Carboxamide, hydrate or solvate, and physiologically compatible salts

 

(57) Abstract:

The invention relates to new carboxamides f-ly 1, where E-N, G-H, lower alkyl, lower alkylene COOH, COO-lower alkyl, lower alkanoyl, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, NH2and others, M-H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl, cycloalkyl, or M and L together with the atoms to which they are linked, form a group - N (het), or E and G spot form a methylene or carbonyl group, and M represents H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl , cycloalkyl, A-H, alkyl, aralkyl, Q represents a group of formula Q1or Q2T-CH2or Oh, R6and R7- H, cerboneschi alkoxy, HE. Connection f-crystals 1 have the ability to inhibit the accumulation of platelets induced by thrombin and clotting of fibrinogen in plasma.

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17 C.p. f-crystals, 1 table.

The invention relates to new carboxamide formula I

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where E denotes hydrogen,

G represents H, lower alkyl or under certain conditions linked through the lowest alkylen COOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, ISSI alkyl, CONHCH2CH2-aryl, CONH-cycloalkyl, CONHCH2-heteroaryl, NH2, NHCOO-lower alkyl, NHCOO-lowest aralkyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH-(3,4-dioxo-2-hydroxycyclopent-1-enyl), NH-[2-lower (alkoxy or-alkenylamine)-3,4-dioxocyclohex-1-enyl], NHCH2-heteroaryl, NHCOCO-(aryl or lower alkyl), NHCOCH2Cl, NHCO-lower alkylene-O-(lower alkyl or aryl), NHCOCH2[aryl, heteroaryl or-N(het)], NHCOC(NOH)-lower alkylene-COOH, NHSO2-N(het),

R10and R20represent H, lower alkyl or phenyl and

M represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl,

L represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl or

M and L together with the atoms to which they are linked, form a group-N(het) or

E and G together form a methylene or carbonyl group, and

M represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl or carboxy-lower alkyl and

L represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl,

R4) (A2)

or if the group Q contains a hydroxyl group and/or if the E and G together represent CH2or CO,

A can represent a group of the formula

-S(O))2R5(A3)

R2denotes lower alkyl, under certain conditions linked through the lowest alkylene aryl, heteroaryl or cycloalkyl, or linked via a lower alkylene Carbo-lower alkoxy, or linked via a lower alkylene - (O or S)-(aryl, heteroaryl or cycloalkyl), and is contained in R2group lower alkylene in - position to the carbonyl group, which is bound R2may be substituted by a hydroxyl group, an amino group or a lower alkanolamine, or

R2means associated through the lowest alkylen halogen, carboxyl group, lower alkoxy, amino, mono - or di-lower alkylamino or linked via a lower alkylene group-N(het), or

R2represents a group-OR22or other22,

R22denotes lower alkyl or under certain conditions linked through the lowest alkylene aryl, heteroaryl or cycloalkyl, or substituted in the fragment of the lower alkyl-aryl, Carbo-lower alkoxy or COOH lower analcime with the N-atom, which they are bound, form a group-N(het),

R5denotes aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl,

-N(het) denotes the N-linked, under certain conditions torn O, S, NH or N-lower alkyl and, under certain conditions, is substituted by up to two substituents from the group of lower alkyl, OH, oxo, COOH, COO-lower alkyl, CH2OH and CH2O-benzyl-N - (CH2)4-9,

Q represents a group of formula Q1or Q2< / BR>
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T represents CH2or O,

one of R6and R7denotes hydrogen or Carbo-lower alkoxy and the other represents hydrogen, Carbo-lower alkoxy or hydroxyl group, and

R represents hydrogen or lower alkyl,

as well as hydrate or solvate, and to the physiologically compatible salts of the aforementioned compounds.

The invention relates further to a method for producing the above-mentioned compounds, pharmaceutical preparations containing such compounds and to the use of these compounds for the manufacture of pharmaceutical preparations.

Examples of applied physiology salts of compounds of formula I are salts with physiologically compatible mineral kislotno, as methanesulfonate acid, p-toluensulfonate acid, 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 as carboxyl group, can also form salts with physiologically compatible bases. Examples of such salts are salts of alkali and alkaline earth metals, ammonium salts and alkylamine as salts of sodium, potassium, calcium or Tetramethylammonium. The compounds of formula 1 can be represented in the form amphoteric ion.

The compounds of formula I may be subject to solvation, primarily hydration. Hydration can be carried out during implementation of the method of receiving according to the invention, or it may occur gradually in the form of a serial number hygroscopic properties initially anhydrous compound of formula I.

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

In the framework of the present invention the definition of "lower" denotes a group containing the selected authentication, denotes a linear or branched, containing 1 to 6, preferably 1-4 C-atoms of the group as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, 2-butyl and pentyl. As the alkyl group, the preferred groups are lower alkyl. One example of the lower alkylene is methylene.

Aryl denotes a group as phenyl and 1 - or 2-naphthyl, under certain conditions, with one or more substituents 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.

Heteroaryl groups are 5-to 10-tier aromatic group comprising one or two rings containing one or more N - and/or O atoms. Examples of such groups are 2-, 3 - or 4-pyridyl also in the form of their N-oxides, furyl, pyrimidyl, indolyl, pyrazinyl, pyridazinyl, tetrazolyl, oxadiazolyl, chinolin or imidazolyl. They can be substituted, for example, oxo, lower-alkyl, as CH3, halogen such as chlorine, or amino.

Cycloalkyl groups contain 3 to 8 C-atoms. Examples of such groups are cyclopropyl, cyclopentyl and cyclohexyl.

Examples under certain conditions torn heteroatom and, under certain conditions, a substituted from Tetra - to monomethylaniline N(het) are hexahydroazepin, morpholino and methylpiperazine.

Examples of compounds according to the invention are the compounds of formula Ia

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where G1represents H, lower alkyl or under certain conditions linked through the lowest alkylen COOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, CONH2, CONHCH2CH2OH, CONHOH, CONHOCH3, CONHO-benzyl, CONHSO2-lower alkyl, CONHCH2CH2-aryl, CONH-cycloalkyl, CONHCH2-heteroaryl, NH2, NHCOO-lower alkyl, NHCOO-lowest aralkyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH-(3,4-dioxo-2-hydroxycyclopent-1-enyl), NH-[2-lower (alkoxy or-alkenylamine)-3,4-dioxocyclohex-1-enyl] , NHCH2-heteroaryl, NHCOCO-(aryl or lower alkyl), NHCOCH2Cl, NHCO-lower alkylene-O-(NREL, heteroaryl or heterocyclyl), NHPO3(R10,R20), heteroaryl or group CO-N(het),

R10and R20represent H, lower alkyl or phenyl, and

M1represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl,

L1represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl, or

M1and L1together with the atoms to which they are linked, form a group-N(het),

A10denotes H, alkyl, lower aralkyl or a group of the formula

-C(O)R2(A1)

-S(O)2N(R3,R4) (A2)

or, if the group Q contains a hydroxyl group,

A10can also be a group of the formula

-S(O))2R5(A3)

R, R2-R5, -N(het) and Q have the above significance.

Other examples of compounds according to the invention are the compounds of formula Ib

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where W denotes a methylene or carbonyl,

M2represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl, or carboxy-lower alkyl, and

L2represents H, lower Alky aralkyl or a group of the formula

-C(O)R2(A1)

-S(O)2N(R3,R4) (A2or

-S(O))2R5(A3), and

R, R2-R5and Q have the above significance.

Among the compounds Ia preferred are those where L1represents hydrogen, and G1- under certain conditions linked through the lowest alkylen COOH, COO-lower alkyl, NHCOO-lowest aralkyl or NHCO (aryl or heteroaryl),

then those of them, where M1represents a lower alkyl or cycloalkyl and/or where A10represents a group of the formula

-C(O)R2(A1)

in which R2represents a group R22, -OR22or other22and R22represents a lower alkyl or under certain conditions linked through the lowest alkylene aryl, heteroaryl or cycloalkyl or in which R2is a is connected through the lower alkylen Carbo-lower alkoxy, or linked via a lower alkylene -(O or S)-(aryl, heteroaryl or heteroaryl), and is contained in R2group lower alkylene in - position to the carbonyl group, which is bound R2may be substituted by OH or lower alkanolamine.

Among other prepost is the SCP OH, or where A10represents morpholinomethyl.

Among the compounds Ia preferred are further those, where L1represents hydrogen, and G1- under certain conditions linked through the lowest alkylen NHCO-lower alkylene-O-(lower alkyl or aryl), NHCOCH2[aryl, heteroaryl or-N(het)], NHCOC(NOH)-lower alkylene-COOH, NHSO2-N(het), NHCO-heterocyclyl or under certain conditions, broken O or S and, under certain conditions, is substituted by up to two substituents from the group of lower alkyl, COOH, COO-lower alkyl, CH2OH and CH2O-benzyl CON(CH2)4-9,

and then those where A10represents lower alkyl, lower aralkyl or a group of the formula

-C(O)R2(A1)

in which R2is a is connected through the lower alkylen halogen, carboxyl group, lower alkoxy, amino, mono - or di-lower alkylamino or linked via a lower alkylene group-N(het) or R2is an-other22where R22represents substituted in the fragment of the lower alkyl-aryl, Carbo-lower alkoxy or COOH group of the lower aralkyl.

The compounds of formula Ia include, for example, the following:

ethyl is ylamino]- acetic acid,

ethyl ester of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-benzyloxycarbonylamino] -cyclopropylamino] - propionic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-benzyloxycarbonylamino] -butylamino] - acetic acid,

ethyl ester of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-benzyloxycarbonylamino]-butylamino]- propionic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2 - benzyloxycarbonylamino]-cyclopropylamino]-acetic acid,

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

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2 - benzyloxycarbonylamino]-butylamino]-acetic acid,

3-[[(S)-3-[(S)-1-aminoiminomethyl)-piperidine-3-letiltasaval] -2 - benzyloxycarbonylamino]-butylamino]-propionic acid,

ethyl ester [[(S)-3-[4-(aminoiminomethyl)-morpholine-2 - letiltasaval] -2-benzyloxycarbonylamino]-cyclopropylamino]- acetic acid,

ethyl ester [[(S)-3-[4-(aminoiminomethyl)-morpholine-2 - ilma is(aminoiminomethyl)-morpholine-2 - letiltasaval]-2-benzyloxycarbonylamino]-cyclopropylamino]- propionic acid,

ethyl ester of 3-[[(S)-3-[4-(aminoiminomethyl)-morpholine-2 - letiltasaval]-2-benzyloxycarbonylamino]-butylamino]- propionic acid,

[[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval]-2 - benzyloxycarbonylamino]-cyclopropylamino]-acetic acid,

3-[[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval]-2 - benzyloxycarbonylamino]-cyclopropylamino]-propionic acid,

3-[[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval]-2 - benzyloxycarbonylamino]-butylamino]-propionic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-cyclohexyloxycarbonyloxy]- cyclopropylamino]-acetic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2 - cyclohexyloxycarbonyloxy]-cyclopropylamino]-acetic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-(3-benzylamino)-propionyl]-cyclopropylamino]- acetic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(3-furan-2-ylmethylamino)-propionyl] -cyclopropylamino]- acetic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(3-furan-2-ylmethylamino)-propionyl] -butylamino]- propionic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2- (3-benzyl-ureido)-propionyl]-cyclopropylamino]-acetic acid,

[[(S)-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2- (3-furan-2-ylmethylamino)-propionyl]-cyclopropylamino]-acetic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2- (3-n-butylurea)-propionyl]-cyclopropylamino]-acetic acid,

[[(S)-[(S)-1-aminoiminomethyl)-piperidine-3-letiltasaval] -2- (3-furan-2-ylmethyl)-ureido)-propionyl]-n-butylamino]-propionic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-pentanediamine]-cyclopropylamino]-acetic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-exaniination]-cyclopropylamino]-acetic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-(4-chloropyridin-2-ylcarbonyl)-propionyl]- cyclopropylamino]-acetic acid,

ethyl ester [[(S)-3-[(S)-1-aminoiminomethyl)-piperidine-3 - letiltasaval]-2-benzylaminocarbonyl]-cyclopropylamino]-acetic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-benzyloxycarbonylamino]-2 - exaniination]-cyclopropylamino]-acetic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2- (4-chloro-pyridine-2-ylcarbonyl)-propionyl]-cyclopropylamino]-acetic acid,

[[(S)-3-[(S)-1-aminoiminomethyl)-piperidine-3-letiltasaval] -2 - benzylaminocarbonyl]-cyclopropylamino]-acetic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2 - benzylcarbamoyl]-cyclopropylamino]-acetic acid,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-tert. - butoxycarbonylamino-N1-cyclopropyl-N1-(2-pyrazin-2-ylcarbonyl)- succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-(3-indol-3-yl-propionamide)-N1-(2-pyrazin-2-incorporatingthe)- succinamide,

methyl ester of (S)-4-[(S)-2-[(S)-1-(aminoiminomethyl)-piperidine-3 - iletileri] -1-[cyclopropyl-(2-pyrazin-2-incorporatingthe)- carbarnoyl]-ethylcarboxyl]-4-hydroxy-butyric acid,

(S)-2-[(S)-2-acetylamino-3-indol-3-ylpropionic] -N4-[(S)- 1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-N1-(2 - pyrazin-2-incorporatingthe)-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-2 - phenoxyacetamide-N1-(2-pyrazin-2-incorporatingthe)-succinamide,

benzyl ether of 2-[[(S)-3-[(S)-1-(aminoindoles acid and

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-2 - morpholine-4-ylsulphonyl-N1-(2-pyrazin-2-incorporatingthe)-succinamic.

Other examples of compounds Ia are

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-2 - morpholine-4-ylsulphonyl-N1-[2-(6-oxo-1,4,5,6-tetrahydropyridine-3 - ylcarbonyl)-ethyl]-succinamic,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-[2-(3 - aminopyrazine-2-ylcarbonyl)-ethyl] -N1-cyclopropyl-2-morpholine-4 - ylsulphonyl-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-(2-methoxyethylamine)-2-morpholine-4-ylsulphonyl-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-(2-morpholine-4-ylacetamide)-2-morpholine-4-ylsulphonyl-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-[2-(4-methylpiperazin-1 ylacetamide)-ethyl] -2-morpholine-4 - ylsulphonyl-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-[2-(3-methoxypropylamine)-ethyl]-2-morpholine-4-ylsulphonyl - succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-(2-imidazol-1-ylacetamide)-2-morpholine-Olin-4-isalphanumeric] - cyclopropylamino] -ethylcarboxyl]-4-gidroksibensana acid,

(S)-N1-(2-amino-ethyl)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3 - ylmethyl] -N1-cyclopropyl-2-morpholine-4-ylsulphonyl-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-[2-(4-methylpiperazin-1 ylsulphonyl)-ethyl] -2-morpholine-4 - ylsulphonyl-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-morpholine-4-ylsulphonyl-N1-(2-morpholine-4-resultoriented)- succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-(3-methoxypropylamine)-N1-(2-pyrazin-2-incorporatingthe)-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-methoxyethylamine-N1-(2-pyrazin-2-incorporatingthe)-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-(4-methylpiperazin-1 ylacetamide)-N1-(2-pyrazin-2-incorporatingthe)- succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(S)-2-amino - 3-phenylpropionylamino] -N1-cyclopropyl-N1-(2-pyrazin-2-incorporatingthe)- succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(R)-2-amino - 3-phenyl-propionamido]-N1-cyclopropyl-N1-(2-pyrazin-2-incorporatingthe)- thylamino] -N1-(2-pyrazin-2 - incorporatingthe)-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-(2-imidazol-1-ylacetamide)-N1-(2-pyrazin-2-incorporatingthe)- succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-[2-(2-oxopiperidin-1-yl)-acetylamino] -N1-(2-pyrazin-2 - incorporatingthe)-succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-(3-dimethylaminopropylamine)-N1-(2-pyrazin-2-incorporatingthe)- succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-(2-dimethylaminoacetyl)-N1-(2-pyrazin-2-incorporatingthe)- succinamide,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-(2,6-dimethylmorpholine-4-ylacetamide)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide,

ethyl ester of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-butylaminoethyl]-cyclopropylamino]-propionic acid,

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

[[(S)-2-amino-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -propionyl]-cyclopropylamino]-acetic acid,

(S)-3-amino-N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -4 - azepin-1-yl-4-oxo-Buti the Ministry of foreign Affairs,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-(3-diphenylmethylene)-propionyl]-cyclopropylamino]- acetic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(3-cyclohexylmaleimide)-propionyl] -cyclopropylamino]- acetic acid,

(S)-N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -4-azepin-1-yl - 3-(3-benzylamino)-4-oxo-butyramide,

methyl ester of (S)-2-[3-[(S)-1-[(S)-(aminoiminomethyl)-piperidine-3 - iletilebilecegi] -2-azepin-1-yl-2-oxoethyl]-ureido]-3-phenylpropionic acid,

methyl ester of (R)-2-[3-[(S)-1-[(S)-(aminoiminomethyl)-piperidine-3 - iletilebilecegi] -2-azepin-1-yl-2-oxoethyl]-ureido]-3-phenylpropionic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2- (3-diphenylmethylene)-propionyl]-cyclopropylamino]-acetic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2- (3-cyclohexylmaleimide)-propionyl]-cyclopropylamino]-acetic acid,

(S)-2-[3-[(S)-1-[(S)-(aminoiminomethyl)-piperidine-3 - iletilebilecegi]-2-azepin-1-yl-2-oxoethyl]-ureido]-3-phenylpropionate acid,

(R)-2-[3-[(S)-1-[(S)-(aminoiminomethyl)-piperidine-3 - iletilebilecegi]-2-azepin-1-yl-2-oxoethyl]-ureido]-3-phenyl who methylcarbamoyl]-propionyl]-cyclopropylamino]-acetic acid,

[[(S)-2-benzyloxycarbonylamino-3-[4-(ethoxycarbonylmethyl)- morpholine-2-letiltasaval]-propionyl]-cyclopropylamino]-acetic acid,

ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-(2-chloroacetamido)-propionyl]-cyclopropylamino]- acetic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-(2-chloroacetamido)-propionyl]-cyclopropylamino]-acetic acid,

Examples of compounds Ib are

N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(S)-4-cyclopentyl - 1-naphthalen-2-ylsulphonyl-3,6-dioxopiperidin-2-yl]-acetamide", she

[3-[(S)-1-(aminoiminomethyl)-piperidine-3-iletilebilecegi] -4 - butylsulfonyl-2-oxopiperidin-1-yl]-acetic acid and

N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(S)-2,6-dioxo - 4-butylpiperazine-2-yl]-ndimethylacetamide.

Other examples of compounds Ib are

N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(S)-4-cyclopropyl - 3,6-dioxo-1-(3-phenylpropyl)-piperazine-2-yl]-acetamide", she

N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(S)-1-naphthalen - 2-ylsulphonyl-3,6-dioxopiperidin-2-yl]-acetamide", she

N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(2S, 5S)-5 - hydroxymethyl-1-naphthalen-2-ylsulphonyl-3,6-dioxopiperidin-the Jn-2-yl)-acetic acid,

ethyl ester of (S)-[2-[(S)-1-(aminoiminomethyl)-piperidine-3 - iletilebilecegi]-4-cyclopropyl-3,6-dioxopiperidin-1-yl]-acetic acid,

[(S)-2-[(S)-1-(aminoiminomethyl)-piperidine-3-iletilebilecegi] - 4-cyclopropyl-3,6-dioxopiperidin-1-yl]-acetic acid,

(S)-1-(aminoiminomethyl)-piperidine-3-ylmethylene(R)- and (S)-(2,4-dimethyl-1-naphthalen-2-ylsulphonyl-3-oxopiperidin-2-yl)-acetic acid.

For the preferred compounds of formula I include the following:

[[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] -2 - benzyloxycarbonylamino]-butylamino]-acetic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]-2 - pentanediamine]-cyclopropylamino]-acetic acid,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-(2-pyrazin-2-incorporatingthe)-2-pyrimidine-2-ylsulphanilamide - succinamide,

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

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-morpholine-4-ylsulphonyl-N1-[2-(6-oxo-1,6-dihydropyridin-3 - incorporatingthe]-succinamic and

N-[(S)-1-(AMD.

Other preferred compounds are the following:

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1 - cyclopropyl-2-morpholine-4-ylacetamide-N1-(2-pyrazin-2-incorporatingthe)- succinamide,

ethyl ester of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(3-phenylpropylamine)-propionyl] -cyclopropylamino] - propionic acid,

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

3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-morpholine-4-isalphanumeric]-cyclopropylamino]-propionic acid.

Proposed according to the invention the connection get by well-known methods as follows:

a) acid formula

< / BR>
subjected to an exchange reaction with an amine of the formula

H2NCH2Q III

or with a salt of the amine under certain conditions with intermediate protection of the functional groups contained in the groups G1M1and A10(II) Q (III), or

b) an amine of the formula

< / BR>
where Q3represents a group of the formula

< / BR>
< / BR>
subjected to an exchange reaction with the tool, misleading under certain uslt exchange reactions with the tool, introducing group A10or

g) the amino acid formula

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either formula

< / BR>
cyclist to the compounds of formula Ib or

d) to obtain a carboxylic acid of the formula Ib, where M2represents a carboxy-lower alkyl, split the corresponding complex lower alkilany ether and

e) in case of need contained in the compound of formula I of the reactive functional group and modify

g) if necessary, the compound of formula I is transferred in a physiologically compatible salt or the salt of the compounds of formula I transferred to the free acid or base.

Preferably the acid II is subjected in a solvent as dimethylformamide (DMF) or methylene chloride, in the presence of a base, such as 4-ethylmorpholine, triethylamine, ethyldiethanolamine (base Chunga) or 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) at room temperature exchange reaction with a salt of the compounds of formula III, for example, trifurcation, bisulfite, nitrate, hydrochloride or hydroiodide, and hexaphosphates benzotriazol-1 yloxy - Tris(dimethylamino)phosphonium (BOP). Contained in the compounds II and III, the intermediate protected functional group, as COOH, NH2and OH, can protect the tell-protected carboxyl group, as COOCH3or COOC2H5to COOH can be carried out using sodium liquor in ethanol. Translation OCONH - or N3group to the free amino group can be carried out by catalytic (Pt/C) hydrogenation in ethanol.

According to variant b) method for obtaining the compounds of formula I, where R6and R7(group Q) is hydrogen, the corresponding compound of formula X can be treated in a solvent like DMF or methanol, in the presence of a base as triethylamine, exchange reactions with formamidinesulfinic or nitrate 3,5-dimethyl-1-pyrazolyl-formamidine, preferably at a temperature of up to 50oC.

To obtain the compounds of formula I, where R6and R7(group Q) represent OH, the compound of formula X may be in a solvent like methylene chloride, while cooling the exchange reaction first with methyl zian, and then with hydroxylamine hydrochloride in the presence of amine like triethylamine.

For the implementation of variant C) of the method Amin XX can be in a solvent like DMF, in the presence of a base, as ethylmorpholine, the exchange reaction with the compound of the formula ClC(O)OR2or ClC(O)R2for example cyclohexene is with sodium bicarbonate and activated carbamate, for example, 2,5-dioxopiperidin-1 silt ether benzylcarbamoyl acid, you get the urethane of formula Ia, where A10represents a group-C(O)other22. If Amin XX expose in a solvent like methylene chloride, the interaction with the carboxylic acid, for example, the pyrimidine-2-teoksessa acid, in the presence of a base, as the base Hunya, and BOP, I get the connection of the formula Ia, in which A10represents a group-C(O)R2where R2represents, for example, is connected through the lower alkylene -(O or S)-(aryl, heteroaryl or cycloalkyl).

The cyclization of d) can be performed in a solvent like DMF, in the presence of a base, such as 4-ethyl-morpholine, and paph.

Splitting e) ether, lower alkyl carboxylic acid to the corresponding carboxylic acid of formula Ib, where M2represents a carboxy-lower alkyl, may be carried out in a solvent as water and ethanol, using an ion exchanger in the form of Cl.

As functional modifications in option (e) of the method include the following:

1. saponification of the ester group as etoxycarbonyl, for example, THF, using the base as water LiOH;

2. cleavage of the Z group (benzyloxycarbonyl) in the Z-protected admingroup NHC(O)-(aryl or heteroaryl), accordingly, the group NHSO2-N(het), for example, by reaction with a carboxylic acid of the formula G-COOH, respectively, with ClSO2-N(het).

Used as the source of the above substances can be obtained by known methods, for example, according to the following schema:

< / BR>
< / BR>
Amin XX can be obtained, for example, by removal of the Z-pool in the compound of the formula Ia, in which group A10represents benzyloxycarbonyloxy group.

Compound XXX is described in European application EP-A-468231. You can get them as well as the compounds of formula Ia.

Used as starting substances esters in variant d) of the method can be obtained in the following way:

< / BR>
In addition to the explanations in some of the following examples contain detailed data regarding the receipt of certain raw materials and intermediate products.

The compounds of formula I, a solvate and their salts have the ability to inhibit both the accumulation of platelets induced by thrombin and thrombin-induced clotting of fibrinogen in the blood plasma. These compounds affect both induced platelet, the BOV, as well as platelet-rich thrombi and can be used for the treatment, respectively prevention of diseases such as thrombosis, apoplexy, cardiac infarction, inflammation and atherosclerosis. In addition, these compounds are effective against tumor cells and prevent the formation of metastases. Because of this they can be used as anticancer agents.

The ability of these compounds to versatile inhibition of thrombin and other serine proteases makes the connection object to retrieve the funds, with the greatest high specificity of their actions and thereby avoid possible side effects. During conducted with the serine-protease experiments along with other factors were identified correlation between the inhibition of trypsin and inhibition of thrombin, which was adopted as the main measurement of specific actions in a given compound (designation through q in the table below), because trypsin as the most nonspecific serine protease can easily inhibited a variety of inhibitors. To be able, despite the use of different substrates for the direct CPA is Anta Kiindependent of the substrate concentration and enzyme.

To confirm the inhibitory effect in relation to the catalytic activity of the above enzymes can be used appropriate chromogenic peptide substrates. Inhibition amylolyticus activity of thrombin and trypsin by the above-mentioned compounds were identified according to the method described below.

The measurements were carried out on tablets for micrometrology at room temperature. With this purpose, based on each perforation in the plate to prepare a mixture of 150 μl of buffer (50 mm Tris, 100 mm NaCl, 0.1% polyethylene glycol; pH 7.8) and 50 μl dissolved in DMSO and diluted in buffer inhibitory substance and the mixture was added 25 μl of human thrombin (final concentration 0.5 nm). After 10 min incubation the reaction was initiated by addition of a chromogenic substrate S-2238 (H-D-Phe-Pip-Arg-paranitroaniline company Kabivitrum; the final concentration of 10 or 50 μm) and the hydrolysis of substrate was monitored spectrophotometrically by using kinetic reader within 5 minutes based On the graphic image curves of inhibition according to the method described in Biochem. Journ. 55, 1955, 170-171, determine the values of Ki. Ing nitroanilin) at a final concentration of 200 and 750 microns.

The results presented in the table.

The compounds of formula I have a low toxicity. So, the products listed in the table of examples when administered intravenously to mice have an LD50 of 125-500 mg/kg

As mentioned above, a medicinal product containing a compound of formula I, MES or salt of this compound, are also subject of the present invention, the subject invention is further a method of obtaining such medicines, characterized in that one or several other valuable therapeutic for substances manufactured drugs in halogen form. Drugs can be injected enterline, for example orally in the form of pills, megkozeliteni and terdoslavich capsules, solutions, emulsions or suspensions, or being made, for example, in the form of suppositories or aerosols can be assigned for rectal administration. The introduction of drugs, for example, in the form of solutions for injection may also be parenteral.

For the manufacture of tablets, lacquered tablets, coated tablets and terdoslavich capsules the active substance can be added pharmaceutically inert, inorganic or organic excerise, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts. As excipients for megkozeliteni capsules are suitable, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, depending on the properties of the active substance for megkozeliteni capsules do not require any of the excipients. For the preparation of 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, glycerine and vegetable oils, and suppositories suitable natural or hardened oils, waxes, fats, semi-liquid or liquid polyols. The pharmaceutical preparations may contain, in addition, and preservatives, substances that contribute to the dissolution, stabilizers, wetting agents, emulsifiers, sweet substances, colorants, flavouring agents, salts for modifying the osmotic pressure, buffers, coating or antioxidants.

In the treatment, respectively prevention of the above diseases, the dosage of the active substance can be varied within wide limits, taking into account, of course, in each case, naprimer intravenously or subcutaneously, the daily dose for adults should be between about 0.1 to about 20 mg/kg, preferably from about 0.5 to about 4 mg/kg of body weight, however, if this proves feasible, the dose can also choose above or below the specified upper limit.

Example 1. 1.A) 3.6 g of tert.-butyl ether (S)-3-benzyloxycarbonylamino-N-cyclopropyl-N-ethoxycarbonylmethylene acid are dissolved in 36 ml of methylene chloride, treated at 0oC 40 ml of 4M hydrochloric acid in acetic ether and stirred for 5 hours the Solution is evaporated and the colorless residue is dissolved in 36 ml of DMF, treated with a 5.1 ml of 4-ethylmorpholine, 3,55 g hexafluorophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (BOP) and 2.02 g of the dihydrochloride of (S)-1-amidino-3-(aminomethyl)piperidine (see European patent application EP-A-468231; example 60 ° C) and stirred over night at room temperature. The reaction mixture is evaporated and the residue chromatographic using a gradient of water/acetonitrile on RP-18. The fractions containing the product, evaporated and filtered using a water/ethanol through the ion exchange resin (Cl). After evaporation produce 2.9 g of colorless ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - ylmethylene is H)+.

1.B) Receiving the original substances

In a solution of 8.0 g tert.-butyl ether N-Z-L-aspartic acid in 80 ml of methylene chloride successively added 5.0 g of the hydrochloride of N-(dimethylaminopropyl)-N'-ethylcarbodiimide, 0.3 g of 4-dimethylaminopyridine and 3.7 g of ethyl ester of N-cyclopropylamine and stirred for 17 h at room temperature. Then the reaction mixture is poured into ice-cold solution consisting of 5% aqueous solution of potassium hydrosulfate and a 10% aqueous solution of potassium sulfate, and extracted with acetic ester. The organic phase is washed with water, dried, evaporated and the residue chromatographic using hexane/acetic ether (3: 1) on silica gel. The result of 8.4 g of colorless, oily tert. -butyl ether (S)-3-benzyloxycarbonylamino-N-cyclopropyl-N - ethoxycarbonylmethylene acid, MS (BTA): 449,2 (M+).

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

a) hydrochloride of the ethyl ester of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-benzyloxycarbonylamino] - cyclopropylamino]-propionic acid, MS (ion bombardment): 545,4 (M+H)+,

b) ethyl ester hydrochloride [[(S)-3-[(S)-1-(amidoamines Bagirova ions): 547,5 (M+H)+,

b) hydrochloride of the ethyl ester of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-benzyloxycarbonylamino] - butylamino] -propionic acid, MS (ion bombardment): 561,4 (M+H)+.

2.B) Receiving the original substances

Analogously to example 1.B), with however the difference that instead of the ethyl ester of N-cyclopropylamine use ethyl ester of N-Ciclopi-alanine, ethyl ester of N-butylglycol, respectively, ethyl ester N-butyl-alanine, get the following intermediate products:

a) tert.-butyl ether (S)-3-benzonorbornadiene-N-cyclopropyl - N-(2-ethoxycarbonylethyl)-succinamic acid, MS (BTA): 463,3 (M+H)+,

b) tert. -butyl ether (S)-3-benzylcarbamoyl-N-butyl-N - ethoxycarbonylmethylene acid, MS (ion bombardment): 465,4 (M+H)+,

C) tert. -butyl ether (S)-3-benzylcarbamoyl-N-butyl-N- (2-ethoxycarbonylethyl)-succinamic acid, MS (BTA): 479,3 (M+H)+.

Example 3. 1.5 g of the hydrochloride of ethyl ether [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2 - benzyloxycarbonylamino] -cyclopropylamino] -acetic acid (example 1) is dissolved in 15 ml of THF, treated with 7.9 ml of 1N. solution hydroxide whether the notes and evaporated. The remainder chromatographic using a gradient of water/acetonitrile on RP-18. The result was 0.63 g of colorless [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2 - benzyloxycarbonylamino]-cyclopropylamino]-acetic acid, MS (ion bombardment): 503,5 (M+H)+.

Example 4. Analogously to example 3, however, based on the ester product from example 2 are given the following acids:

a) 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-benzyloxycarbonylamino] -cyclopropylamino] -propionic acid, MS (ion bombardment): 517,4 (M+H)+,

b) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- 2-benzyloxycarbonylamino]-butylamino]-acetic acid, MS (ion bombardment): 519,4 (M+H)+,

C) 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-benzyloxycarbonylamino] -butylamino] -propionic acid, MS (ion bombardment): 533,5 (M+H)+.

Example 5. Analogously to example 1, using, however, instead dihydrochloride (S)-1-amidino-3-(aminomethyl)of the piperidine dihydrochloride rat-2-aminomethyl-4-morpholinosydnonimine receive the following connections:

a) from tert.-butyl ether (S)-3-benzyloxy the(S)-3-[4-aminoiminomethyl)-morpholine-2 - letiltasaval]-2-benzyloxycarbonylamino] -cyclopropylamino] - acetic acid (1:1), MS (ion bombardment): 533,4 (M+H)+,

b) of tert. -butyl ether (S)-3-benzyloxycarbonylamino-N-butyl-N - ethoxycarbonylmethylene acid get hydrochloride ethyl ester [[(S)-3-[4-(aminoiminomethyl)-morpholine-2 - letiltasaval] -2-benzyloxycarbonylamino]-butylamino]- acetic acid (1:1), MS (ion bombardment): 549,4 (M+H)+,

in) of tert. -butyl ether (S)-3-benzylcarbamoyl-N-cyclopropyl - N-(2-ethoxycarbonylethyl)-succinamic acid get hydrochloride ethyl ester 3-[[(S)-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] - 2-benzyloxycarbonylamino]-cyclopropylamino]-propionic acid (1:1), MS (ion bombardment): 547,5 (M+H)+,

g) of tert.-butyl ether (S)-3-benzyloxycarbonylamino-N-butyl - N-(2-ethoxycarbonylethyl)-succinamic acid get hydrochloride ethyl ester 3-[[(S)-3-[4-(aminoiminomethyl)-morpholine-2 - letiltasaval] -2-benzyloxycarbonylamino] -butylamino] - propionic acid (1:1), MS (ion bombardment): 563,5 (M+H)+.

Example 6. Analogously to example 3, however, based on esters from example 5 are given the following acids:

a) [[(S)-3-[4-aminoiminomethyl)-morpholine-2-elmet the ions): 505,0 (M+H)+,

b) [[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] -2 - benzyloxycarbonylamino] -butylamino] -acetic acid (1: 1), MS (ion bombardment): 521,1 (M+H)+,

C) 3-[[(S)-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] -2 - benzyloxycarbonylamino]-cyclopropylamino]-propionic acid (1:1), MS (ion bombardment): 519,4 (M+H)+,

g) 3-[[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval]-2 - benzyloxycarbonylamino] -butylamino] -propionic acid (1: 1), MS (ion bombardment): 535,4 (M+H)+.

Example 7.

7. A) 4.4 g of product from example 1.A) is dissolved in 44 ml of ethanol, treated with 7.7 ml of 1N. hydrochloric acid and 0.44 g of Pd/C and hydronaut for 1 h at room temperature. After filtration and evaporation of the solution obtain 3.4 g of colorless ethyl ester dihydrochloride [[(S)-2-amino-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - propionyl] -cyclopropylamino]-acetic acid, MS (ion bombardment): 397,4 (M+H)+,

7. B) Analogously to example 7.A) on the basis, however, of the products of example 2. A) receive the following amines:

7. B)a) dihydrochloride ethyl ester 3-[[(S)-2-amino-3-[(S)- 1-(aminoiminomethyl)-piperidine-3-letiltasaval] -propion aminomethyl)-piperidine-3-letiltasaval] -propionyl]-butylamino]- acetic acid,

7. B)C) dihydrochloride ethyl ester 3-[[(S)-2-amino-3-[(S)- 1-(aminoiminomethyl)-piperidine-3-letiltasaval] -propionyl] -butylamino] - propionic acid, MS (ion bombardment): 427,4 (M+H)+.

7. C) Analogously to example 7.A) on the basis, however, of the product of example 3, 4B, respectively), given the following amines:

7. In a)hydrochloride [[(S)-2-amino-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -propionyl] -cyclopropylamino] -acetic acid, MS (ion bombardment): 369,4 (M+H)+,

7. B)b) hydrochloride of 3-[[(S)-2-amino-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -propionyl] -butylamino] -propionic acid, MS (ion bombardment): RUB 399.4 (M+H)+.

7. G) In a solution of 1.7 g of lineproduct of example 7.A) in 18 ml of DMF added to 2.4 ml of 4-ethylmorpholine and 0.73 g cyclohexylmethanol ether Harborview acid and stirred overnight at room temperature. The reaction mixture was evaporated, treated with 1N. hydrochloric acid, then re-evaporated and the residue chromatographic using a gradient of acetonitrile/water on RP-18. After evaporation containing the product fractions obtain 1.6 g of the hydrochloride of ethyl ether [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] - 537,6 (M+H)+.

Example 8.

Analogously to example 3, however, based on a complex ester of example 7.G) receive the following acid:

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2 - cyclohexyloxycarbonyloxy] -cyclopropylamino] -acetic acid, MS (ion bombardment): 509,5 (M+H)+.

Example 9.

9.(A) the receipt of the products:

9. (A) (a) 1.7 g of lineproduct of example 7.A) are dissolved in 17 ml of acetonitrile and 17 ml of water. Then add successively 0.6 g of sodium bicarbonate and 1.35 g of 2,5-dioxopiperidin-1 silt ether benzylcarbamoyl acid and stirred for 17 h at room temperature. The reaction mixture is evaporated and the residue purified on column (RP-18, gradient acetonitrile/water. Allocation receive 0.6 g of colorless ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(3-benzylamino)-propionyl] -cyclopropylamino]- acetic acid, MS (ion bombardment): 530,5 (M+H)+.

9. A)b) in a Similar way, however, using the appropriate activated carbamates, receive the following connections:

9. A)b)1) hydrochloride ethyl ester [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-ions): 520,5 (M+H)+,

9. A)b)2) ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-(3-butylurea)-propionyl] - cyclopropylamino]-acetic acid, MS (ion bombardment): 496,6 (M+H)+.

9.B) Obtaining raw materials:

9. B)a) In a solution of 6.4 g of benzylamine in 150 ml of acetonitrile and 5oC for 5 min in small portions add to 18.4 g of N,N'-disuccinimidyl. The reaction mixture was stirred at room temperature and then evaporated. The residue is dissolved in acetic ether and washed with water. The organic phase is dried, concentrated, then the residue is recrystallized from methylene chloride/hexane. Allocation receive 11.3 g of colorless 2.5 dioxo-pyrrolidin-1 silt ether benzylcarbamoyl acid, MS (BTA): 133 (M-HO-succ.).

9. B)b) in a Similar way, but instead of using benzylamine corresponding amines get these activated carbamates:

9. B)b)1) 2.5-dioxotetrahydrofuran-1 silt ether furan-2-iletilerinindeki acid, MS (BTA): 123 (M-HO-succ.),

9. B)b)2) 2,5-dioxopiperidin-1 silt ether pyridine-3-iletilerinindeki acid, MS (BTA): 151 (M-succ.),

9. B)b)3) 2,5-dioxopiperidin-1 silt ether butikerna the point 7.B. in) and using complex the activated ester from step 9.B)b)1), get the following esters:

hydrochloride ethyl ester 3-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-(3-furan-2-ylmethylamino)-propionyl] - butylamino]-propionic acid, MS (ion bombardment): 550,4 (M+H)+.

Example 11.

2.5 g of the product from example 7.In a)are dissolved in 25 ml of acetonitrile and 25 ml of water. Then add sequentially 1.0 g of sodium bicarbonate and 2.3 g of 2,5-dioxo-pyrrolidin-1 silt ether benzylcarbamoyl acid and stirred for 5 h at room temperature. The reaction mixture is evaporated and the residue purified on column (RP-18, gradient acetonitrile/water. Allocation receive 0.8 g of colorless [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-(3-benzylamino)-propionyl] - cyclopropylamino]-acetic acid, MS (ion bombardment): 502,4 (M+H)+.

Example 12.

Analogously to example 3, however, based on esters of examples 9. A)b)1), 9.A)b)2) and 10 receive the following acids:

a) [[(S)-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- 2-(3-furan-2-ylmethylamino)-propionyl] -cyclopropylamino] -acetic acid, MS (ion bombardment): 492,5 (M+H)+,

b) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine): 468,4 (M+H)+,

C) [[(S)-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- 2-(3-furan-2-ylmethylamino)-propionyl] -n-butylamino] -propionic acid, MS (ion bombardment): 522,4 (M+H)+.

Example 13.

A) Analogously to example 1 given the following connections:

a) ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval]-2-pentanediamine]- cyclopropylamino]-acetic acid, MS (ion bombardment): 481,5 (M+H)+,

b) ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval]-2-exaniination]- cyclopropylamino]-acetic acid, MS (ion bombardment): 495,6 (M+H)+,

C) ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-(4-chloropyridin-2-ylcarbonyl)- propionyl] -cyclopropylamino] -acetic acid, MS (ion bombardment): to 536.5 (M+H)+,

g) of the hydrochloride of ethyl ether [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-benzylaminocarbonyl] - cyclopropylamino]-acetic acid, MS (ion bombardment): 501,6 (M+H)+,

e) ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-benzyloxycarbonylglycine raw materials:

a) a Solution of 16.6 g of tert.-butyl (S)-2-(2-tert.-butoxyphenyl)-N - cyclopropyl-N-[(etoxycarbonyl]methyl]succinamic (getting the same product from example 1.B) in 170 ml of dioxane is treated 19,0 g of the monohydrate of p-toluenesulfonic acid and stirred for 30 h at room temperature. Then the solution when cooled first process of 17.8 ml of pyridine, and then with 9.6 ml of chloride of Valerie and stirred over night at room temperature. For further processing, the reaction mixture was poured into ice-cold solution consisting of 5% aqueous solution of potassium hydrosulfate and a 10% aqueous solution of potassium sulfate, and then extracted with acetic ester. The organic phase is washed with diluted sodium chloride solution, dried and evaporated. After chromatography of the residue on silica gel using hexane/acetic ether (2:1) allocate 4.8 g of colorless tert.-butyl ether (S)-N-cyclopropyl-N-ethoxycarbonylmethyl-3-pentanedionato acid, MS (ion bombardment): RUB 399.4 (M+H)+.

b) in a Similar way, but using instead of the chloride of Valerie corresponding acid chlorides receive the following tert.-butyl esters:

b)1) tert. -butyl ether (S)-N-cyclopropyl-N-amoxilamoxycillin-2-(4-chloropyridin - 2-ylcarbonyl)-propionyl]-cyclopropylamino]-acetic acid, MS (BTA): 213 (M+H)+,

b)3) tert.-butyl ether (S)-3-benzoylamine N-cyclopropyl-N - ethoxycarbonylmethylene acid, MS (BTA): 419 (M+H)+,

b)4) tert. -butyl ether (S)-2-benzylcarbamoyl-N-cyclopropyl-N - ethoxycarbonylmethylene acid, MS (ion bombardment): 433,1 (M+H)+.

Example 14.

Analogously to example 3, however, based on esters from example 13A), get the following acids:

a) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- 2-pentanediamine]-cyclopropylamino]-acetic acid, MS (ion bombardment): 453,4 (M+H)+,

b) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-exaniination]-cyclopropylamino]-acetic acid, MS (ion bombardment): 467,4 (M+H)+,

C) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-(4-chloropyridin-2-ylcarbonyl)-propionyl] -cyclopropylamino] -acetic acid, MS (ion bombardment): 508,5 (M+H)+,

g) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- 2-benzylaminocarbonyl] -cyclopropylamino] -acetic acid, MS (ion bombardment): to 473.6 (M+H)+,

e) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- 2-be is SS="ptx2">

Example 15.

A solution of N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(naphthalen - 2-ylsulphonyl)-L-asparaginyl]-N-cyclopropylamine

- (from - tert.-butyl ester of N-Boc-L-aspartic acid and ethyl ester of N-cyclopropylamino acid, via tert.-butyl (S)-3-(1-t-butoxyphenyl)-N-cyclopropyl - N-[(ethoxycarbonyl)methyl]succinamic and through tert. -butyl(S)-N-cyclopropyl - N-[(etoxycarbonyl)methyl]-3-(naphthalen-2-ylsulphonyl)-succinamic) -

in 30 ml of DMF is treated with 1.7 ml of 4-ethylmorpholine and 1.2 g of BOP and stirred over night at room temperature. Then the reaction mixture was evaporated, treated with 1N. hydrochloric acid and again evaporated. The remainder chromatographic using a gradient of acetonitrile/water column RP-18. Containing the product fractions are concentrated, and then allocate 0.7 g of the hydrochloride of N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(S)-4-cyclopropyl - 1-naphthalen-2-ylsulphonyl-3,6-dioxopiperidin-2-yl]-ndimethylacetamide, MS (ion bombardment): to 541.5 (M+H)+.

Example 16.

In the same way as described in example 15, is obtained from (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-carboxymethyl - N1-cyclopentyl-2-(naphthalene-2-sulfonylamino)-succinamide

- (polit.-butyl-(S)-3- (1-t-butoxyphenyl)-N-cyclopentyl-N-[(ethoxycarbonyl)methyl] succinamic and through tert. -butyl(S)-N-cyclopentyl-N-[(textcursor)methyl] - 3-(naphthalen-2-ylsulphonyl)succinamic) -

the hydrochloride of N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-2-[(S)- 4-cyclopentyl-1-naphthalen-2-ylsulphonyl-3,6-dioxopiperidin-2-yl]-ndimethylacetamide, MS (ion bombardment): 569,4 (M+H)+.

Example 17.

A) Obtaining product:

0.8 g of (RS)-(4-tert.-butoxycarbonylmethyl-1-butylsulfonyl-3 - oxopiperidin-2-yl)-acetic acid are dissolved in 15 ml of DMF and then treated sequentially 1.3 ml of 4-ethylmorpholine, 0,92 g of BOP and 0.72 g of the dihydrochloride of (S)-1-amidino-3-(aminomethyl)piperidine. The reaction mixture was stirred over night at room temperature, then evaporated and the residue chromatographic using a gradient of water/acetonitrile column RP-18. Containing the product fractions evaporated and filtered water/ethanol through the ion exchange resin (Cl). After evaporation produce colorless [3-[(S)-1-(aminoiminomethyl)- piperidine-3-iletilebilecegi]-4-butylsulfonyl-2-oxopiperidin-1-yl]- acetic acid, MS (ion bombardment): to 475.6 (M+H)+.

B) Obtaining source material:

a) 15.0 g of ethyl-2-piperazine-3-one-acetate are dissolved in 150 ml of pyridine and treated at room temperature with 12.5 ml of 1-butanesulfonate residue on silica gel with acetic ester/hexane obtain 23.1 g of colorless ethyl ester of (RS)-(1-butylsulfonyl-3-oxopiperidin - 2-yl)-acetic acid, MS (BTA): 261 (M-OEt).

b) a solution of 2.0 g obtained in paragraph (a) substances in 20 ml DMF at -15oC add sequentially 520 mg of a 60% dispersion of sodium hydride and a solution of 1.9 ml of tert.-butyl ether bromoxynil acid in 30 ml of DMF. The reaction mixture was stirred at room temperature, then treated with water and extracted with acetic ester. The organic phase is washed with water, dried and evaporated. The remainder chromatographic using acetic ester/hexane on silica gel and produce 1.8 g of colorless tert.-butyl ether (RS)-3-etoxycarbonyl-2-oxo-4-butylsulfonyl-1-luxusni acid, MS (BTA): 375 (M-OEt).

in) 1.7 g obtained in paragraph (a) of a substance is dissolved in 17 ml of THF, treated with 12 ml of 1N. solution of lithium hydroxide and stirred for 2 h at room temperature. Then add 10 ml of acetic acid, after which the reaction mixture is evaporated. The residue is dissolved in acetic ether and washed with ice-cold solution consisting of 5% aqueous solution of potassium hydrosulfate and a 10% aqueous solution of potassium sulfate and water. The organic phase is dried and evaporated. The result is 0.8 (RS)-(4-tert.-butoxycarbonylmethyl-1-butylsulfonyl-3-oxopiperidin - 2-yl)-acetic acid, MS (the bombing of the[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-benzyloxycarbonylamino]-butylamino]-acetic acid (example 2.A)b)) are dissolved in 13 ml of ethanol and 13 ml of 1N. hydrochloric acid, treated with 0.13 g of Pd/C and hydronaut for 90 min at room temperature. After filtering the reaction mixture, evaporation of the filtrate and chromatography of the residue using gradient of acetonitrile/water column RP-18 emit 0.4 g of the hydrochloride of N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2-[(S)-2,6-dioxo - 4-butyl-piperazine-2-yl]-ndimethylacetamide, MS (ion bombardment): 367,4 (M+H)+.

Example 19.

4.1 g of the hydrochloride cyclopropyl-2-(pyrazin-2-ylcarbonyl)ethylamine (1:2), to 4.98 g of Z-Asp(OtBu)-OH and 7,37 g of BOP are dissolved in 100 ml of methylene chloride and stirring process 10,06 ml base Hunga. After stirring for 2 h at room temperature the mixture is dissolved in a simple ether and washed with water. After evaporation exploiting phase and chromatography of the residue on silica gel get 7,06 g of tert.-butyl ether (S)-2-benzyloxycarbonylamino-N1-cyclopropyl - N1-(2-pyrazin-2-incorporatingthe)-succinamic acid, MS (ion bombardment): 512 (M+H).

From 7,06 g of tert.-butyl ether (S)-2-benzyloxycarbonylamino - N1-cyclopropyl-N1-(2-pyrazin-2-incorporatingthe)-female room temperature. After evaporation of the acetic ester is dissolved in 70 ml of methylene chloride and add 3,96 ml base Hunga and 2.52 g of di-tert.-BUTYLCARBAMATE, after which the mixture was stirred at room temperature. The mixture is then concentrated, the residue is dissolved in 70 ml of methylene chloride and added with stirring consistently to 2.75 g of the dihydrochloride of (S)-amidino-3-(aminomethyl)piperidine, 10,27 ml base Hunga and 5.31g BOP and stirred at room temperature. After evaporation the residue chromatographic over silica gel with acetic ether/acetone/water/glacial acetic acid (ratio 6:2:1:1). The result 3,17 g of pure acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - 2-tert. -butoxycarbonylamino-N1-cyclopropyl-N1-(2-pyrazin-2 - ylcarbonyl)-succinamide (1:2), MS (ion bombardment): 560,5 (M+H).

Obtaining source material:

5 g of the hydrochloride benzyl ester 2-cyclopropanedicarboxylic acid (1: 1) (from Z-glycine and cyclopropylamine through cyclopropylamino benzyloxycarbonylamino acid) at room temperature is treated with stirring 4,36 g di-tert.-BUTYLCARBAMATE, is 3.08 ml of triethylamine and 100 mg of dimethylaminopyridine. After mixing the acid and water. The ether phase is concentrated. The oil obtained is dissolved in 100 ml of methanol, treated with 200 mg of Pd/C (10%) and hydronaut. After filtering off the catalyst, the methanol solution is concentrated. A solution of the residue in 100 ml of methylene chloride is treated 2,34 g pyrazinecarboxamide acid, and 9.5 ml of base Hunga and 8.44 grams of paph. After stirring at room temperature the mixture is dissolved in a simple ether and the ether phase washed with water. The remainder chromatographic over silica gel with acetic ether/hexane (1: 1). The oil obtained is dissolved in 40 ml of simple ether and treated with 30 ml of 5N. hydrochloric acid (in dioxane). After stirring a simple ether and filtered off the precipitated crystals. The result is 4.1 g of white crystalline hydrochloride cyclopropyl-2-(pyrazin-2-ylcarbonyl)ethylamine (1:2), MS (bombardment by a stream of electrons): 207 (M+H).

Example 20.

300 mg acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - 2-tert. -butoxycarbonylamino-N1-cyclopropyl-N1-(2-pyrazin-2 - ylcarbonyl)-succinamide (1: 2) dissolved in 2 ml of dioxane and treated with this solution 5 ml of 4n. hydrochloric acid (in dioxane). Then stirred for 2 h, after which the dioxane is evaporated. The residue is placed Hunga and 206 mg of BOP. The mixture is stirred at room temperature and then concentrated. The remainder chromatographic over silica gel with acetic ether/acetone/water/glacial acetic acid in the ratio 4: 2:1:1. The result is 167 mg acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-(2-pyrazin-2-incorporatingthe)-2-pyrimidine-2 - issulpiridathesameasdiazepam (1:2), MS (ion bombardment): 612,5 (M+H).

Example 21.

Analogously to example 20 receive the following connections:

(a) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-cyclopropyl-2-(3-indol-3-ylpropionic)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:2), MS (ion bombardment): 631,5 (M+H),

b) acetate methyl ester (S)-4-[(S)-2-[(S)-1-(aminoiminomethyl)- piperidine-3-iletileri] -1-[cyclopropyl-(2-pyrazin-2 - incorporatingthe)-carbarnoyl]-ethylcarboxyl]-4-hydroxybutiric acid (1:2), MS (ion bombardment): 604,5 (M+H),

in) acetate (S)-2-[(S)-2-acetylamino-3-indol-3-ylpropionic] - N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]-N1-cyclopropyl - N1-(2-pyrazin-2-incorporatingthe)-succinamide (1:2), MS (ion bombardment): 688,6 (M+H),

g) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1 - cyclopropyl-is instead than pyrimidinethione acid using the appropriate carboxylic acid.

Example 22.

354 mg of tert.-butyl ether (S)-3-[(S)-3-[cyclopropyl-(2-pyrazin - 2-incorporatingthe)-carbarnoyl]-3-(naphthalen-2-ylsulphonyl)- propenolatomethyl]-piperidine-1-carboxylic acid

- (from the hydrochloride benzyl ester 2-cyclopropanedicarboxylic acid through hydrochloride tert.-butyl ether (S)-3-[(S)-3-[(2-amino-ethyl)-cyclopropanecarbonyl] - 3-(naphthalen-2-ylsulphonyl)-propenolatomethyl]-piperidine-1 - carboxylic acid) -

dissolved in 3 ml of methylene chloride and treated with this solution 5 ml of 5N. hydrochloric acid (in dioxane). After stirring for 1 h the solution is concentrated and the residue azeotropic first with water and then with acetic ether. The residue is stirred in 3 ml of methylene chloride and, while cooling with ice add 53 mg of bromine cyan, and then added dropwise to 0.14 ml of triethylamine in 1 ml of methylene chloride. After stirring at room temperature add 70 mg of hydroxylamine hydrochloride and again of 0.14 ml of triethylamine. The mixture is stirred for 20 h, then concentrated and chromatographic by column over silica gel with acetic ether/acetone/water/glacial acetic acid in the ratio 6:2:1:1. The result is 60 mg acetamin-2 - ylcarbonyl)-ethyl] -succinamide (1:1), MS (ion bombardment): 666,3 (M+H).

Example 23.

1.0 g of benzyl ester of (S)-N1-[3-(benzyloxycarbonylamino)-ethyl]- N1-cyclopropyl-2-(morpholinomethyl)-aminosuccinic acid dissolved in 10 ml of THF and added 3.4 ml of 1N. the LiOH solution. After stirring for 1 h, the solution is treated with 3.4 ml of 1N. of hydrochloric acid. Then the solution was diluted with acetic ether and washed with water. After evaporation of the acetic ester receive 997 mg of the free acid, which is then dissolved in 10 ml of methylene chloride is treated with 1 ml N-ethylmorpholine, 360 mg of the dihydrochloride (S)-1-amidino-3-(aminomethyl)of piperidine and 715 mg of BOP. The mixture is stirred at room temperature and then concentrated. The remainder chromatographic over silica gel with acetic ether/acetone/water/glacial acetic acid in the ratio 6: 2: 1: 1, and the result is 740 mg benzyl ester 2-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2 - morpholine-4-isalphanumeric]-cyclopropylamino]-ethylcarbamate acid, MS (ion bombardment): 637,5 (M+H).

Obtaining source material:

5.0 g of the hydrochloride benzyl ester 2-cyclopropylamino-ethylcarbamate acid (1:1), 5,97 g of Boc-Asp(OBzl)-OH and 7,16 g base Hunig matney temperature the solution is diluted with simple ether and the ether phase is washed with 1N. hydrochloric acid, water, bicarbonate solution and again with water. Formed after evaporation the residue chromatographic over silica gel with acetic ether/hexane in the ratio of 1: 2. Of 9.6 g of the intermediate product obtained after chromatography of 1.76 g dissolved in 19 ml of THF and treated with the solution of 6 ml of 4n. hydrochloric acid (in dioxane). After stirring at room temperature the mixture is evaporated. From to 2.29 g of the obtained oil 1.54 g dissolved in 18 ml of methylene chloride, then add 1.2 g morpholine-N-sulfochloride and 2.2 ml of base Hunga. The mixture is stirred for 20 h, dissolved in acetic ether and washed with 1N. hydrochloric acid and water. After drying and evaporation the residue chromatographic by column over silica gel with acetic ether/hexane in the ratio of 1:1. The result is 920 mg benzyl ester (S)-N1-[3-(benzyloxycarbonylamino)-ethyl]-N1 - cyclopropyl-2-(morpholinomethyl)-aminosuccinic acid, MS (BTA): 589,1 (M+H).

Example 24.

325 mg benzyl ester 2-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-morpholine-4-isalphanumeric] - cyclopropylamino] -ethylcarbamate acid dissolved in 10 ml of methanol. After the addition of 35 mg of Pd/C (10%) who headed the remainder of dissolved in 4 ml of methylene chloride and added with stirring 48 mg pyrazinecarboxamide acid, of 0.24 ml of N-ethylmorpholine and 178 mg of BOP. After stirring at room temperature the mixture is concentrated and the residue chromatographic over silica gel with acetic ether/acetone/water/glacial acetic acid in the ratio 6:2:1:1. The result is 181 mg acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - 2-morpholine-4-ylsulphonyl-N1-(2-pyrazin-2-incorporatingthe)- succinamide (1:1), MS (ion bombardment): 609,5 (M+H).

Example 25.

If instead used in example 24 pyrazinecarboxamide acid to apply 2,3-dihydro-3-oxopyridine-6-carboxylic acid, receive acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-2-morpholine-4-ylsulphonyl-N1-[2-(6-oxo-1,6 - dihydropyridin-3-incorporatingthe]-succinamide (1:1), MS (ion bombardment): 625,4 (M+H).

Example 26.

If instead used in example 24 pyrazinecarboxamide acid to apply the following acids:

a) 6-oxo-1,4,5,6-tetrahydropyridine acid,

b) 3-aminopyrazine-2-carboxylic acid,

in) methoxybutanol acid,

g) morpholinothio acid,

d) 4-methylpiperazin-1-acetic acid,

e) 3-methoxypropionate acid,

W) 1-blowing products:

(a) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-cyclopropyl-2-morpholine-4-ylsulphonyl-N1-[2-(6-oxo-1,4,5,6 - tetrahydropyridine-3-ylcarbonyl)-ethyl]-succinamide (1:1), MS (ion bombardment): 627,6 (M+H),

b) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-[2-(3-aminopyrazine-2-ylcarbonyl)-ethyl] -N1-cyclopropyl-2 - morpholine-4-resultoriented (1:1), MS (ion bombardment): 624,6 (M+H),

in) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-N1-(2-methoxyethylamine)-2-morpholine-4 - resultoriented (1:1), MS (ion bombardment): 575,5 (M+H),

g) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-cyclopropyl-N1-(2-morpholine-4-ylacetamide)-2-morpholine-4 - resultoriented (1:1), MS (ion bombardment): 630,6 (M+H) and 316,2 (M+2H),

d) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-cyclopropyl-N1-[2-(4-methylpiperazin-1 ylacetamide)-ethyl]-2 - morpholine-4-resultoriented (1:1), MS (ion bombardment): 643,6 (M+H),

(e) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-N1-[2-(3-methoxypropylamine)-ethyl] -2-morpholine-4 - resultoriented (1:1), MS (ion bombardment): 589,6 (M+H),

W) acetate (S)-N4-[(S (1:1), MS (ion bombardment): 611,6 (M+H),

h) acetate (E)- and (Z)-4-[2-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval]-2-morpholine-4-isalphanumeric]- cyclopropylamino] -ethylcarboxyl]-4-gidroksiiminobetulonovoi acid (1:1), MS (ion bombardment): 646,5 (M+H).

Example 27.

2,77 g benzyl ester 2-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval]-2-morpholine-4-isalphanumeric]- cyclopropylamino] -ethylcarbamate acid (example 23) was dissolved in 90 ml of methanol. After the addition 2,14 ml of 2n. hydrochloric acid and 300 mg of Pd/C (10%) conduct hydrogenation for 1.5 h at room temperature, then the catalyst is filtered off and the filtrate concentrated. The residue was dispersed using a simple ether, then filtered off white crystals. The result of 2.44 g of crystalline hydrochloride of (S)-N1-(2-amino-ethyl)-N4-[(S)-1- (aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-2-morpholine-4 - resultoriented (1:2), MS (ion bombardment): 503,4 (M+H).

Example 28.

330 mg of the hydrochloride of (S)-N1-(2-amino-ethyl)-N4-[(S)-1- (aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-2-morpholine-4 - resultoriented stirred for 20 h at room temperature Y. mixture chromatographic over silica gel with acetic ether/acetone/glacial acetic acid/water in the ratio 2:2:2:1. The result 149,1 mg of pure crystalline acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl - N1-[2-(4-methylpiperazin-1 ylsulphonyl)-ethyl] -2-morpholine-4 - resultoriented (1:2), MS (ion bombardment): 665,6 (M+H) and 333,7 (M+2H).

Example 29.

Analogously to example 28, using instead 4-methylpiperazin-1 - ylsulphonyl morpholinosydnonimine receive acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1 - cyclopropyl-2-morpholine-4-ylsulphonyl-N1-(2-morpholine-4 - resultoriented)-succinamide (1:1), MS (ion bombardment): 652,5 (M+H).

Example 30.

Analogously to example 20, using, however, instead pyrimidinethione acid, respectively, one of the carboxylic acid:

a) 3-methoxypropionate acid,

b) morpholinothio acid,

in) methoxybutanol acid,

g) 4-methylpiperazin-1-acetic acid,

d) (L)-phenylalanine,

(e) (D)-phenylalanine,

g) 4-hydroxypiperidine-1-uksnow acid,

C) 1-imidazolylalkyl acid,

and) 2-piperidin-1-acetic acid,

K) 3-dimethylaminopropanol acid,

l) dimethylaminoethanol acid, respectively

m) of 2,6-dimethylmorpholine-4-acetic Ki is chlorophyl-2-(3-methoxypropylamine)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:2), MS (ion bombardment): 546,5 (M+H),

b) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-cyclopropyl-2-morpholine-4-ylacetamide-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:3), MS (bombardment by a stream of electrons): 587,3 (M+H),

in) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-cyclopropyl-2-methoxyethylamine-N1-(2-pyrazin-2-incorporatingthe)- succinamide (1:2), MS (ion bombardment): 532,6 (M+H),

g) acetate (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- N1-cyclopropyl-2-(4-methylpiperazin-1 ylacetamide)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:3), MS (ion bombardment): 600,6 (M+H),

d) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - 2-[(S)-2-amino-3-phenylpropionylamino]-N1-cyclopropyl-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:2), MS (ion bombardment): 607,5 (M+H),

e) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - 2-[(R)-2-amino-3-phenylpropionylamino]-N1-cyclopropyl-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:2), MS (ion bombardment): 607,5 (M+H) and 304,6 (M+2H),

W) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-2-[2-(4-hydroxypiperidine-1-yl)-acetylamino] -N1-(2 - pyrazin-2-incorporatingthe)-succinamide (1: 2), MS (BOM-(2-imidazol-1-ylacetamide)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:2), MS (ion bombardment): 568,5 (M+H),

and) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-2-[2-(2-oxopiperidin-1-yl)-acetylamino)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1: 2), MS (ion bombardment): 599,5 (M+H),

K) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-2-(3-dimethylaminopropylamine)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:3), MS (ion bombardment): byr559.6 (M+H),

l) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-2-(2-dimethylaminoacetyl)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:3), MS (ion bombardment): 545,6 (M+H),

m) hydrochloride (S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - N1-cyclopropyl-2-(2,6-dimethylmorpholine-4-ylacetamide)-N1-(2-pyrazin-2 - incorporatingthe)-succinamide (1:2) (R:S=1:1 for C2 and C6 in morpholinium ring), MS: 615,4 (M+H).

Example 31.

A solution of 3.0 g of product from example 7.B)a) in 63 ml of ethanol and 7 ml of water is treated with 0.95 ml of cinnamic aldehyde and 1.6 ml of 4-ethylmorpholine and stirred for 20 min at room temperature. To this solution was added 0.3 g of Pd/C catalyst and the reaction mixture hydronaut for 6 h under normal conditions. Then the catalyst otfit which Contains the product fractions evaporated and filtered using a water/ethanol through the ion exchange resin (Cl). After evaporation produce colorless hydrochloride of the ethyl ester of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-(3-phenylpropylamine)-propionyl]- cyclopropylamino]-propionic acid (1:2), MS (ion bombardment): 529,6 (M+H)+.

Example 32.

Analogously to example 31 receive the following product: hydrochloride ethyl ester 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval]-2-butylaminoethyl] -cyclopropylamino] -propionic acid (1: 2), MS (ion bombardment): 467,6 (M+H)+.

Example 33.

Analogously to example 3, but with additional filtering of the final product with water/ethanol through the ion exchange resin (Cl) receive the following products:

a) hydrochloride of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-(3-phenylpropylamine)-propionyl] -cyclopropylamino]- propionic acid (1:1), MS (ion bombardment): 501,7 (M+H)+,

b) hydrochloride of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-butylaminoethyl] -cyclopropylamino]-propionic acid (1:1), MS (ion bombardment): 439,6 (M+H)+.

Example 34.

In a solution of 3.4 g of the product from example 3 in 34 ml of ethanol and 6.8 ml of 1N hydrochloric acid add revival and the filtrate evaporated. In this way produce a colorless hydrochloride [[(S)-2-amino-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- propionyl]-cyclopropylamino]-acetic acid (1:1), MS (ion bombardment): 369,4 (M+H)+.

Example 35.

Analogously to example 34 from the product of example 37 receives the following link:

hydrochloride (S)-3-amino-N-[(S)-1-(aminoiminomethyl)-piperidine-3 - ylmethyl] -4-azepin-1-yl-4-oxobutanamide (1: 2), MS (ion bombardment): 353,4 (M+H)+.

Example 36.

2.1 g of product from example 7.A) is dissolved in 45 ml of ethanol and 5 ml of water, then treated with 0.7 g of cinnamic aldehyde and 1.1 ml of 4-ethylmorpholine and stirred for 15 min at room temperature. Then add 0.2 g of Pd/C catalyst and hydronaut for 6 h under normal conditions. The catalyst is filtered off, the filtrate evaporated and the residue chromatographic using a gradient of water/acetonitrile column RP-18. Containing the product fractions evaporated and the residue is filtered through an ion exchanger (Dowex, in the form of Cl). After evaporation produce 0.5 g of the hydrochloride of N-[(S)-1-(aminoiminomethyl)- piperidine-3-ylmethyl]-2-[(S)-4-cyclopropyl-3,6-dioxo-1-(3-phenylpropyl)- piperazine-2-yl]-ndimethylacetamide (1:1), MS (ion bombardment): 469,5 (M+H)+.

When the Teal)-piperidine-3-ylmethyl]- 4-azepin-1-yl-3-benzyloxycarbonylamino-4-oxobutanamide (1:1), MS (ion bombardment): 487,5 (M+H)+.

Obtaining source material:

Analogously to example 1.B) using, however, instead of the ethyl ester of N-cyclopropylamine hexamethylenimine, get the next intermediate product: tert. -butyl ether (S)-4-azepin-1-yl-3-benzyloxycarbonylamino-4 - oxomalonate acid, MS (ion bombardment): 405,2 (M+H)+.

Example 38.

Analogously to example 9, however, using the appropriate activated carbamates, receive the following connections:

a) ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-(3-diphenylmethylene)-propionyl] - cyclopropylamino]-acetic acid (1:1), MS (ion bombardment): 606,6 (M+H)+,

b) ethyl ester hydrochloride [[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval]-2-(3-cyclohexylmaleimide)-propionyl]- cyclopropylamino]-acetic acid (1:1), MS (ion bombardment): to 536.5 (M+H)+.

Obtaining raw materials:

Analogously to example 9.B)b) receive the following activated carbamates:

2,5-dioxopiperidin-1 silt ether diphenylcarbinol acid, MS (BTA): 309 (M-hydroxysuccinimide),

2,5-dioxopiperidin-1 silt is>Analogously to example 9, however, based on amine from example 35 and using the appropriate activated carbamates, receive the following connections:

a) hydrochloride (S)-N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- 4-azepin-1-yl-3-(3-benzylamino)-4-oxobutanamide (1:1), MS (ion bombardment): 486,4 (M+H)+,

b) hydrochloride of the methyl ester of (S)-2-[3-[(S)-1-[(S)-(aminoiminomethyl)- piperidine-3-iletilebilecegi]-2-azepin-1-yl-2-oxoethyl]-ureido]-3 - phenylpropionic acid (1:1), MS (ion bombardment): 558,5 (M+H)+,

b) hydrochloride of the methyl ester of (R)-2-[3-[(S)-1-[(S)-(aminoiminomethyl)- piperidine-3-iletilebilecegi]-2-azepin-1-yl-2-oxoethyl]-ureido]-3 - phenylpropionic acid (1:1), MS (ion bombardment): 558,5 (M+H)+.

Obtaining raw materials:

Analogously to example 9.B)b) receive the following activated carbamates:

a) 2,5-dioxopiperidin-1 silt ether benzylcarbamoyl acid, MS (BTA): 133 (M-hydroxysuccinimide),

b) methyl ester of (R)-2-(2,5-dioxopiperidin-1 eloxierarbeiten)- 3-phenylpropionic acid, MS (BTA): 133 (M-hydroxysuccinimide),

C) methyl ester of (S)-2-(2,5-dioxopiperidin-1 eloxierarbeiten)- 3-phenylpropionic acid, MS (BTA): 162 (M-H2-NCOO-succin shall receive the following products:

a) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-(3-diphenylmethylene)-propionyl] -cyclopropylamino] -acetic acid, MS (ion bombardment): 578,3 (M+H)+,

b) [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-(3-cyclohexylmaleimide)-propionyl]-cyclopropylamino]-acetic acid, MS (ion bombardment): 508,5 (M+H)+,

C) (S)-2-[3-[(S)-1-[(S)-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-azepin-1-yl-2-oxoethyl] -ureido] -3-phenylpropionate acid, MS (ion bombardment): 544,5 (M+H)+,

g) (R)-2-[3-[(S)-1-[(S)-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-azepin-1-yl-2-oxoethyl] -ureido] -3-phenylpropionate acid, MS (ion bombardment): 544,6 (M+H)+.

Example 41.

Analogously to example 1, using, however, instead dihydrochloride (S)-1-amidino-3-(aminomethyl)piperidine hydrochloride ethyl ester (S)-(3-aminomethylpyridine-1-yl)-aminomethylenemalonate acid, get [[(S)-2-benzyloxycarbonylamino-3-[(S)-1- (ethoxycarbonylmethyl)-piperidine-3-letiltasaval]-propionyl]- cyclopropylamino]-acetic acid, MS (ion bombardment): 575,5 (M+H)+.

Example 42.

Analogously to example 41, using, however, instead of Gido ether (RS)-(2-aminomethylation-4-yl)- aminomethylenemalonate acid, get [[(S)-2-benzyloxycarbonylamino - 3-[4-(ethoxycarbonylmethyl)morpholine-2-letiltasaval] -propionyl] -cyclopropylamino] -acetic acid (R: S= 1: 1 in morpholinium ring), MS (ion bombardment): 577,5 (M+H)+.

Example 43.

Analogously to example 15, but on the basis of

a) [(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] - 2-naphthalen-2-ylsulphanilamide]-acetic acid, respectively,

b) (S)-2-[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- 2-naphthalen-2-ylsulphanilamide]-3-hydroxypropionic acid,

receive the following products:

a) hydrochloride of N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] - 2-[(S)-1-naphthalen-2-ylsulphonyl-3,6-dioxopiperidin-2-yl] -ndimethylacetamide (1:1), MS (ion bombardment): 501,4 (M+H)+,

b) hydrochloride of N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl]- 2-[(2S, 5S)-5-hydroxymethyl-1-naphthalen-2-ylsulphonyl-3,6-dioxopiperidin - 2-yl] -ndimethylacetamide (1:1), MS (ion bombardment): 531,4 (M+H)+.

Obtaining raw materials:

1. On the basis of tert.-butyl ester of N-BOC-L-aspartic acid and ethyl ester of glycine, respectively serine methyl ester is obtained through

1.a) tert.-butyl-(S)-3-(1-is taxidermied)-N-[1-(2-hydroxy - 1-methoxycarbonyl)-ethyl]succinamic, through

2. a) tert.-butyl-(S)-N-[(etoxycarbonyl)methyl]-3-(naphthalen-2 - ylsulphonyl)succinamic, respectively

2. b) tert. -butyl(S)-N-[1-(2-hydroxy-1-methoxycarbonyl)-ethyl] - 3-(naphthalen-2-ylsulphonyl)succinamic and through

3. a) ethyl ester hydrochloride [(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-naphthalen-2 - resultadosoperacionales acid (1:1), MS (ion bombardment): 547,4 (M+H)+,

3.b) ethyl ester hydrochloride [(S)-2-[(S)-3-[(S)-1-(aminoiminomethyl)- piperidine-3-letiltasaval] -2-naphthalen-2-ylsulphanilamide]- 3-hydroxypropanoic acid (1:1), MS (ion bombardment): 563,4 (M+H)+through

4. a) [(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval]- 2-naphthalen-2-ylsulphanilamide]-acetic acid, MS (ion bombardment): 519,4 (M+H)+accordingly

4.b) [(S)-2-[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-naphthalen-2-ylsulphanilamide]-3 - hydroxypropionic acid, MS (ion bombardment): 549,3 (M+H)+.

Example 44.

Analogously to example 1.A) from a mixture (1:1) containing tert.-butyl ester of (2S, 5R)- and (2S,5S)-(5-benzyl-3,6-dioxo-4 - propylpiperazine-2-yl)-acetic acid, receive perazin-2-yl)-acetic acid (1:1), MS (ion bombardment): 443,6 (M+H)+.

Obtaining source material:

Based on tert. -butyl ether N-BOC-L-aspartic acid and the methyl ester rat-N-propylaniline through tert.-butyl ether (S)-2-tert. -butoxycarbonylamino-N-[(R)- and [(S)-1-methoxycarbonyl-2-phenylethyl] -N-prophylactically acid, MS ion bombardment): 493,5 (M+H)+get rubs. -butyl ester (2S,5R)- and (2S,5S)-(5-benzyl-3,6-dioxo-4-propylpiperazine-2-yl)-acetic acid, MS (BTA): 360 (M+).

Example 45.

Analogously to example 1.A) from tert.-butyl ether (S)-(4-cyclopropyl-1-ethoxycarbonylmethyl-3,6-dioxopiperidin-2-yl)- acetic acid to obtain hydrochloride of the ethyl ester of (S)-[2-[(S)-1-(aminoiminomethyl)-piperidine-3-iletilebilecegi] -4 - cyclopropyl-3,6-dioxopiperidin-1-yl] -acetic acid (1:1), MS (ion bombardment): 437,5 (M+H)+.

Obtaining source material:

a) of 0.67 g of the product of example 7.A) are dissolved in 7 ml of DMF, treated with 0.5 ml of 4-ethylmorpholine and stirred over night at 80oC. the Reaction mixture is evaporated and the residue chromatographic using acetic ether/methanol (99: 1) on silica gel. In this way gain of 0.43 g of colorless tert.-butyl afire> b) a solution of 3.45 g obtained in paragraph (a) of the product in 50 ml of DMF added to 1.9 g of 80% dispersion of sodium hydride, and then with 3 to 10oC added dropwise and 7.1 ml of ethyl ether bromoxynil acid. Then stirred for 4 h at room temperature, the reaction mixture was poured onto water and extracted with acetic ester. The organic phase is washed with saline, dried and concentrated. After chromatography of the residue with acetic ether/hexane (1:1) on silica gel obtain 1.6 g of tert.-butyl ether (S)-(4-cyclopropyl-1-ethoxycarbonylmethyl-3,6-dioxopiperidin - 2-yl)-acetic acid as a yellow resin, MS (ion bombardment): 355,4 (M+H)+.

Example 46.

Analogously to example 3 of the product from example 45 get [(S)-2-[(S)-1-(aminoiminomethyl)-piperidine-3-iletilebilecegi] -4 - cyclopropyl-3,6-dioxopiperidin-1-yl] -acetic acid, MS (ion bombardment): 409,5 (M+H)+.

Example 47.

A solution of 6.5 g of (RS)-(2,4-dimethyl-1-naphthalen-2-ylsulphonyl-3 - oxopiperidin-2-yl)-acetic acid in 65 ml of DMF is treated consistently of 7.64 g of BOP, and 6.5 ml of 4-ethylmorpholine and 4.35 g of dihydrochloride of (S)-1-amidino-3-(aminomethyl)-piperidine and stirred for overnight at commital on column RP-18. Containing the product fractions evaporated and the residue is filtered through an ion exchanger (Dowex, in the form of Cl). After evaporation allocate 0.8 g of a mixture (1:1) of the hydrochloride of (S)-1-(aminoiminomethyl)-piperidine-3-ylmethylamino (R)- and (S)-(2,4-dimethyl-1-naphthalen-2-ylsulphonyl-3-oxo-piperazine-2-yl)-acetic acid, MS (ion bombardment): 515,6 (M+H)+.

Obtaining source material:

a) a Solution of 10 g of ethyl-2-pyrazin-3-oncelate in 100 ml of dioxane is treated with 6.8 ml 4-ethylmorpholine and a solution of 12.9 g of di-tert.-BUTYLCARBAMATE in 50 ml of dioxane and stirred for 6 h at room temperature. Then the solvent is evaporated and the residue purified acetic ether/hexane (1: 1) on silica gel. The result of 15.4 g of tert.-butyl ether (RS)-2-ethoxycarbonylmethyl-3-oxo - piperazine-1-carboxylic acid, MS (ion bombardment): 287,3 (M+H)+.

b) a Solution of 15.0 g obtained in paragraph (a) compound in 200 ml of DMF is treated with 7.9 g of 80% dispersion of sodium hydride. Then when 3 to 10oC is added dropwise and 16.3 ml of methyliodide, stirred for 4 h at room temperature, after which the reaction mixture is poured on water and extracted with acetic ester. The organic phase is washed with water, dried and evaporated. The remainder of chromatog is (RS)-2-ethoxycarbonylmethyl-2,4-dimethyl-3-oxopiperidin-1-carboxylic acid, MS (BTA): 314 (M+).

C) a solution of the product of p. b) in acetonitrile is treated with monohydrate p-toluenesulfonic acid. After evaporation of the solution of the obtained residue in dioxane process - afterculture. In this way receive the ethyl ester of (RS)-(2,4-dimethyl-1-naphthalen-2-ylsulphonyl-3-oxopiperidin - 2-yl)-acetic acid, MS (BTA): 405 (M+H)+.

d) Analogously to example 3 from the product p. in) receive (RS)-(2,4-dimethyl-1-naphthalen-2-ylsulphonyl-3-oxopiperidin-2-yl)-acetic acid, MS (ion bombardment): 375,4 (M-H)-.

Example 48.

2,35 g lineproduct of example 7.A) is treated with 25 ml of DMF 3.2 ml 4-ethylmorpholine and 0.5 ml of chloride Chloroacetic acid and stirred overnight at room temperature. The reaction mixture is evaporated and the residue chromatographic on column RP-18 using a gradient of water/acetonitrile. Of containing the product fractions after evaporation obtain 0.5 g of the hydrochloride of ethyl ether [[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2-(2 - chloroacetamido)-propionyl]-cyclopropylamino]-acetic acid (1:1), MS (ion bombardment): 473,4 (M+H)+.

Example 49.

Analogously to example 3 of the product in example 48 get [[(S)-3-ing acid, MS (ion bombardment): 445,4 (M+H)+.

Example 50.

0.9 g of lineproduct of example 7.A) together with 0.5 g of hydrocarbonate sodium dissolved in 9 ml of THF and 9 ml of water, then treated 0,82 g morpholine-N-sulfochloride in 8 ml of THF and 1.9 ml of 1N. sodium liquor and stirred for 48 h at room temperature. The reaction mixtures by 1H. hydrochloric acid to give an acidic character, evaporated and the residue chromatographic on column RP-18 using a gradient of water/acetonitrile. Of containing the product fractions after evaporation obtain 0.2 g of colorless hydrochloride of the ethyl ester of 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3 - letiltasaval] -2-morpholine-4-isalphanumeric]- cyclopropylamino]-propionic acid (1:1), MS (ion bombardment): 560,5 (M+H)+.

Example 51.

Analogously to example 3 of the product from example 50 receive 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2 - morpholine-4-isalphanumeric]-cyclopropylamino]-propionic acid, MS (ion bombardment): 532,5 (M+H)+.

The compound of formula I, MES or salt of this compound can be applied by well-known methods as the active substance for the manufacture of farmacevticheskoe substance - 200 mg

Microcrystalline cellulose - 155 mg

Corn starch 25 mg

Talc 25 mg

The hypromellose 20 mg- --- - 425 mg

Example B

One capsule

Active substance 100.0 mg

Corn starch - 20.0 mg

Milk sugar - 95,0 mg

Talc - 4.5 mg

Magnesium stearate 0.5 mg- --- - 220,0 MHI

1. Carboxamide formula I

< / BR>
where E denotes hydrogen;

G represents H, lower alkyl or under certain conditions linked through the lowest alkylen COOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, CONH2, CONHCH2CH2OH, CONHOH, CONHOCH3, CONHO-benzyl, CONHSO2-lower alkyl, CONHCH2CH2-aryl, CONH-cycloalkyl, CNHCH2-heteroaryl, NH2, NHCOO-lower alkyl, NHCOO-lowest aralkyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH - (3,4-dioxo-2-hydroxycyclopent-1-enyl), NH-[2-lower (alkoxy or-alkenylamine)-3,4-dioxocyclohex-1-enyl] , NHCH2-heteroaryl, NHCOCO-(aryl or lower alkyl), NHCOCH2Cl, NHCO-lower alkylene-O-(lower alkyl or aryl), NHCOCH2[aryl, heteroaryl or-N(het)], NHCOC(NOH)-lower alkylene-COOH, NHSO2-N(het), NHCO-(SUP>20represent H, lower alkyl or phenyl and M is H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl,

L represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl or M, and L, together with the atoms to which they are linked, form a group-N(het) or E and G together form a methylene or carbonyl group, and

M represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl or carboxy-lower alkyl and

L represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl,

A stands for H, alkyl, lower aralkyl or a group of the formula

-C(O)R2(A1)

-S(O)2N(R3,R4) (A2)

or, if the group Q contains a hydroxyl group and/or if the E and G together represent CH2or CO,

A can represent a group of the formula

-S(O)2R5(A3)

R2denotes lower alkyl, under certain conditions linked through the lowest alkylene aryl, heteroaryl or cycloalkyl, or linked via a lower alkylene Carbo-lower alkoxy, or linked through Nisa in-position to the carbonyl group, associated R2may substituted hydroxyl group, an amino group or a lower alkanolamine, or

R2means associated through the lowest alkylen halogen, carboxyl group, lower alkoxy, amino, mono - or di-lower alkylamino or linked via a lower alkylene group-N(het) or

R2represent a group-OR22or other22,

R22denotes lower alkyl or under certain conditions linked through the lowest alkylene aryl, heteroaryl or cycloalkyl, or substituted in the fragment of the lower alkyl-aryl, Carbo-lower alkoxy or COOH lower aralkyl,

R3and R4independently of one another denote hydrogen, alkyl or aryl-lower alkyl, or together with N-atom to which they are bound, form a group-N(het),

R5denotes aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl, -N(het) denotes the N-linked, under certain conditions torn O, S, NH or N-lower alkyl and, under certain conditions, is substituted by up to two substituents from the group of lower alkyl, OH, oxo, COOH, COO-lower alkyl, CH2OH and CH2O-benzyl-N - (CH2)4-9,

Q represents a group of formula Q1or Q2< / BR>
< / BR>


R represents hydrogen or lower alkyl,

as well as the hydrate or the solvate and the physiologically compatible salts of the aforementioned compounds.

2. Carboxamide under item 1, where

E represents hydrogen,

G represents H, lower alkyl or under certain conditions linked through the lowest alkylen COOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, CONH2, CONHCH2CH2OH, CONHOH, CONHOCH3, CONHO-benzyl, CONHSO2-lower alkyl, CONHCH2CH2-aryl, CONH-cycloalkyl, CNHCH2-heteroaryl, NH2, NHCOO-lower alkyl, NHCOO-lowest aralkyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH-(3,4-dioxo-2-hydroxy-cyclobuta-1-enyl), NH-[2-lower (alkoxy or-alkenylamine)-3,4-dioxocyclohex-1-enyl], NHCH2-heteroaryl, NHCOCO-(aryl or lower alkyl), NHCOCH2Cl, NHCOCH2O-aryl, NHCOCH2-aryl, NHCO-(aryl or heteroaryl), NHPO3(R10, R20), heteroaryl, or under certain conditions, broken O or S and, under certain conditions, a substituted substituents up to two from the group of lower alkyl, COOH, COO is the second alkyl or phenyl,

M represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl,

L represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl, or

M and L together with the atoms through which they are linked, form under certain conditions torn O or S and, under certain conditions, a substituted substituents up to 2 from the group of lower alkyl, COOH, COO-lower alkyl, CH2OH, CH2O-benzyl N - (CH2)4-9or

E and G together form a methylene or carbonyl group, and

M represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or (aryl, generaal or cycloalkyl)-lower alkyl, or carboxy-lower alkyl, and

L represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl,

A can represent a group of the formula:

-C(O)R2(A1)

-S(O)2N(R3, R4) (A2)

or, if the group Q contains a hydroxyl group, A may represent a group of the formula

-S(O)2R5(A3)

or, if E and G together represent CH2or CO, A can represent an H, alkyl or a group of the formula:
< , and

R22denotes lower alkyl or under certain conditions linked through the lowest alkylene aryl, heteroaryl or cycloalkyl, or

R2means associated through the lowest alkylen Carbo-lower alkoxy or linked via a lower alkylene - (O or S)-(aryl, heteroaryl or cycloalkyl), and is contained in R2group lower alkylene in-position to the carbonyl group, which is bound R2may be substituted with hydroxyl group, amino or lower alkanolamine,

R3and R4independently of one another denote hydrogen, alkyl or aryl-lower alkyl, or together with N-atom to which they are linked, represent, under certain conditions, broken O or S-N(CH2)4-9, R5denotes aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl,

Q represents a group of formula Q1or Q2< / BR>
< / BR>
< / BR>
where T denotes CH2or O;

one of R6and R7denotes hydrogen or Carbo-lower alkoxy and the other represents hydrogen, Carbo-lower alkoxy or hydroxyl group, and

R denotes hydrogen,

as well as the hydrate or the solvate and the physiologically compatible salts named the specific conditions associated through the lowest alkylen COOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, CONH2, CONHCH2CH2OH, CONHOH, CONHOCH3, CONHO-benzyl, CONHSO2-lower alkyl, CONHCH2CH2-aryl, CONH-cycloalkyl, CONHCH2-heteroaryl, NH2, NHCOO-lower-alkyl, NHCOO-lowest-aralkyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH-(3,4-dioxo-2-hydroxy-cyclobuta-1-enyl), NH-[2-lower (alkoxy or-alkenylamine)-3,4-dioxocyclohex-1-enyl] , NHCH2-heteroaryl, NHCOCO-(aryl or lower alkyl), NHCOCH2Cl, NHCO-lower alkylene-O-(lower alkyl or aryl), NHCOCH2[aryl, heteroaryl or-N(het)] , NHCOC(NOH)-lower alkylene-COOH, NHSO2-N(het), NHCO-(aryl, heteroaryl or a heterocycle), NHPO3(R10, R20), heteroaryl or group CO-N(het),

R10and R20represent H, lower alkyl or phenyl and

M1represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl,

L1represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl or M1and L1together with the atoms to which they are linked, form a group-N(het),

A10the seat(A2)

or, if the group Q contains a hydroxyl group,

A10can also be a group of the formula

-S(O)2R5(A3), and R, R2- R5, -N(het) and Q have the same meaning as in paragraph 1,

as well as the hydrate or the solvate and the physiologically compatible salts of the aforementioned compounds.

4. Carboxamide under item 1 and formula Ib

< / BR>
where W denotes a methylene or carbonyl,

M2represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl, or carboxy-lower alkyl, and

L2represents H, lower alkyl, aryl, cycloalkyl, or (aryl or cycloalkyl)-lower alkyl, and

A11represents H, alkyl, lower aralkyl or a group of the formula

-C(O)R2(A1)

-S(O)2N(R3, R4) (A2or

-S(O)2R5(A3), and

R, R2- R5and Q have the same meaning as in paragraph 1,

as well as the hydrate or the solvate and the physiologically compatible salts of the aforementioned compounds.

5. Carboxamide on p. 3, where

G1represents H, lower alkyl or under certain conditions linked through the lowest alkylen COOH, COO-lower alkyl, lower SUB>, CONHO-benzyl, CONHSO2-lower alkyl, CONHCH2CH2-aryl, CONH-cycloalkyl, CONHCH2-heteroaryl, NH2, NHCOO-lower alkyl, NHCOO-lowest aralkyl, NHSO3H, (NHSO2or NHSO3)-lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH-(3,4-dioxo-2-hydroxy-cyclobuta-1-enyl), NH-[2-lower (alkoxy or-alkenylamine)-3,4-dioxocyclohex-1-enyl], NHCH2-heteroaryl, NHCOCO-(aryl or lower alkyl), NHCOCH2Cl, NHCOCH2O-aryl, NHCOCH2-aryl, NHCO-(aryl or heteroaryl), NHPO3(R10, R20), heteroaryl, or under certain conditions, broken O or S and, under certain conditions, a substituted substituents up to 2 from the group of lower alkyl, COOH, COO-lower alkyl, CH2OH and CH2O-benzyl CON(CH2)4-9and

R10and R20represent H, lower alkyl or phenyl,

M1represents H, lower alkyl or lower alkenyl, aryl, heteroaryl, cycloalkyl or aryl, heteroaryl or cycloalkyl)-lower alkyl,

L1represents H, lower alkyl, aryl, cycloalkyl or (aryl or cycloalkyl)-lower alkyl, or

M1and L1together with atoms on which they are linked, form under certain conditions torn O or S and, under certain conditions Samedan/SUB>)4-9,

A10represents a group of the formula:

-C(O)R2(A1)

-S(O)2N(R3, R4) (A2)

or, if the group Q contains a hydroxyl group,

A10can also be a group of the formula

-S(O)2R5(A3)

R denotes hydrogen and

R2- R5and Q have the same meaning as in paragraph 3,

as well as the hydrate or the solvate and the physiologically compatible salts of the aforementioned compounds.

6. Carboxamide under item 4, where

R denotes hydrogen,

A11represents H, alkyl or a group of the formula:

-C(O)R2(A1)

-S(O)2N(R3, R4) (A2)

or-S(O)2R5(A3)

and L2M2, W, R2- R5and Q have the same meaning as in paragraph 4,

as well as the hydrate or the solvate and the physiologically compatible salts of the aforementioned compounds.

7. Carboxamide formula Ia under item 3, where L1denotes hydrogen and G1means under certain conditions linked through the lowest alkylen NHCO-lower alkylene-O-(lower alkyl or aryl), NHCOCH2[aryl, heteroaryl or-N(het)], NHCOC(NOH)-lower alkylene-COOH, NHSO2-N(het), NHCO-heterocyclyl or under certain use alkyl, COOH, COO-lower alkyl, CH2OH and CH2O-benzyl CON(CH2)4-9.

8. Carboxamide formula Ia under item 3, where L1represents hydrogen and G1represents under certain conditions linked through the lowest alkylen COOH, COO-lower alkyl, NHCOO-lowest aralkyl or NHCO(aryl or heteroaryl).

9. Carboxamide formula Ia under item 3, 7, or 8, where M1represents a lower alkyl or cycloalkyl.

10. Carboxamide formula Ia under item 3 or PP.7 - 9, where A10represents H, lower alkyl, lower aralkyl or group

-C(O)-R2(A1)

in which R2is a is connected through the lower alkylen halogen, carboxyl group, lower alkoxy, amino, mono - or di-lower alkylamino or linked via a lower alkylene group-N(het) or R2represents the group-other22where R22represents a group of the lowest aralkyl substituted in signalcolor the fragment aryl, carbonitril alkoxy or COOH.

11. Carboxamide formula Ia under item 3 or PP.7 to 10, where A10represents a group of the formula

-C(O)-R2(A1)

in which R2represents a group R22, -OR22or other22and R222is a is connected through the lower alkylen Carbo-lower alkoxy, or linked via a lower alkylene -(O or S)-(aryl or heteroaryl), and is contained in R2group lower alkylene in-position to the carbonyl group, which is bound R2may be substituted by OH or lower alkanolamine.

12. Carboxamide formula Ia under item 3, 8 or 9 where A10represents morpholinomethyl.

13. Carboxamide formula Ia under item 3, 8 or 9 where A10contains a group-S(O)2aryl, and Q contains a hydroxyl group.

14. Carboxamide formula Ib according to p. 4, where L2represents hydrogen, and M2represents lower alkyl, cycloalkyl or carboxy-lower alkyl.

15. Carboxamide formula Ib under item 4 or 14, where A11represents hydrogen, lower alkylsulfonyl or arylsulfonyl.

16. Carboxamide on one of the PP.1 - 15, where Q represents a group of formula Q1in which one of R6and R7represents hydrogen and the other represents a hydrogen or hydroxyl group.

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

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-Elmer 3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2-(3-phenylpropylamine)propionyl] -cyclopropylamino] -propionic acid,

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

3-[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2-morpholine-4-isalphanumeric]-cyclopropylamino]-propionic acid.

18. Connection on p. 2 of the following groups:

[[(S)-3-[4-(aminoiminomethyl)-morpholine-2-letiltasaval] -2-benzyloxycarbonylamino]-butylamino]-acetic acid,

[[(S)-3-[(S)-1-(aminoiminomethyl)-piperidine-3-letiltasaval] -2-pentanediamine]-cyclopropylamino]-acetic acid,

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-N1-(2-pyrazin-2-incorporatingthe)-2-pyrimidine-2-isalphanumericastring,

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

(S)-N4-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -N1-cyclopropyl-2-morpholine-4-ylsulphonyl)-N1-[2-(6-oxo-1,6-dihydropyridin-3-incorporatingthe]-succinamic and

N-[(S)-1-(aminoiminomethyl)-piperidine-3-ylmethyl] -2[(S)-4-cyclopropyl-1-naphthalen-2-ylsulphonyl-3,6-dioxopiperidin-2-yl]-ndimethylacetamide.

The priority attribute-COOH,NHSO2-N(het), NHCO-(aryl, heteroaryl or heterocyclyl), R is lower alkyl, M and L, together with the atoms to which they are linked, form a group - N(het), R3and R4together with N-atom to which they are bound, form a group-N(het), -N(het) denotes the N-linked, under certain conditions torn O, S, NH or N - lower alkyl and, under certain conditions, is substituted by up to two substituents from the group of lower alkyl, OH, oxo, COOH, COO - lower alkyl, CH2OH and CH2O - benzyl-N - (CH2)4-9.

 

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The invention relates to certain condensed to errorcorrection that selectively associated with GABA receptors

The invention relates to new triazolylmethyl tertiary amine of the formula I, where A is a simple bond or lower Allenova group; B is a lower alkyl, a group (a), naphthyl, pyridyl, thienyl, thiazolyl, benzothiazolyl, hinely, benzofurazanyl or benzothiazolyl, possibly substituted with halogen or alkyl; D - ring group, (b) or benzofurazanyl; E - ring - 4H-1,2,4-triazole or 1H-1,2,4-triazolyl; R1- H, halogen, cyano-, nitro-group, CF3, lower alkyl or alkoxy; R2is hydrogen or halogen; R3- halogen, cyano-, nitro-, CF3or amino group, provided that when both R1and R2are chlorine atoms, And a methylene

The invention relates to the derivatives of pyrazine formula I, where R1- H or C1-8-alkyl, R2- C1-8-alkyl, unsubstituted or substituted C1-4-alkoxyl, hydroxyl, fenoxaprop, which in turn is one - or multi-substituted C1-4-alkyl, C1-4-alkoxyl, alkoxyalkyl or cyano, aminowhere R3- H or C1-4-alkyl, R4-phenyl, repeatedly substituted C1-4-alkyl, a substituted amino group dichlorobenzenesulfonyl, C1-4-alkyl, unsubstituted or substituted residues selected from the group of hydroxyl, fenoxaprop, in turn multiply substituted by halogen or alkoxyalkyl, carbonylation formula II, where X is oxygen or-NH-, piperidinyl, N-substituted C1-8-alkyl, and phenyl unsubstituted or substituted C1-4-alkoxyl, amidinopropane formulawhere R5is phenyl, substituted by halogen or C1-4-alkyl, and a group of the formula III, where R1- H, or R1and R2together with the nitrogen atom to which they are bound, form a pieperazinove ring, unsubstituted or substituted in position 4 by a group IV, V,-alkyl, or alkoxyalkyl, and-naftussya, and if R1- H, R2does not mean alkyl, benzyl, fluorine - or chlorbenzyl, phenethyl, hydroxyethyl or HOCH2- (CHOH)4- CH2or if R1- C1-3-alkyl, R2does not mean C1-4-alkyl, and an acid additive salt

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to novel 4,5-dihydro-1H-2,4-allowin the benzodiazepines and benzodiazipine appropriate diamines and aminoamides, to methods for their preparation and to methods and compositions for treating arrhythmia in mammals with said 4,5-dihydro-1H-2,4-ariovich of benzodiazepines and benzodiazipines

-aminocarbonyl acids possessing antiarrhythmic and antifibrillatory activity" target="_blank">

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to new derivatives phenylbenzimidazol formula I listed in the description, in which R1and R2identical or different, represent a hydrogen atom or a halogen or an alkyl radical, possibly halogenated, and R3and R4identical or different, represent alkyl, C1- C4or can form together with the nitrogen atom to which they are linked, a cycle of morpholino

The invention relates to novel 1,2,4-substituted piperidines formula 1, where R1is unsubstituted or substituted with halogen and/or trifluoromethyl phenyl or diphenyl-C1-C4-alkyl, ; 9-fluorenyl, pyridil-C1-C4-alkyl; chinolin-C1-C4-alkyl; 5-chloro-2-[1H-1,2,4-triazolyl-1-yl]-phenoxy-C1-C4-alkyl, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkoxyl, hydroxyl, halogen, trifluoromethyl, di-C1-C4-alkylamino-group and/or cyano benzoyl; naphtol; 2-fluorenyl; phenyl - or diphenyl-C2-C4-alkanoyl; naphthyl-C2-C4-alkanoyl; dimethylcyclohexanols; hinolincarbonova; pyridyl-C2-C4-alkanoyl; benzyloxycarbonyl, unsubstituted or substituted by acetyl or 4-carboxymethylation phenylalanine or phenylcarbamoyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-3-yl-carbonyl; R2is unsubstituted or substituted with halogen phenyl or naphthyl; R3is hydrogen, C1-C4-alkyl, cyclohexyl or phenylcarbamoyl, or 3-aminocarbonylmethyl; R4- if necessary substituted C1-C4-alkyl or C1-C4-alkoxyl phenyl, naphthyl, benzyl, pyridyl, if necessary, C-Zam the sludge; if necessary substituted C1-C4the alkyl benzothiophenes, dihydrobenzofuranyl or aniline group, X1- simple bond, methylene, hydroxymethylene or carbonyl, X2- a simple link, X3- simple bond, methylene, ethylene, benzylidene or carbonyl or their salts

The invention relates to new derivatives of arylalkylamines, as well as containing their farbkomposition, which can find application in pathological conditions involving the system of neurokinin

The invention relates to new biologically active compounds derived pyrimidine-4-or their pharmaceutically acceptable salts with serotoninergicheskoi, dopaminergically, antihistaminic activity, and compositions on their basis

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid
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