Substituted n-(indole-2-carbonyl)--alaninemia and their derivatives, method for the treatment glycolipoprotein diseases, the prevention of ischemic myocardial damage, the pharmaceutical composition

 

(57) Abstract:

The invention relates to derivatives of indole-2-carboxamide that can be used as inhibitors of glycogen phosphorylase, and to methods of treatment of glycogenolysis-dependent diseases or conditions using these compounds and pharmaceutical compositions containing these compounds. The invention provides for the use of the claimed compounds for the treatment of diabetes, hyperglycemia, hypercholesterolemia, hypertension and other disorders. 3 S. and 33 C.p. f-crystals.

The present invention relates to inhibitors of glycogen phosphorylase; to pharmaceutical compositions containing such inhibitors and the use of these inhibitors for the treatment of diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipemia, atherosclerosis, and myocardial ischemia in mammals.

Despite already made the discovery of insulin and its subsequent widespread use for the treatment of diabetes, and the later discovery of the potential use of sulfonylureas (e.g. ChlorpropamideTM(Pfiger), TolbutamideTM(Decision Upjohn), AcetohexamideTM(I. E. Zilly), Tolasam peroralnyh hypoglycemic agents, treatment of diabetes by these means does not give satisfactory results. The use of insulin required for almost 10% of patients with diabetes, for which synthetic hypoglycemic agents are ineffective (type 1 diabetes, insulin-dependent diabetes), requires a daily injection of repeated doses, usually by injection, carried out by the patient. The determination of the exact dose of insulin requires frequent testing of urine or blood sugar. Introduction excessive dose of insulin may cause hypoglycemia with varying degrees of severity, ranging from mild changes in the level of glucose in the blood to coma or even death. Treatment of insulin-independent diabetes (diabetes type 11, NIDDM) usually involves the application of complex measures, namely, diet; exercise; oral preparations, for example, sulfonylureas; and, in more severe cases, insulin injections. However, available clinical drugs hypoglycemic action may have other side effects that limit their use. In any case, where one of these drugs does not give the desired result, can be successfully used another drug. Therefore, constant and would be more effective compared to other available means, it is obvious fact.

As was already recognized by specialists, atherosclerosis (systemic lesions of the arteries) is one of the main causes of death in the United States and Western Europe. Chain pathologies, leading to atherosclerosis and occlusal heart disease, is well known. At an early stage of this pathological chain, the formation of "fat layers in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow due to the presence of lipid deposits found primarily in the smooth muscle cells and in macrophages of the inner lining (intima) of arteries and aorta. In addition, it was suggested that a large part of the cholesterol in the specified fat layers, in turn, causes the development of atherosclerotic plaques, which consist of accumulated cells intimal smooth muscle, Laden with lipid and surrounded by extracellular lipid, collagen, elastin and proteoglycans. These cells together with the matrix to form a connective tissue layer that covers the deeper sediment cellular debris, and above them the cellular lipid. This lipid is osnovnoe, and eventually undergoes calcification and necrosis that leads to the development of "complications", which is a cause of arterial occlusion, and contributing to the emergence parietal thrombosis and spasm of the arterial muscles, i.e., signs of progressive atherosclerosis.

Epidemiological data clearly indicate that hyperlipidemia is a major risk factor for cardiovascular disease (CVD) due to atherosclerosis. In recent years, leading experts from the medical field attach special importance to reduce the level of cholesterol in the blood, and especially cholesterol, low density, as the main measures to prevent CVD. In this case, the upper limits of "normal" cholesterol level should be, according to experts, much lower than those levels which have been recognized to date. Based on these considerations, it is obvious that a large part of the population of Western Europe and America is the high-risk group. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and male gender. Cardiovascular diseases are most often found in patients diabeto risk. Therefore, successful treatment of hyperlipidemia in the General population and, in particular, diabetic patients, is crucial.

Hypertension (or high blood pressure) is a condition of the person, which has a secondary character, and is only a symptom associated with various other abnormalities of organs or systems, such as renal artery stenosis, pheochromocytoma, or endocrine disorders. However, hypertension can also occur in many patients who do not have any characteristic of hypertension etiological factors or disorders. Although such "primary" hypertension is often associated with various disorders such as obesity, diabetes, and hypertriglyceridemia, however, the direct connection hypertension with these disorders has not been established. In addition, symptoms of high blood pressure are observed in patients who have absolutely no signs of any other disease or disorders.

It is known that hypertension can lead to heart failure, kidney failure and stroke (bleeding in the brain). These conditions can lead to skarabost heart. These diseases gradually weaken the patient and can, eventually, slowly lead to death.

The exact cause of primary hypertension is still unknown, although there are some assumptions about the number of factors contributing to the emergence of this disease. Such factors are, for example, stress; uncontrolled emotions; unregulated release of hormones (renin, angiotensin, aldosterone system); an excessive amount of salt and water in the body due to insufficient kidney function; thickening of the wall and hypertrophy of the vascular network, resulting in a narrowing of the blood vessels; and genetic factors.

Considering the above factors, attempts were made in the treatment of primary hypertension. In this regard, was developed a wide range of beta-blockers, vasoconstrictor agents, inhibitors of angiotensin-convertase (i.e., the enzyme that converts angiotensin), etc. which were classified as antihypertensives. Treatment of hypertension with the use of these compounds was found to be successful for the prevention of sudden death, for example, from heart failure, renal failure and hemorrhage of the heart, due to hypertension, occurring over a long period of time. This means that, although such means may be reduced blood pressure, however, these funds cannot eliminate the cause underlying the occurrence of primary hypertension.

Hypertension is also associated with elevated levels of insulin in the blood, i.e., a condition known as hyperinsulinemia. The insulin is a peptide hormone that stimulates glucose utilization, peptide synthesis, and the formation and preservation of neutral lipids, as well as, among other things, it stimulates the growth of vascular cells and contributes to sodium retention in the kidneys. These last two functions of insulin can be administered regardless of the levels of glucose in the blood and are known causes of hypertension. For example, the increase in peripheral vascular network can cause narrowing of peripheral capillaries; and increasing the concentration of sodium increases blood volume. Therefore, the reduction of insulin levels during hyperinsulinemia may help to prevent abnormal growth of vascular tissue, and increase in the content of sodium in the kidneys, due to the high level is hypertensia.

Hyperopia heart is a major risk factor causing sudden death, myocardial infarction and congestive heart failure. These phenomena, at least in part, due to the high susceptibility of the patient to myocardial injury after ischemia and reperfusion, which may occur in ambulatory patients, as well as during operation. However, there is no suitable medicines, which would avoid or minimize adverse outcome of heart surgery, especially surgery for myocardial infarction. Any surgical operation, even if it is not on the heart, is associated with a significant risk of myocardial infarction, and sometimes can cause the aircraft to the outcome. Approximately 7 million people exposed to operations not related to heart surgery, 20-25% of patients either die during surgery or have a serious heart complications. In addition, because of 400,000 patients annually undergo heart surgery with the use of artificial blood circulation, 1-2% of patients die during surgery, and 5% in the course of the operation occurs myocardial infarction. At present in the cardiac tissue during the operation with regard to myocardial ischemia, with increasing resistance of cardiac tissue to bouts of ischemia. This therapy, as expected, could reduce the life of patients, reduce hospitalizations, and improve quality of life and reduce the cost of medical care for patients of high risk group.

The production of glucose in the liver is an important factor in the treatment of insulin-independent diabetes mellitus (NIDDM). The list is the main regulator of glucose levels in the blood in postabsorptive (hungry) state; however, in patients with NIDDM, the rate of production of glucose is significantly higher than in normal individuals. Similarly, after a meal, when the liver plays a relatively smaller role in the overall delivery of glucose into the blood plasma and the production of glucose in the liver in patients with NIDDM is abnormally high.

One of the main ways to prevent the formation of glucose in the liver is the termination of the process of glycogenolysis. The liver produces glucose through the process of glycogenolysis (the breakdown of glucose residues glycogen polymer) and gluconeogenesis (synthesis of glucose from 2 - and 3-carbon precursors). There is some evidence that glycogenolysis can VNO is 75% of the production of glucose in the liver in normal individuals in postabsorptive condition due to glycogenolysis. And secondly, in patients suffering from a disease associated with abnormal accumulation of glycogen in the liver, including disease of the Gers (deficiency glycogen phosphorylase in the liver), there is episodic hypoglycemia. These observations suggest that the glycogenolysis can play an important role in the production of glucose in the liver.

Glycogenolysis in the liver, muscle and brain is catalyzed by tissue-specific isoforms of the enzyme glycogen phosphorylase. This enzyme breaks down the glycogen macromolecule with the formation of glucose-1-phosphate and a new shortened molecule of glycogen. Currently, there are two types of inhibitors of glycogen phosphorylase: glucose and analogues of glucose (Martin. J. L. et al. Biochemistry, 1991, 30, 10101), and caffeine and other purine analogues (Kasvinsky. P. J. et al., J. Biol. Chem., 1978, 253, 3343-3351 and 9102-9106). It has been suggested that these compounds and inhibitors of glycogen phosphorylase, in General, can be used for the treatment of insulin-independent diabetes by reducing the production of glucose in the liver and decreased glucose levels in the blood (Blundell, T. B. et al., Diabtologia 1992, 35, Suppl 2, 569-576; and Martin et al., Biochemistry 1991, 30, 10101).

The mechanism (or mechanisms) susceptibility of the organism to the damages. llaro et al., Am. J. Physiol, 267, H66-H74, 1994) that "in rats with cardiac hypertrophy, predicamento restore glycogen... is associated with improved postischemic recovery of left ventricular function".

Thus, although there are several ways to treat hyperglycemia, hypercholesterolemia, hypertension, hyperlipidemia, atherosclerosis and myocardial ischemia, however, the need for new drugs is still relevant, and it is therefore necessary to continue the search for alternative methods of treatment.

The present invention relates to compounds of formula I, inhibiting glycogenolysis and intended for use in the treatment of diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia.

The compounds of the present invention are the compounds of formula I:

< / BR>
and their pharmaceutically acceptable salts and proletarienne predecessors,

where:

the dashed line (---) indicates an optional bond;

A represents-C(H)=, -C((C1-C4)alkyl)= or-C(halogen)= if a dashed line indicates a bond; or A represents a methylene or-CH(C1-C4)alkyl, Algologie, 4-, 6 - or 7-nitro, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, Porometer, deformity or trifluromethyl;

R2represents H;

R3represents H or (C1-C5)alkyl;

R4represents H, methyl, ethyl, n-propyl, hydroxy(C1-C3)alkyl, (C1-C3)alkoxy(C1-C3)alkyl, phenyl(C1-C4)alkyl, phenylketone(C1-C4)alkyl,

phenyl(C1-C4)alkoxy(C1-C4)alkyl, Tien-2 - or-3-yl(C1-C4)alkyl or FSD-2 - or-3-yl(C1-C4)alkyl, where these rings R4are independently mono-, di - or tri-substituted at the carbon atom of hydrogen, halogen, (C1-C4)alkyla(C1-C4)alkoxy, trifloromethyl, hydroxy, amino or cyano; or

R4represents pyrid-2-, -3 - or-4-yl(C1-C4)alkyl, triazole-2-, -4 - or-5-yl(C1-C4)alkyl, imidazol-1-, -4 - or-5-yl(C1-C4)alkyl, pyrrol-2 - or-3-yl(C1-C4)alkyl, oxazol-2-, -4 - or-5-yl-(C1-C4)alkyl, pyrazole-3-, -4 - or-5-yl(C1-C4)alkyl, isoxazol-3-, -4 - or-5-yl(C1-C4)alkyl, isothiazol-3-, -4 - or-5-yl(C1-C4)alkyl, pyridazin-3 - or-4-yl(C1-C4)alkyl; and previous heterocycles R4are independently and optionally mono - or di-substituted by halogen, trifluromethyl, (C1-C4)alkyl, (C1-C4)alkoxy, amino or hydroxy, and the above mono - or di-substituents bound to carbon;

R5represents H, hydroxy, fluorine, (C1-C5)-alkyl, (C1-C5)alkoxy, (C1-C5)alkanoyl, amino(C1-C4)alkoxy, mono-N - or di-N,N-(C1-C4)alkylamino(C1-C4)alkoxy, carboxy(C1-C4)alkoxy, (C1-C5)alkoxy-carbonyl (C1-C4)alkoxy, benzyloxycarbonyl, (C1-C4)alkoxy or carbonyloxy, where specified, carbonyloxy group is a carbon-carbon linked with phenyl, triazolyl, imidazolyl, 1H-indolium, fullam, pirrallo, oxazolium, isoxazolyl, isothiazolines, pyridazinyl, pyrimidinyl, pyrazinium or 1,3,5-triazinyl, and where the above rings R5are optionally mono-substituted with halogen, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, amino or trifloromethyl, and these mono-substituents linked to the carbon atom;

R7represents H, is;

R6represents carboxy, (C1-C8)alkoxycarbonyl, C(O)NR8R9or (CO)R12where:

R8represents H, (C1-C3)alkyl, hydroxy or (C1-C3)alkoxy; and

R9represents H, (C1-C8) alkyl, hydroxy, (C1-C8)-alkoxy, methylene-perfluorinated (C1-C8)alkyl, phenyl, pyridyl, Tennille, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolidine, isoxazole, isothiazole, pyranyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinil or 1,3,5-triazinyl, where the above rings R9attached via the linking carbon-nitrogen; or

R9represents a mono-, di - or tri-substituted (C1-C5)alkyl, where these substituents independently represent H, hydroxy, amino, mono-N - or di - N,N-(C1-C5)alkylamino; or

R9is mono - or di-substituted (C1-C5)alkyl, where these substituents independently represent a phenyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolyl, pyrazolidine, isoxazole, isothiazole, pyranyl, pyridinyl, piperidine nitrogen-containing ring R9are optionally substituted at the nitrogen atom (C1-C6)alkyl, benzyl, benzoyl or (C1-C6)alkoxycarbonyl; and where the ring R9are optionally monosubstituted at a carbon atom by halogen, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, amino or mono - N - or di - N,N-(C1-C5)alkylamino, provided that there is no stereoselectivity nitrogen, and no communication nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halogen;

R12represents piperazine-1-yl, 4-(C1-C4)alkylpiperazine-1-yl, 4-formylpiperazine-1-yl, morpholino, thiomorpholine, 1 Osotimehin, 1,1-dioxo-thiomorpholine, thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl, 1,1-dioxo-thiazolidin-3-yl, 2-(C1-C5)alkoxycarbonyl-1-yl, oxazolidin-3-yl or 2(R)-hydroxyethylpyrrolidine-1-yl; or

R12represents a 3 - or 4-mono - or di-substituted oxazolidin-2-yl, 2-, 4 - and/or 5-mono - or di-substituted oxazolidin-3-yl, 2-, 4 - and/or 5-mono or di-substituted, thiazolidin-3-yl, 2-, 4 - and/or 5-mono - or di-substituted 1-oxothiazolidine-3-yl, 2-, 4 and/or 5-mono - or di-substituted 1,1-dioxothiazolidine-3-yl, 3 - or 4-, mono - or di-substituted pyrrolidin-1-yl, 3-, 4 - and/or 5-mono-, di - or tri-Samedan is about - or di-substituted 1,2-oxazine-2-yl, 3 and/or 4-mono - or di-substituted pyrazolidine-1-yl, 4 - and/or 5-mono - or di-substituted isoxazolidine-2-yl, 4 - and/or 5-mono - and/or di-substituted isothiazolin-2-yl, where these R12-the substituents independently represent H, halogen, (C1-C5)alkyl, hydroxy, amino, mono - N - or di - N,N-(C1-C5)alkylamino, formyl, oxo, hydroxyimino, (C1-C5)alkoxy, carboxy, carbarnoyl, mono-N - or di-N,N-(C1-C4)allylcarbamate, (C1-C4)alkoxyimino, (C1-C4)alkoxymethyl, (C1-C6)alkoxycarbonyl, carboxy (C1-C5)alkyl or hydroxy(C1-C5)alkyl;

provided that, if R4is H, stands, ethyl or n-propylene, R5is OH;

provided that, if R5and R7are H, R4is not H, stands, ethyl, n-propylene, hydroxy(C1-C3)alkyl or (C1-C3)alkoxy(C1-C3)alkyl, and R6is (C(O)NR8R9C(O)R12or (C1-C4)alkoxycarbonyl.

The first group of preferred compounds of formula I consists of compounds in which:

R1represents a 5-H, 5-halo, 5-methyl or 5-cyano;

R10and R11

R4represents phenyl(C1-C2)alkyl, where the phenyl groups are independently mono-, di - or tri-substituted by hydrogen or halogen, or they are independently mono - or di-substituted by hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, trifloromethyl, hydroxy, amino or cyano; or

R4represents Tien-2 - or-3-yl(C1-C2)alkyl, pyrid-2-, -3 - or-4-yl(C1-C2)alkyl, thiazol-2-, -4 - or-5-yl(C1-C2)alkyl, imidazol, -1-, -2-, -4- or-5-yl(C1-C2)alkyl, FSD-2 - or-3-yl(C1-C2)alkyl, pyrrol-2 - or-3-yl(C1-C2)alkyl, oxazol-2-, -4 - or-5-yl(C1-C2)alkyl, pyrazole-3-, -4 - or-5-yl(C1-C2)alkyl, isoxazol-3-, -4 - or-5-yl(C1-C2)alkyl, where the above heterocycles R4are optionally and independently mono - or di-substituted by halogen, trifluromethyl, (C1-C4)alkyl, (C1-C4)alkoxy, amino or hydroxy; and the above mono - or di-substituents bound to carbon;

R5represents hydroxy;

R6represents C(O)NR8R9or C(O)R12;

R7represents H.

From vysheukazannoe compounds where:

the carbon atom has a S-configuration;

the carbon atom b has an R configuration; R4represents phenyl(C1-C2)alkyl, Tien-2-yl-(C1-C2)alkyl, Tien-3-yl-(C1-C2)alkyl, FSD-2-yl-(C1-C2)alkyl or FSD-3-yl(C1-C2)alkyl, where these rings are independently mono - or di-substituted by hydrogen or fluorine;

R6represents C(O)NR8R9;

R8is a (C1-C3)alkyl, hydroxy or (C1-C3)alkoxy; and

R9represents H, (C1-C8)alkyl, hydroxy, hydroxy(C1-C6)alkyl, (C1-C8)alkoxy, pyridyl, morpholinyl, piperazinil, piperidinyl, imidazolyl or thiazolyl, or (C1-C4)alkyl, mono-substituted by pyridium, morpholinium, piperazinil, pyrrolidinium, piperidinium, imidazolium or thiazolium.

From the above first group of especially preferred compounds, the most preferred compounds are:

5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R)-hydroxy-dimethylcarbamoyl-methyl)-2-phenyl-ethyl]-amide;

5,6-sodium dichloro-1H-indole-2-carboxylic acid { (1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-Tyl]-2-phenyl-ethyl}-amino;

5-Chloro-1H-indole-2-carboxylic acid ((1S)-{(R)-hydroxy[(2-hydroxy-ethyl)-methyl-carbarnoyl]-methyl}-2 - phenyl-ethyl) - amide;

5-Chloro-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(methyl-pyridin-2-yl-carbarnoyl)-methyl]-2-phenyl-ethyl}amide;

or 5-Chloro-1H-indole-2-carboxylic acid ((1S)-{(R)-hydroxy-[methyl-(2-pyridin-2-yl-ethyl)carbarnoyl]-methyl}-2 - phenyl-ethyl)-amide.

In the above first group of especially preferred compounds includes compounds in which:

a. R1represents 5-Chloro;

R10and R11represent H;

R4represents benzyl;

R8represents methyl; and

R9represents methyl;

b. R1represents 5-chloro;

R11represents H;

R10represents a 6-chloro;

R4represents benzyl;

R8represents methyl; and

R9represents methoxy;

c. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl;

R8represents methyl; and

R9represents methoxy;

d. R1represents 5-chloro;

R10ethyl; and

R9represents a 2-(hydroxy)ethyl;

e. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl;

R8represents methyl; and

R9represents pyridin-2-yl; and

f. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl;

R8represents methyl; and

R9represents a 2-(pyridine-2-yl)ethyl.

From the above first group of preferred compounds of formula I, the second group of especially preferred compounds consists of compounds in which:

the carbon atom a is (S)-configuration;

the carbon atom b is (R)-configuration;

R4represents phenyl(C1-C2)alkyl, Tien-2-yl-(C1-C2)alkyl; Tien-3-yl(C1-C2)alkyl, FSD-2-yl-(C1-C2)alkyl or FSD-3-yl-(C1-C2)alkyl, where these rings are independently mono - or di-substituted by hydrogen or fluorine;

R6represents C(O)R12;

R12represents morpholino, 4-(C1-C4)alkylpiperazine-1-yl, 3-substituted azeti and/or 5-mono - or di-substituted 1,2-oxazine-2-yl, where these substituents independently represent H, halogen, hydroxy, amino, mono - N - or di-N,N-(C1-C6)alkylamino, oxo, hydroxyimino or alkoxy.

From the above second group of especially preferred compounds, the most preferred are the following compounds:

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(4-methyl-piperazine-1-yl)-3-oxo-propyl]amide hydrochloride;

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(3-hydroxy-azetidin-1-yl)-3-oxo-propyl]amide;

5-Chloro-1H-indole-2-carboxylic acid (1S)-benzyl-(2R)-hydroxy-3-isoxazolidine-2-yl-3-oxo-propyl)-amide;

5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-[1,2] oxazine-2-yl-3-oxo-propyl)-amide;

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(3S)-hydroxy-pyrrolidin-1-yl)-3-oxo-propyl amide;

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3S, 4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3 - oxo-propyl]-amide;

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3R, 4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3 - oxo-propyl]amide;

5-Chloro-1H-indole-2-carboxylic acid ((S)-benzyl-(2R)-hydroxy-3-morpholine-4-yl-3-oxo-propyl)-amide.

In vysheukazannye a 5-chloro;

R10and R11represent H;

R4represents benzyl; and

R12is a 4-methylpiperazin-1-yl;

b. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl; and

R12is a 3-hydroxyazetidine-1-yl;

c. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl; and

R12is isoxazolidine-2-yl;

d. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl; and

R12is a (1,2)-oxazine-2-yl;

e. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl; and

R12is a 3(S)-hydroxypyrrolidine-1-yl;

f. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl; and

R12is a (3S,4S)-dihydroxypyrrolidine-1-yl;

g. R1represents 5-chloro;

R10and R11imagine Wal-yl; and

h. R1represents 5-chloro;

R10and R11represent H;

R4represents benzyl; and

R12represents morpholino.

The second group of preferred compounds of formula I consists of compounds in which:

R1represents H, halogen, methyl or cyano;

R10and R11independently represent H or halogen;

A represents-C(H)=;

R2and R3represent H;

R4represents phenyl(C1-C2)alkyl, where the above phenyl groups are independently mono-, di - or tri-substituted by H or halogen, or they are independently mono - or di-substituted by H, halogen, (C1-C4)alkyl, (C1-C4)-alkoxy, trifloromethyl, hydroxy, amino or cyano; or

R4represents Tien-2 - or-3-yl(C1-C2)alkyl, pyrid-2-, -3 - or-4-yl(C1-C2)alkyl, thiazol-2-, -4 - or-5-yl(C1-C2)alkyl, imidazol-1-, -2-, -4- or-5-yl(C1-C2)alkyl, FSD-2 - or-3-yl(C1-C2)alkyl, pyrrol-2 - or-3-yl(C1-C2)alkyl, oxazol-2-, -4 - or-5-yl(C1-C2)alkyl, Persil-3-, -4 - or-5-yl(C1-C2)alkyl, ISOC ezavisimo mono - or di-substituted by halogen, by trifluoromethyl, (C1-C4)alkyl, (C1-C4)alkoxy, amino or hydroxy; and the above mono - or di-substituents bound to carbon;

R5represents carboxy;

R6represents carboxy or (C1-C8)alkoxycarbonyl; and

R7represents H, fluorescent or (C1-C6)alkyl.

From the second group of preferred compounds of formula I, a group of especially preferred compounds are compounds in which:

the carbon atom a is (S)-configuration;

the carbon atom b is (R)-configuration;

R4represents phenyl(C1-C2)alkyl, Tien-2-yl(C1-C2)alkyl, Tien-3-yl(C1-C2)alkyl, FSD-2-yl(C1-C2)alkyl or FSD-3-yl(C1-C2)alkyl, where these rings are independently mono - or di-substituted by hydrogen or fluorine;

R10and R11represent H;

R6represents carboxy; and

R7represents H.

Of the immediately preceding group of compounds, preferred are compounds in which:

R1represents 5-chloro;

R10and R11represent I consists of compounds where:

R1represents H, halogen, methyl or cyano;

R10and R11independently represent H or halogen;

A represents-C(H)=;

R2and R3represent H;

R4represents phenyl(C1-C2)alkyl, where the above phenyl groups are independently mono-, di - or tri-substituted by H or halogen, or they are independently mono - or di-substituted by H, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, trifloromethyl, hydroxy, amino or cyano; or

R4represents Tien-2 - or-3-yl(C1-C2)alkyl, pyrid-2-, -3 - or-4-yl(C1-C2)alkyl, thiazol-2-, -4 - or-5-yl(C1-C2)alkyl, imidazol-1-, -2-, -4- or-5-yl(C1-C2)alkyl, FSD-2 - or-3-yl(C1-C2)alkyl, pyrrol-2 - or-3-yl(C1-C2)alkyl, oxazol-2-, -4 - or-5-yl(C1-C2)alkyl, pyrazole-3-, -4 - or-5-yl(C1-C2)alkyl, isoxazol-3-, -4 - or-5-yl(C1-C2)alkyl, where the above heterocycles R4are independently and optionally mono - or di-substituted by halogen, trifluromethyl, (C1-C4)alkyl, (C1-C4)alkoxy, amino or hydroxy; and the above mono - or di timestalkers, amino(C1-C4)alkoxy, mono-N - or di-N,N-(C1-C4)alkylamino-(C1-C4)alkoxy, carboxy(C1-C4)alkoxy, (C1-C5)alkoxy-carbonyl(C1-C4)alkoxy, benzyloxycarbonyl(C1-C4)alkoxy;

R6represents carboxy or (C1-C8)alkoxycarbonyl; and

R7represents H, fluorine or (C1-C6)alkyl.

The fourth group of preferred compounds of formula I consists of compounds in which:

R1represents H, halogen, methyl or cyano;

R10and R11independently represent H or halogen;

A represents-C(H)=;

R2and R3represent H;

R4represents phenyl(C1-C2)alkyl, where the above phenyl groups are independently mono-, di - or tri-substituted by H or halogen, or they are independently mono - or di-substituted by H, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, trifloromethyl, hydroxy, amino or cyano; or

R4represents Tien-2 - or-3-yl(C1-C2)alkyl, thiazol-2-, -4 - or-5-yl(C1-C2)alkyl, imidazol-1-, -2-, -4- or-5-yl(C1-C2B>1-C2)alkyl, pyrazole-3-, -4 - or-5-yl(C1-C2)alkyl, isoxazol-3-, -4 - or-5-yl(C1-C2)alkyl, where the above heterocycles R4are optionally and independently mono - or di-substituted by halogen, trifluromethyl, (C1-C4)alkyl, (C1-C4)alkoxy, amino or hydroxy; and the above mono - or di-substituents bound to carbon;

R5represents fluorine, (C1-C4)alkyl, (C1-C5)alkoxy, amino(C1-C4)alkoxy, mono-N - or di-N,N-(C1-C4)alkylamino-(C1-C4)alkoxy, carboxy(C1-C4)alkoxy, (C1-C5)alkoxy-carbonyl(C1-C4)alkoxy, benzyloxycarbonyl(C1-C4)alkoxy;

R6represents C(O)NR8R9or C(O)R12;

R7represents H, fluorine or (C1-C6)alkyl.

In another aspect, the present invention relates to a method of treatment of glycogenolysis-dependent diseases or conditions in a mammal by injecting the mammal suffering from the specified disease or condition, is effective for such treatment of a number of compounds of formula I.

In another aspect, the mu suffering from hyperglycemia, effective for such treatment of a number of compounds of formula I.

In another aspect, the present invention relates to a method of treating diabetes in a mammal by injecting a mammal suffering from diabetes, effective against diabetes quantities of the compounds of formula I.

In another aspect, the present invention relates to a method of treating hypercholesterolemia in a mammal by injecting a mammal suffering from hypercholesterolemia, effective for the treatment of hypercholesterolemia amount of the compounds of formula I. Treatment of diabetes also provides for the prevention or mitigation of chronic complications such as neuropathy, nephropathy, retinopathy or cataracts.

In another aspect, the present invention relates to a method of treating atherosclerosis in a mammal by injecting a mammal suffering from atherosclerosis, effective for the treatment of atherosclerosis amount of the compounds of formula I.

In another aspect, the present invention relates to a method of treating hyperinsulinemia in a mammal by injecting a mammal suffering from hyperinsulinemia, effective is it the invention relates to a method of treating hypertension in a mammal by injecting a mammal suffering from hypertension, effective for the treatment of hypertension amounts of compounds of formula I.

In another aspect, the present invention relates to a method of treating hyperlipidemia in a mammal by injecting a mammal suffering from hyperlipidemia, effective for the treatment of hyperlipidemia amount of the compounds of formula I.

In another aspect, the present invention relates to a method for prevention of ischemic damage to the myocardium in a mammal by injecting a mammal at risk of myocardial ischemic injury during surgery, effective to prevent the specified ischemic damage to the amount of the compounds of formula I.

In another aspect, the present invention relates to a method for prevention of ischemic damage to the myocardium in a mammal by injecting a mammal at risk of myocardial ischemic injury during surgery, effective to prevent the specified ischemic damage amount of an inhibitor of glycogen phosphorylase.

The present invention also relates to pharmaceutical compositions containing a therapeutically effective colormatches composition for the treatment of glycogenolysis-dependent diseases or conditions in mammals, contains effective for the treatment of glycogenolysis-dependent diseases or conditions a number of the compounds of formula I and a pharmaceutically acceptable carrier.

In another aspect, the present invention relates to pharmaceutical compositions for the treatment of diabetes containing a therapeutically effective amount of a glycogen phosphorylase inhibitor;

one or more antidiabetic agents such as insulin or its analogues (e.g., LysPro insulin); GLP-1 (7-37) (insulinotropic) and GLP-1 (7-36) - H2; sulfobetaine and their analogues; chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride, Repaglinide, meglitinide; biguanides: Metformin, phenformin, buformin; 2-antagonists and imidazolines: midaglizole, Salida, deriglidole, idazoxan, efaroxan, flyproxy; other means of enhancing insulin secretion; linogliride, A-4166, glitazone: ciglitazone, pioglitazone, englitazone, troglitazone, dilitazem, BP 49653; inhibitors of fatty acid oxidation: clamoxyl, etomoxir; inhibitors of a-glucosidase: miglitol, acarbose, emiglitate, voglibose, MDL-25637, camiglibose, MDL-73945; agonists: BPL 35135, BPL 37344, Ro 16-8714, 1C1 D7114, CL 316243; a phosphodiesterase inhibitor; L-386398; means decreases the si (for example, NegovanRand peroxovanadate complexes; Amylin antagonists; glucagon antagonists; inhibitors of gluconeogenesis; analogs of somatostatin; antilipolytic tools: nicotinic acid, acipimox, WAG994; and

optional pharmaceutically acceptable carrier;

Of the above group of compositions, preferred are pharmaceutical compositions in which the glycogen phosphorylase inhibitor is a compound of formula I.

In another aspect, the present invention relates to a method of treating diabetes in a mammal using the above complex compositions.

To glycogenolysis-dependent diseases or conditions are those conditions that partially or fully mediated by, initiated or supported by the splitting of glycogen macromolecule glikogenogeneza, resulting in the release of glucose-1-phosphate and a new shorter molecule of glycogen. These States are characterized by increased glycolipoprotein activity, and decreased intensity of the symptoms of these conditions can be achieved by reducing such activity. Examples of such diseases or costermongers and myocardial ischemia.

The term "glycogen phosphorylase inhibitor" refers to any compound or agent, or combination of compounds and/or tools that reduce, slow down or stop the enzymatic action of glycogen phosphorylase. Currently known action of glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reactions of macromolecules glycogen and inorganic phosphate with the formation of glucose-1-phosphate and glycogen macromolecule, which is becoming one glucosaminyl residue shorter than the original molecule of glycogen (glycogenolysis).

The term "treatment" used in the present description, refers to a warning (e.g., prophylactic) and palliative treatment.

The term "halogen" means chlorine, bromine, iodine or fluorine.

The term "alkyl" means saturated hydrocarbons with straight or branched chain. Examples of such alkyl groups (the length of which is determined by the specific example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

The term "alkoxy" means a saturated straight or branched alkyl, which is connected through about ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentox, isopentane, hexose, isohexane.

The expression "pharmaceutically acceptable anionic salt" refers to non-toxic anionic salts containing anions (but are not limited to) such as chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluensulfonate.

The expression "pharmaceutically acceptable cationic salt" refers to non-toxic cationic salts (but not limited to), such as salts of sodium, potassium, calcium, magnesium, ammonium, or the protonated benzathine(N,N-dibenziletilendiaminom), choline, ethanolamine, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylpenicillin), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propandiol).

The expression "prodrug" refers to compounds, which are precursors of the medicinal product and that, after their introduction, contribute to the release of in vivo drug by some chemical or physiological process (e.g., a prodrug, after its introduction into the environment with physiological pH, turns into nnuu acid, and such hydrolyzable afrobrazil remnants of the compounds of the present invention include, but are not limited to, carbon-acid substituents (e.g., R6is carboxy, or R8, R9or R12contain carboxy), where the free hydrogen is replaced by (C1-C4)alkyl, (C2-C12)alkanoyloxy, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5-10 carbon atoms, alkoxycarbonylmethyl having 3-6 carbon atoms, 1-(alkoxycarbonyl)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyl)ethyl having 5-8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3-9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotononitrile, gamma-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as-dimethylaminoethyl), carbarnoyl-(C1-C2)alkyl, N, N-di(C1-C2-allylcarbamate-(C1-C2)alkyl and piperidino-, pyrrolidino or morpholino(C2-C3)alkyl.

Other typical prodrugs release an alcohol of formula I, where free hydrogen hydroxy-substituent (napravleniax)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)-ethyl, (C1-C6)alkoxycarbonylmethyl, N-(C1-C6)alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl,

-amino-(C1-C4)alkanoyl, arylation and a-aminoacyl, or-aminoacyl-aminoacyl (where specified-aminoaniline radicals independently represent any natural L-amino acids present in proteins, P(O)(OH)2, -P(O)(O)(C1-C6)-alkyl)2, Ohm or glikozidom (the radical resulting from the removal of the hydroxyl polyacetale carbohydrate).

Other typical prodrugs include, but are not limited to, derivatives of formula I, where R2is the free hydrogen, which is replaced by R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' independently represent a ((C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl; or R-carbonyl is a natural aminoacyl-natural-aminoacyl, -C(OH)C(O)OY where Y is H, (C1-C6)alkyl or benzyl, -C(OY0)Y1where Y0is a (C1-C4)alkyl, and Y1is a (C1-C6)alkyl, carboxy(C1-C6)alkyl, AMI is represents H or methyl, and Y3is a mono-N - or di-N,N-(C1-C6)alkylamino, morpholino, piperidine-1-yl or pyrrolidin-1-yl.

Other examples of prodrugs are cyclic structures, such as the compounds of formula I, where R2and R3have a total carbon, forming, thereby, a 5-membered ring. This linking carbon may be independently mono or di-substituted H, (C1-C6)alkyl, (C3-C6)cycloalkyl or phenyl. Alternative, R3and R5taken together, may form oxazolidinone ring, and two carbon oxazolidinone rings may be independently mono or di-substituted H, (C1-C6)alkyl, (C3-C6)cycloalkyl, or phenyl. Alternatively, proletarienne forms of the compounds of formula I are compounds in which R5taken together with R8or R9, can form the oxazoline-4-it TV ring, and the 2 carbon atom of the ring may be independently mono or di-substituted H, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl or oxo group.

Used in the present description, the expression "reaction-inert solvent" and "inert rastvoriteli, intermediate compounds or reaction products, and has no adverse effect on the yield of the target product.

Each secondary specialist clear that certain compounds of the present invention contain one or more atoms, which may be in a particular stereochemical or geometric configuration, forming the stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in the scope of the present invention. In addition, the scope of the present invention also includes hydrates of the compounds of the present invention.

Each secondary specialist clear that certain combinations of substituents containing a heteroatom and included in the scope of the present invention, identify the connections that are less stable under physiological conditions (for example, compounds containing acetylene or analnye communication). Therefore, such compounds are less preferred.

The term "ring Rx", where x is an integer, for example, "ring of R9", "ring of R12or ring R4"used in this description when referring to the substitution on the ring, refers to those parts of the molecule, where the ring is RIsani the term "mono-N - or di-N,N-(C1-Cx)alkyl. .. refers to a (C1-Cx)the alkyl radical, taken separately, in cases when it is di-N,N-(C1-Cx)alkyl... (where x is an integer).

Other distinctive features and advantages of the present invention are evident from the following detailed descriptions and claims of the present invention.

In General, the compounds of formula I can be obtained by methods known to experts-chemists, especially in light of the following detailed description of the invention. However, some methods of making compounds of formula I are the distinctive characteristics of the present invention, and therefore these methods are illustrated by reaction schemes (see below).

In accordance with reaction scheme I, the compounds of formula I, where R1, R10, R11, A1, R2, R3, R4, R5, R6and R7defined above, can be obtained in either of two main ways. In the first method, the desired compound of formula I can be obtained by the reaction of interaction of the corresponding indole--2-carboxylic acid or indolin-2-carboxylic acid of formula I with an appropriate amine of formula III (i.e., reaction acceleratesthe compounds of formula IV (i.e., the compounds of formula I in which R6represents a carboxy group) with an appropriate alcohol or amine of formula R8R9NH or R12H, or alcohol, where R8, R9and R12defined above (i.e., the reaction of acylation of amine or alcohol).

Typically, the compound of formula II together with a compound of formula III (or compound of formula IV unite with the appropriate amine (e.g., R12H, or R8R9NH)) or alcohol in the presence of an appropriate coupling agent. Suitable binding agent is a substance which converts the carboxylic acid to the corresponding reactive compound that forms an amide or ester bond in the interaction with the amine or alcohol.

Such condensing agent may be a reagent, which after mixing with carboxylic acid and amine or alcohol in the same reaction vessel carries out the condensation reaction. If you carry out the condensation reaction of the acid with the alcohol, then the alcohol as the reaction solvent is preferably used in large excess without addition or with the addition of 1.0 to 1.5 equivalent of dimethylaminopyridine. Examples of the condensing reagents are logicalgroove/hydroxybenzotriazole (HBT), 2 ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole/HBT, diethylphosphinic. This reaction interaction takes place in an inert solvent, preferably in an aprotic solvent at a temperature of from about -20oC to about 50oC during the period of time from about 1 hour to about 48 hours. Examples of solvents are acetonitrile, dichloromethane, dimethylformamide and chloroform. Examples of suitable methods of carrying out the condensation reaction is A Method described below (just before the examples).

The condensing agent may be an agent, converting the carboxylic acid to an activated intermediate compound, which emit and/or after its formation in the first stage, leave for the reaction with the amine or alcohol in the second stage. Examples of such condensing agents and activated intermediates are thionyl chloride or oxalicacid, which forms the acid chloride; floramite cyanuric acid, which forms floramite; or alkylchloride, such as isobutyl or isopropenylacetate (with base such as tertiary amine), which forms a mixed anhydride of carboxylic acid is sustained fashion to use a small amount of dimethylformamide as a co-solvent with another solvent (such as dichloromethane). The choice of condensing agents, appropriate solvents and temperatures can easily be made by a specialist, or determined from the literature. These and other reaction conditions of the condensation of carboxylic acids described in Houben-Weyl, vol. XV, part 11, E. Wunsch. bd. G. Thieme Verlad, 1974, Stuttgart, & M. Bodansky, Principles of Peptide Synthesis, Springer. Verlag Berlin 1984, and The Peptides Analysis, Synthesis and Biology (ed. E. Gross &J. Meienhofer), vols. 1-5 (Academic Press NY 1979-1983).

The compounds of formula IV, where R1, R10, R11, A, R2, R3, R4, R5and R7defined above, can be obtained from the corresponding complex ester of the formula V (i.e., compounds of formula I, where R6is a (C1-C5)alkoxycarbonyl or benzyloxycarbonyl) by hydrolysis with an aqueous alkali solution at a temperature of from about -20oC to about 100oC, typically at a temperature of about 20oC, during the period of time from about 30 minutes to about 24 hours.

Alternatively, the compounds of formula IV can be obtained by activation indolocarbazoles acid of formula II using a condensing agent (described above), resulting in a get activated intermediate connection (such as harangi the 3
, R4, R5and R7defined above, and R6represents a carboxy group) in a suitable solvent and in the presence of a suitable base. Suitable solvents are water or methanol, or a mixture thereof, together with a cosolvent such as dichloromethane, tetrahydrofuran, or dioxane. Suitable bases are hydroxides of sodium, potassium or lithium, sodium bicarbonate or potassium or sodium carbonate or potassium, or potassium carbonate together with tetrabutylammonium bromide (1 equivalent), taken in sufficient quantity for the consumption of acid released by the reaction (usually, this amount is sufficient to maintain the pH of the reaction to a value of more than 8). To obtain a desired pH value of the reaction, the base can be added gradually together with the activated intermediate connection. Usually, the reaction is carried out at a temperature of from -20oC to 50oC. Methods of selection to remove impurities may be developed by the specialist, but, typically, this technique involves removing miscible with water co-solvents by evaporation, extraction of impurities at high pH with the use of organic solvents, acidification to lower pH (1-2) and file dichloromethane.

The compound of formula V can be obtained by the reaction of interaction of the compounds of formula III, where R6is alkoxycarbonyl, with a corresponding compound of formula II in accordance with methods similar to those described above (for example, Method A).

Alternatively, the compounds of formula I which contain sulfur atoms in the state sulfoxide or sulfonic oxidation, can be obtained from corresponding compounds of formula I, having the sulfur atom in the unoxidized state, processing the appropriate oxidant, such as m-chloroperoxybenzoic acid in dichloromethane, at a temperature of from about 0oC to about 25oC during the period of time from about 1 to about 48 hours, from about 1 to about 1.3 equivalents for conversion into state sulfoxide oxidation, and using more than about 2 equivalents to become the state sulfonic oxidation.

Alternatively, the compounds of formula I, which are mono - or di-alkylated at aminoethoxy group, R5can be obtained from the corresponding compounds of formula I, where R5is aminoethoxy-group monoalkylammonium or dialkylammonium by Amin R5with connections, in which R5is aminoethoxy, 1 equivalent of the corresponding carbonyl compounds (for monoalkylamines) or more than 2 equivalents of the corresponding carbonyl compounds (for dialkylamide) and an appropriate reducing agent in a suitable solvent. Suitable conditions for the reaction of recovery are using cyanoborohydride sodium or sodium borohydride in methanol or ethanol, or hydrogenation catalyst in heterogeneous catalysis, such as palladium-on-coal) in a polar solvent such as water, methanol or ethanol at a temperature of about 0-60oC for 1 to 48 hours.

Alternatively, the compounds of formula I in which R5is alkanoyloxy (RCOO-), can be obtained by O-acylation of the corresponding compounds of formula I with an appropriate acid chloride or other activated acid derivative in the presence of, if necessary, the appropriate base (e.g. a tertiary base, such as trialkylamine or pyridine), preferably in an aprotic solvent such as tetrahydrofuran or dichloromethane, at a temperature of from about 0oC to about 50oC, for about 0.5 to the Wallpaper oxoprop, can be obtained by oxidation of the corresponding compounds of formula I, for example, compounds in which R5is a hydroxy-group, and R7is hydrogen, with a suitable oxidant. Examples of such oxidizing agents are reagent dess-Martin chloromethane, carbodiimide, dimethyl sulfoxide, and an acid catalyst (oxidation Pfitzner-Moffet or its modification, for example, using water-soluble carbodiimide; or reaction type Swarna, for example, using oxalicacid /DMSO/triethylamine). The compounds of formula I with other oxidation-sensitive functional groups, can be obtained from the appropriate protection and release of such groups.

Some ways to obtain the compounds described in this application, may require protection of leaving functional groups (e.g., primary amine, secondary amine, carboxyl in the precursor compounds of the formula (I). The need for such protection may vary depending on the nature of the leaving functional groups and conditions specific getters. The need for such protection can be easily installed by a specialist. From the use described, for example, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

For example, in reaction scheme I, some of the compounds of formula I contain a primary amino group, secondary amino group or carbonisation functional group in a molecule, a specific R5or R6that could interfere with the desired reaction of interaction carried out in accordance with reaction scheme I, in that case, if the intermediate compound of formula III, or Amin R12H, or R8R9NH remains unprotected. Therefore, the primary or secondary functional amino group, if it is present in the radicals R5or R6intermediate compounds of formula III or amine R8R9NH or R12H, can be protected with appropriate protective groups in the reaction of interaction of reaction scheme I. the Product of this reaction interaction is a compound of the formula I containing a protective group. In the subsequent stage, this protective group is removed to obtain the compounds of formula I. Suitable protective groups for protecting amino groups and carbonatites group is a protective group commonly used in peptide synthesis (e.g., such as Silovye esters for carbonisation groups), which do not enter into chemical reaction under conditions of condensation described above (and in the method A, described immediately before the examples), and which can be removed without any chemical impacts on other functional groups in the compounds of formula I.

The source of indole-2-carboxylic acid and indolin-2-carboxylic acid used in reaction scheme I, if they are not commercially available or known compounds (such that is widely described in the literature) can be obtained by standard synthesis. For example, according to reaction scheme II, ester indole of formula VII can be obtained from compounds of formula VI (where Q is chosen so as to obtain the desired A, defined above) through the synthesis of indoles Fisher (see The Fischer Indole Synthesis, Robinson, B. (Wiley, New York, 1982) and subsequent saponification of ester obtained indole of formula VII to obtain the corresponding acid of formula VIII. Source arylhydrazones can be obtained by condensation of readily available hydrazine with the corresponding carbonium derivative, or through reaction of the Japp-Klingemann (see , Organic Reactions, Phillips, R. R. 1959, 10, 143).

Alternatively, the indole-2-carboxylic acid of the formula VIIIA my recovery nitro group and subsequent hydrolysis.

This three-stage method for the synthesis of indoles known as reaction Reissert (Reissert, Chemische Berichte, 1987, 30, 1030). Conditions for the implementation of this method, and links related to the synthesis described in the literature (Kermack et al., J. Chem. Soc. 1921, 119, 1609; Cannon et al., J. Med. Chem. 1981, 24, 238; Julian et al., in Heterocyclic Compounds, vol. 3 (Wiley, New York, NY, 1962, R. C. Elderfield, ed.) p. 18). Examples of specific implementation of this method is given in the present description (examples 10A-10C).

3 Halogeno-5-chloro-1H-indole-2-carboxylic acid can also be obtained by halogenoalkanes 5-chloro-1H-indole-2-carboxylic acid.

Alternative (reaction scheme II), substituted indoles of formula XIV can be obtained by reduction of the corresponding indoles of formula XV using a reducing agent, such as magnesium in methanol, at a temperature of from about 25oC to about 65oC for a time from about 1 hour to about 48 hours (reaction scheme III).

Indolinecarboxylic acid of formula XVI is obtained by saponification of the corresponding complex ester of formula XVII (reaction formula (III). The compound of formula XVII receive the appropriate recovery of ester indole of formula VII using a reducing agent, such as magnesium in methanol, as opisanych amines, used in the above reaction schemes.

In accordance with reaction scheme IV, compounds of formula XXII (amines of the formula III in the reaction scheme, where R5is OH; R7is H; and R6a complex air), or the compounds of formula XXVI (where R6is C(O)NR8R9or C(O)R12) get on the basis of N-protected (indicated by PT) aldehyde of formula XX. The aldehyde of formula XX or attributability adduct of the aldehyde of formula XX is treated with potassium cyanide or sodium in an aqueous solution with a co-solvent, such as dioxane or ethyl acetate, at a temperature of from about 0oC to about 50oC, resulting in a gain cyanohydrin formula XXI. Cyanohydrin formula XXI is treated with alcohol (for example, (C1-C6)alkanol such as methanol) in the presence of a catalyst based on a strong acid such as hydrogen chloride, at a temperature of from about 0oC to about 50oC followed by the addition of water if necessary. Then the protective group (PT) remove, if present, by a method corresponding release, resulting in the receive connection of the formula XXII. For example, if the N-protective group PT(formula XX) represents the formula XXI, and adding water is not required. The compound of formula XXII can be protected at the nitrogen atom of the corresponding protective group to form compounds of formula XXIII and the subsequent hydrolysis of ester aqueous alkali at a temperature of from about 0oC to about 50oC in an inert solvent, resulting in formation of hydroxy-acids of formula XXIV. The compound of formula XXIV is subjected to interaction (similar to the reaction described in reaction scheme I) with the appropriate amine R8R9NH or HR12and I get the connection formula XXV, which is then subjected to release, resulting in the receive connection of formula XXVI (i.e., the compound of formula III in which R5is OH, R7is H, and R6is C(O)R12or C(O)NR8R9). Example reactions of cyanohydrin formula XXI to the corresponding methyl ester of formula XXII with the removal of the protective group is t-Boc described in PCT publication WO/9325574 in example 1a. Other examples of transformations of cyanohydrin in the lower alkalemia esters of formula XXIII can be found in U.S. patent N 4814342 and EPO publication 0438233.

Some compounds of formula I are stereoisomers due to the stereochemical configuration at the ATO is filling compounds of formulas XXII and XXVI with the desired stereochemistry. For example, the aldehyde of formula XX in any enantiomeric form (the stereochemistry at the a) can be easily derived from the standard techniques described below (see reaction scheme V). Cyanohydrin formula XXI can be obtained from compounds of formula XX by treatment with sodium cyanide or potassium, as described above, retaining, however, the stereochemistry at the carbon atom a, resulting in a mixture of stereoisomers at carbon b.

For the separation of isomers or to highlight a single isomer at this stage you can use the method of crystallization.

For example, obtaining the compounds of formula XXI, where PTis Boc, R3is H, R4is benzyl, and the carbon atoms a and b have a configuration (S) and (R), respectively, followed by purification by recrystallization as described in Bio-Chemistry 1992, 31, 8125-8141.

Alternatively, separation of the isomers can be carried out using the technique of chromatography or recrystallization after the conversion of compounds of formula XXI (mixture of isomers) in the compound of formula XXII, XXIII, XXIV, XXV, XXVI, X, IV or I in accordance with the methods and/or reaction schemes described in this application. Intermediate compounds of formula XXI, with the specific stereochemistry of the atoms ug alcohol in the presence of a strong acid as catalyst, then add water, if necessary, as described above.

Alternatively, the desired isomer of the compounds of formula XXI can be obtained by derivatization of the intermediate compounds of formula XXI and chromatographic separation of the diastereomeric derivatives (for example, using trimethylsilylpropyne (TMS) or t-butyldimethylsilyloxy (TBDMS) to obtain the O-TMS - or O-TBDMS derivatives). For example, in example 24D (as shown in the present application) describes the separation of the diastereomeric derivatives of the formula XXI. Silloway derived intermediate compounds of formula XXI with a single stereoisomeric form of the carbon atoms a and b, turn with retention of stereochemistry, the intermediate compound of formula XXII (if at this stage silyl group is not removed, it is removed in the subsequent stage using the appropriate methods, for example, by treatment with tetrabutylammonium fluoride in tetrahydrofuran) in accordance with the methodology described above for the conversion of compounds of formula XXI in the compound of formula XXII (see example 24C below, which describes the transformation of the silyl derivative of formula XXI in one isomer of formula XXII with the loss of the silyl group).

The fit is ejstvujuschij amino acids of formula XXX. Amino acids of formula XXX are N-protected by a protective group (PT), such as Vos. A secure connection is subjected to esterification with alcohol and converted into an ester, preferably the methyl or ethyl ester of compounds of formula XXXI. This reaction can be carried out by treating the compounds of formula XXX methyl - or ethyliodide in the presence of a suitable base (e.g., K2CO3) in a polar solvent such as dimethylformamide. The compound of formula XXXI is subjected to reduction reaction of, for example, a hydride of diisobutylamine in hexane or toluene or mixtures thereof at temperatures from about -78oC to about -50oC, followed by quenching the reaction with methanol at -78oC, as described in J. Med. Chem. , 1985, 28, 1779-1790, resulting in a gain aldehyde of formula XX. Alternative (reaction scheme V not shown) similar to the N-methoxyethylamine, corresponding to the compound of formula XXXI in which alcohol Deputy of ester is replaced by N(OMe)Me, is obtained from the compounds of formula XXX, N, O-dimethylhydroxylamine and appropriate condensing agent (for example, hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DEC)), as described in Method A. the resulting ether or tetrahydrofuran, at a temperature of from about 0oC to about 25oC, resulting in a gain aldehyde of formula XX. This two-step method is a General method of conversion of N-protected-amino acids into aldehydes of formula XX (Fehenz & Castro, Synthesis 1983, 676-678).

Alternatively, the aldehydes of formula XX can be obtained by oxidation protected aminoalcohols of formula XXXIII, for example, using pyridine-SO3at a temperature of from about -10oC to 40oC in an inert solvent, preferably dimethylsulfoxide. Protected aminoalcohols of formula XXXIII, if they are not commercial products, can be obtained by protecting the aminoalcohols of formula XXXII. The aminoalcohols of formula XXXII is obtained by recovery of amino acids of formula XXX. This reduction is performed by treatment of compounds of formula XXX with lithium aluminum hydride according to the method described by Dickman et al., Organic Synthesis; Wiley, New York, 1990; vol Collect.VII, p 530, or sulfuric acid with sodium borohydride in accordance with the methodology described Abiko & Masamune, Ttrahedron Lett. 1992, 333, 5517-5518; or iodobromide sodium in accordance with the methodology described McKennon & Meyers, J. Org.Chem. 1993, 58, 3568-3571, where also provides a review of other methods of conversion of amino acids form ishemia in reaction scheme V, can be obtained as described below. Amino acids of formula XLI can be obtained by N-alkylation of the protected (PT) amino acids of formula XL by treatment with an appropriate base and an alkylating agent. Specific methodology for such alkylation described Benoiton, Can. J. Chem. 1977, 55, 906-910, and Hansen, J. Org.Chem.1985, 50, 945-950. For example, if R3is stands, using sodium hydride and methyliodide in tetrahydrofuran. After the release of the compounds of formula XLI obtain the desired compound of formula XXX.

Alternatively, the amino acid of formula XLII can be subjected to N-alkylation using a three-stage method, providing for recovery benzylidene (for example, using benzaldehyde in the presence of catalytic hydrogenation with Pd/C) to give the mono-N-benzyl derivative; and reductive amination using an appropriate acyl compounds (e.g. formaldehyde and cyanoborohydride sodium for injection R3as a methyl group) to obtain N-benzyl-N-R3-substituted amino acids. N-benzyl protective group is then removed (for example, by hydrogenation using an appropriate kataliza Reinhold et. al., J. Med.Chem. 1968, 11, 258-260.

The above method can also be used for introduction of the radical R3in the intermediate compound of formula XLIV with the formation of intermediate compounds of formula XLV (which is an intermediate compound of formula III, where R7is OH). This method can also be used for introduction of the radical R3in the intermediate compound of formula IIIa (which is an intermediate compound of formula III, where R3is H).

Amino acids used in the described reaction schemes (e.g., schemas, XL, XLII), if they are not commercially available, can be obtained by various methods, well known to specialists. For example, for this purpose can be used in the synthesis of Strecker or its variants. In accordance with this method, the aldehyde (R4CHO), sodium cyanide or potassium, and the ammonium chloride is subjected to the reaction to obtain the corresponding aminonitriles. This aminonitriles then hydrolyzing with a mineral acid and get the desired amino acid R4C(NH2)COOH formula XLII. Alternatively, one can use the method of Bucherer-Berg, where as can be formed by heating naprimer, with the use of barium hydroxide in boiling dioxane) to give the desired amino acids of formula XLII (R4C(NH2)COOH).

The literature also describes other methods of synthesis of amino acids, which allow the specialist to obtain the desired intermediate compound R4C(NH2)COOH formula XLII, required for the synthesis of compounds of formula I.

Suitable methods of synthesis or secretion of compounds of formulas can be found in review papers Duthaler (Tetrahedron, 1994, 50, 1539-1650), or Williams (P. M. Williams, Synthesis of optically active amino acids. Pergamon: Oxford.U. K. 1989).

In particular, the synthesis of intermediate compounds of formula XLII in any enantiomeric form from the corresponding intermediate compounds R4X (X=C1, Br or I) may be carried out by the method of Piranha and Krishnamurty (J. Org.Chem. 1993, 58, 957-958) or by the method of O Donnel et al. (J. Am.Chem.Soc. 1989, 111, 2353-2355). The desired intermediate compound R4X can be easily obtained by many methods known in the art. For example, compounds where R4X is ArCH2X, can be obtained by radical halogenoalkanes connections ArCH3or formirovanie arena Ar-H and conversion of the alcohol to the bromide.

Another specific method for the synthesis of intermediate compounds foie formula R4CH(OH)CCl3enantiospecific restore to the intermediate R4CH(OH)CCl3that restores catalytic hydrogenation, resulting in getting the desired compound of formula XLII. Necessary trichloromethylthio R4COCCl3obtained by reaction of the aldehyde R4CHO with trichloromethyl-anion with subsequent oxidation (Gallina & Giordano, Synthesis 1989, 466-468).

The intermediate amines of formula III (used in Reaction scheme I), where R5and R7are H, can be obtained in accordance with Reaction scheme VII. Amino acid formula L (appropriately substituted (PT)) triggers the transformation into the acid chloride, floramite or a mixed anhydride (for example, using isobutylacetate and triethylamine in an inert solvent, such as tetrahydrofuran or dioxane at a temperature from about -0oC to about -40oC), and after processing of the activated intermediate with diazomethane get diazoketone formula LI. Diazoketone formula LI is treated with an alcohol (ROH) (for example, (C1-C6) alkanol such as methanol) by heating or by using a suitable catalyst, such as oxide seaut to release with the formation of compounds of formula IIIA (Wolff rearrangement). Alternatively, the ester of formula LII hydrolyzing, for example, an alkali, and then subjected to reaction with the appropriate amine R12H or HNR8R9, resulting in the receive connection of the formula IIIB, as described earlier.

In accordance with the Reaction scheme VIII, the intermediate amines of formula III, where R5represents associated with oxygen Deputy (e.g., alkoxy) (used in reaction scheme I) can be obtained as follows. The compound of formula XI is subjected to O-alkylation by treatment of the appropriate alkylating agent (for example, alkylation, alkylbromides, alkylchloride or alkyllithium) and sufficient reason with the formation of the alkoxide (sodium hydride or potassium hydroxide) in a suitable polar aprotic solvent (e.g. dimethylformamide or tetrahydrofuran) at a temperature of from about 0oC to about 150oC, resulting in the receive connection of the formula XII. The compound of formula LXII will unlock, and get the desired amine intermediate connection.

The intermediate amines of formula III, where R5is a (C1-C6) alkoxycarbonyl-group (used in Reaction scheme I) can be obtained in the trail of the t connection formula LXIII, which then will unlock with obtaining the desired amine. This acid can be obtained by hydrolysis of ester using aqueous alkali in an appropriate solvent. Amines of the formula III, where R6contains ester group, and R5contains carboxypropyl, can be obtained from the amine of formula XIII (obtained as described above), where R5contains carbonation functional group, such as t-butyl ester by treatment with anhydrous acid to obtain the corresponding acid without hydrolysis of ester in position R6.

The compounds of formula LXVI (intermediate amines of formula III in which R5is protected aminoethoxy-group) can be obtained from compounds of formula LXI. The compound of formula LXI alkylate using halogeno-alkane-nitrile, and obtain the connection formula XIV. The compound of formula LXIV subjected to restore to the primary amine by treatment with hydrogen and an appropriate catalyst (for example, rhodium-on-coal) in the presence of ammonia, preferably in proton polar solvent, such as water, methanol or ethanol, resulting in a gain of the primary amine of formula LXV. Connection fornasini to another protective group (PT), with the subsequent release of the protective group PTresulting in getting the desired compound of formula III. The protected compound of formula III is subjected to interaction with the corresponding compound of formula II, resulting in getting a secure connection of the formula I, which is unprotected.

Compounds of formula LXIII and LXIV, where n = 2, get, preferably by treating compound of formula LXI excessive amount of ester of acrylic acid or Acrylonitrile, respectively, in the presence of a suitable base, such as potassium hydroxide or sodium, in a suitable solvent, preferably in proton polar solvent.

In accordance with reaction scheme I, the compounds of formula LXVII and formula LXIX (compounds of formula III, where R5is F or R5and R7both are F) can be obtained from compounds of formula LXI. The compound of formula LXI is treated with a suitable fluorinating agent such as TRIFLUORIDE diethylaminoethyl in an inert solvent such as an aprotic solvent, preferably dichloromethane, resulting in the receive connection of formula LXVII. The compound of formula LXVII is usually subjected to release.

of the formula I, where R5and R7taken together form an oxo group. The compound of formula LXVIII are detonirovanie in suitable conditions (for example, using the TRIFLUORIDE diethylaminoethyl in dichloromethane).

In accordance with the reaction scheme X, the compound of formula LXXIII or the compound of formula LXIV, where R7is alkyl (i.e., the compound of formula III, where R7is alkyl), obtained from the compounds of formula LXX (see also reaction scheme V to obtain similar amines). The compound of formula LXX process ORGANOMETALLIC reagent R7M, and the resulting secondary alcohol is oxidized as described above to form compounds of formula LXXI. The compound of formula LXXI

turn through cyanohydrin formula LXXII in the compound of formula LXXIII using these same conditions that were used for the conversion of compounds of formula XXI in the compound of formula XXII in reaction scheme IV.

Alternatively, the compound of formula LXXII converted into the compound of formula LXIV, as described above for the conversion of the intermediate cyano compound to amide in the Reaction scheme V.

The compound of formula R8NH2or R9NH2put m the state, in suitable conditions, reductive amination, resulting in a gain amine of formula R8R9NH. Avoid dialkylamide, it is preferable to protect amines R8NH2or R9NH2a suitable protecting group PTobtaining R8(PT)NH or R9(PT)NH, for example, by reaction with benzaldehyde and a reducing agent. Protected amines are monoalkylammonium using carbonyl compounds in accordance with R9or R8in suitable conditions, reductive amination, resulting in a gain of R8R9N(PT). After removal of the protective group (PT) (e.g., by exhaustive catalytic hydrogenation, if PTis benzyl), obtain the connection formula R8R9NH. Suitable conditions for reductive amination any specialist can be found in the literature. Such conditions are described Borch and others (J. Am.Chem.Soc., 1971, 2897-2904), review papers Emerson (Organic Reaction, Wiley. New York, 1948 (14), 174), Hufchins and others (Org. Prep. Proced. Int. 1979 (11), 20; and Lans etc. (Synthesis 1975, 135). Conditions reductive amination conducive N-monoalkylammonium described Morales and others (Systhetic Communications 1984, 1213-1200) and Ve using R9X or R8X, respectively, where X is chloride, bromide, tosylate or mesilate. Alternatively, the intermediate compound of formula R8(PT)NH or R9(PT)NH may be subjected to alkylation using R9X or R8X with the subsequent removal of the protective group and the formation of compound of formula R8R9NH.

To obtain the amines of the formula R8R9NH, where R8-NH or R9-NH have oxygen-nitrogen bond, can be used other methods. For example, readily accessible compound of formula (C1-C4)alkoxycarbonyl-NHOH or NH2CONHOH are dialkylamino on the nitrogen atom and the oxygen atom by treatment with a base and excess amount of a suitable alkylating agent (R-X), resulting in a gain corresponding (C1-C4) alkoxycarbonyl-N(R)OP, which is then hydrolized, and receive the desired compound having the formula R8R9NH (where R8=R9=R). Suitable conditions for this reaction, the base and the alkylating agents described Jorl & Kroll (org. Prep.Procad. Int. 1987, 19, 75-78) and Major and Fleck (J. Am. Chem. Soc., 1928, 50, 1479).

Alternatively, the amine of the formula NH2CONH(OH) can be alkylated, the CON(R") (OR') by successive treatment with alkylating agents R X and R X, accordingly, in the presence of a suitable base. Suitable base and alkylating agents described Kreutzkamp and Messinger (Chem.Ber. 100, 3463-3465 (1967) and Danen and others (J. Am. Chem. Soc. 1973, 95, 5716-5724). After hydrolysis of these alkyl derivatives of hydroxyacetone get amines R ONH2and R ONHR", which correspond to some of the amines of the formula R8R9NH. Any expert chemist can modify the above method to other alkylating agents R, R' and R"-X in order to obtain other amines of formula R8R9NH, where R8-N or R9-N have kislorod-nitrogen bond. Uno and others (Synlett, 1991, 559-560) describe BF3-catalyzed reaction accession ORGANOMETALLIC reagent R-Li; O-alkylation formula R-CH=N-OR', which receive the compounds of formula R RCH-NH(OR"). This method can also be used to obtain the compounds of formula R8R9NH, where one of R8NH or R9-NH has an oxygen-nitrogen bond.

Proletarienne forms of the compounds of the present invention where a carboxyl group in a carboxylic acid of formula I is replaced by an ester may be obtained by reaction of carboxylic acid with the appropriate alkylhalogenide in the presence of a base, tako the/SUP>C during the period of time from about 1 to about 24 hours. Alternatively, the above acid is subjected to reaction with the corresponding alcohol used as a solvent in the presence of catalytic amount of acid such as concentrated sulfuric acid at a temperature of from about 20oC to 120oC, preferably at the boiling temperature of the solvent, during the period of time from about 1 hour to about 24 hours. Another method involves conducting the reaction of the specified acid with the stoichiometric amount of the alcohol in the presence of catalytic amount of acid in an inert solvent, such as tetrahydrofuran, and with concurrent removal of allocated water physical (for example, using traps Dean-stark) or chemical (for example, using molecular sieves) means.

Proletarienne forms of the compounds of the present invention, in which an alcohol functional group was transformed into the ester group can be obtained by reaction of the alcohol with the appropriate alkylbromides or alkylation in the presence of a base such as potassium carbonate in an inert solvent, such as dimethylformamide, at a temperature of from about 0oC to 100o is to be obtained by the reaction of alcohol with bis-(alkanolamine)methane in the presence of catalytic amount of acid in an inert solvent, such as tetrahydrofuran, in accordance with the method described in U.S. patent 4997984. Alternatively, these compounds can be obtained by the methods described by Hoffman and others in J. Org.Chem. 1994, 59, 3530.

Esters dialkylphosphorous acid (dialkylphosphate) can be obtained by reaction of the alcohol with dialkylphosphate in the presence of a base in an inert solvent, such as tetrahydrofuran. Biphosphate can be obtained by the reaction of alcohol with diaryl - or dibenzylideneacetone, as described above, followed by hydrolysis or hydrogenation in the presence of a catalyst based on a noble metal, respectively.

The glycosides obtained by reaction of an alcohol with carbon in an inert solvent, such as toluene and in the presence of acid. Water, usually formed during the reaction is removed as described above. An alternative method involves conducting the reaction with a suitably protected by glycosylation in the presence of a base and subsequent release.

N-(1-hydroxyalkyl)amides, N-(1-hydroxy-1-(alkoxycarbonyl)methyl)amides, in which R2was replaced by C(OH)C(O)OY, can be obtained by the reaction of the original amide or indole with an appropriate aldehyde is 25-70oC. N-alkoxymethyl or N-1-(alkoxy)alkylidene can be obtained by the reaction of N-unsubstituted indole with the right alkylhalogenide in the presence of a base in an inert solvent. 1-(N, N-dialkylaminomethyl)indole, 1-(1-(N, N-dialkylamino)ethyl)indole and N,N-dialkylaminomethyl (for example, R3=CH2(CH3)2can be obtained by reaction of the starting compound N-H with the appropriate aldehyde and amine in an alcohol solvent at 25-70oC.

The above proletarienne forms (for example, prodrugs of the present invention, in which R2and R3are the common carbon) can be obtained by reaction of the starting compound (drug) with aldehyde or ketone or dimethylacetal in an inert solvent in the presence of catalytic amount of acid, and with concomitant removal of water or methanol. Alternatively, these compounds can be obtained by the reaction of amerosport or hydroxyamide with heme-dibromoethane in the presence of a base (e.g. potassium carbonate) in an inert solvent (e.g. dimethylformamide).

Although getting most of the starting compounds and reagents used in the above reaction schemes is isano in this application, however, all these compounds can be easily obtained by the specialist in accordance with standard methods of organic synthesis. For example, many intermediate compounds used to obtain the compounds of formula I, are related natural amino acids or come from these amino acids, and are of great scientific and commercial interest, and therefore, most of these intermediate compounds are produced by the industry, or are widely described in the literature, or they can be easily obtained from known compounds by methods described in the literature. Such intermediate compounds are, for example, compounds of formula XX, formula XXX, formulas and formulas XXXI XXXII.

The compounds of formula I have asymmetric carbon atoms and therefore can form the enantiomers or diastereomers. Diastereomeric mixtures can be separated by obtaining the individual diastereomers by methods known per se and is based on the physical and chemical differences of these diastereomers, for example by chromatography and/or fractional crystallization. Enantiomers (for example, the compounds of formula III, VIII or IX) can be separated by turning the enantiomeric CME is sleduyushim the separation of these diastereomers and converting (e.g., by hydrolysis) the individual diastereomers to the corresponding pure enantiomers. All of these isomers, including diastereomers, enantiomers and mixtures thereof, are included in the scope of the present invention.

Although many of the compounds of the present invention is not ionized under physiological conditions, however, some compounds of the present invention is an ionisable under physiological conditions. Examples of such an ionisable compounds are acid forms of the compounds of the present invention, which form salts with pharmaceutically acceptable cation. All these salts are included in the scope of the present invention and can be obtained by standard methods. For example, they can be obtained by the interaction of the acidic and basic molecules taken, usually in stereochemical ratio, in an aqueous, anhydrous or partially aqueous medium. These salts can be isolated by filtration, by precipitation of the anhydrous solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, if appropriate.

In addition, some of the compounds of the present invention are basic and can form salts with pharmaceutically Name methods. For example, these salts can be obtained through the interaction of acidic and basic molecules taken, usually in a stoichiometric ratio, in an aqueous, anhydrous or partially aqueous medium. These salts can be isolated by filtration, by precipitation of the anhydrous solvent followed by filtration, evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, if appropriate. In addition, if the compounds of the present invention form a hydrate or a solvate, they are also included in the scope of the present invention.

The usefulness of the compounds of the present invention as therapeutic agents for the treatment of diseases associated with impaired metabolism (described in detail in this application), in mammals (e.g. humans), was confirmed by the activity of these compounds in standard analyses, and in vitro - in vivo assays described below. These analyses can also compare the activity of the compounds of the present invention with the activities of other known compounds. The results of these comparisons were used to determine the dose needed for treatment of mammals, including humans, from these diseases.

Expression and fermentation

HLGP-cDNA was expressed from a plasmid RCC-2 (Pharmacia Biotech. Inc. , Piscataway, New Jersey) strain XL-1 Blue E. coli (Stratagene Cloning Systems, LaJolla, CA). This strain was inoculable in LB-medium (consisting of 10 g of tryptone, 5 g yeast extract, 5 g NaCl, and 1 ml of 1 N. NaOH per liter), to which were added 100 mg/l ampicillin, 100 mg/l pyridoxine and 600 mg/l MnCl2, and were cultured at 37oC up until OP550(optical density at 550 nm) was not equal to 1.0. At this stage, cells induced 1 mm isopropyl-1-thio--D-galactoside (IPTG). Three hours after induction, cells were collected by cetrifugation, and the cell sediment was frozen at -70oC and kept up as long as they do not need to clean.

Purification of glycogen phosphorylase

The cell precipitate obtained as described above, resuspendable 25 mm glycerol (pH 7.0) containing 0.2 mm DTT, 1 mm MgCl2and the following protease inhibitors:

0,7 µg/ml pepstatin A

0.5 μg/ml leupeptin

0.2 mm of phenylmethylsulfonyl (PMSF), and

0.5 mm EDTA.

and literally by pre-treatment with 200 μg/ml lysozyme and 3 µg/ml Gnkazy followed by sonication in 250-millimeter parties within 5 who Saty was purified by centrifugation at 35 000 Hg within 1 hour and then by filtration through a 0.45 µm filter. HLGP in the soluble fraction of lysates (component, as it was estimated that less than 1% of total protein) was purified by permanent monitoring of the enzyme activity (as described below, in the Chapter Analysis for HLGP activity) in the fractions obtained in the course of the chromatography was carried out (for more details see below).

Chromatography-based tool immobilized metal (Immobilized Metal Affinity Chromatography) (IMAC).

This stage is based on the method Zuong and others (Zuong et al., Journal of Chromatography(1992), 584, 77-84). 500 ml filtered soluble fraction of cell lysates (obtained approximately 160 g of the original cell sediment) were loaded into 130 ml IMAC column with chelat forming Separate (Pharmacia LKB Biotechnology, Piscataway, New Jersey), which was loaded with 50 mm CuCl2and 25 mm glycerol, 250 mm NaCl and 1 mm imidazole using equilibrating buffer at pH 7. The column was washed balanced buffer up until A280did not return to its original value (i.e., the background value). Then the sample was suirable column with the same buffer containing 100 mm imidazole to remove associated HLGP and other related proteins. The fractions containing HLGP activity were collected and oblmashininform (PMSF), leupeptin and pepstatin A to obtain a concentration of these compounds: 0.3 mm, 0.2 mm, 0.2 mm, 0.5 μg/ml and 0.7 mg/ml, respectively. Received United HLGP was absoluely on a column of Sephadex G-25 (Sigma Chemical Co. St.Louis, Missoceri), balanced with buffer A (25 mm Tris-HCl, pH 7.3, 3 mm DTT) to remove imidazole and kept on ice prior to the second chromatographic stage.

Chromatography on 5'-AMR-Sepharose

The sample is desalted United HLGH (approximately 600 ml) was mixed with 70 ml of 5'-arm Sepharose (Pharmacia, LKB, Biotechnology, Piscataway, New Jersey, Sepharose), and then balanced with buffer A (see above). The resulting mixture was gently stirring his for 1 hour at 22oC, and then loaded into a column and washed with buffer A until such time as A280did not return to its original value. HLGP and other proteins were suirable column with Buffer B (25 mm Tris-HCl, 0.2 mm DTT and 10 mm adenosine-5-monophosphate (AMR), pH 7.3). HLGP-containing fractions were identified on glucosephosphate activity (as described below) and visually observed band HLGP-protein with Mg- 97 kDa by electrophoresis in polyacrylamide gel with sodium dodecyl sulfate (LTOs-page) followed by silver staining (2D-Silver Stain 11 "Daiichi Kit, Daiichi Pure Chemicals Co. Co., Ltd., Tokyo, Japan), and then merge is to use.

The definition of HLGP-enzymatic activity

A) Activation of HLGP: the Transformation of HLGP in HLGPa

Before defining HLGP-enzymatic activity, inactive form of the enzyme HLGP, expressed in strain XL-1 Blue E. coli indicated HLGPb)(Stratagene Cloning Systems, La Jolla California) is converted into the active form (designated HLGPa) by phosphorylation HLGP using phosphorylase kinase by the method described below.

The reaction HLGPb with immobilized phosphorylase kinase

The phosphorylase kinase (Sigma Chemical Company, St.Zouis, MO) immobilizerpower on the granules Affi-Gel 10 (BioRad Corp., Melvile, NY) according to manufacturer's instructions. For this purpose, the enzyme phosphorylase kinase (10 mg) were incubated with the washed granules Affi-Jel (1 ml) in 2.5 ml of 100 mm HEPES and 80 mm CaCl2at pH 7.4 for 4 hours at 4oC. Then, the pellet was washed once with the same buffer, and then subjected to blocking using 50 mm HEPES and 1 M of ester of glycine at pH 8.0 for 1 hour at room temperature. After that, the blocking buffer was removed and replaced with 50 mm HEPES (pH of 7.4), 1 mm-mercaptoethanol, and 0.2% NaN3for storage. Before conducting the reaction conversion HLGPb in HLGPa, granules Affi-Gel with immobilized phosphorylase kinase balanced by washing in Ei pH 7.8 (buffer for kinase analysis).

Partially purified inactive HLGPb obtained by chromatography on a 5'AMR-Sepharose, as described above, were diluted in the ratio 1:10 buffer for kinase analysis, and then mixed with the above phosphorylase kinase immobilized on the granules Affi-Gel. Then added NaATP to 5 mm MgCl2to 6 mm. The resulting mixture was gently stirring his for 30-60 minutes at 25oC. these pellets were taken the sample and the percentage of activation HLGPb through its transformation into HLGPa was assessed by determining HLGP-enzymatic activity in the absence or in the presence of 3.3 mm AMR. The percentage of full HLGP-enzymatic activity due to enzyme activity HLGPa (AMR-independent), was calculated as follows:

< / BR>
B. Analysis on HLGPa-activity

Hypoglycemic activity (and activity, contributing to the treatment/prevention of other diseases/conditions) of the compounds of the present invention can be directly determined by assessing the effects of compounds of the present invention on the activity of the activated form of glycogen phosphorylase (GPa) using one of two methods: namely, in one method, glycogenolysis activity measured in the forward direction by Pern activity measured in the reverse direction by estimating the synthesis of glycogen from glucose-1-phosphate with release of inorganic phosphate. All reactions were carried out in triple repetition in 96-well tablets and the change in optical density due to the formation of the reaction product, was measured at the wavelength specified below, ELISA reader MCC/340 MK (Lao Systems, Finland) connected to the receiver Fitertech Microplate Stacker (ICN Biomedical Co., Huntsvillc, Alabama).

For measurement of HLGPa enzyme activity in the forward direction, producing glucose-1-phosphate from glycogen was assessed in accordance with the General method of multienzyme binding described Pesce and others (Pesce, M. A., Bodocerian, S. H., Harris, P. C., & Nicholson, J. F.(1977) Clinical Chemistry 23, 1711-1717) and modified as follows: 1-100 µg phosphorylase a 10% phosphoglucomutase and 15 units glucose-6-phosphate-dehydrogenase (Bochringer Mannheim Biochemicals, Indianapolis, IN) diluted to 1 ml in Buffer A (described above). Buffer A (pH of 7.2) containing 50 mm HEPES, 100 mm Kl, 2.5 mm etilenditiodiuksusnoi acid (ECTA), 2.5 mm MgCl23.5 mm KH2PO4and 0.5 mm dithiothreitol. 20 µl of this stock solution was added to 80 μl of Buffer A containing 0,47 mg/ml glycogen, 9.4 mm glucose, 0,63 mm oxidized form of nicotinamide-dinucleotide phosphate (NADP+). Before adding the enzyme, was added compound in the form of 5 ál of solution in 14% of dimethyl sulfoxide (DMSO). N 14% DMSO, and completely inhibited the level of HLGPa enzyme activity was obtained by adding 20 μl of 50 mm caffeine (positive control). Over the course of the reaction taking place at room temperature, followed by evaluation of the conversion of the oxidized NADP+in the restored NADPH at 340 nm.

For measurement of HLGPa enzyme activity in the reverse direction, the conversion of glucose-1-phosphate into glycogen with the release of inorganic phosphate was evaluated in accordance with the General procedure described Engers and others (Engers, H. D., Shechovsky S. & Madsen, N. B. 91970) Can.J.Biochem, 48, 746-754), and modified in the following way: 1 - 100 µg HLGPa was diluted to 1 ml in Buffer B (described above). Buffer B (pH of 7.2) containing 50 mm HEPES, 100 mm KCl, 2.5 mm EGTA, 2.5 mm MgCl2and 0.5 mm dithiothreitol. 20 ál of solution was added to 80 μl of Buffer B containing 1.25 mg/ml glycogen, 9.4 mm glucose, and 0.63 mm glucose-1-phosphate. Before adding the enzyme, was added compound in the form of 5 ál of solution in 14% DMSO. The initial level of HLGPa enzyme activity in the absence of inhibitors was determined by adding 5 μl of 14% DMSO and a fully-inhibited level of HLGPa enzyme activity was obtained by adding 20 μl of 50 mm caffeine. This mixture is incubated in the course is accordance with the General method described by Lanzetta and others (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach & Candia, O. A. (1979) Anal. Biochem. 100, 95-97), and modified as follows: 150 mcg 10 mg/ml ammonium molybdate, 0,38 mg/ml malachite green in 1 N. HCl was added to 100 ál of enzyme mixture. After a 20 minute incubation at room temperature was measured by optical density at 620 nm.

Compounds of the present invention can be readily adapted to clinical use as hypoglycemic agents. The hypoglycemic activity of the compounds of the present invention can be determined by estimating the number of test compounds, contributing to lower glucose levels compared to glucose levels obtained using only filler (without test compound), injected ob/ob-mice-males. This test can also determine the approximate value of the minimum effective dose (MED) for in vivo reduction of glucose concentration in the blood plasma of these mice with the use of the tested compounds.

Since the concentration of glucose in the blood is closely linked with the development of diabetes, these compounds due to their hypoglycemic activity, have the ability to warn, suspend and/or the scientists from the Jackson Laboratory, Bar Harbor, ME) were placed in cages (five animals per cage) in standard conditions that are commonly applied to animals. After a week of acclimatization period, animals were weighed, and before each treatment in mice took the blood (25 μl) of retroorbital cavity. The blood sample was immediately diluted 1:5 with saline containing 0.025% sodium heparin, and kept on ice for analysis of metabolites. Animals were distributed into groups of processing so that each group had the same average concentration of glucose in blood plasma. After dividing into groups, the animals every day for 4 days oral injected dose filler containing either:

1) 0.25% of mass. methylcellulose in water without pH correction; or

2) to 0.1% surfactant, block copolymer PluronicP105 (BASF Corporation, Parsippany, NY) in 0.1% saline without pH correction. On day 5 animals were again weighed, and then was administered oral dose of the test compound or filler. All drugs were injected in the filler consisting of either:

1) of 0.25% wt/vol. methylcellulose in water without pH correction; or 2) 10% DMSO/0.1% of PluronicP105 (BASF Corporation, Parsippany, ny) in 0.1% saline RA is I levels of metabolites in the blood. Freshly harvested samples were centrifuged for two minutes at 10,000 x g at room temperature. The supernatant was analyzed for glucose using, for example, Abbott VPTM(Abbott Laboratiries, Diagnostics Division, Irving, TX) and an automatic analyzer (VP Super SystemAutoanalyzer, Abbott Laboratories, Irving, TX), using the test system of reagents A-GentTMGlucose-UV (Abbott Laboratories, Irving TX) (modification of the method of Richterich & Dauwalder, Schweizerische Medizinische Wochenschrift, 101, 860 (1971)) (hexokinase method), and using 100 mg/DL standard. The level of glucose in the plasma was calculated by the following equation: Glucose in plasma (mg/ml) = Measured value for a given sample x 5 x 1,784 = 8,92 x measured value

x) where 5 is the multiplicity of cultivation, and 1,784 - amendment to hematocrite the number of plasma (which is equal to 44%).

In animals that were injected dose of only one filler, was observed mainly unchanged hyperglycemic glucose levels in the blood (for example, equal to or greater than 250 mg/DL), and in animals that were injected compound in appropriate doses, there was a significant decrease of glucose levels in the blood. The hypoglycemic activity of the tested compounds was determined by statistical analysis (unpaired t-test, With whom, and the group, which was put filler on the 5th day. The above analysis was carried out using a range of doses of the tested compounds, which allowed us to determine the approximate value of the minimum effective dose (MED) for in vivo reduction of glucose concentration in plasma.

Compounds of the present invention can be readily adapted to clinical use as a means of reducing the level of insulin in the blood to normal; as a means of reducing the concentration of triglycerides in the blood, and as hypocholesterolemic funds. Such activity can be determined by estimating the number of test compounds, contributing to lower levels of insulin, triglyceride, or cholesterol in the blood, compared with the control (i.e., the control ob/ob/mice-males injected with a filler without the test compound).

Since the concentration of cholesterol in the blood is closely linked with the development of cardiovascular diseases and circulatory disorders, cerebral and peripheral circulatory system, the compounds of the present invention, due to their hypocholesterolemic activity, can prevent, suspend and/or duration of the stimulation of growth of vascular cells and increase the accumulation of sodium in the kidneys (in addition to all other functions, for example, stimulation of glucose utilization), and these functions are known to lead to the development of hypertension, the compounds of the present invention, due to their hypoinsulinemia action, is able to warn, suspend and/or call back the development of hypertension.

Since the concentration of triglycerides in the blood contributes to the overall level of lipids in the blood, the compounds of the present invention, thanks to their action, resulting in lower levels of triglycerides, is able to warn, suspend and/or call back the development of hyperlipidemia.

Mice male C57BL/6J-ob/ob ages 5 to 8 weeks (obtained from Jackson Laboratory, Bar Harbor, ME) were placed in cages (five animals per cage) in standard conditions, which usually includes animals, and fed ad libitum a standard diet for rodents. After a week of acclimatization period, animals were weighed, and before each treatment, from retroorbital sinus took 25 Microlitre blood. Blood samples were immediately diluted 1: 5 with saline containing 0.025% sodium heparin, and kept on ice for the analysis of glucose in plasma. Animals were distributed into groups of processing so that each ¡gastric probe in the form of approximately 0.02%/ - a 2.0% solution (mass/volume(mass. /about. )) either: 1) 10% DMSO/0.1% of PluronicP105 (surfactant, block copolymer) (BASF Corporation, Parsippany, NY) in 0.1% saline without pH correction; or: 2) of 0.25% (wt./about.) the methylcellulose in water without pH correction. These compounds were administered daily for 1 to 15 days in the form of a single dose (s.i.d.), or in divided doses twice a day (b. i. d. ). Control mice received 10% DMSO/0.1% of PluronicP105 in 0.1% saline without pH correction, or up to 0.25% (wt./about.) methylcellulose in water without pH correction.

Three hours after the last dose, mice were killed by decapetala (decapitation), and blood was collected in 0.5-ml tubes separator to separate the serum containing 3.6 mg of a mixture of sodium fluoride and potassium oxalate (1:1 wt./mass.). Freshly harvested samples were centrifuged for two minutes at 10,000 x g at room temperature, and the serum supernatant was collected and diluted (1:1 vol./about.) 1 TME/ml (TME - international tuberculin units) of a solution of Aprotinin in 0.1% saline without pH correction.

Diluted plasma samples were stored at -80oC before use in assays. After thawing, divorced crank was determined using sets EquateP1A INSULIN (in accordance with the method of double antibody as described by the manufacturer), which were purchased from a company Binax, South Portland, ME. The coefficient of variation for a series of tests was 10%. The level of triglycerides in serum were determined using an automatic analyzer Abbott VPTMand VP Super SystemAutoanalyzer (Abbott Laboratories, Irving, TX) and the test system of reagents A-GentTMTriglycerides Test reagent System (Abbott Laboratories, Diagnostics Division, Irving, TX) (immunoassay method using lipase: a modification of the method of Sampson (Sampson et al., Clinical Chemistry 21. 1983 (1975). The level of total cholesterol in serum were determined using an automatic analyzer Abbott VPTMand VP Super SystemRAutoanalyzer (Abbott Laboratories, Irving TX) and the test system of reagents A-JentTMCholesterol Test reagent System (enzyme Immunoassay method using cholesterylester; modification of the method of Allen (Allain, et al., Clinical Chemistry 20, 470 (1974)), using 100 and 300 mg/DL standards. Levels of insulin, triglycerides, and total cholesterol in serum was calculated by the following equation:

Insulin levels in serum (MCAD./ml)=Measured value for a given sample x 2

The level of triglycerides in serum (mg/DL) = measured value for a given sample x 2

The level is ASS="ptx2">

In animals that were administered doses of a single filler was observed largely constant elevated levels of insulin (e.g., 225 MCAD), triglyceride levels (for example, 225 mg/DL) and the levels of total cholesterol (for example, 160 mg/DL) in serum, whereas in animals treated with compounds of the present invention, it was observed a reduction in serum levels of insulin, triglycerides and total cholesterol. The activity of the compounds of the present invention, aimed at reducing serum levels of insulin, triglycerides and total cholesterol were determined using statistical analysis (unpaired t-student test) average concentrations of insulin, triglycerides, or total cholesterol in serum by comparing the results obtained for the group treated with test compounds and the control group treated with only one filler.

The activity of the compounds of the present invention, aimed at protecting cardiac tissue from damage that can be demonstrated in vitro using the methods proposed in Butwell, etc. (Am.J.Physiol., 264, H1884-H1889, 1993) and Allard and others (Am.J.Physiol., 1994, 267, H66-H74). The experiments were carried out using isochoric preparations of the heart in rats, obtained by Kia, induced by operations with blocks of the aorta; male rats BB/W with rapidly progressive diabetes; or control rats appropriate age (BB/W), without diabetes, previously treated with heparin (1000 units, i.p.), and then pentobarbital (65 mg/kg, i.p.). After the rats of the state of deep anesthesia (determined by the reflex of the limb), the heart was rapidly dissected and placed in ice saline. Within 2 minutes, the heart was subjected to retrograde perfusion through the aorta. Heart rate and intraventricular pressure was determined using in the left ventricle latex balloon with high-pressure hose connected to the pressure sensor. Perfusion of the heart was performed perfusion solution containing 118 mm NaCl, of 4.7 mm KCl, 1.2 mm MgCl2, 1.2 mm CaCl2, 25 mm NaHCO3, 11 mm glucose. The perfusion apparatus was equipped with a heated bath for direct temperature control of the perfusion solution and water, circulating around perfusion of the hose to maintain the temperature of the heart 37oC. oxygenation of the perfusion solution was performed using the pediatric fiber oxygenator (Capiax, Terumo Corp., Tokyo, Japan) in close proximity to the heart is more, then, within 20 minutes, hearts were subjected to global ischemia, and after that, within 60 minutes has been reperfusion in the absence of the test compound. Heart rate control and for hearts treated with the test compound compared over a period of time after ischemia. In addition, for a period of time after ischemia compared the pressure inside the left ventricle to control hearts and hearts treated with the test compound. At the end of the experiment, hearts were subjected to perfusion and staining to determine the level infarction areas in relation to risk areas (% 1A/AAP), as described below.

therapeutic effect of the compounds of the present invention, contributing to the prevention of damage to the heart tissue resulting from ischemic circulatory disorders, can also be demonstrated in vivo in accordance with the method proposed by Liu and others (Circulation Vol. 84, No. 1 (July 1991)) and is described below. In this in vivo analysis was performed tests of the compounds of the present invention for their ability to protect the heart tissue compared with the control group, which was introduced filler (physiological solution). As basic information should be noted is it the heart against subsequent severe myocardial ischemia (Murry et al., Circulation 74:1124-1136, 1986). Protection of cardiac tissue, defined as the reduction in areas of myocardial tissue that is prone to necrosis (infarction), can be induced pharmacologically by the intravenous administration of agonists of the adenosine receptor intact shot rabbits, studied as an in situ model for the preliminary preparation of experiments for the study of myocardial ischemia (Liu et al. Circulation 84: 350-356, 1991). In this in vivo experiment conducted research on the ability of the compounds to provide pharmacological protection of cardiac tissue, i.e., the ability of these compounds to reduce areas of myocardial infarction in injecting intact shot rabbits. These compounds can then be compared with the results obtained for rabbits with pre-ischemic training using agonist adenosine Al, N6-1-(phenyl-2P-isopropyl)adenosine (P1A), which, as shown, provides pharmacological protection of cardiac tissue in the intact shot rabbits studied in situ (Liu et al., Circulation 84: 350-356, 1991). The exact methodology of this experiment are described below.

Surgery: Male new Zealand white rabbits (3-4 kg) were anestesiologi sodium pentiumiii artificial lung ventilation with 100% oxygen using artificial ventilation with positive pressure. For the introduction of drugs into the left jugular vein is injected with a catheter in the left carotid artery is injected with a catheter for measuring blood pressure. Then the heart was exposed through a left thoracotomy, and the overhanging branch of the left coronary artery wore loop (silk OO). Ischemia was induced by tight tighten the loop and its fastening clip. For reperfusion of the affected area of the loop was released. Myocardial ischemia is characterized by regional cyanosis; and reperfusion is characterized restored hyperemia.

Protocol: the Experiment was started after stabilization of blood pressure and heart rate for at least 30 minutes. Pre-ischemic state induced by double occlusion (perimene) coronary artery for 5 minutes followed by reperfusion for 10 minutes. Prior pharmacological treatment was carried out by the double influence of the test compounds, for example, within 5 minutes with a break for 10 minutes before the second injection, or by infusion of the agonist adenosine P1A (0.25 mg/kg). After induction of ischemic status, preliminary pharmacological treatment or Otsu then subjected to reperfusion for two hours to induce myocardial infarction. Test the connection and P1A was dissolved in saline or other suitable filler and was administered at a dose of 1 to 5 ml/kg, respectively.

Staining: (Liu et al., Circulation 84:350-356, 1991): after a 2-hour reperfusion period, the hearts were rapidly removed, hung on the apparatus Langendorf, and within 1 min, washed in a strong stream of normal saline warmed to body temperature (38oC). Then a loop (of silk, used for surgical sutures) tight delayed for re-occlusion of the artery and perfusion solution was poured a 0.5% suspension of fluorescent particles (1 µm and 10 µm) for staining of the entire myocardium except risk areas (afluorescent ventricle). Then the hearts were rapidly frozen and stored overnight at -20oC. the next day, the heart was cut into 2-ml environments, and these environments were stained with 1% chloride triphenyltetrazolium (IDT). Since TTC reacts with live tissue, this painting allows vivid fabric (dyed red) from dead tissue (unstained tissue, subjected to a heart attack). Infarction zone (unpainted) and risk zones (no fluorescent particles) was calculated for each of the implementation data of ischemic damage due to differences in risk areas have different hearts, these data were expressed as the ratio of the areas damaged by the heart attack, the risk zone (% 1A/AAP). All data represent average values of the average square deviation; however, the comparison was performed using one-way ANOVA ANOVA or unpaired t-student test. Statistical significance was p < 0,05.

Introduction compounds of the present invention can be carried out by any method that ensures the delivery of these compounds is preferably in the tissue of the liver and/or heart. Such methods are oral, parenteral, intraduodenal introduction, etc. Usually, the compounds of the present invention is administered in the form of a single (e.g., once daily) dose or in divided doses.

However, it is obvious that the number and mode of administration of the compounds of the present invention depends on the specific disease/condition, from a particular individual undergoing treatment, the severity of the condition, the route of administration and from the doctor's appointment. Thus, depending on the individuality of each patient, the doctor may adjust the dose of the medication to achieve the desired activity (e.g., activehome of the desired degree of activity, the attending physician must take into account such factors as the initial level, other risk factors (cardiovascular factors), the presence of previous diseases, age and complaints of the patient.

Basically, the effective dose to achieve the desired activity of the compounds of the present invention, aimed, for example, to decrease the levels of glucose, triglycerides, cholesterol and insulin in the blood is in the range of 0.005-50 mg/kg/day, preferably from 0.01 to 25 mg/kg/day, and most preferably from 0.1 to 15 mg/kg/day.

Compounds of the present invention are primarily designed for oral administration, but in some cases, can also be used parenteral (e.g. intravenous, intramuscular, subcutaneous or intramedullary (in bone marrow), for example, in cases where oral administration is not acceptable for this specific purpose, or when the patient is unable to swallow the drug. The compound of the present invention may be introduced by local applications, for example, in cases where the patient suffers from gastro-intestinal disorders, or in those cases where in the opinion of the physician, the best effect can be achieved of Palpatine is usually administered in the form of pharmaceutical compositions containing at least one of the compounds of the present invention in combination with a pharmaceutically acceptable excipient or diluent. Thus, the compounds of the present invention can be introduced separately or in a mixture as a standard oral or parenteral dosage forms, either as a dosage form for intradermal injection.

Pharmaceutical composition for oral administration can be produced in the form of solutions, suspensions, tablets, pills, capsules, powders, etc. Tablets, in addition to various excipients such as sodium citrate, calcium carbonate and calcium phosphate may contain various dezintegriruetsja agents, such as starch, preferably potato or manioc starch; some silicate complexes; binding agents such as polyvinylpyrrolidone, sugar, gelatin and Arabic gum. In addition, in the manufacture of tablets are often used lubricating agents such as magnesium stearate,

sodium lauryl sulfate, and talc. Solid compositions of a similar type may also be used to perform soft and hard gelatin capsules; preferred materials in this case is about the introduction of the used aqueous suspensions and/or elixirs, in this case, the compounds of the present invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspendresume agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For parenteral administration, can be used solutions in sesame or peanut oil or in aqueous propylene glycol; and sterile water solutions of the corresponding water-soluble salts. If necessary, the aqueous solutions may be buffered, and the liquid diluent give isotonicity with sufficient saline or glucose. Such aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, it should be noted that sterile aqueous solutions can be easily obtained in accordance with standard methods well known to specialists.

For intradermal injection (for example, for external application) can be used diluted with sterile aqueous or partially aqueous solutions (usually in a concentration of about 0.1 - ticheskih compositions with a certain amount of the active ingredient is well known in the art and can be easily carried out, based on the above description. See, for example, Remington''s Pharmaceutical science, Mack Publishing Company, baster. PA. 15th Edition (1975).

The pharmaceutical compositions of the present invention may contain 0.1 to 95% of the compound (or compounds) of the present invention, and preferably 1 to 70% of the specified connection. In any case, the input composition or product must contain this number of compounds (compounds) of the present invention, which is effective for the treatment of the disease/condition, in particular, glycogenolysis-dependent disease/condition.

Methods

NMR spectra were obtained on a spectrometer Varian X1 - 300 (Varian Co., Palo Alto, Calif.) or Boucker AM-330 (Boucker. Billerics Massachusetts) at around 23oC and at 300 MHz for proton and 75.4 MHz for carbon nuclei. Chemical shifts were measured relative to trimethylsilane and expressed in ppm. Resonances, defined as the exchange was not observed in a separate NMR experiments, where the sample was shaken with a few drops of D2About in the same solvent. Mass-spectroscopy by fast atom bombardment (FAB-MS) was performed on the spectrometer VG70-2505 (V4 Analytical D., Wythanshaw, Manchester, UK) using the m electron impact (TSPMS) was performed on the spectrometer (Fisons Trio - 1000 (Fisons Co., Valencia California) using ionization of ammonia. Mass spectra with chemical ionization were obtained using the device Hewlett-Packard 5989 (Hewlett-Packard Co. , Palo Alto, California) (the ionization of ammonia, PBMS). Where describes the intensity of the chlorine - or bromine-containing ions, observed the expected level of intensity (approximately 3:135Cl/37Cl - containing ions and 1:1 for79Br/81Br - containing ions, in this case, intensity data are given only for ions with smaller mass.

GHUR carried out with detection at 214 nm on a C-18-column (250 x 4.6 mm) Rainin Microsord (Rainin Co., Woburn, Massachusetts) using a system with two pumps/mixers for isocratic elution with a mixture of acetonitrile and water with 0.1 M KH2PO4(pH 2,1, H3PO4) at a flow rate of 1.5 ml/min, the Samples were introduced into the mixture (1:1) acetonitrile and phosphate buffer pH 7.0 (0.025 M in each of Na2HPO4and KH2PO4). The percentage purity refers to the percentage complete of the total area within a 10-15 minute run. The melting point was not correct and was determined on the device Buchi 510 (Buchi Laboratorums-Technic AO., Jlawi, Switzerland), which were obtained of melting point 120 - 122oC for benzoic acid and 237,5o- to 240.5oC for p-chlorobenzoyl the D Vision, W. P. Grace & Co., Beverly, Mass. ) in glass columns under low nitrogen pressure. Unless specifically indicated, were used reagents obtained from commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran, and dichloromethane is used as the reaction solvents were anhydrous and delivered by the company Aldrich Chemical Company (Milwaukee, Wisconson). The analyses were carried out laboratory Schwartzkopf Microanalytical Laboratory, Woodside, NY. The terms "concentrated" and "together evaporated" refer to removal of solvent using vacuum evaporation rotary evaporator with a bath temperature of less than 45oC.

Method A (Peptide synthesis using DEC)

0.1-0.7 M solution of the primary amine (1.0 EQ. or hydrochloride primary amine, and 1.0-1.3 EQ. triethylamine one EQ. HCl) in dichloromethane (unless specifically indicated) was sequentially treated at 25oC of 0.95 to 1.2 equivalents specified carboxylic acid, 1,2-1,8 equivalents of hydroxybenzotriazole hydrate (typically 1.5 EQ. in relation to the carboxylic acid) and 0.95 to 1.2 equivalents (molar ratio to the carboxylic acid) 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride (DEC), and the mixture was stirred for 1. ), after which the organic layer was dried over MgSO4concentrated, and then purified by chromatography on silica gel, trituration or recrystallization using the specified solvents. Purified products were analyzed with the help OF GHUR, which confirmed the purity of the product is more than 95%, unless specifically indicated. Changes in the method A, if available, are listed separately below. The reaction was carried out at 0-25oC with the initial cooling of the vessel in an isolated ice bath, which allowed to leave the mixture for several hours to heat it to room temperature.

Note 1: When large-scale reactions (> 50 ml solvent) and the mixture was concentrated at this stage, and the residue was dissolved in ethyl acetate.

Note 2: If the product contains an ionisable functional amino group, leaching acid did not.

Example 1

(3S)-[(5-chloro-1H-indole-2-carbonyl)amino]-(2R)-hydroxy-4 - phenylalkanoic acid isopropyl ester.

To a solution containing (3S)-amino-4-phenyl-(2R)- hydroxybutiric acid isopropyl ester (1.35 g, is 4.93 mm) 5-chloro-1H-indole-2-carboxylic acid (1.06 g, 5.4 mm), and the hydrate of 1-hydroxybenzotriazole (1,carbodiimide hydrochloride (DEC, 1,03 g, 5,38 mm). The resulting mixture was stirred for 18 hours at a temperature of 25oC, and then diluted with ethyl acetate, after which the resulting solution was twice washed 2 N. sodium hydroxide and twice washed 2 N. hydrochloric acid. Then the solution was dried with magnesium sulfate and concentrated. The residue was chromatographically 112 g of silica using as eluent first ethyl acetate/hexane (1: 4, 1.5 l), and then ethyl acetate/hexane (1:3), resulting in a received target connection. Yield: 91%; VRIJ (70/30): 5,69 minutes (78%) and 21.5 minutes (19%). TSPMS 415/417 (MH+, 100%).

1H-NMR (CDCl3) : 9,7 (s, 1H), EUR 7.57 (d, 1H, J=2 Hz), 7,38-to 7.18 (m, 7-8H), 6.73 x (d, 1H, J = CA. 2 Hz), to 6.57 (d, 1H, J=9.7 Hz) 5,04 (septet, 1H, J= 6.3 Hz), a 4.83 (m, 1H), 4,19 (DD, 1H, J=2 Hz), 3,51 (d, 1H, J=3.6 Hz), 3,05 (m, 2H), by 1.17 (d, 3H, J=6.3 Hz), is 1.11 (d, 3H, J=6.3 Hz). Also attended approximately 15% of another substance, which is preferably N, O-bis(5-chloro-1H-indole-2-carbonylbis derived): D. (frequency): 9,80 (s, 1H), 5,28 (DD, 1H, indole-CO2CH).

Example 1A

3(S), 2(R)-3-Amino-2-hydroxy-4-phenylalkanoic acid isopropyl ester

A solution of 3(S), 2(R)-N-[(1,1-dimethylmethoxy)carbonyl] -3-amino-2 - hydroxy-4-phenylbutyramide (Parris et al. , Biochemistry 1992, 31, 8125-8141 (252 g, 0,912 M)) in anhydrous 2-propanol (6 l) treatment is 20 hours at a temperature of 25oC (protected from the weather by a tube with desiccant Drierit). After adding another 348 g of anhydrous hydrogen chloride at a temperature of less than 10oC, the mixture was stirred for 72 hours at a temperature of 25oC. the resulting mixture was concentrated and the resulting residue was dissolved in 0.1 N. hydrochloric acid. After standing for one hour at a temperature of 25oC, this solution was extracted with ether (3 x 1 l) and the aqueous layer was brought to pH 12 by addition of 6 n sodium hydroxide (about 450 ml). The resulting suspension was extracted with ethyl acetate (4 x 1 l), after which the extracts were washed with water (500 ml) and brine (500 ml), then dried and concentrated, resulting in a received 177 g of yellow solid. This solid was dissolved in boiling isopropyl ether (2 liters) was filtered in hot state and then concentrated by boiling to a volume of 1.4 liters. Formed after cooling down, the solid was collected by filtration, washed with cold isopropyl ether and was dried (107 g). The second collection (12.2 g) was obtained from the mother liquor. Solid collection was obtained by chromatographytandem concentrated mother solutions on silica gel (gradient 2-propanol,6 g, 57%), so pl. 106-109oC;

1H-NMR (CDCl3) : 7,35 to 7.2 (m, 5H), 5,11 (septet, 1H, J=6.2 Hz), 4,01 (d, 1H, J=2.2 Hz), 3,30 (DDD, 1H), 2.91 in (A of AB, 1H, J=6.3 and 13.3 Hz), 2,71 (B of AB, 1H, J=8.5 and 13.3 Hz), 1.8 m (W, 2-3H), of 1.25 (d, 6H, J=6.2 Hz), TSP-MS: 238 (MH+).

Example 2

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)- hydroxy-3-(4-methyl-piperazine-1-yl)-3-oxo-propyl]-amide hydrochloride

The dihydrochloride of (3S)-amino(2R)-hydroxy-1-(4-methylpiperazin - 1-yl)-4-phenyl-butane-1-she (0.25 mm) and 5-chloro-1H-indole-2-carboxylic acid (0.30 mm) was subjected to the reaction of interaction in accordance with method A, after which the product was purified by chromatography on silica gel, using as eluent 0.5 to 8% ethanol in dichloromethane, the resulting target compound (42% yield). This connection, together with a less polar compound (13%) was analyzed by NMR, which indicated the similarity of the obtained compound with N,O-bis(5-chloro-1H-indole-2-carbonylbis derived). Target the more polar compound (48 mg) was dissolved in a mixture of methanol and 0.25 ml of 1 N. hydrochloric acid, and then, the resulting solution was concentrated, and the resulting solid triturated with ether, the result of which was obtained 42 mg of the desired product; VRIJ (70/30), 2,53 min (80%), of 4.04 min (13%), and the military, as explained above.

1H-NMR (D2O) : of 7.70 (s, 1H), 7.5 to about 7.2 (m, 7H), 7,05 (s, 1H), 4,57 (m, 1H), 4,47 (m, 1H), Android 4.04 (m, 1H), to 3.58 (m, 4H), to 3.34 (m, 4-5H), 2,97 (s, 1.5 H), 2,97 (s, 1.5 H), 2.91 in (s, 1.5 H).

PBMC: 455/457 (MH+, 100%).

Example 2A

(3S)-Amino-(2R)-hydroxy-1-(4-methyl-piperazine-1-yl)-4 - phenylbutane-1-it dihydrochloride

[(1S)-Benzyl-(2R)-hydroxy-3-(4-methyl-piperazine-1-yl)- 3-oxo-propyl]-carbamino acid tert-butyl ester (0,190 g, 0.5 mm) was dissolved in 4 M of the mixture of hydrochloric acid - dioxane at a temperature of 25oC for 0.5 hours. The mixture was concentrated, and the residue triturated with ether, and then dried. Output: 212 mg, VRIJ (15/85) to 2.85 min; PB-MC 278 (MH+, 100%).

Example 2B

[(1S)-Benzyl-(2R)-hydroxy-3-(4-methyl-piperazine-1-yl)-3 - oxopropyl] -carbamino acid tert-butyl ester

N-Methylpiperazine (75 mg, 0.75 mm) and (2R, 3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylalanyl acid (0.200 g, 0.68 mm) was subjected to the reaction of interaction in accordance with method A, which was obtained a colorless foam, which was used without purification. Yield: 225 mg (88%); PB-MS: 378 (MH+, 100%).

Example 3

5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R)- hydroxymethyluracil-methyl)-2-phenyl-ethyl-amide

Hydrochlo the Ali response interaction in accordance with method A (using DMF, when 0-25oC), and the crude product was purified by chromatography on silica gel (eluent: 1-8% ethanol in dichloromethane and 0.5 % ammonium hydroxide), resulting in a received target connection. Yield: 82%; VRIJ (70/30), to 3.09 min (98%); PB-MC 386/388 (MH+, 100%).

Analysis for C20H20ClN3O3+ 0,25 H2O;

Calculated: C 61,54; H of 5.29; N 10,76;

Found: C 61,17; H 5,63; N 10,83.

Example 4

(3S)-[(5-Fluorescent-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy - 4-phenylalkanoic acid methyl ester

(3S)-Amino-(2R)-hydroxy-4-phenylalkanoic acid methyl ester (0.8 mm, WO 9325574 Example 1A) and 5-fluorescent-1H-indole-2-carboxylic acid (0.8 mm) was subjected to the reaction of interaction in accordance with procedure A (0-25oC and extraction with acid, then base) and the crude product was purified by trituration with ether; Yield = 71%, VRIJ (60/40), 4,51 min (98%), so pl. to 219.5-210oC, PBMC: 371 (MH+100%).

Analysis for C20H19FN2O4+ 0,25 H2O;

Calculated: C 64,08; H 5,27; N 7,44;

Found: C 64,14; H And 5.30; N Of 7.48.

Example 5

(3S) [(5-Bromo-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4 - phenylalkanoic acid methyl ester

(3S)-Amino-(2R)-hydroxy-4-phenylalkanoic reaction interaction in accordance with Method A (except the temperature was 0-25oC). The crude product containing 25% N,O-bis-acylated compound (URGH-analysis) was used in subsequent reactions without further purification; Yield = 97%, VRIJ (70/30), a 4.03 min (73%), and 11.8 min (25%). Sample triturated with ether/hexane to identify and biological testing: URGH (70/30) is 4.03 min (94%), of 11.7 min (4%), FAB-MC 431/433 (MH+, 35%), 307 (100%).

1H-NMR (CDCl3) : 9,31 (width, 1H), of 7.75 (d, 1H, J=CA. 2 Hz), 7,35-7,20 (m, 7H), was 6.73 (d, 1H, J=1.6 Hz), 6,47 (d, 1H, J=9.6 Hz), 4,80 (m, 1H), 4,21 (DD, 1H, J=2.5 Hz), and 3.72 (s, 3H), 3.33 and (d, 1H, J=4 Hz), 3,06 (m, 2H).

Analysis for C20H19BrN2O4:

Calculated: C 55,70; H of 4.44; N 6,50;

Found: C 56,12; H To 4.62; N 6,16.

Example 6

5-Fluorescent-1H-indole-2-carboxylic acid [(1S)-((R)- dimethylcarbamoyl-hydroxy-methyl)-2-phenyl-ethyl]-amide

Hydrochloride, dimethylamine (0,52 mm) and (3R)-[(5-fluorescent-1H-indole-2-carbonyl)-amino] -(2S)-hydroxy-4-phenylalanyl acid (0,43 mm) was subjected to the reaction of interaction in accordance with Method A (except that the temperature was 0-25oC). The crude product was dissolved in dichloromethane, after which the resulting solution was stirred for one hour with approximately 200 mg of the mixture of dimethylaminopyridine/polystyrene resins (de colorless solid: Yield = 62%, URGH (60/40), 4,15 min (97%), so pl. 213-214oC; TSP-MS: 384 (MH+, 100%).

Analysis for C21H22FN3O3:

Calculated: C 65,78; H 5,78; N 10,96;

Found: C 65,89; H 6,16; N 11,00.

Example 7.

5-Bromo-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl}-amide

(3S)-Amino-(2R)-hydroxy-N-methoxy-N-methyl-4-phenyl-butyramide hydrochloride (0.36 mm) and 3-[(5-bromo-1H-indole-2-carbonyl)-amino]-2-hydroxy-4-phenylalanyl acid (0.36 mm) was subjected to the reaction of interaction in accordance with Method A, and then, the crude product was purified by chromatography on silica gel (eluent: 30% - 40% mixture of ethyl acetate/hexane) and by rubbing with a mixture of ether/hexane (1:1). Yield: 65%, VRIJ (60/40), 5,77 min (100%); PB-MS 460/462 (MN+, 90%).

Analysis for C21H22BrN3O4:

Calculated: C 54,79; H 4,82; N 9,13;

Found: C 54,88; H 5,22; N 8,83.

Example 8

5-Chloro-3-methyl-1H-indole-2-carboxylic acid [(1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl]-amide

(3S)-Amino-(2R)-hydroxy-N-methoxy-N-methyl-4-phenylbutyramide hydrochloride (0.3 mm) and 5-chloro-3-methyl-1H-indole-2-carboxylic acid (0.3 mm) was subjected to the reaction of interaction in accordance with method A, and UP>, 100/40%).

1H-NMR (CDCl3) : 8,98 (width, 1H), 7,56 (d, 1H, J=2 Hz), between 7.4 to 7.15 (m, 7H), 6.35mm (d, 1H, J = 9 Hz), of 4.95 (m, 1H), 4,32 (d, 1H, J=5,1 Hz), 3,81 (d, 1H, J= 5 Hz) to 3.36 (s, 3H), 3.15 in (s, 3H), 3.15 in (DD, 1H), 3,03 (DD, 1H, J= 13,16 Hz), of 2.51 (s, 3H).

Analysis for C22H24ClN3O4:

Calculated: C 61,46; H 5,63; N 9,77;

Found: C 61,13; H Of 5.53; N 9,74.

Example 8A

5-Chloro-3-methyl-1H-indole-2-carboxylic acid

To a suspension consisting of complex ethyl ester 5-chloro-3-methyl-1H-indole-2-carboxylic acid (7.0 g, 29,4 mm) and methanol (50 ml), was added 20 ml of 2 n sodium hydroxide, and the resulting mixture was stirred for 18 hours at a temperature of 25oC. After adding 100 ml of tetrahydrofuran, the resulting solution was heated under reflux for 30 minutes and concentrated. The residue was dissolved in water and the resulting solution was extracted twice with ethyl acetate. The aqueous layer was acidified, and then the precipitate was collected by filtration and washed with water (5,24 g).

Example 8B

5-Chloro-3-methyl-1H-indole-2-carboxylic acid ethyl ester

p-Chlorophenylhydrazone ethyl-2-oxobutanoate was obtained by a modification reaction of the Japp-Klingemann described Lions & Hughes (J. Proc. Roy. Soc. N. S. Wales 1939.71: 445) to obtain the p-Chloroaniline and ethyl-2-utilize Lions & Heghes (J. Proc. Roy. Soc. N. S. Wales 1939, 71: 445 to obtain the corresponding bromophenylacetate. After the concentrated suspension of the residue in water, the target compound as an orange solid substance was collected by filtration.

Example 8C

(3S)-Amino-(2R)-hydroxy-N-methoxy-N-methyl-4-phenyl-butyramide hydrochloride 31055-274-2.31055-85-1

(1S)-[(R)-Hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-methyl-phenyl-ethyl]- carbamino acid tert-butyl ester (791 mg, 2.3 mm) was dissolved in 4 M HCl/dioxane for 45 minutes at a temperature of 25oC, and then, the solution was concentrated. The residue is evaporated with ether, suspended in ether and filtered, resulting in a received 583 mg (91%) of the target product.

Example 8

{ (1S)-[(R)-Hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl] -carbamino acid complex tert-butyl ether

(3S)-tert-Butoxycarbonylamino-(2R)-hydroxy-4-phenylmethanol acid (10,06 g, 34,1 mm; Schweizerhalls, Inc., S,Plainfield, N. J.) and N,O-dimethylhydroxylamine hydrochloride (3,49 g, 35.7 mm) was subjected to the reaction of interaction in accordance with procedure A and the crude product (10.7 g) was purified by chromatography on silica gel (eluent: 25-50% ethyl acetate/hexane), resulting in the received TS is Dol-2-carbonyl)-amino]-(2R)-hydroxy-4 - phenylalkanoic acid methyl ester

(3S)-Amino-(2R)-hydroxy-4-phenylalkanoic acid methyl ester (1.2 mm) and 5,6-sodium dichloro-1H-indole-2-carboxylic acid (1.2 mm) was subjected to the reaction of interaction in accordance with method A (reaction time = 72 hours), and the obtained product was purified by chromatography on silica (eluent: 20-40% ethyl acetate/hexane). Yield 52%;

so pl. 198-202oC; TSP-MC 421/423 (MN+, 100%).

Analysis for C20H18Cl N2O4+ 0,25 H2O:

Calculated: C 56,42; H to 4.38; N TO 6.58;

Found: C 56,25; H 4,17; N 6,58.

Example 9A

5,6-sodium dichloro-1H-indole-2-carboxylic acid

The hot solution of 3,4-sodium dichloro-5-nitrophenylpyruvic acid (1.5 g, 5.4 mm) in acetic acid (15 ml) was slowly added zinc dust (3,52 g 54 mm). After a few minutes they were in a strong exothermic reaction. After heating the solution to 80oC, the reaction was completed, as evidenced by TLC analysis. The resulting mixture was filtered and then the filtered solids were washed with acetic acid, and the filtrate was concentrated. The residue was dissolved in 2N NaOH and the resulting solution was three times washed with ether, twice with dichloromethane and acidified to pH 1 by adding 6N hydrochloric acid. After extradinary in the form of a light brown solid. URGH (60/40), 5,31 min (93%).

Example 9B

3,4-sodium dichloro-5-nitrophenylpyruvic acid potassium salt

To a stirred mixture consisting of metallic potassium (2.67 g, 68 mm) and ether (100 ml), was added 25 ml of absolute ethanol at a temperature of 3-15oC. the resulting solution was treated at a temperature of 3oC solution diethyloxalate (10.0 g, 62 mm) in 2-methyl-3,4-sodium dichloro-1-nitrobenzene (10.0 g, 62 mm) for 5-10 minutes and then the solution was stirred for 30 minutes at 3oC and for 18 hours at 25oC. the resulting mixture was filtered, and the resulting solid was washed with ether, and dried (13,7 g). 12.7 g of the obtained substance was dissolved in 400 ml of hot water, and then, the solution was cooled and was extracted with ether. Then, the aqueous layer was acidified to pH 2 by adding concentrated hydrochloric acid, and the ether layer was separated, dried and concentrated, to obtain 7.5 g of solid, which was washed with hexane, and received the target compound as yellow solid (7.01 g, 41%).

Example 10

5-Cyano-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl}-amide

(3S)-Amino-(2R)-hydroxy-N-methoxy-N-methyl-4-phenyl-butyramide hydroch what codici A (reaction time = 5 days). The crude product was dissolved in methanol containing 1.0 equivalent of 1N NaOH at 25oC for 45 minutes and then concentrated. The residue was dissolved in ethyl acetate, after which the solution was washed twice 2N hydrochloric acid and twice 2N sodium hydroxide, and then dried and concentrated. The obtained residue was chromatographically on silica gel, using as eluent a mixture of hexane/ethyl acetate (20-25%). The purified product was rubbed with a mixture of ether/hexane (1: 1) and received the target connection. Yield: 66%, VRIJ (60/40); 3.9 minutes (100%), so pl. 210-211oC; RVM: 407 (MN+100%).

1H-NMR (CDCl3) : 9,83 (width, 1H), of 7.97 (s,1H), 7,46 (m, 2H), was 7.36 (m, 4H), to 6.88 (d, 1H, J=2 Hz), 6,56 (d, 1H, J=10 Hz), of 4.95 (m, 1H), 4,32 (d,1H, J=5.5 Hz), 3,83 (d, 1H, J=5.4 Hz), to 3.36 (s, 3H), of 3.13 (s, 3H), 3,10 (m, 2H).

Analysis for C22H22N4O4:

Calculated: C 65,01; H 5,46; N 13,78;

Found: C 64,92; H Ceiling Of 5.60; N 13,78.

Example 10A

5-Cyano-1H-indole-2-carboxylic acid

To a solution containing ethanol (10 ml) and potassium hydroxide (2 g) was added complicated ethyl ester 5-cyano-1H-indole-2-carboxylic acid (1,71 g, 8.0 mm), and the resulting mixture was heated under reflux for one hour. To dissolve the precipitate, to the mixture was added water, and the pH was brought to 1 dobavlyali, and the resulting colourless solid was washed with cold water and dried (1.51 g). A portion (1.4 g) of this substance suspended in hot acetic acid (40 ml) and cooled, resulting in the obtained solid substance was filtered off, washed with cold ethyl acetate and dried. Output: 980 mg (70%); VRIJ (60/40) 3.09 minutes (97%).

Example 10B

5-Cyano-1H-indole-2-carboxylic acid complex ethyl ester

The hot suspension containing complex ethyl ester of 3-cyano-5-nitrophenylpyruvic acid (23,2 g, 88 mm) in acetic acid (225 ml) and water (225 ml) was added zinc dust (of 57.8 g, 887 mm) (Attention! occurs exothermic reaction) so as to maintain the reflux, and then the reaction mixture was heated under reflux for half an hour. After filtration of the mixture, filtered salt was washed with 150 liters of hot acetic acid and the filtrate was cooled overnight to obtain crystals, which were filtered, washed with cold mixture of acetic acid and water (1:1), and then water, and finally dried (10,11 g, 53%). After concentration of the filtrate, the residue was dissolved in ethyl acetate and the resulting solution was washed with a saturated aqueous solution of bicarbonate on the matter (of 5.05 g).

The main party of the substance was used in the subsequent reactions.

Example 10C

3-Cyano-5-nitrophenylpyruvic acid ethyl ester

To a mixture of distilled diethyloxalate (120 g, 821 mm) and 3-methyl-4-nitrobenzonitrile (32 g, 197 mm) at 0oC was added a solution of ethoxide sodium in ethanol (2.2 g 400 mm metallic sodium in 400 ml of ethanol). The resulting red solution was heated for 18 hours at a temperature of 40oC. the Cooled mixture was diluted with 600 l of water and acidified to pH 2.1 adding concentrated hydrochloric acid. The precipitate was collected by filtration of the mixture (13oC), and then was dried and purified by chromatography on silica, elwira 15%, 30% and 50% acetone/hexane, resulting in a received target compound in the form of an orange solid product which was used without purification (23,6 g, 31%).

Example 11

5-Methyl-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl}-amide

(3S)-Amino-(2R)-hydroxy-N-methoxy-N-methyl-4-phenylbutyramide hydrochloride (0.5 mm) and 5-methyl-1H-indole-2-carboxylic acid (0.5 mm) was subjected to the reaction of interaction in accordance with method A (except that the temperature is th product chromatographically on silica (eluent: a mixture of 20-50% ethyl acetate/hexane). Yield: 75%; VRIJ (60/40%), 5,06 minutes (99%), PB-MS 396 (MN+, 100%).

1H-NMR (CDCl3) : 9,14 (width, 1H), and 7.4 to 7.2 (m, 6H), 7,07 (DD, 1H, J=2, approx. 8 Hz), 6,76 (d, 1H, J=2 Hz), 6,45 (d, 1H, J=9.7 Hz), the 4.90 (m, 1H), 4,29 (d, 1H, J=5.5 Hz), 3,83 (d, 1H, J=5.5 Hz), the 3.35 (s, 3H), 3,13 (c, 3H), to 3.09 (DD, 1H, J=6,13 Hz) of 3.00 (DD, 1H, J=9,13 Hz), 2,42 (c, 3H).

Analysis for C22H25N3O4:

Calculated: C 66,82; H 6,37; N 10,18;

Found: C 66,97; H 6,48; N 10,33.

Example 12

5-Fluorescent-1H-indole-2-carboxylic acid [(1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl]-amide

(3S)-Amino-(2R)-hydroxy-N-methoxy-N-methyl-4-phenylbutyramide hydrochloride (0.5 mm) and 5-fluorescent-1H-indole-2-carboxylic acid (0.5 mm) was subjected to the reaction of interaction in accordance with method A (except that washing was carried out with acid, then base) and the resulting product was purified using chromatography on silica gel (eluent: a mixture of 20-25% ethyl acetate and hexane). Yield: 69%, VRIJ (60/40), 4,55 minutes (95%); PB-MC: 400 (MH+, 100%).

1H-NMR (CDCl3) : 9,34 (width, 1H), and 7.4 to 7.2 (m, 7H), 7,00 (dt, 1H, J = 2.5 and 9.1 Hz), to 6.80 (d, 1H, J = 1.6 Hz), 6.48 in (d, 1H, J = 9 Hz), is 4.93 (m, 1H), 4,30 (d, 1H, J = 5.3 Hz), 3,83 (d, 1H, J = 5.3 Hz), the 3.35 (s, 3H), 3,14 (s, 3H), is 3.08 (DD, 1H, A of AB), to 3.02 (DD, 1H, J = 5,11 Hz, B of AB).

Analysis for C11H22FN3O4:

islote { (1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl}-amide

(3S)-Amino-(2R)-hydroxy-N-methoxy-N-methyl-4-phenyl-butyramide hydrochloride (0,26 mm) and 1H-indole-2-carboxylic acid (0.28 mm) was subjected to the reaction of interaction in accordance with method A (except, would or would the reaction temperature was 0-25oC), and the obtained product was purified by chromatography on silica gel (eluent: a mixture of ethyl acetate/hexane, 20-50%). Yield: 87%, VRIJ (60/40), 4.26 deaths of minutes

(96%); PB-MC 382 (MH+, 100%);

1H-NMR (CDCl3) : 9,24 (width, 1H), 7,63 (d, 1H, J = 8.0 Hz), between 7.4 to 7.15 (m, 8H), 7,11 (dt, 1H, J = 8,0 1,5 Hz), 6,85 (d, 1H, J = 1.5 Hz), 6.48 in (d, 1H, J = 9.8 Hz), 4,94 (m, 1H), 4,30 (d, 1H, J = 5.5 Hz), 3,84 (d, 1H, J = 1.5 Hz), to 3.36 (s, 3H), as 3.14 (s, 3H), to 3.09 (DD, 1H, J = 6,13 Hz, A of AB), 3,03 (DD, 1H, J = 10,13 Hz, B of AB).

Analysis for C21H23N3O4:

Calculated: C 66,13; H Between 6.08; N 11,02.

Found: C 66,19; H Between 6.08; N 11,02.

Example 14

5-Chloro-1H-indole-2-carboxylic acid { [(1S)-[(methoxy-methyl-carbarnoyl-methyl]-2-phenyl-ethyl}-amide

(3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -4-phenylalanyl acid (357 mg, 1.0 mm) and 98% N,O-dimethylhydroxylamine hydrochloride (98 mg, 1.0 mm) was subjected to the reaction of interaction in accordance with method A (except that the solvent used dimethylformamide). The resulting substance in the form of foam rubbed Raleigh with hexane. Yield: 215 mg, 54%; VRIJ (60/40), 6.38 minutes (98%) PB-MC 400/402 (MH+, 100%).

Analysis for C21H22ClN3O3:

Calculated: C 63,08; H Of 5.55; N 10,51.

Found: C 62,91; H 5,79; N Of 10.21.

Example 14A

(3S)-[(5-Chloro-1H-indole-2-carbonyl)amino]-4-fenilalanina acid

To a suspension containing the methyl ester of (3S)-[(5 - chloro-1H-indole-2-carbonyl)amino-4-phenyl-butyric acid (1.28 g, 3.45 mm) in methanol (10 ml) at 25oC was added 3.0 ml of 2N NaOH. After incubation for 18 hours, the reaction mixture was diluted with tetrahydrofuran (10 ml), and then, the solution was heated under reflux for 10 minutes and concentrated. The obtained solid was stirred with 6N hydrochloric acid for 15 minutes, and then, the suspension was filtered and the obtained solid is washed with 2N hydrochloric acid and dried off. Output: 1,15 g (93%); VRIJ (60/40), 5.18 minutes (100%).

Example 15

(3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4 - phenylalkanoic acid methyl ester

To a mixture containing methyl ester (3S)-amino-(2R)-hydroxy-4-phenylalkanoic acid (WO 93/25574, example 1A, 77,5 g, 370 mm), 5-chloro-1H-indole-2-carboxylic acid (72,45 grams, 370 mm) and 1-hydroxybenzotriazole hydrate in dichloromethane (640 ml) at 25owhether for 18 hours, concentrated, and the residue was dissolved in ethyl acetate, and the resulting solution was washed twice 2N sodium hydroxide and twice 1N hydrochloric acid and then brine. After drying and concentration was obtained target compound as a yellow foam (140,7 g, 98%) which was used in the subsequent hydrolysis without further purification (VRIJ (70/30), 3,61 minutes (82%), to 9.57 minutes (13%). A pure sample was obtained by chromatography on silica (eluent: a mixture of ethyl acetate/hexane), so pl. 180-183oC.

1H-NMR (CDCl3) : 9,52 (width, 1H), 7,55 (d, 1H, J = 2 Hz), 7,35 - to 7.15 (m, 7H), 6,70 (d, 1H, J = 2 Hz), 6,50 (d, 1H, J = 10 Hz), 4,82 (m, 1H), 4,22 (s, 1H), and 3.72 (s, 3H), 3,4 (width, 1H), 3,05 (m, 2H).

13C-NMR (CDCl3, 75.5 MHz) : 174,2, 164,4, 137,1, 135,0, 131,1, 129,8, 128,8, 128,3, 127,0, 127,0, 126,2, 125,0, 121,0, 113,2, 102,3, 70,4, 43,3, 43,1, 38,1.

TS-MS 387/389 (MH+, 100/30%).

Analysis for C20H19ClN2O4+ 0,5 H2O:

Calculated: C 60,69; H 5,09; N 7,08.

Found: C 60,30; H To 4.98; N 6,86.

Example 16

3-[(5-Chloro-1H-indole-2-carbonyl)-amino] -(2RS)-hydroxy-propionic acid

Hydrochloride complex of methyl ester of (RS)-3-amino-2-hydroxypropionic acid (6,6 mm) and 5-chloro-1H-indole-2-carboxylic acid (6,6 mm) was subjected to reaction interaction in cooties, and during the acid formed precipitate, after which the mixture was filtered and the filtrate was used as described in Method A). The crude product (920 mg) was dissolved in methanol and treated with 6.6 ml of 1N sodium hydroxide for 2 hours at 25oC. After addition of 6.6 ml of 1N NaOH, the mixture was concentrated and the resulting residue was dissolved in ethyl acetate. The resulting solution was washed with 2N hydrochloric acid and brine, and then dried and concentrated. The resulting colourless solid was stirred with chloroform and filtered, resulting in a received target product:

Output: 763 mg (40%); VRIJ (60/40), 2.86 minutes (89%), so pl. 214-215oC, PB-MC 283/285 (MH+, 100%).

1H-NMR (DMSO-d6) : 11,78 (s, 1H), to 8.62 (t, 1H), of 7.70 (d, 1H, J = 2 Hz), 7,42 (d, 1H, J = 8.7 Hz), 7,17 (DD, 1H, J = 2, 8.7 Hz), 7,14 (d, 1H, J = 2 Hz), 4,18 (DD, 1H, J = 5.8 Hz), to 3.58 (m, 2H).

Analysis for C12H11ClN2O4+ 0,1 H2O:

Calculated: C 50,66; H Of 3.97; N 9,85.

Found: C 50,80; H 4,06; N 9,48.

Example 16A

(RS)-3-Amino-2-hydroxypropionic acid methyl ester hydrochloride

A mixture of D, L-azaserine from 2.06 g, 19,6 mm), methanol (20 ml) and chlorotrimethylsilane (9.5 g, 88 mm) was heated under reflux for 5 hours, and then 5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R)-methoxy-methylcarbamoyl-methyl)-2-phenyl-ethyl]-amide

(3S)-Amino-(2R)-methoxy-N,N-dimethyl-4-phenyl-butyramide hydrochloride (0.84 mm) and 5-chloro-1H-indole-2-carboxylic acid (0.80 mm) was subjected to the reaction of interaction in accordance with method A (except that the reaction temperature was 0-25oC, and as the solvent used a mixture (2:1) dichloromethane/dimethylformamide), and the obtained product was purified by chromatography on silica (eluent: a mixture of ethyl acetate/hexane (1: 1). Yield: 81%; VRIJ (60/40), 5,44 minutes (100%), TSP-MC 414/416 (MH+, 100/30%).

1H-NMR (CDCl3) : 9,38 (width, 1H), 7,60 (d, 1H, J = 2 Hz), between 7.4 to 7.2 (m, 6H), 7,20 (DD, 1H, J = 2,9 Hz), 7,03 (d, 1H, J = 8 Hz), 6,92 (d, 1H, J = 2 Hz), 4,50 (m, 1H), 4.00 points (d, 1H, J = 2 Hz), 3,40 (, 3H), up 3.22 (DD, A of AB, 1H, J = 5,13 Hz), 3,00 (DD, B of AB, 1H, J = 10,13 Hz), of 2.86 (s, 3H), 2,65 (s, 3H).

Analysis for C22H24ClN3O3:

Calculated: C 63,48; H Of 5.84; N 10,15.

Found: C 63,48; H 5,97; N Becomes 9.97.

Example 17A

(3S)-Amino-(2R)- methoxy-N,N-dimethyl-4-phenyl-butyramide hydrochloride

(1S, 2R)-(1-Benzyl-2-dimethylcarbamoyl-2-methoxy-ethylcarbamate acid tert-butyl ester (283 mg, 0.84 mm) was dissolved in a mixture of 4N HCl dioxide (1 ml) for 1.5 hours at a temperature of 25oC and concentrated. The residue is evaporated with ether and dried.

Example 17B

o
C was added sodium hydride (53 mg, 50% dispersion in oil). After the rapid liberation of gas bubbles was completed (a few minutes), to the mixture was added methyliodide (155 mg), and after 15 minutes, to this mixture was added 11 mg of dispersion of sodium hydride in oil and 23 mg under the conditions. After another 15 minutes to the mixture was added an aqueous solution of ammonium chloride and ethyl acetate, then the organic layer was separated, washed with water and 2N sodium hydroxide, and then was dried and concentrated, resulting in the received viscous oily substance, which was used without further purification. Output: 283 mg, 84%.

Example 17C

(1S, 2R)-1-Benzyl-2-dimethylcarbamoyl-2-hydroxy-ethyl)-carbamino acid tert-butyl ether

(3S)-Tert-butoxycarbonylamino-(2R)-hydroxy-4-phenylalanyl acid (Schweizerhall, Ins., S. Plainfield, nI, of 1.02 g, 3.4 mm) and dimethylamine hydrochloride (338 g, 4.1 mm)

was subjected to the reaction of interaction in accordance with method A (except that the reaction temperature was 0-25oC, the solvent used is a mixture of dimethylformamide and dichloromethane, and the extraction was carried out with acid, then base) and received untreated prodego received substance in the form of foam. Output: 995 mg, 91%.

Example 18

5-Chloro-1H-indole-2-carboxylic acid (3-azetidin-1-yl-(1S)-benzyl-(2R)-hydroxy-3-oxo-propyl)-amide

Azetidin (0.44 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenylalanyl acid (0.4 mm) was subjected to the reaction of interaction in accordance with method A (except that the solvent used a mixture (1: 1) of dimethylformamide and dichloromethane), and received the desired substance. Yield: 94%, VRIJ (60/40), 4,55 minutes (> 98%); PB-MC 412/414 (MH+, 100%).

Analysis for C22H22ClN3O3+ 0,25 H2O:

Calculated: C 63,46; H The 5.45; N Of 10.09.

Found: C 63,61; H 5,66; N 10,27.

Example 19

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-methoxy-2-(methoxy-methyl-carbarnoyl)-ethyl]-amide

(3S, 2R)-3-Amino-(2R)N-dimethoxy-N-methyl-4-phenylbutyramide (0,31 mm) and 5-chloro-1H-indole-2-carboxylic acid (0,31 mm) was subjected to reaction interaction in accordance with Method A, and the obtained product was purified by chromatography on silica gel (eluent: a mixture of (20-40%) ethyl acetate-hexane). Yield: 81%, VRIJ (60/40), 7,39 minutes (98%), PB-MC 430/432 (MH+, 100%).

1H-NMR (CDCl3) : 9,44 (s, 1H), 7,58 (d, 1H, J = CA. 2 Hz), 7,4 - 7,22 (m, 6H), 7,19 (DD, 1H, J = a 2.0 and 8.8 Hz), 6.89 in (d, 1H, J = CA. 2 Hz), to 6.80 (d, 1H,"ptx2">

Analysis for C22H24ClN3O4+ 0,33 C6H14:

Calculated: C 62,85; H 6,30; N 9,16.

Found: C 62,91; H 6,29; N 8,95.

Example 19A

(3S,2R)-3-Amino-(2R), N-dimethoxy-N-methyl-4-phenyl-butyramide

Tert-butyl ether (1S, 2R)-(1-benzyl-2-methoxy-methylcarbamoyl-2-methoxy-ethyl)-carbamino acid (113 mg, 0.32 mm) was dissolved in a mixture of 4N hydrochloric acid and dioxane (4 ml) at a temperature of 25oC for 1 hour and then concentrated, then the residue is triturated with ether, and obtained the desired product (93 mg, 100%).

Example 19B

(1S, 2R)-(1-Benzyl-2-methoxy-methyl-carbarnoyl-2-methoxy - ethylcarbamate acid tert-butyl ether.

To a solution of tert-butyl methyl ether (1S,2R)-(1-benzyl-2-methoxy-methyl-carbarnoyl-2-hydroxy-ethyl)-carbamino acid in tetrahydrofuran (2 ml) at 0oC was added a dispersion of sodium hydride (30 mg, 50% dispersion in oil). After keeping for 5 minutes, to the mixture was added methyliodide (175 mg), and the mixture is left for 18 hours at a temperature of 25oC. After adding ethyl acetate and saturated aqueous solution of ammonium chloride, the organic layer was separated, washed with water, dried, concentrated and chromatographically on silica (eluent: from { (2S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -(1R)-(methoxy-methyl-carbarnoyl) -1-phenyl-propoxy}-acetic acid benzyl ester.

Hydrochloride benzyl ester (1R,2S)-[2-amino-1-(methoxy-methyl-carbarnoyl)-3-phenyl-propoxy] -acetic acid (162 mg, 0.38 mm) and 5-chloro-1H-indole-2-carboxylic acid (77 mg, 0.36 mm) was subjected to the reaction of interaction in accordance with method A (except that the reaction temperature was 0 - 25oC), and the crude product was purified by chromatography on silica gel (eluent: a mixture of 20-75% ethyl acetate in hexane), resulting in a received target compound in the form of a glassy solid. Yield: 61%, TSP-MC 564/566 (MH+, 90/60%), 581/583 (MN++NH3, 100/50%).

Example 20A

(1R,2S)-[2-Amino-1-(methoxy-methyl-carbarnoyl)-3-phenyl-propoxy]- acetic acid benzyl ester hydrochloride

Benzyl ether of (1R, 2S)-[2-tert-butoxycarbonylamino-1- (methoxy-methyl-carbarnoyl)-3-phenyl-propoxy] -acetic acid (170 mg, 0.35 mm) was dissolved in a mixture of 4N hydrochloric acid and dioxane (2 ml) at 25oC for one and a half hours, and then concentrated, and the resulting residue is evaporated with ether, and dried to obtain an oily substance (163 mg), MS:387 (MH+, 100%).

Example 20B

(1R, 2S)-[2-tert-butoxycarbonylamino-1-(methoxy-methyl-carbarnoyl)- 3-phenyl-propoxy]-acetic who email)-2-hydroxy-ethyl-carbamino acid (858 mg, 2.5 mm) in tetrahydrofuran (8 ml) at 0oC was added a dispersion of sodium hydride (120 mg of a 50% dispersion in oil, 2.8 mm). After cessation of rapid allocation of gas bubbles, to the mixture was added benzylbromide (0.56 g, 2.5 mm) and the mixture was heated to 25oC. After two hours, to the mixture was added 12 mg of dispersion of sodium hydride, and the resulting mixture was stirred for one hour, diluted with ethyl acetate and saturated ammonium chloride, and the organic layer was separated, washed with water, dried and concentrated to obtain an oily substance, which was chromatographically on silica gel (eluent: a mixture (20 - 75%) ethyl acetate/hexane). The most pure fractions were combined and obtained oily substance (175 mg, 15%), MS: 487 (MN+), 387 (100%).

Example 21

{ (2S)-[(5-Chloro-1H-indole-2-carbonyl)-amino]-(1R)-(methoxy - methyl-carbarnoyl)-3-phenyl-propoxy}-acetic acid

A mixture containing benzyl ether {(2S)-[(5-chloro-1H-indole - 2-carbonyl)amino]-(1R)-(methoxy-methyl-carbarnoyl)-3-phenyl-propoxy}- acetic acid (120 mg, 0.2 mm) and 50% wet palladium hydroxide-on-coal-methanol (50 mg), was stirred by shaking for one hour at a temperature of 25oC and under a hydrogen pressure of 40 pounds per square inch (2,812 kg/cm2). Powertogo substances, which was chromatographically on silica (eluent: a mixture of ethyl acetate/hexane, 25-100%), resulting in a received 84 mg solids: URGH (60/40), 40,81 min (37%) and 6,24 min (63%).1H-NMR analysis and MC analysis indicated the presence of methyl esters of 5-des-Cl and the target product, respectively. The obtained solid substance was dissolved in tetrahydrofuran and treated with 170 μl of 1N sodium hydroxide at 25oC for 30 minutes, after which the solution was concentrated and the resulting residue was distributed between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water, dried and concentrated, resulting in the obtained mixture of the target compounds and analogue des-5-Cl: Yield: 85 mg (71%); VRIJ (60/40), 3.49 minutes (37%), 4,23 minutes (61%), MS: 338 (MH+, 100%); TSP-MC: 474/476 (MN+for the target compounds, 40%), 440 (MN+for analogue des-5-Cl, 95%).

Example 22

(3S)-[(1-Indole-2-carbonyl)amino]-(2R)-hydroxy-4-phenyl - butyramide

(2R,3S)-3-amino-2-hydroxy-4-phenylbutyramide (0,59 mm, WS 4599198, example 1D) and indole-2-carboxylic acid (0.71 mm) was subjected to the reaction of interaction in accordance with method A (except that washed first with acid, then base) and the resulting product was purified on the pont) 99%; MS: 338 (MH+, 100%),1H-NMR (DMSO-d6) : 11,53 (s, 1H), 7,95 (d, 1H, J=9 Hz), 7,63 (d, 1H, J=8 Hz), 7.5 to to 7.15 (m,7-8 Hz),7,12 (d, 1H, J=CA. 7 Hz), to 7.09 (d, 1H, J=CA. 8 Hz), 5,95 (d, 1H, J=6 Hz), 4,55 (m, 1H), 3,93 (m, 1H), 2,98 (DD, 1H, A of AB, J=6,13 Hz), is 2.88 (DD, 1H, B of AB, J=8,13 Hz).

Example 23

{ (3S)-[(5-Chloro-1H-indole-2-carbonyl)amino] -(2S)-hydroxy-4 - phenylbutyramide

To the solution containing the hydrochloride, (2S,3S)-3-amino-2-hydroxy - 4-phenylbutyramide (0,319 g, 1,61 mm) and triethylamine (145 mg, 1,42 mm) in dichloromethane (2 ml) at 25oC, was added 5-chloro-1H-indole-2-carbonylchloride (0,30 g of 1.29 mm).

After 18 hours, the mixture was diluted with ethyl acetate, and the resulting solution was twice washed with 1N hydrochloric acid, twice with saturated aqueous sodium bicarbonate solution and once with saline, and then dried and concentrated. The residue was chromatographically on silica (eluent: a mixture of 50 to 100% ethyl acetate/hexane) and was obtained 0.31 g of the desired product in the form of a solid, which was recrystallized from isopropyl alcohol. Output: 0,020 g; FAB-MC 372/374 (MH+, 21%), 217 (100%),1H-NMR (DMSO-d6, partial) : 8,5 (d, 1H, J=9 Hz), of 7.48 (d, 1H, J=2 Hz), between 7.4 and 7.1 (m, 9H), 5,95 (d, 1H, J=7 Hz), 4,56 (m, 1H), 4,08 (m, 1H), 2,92 (DD, 1H, J=11,13 Hz), 2,68 (DD, J=3,13 Hz).

Example 23A

5-Chloro-1H-indole-2-carbonylchloride

Rastvorov, containing fluoride, cyanuric acid (2.76 g, 20,4 mm) in acetonitrile (only 340 ml) at a temperature of 25oC. the Reaction was analyzed using TCX on the aliquot, and then extinguished by the addition of butylamine, after which, the reaction was completed in approximately 1 hour. The resulting mixture was poured into ice, extracted with ether, dried over sodium sulfate and concentrated to obtain solid, which was used without further purification (10.0 g, 99%). TCX-analysis of the aliquot, quenched by the addition of butylamine, indicated the presence of a certain number of 5-chloroindole-2-carboxylic acid and less polar N-butylamine. The sample was purified by chromatography on silica gel, elwira a mixture of ethyl acetate/hexane (50-100%) for subsequent identification (16368-130-1).

Example 23B

(2S,3S)-3-Amino-2-hydroxy-4-phenyl-butyramide hydrochloride

(1S)-[(S)-Carbarnoyl-hydroxy-methyl)-2-phenyl-ethyl] -carbamino acid tert-butyl ester (0.50 g, 1.7 mm) was dissolved in a mixture of 4 M HCl/dioxane for one hour at 25oC. After concentrating the mixture, the residue is triturated with ether, and obtained a colorless solid (430 mg).

URGH (60/40), 2,68 min (100%).

Example 23C)

{ (1S)-((S)-Carbarnoyl-Hydra is tilby ether {(1S)-[(S)-(tert - butyl-dimethyl-silyloxy)-carbarnoyl-methyl]-2-phenyl-ethyl]- carbamino acid in tetrahydrofuran (6 ml) at 0oC was added tetrabutylammonium fluoride (23 ml of 1 M solution in tetrahydrofuran). After 30 minutes, the mixture was diluted with ethyl acetate and water and the organic layer was separated, washed with water and then two times with 1N hydrochloric acid, two times with 1N sodium bicarbonate and once with brine. The resulting emulsion was filtered, and the filtrate was dried and concentrated to obtain a colorless solid (0.5 g, 20%). Part (3.1 g) filtered solids (3.3 grams) was recrystallized from hot ethyl acetate, and got to 1.33 g of the desired product as a colourless solid.

Example 23D

{(1S)-(S)-(Tert-butyl-dimethyl-silyloxy)carbarnoyl-methyl]-2-phenyl-ethyl] -carbamino acid tert-butyl ether

To a solution containing tert-butyl ester {1(S)-benzyl-(2S)-(tert-butyl-dimethyl-silyloxy)-2-cyanoethyl} - carbamino acid (example 24D, 5.0 g, 12.8 mm) and 1N NaOH (22 ml) in ethanol (110 ml) at a temperature of 0oC for 15 minutes was added 30% hydrogen peroxide (7.2 ml 64 mm). The resulting mixture was stirred for one and a half hours, was treated with 175 ml of an aqueous solution of 10% sodium thiosulfate, concentrated and extracted with ethyl acetate. The extracts were dried with sodium sulfate and concentrated. Astatkie in the form of a colorless solid (3,17 g, 61%).

Example 24

5-Chloro-1H-indole-2-carboxylic acid { (1S)-[(S)-hydroxy(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl}-amide

N, O-Dimethylhydroxylamine hydrochloride (0.4 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)amino] -(2S)-hydroxy-4-phenyl - butyric acid (0.38 mm) was subjected to the reaction of interaction in accordance with method A, and the obtained product was purified by chromatography on silica (eluent: a mixture of 20 to 50% ethyl acetate/hexane), yield=72%; VRIJ (60/40), of 5.05 minutes (98%);< / BR>
PB-MC 416/418 (MH+, 100%).

1H-NMR (CDCl3) : of 9.30 (Shir. 1H), 7,60 (d, 1H, J=2 Hz), 7,33 (d, 1H, J=8 Hz), 7.3 to to 7.15 (m, 6-7H), to 6.75 (m, 2H), 5,00 (m, 1H) and 4.65 (d, 1H, J=4 Hz), 3,71 (s, 3H), 3,06 (s, 3H), 2,87 (m, 2H), 1,6 (W).

Analysis for C21H22ClN3O4+0,35 H2O:

Calculated: C 59,74; H 5,42; N 9,95.

Found: C 60,14; H 5,65; N Of 9.55.

Example 24A

(3S)-[(5-Chloro-1H-indole-2-carbonyl)amino] -(2S)hydroxy-4 - fenilalanina acid

To a solution containing methyl ester (3S)-[(5-chloro-1H-indole-2-carbonyl)amino] -(2S)-hydroxy-4 - phenylalkanoic acid (500 mg, 1,29 mm) in methanol at 25oC was added to 2.6 ml of aqueous 1N NaOH. After 18 hours, the mixture was concentrated, and the residue was dissolved in ethyl acetate and water, after which the resulting solution was acidified to pH 1 EXT is th layer was combined, was dried and concentrated, resulting in the obtained solid (417 mg, 87%); VRIJ (60/40), to 4.23 min (>98%).

Example 24B

{ ((3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -(2S)-hydroxy-4 - phenylalkanoic acid methyl ester

(3S)-Amino-(2S)-hydroxy-4-phenylalkanoic acid methyl ester (1.4 mm) and 5-chloro-1H-indole-2-carboxylic acid (1,37 mm) was subjected to the reaction of interaction in accordance with method A (reaction temperature = 0-25oC, time reaction time = 40 hours; solvent: a mixture of dichloromethane and dimethylformamide), resulting in a received target product, yield: 94%; VRIJ (60/40), 5,38 minutes (97%), so pl. 214-221oC; PB-MS 387/389 (MH+, 100%).

Analysis for C20H19ClN2O4:

Calculated: C 62,10; H Of 4.95; N 7,24.

Found: C 62,12; H 5,07; N 7,11.

Example 24C

(3S)-Amino-(2S)-hydroxy-4-phenylalkanoic acid methyl ester

To a solution of anhydrous hydrochloric acid (3.2 g) and methanol (20 ml) was added [(1(S)-benzyl-(2S)-(tert-butyl-dimethylsiloxy)-2-cyano - ethyl]-carbamino acid tert-butyl ester (417 mg) and the resulting solution was closed tube and kept for 5 days at a temperature of 25oC. the Mixture was concentrated to obtain 308 mg of colorless solid ve the social equivalent substance, obtained in the same manner from 400 mg is similar to the original connection, and all this mixture was dissolved in a saturated aqueous solution of sodium bicarbonate and was extracted ten times with chloroform. The combined extracts were dried and concentrated, resulting in a received target compound (328 mg, 75%).

Example 24

[1(S)-Benzyl-(2S)-(tert-butyl-dimethyl-silyloxy)-2-cyanoethyl] - carbamino acid tert-butyl ether

N-t-Butoxycarbonyl-(3S)-amino-(2RS)-hydroxy-4-phenylbutyramide transformed into the corresponding O-tert-butyldimethylsilyl esters using methods described in example 1B of U.S. patent N 4599198, and the isomers were separated by chromatography on silica gel (eluent: 7-8% ether/hexane). The target compound was separated from the least polar isomer 2R (the last example 1B in U.S. patent N 4599198).

Example 24E

N-t-Butoxycarbonyl-(3S)-amino-(2RS)-hydroxy-4-phenylbutyramide

To a solution containing N-t-butoxycarbonyl-N-phenylalanine (J. Med. Chem. 1985, Vol. 28, 1799-1790, 10.0 g, 40,1 mm) dimethoxyethane (100 ml) at a temperature of 0-5oC solution was added (5oC) sodium bisulfite (to 4.38 g) in water (100 ml). The resulting mixture was stirred for 2 hours at 0oC, and then overnight at 25oandom potassium (2,61 g, 40,1 mm). After incubation for 4 hours at a temperature of 25oC, the organic layer was separated, washed twice with water and once with saline, and then dried and concentrated. The obtained oily substance was led from a mixture of ether/hexane and was obtained a colorless solid (3,53 g, so pl. 95-98oC). The second collection was obtained by recrystallization of the mother liquor (5.0 g) from a mixture of ether/hexane (colourless solid 2,44 g) (so pl. 88-92oC). The second substance having a low melting point used in the subsequent reaction sililirovanie.

Example 25

(3S)-[(5-Chloro-1H-indole-2-carbonyl)amino] -(2R)-hydroxy-4-fenilalanina acid

To a solution containing crude (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenylalkanoic acid methyl ester (containing as impurities 13% N,O-bis-5-chloro-1H-indole-2-carbonyl) (140,7 g, 363 mm) and methanol (1900 ml) at a temperature 10-22oC was added 375 ml of an aqueous solution of 2N NaOH, and the resulting mixture was stirred at a temperature of 25oC. After two hours, the solution was concentrated, and the residue was dissolved in 2 l of ethyl acetate and 500 ml of 2N hydrochloric acid. The aqueous layer was separated and twice washed with 2N hydrochloric acid, and organic and 100 ml of hot ethyl acetate (obtaining suspensions), was added to 1300 ml of chloroform, and the suspension was heated under reflux for 5 minutes with mechanical stirring, and then filtered in the hot state, and the filtered solids were washed with a mixture of chloroform and ethyl acetate (3: 1, 400 ml) at a temperature close to the boiling point. The obtained solid was dried in vacuum until a constant mass (101 g, 75%). The filtrate was concentrated and recrystallized by dissolving in hot tetrahydrofuran (70 ml), the addition of hot hexane (200 ml), cooled overnight, filtering and washing the obtained solid with a mixture of tetrahydrofuran/hexane (1:5) to obtain the 7,03 g (5%) of the desired product. Royal solutions with the last phase was concentrated and recrystallized in the same manner, resulting in a received 11,07 grams (8%) of the desired substance. All three products were analyzed using URGH (60/40), 4,2 min (>98%). Analysis for the presence of 5-chloro-1H-indole-2-carboxylic acid was carried out VRIJ (C8, Bond column 15 cm (600:400:2:1) water/acetonitrile/triethylamine/acetic acid, 600:400:2:1), which indicated the presence of three products 0.4%, 0.7% and 21%, respectively, as described above. Data for the main products is to 9.1 Hz), 7,71 (d, 1H, J = 2 Hz), 7,39 (d, 1H, J = 8.7 Hz), 7,28 (m, 4H), 7,17 (m, 3H), 5,55 (width, 1H), 4,57 (m, 1H), 4,05 (d, 1H, J = 3.6 Hz), 2,97 (DD, 1H, A of AB, J = 6.5 and 13.5 Hz), 2,87 (DD, 1H, B of AB, J = 8.5 and 13.5 Hz).

Analysis for C19H17ClN2O4:

Calculated: C 61,21; H 4,60; N 7,51.

Found: C 61,09; H 4,63; N To 7.59.

Example 26

(3R)-[(5-fluorescent-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4 - phenyl-butyric acid

The solution containing the methyl ester of (3S)-[(5-fluorescent-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenyl-butyric acid (190 mg, 0.5 mm), 1N NaOH (1 ml) and methanol (5 ml) was stirred for 18 hours at a temperature of 25oC, pH brought up to 1-2 by adding 1N hydrochloric acid, and then the solution was concentrated, and the resulting solids were placed in water at 25oC and filtered. The obtained solid was washed with ether and dried, resulting in the obtained colorless glassy substance (160 mg, 87%); VRIJ (60/40), 3.49 minutes (99%);1H-NMR (partial, DMSO-d6) : 8,15 (d, 1H, J = 8 Hz), 7,42 (m, 2H), and 7.3 (m, 4H), to 7.15 (m, 2H), 7,03 (dt, 1H), 4,60 (m, 1H), a 4.03 (d, 1H), 3,00 (DD, 1H, J = 8,13 Hz), 2.90 (DD, 1H, J = 8,13 Hz).

Example 27

(3S)-[(5-Bromo-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-fenilalanina acid

To a solution containing methyl ester (3S)-[(5-bromo-1H-indole-2-carbonyl)-Amin is a solution of 1N NaOH (60 ml). After 2 hours the mixture was concentrated and distributed between ethyl acetate and 2N hydrochloric acid. The aqueous layer was separated and was extracted with ethyl acetate, and the combined organic layers are washed with 1N hydrochloric acid and brine, and then dried and concentrated. The obtained solid is triturated with chloroform at 25oC. Yield: 85%; VRIJ (60/40), 4,24 minutes (100%); so pl. 213-216oC; TSP-MS 417/419 (MH+, 98%).

1H-NMR (partial, DMSO-d6) : 11,72 (width, 1H), to 8.20 (d, 1H, J = 10 Hz), 7,86 (d, 1H, J = 2 Hz), between 7.4 and 7.1 (m, 8H), 4,60 (m, 1H), Android 4.04 (d, 1H, J = 3.5 Hz), of 3.00 (DD, A of AB, J = 7,13 Hz), is 2.88 (DD, 1H, B of AB, J = 8.5 and 13 Hz).

Analysis for C19H17BrN2O4+ 0,25 H2O:

Calculated: C 54,11; H 4,18; N 6,64.

Found: C EUR 54.15; H 4,15; N 6,64.

Example 28

(3S)-[(5,6-sodium dichloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4 - fenilalanina acid

To the suspension containing the methyl ester of (3S)-[(5,6-sodium dichloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (249 mg, 0.6 mm) and methanol (5 ml) at a temperature of 25oC, was added an aqueous solution of 1N NaOH (1,18 ml). After settling for 18 hours, the mixture was concentrated and the resulting residue was distributed between excessive amount of 2N hydrochloric acid and ethyl acetate. The water layer is about is centered, the result was a yellow solid, exit 259 mg; VRIJ (60/40), 4,96 minutes (100%); TSP-MS 407/409 (MH+, 100/40%);

1H-NMR (partial, DMSO-d6) : 11.8 in (lat., 1H), 8,28 (d, 1H, J = 9 Hz), 7,98 (s, 1H), 7,58 (s, 1H), 7.3 to to 7.15 (m, 6H), 4,60 (m, 1H), 4,07 (d, 1H, J = 3-4 Hz), 2,98 (DD, 1H, A of AB, J = 6,13 Hz), is 2.88 (DD, 1H, J = 9,13 Hz).

Analysis for C19H16Cl2N2O4+ 0,5 H2O:

Calculated: C 54,82; H 4,12; N Of 6.73.

Found: C 54,86; H 4,08; N 6,76.

Example 29

(3R)-[(5-Chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-fenilalanina acid

To the suspension containing the methyl ester of (3R)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenylalkanoic acid (326 mg, 0.8 mm) and methanol at 25oC, was added an aqueous solution of 1 N. NaOH (1,69 ml). After 2.5 hours, the mixture was concentrated (found the original product) and was dissolved in methanol and an aqueous solution of 1 N. NaOH (0.5 ml). After one hour, the mixture was concentrated, and the residue was distributed between excess 2N hydrochloric acid and ethyl acetate, then the organic layer was separated, dried and concentrated. Output: 288 mg (92%); VRIJ (60/40), 3,89 minutes (93%); so pl. 215-223oC; TSP-MS 375/373 (MH+, 100%).

1H-NMR (DMSO-d6) : 12.7mm (width, 1H), 11,65 (s, 1H), and 8.50 (d, 1H, J = 8,8 Hz), of 7.70 (d, 1H, J = 2 Hz), 7,37 (d, H1, J = 8.7 Hz), 7,4-7,1 ( C19H17ClN2O4+ 0,1 H2O:

Calculated: C 60,92; H 4,63; N Of 7.48.

Found: C RUR 60,72; H 4,78; N 7,53.

Example 29A

(3R)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4 - phenyl-butyric acid methyl ester

Hydrochloride methyl ester (2R,3R)-3-amino-2-hydroxy-4-phenylalkanoic acid (239 mg, 1.0 mm) and 5-chloro-1H-indole-2-carboxylic acid (200 mg, of 1.05 mm) was subjected to the reaction of interaction in accordance with method A (except that the reaction temperature was 0-25oC, and washing was carried out first with acid, then base), resulting in the obtained crude product which was used without further purification. Output: 328 mg, 87%.

Example 29B

(2R, 3R)-Amino-2-hydroxy-4-phenylalkanoic acid methyl ester hydrochloride

A mixture of (2R, 3R)-3-amino-2-hydroxy-4-phenylalkanoic acid (200 mg, 1.0 mm, Sigma Chemical Co. (St. Louis, MO), chlorotrimethylsilane (500 mg, 4.6 mm) and methanol (2 ml) was heated under reflux for 5.5 hours and then concentrated, resulting in a received target compound in the form of foam. Output: 244 mg (100%).

Example 30

5-Chloro-1H-indole-2-carboxylic acid [(2R)-hydroxy-2-(methoxy-methyl-carbarnoyl)-ethyl]-amide

N, O-Timeteller who has vergili reaction interaction in accordance with method A (except that the reaction temperature was 0-25oC, and washing was carried out first with acid, then base) and the resulting crude product is triturated with ether, the resulting received a colorless solid substance. Yield: 69%; VRIJ (60/40), 3.18 minutes (96%); so pl. 192-192,5oC; RVMS 326/328 (MH+, 100%).

1H-NMR (DMSO-d6) : RS 11.80 (s, 1H), to 8.62 (t, 1H), of 7.70 (d, 1H, J = 2 Hz), 7,41 (d, 1H, J = 8,8 Hz), 7,17 (DD, 1H, J = 2 and 8.7 Hz), 7,13 (s, 1H), 5,35 (m, 1H) and 4.65 (m, 1H), 3,69 (s, 3H), 3,47 (m, 2H), 3,34 (s, 3H).

Analysis for C14H16ClN3O4:

Calculated: C 51,62; H Of 4.95; N 12,90.

Found: C 51,78; H 5,07; N Was 12.75.

Example 31

(3S)-[(5-Chloro-1H-indole-2-carbonyl)Amio]-(2R)-hydroxy-4-phenylbutyramide

An excess of anhydrous ammonia was introduced into a solution containing (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenylalkanoic acid methyl ester (100 mg, 0.27 mm) in methanol (10 ml) and the resulting mixture was heated in a Parr reactor stainless steel under pressure of 50 psi (3,515 kg/cm2) at 70oC for 48 hours. The mixture was cooled, concentrated and the resulting solid triturated with ether. Output: approx. 60%, URGH= 3,52 minutes (95%), PB-MC 372/374 (MH+, 100%).

1H-NMR (partial, DMSO-d6) : 1 is from C19H18ClN3O3+ 0,5 H2O:

Calculated: C 59,92; H To 5.03; N 11,03.

Found: C 59,66; H 5,10; N 11,40.

Example 32

5,6-sodium dichloro-1H-indole-2-carboxylic acid [(1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl]-amide

N, O-Dimethylhydroxylamine hydrochloride (0.24 mm) and (3S)-[(5,6-sodium dichloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenylalanyl acid (0.22 mm) was subjected to the reaction of interaction in accordance with method A (except that time the reaction was 96 hours, and washing was carried out first with acid, then base) and the resulting product was purified using chromatography on silica (eluent: a mixture of 20-40% ethyl acetate/hexane). Yield: 72%; VRIJ (60/40), 7,2 min (99%); so pl. 210-211,5oC, PB-MC: 450/452 (M+, 100%). 1H-NMR (CDCl3) : 10,41 (width, 1H), 7,73 (s, 1H), 7,68 (s, 1H), and 7.4 to 7.2 (m, 6H), is 6.78 (d, 1H, J = CA. 1 Hz), to 6.58 (d, 1H, J = 10 Hz), to 5.03 (m, 1H), 4,34 (d, 1H, J = 5 Hz), 3,85 (d, 1H, J = 5 Hz), 3,37 (s, 3H), 3,2 - 3,0 (m, 2H), 3,10 (s, 3H).

Analysis for C21H21Cl2N3O4:

Calculated: C 56,01; H 4,70; N Was 9.33.

Found: C 55,61; H To 4.68; N Which 9.22.

Example 33

5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R)-hydroxy-dimethylcarbamoyl-methyl)-2-phenyl-ethyl]-amide

Dimethylamine ghidrah the Gali reaction interaction in DMF (4 ml) using triethylamine (530 mg, 3,22 mm), hydrate (2-hydroxybenzotriazole (612 mg, 4 mm), and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide at a temperature of 25oC for 18 hours. The resulting mixture was diluted with chloroform (80 ml) and ethyl acetate (10 ml) and then washed with 2N sodium hydroxide and 2N hydrochloric acid, dried and concentrated to obtain 1.2 g of the substance as a colorless foam. This substance was dissolved in ethyl acetate, and the resulting solution was twice washed with 2N sodium hydroxide, and then was dried and concentrated to obtain 1,02 g colorless solid. The resulting substance was injected in 10 ml of cold ether and filtered by washing with 5 ml of cold ether, and after drying was obtained the desired product as a colourless solid. Output: 715 mg, 67%; so pl. 190-192oC; VRIJ (60/40), 4,53 min (100%); F-MS 400/402 (MH+, 80%), 178 (100%).

1H-NMR (CDCl3) : 9,40 (s, 1H), 7,55 (s, 1H), and 7.4 to 7.1 (m, 7H), 6,86 (d, 1H, J = 2 Hz), 6,62 (d, 1H, J = 9.6 Hz) and 4.65 (m, 1H), and 4.40 (m, 2H), 3,10 (m, 2H), 2,88 (s, 3H), of 2.72 (s, 3H).

Analysis for C21H22ClN3O3:

Calculated: C 63,08; H Of 5.55; N 10,51.

Found: C 63,03; H Of 5.68; N Of 10.25.

Example 34

5-Chloro-1H-indole-2-carboxylic acid [(1S)-(R)-hydroxy-(hydroxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl]-amide

N-the th acid (373 mg, 10 mm) were subjected to reaction interaction in accordance with method A (except that the solvent used is dimethylformamide, and washing the basis of neglected), and the crude product was purified by chromatography on silica (eluent: a mixture of 0.5-4% ethanol in dichloromethane containing 0.5% acetic acid). The purified product was rubbed with a mixture of hexane/ether. Yield: 13%; VRIJ (60/40), 4.26 deaths / min (97%); so pl. 182-184,5oC; TSP-MC 402/404 (MH+, 100%).

1H-NMR (DMSO-d6, partial) : 11,67 (width, 1H), 9,89 (width, 1H), 8,08 (d, 1H, J = 10 Hz), 7,71 (d, 1H, J = 1.9 Hz), 7,39 (d, 1H, J = 8,8 Hz), 7,35 to 7.1 (m, 7H), to 4.73 (m, 2H), 4,51 (m, 1H), 3,05 (m, 1H), 3,05 (s, 3H), of 2.93 (m, 2H).

Example 35

5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R)-hydroxymatairesinol-methyl)-2-phenyl-ethyl]-amide

N-Methoxyamine hydrochloride (0.77 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.70 mm) was subjected to the reaction of interaction in accordance with Method A (using as a solvent of dimethylformamide, and the resulting product was purified by chromatography on silica (eluent: a mixture of 1 - 10% ethanol in dichloromethane), and then triturated with ether/hexane.

Yield: 72%; VRIJ (60/40), 3,35 min (> 99%); so pl. 22O:

Calculated: C 57,96; H 5,20; N 10,14.

Found: C 57,90; H 5,15; N 10,10.

Example 36

5-Chloro-1H-indole-2-carboxylic acid [(1S)-{(R)-hydroxy-(methoxy-methyl-carbarnoyl-methyl]-2-phenyl-ethyl}-amide

N, O-Dimethylhydroxylamine hydrochloride (7.4 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (6.7 mm) was subjected to the reaction of interaction in accordance with Method A (using dimethylformamide as solvent), and obtained the crude product, which was chromatographically on silica (eluent: 40-50% ethyl acetate/hexane) to give the crude product, which was stirred overnight with a mixture of ether/hexane (1:1), and obtained solid substance was collected by filtration and dried. Yield: 70%, VRIJ (60/40), are 5.36 minutes (99%); so pl. 189-190oC;

1H-NMR (CDCl3) : 9,52 (width, 1H), 7,56 (d, 1H, J = 2.0 Hz), between 7.4 and 7.3 (m, 5H), 7,38 (m, 1H), 7,18 (DD, 1H, J = a 2.0 and 8.8 Hz), 6,76 (d, 1H, J = 1.4 Hz), 6,53 (d, 1H, J = 9 Hz), 4,94 (m, 1H), or 4.31 (d, 1H, J = 5,2 Hz, collapse to a singlet with D2O), 3,86 (d, 1H, J = 5.6 Hz, exchanges with D2O) to 3.35 (s, 3H), of 3.13 (s, 3H), 3,13 are 2.98 (m, 2H); PB-MC 593/595 (MH+, 65%), 200 (100%).

The following is an analysis of the substance, recrystallized from ethyl acetate/hexane (1:3) (shrinkage at 150oC, I. pl. 189-190oC); measures 37

5-Chloro-1H-indole-2-carboxylic acid (2S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(1R)-(methoxy-methyl-carbarnoyl)- 3-phenyl-propyl ether

(3S)-Amino-(2R)-hikkoshi-N-methoxy-N-methyl-4-phenyl-butyramide hydrochloride (4.2 mm) and 5-chloro-1H-indole-2-carboxylic acid (4.2 mm) was subjected to the reaction of interaction in accordance with Method A. the resulting mixture was purified by chromatography on silica (eluent: approximately 33-50% ethyl acetate/hexane, and received the target compound (100 mg) and the more polar the main connection, namely, 5-chloro-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(metacase-methyl-carbarnoyl)-methyl] -2-phenyl-ethyl} -amide (970 mg) and a mixture of two compounds (159 mg the most polar product). Data for the target connection: PB-MS 593/595 (MH+, 60%), 400 (100%).

1H-NMR (CDCl3) : 9,62 (width, 2H), 7,69 (d, 1H, J = 2 Hz), 7,56 (d, 1H, J = 2 Hz), between 7.4 to 7.2 (m, 10H),? 7.04 baby mortality (d, 1H, J = 8,8 Hz) 6,91 (d, 1H, J = 1-2 Hz), of 5.50 (d, 1H, J = 2 Hz), 5,09 (m, 1H), 3,47 (s, 3H), 3,26 (DD, 1H, J = 6,13 Hz), as 3.14 (s, 3H), 2,99 (DD, 1H, J = 10,13 Hz).

Example 38

5-Chloro-1H-indole-2-carboxylic acid (1S)-benzyl-(2R)-hydroxy-3-oxo-3-pyrrolidin-1-yl-propyl)-amide

Pyrrolidine (0.5 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenyl-butyric acid (0.5 mm) was subjected to the reaction of interaction in accordance with the who triturated with ether.

Yield: 65%; VRIJ (60/40), 6,3 min (98%); PB-MC 426/428 (MH+, 100%);

Analysis for C23H24ClN3O3+ 0,25 H2O:

Calculated: C 64,18; H 5,74; N 9,76.

Found: C 64,02; H 5,71; N Being 9.61.

Example 39

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(3-hydroxy-azetidin-1-yl)-3-oxo-propyl]-amide

3-Hydroxyazetidine hydrochloride (0.56 mm) and (3S)-[(5 - chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenylalanyl acid (0.5 mm) was subjected to the reaction of interaction in accordance with Method A (except that the reaction temperature was 0-25oC, and as the solvent used a mixture of dichloromethane/dimethylformamide (1:1)), and the crude product was purified by chromatography on silica using as eluent 2 to 10% ethanol/dichloromethane. Yield: 69%, VRIJ (60/40), 3.38 minutes (96%); PB-MS 428/430 (MH+, 100%).

Analysis for C22H22ClN3O4+ 0,125 H2O:

Calculated: C 61,43; H To 5.21; N 9,77.

Found: C 61,09; H To 5.57; N 9,68.

Example 40

5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-isoxazolidine-2-yl-3-oxo-propyl)-amide

Isoxazolidine hydrochloride (Cupps T. L, et al., J. Org. Chem, 1985, 50, 3972-3979, or 0.83 mm) and (3S)-[(5-in accordance with Method A, and the product was purified by chromatography on silica gel, using as eluent 50% and 75% ethyl acetate/hexane. Output = 75%; VRIJ (60/40), 4,94 minutes (95%); TSP-MC 428/430 (MH+, 100%).

1H-NMR (DMSO-d6) : 11,70 (s, 1H), 8,17 (d, 1H, J = 9.3 Hz), 7,71 (s, 1H, J = 2 Hz), 7,38 (d, 1H, J = 8.7 Hz), 7,27 (m, 4H), to 7.15 (m, 3H), 5,02 (d, 1H), br4.61 (m, 1H), 4,42 (DD, 1H), 4,10 (m, 1H), 3,93 (m, 1H), 3,55 (m, 1H), 2,95 (m, 2H), and 2.26 (m, 2H).

Analysis for C22H22ClN3O4:

Calculated: C 61,75; H 5,18; N 9,82;

Found: C 61,59; H 5,35; N 9,44.

Example 41

5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R)-diethylcarbamoyl-hydroxy-methyl)-2-phenyl-ethyl]-amide

Diethylamine (0.45 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] - (2R)-hydroxy-4-phenylalanyl acid (0.4 mm) was subjected to the reaction of interaction in accordance with method A, and the obtained product was purified by chromatography on silica (eluent: 10-25% ethyl acetate/hexane). Yield = 35%; VRIJ (60/40), 7,06 minutes (96%); so pl. 218-222oC, PB-MS 428/430 (MH+, 100%).

1H-NMR (CDCl3) : 9,14 (s, 1H), to 7.61 (s, 1H), 7,44-to 7.15 (m, 7H), for 6.81 (d, 1,3 H), 6,55 (d, 1H, J = 10 Hz), 4,55 (m, 1H), 4,37 (d, 1H, J = 5,2 Hz), the 4.29 (d, 1H, J = 5.3 Hz), 3.43 points (m, 1H), 3,2-3,0 (m, 3H), 2,88 (square, 2H, J = 7 Hz), of 1.05 (t, 3H, J = 7,1 Hz), and 0.98 (t, 3H, J = 7,1 Hz).

Example 42

5-Chloro-1H-indole-2-carboxylic acid { (1S (0.77 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenyl-butyric acid (0.70 mm) was subjected to the reaction of interaction in accordance with method A (except that the solvent used is dimethylformamide, and the extraction was carried out with acid, then base) and the resulting product was purified by chromatography on silica (eluent: 0.5 to 8% ethanol/dichloromethane) and triturated with ether/hexane. Yield: 65%; VRIJ (60/40), to 3.67 min (93%); so pl. 192.5 kg-195oC; TSP-MS 430/432 (MH+, 100%).

1H-NMR (CDCl3) : 9,18 (width, 1H), 7,60 (d, 1H, J = 2 Hz), 7,4-7,25 (m, 6H), 7,24 (DD, 1H, J = 2,9 Hz), 6,85 (d, 1H, J = 2 Hz), 6,63 (d, 1H, J = 9 Hz), is 4.85 (m, 1H), 4,47 (m, 1H), 4,06 (m, 1H), 3,63 (m, 2H), 3,12 (m, 2H), 2.95 and (C, 3H), 2,85 (m, 1H), 2,5 (width, 2H).

Analysis for C22H24ClN3O4:

Calculated: C 61,46; H 5,63; N 9,77.

Found: C 61,45; H 5,95; N 9,85.

Example 43

5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-oxo-3-piperidine-1-yl-propyl)-amide

Piperidine hydrochloride (0,42 mm) and (3S)-[(5-chloro-1H-indole-2 - carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.4 mm) was subjected to the reaction of interaction in accordance with method A (using as solvent dichloromethane/dimethylformamide, 1:1), and the obtained product was purified by chromatography on silica (eluent: 20% to 25% ethyl acetate/hexane). The output is 97%; VRIJ (60/40), 6.92 minutes (100%); PB-MS 440/442 (MH+, 100%).

Analysis>/P>Example 44

5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-2(R)-hydroxy-3-morpholine-4-yl-3-oxo-propyl)-amide

Morpholine (0.55 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]- (2R)-hydroxy-4-phenyl-butyric acid (0.5 mm) was subjected to the reaction of interaction in accordance with method A (solvent: dimethylformamide), and the obtained product was purified by rubbing with ether. Yield: 50%; VRIJ (60/40), 5.37 min (>98%); TSP-MS 442/444 (MH+, 100%);

1H-NMR (CDCl3) : 9,13 (width, 1H), to 7.59 (d, 1H, J = 2 Hz), 7,35 to 7.1 (m, 7H), 6,79 (d, 1H, J = 2 Hz), 6,51 (d, 1H, J = 9 Hz), 4,55 (m, 1H), 4,30 (m, 1H), 4,27 (m, 1H), of 3.77 (m, 1H), 3,62 (m, 2H), 3,50 (m, 3H), 3,05 (m, 3H), to 2.94 (m, 1H).

Analysis for C23H24ClN3O4:

Calculated: C 62,51; H Vs. 5.47; N 9,51.

Found: C 62,11; H 5,39; N 9,19.

Example 45

5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-[1,2] oxazine-2-yl-3-oxo-propyl)-amide

[1,2] Oxazinone hydrochloride (0,42 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.4 mm) was subjected to the reaction of interaction in accordance with method A (solvent: a mixture of dichloromethane/DMF (dimethylformamide), 1:1), and the obtained product was purified by chromatography on silica (eluent: 25% ethyl acetate/hexane). Yield: 76%; VRIJ (60/40), 6.07 minutes (99%); Rvac), 6,55 (d, 1H, J = 9 Hz), 4,89 (m, 1H), 4,58 (s, 1H), 4.00 points (m, 1H), to 3.67 (m, 3H), 3,10 (m, 2H), 1.9m (W), of 1.7 (m, 4H).

Analysis for C23H24ClN3O4:

Calculated: C 62,51; H Vs. 5.47; N 9,51.

Found: C 62,18; H 5,59; N 9,29.

Example 46

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy - 3-((3S)-hydroxy-pyrrolidin-1-yl)-3-oxo-propyl]-amide

(R)-3-Hydroxypyrrolidine (0.58 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenylalanyl acid (0.56 mm) was subjected to the reaction of interaction in accordance with method A, and the resulting product was twice purified by chromatography on silica (eluent: 25-100% ethyl acetate/hexane). Yield = 9%; VRIJ (60/40), 3.87 minutes (96%); PB-MS 442/444 (MH+, 100%).

Example 47

5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R)-tert-butoxycarbonyl-hydroxy-methyl)-2-phenyl-ethyl]-amide

5-Chloro-O-tert-butylhydroxytoluene hydrochloride (2.0 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (1.0 mm) was subjected to the reaction of interaction in accordance with method A (except that the solvent used is dimethylformamide, and washing acid neglected), and the obtained product was purified by chromatography on silica (eluent: CDCl3) : 9,38 (width, 1H), 9,18 (width, 1H), 7,85 (W, H), 7,53 (s, 1H), 7.3 to a 7.0 (m, 7H), 6.87 in (s, 1H), and 4.40 (d, 1H, J = 4 Hz), 4,30 (m, 1H), 3,20 (m, 2H), 1,12 (s, 9H).

Example 48

5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-oxo-3-thiazolidin-3-yl-propyl)-amide

Thiazolidin (0.70 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.67 mm) was subjected to the reaction of interaction in accordance with method A (except that the solvent used a mixture of dichloromethane/DMF (dimethylformamide), 1:1), and received a product that was used without additional purification. Yield: 93%; VRIJ (60/40) 5,78 minutes (96%); PB-MS 444/446 (MH+, 100%).

Analysis for C22H22ClN3O3:

Calculated: C 59,52; H 5,00; N For 9.47.

Found: C 59,29; H 5,22; N Which 9.22.

Example 49

5-Bromo-1H-indole-2-carboxylic acid [(1S)-((R)-dimethylcarbamoyl-hydroxy-methyl)-2-phenyl-ethyl]-amide

Dimethylamine hydrochloride (0,39 mm) and (3S)-[(5-bromo-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.32 mm) was subjected to the reaction of interaction in accordance with method A (reaction temperature = 0-25oC). The crude product (159 mg) was mixed with 200 mg of polystyrene-DMAP (Aldrich Chemical Co., Milwaukee, WI) in dichloromethane at 25oC 1-176oC; TSP-MS 444/446 (MH+, 85%);

Analysis for C21H22N3O3Br:

Calculated: C 56,77; H 4,99; N 9,46.

Found: C 56,42; H 5,33; N Remaining 9.08.

Example 50

5-Chloro-1H-indole-2-carboxylic acid [(1S)-[(R)-hydroxy-(pyridine-3-ylcarbonyl)-methyl]-2-phenyl-ethyl]-amide

3-Aminopyridine (0.7 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenyl-butyric acid (0.70 mm) was subjected to the reaction of interaction in accordance with method A (using as a solvent of dimethylformamide, and the resulting product was purified by chromatography on silica, elwira 0.5 to 8% ethanol in dichloromethane containing 0.5% ammonium hydroxide, and then triturated with ether. Yield = 45%; VRIJ (60/40) is 3.08 min (>99%); TSP-MS 449/451 (MH+, 100%);

Analysis for C24H21ClN4O3+ 0,3 H2O:

Calculated: C 63,45; H 4,79; N Of 12.33.

Found: C 63,35; H To 5.03; N 12,37.

Example 51

5-Chloro-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(2,2,2-triflora-ethylcarbamate)-methyl]-2-phenyl}-ethyl]-amide

2,2,2-Trichoroethylene (0.28 mmol) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.28 mm) was subjected to the reaction of interaction in accordance with method A (using dimethyl what course = 81%; PB-MS 454/456 (100%, MH+), 471/473 (MH+, NH3, 80%).

Analysis for C21H19ClF3N3O3:

Calculated: C 55,58; H 4,22; N 9,26.

Found: C 55,29; H 4,25; N 9,04.

Example 52

(S)-5-Chloro-1H-indole-2-carboxylic acid [1-(methoxy-methyl-carbamoylmethyl)-2-phenyl-ethyl]-amide

To a solution of anhydrous dimethyl sulfoxide (4 ml) and anhydrous toluene (4 ml) at 0oC was sequentially added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC, 790 mg, 4,12 mm), dichloracetic acid (136 mg, of 1.06 mm) and 5-chloro-1H-indole-2-carboxylic acid [(1S)-[(R)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl]-amide (287 mg, 0,69 mm). After storage for 18 hours at a temperature of 25oC, the reaction mixture was diluted with ethyl acetate, and the resulting solution was washed with 2N hydrochloric acid and saturated aqueous sodium bicarbonate. The organic layer was dried and concentrated. The resulting substance in the form of foam was recrystallized from ether. Output = 100 mg, 35%; VRIJ (60/40) of 10.72 minutes (87%); the original product was suirable within 6,68 minutes, output = >0,5%; PB-MS 414/416 (MN+, 70%), 384/386 (100%).

1H-NMR (CDCl3containing 10-20% DMSO-d6) : 9,90 (width, 1H), 7,54 (d, 1H, J=1.7 Hz), and 7.3, and 7.1 (m, approx. Oty [(1S)-benzyl-(2R)-hydroxy-3-(4-hydroxy-piperidine-1-yl)-3-oxo-propyl]-amide

4-Hydroxypiperidine hydrochloride (0.51 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4 - phenylalanyl acid (0.48 mm) was subjected to the reaction of interaction in accordance with Method A (except that the reaction temperature was 0-25oC), and the obtained product was purified by rubbing with ether, and then rubbing in boiling ethyl acetate, after which the product was chromatographically on silica (eluent: 50-100% ethyl acetate/hexane). Yield: 57%; VRIJ (60/40) to 3.92 min (96%); so pl. 230-232oC; TSP-MC 456/458 (MN+,100%).

1H-NMR (DMSO-d6) : 11,65 (width, 0.5 H), 11,60 (width, 0.5 H), 8,24 (m, 1H), of 7.70 (d, 1H, J=2 Hz), 7,38 (d, 0.5 H, J=9 Hz), 7,37 (d, 0.5 H, J=9 Hz), and 7.3, and 7.1 (m, 7H), 4,0-4,7 (m, 2H), and 4.5 (m, 2H), 3.8 to the 3.65 (m, 3H), 3,2 (m, 1H), 3,1 (DD, 1H), 3,0 (DD, 1H), 1,95 (m, 0.5 H), 1,7-of 1.65 (m, 2H), 1,4-1,25 (m, 1, 5H).

Example 54

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl(2R)-hydroxy - 3-((3R, S)-hydroxy-piperidine-1-yl)-3-oxo-propyl]-amide

3-Hydroxypiperidine (0.56 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0,54 mm) was subjected to the reaction of interaction in accordance with method A, and the obtained product was purified by chromatography on silica (eluent: 20-40% ethyl acetate/hexane) and then by rubbing with a mixture of ether/hexane (1:1). O the UB>:

Calculated: C 63,22; H Of 5.75; N Which 9.22.

Found: C 62,93; H 5,90; N 8,92.

Example 55

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((2R)-hydroxymethyl-pyrrolidin-1-yl)-3 - oxo-propyl]-amide

P-2-Pyrrolidineethanol (1.1 Mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (1.1 mm) was subjected to the reaction of interaction in accordance with Method A, and the obtained product was purified by chromatography on silica using as eluent 1-8% ethanol/dichloromethane, and then, using chromatography on silica using as eluent 50% ethyl acetate/hexane. Yield = 9%; VRIJ (60/40) 5.17 minutes (84%); so pl. 236-239oC; TSP-MC 456/458 (MN+, 100%).

Analysis for C24H26ClN3O4:

Calculated: C 63,22; H Of 5.75; N Which 9.22.

Found C 63,23; H 6,11; N Charged 8.52.

Example 56

5-Chloro-1H-indole-2-carboxylic acid ((1S)-{ (R)-[(2-dimethylaminoethyl)-methyl-carbarnoyl]-hydroxy-methyl}-2-phenyl - ethyl)-amide

N-(2-Dimethylaminoethyl)methylamine (0.77 mm) and (3S)-[(5-chloro-1H - indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.70 mm) was subjected to the reaction of interaction in accordance with method A (solvent: dimethylformamide), and the resulting product acidulated, by trituration with ether/hexane. Yield =87%; VRIJ (60/40) 2,89 min (96%); S-MS 457/549 (MN+, 100%).

Analysis for C24H29ClN4O3+ 0,2 H2O:

Calculated: C 62,59; H To 6.43; N 12,16.

Found: C 62,85; H 6,82; N 12,06.

Example 57

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3R, 4R)-dihydroxy-pyrrolidin-1-yl)-2-hydroxy-3-oxo-propyl)-amide

(3R,4R) -3,4-Dihydroxypyrrolidine (2S,3S -(-)-tartaric acid (synthetic isomer) using the techniques described in U.S. Patent N 4634775 (1.0 mm), and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenyl - butyric acid (1.0 mm) was subjected to the reaction of interaction in accordance with method A (solvent: dimethylformamide), and the product was purified by chromatography on silica (eluent: ethyl acetate), and then rubbing with ether. Yield=72%; VRIJ (60/40) is 3.21 min (97%); TSP-MC 458/460 (MN+, 100%).

Analysis for C23H24ClN3O5:

Calculated: C 60,33; H 5,28; N 9,18.

Found: C 60,09; H To 5.21; N Remaining 9.08.

Example 58

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3S, 4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide

(3S, 4S)-Dihydroxypyrrolidine derived from the 2R,3R -(+)-tartaric acid (U.S. Patent N interaction in accordance with Method A ( using as a solvent of dimethylformamide), and the obtained product was purified by chromatography on silica (eluent: ethyl acetate), and then rubbing with ether. Output-60%; VRIJ (60/40) to 3.02 min (98%); S-MS 458/460 (MN+, 100%).

Analysis for C23H24ClN3O5:

Calculated: C 59,16; H Of 5.40; N 9,00.

Found: C 59,44; H Of 5.29; N 8,95.

1H-NMR (DMSO-d6) : 11,7 (width,1H), 8,18 (d, 1H, J=9 Hz), of 7.70 (d, 1H, J= 2 Hz), 7,38 (d,1H, J=8.6 Hz), 7,26 (m,4H), to 7.15 (m,3H), by 5.18 (d,1H, J=4.0 Hz, currency), 5,11 (d,1H), 5,08 (d, 1H), 4,47 (m, 1H), 4,27 (DD, 1H, J=5,9 Hz, collapse to a doublet with D2O) 3,95 (m, 1H), with 3.89 (m, 1H), 3,64 (DD, 1H, J= 4,9 Hz) to 3.34 (m, 3H), of 2.92 (m, 2H).

Example 59

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzene-3-((3R, 4S)-dihydroxy-pyrrolidin-1-yl)-(2S)-hydroxy-3-oxo-propyl]-amide

(3R, 4S)-Dihydroxypyrrolidine hydrochloride (CIS - or meso-isomer, 0,86 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0,82 mm) was subjected to the reaction of interaction in accordance with method A (using as a solvent of dimethylformamide, and the resulting product was purified by chromatography on silica (eluent: 1-10% ethanol in dichloromethane). Yield: 39%; VRIJ (60/40) 2,92 min (96%); PB-MS 458/460 (MN+, 100%).

Analysis for C23H24ClN3O5+ 0,75 H2O:

CIS-3,4-dihydroxypyrrolidine-2,5-dihydro-pyrrol-1-carboxylic acid tert-butyl ether (1,99 g, 9.8 mm) was dissolved in a mixture of 4 M hydrochloric acid and dioxane at a temperature of 5oC, and the resulting suspension was stirred for 1 hour at a temperature of 25oC. the mixture was concentrated and the residue is triturated with ether, resulting in the received target product as a pale purple powder (1,30 g, 95%).

Example 59B

CIS-3,4-dihydroxy-pyrrolidin-1-carboxylic acid tert-butyl ester

A solution of the crude tert-butyl ester 2,5-dihydropyrrol-1-carboxylic acid was sequentially treated with osmium tetroxide (2.5% in t-butanol, 6 ml) and N-methylmorpholin-N-oxide at a temperature of 25oC. After 48 hours, to the mixture was added an aqueous solution of 10% sodium thiosulfate, and the mixture was stirred for 30 minutes, partially concentrated to remove tetrahydrofuran, and then, the resulting aqueous mixture was extracted twice with ether. The ether extracts were washed with 10% sodium thiosulfate and 0.1 M hydrochloric acid, and then dried and concentrated. The obtained dark orange oily substance was chromatographically on silica (eluent: 1%, 2%, 4%, 8% and 10% ethanol-dichloromethane), financial p the draw-pyrrole-1-carboxylic acid tert-butyl ether

Di-t-BUTYLCARBAMATE (83 g, 380 mm) was added to a solution of 3-pyrrolidine (containing 35% pyrrolidin; 25 g, 362 mm) in tetrahydrofuran (500 ml) at a temperature of 0oC. the resulting mixture was stirred for 1 hour at a temperature of 25oC, and then concentrated, resulting in a received 76,2 g yellow oily substance, which was used without further purification.

Example 60

5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-oxo-3-thiomorpholine-4-yl-propyl)-amide

Thiomorpholine (0,52 mm) and (3S)-[3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl - butyric acid (0,49 mm) was subjected to the reaction of interaction in accordance with method A (except that the reaction temperature was 0-25oC), and the obtained product was purified by chromatography on silica (eluent: a mixture of ethyl acetate/hexane). Output = 75%, VRIJ (60/40) 7,12 minutes (97%); PB-MC 458/460 (MH+, 100%).

1H-NMR (CDCl3, partial) : 9,15 (width, 1H), 7,60 (d, 1H, J = 2 Hz), between 7.4 to 7.2 (m, 7H), to 6.80 (d, 1H, J = 2 Hz), of 6.52 (d, 1H, J = 9 Hz), 4,55 (m, 1H), 4,29 (s, 1H), 4,10 (m, 1H), 3,48 (m, 1H), 3,30 (m, 1H), 3,2 - to 2.85 (m, 4H), 2,62 (m, 1H), 2,5 (m, 1H), 2,4 (m, 1H).

Example 61

5-Chloro-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(methyl-pyridine-1-yl-carb and-4-phenyl-butyric acid (4.4 mm) was subjected to the reaction of interaction in accordance with method A (except as a solvent used dimethylformamide, instead of 1-hydroxy-7-isobenzofuranone used 1-hydroxybenzotriazole, except the reaction time was 18 hours, and washing the acid did not), and the product was purified by chromatography on silica (eluent: 0.5 to 4% ethanol in dichloromethane), and then by four-fold trituration with ether. Yield = 5%; VRIJ (60/40) to 5.57 min (95%): TSP-MC 463/464 (MH+, 100%).

1H-NMR (DMSO-d6) : 11,73 (width, 1H), 8,24 (m, 1H), 8,18 (d, 1H, J = 9 Hz), 7,78 (dt., 1H, J = 2,9 Hz), 7,72 (d, 1H, J = 2 Hz), the 7.43 (s, 1H), 7,41 (s, 1H), 7,28 (m, 1H), 7,25 to 7.1 (m, 5H), 7,02 (m, 2H), of 5.05 (d, 1H, J = 9 Hz), 4,60 (m, 1H), 4,35 (m, 1H), up 3.22 (s, 3H), 2,70 (m, 2H).

Analysis for C25H23ClN4O3+ 1,3 H2O;

Calculated: C 61,74; H 5,31; N To 11.52.

Found: C 61,84; H 5,00; N To 11.52.

Example 62

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-(4-formylpiperazine-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide

3-Formylpiperazine (0.77 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.70 mm) was subjected to the reaction of interaction in accordance with method A (except that the solvent used is dimethylformamide, and washing was carried out with acid, then base) and polucheniya with ether/hexane. Yield = 78%; VRIJ (60/40) 3.45 minutes (96%), PB-MC 469/471 (MH+, 100%).

Analysis for C24H25ClN4O4+ 0,3 H2O:

Calculated: C 60,77; H 5,44; N 11,81.

Found: C 60,65; H 5,70; N 11,85.

Example 63

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(4-hydroxymethyl-piperidine-1-yl)-3-oxo-propyl] -amide

4-(Hydroxymethyl)piperidine (1.5 mm) (J. Med. Chem, 1991, 34, 1073) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (1.4 mm) was subjected to the reaction of interaction in accordance with Method A, and the obtained product was purified by chromatography on silica (eluent: 50-100% ethyl acetate/hexane). Yield = 70%; VRIJ (60/40) 4.09 to min (97%); TSP-MC 470/472 (MH+, 100%).

Analysis for C25H28ClN3O4+ 0,25 H2O:

Calculated: C 63,29; H Equal To 6.05; N 8,86.

Found: C 63,39; H 6,00; N 8,63.

Example 64

5-Chloro-1H-indole-2-carboxylic acid ((1S)-[(R)-hydroxy-[methyl(2-pyridin-2-yl-ethyl)-carbarnoyl]-methyl]-2-phenyl - ethyl)-amide

Methyl-(2-pyridin-2-yl-ethyl)-amine (0.77 mm) and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.70 mm) was subjected to the reaction of interaction in accordance with Method A (using as solvent, demetillo Omnia, yield = 82%, VRIJ (60/40) 3.33 minutes (97%); TSP-MC 491/493 (MH+, 100%).

1H-NMR (CDCl3) : 9,84 (width, 0,67 H), 9,35 (width, 0,3 H), 8,49 (m, 1H), 7,7 - 7.5 (m, 2H), and 7.4 to 7.1 (m, 9H), 6,92 (d, 0,3 H, J = 8 Hz), 6,8 (m, 14H), of 6.65 (d, 0,3 H, J = 9 Hz), to 4.62 (m, 1.5 H), and 4.5 (m, 0.5 H), 4,34 (s, 0,7 H), the 4.29 (s, 0,3 H), 3,82 (m, 1H), of 3.48 (m, 2H), 3,05 (m, 3H), 2,86 (s, 1H), 2,70 (s, 2H).

Analysis for C27H27ClN4O3+ 0,2 H2O:

Calculated: C 65,57; H 5,58; N 11,33.

Found: C 65,56; N Of 5.84; N 11,36.

Example 65

1-[(3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl - butisol]-piperidine-4-carboxylic acid ethyl ester.

Utilizedabated and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4-phenyl-butyric acid (0.75 mm) was subjected to the reaction of interaction in accordance with method A, and the obtained product was purified by chromatography on silica using as eluent 20-40% ethyl acetate/hexane. Yield = 95%; VRIJ (60/40) of 7.96 minutes (95%): PM-MC 512/514 (MH+, 100%).

Example 66

1-[(3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl - butyryl-pyrrolidin-2(S)-carboxylic acid tert-butyl ether

(S)-Pyrrolidin-2-carboxylic acid tert-butyl ester and (3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (2.1 mm) was subjected to reaction satorii on silica (eluent: 25-50% ethyl acetate/hexane). Yield: 74%, VRIJ (60/40) of 8.27 minutes (99%), TSP-MC (MH+, 100%).

Analysis for C28H32ClN3O5:

Calculated: C 63,93; H 6,13; N 7,99.

Found: C 64,05; H 6,32; N 7,79.

Example 67

5-Chloro-1H-indole-2-carboxylic acid [(1R)-[(S)-hydroxy-(methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl]-amide

5-Chloro-1H-indole-2-carboxylic acid (0.25 mm) and (2S,3R)-3-amino-2-hydroxy-N-methoxy-N-methyl-4-phenylbutyramide hydrochloride (0.25 mm) was subjected to the reaction of interaction in accordance with method A (except that the reaction temperature was 0-25oC, and washing was carried out first with acid, then base). The crude product was dissolved in methanol containing 0.25 equivalent of 1 N. NaOH at 25oC for 2 hours, and another hour was dissolved in methanol containing 0.25 equivalent of 1N NaOH (for hydrolysis of the less polar N,O-bis-5-chloro-1H-indocarbocyanine derived), and then, the solution was concentrated, the residue was dissolved in ethyl acetate, and the resulting solution was washed with 2N hydrochloric acid and brine, then dried and concentrated. The residue was purified by chromatography on silica, elwira 30-50% ethyl acetate/hexane. Chromatographytandem substance (containing Li and concentrated. Yield = 57%; VRIJ (60/40) are 5.36 min (98%); so pl. 165-167oC; PB-MC 416/418 (MH+, 100%).

1H-NMR (CDCl3) : 9,4 (width, 1H), 7,58 (d, 1H, J = 2 Hz), between 7.4 and 7.1 (m, 7H), 6,77 (d, 1H, J = 2 Hz), 6,51 (d, 1H, J = 10 Hz), 4,91 (m, 1H), 4,30 (d, 1H, J = 5 Hz), 3,83 (d, 1H, J = 5 Hz), the 3.35 (s, 3H), of 3.13 (s, 3H), to 3.09 (m, 2H).

Analysis for C21H22ClN3O4+ 1,0 H2O:

Calculated: C 58,13; H 5,58; N 9,68.

Found: C 58,05; H 5,24; N 9,54.

Example 67A

(2S, 3R)-3-Amino-2-hydroxy-N-methoxy-N-methyl-4-phenyl-butyramide hydrochloride

{ 1(R)-[Hydroxy-((S)-methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl} -carbamino acid (285 mg, 0.8 mm) was dissolved in a cold mixture of 4N HCl and dioxane, and the resulting solution was stirred for one hour at a temperature of 0oC. Then, the mixture was concentrated and the residue is triturated with ether and dried, resulting in a received 207 mg (90%) solids.

Example 67B

{(1S)-[Hydroxy-((R)-methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl}- karamanova acid

(2S, 3R)-3-(t-Butoxycarbonylamino)-2-hydroxy-4-phenyl-butyric acid (300 mg, 1.0 mm, Sigma Chemical Co., St. Louis, MO) and N,O-dimethylhydroxylamine hydrochloride (104 mg, 1.1 mm) was subjected to the reaction of interaction in accordance with method A (except that the reaction temperature of the composition is [(1R)-[hydroxy-((R)-methoxy-methyl-carbarnoyl)-methyl]-2-phenyl-ethyl]-amide

N, O-Dimethylhydroxylamine the dihydrochloride (0.32 mm) and (3R)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyric acid (0.3 mm) was subjected to the reaction of interaction in accordance with method A (except that the reaction temperature was 0-25oC, and washing was carried out first with acid, then base) and the resulting product was purified using chromatography on silica (eluent: 20-50% ethyl acetate/hexane). Yield: 73%; VRIJ (60/40) a 4.86 min (95%); PB-MC 416/418 (MH+, 100%).

1H-NMR (CDCl3) : for 9.47 (width, 1H), 7,58 (d, 1H, J = 1.7 Hz), 7,31 (d, 1H, J = 8.7 Hz), 7,30 - 7,10 (m, 6H), is 6.78 (d, 1H, J = 10 Hz), 6,74 (s, 1H), 5,00 (m, 1H), 4,63 (m, 1H), 3,80 (width, approx. 1H), 3,70 (s, 3H), 3.04 from (s, 3H), 2,87 (m, 2H).

Analysis for C21H22ClN3O4+ 0,1 H2O:

Calculated: C 60,39; H Are 5.36; N 10,06.

Found: C 60,76; H 5,74; N 9,78.

Example 69

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-oxo-3-(1-oxo-1-thiazolidin-3-yl)-propyl]-amide

To a solution containing 5-chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-oxo-3-thiazolidin-3-yl-propyl)-amide (80 mg, 0.18 mm) in dichloromethane (2 ml) at a temperature of 25oC was added m-chloroperoxybenzoic acid (62 mg of a 50% solution, 0.18 mm). After conditioning in the course is a 10% sodium thiosulfate (12 ml) and ethyl acetate. The aqueous layer was separated and was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium bicarbonate, dried and concentrated, resulting in a yellow oily substance (80 mg, 96%), VRIJ (60/40) 3,37 min (97%), PB-MC: 460/462 (MH+, 100%).

Examples 70 and 71

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-oxo-3-(1-oxo-1-tiopronin-4-yl)-propyl]- amide

(Example 70) and

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-(1,1-dioxo-1-thiomorpholine-4-yl)-(2R)-hydroxy-3-oxo - propyl]-amide (Example 71)

To a solution containing 5-chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-oxo-3-thiomorpholine-4-yl-propyl)-amide (60 mg, 0.13 mm) in dichloromethane (1.5 ml) at a temperature of 25oC was added m-chloroperoxybenzoic acid (45 mg, 50% solution, 0.13 mm). After one hour, the mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (12 ml), aqueous 10% sodium thiosulfate (12 ml) and ethyl acetate. The aqueous layer was separated and was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium bicarbonate, dried and concentrated to obtain the desired sulfoxide (example 70) in the form of a yellow solid fuel is Output = 44 mg, 72%, VRIJ (60/40) 6,14 min (98%); PB-MC 474/476 (MH+, 100%). Was allocated less polar product (8 mg), which is identical to a target sulfone (example 71): URGH (60/40) 6,44 min (96%); PB-MC 490/492 (MH+, 100%).

Example 72

1-[(3S)-{ (5-Chloro-1H-indole-2-carbonyl)-amino} -(2R)-hydroxy-4 - phenyl-butyryl]-piperidine-4-carboxylic acid

To a solution containing ethyl ester 1-{(3S)-[(5-chloro-1H-indole-2-carbonyl)-amino] -(2R)-hydroxy-4-phenyl-butyryl} - piperidine-4-carboxylic acid (111 mg, 0.22 mm) in tetrahydrofuran (2 ml) at a temperature of 25oC solution was added lithium hydroxide (0.2 ml of 1 n solution in water). After settling for 18 hours, the mixture was concentrated and the residue triturated with ether. The obtained solid substance was distributed between water and ethyl acetate, and then brought to pH 1 by adding 6N hydrochloric acid. The organic layer was separated, dried and concentrated, resulting in a received 109 mg (100%) connection in the form of solids.

URGH (60/40) 3,79 min (99%); TSP-MC 484/486 (MH+, 100%).

1H-NMR (DMSO-d6) : 12,25 (width, 1H), 11,65 (width, 1H), 8,17 (d, 0.5 H, J= 9 Hz), 8,14 (d, 0.5 H, J=9 Hz), of 7.70 (d, 1H, J=2 Hz), 7,38 (d, 1H, J=8,8 Hz), 7,35 to 7.1 (m, 7H), 4,78 (m, 1H, exchanges with D2O), and 4.5 (m, 2H), 4,1 (m, 1H), and 3.8 (m, 0.5 H), and 3.7 (m, 0.5 H) and 3.15 (m, 0.5 H), and 3.0 (m, 2-2,5 H), to 2.75 (m, 1H), 1,2O:

Calculated: C 60,80; H Of 5.53; N 8,51.

Found: C 61,15; H Of 5.68; N 8,11.

Example 73

5-Chloro-1H-indole-2-carboxylic acid [(1S)-((R)-hydroxy - hydroxycarbamoyl-methyl)-2-phenyl-ethyl]-amide

To a solution containing 5-chloro-1H-indole-4-carboxylic acid [(1S)-((R)-tert-butoxycarbonyl-hydroxy-methyl-2-phenyl-ethyl-amide (256 mg, 0.58 mm) in dichloromethane (2 ml) was added triperoxonane acid (2 ml) and the resulting solution was stirred for 18 hours at a temperature of 25oC. After adding another 2 ml triperoxonane acid, and the mixture was left for 72 hours, and then concentrated, and the residue was chromatographically on silica gel (eluent: 2,5%, 5% and 10% ethanol/dichloromethane containing 1% acetic acid). The purified product was rubbed with a mixture of ether/hexane and dried. Yield: 70 mg, 31%, VRIJ (60/40) 3,11 min (96%).

Analysis for C19H18ClN3O + 1,0 OH2O:

Calculated: C 56,23; H Equal To 4.97; N 10,35.

Found: C 56,63; H 4,94; N 9,95.

Example 74

5-Chloro-1H-indole-2-carboxylic acid ((1S)-{ [(benzyl - piperidine-4-yl)-methyl-carbarnoyl]-(R)-hydroxy-methyl]-2-phenyl-ethyl)- amide

(3S)-[(5-Chloro-1H-indole-2-carbonyl)amino]-(2R)-hydroxy-4 - phenylalanyl acid (310 mg, 0.8 mm) and (1-benzyl-piperidine-4-yl)- methyl-amine hydrochloride (Publications is dimetilformamid). The crude product was purified by chromatography on silica gel (eluent: 0.5 to 4% ethanol in dichloromethane containing 0.5% ammonium hydroxide), and received the target compound as a colourless foam. Output = 140 mg, 30%, VRIJ (60/40); 4,15 min (95%); TSP-MC 559/562 (MH+, 100%).

Analysis for C32H35ClN4O3+ HCl + 1,5 H2O:

Calculated: C 61,73; H Of 6.31; N 9,00.

Found: C 61,61; H 6,29; N 8,71.

Example 75

4-({ 3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] - (2R)-hydroxy-4-phenyl-butyryl] -methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester

(3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino]-(2R)-hydroxy-4 - phenyl-butyric acid (1.0 g, 2.6 mm) and 4-methylamino - piperidine-1-carboxylic acid tert-butyl ester (575 mg, 2.6 mm) was subjected to the reaction of interaction in accordance with Method A (solvent : dimethylformamide). The crude product was purified by chromatography on silica gel, elwira 20%, 30%, 40%, 50% and 75% ethyl acetate/hexane. Output = 319 mg, 21%, VRIJ (60/40) 10,31 min (94%); 569/571 (MH+, 100%).

Example 75A

4-Methylamino-piperidine-1-carboxylic acid tert-butyl ether

To a solution of tert-butyl methyl ether 4-oxopiperidin-1-carboxylic acid in methanol (400 ml) at a temperature of 0oC th is zitat sodium (41,21 g, 502 mm) and 95% cyanoborohydride sodium (3,99 g, 60 mm), after which the mixture was heated to 25oC for several hours. After incubation for 18 hours at a temperature of 25oC, the reaction mixture was filtered through Celitesolid residues were washed with methanol and ethyl acetate, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, and then, the resulting solution was twice washed with 2N sodium hydroxide and once with saline. After drying and concentrating the received target oily substance (12,79 g, 119%).

Example 76

5-Chloro-1H-indole-2-carboxylic acid {[(1-S)-(R)-hydroxy- (methyl-piperidine-4-yl-carbarnoyl)-methyl]-2-phenyl-ethyl}-amide hydrochloride

4-({ (3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino]-(2R)- hydroxy-4-phenyl-butyryl-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (292 mg, 0.5 mm) was dissolved in 4 M HCl/dioxane at a temperature of 0oC, and the resulting solution was stirred for one hour at room temperature. The mixture was concentrated and then the residue is triturated with ether and dried. Output = 249 mg, 96%; VRIJ (60/40) 2.59 minutes (96%); PB-MC 469/471 (MH+, 100%).

1H-NMR (DMCO-d6) : 11,7 (s, 0,3 H), and 11.6 (s, 0,7 H) 8,75 (width, 2H, exchanges with D2O), of 7.70 (d, 1H, J=2 ), of 3.9 (m, 0,3 H), 3,4-3,2 (m, approx. 1,5 H), 2,95 (m, 2H), 2,15-1,8 (m, approx. 2,5 H), a 1.75-1,50 (m, 2H).

Analysis for C25H29ClN4O3+HCl + 0,7 H2O:

Calculated: C 57,96; H 6,11; N 10,82.

Found: C 58,22; H 6,23; N 10,46.

Example 77

5-Chloro-1H-indole-2-carboxylic acid { ((1S)-(R)-hydroxy-[methyl-(1-methyl-piperidine-4-yl)-carbarnoyl]-methyl}- 2-phenyl-ethyl)amide hydrochloride

To the solution containing the hydrochloride (1S)-[(R)-hydroxy -(methyl-piperidine-4-yl-carbarnoyl)-methyl] -2-phenyl-ethyl] -amide 5-chloro-1H-indole-2-carboxylic acid (100 mg, 0.2 mm) in methanol (2 ml) at a temperature of 25oC was sequentially added 100 mg of powdered molecular sieves 3A, 22 mg of triethylamine (0.2 mm), glacial acetic acid (64 mg, 1.1 mm), cyanoborohydride sodium (95%, 18 mg, 0.3 mm) and an aqueous solution of formaldehyde (37 wt.% in water, 22 mg, 0.3 mm). After incubation for 18 hours, the reaction mixture was filtered through Celiteand the solids were washed with methanol and concentrated. The residue was dissolved in ethyl acetate, and the resulting solution was twice washed with 2N sodium hydroxide at once with saline, and then dried and concentrated. The colorless solid residue was purified by chromatography on silica gel (eluent: 1-8% ethanol and the temperature at 0oC, and the resulting solution was treated to 0.21 litres 1,01 N. hydrochloric acid, and then immediately concentrated. The residue is triturated with ether and dried. Output = 87 mg, 79%; VRIJ (60/40) of 2.86 min (95%); TSP-MC 483/485 (MH+, 100%).

Example 78

(3S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -4-phenyl-butyric acid methyl ester

(3S)-3-Amino-4-phenyl-butyric acid methyl complex ester hydrochloride (1,15 g, 5 mm) and 5-chloro-1H-indole-2-carboxylic acid was subjected to the reaction of interaction in accordance with method A. the product was purified by trituration with ether. Output: 1,46 g (79%), VRIJ (60/40) cent to 8.85 min (100%); PB-MC 371/373 (MH+, 100%/35%).

Analysis for C20H19ClN2O3:

Calculated: C 64,78; H 5,16; N 7,55.

Found: C 64,81: H Of 5.34; N 7,46.

Example 78A

(3S)-Amino-4-phenyl-butyric acid methyl complex ester hydrochloride

(3S)-Tert-butoxycarbonylamino-4-phenyl-butyric acid methyl ester (see Heferocyles p. 1835 (1989) and J. Med, Chem. 1975, page 761, 3,49 g, 12,1 mm) was dissolved in a mixture of 4 M HCl/dioxane at 0oC, and then, the solution was stirred for half an hour at 2-25oC. the resulting mixture was concentrated, and the residue triturated with ether and dried. Output = 2,56 g (92%).

It should be borne in VI to be made various changes and modifications, does not extend, however, beyond being and scope of the invention, formulated in the following claims.

1. Derivatives of substituted N-(indole-2-carbonyl) - alaninemia General formula I

< / BR>
and their pharmaceutically acceptable salts and esters,

where the dashed line (---) indicates the connection;

Rather it represents a-C(H)=- C((C1- C4)alkyl)= or-C(halogen);

R1, R10, R11independently represent hydrogen, halogen, cyano, (C1- C4) alkyl, (C1- C4) alkoxy;

R2represents hydrogen;

R3represents hydrogen;

R4represents hydrogen, methyl, ethyl, n-propyl, hydroxy(C1- C3) alkyl, (C1- C3) alkoxy (C1- C3) alkyl, phenyl (C1- C4) alkyl, Tien-2 - or-3-yl(C1- C4) alkyl, where these rings R4are independently mono - or disubstituted y carbon atoms by halogen;

R5represents hydrogen, hydroxy, (C1- C5) alkyl, (C1- C5)alkoxy, benzyloxycarbonyl(C1-C4)alkoxy, carboxy(C1-C4)alkoxy, 5-chloro-1H-indole-2-carbonyloxy;

R7represents hydrogen, (C1 is, (C1-C8) alkoxycarbonyl, C(O)NR8R9or C(O)R12where R8represents hydrogen, (C1-C3) alkyl, hydroxy, (C1-C3) alkoxy and R9represents hydrogen, (C1-C8)alkyl, hydroxy, hydroxy (C1-C5) alkyl, (C1-C8) alkoxy, metalunderground (C1-C8) alkyl, pyridyl, piperidinyl, where the above rings R9attached via the linking carbon - nitrogen, where non-aromatic nitrogen-containing ring R9are optionally substituted by y nitrogen atom (C1-C4)alkyl, benzyl, (C1-C6) alkoxycarbonyl;

R12represents piperazine-1-yl, 4-(C1-C4) alkylpiperazine-1-yl, 4-formylpiperazine-1-yl, morpholino, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, thiazolidin-3-yl, 1-oxothiazolidine-3-yl, or R12represents 2-, 4 - and/or 5-mono - or disubstituted, thiazolidin-3-yl, 3 - or 4-mono - or disubstituted pyrrolidin-1-yl, 3-, 4 - and/or 5-mono-, di - or tizamidine piperidine-1-yl, 3-, 4 - and/or 5-mono-, di - or tizamidine piperazine-1-yl, 3-substituted, azetidin-1-yl, 4 and/or 5-mono - or disubstituted 1,2-oxazine-2-yl, 4 - and/or 5-mono or disubstituted isoxazol is and (C1-C6) alkoxycarbonyl or hydroxy (C1-C5) alkyl;

provided that if R4is hydrogen, stands, ethyl or n-propylene, R5is IT;

provided that if R5and R7are hydrogen, R4is not hydrogen, stands, ethyl, n-propylene, hydroxy (C1-C3) alkyl, and R6is C(O)NR8R9WITH(O)R12or (C1-C4) alkoxycarbonyl.

2. Connection on p. 1, where R1represents a 5-H, 5-halo, 5-methyl or 5-cyano; R10and R11independently represent H or halogen; a represents a-C(H)=; R2and R3represent H; R4represents phenyl (C1-C2) alkyl, where the above phenyl groups are independently mono-, disubstituted with halogen, or R4represents Tien-2 - or-3-yl (C1-C2) alkyl; R5represents hydroxy; R6represents C(O)NR8R9or C(O)R12and R7represents N.

3. Connection on p. 2, where the carbon atom and has the S-configuration; and the carbon atom b has an R configuration; R4represents phenyl (C1-C2) alkyl, mo mono - or disubstituted by fluorine; R6represents C(O)NR8R9; R8is a (C1-C3) alkyl, hydroxy or (C1-C3) alkoxy, R9represents H, (C1-C8) alkyl, hydroxy (C1-C6) alkyl, (C1-C8) alkoxy, pyridyl, piperidinyl.

4. Connection on p. 3, selected from the group comprising 5-chloro-1H-indole-2-carboxylic acid [(1S)-{(R)-hydroxy-dimethylcarbamoyl}-2-phenyl-ethyl] -amide; 5,6-sodium dichloro-1H-indole-2-carboxylic acid [(1S)-{(R)-hydroxy-(methoxy-methylcarbamoyl)-methyl} -2-phenyl-ethyl] -amide; 5-chloro-1H-indole-2-carboxylic acid { (1S)-[(R)-hydroxy-(methoxy-methylcarbamoyl)-methyl] -2-phenyl-ethyl} -amide; 5-chloro-1H-indole-2-carboxylic acid ((1S)-[(R)-hydroxy-[(2-hydroxy-ethylmethyl-carbarnoyl)-methyl] -2-phenyl-ethyl)-amide; 5-chloro-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(methyl-pyridin-2-yl-carbarnoyl)-methyl] -2-phenyl-ethyl}-amide or 5-chloro-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-methyl-(2-pyridin-2-yl-ethyl)-carbarnoyl]-methyl)-2-phenyl-ethyl}-amide.

5. Connection on p. 3, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl; R8represents methyl and R9represents sobn; R10represents a 6-chloro; R4represents benzyl; R8represents methyl and R9represents methoxy.

7. Connection on p. 3, where R1represents 5-chloro; R10and R11represents H; R4represents benzyl; R8represents methyl and R9represents methoxy.

8. Connection on p. 3, where R1represents 5-chloro; R10and R11represents H; R4represents benzyl; R8represents methyl and R9represents a 2-(hydroxy) ethyl.

9. Connection on p. 3, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl; R8represents methyl and R9represents pyridin-2-yl.

10. Connection on p. 3, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl; R8represents methyl and R9represents a 2-(pyridine-2-yl) ethyl.

11. Connection on p. 2, where the carbon atom and has the (S)-configuration; and the carbon atom b is (R)-configuration; R4represents Azania rings are independently mono - or disubstituted by fluorine; R6represents C(O)R12and R12represents morpholino, 4-(C1-C4) alkylpiperazine-1-yl, 3-substituted, azetidin-1-yl, 3 - or 4-mono - or disubstituted pyrrolidin-1-yl, 4 - and/or 5-mono or disubstituted, isoxazolidine-2-yl, 4 - and/or 5-mono - or disubstituted 1,2-oxazine-2-yl, where these substituents independently represent hydrogen, hydroxy, oxo.

12. Connection on p. 1, selected from the group comprising 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(4-methylpiperazin-1-yl)-3-oxo-propyl] -amide hydrochloride; 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(3-hydroxyazetidine-1-yl)-3-oxo-propyl] -amide; 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-isoxazolidine-2-yl-3-oxo-propyl] -amide; 5-chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-[1,2] -oxazine-2-yl-3-oxo-propyl)-amide; 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3S)-hydroxy-pyrrolidin-1-yl)-3-oxo-propyl] -amide; 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3S), 4S)-dihydroxypyrrolidine-1-yl)-(2R)-hydroxy-3-oxo-propyl] -amide; 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3R, 4S)-dihydroxypyrrolidine-1-yl)-(2R)-hydroxy-3-oxo-propyl] -amide; or 5-Gloria by p. 11, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl and R12is a 4-methylpiperazin-1-yl.

14. Connection on p. 11, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl and R12is a 3-hydroxyazetidine-1-yl.

15. Connection on p. 11, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl and R12is isoxazolidine-2-yl.

16. Connection on p. 11, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl and R12is a (1,2)-oxazine-2-yl.

17. Connection on p. 11, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl and R12is a 3(S)-hydroxypyrrolidine-1-yl.

18. Connection on p. 11, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl and R12is a (3S, 4S)-dihydroxypyrrolidine-1-yl.

20. Connection on p. 11, where R1represents 5-chloro; R10and R11represent H; R4represents benzyl and R12represents morpholino.

21. Connection on p. 1, where R1represents hydrogen, halogen, methyl or cyano; R10and R11independently represent H or halogen; a represents a-C(H)= ; R2and R3represent H; R4represents phenyl (C1-C2) alkyl, where the above phenyl groups are independently mono-, disubstituted with halogen, or R4represents Tien-2 - or-3-yl(C1-C2) alkyl, R5represents hydroxy; R6represents carboxy or (C1-C8) alkoxycarbonyl and R7represents hydrogen, (C1-C6) alkyl.

22. Connection on p. 21, where the carbon atom and has the (S)-configuration; and the carbon atom b is (R)-configuration; R4represents phenyl (C1-C2) alkyl, Tien-2-yl-(C1-C2) alkyl, Tien-3-yl-(C1-C2) alkyl, where these rings are independently m and R7represents N.

23. Connection on p. 22, where R1represents 5-chloro; R10and R11represent N and R4represents benzyl.

24. Connection on p. 1, where R1represents H, halogen, methyl or cyano; R10and R11independently represent hydrogen or halogen; a represents a-C(H)= ; R2and R3represent H; R4represents phenyl (C1-C2) alkyl, where the above phenyl groups are independently mono-, disubstituted with halogen, or R4represents Tien-2 - or 3-yl(C1-C2) alkyl; R5is a (C1-C4) alkyl, (C1-C5)-alkoxy, carboxy (C1- C4) alkoxy, benzyloxycarbonyl (C1-C4) alkoxy; R6represents carboxy or (C1-C8) alkoxycarbonyl and R7represents H, (C1-C6) alkyl.

25. Connection on p. 1, where R1represents H, halogen, methyl or cyano; R10and R11independently represent H or halogen; a represents a-C(H)= ; R2and R3represent H; R4represents phenyl (C1 represents Tien-2 - or 3-(C1-C2) alkyl; R5is a (C1-C4) alkyl, (C1-C5)-alkoxy, carboxy (C2-C4) alkoxy, benzyloxycarbonyl (C1-C4) alkoxy; R6represents C(O)NR8R9or C(O)R12and R7represents hydrogen, (C1-C6) alkyl.

26. The method of treatment glycolipoprotein disease or condition in a mammal, involving the administration to a mammal suffering glycolipoprotein the disease or condition, a therapeutically effective for the treatment of the specified disease or condition number of the connection on p. 1.

27. The method according to p. 26 for the treatment of hyperglycemia in a mammal, involving the administration to a mammal suffering from hyperglycemia, is effective for the treatment of hyperglycemia in the number of connections on p. 1.

28. The method according to p. 26 for treating diabetes in a mammal, involving the administration to a mammal suffering from diabetes, effective for the treatment of diabetes the number of connections on p. 1.

29. The method according to p. 26 for the treatment of hypercholesterolemia in a mammal, providing velicescu connection on p. 1.

30. The method according to p. 26 for the treatment of atherosclerosis in a mammal, involving the administration to a mammal suffering from atherosclerosis, effective for the treatment of atherosclerosis number of connections on p. 1.

31. The method according to p. 26 for treating hyperinsulinemia in a mammal, involving the administration to a mammal suffering from hyperinsulinemia, effective for the treatment of hyperinsulinemia number of connections on p. 1.

32. The method according to p. 26 for treating hypertension in a mammal, involving the administration to a mammal suffering from hypertension, it is effective for the treatment of hypertension in the number of connections on p. 1.

33. The method according to p. 26 for the treatment of hyperlipidemia in a mammal, involving the administration to a mammal suffering from hyperlipidemia, effective for the treatment of hyperlipidemia number of connections on p. 1.

34. The method according to p. 26 to prevent ischemic damage to the myocardium in a mammal, involving the administration to a mammal at risk of myocardial ischemic injury during the operation, effective to prevent the specified damage number of connections on p. 1.

35. Pharmaceutical HDMI is active number of connections on p. 1 and a pharmaceutically acceptable carrier.

36. The pharmaceutical composition according to p. 35, intended for the treatment of glycohemoglobin diseases or conditions in mammals and includes a therapeutically effective for the treatment of specified diseases or conditions, the number of connections on p. 1 and a pharmaceutically acceptable carrier.

 

Same patents:

The invention relates to new derivatives of chromone General formula 1, in which ring a is unsubstituted or one-deputizing halogen, and where the ring is unsubstituted or substituted by one to four substituents selected from the group consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts, also describes a method of production thereof and pharmaceutical composition based on compounds of the formula I, which has antagonistic activity against neirokinina 1

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

The invention relates to new derivatives of phenyl-oxo-alkyl-(4-piperidinyl)benzoate of formula I, their N-oxide forms, salts and steric isomer forms, where R1- halogen, R2is hydrogen, R3- C1-6-alkyl, or R2and R3form together a bivalent radical of the formula -(CH2)2- or -(CH2)3-, Alk-C1-6-alcander, R4is hydrogen or C1-6-alkoxy, R5, R6and R7is hydrogen, halogen, C1-6-alkyl, C1-6-alkyloxy or R5and R6taken together , form a bivalent radical of the formula-NR8-C(O)-NR9- or-NH-C(NH-R10)=N-, where R8and R9is hydrogen, C1-6-alkyl, R10is hydrogen, C1-6-alkylsulphonyl, C1-6-allyloxycarbonyl

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The invention relates to substituted azetidinone General formula I listed in the description

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The invention relates to new derivatives of benzimidazole and their salts formed by the addition of acids, the way they are received and microbicide tool based on them

The invention relates to the derivatives of hintline formula (I), where n = 2 and each R2independently halogen; R3- (1-4C)alkoxy; R1di-[(1-4C)alkyl]amino(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)-alkoxy-(2-4C)alkyl] amino-(2-4C)alkoxy, and any R1containing methylene group, which is not linked to the nitrogen atom or oxygen atom, and optionally contains in the indicated methylene group, a hydroxyl Deputy, or their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions containing these compounds, and the use of inhibitory activity of compounds to inhibit the receptor tyrosinekinase in the treatment of proliferative diseases, such as cancer

The invention relates to substituted azetidinone General formula I listed in the description

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The invention relates to inhibitors of glycogen phosphorylase, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia in mammals

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity
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