Peptidyl heterocycles used in the treatment of combinazioni diseases

 

(57) Abstract:

The invention describes compounds of formula (I) and their N-alkylated derivatives, where the substituents have the values. Describes obtaining a pharmaceutical composition having an ability of inhibiting thrombin comprising a therapeutically effective amount of the compounds of formula (I) and a pharmaceutically acceptable carrier. Provides methods of inhibiting thrombin and trypsin, comprising contacting the compounds of formula (I) with medium containing thrombin or trypsin, respectively. 4 C. and 31 C.p. f-crystals, 1 PL.

The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions. The compounds are inhibitors of serine proteases, especially thrombin, and can be used in a variety of thrombin associated diseases, such as thrombosis and thrombosis of arteries.

With quickly increasing the spread of the disease vascular system greatly affect our society. Arterial thrombosis is the main cause of death from heart attack and strokes, have a look at stwa or after a prolonged period of immobility.

Thrombin is a multifunctional serine protease, plays a crucial role in thrombosis and hemostasis was described in various sources of information (See. mainly, Tapparelli et al., TIPS 1993, 14, 366-76). Thrombin acts as procoagulant by proteolytic cleavage of fibrinogen to form fibrin and as an anticoagulant through activation of traces of protein (with subsequent inactivation of clotting factors V and VIII). The concentration of active thrombin is limited by a large number of feedback mechanisms, including endogenous factors and proteins. In addition to protein C antithrombin III is another regulatory protein that forms a complex with endogenous heparin. This complex is attached to the active thrombin, thus inactivating it.

Currently on anticoagulant therapy consists of three classes of compounds: heparins, coumarins and heparins, low-molecular weight. These drugs act indirectly to limit the concentration of the active ingredient. The heparins and low molecular weight heparins masses interact with antithrombin III and coumarins inhibit a number of vitamins K dependent coagulation factors. Although these medications are prescribed for diseases the full effects slow onset of action and only coumarins are orally active (warfarin and dicumarol).

It has been shown that indirect thrombin inhibitors are less effective at suppressing related diseases than direct thrombin inhibitors. Thus, the search for orally active direct thrombin inhibitors is carried out in many laboratories.

As a result of these efforts was obtained a number of small peptidergic compounds that directly inhibit thrombin. RACK, argatroban, (D)-NAPAP and DUP 714 are of interest examples of direct thrombin inhibitors.

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Unfortunately, only a few of these compounds are mild oral and most have poor selectivity against thrombin against other serine proteases. Thus, there remains a need in direct inhibitors that possess good selectivity against other serine proteases and are orally active.

The invention relates to new compounds of formula I:

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where a is selected from the group comprising C1-8alkyl, carboxy1-4alkyl, C1-4alkoxycarbonyl1-4alkyl, panels1-4alkyl, sulkily, perftools1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), formyl, C1-4alkoxycarbonyl,1-12alkylsulphonyl, phenyl-C1-4alkoxycarbonyl,3-7cycloalkylcarbonyl, phenylcarbinol, substituted phenylcarbamoyl (where the phenyl substituents are independently selected from one or more of the1-4the alkyl, PERFLUORO-C1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl)1-4alkylsulfonyl, C1-4alkoxycarbonyl, perfors1-4alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl (where the phenyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 10-camphorsulfonic, panels1-4alkylsulfonyl, substituted phenyls1-4alkylsulfonyl, C1-4alkylsulfonyl, perfors1-4alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl (where replace alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), panels1-4alkylsulfonyl, substituted phenyls1-4alkylsulfonyl, 1-naphthylmethyl, 2-naphthylmethyl or substituted naphthylmethyl (where the naphthyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, carboxy or1-4alkoxycarbonyl), 1-naphthylmethyl, 2-naphthylmethyl or substituted naphthylmethyl (where the naphthyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl);

D - or L-amino acid attached to its carbonsilicon to nitrogen indicated in formula I and is selected from the group consisting of alanine, asparagine, 2-azetidinone acid, glycine, N-C1-8allylglycine, Proline, 1-amino-1-cyclo-C3-8alkalicarbonate acid, thiazolidine-4-carboxylic acid, 5,5-dimethylthiazolidine-4-carboxylic acid, oxazolidine-4-carboxylic acid, piplani, 1-naftalin, 2-naftalin, 2-titillans, 3-titillans, [1,2,3,4]-tetrahydroisoquinoline-1-carboxylic acid and [1,2,3,4]-tetrahydroisoquinoline-2-carboxylic acid, where the amine ends of this amino acid are associated with a member selected from the group comprising FROM1-4alkyl, tetrazol-5-yl-C1-2alkyl, carboxy1-4alkyl, C1-4alkoxycarbonyl1-4alkyl, panels1-4alkyl, substituted phenyls1-4alkyl (where the phenyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 1,1-diphenyls1-4alkyl, 3-phenyl-2-hydroxypropionic, 2,2-diphenyl-1-hydrooximethylcarbamil, [1,2,3,4]-tetrahydro-isoquinoline-1-carbonyl, [1,2,3,4] -tetrahydroisoquinoline-3-carbonyl, 1-methylamino-1-cyclohexanecarbonyl, 1-hydroxy-1-cyclohexanecarbonyl, 1-hydroxy-1-phenylacetyl, 1-cyclohexyl-1-hydroxyacetic, 3-phenyl-2-hydroxy-propionyl, 3,3-diphenyl-2-hydroxypropionic, 3-cyclohexyl-2-hydroxypropionic, formyl, WITH1-4alkoxycarbonyl,1-12alkylsulphonyl, perfors1-4alkyls0-4alkylsulphonyl, panels1-4alkylaryl,x from C1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 1,1-diphenyls1-4alkylaryl, substituted 1,1-diphenyls1-4alkylsulphonyl (where the phenyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), perfors1-4alkylsulfonyl, C1-4alkylsulfonyl, C1-4alkoxycarbonyl, phenylsulfonyl, substituted phenylsulfonyl (where the phenyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 10-camphorsulfonic, panels1-4alkylsulfonyl, substituted phenyls1-4alkylsulfonyl, perfors1-4alkylsulfonyl,1-4alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl (where the phenyl substituents are independently selected from one or more of the1-4UB>1-4dialkylamino, carboxy or1-4alkoxycarbonyl), panels1-4alkylsulfonyl, substituted phenyls1-4pcrsonnel (where the phenyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 1-naphthylmethyl, 2-naphthylmethyl, substituted naphthylmethyl (where the naphthyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl); 1-naphthylmethyl, 2-naphthylmethyl and substituted naphthylmethyl (where the naphthyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl);

or a polypeptide that contains two amino acids, where the first amino acid is D - or L-amino acid attached through its carboxy end to AZ is Borovoy acid, Proline, thiazolidine-4-carboxylic acid, 5,5-dimethyl-thiazolidin-4-carboxylic acid, oxazolidine-4-carboxylic acid, 1-amino-1-ciclos3-8alkalicarbonate acid, 3-hydroxyproline, 4-hydroxyproline, 3-(C1-4alkoxy) Proline, 4-(C1-4alkoxy)Proline, 3,4-dihydropyran, 2,2-dimethyl-4-thiazolidinones acid, 2,2-dimethyl-4-oxazolidin-carboxylic acid, pipecolinic acid, valine, methionine, cysteine, asparagine, serine, threonine, leucine, tert-leucine, isoleucine, phenylalanine, 1-naftalin, 2-naftalin, 2-titillans, 3-titillans, [1,2,3,4] -tetrahydroisoquinoline-1-carboxylic acid, [1,2,3,4] -tetrahydroisoquinoline-2-carboxylic acid, 4-C1-4alkilany ester of aspartic acid and 5-C1-4alkilany ester of glutamic acid, and the second D or L amino acid attached to aminobenzo specified first amino acid and is selected from the group consisting of phenylalanine, 4-benzylpenicillin, 4-carboxyaniline, 4-(carboxyo-20alkyl)phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carbarsone acid, 2-pyridylamine, 3-pyridylamine, 4-thiazolidinone, 2-titillans, 3-(3-benzothiazyl)alanine, 3-titillans, tryptophan, tyrosine, asparagine, 3-three-C1-4alkylsilanes, cyclohexylglycine, diphenylglycine, phenylglycine, methanesulfonic, methanesulfonic, 2,2-dicyclohexylamine, 2-(1-nafcillin), 2-(2-nafcillin), phenylselenenyl phenylalanine (where the substituents are selected from C1-4of alkyl, perfors1-4of alkyl, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), aspartic acid, 4-C1-4alkilany ester of aspartic acid, glutamic acid, 5-C1-4alkilany ester of glutamic acid, ciclos3-8alkilany, substituted ciclos3-8alkilani (where the ring substituents are carboxy, C1-4alkylcarboxylic,1-4alkoxycarbonyl or aminocarbonyl), 2,2-diphenylalanine and all alpha1-5alkyl derivatives of all amino acids, where the amine ends of the second specified amino acids are unsubstituted or monogamist a member of the group consisting of formyl, C1-12alkyl, tetrazol-5-ILS1-2alkyl, carboxy1-8alkyl, caballes1-4alkyl, panels1-4alkyl, Sames is Lila, perftools1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 1,1-diphenyls1-4alkyl, C1-6alkoxycarbonyl, panels1-6alkoxycarbonyl,1-12alkylsulphonyl, perfors1-4alkyls0-4alkylsulphonyl, phenyl-C1-4alkylaryl, substituted phenyls1-4alkylsulphonyl (where the phenyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 1,1-diphenyls1-4alkylsulphonyl,1-4alkylsulfonyl, C1-4alkoxycarbonyl, perfors1-4alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl (where the phenyl substituents are independently selected from one or more of the1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 10-camphorsulfonic, phenyl-C1-4alkyl sulfonyl, substituted phenyls1-4alkyl sulfonyl, perfors1-41-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), panels1-4alkylsulfonyl, substituted phenyl-C1-4alkylsulfonyl, 1-naphthylmethyl, 2-naphthylmethyl, substituted naphthylmethyl (where Deputy naphthyl selected from C1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl), 1-naphthylmethyl, 2-naphthylmethyl and substituted naphthylmethyl (where Deputy naphthyl selected from C1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy or1-4alkoxycarbonyl);

R1selected from the group comprising hydrogen and C1-5alkyl;

R2selected from the group comprising amines2-5alkyl, guanidino-C2-5alkyl, C1-4alkylguanine2-5alkyl, dis1-4alkylguanine-C2-5alkyl, amidino2-5alkyl, C1-4alkylamides2-5alkyl, CI-C1-4alkylamides2-5alkyl, C1-3from amino, amidino, guanidino,1-4alkylamino,1-4dialkylamino, halogen, perfors1-4of alkyl, C1-3alkoxy or nitro), benzyl, phenylselenenyl benzyl (where the substituents are independently selected from one or more of amino, amidino, guanidino,1-4alkylamino,1-4dialkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy or nitro), hydroxys2-5alkyl, C1-5alkylamino2-5alkyl, C1-5dialkylamino2-5alkyl, 4-aminocyclohexane0-2alkyl and C1-5alkyl;

p = 0 or 1;

In stands

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where n = is 0-3, R3denotes N or C1-5alkyl and carbonyl radical attached to E;

E represents a heterocycle selected from the group consisting of oxazoline-2-yl, oxazol-2-yl, thiazol-2-yl, thiazol-5-yl, thiazol-4-yl, thiazolin-2-yl, imidazol-2-yl, 4-oxo-2-cinoxacin-2-yl, 2-pyridyl, 3-pyridyl, benzo[b]thiophene-2-yl, benzoxazol-2-yl, benzimidazole-2-yl, benzothiazol-2-yl, the thiazole-6-yl, tetrazol-2-yl, pyrimidine-2-yl, quinoline-2-yl, indol-2-yl, pyrazole-2-yl, 4,5,6,7-tetrahydroindazole-2-yl, oil-[2,1-d] thiazole-2-yl, oil[1,2-d] thiazol-2-yl, cinoxacin-2-yl, isoquinoline-1-yl, isoquinoline-3-yl, benzo[b] furan-2-yl, pyrazin-2-yl, hinzelin-2-yl, isothiazol-5-yl, and the>is Lila,1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy, C1-4alkoxycarbonyl, hydroxy or panels1-4alkylaminocarbonyl);

or their pharmaceutically acceptable salts.

The terms used in the description of the invention, are commonly used and well-known experts in this field. However, terms that may have different values, defined particularly. "Independently" means that when there is more than one substituent, the substituents may be different. The term "alkyl" refers to straight, cyclic and branched chain alkyl groups, and alkoxy" refers to-0-alkyl, where alkyl is defined above. "CBZ" refers to benzyloxycarbonyl. "SIDE" refers to tert-butoxycarbonyl and "Ts" refers to toluensulfonyl. "DCC" refers to 4-N,N-dimethylaminopyridine and NOT" refers to the hydrate of 1-hydroxybenzotriazole. "Dansyl" refers to 5-dimethylamino-1-naphthalenesulfonate and "FMoc" refers to N-(9-fluorenylmethoxycarbonyl).

Compounds according to the invention can be obtained as illustrated in scheme I. For illustrating examples get a connection. where a denotes a polypeptide, where the first s - C4alkyl, p = 0 and E represents benzoxazol-2-yl. Other compounds that can be obtained by this General scheme are listed below with the appropriate modifications.

Natural and non-natural amino acid is the starting point for the scheme. Compound Ia get by known methods of synthesis of obtaining protected amino acids, where the amino group is protected with TS. Culvenor, et al., J. Chem. Soc. D. 1969, 19, 1091. The protective group can vary. In scheme I-amino - and-aminosidine group must be stable in redneckish conditions, and deleted in ways that are mutually exclusive. Examples of suitable-amino - and-aminosidine group lists respectively: FMOC-TS, FMOC-NO2CBZ-NO2. For example, other appropriate protective group, see Green, Theodora. Protecting Groups In Organic Synthesis; John Wiley & Sons. New York, 1981.

Compound Ia added to 1,1'-carbonyldiimidazole in THF at 0 to 10oWith subsequent processing DIBAL/hexane at -42oWith obtaining aldehyde Ib, using the method described by Greco et al. Journal Of The American Chemical Society, 1995, 117, 1225. Direct conversion of Ia to Ib can be carried out using bis(N-methylpiperazine)aluminiumhydride in toluene at 0oWith up to temperature cipral in THF at 25oC to the boiling temperature. Brown, et al., Synthesis, 1979, 704. Another way is to convert carboxylic acids into the corresponding Weinreb amide using triethylamine, the THIEF and the hydrochloride of N,0-dimethylhydroxylamine. Recovery of the resulting amine with LAH in THF gives the corresponding aldehyde.

Lamborghini IC is obtained by addition of KCN to the emulsion aldehyde Ib H2Oh, Meon and ethyl acetate at room temperature. Alternatively, the connection of the IC can be obtained by the interaction of the aldehyde Ib, acetonecyanohydrin and triethylamine in dichloromethane at room temperature. Imidate Id is obtained by processing IC gaseous Hcl in methanol. Benzoxazol If get by heating with Id S in ethanol by boiling.

Amin Ig obtained by hydrogenation If using Pd(OH)2/C as a catalyst at room temperature at atmospheric or at elevated pressure, using solvent-donor hydrogen. In a suitable reaction conditions can be used with other catalysts, such as Pd/C or Pd-mobile. Other reagents that can be used to remove the CBZ group include: hydrazine, attributegrammarsystem acid/anisole and tribromide Bo is getting linked alcohol Ii. Other suitable reagents for binding include: thief, thief, THIEF-C1 and Rumor.

Compound Ii oxidizes in connection Ij using periodinane in anhydrous aprotic solvent. The final stage of scheme I is to remove protection from Ii using HF in the presence catcher carbocations, such as anisole, thioanisole, pentamethylbenzyl, dimethyldisulfide and cresol followed by chromatography with reversed phase with the final product Ik.

To obtain the compounds according to the invention, where a denotes a1-4alkyl, panels1-4alkyl and substituted phenyls1-4alkyl, original product according to the scheme I modify. Treatment of compound Ia with two equivalents of sodium hydride in DMF at a temperature of from 0oWith up to the room and then alkylhalogenide gives N-alkilirovanny carboxylic acid. This acid can be processed in the same reaction conditions that are used according to scheme I, to obtain the desired compounds as shown in scheme IA.

When And indicates WITH1-4alkoxycarbonyl, panels1-4alkoxycarbonyl,3-7cycloalkylcarbonyl, phenylcarbinol and substituted phenylcarbinol, scheme I can be again modified. The CBZ group in snanam. Examples of such compounds are benzoyl chloride, propionate, methylchloroform, cyclohexanecarbonitrile, benzylchloride and the like. This original product is used in scheme IB with obtaining the desired compounds as shown in scheme IA.

Similarly, when And indicates WITH1-4alkylsulfonyl, perfors1-4alkylsulfonyl, substituted phenylsulfonyl,1-4alkylsulfonyl, perfors1-4alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, 1-naphthylmethyl, 2-naphthylmethyl and substituted naphthylmethyl, 1-naphthylmethyl, 2-naphthylmethyl or substituted naphthylmethyl; the desired compound can be obtained from their respective commercially available arylsulfonyl and arylsulfonyl-halides under the scheme IB.

When a is an amino acid, aminocore which is attached to another group, can be re-used scheme I. N-attached amino acid (optionally protected) replaces Ih in scheme I, using the same reaction conditions. Alanine, asparagine, 2-azetidinone acid, glycine, Proline, pipecolinate acid, valine, methionine, cysteine, serine, threonine, leucine, tert-leucine, and isoleucine can especially panels1-4the alkyl), (1,1-diphenyls1-4the alkyl-3-phenyl-2-hydroxypropionate), (2,2-diphenyl-1-hydrooximethylcarbamile), ([1,2,3,4]-tetrahydroisoquinoline-1-carbonyl), ([1,2,3,4]-tetrahydroisoquinoline-3-carbonyl), (1-methylamino-1-cyclohexanecarbonyl), (1-hydroxy-1-cyclohexanecarbonyl), (1-hydroxy-1-phenylacetyl), 1-cyclohexyl-1-hydroxyacetone, 3-phenyl-2-hydroxypropionate, 3,3-diphenyl-2-hydroxypropionic, 3-cyclohexyl-2-hydroxypropionic, formyl, C1-4alkoxycarbonyl,1-4alkylcarboxylic, perfors1-4alkyls0-4alkylcarboxylic, panels1-4alkylcarboxylic, substituted phenyls1-4alkylcarboxylic, 1,1-diphenyls1-4alkylcarboxylic, substituted 1,1-diphenyls1-4alkylcarboxylic, perfors1-4alkylsulfonyl, C1-4alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, perfors1-4alkylsulfonyl,1-4alkylsulfonyl, phenylsulfonyl, replaced phenylsulfinyl, 1-naphthylmethyl, 2-naphthylmethyl, substituted naphthylmethyl, 1-naphthylmethyl, 2-naphthylmethyl and replaced naphthylmethyl.

When a is a dipeptide, aminocore which is attached to another group, can be re-used scheme I. in One example, one is about the product, essentially the same reaction conditions as in scheme I.

To obtain compounds where R1denotes N and R2denotes aminos2-5alkyl, guanidino2-5alkyl, amidino2-5alkyl, C1-3alkoxyl2-5alkyl, phenyl, substituted phenyl (where the substituents are selected from amidino, guanidino,1-4alkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy and nitro), benzyl, aryl-substituted benzyl (where the substituents are selected from amidino, guanidino,1-4alkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy and nitro), (pyridine-4-yl)amino1-4alkyl, (pyridin-3-yl)amino1-4alkyl, C1-4alkylamino2-5alkyl and C1-5alkyl, can be re-used scheme I. the starting product Ia can be replaced with commercially available amino acids such as arginine, leucine, phenylalanine, lysine, p-amidinopropane, methoxypropylamine and 2-(3-pyridyl)-alanine, an amino group, and any other reactive substituents are protected with CBZ, Ts or FMOC that fits. If desired, the substituents are not commercially available, as in the case when R2is substituted by phenyl or substituted benzil-5540).

To obtain compounds where E denotes 4-oxo-2-cinoxacin-2-yl, benzimidazole-2-yl and benzothiazol-2-yl, can be re-used scheme I. Replacing Their 2-aminothiophenol gives the derivatives of benzothiazole following the same reaction conditions as in scheme I; provided that you cannot use Pd to remove the CBZ group. However, it can be used any of the other methods listed previously.

If E denotes a 5-carbomethoxyamino-2-yl, scheme I may be modified to obtain the desired compounds as shown in scheme IC. Replacement connection on Their hydrochloride ethyl ester cysteine derivative gives thiazoline II at room temperature with the use of CH2Cl2as a solvent. Oxidation thiazolino ring compounds Il using MnO2at room temperature gives the thiazole Im. Oxidation of the hydroxyl group Im with the subsequent removal aminosidine groups with HF/anisole gives carboethoxy derived In.

To obtain the ester derivative In carboethoxy group in any of Il, In or Im may be modified using known chemical methods. Thus we can obtain the following ester derivatives: carboxy method of preparing compounds according to the invention is illustrated in scheme II. An illustrative example of a compound where a is L-Proline, which is attached at its N-end (1,1-diphenyls2alkylcarboxylic), R1denotes hydrogen, R2denotes guanidino3alkyl, p is 0 and E denotes thiazol-2-yl. Other compounds that can be obtained from this General scheme are listed below with the appropriate modifications.

Commercially available acid IIA is the starting point for this scheme. This acid is converted into an activated ester derivative IIb by processing DCG and 2,4,5-trichlorophenol at -20oWith 0oWith in an inert solvent, such as THF. Derived Proline IId obtained by processing IIb using IIC, triethylamine and pyridine. Alternatively, IId can be obtained directly by treating the acid IIa amino acid IIc in the presence of any binding peptides agents listed in scheme I.

Weinrab amide NBoc-Nw-tilarginine, IIE, was obtained by a known literature method from protected acid. DiMaio, et al., Journal of Medicinal Chemistry 1992, 35, 3351. Amide is treated IIf at -78oC in THF with obtaining ketone IIg. This ketone can be recovered hydride, postanal the coy TFU at room temperature to obtain the corresponding amine IIh.

Linking IIh and IId in the presence DCC and NOT at room temperature in acetonitrile gives the associated alcohol IIi. Other peptide binding reagents that can be used for these reactions include: benzotriazol-1 yloxy-Tris(dimethylamino)fosfodiesterasa, the acid chloride of bis(2-oxo-3-oxazolidinyl)postnasal acid, hydrochloride 2-dimethylaminopropylamine and bromo-Tris-pyrrolidinedithiocarbamate. The IIi oxidation to the ketone using periodinane in CH2Cl2with the subsequent removal --aminosidine group with HF and anisole gives the desired product IIj.

To obtain the compounds according to the invention, where a denotes a1-4alkyl, panels1-4alkyl or substituted phenyls1-4alkyl, original product according to scheme II can be modified and used as shown in scheme IIA.

Starting material for scheme IIA is obtained from protected Weinrab amide, IIE. The amide remove protection using THF, is subjected to reductive alkylation of the corresponding substrate and lamborghini.com sodium and protect with VOS to N-alkylated original product. In illustrating examples using benzaldehyde as substrate for in what gentami, as scheme II to obtain the desired compounds.

When And denotes formyl, C1-4alkoxycarbonyl, panels1-4alkoxycarbonyl,1-4alkylsulphonyl,3-7cycloalkylcarbonyl, phenylcarbinol and substituted phenylcarbinol, scheme II can be re-modified. The biofeedback group IIE is removed using TFU at room temperature and the resulting free amine is subjected to interaction with a suitable commercially available carbonyl compound. Examples of such compounds are formic acid/acetic anhydride, benzoyl chloride, propionate, methylchloroform, cyclohexanecarbonitrile and the like. This original product is used under the same conditions as in scheme IIA with obtaining the desired compounds.

Similarly, when And indicates:1-4alkylsulfonyl, perfors1-4alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl,1-4alkylsulfonyl, perfors1-4alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, 1-naphthylmethyl, 2-naphthylmethyl and substituted naphthylmethyl, 1-naphthylmethyl, 2-naphthylmethyl and substituted naphthylmethyl; the desired compound can be obtained from their respective commerced amino acid, aminocore which is attached to another group, can be re-used scheme II. N-Attached amino acid may be purchased or obtained by known methods. This amino acid will be replaced by Ih in scheme II using the same reaction conditions. Alanine, asparagine, 2-azetidinone acid, glycine, Proline, pipecolinate acid, valine, methionine, cysteine, serine, threonine, leucine, tert-leucine, and isoleucine can be used according to this scheme, where the amino group is attached to C1-4the alkyl, panels1-4the alkyl, substituted phenyls1-4the alkyl, 1,1-diphenyls1-4the alkyl, 3-phenyl-2-hydroxypropionate, 2,2-diphenyl-1-hydrooximethylcarbamile, [1,2,3,4]-tetrahydroisoquinoline-1-carbonyl, [1,2,3,4] -Tetra-hydroisoquinoline-3-carbonyl, 1-methylamino-1-cyclohexanecarbonyl, 1-hydroxy-1-cyclohexanecarbonyl, 1-hydroxy-1-phenylacetyl, 1-cyclohexyl-1-hydroxyacetone, 3-phenyl-2-hydroxypropionate, 3,3-diphenyl-2-hydroxypropionate, 3-cyclohexyl-2-hydroxypropionic, formyl, WITH1-4alkoxycarbonyl,1-4alkylcarboxylic, perfors1-4alkyls0-4alkylcarboxylic, panels1-4alkylcarboxylic, substituted phenyls1-4alkylcarboxylic, 1,1-diphenyls1-4alkylcarboxylic, C is phenylsulfonyl, substituted phenylsulfonyl, perfors1-4alkylsulfonyl,1-4alkylsulfonyl, phenylsulfonyl, replaced phenylsulfinyl, 1-naphthylmethyl, 2-naphthylmethyl and substituted naphthylmethyl, 1-naphthylmethyl, 2-naphthylmethyl and replaced naphthylmethyl.

When a is a dipeptide, aminocore which is attached to another group, can be re-used scheme II. One example is the replacement of IId N-were-alaninemia acid to obtain the corresponding final product using essentially the same reaction conditions as in scheme II.

To obtain compounds where R1denotes N and R2denotes aminos2-5alkyl, guanidino2-5alkyl, amidino2-5alkyl, C1-3alkoxyl2-5alkyl, phenyl, substituted phenyl (where the substituents are selected from amidino, guanidino,1-4alkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy and nitro), benzyl, aryl-substituted benzyl (where the substituents are selected from amidino, guanidino,1-4alkylamino, halogen, perfors1-4of alkyl, C1-4of alkyl, C1-3alkoxy and nitro), (pyridine-4-yl)amino1-4alkyl, (pyridine-3-and the Hema II. Using the methods DiMaio, et al., Journal of Medicinal Chemistry 1992, 35, 3331, can be obtained Weinreb amides known protected amino acids. These compounds replace the connection IIE in scheme II and treated in the same reaction conditions as shown in scheme II.

Scheme II can be used again to obtain the compounds according to the invention, where E denotes oxazol-2-yl, thiazol-2-yl, thiazol-5-yl, thiazol-4-yl, 1-alkylimidazole-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, benzo[b]thiophene-2-yl, benzoxazol-2-yl, 1-alkylbenzenes-1-yl, benzothiazol-2-yl, 1-alcheringa-2-yl, 4,5,6,7-tetrahydroindazole-2-yl, oil-[2,1-d]thiazole-2-yl, oil[1,2-d] thiazol-2-yl, pyrimidine-2-yl, cinoxacin-2-yl, benzo[b]furan-2-yl, pyrazin-2-yl, hinzelin-2-yl, isothiazol-5-yl, isothiazol-3-yl. When the nitrogen in position 1 protected resistant to the base of the protective group (for example, TMS, WOS, Ts and so on), scheme II can be used to obtain the compounds according to the invention, where E denotes imidazol-2-yl, pyrazole-2-yl, triazole-2-yl, triazole-4-yl, triazole-6-yl, tetrazol-2-yl, quinoline-2-yl, indol-2-yl, isoquinoline-1-yl, isoquinoline-3-yl and the purine-8-yl (requires protection in position 7 instead of 1). Replacement IIf any of the known listed litrownik heterocycles gives the desired sooo illustrating examples get the connection, where a is a polypeptide, where the first amino acid is L-Proline and the second amino acid is N-methyl-D-phenylalanine, R1is hydrogen, R2is (guanidino3alkyl), R = 1, n = 0, R3is N and E denotes thiazol-2-yl.

Compounds according to the invention, where E denotes the pyrazole-3-yl, can be obtained by 1,3-dipolar addition of diazoketones to alkynes (Padwa et al. , "1,3-Dipolar Cycloaddition Chemistry", 2 vols., Wiley, New York, 1984), as shown in scheme IV. Diazoketone intermediate compound IVa (US Patent 4318904) may be subjected to interaction with Alcina IVb boiling in benzene to obtain the pyrazole IVc, which can be further converted into the pyrazole IVd, as described earlier.

Compounds according to the invention, where E denotes the thiazol-2-yl and oxazol-2-yl, can be obtained as shown in scheme V. the Cyclization of alcohols Va and Vb using the Burgess reagent in the corresponding thiazoline and oxazoline, followed by oxidation with MnO2or NiO2leads to Vc and Vd (P. Wipf et al., Tetrahedron Letters, 1992, 33, 6267-6270). Similarly, aldehyde Ve can be converted into Vd using triphenylphosphine/iodine in the presence of triethylamine (P. Wipf et al., Journal of Organic Chemistry, 1993, 58, 3604-3606).

Although the statements of formula I include:

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Particularly preferred "And" are:

1-naphthylmethyl, 2-naphthylmethyl, substituted aftersurgery (where the substituents are selected from C1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy and C1-4alkoxycarbonyl);

and L-amino acid such as glycine or Proline, where aminocore are unsubstituted or monosubstituted with a member of the group comprising 1-naphthylmethyl, 2-naphthylmethyl and substituted aftersurgery (where the substituents are selected from C1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy and C1-4alkoxycarbonyl); or

polypeptide that contains two amino acids, where the first acid is L-Proline or L-pipecolinate and the second amino acid is D-phenylalanine, D-cyclohexylamino, D-diphenylalanine or (2,3,4,5,6-pentafluorophenyl) - alanine, where aminocore specified second amino acid is unsubstituted or monosubstituted with a member of the group, including WITH1-5and is methyl.

Particularly preferred R2selected from the group including:

aminos2-5alkyl, guanidino2-5alkyl, amidino2-5alkyl, C1-5alkylamino2-5alkyl, C1-5dialkylamino2-5alkyl, 4-aminocyclohexane0-2alkyl, 3-aminocyclohexane0-2alkyl and C1-5alkyl.

Particularly preferred "E" heterocycles are selected from the group including:

the thiazole-2-yl, thiazol-5-yl, thiazol-4-yl, thiazolin-2-yl, benzoxazol-2-yl, benzimidazole-2-yl, imidazol-2-yl, 4-oxo-2-cinoxacin-2-yl, benzothiazol-2-yl, thiazol-4-yl, thiazol-6-yl, tetrazol-2-yl, pyrimidine-2-yl, quinoline-2-yl, pyrazole-2-yl, [4,5,6,7]-tetrahydrobenzoic-2-yl, oil[2,1-d]thiazole-2-yl, oil[1,2-d] thiazol-2-yl, cinoxacin-2-yl, hinzelin-2-yl, isothiazol-5-yl, isothiazol-3-yl, purine-8-yl and a substituted heterocycle where the substituents are selected from C1-4of alkyl, perfors1-4of alkyl, C1-4alkoxy, hydroxy, halogen, amido, nitro, amino, C1-4alkylamino,1-4dialkylamino, carboxy, C1-4alkoxycarbonyl and hydroxy.

Compounds according to the invention were investigated for their ability to inhibit mediated thrombin hydrolysis. Studies have been conducted both in vitro and ex vivo. Kremasti.

Speed catalyzed by thrombin hydrolysis was measured spectrophotometrically using the sales of alpha-thrombin (American Diagnostica), a chromogenic substrate SpectozymeTH (H-D-HHT-Ala-Arg-pNA-2AcOH), American Diagnostica) in aqueous buffer (10 mm Tris, 10 mm HEPES, 150 mm NaCl, 0.1% PEG; pH 7,4) and microplate reader (Molecular Devices). Record changes in absorbance at 405 nm (Softmax, Molecular Devices) adding enzyme with inhibitor and without inhibitor at 37oFor more than 30 minutes. IC50determined by fixing the concentrations of enzyme and substrate and changes in the concentration of the inhibitor (1 nm thrombin, 50 μm SpectosymeTH). Was applied kinetics Michaelis-Menton for the initial reaction beveled solid environment. The inhibition constants (Ki) were determined by fixing the concentrations of enzyme and inhibitor and changes in substrate concentration (1 nm thrombin, 5-100 μm SpectosymeTH). Was applied kinetics Michaelis-Menton for the initial reaction beveled solid media using KCat (Bio Metallics Inc.).

Speed catalyzed by trypsin hydrolysis was measured using the same method as in method thrombin. Bovine trypsin type 1 (Sigma) and SpectosymeTRY (Gbo-Gly-ctosyme.

IC50for representative compounds are presented in table A. Representative Ki presents instead of the IC50for selected compounds. As reference standards were used N-Me PPACK aldehyde and argatroban and their values are listed below. The numbers of the compounds in the table correspond to the examples presented below.

Analysis of the ex vivo studies were performed to determine the duration of action of the compounds of formula I. For this purpose, intravenous analysis to male rats (Long Evans, 300-500 g) were implanted Teflon cannula through the femoral artery (phenobarbital, intraperitoneally, 35 mg/kg). After surgery the animals were separately placed in standard cages, were fed mouse chow (Hanlan, #8604) and was continuously infused saline solution to maintain the open condition of the artery (0.5 ml/h, intraarterially) using spring-shielded swivelling tether attached to the infusion system. After surgery the animals allowed to recover for at least 24 hours.

Blood samples taken from animals for 15 minutes before dosing of inhibitor (0.25 ml of blood is taken in a syringe containing 0.025 ml Sigma sodium citrate). The compounds of disperser is 80% inhibition of V0in the plasma sample after 5 min after infusion. Blood taken from an artery (blood:sodium citrate, 0.25 in/0,025 ml) at certain intervals(5, 10, 15, 30, 60 and 120 min) and placed in a centrifuge tube. A sample of plasma is obtained by centrifugation of blood at 10,000 rpm for 5 minutes the sample is examined for the inhibition of thrombin using chromogenic analysis, described below.

The rate of increase of absorbance at 405 nm of synthetic peptides (50 μm SpectozymeTH (H-D-HHT-Ala-Arg-pNA-2AcOH), American Diagnostica) was measured in the presence of plasma using micro tablet reader (Molecular Devices) at 37oWith out using aqueous buffer (10 mm Tris, 10 mm HEPES, 150 mm NaCl, 0.1% PEG; pH 7,4). The buffer is added to the plasma samples diluted (1: 1) before being placed on the microplate (1:5 and 1:50 to the end of dilutions of plasma 1:10 and 1:100, respectively) and then add the enzyme (1 nm human thrombin). Data are collected for more than 30 min and the initial rate of hydrolysis of the substrate (V0(OD/min)) are estimated using an analyzing software (Softmax, Molecular Devices).

Time for elimination the plasma half (1/2 t) calculated from the slanted agar V0against time, using the following equation: t , is the quiet include the speed of hydrolysis with the introduction of a drug as an intravenous and oral. This analysis of male rats supply, as described above, the Teflon tube

implanted in the femoral vein. Animals take blood for 15 min before dosing of inhibitor (0.25 ml of blood is taken in a syringe containing 0.025 ml Sigma sodium citrate) and used in the analysis. The compounds dispersed in water (0.3-3.0 mg/ml final concentration) and injected animal (0.25 ml) either intravenously or orally. Blood taken from an artery (blood: sodium citrate, 0.25 in/0,025 ml) at certain intervals (0,25, 0,5, 1,0, 2.0 and 3.0 h) and plasma obtained by centrifugation of blood at 10,000 rpm for 5 minutes the sample is examined for the inhibition of thrombin using chromogenic analysis, described below.

The rate of increase of absorbance at 405 nm of synthetic peptides (50 μm SpectozymeTH (H-D-HHT-Ala-Arg-pNA-2AcOH), American Diagnostica) was measured in the presence of plasma using micro tablet reader (Molecular Devices) at 37oWith out using aqueous buffer (10 mm Tris, 10 mm HEPES, 150 mm NaCl, 0.1% PEG; pH 7,4). The buffer is added to the plasma samples diluted (1: 1) before being placed on the microplate (1:5 and 1:50 prior to the data collected for more than 30 min and the initial rate of hydrolysis of the substrate (V0(D/min)) are estimated using an analyzing software (Softmax, Molecular Devices).

A standard curve is obtained by adding a drug or solvent (100 ál) of whole blood (900 μl) followed by incubation (5 min) and centrifugation to obtain plasma. The percentage of inhibition of thrombin was calculated by comparing the V0solvent with V0treated drug samples. Data from some of these definitions were normalized using statistical analysis (SAS) to obtain the standard curve.

The percentage of inhibition of thrombin in the treatment of animals was calculated by comparing the V0before processing with V0obtained from samples collected after treatment. The percentage of inhibition was plotted on the standard curve (obtained above) using statistical analysis (SAS) and the amount of drug in the sample extrapolate.

Bioavailability (Biodot. ) calculated from plots extrapolated drugs in the sample in relation to intravenous and oral administration using the following equation:

% Of biodot. = (intravenous dose/dose oral is

Argatroban: Ki=0,070; Ki=2,9.

As shown in table a, the compounds of formula I can be used in pharmaceutical compositions to treat patients (humans and other primates) with thrombotic diseases in the same way as known heparins and coumarins. The compounds may be introduced by any parenteral (intravenous, intraperitoneal, subcutaneous, using plates on the skin), where the preferred route is intravenous infusion). Dose for injection may be in the region of 0.1 to 300 mcg/kg/min of inhibitor in a mixture with a pharmaceutically acceptable carrier during the period of time in the range from several minutes to several days. Selected compounds can also be administered orally in dosages of about 1-100 mg/kg

The pharmaceutical compositions can be obtained using conventional pharmaceutical excipients and conventional methods of production. Oral standard dosage forms can be submitted elixirs, syrups, capsules, tablets and the like. Typical solid carrier is an inert substance, such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol and the like; and typical liquid if necessary, with leavening agents, diluents, granulating agents, lubricating agents, binders and the like, using conventional methods known to experts in this field obtain a standard dosage forms. Parenteral standard dosage forms can be obtained using water or other sterile media.

Usually the compounds of formula I is isolated and used in the form of their pharmaceutically acceptable salts. Examples of such salts include the hydrobromide salt, hydroiodide, hydrochloride, perchloro acid, sulfuric acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, almond acid, methanesulfonic acid, hydroethanolic acid, benzosulfimide acid, oxalic acid, Paveway acid, 2-naphtalenesulfonic acid, p-toluensulfonate acid, cyclohexanesulfamic acid and saccharin.

In addition to the treatment of thrombotic diseases, the compounds of formula I can be used to prevent coagulation of stored blood samples and as coatings for medical devices such as stents and orthopedic devices.

Usually is in contact with the environment, containing thrombin. For these compounds, the use of which as antikoaguliruyuschee funds was confirmed by the examples, can be various other methods of application as inhibitors of thrombin in accordance with the present invention. These application methods are considered as included in the scope of the present invention, the present invention describes the use of compounds of the formula I as antithrombotic funds.

Still another use of the compounds according to the invention is the use as inhibitors of trypsin. Trypsin inhibitors have been used clinically when pancreatitic diseases, such as pancreatitis. The value of the IC50compounds according to the invention have advantages when compared with pancreatitis means chemostat the mesilate and nafamostat (IC50, 110-8and 1,310-8, respectively). The compounds of formula I can be used in the same manner as specified therapeutic agent.

To illustrate the invention the following examples are provided. These examples do not limit the invention. They are intended only to confirm the practical implementation of the invention. Special is innymi. However, it is assumed that these methods are included in the scope of this invention.

EXAMPLES 1 AND 2

N-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

Conn.1

N-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1R-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

Conn.2

Stage and

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A mixture of N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline-Ng-Z-L-orgininally (9,92 g, 14.5 mmol; U.S. patent 4703036), CH2Cl2(48 ml), acetonecyanohydrin (4,0 ml, about 43.4 mmol) and triethylamine (1.2 ml, 8,7 mmol) was stirred at room temperature in an argon atmosphere for 3 hours After another hour of stirring an additional portion of acetonecyanohydrin (1.3 ml, of 14.2 mmol). The mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The obtained organic layer was washed with portions of water and brine, dried (Na2SO4) and concentrated in vacuo. The residue is triturated with several portions of hexane and the resulting solid residue is dried in vacuum, obtaining longerenong intermediate product 1A in the form of a solid product.

Stage b

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Gaseous HCl (51 g) is bubbled into the solution cyanhydrin 1A (9.3 g, 13,1 mmol) work 0oTo determine its characteristics (TLC and NMR) for more than 3 days and placed in a separating funnel in an argon atmosphere. The reaction mixture was added dropwise to a stirred mixture of water (700 ml), ethyl acetate (250 ml) and NaHCO3(159 g, 1.4 mol) at 0-6oC. the pH of the Solution for damping control and not allowed to fall below pH 6.8. Add additional portions of water and Panso3(as dictated by pH measurement) up until the reaction mixture becomes neutral. The resulting mixture was filtered through auxiliary filtering material, leaving a filtrate, which was washed with several portions of ethyl acetate. The combined organic layers washed with brine, dried (Na2SO4) and concentrated in vacuo to obtain the HCl salt of intermediate product 1b in the form of a solid product.

Stage

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2-Aminothiophenol (18,53 g holds 18.52 mmol) was added to a degassed solution of imidate 1b (of 7.23 g, 9,26 mmol) in absolute ethanol (290 ml) at room temperature in argon atmosphere. The resulting mixture was heated under reflux in a period of 4.75 hours, cooled to room temperature, exposed to oxygen atmosphere at room temperature for 18 h and com (95: 5) to give the intermediate hydroxybenzothiazole 1C as a white foam.

Stage d

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Periodinane dess-Martin (Dess-Martin) (1,59 g, 3,76 mmol) was added to a solution of CH2Cl2(40 ml) at room temperature in argon. The resulting mixture was stirred for 45 min and add additional portion periodinane (1.2 g, and 2.83 mmol), then stirred for further 15 minutes the Excess periodinane quenched by addition of 8 ml of quenching solution (25 g of Na2S2O3100 ml saturated aqueous Panso3), diluted with ethyl acetate (300 ml) and stirred at room temperature for 15 minutes the resulting aqueous layer is separated and extracted with several portions of ethyl acetate and the combined organic extracts are washed with successive portions of water and brine, dried (Na2SO4) and concentrated in vacuo to obtain ketone 1d as a white foam.

Stage e

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The intermediate ketone 1d (2,97 g, 3.63 mmol) and anisole (10 ml) was placed in a Teflon reaction tube HF apparatus under anhydrous environment and cooled to -78oC. HF (15-20 ml) is distilled into this tube and after complete addition, the temperature of the mixture is allowed to rise to 0oC. the Mixture is stirred for 2 h, concentrated in vacuo and triturated in several portions of ether with getting the TFU (70:30:0,2) to obtain compounds 1 and 2. Each diastereoisomer lyophilized with obtaining the desired product as a white foam, where compound 1 is 95% of the harvested product.

Connection 1 (diastereoisomer of L-arginine): FAB-MS m/z 550 (MH+); []20D= -72,5 (1/00, Meon).

Analysis. The calculation for C28H35N7O3S2,THU,5H2O:

Calculated: 46,12; N To 4.47%; N 11,24; H2O 1,03.

Found: 46,13; N 4,37; N 11,35; N2O 1,27.

Compound 2 (diastereoisomer D-arginine): FAB-MS m/z 550 (MH+); []20D= -67,5 (from 0.67, Meon).

Analysis. The calculation for C28H35N7ABOUT3S3T2H2O:

Calculated: 44,01; N 4,56; N 10,57; H2O 3,88.

Found: 44,11; N 4,34; N 10,96; H2O 3,80.

EXAMPLE 3

Stage and

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The solution dicyclohexylcarbodiimide (18,24 g, to 88.4 mmol) in THF (35 ml) was added dropwise to a stirred solution of 3,3-diphenylpropionic acid (20,0 g, to 88.4 mmol), 2,4,5-trichlorophenol (17,45 ml, to 88.4 mmol) in THF (50 ml) in an argon atmosphere at -20oC. the Reaction mixture was stirred at -20oC for 2.5 h, placed in a refrigerator at 0oC for 16 h and filtered through an auxiliary filter material. The mother liquor was concentrated in vacuo and recrystallized from the new ether 3A (15.0 g, 37,0 mmol) was added to a mixture of L-Proline (4.26 deaths / g, up 37.0 mmol), triethylamine (5,15 ml) and pyridine (45 ml) and 5oC in argon atmosphere. The reaction mixture is allowed to warm to room temperature, stirred for 76 h and concentrated in vacuo. To the residue was added an aqueous solution Panso3(3.42 g/130 ml) and ether (100 ml) and the resulting mixture was stirred at room temperature for 45 minutes the Organic layer is extracted several times with water. The combined aqueous layers extracted with two portions of ether, acidified with 1 N. Hcl and extracted with several portions of ethyl acetate. United an ethyl acetate layers washed with brine, dried (Na2SO4) and concentrated in vacuo to obtain an intermediate product 3b in the form of a solid product.

Stage

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1.6 M n-Utility/hexane (16 ml, 25.6 mmol) was added to a solution of benzothiazole (3,7 ml, to 33.9 mmol) and anhydrous THF (114 ml) at -78oC in argon atmosphere. The reaction mixture was stirred at -78oC for 15 min and the cannula was added N-BOC-NG-tosyl-L-arginine N,0-dimethylamide (800 mg, 1,69 mmol; DiMaio, et al. Journal of Medicinal Chemistry 1992, 35, 3331) and THF (43 ml) keeping the temperature below 70oC. the mixture is stirred during the 15 min and extracted with several portions of ethyl acetate. United an ethyl acetate extracts are washed with successive portions of water and brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified column chromatography on silica gel, elwira with ethyl acetate/hexane (5:2) to give the intermediate benzothiazole 3C in the form of butter.

Stage d

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Sodium borohydride (63,8 mg, was 1.69 mmol) was added dropwise to a solution of benzothiazole 2C (307 mg, 0,563 mmol) in Meon (10 ml) at -20oWith argon. The mixture was stirred at about -20oC for 40 min and slowly add acetone (2 ml). The reaction mixture is allowed to warm to room temperature for 1.25 h, concentrated in vacuo and distributed between ethyl acetate and water. The aqueous layer was extracted with several portions of ethyl acetate. United an ethyl acetate layers washed with brine, dried (Na2SO4) and concentrated in vacuo to obtain the intermediate alcohol 3d in the form of a pale yellow foam.

Stage e

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The alcoholic solution of 3d (0.27 g, 0.49 mmol) in 10 ml of TFU/CH2CL2(1:4) was stirred at room temperature in an argon atmosphere for 1.5 hours the mixture was concentrated in vacuo to obtain TFU salt 3E in the form of oil.3and brine; dried (Na2SO4) and concentrated in vacuo. The residue is purified using preparative TLC on silica gel, elwira using l3/Meon benzothiazole 3f in the form of needle-like solid product.

Stage g

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A mixture of 3f (7.2 mg, 0,0096 mmol), CH2Cl2(1 ml) and peridinin dess-Martin (Dess-Martin) (8.1 mg, 0.019 mmol) was stirred at room temperature under nitrogen for 1 hour, treated with 4 ml of quenching solution (25 g of Na2S2O3100 ml of saturated aqueous NaHCO3) and diluted with water and CH2Cl2. The obtained organic layer was washed with water, dried (Na2SO4) and concentrated in vacuo to obtain ketone 3g in the form of foam.

Stage h< the tube, attached to the HF apparatus and cooled to -78oC. HF (5 ml) is distilled into the reaction tube and the mixture was stirred at 0oC for 3 h HF is removed in vacuo and the mixture is triturated with three portions of ether. The precipitate was filtered, air-dried, dissolved in acetonitrile/water (1: 1) and purified HPLC with reversed phase, using CH3SP+2% TFU/N2O+0,016% TFU as eluent. The desired fraction was concentrated in vacuo and lyophilized obtaining compound 2 in a 1:3 mixture of D and L diastereomers arginine; IR (KBR, cm-1) 1674, 1450, 1204, 1135; []19D= -74,0 (0,60, Meon). So pl. 106-120oC.

Analysis. The calculation for C33H36N6O3S1,75 THU,N2ABOUT:

Calculated: 52,96; N 5,02; N 10,15; H2O 3,81.

Found: 53,27; N 5,13; N 10,34; N2About 3/86.

EXAMPLE 4

Stage and

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1,1-carbonyldiimidazole (0.65 g, of 4.05 mmol) was added to a mixture of N--Boc-NGNG'di Z-L-arginine (92.0 g, of 3.69 mmol) and THF at 0oWith argon and the resulting mixture is stirred for hours atoC. the Mixture is cooled to -48oAnd add a solution of 1M DIBAL/hexane (10.3 ml, or 10.3 mmol) at a rate at which the temperature of the reaction between -48oC and -42oC. Polucen the re between -40 and -28oC. the Mixture is allowed to warm to room temperature. Add CH2Cl2and the obtained solid product was filtered and washed with additional portions of CH2Cl2. The collected filtrates are washed with water, dried (gSO4) and concentrated in vacuo. The residue is purified by crystallization from ISO-Gon and hexane to obtain aldehyde 4A in the form of a solid product.

Stage b

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A mixture of aldehyde 4A (0,765 g of 1.36 mmol), CH2CL2(5 ml) and 2-(trimethylsilyl)thiazole (1.07 g, 6.8 mmol) was stirred at room temperature in an argon atmosphere for 16 hours, the Reaction mixture was concentrated in vacuo to obtain 4b in the form of butter.

Stage

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Triperoxonane acid (6 ml) is slowly added to a stirred mixture of thiazole 4b (1,36 mmol) and CH2Cl2(30 ml) at room temperature in argon atmosphere. The reaction mixture was stirred for 6 h and concentrated in vacuo. The residue is purified flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (95:4,5:0,5) as eluent with a single diastereoisomer. The isolated product was dissolved in CH2C12, dried (K2CO3), filtered and concentrated in vacuo to half the mixture to the alcohol 4 (0.18 g, 0.35 mmol), (CBZ)-N-methyl-D-i.e. phenylalanyl-L-Proline (0.14 g, 0.35 mmol; U.S. patent 4703036), hydroxybenzo-triazole (0,053 g, 0.38 mmol) and CH3CN (4.5 ml) at room temperature. The reaction mixture was stirred for 3.5 h and the resulting solid product is washed with portions of CH3The JV. The combined filtrates concentrated in vacuo and distributed between ethyl acetate and water. The organic layer was washed with successive portions of water and brine; dried (MgSO4) and concentrated in vacuo. The residue is purified chromatographically (silica gel, CH2Cl2/MeOH (95/5)) associated with obtaining alcohol 4d as a white foam.

Stage e

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A solution of alcohol 4d (0.14 mg, 0.15 mmol) and CH2Cl2(3 ml) was added in one portion to a mixture of periodinane dess-Martin (76 mg, 0,179 mmol) and CH2Cl2(4 ml) at room temperature. The reaction mixture was stirred for 35 min and add a little extra milligrams periodinane dess-Martin. The resulting mixture was stirred for further 10 min and add 4 ml of quenching solution (25 g of Na2S2O3100 ml of saturated aqueous NaHCO3) and then stirred for further 10 minutes the mixture is distributed between ethyl acetate and water and stirred for further 5 Got in vacuum to obtain ketone 4E in the form of a colorless glassy product.

Stage f

< / BR>
Compound 4 (RWJ 50026)

Ketone 4E (0,13 g, 0.144 mmol) and anisole (1 ml) was placed in a Teflon reaction tube HF apparatus under anhydrous environment and cooled to -78oC. HF (5-10 ml) is distilled directly into the flask, the temperature of the mixture is allowed to rise to 0oAnd this mixture is stirred for 1.5 h HF is removed in vacuo and the residue triturated in several portions of ether to obtain a solid product. This solid product was then purified HPLC with reversed phase, elwira water/acetonitrile/TFU (50: 50:0.2) and concentrated in vacuo. The residue is dissolved in water and set pH 6.48 in using sizepolicy ionoobmennoi resin AmberliteIRA-400 (HE-) and water with 0.1 TFU. The solids are filtered and the filtrate lyophilized obtaining compound 4 as a white solid product.

Analysis. The calculation for C24H33N7O3S2,75S2HF3O40,2 H2O

Calculated: 44,88; N. OF 5.03; N 13,08; N2About 2,88.

Found: 44,49; N IS 4.93; N 12,98; N2About 2,64.

EXAMPLE 5

Stage and

< / BR>
1,1'-Carbonyldiimidazole (of 9.89 g, 0,053 mmol) was added in one portion to a stirred solution of N-Z-NG-tosyl-L-arginine (25,2 g, mmol) and THF (160 ml) at 0-10oC. After 1 h the other mixture is stirred for further 30 min at -42oC. the Reaction mixture was quenched by slow addition of 1.2 M HCl (365 ml) and the reaction temperature allowed to reach room temperature. The mixture is treated with 0.6 M HCl (360 ml) and HCl3(400 ml) and stirred at room temperature for 2.5 hours the Aqueous phase is washed with several portions HCl3and the combined organic extracts are washed with successive portions of water, dried (MgSO4) and concentrated in vacuo to obtain aldehyde 5A in the form of a solid; FAB-MS m/z 447 (MH)+.

Stage b

< / BR>
KCN (6.0 g, 92 mmol) was added to a stirred mixture of aldehyde 4A (22,0 g, 49 mmol) in Meon (60 ml), N2O (60 ml) and ethyl acetate (110 ml) and stirred at 22oC for 16 h the resulting aqueous layer is extracted with several portions of ethyl acetate and the combined organic extracts washed with water, dried (Na2SO4) and concentrated in vacuo to obtain nitrile 5b in the form of foam; FAB-MS m/z 474 (MH)+.

Stage

< / BR>
Anhydrous Hcl (g) is bubbled into a solution of nitrile 5b (8.0 g, to 16.9 mmol) and anhydrous Meon (162 ml) at -78oWith such a rate that the temperature did not exceed -40oC. After the addition the reaction mixture was stirred for 30 min at 0oC. the Reaction is ustanavlivaut pH 4.0 by addition of glacial acetic acid and ethyl acetate (350 ml). The mixture is stirred for 4 h, separated and the aqueous layer was extracted three times with ethyl acetate. United an ethyl acetate extracts washed with water, saturated aqueous Panso3and brine, dried (Na2SO4) and concentrated in vacuo to obtain an intermediate product 5C as a white solid; FAB-MS m/z 507 (MH)+.

Stage d

< / BR>
A solution of intermediate 5C (1,00 g of 1.84 mmol), 2-aminophenol (0,22 g, 2.03 mmol) and absolute EtOH (40 ml) is heated under reflux in N2within 24 h and concentrated in vacuo. The residue is purified chromatographically on silica gel, elwira CH2CL2/Meon (95:5) to produce benzoxazole 5d as a white foam: So pl. 81-91oC; []25D= -2,9 (0,68, l3).

Analysis. The calculation for C28H31N5O6S0,6N2ABOUT:

Calculated: 58,34; N 5,14; N 12,15; H2About 1,87.

Found: 58,32; N 5,14; N of $ 11.97; H2O 1,67.

Stage e

< / BR>
A mixture of 5d (0.87 g, 1.53 mmol), 20% Pd(OH)4/C (0.21 g) and absolute EtOH (19 ml) is placed in the atmospheric Hydrator and stirred in an atmosphere of H2within 16 hours the mixture is filtered through auxiliary filtering material and concentrated in vacuo and CH3CN (1 ml) was added dropwise to a solution of hydrate of 1-hydroxybenzo-triazole (0.16 g, 1.2 mmol), amine 5e (of 0.47 g, 1.1 mmol), (CBZ)-N-methyl-i.e. phenylalanyl-L-Proline (of 0.44 g, 1.1 mmol) and CH3CN (15 ml) in N2. The reaction mixture was stirred for 3.5 h, filtered and the resulting cake on the filter is washed with several portions of CH3The JV. The combined filtrates concentrated in vacuo, dissolved in ethyl acetate, washed with successive portions of water and brine; dried (gSO4) and concentrated in vacuo. The residue is purified column chromatography on silica gel, elwira CH2Cl2/MeOH (93:7)) to obtain the associated alcohol 5f as a yellow glassy product.

Stage g

< / BR>
A solution of alcohol 5f (0.45 g, 0,56 mmol) and anhydrous CH2Cl2(5 ml) was added to stir the mixture periodinane dess-Martin (300 mg, 0.73 mmol) and anhydrous CH2Cl2(20 ml) at room temperature in argon. The reaction mixture was stirred for 30 min and add another portion periodinane dess-Martin (50 mg, 0.12 mmol) followed by stirring for another 10 min at room temperature. To stir the mixture was added 30 ml of quenching solution (25 g PA2S2O3in 100 ml nastolnye portions of saturated aqueous Panso3and brine, dried (MgSO4) and concentrated in vacuo to obtain ketone 5g in the form of foam; FAB-MS m/z 882 (MH+).

Stage h

< / BR>
Ketone 5g (0.45 g, 0.54 mmol) and anisole (approximately 2.0 ml) was placed in a Teflon reaction tube HF apparatus under anhydrous environment and cooled to -78oC. HF (0.5-1.0 ml) is distilled directly into the flask, the temperature of the mixture is allowed to rise to 0oTo this mixture was stirred at 0oC for 4 h to Remove HF in vacuo and the residue triturated in several portions of ether to obtain a yellow solid product, which was purified HPLC with reversed phase using water/acetonitrile/TFU (70:30:0.2) and lyophilized obtaining compound 5 in the form of a powder; So pl. 81-91oC; []25D= -63,3 (0/58, Meon); FAB-MS m/z 534 (MH)+.

Analysis. The calculation for C28H35N7O44(C2HF3O2)2,5 H2O.

Calculated: 41,97; N 4,25; N 9,52; N2About 3,93.

Found: 42,26; N WAS 4.42; N 9,87; N2About 4,27.

EXAMPLE 6

Stage and

< / BR>
1,1'-Carbonyldiimidazole (1.8 g, 11.0 mmol) was added to a solution of N--Fm-NG-tosyl-L-arginine (6.0 g, 10.0 mmol) in anhydrous THF (30 ml) at 0oIn an argon atmosphere and stirred at 0oWith over 1,5 hours Reactions stirred for another 1.5 h with stirring 1,2 N. HCl (67 ml). Mixture is allowed to warm to room temperature and partitioned between 0,6 N. Hcl (65 ml) and chloroform. The resulting aqueous layer was washed with several portions of chloroform. The combined organic extracts are washed with successive portions of water and brine, dried (Na2SO4) and concentrated in vacuo to obtain aldehyde 6A in the form of a white flocculent solid product.

Stage b

< / BR>
A solution of KCN (1.44 g, 22 mmol) and N2O (125 ml) was added to a solution of aldehyde 6A (5.9 g, 11.0 mmol) in ethyl acetate (250 ml) and the resulting mixture stirred for 40 h at room temperature in argon. The organic layer is separated and the aqueous layer washed with three portions of ethyl acetate. United an ethyl acetate extracts washed with brine, dried (Na2SO4), concentrated in vacuo and stored in the refrigerator in an argon atmosphere. The residue is distributed between ethyl acetate (100 ml) and saturated aqueous Panso3(200 ml) and pH support to 7.0 by adding Panso3. Solid Panso3removed by filtration and the resulting aqueous layer was washed with several portions of ethyl acetate. The combined organic layer is washed twice with saline, dried (gS CLASS="ptx2">

Stage

< / BR>
HCl (21 g) is bubbled into a solution of nitrile 6b (3.0 g, of 5.34 mmol) and methanol (53 ml) in argon at temperatures below -40oWith for more than 20 minutes, the Reaction vessel is closed under nitrogen atmosphere and placed in a freezer at -15oC for 46 h and concentrated in vacuo at room temperature. The residue is partitioned between a saturated solution of water Panso3(250 ml) and ethyl acetate. The organic layer is washed twice with saline, dried (gSO4) and concentrated in vacuo to obtain imidate 6C in the form of a solid product.

Stage d

< / BR>
The hydrochloride of the ethyl ester of cysteine (1.97 g, 10.6 mmol) are added to a solution of imidate 6s (3,30 g, 5.3 mmol) and CH2CL2(100 ml) and the resulting mixture is stirred in an argon atmosphere at room temperature for 3 hours Solid precipitate is removed by filtration and the filtrate concentrated in vacuo. The residue is purified chromatographically using CH2CL2/Meon (97:3) as eluent to obtain derived thiazoline 6d in the form of a solid; FAB-MS m/z 694 (MH)+.

Stage e

< / BR>
Diethylamine (2.5 ml, and 24.2 mmol) is added dropwise to a stirred solution derived 6d (2.20 g, 3,17 mmol) in anhydrous, Aceto the STATCOM was concentrated in vacuo, dissolved in CH2Cl2and concentrated in vacuo. The residue is triturated in several portions of hexane and concentrated in vacuo to obtain amine 6E in the form of oil; FAB-MS m/z 472 (MH)+.

Stage f

< / BR>
Dansyl chloride (890 mg, 3.3 mmol) are added to a solution of amine 6E (2,21 g, 3.1 mmol) and CH2Cl2when -5oWith argon. After completion of addition, the reaction mixture is stirred at room temperature for 1 h the mixture was concentrated in vacuo and partitioned between HCl3and saturated aqueous Panso3. The organic layer was washed with brine, dried (K2CO3) and concentrated in vacuo. The residue is purified chromatographically on silica gel, elwira CH2Cl2/MeOH (97:3) to give the protected amine 6f; FAB-MS m/z 705 (MH)+.

Stage g

< / BR>
Activated MnO2(0.75 g) is added to a solution of amine 6f (0,70 g, 1,49 mmol) and CH2Cl2(25 ml) and the resulting mixture is stirred over night at room temperature. Add an additional portion of MnO2(0.75 g) and the mixture stirred for 4 h at room temperature. Add another portion of MnO2(0.75 g) and the resulting mixture stirred for 16 h at room temperatur Nylon 66 (0.45 µm), using HCl3/Meon for washing cakes on the filter. The combined washings are dried (Na2SO4) and concentrated in vacuo. The residue is purified by HPLC using silica gel and CH2Cl2/MeOH (97:3) as eluent to obtain thiazole 6g in the form of a solid; FAB-MS m/z 701 (MH)+.

Stage h

< / BR>
Connection 6

A solution of thiazole 6g (141 mg, 0.20 mmol) and anisole are placed in the reaction vessel HF apparatus under anhydrous environment and cooled to -78oC. Anhydrous HF (4,5-6,0 ml) is distilled into the vessel and the reaction mixture allowed to warm to 5oC and stirred at 5oWith over 3.5 hours to Remove HF in vacuo and the residue triturated in several portions of ether to obtain a yellow solid product. The solid product was then purified HPLC with reversed phase, elwira H2O/CH3SP/TFU (30: 20: 0,2) obtaining oil. This oil is dissolved in distilled water and neutralized to a pH of 6.20 by adding resin AmberliteIRA-400 (HE-). The solid product is filtered and lyophilized getting connection 6 in the form of a solid product; So pl. 90-98oC; FAB-MS m/z 547 (MH)+.

EXAMPLE 7

Stage and

< / BR>
(+)-N-tert-Butoxycarbonyl-2-piperidinecarboxylate (2,13 g, 10.0 mmol; Hassner, et al. Jou the sphere of argon. The reaction mixture was stirred for 6 h, then diluted with anhydrous THF (100 ml) and 5 ml of 1.0 tetrabutylammonium/THF, stirred for another 40 min and concentrated in vacuo. The residue is dissolved in ethyl acetate and washed with saturated aqueous Panso3, dried (PA2SO4) and concentrated in vacuo to obtain thiazole 7a in the form of a solid; FAB-MS m/z 299 (MH)+.

Stage b

< / BR>
A solution of thiazole 7a (3,22 t, 9.0 mmol), CH2Cl2(100 ml) and TFU (20 ml) is stirred under argon at room temperature for 3 hours and concentrated in vacuo. The residue is partitioned between l3(100 ml) and 50% NaOH (20 ml), then stirred under argon at room temperature. Add another portion l3(100 ml) and the mixture is again stirred. The organic layer is removed and the resulting aqueous layer was washed with several portions l3. The combined organic washings are dried (K2CO3) and concentrated in vacuo. The residue is purified chromatographically on silica gel, elwira EtOAc/MeOH/NH4OH (97: 3: 1) to give the piperidine derivative 7b in the form of separate diastereomers.

Stage

< / BR>
N-Methylmorpholin (0,48 g, and 4.68 mmol) was added to a mixture of N--Boc-NG-nitro-L-arginin/3Et2oC and the resulting mixture was stirred for 35 minutes, Add a solution of piperidine derivative 7b (0,85 g, 4.2 mmol) and anhydrous THF (30 ml) in an argon atmosphere at -20oC. the Mixture was stirred at -15oC for 45 min, allowed to warm to room temperature over 3 h and placed in a refrigerator at 0oC for 16 h, the Reaction mixture was filtered and the filtrate concentrated in vacuo. The residue is dissolved in l3and the organic layer was washed with successive portions of water Panso3and brine, dried (Na2SO4) and concentrated in vacuo to obtain a derivative of arginine 7C in the form of a solid; FAB-MS m/z 500 (MH)+.

Stage d

< / BR>
6 N. HCl/EtOH (40 ml) is added to argon to a solution of arginine 7C (1.75 g, 3.5 mmol) and anhydrous THF (30 ml) at room temperature. The reaction mixture is stirred for 1 hour and add another portion 6 N. HCl/EtOH (10 ml) and then further stirred (2 h). Another portion 6 N. HCl/EtOH (10 ml) was added and then stirred for another hour. The reaction mixture was concentrated in vacuo and triturated in THF to obtain a solid product. Part of this solid product (1.26 g, 2,30 mmol) was stirred with anhydrous THF (45 ml) and triethylamin the round. Add another portion of triethylamine (0.25 g) and dansyl chloride (0.20 g) and the reaction mixture is stirred for another hour at room temperature. The solid product was then purified column chromatography on silica gel, elwira EtOAc/MeOH/NH4OH (96: 3:1) to obtain the 7d in the form of a solid; FAB-MS m/z 633 (MH)+.

Stage e

< / BR>
Stage 7

Periodinane dess-Martin add to stir the solution derived 7d (0,19 g, 0.30 mmol) and CH2Cl2(10 ml) at room temperature in argon. The resulting mixture was stirred for 1.5 h and treated with quenching solution (25 g PA2S2O3100 ml saturated aqueous Panso3). The obtained organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is placed in the reaction vessel HF apparatus with anisole and cooled to -78oC. HF is distilled into the reaction vessel and the temperature of the vessel is allowed to warm to 5oWith and support it within 40 minutes the Mixture was concentrated in vacuo and triturated in ether to obtain needle-like solid product. The solid product was then purified HPLC with reversed phase, elwira H2O/CH3CH/TFU (60: 40:0,2) to give compound 7 as a mixture of diastereoisomers; So pl. 85-100oSUB>7
O4S2C2HF3O20,2 H2O:

Calculated: 44,44; N A 4.53; N to 11.52; H2O 1,05.

Found: 44,36; N. Of 4.44; N 11,54; H2O 0,92.

EXAMPLE 8

Stage and

< / BR>
Methyl(triphenylphosphorane)acetate (4,89 g, 114,6 mmol) is added in portions to a solution of ()-N-(tert-butoxycarbonyl)piperidine-2-carboxaldehyde (3.12 g, 14.6 mmol) and anhydrous THF (30 ml) at room temperature in argon atmosphere. The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. The residue is treated with ether (25 ml) and the precipitate removed by filtration. The filtrate was concentrated in vacuo and the residue purified column chromatography on silica gel using hexane/ether (4:1) as eluent to obtain the derived ester 8A in the form of butter.

Stage b

< / BR>
The lithium chloride (1.04 g, 24.5 mmol) was added to a solution of 8A (2.20 g, 8.2 mmol) and anhydrous THF (24 ml). Sodium borohydride (0,93 ml, 24.5 mmol) was added to the mixture, and then absolute ethanol (29 ml) and the resulting mixture was stirred at room temperature for 48 hours. The mixture is cooled to 0oC and add 10% aqueous citric acid to bring the pH to 4. The resulting mixture was concentrated in vacuo, the shape several portions of CH2CL2and the combined organic extracts washed with brine, dried (Na2SO4) and concentrated in vacuo to obtain an alcohol derivative 8b in the form of oil: GC/MS (El) m/z 227 (M)+.

Stage

< / BR>
A solution of alcohol 8b (of 2.06 g, 8.2 mmol) and CH2Cl2(20 ml) was added over 20 min to a mixture of pyridine of chloroformiate (2.64 g, 12.3 mmol) and CH2Cl2at room temperature. The mixture is stirred for 30 min, add ether (200 ml) and the resulting solid precipitate is filtered off. The solid product is washed with several portions of ether/CH2CL2(2:1) and the combined filtrate and organic washing is filtered through silica gel. The organic solution is dried (PA2SO4) and concentrated in vacuo to obtain aldehyde derivative 8C in the form of butter.

Stage d

< / BR>
2-Trimethylsilylimidazole (1.63 g, 8,8 mmol) was added to the aldehyde 8C (1,93 g, 8.0 mmol) at room temperature. The resulting reaction mixture is stirred for 3,25 h, diluted with anhydrous THF and added dropwise 1.0 M of tetrabutylammonium/THF (4.0 ml), stirred for 30 min and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with saturated aqueous Panso

Stage e

< / BR>
Triperoxonane acid (16 ml) was added to the solution derived thiazole 8b (2,48 g, 7.6 mmol) and CH2Cl2(50 ml) at room temperature in argon atmosphere. The reaction mixture was stirred for 2 h, concentrated in vacuo and dissolved in l3(60 ml). The solution is alkalinized 50% aqueous NaOH (20 ml) and the aqueous layer was washed with several portions l3/2-propanol (20: 1). The combined organic extracts dried (K2CO3) and concentrated in vacuo to obtain an oil. This oil is purified chromatographically on silica gel, elwira with ethyl acetate/Meon/NH4HE (97:3:1) to give the thiazole with remote protection 8E; FAB-MS m/z 227 (MH)+.

Stage f

< / BR>
Isobutylparaben (0.39 g, 2,87 mmol) was added to a solution of N--Boc-NG-nitro-L-arginin/3Et2O1/4EtOAc (1.12 g, 2,87 mmol), N-methylmorpholine (0.32 g, 3,20 mmol) and anhydrous THF (20 ml) at -20oC in argon atmosphere. The reaction mixture is stirred at -5 - -10oC for 30 min and cooled to -20oC. is Added dropwise a solution derived thiazole 8E (0.65 g, 2,87 mmol) and THF (20 ml) for more than 2-3 min and the resulting mixture was stirred at -15 - -10oC for 45 min and stirred at room temperat (0.16 g, 1.6 mmol) and isobutylphthalate (of € 0.195 g, 1.44 mmol) prepared as described above and stirred at -15 - -10oC for 1 h and added to the initial reaction mixture. The resulting mixture was stirred at -15 - -10oC for 1 h and at room temperature for 16 hours, the Reaction mixture was filtered and concentrated in vacuo and dissolved in l3. The organic layer was washed with successive portions of saturated aqueous Panso3and brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified by HPLC using ethyl acetate/Meon/NH4HE (30:3:1) to obtain the derivative of arginine 8f in the form of a solid product.

Stage g

< / BR>
Ethanol 6 N. Hcl (20 ml) is added slowly to a stirred solution derived arginine 8f (0.87 g, of 1.65 mmol) and anhydrous THF (15 ml) at room temperature in argon atmosphere. The reaction mixture was stirred for 45 min, concentrated in vacuo and dissolved in THF (20 ml). Added triethylamine (0.75 g, 7.4 mmol) and then dansyl chloride (0,46 g, 1.70 mmol) and the resulting mixture was stirred at room temperature in an argon atmosphere for 18 hours Add another portion of triethylamine (0.50 g, 4.9 mmol) and dansyl chloride (0,23 g, will astonaut in several portions of ether to obtain the derivative of dansili 8g in the form of a solid product, which is used without further purification; FAB-MS m/z 661 (MH)+.

Stage h

< / BR>
Perioding dess-Martin (0,72 g, 1.70 mmol) was added in portions to a stirred mixture derived dancila 8f (1.20 g, of 1.36 mmol) and anhydrous CH2Cl2(40 ml) at 5oC in argon atmosphere. The reaction mixture is allowed to warm to room temperature, stirred for 1.5 h, treated with 100 ml of quenching solution (25 g PA2S2O3100 ml saturated aqueous Panso3) and extracted with l3(50 ml) and the resulting aqueous layer was washed with several portions l3. The combined organic extracts washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified chromatographically (silica gel), elwira with ethyl acetate/Meon/NH4HE (95:5:1). The desired fraction was concentrated in vacuo, dissolved in CH2Cl2, dried (Na2SO4) and concentrated in vacuo to obtain the derived ketone 8h in the form of a solid; FAB-MS m/z 882 (MH)+.

Stage i

< / BR>
Compound 8

The derived ketone 8h (160 mg, 0.2 mmol) was placed in the reaction vessel HF apparatus, add anhydrous anisole (2 ml) and the mixture is cooled to -78oC. HF (5 ml) agonafir (25 ml) and the mixture was stored in a refrigerator at 0oC in argon atmosphere for 16 hours, the Ether removed and the solid residue triturated in several portions of ether, isolated and dried in vacuum. The residue is purified column chromatography (reversed-phase), elwira CH3SP/N2O/TFU (93:7:0,2) to obtain compound 8 in the form of 1:1-mixture of diastereomers; So pl. 65-70oC; []25D= +35,6 (0,52, Meon); FAB-MS m/z 614(MH)+.

Analysis. The calculation for C29H39N7O4S23,5 S2HF3ABOUT20.5 N2O:

Calculated: 42,71; N 4,29; N 9,59; N2O 0,88.

Found: 42,76; N. Of 4.44; N 9,67; H2O 0,81.

EXAMPLE 9

Stage and

< / BR>
A solution of 2-naphthalenesulfonate (4.52 g, 20 mmol) and ether (50 ml) is added to a stirred solution of glycine (1.5 g, 20 mmol) and 1 N. NaOH (40 ml) at room temperature. This mixture is stirred for 6 h, the ether layer was separated and the aqueous layer was washed with several portions of ether. the pH of the Aqueous layer was installed 1 by 1 N. Hcl and diluted with N2About (50 ml). Resulting solid precipitate is isolated and dried in vacuum to obtain acid 9a in the form of a solid product.

Stage b

< / BR>
The solution DCC (0.55 g, to 2.67 mmol) and CH3SP (10 ml) was added dropwise to a solution of hydrate of 1-hydroxybenzo is(20 ml) in an argon atmosphere. The mixture is stirred at room temperature for 2 h, filtered and concentrated in vacuo. The residue is dissolved in water, washed with successive portions of saturated aqueous Panso3and brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified by chromatography, elwira with ethyl acetate/Meon/NH4HE (95:5:1) as eluent. The desired fractions are combined, dried (Na2SO4) and concentrated in vacuo to obtain the associated intermediate 9b in the form of a mixture of diastereomers; FAB-MS m/z 719 (MH)+.

Stage

< / BR>
Activated MnO2(0,90 g, 10.4 mmol) is added to a stirred solution of intermediate 9b (0,85 g, 1.18 mmol) and CH2Cl2(35 ml) at room temperature. The reaction mixture was stirred at room temperature for 48 h, filtered through a Nylon filter 66 (0.45 μm) and concentrated in vacuo. The residue is purified by chromatography on silica gel, elwira with ethyl acetate/Meon (95: 5) as eluent. The desired fractions are combined dissolved in CH2CL2, dried (Na2SO4) and concentrated in vacuo to obtain a derivative of thiazole 9c in the form of a mixture of diastereomers: FAB-MS m/z 717 (MH)+.

Stage d

< / BR>
PE is 2Cl2(5 ml) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched by adding 5 ml of quenching solution (25 g PA2S2O3100 ml saturated aqueous Panso3), ethyl acetate (20 ml) followed by stirring for 40 minutes the organic layer was separated and the aqueous layer was washed with portions of ethyl acetate. The combined organic extracts are washed with successive portions of saturated aqueous Panso3and brine, dried (Na2SO4) and concentrated in vacuo to obtain ketone 9d in the form of a mixture of diastereomers; FAB-MS m/z 715 (MH)+.

Stage e

< / BR>
Ketone 9d (190 mg, 0.26 mmol) and anisole (2 ml) are combined in a Teflon reaction tube HF apparatus. HF (10 ml) is distilled into the flask at -78oC, the resulting mixture was heated to 0oC and stirred at 0oC for 3 h HF is removed in vacuo add ether (25 ml) and the closed stopper the flask in the refrigerator for 16 hours resulting solid product is collected by filtration, washed with several portions of ether and dried in a stream of nitrogen. The solid product was then purified HPLC with reversed phase using H2O/CH3SP/TFU (60:40:0,2) PoluchenieoC;

Analysis. The calculation for C24H28N6O6S2WITH2HF3O2H2O:

Calculated: 45,08; N 4,51; N 12,13; N2About 2,60.

Found: 44,96; N 4.26 DEATHS; of $ 11.97 N; N2O 2,99.

EXAMPLE 10

Stage and

< / BR>
A solution of di-tert-BUTYLCARBAMATE (21.8 g, 0.10 mol) and anhydrous CH2Cl2(200 ml) was added dropwise to a stirred solution of ()-2-piperidinemethanol (12.9 g, 0.10 mol) and CH2Cl2(200 ml) at 0oWith argon for more than 30 minutes the Reaction mixture is allowed to warm to room temperature and stirred for 5 hours, the Reaction mixture is extracted twice 1 N. Hcl, once with saturated aqueous Panso3and once with brine, dried (Na2SO4) and concentrated in vacuo to obtain the protected amine 10A in the form of butter.

Stage b

< / BR>
A solution of amine 10A (10.3 g, 45 mmol) and CH2Cl2(100 ml) was added over 15 min to a stirred solution of pyridine of chloroformiate (14.5 g, of 67.5 mmol) at room temperature. The resulting mixture was stirred for 4 h and diluted with ether (600 ml). The entire reaction mixture is filtered through auxiliary filtering material and concentrated in vacuo to obtain AK) was added in portions to a solution of aldehyde 10b (9,14 g, of 40.3 mmol) and THF (100 ml) at room temperature in argon atmosphere. The reaction mixture was stirred for 16 h and concentrated in vacuo. The residue is triturated in several portions of ether. The combined ether extracts are dried (Na2SO4) and concentrated in vacuo to obtain ester 10C in the form of butter.

Stage d

< / BR>
A solution of ester 10 (of 7.75 g of 27.3 mmol) and LiCl (3,49 g, 82 mmol) in anhydrous THF (80 ml) was treated with NaBH4(3.12 g, 82 mmol) under stirring at room temperature in argon atmosphere. Added EtOH (97 ml) and the resulting mixture was stirred at room temperature for 62 hours the mixture is cooled to 0oAnd with 10% aqueous citric acid to establish a pH of 4. The mixture was concentrated in vacuo to obtain a water layer. the pH of this layer set with 10% aqueous citric acid as pH 4, stirred at room temperature for 30 min and extracted several times CH2Cl2. The combined organic extracts washed with brine, dried and concentrated in vacuo to obtain alcohol 10d in the form of butter.

Stage e

< / BR>
A solution of alcohol 10d (6,06 g, 23.5 mmol) and CH2Cl2(50 ml) was added to a mixture of pyridine ri room temperature for 2 hours Add diethyl ether (250 ml) and the resulting mixture was filtered through a plug of silica gel, which in turn was washed with CH2Cl2/Et2O (1: 1). The filtrate is dried (Na2SO4) and concentrated in vacuo and the residue purified by chromatography on silica gel, elwira with ethyl acetate/hexane to obtain aldehyde 10th in the form of butter.

Stage f

< / BR>
2-(Trimethylsilyl)thiazole (1.70 g, 9.2 mmol) was added to the aldehyde 10th (2,07 g, 8.1 mmol) at room temperature in argon atmosphere. The reaction mixture was stirred for 4 h, diluted with THF (60 ml) and added dropwise 1.0 M of tetrabutylammonium/THF, followed by stirring for 15 minutes the mixture was concentrated in vacuo, diluted with ethyl acetate, washed with several successive portions of saturated aqueous Panso3and brine, dried (Na2SO4) and concentrated in vacuo to obtain a derivative of thiazole 10f in the form of butter.

Stage g

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Triperoxonane acid (16 ml) was added to a stirred solution of thiazole 10f (2,90 g, 8.0 mmol) and CH2Cl2(90 ml) at room temperature in argon atmosphere. The mixture is stirred for 1 h, concentrated in vacuo and diluted with CH24OH (95: 5: 2). The desired fraction was concentrated in vacuo, dissolved in CH2Cl2, dried (K2CO3) and concentrated in vacuo to obtain amine 10g as a mixture of diastereoisomers.

Stage h

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Isobutylparaben (0.55 g, 4.0 mmol) was added to a stirred mixture of N-Boc-NG-nitro-L-arginin/3Et2O1/4EtOAc (1.56 g, 4.0 mmol), N-methylmorpholine (of 0.44 g, 4.4 mmol) and anhydrous THF (25 ml) at -20 - -15oIn an argon atmosphere and the temperature of the reaction support at -15 - -10oWith for 1.5 hours At 60 seconds add a solution of amine 10f (0,85 g, 3.54 mmol) and THF (5 ml) at -10oC. the Reaction mixture is stirred at -10oC for 1 h, allowed to warm to room temperature and stirred for 16 hours Add a drop of DMF, the mixture was stirred for further 2 h at room temperature and filtered. The filtrate was concentrated in vacuo and dissolved in HCl3. The organic layer was washed with successive portions of saturated aqueous Panso3and brine, dried (Na2SO4) and concentrated in vacuo to obtain the associated derived 10h in the form of a solid product.

Stage i

< / BR>
Ethanol 6 n Hcl add the mixture is stirred for 2.5 h, concentrated in vacuo, dissolved in THF (25 ml) and again concentrated to obtain oil. The residue is dissolved in THF (40 ml) together with triethylamine (15 mmol) and process dansyl chloride (0.84 g, 3.1 mmol). The mixture is stirred at room temperature in an argon atmosphere for 16 hours the mixture is filtered, the filtrate was concentrated in vacuo and the residue triturated twice with ether to obtain the derivative of dansili 10i in the form of a solid product which is used without additional purification stages.

Stage j

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Periodinane dess-Martin (of 0.90 g, 2.1 mmol) was added to stir the mixture derived 10i (1,02 g, 1.5 mmol) and CH2Cl2(30 ml) at room temperature in argon atmosphere. The mixture is stirred for 1.5 h at room temperature, treated with 50 ml of quenching solution (25 g of Na2S2O3100 ml of saturated aqueous NaHCO3) and stirred for 40 minutes the Organic layer was separated and the aqueous layer was twice extracted with CH2Cl2. United CH2Cl2the extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is dissolved in ethyl acetate (10 ml) and Meon (3 ml), purified chromatographically on silica gel, Elwell>2SO4) and concentrated in vacuo to obtain the derived ketone 10j in the form of a solid product.

Stage k

< / BR>
Connection 10

Ketone 10j (0.32 g, 0.47 mmol) and anisole (5 ml) was placed in a Teflon reaction tube HF apparatus under anhydrous conditions and cooled to -78oC. HF (20 ml) was distilled directly into the vessel and the temperature of the mixture is allowed to rise to 0oC. the Mixture is stirred for 1 h, HF is removed in vacuo and the residue is dissolved in ether (25 ml) and stored in the refrigerator in anhydrous conditions during the night. The ether layer is removed and the resulting residue triturated in several portions of ether to obtain a solid product. The solid product was then purified HPLC with reversed phase, using H2O/CH3SP/TFU (60:40:0,2) to give compound 10 as a mixture of diastereoisomers; T. pl. 81-91oC; []25D= +25,9 (from 0.26, Meon); FAB-MS m/z 628,9 (MH)+.

Analysis. The calculation for C30H41N7O4S23C2HF3O2H2O:

Calculated: 43,77; N 4,69; N 9,92; N2O 1,82.

Found: 43,77; N 4,56; 10,00 N; N2About 1,82.

EXAMPLE 11

N-METHYL-D-I.E. PHENYLALANYL-N-[5-[(AMINOIMINOMETHYL)AMINO] -1S-[(BENZOTHIAZOL-2-YL)CARBONYL]PENTYL]-L-PROLINAMIDE

Stage and

< / BR>
ode cooled to 5oAnd pH is adjusted to 11.0 using 3 n NaOH. Benzylchloride (6,00 ml, 42 mmol) was added dropwise over 4 h under stirring in an argon atmosphere at 5oC. the Reaction mixture is allowed to slowly warm to 22oWith over 16 h and then extracted three times with ether. The aqueous layer was cooled to 5oTo establish a pH of 2.0 using 3 N. Hcl and extracted with three portions of ethyl acetate. In the cooled acidic aqueous layer establish a pH of 11.0 with 3 N. NaOH and diluted with 175 ml of dioxane. One portion was added di-tert-BUTYLCARBAMATE (38,2 g, 175 mmol) in 5oWith under stirring in argon atmosphere. The reaction mixture is allowed to slowly warm to 22oWith over 16 h, the set pH of 11.0 with 3 N. NaOH and add another portion of di-tert-BUTYLCARBAMATE (38,2 g, 175 mmol) and stirred at 22oC for more than 24 hours, the Dioxane is removed in vacuum at 40oWith and establish a pH of 11.0 reaction mixture using 3 N. NaOH, extracted three times with ether, cooled to 5oWith, and saturated NaCl. Added ethyl acetate (100 ml) and set pH 4.0 with 25% citric acid (CAUTION: the allocation of CO2) under stirring at 5oC. the Layers are separated and the acidic aqueous layer extragere the Celaform FW-14 and concentrated in vacuo at 40oWith obtaining 3,70 g (56%) as a transparent glass-like product; FAB-MS m/z 381 (MH+).

Stage b

< / BR>
Compound 11a (6,86 g, 18 mmol) is dissolved in 180 ml of methanol and added to 1.37 g of 20% Pd(OH)2/C and placed under pressure 60 psi N2in a Parr apparatus for 18 hours, the Reaction mixture was filtered and the cake on the filter with 150 ml portions of methanol (CAREFULLY). The combined methanol extracts filtered through Celaform FW-14 and concentrated in vacuo at 40oWith obtaining 3.5 g (79%) of compound 11b as a white solid; FAB-MS m/z 247 (MH+).

Stage

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Compound 11b (3,40 g of 13.8 mmol) are combined with triethylamine (5,77 ml, up 41.4 mmol) in DMF (75 ml) and the resulting suspension was added N,N'-bis(benzylcarbamoyl)-3-methylisothiazoline (7,42 g of 20.7 mmol; ibid.). The resulting mixture was stirred at 22oC in nitrogen atmosphere for 40 h, treated with triethylamine (2.0 ml, 14.4 mmol) and N,N'-bis(benzylcarbamoyl)-3-methylisothiazoline (0,78 g, 2.2 mmol), stirred for 24 h, again treated with triethylamine (2.0 ml, 14/4 mmol) and N,N'-bis(benzylcarbamoyl)-S-methylisothiazoline (1.48 g, 4.1 mmol) and stirred at 22oWith in 3 days. The crude reaction mixture was filtered through Celaform FW-14 and udelay layer is extracted four times with ether, cooled to 5oWith, rasclaat with ethyl acetate and establish pH 3.5 with citric acid. The layers are separated and the acidic aqueous layer is extracted four times with ethyl acetate. United an ethyl acetate extracts are dried (Na2SO4), filtered through Celaform FW-14 and concentrated in vacuo at 40oC. the Residue is purified HPLC on silica gel, elwira CH2Cl2/MeOH (95:5) to obtain the 5,94 g (77%) of 11C as a white foam; FAB-MS m/z 557 (MH)+.

Stage d

< / BR>
To a solution of compound 11C (5,86 g, 10.5 mmol) in 210 ml of methanol was added 20% Pd(OH)2/C (1.47 g) and the mixture is placed under a pressure of 60 psi hydrogen in a Parr apparatus for hydrogenation. After 24 hours add another portion of 20% Pd(OH)2/C (0.74 g) and the mixture is placed under a pressure of 60 psi of hydrogen for 6 hours the Crude reaction mixture was filtered through Celaform FW-14 and concentrated in vacuo at 40oWith obtain 3.03 g (100%) of a white foam; FAB-MS m/z 289 (MH+).

Stage e

< / BR>
Compound 11d (519 mg, of 1.80 mmol) was dissolved in 2.7 ml of 4 n KOH and diluted with 9.0 ml of acetone and cooled to -18oC. To this solution was added a solution of p-toluensulfonate (686 mg, 3.6 mmol) in 3.6 ml of acetone for more than 15 min with vigorous stirring. After 1 h at -18 - -15oWith the reaction mixture Doc diluted with 25 ml of water and extracted three times with ether. The aqueous layer was saturated with NaCl, rasclaat with ethyl acetate, cooled to 5oWith and establish pH 3.5 with 1 N. Hcl. The acidic aqueous layer is extracted with more than four times with ethyl acetate and the combined an ethyl acetate extracts are washed twice with saline, dried (Na2SO4) and concentrated in vacuo at to obtain 720 mg (90%) 11e in the form of a white foam; FAB-MS m/z 443 (MH)+.

Stage f

< / BR>
Mix a solution of 11e in 29 ml of CH2Cl2/MeOH (9:1) is cooled to 5oC and treated dropwise 2M (trimethylsilyl) diazomethane in hexane (4.3 ml, 8,63 mmol). After 10 min the reaction mixture was concentrated in vacuo at 22oWith and the residue purified HPLC on silica gel, elwira with ethyl acetate/hexane (3:2) to obtain 1.06 g (81%) 11f in the form of a white foam; FAB-MS m/z 457 (MH)+.

Stage g

< / BR>
A solution of benzothiazole (2,63 g of 19.5 mmol) in 20 ml of THF is cooled to -75oWith under stirring in nitrogen atmosphere, n-Utility (1.6 M in hexane, 9,46 ml, 15.1 mmol) was added dropwise over 15 min at -75 - -65oC and then stirred at -75 - -65oC for 15 minutes To this solution are added dropwise over 15 min a solution of 11f (461 mg, 1.0 mmol) in 10 ml THF at -75 - -70oC. the Reaction mixture was stirred at-Dom. United an ethyl acetate extracts are washed three times with saline, dried (Na2SO4) and concentrated in vacuo. The residue is triturated three times with hexane, dissolved in 150 ml of ethyl acetate/hexane (3: 2), filtered through Celaform FW-14 and the residue purified HPLC on silica gel, elwira with ethyl acetate/hexane (3:2) to obtain the 0,42 g (74%) 11g in the form of a transparent glass-like product; FAB-MS m/z 560 (MH)+.

Stage h

< / BR>
Compound 11g (0,389 g, 693 mmol) was dissolved in 14 ml of CF3CO3N/A CH2CL2(1:4), stirred at 22oC for 2 h in nitrogen atmosphere and concentrated in vacuo at 10oC. the Residue partitioned between 20 ml of water 1 N. NaOH, pre-saturated NaCl and 20 ml of CH2Cl2. Basically the aqueous layer was extracted with more than three times CH2Cl2and United CH2Cl2the extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo to obtain 319 g (100%) 11h as a brown amorphous solid; FAB-MS m/z 462 (MH)+.

Stage i

< / BR>
Solution (CBZ)-N-methyl-D-i.e. phenylalanyl-L-Proline (0,309 g, 0,753 mmol; U.S. patent 4703036) and diisopropylethylamine (132 μl, 0,758 mmol) in 10 ml anhydrous CH2Cl2cooled to 5oC, stirred the mixture is stirred for 15 minutes For more than 10 min was added a solution of 10h (0,316 g, 0,685 mmol) and diisopropylethylamine (119 μl, 0,684 mmol) in 10 ml anhydrous CH2Cl2when 5oC and the reaction mixture allowed to warm to 22oC for 4.5 h, the Reaction mixture was concentrated in vacuo at 40oWith and the residue distributed between ethyl acetate and aqueous 1 M KHSO4. The organic layer is extracted with two times water 1 M KHSO4three times with saturated aqueous NaHCO3twice with saline, dried (Na2SO4) and concentrated in vacuo at 40oC. the Residue is purified chromatographically on silica gel, elwira with ethyl acetate/hexane (4:1) to obtain the 0,381 g (65%) 11i in the form of a white foam; FAB-MS m/z 855 (MH)+.

Stage j

< / BR>
Connection 11i (0,359 g, 0,420 mmol) dissolved in 6 ml anhydrous CH2C12. Add periodinane dess-Martin (0,304 g, 0,717 mmol) and the reaction mixture stirred at 22oC in argon atmosphere. Excess periodinane removed by addition of 20 ml of quenching solution (25 g of Na2S2O3100 ml saturated aqueous Panso3), diluted with ethyl acetate (60 ml) and stirred at room temperature for 15 minutes Remaining aqueous layer was separated and extracted several then the solution, dried (Na2SO4) and concentrated in vacuo to obtain 0,336 g (94%) of ketone 11j in the form of a white foam; FAB-MS m/z 853 (MH)+.

Stage k

< / BR>
Connection 11

Connection 10j (0,336 g, 0,394 mmol) dissolved in 3 ml of anhydrous thioanisole, placed in a Teflon reaction tube HF apparatus under anhydrous conditions and cooled to -78oC. Anhydrous HF (3-4 ml) was distilled directly into this tube and upon completion of addition, the temperature of the mixture is allowed to rise to 0oC. This mixture was stirred at 0oC for 4 h, concentrated in vacuo and triturated in several portions of ether to obtain a white solid product. The solid product was then purified HPLC with reversed phase, elwira H2O/acetonitrile/TFU (60: 40:0,2). The fractions containing the compound 10 are pooled, concentrated in vacuo and lyophilized obtaining 0,094 g (28%) of compound 11 as a white solid product; So pl. 122-130oC; []25D= - 85,3 (from 0.26, Meon); FAB-MS m/z 853 (MH)+.

Analysis. The calculation for C29H37N7O3S2,TFU,N2ABOUT:

Calculated: 46,92; N. Of 5.05; N 11,40; F 15,24; H2O 3,98.

Found: 46,59; 5,00; N 11,17; F 15,16; H2O 3,40.

EXAMPLE 12

N-METHYL-D-i.e. phenylalanyl-N-[4-[(AMINOIMINOMETHYL)AMINO] -2S-[(6-METHOXYCARBONYL the mol) are added dropwise to a stirred solution of benzothiazole-6-carboxylic acid (11.5 g, 64,17 mmol) in THF (100 ml) at -78oC in nitrogen atmosphere with such speed that the reaction temperature was below -70oC. After completion of addition, the reaction mixture is stirred for 30 min at -78oWith and added N-BOC-NG-tosyl-L-arginine N, 0-dimethylamide (800 mg, 1,69 mmol; DiMaio, et al. Journal of Medicinal Chemistry 1992, 35, 3331) (2,52 g to 5.35 mmol) in THF (150 ml) at such a speed as to maintain the temperature below 70oC. the resulting mixture was stirred for 2 h at -78oC, heated to -20oWith and diluted with saturated aqueous NH4Cl (700 ml). The obtained organic layer was separated and the aqueous layer was washed with several portions of EtOAc. United an ethyl acetate extracts washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude mixture is purified by chromatography on silica gel, elwira CH2Cl2/MeOH (8:1) to obtain the associated intermediate benzothiazole 12A in the form of a solid product.

Stage b

< / BR>
Sodium borohydride (1.42 g, of 37.6 mmol) was added in one portion to a solution of 12A (3.5 g, 5.9 mmol) in Meon (130 ml) at -25 to -20oC and the reaction mixture is stirred for 40 minutes Added acetone (20 ml), the mixture is allowed to warm to room temperature and to whom they are portions of EtOAc. The combined extracts washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue is dissolved in CH2Cl2/MeOH (6: 1) and cooled to 0oC. are Added dropwise trimethylsilyldiazomethane (2M in hexane) over a 5 min until the yellow color and the reaction mixture is stirred for another 25 minutes the mixture was concentrated in vacuo and purified column chromatography, elwira EtOAc/hexane (3:1 to 6:1) to give the alcohol 12b in the form of a solid product.

Stage

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A solution of 12b (3.1 g, 4,56 mmol), TFU (26 ml) in CH2Cl2(104 ml) was stirred at room temperature for 1 h and concentrated in vacuo. The residue was diluted with CH2Cl2and concentrated in high vacuum to obtain the crude product 12C in the form of butter.

Stage d

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A solution of 12C (2.3 g, 4,56 mmol) and NOT (1,32 g, 9,12 mmol) in CH3SP (210 ml), neutralized by addition of triethylamine (approx. 5 ml) in an atmosphere of N2. To this solution was added DCC (1.4 g, at 6.84 mmol) and N-methyl-N-(CBZ)-D-i.e. phenylalanyl-L-Proline in one portion and the mixture stirred for 2 h at room temperature and filtered. The filtrate was concentrated in vacuo and dissolved in EtOAc. Organic rest is their vacuum associated with obtaining product 12d in the form of a solid product.

Stage e

< / BR>
Periodinane dess-Martin (680 mg, 1,60 mmol) was added to a solution of 12d (720 mg, 3,76 mmol) in CH2Cl2(40 ml) at room temperature in an atmosphere of N2and the resulting mixture is stirred for 25 minutes Excess periodinane removed by adding 30 ml of quenching solution (25 g PA2S2O3100 ml saturated aqueous Panso3to stir the reaction mixture. The obtained aqueous layer was isolated and extracted with several portions of CH2Cl2and the combined organic extracts are washed with successive portions of water and brine, dried (Na2SO4) and concentrated in vacuo to obtain the ketone 12 in the form of a solid product.

Stage f

< / BR>
Connection 12

The intermediate ketone 12E (730 mg, 0.81 mmol) and anisole (3 ml) was placed in a Teflon reaction tube HF apparatus under anhydrous conditions and cooled to -78oC. HF (15-20 ml) was distilled directly into the vessel and the temperature of the mixture is allowed to rise to 0oC. the Mixture is stirred for 3.5 h, concentrated in vacuo and triturated in several portions of ether to obtain a solid product. This solid product was then purified HPLC with reversed phase, using water/acetonitrile/TFU (70MS m/z 608,3(MH)+.

Analysis. The calculation for C30H37N7O5S2,5CF3CO2H1,7H2ABOUT:

Calculated: 45,53; N 4,68; F 15,43; N to 10.62; H2About 3,32.

Found: 45,51; N 4,53; F 15,19; N 10,54; N2About 3,32.

EXAMPLE 13

N-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(6-CARBOXYPROPYLBETAINE-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
Connection 13

Connection 13 get modifying the example 12. A solution of anhydrous LiOH (400 mg, and 16.7 mmol) in water (12 ml) was added stirred solution of compound 12d (5.0 g, to 5.57 mmol) in dioxane (100 ml) at room temperature. The mixture is stirred for 4 h and added an additional portion of LiOH (300 mg, 12.5 mmol) in water (7 ml) followed by stirring for 3 hours the mixture is acidified Et (pH 3-4) and extracted with EtOAc several times. The combined organic extracts washed with water and brine, dried (Na2SO4) and concentrate to obtain carboxybenzeneboronic derivative 6. This derivative is converted into the desired compound by a subsequent stage e in the outer 25% water PA2S2O3and stage f of example 12 to obtain compound 13 in the form of a solid product; T. pl. 125oC; []25D= -79,6 (1,0, O:

Calculated: 45,54; N. OF 4.44; F 15,89; N OF 10.93; N2O 2,01.

Found: 45,59; N 4,59; F 15,60; N 10,76; N2O 2,09.

EXAMPLE 14

N-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(6-CARBOXAMIDATES-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 14

The connection 14 get modifying the example 12. NOT (138 mg, is 0.102 mmol) and DCC (14 mg, 0,068 mmol) was added to a stirred solution of compound 12C (30 mg, 0,034 mmol) in CH2C12/DMF (4:1, 2 ml) at room temperature in an atmosphere of N2. The reaction mixture was stirred for 30 min and add water 29% NH4OH (50 μl, 0.38 mmol). The mixture is stirred for 5 h and added another portion of NEWT (7 mg), DCC (7 mg) and water 29% NH4OH (20 µl). After stirring for another 2 h the mixture was diluted with CH2Cl2. The obtained organic layer was washed with successive portions of water and brine, dried (Na2SO4) and concentrate to obtain the corresponding 6-carboxamidotryptamine derived. This derivative is converted into the desired compound by using the following steps e and f of example 12 with the connection 14 in the form of a solid product; So pl. 130-143oC; []25D= -76,0 0.3, Meon); FAB-MS m/z 59 Calculated: 42,61; N 4,65; F 16,85; N 12,42; H2O by 5.87.

Found: 42,16; N 4,35; F 16,19; N OF 11.45; N2O lower than the 5.37.

EXAMPLES 15 AND 16

N-METHYL-D-FERMANI-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(6-HYDROXYMETHYLBENZENE-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE Conn. 15

N-METHYL-D-i.e. phenylalanyl-N-[4-[(AMINOIMINOMETHYL)AMINO] -1R-[(6-HYDROXYMETHYLBENZENE-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE Conn. 16

Stage and

< / BR>
15a; X=O; 15e; X=H, h

The connection 15 get modifying the example 12. 1.0 M DIBAL (10 ml, 10 mmol) was added dropwise to a stirred solution of compound 12C (1.5 g, 1,67 mmol) in dry CH2Cl2(160 ml) at -78oC in an atmosphere of N2. The temperature of the reaction mixture is kept lower than -74oIn the process of adding. The mixture is stirred for 45 min and quenched with concentrated aqueous NH4OH (50 ml). Add part 1 N. Hcl to separate the aqueous and organic layers and the resulting aqueous layer was washed with CH2Cl2. The combined organic extracts are washed with successive portions of saturated Panso3, water and brine, dried (Na2SO4) and concentrate to obtain 15A and the corresponding derivative of methylene 15th in the form of a mixture, which is used without purification.

Steribeam solution 15A and 15th (9,2 mg) at 0oC in an atmosphere of N2. One portion was added a solution of tributyltinchloride (45,3 mg, 0.30 mmol) in CH2Cl2(15 ml) and the reaction mixture is allowed to rise to room temperature and stirred for 8 hours the mixture was diluted with CH2Cl2and washed with successive portions of 10% citric acid, saturated aqueous NaHCO3N2Oh and saline. The obtained organic layer is dried (Na2SO4) and concentrated in vacuo to obtain a mixture of 15b and the corresponding methylene 15f, which is used without further purification.

Stage

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15c; X=O; 15g; X=H, h

Periodinane dess-Martin (142 mg, 0,334 mmol) was added to a solution of 15b and 15f (160 mg) in CH2Cl2(20 ml) at room temperature in an atmosphere of N2and the resulting mixture is stirred for 30 minutes, the Excess periodinane removed by adding 10 ml of quenching solution (25 g of Na2S2ABOUT3100 ml saturated aqueous Panso3to stir the reaction mixture. The obtained aqueous layer was isolated and extracted with several portions of CH2Cl2and the combined organic extracts are washed with successive portions of saturated aqueous whom thou ketone 15C and the corresponding methylene derivative 15g in the form of a solid product.

Stage d

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Intermediate products 15C and 15g (170 mg, 0,17 mmol) and anisole (2.5 ml) was placed in a Teflon reaction tube HF apparatus under anhydrous conditions and cooled to -78oC. HF (5 ml) is distilled into the vessel and after completion of addition, the temperature of the mixture is allowed to rise to 0oC. the Mixture is stirred for 3.5 h, concentrated in vacuo and triturated in several portions of ether to obtain a solid product. This solid product was then purified HPLC with reversed phase, using water/acetonitrile/TFU (70:30:0,2) to obtain the compounds 15 and 16 in the form of a pure solid products:

The connection 15: FAB-MS m/z 580 (MH)+.

The connection 16: So pl. 75-85oC; []25D= -82,6 (0,32, Meon); FAB-MS m/z 580 (MH)+.

Analysis. The calculation for C30H37N7O5S2,5F3CO2N1,7H2O:

Calculated: 43,74; N Is 4.85; N Of 10.09.

Found: 43,96; N Was 4.76; N 9,95.

EXAMPLES 17 AND 18

N-METHYL-D-i.e. phenylalanyl-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(6-FERMENTATION-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE Conn. 17

N-METHYL-D-i.e. phenylalanyl-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(6-FERMENTATION-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE Conn. 18

< / BR>
Compounds 17 and 18 receive modifying the example 12. Source benzothiazole with the positive changes. 6-Fermentational obtained as follows. A solution of sodium nitrite (24.6 g, 35,7 mmol) in water (80 ml) was added dropwise to a stirred solution of 2-amino-6-triftoratsetata (10.0 g, 59.5 mmol) in 85% H3RHO4if -10oWith such a way that the temperature did not exceed -4oC. the Mixture is maintained at -8oC for 1 h, poured into 50% H3PO4at 0oC and allowed to warm to room temperature over 2 hours Add water to achieve total volume of 3 l and the resulting mixture is neutralized with N2CO3. The aqueous layer and the solid residue is extracted with several portions CHCl3/EtOAc (1:1) and the combined organic extracts washed with brine, dried (Na2SO4) and concentrate to obtain 6-perbenzoate in the form of a solid product.

The connection 17: So pl. 65-80oC; []25D= was 72.9C (0,32, Meon) FAB-MS m/z 568 (MH+);

Analysis. The calculation for C28H34FN7O3S3,0CF3CO2H1,1H2O:

Calculated: 43,94; F 20,44; N 4,25; N 10,55; N2About 2,13.

Found: 43,96; F 20,57; N 4,22; N 10,82; N2About 2,22.

The connection 18: So pl. 85-100oC; []25D= -61,6C (0,85, Meon) FAB-MS m/z 568 (MH+);

A9 39; N OF 4.35; N 10,99; N2O 1,82.

Found: 45,01; F 19,61; N 4,24; N OF 11.15; N2O 1,84.

EXAMPLES 19 AND 20

N-METHYL-D-i.e. phenylalanyl-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(4-ETHOXYCARBONYLMETHYL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE Conn. 19

N-METHYL-D-i.e. phenylalanyl-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(4-ETHOXYCARBONYLMETHYL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE Conn. 20

< / BR>
Compounds 19 and 20 receive modifying the example 9. N-(CBZ)-N-methyl-D-i.e. phenylalanyl-L-Proline is used instead of intermediate 9a and the other stages of the reaction sequence is carried out on the corresponding arginine-epimeric with only minor changes with obtaining specified in the connection header in the form of a solid product.

The connection 19: So pl. 85-100oC; []25D= -61,6C (0,85, Meon); FAB-MS m/z 572 (MH+);

Analysis. The calculation for C27H37N7O5S2,3F3CO2N1,5H2O:

Calculated: 44,08; N. OF 4.95; N IS 11.39; N2About 3,14.

Found: 44,25; N TO 4.68; N 11,29; N2About 3,29.

The connection 20: So pl. 85-100oC; []25D= -61,6C (0,85, Meon); FAB-MS m/z 572 (MH+);

Analysis. The calculation for C27H37N7O5S2,75F3CO2H2,HE2About 4,21.

EXAMPLE 21

< / BR>
Connection 21

Connection 21 get modifying the method according to example 5. 1,2-Phenylenediamine substituted 2-aminophenol in stage d of example, to obtain the corresponding derivative of benzimidazole. This derivative is subjected to the other stages when only minor changes with obtaining specified in the connection header in the form of a solid product: So pl. 70-80oC; []25D= -63,1C (C=1.00 m, N2O); FAB-MS m/z 533 (MH+);

Analysis. The calculation for C28H36N8O33,75 CF3CO2NN2ABOUT:

Calculated: 43,59; N 4,30; N OF 11.45; N2About 1,84.

Found: 43,66; N 4,37; N OF 11.45; N2About 1,84.

EXAMPLE 22

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The connection 22

The connection 22 receive, following the General method of example 12. N-Mei is used instead of benzothiazole on stage and getting the imidazole analog of intermediate 12A. This intermediate compound is subjected to the other stages of obtaining connection 22 in the form of a solid product: So pl. 85-100oC; []25D= -61,6C (C=0,85, Meon); FAB-MS m/z 497 (MH+);

Analysis. The calculation for C28H34FN7O3S2,7CF3CO2H0,9H2O:

Calculated: 44/BR>< / BR>
The connection 23

The connection 23 receive, using the method according to example 12. Benzothiazole-6-carboxylic acid to replace 2-bromopyridine obtaining specified in the connection header in the form of a solid product: So pl. 40-68oC; FAB-MS m/z 494 (MH+);

Analysis. The calculation for C28H34FN7O32,7 CF3CO2H0,N2O:

Calculated: 44,99; F 19,39; N. OF 4.35; N 10,99; N2About 1,82.

Found: 45,01; F 19,61; N 4,24; N 11,25; N2About 1,84.

EXAMPLE 24

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Connection 24

Connection 24 receive, using the method of example 5, substituting 2-aminophenol Anthranilic acid with obtaining specified in the connection header in the form of a solid product: So pl. 122-138oC; FAB-MS m/z 561 (MH+);

Analysis. The calculation for C29H36N8O42,62H2ABOUT43,HE2ABOUT:

Calculated: 45,08; N Is 4.93; N 12,30; H2O 5,93.

Found: 45,05; N 4,79; N 12,57; H2O 5,99.

EXAMPLE 25

N-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(6-HYDROXYBENZOTHIAZOLE-2-YL)CARBONYL]BUTYL]-L-PROLINE

< / BR>
The connection 25

The connection 25 receive, using the method of example 12, replacing benzothiazole-6-carboxylic acid, 5-(tert-butyldiphenylsilyl)benzothiazole with getting even for C28H35N7O4S2C2H2O41,5 H2O:

Calculated: 46,83; N 4,79; N 11,95; N2About 3,29.

Found: 46,79; N 4,79; N 12,15; N2About 3,29.

EXAMPLE 26

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The connection 26

The connection 26 to receive the subsequent separation of the individual diastereomers of compound 8 HPLC with reversed phase with obtaining specified in the connection header in the form of a solid product: So pl. 90-110oC; FAB-MS m/z 614 (MH+).

EXAMPLE 27

< / BR>
Connection 27

Connection 27 get further separation of the individual diastereomers of compound 8 HPLC with reversed phase with obtaining specified in the connection header in the form of a solid product: So pl. 60-75oC; FAB-MS m/z 614 (MH+).

EXAMPLE 28

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The connection 28

The connection 28 receive, using the method of example 12, replacing benzothiazole-6-carboxylic acid, 1-methylbenzimidazole obtaining specified in the connection header in the form of a solid product: So pl. 118-128oC; FAB-MS m/z 566 (MH+);

Analysis. The calculation for C29H38N8O33,22H2O41,1 N2O:

Calculated: 45,65; F 19,58; N 4,70; N A 12.03; N2O 2,13.

Found: 45,66; F 19,19; N 4,51; N 12,02; H2O 1,77.

PRIMAMED

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The connection 29

The connection 29 to receive, following the General method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole in stage a and Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-Boc-N-methyl-D-cyclohexylethyl-L-Proline in stage d of obtaining specified in the connection header in the form of a solid product: So pl. 90-100oC []25D= -40,96 (=0,708, Meon); FAB-MS m/z 497 (MH+);

Analysis. The calculation for C28H41N7O3S3CF3CO2H0,75H2O:

Calculated: 44,81; F 18,76; N. Of 4.35; N 10,76; H2O 1,48.

Found: 44,92; F 18,83; N. Of 5.03; N 10,80; H2O 1,37.

EXAMPLE 30

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The connection 30

The connection 30 receive, following the General method of example 12. N-Z-N-Methyl-D-i.e. phenylalanyl-L-Proline substituted N-Boc-N-methyl-D-(pentafluorophenyl)alanyl-L-Proline with obtaining specified in the connection header in the form of a solid product: So pl. 98-125oC; FAB-MS m/z 640 (MH+);

Analysis. The calculation for C28H31F5N7O3S2,25F3CO2N1,25N2ABOUT:

Calculated: 42,48; F 24,29; H 3,81; N 10,67; N2About 2,45.

Found: 42,75; F 24,12; N. OF 3.85; N 10,66; N2About 2,61.

EXAMPLE 31

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The connection 31

The connection 31 receive, following the General method of example 12. Beano obtaining specified in the connection header in the form of a solid product: So pl. 60-70oC; []20D= +5,1 (=0,68, Meon); FAB-MS m/z 388 (MH+);

Analysis. The calculation for C19H25N5O2S1,25F3CO2H0,N2ABOUT:

Calculated: 47,50; F 13,10; N 5,14; N 12,88; H2O 2,48.

Found: 47,50; F 13,19; N 4,99; N 13,19; N2About 2,37.

EXAMPLE 32

N-METHYL-D-(4-FORFINAL)ALANYL-N-[4-[(AMINOIMINOMETHYL)-AMINO] -1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 32

The connection 32 receive, following the method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole and N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-BOC-N-methyl-D-(4-forfinal)alanyl-L-Proline d with obtaining specified in the connection header in the form of a solid product: So pl. 70-125oC; []25D= -79,7 (C=1.0, the Meon); FAB-MS m/z 568 (MH+);

Analysis. The calculation for C28H34N7O3S2,1F3CO2N1,1H2O:

Calculated: OF 46.77; F 16,77; N. OF 4.67; N UP 11,86; N2About 2,40.

Found: 46,42; F 16,69; N. OF 4.67; N 11,82; N2About 2,54.

EXAMPLES 33 AND 34

N-METHYL-D-PHENYLGLYCYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

Conn. 33

Conn. 34

< / BR>
The connection 33 and 34

The connection 33 receive, following the method of example 12. Benzothiazole-6-CT what-L-Proline with getting diastereomers 33 and 34, shared by HPLC with reversed phase:

Compound 33: So pl. 60(s)-125oC; []20D= -43,0 (C=1.0, the Meon); FAB-MS m/z 536 (MH+);

Analysis. The calculation for C27H33N7O3S2,1F3CO2N1,N2O:

Calculated: 46,30; F 14,78; N 4,84; N 12,11; N2About to 4.23.

Found: 46,52; F 15,09; N 4,84; N 12,29; N2About 4,53.

Compound 34: So pl. 65(s)-125oC; []20D= -1,3 --------- (c=1,0, MeOH); FAB-MS m/z 536 (MH+);

Analysis. The calculation for C27H33N7O3S2,25F3CO2N1,N2ABOUT:

Calculated: 45,93; F 15,57; N 4,74; N 11,90; N2About 3,83.

Found: 46,21; F 15,67; N. OF 4.90; N 12,09; N2About 4,22.

EXAMPLE 35

N-METHYL-D-(DIPHENYL)ALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO]-1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 35

The connection 35 receive, using the method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole and N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-acetyl-D-i.e. phenylalanyl-L-Proline with obtaining specified in the connection header in the form of a solid product: So pl. 65-125oC; FAB-MS m/z 578 (MH+);

Analysis. The calculation for C29H35N7O4S1,4F3CO2NN2O:

Calculated: 50,57; F 10,56; N 5,12; N 12,98; H2O 2,38 is connected 36 get using the method of example 12. N-BOC-N-methyl-D,L-phenylglycyl-L-Proline substituted N-CBZ-N-methyl-D-i.e. phenylalanyl-L-Proline and benzothiazole substituted benzothiazole-6-carboxylic acid with obtaining specified in the connection header in the form of a solid product: So pl. 65-125oC; FAB-MS m/z 578 (MH+).

Analysis. The calculation for C29H35N7O3S2,25F3CO2N1,N2O:

Calculated: 50,45; F 13,99; N. OF 4.95; N 10,69; N2About to 3.73.

Found: 50, 20MM; F 10,70; N 4,78; N 13,62; N2About 3,34.

EXAMPLE 37

N-METHYL-D-CYCLOHEXYLGLYCINE-[4-[(AMINOIMINOMETHYL)AMINO]-1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 37

The connection 37 receive, using the method of example 12. N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-BOC-N-methyl-D-cyclohexylglycine-L-Proline and benzothiazole-6-carboxylic acid replaced with benzothiazole obtaining specified in the connection header in the form of a solid product: So pl. 65-125oC; FAB-MS m/z 542 (MH+);

Analysis. The calculation for C27H39N7O3S2,0F3CO2H2,0H2ABOUT:

Calculated: 46,21; F 14,15; N 5,63; N 12,17; N2About 4,47.

Found: 45,96; F 14,39; N 5,71; N 12,07; N2O to 4.41.

EXAMPLE 38

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Compound 38

Compound 38 poluchalasy and benzothiazole-6-carboxylic acid replaced with benzothiazole in stage A. The remaining stages of the reaction sequence is carried out with minor changes with obtaining specified in the connection header in the form of a solid product: So pl. 74-95oC; []25D= -45,3 (C=1.00, the Meon); FAB-MS m/z 541 (MH+);

Analysis. The calculation for C31H32N4O31,5 CF3CO2H0,7H2ABOUT:

Calculated: 56,38; F 11.8, N A 4.86; N 7,73; H2O 1,74.

Found: 56,62; F 11,48; N 4,48; N TO 7.61; N2O 1,76.

EXAMPLE 39

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Connection 39

The connection 39 to receive, using the method of example 12. N,O-Dimethylamide N--BOC-NG-tosyl-L-arginine substituted N,O-dimethylamide N-Boc-L-norleucine and benzothiazole-6-carboxylic acid replaced with benzothiazole in stage A. The remaining stages of the reaction sequence is carried out with minor changes with obtaining specified in the connection header in the form of a solid product: []25D= -80,7 (C=1.00, the Meon); FAB-MS m/z: 507 (MH+);

Analysis. The calculation for C28H34N4O31,5 CF3CO2H0,3H2ABOUT:

Calculated: 54,51; F To 12.52; N 5,33; N 8,2; H2O 0,79.

Found: 54,6; F To 12.28; N 5,38; N 8,18; H2O 0,60.

EXAMPLE 40

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The connection 40

The connection 40 receive, using the method of example 12. N,O-Dimethylamide N--In which about acid replaced with benzothiazole on stage and perform stage b and C. Stage d requires the use of bis(2-oxo-3-oxazolidinyl)Gostinichnaya (THIEF-C1) as a binding agent. The remaining stages of the reaction sequence is carried out with only minor changes with obtaining specified in the connection header in the form of a solid product: []25D= -91,3 (C=1.00, the Meon); FAB-MS m/z 564 (MH+);

Analysis. The calculation for C29H37N7O3S2,3F3CO2N1,1H2O:

Calculated: 47,72; F 15,5; N. OF 4.95; N 11,59; N2About 2,34.

Found: 47,58; F 15,69; N 4,89; N 11,58; N2O 2,36.

EXAMPLE 41

D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 41

The connection 41 receive, using the method of example 12. N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-CBZ-D-phenyl-alanyl-L-Proline and benzothiazole-6-carboxylic acid replaced with benzothiazole obtaining specified in the connection header in the form of a solid: FAB-MS m/z 540 (MH+);

Analysis. The calculation for C27H33N7O3S2,4F3CO2H0,N2ABOUT:

Calculated: 46,27; F 16,57; N. OF 4.54; N, 11.8, N2O 1,96.

Found: 46,22; F 16,01; N 4,59; N 12,02; N2About 1,6.

EXAMPLE 42

N-METHYL-D-i.e. phenylalanyl-N-[4-[(AMINOIMINOMETHYL 42 get using the method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole and N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-Boc-N-methyl-i.e. phenylalanyl-L-homopolymer at the stage d with obtaining specified in the connection header in the form of a solid: FAB-MS m/z 564 (MH+);

Analysis. The calculation for C29H37N7O3S2,4F3CO2H1,3H2ABOUT:

Calculated: 47,16; F 15,89; N To 4.92; N is 11.39; H2O 2,72.

Found: 46,76; F 15.62 WIDE; N. OF 4.95; N IS 11.39; N2O 2,28.

EXAMPLE 43

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The connection 43

The connection 43 to receive, using the method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole and N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-BOC-N-methyl-D-Val-L-Proline in stage d of obtaining specified in the connection header in the form of a solid: FAB-MS m/z 552 (MH+);

Analysis. The calculation for C28H37N7O3S2,3F3CO2NN2ABOUT:

Calculated: 47,06; F 15,76; 5,00; N 11,78; H2O 2,16.

Found: 46,89; F 16,22; N IS 5.06; N 12,11; N2O was 2.76.

EXAMPLE 44

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The connection 44

The connection 44 is obtained by processing the intermediate product 3E boiling under reflux ethylformate, oxidation of the resulting product periodinane DESSO product: FAB-MS m/z 560 (MH+);

Analysis. The calculation for C14H17N5O2S1,32F3CO2H0,N2ABOUT:

Calculated: 41,59; F 15,60; H 4,12; N 14,50; N2O 2,66.

Found: 41,04; F 15,49; N. OF 3.97; N 14,84; N2O of 2.26.

EXAMPLE 45

1-(N-METHYLAMINO)-1-CYCLOHEXYLCARBONYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 45

The connection 45 receive, using the method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole in stage a and N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline replace 1-(N-Boc-N-methylamino)-1-cyclohexanecarbonyl-L-Proline in stage d. The remaining stages of the scheme is carried out with minor modifications to obtain specified in the connection header in the form of a solid: FAB-MS m/z 528 (MH+);

Analysis. The calculation for C26H37N7O3S2,3F3CO2N1,8H2O:

Calculated: 44,69; F 15,94; N 5,26; N 11,92; N2About 3,94.

Found: 44,37; F 15,8; N 4,89; N 11,75; H2O 3,11.

EXAMPLE 46

2.2-DIPHENYLGLYCINE-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 46

The connection 46 receive, using the method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole n the data in the title compound in the form of a solid: FAB-MS m/z 598 (MH+);

Analysis. The calculation for C32H35N7O3S2,6F3CO2N1,2H2ABOUT:

Calculated: 48,79; F 16,18; N 4,40; N 10,71; N2O 2,36.

Found: 48,70; F 15,78; N 4,22; N 10,63; H2O 1,37.

EXAMPLE 47

-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(BENZOTHIAZOL-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
Connection 47

Connection 47 receive, using the method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole in stage a and N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-BOC--methyl-D-i.e. phenylalanyl-L-Proline in stage d of obtaining specified in the connection header in the form of a solid: FAB-MS m/z 550 (MH+);

Analysis. The calculation for C28H35N7O3S2,6F3CO2N1,5H2O:

Calculated: 45,67; F 16,97; N 4,69; N 11,23.

Found: 45,28; F 16,91; N To 4.46; N 11,00.

EXAMPLE 48

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The connection 48

The connection 48 receive, using the method of example 12. Benzothiazole-6-carboxylic acid replaced with benzothiazole in stage a and N-Z-N-methyl-D-i.e. phenylalanyl-L-Proline substituted N-Boc-L-Proline in stage d of obtaining specified in the connection header in the form of a solid: FAB-MS m/z 389 (MH+);

Analysis. The calculation for C18H24N6O2; 17,69; N 4,20; N OF 13.18; N2About 2,61.

EXAMPLE 49

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The connection 49

The connection 49 receive, using the method of example 12. Benzothiazole-6-carboxylic acid substituted benzo[b] thiophene on stage and the other stages of the sequence is carried out with only minor changes with obtaining specified in the connection header in the form of a solid product: ]25D= -78,3 (C=1.00, the Meon); FAB-MS m/z 549 (MH+);

Analysis. The calculation for C29H36N6O3S2,4F3CO2N1,5H2ABOUT:

Calculated: 47,80; F 16,10; N 4,91; N 9,89; N2About 3,18.

Found: 47,68; F 15,81; N 4,82; N 9,74; N2About 3,18.

EXAMPLE 50

N-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(6-METHOXYBENZOTHIAZOLE-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 50

The connection 50 receive, using the method of example 12. Benzothiazole-6-carboxylic acid substituted 6 - methoxybenzothiazole on stage and. The remaining stages of the sequence is carried out with only minor changes with obtaining specified in the connection header in the form of a solid product: []25D= -76,6 (s=0,73, Meon); FAB-MS m/z 549 (MH+);

Analysis. The calculation for C29H37N7O4S2,3F3CO2N1,75H2O:

EXAMPLE 51

N-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(4,5,6,7-TETRAHYDROINDAZOLE-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 51

The connection 51 receive, using the method of example 12. Benzothiazole-6-carboxylic acid substituted 4,5,6,7-Tetra-hydrobiostation on stage and perform other stage sequence with obtaining specified in the connection header in the form of a solid product: So pl. 50-60oC; FAB-MS m/z 554 (MH+);

Analysis. The calculation for C28H39N7O3S2,6F3CO2N1,4H2ABOUT:

Calculated: 45,55; F 16,93; N 5,11; N 11,20; N2O 2,88.

Found: 45,71; F 17,16; N 5,31; N 11,34; N2About 2,96.

EXAMPLE 52

N-METHYL-D-I.E. PHENYLALANYL-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(OIL[2,1-D] THIAZOLE-2-YL)CARBONYL]BUTYL]-L-PROLINAMIDE

< / BR>
The connection 52

The connection 52 receive, using the method of example 12, substituting 6-carboxybenzoyl the oil[2,1-d] thiazole obtaining in the form of a solid product: []25D= -103,0 (C=1.00, the Meon); FAB-MS m/z 560 (MH+);

Analysis. The calculation for C32H37N7O3S3,46F3CO2H1,3H2ABOUT:

Calculated: 45,93; F 19,38; N 4.26 DEATHS; N 9,36; N2About 2,30.

Found: 45,60; F 19,06; N Is 4.03; N 9,70; H2O 1,96.

EXAMPLE 53
oWith under stirring in argon atmosphere. To the reaction mixture is added dropwise pivaloate (6,80 g 0,057 mol) over 15 min at -78oC. After 15 min the reaction mixture is heated to 0oC, stirred for 1.5 h and then cooled to -78oC.

Meanwhile, to a solution of (4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone (16.4 g, 0,093 mol) in 100 ml anhydrous THF over 30 min with stirring in an argon atmosphere at -78oWith added dropwise n-BuLi (58 ml, 1.6 M in hexane, 0,093 mol). After 15 minutes under stirring in an argon atmosphere at -78oWith this, the reaction mixture was slowly added into the above anhydrous reaction mixture. The reaction mixture is allowed to slowly warm to room temperature over 18 h, quenched with 1 N. aqueous KHSO4and the solvents removed in vacuum at 40oC. the Residue is partitioned between water and CH2Cl2and the aqueous layer was extracted three times CH2Cl2. United CH2Cl2the extracts are washed twice with saline, dried over anhydrous Na2SO4and concentrated in vacuo at 40oC. the Residue is purified chromatographically on silica gel elwira CH2/BR>< / BR>
Compound 53A (3,81 g of 0.013 mol) are subjected to interaction with di-tert-utilizadorescialis (0,48 g, 0.015 mol) in accordance with the General method D. A. Evans et al. (Tetrahedron 1988, 44, 5525-5540) with raw 53b. The crude product is purified chromatographically on silica gel, elwira CH2CL2/hexane/acetonitrile (70: 30: 7) to give the pure 53b (2,33 g, 33%) as a white solid; FAB-MS m/z 522 (MH+).

Stage

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Connection 53b (2,33 g, 0,0045 mol) is dissolved in 18 ml of THF, cooled to 0oWith, and treated with a solution of LiOH-H2O (0,46 g, 0,0107 mol) in 9 ml of N2O. Add water N2ABOUT2(1.1 ml of 30% 0,010 mol) and the reaction mixture was stirred at 0oC for 3 hours, the Reaction mixture was partitioned between water 1 N. Hcl and CH2Cl2and the acidic aqueous layer was extracted with CH2Cl2. United CH2Cl2the extracts are washed with saline, dried over anhydrous gSO4and concentrated in vacuo at 40oC. the Residue is purified by chromatography on silica gel, elwira EtOAc/hexane/SPLA obtaining s in the form of a white solid; FAB-MS m/z 363 (MH+).

Stage d

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Connection s (2.15 g, 0,0593 mol) is dissolved in 215 ml of TFU/CH2CL2(1:4 by volume is at 20oWith obtaining 53d (2,07 g): FAB-MS m/z 163 (MH+).

Stage e

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Connection 53d dissolved in absolute ethanol (100 ml), combined with PtO2(0,300 g) and placed in a Parr apparatus under pressure (55 psi) at room temperature for more than 24 hours, the Reaction mixture was dissolved in methanol (50 ml) and set pH 8 with Et3N (approx. 2 ml). The solution is cooled to 0oC, treated with di-tert-BUTYLCARBAMATE (2.0 g, 0,009 mol) and give to slowly warm to room temperature over 20 hours, the Reaction mixture was concentrated in vacuo at 40oC and partitioned between EtOAc (50 ml) and chilled (5oC) 1 N. Hcl (50 ml), washed with water, brine, dried over anhydrous Na2SO4and concentrated in vacuo at 40oWith obtaining e (2.15 g) as a white solid; FAB-MS m/z 248 (MH+).

Stage f

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Connection e (1.48 g, 0,0060 mol) is dissolved in 70 ml of anhydrous CH2Cl2combine with the hydrochloride of N, O-dimethyl-hydroxylamine (of 0.878 g, 0,0090 mol). In the resulting reaction mixture set pH 8 with Et3N and treated with the acid chloride of bis(2-oxo-3-oxazolidinyl)-phosphinic acid (THIEF-CL; to 2.29 g, 0,0090 mol) with stirring at room temperature innocence layer extracted with saturated Panso3, saline solution, dried over anhydrous gSO4and concentrated in vacuo. The remainder of the partially dissolved in methanol and the undissolved precipitate is removed by filtration. The filtrate was concentrated in vacuo to obtain 53f (1,00 g, 57%) as a white solid; FAB-MS m/z 291 (MH+).

Stage g

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The connection 53

Amide 53f is converted into compound 53 following the General methods of example 3. Connection 53f is subjected to interaction with 2-letobascerou as described for stage 3C. The obtained intermediate ketone is subjected to processing that is applied on the 3d stages. and 3rd, and received amerosport consistently associated with (CBZ)-N-methyl-D-i.e. phenylalanyl-L-Proline according to the method of stage 3f. This intermediate product is similarly subjected to the other stages of the example 3, elwira using H2O/acetonitrile/TFU (50:50:0,2) to give compound 53 as a white solid; []25D= -85,3 (=0,26, Meon); FAB-MS m/z 853 (MH+);

Analysis. The calculation for C28H34N4O4S2,THU,1H2O:

Calculated: 51,12; N 5,33; N A 7.85; F 11,98; H2O 2,77.

Found: 51,16; N. Of 5.17; N 7,87; F 11,58; H2O 2,45.

EXAMPLE 54

N-METHYL-D-i.e. phenylalanyl-N-[4-[(AMINOIMINOMETHYL)AMINO] -1S-[(4-CARBOXYMETHY-2-YL)TO the initial ester L-l (2/42 g, of 13.05 mmol) in anhydrous CH2Cl2(127 ml) was stirred at room temperature in an argon atmosphere for more than 16 hours the mixture is filtered through auxiliary filtering material, concentrated in vacuo and partitioned between brine and ethyl acetate. The aqueous layer was extracted with several portions of ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo. The residue is purified chromatographically on silica gel, elwira CH2CL2:Meon:NH4HE (90:9:1) to obtain 54A in the form of a white foam.

Stage b

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Compound 54A (1.0 g, 1.18 mmol) and Mno2(1,00 g, 14,38 mmol) in anhydrous CH2Cl2(28 ml) was stirred at room temperature in an argon atmosphere for 4.5 hours Add an additional portion of Mno2(0.25 g) and the mixture is stirred for another 2.5 hours. The resulting mixture was filtered through auxiliary filtering material and concentrated in vacuo to obtain thiazole 54b in the form of crude solid product.

Stage

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LiOH (65 mg, of 2.64 mmol) and H2O (0.1 ml) in dioxane (0.9 ml) is stirred in an argon atmosphere for 3 hours the mixture was diluted with H2O and extracted several 2
Cl2. United CH2Cl2the extracts are washed with saline, dried PA2SO4and concentrated in vacuo to obtain acid 54b in the form of a solid product.

Stage d

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The mixture s (252 mg, 0.31 mmol) and peridinin (197 mg, 0,464 mmol) in CH2Cl2(10 ml) was stirred at room temperature in N2within 1 h Add additional portion periodinane (132 mg, 0.31 mmol) over 3 h and the resulting mixture was quenched with aqueous Na2S2O3. The aqueous layer was acidified to pH 3.0 with acetic acid, then washed with brine, filtered through diatomaceous earth and concentrated in vacuo. The residue is purified HPLC with reversed phase, using CH3JV:N2About:TFU (50:50:0,2) to give the ketone 54d in the form of a solid product.

Stage e

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The connection 54

The intermediate ketone 54d (140 mg, 0,17 mmol) and anisole (4 ml) was placed in a Teflon reaction tube HF apparatus under anhydrous conditions and cooled to -78oC. HF (8 ml) were diluted in the tube and upon completion of addition, the temperature of the mixture is allowed to rise to -10oC. This mixture is stirred for 1 h at -20 to -10oC, concentrated in vacuo and triturated in a few stands on the/acetonitrile/TFU (70:30:0,2), and lyophilized obtaining connection 54 in the form of a pure solid products: []25D= -86,5 (0,65, H2O); FAB-MS m/z 860 (MH)+.

Analysis. The calculation for C25H33N7O5S2,5F3CO2N1,7H2O:

Calculated: 41,93; N 4,56; N 11,41; H2O 3,56.

Found: 41,59; N A 4.53; N 11,84; H2O 3,40.

EXAMPLES 55 and 56

< / BR>
< / BR>
Connections 55 and 56 receive, modifying the example 54. THIEF-CL (13 mg, 0.03 mmol) was added to a stirred mixture of intermediate product C (21,8 mg, or 0.027 mmol), triethylamine (5,6 mcg, 0,077 mmol), DMF (1.5 ml) and phenethylamine (5 ág, 0,041 mmol) in 5oC in argon atmosphere. The resulting mixture was stirred for 16 h, concentrated in vacuo and distributed between ethyl acetate and saturated aqueous Paso3. The aqueous layer was extracted with several portions of ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to obtain the protected amide. This amide is subjected to removal of protection similar to example 54 with obtaining relevant specified in the header of the compounds in the form of solid products:

Compound 55: []25D= -67,5 (s=0,74, H2O); FAB-MS m/z 647 (MH)+.

Analysis. The calculation for C33H42N82About 3,40.

The connection 56: FAB-MS m/z 647 (MH+).

EXAMPLES 57

Stage and

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4-Cyanoaniline (36,1 g 0,19 mmol; EP 0513675 Al) combined with Et3N (26 ml, 0,19 mmol) in 550 ml of N2O. the resulting solution was treated with di-tert-BUTYLCARBAMATE (68,0 g, 0.31 mmol), stirred at room temperature over 18 h and cooled to 5oC. Establish a pH of 1 using concentrated Hcl and the acidic aqueous layer is extracted with EtOAc twice (500 ml). EtOAc layers are washed twice with saline solution (200 ml), dried over anhydrous Na2SO4and concentrated in vacuo. The residue is triturated in hexane to obtain 57a in the form of a light pink color (50.0 g, 87%): So pl. 145-147oC (decomposition); []25D= +3.3V (1,0, Meon); FAB-MS m/z 291 (MH+).

Stage b

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A solution of 57a (25 g, 0,086 mol) of the hydrochloride of N,O-dimethylhydroxylamine (12.7 g, 0,130 mol) in anhydrous DMF (500 ml) cooled to 0oWith under stirring in an argon atmosphere and treated with Et3N (23,3 ml, 0,230 mol). For more than 10 min portions added hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium (THIEF; 42,1 g 0,095 mmol) and the reaction mixture was stirred at 0-5oWith over 18 h, keeping pH 8-9 by arr(500 ml) and N2O (250 ml). The organic layer is washed with 50 ml of 5% aqueous Paso3, 50 ml of 1 N. aqueous Hcl, 100 ml of H2Oh, dried over anhydrous Na2SO4and concentrated in vacuo. The residue is purified chromatographically on silica gel, elwira CH2Cl2/MeOH (95:5) to obtain 54b in the form of a yellow solid (22.1 g, 70%): FAB-MS m/z 334 (MH)+.

Stage

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The solution 57b (28,7 g, 0,0861 mol) and Et3N (100 ml, to 0.72 mol) is dissolved in pyridine (400 ml). For more than 3 h in this solution at room temperature and bubbled anhydrous N2S. the Reaction vessel give then to stand at room temperature for 60 h and concentrated in vacuo at 30oC. the Residue is diluted with N2O (500 ml), cooled to 5oC, acidified to pH 4-5 with concentrated aqueous Hcl and extracted with EtOAc (500 ml). The organic layer is extracted with twice 250 ml water 1 N. Hcl, twice with 200 ml of a solution of a salt solution, dried over anhydrous gSO4and concentrated in vacuo to obtain s (27.8 g, 88%): FAB-MS m/z 368 (MH)+.

Stage d

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The solution s (27,0 g 0,074 mol) and methyliodide (75 ml) in acetone (750 ml) is heated under reflux with stirring in an argon atmosphere for 1 h After cooling to room the product, which is used directly in the next stage; FAB-MS m/z 381 (MH)+.

Stage e

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Connection 57d (38.0 g, 0,075 mol) was added to a solution of ammonium acetate (8,70 g, 0,112 mmol) in methanol (200 ml) and heated under reflux with stirring in an argon atmosphere for 3.5 hours After cooling to room, the reaction mixture was concentrated in vacuo and the residue partitioned between l3(500 ml) and saturated aqueous Panso3. l3filtered, washed with saline, dried over anhydrous Na2SO4and concentrated in vacuo to obtain a in the form of a pale yellow glassy product: FAB-MS m/z 351 (MH)+.

Stage f

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The solution e (24.3 g, 0,069 mol) and taillored (14.6 g, 0,076 mol) in acetone (500 ml) is cooled to -15oC. for more than 45 minutes dropwise with stirring at -15oWith added 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU; 21,4 g, 0,139 mol) and this mixture is allowed to slowly warm to room temperature over 3 hours, the Reaction mixture is diluted with 100 ml of methanol and concentrated in vacuo. The residue is purified chromatographically on silica gel, elwira EtOAc/hexane (3: 1) to obtain 57f (14.4 g, 41%) as a white solid; FAB-MS m/z: 505 (MH)+.

< / BR>subjected to interaction with 2-letobascerou, as described for stage 3C. The obtained intermediate ketone processed, used on stage 3d and 3E, and the resulting aminoplast consistently associated with (CBZ)-N-methyl-D-i.e. phenylalanyl-L-Proline according to the method of stage 3f. This intermediate product is similarly subjected to the other stages of the example 3; given that off stage HF (stage h) requires a 6 h at room temperature instead of 3 h at 0oC. the compound Obtained 57 cleanse HPLC with reversed phase, elwira using H2O/acetonitrile/TFU (65:35:0,2) to give compound 57 as a white solid; FAB-MS m/z 583 (MH+);

Analysis. The calculation for C32H34N6ABOUT3S2,THU,0H2ABOUT:

Calculated: 51,14; N 4,50; N 9,80; F 14,96; S 3,74; H2O 2,10.

Found: 50,96; N 4,39; N 9,60; F 14,66; S of 3.77; H2O 1,72.

EXAMPLES 58

Stage and

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N--Methyl-L-lysine is subjected to interaction with 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr) in accordance with the method used to obtain the N--Mtr-L-lysine, described M. Fujino et al., Chem. Pharm. Bull. Jpn. 1982, 30, 2766. The N--methyl-N----Mtr-L-lysine (5,00 g, 0,0134 mol) is dissolved in dioxane (52 ml), diluted with H2(952 ml), cooled to 0oWith and establish pH 11 with aqueous 3 N. NaOH. Priba the 11 for more than 18 hours The solvents are removed in vacuo and the residue partitioned between H2O (100 ml) and ether. Basically the aqueous layer (pH 11) again extracted with ether (2x), cooled to 0oWith a set pH 3 with aqueous 3 N. Hcl and extracted with EtOAc (3x). The combined EtOAc extracts are washed with saline, dried over anhydrous Na2SO4and concentrated in vacuo to obtain 58A (3,34 g, 53%) as a white foam; FAB-MS m/z 473 (MH)+.

Stage b

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Connection 58b is subjected to interaction with the hydrochloride of N,O-dimethylhydroxylamine in accordance with the General method used to obtain 57b, resulting 58b in the form of a white solid; FAB-MS m/z 516 (MH+).

Stage

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Amide 58b is converted into 58d following General methods of example 3. Connection 58b is subjected to interaction with 2-litio-benzothiazole as described for stage 3C. The obtained intermediate ketone processed, used on stage 3d and 3E, and the resulting aminoplast consistently associated with (CBZ)-N-methyl-D-i.e. phenylalanyl-L-Proline according to the method of stage 3f. This intermediate product is oxidized by periodinane dess-Martin, as described for 3g connection 58d; FAB-MS m/z 883 (MH+).

Stage d

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Connect the water triperoxonane acid and cooled to 5oWith under stirring in argon atmosphere. Through the solution for more than 15 min bubbled gaseous anhydrous NVG and the reaction mixture is allowed to slowly warm to room temperature over 15 hours. The solvents are removed in vacuo and the resulting residue is triturated in anhydrous ether and purified HPLC with reversed phase, elwira H2O/acetonitrile/TFU (60:40:0,2) to give compound 58 as a white solid; FAB-MS m/z 536 (MH+).

1. The compound of formula I or its N-alkilirovanie derived

< / BR>
where a is selected from the group including formyl, C3-7cycloalkylcarbonyl, substituted naphthylmethyl and aftercooler (where the naphthyl substituents are independently selected from one or more amino or1-4dialkylamino);

D - or L-amino acid attached to its carbonsilicon to nitrogen indicated in formula I and is selected from the group comprising Proline, glycine and valine, where the amine ends of the specified amino acids is not necessarily associated with a member selected from the group comprising naphthylmethyl, substituted phenyl WITH1-4alkyl (where the Deputy phenyl is1-4alkylamino), 1-C1-4alkylamino-1-cyclohexanecarbonyl,1-4alkylsulphonyl, the substituted amino acid is a D - or L-amino acid, attached via its carboxylic to nitrogen indicated in formula I, and represents a Proline, homopolar or valine,

and the second D - or L-amino acid is attached to aminobenzo specified first amino acid and selected from the group comprising phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more1-4of alkyl, halogen or1-4alkoxycarbonyl), 2,2-diphenylalanine, 4-biphenylene, substituted or unsubstituted cyclohexylglycine or cyclohexylamine (where the Deputy is1-4alkyl), diphenylglycine or phenylglycine, where the amine ends of the second specified amino acids are unsubstituted or monogamist a member of the group, including WITH1-12alkyl or C2-5acyl;

R1selected from the group comprising hydrogen and C1-4alkyl;

R2selected from the group comprising amines2-5alkyl, C1-4alkylamino2-5alkyl, guanidino2-5alkyl, C1-3alkoxyl2-5alkyl, phenyl, substituted phenyl (where the substituents are independently selected from one or more amidinopropane), benzyl, substituted benzyl (where the substituents are independently selected from one or more amidinopropane) and (C1-5alkyl;

linked to E;

E denotes a substituted imidazol-2-yl (where the Deputy is1-4alkyl) thiazol-2-yl, substituted thiazol-2-yl (where the substituents independently selected from carboxy, C1-4alkoxycarbonyl or penicillinonline), 4-oxo-2-cinoxacin-2-yl, 2-pyridyl, benzothiophen-2-yl, benzoxazol-2-yl, benzimidazole-2-yl, substituted benzimidazole-2-yl (where the Deputy is1-4alkyl), benzothiazole-2-yl, 4,5,6,7-tetrahydroindazole-2-yl, oil[2,1-d] thiazole-2-yl and substituted benzothiazol-2-yl (where the Deputy is selected from C1-4of alkyl, C1-4alkoxy, hydroxy, halogen, carboxy, C1-4alkoxycarbonyl, aminocarbonyl or hydroxy WITH1-4the alkyl).

2. Connection on p. 1, characterized in that the A - polypeptide that contains two amino acids, where p = 0.

3. Connection on p. 2, wherein the first amino acid is an L-amino acid selected from Proline or valine,

and the second amino acid is a D-amino acid selected from the group comprising phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more1-4of alkyl, halogen or1-4alkoxycarbonyl), 2,2-diphenylalanine, 4-biphenylene, replaced iglitzin or phenylglycine, where the amine ends of the second specified amino acids are unsubstituted or monogamist a member of the group, including WITH1-12alkyl or C2-5acyl.

4. Connection on p. 3, wherein R2selected from the group comprising amines2-5alkyl, C1-4alkylamino2-5alkyl, guanidino2-5alkyl and C1-5alkyl.

5. Connection on p. 4, wherein E denotes a substituted imidazol-2-yl (where the Deputy is1-4alkyl) thiazol-2-yl, substituted thiazol-2-yl (where the substituents independently selected from carboxy, C1-4alkoxycarbonyl or penicillinonline), 4-oxo-2-cinoxacin-2-yl, 2-pyridyl, benzo[b]thiophene-2-yl, benzoxazol-2-yl, benzimidazole-2-yl, substituted benzimidazole-2-yl (where the Deputy is1-4alkyl), benzothiazole-2-yl, 4,5,6,7-tetrahydroindazole-2-yl, oil[2,1-d]thiazole-2-yl or substituted benzothiazol-2-yl (where the Deputy is selected from1-4of alkyl, C1-4alkoxy, hydroxy, halogen, carboxy, C1-4alkoxycarbonyl, aminocarbonyl or hydraxis1-4the alkyl).

6. Connection on p. 5, wherein E denotes a substituted imidazol-2-yl (where the Deputy is1-4alkyl) thiazol-2-yl, substituted is-tetrahydrobenzoic-2-yl or oil[2,1-d]thiazole-2-yl.

7. Connection on p. 6, wherein E denotes thiazol-2-yl, substituted thiazol-2-yl (where the substituents independently selected from carboxy or1-4alkoxycarbonyl), 4,5,6,7-tetrahydroindazole-2-yl or oil[2,1-d] thiazol-2-yl.

8. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(benzothiazol-2-yl)carbonyl]butyl]-L-prolinamide.

9. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[5-[(aminoiminomethyl)amino] -1S-[(benzothiazol-2-yl)carbonyl]pentyl]-L-prolinamide.

10. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -2S-[(6-methoxycarbonylmethyl-2-yl)carbonyl]butyl]-L-prolinamide.

11. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(6-carboxybenzene-2-yl)carbonyl]butyl]-L-prolinamide.

12. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(6-carboxamidates-2-yl)carbonyl]butyl]-L-prolinamide.

13. Connection on p. 1, characterized in that a represents a N-METI is S="ptx2">

14. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(6-fermentation-2-yl)carbonyl]butyl]-L-prolinamide.

15. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(4-ethoxycarbonylmethyl-2-yl)carbonyl]butyl]-L-prolinamide.

16. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(4-carboxy-thiazol-2-yl)carbonyl]butyl]-L-prolinamide.

17. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(6-methoxybenzothiazole-2-yl)carbonyl]butyl]-L-prolinamide

18. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(6-hydroxy-benzothiazol-2-yl)carbonyl]butyl]-L-prolinamide.

19. Connection on p. 1, wherein a represents N-methyl-D-cyclohexylethyl-N-[4-[(aminoiminomethyl)amino] -1S-[(benzo-thiazol-2-yl)carbonyl]butyl]-L-prolinamide.

20. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(oil[2,1-d] thiazole-2-yl-D-(4-forfinal)alanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(benzothiazol-2-yl)carbonyl]butyl]-L-prolinamide.

22. Connection on p. 1, wherein a represents N-methyl-D-phenylglycyl-N-[4-[(aminoiminomethyl)amino]-1S-[(benzothiazol-2-yl)carbonyl]butyl]-L-prolinamide.

23. Connection on p. 1, wherein a represents N-methyl-D-(diphenyl)alanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(benzo-thiazol-2-yl)carbonyl]butyl]-L-prolinamide.

24. Connection on p. 1, wherein a represents N-methyl-D-cyclohexylglycine-N-[4-[(aminoiminomethyl)amino] -1S-[(benzo-thiazol-2-yl)carbonyl]butyl]-L-prolinamide.

25. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(4,5,6,7-tetrahydroindazole-2-yl)carbonyl]butyl]-L-prolinamide.

26. Connection on p. 1, characterized in that a represents a D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(benzothiazol-2-yl)carbonyl] butyl]-L-prolinamide.

27. Connection on p. 1, wherein a represents N-methyl-D-i.e. phenylalanyl-N-[4-[(aminoiminomethyl)amino] -1S-[(benzothiazol-2-yl)carbonyl]butyl]-2S-piperazinecarboxamide.

28. Connection on p. 1, characterized in that it is a 2.2-diphenylmethyl-N-[4-[(aminoiminomethyl)amino] -1S-[(benzothiazol-2-yl)carbonyl] butyl]-L-cast new iminomethyl)amino] -1S-[(benzothiazol-2-yl)carbonyl] butyl]-L-prolinamide.

30. Connection on p. 1, characterized in that a represents a 1-(N-methylamino)-1-cyclohexylcarbonyl-N-[4-[(aminoiminomethyl)amino]-1S[(benzothiazol-2-yl)carbonyl]butyl]-L-prolinamide.

31. Pharmaceutical composition having the ability to inhibit thrombin containing a therapeutically effective amount of the compounds on p. 1 and a pharmaceutically acceptable carrier.

32. A method of inhibiting thrombin comprising contacting compounds on p. 1 with medium containing thrombin.

33. The method according to p. 32, characterized in that the connection is in contact with the environment through an orthopedic or surgical devices.

34. The method according to p. 32, characterized in that environment is the blood of the mammal.

35. Method of inhibiting trypsin, comprising contacting compounds on p. 1 with medium containing trypsin.

 

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< / BR>
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< / BR>
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