Derivatives of piperazines, methods for their preparation and pharmaceutical composition

 

(57) Abstract:

Describes the new derivatives of piperazines of the formula I Y-(CmH2m-CHR1)n-CO-(NH-CHR2-CO)g-Z, where Y denotes (a) or (b), Z represents (in), or, if Y denotes (a) implies (d), R1, R2and R7each means-CtH2t-R9, R3means H or H2N-C(=NH)-, R4and R6each mean (N, N) or = O, R5means N2N-C(=NH)-, or H2N-C(=NH)-NH, R8IT means, or OA, R9denotes H or COOH, And means alkyl with 1-4 C-atoms, m and t each is 0, 1 or 2, n and r each denotes 0 or 1 and p is 0, 1 or 2, and their salts. The compounds of formula (I) inhibit the binding of fibrinogen, fibronectin and factor of Villebranda with the fibrinogen receptor of blood platelets and can find application as anticancer agents. Describes how to obtain the compounds of formula (I) and pharmaceutical compositions on the basis of the above compounds. 7 c. and 2 C.p. f-crystals, 1 PL.

< / BR>
< / BR>
< / BR>

The invention relates to new compounds of the formula I

Y-(CmH2m-CHR1)n-CO- (NH-CHR2CO)r-Z

where Y denotes

< / BR>
or
each means-CtH2t-R9,

R3means H or H2N-C(=NH)-,

R4and R6each means (H,H) or =O,

R5means H2N-C(=NH) -, or H2N-C(=NH)-NH,

R8means OH or OA,

R9denotes H or COOH,

A denotes alkyl with 1-4 C-atoms,

m and t each is 0, 1 or 2,

n and r each denotes 0 or 1 and

p is 0, 1 or 2,

and also their salts.

Similar compounds known from EP-A1 0381033.

The objective of the invention is to obtain compounds with valuable properties, which can be used for getting medicines.

The problem is solved by obtaining the compounds of formula I and their salts with good compatibility and valuable pharmacological properties. In particular, they inhibit the binding of fibrinogen, fibronectin and von Willebrand factor to the fibrinogen receptor of blood platelets (glycoprotein IIb/IIIa) and their linking and binding proteins with adhesive properties, as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. Thus compounds affect the interaction of cell-cell and cell-matrix. They prevent, exii, myocardial infarction, inflammatory processes of atherosclerosis. Further connections have an impact on tumor cells, inhibiting metastasis. Thus they can also be used as anticancer agents.

Connection properties can be confirmed using the methods described in EP-A1 0462960. Inhibition of binding of fibrinogen to the fibrinogen receptor can be proved using the method specified in EP-A1 0381033. Effect, inhibiting platelet aggregation, it is possible to prove in vitro according to the method of born (Nature, 4832, 927-929, 1962). The subject invention are also methods for obtaining the compounds of formula I and their salts.

The method of obtaining of piperazine derivatives of formula I and its salts according to the invention is that the piperazine derivatives of the formula I is recovered from one of its functional derivatives by using solvolysis or hydrogenolysis tools.

Following receipt of piperazine derivatives of the formula I and their salts is that carried out the interaction of carboxylic acids of the formula II

Y-(CmH2m-CHR1)n-CO-OH, (II)

where

Y, R1, m, n have the above meanings, UP>-CO/r-Z, (III)

where

Z, R2r have the above values.

The subject of the invention is also a method of obtaining derivatives of piperazine, namely, that spend the interaction of carboxylic acids of the formula II

Y-(CmH2m-CHR1)n-CO-G1-OH, (II)

where

G1denotes-NH-CHR2-CO-,

Y, R1, R2, m, n have the above meanings, or one of its reactive derivatives interacts with aminoguanidinium formula III

H-Z (III)

Z have the above values.

According to the invention the following method of obtaining of piperazine derivatives of the formula I and their salts, is that carried out the interaction of the carboxylic acid of the formula II

Y-(CmH2m-CHR1)n-CO-G1-OH, (II)

where

G1does

Y, R1, R2, m, n and r have the above values, or one of its reactive derivatives interacts with aminoguanidinium formula III

H-G2(III)

where

G2denotes-NH-CpH2p-CHR7-CO-R8,

Z, R7, R8and p have the above values.

Derivatives of piperazine of General formula I, ukazannye values, and R3or R5denotes H2N-C(= NH)-, can be obtained according to the invention by the fact that the corresponding nitrile is treated with ammonia and/or if necessary omelet ester of formula I (R8=OH) and/or the compound of formula I by treatment with acid or base was transferred to his salt.

Individual compounds of formula I have chiral centers and therefore can be represented in several enantiomeric forms. All of these forms (for example, D - and L-forms) and mixtures thereof (for example the DL forms) are included in formula I.

Above - and below residues, respectively, the parameters Y, Z, R1-R9, A, G1, G2, m, n, p, r and t have the meanings indicated in formula I, II or III, except where specifically stated otherwise.

Group A mean alkyl groups with 1-4, mostly 1 or 2 C-atoms, in particular methyl or ethyl, a propyl, isopropyl, butyl, isobutyl, secondary butyl or tert.butyl. If in the compound of formula I there are several groups A, then they can have the same or a different value.

The parameter m means mostly 0 or 1; t mean mostly 0, but also 1, 2, 3 or 4; n means mostly 1, but also 0; r oznachaet NH-CpH2p-CHR7-CO - may, in particular, to mean residues of the amino acids occurring in nature, mostly-NH-CH2-CO- (glycine residue), but also the remains of an L - or D-alanine, L - or D-valine, L - or D-leucine, L - or D-isoleucine, L - or D-phenylalanine, L - or D-tyrosine, L - or D-histidine, L - or D-tryptophan, L - or D-serine, L - or D-threonine, L - or D-ornithine, L - or D-lysine, L - or D - cysteine, L - or D - methionine, L - or D - aspartic acid, L - or D - asparagine, L - or D - arginine. The group-NH-CpH2p-CHR7-CO - refers mainly well-NH-CH2CH2-CO- (remainder - alanine) or-NH-/CH2/3-CO- (remainder 4-aminobutyric acid).

R1, R2, R7or R9can preferably denote H, R3mostly H2N-C/= NH/- (amidino), R4and R6can indicate predominantly (H,H), R5preferably H2N-C/= NH/NH- (guanidino), R8preferably OH, also preferably OA, in particular OCH3or OC2H5.

Accordingly, the group -/CmH2m-CHR1/n-CO-/NH-CHR2CO/ris preferably-CO-, -CH2-CO-, -CO-NH-CH2-CO - or-CH2CH2-CO-.

Piperazinovogo rings can bet piperazinone rings are 2-methyl-1,4-piperazinyl, 2,5-dimethyl-1,4-piperazinyl, 2,6-dimethyl-1,4-piperazinyl and 2,3,5,6-tetramethyl-1,4-piperazinyl.

Among the compounds of formula I, preferred are such compounds in which at least one of these residues, one of these groups and/or one of the specified parameters is one of these preferred values. Some preferred group of compounds expressed by formulas 1a-1g corresponding to the formula I and where the remains and/or parameters that do not have more detailed specifications, shall have the meanings indicated in formula I, where, however,

in Ia y denotes

in Ib y denotes

in Ic x denotes

z denotes

in Id y denotes

z denotes

in Ie and y denotes

If y denotes

in Ig y denotes

Further preferred are compounds of formula Ih, and Iah - Igh, which correspond to formulae I and Ia-Ig, where, however, the advanced group -(CmH2m-CHR1)n- CO-(NH-CHR2-CO)rmeans

-CO-, -CH2-CO-, -CO-NH-CH2-CO - or-CH2CH2CO.

Further preferred compounds of formula Ii, Iai-Ihi, as well as Iahi-Ighi are those that correspond to formulas I, Ia-Ih, and Iah-Igh, where one -(CH2)3-COOH, -CH(COOH)-CH2COOH, -CH2COOA, -CH2CH2COOA, -(CH2)3-COOA or-CH(COOA)-CH2COOA.

The compounds of formula I, as well as source materials for their production receive, however, known methods as are described in the literature (for example, in Houben-Weil, "Methods of organic chemistry", publisher George Thieme, the city of Stuttgart; also in EP-A1 0381033, EP-A1 0462960), and in those reaction conditions which are known and suitable for the specified interactions. While here you can also use the well-known themselves options that are not mentioned here in detail.

Source substances, if required, can also be obtained in situ, so they are not isolated from the reaction mixture, and immediately converted into the compounds of formula I.

The compounds of formula I can be obtained by selecting them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

The preferred initial agents for the solvolysis respectively hydrogenolysis are those which generally correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxy-group, p is the spine of such which instead of H2N-groups have R'-NH-group, where R' denotes aminosidine group, and/or such that instead of the H atom of the hydroxy-group have hydroxyamino group, for example those which correspond to the formula I, but instead of group-CtH2t-R9have the group-CtH2t-OR" and/or instead of the group R8group-OR", where R" denotes hydroxyamino group.

In the molecule of the original substance may also be some which have the same or different is - protected amino and/or hydroxy-group. If the existing protective groups differ from each other, they can in many cases be chipped off selectively.

The expression "aminosidine group" generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can be easily removed once held the required chemical reaction in another fragment of the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl (for example, 2,4-dinitrophenyl(DNP)), raloxisene (for example, benzoyloxymethyl (BPO) or kalkilya group (for example, benzyl, 4-nitrobenzyl, triphenylmethyl what size are not critical; however, preferred are those groups which have 1-20, in particular 1-8 C-atoms. The expression "acyl group" should be understood in connection with the present method in the broadest sense of the word. It includes acyl groups, in particular alkoxycarbonyl, aryloxyalkyl and primarily alcoxycarbenium group formed from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic or sulphonic acids. Examples of such acyl groups are alkanoyl as acetyl, propionyl, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, isopropoxycarbonyl, tert.butoxycarbonyl (SIDE), 2-iodoxybenzoic, Uralelectromed as benzyloxycarbonyl (CBZ), 4-methoxybenzeneboronic, 9-fertilitycare (FMOC). Preferred aminosidine groups are the SIDE DNF and BOM, then CBZ, benzyl and acetyl. The expression "hidroxizina group" also generally known and relates to groups which are suitable for protecting a hydroxy-group from chemical reactions but which can be easily removed after it is yaytsa the abovementioned unsubstituted or substituted aryl, kalkilya or acyl group, hereinafter also referred to as alkyl groups. The nature and size hydroxyamine groups are not critical, as they again removed after the desired chemical reaction or reaction sequence of reactions; preferred group with 1-20, in particular 1-10, C atoms. Examples hydroxyamine groups are, in particular, tert.butyl, benzyl, p-nitrobenzoyl, p-toluensulfonyl and acetyl, with benzyl and acetyl is particularly preferred.

Used as starting substances functional derivatives of compounds of formula I can be obtained by the known methods of amino acid and peptide synthesis, as described, for example, in the above reference publications and patent applications, for example, using solid-phase synthesis according to Merrifield.

The emission of compounds of the formula I from their functional derivatives could be achieved depending on the protective group, for example using strong acids, expediently using triperoxonane acid or perchloro acid, but also using other strong inorganic acids, such as hydrochloric or sulfuric acid, with strong organic carboxylic acids, as trichloroacetic acid or saltsa possible but it is not always necessary.

As the inert solvent is preferably suitable organic, for example carboxylic acids, as acetic acid, ethers, like tetrahydrofuran or dioxane, amides, as dimethylformamide (DMF), halogenated hydrocarbons like dichloromethane, also referred to as alcohols like methanol, ethanol or isopropanol, and also water. Also we can talk about mixtures of the above solvents. Triperoxonane acid is preferably used in excess without the addition of another solvent, perchloro acid in a mixture of acetic acid with 70% perchloro acid in the ratio 9:1. Reaction temperatures for the cleavage are suitable between about 0 and about 50oC; preferably this process is carried out between 15 and 30oC (room temperature).

SIDE-group can, for example, it is preferable to split with 40% triperoxonane acid in dichloromethane or using approximately 3 to 5 N. HCl in dioxane at 15-60oC, FMOC-group using 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-50oC. Cleavage DNP group can, for example, to make using 3-10% solution of 2-mercaptoethanol in the mixture is or benzyl), can be split, for example, by treatment with hydrogen in the presence of a catalyst (for example, a catalyst made of noble metal, such as palladium, expediently on a medium such as coal). As solvents in this approach the above-mentioned solvents, in particular alcohols, like methanol or ethanol, or amides, as DMF. The hydrogenolysis is conducted usually at temperatures between about 0 and 100oC and a pressure of between about 1 and 200 bar, preferably at 20-30oC and 1-10 bar. Hydrogenolysis CBZ group can, for example, a good 5-10% palladium-carbon catalyst in methanol at 20-30oC.

The compounds of formula I can also be obtained by direct condensation of the carboxylic acid component (formula II) and aminocompounds (formula III). As components of carboxylic acids are suitable, for example, components such formulas

(a) y/CmH2m-CHR1/-COOH,

(b) y/CmH2m-CHR1/n-CO-NH-CHR2-COOH or

(c) y/CmH2m-CHR1/n-CO-/NH-CHR2-CO/r-

as aminocompounds such formulas

(a) H/NH-CHR2-CO/r-Z

(b) H-Z, or

(C) H2N-CpH2p-CHR7CO-Rthe us in Houben-Weil, 1. C., vol 15/11 p. 1-806 (1974).

The reaction could mainly be held in the presence of dehydrating, such as a carbodiimide, as dicyclohexylcarbodiimide (DCCI) or N-dimethylaminopropyl-N'-ethylcarbodiimide (DAPECI), anhydride papapostolou acid (compare Angew. Chem. (92, 129/1980)), diphenylphosphinite or 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline, in an inert solvent such as halogenated hydrocarbon like dichloromethane, ether like THF or dioxane, amide as DMF or dimethylacetamide, a nitrile as acetonitrile, at temperatures between about -10 and 40oC, preferably between 0 and 30oC.

Instead II III can be introduced into the reaction also suitable reactive derivatives of these substances, for example those in which reactive groups are blocked intermediate with protective groups. Acid derivatives II can, for example, be applied in the form of their complex activated esters, which are expediently formed in situ, for example by adding hydroxybenzotriazole or N-hydroxysuccinimide.

To obtain amidine formula I [R3or R5=H2N-C(=NH)-] can then be attached to the nitrile, which respectively multistage by turning in a known manner a) nitrile with H2S tioned, translated using alkylating agents, such CH3J, the corresponding complex S-alkyl-imitation, which, on its part reacts with NH3with the formation of amidine, b) by transformation of the nitrile with an alcohol, for example ethanol, in the presence of HCl into the corresponding complex aminoether, and treating it with ammonia, or c) by the interaction of the nitrile with lithium bis-(trimethylsilyl)-Amida and the product immediately for this is subjected to hydrolysis.

The source materials for these variants of the method, for example these starting substances of the formulae II and III, partially known. If they are unknown, they can be obtained with known methods, for example the above-mentioned methods of condensation and removal of protective groups.

If required, it is possible in connection formulas I to carry out the esterification of the carboxylic acid group or bring a group of hydroxamic acid or spend saponification group of ester.

For the esterification can handle the acid of formula I (R8=OH) using an excess of the alcohol of the formula R-OH, it is advisable in the presence of a strong acid like hydrochloric acid or sulfuric acid at temperatures between 0 and 100o8=OA) with hydroxylamine, which can be distinguished on one of its salts, such as hydrochloride, using an alkali metal alcoholate, such as ethylate sodium (Adriatica). The process is carried out expediently in the presence of an inert solvent, for example alcohol, like methanol, ethanol or isopropanol at temperatures between 0 and 40oC, preferably between 15 and 30oC.

Further, the compounds of formula I, where R8denotes OA, can be converted into the corresponding compound of formula I, where R8denotes OH, it is advisable with the help of selective solvolysis one of the above methods, for example with NaOH or KOH in a mixture of water with dioxane at temperatures between 0 and 40oWith, preferably between 10 and 30oC.

Next, in the connection of the formula I H-atom can be replaced by processing using amenitieshere means aminidivi group. As starting substances are preferably suitable derivatives of piperazines, where R3=H; as amidaniel means the preferred 1-amidino-3,5-dimethylpyrazole, which is used, in particular, in the form of its nitrate. Is advisable to carry out this process by adding bases, such as triethylamine or the nom at temperatures between 0 and 120oC, preferably between 60 and 120oC.

The basis of the formula I can be translated using acid to the corresponding salt of the acid attached. For this interaction, in particular, suitable acids which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulphuric, nitric, halogenation acid as hydrochloric or Hydrobromic acid, phosphoric acid, like phosphoric acid, sulfamic acid, also limit acids, in particular aliphatic, alicyclic, arylaliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, triperoxonane acid, propionic acid, trimethylhexane acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultancy, ethicalfashion, 2-hydroxyethanesulfonic, benzosulphate is acceptable acids, for example, the picrate, can be used for identifying and/or purifying compounds of formula I.

The new compounds of formula I and their physiologically acceptable salts can be used to obtain pharmaceutical drugs, bringing them together with at least one carrier and/or auxiliary substance and, if necessary, together with one (or several other) active substance (active substance) in a suitable finished dosage form. The finished products, thus obtained, can be used as drugs in medicine or veterinary medicine. As substances vehicles we can talk about organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or application in the form of an inhalation spray and not reagiert (do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other glycerides of the fatty acid series, gelatin, soy lecithin, carbohydrates as lactose or starch, magnesium stearate, talc, cellulose. For oral administration, in particular, the use of tablets, coated tablets, capsules, syrups, juices sludge to the action of gastric juice, accordingly, the capsule is coated. For rectal use suppositories, for parenteral use - solutions, mainly oily or aqueous solutions, and also suspensions, emulsions or implants.

For use as an inhalation spray, you can use sprays that contain active substance, or dissolved or suspended in the spray of the gas mixture. If this is the appropriate use of the active substance in micronized form, this may be one or more additional physiologically compatible solvents, such as ethanol. Inhalation solutions can be applied in the form of conventional inhalers. The new compounds can also be lyophilized and the resulting lyophilizate can be applied, for example, to obtain drugs for injection. These preparations can be sterilized and may contain and/or auxiliary substances, such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing not the osmotic pressure, buffer substances, colorants and/or aromatic substances. They can, if this is required, also contain one or more active videso analogy with other known commercially available peptides, in particular, similar to the one described in EP-A 249096 compounds, mainly in dosages between about 5 mg and 1 g, in particular between 50 and 500 mg per unit dose of the medication. Daily dose medications is preferably about 0.1-20 mg/kg, in particular 1-10 mg/kg body weight. However, each special dose of medication dose for each particular patient depends on various factors, such as efficiency used special connections, age, body weight, General health, sex, diet, time of medication and method of drug administration, rate of excretion, combination of drugs and the severity of the relevant disease, belongs to this treatment. Oral administration has the advantage.

Throughout the application, all temperatures are given in the 0oC.

In the following examples, "conventional treatment" means the following: add, if necessary, water shall be established depending on the structure of the final product pH values between 2 and 8, extracted with ethyl acetate or dichloromethane, separated, the organic phase is dried using sodium sulfate, evaporated and purified by chromatography is jiroveci fast atom".

Example 1

A mixture of 10 g of complex ethyl ester 3-/4-/4-/3-SIDE-guanidino/-benzoyl/-2-oxo-piperazinil/-propionic acid, melting point 143o; FAB 462; it was obtained by condensation of 4-/3-SIDE-guanidino/-benzoic acid with a complex ethyl ester, 3-/2-oxo-1-piperazinil/-propionic acid, 400 ml of dioxane and 56 ml of 1 N. aqueous NaOH solution is stirred for 5 h at 20o. Is evaporated, the residue is dissolved in water, washed repeatedly with ethyl acetate. Extracted with ethyl acetate, dried, evaporated, dissolved the crude 3-/4-/4-/3-SIDE-guanidino)-benzoyl/-2-oxo-1-piperazinil/-propionic acid in 200 ml of 4 N. HCl in dioxane, stirred for 3 h at 20oprocess as usual and get 3-/4-/4-guanidino-benzoyl/-2-oxo-1-piperazinil/-propionic acid, melting point 110o(decomposition).

Similarly obtained from complex ethyl ester 4-/4-/3-SIDE-guanidino/benzoyl-2-oxo-1-piperazinil-acetic acid/oil; FAB 448; it was obtained by condensation of 4-/3-SIDE-guanidino/-benzoic acid with a complex ethyl ester, 2-oxo-1-piperazinil-acetic acid by saponification and subsequent (following directly behind it) off the SIDE,

Similarly obtained from 4-/4-SIDE-amidino-benzimidazolyl/-1-piperazinil-acetic acid/ FAB 448; obtained by condensation of 4-SIDE-amidino-benzamidoxime acid complex benzyl ester 1-piperazinil-acetic acid, with formation of complex benzyl ester 4-/4-SIDE-amidino-benzimidazolyl/-1-piperazinil-acetic acid and hydrogenolysis group complex benzyl ester:

4-/4-amidino-benzamido-acetyl - /-1-piperazinil-acetic acid, FAB 348.

Example 2

A solution of 1 g of complex benzyl ester 4-/4-(3-CBZ-guanidine/-benzoyl/-1-piperazinil/-butyric acid [FAB 558; the resulting condensation complex benzyl ester 4-/3-CBZ-guanidine)-benzoic acid with a complex benzyl ester 4-/1-piperazinil/-butyric acid] in a mixture of 38 ml of methanol, 6 ml of water and 6 ml of acetic acid is subjected to hydrogenation at 0.6 g of 5% palladium-carbon catalyst at 20oand a pressure of 1 bar until the end of the absorption of H2. Filtered, the filtrate is evaporated, the residue is crystallized from ethyl acetate and receive 4-/4-(4-guanidino-benzoyl)-1-piperazinil/-butyric acid, FAB 334.

Similarly receive the hydrogenolysis:

from complex benzyl ester 3-/3-4-To the one butyl ester 1-piperazinil-acetic acid with N-CBZ-S-methyl-estimaciones with the formation of tert. difficult butyl ether 4-CBZ-amidino-1-piperazinil-acetic acid, removal of tert. butilkoi group with 4h. HCl in dioxane and condensation obtained 4-CBZ-amidino-1-piperazinil-acetic acid complex benzyl ether 3-3-amino-benzamido/-propionic acid]:

3-[3-/4-amidino-1-piperazinil-acetamido/-benzamido]-propionic acid, melting point 270o(decomposition);

from complex benzyl ester 4-/4-guanidino-benzimidazolyl/-1-piperazinil-acetic acid (melting point 248o; obtained by condensation of 4-guanidino-benzoic acid with a complex benzyl ester 4-aminoacetyl-1-piperazinil-acetic acid):

4-/4-guanidino-benzamido-acetyl - /-1-piperazinil-acetic acid; hydrochloride, melting point 124o(decomposition); from complex benzyl ester 3-/3-/4-CBZ-1-piperazinil-carboxamido-acetamido/-benzamido/-propionic acid [FAB 602; obtained from the reaction of 1-CBZ-piperazine complex benzyl ester 3-/3-isocyanatoacetate/-benzamido/-propionic acid];

3-/3-/1-piperazinil-carboxamido-acetamido/-benzamido/-propionic acid; melting point 123o;

from complex benzyl ester 3-[3-/4-CBZ-amidino-1 piperazinecarboxamide-ACET ansilove ether 3-/3-isocyanato-acetamido-benzamido/-propionic acid]:

3-/3-/4-amidino-1-piperazinil-carboxamido-acetamido/-benzamido/- propionic acid; hydrochloride of the Belarusian library Association 420;

from complex benzyl ester 4-/4-CBZ-amidino-1-piperazinil-acetyl - /-1-piperazinil-acetic acid [Rf0,44 (a mixture of dichloromethane with methanol in the ratio 9: 1) was obtained by condensation of 4-CBZ-amidino-1-piperazinil-acetic acid complex benzyl ester 1-piperazinil-acetic acid]:

4-/4-amidino-1-piperazinil-acetyl - /-1-piperazinil-acetic acid, melting point 272o(decomposition); from complex benzyl ester 3-/3-/4-CBZ-2-oxo-1-piperazinil-acetamido/-benzamido/-propionic acid [FAB 573; obtained by condensation of 4-CBZ-2-oxo-1-piperazinil-acetic acid complex benzyl ester 3-/3-amino-benzamido/-propionic acid]:

3-/3-/2-oxo-1-piperazinil-acetamido/-benzamido/-propionic acid; melting point 225o;

from complex benzyl ester 3-/4-CBZ-2-oxo-1-piperazinil-acetamido/-benzamido-acetic acid [FAB 559; obtained from 3-/4-CBZ-2-oxo-1-piperazinil-acetamido/-benzoic acid and glycine complex-benzyl ether]:

3-/2-oxo-1-piperazinil-acetamido/-benzamido-acetic acid, melting point 167o;

from complex benzite condensation of 3-/4-CBZ-amidino-2-oxo-1-piperidineacetic/-benzoic acid with a complex licenseserver ether]:

3-/4-amidino-2-oxo-1-piperazinil-acetamido/-benzamido-acetic acid; melting point > 300o;

from complex benzyl ester 3-/3-4-CBS-oxo-1-piperazinyl-acetamido/-benzamido/-propionic acid [FAB 573; obtained from 3-/4-CBZ-2-oxo-1-piperazinil-acetamido/-benzoic acid and complex-alanine benzyl ester]:

3-/3/-2-oxo-1-piperazinil-acetamido/-benzamido/-propionic acid; FAB 349;

from complex benzyl ether 3/3-/4-CBZ-amidino-2-oxo-1-piperazinil-acetamido/-benzamido/- propionic acid [FAB 615; the resulting condensation 3/4-CBS-amidino-2-oxo-1-piperazinil-acetamido/-benzoic acid with a complex-alanine benzyl ether]:

3-[3-/4-amidino-2-oxo-1-piperazinil-acetamido/-benzamido] - propionic acid, melting point 283o(decomposition);

from complex benzyl ester 4-/4-CBZ-1-piperazinil-carboxamidates/-1-piperazinil-acetic acid [FAB 538, obtained by condensation of 4-CBZ-1-piperazinil-carboxamide-acetic acid complex benzyl ester 1-piperazinil-acetic acid]:

4-/1-piperazinil-carboxamido-acetyl - /-1-piperazinil-acetic acid, melting point 150o(decomposition);

from complex benzyl ester 4-/4-CBZ-amidino-1-PI is idine-1-piperazinil-carboxamido - acetic acid complex benzyl ester 1-piperazinil-acetic acid]:

4-/4-amidino-1-piperazinil-carboxamido-acetyl - /-1 - piperidinyloxy acid, melting point 190-198o(decomposition);

from complex benzyl ester 4-/4-/3-CBZ-guanidine/-benzoyl/-2 - oxo-1-piperazinil-acetic acid [FAB 544; obtained by condensation of 4-/3-CB-guanidino/-benzoic acid with a complex benzyl ester 2-oxo-1-piperazinil-acetic acid]:

4/4-guanidinopentanoic/-2-oxo-1-piperazinil-acetic acid, melting point 98o(decomposition);

from complex benzyl ester 3-/4-CBZ-1-piperazinil-carboxymethylamino/-benzamido-acetic acid [FAB 588; obtained from 3-/4-CBZ-1-piperazinil-carboxamido-acetamido/-benzoic acid and glycine complex-benzyl ether]:

3-/1-piperazinil-carboxamido-acetamido/-benzamido-acetic acid, melting point 188o;

from complex benzyl ester 3-/4-CBZ-amidino-1 piperazinecarboxamide-acetamido/-benzamido-acetic acid [FAB 630; obtained by condensation of 4-CBZ-amidino-1-piperazinil-carboxamido-acetic acid complex benzyl ester 3-amino-benzamidoxime acid]:

3-/4-amidino-1-piperazinil-carboxamido-acetamido/-benzamido-acetic acid, melting point 284o;

from the complex is Tate condensation of 3-/4-CBZ-amidino-1-piperazinil-acetamido/-benzoic acid with glycine complex-benzyl ether]:

3-/4-amidino-1-piperazinil-acetamido-/benzamido-acetic acid, melting point 180-185o(decomposition);

from complex benzyl ester 4-[4-CBZ-amidino-1-piperazinil-acetyl - /-1-piperazinil] -butyric acid [FAB 565; obtained by condensation of 4-CBZ-amidino-1-piperazinil-acetic acid (melting point 124ocomplex benzyl ester 4-/1-piperazinil/-butyric acid]:

4-[4-/4-amidino-1-piperazinil-acetyl/1-piperazinil] -butyric acid, melting point 253o(decomposition);

from complex benzyl ester 3-/4-/4-/3-CBZ-guanidinopentanoic/-2-oxo-1-piperazinil/-propionic acid [FAB 558; obtained by condensation of 4-/3 CBS-guanidino/-benzoic acid with a complex benzyl ester 3-/2-oxo-1-piperazinil/-propionic acid]:

3-[4-/4-guanidino-benzoyl/2-oxo-1-piperazinil] -propionic acid, melting point 110o(decomposition);

from complex benzyl ester 3-[3-/4-CBZ-1 piperazinecarboxamide/-benzamido] -propionic acid [FAB 545; result for indexing 3-(4-CBZ-1 piperazinecarboxamide)-benzoic acid and complex-alanine-benzilovogo ether]:

3-[3-/1-piperazinil-carboxamido/-benzamido] -propionic acid, FAB 321;

from complex benzile the ATA condensation of 3-(4-CBZ-amidino-1-piperazinil-carboxamido)-benzoic acid with a complex-alanine benzyl ether]:

3-[3-/4-amidino-1-piperazinil-carboxamido/-benzamido]- propionic acid, melting point 234o(decomposition);

from complex benzyl ester 3-/4-CBZ-1 piperazinecarboxamide/-benzamido-acetic acid [FAB 531; obtained by condensation of 3-(4-CBZ-1-piperazinil - carboxamido)-benzoic acid with glycine complex-benzyl ether]:

3-/1-piperazinil-carboxamido/-benzamido-acetic acid, FAB 307;

from complex benzyl ester 3-(4-CBZ-amidino-1-piperazinil-carboxamido)-benzamido-acetic acid [FAB 573; obtained by condensation of 3-/4-CBZ-amidino-1-piperazinil-carboxamido/-benzoic acid with glycine complex-benzyl ether]:

3-(4-amidino-1-piperazinil-carboxamido)-benzamidoxime acid, melting point 117o;

from complex dimensional ester N-[3-/4-CBZ-2-oxo-1-piperidineacetic/-benzoyl] -L-aspartic acid [FAB 707; obtained by condensation of 3-/4-CBZ-2-oxo - 1-piperazinil-acetamido/-benzoic acid with a complex diversilobum ester of L-aspartic acid]:

N-[3-/2-oxo-1-piperazinil-acetamido-benzoyl] -L-aspartic acid, FAB 393;

from complex dimensional ester N-[3-(4-CBZ-amidino-2-oxo-1 - piperazinil-acetamido)-benzoyl] -1-TSA is Noah acid complex diversilobum ester of L-aspartic acid]:

N-[3-(4-amidino-2-oxo-1-piperazinil-acetamido)-benzoyl] aspartic acid, melting point 179o;

from complex benzyl ester 4-[3(4-CBZ-1-piperazinil-carboxamido)-benzamido] -butyric acid [FAB 559; obtained by condensation of 3-(4-CBZ-1-piperazinil-carboxamido)-benzoic acid with a complex benzyl ether of 4-aminobutyric acid]:

4-[3-/1-piperazinil-carboxamido/-benzamido]-butyric acid, FAB 335;

from complex benzyl ester 4-[3-(4-CBZ-amidino-1-piperazinil-carboxamido)-benzamido] -butyric acid [FAB 601; obtained by condensation of 3-(4-CBZ-amidino-1-piperazinyl-carboxamido)-benzoic acid with a complex benzyl ether of 4-aminobutyric acid]:

4-[3-(4-amidino-1-piperazinil-carboxamido)-benzamido] - butyric acid, melting point 215o;

from complex benzyl ester 4-[3-(4-CBZ-2-oxo-1 - piperazinil-acetamido)-benzamido]-butyric acid [FAB 587; obtained by condensation of 3-(4-CBZ-2-oxo-1-piperazinil-acetamido)-benzoic acid with a complex benzyl ether of 4-aminobutyric acid]:

4-[3-(2-oxo-1-piperazinil-acetamido)-benzamido] -butyric acid, FAB 363;

from complex benzyl ester 4-[3-(4-CBZ-amidino-1-oxo-1 - piperazinil-acetanilide)-benzoic acid with a complex benzyl ether of 4-aminobutyric acid]:

4-[3/(4-amidino-2-oxo-1-piperazinil-acetamido)-benzamido] -butyric acid, melting point 269o;

from complex benzyl ester 4-[3-(4-CBZ-amidino-1-piperazinil-acetamido)-benzamido]-butyric acid [FAB 615 obtained by condensing 3-(4-CBZ-amidino-1-piperazinil-acetamido)-benzoic acid with a complex benzyl ether of 4-aminobutyric acid]:

4-[3-(amidino-1-piperazinil-acetamido)-benzamido] -butyric acid, melting point 115o;

from complex benzyl ester 3-[3(-CBZ-amidino-1-piperazinil)-propionamido] -benzamido-acetic acid [FAB 601; obtained by condensation of 3-[3-(4-CBZ-amidino-1-piperazinil)-propionamido]-benzoic acid with a complex glycine benzyl ester:

3-[3-(4-amidino-1-piperazinil)-propionamido]-benzamido-acetic acid, FAB 377; melting point 268o;

from complex banilower ether 3-[3-[3-(4-CBZ-amidino-1-piperazinil)-propionamido]-benzamido]- propionic acid [FAB 615; obtained by condensation of 3-/3-/4-CBZ-amidino-1-piperazinil)-propionamido/-benzoic acid with a complex-aluminasilica ether]:

3-[3-[3-(4-amidino-1-piperazinil)-propionamido] -benzamido] propionic acid, FAB 391; melting point 200o;

from complex 4; obtained by condensation of 4-CBZ-amidino-1-piperazinil-carboxymethoxy acid complex benzyl ester 3-(1-piperazinil)-propionic acid]:

3-[4[(4-amidino-1-piperacillin-carboxamido-acetyl)-1 - piperazinil]-propionic acid, FAB 370; melting point 141o;

from complex benzyl ester 3-[4-(4-CBZ-amidino-1 - piperazinil-acetyl)-1-piperazinil]-propionic acid [FAB 551; obtained by condensation of 4-CBZ-amidino-1-piperazinil-acetic acid complex benzyl ester 3-/1-piperazinil/-propionic acid]:

3-[4-(4-amidino-1-piperazinil)-acetyl] -1-piperazinil-propionic acid, melting point 280o;

from the complicated methyl ester 3-[3-(4-CBZ-amidino-1 - piperazinil-acetamido)-benzamido] -propionic acid [FAB 525; obtained by condensation of 4-CBZ-amidino-1-piperazinil-acetic acid complex methyl ether 3-(3-aminobenzamide)-propionic acid]:

methyl ester 3-[3-(4-amidino-1-piperazinil-acetamido)-benzamido]-propionic acid, dihydrochloride, melting point 222o;

from complex benzyl ester 3-[4-[4-(3-CBZ-guanidine)-benzoyl]-1-piperazinil] -propionic acid [FAB 544; obtained by condensation of 4-(3-CBZ-guanidyl)-1-piperazinil]- propionic acid, FAB 320;

from complex benzyl ester 4-[4-(3-CBZ-guanidine)- benzimidazolyl] -1-piperazinil-acetic acid [FAB 587; obtained by condensation of 4-(3-CBZ-guanidine)-benzamidoxime acid complex benzyl ester 1-piperazinil-acetic acid]:

4-(4-guanidino-benzamido-acetyl)-1-piperazinil-acetic acid, FAB 363.

Example 3

(a) a Mixture of 1.86 g of 4-amino-1-piperazinil-acetic acid with 2,22 g complex methyl ester 3-/3-aminobenzamide/-propionic acid, 1.92 g of CAPACI-hydrochloride, 1.01 g of N-methylmorpholine and 70 ml of DMF is stirred for 16 h at 20o. Is evaporated, treated with a mixture of ethyl acetate with 5% solution of NaHCO3and get methyl ester 3-[3-/4-amidino-1-piperazinil-acetamido/-benzamido] -propionic acid. The dihydrochloride, melting point 222o.

Similarly receive as a result of condensation:

4-guanidino-benzoic acid with a complex of methyl ester of 4-(1 - piperazinil)-butyric acid:

methyl ester of 4-[4-(4-guanidino-benzoyl)-1-piperazinil] butyric acid;

4-guanidino-benzoic acid with a complex methyl ether 4-amino-acetyl-1-piperazinil-acetic acid:

methyl ester of 4-(4-g is oinoi acid complex glycine methyl ester:

methyl ester 3-/1-piperazinil-carboxamido-acetamido/- benzamido-acetic acid;

3-/4-amidino-1-piperazinil-carboxamido-acetamido/-benzoic acid with a complex - alanyl methyl ester:

methyl ester 3-[3-/4-amidino-1-piperazinil - carboxamido-acetamido)-benzamido]-propionic acid;

4-amidino-1-piperazine derivatives - acetic acid complex methyl ether 1-piperazinil-acetic acid:

methyl ester 4-/4-amidino-1-piperazinil-acetyl)-1 - piperazinil-acetic acid;

3-/2-oxo-1-piperazinil-acetamido/-benzoic acid with a complex - alanine methyl ester:

methyl ester 3-/3-/2-oxo-1-piperazinil-acetamido/ benzamidopiperidine acid;

3-/4-amidino-2-oxo-1-piperazinil-acetamido/-benzoic acid with a complex glycine methyl ester:

methyl ester 3-/4-amidino-2-oxo-1-piperazinil - acetamido/-benzamidoxime acid;

3-/4-amidino-2-oxo-1-piperazinil-acetamido/-benzoic acid with a complex - alanine methyl ester:

methyl ester 3-/3-/4-amidino-2-oxo-1-piperazinil - acetamido/-benzamido/-propionic acid;

4-amidino-1-piperazinil-carboxamido-acetic acid with complex metalowymi)-1-piperazinil-acetic acid;

4-guanidino-benzoic acid with a complex methyl ether 2-oxo-1-piperazinil-acetic acid:

methyl ester 4-/4-guanidino-benzoyl/-2-oxo-1 - piperazinil-acetic acid;

3-/4-amidino-1-piperazinil-carboxamido-acetamido/-benzoic acid with a complex glycine methyl ester:

methyl ester 3-/4-amidino-1-piperazinil-carboxamido-acetamido/-benzamidoxime acid;

3-/4-amidino-1-piperazinil-acetamido/-benzoic acid with a complex glycine methyl ester:

methyl ester 3-/4-amidino-1-piperazinil-acetamido/-benzamidoxime acid;

4-amidino-1-piperazinil-acetic acid complex methyl ether 4-/1-piperazinil/-butyric acid:

methyl ester 4-/4-/4-amidino-1-piperazinylmethyl/-1 - piperazinil-butyric acid;

4-guanidino-benzoic acid with a complex methyl ether 3-/2-oxo-1-piperazinil-propionic acid:

methyl ester 3-[4-(4-guanidino-benzoyl)-2-oxo-1 - 1-piperazinil]-propionic acid;

3-/4-amidino-1-piperazinil-carboxamido/-benzoic acid with a complex - alanine methyl ester:

methyl ester 3-[3-/4-amidino-1-piperazinil-carboxamido)-benzamido]-propionic sour is false methyl ether 3-/4-amidino-1-piperazinil-carboxamido/-benzamidoxime acid;

3-/4-amidino-2-oxo-1-piperazinil-acetamido/-benzoic acid with a complex of dimethyl ester of L-aspartic acid:

complex dimethyl ether N-/3-/4-amidino-2-oxo-1-piperazinil-acetamido-benzoyl-L-aspartic acid;

3-/4-amidino-1-piperazinil-carboxamido/-benzoic acid with a complex methyl ether 4-aminobutyric acid:

methyl ester 4-[3-(4-amidino-1-piperazinil-carboxamido-benzamido]-butyric acid;

3-/4-amidino-2-oxo-1-piperazinil-acetamido/-benzoic acid with a complex methyl ether 4-aminobutyric acid;

methyl ester 4-[3-/4-amidino-2-oxo-1-piperazinil-acetamido-benzamido]-butyric acid;

3-(4-amidino-2-oxo-1-piperazinil-acetamido)-benzoic acid with a complex methyl ether 4-aminobutyric acid:

methyl ester 4-[3-(4-amidino-2-oxo-1-piperazinil-acetamido)-benzamido]-butyric acid;

3-[3-(4-amidino-1-piperazinil)-propionamido] -benzoic acid with a complex glycine methyl ester:

methyl ester 3-[3-(4-amidino-1-piperazinil)-propionamido]-benzamidoxime acid;

3-[3-(4-amidino-1-piperazinil)-propionamido] -benzoic acid complex - alanine methyl ester:

complex m is erazine-carboxymethoxy acid complex methyl ether 3-(1-piperazinil)-propionic acid:

methyl ester 3-[4-(4-amidino-1-piperazinil-carboxamido-acetyl)-1-piperazinil]- propionic acid;

4-amidino-1-piperazinil-acetic acid complex methyl ether 3-(1-piperazinil)-propionic acid:

methyl ester 3-[4-(4-amidino-1-piperazinil-acetyl)-1-piperazinil]-propionic acid:

3-(4-amidino-1-piperazinil-acetyl)benzoic acid with a complex - alanine ethyl ester;

complex ethyl ester of 3-[3-/4-amidino-1-piperazinil-acetamido]- propionic acid.

Example 4

(a) From C4H9Li and 1.13 g hexamethyldisilazane freshly prepared solution of Li-N/Si/CH3/3/2in 20 ml of THF are added dropwise with stirring at -78oin a solution of 3.15 g of complex ethyl ester 3-[4-(4-lebensohl)-1-piperazinil] -propionic acid [FAB 316; obtained by the reaction of 4-canbesold with complex ethyl ester, 1-piperazinil-propionic acid] in 50 ml of THF.

Heated with stirring to 20oadd aqueous hydrochloric acid, washed with ethyl acetate, add a solution of sodium hydroxide until pH = 7.5, process as usual, is evaporated and receive complex ethyl ester 3-[4-(4 - amidinophenoxy)-1-pentyl)-1-piperazinil]-butyric acid [FAB 330]:

complex ethyl ester 4-[4-(4-amidinophenoxy)-1-piperazinil]-butyric acid, FAB 347.

(b) By saponification analogously to example 1 are obtained from a complex of ethyl esters listed above in paragraph (a):

3-[4-(4-amidinophenoxy)-1-piperazinil]-propionic acid, FAB 305;

4-[4-(4-amidinophenoxy)-1-piperazinil]-butyric acid, FAB 319.

Example 5

A solution of 201 mg of 1-amidino-3,5-dimethylpyrazol-nitrate in 17 ml of dioxane and 5 ml of water is mixed with 0.17 ml of ethyl-Diisopropylamine and stirred for 15 minutes Then add 357 mg of the hydrochloride of 3-[3-(1-piperazinil-carboxamido)-benzamido] -propionic acid [FAB 321; the resulting reaction complex benzyl ester 3-(3-aminobenzamide)-propionic acid with diphosgene with the formation of complex benzyl ester 3-/3-isocyanato-benzamido/-propionic acid, accession 1-BOC-piperazine to complex benzyl ether, 3-[3-(4-BOC-1-piperazinil-carboxamido)-benzamido]-propionic acid, removal of the BOC-group with 4 N. HCl in dioxane with the formation of the hydrochloride benzyl ester 3-[3-(1-piperazinil-carboxamido)-benzamido]-propionic acid [FAB 411] and hydrogenolysis 5% palladium-carbon catalyst) and 0.17 ml of ethyl-Diisopropylamine, boil the mixture in the Yu ethyl acetate again evaporated and receive 3-[3-(4-amidino-1-piperazinil-carboxamido)benzamido] -propionic acid, the melting point 234o(decomposition).

Similarly obtained from the corresponding derivatives of piperazines 4-amidino-piperazinoazepine specified in example 2.

Example 6

Analogously to example 5 was produced using the 1-amidino-3,5-dimethylbenzonitrile;

from 3-[4-(1-piperazinil-carboxamido-acetyl)-1H-piperazinil] propionic acid:

3-[4-(4-amidino-1-piperazinil-carboxamido-acetyl)-1-piperazinil] -propionic acid, melting point 141o;

from 3-[3-(1-piperazinil)-propionamido]-benzamido-acetic acid:

3-[3-(4-amidino-1-piperazinil)-propionamido] -benzamidoxime acid, melting point 268o;

from 3-[3-[3-(1-piperazinil)-propionamido]-benzamido]-propionic acid:

3-[3-[3-(4-amidino-1-piperazinil)-propionamido] -benzamido]- propionic acid, melting point 200o;

from 3-[3-[2-(1-piperazinil)propionamido]-benzamido]- propionic acid:

3-[3-[2-(4-amidino-1-piperazinil)-propionamido] -benzamido]- propionic acid, melting point 171o;

from 3-[3-(1-piperazinil-acetamido)-benzamido]-propionic acid:

3-[3-(4-amidino-1-piperazinil-acetamido)-benzamido] - propionic acid. The dihydrochloride, melting point 272o
A mixture of 1 kg of active substance of the formula I, 1.4 kg of lactose, 1.2 kg of corn starch, 200 g of talc and 100 g of magnesium stearate is pressed in the usual manner into tablets such that each tablet contains 100 mg of active substance.

Example B: bean

Analogously to example A pressed tablet, which is directly behind this cover as usual coating consisting of sucrose, corn starch, talc, tragant and dye.

Example C: capsules

500 g of the active substance of the formula I fill in the usual way in capsules of hard gelatin, so that each capsule contains 500 mg of active substance.

Example D: vessels for injection

A solution of 100 g of the active substance of the formula I in 4 l of bidistilled water is adjusted to a pH equal to 6.5 using 2 N. hydrochloric acid, filtered under sterile conditions and filled with a solution of vessels for injection. Lyophilizer in sterile sterile conditions and sealed. Each vessel for injection contains 50 mg of active substance.

Example E: suppositories

Melt 50 g of the active substance of the formula I with 10 g of soya lecithin and 140 g of cocoa butter, poured into moulds and cooled. Each suppository contains 250 mg active is the key fibrinogenesis receptor) are given for the following compounds of General formula I (see. table. 1).

1. Derivatives of piperazines of the formula I

Y-(CmH2m-CHR1)n-CO-(NH-CHR2-CO)r-Z

where Y denotes

< / BR>
or

< / BR>
Z denotes

< / BR>
or, if Y denotes

< / BR>
also means

< / BR>
R1, R2and R7each means-CtH2t-R9,

R3means H or H2N-C(=NH)-,

R4and R6each means (H, H) or =0,

R5means H2N-C(=NH) -, or H2N-C(=NH)-NH,

R8means HE or OA,

R9denotes H or COOH,

A denotes alkyl with 1-4 C-atoms,

m and t each is 0, 1 or 2,

n and r each denotes 0 or 1 and

p is 0, 1 or 2,

and also their salts.

2. A derivative of piperazine under item 1, representing 3-[3-(4-amidino-1-piperazinil-acetamido)-benzamido]-propionic acid.

3. Way to obtain the piperazine derivatives of General formula I on p. 1 or their salts, characterized in that the piperazine derivative or its salt of the formula I, where instead of one or more free amino and/or hydroxy groups are protected amino and/or hydroxy-group, is subjected to solvolysis or hydrogenolysis.

4. The method of obtaining proizvodnja, characterized in that the carboxylic acid of General formula II

Y-(CmH2m-CHR1)n-CO-OH,

where Y, R1, m and n have the above values,

or one of its reactive derivatives is subjected to interaction with aminoguanidinium General formula III

H-(NH-CHR2-CO)r-Z

where R2, Z and r have the above values.

5. Way to obtain the piperazine derivatives of General formula I on p. 1 or their salts, where Y, R1, R2, Z, m and n have the above significance, and r is 1, characterized in that the carboxylic acid of General formula II'

Y-(CmH2m-CHR1)n-CO-G'-OH,

where Y, R1, m and n have the above values,

G1means

-NH-CHR2-CO-,

where R2has the above value,

or one of its reactive derivatives is subjected to interaction with aminoguanidinium General formula III'

H-Z

where Z has the above values.

6. Way to obtain the piperazine derivatives of General formula I on p. 1 or their salts, where R1, R2, m, n and r have the above values,

Y means

< / BR>
where R3, R4have the above values, and Z signifies

th formula II"

Y-(CmH2m-CHR1)n-CO-G'-OH,

where G' means

< / BR>
Y, R1, R2, m, n and r have the above values,

or one of its reactive derivatives is subjected to interaction with aminoguanidinium General formula

H-G2,

where G2means

-NH-CpH2p-CHR7-CO-R8,

R7, R8and p have the above values.

7. Way to obtain the piperazine derivatives of General formula I on p. 1, where R3and R5denotes H2N-C(=NH)-, and the remaining radicals are listed in paragraph 1 values, wherein the corresponding nitrile is treated with ammonia and/or, if necessary, amyraut ester of formula I (R8=OH) and/or the compound of formula I by treatment with acid or base was transferred to his salt.

8. The pharmaceutical composition inhibiting fibrinogenolysis receptor containing the active substance and excipients, characterized in that the active substance it contains at least one compound of formula I under item 1 and/or one of its physiologically acceptable salt in an effective amount.

9. Derivatives of piperazines of formula I under item 1 and the

 

Same patents:

The invention relates to a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and method thereof

The invention relates to new derivatives of 2-aminobenzothiazole, and to their use in pharmaceutical compositions having activity against convulsions induced by glutamate

The invention relates to the field of chemistry, to a method for the chemical substance that manifests anthelminthic properties, and can be used in agriculture to treat animals

The invention relates to new biologically active compounds 2-piperazinone, namely 3-(21-naphthylmethyl)-piperazine-2-ONU (I) and 1-N-ventilationperfusion-2-ONU (II) formula:

< / BR>
I R 2-naphthyl; RI=H;

II R C6H5; RIC6H5

The invention relates to the production of 2-piperazinone

The invention relates to medicine and veterinary medicine, namely to medical and veterinary helminthology, and can be used for larval treatment of hydatid cysts and other castadot human and animal
The invention relates to medicine, in particular dermatology, and can be used for the treatment of psoriasis
The invention relates to pharmaceutical industry and relates to injection or infusion solution of enrofloxacin

The invention relates to new compounds with strong anti-tumor activity that meets the General formula (I), where the values of R1- R7, A, Z, Y, X specified in paragraph 1 of the formula
Up!