Selectively acting thrombin inhibitors and pharmaceutical compositions on their basis

 

(57) Abstract:

Describes the new selectively acting thrombin inhibitors having the following formula I

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also effective oral application. Values of R1, R6, R7X specified in paragraph 1 of the claims. Also described pharmaceutical composition based on compounds of the formula II to inhibit the activity of thrombin. 2 S. and 2 C.p. f-crystals, 7 PL.

The technical field.

The present invention relates to new and selectively acting thrombin inhibitors having the following formula (I):

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in which

R1represents acetyl, substituted aryl or aryloxy, or is sulfonyl, replaced by a substituted or unsubstituted aryl or N-containing heterocyclic group,

X represents a group of the formula

R2and R3independently of one another represent hydrogen; cycloalkyl, substituted or unsubstituted carboxyla or alkoxycarbonyl; arylalkylamine; hydroxy; or lower alkyl, substituted or unsubstituted carboxyla, alkoxycarbonyl or hydroxy, or

R2and R3together with the nitrogen atom to which they join the represents hydrogen, lower alkyl or lower alkoxy,

R5represents alkanesulfonyl; alkoxycarbonyl; alkylsulphonyl; formyl; lower alkyl; aryl, substituted or unsubstituted alkoxy or halogenation; or replacement lower alkyl, and

R6and R7independently from each other represent hydrogen, lower alkyl or amino.

Some compounds of formula (I) can exhibit high inhibitory activity against thrombin even in oral administration and, thus, are of great value.

The present invention also relates to a method for obtaining compounds of formula (I) and pharmaceutical compositions to inhibit the activity of thrombin, which contains a compound of the formula (I) as an active ingredient.

BACKGROUND.

It is widely known that the process of blood clotting involves a lot of complex enzymatic reactions, the final stage which involves the reaction of conversion of prothrombin to thrombin. Thrombin, resulting from the final stage of blood coagulation, activates platelets and converts fibrinogen into fibrin, which is then converted in Vysokomolekulyarnye blood XIII with the formation of insoluble blood clot. Accordingly, thrombin plays an important role in the blood clotting process. Thrombin also activates blood factors V and VIII, which, in turn, accelerate the clotting of blood through the feedback mechanism.

Thus, since thrombin inhibitors are as effective anticoagulants and, at the same time, can suppress the activation of platelets and the production and stabilization of fibrin, a long time there have been many attempts to find a way to prevent blood clotting and treatment of thrombosis of various kinds, using a new connection, which is able to inhibit the activity of thrombin.

However, the connection that can only suppress the activity of thrombin, limited in application as an effective anticoagulation and thrombolytic funds. The reason is the fact that, since thrombin is one of the serine proteases, and in the human body, especially in blood, there are a large number of serine proteases like trypsin, usually plasmin, an effective inhibitor of thrombin, as a rule, has a high inhibitory activity towards serine proteases. In accordance with such characteristic feature of thrombin, Bermuda activity in relation to the prototype of serine proteases, such as trypsin, than against thrombin.

Under such conditions was carried out a large number of studies with the aim of developing a selectively acting thrombin inhibitors, which could effectively inhibit the activity of thrombin and, at the same time, would have a low inhibitory activity against trypsin. The result was developed Argatroban (Argatroban), having the following formula (A), derived arylsulfonamides (U.S. patent 4258192 and 4201863).

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Argatroban shows high inhibitory activity against thrombin, which is 250 times higher than the activity against trypsin (Biochemistry 1984, 23, S. 85-90). However, it can only be obtained by complex method of synthesis. It was released in Japan in 1990.

In addition, was also developed NAPAP, having the following formula (B), arylsulfonyl derived benzamidine.

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This compound can be easily synthesized and has a high inhibitory activity against thrombin. However, it has the disadvantage that the inhibitory activity against thrombin only 50 times the activity towards trypsin (J. Biol. Chem. 1991, 266, C. and high selectivity against thrombin compared to trypsin. This connection indicates the possibility of developing intravenous composition due to its short half-life in blood, but does not allow oral administration (J. Med. Chem. 1994, 37, 3889-3901).

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In addition, it was reported recently developed the connection based on piperazine how about giving, to some extent, the possibility of oral administration in rats, but with low selectivity against thrombin (WO 94/18185). Thus, it is not expected that such connections in this area are promising.

Thus, the authors of the present invention have conducted extensive studies in order to develop a specific connection, which can be easily synthesized, has higher inhibitory activity against thrombin, than against trypsin, and can also be administered orally. In the result, the applicants have found that thrombin inhibitor of formula (I) according to the present invention meets these requirements and thus created the present invention.

DESCRIPTION OF THE INVENTION.

Accordingly, an object of the present invention is a new thrombin inhibitor of formula (I) as defined above, which

Another object of the present invention is a method of obtaining thrombin inhibitor of formula (I).

Further, another object of the present invention is a pharmaceutical composition for preventing blood coagulation and treatment of thrombosis of various kinds, which contains a thrombin inhibitor of formula (I) as an active ingredient.

THE PREFERRED METHOD OF CARRYING OUT THE INVENTION.

On the one hand, the present invention relates to a new compound represented by the following formula (I):

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its pharmaceutically acceptable salt, hydrate, MES and the isomer in which

R1represents acetyl, substituted aryl or aryloxy, or is sulfonyl, replaced by a substituted or unsubstituted aryl or N-containing heterocyclic group,

X represents a group of the formula

R2and R3independently of one another represent hydrogen; cycloalkyl, substituted or unsubstituted carboxyla or alkoxycarbonyl; arylalkylamine; hydroxy; or lower alkyl, substituted or unsubstituted carboxyla, alkoxycarbonyl or hydroxy, or

R2and R3together with the atom azo is carbonyl,

R4represents hydrogen, lower alkyl or lower alkoxy,

R5represents alkanesulfonyl; alkoxycarbonyl; alkylsulphonyl; formyl; lower alkyl; aryl, substituted or unsubstituted alkoxy or halogenation; or replacement of lower alkyl,

and

R6and R7independently from each other represent hydrogen, lower alkyl or amino.

The definition of each substituent of compounds of formula (I) according to the present invention, the term "lower alkyl" means a saturated, unbranched or branched hydrocarbon radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl, isobutyl, tert-butyl etc; the term "aralkylated" means alkoxygroup, substituted aromatic ring, such as benzyloxy, and so on; and the term "cycloalkyl" means a cyclic alkyl group containing 3 to 8 carbon atoms, such as cyclopentyl.

Among the compounds of formula (I) above, preferred is a compound in which

R1represents acetyl, substituted naphthyl or naphthyloxy, or is sulfonyl, substituted naphthyl or phenyl which may be substituted or not soulkilling,

X represents a group of the formula

R2and R3independently of one another represent C3-6-cycloalkyl, substituted or unsubstituted carboxyla or methoxycarbonyl; benzyloxy; lower alkyl, substituted or unsubstituted carboxyla, methoxycarbonyl or hydroxy; or hydroxy, or

R2and R3together with the nitrogen atom to which they are attached, may form piperidino group, substituted carboxyla or methoxycarbonyl,

R4represents hydrogen,

R5represents methanesulfonyl, etoxycarbonyl, formyl, ethyl, phenyl, methylcarbamyl, hydroxyethyl or phenyl which may be substituted or not substituted by trifluoromethyl or ethoxy, and

R6and R7independently of one another represent hydrogen, methyl or amino.

A typical example of the compounds of formula (I) according to the present invention includes the following:

(S)-N-cyclopentyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide,

(S)-N-butyl-N-methyl-3-(4-emersonian)-2-(2 - naphthylamine)propionamide,

(S)-N-cyclopentyl-N-propyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide,

(S)-N-cyclopentyl-N-(2-benzyl shall openil)-2-(2-naphthylamine)propionamide,

(S)-N-cyclopentyl-N-ethyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide,

(S)-N-cyclopentyl-N-methyl-3-[4-(methylamino)phenyl] -2-(2-naphthylamine)propionamide,

(S)-N-cyclopentyl-N-methyl-3-[4-(1,1-dimethylamino)phenyl] -2-(2-naphthylamine)propionamide,

(S)-N-cyclopentyl-N-methyl-3-(4-emersonian)-2-[(4-methoxy-2,3,6-trimethylbenzene)sulfonylamino]propionamide,

(S)-N-cyclopentyl-N-hydroxy-3-(4-emersonian)-2-(2-naphthylamine)propionamide,

(S)-N-cyclopentyl-N-(2-hydroxyethyl)-3-(4-amerzone-phenyl)-2-(2-naphthylamine)propionamide,

(S)-N-cyclopentyl-N-methyl-3-[4-(methylamino)phenyl] -2-[(4-methoxy-2,3,6-trimethylbenzene)sulfonylamino]propionamide,

(S)-N,N-dimethyl-3-(4-emersonian]-2-(2-naphthylamine)propionamide,

(S)-N, N-dimethyl-3-[4-(1-methylamino)phenyl] -2-(2-naphthylamine)propionamide,

(S)-N-cyclohexyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide,

(S)-N-cyclopropyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide,

(S)-3-[4-(emigrate)phenyl]-N-cyclopentyl-N-methyl-2-(2-naphthalene-1-ylacetamide)propionamide,

(S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(5-dimethylaminonaphthalene-1 sulfonylamino)send

(S)-3-[4-(emigrate)phenyl]-N-cyclopentyl-N-methyl-2-(6,7-dimethoxyaniline-2-sulfonylamino)propionamide,

(S)-3-[4-(methylamino)phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylaminonaphthalene-1 sulfonylamino)propionamide,

(S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(naphthalene-2-sulfonylamino)propionamide,

(S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-[2-(naphthalene-1-yloxy)acetylamino)propionamide,

(S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-yloxy)acetylamino)propionamide,

methyl ester {[3-(4-(emersonian)-(S)-2-(naphthalene-2 - sulfonylamino)propionyl]methylamino}acetic acid,

{ [3-(4-(emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}acetic acid,

methyl ether (S)-2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid,

(S)-2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino) propionyl]methylamino}propionic acid,

methyl ester (R)-2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid,

(R)-2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid,

methyl ester (R)-2-{[3-(4-emersonian)-(S)-naphthalene-2 - sulfonylamino)propionyl]methylamino}-3-matlakala acid,

methyl ester of 3-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid,

3-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}propionic acid,

methyl ester of 4-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}butyric acid,

4-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}butyric acid,

methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]cyclopropylamino}acetic acid,

{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] cyclopropylamino}acetic acid,

methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]butylamino}acetic acid,

{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] butylamino}acetic acid,

methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]cyclopentylamine}acetic acid,

{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] cyclopentylamine}acetic acid,

methyl ester 1-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}cyclopentanecarbonyl acid,

methyl ester 1-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}cyclopentanecarboxylic acid,

1-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}cyclopentanecarbonyl acid,

ethyl ester of 2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}cyclopentanecarboxylic acid,

2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}cyclopentanecarbonyl acid,

methyl ether (S)-2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}-3-methylmalonic acid,

methyl ether of 1-[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]piperidine-(R)-2-carboxylic acid,

1-[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] piperidine-(R)-2-carboxylic acid,

[1-(4-amerzone)benzyl-2-oxo-2-(4-methylsulfonylbenzoyl)ethyl] amide (S)-naphthalene-2-sulfonic acid,

[1-(4-amerzone)benzyl-2-(4-formylpiperazine)-2-oxoethyl] amide (S)-naphthalene-2-sulfonic acid,

[1-(4-amerzone)benzyl-2-(4-ethylpiperazine)-2-oxoethyl]amide (S)-naphthalene-2-sulfonic acid,

[1-(4-amerzone)benzyl-2-oxo-2-(4-phenylpiperazine)ethyl] amide (S)-naftaplin-2-sulfonic acid,

[2-(4-acetylpiperidine)-1-(4-amerzone)benzyl-2-oxoethyl]amide (S)-naphthalene-2-sulfonic acid,

[1-(4-amerzone)benzyl-2-oxo-2-[4-(2-hydroxyethyl)piperazinil] ethyl] amide (S)-naphthalene-2-sulfonic acid,

and

[1-(4-amerzone)benzyl-2-oxo-2-[4-(2-ethoxyphenyl)piperazinil]ethyl]amide (S)-naphthalene-2-sulfonic acid.

The compound of formula (I) according to the present invention can also form pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts of compound (I) may include salt added acids formed by the acids that can form non-toxic salt of the added acid containing pharmaceutically acceptable anion, for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrobromic acid, itestosterone acid, etc. and organic carboxylic acids, such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and so on, sulfonic acids, such as methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate compound of formula (I) according to the present invention may contain an asymmetric carbon atom, it can be in the form of a racemate, a mixture of diastereoisomers and single diastereoisomer. All such isomers are included within the scope of the present invention. That is, the isomers of the compounds of formula (I) can be represented as follows:

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in which R6represents methyl or amino.

From another point of view, the present invention also relates to a method for obtaining compounds of formula (I) as defined above.

In accordance with the present invention, the compound of formula (I) can be obtained by reacting the compounds of formula (II) with the compound of the formula (III), as shown in the following reaction scheme 1.

The reaction scheme 1.

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In the above reaction scheme X, R1, R6and R7determined as described above.

As shown in the above reaction scheme 1, the compound of formula (I) according to the present invention can be obtained by reacting methylmercaptopurine formula (II) with the amine derivative of formula (III) as a nucleophilic substances. This reaction may be preferably conducted in the presence of a solvent. Although this reaction can be used any organic solvent which coy as methanol, ethanol, propanol, etc.

In the above reactions, the reaction conditions, including the number of reagents, reaction temperature, reaction time, etc. can be defined depending on the specific type of reagent used by a skilled person in this field. Although the reaction temperature can vary within a substantial interval, as a rule, especially, it is preferable to conduct the reaction at 0oC to 50oC. In addition, the reaction typically takes from 0.5 to 5 hours and preferably can be carried out for 1 to 2 hours.

After the reaction terminated, the reaction product may be separated and purified in accordance with conventional processing techniques, such as chromatography, recrystallization, etc.

Methylmercaptopurine formula (II) used as an intermediate product to obtain the compounds of formula (I) in the reaction scheme 1, can be obtained in accordance with reaction scheme 2 or 3, as described below.

The reaction scheme 2:

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The reaction scheme 3:

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In the above schemes reactions

X, R1, R6and R7defined as opisanie.

In the reaction scheme for the first 2 to C-end of the link [1] attach the amino group X in a compound [2], amino-protective group from the N-end of which is removed to obtain the compound [3]. Then deprived of the protection of the N-end of the link [3] introduce the group R1obtaining compounds [4]. Alternatively, in accordance with reaction scheme 3, first to N-end connections [7] introduce the group R1and then to the C-end is attached to the amino group X in a compound [4].

Specifically, in accordance with reaction scheme 2, the compound of the formula [1] attached aminopropane corresponding to the Deputy X with obtaining the compounds of formula [2] , with N-Terminus which removes aminosidine group to obtain the compounds of formula [3]. Then on the N-end of the connection formula [3] introduce the group R1obtaining a nitrile derivative of formula [4], which is then saturated with hydrogen sulfide in the presence of pyridine and triethylamine to obtain thioamide the compounds of formula [5]. This thioamide connection then was identified in using meteorologi agent, such as itmean, dimethylsulfate, metalcraft and so on, to obtain the desired methylmercaptopurine formula (II).

In accordance with reaction scheme 3, snachimoy [6] and then on the C-end of the obtained compound of the formula [8] introduce the amino group by joining the connection [8] aminpirizvodnoe connection the appropriate Deputy X, obtaining the compounds of formula [4], which is then subjected to the same procedure as in reaction scheme 2, to give the desired methylmercaptopurine formula (II).

A crosslinking agent that can be applied to the accession process in the schemes of reactions 2 and 3, includes one or more substances selected from the group comprising dicyclohexylcarbodiimide (DCC), 3-ethyl-3'-(dimethylamino)propellerpowered (EDC), the acid chloride of bis-(2-oxo-3-oxazolidinyl)phosphinic acid (BOP-C1) and diphenylphosphoryl (DFFA), but is not limited to them.

Although the connection - carboxylic acid [1] and [7], the schemes used in the reactions 2 and 3 can be applied in the form of free acids, preferably they can be used in the form of its reactive derivatives, for example halogenosilanes derivative or other activated ester derivative in order to facilitate the reaction. For the reactions of addition of amine compounds with the formation of amide linkages, or the reactions of addition of the alcohol with the formation of ester bonds is especially necessary activated ester carboxylic acid derivative. Such reactive production is Oh in the art. For example, included halogenosilanes derived acid chloride; and an activated ester derivative includes an anhydride of carboxylic acid, a derivative alkoxycarbonylmethyl, such as methoxycarbonylamino, isobutylacetophenone and so on, and a crosslinking agent, ester derived N-hydroxyphthalimide, ester derivative of N-hydroxysuccinimide, ester derivative of N-hydroxy-5-Narbonne-2',3'-dicarboximide, ester derived 2,4,5-trichlorophenol, and so on, but is not limited to them.

The effect of inhibition of thrombin compounds of formula (I) according to the present invention can be detected by determining the dissociation constants Kirepresented by the following equation, in accordance with known methods described in the literature (Methods in Enzymology, I. 80, S. 341-361; Biochemistry 27, S. 2144-2151 (1988)).

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*[E] is the concentration of free enzyme;

**[I] is the concentration of unbound inhibitor;

***[EI] is the concentration of the complex enzyme-inhibitor.

The dissociation constant Kiindicates the degree of dissociation of the complex enzyme-inhibitor of thrombin. Accordingly, the low value of the dissociation constants howaida, what thrombin inhibitor has a high inhibitory activity against thrombin. Such a dissociation constant can be determined by the interaction of thrombin with a specific substrate, which gives the painting, being hydrolyzed by the action of thrombin and the subsequent measurement of the degree of development of the color depending on the time by the method of spectrophotometry.

In the present invention as a substrate material for thrombin used Glomosim TN (Chromozym th) and (Gly-Pro-Arg-4-nitroanilide), which gives the color under the action of thrombin. Chromosom TN hydrolyzed by thrombin with a yellow para-nitroaniline. Accordingly, the number thus obtained yellow para-nitroaniline can be measured as the change in absorption over time to determine the inhibitory activity against thrombin compounds of the present invention. The enzyme activity can be determined from the rate of change of absorption and can then be directly related to the ability of the thrombin inhibitor to inhibit the enzyme activity (Methods in Enzymology, I. 80, S. 341-361; Biochemistry 27, S. 2144-2151, 1988).

To determine the selectivity of the compounds in the extract of the Oia formula (I) with respect to trypsin as the value of Kiin accordance with the same method as the above method for determining the inhibitory activity against thrombin, and then calculate the ratio of activity against trypsin activity against thrombin. In this case, the procedure for determining inhibitory activity against trypsin substantially identical to that of thrombin, except that as the substrate used N-benzoyl-Val-Gly-Arg-para-nitronylnitroxide.

As a result of the determination of inhibitory activity against thrombin and trypsin compounds of formula (I) according to the present invention can be established that the compound of the present invention exhibits excellent inhibitory activity against thrombin and, moreover, has a high selectivity against thrombin compared to trypsin. In particular, the values of the selectivity of the compounds of Examples 1 and 7 with respect to thrombin compared with trypsin approximately 2900 times and 26304 times, respectively, whereas the values of the selectivity of known inhibitors of thrombin, argatroban (A) and NAPAP (B), are only 250 times and 50 times, respectively. Accordingly, it can be replaced is the compared to thrombin compared with trypsin.

As mentioned above, since the new compound of the formula (I) according to the present invention is a thrombin inhibitor, which exhibits a high inhibitory activity against thrombin even when administered orally and also has a high selectivity against thrombin compared to trypsin, it can be used for the prevention of blood clotting and treatment of thrombosis of various kinds.

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

When the compound of formula (I) according to the present invention is administered to a subject in a clinical purposes, the daily dose of compound (I) can vary, preferably, in the range from 0.001 mg to 10 mg per 1 kg of body weight. However, when the treatment of a patient can be assigned a special dose in excess of the stated interval of doses depending on the particular applicable connections, weight, sex and health of the patient, diet, time and route of administration, rate of excretion of the compound, d is="ptx2">

The compound of the present invention may be in the form of the drug for injection or preparation for oral administration in accordance with the intended purpose.

The preparation for injection, for example sterilized aqueous or oily suspension for injection, can be prepared using a suitable dispersing agent, wetting agent or a suspending agent in accordance with known methods, typically used in the preparation of drugs for injection. As the aqueous solvent suitable for this purpose may be employed are water, ringer's solution or isotonic NaCI. In addition, although sterilized non-volatile oil may be used as solvent or suspendida environment, does not cause any irritation non-volatile oil, including mono - and diglycerides may be used for the same purposes. Moreover, in preparation for injection may be added fatty acid such as oleic acid.

Solid preparation for oral administration may be in the form of capsules, tablets, pills, powders and granules, and the composition in the form of capsules or tablets is the most preferred. Tablet is no solid preparation of active compound of the formula (I) according to the present invention can be combined with a pharmaceutically acceptable carrier, for example with one or more inert diluents such as sucrose, lactose, starch, etc., lubricating agents such as magnesium silicate, disintegrators, binders and the like.

One of the main characteristics of the compounds of formula (I) according to the present invention is that the compound of formula (I) exhibits good pharmacological effect, even when it is prepared in the form of a preparation for oral administration and then administered orally. This can be demonstrated based on the results of pharmacokinetic experiments on rats and dogs as experimental animals. In such experiments can be found that the active compound of the present invention remains in the blood for an extended period of time, being administered orally. Accordingly, the compound of formula (I) according to the present invention is more applicable in light of the fact that it can be effectively applied in the form of a preparation for oral administration.

Next, on the basis of pharmacokinetic experiments can be also found that the active compound of the present invention may allow to achieve W the Binah of the present invention is administered in order to receive anticoagulation and thrombolytic effects, it can be entered in combination with one or more substance(s) selected from the group including thrombolytic means and means to inhibit the activity of platelets. As a thrombolytic agent that can be used for this purpose may be mentioned t-PA, urokinase, streptokinase; and aspirin, ticlopidine (ticlopidin), clopidrogel (clopidrogel), a monoclonal antibody E, etc. can be used as a tool to suppress the activity of platelets.

Note, however, that the preparation containing the active compound of the present invention for the treatment and prevention of thrombosis, is not limited to those described above and may include any drug that is applicable for this purpose.

Further, the present invention will be explained more specifically with working examples. Note, however, that the examples are only for purposes of explanation of the present invention and are not intended to limit the present invention in any way.

Receiving 1.

Getting cyclopentylamine. To a solution of Cyclopentanone (10 ml, 113 mmol) in methanol (50 ml) and water (50 ml) was added methylaminopropane (7.6 g, 113 mmol) and C. The methanol is evaporated under reduced pressure and the residue was cooled to 0oC, brought to pH 2 using 3h. hydrochloric acid, and then washed three times with diethyl ether. The aqueous layer was again cooled to 0oC and then brought to pH 11 using 6N. the sodium hydroxide solution. To this mixture was added to the anhydride of tertbutyloxycarbonyl (24.5 g, 113 mmol) in dioxane (50 ml). The solution was stirred for 3 hours at room temperature and then concentrated under reduced pressure to about 30 ml, the Residue was extracted by adding ethyl acetate and washed with an aqueous solution of 0.5 G. hydrochloric acid and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain white solid, which was then purified according to the method of column chromatography (eluent = ethyl acetate: hexane = 7:3 (by volume)). At the end of treatment resulting solid product was dissolved in a solution of 4n. HCl-dioxane (60 ml) and the resulting solution was stirred for 30 minutes at room temperature. The solvent is evaporated in vacuum to obtain specified in the connection header (13,7, Output: 90,5%).

Obtain (S)-N-cyclopentyl-N-methyl-3-(4-cyanophenyl)-2-(butyloxycarbonyl)propionamide.

To a solution of (S)-3-(4-cyanophenyl)-2-(butyloxycarbonyl)propionic acid (0.7 g, 2.14 mmol) in dimethylformamide (DMF, 6 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 0.7 g) and 1-hydroxybenzo-triazolide (HOBT, 0.4 g) at 0oC. the Mixture was stirred until then, until they are fully dissolved. To this reaction mixture was added the compound (0.4 g, 2,96 mmol) obtained in the Obtaining 1, and N-methylmorpholine (1.0 ml) and then the reaction temperature was slowly raised to room temperature. The reaction solution was stirred for 3.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove volatile substances and the resulting residue was diluted with ethyl acetate, thoroughly washed with aqueous saturated sodium hydrogen carbonate solution, diluted hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified by the method of column chromatography (eluent = ethyl acetate:hexane = 7:3 (by volume)) to obtain the purified compound indicated in heading (0,65, Output: 73,0%).

Mass (FAB, m/e): 372 (M++1).

Getting 3.

Obtain (S)-N-cyclopentyl-N-methyl-3-(4-cyanophenyl)-2-(2-naphthylamine)propionamide.

The compound (0.65 g, a 1.75 mmol), obtained in the Obtaining 2, was dissolved in dichloromethane (3 ml) and then cooled to -10oC and to it was added triperoxonane acid (TFU, 1 ml). The reaction mixture was stirred for 5 minutes, slowly warmed up to room temperature, was stirred for 30 minutes and then concentrated under reduced pressure to remove volatiles. The residue was dried using a vacuum pump and then to it was added 6 ml of DMF. The mixture was cooled to 0oC was added N,N-diisopropylethylamine (1 ml). The reaction mixture was heated to room temperature and was stirred for approximately 5 minutes. After adding 2-naphthalenesulfonate (0,47 g 2,07 mmol) the reaction mixture was stirred for one hour to complete the reaction and then concentrated under reduced pressure to remove volatiles. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. asanoha in the connection header (0,65, Yield: 80.2 per cent).

1H NMR (CDCl3millions of shares) : 8,28 (m, 1H), 7,87 (m, 3H), 7,73 (m, 3H), 7,49 (m, 2H), of 5.92 (m, 1H), 4,50, 4,32, 3,76 (m, m, m, 2H), 2.95 and (m, 2H), 2,36, 2,22 (s, 3H), 1.60-to of 1.20 (m, 6N), 0,98, 0,80, of 0.47 (m, m, m, 2H).

Mass (FAB, m/e): 462 (M++1).

Example 1.

Obtain (S)-N-cyclopentyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

The compound (0.65 g, of 1.41 mmol) obtained in the Obtaining 3, was dissolved in pyridine (10 ml) and the resulting solution was placed in a flask with fittings to which was added triethylamine (0.45 ml). The reaction flask was equipped in such a way that gaseous hydrogen sulfide (H2S) could be entered through a single fitting bulb, and output through the other fitting. The reaction solution was saturated with gaseous hydrogen sulfide with stirring for about 10 minutes, colorless solution was purchased green color and then gradually - dark brown. The flask was closed with a rubber stopper and left to stand for 3 days at room temperature to complete the reaction. Then the reaction solution was distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. To the resulting yellow solid substance was added minutes. This reaction mixture was again distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. The residue was dissolved in absolute methanol (8 ml) and then stirred. To this mixture portions three times with an interval of 10 minutes was added hydrazine hydrate (H2NNH2H2O, 0,12 ml of 1.98 mmol). After the reaction was completed, the reaction solution was concentrated and was purified according to the method GHUR obtaining specified in the connection header (0,63, Output: 73,0%).

Conditions GHUR:

eluent = methanol: water (75:25 by volume), both contain CF3COOH in a concentration of 0.1%

wavelength = 215 nm

the rate of elution of = 20 ml/min

column = Delta CANCER C 18 100 (30 x 300 mm)

1H NMR (CD3OD, millionths) : of 8.28 (d, 1H), 7,92 (m, 3H), 7,70-to 7.50 (m, 5H), 7,35 (DD, 2H), 4,60, of 4.45 (t, t, 1H), 4,12, 3,99 (m, m, 1H), 3.00 and, 2,87 (m, m, 2H), 2,49, and 2.26 (s, 3H), 1,60-1,00, 0,73-0,52 (m, m, 8H).

Mass (FAB, m/e): 494 (M++1).

Getting 4.

Getting triperoxonane salt butylmethylamine.

N-butyloxycarbonyl (140 mg, 0.80 mmol) was dissolved in DMF (8 ml) and to it was added sodium hydride (NaH (20 mg, 1 EQ. weight) and itmean (0.10 ml, 2 EQ. mass). The reaction mixture was stirred receiring pressure to remove solvent. The residue was diluted with ethyl acetate, washed with 0.5 n aqueous solution of hydrochloric acid, 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 0oC. To this mixture was added 1 ml triperoxonane acid (TFU). The reaction solution was stirred for 30 minutes at room temperature, concentrated under reduced pressure and then dried using a vacuum pump to obtain specified in the title compound (0.16 g) in quantitative yield.

1H NMR (CDCl3millions of shares) : of 1.02 (t, 3H), of 1.30 and 1.80 (m, 4H), 3.04 from (s, 3H), 3,52 (t, 2H), to 8.20 (s, 2H).

Example 2.

Obtain (S)-N-butyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

Carried out the reaction of the compound obtained in the Obtaining 4, in accordance with the same method that Receives, 2 and 3, to obtain the intermediate (S)-N-butyl-N-methyl-3-(4-cyanophenyl)-2-(2-naphthylamine)propionamide (0,23 g), which was used as the source of the product. This original product was treated with the ke (0,1, Output: 40,0%).

1H NMR (CD3OD, millionths) : 8,30 (d, 1H), 7,98 (m, 3H), 7,81-7,30 (m, 7H), 4,50 (m, 1H), 3.25 to to 2.55 (m, 4H), 2,78, 2,45 (2 s, 3H), 1,40-0,50 (m, 7H).

Mass (FAB, m/e): 482 (M++1).

Example 3.

Obtain (S)-N-cyclopentyl-N-propyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

Used the same technique as in Getting 1, except that instead of methylamine was used Propylamine, obtaining cyclopentylpropionate, which is then processed in accordance with the same method that Receives, 2 and 3, to obtain the intermediate (S)-N-cyclopentyl-N-propyl-3-(4-cyanophenyl)-2-(2-naphthylamine)propionamide (0.15 g). This intermediate compound was used as a source of product and process in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (0,089, Output: 55.1 per cent).

1H NMR (CD3OD, millionths) : 8,35-7,35 (m, 11N), 4,62-4,32 (m, m, 1H), 3,90, 3,70 (m, m, 1H), 3,10-of 2.50 (m, 4H), 1.70 to 0,50 (m, 13H).

Mass (FAB, m/e): 522 (M++1).

Example 4.

Obtain (S)-N-cyclopentyl-N-(2-benzyloxyethyl)-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

1H NMR (CD3OD, millionths) : 8,30-to 7.15 (m, N), with 4.64 (m, 1H), 4,48, 4,39 (s, 1H), 4,14, 4,00, 3,75, 3,45 (m, m, m, m, 3H), 3,10-2,70 (m, 5H), 1,62 of 1.00 (m, 8H).

Mass (FAB, m/e): 614 (M++1).

Example 5.

Obtain (S)-N-cyclopentyl-N-butyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

Used the same technique as in Getting 1, except that instead of methylamine was used butylamine, obtaining butylcyclopentadienyl, which is then processed in accordance with the same method that Receives, 2 and 3, to obtain the intermediate (S)-N-cyclopentyl-N-butyl-3-(4-cyanophenyl)-2-(2-naphthylamine)propionamide (0.28 g). This intermediate soomere 1, obtaining a purified compound indicated in heading (0,18, Yield: 60%).

1H NMR (CD3OD, millionths) : 8,32 (d, 1H), of 7.96 (m, 3H), 7,78-of 7.55 (m, 5H), 7,42 (DD, 2H), 4,62, 4,30 (m, m, 1H), was 4.02, 3,90 (m, m, 1H), 3,10-2,75, to 2.55 (m, m, 4H), 1,65-0,80 (m, N), of 0.65 (t, 3H).

Mass (FAB, m/e): 536 (M++1).

Example 6.

Obtain (S)-N-cyclopentyl-N-ethyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

Used the same technique as in Getting 1, except that instead of methylamine was used ethylamine, obtaining cyclopentadienylcobalt, which is then processed in accordance with the same method that Receives, 2 and 3, to obtain the intermediate (S)-N-cyclopentyl-N-ethyl-3-(4-cyanophenyl)-2-(2-naphthylamine)propionamide (0.21 g). This intermediate compound was used as a source of product and process in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (0,11, Output: 50,0%).

1H NMR (CD3OD, millionths) : 8,32 (d, 1H), 7,97 (m, 3H), 7,75-of 7.55 (m, 5H), 7,42 (m, 2H), 4,60, to 4.38 (m, m, 1H), 3,98, a 3.87 (m, m, 1H), 3,20-2,70 (m, 4H), of 1.65 to 1.00 (m, 8H), 0.95, and of 0.68 (t, t, 3H).

Mass (FAB, m/e): 508 (M++1).

Example.

The intermediate compound obtained in the Obtaining 3, was used as a source of product and process in accordance with the same method as in Example 1, except that methylamine unlike hydrazine was added three times at intervals of one hour, to obtain the purified compound indicated in heading (0,064, Yield: 8%).

1H NMR (CD3OD, millionths) : from 0.50 to 1.60 (m, 8H), from 2.00-2.49 USD (2 s, 3H), 2,84 (m, 1H), 2,96 (m, 1H), 3.00 and (s, 3H), of 4.05 (m, 1H), 4,50 (m, 1H), 7,20-8,30 (m, 11N).

Mass (FAB, m/e): 493 (M++1).

Example 8.

Obtain (S)-N-cyclopentyl-N-methyl-3-[4-(1,1-dimethylamino)phenyl]-2-(2-naphthylamine)propionamide.

The intermediate compound obtained in the Obtaining 3, was used as a source of product and process in accordance with the same method as in Example 1, except that the dimethylamine unlike hydrazine was added three times at intervals of one hour, to obtain the purified compound indicated in heading (0,18, Yield: 22%).

1H NMR (CD3OD, millionths) : 0,60-to 1.60 (m, 8H), 2,29, 2,54 (2 s, 3H), 2.95 and (m, 1H), 3,06 (m, 1H), to 3.09 (s, 3H), and 3.31 (s, 3H), of 4.16 (m, 1H), 4,60 (m, 1H), 7,20-8,30 (m, 11N).

Mass (FAB, m/e): 507 (M++1).

Example 9.

The compound obtained in the Obtaining 2, were processed in accordance with the same method as in Getting 3, except that instead of 2-naphthalenesulfonate used 4-methoxy-2,3,6-trimethylbenzenesulfonyl, to obtain the intermediate (S)-N-cyclopentyl-N-methyl-3-(4-cyanophenyl)-2-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)propionamide (0.27 g). This intermediate compound was used as a source of product and process in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (0,16, Output: 57,1%).

1H NMR (CD3OD, millionths) : a 7.62 (d, 2H), 7,40 (DD, 2H), 6,70 (d, 1H), 4,35, 3,90 (m, m, 2H), 3,83 (d, 3H), of 3.00 (m, 2H), 2,50 (m, N), 2,1 (s, 3H), 1,75-of 0.90 (m, 8H).

Mass (FAB, m/e): 516 (M++1).

Getting 5.

Getting Cyclopentasiloxane.

Gidroxinimesoulid (H2NOHHCl, 5.0 g, 71,95 mmol) was dissolved in water (14 ml) and to it was added methanol (30 ml) and Cyclopentanone (5,1 ml, 57,66 mmol). The mixture was stirred, cooled to 0oC, and the pH is then brought to 8 by adding 6N. an aqueous solution of sodium hydroxide. To the mixture was added cyanoborohydride sodium (NaBH3CN, 1.9 grams, 30,24 mmol). The mixture heating the portions of adding a mixed solution of 6N. HCl (20 ml) and methanol (30 ml) over the course of the reaction. After 5 hours the pH of the reaction mixture was set at 7 and distilled under reduced pressure to remove methanol. The remaining reaction solution was cooled to 0oC, the pH value is again brought up to 11, saturated with sodium chloride and then four times were extracted by adding chloroform. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain specified in the connection header (3,4, Output: 58,3%).

1H NMR (CDCl3millions of shares) : 7,20-5,00 (user. s, 1H), of 3.56 (m, 1H), 1,90-of 1.45 (m, N).

Example 10.

Obtain (S)-N-cyclopentyl-N-hydroxy-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

The compound obtained in the Obtaining 5, processed in accordance with the same method that Receives, 2 and 3, to obtain the intermediate (S)-N-cyclopentyl-N-hydroxy-3-(4-cyanophenyl)-2-(2-afterculture)propionamide (0.1 g). This intermediate compound was used as a source of product and process in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (0,07, Output: 63,6%).

1H NMR (CD>+1).

Example 11.

Obtain (S)-N-cyclopentyl-N-(2-hydroxyethyl)-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

The compound (0.15 g, 0.24 mmol) obtained in Example 4 was dissolved in methanol (10 ml), and then thereto was added palladium hydroxide (0,02 ml). To the reaction vessel was attached to the balloon with hydrogen. After stirring for 2 days the reaction mixture was filtered through a layer of celite and concentrated. The residue was purified by the method GHUR obtaining specified in the connection header (0,08 g Output: 63,7%). Conditions GHUR were identical to those used in Example 1.

1H NMR (CD3OD, millionths) : 7,80-to 7.00 (m, 11H), 4,47 (m, 1H), 4.00 points (m, 1H), 3,60 (m, 2H), 3,10-2,70 (m, 4H), 1.70 to 1,10 (m, 8H).

Mass (FAB, m/e): 524 (M++1).

Example 12.

Obtain (S)-N-cyclopentyl-N-methyl-3-[4-(1,1-dimethylamino)phenyl]-2-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)propionamide.

Used the same technique as in Example 9, except that instead of hydrazine three times with an interval of one hour was added methylamine, to obtain the purified compound indicated in heading (0,08 g Output: 28,3%).

1H NMR (CD3OD, millionths) : the 7.65 (d, 2H), 7,40 (THE/SUP>+1).

Example 13.

Obtain (S)-N, N-dimethyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

Used the same technique as in the Making 2 and 3, except that used dimethylamine, to obtain the intermediate (S)-N, N-dimethyl-3-(4-cyanophenyl)-2-(2-naphthylamine)propionamide (0.11 g). This intermediate compound was used as a source of product and process in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (0,080, Yield: 53%).

1H NMR (CD3OD, millionths) : 2,19 (s, 3H), 2,62 (s, 3H), 2,70-2,95 (m, 2H), to 4.41 (m, 1H), 7,20-8,30 (m, 11N).

Mass (FAB, m/e): 440 (M++1).

Example. 14.

Obtain (S)-N, N-dimethyl-3-[4-(1,1-dimethylamino)phenyl]-2-(2-naphthylamine)propionamide.

Used the same technique as in Example 13, except that instead of hydrazine from the methodology of Example 1, three times with an interval of one hour was added methylamine, to obtain the purified compound indicated in heading (0,10, Yield: 48%).

1H NMR (CD3OD, millionths) : 2,31 (s, 3H), of 2.75 (s, 3H), 2,80 was 3.05 (m, 2H), of 3.07 (s, 3H), of 4.54 (m, 1H), 7,30-to 8.40 (m, 11H).

Mass-naphthylamine)propionamide.

Used the same technique as in Getting 1, except that instead of Cyclopentanone was used cyclohexanone, to obtain cyclohexylmaleimide, which is then processed in accordance with the same method that Receives, 2 and 3, to obtain the intermediate (S)-N-cyclohexyl-N-methyl-3-(4-cyanophenyl)-2-(2-naphthylamine)propionamide (0.21 g). This intermediate compound was used as a source of product and process in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (0,17, Output: 73,9%).

1H NMR (CD3OD, millionths) : 8,32 (d, 1H), 7,95 (m, 3H), 7,75-7,53 (m, 5H), 7,40 (DD, 2H), 4,50, 4,21, 3,62 (m, m, m, 2H), 3,05 (m, 1H), 2,90 (m, 1H), 2,55-to 2.40 (s, 3H), 1,80-of 0.62 (m, 10H).

Mass (FAB, m/e): 508 (M++1).

Example 16.

Obtain (S)-N-cyclopropyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide.

Used the same technique as in Getting 1, except that instead of Cyclopentanone was used cyclopropane, obtaining cyclopropanecarboxamide, which is then processed in accordance with the same method that Receives, 2 and 3, to obtain the prom is an intermediate compound used as source of product and process in accordance with the same method, as in Example 1, to obtain the purified compound indicated in heading (0,06, Yield: 12%).

1H NMR (CD3OD, millionths) : 0,40-of 0.90 (m, 4H), 2.40 a (s, 3H), of 2.75 (m, 1H), 2.95 and (m, 1H), 7,20-8,30 (m, 11H).

Mass (FAB, m/e): 466 (M++1).

Getting 6.

Obtain (S)-3-(4-cyanophenyl)-N-cyclopentyl-N-methyl-2-(2-naphthalene-1-yl-acetylamino)propionamide.

The compound (0.51 g, of 1.34 mmol) obtained in the Obtaining 2, was dissolved in dichloromethane (3 ml) and then cooled to -10oC and to it was added triperoxonane acid (TFU, 3 ml). The reaction mixture was stirred for 5 minutes, slowly warmed up to room temperature, was again stirred for 30 minutes and then distilled under reduced pressure to remove volatiles. The residue was dried using a vacuum pump and then to it was added DMF (10 ml). This solution was cooled to -10oC and to it was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 0.4 g) and 1-hydroxybenzotriazole (HOBT, 0.2 g) and then stirred until then, until they are fully dissolved. To the resulting solution was added 1-naphthalenyloxy acid (0.26 g, 1.4 mmol) and N,N-diisopropylethylamine (1.2 ml). The reaction mixture was slowly heated to the under reduced pressure to remove volatiles. The residue was diluted with ethyl acetate, thoroughly washed with a saturated solution of sodium bicarbonate, diluted hydrochloric acid and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by the method of column chromatography (methanol: chloroform = 1:99 (by volume)) to obtain specified in the connection header (0,42, Yield: 68%).

1H NMR (CDCl3millions of shares) : 8,0-6,8 (m, 11H), 6,5 (m, 1H), 5,1-5,3 (m, 1H), 4,8-4,2 (m, 1H), 4,1 to 3.8 (m, 2H), from 3.0 to 2.6 (m, 5H), 1,8-1,3 (m, 8H).

Example 17.

Obtain (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(2-naphthalene-1-yl-acetylamino)propionamide.

The compound (0.21 g, 0.48 mmol) obtained in the Obtaining 6, was dissolved in pyridine (3 ml) and the resulting solution was placed in a flask with fittings to which was added triethylamine (0.2 ml). The reaction flask was equipped in such a way that gaseous hydrogen sulfide (H2S) could be entered through a single fitting bulb, and output through the other fitting. The reaction solution was saturated with gaseous hydrogen sulfide with stirring for about 10 minutes, and colorless solution was purchased green color and then gradually - dark brown. The flask was closed with R the reaction solution was distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. To the resulting yellow solid substance was added together acetone (10 ml) and itmean (CH3I, 0.3 ml) and the mixture was heated under reflux for 30 minutes. This reaction mixture was again distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. The residue was dissolved in absolute methanol (5 ml) and then stirred. To this mixture portions three times with an interval of 10 minutes was added hydrazine hydrate (H2NNH2H2O, 0.04 ml to 0.72 mmol). After the reaction was completed, the reaction solution was concentrated and was purified according to the method GHUR obtaining specified in the connection header (0,16, Yield: 70%).

1H NMR (CD3OD, millionths) : 8,0-to 7.3 (m, 11N), 5,3-5,1 (m, 1H), 4,8-4,2 (m, 1H), 3,9 (s, 2H), 3,2-a 2.9 (m, 2H), 2,78, 2,72 (2 s, 3H), 1,8-1,3 (m, 8H).

Mass (FAB, m/e): 472 (M++1).

Example 18.

Obtain (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(5-dimethylaminonaphthalene-1 sulfonylamino)propionamide.

Used the same technique as in Getting 3, except that instead of 2-naphthalenesulfonate applied 5-(N,N-dimethylamino)-1-naphthalenesulfonate, to obtain the intermediate (S)-3-(4-cyanophenyl)-N-the second connection is then processed in accordance with the same method, as in Example 1, to obtain the purified compound indicated in heading (0,35, Yield: 60%).

1H NMR (CD3OD, millionths) : 8.6 out of 7.3 (m, 10H), the 4.9 to 3.9 (m, 2H), 3,11 (s, 3H), 3.0 a (s, 3H), 3,05-2,8 (m, 2H), 2,5, 2,4 (2 s, 3H), 1,7-0,9 (m, 10H).

Mass (FAB, m/e): 537 (M++1).

Example 19.

Obtain (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(5-methoxynaphthalene-1 sulfonylamino)propionamide.

Used the same technique as in Getting 3, except that instead of 2-naphthalenesulfonate used 5-methoxy-1-naphthalenesulfonate, to obtain the intermediate (S)-3-(4-cyanophenyl)-N-cyclopentyl-N-methyl-2-(5-methoxynaphthalene-1 sulfonylamino)propionamide (0.18 g, of 0.37 mmol). This intermediate compound is then treated in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (0,12, Yield: 65%).

1H NMR (CD3OD, millionths) : 8,5-of 7.0 (m, 10H), 4,6-4,0 (m, 2H), 4.2V (s, 3H), from 3.0 to 2.8 (m, 2H), 2,48-2,45 (2 s, 3H), 1,7-1,0 (m, 8H).

Mass (FAB, m/e): 523 (M++1).

Example 20.

Obtain (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(6,7-dimethoxyaniline-2-sulfonylamino)propionamide.

Ispolzovaniya-2-naphthalenesulfonate, obtaining an intermediate product (S)-3-(4-cyanophenyl)-N-cyclopentyl-N-methyl-2-(6,7-dimethoxyaniline-2-sulfonylamino)propionamide (2.2 g, 2.2 mmol). This intermediate compound is then treated in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (1,55, Yield: 67%).

1H NMR (CD3OD, millionths) : 8,4 was 7.3 (m, N), 4,7-4,0 (m, 2H), 4,2-4,0 (2, 6N), the 3.2 to 2.8 (m, 2H), 2,6-2,2 (2 s, 3H), 1,7-1,0 (m, 8H).

Mass (FAB, m/e): 554 (M++1).

Example 21.

Obtain (S)-3-[4-(methylamino)phenyl] -N-cyclopentyl-N-methyl-2-(5-dimethylaminonaphthalene-1 sulfonylamino)propionamide.

Used the same technique as in Getting 3, except that instead of 2-naphthalenesulfonate when changed 5-(N,N-dimethylamino)-1-naphthalenesulfonate, to obtain the intermediate (S)-3-(4-cyanophenyl)-N-cyclopentyl-N-methyl-2-(5-dimethylaminonaphthalene-1 sulfonylamino)propionamide (0.3 g, 0.6 mmol). This intermediate compound is then treated in accordance with the same method as in Example 1, except that instead of 80% hydrazine hydrate was used methylamine, to obtain the purified compound indicated in heading (0,08, Yield: 25%).

Mass (FAB, m/e): 536 (M++1).

Example 22.

Obtain (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(naphthalene-2-sulfonylamino)propionamide.

Used the same technique as in Getting 3, except that instead of 2-naphthalenesulfonate used 1-naphthalenesulfonate, to obtain the intermediate (S)-3-(4-cyanophenyl)-N-cyclopentyl-N-methyl-2-(naphthalene-2-sulfonylamino)propionamide (0.5 g, 1 mmol). This intermediate compound is then treated in accordance with the same method as in Example 1, to obtain the purified compound indicated in heading (0,2, Yield: 40%).

1H NMR (CD3OD, millionths) : 8,61-7,28 (m, 11N), 4,55-to 4.41 (m, 2H), 4,23-4,00 (m, 2H), 3.00 and-2,84 (m, 2H), 2,49, 2,41 (2 s, 3H), 1.70 to 1.00 and (m, 8H).

Mass (FAB, m/e): 494 (M++1).

Example 23.

Obtain (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-[2-(naphthalene-1-yloxy)acetylamino]propionamide.

Used the same technique as in Getting 6, except that instead of 1-naftiluksusnoi acid was used (1 naphthoxy)acetic acid, to obtain the intermediate (S)-3-(4-cyanophenyl)-N-cyclopentyl-N-methyl-2-[2-whether in accordance with the same method, as in Example 17, to obtain the purified compound indicated in heading (0,38, Yield: 60%).

1H NMR (CD3OD, millionths) : 8,25 to 6.8 (m, 11N), 5,38 with 5.22 (m, 2H), 4,77-4,39 (m, 2H), 4,70 (s, 2H), 3,21 was 3.05 (m, 2H), 2,88-2,77 (2 s, 3H), 1,92-of 1.40 (m, 8H).

Mass (FAB, m/e): 488 (M++1).

Example 24.

Obtain (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-yloxy)acetylamino]propionamide.

Used the same technique as in Getting 6, except that instead of 1-naftiluksusnoi acid was used (2-naphthoxy)acetic acid, to obtain the intermediate (S)-3-[4-(aminoketone)phenyl] -N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-yloxy)acetylamino]propionamide (0.7 g, 1.54 mmol). This intermediate compound is then treated in accordance with the same method as in Example 17, to obtain the purified compound indicated in heading (0,59, Yield: 63%).

1H NMR (CD3OD, millionths) : 7,80-7,14 (m, 11N), 5,35-by 5.18 (m, 1H), 4,76 is 4.35 (m, 1H), br4.61 (s, 2H), 3,18 was 3.05 (m, 2H), 2,85-2,75 (2 s, 3H), 1.85 to 1,25 (m, 8H).

Mass (FAB, m/e): 488 (M++1).

Getting 7.

Obtain methyl ester of N-tert-butoxycarbonyl-N-methylaminoethanol acid.

Hydrochloride it is worth noting were added 1,4-dioxane. To this mixture was added di-tert-BUTYLCARBAMATE (2.2 g, 9.8 mmol) at 0oC and the mixture was heated to room temperature and was stirred for 2 hours. Volatiles were removed from the reaction mixture under reduced pressure and the residue was diluted with ethyl acetate, thoroughly washed with aqueous saturated sodium hydrogen carbonate solution, diluted hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated. The obtained product was dissolved in dimethylformamide (DMF, 10 ml). To this solution was slowly added sodium hydride (NaH, 0.25 g, 6.4 mmol) and then was added dropwise itmean (CH3I, 1.1 ml). The mixture was slowly heated to room temperature and was stirred for 3 hours at the same temperature. The mixture was filtered through a layer of celite and concentrated under reduced pressure. The residue was diluted with ethyl acetate, thoroughly washed with aqueous saturated sodium hydrogen carbonate solution, diluted hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified by the method of column chromatography using ethyl acetate/hexane as eluent to p is linnie share) : 1,45 (d, N), 2,95 (s, 3H), of 3.78 (s, 3H), 3,92 (s, 1H), 4.00 points (s, 1H).

Mass (FAB, m/e): 204 (M+1).

Getting 8.

Obtaining methyl ester {[(S)-2-(tert-butoxycarbonylamino)-3- (4-cyanophenyl)propionyl]methylamino}acetic acid.

(S)-2-(tert-Butoxycarbonylamino)-3-(4-cyanophenyl)propionic acid (0.5 g, 1,72 mmol) was dissolved in dimethylformamide (DMF). The resulting solution was cooled to 0oC and then to it was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 0.39 g) and 1-hydroxybenzotriazole (HOBT, 0.28 g) and then stirred until then, until they are fully dissolved. Apart from them, the compound (0.35 g, 1,72 mmol) obtained in the Obtaining 7, was dissolved in dichloromethane (2 ml) and cooled to -10oC. thereto was added triperoxonane acid (2 ml) and the mixture was stirred for 5 minutes, slowly warmed up to room temperature, was again stirred for 30 minutes and then distilled under reduced pressure to remove volatiles. Thus obtained compound and N-methylmorpholine (1 ml) was added to the solution, as was achieved above, and then the reaction solution was slowly heated to room temperature and was stirred for 3.5 hours. Upon completion of the reaction reassimilation, carefully washed with aqueous saturated sodium hydrogen carbonate solution, diluted hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then koncentrirebuli, the Residue was purified by the method of column chromatography using ethyl acetate/hexane (3/7 by volume) as eluent, to obtain specified in the connection header of 0.58, Yield: 90%).

1H NMR (CDCl3millions of shares) : 1,40 (m, N), is 3.08 (s, 3H), 2.95 and is 3.25 (m, 2H), of 3.78 (s, 3H), 3,89 is 4.35 (m, 2H), 4.95 points (m, 1H), 5,52 (d, 1H), 7,35 (m, 2H), 7,60 (m, 2H).

Mass (FAB, m/e): 376 (M+1).

9.

Obtaining methyl ester 1-{ [3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}acetic acid.

Connection (0,57 g of 1.52 mmol) obtained in the Obtaining 8, was dissolved in dichloromethane (2 ml) and then cooled to -10oC and to it was added triperoxonane acid (TFU, 2 ml). The reaction mixture was stirred for 5 minutes, slowly warmed up to room temperature, was stirred for 30 minutes and then concentrated under reduced pressure to remove volatiles. The residue was dried using a vacuum pump and then to it was added DMF (10 ml). This solution was cooled to-anerror and was stirred for approximately 5 minutes and then there was added 2-naphthalenesulfonate (0,41 g, 1.82 mmol). The reaction mixture was stirred for one hour to complete the reaction and then distilled under reduced pressure to remove volatiles. The residue was diluted with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and the residue was purified by the method of column chromatography using ethyl acetate/hexane (1/1, by volume) as eluent, to obtain the purified compound indicated in heading (0,55, Yield: 78%).

1H NMR (CDCl3millions of shares) : is 2.88 (s, 3H), 2,80-3,20 (m, 2H), 3,80 (d, 3H), of 4.12 (d, 2H), 4,58 (m, 1H), 6,40 (d, 1H), 7,20-to 8.40 (m, 11N).

Mass (FAB, m/e): 466 (M+1).

Example 25.

Obtaining methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}acetic acid.

The compound (0.55 g, 1.18 mmol) obtained in the Obtaining 9, was dissolved in pyridine (10 ml) and the resulting solution was placed in a flask with fittings to which was added triethylamine (0.45 ml). The reaction flask was equipped in such a way that gaseous hydrogen sulfide (H2S) could be entered through a single fitting bulb, and output through the other fitting. The reaction solution was saturated with gaseous Sernovodsk and then gradually dark brown. The flask was closed with a rubber stopper and left to stand for 3 days at room temperature. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. To the resulting yellow solid substance was added together acetone (10 ml) and itmean (CH3I, of 0.55 ml) and the mixture heated under reflux for 30 minutes. This reaction mixture was again distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. The residue was dissolved in absolute methanol (5 ml) and then stirred. To this solution in portions three times with an interval of 10 minutes was added 80% hydrazine hydrate (H2NNH2H2O, of 0.11 ml, 1.77 mmol). After the reaction was completed, the reaction solution was concentrated and was purified according to the method GHUR obtaining specified in the connection header (0,25, Yield: 43%).

1H NMR (CD3OD, millionths) : 2,95 (s, 3H), 2,70-3,20 (m, 2H), 3,54 (s, 3H), 3,80 (d, 2H), 4,55 (m, 1H), 7,20-8,30 (m, 11N).

Mass (FAB, m/e): 498 (M+1).

Example 26.

Receive { [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]metalmaterial (4 ml) of methanol and water (3:1). To this solution was slowly added a hydrate of lithium hydroxide (LiOHH2O 0,016 g, 0.38 mmol) at 0oC and the mixture was stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction solution was concentrated and was purified according to the method GHUR obtaining specified in the title compound (50 mg) Yield: 32%).

1H NMR (CD3OD, millionths) : 2,20-2,60 (m, 2H), 2,48 (s, 3H), 2,78 (s, 3H), 2,32 (m, 2H), 4,12 (m, 1H), 6,80-7,80 (m, 11N).

Mass (FAB, m/e): 484 (M+1).

Example 27.

Obtaining methyl ester (S)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid.

Used the same technique as in Obtaining 7, except that instead of methyl ester of glycine was used methyl ester (L)-alanine, to obtain the methyl ester (L)-(N-tert-butoxycarbonyl-N-methyl)alanine, which is then processed in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester (S)-2-{ [3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino]propionyl]methylamino} propionic acid (1,43 g). This intermediate compound was treated according to the same method as in Example 25, with the receipt of cleansing: 0,69, to 0.88 (d, d, 3H), 2,79, 2,95 (s, 3H), 2,80, a 3.06 (m, m, 2H), 3,48, of 3.57 (s, 3H), 4,29 (m, 1H), 4,55 (m, 1H), 7,30-8,30 (m, 11N).

Mass (FAB, m/e): 512 (M+1).

Example 28.

Receipt (S)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid.

The compound obtained in Example 27, was treated in accordance with the same method as in Example 26, to obtain the purified compound indicated in heading (0,06, Yield: 41%).

1H NMR (CD3OD, millionths) : 0,64, of 0.95 (d, d, 3H), was 2.76, of 2.92 (s, 3H), 2,83, to 3.09 (m, m, 2H), 4,37 (m, 1H), 4,54 (m, 1H), 7,30-to 8.40 (m, 11N).

Mass (FAB, m/e): 498 (M+1).

Example 29.

Obtaining methyl ester (R)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid.

Used the same technique as in Obtaining 7, except that instead of methyl ester of glycine was used methyl ether (D)-alanine, to obtain the methyl ester (D)-(N-tert-butoxycarbonyl-N-methyl)alanine, which is then processed in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester (R)-2-{ [3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino]propionyl]methylamino} about the in Example 25, obtaining a purified compound indicated in heading (0,58, Yield: 70%).

1H NMR (CD3OD, millionths) : 0,89, to 1.21 (d, d, 3H), 2,46, to 2.94 (s, 3H), 2,80, is 3.08 (m, m, 2H), 3,49, of 3.78 (s, 3H), 4,29 (m, 1H), 4,59 (m, 1H), 7,30-to 8.40 (m, 11N).

Mass (FAB, m/e): 512 (M+1).

Example 30.

Receive (R)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid.

The compound (0.03 g, 0,059 mmol) obtained in Example 29, was treated in accordance with the same method as in Example 26, to obtain the purified compound indicated in heading (0,01, Yield: 33%).

1H NMR (CD3OD, millionths) : 0,90, of 1.18 (d, d, 3H), 2,44, of 2.92 (s, 3H), 2,82, is 3.08 (m, m, 2H), 4,33 (m, 1H), to 4.62 (m, 1H), 7,30-to 8.40 (m, 11N).

Mass (FAB, m/e): 498 (M+1).

Example 31.

Obtaining methyl ester (R)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}-3-methylmalonic acid.

Used the same technique as in Obtaining 7, except that instead of methyl ester of glycine was used methyl ether (D)-valine, to obtain the methyl ester (D)-(N-tert-butoxycarbonyl-N-methyl)valine, which is then processed in accordance with the same method, and that is ffonline] propionyl] methylamino}-3-methylmalonic acid (0,19 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,11, Yield: 55%).

1H NMR (CD3OD, millionths) : 0,59, 0,70 (d, d, 3H), 0,89, and 0.98 (d, d, 3H), 2,09, of 2.21 (m, m, 1H), 2,75, a 3.06 (s, 3H), 3,40, 3,68 (s, 3H), 4,34, to 4.38 (d, d, 1H), 4,63, 4,70 (m, m, 1H), 7,20-to 8.40 (m, 11N).

Mass (FAB, m/e): 540 (M++1).

Example 32.

Receive (R)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}-3-methylmalonic acid.

The compound obtained in Example 31, was treated in accordance with the same method as in Example 26, to obtain the purified compound indicated in heading (0,04, Yield: 40%).

1H NMR (CD3OD, millionths) : 0,57, 0,63 (d, d, 3H), 0,92, 0,99 (d, d, 3H), 2,09, to 2.18 (m, m, 1H), 2,74, is 3.08 (s, 3H), 4,18, 4,36 (d, d, 1H), with 4.64, 4,70 (m, m, 1H), 7,20-to 8.40 (m, 11N).

Mass (FAB, m/e): 526 (M+1).

Example 33.

Obtaining methyl ester 3-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid.

Used the same technique as in Obtaining 7, except that instead of methyl ester of glycine was used methyl ether 3-aminopropyl then processed in accordance with the same method, that and Making 8 and 9, to obtain the intermediate product methyl ester 3-{[3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino]propionyl]methylamino}propionic acid (0,69 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,55, Yield: 74%).

1H NMR (CD3OD, millionths) : 8,31, 7,97, 7,68, 7,48 (d, m, m, m, 11N), 4,62, 4,51 (m, m, 1H), 3,62, 3,55 (s, 3H), 3,05, 2,85 (m, m, 4H), 2,80, of 2.45 (s, 3H), 2,38, at 1.91 (m, m, 2H).

Mass (FAB, m/e): 512 (M++1).

Example 34.

Obtain 3-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid.

The compound obtained in Example 33, was treated in accordance with the same method as in Example 26, to obtain the purified compound indicated in heading (0,17, Yield: 32%).

1H NMR (CD3OD, millionths) : 8,31, 7,98, 7,78-7,37 (d, m, m, 11H), 4,65, to 4.52 (m, m, 1H), 3,20-to 2.85 (m, 4H), 2,80, of 2.45 (s, 3H), 2,38, at 1.91 (m, m, 2H).

Mass (FAB, m.e): 498 (M++1).

Example 35.

Obtaining methyl ester 4-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}butyric acid.

Ispolniteley ether 4-aminobutyric acid, obtaining methyl ester (D)-(N-tert-butoxycarbonyl-N-methyl)valine, which is then processed in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester 4-{ [3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino] propionyl]methylamino}aminobutyric acid (0.51 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,40, Yield: 74%).

1H NMR (CD3OD, millionths) : 8,32 (s, 1H), 7,98 (m, 3H), 7,78 and 7.36 (m, 7H), 4,55 (m, 1H), 3.72 points, of 3.60 (s, 3H), 3,10, of 2.81 (m, m, 4H), 2,79, to 2.55 (s, 3H), 2,22 (m, 1H), 1,89 (m, 1H), 1,63, of 1.42 (m, m, 1H), 1,18 (m, 1H).

Mass (FAB, m/e): 526 (M++1).

Example 36.

Getting 4-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}butyric acid.

The compound obtained in Example 35, was treated in accordance with the same method as in Example 26, to obtain the purified compound indicated in heading (0,12, Yield: 32%).

1H NMR (CD3OD, millionths) : 8,32 (m, 1H), 7,98 (m, 3H), 7,78-7,35 (m, 7H), 4,55 (m, 1H), 3,05, of 2.81 (m, m, 4H), 2,79, of 2.50 (s, 3H), 2,18 (m, 1H), 1,89 (m, 1H), 1,35 (m, 1H), 1,16 (m, 1H).

Mass (FAB, m/e): 512 is luxusni acid.

Cyclopropylamine (1,34 g, 23,49 mmol) was mixed with DMF (15 ml) and triethylamine (3 ml) and the mixture was placed in a reaction vessel. In an addition funnel was placed methylbromide (2.2 ml, 23,49 mmol) and DMF (5 ml). The reaction vessel was cooled to 0oC and then the solution contained in the drip funnel was added dropwise into the reaction vessel. After the addition was finished the reaction mixture was heated to room temperature and allowed the reaction to proceed for 3.5 hours. After the reaction was completed, it was added water (10 ml) and 3 n sodium hydroxide. To the reaction mixture was added 1,4-dioxane (10 ml) followed by the addition of the anhydride of butyloxycarbonyl (6,1 g 27,95 mmol). The reaction mixture was left for reaction for 3 hours at room temperature and distilled under reduced pressure to remove volatiles. The residue was diluted with ethyl acetate, thoroughly washed with a saturated solution of sodium bicarbonate, diluted hydrochloric acid and brine. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure. The residue was purified by the method of column chromatography (eluent: ethyl acetate/hexa is H NMR (CDCl3millions of shares) : 3,95 (m, 2H), and 3.72 (m, 3H), 2,75, 2,52 (user. with user. s, 1H), 1,45, of 1.47 (s, N), 0,80-of 0.45 (m, 4H).

Mass (FAB, m/e): 230 (M++1).

Example 37.

Obtaining methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]cyclopropylamino}acetic acid.

The compound obtained in the Obtaining 10, processed in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester { [3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino]propionyl]cyclopropylamino}acetic acid (0,30 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,25, Yield: 77%).

1H NMR (CD3OD, millionths) : 8,24 (s, 1H), to 7.93 (m, 3H), of 7.65 (m, 3H), 7,42 (d, 2H), 7,35 (d, 2H), 5,02 (m, 1H), 3,92 (d, 1H), 3,64 (d, 1H), 3,60 (s, 3H), 3,19 (DD, 1H), 2,80 (m, 2H), 0.95, and 0.85 are 0,61 (m, m, m, 4H).

Mass (FAB, m/e): 524 (M++1).

Example 38.

Receive { [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]cyclopropylamino}acetic acid.

The compound obtained in Example 37, was treated in accordance with the same method as in Example 26, with millions of shares) : 8,24 (s, 1H), to 7.93 (m, 3H), 7,42 (d, 2H), 7,35 (d, 2H), 5,02 (m, 1H), 3,95 (d, 1H), 3,54 (d, 1H), 3,20 (DD, 1H), 2,80 (m, 2H), 0.95, and 0.85 are 0,61 (m, m, m, 4H).

Mass (FAB, m/e): 510 (M++1).

Example 39.

Obtaining methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]butylamino}acetic acid.

Used the same technique as in getting a 10, except that instead of cyclopropylamine used butylamine, to obtain the methyl ester of N-tert-butoxycarbonyl-N-butylaminoethyl acid, which is then processed in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester {[3- (4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino]propionyl]butylamino}acetic acid (0.31 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,19, Yield: 58%).

1H NMR (CD3OD, millionths) : 8,30-7,32 (m, 11N), 4,32-4.09 to (m, 3H), 3,55 (s, 3H), 3,57-of 2.50 (m, 4H), 1.26 in-0,50 (m, 7H).

Mass (FAB, m/e): 540 (M++1).

Example 40.

Receive { [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]butylamino}acetic acid.

The unique purified compounds specified in the header (0,12, Yield: 67%).

1H NMR (CD3OD, millionths) : 8,30-7,10 (m, 11N), or 4.31-4,10 (m, 3H), 3,52 is 2.55 (m, 4H), 1,25-0,50 (m, 7H).

Mass (FAB, m/e): 526 (M+1).

Example 41.

Obtaining methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]cyclopentylamine}acetic acid.

Used the same technique as in getting a 10, except that instead of cyclopropylamine used cyclopentylamine, to obtain the methyl ester of N-tert-butoxycarbonyl-N-Cyclopentasiloxane acid, which is then processed in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester {[3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino] propionyl] cyclopentylamine} acetic acid (0,23 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,12, Yield: 50%).

1H NMR (CD3OD, millionths) : 8,35-7,35 (m, 11N), 4,66, to 4.33 (m, m, 1H), 4,15 (m, 1H), 3,75, of 3.53 (m, m, 1H), 3,61 (s, 3H), 3,40 is 2.80 (m, 3H), 1,90 is 0.60 (m, 8H).

Mass (FAB, m/e): 552 (M++1).

Example 42.

Receive { [3-(4-imidazoline in Example 41, processed in accordance with the same method as in Example 26, to obtain the purified compound indicated in heading (0,4, Yield: 33%).

1H NMR (CD3OD, millionths) : 8,35-7,35 (m, 1H), 4,65, 4,32 (m, m, 1H), 4,15 (m, 1H), 3,75, to 3.52 (m, m, 1H), 3,41, 3,28-3,10, 2,80 (m, m, m, 3H), 1,90 is 0.60 (m, 8H).

Mass (FAB, m/e): 538 (M++1).

Receipt 11.

Obtaining methyl ester 1-(N-tert-butoxycarbonyl-N-methylamino)cyclopentanecarbonyl acid.

Cycloleucine (3 g, 23.2 mmol) was dissolved in 1N. aqueous solution of sodium hydroxide (23,2 ml) and distilled water (7 ml), and then thereto was added 1,4-dioxane (30 ml). To this mixture was added di-tert-BUTYLCARBAMATE (6,1 g, 27.8 mmol) at 0oC, the mixture was heated to room temperature and was stirred for 2 hours. Volatiles were removed from the reaction mixture under reduced pressure and the residue was diluted with ethyl acetate, thoroughly washed with aqueous saturated sodium hydrogen carbonate solution, diluted hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated. The obtained white solid product was dissolved in dimethylformamide (DMF, 30 ml). To this solution was added to the carbonate Kali the hours at room temperature and distilled under reduced pressure to remove volatiles. The remaining solution was diluted with ethyl acetate, thoroughly washed with aqueous saturated sodium hydrogen carbonate solution, diluted hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated. The obtained product was dissolved in dimethylformamide (DMF, 20 ml). To this solution was slowly added 60% sodium hydride (NaH, and 0.46 g of 11.4 mmol) at 0oC and then added dropwise itmean (CH3I, 1.8 ml, 28.4 mmol). The mixture was slowly heated to room temperature and was stirred for 3 hours at the same temperature. In the reaction mixture were added water in order to remove the remaining sodium hydride. The mixture was filtered and concentrated under reduced pressure. The residue was diluted with ethyl acetate, thoroughly washed with aqueous saturated sodium hydrogen carbonate solution, diluted hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified by the method of column chromatography using ethyl acetate/hexane (3/7 by volume) as an eluent to obtain purified compound indicated in heading (2,0, Yield: 34%).

1H NMR (CDCl3, milliner 43.

Obtaining methyl ester 1-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}cyclopentanecarboxylic acid.

The compound obtained in the Obtaining 11, were treated in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester 1-{ [3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino] propionyl] cyclopropylamino} cyclopentanecarboxylic acid (0.28 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,56, Yield: 53%).

1H NMR (CD3OD, millionths) : 0,52 (m, 1H), 0,89 (m, 2H), 1,29 (m, 2H), of 1.52 (m, 1H), 1,76 (m, 2H), 2.05 is (m, 1H), 2,75, 3,00 (m, m, 2H), 2,88 (s, 3H), 3,50 (s, 3H), 4,48 (m, 1H), 6,38 (m, 1H), 7,30-to 8.40 (m, 11N).

Mass (FAB, m/e): 552 (M+1).

Example 44.

Obtain 1-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}cyclopentanecarboxylic acid.

The compound obtained in Example 43 was treated in accordance with the same method as in Example 26, to obtain the purified compound indicated in heading (0,01, Yield: 17%).

1H NMR (CD3OD, millionths) : 0,42 (m, 1H),e): 538 (M+1).

Getting 12.

Obtaining the ethyl ester of 2-(N-tert-butoxycarbonyl-N-methyl)aminocyclopentane acid.

In the reaction vessel was placed ethyl-2-oxocyclopentanecarboxylate (10 ml, 67,49 mmol) with ethanol (100 ml). Then to dissolve the reagents, there was added methylaminopropane (4,69 g, 68,13 mmol) and water (10 ml). In the reaction vessel was added cyanoborohydride sodium (4.3 g, 68,43 mmol) and the pH of the mixture was brought to 6 and then left it for a reaction time of 12 hours or more at from 30 to 40oC. the Reaction mixture was then concentrated under reduced pressure, cooled to 0oC, brought the pH to 2 using 6 N. hydrochloric acid and washed three times with diethyl ether. The pH of the aqueous layer is again brought up to 10 and to it was added the same amount of dioxane. To this mixture was added 1 equivalent weight of the anhydride of butyloxycarbonyl. This reaction mixture was left for reaction for 3 hours at room temperature. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove volatile substances, diluted with ethyl acetate and thoroughly washed with a saturated solution of bicarbonate intothree the blockhead magnesium, was filtered and distilled under reduced pressure to remove solvent. The residue was purified by the method of column chromatography (eluent = ethyl acetate:hexane = 1:1 (by volume)) to obtain the purified compound indicated in the title (of 5.82, Yield: 32%).

1H NMR (CDCl3millions of shares) : 4,55 (m, 1H), 4,10 (m, 2H), and 2.79 (s, 3H), 2,73 (s, 1H), 2.00 in of 1.40 (m, 6N), 1,45 (s, N), of 1.24 (t, 3H).

Mass (FAB, m/e): 272 (M++1).

Example 45.

Obtaining the ethyl ester of 2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}cyclopentanecarboxylic acid.

The compound obtained in the Obtaining 12, were treated in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester 2-{ [3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino] propionyl] cyclopropylamino} cyclopentanecarboxylic acid (0,48 g). This intermediate compound is then treated in accordance with the same method as in Example 25, to obtain the purified compound indicated in heading (0,36, Yield: 71%).

1H NMR (CD3OD, millionths) : 8,39-7,25 (m, 11N), 4,78-and 4.40 (m, 2H), of 4.05 (m, 2H), 3,05 (m, 1H), 2,90-to 2.65 (m, 3H), 2,50-to 2.40 (m, 2H), 2,05, 1,90-1,30, 0,85 (m, m, m, 6N), 1,28-of 1.15 (m, 3H).

The compound obtained in Example 45, was treated in accordance with the same method as in Example 26, to obtain the purified compound indicated in heading (0,086, Yield: 25%).

1H NMR (CD3OD, millionths) : 8,39-7,20 (m, 11N), 4,78-4,50 (m, m, 2H), 3,05 (m, 1H), 2,90-to 2.40 (m, 5H), 2,10, 1,90-1,20, 0,75 (m, m, m, 6N).

Mass (FAB, m/e): 538 (M++1).

Example 47.

Obtaining methyl ester (S)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}-3-methylmalonic acid.

Carried out the same procedure as in Obtaining 7, except that instead of methyl ester of glycine was used methyl ester (L)-valine, to obtain the methyl ester (L)-(N-tert-butoxycarbonyl-N-methyl)valine, which is then processed in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester (S)-2-{ [3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino] propionyl] methylamino}-3-methylmalonic acid (0,13 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,09, Yield: 69%).

1H NMR (CD3OD, millionths) : 8,30, 7.95 Mass (FAB, m/e): 540 (M++1).

Example 48.

Obtaining methyl ester 1-([3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]piperidine-(R)-2-carboxylic acid.

Used the same technique as in Obtaining 7, except that instead of methyl ester of glycine was used methyl ether (D)-pipecolinic acid, and the resulting product is then treated in accordance with the same method that Receives, 8 and 9, to obtain the intermediate product methyl ester 1-{[3-(4-cyanophenyl)-(S)-2-(naphthalene-2-sulfonylamino]propionyl] piperidine-(R)-carboxylic acid (0.18 g). This intermediate compound was treated according to the same method as in Example 25, to obtain the purified compound indicated in heading (0,16, Yield: 84%).

1H NMR (CD3OD, millionths) : 8,32, 7,95, 7,78-7,35 (m, m, m, 11H), 4,71, to 4.52 (m, m, 1H), 3,97, of 3.80 (d, d, 1H), to 3.73, 3,43 (c, c, 3H), 3,10, 2,83, 2,39 (m, m, m, 3H), of 1.65 to 1.00, 0,30 (m, m, 6H).

Mass (FAB, m/e): 538 (M++1).

Example 49.

Obtaining 1-[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]piperidine-(R)-2-carboxylic acid.

The compound obtained in Example 48, was treated in accordance with the same method as in PR is SUB>3
OD, millionths) : 8,35, 8,00, 7,75-7,30 (m, m, m, 11N), 4,50, 4,20 (m, m, 1H), with 3.89 (m, 1H), 3,10, 2,82, of 2.45 (m, m, m, 3H), 2,10 (m, 1H), 1,65 of 1.00, 0.25 in (m, m, 6N).

Mass (FAB, m/e): 524 (M++1).

13.

Obtain (S)-4-[2-(butyloxycarbonyl)-3-(4-methylsulfonylbenzoyl)-3-oxopropyl]benzonitrile.

(S)-3-(4-Cyanophenyl)-2-(butyloxycarbonyl)propionic acid (0.5 g, 1.7 mmol) was dissolved in dimethylformamide (DMF, 20 ml) and then cooled to 0oC. Then, to this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 0.5 g) and 1-hydroxybenzotriazole (HOBT, 0.3 g) and stirred until then, until they are fully dissolved therein. To this reaction mixture was added 1-methanesulfonate (0.3 g) and N-methylmorpholine (0.2 ml) and then the reaction temperature was slowly raised to room temperature. The reaction solution was stirred for 3.5 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove volatile substances and the remaining solution was diluted with ethyl acetate, thoroughly washed with aqueous saturated sodium hydrogen carbonate solution, diluted hydrochloric acid and saturated saline, dried over anhydrous su is changing ethyl acetate/hexane (6/4, by volume) as eluent, to obtain the purified compound indicated in heading (0,7, Yield: 93%).

1H NMR (CDCl3millions of shares) : of 7.7 to 7.3 (m, 4H), to 5.3 (m, 1H), and 4.8 (m, 1H), 3,9-3,55 (m, 2H), 3,55-2,8 (m, 8H), and 2.7 (s, 3H), 1.5 a (s, N).

Getting 14.

Obtain [1-(4-cyanobenzyl)-2-(4-methylsulfonylbenzoyl)-2-oxoethyl] amide (S)-naphthalene-2-sulfonic acid.

Compound (0.7 g, 1.6 mmol) obtained in the Obtaining 13, was dissolved in dichloromethane (3 ml) and then cooled to -10oC and to it was added triperoxonane acid (TFU, 3 ml). The reaction mixture was stirred for 5 minutes, slowly warmed up to room temperature, was stirred for 3 minutes and then distilled under reduced pressure to remove volatiles. The remaining solution was dried using a vacuum pump and then to it was added 20 ml of DMF. The mixture was cooled to 0oC and to it was added 2-naphthalenesulfonate (0.5 g) and diisopropylethylamine (0.9 ml). This mixture was stirred until then, until all the reactants are not completely dissolved. The reaction mixture was slowly heated to room temperature and was stirred for 3 hours. The reaction solution was distilled under reduced pressure to do what astora of sodium bicarbonate, diluted hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by the method of column chromatography, using chloroform/methanol (95/5 by volume) as eluent, to obtain the purified compound indicated in heading (0,8, Yield: 95%).

1H NMR (CDCl3,, millionths) : of 8.3 to 7.2 (m, 11N), and 5.8 (m, 1H), and 4.5 (m, 1H), 3,5-3,2 (m, 2H), of 2.45 (s, 3H), 3,1-2,3 (m, 8H).

Example 50.

Obtain [1-(4-amerzone)benzyl] -2-(4-methylsulfonylbenzoyl)-2-oxoethyl]amide (S)-naphthalene-2-sulfonic acid.

Compound (0.4 g, from 0.76 mmol) obtained in the Obtaining 14, was dissolved in pyridine (5 ml) and the resulting solution was placed in a flask with fittings to which was added triethylamine (0.3 ml). The reaction flask was equipped in such a way that gaseous hydrogen sulfide (H2S) could slowly be introduced through one fitting bulb, and output through the other fitting. The reaction solution was saturated with gaseous hydrogen sulfide with stirring for about 10 minutes, and colorless solution was purchased green color and then gradually - dark brown. The flask was closed with a rubber stopper and left to stand for 3 days at to the of whcih substances and dried using a vacuum pump. To the resulting yellow solid substance was added together acetone (10 ml) and itmean (0.5 ml) and the mixture heated under reflux for 30 minutes. This reaction mixture was again distilled under reduced pressure to remove volatile substances and dried using a vacuum pump. The residue was dissolved in absolute methanol (5 ml) and then stirred. To this solution in portions three times with an interval of 10 minutes was added 80% hydrazine hydrate (0.06 ml). After the reaction was completed, the reaction solution was concentrated and then purified according to the method GHUR obtaining specified in the connection header (0,3, Yield: 65%).

1H NMR (CD3OD, millionths) : an 8.4 to 7.4 (m, 11N), and 4.6 (m, 1H), 3,5-3,2 (m, 2H), by 2.55 (s, 3H), 3,1-2,2 (m, 8H).

Mass (FAB, m/e): 559 (M++1).

Example 51.

Obtain [1-(4-amerzone)benzyl-2-oxo-2-(4-ethoxycarbonylphenyl)ethyl]amide (S)-naphthalene-2-sulfonic acid.

Used the same technique as in Obtaining 13, except that instead of 1-methysulfonylmethane used 1-piperidinecarboxylate, and the resulting product is then treated in accordance with the same method as in Obtaining 14, intermediate the, 1.9 mmol). This intermediate compound was treated according to the same method as in Example 50, to obtain the purified compound indicated in heading (0,6, Yield: 56%).

1H NMR (CD3OD, millionths) : 8,5-to 7.3 (m, 11N), 4,55 (m, 1H), of 4.05 (m, 2H), 3,2-2,4 (m, 10H), 1,2 (m, 3H).

Mass (FAB, m/e): 553 (M++1).

Example 52.

Obtain [1-(4-amerzone)benzyl-2-(4-formylpiperazine)-2-oxoethyl] amide (S)-naphthalene-2-sulfonic acid.

Used the same technique as in Obtaining 13, except that instead of 1-methysulfonylmethane used 1-piperazinecarboxamide, and the resulting product is then treated in accordance with the same method as in Obtaining 14, to obtain the intermediate product [1-(4-cyanobenzyl)-2-(4-formylpiperazine)-2-oxoethyl] amide (S)-naphthalene-2-sulfonic acid (7 g, 1.6 mmol). This intermediate compound was treated according to the same method as in Example 50, to obtain the purified compound indicated in heading (0,5, Yield: 62%).

1H NMR (CD3OD, millionths) : at 8.36-7,44 (m, 11N), 4,60 (m, 1H), 3.46 in is 2.80 (m, N), to 2.55 (m, 1H).

Mass (FAB, m/e): 509 (M++1).

Example 53.

The floor is Used the same technique that and Getting 13, except that instead of 1-methysulfonylmethane used 1-ethylpiperazin, and the resulting product is then treated in accordance with the same method as in Obtaining 14, to obtain the intermediate product [1-(4-cyanobenzyl)-2-(4-ethylpiperazine)-2-oxoethyl]amide (S)-naphthalene-2-sulfonic acid (0.3 g, 0.6 mmol). This intermediate compound was treated according to the same method as in Example 50, to obtain the purified compound indicated in heading (0,2, Yield: 56%).

1H NMR (CD3OD, millionths) : 8,5-to 7.3 (m, 11N), and 4.6 (m, 1H), 3,5-2,7 (m, 10H), 2,2 (s, 2H), 1,4-1,2 (m, 3H).

Mass (FAB, m/e): 509 (M++1).

Example 54.

Obtain [1-(4-amerzone)benzyl-2-oxo-2-(4-phenylpiperazine)ethyl] amide (S)-naphthalene-2-sulfonic acid.

Used the same technique as in Obtaining 13, except that instead of 1-methysulfonylmethane used 1-phenylpiperazin, and the resulting product is then treated in accordance with the same method as in Obtaining 14, to obtain the intermediate product [1-(4-cyanobenzyl)-2-oxo-2-(4-phenylpiperazine)ethyl] amide (S)-naphthalene-2-sulphonic acid (0.5 g, 0.97 mmol). This intermediate swedicising in the header (0,3, Yield: 57%).

1H NMR (CD3OD, millionths) : 8,35-rate of 7.54 (m, 11N), 7,20 (m, 2H), 6,86 (m, 1H), 6,67 (m, 2H), 4,56 (m, 1H), of 3.45 (m, 1H), 3.25 to 2,92 (m, 5H), and 3.72 (m, 2H), 2,42 (m, 1H), 2.05 is (m, 1H).

Mass (FAB, m/e): 557 (M++1).

Example 55.

Obtain [1-(4-amerzone)benzyl-2-oxo-2-[4-(3-triptoreline)piperazinil]ethyl]amide (S)-naphthalene-2-sulfonic acid.

Used the same technique as in Obtaining 13, except that instead of 1-methysulfonylmethane used 1-(,,--trifter-m-tolyl)piperazine, and the resulting product is then treated in accordance with the same method as in Obtaining 14, to obtain the intermediate product [1-(4-cyanobenzyl)-2-oxo-2-[4-(3-triptoreline)piperazinil)ethyl] amide (S)-naphthalene-2-sulphonic acid (0.5 g, 0.8 mmol). This intermediate compound was treated according to the same method as in Example 50, to obtain the purified compound indicated in heading (0,3, Yield: 55%).

1H NMR (CD3OD, millionths) : 8,35 to 6.7 (m, 15 NM), 3,47 (m, 1H), 3,3-3,0 (m, 5H), 3,76 (m, 2H), 2,45 (m, 1H), 2,03 (m, 1H).

Mass (FAB, m/e): 625 (M++1).

Example 56.

Obtaining [2-(4-acetylpiperidine)-1-(4-amerzone)benzyl-2-oxoethyl]amide (S)-naphthalene-2-sulfamethoxypyrazine used 1-acetylpiperidine, and the resulting product is then treated in accordance with the same method as in Obtaining 14, to obtain the intermediate product [2-(4-acetylpiperidine)-1-(4-cyanobenzyl)-2-oxoethyl] amide (S)-naphthalene-2-sulfonic acid (1.25 g, 2.55 mmol). This intermediate compound was treated according to the same method as in Example 50, to obtain the purified compound indicated in heading (0,7, Yield: 53%).

1H NMR (CD3OD, millionths) : an 8.4 to 7.4 (m, 11N), and 4.5 (m, 1H), 3,5-3,2 (m, 2H), 3,1-2,2 (m, 8H), 2,0 (s, 3H).

Mass (FAB, m/e): 523 (M++1).

Example 57.

Obtain [1-(4-amerzone)benzyl-2-oxo-2-[4-(2-hydroxy)ethylpiperazine]ethyl]amide (S)-naphthalene-2-sulfonic acid.

Used the same technique as in Obtaining 13, except that instead of 1-methysulfonylmethane used 1-piperazine, and the resulting product is then treated in accordance with the same method as in Obtaining 14, to obtain the intermediate product [1-(4-cyanobenzyl)-2-oxo-2-[4-(2-hydroxyethyl)piperazinil] ethyl]amide (S)-naphthalene-2-sulfonic acid (0.07 g, 0.14 mmol). This intermediate compound was treated according to the same method as in Example 50, with Poluchenie share) : 8,35-7,30 (m, 11N), 4,60 (m, 1H), 3.96 points to 3.7 (m, 4H), 3,70 is 2.80 (m, 10H).

Mass (FAB, m/e): 525 (M++1).

Example 58.

Obtain [1-(4-amerzone)benzyl-2-oxo-2-[4-(2-ethoxyphenyl)ethylpiperazine]ethyl]amide (S)-naphthalene-2-sulfonic acid.

Used the same technique as in Obtaining 13, except that instead of 1-methysulfonylmethane used 1-(2-ethoxyphenyl)piperazine, and the resulting product is then treated in accordance with the same method as in Obtaining 14, to obtain the intermediate product [1-(4-cyanobenzyl)-2-oxo-2-[4-(2-ethoxyphenyl)piperazinil] ethyl] amide (S)-naphthalene-2-sulfonic acid (0.4 g, 0.7 mmol). This intermediate compound was treated according to the same method as in Example 50, to obtain the purified compound indicated in heading (0,26, Yield: 62%).

1H NMR (CD3OD, millionths) : at 8.36-6,54 (m, 15 NM), and 4.6 (m, 1H), 4,01 (m, 2H), 3,48 (m, 1H), 3,28-is 3.08 (m, 5H), 2,69 (m, 2H), of 2.38 (m, 1H), 2,08 (m, 1H), 1,35 (m, 3H).

Mass (FAB, m/e): 601 (M++1).

Test 1: inhibitory activity against thrombin.

The ability of the compounds of the present invention to inhibit the activity of thrombin was determined as described in further.

1.5 ml of cell Dona weight of about 8000). Chromosom TN was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mm and the resulting solution was diluted specified Tris-buffer solution to a concentration of 0.1 mm, which is then used as the substrate solution. In the cuvette was added 225 ál of 0.1 mm thus prepared substrate solution. The inhibitor solution was prepared by dissolving compounds of the thrombin inhibitor according to the present invention in dimethyl sulfoxide at a concentration of 10 mg/ml and further diluting the resulting solution specified Tris-buffer solution to a concentration of 0.1 mg/ml, 0.01 mg/ml, 0.001 mg/ml and 0.0001 mg/ml of the resulting solution of the inhibitor was taken in an amount corresponding to the value from 0 to 10 μg of inhibitor and then diluted with Tris buffer to a total volume of 100 μl, which was then added to the cuvette.

15 μl of a solution of bovine thrombin dissolved in the above Tris buffer solution at a concentration of 0.1 mg/ml, was added to the cuvette to initiate the reaction of enzymatic hydrolysis. The number of para-nitroaniline formed within 2 minutes after the introduction of the enzyme was monitored by measuring the absorption at 381 nm. Was received continuous absorption spectrum for the reaction time. Such expertise is I each spectrum, based on the value of the angle in the first 30 seconds of reaction time, received the value of the initial velocity Viand then build the graph of the inverse of the initial velocity (1/Vi) on the concentration of the inhibitor. Based on the graph, received primary equation, corresponding to the points shown on the graph, and then calculated the value of Kion the basis of cut, clip on the x-axis of the primary equation, using equation enzymatic reaction. The value of Kmapplied for this calculation, was 8.3 μm, which was obtained by changing the substrate concentration at a constant concentration of enzyme.

The value of the rate constant Ksreceived, applying the same solution in the same concentration as in the determination of the values of Kibut using the following methodology of the experiment.

Namely, in a 1.5 ml cuvette was added 1160 μl of buffer solution and there was added 15 μl of a solution of bovine thrombin, having a concentration of 0.1 mg/ml, and 100 μl of the inhibitor solution. The mixture was stirred at room temperature for 15 minutes. Then when you add 225 ál of 0.1 mm solution of the substrate was monitored by absorption changes over time within 2 minmachine Vs. A similar experiment was carried out with different concentrations of the inhibitor, thus obtaining the value of Vsfor each concentration of inhibitor, which built a plot of 1/Vsconcentration of inhibitor. Based on the graph, received primary equation, corresponding to the points shown on the graph, and then calculated the value of Kion the basis of cut, clip on the x-axis of the primary equation, using equation enzymatic reaction.

Regardless of this, in the same way as when determining inhibitory activity against thrombin, as described above, determined the inhibitory activity of the compounds of the present invention with respect to trypsin.

As the substrate was applied a 20 μm solution of N-benzoyl-Val-Gly-Arg-p-nitroanilide, and the inhibitor was used in various concentrations in the range from 0 to 120 mcg. In addition, in HCl 0.1 N. dissolve trypsin, brought to a concentration of 45 μg/ml of the specified buffer solution immediately before the experiment and then used in the amount of 40 μl. As in the experiment with thrombin, the total volume of the reaction solution was 1.5 ml and the remaining procedures were performed in the same way. The Value Of Carimate, described above, and it was 20.2 microns.

Inhibitory activity of the compounds of the present invention in relation to the activity of any enzyme, which was determined in accordance with the above methodology, presented in the form of values of Kiand Ksand selectivity against thrombin was represented by the value of the ratio of inhibitory activity against trypsin/inhibitory activity against thrombin. Thus obtained results are described in table. 1.

Test 2: pharmacokinetic test.

The methodology for conducting the test.

Male rats were subjected to fasting for 24 hours and used as experimental animals. Prepared 1% solution (10 mg/ml) of the compound from Example 1, using saline solution and then introduced his experimental animals intravenously and orally. At set intervals the animals were taken blood samples and immediately mixed with methanol and zinc sulfate. Finally, the top layer of the mixture was subjected to quantitative analysis in the ultraviolet region at a wavelength of 231 nm according to the method GHUR for measuring the concentration of drug in the blood.

Re the I from Example 1 after intravenous and oral administration are shown in table. 2 - 7. When the compound from Example 1 was injected intravenously, it was quickly distributed and then for a long time disappeared as in the case of rats, and dogs, whereas the half-life connections in dogs was twice or more higher than in rats. Moreover, the half-life of the compound from Example 1 was twice or more higher than such sales argatroban (40 minutes) the person (Osamu et al. Pharmacology and Therapy, volume 14, app. 5, 1986). Meanwhile, can also be determined that the bioavailability of the compound from Example 1 was 15% for rats and 61% for dogs by oral administration. However, it was reported that argatroban not absorbed in the animal and human organism, introduced orally.

As can be seen from the above results, the compound of Example 1 showed a better pharmacokinetic characteristics than argatroban, suction oral application time and half-life.

Although this invention is described in its preferred form with a certain degree of specificity, specialists in this area take into account the fact that the present description of a preferred form is shown only as an example and that you can resort to numerous S="ptx2">

1. Selectively acting thrombin inhibitors of General formula I

< / BR>
and their isomers,

where R1represents acetyl, substituted naphthyl or naphthyloxy, or sulfonyl, substituted naphthyl, which, in turn, can be substituted by a lower alkoxy group, dialkylamino; or substituted by phenyl which, in turn, substituted lower alkyl, lower alkoxygroup;

X represents a group of formula or

R2and R3independently of one another represent hydrogen, C3- C6-cycloalkyl, which can be substituted by carboxyla; hydroxy; lower alkyl, unsubstituted or substituted by methoxycarbonyl, hydroxy, carboxyla; or R2and R3together with the nitrogen atom to which they are attached, may form piperidino group, substituted carboxyla;

R4represents hydrogen;

R5represents methanesulfonyl, formyl, alkoxycarbonyl, phenyl, unsubstituted or substituted by trifluoromethyl or alkoxygroup,

R6represents hydrogen;

R7represents lower alkyl, amino; provided that when R1- naphthyl, X cannot be a group

in which R2
R2and R3independently of one another represent C3-6cycloalkyl, which can be substituted by carboxyla; lower alkyl, substituted or unsubstituted carboxyla, methoxycarbonyl or hydroxy; or hydroxy, or R2and R3together with the nitrogen atom to which they are attached, may form piperidino group, substituted carboxyla, R4represents hydrogen, R5represents methanesulfonyl, etoxycarbonyl, formyl, or phenyl which can be substituted by trifluoromethyl or ethoxy, R6represents hydrogen and R7represents a methyl or amino.

3. The compound of formula I on p. 2, where the compound is selected from the group including: (S)-N-cyclopentyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide, (S)-N-butyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide, (S)-N-cyclopentyl-N-propyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide, (S)-N-cyclopentyl-N-butyl-3-(4-emersonian)-2-(2-naphthylamine)Protel-3-[4-(methylamino)phenyl] -2-(2-naphthylamine)propionamide, (S)-N-cyclopentyl-N-methyl-3-[4-(1,1-dimethylamino)phenyl] -2-(2-naphthylamine)propionamide, (S)-N-cyclopentyl-N-methyl-3-(4-emersonian)-2-[(4-methoxy-2,3,6-triptoreline)sulfonylamino] propionamide, (S)-N-cyclopentyl-N-hydroxy-3-(4-emersonian)-2-(2-naphthylamine)propionamide, (S)-N-cyclopentyl-N-(2-hydroxyethyl)-3-(4-emersonian)-2-(2-naphthylamine)propionamide, (S)-N-cyclopentyl-N-methyl-3-[4-(methylamino)phenyl]-2-[(4-methoxy-2,3,6-trimethylbenzene)sulfonylamino] propionamide, (S)-N,N-dimethyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide, (S)-N, N-dimethyl-3-[4-(1-methylamino)phenyl] -2-(2-naphthylamine)propionamide, (S)-N-cyclohexyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide, (S)-N-cyclopropyl-N-methyl-3-(4-emersonian)-2-(2-naphthylamine)propionamide, (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(2-naphthalene-1-ylacetamide)propionamide, (S)-3-[4-(emigrate)phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylaminonaphthalene-1 sulfonylamino)propionamide, (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(5-methoxynaphthalene-1 sulfonylamino)propionamide, (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-(6,7-dimethoxyaniline-2-sulfonylamino)propionamide, (S)-3-[4-(methylamino)phenyl] -N-Ciclopi-2-(naphthalene-2-sulfonylamino)propionamide, (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-[2-(naphthalene-1-yloxy)acetylamino] propionamide, (S)-3-[4-(emigrate)phenyl] -N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-yloxy)acetylamino] propionamide, methyl ester {[3-(4-(emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino} acetic acid, {[3-(4-(emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino} acetic acid, methyl ester (S)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}propionic acid, (S)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino} propionic acid, methyl ester (R)-2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino} propionic acid, (R)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino} propionic acid, methyl ester (R)-2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}-3-methylmalonic acid, (R)-2-{ [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]methylamino}-3-methylmalonyl acid, methyl ester 3-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino} propionic acid, 3-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propio is of IMT] methylamino}butyric acid, 4-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}butyric acid methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] cyclopropylamino}acetic acid, {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] cyclopropylamino} acetic acid, methyl ester {[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] butylamino} acetic acid, { [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] butylamino} acetic acid, methyl ester { [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] cyclopentylamine} acetic acid, { [3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] cyclopentylamine} acetic acid, methyl ester 1-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino} cyclopentanecarbonyl acid, 1-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}cyclopentanecarbonyl acid, ethyl ester of 2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino} cyclopentanecarbonyl acid, 2-{[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] methylamino}cyclopentanecarbonyl acid, methyl ester (S)-2-{[3-(4-amid emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl] piperidine-(R)-2-carboxylic acid, 1-[3-(4-emersonian)-(S)-2-(naphthalene-2-sulfonylamino)propionyl]piperidine-(R)-2-carboxylic acid [1-(4-amerzone)benzyl-2-oxo-2-(4-methylsulfonylbenzoyl)-2-oxoethyl] -amide (S)-naphthalene-2-sulfonic acid [1-(4-amerzone)benzyl-2-oxo-2-(4-ethoxycarbonylphenyl)ethyl] -amide (S)-naphthalene-2-sulfonic acid [1-(4-amerzone)benzyl-2-(4-formylpiperazine)-2-oxoethyl] -amide (S)-naphthalene-2-sulfonic acid [1-(4-amerzone)benzyl-2-(4-ethylpiperazine)-2-oxoethyl] amide (S)-naphthalene-2-sulfonic acid [1-(4-amerzone)benzyl-2-oxo-2-(4-phenylpiperazine)ethyl] amide (S)-naphthalene-2-sulfonic acid [1-(4-amerzone)benzyl-2-oxo-2-[4-(3-triptoreline)-piperazinil)ethyl]amide (S)-naphthalene-2-sulfonic acid [2-(4-acetylpiperidine)-1-(4-amerzone)benzyl-2-oxoethyl] amide (S)-naphthalene-2-sulfonic acid [1-(4-amerzone)benzyl-2-oxo-2-(4-(2-hydroxyethyl)piperazinil)ethyl] amide (S)-naphthalene-2-sulfonic acid [1-(4-amerzone)benzyl-2-oxo-2-(4-(2-ethoxyphenyl)piperazinil)ethyl]amide (S)-naphthalene-2-sulfonic acid.

4. Pharmaceutical composition having inhibitory activity against thrombin, including an active ingredient and a pharmaceutically acceptable carrier, characterized in that quality

 

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