Derivatives aydinonat and pharmaceutical composition

 

(57) Abstract:

The proposed derivatives aydinonat General formula (I), where R1represents hydrogen or a group-A-W-R4, A denotes a group of formula a group of the formula or-SO2-, X is oxygen atom or sulfur, W is a simple bond or a group of the formula NR5, R4is hydroxyl, lower alkoxy, lower alkyl which may be substituted, cycloalkyl, which may be substituted, aryl which may be substituted, or heteroaryl containing 1-2 heteroatoms selected from sulfur and nitrogen, which may be substituted, provided that when W is a group of the formula NR5, R4may additionally represent a hydrogen atom, but not be hydroxyl or lower alkoxygroup, R5is a hydrogen atom, carbarnoyl, lower alkoxycarbonyl, mono - or di-lower alkylaminocarbonyl, lower alkylsulfonyl, mono - or di - lower alkylaminocarbonyl, lower alkyl which may be substituted, or lower alkanoyl, which may be substituted; R2represents lower alkyl; R3represents a hydrogen atom or a lower alkoxycarbonyl; represents the lowest alkylene or carbonyl; n = 0 or 1, or their pharmaceutically acceptable salts, which cell factor X coagulation, and useful for use as agents for preventing the formation of blood clots. Proposed intermediate compounds for their preparation and pharmaceutical compositions containing these derivatives. 4 C. and 7 C. p. F.-ly, 11 PL.

Scope

The invention relates to a derived aydinonat or salts thereof, useful for use as a medicine, particularly as an inhibitor of activated factor X coagulation.

Art

Despite the changes that have occurred in the life style of the population of Europe and America, and the increase in recent years in the number of older age groups, the number of patients suffering from thromboembolic disease, including myocardial infarction, cerebral and peripheral arterial thrombosis, from year to year increased, and the social significance of their treatment grew stronger and stronger. As well as fibrinolysis and antiplatelet therapy, anticoagulant therapy is part of the treatment method and prevention of thrombosis (Sogo Rinsyo, 41, 2141-2145, 1989). In particular, the security, which is opposed to long-term medication, as well as accurate and correct expression of anticoagulant aktywnych in the world practice as the sole anticoagulant for oral administration. However, this medication is extremely difficult to apply in clinical practice, since it is difficult to control its anticoagulatory ability, due to the characteristics based on the mechanism of its action (J. Clinical Pharmacology, 32, 196-209, 1992; and N. Eng. Mod. , 324, 26, 1865-1875, 1991), therefore, the main focus was on the development of a more useful and easy to use anticoagulant.

Because thrombin controls the conversion of fibrinogen into fibrin, which is the final stage of coagulation, and is closely associated with the activation and aggregation of platelets (T-PA and Pro-UK, ed. O. Matsuo, Gakusai Kikaku, pp. 5-40, Blood Coagulation, 1986), its inhibitor was the center for the study of the process of anticoagulation and became the object on which aimed to develop new drugs. However, until now in the literature no reports of thrombin inhibitors, prescribed orally, due to their low bioavailability when administered orally and problems associated with the security application (Biomed. Biochim. Acta, 44, 1201-1210, 1985).

Activated factor X coagulation is a key enzyme, which is located at the junction of the external and internal cascade reactions of blood coagulation and is localized to the left and up from the about, than the inhibition of thrombin, and that this inhibitor was able to slow down the coagulation system in a specific way (THROMBOSIS RESEARCH, 19, 339-349, 1980).

As a reference, which discloses a compound that has inhibitory activity against activated factor X clotting can lead unexamined published Japanese patent application (Kokai) No. 5-208946, which describes the derived amidinohydrolase following General formula or its salt

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(in the formula, where is the number of given values is omitted, A is alkylene containing 1-4 carbon atoms which may be substituted by 1-2 hydroxyalkyl, carboxyla, alkoxycarbonyl, carboxylation or alkoxycarbonylmethyl; Y represents a saturated or unsaturated 5-6-membered heterocyclic group or a cyclic hydrocarbon group or the like, which may have a Deputy,... the rest of the values are omitted).

However, the connection is declared in the present invention is a new compound, which clearly differs from the above-described structure, since amidinothiourea or amidinothiourea group is associated with substituted phenyl posredstwom higher activity as inhibitor of activated blood coagulation factor X, in comparison with the known.

Description of the invention

In order to obtain the compounds having excellent activity inhibitor of activated factor X coagulation, the inventors have conducted extensive studies, which found that the connection that amidinothiourea or amidinothiourea group is linked to a substituted phenyl group via a nitrogen atom, in particular, the connection, where a group of the formula-A-W-R4substituted by a nitrogen atom, has a markedly superior inhibitory activity against activated blood coagulation factor X, thereby leading to the achievement of problems.

Accordingly, the present invention relates to a derived aydinonat General formula (I) or its pharmaceutically acceptable salt

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where the symbols have the following meanings:

R1represents hydrogen or a group of the formula-A-W-R4where A group of formula a group of the formula or-SO2-,

X is oxygen atom or sulfur, W is a simple bond or a group of the formula NR5, R4is hydroxyl, lower alkoxy, lower alkyl which may be substituted, cycloalkyl, which can be W - a group of the formula NR5, R4may additionally represent a hydrogen atom, but not be hydroxyl or lower alkoxygroup, R5is a hydrogen atom, carbarnoyl, lower alkoxycarbonyl, mono - or di-lower alkylaminocarbonyl, lower alkylsulfonyl, mono - or di-lower alkylaminocarbonyl, lower alkyl which may be substituted, or lower alkanoyl, which may be substituted;

R2represents lower alkyl;

R3represents a hydrogen atom, halogen atom, carboxyl, amino, cyano, nitro, hydroxyl, lower alkoxy, lower alkyl or lower alkoxycarbonyl;

Represents a lower alkylene or carbonyl; n = 0 or 1. The same values of the substituents used in the future.

Connection (1), as claimed in the present invention, preferably is a derivative aydinonat or its pharmaceutically acceptable salt, where the lower alkyl which may be substituted in the value of R4or R5cycloalkyl, which can be substituted in the value of R4or lower alkanoyl, which can be substituted in the value of R5represents lower alkyl, cycloalkyl or lower alkanoyl, which may be substituted klenot substituted in the value of R4represents aryl or heteroaryl, which may be substituted by a member of the following group of substituents D, and group C includes the following substituents: halogen, carboxyl, carbarnoyl, amino, cyano, nitro, lower alkanoyl, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino, aryl, aralkylated, aryloxy, mercapto, lower alkylthio, lower alkylthiomethyl, hydroxyl or mono - or di - lower alkylaminocarbonyl, and group D consists of the following substituents: halogen, carboxyl, amino, cyano, nitro, hydroxyl, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino, lower alkanoyl or lower alkyl which may be substituted by a member of group C;

more preferably, it is a derivative aydinonat or its pharmaceutically acceptable salt, where R4represents a hydroxy-group; lower alkoxy; lower alkyl which may be substituted with halogen, carboxyla, carbamoyl, amino, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino or phenyl; cycloalkyl, which may be substituted with halogen, carboxyla, carbamoyl, amino, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino is whether lower alkoxy; heteroaryl, which may be substituted with halogen, carboxyla, amino, nitro, lower alkoxycarbonyl or lower alkoxy (provided that when W is a group of the formula NR5, R4may additionally represent a hydrogen atom, but not be hydroxyl or lower alkoxygroup),

R5is a hydrogen atom; carbarnoyl; carboxyl; lower alkoxycarbonyl; lower alkanoyl; mono - or di-lower alkylaminocarbonyl; or lower alkyl which may be substituted with halogen, carbamoyl, amino, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino or phenyl; and

R3represents a hydrogen atom, halogen atom, carboxyl, lower alkoxy, lower alkyl or lower alkoxycarbonyl.

Most preferred is derived aydinonat or its pharmaceutically acceptable salt, where a group of the formula-A-W-R4represents a group selected from lower alkanoyl, which may be substituted by lower alkoxy, lower alkoxycarbonyl or mono - or di-lower alkylamino; aminocarbonyl, which may be substituted by lower alkoxycarbonyl; lower alkylsulfonyl, which may be substituted with halogen, carboxyla, carbamoyl, Nissi the sludge or lower alkoxycarbonyl; aminosulfonyl, which may be substituted by lower alkoxycarbonyl; mono - or di-lower alkylaminocarbonyl, which can be substituted by carboxyla, carbamoyl or lower alkoxycarbonyl; N-lower alkyl-N-lower alkoxycarbonylmethyl, which can be substituted by carboxyla or lower alkoxycarbonyl; benzoyl which may be substituted by carboxyla, lower alkoxycarbonyl, halogen or lower alkoxy; benzosulfimide, which may be substituted amino, nitro, carboxyla or lower alkoxycarbonyl; Naftoli, mono-lower alkylaminocarbonyl; pyridylcarbonyl; taylorsville; aminoacetyl; or cycloalkylcarbonyl; and R3represents a hydrogen atom or a lower alkoxycarbonyl.

In addition, preferred is derived aydinonat or its pharmaceutically acceptable salt, where A group of the formula or the group-SO2-.

Another objective of the present invention is to obtain the compound of General formula (I') or its salt, which is useful for use as an intermediate to obtain the target compounds of formula (I).

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Another objective of the present invention is cry as the active ingredient contains a derivative of amidinohydrolase General formula (I) or its salt.

The following is a detailed description of the present invention.

Unless otherwise specified, in the definition of groups in the description, the term "lower" means a straight or branched carbon chain having from 1 to 6 carbon atoms.

Therefore illustrative examples of "lower alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2 - methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl from which group having from 1 to 3 carbon atoms, are preferred, and methyl and ethyl are particularly preferred.

Illustrative examples of "lower alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentylamine, neopentylene, tert-pentyloxy, 2-methylbutoxy, 1,2-DIMETHYLPROPANE, 1 ethylpropoxy, hexyloxy and others, isohexyl, 1-methylpentyl, 2-methylpentyl is methoxy, ethoxy are particularly preferred.

Examples of "cycloalkyl include cycloalkyl having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, of which cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the like are preferred.

Illustrative examples of "aryl" includes aryl hydrocarbon ring group having 6 to 14 carbon atoms, such as phenyl, naphthyl, biphenyl, antril and the like, of which the phenyl and naphthyl are preferred.

"Heteroaryl" represents a single or condensed ring containing 1 to 3 heteroatoms, including oxygen, nitrogen, sulfur, and so on, and their illustrative examples include furyl, Tinel, pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, isoxazolyl, pyridyl, pyrimidinyl, hinely, ethanolic, hintline, hemolysins, honokalani, cinnoline, benzimidazolyl, imidazopyridine, naphthyridine, 1,2-benzisoxazole, benzoxazole, benzothiazole, oxazolopyridine, isothiazolones, sensational and the like, of which such heteroaryl groups, as furyl, thienyl, pyrrolyl, imidazolyl, pyridyl and the like are preferred.

"Lower alkoxycarbonyl is, and carboxyl by esterification, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second - butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol, tert - pentyloxybenzoyl, hexyloxybenzoyl and the like, of which such groups have 1-3 carbon atoms, are preferred, and methoxycarbonyl and etoxycarbonyl are particularly preferred.

"Mono - or di-lower alkylaminocarbonyl" represents a group in which one or two hydrogen atoms of the substituted amino group(s) described above "lower alkyl". Illustrative examples of mono-lower alkylaminocarbonyl include methylaminomethyl, ethylaminomethyl, propylaminoethyl, isopropylaminocarbonyl, butylaminoethyl, isobutylparaben, intramyocardial, isopentylamine, mexiletineciclovir, isohexadecane and the like. Illustrative examples of dialkylaminoalkyl include symmetric dialkylaminoalkyl group, which is twice substituted straight or branched alkyl groups having 1-6 carbon atoms, such as dimethyl, dipentyldithiocarbamate and the like, and asymmetric dialkylaminoalkyl groups that twice various substituted straight or branched alkyl groups having 1-6 carbon atoms, such as ethylmethylamino, methylpropylamine, ethylpropylamine, butylmethylamine, butylethylenediamine, buyprednisoneonli and the like.

Illustrative examples of the "lower alkylsulfonyl include methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, isobutylphenyl, peterculter, ISO-peterculter, hexylsilane, isohexanol and the like.

"Mono - or di-lower alkylaminocarbonyl" represents a group in which one or two hydrogen atoms of the substituted amino group(s) described above "lower alkyl". Illustrative examples of mono-lower alkylaminocarbonyl include methylenedioxybenzyl, ethylaminoethanol, isopropylaminocarbonyl, butylaminoethyl, isobutyleneisoprene, pentylenetetrazol, isopentenyladenosine, vexillationes, isohexadecane and the like. Illustrative examples for dialkylaminoalkyl is undertaken alkyl groups, having 1-6 carbon atoms, such as dimethylaminostyryl, diethylaminocoumarin, dipropylenetriamine, diisopropylaminoethanol, dibutylaminoethanol, dipentyldithiocarbamate and the like, and asymmetric dialkyldithiocarbamate groups that twice various substituted straight or branched alkyl groups having 1-6 carbon atoms, such as ethylethylenediamine, methylpropylketone, ethylpropylamine, butylethylenediamine, butylethylenediamine, buildimplementation and the like.

Illustrative examples of the "lower alkanoyl" include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like, of which the acetyl, propionyl, butyryl are preferred, and acetyl and propionyl are the most preferred.

"Lower alkylene" is alkylene having 1-6 carbon atoms, and its illustrative examples include methylene, ethylene, METROTILE, trimethylene, dimethylmethylene, tetramethylene, metallisation, ethylethylene, dimethylethylene, ethylmethylamine, pentamethylene, methyltyramine, dimethyltrimethylene, trimethicone, having 1-3 carbon atoms, such as methylene, ethylene, METROTILE, trimethylene and dimethylmethylene are preferred, methylene and ethylene are preferable, and a methylene is preferable.

Regarding the definition of the substituent in the terms "lower alkyl which may be substituted", "cycloalkyl, which may be substituted" or "low alkanoyl, which may be substituted", use any group, which may be substituents on the lower alkyl, cycloalkyl or lower alkanoyl, however, a member of the group of substituents C can be used preferably. In addition, in the definition of substituent for the "aryl which may be substituted" or "heteroaryl, which may be substituted" is used by any group, which may be substituents on the aryl or heteroaryl, however, a member of the group of substituents D can be used preferably. The above groups such as lower alkyl, cycloalkyl, lower alkanoyl, aryl or heteroaryl can be substituted by one or more substituents, preferably one to three.

Group C consists of the following substituents: halogen, carboxyl, carbarnoyl, amino, cyano, nitro, lower alkanoyl, the bottom is the culmination of alkylthio, lowest alkylthiomethyl, hydroxyl or mono - or di-lower alkylaminocarbonyl, and group D consists of the following substituents: halogen, carboxyl, amino, cyano, nitro, hydroxyl, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino, lower alkanoyl or lower alkyl which may be substituted by a member of group C.

Examples of the halogen include fluorine atoms, chlorine, iodine and bromine, and examples of mono - or di-lower alkylamino include mono-lower alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamine, isopentylamine, hexylamine, isohexane and the like, or a straight or branched, symmetric or asymmetric di-lower alkylamino group having from 1 to 6 carbon atoms, such as dimethylamino, methylethylamine, diethylamine, dipropylamine, ethylpropylamine, dibutylamino, diphenhydamine and the like. The term "aralkylated" means a group in which optional hydrogen atom "lower alkoxy" is substituted by the aforementioned "aryl", and its illustrative examples include benzyloxy, naphthalenyloxy, penetrate, phenylpropoxy and others like them, and the term "aryloxy" means a group in which hydrogen at the other, the like.

The term "alkylthio" means a group in which a hydrogen atom of mercaptopropyl substituted by the above-mentioned "lower alkyl", and its illustrative examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, pentylthio, isopentyl, hexylthio and the like, and the term "lower alkylthiomethyl" means a group in which the carbonyl group of the above-mentioned "lower alkanoyl" substituted thiocarbonyl group, and its illustrative examples include methylthiomethyl, ethylthiomethyl, propiltiourazil, ISO-propiltiourazil, butylthioethyl, isobutylthiazole, petitionable, isopentylamine, existieren and the like.

"Mono - or di-lower alkylaminocarbonyl" means a group in which one or two hydrogen atom aminosulfonyl group substituted by the above-mentioned "lower alkyl". Illustrative examples of the "mono-lower alkylaminocarbonyl include methylaminomethyl, ethylaminomethyl, propylaminosulfonyl, isopropylaminocarbonyl, butylaminoethyl, sibutraminesolution, intramyocellular, ISO-intramyocellular, exelonexelon, isohexanoate and the like. Illustrate the e double-substituted straight or branched alkyl groups, having 1-6 carbon atoms, such as dimethylaminomethyl, diethylaminomethyl, dipropyleneglycol, diisopropylaminoethanol, dibutylaminoethanol, dipentylester and the like, and asymmetric dialkylaminoalkyl groups that twice various substituted straight or branched alkyl groups having 1-6 carbon atoms, such as ethylmethanesulfonate, methylpropanesulfonic, ethylpropylamine, butylmethylether, butylethylmagnesium, buypropranolol and the like.

The term "N-lower alkyl-N-lower alkoxycarbonylmethyl" means a group in which a hydrogen atom aminosulfonyl group substituted by the aforementioned "lower alkyl" or "lower alkoxycarbonyl". Its illustrative examples include N-methyl-N - methoxycarbonylaminophenyl, N-methyl-N - ethoxycarbonylmethyl, N-ethyl-N-methoxycarbonylaminophenyl, N-ethyl-N-ethoxycarbonylmethyl, N-methyl-N - propoxycarbonylphenoxide, N-ethyl-N - propoxycarbonylphenoxide, N-propyl-N - propoxycarbonylphenoxide, N-butyl-N - methoxycarbonylaminophenyl, N-butyl-N - ethoxycarbonylmethyl and the like, to the, what is preferred.

An illustrative example of the most preferred compounds among the target product, as claimed in the present invention, refers to a derivative aydinonat or its pharmaceutically acceptable salt selected from the group including:

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7 - amidino-2-naphthyl)methyl-N'-methylsulfonyl;

ethyl-N-[N-4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]carbamate;

4-[N-4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]benzoic acid;

[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7 - amidino-2-naphthyl) methyl]sulfamoyl]acetic acid;

ethyl-N-[N-4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]glycinate;

N-[N-4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7 - amidino-2-naphthyl)methyl]sulfamoyl]-N-ethoxycarbonylphenyl; and

N-[N-4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]glycine.

Because of the claimed compounds contain in some cases asymmetric carbon atoms, in the present invention includes various isomers such as geometric isomers, tautomers, OE formula (I) form acid additive salt. In addition, depending on the type of substituent, they may form a salt with a base. Illustrative examples of such salts include acid additive salts with inorganic acids such as hydrochloric, Hydrobromic and itestosterone acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with organic acids such as formic, acetic, propionic, xalilov, malonic, succinic, fumaric, maleic, lactic, malic, tartaric and citric acids, methansulfonate and econsultancy acid, aspartic acid, glutamic acid and the like, and salts with inorganic bases, such as sodium, potassium, magnesium, calcium, aluminum and the like, or organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like, and ammonium salts and other similar compounds.

Furthermore, the subject invention form hydrates, pharmaceutically acceptable various solvate and polymorph form the compounds of formula (I). Actually, the present invention is not limited to the compounds described in the following examples, but includes all proizvodnye Lucene

This section describes a typical way to obtain the new compounds of formula (I). In addition, since the compound of General formula (I') as the subject of the invention is a new compound, its getting described in the first stage of the proposed method.

The first stage

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In the above formula, P represents aminosidine group.

As aminosidine group P can be used without any restrictions group commonly used for this circuit, such as a lower alkoxycarbonyl, acyl, lower alkyl, aralkyl, sulfonyl and the like.

The compound of General formula (I') can be synthesized by the following methods (i), (ii) or (iii).

(i) the Way in which the nitrile is transferred to imidate, and then condensed with the amine.

The nitrile (II) reacts with an alcohol, such as methanol, ethanol or the like, at temperatures from -40oC and 0oC in the presence of gaseous hydrogen chloride, and then the resulting imidate reacts with ammonia, ammonium carbonate, ammonium chloride or other amine or amine salt. As the solvent used methanol, ethanol, acetone, tetrahydrofuran and the like compounds.

The nitrile (II) reacts with hydrogen sulfide in the presence of organic bases such as methylamine, triethylamine, pyridine, picoline, obtaining thioamide. The latter is obtained also by reacting the nitrile (II) with o-diethyldithiophosphate in the presence of hydrogen chloride.

Received tioned communicates with the lower haloidalkyls, such as methyl iodide, ethyl iodide or the like, to translate it into thioimidate, which then reacts with ammonia, ammonium carbonate, ammonium chloride, ammonium acetate, or other amine or amine salt. As the solvent used methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, and the like compounds.

(iii) the Method by which amine, amine salt, amide metal or a Grignard reagent directly added to the nitrile.

The synthesis is carried out by adding to the nitrile (II) reagent such as ammonia, ammonium chloride, ammonium thiocyanate, a thiocyanate of alkylamine, eAl(Cl)NH2, NaNH2, (CH3)2NMgBr or similar compounds in an appropriate solvent or in his absence. The solvent can be used chloroform, methanol, ethanol, acetone, tetrahydrofuran, toluene, dimetilan the evidence (for example, hydride such as sodium, aluminium chloride or acid (for example, para-toluenesulfonic acid). The reaction is carried out at a temperature of from cooling to room or when heated.

During the translation of the nitrile in amidinopropane protection nitrile P you can delete or not delete. In those cases, when the protective group P is not removed, the compound (I') is obtained by removal of the protective group P suitable method, for example, in an acidic medium with hydrochloric, acetic, triperoxonane acid and the like.

In addition, when alkoxycarbonyl group attached to the compound (II) can be translated alkoxycarbonyl group carbamoyl simultaneously with the reaction of formation of amidinopropane.

The second stage

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The compound of formula (I) are obtained by reacting the compound (I'), which has a secondary amino group and which is obtained on the above-described first stage, with imidates in an appropriate solvent in the presence of a base in the temperature range from cooling to room.

Examples of the solvent include water, alcohols containing 1-4 carbon atoms, such as ethanol, propanol and the like, aliphatic ethers, such as diethyl ether is their solvents.

Examples of bases include N - methylmorpholine, triethylamine, trimethylamine, sodium hydroxide, potassium hydroxide and other similar reasons.

When alkoxycarbonyl group attached to the compound of formula (I), the hydrolysis is carried out in the usual way and, if necessary, in an alkaline, acidic or neutral environment.

Examples of bases used in an alkaline environment, include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like, examples of acids for the hydrolysis is conducted in an acidic environment, include a Lewis acid such as hydrochloric acid, sulfuric acid, trichloride boron and the like, triperoxonane acid, p-toluensulfonate and the like, and examples of reagents used in a neutral environment, include halogen ions such as lithium iodide, lithium bromide and the like, alkali metal salts of thiol and zanolla, attributively and enzyme such as esterase. Examples of solvents used in the reaction include water, alcohol (e.g. methanol and ethanol), acetone, dioxane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, formic acid, pyridylacetate, lutidine, kallidin and others. These solvents are used in bhodemon in some cases to implement it in an ice bath or under heating, so that it can be selected in the usual way.

In addition, the compound of General formula (I) can be obtained by an optional combining known reactions, which are usually used by professionals, such as alkylation, acylation, oxidation, reduction, hydrolysis, etc.

The method of obtaining the source connection

The initial compounds IVa, IVb, IVc, IVd, IVe and VII to obtain the claimed compounds of formula I, where R1represents a group-A-W-R4- receive the following ways (a) to(f).

(a) Method of obtaining the amide compounds (IV)

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In the above formula, Ragroup represented by the radical Raor a group of the formula where Ra1represents lower alkyl which may have a substitute, or cycloalkyl, which may also have a Deputy, or lower alkoxy. The compound (IVa), which amidon, obtained by introducing into the reaction acylation of amine (III) and active carboxylic acid derivative in an appropriate solvent.

Examples of active carboxylic acid derivative include active ester obtained by reacting with a phenol derivative (for example, p-NITROPHENOL) or production is mesh acid anhydrides, produced by the interaction with an organic acid, or a mixture of anhydrides of phosphoric acid, produced by the interaction of diphenylphosphinylchloride with N-methylmorpholine; acid azide, produced by the interaction of ester with hydrazine or alkylation; galoyanized (for example, acid chloride or bromohydrin); a symmetrical acid anhydride, and others.

Alternatively amide (IVa) can be obtained by subjecting a carboxylic acid acylation reaction in an appropriate solvent in the presence of a condensing agent. In this case, as a condensing agent, it is preferable to use N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-(N, N - dimethylamino) propyl) carbodiimide, carbonyldiimidazole, diphenylphosphoryl (DFFA), diethylphosphoramidite and others, and the like compounds.

The reaction is carried out usually in a solvent in the temperature range from cooling down to room temperature. It used solvents are organic solvents that do not participate in the reaction, such as dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, diethyl ether, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethyl organic solvents optionally selected depending on the applied method. Depending on the type of reaction acylation occurs the necessity of carrying out the reaction in an anhydrous environment.

In addition, depending on the applied method is sometimes desirable for carrying out the reaction under mild conditions in the presence of a base, such as N-methylmorpholin, triethylamine, trimethylamine, pyridine, sodium hydride, tert-piperonyl potassium, utility, sodium amide, or to use the base as a solvent.

(b) Method of obtaining compounds of urea (IVb)

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Connection urea (IVb) is produced by the interaction of the amine (III) with an isocyanate derivative in an appropriate solvent in the temperature range from cooling to a temperature of education phlegmy.

Alternatively derived urea (IVb) is produced by the interaction of the amine (III) with phosgene, diphosgene or triphosgene in an appropriate solvent in the temperature range from cooling to a temperature of education phlegmy subsequent interaction of the obtained carbamoylated with amine derivatives.

It used solvents are organic solvents that do not participate in the reaction, and their illustrative examples include dimethylformamide, dimethylamine, dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethyl sulfoxide and the like, and mixtures thereof, and the organic solvents optionally selected depending on the applied method.

Depending on the applied method is sometimes desirable for carrying out the reaction under mild conditions in the presence of a base, such as triethylamine, trimethylamine, sodium hydride, tert-piperonyl potassium, utility, sodium amide and the like.

(C) a Method of producing thiourea (IVc)

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Derived thiourea (IVc) is produced by the interaction of the amine (III) with isothiocyanates derived in a proper solvent in the temperature range from cooling to a temperature of education phlegmy. It used solvents are organic solvents that do not participate in the reaction, and their illustrative examples include dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, diethyl ether, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethyl sulfoxide and the like, and mixtures thereof, and the organic solvents optionally selected depending on the applied method.

In the head of the project, such as triethylamine, trimethylamine, sodium hydride, tert-piperonyl potassium, utility, sodium amide and the like compounds.

(d) a method of obtaining a urethane derived (IVd)

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In the formula, R4represents lower alkyl which may have a Deputy.

Derived urethane (lVd) is produced by the interaction of the amine (III) with possibly substituted by alkylchlorosilanes, possibly substituted by alkylsulfonates or alkalicarbonate, which may also have a Deputy, in the appropriate solvent and in the temperature range from cooling to a temperature of education phlegmy.

Used solvent is an organic solvent not participating in the reaction, and its illustrative examples include dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, diethyl ether, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethyl sulfoxide and the like solvents, and mixtures thereof, and these organic solvents optionally selected depending on the applied method.

Depending on the applied method sometimes gelfeld sodium, tert-piperonyl potassium, utility, sodium amide and the like compounds.

Oxalate connection get the same reaction conditions, except that as the starting product used is derived halogenosilanes acid.

(e) the Method of obtaining sulfonamidnuyu derived (IVe)

< / BR>
Derived sulfonamida (IVe) is produced by the interaction of the amine (III) with sulphonylchloride and anhydride of sulfonic acids (sulfonic anhydride) usually in the presence of a base, in an appropriate solvent and in the temperature range from cooling to a temperature of education phlegmy.

Used solvent is an organic solvent not participating in the reaction, and its illustrative examples include dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, diethyl ether, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethyl sulfoxide and the like solvents, and mixtures thereof, and these organic solvents optionally selected depending on the applied method. Illustrative examples of the base include N-methylmorpholin, triethylamine, t is some cases, you can use this base as a solvent.

(f) Alkylation

The alkylation reaction is well known in organic chemistry. Although it is explained below with reference to illustrative examples, alkylation reaction, other than those described in the examples, also carried out in similar conditions.

In the formula, Y represents alkylammonium group, such as halogen, methylsulfonylamino, tripterocalyx, paratoluenesulfonyl and the like.

< / BR>
Derived alkylamine of the General formula (VII) is obtained by introducing the amine derivative of General formula (V) in the reaction of alkylation using an alkylating agent of General formula (VI). The alkylation reaction carried out using the compound (V) and equivalent reaction or excessive amounts of alkylating agent (VI), in an appropriate solvent and in the temperature range from cooling to a temperature of education phlegmy, preferably from room temperature to the temperature of phlegmy. In some cases it is advantageous to add an equivalent or excess amount of the base to achieve a smooth response.

As a solvent not participating in the reaction, optional use alcohols (nepetifolia, the sulfoxide and the like compounds, although in some cases the implementation of the reaction and in the absence of solvents.

Examples of the bases used in this reaction include organic bases such as triethylamine, pyridine and the like, inorganic salts of strong bases such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride and the like bases. When the base is a liquid, it can also be used as solvent.

In addition, the source connection you can get an optional combination of alkylation, oxidation, recovery, hydrolysis and other reactions known to any specialist.

For example, when using the method of alkylation alkyl substituted sulfonamidnuyu derived can be obtained from the derived sulfonamida in the presence of an equivalent or excess amount of an alcohol (e.g. methanol and ethanol), triphenylphosphine or diethylazodicarboxylate in an inert solvent (e.g. tetrahydrofuran, benzene, dichloromethane, etc.) under stirring at room temperature or when heated.

The method of recovery used in those cases the use of metal (for example, zinc and tin), a technique where the use of a metal hydride (for example, sociallyengaged LiAlH4), and a catalytic reduction method, which use a catalyst, such as palladium on carbon, and each of these methods is carried out in an inert solvent at room temperature or when heated.

The connection, as claimed in the present invention, obtained in this way is isolated and purified by the known methods, which include extraction, precipitation, chromatographic separation, fractionated crystallization, recrystallization, and others. In addition, the claimed compound can be converted to the desired salt by a conventional salt-forming reaction.

The claimed compound can exist as optical isomers, when it has a symmetrical carbon atoms. These optical isomers share the standard method fractionated crystallization, which isomer is recrystallized along with a corresponding salt, or by chromatography on a column.

Industrial applicability

The connection, as claimed in the present invention, has a strong anticoagulate action through specific ingibiruyutza blood coagulation or medicines for the prevention or treatment of diseases, caused by thrombi or emboli. Examples of such diseases are cerebralischemia disorders, such as cerebral infarction, cerebral thrombosis, cerebral embolism, the attack transient ischemia, subarachnoid hemorrhage, and other ischemic heart diseases such as acute or chronic myocardial infarction, unstable angina, thrombosis coronary artery and other, pulmonary vascular disorders such as pulmonary thrombosis, pulmonary embolism and other various vascular diseases, such as blockage of peripherally artery, deep venous thrombosis, disseminated intravascular coagulation, the formation of a blood clot after surgery, artificial blood vessels, or after replacement of the artificial heart valve reocclusion and restricture after surgery bypass coronary artery reocclusion and restricture after surgery with percutaneous catheter-koronarospastical and a blood clot in the artificial circulation. In addition, offers the possibility of using the inventive compounds as a medicine for the prevention or treatment of influenza, based on activity of this compound to inhibit the virus gripka Japan, kokai, N 6 - 227971).

The excellent activity of the claimed compounds to inhibit activated factor X coagulation confirmed by the following tests.

1) Test for the measurement of coagulation time of through human activated factor X clotting

Human activated factor X coagulation, manufactured by Cosmo Bio (Cosmo Bio), dissolved in 0.05 M buffer Tris-HCl (pH 7,40) to obtain a solution with a concentration of 0.05 u/ml of the blood Sample, selected using 1/10 volume of 3.8% solution of sodium citrate, centrifuged at a speed of 3000 rpm for 10 minutes. Then portion into 90 ál of selected human plasma is mixed with 10 µl of each drug, diluted by dissolving in physiological solution, and 50 μl of a solution of the above-mentioned activated factor X coagulation and the resulting mixture is incubated at a temperature of 37oC for 3 minutes. Then add 100 ál of 20 mm solution of CaCl2and measure the coagulation time using this circuit CSA manufactured by Amelung (Amelung). The dose, which doubles the clotting time (hereinafter referred to ST2), calculated on the basis of the period of time that tats are shown in table 1.

2) Test for the measurement of clotting time of blood by bovine thrombin

Human fibrinogen produced by the company Sigma (Sigma) by the method of lyophilization, dissolved in 0.05 M buffer Tris-HCl (pH 7,40) to obtain a solution with a concentration of 6 mg/ml Bovine thrombin (500 IU/vial) manufactured by Mochida pharmaceutical (Mochida Pharmaceutical), dissolved in saline solution to prepare solutions of different concentrations of thrombin. Then portion 100 μl of the above human fibrinogen is mixed with 100 µl of physiological solution and the resulting mixture is incubated at a temperature of 37oC for 3 minutes. Then add 100 μl of thrombin solution for measuring clotting time and determine the concentration of thrombin, which causes the coagulation of blood after 20 seconds. Next batch of 100 µl of each drug, obtained by dilution with saline, added to 100 μl of a solution of fibrinogen and measure the clotting time using this circuit KC4A manufactured by Amelung (Amelung). The dose, which doubles the coagulation time of the blood (hereinafter referred to ST2), calculated on the basis of the time period, which is obtained by adding instead of generic) Test for the measurement of Enzyme inhibition method, synthetic substrate

Human activated factor X coagulation, manufactured by Cosmo Bio (Cosmo Bio), dissolved in 0.02 M buffer Tris-HCl (pH 7,40) containing 0.15 M sodium chloride, and get solution with a concentration of 6 u/ml Synthetic substrate S-2222, manufactured by Daiichi to KAGAKU Yakuhin (Daiichi Depending Yakuhin), dissolved in purified water, obtaining a solution with a concentration of 0.75 mg/ml. Portion 25 µl of each drug, obtained by dissolving the drug in physiological solution, mixed with 170 μl of 0.0 M buffer Tris - HCl (pH 8,40) and 50 µl of substrate solution of S-2222. Then add 10 ál of a solution of human activated factor X coagulation and the resulting mixture is incubated at a temperature of 37oC for 3 minutes. The reaction is stopped by adding 50 μl of 60% acetic acid, measure the absorption of the solution at 405 nm and calculate the value of the IC50. To measure the use of the spectrophotometer, Bio-Rad model 3550. The reaction mixture obtained by adding physiological saline instead of drugs and 60% acetic acid prior to introduction of the solution of human activated factor X clotting, is used as a blank (control) samples. The concentration at 50% inhibition of the show, the compound of example 79 shows the value of the IC50equal 0,091 μm, and the compound of Example 88 - 0,047 microns.

The results of tests 1), 2) and (3) confirm that the compounds claimed in the present invention, specifically inhibit human activated factor X clotting and have excellent anticoagulate action by increasing clotting time of blood at low concentrations of the active substance in comparison with the substance of the comparison, which will be discussed below.

4) Test ex vivo measurement of coagulation time of mice (intravenous)

Every drug, dissolved in saline solution, administered by a single injection into the tail vein of male mouse ICR (weighing 20-30 g) after fasting for 12 hours or more, and then after a minute under anesthesia (diethyl ether) is selected from the aorta 0.6 ml of blood into 1/10 volume of 3.8% solution of sodium citrate and centrifuged for 10 minutes at a rotation speed of 3000 rpm to separate the plasma. Using the obtained plasma, in accordance with the following methods (a) and (b) measure the external (PTT) (partial thromboplastin time) and internal (ART) (activated partial thrombus is plastikovie time)

Tissue thromboplastin (54 mg/ampoule) received by the company ortho) method lyophilization, dissolved in 2.5 ml of distilled water and preincubated when 3,7oC. Portion 50 μl of blood plasma is incubated at a temperature of 37oC for 1 min, and then mixed with 50 μl of a solution of thromboplastin and measure the clotting time using this circuit KC4A manufactured by Amelung (Amelung). As idle experience determine the clotting time for the case when instead of medication injected with physiological saline solution; the activity of the drug expressed as relative values with respect to unmarried experience that is taken for 1.

b) the internal blood clotting (ART) (activated partial thromboplastin time)

The coagulation time was measured by incubating 50 μl of activated tambopaxi (firm ortho) and 50 μl of blood plasma at a temperature of 37oWith and then adding 50 μl of a 20 mm solution of CaCl2that preincubated at 37oC. To measure the use of KC4A manufactured by Amelung (Amelung). As idle experience determine the clotting time for the case when instead of medication administered physiological saline; active is also determine the dependence of the dose and periodic changes anticoagulative effect by changing the led of the dose or the time of blood collection. According to the results of the performed tests, mark the excellent effect of the drug to increase the clotting time of blood by intravenous injection of the claimed compounds.

5) Test ex vivo measurement of coagulation time of mice (oral administration)

The procedure described above for test 4) is repeated, except that instead of injection into the tail vein using forced oral administration by means of the probe and the blood is collected after 30 minutes.

According to the results of the performed tests, mark the effect of the drug to increase the clotting time of blood by oral administration of the claimed compounds.

Pharmaceutical composition containing one, two or more compounds of General formula I or their pharmaceutically acceptable salts as the active ingredient, are prepared in the form of tablets, powders, fine granules, normal, granules, capsules, pills, solutions, injections, suppositories, ointments, adhesive preparations, etc. using well-known pharmaceutical carriers, fillers and other the rights is determined individually for each patient depending on the symptoms, body weight, age, sex and other factors, but typically is in the range from 0.1 to 500 mg for oral administration or from 0.01 to 100 mg for parenteral and this daily dose is divided into one to several doses. Since it varies with different States, and smaller, in comparison with the above intervals, the dose may in some cases be sufficient.

A solid composition for oral administration is used in the form of tablets, powders, granules and other pharmaceutical forms. In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid or magnesium aluminate. As a rule, in addition to inert diluents, compositions can contain additives such as lubricants (e.g. magnesium stearate), disintegrators (e.g., calcium acetyl cellulose), stabilizers (e.g., lactose) and solubilizing agents or substances that promote solubilization (for example, glutamic or aspartic acid). If necessary, tablets or pills cover gastric or enterology and others.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and other forms and contain conventional inert diluent such as purified water or ethanol. In addition to the inert diluent, this composition contains auxiliary agents, such as solubilizers agent or substance that promotes solubilization, moisturizing and suspendisse agents and others, as well as sweeteners, flavoring additives, flavorings and preservatives.

Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, emulsions and suspensions. The diluents for use in aqueous solutions and suspensions include distilled water for injection and physiological saline. The diluents for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oil (e.g. olive oil), alcohol (e.g. ethanol), Polysorbate 80 (trade name) and other substances. Such a composition may further contain additives such as an isotonic agent, a preservative, a humectant, emulsifier, dispersant, stabilizer (e.g., lactose) and salubria through a bacterial filter, mixing with bactericidal drugs or irradiation. In another case, you can use them, receiving a first sterile solid compositions, and then dissolving before use in sterile water or a sterile solvent for injection. When the claimed compound has poor solubility, it is subjected to special treatment. The solubilization carried out by the known methods usually used for pharmaceutical preparations, such as a method where a mixture of surface-active substances (polyoxyethylene hardened castor oil, polyoxyethylene esters of higher fatty acids and sorbitan, copolymers of polyoxyethylene and polyoxypropylene, esters of fatty acids and sucrose and other products), and the method where the medicine is made in the form of a solid suspension with solubilization agent such as a polymer (for example, water-soluble high molecular weight polymer, such as hypromellose - GPMC, polyvinylpyrrolidone - PVP, polyethylene glycol - PEG, or intersolubility polymer, such as karboksimetiltselljuloza - KMAC, phthalate of hydroxypropylmethylcellulose - HPMCP and copolymer of methacrylic acid and of methyl methacrylate EA medicine made in the form of soluble salts, or method, when the connection enable receive using cyclodextrin or similar connection. The method of solubilization is selected depending on individual drugs [see Saikin on seizaigijyutu to sono oyo (Recent Pharmaceutical Technology and Application), 1. Utsumi et a1., lyaku Journal, 157-159, 1983; Yakugaku Monograph No. 1, "Bioavailability", K. Nagai et a1., published by Soft Science, 78 - 82, 1988]. Of the above methods preferably use a method in which the solubility of drugs improve through education of its solid dispersion with solubilization agent (unexamined published Japanese patent application (kokai) N 56-49314, FR 2460667).

The best choice for carrying out the invention

This section describes how to obtain the compounds claimed in the present invention with reference to illustrative examples. As new connections are among the ingredients used for specified target compounds, their synthesis are described in the corresponding reference examples.

Legend for the characteristics of the spectra: s - singlet; d - doublet; t - triplet; m - multiplet; q - quadruplet; brs, broad singlet; Hz - Hz.

Reference Example 1

Tetrafluoroborate silver (1,168 mg) are suspended in 6 ml of dimethylsulfoxide, to the temperature for 14 hours. The reaction mixture is filtered, the mother liquor, water is added and the mixture extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and then evaporated. The resulting residue is purified by chromatography on a column of silica gel, using as eluent a mixture of hexane and ethyl acetate, and receive 543 mg of 7-formyl-2-naphthaleneacetic in a solid white color.

These NMR spectrum (CDCl3, internal standard TMS):

: 7.78 (1H, dd, J=1.2, 8.5 Hz), 8.01 (1H, d, J=8.5 Hz), 8.02 (1H, dd, J=1.2, 8.5 Hz), 8.13 (1H, dd, J=1.2, 8.5 Hz), 8.40 (2H, s), 10.21 (1H, s).

Reference example 2

7-formyl-2-naphthaleneacetic obtained in reference example 1 (849 mg), and 1,370 mg 4-[(1-tert-butoxycarbonyl-4 - piperidyl)-oxy]aniline dissolved in 10 ml of dichloromethane and the resulting solution was added to 2.7 ml of acetic acid, 1,290 mg triacetoxyborohydride sodium and the mixture is stirred at room temperature for 45 minutes. The mixture is then washed successively with 2 m potassium carbonate solution, water and 10% aqueous citric acid solution, dried over anhydrous sodium sulfate and then evaporated. After recrystallization of the resulting residue from methanol receive 1,698 mg 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] the R spectrum (CDCl3, internal standard TMS):

: 1.46 (9H, s), 1.63-1.74 (2H, m), 1.80-1.92 (2H, m), 3.21-3.30 (2H, m), 3.65-3.77 (2H, m), 4.00 (1H, bs), 4.21-4.28 (1H, m), 4.49 (1H, s), 6.59 (2H, d, J=8.8 Hz), 6.79 (2H, d, J=8.8 Hz), 7.59 (1H, d, J-8.3 Hz), 7.66 (1H, d, J=8.8 Hz), 7.84-7.92 (3H, m), 8.19 (1H, s).

Reference Example 3

7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline] -methyl]-2-naphthaleneacetic obtained in reference example 2 (150 mg), dissolved in 1 ml of pyridine, the solution was added 268 mg of acetic anhydride and 10 mg of 4-dimethylaminopyridine and the resulting mixture was stirred at room temperature for 15 hours. To the reaction mixture are added ethyl acetate and the mixture washed sequentially with 10% aqueous citric acid solution and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and then evaporated. After recrystallization of the resulting residue from ethanol obtain 139 mg of N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)-oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]ndimethylacetamide.

Data mass spectrum (m/z): 500 (M+l)+.

These NMR spectrum (CDCl3internal standard TMS):

: 1.46 (9H, s), 1.67-1.77 (2H, m), 1.85-1.97 (5H, s), 3.27-3.36 (2H, m), 3.63-3.76 (2H, m) 4.37-4.45 (1H, m), 5.02 (2H, s), 6.81 (2H, d, =8.8 Hz), to 6.88 (2H, d, J=8.8 Hz), 7.56-7.65 (3H, m), 7.83 (1H, d, J=8.3 Hz), 7.89 (1H, d, J=8.3 Hz), 8.13 (1H, s).

Reference example 4

7-[[4-[(tre mg), dissolved in 2 ml of dichloromethane, to the solution was added 299 mg of etylchlorhydrine and 266 mg of triethylamine and the resulting mixture was stirred at room temperature for 15 hours. To the reaction mixture are added ethyl acetate and the mixture washed sequentially with 10% aqueous citric acid solution and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and then evaporated. The resulting residue is purified by chromatography on a column of silica gel, using as eluent a mixture of hexane and ethyl acetate (8:2), and obtain 241 mg of N-[4-[(1-tert - butoxycarbonyl-4-piperidyl)-oxy] phenyl]-N-[(7-cyano-2 - naphthyl)methyl]-oxamate.

Data mass spectrum (m/z): 557 (M)+.

These NMR spectrum (CDCl3internal standard TMS):

: 1.01 (3H, t, J=7.1 Hz), 1.46 (9H, s), 1.63-1.75 (2H, m), 1.82-1.94 (2H, m), 3.25-3.36 (2H, m), 4.04 (2H, q, J=7.1 Hz), 4.35-4.45 (1H, m), 5.07 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.58-7.63 (2H, m), 7.68 (1H, s), 7.86 (1H, d, J=8.3 Hz), 7.90 (1H, d, J=8.8 Hz), 8.15 (1H, s).

The following compounds of reference examples 5-13 receive according to the method described in reference Example 4.

Reference example 5

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)-oxy] phenyl]- N-[(7-cyano-2-naphthyl)methyl]cyclopropanecarboxamide.

The source connection: 7-[[4-[(1-tert-BU is>Data mass spectrum (m/z): 526 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 0.59-0.78 (2H, m), 0.94-1.13 (2H, m), 1.24-1.31 (1H, m), 1.46 (9H, s), 1.52-1.62 (2H, m), 1.65-1.92 (2H, m), 3.12-3.47 (2H, m), 3.54-3.74 (2H, m), 4.31-4.56 (1H, m), 5.04 (2H, s), 6.90-7.05 (4H, m), 7.51-7.98 (5H, m), 8.14 (1H, s).

Reference example 6

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)-oxy] phenyl] -N-[(7-cyano-2-naphthyl)methyl]benzamide.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]-methyl]-2-naphthaleneacetic, benzoyl chloride.

Data mass spectrum (m/z: 562 (M+l)+. These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (9H, s), 1.54-1.84 (4H, m), 3.21-3.82 (4H, m), 4.22 - 4.41 (1H, m), 5.27 (2H, s), 6.53-6.94 (4H, m), 7.12-8.00 (10H, m), 8.18 (1H, s).

Reference example 7

N-[4-[(1 - tert-butoxycarbonyl-4-piperidyl)-oxy]phenyl]-N- [(7-cyano-2-naphthyl)methyl]ethanolbased.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl) oxy] aniline]methyl] -2 - naphthaleneacetic, propanolol.

Data mass spectrum (m/z): 514 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.05 (3H, t, J=7.0 Hz), 1.46 (9H, s), 1.54-2.02 (6H, m), 3.01-3.38 (2H, m), 3.50-3.74 (2H, m), 4.34-4.51 (1H, m), 5.01 (2H, s), 6.91-7.12 (4H, m), 7.45-7.88 (5H, m), 8.14 (1H, s).

Reference example CLASS="ptx2">

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, cyclohexanecarbonitrile.

Data mass spectrum (m/z): 568 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 0.89-1.31 (5H, m), 1.46 (9H, s), 1.54-1.98 (10H, m), 3.17-3.48 (2H, m), 3.54-3.82 (2H, m), 4.34-4.51 (1H, m), 4.99 (2H, s), 6.82-7.07 (4H, m), 7.68-7.91 (5H, m), 8.12 (1H, s).

Reference example 9

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)-oxy] phenyl]- N-[(7-cyano-2-naphthyl)methyl]-1-naphthaleneboronic.

The source connection: 7-[[4-[(1-tert - butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2 - naphthaleneacetic, 1-naphthaleneboronic.

Data mass spectrum (m/z): 612 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.43 (9H, s), 1.54-1.79 (4H, m), 3.04-3.39 (2H, m), 3.42-3.70 (2H, m), 4.04-4.31 (1H, m), 5.34 (2H, s), 6.35-6.82 (4H, m), 7.15-8.13 (12H, m), 8.18 (1H, s).

Reference example 10

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N- [(7-cyano-2-naphthyl)methyl]-2-perbenzoic.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl - 4-piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, 2 - perbenzoate.

Data mass spectrum (m/z): 580 (M+l)+.

These NMR spectrum (CDCl3

Reference example 11

N-[4-[(1 - tert - butoxycarbonyl-4-piperidyl)oxy]phenyl] -N-[(7-cyano-2-naphthyl)methyl]-3-methoxybenzamide.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2 - naphthaleneacetic, 3-methoxybenzophenone.

Data mass spectrum (m/z): 592 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (9H, s), 1.59-1.90 (4H, m), 3.07-3.45 (4H, m), 3.65 (3H, s), 4.21-4.48 (1H, m), 5.25 (2H, s), 6.58-7.10 (8H, m), 7.54 - 7.67 (1H, m), 7.69-7.95 (4H, m), 8.14 (1H, s).

Reference example 12

N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)-oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]-2 - typename.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, toenailed.

Data mass spectrum (m/z): 567 (M)+. These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (9H, s), 1.64-1.97 (4H, m), 3.14-3.48 (2H, m), 3.52-3.77 (2H, m), 4.35-4.60 (1H, m), 5.22 (2H, s), 6.74-7.18 (5H, m), 7.28-7.38 (1H, m), 7.52-7.69 (2H, m), 7.70-7.95 (4H, m), 8.12 (1H, s).

Reference example 13

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)-oxy] phenyl]- N-[(7-cyano-2-naphthyl)methyl]-3-pyridinecarboxamide.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy] Anil the/SUP>.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.47 (9H, s), 1.65-1.94 (4H, m), 3.10-3.42 (2H, m), 3.51-3.87 (2H, m), 4.21-4.42 (1H, m), 5.32 (2H, s), 6.72-6.98 (2H, m), 7.62-7.79 (9H, m), 8.17 (1H, s), 8.41 - 8.67 (2H, m).

Reference example 14

7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline] -methyl]-2-naphthaleneacetic obtained in reference example 2 (150 mg), dissolved in 2 ml of dichloromethane, to the solution was added 35 mg utilizationof and the resulting mixture was stirred at room temperature for 15 hours. To the reaction mixture was added 117 mg utilizationof and the mixture is stirred at room temperature for a further 6 hours and the resulting solution is evaporated. The residue is purified by chromatography on a column of silica gel, using as eluent a mixture of hexane and ethyl acetate (65:35), and obtain 154 mg of 1-[4-[(1-tert - butoxycarbonyl-4-piperidyl)oxy]phenyl]-1-[(7-cyano-2 - naphthyl)methyl]-3-utilmately.

Data mass spectrum (m/z): 528 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.06 (3H, t, J=7.3 Hz), 1.46 (9H, s), 1.65-1.78 (2H, m), 1.82-1.95 (2H, m), 3.20-3.37 (4H, m), 3.62-3.75 (2H, m), 4.24 (1H, t, J=5.5 Hz), 4.36-4.44 (1H, m), 4.99 (2H, s), 6.83 (2H, d, J=7.0 Hz), 6.96 (2H, d, J=7.3 Hz), 7.57 (1H, d, J=8.5 Hz), 7.62-7.68 (2H, m), 7.83 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=8.5 Hz), 8.13 (1H, s).

Following connection of the SS is Ethyl-3- [4- [(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-3-[(7-cyano-2-naphthyl)methyl]ureido-1-acetate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, utilizationfocused.

Data mass spectrum (m/z): 586 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.27 (3H, t, J=7.3 Hz), 1.46 (9H, s), 1.65-1.80 (2H, m), 1.80-1.96 (2H, m), 3.25-3.38 (2H, m), 3.60-3.75 (2H, m), 4.00 (2H, d, J=5.9 Hz), 4.19 (2H, q, J=7.3 Hz), 4.35-4.45 (1H, m), 4.80 (1H, t, J=5.6 Hz), 5.01 (2H, s), 6.84 (2H, d, J=9.2 Hz), 7.05 (2H, d, J=8.8 Hz), 7.57 (1H, d, J=8.3 Hz), 7.64 (1H, d, J=8.3 Hz), 7.68 (1H, s), 7.83 (1H, d, J=8.3 Hz), 7.88 (1H, d, J=8.3 Hz), 8.15 (1H, s).

Reference example 16

7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]aniline] -methyl]-2-naphthaleneacetic obtained in reference example 2 (150 mg), dissolved in 2 ml of dimethylformamide, to the solution was added 178 mg ethylchloride and 271 mg of potassium carbonate, the resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture is evaporated and the resulting residue purified by chromatography on a column of silica gel, using as eluent a mixture of acetate and hexane (2:8), and obtain 169 mg of ethyl-N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]carbamate.

Data mass spectrum (m/z): 529 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.15-1.3 (3H,58 (2H, d, J=9.5 Hz), 7.68 (1H, s), 7.84 (1H, d, J=8.3 Hz), 7.89 (1H, d, J=8.8 Hz), 8.15 (1H, s).

Reference Example 17

7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline] -methyl] -2-naphthaleneacetic obtained in reference example 2 (150 mg), dissolved in 4 ml of acetonitrile, the solution was added 710 mg utiliization and the resulting mixture is heated at a temperature of education phlegmy within 4 days. The reaction mixture is evaporated and the resulting residue purified by chromatography on a column of silica gel, using as eluent a mixture of hexane:ethyl acetate (7: 3), and obtain 171 mg of 1-[4-[(1-tert-butoxycarbonyl-4-piperidyl)-oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]-3-ethylthiophene.

Data mass spectrum (m/z): 545 (M+l)+.

These NMR spectrum (CDCl3internal standard TMS):

: 1.11 (3H, t, J=7.I Hz), 1.46 (9H, s), 1.66-1.76 (2H, m), 1.83-1.94 (2H, m), 3.25-3.35 (2H, m), 3.60-3.75 (4H, m), 4.36 - 4.44 (1H, m), 5.39 (1H, t, J=5.1 Hz), 5.65 (2H, s), 6.84 (2H, d, J=8.3 Hz), 6.90 (2H, d, J=8.3 Hz), 7.57 (2H, d, J=8.3 Hz), 7.69 (1H, s), 7.77-7.84 (2H, m), 7.88 (1H, d, J=8.3 Hz), 8.14 (1H, s).

Reference Example 18

7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline] -methyl] -2-naphthaleneacetic obtained in reference example 2 (150 mg), dissolved in 1 ml of pyridine, the solution was added 211 mg acanaloniidae and the resulting mixture paramashiva mixture are added ethyl acetate and the mixture washed sequentially with 10% aqueous citric acid solution and brine, dried over anhydrous sodium sulfate and then evaporated. The residue is purified by chromatography on a column of silica gel, using as eluent a mixture of hexane and ethyl acetate (75:25), and obtain 176 mg of N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -phenyl] -N- [(7-cyano-2-naphthyl)methyl]acanalonia.

Data mass spectrum (m/z): 550 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.43-1.50 (12H, m), 1.63-1.73 (2H, m), 1.80-1.91 (2H, m), 3.12 (2H, q, J=7.3 Hz), 3.25-3.36 (2H, m), 3.60-3.70 (2H, m), 4.33-4.41 (1H, m), 5.00 (2H, s), 6.78 (2H, d, J=6.8 Hz), 7.15 (2H, d, J=6.8 Hz), 7.58 (1H, d, J=8.5 Hz), 7.64 (1H, s), 7.69 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=8.3 Hz), 7.88 (1H, d, J=8.3 Hz), 8.13 (1H, s).

The following compounds of reference examples 19-27 receive according to the method described in reference example 4.

Reference example 19

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7-cyano-2-naphthyl)methyl]-2-methoxybenzamide.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, 2-methoxy-benzoyl chloride.

Data mass spectrum (m/z): 592 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.44 (9H, s), 1.54-1.93 (4H, m), 3.02-3.58 (4H, m), 3.69 (3H, s), 4.14-4.39 (1H, m), 5.25 (2H, s), 6.44-7.36 (8H, m), 7.46-7.73 (1H, m), 7.75-8.00 (4H, m), 8.13 (1H, s).

ansamed.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy] aniline]methyl]-2-naphthaleneacetic, 4-methoxy-benzoyl chloride.

Data mass spectrum (m/z): 592 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.50 (9H, s.), 1.67-1.95 (4H, m), 3.11-3.67 (4H, m), 3.76 (3H, s), 4.28-4.50 (1H, m), 5.32 (2H, s), 6.60-7.01 (8H, m), 7.77 - 7.90 (5H, m), 8.14 (1H, s).

Reference Example 21

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -phenyl] -N-[(7-cyano-2-naphthyl)methyl]-4-pyridinecarboxamide.

The source connection: 7-[[4-[(1-tert - butoxycarbonyl-4-piperidyl)oxy] aniline] methyl]-2 - naphthaleneacetic, nicotinoyldihydrocodeine.

Data mass spectrum (m/z): 563 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.48 (9H, s), 1.58-2.02 (4H, m), 3.07-3.82 (4H, m), 4.17 - 4.51 (1H, m), 5.29 (2H, s), 6.62-7.05 (4H, m), 7.12-7.41 (2H, m), 7.49-8.08 (6H, m), 8.17 (1H, s), 8.42-8.61 (2H, m).

Reference Example 22

N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]-phenyl]-N-[(7-cyano-2-naphthyl)methyl]-2 - pyridinecarboxamide.

The source connection: 7-[[4-[(1-tert - butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2 - naphthaleneacetic, picolinoylhydrazone.

Data mass spectrum (m/z): 563 (M+1)+.

These NMR SP is -7.31 (2H, m), 7.43-7.72 (2H, m), 7.76-8.03 (4H, m), 8.15 (1H, s), 8.32-8.49 (2H, m).

Reference example 23

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -phenyl] -N-[(7-cyano-2-naphthyl)methyl]-2-methoxyacetate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy] aniline]methyl]-2-naphthaleneacetic, methoxyacetanilide.

Data mass spectrum (m/z): 530 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: to 1.47 (9H, s), 1.64-2.07 (4H, m), 3.38 (3H, s), 3.45 - 3.77 (4H, m), 3.82 (2H, s), 4.31-4.58 (1H, m), 5-03 (2H, s), 6.79-6.98 (4H, m), 7.49-7.61 (1H, m), 7.77-8.00 (4H, m), 8.12 (1H, s).

Reference example 24

Ethyl-N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7-cyano-2-naphthyl)methyl]malonamate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, ethylmalonate.

Data mass spectrum (m/z): 572 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.28 (3H, t, J=8.1 Hz), 1.46 (9H, s), 1.62-1.97 (4H, m), 3.28 (2H, s), 3.36-3.84 (4H, m), 4.14 (2H, q, J=9.0 Hz), 4.32 - 4.56 (1H, s), 5.06 (2H, s), 6.67-7.06 (4H, m), 7.52-8.03 (5H, m), 8.15 (1H, s).

Reference example 25

Ethyl-N-[4-[(1 - tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]succinamic.

The source connection: 7-[[4-[(1-t the data of the mass spectrum (m/z): 586 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.26 (3H, t, J=8.7 Hz), 1.46 (9H, s), 1.64-1.97 (4H, m), 2.27-2.73 (4H, m), 3.15-3.88 (4H, m), 4.13 (2H, q, J=9.0 Hz), 4.32-4.54 (1H, m), 5.04 (2H, s), 6.72-7.07 (4H, m), 7.47-8.03 (5H, m), 8.17 (1H, s).

Reference example 26

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -phenyl] -N-[(7-cyano-2-naphthyl)methyl]-2,6-diflorasone.

The source connection: 7-[[4-[(1-tert - butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2 - naphthaleneacetic, 2,6-differentiald.

Data mass spectrum (m/z): 598 (M+l)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.44 (9H, s), 1.54-1.83 (4H, m), 3.05-3.80 (4H, m), 4.16-4.43 (1H, m), 5.23 (2H, s), 6.48-7.22 (7H, m), 7.46-8.01 (5H, m), 8.13 (1H, s).

Reference example 27

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N- [(7-cyano-2-naphthyl)methyl]-2-bromoacetamide.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline] methyl]-2-naphthaleneacetic, bromacetyl - bromide.

Data mass spectrum (m/z): 578 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.46 (9H, s), 1.64-2.00 (4H, m), 3.14-3.66 (4H, m), 3.73 (2H, s), 4.30-4.56 (1H, m), 5.04 (2H, s), 6.75-7.12 (4H, m), 7.46 - 7.79 (5H, m), 8.12 (1H, s).

Reference Example 28

N-[4-[(1-tert-butoxycarbonyl-4-Aut in 1 ml of methanol, to the solution was added 10 ml of 40% aqueous dimethylamine and the mixture was stirred at 60oC for 12 hours. The reaction mixture was evaporated and to the obtained residue was added chloroform. The mixture is washed successively with water and brine, dried over anhydrous sodium sulfate and then evaporated, getting 247 mg of N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl) -oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]-2-dimethylaminoacetyl.

Data mass spectrum (m/z): 543 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.46 (9H, s), 1.62-2.10 (4H, m), 2.28 (6H, s), 3.07-3.89 (4H, m), 4.30-4.55 (1H, m), 5.02 (2H, s), 6.75-6.98 (4H, m), 7.39-7.97 (5H, m), 8.27 (1H, s).

Reference Example 29

The compound of reference Example 29 receive according to the method described in reference example 14.

Ethyl-N-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7-cyano-2-naphthyl)methyl]carbarnoyl]carbonate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, ethoxycarbonylethyl.

Data mass spectrum (m/z: 573 (M+1)+< / BR>
These NMR spectrum (CDCl3, internal standard TMS):

: 1.26 (3H, t, J=7.1 Hz), 1.47 (9H, s), 1,53-1.97 (4H, m), 3.17-3.88 (4H, m), 4.18 (2H, q, J=7.1 Hz), 4.33-4.56 (1H, m) the same method, that described in reference example 18.

Reference Example 30

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N- [(7-cyano-2-naphthyl)methyl]benzosulfimide.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]- 2-naphthaleneacetic, benzosulphochloride.

Data mass spectrum (m/z): 597 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (S, s), 1.60-1.70 (2H, m), 1.80-1.90 (2H, m), 3.23-3.33 (2H, m), 3.60-3.70 (2H, m), 4.30-4.38 (1H, m), 4.86 (2H, s), 6.69 (2H, d, J= 8.8 Hz), 6.86 (2H, d, J=8.8 Hz), 7.48-7.73 (8H, m), 7.82 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=8.3 Hz), 8.09 (1H, s).

Reference Example 31

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -phenyl] -N-[(7-cyano-2 - naphthyl)methyl]methanesulfonamide.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline]methyl] -2-naphthaleneacetic, methansulfonate.

Data mass spectrum (m/z): 536 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (S, s), 1.63-1.73 (2H, m), 1.80-1.90 (2H, m), 2.99 (3H, s), 3.25-3.35 (2H, m), 3.60-3.70 (2H, m), 4.34-4.40 (1H, m), 4.97 (2H, s), 6.80 (2H, d, J= 8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 7.59 (1H, dd, J=8.8, 1.5 Hz), 7.63-7.72 (2H, m), 7.85 (1H, d, J=8.3 Hz), 7.88 (1H, d, J=8.8 Hz), 8.13 (1H, s).

Reference Example 32

N-[4-[(1-tert-butoxycarbonyl-4--butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, benzolsulfonate.

Data mass spectrum (m/z): 611 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.46 (9H, s), 1.63-1.74 (2H, m), 1.81-1.93 (2H, m), 3.25-3.36 (2H, m), 3.61-3.72 (2H, m), 4.33-4.41 (3H, m), 4.64 (2H, s), 6.77 (2H, d, J= 8.8 Hz), 7.08 (2H,d, J=8.8 Hz), 7.41-7.59 (8H, m), 7.77 (1H, d, J=8.8 Hz), 7.84 (1H, d, J=8.2 Hz), 8.06 (1H, s).

Reference Example 33

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]propanesulfonate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2 - naphthaleneacetic, propane-sulphonylchloride.

Data mass spectrum (m/z): 563 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.08 (3H, t, J=7.3 Hz), 1.45 (9H, s), 1.63-1.73 (2H, m), 1.80-2.00 (4H, m), 3.02-3.09 (2H, m), 3.24-3.34 (2H, m), 3.59 - 3.69 (2H, m), 4.33-4.41 (1H, m), 4.98 (2H, s), 6.79 (2H, d, J=9.3 Hz), 7.15 (2H, d, J=9.3 Hz), 7.58 (1H, dd, J=8.3, 1.5 Hz), 7.64 (1H, s), 7.69 (1H, dd, J=8.8, 1.5 Hz), 7.84 (1H, d, J=8.3 Hz), 7.87 (1H, d, J=8.3 Hz), 8.12 (1H, s).

Reference Example 34

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7-cyano-2-naphthyl) methyl]butanesulfonate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]-methyl]-2-naphthaleneacetic, 1-butanesulfonate.

Data mass spectrum (m/z): 517 (M)+.

Reference Example 35

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7-cyano-2 - naphthyl)methyl]triftormetilfullerenov.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperonyl)oxy] aniline]methyl]-2-naphthaleneacetic, triftormetilfullerenov anhydride.

Data mass spectrum (m/z): 590 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (S, s), 1.56-1.92 (4H, m), 3.11-3.82 (4H, m), 4.22-4.51 (1H, m), 5.02 (2H, s), 6.65-7.18 (4H, m), 7.46-7.97 (5H, m), 8.11 (1H, s).

Reference Example 36

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N- [(7-cyano-2-naphthyl)methyl]isopropanolamide.

The source connection: 7-[[4-[(1- tert-butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2 - naphthaleneacetic, isopropylacetanilide.

Data mass spectrum (m/z): 563 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (S, s), 1.46 (6N, d, J=6.8 Hz), 1.59-1.93 (4H, m), 2.97-3.84 (5H, m), 4.20-4.52 (1H, m), 5.03 (2H, s), 6.64-7.26 (4H, m), 7.44-7.96 (5H, m), 8.08 (1H, s).

Reference Example 37

Ethyl-N-[N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]-phenyl]-N-[(7-cyano-2 - naphthyl)methyl]sulfamoyl]carbamate.

IP is loralei)carbamate. Ethyl(chlorosulfonyl)carbamate get as well as tert-butyl(chlorosulfonyl)carbamate described in Tetrahedron, 49(1), 65 (1993).

Data mass spectrum (m/z): 608 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.37 (3H, t, J=7.1 Hz), 1.45 (S, s), 1.62-1.74 (2H, m), 1.80-1.92 (2H, m), 3.25-3.34 (2H, m), 3.60-3.71 (2H, m), 4.29-4.42 (3H, m), 5.21 (2H, s), 6.80 (2H, d, J=8.8 Hz), 7.08-7.20 (3H, m), 7.58 (1H, dd, J=8.3, 1.5 Hz), 7.62-7.69 (2H, m), 7.84 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=8.3 Hz), 8.13 (1H, s).

Reference Example 38

N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]-4 - nitrobenzenesulfonamide.

The source connection: 7-[[4-[(1-tert - butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic, 4-nitro-benzosulphochloride.

Data mass spectrum (m/z): 642 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (S, s), 1.62-1.94 (4H, m), 3.07-3.83 (4H, m), 4.21-4.48 (1H, m), 4.90 (2H, s), 6.61-6.92 (4H, m), 7.50-8.04 (7H, m), 8.10 (1H, s), 8.31 (1H, s), 8.41 (1H, s).

Reference Example 39

4-[N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]benzoic acid.

The source connection: 7- [[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2 - naphthaleneacetic, 4-(chlorosulfonyl)benzoic sour THE MS):

: 1.32-1.47 (11N, m), 7.5-8.6 (2H, m), 3.0-3.15 (2H, m), 3.55-3.66 (2H, m), 4.37-4.47 (1H, m), 4.97 (2H, s), 6.80 (2H, d, J=8.8 Hz), 6.96 (2H, d, J= 9.3 Hz), 7.67 (1H, d, J=8.8 Hz), 7.74 (1H, dd, J=1.5, 8.3 Hz), 7.81 (2H, d, J= 8.3 Hz), 7.89 (1H, s), 8.00 (1H, d, J=8.3 Hz), 8.07 (1H, d, J=8.8 Hz), 8.15 (2H, d, J=8.3 Hz), 8.52 (1H, s), 13.52 (1H, bs).

Reference Example 40

3-N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N- [(7-cyano-2-naphthyl)methyl]sulfamoyl]benzoic acid.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline]-methyl]-2 - naphthaleneacetic, 3-(chlorosulfonyl)benzoic acid.

Data mass spectrum (m/z): 640 (M-1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.32-1.46 (11N, m), 1.72-1.85 (2H, m), 3.02-3.15 (2H, m), 3.52-3.66 (2H, m), 4.37-4.47 (1H, m), 4.96 (2H, s), 6.81 (2H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.66 (1H, d, J=8.3 Hz), 7.70-7.83 (2H, m), 7.90 (1H, s), 7.92-8.09 (4H, m), 8.27 (1H, d, J=7.8 Hz), 8.51 (1H, s), 13.51 (1H, s).

Reference Example 41

Methyl-2-N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]-phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]benzoate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline]methyl]-2 - naphthaleneacetic, methyl-2-(chlorosulfonyl)benzoate.

Data mass spectrum (m/z): 655 (M)+.

These NMR spectrum (CDCl3internal standard TMS):

: 1.55 (9H, s.52-7.62 (3H, m), 7.65 (1H, s), 7.70 (1H, d, J=8.5 Hz), 7.83 (1H, d, J=8.6 Hz), 7.87 (1H, d, J=8.6 Hz), 8.11 (1H, s).

Reference Example 42

Tert-butyl N-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -phenyl]-N- [(7-cyano-2-naphthyl)methyl]sulfamoyl]carbamate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline] methyl] -2 - naphthaleneacetic, tert-butyl(chlorosulfonyl)carbamate. The technique of synthesis of tert-butyl(chlorosulfonyl)carbamate described in Tetrahedron, 49(1), 65 (1993).

Data mass spectrum (m/z): 636 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (9H, s), 1.57 (M, s), 1.63-1.73 (2H, m), 1.80-1.91 (2H, m), 3.25-3.35 (2H, m), 3.60-3.70 (2H, m), 4.33-4.43 (1H, m), 5.21 (2H, s), 6.80 (2H, d, J=9.3 Hz), 7.00 (1H, bs), 7.18 (2H, d, J=8.8 Hz), 7.58 (1H, dd, J=1.7, 8.5 Hz), 7.62-7.70 (2H, m), 7.84 (1H, d, J=6.6 Hz), 7.87 (1H, d, J=8.3 Hz), 8.13 (1H, s).

Reference Example 43

Ethyl-N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]acetate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline] methyl] -2-naphthaleneacetic, ethyl-(chlorosulfonyl)acetate. The technique of synthesis of ethyl(chlorosulfonyl)acetate described in Synthetic Letters, 321, 1975.

Data mass spectrum (m/z): 608 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):
Ethyl-3-N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -phenyl] - N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]propionate.

The source connection: 7-[[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] aniline] methyl] - 2-naphthaleneacetic, ethyl-3-(chlorosulfonyl)propionate obtained by the method similar to ethyl(chlorosulfonyl)acetate.

Data mass spectrum (m/z): 622 (M+1)+.

These NMR spectrum (CDCl3internal standard TMS):

: 1.28 (3H, t, J=7.3 Hz), 1.45 (S, s), 1.56-1.94 (4H, m), 2.71 - 3.08 (2H, m), 3.00-3.82 (6N, m), 4.19 (2H, q, J=7.1 Hz), 4.35-4.53 (1H, m), 4.96 (2H, s), 6.71-7.24 (4H, m), 7.48-7.94 (5H, m), 8.12 (1H, s).

Reference Example 45

Tert-butyl N-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -phenyl]-N- [(7-cyano-2-naphthyl)methyl]sulfamoyl]carbamate obtained in reference Example 42 (172 mg), dissolved in 0.7 ml of tetrahydrofuran, to the solution at 0oC give 139 mg of triphenylphosphine, 32 μl of methanol and 83 μl of diethylazodicarboxylate and the resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture is evaporated and the resulting residue purified by chromatography on a column of silica gel, using as eluent a mixture of hexane and ethyl acetate (85: 15), and obtain 153 mg of Tert-butyl N-[N-[4-[(1 - tert-butoxycarbonyl-4-Pipa is M)+< / BR>
These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (S, s), 1.57-1.73 (11N, m), 1.80-1.92 (2H, m), 2.93 (3H, s), 3.24-3.35 (2H, m), 3.60-3.72 (2H, m), 4.33-4.42 (1H, m), 5.19 (2H, s), 6.79 (2H, d, J= 9.3 Hz), 7.15 (2H, d, J=8.8 Hz), 7.57 (1H, dd, J=1.5, 8.3 Hz), 7.64-7.70 (2H, m), 7.84 (1H, d, J=8.3 Hz), 7.87 (1H, d, J=8.3 Hz), 8.13 (1H, s).

Reference Example 46

7-formyl-2 - naphthaleneacetic obtained in reference Example 1 (3.0 g), dissolved in 50 ml of acetone. The solution is cooled to 0oC with stirring, and adding thereto a solution prepared by dissolving 10 g of chromium oxide (IV) in 11 ml of concentrated sulfuric acid, and 50 ml of water until, until the mixture will turn yellow-orange color. The solution was stirred at 0oC for 90 minutes and then at room temperature for 45 minutes and then add 2 ml of isopropyl alcohol. The mixture is evaporated, to the residue water is added, and then extracted with ethyl acetate. An ethyl acetate layer is extracted with saturated aqueous sodium bicarbonate, attributability extract was adjusted to pH 1 using concentrated sulfuric acid and the resulting solid precipitate is filtered, receiving of 1.94 g of 7-cyano-2-naphthaleneboronic acid.

Data mass spectrum (m/z): 197 (M)+.

These NMR spectrum (DMSO, internal one hundred the ANO-2-naphthaleneboronic acid, obtained in reference Example 46 (1.5 g), and 2.2 g of 4-[(1-tert - butoxycarbonyl-4-piperidyl)oxy]aniline are dissolved in 30 ml of dimethylformamide, to the solution was added to 1.75 g of 1-ethyl-3-(3 - dimethylaminopropyl)-carbodiimides, of 1.03 g of 1-hydroxybenzotriazole and 1.26 ml of triethylamine and the resulting mixture was stirred at room temperature for one day. The reaction mixture is filtered and the filtrate evaporated. The obtained residue is recrystallized from ethanol, obtaining 2.7 g of N-[4-[(1 - tert-butoxycarbonyl-4-piperidyl)-oxy] phenyl] -7-cyano-2 - naphthaleneboronic.

Data mass spectrum (m/z): 471 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.48 (S, s), 1.70-1.80 (2H, m), 1.85-1.98 (2H, m), 3.28-3.40 (2H, m), 3.65-3.7 (2H, m), 4.41-4.50 (1H, m), 6.94 (2H, d, J=8.8 Hz), 7.59 (2H,d, J= 8.8 Hz), 7.71 (1H, d, J=9.0 Hz), 7.94-8.03 (2H, m), 8.06-8.15 (2H, m), 8.29 (1H, s), 8.41 (1H, s).

Reference Example 48

N-[4-[(1-tert-butoxycarbonyl-4-piperidyl) -oxy] phenyl]-7-cyano-2-naphthaleneboronic obtained in reference Example 47 (200 mg), dissolved in 4 ml of dimethylformamide, to the solution was added 52 mg of sodium hydride (60%) and the resulting mixture was stirred at room temperature for 20 minutes. Next, with stirring, to the reaction mixture at 0oC dropwise pribavlenie at room temperature. The reaction mixture was evaporated and to the obtained residue is added ethyl acetate. The mixture is washed successively with a saturated aqueous solution of sodium bicarbonate and 10% citric acid, dried over anhydrous sodium sulfate and then evaporated. The resulting residue is purified by chromatography on a column of silica gel, using as eluent a mixture of hexane:ethyl acetate (8:2-7:3), and obtain 143 mg of N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)-oxy] phenyl]-7-cyano-N-methylsulphonyl-2-naphthaleneboronic.

Data mass spectrum (m/z): 550 (M+1)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.45 (S, s), 1.59-1.71 (2H, m), 1.79-1.89 (2H, m), 3.23-3.33 (2H, m), 3.48 (3H, s), 3.58-3.69 (2H, m), 4.33-4.41 (1H, m), 6.80 (2H, d, J= 8.8 Hz), 7.21 (2H, d, J=8.8 Hz), 7.63-7.77 (3H, m), 7.86 (1H, d, J=8.3 Hz), 8.12 (2H, s).

The following compound of reference Example 49 receive the same manner as in reference Example 45.

Reference Example 49

Ethyl-N-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7 - cyano-2-naphthyl)methyl]sulfamoyl]-N-methylcarbamate.

Starting compound: Ethyl-N-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N- [(7-cyano-2-naphthyl)methyl]sulfamoyl]-carbamate, methanol.

Data mass spectrum (m/z): 622 (M)+.

Dannie.61-3.71 (2H, m), 4.33-4.45 (3H, m), 5.18 (2H, s), 6.79 (2H, d, J=9.3 Hz), 7.11 (2H, d, J=8.8 Hz), 7.58 (1H, dd, J=1.5, 8.8 Hz), 7.62-7.70 (2H, m), 7.85 (1H, d, J=8.3 Hz), 7.88 (1H, d, J-8.3 Hz), 8.13 (1H, s).

Reference Example 50

Ethyl-N-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] - N-[(7-cyano-2-naphthyl)methyl] sulfamoyl] carbamate (1 g) dissolved in 10 ml of dimethylformamide, to the solution was added 376 mg methylpropanoate, 339 mg of potassium carbonate and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated and to the residue water is added and the mixture extracted with chloroform. The extract is dried over anhydrous sodium sulfate and then evaporated. The resulting residue is purified by chromatography on a column of silica gel, using as eluent a mixture of hexane:ethyl acetate (8:2), and get 1,097 g of methyl N-[N-[4-[(1 - tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] N-(7-cyano-2 - naphthyl)methyl]sulfamoyl]-N-ethoxycarbonylphenyl

Data mass spectrum (m/z): 680 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.38 (3H, t, J=7.1 Hz), 1.45 (S, s), 1.62-1.74 (2H, m), 1.80-1.91 (2H, m), 3.24-3.35 (2H, m), 3.60-3.71 (5H, m), 4.21 (2H, s), 4.34-4.44 (3H, m), 5.19 (2H, m), 6.78 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz), 7.58 (1H, d, J= 8.5 Hz), 7.62-7.69 (2H, m), 7.84 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=8.8 Hz), 8.12 (1H, s).

Following connection of the reference P(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N- [(7-cyano-2-naphthyl)methyl]sulfamoyl]-N-tert-butoxycarbonylmethyl.

Starting compound: tert-butyl N-[N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]-sulfamoyl]carbamate, ethylbromoacetate.

Data mass spectrum (m/z): 722 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.24 (3H, t, J=7.1 Hz), 1.45 (S, s), 1.58 (9H, s), 1.60-1.76 (2H, m), 1.80-1.92 (2H, m), 3.24-3.35 (2H, m), 3.60-3.71 (2H, m), 4.08-4.20 (4H, m), 4.32-4.42 (1H, m), 5.19 (2H, s), 6.77 (2H, d, J=8.8 Hz), 7.15 (2H, d, J= 8.8 Hz), 7.57 (1H, d, J=8.3 Hz), 7.62-7.70 (2H, m), 7.83 (1H, d, J=8.3 Hz), 7.87 (1H, d, J=8.3 Hz), 8.12 (1H, s).

Reference Example 52

Methyl-5-hydroxyanthranilate (835 mg) dissolved in 10 ml of tetrahydrofuran, to the solution was added 863 mg of 1-tert-butoxy-carbonyl-4-hydroxypiperidine, 1,572 mg of triphenylphosphine and 1,044 mg of diethylazodicarboxylate and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was evaporated and to the obtained residue is added ethyl acetate. The mixture is washed successively with a saturated aqueous solution of sodium bicarbonate and 10% citric acid, dried over anhydrous sodium sulfate and then evaporated. The resulting residue is purified by chromatography on a column of silica gel, using as eluent a mixture of hexane:ethyl acetate (85:15), and receive 716 mg of methyl-5-[(1-tert - butoxycarbonyl-4-piperidyl)-oxy]anthra the art TMS):

: 1.47 (9H, s), 1.63-1.76 (2H, m), 1.80-1.93 (2H, m), 3.22-3.32 (2H, m), 3.62-3.75 (2H, m), 3.87 (3H, s), 4.23-4.31 (1H, m), 5.47 (2H, bs), 6.63 (1H, d, J=8.5 Hz), 6.96 (1H, dd, J=8.5, 3.1 Hz), 7.41 (1H, d, J=3.1 Hz).

The following compound of reference Example 53 receive the same manner as in reference Example 2.

Reference Example 53

Methyl-5-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -N-[(7-cyano-2-naphthyl) methyl]anthranilate.

Starting compound: methyl-5-[(1-tert - butoxycarbonyl-4-piperidyl)oxy] anthranilate, 7-formyl-2-naphthaleneacetic.

Data mass spectrum (m/z): 515 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.46 (9H, s), 1.61-1.73 (2H, m), 1.79-1.91 (2H, m), 3.21-3.31 (2H, m), 3.61-3.73 (2H, m), 3.89 (3H, s), 4.21-4.30 (1H, m), 4.62 (2H, s), 6.55 (1H, d, J=9.1 Hz), 6.95 (1H, dd, J=9.1, 3.1 Hz), 7.52 (1H, d, J=3.0 Hz), 7.58 (1H, d, J= 8.2 Hz), 7.64 (1H, d, J=8.5 Hz), 7.83 (1H, s), 7.87 (1H, d, J= 8.5 Hz), 7.89 (1H, d, J=8.5 Hz), 8.05 (1H, bs), 8.18 (1H, s).

The following compound of reference Example 54 receive the same manner as in reference Example 2.

Reference Example 54

7-[[4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]- aniline]methyl] -2-naphthaleneacetic.

Starting compound: 7-formyl-2-naphthaleneacetic, 4-[[(3S)-1-tert-butoxycarbonyl-4 - pyrrolidinyl]oxy]aniline.

Data mass spectrum (m/z): 443 (M)<0 (1H, bs), 4.50 (2H, s), 4.68-4.77 (1H, m), 6.54-6.66 (2H, m), 6.74 (2H, d, J=8.8 Hz), 7.58 (1H, d, J=8.3 Hz), 7.66 (1H, d, J=9.8 Hz), 7.85-7.93 (3H, m), 8.17-8.23 (1H, m).

The following compound of reference Example 55 receive the same manner as in reference Example 18.

Reference Example 55

Ethyl-N-[N-[[4-[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl] -oxy] phenyl] -N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]carbamate.

The source connection: 7-[[4-[[(3S)-1-tert-butoxycarbonyl-3 - pyrrolidinyl]oxy]aniline]methyl]-2-naphthaleneacetic.

Data mass spectrum (m/z): 594 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 1.36 (3H, t, J=6.8 Hz), 1.44 (9H, s), 1.96-2.20 (2H, m), 3.39-3.60 (4H, m), 4.33 (2H, q, J=6.8 Hz), 4.70-4.82 (1H, m), 5.21 (2H, s), 6.75 (2H, d, J= 8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 7.32 (1H, bs), 7.58 (1H, d, J=8.6 Hz), 7.62-7.70 (2H, m), 7.84 (1H, d, J=8.3 Hz), 7.87 (1H, d, J=8.3 Hz), 8.13 (1H, s).

Reference Example 56

Ethyl-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl] sulfamoyl]acetate (500 mg) dissolved in 10 ml of acetonitrile, the solution is added to the value of 0.52 ml of methyl iodide and 136 mg of potassium carbonate and the resulting mixture is stirred at a temperature of education phlegmy within 5 hours and 30 minutes. After cooling the reaction mixture, the precipitate is filtered off, the filtrate is concentrated under reduced pressure. EN: ethyl acetate (3: 1), and get 415 mg of ethyl 2-[N-[-4-[(1 - tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7-cyano-2-naphthyl) methyl]sulfamoyl] propionate.

Data mass spectrum (m/z): 621 (M)+.

These NMR spectrum (CDCl3internal standard TMS):

: 1.25-2.15 (19H, m), 3.08-3.79 (4H, m), 4.00-5.32 (6N, m), 6.65-6.89 (2H, m), 7.18-7.38 (2H, m), 7.41-8.07 (6N, m).

The following compounds of reference Examples 57 and 58 receive the same manner as in reference Example 56.

Reference Example 57

Ethyl-2-[N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]butyl.

Starting compound: ethyl-N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2 - naphthyl)methyl]sulfanilate.

Data mass spectrum (m/z): 635 (M)+.

These NMR spectrum (CDCl3, internal standard TMS):

: 0.90-1.11 (6N, m), 1.45 (S, s), 1.50-2.32 (6N, m), 3.12 - 4.10 (4H, m), 4.14-5.25 (6N, m), 6.67-6.87 (2H, m), 7.16-7.32 (2H, m), 7.44-7.92 (7H, m), 8.05 (1H, s).

Reference Example 58

Ethyl-2-[N-[4-[(1-tert-butoxycarbonyl 4 piperidyl] oxy]phenyl]-N- [(7-cyano-2 - naphthyl)methyl]sulfamoyl]valerate.

Starting compound: ethyl-[N-[4- [(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2 - naphthyl)methyl]sulfamoyl]acetate.

Data M06 (6N, m), 1.15-1.40 (4H, m), 1.45 (S, s), 1.54-2.32 (4H, m), 3.08-3.83 (4H, m), 3.92-5.28 (6N, m), 6.71-6.89 (2H, m), 7.19-7.36 (2H, m), 7.45-7.94 (7H, m), 8.05 (1H, s).

EXAMPLE 1

N-[4-[1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano - 2-naphthyl)methyl] acetamide", she obtained in reference Example 3 (128 mg), dissolved in a mixed solvent of 2 ml of dichloromethane and 5 ml of ethanol. With stirring, the solution is cooled to -20oC and saturated with hydrogen chloride. The mixture was stirred at 5oC for 4 days and then evaporated. To the obtained residue was added ethanol solution (5 ml) saturated with ammonia at 10oC, and the mixture was stirred at 5oC for 6 days. The reaction mixture is evaporated, the obtained residue is purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70), using as eluent a mixture of methanol:water (2:98), and then add a small amount of 1N hydrochloric acid and lyophilizers, receiving 92 mg of N-[(7-amidino-2-naphthyl)methyl]-N-[4-[(4 - piperidyl)oxy]phenyl]acetamidomalonate.

Data mass spectrum (m/z): 417 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.75-7.85 (2H, m), 1.86 (3H, s), 2.03-2.11 (2H, m), 2.96-3.05 (2H, m), 3.13-3.22 (2H, m), 4.53-4.64 (1H, m), 5.03 (2H, s), 6.96 (2H, d, J= 8.5 Hz), 7.15 (2H, d, J=8.5 Hz), 7.59 (1H, d, J=8.6 Hz), 7.81 (1H, d, J=8.6 Hz), 7.85 (1H, s), 8.01 (1H, shall obtain in the same way, as the compound of EXAMPLE 1.

EXAMPLE 2

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl] oksamida the dihydrochloride.

Starting compound: ethyl-N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N- [(7-cyano-2-naphthyl)methyl]oximat.

Data mass spectrum (m/z): 446 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 1.72-1.80 (2H, m), 2.00-2.09 (2H, m), 2.95-3.05 (2H, m), 3.11-3.21 (2H, m), 4.52-4.60 (1H, m), 5.01 (2H, s), 6.90 (2H, d, J=9.2 Hz), 7.15 (2H, d, J= 8.5 Hz), 7.47 (1H, s), 7.61 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.89 (1H, s), 8.04 (2H, d, J=8.5 Hz), 8.08-8.13 (3H, m), 8.46 (1H, s), 9.05 (1H, bs), 9.13 (1H, bs), 9.29 (2H, s), 9.52 (2H, s).

EXAMPLE 3

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl] - cyclopropanecarboxamide the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl] cyclopropanecarboxamide.

Data mass spectrum (m/z): 443 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.67-0.63 (2H, m), 0.80-0.88 (2H, m), 1.34-1.38 (1H, m), 1.80-1.82 (2H, m), 2.00-2.10 (2H, m), 3.01-3.04 (2H, m), 3.12-3.18 (2H, m), 4.60-4.62 (1H, m), 5.06 (2H, s), 6.98 (2H, d, J=9.2 Hz), 7.16 (2H, d, J=9.2 Hz), 7.54 (1H, d, J= 8.0 Hz), 7.81 (1H, s), 7.82 (1H, d, J=9.8 Hz), 8.01 (1H, d, J= 8.6 Hz), 8.10 (1H, d, J=9.2 Hz), 8.48 (1H, s), 9.17 (1H, bs), 9.24 (1H, bs), 9.33 (2H, s), 9.52 (2H, s).

An EXAMPLE is Obedinenie: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]benzamide.

Data mass spectrum (m/z): 479 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.72-1.74 (2H, m), 1.97-2.00 (2H, m), 2.95-2.98 (2H, m), 3.10-3.12 (2H, m), 4.49-4.51 (1H, m), 5.26 (2H, s), 6.78 (2H, d, J=9.2 Hz), 7.03 (2H, d, J= 8.6 Hz), 7.24-7.30 (3H, m), 7.36 (2H, d, J=7.3 Hz), 7.68 (1H, d, J= 8.5 Hz), 7.84 (1H, d, J=8.5 Hz), 7.97 (1H, s), 8.03 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.55 (1H, s), 9.23 (1H, bs), 9.32 (1H, bs), 9.41 (2H, s), 9.58 (2H, s).

EXAMPLE 5

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]-ethanolbased the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]ethanolbased.

Data mass spectrum (m/z): 431 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 0.99 (3H, t, J=7.3 Hz), 1.84-1.85 (2H, m), 2.09-2.10 (4H, m), 3.02-3.04 (2H, m), 3.14-3.16 (2H, m), 5.04 (2H, s), 6.97 (2H, d, J=9.1 Hz), 7.12 (2H, d, J= 9.0 Hz), 7.68 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=8.5 Hz), 7.88 (1H, s), 8.01-8.11 (2H, m), 8.56 (1H, s), 9.20 (1H, bs), 9.32 (1H, bs), 9.52 (2H, s), 9.69 (2H, s).

EXAMPLE 6

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy] phenyl] -cyclohexanecarboxylic the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl] cyclohexanecarboxylic.

Data mass spectrum (m/z): 485 (M-2HCl + 1)+.

Da (4H, m), 1.81-1.83 (2H, m), 2.06-2.10 (2H, m), 2.18-2.23 (1H, m), 3.00-3.04 (2H, m), 3.16-3.18 (2H, m), 4.60-4.62 (1H, m), 4.98 (2H, s), 6.97 (2H, d, J=8.6 Hz), 7.09 (2H, d, J=8.5 Hz), 7.54 (1H, d, J=7.3 Hz), 7.79 (1H, s), 7.83 (1H, d, J=6.7 Hz), 8.01 (1H, d, J=8.6 Hz), 8.10 (1H, drJ= 9.2 Hz), 8.49 (1H, s), 9.22 (1H, bs), 9.29 (1H, bs), 9.37 (2H,. s), 9.55 (2H, s).

EXAMPLE 7

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl) oxy]phenyl]-1-naphthaleneboronic the dihydrochloride.

Starting compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]-1-naphthaleneboronic.

Data mass spectrum (m/z): 529 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.60-1.64 (2H, m), 1.84-1.89 (2H, m), 2.86-2.90 (2H, m), 3.01-3.05 (2H, m), 4.32-4.36 (1H, m), 5.40 (1H, s), 6.59 (2H, d, J=9.2 Hz), 6.95 (2H, d, J= 8.5 Hz), 7.34 (1H, t, J=7.9 Hz), 7.44 (1H, d, J=7.3 Hz), 7.52 (1H, t, J= 7.3 Hz), 7.61 (1H, t, J=7.9 Hz), 7.81 (2H, t, J=8.5 Hz), 7.87 (2H, d, J=7.3 Hz), 8.03 (1H, s), 8.07 - 8.15 (3H, m), 8.61 (1H, s), 9.20 (1H, bs), 9.30 (1H, bs), 9.45 (2H, s), 9.64 (2H, s).

EXAMPLE 8

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy] phenyl]-2-fermentated the dihydrochloride.

Starting compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]- N-[(7-cyano-2-naphthyl)methyl]-2-perbenzoic.

Data mass spectrum (m/z): 497 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.68-1.71 (2H, m), 1.90-1.96 (2H, m), 2J=6.1 Hz), 7.69 (1H, d, J=8.6 Hz), 7.85 (1H, d, J=8.5 Hz), 7.96 (1H, s), 8.07 (1H, d, J=8.6 Hz), 8.13 (1H, d, J=8.5 Hz), 8.53 (1H, s), 9.18 (1H, bs), 9.26 (1H, bs), 9.39 (2H, s), 9.58 (2H, s).

EXAMPLE 9

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]-3-methoxybenzamide the dihydrochloride.

Starting compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl] -3-methoxybenzamide.

Data mass spectrum (m/z): 509 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.70-1.76 (2H, m), 1.92-2.01 (2H, m), 2.91-2.97 (2H, m), 3.11-3.16 (2H, m), 3.64 (3H, s), 4.50 - 4.52 (1H, m), 5.26 (2H, s), 6.80 (2H, d, J= 9.2 Hz), 6.85 (1H, d, J=6.1 Hz), 6.90-6.93 (2H, m), 7.05 (2H, d, J=7.9 Hz), 7.15 (1H, t, J=7.9 Hz), 7.68 (1H, d, J=9.8 Hz), 7.83 (1H, d, J=6.7 Hz), 7.95 (1H, s), 8.03 (1H, d, J=8.5 Hz), 8.11 (1H, d, J=8.55 Hz), 8.54 (1H, s), 9.18 (1H, bs), 9.24 (1H, bs), 9.36 (2H, s), 9.55 (2H, s).

EXAMPLE 10

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]-2-typename the dihydrochloride.

Starting compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]-2-typename.

Data mass spectrum (m/z): 485 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.81-1.83 (2H, m), 2.03-2.07 (2H, m), 3.00-3.07 (2H, m), 3.15-3.18 (2H, m), 4.61-4.65 (1H, m), 5.20 (2H, s), 6.76 (1H, s), 6.93 (1H, t, J= 4.3 Hz), 6.98 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.6 Hz), 7.65-7.68 (2H, m), 7.83 (1H, d, J=8.6 Hz), 7.94 (1H, s), 8.-N-[4-[(4-piperidyl)oxy]phenyl]-2 - pyridinecarboxamide trihydrochloride.

Starting compound: N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]-3 - pyridine-carboxamide.

Data mass spectrum (m/z): 480 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.71-1.75 (2H, m), 1.96-1.99 (2H, m), 2.95-2.97 (2H, m), 3.00-3.17 (2H, m), 4.50-4.52 (1H, m), 5.30 (1H, s), 6.82 (2H, d, J=8.6 Hz), 7.15 (2H, d, J= 8.5 Hz), 7.65-7.67 (1H, m), 7.73 (1H, d, J=8.6 Hz), 7.84 (1H, d, J= 8.6 HZ), 8.01 (1H, s), 8.04 (1H, d, J=7.9 Hz), 8.12 (1H, d, J=8.6 Hz), 8.14-8.15 (1H, m), 8.56 (1H, s), 8.66 (1H, s), 8.75 (1H, s), 9.21 (2H, bs), 9.38 (1H, bs), 9.40 (2H, s), 9.58 (2H, s).

EXAMPLE 12

N-[(7-amidino-2 - naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]phenyl]-ndimethylacetamide the dihydrochloride (56 mg) dissolved in 2 ml of ethanol, to the solution was added 28 mg of ethylacetoacetate and 36 mg of triethylamine and the mixture is stirred at room temperature for 2 days and then evaporated. The resulting residue is purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70), using as eluent a mixture of methanol: water (2:98), and then add a small amount of 1N hydrochloric acid and lyophilizers, receiving 60 mg of N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7 - amidino-2-naphthyl)methyl]-acetamidomalonate.

Data mass spectrum (m/z): 458 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

The following compounds of EXAMPLES 13-22 receive the same manner as the compound of EXAMPLE 12.

EXAMPLE 13

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]oksamida the dihydrochloride.

Starting compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy]phenyl]oksamida the dihydrochloride

Data mass spectrum (m/z): 487 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.61-1.75 (2H, m), 1.95-2.05 (2H, m), 2.27 (3H, s), 3.43-3.54 (2H, m), 3.45-3.75 (1H, m), 3.75-3.82 (1H, m), 4.61 (1H, bs), 5.08 (2H, s), 6.91 (2H, d, J= 8.5 Hz), 7.15 (1H, d, J=8.5 Hz), 7.47 (1H, s), 7.62 (1H, d, J= 8.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.90 (1H, s), 8.04 (1H, d, J=8.5 Hz), 8.10-8.15 (2H, m), 8.46 (1H, s), 8.75 (1H, s), 8.24 (2H, s), 8.27 (1H, s), 9.50 (2H, s).

EXAMPLE 14

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl] cyclopropanecarboxamide the dihydrochloride.

Starting compound: N-[(7 - amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy]phenyl] cyclopropanecarboxamide the dihydrochloride.

Data mass spectrum (m/z): 484 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.64-0.68 (2H, m), 0.84-0.89 (2H, m), 1.37 - 1.39 (1H, m), 1.68-1.75 (2H, m, .01 (1H, d, J=8.6 Hz), 8.10 (1H, d, J=8.6 Hz), 8.47 (1H, s), 8.79 (1H, s), 9.22-9.30 (3H, m), 9.49 (2H, s).

EXAMPLE 12

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]benzamide the dihydrochloride.

Starting compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]benzamide the dihydrochloride.

Data mass spectrum (m/z): 520 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.51-1.61 (2H, m), 1.87-1.99 (2H, m), 2.26 (3H, m), 3.02-3.08 (2H, m), 3.62-3.71 (2H, m), 4.52-4.59 (1H, m), 5.27 (2H, s), 6.79 (2H, d, J= 8.6 Hz), 7.02 (2H, d, J=8.5 Hz), 7.13 (1H, s), 7.23-7.35 (4H, m), 7.69 (1H, d, J= 8.4 Hz), 7.81 (1H, d, J=8.5 Hz), 7.97 (1H, s), 8.03 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.52 (1H, s), 8.74 (1H, s), 9.27 (3H, s), 9.50 (2H, s).

EXAMPLE 16

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -M-[(7-amidino - 2-naphthyl)methyl]ethanolbased the dihydrochloride.

Starting compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl]ethanolbased the dihydrochloride.

Data mass spectrum (m/z): 472 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.99 (3H, t, J=9.3 Hz), 1.64-1.80 (2H, m), 1.94-2.14 (4H, m), 2.28 (3H, s), 3.02-3.09 (2H, m), 3.62-3.80 (2H, m), 4.60-4.64 (1H, m), 5.03 (2H, s), 6.95 (2H, d, J=9.2 Hz), 7.12 (2H, d, J=8.5 Hz), 7.48 (1H, d, J=8.5 Hz), 7.78-7.86 (2H, m), 8.00 (1H, d, J=8.4 Hz), 8.11 (1H, d, J=8.6 Hz), 8.48 (1H, s), 8.82 (1H, s), 9.30 (3H, s), 9.51 (2H, s).

Starting compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]cyclohexanecarboxylic the dihydrochloride.

Data mass spectrum (m/z): 526 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.90-0.93 (2H, m), 1.13-1.16 (1H, m), 1.43-1.46 (2H, m), 1.50-1.53 (1H, m), 1.64-1.70 (6N, m), 2.00-2.10 (2H, m), 2.10-2.21 (1H, m), 2.28 (3H, s), 3.45-3.49 (2H, m), 3.69-3.80 (2H, m), 4.64-4.68 (1H, m), 4.99 (2H, s), 6.97 (2H, d, J=8.6 Hz), 7.09 (2H, d, J=8.5 Hz), 7.54 (1H, d, J=8.5 Hz), 7.79-7.83 (2H, m), 8.01 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.47 (1H, s), 8.80 (1H, s), 9.30 (3H, s), 9.51 (2H, s).

EXAMPLE 18

N-[4-[(1-acetimidoyl - 4 - piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl]-1-naphthaleneboronic the dihydrochloride.

Starting compound: N-[(7-amidino-2-naphthyl)methyl] - N-[4-[(4-piperidyl)oxy]phenyl]-1-naphthaleneboronic the dihydrochloride.

Data mass spectrum (m/z): 570 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 1.42-1.55 (2H, m), 1.78-1.89 (2H, m), 2.27 (3H, s), 3.37-3.42 (2H, m), 3.57-3.65 (2H, m), 4.38-4.44 (1H, m), 5.39 (2H, s), 6.59 (2H, d, J= 8.8 Hz), 6.95 (2H, d, J=8.3 Hz), 7.34 (1H, t, J=7.8 Hz), 7.43 (1H, d, J=6.8 Hz), 7.53 (1H, t, J=7.3 Hz), 7.62 (1H, t, J=7.3 Hz), 7.79-7.89 (4H, m), 8.04-8.17 (4H, m), 8.53 (1H, s), 8.61 (1H, s), 9.17 (3H, s), 9.48 (2H, s).

EXAMPLE 19

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]-2-fermentated the dihydrochloride.rochloride.

Data mass spectrum (m/z): 538 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.52-1.62 (2H, m), 1.86-1.94 (2H, m), 2.25 (3H, s), 3.40-3.45 (2H, m), 3.65-3.73 (2H, m), 4.46-4.56 (1H, m), 5.26 (2H, s), 6.75 (2H, d, J= 8.6 Hz), 6.99 (2H, d, J=8.6 Hz), 7.05 (1H, t, J=8.5 Hz), 7.11 (1H, t, J=7.3 Hz), 7.30-7.32 (1H, m), 7.69 (1H, d, J=7.9 Hz), 7.83 (1H, d, J=8.6 Hz), 7.96 (1H, s), 8.07 (1H, d, J=8.6 Hz), 8.13 (1H, d, J=8.5 Hz), 8.50 (1H, s), 8.76 (1H, s), 9.31 (3H, s), 9.53 (2H, s).

EXAMPLE 20

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]-3-methoxybenzamide the dihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]-3-methoxybenzamide the dihydrochloride.

Data mass spectrum (m/z: 549 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.5.7-1.68 (2H, m), 1.90-1.98 (2H, m), 2.25 (3H, s), 3.41-3.48 (2H, m), 3.63 (3H, s), 3.70-3.78 (2H, m), 4.54-4.58 (1H, m), 5.26 (2H, s), 6.80 (2H, d, J=9.2 Hz), 6.85-6.94 (3H, m), 7.05 (2H, d, J=7.9 Hz), 7.16 (1H, t, J= 7.9 Hz), 7.68 (1H, d, J=8.5 Hz), 7.81 (1H, d, J=7.3 Hz), 7.97 (1H, s), 8.03 (1H, d, J= 8.5 Hz), 8.11 (1H, d, J=8.6 Hz), 8.51 (1H, s), 8.72 (1H, s), 9.24 (3H, s), 9.49 (2H, s).

EXAMPLE 21

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7 - amidino-2-naphthyl)methyl]typenames the dihydrochloride.

Source connection:

N-[(7-amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl) oxy]phenyl]-2-typename the dihydrochloride.

R>
: 1.64-1.71 (2H, m), 1.98-2.08 (2H, m), 2.29 (3H, s), 3.42-3.58 (2H, m), 3.71-3.82 (2H, m), 4.62-4.72 (1H, m), 5.20 (2H, s), 6.76 (1H, d, J= 3.1 Hz), 6.93 (1H, t, J=4.9 Hz), 6.99 (2H, d, J=8.6 Hz), 7.17 (2H, d, J=8.6 Hz), 7.65 (1H, d, J=10.4 Hz), 7.69 (1H, d, J=4.3 Hz), 7.83 (1H, d, J=8.6 Hz), 7.95 (1H, s), 8.03 (1H, d, J=8.5 Hz), 8.11 (1H, d, J=8.6 Hz), 8.51 (1H, s), 8.85 (1H, s), 9.37 (3H, s), 9.52 (2H, s).

EXAMPLE 22

N-[4-[(1-acetimidoyl-4 - piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl]-3 - pyridinecarboxamide trihydrochloride.

Starting compound: N-[(7-amidino-2-naphthyl)methyl]-N-[4-[(4-

piperidyl)oxy]phenyl]-2-pyridinecarboxamide trihydrochloride.

Data mass spectrum (m/z): 521 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.56-1.64 (2H, m), 1.91-1.99 (2H, m), 2.27 (3H, s), 3.41-3.52 (2H, m), 3.64-3.80 (2H, m), 4.52-4.58 (1H, m), 5.30 (2H, s), 6.83 (2H, d, J= 7.9 Hz), 7.14 (2H, d, J=7.9 Hz), 7.28-7.31 (2H, m), 7.61-7.66 (1H, m), 7.72 (1H, d, J= 8.6 Hz), 7.86 (1H, d, J=8.5 Hz), 8.00 (1H, s), 8.04 (1H, d, J= 8.6 Hz), 8.12 (1H, d, J=8.6 Hz), 8.58 (1H, s), 8.74-8.79 (1H, m), 8.92 (1H, s), 9.45 (4H, s), 9.62 (2H, s).

EXAMPLE 23

Ethyl-N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl] oximat obtained in reference Example 4 (325 mg), dissolved in a mixed solvent of 2 ml of dichloromethane and 5 ml of ethanol. The solution with stirring, cooled to -20oC and saturated with hydrogen chloride. The mixture was stirred at 5oC for 2 stoneshot for 3 days at 5oC and then at room temperature for one day. The reaction mixture is evaporated and the resulting residue purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70). Partially purified ethyl-N- [(7-amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl)- oxy]phenyl]oximat get from the faction, elyuirovaniya methanol. Partially purified ethyl-N-[(7-amidino-2-naphthyl)methyl] -N-[4- [(4-piperidyl)oxy]phenyl]oximat (236 mg) was dissolved in 5 ml of ethanol and to the solution was added 123 mg ethylacetoacetate and 156 mg of triethylamine and the mixture is stirred at room temperature for 15 hours and then evaporated. The resulting residue is purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70), using as eluent a mixture of methanol:water (5:95), and then add a small amount of 1N hydrochloric acid and lyophilizers getting 194 mg of N-[4-[(1 - acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2 - naphthyl)methyl]oxamate dihydrochloride.

Data mass spectrum (m/z): 516 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.89 (3H, t, J=7.3 Hz), 1.60-1.73 (2H, m), 1.94-2.05 (2H, m), 2.27 (3H, s), 3.42-3.55 (2H, m), 3.64-3.72 (1H, m), 3.72-3.81 (1H, m), 3.99 (2H, q, J= 7.3 Hz), 4.62-4.68 (1H, m), 5.13 (2H, s), 6.97 (2H, d, J=9.2 Hz), 7.13 (2H, d, J= 9.2 Hz), 7.55 (1H, d, J=8.6 Hz), 7.83 (1H, d, J=8.6 Hz), 7.88 (1H, s), 8.05 (1H, d, J=8.6 Hz), 8.13 (1H, d, J=8.6 Hz),idine - 2-naphthyl)methyl]-3-utilmately the dihydrochloride.

The source connection: 1-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-1-[(7-cyano-2-naphthyl)methyl]-3-atilmotin.

Data mass spectrum (m/z): 487 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.99 (3H, t, J=7.3 Hz), 1.61-1.73 (2H, m), 1.95-2.05 (2H, m), 2.28 (3H, s), 3.01-3.13 (2H, m), 3.45-3.59 (2H, m), 3.64-3.84 (2H, m), 4.58-4.65 (1H, m), 4.97 (2H, s), 5.73 (1H, t, J=5.5 Hz), 6.93 (2H, d, J=8.6 Hz), 7.08 (2H, d, J=9.2 Hz), 7.60 (1H, d, J=8.5 Hz), 7.75-7.86 (2H, m), 8.00 (1H, d, J= 8.5 Hz), 8.10 (1H, d, J=9.2 Hz), 8.46 (1H, s), 8.85 (1H, s), 9.23-9.40 (1H, m), 9.51 (2H, s).

EXAMPLE 25

Ethyl-3-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -3-[(7 - amidino-2-naphthyl)methyl]ureido-1-acetate dihydrochloride.

Starting compound: ethyl-3-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-3-[(7-cyano-2-naphthyl)methyl]ureido-1 - acetate.

Data mass spectrum (m/z): 545 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.21 (3H, t, J=6.7 Hz), 1.52-1.67 (2H, m), 1.95-2.06 (2H, m), 2.28 (3H, s), 3.44-3.58 (2H, m), 3.65-3.83 (4H, m), 4.10 (2H, q, J=6.7 Hz), 4.60 - 4.66 (1H, m), 4.99 (2H, s), 6.12 (1H, t, J=5.8 Hz), 6.96 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=9.2 Hz), 7.63 (1H, d, J=8.6 Hz), 7.81 (1H, d, J=8.6 Hz), 7.83 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.43 (1H, s), 8.82 (1H, s), 8.28 (2H, s), 9.33 (1H, s). 9.50 (2H, s).

EXAMPLE 26

Ethyl-N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]carbamate digit ftil)methyl]carbamate.

Data mass spectrum (m/z): 488 (M-2HCl + 1)+< / BR>
These NMR spectrum (DMSO-d6internal standard TMS):

: 1.16 (3H, t, J=7.0 Hz), 1.61-1.77 (2H, m), 1.95-2.06 (2H, m), 2.29 (3H, s), 3.43-3.57 (2H, m), 3.65-3.75 (1H, m), 3.75-3.83 (1H, m), 4.12 (2H, q, J= 7.0 Hz), 4.58-4.65 (1H, m), 5.03 (2H, s), 6.91 (2H, d, J=8.5 Hz), 7.15 (2H, d, J= 8.5 Hz), 7.60 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.86 (1H, s), 8.03 (1H, d, J=8.5 Hz), 8.11 (1H, d, J=8.5 Hz), 8.50 (1H, s), 8.81 (1H, s), 9.33 (2H, s), 9.35 (1H, s), 9.53 (2H, s).

EXAMPLE 27

1-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -1-[(7-amidino-2 - naphthyl)methyl]-3-ethylthiophene the dihydrochloride.

The source connection: 1-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-1-[(7-cyano-2-naphthyl)methyl]-3-ethylthiophene.

Data mass spectrum (m/z): 503 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.60 (3H, t), 1.61-1.76 (2H, m), 1.94-2.05 (2H, m), 2.28 (3H, s), 3.40-3.55 (4H, m), 3.64-3.74 (1H, m), 3.74-3.83 (1H, m), 6.97 (2H, d, J= 8.9 Hz), 7.01 (1H, t, J=5.5 Hz), 7.05 (2H, d, J=8.9 Hz), 7.69 (1H, d, J=8.5 Hz), 7.81 (1H, d, J=10.4 Hz), 7.88 (1H, s), 8.00 (1H, d, J=8.5 Hz), 8.10 (1H, d, J= 8.5 Hz), 8.46 (1H, s), 8.84 (1H, s), 9.28 (2H, s), 9.34 (1H, s), 9.50 (2H, s).

EXAMPLE 28

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]acanalonia the dihydrochloride.

Starting compound: N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]econsultant.

EXAMPLE 29

Ethyl-N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl] oximat obtained in Example 23 (100 mg), was dissolved in 20 ml of concentrated hydrochloric acid and the resulting solution is kept at 5oC for 9 days. The reaction mixture is evaporated and the resulting residue purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70), using as eluent a mixture of methanol:water (3:97), and then add a small amount of 1N hydrochloric acid and lyophilizers, receiving 23 mg of the dihydrochloride of N-[4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]-N-[(7-amidino-2-naphthyl)methyl]-Aksakovo acid.

Data mass spectrum (m/z): 488 (M-2HC1 + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.60-1.75 (2H, m), 1.94-2.04 (2H, m), 2.27 (3H, s), 3.40-3.52 (2H, m), 3.64-3.81 (2H, m), 4.57-4.65 (1H, m), 5.09 (2H, s), 6.94 (2H, d, J= 8.5 Hz), 7.16 (2H, d, J=8.5 Hz), 7.56 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.2 Hz), 7.89 (1H, s), 8.04 (1H, d, J=8.5 Hz), 8.12 (1H, d, J=8.5 Hz), 8.46 (1H, s), 8.72 (1H, s), 9.17-9.30 (3H, m), 9.46 (2H, s), 14.0 (1H, bs).

EXAMPLE 30

Ethyl-3- [4-[(1-acetoacet in 20 ml of 1 n hydrochloric acid and the resulting solution was heated at distillation temperature for 10 minutes. The reaction mixture is evaporated, the obtained residue is purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70), using as eluent a mixture of methanol:water (5:95), and then add a small amount of 1N hydrochloric acid and lyophilizers getting 74 mg of the dihydrochloride of 3-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl] -N-[(7-amidino-2-naphthyl)methyl] ureido-1-acetic acid.

Data mass spectrum (m/z): 517 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.62-1.78 (2H, m), 1.93-2.08 (2H, m), 2.28 (3H, s), 3.40-3.85 (6N, m), 4.58-4.68 (1H, m), 4.99 (2H, s), 6.01 (1H, t, J=5.6 Hz), 6.96 (2H, d, J= 8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.62 (1H, d, J=8.3 Hz), 7.81 (1H, d, J=8.8 Hz), 7.86 (1H, s), 8.01 (1H, d, J=8.3 Hz), 8.11 (1H, d, J=8.8 Hz), 8.84 (1H, s), 9.31 (2H, s), 9.35 (1H, s), 9.51 (2H, s).

The following connection receive the same method as the compound of EXAMPLE 23.

EXAMPLE 31

7-[4-[(1-acetimidoyl-4-piperidyl)oxy] aniline] methyl] -2-natamycin trihydrochloride.

The original connection: 7-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] aniline]methyl]-2-naphthaleneacetic.

Data mass spectrum (m/z): 416 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.60-1.73 (2H, m), 1.88-1.99 (2H, m), 2.27 (3H, s), 3.42-3.55 (2H, m), 3.63-3.77 (2H, m), 4.35 - 4.42 (1H, m), 4.45 (2H, d, J=6.1 Hz), 6.16 (1H, d, J= 6.1 Hz), 6.55 EXAMPLE 32

N-[4-[1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7 - cyano-2-naphthyl)methyl] -2-methoxybenzamide obtained in reference Example 19 (80 mg), dissolved in 5 ml of ethanol. With stirring, the solution is cooled to -70oC and saturated with hydrogen chloride. The mixture was stirred at 5oC for 16 hours and then evaporated. The resulting residue is dissolved in 5 ml of ethanol, was added 52 mg of ammonium acetate and the mixture is stirred at room temperature for 3 days. The reaction mixture is evaporated, the obtained residue is purified ODS chromatography on a column (YMC-GEL ODS-A RO-230/70), using as eluent a mixture of methanol:water (100:0), and then add a small amount of 1N hydrochloric acid and lyophilizers, receiving 80 mg of N-[(7-amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl)-oxy]phenyl]-2 - methoxybenzenesulfonamide.

Data mass spectrum (m/z): 509 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.62-1.74 (2H, m), 1.90-2.00 (2H, m), 2.87-3.00 (2H, m), 3.02-3.14 (2H, m), 3.81 (3H, s), 4.41-4.50 (1H, m), 5.22 (2H, s), 6.69 (2H, d, J= 9.2 Hz), 6.83 (2H, d, J=8.6 Hz), 6.95 (2H, d, J=9.2 Hz), 7.20-7.24 (1H, m), 7.27 (1H, d, J=7.9 Hz), 7.73-7.75 (1H, m), 7.84 (1H, d, J=8.6 Hz), 7.99 (1H, s), 8.07 (1H, d, J=8.6 Hz), 8.13 (1H, d, J=8.5 Hz), 8.50 (1H, s), 9.10 (1H, brs), 9.20 (1H, brs), 9.36 (2H, s), 9.57 (2H, s)

The following compound of EXAMPLE 33 receive e-amidino-2-naphthyl) methyl]-2-methoxybenzamide the dihydrochloride.

Parent compound: N-[(7 - amidino-2-naphthyl)methyl] -N-[[(4-piperidyl)oxy]phenyl]-2 - methoxybenzamide the dihydrochloride.

Data mass spectrum (m/z): 550 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.44-1.62 (2H, m), 1.82-1.86 (2H, m), 2.26 (3H, s), 3.40-3.46 (2H, m), 3.63-3.79 (2H, m), 3.70 (3H, m), 4.46-4.50 (1H, m), 5.23 (2H, s), 6.69 (2H, d, J=9.2 Hz),6.83 (2H, d, J=7.9 Hz), 6.95 (2H, d, J=8.5 Hz), 7.20 (1H, t, J= 8.6 Hz), 7.27 (1H, d, J=7.3 Hz), 7.23 (1H, d, J=8.6 Hz), 7.85 (1H, d, J= 8.5 Hz), 7.99 (1H, s), 8.08 (1H, d, J=8.6 Hz), 8.13 (1H, d, J=8.5 Hz), 8.52 (1H, s), 8.86 (1H, s), 9.41 (3H, s), 9.60 (2H, s)

The following compound of EXAMPLE 34 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 34

N-[(7-amidino-2-naphthyl)methyl] -N-[[(4-piperidyl)oxy] phenyl]-4 - methoxybenzamide the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl] -4-methoxybenzamide.

Data mass spectrum (m/z): 509 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.70-1.81 (2H, m), 1.96-2.07 (2H, m), 2.96-3.00 (2H, m), 3.07-3.18 (2H, m), 3.71 (3H, s), 4.48-4.56 (1H, m), 5.26 (2H, s), 6.79 (2H, d, J= 8.6 Hz), 6.82 (2H, d, J=9.2 Hz), 7.03 (2H, d, J=8.6 Hz), 7.31 (2H, d, J=8.6 Hz), 7.67 (1H, d, J=9.8 Hz), 7.84 (1H, d, J=6.7 Hz), 7.95 (1H, s), 8.02 (1H, d, J= 8.5 Hz), 8.10 (1H, d, J=8.5 Hz), 8.54 (1H, s), 9.24 (1H, brs), 9.33 (1H, brs), 9.41 (2H, s), 9.58 (2H, s).

The following compound of EXAMPLE 3)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]-4-methoxybenzamide the dihydrochloride.

Parent compound: N-[(7 - amidino-2-naphthyl)methyl] -N-[4-(4-piperidyl)oxy]phenyl]-4 - methoxybenzamide the dihydrochloride.

Data mass spectrum (m/z): 550 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.55-1.68 (2H, m), 1.86-2.00 (2H, m), 2.27 (3H, s), 3.41-3.49 (2H, m), 3.66-3.78 (2H, m), 3.72 (3H, s), 4.54-4.60 (1H, m), 5.26 (2H, s), 6.79 (2H, d, J=9.2 Hz), 6.82 (2H, d, J=9.2 Hz), 7.03 (2H, d, J=8.5 Hz), 7.31 (2H, d, J= 8.6 Hz), 7.68 (1H, t, J=10.4 Hz), 7.82 (1H, d, J=8.5 Hz), 7.95 (1H, s), 8.02 (1H, d, J= 8.5 Hz), 8.10 (1H, d, J=8.6 Hz), 8.52 (1H, s), 8.85 (1H, s), 9.37 (3H, s), 9.55 (2H, s).

The following compound of EXAMPLE 36 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 36

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl) oxy]phenyl]-4-pyridinecarboxamide trihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2 - naphthyl)methyl] -4-pyridinecarboxamide.

Data mass spectrum (m/z): 480 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.68-1.78 (2H, m), 1.92-2.01 (2H, m), 2.84-3.00 (2H, m), 3.02-3.18 (2H, m), 4.44-4.57 (1H, m), 5.30 (2H, s), 6.80 (2H, d, J=9.2 Hz), 7.15 (2H, d, J= 8.5 Hz), 7.74 (1H, d, J=8.6 Hz), 7.85-7.87 (3H, m), 8.01 (1H, s), 8.05 (1H, d, J=8.5 Hz), 8.13 (1H, d, J=8.5 Hz), 8.60 (1H, s), 8.78 (2H, brs), 9.28 (2H, brs), 9.37 (1H, brs), 9.44 (2H, s), 9.62 (2H, s)

The following compound of EXAMPLE 37 receive the same method naphthyl) methyl]-4-pyridinecarboxamide trihydrochloride.

Parent compound: N-[(7 - amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy]phenyl]-4 - pyridinecarboxamide trihydrochloride.

Data mass spectrum (m/z): 521 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.55-1.62 (2H, m), 1.92-2.02 (2H, m), 2.28 (3H, s), 3.40-3.50 (2H, m), 3.64-3.81 (2H, m), 4.54-4.57 (1H, m), 5.31 (2H, s), 6.81 (2H, d, J= 8.5 Hz), 7.16 (2H, d, J=8.5 Hz), 7.75 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=8.5 Hz), 8.00 (2H, br), 8.06 (1H, d, J=8.5 Hz), 8.13 (1H, d, J=8.5 Hz), 8.63 (1H, s), 8.46 (2H, br), 8.85 (1H, s), 9.50 (3H, s), 9.68 (2H, s)

The following compound of EXAMPLE 38 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 38

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy] phenyl]-2-pyridinecarboxamide trihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]-2-pyridinecarboxamide.

Data mass spectrum (m/z): 480 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.62-1.78 (2H, m), 1.89-2.05 (2H, m), 2.88-3.00 (2H, m), 3.04-3.16 (2H, m), 4.00-4.10 (1H, m), 5.28 (2H, s), 6.75 (2H, d, J=8.5 Hz), 7.03 (2H, d, J= 8.5 Hz), 7.32-7.41 (1H, m), 7.56-7-.64 (1H, m), 7.73 (1H, d, J=8.6 Hz), 7.76 (1H, d, J=8.6 Hz), 7.80-7.89 (1H, m), 8.00 (1H, s), 8.05-8.09 (1H, m), 8.09 (1H, d, J=8.5 Hz), 8.43 (1H, s), 8.56 (1H, s), 9.12 (2H, brs), 9.26 (3H, brs), 9.38 (2H, s), 9.57 (2H, s).

The following compound of EXAMPLE 39 receive the same midino-2-naphthyl)methyl]-2-pyridinecarboxamide trihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]-2-pyridinecarboxamide trihydrochloride.

Data mass spectrum (m/z): 521 (M-3HCl + 1)+.

These NMR spectrum (DMSO - d6internal standard TMS):

: 1.52-1.64 (2H, m), 1.86-1.97 (2H, m), 2.25 (3H, s), 3.36-3.48 (2H, m), 3.60-3.79 (2H, m), 4.46-4.52 (1H, m), 5.27 (2H, s), 6.67-6.75 (2H, br), 6.91-7.00 (2H, m), 7.22-7.28 (1H, br), 7.51-7.58 (1H, br), 7.72 (1H, d, J= 8.5 Hz), 7.76 (2H, d, J=7.9 Hz), 7.95 (1H, s), 8.02-8.04 (1H, br), 8.09 (1H, d, J= 8.5 Hz), 8.36 (1H, s), 8.57 (1H, s), 8.72 (1H, s), 9.28 (3H, s), 9.50 (2H, s)

The following compound of EXAMPLE 40 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 40

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl] -2-methoxyacetate the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl] -2-methoxyacetate.

Data mass spectrum (m/z): 447 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.78-1.84 (2H, m), 2.01-2.10 (2H, m), 2.97-3.05 (2H, m), 3.10-3.1.9 (2H, m), 3.83 (3H, s), 4.57-4.62 (1H, m), 5.00 (2H, s), 6.95 (2H, d, J= 9.2 Hz), 7.15 (2H, d, J=8.5 Hz), 7.59 (1H, d, J=8.6 Hz), 7.82 (1H, d, J=6.7 Hz), 7.86 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.48 (1H, s), 9.19 (1H,brs), 9.26 (1H, brs), 9.35 (2H, s), 9.54 (2H, s)

The following compound of EXAMPLE 41 receive the same method as the compound of EXAMPLE 12.

Parent compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]-2-methoxyacetanilide the dihydrochloride.

Data mass spectrum (m/z): 488 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.60-1.78 (2H, m), 1.96-2.03 (2H, m), 2.28 (3H, s), 3.25 (3H, s), 3.40-3.58 (2H, m), 3.60-3.75 (2H, m), 3.83 (2H, s), 4.60-4.68 (1H, m), 5.03 (2H, s), 6.95 (2H, d, J= 9.2 Hz), 7.15 (2H, d, J=8.5 Hz), 7.59 (1H, d, J= 8.6 Hz), 7.82 (1H, d, J=8.5 Hz), 7.86 (1H, s), 8.02 (1H, d, J=8.5 Hz), 8.11 (1H, d, J=8.6 Hz), 8.46 (1H, s), 8.83 (1H, s), 8.33 (3H, s), 9.53 (2H, s).

The following compound of EXAMPLE 42 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 42

Ethyl-N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]-phenyl]malonamate the dihydrochloride.

Source connection: ethyl-N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]malonamate the dihydrochloride.

Data mass spectrum (m/z): 489 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.37 (3H, t, J=6.7 Hz), 1.74-1.83 (2H, m), 2.01-2.10 (2H, m), 2.96-3.03 (2H, m), 3.10-3.21 (2H, m), 3.30 (2H, s), 4.02 (2H, q, J=7.3 Hz), 4.56-4.62 (1H, m), 5.05 (2H, s), 6.96 (2H, d, J=8.6 Hz), 7.14 (2H, d, J= 6.1 Hz), 7.63 (1H, d, J=6.7 Hz), 7.76 (1H, d, J=7.3 Hz), 7.85 (1H, s), 8.03 (1H, d, J=8.5 Hz), 8.11 (1H, d, J=8.6 Hz), 8.49 (1H, s), 9.20 (1H, brs), 9.29 (1H, brs), 9.39 (2H, s), 9.57 (2H, s).

The following compound of EXAMPLE 43 get t enyl] -N-[(7-amidino-2-naphthyl)methyl malonamate the dihydrochloride.

Source connection: ethyl-N-[(7-amidino-2-naphthyl)methyl] - N-[4-[(4-piperidyl)oxy]phenyl]malonamate the dihydrochloride.

Data mass spectrum (m/z): 530 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.14 (3H, t, J=7.3 Hz), 1.60-1.75 (2H, m), 1.95-2.06 (2H, m), 2.27 (3H, s), 3.29 (2H, s), 3.38-3.55 (2H, m), 3.64-3.83 (2H, m), 4.01 (2H, q, J= 7.3 Hz), 4.60-4.64 (1H, m), 5.07 (2H, s), 6.96 (2H, d, J=8.6 Hz), 7.13 (2H, d, J= 9.2 Hz), 7.62 (1H, d, J=8.5 Hz), 7.81 (1H, d, J=8.5 Hz), 7.87 (1H, s), 8.03 (1H, d, J= 8.5 Hz), 8.12 (1H, d, J=8.6 Hz), 8.43 (1H, s), 8.76 (1H, s), 8.26 (3H, s), 9.50 (2H, s).

The following compound of EXAMPLE 44 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 44

Ethyl-N-[(7-amidino-2 - naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]-phenyl]succinamic the dihydrochloride.

Source connection: ethyl-N-[4-[(1-tert - butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2 - naphthyl)methyl]succinamic the dihydrochloride.

Data mass spectrum (m/z): 503 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.18 (3H, t, J=6.7 Hz), 1.78-1.84 (2H, m), 2.04-2.14 (2H, m), 2.34 (2H, t, J=6.1 Hz), 2.56 (2H, t, J=6.1 Hz), 2.94-3.06 (2H, m), 3.12-3.22 (2H, m), 4.06 (2H, q, J=6.7 Hz), 4.56-4.64 (1H, m), 5.03 (2H, s), 6.98 (2H, d, J= 9.2 Hz), 7.15 (2H, d, J=8.6 Hz), 7.58 (1H, d, J=9.2 Hz), 7.83-7.85 (2H, m), 8.01 (1H, d, J=8.6 Hz), 8.08-8.12 (1H, m), 8.48 (1H, s), 9.29 (1H, brs), 9.38 (1H, brs), 9.41 (2H, s), 9.58 (2H, s)

The following connection WITH piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]succinate the dihydrochloride.

Source connection: ethyl-N-[(7-amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]phenyl] succinamic the dihydrochloride.

Data mass spectrum (m/z): 544 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.18 (3H, t, J=6.7 Hz), 1.61-1.76 (2H, m), 1.96-2.08 (2H, m), 2.29 (3H, s), 2.34 (2H, t, J=6.1 Hz), 2.55 (2H, t, J=6.1 Hz), 3.43-3.55 (2H, m), 3.64-3.86 (2H, m), 4.06 (2H, q, J=6.7 Hz), 4.60-4.69 (1H, m), 5.03 (2H, s), 6.98 (2H, d, J= 9.15 Hz), 7.14 (2H, d, J=8.6 Hz), 7.58 (1H, d, J=8.5 Hz), 7.80-7.92 (2H, m), 8.01 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.48 (1H, s), 8.93 (1H, s), 9.43 (3H, s), 9.59 (2H, s).

The following compound of EXAMPLE 46 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 46

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl]- 2,6-differentated the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N- [(7-cyano-2-naphthyl)methyl]-2,6-differentated the dihydrochloride.

Data mass spectrum (m/z): 515 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.64-1.72 (2H, m), 1.91-2.00 (2H, m), 2.87-3.00 (2H, m), 3.02-3.17 (2H, m), 4.41-4.50 (1H, m), 5.27 (1H, s), 6.79 (2H, d, J=8.6 Hz), 6.97-7.03 (4H, m), 7.35-7.38 (1H, m), 7.67 (1H, d, J=9.8 Hz), 7.86 (1H, d, J=8.6 Hz), 7.93 (1H, s), 8.10 (1H, d, J=8.5 Hz), 8.14 (1H, d, J=8.6 Hz), 8.47 (1H, s), 9.08 (1H, brs), 9.19 (1H, brs), 9.34 (2H, s), 9.55 (2H, s).

The following compound of EXAMPLE 47 poluchenii] -N-[(7-amidino-2-naphthyl)methyl]-2,6-differentated the dihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl) oxy]phenyl]-2,6-differentated the dihydrochloride.

Data mass spectrum (m/z): 556 (M - 2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.54-1.61 (2H, m), 1.85-1.96 (2H, m), 2.28 (3H, s), 3.38-3.45 (2H, m), 3.63-3.73 (2H, m), 4.50-4.57 (1H, m), 5.26 (2H, s), 6.80 (2H, d,J= 9.2 Hz), 6.97-7.03 (4H, m), 7.34-7.38 (1H, m), 7.67 (1H, d, J=8.5 Hz), 7.84 (1H, d, J= 8.5 Hz), 7.93 (1H, s), 8.09 (1H, d, J=8.5 Hz), 8.14 (1H, d, J= 8.6 Hz), 8.46 (1H, s), 8.75 (1H, s), 9.28 (3H, s), 9.52 (2H, s).

The following compound of EXAMPLE 48 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 48

N-[(7-amidino-2-naphthyl) methyl]-N-[4-[(4-piperidyl)oxy]phenyl]-2-dimethylaminoacetyl trihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2 - naphthyl)methyl]-2-dimethylaminoacetyl.

Data mass spectrum (m/z): 460 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.77-1.89 (2H, m), 2.01-2.14 (2H, m), 2.82 (6H, s), 2.96-3.08 (2H, m), 3.11-3.23 (2H, m), 3.97 (2H, s), 4.41-4.45 (1H, m), 5.07 (2H, s), 7.02 (2H, d, J= 9.3 Hz), 7.22 (2H, d, J=8.8 Hz), 7.50 (1H, d, J=8.8 Hz), 7.79 (1H, s), 7.94-7.96 (3H, m), 8.45 (1H, s), 9.43 (2H, brs), 9.49 (1H, brs), 9.99 (4H, s).

The following compound of EXAMPLE 49 receive the same method as the compound of EXAMPLE 12.

An EXAMPLE is chlorid.

Parent compound: N-[(7 - amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy]phenyl]-2 - dimethylaminoacetyl trihydrochloride.

Data mass spectrum (m/z): 501 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.64-1.73 (2H, m), 1.93-2.10 (2H, m), 2.31 (3H, s), 2.82 (6N, s), 3.46-3.61 (2H, m), 3.69-3.86 (2H, m), 3.98 (2H, s), 4.68-4.69 (1H, m), 5.24 (2H, s), 7.02 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz), 7.43-7.55 (2H, m), 7.78 (1H, s), 7.93-7.95 (2H, m), 8.11-8.18 (1H, brs), 8.45 (1H, s), 9.05 (1H, s), 9.54 (1H, s), 10.03 (1H, s).

The following compound of EXAMPLE 50 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 50

Ethyl-N-[(7 - amidino-2-naphthyl)methyl]carbarnoyl]-N-[N-[4-(4-piperidyl)oxy] phenyl]carbonate the dihydrochloride.

Source connection: ethyl-N-[N-[4-(1-tert - butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2 - naphthyl)methyl]carbarnoyl]carbonate.

Data mass spectrum (m/z): 490 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 1.12 (3H, t, J=6.7 Hz), 1.74-1.82 (2H, m), 2.01-2.10 (2H, m), 2.98-3.03 (2H, m), 3.10-3.19 (2H, m), 4.01 (2H, q, J=6.7 Hz), 4.56-4.62 (1H, m), 5.02 (2H, s), 6.93 (2H, d, J=9.2 Hz), 7.13 (2H, d, J=8.5 Hz), 7.62 (1H, d, J= 8.5 Hz), 7.75 (1H, d, J=6.7 Hz), 7.86 (1H, s), 8.00 (1H, d, J=8.6 Hz),8.07 (1H, d, J= 7.9 Hz), 8.51 (1H, s), 8.89 (1H, s), 9.12 (1H, brs), 9.20 (1H, brs), 9.32 (2H, s), 9.51 (2H, s).

The following compound of EXAMPLE 51 receive the same m is N-[(7-amidino-2-naphthyl)methyl]carbarnoyl] the carbonate dihydrochloride.

Source connection: ethyl-N-[(7 - amidino-2-naphthyl)methyl]carbarnoyl]-N-[N-[4-(4 - piperidyl)oxy]phenyl]carbonate the dihydrochloride.

Data mass spectrum (m/z): 531 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.12 (3H, t, J=7.3 Hz), 1.71-1.75 (2H, m), 1.94-2.08 (2H, m), 2.28 (3H, s), 3.48-3.54 (2H, m), 3.69 - 3.83 (2H, m), 4.01 (2H, q, J=7.3 Hz), 4.60-4.68 (1H, m), 5.03 (2H, s), 6.94 (2H, d, J=9.3 Hz), 7.12 (2H, d, J= 8.8 Hz), 7.60 (1H, d, J=9.8 Hz), 7.81 (1H, d, J=6.8 Hz), 7.90 (1H, s), 8.01 (1H, d, J= 8.8 Hz), 8.11 (1H, d, J=8.8 Hz), 8.45 (1H, s), 8.82 (1H, s), 8.97 (1H, s), 9.29 (3H, s), 9.52 (2H, s).

The following compound of EXAMPLE 52 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 52

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)-oxy] phenyl] benzosulfimide the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl - 4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]benzosulfimide.

Data mass spectrum (m/z): 515 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.68-1.80 (2H, m), 1.97-2.07 (2H, m), 2.93-3.06 (2H, m), 3.10-3.22 (2H, m), 4.50-4.57 (1H, m), 4.99 (2H, s), 6.84 (2H, d, J=8.5 Hz), 6.98 (2H, d, J= 9.2 Hz), 7.64-7.72 (5H, m), 7.76 (1H, t, J=7.3 Hz), 7.81 (1H, d, J= 8.5 Hz), 7.92 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.08 (1H, d, J=8.6 Hz), 8.45 (1H, s), 9.04 (1H, brs), 9.11 (1H, brs), 9.28 (2H, s), 9.50 (2H, s).

The following compound of EXAMPLE 53 receive the(7-amidino-2 - naphthyl)methyl]benzosulfimide the dihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]benzosulfimide the dihydrochloride.

Data mass spectrum (m/z): 556 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.58-1.70 (2H, m), 1.91-2.03 (2H, m), 2.27 (3H, s), 3.42-3.49 (2H, m), 3.67-3.77 (2H, m), 4.58-4.61 (1H, m), 4.99 (2H, s), 6.84 (2H, d, J= 9.2 Hz), 6.98 (2H, d, J=8.5 Hz), 7.64-7.76 (6H, m), 7.82 (1H, d, J=10.4 Hz), 7.92 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.09 (1H, d, J=8.5 Hz), 8.46 (1H, s), 8.81 (1H, s), 9.34 (3H, s), 9.53 (2H, s).

The following compound of EXAMPLE 54 receive the same method as the compound of EXAMPLE 23.

EXAMPLE 54

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]methanesulfonamide the dihydrochloride.

Parent compound: N-[4-[(1 - tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2 - naphthyl)methyl]methanesulfonamide.

Data mass spectrum (m/z): 494 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.60-1.74 (2H, m), 1.94-2.03 (2H, m), 2.27 (3H, s), 3.13 (3H, s), 3.43-4.55 (2H, m), 3.63-3.73 (1H, m), 3.73-3.80 (1H, m), 4.60-4.65 (1H, m), 5.03 (2H, s), 6.93 (2H, d, J=9.2 Hz), 7.34 (2H, d, J=8.5 Hz), 7.66 (1H, dd, J= 8.6, 1.2 Hz), 7.81 (1H, dd, J=8.6, 1.8 Hz), 7.91 (1H, s), 8.01 (1H, d, J= 8.6 Hz), 8.09 (1H, d, J=8.5 Hz), 8.47 (1H, s), 8.74 (1H, s), 9.20-9.11 (3H, m), 9.48 (2H, s).

The following compound of EXAMPLE 55 receive the same method as Soeder]benzylmaleimide the dihydrochloride.

Parent compound: N-[4-[(1 - tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl) methyl]benzylmalonate.

Data mass spectrum (m/z): 570 (M-2HCl + 1)6.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.61-1.74 (2H, m), 1.94-2.04 (2H, m), 2.27 (3H, s), 3.42-3.55 (2H, m), 3.64-3.80 (2H, m), 4.58-4.62 (1H, m), 4.62 (2H, s), 4.97 (2H, s), 6.88 (2H, d, J=9.2 Hz), 7.22 (2H, d, J=9.2 Hz), 7.39-7.5.1 (5H, m), 7.62 (1H, dd, J= 1.2, 8.6 Hz), 7.75 (1H, dd, J=1.5, 8.9 Hz), 7.89 (1H, s), 8.00 (1H, d, J= 8.5 Hz), 8.09 (1H, d, J=8.6 Hz), 8.45 (1H, s), 8.72 (1H, bs), 9.16-9.29 (3H, m), 9.47 (2H, bs).

The following compound of EXAMPLE 56 receive the same method as the compound of EXAMPLE 23.

EXAMPLE 56

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]propanesulfinamide the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]- N-[(7-cyano-2-naphthyl)methyl]propanesulfonate.

Data mass spectrum (m/z): 522 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.03 (3H, t, J=7.6 Hz), 1.60-1.73 (2H, m), 1.74-1.85 (2H, m), 1.93-2.03 (2H, m), 2.27 (3H, s), 3.21-3.25 (2H, m), 3.42-3.56 (2H, m), 3.63-3.71 (1H, m), 3.75-3.82 (1H, m), 4.59-4.63 (1H, m), 5.05 (2H, s), 6.92 (2H, d, J= 8.5 Hz), 7.33 (2H, d, J=8.5 Hz), 7.66 (1H, dd, J=8.6, 1.2 Hz), 7.82 (1H, dd, J= 8.5, 1.8 Hz), 7.89 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.09 (1H, d, J=8.5 Hz), 8.48 (1H, s), 8.80 (1H, s), 9.28-9.38 (3H, m), 9.52 (2H, s).

After the-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl] - butanesulfinamide the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl) methyl]butanesulfonate.

Data mass spectrum (m/z): 495 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.92 (3H, t, J=7.3 Hz), 1.41-1.46 (2H, m), 1.70-1.82 (2H, m), 2.03-2.06 (4H, m), 2.92-3.04 (2H, m), 3.10-3.20 (2H, m), 3.24 (2H, t, J=7.9 Hz), 4.52-4.60 (1H, m), 5.06 (2H, s), 6.91 (2H, d, J=9.2 Hz), 7.33 (2H, d, J= 9.2 Hz), 7.65 (1H, d, J=8.6 Hz), 7.80 (1H, d, J=8.6 Hz), 7.89 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.09 (1H, d, J=8.6 Hz), 8.46 (1H, s), 9.02 (1H, brs), 9.10 (1H, brs), 9.27 (2H, s), 9.49 (2H, s).

The following compound of EXAMPLE 58 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 58

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] - N-[(7-amidino-2-naphthyl)methyl]butanesulfinamide the dihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-(4 - piperidyl)oxy]phenyl]butanesulfinamide the dihydrochloride.

Data mass spectrum (m/z): 536 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.92 (3H, t, J=7.3 Hz), 1.41-1.46 (2H, m), 1.62-1.78 (4H, m), 1.91-2.01 (2H, m), 2.27 (3H, s), 3.24 (2H, t, J=7.9 Hz), 4.58-4.62 (1H, m), 5.06 (2H, s), 6.91 (2H, d, J= 9.2 Hz), 7.33 (2H, d, J=9.2 Hz), 7.65 (1H, d, J= 8.5 Hz), 7.80 (1H, d, J=6.7 Hz), 7.90 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.09 (1H, d, J=8.5 Hz), 8.46 (1H, s), 7.12 (1H, s), 9.22 (3H, s), 9.47 (2H, s).

SLE-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl]- triftoratsetofenona the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2 - naphthyl)methyl]triftormetilfullerenov.

Data mass spectrum (m/z): 507 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.72-1.81 (2H, m), 1.97-2.08 (2H, m), 2.96-3.06 (2H, m), 3.09-3.20 (2H, m), 4.56-4.62 (1H, m), 5.25 (2H, s), 6.95 (2H, d, J=9.2 Hz), 7.29 (2H, d, J= 9.2 Hz), 7.61 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=8.5 Hz), 7.91 (1H, s), 8.03 (1H, d, J=7.9 Hz), 8.11 (1H, d, J=9.2 Hz), 8.51 (1H, s), 9.13 (1H, brs), 9.21 (1H, brs), 9.35 (2H, s), 9.54 (2H, s).

The following compound of EXAMPLE 60 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 60

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl] triftoratsetofenona the dihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-(4 - piperidyl)oxy]phenyl]triftoratsetofenona the dihydrochloride.

Data mass spectrum (m/z): 548 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 1.60-1.74 (2H, m), 1.92 - 2.05 (2H, m), 2.26 (3H, s), 3.44-3.50 (2H, m), 3.67-3.76 (2H, m), 4.63-4.65 (1H, m), 5.25.(2H, s), 6.95 (2H, d, J= 9.2 Hz), 7.30 (2H, d, J=9.2 Hz), 7.60 (1H, d, J=6.7 Hz), 7.83 (1H, d, J=7.3 Hz), 7.92 (1H, s), 8.04 (1H, d, J=8.6 Hz), 8.12 (1H, d, J=8.6 Hz), 8.48 (1H, s), 8.68 (1H, s), 9.20 (3H, s), 9.47 (2H, s)

The following compound of EXAMPLE 61 receive the same method as the connection WITH the as the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]isopropanolamide.

Data mass spectrum (m/z): 481 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.35 (6N, d, J=6.4 Hz), 1.69-1.80 (2H, m), 1.96-2.06 (2H, m), 2.94-3.06 (2H, m), 3.11-3.27 (3H, m), 4.50-4.57 (1H, m), 5.11 (2H, s), 6.89 (2H, d, J= 8.8 Hz), 7.33 (2H, d, J=8.8 Hz), 7.64 (1H, d, J=8.3 Hz), 7.79 (1H, d, J= 8.8 Hz), 7.88 (1H, s), 8.01 (1H, d, J=8.8 Hz), 8.09 (1H, d, J=8.8 Hz), 8.44 (1H, s), 8.81 (1H, brs), 8.86 (1H, brs), 9.15 (2H, s), 9.45 (2H, s).

The following compound of EXAMPLE 62 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 62

N-[4-[(1-acetimidoyl-4 - piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl] isopropanolamide the dihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-(4 - piperidyl)oxy]phenyl]isopropanolamide the dihydrochloride.

Data mass spectrum (m/z): 522 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.35. (d, 6N, J=6.8 Hz), 1.60-1.73 (2H, m), 1.92-2.01 (2H, m), 2.26 (3H, s), 3.03-3.10 (1H, m), 3.40-3.49 (2H, m), 3.67-3.76 (2H, m), 4.60-4.67 (1H, m), 5.11 (2H, s), 6.90 (2H, d, J=9.3 Hz), 7.32 (2H, d, J=9.3 Hz), 7.64 (1H, d, J= 8.8 Hz), 7.80 (1H, d, J=6.8 Hz), 7.88 (1H, s), 8.01 (1H, d, J= 8.3 Hz), 8.09 (1H, d, J=8.8 Hz), 8.46 (1H, s), 8.72 (1H, s), 9.23 (3H, s), 9.58 (2H, s).

The following compound of EXAMPLE 63 poluchasa] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]the carbamate dihydrochloride.

Source connection: ethyl-N-[N-[4-(1-tert-butoxycarbonyl-4-piperidyl) oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]-carbamate.

Data mass spectrum (m/z): 567 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.27 (3H, t, J=7.3 Hz), 1.60-1.75 (2H, m), 1.95-2.03 (2H, m), 2.27 (3H, s), 3.41-3.57 (2H, m), 3.63-3.73 (1H, m), 3.73-3.82 (1H, m), 4.23 (2H, q, J= 7.3 Hz), 4.60-4.67 (1H, m), 5.17 (2H, s), 6.96 (2H, d, J=9.2 Hz), 7.23 (2H, d, J= 8.5 Hz), 7.65 (1H, d, J=7.3 Hz), 7.82 (1H, d, J=8.5 Hz), 7.91 (1H, s), 8.03 (1H, d, J=8.5 Hz), 8.10 (1H, d, J=8.5 Hz), 8.47 (1H, s), 8.81 (1H, bs), 9.23-9.40 (3H, m), 9.51 (2H, s), 11.52 (1H, s).

The following compound of EXAMPLE 64 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 64

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] - phenyl]-4-nitrobenzenesulfonamide the dihydrochloride.

Parent compound: N-[4-[(1-tert-butoxycarbonyl-4 - piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]-4 - nitrobenzenesulfonamide.

Data mass spectrum (m/z): 560 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 1.71-1.82 (2H, m), 2.00-2.08 (2H, m), 2.91-3.03 (2H, m), 3.08-3.19 (2H, m), 4.51-4.60 (1H, m), 5.03 (2H, s), 6.86 (2H, d, J=8.6 Hz), 7.02 (2H, d, J= 9.2 Hz), 7.66 (1H, d, J=8.6 Hz), 7.83 (1H, d, J=6.7 Hz), 7.90 (1H, s), 7.98 (2H, d, J=8.6 Hz), 8.02 (1H, d, J=8.5 Hz), 8.09 (1H, d, J=8.5 Hz), 8.45 (2H, d, J= 9.2 Hz), 8.48 (1H, s), 9.22 (1H, brs), 9.29 (1H, brs), 9.38 (2H, s), 9.56 (2H, s).


N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]-4-nitrobenzenesulfonamide the dihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl] -N-[4-(4 - piperidyl)oxy]phenyl]-4-nitrobenzenesulfonamide the dihydrochloride.

Data mass spectrum (m/z): 601 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.63-1.68 (2H, m), 1.84-2.02 (2H, m), 2.27 (3H, s), 3.47-3.51 (2H, m), 3.66-3.79 (2H, m), 4.58-4.62 (1H, m), 5.03 (2H, s), 6.86 (2H, d, J= 8.5 Hz), 7.02 (2H, d, J=9.2 Hz), 7.66 (1H, d, J=8.5 Hz), 7.83 (1H, d, J=8.6 Hz), 7.91 (1H, s), 7.98 (1H, d, J=9.2 Hz), 8.02 (1H, d, J=8.5 Hz), 8.09 (1H, d, J= 8.6 Hz), 8.45-8.48 (3H, m), 8.82 (1H, s), 9.34 (3H, s), 9.54 (2H, s).

The following compound of EXAMPLE 66 receive the same method as the compound of EXAMPLE 23.

EXAMPLE 66

Ethyl-4-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino - 2-naphthyl)methyl]sulfamoyl]the benzoate dihydrochloride.

Source connection: 4-N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]-benzoic acid.

Data mass spectrum (m/z): 628 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.37 (3H, t, J=7.0 Hz), 1.57-1.73 (2H, m), 1.92-2.02 (2H, m), 2.26 (3H, s), 3.40-3.50 (2H, m), 3.62-3.80 (2H, m), 4.39 (2H, q, J=7.0 Hz), 4.55-4.62 (1H, m), 5.00 (2H, s), 6.85 (2H, d, J=9.2 Hz), 6.99 (2H, d, J= 8.9.27 (3H, m), 9.47 (2H, s).

The following compound of EXAMPLE 67 receive the same method as the compound of EXAMPLE 23.

EXAMPLE 67

Ethyl-3-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]the benzoate dihydrochloride.

Source connection: 3-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy] phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]benzoic acid.

Data mass spectrum (m/z): 628 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.33 (3H, t, J=7.0 Hz), 1.58-1.72 (2H, m), 1.93-2.02 (2H, m), 2.26 (3H, s), 3.41-3.52 (2H, m), 3.63-3.80 (2H, m), 4.36 (2H, q, J=7.0 Hz), 4.56-4.63 (1H, m), 4.99 (2H, s), 6.86 (2H, d, J=9.2 Hz), 7.02 (2H, d, J= 8.5 Hz), 7.67 (1H, d, J=8.6 Hz), 7.78-7.86 (2H, m), 7.93 (1H, s), 7.99-8.03 (2H, m), 8.05-8.12 (2H, m), 8.30 (1H, d, J=7.9 Hz), 8.44 (1H, s), 8.71 (1H, bs), 9.14-9.30 (3H, m), 9.47 (2H, s).

The following compound of EXAMPLE 68 receive the same method as the compound of EXAMPLE 23.

EXAMPLE 68

Methyl-2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7 - amidino-2-naphthyl)methyl]sulfamoyl]the benzoate dihydrochloride.

Source connection: methyl-2-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]benzoate.

Data mass spectrum (m/z): 614 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6

The following compound of EXAMPLE 69 receive the same method as the compound of EXAMPLE 23.

EXAMPLE 69

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]sulfonamida the dihydrochloride.

Parent compound: tert-butyl N-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N- [(7-cyano-2-naphthyl)methyl]sulfamoyl]carbamate.

Data mass spectrum (m/z): 495 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.59-1.74 (2H, m), 1.93-2.03 (2H, m), 2.27 (3H, s), 3.43-3.57 (2H, m), 3.63-3.71 (1H, m), 3.73-3.81 (1H, m), 4.56-4.63 (1H, m), 4.90 (2H, s), 6.89 (2H, d, J=9.2 Hz), 7.20 (2H, s), 7.27 (2H, d, J=9.2 Hz), 7.71 (1H, d, J= 7.6 Hz), 7.80 (1H, dd, J=1.8, 8.6 Hz), 7.92 (1H, s), 7.99 (1H, d, J=8.5 Hz), 8.08 (1H, d, J=8.6 Hz), 8.44 (1H, s), 8.80 (1H, bs), 9.24-9.37 (3H, m), 9.51 (2H, s).

The following compound of EXAMPLE 70 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 70

Ethyl-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl]sulfamoyl]acetate dihydrochloride.

Source connection: ethyl-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]acetate.

Data mass spectrum (m/z): 525 (is (2H, m), 1.97-2.09 (2H, m), 2.97-3.04 (2H, m), 3.10-3.21 (2H, m), 3.23 (2H, q, J=6.7 Hz), 4.43 (2H, s), 4.51-4.62 (1H, m), 5.05 (2H, s), 6.94 (2H, d, J=9.2 Hz), 7.32 (2H, d, J= 9.2 Hz), 7.64 (1H, d, J=9.8 Hz), 7.80 (1H, d, J=8.6 Hz), 7.90 (1H, s), 8.01 (1H, d, J=9.2 Hz), 8.09 (1H, d, J=8.5 Hz), 8.46 (1H, s), 8.98 (1H, brs), 9.05 (1H, brs), 9.25 (2H, s), 9.48 (2H, s).

The following compound of EXAMPLE 71 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 71

Ethyl-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]acetate dihydrochloride.

Source connection: ethyl-[N-[(7-amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]phenyl] sulfamoyl]acetate dihydrochloride.

Data mass spectrum (m/z): 566 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.25 (3H, t, J=7.3 Hz), 1.61-1.74 (2H, m), 1.94-2.04 (2H, m), 2.26 (3H, s), 3.43-3.51 (2H, m), 3.64-3.78 (2H, m), 4.23 (2H, q, J=7.3 Hz), 4.43 (2H, s), 4.59-4.65 (1H, m), 5.05 (2H, s), 6.94 (2H, d, J=9.2 Hz), 7.32 (2H, d, J= 9.2 Hz), 7.64 (1H, d, J=8.5 Hz), 7.79 (1H, d, J=8.6 Hz), 7.92 (1H, s), 8.01 (1H, d, J=8.0 Hz), 8.10 (1H, d, J=8.5 Hz), 8.45 (1H, s), 8.64 (1H, s), 9.12 (3H, s), 9.43 (2H, s).

The following compound of EXAMPLE 72 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 72

Ethyl-3-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl] sulfamoyl]propionate dihydrochloride.

Source connection: ethyl-3-[N-[4-[(1-tert-butoxycarbonyl-4 - Poperty (m/z): 539 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 1.20 (3H, t, J=7.3 Hz), 1.72-1.84 (2H, m), 1.99-2.13 (2H, m), 2.82 (2H, t, J= 7.3 Hz), 2.97-3.10 (2H, m), 3.12-3.22 (2H, m), 3.53 (2H, t, J= 7.3 Hz), 4.11 (2H, q, J=6.7 Hz), 4.56-4.62 (1H, m), 5.07 (2H, s), 6.92 (2H, d, J= 8.5 Hz), 7.35 (2H, d, J=8.6 Hz), 7.64 (1H, d, J=8.5 Hz), 7.82 (1H, d, J= 8.5 Hz), 7.89 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.09 (1H, d, J=8.5 Hz), 8.43 (1H, s), 9.12 (1H, brs), 9.21 (1H, brs), 9.33 (2H, s), 9.52 (2H, s).

The following compound of EXAMPLE 73 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 73

Ethyl-3-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]propionate dihydrochloride.

Source connection: ethyl-3-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-(4 - piperidyl)oxy]phenyl]sulfamoyl]propionate dihydrochloride.

Data mass spectrum (m/z): 580 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.20 (3H, t, J=7.3 Hz), 1.58-1.73 (2H, m), 1.94-2.08 (2H, m), 2.29 (3H, s), 2.82 (2H, t, J=7.3 Hz), 3.47-3.49 (2H, m), 3.53 (2H, t, J=7.3 Hz), 3.68-3.75 (2H, m), 4.11 (2H, q, J=7.3 Hz), 4.58-4.64 (1H, m), 5.07 (2H, s), 6.92 (2H, d, J=8.6 Hz), 7.35 (2H, d, J=8.6 Hz), 7.64 (1H, d, J=8.5 Hz), 7.79 (1H, d, J= 8.6 Hz), 7.90 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.09 (1H, d, J= 9.1 Hz), 8.45 (1H, s), 8.66 (1H, s), 9.16 (3H, s), 9.45 (2H, s).

The following compound of EXAMPLE 74 receive the same method as the compound of EXAMPLE 30.

EXAMPLE 74

4-[N-[4-[(1-acetamid the/P> Source connection: ethyl-4-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]the benzoate dihydrochloride.

Data mass spectrum (m/z): 600 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.57-1.72 (2H, m), 1.91-2.02 (2H, m), 2.26 (3H, s), 3.40-3.51 (2H, m), 3.62-3.80 (2H, m), 4.55-4.62 (1H, m), 5.01 (2H, s), 6.85 (2H, d, J= 9.2 Hz), 7.00 (2H, d, J=9.2 Hz), 7.67 (1H, d, J=9.5 Hz), 7.77-7.85 (3H, m), 7.92 (1H, s), 8.02 (1H, d, J=8.6 Hz), 8.09 (1H, d, J=8.5 Hz), 8.16 (2H, d, J= 8.6 Hz), 8.45 (1H, s), 8.74 (1H, s), 9.18-9.34 (3H, m), 9.49 (2H, s), 13.53 (1H, bs).

The following compound of EXAMPLE 75 receive the same method as the compound of EXAMPLE 30.

EXAMPLE 75

[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] -phenyl]-N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]acetic acid, dihydrochloride.

Source connection: ethyl-[N-[4-[(1-acetimidoyl-4 - piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]-acetate dihydrochloride.

Data mass spectrum (m/z): 538 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.61-1.75 (2H, m), 1.92-2.04 (2H, m), 2.27 (3H, s), 3.47-3.52 (2H, m), 3.68-3.78 (2H, m), 4.30 (2H, s), 4.58-4.64 (1H, m), 5.05 (2H, s), 6.94 (2H, d, J=9.2 Hz), 7.32 (2H, d, J=8.5 Hz), 7.65 (1H, d, J=8.6 Hz), 7.82 (1H, d, J= 8.5 Hz), 7.90 (1H, s), 8.01 (1H, d, J=8.6 Hz), 8.09 (1H, d, J=9.2 Hz), 8.48 (1H, s), 8.80 (1H, s), 9.33 (3H, s), 9.52 (2H, s).

EXAMPLE 76

the tion in reference Example 38 (450 mg), dissolved in 10 ml of ethyl acetate, the solution was added 1.6 g of dihydrate of tin chloride and the mixture is heated at a temperature of education phlegmy for 5 hours. The mixture is cooled, add saturated aqueous sodium bicarbonate solution and the resulting precipitate filtered through celite. The organic layer is successively washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The resulting crude N-[(7 - cyano-2-naphthyl)methyl]-N-[4-[(4-piperidyl)oxy] phenyl] -4-aminobenzoyl-sulfonamide are dissolved in a mixed solvent of 5 ml ethanol and 5 ml of chloroform. The solution with stirring, cooled to -70oC and saturated with hydrogen chloride. The mixture is stirred at room temperature for 2 days and then evaporated. The resulting residue is dissolved in 5 ml of ethanol, are added 1 g of ammonium acetate and the mixture is stirred for 4 days at room temperature. The reaction mixture is evaporated, the residue is purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70), using as eluent a mixture of methanol: water (100:0), and then add a small amount of 1N hydrochloric acid and lyophilizers getting 109 mg of N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]-4-aminobenzoyl-sulphamethizole.

Yes the BR>
: 1.71-1.80 (2H, m), 1.98-2.06 (2H, m), 2.91-3.02 (2H, m), 3.10-3.21 (2H, m), 4.51-4.57 (1H, m), 4.88 (2H, s), 6.69 (2H, d, J=9.15 Hz), 6.83 (2H, d, J= 9.2 Hz), 6.99 (2H, d, J=9.2 Hz), 7.32 (2H, d, J=8.5 Hz), 7.66 (1H, d, J= 8.5 Hz), 7.79 (1H, d, J=8.6 Hz), 7.90 (1H, s), 7.92 (1H, d, J=8.5 Hz), 8.07 (1H, d, J= 8.6 Hz), 8.43 (1H, s), 9.10 (1H, brs), 9.19 (1H, brs), 9.32 (2H, s), 9.51 (2H, s).

The following compound of EXAMPLE 77 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 77

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl]- 4-aminobenzenesulfonamide trihydrochloride.

Source connection:

N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)oxy] phenyl]- 4-aminobenzenesulfonamide trihydrochloride.

Data mass spectrum (m/z): 571 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.57-1.72 (2H, m), 1.91-2.02 (2H, m), 2.28 (3H, s), 3.40-3.53 (2H, m), 3.66-3.76 (2H, m), 4.20-4.25 (2H, br), 4.52-4.61 (1H, m), 4.87 (2H, s), 6.65 (2H, d, J=8.8 Hz), 6.83 (2H, d, J=8.8 Hz), 6.99 (2H, d, J=8.8 Hz), 7.30 (2H, d, J=8.8 Hz), 7.66. (1H, d, J=8.8 Hz), 7.79 (1H, d, J=10.3 Hz), 7.91 (1H, s), 7.98 (1H, d, J=8.8 Hz), 8.07 (1H, d, J=8.3 Hz), 8.43 (1H, s), 8.76 (1H, s), 9.27 (3H, s), 9.49 (2H, s).

The following compound of EXAMPLE 78 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 78

N-[(7-amidino-2-naphthyl)methyl] -N'-methyl-N- [4-[(4-piperidyl)-oxy]phenyl] the sulphonamide dihydrochloride.

Parent compound: tert-butyl N-[N-[4-[(1-The Data of the mass spectrum (m/z): 468 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.70-1.82 (2H, m), 1.96-2.08 (2H, m), 2.67 (3H, d, J=4.9 Hz), 2.93-3.06 (2H, m), 3.11-3.21 (2H, m), 4.49-4.59 (1H, m), 4.96 (2H, s), 6.89 (2H, d, J= 8.8 Hz), 7.27 (2H, d, J=9.3 Hz), 7.38-7.46 (1H, m), 7.65 (1H, d, J= 8.3 Hz), 7.80 (1H, d, J=8.8 Hz), 7.89 (1H, s), 7.99 (1H, d, J=8.3 Hz), 8.08 (1H, d, J=8.8 Hz), 8.43 (1H, s), 8.90-9.13 (2H, m), 9.23 (2H, s), 9.48 (2H, s).

The following compound of EXAMPLE 79 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 79

N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl] -N'-methylsulfanyl the dihydrochloride.

Parent compound: N-[(7-amidino-2-naphthyl)methyl]-N'-methyl-N-[4-[(4-piperidyl)oxy]phenyl] the sulphonamide dihydrochloride.

Data mass spectrum (m/z): 509 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.59-1.73 (2H, m), 1.92-2.03 (2H, m), 2.27 (3H, s), 2.67 (3H, d, J= 4.9 Hz), 3.41-3.55 (2H, m), 3.63-3.72 (1H, m), 3.72-3.81 (1H, m), 4.56-4.63 (1H, m), 4.96 (2H, s), 6.89.(2H, d, J=9.2 Hz), 7.27 (2H, d, J=8.5 Hz), 7.39-7.46 (1H, m), 7.66 (1H, d, J=8.6 Hz), 7.81 (1H, dd, J=1.5, 8.8 Hz), 7.89 (1H, s), 8.00 (1H, d, J=8.5 Hz), 8.09 (1H, d, J=8.6 Hz), 8.45 (1H, s), 8.79 (1H, s), 9.23-9.40 (3H, m), 9.52 (2H, s).

The following compound of EXAMPLE 80 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 80

< / BR>
7-amidino-N-methylsulphonyl-N-[4-[(4-piperidyl)oxy] phenyl] - 2-naphthaleneboronic dihydroindol-2-naphthaleneboronic.

Data mass spectrum (m/z): 467 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 1.65-1.77 (2H, m), 1.84-2.06 (2H, m), 2.92-3.04 (2H, m), 3.09-3.20 (2H, m), 3.59 (3H, s), 4.51-4.61 (1H, m), 6.90 (2H, d, J=8.8 Hz), 7.42 (2H, d, J= 8.8 Hz), 7.72 (1H, dd, J=8.8, 1.5 Hz), 7.87 (1H, d, J=9.5 Hz), 7.94 (1H, d, J= 8.8 Hz), 8.11 (1H, d, J=8.8 Hz), 8.34 (1H, s), 8.49 (1H, s), 8.71-8.92 (2H, m), 9.20 (2H, s), 9.51 (2H, s).

The following compound of EXAMPLE 81 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 81

< / BR>
N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -7-amidino-N - methylsulphonyl-2-naphthaleneboronic the dihydrochloride.

Source connection: 7-amidino-N-methylsulphonyl-N-[4-[(4 - piperidyl)oxy]phenyl]-2-naphthaleneboronic the dihydrochloride.

Data mass spectrum (m/z): 508 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.55-1.70 (2H, m), 1.89-2.00 (2H, m), 2.26 (3H, s), 3.40-3.50 (2H, m), 3.60 (3H, s), 3.62-3.69 (1H, m), 3.69-3.78 (1H, m), 4.57-4.67 (1H, m), 6.91 (2H, d, J=9.2 Hz), 7.42 (2H, d, J=9.2 Hz), 7.72 (1H, dd, J=1.5, 8.9 Hz), 7.89 (1H, dd, J=1.8, 8.5 Hz), 7.94 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.34 (1H, s), 8.51 (1H, s), 8.65-8.74 (1H, m), 9.17-9.31 (3H, m), 9.54 (2H, s).

The following compound of EXAMPLE 82 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 82

Ethyl-N-[N-[(7-amidino-2-naphthyl)methyl]-N- [(4-piperidyl)oxy]phenyl]sulfamoyl]-N-m is XI]phenyl]-N-[(7-cyano-2 - naphthyl)methyl]sulfamoyl]-N-methylcarbamate.

Data mass spectrum (m/z): 540 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.35 (3H, t, J=7.0 Hz), 1.70-1.82 (2H, m), 1.96-2.10 (2H, m), 2.92 (3H, s), 2.94-3.08 (2H, m), 3.10-3.21 (2H, m), 4.36 (2H, q, J=7.0 Hz), 4.55-4.63 (1H, m), 5.18 (2H, s), 6.98 (2H, d, J=9.2 Hz), 7.22 (2H, d, J= 9.2 Hz), 7.64 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.93 (1H, s), 8.04 (1H, d, J= 8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.47 (1H, s), 8.90-9.32 (3H, m), 9.49 (3H, s).

EXAMPLE 83

Ethyl-N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]-N-methylcarbamoylmethyl.

Source connection: ethyl-N-[N-[(7 - amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]phenyl]sulfamoyl]- N-methylcarbamate.

Data mass spectrum (m/z): 581 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.35 (3H, t, J=7.0 Hz), 1.51-1.75 (2H, m), 1.94-2.06 (2H, m), 2.27 (3H, s), 2.92 (3H, s), 3.41-3.53 (2H, m), 3.64-3.73 (1H, m), 3.73-3.82 (1H, m), 4.36 (2H, q, J=7.0 Hz), 4.61-4.68 (1H, m), 5.18 (2H, s), 6.98 (2H, d, J= 9.2 Hz), 7.22 (2H, d, J=9.2 Hz), 7.64 (1H, dd, J=1.2, 8.5 Hz), 7.83 (1H, dd, J= 1.8, 8.5 Hz), 7.93 (1H, s), 8.05 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.48 (1H, s), 8.76 (1H, bs), 9.22-9.35 (3H, m), 9.51 (2H, s).

The following compound of EXAMPLE 84 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 84

Methyl-N-[N-[(7-amidino-2 - naphthyl)methyl]-N-[4-[(4-piperidyl)-oxy]phenyl] sulfamoyl]-N - ethoxycarbonylphenyl the dihydrochloride.

Data mass spectrum (m/z): 598 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.30 (3H, t, J=7.0 Hz), 1.71-1.83 (2H, m), 1.98-2.09 (2H, m), 2.93-3.04 (2H, m), 3.10-3.21 (2H, m), 3.62 (3H, s), 4.17 (2H, s), 4.35 (2H, q, J= 7.0 Hz), 4.54-4.62 (1H, m), 5.19 (2H, s), 6.96 (2H, d, J=9.2 Hz), 7.23 (2H, d, J= 9.2 Hz), 7.63 (1H, d, J=9.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.91 (1H, s), 8.03 (1H, d, J= 8.5 Hz), 8.11 (1H, d, J=8.6 Hz), 8.46 (1H, s), 8.95-9.15 (2H, m), 9.26 (2H, s), 9.50 (2H, s).

The following compound of EXAMPLE 85 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 85

Methyl-N-[N-[4-[(1-acetimidoyl-4 - piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]-N - ethoxycarbonylphenyl the dihydrochloride.

Source connection: methyl N-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]sulfamoyl]-N-ethoxycarbonylphenyl the dihydrochloride.

Data mass spectrum (m/z): 639 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.30 (3H, t, J=7.0 Hz), 1.60-1.75 (2H, m), 1.95-2.05 (2H, m), 2.27 (3H, s), 3.41-3.53 (2H, m), 3.62 (3H, s), 3.65-3.72 (1H, m), 3.75-3.82 (1H, m), 4.17 (2H, s), 4.35 (2H, q, J=7.0 Hz), 4.60-4.67 (1H, m), 5.19 (2H, s), 6.96 (2H, d, J=9.2 Hz), 7.23 (2H, d, J=9.2 Hz), 7.63 (1H, d, J=8.6 Hz), 7.83 (1H, d, J= 8.6 Hz), 7.91 (1H, s), 8.04 (1H, d, J=8.6 Hz), 8.11 (1H, d, J= 8.6 Hz), 8.47 (1H, s), 8.79 (1H, s), 9.26-9.35 (3H, m), 9.52 (2H, s).

The following compound of EXAMPLE 86 receive the same method as compound Premail]-N-ethoxycarbonylphenyl the dihydrochloride.

Source connection: methyl N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino - 2-naphthyl)methyl]sulfamoyl]-N-ethoxycarbonylphenyl the dihydrochloride.

Data mass spectrum (m/z): 625 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 1.30 (3H, t, J=7.0 Hz), 1.61-1.73 (2H, m), 1.95-2.05 (2H, m), 2.27 (3H, s), 3.41-3.53 (2H, m), 3.62-3.72 (1H, m), 3.72-3.82 (1H, m), 4.01 (2H, s), 4.34 (2H, q, J=7.0 Hz), 4.59-4.68 (1H, m), 5.19 (2H, s), 6.96 (2H, d, J= 9.2 Hz), 7.23 (2H, d, J=9.2 Hz), 7.64 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.92 (1H, s), 8.03 (1H, d, J=8.5 Hz), 8.11 (1H, d, J=8.6 Hz), 8.46 (1H, s), 8.74 (1H, s), 9.20-9.40 (3H, m), 9.48 (2H, s), 13.01 (1H, bs).

The following compound of EXAMPLE 87 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 87

Ethyl-N-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)-oxy] phenyl] sulfamoyl]glycinate the dihydrochloride.

Source connection: ethyl-N-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] phenyl] -N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]-N-tert-butoxycarbonylmethyl.

Data mass spectrum (m/z): 540 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.21 (3H, t, J=7.0 Hz), 1.70-1.81 (2H, m), 1.95-2.06 (2H, m), 2.93-3.05 (2H, m), 3.07-3.19 (2H, m), 3.83 (2H, d, J=6.7 Hz), 4.14 (2H, q, J= 7.0 Hz), 4.49-4.57 (1H, m), 4.94 (2H, s), 6.88 (2H, d, J=8.5 Hz), 7.28 (2H, d, J= 8.6 Hz), 7.65 (1H, d, J=8.5 Hz), 7.80 (1H, d, J=8.6 Hz), 7.88 (1H, s), 7.98 (the m method, as the compound of EXAMPLE 12.

EXAMPLE 88

Ethyl-N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]glycinate the dihydrochloride.

Source connection: ethyl-N-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]sulfamoyl]glycinate the dihydrochloride.

Data mass spectrum (m/z): 581 (M-2HCl + 1)+.

These NMR spectrum (DMSO - d6, internal standard TMS):

: 1.21 (3H, t, J=7.3 Hz), 1.60-1.73 (2H, m), 1.92-2.02 (2H, m), 2.27 (3H, s), 3.42-3.55 (2H, m), 3.63-3.70 (1H, m), 3.70-3.80 (1H, m), 3.83 (2H, d, J= 6.1 Hz), 4.14 (2H, q, J=7.3 Hz), 4.56-4.62 (1H, m), 4.94 (2H, s), 6.89 (2H, d, J=9.2 Hz), 7.28 (2H, d, J=9.2 Hz), 7.65 (1H, d, J=8.5 Hz), 7.80 (1H, d, J= 8.6 Hz), 7.89 (1H, s), 7.99 (1H, d, J=8.5 Hz), 8.04-8.10 (2H, m), 8.43 (1H, s), 8.74 (1H, s), 9.20-9.31 (3H, m), 9.48 (2H, s).

The following compound of EXAMPLE 89 receive the same method as the compound of EXAMPLE 29.

EXAMPLE 89

N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino - 2-naphthyl)methyl]sulfamoyl]the glycine dihydrochloride.

Source connection: ethyl-N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]glycinate the dihydrochloride.

Data mass spectrum (m/z): 553 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.60-1.71 (2H, m), 1.90-2.02 (2H, m), 2.26 (3H, s), 3.40 J=8.6 Hz), 8.07 (1H, d, J=8.6 Hz), 8.42 (1H, s), 8.71 (1H, s), 9.26 (1H, s), 9.30-9.50 (4H, m), 12.8 (bs).

EXAMPLE 90

Ethanol saturated with ammonia at 10oC (30 ml), was added to 384 mg ethyl-N-[N-[(7-amidino-2-naphthyl)methyl]-N-[4- [(4-piperidyl)oxy]-phenyl]sulfamoyl]glycidaldehyde and the mixture was stirred at 5oC for 5 days. The mixture is evaporated and the resulting residue is dissolved in 5 ml ethanol and 10 ml of methanol. Next, to the solution was added 1,007 mg ethylacetoacetate and 956 mg of triethylamine and the mixture is stirred overnight at room temperature. The reaction mixture is evaporated, the residue is purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70), using as eluent a mixture of methanol: water (1: 99), and then add a small amount of 1N hydrochloric acid and lyophilizers getting 260 mg of N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]glacialinterglacial.

Data mass spectrum (m/z): 552 (M-3HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.60-1.73 (2H, m), 1.91-2.02 (2H, m), 2.26 (3H, s), 3.42-3.51 (2H, m), 3.60-3.79 (4H, m), 4.57-4.62 (1H, m), 4.95 (2H, s), 6.87 (2H, d, J= 8.5 Hz), 7.22 (1H, s), 7.29 (2H, d, J=8.6 Hz), 7.40 (1H, s), 7.65 (1H, d, J= 8.5 Hz), 7.76-7.82 (2H, m), 7.89 (1H, s), 7.98 (1H, d, J=8.6 Hz), 8.08 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.69 (1H, s), 9.15-9.25 (3H, m), 9.47 (2H, s).

The

Methyl-N-[(7-amidino-2-naphthyl)methyl] -5-[(4-piperidyl)- oxy]anthranilate the dihydrochloride.

Source connection: methyl-5-[(1-tert-butoxycarbonyl-4-piperidyl)oxy] -N-[(7-cyano-2-naphthyl)methyl]anthranilate.

Data mass spectrum (m/z): 433 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.71-1.82 (2H, m), 1.95-2.06 (2H, m), 2.93-3.05 (2H, m), 3.12-3.22 (2H, m), 3.84 (3H, s), 4.36-4.42 (1H, m), 4.69 (2H, s), 6.68 (1H, d, J= 9.2 Hz), 7.09 (1H, dd, J=9.1, 3.1 Hz), 7.43 (1H, d, J=3.1 Hz), 7.72 (1H, d, J= 8.5 Hz), 7.81 (1H, d, J=8.5 Hz), 7.90 (1H, s), 7.98 (1H, bs), 8.06 (1H, d, J= 8.5 Hz), 8.12 (1H, d, J=8.5 Hz), 8.45 (1H, s), 8.80-9.03 (2H, m), 9.22 (2H, s), 9.47 (2H, s).

The following compound of EXAMPLE 92 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 92.

< / BR>
Methyl-N-[(7-amidino-2-naphthyl)methyl] -5-[(1-acetimidoyl - 4-piperidyl)oxy]anthranilate the dihydrochloride.

Source connection: methyl-N-[(7-amidino-2-naphthyl)methyl]-5-(4 - piperidyl)oxy]anthranilate the dihydrochloride.

Data mass spectrum (m/z): 474 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.61-1.76 (2H, m), 1.90-2.01 (2H, m), 2.28 (3H, s), 3.45-3.80 (4H, m), 3.84 (3H, s), 4.42-4.49 (1H, m), 4.70 (2H, s), 6.69 (1H, d, J=9.1 Hz), 7.10 (1H, dd, J=9.1, 3.0 Hz), 7.43 (1H, d, J=3.1 Hz), 7.72 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.97 (1H, s), 8.0 (1H, bs), 8.06 (1H, d, J=8.5 Hz), 8.13 (1H, d, J=8.5 Hz), 8.47 (1H, s), 8.78 (1H, livemail]acetate dihydrochloride (490 mg) was dissolved in 1 ml of ethanol, add 5 ml of ethanol saturated with ammonia at 10oC, and the mixture is stirred for 2 days at 0oC. the Reaction mixture is evaporated, the residue is purified ODS chromatography on a column (YMC-GEL ODS-A 120-230/70), using as eluent water, receiving 318 mg [N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]-phenyl]sulfamoyl]ndimethylacetamide.

Data mass spectrum (m/z): 496 (M + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.50-1.98 (2H, m), 1.86-1.94 (2H, m), 2.68-2.73 (2H, s), 2.96-3.06 (2H, m), 4.08 (2H, s), 4.38-4.42 (1H, m), 5.01 (2H, s), 6.89 (2H, d, J= 8.6 Hz), 7.36 (2H, d, J=8.5 Hz), 7.53 (1H, s), 7.65 (1H, d, J=8.6 Hz), 7.89 (1H, d, J= 6.7 Hz), 7.88 (2H, s), 8.00 (1H, d, J=8.5 Hz), 8.07 (1H, d, J= 9.2 Hz), 8.42 (1H, s).

The following compound of EXAMPLE 94 receive the same method as the compound of EXAMPLE 23.

EXAMPLE 94

< / BR>
Ethyl-N-[N-[4-[[(3S)-1-acetimidoyl-3 - pyrrolidinyl)oxy] phenyl]-N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]the carbamate dihydrochloride.

Source connection: ethyl-N-[N-[4-[[(3S)-1-tert-butoxycarbonyl-3 - pyrrolidinyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]-sulfamoyl]carbamate.

Data mass spectrum (m/z): 553 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.27 (3H, t, J=7.3 Hz), 2.07-2.30 (5H, m), 3.33-3.95 (4H, m), 4.23 (2H, q, J=7.3 Hz), 5.05-5.22 (2H, 8 (2H, s), 11.54 (1H, s).

The following compounds of EXAMPLES 95-97 receive the same method as the compound of EXAMPLE 32.

EXAMPLE 95

Ethyl-2-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl)- oxy]phenyl] sulfamoyl]propionate dihydrochloride.

Source connection: ethyl-2-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]propionate.

Data mass spectrum (m/z): 539 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.29 (3H, t, J=7.3 Hz), 1.50-1.55 (5H, m), 1.84-1.96 (2H, m), 2.69-2.73 (2H, m), 2.99-3.02 (2H, m), 4.25-4.29 (2H, m), 4.39-4.42 (2H, m), 4.99 (1H, d, J=19.3 Hz), 5.11 (1H, d, J=15.9 Hz), 6.91 (2H, d, J=9.2 Hz), 7.32 (2H, d, J= 9.2 Hz), 7.65 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.89 (1H, s), 8.03 (1H, d, J=8.5 Hz), 8.00 (1H, d, J=8.5 Hz), 8.44 (1H, s).

EXAMPLE 96

Ethyl-2-[N-[(7-amidino-2-naphthyl)methyl] -N-[4- [(4-piperidyl)-oxy]phenyl] sulfamoyl]valerate the dihydrochloride.

Source connection: ethyl-2-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]valerate.

Data mass spectrum (m/z): 567 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.89 (3H, t, J= 7.3 Hz), 1.25 (3H, t, J=7.3 Hz), 1.30-1.36 (2H, m), 1.51-1.55 (2H, m), 1.81-2.02 (4H, m), 2.68-2.72 (2H, m), 2.97-3.00 (2H, m), 4.24-4.29 (3H, m), 4.40-4.43 (1H, m), 5.00 (1H, d, J=15.2 HCLASS="ptx2">

EXAMPLE 97

Ethyl-2-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4-piperidyl) oxy] phenyl] sulfamoyl]the butyl dihydrochloride.

Source connection: ethyl-2-[N-[4-[(1-tert-butoxycarbonyl-4-piperidyl) oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]butyl.

Data mass spectrum (m/z): 553 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.94 (3H, t, J= 7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.49-1.51 (2H, m), 1.88-1.90 (2H, m), 1.98-2.05 (2H, m), 2.50-2.69 (2H, m), 2.96-2.99 (2H, m), 4.22-4.29 (3H, m), 4.38-4.40 (1H, m), 4.98 (1H, d, J=15.3 Hz), 5.06 (1H, d, J= 15.3 Hz), 6.87 (2H, d, J=9.2 Hz), 7.28 (2H, d, J=8.5 Hz), 7.62 (1H, d, J= 8.5 Hz), 7.80 (1H, d, J=8.6 Hz), 7.86 (1H, s), 8.00 (1H, d, J=8.6 Hz), 8.08 (1H, d, J=8.5 Hz), 8.41 (1H, s).

The following compounds of EXAMPLES 98-107 receive the same method as the compound of EXAMPLE 12.

EXAMPLE 98

Ethyl-2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]propionate dihydrochloride.

Source connection: ethyl-2-[N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]sulfamoyl]propionate dihydrochloride.

Data mass spectrum (m/z): 580 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.27 (3H, t, J= 7.3 Hz), 1.53 (3H, d, J=7.3 Hz), 1.61-1.76 (2H, m), 1.92-2.06 (2H, m), 2.29 (3H, s), 3.42-3.52 (2H, m), 3.62-3.80 (2H, m), 4.25 (2H, q, J=7.3 Hz), 4.41 (1H, q, J=6.7 H=8.5 Hz), 8.50 (1H, s), 9.37 (6H, br).

EXAMPLE 99

Ethyl-2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7 - amidino-2-naphthyl)methyl]sulfamoyl]the butyl dihydrochloride.

Source connection: ethyl-2-[N-[(7-amidino-2 - naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]phenyl]sulfamoyl]the butyl dihydrochloride.

Data mass spectrum (m/z): 594 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 0.95 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.50-1.66 (2H, br), 1.99-2.08 (4H, m), 2.29 (3H, s), 3.40-3.51 (2H, br), 3.71-3.79 (2H, br), 4.24-4.30 (3H, m), 4.63-4.64 (1H, m), 5.03 (1H, d, J=15.3 Hz), 5.05 (1H, d, J= 15.3 Hz), 6.93 (2H, d, J=9.2 Hz), 7.31 (2H, d, J=9.2 Hz), 7.63 (1H, d, J= 9.8 Hz), 7.85-7.87 (2H, m), 8.02 (1H, d, J=8.5 Hz), 8.09 (1H, d, J=8.5 Hz), 8.51 (1H, s), 9.43 (6N, br).

EXAMPLE 100

Ethyl-2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]valerate the dihydrochloride.

Source connection: ethyl-2-[N-[(7-amidino-2 - naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]phenyl]sulfamoyl]valerate the dihydrochloride.

Data mass spectrum (m/z): 608 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6internal standard TMS):

: 0.89 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz), 1.30-1.36 (2H, m), 1.67 (2H, br), 1.88-2.00 (4H, m), 2.28 (3H, s), 3.49 (2H, br), 3.75 (2H, br), 4.24-4.28 (3H, m), 4.60-4.68 (1H, m), 5.01 (1H, d, J=15.9 Hz), 5.08 (1H, d, J= 15.9 Hz), 6.94 (2H, d, J=9.2 Hz), 7.31 (2H, d, J=8.6 Hz), 7.63 (1H, d, J= 8.6 Hz), 7.84 (who Ridel)oxy] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]ndimethylacetamide the dihydrochloride.

The source of the link: [N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(4 - piperidyl)oxy]phenyl]sulfamoyl]ndimethylacetamide.

Data mass spectrum (m/z): 537 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.60-1.72 (2H, m), 1.94-2.02 (2H, m), 2.26 (3H, s), 3.42-3.51 (2H, m), 3.64-3.78 (2H, m), 4.07 (2H, s), 4.58-4.64 (1H, m), 5.01 (2H, s), 6.93 (2H, d, J= 8.6 Hz), 7.38 (2H, d, J=9.2 Hz), 7.52 (1H, s), 7.66 (1H, d, J= 8.6 Hz), 7.80 (1H, d, J=8.6 Hz), 7.84 (1H, s), 7.90 (1H, s), 8.00 (1H, d, J= 8.6 Hz), 8.08 (1H, d, J=9.2 Hz), 8.44 (1H, s), 8.84-9.14 (5H, br).

The following compound of EXAMPLE 102 receive the same method as the compound of EXAMPLE 30.

EXAMPLE 102

2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl) methyl]sulfamoyl]propionic acid dihydrochloride.

Source connection: ethyl-2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]-propionate dihydrochloride.

Data mass spectrum (m/z): 552 (M-2HCl + 1)+.

These NMR spectrum (DMSO-d6, internal standard TMS):

: 1.50 (3H, d, J=6.7 Hz), 1.57-1.71 (2H, m), 1.91-2.04 (2H, m), 2.27 (3H, s), 3.40-3.54 (2H, m), 3.64-3.82 (2H, m), 4.25-4.29 (1H, m), 4.58-4.62 (1H, m), 4.97 (1H, d, J=15.3 Hz), 5.10 (1H, d, J=15.3 Hz), 6.92 (2H, d, J= 9.2 Hz), 7.33 (2H, d, J=9.2 Hz), 7.64 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.5 Hz), 7.88 (1H, s), 8.02 (1H, d, J=8.5 Hz), 8.09 (1H, d, J=9.2 Hz), 8.47 (1H, s), 8.79 (1H, s), 9.31-9.33 (3H, br), 9.51 (2H, s).

The chemical structure of the following compound (1A) to(53A) can easily get almost the same way as described in the above EXAMPLES, and methods of obtaining them contain minor modifications, obvious to any expert.

(1A) [N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]-2-thiophenesulfonyl the dihydrochloride;

(2A) [N-[4-[(1-acetimidoyl-4 - piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]-2 - forbindelsesfaneblad the dihydrochloride;

(3A) [N-[4-[(1-acetimidoyl - 4-piperidyl)oxy] phenyl]-N-[(7-amidino-2 - naphthyl)methyl]methylsulfonylmethane the dihydrochloride;

(4A) [N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(6-amidino-2 - naphthyl)methyl]oksamida the dihydrochloride;

(5A) [N-[4-[(1-acetimidoyl - 4-piperidyl)oxy]phenyl]-N-[(5-amidino-2-naphthyl)methyl]oksamida the dihydrochloride;

(6A) [N-[4-[(1-acetimidoyl-4 - piperidyl)oxy]phenyl]-N-[(8-amidino-2-naphthyl)methyl]oksamida the dihydrochloride;

(7A) [N-[4-[(1-acetimidoyl-3-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl]oksamida the dihydrochloride;

(8A) [N-[4-[(l-acetimidoyl-2-piperidyl)oxy] phenyl] -N-[(7-amidino-2 - naphthyl)methyl]oksamida the dihydrochloride;

(9A) N-[(7-amidino-2 - naphthyl)methyl] -N-[4-[(1-aminopropyl-4-piperidyl)oxy]phenyl]oksamida the dihydrochloride;

(10A) N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(3 - pyrrolidinyl)oxy]phenyl] oksamida the dihydrochloride;
what about the-2-naphthyl)methyl]-1-[4-[(3-pyrrolidinyl)-oxy] phenyl] -3-utilmately the dihydrochloride;

(13A) N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(3-pyrrolidinyl)oxy] phenyl] ethoxycarbonylmethylene the dihydrochloride;

(14A) N-[(7-amidino-2-naphthyl)methyl]-N-[4-[(3-pyrrolidinyl)-oxy] phenyl] ndimethylacetamide the dihydrochloride;

(15A) N-[(7-amidino-2-naphthyl)methyl] -N-[4-[(3-pyrrolidinyl)oxy] phenyl] acanalonia the dihydrochloride;

(16A) N-[4-[(1-acetimidoyl-3-pyrrolidinyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]oksamida the dihydrochloride;

(17A) N-[4-[(1-acetimidoyl-3-pyrrolidinyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]oxamate the dihydrochloride;

(18A) 1-[4-[(1-acetimidoyl-3-pyrrolidinyl)oxy]phenyl]-1- [(7-amidino-2-naphthyl)methyl]-3-utilmately the dihydrochloride;

(19A) N-[4-[(1-acetimidoyl-3-pyrrolidinyl)oxy] phenyl]-N-[(7-amidino-2-naphthyl)methyl]ethoxycarbonylmethylene the dihydrochloride;

(20A) N-[4-[(1-acetimidoyl-3-pyrrolidinyl)oxy] phenyl]-N-[(7-amidino-2-naphthyl)methyl]ndimethylacetamide the dihydrochloride;

(21A) N-[4-[(1-acetimidoyl-3-pyrrolidinyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]acanalonia the dihydrochloride;

(22A) N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]-2-aminoethanesulfonic the dihydrochloride;

(23A) N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7-amidino - 2-naphthyl)methyl]-2-dimethylbenzenesulfonamide trihydrochloride;
(25A) N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl]-2-methoxybenzenesulfonamide the dihydrochloride;

(26A) [N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]propionic acid dihydrochloride;

(27A) Methyl-N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]glycinate the dihydrochloride;

(28A) of N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy] phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]-N-methylglycine the dihydrochloride;

(29A) Methyl-N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]-N-methylglycine the dihydrochloride;

(30A) of N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy] phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]-N - methylglucamide the dihydrochloride;

(31A) N-[N-[4-[l-acetimidoyl-4 - piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]- N-ethoxycarbonylpyrimidine the dihydrochloride;

(32A) Methyl-N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy]phenyl] -N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]the carbamate dihydrochloride;

(33A) N-[4-[1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2 - naphtol)sulfamoyl]acetic acid dihydrochloride;

(34A) Ethyl-N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7 - amidino-2-naphtol)sulfamoyl]carbamate of digit

(36A) of N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]-N'-metalmachine;

(37A) of N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]methanesulfonamide;

(38A) N-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7-amidino-2-naphthyl) methyl]sulfamoyl]-N'-metalmachine;

(39A) N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N'-acetyl-N- [(7-amidino-2-naphthyl)methyl]sulphonamide;

(40A) 2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl]-N-[(7-amidino-2-naphthyl) methyl]sulfamoyl]butyric acid;

(41A) 2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]valeric acid;

(42A) 2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]isovalerianic acid;

(43A) 2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl] -N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]-3-phenylpropionate acid;

(44A) N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino - 2-naphthyl)methyl]DIPEROXY acid;

(45A) 2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]somalina acid;

(46A) 2-[N-[4-[(1 - acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl] sulfamoyl]-2-ethylmalonate sour robonova acid;

(48A) Ethyl-2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]isovalerate;

(49A) Ethyl-2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]-3-phenylpropionate;

(50A) Ethyl-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]deflorated;

(51A) Ethyl-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N- [(7-amidino-2-naphthyl)methyl]sulfamoyl]isobutyrate;

(52A) Ethyl-2-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]-2-ethyl butyrate;

(53A) Ethyl-1-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2 - naphthyl)methyl]sulfamoyl]-1-cyclohexanecarboxylate. 1. Derivatives aydinonat General formula (I)

< / BR>
where R1represents hydrogen or a group-A-W-R4And means a group of formula a group of the formula or-SO2-, X is oxygen atom or sulfur, W is a simple bond or a group of the formula NR5, R4is hydroxyl, lower alkoxy, lower alkyl which may be substituted, cycloalkyl, which may be substituted, aryl which may be substituted, or heteroaryl containing 1 to 2 heteroatoms selected from sulfur and nitrogen, which may be substituted, provided that when W is a group of four is SSA alkoxygroup, R5is a hydrogen atom, carbarnoyl, lower alkoxycarbonyl, mono - or di-lower alkylaminocarbonyl, lower alkylsulfonyl, mono - or di-lower alkylaminocarbonyl, lower alkyl which may be substituted, or lower alkanoyl, which may be substituted;

R2represents lower alkyl;

R3represents a hydrogen atom or a lower alkoxycarbonyl;

Represents a lower alkylene or carbonyl;

n = 0 or 1, or its pharmaceutically acceptable salt.

2. Derivatives aydinonat or their pharmaceutically acceptable salts under item 1, where the lower alkyl which may be substituted in the value of R4or R5cycloalkyl, which can be substituted in the value of R4or lower alkanoyl, which can be substituted in the value of R5represent lower alkyl, cycloalkyl or lower alkanoyl, which may be substituted by one of the following group of substituents; and the aryl which may be substituted, or heteroaryl, which can be substituted in the value of R4represent aryl or heteroaryl, which may be substituted by one of the following group of substituents D, and the group includes the following substituents: halogen, carb is s, alkylamino, aryl, aralkylated, aryloxy, mercapto, lower alkylthio, lower alkylthiomethyl, hydroxyl or mono - or di-lower alkylaminocarbonyl, and D consists of the following substituents: halogen, carboxyl, amino, cyano, nitro, hydroxyl, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino, lower alkanoyl or lower alkyl which may be substituted by a member of group C.

3. Derivatives aydinonat or their pharmaceutically acceptable salts under item 2, where R4is a group of hydroxy; lower alkoxy; lower alkyl which may be substituted with halogen, carboxyla, carbamoyl, amino, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino or phenyl; cycloalkyl, which may be substituted with halogen, carboxyla, carbamoyl, amino, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino or phenyl; aryl which may be substituted with halogen, carboxyla, amino, nitro, lower alkoxycarbonyl or lower alkoxy; heteroaryl, which may be substituted with halogen, carboxyla, amino, nitro, lower alkoxycarbonyl or lower alkoxy, provided that when W is a group of the formula NR5, R4may additionally be alkoxycarbonyl; lowest alkanoyl; mono - or di-lower alkylaminocarbonyl; or lower alkyl which may be substituted with halogen, carbamoyl, amino, lower alkoxy, lower alkoxycarbonyl, mono - or di-lower alkylamino or phenyl; and R3represents a hydrogen atom or a lower alkoxycarbonyl.

4. Derivatives or their pharmaceutically acceptable salts under item 3, where a group of the formula-A-W-R4represents a group selected from lower alkanoyl, which may be substituted by lower alkoxy, lower alkoxycarbonyl or mono - or di-lower alkylamino; aminocarbonyl, which may be substituted by lower alkoxycarbonyl; lower alkylsulfonyl, which may be substituted with halogen, carboxyla, carbamoyl, lower alkoxycarbonyl or phenyl; mono - or di-lower alkylaminocarbonyl, which can be substituted by carboxyla or lower alkoxycarbonyl; aminosulfonyl, which may be substituted by lower alkoxycarbonyl; mono - or di-lower alkylaminocarbonyl, which can be substituted by carboxyla, carbamoyl or lower alkoxycarbonyl; N-lower alkyl-N-lower alkoxycarbonylmethyl, which can be substituted by carboxyla or lower alkoxycarbonyl; solarpanel, which may be substituted amino, nitro, carboxyla or lower alkoxycarbonyl; Naftoli; mononessa of alkylaminocarbonyl; pyridylcarbonyl; taylorsville; aminoacetyl; or cycloalkylcarbonyl; and R3represents a hydrogen atom or a lower alkoxycarbonyl.

5. Derived aydinonat or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 3, where a group of the formula .

6. Derivatives aydinonat or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 3, where a group of the formula-SO2-.

7. Derived aydinonat selected from the group that includes the following connections:

N-[4-[(1-acetimidoyl-4-piperidyl)oxyl] phenyl] -N-[(7-amidino-2-naphthyl)methyl]-N'-methylsulfonyl;

ethyl-N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]carbamate;

4-[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]benzoic acid;

[N-[4-[(1-acetimidoyl-4-piperidyl)oxy] phenyl] N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]acetic acid;

ethyl-N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy] phenyl] -N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]glycinate;

N-[N-[4-[1-acetimidoyl-4-piperidyl)oxy] phenyl] the yl] -N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]glycine,

or their pharmaceutically acceptable salts.

8. Derived aydinonat General formula (1')

< / BR>
where R1represents hydrogen or a group-A-W-R4, A denotes a group of formula a group of the formula or-SO2-, X is oxygen atom or sulfur, W is a simple bond or a group of the formula NR5, R4is hydroxyl, lower alkoxy, lower alkyl which may be substituted, cycloalkyl, which may be substituted, aryl which may be substituted, or heteroaryl containing 1 to 2 heteroatoms selected from sulfur and nitrogen, which may be substituted, provided that when W is a group of the formula NR5, R4may additionally represent a hydrogen atom, but not be hydroxyl or lower alkoxygroup, R5is a hydrogen atom, carbarnoyl, lower alkoxycarbonyl, mono - or di-lower alkylaminocarbonyl, lower alkylsulfonyl, mono - or di-lower alkylaminocarbonyl, lower alkyl which may be substituted or a lower alkanoyl, which may be substituted;

R3represents a hydrogen atom or a lower alkoxycarbonyl;

Represents a lower alkylene or carbonyl;

n = 0 or 1,

or their pharmaceutically acceptable salts.

9. Pharmaceutical is the one active ingredient, the pharmaceutical carrier, fillers and other additives, characterized in that as the active ingredient includes a derived aydinonat or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 7 in an effective amount.

10. The pharmaceutical composition under item 9, which is an inhibitor of blood coagulation.

11. The pharmaceutical composition according to p. 9, characterized in that it is used for prevention and/or treatment of diseases caused by thrombus or embolus.

Priority points and features:

02.12.94 - p. 1, where In a matter-CH2-, R3-H;

28.04.95 - p. 1, where is the rest of the values, R3- N.; p. 7 - the first four compounds;

03.08.95 - p. 1 (all other connections), p. 7 - the last three compounds.

 

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