Derivatives of the peptides or their pharmaceutically acceptable salts, methods for their preparation, pharmaceutical composition, method of prevention and suppression of thrombosis

 

(57) Abstract:

Usage: medicine for the prevention and elimination of blood clots. The essence of the invention: derivatives of the peptides of General formula I:

< / BR>
where R1- aryl, which may contains 1-3 substituent selected from amidino and secure amidinopropane; R2- carboxy /lowest/ the alkyl or protected carboxy /lower/ alkyl; R3- carboxy or protected carboxypropyl, A1- alkylene, which can contains 1-3 substituent selected from amino and protected amino; A2- -N(R4)CH2CO-, where R4- lower alkyl or A2group-NHCH2CH2CO-; A3lowest alkylene that contains 1-3 substituent selected from lower alkyl, mono-, di - or tri phenyl /lower/ alkyl containing 1-3 substituent selected from the group of hydroxy, lower alkoxy, protected hydroxy, hydroxy /lower/ alkyl; protected hydroxy /lower/ alkyl; [cyclo /lower/ alkyl]-/low/ alkyl, pyridyl /lowest/ the alkyl, l, m and n are identical or different and represent an integer of 0 or 1, provided that A2may not be a group-NHCH2CH2CO-, if l = 0, or pharmaceutical salts; peptides can be obtained TLD is t obtained condensation products of otscheplaut protective group; or b/ interaction of compounds IV with compounds of the formula V: H2NCHR2CONHA3R3or their reactive to amino derivatives; pharmaceutical composition comprising as an active ingredient derived peptides of formula I in an effective amount and method of prevention and suppression of thrombosis in mammals by introduction of derivatives of formula I in a daily dose of 0.001-200 mg/kg in 2-4 intakes. 5 C. and 7 C.p. f-crystals, 3 tables.

The invention relates to new peptide compound and its salts. More specifically, it relates to new peptide compound and its salt, which is an antagonist IIb/IIa of glycoprotein and inhibitor of the aggregation of platelets and used as

medicine for prevention or treatment of diseases caused by thrombus formation, such as arterial thrombosis; atherosclerosis; coronary heart disease (e.g. angina (e.g., stable angina, unstable angina, including the threat of a heart attack, and so on), myocardial infarction (e.g., acute myocardial infarction and other), coronary thrombosis, and so on); ischemic brain (for example, cerebral infarction {e.g., cerebral thrombosis (naprjaschennymi spasm after arachnoidal bleeding and others), etc.; pulmonary vascular disease (eg, pulmonary thrombosis, pulmonary embolism and other); disorders of the peripheral circulation (e.g., obliterative arteriosclerosis, obliterating thromboangiitis (i.e., Buerger's disease, Raynaud's disease, complications of diabetes (eg, diabetic angiopathy and others), phlebotomus (for example, deep vein thrombosis, and others), etc.;

medicine for prevention or treatment of restenosis and/or reocclusion, as, for example, restenosis and/or reocclusion after subcutaneous transluminal coronary angioplasty (RTSA), restenosis and/or reocclusion after the introduction of tissue plasminogen activator (TPA), etc.;

medicine for adjunctive therapy in the treatment of thrombolytic agents (e.g., TRA and others) or anticoagulant (e.g. heparin, and others);

medicine for the prevention and/or treatment of diffuse intravascular coagulation (DIC), thrombotic thrombocytopenia, primary thrombosis, inflammatory diseases (e.g., jade, and others), immune system diseases, etc.;

medicine for the prevention and/or treatment of blood clots in the case of vascular surgery, valve replacement, extracorporeal circulation (e.g. renal dialysis on peptide compound according to this invention will be useful as an inhibitor of cell adhesion and therefore, drugs for prevention and/or biscuits diffuse intravascular blood coagulation (DIC), thrombotic thrombopenia, primary thrombosis, inflammation (for example, jade and others), diseases of the immune system and so on; drugs to suppress metastasis, etc.

Accordingly, one purpose of the invention is the creation of a new peptide compound or its salts that can be used as indicated above.

Another objective of the invention is the provision of means of receipt of a new peptide compounds or salts thereof.

The aim of the invention is to further provide a pharmaceutical composition comprising, as an active ingredient specified peptide compound go its salt.

Further, the purpose of the invention is to develop methods of using the peptide compounds or salts thereof for prophylaxis and/or treatment of the above diseases in human beings or animal.

The target peptide compound according to this invention can be represented by the following formula (I):

< / BR>
where R1this is aryl, which may bear one or more suitable substituents;

A1this alkylen, which may have one or more suitable substituents,

A2this is a group of the formula:

< / BR>
where R4this is a lower alkyl or a group of the formula:

-NHCH2CH2CO-,

A3this is the lowest alkylene, which may have one or more suitable substituents,

l, m and n are each, same or different, is an integer from 0 to 1,

provided that A2does not represent a group of the formula:

-NHCH2CH2CO-,

when l is an integer equal to 0.

The target compound (I) or its salt can be obtained in the following ways:

< / BR>
< / BR>
< / BR>
< / BR>
where R1, R2, R3, A1, A3, l, m and n are each as defined above,

R1ait aryl, bearing protected amidino group

R1bit aryl, bearing amidino group

R1cit aryl, bearing thiocarbamoyl,

R2athis is a protected carboxy(lower)alkyl,

R2bthis is carboxy(lower)alkyl,

R3athis is a protected carboxy group,

R3bthis is a carboxy-group,

A3athis is the lowest alkylen having protected hydroxy /lowest/the alkyl or lower Alky the/the lower/the alkyl or lower alkylene, with /hydroxy/ar/lower/alkyl.

Among the starting compounds (II), (III), (IV), (V) and (VI) are new compounds. They can be obtained from known compounds are traditional for this region methods or methods similar to those described in Preparations and/or Examples of this specification.

Suitable pharmaceutically acceptable salt of the target compound (I) are conventional non-toxic salts, including metal salts, such as alkali metal salt (e.g. sodium salt, potassium and so on), and salts of alkaline earth metal (e.g. calcium salt, magnesium salt and the like), ammonium salt, salt with organic base (e.g., salt of trimethylamine, salt, triethylamine salt of pyridine, picoline salt, salt dicyclohexylamine, salt N,N-dibenziletilendiaminom and so on), salt accession of organic acids (e.g., formate, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, toluensulfonate and so on), salt accession inorganic acid (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.,), salt, amino acids (e.g., salt, arginine salt, aspartic acid salt, glutamic acid, etc.,) and other

In the description from the box is used to indicate from 1 to 6 carbon atoms, if not specified differently.

Suitable "aryl" may include phenyl, naphthyl (e.g. 1-naphthyl, 2-naphthyl), until (for example, 1-antrel, 2-antrel, 9-antral and others), etc., and the preferred aryl is phenyl.

This "aryl" may have one or more (preferably 1 to 3) suitable substituents, such as amidino-protected amidino group, etc.

Suitable protective group in the protected amidino group" may include ar(lower)alkyl such as mono-, or di-, or triphenyl(lower)alkyl (e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl and etc.), acyl, as will be shown below, etc.

Suitable acyl residues may represent an aliphatic acyl, aromatic acyl, arylaliphatic acyl and hetero-cyclo-aliphatic acyl residues, which are derivatives of carboxylic acid, of carbonic acid, carbamino acid, sulfonic acid, etc.

As an example, acyl groups in accordance with this explanation can lead to lower alkanoyl (for example, formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc. ), mono (or di or three) halogen(lower)alkanoyl (e.g., chloroacetyl, TRIFLUOROACETYL, and others ), lower alkoxycarbonyl (for example, meloxicam and three) halogen(lower) alkoxycarbonyl (for example, chlorocarbons, dichlorocarbene, trichlorocyanuric and others), aroyl (for example, benzoyl, toluoyl, xyloyl, naphtol and others), ar(lower)alkanoyl, such as phenyl(lower)alkanoyl (for example, phenylacetyl, phenylpropionyl and others), aryloxyalkyl (for example, vinyloxycarbonyl, naphthalocyanines and others), aryloxy(lower)alkanoyl, such as phenoxy(lower)alkanoyl (for example, phenoxyacetyl, phenoxypropionyl and others ), acilglycerol (for example, phenylglyoxylic, afterpotential, and others ), aryl(lower)alkoxycarbonyl, which may have suitable substituents, such as phenyl(lower)alkoxycarbonyl, which may include nitro or lower alkoxy group (for example, benzyloxycarbonyl, phenoxycarbonyl, p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl and others), titilate, imidazolylalkyl, ferilizer, tetrazolate, triazolylmethyl, thiadiazolyl, tanypodinae, thiadiazolidine, lower alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropoxyphenyl, peterculter, butylsulfonyl and others ), arylsulfonyl (for example, phenylsulfonyl, tolyl sulfonyl, cellsurface, naphthylmethyl and others), aryl/lower/alkylsulfonyl, such as Fenix">

Preferable example of "protected amidino group can serve as an N-aryl/lower/alkoxycarbonylmethyl, more preferred may be N-phenyl/lower/alkoxycarbonyl-amidino is much more preferable example may be N-phenyl/C1-C4/alkoxycarbonylmethyl group, and most preferable example is an N-benzyloxycarbonylamino group.

Suitable "lower alkilani" can be alkali straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., preferred among which may be /C1-C4/alkyl, and a suitable balance "lower alkyl" in the "carboxy(lower)alkyl" may refer to the specified "lower alkyl".

Suitable examples of "carboxy(lower)alkyl" may include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxybutyl, 2-carboxy-1,1-dimethylethyl, 5-carboxypentyl, 6-carboxyethyl etc., preferred among which may be carboxy/C1-C4/alkyl and more preferred carboxymethyl or 2-carboxyethyl.

Suitable balance "protected carboxy group" in the "protected carboxy(lower is Karami residue of ester in the specified esterified carboxy group can serve as such as an ester of a lower alkyl (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl methyl ether, pentalogy ester, hexyl ester, 1-cyclopropylethyl ether and others ), which may contain suitable substituents, for example, lower alkanoyloxy/lower/alkilany ether /for example, acetoxymethyl ether, propionylacetate ether, butyrylacetate ether, veterinarinary ether, pivaloyloxymethyl ether, 1-acetilacetonei ether, 1-propionylacetate ether, pivaloyloxymethyl ether, 2-propionylacetate ether, hexaniacinate ether, etc./ lowest alkanesulfonyl/lower/alkilany ether /for example, 2-mutilative ether, etc./ or mono, di, or three/halogen/low/alkilany ether /for example, 2-iodoethylene ether, 2,2,2-trichlorethylene ether, etc./; lower alkenilovyh ether /for example, vinyl ether, allyl ether, etc./; lower alkinilovymi ether (for example, atinlay ether, propenyloxy ether and other); aryl/lower/alkilany ether, which may contain suitable substituents (e.g., benzyl ester, 4-methoxybenzyloxy ether, 4-nitrobenzyloxy ether, finitely ether, trailovic ether, benzhydrylamine ether, bis(mety ether, which may contain suitable substituents (e.g. phenyl ester, 4-hlorfenilovy ether, tallowy ether, 4-tert-butylphenoxy ether, Kilroy ether, mesityloxy ether, comenjoy ether and others); or similar, preferred among which may be mono-, or di-, or triphenyl/C1-C4/alkilany ether, and the most preferable one may be benzyl ether.

A suitable balance "lower alkyl", "protected carboxy/lower/alkyl" may refer to the above "lower alkyl".

As a suitable example of the "protected carboxy/lower/alkyl" may be mentioned phenyl/lower/alkoxycarbonyl/lower/alkali, among which preferred may be the /C1-C4/alkoxycarbonyl/C1-C4alkyl, and more preferred is benzyloxycarbonyl or 2-benzyloxycarbonylation.

Suitable "protected carboxy" may include the groups described as examples of "protected carboxy" leftovers "protected carboxy/lower/alkyl".

Suitable examples of "protected carboxy" may include phenyl/lower/alkoxycarbonyl, may be preferred, phenyl/C1-C4/alkoxycarbonyl, and more UB>1-C4/alkoxycarbonyl and preferred - methoxycarbonyl or etoxycarbonyl.

Fit alkylene" can be alkylene containing from 1 to 12 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene, nonmotile, decamethrin, undeletion, dodecamethyl, etc. preferred may be /C1-C10/-alkylen and more preferred is methylene, ethylene, trimethylene, tetramethylene, pentamethylene or heptamethine.

This alkylene" may contain one or more (preferably 1 to 3) suitable substituents, such as amino, protected amino, etc.

Suitable protective groups specified in the "protected amino" may include the groups described as examples of "protected amidino group".

Preferable example of "protected amino" may serve as a lower alkylamino or lower alkoxycarbonyl, where more preferred may be /C1-C4/alkanolamine or /C1-C4/alkoxycarbonyl and most preferred is acetylamino or tert-butoxycarbonylamino.

Suitable "lower alkylene" may include methyl/SUB>-C4/alkylen, and more preferred is methylene or trimethylene.

Such "low alkylene" may contain one or more (preferably 1 to 3) suitable substituents, such as the aforementioned lower alkyl; aryl/lower/alkyl which may contain one or more suitable substituents, the values of which will be explained below; hydroxy/lower/alkyl /for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxyphenyl, 6-hydroxyhexyl etc./; protected hydroxy/lowest/the alkyl, the value of which will be explained later; /cyclo/lower/alkyl/-/lower/alkyl (for example, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, 2-cyclopentylmethyl, 1-cyclohexylethyl, 3-cyclopentylpropionyl, 2-cyclohexylethyl, 1,1-dimethyl-2-cyclopropylethyl, 5-cyclobutylmethyl, 6-cyclohexylethyl and others); heterocycle/lower/alkyl whose value will be given later, etc.

Suitable "aryl/lower/alkyl" or "lower alkylene", described above, may include mono, di, or three-phenyl/lower/alkyl such as benzyl, phenethyl, 2-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-fenilpentil, 6-phenylhexa, diphenylmethyl, 1,2-diphenylether, trityl, 1,2,3-trienyl.

Such aryl/lowest/the alkyl may contain one or more (preferably 1 to 3) suitable substituents, such as hydroxy; protected hydroxy for example, the aryl/lowest/-alkyloxy, where "aryl residue/low/alkyl" may refer to the above as examples; acyloxy, where the remainder of the "acyl" may refer to videopreteen and others); a lower alkoxy group (e.g. methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and others); and so on, where the preferred group may be hydroxy, phenyl/C1-C4/-alkyloxy or /C1-C4/alkoxy, and more preferred is hydroxy, benzyloxy, methoxy or ethoxy.

Suitable "protected hydroxy/lower/alkili" may include aryl/lower/alkyloxy/lowest/the alkyl, acyloxy/lowest/the alkyl, etc., where the remainder of the "aryl/lower/alkyl", the rest "acyl" and the remainder "/low/alkyl" may refer to the above.

Preferred protected hydroxy/lower/alkyl" may be a phenyl/C1-C4/alkyloxy/C1-C4/alkyl, and more preferred is benzoyloxymethyl or 1-benzyloxyethyl.

Suitable "heterocyclic" balance "heterocycle-/low/alkyl" denotes Nina least one heteroatom, such as oxygen, sulfur, nitrogen, etc., And especially preferable heterocyclic group may be such as unsaturated 3-8-membered heterocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and others), tetrazolyl (for example, 1H-tetrazolyl 2N-tetrazolyl and others ), dihydrotriazine (for example, 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, and others), etc.;

saturated 3 to 8-membered heterophilically group containing 1 to 4 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, piperidyl (for example, piperidino, and others), piperazinil and others;

unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl, tetrasulphides, tetrachloropyridine (for example, tetrazolo/1,5 /pyridazinyl, and others);

unsaturated 3-8-membered heterophilically group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl, (for example, 1,2,4-oxadiazoles from 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl, oxazolidinyl (for example, 1,3-oxazolidinyl and others), and so on;

unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazole and others;

unsaturated 3-8-membered heterophilically group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolyl, thiadiazolyl (for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl), etc.;

saturated 3 to 8-membered heterophilically group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, diazolidinyl and others;

unsaturated 3-8-membered heterophilically group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzothiadiazole and others;

unsaturated 3-8-membered heterophilically group containing 1 to 2 oxygen atoms, for example, furyl, pyranyl, dioxolan and others;

saturated 3 to 8-membered heterophilically group containing 1 to 2 oxygen atoms, for example, oxalyl, tetrahydropyranyl (for example, tetrahydro-2H-Piran-2-yl, and others), DIOXOLANYL etc.;

unsaturated condensed heterocyclic g is dihydrobromide (for example, 3,4-dihydro-2H-chromen-4-yl, and others), and others; and so on

Preferred "heterocyclic" the balance can be 3-8-membered heterophilically group containing 1 to 4 nitrogen atoms, in the preferred embodiment, this may be pyridyl.

Among suitable substituents "lower alkylene" preferred may be /C1-C4/alkyl; phenyl/C1-C4/alkyl, which may include from 1 to 3 hydroxy, phenyl/C1-C4/alkyloxy or /C1-C4/alkoxy groups; hydroxy/C1-C4/alkyl; phenyl-/C1-C4/alkyloxy/C1-C4/alkyl; cyclo/C5-C6/alkyl/C1-C4/alkyl; or pyridyl/C1-C4/alkyl, and more preferred may be methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, benzyl, /4-hydroxyphenyl/methyl /4-benzyloxyphenyl/methyl /4-methoxyphenyl/methyl /4-ethoxyphenyl/-methyl, hydroxymethyl, 1-hydroxyethyl, benzyloxyethyl, 1-benzyloxyethyl, cyclohexylmethyl or 2-pyridylmethyl.

The term "/hydroxy/aryl/lower/alkyl" refers to aryl/lower/alkyl containing hydroxy group.

The term "/protected hydroxy/aryl/lower/alkyl" refers to aryl/lowest/the alkyl, soderjatelinii of the present invention.

Method 1

The target compound (I) or its salt can be obtained by a reaction between the compound (II) or its reactive derivative of the carboxy group, or its salt with the compound (III) or its reactive derivative at the amino group or its salt.

Suitable reactive derivative at carboxy group of compound (II) may include halogenide, acid anhydride, activated amide, an activated ester, etc.

Suitable examples of the reactive derivatives may serve as chlorine dioxide; acid azide; a mixed anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphorous acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, and others), dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, sulfonic acid, (for example, methanesulfonate acid and others), aliphatic carboxylic acid (e.g. acetic acid, propionic acid, butyric acid, somalina acid, trimethylhexane acid, valeric acid, isovalerianic acid, 2-ethylmalonate acid, trichloroacetic acid, the ITA; activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester, for example, cinematology ether, methoxymethyl ether, dimethylaminomethylene ether, methoxymethyl ether, dimethylaminomethylene ether /(CH3)2N+=CH/ a, vinyl ester, propargilovyh ether, p-nitrophenyloctyl ether, 2,4-dinitrophenoxy ether, trichloranisole ether, pentachlorphenol ether, methylphenylene ether, phenylazophenyl ester, a phenyl thioether, R-nitrophenyloctyl tiefer, R-crazily tiefer, carboxymethoxy tiefer, paranjoy ether, pyridyloxy ether, piperidinyl ether, 8-hinolinovy ether and others) or an ester with N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and others), etc., These reactive derivatives can be arbitrarily selected from the above, in accordance with the type of compound (II).

Suitable salts of the compound (II) and its reactive derivative can be considered as those examples which are given for the compound (I).

Suitable reactive, proizvoda of enamine, obtained by the reaction of compound (III) with a carbonyl compound such as aldehyde, ketone or similar; derived silila obtained by the reaction of compound (III) with a silyl compound such as bis/(trimethylsilyl)/ndimethylacetamide, mono/(trimethylsilyl)/-ndimethylacetamide, bis/(trimethylsilyl)/urea, etc.; derivative obtained by the reaction of compound (II) with trichloride phosphorus or with phosgene, etc.

Suitable salts of the compound (III) and its reactive derivative can be referred to the examples of compound (I).

The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol and others), acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent not adversely affecting the reaction. These traditional solvents can also be used in mixture with water.

When the compound (II) is used in the form of the free acid or in the form of its salts, the reaction should be carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinobutyrophenone; N-cyclohexyl-N'-/4-diethyl-is/carbodiimide; N,N'-carbonyl-bis-/2-Mei/; pentamethylene-N-cyclohexylamine; diphenylmethane-N-cyclohexylamine; ethoxyacetylene; 1-alkoxy-1-chlorethylene, trialkylphosphites; etiloleat; isopropylpalmitate; oxychloride trivalent phosphorus (chloride of phosphoryla); trichloride phosphorus; thionyl chloride; oxacillin; halogenfree lower alkyl (e.g., ethylchloride, isopropylcarbamate and others); triphenylphosphine; 2-ethyl-7-hydroxybenzimidazole salt; intramolecular salt of 2-ethyl-5-/m-sulfophenyl/isoxazoline hydroxide; 1-/R-chlorobenzenesulfonate/-6-chloro-1H-benzotriazol; the so-called reagent Vilsmeier obtained by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trihloretilamina, phosphorus oxychloride, methanesulfonamido and others; etc.

The reaction can also be carried out in the presence of inorganic or organic bases such as carbonate, alkali metal bicarbonate, alkali metal, three/lower/alkyl-amine, pyridine, N-/low/alkylboron, N,N-di/lowest/-alkylbenzenes etc.

The reaction temperature is not critical, and generally the reaction is carried out in various conditions - from "cold" to "when heated".

Method 2

Selivanovo the derivative of the carboxy group, or its salt with the compound (V) or its reactive derivative at the amino group or its salt.

This reaction can be performed similarly to the above-mentioned Method 1, and, consequently, the type and conditions of the reaction (for example, a reactive derivative, solvent, reaction temperature, and others) are as described in Method 1.

Method 3

The target compound (Ic) or its salt can be obtained by introducing a compound (Ib) or its salt in the reaction removal midinotate group.

This reaction is carried out in accordance with conventional methods, such as hydrolysis, recovery, etc.

The hydrolysis is usually carried out in the presence of a base or an acid including Lewis acid. Suitable base may include inorganic bases and organic bases, such as alkali metal (e.g. sodium, potassium, and others), alkaline earth metal (e.g. magnesium, calcium, and others), hydroxide, or carbonate, or bicarbonate, trialkylamine (for example, trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo/4.3.0/non-5-ene, 1,4-diazabicyclo/2.2.2/octane 1,8-diazabicyclo/5.4.0/undec-7-ene, etc.,

Suitable acid may include an organic acid (for example the lot and others) and mineral acid (e.g., hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, and others).

The reaction of removal using Lozovoy acid, such as trigalogenmetany acid (e.g., trichloroacetic acid, triperoxonane acid and others ), preferably carried out in the presence of cationic binding agents (e.g. anisole, phenol, and others).

The reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol and others ), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent not adversely affecting the reaction. The solvent can also use a liquid base or acid. The reaction temperature is not critical and the reaction is usually carried out in conditions from "cold" to "when heated".

The repair method is applicable for the reaction of removal may include chemical reduction or catalytic reduction.

Suitable for use in this reaction, the reducing agent is a combination of a metal (e.g. tin, zinc, iron and others) or compound of the metal (e.g. chromium chloride, chromium acetate, and others) and olorunsola acid, R-toluensulfonate acid, hydrochloric acid, Hydrobromic acid, and others).

Catalysts suitable for use in the catalytic reduction, are conventional catalysts, such as platinum (e.g., platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, and others), palladium catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium-on-charcoal, colloidal palladium, palladium-on-barium sulfate, palladium-on-barium carbonate and other), Nickel catalysts (e.g., the recovered Nickel, Nickel oxide, Raney Nickel, and others), cobalt catalysts (e.g., the recovered cobalt, Raney cobalt and others), iron catalysts (e.g. reduced iron, the iron of Renee and others), copper catalysts (for example, the recovered copper, copper of Renee, copper, Ullman and others), etc.

Recovery is usually carried out in an environment of conventional solvent which does not affect adversely on the reaction, such as water, methanol, ethanol, propanol, N,N-dimethylformamide or a mixture thereof. In addition, when the above-mentioned acid used for hemodialysis for catalytic reduction of the solvent may be the above-mentioned solvent, and other traditional solvents, such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.

The reaction temperature such recovery is not critical and the reaction is usually carried out in conditions from "cold" to "when heated".

In the scope of the present invention includes a case where a protected carboxy/lowest/the alkyl in R2transformed into carboxy/lower/alkyl case, when the protected carboxy group in R3turns into a carboxy group, as well as the case when the lowest alkylene containing protected hydroxy/lower/alkyl, or lower alkylene containing /protected hydroxy/-aryl-/low/alkyl in A3converted to lower alkylene containing hydroxy/lowest/the alkyl or lower alkylene containing /hydroxy/aryl/lower/alkyl.

Method 4

The target compound (Ie) or its salt can be obtained by subjecting the compound (Id) or its salt of the reaction remove the carboxy-protective group.

This reaction can be performed similarly to the reaction of Method 3, described above, so that the mode and conditions of the reaction (e.g., base, acid, catalyst, solvent, reaction temperature, etc.) correspond to specify the foam in R1becomes aryl containing amidino-group, case when protected carboxy-protected group in R3turns into a carboxy group, as well as the case when the lowest alkylene containing protected hydroxy/lower/alkyl, or lower alkylene containing /protected hydroxy/aryl/lowest/the alkyl in A3becomes lower alkylene containing hydroxy/lower/alkyl, or lower alkylene containing /hydroxy/aryl/lower/alkyl.

Method 5

The target compound (Ig) or its salt can be obtained by subjecting the compound (If) or its salt of the reaction remove the hydroxy-protective group.

This reaction can be performed similarly to the reaction of the above-mentioned Method 3, so that the mode and conditions of the reaction (e.g., base, acid, catalyst, solvent, reaction temperature, etc.) correspond discussed in Method 3.

This invention includes the case where the aryl having protected amidino-group in R1becomes aryl having amidino-group, case when protected carboxy/lowest/the alkyl in R2is converted into a carboxy/lowest/the alkyl, and the case when the protected carboxy group in R3converted into a carboxy group.

Spalania carboxy-protective group.

This reaction can be performed similarly to the reaction of the above-mentioned Method 3, and therefore, the mode and conditions of the reaction (e.g., base, acid, catalyst, solvent, reaction temperature, etc.) correspond discussed in the description of Method 3.

In the scope of the present invention includes the case where the aryl having protected amidino-group in R1becomes aryl containing amidino-group, case when protected carboxy/lowest/the alkyl in R2turns into a carboxy/lowest/the alkyl, and the case when the lowest alkylene containing protected hydroxy/lower/alkyl, or lower alkylene containing /protected hydroxy/aryl/lowest/the alkyl in A3becomes lower alkylene having hydroxy/lowest/the alkyl or lower alkylene with /hydroxy/aryl/lower/alkyl.

Method 7

The target compound (Ij) or its salt can be obtained by the reaction of transformation of a group of thiocarbamoyl compound (VI) or its salt in amidino group.

Suitable salts of the compounds (Ij) and (VI) can be considered as examples in the description of compound (I).

This reaction can be carried out as a reaction of interaction of the compound (VI) or its salt with an alkylating and the om as acetone, dioxane, tetrahydrofuran, etc. at room temperature, warm, or when heated, and then as the interaction of the obtained intermediate product, emitting or without, with ammonia or its derivatives, such as ammonium acetate, ammonium halide (e.g., ammonium chloride, and others), in a suitable solvent, such as alcohol (e.g. methanol, ethanol and others), N, N-dimethylformamide, etc. in the heat or when heated.

In those cases, when the compound (I) obtained by the above methods is in a free form, it can be converted into a salt by conventional methods. On the other hand, when the thus obtained target compound (I) is a salt, it can be translated in a free state or to another salt form are also known methods.

It should be noted that the target compound (I) may include stereoisomers due to the presence of asymmetric atom (atoms) of carbon.

Next, to demonstrate the usefulness of the target compound (I) will be shown some evidence of pharmacological tests of representatives of the compounds (I) according to this invention.

Test 1: Effect on adhesion of platelets caused by adenosin-diphosphate (ADP) COI and platelet-rich plasma (PRP), which contains 3 to 108platelets/ml To 225 μl of PRP was added 25 μl of a solution of the drug, and then was stirred for 2 min at 37oC. To the solution was added 5 μl of ADR (finally 2.5 μm) as an initiator agglutination. The degree of agglutination was determined by using a device for measuring agglutination (NKK HEMA-TPACEP I). The activity of the inhibitor (test compound) was expressed as the number of IC50, i.e. the dose required to suppress the adhesion of platelets by 50%.

Solution medicationx- the test compound was dissolved in dimethyl sulfoxide.

The results of the test

The test compound IC50/M/

(I) 1,010-7< / BR>
Test 2: the Binding of fibrinogen with platelets

Test connection

the same compound (I) as in Test 1

Method test

Washed human platelets were obtained from platelet-rich plasma by gel filtration. Washed platelets were activated by the action of 20 μm ADR for 10 min, and then fixed for 30 min 0,8% paraformaldehyde. Then the platelets were washed by centrifugation and prepared suspension in the buffer HEPES-Tyrodes containing 2 mm CaCl2and 1 mm MgCl2.

350 μl of Platelets the organisations. The reaction was continued for 30 min at room temperature. Then in 20% sucrose caused a layer of the three portions of 100 μl and received a pellet of platelets in the centrifugation at 10 000 rpm for 5 min, the Pellet was separated by cutting off the tip of the tube with the blade and counted on the meter gamma radiation.

Specific binding was calculated by subtracting the binding in the presence of 50-fold excess of its fibrinogen. The results were expressed as the number of IC50i.e., in the form of doses required to inhibit binding by 50%.

The results of the test

The test compound IC50< / BR>
(I) 2.9 10-8< / BR>
Test 3: Test at improving thrombolytic activity of TPA in the simulation thrombosis in Guinea pigs

Test connection

(I) the target compound (13) of Example 13

The methods of testing

Male Guinea pigs, Hartley (500-800 g) made of anesthesia with urethane (1.25 g/kg intraperitoneally). Carotid artery and jugular vein is carefully investigated after in the middle of the neck was made the cut. In Vienna introduced the cannula polyethylene catheter (RE; Becton Dikinson, USA) for injection and infusion drugs. Around the carotid artery was placed pulse Dopplar flow probe for what was caused by the method of FeCl3according to the following procedure:

square (1 mm x 1 mm) filter paper type ADVANTEC No. 2, soaked in 20% FeCl3, was placed on the carotid artery which is blocked by a blood clot.

When the rate of blood flow fell to zero, the filter paper was removed from the vessel and washed carotid artery more than 4 times with saline. After 3 min after washing entered the test compound or saline, and after 3 min g-TRA (trade mark Actilyse, Bochringer Ingelheim Ltd.) poured within 60 minutes

The animals were divided into following groups.

Group 1 (5 animals): saline and t-TRA at 0.30 mg/kg ball intravenous + 1.0 mg/kg/h intravenous infusion.

Group 2 (5 animals): Test the connection when 0,32 mg/kg intravenous ball and t-TRA at 0.30 mg/kg intravenous ball + 1.0 mg/kg/h intravenous infusion.

Re-perfusion was defined as a 50% recovery rate of blood flow in the carotid artery compared with the initial value. The blood flow was restored in 90 minutes

The results of the test

The number of animals in whom reperfusion was observed in each group was as follows.

Group Number of animals, which saw ride pharmaceutical drug, for example, in the form of solid, semi-solid or liquid form, which contains the target compound (I) or its pharmaceutically acceptable salt as the active ingredient mixed with organic or inorganic carrier or excipient suitable for injection or rectal insufflation, in the lungs (nasal or buccal inhalation), nasal, eyes, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular injection).

The active ingredient may be mixed, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pills, lozenges, capsules, suppositories, creams, ointments, aerosols, powders for injection, solutions, emulsions, suspensions, and any other usable forms. And, if necessary, can be used, in addition, stabilizing, auxiliary additives, thickeners and colorants, as well as odeski.

The target compound (I) or its pharmaceutically acceptable salt is/are included in the pharmaceutical composition in a quantity sufficient to create the desired effect on the development of a condition or disease.

Pharmaceutical composition for this ISI the compositions of this invention can be applied methodology, usually used to improve the bioavailability of drugs.

For the introduction of composition a human being or animal, it is preferable to use the intravenous route (including intravenous infusion), intramuscular, pulmonary or oral administration or injection, including aerosols, by using the inhaler, giving metered dose spray or dry powder inhaler.

While the dosage of therapeutically effective amount of the target compound (I) varies and depends on the age and condition of each individual patient, for the prevention and/or treatment of the above diseases of humans and animals is given, as a rule, in the case of intravenous administration: daily dose of 0.001-100 mg of the target compound (I) per kg weight of a human body or an animal, in the case of injection intramuscularly, daily dose of 0.001-100 mg of the target compound (I) per kg weight of a human body or an animal, in the case of injection intramuscularly, daily dose of 0.001-100 mg of the target compound (I) per kg weight of a human body or an animal, in the case of the introduction of oral, daily dose of 0.001-200 mg of the target compound (I) per kg weight of a human body or animal.

Examples of pharmaceutical compositions.

Dry ka is the Association of the example 7 - 100

Lactose - 45,8

Magnesium stearate - 4.2V

- 150

The ingredients are crushed into powder to the specified particle size, stirred for about 10 minutes and placed in a dry gelatin capsules.

Tablets

Ingredient - the Number of mg per pill

The compound of example 13 - 100

Pregelatinization corn starch - 72

Microcrystalline cellulose - 77

Magnesium stearate - 1

- 250

The connection is finely pulverized and mixed with powdered inert ingredients according to the recipe, and then pressed into tablets using the standard method of installation for pressing tablets.

Method of obtaining 1.

A mixture of 4-cyanophora (5,95 g), ethyl-5-bromovalerate (11.5g), potassium carbonate (7.6 g) in N,N-dimethylformamide (60 ml) was stirred at room temperature for 14 h

The reaction mixture is poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution, water and aqueous solution of sodium chloride, then dried over magnesium sulfate. After filtration, dried under vacuum filtrate, and the precipitate washed with diethyl ether, receiving ethyl-5-(4-cianfrocca)valerate (11,21,)

so, multiplet, is 2.37 (2H, triplet, J=7 Hz), 3,8-4,13 (4H, multiplet), and 7.1 (2H, doublet, J= 8,9 Hz), 7,76 (2H, doublet, J=8,9 Hz)

MS (M/Z): 247 (M+)

The following compounds (getter 2 and 3) were obtained similarly to the Method of obtaining 1.

Method of obtaining 2

Ethyl-4-(4-cianfrocca)butyrate

so pl.: 56-57oC

IR (nujol): 2220, 1735, 1610, 1510 cm-1< / BR>
NMR (DMSO-d6, ): of 1.18 (3H, triplet, J=4,7 Hz), 2,00 (2H, multiplet), 2,47 (2H, triplet, J=4,8 Hz), 4,07 (4H, multiplet), to 7.09 (2H, doublet, J=4.6 Hz), 7,76 (2H, doublet, J=4,6 Hz)

MS (M/Z: 233 (M+)

Method of obtaining 3

Ethyl-6-(4-cianfrocca)hexanoate

so pl.: 45-46oC

IR nujol): 2220, 1720, 1590, 1565 cm-1< / BR>
NMR (DMSO-d6, ): of 1.18 (3H, triplet, J=7,1 Hz), 1,3-1,83 (6N, multiplet), 2,31 (2H, triplet, J= 7,1 Hz), 3,9-4,2 (4H, multiplet), to 7.09 (2H, doublet, J=8,9 Hz), of 7.75 (2H, doublet, J=8,9 Hz)

MS (M/Z: 261 (M+)

Method of obtaining 4

Through a solution of ethyl-5-(4-cianfrocca)valerate (2,47 g) in ethanol (250 ml) was barbotirovany hydrogen chloride while cooling with ice water within 4 hours After completion of the reaction was determined by thin layer chromatography at room temperature was barbotirovany nitrogen has boiled away the resulting mixture under vacuum and washed the precipitate dietology is C (decomp.)

IR (nujol): 1720, 1635, 1600 cm-1< / BR>
NMR (DMSO-d6, ): of 1.18 (3H, triplet, J=7,1 Hz), 1,47 (3H, triplet, J=7 Hz), of 1.5-1.9 (4H, multiplet), of 2.38 (2H, triplet, J=7 Hz), of 4.05 (2H, Quartet, J= 7,1 Hz), of 4.12 (2H, triplet, J=5.8 Hz), br4.61 (2H, Quartet, J=7 Hz), 7,16 (2H, doublet, J=9 Hz), 8,14 (2H, doublet, J=9 Hz), 11,54 (1H, broad singlet)

MS (M/Z): 293 (M+free)

The following compounds (getter 5 and 6) is obtained similarly to the Method of obtaining 4.

Method of obtaining 5

Ethyl-4-/4-(1-(ethoxy)iminomethyl)phenoxy/butyrate hydrochloride.

so pl. 102-104oC

IR (nujol): 3420, 1735, 1610 cm-1< / BR>
NMR (DMSO-d6, ): of 1.18 (3H, triplet, J=4,7 Hz), 1,47 (3H, triplet, J=4.6 Hz), a 2.01 (2H, multiplet), 2,48 (2H, triplet, J=4,8 Hz), 4.09 to (4H, multiplet), 4,60 (2H, J=4.6 Hz), 7,16 (2H, doublet, J=4.6 Hz), 8,15 (2H, doublet, J= 4,6 Hz)

Method of obtaining 6

Ethyl-6-/4-(1-(ethoxy)iminomethyl)phenoxy)hexanoate hydrochloride

so pl.: 107oC (decomp.)

IR (nujol): 1720, 1600, 1580, 1510 cm-1< / BR>
NMR (DMSO-d6, ): of 1.17 (3H, triplet, J=7 Hz), 1,3-1,84 (6N, multiplet), of 1.47 (3H, triplet, J= 7 Hz), 2,31 (2H, triplet, J=7,1 Hz), 3,92 to 4.2 (4H, multiplet), br4.61 (2H, Quartet, J=7 Hz), 7,16 (2H, doublet, J=9 Hz), 8,14 (2H, doublet, J=9 Hz), 11,54 (1H, broad singlet)< / BR>
MS( M/Z): 307 (M+free)

Method of obtaining 7

A mixture of ethyl-5-/4-(1-(this is) in ethanol (300 ml) was stirred and heated under reflux for 15 hours After cooling to room temperature the mixture was filtered, the filtrate is boiled away in vacuum and the obtained residue was washed with diethyl ether, resulting in ethyl-5-(4-amidinophenoxy)valerate hydrochloride (27,28 g).

so pl.: 150-155oC (Razlog.)

IR (nujol): 3350, 1710, 1660, 1490 cm-1< / BR>
NMR (DMSO-d6, ): of 1.18 (3H, triplet, J=7,1 Hz), 1,5-of 1.85 (4H, multiplet), of 2.38 (2H, triplet, J=7,1 Hz), of 4.05 (2H, Quartet, J=7,1 Hz), 4,1 (2H, triplet, J= 5.8 Hz), to 7.15 (2H, doublet, J=8,9 Hz), the 7.85 (2H, doublet, J=8,9 Hz), 8,65 (4H, extended)

MS (M/Z): 264 (M+- free)

The following compounds (getter 8 and 9) is obtained similarly to the Method of obtaining 7.

Method to obtain 8

Ethyl-4-(4-amidinophenoxy)butyrate hydrochloride

so pl.: 81-84oC (Razlog.)

IR (nujol): 3420, 3250, 3100, 1720, 1670, 1600 cm-1< / BR>
NMR (DMSO-d6, ): of 1.18 (3H, triplet, J=7,1 Hz), 1,9-2,1 (2H, multiplet), 2,47 (2H, triplet, J=7,3 Hz), 3.95 to to 4.23 (4H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,88 (2H, doublet, J=8,9 Hz), 8,93 (4H, broad singlet)

MS (M/Z): 250 (M+free)

Method of obtaining 9

Ethyl-6-(4-amidinophenoxy)hexanoate hydrochloride

so pl.: 135oC (Razlog.)

IR (nujol): 3420, 3260, 3100, 1720, 1660, 1600 cm-1< / BR>
NMR (DMSO-d6, ): of 1.17 (3H, triplet, J=7,1 Hz), 1,31-1,85 (6N, BR> MS (M/Z; 278 (M+free)

Method of obtaining 10

To a mixture of ethyl-5-(4-amidinophenoxy)valerate hydrochloride (14.6 g) in a mixture of tetrahydrofuran (150 ml) and 1 n sodium hydroxide solution was added benzyloxycarbonyl (10.4 ml) under cooling with ice water for 1 h and the Mixture was stirred for 2 h at 10oC, maintaining a pH = 10 with 1 n sodium hydroxide solution. The reaction mixture was poured into ethyl acetate (300 ml) and the separated organic layer was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. Obtained after filtration the filtrate is boiled away in vacuum and the precipitate washed with diethyl ether, receiving ethyl-5-/4-(N-benzyloxycarbonylamino)phenoxy/valerate (17,48 g).

so pl.: 88-90oC

IR (nujol): 3420, 3280, 1715, 1660, 1590, 1560 cm-1< / BR>
NMR (DMSO-d6, ): of 1.17 (3H, triplet, J=7,1 Hz), 1,55-of 1.85 (4H, multiplet), is 2.37 (2H, triplet, J= 7 Hz), Android 4.04 (2H, Quartet, J=7 Hz), of 4.05 (2H, triplet, J=5.8 Hz), 5,1 (2H, singlet), 7,0 (2H, doublet, J=8,9 Hz), 7.24 to 7,46 (5H, multiplet), 7,98 (2H, doublet, J=8,9 Hz), 9,11 (2H, broad singlet)

MS (M/Z): 398 (M+)

The following compounds (getter 11 and 12) were obtained similarly to the Method of obtaining 10.

Method of obtaining 11

Ethyl-4-/4-(N-benzyloxycarbonylamino the/SUB>, ): of 1.18 (3H, triplet, J=7,1 Hz), 1,84 is 2.1 (2H, multiplet), 2,46 (2H, triplet, J=7,1 Hz), 3,9-4,19 (4H, multiplet), 5,12 (2H, singlet), 7,01 (2H, doublet, J=8,9 Hz), 7.23 percent and 7.5 (5H, multiplet), of 7.97 (2H, doublet, J=8,9 Hz), 9,31 (2H, broad singlet)

MS (M/Z): 384 (M+)

method of obtaining 12

Ethyl-6-/4-(N-benzyloxycarbonylamino)phenoxy/hexanoate

so pl.: 96-99oC

IR (nujol): 3430, 3300, 1725, 1660, 1600, 1570, 1490 cm-1< / BR>
NMR (DMSO-d6, ): of 1.17 (3H, triplet, J=7,1 Hz), 1,3-1,84 (6N, multiplet), 2,31 (2H, triplet, J=7,1 Hz), 3,92-4,16 (4H, multiplet), a 5.1 (2H, singlet), 7,0 (2H, doublet, J=8,9 Hz), of 7.25 and 7.5 (5H, multiplet), to 7.99 (2H, doublet, J=8,9 Hz), 9,12 (2H, broad singlet)

MS (M/Z): 412 (M+)

Method of obtaining 13

A mixture of ethyl-5-/4-(N-benzylcarbamoyl)phenoxy/-valerate (17,4 g) in 10% hydrochloric acid (150 ml) and acetic acid (100 ml) was stirred at 50oC for 1.5 h, After cooling to room temperature the reaction mixture is brought to pH 4.0, using 4 n sodium hydroxide solution. Collected precipitate formed and was 5-/4-(N-benzyloxycarbonylamino)-phenoxy/valeric acid (14,87 g).

so pl.: 103oC (Razlog.)

IR (nujol): 3300, 1735, 1640, 1600, 1560, 1510 cm-1< / BR>
NMR (DMSO-d6, ): 1,53-of 1.85 (4H, multiplet), to 2.29 (2H, triplet, J=7,2 Hz), 4,06 (2H, triple is, sireny)

MS (M/Z): 370 (M+)

The following compounds (getter 14 and 15) were obtained similarly to the method a Method of obtaining 13.

Method of obtaining 14

4-/4-(N-Benzyloxycarbonylamino)phenoxy/butyric acid

so pl.: 143oC (Razlog.)

IR (nujol): 1730, 1600, 1560 cm-1< / BR>
NMR (DMSO-d6, ): 1,3-1,8 (6N, multiplet), 2,24 (2H, triplet, J=7 Hz), a 4.03 (2H, triplet, J= 6.4 Hz), 5,11 (2H, singlet), 7,0 (2H, doublet, J=8,9 Hz), 7,2-of 7.55 (5H, multiplet), 7,98 (2H, doublet, J=8,9 Hz), which 9.22 (1H, broadened), 12,02 (1H, broadened)

The formula of the parent compounds and target compounds represented in the following Examples in the table.1

In the above table.1 the formula Am(Z) denotes the N-benzyloxycarbonylamino, Ammeans amidino, Asp mean Z-aspartic acid, VaI means of Z-valine, Sar means sarcosin, Leu mean L-leucine, BZI means benzyl andtBu means tert-butyl.

Example 1

To a mixture of 5-/4-(N-benzyloxycarbonylamino)phenoxy/valerianic acid (0.5 g), starting compound (I) (0,61 g) and 1-hydroxy-1H-benzotriazole (0.21 g) in N,N-dimethylformamide (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.25 ml) and the mixture was stirred at room temperature for 2 hours the thief of sodium hydroxide. The separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride and dried over magnesium sulfate. The filtrate obtained after filtration, boiled away in the vacuum, which gave the target compound (I) (1.08 g) in the form of butter.

NMR (DMSO-d6, ): 0,83 (6N, doublet, J=6,7 Hz), 1,53-1,8 (4H, multiplet), of 2.16 (2H, multiplet), a 2.5 to 2.85 (2H, multiplet), to 4.01 (2H, type triplet), 4,15-to 4.28 (1H, multiplet), 5,0-5,23 (7H, multiplet), of 6.99 (2H, doublet, J= 8,9 Hz), 7,2-7,5 (15 NM, multiplet), 7,98 (2H, doublet, J=8,9 Hz), of 8.15 (1H, doublet, J=8,2 Hz), of 8.25 (1H, doublet, J=8,1 Hz), and 9.1 (1H, broadened)

Example 2

The target compound (2) obtained from the starting compound (2A) and the parent compound (28) by the procedure similar to that described in Example 1.

NMR (DMSO-d6, ): 0,84 (6N, doublet, J=6,7 Hz), 1,8-2,2 (3H, multiplet in), 2.25 (2H, type triplet), 2,5-2,9 (2H, multiplet), to 4.01 (2H, type triplet), 4,20 (1H, multiplet), was 4.76 (1H, multiplet), 5,0-5,2 (1H, multiplet), 5,07 (2H, singlet), 5,10 (2H, singlet), 5,11 (2H, singlet), of 6.99 (2H, doublet, J=8,9 Hz), 7.24 to 7,53 (15 NM, multiplet), 7,98 (2H, doublet, J=9 Hz), 8,16 (1H, doublet, J=8 Hz), 8,30 (1H, doublet, J=7,9) 9,11 (1H, broadened)

Example 3

The target compound (3) obtained from the starting compound (3A) and the parent compound (3B) in accordance with methodical the 0,83 (6N, doublet, J=6,7 Hz), 1,3-1,8 (6N, multiplet), 1,9-2,2 (3H, multiplet), 2,5-2,9 (2H, multiplet), to 4.01 (2H, type triplet), 4,13-of 4.25 (1H, multiplet), 4,66 of 4.83 (1H, multiplet), 5,0-of 5.15 (2H, multiplet), 6,98 (2H, doublet, J=8,9 Hz), 7,2-7,52 (15 NM, multiplet), 7,98 (2H, doublet, J=8,9 Hz), 8,05 to 8.3 (2H, multiplet), and 9.1 (1H, broadened)

Example 4

The target compound (4) was obtained from the starting compound (4A) and the parent compound (4B) by the method similar to the method of Example 1.

so pl.: 45-50oC

IR (nujol): 3200 (br), 1640, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 1,84 (6N, doublet, J=6,7 Hz), was 2.05 (1H, multiplet), 2,6-2,9 (4N, multiplet), 2,78, and of 2.97 (3H, each singlet), 3,96 and a 4.03 (2H, each singlet), 4,18 (1H, multiplet), 4,84 (1H, broad singlet), a 5.0 to 5.1 (8H, multiplet), of 6.99 (2H, doublet, J=8,9 Hz), 7,2-7,5 (15 NM, multiplet), of 7.96 (2H, doublet, J=9.8 Hz), 8,13 and at 8.60 (1H, each doublet, J=8.0 Hz, 7.9 Hz), a 8.34 (1H, multiplet), 9,11 (2H, broad singlet)

Example 5

The mixture of starting compound (5) (1 g) and 10% Pd-C (0.6 g) in a mixture of 1 N. hydrochloric acid (5 ml) and tetrahydrofuran (10 ml) was stirred in an atmosphere of gaseous H2at room temperature for 6 hours

Obtained after filtration the filtrate is boiled away in a vacuum. The resulting material was subjected to preparative HPLC and got the target compounds is of : CH3CN: 0.1% aqueous solution triperoxonane acid = 1:4

thread : 118 ml/min

retention time : 8 min

so pl.: 147oC

IR (nujol): 3300, 3080, 1660, 1600, 1530 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 (6N, doublet, J=6,7 Hz), 1,54-of 1.84 (4H, multiplet), 2,03 (1H, multiplet), 2,19 (2H, type triplet), a 2.36-2,78 (2H, multiplet), 3,97 to 4.2 (3H, multiplet) and 4.65 (1H, multiplet), to 7.15 (2H, doublet, J= 8,9 Hz), 7,76 (1H, doublet, J=7,8 Hz), 7,81 (2H, doublet, J=8,9 Hz), of 8.25 (1H, doublet, J=7,8 Hz), 9,05 (2H, singlet), 9,14 (2H, singlet)

MS (M/Z) : 451 (M + 1 free)

Example 6

The target compound (6) was obtained from the starting compound (6) by the procedure analogous to Example 5.

Conditions for HPLC

column : UMC-RATED R-ODS-15 S-15 120A ODS 50 x 250 mm

elution : CH3CN : 0.1% aqueous solution triperoxonane acid = 17: 83

thread : 118 ml/min

retention time : 7,355 min

so pl.: 195oC (Razlog.)

IR (nujol): 3320, 3100, 1655, 1610, 1540, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 (6N, doublet, J=6,7 Hz), 1,8-of 2.16 (3H, multiplet), 2,3 (2H, triplet, J=7,3 Hz), 2,3-2,8 (2H, multiplet), 3,98 to 4.2 (3H, multiplet) and 4.65 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,79 (1H, doublet, J=8.5 Hz), 7,82 (2H, doublet, J=8,9 Hz), 8,30 (1H, doublet, J=7,7 Hz), 9,03 (2H, singlet), 9,14 (2H, singlet)

Example 7

The target compound (7) if the

column: UMC-RATED R-ODS-15 S-15 120A ODS : 50 x 250 mm

elution : CH3CN: 0.1% aqueous solution triperoxonane acid = 1,1: 4,4

thread: 118 ml/min

retention time : 9,784 min

so pl.: 190oC (Razlog.)

IR (nujol): 3320, 3100, 1670, 1610, 1540, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 (6N, doublet, J=5.7 Hz), 1,3-1,85 (6N, multiplet), 1,93 was 2.25 (3H, multiplet), a 2.36-and 2.79 (2H, multiplet), 3,97-is 4.21 (3H, multiplet), 4,5 was 4.76 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,72 (1H, doublet, J=8.6 Hz), 7,81 (2H, doublet, J=8,9 Hz), 8,23 (1H, doublet, J=7,8 Hz), and 9.0 (2H, singlet), 9,14 (2H, singlet)

MS (M/Z): 465 (M+1 free)

Example 8

The target compound (8) obtained from the starting compound (8) by the procedure analogous to Example 5.

Conditions for HPLC

elution : CH3CH : 0.1% aqueous solution triperoxonane acid = 15: 85

retention time : 8.0 minutes

(column and the flow are the same as in Example 5)

so pl.: 62-68oC

IR (nujol): 3200 (br), 1640 cm-1< / BR>
NMR (DMSO-d6, ) : 0,86 (6N, doublet, J=6.8 Hz), 2,04 (1H, multiplet), 2.4 to 2.8 (2H, multiplet), and 3,00 2,80 (3H, each singlet), 3,8-4,2 (3H, multiplet), and 4.68 (1H, multiplet), 4,94 and of 5.05 (2H, each singlet), 7,13 (2H, doublet, J=8,9 Hz), 7,98 (2H, doublet, J=8,9 Hz), 7,9 and 8.00 (1H, each doublet, J=7,0, 8.5 Hz), 8.30 and 8,59 (1H, each doublet, J=8 is dicarbonylnickel)phenoxy/acetic acid and of the parent compound (9A) according to the method similar to Example 1.

The mixture thus obtained starting compound (9B), anisole (20 ml) and triperoxonane acid (80 ml) was stirred for 2 hours and 45 minutes

Removed triperoxonane acid under reduced pressure, and the residue was washed with diethyl ether, which gave the original compound (9C) (19,49 g).

so pl.: 152-156oC

IR (nujol): 1630, 1600, 1560, 1500 cm-1< / BR>
NMR (DMSO-d6, ): 2,84 3.06 (3H, each singlet), 4,01 and 4.19 (2H, each singlet), 4,91 and 5,09 (2H, each singlet), of 5.34 (2H, singlet), 7,06 and was 7.08 (2H, each doublet, J=8,8 Hz), and 7.3 and 7.6 (5H, multiplet), 7,78 (2H, doublet, J=8,8 Hz)

(2) the Target compound (9A) was obtained from the thus obtained starting compound (9C) and of the starting compound (9D) by the procedure similar to that described in Example 1.

The protective group of the target compound (9A) was removed as in Example 5 and was obtained target compound (9B).

so pl.: 41-45oC

IR (nujol): 3250, 1630, 1610 cm-1< / BR>
NMR (DMSO-d6, ): 0,7-1,0 (6N, multiplet), 1.3 to 1.7 (3H, multiplet), 2,3-2,8 (2H, multiplet), and 3,00 2,80 (3H, each singlet), 3,97 and 4.04 (2H, each singlet), 4,18 (1H, multiplet), of 4.67 (1H, multiplet), 5,93 and of 5.05 (2H, each singlet), 7,13 (2H, doublet, J=8.7 Hz), to 7.77 (2H, doublet, J=8.7 Hz), 7,98 and 8,17 (1H, each is Ogadenia HPLC

elution: CH3CN: 0.1% aqueous solution triperoxonane acid = 17:83

retention time: 11.0 minutes

(column and the flow are the same as in Example 5)

The following compounds (Examples 10 and 12) were obtained from the corresponding salts triperoxonane acid in the traditional way.

Example 10

The target compound (10)

IR (nujol): 3420, 3270, 1690, 1635, 1600, 1540, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 (6N, doublet, J=6.3 Hz), 1,8-2,2 (3H, multiplet), 2,3 (2H, triplet, J=7,3 Hz), 2,3-2,8 (2H, multiplet), 3.96 points to 4.2 (3H, multiplet) and 4.65 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), and 7.8 (1H, doublet, J= 8.5 Hz), the 7.85 (2H, doublet, J=8,9 Hz), 8,35 (1H, doublet, J=7,7 Hz), 9,04 (2H, singlet, 9,24 (2H, singlet), 12,51 (1H, broad singlet)

Elemental analysis

C20H28N4O7HClH2O

Calculated: C 48,93; H 6,36; N 11,41; Cl 7,22

Found: C 48,77; H of 6.52; N 11,22; Cl 6,98

so pl.: 198oC (Razlog.)

Example 11

The target compound (11)

so pl.: 163oC (Razlog.)

IR (nujol): 3270, 1700, 1665, 1630, 1605, 1535, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 (6N, doublet, J=6,1 Hz), 1,29-1,85 (6N, multiplet), 1,91-of 2.23 (3H, multiplet), 2,35-2,78 (2H, multiplet), 3,98 to 4.2 (3H, multiplet), 4,55-to 4.73 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,72 (1H, doublet, J=8.7 Hz), 7,83 (2H, doublet, J=8,9 Hz), of 8.25 (1H, doublet, J=7.7 (nujol): 3000-3300 (broad singlet), 1710 (shoulder), 1630 (wide brs singlet) cm-1< / BR>
NMR (DMSO-d6, ): 0,86 (6N, doublet, J=6.8 Hz), was 2.05 (1H, multiplet), 2,80, and a 3.01 (3H, each singlet), 2.4 to 2.8 (2H, multiplet), 3,8-4,2 (3H, multiplet), and 4.68 (1H, multiplet), 4,94 and is 5.06 (2H, each singlet), 7,13 (2H, doublet, J=8,8 Hz), 7,80 (2H, doublet, J=8,8 Hz), and 7.8 and 8.0 (1H, each doublet, J= 7.0 and 8.5 Hz), of 8.37 and 8,68 (1H, each doublet, J=8.0 and 7.9 Hz), 9,05 (2H, singlet), 9,24 (2H, singlet)

MS (M/Z): 480 (M++ 1)

Conditions for HPLC

column: UMC-RATED R-ODS-15 S-15 120A ODS 50 x 250 mm

elution: CH3CN: 0.1% aqueous solution triperoxonane acid = 15:85

flow: 1 ml/min

retention time: 8,1 min

Formula source and target connections in the following Example 13 can be represented as follows.

< / BR>
(Am, Asr and VaI each as defined above)

Example 13

A solution of starting compound (13) (79 g) in 0.02 M buffer pyridine-acetic acid (pH 5) (1 l) was subjected to column chromatography on ion-exchange resin (2 l), elwira 0.5 M buffer pyridine-acetic acid.

The fractions containing the target compound were combined and concentrated under reduced pressure, obtaining the target compound (13) (62,54 g).

so pl.: 171oC (Razlog.)

IR (nujol): 3310, 1650, 1600, 1520 cm-1< / BR>
By, J= 8,8 Hz), 7,44 (1H, doublet, J=8.1 Hz), 7,74 (2H, doublet, J=8.7 Hz), 8,39 (1H, doublet, J=7,6 Hz), 8,75 (1,5 H, singlet), 11,25 (1,5 H, singlet)

MS (M/Z): 437 (M++1)

Elemental analysis

C20H28N4O71,2 H2O

< / BR>
Method of obtaining 16

A mixture of DL-4-cyano-N-acetylphenylalanine (114,0 g), cobalt chloride (11) (0,63 g) and acylase Amano 15000 (trade mark) (6,27 g) 1 N. aqueous sodium hydroxide solution (492 ml) was brought to pH 7.5 by adding 0.1 G. of hydrochloric acid and 0.1 G. of aqueous solution of sodium chloride, and then stirred at 33-36oC for 20 h, the Reaction mixture was brought to pH 1 with 10% hydrochloric acid, and then washed with ethyl acetate and collected by filtration the precipitate. The precipitate was washed with 10% hydrochloric acid and water, having a 4-cyano-N-acetyl-D-phenylalanine (32,00 g).

so pl.: 173-175oC

()D(C=1, MeOH) = - 12,9< / BR>
IR (nujol): 2210, 1715, 1600, 1520 cm-1< / BR>
NMR (DMSO-d6, ): 1,78 (3H, singlet), of 2.92 (1H, double doublet, J=13,8, or 9.8 Hz) and 3.15 (1H, double doublet, J=13,8 Hz, 4.9 Hz), 4,48 (1H, multiplet), 7,44 (2H, doublet, J=8,2 Hz), 7,76 (2H, doublet, J=8,2 Hz), of 8.25 (1H, doublet, J=8,2 Hz)

The acidic aqueous layer was brought to pH 7.5 by adding an aqueous solution of sodium hydroxide, was added triethylamine (32,2 ml) and di - to pH to 6.0 with 10% hydrochloric acid and was extracted with ethyl acetate. The separated organic layer was washed with water and salt solution and dried over magnesium sulfate. After evaporation in vacuo the residue was washed with n-hexane, having a 4-cyano-N-tert-butoxycarbonyl-L-phenylalanine (43,50 g)

so pl.: 149-150oC

()D(C=1, MeOH) = + 6,1< / BR>
IR (nujol): 3350, 3180, 2240, 1730, 1680, 1600, 1505 cm-1< / BR>
NMR (DMSO-d6, ): 1,31 (N, singlet), only 2.91 (1H, double doublet, J=13,7 Hz, up 10.9 Hz), 3,14 (1H, double doublet, J=of 13.7 Hz, J=10,9 Hz), 4,18 (1H, multiplet), 7,20 (1H, doublet, J=8.6 Hz), 7,46 (2H, doublet, J=8.1 Hz), 7,76 (2H, doublet, J=8,1 Hz)

Elemental analysis

Calculated: C 62,05; H 6,24; N 9,24

Found: C 62,38; H 6,32; N OF 9.55

Method get 17

Through a solution of 4-cyano-N-tert-butoxycarbonyl-L-phenylalanine (31,50 g) in pyridine (400 ml) and triethylamine (190 ml) was barbotirovany hydrogen sulfide at room temperature for 2 h, and leaving the mixture at room temperature overnight. The reaction mixture was diluted with water and ethyl acetate and brought to pH 4.5 by adding concentrated hydrochloric acid, and was extracted with ethyl acetate. The separated organic layer was washed with diluted hydrochloric acid and water and dried over magnesium sulfate. After evaporation in vacuo the residue was collected by filtration and washed n is the lag.)

()D(MeOH, C=1) = +29,40< / BR>
IR (nujol): 3280, 3110, 1670, 1605, 1510 cm-1< / BR>
NMR (DMSO-d6, ): 1,32 (N, singlet), 2,87 (1H, double doublet, J=of 13.7 Hz, J= 10.3 Hz), 3,05 (1H, double doublet, J=of 13.7 Hz, J=4.5 Hz), 4,12 (1H, multiplet), to 7.15 (1H, doublet, J=8,4 Hz), 7,28 (2H, doublet, J=8,2 Hz), 7,83 (2H, doublet, J= 8,2 Hz), 9,43 (1H, broad singlet), 9,80 (1H, broad singlet)

Elemental analysis

Found: C 55,19, H 6,32, S 9,99 N SCORED 8.38

Calculated: C 55,53, H 6,21, S 9,88 N 8,63

Method of obtaining 18

A solution of 4-thiocarbamoyl-N-tert-butoxycarbonyl-L-phenylalanine (30,06 g) and under the conditions (63.5 ml) in acetone (300 ml) was stirred and heated under reflux for 40 minutes, after which the solvent was removed under vacuum. The resulting substance was dissolved in methanol (300 ml) was added ammonium acetate (10,71 g), and then the mixture was heated under reflux with stirring for 4 hours 30 minutes, the Reaction mixture was cooled and the precipitate was filtered. The filtrate is boiled away under vacuum, the obtained substance was washed with ethanol and diethyl ether and washed with diethyl ether, having a 4-amidino-N-tertbutoxycarbonyl-L-phenylalanine hydroiodide (13,83 g).

so pl.: 184-188oC (Razlog.)

IR (nujol): 1670, 1600, 1560 cm-1< / BR>
NMR (DMSO-d6, ): 1,33 (9>+1)

Method get 19

To a mixture of 4-amidino-N-tert-butoxycarbonyl-L-phenylalanine of hydroiodide (1,00 g), 4 N. aqueous sodium hydroxide solution (1,15 ml), tetrahydrofuran (2 ml) and water (10 ml) was added a solution of benzyloxycarbonylamino in tetrahydrofuran (2 ml), the pH is increased to 1212,5 using 4 N. aqueous sodium hydroxide solution. The reaction mixture was diluted with water and diethyl ether, the separated aqueous layer was neutralized with 10% hydrochloric acid, was extracted with ethyl acetate, washed with water and salt solution and dried over magnesium sulfate. The residue obtained after evaporation in vacuum, collected by filtration and washed with diethyl ether gave 4-(N-benzyloxycarbonylamino)-N-tert-butoxycarbonyl-L-phenylalanine (0,53 g).

so pl.: 112-115oC

IR (nujol): 3300, 1680, 1620, 1560, 1500 cm-1< / BR>
NMR (DMSO-d6, ): 1,31 (N, singlet), is 2.8-3.2 (2H, multiplet), of 4.12 (1H, multiplet), 5,11 (1H, singlet), 7,12 (1H, doublet, J=8,3 Hz), 7,3-7,5 (7H, multiplet), to $ 7.91 (2H, doublet, J=8,3 Hz), 9,14 (broad singlet)

Method of obtaining 20

4-(N-Benzyloxycarbonylamino)-N-acetyl-D-phenylalanine was obtained from 4-cyano-N-acetyl-D-phenylalanine according to methods analogous to the methods of methods of obtaining 17, 18 and 19.

so pl.: 140-145is nget), 2,90 (1H, double doublet, J=13,8, 10,0 Hz), and 3.16 (1H, double doublet, J=13,8, and 4.5 Hz), 4,46 (1H, multiplet), 5,27 (2H, singlet), 7,2-7,5 (7H, multiplet), 7,80 (2H, doublet, J=8,2 Hz), 8,32 (1H, doublet, J=8,2 Hz)

Method get 21

A mixture of ethyl-5-(4-amidinophenoxy)-2,4-pentadienoic hydrochloride (20,00 g) and 10% Pd-C (5,00 g) in ethanol (500 ml) was stirred in an atmosphere of gaseous H2at room temperature within 3 hours After filtration, the filtrate is boiled away in a vacuum. The precipitate was washed with diethyl ether and received 5-/4-lidinopril/pentanoate hydrochloride /19.32 g/.

IR /nocol/: 3400, 3100, 1730, 1660 cm-1< / BR>
NMR (DMSO-d6, ): 1,16 /3H, triplet, J=7,1 Hz/, 1,52-1,61 /4H, multiplet/, 2,32 (2H, triplet, J=6,9 Hz/, 2,66 /2H, triplet, J=7,0 Hz/, 4,04 /2H, Quartet, J= 7,1 Hz/, 7,45 /2H, doublet, J=8,8 Hz/, 7,78 /2H, doublet, J=8,3 Hz/, of 9.21 /2H, singlet/, 9,26 /2N, the singlet/

MS /m/z/: 248 /M+/

Method of obtaining 22

Ethyl-3-/4-lidinopril/propionate hydrochloride obtained by the method similar to Example 21.

IR /nocol/: 3350, 3150, 1720, 1670, 1210 cm-1< / BR>
NMR (DMSO-d6, ): 1,16 /3H, triplet, J=7,1/, 2,69 /2H, triplet, J=7,4 Hz/, 2,95 /2H, doublet, J=8,3 Hz/, 4.09 to /2H, Quartet, J=7,1 Hz/, of 7.48 /2H, doublet, J=8,3 Hz/, 7,82 /2H, doublet, J=8,3 Hz/, 8,94 /4H, broad singlet/

MS /m/z/: 220 /M+/

The following compounds of (Meth
Ethyl-3-/4-(N-benzyloxycarbonylamino)phenyl/propionate

NMR (DMSO-d6, ): 1,15 /3H, triplet, J=7,1 Hz/, 2,65 /2H, triplet, J=7,4 Hz/, 2,91 /2H, triplet, J=7,4 Hz/, 4,03 /2H, Quartet, J=7,1 Hz/, 5,10 /2H, singlet/, 7,31-7,41 /7H, multiplet/, of 7.90 /2H, doublet, J=8,3 Hz/, 9,13 /2H, broad singlet/

MS (m/z): 354 /M+/

Method of obtaining 24

Ethyl-5-/4-(N-benzyloxycarbonylamino)phenyl/pentanoate

IR (nujol/: 3450, 3300, 1730, 1600, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1,16 /3H, triplet, J=7,1 Hz/, 1,56-1,58 /4H, multiplet/, 2,31 /2H, triplet, J=6,9 Hz/, 2,64 /2H, triplet, J=7,0 Hz/, 4,03 /2H, Quartet, J= 7,1 Hz/, 5,11 /2H, singlet/, of 7.23-7,40 /7H, multiplet/, of 7.90 /2H, doublet, J=8,3 Hz/, 9,23 /2H, broad singlet/

Method of obtaining 25

Ethyl-8-/4-(N-benzyloxycarbonylamino)phenoxy/octanoate

so pl.: 93-95oC

IR /nocol/: 3420, 3290, 1720, 1650, 1590, 1560, 480 cm-1< / BR>
NMR (DMSO-d6, ): 1,17 /3H, triplet, J=7,1/, 1,15-1,83 /10H, multiplet/, 2,27 /2H, triplet, J=7,2/, 4,01 /2N, type triplet/, 4,04 /2H, Quartet, J= 7,1 Hz/, 5,10 /2H, singlet/, 7,0 /2H, doublet, J=8,9 Hz/, of 7.36 /5H, multiplet/, 7,98 /2H, doublet, J=8,9 Hz/, which is 9.09 /2N, a broad singlet/

Method of obtaining 26

Ethyl-5-/4-(N-benzyloxycarbonylamino)/pentanoate (22,00 g) in concentrated hydrochloric acid (220 ml) was stirred at room temperature for 3 weeks is 10,50, adding an aqueous solution of sodium hydroxide, the pH of the separated aqueous layer was brought to 4.5 by adding 10% hydrochloric acid, and was extracted with ethyl acetate and the separated organic layer was washed with salt solution and dried over magnesium sulfate, the filtrate obtained after filtration, boiled away in vacuum, and the resulting residue was washed with diisopropyl ether and received 5-[4-(N-benzyloxycarbonylamino)]-pentane acid (12.0 g).

IR (nujol): 3350, 3200, 1700, 1660, 1620, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1,50-1,60 (4H, multiplet), of 2.23 (2H, triplet, J=6,9 Hz) of 2.64 (2H, triplet, J= 7.0 Hz), 5,10 (2H, singlet), 7,27-7,42 (7H, multiplet), of 7.90 (2H, doublet, J=8,3 Hz), 9,11 (2H, broad singlet), 12.01 (1H, broad singlet)

MS (m/z): 355 (M++1)

Method of obtaining 27

3-/4(N-Benzyloxycarbonylamino)phenyl/propionic acid obtained by the method similar to that described in the Method of obtaining 26.

NMR (DMSO-d6, ): of 2.56 (2H, triplet, J=7.4 Hz), is 2.88 (2H, triplet, J=7.4 Hz), 5,10 (2H, singlet), 7,32-7,38 (8H, multiplet), of 7.90 (2H, doublet, J=8,3 Hz), the remaining 9.08 (1H, broad singlet)

Method of obtaining 28

8-/4(N-Benzyloxycarbonylamino)phenoxy/octanoic acid was obtained similarly to the Method of obtaining 13.

so pl.: 130oC (Razlog.)

IR (well, =6,4 Hz), 5,27 (2H, singlet), to 7.09 (2H, doublet, J= 8,9 Hz), and 10.0 (1H, broadened), 12,0 (1H, broadened)

Method of obtaining 29

A mixture of ethyl-4-(4-cianfrocca)butyrate (4.7 g) in tetrahydrofuran (23,5 ml) and 1 n sodium hydroxide solution (40,2 ml) was heated under reflux for 2 h under stirring. The reaction mixture is brought to a pH of 2.0 by adding 10% hydrochloric acid, and the precipitate collected by filtration, obtaining 4-(4-cianfrocca)butyric acid (4,06 g).

so pl.: 210oC

IR (nujol): 3175, 2220, 1730, 1600, 1510 cm-1< / BR>
NMR (DMSO-d6, ): a 1.96 (2H, multiplet), 2,39 (2H, multiplet), 4,08 (2H, multiplet), was 7.08 (2H, doublet, J=8,9 Hz), 7,76 (2H, doublet, J=8,9 Hz), 12,18 (1H, singlet)

Method of obtaining 30

5-(4-Cianfrocca)pentane acid obtained by the method similar to that described in the Method of obtaining 29.

so pl.: 160oC

IR (nujol): 3200, 2225, 1720, 1600, 1560, 1505 cm-1< / BR>
NMR (DMSO-d6, ): 1,5-of 1.85 (4H, multiplet), to 2.29 (2H, tripleoption), of 4.05 (2H, multiplet), to 7.09 (2H, doublet, J=6,9 Hz), 7,76 (2H, doublet, J=6,9 Hz)

Method of obtaining 31

A mixture of 4-(4-cianfrocca)butyric acid (1 g), triethylamine (0.75 ml) and diphenylphosphinite (1,16 ml) in tetrahydrofuran (10 ml) was heated under reflux for 6 h p is ü stirred under the same conditions for 15 hours The reaction mixture was poured into a mixture of ethyl acetate (30 ml) and water (100 ml) and brought to pH 10 by adding 4 n sodium hydroxide solution. The separated organic layer was washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate, water and salt solution, dried over magnesium sulfate and boiled away in vacuum, obtaining the target compound (P-31) (1.7 g).

so pl.: 106-109oC

IR (nujol): 3360, 3300, 3270, 2225, 1725, 1630, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 0,82 (6N, doublet, J=5.6 Hz) and 1.83 (2H, triplet, J=6.3 Hz), was 2.05 (1H, multiplet), 2.4 to 2.8 (2H, multiplet) and 3.15 (2H, multiplet), of 4.05 (2H, triplet, J=6.2 Hz), 4,23 (1H, multiplet), br4.61 (1H, multiplet), of 5.05 (2H, singlet), 5,10 (2H, singlet), from 6.22 to 6.4 (2H, multiplet), was 7.08 (2H, doublet, J=8,9 Hz), 7,35 (10H, multiplet), of 7.75 (2H, doublet, J=8,9 Hz), 8,15 (1H, doublet, J=8,3 Hz)

FAB-MASS: 615 (M++1)

Method of obtaining 32

The target compound (P-32) obtained by the method similar to the Method of obtaining 31.

so pl.: 115-122oC

IR (nujol): 3300, 2220, 1730, 1625, 1600, 1540 cm-1< / BR>
NMR (DMSO-d6, ): 0,83 (6N, doublet, J=6,7 Hz), of 1.52 (2H, multiplet), was 1.69 (2H, multiplet), to 2.06 (1H, multiplet), of 2.5-2.8 (2H, multiplet), was 3.05 (2H, multiplet), of 4.05 (2H, triplet, J=6.2 Hz), 4,23 (1H, multiplet), 4,63 (1H, multiplet), is 5.06 (2H, singlet), 5,11 (2H, singlesided connection (getter 33 and 34) were obtained by the method, similar to the Method of obtaining 17.

Method of obtaining 33

The target compound (R-33)

so pl.: 139oC

IR (nujol): 3430, 3320, 3200, 1730, 1715, 1630, 1540 cm-1< / BR>
NMR (DMSO-d6, ): 0,83 (6N, doublet, J=6.5 Hz), of 1.93 (2H, tripleoption), was 2.05 (1H, multiplet), 2.4 to 2.8 (2H, multiplet) and 3.15 (2H, multiplet), a 4.03 (2H, tripleoption), to 4.23 (1H, multiplet), to 4.62 (1H, multiplet), is 5.06 (2H, singlet), 5,11 (2H, singlet), 6,2-6.42 per (2H, multiplet), 6,93 (2H, doublet, J=8,8 Hz), 7,34 (10H, multiplet), 7,95 (2H, doublet, J=8,8 Hz), 8,15 (1H, doublet, J=8,2 Hz), to 9.32 (1H, singlet), for 9.64 (1H, singlet)

Method of obtaining 34

The target compound (R-34)

so pl.: 130oC

NMR (DMSO-d6, ): 0,83 (6N, doublet, J=5.8 Hz), of 1.52 (2H, multiplet), was 1.69 (2H, multiplet), to 2.06 (2H, multiplet), 2.4 to 2.8 (2H, multiplet), was 3.05 (2H, multiplet), to 4.01 (2H, triplet, J=6.0 Hz), 4,23 (1H, multiplet), to 4.62 (1H, multiplet), is 5.06 (2H, singlet), 5,11 (2H, singlet), 6,2-6,4 (2H, multiplet), 6,93 (2H, doublet, J= 8,9 Hz), 7,35 (10H, multiplet), 7,95 (2H, doublet, J= 8,9 Hz), 8,15 (1H, doublet, J=8,3 Hz), to 9.32 (1H, singlet), for 9.64 (1H, singlet)

In the above Methods to obtain 31-34 formula source and target compounds are the following, listed in table.2 (in the formula Asp VaI and BZI each as explained in table. 2).

Method of obtaining 35

A mixture of 60% sodium hydride (7,92 g) Lily ethyl-5-diethoxyphosphoryl-3-pentenoate (49,61 g) and was stirred for 1 h at -10oC. the reaction mixture is poured p-cyanobenzaldehyde (20,00 g) in tetrahydrofuran (50 ml) and was stirred for 3 h at 0oC. the Reaction mixture was poured into a mixture of brine and ethyl acetate. The separated organic layer was dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate is boiled away in a vacuum. The residue was subjected to column chromatography on silica gel and was suirable a mixture of ethyl acetate/n-hexane = 1:4. The fractions containing the target compound were combined and boiled away in vacuum, obtaining 5-(4-cyanophenyl)-2,4-pentadienoic (10,04 g).

IR (nujol): 2250, 1720, 1630, 1250 cm-1< / BR>
NMR (DMSO-d6, ): to 1.24 (3H, triplet, J=7,1 Hz) to 4.16 (2H, Quartet, J=7,1 Hz), 6,18 (1H, doublet, J=12,5 Hz), 7,13-7,49 (3H, multiplet), 7,74 (2H, doublet, J=8.5 Hz), the 7.85 (2H, doublet, J=8.5 Hz)

MS (m/z: 227 (M+)

The following compounds (getter 36 and 37) were obtained by the method similar to the Method of obtaining 4.

Method of obtaining 36

Ethyl-3-/4-(1-(ethoxy)iminomethyl)phenyl/acrylate hydrochloride

IR (nujol): 1720, 1640, 1320, 1180 cm-1< / BR>
NMR (DMSO-d6, ): of 1.28 (3H, triplet, J=7,1 Hz), for 1.49 (3H, triplet, J=7.0 Hz), is 4.21 (2H, Quartet, J=7,1 Hz), of 4.66 (2H, Quartet, J=7.0 Hz), 6,86 (1H, doublet, J= 16.0 Hz), to 7.59 (1H, doublet, J=16.0 Hz), 7,79 (2H, doublet, J=8.7 Hz)l/-2,4-pentadienoic hydrochloride

IR (nujol): 3400, 1720, 1620, 1250 cm-1< / BR>
NMR (DMSO-d6, ): a 1.25 (3H, triplet, J=7,1 Hz), for 1.49 (3H, triplet, J=7,0 Hz) to 4.16 (2H, Quartet, J=7,1 Hz), 4,63 (2H, Quartet, J=7.0 Hz), of 6.20 (1H, doublet, J=14,2 Hz), 7,17-7,46 (3H, multiplet), to 7.84 (2H, doublet, J=8.5 Hz), 8,15 (2H, doublet, J=8.5 Hz)

MS (m/z): 273 (M+)

Method of obtaining 38

In a mixture of ethyl-5-/4-((1-ethoxy)iminomethyl)phenyl/-2,4-pentadienoic hydrochloride (22,00 g) in ethanol (220 ml) was poured 9 n solution of ammonia in ethanol (19.7 ml) and was heated under reflux for 15 hours After cooling to room temperature the reaction mixture is boiled away in vacuum, the residue is washed diisopropyl ether and obtained ethyl-5-(4-amidinophenoxy)-2,4-pentadienoic hydrochloride (20,15 g).

IR (nujol): 3400, 1720, 1630, 1250 cm-1< / BR>
NMR (DMSO-d6, ): a 1.25 (3H, triplet, J=7,1 Hz), 4,17 (2H, Quartet, J=7,1 Hz), 6,18 (1H, doublet, J=14.4 Hz), 7,15-7,51 (3H, multiplet), 7,78 (2H, doublet, J=8.5 Hz), 7,89 (2H, doublet, J=8.5 Hz), of 9.30 (2H, singlet), 9,48 (2H, singlet)

MS (m/z: 244 (M+)

Method of obtaining 39

Ethyl-3-(4-amidinophenoxy)acrylate hydrochloride is obtained analogously to the Method of obtaining 7.

IR (nujol): 3400, 1720, 1320, 1200 cm-1< / BR>
NMR (DMSO-d6, ): of 1.28 (3H, triplet, J=7,1 Hz), 4,22 (2H, Quartet, J=7,1 Hz) 6,86 (1H, doublet, J=16.1 Hz), 7,73 (1H, doublet, J=16.1 Hz), to $ 7.91 0

3-/4-(N-Benzyloxycarbonylamino)phenyl/propionic acid obtained by the method similar to the Method of obtaining 26.

NMR (DMSO-d6, ): of 2.56 (2H, triplet, J=7.4 Hz), is 2.88 (2H, triplet, J=7.4 Hz), 5,10 (2H, singlet), 7,32-7,38 (8H, multiplet), of 7.90 (2H, doublet, J=8,3 Hz), the remaining 9.08 (1H, broad singlet)

Formula source and target compounds in the following Examples shown in table.3.

In the formulas given in table. 3 Am/Z/, Am, Bzl, Asp, Val, Sar and Leu corresponds to each of the definitions above, Tyr mean 1-tyrosine, Ser means of L-serine, means Gly glycine, Ala means of L-alanine, Ala is alanine, Phe means of L-phenylalanine, D-VaI means D-valine, Thr means of L-threonine, Ile means of L-isoleucine, Nle means L-norleucine, Glu means of L-glutamic acid, Me means methyl, Et means ethyl, Ac means acetyl and Boc means tert-butoxycarbonyl.

The following compounds (examples 14 to 20) were obtained by the method similar to the method of Example 1.

Example 14

The target compound (14)

so pl.: 95-100oC

IR (nujol): 3300, 1730, 1710, 1650, 1625, 1530 cm-1< / BR>
NMR (DMSO-d6, ): 0,82 (6N, doublet, J=6.6 Hz), 1,34 by 1.68 (4H, multiplet), 1,92-2,22 (3H, multiplet), 2,4-2,85 (4H, multiplet), 4,1-be 4.29 (1H, multiplet), 4,65 of 5.84 (1H, multiplet), 4,1-be 4.29 (1H, mullet, J=8,2 Hz), by 8.22 (1H, doublet, J=7.9 Hz), 9,12 (2H, broad singlet)

Example 15

The target connection (15)

so pl.: 125oC /colour / div./

IR (nujol): 3300, 1725, 1650, 1605, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 1,5-of 1.85 (4H, multiplet), and 2.14 (2H, type triplet), 2,5-a 3.01 (4H, multiplet), of 3.56 (3H, singlet), to 4.01 (2H, multiplet), 4,36 (1H, multiplet), to 4.73 (1H, multiplet), 5,07 (2H, singlet), a 5.1 (2H, singlet), of 6.65 (2H, doublet, J=8,4 Hz), 6,9-7,1 (4H, multiplet), 7,24-7,5 (N, multiplet), 7,98 (2H, doublet, J=8,9 Hz), 8,17 (2H, doublet, J=6,7 Hz), 8,95-9,37 (2H, broad)

Example 16

The target connection (16)

so pl.: 128oC /colour / div./

IR (nujol): 3300, 1730, 1640, 1600, 1530 cm-1< / BR>
NMR (DMSO-d6, 1.5 to to 1.83 (4H, multiplet), and 2.14 (2H, type triplet), 2,5-3,05 (4H, multiplet), to 3.58 (3H, singlet), of 3.69 (3H, singlet), to 4.01 (2H, type triplet), and 4.40 (1H, multiplet), 4,72 (1H, multiplet), 5,07 (2H, singlet), 5,10 (2H, singlet), PC 6.82 (2H, doublet, J=8.6 Hz), 6,99 (2H, doublet, J= 8,9 Hz), 7,10 (2H, doublet, J=8.6 Hz), 7,22-7,50 (N, multiplet), to 7.99 (2H, doublet, J=8,8 Hz), 8,1-8,29 (2H, multiplet), 9,14 (1H, broad singlet)

Example 17

The target compound (17)

so pl.: 120oC /colour / div./

IR (nujol): 3300, 1730, 1640, 1605, 1500 cm-1< / BR>
NMR (DMSO-d6, ): 1,48-1,8 (4H, multiplet) by 2.13 (2H, type triplet), 2,4-of 3.06 (4H, multiplet), of 3.69 (3H, singlet), of 4.00 (2H, type triplet), to 4.46 (1H, mullet, J=8.6 Hz), 7,17-7,5 (15 NM, multiplet), 7,98 (2H, doublet, J=8,9 Hz), 8,16 (1H, doublet, J=8.1 Hz), 8,29 (1H, doublet, J=7,4 Hz), 9,16 (1H, broad singlet)

Example 18

The target compound (18)

so pl.: 86-90oC

IR (nujol): 3300, 1720, 1610, 1595 cm-1< / BR>
NMR (DMSO-d6, ): 1,71 (4H, broad singlet), 2,22 (2H, broad singlet), to 2.67 (1H, double doublet, J=17,4 Hz, J=5,9 Hz), 3,05 (1H, double doublet, J= and 17.7 Hz, J=9,2 Hz), 3,7-4,2 (4H, multiplet), to 4.52 (4H, broad singlet), 5,0-5,2 (6N, multiplet), 7,00 (2H, doublet, J=8,3 Hz), 7,2-7,6 /N/, 7,99 /2H, doublet, J=8,4 Hz/, 8,69 /1H, doublet, J=7,4 Hz)

Example 19

The target connection /19/

so pl.: 55-60oC

IR (nujol): 3260, 1725, 1645, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 2,6-3,1 /4H, multiplet/, 2,77, and 2,96 /3H, each singlet/, 3,56 /3H, singlet/, 3,69 /3H, singlet/, 3,97 and 4,01 /2H, each singlet/, 4,4 /1H, multiplet/, 4,7-5,3 /7H, multiplet/, 6,80 /2H, multiplet/, 6,95-7,2 /4H, multiplet/, 7,35 /10H, multiplet/, 7,97 /2H, doublet, J=7.9 Hz/, of 8.2 to 8.3 /1H, multiplet/, 8,4-8,6 /1H, multiplet/

Example 20

The target connection /20/

so pl.: 50-55oC

IR (nujol): 3250 /extended/, 1720, 1640, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 2,4-3,1 /4H, multiplet/, was 2.76 and 2.95 /3H, each singlet/, 3.68 and 3,69 /3H, each singlet/, 3,95 and 3,99 /2H, each singlet/, 4,43 /1H, multiplet/, 4,6-5,3 /N, multiplet/, 6,79 /2H, multiplet/, 6,99 /tiplet/

Example 21

The target connection /21/ received according to the method similar to the method of Example 1.

To a mixture of crude source composition /21/ /0,787 mmol) and anisole /1 ml/ added triperoxonane acid /4 ml at room temperature and the mixture was stirred at room temperature for 1 h After evaporation was added to the obtained substance mixture of 4 N. hydrochloric acid/dioxa /5 ml, the mixture is then evaporated in vacuum and rubbed the resulting material with diethyl ether, washed with diethyl ether, resulting in the target connection /21/ /0,58 g/.

so pl.: 105-110oC

IR (nujol): 1730, 1650 cm-1< / BR>
NMR (DMSO-d6, ): 0,80 /6N, multiplet/, 2,05 /1H, multiplet/, to 2.65 and 2.75 /3H, each singlet/, 2,6-2,9 /2H, multiplet/, 3,19 /2H, multiplet/, 3,6-4,4 /3H, multiplet/, 4,5-4,8 /2H, multiplet/, 5,09 /4H, singlet/, 5,33 /2H, singlet/, 7,2-7,6 /17H, multiplet/, 7,80 /2H, doublet, J=8.0 Hz/, 8,17 and at 8.36 /1H, each doublet, J=8,1 Hz/, 8,2-8,8 /4H, multiplet/

Example 22

To a mixture of 4-/4-(N-benzyloxycarbonylamino)-phenoxy/butyric acid /1.18 g/, the source of the link /22/ /2,00 g/ and 1-hydroxy-1H-benzothiazole /0.51 g/ N,N-dimethylformamide /30 ml/ -20oC was added 1-/3-dimethylaminopropyl/-3-ethylcarbodiimide /0,61/ ml and stirred the mixture is eaten to 10.50 using sodium hydroxide solution. The separated organic layer was washed with 0.5 N. hydrochloric acid, saturated sodium bicarbonate, water and salt solution and dried over magnesium sulfate. Obtained after filtration the filtrate is boiled away in vacuum, the residue is washed diisopropyl ether and received the target connection /22/ /2,04 g/.

IR (nujol): 3300, 1730, 1650, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 1,92 /2H, multiplet/, 2,25 /2H, triplet, J=6,4 Hz/, 2,54-2,78 /2H, multiplet/, 2,85-2,93 /2H, multiplet/, 4,01 /2H, triplet, J=6,8 Hz/, was 4.42 (1H, multiplet/, 4,70 /1H, multiplet/, 4,99 /2H, singlet/, 5,03 /2H, singlet/, of 5.05 /2H, singlet/, 5,10 /2H, singlet/, 6,87 /2H, doublet, J= 8,9 Hz/, 6,98 /2H, doublet, J=8.6 Hz/, 7,08 /2H, doublet, J=8.6 Hz/, 7,24-7,39 /20N, multiplet/, 7,98 /2H, doublet, J=8,9 Hz/, by 8.22 /1H, doublet, J=8,1 Hz/, 8,31 /1H, doublet, J=7,4 Hz/, 9,11 /2H, broad singlet/

MS (m/z): 905 /M+/

The following connections /Examples 23 to 36/ were obtained by the method similar to the method of Example 22.

Example 23

The target connection /23/

IR (nujol): 3400, 1740, 1620, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1,92 /2H, multiplet/, 2,25 /2H, triplet, J=6,4 Hz/, 2,54-2,78 /2H, multiplet/, 2,88-2,95 /2H, multiplet/, 3,60 /3H, singlet/, 4,01 /2H, triplet, J=6,8 Hz/, 4,45 /1H, multiplet/, 4,73 /1H, multiplet/, 4,79 /2H, singlet/, 4,94 /2H, singlet/, 5,10 /2H, singlet/, 6,79 /2N, the em J=8,1 Hz/, 8,31 /1H, doublet, J=7,4 Hz/, 9,10 /2H, broad singlet/,

MS (m/z): 829 /M++ 1/

Example 24

The target connection /24/

IR (nujol): 3400, 3300, 1730, 1700, 1650, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1,40-1,50 /4H, multiplet/2,08 /2N, type triplet/, 2.57 m /2N, type triplet/, 2,66 was 2.76 /2H, multiplet/, 2,89-2,93 /2H, multiplet/, 3,69 /3H, singlet/, 4,45 /1H, multiplet/, to 4.41 /1H, multiplet/, 5,04 /2H, singlet/, 5,10 /2H, singlet/, 5,20 /2H, singlet/, 6,78 /2H, doublet, J= 8,9 Hz/, 7,07 /2H, doublet, J=8.6 Hz/, of 7.23-7,40 /17H, multiplet/, to $ 7.91 /2H, doublet, J=8,9 Hz/, 8,13 /1H, doublet, J=8,1 Hz/, compared to 8.26 /1H, doublet, J=7,4 Hz/, 9,12 /2H, broad singlet/

Example 25

The target connection /25/

IR (nujol): 3300, 1740, 1700, 1650, 1600, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1,06-1,35 /4H, multiplet/, 1,39-1,51 /2H, multiplet/, to 2.06 /2H triplet, J=6,9 Hz/, 2,49-2,77 /2H, multiplet/, 2,85-2,93 /2H, multiplet/, 3,70 /3H, singlet/, 3,99 /2H, triplet, J=6,4 Hz/, of 4.44 /1H, multiplet/, 4,71 /1H, multiplet/, 4,99 /2H, singlet/, 5,01 /2H, singlet/, 5,09 /2H, singlet/, 6,78 /2H, doublet, J=8,9 Hz/, 6,98 /2H, doublet, J=8.6 Hz/, 7,07 /2H, doublet, J=8.6 Hz/, 7,24-7,89 /15 NM, multiplet/, 7,97 /2H, doublet, J=8,9 Hz/, 8,12 /1H, doublet, J=8,1 Hz/, 8,25 /1H, doublet, J=7,4 Hz/, 9,10 /2H, broad singlet/

MS (m/z): 857 /M++ 1/

Example 26

The target connection /26/

NMR (DMSO-d6, ): 0,80 /3H, doublet, J=6.0 Hz/, 0,85 /3H, doublet, J=6.0 Hz/, 1,40 years/, 5,09 /2H, singlet/, 5,10 /2H, singlet/, 7,26-7,49 /17H, multiplet/, to $ 7.91 /2H, doublet, J=8,9 Hz/, 8,15 /1H, doublet, J=8,1 Hz/, 8,30 /1H, doublet, J=7,6 Hz/, 9,12 /2H, broad singlet/

MS (m/z): 763 /M++ 1/

Example 27

The target connection /27/

IR (nujol): 3380, 3300, 1740, 1630, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1,87-2,02 /2H, multiplet/, 2,28 /2H, triplet, J=7,0 Hz/, 2,64-2,83 /2H, multiplet/, a 3.87 /2H, doublet, J=6,5 Hz/, was 4.02 /2H, triplet, J=6,4 Hz/, 4,73 /1H, multiplet/, 5,06 /2H, singlet/, 5,10 /2H, singlet/, 5,11 /2H, singlet/, 6,99 /2H, doublet, J=8,9 Hz/, 7,31-7,37 /15 NM, multiplet/, 7,98 /2H, doublet, J=8,9 Hz/, of 8.27-8.34 per /2H, multiplet/, 9,07 /2H, broad singlet/

MS (m/z): 709 /M++ 1/

Example 28

The target connection /28/

NMR (DMSO-d6, ): 1,29 /3H, doublet, J=7,3 Hz/, 1,92 /2H, multiplet/, 2,27 /2H, triplet, J=7,3 Hz/, 2,55-2,78 /2H, multiplet/, was 4.02 /2H, triplet, J=6.3 Hz/, or 4.31 /1H, multiplet/, 4,72 /1H, multiplet/, of 5.05 /2H, singlet/, 5,06 /2H, singlet/, 5,10 /2H, singlet/, 6,99 /2H, doublet, J=8,9 Hz/, 7,34-7,40 /15 NM, multiplet/, 7,98 /2H, doublet, J=8,9 Hz/, 8,24 /1H, doublet, J=8,2 Hz/, 8,43 /1H, doublet, J=7,2 Hz/, 9,10 /2H, broad singlet/

Example 29

The target connection /29/

IR (nujol): 3300, 1740, 1650, 1600, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1,88-1,99 /2H, multiplet/, 2,25 /2H, triplet, J=7,1 Hz/, 2,52-2,60 /2H, multiplet/, 2,97-3,07 /2H, multiplet/, 4,03 /2H, triplet, J=6,4 Hz/, to 4.52 /1H, mullet/, 8,00 /2H, doublet, J=8,9 Hz/, by 8.22 /1H, doublet, J=8,1 Hz/, at 8.36 /1H, doublet, J=7,4 Hz/, 9,16 /2H, broad singlet/

MS (m/z): 799 /M++1/

Example 30

The target connection /30/

IR (nujol): 3300, 1740, 1650, 1600, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1,12 /3H, triplet, J=7,1 Hz/, 1,56-1,64 /2H, multiplet/, 1,90-1,97 /2H, multiplet/, 2,18-2,30 /4H, multiplet/, to 2.57-2,79 /4H, multiplet/, 3,90-4,06 /5H, multiplet/, with 4.64 /1H, multiplet/, 5,06 /2H, singlet/, 5,11 /2H, singlet/, 7,00 /2H, doublet, J=8,9 Hz/, 7,14-7,40 /15 NM, multiplet/, 7,68 /1H, doublet, J=7.9 Hz/, 8,00 /2H, doublet, J=8,9 Hz/, 8,16 /1H, doublet, J=8,1 Hz/, 9,12 /2H, broad singlet/

MS (m/z): 765 /M++1/

Example 31

The target connection /31/

NMR (DMSO-d6, ): 0,68-0,95 /2H, multiplet/, 1,01-1,35 /5H, multiplet/, 1,39-1,61 /10H, multiplet/, 2,11 /2N, type triplet/, 2,60-2,75 /4H, multiplet/, or 4.31 /1H, multiplet/, 4,71 /1H, multiplet/, 5,04 /2H, singlet/, 5,07 /2H, singlet/, 5,09 /2H, singlet/, 7,26-7,37 /15 NM, multiplet/, of 7.90 /2H, doublet, J=8,9 Hz/, 8,15 /1H, doublet, J=8,1 Hz/, 8,27 /1H, doublet, J=7,4 Hz/, 9,11 /2H, broad singlet/

MS (m/z): 803 /M+/

Example 32

The target connection /32/

NMR (DMSO-d6, ): 0,84 /3H, triplet, J=7,4 Hz/, 1,60-1,67 /2H, multiplet/, 1,95 /2H, multiplet/, 2,27 /2H, triplet, J=6,4 Hz/, to 2.57-2,80 /2H, multiplet/, was 4.02 /2H, triplet, J=6,8 Hz/, 4,20 /1H, multiplet/, 4,76 /1H, multiplet/, 5,00 /2H, singlet/, 5,06 /2N, ,12 /2H, broad singlet/,

MS (m/z): 737 /M++1/

Example 33

The target connection /33/

NMR (DMSO-d6, ): 0,82 /3H, triplet, J=7,3 Hz/, of 1.23 to 1.34 /2H, multiplet/, 1,64 /2H, multiplet/, 1,92-2,10 /2H, multiplet/, 2,24 /2H, triplet, J= 6,4 Hz/, 2,56-2,78 /2H, multiplet/, 4,05 /2H, triplet, J=6,8 Hz/, 4,25 /1H, multiplet/, 4,72 /1H, multiplet/, of 5.05 /2H, singlet/, 5,06 /2N, the singlet/, 5,09 /2H, singlet/, 6,99 /2H, doublet, J=8,9 Hz/, 7,31-7,40 /15 NM, multiplet/, 7,98 /2H, doublet, J=8,9 Hz/, 8,25 /1H, doublet, J=8.0 Hz/, 8,32 /1H, doublet, J=7,4 Hz/, 9,10 /2H, broad singlet/

Example 34

The target connection /34/

NMR (DMSO-d6, ): 0,62-0,97 /2H, multiplet/, 1,01-1,18 /5H, multiplet/, 1,42-1,69 /6N, multiplet/, 1,94 /2H, multiplet/, 2,24 /2H, triplet, J= 6,4 Hz/, 2,56 was 2.76 /2H, multiplet/, was 4.02 /2H, triplet, J=6,8 Hz/, 4,32 /1H, multiplet/, 4,72 /1H, multiplet/, of 5.05 /2H, singlet/, 5,06 /2H, singlet/, 5,08 /2H, singlet/, 6,98 /2H, doublet, J=8,9 Hz/, of 7.23-7,39 /15 NM, multiplet/, 7,98 /2H, doublet, J=8,9 Hz/, 8,23 is 8.38 /2H, multiplet/, 9,13 /2H, broad singlet/

MS (m/z): 805 /M++1/

Example 35

The target connection /35/

NMR (DMSO-d6, ): 2,52-2,98 /3H, multiplet/, 2,90 /3H, singlet/, 3,70 /3H, singlet/, 3,92 /2H, multiplet/, 4,43 /1H, multiplet/, 4,72 /1H, multiplet/, 5,04 /2H, singlet/, 5,07 /2H, singlet/, 5,10 /2H, singlet/, 6,77 /1H, multiplet/, 7,09 /2H, multiplet/, 7,26-7,37 /N, multiplet/, 7,82-7,95 /NR (DMSO-d6, ): 0,72-0,98 /2H, multiplet/, 1,01-1,38 /5H, multiplet/, 1,41-1,68 /6N, multiplet/, 2,60-2,88 /2H, multiplet/, 2,77 /3H, singlet/, 3,98 /2H, multiplet/, 4,29 /1H, multiplet/, 4,80 /1H, multiplet/, of 5.05 /2H, singlet/, 5,06 /2H, singlet/, 5,06 /2H, singlet/, 5,09 /2H, singlet/, 6,99 /2N, doublet, J=8,9 Hz/, 7,33-7,37 /15 NM, multiplet/, 7,95 /2H, doublet, J= 8,9 Hz/, 8,28-8,33 /1H, multiplet/, 8,46 at 8.60 /1H, multiplet/, 9,12 /2H, broad singlet/

MS (m/z): 848 /M++1/

Example 37

The mixture of starting compound /37/ /1.70 g/ and 10% Pd-C /0,80 g/ in a mixture of 1N hydrochloric acid /2,25 ml/ tetrahydrofuran /20 ml/ was stirred in an atmosphere of H2at room temperature for 6 hours After filtration, the filtrate is boiled away in a vacuum. The target substance was washed in isotonic solution of sodium chloride and isolated target connection /37/ /0,60 g/.

so pl.: 180-183oC

IR (nujol): 3250, 1670, 1640, 1600, 1260 cm-1< / BR>
NMR (DMSO-d6, ): 1,94 /2H, multiplet/, 2,27 /2N, type triplet/, 2,63-2,72 /2H, multiplet/, 2,80-2,87 /2H, multiplet/, 4,08 /2N, type triplet/, 4,30 /1H, multiplet/, 4,62 /1H, multiplet/, 6,66 /2H, doublet, J=8,9 Hz/, 6,97 /2H, doublet, J=8.6 Hz/, 7,14 /2H, doublet, J=8.6 Hz/, a 7.85 /3H, multiplet/, 8,25 /1H, doublet, J=7,4 Hz/, 9,05 /2H, singlet/, 9,25 /3H, multiplet/, 12,51 /2H, broad singlet/

MS (m/z): 501 /M+/

The following connections /Debate /38/

so pl.: 204-206oC

IR (nujol): 3350, 3300, 1670, 1640, 1540, 1260 cm-1< / BR>
NMR (DMSO-d6, ): 1,94 /2H, multiplet/, 2,31 /2H, triplet, J=6,4 Hz/, 2,45-2,62 /2H, multiplet/, 2,79-2,96 /2H, multiplet/, 3,70 /3H, singlet/, 4,08 /2H, triplet, J=6,8 Hz/, 4,35 /1H, multiplet/, br4.61 /1H, multiplet/, for 6.81 /2H, doublet, J= 8,9 Hz/, 7,10-7,16 /4H, multiplet/, 7,84-7,93 /3H, multiplet/, compared to 8.26 /1H, doublet, J= 7,8 Hz/, which is 9.09 /2H, singlet/, 9,27 /2H, singlet/, 12,00 /2H, broad singlet/

MS (m/z): 515 /M+/

Example 39

The target connection /39/

so pl.: 163oC /colour / div./

IR (nujol): 3270, 1700, 1665, 1630, 1605, 1535, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 /6N, doublet, J=6,1 Hz/, 1,29-1,85 /6N, multiplet/, 1,91-2,23 /3H, multiplet/, 2,35-2,78 /2H, multiplet/, 3,98-4,2 /3H, multiplet/, 4,55-4,73 /1H, multiplet/, 7,14 /2H, doublet, J=8,9 Hz/, 7,72 /1H, doublet, J=8.7 Hz/, 7,83 /2H, doublet, J=8,9 Hz/, 8,25 /1H, doublet, J=7,7 Hz/, 8,94 /2H, singlet/, 9,20 /2H, singlet/

Elemental analysis of C22H32N4O7HCl1H2O

Calculated: C 50,91, H 6,79, N 10,79, Cl 6,83

Found: C 51,14, H for 6.81, N A 10.74, Cl 6,37

Example 40

The target connection /40/

IR (nujol): 3300, /wide/, 1720, 1650 cm-1< / BR>
NMR (DMSO-d6, ): 0,83 /6N, doublet, J=6,7 Hz/, of 1.35 to 1.7 /4H, multiplet/, 1,9-2,25 /3H, multiplet/, 2,33-2,8 /4H, multiplet/, a 4.03-4,2 /1H, multiplet/, 4,5-4,7 /1H, multiplet/, 7,44 /2H, doublet, J=8,2 41

The target connection /41/

so pl.: 87-90oC

IR (nujol): 3200 /wide/, 1640, 1595, 1530 cm-1< / BR>
NMR (DMSO-d6, ): 2,4-3,1 /4H, multiplet/, 2,77, and 2,97 /3H, each singlet/, of 3.69 and 3.70 /3H, each singlet/, 3,96 and £ 4.02 /2H, each singlet/, 4,33 /1H, multiplet/, 4,65 /1H, multiplet/, 4,93 and 5,06 /2H, each singlet/, 6,82 /2H, multiplet/, 7,12 /4H, doublet, J=8,8 Hz/, 7,80 /2H, doublet, J=8,8 Hz/, 7.95 and 8,17 /1H, each doublet, each J=7,7 Hz/, 8,28 and 8,59 /1H, each doublet, each J=8,2 Hz/, 9,02 and which 9.22 /4H, each singlet/

MS (m/z): 558 /M++1/

The following connections /Examples 42 - 58/ received according to the method similar to that described in Example 5

Example 42

The target connection /42/

so pl.: 200-202oC

IR (nujol): 3300, 1640, 1270 cm-1< / BR>
NMR (DMSO-d6, ): 1,06-1,35 /4H, multiplet/, 1,39-1,51 /2H, multiplet/, to 2.06 /2H, triplet, J=6,9 Hz/, 2,49-2,77 /2H, multiplet/, 2,84-2,94 /2H, multiplet/, 3,70 /3H, singlet/, 4,04 /2H, triplet, J=6,4 Hz/, to 4.38 /1H, multiplet/, 4,62 /1H, multiplet/, 6,80 /2H, doublet, J=8,9 Hz/, 7,05-7,20 /4H, multiplet/, 7,76 /2H, multiplet/, 8,15 /1H, doublet, J=7,4 Hz/, 8,91-9,80 /1H, broad singlet/, 9,10-of 9.21 /2H, broad singlet/

MS (M/z): 543 /M++1/

Example 43

The target connection /43/

so pl.: 205-207oC

IR (nujol): 3280, 1640, 1550, 1210 cm-1< / BR>
NMR (DMSO-d6, ): 1,39-1,62 /4H, multip the 4,39 /1H, multiplet/, 4,58 /1H, multiplet/, 6,80 /2H, doublet, J= 8,9 Hz/, 7,10 /2H, doublet, J=8.6 Hz/, 7,43 /2H, doublet, J=8,8 Hz/, 7,73 /2H, doublet, J=8,9 Hz/, 7,83 /1H, doublet, J=7,7 Hz/, 8,10 /1H, doublet, J=8.0 Hz/, 9,18 /2H, singlet/, 9,23 /2H, singlet/, 12,54 /2N, a broad singlet/

MS (m/z): 513 /M++1/

Example 44

The target connection /44/

so pl.: 150oC /Razlog./

IR (nujol): 3300, 3100, 1720, 1670, 1610, 1540 cm-1< / BR>
NMR (DMSO-d6, ): 1,51-1,84 /4H, multiplet/, 2,16 /2N, tripleoption/, 2,31-3,0 /4H, multiplet/, to 3.58 /3H, singlet/, 4,08 /2N, tripleoption/, 4,35 /1H, multiplet/, br4.61 /1H, multiplet/, 6,66 /2H, doublet, J= 8,4 Hz/, 6,97 /2H, doublet, J=8,4 Hz/, 7,15 /2H, doublet, J=8,9 Hz/, 7,82 /2H, doublet, J=8,8 Hz/, 8,06 /1H, doublet, J=7,4 Hz/, 8,13 /1H, doublet, J=7.9 Hz/, the remaining 9.08 /2H, singlet/, 9,14 /2H, singlet/

MS (m/z): 529 /M++1/

Example 45

The target connection /45/

so pl.: 208oC /Razlog./

IR (nujol): 3280, 3090, 1730, 1705, 1660, 1640, 1605, 1540 cm-1< / BR>
NMR (DMSO-d6, ): 1,51-1,96 /4H, multiplet/, 2,15 /2N, tripleoption/, 2,32-3,0 /4H, multiplet/, to 3.58 /3H, singlet/, 3,70 /3H, singlet/, 4,07 /2N, tripleoption/, to 4.38 /1H, multiplet/, 4,60 /1H, multiplet/, 6,82 /2H, doublet, J=8.6 Hz/, 7,10 /2H, doublet, J=8.6 Hz/, 7,15 /2H, doublet, J=8,9 Hz/, 7,81 /2H, doublet, J=8,9 Hz/, 8,11 /2H, multiplet/, 9,04 /2H, singlet/, 9,14 /2H, singlet/

MS (m/z): 543 /M++1/

Example 46

what ABOUT THE-d6+TFA, ): 1,5-1,8 /4H, multiplet/, 2,14 /2N, tripleoption/, 2,25-3,10 /4H, multiplet/, 3,69 /3H, singlet/, 4,05 /2N, tripleoption/, 4,32 /1H, multiplet/, 4,59 /1H, multiplet/, 6,80 /2H, doublet, J= 8.6 Hz/, 7,09 /2H, doublet, J=8.6 Hz/, 7,13 /2H, doublet, J=8,9 Hz/, 7,79 /2H, doublet, J=8,9 Hz/, a 7.85 /1H, doublet, J=7,7 Hz/, 8,11 /1H, doublet, J=7.9 Hz/, 8,90 /2H, singlet/, 9,11 /2H, singlet/

MS (m/z): 529 /M++1/

Example 47

The target connection /47/

so pl.: 162-164oC

IR (nujol): 3300, 3100, 1660, 1270, 1200 cm-1< / BR>
NMR (DMSO-d6, ): 1,93-2,00 /2H, multiplet/, 2,31 /2H, triplet, J=7,1 Hz/, 2,64-2,75 /2H, multiplet/, to 3.73 /2H, doublet, J=5.7 Hz/, 4,10 /2H, triplet, J=6,5 Hz/, with 4.64 /1H, multiplet/, 7,15 /2H, doublet, J=8,9 Hz/, 7,81 /2H, doublet, J=8,9 Hz/, 8,10 /1H, triplet, J=5.7 Hz/, 8,23 /1H, doublet, J= 8,1 Hz/, 9,01 /2H, singlet/, 9,14 /2H, singlet/

MS (m/z): 395 /M++1/

Example 48

The target connection /48/

so pl.: 160-162oC

IR (nujol): 3300, 1670, 1600, 1270, 1200 cm-1< / BR>
NMR (DMSO-d6, ): 1,25 /3H, doublet, J=7,3 Hz/, 1,95 /2H, multiplet/, to 2.29 /2H, triplet, J=7,1 Hz/, 2,42-2,72 /2H, multiplet/, 4.09 to /2H, triplet, J= 6,4 Hz/, 4,14 /1H, multiplet/, 4,62 /1H, multiplet/, 7,15 /2H, doublet, J= 8,9 Hz/, 7,81 /2H, doublet, J=8,9 Hz/, 8,12 /1H, doublet, J=7,3 Hz/, 8,19 /1H, doublet, J=7.9 Hz/, 8,99 /2H, singlet/, 9,14 /2H, singlet/

MS (m/z): 409 /M++1/

Example 49

The target connection /49/
MS (M/z): 439 /M++1/

Example 50

The target connection /50/

so pl.: 207-209oC

IR (nujol): 3300, 1720, 1640, 1270, 1200 cm-1< / BR>
NMR (DMSO-d6, ): 1,83-2,02 /2H, multiplet/, 2,25 /2H, triplet, J=7,0 Hz/, 2,34 of 2.68 /2H, multiplet/, 2,92-3,02 /2H, multiplet/, 4,07 /2H, triplet, J=6.3 Hz/, to 4.38 /1H, multiplet/, 4,62 /1H, multiplet/, 7,12-7,26 /7H, multiplet/, 7,80 /2H, doublet, J=8,9 Hz/, 7,94 /1H, doublet, J=7,6 Hz/, 8,17 /1H, doublet, J=7.9 Hz/, 8,90 /2H, singlet/, 9,12 /2H, singlet/, 12,55 /2H, broad singlet/

MS (m/z): 485 /M++1/

Example 51

The target connection /51/

so pl.: 172-175oC

IR (nujol): 3300, 3100, 1660, 1550, 1200 cm-1< / BR>
NMR (DMSO-d6, ): 0,80 /3H, doublet, J=6.2 Hz/, 0,85 /3H, doublet, J=6.2 Hz/, 1,41-1,65 /7H, multiplet/, 2,13 /2H, triplet, J=6.2 Hz/, 2,40-2,71 /4H, multiplet/, 4,16 /1H, multiplet/, 4,58 /1H, multiplet/, 7,44 /2H, doublet, J=8,9 Hz/, 7,74 /2H, doublet, J=8,9 Hz/, 7,97 /1H, doublet, J=8.0 Hz/, 8,11 /1H, doublet, J=7.9 Hz/, 9,13 /2H, singlet/, 9,23 /2H, singlet/

MS (M/z): 449 /M++1/

Example 52

The target connection /52/

so pl.: 177-180oC<, reply, J=6,5 Hz/, of 2.51-2,70 /2H, multiplet/, 4,06-4,16 /3H, multiplet/, 4,63 /1H, multiplet/, 7,14 /2H, doublet, J=8,9 Hz/, 7,80 /2H, doublet, J=8,9 Hz/, 7,99 /1H, doublet, J= 7,8 Hz/, 8,20 /1H, doublet, J=7.9 Hz/, 8,87 /2H, singlet/, 9,13 /2H, singlet/, 12,4 /2N, a broad singlet/

MS (m/z): 437 /M++1/

Example 53

The target connection /53/

so pl.: 217-219oC

NMR (DMSO-d6, ): 0,71-0,98 /2H, multiplet/, 1,01-1,39 /5H, multiplet/, 1,47-1,71 /6N, multiplet/, 1,97 /2H, multiplet/, 2,25 /2H, triplet, J=6,4 /, 2,62-2,70 /2H, multiplet/, 4.09 to /2H, triplet, J=6,8 Hz/, 4,21 /1H, multiplet/ 4,62 /1H, multiplet/, 7,14 /2H, doublet, J=8,9 Hz/, 7,80 /2H, doublet, J=8,9 Hz/, 7,99 /1H, doublet, J=7.9 Hz/, 8,20 /1H, doublet, J=7.9 Hz/, 8,95 /2H, singlet/, 9,13 /2H, singlet/, 12,43 /2H, broad singlet/

MS (m/z): 491 /M++1/

Example 54

The target connection /54/

so pl.: 220-221oC

IR (nujol): 3300, 1670, 1650, 1250, cm-1< / BR>
NMR (DMSO-d6, ): 1,45-1,79 /2H, multiplet/, 1,92-2,01 /2H, multiplet/, 2,10-2,29 /4H, multiplet/, 2,37 of 2.68 /4H, multiplet/, 3,88 /1H, multiplet/, 4.09 to /2H, triplet, J=6,4 Hz/, to 4.52 /1H, multiplet/, 7,12-7,24 /7H, multiplet/, 7,71 /1H, doublet, J=8,5 Hz/, 7,81 /2H, doublet, J=8,9 Hz/, 8,09 /1H, doublet, J=7.9 Hz/, 8,99 /2H, singlet/, 9,13 /2H, singlet/, 12,13 /2H, broad singlet/

MS (m/z): 513 /M++1/

Example 55

so pl.: 186-188oC

IR (nujol): 3300, 1670, 1210 cm-1< / BR>
MS (m/z): 489 /M++1/

Example 56

The target connection /56/

so pl.: 65-73oC

IR (nujol): 3270 /wide/, 1650, 1610, 1510 cm-1< / BR>
NMR (DMSO-d6, ): 2,3-3,1 /4H, multiplet/, 2,78, and 2,98 /3H, each singlet/, 3,56 /3H, singlet/, 3,70 /3H, singlet/ 3,96 and £ 4.02 /2H, each singlet/, 4,37 /1H, multiplet/, 4,65 /1H, multiplet/, 4,93 and of 5.05 /2H, each singlet/, 6,82 /2H, multiplet/, 7,12 /4H, multiplet/, to 7.77 /2H, doublet, J=8,3 Hz/, 8,14 and 8,23 /1H, each doublet, J=7,3 Hz (8,14), J=8,0 Hz /8,23), of 8.37 and 8,53 /1H, each doublet, J=7,6 Hz (of 8.37), J=8,0 Hz (8,53), 9,00 and 9,13 /4H, each singlet/

Example 57

The target connection /57/

so pl.: 90-92oC /colour / div./

IR (nujol): 1650, 1300, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 2,58-2,98 /8H, multiplet/, 2,75 /3H, singlet/, 3,71 /3H, singlet/, 3,94 /2H, multiplet/, 4,32 /1H, multiplet/, 4,62 /1H, multiplet/, for 6.81 /2H, multiplet/, 7,12 /2H, multiplet/, 7,47 /2H, multiplet/, 7,71 /2H, multiplet/, of 7.90-8,18 /1H, multiplet/, 8.07-a 8,32 /1H, multiplet/, 9,94 /2H, singlet/, which 9.22 /2H, singlet/

MS (m/z): 556 /M++1/

Example 58

The target connection /58/

so pl.: 95-98oC

Ignitible/, 2,63-3,02 /2H, multiplet/, 2,79 /3H, singlet/, 4,00 /1H, singlet/, 4,04 /1H, singlet/, 4,22 /1H, multiplet/, 4,65 /1H, multiplet/, 4,94 /1H, singlet/, 5,04 /1H, singlet/, 7,13 /2H, doublet, J=8,9 Hz/, to 7.77 /2H, doublet, J=8,9 Hz/, 8,00-8,18 /1H, multiplet/, 8,19-8,56 /1H, multiplet/, 8,86 /2H, singlet/, 9,12 /2H, singlet/

MS (m/z): 534 /M++1/

Example 59

The target connection /59/ obtained similarly to the method of Example 5.

Liofilizirovanny mixture of the target compounds /59/ 1 N. hydrochloric acid /200 ml/. Dried the resulting powder, which gave the target compound /59-/ /5,33 g/.

so pl.: 198oC /Razlog./

IR (nujol): 3270, 1690, 1635, 1600, 1540 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 /6N, doublet, J=6,4 Hz/, 1,8-2,05 /3H, multiplet/, 2,3 /2H, triplet, J=7 Hz/, 2,3-2,8 /2H, multiplet/, 3,97-4,22 /3H, multiplet/, 4,65 /1H, multiplet/, 7,14 /2H, doublet, J=8,9 Hz/, 7,8 /1H, doublet, J=8,5 Hz/, a 7.85 /2H, doublet, J=8,9 Hz/, 8,35 /1H, doublet, J=7,7 Hz/, 9,04 /2H, singlet/, 9,24 /2H, singlet/, 12,51 /1H, broad singlet/

Elemental analysis: C20H28N4O7HCl1H2O

Calculated: C 48,93 H 6,36 N 11,41 Cl 7,22

Found: C 48,77 H 6,52 N 11,22 Cl 6,98

Example 60

The mixture of starting compound /60/ /0.7 g/ tetrahydrofuran /3.5 ml/ 1 N. aqueous sodium hydroxide solution /3,49 ml/ was stirred at room temperature is, which precipitate by filtration, after receiving the target connection /60/ /0.5 g/.

so pl.: 220oC /Razlog./

IR (nujol): 3280, 1650, 1605, 1550, 1490 cm-1< / BR>
NMR (DMSO-d6+ TFA, 1.5 to 1,85 /4H, multiplet/, 2,19 /2N, tripleoption/, 2,3-3,0 /4H, multiplet/, 4,08 /2N, tripleoption/, or 4.31 /1H, multiplet/, br4.61 /1H, multiplet/, 6,65 /2H, doublet, J=8,4 Hz/, 6,97 /2H, doublet, J=8,4 Hz/, 7,15 /2H, doublet, J=8,9 Hz/, 7,81 /2H, doublet, J=8,8 Hz/, 7,83 /1H, doublet, J=7,8 Hz/, 8,15 /1H, doublet, J=8 Hz/, 8,98 /2H, singlet/, 9,13 /2H, singlet/

MS /m/z/: 515 /M++1/

Elemental analysis: C25H30N4O82H2O

Calculated: C 54,53 H 6,22 N 10,17

Found: C 54,32 H 6,04 N 10,08

Example 61

To a solution of starting compound /61/ /0,53 g/ triethylamine /0,20/ ml in methylene chloride /5 ml/ added acetic anhydride /of 0.066 ml/ under ice cooling, and the mixture was stirred at room temperature for 4 h, the Reaction mixture was diluted with water and extracted with ethyl acetate, the separated organic layer was washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate, water and salt solution, dried over magnesium sulfate and boiled away in the vacuum, which gave the target compound /61/ /raw/ /this connection is not allocated/.

From the specified connection /61/ received Sladek (nujol): 1640 /broad singlet/, 1530 cm-1< / BR>
NMR (DMSO-d6, ): 0,86 /6N, multiplet/, 1.71 and 1,76 /3H, each singlet/, 2,04 /1H, multiplet/, 2,80 and 3,03 /3H, each singlet/, 2,4-3,2 /4H, multiplet/, 3,8-5,1 /5H, multiplet/, 7,49 /2H, multiplet/, 7,72 /2H, multiplet/, 7,6-8,6 /3H, multiplet/, 9,15 and 9,26 /4H, each singlet/

MS (m/z): 535 /M++1/

Conditions for HPLC

column: MS-RUSK P-ODS-15 S-15 120A ODS 50 x 250

elution: CH3CN : 0,1% triperoxonane acid /15:85/

thread: 118 ml/min

retention time: 7.6 minutes

Example 62

The target connection /62/ received from the source connection /62/ by the method similar to the method of Examples 37 and 13,

so pl.: 175-177oC /Razlog./

IR (nujol): 3300, 1640, 1600, 1260 cm-1< / BR>
NMR (DMSO-d6, ): 0,75 /3H, triplet, J=7,2 Hz/, 1,60-1,72 /2H, multiplet/, 1,94 /2H, multiplet/, 2,31 /2N, tripleoption/, 2,60 of 2.68 /2H, multiplet/, 3,90 /1H, multiplet, 4,07 /2N, tripleoption/, 4,56 /1H, multiplet/, 7,09 /2H, doublet, J=8,9 Hz/, 7,56 /1H, doublet, J=6,6 Hz/, 7,72 /2H, doublet, J=8,9 Hz/, scored 8.38 /1H, doublet, J=7,6 Hz/, 8,75 /2H, broad singlet/, 11,18 /2H, broad singlet/

MS (m/z): 423 /M++1/

Example 63

The target connection /63/ received from the source connections /63/ and /63-In/ according to the method similar to the method of Example 22.

IR (nujol): 3300, 1720, 1640, 1250 cm-13,57 /3H, the singlet/, 3,98-4,04 /3H, multiplet/ and 4.65-4.72 in /1H, multiplet/, 5,06 /2H, singlet/, 5,11 /2H, singlet/, 6,99 /2H, doublet, J=8,9 Hz/, 7,18-7,26 /2H, multiplet/, 7,34-7,40 /10H, multiplet/, of 7.64-7,72 /1H, multiplet/, 7,99 /2H, doublet, J= 8,9 Hz/, 8,24 /1H, doublet, J=8,1 Hz/, of 8.37 /1H, doublet, J=7,6 Hz/, 8,46 /1H, doublet, J=4.0 Hz/, 9,15 /2H, broad singlet/

MS (m/z): 724 /M++1/

Example 64

The target connection /64/ obtained similarly to the method of Example 5.

so pl.: 120-125oC

IR (nujol): 3300, 1740, 1660, 1200 cm-1< / BR>
NMR (DMSO-d6, ): 1,91 /2H, multiplet/, 2,28 /2H, triplet, J=7,2 Hz/, 2,53-2,67 /2H, multiplet/, 3,20-to 3.33 /2H, multiplet/, 3,60 /3H, singlet/, 4,07 /2H, triplet, J=6,4 Hz/, 4,55 /1H, multiplet/, 4,72 /1H, multiplet/, 7,14 /21, doublet, J=8,9 Hz/, 7,55 /2H, doublet, J=7,8 Hz/, of 7.82 /2H, doublet, J= 8,9 Hz/, 8,02 /1H, multiplet/, 8,19 /1H, doublet, J=7,8 Hz/, 8,40 /1H, doublet, J= 7,8 Hz/, 8,63 /1H, doublet, J=4,9 Hz/, 9,13 /2H, singlet/, 9,16 /2H, singlet/

MS (m/z): 500 /M++1

Example 65

The target compound (65-a) received from the parent compound (65-a) and the source connection (65) according to the method similar to that described in Example 1.

The target compound (65) was obtained from the thus obtained target compound (65-A) according to the method similar to that described in Example 5.

so pl.: 50-54oC (Razlog.)

IR (nujol): 1640 (br is every - singlet), 3,8-4,2 (3H, multiplet), 4,7 (1H, multiplet), 4,94 and 5,06 ) (2H, each singlet), 7,13 (2H, doublet, J=7,4 Hz), 7,78 (2H, doublet, J=7,4 Hz), 7,78 and with 8.05 (1H, each doublet, each J= 8,8 Hz), 8,27, and to 8.57 (1H, each doublet, each J=8.0 Hz), 9,00 and 9,13 (4H, each singlet).

Example 66

The target compound (66-A) received from the parent compound (66-a) and the source connection (66-In) by the procedure similar to that described in Example 1.

The target compound (66-In) received from the thus obtained target compound (66-A) according to the method similar to that described in Example 5.

so pl.: 67-72oC

IR (nujol): 1640 (br), 1530 cm-1< / BR>
NMR (DMSO-d6, ): 0,86 (6N, multiplet), was 2.05 (1H, multiplet), 2,3-2,8 (2H, multiplet), 2,82 and 3,03 (3H, each singlet), 3,74, and the 3.89 (2H, each singlet), 3,8-4,2 (3H, multiplet), and 4.68 (1H, multiplet), and 7.4 (2H, multiplet), and 7.7 (2H, multiplet), 7,8 and of 7.97 (1H, multiplet and a doublet (J=8,5 Hz)), 8,3 and charged 8.52 (1H, each doublet, J=7.9 Hz), 9,24 and 9.28 are (4H, each singlet)

MS (m/z): 464 (M++1/

Example 67

The target compound (67-A) received from the parent compound (67-a) and the source connection (67) by the procedure similar to that described in Example 1.

The target compound (67) was obtained from the thus obtained target compound (67-a) method is NMR (DMSO-d6, ): 0,85 (6N, multiplet), was 2.05 (1H, multiplet), 2,4-3,0 (6N, multiplet), 2,78, and 2,96 (3H, each singlet), 3,9-4,2 (3H, multiplet), of 4.66 (1H, multiplet), of 7.48 (2H, multiplet), 7,71 (2H, multiplet), 7,7 and a 7.92 (1H, multiplet and a doublet (J=8,56 Hz), 8,28 and 8,46 (1H, each doublet, J=7.9 Hz), 9,15 and 9,24 (4H, each singlet)

MS (m/z): 478 (M++1)

Example 68

The target compound (68-A) received from the parent compound (68-a) and the source connection (68) by the procedure similar to that described in Example 1.

The target compound (68) was obtained from the thus obtained target compound (68-A) according to the method similar to that described in Example 5.

so pl.: 88-94oC

IR (nujol): 1610 (broad singlet), 1510 cm-1< / BR>
NMR (DMSO-d6, ): 0,85 (6N, multiplet), 1,71 and 1.76 (3H, each singlet), 2,08 (1H, multiplet), 2,80 and 3,03 (3H, each singlet), 2,4-3,2 (4H, multiplet), 3,8-5,1 (5H, multiplet), 7,49 (2H, multiplet), 7,72 (2H, multiplet), and 7.6 and 8.6 (3H, multiplet), 9,18 and 9,26 (4H, each singlet)

MS (m/z): 535 (M++1)

Example 69

The target compound (69-a) received from the parent compound (69-a) and the source connection (69) according to the method similar to that described in Example 1.

The target compound (69) was obtained from the thus obtained target compound (69-the 1610, 1490 cm-1< / BR>
NMR (DMSO-d6, ): of 1.05 (3H, doublet, J=6,1 Hz), 2,4-2,8 /3H, multiplet/, 2,80 and 3,01 /3H, each singlet/, 3,9-4,2 /3H, multiplet/, 4,7 /1H, multiplet/, 4,95 and 5,06 /2H, each singlet/, 7,13 /2H, doublet, J=8,9 Hz/, 7,58 and 7,74 /1H, doublet, J=8.5 Hz) and a multiplet/, 7,78 /2H, doublet, J=8,9 Hz/, and scored 8.38 8,70 /1H, each doublet, J=8,1 Hz/, from 9.0 to 9.3 /4H, multiplet/

MS /m/z/: 482 /M++1/

Example 70

The target connection /70/ received from the source connection /70/ original composition /70-In/ according to the method similar to that described in Example 1.

The target connection /70-To/ received from the target connection /70-a/ according to the method described in Example 5

so pl.: 170oC /colour / div./

IR (nujol): 3300, 3100, 1725, 1660, 1640, 1610, 1540, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 0,85 /6N, doublet, J=6,7 Hz/, 1,8-2,1 /3H, multiplet/, to 2.29 /2N, type triplet/, 2,3 was 2.76 /2H, multiplet/, 3,63 /3H, singlet/, 4,0-4,2 /3H, multiplet/, 4,65 /1H, multiplet/, 7,14 /2H, doublet, J=8,8 Hz/, 7,81 /2H, doublet, J=8,8 Hz/, 8,03 /1H, doublet, J=8,2 Hz/, 8,27 /1H, doublet, J=7,7 Hz/, 9,04 /2H, singlet/, 9,14 /2H, singlet/

FAB-MS: 451 /M++1/

Example 71

The target connection /71/ received from the source connection /71/ original composition /71-In/ according to the method similar to that described in Example 1.

The target connection /71-To/ received from the target seediness /colour / div./

IR (nujol): 3280, 3100, 1710, 1660, 1600, 1540, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 (6N, doublet, J=6.8 Hz), 1,16-1,8 (10H, multiplet), 1,94-2,2 (3H, multiplet), 2,33-2,8 (2H, multiplet), 3,9-of 4.25 (3H, multiplet) and 4.65 (1H, multiplet), to 7.15 (2H, doublet, J=8,9 Hz), of 7.70 (1H, doublet, J=8.7 Hz), 7,81 (2H, doublet, J=8,9 Hz), 8,21 (1H, doublet, J=7,8 Hz, 8,97 (2H, singlet)), 9,13 2H, singlet.

Example 72

The target compound (72-A) derived from the parent compound (72-a) and the source connection (72-In) by the procedure similar to that described in Example 1.

The target compound (72-In) received from the thus obtained target compound (72-A) according to the method similar to that described in Example 5.

so pl.: 210oC /colour / div./

IR (nujol): 3300, 3080, 1660, 1630, 1540, 1510 cm-1< / BR>
NMR (DMSO-d6, ): 1,3 (3H, triplet, J=6,9 Hz) and 1.51 (4H, multiplet), 2,1 (2H, type triplet), 2,3-3,1 (6N, multiplet), of 3.97 (2H, Quartet, J=6.9 Hz), 4,34 (1H, multiplet), 4,59 (1H, multiplet), 6,79 (2H, doublet, J=8.6 Hz), was 7.08 (2H, doublet, J=8,8 Hz), the 7.43 (2H, doublet, J=8,3 Hz), 7,74 (2H, doublet, J=8,3 Hz), 7,83 (1H, doublet, J=7,7 Hz), 8,11 (1H, doublet, J=7.9 Hz), 9,24 (4H, singlet)

Example 73

The target connection /73/ received their initial connection /73/ original composition /73-In/ according to the method similar to that described in Example 1.

The target connection /73-/ 5.

so pl.: 145oC /colour / div./

IR (nujol): 3320, 3100, 1660, 1610, 1530, 1490 cm-1< / BR>
NMR (DMSO-d6, ): of 1.02 (3H, doublet, J=6.3 Hz), of 1.97 (2H, multiplet), 2,31 (2H, type triplet), 2,35-2,8 (2H, multiplet), 3,95-of 4.25 (4H, multiplet), and 4.68 (1H, multiplet), to 7.15 (2H, doublet, J=8,9 Hz), 7,55 (1H, doublet, J= 8.6 Hz), 7,81 (2H, doublet, J=8,9 Hz), a 8.34 (1H, doublet, J=7.9 Hz), 8,98 (2H, singlet), 9,13 (2H, singlet)

Example 74

Target link /74/ received from the source of the link /74/ original link /74-In/ according to the method similar to that described in Example 1.

The target connection /74-In/ received from the thus obtained target compound /74/ by the procedure similar to that described in Example 5.

so pl.: 136oC /colour / div./

IR (nujol): 3300, 3100, 1720, 1670, 1540, 1490 cm-1< / BR>
NMR (DMSO-d6, ): of 1.02 (3H, doublet, J=6.3 Hz), 1,53 (4H, multiplet), of 2.15 (2H, type triplet), 2,35 and 2.9 (4H, multiplet), 4,0-4,2 (2H, multiplet) and 4.65 (1H, multiplet), was 7.45 (2H, doublet, J=8,3 Hz), 7,51 (1H, doublet, J= 8.6 Hz), 7,74 (2H, doublet, J=8,3 Hz), 8,24 (1H, doublet, J=7.9 Hz), 9,15 (2H, singlet), 9,23 (2H, singlet)

Example 75

The target connection /75/ received from the source connection /75/ original composition /75-In/ according to the method similar to that described in Example 1.

The target connection /75-To/ received from the resulting tar>C /colour / div./

IR (nujol): 3280, 1630, 1600, 1540, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 (6N, multiplet), 1,34-1,72 (3H, multiplet), of 1.97 (2H, multiplet), 2,15 and-2.8 (4H, multiplet), 3,9-4,27 (3H, multiplet), of 4.57 (1H, multiplet), 7,11 (2H, doublet, J=8,8 Hz), 7,68 (1H, doublet, J=7,8 Hz), of 7.75 (2H, doublet, J=8.7 Hz), 8,29 (1H, doublet, J=7.8 Hz), 8,82 (1,5 H, singlet), or 10.9 (1.5 N, singlet)

Example 76

The target connection /76-A/ received from the source connection /76-A/ and the source connection /76-In/ according to the method similar to that described in Example 1.

The target connection /76-In/ received from the target connection /76-A/, thus obtained according to the method similar to that described in Example 5.

so pl.: 204oC /colour / div./

IR (nujol): 3275, 1625, 1535, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 0,7-1,0 (6N, multiplet), 1,0-of 1.57 (2H, multiplet), 1,74 (1H, multiplet), 1,98 /2H, multiplet/, was 2.34 (2H, type triplet), 2,3-2,8 (2H, multiplet), of 3.97 (1H, multiplet), 4.09 to (2N, type triplet), 4,56 (1H, multiplet), 7,10 (2H, doublet, J=8,8 Hz), of 7.48 (2H, doublet, J=7.8 Hz), 7,73 (2H, doublet, J=8.6 Hz), 8,39 (1H, doublet, J=7,6 Hz), 8,73 (1,5 H, singlet), 11,29 (1,5 H, singlet)

Example 77

The target connection /77/ received from the source connection /77/ original composition /77-In/ according to the method similar to that described in Example 1.

The target connection /are 5.

IR (nujol): 3275, 3080, 1700, 1630, 1600, 1540, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,7-1,0 (6N, multiplet), 1,0-is 1.51 (2H, multiplet), and 1.7 (5H, multiplet), 2,19 (2H, type triplet), 2,25-and 2.79 (2H, multiplet), 3,97-of 4.25 (3H, multiplet), 4,63 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,76 (1H, doublet, J=9.5 Hz), 7,80 (2H, doublet, J=8,9 Hz), 8,24 (1H, doublet, J=7,7 Hz), of 9.02 (2H, singlet), 9,13 (2H, singlet), to 12.52 (1,5 H, singlet)

Example 78

The target connection /78/ received from the source connection /78-A/ and the parent compound by the procedure similar to that described in Example 1.

The target connection /78-In/ received from the target connection /78-A/, thus obtained according to the method similar to that described in Example 5.

so pl.: 118oC /colour / div./

IR (nujol): 3300, 3080, 1655, 1600, 1530, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,7-0,92 (6N, multiplet), 1,0-1,8 (M, multiplet), and 2.14 (2H, type triplet), 2,35-2,77 (2H, multiplet), 3,94-4,27 (3H, multiplet), 4,63 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,73 (1H, doublet, J= 8.5 Hz), 7,80 (2H, doublet, J=8,9 Hz) to 8.12 (1H, doublet, J=7,7 Hz), 8,83 (2H, singlet), 9,13 (2H, singlet)

Example 79

The target connection /79/ received from the source connection /79/ original composition /79-In/ according to the method similar to that described in Example 1.

The target connection /79-To/ received from the target is l: 196-200oC

IR (nujol): 3300, 1710, 1640, 1615, 1540, 1490 cm-1< / BR>
NMR (DMSO-d6, ): or 0.83 (3H, broad singlet), 1,22 (4H, multiplet), of 1.62 (2H, multiplet), a 1.96 (2H, multiplet), to 2.29 (2H, multiplet), 2,2-2,8 (2H, multiplet), 4.09 to (3H, multiplet), to 4.62 (1H, multiplet), 7,13 (2H, doublet, J=8.5 Hz), 7,81 (2H, doublet, J=8.5 Hz), 7,80 (1H, multiplet), 8,24 (1H, multiplet), 9,10 and 9,40 (4H, each singlet)

Example 80

The target connection /80/ received from the source connection /80/ original composition /80-B/ by the procedure similar to that described in Example 1.

The target connection /80-To/ received from the target connection /80-a/, thus obtained according to the method similar to that described in Example 5.

so pl.: 216oC /colour / div./

IR (nujol): 3275, 1680, 1630, 1600, 1540, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,81 (3H, type triplet), 1,19 (4H, multiplet), 1,4-1,8 (2H, multiplet), of 1.85 and 2.1 (2H, multiplet), 2,2-2,9 (4H, multiplet), 3,93 (1H, multiplet), 4,08 (2H, multiplet), 4,56 (1H, multiplet), to 7.09 (2H, doublet, J=8,9 Hz), EUR 7.57 (1H, doublet, J=6,9 Hz), 7,72 2H, doublet, J=8,8 Hz), of 8.37 (1H, doublet, J=7.9 Hz), the rate of 8.75 (2H, singlet), 11,19 (2H, singlet)

Example 81

The target connection /81/ received from the source of the link /81/ original composition /81-In/ according to the method similar to that described in Example 1.

Target when authorized in Example 5.

so pl.: 175oC /colour / div./

IR (nujol): 3300, 3100, 1660, 1600, 1530, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,87 (N, singlet), 1,45-1,71 (2H, multiplet), was 1.94 (2H, multiplet), and 2.27 (2H, type triplet), 2,3-2,8 (2H, multiplet), 4.09 to (2N, type triplet), is 4.21 (1H, multiplet), 4,59 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,82 (2H, doublet, J=8,9 Hz), 8,02 (1H, doublet, J=8,2 Hz)that is 8.16 (1H, doublet, J=8.0 Hz), 9,06 (2H, singlet), 9,14 (2H, singlet)

Example 82

The target connection /82/ received from the source connection /82/ source connection /82-In/ according to the method similar to that described in Example 1.

The target connection /82-In/ received from the target connection /82-a/, thus obtained according to the method similar to that described in Example 5.

so pl.: 202oC /colour / div./

IR (nujol): 3270, 3075, 1690, 1640, 1600, 1530, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 1,68 (4H, multiplet), of 2.15 (2H, type triplet), 2,3-2,75 (2H, multiplet), 2,78 is 3.15 (2H, multiplet), 4,07 (2H, type triplet), 4,39 (1H, multiplet), 4,6 (1H, multiplet), 7,05-7,37 (7H, multiplet), 7,81 (2H, doublet, J=8,9 Hz), 7,92 (1H, doublet, J=7,7 Hz), 8,13 (1H, doublet, J=8 Hz), and 9.1 (2H, singlet), 9,14 (2H, singlet), to 12.58 (1H, singlet)

FAB-MS: 499 /M++1/

Example 83

The target connection /83/ received from the source of the link /83/ original composition /83-In/ according to the methods Anuchino thus according to the method similar to that described in Example 5.

so pl.: 168-170oC /colour / div./

IR (nujol): 3300, 1670, 1200 cm-1< / BR>
NMR (DMSO-d6, ): or 0.83 (3H, triplet, J=7.4 Hz), 1,21-to 1.38 (2H, multiplet), 1,40 by 1.68 (4H, multiplet), 2,12 (2N type of triplet), 2,63-2,71 (6N, multiplet), is 4.15 (1H, multiplet), br4.61 (1H, multiplet), 7,44 (2H, doublet, J= 8,9 Hz), 7,73 (2H, doublet, J=8,9 Hz), 7,92 (1H, doublet, J=7.9 Hz), 8,11 (1H, doublet, J= 7,8 Hz), 9,01 (2H, singlet), which 9.22 (2H, singlet), 12,41 2H, broad singlet)

MS (m/z): 435 /M++1/

Example 84

The target connection /84/ received from the source of the link /84/ original composition /84-In/ according to the method similar to that described in Example 1.

The target connection /84-In/ received from the target connection /84-A/, thus obtained according to the method similar to that described in Example 5.

IR (nujol): 3280, 3100, 1650, 1605, 1530, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 0,88 (6N, doublet, J=6.8 Hz), 1,6-2,44 (N, multiplet), 3,9-4,2 (3H, multiplet), to 4.38 (1H, multiplet), 7,14 (2H, doublet, J= 8,9 Hz), 7,81 (2H, doublet, J=8,9 Hz), 7,95 (1H, doublet, J=8,3 Hz), 8,08 (1H, doublet, J=8 Hz), 9,05 (2H, singlet), 9,14 (2H, singlet)

Example 85

The target connection /85/ received from the source connection /85/ original composition /85-In/ according to the method similar to that described in Example 1.

Target soy is Oh in Example 5.

so pl.: 199oC /colour / div./

IR (nujol): 3320, 3100, 1700, 1660, 1610, 1530, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 0,85 (6N, doublet, J=6.6 Hz), was 2.05 (1H, multiplet), of 2.5-2.8 (2H, multiplet), of 4.12 (1H, multiplet), and 4.68 (2H, singlet), 4,74 (1H, multiplet), to 7.15 (2H, doublet, J=8,9 Hz), 7,81 (2H, doublet, J=8,9 Hz), of 7.96 (1H, doublet, J=9.5 Hz), 8,48 (1H, doublet, J=8 Hz), 9,04 (2H, singlet), 9,16 (2H, singlet), 12,54 (1H, singlet)

Example 86

The target connection /86/ received from the source connection /86/ original composition /86/ by the procedure similar to that described in Example 1.

The target connection /86/ received from the target connection /86/, thus obtained according to the method similar to that described in Example 5.

so pl.: 150oC /colour / div./

IR (nujol): 3300, 3100, 1660, 1610, 1540, 1490 cm-1< / BR>
NMR (DMSO-d6, ): 0,82 (3H, doublet, J=6.2 Hz), of 0.87 (3H, doublet, J=6.2 Hz), 1,25-1,85 (N, multiplet) by 2.13 (2H, type triplet), 2,3-2,75 (2H, multiplet), 4,07 (2H, type triplet), 4,19 (1H, multiplet), br4.61 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,81 (2H, doublet, J=8,9 Hz), of 7.95 (1H, doublet, J= 8.0 Hz), 8,11 (1H, doublet, J=8.0 Hz), 8,96 (2H, singlet), 9,13 (2H, singlet)

Example 87

The target connection /87/ received from the source connection /87/ original composition /87-/ by the procedure similar to that described in Example 1.

so pl.: 189-191oC

IR (nujol): 1665, 1615, 1525, 1495 cm-1< / BR>
NMR (DMSO-d6, ): 0,91 (N, singlet), of 1.97 (2H, multiplet), 2,2-2,6 (3H, multiplet), 2,70 (1H, double doublet, J=16,7 Hz, J=5,9 Hz), 4,0-4,2 (3H, multiplet), of 4.66 (1H, multiplet), 7,14 (2H, doublet, J=8,9 Hz), 7,66 (1H, doublet, J=9,2 Hz), 7,83 (2H, doublet, J=8,9 Hz), 8,40 (1H, doublet, J=7,6 Hz), 9,16 and of 9.21 (4H, each singlet)

MS (m/z): 451,2 /M++1/

Example 88

The target connection /88/ received from the source of the link /88-source connection /88-In/ according to the method similar to that described in Example 1.

The target connection /88-To/ received from the target connection /88 And/ thus obtained according to the method similar to that described in Example 5.

so pl.: 76-82oC

IR (nujol): 1640, 1520 cm-1< / BR>
NMR (DMSO-d6, ): 0,93 0,92 and (N, each singlet), 2,3-2,8 (2H, multiplet), and 3,00 2,80 (3H, each singlet), 3,8-4,2 (3H, multiplet), to 4.73 (1H, multiplet), 4,94 and is 5.06 (2H, each singlet), 7,13 (2H, doublet, J=8,9 Hz), 7,78 (2H, doublet, J=8,9 Hz), and 7.6 to 8.0 (1H, multiplet), of 8.37 and 8,65 (1H, each doublet, J=7,8 Hz and 7.7 Hz), and the remaining 9.08 9,14 (4H, each singlet)

MS (m/z): 494 /M++1/

Example 89

The target connection /89/ received from the source connection /89/ original composition /89-In/ according to the method similar to that described in Example 1.

so pl.: 170oC /colour / div./

IR (nujol): 3320, 1700, 1660, 1610, 1540, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,87 (6N, doublet, J=6,7 Hz), was 2.05 (1H, multiplet), was 2.34 (2H, type triplet), 2,35-2,8 (2H, multiplet), to 3.34 (2H, multiplet), of 4.12 (1H, multiplet), br4.61 (2H, singlet), with 4.64 (1H, multiplet), to 7.15 (2H, doublet, J=8,9 Hz), 7,81 (2H, doublet, J=8,9 Hz), 7,82 (1H, doublet, J=8,5 Hz and 8.2 (1H, type a triplet)), 8,32 (1H, doublet, J=7,7 Hz), 9,03 (2H, singlet), 9,16 (2H, singlet)

Example 90

The target connection /90/ received from the source connection /90/ by the procedure similar to that described in Method get 18.

so pl.: 210oC /colour / div./

IR (nujol): 3300, 1730, 1650, 1600, 1550 cm-1< / BR>
NMR (DMSO-d6, ): 0,83 (6N, doublet, J=6.4 Hz), equal to 1.82 (2H, type triplet), was 2.05 (1H, multiplet), 2.4 to 2.8 (2H, multiplet), 3,14 (2H, multiplet), of 4.05 (2H, type triplet), to 4.23 (1H, multiplet), 4,6 (1H, multiplet), is 5.06 (2H, singlet), 5,10, (2H, singlet), from 6.25 to 6.4 (2H, multiplet), 7,13 (2H, doublet, J= 8,9 Hz), 7,34 (10H, multiplet), 7,79 (2H, doublet, J=8,9 Hz), 8,16 (1H, doublet, J=8,3 Hz),

FAB-MS: 632 /M+1/

Example 91

The target connection /91/ received from the source connection /91/ by the procedure similar to that described in Method get 18

so pl.: 190oC /colour / div./

IR (nujol): 3300, 3100, 1725, 1670, 1630, 1610, 1550, 1490 cm-1< / BR>
iple), a 3.06 (2H, multiplet), 4,07 (2H, triplet, J=6,1 Hz), 4,22 (1H, multiplet), to 4.62 (1H, multiplet), is 5.06 (2H, singlet), 5,11 (2H, singlet), 6,2-6,4 (2H, multiplet), 7,14 (2H, doublet, J= 8,9 Hz), 7,35 (10H, multiplet), 7,81 (2H, doublet, J= 8,9 Hz), 8,16 (1H, doublet, J=8,3 Hz), 9,03 (2H, singlet), 9,14 (2H, singlet)

The following connections /Examples 92 and 93/ received according to the method similar to that described in Example 5.

Example 92

The target connection /92/

so pl.: 188oC /colour / div./

IR (nujol): 3300, 1710, 1650, 1600, 1550 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 (6N, doublet, J=5.4 Hz), of 1.85 (2H, triplet, J=6.4 Hz), 1,9-of 2.28 (1H, multiplet), 2,35-of 2.72 (2H, multiplet), 3,17 (2H, multiplet), of 4.05 (1H, multiplet), 4,10 (2H, type triplet), of 4.49 (1H, multiplet), 6.42 per (2H, multiplet), to 7.15 (2H, doublet, J=8,8 Hz), of 7.75 (1H, doublet, J= 8,8 Hz), to 7.84 (2H, doublet, J=8,8 Hz), 9,0 /2H, singlet/, 9,23 /2H, singlet/

MS: 452 /M+1/

Example 93

The target connection /93/

so pl.: 183oC /colour / div./

IR (nujol): 3310, 1700, 1650, 1635, 1600, 1560, 1540, 1480 cm-1< / BR>
NMR (DMSO-d6, ): 0,84 /6N, doublet, J=5.7 Hz/, 1,4-1,8 /4H, multiplet/, 2,04 /1H, multiplet/, 2,3-2,5 /2H, multiplet/, 3,07 /2H, multiplet/, 4,0-4,2 /3H, multiplet/, 4,48 /1H, multiplet/, 6,2-6,45 /2H, multiplet/, 7,14 /2H, doublet, J=8,8 Hz/, 7,73 /1H, doublet, J=8,9 Hz/, 7,81 /2N, doublet, J= 8,8 Hz/, 9,02 /2H, singlet/, 9,14 /2H, singlet/, 12,51 /1H, broad singlet/

so pl.: 133-140oC.

IR (nujol): 1620-1660 /wide/, 1530 cm-1< / BR>
NMR (DMSO-d6, ): 0,86 /6N, doublet, J=6,8 Hz/, 2,04 /1H, multiplet/, 2,2-2,8 /2H, multiplet/, 2,80 and 3.0 /3H, each singlet/, 3,8-4,2 /3H, multiplet/, 4,6 /1H, multiplet/, 5,06 and 5,41 /2H, each singlet/, 7,13 /2H, doublet, J=8,8 Hz/, 8,00 /2H, doublet, J=8,8 Hz/, 7,80-8,20 /1H, multiplet/, 8,27 and 8,68 /1H, each doublet, J=7,8 Hz/, 9,05 and a 9.25 /4H, each singlet/

MS (m/z): 480 /M++1/

Example 95

The mixture of starting compound /95/ /19,61 g/ and water /50 ml/ brought to pH 6,05 aqueous solution of ammonia and the mixture liofilizirovanny. The resulting powder was dried and identified the target connection /95/ /19,17 g/.

So pl.: 167-170oC

IR (nujol): 3260, 1640 wide/, 1540, 1485 cm-1< / BR>
NMR (DMSO-d6, ): 0,80 /6N, doublet, J=4,9 Hz/, 2,03 /1H, multiplet/, 2,2-2,8 /2H, multiplet/, 2,80 and 3,03 /3H, each singlet/, 3,8-4,7 /4H, multiplet/, 4,94 and 5,04 /2H, each singlet/, 7,10 /2H, doublet, J=8,2 Hz/, to 7.59 /1H, multiplet/, 7,73 /2H, multiplet/, 8.45 and 8,72 /1H, multiplet/

MS (m/z): 480 /M++1/

1. Derivatives of the peptides of General formula I

< / BR>
where R1aryl, which may contain from 1 to 3 substituents selected from the group consisting of amidino and protection is UP> carboxy - or protected carboxypropyl;

AND1alkylene, which may contain from 1 to 3 substituents selected from amino and protected amino;

AND2a group of the formula

< / BR>
where R4lower alkyl, or a2a group of the formula-NH-CH2-CH2-CO-;

AND3lowest alkylene, which may contain 1 to 3 suitable substituent selected from lower alkyl, mono-, or di-, or triphenyl(lower)alkyl containing 1 to 3 substituent selected from the group consisting of hydroxy, lower alkoxy, and protected hydroxy, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, (cyclo)lower(alkyl) (lower)alkyl, pyridyl(lower)alkyl;

l, m and n are the same or different, an integer of 0 or 1, provided that A2is not a group of the formula

-NHCH2CH2CO-,

if l is an integer equal to 0,

or their pharmaceutically acceptable salts.

2. Derivatives under item 1, where l 1.

3. Derivatives under item 2, where R1aryl, which may contain from 1 to 3 substituents selected from the group comprising amidino-, N-phenyl(lower)alkoxycarbonylmethyl, AND1alkylene, which may contain from 1 to 7 carbon atoms, AND3lowest alkylen, to ISSI)alkyl, which may contain from 1 to 3 suitable substituents selected from the group comprising hydroxy, phenyl(lower)alkoxy and lower alkoxygroup, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, (cyclo)lower(alkyl) (lower)alkyl and pyridyl(lower)alkyl.

4. Derivatives under item 3, where m n 0.

5. Derivatives under item 4, where a3lowest alkylene, which may contain a Deputy selected from the group consisting of lower alkyl, phenyl(lower)alkyl, which may contain hydroxy, phenyl(lower)alkoxy - or lower alkoxygroup, and [cyclo(lower)alkyl] (lower)alkyl.

6. Derivatives under item 5, where R1phenyl containing amidinopropane, R2carboxy(lower)alkyl, R3carboxypropyl, AND3lowest alkylene containing as a substituent a lower alkyl.

7. Derivatives under item 6, where R14-lidinopril, R2carboxymethyl, AND1trimethylene, And methylene containing as Deputy isopropyl.

8. Derivatives of the peptides of General formula I on p. 1 or their pharmaceutically acceptable salts, possessing inhibitory activity against blood clots.

9. The method of obtaining derivatives of the peptides of General formula I



< / BR>
where R1AND1, l, and m have the above values,

or its reactive derivative at carboxypropyl,

or their salts enter into an interaction with compounds of General formula III

< / BR>
where R2R3AND2AND3and n have the specified values,

or their salts, and from the resulting derivatives of the formula I, where R1aryl containing amidinopropane, otscheplaut midinotate group, or derived from formula I where R2protected carboxy(lower)alkyl, otscheplaut carboxyamide group to obtain compounds of General formula I, where R2carboxy(lower)Akil, or obtained from compounds of the formula I, where a3lowest alkylene containing mono(or di-or tri-) (protected hydroxy)-phenyl(lower) alkyl, or salts, or obtained from compounds of the formula I, where R3protected carboxypropyl, or their salts otscheplaut carboxyamide group to form compounds of the formula I, where R3carboxypropyl, or their salts.

10. The method of obtaining derivatives of the peptides of General formula I

< / BR>
where the values of the radicals listed in paragraph 1,

or their pharmaceutically acceptable salts, characterized in that compounds of the formula IV
nye in p. 1 values

or their salts enter into an interaction with compounds of formula V

< / BR>
where R2, R3and3are specified in paragraph 1 values

or their reactive to amino derivatives or their salts.

11. Pharmaceutical composition having inhibitory activity against blood clots, characterized in that as the active ingredient contains the derivatives of the peptides of formula I under item 1 in an effective amount.

12. Method of prevention and suppression of thrombosis in a mammal by introducing substances with inhibitory activity against blood clots, characterized in that the injected derivatives of the formula I on p. 1 in a daily dose of 0.001 to 200 mg/kg of body weight in 1 4 admission.

 

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FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.

EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry and drugs.

SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.

EFFECT: effective interleikyn-1beta converting enzyme inhibitors.

64 cl, 35 ex, 35 tbl, 21 dwg

FIELD: medicine, gastroenterology.

SUBSTANCE: traditional eradication therapy should be supplemented with licopid at the dosage of 10 mg per os once daily before breakfast for 10 d. The present innovation prevents transfer of microorganisms into inactive form, accelerates restoration of mucosal epithelial layer in gastroduodenal area, provides complete eradication of microorganisms, that in its turn, favors to prevent disease exacerbation and restoration of gastroduodenal functions.

EFFECT: higher efficiency of therapy.

3 dwg, 2 ex

FIELD: biotechnology, biochemistry.

SUBSTANCE: invention relates to producing the biologically active complex eliciting antioxidant and immunomodulating activity and used in medicine, cosmetics, veterinary science and food industry. The biologically active complex preparing by enzymatic hydrolysis of muscle tissue represents complex of biologically active compounds involving carnosine and anserine in the amount 85-97 wt.-% of the native content of these components in poultry muscle tissue, 1-7 weight parts of amino acids, 0.5-12 weight parts of oligopeptides of molecular mass 10 kDa, not above, and 0.1-15 weight parts of cyclic and polycyclic phenolic compounds as measured for 1 weight part of carnosine and anserine in the complex. This complex is prepared by enzymatic hydrolysis of milled and homogenized water muscle tissue in preferable dilution homogenate with water in the range 0.2-0.6 and with using proteolytic enzymes in the amount 2-5 wt.-% of the protein content and working at pH 4.5-8.5 and at enhanced temperature being preferably at 45-65°C. Product is isolated as extract or powder prepared in drying the extract. Invention provides enhancing effectiveness of the claimed complex.

EFFECT: improved method for preparing, valuable properties of complex.

7 cl, 6 tbl, 6 ex

FIELD: medicine, cardiology, gastroenterology.

SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.

EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new inhibitors of thrombin of the formula (I)

,

method for their preparing, intermediate compounds used for their preparing of the formula (II)

and a pharmaceutical composition comprising compounds of the formula (I). Invention provides enhancing effectiveness in inhibition of thrombin.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

23 cl, 61 ex

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