent can be selected from the monoxide chlorine, hypochlorites, such NaOCl, or leads to compounds, which lead, in the presence of iodine.

II. The phenyl group of compound Ib was turned into a carboxyl group in the presence of an oxidizing agent, such NaIO4/RuCl3when the ambient temperature with the formation of Ic.

III. Carboxyl group of compound Ic was turned into a complex alkilany ether, ketogroup protected 1,2-diola, such as 1,2-ethanediol or 1,3-diola, such as 1,3-propandiol in the presence of organic solvents such as benzene or toluene, at a temperature of boiling under reflux, using an acid catalyst such as p-TSA, CSA and athirat BF3.At the next stage ester was recovered in alcohol regenerating agent such as LiAlH4, NaBH4and DIBAl-H in an inert solvent like THF, simple ether or their mixtures or the pits at a temperature of approximately 0 ° C with the formation of the Id.

Scheme III

Scheme III describes the following stages:

Ia. The hydroxy-group Ia in position 5 alkilirovanie alkylating agent, such alkylhalogenide (such as CH3I, CH3Br or isopropylphenyl) with the use of strong bases such as NaH, KH or NaOCH3with the formation of 5-hydroxyadamantane, with subsequent narrowing of the rings.

Ib. 5-Alkoxylation turned into 5-alkoxysilylated by turning it into a 2-methyl-5-alkoxyamino-2-ol by reaction of Grignard reagent with subsequent constriction rings of adamantanone in noradsanta in the presence of an oxidizing agent in a solvent, like water, THF, benzene, or a combination of such solvents, followed by treatment with a base in the proton solvent such as water, alcohols or mixtures thereof, with the formation of 5-alkoxysilylated.

IIa. Atanasova group in the compound obtained in stage 1, was converted to carboxylic acid by treatment oxidizing agent, such hypobromites, hypochlorites (such as NaOBr, NaOCl), approximately at 0OC followed by stage amination.

IIb. The acid was converted into the amine function by treatment with azide, such NaN3or nBu4NN3in acidic conditions in the presence of solvents, such CHCl3CH2Cl2CH3CN at a temperature of approx the tion from 35 to 50 º C with getting alkoxycarbonylmethylamino (1).

IIIa. Another way of synthesis of the hydroxyl group of compound Ia was Basilashvili interaction with benzylchloride like benzylbromide, in a solvent (such as THF, DMF, NMP) at approximately 0 ° C for about 10-18 hours with the formation of benzyloxyacetophenone, with subsequent narrowing of the ring with the formation of benzyloxycarbonylation.

IV. Benzyloxycarbonylation obtained at stage III, was converted to the corresponding acid by an oxidizing agent, followed by stage amination (b). Thus obtained amine was protected common groups for amine protection, like Boc, Cbz or Fmoc subsequent dibenzylammonium (d). Dibenzylamine carried out in an atmosphere of H2c Pd/C catalyst in proton solvents such as methanol, ethanol or IPA at room temperature for 1-3 h with the formation of hydroxynortriptyline, where the amino group is protected.

V. Halogenoalkanes hydroxyl group with the subsequent removal of the protection of the amine compound obtained in stage IVd, got halogensubstituted noradrenalin in salt form 2.

VI. Remove protection amine compound obtained in stage IVd, received the replacement noradrenalin in salt form 3.

Thus obtained intermediate compound 1, 2, 3 were subjected to reaction with chloroacetyl what anpirtoline with the formation of the respective end connections, in accordance with scheme I.

Scheme IV

X1is a halogen; Y1represents the SO2, CO; P represents Boc, CBz, Fmoc; k represents 1, 2, 3.

Scheme IV is described as follows.

Ia. The phenyl group of compound Ib (obtained according to the scheme I) was netravali nitrouse mixture by conventional methods HNO3/H2SO4at approximately 0OC.

Ib. Nitrophenylacetylene obtained in stage Ia, was oxidized to convert ethanone to the corresponding acid is an oxidizing agent followed by stage amination.

Ic. The conversion of acid to amine was performed by treatment with azide, such NaN3or n-BuNN3in acidic conditions in the presence of solvents, such CHCl3CH2Cl2or acetonitrile at a temperature of from about 35 to 50'C.

IIa. The amino group in the compound obtained in stage I, defended accepted for amine protective groups such as Boc, Cbz or Fmoc.

IIb. The nitrogroup restored in the amine reducing agents, such as Pd/C, Pd(OAc)2, Zn/ammonium formate or Fe/NH4Cl, etc. in the presence of solvents, such as esters (e.g. ethyl acetate), alcohols (e.g. methanol, ethanol, THF, water or a combination thereof with the formation of Fenelon is rosediana (4).

III. Phenylimidazoline (4), obtained in stage II were subjected to interaction with X1(CH2)nY1X1where X1represents a halogen group selected from F, Cl, Br, I, Y1represents the SO2or, in the presence of an organic base such as triethylamine or DBU, and an inert solvent like THF, CH2Cl2, acetonitrile or DMF) followed by cyclization in the presence of hydroxides of alkali metals, such as LiOH, NaOH or KOH in water with interphase catalyst, such as tetraalkylammonium (for example, tetrabutylammonium) and removing the protective group of the amine to obtain the corresponding heterocyclization phenylenedimethylene connection (5).

IV. In another method, the compound (2)obtained in stage II were subjected to interaction with X1(CH2)NCO in the presence of organic bases such as triethylamine or DBU, solvent, like THF, CH2Cl2, acetonitrile, DMF or their mixtures, followed by cyclization to obtain the corresponding heterocyclization connection, which by further removal of protection of the amine formed corresponding heterocyclization phenylenedimethylene connection (6).

V. In another way phenylimidazoline (2)obtained at the second stage, experience and interaction with 2.5-dimethoxytetrahydrofuran in glacial acetic acid at the boiling temperature under reflux with the formation of substituted pyrrole compounds after removal of the protection of the amine formed corresponding perosamine phenylenedimethylene connection (7).

VIa. Atanasova group of phenylenedimethylene (Ib) (obtained according to scheme II) was converted into the acid group with an oxidizing agent followed by stage amination.

VIb. The conversion of acid to amine using azides, as indicated above, had been duly phenylsilane noradenaline connection (8).

The obtained intermediate amine compounds 4, 5, 6, 7, 8 were subjected to interaction with chloroacetanilide with formation of the corresponding final compounds according to scheme I.

Scheme V

Scheme V describes as follows:

Ia. The carboxylic acid group of compound Ic (obtained according to scheme II) was converted to the amine by treatment with azide, such NaN3in an acid environment or diphenylphosphorylacetate in the presence of organic bases such as triethylamine, solvents such as benzene or toluene at the boiling temperature under reflux.

IIb. Amine group compounds If received at stage I, defended accepted for amine protecting group, such BOC, Cbz or Fmoc, followed by a stage of oxidation.

IIIc. Oxidation of the compound obtained in stage II, carried out omissus the agents with obtaining a carboxylic acid derivative.

IIId. Such a group of the carboxylic acid compound obtained in stage IIIc, was turned into an amine by treatment with azide, for example NaN3in an acid environment or diphenylphosphorylacetate in the presence of organic bases such as triethylamine, in a solvent such as benzene or toluene, at a temperature of boiling under reflux, followed by hydrolysis of the metal hydroxide, such as KOH, NaOH, LiOH, in water at room temperature with formation of the corresponding substituted amine of nordmanniana (9).

IV. Aminosidine (If)obtained at the first stage were subjected to interaction with X1(CH2)nY1X1where X1represents a halogen and Y1represents-SO2or

-CO-, in the presence of organic bases such as triethylamine, and a solvent like THF or CH2Cl2with subsequent cyclization using hydroxides of alkali metals, in water, with interphase catalyst, such as tetrabutylammonium, obtaining relevant heterocyclization connections Atanasova the group stages after oxidation and amination as shown in the diagrams IIIc and IIId, was converted into the corresponding substituted by a heterocycle nordmanniana (10).

The obtained amine intermediate compounds 9 and 10 were subjected to wsimages the view with chloroacetanilide with the formation of the respective end connections, in accordance with scheme I.

Scheme VI:

Scheme VI describes as follows:

I. For connection Ie hydroxyl group

connection Id turned in the deleted group L, for example, metilirovaniem, coleserveritem or halogenoalkanes in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, NMP or N-methylmorpholine at a temperature of approximately 0 ° C.

II. Tsepliaeva group L Ie was substituted by a group R11in the presence of base and solvent, at a temperature of approximately 80-120 ºC with education Ii. Base selected from carbonates or bicarbonates of alkali metals like Na2CO3, NaHCO3, K2CO3or KHCO3. The solvent selected from dimethylformamide, DMSO, NMP or similar solvent.

IIIa. Remove the protective group in the protected ketogroup of compound (Ii) obtained at the second stage, for example, the interaction with p-TSA in acetone at boiling temperature under reflux, with the formation of atenololo connection.

IIIb. Atanasova compound was oxidized to the corresponding carboxylic acid in the presence of an oxidizing agent, which you can choose from monoxide chlorine, hypochlorites, such NaOCl or leads to compounds, which lead, in the presence of iodine.

IIIc. The carboxylic acid was converted is in the amine interaction with azide, like NaN3in acidic conditions, in the presence of solvents, such CHCl3CH2Cl2or acetonitrile, at approximately 35-45 º C with the formation of substituted R11nordmanniana (11).

IV. In another way hydroxyl group Id, which was obtained according to scheme II, was Basilashvili interaction with benzylchloride like benzylbromide, in solvents like THF, DMF or NMP at approximately 0 ° C for approximately 10-18 h with education having a protected ketogroup of benzyloxyacetophenone (Ig).

Va. The compound Ig was removed protection ketogroup getting ethanone, as described in stage IIIa.

Vb. Atanasova group benzyloxycarbonylamino compounds were oxidized with obtaining carboxylic acids, as described for stage IIIb.

Vc. Carboxyl group of the compound obtained in stage Vb, turned in the amine interaction with diphenylphosphorylacetate, in the presence of organic bases such as triethylamine, in a solvent such as benzene or toluene, at a temperature of boiling under reflux, followed by hydrolysis of metal hydroxides, such as KOH, NaOH or LiOH in water at room temperature with the formation of benzyloxycarbonylamino (Ih).

Via. The amino group of compound Ih obtained at the stage Vc, defended accepted for amine protection of the indigenous groups, for example, such as described previously, with the subsequent stage of dibenzylamine.

VIb. Dibenzylamine carried out in an atmosphere of H2with Pd/C in proton solvents such as methanol, ethanol or IPA at room temperature for 1-3 h with the formation of compound Ij.

VIIa. Hydroxyl group of the compound Ij was metilirovanie, tailorable or halogenerator with the formation of the deleted group, in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, N-methylpiperidine or N-methylmorpholine at ambient temperature.

VIIb. The compound obtained in stage VIIa were subjected to interaction with R11group in the presence of base and solvent at a temperature in the range of approximately 80 to 120 ºC. Base selected from carbonates or bicarbonates of alkali metals like Na2CO3, NaHCO3, K2CO3and KHCO3. The solvents selected from DMF, DMSO, NMP, and others.

VIIc. The protected amino group is substituted by an R11the compound obtained in stage VIIb, removed the protection of conventional ways, for example by treatment with dry HCl in a solvent, such EtOAc, simple ether or 1,4-dioxane at a temperature from 0 ° C to room temperature with the formation of R11-substituted nordmanniana in the form of a hydrochloric salt (12).

VIIIa. In other the th way hydroxyl group Ij were subjected to interaction with R 11group in the presence of triphenylphosphine, diisopropylcarbodiimide, and an organic solvent such as benzene, toluene or THF, at a temperature of from approximately 20 to approximately 110 º C for about 2-6 hours with the formation of R11-substituted compounds.

VIIIb. The protective group of amino group, R11-substituted compounds obtained in stage VIIIa were removed by treatment triperoxonane acid in a solvent, such CH2Cl2or Cl3at approximately 0 ° C with the formation of R11-substituted noradrenalin, as, for example, salt with TFA (13). The obtained intermediate compounds 11, 12 and 13 were subjected to interaction with chloroacetanilide with the formation of the respective end connections, in accordance with scheme I.

Scheme VII:

Scheme VII describes as follows.

Ia. For education to be deleted group L the hydroxy-group connection Ij was metilirovanie, tailorable or halogenerator in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, N-methylpiperidine or N-methylmorpholine at ambient temperature. Connection received from Ia were subjected to interaction with tianyoude agent, such NaCN in the presence of an aprotic solvent like DMF, pri-110 º C for about 12-15 hours to obtain the compound (Ik).

IIa. Connection Ik subjected to interaction with hydroxylamine hydrochloride with education amidoxime, which was then subjected to interaction with triethylorthoformate in the presence of catalytic amounts of camphorsulfonate. In the end after removal of the protection received connection 14.

The obtained intermediate compound 14 was subjected to interaction with chloroacetanilide with the formation of the respective end connections, in accordance with scheme I.

It is clear that in any of the above schemes, any reactive group in the substrate molecule can be protected in accordance with any conventional technique known in the prior art. Suitable protective groups include tetraarylborates, methoxymethyl, triphenylmethyl, benzyloxycarbonyl, TPR, etc. for protection of hydroxyl or phenolic hydroxy groups; N-BOC, N-Cbz, N-Fmoc and benzophenone to protect amino or inlinegroup; acatalog protection for aldehydes, catalog protection for ketones. Methods of formation and removal of such protective groups which are known in the technical field depend on molecules that protect.

Also part of the invention is that by carrying out the invention, wherever there tsepliaeva group can be selected from the group comprising halogen atoms is in (such as chlorine, the bromine), toluensulfonyl, o-methylsulphonyl.

The stereoisomers of the compounds in accordance with this invention, can be obtained with the use of reagents in separate enantiomeric form in the way that, wherever possible, or by performing the reaction in the presence of reagents or catalysts in the form of a single enantiomer, or a separation of a mixture of stereoisomers in a common manner. Some of the preferred methods include the use of microbial separation, separation of the diastereomeric salts formed with chiral acids such as mendelova acid, camphorsulfonic acid, tartaric acid or lactic acid, wherever applicable, or chiral bases such as brucine, quinine alkaloids or derivatives thereof.

Pharmaceutically acceptable salts can be obtained by the coupling of compounds of formula I with about 1-5 equivalents of bases, such as hydroxides of alkali metals, alkoxides of alkali metals, calcium hydroxide or magnesium hydroxide, in a proton or aprotic solvents such as methanol, ethanol, propanol, IPA, simple, ether, THF, dioxane, etc. In the alternative case, wherever applicable, additive salts with acid was obtained by treatment with acids such as halogen acids, like HCl, HBr; nitric acid, sulfuric acid, FOSFA the NSS acid, p-toluensulfonate acid, methanesulfonate acid, acetic acid or citric acid, in a solvent that includes at least one selected from ethyl acetate, ethers, alcohols, acetone, THF, dioxane or mixtures thereof.

Different polymorphs of the compounds of General formula I of the present invention can be obtained by crystallization of the compounds of formula I under different conditions. For example, with the use of commonly used solvents or their mixtures for recrystallization, crystallization at various temperature ranges, different methods of cooling, such as from very fast to very slow cooling during crystallization, curing compounds at ambient temperature, by heating or melting it with subsequent gradual cooling, etc. the Presence of polymorphs may be determined by one of several methods, such as NMR spectroscopy and solid probe, DSC, TGA, x-ray or infrared spectroscopy.

In another embodiment of the present invention compounds can be treated using methods such as crystallization from solvents such as pentane, simple diethyl ether, simple, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or a combination thereof, or the compound I can acidat the column chromatography using alumina or silica gel and elution of the column such solvents, as hexane, petroleum ether, dichloromethane, chloroform, ethyl acetate, acetone, methanol or combinations thereof.

The present invention also provides pharmaceutical compositions containing the compounds as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, bioisostere, polymorphs, enantiomers, diastereoisomers, pharmaceutically acceptable salt or pharmaceutically acceptable solvate in combination with appropriate pharmaceutically acceptable carriers or diluents. Pharmaceutical compositions in accordance with the present invention is applicable as antidiabetics, lipid or antihypercholesterolemic funds.

Suitable pharmaceutically acceptable carriers include solid fillers, diluents and sterile aqueous or organic solutions. The active ingredient will be present in such pharmaceutical compositions in amounts sufficient to provide the desired effect, as described above. Therefore, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to education, for example, capsules, tablets, powders, syrups, solutions or suspensions. The pharmaceutical compositions can, if desired, contain additional components, such to the to the corrigentov, sweeteners or excipients.

By introducing may be oral, nasal, pulmonary, transbukkalno, subcutaneous, intracutaneous, percutaneous or parenteral e.g. rectal, depot, subcutaneous, intravenous, be, intramuscular, intranasal, in the form of an ophthalmic solution or ointment, which effectively transports the active compound of the present invention which inhibits the enzymatic activity of DPPIV in the appropriate or desired site of action. For oral administration, if used solid media, the drug may be in the form of tablets, or may be placed in a hard gelatin capsule in powder form or granules, or it may be in the form of lozenges or candy. If you use a carrier liquid, the preparation may be in the form of a syrup, emulsion, hard gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. For nasal introduction applied as a spray application of liquid media, particularly aqueous media. For parenteral application suitable compositions are injectable solutions or suspensions, preferably aqueous solutions.

An additional aspect of the present invention is the use of compounds of the invention as pharmacist the political composition in a therapeutically effective amount for the treatment of metabolic disorders reduce the level of glucose in the blood, for the treatment of type II diabetes, for the treatment of worsening glucose tolerance, for the treatment of lower fasting glucose levels, for the treatment of obesity, for the prevention of hyperglycemia, for treatment of dyslipidemia, hypercholesterolemia, hypolipidemia or to reduce body weight or diabetic complications, including coronary artery disease, stroke, hypertension, nephropathy, peripheral vascular disease, neuropathy or retinopathy.

Compounds of the present invention are effective throughout a wide range of doses. For example, in the treatment of people dose can be from about 0.05 to 1000 mg and preferably from about 0.1 to 500 mg per day. The exact dose depends on the method of administration, from therapeutic requirements, form in which administered the active ingredient, and the patient being treated, the body weight of the subject to treatment and the preferences and experience of the doctor in the house. Here, as the subject considers the human being.

The invention also includes proletarienne derivatives of the compounds of the invention that after the introduction undergo chemical conversion by metabolic processes before becoming active pharmacological substances. Typically, such proletarienne derivatives will be fun is performance communications derivatives of the compounds of the invention, which is easily converted in vivo into compounds of the invention.

The invention also includes active metabolites of compounds of the present invention.

Test activity dipeptidylpeptidase IV

Inhibition of the proteolytic activity of DPP-IV was tested using the hydrolysis of Ala-Pro-7-amino-4-triptorelin (Ala-Pro-AFC) and subsequent fluorometric quantification selected AFC. For tests used human recombinant DPP-IV (expressed in cells Sf9 insect). Test compounds were dissolved in dimethyl sulfoxide (DMSO). Typically, the enzyme (approximately 20 ng/ml in 100 mm buffer Tris-HCl, pH 8.0) pre-incubated in the absence (1% DMSO) and in the presence of various concentrations of test compounds for 15 min at 37º. The reaction was initiated by adding 20 μm Ala-Pro-AFC and additionally incubated for 30 min at 37º. The amount AFC was measured by a spectrophotometer with excitation wavelengths and emission at 400 nm and 510 nm, respectively. The results were expressed as percent inhibition of enzyme activity. The study has always included a reference standard (a known inhibitor of DPP-IV).

Found that the compounds of the present invention inhibit induced DPPIV fluorescence with inhibition constants in the range of approximately the t of 0.5 nm to 500 nm. In the preferred area, the compounds of the present invention inhibited induced DPPIV fluorescence with an inhibition constant of approximately 0.1 nm to 300 nm and more preferred field of compounds of the present invention inhibited induced DPPIV fluorescence with the inhibition constant Ki of approximately 1 nm to 120 nm.

As shown in the table below, the compounds of examples cause strong inhibition of DPP-IV.

ConnectionThe value of the IC50in nmConnectionThe value of the IC50in nm
Example 18,1Example 178,7
Example 22,8Example 18~30
Example 3>300Example 1915,4
Example 47Example 2030
Example 511Example 21 64,5
Example 6100Example 2230
Example 730Example 2311,9
Example 822Example 24100
Example 931,2Example 25100
Example 10~30Example 2621,8
Example 1120Example 2730
Example 125Example 2830
Example 13300Example 29~30
Example 146,4Example 30~32,4
Example 154Example 3121,0
Example 160,95Example 3253,6

The following examples provide an opportunity specialist in the field of machinery for the practical implementation of the invention and represent only an illustration of the invention but do not limit the scope of the invention.

The intermediate compounds

The drug 1

1-(1-Fenestrelle[3,3,1,03,7]non-3-yl)alanon

Stage I:Adamantane (12 g, 80 mmol) was added under stirring to nitric acid (98%, 100 ml) at a temperature bath with ice for 15 minutes. The reaction mixture was stirred at room temperature for 72 h and then was heated up to 60 ° C for 2 h until, until you evaporate a large portion of nitrogen dioxide. The excess nitric acid drove away under reduced pressure. A light yellow oil hardened after cooling (adduct NO3with hydroxyketone). Was added water (40 ml) and conc. H2SO4(98%, 15 ml). The obtained transparent yellow solution was heated on the steam bath in a fume hood (in a stream of nitrogen) for 1 h Then the solution was cooled and was extracted with a mixture of 2:1 n-hexane and simple diethyl ether to remove the unreacted adamantanone (1.0 g). The acid layer was neutralized 30% water. RAS is a thief NaOH and the solution was warm, was extracted with chloroform. The extracts were combined, washed with saturated salt solution and concentrated in vacuum. The crude product was dissolved in CH2Cl2(15 ml) and hexane was added until the termination of the sediment. The solid was isolated by filtration and dried to obtain 5-hydroxyadamantane-2-it. Yield: 9.0 g (70%). The solid. TPL: much as 278.8-300 (decomposition) m/z (M+1) 167;1H NMR (CDCl3) 300 MHz δ 2,70 is 2.55 (m, 2H), 2,36 of-2.32 (m, 1H), 2,11-of 1.93 (m, 10H).13With NMR (CDCl3) 75 MHz δ 217,0, 66,7, 46,7, 46,6, 44,7 (2C), 43,8, 37,9 (2C), 29,5.

Stage II: To a stirred solution of compound 5-hydroxyadamantane-2-she (10.0 g, a 60.2 mmol) in benzene (180 ml) was added triftormetilfullerenov acid (5.3 ml of 60.2 mmol) over a period of 30 minutes at room temperature. After stirring the reaction mixture for 5 minutes at room temp. the mixture was boiled under reflux for 4 hours, the Reaction mixture was cooled to 0º and added a saturated aqueous solution of NaHCO3(76 ml) over a period of 30 minutes. Two layers were separated, the aqueous layer was extracted with simple ether and the combined layer was washed with water and saturated salt solution, dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain 5-phenylalamine-2-she (10.5 g) as a white solid with a yield of 80%. TPL: 53,8-60,9º. m/z (M+1) 227; IR(cm -1): 2921, 2853, 1717, 1446, 1060, 758, 698.1H NMR (CDCl3) 300 MHz δ 7,37-7,30 (m, 4H), 7,26-7,19 (m, 1H), 2,70 2.63 in (m, 2H), 2,30-2,0 (m, 11N).13With NMR (CDCl3) 75 MHz δ 217,8, 147,8, 128,3 (2C), 126,1, 124,6 (2C), 46,9 (2C), 44,3 (2C), 41,9, 35,9, 38,4 (2C), 28,0.

Stage III:Just received methylmagnesium simple ether (1 M 85 ml) was added through a tube to the 5-phenylalamine-2-ONU (9.6 g, 42,5 mmol)obtained in stage II, in THF (85 ml) at 0OC. After stirring at 0 ° C for 0.5 h, the reaction mixture was suppressed by the addition of saturated aqueous solution of NH4Cl. The organic layer was separated and the aqueous layer was extracted with simple diisopropyl ether. The combined organic layers were washed with water and saturated salt solution, dried over anhydrous Na2SO4and the solvent was removed under reduced pressure to obtain 2-methyl-5-phenylalamine-2-ol (9,9 g) in the form of not-quite-white solid with a yield of 97%. TPL: 98-100,4ºC. m/z (M+23) 265;1H NMR (CDCl3) 300 MHz δ 7,42-7,28 (m, 4H), 7.24 to to 7.18 (m, 1H), 2,47-of 2.26 (m, 2H), 2,14-of 2.09 (m, 3H), 1,96 is 1.70 (m, 6N), 1,61-of 1.57 (m, 2H), 1,42 (s, 3H).13With NMR (CDCl3) 75 MHz δ 150,0, 128,1 (2C), 125,7, OF 124.8 (2C), 73,3, 44,0 (2C), 40,5 (2C), 39,6 (2C), 35,9, 32,0, 27,6.

Stage IV:2-Methyl-5-phenylalamine-2-ol (20 g, to 82.6 mmol)obtained in stage III (86 g, 355,4 mmol), dissolved in a mixture of Asón (76,3 ml) and THF (360 ml)was added dropwise through a funnel attached to chilled in an ice bath, the solution aOCl (4%, 3.5 l) over a period of 15 minutes. Was added solid n-Bu4NI (13,1 g of 35.6 mmol) and the reaction mixture was stirred for 1.5 hours Two layers were separated, the aqueous layer was extracted with simple diisopropyl ether and the combined organic layer was washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The residue was dissolved in methanol (165 ml), was added KOH (39,8 g, 300 mmol) and the mixture is boiled under reflux for 1 h the Solvent is evaporated under reduced pressure and the crude product was purified column chromatography to obtain compound 1-(1-fenestrelle[3,3,1,03,7]non-3-yl)alanon (50.0 g) with a yield of 59% in the form of a viscous liquid. M/z (M+1) 241; IR (cm-1): 2924, 2867, 1697, 1445, 1356, 1223, 757, 699.1H NMR (CDCl3) 300 MHz δ 7,38-7,19 (m, 5H), 2,86 is 2.80 (m, 1H), 2,59-of 2.50 (m, 1H), 2,32 was 2.25 (m, 1H), of 2.23 (s, 3H), 2,10-1,99 (m, 4H), 1,90-to 1.79 (m, 4H), 1,78-1,71 (m, 1H).13With NMR (CDCl3) 75 MHz δ 211,7, 146,7, 128,2 (2C), 125,7 (2C), 124,7, 61,9, 50,2, 49,0, 47,9, 45,7, 42,4, 42,3, 37,6, 26,4.

The product 2

[3-(2-Methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methylmethanesulfonate

Stage I: To stir a mixture of 1-(ventriculo[3,3,1,03,7]non-3-yl)ethanone (8.0 g, 33.3 mmol), obtained as described previously (product I), carbon tetrachloride (66 ml), acetonitrile (66 ml) and water (100 ml), obladenno is to 0OC, added periodate sodium (31,9 g, 149 mmol) and hydrate chloride ruthenium (III) (0,44 g, 1.7 mmol). The reaction mixture was slowly heated to ambient temperature and was stirred for 2 hours, the Reaction mixture was diluted simple diisopropyl ether (100 ml) and was stirred for 15 min before the deposition of the dark matter RUO Li2. Then the reaction mixture was filtered through a layer of celite and the organic layer was extracted with 1N NaOH solution (3×25 ml). The organic layer was dried over Na2SO4and the solvent evaporated in vacuum to obtain unreacted educt (3.04 from g 12,67 mmol). The aqueous layer was acidified using conc. HCl and was extracted with EtOAc. The combined organic layers were washed with water, saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 3-acetylthiazole[3,3,1,03,7]nonan-1-carboxylic acid (4.0 g) in the form of not-quite-white solid with a yield of 57%. TPL: 90-95,0OC. m/z (M+1) 209. IR cm-12935, 1694, 1413, 1357, 974, 746.1H NMR (CDCl3) 300 MHz δ 2.77-to 2,73 (m, 1H), 2,54-2,48 (m, 1H), 2,44-of 2.34 (m, 1H), measuring 2.20 (s, 3H), 2,18-of 2.09 (m, 1H), 7,38-7,19 (m, 5H), 2,86 is 2.80 (m, 1H), 2,59-of 2.50 (m, 1H), 2,32 was 2.25 (m, 1H), of 2.23 (s, 3H), 2,18-of 2.09 (m, 1H), 2.06 to around 1.74 (m, 7H), 1,73-to 1.61 (m, 1H).13With NMR (CDCl3) 75 MHz δ 211,0, 181,3, 61,5, 50,3, 47,9, 45,9, 45,6, 42,6, 41,9, 36,8, 35,6, 26,4.

Stage II:3-acetylthiazole[3,3,1,03,7]nonan-1-carboxylic acid (2.4 g, 11.4 m is ol), received at stage I, in the Meon (48 ml), cooled to a temperature bath with ice, was added acetylchloride (1,64 ml of 22.8 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 2 hours, Volatile products were removed under reduced pressure and the crude substance was purified column chromatography to obtain methyl-3-acetylthiazole[3,3,1,03,7]nonan-1-carboxylate (2.4 g) with a yield of 93% in the form of a viscous liquid. M/z (M+1) 223. IR cm-12953, 1728, 1698, 1461, 1234, 1078, 755.1H NMR (CDCl3) 300 MHz δ 3,66 (s, 3H), of 2,75 2,70 (m, 1H), 2,53 is 2.46 (m, 1H), 2,40 of-2.32 (m, 1H), 2,19 (s, 3H), 2,15-2,05 (m, 1H), 2,03 is 1.60 (m, 8H).13With NMR (CDCl3) 75 MHz δ 210,9, 175,3, 61,4, 53,4, 51,6, 50,5, 48,0, 45,9, 45,6, 42,6, 41,9, 36,8, 35,9, 26,4.

Stage III:A mixture of methyl-3-acetylthiazole[3,3,1,03,7]nonan-1-carboxylate (2.0 g, 8.9 mmol), obtained in stage II, 1,2-ethanediol (8,9 ml), p-TSA (47 mg, 5 mol.%) and benzene (36 ml) was boiled under reflux with the use of the device, Dean-stark for 1 h, the Reaction mixture was cooled to room temperature, was added 10% water. NaHCO3(36 ml) and separated the two layers. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated salt solution, dried over Na2SO4and the solvent evaporated under reduced pressure to obtain methyl 3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]nonan-1-carboxylate (2.2 g) with vyhoda% in the form of a viscous liquid. M/z (M+1) 267. IR cm-12954, 1731, 1698, 1460, 1236, 1046, 752.1H NMR (CDCl3) 300 MHz δ 4,07-of 3.94 (m, 4H), 3,66 (s, 3H), 2,44-of 2.36 (m, 2H), 2,27-to 2.18 (m, 1H), 2,12-2,02 (m, 1H), 1,94-of 1.81 (m, 8H), of 1.30 (s, 3H).

Stage IV:Methyl-3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]nonan-1-carboxylate (2.3 g, 8,64 mmol)obtained in stage III, in THF (15 ml) was slowly added in an atmosphere of N2through an addition funnel to a suspension of LiAlH4(0.32 g, 8,64 mmol) in a simple ether (15 ml) at a temperature bath with ice. The reaction mixture was stirred for 30 minutes before quenching the reaction by addition of a saturated aqueous solution of NH4Cl (9 ml), followed by 1N NaOH solution (9 ml)and the reaction mixture was stirred at room temperature for 15 min before filtering the mixture through a layer of celite. The organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent evaporated under reduced pressure to obtain [3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methanol (1.9 g) with a yield of 94% in the form of a viscous liquid. M/z (M+1) 269; IR cm-13436, 2936, 1634, 1459, 1373, 1309, 1047, 757.1H NMR (CDCl3) 300 MHz δ 4,15-of 3.80 (m, 4H), 3,53 (s, 3H), 2,50-of 2.30 (m, 2H), 1,90-of 1.30 (m, 10H), of 1.29 (s, 3H).

Stage V:To a solution of [3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methanol (2.0 g, of 8.47 mmol)obtained in stage IV, in THF (35 ml) at a temperature bath with ice, succession of the nutrient was added triethylamine (3.5 ml, to 25.4 mmol), DMAP (52 mg, 0.42 mmol) and methanesulfonamide (0,97 ml, 12.7 mmol). After stirring the reaction mixture at the same temperature for 0.5 h, the mixture was diluted with water and was extracted with EtOAc. The combined organic layers were washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain the above compound [3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methylmethanesulfonate (2.4 g) with a yield of 90% in the form of a viscous liquid. m/z (M+1) 317. IR cm-12954, 1461, 1356, 1216, 1174, 1048, 756.

1NMR (CDCl3) 300 MHz δ 4,15-3,90 (m, 4H), of 3.00 (s, 3H), 2,44-of 2.36 (m, 2H), 1,89-to 1.79 (m, 2H), 1,78-of 1.42 (m, 8H), of 1.29 (s, 3H).13With NMR (CDCl3) 75 MHz δ 112,1, 76,3, 64,95, 64,9, 57,3, 46,6, 45,3, 44,9, 44,5, 42,9, 39,8, 36,9, 36,7, 36,3, 20.

Drug 3

{3-[(tert-butoxycarbonyl)amino]tricyclo[3,3,1,03,7]non-1-yl}methylmethanesulfonate

Stage I:To a suspension of NaH (60% dispersion in medical oil, 3,36 g, 21 mmol) in THF (84 ml), cooled to a temperature bath with ice, was added a solution of [3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methanol (10.0 g, 42.0 mmol) (which was obtained as described previously (preparation 2), stage IV) in THF (84 ml) via syringe over a period of 30 minutes. After stirring the reaction mixture for 30 minutes in to the room temperature, consistently added nBu4NI (0,37 g, 1.0 mmol); followed by the addition of benzylbromide (5.0 ml, 42.0 mmol). The reaction mixture was heated to room temperature and was stirred for 16 h before detectable by TLC completion of the reaction. After cooling the reaction mixture to a temperature bath with ice, the excess NaH was suppressed by the addition of saturated aqueous solution of NH4Cl. Two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated salt solution, dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to get crude mass of the substance, which was purified column chromatography to obtain 2-[1-(benzoyloxymethyl)tricyclo[3,3,1,03,7]non-3-yl]-2-methyl-1,3-dioxolane (11,0 g) as a viscous liquid with a yield of 80%. m/z (M+1) 329;1H NMR (CDCl3) 300 MHz δ 7,38-7,22 (m, 5H), 4,50 (s, 2H), was 4.02-to 3.92 (m, 4H), 3,24 (s, 2H), 2,38-of 2.30 (m, 2H), 1,88-1,71 (m, 2H), 1.70 to to 1.60 (m, 4H), 1,55-of 1.39 (m, 4H), of 1.27 (s, 3H).

Stage II:A mixture of 2-[1-(benzoyloxymethyl)tricyclo[3,3,1,03,7]non-3-yl]-2-methyl-1,3-dioxolane (2.6 g, 7.9 mmol), p-toluensulfonate acid (0.3 g, 1.6 mmol) and acetone (31,6 ml) was boiled under reflux for 4 hours Volatiles were removed in vacuum and the residue was diluted with EtOAc, washed with 10% water. NaHCO3and saturated salt solution, dried over Na2SO4and Rast is oritel evaporated under reduced pressure to obtain 1-{1-[(benzyloxy)methyl]tricyclo[3,3,1,0 3,7]non-3-yl}ethanone (2.1 g) as a viscous liquid with a yield of 93%. m/z (M+1) 285;1H NMR (CDCl3) 300 MHz δ 7,40-7,22 (m, 5H), 4,50 (s, 2H), 3.27 to (s, 2H), 2,70-2,62 (m, 1H), 2,47-to 2.40 (m, 1H), 2,16 (s, 2H), 2.0 to 1,90 (m, 2H), 1,81-of 1.56 (m, 7H), 1,50 (DD, J=3.0 a, and 11.0 Hz, 1H).

Stage III:To a mixture of NaOH (30,6 g, 765 mmol), N2(255 ml) and 1,4-dioxane (51 ml) at a temperature bath with ice was added Br2(15.2 ml, 285,6 mmol) and was stirred for 15 minutes. This hypobromite solution was added dropwise to a stirred solution of 1-{1-[(benzyloxy)methyl]tricyclo[3,3,1,03,7]non-3-yl}ethanone (14.5 g, 51,0 mmol) in 1,4-dioxane (51 ml) at a temperature bath with ice. The reaction mixture was gradually heated to room temperature and was stirred for 1 h, the Reaction mixture was cooled to a temperature bath with ice and extinguished the addition of Asón them (46.7 ml, 765 mmol). The reaction mixture was diluted with water, was extracted with EtOAc, the combined organic layers were washed with saturated salt solution, dried over Na2SO4the solvent was removed under reduced pressure to obtain 1-{1-[(benzyloxy)methyl]tricyclo[3,3,1,03,7]nonan-3-carboxylic acid (8.0 g) as a white solid with a yield of 55%. m/z (M-1), 285;1H NMR (CDCl3) 300 MHz δ 7,40-7,22 (m, 5H), 4,50 (s, 2H), 3.27 to (s, 2H), 2,70-2,62 (m, 1H), 3,47-to 3.38 (m, 1H), 2,16 (s, 2H), 2,12-to 1.98 (m, 2H), 1,90-of 1.55 (m, 7H), 1,50 (DD, J=3.0 a, and 11.0 Hz, 1H).

Stage IV:To stir a mixture of 1-[(benzyloxy is)methyl]tricyclo[3,3,1,0 3,7]nonan-3-carboxylic acid (1.8 g, 6.3 mmol), obtained in stage III, triethylamine (2.6 ml, of 18.9 mmol) and toluene (25 ml) at a temperature bath with ice was added diphenylphosphoryl (1.5 ml, 6,93 mmol). The reaction mixture was heated to room temperature, was stirred for one hour and then boiled under reflux for 4 hours After completion of the reaction, the reaction mixture was transferred into a separating funnel and washed with water. The organic layer was stirred with water. a solution of KOH (50 wt%./about., of 12.6 ml) and nBu4NI (120 mg, 0.32 mmol) for 2 hours the Reaction mixture was cooled to a temperature bath with ice, acidified 2n KHSO4to pH 2, extracted with simple ether, the aqueous layer was podslushivaet aqueous solution of NaOH (50 wt%./about.) and was extracted with chloroform. The combined organic layers were dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain 1-[(benzyloxy)methyl]tricyclo[3,3,1,03,7]nonan-3-amine (0,82 g) in the form of a viscous liquid in 51%yield. m/z (M+1) 258;1H NMR (CDCl3) 300 MHz δ 7,37-of 7.24 (m, 5H), 4,50 (s, 2H), 3,24 (s, 2H), 2,37-to 2.29 (m, 1H), 2.0 to is 1.81 (m, 3H), 1,78 is 1.70 (m, 1H), 1.70 to a 1.45 (m, 7H), 1,40 (DD, J=2,9 and 10.7 Hz, 1H).

Stage V: To a stirred solution of 1-[(benzyloxy)methyl]tricyclo[3,3,1,03,7]nonan-3-amine (about 0.82 g, 3.2 mmol)obtained in stage IV, in dichloromethane (13 ml) at a temperature bath with l the house was added Et 3N (of 0.67 ml, 4.8 mmol) and di-tert-BUTYLCARBAMATE (0,77 g, 3.5 mmol). After stirring the reaction mixture at room temperature for 1 h, volatiles were removed under reduced pressure and the crude substance was purified column chromatography to obtain tert-butyl[1-(benzoyloxymethyl)tricyclo[3,3,1,03,7]non-3-yl]carbamate as a viscous liquid (1.0 g) with a yield of 88%. m/z (M+1) 358;1H NMR (CDCl3) 300 MHz δ 7,37-of 7.24 (m, 5H), of 4.49 (s, 2H), 3,25 (s, 2H), 2,48-of 2.38 (m, 1H), 2,37-of 2.30 (m, 1H), 2,10-to 1.87 (m, 2H), 1,82-to 1.67 (m, 2H), 1,67-of 1.39 (m, 6N), the 1.44 (s, N).

Stage VI: To a stirred mixture of tert-butyl[1-(benzoyloxymethyl)tricyclo[3,3,1,03,7]non-3-yl]carbamate (1.0 g, 2.8 mmol)obtained in stage V, in the Meon (11 ml), was added Pd/C (10%, 0.2 g). Then was applied from a container under pressure of H2within 2 hours the Reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure to obtain tert-butyl[1-(hydroxymethyl)tricyclo[3,3,1,03,7]non-3-yl]carbamate as a viscous liquid (0.7 g) with a yield of 95%. m/z (M+1) 268;1H NMR (CDCl3) 300 MHz δ 4,74 ((user), 1H), 3.45 points (s, 2H), 2,50-to 2.40 (m, 1H), 2.40 a is 2.33 (m, 1H), 2.05 is-to 1.87 (m, 4H), of 1.80 (DD, J=2,4, or 10.3 Hz, 1H), 1,65 (DD, J=3,0, 10,0 Hz, 1H), 1,54-of 1.40 (m, 3H), 1,45 (s, N), to 1.37 (DD, J=3,1, 10,0 Hz, 1H).

Stage VII: To a stirred solution of tert-butyl[1-(hydroxymethyl)tricyclo[3,3,1,03,7]non-3-yl]carbamate (0.65 g, 2.45 mmol), obtained in stage VI, wtgf (10 ml) at a temperature bath with ice consistently added Et 3N (1.0 ml, of 7.35 mmol), DMAP (20 mg, 0.16 mmol) and methanesulfonamide (0,29 ml, 3.7 mmol). After stirring at the same temperature for 0.5 h, the reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layers were washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain the specified connection {3-[(tert-butoxycarbonyl)amino]tricyclo[3,3,1,03,7]non-1-yl}methylmethanesulfonate in the form of a viscous liquid (0.84 g) with a yield of 100%. m/z (M+1) 358;1H NMR (CDCl3) 300 MHz δ 4,76 ((user), 1H), was 4.02 (s, 2H), 3,01 (s, 2H), 2,99 (s, 3H), 2,54 is 2.44 (m, 1H), 2,42 to 2.35 (m, 1H), 2,20-to 1.87 (m, 4H), equal to 1.82 (DD, J=2.2, while the 10.5 Hz, 1H), 1,76 is 1.58 (m, 4H), 1,57 is 1.48 (m, 1H), 1,45 (s, N).

The product 4

Benzyl-[2-(4-AMINOPHENYL)hexahydro-2,5-methamphetamin-3A(1H)-yl]carbamate

Stage I:Mixture for nitration (1 ml) [mixture for nitration was obtained by mixing of 10.5 g of nitric acid (d 1,375 when 22º), 180,0 g conc. sulfuric acid (d 1,84 when 22º) and 16 g of N2O] was added dropwise to a stirred solution of 1-(1-fenestrelle[3,3,1,03,7]non-3-yl)ethanone (240 mg, 1.0 mmol), obtained as described previously (preparation 1)in nitromethane (4 ml) at 0OC. After stirring for 2 h the reaction mixture was poured into ice water and was extracted with EtOAc, yedinenye organic layers were washed with saturated salt solution and dried over Na 2SO4. The solvent is evaporated under reduced pressure and the crude substance was purified column chromatography to obtain 1-[1-(4-nitrophenyl)tricyclo[3,3,1,03,7]non-3-yl]ethanone as not quite white solid (250 mg) with a yield of 88%. TPL: 61,3-66,6º, m/z (M+1) 286; IR cm-12953, 1697, 1598, 1519, 1217, 1110, 852, 768.1H NMR (CDCl3) 300 MHz δ 8,17 (d, J=8.7 Hz, 2H), 7,43 (d, J=8.7 Hz, 2H), 2,87-2,80, (m, 1H), 2,61 is 2.55 (m, 1H), 2,34-of 2.26 (m, 1H), of 2.23 (s, 3H), 2,13-to 1.98 (m, 4H), 1,90-1,71 (m, 5H).

Stage II:To a stirred solution of NaOH (6.3 g, to 158.0 mmol), N2On (54,0 ml) and 1,4-dioxane (7 ml) at a temperature bath with ice was added Br2(3.2 ml, or 59.0 mmol) and was stirred for 5 minutes. Educated hypobromite solution was added dropwise to a stirred solution of 1-[1-(4-nitrophenyl)tricyclo[3,3,1,03,7]non-3-yl]ethanone (3.0 g, 10,53 mmol), obtained at stage I in 1,4-dioxane (14 ml) at a temperature bath with ice. The reaction mixture was gradually heated to room temperature and after 1 hour the mixture was cooled to a temperature bath with ice and acidified using conc. HCl, diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-(4-nitrophenyl)tricyclo[3,3,1,03,7]nonan-3-carboxylic acid (2,27 g) with a yield of 75%, as not quite Belogorodka substances; TPL: 145-150 º C, m/z (M-1) 286; IR cm-13437, 2945, 1693, 1596, 1511, 1408, 1352, 946, 839, 749.1H NMR (CDCl3) 300 MHz δ is 8.16 (d, J=8,8 Hz, 2H), 7,42 (d, J=8,8 Hz, 2H), 2,96-is 2.88 (m, 1H), 2,59-2,52 (m, 1H), 2,44 is 2.33 (m, 1H), 2,23-2,03 (m, 4H), 2,02 by 1.68 (m, 5H).

Stage III:To a stirred solution of 1-(4-nitrophenyl)tricyclo[3,3,1,03,7]nonan-3-carboxylic acid (3.0 g, 10,45 mmol)obtained in stage II, in CHCl3(21 ml) was added conc. H2SO4(4,2 ml, 78,9 mmol), then portions was added solid NaN3so that the temperature of the reaction mixture did not rise above 40ºC. The reaction mixture was heated to 45 º C and after stirring for 2 hours and again cooled to a temperature bath with ice, diluted with water and was extracted with EtOAc. The aqueous layer was podslushivaet 50% NaOH solution and was extracted with CHCl3. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-(4-nitrophenyl)tricyclo[3,3,1,03,7]nonan-3-amine in the form of not-quite-white solid (2.0 g) with a yield of 74%. TPL: 201,0-205,9º, m/z (M+1) 259; IR cm-13435, 2941, 1643, 1596, 1518, 1400, 1349, 1013, 750.1H NMR (CDCl3) 300 MHz δ to 8.14 (d, J=8,8 Hz, 2H), 7,39 (d, J=8,8 Hz, 2H), 3,70-3,60 (d (user), 2H), 2,62-of 2.50 (m, 2H), 2,38-of 2.23 (m, 3H), 2,15-2,0 (m, 3H), 1,95-to 1.60 (m, 4H).

Stage IV:To stir a mixture of 1-(4-nitrophenyl)tricyclo[3,3,1,03,7]nonan-3-amine (2.0 g, 8.0 mmol), polucen is th at stage III, To2CO3(3.5 g, 24 mmol) in THF (80 ml), cooled to a temperature bath with ice, was added benzylchloride (50% wt./about. in toluene, 2.2 ml, 12 mmol). After stirring at Komnas temperature for 2 h, the reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layers were washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain benzyl-[2-(4-nitrophenyl)hexahydro-2,5-methamphetamin-3A(1H)-yl]carbamate in the form of not-quite-white solid (2.1 g) with a yield of 70%. TPL: 104,1-105,9º; m/z (M+1) 393; IR cm-13440, 2952, 1714, 1518, 1349, 1216, 757;1H NMR (CDCl3) 300 MHz δ to 8.12 (d, J=8,8 Hz, 2H), 7,50-7,27 (m, 7H), 5,20 to 5.0 (with (user), 2H), 2,65 is 2.55 (m, 1H), 2,50-of 1.55 (m, 11N).13With NMR (CDCl3) 75 MHz δ 155,1, 154,2, 146,1, 136,4, 131,1, 128,5 (2C), 128,1 (2C), 126,6 (2C), 123,4 (2C), 66,3, 64,4, 49,2, 48,0, 47,5, 43,8, 42,1, 40,8, 37,0.

Stage V:To a stirred solution of benzyl[2-(4-nitrophenyl)hexahydro-2,5-methamphetamin-3A(1H)-yl]carbamate (1.0 g, 2.55 mmol), obtained in stage IV in a mixture of 1:2:4 water, THF and ethanol, respectively (10 ml) was added solid NH4Cl (0.5 g, 9.3 mmol) and Fe powder (0.5 g, 9.0 mmol). The reaction mixture was heated at boiling temperature under reflux for 2 hours, the Reaction mixture was cooled to room temperature and filtered through a small layer of celite. The filtrate is evaporated p. and reduced pressure, and the residue was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain benzyl-[2-(4-AMINOPHENYL)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate in the form of not-quite-white solid (0.75 g) with a yield of 81%. m/z (M+1) 363; IR cm-13441, 2950, 1715, 1517, 1346, 1216, 756.1H NMR (CDCl3) 300 MHz δ 7,45-7,05 (m, N), 5,20 to 5.0 (with (user), 2H), 2,65-of 2.50 (m, 1H), 2,50-to 2.40 (m, 1H), 2,36-of 1.57 (m, 10H).

The drug 5

(2S,4S)-1-(chloroacetyl)-4-ftorpirimidinu-2-carbonitril

Stage I: To a stirred solution of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) in methanol (400 ml), cooled to 0 ° C, was added acetylchloride (14,3 ml, 0.2 mol) over a period of 30 minutes, the Reaction mixture was heated to room temperature and was stirred for 2 hours Volatiles were removed under reduced pressure and the residue awhile rubbed with simple ether to obtain hydrochloric salt of (2S,4R)-4-hydroxypyrrolidine-2-carboxylate as a white powder (14.5 g output to 100%. m/z (M+1) 145;1H NMR (DMSO-d6) 300 MHz δ 5,7-5,5 ((user), 1H), 4,55 is 4.35 (m, 2H), 3,76 (s, 3H), 3,35 (d, J=12 Hz, 1H), 3,10 (d, J=12 Hz, 1H), 2,25-2,0 (m, 2H).

Stage II: To a stirred suspension of hydrochloric salts obtained by CT the Hai I (14.5 g, 0.1 mol)in CH2Cl2(400 ml), cooled to 0 ° C was added Et3N (28 ml, 0.2 mol), DMAP (and 0.61 g, 5 mmol) and the anhydride Vos (27.5 ml, 0.12 mol). The reaction mixture was gradually heated to room temperature and was stirred for 2 h Then the solvent was removed in vacuum and added a simple ether to the remaining solid matter. The solid was filtered through a funnel with a filter of sintered glass and thoroughly washed simple ether. The filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2and washed the feast upon. NaCl and feast upon. NaHCO3c followed by drying over anhydrous Na2SO4. The solvent is evaporated under reduced pressure to obtain light yellow oil, which was hardened in a high vacuum. The obtained solid substance some time triturated with hexane. The solid was dried in high vacuum to obtain 1-tert-butyl-2-methyl-(2S,4R)-4-hydroxypyrrolidine-1,2-in primary forms in the form of a white solid (24.5 g) with a yield of 100%. (M+1) 245;1H NMR (CDCl3) 300 MHz δ 4,54-4,37 (m, 2H), of 3.75 (s, 3H), 3,70 is 3.40 (m, 2H), 2,48-of 2.21 (m, 2H), 2,13-2,0 (m, 1H), 1,46 (s, 3H), 1.41 to (C, 6N).

Stage III: To a stirred solution of compound obtained in stage II (24.5 g, 0.1 mol)in 1,2-dichloroethane (300 ml), cooled to -10 º C, was added diethylaminosulfur (19.7 ml, 0.15 mol) over a period of 30 minutes. The reaction mixture was stirred at this temperature for 1 h, then at room temperature for 16 hours, the Reaction mixture was suppressed by addition of a mixture of crushed ice (300 g) and solid NaHCO3(25,2 g, 0.3 mol). Two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated salt solution, dried over anhydrous Na2SO4and the solvent was removed under reduced pressure to obtain 1-tert-butyl-2-methyl-(2S,4S)-4-ftorpirimidinu-1,2-in primary forms in the form of a viscous liquid (24,7 g) with a yield of 100%. [α]D-53,3, (C, 1,0, CDCl3). m/z (M+1) 248;1H NMR (CDCl3) 300 MHz δ 5,20 (DDD, J=3,8, 3,8, 49,1 Hz, 1H), 4,55 (d, J=9.5 Hz, ½ H), 4,42 (d, J=9.5 Hz, ½ H), 3,90-3,55 (m, 2H), of 3.75 (s, 3H), 2,55-of 2.20 (m, 2H), 1,46 (s, 3H), 1.41 to (C, 6N).

Stage IV: To a stirred solution of 1-tert-butyl-2-methyl-(2S,4S)-4-ftorpirimidinu-1,2-in primary forms (to 24.7 g, 0.1 mol), obtained in stage III in THF (200 ml), cooled to 0 ° C, was added LiOH solution (3.6 g, 0.15 mol) in water (200 ml) over a period of 30 minutes, the Reaction mixture was heated to room temperature and was stirred for 12 h prior to detection by TLC completion of the reaction. The reaction mixture was diluted with water, simple ether and two layers were separated. The aqueous layer was acidified using conc. HCl and was extracted with EtOAc. The combined organic layer was washed with water and saturated salt solution, sushi is whether over anhydrous Na 2SO4and the solvent evaporated under reduced pressure to obtain (2S,4S)-1-(tert-butoxycarbonyl)-4-ftorpirimidinu-2-carboxylic acid in the form of not-quite-white solid (21 g) with a yield of 90%. [α]D-65,7 (C, 1,0, CDCl3); m/z (M-1) 232;1H NMR (CDCl3) 300 MHz δ 5,22 (DDD, J=3,8, 3,8, 52,3 Hz, 1H), 4,60-and 4.40 (m, 1H), 3.95 to a 3.50 (m, 2H), 2,78-of 2.15 (m, 2H), 1,6-of 1.35 (m, N).

Stage V: To a stirred solution of the acid obtained in stage IV (17.3 g, 0,074 mol)in acetonitrile (220 ml) at room temperature was added pyridine (6.6 ml, 0,082 mol), anhydride Vos (20 ml, 0,089 mol). After 1 h was added solid NH4HCO3(9.4 g, 0.12 mol) and the reaction mixture was stirred for 12 h the Reaction mixture was diluted with EtOAc and washed with a mixture (1:1 vol./about.) saturated salt solution and 1N HCl. The organic layer was dried over anhydrous Na2SO4and the solvent was removed in vacuum to obtain tert-butyl(2S,4S)-2-(aminocarbonyl)-4-ftorpirimidinu-1-carboxylate (17 g) as a viscous liquid. The substance was used for the next reaction without further purification. m/z (M+1) 233;1H NMR (CDCl3) 300 MHz δ 6,70-6,60 ((user), ½ H), 6.30-in-6,10 ((user), ½ N), 5,50-5,40 ((user), 1H), 5,22 (DDD, J=3,4, 3,4, 52,0 Hz, 1H), 4,50-4,30 (m, 1H), 3.95 to a 3.50 (m, 2H), 2,90 is 2.10 (m, 2H), 1,48 (s, N).

Stage VI: To a stirred solution of amide obtained in the previous phase (17.9 g, 0,077 mol) in EtAc (35 ml) at 0OC was added dry HCl EtAc (4h, 225 ml) over a period of 30 minutes After stirring at 0 ° C for 1 h, volatiles were removed under reduced pressure and the residue awhile rubbed with simple ether to obtain hydrochloric salt of (2S,4S)-4-ftorpirimidinu-2-carboxamide in the form of not quite white powder (12 g) with a yield of 92%. m/z (M+1) 133;1H NMR (DMSO-d6) 300 MHz δ or 10.60-10,30 ((user), ½ N), 8,90 at 8.60 ((user), ½ N), 8,10 ((user), 1H), 7,72 ((user), 1H), 5,38 (DDD, J=3,7, 3,7, 52,4 Hz, 1H), 4,32 (d, J=10.5 Hz, 1H), 4,28 (d, J=10.4 Hz, 1H), 3,64 be 3.29 (m, 2H), 2,73 costs 2.50 (m, 1H), 2,41-of 2.24 (m, 1H).

Stage VII: To a stirred suspension hydrochloric salt, which is obtained at stage VI (12 g, 0,071 mol) in dichloromethane (140 ml), cooled to 0 ° C was added Et3N (30 ml, 0,213 mol), chlorocatechol (8.1 ml, 0,107 mol). The reaction mixture was gradually heated to room temp. and was stirred for 1 h, the Reaction mass was filtered through a funnel with a filter of sintered glass, washed with a layer of salt simple ether and the filtrate evaporated in vacuo to obtain the crude substance (2S,4S)-1-(chloroacetyl)-4-ftorpirimidinu-2-carboxamide (14.8 g) as a viscous liquid in the form of a mixture of retamero 3:1. m/z (M+1) 209;1H NMR (DMSO-d6) 300 MHz δ 7,26 ((user), ½ N),? 7.04 baby mortality ((user), ½ N)of 5.34 (d, J=52,5 Hz, 0.8 H), a 5.25 (d, J=53,0 Hz, 0,2N), 4,58-4,30 (m, 3H), 3,90-to 3.50 (m, 2H), 2,60-of 2.20 (m, 2H).

Stage VIII: To a stirred solution of the compound obtained in the study is VII (14,7 g, 0.07 mol) in dry THF (140 ml) in an atmosphere of N2at 0 ° C was added anhydride triperoxonane acid (15 ml, 0,107 mol). The reaction mixture was gradually heated to room temp. and was stirred for 1 h was Added water and the two layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with saturated salt solution, dried over anhydrous Na2SO4. The solvent is evaporated under reduced pressure to get crude material, which was purified column chromatography to obtain (2S,4S)-1-(chloroacetyl)-4-ftorpirimidinu-2-carbonitrile in the form of a yellowish-brown solid (8.7 g) with a yield of 64% (mixture of 3:1 two retamero). [α]D-51,0 (C, 1,0, l3); IR cm-13031, 3007, 2962, 2241, 1679, 1407, 1280, 1225, 1076, 860; m/z (M+1), 191;1H NMR (DCl3) 300 MHz δ of 5.45 (DDD, J=3,4, 3,4, 51,3 Hz, 0.8 H), lower than the 5.37 (DDD, J=3,4, 3,4, 51,0 Hz, 0.2 H), is 5.06 (d, J=8,9 Hz, 0.2 H), of 4.95 (d, 9,3, Hz, 0.8 H), 4,30-3,55 (m, 2 H)4,06 (s, 2H), 2,65 is 2.55 (m, 1H), 2,50 was 2.25 (m, 1 H).

The drug 6

(2S,4R)-1-(2-chloroacetyl)-4-ftorpirimidinu-2-carbonitril

The compound (2S,4R)-1-(2-chloroacetyl)-4-ftorpirimidinu-2-carbonitrile was synthesized from (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid using the same sequence of stages and methods as described above for (2S,4S)-1-(2-chloroacetyl)-4-ftorpirimidinu-2-carbonitrile on the basis of (2S,4R)-4-hydroxypyrrolidine the-2-carboxylic acid. (2S,4R)-1-(2-Chloroacetyl)-4-ftorpirimidinu-2-carbonitrile: solid, mixture of 4:1 two rotamers; m/z (M+1) 191;1H NMR (CDCl3) 300 MHz δ 5,38 (d (user), J=51,3 Hz, 0,8H), 5,33 (d (t), J=51,0 Hz, 0,2N), 5,02 (d, J=8,5 Hz, 0,2H), 4.72 in (d, 8.5 Hz, 0,8H), 4,40-3,30 (m, 2H), 4,06 (s, 2H), 3,0-to 2.65 (m, 1H), 2,62-to 2.40 (m, 1H).

Preparation 7

(4R)-3-(chloroacetyl)-1,3-thiazolidin-4-carbonitrile

Stage I:To a mixed aqueous solution of 40% formaldehyde (40 ml) at 0 ° C was added solid portions of L-cysteine (12.1 g, 0.1 mol) over a period of 30 minutes. The reaction mixture was stirred for 4 h, after which the reaction mixture was filtered through a funnel with a filter of sintered glass. The solids were washed with absolute ethanol, then simple diethyl ether. The solids were dried in high vacuum to obtain (4R)-1,3-thiazolidin-4-carboxylic acid (12.5 g) with a yield of 94%. TPL 215-217º; m/z (M+1) 134; IR cm-13429, 3049, 2357, 1629, 1463, 1383, 1343, 1014, 862;1H NMR (D2O) 300 MHz δ 4,40-4,30 (m, 2H), 4,30-4,22 (m, 1H), 3,40-3,18 (m, 2H).

Stage II:To a stirred mixture of compound obtained in stage I (13.3 g, 0.1 mol)in acetonitrile (400 ml), cooled to 0 ° C was added pyridine (20,1 ml, 0.22 mol) and the anhydride Vos (58 ml, 0.24 mol). After stirring the reaction mixture for 1 h at room temperature was added solid NH4HCO3(11.8 g, 0.15 mol) and the reaction mixture is displaced is ivali within the next 2 hours The reaction mixture was distributed between ethyl acetate and a mixture of 2n Hcl and saturated salt solution 1:1. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain tert-butyl(4R)-4-(aminocarbonyl)-1,3-thiazolidin-3-carboxylate (23 g) in the form of a resinous liquid with a quantitative yield. The substance was used in the next reaction without further purification. m/z (M+1) 233; IR cm-13334, 2978, 2932, 1682, 1392, 1163, 763;1H NMR (CDCl3) 300 MHz δ 5,70-5,50 ((user), 1H), 4.80 to 4,60 (m, 2H), 4,48-4,30 (m, 1H), 3,50-3,10 (m, 2H).

Stage III:To a stirred solution of tert-butyl(4R)-4-(aminocarbonyl)-1,3-thiazolidin-3-carboxylate (23 g, 0.1 mol) in ethyl acetate (50 ml) at 0OC was added dry HCl in ethyl acetate (3.5 n, 250 ml). The resulting mixture was stirred at room temperature for 2 h, the volatiles were removed under reduced pressure and the residue triturated some time with ethyl acetate to obtain hydrochloric salt of (4R)-1,3-thiazolidin-4-carboxamide in the form of not quite white powder (16.5 g) in quantitative yield. TPL 201,8 thousand cub.-203,9º; m/z (M+1) 133; IR cm-13387, 3250, 3189, 2857, 1706, 1675, 1612, 1371, 1123, 894;1H NMR (DMSO-d6) 300 MHz δ 10.30 a.m.-9,60 ((user), 1/2H), 8,10 ((user), 1/2N), to 7.77 ((user), 1H), and 4.40 (t, J=7,0 Hz, 1H), or 4.31 (d, J=9.6 Hz, 1H), 4,25 (d, J=9.6 Hz, 1H), 3,50-3,30 (m, 1H), 3.15 in (DD, J=7,0, 11.7 Hz, 1 Prov.).

Stage IV:To a stirred suspension hydrochloric salt obtained in stage III (16.5 g, 0.1 mol)in dichloromethane (200 ml), cooled to 0 ° C was added Et3N (41 ml, 0.3 mol) and chlorocatechol (8,8 ml, 0.11 mol). The reaction mixture was slowly heated to room temperature and was stirred for 1 h, the Reaction mass was filtered through a funnel with a filter of sintered glass, a layer of salt was washed simple ether and the filtrate evaporated in vacuum to obtain crude compound (4R)-3-(chloroacetyl)-1,3-thiazolidin-4-carboxamide (20,8 g) as a viscous liquid, which was used on studyusa stage without additional purification. m/z (M+1) 209; IR cm-13418, 2925, 1736, 1667, 1416, 1219, 771;1H NMR (CDCl3) 300 MHz δ 6,60-6,30 ((user), 1/2H), 6,0-5,65 ((user), ½ N), 5,02 (DD, J=3,6, 6,9 Hz, 0,8H), 4,88-of 4.75 (m, 0,4H), 4,70 (d, J=8,8 Hz, 0,8H), to 4.62 (d, J=8,8 Hz, 0,8H), 4,51 (d, J=10.0 Hz, 0,2N), of 4.16 (s, 1,6N), 4,11 (s, 0,4H), of 3.56 (DD, J=3,4, and 11.8 Hz, 0,8H), 3,44 (DD, J=4,7, 8.0 Hz, 0,4N)and 3.15 (DD, J=7,1, 11.8 Hz, 0,8H), 1.28 (in, 1,6N), 1,25 (s, 7,4H).

Stage V:To a stirred solution of compound obtained in stage IV (20.7 g, 0.1 mol)in dry THF (200 ml) in an atmosphere of N2at 0 ° C was added anhydride triperoxonane acid (21 ml, 0.15 mol). The reaction mixture was gradually heated to room temperature and was stirred for 1 h, the Reaction mixture was diluted with water and the two layers were separated. The aqueous layer was extracted with EtOc and the combined organic layers were washed with saturated salt solution and dried over anhydrous Na 2SO4. The solvent is evaporated under reduced pressure and the residue was purified column chromatography to obtain (4R)-3-(chloroacetyl)-1,3-thiazolidin-4-carbonitrile (10.0 g) in the form of not-quite-white solid with a yield of 53%. [α]D-147,24 (with, of 0.5, CHCl3); TPL 85,9-87,3 º C; m/z (M+1) 191; IR cm-12982, 2936, 2245, 1679, 1666, 1393, 1284, 1261, 984, 788;1H (CDCl3) 300 MHz δ of 5.29 (t, J=4.3 Hz), 4.72 in (d, J=8,8 Hz, 1H), 4,66 (d, J=8,8 Hz, 1H), 3,45-3,30 (m, 2H).

Preparation 8

Tert-Butyl(3-aminotriazole[3,3,1,03,7]non-1-yl)carbamate

Stage I: To a solution of carboxylic acid, obtained in stage I (preparation 2) (2.7 g, 12.9 mmol)in toluene (52 ml) at a temperature bath with ice was added Et3N (5.8 ml, of 38.7 mmol) and diphenylphosphoryl (3,3 ml of 15.5 mmol). The reaction mixture was gradually heated to room temperature, was stirred for one hour and boiled under reflux for 4 hours After cooling to room temperature the reaction mixture was transferred into a separating funnel and washed once with water. The organic layer was transferred into a round bottom flask, cooled to a temperature bath with ice and added aq. a solution of KOH (50 wt%./about., 26 ml) and nBu4NI (476 mg, 1,29 mmol). The mixture was stirred at room temperature for 2 hours After completion of the reaction, the reaction mixture was cooled to a temperature bath with the ice, acidified to pH 2 conc. HCl, and was extracted once simple ether, the aqueous layer was podslushivaet aq. NaOH solution (50% wt./about.) and was extracted with chloroform. The combined organic layers were dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain amino compounds 1-(1-aminotriazole[3,3,1,03,7]non-3-yl]ethanone in the form of a viscous liquid (1.3 g) with a yield of 56%. m/z (M+1) 180;1H NMR (CDCl3) 300 MHz δ 2,68-2,61 (m, 1H), 2.49 USD is 2.43 (m, 1H), 2,17 (s, 3H), of 2.05 (DDD, J=2,3, 2,3, a 10.6 Hz, 1H), 1,95-of 1.78 (m, 3H), 1,78 was 1.43 (m, 6N).

Stage II: To a stirred solution of the amino compounds obtained in stage I (1.3 g, 7,26 mmol), in dichloromethane (29 ml) at a temperature bath with ice Et3N (2 ml, 14.5 mmol)was added anhydride Vos (2.1 ml to 8.7 mmol) and DMAP (44 mg, 0.36 mmol). After stirring for 1 h at room temp. the solvent was removed under reduced pressure and the crude reaction mass was purified column chromatography to obtain tert-butyl(3-acetylthiazole[3,3,1,03,7]non-1-yl)carbamate (1.8 g) as a viscous liquid with a yield of 90%. m/z (M+1) 280;1H NMR (CDCl3) 300 MHz δ 4,73 ((user), 1H), 2,72-of 2.64 (m, 1H), 2,17 (s, 3H), 2,10-of 1.78 (m, 8H), 1,78 by 1.68 (m, 2H), USD 1.43 (s, N).

Stage III:To a mixture of NaOH (1,32 g, 33.0 mmol), N2On (8,8 ml) and 1,4-dioxane (2 ml) with a bath temperature of ice was added Br2(0.6 ml, 12.3 mmol) and was stirred for 5 minutes. The floor is secured hypobromite solution was added dropwise to a stirred solution of the compound, obtained in phase II (0.6 g, 2.2 mmol) in 1,4-dioxane (2.4 ml) at approximately 10ºC. The reaction mixture was gradually heated to room temp., was stirred for 1 h, then was cooled to 0 ° C and was suppressed by the addition of acetic acid (2 ml, of 36.3 mmol). The mixture was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-[(tert-butoxycarbonyl)amino]tricyclo[3,3,1,03,7]-nonan-3-carboxylic acid (0.54 g) as a viscous liquid with a yield of 87%. m/z (M-1) 280;1H NMR (CDCl3) 300 MHz δ 4,75 ((user), 1H), 2,78-2,60 (m, 1H), 2,47-to 2.40 (m, 1H), 2,33-2,22 (m, 1H), 2,18-1,72 (m, 8H), 1,62-of 1.53 (m, 1H), USD 1.43 (s, N).

Stage IV:To a solution of acid (0.55 g, 1,95 mmol)obtained in stage III in toluene (8 ml) at a temperature bath with ice was added Et3N (1.2 ml, 8,8 mmol) and diphenylphosphoryl (0.5 ml, 2.3 mmol). The reaction mixture was gradually heated to room temp., was stirred for one hour and then heated at the boil under reflux for 4 hours After cooling to room temperature the reaction mixture was transferred into a separating funnel and washed once with water. The organic layer was transferred into a round bottom flask, cooled to a temperature bath with ice and added aq. a solution of KOH (50 wt%./about., 4 ml) and nBu4 NI (10 mg, 0.02 mmol). The reaction mixture was stirred at room temperature for 2 hours After completion of the reaction, the reaction mixture was cooled to a temperature bath with ice, acidified to pH 2 conc. HCl, and was extracted once simple ether and the aqueous layer was podslushivaet aq. NaOH solution (50% wt./about.) and was extracted with chloroform. The combined organic layers were dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain the above compound tert-butyl(3-aminotriazole[3,3,1,03,7]non-1-yl)carbamate as a viscous liquid (0.3 g) with a yield of 60%. m/z (M+1) 253;1H NMR (CDCl3) 300 MHz δ 2,35-of 2.28 (m, 1H), 2,20-of 1.80 (m, 5H), 1,78-of 1.53 (m, 5H), of 1.52 to 1.47 (m, 1H), USD 1.43 (s, N).

Preparation 9

1-(3-Aminotriazole[3,3,1,03,7]non-1-yl)pyrrolidin-2-he

Stage I:To a stirred solution of the compound obtained as described previously (phase I, preparation 8) (0.9 g, 5.0 mmol)in THF (20 ml) at 0 ° C was added Et3N (2.1 ml, 15 mmol) and 4-chlorobutyrophenone (1,02 g, 7.5 mmol). After stirring the reaction mixture at room temperature for 1 h was added dropwise an aqueous solution of NaOH (50%, 10 ml), followed by adding n-Bu4NI (182 mg, 10 mol.%). After stirring for 16 h the reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layers were washed asystem salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude compound was purified column chromatography to obtain 1-(3-acetylthiazole[3,3,1,03,7]non-1-yl)pyrrolidin-2-it is in the form of a viscous liquid (1.0 g) with a yield of 81%. m/z (M+1) 248;1H NMR (CDCl3) 300 MHz δ of 3.42 (t, J=6.5 Hz, 2H), 2,72-of 2.66 (m, 1H), of 2.51-2.40 a (m, 2H), 2,32 (t, J=7.8 Hz, 2H), 2,28-2,12 (m, 2H), 2,18 (s, 3H), 2,10-to 1.87 (m, 5H), 1,81 was 1.69 (m, 2H), 1,67-to 1.60 (m, 2H).

Stage II:To a stirred mixture of NaOH (2.4 g, to 60.6 mmol), N2O (16 ml) and 1,4-dioxane (4 ml) at a temperature bath with ice was added Br2(1.13 ml, and 22.6 mmol) and was stirred for 5 minutes. Received the hypobromite solution was added dropwise to a stirred solution of compound obtained in stage I (1.0 g, 4.04 mmol)in 1,4-dioxane (18 ml) at 10ºC. The temperature of the reaction mixture was raised to room temperature and the reaction mixture was stirred for 1 h Then the mixture was cooled to a temperature bath with ice and was suppressed by the addition of acetic acid (3.9 ml, and 65.7 mmol). The reaction mixture was diluted with water, was extracted with EtOAc and the combined organic layers were washed with saturated salt solution and dried over Na2SO4. The solvent was removed under reduced pressure to obtain 1-(2-oxopyrrolidin-1-yl)tricyclo[3,3,1,03,7]nonan-3-carboxylic acid as a viscous liquid (1.3 g) with a yield of 100%. m/z (M+1) 250;1N I Is R (CDCl 3) 300 MHz δ of 3.42 (t, J=7,0 Hz, 2H), 2,78-a 2.71 (m, 1H), 2,47-of 2.23 (m, 6N), 2,08-1,90 (m, 6N), 1.85 to 1,72 (m, 2H), 1,62 (DD, J=2,4 and 11.0 Hz, 1H).

Stage III:To a stirred solution of the acid obtained in stage II (0.5 g, 2.0 mmol) in CHCl3(21 ml) at room temperature was added conc. H2SO4(1.0 ml, 20 mmol) followed by the addition portions NaN3(0.39 g, 6.0 mmol) over a period of 30 min, so that the temperature of the reaction mixture did not rise above 40ºC. The reaction mixture was heated to 45 º C and was stirred for 2 h, then cooled to a temperature bath with ice, diluted with water and was extracted with EtOAc. The aqueous layer was podslushivaet by adding 50% NaOH solution and was extracted with CHCl3. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-(3-aminotriazole[3,3,1,03,7]non-1-yl)pyrrolidin-2-she is not quite white solid (0.25 g) with a yield of 74%. m/z (M+1) 221;1H NMR (CDCl3) 300 MHz δ is 3.41 (t, J=7,0 Hz, 2H), 2,46 (DD, J=2,4, or 10.3 Hz, 1H), 2,38-of 2.28 (m, 1H), 2,30 (t, J=8,3 Hz, 2H), 2,16-to 1.82 (m, N), of 1.78 (DD, J=2,6, and 10.8 Hz, 1H), 1,66 is 1.58 (m, 1H)and 1.51 (DD, J=2,5, and 10.8 Hz, 1H).

The drug 10

1-(1,1-Dioxothiazolidine-2-yl)tricyclo[3,3,1,03,7]nonan-3-amine

Stage I:To a stirred solution of the compound obtained as described wound is (stage I, preparation 8) (1.0 g, 5.6 mmol) in THF (23 ml) at 0 ° C was added Et3N (1.2 ml, 8.4 mmol), followed by addition of 4-chlorobutyronitrile (1,02 g, 7.5 mmol). After stirring the reaction mixture at room temp. within 1 h was added aqueous NaOH solution (50% wt./about., 11 ml); and then adding n-Bu4NI (182 mg, 0,56 mmol). The reaction mixture was stirred for 16 h, diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain 1-[1-(1,1-dioxothiazolidine-2-yl)tricyclo[3,3,1,03,7]non-3-yl]ethanone in the form of a viscous liquid (1.0 g) with a yield of 61%. m/z (M+1) 284;1H NMR (CDCl3) 300 MHz δ 3,37 (t, J=6.6 Hz, 2H), and 3.16 (t, J=7.5 Hz, 2H), was 2.76-2,69 (m, 1H), 2,53-2,47 (m, 1H), 2,39-of 2.26 (m, 3H), of 2.18 (s, 3H), 2,22-2,07 (m, 4H), of 2.20 (DD, J=3.2, and the 11.0 Hz, 1H), 1,96-1,89 (m, 1H), 1,78 was 1.69 (m, 2H), 1,61 (DD, J=2,7 11,0 Hz, 1H).

Stage II:To a stirred mixture of NaOH (2.1 g, to 53.0 mmol), N2(14 ml) and 1,4-dioxane (4 ml) at a temperature bath with ice was added Br2(1.0 ml, to 19.8 mmol) and the mixture was stirred for 5 minutes. Thus obtained hypobromite solution was added dropwise to a stirred solution of compound obtained in stage I (1.0 g, of 3.53 mmol) in 1,4-dioxane (7 ml) at 10ºC. The temperature of the reaction mixture pic is upendo was raised to room temperature and the reaction mixture was stirred for 1 h, the mixture is then cooled to a temperature bath with ice and extinguished the addition of Asón (3.9 ml, and 65.7 mmol). The reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-(1,1-dioxothiazolidine-2-yl)tricyclo[3,3,1,03,7]nonan-3-carboxylic acid as a viscous liquid (0.9 g) with a yield of 90%. m/z (M+1) 286;1H NMR (CDCl3) 300 MHz δ 3,37 (t, J=6.6 Hz, 2H), and 3.16 (t, J=7.8 Hz, 2H), 2,84 was 2.76 (m, 1H), 2,52-to 2.41 (m, 2H), 2,38-of 2.26 (m, 2H), 2,25-to 1.98 (m, 6N), 1.85 to 1,72 (m, 2H), 1,61 (DD, J=2,2, 11.3 Hz, 1H).

Stage III:To mix the acid solution obtained in phase II (to 0.29 g, 1.0 mmol) in CHCl3(5 ml) at room temperature was added conc. H2SO4(of 0.53 ml, 10 mmol) followed by the addition portions NaN3(0.2 g, 3.0 mmol) over a period of 30 min, maintaining at the same time the temperature below 40ºC. The reaction mixture was heated to 45 º C and was stirred for 2 hours, the Reaction mixture was cooled to a temperature bath with ice, diluted with water and was extracted with EtOAc. The aqueous layer was podslushivaet by adding 50% NaOH solution and was extracted with CHCl3. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-(1,1-dioxido sociability-2-yl)tricyclo[3,3,1,0 3,7]nonan-3-amine in the form of a viscous liquid (0.17 g) with a yield of 66%. m/z (M+1) 257;1H NMR (CDCl3) 300 MHz δ to 3.36 (t, J=6.6 Hz, 2H), 3.15 in (t, J=7.5 Hz, 2H), 2.40 a-2,24 (m, 4H), to 2.18 (DD, J=3,0, 10.4 Hz, 1H), 2,13-to 1.83 (m, 6N), to 1.76 (DD, J=2,4, and 10.8 Hz, 1H), 1,65 is 1.58 (m, 1H), 1,48 (DD, J=2,4, and 10.8 Hz, 1H).

Preparation 11

Tert-butyl(1-hydroxytriazine[3,3,1,03,7]non-3-yl)carbamate

Stage I:To a suspension of NaH (60% dispersion in medical oil, 1.92 g, 80 mmol) in THF (80 ml), cooled to a temperature bath with ice, was added 4-hydroxyadamantane (6,64 g, 40 mmol)dissolved in THF (80 ml)via syringe over a period of 15 minutes. After stirring the reaction mixture for 30 min, was added nBu4NI (1.4 g, 4 mmol) followed by the addition of benzylbromide (5,26 ml). The reaction mixture was heated to room temperature and was stirred for 16 h before detection by TLC for the disappearance of hydroxyadamantane. The excess NaH was suppressed by adding a feast upon. aq. solution of NH4Cl to the reaction mixture, cooled with ice. Two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain the crude reaction mixture, which was purified column chromatography to obtain 5-(benzyloxy)adamantane-2-it is in the de resinous liquid (of 7.93 g) with a yield of 77%. m/z (M+1) 257;1H NMR (CDCl3) 300 MHz δ 7,60-7,20 (m, 5H), 4,51 (s, 2H), 2,72 2.63 in (m, 2H), 2.40 a-a 2.36 (m, 1H), 2,35-of 1.92 (m, 10H).

Stage II:Freshly methylmagnesium simple ether (0,5M, 114 ml) was added through a tube to the compound obtained in stage I (7,3 g, 28.5 mmol) in THF (57 ml) at 0OC). After stirring for 0.5 h the reaction mixture was suppressed by adding a feast upon. aq. solution of NH4Cl. The organic layer was separated and the aqueous layer was extracted with simple isopropyl ether. The combined organic layer was washed with water and saturated salt solution, dried over anhydrous Na2SO4and the solvent was removed under reduced pressure to obtain 5-(benzyloxy)-2-methyladipate-2-ol in the form of a resinous liquid (mixture of 4:6 of the α and β isomers) (7.5 g) with a yield of 95%. m/z (M+1) 273;1H NMR (CDCl3) 300 MHz δ 7,42-7,20 (m, 5H), 4,51 (s, 0,8H), 4,48 (s, 1,2N), 2,40-of 1.30 (m, 13H), of 1.40 (s, 1,2N), of 1.35 (s, 1,8H).

Stage III:The compound obtained in stage II (7.5 g, 27.5 mmol), was dissolved in a mixture of Asón (5.5 ml) and THF (28 ml) and added dropwise through a funnel attached to a cooled with ice to a solution of NaOCl (4%, 275 ml) during 15 minutes. Added nBu4NI (210 mg, 2 mol%) and the reaction mixture was stirred for 1.5 hours, the Reaction mixture was poured into a separating funnel and the two layers were separated. The aqueous layer was extracted with simple diisopropyl ether and the combined org the organic layer was washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was boiled under reflux with methanolic solution of KOH (3.0 g KOH in 55 ml Meon) for 1 h, the Solvent evaporated under reduced pressure and product was purified column chromatography to obtain ketone-1-[1-(benzyloxy)tricyclo[3,3,1,03,7]non-3-yl]ethanone in the form of a resinous liquid (4,84 g), yield 65%. m/z (M+1) 271;1H NMR (CDCl3) 300 MHz 7,40-7,20 (m, 5H), to 4.52 (s, 2H), 2,70-of 2.64 (m, 1H), 2,58-2,52 (m, 1H), 2,33-of 2.27 (m, 1H), 2,18 (s, 3H), 2,11-of 1.88 (m, 5H), 1,78 is 1.58 (m, 4H).

Stage IV:To a mixture of NaOH (10.8 g, 270 mmol), N2(72 ml) and 1,4-dioxane (20 ml) at a temperature bath with ice was added Br2(5.2 ml, 100,8 mmol) and was stirred for 5 minutes. The hypobromite solution was added dropwise to a solution of compound obtained in stage III (4,84 g, 18 mmol) in 1,4-dioxane (18 ml), maintaining at the bath temperature with ice. The reaction mixture was gradually heated to room temperature and was stirred for 1 h, then cooled to a temperature bath with ice and extinguished the addition of Asón (3.9 ml, and 65.7 mmol), was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-(benzyloxy)tricyclo[3,3,1,03,7]nonan-3-Carbo the OIC acid in the form of a resinous liquid (4.1 g) with a yield of 83%. m/z (M+1) 273;1H NMR (CDCl3) 300 MHz δ 7,40-7,20 (m, 5H), to 4.52 (s, 2H), 2,78-2,70 (m, 1H), 2,58-2,48 (m, 1H), 2,45-is 2.37 (m, 1H), 2,18-1,50 (m, N).

Stage V:To a solution of the acid obtained in stage IV (1,36 g, 5 mmol) in toluene (20 ml) at a temperature bath with ice was added Et3N (2.1 ml, 15 mmol) and diphenylphosphoryl (DPPA, 1.3 ml, 6 mmol). The reaction mixture was slowly heated to room temperature and was stirred for one hour, after which the temperature was raised to boiling temperature under reflux for 4 hours After cooling to room temperature the mixture was transferred into a separating funnel and washed once with water. The organic layer was transferred into a round bottom flask, cooled to a temperature bath with ice and added aq. a solution of KOH (50 wt%./about., 10 ml) and nBu4NI (92 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 2 hours After completion of the reaction, the reaction mixture was cooled to a temperature bath with ice, acidified to pH 2 conc. HCl, and was extracted once simple ether and the aqueous layer was podslushivaet aq. NaOH solution (50% wt./about.) and was extracted with chloroform. The combined organic layer was dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain pure amine 1-(benzyloxy)tricyclo[3,3,1,03,7]nonan-3-amine in the form of a resinous liquid(614 mg) with a yield of 80%. m/z (M+1) 244;1H NMR (CDCl3) 300 MHz δ 2,40-of 2.20 (m, 5H), 2,70-2,48 (m, 3H), 2.40 a ((user), 1H), 2,27-of 2.16 (m, 1H), 2,10-of 1.40 (m, N).

Stage VI:To a solution of amino compounds obtained in stage V (590 mg, 2.4 mmol), in dichloromethane (10 ml) at a temperature bath with ice was added Et3N (0.5 ml, 3.6 mmol) followed by the addition of the anhydride Vos (654 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 1 h the Solvent was removed under reduced pressure and the crude reaction mass was purified column chromatography using as eluent a mixture of EtOAc/hexane with derivatization Vos tert-butyl-(1-benzyloxyethyl[3,3,1,03,7]non-3-yl)carbamate in the form of a resinous liquid (740 mg) with a yield of 90%. m/z (M+1) 343;1H NMR (CDCl3) 300 MHz δ 7,40-7,20 (m, 5H), 4.80 to 4,70 ((user), 1H), 4,51 (s, 2H), 2,50 was 2.25 (m, 4H), 2.0 to about 1.75 (m, 6N), 1,65 of 1.50 (m, 2H), 1,46 (s, N).

Stage VII:The mixture of compounds obtained in stage VI (730 g, 2.1 mmol) and Pd(OH)2/C (20% wet., 150 mg) in the Meon (9 ml) was stirred in an atmosphere of H2at room temperature for 2 hours, the Reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure to obtain tert-butyl(1-hydroxytriazine[3,3,1,03,7]non-3-yl)carbamate in the form of not-quite-white solid (520 mg) with a yield of 97%. M/z (M+1) 254;1H NMR (CDCl3) 300 MHz δ 4.72 in ((user), 1H), 2,48-2,3 (m, 2H), 2,32-to 2.18 (m, 2H), 1.93 and is 1.70 (m, 6N), of 1.55 and 1.35 (m, 2H), 1,45 (s, N).

Example 1

Stage I:Stir a mixture of [3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methylmethanesulfonate (2.4 g, 7.5 mmol) [obtained as described previously (drug 2)], K2CO3(4.5 g, 34,2 mmol) and 1,2,4-triazole (1.5 g, to 22.5 mmol) in DMF (30 ml) was heated to 110 º C for 5 h, the Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain 1-{[3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methyl}-1H-1,2,4-triazole (1,82 g) as a viscous liquid with a yield of 85%. m/z (M+1) 290; IR cm-12932, 1668, 1506, 1441, 1373, 1311, 1211, 1140, 1047, 876, 753.1H NMR (CDCl3) 300 MHz δ to 7.99 (s, 1H), to 7.93 (s, 1H), 4,07 (s, 2H), 4,03-to 3.92 (m, 4H), 2,42 of-2.32 (m, 2H), 1,86-to 1.79 (m, 1H), 1,74-of 1.65 (m, 2H), 1,52 to 1.37 (m, 8H), 1.26 in (s, 3H).

Stage II:Mix a solution of 1-{[3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methyl}-1H-1,2,4-triazole (2.6 g, 9.09 mmol), obtained in stage I, and p-toluensulfonate acid (0.16 g) in acetone (36 ml) was boiled under reflux for 4 hours the Volatile compounds were removed under reduced pressure and the STATCOM was diluted with ethyl acetate, washed with 10% aq. a solution of NaHCO3and saturated salt solution, dried over Na2SO4and the solvent evaporated under reduced pressure to obtain 1-[1-(1H-1,2,4-triazole-1-ylmethyl)tricyclo[3,3,1,03,7]non-3-yl]ethanone (2.2 g, yield 86%) as a viscous liquid. m/z (M+1) 246;1H NMR (CDCl3) 300 MHz δ to 7.99 (s, 1H), to 7.93 (s, 1H), 4,10 (s, 2H), 2,75-to 2.65 (m, 1H), 2,49-to 2.42 (m, 1H), 2,16 (s, 3H), 2.0 to a 1.45 (m, 10H),13With NMR (CDCl3) 75 MHz δ 211,0, 151,6, 143,6, 61,6, 56,9, 48,2, 45,9, 45,7, 42,6, 41,9, 37,3, 36,6, 26,3.

Stage III:To a stirred solution of NaOH (1.75 g, while 43.8 mmol), N2On (14.6 ml) and 1,4-dioxane (2 ml) with a bath temperature of ice was added Br2(0.8 ml, 16.4 mmol) and the mixture was stirred for 5 minutes. Received the hypobromite solution was added dropwise to a stirred solution of 1-[1-(1H-1,2,4-triazole-1-ylmethyl)tricyclo[3,3,1,03,7]non-3-yl]ethanone (0.7 g, of 2.92 mmol) in 1,4-dioxane (4 ml) at a temperature bath with ice. The reaction mixture was gradually heated to room temperature and was stirred for 1 h Then the mixture was cooled to a temperature bath with ice and extinguished the addition of Asón (3.9 ml, and 65.7 mmol). The crude reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-(1H-1,2,4-triazole-1-ylmethyl)tricyclo[33,1,0 3,7]nonan-3-carboxylic acid (0.54 g) with a yield of 75% as not quite white solid. TPL: 230-235º. m/z (M+1) 248. IR cm-13436, 3102, 2924, 2511, 1937, 1689, 1523, 1308, 1137, 979, 732.1H NMR (CD3OD) 300 MHz δ 8,43 (s, 1H), and 7.9 (s, 1H), 4,17 (s, 2H), 2,70-2,62 (m, 1H), 2.40 a is 2.33 (m, 1H), 2.06 to 1,95 (m, 2H), 1,84 was 1.43 (m, 8H).

Stage IV: To a stirred suspension of 1-(1H-1,2,4-triazole-1-ylmethyl)tricyclo[3,3,1,03,7]nonan-3-carboxylic acid (of 0.13 g, 0.52 mmol)obtained in stage III, in CHCl3(2.6 ml) was added conc. H2SO4(0.25 ml, 5.2 mmol). To the resulting homogeneous solution was added in portions NaN3(0.1 g, 1.56 mmol) over a period of 30 minutes, maintaining the temperature of the reaction mixture below 40 ºC. After stirring the reaction mixture for 2 h at room temp. the reaction mixture was cooled to a temperature bath with ice, diluted with water and was extracted with EtOAc. The aqueous layer was podslushivaet the addition of 50% aq. NaOH solution and was extracted with CHCl3. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-(1H-1,2,4-triazole-1-ylmethyl)tricyclo[3,3,1,03,7]nonan-3-amine (0.08 g) as a viscous liquid with a yield of 70%. m/z (M+1) 219;1H NMR (CDCl3) 300 MHz δ 7,98 (s, 1H), to 7.93 (s, 1H), 4,07 (s, 2H), 2,38-of 2.30 (m, 1H), 2.06 to to 1.98 (m, 1H), 1,96 and 1.80 (m, 2H), 1,72-of 1.57 (m, 4H), 1,55-of 1.36 (m, 4H).

Stage V: Re achiveve a mixture of 1-(1H-1,2,4-triazole-1-ylmethyl)tricyclo[3,3,1,0 3,7]nonan-3-amine (0.06 g, 0.38 mmol) and K2CO3(of 0.13 g, 0.96 mmol) in DMSO (1 ml) with a bath temperature of ice was added the compound (2S)-1-(chloroacetyl)pyrrolidin-2-carbonitrile (0.07 g, 0.32 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC), the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain the derived triazole (2S)-1-[1H-1,2,4-triazole-1-ylmethyl(tricyclo[3,3,1,03,7]non-3-ylamino)acetyl]pyrrolidin-2-carbonitrile (0.07 g) with a yield of 60% as not quite white solid. TPL: 230-235º. m/z (M+1) 355. IR cm-13429, 2929, 2224, 1658, 1511, 1426, 1330, 1276, 1141, 1018, 747.1H NMR (CDCl3) 300 MHz δ of 8.0 (s, 1H), and 7.9 (s, 1H), 4,78 (user. d, J=6.3 Hz, 1H), 4.09 to (s, 2H), 3,65-to 3.35 (m, 4H), 2.40 a-2,05 (m, 8H), 1,80-of 1.62 (m, 4H), 1,58-of 1.32 (m, 4H).

Example 2

To a stirred mixture of triazoline, which is obtained at stage IV of example 1 (0.65 g, 3 mmol) and K2CO3(1.24 g, 9 mmol) in DMSO (12 ml) at a temperature bath with ice was added (2S,4S)-1-(chloroacetyl)-4-ftorpirimidinu-2-carbonitrile (or 0.57 g, 3 mmol). The reaction mixture was gradually heated to room temperature and was stirred tip is of 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S,4S)-4-fluoro-1-{N-[2-(1H-1,2,4-triazole-1-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white powder (0.4 g) with a yield of 36%. IR cm-13444, 2951, 1672, 1518, 1416, 1301, 1135, 935; m/z (M+1) 373;1H NMR (CDCl3) 300 MHz δ of 8.0 (s, 1H), 7,92 (s, 1H), 5,44 (DDD, J=3,4, 3,4, 51,2 Hz, 0,8H), to 5.35 (DDD, J=3,4, 3,4, 51,3 Hz, 0,2N), 5,04 (t, J=8,8 Hz, 0,2N), of 4.95 (d, 9,2 Hz, 0,8H), 4,10 (s, 2H), 4,05-3,51 (m, 2,4H), 3,4 ((user), 1,6N), 2,82-2,62 (m, 1H), 2,45-of 2.16 (m, 5H), 1,91 was 1.69 (m, 4H), 1,57-to 1.38 (m, 4H).

Example 3

To a stirred mixture of triazoline, which is obtained at stage IV in example 1 (0.4 g, to 1.83 mmol) and K2CO3(0.4 g, 2.8 mmol) in DMSO (4 ml) at a temperature bath with ice was added (2S,4R)-1-(chloroacetyl)-4-ftorpirimidinu-2-carbonitrile (0.35 g, to 1.83 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. Untreated in the society was purified column chromatography to obtain (2S,4R)-4-fluoro-1-{N-[2-(1H-1,2,4-triazole-1-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile in the form of a resinous liquid (0.21 g) as a mixture of two rotamers with the release of 25%. m/z (M+1) 373;1H NMR (CDCl3) 300 MHz δ of 8.0 (s, 1H), 7,92 (s, 1H), 5,35 (d (user), J=51,5 Hz, 0,8H), and 5.30 (d (user), J=51,3 Hz, 0,2N), equal to 4.97 (t, J=8,4 Hz, 0,2N), 4,80 (t, 8,4 Hz, 0,8H), 4,20-of 3.32 (m, 4H), 4,10 (s, 2H), 2,87-to 2.40 (m, 1H), 2.40 a is 2.33 (m, 1H), 2,25-of 2.15 (m, 1H), 1,98-to 1.38 (m, 11N).

Example 4

To a stirred mixture of triazoline, which is obtained at stage IV of example 1 (0.27 g, 1.05 mmol) and K2CO3(of 0.58 g, 4.2 mmol) in DMSO (4 ml) at a temperature bath with ice was added (4R)-3-(chloroacetyl)-1,3-thiazolidin-4-carbonitrile (0.2 g, 1.05 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (4R)-3-{N-[2-(1H-1,2,4-triazole-1-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-1,3-thiazolidin-4-carbonitrile in the form of light yellow solid (0.18 g) with a yield of 46%. m/z (M+1) 373;1H NMR (CDCl3) 300 MHz δ to 7.99 (s, 1H), 7,92 (s, 1H), 5,32 (t, J=4,1 Hz, 1H), 4,70-4,55 (m, 2H), 4,08 (s, 2H), 3,62-of 3.48 (m, 2H), 3,40-3,26 (m, 2H), 2,42 to 2.35 (m, 1H), 2,25-of 2.15 (m, 1H), 1,90-of 1.39 (m, 10H).

Example 5

Stage I: A mixture of {3-[(tert-butoxycarbonyl)amino]-tricyclo[3,3,1,03,7]n is n-1-yl}methylmethanesulfonate, obtained as described previously (preparation 3) (0.8 g, 2.3 mmol), K2CO3(0.95 g, 6,9 mmol), tetrazole (0.24 g, of 3.45 mmol) and DMF (10.0 ml) was heated to 110 º C for 12 h, the Reaction mixture was cooled to room temperature, diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain tert-butyl[1-(1H-tetrazol-1-ylmethyl)tricyclo[3,3,1,03,7]non-3-yl]carbamate as a viscous liquid (0.2 g) with a yield of 27%. m/z (M+1) 320;1H NMR (CDCl3) 300 MHz δ 8,48 (s, 1H), 4.72 in ((user), 1H), 4,56 (s, 2H), 2,52 is 2.43 (m, 1H), 2,37-of 2.30 (m, 1H), 2,20-of 1.80 (m, 4H), 1,72 (DDD, J=2,7, 12,3, to 15.4 Hz, 2H), 1.56 to to 1.38 (m, 4H), of 1.44 (s, N).

Stage II:To a stirred solution of compound obtained in stage I above (0.2 g, of 0.62 mmol) in EtOAc (2.0 ml), cooled to a temperature bath with ice, was added a solution of dry HCl in EtOAc (3h, 3 ml). The reaction mixture was stirred at the same temperature for 2 h and volatile compounds were removed under reduced pressure to get crude substance, which rubbed some time with simple ether to obtain pure hydrochloric salt of 1-(1H-tetrazol-1-ylmethyl)tricyclo[3,3,1,03,7]nonan-3-amine (160 mg) with a yield of 100%. m/z (M+1) 220;1H NMR (CD3 OD) 300 MHz δ 8,72 (s,1H), 4,70 (s, 2H), 2,52 is 2.43 (m, 1H), 2,42-is 2.37 (m, 1H), 2,0 and 1.80 (m, 5H), 1.70 to 1,50 (m, 5H).

Stage III:To mix the hydrochloric salt obtained in stage II (rate £ 0.162 g of 0.62 mmol)in DMSO (2.5 ml) at room temperature under nitrogen atmosphere was added (2S)-1-(chloroacetyl)pyrrolidin-2-carbonitrile (0.11 g, of 0.62 mmol) and K2CO3(0.34 g, 2.48 mmol). After stirring for 3 h the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-(1H-tetrazol-1-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (0.09 g) with a yield of 40%. m/z (M+1) 355;1H NMR (CDCl3) 300 MHz δ 8,49 (s, 1H), 4,77 (d, J=6,7 Hz, 1H), 4,56 (s, 2H), 3,64-to 3.38 (m, 2H), 3,40 (s, 2H), 2.40 a-2,05 (m, 6N), 1,80-of 1.65 (m, 5H), 1.60-to of 1.40 (m, 5H).

Example 5A: Hydrochloric salt: To a stirred solution of the compound obtained in example 5 (36 mg, 0.1 mmol), in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue triturated some time with simple ether with getting not quite white monohydrochloride salt of (2S)-1-{N-[2-(1H-tetrazol-1-ylmethyl)hexahydro-2,5-methanoindan-3A(N)-yl]glycyl}pyrrolidine-2-carbonitrile (38 mg).

Example 6

Stage I:A mixture of {3-[(tert-butoxycarbonyl)amino]-tricyclo[3,3,1,03,7]non-1-yl}methylmethanesulfonate, which were obtained as described previously (preparation 3) of 0.85 g, 2.4 mmol), K2CO3(1.0 g, 7.2 mmol), N-methylpiperazine (0,37 ml, 3.6 mmol) and DMF (10.0 ml) was heated to 110 º C for 12 h, the Reaction mixture was cooled to room temperature, diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain tert-butyl[1-(4-methylpiperazin-1-yl)methyl]tricyclo[3,3,1,03,7]non-3-yl]carbamate as a viscous liquid (0.39 g) with a yield of 46%. m/z (M+1) 350;1H NMR (CDCl3) 300 MHz δ 4.72 in ((user), 1H), 2,55 was 2.25 (m, 10H), 2,48 (s, 3H), of 2.38 (s, 2H), 2,0-of 1.85 (m, 4H), 1,80-1,72 (m, 1H), 1.70 to of 1.40 (m, 4H), 1,45 (s, N), 1,35-1,22 (m, 1H).

Stage II:To a stirred solution of the compound obtained in accordance with stage I (0,38 g of 1.09 mmol) in EtOAc (4.0 ml), cooled to a temperature bath with ice, was added a solution of dry HCl in EtOAc (3h, 6 ml). The reaction mixture was stirred at the same temperature for 2 h and the volatiles were removed under reduced pressure to get crude substances, which rubbed some time with simple diet the gross ether to obtain hydrochloric salt of 1-[(4-methylpiperazin-1-yl)methyl]tricyclo[3,3,1,0 3,7]nonan-3-amine (330 mg) with a yield of 85%.

Stage III:To a stirred solution of hydrochloride (0.33 g, to 0.92 mmol)obtained in stage II, in DMSO (3,7 ml) at room temperature under nitrogen atmosphere was added (2S)-1-(chloroacetyl)pyrrolidin-2-carbonitrile (0.16 g, to 0.92 mmol) and K2CO3(0,76 g of 5.53 mmol). After stirring for 3 h the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (0.12 g) with a yield of 47%. m/z (M+1) 386;1H NMR (CDCl3+CD3OD) 300 MHz δ 4,78 (d, J=5.7 Hz, 1H), 3,85-to 3.50 (m, 4H), 3,30-3,10 (m, 5H), 2,85-2,70 (m, 8H), 2,52 at 2.45 (m, 2H), 2,38-of 2.20 (m, 4H), 2,10-1,90 (m, 4H), 1.70 to of 1.40 (m, 5H), 1,40-of 1.27 (m, 1H).

Example 6A: Hydrochloric salt: To a stirred solution of the compound obtained in example 7 (39 mg, 0.1 mmol) in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatile compounds were removed under reduced pressure and the residue triturated some time with a simple diethyl ether to obtain hydrochloric salt of (2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-and the]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (41 mg).

Example 7

Stage I: A mixture of {3-[(tert-butoxycarbonyl)amino]-tricyclo[3,3,1,03,7]non-1-yl}methylmethanesulfonate, who received, as described previously (preparation 3) of 0.85 g, 2.4 mmol), K2CO3(1.0 g, 7.2 mmol), thiomorpholine (0.4 ml, 3.6 mmol) and DMF (10.0 ml) was heated to 110 º C for 12 h, the Reaction mixture was cooled to room temperature, diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain tert-butyl[1-(thiomorpholine-4-ylmethyl)tricyclo[3,3,1,03,7]non-3-yl]carbamate as a viscous liquid (0.18 g) with a yield of 21%. m/z (M+1) 353;1H NMR (CDCl3) 300 MHz δ 4.72 in ((user), 2,75-of 2.66 (m, 4H), 2,65-of 2.58 (m, 4H), 2.40 a-2,28 (m, 2H), 2,17 (s, 2H), 2,0-of 1.85 (m, 4H), 1,80-1,72 (m, 1H), 1,62 of 1.50 (m, 4H), 1,45 (s, N), 1,35-1,20 (m, 1H).

Stage II: To a stirred solution of compound (0,22 g, to 0.63 mmol)obtained in stage I, in EtOAc (2.0 ml), cooled to a temperature bath with ice, was added a solution of dry HCl in EtOAc (3h), 4 ml). The reaction mixture was stirred at the same temperature for 2 h and the solvent was removed under reduced pressure to get crude substance, which rubbed some time with a simple diethyl ether and n is the receiving hydrochloric salt of 1-(thiomorpholine-4-ylmethyl)tricyclo[3,3,1,0 3,7]nonan-3-amine (180 mg) with a yield of 88%.

Stage III: To mix the hydrochloric salt (0.17 g, 0.51 mmol)obtained in phase II (above) in DMSO (2.0 ml) at room temperature under nitrogen atmosphere was added (2S)-1-(chloroacetyl)pyrrolidin-2-carbonitrile (0.09 g, 0.52 mmol) and K2CO3(0.35 g, 2.55 mmol). After stirring for 3 h the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-thiomorpholine-4-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (0.07 g) with a yield of 35%. m/z (M+1) 389;1H NMR (CDCl3) 300 MHz δ a 4.83-4.75 in (m, 1H), 3,90 is-3.45 (m, 4H), 2,85-2,70 (m, 4H), 2,70-2,60 (m, 4H), 2,48 to 2.35 (m, 2H), 2,35-of 2.15 (m, 4H), 2.0 to about 1.75 (m, 4H), 1,68-of 1.40 (m, 5H), 1,38-1,25 (m, 1H).

Example 7A: Hydrochloric salt: To a stirred solution of the compound obtained in accordance with example 7 (39 mg, 0.1 mmol), in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue triturated some time with a simple diethyl ether to obtain hydrochloric salt of (2S)-1-{N-[2-thiomorpholine-4-ylmethyl)hexahydro-2,5-metanode talen-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (41 mg).

Example 8

Stage I:Stir a mixture of [3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methylmethanesulfonate, which is obtained as described previously (drug 2) (1.0 g, 2.9 mmol), K2CO3(1,16 g, 8,7 mmol) and isothiazoline-1,1-dioxide (0,53 g, 4.35 mmol) in DMF (12.0 ml) was heated at 110 º C for 16 hours the Reaction mixture was cooled to room temperature, diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain 2-{[3-(2-methyl-1,3-dioxolane-2-yl)tricyclo[3,3,1,03,7]non-1-yl]methyl}isothiazolin-1,1-dioxide in the form of a viscous liquid (0,69 g) with a yield of 70%. m/z (M+1) 342;1H NMR (CDCl3) 300 MHz δ 4,04-to 3.92 (m, 4H), 3,30 (t, J=6,8 Hz, 2H), 3,10 (t, J=7.4 Hz, 2H), 2,94 (d, J=14.6 Hz, 1H), 2,87 (d, J=14.6 Hz, 1H), 2,40-of 2.27 (m, 4H), 1,88-1,72 (m, 2H), 1,72-of 1.55 (m, 4H), 1,55-to 1.38 (m, 4H), 1.27mm (, 3H).

Stage II:Stir a solution of the compound obtained in stage I (0.68 g, 2.0 mmol)and p-toluenesulfonic acid (38 mg, 0.2 mmol) in acetone (8 ml) was boiled under reflux for 4 hours the Reaction mixture was diluted with EtOAc and washed with 10% aq. NaHCO3and saturated salt solution, dried over Na2SO4and the solvent evaporated when pengendalian to obtain 1-{1-[1,1-dioxothiazolidine-2-yl)methyl]tricyclo[3,3,1,0 3,7]non-3-yl}ethanone (0.55 g) with a yield of 92% in the form of a viscous liquid.

Stage III:To a stirred mixture of NaOH (1.2 g, 27.8 mmol), N2O (8 ml) and 1,4-dioxane (1 ml) with a bath temperature of ice was added Br2high (0.56 ml, 10.4 mmol) and the mixture was stirred for 15 minutes. Received the hypobromite solution was added dropwise to a stirred solution of compound obtained in stage II (0.55 g, of 1.85 mmol) in 1,4-dioxane (3 ml) at a temperature bath with ice. The reaction mixture was gradually heated to room temperature and then was stirred for 1 h, the mixture was cooled to a temperature bath with ice and extinguished the addition of Asón (1.7 ml, 27.8 mmol). The reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-[(1,1-dioxothiazolidine-2-yl)methyl]tricyclo[3,3,1,03,7]nonan-3-carboxylic acid (0.39 g) with a yield of 70%. m/z (M-1) 298;1H NMR (CDCl3) 300 MHz δ of 3.32 (t, J=6,8 Hz, 2H), 3,10 (t, J=7.4 Hz, 2H), 2.95 and (s, 2H), 2,80-by 2.73 (m, 1H), 2,43-to 2.41 (m, 1H), 2.40 a-to 2.29 (m, 2H), 2,10-2,0 (m, 2H), 1,82-1,72 (m, 3H), 1,67-and 1.54 (m, 4H), of 1.46 (DD, J=3,2 11,0 Hz, 1H).

Stage IV:To a stirred solution of the acid obtained in stage III (0.39 g, 1,31 mmol) in CHCl3(7 ml) was added conc. H2SO4(1,4 ml, 26 mmol). Slowly, portions was added solid is th NaN 3(0.26 g, 3.93 mmol), maintaining the reaction temperature below 40ºC. The reaction mixture was stirred at room temp. within 2 h, and then cooled to a temperature bath with ice, diluted with water and was extracted with EtOAc. The aqueous layer was podslushivaet by adding 50% NaOH solution and was extracted with Cl3. The combined organic layer was washed with saturated salt solution, dried over Na2SO4the solvent is evaporated under reduced pressure to obtain 1-[(1,1-dioxothiazolidine-2-yl)methyl]tricyclo[3,3,1,03,7]nonan-3-amine (0.26 g) as a viscous liquid with a yield of 74%. m/z (M+1) 271;1H NMR (CDCl3) 300 MHz δ of 3.32 (t, J=6,8 Hz, 2H), 3,10 (t, J=7.4 Hz, 2H), 2,92 (s, 2H), 2.40 a-2,28 (m, 3H), 2,01 of-1.83 (m, 3H), 1,75-of 1.52 (m, 6N), 1,50 was 1.43 (m, 1H), 1,39-1,32 (m, 1H).

Stage V:To a stirred mixture of the amine obtained in stage IV (0.26 g, 0.96 mmol), and K2CO3(0,42 g, 2.9 mmol) in DMSO (4.0 ml) at a temperature bath with ice in a nitrogen atmosphere was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.17 g, 1.0 mmol). After stirring for 3 h at room temp. the reaction mixture was diluted with EtOAc, washed with water and saturated salt solution, dried over Na2SO4and the solvent evaporated under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-[(1,1-dioxothiazolidine-2-yl)methyl]hexahydro-2,5-methamphetamin-3A(1H)-illicit}pyrrolidin-2-carbonitrile as not quite white solid (0.17 g) with a yield of 43%. m/z (M+1) 407;1H NMR (CDCl3) 300 MHz δ 4,87 was 4.76 (m, 1H), 3,70 is 3.40 (m, 2H), 3,44 (s, 2H), 3,32 (m, J=6,7 Hz, 2H), 3,10 (t, J=7.5 Hz, 2H), 2,93 (s, 2H), 2,41 is 2.10 (m, 8H), 1,90 of 1.46 (m, 7H), 1,43-of 1.35 (m, 1H).

Example 9

Stage I:The mixture of compounds obtained as described previously (preparation 3) (0.9 g, 2.6 mmol), K2CO3(1.1 g, 7.8 mmol) and thiazolidine-2,4-dione (of 0.47 g, 4.0 mmol) in DMF (10.5 ml) was heated at 110 º C for 12 h, the Reaction mixture was cooled to room temperature, diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain 3{3-[(tert-butoxycarbonyl)amino]tricyclo[3,3,1,03,7]non-1-yl}methyl-1,3-thiazolidin-2,4-dione in the form of a viscous liquid (0.28 g) with a yield of 25%. m/z (M+1) 367;1H NMR (CDCl3) 300 MHz δ 4.72 in ((user), 1H), 3.96 points (s, 2H), only 3.57 (s, 2H), 2,46-of 2.38 (m, 1H), 2,38-of 2.30 (m, 1H), 2,02-of 1.85 (m, 4H), 1,80 is 1.70 (m, 1H), and 1.63 (DD, J=2,9, 10.5 Hz, 1H), 1,52-of 1.40 (m, 3H), of 1.44 (s, N), to 1.37 (DD, J=3,0, and 11.0 Hz, 1H).

Stage II:To a stirred solution of compound obtained in stage I (0.2 g, 0.54 mmol) in EtOAc (2.0 ml), cooled to a temperature bath with ice, was added a solution of dry HCl in EtOAc (3h, 3 ml). The reaction mixture was stirred at the same temperature for 2 h and the solvent was removed when ponie nom the pressure to get the crude substance, that rubbed some time with a simple diethyl ether to obtain hydrochloric salt (165 mg) with a yield of 100%. M/z (M+1) 267;1H NMR (CD3OD) 300 MHz δ of 4.10 (s, 2H), 3,60 (DD, J=9,0, of 11.0 Hz, 2H), 2,48-to 2.42 (m, 1H), 2,34 (DDD, J=1,6, 6,9, 8.5 Hz, 1H), 1,88 by 1.68 (m, 6N), 1,68-of 1.53 (m, 3H), 1,50 (DD, J=2.0 a, and 11.4 Hz, 1H).

Stage III: To a stirred solution of hydrochloric salt obtained in stage II (0,165 g, 0.54 mmol) in DMSO (2.2 ml) at room temperature under nitrogen atmosphere was slowly added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.1 g, 0.54 mmol) and K2CO3(0,23 g of 1.62 mmol). After stirring for 3 h the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-[(2,4-dioxo-1,3-thiazolidin-3-yl)methyl]hexahydro-2,5-methamphetamin-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (0.11 g) with a yield of 50%. m/z (M+1) 358;1H NMR (CDCl3) 300 MHz δ of 4.77 (d, J=7,4 Hz, 1H), 3.96 points (s, 2H), 3.75 to to 3.38 (m, 2H), of 3.56 (s, 2H), 3,41 (s, 2H), 2.40 a is 2.10 (m, 6N), 1,90-of 1.57 (m, 10H), 1.57 in and 1.33 (m, 4H).

Example 10

Stage I: To a stirred solution of tert-butyl[1-(hydroxymethyl)tricyclo[3,3,1,03,7]non-3-yl]carbamate (obtained in stage VI (product 3)) (0,67 is, 2.5 mmol) in toluene (10 ml) was added phthalimide (0.52 g, 3.5 mmol), triphenylphosphine (of 1.05 g, 4.0 mmol) and diisopropylethylamine (0.8 ml, 4.0 mmol). The reaction mixture was heated at 90ºC for 4 hours Volatiles were removed under reduced pressure and the residue was purified column chromatography to obtain tert-butyl[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate (0.45 g) as a viscous liquid with a yield of 46%. m/z (M+1) 397;1H NMR (CDCl3) 300 MHz δ of 7.90-7,80 (m, 2H), to 7.77-to 7.68 (m, 2H), 4.75 in ((user), 1H), 3,60 (s, 2H), 2,47 to 2.35 (m, 1H), 2,36-to 2.29 (m, 1H), 2,02-of 1.84 (m, 4H), 1.77 in-of 1.65 (m, 2H), 1,64-of 1.35 (m, 5H), of 1.41 (s, N), 1,34-1,24 (m, 1H).

Stage II: To a stirred solution of compound obtained in stage I (0.45 g, 1.12 mmol) in dichloromethane (1.1 ml) at 0OC was added triperoxonane acid (1.1 ml). The reaction mixture was gradually heated to room temperature and was stirred for 1 h Volatiles were removed in vacuo and the residue triturated some time with a simple diethyl ether to obtain 2-[(3-aminotriazole[3,3,1,03,7]non-1-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.4 g) in the form of a salt with triperoxonane acid with a yield of 86%. m/z (M+1) 297;1H NMR (DMSO-d6) 300 MHz δ 8,05 ((user), 2H), 7,92-7,80 (m, 4H), 3,51 (s, 2H), 2,38-of 2.30 (m, 1H), 2,30-2,22 (m, 1H), 1.85 to of 1.66 (m, 6N), 1,60-1,50 (m, 3H), 1,45-to 1.38 (m, 1H).

Stage III: To a stirred mixture of compound obtained in stadii (0.4 g, 0.98 mmol), and K2CO3(0.54 g, to 3.92 mmol) in DMSO (4.0 ml) at a temperature bath with ice in a nitrogen atmosphere was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.17 g, 1.0 mmol). After stirring at room temp. within 3 h, the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (S)-1-{N-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (0.18 g) with a yield of 43%. m/z (M+1) 433;1H NMR (CDCl3) 300 MHz δ of 7.90-7,80 (m, 2H), 7,75-the 7.65 (m, 2H), 4,86-4,72 (m, 1H), 3.72 points-to 3.38 (m, 2H), 3,60 (s, 2H), 3,40 (s, 2H), 2.40 a-2,05 (m, 7H), 1,90-of 1.78 (m, 2H), 1.70 to of 1.40 (m, 3H).

Example 11

Stage I:To a stirred solution of benzyl-[2-(4-AMINOPHENYL)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate (1.1 g, 3.03 mmol), obtained as described previously (preparation 4), in THF (30 ml) at 0 ° C was added Et3N (0,66 ml, 4.6 mmol) and 3-chloropropanesulfonyl (0,42 ml, 3.3 mmol). The reaction mixture was heated to room temperature and was stirred for 1 h was Added aqueous NaOH solution (50% wt./about., 6 ml) followed by addition of n-Bu4NI (56 mg, 0.15 mmol). After stirring for 16 h reacciona the mixture was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure and the crude substance was purified column chromatography to obtain benzyl-[2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate in the form of not-quite-white solid (0,93 g) with a yield of 66%. TPL: 215,6-219,2C, m/z (M+1) 467; IR cm-13441, 2953, 1716, 1516, 1314, 1215, 770.1H NMR (CDCl3) 300 MHz δ 7,40-7,16 (m, N), 5,13-5,0 (users 2N in), 3.75 (t, J=6.6 Hz, 2H), 3,35 (t, J=7.5 Hz, 2H), 2,59-of 2.38 (m, 4H), 2,30-to 1.60 (m, 10H).

Stage II:A mixture of benzyl-[2-(4-(1,1-dioxothiazolidine-2-yl)phenyl)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate (0.8 g, 1.7 mmol)obtained in stage I, Pd/C (10%, 0.4 g) in Meon (17 ml) was stirred at room temperature in an atmosphere of H2within 2 hours the Reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure to obtain 1-[4-(1,1-dioxothiazolidine-2-yl)phenyl]tricyclo[3,3,1,03,7]nonan-3-amine in the form of not-quite-white solid (0,49 g) with a yield of 85%. m/z (M+1) 333; IR cm-13418, 1652, 1137, 772.1H NMR (CDCl3) 300 MHz δ 7,31 (d, J=8,8 Hz, 2H), 7,22 (d, J=8,8 Hz, 2H), 3,78 (t, J=6.6 Hz, 2H), 3.43 points (t, J=7.4 Hz, 2H), 2,58-2,47 (m, 3H), 2.40 a-2,34 (m, 1H), 2,27-2,11 (m, 2H), 2,10-of 1.95 (m, 4H), 1.93 and is 1.70 (m, 4H).

Stage III:To stir a mixture of 1-[4-(1,1-deoxidization-2-yl)Hairdryer is l]tricyclo[3,3,1,0 3,7]nonan-3-amine (0.4 g, 1.2 mmol) and K2CO3(of 0.48 g, 3.6 mmol) in DMSO (4.8 ml) at a temperature bath with ice was added (2S)-1-(chloroacetyl)pyrrolidin-2-carbonitrile (0.25 g, 1.44 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-[4-(1,1-deoxidization-2-yl)phenyl]hexahydro-2,5-methanoindan-3A(N)-yl]glycyl}pyrrolidine-2-carbonitrile in the form of a white solid (0.28 g) with a yield of 50%. TPL 214-216º, m/z (M+1) 469; IR-13436, 2932, 2240, 1658, 1517, 1414, 1308, 1137, 952, 740.1H NMR (300 MHz, CD3OD) δ: to 7.35 (d, J=8.5 Hz, 2H), 7.23 percent (d, J=8.5 Hz, 2H), 4,85 (t, J=5.4 Hz, 1H), 4,15-3,95 (m, 2H), 3,81-3,70 (m, 3H), 3,60-to 3.50 (m, 1H), 3,42 (t, J=7.4 Hz, 2H), 2,65 at 2.45 (m, 4H), 2.40 a is 1.75 (m, 14N).

Example 12

To stir a mixture of 1-[4-(1,1-deoxidization-2-yl)phenyl]tricyclo[3,3,1,03,7]nonan-3-amine (obtained in stage II of example 8) (0.17 g, 0.5 mmol) and K2CO3(0.21 g, 1.5 mmol) in DMSO (2 ml) with a bath temperature of ice was added (2S,4S)-1-chloroacetyl)-4-ftorpirimidinu-2-carbonitrile (0.1 g, 0.5 mmol). The reaction mixture gradually agrawala to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S,4S)-1-{N-[2-[4-(1,1-deoxidization-2-yl)phenyl]hexahydro-2,5-methanoindan-3A(N)-yl]glycyl}-4-ftorpirimidinu-2-carbonitrile as not quite white powder (0.09 g) with a yield of 37% in the form of a mixture of 3:1 two retamero. IR cm-13438, 2953, 2776, 1673, 1518, 1427, 1301, 1135, 1078, 955; m/z (M+1) 487;1H NMR (CDCl3) 300 MHz δ of 7.25 (d, J=6.2 Hz, 2H), 7,20 (d, J=8.6 Hz, 2H), 5,42 (d (user), J=51,0 Hz, 0,8H), of 5.34 (d (user), J=50,4 Hz, 0,2N), of 5.15 (d, J=10,2 Hz, 0,2N), to 4.98 (d, J=7,4 Hz, 0,8H), 4,0-to 3.50 (m, 4H), 3,76 (t, J=6.5 Hz, 2H), 3,35 (t, J=6.5 Hz, 2H), 2,80-of 2.28 (m, 6N), 2,15 is 1.58 (m, 10H).

Example 13

To stir a mixture of 1-[4-(1,1-deoxidization-2-yl)phenyl]tricyclo[3,3,1,03,7]nonan-3-amine, obtained in stage II of example 8 (0,22 g, 0.7 mmol) and K2CO3(0.3 g, 2.1 mmol) in DMSO (3.4 ml) at a temperature bath with ice was added (2S,4R)-1-(chloroacetyl)-4-ftorpirimidinu-2-carbonitrile (0,13 g, 2.1 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated RA is tworoom salt, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S,4R)-1-{N-[2-[4-(1,1-dioxothiazolidine-2-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-4-ftorpirimidinu-2-carbonitrile as not quite white powder (0.14 g) in the form of a mixture of 3:1 two rotamers, with the release of 43%. m/z (M+1) 487;1H NMR (CDCl3) 300 MHz δ of 7.25 (d, J=7.9 Hz, 2H), 7,20 (d, J=8.7 Hz, 2H), 5,35 (d (user), J=51,4 Hz, 0,8H), 5,28 (d (user), J=50,7 Hz, 0,2N), 5,02 (t, J=7.2 Hz, 0,2N), 4,80 (t, J=8,4 Hz, 0,8H), was 4.02-to 3.41 (m, 4H), 3,76 (t, J=6.6 Hz, 2H), 3,37 (t, J=7.4 Hz, 2H), 2,85 was 2.25 (m, 6N), 2,15-of 1.55 (m, 10H).

Example 14

To stir a mixture of 1-[4-(1,1-dioxothiazolidine-2-yl)phenyl]tricyclo[3,3,1,03,7]nonan-3-amine, obtained in stage II of example 8 (0.25 g, 1.1 mmol), and K2CO3(and 0.46 g, 3.3 mmol) in DMSO (5 ml) at a temperature bath with ice was added (4R)-3-(chloroacetyl)-1,3-thiazolidin-4-carbonitrile (0.2 g, 1.1 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (4R)-3-{N-[2-[4-(1,1-dioxides is thiazolidin-2-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-1,3-thiazolidin-4-carbonitrile as not quite white powder (0.1 g) with a yield of 40%. m/z (M+1) 487; IR cm-13444, 2952, 2873, 1672, 1518, 1416, 1301, 1135, 953;1H NMR (CDCl3) 300 MHz δ of 7.25 (d, J=6.2 Hz, 2H), 7,20 (d, J=8.6 Hz, 2H), 5,38-of 5.48 (m, 1H), 4.72 in-4,51 (m, 2H), 3,75 (t, J=6.6 Hz, 2H), 3,70-3,55 (m, 1H), 3,36 (t, J=7.4 Hz, 2H), 3,32-3,20 (m, 1H), 2,60-to 2.40 (m, 4H), 2,20-1,58 (m, 10H).

Example 15

Stage I:To a stirred solution of benzyl-[2-(4-AMINOPHENYL)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate (1.1 g, 3.03 mmol), obtained as described previously (preparation 4), in THF (30 ml) at 0 ° C was sequentially added Et3N (0,66 ml, 4.6 mmol) and 4-chlorobutyrate (0,37 ml, 3.3 mmol). The reaction mixture was heated to room temperature and was stirred for 1 h was Added aqueous NaOH solution (50% wt./about., 6 ml) followed by addition of n-Bu4NI (56 mg, 0.15 mmol) and the reaction mixture was stirred for 16 hours, the Reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4the solvent was removed under reduced pressure and the crude substance was purified column chromatography to obtain benzyl-[2-[4-(2-oxopyrrolidin-1-yl)phenyl)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate in the form of not-quite-white solid (0.9 g, yield 69%). m/z (M+1) 431;1H NMR (CDCl3) 300 MHz δ of 7.55 (d, J=8.6 Hz, 2H), 7,42-7,20 (m, 7H), 5,15-5,0 (user. s, 2H), a 3.87 (t, J=7,0 Hz, 2H), 2,67 of $ 2.53 (m, 3H), 2,48-to 2.42 (m, 1H), 2,35-of 1.55(m, N).

Stage II:A mixture of benzyl-[2-[4-(2-oxopyrrolidin-1-yl)phenyl)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate (0.73 g, 1.7 mmol)obtained in stage I, and Pd/C (10%, 0.4 g) in Meon (17 ml) was stirred at room temperature in an atmosphere of H2within 2 hours the Reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure to obtain 1-[4-(3-aminotriazole[3,3,1,03,7]non-1-yl)phenyl]pyrrolidin-2-she is not quite white solid (0,43 g, 85% yield). m/z (M+1) 297;1H NMR (CDCl3) 300 MHz δ 7,52 (d, J=8.6 Hz, 2H), 7,25 (d, J=8.6 Hz, 2H), 3,86 (t, J=6.9 Hz, 2H), 2,62 (t, J=7.9 Hz, 2H), 2,52-to 2.42 (m, 1H), 2,32 is 1.60 (m, 13H).

Stage III:To a stirred solution of 1-[4-(3-aminotriazole[3,3,1,03,7]non-1-yl)phenyl]pyrrolidin-2-it received in phase II (0.36 g, 1.2 mmol)in DMSO (4.8 ml) at a temperature bath with ice in a nitrogen atmosphere was added To a2CO3(of 0.48 g, 3.6 mmol) followed by addition of (2S)-1-(chloroacetyl)pyrrolidin-2-carbonitrile (0.21 g, 1.2 mmol). After stirring at room temp. within 3 h, the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain the above compound (2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanoindan-3 is(1H)-yl]glycyl}pyrrolidine-2-carbonitrile in the form of a white solid (0.26 g) with a yield of 50%. Tel: 254-256º; m/z (M+1) 433;1H NMR (300 MHz, CDCl3) δ: rate of 7.54 (d, J=8.5 Hz, 2H), 7.23 percent (d, J=8.5 Hz, 2H), 4,30-4,20 (m, 1H), 4,06-4,18 (m, 2H), a 3.87 (t, J=7,0 Hz, 1H), 3,80-to 3.50 (m, 4H), of 2.64 (t, J=7.8 Hz, 2H), 2,58 is 1.60 (m, N).

Example 16

To stir the mixture lactamania, 1-[4-(3-aminotriazole[3,3,1,03,7]non-1-yl)phenyl]pyrrolidin-2-it, which is obtained at the second stage of example 12 (0.15 g, 0.5 mmol), and K2CO3(0.21 g, 1.5 mmol) in DMSO (2 ml) with a bath temperature of ice was added (2S,4S)-1-(chloroacetyl-4-ftorpirimidinu-2-carbonitrile (0.1 g, 0.5 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S,4S)-4-fluoro-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white powder (0.11 g) with a yield of 49%. m/z (M+1) 451;1H NMR (CDCl3) 300 MHz δ 7,51 (d, J=8.5 Hz, 2H), 7,25 (d, J=8.5 Hz, 2H), 5,43 (DDD, J=3,1, 3,1, 51,3 Hz, 1H), 5,12 (d, J=8.7 Hz, 0,2N), equal to 4.97 (d, J=9.5 H), 4,05-3,62 (m, 2H), 3,85 (t, J=6.9 Hz, 2H), 3,55 is 3.40 (m, 2H), 2,81-2,61 (m, 1H), 2,60 (t, J=8,2 Hz, 2H), 2,49-to 2.40 (m, 1H), 2,32 was 2.25 (m, 1H), 2.21 are of 2.05 (m, 4H), 2.0 to to 1.60 (m, N).

Example 17

To stir the mixture lactamania obtained in phase II of example 12 (0.15 g, 0.5 mmol), and K2CO3(0.21 g, 1.5 mmol) in DMSO (2 ml) with a bath temperature of ice was added (4R)-3-(chloroacetyl)-1,3-thiazolidin-4-carbonitrile (0.1 g, 1.1 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (4R)-3-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}-1,3-thiazolidin-4-carbonitrile as not quite white powder (0.09 g) with a yield of 40%. m/z (M+1) 451;1H NMR (CDCl3) 300 MHz δ 7,51 (d, J=6,7 Hz, 2H), 7,24 (d, J=7,0 Hz, 2H), of 5.34 (t, J=4,1 Hz, 1H)and 4.65 (d, J=7.5 Hz, 1H), 4,60 (d, J=7.5 Hz, 1H), 3,85 (t, J=6.9 Hz, 2H), 3,70-3,55 m, 2H), 3,40-of 3.25 (m, 2H), 2,60 (t, J=7,8 Hz, 2H), 2,49-to 2.42 (m, 1H), 2,33 was 2.25 (m, 1H), 2.21 are represented 2.02 (m, 4H), of 2.0 to 1.6 (m, 8H).

Example 18

Stage I:To a stirred solution of benzyl-[2-(4-AMINOPHENYL)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate obtained as described previously (preparation 4) (1,09 g, 3.0 mmol)in glacial acetic acid (12 ml) was added 2,5-dimethoxytetrahydrofuran (0,44 g, 3.3 mmol). The reaction mixture n is gravely boiling under reflux for 1 h The mixture was diluted with ethyl acetate, washed with water, 10% aq. NaHCO3and a saturated solution of salt. The combined organic layer was dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure. The crude substance was purified column chromatography to obtain benzyl-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate (0.8 g) with a yield of 65% in the form of a viscous liquid. m/z (M+1) 413;1H NMR (CDCl3) 300 MHz δ 7,50-7,20 (m, N), 7,08? 7.04 baby mortality (m, 2H), 6,37-6,30 (m, 2H), 5,10 (s, 2H), 2,65-2,52 (m, 1H), 2,50-to 2.42 (m, 1H), 2.40 a-2,12 (m, 2H), 2,10-to 1.70 (m, 6N), 1,70-of 1.52 (m, 2H).

Stage II:To a stirred solution of compound obtained in stage I (0.8 g, 1.94 mmol) in Meon (20 ml) was added Pd/C (10%, 0.1 g). The reaction mixture was stirred at room temp. within 2 h pressure H2supplied from a cylinder. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure to obtain 2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-amine as a viscous liquid (0.45 g) with a yield of 83%. m/z (M+1) 279;1H NMR (CD3D) 300 MHz δ 7,40-7,25 (m, 4H), 7,20-7,05 (m, 2H), 6.30-in-of 6.20 (m, 2H), 2.57 m) is 2.46 (m, 1H), 2,46-of 2.38 (m, 1H), 2,30 and 2.13 (m, 2H), 2,13-of 1.81 (m, 7H), 1,80 is 1.70 (m, 1H).

Stage III:To a stirred mixture of compound obtained in stage II (0,41 g, 1.5 mmol), and K2CO3(of 0.62 g, 4.5 mmol) in DMSO (6 ml) with a bath temperature of ice in the atmosphere is fere N 2was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.26 g, 1.5 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solids (0.2 g) with a yield of 32%. m/z (M+1) 415;1H NMR (CDCl3) 300 MHz δ 7,38-7,26 (m, 4H), 7,10-7,05 (m, 2H), 6,36-6,32 (m, 2H), 4,84-4,78 (m, 1H), 3.75 to is 3.40 (m, 2H), 3,50 (s, 2H), 2,50-to 2.42 (m, 1H), 2,38-of 2.28 (m, 2H), 2,25-2,0 (m, 6N), 2,0 is 1.70 (m, 7H).

Example 19

Stage I:To a stirred solution of benzyl-[2-(4-AMINOPHENYL)hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate obtained as described previously (preparation 4) (1,09 g, 3.0 mmol)in THF (12 ml) at 0 ° C was added Et3N (0,65 ml, 4.5 mmol), followed by adding 2-chlorotriazine (0.3 ml, 3.3 mmol). The reaction mixture was heated to room temperature and was stirred for 1 h was Added aqueous NaOH solution (50% wt./about., 6 ml) followed by addition of n-Bu4NI (55 mg, 0.15 mmol) and the reaction mixture was stirred in ECENA 16 PM Two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent evaporated under reduced pressure. The crude substance was purified column chromatography to obtain benzyl-[2-[4-(2-Oxymetazoline-1-yl]hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate (0.7 g) in the form of not-quite-white solid with a yield of 54%. m/z (M+1) 432;1H NMR (CDCl3) 300 MHz δ 7,44 (d, J=8,8 Hz, 2H), 7,40-7,30 (m, 5H), 7,21 (d, J=8,8 Hz, 2H), 5,09 (s, 2H), 3,92 (t, J=7.4 Hz, 3H), 3,55 (t, J=8.5 Hz, 2H), 2,59-of 2.50 (m, 1H), 2,44-of 2.38 (m, 1H), 2,30-2,11 (m, 3H), 2,11-1,90 m, 3H), 1,89-of 1.66 (m, 2H), 1,64 of 1.46 (m, 2H).

Stage II:To a stirred solution of compound obtained in stage I (0.65 g, 1.5 mmol), Meon (15 ml) was added Pd/C (10%, 0.1 g). The reaction mixture was stirred at room temperature for 2 h under a pressure of H2supplied from a cylinder. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure to obtain 1-[4-(3-aminotriazole[3,3,1,03,7]non-1-yl)phenyl]imidazolidin-2-she (0.4 g) in the form of not-quite-white solid with a yield of 90%. TPL: 215-220º; m/z (M+1) 298; IR cm-13412, 3245, 2955, 1687, 1518, 1485, 1263, 805;1H NMR (CDCl3+DMSO-d6) 300 MHz δ compared to 8.26 ((user), 2H), 7,46 (d, J=8.7 Hz, 2H), 7,16 (d, J=8.7 Hz, 2H), 6,70 ((user), 1H), 3,86 (t, J=7,3 Hz, 2H), 3,48 (t, J=7,3 Hz, 2H), 2,50 at 2.45 (m, 1H), 2,22-2,07 (m, 3H) 2,02-to 1.63 (m, 8H).

Stage III:To a stirred mixture of compound obtained in stage II (0.4 g, 1.35 mmol), and K2CO3(0.56 g of 4.05 mmol) in DMSO (6 ml) with a bath temperature of ice in the atmosphere N2was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0,23 g, 1.35 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent evaporated under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-[4-(2-Oxymetazoline-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (0.21 g) with a yield of 36%. m/z (M+1) 434;1H NMR (CDCl3) 300 MHz δ was 7.45 (d, J=8,8 Hz, 3H), of 7.23 (d, J=8,8 Hz, 2H), 4,86 was 4.76 (m, 1H), 4,67 ((user), 1H), 3,93 (t, J=7.4 Hz, 2H), 3.75 to is 3.40 (m, 4H), of 3.48 (s, 2H), 3.46 in-of 2.38 (m, 1H), 2,36-of 2.23 (m, 2H), 2,23 is 1.70 (m, N), 1,65-of 1.57 (m, 1H).

Example 20

Stage I:To stir the mixture tricyclo[3,3,1,03,7]nonan-3-amine (0.28 g, 2.0 mmol) and K2CO3(0,83 g, 6.0 mmol) in DMSO (8 ml) with a bath temperature of ice in the atmosphere N2was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.34 g, 2.0 mmol). The reaction mixture is tapeno was heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-[(tricyclo[3,3,1,03,7]non-3-ylamino)acetyl]pyrrolidin-2-carbonitrile in the form of a viscous liquid (0,23 g) with a yield of 42%. m/z (M+1) 274;1H NMR (CDCl3) 300 MHz δ 4,87 was 4.76 (m, 1H), 3,71 is 3.40 (m, 2H), 3,41 (s, 2H), 2,35-2,05 (s, 7H), 1,92-of 1.74 (m, 6N), 1,68 is 1.48 (m, 4H).

Example 19A: Hydrochloric salt: To a stirred solution of the compound obtained in example 18 (27 mg, 0.1 mmol) in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatile compounds were removed under reduced pressure and the residue triturated some time with a simple diethyl ether to obtain hydrochloric salt of (2S)-1-[(tricyclo[3,3,1,03,7]non-3-ylamino)acetyl]pyrrolidin-2-carbonitrile as not quite white solid (31 mg). m/z (M+1) 274;1H NMR (DMSO-d6) 300 MHz δ 9,44 ((user), 2N), a 4.86 (DD, J=4,4 7,0 Hz, 1H), 4,10-3,88 (m, 2H), 3,78-the 3.65 (m, 1H), 3,60-3,47 (m, 1H), 2,48-to 2.41 (m, 1H), 2,34-of 2.27 (m, 2H), 2.26 and-2,17 (m, 2H), 2,10-1,99 (m, 2H), 1,99 of-1.83 (m, 6N), 1,63 was 1.43 (m, 4H).

Example 21

Stage I:To a stirred solution of tert-butyl(1-hydroxytriazine[3,3,1,03,7]non-3-yl)CT is Amata, which is obtained as described previously (preparation 11) (500 mg, 1.97 mmol) in EtOAc (5 ml), cooled to a temperature bath with ice, was added a solution of dry HCl in EtOAc (4n, 5 ml). Then the reaction mixture was stirred for 2 h, the volatiles were removed under reduced pressure. The crude substance was rubbed some time with a simple diethyl ether to obtain the hydrochloride of 3-aminotriazole[3,3,1,03,7]nonan-1-ol (280 mg) with a yield of 75%. m/z (M+1) 154;1H NMR (CD3OD) 300 MHz δ of 2.51 is 2.44 (m, 1H), 2,34 (DDD, J=2,0, 7,0, a 8.9 Hz, 1H), 2,17-2,04 (m, 2H), 1,94-1,71 (m, 6N), 1,60-of 1.53 (m, 2H).

Stage II:To a stirred mixture of compound obtained in stage I (280 mg, 1.5 mmol), and K2CO3(820 mg, 6 mmol) in DMSO (6 ml) with a bath temperature of ice in the atmosphere N2was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (205 mg, 1.2 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{[(1-hydroxytriazine[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile in the form of a viscous liquid (150 mg) with a yield of 35%. m/z (M+1) 291;1H NMR (DCl 3) 300 MHz δ 4,78 (d, J=7,0 Hz, 1H), 3.75 to to 3.38 (m, 2H), 3.43 points (s, 2H), 2,45-is 2.37 (m, 1H), 2,35-of 1.95 (m, 8H), 1,90-to 1.60 (m, 6N), 1,53-of 1.40 (m, 2H).

Example 22

Stage I:To a suspension of NaH (60% dispersion in medical oil, 0.96 g, 24 mmol) in THF (40 ml), cooled to a temperature of Bini with ice, was added through a syringe hydroxyadamantane (of 3.32 g, 20 mmol)dissolved in THF (40 ml)over a period of 15 minutes. After stirring the reaction mixture for 30 min was added itmean (1,38 ml, 22 mmol). The reaction mixture was heated to room temperature and was stirred for 16 h before until the TLC did not detect the completion of the reaction. The excess NaH was suppressed by the addition of saturated aq. solution of NH4Cl cooled to ice the reaction mixture. Two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain the crude reaction mixture, which was purified column chromatography to obtain 5-methoxyamino-2-she (3.0 g) with a yield of 83%. m/z (M+1) 181;1H NMR (DCl3) 300 MHz δ 3,26 (s, 3H), 2,67-2,61 (m, 2H), 2,39 is 2.33 (m, 1H), 2,20-of 1.93 (m, 10H).

Stage II:Just received methylmagnesium simple ether (1M, 32 ml) through a tube was added to 5-methoxyamino-2-ONU (3.0 g, 16 mmol)in THF (32 ml) at 0OC. After stirring the mixture at 0 ° C for 0.5 h, the reaction mixture was suppressed by the addition of saturated aq. solution of NH4Cl. The organic layer was separated and the aqueous layer was extracted with simple diethyl ether. The combined organic layer was washed with water and saturated salt solution, dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain 5-methoxy-2-methyladipate-2-ol as a mixture of anomers of 1:1 (yield 3.0 g, 96%). m/z (M+23 219;1H NMR (CDCl3) 300 MHz δ 3.24 in (C, 1½ H), 3,23 (s, 1½ H), 2,68-2,62 (m, 1H), 2,40-of 1.55 (m, 10H), 1,53-of 1.35 (m, 2H), 1,38 (s, 3H).

Stage III:5-Methoxy-2-methyladipate-2-ol (3.0 g, 15 mmol), dissolved in a mixture of Asón (3.0 ml) and THF (15 ml) (15 ml) was added dropwise via the dropping funnel to chilled in a bath with ice to a solution of NaOCl (4%, 150 ml) over a period of 15 minutes. Was added n-Bu4NI (0.55 g, 1.5 mmol) and the reaction mixture was stirred for 1.5 hours, the Reaction mixture separated into two layers. The aqueous layer was extracted with simple diisopropyl ether and the combined organic layer was washed with water and saturated salt solution, dried over Na2SO4and the solvent evaporated under reduced pressure to get hypochlorite, which was diluted with methanol (30 ml) was added solid KOH (1.68 g, 30 mmol). The reaction mixture is boiled under reflux for 1H. Volatiles were removed and the crude substance was diluted simple ether, washed with water, saturated salt solution, dried over anhydrous Na2SO4and the solvent evaporated in vacuum. The crude substance was purified column chromatography to obtain 1-(1-methoxytrityl[3,3,1,03,7]non-3-yl)ethanone (1.92 g) with a yield of 66%. m/z (M+1) 195;1H NMR (CDCl3) 300 MHz δ 3,29 (s, 3H), 2,69-2,62 (m, 1H), 2.57 m-2,50 (m, 1H), 2.26 and-of 2.16 (m, 1H), 2,18 (s, 3H), 2,10-to 1.61 (m, 7H), 1,59-of 1.52 (m, 2H).

Stage IV:To a mixture of NaOH (0,58 g, 147 mmol), N2On (40,0 ml) and 1,4-dioxane (10 ml) at a temperature bath with ice was added Br2(2.8 ml, 55,0 mmol) and was stirred for 5 minutes. Received the hypobromite solution was added dropwise to a stirred solution of 1-(1-methoxytrityl[3,3,1,03,7]non-3-yl)ethanone obtained at stage III (1.9 g, 9.8 mmol) in 1,4-dioxane (10 ml) at a temperature bath with ice. The reaction mixture was gradually heated to room temperature and was stirred for 1 h, the Reaction mixture was cooled to a temperature bath with ice and added Asón (3.9 ml, and 65.7 mmol). The reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-methoxytrityl[3,3,1,03,7]nonan-3-carboxylic acid (1.3 g) in the course of 72%. m/z (M+1) 197;1H NMR (CDCl3) 300 MHz δ 3,30 (s, 3H), 2,78-2,70 (m, 1H), 2.57 m-2,48 (m, 1H), 2,38-of 2.28 (m, 1H), 2,11-2,0 (m, 2H), 1,86 was 1.69 (m, 5H), 1,59-is 1.51 (m, 2H).

Stage V:To a suspension of 1-methoxytrityl[3,3,1,03,7]nonan-3-carboxylic acid, obtained in stage IV (0.39 g, 2.0 mmol)in CHCl3(10 ml) was added conc. H2SO4(1.0 ml, 20 mmol). Added solid portions NaN3(0.39 g, 6.0 mmol), maintaining the temperature of the reaction mixture below 40 ºC. After stirring at room temperature for 2 h the reaction mixture was cooled to a temperature bath with ice, diluted with water and was extracted with EtOAc. The aqueous layer was podslushivaet by adding 50% NaOH solution and was extracted with CHCl3. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-methoxytrityl[3,3,1,03,7]nonan-3-amine (0,23 g) with a yield of 69%. m/z (M+1) 168;1H NMR (CDCl3) 300 MHz δ of 3.27 (s, 3H), 2.40 a-2,34 (m, 1H), 2,16-of 2.08 (m, 1H), 1,97 (DDD, J=2.0 a, 6,8, and 8.7 Hz, 1H), 1,92-of 1.53 (m, 7H), 1,51-to 1.38 (m, 2H).

Stage VI:To a stirred solution of the amino compounds obtained in stage V (0.16 g, 0.95 mmol) in DMSO (4.0 ml) was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.17 g, 0.96 mmol) and K2CO3(0.4 g, 2.9 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours the Reactions is nnow the mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{[(1-methoxytrityl[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile (0.12 g) with a yield of 41%. m/z (M+1) 304;1H NMR (CDCl3) 300 MHz δ 4,82-of 4.75 (m, 1H), 3.75 to is 3.40 (m, 4H), of 3.27 (s, 3H), 2,47-to 2.40 (m, 1H), 2,35-1,68 (13H), 1,57-of 1.41 (m, 2H).

Example 16A: Hydrochloric salt:To a stirred solution of the compound obtained in example 16 (30 mg, 0.1 mmol) in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue triturated some time with a simple diethyl ether to obtain hydrochloric salt of (2S)-1-{[1-methoxytrityl[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile as not quite white solid (30 mg).

Example 23

The method is the same as described for methoxyamine obtained in example 16, characterized in that the first stage was used emilyrose agent n-Bu4NI and ethylbromide, in the rest of the way similar to the above.

Stage I:To a suspension of NaH (60% dispersion in medical oil, 0.96 g, 24 mmol) in THF (40 ml), cooled to a temperature bath with ice, was added hydroxyadamantane (of 3.32 g, 20 mmol)dissolved in THF (40 m is) via syringe over a period of 15 minutes. The reaction mixture was stirred for 30 min, then was added n-Bu4NI (0.74 g, 2 mmol) and ethylbromide (1.6 ml, 22 mmol). The reaction mixture was heated to room temperature and was stirred for 16 hours, After cooling the reaction mixture to 0 ° C the excess NaH was suppressed by adding a feast upon. aq. solution of NH4Cl. Two layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain the crude reaction mixture, which was purified column chromatography to obtain 5-antoxidants-2-she (3.0 g) with a yield of 77%. M/z (M+1) 195;1H NMR (CDCl3) 300 MHz δ 3,47 (kV, J=7,0 Hz, 2H), 2,67-2,60 (m, 2H), 2,38-of 2.30 (m, 1H), 2,13-of 1.78 (m, 10H), of 1.17 (t, J=7.0 Hz, 3H).

Stage II:5-Ethoxy-2-methyladipate-2-olwas obtained from 5-antoxidants-2-it is in the form of a mixture of anomers of 1:1 (1.6 g) with a yield of 99%. m/z (M+23) 233;1H NMR (CDCl3) 300 MHz δ 3,51-to 3.41 (m, 2H), 2,31-of 2.23 (m, 1H), 2,18-2,05 (m, 2H), 2,02 and 1.80 (m, 4H), 1,79 to 1.47 (m, 7H), 1,46-of 1.32 (m, 4H), of 1.16 (t, J=6.5 Hz, 3H).

Stage III:1-(1-Amoxicilina[3,3,1,03,7]non-3-yl)alanonwas obtained from 5-ethoxy-2-methyladipate-2-ol with a yield of 66%. m/z (M+1) 209;1H NMR (CDCl3) 300 MHz δ 3,49 (kV, J=7,1 Hz, 2H), 2,69-2,61 (m, 1H), 2,56-2,48 (m, 1H), 2,22-to 2.18 (m, 1H), 2,17 (s, 3H), 2,02-of 1.84 (m, 4H), 1,78 of 1.50 (m, 5H), of 1.18 (t, J=7,1 Hz, 3H).

Stage IV:1-This is citricola[3,3,1,0 3,7]nonan-3-carboxylic acidwas obtained from 1-(1-amoxicilina[3,3,1,03,7]non-3-yl)ethanone with yield 68%. m/z (M+1) 195;1H NMR (CDCl3) 300 MHz δ 3,49 (kV, J=6,7 Hz, 2H), 2,75 of 2.68 (m, 1H), 2,52-2,47 (m, 1H), 2,36-of 2.28 (m, 1H), 2,10-of 1.95 (m, 2H)and 1.83 (s, 1,86 by 1.68 (m, 5H), and 1.54 (DDD, J=3,0, 10,9, to 13.6 Hz, 2H), of 1.18 (t, J=6,7 Hz, 3H).

Stage V:1-Amoxicilina[3,3,1,03,7]nonan-3-aminewas obtained from 1-amoxicilina[3,3,1,03,7]nonan-3-carboxylic acid with a yield of 53%. m/z (M+1) 182;1H NMR (CDCl3) 300 MHz δ 3,49 (kV, J=7,0 Hz, 2H), 2,39 of-2.32 (m, 1H), 2,16-2,07 (m, 1H), 1,99-of 1.92 (m, 1H), 1,92 is 1.75 (m, 5H), 1,71-to 1.38 (m, 4H), of 1.17 (t, J=7.0 Hz, 3H).

Stage VI:The reaction of interaction of the amine obtained in stage V, and cyanopyrrolidines connection received(2S)-1-{[1-amoxicilina[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrilewith the release of 41%. m/z (M+1) 318;1H NMR (CDCl3) 300 MHz δ to 4.81-4.75 in (m, 1H), 3.75 to is 3.40 (m, 6N), 2,45-is 2.37 (m, 1H), 2,36 and 2.13 (m, 4H), 2,12-of 1.95 (m, 2H), 1,88 by 1.68 (m, 6N), and 1.56 (DDD, J=3,0, 3,0, 10.5 Hz, 1H), 1,49-of 1.41 (m, 1H), 1,17 (t, J=7.0 Hz, 3H).

Example 17A: Hydrochloric salt: To a stirred solution of the compound obtained in example 17 (32 mg, 0.1 mmol), in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatile compounds were removed under reduced pressure and the residue triturated some time with a simple diethyl ether to obtain hydrochloric salt of (2S)-1-{[(1-atoxicity the lo[3,3,1,0 3,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile as not quite white solid (30 mg). m/z (M+1) 318;1H NMR (DMSO-d6) 300 MHz δ 9,41 ((user), 2N), a 4.86 (DD, J=4,6, 6,8 Hz, 1H), 4,10-3,90 (m, 2H), 3.75 to the 3.65 (m, 1H), 3,57 is 3.25 (m, 3H), 2,48-of 2.38 (m, 2H), 2,30-2,17 (m, 2H), 2,16 to 2.0 (m, 4H), 1,90-1,14 (m, 6N), 1,53-of 1.40 (m, 2H), of 1.06 (t, J=7.0 Hz, 3H).

Example 24

Stage I:To a stirred mixture of compound obtained as described previously (preparation 8) (0.3 g, 1.2 mmol), and K2CO3(0.5 g, 3.6 mmol) in DMSO (5 ml) with a bath temperature of ice in the atmosphere N2was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.14 g, 0.83 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain tert-butyl(2S)-1-{[(1-aminotriazole[3,3,1,03,7]non-3-yl)carbamate]acetyl}pyrrolidin-2-carbonitrile in the form of a viscous liquid (0.18 g) with a yield of 40%. m/z (M+1) 389;1H NMR (CDCl3) 300 MHz δ 4,79 (d, J=7.5 Hz, 1H), 4,70 ((user), 1H), 3,70 is 3.40 (m, 2H), 3.46 in (s, 2H), 2,40 of-2.32 (m, 1H), 2,32-1,90 (m, 6N), 1,90-to 1.63 (m, 5H), 1,55 was 1.43 (m, 1H).

Stage II:To a stirred solution of compound obtained in stage I (0.04 g, 0.1 mmol)in EtOAc (2 ml), cooled to a temperature bath with ice, was added a solution of dry HCl in EtOAc (3h, 2 ml). The reaction mixture was stirred for 2 h and the solvent was removed under reduced pressure to get crude substance, which rubbed some time with a simple diethyl ether to obtain dihydrochloride salt of (2S)-1-{[(1-aminotriazole[3,3,1,03,7]non-3-yl)amino]acetyl}pyrrolidin-2-carbonitrile (0.02 g) with a yield of 69%. m/z (M+1) 289;1H NMR (DMSO-d6) 300 MHz δ RS 9.69 ((user), 2N), to 8.57 ((user), 3H), a 4.86 (DD, J=4,4, 7,0 Hz, 1H), 4,16-3,90 (m, 2H), 3,78-the 3.65 (m, 1H), 3,65-to 3.50 (m, 1H), 2,60-to 2.55 (m, 1H), 2,50 is 2.43 (m, 1H), 2,35-to 2.18 (m, 4H), 2,13-to 1.98 (m, 2H), 2,10-2,0 (m, 3H), 1,96 is 1.70 (m, 5H), 1,68 is 1.60 (m, 1H), 1,50 was 1.43 (m, 2H).

Example 25

Stage I: To a stirred solution of tert-butyl(1-hydroxytriazine[3,3,1,03,7]non-3-yl)carbamate, obtained as described previously (preparation 11) (1.1 g, 4,34 mmol), in dichloromethane, cooled to 15 ° C in an atmosphere of N2added diethylaminosulfur of 0.85 ml, 6,51 mmol). The reaction mixture was stirred at this temperature for 1 h and subsequently stirred at room temperature for 16 hours the Reaction mixture was cooled to a temperature bath with ice and was suppressed by addition of a mixture of crushed ice and the solid NaHCO3(1.1 g, 13 mmol). Two layers were separated and the aqueous layer was extracted with chloroform. Joint who United the organic layer was washed with saturated salt solution, was dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure. The crude substance was purified column chromatography to obtain tert-butyl(1-Portillo[3,3,1,03,7]non-3-yl)carbamate (0.26 g) as a viscous liquid with a yield of 24%. m/z (M-1) 254;1H NMR (CDCl3) 300 MHz δ 2,55-to 2.40 (m, 1H), 2.0 to about 1.75 (m, 2H), 1.70 to of 1.40 (m, N), of 1.57 (s, 6N), 1,45 (s, 3H).

Stage II: To a stirred solution of compound obtained in stage I (0.25 g, 0.98 mmol), in EtOAc (1 ml), cooled to a temperature bath with ice, was added a solution of dry HCl in EtOAc (3h, 3 ml). After stirring the reaction mixture for 2 h, volatiles were removed under reduced pressure. The crude substance was rubbed some time with simple ether to obtain hydrochloric salt 1-Portillo[3,3,1,03,7]nonan-3-amine (0,19 g) with a yield of 99%. m/z (M+1) 156;1H NMR (DMSO-d6) 300 MHz δ 8,45 ((user), 2H), 2,47-to 2.18 (m, 4H), 1,96-1,72 (m, 6N), and 1.63 (DD, J=2,6, 9.6 Hz, 1H), 1,50-of 1.42 (m, 1H).

Stage III: To stir a mixture of hydrochloric salts obtained in phase II (to 0.19 g, 0.98 mmol), and K2CO3(of 0.53 g, 4.0 mmol) in DMSO (4.0 ml) at a temperature bath with ice in a nitrogen atmosphere was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.17 g, 1.0 mmol). After stirring at room temp. within 3 h, the reaction mixture was diluted with EtOAc and washed with water and saturated concrete is salt, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-[N-(2-targetsaver-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as not quite white solid (0.11 g) with a yield of 38%. m/z (M+1) 292;1H NMR (CDCl3) 300 MHz δ 4.80 to to 4.73 (m, 1H), of 3.77-of 3.32 (m, 2H), 3,52 (s, 2H), 2,50-to 2.42 (m, 1H), 2,87-of 2.08 (m, 6N), 1,50-of 1.42 (m, 1H).

Example 23A: Hydrochloric salt: To a stirred solution of the compound obtained in example 23 (29 mg, 0.1 mmol) in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue awhile rubbed with simple ether to obtain hydrochloric salt of (2S)-1-[N-(2-targetsaver-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as not quite white solid (30 mg).

Example 26

Stage I:To stir a mixture of 1-(3-aminotriazole[3,3,1,03,7]non-1-yl)pyrrolidin-2-it, obtained as described previously (preparation 9) (0.25 g, 1.1 mmol), and K2CO3(and 0.46 g, 3.3 mmol) in DMSO (5 ml) at a temperature bath with ice was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.2 g, 1.1 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours At the Le completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile in the form of a viscous liquid (0.16 g) with output 40. m/z (M+1) 357;1H NMR (CDCl3) 300 MHz δ 4,78 (d, J=7,4 Hz, 1H), 3,70-to 3.38 (m, 2H), 3.46 in (s, 2H), 3,41 (t, J=7,0 Hz, 2H), 2,60 (DD, J=4,0, 10,2 Hz, 1H), 2.40 a is 1.75 (m, 17H), 1,72-of 1.62 (m, 1H), 1,58 of 1.50 (m, 1H).

Example 20A: Hydrochloric salt:To a stirred solution of the compound obtained in example 19 (36 mg, 0.1 mmol) in methanol (2 ml), cooled to 0 ° C was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue awhile rubbed with simple ether to obtain hydrochloric salt of (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (38 mg).

Example 27

Stage I:To stir a mixture of 1-(1,1-dioxothiazolidine-2-yl)tricyclo[3,3,1,03,7]nonan-3-amine, obtained as described previously (preparation 10) (0.17 g, 0.66 mmol), and K2CO3(0.28 g, 2.0 mmol) in DMSO (2.6 ml) at a temperature bath with ice was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile made (0.13 g, 0.66 mmol). The reaction mixture postopen is heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-{N-[2(1,1-dioxothiazolidine-2-yl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile in the form of a viscous liquid (0.1 g) with a yield of 40%. m/z (M+1) 393;1H NMR (CDCl3) 300 MHz δ 4.80 to the 4.75 (m, 1H), 3,70-3,37 (m, 4H), to 3.36 (t, J=6.6 Hz, 2H), and 3.16 (t, J=7.4 Hz, 2H), 2,43-is 2.37 (m, 1H), 2,35 and 2.13 (m, N), 2,05 of 1.99 (m, 1H), 1,95 is 1.75 (m, 5H), 1.70 to to 1.63 (m, 1H), 1,54 to 1.47 (m, 1H).

Example 21A: Hydrochloric salt:To a stirred solution of the compound obtained in example 20 (39 mg, 0.1 mmol) in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue awhile rubbed with a simple diethyl ether to obtain hydrochloric salt of (2S)-1-{N-[2-(1,1-dioxothiazolidine-2-yl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (41 mg). m/z (M+1) 393;1H NMR (DMSO-d6) 300 MHz δ 9,60 ((user), 2N), a 4.86 (DD, J=4,4, 7,0 Hz, 1H), 4,12-of 3.96 (m, 2H), 3,59-3,47 (m, 2H), or 3.28 (t, J=6,8 Hz, 2H), 3,19 (t, J=7.5 Hz, 2H), 2,43-is 2.37 (m, 1H), 2,31 and 2.13 (m, 8H), 2,10-of 1.97 (m, 3H), 1,96-1,76 (m, 5H), 1,50 was 1.43 (m, 1H).

Example 28

Stage I:To a stirred mixture of NaOH (2.4 g, 60,0 mmol), N2O (16 ml) and 1,4-dioxane (2 ml) with a bath temperature of ice was added Br2high (0.56 ml, 10.4 mmol) and was stirred for 15 minutes. Received the hypobromite solution was added dropwise to a stirred solution of 1-(1-fenestrelle[3,3,1,03,7]non-3-yl)ethanone obtained as described previously (product I), (1.0 g, 4.0 mmol) in 1,4-dioxane (6 ml)at a temperature bath with ice. After stirring at room temp. within 1 h the reaction mixture was again cooled to a temperature bath with ice and extinguished the addition of Asón (3.6 ml, 60 mmol). The reaction mixture was diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure to obtain 1-fenestrelle[3,3,1,03,7]nonan-3-carboxylic acid (0,62 g) with a yield of 64%. m/z (M+1) 243;1H NMR δ 7,40-7,25 (m, 4H), 7,25-to 7.18 (m, 1H), 2,90-of 2.86 (m, 1H), 2,54-2,48 (m, 1H), of 2.38 (DDD, J=2,0, 2,0, of 11.0 Hz, 1H), 2,20-2,05 (m, 4H), 1,98-of 1.78 (m, 5H), 1.70 to (DD, J=2,8, and 11.5 Hz, 1H).

Stage II:To a stirred solution of 1-fenestrelle[3,3,1,03,7]nonan-3-carboxylic acid (0.6 g, 2.48 mmol), obtained in stage I, and triethylamine (1.0 ml, 7,44 mmol) in toluene (10 ml) in an atmosphere of N2when the bath temperature with ice was added diphenylphosphoryl (of 0.64 ml, 3.0 mmol). The reaction mixture was naked evali to room temperature and was stirred for 1 h, then boiled under reflux for 4 hours, the Reaction mixture was cooled to room temp., washed with water and mixed with a water solution of KOH (50 wt%./about., 5.0 ml) and nBu4NI (92 mg, 0.25 mmol) for 2 h at room temp. The reaction mixture was cooled to a temperature bath with ice, acidified using conc. HCl to pH 2, extracted with simple diethyl ether. The aqueous layer was podslushivaet aq. NaOH solution (50% wt./about.) and was extracted with chloroform. The combined organic layer was dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain 1-fenestrelle[3.3.1.03,7]nonan-3-amine (0.33 g) as a viscous liquid with a yield of 62%. m/z (M+1) 214;1H NMR (CDCl3) 300 MHz δ 7,40-7,22 (m, 4H), 7,22-to 7.15 (m, 1H), 2,42 to 2.35 (m, 1H), 2,20-2,05 (m, 2H), 2,02-of 1.52 (m, N).

Stage III:To a stirred mixture of compound obtained in stage II (0.2 g, were 0.94 mmol), and K2CO3(0.39 g, 2.8 mmol) in DMSO (4.0 ml) at a temperature bath with ice in a nitrogen atmosphere was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.16 g, were 0.94 mmol). After stirring for 3 h at room temp. the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain (2S)-1-[N-(2-phenylhexane is about-2.5 to methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as not quite white solid (0.16 g) with a yield of 48%. m/z (M+1) 350;1H NMR (CDCl3) 300 MHz δ 7,35-7,16 (m, 5H), 4,85 was 4.76 (m, 1H), 3,76 is 3.40 (m, 2H), 3,50 (s, 2H), 2,48-to 2.41 (m, 1H), 2,36-of 2.27 (m, 2H), 2.23 to-2,0 (m, 6N), 1,94 by 1.68 (m, 4H), 1,66-to 1.60 (m, 1H).

Example 26A: Hydrochloric salt:To a stirred solution of the compound obtained in example 26 (35 mg, 0.1 mmol) in methanol (2 ml), cooled to 0 ° C, was added TMS-Cl (25 μl, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue triturated some time with a simple diethyl ether to obtain hydrochloric salt of (2S)-1-[N-(2-phenylhexane-2,5-methanoindan-3A(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as not quite white solid (38 mg).

Example 29

To stir a mixture of 1-(4-nitrophenyl)tricyclo[3,3,1,03,7]nonan-3-amine, obtained as described previously (stage III, preparation 4) (0,77 g, 3.0 mmol), and K2CO3(1.25 g, 9.0 mmol) in DMSO (12 ml) with a bath temperature of ice in the atmosphere N2was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.51 g, 3.0 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction, the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified in a column of HRO what ecografia to obtain (2S)-1-{N-[2-(4-nitrophenyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (0.5 g) with a yield of 42%. m/z (M+1) 395;1H NMR (CDCl3) 300 MHz δ to 8.14 (d, J=8,9 Hz, 2H), 7,41 (d, J=8,9 Hz, 2H), a 4.83-to 4.73 (m, 1H), 3,78 is 3.40 (m, 2H), 3,48 (s, 2H), of 2.51 at 2.45 (m, 1H), 2,37-to 2.06 (m, 6N), 2,02 is 1.60 (m, N).

Example 30

To a stirred solution of the compound obtained in example 29 (0.2 g, 0.51 mmol)in a mixture of water, THF and ethanol 1:2:4 (7 ml), respectively sequentially added solid NH4Cl (0.1 g, of 1.87 mmol) and Fe powder (0.1 g, 1.78 mmol). The reaction mixture was heated at the boil under reflux for 2H. After cooling to room temperature the reaction mixture was filtered through a small layer of celite and washed with EtOAc layer. The filtrate was evaporated under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layer was washed with water, dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure to obtain (2S)-1-{N-[2-(4-AMINOPHENYL)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as not quite white solid (0.09 g) with a yield of 50%. m/z (M+1) 365;1H NMR (CDCl3) 300 MHz δ 7,05 (d, J=8.5 Hz, 2H), 6,63 (d, J=8.5 Hz, 2H), 4,90-of 4.75 (m, 1H), 3,80 is 3.40 (m, 4H), 2,45 is 1.70 (m, 15 NM), 1,65-of 1.57 (m, 1H).

Example 31

Stage I:Stir the mixture of compounds obtained as described previously (preparation 3) (1.1 g, 3,18 mmol), sodium cyanide (0,164 g, 3.5 mmol) in DMF is (7,0 ml) was heated to 110 º C for 12 hours The reaction mixture was cooled to room temperature, diluted with water and was extracted with EtOAc. The combined organic layer was washed with saturated salt solution, dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain tert-butyl[1-(cyanomethyl)tricyclo[3,3,1,03,7]non-3-yl]carbamate as a viscous liquid (0.3 g) with a yield of 34%. m/z (M+1) 277;1H NMR (CDCl3) 300 MHz δ 4,73 (user. s, 1H), 2,60 to 2.35 (m, 2H), 2,31 (s, 2H), 2,20-of 1.40 (s, 10H), 1,45 (s, N).

Stage II:To a stirred solution of compound obtained in stage I (0.25 g, 0.9 mmol) in a mixture of ethanol and water 1:1 (9 ml) at room temperature was added hydroxylamine hydrochloride (0.32 g, 4.5 mmol), followed by addition of solid Na2CO3(0,57 g, 5.4 mmol). The reaction mixture is boiled under reflux for 12 hours Volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4and evaporated under reduced pressure. The residue was dissolved in triethylorthoformate (0.2 ml) was added a catalytic amount camphorsulfonic acid. The reaction mixture is boiled under reflux for 4 hours Volatiles were removed under reduced pressure and the crude is emesto was purified column chromatography to obtain tert-butyl[1-(1,2,4-oxadiazol-3-ylmethyl)tricyclo[3.3.1.0 3,7]non-3-yl]carbamate (0.15 g) in 51% yield as a viscous liquid. m/z (M+1) 320;1H NMR (CDCl3) 300 MHz δ to 8.62 (s, 1H), 4,71 (user. s, 1H), and 2.79 (s, 2H), 2,48-of 2.38 (m, 1H), 2,35-of 2.28 (m, 1H), 2,10-of 1.88 (m, 4H), 1,74 (DD, J=2,8, 10.5 Hz, 2H), 1,65-to 1.38 (m, 4H), USD 1.43 (s, (N),

Stage III:To a stirred solution of compound obtained in stage II (0.15 g, 0.47 mmol) in CH2Cl2(2 ml), cooled to 0 ° C, was added triperoxonane acid (0.5 ml). The reaction mixture was gradually heated to room temperature and was stirred for 1 h Volatiles were removed under reduced pressure and the residue awhile rubbed with simple ether with getting triperoxonane salt of 1-(1,2,4-oxadiazol-3-ylmethyl)tricyclo[3,3,1,03,7]nonan-3-amine as a white powder (0.12 g) with a yield of 77%. m/z (M+1) 220;1H NMR (DMSO-d6) 300 MHz δ at 9.53 (s, 1H), 8,09 (user. s, 3H), 2,78 (s, 2H), 2,38 was 2.25 (m, 2H), 1,88 is 1.70 (m, 6N), 1,60-of 1.42 (m, 4H).

Stage IV:To a stirred solution of compound obtained in stage III (0.12 g, 0.36 mmol)in DMSO (1.5 ml) at room temperature under nitrogen atmosphere was added (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.06 g, 0.36 mmol) and K2CO3(0.2 g, 1.44 mmol). After stirring for 3 h the reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. Untreated prophetic the STV was purified column chromatography to obtain ((2S)-1-{N-[2-(1,2,4-oxadiazol-3-ylmethyl)hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-yl)acetonitrile as not quite white solid (0.05 g) with a yield of 40%. m/z (M+1) 356;1H NMR (CDCl3) 300 MHz δ 8,64 (s, 1H), 4,84-of 4.75 (m, 1H), 3.75 to is 3.40 (m, 2H), 3,49 (s, 2H), 2,81 (s, 2H), 2.40 a is 2.10 (m, 6N), 1,92 is 1.70 (m, 6N), 1,68 is 1.48 (m, 4H).

Example 31A: Hydrochloric salt:To a stirred solution of the compound obtained in example 31 (20 mg, 0,056 mmol) in methanol (1 ml), cooled to 0º, was added TMS-Cl (15 μl, 0.12 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue awhile rubbed with simple ether to obtain hydrochloric salt of compound in the form of not-quite-white solid (21 mg).

Example 32

Stage I:To a stirred suspension of NaH (50% dispersion in medical oil, 50 mg, 1.05 mmol) in THF (3 ml), cooled to 0 ° C in an atmosphere of N2was added dropwise via syringe a solution of the compound obtained in stage I of example 19 (0.3 g, 0.7 mmol) in THF (4 ml). After stirring at room temperature for 30 minutes, the reaction mixture was again cooled to a temperature bath with ice and added MeI (0.1 ml, 1.5 mmol). The reaction mixture was slowly heated to room temperature and was stirred for 2 hours, the Excess NaH was suppressed by addition of aq. solution of NH4Cl after cooling the reaction mixture to a temperature bath with ice. Two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed saturated with the second salt solution, was dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain tert-butyl[2-[4-(3-methyl-2-Oxymetazoline-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]carbamate (250 mg) in the form of not-quite-white solid with a yield of 80%. m/z (M+1) 446;1H NMR (CDCl3) 300 MHz δ of 7.48 (d, J=8.7 Hz, 2H), 7,43-7,30 (m, 5H), 7,28-to 7.18 (m, 2H), 5,17-to 5.03 (m, 3H), 3,80 (t, J=7.2 Hz, 2H), 3,47 (t, J=7.2 Hz, 2H), 2.91 in (s, 3H), 2,61-2,52 (m, 1H), 2,48-to 2.40 (m, 1H), 2,32 is 2.55 (m, 10H).

Stage II:To a stirred solution of compound obtained in stage I (0.25 g, 0,56 mmol) in a mixture of CH2Cl2and Meon 1:1 (10 ml) was added Pd/C (10% mass/mass, 0.1 g) and stirred at room temperature in an atmosphere of H2within 2 hours the Reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure to obtain 1-[4-(3A-aminohexyl-2,5-methanoindan-2(1H)-yl)phenyl]-3-methylimidazolidine-2-she (0.15 g) in the form of not-quite-white solid with a yield of 86%. TPL 227-230º; m/z (M+1) 312; IR cm-13416, 3249, 2964, 1682, 1519, 1485, 1261, 810;1H NMR (CDCl3+DMSO-d6) 300 MHz δ scored 8.38 (user. s, 2H), 7,47 (d, J=8.6 Hz, 2H), 7,19, (d, J=8.6 Hz, 2H), 3,76 (t, J=7.4 Hz, 2H), 3.43 points (t, J=7.4 Hz, 2H), 2,77 (s, 3H), 2,48-to 2.40 (m, 2H), 2,22 with 2.14 (m, 1H), 2,10-2,0 (m, 2H), 2,0 is 1.86 (m, 4H), 1,80-1,60 (m, 3H).

Stage III:To a stirred mixture of compound obtained in stage II (0.15 g, 0,mol), and K2CO3(0.21 g, 1.5 mmol) in DMSO (2 ml) with a bath temperature of ice was added compound (S)-1-(2-chloroacetyl)pyrrolidin-2-carbonitrile (0.09 g, 0.5 mmol). The reaction mixture was gradually heated to room temperature and was stirred for 3 hours After completion of the reaction (controlled by TLC) the reaction mixture was diluted with EtAc and washed with water and saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure. The crude substance was purified column chromatography to obtain ((2S)-1-{N-[2-[4-(3-methyl-2-Oxymetazoline-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-yl)acetonitrile as not quite white solid (0.09 g) with a yield of 42%. m/z (M+1) 449;1H NMR (CDCl3) 300 MHz δ 7,47 (d, J=8.6 Hz, 2H), 7,22 (t, J=8.6 Hz, 2H), 4,85 was 4.76 (m, 1H), 3,79 (t, J=7,3 Hz, 2H), 3.75 to is 3.40 (m, 4H), of 3.48 (s, 2H), 2,89 (s, 3H), 2,46-2,39 (m, 1H), 2,36-of 2.15 (m, 3H), 2,12-1,58 (m, N).

1. The compound of formula I,

its pharmaceutically acceptable salts, where
X represents CH2, CHF or S,
Y represents CN,
R1, R2, R3and R4represent hydrogen,
n represents 1,
m represents 0 or 1,
R is a R11, R12or R13where
R11includes at least one of the groups selected from the following (b) or (is), where the optionally substituted heterocyclyl and heteroaryl groups are linked with noradrenaline part, either directly or through a methylene adjacent group, or a C-C bond or C-N bond;
b) substituted 5-membered heteroaryl group, which heteroaryl ring is a monocyclic aromatic ring system containing two or more heteroatoms selected from nitrogen and oxygen;
C) heterocyclyl group optionally substituted C1-C3alkyl or exography, where the heterocyclic ring system is a 5 to 9 membered mono - or bicyclic ring system with one or more heteroatoms selected from the group consisting of nitrogen and sulfur, where the heteroatoms may also be present as functional groups,
where the heterocyclic ring system may contain one or two double bonds, and
where a monocyclic heterocyclic ring may be condensed with a phenyl ring,
R12selected from hydrogen, halogen, hydroxy, amino and C1-C4alkoxy;
R13is a substituted phenyl, where the substituents, which may be the same or different, include at least one of the groups selected from
a)hydrogen;
(b) nitro, amino;
c) saturated or unsaturated monocyclic the definition heterocyclic ring system optionally substituted by one or more groups, selected from C1-C3the alkyl and oxo, where the heterocyclic ring system is a 5-membered ring with one or more heteroatoms selected from the group consisting of nitrogen and sulfur,
where the heteroatoms may also be present as functional groups.

2. The compound according to claim 1, where
R is a R11,
m represents 1,
R11matter as defined in claim 1.

3. The compound according to claim 1, where
R is a R11or R12,
m represents 0,
R11and R12have the meaning as indicated in claim 1.

4. The compound according to claim 1, where
R is a R13,
m represents 0,
R13matter as defined in claim 1.

5. A compound selected from the group consisting of
(2S)-1-[1H-1,2,4-triazole-1-ylmethyl-(tricyclo[3,3,1,03,7]non-3-ylamino)acetyl]pyrrolidin-2-carbonitrile,
(2S)-1-{N-[2-[(1,1-dioxothiazolidine-2-yl)methyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile,
(2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanoindan-3A(1H)-yl]glycyl}pyrrolidine-2-carbonitrile.

6. The method of obtaining the compounds of formula I

including the binding of the compounds of formula II, which is in free form, in salt form or in protected form, with a compound of formula III

where R represents hydrogen or a protective group selected from tert-butoxycarbonyl (VOS) and carbobenzoxy (Cbz), L represents a removable group selected from halogen, O-toluensulfonyl and O-methylsulfonyl, and R, R1, R2, R3, R4X, Y, n and m have the meaning as indicated in claim 1.

7. The method according to claim 6, where the binding reaction is carried out in an inert solvent selected from dichloromethane, dimethylformamide, DMSO, tetrahydrofuran and acetonitrile, and in the presence of a base selected from tertiary amines, carbonates, hydroxides, and mixtures thereof.

8. The intermediate compound selected from
1-(1H-1,2,4-triazole-1-ylmethyl)tricyclo[3,3,1,03,7]nonan-3-amine,
1-[(1,1-dioxothiazolidine-2-yl)methyl]tricyclo[3,3,1,03,7]nonan-3-amine,
1-[4-(3-aminotriazole[3,3,1,03,7]non-1-yl)phenyl]pyrrolidin-2-it.

9. Pharmaceutical composition having inhibitory activity of DPP-IV, comprising a) a compound of formula I, its pharmaceutically acceptable salt according to any one of claims 1 to 6, and b) at least one pharmaceutically acceptable carrier, diluent or excipient.

10. The use of the compounds of formula I, its pharmaceutically acceptable salt according to any one of claims 1 to 6 to obtain a pharmaceutical composition for the treatment and/or prevention of type II diabetes, for the treatment of metabolic violated the th, reduce the level of glucose in the blood, deterioration in glucose tolerance, reduction of fasting glucose, dyslipidemia, hypercholesterolemia, hypolipidemia or obesity, to prevent hyperglycemia or for reducing body weight or diabetic complications, including coronary artery disease, stroke, hypertension, nephropathy, peripheral vascular disease, neuropathy or retinopathy.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the chemistry of N,N-disubstituted nicotinamide-(Z)-O-methyloximes with the general formula I where if X denotes a methylene group, then R denotes phenyl, benzyl or 2-furyl, R' denotes methyl or n-chlorophenyl, if X denotes a carbonyl group, then R denotes styryl, n-chlorostyryl or benzyl, R' denotes methyl that is characterized by the fungicidal activity.

EFFECT: new compounds that can be efficient against maleficent fungi.

1 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oxadiazolidinone compounds presented by following formula (I), or to their pharmaceutically acceptable salts, (symbols in the presented formula represent the following values, R1: -H, R0: lower alkyl, Rz: the same or different from each other, and each represents -H or lower alkyl, L: *-CH2-O- or *-CH2-NH-, where the symbol * in L represents binding with the ring A and a substitution position in the group L in the ring B represents the 4-position, the ring A: benzole, the ring B: benzole or pyridine, R2; the same or different respectively, and each represents -halogen or -R0, n: 0 or 1, R3: phenyl which can be substituted by a group selected from the group G3, The group G3: halogen, -R0, halogen-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroring group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-COR2, -O-lower alkylene-N(RZ)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by the group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz)-cycloalkyl, -O-lower alkylene-heteroring group and -O-lower alkylene-CON(Rz)-heteroring group, where lower alkylene in the group G3 can be substituted by halogen or -ORz, and cycloalkyl and the heteroring group in the group G3 can be substituted by the group selected by the group G1, The group G1: halogen, cyano, -R0, -ORz, -N(RZ)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-R2, -CON(Rz)2, -CON(Rz)-lower alkylene-OR2, -N(Rz)CO-Rz, oxo, -(lower alkylene which can be substituted by the group -ORz)-aryl, heteroring group and lower alkylene-heteroring group where aryl and the heteroring group in the group G1 can be substituted by the group selected from the following group G2, the group G2: halogen, cyano where the heteroring group means a group containing a ring selected from i) a monocyclic 5-7-members, saturated or unsaturated heteroring containing 1 to 3 heteroatoms selected from O, S and N, ii) a bicyclic heteroring in which the heterorings selected in i) mentioned above are ring-condensed where the condensed rings can be the same or different, and iii) the bicyclic heteroring in which the heteroring selected in i) mentioned above is condensed with a benzoic ring or 5-7-members cycloalkane, R4: -H. The invention refers to a pharmaceutical composition, to application of the compounds under cl.1, as well as to a method for preventing and/or treating diabetes.

EFFECT: making new biologically active compounds representing GPR40 agonist, an agent stimulating insulin secretion and/or an agent for preventing and/or treating diabetes.

9 cl, 27 ex, 138 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), in which (i) R1 denotes C1-C6-alkyl or hydrogen; and R2 denotes hydrogen or a -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7 or -Z-C(O)-R7 group; and R3 denotes an undefined pair or C1-C6-alkyl; or (ii) R1 and R3 together with a nitrogen atom with which they are bonded form a 5-6-member heterocycloalkyl ring; and R2 denotes an undefined pair or a -R7 , -Z-Y-R7 group; or (iii) R1 and R2 together with a nitrogen atom with which they are bonded form a 6-member heterocycloalkyl ring, where said ring is substituted with a -Y-R7 group, and R3 denotes an undefined pair or C1-C6-alkyl; R4 and R5 are independently selected from a group consisting of phenyl, C3-C6-cycloalkyl; R6 denotes -OH, C1-C6-alkyl, C1-C6-alkoxy or a hydrogen atom; A denotes an oxygen or sulphur atom; X denotes a C1-C6-alkylene group; R7 denotes C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl in group R7 can be optionally substituted with one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulphonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine in group R7 can be optionaly substituted with C1-C6-alkyl; R8 denotes C1-C6-alkyl or a hydrogen atom; Z denotes a C1-C10-alkylene or C2-C10-alkenylene group; Y denotes a bond or an oxygen atom; R9 and R10 independently denote a hydrogen atom, C1-C6-alkyl group, isoxazole or 8-hydroxy-1H-quinolin-2-one-(C1-C6-hydroxyalkyl); and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition having activity with respect to M3 muscarinic receptor; use of the compounds of formula (I) to produce a medicinal agent for treating and a method of treating diseases or conditions in which M3 muscarinic receptor activity is involved.

EFFECT: compounds of given formula have activity with respect to M3 muscarinic receptor.

26 cl, 8 dwg, 91 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

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