Substituted n-(indole-2-carbonyl)-glycinamide and their derivatives, methods of treatment and farmcampsite

 

(57) Abstract:

Describes substituted N-(indole-2-carbonyl)-glycinamide and their derivatives of General formula (I), where the values of R1- R6, R10, R11and As stated in paragraph 1 of the claims, which exhibit the properties of inhibitors of glycogen phosphorylase. Also described is a method of treatment and farmcampsite on the basis of the compounds of formula (I) to reduce the activity of glycogen phosphorylase in mammals. 4 C. and 51 C.p. f-crystals, 1 PL.

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.

Despite the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas (e.g. chlorpropamideTM(Pfizer), tolbutamideTM(Decision Upjohn), acetohexamideTM(E. I. Lilly), tolazamideTM(Decision Upjohn)) and biguanides (for example, phenforminTM(Ciba Geigy), MetforminTM(G. D. Searle)) as oral hypogo approximately 10% of patients with diabetes, for which synthetic hypoglycemic agents ineffective (diabetes type I, insulin dependent diabetes mellitus), requires multiple daily injection, usually by self-injection. Determination of the appropriate dosage of insulin requires frequent determination of sugar in urine or blood. Introduction excessive dose of insulin causes hypoglycemia with effects varying from mild abnormalities of glucose in the blood to coma or even death. Treatment of insulin-independent diabetes (type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral means, such as the sulfonylureas, and in more severe cases, insulin injections. However, clinically available hypoglycemic agents may have other side effects that limit their use. In any case, when one of these drugs may be ineffective in some particular case, the other can provide success. The remaining need for hypoglycemic tools that have fewer side effects or yield success when other ineffective obvious.

Atherosclerosis, a disease of the arteries, as installed, is chiefly the memory and the occlusal disease of the heart, well known. The early stage of this chain is the formation of "fat bars" in the carotid arteries, coronary and cerebral arteries and in the aorta. These lesions have a yellow color due to the presence of fat found mainly in the smooth muscle cells and in macrophages of the inner layer of arteries and aorta. In addition, it was found that a large part of the cholesterol found in fatty streaks, in turn, causes the development of fibrous plaques, which consist of clusters of internal smooth muscle cells loaded with lipid and surrounded by extracellular fat, collagen, elastin and proteoglycans. Cells plus matrix form fibrous thickening, which covers a deeper deposition of cell residues and additional extracellular lipids. Lipid represented mainly by free or esterified cholesterol. The fibrous plaque is formed slowly and, probably, in due time becomes calcified and necrotic, resulting in "complicated defeat" than due to arterial occlusion and the tendency to intramural thrombosis and spasm of the muscles of the arteries, which are the characteristic features of advanced atherosclerosis.

Hypertension (or high blood pressure) is a condition that occurs in humans as a secondary symptom of various other diseases, such as renal artery stenosis, pheochromocytoma, or endocrine disorders. However, hypertension is observed in many is related to diseases, such as obesity, diabetes, and hypertriglyceridemia, the relationship between these diseases is not clear. In addition, many patients manifest symptoms of high blood pressure in the complete absence of any other signs of disease or disorders.

It is known that hypertension can lead to heart failure, kidney failure and stroke (bleeding in the brain). These conditions may be a cause of sudden death of the patient. Hypertension may also contribute to the development of atherosclerosis and coronary artery disease. These States gradually weaken the patient and can lead to death after a prolonged illness.

The exact cause of hypertension is unknown, although several factors are believed to contribute to disease onset. Among these factors are stress, uncontrolled emotions, unregulated secretion of hormones (renin, angiotensin, aldosterone system), excess salt and water due to poor kidney function, the thickening of the vascular wall and hypertrophy of the vascular network, leading to constriction of blood vessels, and genetic factors.

Treatment of hypertension was made taking into account the above factors. To drugs enzyme inhibitors, angiotensin converting, and the like, as antihypertensive agents. Treatment of hypertension with the use of these compounds have been proven beneficial to prevent sudden death as a result of such conditions as heart failure, kidney failure and bleeding in the brain. However, the development of atherosclerosis or heart disease over a long period of time remains an unsolved problem. This means that although high blood pressure is reduced, the main cause of hypertension does not respond to this treatment.

A connection was established hypertension with elevated levels of insulin in the blood, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary action is to stimulate glucose utilization, protein synthesis and the formation and accumulation of neutral fats, also acts as a growth stimulator cells of blood vessels and increases renal sodium retention, among others. These latter functions can be performed without affecting glucose levels and is known to cause hypertension. The growth of the peripheral vasculature, for example, can cause narrowing of perifereia with hyperinsulinemia can prevent abnormal growth of a network of vessels and renal sodium retention, due to high levels of insulin, and thereby alleviate hypertension.

Cardiac hypertrophy is a major risk factor in the occurrence of sudden death, myocardial infarction and congestive heart failure under overload conditions. These cardiac effects associated at least partially with a heightened sensitivity to myocardial injury after ischemia and resumed perfusion, which may occur in the ambulatory patient, as well as operating conditions. There is unmet need in medicine to prevent or minimize adverse outcomes of operations to attack, especially myocardial infarction before and after surgery. As non-cardiac and cardiac surgery are associated with significant risk of myocardial infarction or death. It is believed that at risk approximately 7 million patients with non-cardiac surgery, with deaths before or after surgery and serious complications for the heart at such a level as 20-25% in some series. In addition, 400000 patients undergoing annually surgery coronary artery bypass graft surgery, the occurrence of myocardial infarction before and after the operation is estimated at 5% and mortality at the level of 1-2%. In nastoiastee myocardial ischemia during surgery or increases cardiac tolerance to episodes of ischemia. This therapy, as suggested, is inesperada and reduces the number of hospitalizations, improves quality of life and reduces the overall cost of treatment of patients with high risk of complications.

The glucose production in the liver is an important target for the treatment of NIDDM. The liver is the main regulator of glucose levels in the plasma in a state after absorption (stable), and the degree of glucose production in the liver in patients with NIDDM significantly increased compared with normal individuals. Similarly in the afternoon (eating) state, when the liver plays a proportionately smaller role in the total intake of glucose in plasma, glucose production in the liver remains abnormally high in patients with NIDDM.

Glycogenolysis is an important target to interrupt the production of glucose in the liver. The liver produces glucose by glycogenolysis (the breakdown of polymer of glucose, glycogen) and gluconeogenesis (synthesis of glucose from precursors of 2 or 3 carbon atoms). Data from several directions show that glycogenolysis can make an important contribution to the glucose output from the liver in NIDDM. First, it is established that a normal person after completion of suction to 75% prokopenya of glycogen in the liver, including disease Gers (glikogenogeneza failure), manifested by episodic hypoglycemia. These observations suggest that the glycogenolysis can be an important process for the production of glucose in the liver.

Glycogenolysis is catalyzed by liver, muscle and brain tissue-specific isoforms of the enzyme glycogen phosphorylase. This enzyme breaks down the glycogen macromolecule with the release of glucose-1-phosphate and a new shortened glycogen macromolecule. To date, reported on the 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 (Kasvinski, P. J. et al. J. Biol. Chem. 1978, 253, 3343-3351 and 9102-9106). These compounds and inhibitors of glycogen phosphorylase, as stated, have the potential for use in the treatment of NIDDM by reducing the production of glucose in the liver and reduce blood glucose (Blundell, T. B. et al. Diabetologia, 1992, 35, Suppl. 2, 569-576 and Martin et al. Biochemistry, 1991, 30, 10101).

The mechanisms responsible for myocardial damage observed after ischemia and resuming perfusion, is still not fully understood. It was reported that (M. F. Allard, et al. Am J. Physiol. 267, N-N, 1994) "predicamento reduction of glycogen. .. associated with improved polysemy the zoom, although there are many methods of treatment of hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia remains a need and research continues in this area to seek alternative therapy.

This invention is directed to the obtaining of glycogen phosphorylase inhibitors - compounds of formula I, used to treat diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hypertension, hyperlipidemia, atherosclerosis and myocardial ischemia.

The compounds of this invention have the formula I

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

where (dashed line (---) is an optional bond;

A is-C(H)=, -C((C1-C4)alkyl) =, -C(halogen)= or-N=, when the dashed line (---) is a bond, or a is a methylene or is-CH((C1-C4)alkyl)-, when the dashed line (---) is not represented by a link;

R1, R10or R11each independently are H, halogen, cyano-, 4-, 6 - or 7-nitro-, (C1-C4)alkyl, (C1-C4)alkoxyl, formation, deformation or trifluoromethyl;

R2is H;

R3the t is C3)-alkyl, (C1-C3)alkoxy (C1-C3)alkyl, phenyl(C1-C4)alkyl, phenylketone(C1-C4)alkyl, (phenyl) ((C1-C4)-alkyl, -alkoxy) (C1-C4)Tien-2 - or-3-yl(C1-C4)alkyl or FSD-2 - or-3-yl (C1-C4) alkyl, and the above rings R4are mono-, di - or tizamidine, independently, a carbon atom, hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxyl, trifluoromethyl, hydroxyl -, amino -, cyano - or 4,5-dihydro-1H-imidazol-2-yl; or

R4is pyrid- -2-, -3 - or-4-yl (C1-C4)alkyl, thiazol-2-, -4 - or-5-yl (C1-C4)alkyl, imidazol-2-, -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, pyrimidine-2-4-, -5 - or-6-yl(C1-C4)alkyl, pyrazin-2 - or-3-yl(C1-C4)alkyl, 1,3,5-triazine-2-yl(C1-C4) alkyl or indol-2--(C1-C4)alkyl, moreover, these previous B>1-C4)alkyl, (C1-C4)alkoxyl, amino, hydroxyl or cyano, and these substituents bound to carbon; or

R4is R15-carbonylmethyl, where R15is phenyl, thiazolyl, imidazolyl, 1H-indolium, fullam, pirrallo, oxazolium, pyrazolyl, isoxazolyl, isothiazolines, pyridium, pyridazinyl, pyrimidinyl, pyrazinium or 1,3,5-triazinium and moreover, these previous ring R15are arbitrarily mono - or di-substituted independently with halogen, amino, hydroxyl, (C1-C4)alkyl, (C1-C4)alkoxyl or trifluoromethyl, and these mono - or di-substituents bound to carbon;

R5is stands, ethyl, n-propylene, hydroxymethyl or hydroxyethyl;

R6is carboxyla, (C1-C8)alkoxycarbonyl, benzyloxycarbonyl, C(O)NR8R9or C(O)R12where

R8is H, (C1-C6)alkyl, cyclo(C3-C6)alkyl, cyclo(C3-C6)alkyl(C1-C5)alkyl, hydroxyl or (C1-C8)alkoxyl; and

R9is H, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkyl (C1-C5)-al is 3-C7)alkyloxy, hydroxyl, methylene-perfluorinated (C1-C8)-alkyl, phenyl or a heterocycle, and said heterocycle is pyridium, fullam, pirrallo, pyrrolidinium, oxazolium, thiazolium, imidazolium, pyrazolyl, pyrazolinones, pyrazolidine, isoxazolyl, isothiazolines, pirania, pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinium, piperazinil, 1,3,5-triazinium, benzothiazolium, benzoxazolium, benzimidazolium, tigermania or tetrahedralisation, and these heterocyclic rings are linked through carbon-nitrogen; or

R9is (C1-C6)alkyl or (C1-C8)alkoxyl, and specified (C1-C6)alkyl or (C1-C8)alkoxy is arbitrarily monosubstituted cyclo(C4-C7)alken-1-yl, phenyl, teinila, pyridium, fullam, pirrallo, pyrrolidinium, oxazolium, thiazolium, imidazolium, pyrazolyl, pyrazolinones, pyrazolidine, isoxazolyl, isothiazolines, pirania, piperidinium, morpholinium, thiomorpholine, 1-OssetiaAlania, 1,1-dioxothiazolidine, pyridazinyl, pyrimidinyl, pyrazinium, Pieper is l are arbitrarily optionally independently mono - or disubstituted by halogen, by hydroxyl, (C1-C5)alkoxyl, amino, mono-N - or di-N,N-(C1-C5)alkylamino-, cyano-, carboxyla or (C1-C4-alkoxycarbonyl; and

moreover, the ring R9are arbitrarily mono - or di-substituted independently at a carbon atom by halogen, (C1-C4)alkyl, (C1-C4-alkoxyl, hydroxyl, hydroxy(C1-C4)alkyl, amino(C1-C4)alkyl, mono-N - or di-N,N-(C1-C4)alkylamino(C1-C4)alkyl, (C1-C4)-alkoxy(C1-C4)alkyl, amino, mono-N - or di-N,N-(C1-C4)alkylamino-, cyano-, carboxyla, (C1-C5)alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl, and the above rings R9can be arbitrarily optionally mono - or di-substituted independently (C1-C5)-alkyl or halogen;

provided that on any one Quaternary nitrogen in any heterocycle R9;

R12is morpholino, thiomorpholine-, 1 Osotimehin-, 1,1-dioxothiazolidine, thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, piperazine-4-yl, azetidin-1-yl, 1,2-oxazine-2-yl, pyrazolin-1--2-yl, 1,3-dihydroindol-2-yl, 3,4-dihydro-2H-China-1-yl, 2,3-dihydrobenzo[1,4]oxazin-4-yl, 2,3-dihydrobenzo[1,4] -thiazin-4-yl, 3,4-dihydro-2H-cinoxacin-1-yl, 3,4-dihydrobenzo[c][1,2]oxazin-1-yl, 1,4-dihydrobenzo[d][1,2]oxazin-3-yl, 3,4-dihydrobenzo[e] [1,2] -oxazin-2-yl, 3H-benzo[d] isoxazol-2-yl, 3H-benzo[c] isoxazol-1-yl or azepin-1-Il,

moreover, these rings R12are arbitrarily mono-, di - or tri-substituted independently with halogen, (C1-C5)alkyl, (C1-C5-alkoxyl, hydroxyl, amino, mono-N - or di-N,N-(C1-C5)alkylamino-, formyl, carboxyla, carbamoyl, mono-N - or di-N,N-(C1-C5)allylcarbamate, (C1-C6)alkoxy(C1-C3)alkoxyl, (C1-C5)alkoxycarbonyl, benzyloxycarbonyl, (C1-C5)alkoxycarbonyl(C1-C5)alkyl, (C1-C4)alkoxycarbonyl,

carboxy(C1-C5)alkyl, carbarnoyl(C1-C5)alkyl, mono-N - or di-N,N-(C1-C5)allylcarbamate(C1-C5)alkyl, hydroxy(C1-C5)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino(C1-C4)alkyl, mono-N - or di-N,N-(C1-C4)alkylamino(C1-C4)aimie of oxo-, hydroxyimino or (C1-C6)alkoxyimino - oxo-, hydroxyimino or (C1-C6)alkoxyimino-are the non-aromatic carbon; and

moreover, the ring R12are arbitrarily optionally mono - or di-substituted independently (C1-C5)alkyl or halogen;

provided that when R6is (C1-C5)alkoxycarbonyl or benzyloxycarbonyl, then R1is 5-halo, 5-(C1-C4)-alkyl or 5-cyano -, and R4is (phenyl) (hydroxy) (C1-C4)alkyl, (phenyl) ((C1-C4)alkoxy)(C1-C4)alkyl, hydroxymethyl or Ar(C1-C2)alkyl, where Ar is Tien-2 - or-3-yl, FSD-2 - or-3-yl or phenyl, with the specified Ar is arbitrarily mono - or di-substituted independently with halogen; provided that when R4is benzyl and R5is stands, R12is not 4-hydroxypiperidine-1-yl or when R4is benzyl and R5is stands, R6is not C(O)N(CH3)2;

provided that when R1and R10and R11are H, R4- no imidazol-4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl;

provided that when both Rwhat Kilom, 5(C1-C5)alkoxyl or trifluoromethyl;

provided that when R12is 3,4-dihydroisoquinolin-2-yl specified 3,4-dihydroisoquinolin-2-yl is not substituted carboxy((C1-C4)alkyl;

provided that when R8is H and R9is (C1-C6)-alkyl, R9not replaced by carboxyla or (C1-C4)alkoxycarbonyl the carbon that is bound to the nitrogen atom N of the other9;

provided that when R6is carboxyla and R1, R10, R11and R5are all H, then R4is not benzyl, H, (phenyl) (hydroxy)stands, stands, ethyl or n-propylene.

The first group of preferred connection with formula I consists of those compounds, where

R1is 5-H, 5-halo, 5-stands, 5-cyano - or-5-trifluoromethyl;

R10and R11are each independently H or halogen;

A is-C(H)=;

R2and R3are H;

R4is H, stands, phenyl (C1-C2)alkyl, where mentioned phenyl groups are mono - or di-substituted independently H, halogen, (C1-C4)alkyl, (C1-C4)alkoxyl, trifluoromethyl, hydroxyl, amino or cyano is Tien Xia-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-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, isothiazol-3-, -4 - or-5-yl(C1-C2)alkyl, pyridazin-3 - or-4-yl(C1-C2)alkyl, pyrimidine-2-, -4-, -5- or-6-yl(C1-C2)alkyl, pyrazin-2 - or-3-yl(C1-C2)-alkyl or 1,3,5-triazine-2-yl(C1-C2)alkyl, where these previous R4heterocycles are arbitrarily mono - or di-substituted independently with halogen, trifluoromethyl, (C1-C4)alkyl, (C1-C4)alkoxyl, amino or hydroxyl, and these mono - or di-substituents linked to the carbon atom;

R5is H; and

R6is C(O)NR8R9or C(O)R12.

Within the above first group of preferred compounds of formula I there is a group of especially preferred compounds, where

R4is H, phenyl(C1-C2)alkyla the Xia mono - or di-substituted independently H or fluorine;

R6is C(O)R12;

R12is morpholino, thiomorpholine-, 1 Osotimehin-, 1,1-dioxothiazolidine, thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, piperazine-4-yl, azetidin-1-yl, 1,2-oxazine-2-yl, isoxazolidine-2-yl, isothiazolin-2-yl, 1,2-oxazolidin-2-yl, oxazolidin-3-yl, 1,3-dihydroindol-2-yl or azepin-1-Il,

where specified R12rings are arbitrarily mono - or di-substituted independently with halogen, (C1-C5)alkyl, (C1-C5)alkoxyl, hydroxyl, amino, mono-N - or di-N,N-(C1-C5)alkylamino-, formyl, carboxyla, carbamoyl, mono-N - or di-N,N-(C1-C5)allylcarbamate, (C1-C5)alkoxycarbonyl, hydroxy(C1-C5)alkyl, amino(C1-C4)alkyl, mono-N - or di-N,N-(C1-C4)alkylamino(C1-C4)alkyl, oxo, hydroxyimino or (C1-C6)alkoxyimino - assuming that only R12the heterocycles of thiazolidin-3-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-4-yl, azetidin-1-yl, 1,2-oxazine-2-yl, isoxazolidine-2-yl, isoxazolidine-2-yl or oxazepine-3-yl are arbitrarily mono - iltsya are arbitrarily optionally mono - or di-substituted independently (C1-C5)alkyl.

In the above group of especially preferred compounds are the compounds:

5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3 - hydroxylaminopurine-1-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [2-(CIS-3,4 - dihydroxypyrrolidine-1-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [2-((3S, 4S)- dihydroxypyrrolidine-1-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [2-(1,1 - dioxothiazolidine-3-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [2-oxo-2-thiazolidin-3-yl - ethyl)-amide,

5-chloro-1H-indole-2-carboxylic acid [(1S)-(4-terbisil)- 2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3RS)- hydroxypiperidine-1-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [2-oxo-2-((1RS)-oxo-1 - thiazolidin-3-yl)ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [(1S)-(2-terbisil) -2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3S, 4S)-dihydroxypyrrolidine-1-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3 - hydroxyazetidine-1-yl)-2-oxoethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3 - iminobiotin-1-yl)-2-oxoethyl]-amide.

In the above group of especially preferred compounds there is a leading group of especially preferred compounds in which

R4is H; and

R12is thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl or oxazolidin-3-yl or specified R12deputies are arbitrarily mono - or di-substituted independently with carboxyla, (C1-C5)alkoxycarbonyl, hydroxy (C1-C3)alkyl, amino(C1-C3)alkyl, mono-N - or di-N,N-(C1-C3)alkylamino(C1-C3)alkyl, or

R12is mono - or di-substituted pyrrolidin-1-yl, and these substituents are independently by carboxyla, (C1-C5)alkoxycarbonyl, (C1-C5)alkoxyl, hydroxyl, hydroxy(C1-C3)alkyl, amino, amino(C1-C3)alkyl, mono-N - or di-N, N-(C1-C3)alkylamino(C1-C3)alkyl or mono-N - or di-N,N-(C1-C4)alkylamino; and

rings R12arbitrarily optionally independently di-substituted (C1-C5)alkyl.

Preferred compounds of the immediately preceding group of especially preferred compounds of the Sabbath.
R12is CIS-3,4-dihydroxypyrrolidine-1-yl;

b. R1is 5-chlorine;

R10and R11are H; and

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

c. R1is 5-chlorine;

R10and R11are H; and

R12is 1,1-dioxothiazolidine-3-yl;

d. R1is 5-chlorine;

R10and R11are H; and

R12is thiazolidin-3-yl; and

that is, R1is 5-chlorine;

R10and R11is H; and

R12is 1-oxothiazolidine-3-yl.

Within the above group of especially preferred compounds is the second group of especially preferred compounds in which

R4is vinylmation, Tien-2 - or-3-elmetron, and R4rings arbitrarily mono - or di-substituted by fluorine; and

R12is thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl or oxazolidin-3-yl, or selected substituents R12random mono - and di-substituted independently with carboxyla, or (C1-C5)alkoxycarbonyl, hydroxy(C1-C3)alkyl, amino(C1-C3)-alkyl or mono-N - or di-N,N-(C1-C3)alkylamino(C1-C5)alkoxycarbonyl, hydroxy(C1-C3)alkyl, amino(C1-C3)alkyl,

mono-N - or di-N, N-(C1-C3)alkylamino -(C1-C3)-alkyl, hydroxyl, (C1-C3)alkoxyl, amino, mono-N - or di-N,N-(C1-C5)alkylamino-, oxo-, hydroxyimino or (C1-C5)alkoxyimino-; and R12rings are arbitrarily optionally mono - or di-substituted independently (C1-C5)alkyl.

Preferred compounds of the immediately preceding group of especially preferred compounds are compounds in which

A. R1is 5-chlorine;

R10and R11are H;

R4is a 4-Formentera;

R12is a 4-hydroxypiperidine-1-yl; and

the stereochemistry of carbon (a) has the (S) form;

b. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R12is a 3-hydroxypiperidine-1-yl; and

the stereochemistry of carbon (a) has the (S) form;

c. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

USD>1
is 5-chlorine;

R10and R11are H; R4is benzyl;

R12is a 3-hydroxylaminopurine-1-yl; and

the stereochemistry of carbon (a) is an (S ) form;

e. R1is 5-chlorine;

R10and R11are H;

R4is a 2-Formentera;

R12is a 4-hydroxypiperidine-1-yl; and

the stereochemistry of carbon (a) has the (S) form;

f. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R12is (3,4)-dihydroxypyrrolidine-1-yl; and

the stereochemistry of carbon (a) is of the form (S);

g. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R12is a 3-hydroxyazetidine-1-yl; and

the stereochemistry of carbon (a) is of the form (S);

h. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R12is a 3-gidroksibenziliden-1-yl; and

the stereochemistry of carbon (a) is an (S) form; and

i. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R12is a 4-hydroxylaminopurine compounds in the leading group of preferred compounds are compounds in which

R4is H, phenyl(C1-C2)alkyl, Tien-2 - or-3-yl-(C1-C2)-alkyl, FSD-2 - or-3-yl(C1-C2)alkyl, and the above rings R4are mono - or di-substituted independently H or fluorine;

R6is C(O)NR8R9;

R8is H, (C1-C2)alkyl, hydroxyl or (C1-C4)alkoxyl; and

R9is H, cyclo(C4-C6)alkyl, cyclo(C3-C6)alkyl(C1-C5)-alkyl, metalunderground(C1-C3)alkyl, pyridium, pyrrolidinium, oxazolium, thiazolium, imidazolium, piperidinium, benzothiazolium or tigermania; or

R9is (C1-C5)alkyl, and specified (C1-C5)alkyl arbitrarily substituted cyclo(C4-C6)alkenyl, phenyl, teinila, pyridium, pyrrolidinium, oxazolium, thiazolium, imidazolium, pyrazolyl, piperidinyl, morpholinyl, thiomorpholine, 1-OssetiaAlania or 1,1-dioxothiazolidine and where indicated (C1-C5)-alkyl or (C1-C4)alkoxyl arbitrarily optionally independently substituted mono - or di-halogen, hydroxyl, (C1-C5)alkoxy what Bonilla; and

moreover, the ring R9are arbitrarily mono - or di-substituted independently at a carbon atom by halogen, (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, amino, mono-N - or di-N,N-(C1-C4)alkylamino, carbamoyl, (C1-C5)alkoxycarbonyl or carbamoyl.

In the directly preceding the second group of especially preferred compounds are compounds in which:

a. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R8is stands; and

R9is 3-(dimethylamino) - propylene;

the stereochemistry of carbon (a) has the (S) form;

b. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R8is stands; and

R9is a 3-pyridium;

the stereochemistry of carbon (a) has the (S) form;

c. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R8is stands; and

R9is 2-hydroxyethyl; and

the stereochemistry of carbon (a) is an (S) form;

d. R1is 5-fluorine;

R10and R11is what morpholinoethyl.

The third group of especially preferred compounds in the leading group of preferred compounds are compounds in which

R4is H, phenyl(C1-C2)alkyl, Tien-2 - or-3-yl-(C1-C2)alkyl, FSD-2 - or-3-yl(C1-C2)alkyl, and the above rings R4are mono - or di-substituted independently H or fluorine;

R6is C(O)NR8R9;

R8is H, (C1-C5)alkyl, hydroxyl or (C1-C5)alkoxyl; and

R9is (C1-C4)alkoxyl, and the specified alkoxyl is arbitrarily substituted cyclo(C4-C6)alkenyl, phenyl, teinila, pyridium, pyrrolidinium, oxazolium, thiazolium, imidazolium, pyrazolyl, piperidinyl, morpholinyl, thiomorpholine, 1-OssetiaAlania or 1,1-dioxothiazolidine and moreover specified (C1-C5)alkyl or (C1-C4)alkoxy is arbitrarily optionally independently mono - or di-substituted by halogen, hydroxyl, (C1-C5)alkoxyl, amino, mono-N - or di-N, N-(C1-C5)alkylamino-, cyano-, carboxyla or (C1-C4)alkoxycarbonyl; and

moreover, the ring R91-C4)alkylamino, carbamoyl, (C1-C5)alkoxycarbonyl or carbamoyl.

In the preceding third group of especially preferred compounds are compounds in which:

a. R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R8is stands; and

R9is a 2-hydroxyethoxy;

the stereochemistry of carbon (a) is an (S) form;

b. R1is 5-chlorine;

R10and R11are H;

R4is a 4-performation;

R8is stands; and

R9is metaxylem;

c. The stereochemistry of carbon (a) is an (S) form;

R1is 5-chlorine;

R10and R11are H;

R4is benzyl;

R8is stands; and

R9is metaxylem;

A second group of preferred compounds of formula I are those compounds in which;

R1is 5-halo, 5-stands, 5-cyano or trifluoromethyl;

R10and R11are, each independently, H or halogen;

A is-C(H)=;

R<>C2)-alkyl, FSD-2 - or-3-yl(C1-C2)alkyl, and these rings are mono - or di-substituted independently H or fluorine;

R5is H; and

R6is (C1-C5)alkoxycarbonyl.

The third group of preferred compounds with formula I represents those compounds in which

R1is 5-halo, 5-stands, 5-cyano or trifluoromethyl;

R10and R11are each independently H or halogen;

A is-C(H)=;

R2and R3are H;

R4is H, stands or phenyl(C1-C2)alkyl, and mentioned phenyl groups are mono - or di-substituted independently H, halogen, (C1-C4)alkyl, (C1-C4)alkoxyl, trifluoromethyl, hydroxyl, amino or cyano and the above phenyl groups are optionally mono - or di-gamesanime independently H or halogen; or

R4is 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-2-, -4 - or-5-yl(C1-C2)alkyl, FSD-2 - or-3-yl(C1-C2)alkyl, pyrrol-2 - or-3-yl(C1-C2)Alki the 3-, -4 - or-5-yl(C1-C2)alkyl, isothiazol-3-, -4 - or-5-yl(C1-C2)alkyl, pyridazin-3 - or-4-yl-(C1-C2)alkyl, pyrimidine-2-, -4-, -5- or-6-yl(C1-C2)alkyl, pyrazin-2 - or-3-yl(C1-C2)alkyl or 1,3,5-triazine-2-yl-(C1-C2)alkyl, moreover, these prior R4heterocycles arbitrarily mono - or di-substituted independently with halogen, trifluoromethyl, (C1-C4)alkyl, (C1-C4)alkoxyl, amino or hydroxyl, and these mono - or di-substituents bound to carbon;

R5is H; and

R6is carboxyla.

In the third group of preferred compounds is a leading group of especially preferred compounds in which

R10and R11are H; and

R4is H.

Particularly preferably in the immediately preceding especially preferred group connection in which

R1is 5-chlorine.

In another aspect this invention is directed to intermediate compounds applicable for some of the compounds of formula I. Intermediate compounds have the formula QZ

< / BR>
where R5is H;

Rbut mono - or di-substituted by fluorine; and

R12is thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl, pyrrolidin-1-yl, piperidine-1-yl, azetidin-1-yl, 1,2-oxazine-2-yl, isoxazolidine-2-yl, isothiazolin-2-yl, 1,2-oxazolidin-2-yl or oxazolidin-3-Il,

moreover, these R12rings are arbitrarily mono - or di-substituted independently with halogen, (C1-C5)alkyl, (C1-C5)alkoxyl, hydroxyl, amino, mono-N - or di-N,N-(C1-C5)alkylamino-, formyl, carboxyla, carbamoyl, mono-N - or di-N,N-(C1-C5)allylcarbamate, (C1-C5) alkoxycarbonyl, hydroxy(C1-C5)alkyl, amino(C1-C4)alkyl, mono-N - or di-N,N-(C1-C4)alkylamino(C1-C4)alkyl, oxo, hydroxyimino or (C1-C6)alkoxyimino - assuming that only R12the heterocycles of thiazolidin-3-yl, pyrrolidin-1-yl, piperidine-1-yl, azetidin-1 - yl, 1,2-oxazine-2-yl, oxazolidin-2-yl or oxazolidin-3-yl are arbitrarily mono - or di-substituted independently with oxo, hydroxyimino-, or (C1-C6)alkoxyimino groups; and

moreover, these R12rings are arbitrarily optionally mono - or di-substituted independent is>C5)alkoxycarbonyl)-4-hydroxypyrrolidine-1-yl, 2-carboxypeptidase-1-yl or 2-((C1-C5)alkoxycarbonyl)-piperidine-1-yl.

Specific compounds within the above group of intermediate compounds are compounds in which

A. R4is H; and

R12is thiazolidin-3-yl;

b. R4is H; and

R12is 1,1-dioxothiazolidine-3-yl; and

c. R4is H; and

R12is 1-oxothiazolidine-3-yl.

The leading group preferred compound with the formula QZ are compounds in which

R4is vinylmation, and the specified phenyl arbitrarily mono - or di-substituted by fluorine; and

R12the 3-mono-substituted, azetidin-1-yl, 3-mono - or 3,4-disubstituted pyrrolidin-1-yl, 3-, 4 - or 5-mono - or disubstituted piperidine-1-yl, thiazolidin-3-yl, 1-oxothiazolidine-3-yl or 1,1-dioxothiazolidine-3-yl, and the specified pyrrolidin-1-yl or piperidine-1-yl are mono - or disubstituted independently with hydroxyl, oxo, hydroxyimino, amino, mono-N - or di-N, N-(C1-C4)-alkylamino, (C1-C5)alkoxycarbonyl or carboxyla

and these R12rings are arbitrarily stage the mi in the above immediately preceding group of preferred compounds are compounds in which

A. R4is benzyl;

R12is a 3-hydroxypyrrolidine-3-yl; and

the stereochemistry of carbon (a) is (S)-form;

b. R4is benzyl;

R12is a 3-hydroxyazetidine-1-yl; and

the stereochemistry of carbon (a) is an (S) form;

c. R4is benzyl;

R12is 3,4-dihydroxypyrrolidine-1-yl; and

the stereochemistry of carbon (a) is represented by (S)-form;

d. R4is benzyl;

R12is a 4-hydroxypiperidine-1-yl;

the stereochemistry of carbon (a) is an (S)-form;

e. R4is a 4-performation;

R12is a 4-hydroxypiperidine-1-yl; and

the stereochemistry of carbon (a) is (S)-form; and

f. R4is benzyl;

R12is a 4-gidroksibenziliden-1-yl; and

the stereochemistry of carbon (a) is (S)-form.

Another aspect of this invention is directed to a method of treating diseases or conditions associated with glucosephosphate, in mammals by introduction of a mammal suffering from a disease or condition dependent on glycogen phosphorylase, the number of compounds with formula I, cures disease or sosecure hyperglycemia in mammals by introduction of a mammal suffering from hyperglycemia, the number of compounds with formula I, treating hyperglycemia.

Another aspect of this invention is directed to a method of treating diabetes in a mammal by injecting a mammal suffering from diabetes, the number of compounds according to formula I, cures diabetes. In the treatment of diabetes includes the prevention or mitigation of delayed complications, such as neuropathy, nephropathy, retinopathy or cataracts.

Another aspect of this invention is directed to a method of treating hypercholesterolemia in a mammal by injecting a mammal suffering from hypercholesterolemia, the number of compounds according to formula I, healing hypercholesterolemia.

Another aspect of this invention is directed to a method of treating atherosclerosis in mammals by introduction of a mammal suffering from atherosclerosis, the number of compounds according to formula I, curing atherosclerosis.

Another aspect of this invention is directed to method

treating hyperinsulinemia in a mammal by injecting a mammal suffering from hyperinsulinemia, the number of compounds according to formula I, cures the hyperinsulinemia.

Another EMU, suffering from hypertension, the number of compounds according to formula I, cures the hypertension.

Another aspect of this invention is directed to a method of treating hyperlipidemia in a mammal by injecting a mammal suffering from hyperlipidemia, the number of compounds according to formula I, healing hyperlipidemia.

Another aspect of this invention is directed to a method of prevention of myocardial ischemic injury in a mammal by injecting a mammal at risk of ischemic myocardial damage in conditions before and after the operation amount of the compound according to formula I, prevent ischemic damage to the myocardium.

Another aspect of this invention is directed to a method of prevention of ischemic lesion of myocardium in a mammal by injecting a mammal at risk of ischemic myocardial damage in conditions before and after the operation amount of an inhibitor of glycogen phosphorylase, warning myocardial ischemia in conditions of operations.

This invention also is directed on creation of pharmaceutical compositions, which include therapeutically effective amount of a compound according to formula I and pharmaceutically p the Oia diseases and conditions, dependent glycogen phosphorylase, in mammals, which contain a number of compounds according to formula I, cures disease or condition dependent on glycogen phosphorylase and a pharmaceutically acceptable carrier.

Another aspect of this invention is directed to creation of pharmaceutical compositions for the treatment of diabetes, which include therapeutically effective amount of a glycogen phosphorylase inhibitor;

one or more of antidiabetic agents such as insulin and insulin analogs (e.g., Lys-Pro-insulin); GLP-1 (7-37) (insulinotropic) and GLP-1 (7-36)-NH2; sulfonmethane and analogues: hlorpropamid, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride, Repaglinide, meglitinide; biguanides: Metformin, phenformin, buformin; 2-antagonists and imidazolines: midaglizole, Salida, deriglidole, idazoxan, efaroxan, flyproxy; others enhance insulin secretion substances: linogliride, A-4166, glitazone: ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, BRL 49653; inhibitors of fatty acid oxidation: clamoxyl, etomoxir; inhibitors of a-glucosidase: acarbose, miglitol, emiglitate, voglibose, MDL-25637, camiglibose, MDL-73945; agonists: BRL 35135, BRL 37344, Ro arena: fenfluramine; Vanadate and vanadium complexes (for example, Negovanand peroxovanadate complexes; milinovi antagonists; glucagonoma antagonists; inhibitors of gluconeogenesis; analogs of somatostatin; antilipolytic tools: nicotinic acid, acipimox, WAG 994; and

arbitrarily, a pharmaceutically acceptable carrier.

Preferred pharmaceutical compositions of the immediately preceding group are those compositions in which the glycogen phosphorylase inhibitor is a compound according to formula I.

Another aspect of this invention is a method of treating diabetes in a mammal using the aforementioned compositions with combinations of drugs.

Diseases or conditions that are dependent on glycogen phosphorylase, are diseases that are mediated by, caused or supported, in whole or in part, by splitting the glycogen macromolecule using glikogenogeneza enzymes with the release of glucose-1-phosphate and a new shortened molecule of glycogen. The state in these diseases is improved by reducing the activity of glycogen phosphorylase and characterized by increased activity of glycogen phosphorylase. Examples include diabetes, the ISU is RDA.

The term glycogen phosphorylase inhibitor refers to any substance or agent or any combination of substances and/or products that reduce, inhibit or eliminate enzymatic activity of glycogen phosphorylase. The known action of glycogen phosphorylase is the destruction of glycogen by catalysis of the reversible reaction of glycogen macromolecule with inorganic phosphate with the formation of glucose-1-phosphate and glycogen macromolecule, which is one Picatinny residue shorter than the original macromolecule glycogen (in the forward direction glycogenolysis).

The term "treatment" as used here includes preventing (e.g., prophylactic) and palliative treatment.

Under the halogen means chlorine, bromine, iodine or fluorine.

Under the alkyl refers to saturated hydrocarbons with straight or branched chain. Examples of such alkyl groups (taking into account the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl and isohexyl.

Under alkoxyl means a saturated alkyl straight or branched chain, swasam specific example) are methoxy, amoxil, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoksil, isobutoxy, hexaxim and isohexanes.

The expression "pharmaceutically acceptable anionic salt" refers to non-toxic anionic salts containing anions, such as (but not limited to, 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, such as (but not limited to) salts of sodium, potassium, calcium, magnesium, ammonium or 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 drug, which after the introduction of excreting the drug in vivo via some chemical or physiological process (e.g., a prodrug, in communicating to physiological pH is converted to the desired form of the drug). Some breakie forming hydrolyzable ester residues of the compounds of this invention include, but not limited to, the Deputy carboxylic acids (for example, R6is carboxyla, or R8, R9or R12contains carboxyl), in which 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 from 5 to 10 carbon atoms, alkoxycarbonylmethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyl)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyl)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 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 cited as examples of prodrugs produce alcohol with formula I, in which free hydrogen of the hydroxyl substituent (e.g., R8, R91-C6)alkanoyloxy)ethyl, (C1-C6-alkoxycarbonylmethyl, N-(C1-C6)alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl, -amino (C1-C4)alkanoyl, arylation and a - aminoacyl, or-aminoacyl - a-aminoacyl, and the above-aminoaniline components are independently any of the naturally occurring L-amino acids found in proteins, P(O)(OH)2, -P(O) (O(C1-C6)alkyl)2or glikozidom (the radical resulting from detachment of the hydroxyl of hemiacetal carbohydrate).

Other examples of prodrugs include, but are not limited to, derivatives of formula I, in which R2is the free hydrogen is replaced by R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural - aminoacyl or natural-aminoacyl-natural - aminoacyl, -C(OH)C(O)OY where Y is H, (C1-C6)alkyl or benzyl; -C(OY0)Y1where Y0is (C1-C4))- alkyl, and Y1is ((C1-C6))- alkyl,

carboxy-(C1-C6)alkyla, the de Y2is H or stands and Y3is mono-N - or di-N,N-(C1-C6)alkylamino, morpholino, piperidine-1-yl or pyrrolidin-1-yl.

Other examples of prodrugs include, but are not limited to, derivatives of formula I bearing hydrolyzable substituents at R3of which is allocated a compound according to formula I, where R3is the free hydrogen after hydrolysis. Such hydrolyzable substituents at R3represent/include 1-hydroxy(C1-C6)alkyl or 1-hydroxy-1-phenylmethyl.

Other examples of prodrugs include cyclic structures, such as compounds according to formula I, in which R2and R3are the common carbon, thus forming a five-membered ring. Linking the carbon may be mono or di-substituted independently H, (C1-C6)alkyl, (C3-C6)cycloalkyl or phenyl.

As used here, the expression "reaction-inert solvent" and "inert solvent" refers to a solvent which does not react with the starting materials, reagents, intermediate compounds or products in a manner that affects the yield of the desired product.

Hee the volume, which can be in a particular stereochemical or geometric configuration, which leads to the formation of stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates of the compounds of this invention are also included as one of the aspects of this invention.

The chemist of ordinary skill will understand that some combinations containing heteroatom substituents listed in this invention, identify the connections that will be less stable under physiological conditions (for example, those that contain acetylene or analnye communication). Accordingly, such compounds are less preferred.

The term "Rxring (Rx), where x is an indicator, integer, such as "R9ring, R12ring" or "R4ring", which are used here in relation to substitution on the ring, refers to the substituents which the ring is Rxand where the ring is contained within Rx.

As it is used here, the term mono-N - or di-N,N-(C1-Cx)alkyl... belongs to (C1-Cx)alkyl Deputy, taken independently, when it is di-N,N-(C1

Basically, the compounds of formula I can be obtained by processes which include processes known in the chemical industry, particularly in light of the present description. Some processes for the production of compounds according to formula I is represented as an additional characteristic of the invention and are illustrated by the following schemes of reactions (see below).

In reaction scheme 1 the compounds of formula I, where R1, R10, R11, A, R2, R3, R4, R5and R6the definition above can be obtained by using either of two basic processes. When the first process, the desired compound according to formula I can be obtained by reacting the corresponding indole-2-carboxylic acid of formula II, indolin-2-carboxylic acid, or a benzimidazole-2-carboxylic acid with the appropriate amine with formula III (i.e., allira Amin). In the second process, the desired compound with the formula I can be obtained by reacting the corresponding compounds of formula IV (i.e., compounds of formula I, where R6is carboxyla) with the appropriate alcohol or amine with the formula, R8R9NH or R12H, the op perate compounds with formula II with compounds of formula (III) is generally preferable, when R4not H, and R5is H.

Typically, the compound of formula II is connected with the connection according to the formula III (or compound of formula IV is connected with the corresponding amine (for example, R12H, or R8R9NH) or alcohol in the presence of a suitable agent combinations. A suitable agent combinations (binding agent) is the one which transforms the carboxylic acid reactive species, which forms an amide or the ester linkage in the reaction with the amine or alcohol, respectively.

As an agent of the combination may be a reagent that produces condensation in a simultaneous process, when mixed with carboxylic acid and amine or alcohol. If acid should condense with alcohol, it is preferable to use a large excess of the alcohol as solvent for the reaction with the addition of 1.0 to 1.5 equivalents of dimethylaminopyridine or without him. Examples linking reagents are 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (DPC/peso), carbonyldiimidazole, dicyclohexylcarbodiimide/hydroxybenzotriazole (peso), 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (AEDH), carbonyldiimidazole/peso, the PCC is realized in an inert solvent, preferably an aprotic solvent at a temperature equal to from about -20oC to about 50oC for from about 1 to about 48 hours at an arbitrary presence of a base in the form of a tertiary amine such as triethylamine. Examples of solvents include acetonitrile, dichloromethane, ethyl acetate, dimethylformamide and chloroform, or a mixture thereof. An example of a suitable connection procedure is A procedure that is contained here (just before the examples).

Agent combinations may also be a substance which converts the carboxylic acid to an activated intermediate compound, which is allocated and/or formed in the first stage and which is allowed to react with an amine or alcohol in the second stage. Examples of such connecting means and activated intermediates are thionyl chloride or oxalicacid for the formation of the acid chloride, lanehead for the formation of fluoride acid or alkylphosphoric, such as isobutyl or isopropenylacetate (tretinoin basis) for the formation of a mixed anhydride of carboxylic acid. If the connecting means is oxalicacid, it is advisable to use a small kolichestvo formation of the acid chloride. This acid chloride can connect by mixing with an intermediate compound of formula III in an appropriate solvent together with a suitable base. Suitable combinations of solvent/base are, for example, dichloromethane, dimethylformamide or acetonitrile, or a mixture thereof in the presence of tretinoin base, such as triethylamine. Other suitable combination of solvent/base include water or (C1-C5)alcohol or a mixture thereof together with a co-solvent, such as dichloromethane, tetrahydrofuran or dioxane and a base such as sodium carbonate or potassium or sodium, potassium or lithium hydroxide or sodium bicarbonate in sufficient quantity to absorb the released acid. The use of interphase catalyst (usually from 1 to 10 mol.%), such as a Quaternary ammonium halide (for example, tetrabutylammonium bromide or methyltrioctylammonium chloride) is appropriate when the mixture is used only partially miscible solvent (for example dichloromethane-water or dichloromethane-methanol). The use of such connecting means and the appropriate choice of solvents and temperatures known in the art and can readily be determined by literary Yes the Weyl, Vol XV, part II, E. Wunsch, Ed. , G. Theime Veriag, 1974, Stuttgart, and M. Bodansky, Principles of Peptide Synthesis, Springer - Verlag Berlin 1984 and The Peptides, Analysis, Synthesis and Biology (ed. E. Gross and J. Meienhofer), vols. 1-5 (Academic Press NY 1979-1983).

The compounds of formula IV, where R1, R10, R11, A, R2, R3, R4and R5given the definition above, can be obtained from the corresponding esters of formula V (i.e., compounds of formula I, where R6is (C1-C5)alkoxycarbonyl or benzyloxycarbonyl) by hydrolysis with an aqueous solution of alkali at a temperature equal to from about -20oC to about 100oC, typically at about 20oC for from about 30 minutes to about 24 hours.

Or otherwise, the compounds of formula IV are obtained by activation indolocarbazoles acid of formula II with the help of agent combinations (described above), which gives the activated intermediate connection (such as the acid chloride acid, floramite acid or a mixed anhydride), which is then allowed to react with a compound of formula III, where R3, R4and R5defined above, and R6is carboxyla, in a suitable solvent in the presence of a suitable base. Suitable solvents include water or methanol or cm shall indicate the hydroxides of sodium, potassium or lithium, sodium bicarbonate or potassium carbonate, sodium or potassium, or potassium carbonate together with tetrabutylammonium bromide (1 equivalent) in sufficient quantity to bind released in the reaction of an acid (basically this is the amount sufficient to maintain the pH of the reaction at the level of more than 8). The base may be added in an increasing number together with the activated intermediate connection for the appropriate regulation of the pH of the reaction mixture. The reaction is generally performed at a temperature of from -20oC to 50oC. procedures for the allocation chosen by a specialist in order to remove the impurities, but usually consist of removing dissolved in water solvent by evaporation, extraction of impurities at high pH with an organic solvent, acidification to a low pH (1-2) and filtration or extraction of the desired product with a suitable solvent, such as ethyl acetate or dichloromethane.

The compounds of formula V can be obtained by linking the corresponding compounds of formula III, where R6is alkoxycarbonyl, and the corresponding compounds of formula II with a procedure similar to that described above (for example, procedure A).

Some of the methods of production described herein may require protection of certain functional groups (i.e., primary amines, secondary amines, carboxy in the precursor compounds with formula (I). The need for such protection will vary depending on the nature of individual functional groups and methods of production. The need for such protection is easily determined by the expert. The use of such methods to protect/delete protection is also within the competence of the specialist. For General descriptions of protective groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

For example, in the reaction scheme 1 some connection formely, define R6that may prevent prednamerennoe reaction compounds according to the reaction scheme 1, if the intermediate compound of formula III or R12H, or R8R9NH-Amin remains unprotected. Accordingly, the functional group of the primary amine, secondary amine or carboxylic acid can be protected, where they are present in the R6-the components of the formula III intermediate R8R9NH or R12H Amin, suitable protective groups during the reaction of the compounds according to the reaction scheme 1. The product of such reactions proceed in this case is a compound according to formula I, containing protecting group. This protecting group is removed at a subsequent stage of obtaining compounds according to formula I. Suitable protecting groups for protection of the amine and carboxylic acid include those protective groups commonly used in peptide synthesis such as N-t-butoxycarbonyl, N-carbobenzoxy - and 9-fertilityerection for amines and esters of lower Akilov or benzyl for carboxylic acids), which are not chemically reactive under the reaction conditions of the merger described above (and directly preceding examples here in the form of a description of the formula I.

The source of indole-2-carboxylic acid and indolin-2-carboxylic acid used in the reaction scheme 1, when they are not commercially available or not known from previous experience (such work is widely published) may be obtained by conventional methods of synthesis. For example, according to reaction scheme II indole ester of formula VII (where A is nitrogen) can be obtained from compounds of formula VI (where O is chosen to achieve the desired A, which given the above definition, except by synthesis of indoles Fisher (see The Fischer indoll Synthesis Robinson. B. (Wiley, New York, 1982) followed by saponification of the resulting complex ester of indole with formula VII to obtain the corresponding acid of formula VIII. Source arylhydrazones can be obtained by condensation of readily available hydrazine with the corresponding carbonyl derivative or by the reaction of the Japp-Klingemann (see Organic Reactions, Phillips, R. R., 1959, 10, 143).

Or otherwise, indole-2-carboxylic acid according to formula VIIIA can be obtained by condensing ortho-methylnitrosoamino by the formula IX with oxalate complex ether to obtain indole complex ester with formula X, followed by reduction of the nitro group and subsequent hydrolysis.

3-Halogen-5-chloro-1H-indole-2-carboxylic acid can also be obtained by halogenation of 5-chloro-1H-indole-2-carboxylic acid.

According to reaction scheme III intermediate compounds of benzimidazole-2-carboxylic acid according to formula XI can be obtained by condensation of arcediano connection according to the formula XIII with glycolic acid, followed by oxidation of the resulting benzimidazole-2-methanol of the formula XII (Bistrzycki, A. and Przeworski, G. Ber. 1912, 45, 3483).

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

Indolinecarboxylic acid according to the formula XVI is obtained by saponification of the corresponding ester of formula XVII (reaction scheme III). An ester of formula XVII is obtained by recovery of the sole, as described for the conversion of compounds of formula XV compound with the formula XIV above.

The following sections describe ways of obtaining various amines, which are used in the diagrams above reactions.

In accordance with reaction scheme IV alpha-amino acid with the formula XXIII can be protected by the corresponding nitrogen protecting group (Pt) (for example, t-Boc) with the formation of compounds with the formula XXIV. The specialist can easily choose an appropriate protecting group, and the method of its introduction. For example, two conventional protective group is t-Boc (introduced by treating the amino acid di-t-BUTYLCARBAMATE in, preferably, a suitable proton solvent or mixture of solvents at high pH) and CBZ (introduced by treating the amino acid with benzylchloride in a suitable, preferably, proton solvent or mixture of solvents and base). Compound with the formula XXIV is connected (when the procedure is similar to the accession process described in reaction scheme 1) with the corresponding R8R9NH or HR12Amin with the formation of compounds with the formula XXV, which is then removed protecting group, resulting in a compound with the formula III is pami are t-Boc, the removal is performed by treating the compound with the formula XXV acid in a suitable, preferably an aprotic solvent. Acid for the removal of protection include HCl, MeSO3H or triperoxonane acid.

In accordance with reaction scheme V, a compound with the formula XXXI (N-protected amine with formula III, where R6is (C1-C8-alkoxycarbonyl or benzyloxycarbonyl) can be obtained from the corresponding unprotected amino acids of formula XXX by protecting the N-(obtaining protected amino acids of formula XXXIII) with subsequent esterification. For example, the compound with the formula XXXIII can be etherification using the corresponding alcohol and acid catalyst such as hydrogen chloride or thionyl chloride, in the case of tert-butanol by treating the amino acid with isobutylene and an acid catalyst such as concentrated sulfuric acid, or by treatment with alkylhalogenide (for example, methyliodide) and a base (e.g. potassium carbonate). Or otherwise, the esterification may be preceded by a stage of protection.

In accordance with reaction scheme VI compounds according to formula XXX, where R3not H, used in the reaction scheme V can be receive the UB>) amino acids by treatment with an appropriate base and an alkylating agent. Specific procedures for this alkylation is described. Benoiton, Can. J. Chem. 1977, 58, 906-910 and Hansen, J. Org. Chem. 1985, 50, 945-950.

For example, when R3is stands, and Ptis Boc, used sodium hydride and methyliodide in tetrahydrofuran. Removing the protective group from compounds of formula XII gives the desired compound with the formula XXX.

Or otherwise, the amino acid with the formula XLII can be N-alkylated using a sequence of three stages, including the recovery benzylidene (such as using benzaldehyde catalyzed by Pd/C hydrogenation) to give the mono-N-benzyl derivative and reductive amination with the corresponding carbonyl compounds (e.g., using formaldehyde and cyanoborohydride sodium for injection R3as bromide) to obtain N-benzyl, N-R3-substituted amino, N-benzyl protecting group is conveniently removed (for example by hydrogenation using a suitable catalyst) to obtain the compounds of formula XXX. Specific conditions for this three-stage alkylation procedures described by Reinhold et al., J. Med. Chem., 1968, 11, 258-260.the Deputy R3in the intermediate compound with the formula IIIa (which is an intermediate compound of formula III, where R3is H).

Amino acids used here in the schemes (for example, XL, XLII), if they are not commercially available or are no publications in the literature, may be obtained through a number of methods known in the art. For example, can be used in the synthesis of Striker or its variants. Accordingly, the aldehyde (R4CHO), sodium cyanide or potassium, and ammonium chloride react with formation of the corresponding aminonitriles. Aminonitriles hydrolyzed with mineral acid with the formation of the desired amino acids with the formula XLII R4C(NH2)COOH. Or otherwise, may be used a method of Bucherer-Bergs, which is formed as by heating aldehyde (R4CHO) with ammonium carbonate and potassium cyanide followed by hydrolysis (e.g. using barium hydroxide by heating in a flask under reflux at the boiling dioxane) acid or base with the formation of the desired amino acids with the formula XLII R4C(NH2)COOH.

The literature also reported other methods of synthesis of amino acids, which should allow the specialist to obtain W is ormula I.

Suitable methods of synthesis and/or separation of the compounds according to the formula XLIi can be found in reviews Duthaler (Tetrahedron 1994, 50, 1539-1650) or Williams (R. M. Williams, Synthesis of optically active amino acids. Pergamon: Oxford, U. K., 1989).

A specific method for the synthesis of intermediate compounds with the formula XLII in any enantiomeric form from the corresponding intermediate compounds R4X (X= Cl, Br or I) is a way of Piranha and Krishnamurti (J. Org. Chem. 1993, 58, 957-958) or according to the method of O'donnell, et al. (J. Am. Chem. Soc, 1989, 111, 2353-2355). The desired intermediate compound R4X is easily obtained using many methods familiar to the skilled chemist. For example, these compounds, when R4X is ArCH2X, can be obtained by radical halogenation of compounds ArCH3or by formirovaniia arena Ar-H and conversion of the alcohol to the bromide.

Another specific method for the synthesis of intermediate compounds of formula XLII in any enantiomeric form is the method of Corey and link (Corey and Link, J. Am. Chew, Soc. 1992, 114, 1906-1908). Thus, an intermediate compound according to the formula R4COCCl3restored enantiospecific to the intermediate R4CH(OH)CCl3that turns when processing azide and a base in an intermediate connection R4COCCl3obtained by reaction of the aldehyde R4CHO with trichlorethylene anion with subsequent oxidation (Gallina and Gicrdano, Synthesis, 1989, 466-468).

The compound according to the formula R8NH2or R9NH2monoalkylethers carbonyl compound corresponding to R8or R9accordingly, the necessary conditions of reductive amination with getting amine with the formula, R8R9NH. To avoid dialkylamide, it may be preferable to protect amines (R8NH2or R9NH2) suitable protecting groups Ptobtaining R8(Pt)NH or R9(Pt)NH, for example by reaction with benzaldehyde and restoring means. Protected amines monoalkylated with carbonyl compounds corresponding to R9or R8accordingly, in the right conditions, reductive amination, obtaining R8R9N(Pt). Protecting group (Pt) is removed (e.g. by exhaustive catalytic hydrogenation, when Ptis benzyl) to give the compounds according to the formula R8R9NH. Appropriate conditions recovery is 7-2904) and consider Emerson (Orhanic Reactions, Wiley; Ney York, 1948(14), 174), Hutchins et al. (Org Prep. Proced Int 1979 (II), 20 and Lane et al. (Synthesis) 1975, 135). Conditions reductive amination conducive N-monoalkylammonium include reported Motales et al. (Synthetic Communications 1984, 1213-1220) and Verardo et al. (Synthesis 1992, 121-125). Amines R8NH2or R9NH2can also be monoalkylated R9X or R8X, respectively, where X is chloride, bromide, tosylate or mesilate. Or intermediate compound with the formula for R8(Pt)NH or R9(Pt)NH can be alkylated R9X or R8X, and the protecting group is removed to obtain compound according to the formula R8R9NH.

To obtain the amines according to the formula R8R9NH, where R8-NH or R9-NH linked through oxygen-nitrogen, can be used additional methods. So readily available compound with the formula (C1-C4)alkoxycarbonyl-NHOH or NH2CONHOH dialkylamide nitrogen and oxygen by treatment with base and an excess of a suitable alkylating funds (R-X) to obtain the corresponding (C1-C4)alkoxycarbonyl-N(R)OR, which is then hydrolyzed to obtain compound with the formula R8R9NH (where R8=R9=R). Suitable conditions based is). Or otherwise, the N-hydroxyurea (NH2CONH(OH)) can be consistently alkilirovanii, first by oxygen with the receipt of NH2CONH(OR'), then the nitrogen with the receipt of NH2CON(R") (OR') by successive treatment with alkylating agents R X and R X, respectively, in the presence of a suitable base. Suitable base and an alkylating substances include described Kreutzkamp and Messinger (Chem. Ber. 100, 3463-3465 (1967) and Danen et al. (J. Am. Chem. Soc. 1973, 95, 5716-5724). The hydrolysis of these alkyl derivatives of hydroxyacetone gives amines R ONH2and R ONHR" that meet certain amines according to the formula R8R9NH. A qualified chemist can adapt the procedures in this section to other alkylating means R, R' and R"-X for other amines with the formula, R8R9NH, where R8-N or R9-N are connected through oxygen-nitrogen. Uno et al. (Syn Lett 1991, 559-560) describe catalyzed BF3join ORGANOMETALLIC reagent R-Li; O-alkyloxy with the formula R-CH= N-OR', to obtain the compounds according to the formula R RCH-NH(OR"). This path can also be used to obtain compounds with the formula R8R9NH, where one of R8-NH or R9-NH linked through oxygen-nitrogen.

Prodrugs of this sputum connection carboxylic acid with the appropriate alkylhalogenide in the presence of a base, such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of from about 0 to 100oC for from about 1 to about 24 hours. Or acid is connected with the corresponding alcohol in the presence of catalytic amount of acid such as concentrated sulfuric acid, at a temperature of from about 20 to 120oC, preferably at the boiling temperature in the flask under reflux for from about 1 to about 24 hours. Another method is the reaction of the acid with the stoichiometric amount of the alcohol in the presence of catalytic amount of acid in an inert solvent, such as tetrahydrofuran, with concomitant removal of water that is produced using physical (for example, the separator Dean-stark) or chemical (e.g., molecular sieves) funds.

Prodrugs of this invention where the functional alcohol group converted into a derivative such as an ester, can be obtained by combining the alcohol with the appropriate alkylbromides or iodide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of from about 0 to 100oC for from about 1 bottom)methane in the presence of catalytic amount of acid in an inert solvent, such as tetrahydrofuran, according to the method described in US 4997984. Or these compounds can be obtained by the methods described by Hoffman et al. in J. Org. Chem. 1994, 59, 3530.

Dialkylphosphate esters can be obtained by reaction of the alcohol with dialkylphosphate in the presence of a base in an inert solvent, such as tetrahydrofuran. Distortionary can be obtained by reaction of the alcohol with diaryl - or dibenzylammonium, as described above, followed by hydrolysis or hydrogenation in the presence of a catalyst made of noble metals, respectively.

Glycosides are obtained by reaction of the alcohol and carbohydrate in an inert solvent such as toluene in the presence of acid. Typically, the water formed during the reaction is removed as soon as formed, as described above. An alternative procedure is the reaction of the alcohol with a correspondingly protected glycosylation in the presence of base, followed by removal of protective groups.

N-(1-Hydroxyalkyl)amides, N-(1-hydroxy-1-(alkoxycarbonyl)-methyl)amides or compounds where R2were substituted C(OH)C(O)OY can be obtained by reaction of the original amide or indole with an appropriate aldehyde under neutral to alkaline conditions (nilendra can be obtained by reaction of N-unsubstituted indole with the necessary 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= CH2N(CH3)2) can be obtained by reaction of the initial N-H compound with the appropriate aldehyde and amine in an alcohol solvent at 25-70oC.

Prodrugs of this invention where R2and R3are a common carbon may be obtained by reaction of the initial compounds (drugs) with benzaldehyde or ketone or its dimethylacetal in an inert solvent in the presence of catalytic amount of acid with the simultaneous removal of water or methanol.

Starting materials and reagents for the above schemes reactions (e.g., amines, substituted indolocarbazole acid, substituted indolinone acids, amino acids), although the majority of them described above, moreover, are easily accessible and can be easily synthesized by qualified specialists conventional methods of organic synthesis. For example, many of the intermediate compounds used here to obtain the compounds according to formula I, are associated with amino acid or derived amino acids found in nature, which compounds are commercially available and have publications in the literature, and they are easy to obtain from other commonly available compounds by methods reported in the literature. Such intermediate compounds include, for example, the compounds of formula XXX, formula XIII, formula and formula XXXII XXXIII.

Some compounds of formula I have asymmetric carbon atoms and therefore are enantiomers or diastereomers. A mixture of diastereoisomers can be separated into the individual diastereomers on the basis of their physical chemical differences by methods known per se, e.g. by chromatography and/or fractional crystallization. Enantiomers (e.g., formula III, VIII or IX) can be separated by transformation of a mixture of enantiomers in a mixture of diastereomers by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., by hydrolysis) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered part of this invention.

Although many compounds of this invention are not ionized under physiological conditions, some compounds of this invention are of an ionisable in physiological povzetek acceptable cation. All such salts are covered by the scope of this invention and they can be obtained by standard methods. For example, they can be obtained simply by linking acidic and basic substances, usually in a stoichiometric ratio or in aqueous or non-aqueous or partially aqueous medium, as necessary. Salt allocate or by filtration, or by deposition using a liquid non-solvent followed by filtration or by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as needed.

In addition, some compounds of this invention are basic, and they form a salt with a pharmaceutically acceptable anion. All such salts are included in the scope of this invention, and they can be obtained by standard methods. For example, they can be obtained simply by linking acidic and basic substances usually in stoichiometric proportions or in aqueous or non-aqueous or partially aqueous medium, as necessary. Salts are distinguished either by filtration or by sedimentation using prestorage fluid with subsequent filtration or by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, Kacie included in the scope of the invention.

The applicability of the compounds of this invention as medicaments in the treatment of metabolic diseases (such are described in detail here) in mammals (e.g. humans) is demonstrated by the activity of the compounds of this invention in conventional researches and studies in vitro and in vivo, are described below. Such studies also provide the means by which the activity of the compounds of this invention can be compared with the activities of other known compounds. The results of this comparison is useful for determining dosage levels in mammals, including humans, for treatment of such diseases.

Purified human liver, glycogenolysis (CPGF) obtained by using the following procedure.

Expression and fermentation

cDNA CPGF is expressed using plasmids RCC-2 (Pharmacia Biotech. Inc. , Piscataway, New Jersey) in E. coli strain XL-1 Blue (Stratagene Cloning systems, La Jolla, CA). The strain is sown in LB medium (consisting of 10 g of tryptone, 5 g yeast extract, 5 g NaCl, and 1 ml of 1N NaCl per liter) plus 100 mg/l ampicillin, 100 mg/l pyridoxine and 600 mg/l MnCl2and grown at 37oC to the density of cells at OD550=1,0. At this point cells induced by 1 mm isopropyl-1-thio --D-galactoside which are stated at -70oC up until not required for cleanup.

Purification of glycogen phosphorylase

Cells in the sediments described above, again suspended in 25 mm-glycerol (pH 7.0) with 0.2 mm DTT, 1 mm MqCl2plus the following protease inhibitors: 0,7 µg/ml - pepstatin A; 0.5 μg/ml - leupeptin; 0.2 mm - phenylmethylsulfonyl (PMSF) and 0.5 mm - EDTU, are lysed by pre-treatment with 200 μg/ml lysozyme and 3 µg/ml Gnkazy with subsequent destruction by ultrasound portions of 250 ml for 5 x 1.5 minutes on ice using an ultrasonic device for cell disruption Branson model 450 (Brancon Sonic Power Co., Danbury CT). Lysates were osvetleni by centrifugation at 35000 xq for one hour followed by filtration through the 0.45-micron filters. CPGF in dissolved fractions of lysates (ozenda, as a component of less than 1% of total protein) purified by controlling enzyme activity (as described in the Definition of activity CPGF below) in several steps of chromatography, detailed below.

Affinity chromatography on immobilizovannoi carrier with metal (IMAC)

This stage is based on the method Luocng et al. (Luong et at. Journal of Chromatography (1992) 584, 77-84). 500 ml of the filtered dissolved fractions of cell lysates (obtained nology Piscataway, New Jersey), which was loaded with 50 mm CuCl2and 25 mm glycerol, 250 mm NaCl and 1 mm imidazole in equilibrating buffer pH 7. The column was washed with equilibrating buffer until such time as A280not returned to the original line. Then the sample elute column with the same buffer containing 100 mm imidazole to remove associated CPGF and other related proteins. Fractions containing active CPGF are pooled (approximately 600 ml) and add ethylenediaminetetraacetic acid (EDTU), DL-dithiothreitol (DTT), phenylmethylsulfonyl (PMSF), leupeptin and pepstatin obtaining a concentration of 0.3 mm, 0.2 mm, 0.2 mm, 0.5 μg/ml and 0.7 mg/ml, respectively. United CPGF was absoluely on column Sephadex G-25 (Sigma. Chemical Co., St. Louis Missouri), balanced, 25 mm Tris-HCl (pH 7.3), 3 mm DTT buffer (buffer A) to remove imidazole and kept on ice until the second phase chromatography.

Chromatography on 5'-AMP sepharose

Desalted combined sample CPGF then mixed with 70 ml of 5'-AMP sepharose (Pharmacia LKB Biotechnology, Piscataway, New Jersey), which was equilibrated with buffer A (see above). The mixture which was slightly over one hour at 22oC, then Packed in a column and washed with buffer A until until the A280 was not returned to the original WRF) at pH 7.3 (buffer B). The fractions containing CPGF, were United after identification by determining the enzymatic activity (described below) and visualisatie M, about 97 KD protein bands CPGF by electrophoresis in polyacrylamide gel with sodium dodecyl sulfate (SDS-PAGE) followed by silver staining (2D silver paint 11 Daiichi Kit; Daiichi Pure Chemicals Co., LTD., Tokyo, Lapan). United CPGF deliberately 25 mm glycerol, 0.2 mm DTT, 0.3 mm EDTU, 200 mm NaCl, pH 7.0 buffer (buffer C) and kept on ice until use.

Determination of enzyme activity CPGF

A) Activation CPGF: Conversion b in Cpgf

Prior to determination of the enzymatic activity CPGF enzyme was converted from an inactive form, which expressives in E. coli strain XL-1 Blue (denoted b) (Stragene Cloning systems, LaJolla, California) in the active form (designated by Cbhfa) by phosphorylation CPGF using phosphorylating as follows:

b reaction with immobilized phosphorylating

Phosphorylations (Siqma Chemical Company, St. Louis, MO) immobilizerpower on Affi-Gel 10 (BioRad Corp., Melvile, NY) according to the manufacturer's instructions. Briefly, the enzyme phosphorylating (10 mg) were incubated with the washed granules Affi-gel (1 ml) in 2.5 ml of 100 mm HEPES and 80 mm CaCl2p what W 50 mm HEPES and 1 M glycymeris ether at pH 8.0 for one hour at room temperature. Blocking buffer was removed and replaced with 50 mm HEPES (pH of 7.4), 1 mm - mercaptoethanol, and 0.2% NaN3for conservation. Before using for the conversion b in Cpgf, granules Affi-gel with immobilized phosphorylating balanced by washing in the buffer used to perform the kinase reaction, consisting of 25 mm glycerol, 0.3 mm DTT and 0.3 mm EDTU at pH 7.8 (buffer for studies with kinase).

Partially purified inactive b received after the above chromatography on 5'-AMP-sepharose diluted 1:10 with buffer for the study of kinases, and then mixed with the above enzyme phosphorylating, immobilizovannoi on the granules Affi-gel. Added Na to 5 mm MgCl2to 6 mm. The resulting mixture was gently stirred at 25oC for from 30 to 60 minutes. The sample was separated from the pellet and set the percentage activation b by transformation in Cpgf by determining the enzymatic activity CPGF in the presence or in the absence of 3.3 mm AMP. The percentage of the total enzymatic activity CPGF associated with the enzymatic activity of Cphf (AMP-independent), then calculated as follows:

< / BR>
B) determining the activity CPGF

Gipoglikemicheskogo of the invention can be directly determined by evaluating the effect of the compounds of this invention on the activity of the activated form of glycogen phosphorylase (GFA) by using one of two methods; the activity of glycogen phosphorylase and measured in the forward direction by monitoring the production of glucose-1-phosphate from glycogen or by following the reverse reaction by measuring the synthesis of glycogen from glucose-1-phosphate by excretion of inorganic phosphate. All reactions were carried out in three replicates in 96-cell boards and the change in absorption associated with the formation of the reaction product, measured at the wavelength specified below, the reader Elisa MCC/340 MK11 (Lab Systems, Finland) connected to the receiver blade (ISN Biomedical Co., Huntsville, Alabama).

To measure the enzymatic activity CPGF in the forward direction, production of glucose-1-phosphate from glycogen tracked using multienzyme combined General method Pesce et al. (Pesce, M. A. Bodourian, S. H., Harris R. C. and Nicholson. J. F. (1977) Clinical Chemistry 23, 1711-1717), modified as follows: from 1 to 100 µg phosphorylase a, 10 units phosphoglucomutase and 15 units glucose-6-phosphate dehydrogenase (Boehringer Mannheim Biochemicals, Indianapolis, IN) was diluted to 1 ml in buffer A (described hereafter). A buffer with A pH of 7.2 containing 50 mm HEPES, 100 mm KCl, 2.5 mm etilenditiodiuksusnoi acid (AGTU), 2.5 mm MgCl23.5 mm KH2PO4and 0.5 mm dithiothreitol. 20 µl of this source, the standard solution is added to 80 μl of state (NADP+). The connection that you want to test, add 5 ál of solution in 14% dimethyl sulfoxide (DMSO) before adding enzymes. The original degree of the enzymatic activity of Cbhfa in the absence of inhibitors is determined by adding 5 μl of 14% DMSO and enzymatic activity when fully suppressed Cphva obtained by adding 20 μl of 50 mm of the positive control test substance, caffeine. The reaction is observed at room temperature by measuring the conversion of oxidized NADP+in the restored NADPH at 340 nm.

To measure enzyme activity in the reverse direction, the conversion of glucose-1-phosphate into glycogen plus inorganic phosphate was measured using the General method described Engers et al. {Engers, H. D. Shechosky, S. and Madsen, N. B. (1970) Can. J. Biochem. 48, 746-754}, modified as follows: 1-100 μg of Cbhfa diluted to 1 ml in buffer B (described hereafter). Buffer B with a pH of 7.2 containing 50 mm HEPES, 100 mm KCl2, 2.5 mm AGTU, 2.5 mm MgCl2and 0.5 mm dithiothreitol. 20 µl of this initial solution is added to 80 μl of buffer B with 1.25 mg/ml glycogen, 9.4 mm glucose, and 0.63 mm glucose-1-phosphate. Compounds to be tested are added to 5 μl of solution in 14% DMSO before dobavlyaetsya by adding 5 μl of 14% DMSO and a fully suppressed enzymatic activity of Cbhfa was obtained by adding 20 μl of 50 mm caffeine. This mixture is incubated at room temperature for 1 hour, inorganic phosphate released from glucose-1-phosphate was determined quantitatively by the General method of Lanzetta et al. {Lanzetta, P. A., Alvarez, L. J., Reinach, P. S. and Candia, O. A. (1979) Anal. Biochem. 100, 95-97}, modified as follows: 150 μl of a solution of ammonium molybdate 10 mg/ml of 0.38 mg/ml malachite green in 1N HCl is added to 100 ál of enzyme mixture. After 20 minutes incubation at room temperature was measured by the absorption at 620 nm.

The compounds of this invention are easily adapted for clinical use as hypoglycemic agents. The hypoglycemic activity of the compounds of this invention can be determined by the amount of test compound that reduces glucose levels compared to the medium without the test compound in male mice ob/ob. The test also gives the possibility of determining the approximate value of the minimum effective dose (MED) to reduce in vivo glucose concentration in the plasma of these mice to a similar test compounds.

As the concentration of glucose in the blood is closely linked with the development of diabetic disorders, these compounds due to its hypoglycemic action alert, ostanavlivajsa C57BL/6J-ob/ob (obtained from Jackson, Laboratory, Bar Harbor, ME) were placed at five in the cage with the standard practice of care for the animals. After a one-week acclimatization period, animals were weighed and selected 25 µl of blood from the retro-orbital sinus before each course of therapy. The blood sample was immediately diluted 1:5 with saline containing 0.025% of heparin-sodium, and kept on ice until metabolic analysis. Animals were divided into groups of therapeutic treatment, so that each group had similar average concentration of glucose in plasma. After dividing into groups to animals orally daily for four days was injected dose media containing one of: 1) 0.25% W/V methylcellulose in water without setting the pH; or (2) of 0.1% PluronicP105 block copolymer surfactant (BASE Corporation, Parsippanay, NJ) in 0.1% salt solution without establishing pH. On day 5 animals were again weighed and then orally injected dose of the test compounds or one carrier. All drugs were injected in a carrier consisting of either: 1) 0.25% W/V methylcellulose in water without establishing pH; or 2) 10% DMSO/0.1% of PluronicP105 (BASF Corporation, Parsippany, NJ) in 0.1% salt solution without establishing pH. Then in animals after three hours of retro-orbits which were garofali for two minutes at 10000xq at room temperature. The supernatant was analyzed for glucose, for example, using the Abbott VPTM(Abbott Laboratories, Diagnostics Division, Irving, TX) and auto-analyzer VP Syper System(Abbott Laboratories, Irving, TX) using a system of reagents for UV determination of glucose A-GentTMGlucose-UN test (Abbott Laboratories, Irving, TX) (modification of the method of Richterich and Dauwalder, Schweizerische Medizinische Wochenschrift, 101, 860 (1971)) (hexokinase method) using 100 mg/DL standard.

The plasma glucose was calculated by the equation:

Plasma glucose (mg/DL) = value for sample x 5 x 1,784 = 8,92 x value for sample,

where 5 is the result of breeding and 1,784 is the correction for hematocrit plasma (assuming that the hematocrit plasma is 44%).

In animals that were injected media, remained essentially unchanged hyperglycemic glucose levels (for example, greater than or equal to 250 mg/DL), the animals were treated with test compounds in the appropriate dosage, had significantly reduced glucose levels. The hypoglycemic activity of the tested compounds is determined by statistical analysis (unpaired t-test) the average concentration of glucose in plasma between the group treated with the test compound, and the group treated with the carrier, on the fifth day. Vicepresidente minimum effective dose (MED) to reduce the concentration of glucose in plasma in vivo.

The compounds of this invention are easily adapted for clinical use as a means of changing the hyperinsulinemia, means for reducing the level of triglycerides and hypocholesterolemic funds. This activity can be determined by the amount of test compound that reduces the level of insulin, triglyceride, or cholesterol compared with control medium without the test compound on the male mice ob/ob.

As the concentration of cholesterol in the blood is closely linked with the development of cardiovascular diseases and diseases of the blood vessels of the brain and peripheral vessels, the compounds of this invention due to its hypocholesterolemic action alert, stop development and/or cause regression of atherosclerosis.

As the concentration of insulin in the blood is associated with the stimulation of cell growth of blood vessels and increased sodium retention by the kidneys (in addition to other actions, such as stimulation of glucose utilization) and these steps are known to cause hypertension, the compounds of this invention due to their hyperinsulinemia action, warn, stop development and/or cause regression of hypertension.

As cobretti, due to their lower levels of triglycerides activity, warn, stop development and/or cause regression of hyperlipidemia.

Five-eight male mice C57BL/6j-ob/ob (obtained from Jackson Laboratory, Bar Harbor, ME) were placed at five per cage under standard practice of animal care and standard diet food for rodents. After a one-week acclimatization period, animals were weighed and from the retro-orbital sinus before any effect was selected 25 Microlitre blood. The blood sample was immediately diluted 1:5 with saline containing 0.025% sodium heparin, and kept on ice for analysis on plasma glucose. Animals were distributed into groups by type produced by the impact, so that each group had similar average concentration of glucose in plasma. The compound to be tested was administered orally using a probe in the form of approximately from 0.02% to 2.0% solution (weight/volume (V/o)) in any 1) 10% DMSO/0.1% of block copolymer surfactant PluronicR (BASE Corporation, Parsippany, NJ) in 0.1% saline without establishing pH, or 2) a 0.25% V/o solution of methylcellulose in water without establishing pH. A single injection per day (O. S. C.) or double introduction to the day (filled with the solution without establishing pH or only 0.25% of the methylcellulose in water without establishing pH.

Three hours after the last injection, animals were scored by decapitation and the blood from the Central blood was collected in 0.5 ml tubes for separation of plasma containing 3.6 mg 1:1 weight/weight mixture of sodium fluoride: potassium oxalate. Freshly harvested samples were centrifuged and for two minutes at 10,000 x g at room temperature, and the serum supernatant was transferred and diluted 1:1 volume/volume solution of Aprotinin 1 TME/ml in 0.1% saline without establishing pH.

Diluted serum samples were then stored at -80oC until analysis. The thawed samples diluted serum was analyzed for insulin, triglycerides and cholesterol. The insulin concentration was determined using sets EquateRIA INSULIN (double or antibody-based test method; as specified by the manufacturer) purchased from Binax, South Portland, ME. The coefficient of variation between the definitions is 10%. Serum triglycerides were determined using autoanalyzer Abbott VMTMand VP Super System(Abbott Laboratories, Irving, TX) using a system of reagents for determination of triglycerides, A-GentTMTriglycerides Test (Abbott Laboratories, Diagnostics Division, Irving, TX) (enzymatic method with an associated lipase; modification of the method of Sampson, et al. Clinical Chemistry 21, P>(Abbott Laboratories, Irving, TX) and reagents for determination of cholesterol A GentTM(enzymatic method with an associated cholesterylester; modification of the method of Allain. et al., Clinical Chemictry 20, 470 (1974)) using standards of 100 and 300 mg/DL. Serum levels of insulin, triglycerides and total cholesterol were then calculated by the equations.

Serum insulin (mked/ml) = the Value for sample x 2.

Serum triglycerides (mg/DL) = Value for sample x 2. Serum total cholesterol (mg/DL) = Value for sample x 2, where 2 is the index of breeding.

In animals that were injected media, remained almost unchanged increased the level of serum insulin (for example, 225 mked/ml), serum triglycerides (e.g., 225 mg/DL) and total serum cholesterol (e.g., 160 mg/DL), while in animals which were treated with test compounds of this invention, generally identified reduced the level of serum insulin, triglycerides and total cholesterol. The activity of the tested compounds on the reduction of serum insulin, triglycerides and total cholesterol were determined using statistical analysis (unpaired t-test) comparing media is STV, and the control group treated with the carrier.

Activity to protect against damage to the heart tissue for compounds of this invention can be demonstrated in vitro in accordance with the present Butwell et al., Am. J. Physiol, 264, H1884-H1889, 1993 and Allard et al., Am. J. Physiol, 1994, 267, H66-H74. The experiments were performed using Sobyanin preparations isolated rat heart essentially the same as described in the above referenced article. Normal male rats Sprague-Dawley prepared so that they had hypertrophy of the heart, by the operation of ligature of the aorta, the male rats BB/W with acute diabetes or appropriate for age control rats BB/W without diabetes pre-injected with heparin (1000 u/b), with the subsequent introduction of phenobarbital (65 mg/kg/b). After he reached deep anesthesia, which was determined by the absence of plantar reflex, the heart was rapidly dissected and placed in ice-cold saline. Heart retrograde was perfesional through the aorta for 2 minutes. Heart rate and ventricular pressure was determined using a latex balloon placed in the left ventricle, with a tube for high pressure connected to the pressure sensor. Heart perfuse the PS - 11. In the device for perfusion strictly regulate the temperature of the heated baths used for perfusion solution and the water jacket around the pipe for perfusion so as to maintain the temperature of the heart at the level of the 37oC. Oxygenation of the perfusion solution was provided by pediatric hollow fiber oxygenator (Capiax, Terumo, Corp., Tokyo, Japan) immediately proximal to the heart. Heart stood with perfusion solution of the test compound for 10 minutes or more, followed by 20 minutes of complete ischemia and 60 minutes resumed perfusion in the absence of the test substance. The heartbeat control and subjected to the action of the tested compounds of the heart compared to the period after ischemia. The pressure in the left ventricle of control and exposed to the test substance of the heart compared to the period after ischemia. At the end of the experiment, the heart was also perfesional and stained to determine the ratio of the area of infarction to the area subjected to negative influence (%PI/STAND), as described below.

therapeutic effects of the compounds of this invention for the prevention of tissue damage in the heart, otherwise resulting ishem 1 (July 1991), how, in particular, described herein. In in vivo tests cardiotoxic of the tested compounds in comparison with the control group, which receives the media in the form of saline solution. As initial information indicated that brief periods of myocardial ischemia with subsequent resumption of perfusion of the coronary arteries protects the heart against subsequent severe myocardial ischemia (Murry et al., Circulation, 74; 1124-1136, 1986). Cardiotoxic, as shown by the recovery of the affected myocardial infarction, can be created pharmacologically with the use of intravenous agonists adenosine receptors intact shot rabbits studied as a model of in situ pre-established myocardial ischemia (Liu et al., Circulation, 84: 350-356, 1991). When in vivo is determined whether the substances to pharmacologically induce cardiotoxic, i.e., to provide a reduced size of myocardial infarction in injecting a shot rabbits. The effects of compounds of this invention on a previously created ischemia can be compared with the use of agonists of the adenosine A1, N6-1-(phenyl-2R-isopropyl)adenosine (FIA), which has been shown to be pharmacologically causes cardiotoxic wick is described below.

Surgery: male new Zealand white rabbits (3-4 kg) were anestesiologi pentobarbital (30 mg/kg, in/in). A tracheotomy was performed through a ventral midline cervical section, and rabbits did artificial ventilation with 100% oxygen using an artificial respirator with creating a positive pressure. Catheters were placed in the left jugular vein for drug administration and in the left carotid artery for blood pressure measurement. Then taken out of the heart through the left thoracotomy and around the selected branches of the left coronary artery was doing a loop (silk 00). Ischemia caused by tight tighten hinges and locking it into place. Releasing the loop, was allowed to resume blood circulation in the affected area. About myocardial ischemia testified regional cyanosis; on resumption of circulation testified reactive hyperemia.

The methodology of the study: if blood pressure and heart rate remained stable for at least 30 minutes, the experiment begin. Pre-condition ischemia is invoked by double occlusion of a coronary artery for 5 minutes, followed 10 min resumption of perfusion. Pharmakologie, for example, 5 minutes, allowing 10 minutes before further intervention, or by infusion of the agonist adenosine, FIA (0.25 mg/kg). After first creating ischemic background, pharmacological background or without prior intervention (without creating a pre-condition monitoring with the introduction of media) produced artery occlusion for 30 minutes and then resumed circulation for two hours to induce myocardial infarction. Test the connection and the FIA was dissolved in saline or other suitable medium, and injected in amounts of 1-5 ml/kg, respectively.

Staining (Liu et al., Circulation 84:350-356, 1991): At the end of the 2 hour period of renewed circulation, the heart was rapidly removed, hung in the apparatus of Langendorf and filled in 1 minute normal saline warmed to body temperature (38oC). Suture silk, used as a loop, then tightly tied again to cause occlusion of the artery, and was produced by the infusion of a 0.5% suspension of fluorescent particles (1-10 μm) perfusion solution for staining of the entire myocardium except for the area that produced a negative impact (effluorescence ventricle). Heart then quickly frozen and kept over night p is AK as TTX react with living tissue, this paint differentiates live (red staining) tissue and dead tissue (unpainted infarction tissue). The area of infarction (unpainted) and negative impacts (no fluorescent particles) are calculated for each slice of the left ventricle using a pre-calibrated image analyzer. To arrange an ischemic lesion of the differences in square negative impacts in different hearts, data were expressed as the ratio of the area of infarction to square a negative influence (%PI/STAND). All data are expressed as the mean value of the mean square error (RMSE) and compared statistically using one-way variance analysis (ANOVA) or unpaired t-test. The value is taken into consideration, when p < 0,05.

Introduction compounds of this invention can occur by any means, which delivers a compound of this invention, preferably in liver and/or cardiac tissue. These routes of administration include oral route, parenteral, intraduodenal route of administration, etc. basically, the compounds of this invention are introduced in the form of a single (e.g., once daily) or multiple injections. the Oia/ want to treat the subject to be treated, the severity of the disease, the route of administration and the judgment prescribing physician. Thus, because of the diversity of conditions patients dosage, given below, is the pilot and the doctor can find the dose to achieve the action (for example, reducing the level of glucose actions) that the physician considers appropriate for the particular patient. Considering the degree of the desired activity, the physician must balance a number of factors, such as initial level, other factors negative effects (cardiovascular), previous diseases, the patient's age and motivation of the patient.

Basically, an effective dosage for the activities of the compounds of this invention, for example, to lower blood glucose, triglycerides and cholesterol, and actions to reverse the development of hyperinsulinemia, is in the range of 0.005 to 50 mg/kg/day, preferably from 0.01 to 25 mg/kg/day and most preferably from 0.1 to 15 mg/kg/day.

In General, the compounds of this invention are introduced orally, but can be used parenteral (e.g. intravenous, intramuscular, subcutaneous or intramedullary), mapimport medicine. Can also be shown through local injection, for example, when the patient is suffering from gastrointestinal disorders or when the medication is best applied on the surface of the tissue or organ, as determined by the treating physician.

The compounds of this invention mainly introduced in the form of pharmaceutical compositions containing at least one of the compounds of this invention together with a pharmaceutically acceptable carrier or solvent. Thus, the compounds of this invention can be administered separately or together in any conventional oral, parenteral or transdermal dosage form.

For oral administration the pharmaceutical composition may take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate, used in conjunction with various disintegrators such as starch and preferably potato starch or tapioca and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum. In addition, often primenews the position of this type are also used as fillers in soft and hard filled gelatin capsules; preferred in this regard, the materials also include lactose or milk sugar, as well as glycols of high molecular weight. If oral administration is desired aqueous suspensions and/or elixirs, the compounds of this invention can be combined with various sweetening means, improving the taste and smell tinted agents, emulsifying agents and/or suspendresume means, and solvents, such as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For parenteral administration can be used, solutions in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions can be suitably buffered, if necessary, and an aqueous solvent first stoneroot with a sufficient amount of a solution of salt or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, the water environment can be easily obtained using standard techniques, well known to experts.

For transdermal is commonly from 0.1% to 5% concentration), or similar to the above solutions for parenteral administration.

Methods of obtaining various pharmaceutical compositions with a certain amount of the active ingredient are known, or will be clear in the light of this description for specialists. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa, 15th Edition (1975).

The pharmaceutical compositions according to this invention may contain 0.1 to 95% of the compound(s) of this invention, preferably 1-70%. In any event, the composition or dosage form for injection will contain the number of the compound(s) according to this invention, effective to treat the disease/condition of the subject to be treated, i.e., disease/condition, dependent on glycogen phosphorylase.

The General procedure of the experiment for sample 1-99 and 166-172

NMR spectra were recorded on a spectrometer Varian XL-300 (Varian Co., Palo Alto, California) or Bruker AM-300 (Bruker Co., Billerica, Massachusetts) with approximately 23oC and 300 MHz for proton and 75.4 MHz for carbon nuclei. The chemical shift is expressed in parts per million down field trimethylsilane. Resonances marked as exchange, do not appear in a separate experiment, NMR, where the sample was shaken with a few drops of D235Cl/37Cl-containing ions and 1:1 for79Br/81Br-containing ions) and given the intensity only for ions of lower mass.

HPLC was performed with detection at 214 nm on h,6 mm column (Rainin Microsorb C-18 (Rainin Co. , Woburn, Massachusetts), which was suirable isocrate using a system of two pumps/mixers, feed this mixture of acetonitrile and water with 0.1 M KH2PO4the pH of 2.1 (with H3PO4), respectively, with a speed of 1.5 ml/min, the Samples were introduced in a mixture of 1:1 acetonitrile and phosphate buffer pH 7.0 (0.025 M each Na2HPO4and KH2PO4). The percentage purity refers to the percentage of the total integrated area usually with a course (course) over 10-15 minutes. The melting temperature uncorrected and were determined in the apparatus for op equal amount of 120.5-122oC for benzoic acid and 237,5-to 240.5oC for p-chlorbenzoyl acid (Aldrich 99+% of degrees). Column chromatography was performed using Amicon silica gel (30 µm, pore size 60A) (Amicon D Vision, W. R. Grace & Co., Beverly, Mass.) in glass columns under low nitrogen pressure. Unless otherwise stated, were used reagents from commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran, and dichloromethane is used as solvent in the reactions were brand "anhydrous" and supplied to the Aldrich Chemical Company (Milwaukee, Misconsin). The analyses were performed using microanalytical laboratory Schwarzkopf (Schwarzkopf Microanalytical Laboratory, Woodside, NY. The terms "concentrated" or semiperennial refer to removal of solvent on a rotary evaporator with a water suction device at a bath temperature of less than 45oC. Reactions conducted at "0-20oC" or "0-25oC", conducted with the initial cooling of the vessel in an isolated ice bath which was allowed to warm to room temperature over several hours. Reducing the "min" and "h" indicate "minutes" and "hours", respectively.

Procedure A (binding peptide using DPC)

0.1-0.7 M solution of the primary amine (1.0 equiv., or primary AMI the second solvent), processed sequentially at 25oC of 0.95 to 1.2 equivalent of the specified carboxylic acid, 1,2-1,8 equivalent hydroxybenzotriazole (usually 1.5 equivalent relative to the carboxylic acid) and 0.95-1.2 equivalent (corresponding to a molar ratio to the number of carboxylic acid) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DPC), and the mixture is stirred for 14-20 hours (see note 1, below). The mixture was diluted with ethyl acetate, washed 2-3 times 1 or 2N NaOH, 2-3 times 1 or 2N HCl (note 2), the organic layer was dried over MgSO4and concentrated to obtain the product crude, which was purified by chromatography on silica gel, trituration, or recrystallization, as specified using the indicated solvents. Purified products were analyzed using HPLC with reversed phase and found that the purity was more than 95% unless otherwise specified. The reaction is conducted at a temperature of 0-25oC, was performed with an initial cooling of the vessel in an isolated ice bath which was allowed to warm to room temperature over several hours.

Note 1: by reacting compounds of larger scale (> 50 ml solvent) mixture at this point conc the national amine group, washing the acid was not included. Exceptions in the application of procedures And are marked separately (where required, below), usually in parentheses, directly after mentioning procedures A.

Example 1.

Methyl ester (2S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -3 - phenylpropionic acid

The hydrochloride of the methyl ester of L-Phenylalanine (77,0 mmol) and 5-chloro-1H-indole-2-carboxylic acid (77 mmol) was linked to procedure A (0-25oC), and the product was purified by chromatography on silica gel in 10 and 20% ethyl acetate-hexano getting connection header as not quite white solid (22,12 g, 81%): so pl. 156-157oC; HPLC (60/40) 9.5 minutes (98%); PBMS 357/359 (MH+100%).

1H NMR (CDCl2) 9,40 (W, 1H), 7,60 (d, 1H, J = 1 Hz), 7,35 (d, 1H, J= 8,9 Hz), and 7.3 to 7.2 (m, 4H), 7,13 (m, 2H), 6,74 (d, 1H, J=1.7 Hz), 6,62 (d, 1H, J=7.5 Hz), 5,11 (m, 1H), of 3.77 (s, 3H), 3,26 (m, 2H);

Anal. Calculated for C19H17ClN2O3: C 63,96; H, 4,80; N, A 7.85. Found: C, 64,24; H, 4,84; N, 8,02.

Example 2.

2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3-phenylpropionate acid

Aqueous 2 M LiOH (33,10 ml) was added to a solution of (2S)-[(5-chloro-1H-indole-2-carbonyl)amino] -3-phenylpropionic acid methyl ester (21,47 g, 60 mmol) in THF (140 ml) at 0-5oC. After 0.5 washed with water and then ether to obtain colorless solid (18,78 g, 91%): so pl. 248-255oC; HPLC (60/40) to 5.21 minutes (98%); TRMS 343/345 (MH+, 100%).

1H NMR (DMSO-d6) 12,85 (Shir. 1H), 11,75 (d, 1H, J 1 Hz), 8,84 (d, 1H, J= 8,4 Hz), 7,35-7,14 (m, 7H) and 4.65 (m, 1H), 3,30 (A of AB, 1H, J=4,5, a 13.9 Hz), 3,07 (B of AB, 1H, J =10,8, to 13.8 Hz);

Anal. Calculated for C18H15ClN2O3: C 63,07, H,4,41; N, 8,17.

Found: C, 62,90; H,4,60; N, 8,04.

Example 3.

Methyl ester [(5-Chloro-1H-ended-2-carbonyl)-amino]-acetic acid

Hydrochloride licensedialog ether (50 mmol) and 5-chloro-1H-indole-2-carboxylic acid (50 mmol) were coupled according to procedure A, substituting the next processing: the reaction mixture was stirred with ethyl acetate (250 ml), hexane (50 ml) and 1N NaOH (50 ml) and the suspension was filtered. The solid is washed with 1N NaOH, 1N HCl, water, ethyl acetate, and dried: yield of 11.5 g, 86%; so pl. 252-254oC with decomposition;

1H NMR (DMSO-d6) 11.87 per (W, 1H), 9,05 (t, 1H, J=6.0 Hz), 7,72 (d, 1H, J= 2.0 Hz), was 7.45 (d, 1H, J=8.7 Hz), 7,19 (DD, 1H, J=2.0 a, 8,7 Hz), of 4.05 (d, 2H, J=6.0 Hz), 3,91 (s, 3H);

Anal. Calculated for C12H11ClN2O3: C 54,05; H, 4,16; N, 10,50.

Found: C, 54,11; H, To 4.23; N, 10,56.

Example 4.

[(5-Chloro-1H-indole-2-carbonyl) - amino]-acetic acid

1N NaOH (35 ml) was added to a suspension of [(5-chloro-1H-indole-2-carbonyl)Wali for 18 hours at 25oC. the Solution was acidified using 6N HCl (7 ml), the mixture was concentrated, the solid suspended in water, filtered and washed with water (7,42 g, 98%): HPLC (60/40) 2,89 minutes (100%);

1H NMR (300 MHz, DMSO-d6) 12,68 (W, 1H), 11,85 (W, 1H), 8,95 (t, 1H, J=5,9 Hz), 7,72 (d, 1H, J=2.0 Hz), 7,44 (d, 1H, J=8.7 Hz), 7,19 (DD, 1H, J=2.0 a, 8,7 Hz), 7,14 (d, 1H, J= < 2 Hz), 3.96 points (d, 2H, J=5,9 Hz).

Anal. Calculated for C11H9N2O3Cl: C, 52,29; H And 3.59; N, 11,09.

Found: C, 52,26; H, To 3.73; N, 11,20.

Example 5.

5-Chloro-1H-indole-2-carboxylic acid [2-((3RS)hydroxypyrrolidine-1-yl)-2-oxoethyl]-amide

3-Pyrrolidine (1.25 mmole) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (1,19 mmole) were coupled according to the procedure And with the following processing: the reaction mixture was diluted with ethyl acetate and 2N HCl, stirred for 1 hour, the mixture was filtered and the resulting solids were washed sequentially 2N HCl, 2N NaOH, 2N HCl, dried, triturated with ether/hexane 1: 1 and dried to obtain not quite white solid: yield 280 mg, 73%; HPLC (60/40) 4,66 minutes (96%);

PBMS 322/324 (MH+, 100%).

1H NMR (DMSO-d6) 11.87 per (W, 1H), 8,71 (kV, 1H), 7,71 (d, 1H, J=2.1 Hz), was 7.45 (d, 1H, J=8,8 Hz), 7,19 (DD, 1H, J=3,1, 8,8 Hz), 7,16 (s, 1H), 5,07 (d, 0.5 H, J=3.6 Hz), equal to 4.97 (d, 0.5 H, J=3.1 Hz), 4,35 (m, 1H), 4,27 (m, 1H),acid [2-(CIS-3,4-dihydroxypyrrolidine-1-yl)-2-oxoethyl]-amide

(3R, 4S)-3,4-Dihydroxypyrrolidine hydrochloride (CIS or mesosoma, to 1.79 mmole) and [(5-chloro-1H-indole-2-carbonyl)-amino]- acetic acid of 0.85 mmole) were coupled according to procedure A (1:1, CH2Cl2/DMF as solvent in the reaction) with the following processing: the reaction mixture was concentrated, the residue is suspended in 10 ml of EtOAc and 10 ml of 2N NaOH, the solid was filtered and washed successively aqueous 1N NaOH and EtOAc, the aqueous 1N HCl, H2O and ether. The washing sequence was repeated and the resulting solid suspended in EtOAc, stirred for 1 hour, filtered and dried: yield 252 mg, 88%; HPLC (60/40) 2,33 minutes (93%); TRMS 338/340 (MH+, 100%);

1H NMR (DMSO-d6) 11,82 (s, 1H) , 8,72 (t, 1H), 7,73 (d, 1H), 7,45 (d, 1H), 7,20 (DD, 1H), 7,15 (s, 1H), of 5.05 (d, 1H), to 4.98 (d, 1H), 4,10 (m, 1H), a 4.03 (m, 3H), 3,68 (DD, 1H), 3,42 (DD, 1H), 3,33 (DD, 1H), 3,23 (DD, 1H).

Example 7.

5-Chloro-1H-indole-2-carboxylic acid [2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide

4-Hydroxypiperidine (or 0.83 mmole) and [(5-chloro-1H-indole-2-carbonyl)-amino] -acetic acid (0.8 mmole) were coupled according to procedure A (dimethylformamidine as solvent for the reaction) with the following processing: the reaction mixture was stirred with ethyl acetate and aqueous 2N HCl, p is 2N HCl, aqueous 2N NaOH, ether and dried: yield 180 mg, 68%; TRMS 336/338

1H NMR (DMSO-d6) 11,84 (W, 1H), 8,68 (W, 1H), 7,71 (d, 1H), 7,43 (d, 1H), 7,17 (DD, 1H), 7,14 (s, 1H), 4,80 (W, 1H), 4,15 (m, 2H), 3,91 (m, 1H), and 3.72 (m, 2H), 3,20 (m, 1H), 3,05 (m, 1H), about 1.75 (m, 2H), 1,48 (m, 1H), to 1.38 (m, 1H).

Example 8.

5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2-(3-hydroxypyrrolidine-1-yl)-2-oxoethyl]-amide

Racemic 3-pyrrolidine (2.0 mmole) and 2-[(5-chloro-1H - indole-2-carbonyl)-amino] -3-phenylpropionate acid (1 mmol) were coupled according to procedure A (0-25oC - the temperature of the reaction, washing first with acid, then base) and the product was purified by column chromatography on silica gel with elution with 0.5-16% ethanol in dichloromethane to obtain a colorless foam: yield 260 mg, 63%; HPLC (60/40) 100%, 3,86 minutes; PBMS 412/414 (NH+, 100%);

Anal. Calculated for C22H22ClN3O3+ 0,2 H2O: C, 63,60; H, 5,43, N, 10,11.

Found: C, 63,90; H, To 5.93; N, 10,11.

Example 9,

5-chloro-1H-indole-2-carboxylic acid (1-diethylcarbamoyl-2-phenyl-ethyl)-amide

Diethylamine (1.2 mmole) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenylpropionate acid (0.6 mmole) were coupled according to procedure A (0-25oC for 5 days) to change the following processing: the crude product of suspect, concentrated and the residue was purified by column chromatography on silica gel with elution 10, 20 and 30% ethyl acetate in hexano: exit 14 mg, 6%; HPLC (60/40) 8,88 minutes (98%); PBMS 398/400 (MN+, 100%);

1H NMR (CDCl3) 9,31 (W, 1H), to 7.61 (d, 1H), 7,32 (d, 1H, J= 8.7 Hz), 7,28-to 7.18 (m, 7H), 6.87 in (d, 1H, J=1.4 Hz), 5,26 (m, 1H), 3,6 (m, 1-1, 5H), of 3.2 and 2.9 (m, 4,5-5H), of 1.07 (t, 3H, J =7.2 Hz), of 1.02 (t, 3H, J=7.2 Hz).

Anal. Calculated for C22H24ClN3O2+ 0,25 H2O: C 65,66; H, 6,14; N 10,44. Found: C, 65,61; H, 6,20; N, 10,11.

Example 10.

4-{ 2-[(5-Chloro-1H-indole-2-carbonyl)-amino] -3-phenylpropionyl} - piperazine-1-carboxylic acid tert-butyl ether

t-Butyl ester 1-Piperazinecarboxamide acid (1.2 mmole) and 2 - [(5-chloro-1H-indole-2-carbonyl)-amino] -3-phenylpropionate acid (0.6 mmole) were coupled according to procedure A (0-25oC - the reaction temperature, a reaction time of 4 days, the first extraction with acid, then base) and the product crude was purified by column chromatography on silica gel with elution 30% ethyl acetate in hexano obtaining a colorless foam: yield 290 mg, 95%; HPLC (70/30) 6,23 min (99%); PBMS 512/514 (MN+, 100%);

1H NMR (CDCl3) to 9.32 (W, 1H), 7,60 (d, 1H, J=1.9 Hz), 7,32 (d, 1H, J= 8.7 Hz), 7,3-to 7.15 (m, 7H), 6.87 in (d, 1H, J=1.5 Hz), 5,33 (m, 1H), 3,65-2,9 (peracre the 96.

Found: C, 63,33; H, 5,97; N, 10,97.

Example 11.

5-Chloro-1H-indole-2-carboxylic acid [1-benzyl-2-(4-methylaminopropyl-1-yl)-2-oxoethyl]amide

Dimethylamine hydrochloride (1.1 mmole), sodium acetate (2.1 mmole), activated 3 a molecular sieve and cyanoborohydride sodium (0.25 mmole) were added in this order to 5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2-oxo-2-(4-oxopiperidin-1-yl)-ethyl] amide (of 0.21 mmole) in methanol (2 ml) at 0oC. After 18 hours the mixture was concentrated, the residue was collected in ethyl acetate, the resulting solution washed with 2N NaOH and brine, dried Na2SO4and concentrated. The product was purified by chromatography on silica gel with elution 1-8% ethanol in dichloromethane containing 0.5% NH4OH, followed by kneading the powder with ether: yield 82%; HPLC (60/40) 2,79 minutes (98%); PBMS 439/441 (MN+, 100%);

1H NMR (DMSO-d6) 11,75 (W, 1H), to 8.94 (d, 0.5 N), J=8,8 Hz), of 8.90 (d, 0.5 H), 7,71 (d, 1H, J=1.8 Hz), 7,40 (d, 1H, J=8.7 Hz), 7,31-7,20 (m, 6-7H), 7,17 (DD, 1H, J=2,1, to 8.7 Hz), 5,15 (m, 1H), 4,22 (m, 0.5 H), 4,08 (m, 0.5 N), of 3.96 (m, 0.5 H), 3,85 (m, 0.5 H), the 3.2 and 2.9 (m, 4H), 2,78 (m, 0.5 H), of 2.72 (m, 0.5 H), of 2.25 (s, 1.5 H), 2,24 (s, 1.5 H) to 1.75 (m, 2H), 1,3-0,8 (m, 2H).

Anal. Calculated for C24H27ClN4O2+ 1,0 H2A: C, 63,08; H, 6,40; N, OF 12.26.

The detection-4-yl-2-oxoethyl)-amide

Morpholine (0,33 mmole) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenylpropionate acid (0.30 mmole) were coupled according to procedure a (reaction temperature 0-25oC, 48 hours reaction time). Product raw was chromatographically on silica gel with elution by ethyl acetate/hexane 1:1, the desired fractions were concentrated and the residue was dissolved in chloroform and methanol, and the resulting solution was stirred 18 hours with about 128 mg dimethylaminopropionitrile resin (Fluka Chemical Co.). The solution was filtered, concentrated and the residue triturated with ether: yield 51%; HPLC (60/40) of 5.92 min (98%).

PBMS 412/414 (MH+, 100%);

1H NMR (DMSO-d6) 11,75 (W, 1H), 8,95 (d, 1H), 7,72 (d, 1H), 7,39 (d, 1H, J=8.7 Hz), 7,35-to 7.15 (m, 7H), 5,13 (m, 1H), 3,65-3,10 (m, 8H), was 3.05 (m, 2H).

Anal. Calculated for C22H22ClN3O3+ 0,33 H2O: C, 63,23; H, VS. 5.47; N, 10,06. Found: C, 63,28; H, 5,32; N, 10,10.

Example 13.

5-chloro-1H-indole-2-carboxylic acid (1-butylcarbamoyl-2 - phenylethyl)-amide

n-Butylamine (0,66 mmole) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenylpropionate acid (0.60 mmole) were coupled according to procedure a (reaction temperature 0-25oC). Product raw was dissolved in chloroform and methanol, and the resulting p is concentrated and the solid was ground into powder with ether: yield 83%; HPLC (60/40) 8,88 minutes (92%); so pl. 192-193oC; TRMS 398/400 (MH+, 100%);

1H NMR (DMSO-d6) 11,71 (W, 1H), to 8.70 (d, 1H, J=8,3 Hz), 8,10 (t, 1H), 7,72 (d, 1H, J=2.0 Hz), 7,39 (d, 1H, J =8.7 Hz), 7,35-to 7.15 (m, 7H), 4,70 (m, 1H), 3,13-of 2.93 (m, 4H), to 1.38 (m, 2H), 0,86 (t, 3H, J=7.2 Hz);

Anal. Calculated for C22H24ClN3N3O2: C, 66,41; H, BETWEEN 6.08; N, 10,56.

Found: C, 65,15; H, 6,04; N, 10,52.

Example 14.

5-Chloro-1H-indole-2-carboxylic acid [1-benzyl-2-oxo-2- (4-oxopiperidin-1-yl)-ethyl]-amide

4-Piperidone monohydrate (2.0 mmole) and 2-[(5-chloro-1H-indole - 2-carbonyl)-amino] -3-phenylpropionate acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC) change the following processing: the reaction mixture was diluted with ethyl acetate, the resulting solution washed with 2N NaOH and 2N HCl, the suspension was filtered and the solid is dried: yield 111 mg, 26%; HPLC (60/40) 8,88 minutes (92%); PBMS 424/426 (MH+, 100%); so pl. 258-261oC; PBMS 424/426 (MH+, 100%);

1H NMR (DMSO-d6) 11,75 (W, 1H), 9,03 (d, 1H, J=8.1 Hz), 7,72 (d, 1H, J=1.9 Hz), 7,39 (d, 1H, J=8.7 Hz), between 7.4 to 7.15 (m, 7H), 5,20 (m, 1H, J=8,2 Hz), 3,88 (m, 1H), to 3.73 (m, 3H), 3,1 (m, 3H), 2,5-2,22 (m, 3H), of 2.05 (m, 1H).

Anal. Calculated for C23H22ClN3O3+ 0,75 H2O: C 63,16; H, 5,42; N BEING 9.61.

The detection is Raiden-1-retil)-amide

Pyrrolidine (0.35 mmole) and 2-[(5-chloro-1H-indole-2-carbonyl)- amino]-3-phenylpropionate acid (0,31 mmole) were coupled according to procedure a (reaction temperature 0-25oC, reaction time of 140 hours) and the product of raw triturated with ether: yield 89 mg, 71%; HPLC (70/30) 7.57 minutes (98%); PBMS 396/398 (MH+, 100 / 80g%);

Anal. Calculated for C22H22ClN3O2+ 0,33 H2O: C, 65,75; H, OF 5.68; N, 10,48.

Found: C, 65,56; H, Of 5.81; N, 10,44.

Example 16.

5-Chloro-1H-indole-2-carboxylic acid [1-[(3-dimethylaminopropyl) methylcarbamoyl]-2-phenylethyl}-amide

N, N,N'-Trimethyl-1,3-diaminopropan (0,31 mmole) and 2-[(5-chloro - 1H-indole-2-carbonyl)amino] -3-phenylpropionate acid (0,28 mmole) were coupled according to procedure a (reaction temperature 0-25oC, response time - 120 hours) and the product was purified by chromatography on silica gel with elution 1-8% ethanol in dichloromethane containing 0.5% ammonium hydroxide: yield 86 mg, 69%; HPLC (40/60) 7.57 min (> 99%); so pl. 187-190,5oC; TRMS 441/443 (MH+, 100%);

Anal. Calculated for C24H29ClN4O2+ 0,25 H2O: C, 64,71, H, OF 6.68; N, 12,58.

Found: C, 64,73; H, 6,94; N, 12,86.

Example 17.

5-Chloro-1H-indole-2-carboxylic acid [1-(3-morpholine-4 - yl-propellerblades)-2-phenylethyl]-amideoC) change the following processing: the reaction mixture was diluted with ethyl acetate, the resulting solution was washed three times with 2 N NaOH and once with brine, dried over Na2SO4and concentrated. The residue was stirred in an atmosphere of ether for 1 hour, the solid was filtered and dried: yield 125 mg, 87%; HPLC (60/40) 2,85 minutes (98%); PBMS 469/471 (MH+, 100/90%);

Anal. Calculated for C25H29ClN4O3+ 0,25 H2O: C, 63,42, H, 6,28, N, 11,83.

Found: C, 63,31; H, To 6.57; N, 12,04.

Example 18.

5-Chloro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenylethyl)-amide

The dimethylamine hydrochloride (0.96 mmole) and 2 - [(5-chloro-1H - indole-2-carbonyl)amino] -3-phenylpropionate acid (from 0.90 mmole) were coupled according to procedure a (reaction temperature 0-25oC, 60 hours reaction time, washed first with acid, then base) and the resulting solid triturated with ether: yield 320 mg, 99%; HPLC (60/40), by 5.87 minutes (100%);

So pl. 224-225oC; PBMS 370/372 (M+, 100%).

A sample recrystallized from ethyl acetate for analysis (so pl. 224-225oC).

Anal. Calculated for C20H20ClN3O2+ 0,5 C4H8O2: C, 63,80; H, of 5.84; N,((3R,4R)-dihydroxypyrrolidine-1-yl)-2-oxoethyl]-amide

(3R, 4R)-3,4-hydroxypyrrolidine (from unnatural tartaric acid by the procedure described in U.S. patent N"4634775, 1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino] acetic acid (1.1 mmole) were coupled according to procedure A (dimethylformamide as solvent in the reaction) change the following processing: the reaction mixture was concentrated, diluted with 20 ml ethyl acetate and 20 ml of 2N NaOH and the suspension was stirred for 0.5 hours, was filtered and the resulting solids were washed sequentially with 2 N NaOH, water, 1N HCl and ethyl acetate: yield 77%; HPLC (40/60, 10.7 minutes (99%); TRMS 338/340 (MH+, 100%);

1H NMR (DMSO-d6) 11,84 (Shir, 1H, exchanges), 8,72 (t, 1H, exchanges), 7,72 (d, 1H, J= 1.9 Hz), 7,44 (d, 1H, J=8.7 Hz), 7,19 (DD, 1H, J=2.1 a, 8,8 Hz), 7,16 (s, 1H), 5,26 (d, 1H, J=4.4 Hz, exchanges), to 5.17 (d, 1H, J=3.2 Hz, exchanges), Android 4.04 (m, 3H), to 3.92 (m, 1H), 3,66 (DD, 1H, 1=4,0, to 10.8 Hz), 3,42 of 3.28 (m, 3H);

Anal. Calculated for C15H16ClN3O4+ 0,25 H2O: C, 52,64; H, A 4.86; N, TO 12.28.

Found: C, 52,61; H, Is 4.85; N, 12,23.

Example 20.

5-Chloro-1H-indole-2-carboxylic acid [2-((3S, 4S)-dihydroxypyrrolidine-1-yl)-2-oxoethyl]amide

(3S, 4S)-3,4-Dihydroxypyrrolidine (from occurring tartaric acid by the procedure described in U.S. patent N 4634775, 1.0 mmol) and [(5-chloro-1H-indole-2-Carboni is enaa the following processing: the reaction mixture was diluted with ethyl acetate and 2N NaOH, the resulting suspension was filtered and the solids washed with ethyl acetate, water and dried: yield 135 mg, 40%; HPLC (40/60) 7.29 minutes (98%); TRMS 338/340 (MH+, 100%);

1H NMR (DMSO-d6) 12,1 (W, 1H), 8,86 (W, 1H), 7,71 (d, 1H, J=2 Hz), the 7.43 (d, 1H, J=8,8 Hz), 7,17 (DD, 1H, J=2, 8,8 Hz), 7,13 (s, 1H), 5,35 (Shir, 1H, exchanges with D2O), 5,28 (Shir, 1H, exchanges with D2O), a 4.03 (m, 3H), 3,92 (s, 1H), 3,66 (DD, 1H, J=4,11 Hz), 3,4-3,2 (m, 3H).

Anal. Calculated for C15H16ClN3O4+ 1,5 H2O: C, OF 49.39; H, 5.25-INCH, N, TO 11.52.

Found: C, 49,50; H, 5,04; N, 11,27.

Example 21.

5-Chloro-1H-indole-2-carboxylic acid [1-benzyl-2- (4-methoxypiperidine-1-yl)-2-oxoethyl]-amide

4-Methoxypiperidine (1.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino] -3-phenylpropionate acid (1.0 mmol) were coupled according to procedure a and the product was purified by chromatography on silica gel with elution by ethyl acetate-hexane 1: 1; output 241 mg, 50%; HPLC (60/40) to 7.67 minutes (94%); PBMS 470/472 (MH+, 100%);

Anal. Calculated for C25H28ClN3O4: C, 63,89; H, 6,01; N, 8,94.

Found: C, 63,91; H; 6,00; N, 8,95.

Example 22.

5-Chloro-1H-indole-2-carboxylic acid [2-phenyl-1-(2,2,6,6-tetramethylpiperidine-4-ylcarbonyl)-ethyl]-amide

2,2,6,6-Teli procedure A. The resulting yellow foam triturated with ether, dichloromethane-ether 1:5. The resulting solid was dissolved in dichloromethane and the resulting solution was treated 0,20 ml of 4N HCl in dioxane. The precipitate, which was filtered, washed with dichloromethane and dried: yield 220 mg, 42%; HPLC (60/40), 3,19 minutes (96%); PBMS 481/483 (MH+, 100%);

Anal. Calculated for C27H33ClN4O2+ HCl + 1,5 H2O: C, 59,56; H, 6,85; N, 10,29. Found: C, 59,30; H, Of 6.90; N, 10,22.

Example 23.

(1-{ 2-[(5-Chloro-1H-indole-2-carbonyl)-amino] -3-phenylpropionyl}- pyrrolidin-(3RS)-yl)carbamino acid tert-butyl ether

Racemic tert-butyl ether pyrrolidin-3-carbamino acid (1.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenylpropionate acid (1.0 mmol) were coupled according to procedure a and the product was purified by chromatography on silica gel with elution ethyl acetate-hexane 1:1: yield 302 mg, 59%; PBMS 511/513 (MH+, 100%);

Anal. Calculated for C27H31ClN4O4: C, 63,46; H, 6,11; N, 10,96.

Found: C, 63,32; H, Of 6.26; N, 10,89.

Example 24.

5-Chloro-1H-indole-2-carboxylic acid (2-morpholine-4-yl-2-oxoethyl)-amide

Morpholine (1.0 mmol) and [(5-chloro-1H-indole-2-Carbo who was enduropale in the air, was filtered and dried to obtain a beige solid: exit 264 mg, 71%; HPLC (60/40) of 3.28 minutes (100%); TRMS 322/324 (MH+, 100%);

1H NMR (DMSO-d6) 11,85 (s, 1H), 8,68 (t, 1H), 7,72 (d, 1H, J=2.0 Hz), the 7.43 (d, 1H, J=8,8 Hz), 7,19 (DD, 1H, J=2.1 a, 8,8 Hz), 7,16 (s, 1H), 4,17 (d, 2H, J=5.7 Hz), 3,65 is-3.45 (m, 8H).

Anal. Calculated for C15H16ClN3O3+ 0,25 H2O: C, 55,22; H, 5,10; N, 12,88.

Found: C, 55,22; H, To 5.08; N, 12,82.

Example 25.

5-Chloro-1H-indole-2-carboxylic acid [(methoxymethanol) methyl]-amide

Methoxyethylamine hydrochloride (1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino] -acetic acid (1.0 mmol) were coupled according to procedure A. the resulting solid is suspended in ether, filtered and dried: yield 158 mg, 53%; PBMS 296/298 (MH+, 100%);

1H NMR (DMSO-d6) 11,82 (s, 1H), 8,77 (t, 1H, J =6 Hz), 7,73 (d, 1H, J= 2.0 Hz), the 7.43 (d, 1H, J=8.7 Hz), 7,19 (DD, 1H, J=2.0 a, 8,7 Hz), 7,16 (s, 1H), 4,22 (d, 2H, J=5.7 Hz), 3,76 (s, 3H), 3,14 (s, 3H).

Anal. Calculated for C13H14ClN3O3: C, 52,80; H, OF 4.77; N, 14,21.

Found: C, 52,51; H, 4,82; N, 14,01.

Example 26.

5-Chloro-1H-indole-2-carboxylic acid [1-benzyl-2- (4-dimethylaminopyridine-1-yl)-2-oxoethyl]-amide

4-Dimethylaminopyridine (1.0 mmol) iosu chromatography on silica gel with elution 5-30% ethanol in dichloromethane, containing 0.5% ammonium hydroxide, followed by rubbing with ether: yield 21 mg, 5%; PBMS 453/455 (MH+, 100%).

1H NMR (DMSO-d6partial) of 11.75 (W, 1H), to 8.94 (m, 1H), 7,72 (d, 1H, J=2 Hz), 7,45-7,10 (m, 8H), to 5.17 (m, 1H), 4.63 to (m) of 4.38 (m), a 4.03 (m) 3,50 (m), 3,15-2,8 (m) of 2.51 (s, 3H), 2.50 each (C, H).

Example 27.

5-Chloro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-piperazine-1-retil)-amide

Triperoxonane acid (4 ml) was added to 4-{2-[(5-Chloro - 1H-indole-2-carbonyl)-amino] -3-phenylpropionyl} piperazine-1-carboxylic acid tert-butyl ether (0.6 mmole) at 0oC and the resulting solution was stirred for 0.3 hours and concentrated. The residue was separated between ethyl acetate and 2 N NaOH, the organic layer was separated and washed with saline, dried Na2SO4was concentrated and the resulting solid triturated with ether: yield 189 mg, 77%; HPLC (60/40) 2,63 minutes (99%); so pl. KZT 166.5-168oC; TRMS 411/413 (MH+, 100%);

Anal. Calculated for C22H23ClN4O2+ 0,5 H2O: C, 62,93; H, USD 5.76; N, 13,34.

Found: C, 62,64; H, 5,52; N, 13,34.

Example 28

5-Chloro-1H-indole-2-carboxylic acid [2-((3RS)-aminopyrrolidine-1-yl)-1-benzyl-2-oxoethyl]-amide

4N HCl in 1,4-dioxane (5 ml) was added to the in ether (0.5 mmole). The resulting solution was stirred at 25oC for 0.5 h, concentrated and the residue triturated with ether: yield 190 mg, 85%; HPLC (60/40) 2,62 minutes (98%); PBMS 411/413 (MN+, 100%);

Anal. Calculated for C22H23ClN4O2+ HCl + 1,7 H2A: C, 55,28; H, 5,78; N, 11,72.

Found: C, 55,14; H, 5,86; N, Of 11.45.

Example 29.

1-{ (2RS)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -3-phenylpropionyl} - pyrrolidin-(2S)-carboxylic acid

Triperoxonane acid was added to 1-{2-(RS)-[(5-chloro-1H - indole-2-carbonyl)-amino] -3-phenylpropionyl} -pyrrolidin-(2S)-carboxylic acid tert-butyl ether (1.0 mmol) at 25oC. After 1.5 hours the reaction mixture was concentrated and the residue triturated first with ether, then with a mixture of ether and hexanol. Yield 360 mg, 82%; HPLC (60/40) 4,84 minutes (99%); PBMS 440/442 (MH+, 40%), 396/398 (MN-44, 100%);

Anal. Calculated for C23H22ClN3O4+ 0,8 H2O: C, 60,81; H, 5,24; N, 9,25.

Found: C, 60,74; H, 5,42; N, 8,96.

Example 29A.

1-{ 2(R, S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenylpropionyl}- pyrrolidin-(2S)-carboxylic acid tert-butyl ether

L-Proline-t-butyl ether (2.0 mmole) and 2-[(5-chloro-1H-indole-2 - carbonyl)-amino] -3-phenylpropionate acid (2.0 mm is ilaclama-hexane 1: 2: output 611 mg, 62%; HPLC (60/40) 13,45 minutes (57%) and of 14.46 minutes (41%).

Example 30.

5-Chloro-1H-indole-2-carboxylic acid ((1S)-methylcarbamoyl-2-thiazol-4-retil)-amide

(S)-2-Amino-N-methyl-3-thiazole-4-ylpropionic hydrochloride (0.6 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0,51 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction - dimethylformamide). Product raw was stirred in ether for 0.5 hours, then filtered to obtain a beige solid: 182 mg, 98%; HPLC (60/40) 3,41 minutes (98%); so pl. 260oC (decomp.); TERMS 363/365 (MH+, 100%);

1H NMR (DMSO-D6) 11,82 (W, 1H), and 9.0 (d, 1H), 8,82 (W, 1H), 8,10 (W, 1H), of 7.70 (m, 1H), 7,44-7,38 (m, 2H), 7,21-to 7.15 (m, 2H), 4,80 (m, 1H), 3,24 (m, 1H), 3,05 (m, 1H), 2,60 (d, 3H).

Example 30A.

(S)-2-Amino-N-methyl-3-thiazole-4-ylpropionic hydrochloride

(S)-(1-Methylcarbamoyl-2-thiazol-4-yl-ethyl) - carbamino acid tert-butyl ester (248 mg, of 0.87 mmole) was dissolved in 4M HCl-dioxane at 0oC. the resulting mixture was stirred for 1 hour at 25oC, concentrated and the residue triturated with ether. The output 202 g, 102%; HPLC (70/30) 2,41 minutes (96%).

Example 30b.

(S)-2-(N-t-Butoxycarbonylamino)-N-methyl-3-thiazol-4-yl-propionamide

Of the methylamine hydroprobivna acid is excluded) and the product used without further purification. Output 250 mg, 88%.

Example 31.

()-[(5-Chloro-1H-indole-2-carbonyl)-amino] -3-hydroxypropionic acid methyl ester

D, L-serine methyl ester hydrochloride (2.1 mmole) and 5-chloro-1H-indole-2-carboxylic acid (2.0 mmole) were coupled according to procedure a (reaction temperature 0-25oC, washed first with acid, then with saturated NaHCO3) and the product was purified by chromatography on silica gel with elution 10, 20, 40 and 60% ethyl acetate in hexano: output 565 mg, 95%; HPLC (60/40) of 3.46 minutes (98%); T. 153 to 155 squareoC; TRMS 297/299 (MH+, 100/40%);

Anal. Calculated for C13H13ClN2O4: C, 52,62; H, WAS 4.42; N, 9,44.

Found: C, 52,62; H, Of 4.54; N, At 9.53.

Example 32

5-Chloro-1H-indole-2-carboxylic acid ((1S)-dimethylcarbamoyl-2 - thiazol-4-yl-ethyl)-amide

(S)-2-Amino-N,N-dimethyl-3-thiazole-4-ylpropionic hydrochloride (0.43 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.40 mmole) were coupled according to procedure a (reaction temperature 0-25oC) and the product of raw triturated first with ether-hexane 1: 1, then hexane. The output 115 mg, 75%; HPLC (60/40) and 3.72 min (99%); so pl. 198-202oC (reduction box with 192oC); PBMS 377/379 (MH+, 100%);

1H NMR (DMSO-d6) of 11.75 (s, 1H), 9,02 (d, 1H, J=2 Hz), 8,9 (d, 1H, J= 8,2 Hz), 7.7 (d, 1H, J6 Hz), of 3.07 (s, 3H), 2,84 (s, 3H).

Anal. Calculated for C13H17ClN4O2S + 0,125 H2O: C, 53,86; H, 4,59; N, 14,78.

Found: C, 53,92; H, To 4.47%; N, 14,42.

Example 32A.

(S)-2-Amino-N,N-dimethyl-3-thiazolyl-4-propionamide hydrochloride

(S)-(1-Dimethylcarbamoyl-2-thiazol-4-retil)-carbamino acid tert-butyl ester was dissolved in 4M HCl-dioxans at 0oC and was stirred at 25oC for 2 hours. The mixture was concentrated and the residue triturated with ether. The output of 3.06 g, 105%; HPLC (70/30), 2.12 minutes (97%); PBMS 200 (MH+, 100%).

Example 32b.

(S)-(1-Dimethylcarbamoyl-2-thiazol-4-retil)-carbamino acid tert-butyl ether

Dimethylamine hydrochloride (1.2 mmole) and BOC-L-3-(4-thiazolyl)-alanine (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC) and the product was purified by chromatography on silica gel with elution 1-16% ethanol in dichloromethane containing 0.5% ammonium hydroxide. The output 124 mg, 41%.

Example 33.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3R, 4S) -dihydroxypyrrolidine-1-yl)-2-oxoethyl]-amide

(3R, 4S)-Dihydroxypyrrolidine hydrochloride (0.5 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.5 mmole) were coupled according to procedure a and the product cleaned the 3,14 minutes (98%); TERMS 428/430 (MH+, 100%);

1H NMR (DMSO-d6) 11,75 (W, 1H), to 8.94 (d, 1H, J=8 Hz), 7,72 (s, 1H), and 7.4 to 7.1 (m, 8H), to 5.03 (d, 0.5 H, J=5 Hz), of 4.95 (d, 0.5 H, J=5 Hz), the 4.90 (d, 1H, J =5 Hz), to 4.87 (m, 1H), 4,08 (m, 0.5 H), of 4.00 (m, 0.5 H), 3,88 (m, 1.5 H), 3,5-3,3 (m, 2.5 H), 3,2 (m, 0.5 H), and 3.0 (m, 2H).

Anal. Calculated for C22H22ClN3O4+ 0,25 H2O: C, 61,11; H, A 5.25; N, 9,72.

Found: C, 60,91; H, 5,46; N, 9,43.

Example 33a.

(CIS-3,4)-Dihydroxypyrrolidine hydrochloride

CIS-3,4-Dihydroxypyrrolidine-1-carboxylic acid tert-butyl ether (1,99 g, 9.8 mmole) was dissolved in 4M HCl-dioxane at 5oC and the resulting suspension was stirred at 25oC for 1 hour. The mixture was concentrated and the residue triturated with ether to obtain a light purple powder (1,30 g, 95%).

Example 33b.

CIS-3,4-Dihydroxypyrrolidine-1-carboxylic acid tert-butyl ether

A solution of the crude 2,5-dihydropyrrol-1-carboxylic acid tert-butyl ester (10.5 g, 62,1 mmole) in tetrahydrofuran (300 ml) was treated sequentially with osmium tetroxide (2.5% in t-butanol, 6 ml) and N-methylmorpholin-N-oxide at 25oC. After 48 hours was added aqueous 10% sodium thiosulfate solution and the mixture was stirred for 30 minutes, partially concentrated distracti washed with 10% sodium thiosulfate, of 0.1 N HCl, dried and concentrated to obtain a dark orange oil, which was chromatographically on silica with elution 1%, 2%, 4%, 8% and 10% ethanol-dichloromethane to obtain an amber syrup (4.09 g).

Example 33C

2.5-Dihydropyrrol-1-carboxylic acid tert-butyl ether

di-t-BUTYLCARBAMATE (83 g, 380 mmol) was added to a solution of 3-pyrroline (containing 35% of pyrrolidine, 25 g, 362 mmole) in tetrahydrofuran (500 ml) at 0oC. the Mixture was stirred at 25oC for 1 hour and then concentrated to obtain the 76.2 g of yellow oil which was used without purification.

Example 34.

(3S)-[(5-Chloro-1H-indole-2-carbonyl)amino] -4-(4-hydroxypiperidine - 1-yl)-4-oxomalonate acid tert-butyl ether

(S)-3-Amino-4-(4-hydroxypiperidine-1-yl)-4-oxomalonate acid tert-butyl ester (0.8 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.8 mmole) were coupled according to procedure a and the product was purified by chromatography on silica gel with elution 25, 40, 50, 75 and 100% ethyl acetate in hexano. The output 330 mg, 94%; HPLC (60/40), 4,18 minutes (97%); TRMS 450/452 (MH+, 100%).

Example 34a.

(S)-3-Amin-4-(4-hydroxypiperidine-1-yl)-4-oxomalonate acid tert-butyl ether

Diethylamine (1.0 mmol) was added ether in dimethylformamide (5 ml) at 25oC. After 1 hour the reaction mixture was concentrated, the residue is suspended in ether/dichloromethane 1:1, filtered and concentrated. The residue was purified by chromatography on silica gel with elution 1-50% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Exit 217 mg, 80%.

Example 34b.

(S)-3-(N-Fluoren-9 ylmethoxycarbonyl)-4-(4 - hydroxypiperidine-1-yl)-4-oxomalonate acid

4-Hydroxypiperidine (2.1 mmole) and N-FMOC-L-aspartic acid - t-butyl ether (2.0 mmole) were coupled according to procedure a (reaction time of 96 hours, washed only acid) and the product was purified by chromatography on silica gel with elution of 1-4% ethanol in dichloromethane. The output 516 mg, 52%: HPLC (60/40) 5,33 minutes (93%).

Example 35.

5-Chloro-1H-ended-2-carboxylic acid [(1R)-benzyl-2-(4 - hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(R)-2-Amino-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-she hydrochloride (3.1 mmole) and 5-chloro-1H-indole-2-carboxylic acid (3.4 mmole) were coupled according to procedure a (reaction temperature 0-25oC, reaction time 60 hours) and the product was purified by chromatography on silica gel with elution 50,75 and 100% ethyl acetate in hexano followed by rubbing with ether-hexane 1:1. Output 1.1 g, 0.25 in H2O: C, 64,18; H, 5,74; N, 9,76.

Found: C, 64,28; H, 5,94; N, 9,41.

Example 35A.

(R)-2-Amino-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-she hydrochloride

(R)-2-(N-t-Butoxycarbonylamino)-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-he (12.5 mmol) was dissolved in 4M HCl-dioxane at 0oC and the resulting suspension was stirred at 25oC for 1 hour. The mixture was concentrated and the residue triturated with ether. Output 3,44 g, 97%.

Example 35b.

(R)-2-(N-t-Butoxycarbonylamino)-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-he

(R)-2-(N-t-Butoxycarbonylamino)-3-phenylpropane-1-on (14 mmol) and 4-hydroxypiperidine (21.5 mmol) were coupled according to procedure a (reaction temperature 0-25oC, washed first with acid, then base) and the product was used without additional purification. Yield 4.7 g, 94%; HPLC (60/40) 3,52 minutes (98%).

Example 36.

1H-Indole-2-carboxylic acid [2-(1,1-dioxo-1 thiazolidin-3-yl)- 2-oxoethyl]-amide

2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-ethanone hydrochloride (1.0 mmol) and 1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC, reaction time 60 hours) with the following processing: the reaction mixture was diluted with ethyl acetate and 2N NaOH obtained is, 100%);

Anal. Calculated for C14H15N3O4+ 0,25 H2O: C, 51,60; H, 4,79; N, 12,90.

Found: C, 51,31; H,4,66; N, 12,88.

Example Sa.

2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-ethanone hydrochloride

[2-(1,1-dioxo-1 Thiazolidin-3-yl)-2-oxoethyl] carbamino acid tert-butyl ester (11 mmol) was dissolved in 4M HCl-dioxane at 0oC and the resulting suspension was stirred at 25oC for 1 hour. The mixture was concentrated and the residue triturated with ether. Output 2.3 g, 100%.

Example 36.

[2-(1,1-Dioxo-1 thiazolidin-3-yl)-2-oxoethyl]-carbamino acid tert-butyl ether

m-Chloroperoxybenzoic acid (35 mmol) was added slowly to (2-oxo-2-thiazolidin-3-retil)-carbamino acid tert-butyl ether (14 mmol) in dichloromethane (35 ml) at 0oC. After the foaming has ceased, the mixture was stirred an additional 2.5 hours at 25oC. the Mixture was diluted with ethyl acetate, the resulting solution was washed three times with a mixture of 1:1 saturated aqueous NaHCO3and 10% aqueous solution NaS2O3once saturated NaHCO3, dried, concentrated and the residue triturated with ether-hexane 1:1. Output 3.6 g, 92%.

Example 3 the th) and Boc-glycine (57 mmol) were coupled according to procedure a (reaction temperature 0-25oC, reaction time of 60 h) and the product was used without purification. Yield 12.7 g, 90%.

Example 37g.

5-fluoro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(4 - hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(S)-2-Amino-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-she hydrochloride (0.65 mmole) and 5-fluoro-1H-indole-2-carboxylic acid (0.73 mmole) were coupled according to procedure a (reaction temperature 0-25oC) and the product was purified by chromatography on silica gel with elution 20, 30, 40, 50, 75 and 100% ethyl acetate in hexano. The output 228 mg, 84%; HPLC (60/40) 3,57 minutes (98%); PBMS 410 (MH+, 100%);

Anal. Calculated for C23H24FN3O3+ 0,25 H2O: C, 66,73; H, 5,97; N, 10,15. Found: C, 66,68; H, To 6.19; N, 9,94.

Example 38.

1H-Indole-2-carboxylic acid [(1S)-benzyl-2-(4 - hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(S)-2-Amino-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-she hydrochloride (3.4 mmole) and 1H-indole-2-carboxylic acid (3.7 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the reaction time to 48 hours). The product was purified by chromatography on silica gel with elution 50, 75 and 100% ethyl acetate in hexano followed by rubbing with ether-hexane 1:1. The output of 1.14 g, 86%; HPLC (60/40) 3,52 minutes (98%); PBMS (MH+, 100%);

: C 69,99; H, 6,72; N, 10,47.

Example 39.

5-fluoro-1H-indole-2-carboxylic acid [(1S)-(4-terbisil)-2-morpholine-4-yl-2-oxoethyl]-amide

(S)-2-Amino-3-(4-forfinal)-1-morpholine-4-improper-1-she hydrochloride (0.48 mmole) and 5-fluoro-1H-indole-2-carboxylic acid (0.48 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the reaction time to 48 hours, washed first with acid, then base) and the product was purified by chromatography on silica gel with elution 20, 30, 40, 50, and 75% ethyl acetate in hexano. Exit 189 mg, 95%; HPLC (60/40) 4,76 minutes (97%); PBMS 414 (MH+, 100%);

1H NMR (CDCl3) 9,23 (W, 1H), and 7.4 to 7.1 (m, 5H), 7,1-6,94 (m, 3H), 6,9 (d, 1H, J= 2 Hz), and 5.30 (m, 1H), 3.72 points-of 3.48 (m, 5H), 3,42 (m, 1H), 3,03 (m, 4H).

Anal. Calculated for C22H21F2N3O3: C, 63,92; H, 5,12; N, 10,16.

Found: C, 64,30; H, Of 5.34; N, 9,82.

Example 39A.

(S)-2-Amino-3-(4-forfinal)-1-morpholine-4-improper-1-she hydrochloride

(S)-2-(N-t-Butoxycarbonylamino)-3-(4-forfinal)-1-morpholine-4 - improper-1-he (3.1 mmole) was dissolved in 4M HCl-dioxane at 0oC and the resulting suspension was stirred at 25oC for 1 hour. The mixture was concentrated and the residue triturated with ether. Exit 776 mg, 88%; HPLC (60/40) 2,31 minutes (99%).

Example 39b.

oC, reaction time of 60 hours, washed first with acid, then base) and the product was purified by chromatography on silica gel with elution 20, 30 and 40% ethyl acetate in hexano. The output of 1.08 g of oil, 87%.

Example 40.

5-fluoro-1H-indole-2-carboxylic acid [(1S)-benzyl-2- (1,1-dioxo-1 thiazolidin-3-yl)-2-oxoethyl]-amide

(S)-2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-3-phenylpropane-1-she hydrochloride (1.0 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC, the reaction time is 48 hours, washed first with acid, then base) and the product was purified by chromatography on silica gel with elution 20, 30, 40 and 50% ethyl acetate in hexano. The output 404 mg, 94%; HPLC (60/40) 4,74 min (98%); PBMS 430 (MH+, 100%);

1H NMR (CDCl3) at 9.53 (width, 0.5 N), 9,44 (width, 0.5 N), 7,44 (d, 0.5 H, J=9 Hz), between 7.4 and 7.1 (m, 7H), 7,02 (m, 1H), 6,84 (C, 0.5 N), for 6.81 (s, 0.5 H), 5,20 (m, 0.5 H), 4,96 (m, 0.5 H), and 4.68 (d, 0.5 H, J=11 Hz), to 4.52 (d, A of AB, 0.5 H, J= 11.5 Hz), 4,37 (d, B of AB, 0.5 H, J=11.5 Hz), 4,20 (m, 0.5 H), a 4.03 (m, 0.5 H), 3,80 (m, 0.5 H), 3,50 (d, 0.5 H, J=11 Hz), 3,3-3,0 (m, 4H), 2,69 (m, 0.5 H).

Example 40A.

(S)-2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-3-phenylpropane-1-she hydrochloride

(S)-2-(N-t-Butoxycarbonylamino)-1-(1,1-dioxo-1 thiazolidin-3-yl)-3 - phenylpropane-1-it was dissolved in 4M HCl-dioxanes. Exit 8 mg, 84%.

Example 40b.

(S)-2-(N-t-Butoxycarbonylamino)-1-(1,1-dioxo-1 thiazolidin-3-yl)-3 - phenylpropane-1-he

A solution of m-chloroperoxybenzoic acid (9 mmol) and (S)-(1-benzyl-2-oxo-2-thiazolidin-3-yl-ethyl)-carbamino acid tert-butyl ether (3 mmole) in dichloromethane (9 ml) was heated in a flask under reflux for 6 hours. The mixture was diluted with ethyl acetate, the resulting solution was washed three times with a mixture of 1: 1 10% aqueous NaS2O3and saturated aqueous NaHCO3, dried and concentrated. The resulting foam was purified by chromatography on silica gel with elution 20, 30 and 40% ethyl acetate in hexano, obtaining a colorless foam (979 mg, 89% yield).

Example 40C.

(S)-(1-Benzyl-2-oxo-2-thiazolidin-3-yl-ethyl)-carbamino acid tert-butyl ether

Thiazolidin (38 mmol) and Boc-L-phenylalanine (19 mmol) were coupled according to procedure a (reaction temperature 0-25oC, washed with acid, then base) and the product was used without additional purification. Yield 5.5 g, 86%.

Example 41.

5-fluoro-1H-indole-2-carboxylic acid [2-(1,1-dioxo-1 thiazolidin-3-yl)-2-oxoethyl]-amide

2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-ethanone Hydra is C, the reaction time is 48 hours) with the following processing. The reaction mixture was diluted with ethyl acetate and 1N HCl, the resulting suspension was filtered and the collected solid is washed with 2N HCl, 2N NaOH and water. The filtered solid was boiled in acetone, filtered and dried. The output 134 mg, 40%; HPLC (60/40) 3,06 minutes (97%); so pl. 239-241oC (decomposition); PBMS 340 (M+, 70%), 357 (100%)

1H NMR (DMSO-d6) 11,74 (s, 1H), 8,82 (m, 1H), 7,43 (m, 2H), 7,17 (s, 1H), 7,05 (d, 1H, J=3,9 Hz), a 4.86 (s, 1.2 H), to 4.52 (s, 0.8 H), 4,27 (l, 0,8 H, J= 5.5 Hz), 4,13 (d, 1,2 H, J=6 Hz, superimposed on m, 1.2 H), 3,86 (t, H 1,2, J= 7,4 Hz) to 3.58 (t, 0,8 H, J=7 Hz), 3.46 in (t, H 1,2, J=7,2 Hz).

Anal. Calculated for C14H14FN3ABOUT4+ 0,6 H2O: C, 48,02; H, TO 4.38; N, 12,00.

Found: C, 47,99; H, Android 4.04; N, 12,00.

Example 42.

5-Cyano-1H-indole-2-carboxylic acid ((1S)-benzyl-2-oxo-2 - thiazolidin-3-yl-ethyl)-amide

(S)-2-Amino-3-phenyl-1-thiazolidin-3-improper-1-she hydrochloride (4.0 mmole) and 5-cyano-1H-indole-2-carboxylic acid (4 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the reaction time to 48 hours) with the following processing; the reaction mixture was diluted with ethyl acetate and 2N HCl, the resulting precipitate was collected by filtration, washed with 2N HCl and 2N NaOH. Product raw was purified is 4 minutes (97%); PBMS 405 (NH+, 100%);

Anal. Calculated for C22H20N4O2S + 0.5 H2O: C, 63,90; H, 5,12; N, 13,55.

Found: C, 64,18; H, 5,04; N, 13,47.

Example 42A.

(S)-2-Aquino-3-phenyl-1-thiazolidin-3-improper-1-she hydrochloride

(S)-(1-Benzyl-2-oxo-2-thiazolidin-3-retil)-carbamino acid tert-butyl ester (16 mmol) was dissolved in 4M HCl-dioxans at 0oC, the solution was stirred at 25oC for 1 hour, the reaction mixture was concentrated and the residue triturated with ether. The output of 4.2 g, 95%.

Example 42b.

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

5-Cyano-1H-indole-2-carboxylic acid ethyl ester (1,71 g, 8.0 mmol) was added to a solution of ethanol (10 ml) and potassium hydroxide (2 g) and the resulting mixture was heated in a flask under reflux for 1 hour. To dissolve the precipitate was added water and 6N HCl was added to bring the pH to 1. Formed precipitate. The mixture was cooled in an ice bath, filtered and the resulting colourless solid was washed with cold water and dried (1.51 g). A portion (1.4 g) suspended in hot acetic acid (40 ml) and cooled to obtain solid, which was filtered off, washed with cold ethyl acetate is [(1S)-benzyl-2-(1,1-dioxo-1 thiazolidin-3-yl)-2-oxoethyl]-amide

(S)-2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-3-phenylpropane - 1-she hydrochloride high (0.56 mmole) and 1H-indole-2-carboxylic acid (of 0.56 mmole) were coupled according to procedure a (reaction temperature 0-25oC) and the product triturated with ether-hexane 1: 1. The output 213 mg, 92%; HPLC (60/40) 4,15 minutes (99%); PBMS 412 (MH+, 100%);

Anal. Calculated for C21H21N3O4O + 0,5 H2O: C, 59,99; H, 5,27; N, 9,99.

Found: C, 60,25; H, 5,27; N, 9,98.

Example 44.

5-Chloro-1H-indole-2-carboxylic acid [2-(1,1-dioxo-1 thiazolidin-3-yl)-2-oxoethyl]-amide

2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-ethanone hydrochloride (0.6 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.6 mmole) were coupled according to procedure a (reaction temperature 0-25oC, reaction time 120 hours) with the following processing: the reaction mixture was diluted with ethyl acetate and 2N HCl, the resulting precipitate was collected by filtration and subsequent washing with 2N HCl, 2N NaOH, water and ether. Yield 110 mg, 52%; HPLC (60/40) 3,37 minutes (99%); so pl. 236-239oC (decomp.); PBMS 356/358 (MH+, 100%);

1H NMR (acetone-d6) 11,0 (W, 1H), 8.0 a (W, 1H), 7,66 (d, 1H, J=2 Hz), 7,55 (d, 1H, J=8.7 Hz), 7,21 (DD, 1H, J=2.0 a, 8,7 Hz), to 7.15 (d, 1H, J=2 Hz), of 4.77 (s, 1,1 N), 4,49 (s, 0.9 H), 4,37 (l, 0,9 H, J=5.3 Hz), 4,27 (d, 1H, J= 5.3 Hz, superimposed on m, 1H), Android 4.04 (t, 1,1 H, J=7 Hz), 3,54 (t, 0,9 H, J=7 Hz of 10.93.

Found: C, 44,05; H, 3,88; N, 10,99.

Example 45.

5-Chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl)-amide

2-Amino-1-thiazolidin-3-ratanana hydrochloride (3.1 mmole) and 5-chloro-1H-indole-2-carboxylic acid (3.4 mmole) were coupled according to procedure A (0-25oC, reaction time 120 hours), replacing the following processing: the reaction mixture was stirred with ethyl acetate and 2N HCl, filtered, and the filtered solid washed with 2N HCl, 2N NaOH and ether. The output of 988 mg, 98%; HPLC (70/30) 3.25 minutes (99%); so pl. 253-255oC (decomp., darkening at 243oC); PBMS 324/326 (MH+, 100%);

1H NMR (acetone-d6) 11,03 (W, 1H), 7,88 (W, 1H), 7,66 (d, 1H, J=2 Hz), 7,54 (d, 1H, J=8,3 Hz), 7,21 (DD, 1H, J=2, 8, 3 Hz), 4,67 (s, 0.8 H), a 4.53 (s, 1.2 H), 4,24 (m, 2H), a 3.87 (t, H 1,2, J=7 Hz), 3,78 (t, 0,8 H, J=7 Hz), 3,18 (t, H 1,2, J=7 Hz), 3,05 (t, 0,8 H, J=7 Hz).

A sample recrystallized from acetic acid for analysis (so pl. 262 to 264oC):

Anal. Calculated for C14H14ClN3O2S: C, 51,93; H, 4,36; N, 12,98.

Found: C, 52,78, H, Of 4.38; N, 12,95.

Example 45A.

2-Amino-1-thiazolidin-3-ratanana hydrochloride

(2-Oxo-2-thiazolidin-3-yl-ethyl) - carbamino acid tert-butyl ether (5,41 g, 22 mmole) was dissolved in 4M HCl-dioxane (80 ml) at 0oC. Obtained the rum. The output of 3.9 g, 97%.

Example 46.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(4 - hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(S)-2-Amino-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-she hydrochloride (0.8 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.9 mmole) were coupled according to procedure a (reaction temperature 0-25oC, reaction time 48 hours) and the product was purified by chromatography on silica gel with elution 50, 75 and 100% ethyl acetate in hexano followed by rubbing with ether-hexane 1:1. Exit 266 mg, 76%; HPLC (60/40) 4.09 to minutes (99%); PBMS 426/428 (MH+, 100%);

Anal. Calculated for C23H24ClN3O3+ 0,33 H2O: C, 63,96; H, 5,76; N 9,73.

Found: C, 63,90; H, 5,74; N, 9,58.

Example 46a.

(S)-2-Amino-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-she hydrochloride

(S)-[1-Benzyl-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl] -carbamino acid tert-butyl ether (3,66 g, 10.5 mmole) was dissolved in 4M HCl-dioxane (39 ml) at 0oC. the Mixture was stirred at 25oC for 1 hour, concentrated and the residue triturated with ether.

The output of 3.06 g, 102%.

Example 46b.

(S)-[1-Benzyl-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-carbamino acid tert-butyl ether

4-HYDR C, the response time is 144 hours) and the product used without further purification. Yield 12.2 g, 96%; HPLC (60/40) 3.45 minutes (97%).

Example 47.

5-Bromo-1H-ended-2-carboxylic acid [(1S)-benzyl-2- (1,1-dioxo-1 thiazolidin-3-yl)-2-oxoethyl]-amide

(S)-2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-3-phenylpropane-1-he hydrochloride (0.3 mmole) and 5-bromo-1H-indole-2-carboxylic acid (0.3 mmole) were coupled according to procedure a (reaction temperature 0-25oC, washed first with acid, then base) and the product was purified by chromatography on silica gel with elution 30, 40 and 50% ethyl acetate in hexano. The product was collected as not quite white foam and triturated with ether-hexane 1:1 to obtain 107 mg, 73%; HPLC (60/40) 6,21 minutes (99%); PBMS 490/492 (MH+, 100%);

1H NMR (CDCl3) at 9.53 (width, 0.5 N), 9,44 (width, 0.5 N), 7,78 (d, 0.5 H, J=2 Hz), 7,76 (d, 0.5 H, J=2 Hz), between 7.4 to 7.2 (m, 7H), 7,10 (d, 0.5 H, J=9 Hz), 7,02 (d, 0.5 H, J=9 Hz), 6,86 (C, 0.5 N), for 6.81 (s, 0.5 H), to 5.21 (m, 0.5 N), of 4.95 (m, 0.5 H), to 4.62 (d, 0.5 H, J=11 Hz), 4,47 (d, A of AB, 0.5 H, J=13 Hz), to 4.38 (d, B of AB, 0.5 H, J=13 Hz), 4,20 (m, 0.5 H), a 4.03 (m, 0.5 H), 3,82 (m, 0.5 H), 3,44 (d, 0.5 H, J=11 Hz), 3,33-3,0 (m, 4H), 2,70 (m, 0.5 H).

Anal. Calculated for C21H20BrN3O4S + 0,2 H2O: C, 51,06; H, 4,16; N, 8,51.

Found: C, 51,44; H, 4,36; N, 7,93.

Example 48.

5-Chloro-1H-indole-2-carboxylic acid is Ried to 0.06 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0,06 mmole) were coupled according to procedure a (reaction temperature 0-25oC, washed first with acid, then base) and the product was purified by chromatography on silica gel with elution 40 and 50% ethyl acetate in hexano, followed by kneading the resulting foam with ether. The output 112 mg, 45%; HPLC (60/40) to 5.13 min (> 99%); PBMS 410/412 (MH+, 100%);

1H NMR (CDCl3) 9,19 (m, 1H), 7,60 (m, 1H), 7.3 to to 7.15 (m, 8H), 6,86 (m, 1H), 4,23 (m, 0.5 H), of 4.95 (m, 0.5 H), of 4.0 to 3.7 (m, 3H), of 3.27 (m, 1H), 3.15 in (m, 1H), 3,05 (m, 0.5 H), 2,85 (d, 0.5 H, J=28 Hz), a 2.45 (m, 1.5 H), of 2.15 (m, 0.5 H).

Anal. Calculated for C22H20ClN3O3+ 0,55 H2O: C, 62,95; H, 5,07; N, 10,01.

Found: C, 63,31; H, 5,09; N, Being 9.61.

Example 48A.

(S)-1-(2-Amino-3-phenylpropionyl)-pyrrolidin-3-one hydrochloride

(S)-[1-Benzyl-2-oxo-2-(3-oxopyrrolidin-1-yl)-ethyl]-carbamino acid tert-butyl ester (552 mg, 1.7 mmole) was dissolved in 4M HCl-dioxane (6.2 ml) at 0oC. the Mixture was stirred at 25oC for 1 hour, concentrated and the residue triturated with ether to obtain glowing brown solid. The output 482 mg, 108%.

Example 48b.

(S)-[1-Benzyl-2-oxo-2-(3-oxopyrrolidin-1-yl)-ethyl] - carbamino acid tert-butyl ether

A solution of dimethyl sulfoxide (4,07 g, 52 mmole) and oxalicacid (3,61 g, 28 mmol) slow the Yali (S)-[1-benzyl-2-(3-hydroxypyrrolidine-1-yl)-2 - oxoethyl] -carbamino acid tert-butyl ester (24 mmole) in dichloromethane (30 ml), the reaction temperature was brought to -30oC for 0.5 hours, then was lowered to -78oC followed by the addition of triethylamine (118 mmol). Then the reaction mixture was heated to 25oC, diluted with ethyl acetate, washed three times with saturated NaHCO3/salt solution, the organic matter was dried MgSO4and concentrated. The resulting foam was purified by chromatography on silica gel with elution 30, 40 and 50% ethyl acetate in hexano obtaining a light yellow foam (7.5 g, 95%).

Example 48S.

(S)-[1-Benzyl-2-(3R,S)-hydroxypyrrolidine-1-yl)-2-oxoethyl]- carbamino acid tert-butyl ether

()-3-Pyrrolidino (75 mmol) and Boc-L-phenylalanine (38 mmol) were coupled according to procedure a (reaction temperature 0-25oC, washed first with acid, then base) and the product was used without additional purification. Yield 12.2 g, 96%; HPLC (60/40) 3.45 minutes (96%).

Example 49.

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

(S)-2-Amino-3-phenyl-1-thiazolidin-3-improper-1-she hydrochloride (2.6 mmole) and 5-chloro-1H-indole-2-carboxylic acid were coupled according to procedure a (reaction temperature 0-25oC, reaction time of 96 hours, washed first keys is) 7,99 minutes (97%); PBMS 414/416 (MH+, 100%);

1H NMR (CDCl3) 9,26 (W,1H), to 7.59 (m, 1H), 7,35-7,20 (m, 8H), at 6.84 (m, 1H), 5,14 (m, 1H), br4.61 (d, A of AB, 0.6 N, J=10.3 Hz), to 4.52 (d, 0,4 H, J= 11,6 Hz), 4,42 (d, B of AB, of 0.6 H, J=10.3 Hz), 3,80-the 3.65 (m, 1.5 H), 3,2 (m, 2,5 H), 3.04 from (m, 0.4 H), 2.95 and is 2.8 (m, 1,2 M), 2.63 in (m, 0.6 H).

Anal. Calculated for C21H20ClN3O2S + 0,6 H2O: C, 59,39; H, TO 5.03; N, 9,89.

Found: C, 59,39; H, 4,96; N, 9,52.

Example 50.

5-Chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-2-oxo-2 - thiomorpholine-4-yl-ethyl)-amide

(S)-2-Amino-3-phenyl-1-thiomorpholine-4-improper-1-she hydrochloride (2.6 mmole) and 5-chloro-1H-indole-2-carboxylic acid (2.6 mmole) were coupled according to procedure a (reaction temperature 0-25oC, washed first with acid, then base). The crude product is then triturated with ether-hexane 1:1 and dried. The output of 1.03 g, 94%; HPLC (60/40), a total of 8.74 minutes (99%); PBMS 428/430 (MH+, 100%);

Anal. Calculated for C22H22ClN3O2S: C, 61,75; H, 5,18; N, 9,82.

Found: C, 62,04; H, To 5.58; N, 9,72.

Example 50A.

(S)-2-Amino-3-phenyl-1-thiomorpholine-4-improper-1-she hydrochloride

(S)-(1-Benzyl-2-oxo-2-thiomorpholine-4-yl-ethyl)-carbamino acid tert-butyl ester (17.8 mmole) was dissolved in 4M HCl-dioxane (67 ml) at 0oC, the solution was stirred at 25o<, 100%).

Example 50b

(S)-(1-Benzyl-2-oxo-2-thiomorpholine-4-yl-ethyl)-carbamino acid tert-butyl ether

Thiomorpholine (38 mmol) and Boc-L-phenylalanine (19 mmol) were coupled according to procedure a (reaction temperature 0-25oC) with the following processing: the reaction mixture was concentrated, diluted with ethyl acetate, then washed first with 1N HCl three times, then 2N NaOH, the organic layer was dried MgSO4and concentrated. The resulting foam was used without additional purification. Output 6.3 g, 95%.

Example 51.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2- (1,1-dioxo-1 thiazolin-3-yl)-2-oxoethyl]-amide

(S)-2-Amino-1-(1,1-dioxo-1 thiazolidin-3-yl)-3-phenylpropane-1-she hydrochloride (0.8 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.8 mmole) were coupled according to procedure a (reaction temperature 0-25oC, washed first with acid, then base). The product was purified by chromatography on silica gel with elution 30, 40 and 50% ethyl acetate in hexano followed by rubbing with ether-hexane 1:1. Exit 266 mg, 75%; HPLC (60/40), 5,52 min (>99%); PBMS 446/448 (MH+, 100%);

1H NMR (CDCl3) of 9.21 (width, 0.5 N), 9,15 (width, 0.5 N), 7.62mm (width, 0.5 H, J= 2 Hz), 7,60 (d, 0.5 H, J=2 Hz), 7,35-7,20 (m, 7H), 7,10 (d, 0.5 H, J=8.5 Hz), 7,02 (d, 0.5 H, J=8.5 Hz), 6.8 meters, 0.5 H), a 4.03 (m, 0.5 H), 3,83 (m, 0.5 H), 3,44 (d, 0.5 H, J=11 Hz), 3,3-3,0 (m, 4H), to 2.67 (m, 0.5 H).

Example 52.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-(4-Chlorobenzyl)- 2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(S)-2-Amino-3-(4-chlorophenyl)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride (0,98 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0,92 mmole) were coupled according to procedure a and the product was purified by chromatography on silica gel with elution 50, 75 and 100% ethyl acetate in hexano. Yield 362 mg, 86%; HPLC (60/40) of 5.06 minutes (97%); so pl. 227-229oC; TRMS 460/462 (NH+, 100%);

Anal. Calculated for C23H23Cl2N3O3: C 60,01; H, 5,04; N, 9,13.

Found: C, 59,83; H, 5,18; N, 9,16.

Example 52a.

(S)-2-Amino-3-(4-chlorophenyl)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride

(S)-[1-(4-Chlorobenzyl)-2-(4-hydroxypiperidine-1-yl)-2 - oxoethyl]-carbamino acid tert-butyl ester (475 mg, 1.2 mmole) was dissolved in 4M HCl-dioxane (5 ml) at 0oC. the Mixture was stirred for 1.5 hours at 25oC, concentrated and the residue triturated with ether. The output 422 mg, 105%; TRMS 283 (MH+, 100%).

Example 52b.

(S)-[1-(4-Chlorobenzyl)-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl] - carbamino acid tert-butyl ether
using chromatography on silica gel with elution by ethyl acetate-hexane 1:1 and 3:1. The output of 662 mg, 69%.

Example 53.

5-Chloro-1H-indole-2-carboxylic acid [2-(4-hydroxypiperidine-1-yl)-(1S)-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-amide

(S)-2-Amino-1-(4-hydroxypiperidine-1-yl)-3-(1H-imidazol-4-yl)- propane-1-she hydrochloride (0.7 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.7 mmole) were coupled according to procedure a (reaction time of 120 hours, washing the acid was excluded). The crude product is twice triturated with ether, the ether-hexane 1:1 and the residue was purified by chromatography on silica gel with elution 5-20% ethanol in dichloromethane containing 0.5% ammonium hydroxide. The output 232 mg, 81%; HPLC (40/60) to 2.57 minutes (98%); PBMS 416/418 (MH+, 100%);

Anal. Calculated for C20H22ClN5O3+ 0,55 H2O: C, 56,42; H, VS. 5.47; N, 16,45.

Found: C, 6,07; H, The 5.65; N, 16,08.

Example 53A.

(S)-2-Amino-1-(4-hydroxypiperidine-12-yl)-3-(1H-imidazol-4-yl)-propane - 1-she hydrochloride

(S)-{ 2-(4-Hydroxypiperidine-1-yl)-2-oxo-1-[l-(toluene-4 - sulfonyl)-1H-imidazol-4-ylmethyl] -ethyl} -carbamino acid tert-butyl ester (512 mg, 1.0 mmol) was dissolved in 4M HCl-dioxane (3 ml) at 0oC. the Mixture was stirred at 25oC for 1.5 hours, concentrated and the residue triturated with ether. The output 422 mg, 105%; TRMS 283 (MH+ylmethyl]-ethyl}-carbamino acid tert-butyl ether

4-Hydroxypiperidine (303 mg, 3.0 mmole), triethylamine (394 mg, 3.9 mmole) and diethylthiophosphate (636 mg, 3.9 mmole) were added in this order to Boc-NiM-tosyl-L-histidine (J. Med. Chem. 30 536 (1987); 1,32 g, 3.9 mmole) in dichloromethane (10 ml) at 25oC. After 120 hours the solution was diluted with ethyl acetate, washed twice with saturated NaHCO3, dried and concentrated. The residue was purified by chromatography on silica gel with elution 1-8% ethanol in dichloromethane. The output of 517 mg, 35%; HPLC (50/50) 4.75 minutes (97%).

Example 54

5-Chloro-1H-indole-2-carboxylic acid (2S)-[(5-chloro-1H - indole-2-carbonyl)-amino]-3-(4-hydroxypiperidine-1-yl)-3-oxopropanoic ether

(S)-2-Amino-3-hydroxy-1-(4-Hydroxypiperidine-1-yl)propane - 1-she hydrochloride (0,89 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0,85 mmole) were coupled according to procedure a and the product was isolated by chromatography on silica gel, together with the more polar serine analogue (40%) in the elution 1-16% ethanol in dichloromethane. Yield 51 mg, 16%; HPLC (60/40) 7,06 minutes (96%); PBMS 348/350 (100%), 543/545 (MH+, 5%).

Anal. Calculated for C26H24Cl2N4O5+ 0,57 H2O: C, 56,40; H, 4,58; N, 10,12.

Found: C, 56,79; H, 4,90; N 9,65.

Example 54A.

(S)-2-Amino-3-hydroxy-1-(4-hydrobaenus acid tert-butyl ester (595 mg, 2.0 mmole) was dissolved in 4M HCl-dioxans (2 ml) at 0oC. the Mixture was stirred at 25oC for 1 hour, concentrated and the residue triturated with ether. The output 506 mg, 105%; 189 MS (MH+100%).

Example 54b

(S)-[1-hydroxymethyl-2-(4-hydroxypiperidine-1-yl)-2 - oxoethyl]-carbamino acid tert-butyl ether

4-Hydroxypiperidine (6,07) and Boc-L-serine (6,04 mmole) were coupled according to procedure A (reaction time 60 hours) with the following processing: the reaction mixture was concentrated, the residue was dissolved in chloroform and 1N NaOH (6 ml) and the resulting solution several times (ten or more) were extracted with chloroform. The chloroform extracts were concentrated and the residue was purified by chromatography on silica gel with elution 1-16% ethanol in dichloromethane. Exit 751 mg, 41%; HPLC (40/60) 2,72 minutes (96%).

Example 55.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-(4-hydroxybenzyl)-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(S)-2-Amino-3-(4-hydroxyphenyl)-1-(4-hydroxypiperidine-1 - yl)-propane-1-she hydrochloride (0.68 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.65 mmole) were coupled according to procedure A (the reaction temperature 0-25oC) with the following processing: the reaction mixture was diluted with ethyl acetate, obtained in the systematic extracts washed with 1N HCl, was dried and concentrated. The residue was purified by chromatography on silica gel with elution 1-16% ethanol in dichloromethane. The output 150 mg, 52%; HPLC (60/40) 3,53 minutes (99%); PBMS 442/444 (NH+, 100%);

Anal. Calculated for C23H24ClN3O4+ 0,5 H2O: C, 61,26; H, 5,59; N, TO 9.32.

Found: C, 61,52; H, Of 5.89; N, 8,98.

Example 55A.

(S)-2-Amino-3-(4-hydroxyphenyl)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride

(S)-[1-(4-Hydroxybenzyl)-2-(4-hydroxypiperidine-1-yl)-2 - oxoethyl]-carbamino acid tert-butyl ester (450 mg, 1.2 mmole) was dissolved in 4M HCl-dioxane (2 ml) at 0oC. the Mixture was stirred at 25oC for 1 hour, concentrated and the residue triturated with ether. 400 mg, 107%; MS 265 (MH+, 100%).

Example 55b.

(S)-[1-(4-Hydroxybenzyl)-2-(4-hydroxypiperidine-1-yl)- 2-oxoethyl]-carbamino acid tert-butyl ether

4-Hydroxypiperidine (3.9 mmole) and Boc-L-tyrosine (3.7 mmole) were coupled according to procedure a (reaction temperature 0-25oC, response time - 60 hours) with the following processing: the reaction mixture was diluted with ethyl acetate and washed once with base, alkaline layer was acidified using 2N HCl and was extracted three times with chloroform, and the chloroform extracts concentrate the I in dichloromethane, containing 0.5% NH4OH. The output of 550 mg, 41%; HPLC (40/60) 5,02 minutes (87%).

Example 56.

5-Chloro-1H-indole-2-carboxylic acid [2(4-hydroxypiperidine-1-yl)- 2-oxo-(1S)-pyridine-3-iletiler]-amide

(S)-2-Amino-1-(4-hydroxypiperidine-1-yl)-3-pyridin-3-yl - propane-1-it dihydrochloride (0.8 mmole) and 5-chloro-1H-indole-2-carboxylic acid were coupled according to procedure a (reaction temperature 0-25oC) and the product was purified by chromatography on silica gel with elution 1-16% ethanol in dichloromethane. Yield 26 mg, 8%; HPLC (50/50) 5,02 minutes (99%); PBMS 427/429 (MH+, 100%);

Anal. Calculated for C22H23ClN4O3+ 0,5 H2O: C, 60,62; H, TO 5.55; N, 12,85.

Found: C, 60,57; H, 5,74; N, 12,53.

Example 56a.

(S)-2-Amino-1-(4-Hydroxypiperidine-1-yl)-3-pyridin-3 - yl-propane-1-it dihydrochloride

(S)-[2-(4-Hydroxypiperidine-1-yl)-2-oxo-1-pyridin-3-yl - methylethyl] -carbamino acid tert-butyl ester (367 mg, 1.05 mmole) was dissolved in 4M HCl-dioxane at 0oC. the resulting suspension was stirred for 1.5 hours at 25oC, concentrated and the residue triturated with ether. The output 450 mg, 100%.

Example 56b.

(S)-[2-(4-Hydroxypiperidine-1-yl)-2-oxo-1-pyridin-3-yl-methylethyl] - carbamino acid is the fool And the reaction temperature 0-25oC, reaction time of 96 hours, washing the acid was excluded) and the product was purified by chromatography on silica gel with elution 1-8% ethanol in dichloromethane. The output 454 mg, 46%; MS 350 (MH+, 100%).

Example 57.

1H-Indole-2-carboxylic acid [(1R)-(4-terbisil)-2- )4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(R)-2-Amino-3-(4-forfinal)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride (0.5 mmole) and 1H-indole-2-carboxylic acid (0.5 mmole) were coupled according to procedure a (reaction temperature 0-25oC) and the product was purified by chromatography on silica gel with elution 25, 30, 50, 75, and 80% ethyl acetate in hexano. The output 150 mg, 60%; HPLC (60/40) 3,66 minutes (97%); so pl. 204-207oC; PBMS 410 (MH+, 100%);

Anal. Calculated for C23H24FN3O3: C, 67,47; H, 5,91; N, 10,26.

Found: C, 67,18; H, 6,03, N, Of 10.21.

Example 57a.

(R)-2-Amino-3-(4-forfinal)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride

(R)-[1-(4-Terbisil)-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl] - carbamino acid tert-butyl ester (2.6 mmole) was dissolved in 4M HCl-dioxane (2 ml) at 0oC. the Solution was stirred 2 hours at 25oC, concentrated and the residue triturated with ether. Yield 920 mg, 124%; HPLC (60/40) 2,23 minutes (98%).
4-Hydroxypiperidine (3.7 mmole) and (R)-N-t-BOC-p-forfinally (3.5 mmole) were coupled according to procedure And obtaining foamy substance, which was used without further purification. Yield 940 mg, 73%; HPLC (60/40) 3.64 minutes (95%); MS 367 (MH+, 100%).

Example 58.

5-Chloro-1H-indole-2-carboxylic acid [(1R)-(4-terbisil)- 2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(R)-2-Amino-3-(4-forfinal)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride (0.6 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.6 mmole) were coupled according to procedure a and the crude product was purified by chromatography on silica gel with elution 50, 75 and 100% ethyl acetate in hexano. Yield 171 mg, 765%; HPLC (60/40) to 4.23 minutes (97%); MS 444/446 (MH+, 200%); TRMS 444/446 (MH+, 100%);

1H NMR (CDCl)39,20 (W, 1H), EUR 7.57 (d, 1H, J=2 Hz), 7,33 (d, 1H, J=8 Hz), and 7.3 to 7.2 (m, 2H), 7,14 (m, 2H), 6,97 (m, 2H), 6,85 (m, 1H), of 5.34 (m, 1H), 4,05-of 3.80 (m, 2H), 3,7-3,3 (m, 1.5 H) at 3.25 (m, 1H), 3,10 (m, 2H), with 2.93 (m, 0.5 H), and 1.9 to 1.7 (m, 2.5 H) of 1.45 (m, 2H) and 1.15 (m, 0.5 H).

Anal. Calculated for C23H23ClFN3O3+ 0,05 H2O: C, 62,11; H, 5,23; N, 9,45.

Found: C, 62,51; H, To 5.66; N, 9,19.

Example 59.

5-fluoro-1H-indole-2-carboxylic acid [(1S)-(4-terbisil)- 2-(4-hydroxypiperidine-12-yl)-2-oxoethyl]-amide

(S)-2-Amino-3 is (0.5 mmole) were coupled according to procedure A. The crude product was washed once with ether-hexane 1: 1 and once with hexane. The resulting solid was boiled in ethyl acetate, the resulting suspension was filtered and the collected solid was dried. The output 103 mg, 48%; HPLC (60/40) 3,69 minutes (95%); PBMS 428 (MH+, 100%);

Anal. Calculated for C23H23F2N3O3+ 0,25 H2O: C, 63,95; H, OF 5.48; N, 9,73.

Found: C, 63,93; H, To 5.66; N, 9,87.

Example 59A.

(S)-2-Amino-3-(4-forfinal)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride

[(S)-1-(4-Terbisil)-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl] - carbamino acid tert-butyl ester (20.2 g, 55 mmol) was dissolved in 4M HCl-dioxane (25 ml) at 25oC. After 3 hours was deposited a thick syrup and added additional 4M HCl-dioxans (10 ml). The mixture was stirred for 2 hours, concentrated and the solid residue suspended in 4M HCl-dioxans. After 2 hours at 25oC the mixture was concentrated and the residue evaporated twice with ether. The resulting solid was stirred in a mixture of ether (75 ml) and hexanol (10 ml) at 25oC for 18 hours, the mixture was filtered and the filtered solid was washed with ether-hexane 1: 1 and dried to obtain the peridin-1-yl)-2-oxoethyl] - carbamino acid tert-butyl ether

4-Hydroxypiperidine (0,29 mmole) and (S)-N-t-Boc-p-forfinally (0,28 mmole) were coupled according to procedure And to obtain the crude product in the form of a foam with a yield of 84%. Part of this substance (81,6 g) was dissolved in hot ethyl acetate (400 ml) was added hexane (25oC) to the resulting solution until, until there appeared a slight haze. The mixture was heated to boiling and the resulting clear solution was allowed to cool to 25oC during the night. The resulting suspension was filtered and the collected solid was washed with ethyl acetate-hexane and dried (68,1 g, 67%) .

Example 60.

1-{ (2S)-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3-phenyl - propionyl}-(4R)-hydroxypyrrolidine-(2S)-carboxylic acid benzyl ester

1-((2S)-Amino-3-phenylpropionyl)-(4R)-hydroxypyrrolidine-(2R)- carboxylic acid benzyl ester hydrochloride high (0.56 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0,53 mmole) were coupled according to procedure a (reaction temperature 0-25oC, reaction time 60 hours) and the product was purified by chromatography on silica gel with elution 20, 30 and 50% ethyl acetate in hexano. Yield 26 mg, 8%; HPLC (60/40) 8,14 minutes (98%); PBMS 546/548 (MH+, 100%);

Anal. Calculated for C30H

1-((2S)-Amino-3-phenylpropionyl)-(4R)-hydroxypyrrolidine- (2S)-carboxylic acid benzyl ester hydrochloride

1-((2S)-tert-Butoxycarbonylamino-3-phenylpropionyl)-(4R)- hydroxypyrrolidine-(2S)-carboxylic acid benzyl ester (3.0 mmole) was dissolved in 4M HCl-dioxane at 0oC. the Mixture was stirred at 25oC for 1 hour, concentrated and the residue triturated with ether. The output of 1.16 g, 96%.

Example 60b.

1-((2S)-tert-Butoxycarbonylamino-3-phenylpropionyl)-(4R)- hydroxypyrrolidine-(2S)-carboxylic acid benzyl ester

TRANS-1-hydroxyproline benzyl ester (3,15 mmole) and 1-Boc-phenylalanine (3.0 mmole) were coupled according to procedure a (reaction temperature 0 to 2oC, dichloromethane/dimethylformamide 1:1) and the product was used without additional purification. The output of 1.31 g, 99%; HPLC (60/40) of 6.1 minutes (95%).

Example 61.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-(4-terbisil)- 2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide

(S)-2-Amino-3-(4-forfinal)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride (0,051 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0,051 mmole) were coupled according to procedure a and the product was purified by chromatography on silica gel with elution 50, 75, 80, and 100% ethyl acetate-hexane with obtaining the rastvoreniya in hot ethyl acetate (approximately 5-7 ml/g) and add an approximately equal volume of hexanol when heated in a flask with reflux condenser with subsequent slow cooling of the solution to 25oC. the Solid was filtered and washed with ethyl acetate-hexane 1:4 and dried (70-90% recovery): so pl. 175-177oC.

1H NMR (CDCl3) 9,41 (m, 0.5 H), 9,36 (m, 0.5 H), to 7.59 (d, 1H, J=2 Hz), 7,37 (d, 1H, J=8 Hz), 7,29 (DD, 1H, J=2,9 Hz), 7,20 (DD, 1H, J=2,0, a 8.9 Hz), 7,14 (m, 2H), 6,95 (m, 2H), 6,86 (m, 1H), of 5.34 (m, 1H), of 4.05 (m, 0.5 N), 3,90 (m, 1.5 H), the 3.65 (m, 0.5 H), of 3.45 (m,1H), 3,25 (m, 1H), 3,10 (m, 2H), 2,93 (m, 0.5 H), 1,88 (Shir, 1H, exchanges with D2O) of 1.80 (m, 1.5 H) to 1.45 (m, 2H), 1,12 (m, 0.5 H).

FBMS 444/446 (MH+, 100%);

Anal. Calculated for C23H23ClFN3O3+ 0,2 H2O: C, 61,73; H, 5,27; N, 9,39.

Found: C, 61,40; H, Lower Than The 5.37; N, 9,11.

Example 62.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-(methoxymethylethoxy)-2-pyridin-3-yl-ethyl]-amide

(2S)-Amino-N-methoxy-N-methyl-3-pyridin-3-yl-propionamide hydrochloride (1.3 mmole) and 5-chloro-1H-indole-2-carboxylic acid (1.25 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction, dichloromethane/DMF 1:1) and the product was purified by chromatography on silica gel with elution by ethyl acetate. The output 313 mg, 65%. HPLC (60/40) 2,84 minutes (99%); TRMS 387/389 (MH+, 100%).

1H NMR (CDCl3) 9,1 (W, 1H), 8,48 (DD, 1H), 8,43 (m, 1H), 7,60 (d, 1H), 7,50 (m, 1H, J=ca, 8 Hz), 7,37 (d, 1H, J=ca, 8 Hz), 7.23 percent (d, 1H), 7,18 (DD, 1H, J=ca, 8 Hz), 7,10 (d, 1H, J=sa, 8 is to maintain for C19H19ClN4O3+ 0,4 H2O: C, 57,91; H, 5,07; N, 14,22.

Found: C, 58,19; H, 5,23; N, 13,82.

Example a.

(2S)-Amino-N-methoxy-N-methyl-3-pyridin-3-ylpropionic the dihydrochloride

[(1S)-(Methoxymethylethoxy)-2-pyridin-3-yl-ethyl] -carbamino acid tert-butyl ester (1.5 mmole) was dissolved in 4M HCl-dioxane at 0oC. the resulting solution was stirred for 2 hours at 25oC, concentrated and the residue triturated with ether. The output 390 mg, 95%.

Example 62b.

(S)-[1-(Methoxymethylethoxy)-2-pyridin-3-yl-ethyl] - carbamino acid tert-butyl ether

N, O-Dimethylhydroxylamine hydrochloride (1.7 mmole) and Boc-3-pyridyl-L-alanine (1.6 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction, dichloromethane/dimethylformamide, washed acid were excluded for drying used Na2SO4). The residue is triturated with ether to obtain 428 mg (86% yield) of yellow solid.

Example 63.

(R, S)-2-[(5-Chloro-1H-indole-2-carbonyl)-amino] -3-(3 - forfinal)-propionic acid methyl ester

(R, S)-2-Amino-3-(3-forfinal)-propionic acid methyl ester (2,05 mmole) and 5-chloro-1H-indole-2-carboxylic'étang/DMF 1: 1) and the product was purified by chromatography on silica gel with elution 10, 20 and 40% ethyl acetate in hexano. The residue is triturated with ether-hexane 1:1 and hexane with getting not quite white solid (484 mg, 63%): HPLC (60/40) 8,13 minutes (95%); TRMS 375/377 (MH+, 100%);

1H NMR (CDCl3) 9,26 (W, 1H), 7,60 (d, 1H, J = 1 Hz), 7,35 (d, 1H, J=8.7 Hz), 7,25 (m, 2H), 6,95 (m, 1H), 6,91 (m, 1H), 6,84 (m, 1H), 6,77 (d, 1H, J=1.5 Hz), 6,63 (d, 1H, J=7,7 Hz), to 5.08 (m, 1H), of 3.78 (s, 3H), of 3.28 (DD, 1H, A of AB, J=5,7,14 Hz), 3,21 (DD, 1H, B of AB, J=5,5,14 Hz).

Anal. Calculated for C19H16ClFN2O3: C, 60,89; H, 4,30; N, 7,47.

Found: C, 60,79; H, 4,58; N, 7.18 In.

Example 63A.

(R, S)-2-Amino-3-(3-forfinal)-propionic acid methyl ester hydrochloride

Trimethylsilane (1.07 g, a 9.9 mmole) was added to a suspension of m-fluoro-DL-phenylalanine (0,404 g, 2.2 mmole) in methanol (4 ml) at 25oC. the resulting solution was boiled in a flask with reflux condenser for 1 hour, cooled and concentrated. The residue is triturated with ether. The output of 515 mg, 100%; HPLC (60/40) 2,31 minutes (95%).

Example 64.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-(methoxymethylethoxy)- 2-thiophene-2-yl-ethyl]-amide

(S)-2-Amino-N-methoxy-N-methyl-3-thiophene-2-yl-propionamide hydrochloride (1.2 mmole) and 5-chloro-1H-indole-2-carboxylic acid (1.2 mmole) were combined in about the crude was purified by chromatography on silica gel with elution 10, 20, 30 and 40% ethyl acetate in hexano. The output of 375 mg, 80%; HPLC (60/40) 6,36 minutes (99%); PBMS 392/394 (MH+, 100%).

1H NMR (CDCl3) was 9.33 (W, 1H), 7,60 (d, 1H, J=4 1 Hz), 7,30 (d, 1H, J= 8,8 Hz), 7,20 (DD, 1H, J=2.0 a, 8,7 Hz), to 7.15 (DD, 1H, J=1, 5.0 Hz), 6,91 (DD, 1H, J=3,4, 5,1 Hz) 6,86 (d, 1H, J=1.6 Hz), at 6.84 (d, 1H, J= 2 Hz), of 5.40 (m, 1H), of 3.77 (s, 3H), of 3.46 (DD, 1H, A of AB, J=6,2, 14 Hz), 3,37 (DD, 1H, B of AB, J=14,2 6,2 Hz) at 3.25 (s, 3H).

Anal. Calculated for C18H18ClN3O3S + 0,25 C4H8O2: C, 55,14, H, 4,87, N, 10,15.

Found: C, 55,41; H, 4,79; N, 10,17.

Example 64A.

(S)-2-Amino-N-methoxy-N-methyl-3-thiophene-2-yl-propionamide hydrochloride

(S)-[1-(Methoxymethylethoxy)-2-thiophene-2-yl-ethyl] -carbamino acid tert-butyl ester (1.3 mmole) was dissolved in 4M HCl-dioxane (1 ml) at 0oC and the resulting solution was stirred at 25oC for 2 hours. The mixture was concentrated and the residue triturated with ether to obtain a yellow solid (321 mg, 96%; HPLC (60/40) 2,24 minutes (98%); MS 215 (M+, 100%).

Example 64b.

(S)-[1-(Methoxymethylethoxy)-2-thiophene-2-yl-ethyl]- carbamino acid tert-butyl ether

N, O-dimethylhydroxylamine hydrochloride (1.4 mmole) and Boc-(2-thienyl)-L-alanine (1.3 mmole) were coupled according to procedure A (temperature reach">

Example 65.

(RS)-2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3-(4-forfinal)- propionic acid methyl ester

(R, S)-2-Amino-3-(3-forfinal)-propionic acid methyl ester (3.0 mmole) and 5-chloro-1H-indole-2-carboxylic acid (2.9 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction, dichloromethane/dimethylformamide 3:2) and the resulting product raw triturated with ether-hexane 1:1. The output of 1.03 g, 92%; HPLC (60/40) 7.95 minutes (96%); PBMS 375/377 (MH+, 100%);

1H NMR (CDCl3) of 9.30 (W, 1H), 7,60 (d, 1H, J= 1 Hz), 7,35 (d, 1H, J= 8,8 Hz), 7,25 (DD, 1H, J=2.0 a, 8,7 Hz), 7,10 (m, 2H), 6,97 (m, 2H), 6,77 (d, 1H, J= 2 Hz), 6,62 (d, 1H, J=7.8 Hz), is 5.06 (m, 1H), of 3.78 (s, 3H), of 3.27 (DD, 1H, A of AB, J=7,14 Hz), 3,19 (DD, 1H, B of AB, J=7,14 Hz).

Anal. Calculated for C19H16ClFN2O3: C, 60,89; H, 4,30; N, 7,47.

Found: C, 60,74; H, 4,36; N, 7,55.

Example 66.

5-Chloro-1H-indole-2-carboxylic acid [2-(4-AMINOPHENYL)- (1S)-dimethylcarbamoyl]-amide hydrochloride

(S)-2-Amino-3-(4-AMINOPHENYL)-N, N-dimethylpropanamide the dihydrochloride (0.7 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0.7 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction of dichloromethane/DMF 3:1, washed only base) and the product was purified with the help concentrated, was dissolved in methanol at 0oC, the resulting solution was treated with a 1.01 N HCl (to 1.05 EQ.). After 5 minutes the reaction mixture was concentrated and the residue triturated with ether to obtain an orange solid (79 mg, yield 29%); TRMS 385/387 (MH+, 100%);

Anal. Calculated for C20H21ClN4O2+ 1,5 HCl: C, 54,65; H, 5,16; N, Was 12.75. Found: C, 54,96; H, Of 5.53; N, 12,53.

Example 66A.

(S)-2-Amino-3-(4-AMINOPHENYL)-N,N-dimethylpropanamide the dihydrochloride

(S)-[2-(4-AMINOPHENYL)-1-dimethylcarbamoyl-ethyl] -carbamino acid tert-butyl ester (214 mg, 0.7 mmole) was dissolved in 4M HCl-dioxane (2 ml) at 0oC and the solution was stirred for 2 hours at 25oC. the Mixture was concentrated and the residue triturated with ether. Exit 294 mg, 102%; PBMS 208 (MH+, 100%).

Example 66b.

(S)-[2-(4-AMINOPHENYL)-1-dimethylcarbamoyl-ethyl]-carbamino acid tert-butyl ether

Dimethylamine hydrochloride (2,04 mmole) and Boc-p-amino-L-phenylalanine (1.7 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction, dichloromethane/dimethylformamide 4:1, washed only basis). The product was purified by chromatography on silica gel with elution 50, 60, 70, and 100% ethyl acetate in 1S)-dimethylcarbamoyl-3 - phenylpropyl)-amide

(S)-2-Amino-N, N-dimethyl-4-phenylbutyramide hydrochloride (from 0.76 mmole) and 5-chloro-1H-indole-2-carboxylic acid (from 0.76 mmole) were coupled according to procedure a (reaction temperature 0-25oC; solvent for the reaction, dichloromethane/DMF 3:1) and the product was purified by chromatography on silica gel with elution 10, 20, 30, 40, 50 and 60% ethyl acetate in hexano. Exit 263 mg, 90%; HPLC (60/40) 7,12 minutes (99%); TRMS 384/386 (MH+100%);

Anal. Calculated for C21H22ClN3O2: C, 65,71; H, 5,78; N, 10,95.

Found: C, 65,34; H, To 5.93; N, 10,91.

Example 67a.

(S)-2-Amino-N,N-dimethyl-4-phenylbutyramide hydrochloride

(S)-(1-Dimethylcarbamoyl-3-phenylpropyl)-carbamino acid tert-butyl ester (235 mg, 0.8 mmole) was dissolved in 4M HCl-dioxane (2 ml) at 0oC. the Mixture was stirred at 25oC for 1.5 hours, concentrated and the residue triturated with ether. Exit 187 mg, 100%; HPLC (60/40) 2,31 minutes (99%).

Example 67b.

(S)-(1-Dimethylcarbamoyl-3-phenylpropyl)-carbamino acid tert-butyl ether

Dimethylamine hydrochloride (1.0 mmol) and (S)-N-t-butoxycarbonyl-2 - amino-4-phenylalanyl acid (from 0.84 mmole) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction of dichloromethane/DMF 3:1) obtained with the

Example 68.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-dimethylcarbamoyl-2- (4-hydroxyphenyl)-ethyl]-amide

(S)-2-Amino-3-(4-hydroxyphenyl)-N, N-dimethylpropanamide hydrochloride (1.05 mmole) and 5-chloro-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction of dichloromethane/DMF 2: 1, washed only acid) and the product was purified by chromatography on silica gel with elution 20, 40, 50, and 75% ethyl acetate in hexano followed by rubbing with ether. 400 mg, 104%; HPLC (60/40) 3,93 minutes (98%); so pl. 228-231oC (decomposition, I came at 210oC); TRMC 386/388 (M+, 100%);

Anal. Calculated for C20H20ClN3O3+ 0,9 H2O: C, 59,75; H, VS. 5.47; N, 10,45.

Found: C, 61,05, H, 5,79; N, 10,08.

Example 68A.

(S)-2-Amino-3-(4-hydroxyphenyl)-N,N-dimethylpropanamide hydrochloride

(S)-[1-Dimethylcarbamoyl-2-(4-hydroxyphenyl)-ethyl] -carbamino acid tert-butyl ester (5.7 g, 18.5 mmole) was dissolved in 4M HCl-dioxane (7 ml) at 0oC. the Mixture was stirred at 25oC for 3 hours, concentrated and the residue triturated with ether. Output, 5,23 g; HPLC (60/40) 3.32 minutes (98%).

Example 68b.

(S)-[1-Dimethylcarbamoyl-2-(4-hydrox (66 mmol) were coupled according to procedure a (reaction temperature 0-25oC, the solvent for the reaction, dichloromethane/DMF 12: 1, response time - 60 hours) and the product was purified by chromatography on silica gel with elution 10, 20, 30, 50 and 70% ethyl acetate in hexano.

Example 69.

5-Chloro-1H-indole-2-carboxylic acid ((1S)-methoxycarbonyl-2-phenylethyl)-amide

(2S)-Amino-N-methoxy-3-phenylpropionamide hydrochloride (1,02 mmole) and 5-chloro-1H-indole-2-carboxylic acid (1,02 mmole) were coupled according to procedure A. the Residue triturated with ether to obtain a light yellow solid. The output 160 mg, 36%; so pl. 210-213oC (Razlog.); PBMS 372/374 (MH+, 100%);

Anal. Calculated for C19H18ClN3O3+ 1,75 H2O: C, 56,58; H, LOWER THAN THE 5.37; N, 10,42.

Found: C, A 56.88; H, 5,09; N, There Is A 10.03.

Example 69A.

(2S)-Amino-N-methoxy-3-phenylpropionamide hydrochloride

[(1S)-(Methoxycarbonyl)-2-phenylethyl] -carbamino acid tert-butyl ester (200 mg, 0.68 mmole) was dissolved in 4M HCl-dioxane at 0oC and the mixture was stirred at 25oC. After 0.5 hours the mixture was concentrated and the residue triturated with ether.

Example 69b.

[(1S)-(Methoxycarbonyl)-2-phenylethyl] -carbamino acid tert-butyl ether

Methoxyamine hydrochloride (83,5 mmole) and Boc-L-phenylalanine (20 metacom/hexane 1:1 and 2:1, followed by rubbing with ether. The output of 1.80 g, 31%.

Example 70.

5-Chloro-1H-indole-2-carboxylic acid ((1R)-methylcarbamoyl-2 - phenylethyl)-amide

(R)-2-Amino-N-methyl-3-phenylpropionamide hydrochloride (from 0.84 mmole) and 5-chloro-1H-indole-2-carboxylic acid (from 0.84 mmole) were coupled according to procedure a (reaction temperature 0-25oC). Product raw triturated with dichloromethane and then with ether and dried. The output 236 mg, 79%: HPLC (60/40) 4,63 minutes (97%); PBMS 356/358 (MH+, 100%);

Anal. Calculated for C19H18ClN3O2+ 0,25 H2O: C, 63,33, H, 5,18; N, 11,66.

Found: C, 63,37; H, 5,50; N, 12,06.

Example 70A.

(R)-2-Amino-N-methyl-3-phenylpropionamide hydrochloride

(R)-(1-Methylcarbamoyl-2-phenylethyl)-carbamino acid tert-butyl ester (722 mg, 2.6 mmole) was dissolved in 4M HCl-dioxane (10 ml) at 0oC. the Mixture was stirred for 1 hour at 25oC, concentrated and the residue triturated with ether. The output of 517 mg, 93%.

Example 70b.

(R)-(1-Methylcarbamoyl-2-phenylethyl)-carbamino acid tert-butyl ether

Of methylamine hydrochloride (3.1 mmole) and Boc-phenylalanine (2.8 mmole) were coupled according to procedure a (reaction temperature 0-25oC, reaction time of 144 hours, washed first with acid, then base) to obtain the product-indole-2-carboxylic acid ((1S)-dimethylcarbamoyl-2-phenylethyl)-amide

(S)-2-Amino-N, N-dimethyl-3-phenylpropionamide hydrochloride (0,06 mmole) and 5,6-dichloro-1H-indole-2-carboxylic acid (0,06 mmole) were coupled according to procedure a (reaction temperature 0-25oC, reaction time of 96 hours). The crude product is triturated with ether-hexane 1:1 and dried. Yield 24 mg, 96%. HPLC (60/40) 8,05 minutes (97%); PBMS 405/407 (MH+, 100%).

Anal. Calculated for C20H19Cl2N3O2+ 0,25 H2O: C, 58,76; H, TO 4.81; N, 10,28.

Found: C, 58,95; H, 4,89; N, 9,90.

Example 71A.

(S)-2-Amino-N,N-dimethyl-3-phenylpropionamide hydrochloride

(1-Dimethylcarbamoyl-2-phenylethyl)-carbamino acid tert-butyl ester (8.6 g, 29 mmol) was dissolved in 4M HCl-dioxane (110 ml) at 0oC and the mixture was stirred at 25oC for 1 hour. The mixture was concentrated and the solids triturated with ether. Yield 6.2 g, 92%; PBMS 193 (MH+, 100%).

Example 71b.

5,6-Dichloro-1H-indole-2-carboxylic acid

Zinc dust (3,52 g, 54 mmole) was slowly added to the warm solution of 3,4-dichloro-5-nitrophenylpyruvic acid (1.5 g, 5.4 mmole) in acetic acid (15 ml). After a few minutes there was a rapid reaction (exothermic). The resulting solution was heated to 80oC and reaction, potou and the filtrate was concentrated. The residue was dissolved in 2N NaOH, the resulting solution was washed with ether (3x), dichloromethane (2x) and acidified to pH 6N HCl and extracted with ethyl acetate. The extracts were dried and concentrated to obtain a light brown solid (458 mg, 34%): HPLC(60/40) 5,31 (93%).

Example s.

3,4-Dichloro-5-nitrophenylpyruvic acid

Absolute ethanol (25 ml) was added 3-15oC to a stirred mixture of potassium metal (2.67 g, 68 mmol) in ether (100 ml). The resulting solution was treated with 3oC solution diethyloxalate (10.0 g, 62 mmole) for 5-10 minutes, and the resulting solution was stirred for 30 minutes at 3oC and 25oC for 18 hours. The mixture was filtered and the obtained solid was washed with ether and dried (13,7 g). This material (12.7 g) was dissolved in 400 ml of hot water, the solution was cooled and was extracted with ether. The resulting aqueous layer was acidified to pH 2 with concentrated HCl and ether layer was separated, dried and concentrated to obtain 7.5 g of solid, which was washed with hexane, receiving the substance header in the form of a yellow solid (7.01 g, 41%).

Example 72.

5-Bromo-1H-indole-2-carboxylic acid ((1S)-dim is an indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC) and the obtained foamy substance is triturated with ether-hexane 1:1 and dried.

Exit 374 mg, 90%; BASH (60/40) 6,17 minutes (98%); so pl. 199-201oC; PBMS 414/416 (MH+, 100%);

Anal. Calculated for C20H20BrN3O2: C 57,98; H, 4,82; N, 10,14.

Found: C, 58,07; H, 5,12; N, 10,08.

Example 73.

5-Methyl-1H-indole-2-carboxylic acid ((1S)-dimethylcarbamoyl-2-phenylethyl)-amide

(S)-2-Amino-N, N-dimethyl-3-phenylpropionamide hydrochloride (1.0 mmol) and 5-methyl-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC). The crude product is triturated with ether-hexane 1: 1 and dried. Yield 302 mg, 87%; HPLC (60/40) 5,46 minutes (99%); so pl. is 198.5-200oC; PBMS 350 (MH+, 100%).

Anal. Calculated for C21H23N3O2: C, 72,18; H, 6,63; N, 12,04.

Found: C, 72,14; H, Of 6.90; N, 12,11.

Example 74.

5-Methoxy-1H-indole-2-carboxylic acid ((1S)-dimethylcarbamoyl-2-phenylethyl)-amide

(S)-2-Amino-N, N-dimethyl-3-phenylpropionamide hydrochloride (1.0 mmol) and 5-methoxy-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC, reaction time 60 hours) and the resulting foamy substance was ground 3O3+ 0,125 H2O: C, 68,60; H, 6,37; N, 11,43.

Found: C, 68,50; H, 6,34; N, Of 11.45.

Example 75.

5-fluoro-1H-indole-2-carboxylic acid ((1S)-dimethylcarbamoyl - 2-phenylethyl)-amide

(S)-2-Amino-N, N-dimethyl-3-phenylpropionamide hydrochloride (1.0 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC, response time - 60 hours) and the resulting solid triturated with ether. The output 320 mg, 91%; HPLC (60/40) 4,74 minutes (100%); so pl. of 229.5-232oC; PBMS 354 (MH+, 100%).

Anal. Calculated for C20H20FN3O2: C, 67,97; H, 5,70; N, 11,89.

Found: C, 67,88; H, 5,74; N, 11,71.

Example 76.

5-Cyano-1H-indole-2-carboxylic acid ((1S)-dimethylcarbamoyl-2 - phenylethyl)-amide

(S)-2-Amino-N, N-dimethyl-3-phenylpropionamide hydrochloride (0.16 mmole) and 5-cyano-1H-indole-2-carboxylic acid (0.16 mmole) were coupled according to procedure a (reaction temperature 0-25oC) and the product was purified by chromatography on silica gel with elution by ethyl acetate/hexane 1:1. Yield 38 mg, 66%; HPLC (60/40) 4,08 minutes (97%); PBMS 361 (MH+, 100%);

1H NMR (DMSO-d6) 12,1 (W, 1H), 9,04 (d, 1H, J=8.1 Hz), of 8.27 (s, 1H), 7,52 (m, 2H), 7,43 (m, 1H), 7,33 (m, 2H), 7,25 (m, 2H), 7,18 (m, 1H), 5,10 (m, 1H), 3,03 (m ; , 15,17.

Found: C, 68,51; H, To 5.66; N, 14,85.

Example 76A.

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

5-Cyano-1H-indole-2-carboxylic acid ethyl ester (1,71 g, 8 mmol) was added to a solution of ethanol (10 ml) and potassium hydroxide (2 g) and the resulting mixture was heated in a flask under reflux for 1 hour. Added water to dissolve the precipitate and 6N HCl was added to bring the pH to 1. The mixture was cooled in an ice bath, filtered and the resulting colourless solid was washed with cold water and dried (1.51 g). A portion (1.4 g) suspended in hot acetic acid (40 ml) and cooled to obtain solid, which was filtered off, washed with cold acetate and dried: yield 980 mg, 70%; HPLC (60/40) 3,09 minutes (97%).

Example 76b.

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

Zinc dust (of 57.8 g, 887 mmol) was added to a hot suspension of 3-cyano-5-nitrophenylpyruvic acid ethyl ester (23,2 g, 88 mmol) in acetic acid (225 ml) and water (225 ml, Caution! originally violently exothermic) such portions to maintain the boiling flask with reflux condenser and the reaction maintaining the boiling was continued for 0.5 hours. Compounds is their nights getting the crystals, which was filtered off, washed with cold acetic acid - water 1: 1 with water and dried (10,11 g, 53%). The filtrate was concentrated, the residue was dissolved in ethyl acetate, and the resulting solution was washed with saturated aqueous sodium bicarbonate, saline, dried and concentrated to obtain a second portion (of 5.05 g). The bulk was used for subsequent transformations.

Example s.

3-Cyano-5-nitrophenylpyruvic acid ethyl ester

The solution ethoxide sodium in ethanol (2.2 g, 400 mmol of metal in 400 ml of ethanol) was added at 0oC to the mixture of distilled diethyloxalate (120 g, 821 mmole) and 3-methyl-4-nitro-benzonitrile (32 g, 197 mmol). The resulting red solution was heated at 40oC for 18 hours. The cooled mixture was diluted with water (600 ml) and acidified with concentrated HCl to a pH of 2.1. The precipitate that formed was collected by filtering the mixture with a temperature of 13oC, dried and purified by chromatography on silica gel with elution 15, 30 and 50% acetone-hexane to obtain an orange solid, which was used without purification (23,6 g, 31%). A sample recrystallized from ethyl acetate to characterize.

N-dimethyl-3-phenylpropionamide hydrochloride (1.0 mmol) and 1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure a (reaction temperature 0-25oC). The resulting solid is triturated with hexane, then with ether. The output 272 mg, 81%; HPLC (70/30), 3,49 minutes (99%); so pl. 199-200oC; PBMS 336 (MH+, 1000).

Anal. Calculated for C20H21N3O2: C 71,62; H, OF 6.31; N, 12,53.

Found: C, 71,45; H, To 6.39; N, 12,50.

Example 78.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3S, 4S) -dihydroxypyrrolidine-1-yl)-2-oxoethyl]-amide

(3S, 4S)-2-Amino-1-(3,4-dihydroxypyrrolidine-1-yl)-3-phenylpropane-1-she hydrochloride (0,94 mmole) and 5-chloro-1H-indole-2-carboxylic acid (of 1.03 mmole) were coupled according to procedure A (reaction time of 170 hours) and the product crude was purified by column chromatography on silica gel with elution by ethyl acetate. The output 150 mg, 37%; HPLC (60/40) is 3.08 minutes (96%);

1H NMR (DMSO-d6) 11,73 (s, 1H), 8,90 (d, 1H, J=8.5 Hz), 7,72 (d, 1H, J= 1.5 Hz), 7,39 (d, 1H, J=8.7 Hz), 7,30 (m, 2H), 7,30 to 7.1 (m, 5H), with 5.22 (m, 1H), 5,13 (m, 1H), 4,91 (m, 1H), 3,97 (m, 1H), 3,91 (m, 1H), 3,60 (m, 2H), 3,5-3,2 (m, 2H), 3,00 (m, 2H).

Anal. Calculated for C22H22ClN3O4: C, 61,75; H, 5,18; N, 9,82.

Found: C, 61,65; H, The 5.45; N, 9,17.

Example 78A.

(3S, 4S)-2-Amino-1-(3,4-dihydroxypyrrolidine-1-yl)-3 - phenylpropane-1-she hydrochloride

(3S, 4S)-[1-Benzyl-2-(3,4-dihydroxypyrrolidine-1-yl oC for 3 hours. The mixture was concentrated and the resulting yellow solid is triturated with ether and dried. The output 304 mg, 103%.

Example 78b.

[1-benzyl-2-(3,4-dihydroxypyrrolidine-1-yl)-2-oxoethyl] - carbamino acid tert-butyl ether

Boc-L-phenylalanine (2.2 mmole) and (3S,4S)-dihydroxypyrrolidine (U.S. patent N 4634775, example 1C, 206 mg, 2.0 mmole) were coupled according to procedure a (reaction temperature 0-25oC) obtaining a colorless solid, which was used without further purification. Exit 431 mg, 61%.

Example 79.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3RS) - hydroxypiperidine-1-yl)-2-oxoethyl]-amide

2(S)-Amino-1-((3RS)-hydroxypiperidine-1-yl)-3-phenylpropane-1-she hydrochloride (570 mg, 2.0 mmole) and 5-chloro-1H-indole-2-carboxylic acid (429 mg, 2.2 mmole) were coupled according to procedure a (solvent dichloromethane-dimethylformamide 5:2) and the product of raw triturated with ether-hexane 1:1. The resulting solid was purified by column chromatography on silica gel with elution by ethyl acetate/hexane 3:2 and 2:1, followed by rubbing with ether-hexane 1: 1. The output 430 mg, 51%: HPLC (60/40) 3.45 minutes (95%);

Anal. Calculated for C23H24ClN3O

(2S)-Amino-1-(3-hydroxypiperidine-1-yl)-3-phenylpropane-1-she hydrochloride

[(1S)-Benzyl-2-((3RS)-hydroxypiperidine-1-yl)-2-oxoethyl] - carbamino acid tert-butyl ether (7,13 g, 20 mmol) was dissolved in 4M HCl-dioxane (40 ml) at 25oC for 3 hours. The mixture was concentrated and the resulting oil was stirred in an atmosphere of ether within 72 hours. The resulting suspension was filtered and the solid was washed with ether and dried. Output 5,64 g, 99%.

Example 79b.

[(1S)-Benzyl-2-((3RS)-hydroxypiperidine-1-yl)-2-oxoethyl] - carbamino acid tert-butyl ether

Boc-L-phenylalanine (8,17 g, 30.8 mmole) and 3-hydroxypiperidine hydrochloride (4,24 g, 30.8 mmole) were coupled according to procedure a with the connection header in the form of oil, which was used without further purification. Output 7,79 g, 73%.

Example 80.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-oxo-2-(3-oxopiperidin-1-yl)-ethyl]-amide

4-((2S)-Amino-3-phenylpropionyl)-piperazine-2-she hydrochloride (140 mg, 0.5 mmole) and 5-chloro-1H-indole-2-carboxylic acid (98 mg, 0.5 mmole) were coupled according to procedure a and the product crude was purified by column chromatography on silica gel with elution by ethyl acetate and 2% ethanol in ethyl Jerusalem.
1H NMR (DMSO-d6) 11,78 (width, 0.5 N), 11,76 (width, 0.5 N), 9,03 (m, 0.5 H), of 9.02 (m, 0.5 H), of 8.06 (m, 0.5 H), of 8.04 (m, 0.5 H), 7,73 (d, 1H, J=2 Hz), 7,38 (d, 1H, J= 8.7 Hz), 7,32 (m, 2H), 7,20 (m, 2H), 7,2, and 7.1 (m, 2H), 5,15 (m, 0.5 N), of 5.05 (m, 0.5 H), 4,20 (d, 0.5 H, J=17 Hz), 4,08 (d, 0.5 H, J=17 Hz), 3,85 (d, 0.5 H, J=17 Hz), 3,9 (m, 0.5 H), and 3.6 (m, 2H), 3,2-a 2.9 (m, 4H).

Example 80A.

4-((2S)-Amino-3-phenylpropionyl)-piperazine-2-she hydrochloride

[(1S)-Benzyl-2-oxo-2-(3-oxopiperidin-1-yl)-ethyl] -carbamino acid tert-butyl ester (400 mg, 1.2 mmole) was dissolved in 4M HCl-dioxane (10 ml) at 25oC for 0.5 hours. The mixture was concentrated and the residue evaporated with dichloromethane, washed with ether and dried. The output 340 mg, 103%.

Example 80b.

[(1S) -Benzyl-2-oxo-2-(3-oxopiperidin-1-yl)-ethyl] - carbamino acid tert-butyl ether

Boc-L-phenylalanine (530 mg, 2 mmole) and piperazine-2-he (J. Am. Chem. Soc., 62, 1202 (1940), 200 mg, 2 mmole) were coupled according to procedure a (solvent for the reaction of dichloromethane/dimethylformamide 2:1, washed with 1N NaOH after washing with acid and the product was used without additional purification. The output 404 mg, 58%.

Example 81.

5-Chloro-1H-indole-2-carboxylic acid ((1S)-methyl-2-morpholine-4-yl-2-oxoethyl)-amide

(2S)-Amino-1-morpholine-4-yl-propane-1-she hydrochloride (195 mg, 1.0 mmol) and 5-chloro-1H-ind is the receiving product raw which is triturated with ether and dried. The output 150 mg, 45%: HPLC (60/40) 3,61 minutes (100%); PBMS 336/338 (MH+, 100%);

Anal. Calculated for C16H18ClN3O3: C, 57,23; H, OF 5.40; N, 12,51.

Found: C, 57,01; H, 5,49; N, 12,24.

Example a.

(2S)-Amino-1-morpholine-4-yl-propane-1-she hydrochloride

((1S)-Methyl-2-morpholine-4-yl-2-oxoethyl)-carbamino acid tert-butyl ester (3.88 g, 15 mmol) was dissolved in 4M HCl-dioxane (20 ml) at 25oC for 1.25 hours. The mixture was concentrated and the residue triturated with ether and dried: yield of 2.51 g, 86%.

Example 81b.

((1S)-Methyl-2-morpholine-4-yl-2-oxoethyl)-carboxylic acid tert-butyl ether

Boc-L-Alanine (3,50 mg, 20 mmol) and morpholine (1,74 g, 20 mmol) were coupled according to procedure A (washed with 1N NaOH after washing with acid) to give a colorless oil which was used without further purification. Yield 3.94 g, 76%.

Example 82.

5-Chloro-1H-indole-2-carboxylic acid ((1S)-methylcarbamoyl-2-phenylethyl)-amide

(2S)-Amino-N-methyl-3-phenylpropionamide hydrochloride (214 mg, 1.0 mmol) and 5-chloro-1H-indole-2-carboxylic acid (195 mg, 1.0 mmol) were coupled according to procedure a and the product raw triturated with ether and dried. The output 160 mg, 45%: HPLC (60/40) 4,60 minutes (100%);

Example a.

(2S)-Amino-N-methyl-3-phenyl-propionamide hydrochloride

[((1S)-1-Methylcarbamoyl-2-phenylethyl)-carbamino acid tert-butyl ester (2.35 g, 8,45 mmole) was dissolved in 4M HCl-dioxane (20 ml) at 25oC for 2 hours. The mixture was concentrated and the residue triturated with ether and dried. Yield 1.70 g, 94%.

Example 82b.

((1S)-1-Methylcarbamoyl-2-phenylethyl)-carbamino acid tert-butyl ether

Boc-N-phenylalanine (2.65 g, 10 mmol) and methylamine hydrochloride (675 mg, 10 mmol) were coupled according to procedure A (washed with 1N NaOH after washing acid) to obtain the substance header in the form of a colorless solid, which was used without further purification. The output is 2.41 g, 87%; HPLC (60/40) 3,83 minutes (100%).

Example 83.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-(methoxymethylethoxy)-ethyl] -amide

(2S)-Amino-N-methoxy-N-methylpropionamide hydrochloride (169 mg, 1.0 mmol) and 5-chloro-1H-indole-2-carboxylic acid were coupled according to procedure A (washed with 1N NaOH after washing acid) to give the product (290 mg, 94%): HPLC (60/40) 4,03 minutes (94%); PBMS 310/312 (MH+, 100%);

Anal. Calculated for C14H16C (2S)-Amino-N-methoxy-N-methylpropionamide hydrochloride

[(1S)-(Methoxymethylethoxy)-ethyl] -carbamino acid tert-butyl ester (3.55 g, 15.3 mmole) was dissolved in 4M HCl-dioxane (20 ml) at 25oC for 0.75 hour. The mixture was concentrated and the residue evaporated with ether and dichloromethane and dried. Yield 2.2 g (86%).

Example 83b.

[1-(Methoxymethylethoxy)-ethyl] -carbamino acid tert-butyl ether

L-Boc-Alanine (3.50 g, 20 mmol) and O,N-dimethylhydroxylamine hydrochloride (1,94 g, 20 mmol) were coupled according to procedure A (washed with 1N NaOH after washing acid) and the resulting colourless solid was used without further purification. Output 3,71 g (80%).

Example 84.

5-Bromo-1H-indole-2-carboxylic acid ((1S)-carbarnoyl-2 - phenylethyl)-amide

L-phenylalaninamide hydrochloride (835 mg, of 4.17 mmole) and 5-bromo-1H-indole-2-carboxylic acid (1.0 g, to 4.17 mmole) were coupled according to the procedure And with the substitution of the following processing: the reaction mixture was diluted with ethyl acetate and 2N NaOH. The resulting suspension was filtered and the collected solid was washed with ethyl acetate, 2N NaOH, 2N HCl, ether and dried. Yield 890 mg, PBMS 386/388 (MH+, 100%);

Anal. Calculated for C18H16BrN3O2: C, 55,97; H, 4,18; N, 10,88.

Found: C, 55,69; H, 4,48; N is l)-amide

(2S)-Amino-N-methoxy-N-methyl-3-phenylpropionamide hydrochloride (317 mg, 1.3 mmole) and 5-chloro-1H-indole-2-carboxylic acid (253 mg, 1.3 mmole) were coupled according to procedure A (0-25oC, washed first with acid, then base). Product raw was purified by column chromatography on silica gel with elution 30 and 40% ethyl acetate in hexano. The obtained foamy substance is triturated with isopropyl ether to obtain not quite white solid (356 mg, 71%): HPLC (60/40) 8,28 minutes (98%);

Anal. Calculated for C20H20ClN3O3: C, 62,26; H, 5,22; N, 10,89.

Found: C, 62,22; H, The Ceiling Of 5.60; N, Of 10.73.

Example 85a.

(2S)-Amino-N-methoxy-N-methyl-3-phenylpropionamide hydrochloride

[(1S)-(Methoxymethylethoxy)-2-phenylethyl] -carbamino acid tert-butyl ether (2,97 g, 9.6 mmole) was dissolved in 4M HCl-dioxane (36 ml) at 0oC. the resulting mixture was stirred at 25oC for 1 hour, concentrated and the residue triturated with ether and dried. The output of 2.27 g, 96%.

Example 85b.

[(1S)-(Methoxymethylethoxy)-2-phenylethyl]-carbamino acid tert-butyl ether

Boc-L-phenylalanine (4.0 g, 15,1 mmole) and N,O-dimethylhydroxylamine hydrochloride (3,82 g of 15.1 mmole) were coupled according to procedure And the TCI (3,22 g, 69%).

Example 86.

(2RS)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -2-methyl-3 - phenylpropionic acid methyl ester

Racemic 2-amino-2-methyl-3-phenylpropionic acid methyl ester (200 mg, 0.87 for mmole) and 5-chloro-1H-indole-2-carboxylic acid (170 mg, of 0.87 mmole) were coupled according to procedure a (solvent dichloromethane/dimethylformamide 2: 1) and the product was purified by chromatography on silica gel with elution with 10% ethyl acetate in hexano. Exit 286 mg, 89%; HPLC (60/40) 9,63 minutes (85%); TRMS 371/373 (MH+, 100>);

1H NMR (CDCl3) 9,31 (s, 1H), EUR 7.57 (d, 1H, J Hz), 7,37 (d, 1H, J=8,8 Hz), 7,20 (m, 4H),? 7.04 baby mortality (m, 2H), at 6.84 (s, 1H), 6,66 (s, 1H), 3,81 (s, 3H), 3,67 (A of AB, 1H, J=13.5 Hz), 3,28 (B of AB, 1H, J=13.5 Hz), of 1.80 (s, 3H).

Example 87.

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

Aqueous 2N LiOH (0.10 ml, and 0.50 mmole) was added to a solution of (2RS)-[(5-chloro-1H-indole-2-carbonyl)-amino)-2-methyl-3-phenyl-propionic acid methyl ester (132 mg, of 0.36 mmole) in tetrahydrofuran (8 ml) at 25oC. the resulting solution was stirred for 1 hour, concentrated and the residue was dissolved in ethyl acetate and water (15 ml). the pH was brought to 1 with 2N HCl at 0oC. the Organic layer was separated, washed with water, brine and dried with recip(99%); TERMS 357/359 (MH+, 100%);

1H NMR (CDCl3) 9,88 (s, 1H), EUR 7.57 (s, 1H), 7,35 (d, 1H, J=8,8 Hz), and 7.3 to 7.2 (m, 5H), 7,16 (m, 2H), 6.75 in (m, 1H), 6,67 (m, 1H), 3,57 (A of AB, 1H, J=13,7 Hz), 3,42 (B of AB, 1H, J=13,7 Hz), of 1.80 (s, 3H).

Anal. Calculated for C19H17ClN2O3+ 0,3 H2O: C, 63,00; H, THE 4.90; N, 7,73.

Found: C, 63,38; H, 5,31; N, 7,42.

Example 88.

5-Chloro-1H-indole-2-carboxylic acid [[1S)-benzyl-2-oxo-2- (1-oxo-1-thiomorpholine-4-yl)-ethyl]-amide

m-Chloroperoxybenzoic acid (80 mg, 50%, 0,23 mmole) was added at 25oC to a solution of 5-chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-2-oxo-2-thiomorpholine-4-retil)amide (100 mg, to 0.23 mmole) in dichloromethane (2 ml). After 1 hour the mixture was diluted with ethyl acetate and washed three times with a 50/50 mixture of saturated aqueous sodium bicarbonate solution and 10% aqueous sodium thiosulfate solution, once with saturated aqueous sodium bicarbonate, brine and dried. Product raw was purified by column chromatography on silica gel with elution with 0.5-8% ethanol in dichloromethane to obtain the compound of the title. Yield 76%; HPLC (60/40) 3,97 minutes (97%); so pl. 230-234oC; TRMS 444/446 (MH+, 100%);

Anal. Calculated for C22H22ClN3O3S + 0.5 H2O: C, 58,34; H, 5,12; N, 9.28 ARE.

Found: C, 56,77; H, 5,15; N, 8,60.

Example 90.

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

m-Chloroperoxybenzoic acid (167 mg, 50%, 0.48 mmole) was added at 25oC to a solution of 5-chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-2-oxo-2-thiazolidin-3-retil)-amide (200 mg, 0.48 mmole) in dichloromethane (4 ml). After 0.5 hours the mixture was diluted with ethyl acetate and washed three times with a mixture of 50/50 on the m sodium salt solution and dried. Product raw concentrated to a yellow solid and was then purified by column chromatography on silica gel with elution 1-8% ethanol in dichloromethane and then triturated with ether to obtain substances header. Yield 151 mg (73%); HPLC (60/40) 3.64 minutes (98%); PBMS 430/432 (MH+, 100%);

Anal. Calculated for C21H20ClN3O3S + 0,6 H2O: C,57,23; H, IS 4.85; N, AT 9.53.

Found: C, 57,00; H, Is 4.85; N, 9,25.

Example 91.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2- (3-hydroxylaminopurine-1-yl)-2-oxoethyl]-amide

Hydroxylamine hydrochloride (68 mg, of 0.82 mmole) and potassium carbonate (136 mg, and 0.98 mmole) was added to a solution of 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-oxo-2- (3-oxopyrrolidin-1-yl)-ethyl]-amide in ethanol (5 ml) and water (1 ml) at 25oC. After 48 hours the reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The resulting solution was washed twice with water and once with brine, dried Na2SO4and concentrated. Two substances, it seems, are the SYN/anti isomers of the oxime separated using chromatography on silica gel with elution with 2.5%, 5% and 10% ethanol in dichloromethane.

Note if 210oC); PBMS 425/427 (MH+, 100%).

1H NMR (SO-d6) 11,75 (W, 1H), 10,87 (s, 0.5 H), 10,86 (s, 0.5 H), of 9.02 (m, 1H), 7,72 (d, 1H, J=2.0 Hz), between 7.4 and 7.1 (m, 8H), of 4.95 (m, 0.5 H), is 4.85 (m, 0.5 H), and 4.40 (d, 0.5 H, J=15 Hz), 4,0 (m, 1.5 H) to 3.9 (m, 0.5 H), 3,61 (m, 1H), 3,5 (m, 0.5 H), 3,10 (m, 2H), 2,8-2,5 (m, 2H);

Anal. Calculated for C22H21ClN4O3: C, 62,19; H, TO 4.98; N, 13,19.

Found: C, 61,82; H, 5,07; N, 12,95.

Example 91 (II)

For the more polar isomer:

Yield 69 mg (20%); HPLC (60/40) to 6.78 min (> 99%); so pl. p.223-224oC (decomp., resin); PBMS 425/427 (MH+, 100%);

1H NMR (DMSO-d6) 11,74 (W, 1H), 10,87 (s, 1H), 10,84 (s, 1H), 9,05 (d, 0.5 H, J= 8.1 Hz), 8,99 (d, 1H, J=8.0 Hz), 7,73 (d, 1H, J=2 Hz), between 7.4 and 7.1 (m, 8H), equal to 4.97 (m, 1H), around 4.85 (m, 1H), 4,47 (d, 0.5 H, J=17 Hz), 3,95 (m, 1.5 N), a 3.87 (m, 0.5 H), 3,65 to 3.4 (m, 1.5 H), 3,10 (m, 2H), 2,7-2,5 (m, 2H).

Anal. Calculated for C22H21ClN4O3: C, 62,19; H, TO 4.98; N, 13,19.

Found: C, 61,85; H, To 5.17; N, 13,16.

Example 92.

5-Chloro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-piperidine-1-retil)-amide

Piperidine hydrochloride (0,34 mmole) and 2 - [(5-chloro-1H-indole-2 - carbonyl)-amino] -3-phenylpropionate acid (0.30 mmole) were coupled according to procedure a (reaction temperature 0-25oC). Product raw was chromatographically PA silica gel with elution 20%, 30%, 40%, 50%, 75% and 100% ethyl acetate in GC (60/40) 9,38 minutes (94%); PBMS 410/412 (MH+, 100%);

Anal. Calculated for C23H24N3O2Cl + 0,5 H2O: C, 65,94; H, OF 6.02; N, THERE IS A 10.03.

Found: C, 65,70; H, To 6.19; N, 9,66.

Example 93.

5-Chloro-1H-indole-2-carboxylic acid carbamoylmethyl

[(5-Chloro-1H-indole-2-carbonyl)-amino] -acetic acid methyl ester (100 mg, 0.40 mmole) was added to a saturated solution of ammonia in methanol ( 3 ml) at 25oC. the Suspension was treated with ultrasound for 1 hour and the resulting solution was concentrated. The residue is triturated with ether/hexane and dried. Yield 77 mg, 77%; HPLC (60/90) 2,78 minutes (98%); PBMS 252/254 (MH+, 100%);

1H NMR (DMSO-d6) 11,82 (W, 1H), 8,80 (t, 1H), 7,71 (d, 1H, J= 1 Hz), the 7.43 (d, 1H, J=7-8 Hz), 7,42 (W, 1H), 7,18 (DD, 1H, J=7-8, 2 Hz), 7,14 (s, 1H), 7,08 (W, 1H), 3,82 (m, 2H).

Anal. Calculated for C11H10ClN3O3+ 0,125 H2O: C, 52,03; H, 4,07; N, 16,55.

Found: C, 52,05; H, 4,08; N, 16,63.

Example 94.

1-{ (2)-[(5-Bromo-1H-indole-2-carbonyl)-amino] -3-phenylpropionyl} - pyrrolidin-(2S)-carboxylic acid

Triperoxonane acid was added to a solution of 1-{(2S)-[(5-bromo-1H-indole-2-carbonyl)-amino] -3-phenylpropionyl} - pyrrolidin-(2S)-carboxylic acid tert-butyl ester (345 kg of 0.64 mmole) in gilormini with obtaining a yellow solid.

Exit 273 mg, 88%; HPLC (70/30) 4.75 minutes (98%); TRMS 484/486 (MH+, 100%);

Anal. Calculated for C23H22BrN3O4+ 0,25 H2O: C, 56,51; H, WITH 4.64; N, 8,60.

Found: C, 56,28; H, 4,78; N, Compared To 8.26.

Example a.

1-{ (2S)-[(5-Bromo-1H-indole-2-carbonyl)-amino] -3-phenylpropionyl}- pyrrolidin-(2S)-carboxylic acid tert-butyl ether

L-Phenylalanine-L-Proline tert-butyl ester (333 mg, 1.0 mmol) and 5-bromo-1H-indole-2-carboxylic acid were coupled according to procedure A (72 hours reaction time). The product was purified by column chromatography on silica gel with elution 15%, 20% and 30% ethyl acetate to obtain a pale yellow foam. Yield 428 mg (79%); HPLC (70/30) of 5.84 minutes (81%).

Example 95.

5-Chloro-1H-indole-2-carboxylic acid [2-oxo-2-(1RS)-oxo-1 - thiazolidin-3-yl)-ethyl]-amide

m-Chloroperoxybenzoic acid (426 mg, 50%, 1.2 mmole) was added at 25oC to a solution of 5-chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl)-amide (400 mg, 1.2 mmole) in dichloromethane (8 ml) at 25oC. After 1 hour the mixture was diluted with ethyl acetate (ca 80 ml) and the resulting solution was washed three times with a mixture of 1:1 saturated aqueous NaHCO3/10% aqueous Na2S2O3saturated aqueous NaHCO3and salt, and dried to obtain a crystalline solid. HPLC (60/40) 2,52 minutes (98,5%); TRMS 340/342 (MH+, 70%), 357 (100%);

1H NMR (DMSO-d6) 11,82 (W, 1H), 3,84 (m, 1H), 7,73 (d, 1H, J=2.0 Hz), the 7.43 (d, 1H, J=8.7 Hz), 7,19 (DD, 1H, J=2.0 a, 8,7 Hz), 7,18 (s, 1H), 4.92 in (DD, 0.5 H, J=12.1 Hz), 4,71 (DD, 0.5 H, J=2,2, 13 Hz), 4,47 (d, 1H, J= 12.1 Hz), 4,4-3,9 (m, 4.5 H), 3,3 (m, 0.5 H), of 3.13 (m, 1H), 3.0 a (m, 0.5 H).

Anal. Calculated for C14H14ClN3O3S + 0,8 H2O: C, 47,47; H, OF 4.44; N, UP 11,86.

Found: C, To 47.46; H, 4,07; N, 11,83.

Example 96.

1-{ (2S)-[(5-Hdor-1H-indole-2-carbonyl)-amino] -3-phenylpropionyl}- (4R)-hydroxypyrrolidine-(2S)-carboxylic acid

An excess of aqueous 2M LiOH was added to a solution of 1-{(2S)- [(5-chloro-1H-indole-2-carbonyl)-amino] -3-phenylpropionyl} -(4R)- hydroxypyrrolidine-(2S)-carboxylic acid benzyl ester (215 mg, 0.40 mmole) in tetrahydrofuran at 25oC. After 2 hours the mixture was diluted with ethyl acetate and ice and the mixture was acidified to pH 1-2 6N HCl. The acid layer was extracted three times with ethyl acetate and the organic layers were combined and dried. The residue is triturated with ether and dried to obtain a colorless solid (190 mg, 106%): HPLC (60/40) 3,43 minutes (94%); TRMS 456/458 (MH+, 100%);

Anal. Calculated for C23H22ClN3O5+ 0,5 C4H8O2: C 60,06; H, 5,24; N, 8,40.

Found: C, 60,27; H, 5,33; N ether

L-Tryptophan methyl ester hydrochloride (1.05 mmole) and 5-chloro-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to procedure A (0-25oC, the solvent for the reaction - dimethylformamide) and the product was purified by chromatography on silica gel with elution 10%, 20%, 30%, 40%, 50% and 60% ethyl acetate in hexano with a yellow foamy substance.

HPLC (60/40) 7,43 minutes (96%);

1H NMR (CDCl3) 11,78 (W, 1H), 10,85 (W,1H), 8,93 (d, 1H, J=7,7 Hz), 7,73 (d, 1H, J=1.9 Hz), EUR 7.57 (d, 1H, J=7,7 Hz), 7,41 (d, 1H, J=8.7 Hz), 7,32 (d, 1H, J=8.0 Hz), 7,22 (m, 2H), 7,18 (DD, 1H, J=2.1 a, 8,8 Hz), 7,06 (m, 1H), 6,99 (m, 1H), 4,74 (m, 1H), the 3.65 (s, 3H), 3,35-3,2 (m, 2H).

Example 98.

()-3-{ [(5-Chloro-1H-indole-2-carbonyl)-amino] -acetyl}- thiazolidin-2-carboxylic acid methyl ester

()-Thiazolidin-2-carboxylic acid methyl ester hydrochloride (1,02 mmole) and [(5-chloro-111-indole-2-carbonyl)-amino]- acetic acid (1,02 mmole) were coupled according to procedure a (solvent dichloromethane-dimethylformamide 1: 1) and the crude product triturated with ether-hexane 1:1 to obtain a light yellow solid. Yield 79%; HPLC (60/40) 4,47 minutes (95%) TPMC 382/384 (MH+, 100%).

1H NMR (DMSO-d6) 11,82 (s, 1H), cent to 8.85 (t, 1H, J=7 Hz), 7,73 (d, 1H, J=2 Hz), the 7.43 (d, 1H, J=8,8 Hz), 7,18 (DD, 1H, J=8,8,2 Hz), 7,17 (s, 1H), 5,44 (s, 1H), 4.25 in 50,33; H, 4,22; N, 11,00.

Found: C, 50,56; H, To 4.46; N, 10,89.

Example 99.

()-3-{ [(5-Chloro-1H-indole-2-carbonyl)-amino] -acetyl}- thiazolidin-2-carboxylic acid

A solution of 3-{[(5-chloro-1H-indole-2-carbonyl)-amino]-acetyl}- thiazolidin-2-carboxylic acid methyl ester (196 mg, 0.5 mmole) in methanol (10 ml) was treated with aqueous 1N NaOH (0.5 ml) at 25oC. After 3 hours, was added 1N NaOH (0.25 ml). The mixture was stirred at 25oC overnight, concentrated, the residue was mixed with ethyl acetate (30 ml) and 1N HCl (5 ml) and the resulting mixture is acidified to a pH of 1.8 aqueous 6N HCl. The aqueous layer was separated and was extracted with ethyl acetate. The organic layers were combined, dried and concentrated to obtain solid, which is triturated with ether-hexane 1:1 and dried. Exit 186 mg, 99%; HPLC (60/40) 3,13 minutes (98%); TRMS 368/370 (MH+), 70%) , 339 (100%).

1H NMR (DMSO-d6) 11,80 (s, 1H), 8,84 (W, 1H), 7.23 percent (s, 1H), 7,44 (d, 1H, J=8,8 Hz), 7,18 (DD, 1H), 7,17 (s, 2H), 4,32 (s, 1H), 4,25 (m, 2H), 4,0 (m, 2H), 3,3 (m, 2H).

Example 99a.

()-Thiazolidin-2-carboxylic acid methyl ester

A mixture of ()-thiazolidin-2-carboxylic acid (1,58 g, 11.9 mmole) and chlorotrimethylsilane (5,1 g, 47 mmol) in methanol (22 ml) was heated in a flask under reflux for 5 hours, Oh the Teal-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3 - phenyl-propionate

Procedure B

To a solution of 5-chloro-1H-indole-2-carboxylic acid (0.50 g, 2.6 mmole), L-phenylalanine tert-butyl ester hydrochloride (0.66 g, 2.6 mmole), triethylamine (of 0.36 ml, 2.6 mmole) and 4-dimethylaminopyridine (0.16 g, 1.3 mmole) in dichloromethane (20 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.73 g, 3.8 mmole). The mixture was stirred at room temperature overnight, diluted with chloroform, washed with 2N HCl, water and brine, dried over magnesium sulfate and concentrated. The product was purified by thin layer chromatography (30% acetone in hexano) and was obtained as a pale yellow foam (0,86 g, 85%).

Anal., est.: C, 66,25; H, OF 5.81, N, 7.03 IS;

Found: C, 66,57; H, 6,11, N, 6,86.

The following examples of compounds (101-122) were obtained using methods similar to procedure B.

Example 101.

R-Methyl-2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionate

From 5-fluoro-1H-indole-2-carboxylic acid and D-phenylalanine methyl ester.

1H NMR (300 MHz, CDCl3) 3,22 (m, 2H), 3,80 (s, 3H), 5,10 (m, 1H), 6,62 (d, 6 Hz, 1H), 6.75 in (d, 2 Hz, 1H), 7,05 (d, 2 Hz, 8 Hz, 1H), 7,10-to 7.15 (m, 2H), 7,25-7,40 (m, 4H), 7,73 (d, 2.1 Hz, 1H), 9,50 (W, 1H).

Example 102.

R-Methyl-2-[(5-7-dichloro-1H-indole-2-carbonyl)-amino]-3 - phenyl-propio(300 MHz, CDC13) of 3.25 (m, 2H), 3,80-of 3.95 (s, 3H), 5,10 (m, 1H), 6,62 (d, 6 Hz, 1H), 6,69 (d, 2 Hz, 1H), 7,10-to 7.15 (m, 2H), 7,25-7,35 (m, 3H), 7,50-7,56 (s, 1H), 9,35 (W, 1H).

Example 102A.

5,7-Dichloro-1H-indole-2-carboxylic acid

A. Ethyl-2-oxopropionate-2,4-dichloropyridazin

A mixture of 2,4-dichloropyridazine (1.0 g, 4.7 mmole), atilirovanie (of 0.53 ml, 4.7 mmole), triethylamine (of 0.65 ml, 4.7 mmole) and ethanol (5 ml) was heated in a flask with reflux during the night. The solvent is evaporated and the residue was collected in chloroform. The solution was washed with water and brine and dried over magnesium sulfate and concentrated, to obtain the remainder in the form of oil (1.1 g, 98%).

B. Ethyl-5,7-dichloro-1H-indole-2-carboxylate

A solution of ethyl-2-oxopropionate-2,4-dichloropyridazine (1.1 g, 4.6 mmole) and anhydrous zinc chloride (10 g, 74 mmole) in glacial acetic acid (12 ml) was heated in a flask under reflux for 1/2 hour. The reaction mixture was poured into water and was extracted twice with ether. The combined organic layers were washed with water and brine, dried with magnesium sulfate and concentrated. The product was purified by thin layer chromatography (30% ethyl acetate in hexano) and received in the form of oil (0,80 g, 67%).

C. 5,7-Dichloro-1H-indole-2-carbon the Wali in the flask under reflux for 3 hours. The methanol was removed under vacuum and the aqueous residue was acidified using 1N HCl and was extracted twice with chloroform. The combined extracts were washed with water and brine, dried with magnesium sulfate and concentrated to education solids (0,58 g, 76%).

The following indole-carboxylic acid were obtained using the same sequence: 4-chloro-5-fluoro-1H-indole-2-carboxylic acid and 6-chloro-5-fluoro-1H-indole-2-carboxylic acid (mixture) of 3-chloro-4-forfamilies; 5,7-debtor-1H-indole-2-carboxylic acid of 2,4-dipohenhydramine.

Example 103.

(A)-ethyl-2-[(5-chloro-1H-indole-2-carbonyl-amino]-3 - phenylpropionate

From 5-chloro-1H-indole-2-carboxylic acid and D,L-phenylalanine ethyl ester. So pl. 146-147oC.

Anal. Est.: C 64,61, H 5,42; N 7,54.

Found: C 64,73, H 5,26, N EUR 7.57.

Example 104.

From 3-bromo-5-chloro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenylethyl)-amide

From 3-bromo-5-chloro-1H-indole-2-carboxylic acid and S-2-amino-N,N-dimethyl-3-phenylpropionamide.

Anal.Est.: C 53,53; H 4,27; N 9,36.

Found: C 53,51, H 4,46, N 9,38.

Example a.

3-Bromo-5-chloro-1H-indole-2-carboxylic acid

To a solution of 5-chloro-1H-indole-2-carbon is (16 ml). After 20 minutes the mixture was poured into water and was extracted twice with chloroform. The combined extracts were twice washed with water and brine, dried with magnesium sulfate and concentrated. The product was obtained as a solid (2.5 g, 89%).

Example 104.

(S)-2-Amino-N,N-dimethyl-3-phenylpropionamide hydrochloride

A. (S)-(1-Dimethylcarbamoyl-2-phenylethyl)-carbamino acid tert-butyl ether

To a solution of tert-Boc-phenylalanine (10 g, 38 mmol), dimethylamine hydrochloride (3.4 g, 41 mmol), triethylamine (5.8 ml, 42 mmole), and hydroxybenzotriazole (6.6 g, 49 mmol) in dichloromethane (300 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (9.4 g, 49 mmol). The mixture was stirred over night, then extinguished 2N HCl and concentrated. The residue was collected in ethyl acetate and this solution was washed with water and brine, dried with magnesium sulfate and concentrated. The residue is triturated with chloroform, the solid was filtered and the filtrate was concentrated to an oil (11 g, 100%).

B. (S)-2-Amino-N,N-dimethyl-3-phenylpropionamide hydrochloride

(S)-(1-Dimethylcarbamoyl-2-phenylethyl)-carbamino acid tert-butyl ether (11,0 g, 38 mmol) was dissolved in ethyl acetate (125 ml) and the solution was passed gaseous HCl is OK triturated with ether, the solid was filtered and dried under high vacuum (8.6 g, 100%).

Example 105.

S-5-Chloro-4-nitro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenylethyl)-amide

From 4-nitro-5-chloro-1H-indole-2-carboxylic acid and N-2-amino-N,N-dimethyl-3-phenylpropionamide.

1H NMR (300 MHz, CDCl3) to 2.75 (s, 3H), of 2.97 (s, 3H), 3,20 (m, 2H), and 5.30 (m, 1H), 7,07 (d, 2 Hz, 1H), 7.24 to to 7.32 (m, 5H), 7,40 (d, 7 Hz, 1H), 8,12 (W, d, 7 Hz, 1H), 9,85 (W, 1H).

Example 105A.

4-Nitro-5-chloro-1H-indole-2-carboxylic acid

A. 2-[(4-Chloro-3-nitrophenyl)-hydrazono]-propionic acid ethyl ester

To a solution of sodium nitrite (2.17 g, 31 mmol) in water (60 ml) and conc. HCl (12 ml) at 0oC was added 4-chloro-3-nitroaniline (5.0 g, 29 mmol). After 5 minutes the solution was added ethylethylenediamine (4,5 ml, 29 mmol) in water (60 ml), ethanol (30 ml) and 50% potassium hydroxide (10 ml) and the reaction mixture was stirred over night. The precipitate was collected (7.0 g, 91%).

B. Ethyl-5-chloro-4-nitro-1H-indole-2-carboxylate

A mixture of 2-[(4-chloro-3-nitrophenyl)-hydrazono]-propionic acid ethyl ester (2.0 g, 6.7 mmole) and polyphosphoric acid (7 g) was heated to 90-110oC for 2 hours. The mixture was cooled, poured into a mixture of ice/water and the solid collected. Thin-layer chrom,31 g, 17%).

C. 4-Nitro-5-chloro-1H-indole-2-carboxylic acid

The connection header was obtained by hydrolysis of the ethyl-5-chloro-4-nitro-1H-indole-2-carboxylate, as described to obtain 5,7-dichloro-1H-indole-2-carboxylic acid.

Example 106.

S-7-Nitro-1H-indole-carboxylic acid (1-dimethyl-carbarnoyl-2-phenylethyl)-amide

From 7-nitro-1H-indole-2-carboxylic acid and N-2-amino-N,N-dimethyl-3-phenylpropionamide.

1H NMR of 2.8 (s, 3H), 3.0 a (s, 3H), 3,1-3,3 (m, 2H), 5,35 (kV, 7 Hz, 1H), 6,95 (s, 1H), 7,15-to 7.3 (m, 6N), and 7.9 (d, 8 Hz, 1H), and 8.2 (d, 8 Hz, 1H) , 10,3 (W, 1H).

Example 107.

()-Methyl-2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3 - phenyl-butyrate

From 5-chloro-1H-indole-2-carboxylic acid and DL-in-methylphenylamine methyl ester.

So pl. 135-136oC.

Anal. Est.: C 64,78, H 5,17, N 7,56;

Found: C 64,76, H, 5,26, N Of 7.64.

Example 108.

()-5-Chloro-1H-indole-2-carboxylic acid [1-(2-terbisil)-2-oxo-2-thiazolidin-3-ileti]-amide

From 5-chloro-1H-indole-2-carboxylic acid and ()-2-amino-3-(2-forfinal)-1-thiazolidin-3-improper-1-it.

So pl. 216-217oC.

Anal. Est.: C 58,40, H 4,43, N 9,73.

Found: C 58,45, H 4,53, N 9,71.

Example 108A.

()-2-Amino-3-(2-forfinal)-1-thiazolidin-3-yl) - Rev. DL-3-pertanyaannya (1.0 g, 5.5 mmole) and triethylamine (1,14 ml, 8.2 mmole) in dichloromethane (20 ml) was added di-tert-butyl-dicarbonate (1.4 g, 6,55 mmole). The mixture was stirred at room temperature overnight, then poured into water, acidified using 1N HCl and was extracted with chloroform

The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The product was purified by thin layer chromatography (chloroform/methanol/acetic acid, 89: 10:1) and obtained as a solid (1.28 g, 83%, so pl. 118-119oC).

B. ()-[1-(2-Terbisil)-2-oxo-2-thiazolidin-3-ileti] carbamino acid tert-butyl ether

To a mixture of 2-tert-butoxycarbonylamino-3-(2-forfinal)propionic acid (0.50 g, 1.77 in mmole), thiazolidine (0.15 ml, of 1.94 mmole) and 4-dimethylaminopyridine (0.21 g, or 1.77 mmole) in dichloromethane (15 ml) was added ejh (0,44 g, 2,31 mmole). The reaction mixture was stirred at room temperature overnight, diluted with chloroform, washed with 2N HCl, water and brine, dried with magnesium sulfate and concentrated. The product was purified by thin layer chromatography (30% acetone in hexano) and obtained as a colourless solid (0.39 g, 62%, so pl. 133-134oC).

C. ()-2-Amino-3-(2-forfinal)-1-thiazol the-3-ileti] -carbamino acid tert-butyl ester (0.39 g, 1.1 mmole) in ethyl acetate (15 ml). The solution was concentrated, the residue is triturated with ether, the solid was filtered and dried (0.27 g, 84%, so pl. 217-218oC).

The following amines were obtained similar methods and in the same sequence:

()-2-amino-3-(2-chlorophenyl)-1-thiazolidin-3-improper-1-he's from DL-2-chlorophenylalanine,

()-2-amino-3-(3-cyanophenyl)-1-thiazolidin-3-improper-1-he's from DL-3-cyanopyrrolidine,

()-2-amino-3-(3-chlorophenyl)-1-thiazolidin-3-improper-1-he's from DL-3-chlorophenylalanine,

()-2-amino-3-(3-triptoreline)-1-thiazolidin-3-improper - 1-he's from DL-3-cryptomaterial,

(S)-2-amino-1-(4-hydroxypiperidine-1-yl)-3-(4-methoxyphenyl)- propane-1-he L-4-methoxyphenylalanine.

Example 109.

()-5-Chloro-1H-indole-2-carboxylic acid [1-(2-Chlorobenzyl)- 2-oxo-2-thiazolidin-3-ileti]-amide

From 5-Chloro-1H-indole-2-carboxylic acid and ()-2-amino-3-(2-chlorophenyl)-1-thiazolidin-3-improper-1-it.

So pl. 214-216oC.

Anal. Est.: C 56.26 VERTICAL, H 4,58, N 9,37.

Found: C 56,27, H Of 4.54, N 9,36.

Example 110.

()-5-Chloro-1H-indole-2-carboxylic acid [2-(3-cyanophenyl)-1-(thiazolidin-3-carbonyl)-ethyl]-amide

From 5-Chloro-1H-indole-2-carboxylic acid and ()-2-amino-3- (3-cyanophenyl)-1-thiazoline: C 60,11, H 4,84, N 12,43.

Example 111.

()-5-Chloro-1H-indole-2-carboxylic acid [1-(3-Chlorobenzyl) 2-oxo-2-thiazolidin-3-ileti]-amide

From 5-chloro-1H-indole-2-carboxylic acid and ()-2-amino-3-(3-chlorophenyl)-1-thiazolidin-3-improper-1-it.

So pl. 188-190oC.

Anal. Est.: C 56.26 VERTICAL, H 4,27, N 9,37.

Found: C 56,38, H 5,04, N 9,04.

Example 112.

()-5-Chloro-1H-indole-2-carboxylic acid [2-oxo-2-thiazolidin-3-yl-1-(3-trifloromethyl)-ethyl]-amide

From 5-chloro-1H-indole-2-carboxylic acid and ()-2-amino-3-(3-triptoreline)-1-thiazolidin-3-improper-1-it.

So pl. 205-207oC.

Anal.Est.: C 54,83, H 3,97, N 8,72.

Found: C 54,44, H 4,14, N 8,88.

Example 113.

S-5-Chloro-1H-indole-2-carboxylic acid [1-(4-methoxybenzyl)-2-oxo-2-thiazolidin-3-ileti]-amide

From 5-chloro-1H-indole-2-carboxylic acid and S-2-amino-3-(4-methoxyphenyl)-1-thiazolidin-3-improper-1-it.

Anal.Est.: C, 59,52, H 5,00, N FOR 9.47.

Found: C 60,00, H 5,55, N 8,90.

Mass spectrum m/e 444 (M++1).

Example 114.

()-5-Chloro-1H-indole-2-carboxylic acid [1-(3-Chlorobenzyl)-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide

From 5-chloro-1H-indole-2-carboxylic acid and ()-2-amino-1-(4-hydroxyprop-benzyl-2-oxo-2-thiazolidin-3-retil)-amide and S-6-chloro-4-fluoro-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-thiazolidin-3-retil)-amide

From a mixture of 5-chloro-4-fluoro-1H-indole-2-carboxylic acid and 6-chloro-4-fluoro-1H-indole-2-carboxylic acid and 5-2-amino-3-phenyl-1-thiazolidin-3-improper-1-it.

So pl. 105-125oC, decomp.

Anal.calculations: C 58,40, H 4,43, N 9,73.

Found: C 58,54, H 4,59, N 9,58.

Example 116.

(+)-2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-propionic acid methyl ester

From 5-chloro-1H-indole-2-carboxylic acid hydrochloride of methyl bromide and DL-alanine.

So pl. 199-201oC.

Anal.raschet. : C 55,63, H 4,67, N 9,98.

Found: C 55,70, H 4,75, N 10,06.

Example 117.

()-2-[(5-Chloro-1H-indole-2-carbonyl)-amino] -3-[4-(4,5- dihydro-1H-imidazol-2-yl)-phenyl]-propionic acid methyl ester

From 5-chloro-1H-indole-2-carboxylic acid and ()-2-amino-3-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-propionic acid methyl ester.

1H NMR (300 MHz, CDC13,) 3,1-3,3 (m, 2H), 3,70 (s, 3H), of 3.95 (s, 4H), around 4.85 (m, 1H), 7,15 (s, 1H), 7,17 (d, 8 Hz, 1H), 7,40 (d, 8 Hz, 1H), 7,65 (d, 7 Hz, 1H), of 7.75 (s, 1H), 7,88 (d, 8 Hz, 1H), 9,10 (W, d, 9 Hz, 1H), the 10.5 (s, 1H), 11.8 in (W, s, 1H).

Example 117a.

()-2-Amino-2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl] - propionic acid methyl ester

A. 2-Acetylamino-2-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzyl]- Malon what you diethyl ether (G. Wagner et al. Pharmazia 1994, 29, 12) (5,3 g, 13 mmol) and Ethylenediamine (4.8 g, 80 mmol) in ethanol (100 ml) was stirred at 60oC for 5 hours. After cooling, the solvent evaporated, to the residue was added water and the solid was filtered and dissolved in hot hydrochloric acid (1N HCl. After cooling, the residue was filtered and dried (3.1 g).

B. ()-2-Amino-3-[4-(4,5-dihydro-1H-imidazol-2-yl)- phenyl]-propionic acid dihydrochloride

2-acetylamino-2-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzyl] - malonic acid diethyl ether (3.0 g, 7.3 mmole) was added glacial acetic acid (50 ml) and 3N HCl (100 ml).

The solution was heated in a flask under reflux for 3 hours, cooled and concentrated before the formation of white solid, which was recrystallized from methanol/ether (2.0 g, so pl. 270-272oC, decomp).

C. ()-2-Amino-3-[4-(4,5-dihydro-1H-imidazol-2-yl)- phenyl]-propionic acid methyl ester

()-2-Amino-3-[4-(4,5-dihydro-1H-imidazol-2-yl)- phenyl]-propionic acid dihydrochloride (0.50 g, 1.6 mmole) were placed in thionyl chloride (1 ml) and methanol (25 ml). The mixture was heated in a flask under reflux for 30 minutes, after this term was added thionyl chloride (3 ml) and methanol (75 ml). After another 3 hours of heating and to cause the deposition, was added ethyl acetate. The solid was collected and dried (0.40 g, so pl. 230oC, decomp.).

Example 118.

(S)-5,7-Debtor-1H-indole-2-carboxylic acid [1-benzyl-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl]-amide

From 5,7-debtor-1H-indole-2-carboxylic acid and (S)-2-amino-1-(4-hydroxypiperidine-1-yl)-3-phenylpropane-1-it.

So pl. 95-110oC.

Example 119.

S-4-chloro-5-fluoro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenylethyl)-amide and S-6-chloro-5-fluoro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenylethyl)-amide

From a mixture of 5-chloro-4-fluoro-1H-indole-2-karbonovoi acid and 6-chloro-4-fluoro-1H-indole-2-carboxylic acid and (S)-2-amino-N,N - dimethyl-3-phenylpropionamide.

So pl. 200-210oC.

Anal.Calculation.: C 61,94, H 4,94, N 10,83.

Found: C 62,21, H 4,99, N 10,84.

Example 120.

(S)-5,7-Debtor-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-thiazolidin-3-retil)-amide

From 5,7-debtor-1H-indole-2-carboxylic acid and (S)-2-amino-3-phenyl-1-thiazolidin-3-improper-1-it.

So pl.: 175-185oC.

Anal.Raschet. : C 60,71, H BR4.61, N 10,11.

Found: C 60,79, H 4,66, N To 9.93.

Example 121

(S)-5,7-debtor-1H-indole-2-carboxylic acid [1-1- (1,1-dioxo-1 thiazolidin-3-yl)-3-phenylpropane-1-she hydrochloride.

So pl. 95-110oC.

MC 448 (MH+).

Example 122.

S-5-Chloro-1H-indole-2-carboxylic acid [1-(2-terbisil)- 2-(4-hydroxypiperidine-1-yl)-2-oxoethyl-amide

Procedure C

To a solution of 5-chloro-1H-indole-2-carboxylic acid (0,49 g, 2.5 mmole), S-2-amino-3-(2-forfinal)-1-(4-hydroxypiperidine-1-yl)- propane-1-it (0,76 g, 2.5 mmole), triethylamine (0.35 ml, 2.5 mmole), and hydroxybenzotriazole (0.34 g, 2.5 mmole) in dichloromethane (6 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,53 g, 2.8 mmole). The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with water, 1N HCl and saturated sodium bicarbonate, dried over magnesium sulfate and concentrated. The product was purified by thin layer chromatography (chloroform/methanol, 8:1) and received in the form of not-quite-white solid (0,82 g, 73%). So pl. 120-122oC.

Example a.

(S)-2-Amino-3-(2-forfinal)-1-(4-hydroxypiperidine-1-yl)- propane-1-she hydrochloride

A. (S)-tert-Butoxycarbonylamino-3-(2-forfinal)-1-thiazolidin-3-yl-propane-1-he

From L-Boc-2-pertanyaannya and 4-hydroxypiperidine using a method similar to the procedure C.

B. (S)-2-Amino-3-(2-forfinal)-1-(4-hydroxypiperidine-1-yl) propane-1-she hydrohalides-3-yl-propane-1-one with HCl according to the method, similar to that described in example 108A, stage C.

The following amines were obtained using similar methods in the same sequence:

S-2-amino-3-(4-methoxyphenyl)-1-thiazolidin-3-improper-1-it;

S-2-amino-3-(2-forfinal)-1-(4-hydroxypiperidine-1-yl)-propane-1-he,

S-2-amino-1-(4-hydroxypiperidine-1-yl)-3-(4-methoxyphenyl)- propane-1-he,

S-2-amino-3-(2-chlorophenyl)-1-(4-hydroxypiperidine-1-yl)- propane-1-he,

S - 2-amino-3-(4-methoxyphenyl)-1-morpholine-4-yl-propane-1-he,

S-2-amino-3-(4-methoxyphenyl)-1-(4-acetylpiperidine)-propane-1-on.

Using a process analogous to process (C) provided the following examples of compounds (122-138).

Example 123.

(2SR), (3RS)-2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3 - hydroxy-3-phenylpropionic acid methyl ester

From 5-chloro-1H-indole-2-carboxylic acid and ()- tert-b-phenylseleno methyl ester.

So pl. 196-197oC.

Example 124.

S-5-fluoro-1H-indole-2-carboxylic acid [1-(4-methoxybenzyl) 2-oxo-2-thiazolidin-3-ileti]amide

From 5-fluoro-1H-indole-2-carboxylic acid and S-2-amino-3-(4 - methoxyphenyl)-1-thiazolidin-3-improper-1-it.

So pl. 90-115oC.

Anal.They have been designed.: C 61,81, H 5,19, N 9,83.

The detection is hydroxypiperidine-1-yl)-2-oxoethyl]-amide

From 5-chloro-1H-indole-2-carboxylic acid and S-2-amino-3-(2 - chlorophenyl)-1-(4-hydroxypiperidine-1-yl)-propane-1-it.

So pl. 127-129oC.

Example 126.

S-5-Chloro-1H-indole-2-carboxylic acid [1-(4-methoxybenzyl)- 2-morpholine-4-yl-2-oxoethyl]-amide

From 5-chloro-1H-indole-2-carboxylic acid S-2-amino-3-(4 - methoxyphenyl)-1-morpholine-4-improper-1-it.

So pl. 95-105oC.

Anal.raschet. : C 62,51, H 5,47, N 9,51.

Found: C 61,82, H 6,05, N 8,97.

Example 127.

S-5-Chloro-1H-indole-2-carboxylic acid [2-(4-acetylpiperidine - 1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-amide

From 5-chloro-1H-indole-2-carboxylic acid and S-2-amino-3-(4-methoxyphenyl)-1-(4-acetylpiperidine)-propane-1-it.

So pl. 120-135oC.

Anal. Raschet.: C 62,17, H 5,64, N 11,60.

Found: C 62,76, H 6,20, N 10,44.

Example 128.

S-5-fluoro-1H-indole-2-carboxylic acid [1-(benzothiazol-2 Il-carbarnoyl)-2-phenylethyl]-amide

From S-2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenylpropionic acid and 2-amino-1,3-benzothiazole.

So pl. 139-141oC.

Example 129.

S-5-fluoro-1H-indole-2-carboxylic acid (1-benzyl-2-morpholine-4-yl-2-oxoethyl)-amide

From S-2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-f is indole-2-carboxylic acid [1S-benzyl-2-oxo-2- (3,3,5 RS-trimethylation-1-yl)-ethyl]-amide

From 2-[(5-fluoro-1H-indole-2-carbonyl)-amino] -3-phenylpropionic acid and ()-3,3,5-trimethylation.

So pl. 125-127oC.

Anal.raschet.: C 72,14, H 7,18, N 9,35.

Found: C 72,00, H 7,58, N 9,10.

Example 131.

5-fluoro-1H-indole-2-carboxylic acid [1S-benzyl-2-(3RS - carbamoylbiphenyl-1-yl)-2-oxoethyl]-amide

From S-2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenylpropionic acid and 3-carbamoylbiphenyl.

So pl. 234-236oC.

Example 132.

5-fluoro-1H-indole-2-carboxylic acid [2-phenyl-1S- (thiochroman-4RS-ylcarbonyl)-ethyl]-amide

From S-2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenylpropionic acid and ()-thiochroman-4-ylamine.

So pl. 225-226oC.

Anal.the expect.: C 68,48, H 5,11, N 8,88.

Found: C 68,40, H 5,64, N 8,61.

Example 133.

S-5-fluoro-1H-indole-2-carboxylic acid [1-(5-methyl-isoxazol-3 - ylcarbonyl)-2-phenylethyl]-amide

From S-2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenylpropionic acid and 5-methylisoxazol-3-ylamine.

So pl. 219-221oC.

Example 134.

S-5-fluoro-1H-indole-2-carboxylic acid [2-phenyl-1-(4,5,6,7-tetrahydroindazole-2-ylcarbonyl)-ethyl]-amide

From S-2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenyl.

S-5-fluoro-1H-indole-2-carboxylic acid [1-(5-methylthiazole 2-ylcarbonyl)-2-phenylethyl]-amide

From S-2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenylpropionic acid and 4-methylthiazole-2-ylamine.

So pl. 211-213oC.

Example 136.

S-5-Methyl-1H-indole-2-carboxylic acid [1-(5-methylisoxazol - 3-ylcarbonyl)-2-phenylethyl]-amide

From S-2[(5-methyl-1H-indole-2-carbonyl)-amino]-3-phenylpropionic acid and 5-methyl-isoxazol-3-ylamine.

So pl. 243-245oC.

Anal.raschet.: C 68,64, H 5,51, N 13,93.

Found: C 68,29, H Of 5.81, N 14,05.

Example 137.

S-5-Methyl-1H-indole-2-carboxylic acid [2-(4-acetylpiperidine - 1-yl)-1-benzyl-2-oxoethyl]-amide

From S-2-[(5-methyl-1H-indole-2-carbonyl)-amino]-3-phenylpropionic acid and 1-piperazine-1-ratanana.

So pl. 221-223oC.

Example 138.

S-5-Chloro-1H-indole-2-carboxylic acid (1-carbarnoyl-2-phenylethyl)-amide

From 5-chloro-1H-indolocarbazoles acid and S-2-amino-3-phenylpropionamide.

So pl. 257-258oC.

Example 139 and 140.

(2RS)-2,3-Dihydro-1H-indole-2-carboxylic acid

(R-1-dimethylcarbamoyl-2-phenylethyl)-amide

To a mixture of DL-indolin-2-carboxylic acid (0,38 g, 2.3 mmole), (R)-2-amino-N, N-dimethyl-3-phenyl) in dichloromethane (5 ml) was added ejh (EDC) (0.64 g, 2.7 mmole). The solution was stirred overnight, diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and concentrated. Two isomeric product was separated using thin-layer chromatography (EtOAc, then EtOAc/MeOH, 20:1).

Example 139.

The less polar isomer (oil, 0,23 g, 30%):

1H NMR (300 MHz, CDCl3) of 2.68 (s, 3H), 2,87 (s, 3H), 3,02-to 3.09 (m, 3H), 3,55 (DD, J=10 Hz, 6 Hz, 1H), br4.61 (m, 1H), 5,10 (kV, J=8 Hz, 1H), 6,95 (d, J=8 Hz, 1H), 7,11-7,30 (m, 8H), 8,12 (W, 1H). MS (Cl, NH3), 394 (M++17).

Example 140.

The more polar isomer (0.11 g, 14%): so pl. 136-140oC.

Examples 141 and 142.

(2RS)-5-Chloro-2,3-dihydro-1H-indole-2-carboxylic acid (1-S-dimethylcarbamoyl-2-phenylethyl)-amide

To a solution of S-5-chloro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenylethyl)-amide (2,60 g, 7.0 mmol) in THF (20 ml) and methanol (20 ml) was added magnesium (1.75 g, 73 mmole) in portions with such a rate as to maintain the course of the reaction without excessive heat. After the reaction had ceased, the reaction mixture was concentrated to a small volume, the residue was divided between 1N HCl and ethyl acetate, the combined an ethyl acetate layers were washed with water and brine, dried over magnesium sulfate and

Example 141.

Less polar isomer:

1H NMR (300 MHz, CDCl3) 2,61 (s, 3H), and 2.83 (s, 3H), 3,00-3,02 (m, 3H), 3,47 (DD, J= 9.9 Hz, 6.4 Hz, 1H), 4,43 (m, 1H), 5,10 (kV, J=7.5 Hz, 1H), only 6.64 (d, J=8,8 Hz, 1H), 7,00 (s, 1H), 7,16-7,29 (m, 7H), 7,70 (W, 1H). MS (Cl, NH3) 372 (M++1).

Example 142.

More polar isomer: so pl. 125oC, decomp.

Examples 143 and 144.

2RS-5-chloro-2,3-dihydro-1H-indole-2-carboxylic acid (1R-dimethylcarbamoyl-2-phenylethyl)-amide

Using a method similar to the method of example 141 and 142 using R-5-chloro-1H-indole-2-carboxylic acid (1-dimethylcarbamoyl-2-phenylethyl)-amide were obtained two diastereoisomer.

Example 143.

Less polar isomer: so pl. 122-124oC, decomp.

Example 144.

More polar isomer:

1H NMR (300 MHz, CDCl3) 2,70 (s, 3H), and 2.83 (s, 3H), 2.77-to of 2.97 (m, 3H), 3,40 (DD, J= 16,6 Hz, 10.8 Hz, 1H), 4,28 (m, 1H), and 4.40 (d, J=5,2 Hz, 1H), 5,12 (kV, J= 7.8 Hz, 1H), 6,56 (d, J=9.0 Hz, 1H), of 6.96 (d, J=7.8 Hz, 1H), 6,99 (s, 1H), 7,03-7,07 (m, 2H), 7,11-to 7.18 (m, 3H), 7,74 (d, J=8,8 Hz, 1H).

Example 145.

3-Chloro-1H-indole-2-carboxylic acid (1R-dimethylcarbamoyl - 2-phenylethyl)-amide

To a solution of 2,3-dihydro-1H-indole-2-carboxylic acid (1R-dimethylcarbamoyl-2-phenylethyl)-amide (less polar isomer, 0.50 g, of 1.42 mmol shall Rivoli and the product was purified by thin layer chromatography (hexane/ethyl acetate, 1:1).

1H NMR (300 MHz, CDCl3) to 2.55 (s, 3H), 2,80 (s, 3H), 3,05-3,20 (m, 2H), 5,32 (m, 1H), 7,10-7,25 (m, 6N), 7,30 (d, 7 Hz, 1H), 7,58 (d, 7 Hz, 1H), 8,11 (W, d, 7 Hz, 1H), 10,20 (W, 1H). MS m/e 370 (M++1).

Example 146.

3-Chloro-1H-indole-2-carboxylic acid (1S-dimethylcarbamoyl 2-phenylethyl)-amide

The compound of the title was obtained by the method similar to the method of example 145 of the more polar isomer of 2,3-dihydro-1H-indole-2-carboxylic acid (1R-dimethylcarbamoyl-2-phenylethyl)-amide.

1H NMR (300 MHz, CDCl3,) to 2.55 (s, 3H), 2,85 (s, 3H), 3,05-3,20 (m, 2H), 5,32 (m, 1H), 7,10-7,25 (m, 6N), 7,35 (d, 7 Hz, 1H), 7,58 (d, 7 Hz, 1H), 8,11 (width d, 7 Hz, 1H), 10.30 a.m. (W, 1H).

MS m/e 370 (M++1).

Conditions of HPLC for sample 147-165: detection wavelength of 215 nm. Retention time in HPLC (in minutes) for column Water's Novapac C18, 3.9 x 150 mm, Eluent A= 50 mm KH2PO3pH 3; eluent B = acetonitrile; flow rate 1.5 ml/min; gradient to 90% A/10% B (5 min) to 40% A/60% B (5 min delay). Retention time at HPLC (RT) are presented in minutes. The percentage value is given in percent of the total of the whole, in connection with a specific peak. By HPLC the original acid is present in amount of less than 5% of the total of the whole, unless otherwise indicated.

Example 147.

(S)-2-[(5-PTO mmol), L-phenylalanine t-butyl ester hydrochloride (6,54 g of 27.9 mmole) and methylene chloride (250 ml) was added 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride (5.53 g of 27.9 mmole) and triethylamine (7,1 ml, 5,13 g, 51 mmol). After stirring for 40 hours at room temperature the reaction mixture was washed with equal volumes of water and then an equal volume of 1N HCl. The aqueous acid solution was extracted with methylene chloride and the combined organic layers are then washed with equal volumes of water (twice) and brine. The organic solution was dried (MgSO4), filtered and concentrated to obtain S-t-butyl-2-[(5-fluoro-1H-indole-2-carbonyl)-amino] -3-phenylpropionate (2,97 g, 31%). It was then diluted with methylene chloride (75 ml) and cooled to 0oC. was Added triperoxonane acid (8 ml) and the reaction mixture was then stirred at room temperature for 2 days and then was heated in a flask under reflux for 6.5 hours. Then the mixture was allowed to reach room temperature overnight and the solution was concentrated to dryness to obtain a brown solid. This substance is then dissolved in a small amount of ether and pentane, filtered to remove particles and concentrated on the floor with the PMC-ion (expected) 327(326);

1H NMR (CDCl3) 9,0 (W, s, 2H), and 7.4 to 7.2 (m, 6N), 7,02 (dt, J=2,4,9,1 Hz, 1H), 6,80 (d, J=7.7 Hz, 1H), 6.75 in (d, J=1.6 Hz, 1H), 5,09 (kV, J=7,6 Hz, 1H), 3,35 (DD, J=5,8 and 7.6 Hz, 1H), 3,26 (DD, J=5,8 and 7.6 Hz, 1H).

Example 148.

(S)-2-[(5-Methyl-1H-indole-2-carbonyl)-amino)-3-phenylpropionate acid

Repeat the above procedure with 5-methylindol-2-carboxylic acid (3.0 g, 17 mmol), methylene chloride (185 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.28 g, 17.1 mmole), L-phenylalanine t-butyl ester hydrochloride (4,01 g, 15.6 mmole) and triethylamine (4.5 ml, of 3.31 g, 32.7 mmole) gave similar butyl ether (2,42 g, 41%). After dilution with methylene chloride (60 ml) and triperoxonane acid (6.6 ml) the reaction mixture was heated in a flask under reflux for 3 hours, allowed to reach room temperature overnight and concentrated. Product raw suspended in ethyl acetate, filtered to remove insoluble material and concentrated (twice) to obtain the compound of the title in the form of a brown foam (2,54 g, quantitative yield).

HPLC RT 5,98; TRMS-ion (expected) 323(322);

1H NMR (CDCl3) 9,9 (W, s, 1H), 8,5 (W,s, 2H), 7,38 (s, 1H), and 7.3, and 7.1 (m, 6N), 6,77 (m, 2H), 5,09 (kV, J=7,6 Hz, 1H), 3,35 (DD, J=5,6, and 7.6 Hz, 1H), 3,26 (DD, J=5,6, 7.6 G is etilcarbitol]-2-phenylethyl]-amide

To 5,0 to McMoRan 2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3 - phenylpropionic acid (50 μl of a 0.1 mm solution in dimethylformamide) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 μl of 0.11 mm solution in DMF), 5.5 mmol) followed by addition of 5-methoxytryptamine (50 μl of 0.11 mm solution in DMF), 5.5 mmol). The reaction mixture which was for 3 days and then concentrated to dryness. Product raw divided between chloroform (0.5 ml) and water (0.25 ml) and the organic layer was then concentrated to obtain the compound of the title.

TRMS ion (expected) 499(499); HPLC RT 6,78 (25%).

In the following examples compounds are obtained analogously to example 149, in the examples 150-156 used 2-[(5-fluoro-1H-indole-2-carbonyl)-amino] -3-phenylpropionate acid and examples 157-163 used 2-[(5-methyl-1H-indole-2-carbonyl)-amino]- 3-phenylpropionate acid.

Example 150.

5-fluoro-1H-indole-2-carboxylic acid {1-[2-(1H-indol-3-yl)-1 - methylethylketon]-2-phenylethyl}-amide

TRMS-ion (expected) 482 (483); HPLC RT is unknown, there were a few small peaks; Hon. the purity of < 10%; % SM (HPLC) not ODA.

Example 151.

5-fluoro-1H-indole-2-carboxylic acid [1-benzyl-2-(2 - ethylpiperidine-1-yl)-2-arbonboy acid (1-cyclohexylcarbonyl-2-phenyl)-amide

TRMS-ion (expected) 408 (407); HPLC RT 6,60/7,11 (the two largest peaks were approximately equal concentrations); Hon. purity (25%).

Example 153.

5-fluoro-1H-indole-2-carboxylic acid {2-phenyl-1-[(thiophene-2 - ylmethyl)-carbarnoyl]-ethyl}-amide

TRMS-ion (expected) 422 (421); HPLC RT 7,50 (50%).

Example 154.

5-fluoro-1H-indole-2-carboxylic acid [1-benzyl-2-(3,4-dihydro - 1H-isoquinoline-2-yl)-2-oxoethyl]-amide

TRMS-ion (expected) 442 (441); HPLC RT 6,78 (35%), 5% of THEM.

Example 155.

5-fluoro-1H-indole-2-carboxylic acid [1-(2-cyclohexane-1-yl-ethylcarbamate)-2-phenylethyl]-amide

TRMS-ion (expected) 434 (433); HPLC RT 6,27/6,60 (the two largest peak is approximately equal concentrations); Hon. purity (35%), 5% of THEM.

Example 156.

5-fluoro-1H-indole-2-carboxylic acid [1-(5-cyanophenylacetic)-2-phenylethyl]-amide

TRMS-ion (expected) 421 (420); HPLC RT 6,61/7,71 (the two largest peak is approximately equal concentrations) (40%).

Example 157.

5-Methyl-1H-indole-2-carboxylic acid [2-phenyl-1-(thiochroman - 4-ylcarbonyl)-ethyl]-amide

TRMS-ion (expected) 470 (470).

Example 158.

5-Methyl-1H-indole-2-carboxylic acid (1-cyclohexylcarbonyl-2-phenylethyl)-amide

TRMS-ion (expected) 404 (404); Aoeti)-amide

TRMS-ion (expected) 392 (391); HPLC RT 6,86 (50%)

Example 160.

5-Methyl-1H-indole-2-carboxylic acid (1-benzyl-2-oxo-2-pyrrolidin-1-retil)-amide

TRMS-ion (expected) 376 (375); HPLC RT 6,50 (40%).

Example 161.

5-Methyl-1H-indole-2-carboxylic acid {2-phenyl-1-[(thiophene - 2-ylmethyl)-carbarnoyl]-ethyl}-amide

TRMS-ion (expected) 418 (417); HPLC RT 7,89 (70%).

Example 162.

5-Methyl-1H-indole-2-carboxylic acid [1-(5-cyanophenylacetic)-2-phenylethyl]-amide

TRMS-ion (expected) 417 (417); HPLC RT of 6.49/6,88 (the two largest peak is approximately equal concentrations); (40%).

Example 163.

5-Methyl-1H-indole-2-carboxylic acid (1-cyclopentanecarbonyl-2-phenylethyl)-amide

TRMS-ion (expected) 390 (389); HPLC RT of 6.96 (55%).

Example 164.

{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3-phenylpropionylamino}- acetic acid methyl ester

To 5 mmol of 5-chloro-1H-indole-2-carboxylic acid (50 ml of 0.1 M solution in acetonitrile) was added 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (50 ml 0.1 M solution in acetonitrile, 5 mmol), 1-hydroxybenzotriazole (50 ml of 0.1 M solution in acetonitrile, 5.0 mmol) followed by addition of (2-amino-3-phenylpropionylamino)-acetic acid methyl and then concentrated to dryness to obtain the connection header.

HPLC RT 8,15 (65%).

Example 165.

2-(S)-[(5-Chloro-1H-indole-2-carbonyl)-amino] -3-phenylpropionic acid benzyl ester

The connection header was obtained by substitution of L-phenylalanine benzyl ester (2-amino-3-phenylpropionylamino)-acetic acid methyl ester using the method analogous to the method of the procedure of example 164.

HPLC RT 8,13 (40%).

Example 166.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3 - hydroxyazetidine-1-yl)-2-oxoethyl]-amide

2-Amino-1-(3-hydroxyazetidine-1-yl)-3-phenylpropane-1-she hydrochloride (1,18 mmole) and 5-chloro-1H-indole-2-carboxylic acid (1,18 mmole) were coupled according to procedure a (solvent for the reaction of dichloromethane-dimethylformamide 4:1) and the product was purified by chromatography on silica gel with elution of 25%, 50%, 75% and 100% ethyl acetate-hexane with obtaining the substance of the title as colorless foam (104 mg, 22%), Was also selected mixture of the less polar products.

Substance title: HPLC (60/40) 4,18 minutes (97%); TRMS 398/400 (MH+, 100%).

Example 166a.

(2S)-Amino-1-(3-hydroxyazetidine-1-yl)-3-phenylpropane-1-she hydrochloride

[(1S)-Benzyl-2-(3-hydroxyazetidine-1-yl)-2-oxoethyl] -carbamino acid tert-butyl ester (515 mg, 1,6 myprivacy with ether to obtain colorless solid (415 mg, 100%).

Example 167.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-gidroksibenziliden-1-yl)-2-oxoethyl]-amide

A solution of 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-oxoazetidin-1-yl)-2-oxoethyl]-amide (product of example 170, 50 mg of 0.13 mmole), sodium acetate of three-hydrate (43 mg, of 0.32 mmole) and hydroxylamine hydrochloride (18 mg, 0.25 mmole) in methanol (2 ml) was heated in a flask under reflux for 8 hours and concentrated. The residue was separated between dichloromethane and saturated aqueous NaHCO3. The organic layer was separated and dried to obtain a colorless solid, which was triturated with ether-hexane and dried (yield 36 mg, 69%): HPLC (50/50) 6,74 min (99%), TRMS 411/413 (MH+, 10%), 180 (100%);

1H NMR (DMSO-d6) 11,75 (W,1H), 11,10 (s, 0.5 H), 11,08 (s, 0.5 H), 8,99 (d, 1H, J=9 Hz), 7,73 (d, 1H, J=2 Hz), between 7.4 and 7.1 (m, 8H), 5,0 (m, 1H), 4,8-to 4.5 (m, 4H), 3,1 (m, 2H).

Example 168.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2- (4-hydroxylaminopurine-1-yl)-2-oxoethyl]-amide

A mixture of 5-Chloro-1H-indole-2-carboxylic acid [1(S)-benzyl - 2-oxo-2-(4-oxopiperidin-1-yl)-ethyl] amide (406 mg, 0.96 mmole), hydroxylamine hydrochloride (80 mg, 1.15 mmole) and potassium carbonate (159 mg, 1.15 mmole) in ethanol (6 ml) and water (1 ml) was stirred at 25<'s what the op was washed with water and dried (411 mg, 98%); HPLC (60/40) 5,13 minutes (97%); TRMS 439/441 (MH+, 100%);

1H NMR (DMSR-d6) 11,75 (W, 1H), 10,45 (s, 0.5 H), 10,44 (s, 0.5 H), of 9.00 (m, 1H), 7,72 (d, 1H, J=2 Hz), 7,40 (d, 1H, J=8,8 Hz), 7,35-to 7.15 (m, 7H), to 5.17 (m, 1H), 5,17 (m, 1H), 3,8-3,5 (m, 4H), 3,1 (m, 2H), 2,45 (m, 2H)by 2.25 (m, 2H).

Example a.

5-Chloro-1H-indole-2-carboxylic acid [1(S)-benzyl-2 - oxo-2-(4-oxopiperidin-1-yl)-ethyl]-amide

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(4 - hydroxypiperidine-1-yl)-2-oxoethyl] -amide (example 46, 669 mg) was added in one portion at 0oC to a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DPC, 1,80 g, 9.4 mmole) and dichloracetic acid (307 mg, 1.5 mmole) in anhydrous toluene (3 ml? ) and anhydrous dimethyl sulfoxide (3 ml). The mixture was stirred at 0-20oC for 2 h, diluted with ethyl acetate and the resulting solution was washed twice 1N HCl, twice with saturated aqueous solution of NaHCO3, dried, concentrated and the residue was purified by chromatography on silica gel with elution of 25%, 50% and 75% ethyl acetate-hexane with getting foamy substance (424 mg, 64%).

Example 169.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(1,3-dihydroindol-2-yl)-2-oxoethyl]-amide

2-Amino-1-(1,3-dihydroindol-2-yl)-3-phenylpropane-1-she hydrochloride (0,20 is matography on silica gel with elution 5%, 10%, 20% and 50% ethyl acetate-hexane (55 mg, 62% yield): HPLC (70/30) to 6.58 minutes;

TERMS 444/446 (MH+, 50%), 180 (1000).

1H NMR (CDCl3) 9,25 (W, 1H), 7,60 (s, 1H), 7,45 (m, 1H), and 7.3, and 7.1 (m ), 6.90 to (a 5.25 (m, 1H), 5.0mm (d, 1H, 16 Hz), is 4.85 (d, 1H, J= 16 Hz), 4,70 (d, 1H, J= 16 Hz), 4,20 (d, 1H, J=16 Hz).

Example a.

(2S)-Amino-1-(1,3-dihydro-isoindole-2-yl)-3-phenyl-propane-1-she hydrochloride

[(1S)-Benzyl-2-(1,3-dihydro-isoindole-2-yl)-2-oxoethyl] - carbamino acid tert-butyl ester (88 mg) was dissolved in cold 4N HCl-dioxane (1.5 ml), stirred 2 h at 25oC and the mixture was concentrated. The residue is triturated with ether and dried (65 mg, 91%). TERMS 267 (MH+, 100%).

Example 169b.

[(1S)-Benzyl-2-(1,3-dihydroindol-2-yl)-2-oxoethyl]- carbamino acid tert-butyl ether

N-t-Boc-L-phenylalanine (1 mmol) and isoindoline (J. Org. Chem., 1988, 53, R. 5382, 70-80% purity, 1 mmol) were coupled according to procedure a and the product was purified by chromatography on silica gel with elution 20% and 50% ethyl acetate-hexane getting amber oil (88 mg, 23%): TRMS 367 (MH+, 100%).

Example 170.

5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-oxoazetidin-1-yl)-2-oxoethyl]-amide

1-((2S)-Amino-3-phenylpropionyl)-azetidin-3-one hydrochloride (3.2 mmole) and 5-chloro-1H-indole-2-ENU was purified by chromatography on silica gel with elution 20%, 30%, 40% and 50% ethyl acetate in hexane, obtaining the substance of the title as colorless foam (600 mg, 47%): HPLC (60/40) 5,09 minutes (98%); TRMS 396 (MH+, 100%);

1H NMR (CDCl3) 9,14 (W, 1H), 7.62mm (d, 1H, J=3 Hz), between 7.4 to 7.2 (m, 7H), 7,11 (d, 1H, J=8.0 Hz), 6,85 (m, 1H), 4,90 (m, 1H), 4,78 (m, 2H), 4,63 (m, 1H), 3,65 (m, 1H), 3,25 (DD, 1H, A of AB, J=5,1, 12.9 Hz), 3,10 (DD, 1H, B of AB, J=10, 12.9 Hz).

Example a.

1-((2S)-Amino-3-phenylpropionyl)-azetidin-3-one hydrochloride

[(1S)-Benzyl-2-oxo-2-(3-oxoazetidin-1-yl)-ethyl] -carbamino acid tert-butyl ester (297 mg, 0.9 mmole) was dissolved in 4N HCl-dioxane (3 ml). The resulting solution was stirred at 25oC for 2 h, concentrated and the residue triturated with ether and dried (196 mg, 82%).

Example 170b.

[(1S)-Benzyl-2-oxo-2-(3-oxoazetidin-1-yl)-ethyl] -carbamino acid tert-butyl ether

[(1S)-Benzyl-2-(3-hydroxyazetidine-1-yl)-2-oxoethyl] -carbamino acid tert-butyl ester (320 mg, 1 mmol) was added in one portion to a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DPC, 575 mg, 3 mmole) and dichloracetic acid (192 mg, 1.5 mmole) in anhydrous toluene (2 ml) and anhydrous dimethyl sulfoxide (2 ml). The mixture was stirred at 0-20oC for 1 h, diluted with ethyl acetate, the resulting solution was washed substances (304 mg, 96%).

Example 170c.

[(1S)-Benzyl-2-(3-hydroxyazetidine-1-yl)-2-oxoethyl] - carbamino acid tert-butyl ester

3-Hydroxyazetidine hydrochloride (J. Chem. Soc., Chem. Commun., 1968, p. 93, 27 mmol) and N-t-Boc-L-phenylalanine (27 mmol) were coupled according to procedure a with obtaining the substance of the title as colorless foam (8,15 g, 93%).

Example 171.

5-Chloro-1H-benzoimidazol-2-carboxylic acid (1-dimethylcarbamoyl-2-phenylethyl)-amide

(S)-2-Amino-N, N-dimethyl-3-phenylpropionamide hydrochloride (2.0 mmole) and 5-chloro-1H-benzoimidazol-2-carboxylic acid (Crowther et al., J. Chem. Soc. , 1949, R. 1268, 2 mmole) were coupled according to procedure a and the product was purified by chromatography on silica gel with elution by ethyl acetate-hexane 1:1 (235 mg, 63%): HPLC (60/40) to 4.92 min (91%); PBMS (MH+, 100%);

1H NMR (CDCl3) 11,25 (width, 0.6 N), 10,9 (width, 0.4 H), at 8.36 (m, 1H), 7,78 (d, 0,4 H, J=7,72 (d, 0,6 H, J=8,8 Hz), 7,52 (d, O,6N, J=2 Hz), 7,41 (d, 0,4 H, J= 8,4 Hz), 7,35 to 7.1 (m, 6N), 7,35 (m, 1H), and 3.16 (m, 2H), 2,90 (s, 3H), 2,68 (s, 2H), 2,67 (C. 1H).

Example 172.

5-Chloro-1H-indole-2-carboxylic acid [1-benzyl-2-oxo-2- (2-oxo-oxazolidin-3-yl)-ethyl]-amide

3-((2S)-Amino-3-phenylpropionyl)-oxazolidin-2-she hydrochloride (0,50 mmole) and 5-chloro-1H-indole-2-carboxylic acid (0,50 mmole) were coupled according to procedure A (will dissolve ASH (60/40) 6.22 per minute (95%); TERMS 429/431 (45%, MH+NH3), 412/414 (30%, MH+, 325/327 (100%).

1H NMR (DMSO-d6) 11,68 (W, 1H), of 8.92 (d, 1H, J=8.5 Hz), of 7.75 (s, 1H), 7,42 (m, 3H), 7,26 (m, 3H), 7,18 (m, 2H), of 5.83 (m, 1H), 4,50 (m, 2H), 4,0 (m, 1H), 3,25 (m, 1H), 2.95 and (m, 1H).

Example a.

3-((2S)-Amino-3-phenylpropionyl)-oxazolidin-2-she hydrochloride

[(1S)-Benzyl-2-oxo-2-(2-oxo-oxazolidin-3-yl)-ethyl] -carbamino acid tert-butyl ether (to 2.29 g of 6.68 mmole) was dissolved in 4M HCl-dioxane (10 ml) at 0oC. the resulting solution was stirred at 25oC for 2 h, concentrated and the residue triturated with ether and dried (1.98 g, 107%).

Example 172b.

[(1S)-Benzyl-2-oxo-2-(2-oxo-oxazolidin-3-yl)-ethyl]- carbamino acid tert-butyl ether

N-Utility (2.35 M in hexano, 11.5 ml) was added at 78oC to a solution of 2-oxazolidinone (2,04 g, 23.4 mmole) in tetrahydrofuran (25 ml). After 30 minutes at 78oC the solution was treated with N-t-Boc-L-phenylalanine N-hydroxysuccinimidyl ether (9,31 g of 25.7 mmole) in tetrahydrofuran (10 ml), and stir the mixture was allowed to warm to 25oC during the night. Was added water (10 ml) and the resulting mixture was concentrated, the residue was dissolved in ethyl acetate, and the resulting solution was washed twice 1N NaOH, once with water, once with Somatom in hexano obtaining a colorless solid (3.42 g, 44%).

It should be clear that the invention is not limited to the specific implementations described herein, but that various changes and modifications can be made, without departing from the nature and scope of this new idea, which is defined by the following claims.

1. Substituted N-(indole-2-carbonyl)-glycinamide and their derivatives of the formula I

< / BR>
and their pharmaceutically acceptable salts,

where the dashed line (---) is an optional bond;

A is-C(H)=, -C((C1- C4)alkyl)=, -C(halogen)= or-N=, when the dashed line (---) is a bond, or a is a methylene or is-CH((C1- C4)alkyl)-, when the dashed line (---) is not represented by a link;

R1, R10or R11each independently is H, halogen, cyano-, 4-, 6 - or 7-nitro-, (C1- C4)alkyl, (C1- C4)alkoxy, formation, deformation or trifluoromethyl;

R2- H;

R3- H or (C1- C5)alkyl;

R4is H, stands, ethyl, n-propylene, hydroxy(C1- C3)alkyl, (C1- C3)alkoxy(C1- C3)alkyl, phenyl(C1- C4)alkyl, phenylketone(C1- C41- C4)alkyl, and the above rings R4are independently mono-, di - or tizamidine at the carbon atom of hydrogen, halogen, (C1- C4)alkyl, (C1- C4)alkoxy, trifluoromethyl, hydroxyl, amino, cyano, or 4,5-dihydro-1H-imidazol-2-yl; or R4is pyrid-2-, -3 - or-4-yl(C1- C4)alkyl, thiazol-2-, -4 - or-5-yl(C1- C4)alkyl, imidazol-2-, -4 - or-5-yl(C1- C4)alkyl or indol-2-(C1- C4)alkyl, moreover, these previous heterocycles R4are optionally mono - or disubstituted independently with halogen, trifluoromethyl, (C1- C4)alkyl, (C1- C4)alkoxy, amino, hydroxyl or cyano, and these substituents bound to carbon;

R5is hydrogen;

R6is carboxyla, (C1- C8)alkoxycarbonyl, benzyloxycarbonyl, C(O)NR8R9or C(O)R12where R8- H, (C1- C6)alkyl, cyclo(C3- C6)alkyl or (C1- C8)alkoxy, R9- H, cyclo(C3- C8)alkyl, cyclo(C3- C8)alkyl(C1- C5)alkyl, cyclo(C4- C7)alkenyl, cyclo(C3- C7)Alki -C8)alkyl, phenyl or a heterocycle, and said heterocycle is thiazolium, isoxazolyl, isothiazolines, morpholinium, benzothiazolium, tigermania or tetrahedralisation where these heterocyclic rings are linked through carbon-nitrogen, or R9is (C1- C6)alkyl or (C1- C8)alkoxy, where specified (C1- C6)alkyl or (C1- C8)alkoxy is optionally monosubstituted cyclo(C4- C7)alken-1-yl, phenyl, teinila, morpholinium or indolium, and where the ring R9are independently optionally mono - or disubstituted at the carbon atom (C1- C4)alkyl, (C1- C4)alkoxy, provided that on any one Quaternary nitrogen in any heterocycle R9;

R12- morpholino, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, piperazine-4-yl, azetidin-1-yl, oxazolidin-3-yl, 3,4-dihydroisoquinoline-2-yl, 1,3-dihydroindol-2-yl, where the aforementioned ring R12are independently optionally mono-, di - or tizamidine halogen, (C1- C5)alkyloxy, carbamoyl, (C1- C6)alkoxy(C1- C3)alkoxy, (C1- C5)alkoxycarbonyl, benzyloxycarbonyl, (C1- C4)alkoxycarbonyl, carboxy(C1- C5)alkyl, oxo, hydroxyimino or (C1- C6)alkoxyimino, and where not more than two substituent selected from oxo, hydroxyimino or (C1- C6)alkoxyimino and oxo, hydroxyimino or (C1- C6)alkoxyimino, are non-aromatic carbon and

provided that when R6is (C1- C5)alkoxycarbonyl or benzyloxycarbonyl, then R1is 5-halo, 5-(C1- C4)alkyl or 5-cyano and R4is (phenyl)(hydroxy)(C1- C4)alkyl, (phenyl)((C1- C4)alkoxy)(C1- C4)alkyl, hydroxymethyl or Ar(C1- C2)alkyl, where Ar - Tien-2 - or-3-yl, FSD-2 - or-3-yl or phenyl, where the specified Ar is optionally mono - or disubstituted independently with halogen; provided that when R4is benzyl and R5is methyl, R12is not 4-hydroxypiperidine-1-yl, or when R4is benzyl and R5is methyl, R6is not C(O)N(CH3)2;

provided that when R1and R10and R9both n-pentyl, R1- 5-chloro, 5-bromo, 5-cyano, 5(C1- C5)alkyl, 5(C1- C5)alkoxy or trifluoromethyl;

provided that when R12- 3,4-dihydroisoquinolin-2-yl specified 3,4-dihydroisoquinolin-2-yl is not substituted carboxy(C1- C4)alkyl; and

provided that when R6- carboxyl and R1, R10, R11and R5all H, then R4is not benzyl, H, (phenyl)(hydroxy)stands, stands, ethyl or n-propylene.

2. Connection on p. 1, in which R1- 5H, 5-halo, 5-methyl, 5-cyano-or 5-trifluoromethyl; R10and R11each independently - H or halogen; A is-C(H)=; R2and R3- H; R4is H, stands, phenyl(C1- C2)alkyl, where mentioned phenyl groups are mono - or disubstituted independently H, halogen, (C1- C4)alkyl, (C1- C4)alkoxyl, trifluoromethyl, hydroxyl, amino or cyano, and where the groups of R4are optionally additionally monosubstituted by halogen, or R4is 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-2-, -4 - or-5-yl(C1- C2)alkyl, where the MSD, by trifluoromethyl, (C1- C4)alkyl, (C1- C4)alkoxy, amino or hydroxyl, and these mono - or designtitle connected with carbon; R5Is H and R6- C(O)NR8R9or C(O)R12.

3. Connection on p. 2, where R4is H, phenyl(C1- C2)alkyl, Tien-2 - or-3-yl(C1- C2)alkyl, FSD-2 - or-3-yl(C1- C2)alkyl, and the above rings R4are mono - or disubstituted independently H or fluorine; R6- C(O)R12and R12is morpholino, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, piperazine-4-yl, azetidin-1-yl, oxazolidin-3-yl, and the above rings R12are optionally mono - or disubstituted independently with halogen, (C1- C5)alkyl, (C1- C5)alkoxy, hydroxyl, amino, mono-N - or di-N,N-(C1- C5)alkylamino, carboxyla, carbamoyl, (C1- C5)alkoxycarbonyl, oxo, hydroxyimino or (C1- C6)alkoxyimino provided that only heterocycles R12thiazolidin-3-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazin is toxaemia or (C1- C6)alkoxyimino.

4. Connection on p. 3, where R4Is H and R12is thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl or oxazolidin-3-yl, or the substituents R12are optionally mono - or disubstituted independently by carboxyla, (C1- C5)alkoxycarbonyl, or R12is mono - or disubstituted pyrrolidin-1-yl, and these substituents are independently by carboxyla, (C1- C5)alkoxycarbonyl, (C1- C5)alkoxy, hydroxyl, amino or mono-N - or di-N,N-(C1- C4)alkylamino.

5. Connection on p. 3, where R4is vinylmation, Tien-2 - or-3-elmetron, and the above rings R4are arbitrarily mono - or disubstituted by fluorine, and R12is thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl or oxazolidin-3-yl, or the substituents R12optionally mono - or tizamidine independent carboxyla or (C1- C5)alkoxycarbonyl, or R12is mono - or disubstituted, azetidin-1-yl, or mono - or disubstituted pyrrolidin-1-yl, or mono - or disubstituted piperidine-1-yl, and these substituents by KSIL, amino, mono-N - or di-N,N-(C1- C5)alkylamino, oxo, hydroxyimino or (C1- C5)alkoxyimino.

6. Connection on p. 3, representing a compound selected from:

[(1S)-benzyl-2-(3-hydroxylaminopurine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

[2-(CIS-3,4-dihydroxypyrrolidine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

[2-((3S, 4S)-dihydroxypyrrolidine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

[(1S)-benzyl-2-(CIS-3,4-dihydroxypyrrolidine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

[2-(1,1-dioxothiazolidine-3-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

(2-oxo-2-thiazolidin-3-retil)amide 5-chloro-1H-indole-2-carboxylic acid,

[(1S)-(4-terbisil)-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

[(1S)-benzyl-2-((3RS)-hydroxypiperidine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

[2-oxo-2-((1RS)-oxo-1-thiazolidin-3-yl)ethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

[(1S)-(2-terbisil)-2-(4-hydroxypiperidine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid,

[(1S)-benzyl-2-((3S, 4S)-dihydroxypyrrolidine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-Carbo is
[(1S)-benzyl-2-(3-gidroksibenziliden-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid, or

[(1S)-benzyl-2-(4-hydroxylaminopurine-1-yl)-2-oxoethyl] amide 5-chloro-1H-indole-2-carboxylic acid.

7. Connection on p. 4, in which R1- 5-chloro, R10and R11Is H and R12- CIS-3,4-dihydroxypyrrolidine-1-yl.

8. Connection on p. 4, in which R1- 5-chloro, R10and R11Is H and R12- (3S, 4S)-dihydroxypyrrolidine-1-yl.

9. Connection on p. 4, in which R1- 5-chloro, R10and R11Is H and R12- 1,1-dioxothiazolidine-3-yl.

10. Connection on p. 4, in which R1- 5-chloro, R10and R11Is H and R12- thiazolidin-3-yl.

11. Connection on p. 4, in which R1- 5-chloro, R10and R11Is H and R12- 1-oxothiazolidine-3-yl.

12. Connection on p. 5, in which R1- 5-chloro, R10and R11- H, R4- 4-tormentil, R12- 4-hydroxypiperidine-1-yl and the stereochemistry of carbon (a) is represented by (S)-form.

13. Connection on p. 5, in which R1- 5-chloro, R10and R11- H, R4is benzyl, R12- 3-hydroxypiperidine-1-yl and the stereochemistry of carbon (a) is represented by (S)-form.

14. Connection on p. 5, in which R1

15. Connection on p. 5, in which R1- 5-chloro, R10and R11- H, R4is benzyl, R12- 3-hydroxylaminopurine-1-yl and the stereochemistry of carbon (a) is represented by (S)-form.

16. Connection on p. 5, in which R1- 5-chloro, R10and R11- H, R4- 2-tormentil, R12- 4-hydroxypiperidine-1-yl and the stereochemistry of carbon (a) is (S)-form.

17. Connection on p. 5, in which R1- 5-chloro, R10and R11- H, R4is benzyl, R12- (3S,4S)-dihydroxypyrrolidine-1-yl and the stereochemistry of carbon (a) is (S)-form.

18. Connection on p. 5, in which R1- 5-chloro, R10and R11- H, R4is benzyl, R12- 3-hydroxyazetidine-1-yl and the stereochemistry of carbon (a) is (S)-form.

19. Connection on p. 5, in which R1- 5-chloro, R10and R11- H, R4is benzyl, R12- 3-gidroksibenziliden-1-yl and the stereochemistry of carbon (a) is (S)-form.

20. Connection on p. 5, in which R1- 5-chloro, R10and R11- H, R4is benzyl, R12- 4-hydroxylaminopurine-1-yl and the stereochemistry of carbon (a) is (S)-form.

21. Connection on p. 2, in which R4Is H, phenyl(C1- C2)alkyl, Tien-2 - or-3-yl(C1- C2)alkyl, where Col C5)alkyl or (C1- C4)alkoxy, and R9- H, cyclo(C4- C6)alkyl, thiazolyl, benzothiazolyl or thiochroman or R9- (C1- C5)alkyl, and specified (C1- C5)alkyl is optionally substituted cyclo(C4- C6)alkenyl, phenyl, teinila, morpholinium, and where the ring R9optionally mono - or tizamidine independently from carbon (C1- C4)alkyl, (C1- C4)alkoxy.

22. Connection on p. 2, where R4is H, phenyl(C1- C2)alkyl, Tien-2 - or-3-yl(C1- C2)alkyl, where these rings R4are independently mono - or disubstituted H or fluorine; R6- C(O)NR8R9and R8- H, (C1- C5)alkyl or (C1- C4)alkoxy and R9- (C1- C4)alkoxy, and specified (C1- C4)alkoxy is optionally substituted cyclo(C4- C6)alkenyl, phenyl, teinila, morpholinium, and where the ring R9are optionally mono - or disubstituted independently of carbon (C1- C4)alkyl, (C1- C4)alkoxy.

23. Connection on p. 21, and R1- 5-chloro, R10and R11- H, R4is benzyl, R810and R11- H, R4is benzyl, R8is methyl.

25. Connection on p. 21, in which the stereochemistry of carbon (a) is (S)-form, R1- 5-chloro, R10and R11- H, R4is benzyl, R8is methyl.

26. Connection on p. 21, in which the stereochemistry of carbon (a) is (S)-form, R1- 5-chloro, R10and R11- H, R4- 4-performer, R8is methyl and R9- 2-morpholinoethyl.

27. Connection on p. 22, in which R1- 5-chloro, R10and R11- H, R4is benzyl, R8is methyl.

28. Connection on p. 22, in which the stereochemistry of carbon (a) is (S)-form, R1- 5-chloro, R10and R11- H, R4- 4-performer, R8is methyl and R9- methoxy.

29. Connection on p. 22, in which the stereochemistry of carbon (a) is (S)-form, R1- 5-chloro, R10and R11- H, R4is benzyl, R8is methyl and R9- methoxy.

30. Connection on p. 1, in which R1is 5-halo, 5-stands, 5-cyano or trifluoromethyl, R10and R11each independently - H or halogen, A is-C(H)=, R2and R3- H, R4is H, phenyl(C1- C2)alkyl, Tien-2 - or-3-yl(C1- C2)alkyl, where these rings are independently Obedinenie under item 1, and R1is 5-halo, 5-stands, 5-cyano or trifluoromethyl, R10and R11each independently - H or halogen, A is-C(H)= , R2and R3- H, R4- H, methyl or phenyl(C1- C2)alkyl, and mentioned phenyl groups are mono - or disubstituted independently H, halogen, (C1- C4)alkyl, (C1- C4)alkoxy, trifluoromethyl, hydroxyl, amino or cyano and the above phenyl groups are optionally mono - or disubstituted independently H or halogen, or R4is 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-2-, -4 - or-5-yl(C1- C2)alkyl, moreover, these previous R4the heterocycles are optionally mono - or disubstituted independently with halogen, trifluoromethyl, (C1- C4)alkyl, (C1- C4)alkoxy, amino or hydroxyl and these mono - or designtitle connected with carbon; R5is hydrogen; R6- carboxyl.

32. Connection on p. 31, in which R10and R11Is H and R4- H.

33. Connection on p. 32, in which R1- 5-chloro.

34. Promezhutochn-elmetron, moreover, these rings are optionally mono - or disubstituted by fluorine;

R12is thiazolidin-3-yl, 1-oxothiazolidine-3-yl, 1,1-dioxothiazolidine-3-yl, pyrrolidin-1-yl, piperidine-1-yl, azetidin-1-yl or oxazolidin-3-yl, where the aforementioned ring R12are optionally mono - or disubstituted independently with halogen, (C1- C5)alkyl, (C1- C5)alkoxy, hydroxyl, amino, mono-N - or di-N,N-(C1- C5)alkylamino, carboxyla, carbamoyl, (C1- C5)alkoxycarbonyl, amino(C1- C4)alkyl, oxo, hydroxyimino or (C1- C6)alkoxyimino assuming that only R12the heterocycles of thiazolidin-3-yl, pyrrolidin-1-yl, piperidine-1-yl, azetidin-1-yl or oxazolidin-3-yl are optionally mono - or disubstituted independently oxo, hydroxyimino or (C1- C6)alkoxyimino, provided that R12is not 2-carboxy-4-hydroxypyrrolidine-1-yl, 2-((C1- C5)alkoxycarbonyl)-4-hydroxypyrrolidine-1-yl, 2-carboxypeptidase-1-yl or 2-((C1- C5)alkoxycarbonyl)piperidine-1-yl.

35. Connection on p. 34, in which R4- phenylmethyl specified phenyl is optionally monooleyl-1-yl-, 3-, 4 - or 5-mono - or disubstituted piperidine-1-yl, thiazolidin-3-yl, 1-oxothiazolidine-3-yl or 1,1-dioxothiazolidine-3-yl, and the specified pyrrolidin-1-yl or piperidine-1-yl is mono - or disubstituted independently with hydroxyl, oxo, hydroxyimino, amino, mono-N - or di-N,N-(C1- C4)alkylamino-, (C1- C5)alkoxycarbonyl or carboxyla.

36. Connection on p. 34, in which R4Is H and R12- thiazolidin-3-yl.

37. Connection on p. 34, in which R4Is H and R12- 1,1-dioxothiazolidine-3-yl.

38. Connection on p. 34, in which R4Is H and R12- 1-oxothiazolidine-3-yl.

39. Connection on p. 35, in which R4is benzyl, R12- 3-hydroxypyrrolidine-1-yl and the stereochemistry of carbon (a) is (S)-form.

40. Connection on p. 35, in which R4is benzyl, R12- 3-hydroxyazetidine-1-yl and the stereochemistry of carbon (a) is (S)-form.

41. Connection on p. 35, in which R4is benzyl, R12- 3,4-dihydroxypyrrolidine-1-yl and the stereochemistry of carbon (a) is (S)-form.

42. Connection on p. 35, in which R4is benzyl, R12- 4-hydroxypiperidine-1-yl and the stereochemistry of carbon (a) is (S)-form.

43. Connection on p. 35, in which R<>/P>44. Connection on p. 35, in which R4is benzyl, R12- 4-gidroksibenziliden-1-yl and the stereochemistry of carbon (a) is (S)-form.

45. The method of treatment of a disease or condition in a mammal characterized by an increased activity of glycogen phosphorylase by reducing activity of the enzyme, characterized in that for reducing the activity of glycogen phosphorylase is administered to the mammal an effective amount of the compounds on p. 1, inhibiting the enzyme.

46. The method according to p. 45, characterized in that for reducing the activity of glycogen phosphorylase a mammal suffering from hyperglycemia, introducing an effective amount of the compounds under item 1 that corrects hyperglycemia.

47. The method according to p. 45, characterized in that for reducing the activity of glycogen phosphorylase a mammal suffering from diabetes, introducing an effective amount of the compounds on p. 1, stopping the development of diabetes.

48. The method according to p. 45, characterized in that for reducing the activity of glycogen phosphorylase a mammal suffering from hypercholesterolemia, introducing an effective amount of the compounds under item 1 for the hypercholesterolemia.

49. The method according to p. 45, characterized in that to reduce aktivnaya under item 1, stopping the development of atherosclerosis.

50. The method according to p. 45, characterized in that for reducing the activity of glycogen phosphorylase a mammal suffering from hyperinsulinemia, introducing an effective amount of the compounds under item 1 for the hyperinsulinemia.

51. The method according to p. 45, characterized in that for reducing the activity of glycogen phosphorylase a mammal suffering from hypertension, introducing an effective amount of the compounds under item 1, for the hypertension.

52. The method according to p. 45, characterized in that for reducing the activity of glycogen phosphorylase a mammal suffering from hyperlipidemia, introducing a therapeutic amount of the compounds on p. 1, eliminating hyperlipidemia.

53. The method according to p. 45, characterized in that for reducing the activity of glycogen phosphorylase a mammal at risk of ischemic myocardial damage during surgery is administered an effective amount of the compounds on p. 1 warning myocardial ischemia.

54. Pharmaceutical composition for treating diseases or conditions in mammals, characterized by an increased activity of glycogen phosphorylase, including an active ingredient and a pharmaceutically preeminent connection on p. 1.

55. The pharmaceutical composition according to p. 54, characterized in that it further includes terapevticheskii anti-diabetic effective amount of a drug selected from insulin and insulin analogs, insulinotropic, sulfonylureas and analogs, biguanides, 2-antagonists and imidazoline, tools that enhance insulin secretion, glitazones, inhibitors of fatty acid oxidation, inhibitors-glucosidase, -agonists, phosphodiesterase inhibitors, funds, reduces the content of lipids, anti-obesity, Vanadate and vanadium complexes and peroxovanadate complexes, milinovich antagonists, glukagonovykh antagonists, inhibitors of gluconeogenesis, somatostatin analogues, antilipolytic funds.

 

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