UA63887C2 - Selective thrombin inhibitors and a pharmaceutical composition based thereon - Google Patents

Abstract

The present invention relates to a novel selective thrombin inhibitor having formula (I), which is also effective by oral administration, in which R1 represents acetyl substituted with aryl or aryloxy, or represents sulfonyl substituted with substituted or unsubstituted aryl or N-containing heterocyclic group, X represents a group of formula (a) or (b). R2 and R3 independently of one another represent hydrogen; cycloalkyl substituted or unsubstituted with carboxyl or alkoxycarbonyl; arylalkyloxy; hydroxy; or lower alkyl substituted or unsubstituted with carboxyl, alkoxycarbonyl or hydroxy, or R2 and R3 together with nitrogen atom to which they are attached can form a piperidine group substituted with carboxyl or alkoxycarbonyl, R4 represents hydrogen, lower alkyl or lower alkoxy, R5 represents alkanesulfonyl; alkoxycarbonyl; alkylcarbonyl; formyl; lower alkyl; aryl substituted or unsubstituted with alkoxy or haloalkyl; or hydroxy-substituted lower alkyl, R6 represents lower alkyl or amino and R7 represent hydrogen and a pharmaceutical composition for thrombin inhibition which comprises the compound of formula (I) as an active ingredient. , .

Description

Description of the invention

This invention belongs to a new selectively acting inhibitor of thrombin, which has the formula (1): хндит уове ; (1)

MD

MN in which

B" is acetyl substituted with aryl or aryloxy, or is sulfonyl substituted with substituted or unsubstituted aryl or a heterocyclic group containing M,

X is a group of the formula

Be Lv dz ok ,- ; listen

B2 and VZ independently of each other constitute hydrogen; cycloalkyl, substituted or unsubstituted by carboxyl or alkoxycarbonyl; arylalkyloxy; hydroxy; or lower alkyl substituted or unsubstituted by carboxyl, alkoxycarbonyl or hydroxy, or

B2 and EZ together with the nitrogen atom to which they are attached can form a piperidine group substituted with carboxyl or alkoxycarbonyl, Ge)

IN? is hydrogen, lower alkyl or lower alkoxy,

IN? is alkanesulfonyl; Alkoxycarbonyl; alkylcarbonyl; formyl; lower alkyl; aryl, substituted or unsubstituted by alkoxy or haloalkyl; or hydroxy-substituted lower alkyl, and the moieties are independently hydrogen, lower alkyl, or amino.

Certain compounds of formula (I) can show effective thrombin inhibitory activity even when administered orally and are therefore very useful. with

This invention also relates to a method of making a compound of formula (I) and a pharmaceutical composition which is intended for thrombin inhibition and which contains a compound of formula (I) as an active ingredient. at

In general, it is known that the method intended for blood coagulation includes several complex enzymatic reactions, Ge) which at the final stage include the reaction of converting protothrombin into thrombin. Thrombin, obtained at the final stage of the blood coagulation process, activates platelets and converts fibrinogen into fibrin, which is further converted into a higher molecular substance due to polymerization and crosslinking due to the action of thrombin-activated blood factor XIII for the purpose of coagulation of undissolved blood. Accordingly, thrombin plays an important role in blood coagulation. Thrombin also activates blood factors M and MI, which in turn accelerate blood coagulation by a feedback mechanism. Thus, since thrombin inhibitors act as effective coagulants and at the same time can "inhibit" platelet activity and the production and stabilization of fibrin for a long time, much attention has been paid to finding a way to prevent blood coagulation and treat various thrombosis with the use

A NEW compound that can inhibit thrombin activity.

However, a compound that is able to inhibit only thrombin activity has limitations in its use as an effective anticoagulant and thrombolytic agent. The reason for this is that, since thrombin is one of o serine proteases, and many trypsin-like serine proteases, typically plasmin, are present in the human body, o especially in the blood, an effective thrombin inhibitor usually also has high inhibitory activity against these serines -protease Due to this characteristic feature of thrombin, in the development of thrombin inhibitors, it is very important that the inhibitory compound has a lower inhibitory activity against the prototype serine protease, such as trypsin, than against thrombin.

Under such conditions, numerous studies have been conducted to create a selectively acting thrombin inhibitor that can effectively inhibit thrombin and at the same time have little trypsin inhibitory activity. As a result, the drug argatroban (Agoaigorap) was created, which has the formula (A) below, as a compound based on arylsulfonylarginine (see US Pat. Nos. 4,258,192 and 4,201,863).

F) dream

Sho vo Toi Vi t yo 65 m

NM sleep,

Argatroban shows high inhibitory activity to thrombin, which is 250 times higher than activity to trypsin (see, Viospetivzigu, 1984, 23, p.85-90). However, it can be obtained only thanks to complex synthesis procedures. It appeared on the Japanese market in 199Or.

In addition, a benzoamidine-based MARAR drug having the following formula (B) was developed. what

M rych shchi oo (B)

H MN,

This compound can be easily synthesized and has effective thrombin inhibitory activity. However, it has the disadvantage that the inhibitory activity to thrombin is only 50 times higher than the activity to trypsin (see, 9. Vioi. Spet. 1991, 266, p. 20085-20093).

In addition, the preparation Ko 46-6240 of formula (C) is described as a compound having a higher selectivity for thrombin than for trypsin. This compound shows the possibility of creation as an intravenous injection composition due to its short storage time in the blood, but does not show any possibility for oral administration (see, C). Honey. Spent 1994, 37, 3889-3901). he «ST o, ovo o i

But (c) m - so "Y y

MN co

In addition, a recently developed compound based on piperazide has been reported to have some potential for oral administration to rats but has low selectivity for thrombin (see US Pat. No. 94/18185). Thus, these compounds are not suitable for use in this field.

As a result, the authors of the present invention have conducted extensive research into the possibility of obtaining a certain compound that can be easily synthesized, shows effective thrombin inhibitory activity with high selectivity for thrombin over trypsin, and can also be administered orally. As a result, it was found that the thrombin inhibitor of formula (1) according to the present invention can achieve such a goal. c Thus, the purpose of the present invention is to obtain a new thrombin inhibitor of formula (1), as defined in "c" above, which can be administered orally and which has a high selectivity for thrombin.

Another goal of the present invention is to create a method for obtaining the thrombin inhibitor of formula (1). 15 In addition, another goal of the present invention is to create a pharmaceutical composition for the prevention of blood coagulation and for the treatment of various thrombosis, which contains the thrombin inhibitor of formula (1) as an active ingredient. (95) In one aspect, the present invention relates to a novel compound having the following formula (1): ee) AX

M so in o) ! -h (1)

Hy

Honey? about its pharmaceutically acceptable salt, hydrate, solvate and isomer, in which de V! is an acetyl substituted by aryl or aryloxy, or is a sulfonyl substituted by a substituted or unsubstituted aryl or a heterocyclic group containing M, 60 X is a group of the formula a - M M-і5 - --рз ог -- , р b5 22 i VZ independently of each other constitute hydrogen; cycloalkyl, substituted or unsubstituted by carboxyl or alkoxycarbonyl; arylalkyloxy; hydroxy; or lower alkyl substituted or unsubstituted by carboxyl, alkoxycarbonyl or hydroxy, or

B2 and EZ, together with the nitrogen atom to which they are attached, can form a piperidine group substituted by carboxyl or alkoxycarbonyl,

B is hydrogen, lower alkyl or lower alkoxy, 2? is alkanesulfonyl; Alkoxycarbonyl; alkylcarbonyl; formyl; lower alkyl; aryl, substituted or unsubstituted by alkoxy or haloalkyl; or hydroxy-substituted lower alkyl, and 25 are independently hydrogen, lower alkyl, or amino.

With regard to each substituent of the compound of formula (1) according to the present invention, the term "lower alkyl" means a saturated, branched or unbranched hydrocarbon radical having from 1 to 4 carbon atoms, for example, methyl, ethyl, isopropyl, Her - butyl, etc. ; the term "aralkyloxy" means alkoxy - a group substituted by an aromatic ring, for example, benzyloxy, etc.; and the term "cycloalkyl" means a cyclic alkyl group having from 3 to 8 carbon atoms, for example, cyclopentyl. 19 Among the above compounds of formula (1), the best compounds are those in which:

B is acetyl substituted with naphthyl or naphthyloxy, or is sulfonyl substituted with naphthyl or phenyl, which may be substituted or unsubstituted with one to four substituents selected from the group consisting of lower alkyl, lower alkoxy and dialkylamino,

X is a group of the formula 7 tt m -M m-n dz og yA-'

Ko village

B2 and BZ independently of each other are C 36 cycloalkyl, substituted or unsubstituted by d) carboxyl or methoxycarbonyl; benzyloxy; lower alkyl substituted or unsubstituted by carboxyl, methoxycarbonyl or hydroxy; or hydroxy, or

B2 and C, together with the nitrogen atom to which they are attached, can create a piperidine group substituted by carboxyl or methoxycarbonyl, -

IN? is hydrogen, (ee)

IN? is methanesulfonyl, ethoxycarbonyl, formyl, phenyl, methylcarbonyl, hydroxyethyl, or co-phenyl, which may be substituted or unsubstituted trifluoromethyl or ethoxy, and 25 are independently hydrogen, methyl, or amino. and)

Typical examples of the compound of formula (1) according to the present invention are the following compounds: "o (5)-M-cyclopentyl-M-methyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, (5)- M-butyl-M-methyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-M-propyl-3-(4-amidrazonophenyl)-2-(2- naphthylsulfonylamino)propionamide, « (5)-M-cyclopentyl-M-(2-benzyloxyethyl)-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, with (5)-M-cyclopentyl-M- butyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-M-ethyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, ; » (5)-M-cyclopentyl-M-methyl-3-I(4--(methylamidino)phenyl|-2-(2--aphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-M-methyl-3- 14-(1,1-dimethylamidino)-phenyl|-2-(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-M-methyl-3-(4-amidrazonophenyl)-2-(4-methoxy-2 ,3,6-trimethylbenzene)sulfonylamino)b propionamide, (5)-M-cyclopentyl-M-hydroxy-3-(4-amidrazonephenyl)-2-(2-nnaphthylsulfonylamino)propionamide, o (5)-M-cyclopentyl- IM-(2-hydroxyethyl)-3-(4-amidrazonephenyl)-2-(2-naphthylsulfonylamino)propionamide,

Go! (5)-M-cyclopentyl-M-methyl-3-(4-(methylamidino)phenyl 1I-2-((4-methoxy-2,3,6-trimethylbenzene) 5-bulphonylamino|propionamide, so (5)-M, M-dimethyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, "M (5)-M,M-dimethyl3-|4-(1-methylamidino)phenyl/|-2-(2- naphthylsulfonylamino)propionamide, (5)-M-cyclohexyl-M-methyl-3-(4-amidrazonophenyl)-2-(-(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopropyl-M-methyl-3-( 4-amidrazonophenyl)-2-(-(2-naphthylsulfonylamino)propionamide, (5)-3-(4-(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(2-naphthalen-1-yl- acetylamino)propionamide, (5)-3-(4-(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(5-dimethylamino-naphthalene-1-sulfonylamino) (F) propionamide, ka (5)- 3-(4-(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(5-methoxynaphthalene-1-sulfonylamino)propionamide, (5)-2-(I4-(amidrazono)phenyl|-M-cyclopentyl -M-methyl-2-(6,7-dimethoxy-naphthalene-2-sulfonylamino) in propionamide, (5)-3-(4-(methylamidino)-phenyl|-M-cyclopentyl-M-methyl-2-( 5-dimethylamino-naphthalene-1-sulfonylamino) propionamide, (5)- 3-(4-(amidrazono)-phenyl|-M-cyclopentyl-M-methyl-2-(naphthalene-1-sulfonylamino)propionamide, (5)-3-(4-(amidrazono)-phenyl|-M-cyclopentyl -M-methyl-2-(2-(naphthalen-1-yl-oxy)acetylamino|-propionamide, 65 (5)-3-(4-(amidrazono)-phenyl|-M-cyclopentyl-M-methyl-2 -(2-(naphthalene-2-yl-oxy)zacetylamino|propionamide, methyl ester of 4Y3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylaminoacetic acid, 1-3 -(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-"methylaminoacetic acid, methyl ether (5)-2-13-(4-amidrazonophenyl)-(5)-2- (naphthalene-2-sulfonylamino)-propionyl|-methylamino) propionic acid, (5)-2-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)propionic acid acid, methyl ester (kK)-2-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl)-methylamino) propionic acid, (k)-2-13-(4 -amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)propionic acid, 70 methyl ether (kK)-2-13-(4-amidrazonophen yl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)-3-methyl butyric acid, (k)-2-13-(4-amidrazonophenyl)-(5)-2-( naphthalene-2-sulfonylamino)-propionyl|-methylamino)-3-methyl butyric acid, methyl ether 3-1C-3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl)-methylamino ) propionic acid, 3-1Й3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|methylamino)propionic acid, methyl ether 4-113-(4-amidrazonophenyl)-(5)- 2-(naphthalene-2-sulfonylamino)-propionyl|-"methylamino)butyric acid, 4-C13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)butyric acid , methyl ether/I3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-cyclopropylamino)acetic acid, 113-(4-amidrazonophenyl)-(5)-2-(naphthalene -2-sulfonylamino)-propionyl|-cyclopropylaminoacetic acid, methyl ether/(3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-butylaminoacetic acid, 113-(4 -amidrazonophenyl)-(5)-2-( naphthalene-2-sulfonylamino)-propionyl|-butylaminoacetic acid, and) methyl ether/(3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-cyclopentylamino)acetic acid, 113 -(4-(amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-cyclopentylaminoacetic acid, M zo methyl ether 1-113-(4-amidrazonophenyl)-(5)-2-(naphthalene- 2-sulfonylamino)-propionyl|-methylamino) cyclopentane carboxylic acid, so 1-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)-cyclopentane carboxylic acid, ethyl o ether 2-1I3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)-cyclopentane «o carboxylic acid, 2-(I3-(4-amidrazonophenyl)-( 5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)cyclopentane carboxylic acid, methyl « 420 ether (z)-2-4I3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2 -sulfonylamino)-propionyl)-methylamino)-3-methyl-butyric acid, methyl;" ether 1-I3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-piperidine-(K)-2-carboxylic acid, 1-I(3-(4-amidrazonophenyl)- (5)-2-(naphthalene-2-sulfonylamino)-propionyl|-piperidine-(K)-2-carboxylic acid, (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-(4 -methylsulfonyl-piperazinyl)-2-oxoethylamide,

He» (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-oxo-2-(4-ethoxycarbonyl-piperazinyl)ethylamide, (5)-naphthalene-2-sulfonic acid|1-(4 -amidrazono)benzyl-2-(4-formyl-piperazinyl)-2-oxoethylamide, o (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-(4-ethyl-piperazinyl)-2 -oxoethylamide,

Go! (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-oxo-2-(4-phenyl-piperazinyl)-ethyl|amide, so 50 (5)-naphthalene-2-sulfonic acid|1 -(4-amidrazono)benzyl-2-oxo-2-(4-(3-trifluoromethylphenyl)-piperazinyl). ethyl amide, "M (5)-naphthalene-2-sulfonic acid|2-(4-acetyl-piperazinyl)-1-(4-amidrazono)benzyl-2-oxoethylamide, (5)-naphthalene-2-sulfonic acid|1- (4-amidrazono)benzyl-2-oxo-2-I4-(2-hydroxyethyl)-piperazinyl|-ethylamide, and (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-oxo- 2-I4-(-2-ethoxyphenyl)-piperazinyl|-ethyl|amide.

A compound of formula (1) according to the present invention may also form a pharmaceutically acceptable salt.

Suitable pharmaceutically acceptable salts for a compound of formula (1) may include an acidic addition salt, (F) formed with acids which can form a non-toxic acidic addition salt containing a pharmaceutically acceptable anion, for example inorganic acids such as hydrochloric acid, sulfuric acid , nitric acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc., organic carbonic acids, such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene sulfonic acid, etc., and similar acids.

In addition, since the compound of formula (1) according to the present invention may include an asymmetric carbon atom in its structure 65, it may exist in the form of a racemate, a diastereometric mixture, and an individual diastereomer. All specified isomers are included in the scope of the present invention.

In another aspect, the present invention also relates to a process for preparing a compound of formula (1) as defined above.

According to the present invention, a compound of formula (I) can be prepared by reacting a compound of formula (I) with a compound of formula (II) as shown in reaction scheme 1 below.

Scheme 1 of the reaction: x

M/y vet about and 70th NM century

SN" (Id

Mn (0

H

M i syu V 9) ve

M. id

МН with 0

In the above scheme, reactions X, 2", 5 and B are defined as described earlier. (o)

As depicted in the above reaction scheme 1, the compound of formula (1) according to the present invention can be obtained by reacting the methyl mercapto compound of formula (II) with an amino derivative of formula (III) as a nucleophilic substance. This reaction can best be carried out in the presence of a solvent. what-

Although any organic solvent that does not adversely affect the reaction can be used in this reaction, it is generally best to use an alcoholic solvent such as methanol, ethanol, propanol, and others for this purpose. co

In the above reaction, the reaction conditions, including the amount of reagents, the reaction temperature, the reaction time, etc., can be determined depending on the type of the particular reagent used by one of ordinary skill in the art. In general, although the reaction temperature can vary over a considerable range, the reaction was particularly best performed at a temperature between 0°C and 5070°C.

In addition, in the general case, the reaction time is from 0.5 to 5 hours, preferably from 1 to 2 hours.

After completion of the specified reaction, the reaction product can be isolated and purified according to the usual developed method, for example, chromatography, recrystallization, etc. 20 The methyl mercapto compound of formula (II), which is used as an intermediate compound for the preparation of compound b-c of formula (I) in reaction scheme 1, can be obtained according to reaction schemes 2 or 3 shown below.

Scheme 2 of the reaction: . and he h

Hn RNU o o (o)

SM an (95) (ee) Pp. ggI (ee) x "M x Y oh vel Y 9) -----zh t VI name) 60 b5 noi chi i" o you" 6), su of

Mn, MN (BI (0

Scheme From the reaction on nm o i-i x - oi H- vv "EM t

N on tsN x what what ; o - 5 -as --- 5 -e

SM hu SM

IVI MI o h r Y still (c)

In o u i- in 5sn so

MN Mn (ee)

IB) (and co

In the above reaction schemes, p

X, B", 9 are defined similarly to those described earlier, and p is an amino protecting group.

Schemes of reactions 2 and C are explained in detail below.

In reaction scheme 2, first C is the end of compound |1| bind to the amino group X to obtain the compound |21, from which the amino-protecting group at the M-end is removed in order to produce the compound |Z). Next, B 7 is introduced to the unprotected M - s-v c end of the compound (III) for the purpose of producing compound (4). In the opposite case, according to the scheme of the reaction, first group B! introduced to the M-end of the compound (7| and then the C-end is connected with the amino group X to "» obtain the compound |4|.

In this case, according to scheme 2 of the reaction, the compound of the formula |1)| bind to an amino compound, which

Corresponds to the substituent X, in order to obtain the compound of formula (2), from which the amino protecting group at the M - (o) end is removed to obtain the compound of formula III). Then group B is introduced to the M-end of the compound of formula (3) in order to obtain the nitrile compound of formula (4), which is further saturated with hydrogen sulfide in the presence of pyridine and triethylamine to produce the thioamide compound of formula (15). The indicated tisamide compound is then methylated with (ee) a methylating agent, for example, iodomethane, dimethyl sulfate, methyl triflate, etc. for bo 50 obtaining the desired methyl mercapto compound of the formula ||.

According to the reaction scheme, first group B! enter to the M - end of the compound of the formula |7/| by the reaction "m of the compound of the formula |7| with the compound of the formula |6), and then the amino group is introduced to the C-end of the obtained compound of the formula

IV) by coupling a compound of formula |8) with an amino compound corresponding to the substituent X to give a compound of formula |4), which is then subjected to the same operations as in reaction scheme 2 in order to obtain the desired 22 methylmercapto compound of formula (CPU.

Gee! The coupling agent that can be used in the coupling operation in reaction schemes 2 and 3 includes one or more substances selected from the group containing dicyclohexylcarbodiimide (DCYUK, 3-ethyl-3-de (dimethylamino)propylcarbodiimide (EDK), bis-(2-oxo-3-oxazolidinyl)phosphoric acid chloride (BOF - SI) and diphenylphosphoryl azide (DFFA), but not limited to the specified substances. 60 Although carboxylic acid compounds |1)| and EI, used in reaction schemes 2 and 3, can be used in the form of their free acids, it is best to use them in the form of their reactive derivatives, for example, a derivative of halodihydride or derivatives of other activated ethers to facilitate the course of the reaction.

In particular, a derivative of an activated carboxylic acid ester is required for a binding reaction with an amino compound to form an amino bond, or for a binding reaction with an alcohol to form an ether bond. Such reactive derivatives include conventional derivatives that can be prepared according to a method widely used in the art. For example, chlorine anhydride is used as a derivative of halogen hydride; and the derivative of the activated ether includes a carboxylic acid anhydride isolated from an alkoxycarbonyl halide, for example, methoxycarbonyl chloride, isobutyloxycarbonyl chloride, etc., and a binding agent, M - hydroxyphthalimide - isolated ether, M - hydroxysuccinimide - isolated ether, M - hydroxy - 5 - norbonin -2, 3-dicarboxyimide - isolated ether, 2, 4, 5 - trichlorophenol - isolated ether, etc., but not limited to the above.

The thrombin-inhibitory effect of the compound of formula (I) according to the present invention can be identified by determining the dissociation constant Ki, which is calculated from the following equation according to a known method described in the literature (see Meijodz ip epgutoIodu M. 80, p341 - 361; Viospetivhigu 27, /0.v2144 - 2151 (1988)).

Oh shit

Ki sho shayazhnttnn to break

IEC where x TE) is the concentration of the free enzyme, y |) is the concentration of the unbound inhibitor, y HE is the concentration of the enzyme-inhibitor complex.

The dissociation constant Ki means the degree of dissociation of the thrombin enzyme-inhibitor complex. Accordingly, a low dissociation constant corresponds to a high degree of binding of the thrombin inhibitor to the enzyme and thus indicates that the thrombin inhibitor has a high thrombin inhibitory activity. This dissociation constant can be determined by reacting thrombin with a certain substrate that changes color when hydrolyzed by thrombin, and then measuring spectrophotometrically the degree of i) color change as a function of time.

In this invention, Spgotogut TN (Su-Rho-Agao-4-nitro-anilide acetate) is used as a substrate substance for thrombin, which changes color under the influence of thrombin. Spgotogut TN is hydrolyzed with thrombin to obtain yellow para-nitroaniline. Accordingly, the amount of paranitroaniline yellow obtained by the above method can be measured as a change in spectral absorbance over time to determine the thrombin inhibitory activity of the compound of the present invention. That is, enzyme activity can be determined from the rate of change in spectral absorbance, and then it can be directly related to the ability of the thrombin inhibitor to inhibit enzyme activity (see Meiodv ip me)

Epgutoiodu, M. 80, p341 - 361, Viospetivhigu 27, p2144-2151, 1988). "at

To identify the selectivity of the compound of the present invention for thrombin relative to trypsin, the inhibitory activity of the compound of formula (I) for trypsin is measured as the value of Ki according to a method that is similar to the previously given method for determining |inhibitory activity for thrombin, and then the ratio of activity to trypsin and activity to thrombin. In this case, the operation to determine the inhibitory activity to trypsin is essentially identical to the operation to determine the inhibitory activity to thrombin, with the exception of the fact that hydrogen chloride M-benzoyl-Mais-su-Agud para-nitroanilide is used as a substrate. ;" As a result of determining the inhibitory activity of the compound of formula (I) according to the present invention to thrombin and trypsin, it can be stated that the compound according to the present invention shows excellent inhibitory activity to thrombin and, in addition, has a high selectivity to thrombin over trypsin. In particular, the selectivity of compounds,

Ge" given in examples 1 and 7, to thrombin relative to trypsin is approximately 2900 times and 26304 times higher, respectively, while similar indicators of known thrombin inhibitors, agrotroban (A) and MARAP (B), are only 250 and 50 times, respectively. Thus, it can be seen that the compound of formula (I) according to the present invention has a significant advantage in selectivity for thrombin over trypsin.

As stated above, since the novel compound of formula (I) according to the present invention is a thrombin inhibitor that shows potential thrombin inhibitory activity even when administered orally, and also has a high "M" selectivity for thrombin over trypsin, it is suitable for the prevention of blood coagulation and treatment of various thrombosis.

Accordingly, the third objective of the present invention is to create a pharmaceutical composition for the prevention of blood coagulation and the treatment of thrombosis, which contains a compound of formula (I) or its pharmaceutically acceptable salt as an active ingredient.

F) When a compound of formula (I) according to the present invention is administered for clinical purposes to a patient, the daily dose of compound (I) may vary preferably in the range of 0.00 µg to 7 µg per kg of body weight. However, depending on the specific patient, a specific dosage may be prescribed that goes beyond the above-mentioned dose range depending on the specific compound used, weight, sex, health status of the specific patient, diet, time and method of administration, degree of secretion of the compound , another active component that is combined, and the degree of the disease that belongs to the treatment.

A compound according to the present invention can be administered as an injectable preparation or an oral preparation according to the desired purpose. 65 An injectable preparation, for example, a sterilized injectable aqueous or oily suspension, may be prepared using a suitable dispersing agent, wetting agent or suspending agent according to known methods commonly used in the injectable industry. Water, Ringer's solution, or isotonic mass solution can be used as an aqueous solvent suitable for this purpose. In addition, although a sterilized fixed oil can be used as a solvent or suspending medium, any non-irritating fixed oil, including mono- or diglycerides, can be used for this purpose. In addition, a fatty acid, for example, oleic acid, can be added to the injectable preparation.

A solid preparation for oral administration can be made in the form of capsules, tablets, pills, powders and granules, with capsule and tablet formulations being particularly suitable. Tablets and pills can 7/0 be made mainly in the form of a drug covered with a shell. As a solid preparation, the active compound of formula (1) according to the present invention can be combined with a pharmaceutically acceptable carrier. For example, with one or more inert solvent(s) such as sucrose, lactose, starch, etc., lubricants such as magnesium silicate, dispersants, binders, etc.

One of the characteristic features of the compound of formula (1) according to the present invention is that the compound of formula (1) /5 shows a good pharmacological effect even when it is prepared as an oral preparation and then administered orally. This can be demonstrated by the results of pharmacokinetic experiments on rats and dogs, which act as experimental animals. That is, in these experiments it was demonstrated that the active compound according to the present invention is retained in the blood for a longer time when it is administered orally. Accordingly, the compound of formula (1) according to the present invention is more suitable in terms of the fact that it can be more effectively administered as an oral preparation.

In addition, it has become clear from pharmacokinetic experiments that the active compound of formula (1) according to the present invention can provide the desired target without severe toxicity in mammals, including rats and dogs.

When the thrombin inhibitor of the present invention is administered to achieve an anticoagulation and thrombolytic effect, it can be administered in combination with one or more substance(s) selected from the group consisting of thrombolytic agents and agents for inhibiting platelet activity. As a thrombolytic i) agent that can be used for this purpose, it is possible to mention Her - RA, urokinase, streptokinase, etc.; as an agent for inhibiting platelet activity, you can use aspirin, ticlopidine, clopidrogel, monoclonal antibody 7EZ, etc. However, it should be understood that a preparation containing an active compound according to the present invention for the treatment and prevention of thrombosis is not limited to the above and may include any preparation suitable for the same purpose. co

The following are examples to illustrate the present invention in more detail. However, it should be understood that these examples are intended only to explain the present invention and in no way limit its scope. co

Drug 1

Synthesis of cyclopentyl-methylamine

To a solution of cyclopentanone (tOml, 113 mM) in methanol (5Oml) and water (HOml) was added methylamine hydrogen chloride (7.bg, 1133mmol) and sodium cyanoborohydride (MvnzsmM) (7.1g, 1133mmol). The mixture was heated to reflux for 12 hours at pH 6. The methanol was evaporated under reduced pressure and the precipitate was cooled to 0°C for 7-3 seconds, the pH was adjusted to 2 using 3M hydrochloric acid, and then washed three times with diethyl ether. The aqueous layer was again cooled to a temperature of 0"C, and then adjusted pH to a value equal to 11, using a solution of caustic soda (6M). Anhydride was added to this mixture

of t-butyloxycarbonyl (24.5g, 1133mmol) in dioxane (50ml). The solution was stirred for 3 hours at room temperature and concentrated under reduced pressure to a volume equal to approximately 30 ml. Precipitate

Ge" was extracted with ethyl acetate and washed with aqueous 0.5M hydrochloric acid and saturated with sodium bicarbonate solutions. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a white solid, which was then purified by

Go! by capillary chromatography (the solution was ethyl acetate:hexane in a volume ratio of 73). After purification, the obtained solid product was dissolved in a solution of 4M NOSI - dioxane (bOml) and the resulting solution was stirred for 30 minutes at room temperature. The solvent was evaporated in a vacuum in order to obtain the above-mentioned compound (13.7 g of the starting product: 90.5 90). ), 2.10 (m, 2H), 1.86 - 1.50 (m, 6H) - "Nuclear magnetic resonance - "7 parts per million

Drug 2

F, Synthesis (5) - M - cyclopentyl - M - methyl - З - (4 - cyanophenyl) - 2 - (but -yloxycarbonylamino)propionamide co To solution (5) - З - (4 - cyanophenyl) - 2 (butyloxycarbonylamino) of propionic acid (0.7g, 2.41mmol) in dimethylformamide (DMF, bml) was added hydrogen chloride 1-(3-dimethylaminopropyl)-Z-ethylcarbodiimide hydrochloride (EDH, 0.7g) and 1-hydroxybenzotriazole hydrate (HOBT, 0.4g ) at a temperature of 0"C. The mixture was stirred until the substances were completely dissolved in the indicated solution. To this reaction mixture was added the compound (0.4 g, 2.9 mmol), obtained as Preparation 1, and M - methylmorpholine (1.0 ml), and then the reaction temperature was slowly increased to room temperature. The reaction solution was stirred for 3.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove volatiles, and the remaining precipitate was dissolved with ethyl acetate, washed successively with saturated aqueous solution acid salt of sodium carbonate, dissolved hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated. The precipitate was purified by column chromatography (at a volume ratio of ethyl acetate:hexane equal to 7:3) to obtain the purified above-mentioned compound (0.65 g, yield: 73 9b). "NIAMR (SOSIZ, chnm) 5 : 7.61 (t, 2H), 7.32 (t, 2H), 5.48, 5.01-4.86, 4.12(Zt, ZN), 2.75, 2.62(28, ZN), 2.90-1.20(t , 17H)

Mass (FSA, t/e") : 372(M7 1) x ratio of mass to charge

Drug Z

Synthesis of (5)-M-cyclopentyl-M-methyl-3-(4-cyanophenyl)-2-(2-naphthylsulfonylamino)propionamide

The compound (0.65 g, 1.75 mmol), prepared as Preparation 2, was dissolved in dichloromethane (3 mL), then cooled to -10°C and trifluoroacetic acid (TFA, mL) was added to it. The reaction mixture was stirred for 5 minutes , slowly heated to room temperature, stirred for 30 minutes, and then concentrated under reduced pressure in order to remove volatile substances. The precipitate was dried using a vacuum pump, and then bml DMK was added to it. The specified mixture was cooled to 0"C and added to it ml of M, M - diisopropylethylamine. The reaction mixture was heated to room temperature and stirred for 5 minutes. After adding 2-naphthalene sulfonyl chloride (0.47 g, 2.07 mmol), the reaction mixture was stirred for 1 hour until the end of the reaction, and then concentrated under reduced pressure to remove volatile substances. The precipitate was dissolved with ethyl acetate, washed in a saturated solution of acidic salt of sodium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The precipitate was purified by column chromatography (at a volume ratio of ethyl acetate:hexane equal to 1:1) to obtain the above-mentioned compound (0.65 g of starting product, 802906). "YAN YMR (SOSI 5, chnm) 5: 8.28 (t, 1H) , 7.87 (t, ЗН), 7.73(t, ЗН) , 7.49(t, 2Н) , 5.92(t, 1Н), 4.50, 29 dAZ2 ... , t, 2H) d)

Mass (FSA, t/e): 462 (M w 1)

Example 1

Synthesis of (5) - M - cyclopentyl - M - methyl-Z - (4 - amidrazonophenyl)-2-(-2-naphthylsulfonylamino) propionamide

The compound (0.65g, 1.41mmol), prepared as Preparation 3, was dissolved in pyridine (10ml) and the resulting solution was placed in a flask equipped with taps, to which triethylamine (0.45ml) was added. The reaction flask was equipped in such a way that hydrogen sulfide (H2O) was able to slowly escape through one of the connections of the flask and flow out through the other connection. The reaction solution was saturated with hydrogen sulfide, stirring constantly for about 10 minutes, while the colorless solution first became green and then gradually changed to a dark brown color. The flask was closed with a rubber stopper and stored for three days at room temperature until the end of the reaction. Then the reaction solution was distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. To obtain a yellow solid, acetone (15 ml) and iodomethane (CH3, 0.65 ml) were added together, and the resulting mixture was heated for 30 minutes until phlegm was obtained. The specified reaction mixture was distilled again under reduced pressure to remove volatile substances and dried using a vacuum pump. The precipitate was dissolved in - t0 pure methanol (8 ml) and then stirred. To this mixture, 80,905 g of hydrazine hydrate (NoMMH, H2O, 0.12 ml, 1.9 v8 mmol) was added three times in portions every 10 minutes. After the reaction, the reaction solution was concentrated and then purified by high pressure liquid chromatography (HPLC) to obtain the title compound (0.63 g, yield: 7390).

Conditions of РХВТ: - solvent - methanol: water (volume ratio 75:25), each of which contains SEZSOOH with a concentration

F 0.196

ОО - wavelength - 215nm - dissolution rate - 20ml/min со - column Оей(а РАК С.8 100 angstroms (ZOxZO0Omm) (ee) 50 TN NMR (SOZO0, chnm) 5 : 8.28(4, 1), 7.92 ( t. 2H), 2.49, 2.26(8, в, ЗН), 1.60-1.00, 0.73-0.52(t, t, 8H)

Mass (FSA, m/e) : 494 (M"--1)

Preparation 4 5B Synthesis of the salt of butyl methylamine trifluoroacetic acid

M - butyloxycarbonylbutylamine (14Omg, 0.8O0mmol) was dissolved in DMF (8ml) and caustic soda (F) (mann, 2Omg, 1 equivalent weight) and iodomethane (0.1Oml, 2 equivalent weights) were added there. The reaction mixture was stirred for 30 minutes at room temperature and filtered through a pad of celite and concentrated under reduced pressure to remove the solvent. The precipitate was dissolved with ethyl acetate, washed in an aqueous solution of 60% hydrochloric acid (0.5 M), dried over anhydrous magnesium sulfate and filtered. The organic layer was concentrated under reduced pressure and dried using a vacuum pump to obtain a white solid, which was then dissolved in dichloromethane and cooled to a temperature of 0"C. To this mixture was added ml of trifluoroacetic acid (TFA). The reaction solution was stirred for 30 minutes at at room temperature, concentrated under reduced pressure, and then dried using a vacuum pump to obtain 65 of the above-mentioned compound (0.16g) in quantitative yield.

TN NMR (SOSI. 3, chnm) 5 : 1.02(Y, ЗН), 1.30-1.80(t, 4Н), 3.04(5, ЗН), 3.52(Й, 2Н), 8.20(в5, 2Н)

Example 2

Synthesis of (5)-M-butyl-M-methyl-Z-(4-amidrazonophenyl)-2-(2-aphthylsulfonylamino)propionamide

The compound prepared as Preparation 4 was reacted according to the same operations as Preparations 2 and 3 in order to obtain the intermediate compound (5) - M - butyl - M - methyl - 3 - (4 - cyanophenyl) - 2 - ( 2-naphthylsulfonylamino)propionamide (0.23 g), which was used as a starting material. The specified starting material was processed according to the same operations as in Example 1 to obtain the purified above-mentioned compound (0.1g, yield: 40.0905).

TN nMR (СО5О0, chnm) 5 : 8.30(9, 1), 7.98(t, ЗН), 7.81-7.30(t, 7Н), 4.50(t, 1Н), 3.25-2.55(t, 4Н), 70. 2.18, 2.45(25, ЗН), 1.40-0.50(t, 7Н)

Mass (FSA, m/e) : 482(M « 1)

Example C

Synthesis of (5)-M-cyclopentyl-M-propyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide

To obtain cyclopentyl-propylamine hydrochloride, the same operations were performed as for the preparation of Preparation 1, except that propylamine was used instead of methylamine. Further, the specified cyclopentyl-propylamine hydrochloride was treated in the same way as Preparations 2 and 3 to obtain the intermediate compound 5)-M-cyclopentyl-M-propyl-3-(4-cyanophenyl)-2--2-naphthylsulfonylamino)propionamide ( 0.15g). The specified intermediate compound was used as a starting material and processed according to the same method as in Example 1 to obtain the purified above-mentioned compound (0.089g, yield: 55.1b). "YAN NMR (SOZO0, chnm) 5 : 8.35-7.35(t, 11Н), 4.62-4.32(t, t, 1Н) , 3.90, 3.70(t, t, 1Н) , 3.10-2.50(t, 4Н), 1.70-0.50 (t, 1ZN)

Mass (FSA, t/e) : 522(M 1)

Example 4 c 29 Synthesis of /(5)-M-cyclopentyl-M-(2-benzyloxyethyl)-3--4-amidrazonophenyl)-2-(2-naphthylsulfonylamino) (U propionamide

To obtain cyclopentyl -(2 benzyloxyethyl)amine hydrochloride, the same operations were performed as for Preparation 1, except that propylamine was used instead of methylamine. Next, the obtained compound was processed according to the same method as Preparations 2 and 3 to obtain the intermediate compound (5)-M-cyclopentyl-M-(2-benzyloxyethyl)-3-(4-cyanophenyl)-2-( 2-naphthylsulfonylamino) propiosnamide with (0.15 g). The indicated intermediate compound was used as a starting material and treated according to the same method as in Example 1 to obtain the purified above-mentioned compound (0.15g, yield: 93.895). co

PTN NMR (SOZO0, chnm) 5 : 8. 30-7.15 (t, 16Н), 4.64 (t, 1Н), 4.48, 4.39(5, 8, 1Н), 4.14, 4.00, 3.75, «о with 3.45(t , t, t, t, ЗН), 3.10-2.70(t, 5Н), 1.62-1.00(t, 8Н) s

Mass (FSA, m/e) : 614 (M 1)

Example 5

Synthesis of (5)-M-cyclopentyl-M-butyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide

For the preparation of butyl diclopentylamine hydrochloride, the same operations were performed as for the preparation of Preparation 1, except that butylamine was used instead of methylamine. Further, the specified -o c compound was processed in the same way as Preparations 2 and 3 to obtain the intermediate compound (5)-M-cyclopentyl-M-butyl-3-(4-cyanophenyl)-2-(2-naphthylsulfonylamino)propionamide (0.28g). The specified intermediate compound was used as a starting material and processed according to the same method as in Example 1 to obtain the purified above-mentioned compound (0.18g, yield: 60905).

ТN NMR (СО3О0, chnm) 6 : 8.32(4, 1Н), 7.96(t, ЗН), 7.78-7.55(t, 5Н), 7.42(da, 2Н), 4.62, 4.30(t, t, 1Н), 4.02,

Gee! 3.90(t, t, 1H), 3.10-2.75, 2.55 (t, t, 4H), 1.65-0.80(t, 12H), 0.65(i, ЗН)

Mass (FSA, m/e) : 536(M i 1) (95)

Example 6 (ee) Synthesis of (5)-M-cyclopentyl-M-ethyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide so 50 To obtain cyclopentyl-ethylamine hydrogen chloride, the same operations as to obtain Preparation 1, except that ethylamine was used instead of methylamine. Further, the specified compound was processed in the same way as Preparations 2 and 3 to obtain the intermediate compound (5)-M-cyclopentyl-M-ethyl-3-(4-cyanophenyl)-2-(2-naphthylsulfonylamino)propionamide (0 , 21g). The indicated intermediate compound was used as a starting material and treated according to the same method as in Example 1 to obtain the purified above-mentioned compound (0.11g, yield: 5090). o TN NMR (SOZOO, chnm) 5: 8.32 (a, 1Н), 7.97 (t, ЗН), 7.75-7.55 (t, 5Н), 7.42 (t, 2Н), 4.60, 4.38 (t, t, 1Н) . XO8(M7 1)

Example 7 60 Synthesis of (5)-M-cyclopentyl-M-methyl-3-I(4-(methylamindino)-phenyl|-2-(-2-naphthylsulfonylamino) propionamide

The intermediate compound prepared as Preparation 3 was used as a starting material and treated according to the same method as in Example 1, except that instead of hydrazine, methylamine was added three times at 1-hour intervals to obtain the purified title compound (0.064g, output: 890).

TN NMR (SOZO0, chnm) 5: 0.50-1.60 (t, 8H), 2.00-2.49 (28, ЗН), 2.84(t, 1Н), 2.96(t, 1Н), 3.00(z, ЗН), bod OB (t, 1H), 4.50 (t, 1H), 7.20-8.30 (t, 11H)

Mass (FSA, m/e) : 493 (M 1)

Example 8

Synthesis of (5)-M-cyclopentyl-M-methyl-3-I4-(1,1-dimethylamidino)-phenyl|-2-(2-n-aphthylsulfonylamino) propionamide

The intermediate compound prepared as Preparation 3 was used as starting material and treated according to the same method as in Example 1, except that instead of hydrazine, dimethylamine was added three times at 1-hour intervals to obtain the purified above-named compound (0.18g , output: 2290).

TN nMR (СО5О0, chnm) 5 : 0.60-1.60(t, 8Н), 2.29, 2.54(25, НН), 2.95(t, 1Н), 3.0b(t, 1Н), 3.09(5, НН), 70 3.31(8, ZN), 4.16(t, 1H), 4.60(t, 1H), 7.20-8.30(t, 11H)

Mass (FSA, t/e) : 507 (M 1)

Example 9

Siatez (5)-M-cyclopentyl-M-methyl-3-(4-amidrazonophenyl)-2-(4-methoxy-2,3,6-trimethylbenzene) sulfonylamino)| propionamide

The compound prepared as Preparation 2 was treated according to the same procedure as Preparation 3, except that 4-methoxy-2,3,6-trimethylbenzenesulfochloride was used instead of 2-naphthalene sulfochloride to give intermediate (5)-M -cyclopentyl-M-methyl-3-(4-cyanophenyl)-2-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)propionamide (0.27g). This intermediate compound was used as a starting material and treated according to the same method as in Example 1 to obtain the purified above-mentioned compound (0.16g, yield: 57.190).

ТN NMR (СО5О0, chnm ) 5 : 7.62(a, 2H), 7.40(a4, 2H), 6.70(a4, 1), 4.35, 3.90(t, t, 2H), 3.83(4, ЗН), 3.00( t, 2H), 2.50(t, 9H), 2.1(8, ЗН), 1.75-0.90(t, 8H)

Mass (FSA, m/e) : 516 (M 1)

The drug is 5 cm r y y y

Synthesis of cyclopentyl-hydroxylamine (o)

Hydrogen chloride hydroxylamine (NOMON Nei, 5.0g, 71.95mmol) was dissolved in water (14ml) and methanol (30ml) and cyclopentanone (5.1ml, 57.6bmmol) were added to it. The mixture was stirred, cooled to a temperature of 0"C, and then the pH was adjusted to a value equal to 8 by adding a 6M aqueous solution of sodium hydroxide. Then sodium cyanoborohydride (MaVvNUSM, 1.9g, 30.24mmol) was added to the specified mixture.

The mixture was warmed to room temperature and then stirred. The pH value of the reaction mixture, which was equal to 4.0, was maintained by portionwise addition of a mixed solution of 6M HCl (200 ml) and methanol (30 ml) during the reaction. After 5 hours, the pH of the reaction mixture was adjusted to 7.0 and distilled under reduced pressure to remove methanol. The residual reaction solution (He) was cooled to a temperature of 0"C, the pH was again adjusted to a value equal to 11, saturated with sodium chloride, and then extracted four times with chloroform. The resulting extract was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the above-mentioned compounds (3.4 g, yield: 58.3 96).

T"N YaMe (SOSI z, chnm) 5: 7.20-5.00 (rv, 1H), 3.56 (t, 1H), 1.90-1.45 (t, 9H) "

Example 10 Synthesis of (5)-M-cyclopentyl-M-hydroxy-3-(4-amidrazonophenyl)-2-(2-n-aphthylsulfonylamino)propionamide

To obtain the intermediate compound (5)-M-cyclopentyl-M-hydroxy-3-(4-cyanophenyl)-2-(2-:3» naphthylsulfonylamino) propionamide (0.1 g), the compound prepared as Preparation 5 was treated according to in the same way as Preparations 2 and 3. The specified intermediate compound was used as a starting material and processed according to the same method as in Example 1 to obtain the purified above-mentioned compound b (0.07g, yield: 63.6 95).

TN NMR (SOZOO, chnm) 5: 8.25-7.30 (t, 11Н), 4.75 (t, 1Н), 4.30 (t, 1Н), 3.10, 2.75 (t, t, 2Н), 1.70-1.00 (t, 8Н ) c Mass (FSA, t/e) : 496 (M 1) (ee) Example 11 c 50 Synthesis of (5)-M-cyclopentyl-M-(2-hydroxyethyl)-3-(4-amidrazonophenyl)-2- (2-naphthylsulfonylamino)propionamide that The compound (0.15g, 0.24mmol), prepared as described in Example 4, was dissolved in methanol (10ml), and then palladium hydroxide (0.02g) was added to it. A hydrogen cylinder was attached to the reaction vessel. After stirring for 2 days, the reaction mixture was filtered through a layer of celite and concentrated. The precipitate was purified by RT to obtain the above-mentioned compound (0.08g, yield: 63.795). The conditions for conducting the RHCVT were the same as in Example 1.

TN NMR (SOSO, chnm) 5 : 7.80-7.00(t, 11Н), 4.47(t, 1Н), 4.00(t, 1Н), 3.60(t, 2Н), 3.10-2.70(t, 4Н), where 1.70 -1.10(t, 8H)

Mass (FSA, t/e) : 524(M" 1) for Example 12

Synthesis of (5)-M-cyclopentyl-M-methyl-3-(4-(methylamidino)-phenyl|-2-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino) propionamide

To obtain the purified above-mentioned compound (0.08g, yield: 28.390), the same method was used as in Example 9, except that instead of hydrazine, methylamine was added three times with an interval of 1 hour.

TN NMR (SOSO, chnm) 5 : 7.65(4, 2H), 7.40(a4, 2), 6.70(4, 1H), 4.40, 3.90(t, t, 2H), 3.85(4, ЗН), 3.20- 2.90(t, 5Н), 2.55(t, 9Н), 2.10(в, ЗН), 1.75-0.90(t, 8Н)

Mass (FSA, t/e) : 515 (M 1)

Example 13

Synthesis of (5)-M,M-dimethyl-3-(4-amidrazonophenyl)-2-(-2-naphthylsulfonylamino) propionamide

The same operations as in the preparation of Preparations 2 and 3, except that dimethylamine was used, were performed in order to obtain the intermediate compound (5) -M,M-dimethyl-3-(4-cyanophenyl)-2-(2 - naphthylsulfonylamino) propionamide (0.11 g). The indicated intermediate compound was used as starting material 70 and treated according to the same operations as in Example 17 to obtain the purified title compound (0.O80g, yield: 53905)

TN NMR (SOZOO, chnm) 5 : 2.19(v, ЗН), 2.62(5, ЗН), 2.70-2.95(t, 2Н), 4.41(t, 1Н), 7.20-8.30(t, 11Н)

Mass (FSA, t/e): 440 (M w 1)

Example 14

Synthesis (5) - М.М -dimethyl - З - 4 - (methylamidino)phenyl| -2-(2-naphthylsulfonylamino) propionamide

To obtain the purified above-mentioned compound (0.10 g, yield: 4895), the same method as in Example 1 was used, except that instead of hydrazine, methylamine was added three times with an interval of 1 hour.

TN NMR (СО30О0, chnm) 5 : 2.31(z, ЗН), 2.75(в, ЗН), 2.80-3.05(t, 2Н), 3.07(в, ЗН), 4.54 (t, 1Н), 7.30-8.40( t, 11H)

Mass (FSA, m/e) : 439(M 7-1)

Example 15

Synthesis of (5)-M-cyclohexyl-M-methyl-3-(4-amidrazono phenyl)-2(2-naphthylsulfonylamino) propionamide

The same operations as in the preparation of preparation 71, except that cyclohexanone was used instead of cyclopentanone, were performed in order to obtain cyclohexyl-c methylamine hydrochloride, which was processed according to the same operations as in the preparation of preparations 2 and 3 for obtaining the intermediate compound (5)-M-cyclohexyl-M-methyl-3-(4-cyanophenyl)-2-(2-naphthylsulfonylamino) o propionamide (0.21 g). The indicated intermediate compound was used as a starting material and treated according to the same operations as in Example 1 to obtain the purified above-mentioned compound (0.17g, yield: 73.99) M

ТN NMR (СО5О0, chnm) 5 : 8.32(4, 1), 7.95 (t, ЗН), 7.75-7.53(t, 5Н), 7.40(da, 2Н), 4.50, 4.21, 3.62(t, t, t , 2H), 3.05(t, 1H), 2.90(t, 1H), 2.55, 2.40(v, 8, ЗН), 1.80-0.62(t, 1OH) 09

Mass (FSA, m/e) : 5ХО8(М 7-1) (ee)

Example 16 p

Synthesis of (5)-M-cyclopropyl-M-methyl-3-(4-amidrazonophenyl)-2(2-naphthylsulfonylamino)propionamide

The same operations as in the preparation of Preparation 1, except that (Ce) cyclopropanone was used instead of cyclopentanone, were performed in order to obtain cyclopropyl hydrogen chloride - methylamine, which was processed according to the same operations as in the preparation of preparations 2 and 3, to obtain the intermediate compound (5)-M-cyclopropyl-M-methyl-3-(4-cyanophenyl)-2-(2-naphthylsulfonylamino) propionamide (0.21 g). The specified intermediate compound was used as a starting material and "treated according to the same operations as in Example 1 to obtain the purified above-mentioned compound (0.06 g, - s yield: 12905) xz" TN NMR (СО30О0, chnm) 5: 0.40-0.90(t, 4H), 2.40(z, ЗН), 2.75(t, 1H), 2.95(t, 1H), 7.20-8.30(t, 11H)

Mass (FSA, m/e) : 466 (M 1)

Drug 5

Synthesis of (5)-3-(4-cyanophenyl)-M-cyclopentyl-M-methyl-2-(2-naphthalen-1-yl-acetylamino)propionamide b Compound (0.51g, 1.34mmol) prepared as 2, was dissolved in 3 ml of dichloromethane and cooled to -10°C, and then trifluoroacetic acid (TFC, 3 ml) was added to the resulting solution. The reaction mixture was stirred for 5 minutes, slowly heated to room temperature, stirred again for 30 minutes, and so then distilled under reduced pressure to remove the volatile matter.The precipitate was dried with

Ge | 20 of the vacuum pump, and then 1 ml of DMK was added to it. The specified solution was cooled to -107C and added. to it hydrogen chloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDH, 0.4 g) and 1-hydroxybenzotriazole in (HOBT, 0.27), and then mixed until complete dissolution. 1-naphthalene acetic acid (0.26 mg, 14 mmol) and M,M-diisopropylethylamine (1.2 ml) were added to the resulting solution. The reaction mixture was slowly heated to room temperature and stirred for 3 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure in order to remove the volatile matter. The precipitate was dissolved in

HF) with ethyl acetate, successively washed with a saturated aqueous solution of the acidic salt of sodium carbonate (Manso), hydrochloric acid solution and saline solution, dried over anhydrous magnesium sulfate and then filtered. The resulting filtrate was concentrated and the precipitate was purified by column chromatography (methanol:chloroform volume ratio equal to 1:99) to obtain the above-mentioned compound (0.42 g, yield: 6890). "YAN YMR (SOSIz, chnm) 5 : 8.0-6.8(t, 11Н), 6.5 (t, 1Н), 5.1-5.3(t, 1Н), 4.8-4.2(t, 1Н), 4.1-3.8(t, 2H), 3.0-2.6(t, 5H), 1.8-1.3(t, 8H)

Example 17 v5 Synthesis of (5)-3-I4-(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(2-naphthalen-1-yl acetylamino)propionamide

The compound (0.21g, 0.4vmmol), prepared as Preparation 6, was dissolved in pyridine (3ml) and the resulting solution was placed in a flask equipped with taps, to which triethylamine (0.2ml) was added. The reaction flask was equipped in such a way that hydrogen sulfide (H2O) was able to slowly escape through one of the ports of the flask and flow out through the other port. The reaction solution was saturated with hydrogen sulfide, with constant stirring for about 10 minutes, while the colorless solution first became green and then gradually changed to dark brown. The flask was closed with a rubber stopper and stored for 3 days at room temperature until the end of the reaction. Then the reaction solution was distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. Acetone (1Oml) and iodomethane (CH3Zi, O0,3ml) were added together to the obtained yellow solid, and the resulting mixture was heated to 7/0 to produce phlegm for 30 minutes. The specified reaction mixture was distilled again under reduced pressure to remove volatile substances and dried using a vacuum pump. The precipitate was distilled in pure methanol (5 ml) and then stirred. 80 percent hydrazine hydrate (NOMMN» .NhO, 0.04ml, 0.72mmol) was added to the indicated mixture three times in portions with an interval of 10 minutes. After completion of the reaction, the reaction solution was concentrated, and then purified by RT to obtain the above compound (0.16g, yield: 70905).

TN NMR (СО5О0, chnm) 5 : 8.0-7.3(t, 11), 5.3-5.1(t, 1Н), 4.8-4.2(t, 1Н), 3.9(5, 2Н). 3.2-2.9(t, 2Н), 2.18, 2.12 (28, ЗН), 1.8-1.3(t, 8Н)

Mass (FSA, m/e) : 472 (M 1)

Example 18

Synthesis of (5)-3-(4-(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(5-dimethylaminonaphthalene-1-sulfonylamino) propionamide

The same operations as in the preparation of Preparation C, except that instead of 2-naphthylsulfonyl chloride (M,M-dimethylamino)-1-naphthalenesulfonyl chloride was used, it was performed in order to obtain the intermediate compound (5)-3-(4) -cyanoonophenyl)-M-cyclopentyl-M-methyl-2-(5-dimethylamino-naphthalene-1-sulfonylamino) propionamide c (0.55 g, 1.09 mmol). The indicated intermediate compound was further processed according to the same operations as in Example 1 to obtain the purified above-mentioned compound (0.35 g of starting product: 60905)

TN NMR (SOZOO, chnm) 5 : 8.6-7.3(t, TON), 4.6-3.9(t, 2H), 3.11(5, ЗН), 3.0(5, ЗН), 3.05-2.8(t, 2Н), 2.5, 2.4(25, ZN), 1.7-0.9(t, TON)

Mass (FSA, t/e) : 537(M 7-1) -

Example 19 (ee)

Synthesis of /(5)-3-(4-amidrazono)-pentyl|-M-cyclopentyl-M-methyl-2-(5-dimethoxy-naphthalene-1-sulfonylamino) propionamide so

The same operations as in the preparation of drug C, except that instead of 2-isonaphthalene sulfochloride, 5-methoxy-1-naphthylsulfochloride was used to obtain the intermediate compound (5)-3-(4-cyanophenyl)-M- cyclopentyl-N-methyl-2-(5-methoxy-naphthalene-1-sulfonylamino) n-o propionamide (0.18 g, 0.37 mmol). The indicated intermediate compound was further worked up according to the same operations as in Example 1 to obtain the purified above-mentioned compound (0.12 g of the starting product: 65) « 20 TO NMR (SOZO0, chnm) 5 : 8.4-7.3 (t, 9Н), 4.7-4.0 (t, 2Н), 4.2-4.0 (285, 6Н ), 3.2-2.8 (t, 2H), -v s 2.6-2.2(28, ЗН), 1.7-1.0(t, 8H) and Mass (FSA, t/e) : 523 (M"-1) and? Example 20

Synthesis of (5)-3-(4-amidrazono)-phenyl|-M-cyclopentyl-M-methyl-2-(6,7-dimethoxy-naphthalene-2-sulfonylamino)propionamide

Ge") The same operations as in the preparation of preparation C, except that instead of 2-naphthalene sulfochloride, 6b,7-dimethoxy-2-naphthalene sulfochloride was used, performed with the aim of obtaining the intermediate compound (5)-3-(4- cyanophenyl)-M-cyclopentyl-M-methyl-2-(6,7-dimethoxy-naphthalene-2-

(Ho)sulfonylamino)propionamide (2.2g, 2.2mmol). Then, the indicated intermediate compound was treated according to the same 5p same operations as described in Example 1 to obtain the purified above-mentioned compound (1.55g, yield: bo 6796). and TN NMR (SOZO0, chnm) 5 : 8.5-7.0 (t, 10Н), 4.6-4.0 (t, 2Н), 4.2(в8, ЗН), 3.0-2.8(t, 2Н), 2.48-2.45(28,

ЗН), 1.7-1.0(t, 8Н)

Mass (FSA, m/e) : 554(M 7-1)

Example 21

Gee! Synthesis of (5)-3-(4-methylamidino)-phenyl|-M-cyclopentyl-M-methyl-2-(5-dimethylamino-naphthalene-1-sulfonylamino)propionami dU

The same operations as in the preparation of preparation C, except that instead of 2-60 naphthalene sulfochloride, 5-(M,M-dimethylamino)-1-n-naphthalene sulfo chloride was used to obtain the intermediate compound (5)-3 -(4-cyanophenyl)-M-cyclopentyl-M-methyl-2-(5-dimethylamino-naphthalene-1-sulfonylamino)propionamide (0.3 g, 0.0000000000000001 mmol). The indicated intermediate was then treated according to the same operations as described in

Example 1, except that methylamine was used instead of B5 80905 of hydrazine hydrate to obtain the purified above-mentioned compound (0.08g, yield: 25965).

TO NMR (SOZO0, chnm) 5 s: 8.52-7.25(t, OH), 4.55-4.42(t, 2H), 4.23-3.98(t, 2H), 3.09(8, ЗН), 3.06-2.80( t, 2H), 2.90(t, 6H), 2.45(v, ЗН), 2.38(5, ЗН), 1.76-0.90(t, 8Н)

Mass (FSA, m/e) : 5Z36(M-1)

Example 22

Synthesis of (5)-3-(4-amidrazono)-phenyl|-M-cyclopentyl-M-methyl-2-(naphthalene-1-sulfonylamino)-propionamide

The same operations as in the preparation of Preparation C, with the exception of the fact that instead of 2-naphthalene sulfochloride, 1-naphthalene sulfochloride was used to obtain the intermediate compound (5)-3-(4-cyanophenyl)-M-cyclopentyl-M-methyl -2-(naphthalene-1-sulfonylamino)propionamide (0.5g, 1mmol). 70 The indicated intermediate was treated according to the same operations as described in Example 1 to obtain the purified title compound (0.2g, yield: 4090).

TN NMR (СО300, chnm) 5 : 8.61-7.28(t, 11Н), 4.55-4.41(t, 2Н), 4.23-4.00(t, 2Н), 3.00-2.84 (t, 2Н), 2.49, 2.41(28 , ZN), 1.70-1.00 (t, 8H)

Mass (FSA, m/e) : 494 (M. 1) 12 Example 23

Synthesis of (5)-3-(4-amidrazono)-phenyl|-M-cyclopentyl-M-methyl-2-(2-(naphthalen-1-yl-oxy)acetalamino|- propionamide

The same operations as in the preparation of preparation b, except that instead of 1-naphthalene acetic acid, (1-naphthoxy)acetic acid was used to obtain the intermediate compound (5)-3-(4-cyanophenyl)- M-cyclopentyl-M-methyl-2-(2-(naphthalen-1-yloxy)-acetylamino|-propionamide (0.59 g, 1.3 mmol). The indicated intermediate was then treated according to the same operations as described in

Example 17, to obtain the purified above-mentioned compound (0.38 g, yield: 60905).

TO NMR (СО3О0, chnm) 5 : 8.25-6.8(t, 11), 5.38-5.22 (t, 2H), 4.77-4.39(t, 2H), 4.70(5, 2H), re 3.21-3.05(t, 2H), 2.88-2.77 (28, ZN), 1.92-1.40 (t, 8H) cm

Mass (FSA, m/e): 488 (M 1) o

Example 24

Synthesis of (5)-3-(4-amidrazono)-phenyl|-M-cyclopentyl-M-methyl-2-(I2-(naphthalen-2-yl-oxy)dacetylamino|-propionamide iso-iso The same operations, the same as in the preparation of drug C, except that instead of 1-naphthalene acetic acid, (2-naphthoxy)acetic acid was used, it was carried out in order to obtain the intermediate compound (5)-3-(4-amino-hydrazonomethyl)-phenyl) -N-cyclopentyl-N-methyl-2-(2-(naphthalen-1-yl-oxy)-coacetylamino|-propionamide (0.7g, 1.54mmol). The indicated intermediate was then treated according to the same operations , which are described in Example 17 to obtain the purified above-mentioned compound (0.59 g, yield: i zv b). (Se)

ТН о NMR (СО3О0, chnm) 5 : 7.80-7.14 (t, 11Н), 5.35-5.18 (t, 1), 4.76-4.35(t, МН), 4.61(5, 2Н), 3.18-3.05(t, 2H), 2.85-2.75(28, ZN), 1.85-1.25(t, 8H)

Mass (FSA, m/e) : 488(M--1) «

Drug 7

Synthesis of the methyl ether of M-i-butoxycarbonyl-M-methylaminoacetic acid - c Glycine hydrogen chloride methyl ether (1.0 g, 8.2 mmol) was dissolved in water (12 ml) and a 1 M aqueous solution of sodium hydroxide (8.2 ml), and then added 1,4-dioxane (2Oml). To this mixture was added di-i-butyldicarbonate (2.2g, 9, mmol) at 0"C and the mixture was warmed to room temperature and stirred for 2 hours. The volatile matter was removed from the reaction mixture under reduced pressure and the precipitate was dissolved with ethyl acetate, washed successively with an aqueous saturated solution of the acidic salt of sodium carbonate, hydrochloric (o) acid and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and then concentrated. The obtained product was dissolved in dimethylformamide (DMF, 10 ml). Before this 6bO9v sodium hydride (Mann, 0.25g, b.4mmol) was slowly added to the solution at 0"C, and then iodomethane (CH with, (ee) 1.ml) was added dropwise. The mixture was slowly heated to room temperature and stirred for 3 hours at the same temperature. The mixture was filtered through a pad of Celite and concentrated under reduced pressure. The precipitate was dissolved with ethyl acetate, successively washed with the initial saturated solution of acidic sodium carbonate salt, hydrochloric acid solution and saline solution, dried over anhydrous sodium sulfate, filtered, and then concentrated. The precipitate was purified by column chromatography using ethyl acetate/hexane (volume ratio 6:4) as a solvent to obtain the purified title compound (1.0g, yield: 6596). o TN NMR (СОЗСО, chnm) 5 : 1.45(y, 9Н), 2.95(з, ЗН), 3.78(з5, ЗН), 3.92 (в, 1Н), 4.00 (в, 1Н)

Mass (FSA, m/e): 204 (M of them 1) where Drug 8

Synthesis of methyl ester 4(5)-2-((butoxycarbonylamino)-3-(4-cyanophenyl)-propionyl|-methylamino) 60 acetic acid (5)-2-(1-butoxycarbonylamino)-3-(4-cyanophenyl) -propionic acid (0.5 g, 1.72 mmol) was dissolved in dimethylformamide (DMF). The resulting solution was cooled to 0"C, and then hydrogen chloride 1-(3-dimethylaminopropyl)-3-methylcarbodiimide (EDH, 0.39 g) and 1-hydrobenzotriazole (HOBT,

O.28 g) and stirred until complete dissolution. Separately, the compound (0.35 g, 1.72 mmol), prepared as Preparation 7, was dissolved in dichloromethane (2 ml) and cooled to -102C. Trifluoroacetic acid (2 ml) was added to the indicated compound and the mixture was stirred for 5 minutes, slowly heated to room temperature, stirred again for 30 minutes, and then distilled under reduced pressure to remove the volatile matter. The compound obtained in this way and M-methylmorpholine (ml) were added to the above solution, and then the reaction solution was slowly heated to room temperature and stirred for 3.5 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure in order to remove the volatile matter. The precipitate was dissolved with ethyl acetate, successively washed with an aqueous saturated solution of an acidic salt of sodium carbonate, a solution of hydrochloric acid and a saline solution, dried over anhydrous sodium sulfate, filtered, and then concentrated. The precipitate was purified by column chromatography using ethyl acetate/hexane (volume ratio C:7) as a solvent to obtain the purified title compound (0.58g, yield: 9090).

TN NMR (CO5SOANM) 5 : 1.40(t, 9H), 3.08 (z, ЗН), 2.95-3.25(t, 2Н), 3.78(5, ЗН), 3.89-4.35(t, 2Н), 4.95(t, 1H), 5.52(49, 1H), 7.35(t, 2H), 7.6F(t, 2H)

Mass (FSA, m/e): 376 (M «t 1)

Drug 9

Synthesis of methyl ether /1-13-(4-cyanophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino) acetic acid

The compound (0.57g, 1.52mmol), prepared as Preparation 8, was dissolved in dichloromethane (2ml) and cooled to -107C, and then trifluoroacetic acid (TFC, 2ml) was added to the solution. The reaction mixture was stirred for 5 minutes, slowly heated to room temperature, stirred again for 30 minutes, and then distilled under reduced pressure to remove volatile matter. The precipitate was dried using a vacuum pump, and then DMF (10 mL) was added to it. The indicated solution was cooled to a temperature of -1407C and M,M - diisopropylethylamine (1 ml) was added to it. The specified reaction solution was heated to room temperature and stirred for about 5 minutes, and then 2 He of naphthalene sulfochloride (0.41 g, 1.82 mmol) was added to it. The reaction mixture was stirred for 1 hour until the reaction was complete and distilled under reduced pressure to remove the volatile matter. The precipitate was dissolved in ethyl acetate, washed twice with water and dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and the precipitate was purified by column chromatography using ethyl acetate/hexane (1:1 v/v) as a solvent to obtain the purified title compound (0.55 g, mc yield: 7890). co

TN NMR (SOZSO, chnm) 5 : 2.88(5, ЗН), 2.80-3.20(t, 2Н), 3.80(9, ЗН), 4.12 (4, 2Н), 4.58(t, 1Н), 6.40(a, 1H), 7.20-8.40 (t, 11H) co

Mass (FSA, m/e): 466 (M « 1) so

Example 25 3 Synthesis of methyl ether 113-(4-imidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-prolionyl|-. "0 methylamino) acetic acid

The compound (0.55g, 1.18mmol), prepared as Preparation 9, was dissolved in pyridine (10ml) and the resulting solution was placed in a flask equipped with taps, to which triethylamine (0.45ml) was added. The reaction flask was "equipped in such a way that hydrogen sulfide (H2O) was able to slowly escape through one of the ports of the flask and to escape through the other port. The reaction solution was saturated with hydrogen sulfide, stirring constantly for about 10 minutes, while the colorless solution first became green, and then gradually changed to a dark brown color. The flask was closed with a rubber stopper and stored for 3 days at room temperature. After the reaction, the reaction solution was distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. Acetone (1 mL) and iodomethane (CH3, 0.55 mL) were added together to the resulting yellow solid, and the resulting mixture was heated to

Me, obtaining phlegm within 30 minutes. The specified reaction mixture was distilled again under reduced pressure to remove volatile substances and dried using a vacuum pump. The precipitate was dissolved in pure methanol (5 ml) and then stirred. To this mixture, 8095% hydrazine hydrate (NOMMN» with H2O, 0 Tml 1.77 mmol) was added three times in portions every 10 minutes. After completion of the reaction, the reaction solution was concentrated, and then oo 50 was purified with the help of HCVT in order to obtain the above-mentioned compound (0.25 g, yield: 4390).

TN NMR (SOZSO, chnm) 5 : 2.95(z, ЗН), 2.70-3.20(t, 2Н), 3.54(з, ЗН), 3.80(4, 2Н), 4.55(t, 1Н), 7.20-8.30( t, 11Н) tm Mass (FSA, t/e) : 498 (M i 1)

Example 26

Synthesis of 4N3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-"methylamino)acetic acid 29 Compound (160mg, 0.32mmol) prepared according to the operations described in Example 25 , dissolved in

HF) solvent, which is a mixture of methanol (4 ml) and water (in a ratio of 3:1). Lithium hydroxide hydrate (GiOH. H2O, 0.016g, O0.Zv8mmol) was slowly added to this solution at 0"C and the mixture was stirred for 2 hours at room temperature. After completion of the reaction, the reaction solution was concentrated and purified using

RHCVT to obtain the above-mentioned compound (5Omg, yield: 3290). for TN NMR (SOZSO, chnm) 5: 2.20-2..60 (t, 2H), 2.48(5, ЗН), 2.78(v, ЗН), 2.32(t, 2Н), 4.12 (t, 1Н), 6.80-7.80 (t, 11Н)

Mass (FSA, m/e): 484 (M of 1)

Example 27

Synthesis of methyl ether (5)-2-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-b methylamino) propionic acid

To obtain methyl ester (I)-(M-butoxycarbonyl-M-methyl)-alanine, the same operations were performed,

as for the preparation of Preparation 7, except that instead of methyl ether of glycine, methyl ether of (I)-aniline was used, which was further processed according to the same method as Preparations 8 and 9, to obtain the intermediate compound of methyl ether (5 )-2-113-(4-cyanophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino) propionic acid (1.43 g). The specified intermediate compound was processed according to the same method as in Example 25 to obtain the purified above-mentioned compound (0.64g, yield: 48905).

TN NMR (SOZSO, chnm) 5 : 0.69, 0.88(a0, 4, ЗН), 2.79, 2.95(85, 8, ЗН), 2.80, 3.06б(t, t, 2Н), 3.48, 3.57(5, 8 , ZN), 4.29(t, 1H), 4.55 (t, 1H), 7.30-8.30(t, 11H) 70 Mass (FSA, t/e) : 512(M « 1)

Example 28

Synthesis of (5) - 2 - IZ - (4 - amidrazonophenyl) - (5) - 2 - (naphthalene - 9 - sulfonylamino) - propionyl) - methylamino) propionic acid

The compound prepared according to the operations described in Example 27 was processed according to the operations described in Example 26 to obtain the purified above-mentioned compound (0.06g, yield: 41905).

ТN NMR (СО5СО, chnm) 5 : 0.64, 0.95 (y, 4, ЗН), 2.76, 2.92(5, 85, ЗН), 2.83, 3.09(t, t, 2Н), 4.37 (t, 1Н), 4.54 (t, 1H) 7.30-8.40 (t, 11H)

Mass (FSA, t/e): 498 (M of 1)

Example 29 20 Synthesis of methyl ether (K) - 2 - 43 - (4 - amidrazonophenyl) - (5) - 2 - (naphthalene - 2 - sulfonylamino) - propionyl| - methylamino) propionic acid

To obtain the methyl ether (0) - (M - Her - butoxycarbonyl - M -methyl) - alanine, the same operations were performed as for the preparation of Preparation 7, except that instead of glycine methyl ether, methyl ether (0) was used - aniline, which was further processed according to the same method as with 25 preparations 8 and 9, to obtain the intermediate compound methyl ether (K) - 2 - 43 - (4 - cyanophenyl) - (5) - 2 o - (naphthalene - 2 - sulfonylamino) - propionyl| - methylamino) propionic acid (0.78g). The indicated intermediate compound was treated according to the same method as in Example 25 to obtain the purified above-mentioned compound (0.58g, yield: 7090).

TN NMR (SOZSO, chnm) 5 : 0.89, 1.21(40, 4, ЗН), 2.46, 2.94(5, 8, ЗН), 2.80, 3.08 (t, t, 2Н), 3.49, 3.78(в, - 30) c, ЗН), 4.29(t, 1H), 4.59 (t, 1H), 7.30-8.40(t, 11H) s

Mass (FSA, t/e): 512 (M 1)

Example 30 so

Synthesis of (K)-2-(3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)propionic acid 3o Compound (0.03g, 0.059mmol) , prepared in accordance with the operations described in Example 29, was processed in accordance with the operations described in Example 26 to obtain the purified above-mentioned compound (0.01 g, yield: 33905). "YAN NMR (СО5СО, chnm) 5 : 0.90 1.18(4, 4, ЗН), 2.44, 2.92(85, 8, ЗН), 2.82, 3.08(t, t, 2Н), 4.33 (t, 1Н), 4.62 (t, 1Н), 7.30-8.40 (t , 11H) "

Mass (FSA, t/e): 498 (M i 1) 70 Example 31 as c Synthesis of methyl ether; with" (k)-2-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)-3-methylbutyric acid

To obtain the methyl ester of (0)-(M-i-butoxycarbonyl-M-methyl)-valine, the same operations were performed,

The same as for the preparation of Preparation 7, except that instead of methyl ether of glycine, methyl ether of (0)-(M-i-butoxycarbonyl-M-methyl)-valine was used, which was further processed according to the same (95) method , as well as preparations 8 and 9, to obtain an intermediate compound of methyl ether (K)-2-13-(4-so cyanophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)-Z -methylbutyric acid (0.19 g).

The indicated intermediate compound was treated according to the same method as in Example 25 to obtain (ee) 50 of the purified above-mentioned compound (0.11g, yield: 5590). "m TN NMR (SOZSO, chnm) 5 : 0.59, 0.70(a, a, ЗН), 0.89, 0.98(40, а, ЗН), 2.09, 2.21(t, t, 1Н), 2.75, 3.06(c, 8, ЗН), 3.40, 3.68(5, 5, ЗН), 4.34, 4.38(4, а, 1Н), 4.63, 4.70(t, t, 1Н), 7.20-8.40(t, 11Н)

Mass (FSA, m/e) : 540 (M-1)

Example 32

Synthesis of (K)-2-Y13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)3-methyl- o butyric acid to Compound prepared according to the operations described in Example 31, was processed according to the operations described in Example 26 to obtain the purified above-mentioned compound (0.04g, yield: 4090). 60 TN NMR (SOZSO, chnm) 5 : 0.57, 0.63(4, а, ЗН), 0.92, 0.99(а, а, ЗН), 2.09, 2.18(t, t, 1Н), 2.74, 3.08(5, 8 , ZN), 4.18, 4.36(a, a, 1H), 4.64, 4.70(t, t, 1H), 7.20-8.40(t, 11H)

Mass (FSA, t/e) : 526 (M i 1)

Example 33

Synthesis of 3-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-65 methylamino)propionic acid methyl ester

To obtain the methyl ester of 3-(N-butoxycarbonyl-M-methyl)-aminopropionic acid, the same operations were performed as for the preparation of Preparation 7, except that instead of methyl ester of glycine, methyl ester of 3-aminopropionic acid was used. which was further processed according to the same method as Preparations 8 and 9 to obtain the methyl ester intermediate 3-113-(4-cyanophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|- methylamino) propionic acid (0.69g). The indicated intermediate compound was treated according to the same method as in Example 25 to obtain the purified above-mentioned compound (0.55g, yield: 74905). "YAN YMR (SOZSO, chnm) 5: 8.31, 7.97, 7.68, 7.48(0, t, t, t, 11Н), 4.62, 4.51(t, t, 1Н), 3.62, 3.55(5, в,

ЗН), 3.05, 2.85(t, t, 4Н), 2.80, 2.45(8, 8, ЗН), 2.38, 1.91(t, t, 2Н)

Mass (FSA, t/e) : 512(M 1)

Example 34

Synthesis of 3-Y3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|- methylamino) propionic acid

The compound prepared according to the operations described in Example 33 was processed according to the operations described in Example 26 to obtain the purified above-mentioned compound (0.17g, yield: 32905).

TN nMR (SOZSO, chnm) 5 : 8.31, 7.98, 7.78-7.37(4, t, t, 11), 4.65, 4.52(t, t, 1Н), 3.20-2.85(t, 4Н), 2.80, 2.45( в8, 8, ЗН), 2.38, 1.91(t, t, 2H)

Mass (FSA, t/e) : 498 (M "w 1)

Example 35

Synthesis of 4-C13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)butyric acid methyl ester

To obtain the methyl ester of 4-(M-i-butoxycarbonyl-M-methyl)-amino-propionic acid, the same operations were performed as for the preparation of Preparation 7, except that instead of methyl ester of glycine, methyl ester of 4-aminobutyric acid was used acid, which was further processed according to the same method 29 as Preparations 8 and 9, to obtain the intermediate compound methyl ether 4-113-(4- ianophenyl)-(5)-2-He) (naphthalene-2- sulfonylamino)-propionyl| methylamino) of butyric acid (0.51 g). The specified intermediate compound was processed according to the same method as in Example 25 to obtain the purified above-mentioned compound (0.40g, yield: 74905). "NYMR(СОЗСО, chnm) 5 : 8.32(8, 1Н), 7.98 (t, ЗН), 7.78-7.36(t, 7Н), 4.55(t, 1Н), 3.72, 3.60(в5, 8, ЗН), - 3.10, 2.81(t, t, 4H), 2.79, 2.55(8, 8, ЗН), 2.22(t, 1H), 1.89(t, 1H), 1.63, 1.42(t, t, 1H), 1.18( t, 1H) d)

Mass (FSA, m/e): 526(M 71) so

Example 36

Synthesis of 4-(I3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino) butyric acid and

The compound prepared as described in Example 35 was worked up according to the operations given in

Example 26 to obtain the purified above-mentioned compound (0.12 g, yield 32965). "IN NMR (SOZSO, chnm) 5: 8.32 (t, 1Н), 7.98 (t, ЗН), 7.78-7.35 (t, 7Н), 4.55 (t, 1Н), 3.05, 2.81 (t, t, 4Н) "

Mass (FSA, m/e) : 512(M71)

Preparation 10 - c Synthesis of M-i-butoxycarbonyl-M-cyclopropyl-acetic acid methyl ether and cyclopropylamine (1.34 g, 23.49 mmol) were mixed with DMF (15 ml) and triethylamine (3 ml) and the specified mixture was introduced into the reaction vessel . Methyl bromoacetate (2.2 ml, 23.49 mmol) and DMF were introduced into the dropping funnel. The reaction vessel was cooled to 0"C, and then the solution contained in the dropper was added dropwise to the reaction vessel. After the addition was completed, the reaction mixture was heated to room temperature and reaction (o) was carried out for 3.5 hours. After completion of the reaction to the indicated water (10ml) and sodium hydroxide (30ml) were added to the mixture. 1,4-dioxane (10ml) was added to the reaction mixture, then butylcarbonyl anhydride (6.1g, 27.95mmol) was added. The reaction of the indicated mixture was carried out for 3 hours at room temperature and distilled (o) under reduced pressure to remove volatiles. The precipitate was dissolved with methyl acetate and CO 50 was washed successively with saturated acidic sodium carbonate solution, hydrochloric acid solution, and brine. The organic layer was separated and dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the filter under reduced pressure. The precipitate was purified by column chromatography (solvent ethyl acetate/hexane (at a volume ratio of 6:4)) to obtain the purified above-mentioned compound (2.3 g, yield: 43965). 29 TN NMR (SOZSO, chnm) 5: 3.95(t, 2Н), 3.72 (t, ЗН), 2.75, 2.52(рв, Б8, 1Н), 1.45, 1.47(5, в, 9Н), 0.80-0.45( t, 4H)

GF) Mass (FSA, m/e) : 230(M 7-1)

Example 37 o Synthesis of methyl ether 113-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|/|- cyclopropylamino) acetic acid 60 To obtain an intermediate compound of methyl ether 4I3-(4-cyanophenyl) )-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-cyclopropylamino)acetic acid (0.30g) The compound obtained as Preparation 10 was processed according to the same operations as Preparations 8 and 9. The indicated intermediate compound was processed according to the same method as in Example 25 to obtain the purified above-mentioned compound (0.25g, yield: 7790). 65 "YAN NMR(SOZSO, chnm) 5: 8.24 (v, 1H), 7.93 (t, ЗН), 7.65 (t, ЗН), 7.42(а, 2), 7.35(а, 2Н), 5.02(t, 1H),

3.92(4, 1H), 3.64(a, 1H), 3.60(z, ЗН), 3.19(aa, 1H), 2.80(t, 2H), 0.95, 0.85, 0.61 (t, t, t, 4H)

Mass (FSA, m/e) : 524(M" 1)

Synthesis of 113-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-cyclopropylamino acid

ACIDS

The compound prepared as described in Example 37 was worked up according to the operations given in

Example 26 to obtain the purified above-mentioned compound (0.07g, yield: 2990).

TN NMR (SOZSO, chnm) 5: 8.24(5, 1Н), 7.93 (t, ЗН), 7.42 (9, 2Н), 7.35(4, 2Н), 5.02(t, 1), 3.95(y, 1Н) , 3.54(4, 1H), 3.20(ad9, 1H), 2.80(t, 2H), 0.95, 0.85, 0.61(t, t, t, 4H)

Mass (FSA, m/e) : 519(M-1)

Example 39

Synthesis of 4I3-(4-amidrazonophenyl)-(5)-2-naphthalene-2-sulfonylamino)-propionyl|-butylamino)acetic acid methyl ester

To obtain M-i-butoxycarbonyl-M-butylamino acetic acid methyl ester, the same 75 operations were carried out as in the preparation of Preparation 10, except that butylamine was used instead of cyclopropylamine. The specified compound was treated according to the same operations as in the manufacture

Preparations 8 and 9, to obtain an intermediate compound of methyl ether 4IZ -(4-cyanophenyl)- (5)-2 - (naphthalene-2-sulfonylamino)-propionyl|-butylamino) acetic acid (0.31 g). The indicated intermediate compound was processed according to the same operations as in Example 25 to obtain the purified title compound (0.19G, yield: 58965).

TN NMR (SOZSO, chnm) 5: 8.30-7.32(t, 11Н), 4.32-4.09(t, ЗН), 3.55(з, ЗН), 3.57-2.50(t, 4Н), 1.26-0.50(t , 7H)

Mass (FSA, m/e) : 540(M--1)

Example 40

Synthesis of 4Y3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-butylamino) acetic acid

The compound prepared as described in Example 39 was worked up according to the operations given in Go)

Example 26 to obtain the purified above-mentioned compound (0.12 g, yield: 6790).

TN NMR (SOZSO, chnm) 5: 8.30-7.10(t, 11Н), 4.31-4.10(t, ЗН), 3.52-2.55(t, 4Н), 1.25-0.50(t, 7Н)

Mass (FSA, m/e) : 526 (M'-1) iso Example 41

Synthesis of 113-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|/|- cyclopentylamino) acetic acid methyl ester

To obtain the methyl ester of M-i-butoxycarbonyl-M-cyclopentylamino acetic acid, the same operations were carried out as in the preparation of Preparation 10, except that instead of cyclopropylamine and c5, cyclopentylamine was used. The specified compound was processed according to the same operations as in the preparation of Preparations 8 and 9, to obtain the intermediate compound 4I3-(4-cyanophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl methyl ether |- cyclopentylamino) acetic acid (0.23 g). The indicated intermediate was treated according to the same operations as in Example 25 to obtain the purified title compound (0.12g, yield: 5090). "

TN NMR (СО5СО, chnm) 5 : 8.35-7.35(t, 11), 4.66, 4.33(t, t, 1Н), 4.15 (t, 1Н), 3.75, 3.53(t, t, 1), с 3.61( 5, ЗН), 3.40-2.80(t, ЗН), 1.90-0.60(t, 8Н) and Mass (FSA, m/e) : 552 (Mk 1) "» Example 42

Synthesis of 113-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-cyclopentylamino)acetic acid (22) The compound prepared as described in Example 41 was processed according to the operations, given in this Example 26, to obtain the purified above-mentioned compound (0.4 g, yield: 3390). "YAN NMR (COzSO, chnm) 5: 8.35-7.35(t, 1Н), 4.65, 4.32(t, t, 1Н), 4.15(t, 1Н), 3.75, 3.52(t, t, 1Н), 3.41, so 3.28-3.10, 2.80(t, t, t, ЗН), 1.90-0.60(t, 8Н) bo o Mass (FSA, m/e) : 538 (M" 1). Preparation 11 in Synthesis of 1-(M-i-butoxycarbonyl-M-methylamino) cyclopentane carboxylic acid methyl ester

Cycloleucine (Zg, 23.2 mmol) was dissolved in 1 M aqueous sodium hydroxide solution (23.2 ml) and distilled water (7 ml), and then 1,4-dioxane (30 ml) was added. Di-butyl dicarbonate (6.1 g, 27.8 mmol) was added to the specified mixture at a temperature of 0" C, and the given mixture was heated to room temperature, and then stirred

GF) within 2 hours. The volatile matter was removed under reduced pressure and the precipitate was dissolved with ethyl acetate, washed successively with saturated aqueous sodium carbonate solution, hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated. The resulting white solid product was dissolved in dimethylformamide (DMF, 3 mL). Potassium carbonate (4.8g, 34.8mmol) was added to the specified solution, and then iodomethane (CH3, 14.4ml, 232mmol) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature for 2 hours and distilled under reduced pressure to remove the volatile matter. The residual solution was dissolved with ethyl acetate, successively washed with an aqueous saturated solution of an acidic salt of sodium carbonate, a solution of hydrochloric acid and a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and then concentrated. The obtained product was dissolved in dimethylformamide (DMF, 20 ml). Sodium 6b09b5 sodium hydride (Mann, 0.46g, 11.4mmol) was slowly added to this solution at room temperature, and then iodomethane (SNHZi, 1.8ml, 28.4mmol) was added dropwise. The specified mixture was slowly heated to room temperature and stirred for 3 hours at the above temperature. Water was added to the reaction mixture to remove residual sodium hydride. The mixture was filtered and concentrated under reduced pressure. The precipitate was dissolved with ethyl acetate, successively washed with an aqueous saturated solution of an acidic salt of sodium carbonate, a solution of hydrochloric acid and a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and then concentrated. The precipitate was purified by column chromatography using ethyl acetate/hexane in a volume ratio of C:7 as a solvent to obtain purified 7/0 of the above-mentioned compound (2.0g, yield: 3490).

T"H NMR (SOZSO, chnm) 5: 1.35(v, 9H), 1.62 (t, 4H), 1.78 (t, 2H), 2.18(t, 2H), 2.90(v, ЗН), 3.62(8, ZN)

Mass (FSA, m/e): 258 (M of 1)

Example 43

Synthesis of methyl ether /1-Y13-(4-amidrazonophenyl)-(5)-2 -(naphthalene-2-sulfonylamino)-propionyl|-75 methylamino)cyclopentane of carboxylic acid

To obtain the intermediate compound methyl ether 1-113-(4-aminohydrazonomethyl)-phenyl-(5)-2-(naphthalene - 2-sulfonylamino)-propionyl|-methylamino) cyclopentane carboxylic acid (0.28g), the compound obtained as

Preparation 11 was processed according to the same operations as Preparations 8 and 9. The indicated intermediate compound was processed according to the same method as in Example 25 to obtain the purified title compound (0.56g, yield: 5390).

TN NMR (SOZSO, chnm) 5: 0.52 (t, 1H), 0.89(t, 1H), 1.29(t, 2H), 1.52 (t, 1H), 1.76(t, 2H), 2.05 (t, 1H) .

Mass (FSA, m/e) : 552 (M of 1)

Example 44 se

Synthesis of /1-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino) cyclopentane o carboxylic acid

The compound prepared as described in Example 43 was worked up according to the operations given in

Example 26 to obtain the purified above-mentioned compound (0.01g, yield: 1790).

TN NMR (SOZSO, chnm) 5 : 0.42 (t, 1Н), 0.74 (t, 1), 1.25 (t, 2Н), 1.50 (t, 1Н), 1.78 (t, 2Н), 2.05 (t, - 1Н ), 2.75, 3.08(t, t, 2H), 2.98(5, ЗН), 4.58(t, 1H), 7.40-8.40(t, 11H) s

Mass (FSA, m/e) : 538 (M of 1)

The drug is 12 so

Synthesis of 2-(M-i-butoxycarbonyl-M-methyl)-amino-cyclopentane carboxylic acid ethyl ether

Ethyl 2-oxycyclopentane carboxylate (1Oml, 67.49mmol) was added together with ethanol (10Oml) to the reaction 3o vessel. Then, methylamine chloride (4.69 g, ee, 68.1 mmol) and water (1 ml) were added to the reagent solution in the specified vessel. Next, sodium cyanoborohydride (4.3 g, 68.4 mmol) was added to the reaction vessel and the pH of the mixture was adjusted to a value equal to 6; and then the reaction was carried out for 12 or more hours at a temperature from 30"C to 40"C. Next, the reaction mixture was concentrated under reduced pressure, cooled to

OS, the pH was adjusted to a value equal to 2 with the help of 1M hydrochloric acid and washed three times with diethyl ether. The pH of the aqueous layer was again adjusted to a value equal to 10, and the same amount of dioxane was added. One equivalent weight of butyloxycarbonyl anhydride was added to the specified mixture.

The reaction of the specified reaction mixture was carried out for 3 hours at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove the volatile matter, dissolved in ethyl acetate, and successively washed with saturated sodium carbonate acid salt solution, hydrochloric acid solution, and saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to remove the solvent. The precipitate was purified by column chromatography (the solvent was ethyl acetate:hexane at a volume ratio of 1:1) to obtain the above-mentioned compound (5.82 g, yield: 3290). co TN NMR (СО5СО, chnm) 5 : 4.55 (t, 1Н), 4.10(t, 2Н), 2.79(з5, НН), 2.73(8, 1Н), 2.00-1.40(t, 6Н), 1.45 (in , 02 20 on), 1240, zn)

I Mass (FSA, t/e) : 272(M 1)

Example 45

Synthesis of 2-C3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|- methylamino) cyclopentane carboxylic acid ethyl ether

To obtain the intermediate compound ethyl ether /2-13-(4-cyanophenyl)-(5)-2-(naphthalene-2- (F) sulfonylamino)-propionyl|-methylamino) cyclopentane carboxylic acid (0.48 g) the compound obtained as Preparation co 12, was processed according to the same operations as Preparations 8 and 9. The indicated intermediate compound was processed according to the same method as in Example 25 to obtain the purified above-mentioned compound. (0.36g, yield: 71906).

TN NMR (SOZSO, chnm) 5 : 8.39-7.25(t, 11Н), 4.78-4.40(t, 2Н), 4.05 (t, 2Н), 3.05(t, 1Н), 2.90-2.65(t,

ЗН), 2.50-2.40(t, 2Н), 2.05, 1.90-1.30, 0.85 (t, t, t, 6Н), 1.28-1.15(t, ЗН)

Mass (FSA, t/e): 566 (M « 1)

Example 46 65 Synthesis of 2-1Y3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)-cyclopentane

The compound prepared as described in Example 45 was worked up according to the operations given in

Example 26 to obtain the purified above-mentioned compound (0.086 g, yield: 2590). "YAN YMR (SOZSO, chnm) 5: 8.39-7.20 (t, 11Н), 4.78-4.50 (t, t, 2Н), 3.05 (t, 1Н), 2.90-2.40 (t, 5Н), 2.10, 1.90- 1.20, 0.75(t, t, t, 6H)

Mass (FSA, t/e): 5Z38(M7 1)

Example 47

Synthesis of methyl ester (5)-2-13-(4-amidzdazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl)-methylamino) 3-methyl butyric acid

To obtain methyl ether (I)-(M-i-butoxycarbonyl-M-methyl)-valine, the same operations were performed 70 as for preparation of Preparation 7, except that methyl ether (I) was used instead of methyl ether of glycine -(N-butoxycarbonyl-N-methyl)-valine, which was further processed according to the same method as 8 and 9, to obtain the methyl ester intermediate (5)-2-N13-(4-cyanophenyl) - (5)-2-(naphthalene-2-sulfonylamino)-propionyl|-methylamino)-3-methyl butyric acid (0.13g). The specified intermediate compound was processed according to the same method as in Example 25 to obtain purified 75 of the above-named compound (0.09g, yield: 6990).

TN NMR (SOZSO, chnm) 5: 8.30, 7.95, 7.75-7.20(t, t, t, 11Н), 4.75-4.25(t, 2Н), 4.65, 3.39(t, t, ЗН), 3.15-2.65( t, 4H), 2.22, 2.15(8, 8, 1H), 2.08, 1.90(t, t, 1H), 1.00-0.55, 0.20(t, t, EN)

Mass (FSA, t/e) : 540 (M 7-1)

Example 48

Synthesis of 1-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-piperidine-(K)-2-carboxylic acid methyl ester

To obtain the intermediate compound methyl ether (1-Y3-(4-cyanophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-piperidine-"K) carboxylic acid (0.18 g) the same procedures were performed operations, as for the preparation of Preparation 7, except that instead of methyl ester of glycine, methyl C 29 ester of (0)-pipecolic acid was used, which was further processed according to the same method as Preparations 8 and 9. (IN

The indicated intermediate compound was treated according to the same method as in Example 25 to obtain the purified above-mentioned compound (0.16g, yield: 8490).

TN NMR (SOZSO, chnm) 5: 8.32, 7.95, 7.78-7.35(t, t, t, 11Н), 4.71, 4.52(t, t, 1Н), 3.97, 3.80(4, а, 1Н), m 20 3.73, 3.43(8, 5, ЗН), 3.10, 2.83, 2.39(t, t, t, ЗН), 2.05(t, 1Н), 1.65-1.00, 0.30(t, t, 6Н)

Mass (FSA, t/e): 538 (M w 1) so

Example 49 so

Synthesis of 1-3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)-propionyl|-piperidine(K)-2-carboxylic acid me)

The compound prepared as described in Example 48 was worked up according to the operations given in

Example 26, to obtain the purified above-mentioned compound (0.03g, yield: 19905).

TN NMR (СО5СО, chnm) 5: 8.35, 8.00, 7.75-7.30(t, t, t, 11Н), 4.50, 4.20(t, t, 1Н), 3.89(t, 1Н), 3.10, 2.82, 2.45( t, t, t, ЗН), 2.10(t, 1Н), 1.65-1.00, 0.25(t, t, 6Н) «

Mass (FSA, t/e) : 524 (M as 1)

Preparation 13 o) c Synthesis of (5)-4-(2-(butyloxycarbonyl-amino)-3--4-methylsulfonyl-piperazinyl)-3-oxo propyl|-benzonitrile "» (5)-3-(4-cyanophenyl )-2-(butyloxycarbonylamino)propionic acid (0.5g, 1.7mmol) was dissolved in dimethylformamide (DMF, 2Oml) and then cooled to a temperature of 0"C. Then, 1-(3-dimethylaminopropyl)-hydrochloride was added to this solution. 3-ethylcarbodiimide (EDH, 0.5g) and 1-hydroxybenzotriazole hydrate (HOBT, 0.3g) and stirred until they were completely dissolved. To this reaction mixture was added 1-methanesulfonyl-piperazine (0.3g) and M -methylmorpholine (0.2 ml), and then the temperature was slowly increased to room temperature. The indicated reaction solution was stirred for 3.5 hours. After the completion of the reaction, the reaction solution was distilled under reduced pressure to remove the volatile matter, dissolved in ethyl acetate and successively washed with saturated aqueous acid salt solution of sodium carbonate, bo 0020 solution of hydrochloric acid and saturated saline solution, dried over anhydrous sodium sulfate, filtered and then concentrated. The precipitate was purified by column chromatography using ethyl acetate/hexane (at a volume ratio of 6:4) as a solvent to obtain the above-mentioned compound (0.7g, yield: 9390).

PTN NMR (SOZSO, chnm) 5: 7.7-7.3 (t, 4H), 5.3 (t, 1H), 4.8(t, 1H), 3.9-3.55(t, 2H), 3.55-2.8(t, 8H), 2.17(8, ЗН), 1.5(in5, 9Н)

Drug 14

HF) Synthesis of (5)-naphthalene-2-sulfonic acid|1-(4-cyanobenzyl)-2-(4-methylsulfonyl-piperazinyl)-2-oxoethyl| amide

The compound (0.7g, 1.bmmol), prepared as Preparation 13, was dissolved in dichloromethane (3ml), and then cooled to -107C and trifluoroacetic acid (TFC, 3ml) was added to this solution. The reaction mixture was stirred for 5 minutes, slowly warmed to room temperature, stirred for 60 minutes, and then distilled under reduced pressure to remove volatile matter. The residual solution was dried using a vacuum pump and then 20 ml of DMF was added to it. The mixture was cooled to 0"C and 2-naphthalene sulfochloride (0.5g) and diisopropylethylamine (0.9ml) were added to it. The specified mixture was stirred until the reactants were completely dissolved. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. After the completion of the reaction, the reaction solution was distilled under reduced pressure to remove the volatile matter. The residual solution was dissolved with chloroform and successively washed with a saturated aqueous solution of sodium carbonate acid salt, hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, filtered and then concentrated The precipitate was purified by column chromatography using chloroform/methanol (volume ratio 95:5) as a solvent to obtain the above compound (0.8g, yield: 9590).

T"H NMR (SOZSO, chnm) 5 : 8.3-7.2(t, 11Н), 5.8(t, 1Н), 4.5 (t, 1Н), 3.5-3.2(t, 2Н), 2.45(v, ЗН), 3.1-2.3(t, 8H)

Example 50

Synthesis of (5)naphthalene-2-sulfonic acid (- 2 2ZhKMMMY (1-(4-amidrazono)-benzyl-2-(4-methylsulfonyl-piperazinyl)-2-oxo-ethyl) amide of Compound 70 (0.4g, 0. 7bmmol), prepared as Preparation 14, was dissolved in pyridine (bml) and the resulting solution was placed in a stoppered flask to which triethylamine (0.3ml) was added. The reaction flask was equipped so that hydrogen sulfide (NaH) could slowly escape through one of the ends of the flask, and flow out through the other end. The reaction solution was saturated with hydrogen sulfide, stirring constantly for about 10 minutes, while the colorless solution first became green and then gradually changed to a dark brown color. The flask was closed with a rubber stopper and stored. for 3 days at room temperature until the end of the reaction. The reaction solution was then distilled under reduced pressure to remove volatiles and dried using a vacuum pump. To the resulting yellow solid was added ra of acetone (10 ml) and iodomethane (CH3Zi, 0.5 ml) and the resulting mixture was heated until phlegm was obtained within 30 minutes. The specified reaction mixture was distilled again under reduced pressure to remove volatile substances and dried using a vacuum pump. The precipitate was dissolved in pure methanol (5 ml) and then stirred. 8095 hydrazine hydrate (NOMMN" was added to this mixture three times in portions

NhO, 0.Obml) every 10 minutes. After completion of the reaction, the reaction solution was concentrated and then purified by high pressure liquid chromatography (HPLC) to obtain the named compound (0.3 g, yield: 6590). si

TN NMR (SOZSO, chnm) 5 : 8.4-7.A(t, 11Н), 4.6 (t, 1Н), 3.5-3.2(t, 2Н), 2.55(z, ЗН), 3.1-2.2(t, ВН ) (5)

Mass (FSA, t/e): 559 (M 1)

Example 51

Synthesis of (5)-naphthalene-2-sulfonic acid-|1-(4-amidrazono)-benzyl-2-oxo-2-(4-ethoxycarbonyl-piperazinyl)-ethyl| amide -

The same operations were performed as for the preparation of Preparation 13, except that instead of 1-methanesulfonyl-piperazine, 1-piperazine ethyl carboxylate was used, and the resulting product was further processed according to the same method as Preparation 14. to obtain the intermediate compound (5) - co-naphthalene-2-sulfonic acid-|1-(4-cyanobenzyl)-2-oxo-2-(4-ethoxycarbonyl-piperazinyl)-ethyl| PU amide so 1.9 mmol). The indicated intermediate compound was processed according to the same method as in Example 50 to obtain the purified above-mentioned compound (0.6g, yield: 5696). X,

TN NMR (SOZSO, chnm) 5 : 8.5-7.3 (t, 11H), 4.55(t, 1H), 4.05(t, 2H), 3.2-2.А(t, 1OH), 1.2(t, ЗН)

Mass (FSA, t/e) : 553 (M w 1)

Example 52 « 20 Synthesis of (5)-naphthalene-2-sulfonic acid-|1-(4-amidrazono)-benzyl-2-(4-formyl-piperazinyl)-2-oxoethyl|amide -o

The same operations were performed as for the preparation of Preparation 13, except that instead of 1-s methanesulfonyl-piperazine, 1-piperazineethylcarboxaldehyde was used, and the resulting product "c" was further processed according to the same method as Preparation 14, to obtain the intermediate compound (5)-naphthalene-2-sulfonic acid-|(1-(4-cyanobenzyl)-2-(4-formyl-piperazinyl)-2-oxoethyl| (7g, 1.bmmol). Specified 415 the intermediate compound was treated according to the same method as in Example 50 to obtain the purified above-mentioned compound (0.5g, yield: 6290).

TN NMR (SOZSO, chnm) 5 : 8.36-7.44(t, 11Н), 4.60 (t, 1Н), 3.46-2.80(t, 9Н), 2.55(t, 1Н) o Mass (FSA, t/e) : 509 (M « 1) (o) Example 53

Synthesis of (5)-naphthalene-2-sulfonic acid-|1-(4-amidrazono)-benzyl-2-(4-ethyl-piperazinyl)-2-oxoethyl| amide

The same operations were performed as for Preparation 13, except that instead of 1-methanesulfonylpiperazine, 1-ethylpiperazine was used, and the product obtained was further processed according to the same method as Preparation 14, to obtain intermediate compound (5)-naphthalene-2-sulfonic acid-|1-(4-cyanobenzyl)-2-(4-ethyl-piperazinyl)-2-oxoethyl|amide (0.3g, 0.bmmol).

The indicated intermediate compound was processed according to the same method as in Example 50 to obtain the purified above-mentioned compound (0.2g, yield: 5690). o T"H NMR (SOZSO, chnm) 5: 8.5-7.3 (t, 11Н), 4.6 (t, 1Н), 3.5-2.7 (t, 1ОН), 2.2 (v, 2Н), 1.4-1.2 (t, ZN) de Massa (FSA, t/e) : BO9 (M 7-1)

Example 54 6o Synthesis of (5)-naphthalene-2-sulfonic acid-|1-(4-amidrazono)-benzyl-2-oxo-2-(4-phenylpiperazinyl)-ethyl| amide

The same operations as for Preparation 13 were performed, except that 1-phenylpiperazine was used instead of 1-methanesulfonylpiperazine, and the resulting product was further processed according to the same method as Preparation 14 to obtain the intermediate compound (5) -naphthalene-2-sulfonic acid-|(1-(4-cyanobenzyl)-2-oxo-2-(4-phenyl-piperazinyl)-ethyl|amide (0.5g, 0.97mmol). the compound was treated according to the same method as in Example 50 to obtain the purified above-named compound (0.3g, yield: 5790).

TN nMR (CO5CO, chnm) 5: 8.35-7.54(t, 11), 7.20(t, 2H), 6.8b(t, 1H), 6.67(t, 2H), 4.56(t, 1H), 3.45(t , 1H), 3.25-2.92 (t, 5H), 3.72 (t, 2H), 2.42 (t, 1H), 2.05(t, 1H)

Mass (FSA, t/e) : 557(M7 1)

Example 55

Synthesis of (5)-naphthalene-2-sulfonic acid-|(1-(4-amidrazono)-benzyl-2-oxo-2-(4-(3-trifluoromethyl-phenyl)-piperazinyl|-ethyl| amide

The same operations were performed as for the preparation of Preparation 13, except that instead of 1-70 methanesulfonylpiperazine, 1-(4, o, o, trifluoro-t-tolyl) piperazine was used, and the resulting product was further processed according to in the same way as Preparation 14, to obtain the intermediate compound (5)-naphthalene-2-sulfonic acid-|1-(4-cyanobenzyl)-2-oxo-2-I(4-trifluoromethyl-phenyl)-piperazinyl| - ethyl| amide (0O0.5g, 0.vmmol). The indicated intermediate compound was treated according to the same method as in Example 50 to obtain the purified above-mentioned compound (0.3g, yield: 5590).

T"H NMR (SOZSO, chnm) 5 : 8.35-6.7 (t, 15H), 3.47(t, 1H), 3.3-3.0 (t, 5H), 3.76(t, 2H), 2.45 (t, 1H), 2.03(t, 1H)

Mass (FSA, t/e): 625(M 1)

Example 56

Synthesis of (5)-naphthalene-2-sulfonic acid-(2-(4-acetyl-piperazinyl)-1-(4-amidrazono)benzyl-2-oxoethyl|amide

The same operations as for Preparation 13 were performed, except that 1-acetyl-piperazine was used instead of 1-methanesulfonylpiperazine, and the resulting product was further processed according to the same method as Preparation 14 to obtain intermediate compound (5) - naphthalene-2-sulfonic acid-|2-(4-acetyl-piperazinyl)-1-(cyanobenzyl)-2-oxo-ethyl| amide (1.25 g, 2.55 mmol).

The indicated intermediate compound was treated according to the same method as in Example 50 to obtain the purified above-mentioned compound (0.7g, yield: 5390). sch » TN NMR (SOZSO, chnm) 5 : 8.4-7.A(t, 11Н), 4.5(t, 1Н), 3.5-3.2(t, 2Н), 3.1-2.2(t, 8Н), 2.0(in , ZN) (o)

Mass (FSA, t/e): 523 (M w 1)

Example 57

Synthesis of (5)-naphthalene-2-sulfonic acid-|1-(4-amidrazono)-benzyl-2-oxo-2-I4-(2-hydroxyethyl)-piperazinyl|- cesoethyl amide

The same operations were performed as for the preparation of Preparation 13, except that instead of 1-co methanesulfonylpiperazine, 1-piperazine ethane was used, and the resulting product was further "3 processed according to the same method as Preparation 14, to obtain the intermediate compound (5)-naphthalene-2-sulfonic acid-|1-(4-cyanobenzyl)-2-oxo-2-I4-(2-hydroxyethyl)-piperazinyl|I-ethyl|! amide (0.07 g, Che O/14 mmol). The specified intermediate compound was processed according to the same method as in Example 50 to obtain the purified above-mentioned compound (0.05g, yield: 68.5905).

TN NMR (SOZSO, chnm) 5: 8.35-7.30(t, 11H), 4.60(t, 1H), 3.96-3.7(t, 4H), 3.70-2.80(t, TON)

Mass (FSA, t/e) : 525(М7 1) «

Example 58

Synthesis of (5)-naphthalene-2-sulfonic acid-|1-(4-amidrazono)-benzyl-2-oxo-2-14-(2-ethoxyphenyl)-piperazinyl|- tsethyl amide h The same operations were performed, as for Preparation 13, except that instead of 1- » methanesulfonylpiperazine, 1-(2-ethoxyphenyl) piperazine was used, and the resulting product was further processed according to the same method as Preparation 14, to obtain intermediate compound (5)- naphthalene-2-sulfonic acid-|1-(4-cyanobenzyl)-2-oxo-2-(4-(2-ethoxyphenyl)-piperazinyl|-ethyl| amide (O.4g, (2) (0.7mmol).The indicated intermediate compound was treated according to the same method as in Example 50 to obtain the purified title compound (0.26g, yield: 62905).

TN NMR (SOZSO, chnm) 5 : 8.36-6.54 (t, 15Н), 4.6 (t, 1Н), 4.01 (t, 2Н), 3.48 (t, 1Н), 3.28-3.08 (t, 5Н), bo 2.69 (t, 2H), 2.38(t, 1H), 2.08(t, 1H), 1.35(t, ЗН) and o Mass (FSA, t/e) : 601(M"-1). Test 1: Inhibitory activity to thrombin and The ability of a compound of the present invention to inhibit thrombin activity was determined as follows.

In a cuvette with a capacity of 1.5 ml, 116 μl of 0.1 M tromethamine (Tris) buffer solution (pH 7.8) was added, which contained 150 mM Masi and 0.195 PEG - 8000 (polyethylene glycol, molecular weight approximately 8000). Chromozyme TN 59 was dissolved in dimethyl sulfoxide (DMSO) at a concentration equal to 10 mM, and the resulting solution

HF) was dissolved using the above-mentioned tromethamine buffer solution to a concentration of 0.1 mM, which was then used as a basic solution. 225 μl of the 0.1 mM basic solution obtained in this way was added to the cuvette. The inhibitor solution was prepared by dissolving the thrombin inhibitory compound according to the present invention in dimethylsulfoxide at a concentration of 10 mg/ml, and then diluting the thus obtained 60 solution with the above tromethamine buffer solution to a concentration of 0.1 mg/ml, 0.001 mg/ml, 0.001 mg/ml ml and 0.0001mg/ml. The obtained inhibitory solution was taken in the amount corresponding to 0-1Okg of the inhibitor, and then dissolved with tromethamine buffer solution to reach a total volume of 100μl and added to the cuvette.

In order to initiate the enzyme hydrolysis reaction, 15 μl of bovine thrombin solution dissolved in the above-mentioned tromethamine buffer solution at a concentration of 0.1 mg/ml was added to the cuvette. Amount of steam -

of nitroaniline, obtained within 2 minutes after the addition of the enzyme, was monitored by absorption at a wavelength of 38 nm. A continuous absorption spectrum was imaged during the reaction time. The same experiments were performed for different inhibitor concentrations to obtain a continuous spectrum.

In each spectrum, the initial rate of Mn was determined by the slope of the curve for the first 30 seconds of the reaction time, and then a graph was made for the inverse value of the initial rate (1/L/n) against the concentration of the inhibitor. From this graph, the first equation satisfying the points on the above graph was obtained, and then, using the equation for the enzyme reaction, the value of Ki was calculated from the X values of the primary equation.

The Km value used for this calculation was 8.3 mM and was obtained by 7/0 Variation of substrate concentration at constant enzyme concentration.

The rate constant Ksh was determined using the same solution at a similar concentration as when determining the value of Ki, but using the following experimental procedure.

In this case, 1160 μl of buffer solution and 15 μl of bovine thrombin solution at a concentration of 0.1mg/ml and 1700 μl of inhibitor solution were added to a cuvette with a capacity of 1.5 ml. The mixture was kept at room temperature for 15 minutes. Further, during the addition of 225 μl of 0.1 mM basic solution for 2 minutes, the change in absorbance was monitored as a function of time. From the obtained continuous spectrum, the slope of the straight section was determined and represented as the value of Msh. A similar experiment was carried out for different concentrations of the inhibitor to determine the value of Msh at each concentration of the inhibitor, and then a graph was made of the dependence of 1//sh as a function of the concentration of the inhibitor.

Using this graph, we obtained the primary equation that satisfies the points on the graph, and then, using the enzyme reaction equation, the value of Ki was calculated from the X values of the primary equation.

In particular, the trypsin inhibitory activity of the compound of the present invention was determined in the same manner as the determination of the thrombin inhibitory activity of the compound described above.

As a substrate, a 20 mM solution of hydrogen chloride M-benzoyl-MaI-Siu-Ago-p-nitroanilide was used, and the SC inhibitor was used at different concentrations in the range from 0 to 12 Ωkg. In addition, trypsin was dissolved in 0.1 M HCl, adjusted to a concentration of 45 μg/ml using the above-mentioned Tris - buffer solution i) immediately before the experiment, and then used in an amount equal to 4 μl.

As in the experiment with thrombin, the total volume of the reaction solution was 1.5 ml, and subsequent operations were carried out in a similar way. The value of Km, which was used to calculate the value of Ki and was determined according to the same method as in the above experiment with thrombin, was equal to 20.2 μM.

The inhibitory activity of the compound according to the present invention relative to the activity of each enzyme, which was determined according to the above method, was represented by the Ki and Ksh values, and the selectivity to thrombin was represented as the ratio of inhibitory activity to trypsin and inhibitory activity to thrombin.

The results obtained in this way are shown in Table 1 below.

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Test 2- Pharmacokinetic test

I

Method of performing the test (o)

Male rats and dogs were fed for 24 hours and used as experimental animals.

Using physiological saline, a 190% solution (1 ug/ml) of the compound was prepared as described in

Example 1, and then administered it to experimental animals intravenously and orally. Blood was taken from the animals at specified time intervals and immediately mixed with methanol and zinc sulfate. Then a quantitative analysis of the surface layer of the mixture was carried out, using ultraviolet radiation at a wavelength (ee) of 231 nm, in order to measure the concentration of drugs in the blood using RVHT.

Test results: so

Drug concentration, pharmacokinetic parameters of the compound shown in Example 1 after intravenous (He) and oral administration are shown in Tables 2-7. Upon intravenous injection of the compound in Example 1, it rapidly spread and then slowly disappeared in both rats and dogs, and the half-life in dogs was two or more times longer than in rats. In addition, the half-life of the compound of Example 1 in dogs was twice or more than that of the commercially available

Argatroban (40 minutes) in humans (see, Ozati ei aiYi., Rpaptasiodu apa TNegaru, my. 14, zirri. 5, 1986). du In the meantime, the bioavailability of the compound of Example 1 was shown to be 1595 in rats and 6190 in dogs when administered orally. However, it was shown that Argatroban is not absorbed in animals and humans when it is administered orally. From the above results, it is clear that the compound shown in Example 1 shows better pharmacokinetic characteristics than Argatroban for oral administration and half-life. with

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Although this invention is described by way of example of its best embodiment with some degree of specificity, it will be understood by those skilled in the art that this description of the best embodiment is made by way of example only and numerous changes in the details of assembly, combination and in the structure of the parts of the invention may be envisaged without deviating from the essence and scope of the present invention. b5

Claims (5)

The formula of the invention 1. The compound of the formula (I) Кк ХО) Н ды З и р? 70 | And according to ЧИ 2 ze de K! is acetyl substituted by aryl or aryloxy, or sulfonyl substituted by substituted or unsubstituted aryl or a heterocyclic group containing M, X selected from the group: 2, m-y -zh33 E -- сч р (о) Б2 ии ВЗ independently one from one is hydrogen, cycloalkyl, substituted or unsubstituted by carboxyl or alkoxycarbonyl, arylalkyloxy, hydroxy or lower alkyl, substituted or unsubstituted by carboxyl, alkoxycarbonyl or hydroxy, or c. B2 and BZ, together with the nitrogen atom to which they are attached, can form a piperidine group, substituted (ee) by carboxyl or alkoxycarbonyl, B is hydrogen, lower alkyl or lower alkoxy, so 2? is alkanesulfonyl, alkoxycarbonyl, alkylcarbonyl, formyl, lower alkyl, aryl, substituted or -- CO unsubstituted alkoxy or haloalkyl, or hydroxy-substituted lower alkyl, C is methyl or amino, B is hydrogen, or its pharmaceutically acceptable salt, hydrate , solvate and isomer. " 2. The compound of formula (I) according to claim 1, which differs in that BC is acetyl substituted with naphthyl or naphthyloxy, or sulfonyl substituted with naphthyl or phenyl, which may be substituted or unsubstituted /-- with from one to four substituents, selected from the group consisting of lower alkyl, lower alkoxy and dialkylamino, and X is selected from the group: (ee) A- 4 (ee) E that the 22nd BZ independently of each other are C3.vcycloalkyl, substituted or unsubstituted by carboxyl or methoxycarbonyl, benzyloxy, lower alkyl, substituted or unsubstituted by carboxyl, methoxycarbonyl or hydroxy, or hydroxy, or B2 and EZ, together with the nitrogen atom to which they are attached, can form a piperidine group substituted by carboxyl or methoxycarbonyl, B" is hydrogen, Co? is methanesulfonyl, ethoxycarbonyl, formyl, ethyl, phenyl, methylcarbonyl, hydroxyethyl or phenyl, which may be substituted or unsubstituted trifluoromethyl or ethoxy 60 3. The compound of formula (I) according to claim 2, which is characterized by the fact that the specified compound is selected from the group containing: (5)-M-cyclopentyl-M-methyl-3-(4-amidrazonophenyl)-2-(2 -nnaphthylsulfonylamino)propionamide, (5)-M-butyl-M-methyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-M-propyl-3-(4 -amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, because (5)-M-cyclopentyl-M-(2-benzyloxyethyl)-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-M-butyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-M-ethyl-3-(4-amidrazonophenyl)-2 -(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-M-methyl-3-I(4--(methylamidino)phenyl|-2-(2--aphthylsulfonylamino)propionamide, (5)-M-cyclopentyl -M-methyl-3-(4-amidrazonophenyl)-2-((4-methoxy-2,3,6-trimethylbenzene)sulfonylamino|propionamide, (5)-M-cyclopentyl-M-hydroxy-3-(4 -amidrazonophenyl)-2-(2-n-naphthylsulfonylamino)propionamide, (5)-M-cyclopentyl-1H-(2-hydroxyethyl)-3-(4-amidrazonophenyl)-2-(2-n-naphthylsulfonylamino)propionamide, (5 )-M-cyclopentyl-M-methyl-3-(4-(methylamidino)phenyl-2-(4-methoxy-2,3,6-trimethylbenzene)sulfonylamino|claim 70 ropionamide, (5)-M,M-dimethyl -3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionamide, (5)-M,M-dimethyl3-|4-(1-methylamidino)phenyl/|-2-(2-naphthylsulfonylamino)propionamide, ( 5)-M-cyclohexyl-M-methyl-3-(4-amidrazonophenyl)-2-(-(2-naphthylsulfonylamino)propionamide, (5)-M-cyclopropyl-M-methyl-3-(4-amidrazonophenyl)- 2-(-(2-petroleum lsulfonylamino)propionamide, (5)-3-(4-(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(2-naphthalen-1-yl-acetylamino)propionamide, (5)-3-(4 -(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(5-dimethylaminonaphthalene-1-sulfonylamino)propionami d, (5)-3-(4-(amidrazono)phenyl|-M-cyclopentyl-M- methyl-2-(5-methoxynaphthalene-1-sulfonylamino)propionamide, (5)-2-(I4-(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(6,7-dimethoxynaphthalene-2-sulfonylamino) )propionamide, (5)-3-(4-(methylamidino)-phenyl|-M-cyclopentyl-M-methyl-2-(5-dimethylaminonaphthalene-1-sulfonylamino)propionamide, (5)-3-(4- (amidrazo)phenyl|-M-cyclopentyl-M-methyl-2-(naphthalene-1-sulfonylamino)propionamide, (5)-3-(4-(amidrazo)phenyl|-M-cyclopentyl-M-methyl-2- (2-(naphthalen-1-yl-oxy)zacetylamino|propionamide, (5)-3-(4-(amidrazono)phenyl|-M-cyclopentyl-M-methyl-2-(I2-(naphthalen-2-yl -oxy)zacetylamino|propionamide, sc methyl ether /3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|methylamino)acetic acid, and) 1-3-(4-amidrazonophenyl) -(5)-2-(naphthalene-2-c sulfonylamino)propionyl|methylaminoacetic acid, methyl ester of (5)-2-113-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|methylamino)propionic acid, M zo (5)-2 -13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|Imethylamino)propionic acid, methyl ether co (k)-2-13-(4-amidrazonophenyl)-(5)- 2-(naphthalene-2-sulfonylamino)propionylmethylamino)propionic acid, so (k)-2-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|methylamino)propionic acid, methyl ether me) (k)-2-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|Imethylamino)-3-methylbutyric acid, "o (k)-2-13- (4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl)methylamino)-3-methylbutyric acid, methyl ester 3-C-3-(4-amidrazonophenyl)-(5)-2-( naphthalene-2-sulfonylamino)propionyl|methylamino)propionic acid, « 3-1І3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|methylamino)propionic acid, with methyl ether 4- 13-(4-amidraz onophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|methylamino)butyric acid, ;» 4-C13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl| methylamino)butyric acid, MZ-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|cyclopropylamino)acetic acid methyl ester, Ge» 1I3-(4-amidrazonophenyl)-(5)-2 -(naphthalene-2-sulfonylamino)propionyl|cyclopropylaminoacetic acid, methyl ester of 113-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|sutylaminoacetic acid, Ho! 113-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|Isoethylaminoacetic acid, methyl ester with 1I3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino) propionyl|cyclopentylaminoacetic acid, "M 113-(4-(amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|cyclopentylaminoacetic acid, methyl ether 1-13-(4-amidrazonophenyl)-(5)- 2-(naphthalene-2-sulfonylamino)propionylmethylamino)ucyclopentanecarboxylic 5B ACIDS, 1-13-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionylmethylamino)ucyclopentanecarboxylic (F, acid, ka ethyl ether 2 -(I3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionylmethylamino)ucyclopentanecarboxylic acids, 2-(I3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2 -sulfonylamino)propionyl|methylamino)ucyclopentanecarboxylic acid, methyl ester of (5)-2-113-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|Imethylamino)-3-methylbutyric acid, 65 1-(3-(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino) methyl ether propionyl|)piperidine-(K)-2-carboxylic acid, 1-(3-«(4-amidrazonophenyl)-(5)-2-(naphthalene-2-sulfonylamino)propionyl|piperidine-(K)-2-carboxylic acid, (5)-naphthalene-2-sulfonic acid|1- (4-amidrazono)benzyl-2-(4-methylsulfonylpiperazinyl)-2-oxoethylamide, (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-oxo-2-(4-ethoxycarbonylpiperazinyl)ethylamide , (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-(4-formylpiperazinyl)-2-oxoethylamide, (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl -2-(4-ethylpiperazinyl)-2-oxoethylamide, (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-oxo-2-(4-phenylpiperazinyl)ethylamide, (5)-naphthalene -2-sulfonic acid|1-(4-amidrazono)benzyl-2-oxo-2-(4-(3-trifluoromethylphenyl)piperazinyl)ethyl/|a copper, 70 (5)-naphthalene-2-sulfonic acid|2-( 4-acetylpiperazinyl)-1-(4-amidrazono)benzyl-2-oxoethylamide, (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-oxo-2-I4-(2-hydroxyethyl) piperazinylethylamide, (5)-naphthalene-2-sulfonic acid|1-(4-amidrazono)benzyl-2-oxo-2-I4-(2-ethoxyphenyl)piperazinylethyl|amide. 4. A pharmaceutical composition for inhibiting thrombin, characterized in that it contains a compound according to any one of claims 1-3 as an active ingredient together with a pharmaceutically acceptable carrier. 5. Pharmaceutical composition according to claim 4, which differs in that it is manufactured as a preparation for oral administration. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 2, 15.02.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s (8) cha so s so (Se) shi s ;" (22) (95) (ee) o 50 that F) has) 60 b5