Sulphametoxazole, their hydrates and physiologically acceptable salts, pharmaceutical composition based on them

 

(57) Abstract:

Describes the new sulphametoxazole General formula (I) where the values a, U, X specified in paragraph 1 of the claims with antiplatelet and anticoagulant activity. Describes their hydrates and physiologically acceptable salts, having the property to suppress amylolyticus the activity of thrombin, as well as pharmaceutical composition based on compounds of the formula (I) having the above properties. 2 C. and 15 C.p. f-crystals, 2 tab.

The invention relates to new sulphonamidesblocked formula

< / BR>
where X is a group of the formula X1or X2< / BR>
< / BR>
T is CH2or O,

R1is hydrogen or-COO-lower alkyl;

R2, R11and R21represent hydrogen;

Y is hydrogen;

A stands for lower alkyl; phenyl, unsubstituted or substituted lower alkyl, triptorelin group, the group-COOH or-COO-lower alkyl, cryptomaterial, cyano, cyclopentyl, phenyl, CONH2, tetrazolium; naphthyl, heterocycle, including heteroaryl consisting of one or two rings containing at least one nitrogen atom and which may carry substituents,-COOH or-COO-lower alkyl;

M is a group M1or M2formulas

< / BR>
where R3represents hydrogen, lower alkyl or alanyl, phenyl, heteroaryl consisting of 6-membered rings with one nitrogen atom, C3-C6-cycloalkyl, lower alkyl, substituted C3-C6-cycloalkyl, phenyl, optionally substituted with halogen or lower alkoxyl, heteroaryl consisting of 6-membered rings with one nitrogen atom;

R4denotes hydrogen or lower alkyl;

R5denotes hydrogen, lower alkyl or optionally linked through the lowest alkylen COOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, lower alkoxy, phenyl-lower alkoxy, CONH2, NHCOO-lower alkyl, CONHCH2CH2OH, CONHOH, CONHOCH3, CONHO-benzyl, CONHSO2-lower alkyl, CONHCH2CH2is phenyl which may be substituted by two OH-groups, CONH-cycloalkyl, NH2, NHCOO-benzyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH-(3,4-dioxo-2-oxocyclopent-1-enyl), NH-[2-lower-alkoxy or-alkenylamine)-3,4-dioxocyclohex-1-enyl], NHCH2-heteroaryl, NHCOCO-(phenyl or lower alkyl), NHCOCH2Cl, NHCOCH2O-phenyl, NHCOCH2-phenyl, NHCO-aryl or heteroa the ideal N-oxide, NHPO3(R9, R10), heteroaryl or optional open oxygen-CON(CH2)4-9;

R9and R10denote hydrogen, lower alkyl or phenyl;

N(R6) - benzylamino or-N(CH2)4-9;

as well as hydrates and their physiologically acceptable salts.

In addition, the invention concerns a method of obtaining the above-mentioned compounds, pharmaceutical compositions containing these compounds, and the use of these compounds to obtain a pharmaceutical composition.

Examples of physiologically usable salts of the compounds of formula I are salts with physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid, sulfurous or phosphoric acid; or with organic acids, such as methanesulfonate, n-toluensulfonate, acetic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula I with acid groups, such as carboxypropyl, can also form salts with physiologically suitable bases. Examples of such salts are alkali metal salts, alkaline earth salt is inane formula I can also be in the form amphoteric ion.

The compound of formula I may also be solvated, in particular gidratirovana. Hydration can be carried out in the course of the method of obtaining or can occur gradually as a consequence of hygroscopic properties initially anhydrous compound of formula I.

The compound of formula I contains at least two asymmetric C atom and therefore can be represented in the form of a mixture of diastereomers or as optically pure compounds.

In the framework of the invention, the expression "lower" means a group containing 1-6, preferably 1-4, carbon atoms. So, lower alkyl refers to groups with unbranched or branched chain containing 1-6, preferably 1-4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl and pentyl. An example for the lowest alkenyl is allyl.

Phenyl and 1 - or 2-naphthyl, under certain conditions, may bear one or more substituents, such as halogen, for example chlorine, or lower alkyl or alkoxy, for example CH3, tert-butyl, OH, OCH3, phenyl, CF3, OCF3cyclopentyl, CN, COOH, COOCH3, COOC2H5, CONH2or tetrazolyl.

Heteroarylboronic are 5-10-membered aromatic GRU is I 2-, 3 - or 4-pyridyl, also in the form of their N-oxides, tetrazolyl, oxadiazolyl, pyrazinyl and finalyl. They can be substituted, for example lower alkyl, such as, for example, CH3or halogen, such as chlorine.

Cycloalkyl groups contain 3 to 6 carbon atoms. Examples are cyclopropyl, cyclopentyl and cyclohexyl.

Heterocyclyl refers to a 5-10 membered non-aromatic, partially or fully saturated group, as, for example, tetrahydropyranyl containing 1 or 2 rings, and at least one heteroatom, for example, one atom of nitrogen and under certain conditions substituted by one or more substituents, such as lower alkyl, for example, stands.

Examples of groups N(CH2)4-9not necessarily open O, are hexahydroazepin and morpholine.

Examples of compounds of formula I are those compounds where: X is a group of X1in which R1and R2denote hydrogen, Y denotes hydrogen, A, Q have the meanings indicated above, M denotes the group of M1in which R3and R4have the meanings specified above, and if Q, R3and R5simultaneously denote hydrogen, R4cannot be hydrogen; R52, NHCOO-lower alkyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-Nishi alkyl or NHPO3(R9, R10), or if Q denotes H, then M can also be a group of M2where N(R6) denotes the N(CH2)4-9.

Other examples of compounds of formula I are those compounds where Y denotes H, X is a group of X2and M is a group M1or M2.

Preferred are compounds where A denotes naphthyl, methilhill, methyltetrahydrofuran, methyl, pyridyl or phenyl, substituted tert-bootrom, triptorelin group, phenyl, cyclopentyl, group-COOH, methoxycarbonyl, etoxycarbonyl, cryptomaterial, CN, CONH2or tetrazolium.

Preferred compounds where Q denotes H, CH3CH2COOH, CH2CH2OH or CH2COOC2H5.

Preferred are compounds where X denotes the group of X1, T denotes CH2one of R1denotes H or COO-(methyl, ethyl, isobutyl or tert-butyl), and R2denotes H.

Another preferred group of compounds are compounds oznachaet H.

In addition, preferred compounds where X denotes the group of X2and R11and R21denote h

Preferred are also compounds, where M denotes the group of M1, R3denotes H, CH3, propyl, isopropyl, butyl, pentyl, allyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, and R4denotes H, isopropyl, 2-butyl, isobutyl, and compounds, where R5matter R50or-CH2R50or-CH2CH2R50where R50denotes H, OH, COO-(H, CH3or C2H5), NHCOOCH3, CONH2, COCH3, NHCOCH3.

In addition, preferred compounds where M denotes the group of M2and N(R6) denotes hexamethylenimine.

Examples of preferred compounds are:

N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl]-N2-(2-naphthyl-sulfonyl)- L-asparaginyl]-N-cyclopropylmethyl,

(S)-[[3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2-(naphthalene - 2-sulfonylamino)propionyl]cyclopropylamino]propionic acid,

[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval]-2-(4 - triftormetilfullerenov)propionylthiocholine]acetic acid.

Other examples before the-3-ylmethyl]-N1-carboxymethyl-N1 - cyclopentyl-2-(naphthalene-2-sulfonylamino)succinamide,

(S)-3-[(S)-2-(aminoiminomethyl)piperidine-3-letiltasaval] -2-(naphthalene-2 - sulfonylamino)propionyl]propylaminosulfonyl acid,

N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-naphthyl-sulfonyl)-L - asparaginyl]-N-(o-Chlorobenzyl)glycine,

[2-[[(S)-3-[(S)-1-(aminoiminomethyl)piperidinyl-3-ylmethyl-carbarnoyl] 2-(naphthalene - 2-sulfonylamino)propionyl]butylamino]ethyl]aksenovoy acid,

(S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-butyl-2- (naphthalene-2-sulfonylamino)-N1-(2-sulfonylated)succinamide,

[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] 2- (4-tert-butylphenylphosphine)-propionylcarnitine]acetic acid.

Preferred compounds representing:

3-[[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-ylcarbonyl] -2- (4-carbamoyltransferase)propionyl]cyclopropylamino]propionic acid.

(S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-cyclopropyl-2- (naphthalene-2-ylsulphonyl)-N1-[2-pyrazin-2-ylcarbonyl)ethyl] succinamic,

(S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-cyclopropyl-N1- [2-(3,4-dioksifenil)ethylcarbamate] -2-(2-naphthylamine)succinamic.

In addition, preferred are the following compounds:
3-[[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-ylcarbonyl] -2-4-sanofisynthelabo)propionyl]cyclopropylamino]propionic acid,

(S)-N(4)-[4-(aminoiminomethyl)morpholine-2-ylmethyl] -N(1)-cyclopropyl-N(1)- (tetrazol-5-yl)ethyl]-2-(naphthalene-2-ylsulphonyl)succinamide,

complex ethyl ester [[(S)-3-[4-(aminoiminomethyl)morpholine-2-letiltasaval] -2-(naphthalene-2 - ylsulphonyl)propionyl] cyclopropylamino]ukusnoj acid,

[[(S)-3-[4-(aminoiminomethyl)morpholine-2-letiltasaval] -2-(naphthalene - 2-ylsulphonyl)propionylthiocholine]acetic acid,

2-[[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2-(naphthalene - 2-ylsulphonyl)propionyl] cyclopropylamino] ethylsulfinyl,

(S)-N4-[(S)-1(aminoiminomethyl)piperidine-3-ylmethyl] -N1(2-chloracetamide)- N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-cyclopropyl-2- (naphthalene-2-ylsulphonyl)-N1-(2-phenoxyethylamine)succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-cyclopropyl-2- (naphthalene-2-ylsulphonyl-N1-[2-(2-oxo-2-phenylacetylamino)ethyl] succinamic,

(S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-cyclopropyl-2- (naphthalene-2-ylsulphonyl)-N1-[aftalen-2-ylsulphonyl)-N1-[2-(pyridine-3-ylcarbonyl)ethyl]succinamic,

(S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-cyclopropyl-2- (naphthalene-2-ylsulphonyl)-N1-[2-(1-oxycodoneonline)ethyl]succinamic.

Videoarchive sulphametoxazole have the ability to suppress amylolyticus the activity of thrombin.

The compounds of formula I can be obtained in a known manner, namely, that

a) acid formula

< / BR>
subjected to interaction with the amine of the formula

Q - NHCH2- X

or its salt, using the protection of functional groups contained in the groups A, Y and M (II) and Q (III) or

b) an amine of the formula

< / BR>
where X3is a group of X31or X32.

< / BR>
subjected to interaction with amidenus agent and

C) optionally, a reactive group contained in the group M or Q the compounds of formula I is converted into another functional group;

g) if necessary, the compound of the formula I is converted into a physiologically suitable salt or the salt of the compounds of formula I is converted into the free acid or base.

It is advisable to process the interaction of acid lead II in a solvent such as dimethylformamide (DMF) or methylene chloride, in the presence of I-7-ene (DBU), using the salt of the compounds of formula III, for example, triptorelin, bisulfite, nitrate, hydrochloride or hydroiodide, and benzotriazol-1 yloxy-Tris(dimethylamino)phosphodiesterase (BOP) at room temperature. Contained in the compounds II and III intermediate protected functional group, such as COOH, NH2and OH can be protected in the form of lower alkilani groups, benzilate or sidegroup or benzyloxy. Cleavage of the protected carboxypropyl, as, for example, COOCH3or COOC2H5to obtain COOH may be sodium hydroxide in ethanol. Translation OCONH - or N3group to the free amino group can be accomplished by catalytic (Pd/C) hydrogenation in ethanol.

According to the variant of the method b) compound IV in a solvent such as, for example, DMF or methanol, in the presence of a base, such as, for example, triethylamine, is subjected to the interaction with formamidinesulfinic or 3,5-dimethyl-1-personaltraining.com, preferably at a temperature of up to 50oC.

As functional transformations on option b) include the following:

1. Saponification of the group of ester, such as, for example, ethoxycarbonyl such as the to, for example, acetoxy, for example, in THF using a base, for example, aqueous LiOH.

2. Hydrogenation of the double bond in alkaleri, for example in ethanol and water in the presence of Pd/C.

3. Hydrogenation of airgroup to obtain the corresponding cycloalkyl, for example, in ethanol in the presence of acetic acid and PD/C

4. The simple splitting of the ether, such as, for example, a simple benzyl ester to obtain the corresponding alcohol, for example, with a solution of tribromide boron in methylene chloride.

5. Etherification of the alcohol, for example, the lower alkylhalogenide, such as methyliodide, in the presence of a solution of DBU in THF.

6. The transformation of the carboxylic acid in the carboxylic acid amide by reaction with an amine, such as morpholine, for example, in DMF in the presence of BOP and 4-ethylmorpholine.

7. a) Converting, if necessary, in the Quaternary amine derivative of the acid, for example, by reaction with 3,4-bis(2-propenyloxy)-3-cyclobutene-1,2-dione in THF at a temperature of 0oC.

b) Catalytic cleavage of 2-propylgroup from those obtained in (a) of the Quaternary derivative of the acid, for example, using a palladium (II) acetate in acetonitrile and water in prisutstvie obtained by reaction of the corresponding reactive derivative of sulfonic acids, as, for example, sulfochloride A-SO2Cl, with the corresponding intermediate protected derivatives of amino acids HN(Y)-M-COO-tert-bootrom, as, for example, described in EP-468231A. Splitting complex tert-butyl methyl ether to obtain the desired acid II can be done triperoxonane acid in CH2Cl2or hydrochloric acid in ethyl acetate.

You can also get amino acids II, where M is a group M1according to the following reaction scheme(1), (2), (3);

< / BR>
< / BR>
where tBu = tert-butoxy; Boc = tert-Bu-OCO

< / BR>
Reaction (1)can be carried out in a solvent such as, for example, toluene, at elevated temperature. Reaction (2) reasonable conduct, as described above, the reaction of II with III. The reaction of VI -> VII carried out in such a way that first received in VI Boc-group otscheplaut from the N atom, for example, acetonitrile or dioxane, n-toluensulfonate, and the compound obtained transform sulfochloride A-SO2Cl in dioxane. Hydrolysis of ester VII to obtain the acid II can be done using triperoxonane acid in methylene chloride.

Receipt of ester VII, in which R5is tetrazolium, passes through the corresponding ester in which R5

Source guanidine III, in which X is a group of X1and R1, R2and Q are H, can be obtained as described in EP-468231A, for example, based on 3-picolylamine or 2-aminomethyl-4-benzylmorphine depending on how desirable do guanidine III with T=CH2or T=o to Obtain optically active guanidine III can be performed as described in example 36B. N-(3-pyridylmethyl)benzamide hydronaut in the presence of Pd/C in ethanol and hydrochloric acid to obtain (RS)-N-piperidine-3-iletilmesine. By salt formation with D-almond acid in methylene chloride after addition of simple diethyl ether may crystallize salt almond acid and (R)-N-piperidine-3-iletilmesine. This salt can then be amidinopropane in DMF with triethylamine and formamidinesulfinic. By heating the solution of the salts in concentrated hydrochloric acid can be obtained (S)-guanidine of the formula III, where X is a group of X1and Q=R1=R2=H.

Guanidine III, where X=X2and Q, R11and R21mean H, can be obtained similarly to the compound, where X=X1, T=CH2and Q, R1and R2mean H, for example, by the following reaction scheme (4) and as described in the following paragraph is to be obtained, for example, through connection type VIII, IX, X according to the following reaction scheme (S) as described in example 48 a) b) C):

< / BR>
Thus the amine III in hexane and water are converted using tetrabutylammonium and 1H of sodium hydroxide and then with benzylchloride. Of the compounds IX Boc group is cleaved with a solution of hydrochloric acid in acetic ether. The product is translated in DMF with triethylamine in formamidinesulfinic in connection X. To protect amidinopropane in connection X the latter is converted, for example, in methylene chloride using complex ethyl ether of Harborview acid. By gidrostaticheskogo removal of the Z groups are derived piperidine III, where X is a group of X1and one of R1and R2is etoxycarbonyl. Similarly you can get the appropriate derivative of the research III (T=O).

To protect amidinopropane received guanidine III, the Boc group can guanidine type X to convert using di-tert-BUTYLCARBAMATE (instead of complex ethyl ether of Harborview acid in dioxane.

Guanidine III QH can be obtained, for example, the following reactions (6) and (7), as described in the following note is Polina (J. Med.Chem. 33, 1990, 1406-1413) dicret-BUTYLCARBAMATE in dioxane,

b) conversion of the received BOC-protected amine by means of NaH and bromide Q-Br in DMF,

C) removal of bansalrupal in the resulting product by hydrogenation in ethanol in the presence of Pd/C, and

g) amidinopropane derived the research, as described above for compounds IV and removal of Boc-group.

Source amines IV receive, for example, the following reaction (8) where W is a protecting group, such as Boc or z

< / BR>
To obtain compound IV, where QH, primary amine XII [can be obtained from 3-hydroxyethylpiperazine, as described in EP-468231A in the following example 12 from a) to g)] is converted in a solvent such as, for example, methylene chloride, in the secondary amine XIII using a base, such as base Gunga and bromide Q-Br. Then the acid II reacts with the amine XIII (as described in the above reaction II+III). Then the protective group Boc otscheplaut using triperoxonane acid in methylene chloride, n-toluenesulfonic acid in acetonitrile or a solution of hydrogen chloride in ethyl acetate. Cleavage of the protective group Z is carried out by hydrogenation in ethanol in the presence of Pd/C To obtain the EOS M is a group M1and R5is NHCOCOO-lower alkyl, through the connection of the formula IV in which R5denotes sidegroup. Conversion of azido in NHCOCOO-lower alkyl may be carried out by catalytic hydrogenation with Pd/C in methanol), followed by converting the resulting amino group in NHCOCOO-lower alkyl by reaction with a mono(lower)alkylbis ester acid chloride of oxalic acid in the presence of pyridine in methylene chloride. If instead of a mono(lower)Olkiluoto ester acid chloride of oxalic acid is used perintalmanna acid in the presence of a base Gunga in methylene chloride, then get a compound IV in which M=M1and R5=NHCO-pyrazinyl.

In addition, some of the following examples contain detailed information regarding the receipt of certain compounds of formulas II, III and IV. The compounds of formula III in which X is a group of X1and at least one of R1, R2and Q is not H, or in which X is a group of X2and the compounds of formula IV in which M is a group M1or if X3is a group of X32or if X is a group of X31and at the same time Q is not H, and/or if A is alkyla the future inventions.

The compounds of formula I, a solvate and salt slows down the accumulation of platelets induced by thrombin, but also caused by thrombin clotting of fibrinogen in the blood plasma. These compounds affect both formed platelets and plasma coagulation. Thus, they prevent, in particular, the formation of blood clots in the coagulation and thrombus with platelets, and can be used in the fight against diseases, such as thrombosis, apoplexy, heart attack, inflammation and atherosclerosis, and to prevent them. In addition, these compounds act on tumor cells and prevent the formation of metastases. Thus, they can also be used as antitumor agents.

Varying degrees of inhibition of thrombin and other serine proteases achieved due to possible high specificity of these compounds and thereby prevent possible side effects. Along with other experienced serine-proteases to estimate the total mass of the specificity of the compounds was taken suppression ratio of trypsin to the suppression of thrombin (q in the table below), as trypsin, as the non-specific serine protease, can easily is whether the various substrates, as suppression was set constant suppression of Kiindependent of the substrate concentration and enzyme.

For evidence of the suppression of the catalytic activity of the above enzymes can be used specific chromogenic substrates peptides.

Suppression amylolyticus activity of thrombin and trypsin by the above compounds was proved in the following example.

The measurements were carried out on microtiterplates at room temperature. For this purpose, the deepening of the plate was mixed with 150 μl of buffer solution (50 mm Tris, 100 mm NaCl, 0.1% polyethylene glycol, pH 7.8) with 50 μl dissolved in dimethyl sulfoxide (DMSO) and diluted in a buffer solution of inhibitor was added 25 μl of human thrombin (0.5 nm final concentration). After 10 minutes incubation period started the reaction by filing a chromogenic substrate S-2238 (H-D-Phe-Pip-Arg-paranitroaniline cabinetry; 10 or 50 μm final concentration) and traced the hydrolysis of the substrate by a spectrophotometric method for the kinetic reader microtiterplate within 5 minutes. Graphic image suppression curve values were determined Kiaccording to the method of description (H-D-Val-Leu-Lys-paranitroaniline) 200 and 750 μm final concentration.

The results are shown in the following table.

The compound of the formula I have a slight toxicity. Thus the compounds listed in the table of examples intravenously have LD50from 125-500 mg/kg mouse.

Pharmaceutical composition having antiplatelet and anticoagulant activity containing a compound of formula I, its MES or salt is also the subject of the present invention. The method of obtaining such a composition is that use one or more other suitable therapeutic agents in galenical form of manufacture. Apply dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, or, for example, in the form of rectal suppositories, or in the form of sprays. However, the administration can also be carried out parenterally, for example, in the form of injection solutions.

For more pills, tablets, lacquered gloss, coated tablets and hard gelatin capsules biologically active substance can be mixed with pharmaceutically inert, inorganic or organic excipients. As such excipients can be used for pills, tablets, lacquered gloss, coated tablets and hard desire is Oli. For soft gelatin capsules as a suitable excipients, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols. Depending on the properties of biologically active substances for soft gelatin capsules may not be required excipients. To obtain solutions and syrups as a suitable excipients, for example, water, polyols, saccharose, invert sugar and glucose. For injection solutions are suitable, for example, water, alcohols, polyols, glycerol, vegetable oils. For suppositories suitable natural or hardened oils, waxes, fats, semi-liquid or liquid polyols. Along with this pharmaceutical composition can contain preservatives, agents, dissolution, stabilizers, wetting, emulsifying, sweet substances, colorants, flavouring agents, salts for modifying the osmotic pressure, buffer solutions, covering substances or antioxidants.

To combat the above diseases or for prevention it is possible to vary the dosage of the biologically active substances in a wide range and, of course, in each individual case it is necessary to observe the individual data. Usually the RNO from 0.1 to 20 mg/kg, preferably from about 0.5 to 4 mg/kg, daily for adults, and these upper bounds can go up or down depending on the indications.

Example 1. A solution of 0.85 g of tert-butyl(S)-N-cyclohexyl-N- [(etoxycarbonyl)methyl]-3-(2-naphthylamide) succinamide in 21 ml of methylene chloride is mixed at 0oC with 2.4 ml triperoxonane acid and stirred at room temperature. The foam obtained after evaporation of the solution, dissolved in 13 ml of DMF, then mixed with and 0.98 ml of 4-ativanonline, 0,68 g benzotriazol-1 yloxy-Tris(dimethylamino)fosfodiesterasa and 0.43 g of dihydrochloride of (S)-1-amidino-3-(aminomethyl)of piperidine and stirred at room temperature. The reaction mixture is evaporated and the residue using ethyl acetate, then ethyl acetate-acetone-acetic acid-water, 16:2:1:1 is subjected to chromatographic separation on silica gel. Allocate diacetate complex ethyl ester of N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N-2-(2-naphthylmethyl)- L-asparaginyl]-N-cyclohexylglycine.

FAB-MS: 629,3 (N+H)+.

Obtaining source material:

a) To a solution 2,89 g complex - tert-butyl ether N-Boc-L-aspartic acid in 50 ml of DMF type of 3.78 ml of 4-ethylmorpholine, 4,4 the Fira N-cyclohexylglycine (J. Hetetocycl. Chem. 23, 1986, 929-933) in 8 ml DMF. The reaction mixture was stirred at room temperature, then evaporated and the residue distributed between ethyl acetate and water. The organic phase is dried, evaporated and the residue chromatographic using ethyl acetate-hexane 1:1 on silica gel. Thereby obtaining 4.5 g of tert-butyl(S)-3-(1-tert-butoxypropan-N-cyclohexyl-N- [(etoxycarbonyl)methyl]succinamic.

FAB-MS: 457 (M+H)+.

b) a Solution of 2.1 g of the product from step a) in 22 ml of acetonitrile combined with 2.2 g of the monohydrate of n-toluenesulfonic acid while stirring. Then the solution is evaporated and dried, 2.4 g of the residue are dissolved in 45 ml of dioxane and mixed with a solution of 1.56 g of afterculture in 15 ml of dioxane. To a mixture of 1.9 g of sodium bicarbonate in 19 ml of water. After stirring the reaction mixture was poured on ice and extracted with ethyl acetate. The organic phase is washed with water, then dried and evaporated. The remainder chromatographic with a mixture of hexane and ethyl acetate 4:1 on silica gel. Gain of 0.85 g of tert-butyl(S)-N-cyclohexyl-N-[(etoxycarbonyl)methyl] -3-(2 - naphthylamide)succinamide.

FAB-MS: 547 (M+H)+< / BR>
Example 2.

2A) Analogously to example 1 given the following connections:

N-cyclopropylamine; MS (ion spray): 587,3 (M+H)+;

b) acetate complex ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2- (2-naphthylamine)propionyl] benzylamino] acetic acid; MS (ion spray): 637,3 (M+H)+;

in) acetate complex methyl ester N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-naphthylmethyl)-L - asparaginyl] -N-cyclopropylamine; MS (ion spray): 629,4 (M+H)+;

g) hydrochloride complex ethyl ester of N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-naphthylmethyl)- L-asparaginyl] -N-methylglycine; MS (ion spray): 561,5 (M+H)+;

d) hydrochloride complex ethyl ester of N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2-naphthylmethyl)-L - asparaginyl]-N-isopropylpyrazine; MS (ion spray): 589,0 (M+H)+;

e) hydrochloride complex ethyl ester (S)-[N-allyl-[3-(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2-(2 - naphthylamine)propionyl]amino]acetic acid; MS (ion spray): 587,0 (M+H)+;

W) hydrochloride complex ethyl ester of N-[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2-(naphthalene-2 - ylsulphonyl)propionyl] butylamino]acetic acid; MS (ion spray): 603,2 (M+H)+;

h) hydrochloride complex is l)glycine; MS (ion spray): 601,2 (M+H)+;

and) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl]-N1-ethoxycarbonylmethyl - N1-cyclopentyl-2-(naphthalene-2-ylsulphonyl)succinamide; MS (ion spray): 615,2 (M+H)+;

K) hydrochloride complex ethyl ester of N-[N4-[[(S)-1-amidino-3 - piperidinyl]methyl]-N2-(2-naphthylmethyl)-L-asparaginyl]-L-leucine; MS (ion spray): 603,0 (M+H)+;

l) hydrochloride complex ethyl ester of N-[N4-[[(S)-1-amidino-3 - piperidinyl]methyl]-N2-(2-naphthylmethyl)-L-asparaginyl]-N-cyclopropyl - alanine; MS (ion spray): 601,3 (M+H)+;

m) hydrochloride complex ethyl ester (S)-3-[allyl-[3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2-(2 - naphthalene-2-ylsulphonyl)propionyl] propionic acid; MS (ion spray): 601,2 (M+N)+;

h) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl]-N1-butyl-N1- (2-ethoxycarbonylethyl)-2-(naphthalene-2-ylsulphonyl)succinamide; MS (ion spray): 617,5 (M+H)+;

o) hydrochloride complex ethyl ester (S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2-(naphthalene-2 - ylsulphonyl)-N-interpopulational acid; MS (ion spray): 617,1 (M+H)+.

2B) Obtaining source merbromine acid and the reaction mixture is heated for 3 hours to 90oC. Then filtered precipitated precipitated salt and the filtrate distil. Obtain 9.5 g of a complex of ethyl ether N-cyclopropyl--alanine, FAB-MS: 157 (M+H)+.

2B) b) Analogously to method 2B) a) when using allylamine or butylamine instead of cyclopropylamine receive the following connections:

1) complex ethyl ester of N-allyl-alanine, FAB-MS: 157 (M+);

2) complex ethyl ester 3-butylenediamine acid, FAB-MS: 173 (M+).

2B) C) Analogously to example 1A), but using N-substituted complex ester of glycine instead of complex ethyl ester of N-cyclohexylglycine get the following complex truefire:

2B)), 1) tert-butyl(S)-2-(2-tert-butoxyphenyl)-N-cyclopropyl-N- [(etoxycarbonyl)methyl]succinamic, FAB-MS: 415 (M+);

2B)), 2) complex butyl ether (S)-N-benzyl-3-tert-butoxycarbonylamino-N-ethoxycarbonylmethylene acid, MS (ion spray): 546,2 (M+H)+;

2B)), 3) complex butyl ether (S)-3-tert-butoxycarbonylamino-N - cyclohexylmethyl-N-methoxycarbonylmethylene acid, MS (ion spray): 457,3 (M+H)+.

2B) g) Analogously to example 1B) receive the following connections:

2B)g)1) complex tert-butyl ether (S)-N-cyclopropyl-N-stor is th tert-butyl ether (S)-N-benzyl-N-ethoxycarbonylmethyl-3-(naphthalene-2-ylsulphonyl)-succinamide acid, MS (ion spray): 555,2 (M + H)+;

2B)g)3) complex tert-butyl ether (S)-N-cyclohexylmethyl-N-methoxycarbonylmethyl-3-(naphthalene-2-ylsulphonyl)-succinamide acid, MS (ion spray): 547,2 (M + H)+;

2B)d) To a solution 5,78 g complex beta-tert-butyl ether N-Boc-L-aspartic acid in 100 ml of methylene chloride successively added to 10.6 ml of 4-ethylmorpholine, 4.6 g of the hydrochloride of N-(dimethylaminopropyl)-N'-ethylcarbodiimide, 244 mg of 4-dimethylaminopyridine and 3.1 g of the hydrochloride complex ethyl ester sarcosine. After stirring the reaction mixture was poured into ice-cold solution of 5% potassium hydrosulfate - 10% potassium sulfate and extracted with ethyl acetate. The organic phase is washed with water, then dried, evaporated and the residue chromatographic a mixture of n-hexane and ethyl acetate (3 : 1) on silica gel. Obtain 6.8 g of complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-ethoxycarbonylmethyl-N-methylsuccinimide acid, MS (ion spray): 389,4 (M + H)+;

2B)e) Similarly 2B)d), but using N-substituted glycine complex esters instead of complex ethyl ester sarcosine obtain the following complex truefire:

2B)e)1) complex tert-butyl ether (S)-3-tert-butoxycarbonyl>2B)e)2) tert-butyl(S)-N-allyl-N-[(etoxycarbonyl)methyl] -3-(1-tert-butoxyphenyl)succinamic, MS (ion spray): 415,2 (M + H)+;

2B)e)3) complex ethyl ester N-[N,3-bis-tert-butoxycarbonyl-L-alanyl] -N-butylglycol, MS (ion spray): 431,2 (M + H)+;

2B)e)4) complex ethyl ester N-[N,3-bis(tert-butoxycarbonyl)-L-alanyl] -N-(cyclopropylmethyl)glycine, MS (ion spray): 428,2 M+;

2B)e)5) a compound tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-cyclopentyl-N - ethoxycarbonylmethylene acid, MS (ion spray): 443,3 (M+H)+;

2B)e)6) a compound tert-butyl ether (S)-3-tert-butoxycarbonylamino-N4-cyclobutyl-N4 - ethoxycarbonylmethylene acid, MS (ion spray): 429,2 (M+H)+;

2B)e)7) a compound tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-tert-butyl-N - ethoxycarbonylmethylene acid, MS (ion spray): 431,2 (M+H)+;

2B)e)8) complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-ethoxycarbonylmethyl-N - interactivemonopoly acid, MS (ion spray): 445,3 (M+H)+;

2B) W) Similarly 2B) d), but using complex ethyl ester of L-leucine instead of a complicated ethyl ester sarcosine get complicated atiori use obtained in example 2B) (a) and (b) esters, get the following complex truefire:

2B)h)1) complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-cyclopropyl-N-(2-ethoxycarbonylethyl)- succinamide acid, MS: 429 (M+H)+;

2B)h)2) complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-allyl-N-(2-ethoxycarbonylethyl)- succinamide acid, MS: 429 (M+H)+;

2B)C)3) complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-butyl-N-(2-ethoxycarbonylethyl)- succinamide acid, MS (ion spray): 445,6 (M+H)+;

2B) and a Solution of 6.7 g of complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-ethoxycarbonylmethyl-N-methylsuccinimide acid in 80 ml of dioxane is mixed from 8.2 g of the monohydrate of n-toluenesulfonic acid. After stirring 43,1 ml 1H of sodium hydroxide, 4,34 g of sodium bicarbonate and a solution of 7.8 g of 2-afterculture in 37 ml of dioxane. After stirring the reaction mixture was poured into ice-cold solution of 5% potassium hydrosulfate - 10% potassium sulfate and extracted with ethyl acetate. The organic phase is washed with diluted aqueous sodium chloride, then dried and evaporated. After chromatographic separation on silica gel with a mixture of hexane and ethyl acetate (3: 1) allocate 2.0 g of tert-butyl(S)-N-[(ethoxycarbonyl ogino 2B)), but when using complex Trifonov examples 2B) e), g) and h) instead of complex Trifonov example 2B) d) receive complex diesters:

2B)K)1) complex ethyl ester of N-[3-(tert-butoxycarbonyl)-N-(2-naphthylmethyl)-L-anali]-N-isopropylaniline, FAB-MS; 433 (M-tert-butoxy);

2B)K)2) complex ethyl ester of N-allyl-N-[3-tert-butoxycarbonyl-N2-(2-naphthylmethyl)-L-alanyl]glycine, MS (ion spray): 505,0 (M+H)-;

2B)K)3) complex tert-butyl ether (S)-N-butyl-N-ethoxycarbonylmethyl-3-(naphthalene-2-ylsulphonyl)- succinamide acid, MS (ion spray): 504 (M+H)+;

2B)K)4) complex ethyl ester of N-(cyclopropylmethyl-N-[4-(tert-butoxycarbonyl)-N-(2-naphthylmethyl)-L - alanyl]glycine, FAB-MS: 445 (M-tert-butoxy);

2B)K)5) complex tert-butyl ether (S)-N-cyclopentyl-N-ethoxycarbonylmethyl-3-(naphthalene-2-ylsulphonyl)- succinamide acid, MS (ion spray): 533,0 (M+H)+;

2B)K)6) complex tert-butyl ether (S)-N-cyclobutyl-N-ethoxycarbonylmethyl-3-(naphthalene-2-ylsulphonyl)- succinamide acid, MS (ion spray): 519,1 (M+H)+;

2B)K)8) complex ethyl ester of (S)-2-[(S)-3-tert-butoxycarbonyl)-2-(naphthalene-2-ylsulphonyl - propionamido]-4-methylpentanoic acid, MS (ion spray): 521,0 (M is -- drank alanine, MS (ion spray): 517,1 (M-H)+;

2B)K)10) complex ethyl ester of N-allyl-N-[O-(tert-butyl)- N-(naphthalene-2-ylsulphonyl)-L-aspartyl] -- alanine, MS (ion spray): 519,4 (M+H)+;

2B)K)11) complex tert-butyl ether (S)-N-butyl-N-(2 - ethoxycarbonylethyl)-3-(naphthalene-2-ylsulphonyl)-succinamide acid, FAB-MS: 479 (M-complex isobutyl ether);

2B)K)12) complex tert-butyl ether (S)-N-ethoxycarbonylmethyl - 3-(naphthalene-2-ylsulphonyl)-N-interactivemonopoly acid, FAB-MS: 479 (M-complex isobutyl ether).

Example 3. A solution of 0.85 g of the diacetate complex ethyl ester of N-[N4-[[(S)-2-amidino-3-piperidinyl] methyl-N2-(2-naphthylmethyl-L - asparaginyl]-N-cyclohexylglycine (example 1) in 6 ml of ethanol is mixed with 6.0 ml of 1N sodium hydroxide. After stirring 6,0 ml of 1N hydrochloric acid, the solution is evaporated and the residue chromatographic water acetonitrile column RP-18. Obtain 0.25 g of N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl-N2-(2-naphthylmethyl)-L - asparaginyl] -N-cyclohexylglycine, MS (ion spray): 601,3 (M+H)-.

Example 4. Analogously to example 3, but based on esters of example 2A) get the following acids:

a) N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2 - naphthylmethyl)-L-asparaginyl]-N-carbamoyl] - 2-(naphthalene-2-ylsulphonyl)-propionyl] -benzylamino] -acetic acid, MS (ion spray): 609,1 (M+H)+;

C) N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2 - naphthylmethyl)-L-asparaginyl]-N-cyclohexylglycine, MS (ion spray): 615,4 (M+H)+;

g) N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2 - naphthylmethyl)-L-asparaginyl]-N-methylglycine, MS (ion spray): 532,9 (M+H)+;

d) N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2 - naphthylmethyl)-L-asparaginyl]-N-isopropylphenyl, MS (ion spray): 561,2 (M+H)+;

e) [[(S)-3-[(S)-1-aminoiminomethyl)piperidine-3-letiltasaval] - 2-(naphthalene-2-ylsulphonyl)propionyl] allylamino] -acetic acid, MS (ion spray): 557,2 (M-H)+;

W) [[(S)-3-[(S)-1-aminoiminomethyl)piperidine-3-letiltasaval] - 2-(naphthalene-2-ylsulphonyl)propionyl] butylamino] -acetic acid, MS (ion spray): 575,3 (M+H)+;

C) N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2 - naphthylmethyl)-L-asparaginyl] -N-(cyclopropylmethyl)glycine, MS (ion spray): 573,3 (M+H)+;

and) (S)-N4-[(S)-(1-aminoiminomethyl)piperidine-3-ylmethyl]-N1 - carboxymethyl-N1-cyclopentyl-2-(naphthalene-2-ylsulphonyl)succinamide, MS (ion spray): 587,2 (M+H)+;

K) N-[N4-[[(S)-1-amidino-3-piperidinylmethyl)piperidine-3-letiltasaval] - 2-(naphthalene-2-ylsulphonyl)propionyl]cyclopropylamino]propionic acid, MS (ion spray): 573,3 (M+H)+;

m) (S)-3-[allyl-[3-[(S)-(1-aminoiminomethyl)piperidine-3 - letiltasaval]-2-(naphthalene-2-ylsulphonyl)propionyl]amino]propionic acid, MS (ion spray): 573,3 (M+H)+;

h) 3-[(S)-3-[(S)-[1-(aminoiminomethyl)piperidine-3-letiltasaval]- N-butyl-2-(naphthalene-2-ylsulphonyl)propionamido] propionic acid, MS (ion spray): 589,4 (M+H)o;

o) [(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] - 2-(naphthalene-2-ylsulphonyl)propionyl] IntelliMouse acid, MS (ion spray): 589,5 (M+H)+.

Example 5. A solution of 50 mg of [[(S)-3-[(S)-1-(aminoiminomethyl)piperidine - 3-letiltasaval] -2-(naphthalene-2-ylsulphonyl)propionyl] allylamino]acetic acid (example 4E) in 4 ml ethanol and 1 ml of water is mixed with 10 mg of Pd/C and hydronaut in normal conditions. After 4 hours the catalyst is filtered off and the filtrate is evaporated. Receive 50 mg of [(S)-3-[(S)-2-(aminoiminomethyl)piperidine-3-letiltasaval] - 2-(naphthalene-2-ylsulphonyl)propionyl] propylenoxide acid, MS (ion spray): 561,3 (M+H)o.

Example 6. Analogously to example 5 is obtained from (S)-3-[allyl-[3-[(S)- [kislota (example 4 m), 3-[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)propionyl] Propylenediamine acid, MS (ion spray): 575,2 (M+H)+.

Example 7.

A) Analogously to example 1 are obtained from complex diesters of examples 2B)and) and), on the one hand, and instead dihydrochloride (S)-1-amidino-3-(aminomethyl)piperidine from trifenatate racemic 2-aminomethyl-4-morpholinylcarbonyl, on the other hand, the following esters:

a) triptorelin complex ethyl ester 3-[N-[(S)-3-[(R, S)- 4-(aminoiminomethyl)-morpholine-2-letiltasaval] -2-(naphthalene-2 - ylsulphonyl)-propionyl] -cyclopropylamino] propionic acid (1:1), MS (ion spray): 603,4 (M+H)+;

b) triptorelin complex ethyl ester 3-[N-allyl-[(S)-3- [(R,S)-4-(aminoiminomethyl)-morpholine-2-letiltasaval]-2-(naphthalene - 2-ylsulphonyl)-propionyl] -amino] propionic acid (1:1), MS (ion spray): 603,5 (M+H)o.

B) the Original triptorelin receive the following way:

a) a Solution of 23.3 g of racemic 2-(aminomethyl)-4-benzylmorphine in 250 ml of dioxane is mixed from 27.1 g of di-tert-BUTYLCARBAMATE in 250 ml of dioxane. After mixing, the solvent is evaporated and the residue chromatographic with the Gain of 25.6 g of tert-butylamino [(4-benzyl-2-morpholinyl)methyl]carbamate.

b) a solution of the product from a) in 500 ml of ethyl acetate and 50 ml of acetic acid is mixed with 2.6 g of Pd/C and hydronaut for 5 hours under normal conditions. After filtration and evaporation the residue is dissolved in 230 ml of DMF, mixed with 46 ml of triethylamine and 10.8 g formamidinesulfinic. After stirring the reaction mixture is evaporated and the residue distributed between ethyl acetate and water. After drying the organic phase and evaporating get hemisulfate tert-butyl racemic [(4-amidino-2-morpholinyl)methyl]carbamate.

C) 6.5 g obtained in stage b) compounds are suspended in 50 ml of methylene chloride and mixed at 0+C with 20 ml of triptoreline (TN). Then the reaction mixture is evaporated and azeotropic ethylenchloride and toluene. Allocate triptorelin racemic 2-(aminomethyl)-4-morpholinylcarbonyl.

Example 8. Analogously to example 3 of the esters of example 7a the following acids:

a) 3-[(S)-3-[(R, S)-4-aminoiminomethyl-2-letiltasaval] - 2-(naphthalene-2-ylsulphonyl)-N-cyclopropylamino]propionic acid, MS (ion spray): 575,5 (M+H),

b) 3-[N-allyl-[(S)-3-[(R,S)-4-(aminoiminomethyl)-morpholine-2 - letiltasaval]-2-(naphthalene-2-ylsulphonyl)-propionyl]amino what about the ether N-[3-(tert-butoxycarbonyl)-N-(2-naphthylmethyl)-L-alanyl] -N-cyclopropyl--alanine (example 2B)K)9) in 23 ml of methylene chloride is mixed with 2oC from 4.1 ml triperoxonane acid. After 5 hours stirring, the solution is evaporated at room temperature, the residue is dissolved in 23 ml of DMF, mixed with 1.7 ml of 4-ethylmorpholine, 1,2 BOP and 0.8 g of the dihydrochloride of racemic 3-[[(2-hydroxyethyl)amino]methyl]-1 - piperazinecarboxamide. After stirring the reaction solution is evaporated and the residue chromatographic water acetonitrile column RP-18. Obtain 0.7 g of the hydrochloride complex ethyl ester 3-[(S)-3-[(R, S)-N-(1-aminoiminomethyl-3-ylmethyl)-2 - hydrooximethylcarbamil] -2-(naphthalene-2-ylsulphonyl)-N - cyclopropylamino] propionic acid (1:1), MS (ion spray): 645,5 (M+H)+.

Getting the source piperazinecarboxamide:

a) To a solution of 20 g of N-(2-hydroxyethyl)-3-picolylamine in 250 ml of dioxane is added a solution of 31.6 g of di-tert-BUTYLCARBAMATE in 100 ml of dioxane. After stirring the reaction mixture is evaporated and the residue chromatographic with ethyl acetate on silica gel. Get to 29.8 g of tert-butyl(2-hydroxyethyl)-(3-pyridylmethyl)carbamate, EI-MS: 253 (M+H)+.

b) Obtained in stage a) compound is dissolved in 150 ml of ethanol, mixed with 3 g of ruthenium on aluminum oxide and hydronaut within 24 hours at 60oC and 100 ATM. After MS: 259 (M+H)+.

C) a solution of the product of stage b) in 500 ml of DMF is mixed with 51 ml of triethylamine and 12.1 of formamidinesulfinic. After stirring the precipitated precipitated product is filtered off, dissolved in ethanol-water 1:1, filtered and the filtrate is evaporated, and subjected to azeotropically with ethanol. The remainder Usacheva simple ether and filtered. Get 24 grams of hemisulfate tert-butyl racemic [(1-amidino-3-piperidinyl)methyl] -(2-hydroxyethyl)carbamate, FAB-MS: 301 (M+H)+.

d) 10.0 g obtained in stage C) the product is dissolved in 90 ml of methylene chloride and 10 ml of methanol, at 0+C is mixed with 100 ml of a 4 molar solution of hydrochloric acid in ethyl acetate. After stirring the reaction mixture is evaporated, get quantitatively the dihydrochloride of racemic 3-[[(2-hydroxyethyl)-amino]methyl]-1 - piperazinecarboxamide, FAB-MS: 201 (M+H)+.

Example 10. Analogously to example 3 of ester of example 9 to obtain (S)-N4-[(R, S)- 1-aminoiminomethyl-3-ylmethyl]-N1-(2-carboxyethyl)-N1-cyclopropyl-N4-(hydroxyethyl)-2-(naphthalene-2-ilafontaine)-succinamide, MS (ion spray): 617,5 (M+H)o.

Example 11. A solution of 0.45 g of tert-butyl(S)-hexahydro--(2-naphthylamide)--oxo-1H-azepin-1-butyrate in 3 ml methylthioamphetamine with toluene and dried. The residue is dissolved in 8 ml of DMF, mixed with of 0.38 ml of 4-ethylmorpholine, 0,49 g of BOP and 0.3 g of the dihydrochloride of racemic 3-[[(2-hydroxyethyl)amino]methyl]-1-piperazinecarboxamide (example 9 g). After stirring the reaction mixture is evaporated and chromatographic a mixture of ethyl acetate, acetone, acetic acid and water (6:2:1:1) on silica gel. The fractions containing the product is evaporated and the residue is filtered with methanol-water (9:1) through Dowex (form of acetate). Obtain 0.4 g of the diacetate (S)-N-[[RS)-1-amidino-3-piperidinyl] methyl]-N-(2-hydroxyethyl)hexahydro -- 2-naphthylamide-1H-1-AtaInsurance, MS (ion raspylenie): 587,2 (M+H)o.

Obtaining source material:

a) To a solution 2,89 g - complex tert-butyl ether N-Boc-L-aspartic acid in 50 ml of methylene chloride add to 1.37 ml of hexamethylenimine, 2.3 g of the hydrochloride of N-(dimethylaminopropyl)-N'-ethylcarbodiimide and 122 mg of dimethylaminopyridine. After stirring the reaction mixture was poured into ice-cold solution of 5% potassium hydrosulfate -10% potassium sulfate and extracted with methylene chloride. The organic phase is washed with water, then dried and evaporated. The remainder chromatographic hexane-ethyl acetate. Receive 2.9 tert-butyl(S)- -- (1-tert-butoxyphenyl)hexahydro-is more from 1.31 g of the monohydrate of p-toluenesulfonic acid. After stirring under ice cooling successively added 6.9 ml 1H of sodium hydroxide, a solution of 0.93 g of 2-afterculture in 5 ml of dioxane and 0.7 g of sodium bicarbonate. After stirring the reaction mixture was poured into ice-cold solution of 5% potassium hydrosulfate 10% potassium sulfate and extracted with ethyl acetate. The organic phase is washed with water and evaporated. After chromatographic separation of hexane and ethyl acetate (2:1) on silica gel obtain 0.55 g of tert-butyl(S)-hexahydro -- (2-naphthylamide) -- oxo-1H-azepin-1-butyrate, MS (ion spray): 483,1 (M+H)4.

Example 12. To a solution of 1.9 difficult tert-butyl ether (S)-3-[N-[(S)-4-(azepin-1-yl)-3-(naphthalene-2-sulfonylamino)-4-oxobutyryl] -N - ethoxycarbonylmethyl] -piperidine-1-carboxylic acid in 20 ml of acetonitrile, add 1.3 g of the monohydrate of p-toluenesulfonic acid. After mixing, the solution is evaporated, the residue is dried, dissolve in 25 ml of DMF and mixed with 1.9 ml of triethylamine and 450 g of formamidinesulfinic. After stirring the reaction mixture is evaporated and the residue chromatographic water acetonitrile column RP-18. Obtain 0.7 g of hemisulfate complex ethyl ester [[(R)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -[(S)-4-(azepin-1-yl)-3-

Getting the source of ester:

a) To a solution of 92.9 g of racemic 3-hydroxyethylpiperazine in 1500 ml of dioxane is added a solution of 211,2 g of di-tert-BUTYLCARBAMATE in 500 ml of dioxane so that the temperature did not exceed 25oC. the Reaction mixture is stirred and then evaporated. The remainder Usacheva in 800 ml of hexane and filtered. Get of 120.7 g of racemic N-tert-butyloxycarbonyl-3-hydroxyethylpiperazine, so pl. 78oC.

b) a Solution of 100 g of the product of stage a) in 4000 ml of methylene chloride is mixed from 56.2 ml of pyridine and cooled to 04C. To the solution is added dropwise 58,3 ml of acid chloride of butyric acid, so that the temperature did not exceed 10oC. After stirring, the suspension is filtered, the filtrate is evaporated and the residue diluted with ethyl acetate. The organic phase is washed with aqueous 10% solution of CuSOo, dried and evaporated. The residue is filtered through silica gel and elute with hexane-ethyl acetate (8:2). Get 119,7 g complex tert-butyl ester of racemic 3-(butylacetyl)-1-piperidinecarboxylic acid.

in) 116,6 g of the product of stage b) emuleret in 2 l of 0.1 M solution of sodium chloride and 80 ml of 0.1 M buffer solution of sodium phosphate, pH 7.0. The pH value using H 1,0 Hydra is) in 10 ml of 0.1 M sodium chloride solution to start the reaction. While stirring by filing 2,0 H of sodium hydroxide, the pH value hold of 7.0. After 14 hours by submitting a 500 ml of methylene chloride the reaction is complete. The reaction mixture is extracted with methylene chloride and the organic phase is dried and evaporated. Chromatographic separation of the residue through silica gel with a mixture of hexane and ethyl acetate gives 36,6 g complex tert-butyl ether (S)-3-hydroxymethyl-1-piperidinecarboxylic acid, so pl. 89-90oC []25365/= +53,5o(C=1,0, EtOH).

g), and 65.7 g fraction of ester stage) emuleret in 1.15 l of 0.1 M solution of sodium chloride and 45 ml of 0.1 M buffer phosphate (pH 7.0) and mixed with 0.50 g of lipase P-30 in 5 ml of 0.1 sodium chloride solution. The pH value by filing 2,0 H of sodium hydroxide with stirring, kept at 7.0. After 40 hours by submitting a 400 ml of methylene chloride the reaction is complete. The reaction mixture is extracted with methylene chloride and the organic phase is dried and evaporated. Chromatographic separation of the residue through silica gel with a mixture of hexane and ethyl acetate gives a 49.5 g complex tert-butyl ether (R)-3-(butyryloxy)-1-piperidinecarboxylic acid. It is dissolved in 250 ml of ethanol, mixed with 88 ml 2H of sodium hydroxide, stirred for overnight what langarica and the organic phase is dried and concentrated. Chromatographic separation of the residue through silica gel with a mixture of hexane and ethyl acetate gives 33,7 g complex tert-butyl ether (R)-3-hydroxymethyl-1-piperidinecarboxylic acid, []25365= -60,7+(C= 1,0, EtOH).

d) a Solution of 5.0 g of the product of stage d) in 100 ml of pyridine is mixed with a 5.4 g of p-chlorosulfonylphenyl. The reaction mixture is stirred, then evaporated, placed in 200 ml ethyl acetate and washed with water and aqueous 10% solution of CuSO+. The organic phase is dried and evaporated. The residue is filtered through silica gel and elute with a mixture of hexane-ethyl acetate (8:2). Obtain 6.5 g of complex tert-butyl ether (R)-3-(p-chlorophenylsulfonyl)-1-piperidinecarboxylic acid.

e) Solution of the product of stage d) in 50 ml of SCM mixed with 3.25 g of sodium azide. The reaction mixture is stirred for 15 hours at a temperature of 50+C and evaporated. The residue is placed in water and simple ether, and washed with water. The ether phase is dried and evaporated. Obtain 4.0 g of complex tert-butyl ether (R)-3-azidomethyl-1-piperidinecarboxylic acid.

W)1) a solution of the product of stage (e) in 100 ml of ethanol hydronaut hydrogen in the presence of 0.6 g of platinum oxide at a pressure of 1 ATM. Then the reaction mixture of 1-piperidinecarboxylic acid, []2D5= 17, 7C+(or=0.6, EtOH).

W)2) Similarly, e), f) and g)1) of the complex tert-butyl ether (S)-3-hydroxymethyl-1-piperidinecarboxylic acid get complicated tert-butyl ether (R)-3-aminomethyl-1-piperidinecarboxylic acid []2D5= +23,0+(C=0,4, EtOH).

C) a Solution of 4.0 g of the product of stage g) in 300 ml of methylene chloride is mixed under argon with a 9.6 ml base Gunga and of 2.08 ml complex ethyl ester bromoxynil acid. After mixing, the solution is evaporated, the residue Usacheva in ethyl acetate, filtered and the filtrate shaken from the water. The organic phase is dried, evaporated and the residue chromatographic with a mixture of hexane and ethyl acetate (1: 1) on silica gel. Obtain 2.3 g of a complex of ethyl ester of N-[[(S)-1-tert-butoxycarbonyl)-3-piperidinyl] methyl] glycine, EI-MS: 243 (M-tert-butyl).

I) a Solution of 1.65 g of tert-butyl(S)-hexahydro -- (2-naphthylamide) -- oxo-1H-azepin-1-butyrate (example 11b) in 50 ml of methylene chloride is mixed at 0+C with 5.5 ml triperoxonane acid. After stirring evaporated. The residue is dissolved in 31 ml of DMF, mixed with 2.3 ml of 4-ethylmorpholine, 1,60 g of BOP and a solution of 1.3 g of the product of stage C) in 2 ml of DMF. After stirring the reaction mixture is evaporated is autographical separation of the residue a mixture of hexane and ethyl acetate on silica gel get 2.0 g complex tert-butyl ether (S)-3-[N-[(S)-4-azepin-1-yl)-3-(naphthalene-2-sulfonylamino)-4-coconutoil] -N - ethoxycarbonylmethylene] -piperidin-1-carboxylic acid. MS (ion spray): 687,3 (M+H)+.

Example 13. A solution of 1.0 product of ester of example 12 in 10 ml of methanol is mixed with 9.0 ml 1H of sodium hydroxide. After stirring at 9.0 ml 1H hydrochloric acid, the solution evaporated, chromatografic the remainder of the water acetonitrile column RP-18 and receive 0.5 g [[(R)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -[(S)-4-(azepin-1-yl-3- (naphthyl-2-sulfonylamino)-4-oxobutyryl] amino] acetic acid, MS (ion spray): 601,2 (M+H)+.

Example 14.

A) Analogously to example 1 receive:

a) from complex tert-butyl ether (S)-N-cyclopropyl-N-ethoxycarbonylmethyl-3-(4-triftormetilfullerenov) -succinamide acid,

the acetate complex ethyl ester [(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2- (4-triftormetilfullerenov)propionylthiocholine] acetic acid (1:1), MS (ion spray): 605,4 (M+H)+.

b) from challenging butyl ether (S) -3-(4-tert-butylphenylphosphine)-N-cyclopropyl-N - ethoxycarbonylmethylene acid,

the acetate complex ethyl ester [(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2- (4-tert-butylphenylphosphine) propionylthiocholine] vinegar-N-cyclopropyl-N - ethoxycarbonylmethylene acid,

hydrochloride complex ethyl ester (S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2- (biphenyl-4-ylsulphonyl)-N-cyclopropanecarboxylic acid (1:2), MS (ion spray): 613,4 (M+H)+,

g) of complex tert-butyl ether (S)-N-cyclopropyl-N-ethoxy-carbonylmethyl-3-(3-methylinosine-8 ylsulphonyl)succinimido acid,

the acetate complex ethyl ester (S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -N-cyclopropyl-2-(3-methylinosine-8 ylsulphonyl)-propionamidoxime acid (1:1), MS (ion spray): 602,2 (M+H)+.

B. Source complex diesters obtained from tert-butyl(S)-2-(1-tert-butoxyphenyl)-N-cyclopropyl-N- [(etoxycarbonyl)methyl]succinate (example 2B)), analogously to example 1B), but using the appropriate arylsulfonamides instead of afterculture:

a) tert-butyl ether (S)-N-cyclopropyl-N-ethoxycarbonylmethyl - 3-(4-triftormetilfullerenov)-succinamide acid, MS (ion spray): 523,0 (M + H)+,

b) tert-butyl ether (S)-3-(4-tert-butylphenylphosphine)- N-cyclopropyl-N-ethoxycarbonylmethylene acid, MS (ion spray): 511,1 (M + H)+,

C) tert-butyl ether (S)-3-): 531,4 (M + H)+,

g) a compound tert-butyl ether (S)-N-cyclopropyl - N-ethoxycarbonylmethyl-3-(3-methylinosine-8 ylsulphonyl)- succinamide acid, MS (ion spray): 520,2 (M + H)+.

Example 15. Analogously to example 3 is obtained from the esters of example 14A) the following acids:

a) [(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval]- 2-(4-triftormetilfullerenov)-propionyl] - cyclopropylmethoxy acid, MS (ion spray): 577,4 (M + H)o,

b) [(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval]- 2-(4-tert-butylphenylphosphine)-propionyl] -N - cyclopropylmethoxy acid, MS (ion spray): 565,2 (M + H)o,

C) [(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] - 2-(biphenyl-4-ylsulphonyl)-N - cyclopropylmethoxy acid, MS (ion spray): 585,4 (M + H)+,

g) [(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] - N-cyclopropyl-2-(3-methylinosine-8 ylsulphonyl)-propionamido - acetic acid, MS (ion spray): 574,4 (M + H)+.

Example 16. A solution of 0.34 g of the product from example 15A)d) in 25 ml of ethanol is mixed with 1 ml of acetic acid and 0.1 g of Pd/C and hydronaut under normal conditions. After filtration and evaporation f is Kohinoor-8 ylsulphonyl)-propionyl] -N-cyclopropylamino - acetic acid (1:1), MS (ion spray): 578,4 (M + H)+.

Example 17. Analogously to example 1 from complex tert-butyl ether (S)-N-cyclopropyl-3-(naphthalene-2-ylsulphonyl)-N-(3-oxobutyl)- succinamide acid get hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-2-(naphthalene - 2-ylsulphonyl)-N1-(3-oxobutyl)succinamide (1:1), MS (ion spray): 571,2 (M + H)+.

Obtaining source material:

a) To a solution of 10 g of complex ethyl ester N-cyclopropyl-alanine in 100 ml of dioxane is added dropwise while cooling add a solution of 13.9 g of di-tert-BUTYLCARBAMATE in 140 ml of dioxane. After stirring the reaction mixture is evaporated. After drying of the residue receive 16 g complex ethyl ester 3-(tert-butoxycarbonyl-N-cyclopropylamino)propionic acid, FAB-MS: 201 (M-isobutylene).

b) To a solution of 15.7 g of the product of stage a) in 160 ml of THF at 0 to 3+C added dropwise 42 ml of a 1.6 molar solution metallice simple ether. After stirring at room temperature the solution is cooled to 0+C and added dropwise to 34.5 ml of a 1.6 molar solution metallice simple ether. After stirring the reaction solution was poured into ice-cold 5% solution of potassium hydrosulfate - 10% solution sosialt and evaporated, the remainder chromatographic with a mixture of hexane and ethyl acetate 4:1 on silica gel. The first faction gain of 8.3 g complex tert-butyl ether cyclopropyl-(3-hydroxy-3-methylbutyl)carbamino acid, FAB-MS: 187 (M-isobutylene).

b) Chromatography of b) in the second fraction allocate 1.7 g complex tert-butyl ether cycloramic-3-oxobutanamide acid, FAB-MS: 171 (M-isobutylene).

g) a Solution of 18.2 g of the product of stage b) in 80 ml of ethyl acetate is mixed with 40 ml of a 4 molar solution of hydrochloric acid in ethyl acetate. After stirring the filtered product that fell into the residue, and washed with ethyl acetate. After drying obtain 3.6 g of the hydrochloride of 4-cyclopropylamino-2-methylbutane-2-ol. FAB-MS: 143 M+.

d) a Solution of 3.1 g of the product of stage C) in 30 ml of ethyl acetate is mixed with 30 ml of a 4 molar solution of hydrochloric acid in ethyl acetate. After mixing, the solution is evaporated and dried. Obtain 2.3 g of 4-cyclopropylamino-2-it.

e) a Solution of 3.9 complex - tert-butyl ether N-Boc-L-aspartic acid in 40 ml of methylene chloride is mixed with 5.5 ml of 4-ethylmorpholine, 3.1 g of the hydrochloride of N-(dimethylaminopropyl)-N'-ethylcarbodiimide and 0.17 g of 4-dimethylaminopyridine. To this solution was added the product polucen 5% solution of potassium hydrosulfate - 10% solution of potassium sulfate and extracted with methylene chloride. The organic phase is washed with sodium chloride solution, then dried and evaporated, and the residue chromatographic with a mixture of hexane and methyl acetate 2:1 on silica gel. Obtain 3.7 g of complex tert-butyl ether (S)-N-(2-acetylethyl)-3-tert - butyloxycarbonyl-N-cyclopropylamino acid, MS (ion spray): 399,3 (M + H)+.

g) of the product of stage (e) analogously to example 2B)and) get complicated tert-butyl ether (S)-N-cyclopropyl-3-(naphthalene-2-ylsulphonyl)-N-(3-oxobutyl) succinimido acid, FAB-MS: 433 (M-isobutylene).

Example 18. Analogously to example 17 of the hydrochloride of 4-cyclopropylamino-2-methylbutane-2-ol (example 17g) through

a) complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-cyclopropyl-N-(3-hydroxy-3 - methylbutyl)succinimido acid, MS (ion spray): 415,4 (M + H)+and

b) complex tert-butyl ether (S)-N-cyclopropyl-N-(3-hydroxy-3-methylbutyl)-2-(naphthalene-2 - sulfonylamino)-succinamide acid, MS (ion spray): 505,3 (M + H)+get:

hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl]- N1-cyclopropyl-N1-(3-hydroxy-3-methylbutyl)-2-(naphthalene-2 - ylsulphonyl)-succinimidylester example 14B) (a), b) or d), you receive the following esters:

(a) acetate complex ethyl ester [(S)-3-[(R,S)-4-(aminoiminomethyl)morpholine-2-letiltasaval] -2-(4-triftormetilfullerenov)-propionyl N - cyclopropylamino]acetic acid (1:1), MS (ion spray): 607,2 (M + H)+,

b) triptorelin complex ethyl ester [(S)-3-[(R,S)-4-(aminoiminomethyl)morpholine-2-letiltasaval] -2-(4-tert-butylphenylphosphine)-propionyl N - cyclopropylamino] acetic acid (1:1), MS (ion spray): 595,3 (M + H)+,

C) triptorelin complex ethyl ester [(S)-3-[(R,S)-4-(aminoiminomethyl)morpholine-2-letiltasaval] -2-(biphenyl-4-ylsulphonyl)-N - cyclopropylamino] acetic acid (1:1), MS (ion spray): 615,3 (M + H)+.

Example 20. Analogously to example 3 from esters of example 19 given the following acids:

a) [(S)-3-[(R,S)-4-(aminoiminomethyl)morpholine-2-letiltasaval]-2-(4-triftormetilfullerenov)-propionyl N - cyclopropylamino] acetic acid, MS (ion spray): 579,1 (M + H)+,

b) [(S)-3-[(R, S)-4-(aminoiminomethyl)morpholine-2-letiltasaval] -2-(tert-butylphenylphosphine)-N - cyclopropylamino]acetic acid, MS (ion spray): 567,4 (M + H)+,

lamino]acetic acid, MS (ion spray): 587,3 (M + H)+.

Example 21. Analogously to example 9, but based on N-methyl-picolylamine (instead of N-(2-hydroxyethyl)-3-picolylamine through

tert-butylmethyl-(3-pyridinylmethyl)carbamate,

tert-butyl-racemic methyl-(3-piperidinylmethyl)carbamate,

bisulphite tert-butyl-racemic [(1-amidino-3 - piperidinyl)methyl]methylcarbamate and

the dihydrochloride of racemic 3-[(methylamino)methyl] -1 - piperazinecarboxamide, FAB-MS: 171 (M + H)o< / BR>
a) when using complex tert-butyl ether (S)-N-butyl-N-(2-ethoxycarbonylethyl)-3-(naphthalene-2-ylsulphonyl) succinimido acid (example 2B)K)11) get:

hydrochloride complex ethyl ester 3-[(S)-3-[(R,S)-[1-(aminoiminomethyl)piperidine-3-ylmethyl)- N-methylcarbamoyl] -N-butyl-2-(naphthalene-2-ylsulphonyl)propionamido] propionic acid (1:1), MS (ion spray): 631,5 (M + H)o,

b) when using N-[3-(tert-butoxycarbonyl)-N-(2 - naphthylmethyl)-L-alanyl]-N-cyclopropyl -- alanine (example 2B)K)9) get:

hydrochloride complex ethyl ester 3-[[(S)-3-[[(R,S)-(1-(aminoiminomethyl)piperidine-3-ylmethyl)] - methylcarbamoyl] -2-(naphthalene-2-ylsulphonyl)propionyl] cyclopropylamino] propionic acid (1:1), MS (ion location is the following acids:

a) 3-[(S)-3-[(R, S)-[1-(aminoiminomethyl)piperidine-3-ylmethyl] -N - methylcarbamoyl] -N-butyl-2-(naphthalene-2-ylsulphonyl)propionamido] propionic acid, MS (ion spray): 603,5 (M + H)+,

b) 3-[[(S)-3-[[(R, S)-2-(aminoiminomethyl)piperidine-3-ylmethyl)] - methylcarbamoyl]-2-(naphthalene-2-ylsulphonyl) propionyl]cyclopropylamino]propionic acid, MS (ion spray): for 587.4 (M + H)-.

Example 23. The complex solution of tert-butyl methyl ether (S)-3-[(S)-3-[(4-chlorbenzyl)-methoxycarbonylmethylene] -3- (naphthalene-2-ylsulphonyl)-propiomelanocortin-1 - carboxylic acid in 20 ml of methylene chloride is mixed with 4 ml triperoxonane acid. After mixing, the solution is evaporated, the residue is dissolved in 2.7 ml of methanol and mixed with 0,93 ml of triethylamine and 330 mg of formamidinesulfinic. Then again add 165 mg formamidinesulfinic and to 0.19 ml of triethylamine. After stirring the reaction mixture was concentrated and chromatographic the residue on silica gel with a mixture of ethyl acetate, the acetate, acetic acid and water 6:2:1:1. Get 516 mg complex methyl ester N-[(N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2 - naphthylmethyl)-L-asparaginyl] -N-(4-chlorbenzyl)glycine (1: 1), MS (ion spray): 657 (M + H)+.

+C add 52,85 ml 2H of sodium hydroxide. After stirring added dropwise 53 ml 1H hydrochloric acid. The reaction mixture is placed in 800 ml of simple ether and phase simple ether/dioxane washed with water. After drying and evaporating the organic phase, the residue is crystallized in a simple ether. After filtering off the crystals get 13,7 g complex 4-tert-butyl ether N-(2-naphthylmethyl)-L-aspartic acid, so pl. 141+C.

b) 20 g of the hydrochloride complex licensedialog ether and 34.8 g of di-tert-BUTYLCARBAMATE in 300 ml of methylene chloride and 10 ml of water are added dropwise to 22.2 ml of triethylamine. After stirring the reaction mixture was concentrated. The residue is placed in a simple ether and the ether phase after submitting 5 ml 1H hydrochloric acid, washed with water. After drying and evaporation receive 30,2 g N-Boc-complex licensedialog ether. Rf = 0,33 (simple ether/hexane 1:1).

To 1.0 g of a crude product of stage b) and 937 mg of 4-chlorobenzylchloride in 10 ml of DMF under ice cooling type 242 mg of sodium hydride (55% in oil). After stirring the reaction mixture was placed in a 100 ml simple ether and washed with water. After drying and evaporating the ether phase balance chromatographic through silica gel cmsuper/hexane 1:2).

g) 1,275 g of the product of stage C) is mixed with 5 ml 10H hydrochloric acid in methanol. The methanol is evaporated and the residue is placed in 20 ml simple ether and filtered. After washing the residue with a simple ether get 0,93 g of the hydrochloride of N-(4-chlorbenzyl)-complex licensedialog ether, Rf = 0,59 (ethyl acetate/acetone/water/glacial acetic acid, 6:2:1:1).

d) Dissolved 567 mg of the product of stage (a), (394 mg of the product of stage d), 636 mg of BOP and 0.5 ml of base Gunga in 8 ml of methylene chloride. After stirring the reaction mixture is extracted with 100 ml of simple ether and the ether phase is washed with hydrochloric acid and water. After drying and evaporating the ether phase balance chromatographic through the simple silica gel with ether/hexane 2:1. Get 926 mg complex tert-butyl ether (S)-N-(4-chlorbenzyl)-N-methoxycarbonylmethyl-3-(naphthalene-2 - ylsulphonyl)-succinamide acid, MS (ion spray): 575 (M+).

e) 926 mg of the product of stage d) is mixed with 6 ml of 5-molar hydrochloric acid in dioxane. After stirring the reaction mixture is extracted with 100 ml of simple ether and the ether phase is washed with water. After drying and evaporation receive 877 mg (S)-N-(4-chlorbenzyl)-N-methoxycarbonylmethyl-3-(naphthalene-2-sulfonylamino)-succinamic the mg tert-butyl ether (S)-3-aminomethyl-1-piperidinecarboxylic acid, 785 mg of BOP and of 0.58 ml base Gunga mixed in 12 ml of methylene chloride. The reaction mixture is extracted with 100 ml of simple ether and the ether phase is washed 1H hydrochloric acid and water. After drying and evaporation phase simple ester residue chromatographic through silica gel with a mixture of ethyl acetate/hexane 4: 1. Get 951 mg complex tert-butyl ether (S)-3-[(S)-3-[(4-chlorbenzyl)-methoxycarbonylmethylene] -3- (naphthalene-2-ylsulphonyl)propiomelanocortin]-1 - carboxylic acid, MS (ion spray): 715 (M + H)+.

Example 24. A solution of 300 mg of the ester product from example 23 in 3 ml of THF is mixed with 1.25 ml 1H LiOH. After mixing and conveying of 2 ml of acetic acid is evaporated and the residue chromatographic on silica gel using ethyl acetate-acetone-acetic acid-water 6:2:1:1. Get 154,5 mg of N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl]-N2-(2-naphthylmethyl)- L-asparaginyl] -N-(4-chlorbenzyl)glycine, MS (ion spray): 641 (M - H)-.

Example 25. Analogously to example 23 receive the following esters:

(a) acetate N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2-naphthylmethyl)- L-asparaginyl] -N-(m-Chlorobenzyl)licensedialog ether (1: 1), MS (ion spray): 657 (M + H)-,

b) acetate N-[N4-[[(S)-1-AMI is Noe spray): 657 (M + H)+,

in) acetate methyl ester [N-[(S)-3-[(S)-1-amidinopropane-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl]-N-(4-methoxybenzyl) amino]acetic acid (1:1), MS (ion spray): 653 (M + H)+,

g) acetate methyl ester [N-[(S)-3-[(S)-1-amidinopropane-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl]-N-(pyridine-2-ylmethyl) amino]acetic acid (1:2), MS (ion spray): 624 (M + H)+,

e) acetate methyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] -(3-methoxybenzyl) amino] acetic acid (1:1), MS (ion spray): 653 (M + H)+.

Example 26. Analogously to example 24 from esters of example 25 receive the following acids:

a) N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-naphthylmethyl)- L-asparaginyl]-N-(m-Chlorobenzyl)glycine, MS (ion spray): 641 (M - H)+,

b) N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-naphthylmethyl)- L-asparaginyl]-N-(o-Chlorobenzyl)glycine, MS (ion spray): 641 (M - H)+,

C) [N-[(S)-3-[(S)-1-amidinopropane-3-letiltasaval]-2- (naphthalene-2-ylsulphonyl)-propionyl] -N-(4-methoxybenzyl) amino]acetic acid, MS (ion spray): 639 (M + H)+,

d) hazemeter) amino]acetic acid, MS (ion spray): 610 (M + H)+,

e) [[(S)-3-[(S)-1-(aminoiminomethyl)piperidinyl-3-yl-methylcarbamoyl] -2- (naphthalene-2-ylsulphonyl)-propionyl] -(3-methoxybenzyl) amino] acetic acid, MS (ion spray): 639 (M + H)+.

Example 27. Analogously to example 23, but using the corresponding esters aminocarbonyl acids instead of hydrochloride of N-(4-chlorbenzyl)licensedialog ester (example 23gr), get the following esters:

(a) acetate complex methyl ester of L-N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2-naphthylmethyl)- L-asparaginyl]-1-phenylglycine (1:1), MS (ion spray): 609 (M + H)+,

b) acetate complex methyl ester N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl]-N2-(2-naphthylmethyl)- L-asparaginyl]-L-isoleucine (1:1), MS (ion spray): 589 (M + H)+,

in) acetate complex methyl ester N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-naphthylmethyl)- L-asparaginyl] -L-valine (1:1), MS (ion spray): 575 (M + H)+,

g) acetate complex methyl ester N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-naphthylmethyl)- L-asparaginyl] -D-leucine (1:1), MS (ion spray): 589 (M + H)+,

e) acetate complex methyl ester N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-NAF methyl ester N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl]-N2-(2-naphthylmethyl)- L-asparaginyl]-N-methyl-L-isoleucine (1:1), MS (ion spray): 603 (M + H)+,

W) acetate complex methyl ester (R)-2-[(S)-3-[(S)-1-(aminoiminomethyl)piperidinyl-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionamido]-3-phenylpropionic acid (1:1), MS (ion spray): 623 (M + H)+.

Example 28. Analogously to example 24 from esters of example 27 receive the following acids:

a) the acetate of L-N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl-N2-(2-naphthylmethyl)-L - asparaginyl]-2-phenylglycine (1:1), MS (ion spray): 595 (M + H)+,

b) N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl-N2-(2-naphthylmethyl)-L - asparaginyl]-L-isoleucine, MS (ion spray): 575 (M + H)+,

C) N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl-N2-(2-naphthylmethyl)-L - asparaginyl]-L-valine, MS (ion spray): 561 (M + H)o,

g) N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl-N2-(2-naphthylmethyl)-L - asparaginyl]-D-leucine, MS (ion spray): 575 (M + H)o,

d) N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl-N2-(2-naphthylmethyl)-L - asparaginyl]-N-methyl-L-isoleucine, MS (ion spray): 589 (M + H)+,

e) N-[N4-[[(S)-1-amidino-3-piperidinyl] methyl] -N2-(2-naphthyl - sulfonyl)-L-asparaginyl]-N-METI-L-valine, MS (ion spray): 575 (M + H)+,

W) (R)-2-[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3 - ilma is (e): 609 (M + H)3.

Example 29. A solution of 1.09 g of complex tert-butyl ether (S)-3-[(S)-3-[butyl[2-(amoxacillin)ethyl] carbarnoyl] -3-(naphthalene-2 - ylsulphonyl)propenolatomethyl]piperidin-1-carboxylic acid in 20 ml of methylene chloride is mixed with 4 ml triperoxonane acid. After stirring the concentrate, the remainder Usacheva simple ether and then after settling simple remove the ether. To the residue add 3 ml of methanol, of 1.06 ml of triethylamine and 377 mg formamidinesulfinic. After stirring again add 1 equivalent of formamidinesulfinic and triethylamine. The mixture of concentrate and chromatographic on silica gel using ethyl acetate-acetone-acetic acid-water 6: 2:1:1. Get 962 mg of the acetate complex methyl ester [2-[[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3 - letiltasaval] -2-(naphthalene-2-ylsulphonyl)-propionyl] butylamino] ethyl] examinados acid (1:1), MS (ion spray): 646 (M + H)3.

Obtaining source material:

a) 7.0 g of the hydrochloride of 2-butylaminoethyl (Org. Synth/IV 1963, 333) is stirred together with 7.9 g of sodium azide in 50 ml of DMF at 502C. After cooling, added dropwise 82 ml 1H of sodium hydroxide. The mixture is extracted with 700 ml of simple ether, washed with water, Phnom phase balance Usacheva simple ether, filtered off the crystals and wash them with a simple ether. Get 5 g of the hydrochloride of 2-butylaminoethyl, Rf = 0,14.

b) For cent to 8.85 g of 4-tert-butyl ether N-(2-naphthylmethyl)-L - aspartic acid (example 23a) in 120 ml of methylene chloride add 5.0 g of the hydrochloride of 2-butylaminoethyl, 10.8 g of BOP and 11,98 ml base Gunga. After stirring to 600 ml of simple ether and the ether phase is washed 1H hydrochloric acid and water. After drying and evaporating the ether phase balance chromatographic through silica gel using methylene chloride/simple ether 19: 1 and get 6,18 g complex tert-butyl ether (S)-[3-[(2-azidoethyl)-butylcarbamoyl]-3- (naphthalene-2-ylsulphonyl)propionic acid, Rf = 0,42 (methylene chloride/simple ether 9:1).

in) 6,18 g of the product of stage b) is mixed with 60 ml 5H hydrochloric acid in dioxane. After stirring extracted with 400 ml of simple ether and the ether phase is washed with water. After drying and evaporating get to 5.58 g (S)-[3-[(2-azidoethyl)-butylcarbamoyl] -3-(naphthalene-2-ylsulphonyl) propionic acid, Rf = 0.21 in (ethyl acetate).

g) to 5.57 g of the product of stage b), 3.3 grams of complex tert-butyl ether (S)-3-aminomethyl-1-piperidinecarboxylic acid, 5,97 g of BOP and 4.4 ml of base Gunga re what slotow and water. After drying and evaporation the product chromatographic on silica gel using ethyl acetate/hexane 4: 1 and get to 6.43 g complex tert-butyl ether (S)-[3-[(2-azidoethyl)-butylcarbamoyl] -3-(naphthalene-2-ylsulphonyl) propenolatomethyl]piperidine-1-carboxylic acid (ethyl acetate/hexane 4:1).

d) to 6.43 g of the product of the previous stage are mixed in 60 ml of methanol with 650 ml of 5% Pd/C and hydronaut in normal conditions. The catalyst is filtered off and the filtrate concentrated. Get 5,86 complex tert-butyl ether (S)-3-[(S)-3-[(2-amino-ethyl)-butylcarbamoyl] -3-(naphthalene-2-ylsulphonyl) propenolatomethyl]piperidine-1-carboxylic acid, Rf = 0,33 (ethyl acetate/acetone/water/acetic acid, 6:2:1:1).

e) To 1.2 g of the product of stage d) and 0.32 ml of pyridine at 0-5+With added dropwise a solution of 0.23 ml of monoethylene ester acid chloride of oxalic acid in 6 ml of methylene chloride. After mixing, the mixture is extracted with 100 ml of simple ether and the ether phase is washed 1H hydrochloric acid and water. After drying and evaporation the product was then purified on silica gel using ethyl acetate. Get 1,09 g complex tert-butyl ether (S)-3-[(S)-3-[butyl[2-(amoxacillin)ethyl]carbarnoyl]-3-(naphthalene-2 - ylsulphonyl)propionamido ester from example 29 6.7 ml of THF is mixed with 2.8 ml of 1H spectrum of a solution of lithium hydroxide. The mixture is then mixed with 4 ml of acetic acid and concentrated. The residue is purified on silica gel using ethyl acetate-acetone-acetic acid-water 6:2:1:1. Receive 461 mg of [2-[[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)propionyl]butylamino]etoloxamine acid, MS (ion spray): 632 (M + H)+.

Example 31. Analogously to example 29, but using the stage a) of acetanhydride, b) methanesulfonamide,) SO+-N(CH+)+complex or g) complex of methyl ether of Harborview acid, instead of monoethylene ester acid chloride of oxalic acid used in example 29 to obtain the following compounds:

(a) acetate (S)-N1-(2-acetylamino)-N4-[(S)-1-(aminoiminomethyl) piperidine-3-ylmethyl]-N1-butyl-2-(naphthalene-2-ylsulphonyl) succinamide (1:1), MS (ion spray): 602 (M + H)o,

b) acetate (S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl]-N1 - butyl-N1-(2-methanesulfonylaminoethyl)-2-(naphthalene-2-sulfonylamino) succinamide (1:1), MS (ion spray): 638 (M + H)+,

C) (S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1 - butyl-2-(naphthalene-2-sulfonylamino)-N1-(sulfamidate) succinamide, MS (ion spray): 640 (M + H)+,

g) acetate difficult is propionyl] butylamino] ethylcarbamate acid (1:1), MS (ion spray): 618 (M + H)+.

Example 32.

A) Analogously to example 29 or 30 will receive the following products:

(a) acetate complex propyl ester 3-[(S)-3-[(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)propionyl]-N-cyclopropylmethoxy acid (1:1), MS (ion spray): 601,3 (M + H)+or

b) acetate (S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-cyclopropyl - N1-(3-hydroxypropyl)-2-(naphthalene-2-ylsulphonyl] succinamide (1:1), MS (ion spray): 559 (M + H)+.

B) Receiving the original amine used instead of hydrochloride of 2-butylaminoethyl (example 29A):

a) To a solution of 6,86 N-Boc-cyclopropylamine and of 13.27 g of 3-(tert-butyldimethylsilyloxy)propyl bromide in 70 ml of DMF added at 0-5+With 2.0 g of sodium hydride (55% in oil). After mixing, the mixture is extracted with simple ether and the ether phase is washed with water. After drying and evaporating the ether phase and chromatography on silica gel using a simple ether/hexane 1:9 receive 11,73 g complex tert-butyl ester [3-(tert-butyldimethylsilyloxy)propyl] -cyclopropylamino acid, Rf = 0,38 (simple ether/hexane 1:4).

b) 11,73 g of the product of stage a) is dissolved and the ether phase is washed with water. After drying and evaporation receive 7,02 g N-Boc-cyclopropylmethanol, Rf = 0,47 (methylene chloride/simple ether 1:1).

C) a Solution of 1.92 g of the product of stage b) in 19 ml of methylene chloride is mixed with the 1.44 ml of pyridine and of 0.89 ml acetanhydride. After mixing, the solution is extracted with simple ether and the ether phase is washed 1H hydrochloric acid and water. After drying and evaporating the ether phase and chromatography on silica gel using a simple ether/hexane 1:2 to obtain 2.3 g of N-Boc-cyclopropanecarboxylate, Rf = 0,18 (simple ether/hexane 1:2).

g) 2.3 g of the product of stage C) is mixed with 23 ml of a 4.3 M hydrochloric acid in dioxane. After evaporation of the solvent the residue Usacheva simple ether and then the ether is removed. After drying gain of 1.61 g of the hydrochloride difficult methyl ester 3-cyclopropylamino acid (1: 1), Rf = 0,17 (ethyl acetate, acetone, acetic acid, water 6:2:1:1).

Example 33. Analogously to example 12 from tert-butyl ether (R)-3-[[(S)-3-(benzylaminocarbonyl)-3-(naphthalene-2-ylsulphonyl)- propionyl] -ethoxycarbonylmethylene]-piperidine-1-carboxylic acid get:

the sulfite complex ethyl ester [[(R)-1-(aminoiminomethyl)- piperidine-3-ylmethyl] -(S)-(benzylaminocarbonyl)-3-(S="ptx2">

Obtaining source material:

To a solution of 7.6 g of 4-complex tert-butyl ether N-(2-naphthylmethyl)-L-aspartic acid (example 23a) in 80 ml of methylene chloride add to 8.1 ml of 4-ethylmorpholine, 4.6 g of the hydrochloride of N-(dimethylaminopropyl)-N'-ethylcarbodiimide, 0.24 g of 4-dimethylaminopyridine and 2.6 ml of N-benzylmethylamine. After stirring the reaction mixture was poured into ice-cold 5% solution of potassium hydrosulfate - 10% solution of potassium sulfate and extracted with methylene chloride. The organic phase is washed with sodium chloride solution, dried and evaporated. The remainder chromatographic using hexane/ethyl acetate (3:1) on silica gel. Allocate 3.4 g complex tert-butyl ether (S)-N-benzyl-N-methyl-3-(naphthalene-2 - ylsulphonyl)succinimido acid, MS (ion spray): 483 (M + H)o.

b) From the product of stage 4 is similar to example 12) get complicated tert-butyl ether (R)-3-[[(S)-3-(benzylaminocarbonyl)-3-(naphthalene-2-ylsulphonyl)- propionyl]ethoxycarbonylmethylene]piperidine-1-carboxylic acid, MS (ion spray): 709,5 (M + H)+.

Example 34. A solution of 0.2 g of ester from example 33 in 10 ml of methanol is mixed with 1.4 ml of 1H of sodium hydroxide. After stirring the reaction solution -18. Allocate 0.1 g of hydrochloride [[(R)-1-(aminoiminomethyl)piperidine-3 - ylmethyl]-[(S)-3-(benzylaminocarbonyl)-3-(naphthalene-2-ylsulphonyl)- propionyl] amino]-acetic acid (1:1), MS (ion spray): 623,3 (M + H)+.

Example 35. Analogously to example 9, but on the basis of 1-tert-butyl ether (S)-N-benzyl-N-methyl-3-(naphthalene-2-ylsulphonyl)succinimido acid (example 33a) receive hydrochloride (S)-N4-[(R,S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-benzyl - N4-(2-hydroxyethyl)-N1-methyl-2-(naphthalene-2-ylsulphonyl)succinamide (1: 1), MS (ion spray): 609,3 (M + H)o.

Example 36. Analogously to example 1 from dihydrochloride complex tert-butyl ether (S)-N-cyclopropyl-N-(2-tetrazol-5-yl-ethyl)-3-naphthalene-2-ylsulphanilamide acid and from dihydrochloride (S)-1-amidino-3-(aminomethyl)piperidine get:

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1 - cyclopropyl-N1-(2-tetrazol-5-yl-ethyl)-2-(naphthyl-2-ylsulphonyl)- succinamide, MS (ISP): 597,4 (M + H)2.

Obtaining raw materials:

AA) Analogously to example 2B)d), but using 3-cyclopropanecarbonitrile instead of complex sarcosinates ether get complicated tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-cyclo using complex ether phase a) instead of complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-ethoxycarbonylmethyl-N - methylsuccinimide acid, get complex tert-butyl ether (S)-N-cyclopropyl-N-(2-cyanoethyl)-3-naphthalene-2 - ylsulphanilamide acid, MS (FAB): 414 (M-isobutylene).

AB) To a solution of 2.3 g of the compound obtained in stage b), in 25 ml of DMF alternately add 0.7 g of ammonium chloride and 0,86 g of sodium azide. The reaction mixture is stirred for 24 hours at 80+C, cooled, filtered and the filtrate is evaporated. After chromatographic separation of the residue on silica gel using ethyl acetate + 0.5% of acetic acid to obtain 0.3 g of complex tert-butyl ether (S)-N-cyclopropyl-N-(2-tetrazol-5-yl-ethyl)-3-naphthalene-2 - ylsulphanilamide acid, MS (ISP): 515,4 (M + H)+.

BA) a Solution of 42.5 g of N-(3-pyridinylmethyl)-benzamide in 220 ml of ethanol and 220 ml 1H hydrochloric acid is mixed with 4.2 g of palladium on coal and hydronaut hydrogen for 24 hours at room temperature and pressures above 100 atmospheres. Then the catalyst is filtered off and the filtrate is evaporated. The residue is extracted with methylene chloride and shaken with 1H sodium hydroxide. The organic phase is washed with water, dried and evaporated. Get 36,1 g (R)-N-piperidine-3-iletilmesine, MS (FAB): 218 M+.

BB) at 36.1 g of the product obtained in the previous phase, westpomerania add 380 ml simple ether. After priming vykristallizovyvalas of 32.5 g of salt. Repeated recrystallization from 420 ml of methylene chloride, 10 ml of methanol and 140 ml of a simple broadcast network 19.5 g (R)-N-piperidine-3-ylmethyl-benemid-(R)-hydroxyphenylacetate (1:1), so pl. 75+With decomposition.

BV) 19.3 g of salt almond acid, obtained in stage IB), suspended in 193 ml of DMF, mixed with 21,7 ml of triethylamine and 7.75 g formamidinesulfinic and stirred at room temperature. The reaction mixture is evaporated and the residue chromatographic on silica gel RP-18 with water-acetonitrile. Allot of 13.4 g (S)-N-[1-(aminoiminomethyl)-piperidine-3-ylmethyl] -benzamide-(R)- oxyphenisatin (1:1), MS (FAB): 218 M-(H+N-CN).

BG) of 13.4 g of salt almond acid obtained in the preceding stage, dissolved in 267 ml of concentrated hydrochloric acid and refluxed. After cooling, the solution is extracted with simple ether, then the aqueous phase is evaporated and use of ethanol is subjected to the azeotropic distillation. The remainder Usacheva in 50 ml of ethanol, cooled in an ice bath and filtered. Obtain 4.6 g of the dihydrochloride of (S)-1-amidino-3-(aminomethyl)piperidine []D= -16,3+(c = 1.0 in water).

Example 37. Analogously to example 1, but with use the of namata, receive hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl] -N1-(2 - carbamoylethyl)-N1-cyclopropyl-2-(naphthyl-2-sulfonylamino)succinamide, MS (ISP): 572,3 (M + H)+.

Example 38.

38A) Analogously to example 1 given the following connections:

AA) of complex tert-butyl ether (S)-3-(4-cyclopentanecarbonyl)-N-cyclopropyl-N-(2-ethoxycarbonylethyl)succinimido acid

hydrochloride complex ethyl ester 3-[cyclopropyl-[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(4-cyclopentadienylmanganese)-propionyl] -amino]propionic acid, MS (FAB): 619,2 (M + H)+.

38 AB) from the complicated methyl ester (S)-2-[2-tert-butoxycarbonyl-1-[cyclopropyl-(2-ethoxycarbonylethyl)- carbarnoyl] ethylsulfanyl] benzoic acid

hydrochloride difficult methyl ester 2-[(S)-2-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -1-[cyclopropyl-(2-ethoxycarbonylethyl)carbarnoyl] - ethylsulfanyl]-benzoic acid, MS (ISP): 609,4 (M + H)+.

AV) of complex tert-butyl ether (S)-N-cyclopropyl-N-ethoxycarbonylmethyl-3-naphthalene-1 - ylsulphanilamide acid

hydrochloride complex ethyl ester [[(S)-3-[(S)-(1-aminoiminomethyl)-piperidine-3-Ilme+.

AG) of complex tert-butyl ether (S)-N-cyclopropyl-N-(2-ethoxycarbonylethyl)-3-(4 - triftormetilfullerenov)succinimido acid

hydrochloride complex ethyl ester 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2- (4-triftormetilfullerenov)-propionyl]cyclopropylamino]propionic acid, MS (ISP): 635,5 (M + H)+.

Ad) of complex tert-butyl ether (S)-3-(4-cyanobenzenesulfonyl)-N-cyclopropyl-N- (2-ethoxycarbonylethyl)succinimido acid

hydrochloride complex ethyl ester 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2- (4-sanofisynthelabo)-propionyl] cyclopropylamino] propionic acid, MS (ISP): 576,7 (M + H)+.

AE) of complex tert-butyl ether (S)-N-cyclopropyl-N-(2-ethoxycarbonylethyl)-3 - methanesulfonylaminoethyl acid

hydrochloride complex ethyl ester 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2 - methylsulfonylbenzoyl]cyclopropylamino]propionic acid, MS (ISP): 489 (M + H)+.

A) of complex tert-butyl ether (S)-N-cyclopropyl-N-(2-ethoxycarbonylethyl)-3-(pyridine-3 - ylsulphonyl]succinamide acid
the INF-3-isalphanumeric] cyclopropylamino]propionic acid, MS (ISP): 552,6 (M + H)+.

38B) Obtaining source material:

The original complex diesters get similar method in example 2B)and from complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N-cyclopropyl-N-(2 - ethoxycarbonylethyl)succinimido acid (example 2B)C)1) using the appropriate arylsulfonamides instead of 2-afterculture:

BA) complex tert-butyl ether (S)-3-(4-cyclopentanecarbonyl)-N-cyclopropyl-N- (2-ethoxycarbonylethyl)succinimido acid, MS (FAB): 481 (M-isobutylene);

B) methyl ester (S)-2-[2-tert-butoxycarbonyl-1-[cyclopropyl-(2 - ethoxycarbonylethyl)-carbarnoyl] ethylsulfanyl] benzoic acid, MS (FAB): 471 (M-isobutyl);

BW) complex tert-butyl ether (S)-N-cyclopropyl-N-ethoxycarbonylmethyl-3-naphthalene-1 - ylsulphanilamide acid, MS (ISP): 505,3 (M + H)+;

BG) complex tert-butyl ether (S)-N-cyclopropyl-N-(2-ethoxycarbonylethyl)-3-(4 - triftormetilfullerenov)succinimido acid, MS (FAB): 497 (M-isobutylene);

BD) complex tert-butyl ether (S)-3-(4-cyanobenzenesulfonyl)-N-cyclopropyl-N-(2 - ethoxycarbonylethyl)succinimido acid, MS (ISP): 494,2 (M + H)+;

Be) complex tert-butyl ether (S)-N-zikbj) complex tert-butyl ether (S)-N-cyclopropyl-N-(2-ethoxycarbonylethyl)-3-(pyridine-3 - ylsulphonyl)succinimido acid, MS (ISP): 470,2 (M + H)+.

Example 39. Analogously to example 3, but based on esters of example 38A, you receive the following acids:

a) 3-[cyclopropyl-[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(4-cyclopentadienylmanganese)-propionyl] amino]propionic acid, MS (FAB): 591,3 (M + H)+;

b) 2-[(S)-2-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-1-[cyclopropyl-(2-ethoxycarbonylethyl)-carbarnoyl] ethylsulfanyl]betinol acid, MS (ISP): 567,2 (M + H)+;

C) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-naphthalene-1-insulinindependent] cyclopropylamino] acetic acid, MS (FAB): 559,4 (M + H)+;

g) 3-[N-cyclopropyl-N-[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-(4-triftormetilfullerenov)- propionyl] amino] propionic acid, MS (FAB): 607,2 (M + H)o;

e) 3-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval]-2-(4-sanofisynthelabo) propionyl]cyclopropylamino]propionic acid, MS (ISP): 548,5 (M + H)+;

e) 3-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval]-2-(4-carbamoyltransferase) propionyl] cyclopropylamino] propionic acid, MS (ISP): 566,6 (M + H)+;

g) 3-[[(S)-3-[(S)-1-(aminoiminomethyl)- Pieper is-;

C) 3-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval]-2-pyridine-3-isalphanumeric] cyclopropylamino]propionic acid, MS (ISP): 524,3 (M + H)-.

Example 40. Analogously to example 1 receive acetate complex ethyl ester 3-[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -N-cyclopropyl-2-(4-tetrazol-5-Elfershausen)- propionamido] propionic acid, MS (ISP): 619,4 (M + H)+.

Obtaining raw materials:

1.4 g of complex diapir obtained in example BD), dissolved in 14 ml of DMF, mixed with 410 mg of ammonium chloride and 500 g of sodium azide and stirred for 24 hours at 80+C. After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated. Allocate 1.8 g complex tert-butyl ether (S)-N-cyclopropyl-N-(2-ethoxycarbonylethyl)-3-(4-tetrazol-5 - Elfershausen)-succinamide acid, MS (ISP): 537,4 (M + H)+.

Example 41. Analogously to example 3 from a complex ester of example 40 receive 3-[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -N - cyclopropyl-2-[4-(tetrazol-5-yl)-phenylcarbonylamino] propionamido] propionic acid, MS (ISP): 591,4 (M + H)o.

Example 42. Analogously to example 1, but p is about ester of N-Boc-D-aspartic acid instead of - complex tert-butyl ether N-Boc-L-aspartic acid:

hydrochloride complex ethyl ester [[(R)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] cyclopropylamino]acetic acid, MS (ISN): 585,4 (M - H)+,

b) of the dihydrochloride of (R)-1-amidino-3-(aminomethyl)piperidine instead dihydrochloride (S)-1-amidino-3-(aminomethyl)piperidine;

hydrochloride complex ethyl ester [[(S)-3-[(R)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] cyclopropylamino]acetic acid, MS (ISN): 585,7 (M - H)+,

in) from complex tert-butyl ether N-Boc-D-aspartic acid instead of complex tert-butyl ether N-Boc-L-aspartic acid dihydrochloride (R)-1-amidino-3-(aminomethyl)-piperidine instead dihydrochloride (S)-1-amidino-3-(aminomethyl)-piperidine

hydrochloride complex ethyl ester [[(R)-3-[(R)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2- (naphthalene-2-ylsulphonyl)- propionyl] cyclopropylamino]acetic acid, MS (ISP): 587,6 (M + H+.

Obtaining initial guanidine of example 42B):

In a manner analogous to example 36B), but when using L-almond acid instead of D-almond acid, (R)-N-[1-(aminoiminomethyl)-piperidine-3-ylmethyl]-benzamide- (S)hydroxyphenylacetate (1:1), MS (ISP): 261,4 (M + H)+< / BR>
- dihydrochloride (R)-1-amidino-3-(aminomethyl)piperidine []2D0= +17,6+(c = 1.0 in water).

Example 43. Analogously to example 3 of the esters of example 42 receive the following acids:

a) [[(R)-3-[(S)-1-(amylinomimetic)-piperidine-3-letiltasaval] -2-(naphthalene-2-ylsulphonyl)-propionyl] cyclopropylamino] acetic acid, MS (ISP): 559,5 (M + H)+,

b) [[(S)-3-[(R)-1-(amylinomimetic)-piperidine-3-letiltasaval] -2-(naphthalene-2-ylsulphonyl)-propionyl] cyclopropylamino] acetic acid, MS (ISP): 559,5 (M + H)+,

C) [[(R)-3-[(R)-1-(amylinomimetic)-piperidine-3-letiltasaval] -2-(naphthalene-2-ylsulphonyl)-propionyl] cyclopropylamino] acetic acid, MS (ISP): 559,5 (M + H)+.

Example 44. Analogously to example 1 from the corresponding complex tert-butyl ester and using trifenatate racemic 2-(aminomethyl)-4-morpholinylcarbonyl (example 7B)instead dihydrochloride (S)-amidino-3-(aminomethyl)-piperidine receive the following products:

a) from complex tert-butyl ether (S)-N-cyclopropyl-N-(2-tetrazol-5-yl-ethyl)-3-(naphthalene-2 - ylsulphonyl)succinimido acid (example IV);

(S)-N(4)-(4-aminoiminomethyl)-morpholine-2-elmete (M + H)+,

b) complex tert-butyl ether (S)-N-cyclopropyl-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl] -3- (naphthalene-2-ylsulphonyl)succinimido acid (example d):

hydrochloride (S)-N(4)-[4-(aminoiminomethyl)-morpholine-2-ylmethyl] - N(1)-cyclopropyl-N(1)-[2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethyl]-2- (naphthalene-2-ylsulphonyl)-succinamide(1: 1), (1:1)-ephemera mixture, MS (ISP): 613,7 (M + H)+.

Example 45. Analogously to example 1 from the corresponding esters using trifenatate racemic 2-(aminomethyl)-4-morpholinylcarbonyl instead dihydrochloride (S)-1-amidino-3-(aminomethyl)piperidine receive the following products:

a) from complex tert-butyl ether (S)-N-cyclopropyl-N-ethoxycarbonylmethyl-3-(naphthalene-2-ylsulphonyl) succinimido acid (example 2B)g)1):

hydrochloride complex ethyl ester [[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] -2-(naphthalene - 2-ylsulphonyl)-propionyl] cyclopropylamino]acetic acid(1:1), (1:1)-ephemera mixture, MS (IPS): 589,5 (M + H)o,

b) esters of example b:

triptorelin difficult methyl ester 2-[(S)-2-[4-(aminoiminomethyl)-morpholine-2-letiltasaval]-1-(2 - ethoxycarbonylethyl)cyclopropanecarbonyl)ethylsulfanyl] benzoic sour the x esters of example 45, get the following acids:

a) [[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] -2- (naphthalene-2-ylsulphonyl)propionyl] cyclopropylamino] acetic acid (1: 1)-ephemera mixture, MS (ISP): 561,4 (M + H)+,

b)1) 2-[(S)-2-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] -1- [cyclopropyl-(2-ethoxycarbonylethyl)carbarnoyl] ethylaminomethyl] benzoic acid (1:1)-ephemera communication, MS (ISP): 597,5 (M + H)+,

b)2) 2-[(S)-2-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] -1- [(2-carboxyethyl)-cyclopropanecarbonyl] ethylaminomethyl] benzoic acid (1:1)-ephemera communication, MS (ISP): 569,4 (M + H)o.

Example 47. Analogously to example 1 receive hydrochloride (S)-N4-[(S)-1- (aminoiminomethyl)-piperidine-3-ylmethyl] -N(1)-cyclopropyl-N(1)-[2- (5-methyl-1,2,4-oxadiazol-3-yl)ethyl] -2-(naphthalene-2-ylsulphonyl) succinamide, MS (ISP): 597,4 (M + H)o.

Obtaining source material:

a) To a solution 29,2 g 3-cyclopropanecarbonitrile in 300 ml of dioxane is added dropwise at room temperature, add a solution of 57.8 g of di-tert-BUTYLCARBAMATE in 300 ml of dioxane. The solution is stirred over night at room temperature and then evaporated. Get to 58.1 g of the crude complex tert-butyl ether (2-cyanoethyl)-cyclopropylamino the La and 23 ml of water is added 6.6 g of hydroxylamine hydrochloride and 13.6 g of decahydrate sodium carbonate. The reaction mixture is refluxed, evaporated, the residue is suspended in hot ethanol and filtered. The filtrate is evaporated and the residue recrystallized from isopropanol-hexane. The resulting crystals are dissolved in 100 ml of acetanhydride and stirred at 80+C. Then the reaction mixture is evaporated, the residue is mixed with a saturated solution of sodium carbonate and extracted with ethyl acetate. The organic phase is evaporated and the residue chromatographic using hexane-ethyl acetate 3:1 on silica gel. Get 5,4 g complex tert-butyl ether cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethylcarbamate acid, MS (FAB): 211 (M-isobutylene).

in) of 5.2 g of the material obtained in stage b), dissolved in 30 ml of ethyl acetate, mixed with a 4 molar solution of hydrochloric acid in ethyl acetate and stirred at room temperature. The solution is evaporated, the residue Usacheva in ethyl acetate and filtered. Allocate 3.7 g of the hydrochloride cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethylamine, MS (FAB): 167 (M+).

g) Similarly to the method of example 2B)d), but using obtained at the previous stage of the amine hydrochloride instead of complex ethyl ester hydrochloride methylaminoethanol acid,yl)ethyl]succinamide acid, MS (ISP): 439,6 (M + H)+.

d) Analogously to the method of example 2B)and), but when using obtained in stage d) complex diapir instead of complex tert-butyl ether (S)-3-tert-butoxycarbonylamino-N - ethoxycarbonylmethyl-N-methylsuccinimide acid, receive complex tert-butyl ether (S)-N-cyclopropyl-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]-3- (naphthalene-2-ylsulphonyl)succinimido acid, MS (FAB): 473 (M-isobutylene).

Example 48. Analogously to example 1 from complex tert-butyl ether (S)-N-cyclopropyl-N-ethoxycarbonylmethyl-3- (naphthalene-2-sulfonylamino)succinimido acid (example 2B)g)1)) when using hydrochloride complex ethyl ester (S)-(3-aminomethylpyridine-1-yl)-aminomethylenemalonate acid instead dihydrochloride (S)-1-amidino-3-(aminomethyl)piperidine get complicated ethyl ester [cyclopropyl-[(S)-[(S)-1-(ethoxycarbonylmethyl)-piperidine - 3-letiltasaval]-2-(naphthalene-2-ylsulphonyl)propionyl)amino] acetic acid, MS (ISP): 659,6 (M + H)+.

Obtaining source material:

a) To a solution of 10 g of complex tert-butyl ether (S)-3-aminomethyl-1-piperidinecarboxylic acid in 400 ml of hexane and 100 ml of water is added 3.7 g of tetramethylpyrrolidine ammonium and 10 is amerivault for 3 hours at room temperature. Then the organic phase is separated, washed with water, 10% citric acid, water and saturated sodium bicarbonate solution, dried and evaporated. Get tert-butyl(S)-3-[(1-benzyloxy)formimidoyl]-1-piperidinecarboxylate.

b) 11.3 g of the product obtained in stage a), is dissolved in 120 ml of ethyl acetate, mixed at 4+With 120 ml of 4M hydrochloric acid in ethyl acetate and stirred for 5 hours at room temperature. Then the reaction solution is concentrated and the residue is dissolved in 265 ml of DMF, mixed with 18 ml of triethylamine and 4.3 g of formamidinesulfinic and stirred for 17 hours at room temperature. The solvent is evaporated, the residue is mixed with 1H hydrochloric acid, again concentrated and chromatographic using water-acetonitrile column RP-18. Allot of 5.4 g of the hydrochloride benzyl-[[(S)-1-amidino-3-piperidinyl]methyl]carbamate.

C) To a solution of 2.0 g of the hydrochloride benzyl-[[(S)-1-amidino-3-piperidinyl] methyl]carbamate in 200 ml of methylene chloride are added dropwise to 0.55 ml complex ethyl ether of Harborview acid. The reaction mixture was cooled to 0+C. With stirring, added dropwise 113 ml 1H of sodium hydroxide. Then stirred in an ice bath, the phase section is-(ethoxycarbonylmethyl)-piperidine-3 - iletilerinindeki acid, MS (FAB): 363,2 (M + H)o.

g) 1.5 g of the product obtained in the preceding stage, dissolved in 30 ml of ethanol and 30 ml of 1H hydrochloric acid, mixed with 0.2 g of palladium on coal and hydronaut. Obtain 1.4 g of the hydrochloride complex ethyl ester (S)-(3-aminomethylpyridine-1-yl)- aminomethylenemalonate acid, MS (ISP): 229,4 (M + H)o.

Example 49. Analogously to example 48, but using complex isobutyl ether of Harborview acid instead of complex ethyl ether of Harborview acid in example 48V) through a complex isobutyl ester [(S)-(3-benzyloxycarbonylamino-1 - yl)aminomethylenemalonate acid, MS (FAB): 390 M+and through hydrochloride complex isobutyl ester [(S)-3-aminomethylpyridine-1-yl)aminomethylenemalonate acid (1:1), MS (thermocapillary): 257 (M + H)+receive

complex ethyl ester [cyclopropyl-[(S)-3-[(S)-1-(isobutoxyethanol)- piperidine-3-letiltasaval] -2-(naphthalene-2-ylsulphonyl)- propionyl]amino]acetic acid or tautomer amidinopropane, MS (ISP): 687 (M + H)+.

Example 50. Analogously to example 48 but using hydrochloride complex ethyl ester of (RS)-(2-aminomethylation-4-yl)-aminomethylenemalonate acid instead of the Ute:

complex ethyl ester [cyclopropyl-[(S)-3-[4-(ethoxycarbonylmethyl)morpholine-2 - letiltasaval] -2-(naphthalene-2-ylsulphonyl)propionyl]amino] acetic acid (1:1)-ephemera mixture, MS (ISP): 661,5 (M + H)-.

Obtaining source material:

a) To a suspension of 10.3 g of hemisulfate tert-butyl-racemic [(4-amidino-2-morpholinyl)methyl] carbamate (example 7B)b) in 1030 ml of methylene chloride add 3,15 ml complex ethyl ether of Harborview acid. The reaction mixture is cooled to 4+C and added dropwise 637,2 ml of 0.1 H of sodium hydroxide. Then stirred at 5+With, the organic phase is separated, washed with water, dried and evaporated. Allot of 10.5 g complex ethyl ester of (RS)-[2- (tert-butoxycarbonylamino)-morpholine-4-yl] aminomethylenemalonate acid, MS (ISP): 331,4 (M + H)+.

b) 8,9 g obtained in stage a) of the product is dissolved in 50 ml of ethyl acetate, mixed with 50 ml of 4M hydrochloric acid in ethyl acetate and stirred at room temperature. After evaporation the resulting suspension gain of 7.3 g of the hydrochloride complex ethyl ester of (RS)-(2-aminomethylation-4-yl)aminomethylenemalonate acid, MS (ISP): 231,4 (M + H)+.

Example 51. Analogously to example 50 from ecoprofile-N-(2-tetrazol-5-yl-ethyl)-3-naphthalene-2 - ylsulphanilamide acid (example IV)

complex ethyl ester [2-[(S)-3-[cyclopropyl-2-(tetrazol-5 - yl)-ethylcarboxyl] -3-(naphthalene-2-ylsulphonyl)propenolatomethyl] morpholine-4-yl]aminomethylenemalonate acid (1:1)-ephemera mixture, MS (ISP): 671,6 (M + H)-.

b) complex ethyl ester N-[3-tert-butoxycarbonyl-N-(2 - naphthylmethyl)-L-alanyl]-N-cyclopropyl alanine (example 2B)K)9)

complex ethyl ester 3-[[(S)-3-[4-(ethoxycarbonylmethyl)-morpholine-2 - letiltasaval] -2-(naphthalene-2-ylsulphonyl)propionyl] cyclopropylamino] propionic acid or tautomer amidinopropane, (1:1)-ephemera mixture, MS (ISP): to 673.5 (M - H)+.

Example 52. Analogously to example 48 from complex tert-butyl ether (S)-N-cyclopropyl-N-(2-tetrazol-5-yl-ethyl)-3-naphthalene-2 - ylsulphanilamide acid (example IV) and the following derivatives AMINOETHYLPIPERAZINE get the appropriate products:

a) of the hydrochloride complex ethyl ester (S)-(3-aminomethylpyridine-1-yl)aminomethylenemalonate acid (example 48g)

complex ethyl ester [(S)-3-](S)-3-[cyclopropyl-2-(tetrazol - 5-yl)-ethylcarboxyl] -3-(naphthalene-2-ylsulphonyl)propenolatomethyl] - piperidine-1-yl]aminomethylenemalonate acid, MS (ISP): 669,6 (M + H)+;

b) from geimer 49)

(S)-N(1)-cyclopropyl-N(4)-[(S)-1-(isobutoxyethanol) piperidine-3-ylmethyl] -2-(naphthalene-2-ylsulphonyl)-N(1)-[2- (tetrazol-5-yl)-ethyl]succinamic, MS (ISP): 697,5 (M+H)o.

Example 53. Analogously to example 48 using the corresponding complex arylsulfonamides instead of complex tert-butyl ether (S)-N-cyclopropyl-N-ethoxycarbonylmethyl-3- (naphthalene-2-ylsulphonyl)succinimido acid will receive the following products:

a) from complex ethyl ester N-[3-(tert-butoxycarbonyl)-N- (2-naphthylmethyl)-L-alanyl]-N-cyclopropyl -- alanine (example 2B)K)9)

complex ethyl ester 3-[[(S)-3-[(S)-1-(ethoxycarbonylmethyl)- piperidine-3-letiltasaval] -2-(naphthalene-2-ylsulphonyl)- propionyl] cyclopropylamino] propionic acid or tautomer amidinopropane, MS (ISP): to 673.5 (M+H)o;

b) from challenging methyl ester (S)-2-[2-tert-butoxycarbonyl - 1-[cyclopropyl-(2-ethoxycarbonylethyl)carbarnoyl] ethylsulfanyl] benzoic acid (example b)

complex ethyl ester 3-[[(S)-3-[(S)-1-(ethoxycarbonylmethyl)- piperidine-3-letiltasaval]-2-(2-methoxycarbonylmethylene)- propionyl] cyclopropylamino] propionic acid or tautomer amidinopropane, MS (ISP): 681,5 (M+H)
54A) of a complex ester of example 51B)

3-[[(S)-3-[4-(ethoxycarbonylmethyl)-morpholine-2 - letiltasaval]-2-(naphthalene-2-ylsulphonyl)-propionyl]- cyclopropylamino]propionic acid or tautomer amidinopropane, (1:1)-ephemera mixture, MS (ISN): 645,2 (M-H)3;

54b) of the complex ester of example 53b)

54b)1) 2-[(S)-1-[(2-carboxyethyl)-cyclopropanecarbonyl] -2-[(S)- 1-(ethoxycarbonylmethyl)-piperidine-3-letiltasaval] ethylsulfanyl]benzoic acid or tautomer amidinopropane, MS (ISP): 639,5 (M+H)3and

54b)2) 2-[(S)-1-[(2-ethoxycarbonylethyl)-cyclopropanecarbonyl]- 2-[(S)-1-(ethoxycarbonylmethyl)-piperidine-3-letiltasaval] ethylsulfanyl] benzoic acid or tautomer amidinopropane, MS (ISP): 667,6 (M+H)o.

Example 55. Analogously to example 29 get through

a) benzyloxycarbonylglycine acetic acid, MS (EI): 248 (M)

b) hydrochloride complex benzyl ester 2-cyclopropanedicarboxylic acid (1:1), MS (EI): 234 (M)

in) hydrochloride complex tert-butyl ether (S)-3-[(S)-3-[(2-amino-ethyl)-cyclopropanecarbonyl] -3-(naphthalene-2 - ylsulphonyl)-propenolatomethyl]piperidine-1-carboxylic acid (1:1) and

g) a compound tert-butyl ether (S)-3-[(S)-3-[-piperidine-1-carboxylic acid, MS (ISP): 708,8 (M+H)

(e) acetate (S)-N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-[2-(pyrazin-2 - ylcarbonyl)-ethylsuccinate (1:3), MS (ISP): 650,7 (M+H).

Obtaining source material:

(a) 24 g of N-benzyloxycarbonylglycine and 8 ml of cyclopropylamine in 240 ml of methylene chloride added with stirring 23.1 g of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (DPC) and stirred for 4 hours at room temperature. The mixture is extracted with simple ether, washed with 1N hydrochloric acid, sodium bicarbonate solution and water. After drying and evaporating the ether phase obtain 23 g of benzyloxycarbonylglycine acetic acid.

b) To 23 g of the product of stage a) in 250 ml of THF are added dropwise to 17.6 ml of borane-dimethyl sulfide when 10-23oC. the Mixture is heated under reflux, then cooled to -10oC. Under ice cooling are added dropwise 75 ml of 2N hydrochloric acid and the mixture is at room temperature, extracted with simple ether. The ether phase is washed with water. The aqueous phase using 90 ml of 2N sodium hydroxide are doing basic and extracted with simple ether. The ether phase is washed with water, then with 2N hydrochloric acid (in dioxane) Podkova benzyl ester 2-cyclopropanedicarboxylic acid.

C) Analogously to example 29b)C)d)e) receive hydrochloride complex tert-butyl ether (S)-3-[(S)-3-[(2-amino-ethyl)-cyclopropanecarbonyl] - 3-(naphthalene-2-ylsulphonyl)-propenolatomethyl] -piperidine-1-carboxylic acid.

g) To 400 mg of the amine hydrochloride from in) and 0.11 ml of base Gunga in 4 ml of methylene chloride added 94 mg pyrazinecarboxamide acid and 127 mg of DPC. The mixture is stirred for 20 hours at room temperature and then extracted it with ethyl acetate. The ethyl acetate phase is washed with water. After drying and evaporation the crude product chromatographic through silica gel using ethyl acetate/methanol (9: 1). Get 288 mg complex tert-butyl ether (S)-3-[(S)-3-[cyclopropyl-(2-pyrazin - 2-incorporatingthe)-carbarnoyl] -3-(naphthalene-2-ylsulphonyl)- propenolatomethyl] -piperidine-1-carboxylic acid.

Example 56. Analogously to example 55, but using the appropriate acid or acid derivatives instead used in example 55) pyrazinecarboxamide acid, namely when using

a) complex nanometrology ester monochlorohydrin oxalic acid,

b) at SO+N(CH+)+,

C) benzylphosphonate,

g) Chloroacetic acid,


C) nicotinic acid,

and) nicotinic acid-N-oxide, or

K) 3,4-dioxygenase acid

receive the following connections:

(a) acetate complex methyl ester N-[2-[[(S)-3-[(S)-1- (aminoiminomethyl)-piperidine-3-letiltasaval]-2-(naphthalene-2 - ylsulphonyl)propionyl] cyclopropylamino] ethyl] examinados acid (1:1), MS (ISP): 630,5 (M+H),

b) 2-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-(naphthalene-2-ylsulphonyl)propionyl] amino] ethylsulfanyl acid, MS (ISP): 624,5 (M+H),

in) acetate complex benzyl ester [2-[[(S)-3-[(S)-1- (aminoiminomethyl)-piperidine-3-letiltasaval] -2-(naphthalene-2 - ylsulphonyl)propionyl]cyclopropylamino]ethylsulfanyl acid, MS (ISP): 624,5 (M+H),

g)) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-(2-chloracetamide)-N1-cyclopropyl-2-(naphthalene-2 - ylsulphonyl)] succinamide (1:1), MS (ISP): 620,4 (M+H),

d) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1 - cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-(2-phenoxyacetamide] succinamide (1:1), MS (ISP): 678,6 (M+H),

(e) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1 - cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-[2-(2-oxo-2-phenylacetylamino) ethyl]succinimide (1:2), MS (ISP): 676,6 (M+isopropanolamine) ethyl] succinimide (1:1), MS (ISP): 614,6 (M+H),

h) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-N1 - cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-[2-(pyridine-3-ylcarbonyl) ethyl]succinimide (1:2), MS (ISP): 649,1 (M+H),

and) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-[2-(oxycodoneonline) ethyl]succinimide (1:1), MS (ISP): of 666.5 (M+H),

K) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-N1-cyclopropyl-N1-[2-(3,4-dihydroxyphenylethylamine)ethyl] -2-(naphthalene-2-ylsulphonyl)succinamide (1:1), MS (ISP): 694,6 (M+H).

Example 57. Analogously to example 3 from a complex ester of example 56a) get the following acid:

N-[2-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-(naphthalene-2-ylsulphonyl)-propionyl] cyclopropylamino]ethyl]aksenovoy acid, MS (ISP): 616,5 (M+H).

Example 58. Analogously to example 29 and 55, but when using hydrochloride difficult methyl ester [(S)-3-aminomethylpyridine-1-yl] aminomethylenemalonate acid (1:2) instead of complex tert-butyl ether (S)-3-aminomethyl-1-piperidinecarboxylic acid (example 29g) get:

methyl ester [(S)-3-[(S)-3-[(2-chloracetamide)- cyclopropanecarbonyl]-3-(naphthalene-2-ylsulphonyl)R>
Analogously to example 48, but using complex methyl ether of Harborview acid instead of complex ethyl ether of Harborview acid (example 48V) receive

hydrochloride difficult methyl ester [(S)-3-aminomethylpyridine-1-yl] aminomethylenemalonate acid (1:2), MS (thermocapillary): 215 (M+H).

Example 59. Analogously to example 58 receive the following connections:

a) methyl ester of N-[2-[cyclopropyl-[[(S)-3-[(S)-1- (aminoethoxyethanol)-piperidine-3-letiltasaval]-2- (naphthalene-2-ylsulphonyl)-propionyl] amino] ethyl]examinados acid, MS (ISP): 702,6 (M+H);

b) complex benzyl ester 2-[cyclopropyl-[[(S)-3-[(S)-1- (methoxycarbonylaminophenyl)-piperidine-3-letiltasaval]-2- (naphthalene-2-ylsulphonyl)-propionyl] amino]ethyl]carbamino acid, MS (ISP): 736,7 (M+H);

C) methyl ester [(S)-3-[(S)-3-[cyclopropyl-(2 - methylsulfonylamino)carbarnoyl] -3-(naphthalene-2-ylsulphonyl)- propenolatomethyl] -piperidine-1-yl]aminomethylenemalonate acid, MS (ISP): 680,5 (M+H).

Example 60. Analogously to example 29, but using complex ethyl ester of N-cyclopropylamine instead of hydrochloride of 2-butylaminoethyl (example 29b)

[[(S)-3-[(S)-1-tert-buoy acid and

tert-butyl ether (S)-3-[(S)-3- (cyclopropanecarbonitrile)-3-(naphthalene-2 - ylsulphonyl)-propenolatomethyl]-piperidine-1-carboxylic acid

get:

acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-N1 - cyclopropyl-N1-methoxycarbonylmethyl-2-(naphthalene-2-ylsulphonyl) succinamide (1:1), MS (ISP): 588,6 (M+H).

Obtaining source material:

500 mg [[(S)-3-[(S)-1-tert-butoxycarbonylamino-3 - letiltasaval] -2-(naphthalene-2-ylsulphonyl)-propionyl] cyclopropylamino]acetic acid is stirred together with 71 mg O-methoxyamphetamine, and 0.28 ml of N-methylmorpholine and 376 mg of BOP in 10 ml of methylene chloride for 20 hours at room temperature. The mixture is extracted with ethyl acetate, washed with 1N hydrochloric acid and then with water. After drying and evaporation the product was then purified through silica gel using ethyl acetate/methanol (9:1). Obtain 282 mg of complex tert-butyl ether (S)-3-[(S)-3-[(cyclopropanecarbonyl-carbarnoyl)] -3- (naphthalene-2-ylsulphonyl)propenolatomethyl] -piperidine-1-carboxylic acid, MS (ISP): 646,6 (M+H).

Example 61. Analogously to example 29 and 60 receive the following connections:

(a) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ilma is
b) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-N1-cyclopropyl-N1 - methylcarbamoylmethyl-2-(naphthalene-2-ylsulphonyl)-succinamide (1:1), MS (ISP): 636,5 (M+H),

in) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-N1-cyclopropanecarbonyl-2-(naphthalene-2-ylsulphonyl) -succinamide (1:1), MS (ISP): 598,6 (M+H),

g) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N-(pyridine-3 - iletilebilecegi)-succinamide (1:2), MS (ISP): 649,5 (M+H),

d) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-N1 - cyclopropyl-N1-[2-(3,4-dioksifenil) ethylcarbamate]-2-(naphthalene-2 - ylsulphonyl)-succinamide (1:2), MS (ISP): 694,5 (M+H),

(e) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-N1-cyclopropyl - N1-(2-hydroxyethylaminomethyl]-2-(naphthalene-2-ylsulphonyl)- succinamide (1:1), MS(ISP): 602,2 (M+H).

Example 62. 2.0 g (S)-N-(3-benzyloxyphenyl)-N-cyclopropyl-3-naphthalene-2 - ylsulphanilamide acid and 1.35 g of the hydrochloride difficult methyl ester [(S)-3-aminomethylpyridine-1-yl]-aminoethylamino acid (1: 2) (example 58), stirred at room temperature together with 1,91 g of BOP and of 2.34 ml of 1,8-diazabicyclo [5.4.0]-undec-7-ene (DBU) in 20 ml methylenchloride 2,35 g complex methyl ester (S)-3-[(S)-3-[(3-benzyloxyphenyl)-cyclopropanecarbonyl] -3-(naphthalene - 2-ylsulphonyl)-Propionaldehyde-1-yl]-aminoethylamino acid.

Obtaining source material:

a) 8,58 g N-BOC-cyclopropylamine and 15 g of O-benzyl-3-bromo-1-propanol in 90 ml of DMF is mixed at 0-5+C with 2.5 g of sodium hydride (55% in oil). The mixture is stirred for 1 hour at 0-5+C and 3 hours at room temperature, and then mixed with a solution of ammonium chloride at 0-5oC. the Mixture is distributed in a simple ether/water, the ether phase washed with water, then dried and concentrated. After chromatographic separation through silica gel using a simple ether/hexane (1:4) of 11.5 g of the product is stirred with 120 ml of 4.8 M hydrochloric acid in dioxane. After concentration the residue is crystallized in a simple ether, filtered off the crystals and wash them with a simple ether. Obtain 9.0 g of hydrochloride (3-benzyloxyphenyl)cyclopropylamine, MS (EI): 206 (M+H).

b) 9.0 g of the product of stage (a) and (11,77 g complex 4-tert-butyl ether N-(2-naphthylmethyl)-L-aspartic acid (example 23a) is stirred together with 14.4 g of BOP and 15.9 ml of base Gunga in 200 ml of methyl chloride. The mixture is extracted with simple ether, the ether phase is washed 1H hydrochloric acid and then with water. After drying and evaporating the ether phase balance chromatographic through silica gel using ethyl acetate/hexane (1:2). Get 14,85 g sloneg the lots, MS (ISN): 565,8 (M-H).

in) 14,85 g of the product of stage b) is dissolved in 60 ml of dioxane and mix this solution with 120 ml of 4.8 M hydrochloric acid in dioxane. The mixture is stirred at room temperature, extracted with simple ether and washed with water. After drying and evaporating the ether phase receive 12,87 g (S)-N-(3-benzyloxyphenyl)-N-cyclopropyl-3-naphthalene-2 - ylsulphanilamide acid, MS (ISN): 509,2 (M-H).

Example 63. 970 ml complex ethyl ester (S)-3-[(S)-[(3-benzyloxyphenyl)-cyclopropanecarbonyl] -3-(naphthalene - 2-ylsulphonyl)-propenolatomethyl] -piperidine-1-yl]- aminoethylamino acid will dissolve in 5 ml of methylene chloride. The resulting solution is mixed with 5 ml of 0.5 M solution of tribromide boron in methylene chloride. After stirring at room temperature for 1.5 hours the mixture is mixed with 20 ml saturated sodium bicarbonate solution. The mixture is distributed between ethyl acetate and water. After drying and evaporating the raw material is purified through silica gel using ethyl acetate/methanol 9:1. Get 465 mg of pure complex methyl ester [(S)-3-[(S)-3-[cyclopropyl-(3-hydroxypropyl)-carbarnoyl] -2-(naphthalene - 2-ylsulphonyl)-propenolatomethyl] -piperidine-1-yl] aminomethylenemalonate acid, MS (ISP):617,7(naphthalene-2 - ylsulphonyl)-propenolatomethyl] -piperidine-1-yl] - aminoethylamino acid (example 63), 1 ml of 1H methyliodide in THF, 2 ml of 1M solution of DBU in THF and 2 ml of methylene chloride are mixed together at room temperature. The mixture is concentrated and the residue chromatographic through silica gel using ethyl acetate/methanol 9:1. Receive 120 mg of (S)-N1-cyclopropyl-N4-[(S)-1-(aminoethoxyethanol)- piperidine-3-ylmethyl] -N1-(3-methoxypropyl)-2-(naphthalene-2-ylsulphonyl) -succinamide, MS (ISO): 631,6 (M+H).

Example 65. Analogously to example 29, but using (a) complex diphenyl ether carboxylic phosphoric acid or (b) a complex of diethyl ether carboxylic phosphoric acid instead of complex monoecious ester acid chloride of oxalic acid (example e) get:

(a) acetate complex diphenyl ether, 2-[[(S)-3-[(S)-1- (aminoiminomethyl)-piperidin-3-letiltasaval] -2-(naphthalene-2 - ylsulphonyl)-propionyl] -butylamino] ethylamide phosphoric acid (1:1), MS (ISP): 792.4 M. (M+H),

b) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-yl]-N1-butyl-N1-(2 - diethoxyphosphoryloxy)-2-(naphthalene-2-ylsulphonyl)-succinamide (1:1), MS (ISP):696,2 (M+H)

Example 66. Analogously to example 48, but using di-tert-BUTYLCARBAMATE instead of complex ethyl ether of Harborview to ylcarbamate acid, MS (thermocapillary):391 (M+H)+and from

complex tert-butyl ether (S)-(3-aminomethylpyridine-1-yl)- aminomethylenemalonate acid, MS (ISP):257,2 (M+H)+get

complex ethyl ester [[(S)-3-[(S)-3-(tert-butoxycarbonyl-aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(naphthalene-2-ylsulphonyl)-propionyl]- cyclopropylamino]acetic acid, MS (ISP): 687,5 (M+H)+.

Example 67. Analogously to example 1, but using dihydrochloride [(4-aminomethylpyridine-1-yl)-iminomethyl] -amine instead dihydrochloride (S)-1-amidino-3-(aminomethyl)-piperidine receive hydrochloride complex ethyl ester (S)-3-[[3-[1-(aminoiminomethyl)piperidine-4-letiltasaval] -2-(naphthalene-2 - ylsulphonyl)-propionyl]-cyclohexylamino]acetic acid, MS (ISP): 629,6 (M+H)+.

Obtaining source material:

a) a Solution of 130 g of 1,1-complex dimethylammonio ether (4-piperidinylmethyl)-carbamino acid in 1300 ml of DMF is mixed with 138 ml of triethylamine and 61.8 g formamidinesulfinic and stirred over night at room temperature. The product precipitated in the sediment, filtered, Usacheva in 500 ml of ethanol, again filtered and dried. Get 65,6 g complex tert-butyl ether-hemisulfate 1-(aminoil is th at the stage a), dissolve in 656 ml 1H hydrochloric acid and stirred for 5 hours at 50+C. the Solvent is evaporated, the residue Usacheva in 500 ml of ethanol, filtered on a suction filter and dried. Get to 48.5 g of the dihydrochloride [(4-aminomethylpyridine-1-yl)-iminomethyl]amine, MS (ISP): 573,5 (M+H)+.

Example 68. Analogously to example 67 from the corresponding complex tert-butyl esters receive the following products:

68A) triptorelin complex ethyl ester [[(S)-3- (1-aminoiminomethyl)-piperidine-4-letiltasaval] -2-(naphthalene-2 - ylsulphonyl)-propionyl]cyclopropylamino]acetic acid, MS (ISP): 587,8 (M+H)+,

B) hydrochloride complex ethyl ester [[(S)-3-(1-aminoiminomethyl)-piperidine-4-letiltasaval] -2-(naphthalene-2 ylsulphonyl)-propionyl] benzylamino]acetic acid (1:1), MS (ISP): 637,7 (M+H)+,

V) hydrochloride complex ethyl ester [[(S)-3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] cyclohexylethylamine] acetic acid , MS (ISP):643,6 (M+H)+,

G) hydrochloride complex ethyl ester [[(S)-3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl]butylamino]acetic acid (1:1), MS (ISP):603,4 (M+H)+Talin-2-ylsulphonyl)-propionyl] cyclopropylamino] propionic acid, MS (ISP):601,6 (M+H)+,

E) hexaphosphate complex ethyl ester (S)-3-[[3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] benzoylamino] propionic acid (1:1), MS (ISP): 651,6 (M+H)+,

G) hexaphosphate complex ethyl ester (S)-3-[[3- [1-(aminoiminomethyl)-piperidine-4-letiltasaval]-2-(naphthalene - 2-ylsulphonyl)-propionyl] -cyclohexylethylamine]propionic acid (1:1), MS (ISP): 657,5 (M+H)+,

Z) hydrochloride (S)-N4-[1-(aminoiminomethyl)-piperidine-4-ylmethyl]-N1-cyclopropyl - 2-(naphthalene-2-ylsulphonyl)-N1-(3-oxobutyl-succinamide, MS (ISP): 571,6 (M+H)+.

Example 69. Analogously to example 3 of the esters of examples 67 and 68 receive the following acids:

a) hydrochloride (S)-3-[[3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval]-2- (naphthalene-2-ylsulphonyl)-propionyl]cyclohexylamino]acetic acid, MS (ISP):601,6 (M+H)+,

b) (S)-[[3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] cyclopropylamino] acetic acid, MS (ISP):byr559.6 (M+H)+,

C) [[(S)-3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] benzylamino] acetic acid, MS (ISP):609,5 (M+H)o,

ylmethylamino] acetic acid, MS (ISP):615,5 (M+H)+,

e) [[(S)-3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] butylamino] acetic acid, MS (ISP): 575,5 (M+H)+,

e) hydrochloride (S)-3-[[3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-ylsulphonyl)-propionyl] cyclopropylamino]propionic acid, MS (ISM): 573,5 (M+H)+,

W) (S)-3-[[3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] benzoylamino]propionic acid, MS (ISP): 623,6 (M+H)+,

C) (S)-3-[[3-[1-(aminoiminomethyl)-piperidine-4-letiltasaval] -2- (naphthalene-2-ylsulphonyl)-propionyl] cyclohexylethylamine] propionic acid, MS (ISP): 629,5.

Example 70. 1.0 g of N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2- (2-naphthylmethyl)-L-asparaginyl-N-cyclopropylamine (example 4a) are dissolved in 10 ml of DMF, mixed with 0.2 ml of the research, 0.8 g of BOP and 1.1 ml of 4-ethylmorpholine and stirred over night at room temperature. The reaction mixture was mixed with 20 ml of 1H hydrochloric acid, evaporated and the residue chromatographic using a gradient of water-acetonitrile column RP-18. Obtain 0.5 g of the hydrochloride of (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-N1 - morpholine-4-ylcarbonyl-2-(n is th ether 2-[[(S)- 3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2-(naphthalene - 2-ylsulphonyl)-propionyl]-cyclopropylamino]-ethylcarbamate acid (example V) in 20 ml of methanol hydronaut after the filing of 0.2 g of palladium on coal for 24 hours at room temperature. The catalyst is filtered off, the filtrate is evaporated and the residue dried. 0,57 g of the thus obtained product in 30 ml of THF are added dropwise to a solution of 0.57 g of 3,4-bis(2-propenyloxy)-3-cyclobutene-1,2-dione in 20 ml of THF at 0 C and the reaction mixture is stirred for 5 hours at room temperature. The solvent is evaporated and the residue chromatographic using ethyl acetate-acetone-acetic acid-water (6:2:1: 1) on silica gel. Fraction of the product is evaporated and after drying of the residue receive 0.6 g of the acetate (S)-N1-[2-(2-allyloxy - 3,4-dioxocyclohex-1-enyl-amino)ethyl]-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-1 - cyclopropyl-2-(naphthalene-2-ylsulphonyl)-succinamide (1:1), MS (ISP):to 680.6 (M+H)V

Example 72. 0.1 g of the product obtained in example 71, dissolved in 10 ml of acetonitrile adding 1 drop of this solution is mixed with 0.03 g of palladium (II)- acetate and 0.08 ml of tricolporate. Then served with 0.13 ml 2H sodium-2-ethylcaproic in water and the reaction mixture was stirred at room temperature for 1.5 hours. The product precipitated precipitated, filtered off, washed with simple ether-hexane and dried the residue on the filter. Will allocate 0,090 g acetate (S)-N4-[(S)- 1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-N1-[2- (3,4-dioxo-2-ox is nelogicno example 3 from the corresponding esters have the following acids:

a) from a complex ester of example 49 [cyclopropyl-[(S)-3- [(S)-1-isobutoxyethanol)-piperidine-3 - letiltasaval] -2-(naphthalene-2-ylsulphonyl)-propionyl]amino] acetic acid or tautomer amidinopropane, MS (ISP): 659,5 (M+H),

b) of ester of example 66 [[(S)-3-[(S)-1-(imino-tert-butoxycarbonylamino)-piperidine-3 - letiltasaval] -2-(naphthalene-2-ylsulphonyl)-propionyl]- cyclopropylamino]-acetic acid or tautomer on the amino group, MS (ISP): 659,7 (M+H)V

The compound of formula I, MES or its salt can be used in a known manner as biologically active substances for pharmaceutical preparations, such as tablets and capsules of the following composition, mg (per tablet).

Example a:

Biologically active substance - 200

Microcrystalline cellulose - 155

Corn starch - 25

Talc - 25

Oksipropilmetiltselljuloza - 20 - 425

Example B:

Biological active substance - 100,0

Corn starch - 20,0

Milk sugar - 95,0

Talc - 4,5

Magnesium stearate and 0.5 - 220,0)

1. Sulphametoxazole formula I

< / BR>
where X is a group of the formula X1< / BR>
< / BR>
or X2< / BR>
< / BR>

Y is hydrogen;

A - lower alkyl, phenyl, unsubstituted or substituted lower alkyl, triptorelin group, the group-COOH or-COO-lower alkyl, cryptomaterial, cyano, cyclopentyl, phenyl, CONH2, tetrazolium; naphthyl, heterocyclyl, including heteroaryl consisting of one or two rings containing at least one nitrogen atom, which may carry substituents such as lower alkyl;

Q is hydrogen, lower alkyl, unsubstituted or substituted by hydroxyl, -COOH or-COO-ness. by alkyl;

M is a group M1formula

< / BR>
or M2formula

< / BR>
where R3is hydrogen, lower alkyl or alkenyl, phenyl, heteroaryl consisting of 6-membered rings with one nitrogen atom, C3- C6-cycloalkyl, lower alkyl, substituted C3- C6-cycloalkyl, phenyl, optionally substituted with halogen or lower alkoxyl, heteroaryl consisting of 6-membered rings with one nitrogen atom;

R4is hydrogen or lower alkyl;

R5is hydrogen, lower alkyl or optionally linked through the lowest alkylen COOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, lower alkoxy, phenyl-lower alkoxy, CONH2, NHCOO-ness.alkyl, CONHCH22, NHCOO-benzyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH-(3,4-dioxo-2-oxocyclopent-1-enyl), NH-[2-lower-alkoxy or-alkenylamine)-3,4-dioxocyclohex-1-enyl] , NHCH2-heteroaryl, NHCOCO-(phenyl or lower alkyl, NHCOCH2Cl, NHCOCH2O-phenyl, NHCOCH2-phenyl, NHCO-aryl or-heteroaryl, consisting of six-membered rings with one or two nitrogen atoms and one atom can be in the form of N-oxide, NHPO3(R9, R10), heteroaryl or optional open oxygen CON(CH2)4-9where R9and R10is hydrogen, lower alkyl or phenyl;

N(R6) - benzylamino or-N(CH2)4-9;

as well as hydrates and their physiologically acceptable salts.

2. Connection on p. 1, where X denotes the group of X1in which R1and R2is hydrogen; Y is hydrogen; A, Q have the meanings specified in paragraph (1; M denotes the group of M1in which R3and R4have the values listed in paragraph 1, and if Q, R3and R5simultaneously denote hydrogen, R4cannot be hydrogen; R5is hydrogen, lower alkyl or optionally linked through the lowest alkylen COOH, COO-lower alkyl, OH, nisl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl or NHPO3(R9, R10), or if Q does not denote hydrogen, then M can also be a group of M2where N(R6) denotes the N(CH2)4-9.

3. Connection on p. 1, where Y is hydrogen; X is a group X2and M - group M1or M2.

4. Connection on p. 1, where A is naphthyl, methilhill, methyltetrahydrofuran, methyl, pyridyl or phenyl, substituted tert-bootrom, triptorelin group, phenyl, cyclopentyl, group-COOH, methoxycarbonyl, etoxycarbonyl, cryptomaterial, CN, CONH2or tetrazolium.

5. Connection on p. 1, where Q is hydrogen, CH3CH2COOH, CH2CH2OH or CH2COOC2H5.

6. Connection on p. 1, where X is the group X1; T - CH2; R1is hydrogen or COO-(methyl, ethyl, isobutyl or tert-butyl), and R2- hydrogen.

7. Connection on p. 1, where X is the group X1, T is oxygen, R1is hydrogen or COOC2H5, R2- hydrogen.

8. Connection on p. 1, where X is the group X2and R11and R21- hydrogen.

9. Connection on p. 1, where M - group M1, R3is hydrogen, CH3, propyl, isopropyl, butyl, pentyl, allyl, cyclepro 10. Connection on p. 1, where R5- R50or CH2R50or CH2CH2R50where R50is hydrogen, OH, COO-(H, CH3or C2H5), NHCOOCH3, CONH2, COCH3, NHCOCH3.

11. Connection on p. 1, where M - group M2and N(R6)-hexamethylenimine.

12. Connection under item 1 or 2, representing:

N/N4//(S)-1-amidino-3-piperidinyl/methyl/-N2-(2-naphthylmethyl)-L-asparaginyl/-N-cyclopropylamine,

(S)-//3-/(S)-1-(aminoiminomethyl)piperidine-3-yl-methylcarbamoyl/-2-(naphthalene-2-sulfonylamino)propionyl/cyclopropylamino/propionic acid,

/(S)-3-/(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval/-2-(4-triftormetilfullerenov)propionylthiocholine/acetic acid.

13. Connection under item 1 or 2, representing:

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl/-N1-carboxymethyl-N1-cyclopentyl-2-(naphthalene-2-sulfonylamino)succinamide,

(S)-3-/(S)-2-(aminoiminomethyl)piperidine-3-letiltasaval/-2-(naphthalene-2-sulfonylamino)propionyl/propylaminosulfonyl acid,

N/N4//(S)-1-amidino-3-piperidinyl/methyl/-N2-(2-naphthylmethyl)-L-asparaginyl/-N-(o-Chlorobenzyl)glycine,

/2-//(S)-3-/(S)-1-(aminoiminomethyl)piperidinyl-3-letiltasaval/-piridin-3-ylmethyl/-N1-butyl-2-(naphthalene-2-sulfonylamino)-N1-(2-sulfonylated)succinamide,

/(S)-3-/(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval/-2-(4-tributyltinchloride)-propionylcarnitine/acetic acid.

14. Connection on p. 1 representing:

3-//(S)-3-/(S)-1-(aminoiminomethyl)piperidine-3-ylcarbonyl/2-(4-carbamoyltransferase)propionyl/cyclopropylamino/propionic acid,

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-yl-methyl/-N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-/2-pyrazin-2-ylcarbonyl)ethyl/succinamide,

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl/-N1-cyclopropyl-N1-/2-(3,4-dioksifenil)ethylcarbamate/-2-ylsulphonyl/succinamic.

15. Connection on p. 1 of the following groups:

2-/(S)-2-/(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval/-1-/cyclopropyl(2-carboxyethyl)carbarnoyl/ethylsulfanyl/benzoic acid,

3-//(S)-3-/(S)-1-(aminoiminomethyl)piperidine-3-ylcarbonyl/-2-(4-sanofisynthelabo)propionyl/cyclopropylamino/propionic acid,

(S)-N(4)-/4-(aminoiminomethyl)morpholine-2-ylmethyl/-N(1)-cyclopropyl-N(1)-/2-(tetrazol-5-yl)ethyl/-2-(naphthalene-2-ylsulphonyl)-succinamide,

complex ethyl ether //(S)-3-/4-(aminoiminomethyl)morpholine-2-letiltasaval/-2-(naphthalene-2-ylsulphonyl)propionyl/cyclopropylamino/UKS is lepapillon/acetic acid,

2-//(S)-3-/(S)-1-(aminoiminomethyl)piperidine-3-letiltasaval/-2-(naphthalene-2-ylsulphonyl)propionyl/cyclopropylamino/ethylsulfinyl,

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl/-N1-(2-chloracetamide)-N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-succinamide,

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-yl-methyl/-N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-(2-phenoxyethylamine)succinamide,

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl/-N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-/2-(2-oxo-2-phenyl-acetylamino)ethyl/succinamide,

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl/-N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-/2-(2-oxopropylidene)ethyl/succinamide,

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl/-N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-/2-pyridine/-3-ylcarbonyl)ethyl/succinamide,

(S)-N4-/(S)-1-(aminoiminomethyl)piperidine-3-ylmethyl/-N1-cyclopropyl-2-(naphthalene-2-ylsulphonyl)-N1-/2-(1-oxycodoneonline)ethyl/succinamic.

16. Sulphametoxazole according to any one of paragraphs. 1 - 15 that has the property to inhibit amylolyticus the activity of thrombin.

17. Pharmaceutical composition having antiplatelet and anticoagulant and is as active substances it contains a compound of General formula I on PP.1 - 16.

Priority points:

06.03.92 - PP.2, 12 and 13;

21.01.93 on PP.1, 3 - 11, 14 - 17.4

 

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