Compound, pharmaceutical composition, applying, method for prophylaxis and treatment of disease

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

 

The technical field

The present invention relates to a derivative of benzamidine and their pharmacologically acceptable salts and prodrugs, which have excellent inhibitory activity against activated coagulation factor X; relates to pharmaceutical compositions for the prevention or treatment of diseases associated with blood clotting, containing the specified derived benzamidine or its pharmacologically acceptable salt or prodrug; refers to the application of the specified derivative of benzamidine or its pharmacologically acceptable salt or prodrug to obtain a therapeutic agent for the prevention or treatment of diseases associated with blood clotting; relates to a method for prevention or treatment of diseases associated with blood clotting, including the introduction of a warm-blooded animal, in need of such prevention or treatment a pharmacologically effective quantity of a specified derivative of benzamidine or its pharmacologically acceptable salt or prodrug; and relates to a method of obtaining the derivatives of benzamidine and their pharmacologically acceptable salts and prodrugs.

Background of invention

Recently, a rising share of the elderly population, and becomes visible uvelichenie patients with diseases of the circulatory system inherent in the aging process.

Diseases associated with formation of blood clots, such as cerebral embolism, myocardial infarction, disease system peripheral circulation, etc. may not only directly cause death of a person, but also lead to personal and social stress, including poor patient recovery and limited personal life of the patient. It is believed that treatment with anticoagulation funds will be increasingly important as a method of treatment of thrombosis.

Blood clotting is caused by formation of fibrin, which is formed by selective decomposition of fibrinogen, which are soluble whey protein, under the action of activated thrombin, which is formed at the end of the amplified multi-stage enzymatic reaction, activated by some stimulus. Fibrin is an insoluble protein and causes coagulation. This process is known as the blood clotting system and includes a process driven from the inside, and the process caused by external factors. Both processes go together with the activation of coagulation factor X. the so Formed activated coagulation factor X is an important enzyme in the blood coagulation system. Ultimately AK is ivireanul the coagulation factor X forms a complex with divalent ions of calcium, fosfatados, activated coagulation factor V and the like, effectively converting prothrombin into thrombin, and reinforcing the clotting mechanism of the blood (see, for example, E.L. Smith, A. White et al., “Principles of Biochemistry: Mammalian Biochemistry, 7thedition”, McGraw-Hill, Inc. (1983)).

Currently as anticoagulation means known warfarin and antithrombin. Warfarin is widely used as oral antithrombotic tool. However, it is known that the regulation of the activity of blood coagulation with warfarin is difficult because it is an antagonist of vitamin K and often interacts with food and tools, combined with warfarin (see, for example, Clin. Pharmacokinet., 30, 416 (1996), and the like). Recently often see the bleeding as the harmful side effects of antithrombin. Therefore the need for improved anticoagulation agent. It is known that activated coagulation factor X directly involved in the formation of thrombin and that inhibitors of activated coagulation factor X exhibit anticoagulant activity. Assume the probability that such an inhibitor may be a new anti-clotting agent (see, for example, Drugs, 49, 856 (1995), and so on).

In this regard, the publication of the patent application of Japan for a number Hei 5-208946 (EP 540051), WO 96/16940 (EP 798295) and WO 00/47553 describes some of the aromatics produced in the water amidine and amidinohydrolase derivatives as competitive antagonists inhibitors of activated blood coagulation factor X. In WO 98/31661 (EP 976722) describes several derivatives of benzamidine, such as DATEFORMAT N-[4-[1-acetimidoyl-4-piperidinyloxy]phenyl]-N-[2-(3-amidinophenoxy)ethyl]sulfamoylbenzoic acid.

Description of the invention

The inventors have in a long time endeavored to search for compounds that have excellent inhibitory activity against activated blood coagulation factor X and investigated the pharmacological activity of various derivatives of benzamidine. Discovered that certain derivatives of benzamidine with a new chemical structure have excellent inhibitory activity against activated blood coagulation factor X and are not inhibiting trypsin activity, and found that these derivatives can be used for prevention or treatment (in particular treatment) of diseases associated with blood clotting. Thus accomplished the present invention.

The present invention relates to a derivative of benzamidine and their pharmacologically acceptable salts or prodrugs, which have excellent inhibitory activity against activated coagulation factor X; processes for their preparation, intermediate compounds used for their production; containing pharmaceutical compositions of labradorite or treatment of diseases, associated with blood clotting, use a specified derivative of benzamidine or its pharmacologically acceptable salt or prodrug to obtain a therapeutic agent for the prevention or treatment of diseases associated with blood clotting; method of prevention or treatment of diseases associated with blood clotting, including the introduction of a warm-blooded animal a pharmacologically effective quantity of a specified derivative of benzamidine or its pharmacologically acceptable salt or prodrug.

The present invention relates to compounds of the following General formula (1) and their pharmacologically acceptable salts or prodrugs:

In the formula

R1represents a hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms or a hydroxyl group;

R2represents a hydrogen atom or a halogen atom;

R3represents a hydrogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms, substituted hydroxyl group, carboxialkilnuyu group with 2-7 carbon atoms, alkoxycarbonylmethyl group 3-13 carbon atoms, alkylsulfonyl group with 1-6 carbon atoms, alkoxycarbonylmethyl group 3-13 carbon atoms, carboxy killalpaninna group with 2-7 carbon atoms or carboxyethylgermanium group with 3-8 carbon atoms;

R4and R5are the same or different, and each represents a hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms, substituted by a halogen atom, alkoxygroup with 1-6 carbon atoms, carboxyl group, alkoxycarbonyl group with 2-7 carbon atoms, karbamoilnuyu group, monoalkylammonium group with 2-7 carbon atoms or dialkylamino group 3-13 carbon atoms;

R6represents a hydrogen atom, alkyl group with 1-6 carbon atoms, cycloalkyl group with 3-8 carbon atoms, aracelio group with 7 to 16 carbon atoms, alkyl group with 1-6 carbon atoms, substituted heterocycle, carboxialkilnuyu group with 2-7 carbon atoms, alkoxycarbonylmethyl group 3-13 carbon atoms, aliphatic acyl group with 2-7 carbon atoms, an aromatic acyl group with 7 to 11 carbon atoms, karbamoilnuyu group, alkylsulfonyl group with 1-6 carbon atoms, aryl group with 6-10 carbon atoms, a heterocycle, formimidoyl group, 1-aminoalkyl group having 3-7 carbon atoms, N-alkyltrimethyl the group with 2-7 carbon atoms or aminoacylation group with 7 to 11 carbon atoms;

each of R7and R8represents a hydrogen atom or alkyl group with 1-6 atoms is carbon; or

R6and R7taken together, or R7and R8taken together, constitute alkylenes group with 2-5 carbon atoms; and

n is 0, 1 or 2.

“Halogen atom” in the definition of R1, R2, R4and R5includes, for example, iodine atom, bromine atom, chlorine atom and a fluorine atom; preferred halogen atom for R1is a bromine atom, a chlorine atom, a fluorine atom or the like, and particularly preferred halogen atom for R1is a fluorine atom; preferred halogen atom for R2is a bromine atom, a chlorine atom or a fluorine atom, and particularly preferred halogen atom for R2is a fluorine atom; preferred halogen atom for each of R4and R5is a bromine atom, a chlorine atom or a fluorine atom, and more preferred halogen atom for each of R4and R5is a fluorine atom or a chlorine atom, and preferred is a chlorine atom.

“An alkyl group with 1-6 carbon atoms” in the definition of R1, R3, R4, R5, R6, R7and R8includes, for example, methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, 2-methylbutanol, neopentyl, 1-ethylpropyl, hexeline, 4-methylpentyl, 3-methylpentyl, 2-meth is pentelow, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl group and similar groups; preferred alkyl group for R1is a methyl group; a preferred alkyl group for R3is methyl, ethyl or ISO-propyl group, and particularly preferred alkyl group for R3is ISO-propyl group; a preferred alkyl group for each of R4and R5is a methyl group; a preferred alkyl group for R6is methyl, ethyl, ISO-propyl or bucilina group, and particularly preferred alkyl group for R6is methyl, ethyl or isopropyl group; a preferred alkyl group for R7is a methyl group; and preferred alkyl group for R8is a methyl group.

The alkyl component in the “alkyl group with 1-6 carbon atoms, substituted hydroxyl group”in the definition of R3has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1-3 carbon atoms; more preferred alkyl component I which is ethyl group, and preferred “alkyl group with 1-6 carbon atoms, substituted hydroxyl group”, is a 2-hydroxyethylene group.

The alkyl component in “carboxialkilnuyu group with 2-7 carbon atoms” in the definition of R3has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1-3 carbon atoms; more preferred alkyl component is a methyl group, and preferred “carboxialkilnuyu group with 2-7 carbon atoms” is carboxymethyl group.

The alkyl component and the alkyl component in alkoxides in “alkoxycarbonylmethyl group 3-13 carbon atoms” in the definition of R3has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1-4 carbon atoms; preferred “alkoxycarbonylmethyl group 3-13 carbon atoms” is methoxycarbonylmethylene group, ethoxycarbonylmethyl group, propoxycarbonyl group or butoxycarbonylmethylene group; more preferred is methoxycarbonylmethylene group or ethoxycarbonylmethylene group, and especially predpochtitelnye ethoxycarbonylmethylene group.

The alkyl component in “carboxypolymethylene group with 2-7 carbon atoms” in the definition of R3has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1-4 carbon atoms; more preferred methyl group, and preferred “carboxypolymethylene group with 2-7 carbon atoms” is carboxymethyllysine group.

The alkyl component in “alkylsulfonyl group with 1-6 carbon atoms” in the definition of R3has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1-4 carbon atoms; more preferred alkyl component is ethyl group, and preferred “alkylsulfonyl group with 1-6 carbon atoms” is acanaloniidae group.

The alkyl component and the alkyl component in alkoxides in “alkoxycarbonylmethyl group 3-13 carbon atoms” in the definition of R3has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1-4 carbon atoms; more preferred is entrusted alkyl component is an alkyl group with 1 or 2 carbon atoms, and preferred “alkoxycarbonylmethyl group 3-13 carbon atoms” is ethoxycarbonylmethylene group.

The alkyl component in “carboxyethylgermanium group with 3-8 carbon atoms” in the definition of R3has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1-4 carbon atoms; more preferred is an alkyl group with 1 carbon atom, and preferred “carboxyethylgermanium group with 3-8 carbon atoms” is carboxyaniline group.

The alkyl component in the “alkyl group with 1-6 carbon atoms, substituted by a halogen atom”in the definition of R4and R5has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1 or 2 carbon atoms; and preferred “alkyl group with 1-6 carbon atoms, substituted by a halogen atom”is triptorelin group.

The alkyl component in alkoxygroup with 1-6 carbon atoms” in the definition of R4and R5has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred Alkylglucoside is an alkyl group with 1-4 carbon atoms; more preferred alkyl component is an alkyl group with 1 carbon atom, and preferred “alkoxygroup with 1-6 carbon atoms” is a methoxy group.

The alkyl component in “alkoxycarbonyl group with 2-7 carbon atoms” in the definition of R4and R5has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1 or 2 carbon atoms, and preferred “alkoxycarbonyl group with 2-7 carbon atoms is ethoxycarbonyl group.

The alkyl component in “monoalkylamines group with 2-7 carbon atoms” in the definition of R4and R5has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1 or 2 carbon atoms, and preferred “monoalkylamines group with 2-7 carbon atoms is N-methylcarbamoyl group.

Each alkyl component in “dialkylanilines group 3-13 carbon atoms” in the definition of R4and R5has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is alkyl GRU is PA with 1 or 2 carbon atoms, and preferred “dialkylanilines group 3-13 carbon atoms is N,N-dimethylcarbamoyl group.

“Cycloalkyl group with 3-8 carbon atoms” in the definition of R6includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptyl and cyclooctyl group and such group, and preferably represents cyclopentyloxy group.

“Arylalkyl group with 7 to 16 carbon atoms” in the definition of R6includes, for example, benzyl, 1-naphthylmethyl, 2-naphthylmethyl and fenetylline group and such group, and preferably represents a benzyl or fenetylline group.

The alkyl component in the “alkyl group with 1-6 carbon atoms, substituted heterocycle”, in the definition of R6has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1 or 2 carbon atoms, and heterocyclic component is a 5-7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and includes, for example aromatic heterocyclic groups such as furilla, thienyl, pyrrolidine, aspenlea, pyrazolidine, imidazolidine, oxazolidine, isaxis lilina, thiazolidine, isothiazolinone, 1,2,3-oxadiazolyl, triazoline, tetrataenia, thiadiazolidine, Pernilla, perederina, pyridinoline, pyrimidinamine and piratininga group; and heterocyclic groups, which are partially or fully hydrogenated aromatic heterocyclic group, the corresponding aromatic heterocyclic groups mentioned above, such as morpholinyl, thiomorpholine, pyrrolidinyl, pyrrolidinone, imidazolidinyl, imidazolidinone, pyrazolidinone, piratininga, piperideine and piperazinilnom group; preferably, this group is a 5-7-membered heterocycle containing at least one nitrogen atom and may optionally contain an oxygen atom or atom sulfur, for example, aromatic heterocyclic group, such as pyrrolyl, azepine, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; or a heterocyclic group, which is a partially or fully gidrirovannoe aromatic heterocyclic group, the corresponding aromatic heterocyclic group mentioned above, such as morpholinyl, thiomorpholine, pyrrolidine, pyrroline, imide is Soldini, imidazolines, pyrazolidine, pyrazoline, piperidyl or piperazinil (for example, 4,5-dihydro-3H-pyrrol-2-yl, 2,3,4,5-tetrahydropyridine-6-yl, 4,5-dihydrooxazolo-2-yl or 5,6-dihydro-2H[1,4]thiazin-3-yl); and the specified “5-7-membered heterocyclic group may optionally be fused with another cyclic group, and such a condensed cyclic group include, for example, isobenzofuranyl, bromanil, xantener, phenoxathiin, indolizinyl, isoindolyl, indolyl, indazoles, purinol, hinolinol, ethanolic, hinely, phthalazine, naphthyridine, honokalani, hintline, carbazolyl, carbolines, acridines, isoindolines and similar groups, and preferable heterocyclic group is Peregrina group. Preferred “alkyl group with 1-6 carbon atoms, substituted heterocycle”is a 2-pyridylmethylene, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl or 2-(4-pyridyl)ethyl group.

The alkyl component in “carboxialkilnuyu group with 2-7 carbon atoms” in the definition of R6has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1 or 2 carbon atoms. Preferred “carboxialkilnuyu group with 2-7 carbon atoms” is one who by carboxymethyl group.

The alkyl component in “alkoxycarbonylmethyl group 3-13 carbon atoms” in the definition of R6has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1 or 2 carbon atoms. Preferred “alkoxycarbonylmethyl group 3-13 carbon atoms” is methoxycarbonylmethylene group.

“Aliphatic acyl group with 2-7 carbon atoms” in the definition of R6includes, for example, acetyl, propionyl, butyryloxy, isobutyryloxy, pivaloyloxy, valerino, isovaleryl, hexanoyl, heptanoyl and octanoyl group and similar groups, and preferred is an acetyl group.

“Aromatic acyl group with 7 to 11 carbon atoms” in the definition of R6includes, for example, benzoyloxy, 1-afterburning and 2-afterburning group and such group, and preferably represents benzoyloxy group.

The alkyl component in “alkylsulfonyl group with 1-6 carbon atoms” in the definition of R6has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 1 or 2 carbon atoms. Preferred ALK is sulfonyloxy group with 1-6 carbon atoms” is methanesulfonyl group.

“Aryl group with 6-10 carbon atoms” in the definition of R6includes, for example, phenyl, 1-naftalina, 2-naftalina and phenanthroline group and such group, and preferably represents a phenyl group.

“Heterocycle” in the definition of R6has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms, substituted heterocycle”, the preferred heterocycle represents a group of one of the following formulas, i.e. 4,5-dihydro-3H-pyrrol-2-yl of the formula (A), 2,3,4,5-tetrahydropyridine-6-yl of the formula (V), 4,5-dihydrooxazolo-2-yl of the formula (C), 5,6-dihydro-2H-[1,4]-thiazin-3-yl of the formula (D) or 4-pyridyloxy group.

The alkyl component 1-aminoalkyl group having 3-7 carbon atoms” in the definition of R6has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl component is an alkyl group with 3 carbon atoms. The preferred “1-aminoalkyl group having 3-7 carbon atoms is 1-aminopropylene group.

The alkyl component in N-alkyltrimethylenedi group with 2-7 carbon atoms” in the definition of R6has the same values, which are specified above in the definition of “alkyl group with 1-6 carbon atoms”; a preferred alkyl is leaving is an alkyl group with 1 or 2 carbon atoms. Preferred N-alkyltrimethylenedi group with 2-7 carbon atoms is N-atinformation group.

“Aminoacyltrna group with 7 to 11 carbon atoms” in the definition of R6includes, for example, aminophenylamino, aminonaphthalene group and such group, and preferably represents aminophenylamino group.

“Allenova group with 2-5 carbon atoms, which form an R6and R7taken together, or R7and R8taken together, include, for example, ethylene, trimethylene, tetramethylene and pentamethylene group and such group, and preferably represents ethylene or trimethylene group.

Preferably, n is 1.

Preferred compounds of the present invention are

(1) connection, where R1represents a hydrogen atom or a hydroxyl group,

(2) connection, where R2represents a hydrogen atom,

(3) connection, where R3represents alkoxycarbonylmethyl group 3-13 carbon atoms or carboxypolymethylene group with 2-7 carbon atoms,

(4) the compound, where R3represents ethoxycarbonylmethylene group or carboxymethylamino group,

(5) the compound, where R4and R5are the same and or different, and each represents a hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms, substituted by a halogen atom, or karbamoilnuyu group,

(6) connection, where R4and R5are the same or different, and each represents a hydrogen atom, chlorine atom, methyl group, triptorelin group or karbamoilnuyu group,

(7) the compound, where R6represents an alkyl group with 1-6 carbon atoms, cycloalkyl group with 3-8 carbon atoms, aracelio group with 7 to 16 carbon atoms, alkyl group with 1-6 carbon atoms, substituted heterocycle, aryl group with 6-10 carbon atoms, a heterocycle, formimidoyl group, 1-aminoalkyl group having 3-7 carbon atoms, aminoacylation group with 7 to 11 carbon atoms or N-alkyltrimethyl group with 2-7 carbon atoms,

(8) the compound, where R6represents methyl, ethyl or ISO-propyl group, cyclopentyloxy group, benzyl or fenetylline group, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl or 2-(4-pyridyl)ethyl group, phenyl group, 4,5-dihydro-3H-pyrrol-2-ilen, 2,3,4,5-tetrahydropyridine-6-ilen, 4,5-dihydrooxazolo-2-ilen, 5,6-dihydro-2H-[1,4]thiazin-3-ilen or 4-pyridyloxy group, f is remedieshow group, 1-aminopropyl group, aminophenylamino group or N-atinformation group,

(9) connection, where each of R7and R8represents a hydrogen atom or alkyl group with 1-6 carbon atoms,

(10) the compound, where R6and R7taken together, or R7and R8taken together, constitute alkylenes group with 2-5 carbon atoms,

(11) the compound wherein R6and R7taken together, or R7and R8taken together form an ethylene or trimethylene group,

(12) the compound where n is 1,

and the connection representing a combination of these compounds, for example, a compound containing a combination of(1), (2), (3), (5), (7), (9) and (12), or a combination(1), (2), (4), (6), (8), (9) and (12), or a similar combination.

Compounds of the present invention can be converted into their salts, preferred salts are alkali metal salts such as sodium salts, potassium salts or lithium salts; salts of alkaline earth metals such as calcium salt or magnesium salt; such salts of metals, such as aluminum salts, iron salts, zinc salts, salts of copper, Nickel salts or cobalt salts; inorganic salts such as ammonium salt, or salts of organic amines, such as salts of tert-octylamine, salt dibenzylamine, salt of the research, glucosamine salt, salt alilovic esters of phenylglycine, Sol is Ethylenediamine, salt-N-methylglucamine salt of guanidine, salts diethylamine, salt, triethylamine salt dicyclohexylamine, salts of N,N’-dibenziletilendiaminom, salt chloroprocaine, salts of procaine, salt, diethanolamine, salts of N-benzylpenicillin, salt, piperazine salt of Tetramethylammonium or salt of Tris(hydroxymethyl)aminomethane; salts of inorganic acids, for example, salts halogenation acids, such as salts of hydrofluoric acid, salts of hydrochloric acid, Hydrobromic acid salt or salt itestosterone acids, salts of nitric acid, salt perchloro acids, salts of sulfuric acid or salts of phosphoric acid; salts of lower alkanesulphonic acids such as salt methansulfonate acids, salts triftormetilfullerenov acid or salt econsultancy acid; salts arylsulfonic acids, such as salts of benzosulfimide acid or salt of p-toluensulfonate acid; organic acid salts such as salts of acetic acid, salts of malic acid, salts of fumaric acid, salts of succinic acid, salts of citric acid, salts of tartaric acid, salts of oxalic acid, salts of maleic acid or salt triperoxonane acid; or salts of amino acids such as salts of glycine, lysine salt, arginine salt, ornithine salts, salts of glutamic acid salt or aspartic acid.

When the connection really is obreteniyu allowed to stand in contact with the atmosphere, it can absorb water or can attach water with the formation of hydrate. The present invention includes hydrates.

The compound of the present invention can absorb the solvent with the formation of MES. The present invention includes a solvate.

When the connection according to this invention contains a hydroxyl group, an amino group, amidinopropane or carboxyl group, its prodrug” is a compound containing a protective group for such groups, respectively, where this protective group can be chipped off a chemical reaction in vivo or can be chipped off biochemically. When the original compound contains hydroxyl group, the amino group or amidinopropane, a group forming a prodrug of the compounds, represents a protective group which can be chipped off by a chemical method or a protective group which can be chipped off by a biological method such as hydrolysis in vivo”.

Such a protective group which can be chipped off by a chemical method”, is the “aliphatic acyl group”, for example, alkylcarboxylic group, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoic, 8-methylnonanoic, 3-ethyloctanoic, 3,7-dimethyloctan the sludge, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, 1-methylpentanol, 14-methylpentadiene, 13,13-dimethylcarbamoyl, heptadecanoyl, 15-methylhexadecanoic, octadecanoyl, 1-methylheptadecyl, nonadecanoic, eicosanoic or heneicosanol group, carbauxilirovanny acylcarnitine group, such as Coccinella, petrolina or dipolma group, halogenated lower alkylcarboxylic group, such as chlorocichla, dichloroacetylene, trichloroethylene or trifluoracetyl group, a (lower alkoxy)(lower alkylcarboxylic) group, such as methoxyacetyl group, unsaturated alkylcarboxylic group, such as (E)-2-methyl-2-butenolide group, or similar group; an “aromatic acyl group”, for example, arylcarbamoyl group, such as benzoline, α-napolina or β-napolina group, halogenated arylcarboxylic group, such as 2-bromobenzoyl or 4-chlorbenzoyl group, lower alkilirovanny arylcarbamoyl group such as 2,4,6-trimethylbenzoyl or 4-toluylene group, lower alkoxycarbonyl arylcarbamoyl group, such as 4-ansorena group, carbauxilirovanny arylcarbamoyl group, such as 2-carboxybenzoyl, 3-carboxybenzoyl or 4-carboxybenzoyl group, nutrinova the Naya arylcarbamoyl group, such as 4-nitrobenzoyl or 2-nitrobenzoyl group, lower alkoxycarbonylmethyl arylcarbamoyl group, such as 2-(methoxycarbonyl)benzoline group, allrounda arylcarbamoyl group, such as 4-phenylbenzyl group, or similar group; “tetrahydropyranyl or tetrahydropyranyl group, such as tetrahydropyran-2-ilen, 3-bromotetradecane-2-ilen, 4-methoxyacridine-4-ilen, tetrahydrothiopyran-2-ilen or 4-methoxytryptamine-4-ilen group; “tetrahydrofuranyl or tetrahydrofuranyl group”such as tetrahydrofuran-2-ilen or tetrahydrothiopyran-2-ilen group; “silyl group”, for example, lower trialkylsilyl group, such as trimethylsilyl, triethylsilyl, isopropylideneuridine, tert-butyldimethylsilyl, methyldiisopropanolamine, methyl-di-tert-butylsilane or triisopropylsilyl group, or three(lower alkyl)silyl group, substituted by 1 or 2 aryl groups, such as diphenylmethylsilane, diphenylmethylsilane, diphenylmethylsilane or phenyldimethylsilane group, or similar group; “alkoxymethyl group”, for example, lower alkoxymethyl group, such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethylene, propoxymethyl, isopropol imerina, butoxymethyl or tert-butoxymethyl group, lower alkoxycarbonyl lower alkoxymethyl group, such as 2-methoxyethoxymethyl group, or halogenated lower alkoxymethyl group, such as 2,2,2-trichloroethylene or bis(2-chloroethoxy)methyl group; “substituted ethyl group, for example, lower alkoxycarbonyl ethyl group such as 1-amoxicilina or 1-(isopropoxy)ethyl group, a halogenated ethyl group such as 2,2,2-trichlorethylene group, or similar group; “kalkilya group”, for example, a lower alkyl group substituted by 1-3 aryl groups, such as benzyl, α-naphthylethylene, β-naphthylethylene, diphenylmethylene, triphenylethylene, α-afterdirectly or 9-intellilink group, or a lower alkyl group substituted by 1-3 aryl groups, where this aryl group is substituted by lower alkyl, lower alkoxy, halogen or cyano, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl or 4-cyanobenzyl group; “alkoxycarbonyl group”, for example, lower alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or isobutoxy Bonilla group, or lower alkoxycarbonyl group substituted by a halogen atom, or three(lower alkyl)silyl group such as 2,2,2-trichlorocarbanilide or 2-trimethylsilylethynyl group, or similar group; “altneratively group, such as vinyloxycarbonyl or allyloxycarbonyl group; “aryloxyalkyl group”, where this aryl group may be optionally substituted by 1 or 2 lower alkoxygroup, nitro groups or halogen atoms, such as phenoxycarbonyl, 4-methoxyphenylalanine, 3,4-dimethoxyaniline, 2-nitrophenoxyacetic, 4-nitroisoquinoline or 4-perfeccionista group; or aracelikarsaalyna group”where the specified aryl group may be optionally substituted by 1 or 2 lower alkoxy or nitro groups, such as benzyloxycarbonyl, 4-methoxybenzylideneamino, 3,4-dimethoxybenzonitrile, 2-nitrobenzisoxazole or 4-nitrobenzisoxazole group.

On the other hand, the “protecting group which can be chipped off by a biological method such as hydrolysis in vivo”is “carbonylcyanide group”, for example, aryloxyalkyl group, such as ethylcarboxylate, pivaloyloxymethyl, dimethylaminoacetonitrile or 1-azet cvetelina group; 1-(alkoxycarbonyl)alkyl group such as 1-(methoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)ethyl, ethoxycarbonylmethyl, 1-(isopropoxycarbonyl)ethyl, 1-(tert-butoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)propyl or 1-(cyclohexyloxycarbonyloxy)ethyl; faldella group; exodeoxyribonuclease group, such as 4-metronidazolegermany or 4-phenylacetonitrile, 2-oxo-1,3-dioxooleana group, or similar group; “aliphatic acyl group”described in this description previously; “aromatic acyl group”described in this description previously; “the rest of Palmyra succinic acid; the residue of the ether phosphoric acid; residue, forming an ester of the amino acid or the like”; carnemolla group; carnemolla group, substituted by 1 or 2 lower alkyl groups; or carbonylcontaining group, such as pivaloyloxymethyl group. This investigational derived injected experimental animal, such as rat or mouse, and then examine body fluids experimental animal. If body fluids experimental animal find the original compound or its pharmacologically acceptable salt, believe that investigated derivative contains protective GRU is PU, which can be split by a biological method such as hydrolysis in vivo; and the preferred protecting group is an acetyl group.

The protective group for amino or amidino has no particular limitation, and preferably such a group is the “aliphatic acyl group”, for example, alkylcarboxylic group, such as formyl, acetyl, propylaniline, Butyrina, isobutylene, pantaneira, bialoleka, valerina, isovaleryl, actinaria, Laurila, palmitoleate or caarolina group, halogenated lower alkylcarboxylic group, such as chlorocichla, dichloroacetylene, trichloroethylene or trifluoracetyl group, a (lower alkoxy)(lower alkylcarboxylic) group, such as methoxyacetyl group, unsaturated alkylcarboxylic group, such as (E)-2-methyl-2-butenolide group, or similar group; an “aromatic acyl group”, for example, arylcarbamoyl group, such as benzoline, α-napolina or β-napolina group, halogenated arylcarboxylic group, such as 2-bromobenzoyl or 4-chlorbenzoyl group, lower alkilirovanny arylcarbamoyl group such as 2,4,6-trimethylbenzoyl or 4-toluylene group, lower alkoxycarbonyl arylcarbamoyl group, such as 4-ansorena group, narrowand what I arylcarbamoyl group, such as 4-nitrobenzoyl or 2-nitrobenzoyl group, lower alkoxycarbonylmethyl arylcarbamoyl group, such as 2-(methoxycarbonyl)benzoline group, allrounda arylcarbamoyl group, such as 4-phenylbenzyl group, or similar group; “alkoxycarbonyl group”, for example, lower alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or solutionline group, or a lower alkoxycarbonyl group substituted by a halogen atom, or three(lower alkyl)silyl group such as 2,2,2-trichlorocarbanilide or 2-trimethylsilylethynyl group; “altneratively group, such as vinyloxycarbonyl or allyloxycarbonyl group; “aryloxyalkyl group”, where this aryl group may be optionally substituted by 1 or 2 lower alkoxygroup or nitro groups or halogen atoms, such as phenoxycarbonyl, 4-methoxyphenylalanine, 3,4-dimethoxyaniline, 2-nitrophenoxyacetic, 4-nitroisoquinoline or 4-perfeccionista group; the preferred protecting group is ethoxycarbonyl group, 1-(propionyloxy)ethoxycarbonyl group or 4-methoxyphenylalanine group or 4-perfeccionista gr is the PAP.

The protective group for the carboxyl group is a protective group that can be chipped off by a biological method such as hydrolysis in vivo” and “protective group that can be chipped off by a chemical process, such as hydrogenation, hydrolysis, electrolysis or photolysis”. “Protecting group which can be chipped off by a chemical method”, is a “lower alkyl group”such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group; “Alchemilla group, such as ethynyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-examilia group; “Alchemilla group, such as ethinyl, 2-PROPYNYL, 1-IU the Il-2-PROPYNYL, 2-butynyl, 1-methyl-2-butenyl, 1-ethyl-2-butinyl, 3-butinyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butinyl, 2-pentenyl, 1-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexylamine group; “halogenated lower alkyl group such as trifluoromethyl, trichloromethyl, deformity, dichloromethyl, dibromomethyl, vermeil, 2,2,2-triptorelin, 2,2,2-trichloroethyl, 2-bromacil, 2-chloroethyl, 2-foretel, 2-codetel, 3-chloropropyl, 4-terbutyl, 6-iohexol or 2,2-dibromoethylene group; “hydroxyl-containing lower alkyl group”such as 2-hydroxyethylene, 2,3-dihydroxypropyl, 3-hydroxiproline, 3,4-dihydroxybutyl or 4-hydroxybutyrate group; “aliphatic acyl(lower alkyl) group, such as acetylecholine group; lower alkyl group substituted by 1-3 aryl groups such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexa, α-naphthylmethyl or 9-intellilink group; or kalkilya group”, which represents a lower alkyl group, a substituted 1-3 aryl groups, where specified aryl group substituted lower alkyl, lower alkoxy, nitro, halogen, cyano or alkoxycarbonyl group, such a spacecraft is 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzaldehyde, bis(2-nitrophenyl)methyl, piperonyl or 4-methoxycarbonylbenzyl group; or a silyl group such as trimethylsilyl, triethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, methyldiisopropanolamine, methyldi-tert-Boticelli, triisopropylsilyl, methyldiphenylamine, isopropylideneglycerol, butyldiphenylsilyl or phenyldimethylsilane group.

Connection with the “protecting group which can be chipped off by a biological method such as hydrolysis in vivo”, is a ester, which forms the free acid or its salt by hydrolysis or similar way in humans. Protecting group, “which can be chipped off by a biological method such as hydrolysis in vivo”is “alkoxy(lower alkyl) group”, for example, (lower alkoxy)(lower alkyl) group, such as methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxide, n-butoxymethyl or tert-butoxymethyl group, lower alkoxycarbonyl (lower alkoxy)(lower alkyl) group, such as 2-methoxyethoxide the ilen group, aryloxy(lower alkyl) group, such as proximately group, halogenated (lower alkoxy)(lower alkyl) group, such as 2,2,2-trichloroethylene or bis(2-chloroethoxy)methyl group, or similar group; “(lower alkoxycarbonyl)(lower alkyl) group, such as methoxycarbonylmethyl group, “lower cyanoaniline group, such as cyanomethylene or 2-cyanoethylene group; “lower alkylthiomethyl group, such as methylthiomethyl or ethylthiomethyl group; “aristomedia group, such as penultimately or naphthylthiourea group; “(lower alkylsulfonyl)(lower alkyl) group which may be optionally substituted by a halogen atom, such as 2-methanesulfonanilide or 2-triftormetilfullerenov group; “arylsulfonyl(lower)alkyl group”such as 2-benzolsulfonate or 2-toluensulfonyl group; “lower aryloxyalkyl group”, for example, lower aliphatic aryloxyalkyl group, such as formyloxyethyl, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl, valerolactone, isovalerylglycine, hexaniacinate, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-valeriansee, 1-isovalerianic, 1-hexane is Eloxatin, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionylacetate, 2-butyrylacetate, 2-pivaloyloxymethyl, 2-valeriansee, 2-isovaleramide, 2-hexaniacinate, 1-formylacetate, 1-acetoxymethyl, 1-propionyloxy, 1-butyryloxy, 1-pivaloyloxymethyl, 1-alariaceae, 1-isovalerylglycine, 1-hexanolactone, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl or 1-pivaloyloxymethyl group(cycloalkylcarbonyl)(lower alkyl) group, such as Cyclopentasiloxane, cyclohexasiloxane, 1-cyclopentylacetyl, 1-cyclohexaneacetic, 1-Cyclopentasiloxane, 1-cyclohexasiloxane, 1-cyclopentanecarbonyl or 1-cyclohexanebutyrate group (aromatic acyloxy)(lower alkyl) group, such as benzoyloxymethyl group, or similar group; “carbonylcyanide group”, for example, (alkoxycarbonyl)alkyl group, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylmethyl, msobuttoniconandcaption, ventilatsioonisusteemi, hexyloxybenzoyl, cyclohexyloxycarbonyloxy, cyclohexyloxycarbonyl is lexi(cyclohexyl)methyl, 1-(methoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)ethyl, 1-(propoxycarbonyl)ethyl, 1-(isopropoxycarbonyl)ethyl, 1-(butoxycarbonylamino)ethyl, 1-(isobutoxyethene)ethyl, 1-(tert-butoxycarbonylamino)ethyl, 1-(ventilatsioonile)ethyl, 1-(hexyloxyethoxy)ethyl, 1-(cyclopentanecarbonyl)ethyl, 1-(cyclopentanecarbonyl)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentanecarbonyl)butyl, 1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyl)propyl, 2-(methoxycarbonylamino)ethyl, 2-(ethoxycarbonyl)ethyl, 2-(propoxycarbonyl)ethyl, 2-(isopropoxycarbonyl)ethyl, 2-(butoxycarbonylamino)ethyl, 2-(isobutoxyethene)ethyl, 2-(ventilatsioonile)ethyl, 2-(hexyloxyethoxy)ethyl, 1-(methoxycarbonylamino)propyl, 1-(propoxycarbonyl)propyl, 1-(isopropoxycarbonyl)propyl, 1-(butoxycarbonylamino)propyl, 1-(isobutoxyethene)propyl, 1-(ventilatsioonile)propyl, 1-(hexyloxyethoxy)propyl, 1-(methoxycarbonyl)butyl, 1-(ethoxycarbonyl)butyl, 1-(propoxycarbonyl)butyl, 1-(isopropoxycarbonyl)butyl, 1-(butoxycarbonylamino)butyl, 1-(isobutoxyethene)butyl, 1-(methoxycarbonylamino)pentyl, 1-(ethoxycarbonyl)pentyl, 1-(methoxycarbonyl)hexyl or 1-(ethoxycarbonyl)gexi the other group; exodeoxyribonuclease group, such as (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl, [5-(4-were)-2-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-forfinal)-2-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolan-4-yl]methyl, (2-oxo-1,3-dioxolan-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolan-4-yl)methyl or (5-butyl-2-oxo-1,3-dioxolan-4-yl)methyl group, or similar group; “felicilda group, such as felicilda, dimethylpropylene or dimethoxytrityl group; “aryl group such as phenyl or indayla group; “alkyl group”described in this description previously; “carboxialkilnuyu group, such as carboxymethyl group; or a residue forming amide amino acids, such as phenylalanine. This investigational derived injected experimental animal, such as rat or mouse, and then examine body fluids experimental animal. If body fluids experimental animal find the original compound or its pharmacologically acceptable salt, believe that investigated derivative contains a protective group which can be split by a biological method such as Hydra is Liz in vivo; and the preferred group is an ethyl group.

Examples of compounds of the present invention are given in table 1. In table 1 the following abbreviations are used: Et represents an ethyl group; MS represents a group-CH2SO2; Ph represents a phenyl group; Pyr represents pyridyloxy group; Pyrm is pyramidalnou group; cPn is cyclopentyloxy group, -(CH2)3-(5) represents a 5-membered cyclic group, where R6and R7taken together, constitute trimethylene group; C3H4NO is a 4,5-dihydrooxazolo-2-ilen group; C4H6N represents a 4,5-dihydro-3H-pyrrol-2-ilen group; C3H4NS represents a 4,5-dihydrothiazolo-2-ilen group; C5H8N represents 2,3,4,5-tetrahydropyridine-6-ilen group; C6H10N represents 3,4,5,6-tetrahydro-2H-azepin-7-ilen group; C4H6NS represents a 5,6-dihydro-2H-[1,4]thiazin-3-ilen group; C5F4N represents 2,3,5,6-tetrafluoropyridine-4-ilen group; N(CH3CH2N)C is an N-atinformation group; -(CH2)2represents an ethylene group which is formed by the combined R7in position 2 and R8in position 6; and Csub> 8H14N represents 3,4,5,6,7,8-hexahydro-2H-asanin-9-ilen group.

3-CH3 Htd align="center"> H H Htr> td align="center"> H H 2-CH3 tr> H Htr> H 0 HOOC-MS 778 H 800 Htd align="center"> Htd align="center"> C5H8N C3H4NO 1054 2-Cltd align="center"> 1231 H EtSO2 H C4H6Ntd align="center"> 2-Ftd align="center"> 1 H H
Table 1

No.R1R2R3R4R5R6R7R8n
1HHEtOOC-MS3-ClHCH3HH1
2HHEtOOC-MS3-ClHCH3CH2HH1
3HHEtOOC-MS3-ClHCH3(CH3)CHHH1
4HHEtOOC-MS3-ClHCH3(CH2)2CH2HH1
5HHEtOOC-MS3-ClHPhCH2HH1
6HHEtOOC-MS3-ClHPh(CH2)2HH1
7HHEtOOC-MS3-ClHPhHH1
8HHEtOOC-MS3-ClHCH3OCOCH2HH1
9HHEtOOC-MS3-ClHCH3COHH1
10HHEtOOC-MS3-ClHH2NCOHH1
11HHEtOOC-MS3-ClHCH3SO2HH1
12HHEtOOC-MS3-ClH2-PyrHH1
13HHEtOOC-MS3-ClH3-PyrH H1
14HHEtOOC-MS3-ClH4-PyrHH1
15HHEtOOC-MS3-ClH2-PyrmHH1
16HHEtOOC-MS3-ClHPyr-3-CH2HH1
17HHEtOOC-MS3-ClHPyr-4-CH2HH1
18HHEtOOC-MS3-ClHPyr-2-(CH2)2HH1
19HHEtOOC-MS3-ClHcPnHH1
20HHEtOOC-MS3-ClHCH32-CH3H1
21HHEtOOC-MS3-ClH -(CH2)3-(5)-H1
22HHEtOOC-MS3-ClHH(NH)CHH1
23HHEtOOC-MS3-ClHCH3CH2(NH)CHH1
24HHEtOOC-MS3-ClHPh(NH)CHH1
25HHEtOOC-MS3-ClHC4H6NHH1
26HHEtOOC-MS3-ClHC5H8NHH1
27HHEtOOC-MS3-ClHC6H10NHH1
28HHEtOOC-MS3-ClHC4H6NSHH1
29H HEtOOC-MS3-CH3HCH3HH1
30HHEtOOC-MS3-CH3HCH3CH2HH1
31HHEtOOC-MS3-CH3HCH3(CH3)CHHH1
32HHEtOOC-MS3-CH3HCH3(CH2)2CH2HH1
33HHEtOOC-MS3-CH3HPhCH2HH1
34HHEtOOC-MS3-CH3HPh(CH2)2HH1
35HHEtOOC-MS3-CH3HPhHH1
36HHEtOOC-MSHCH3OCOCH2HH1
37HHEtOOC-MS3-CH3HCH3COHH1
38HHEtOOC-MS3-CH3HH2NCOHH1
39HHEtOOC-MS3-CH3HCH3SO2HH1
40HHEtOOC-MS3-CH3H2-PyrHH1
41HHEtOOC-MS3-CH3H3-PyrHH1
42HHEtOOC-MS3-CH3H4-PyrHH1
43HHEtOOC-MS3-CH3H2-PyrmHH 1
44HHEtOOC-MS3-CH3HPyr-3-CH2HH1
45HHEtOOC-MS3-CH3HPyr-4-CH2HH1
46HHEtOOC-MS3-CH3HPyr-2-(CH2)2HH1
47HHEtOOC-MS3-CH3HcPnHH1
48HHEtOOC-MS3-CH3HCH32-CH3H1
49HHEtOOC-MS3-CH3H-(CH2)3-(5)-H1
50HHEtOOC-MS3-CH3HH(NH)CHH1
51HH EtOOC-MS3-CH3HCH3CH2(NH)CHH1
52HHEtOOC-MS3-CH3HPh(NH)CHH1
53HHEtOOC-MS3-CH3HC4H6NHH1
54HHEtOOC-MS3-CH3HC5H8NHH1
55HHEtOOC-MS3-CH3HC6H10NHH1
56HHEtOOC-MS3-CH3HC4H6NSHH1
57HHEtOOC-MSHHCH3HH1
58HHEtOOC-MSHHCH CH2HH1
59HHEtOOC-MSHHCH3(CH3)CHHH1
60HHEtOOC-MSHHCH3(CH2)2CH2HH1
61HHEtOOC-MSHHPhCH2HH1
62HHEtOOC-MSHHPh(CH2)2HH1
63HHEtOOC-MSHHPhHH1
64HHEtOOC-MSHHCH3OCOCH2HH1
65HHEtOOC-MSHHCH3COHH1
66H HEtOOC-MSHHH2NCOHH1
67HHEtOOC-MSHHCH3SO2HH1
68HHEtOOC-MSHH2-PyrHH1
69HHEtOOC-MSHH3-PyrHH1
70HHEtOOC-MSHH4-PyrHH1
71HHEtOOC-MSHH2-PyrmHH1
72HHEtOOC-MSHHPyr-3-CH2HH1
73HHEtOOC-MSHHPyr-4-CH2HH1
74HEtOOC-MSHHPyr-2-(CH2)2HH1
75HHEtOOC-MSHHcPnHH1
76HHEtOOC-MSHHCH32-CH3H1
77HHEtOOC-MSHH-(CH2)3-(5)-H1
78HHEtOOC-MSHHH(NH)CHH1
79HHEtOOC-MSHHCH3CH2(NH)CHH1
80HHEtOOC-MSHHPh(NH)CHH1
81HHEtOOC-MSHHC4H6NHH82HHEtOOC-MSHHC5H8NHH1
83HHEtOOC-MSHHC6H10NHH1
84HHEtOOC-MSHHC4H6NSHH1
85HHEtOOC-MS3-CF3HCH3HH1
86HHEtOOC-MS3-CF3HCH3CH2HH1
87HHEtOOC-MS3-CF3HCH3(CH3)CHHH1
88HHEtOOC-MS3-CF3HCH3(CH2)2CH2HH1
89HEtOOC-MS3-CF3HPhCH2HH1
90HHEtOOC-MS3-CF3HPh(CH2)2HH1
91HHEtOOC-MS3-CF3HPhHH1
92HHEtOOC-MS3-CF3HCH3OCOCH2HH1
93HHEtOOC-MS3-CF3HCH3COHH1
94HHEtOOC-MS3-CF3HH2NCOHH1
95HHEtOOC-MS3-CF3HCH3SO2HH1
96HHEtOOC-MS3-CF3H 2-PyrHH1
97HHEtOOC-MS3-CF3H3-PyrHH1
98HHEtOOC-MS3-CF3H4-PyrHH1
99HHEtOOC-MS3-CF3H2-PyrmHH1
100HHEtOOC-MS3-CF3HPyr-3-CH2HH1
101HHEtOOC-MS3-CF3HPyr-4-CH2HH1
102HHEtOOC-MS3-CF3HPyr-2-(CH2)2HH1
103HHEtOOC-MS3-CF3HcPnHH1
104 HHEtOOC-MS3-CF3HCH32-CH3H1
105HHEtOOC-MS3-CF3H-(CH2)3-(5)-H1
106HHEtOOC-MS3-CF3HH(NH)CHH1
107HHEtOOC-MS3-CF3HCH3CH2(NH)CHH1
108HHEtOOC-MS3-CF3HPh(NH)CHH1
109HHEtOOC-MS3-CF3HC4H6NHH1
110HHEtOOC-MS3-CF3HC5H8NHH1
111HHEtOOC-MS 3-CF3HC6H10NHH1
112HHEtOOC-MS3-CF3HC4H6NSHH1
113HHEtOOC-MS3-H2NCOHCH3HH1
114HHEtOOC-MS3-H2NCOHCH3CH2HH1
115HHEtOOC-MS3-H2NCOHCH3(CH3)CHHH1
116HHEtOOC-MS3-H2NCOHCH3(CH2)2CH2HH1
117HHEtOOC-MS3-H2NCOHPhCH2HH1
118HHEtOOC-MS3-H2NO HPh(CH2)2HH1
119HHEtOOC-MS3-H2NCOHPhHH1
120HHEtOOC-MS3-H2NCOHCH3OCOCH2HH1
121HHEtOOC-MS3-H2NCOHCH3COHH1
122HHEtOOC-MS3-H2NCOHH2NCOHH1
123HHEtOOC-MS3-H2NCOHCH3SO2HH1
124HHEtOOC-MS3-H2NCOH2-PyrHH1
125HHEtOOC-MS3-H2NCOH3-PyrH H1
126HHEtOOC-MS3-H2NCOH4-PyrHH1
127HHEtOOC-MS3-H2NCOH2-PyrmHH1
128HHEtOOC-MS3-H2NCOHPyr-3-CH2HH1
129HHEtOOC-MS3-H2NCOHPyr-4-CH2HH1
130HHEtOOC-MS3-H2NCOHPyr-2-(CH2)2HH1
131HHEtOOC-MS3-H2NCOHcPnHH1
132HHEtOOC-MS3-H2NCOHCH32-CH3H1
133H HEtOOC-MS3-H2NCOH-(CH2)3-(5)-H1
134HHEtOOC-MS3-H2NCOHH(NH)CHH1
135HHEtOOC-MS3-H2NCOHCH3CH2(NH)CHH1
136HHEtOOC-MS3-H2NCOHPh(NH)CHH1
137HHEtOOC-MS3-H2NCOHC4H6NHH1
138HHEtOOC-MS3-H2NCOHC5H8NHH1
139HHEtOOC-MS3-H2NCOHC6H10NHH1
140HHEtOOC-MS3- 2NCOHC4H6NSHH1
141HHEtOOC-MS3-FHCH3HH1
142HHEtOOC-MS3-FHCH3CH2HH1
143HHEtOOC-MS3-FHCH3(CH3)CHHH1
144HHEtOOC-MS3-FHCH3(CH2)2CH2HH1
145HHEtOOC-MS3-FHPhCH2HH1
146HHEtOOC-MS3-FHPh(CH2)2HH1
147HHEtOOC-MS3-FHPhHH 1
148HHEtOOC-MS3-FHCH3OCOCH2HH1
149HHEtOOC-MS3-FHCH3COHH1
150HHEtOOC-MS3-FHH2NCOHH1
151HHEtOOC-MS3-FHCH3SO2HH1
152HHEtOOC-MS3-FH2-PyrHH1
153HHEtOOC-MS3-FH3-PyrHH1
154HHEtOOC-MS3-FH4-PyrHH1
155HHEtOOC-MS3-FH2-PyrmH H1
156HHEtOOC-MS3-FHPyr-3-CH2HH1
157HHEtOOC-MS3-FHPyr-4-CH2HH1
158HHEtOOC-MS3-FHPyr-2-(CH2)2HH1
159HHEtOOC-MS3-FHcPnHH1
160HHEtOOC-MS3-FHCH32-CH3H1
161HHEtOOC-MS3-FH-(CH2)3-(5)-H1
162HHEtOOC-MS3-FHH(NH)CHH1
163HHEtOOC-MS-F HCH3CH2(NH)CHH1
164HHEtOOC-MS3-FHPh(NH)CHH1
165HHEtOOC-MS3-FHC4H6NHH1
166HHEtOOC-MS3-FHC5H8NHH1
167HHEtOOC-MS3-FHC6H10NHH1
168HHEtOOC-MS3-FHC4H6NSHH1
169HHEtOOC-MS3-ClHCH3HH0
170HHEtOOC-MS3-ClHCH3CH2HH0
171HHEtOOC-MS3-ClHCH3(CH3)CHHH0
172HHEtOOC-MS3-ClHCH3(CH2)2CH2HH0
173HHEtOOC-MS3-ClHPhCH2HH0
174HHEtOOC-MS3-ClHPh(CH2)2HH0
175HHEtOOC-MS3-ClHPhHH0
176HHEtOOC-MS3-ClHCH3OCOCH2HH0
177HHEtOOC-MS3-ClHCH3COHH0
178HHEtOOC-MS3-ClH2NCOHH0
179HHEtOOC-MS3-ClHCH3SO2HH0
180HHEtOOC-MS3-ClH2-PyrHH0
181HHEtOOC-MS3-ClH3-PyrHH0
182HHEtOOC-MS3-ClH4-PyrHH0
183HHEtOOC-MS3-ClH2-PyrmHH0
184HHEtOOC-MS3-ClHPyr-3-CH2HH0
185HHEtOOC-MS3-ClHPyr-4-CH2HH0
186HHEtOOC-MS 3-ClHPyr-2-(CH2)2HH0
187HHEtOOC-MS3-ClHcPnHH0
188HHEtOOC-MS3-ClHCH32-CH3H0
189HHEtOOC-MS3-ClH-(CH2)3-(5)-H0
190HHEtOOC-MS3-ClHH(NH)CHH0
191HHEtOOC-MS3-ClHCH3CH2(NH)CHH0
192HHEtOOC-MS3-ClHPh(NH)CHH0
193HHEtOOC-MS3-ClHC4H6NHH0
194HHEtOOC-MS3-ClHC5H8NHH0
195HHEtOOC-MS3-ClHC6H10NHH0
196HHEtOOC-MS3-ClHC4H6NSHH0
197HHEtOOC-MS3-CH3HCH3HH0
198HHEtOOC-MS3-CH3HCH3CH2HH0
199HHEtOOC-MS3-CH3HCH3(CH3)CHHH0
200HHEtOOC-MS3-CH3HCH3(CH2)2CH2HH0
201HH/td> EtOOC-MS3-CH3HPhCH2HH0
202HHEtOOC-MS3-CH3HPh(CH2)2HH0
203HHEtOOC-MS3-CH3HPhHH0
204HHEtOOC-MS3-CH3HCH3OCOCH2HH0
205HHEtOOC-MS3-CH3HCH3COHH0
206HHEtOOC-MS3-CH3HH2NCOHH0
207HHEtOOC-MS3-CH3HCH3SO2HH0
208HHEtOOC-MS3-CH3H 2-PyrHH0
209HHEtOOC-MS3-CH3H3-PyrHH0
210HHEtOOC-MS3-CH3H4-PyrHH0
211HHEtOOC-MS3-CH3H2-PyrmHH0
212HHEtOOC-MS3-CH3HPyr-3-CH2HH0
213HHEtOOC-MS3-CH3HPyr-4-CH2HH0
214HHEtOOC-MS3-CH3HPyr-2-(CH2)2HH0
215HHEtOOC-MS3-CH3HcPnHH0
216 HHEtOOC-MS3-CH3HCH32-CH3H0
217HHEtOOC-MS3-CH3H-(CH2)3-(5)-H0
218HHEtOOC-MS3-CH3HH(NH)CHH0
219HHEtOOC-MS3-CH3HCH3CH2(NH)CHH0
220HHEtOOC-MS3-CH3HPh(NH)CHH0
221HHEtOOC-MS3-CH3HC4H6NHH0
222HHEtOOC-MS3-CH3HC5H8NHH0
223HHEtOOC-MS 3-CH3HC6H10NHH0
224HHEtOOC-MS3-CH3HC4H6NSHH0
225HHEtOOC-MSHHCH3HH0
226HHEtOOC-MSHHCH3CH2HH0
227HHEtOOC-MSHHCH3(CH3)CHHH0
228HHEtOOC-MSHHCH3(CH2)2CH2HH0
229HHEtOOC-MSHHPhCH2HH0
230HHEtOOC-MSHHPh(CH2)2H H0
231HHEtOOC-MSHHPhHH0
232HHEtOOC-MSHHCH3OCOCH2HH0
233HHEtOOC-MSHHCH3COHH0
234HHEtOOC-MSHHH2NCOHH0
235HHEtOOC-MSHHCH3SO2HH0
236HHEtOOC-MSHH2-PyrHH0
237HHEtOOC-MSHH3-PyrHH0
238HHEtOOC-MSHH4-Pyr/td> HH0
239HHEtOOC-MSHH2-PyrmHH0
240HHEtOOC-MSHHPyr-3-CH2HH0
241HHEtOOC-MSHHPyr-4-CH2HH0
242HHEtOOC-MSHHPyr-2-(CH2)2HH0
243HHEtOOC-MSHHcPnHH0
244HHEtOOC-MSHHCH32-CH3H0
245HHEtOOC-MSHH-(CH2)3-(5)-H0
246HHEtOOC-MS HHH(NH)CHH0
247HHEtOOC-MSHHCH3CH2(NH)CHH0
248HHEtOOC-MSHHPh(NH)CHH0
249HHEtOOC-MSHHC4H6NHH0
250HHEtOOC-MSHHC5H8NHH0
251HHEtOOC-MSHHC6H10NHH0
252HHEtOOC-MSHHC4H6NSHH0
253HHEtOOC-MS3-CF3HCH3HH0
254HHEtOOC-MS3-CF3HCH3CH2HH0
255HHEtOOC-MS3-CF3HCH3(CH3)CHHH0
256HHEtOOC-MS3-CF3HCH3(CH2)2CH2HH0
257HHEtOOC-MS3-CF3HPhCH2HH0
258HHEtOOC-MS3-CF3HPh(CH2)2HH0
259HHEtOOC-MS3-CF3HPhHH0
260HHEtOOC-MS3-CF3HCH3OCOCH2HH0
261HEtOOC-MS3-CF3HCH3COHH0
262HHEtOOC-MS3-CF3HH2NCOHH0
263HHEtOOC-MS3-CF3HCH3SO2HH0
264HHEtOOC-MS3-CF3H2-PyrHH0
265HHEtOOC-MS3-CF3H3-PyrHH0
266HHEtOOC-MS3-CF3H4-PyrHH0
267HHEtOOC-MS3-CF3H2-PyrmHH0
268HHEtOOC-MS3-CF3HPyr-3-CH2 HH0
269HHEtOOC-MS3-CF3HPyr-4-CH2HH0
270HHEtOOC-MS3-CF3HPyr-2-(CH2)2HH0
271HHEtOOC-MS3-CF3HcPnHH0
272HHEtOOC-MS3-CF3HCH32-CH3H0
273HHEtOOC-MS3-CF3H-(CH2)3-(5)-H0
274HHEtOOC-MS3-CF3HH(NH)CHH0
275HHEtOOC-MS3-CF3HCH3CH2(NH)CHH0
276HHEtOOC-MS3-CF3HPh(NH)CHH0
277HHEtOOC-MS3-CF3HC4H6NHH0
278HHEtOOC-MS3-CF3HC5H8NHH0
279HHEtOOC-MS3-CF3HC6H10NHH0
280HHEtOOC-MS3-CF3HC4H6NSHH0
281HHEtOOC-MS3-H2NCOHCH3HH0
282HHEtOOC-MS3-H2NCOHCH3CH2HH0
283HH EtOOC-MS3-H2NCOHCH3(CH3)CHHH0
284HHEtOOC-MS3-H2NCOHCH3(CH2)2CH2HH0
285HHEtOOC-MS3-H2NCOHPhCH2HH0
286HHEtOOC-MS3-H2NCOHPh(CH2)2HH0
287HHEtOOC-MS3-H2NCOHPhHH0
288HHEtOOC-MS3-H2NCOHCH3OCOCH2HH0
289HHEtOOC-MS3-H2NCOHCH3COHH0
290HHEtOOC-MS3-Hsub> 2NCOHH2NCOHH0
291HHEtOOC-MS3-H2NCOHCH3SO2HH0
292HHEtOOC-MS3-H2NCOH2-PyrHH0
293HHEtOOC-MS3-H2NCOH3-PyrHH0
294HHEtOOC-MS3-H2NCOH4-PyrHH0
295HHEtOOC-MS3-H2NCOH2-PyrmHH0
296HHEtOOC-MS3-H2NCOHPyr-3-CH2HH0
297HHEtOOC-MS3-H2NCOHPyr-4-CH2HH 0
298HHEtOOC-MS3-H2NCOHPyr-2-(CH2)2HH0
299HHEtOOC-MS3-H2NCOHcPnHH0
300HHEtOOC-MS3-H2NCOHCH32-CH3H0
301HHEtOOC-MS3-H2NCOH-(CH2)3-(5)-H0
302HHEtOOC-MS3-H2NCOHH(NH)CHH0
303HHEtOOC-MS3-H2NCOHCH3CH2(NH)CHH0
304HHEtOOC-MS3-H2NCOHPh(NH)CHH0
305H HEtOOC-MS3-H2NCOHC4H6NHH0
306HHEtOOC-MS3-H2NCOHC5H8NHH0
307HHEtOOC-MS3-H2NCOHC6H10NHH0
308HHEtOOC-MS3-H2NCOHC4H6NSHH0
309HHEtOOC-MS3-FHCH3HH0
310HHEtOOC-MS3-FHCH3CH2HH0
311HHEtOOC-MS3-FHCH3(CH3)CHHH0
312HHEtOOC-MS3-F HCH3(CH2)2CH2HH0
313HHEtOOC-MS3-FHPhCH2HH0
314HHEtOOC-MS3-FHPh(CH2)2HH0
315HHEtOOC-MS3-FHPhHH0
316HHEtOOC-MS3-FHCH3OCOCH2HH0
317HHEtOOC-MS3-FHCH3COHH0
318HHEtOOC-MS3-FHH2NCOHH0
319HHEtOOC-MS3-FHCH3SO2HH0
HHEtOOC-MS3-FH2-PyrHH0
321HHEtOOC-MS3-FH3-PyrHH0
322HHEtOOC-MS3-FH4-PyrHH0
323HHEtOOC-MS3-FH2-PyrmHH0
324HHEtOOC-MS3-FHPyr-3-CH2HH0
325HHEtOOC-MS3-FHPyr-4-CH2HH0
326HHEtOOC-MS3-FHPyr-2-(CH2)2HH0
327HHEtOOC-MS3-FHcPnHH0
328HHEtOOC-MS3-FHCH32-CH3H0
329HHEtOOC-MS3-FH-(CH2)3-(5)-H0
330HHEtOOC-MS3-FHH(NH)CHH0
331HHEtOOC-MS3-FHCH3CH2(NH)CHH0
332HHEtOOC-MS3-FHPh(NH)CHH0
333HHEtOOC-MS3-FHC4H6NHH0
334HHEtOOC-MS3-FHC5H8NHH0
335HHEtOOC-MS3-FH C6H10NHH0
336HHEtOOC-MS3-FHC4H6NSHH0
337HHEtOOC-MS3-ClHCH3HH2
338HHEtOOC-MS3-ClHCH3CH2HH2
339HHEtOOC-MS3-ClHCH3(CH3)CHHH2
340HHEtOOC-MS3-ClHCH3(CH2)2CH2HH2
341HHEtOOC-MS3-ClHPhCH2HH2
342HHEtOOC-MS3-ClHPh(CH2)2HH 2
343HHEtOOC-MS3-ClHPhHH2
344HHEtOOC-MS3-ClHCH3OCOCH2HH2
345HHEtOOC-MS3-ClHCH3COHH2
346HHEtOOC-MS3-ClHH2NCOHH2
347HHEtOOC-MS3-ClHCH3SO2HH2
348HHEtOOC-MS3-ClH2-PyrHH2
349HHEtOOC-MS3-ClH3-PyrHH2
350HHEtOOC-MS3-ClH4-Pyr H2
351HHEtOOC-MS3-ClH2-PyrmHH2
352HHEtOOC-MS3-ClHPyr-3-CH2HH2
353HHEtOOC-MS3-ClHPyr-4-CH2HH2
354HHEtOOC-MS3-ClHPyr-2-(CH2)2HH2
355HHEtOOC-MS3-ClHcPnHH2
356HHEtOOC-MS3-ClHCH32-CH3H2
357HHEtOOC-MS3-ClH-(CH2)3-(5)-H2
358HHEtOOC-MS 3-ClHH(NH)CHH2
359HHEtOOC-MS3-ClHCH3CH2(NH)CHH2
360HHEtOOC-MS3-ClHPh(NH)CHH2
361HHEtOOC-MS3-ClHC4H6NHH2
362HHEtOOC-MS3-ClHC5H8NHH2
363HHEtOOC-MS3-ClHC6H10NHH2
364HHEtOOC-MS3-ClHC4H6NSHH2
365HHEtOOC-MS3-CH3HCH3HH2
366HHEtOOC-MS3-CH3HCH3CH2HH2
367HHEtOOC-MS3-CH3HCH3(CH3)CHHH2
368HHEtOOC-MS3-CH3HCH3(CH2)2CH2HH2
369HHEtOOC-MS3-CH3HPhCH2HH2
370HHEtOOC-MS3-CH3HPh(CH2)2HH2
371HHEtOOC-MS3-CH3HPhHH2
372HHEtOOC-MS3-CH3HCH3OCOCH2HH2
373 HHEtOOC-MS3-CH3HCH3COHH2
374HHEtOOC-MS3-CH3HH2NCOHH2
375HHEtOOC-MS3-CH3HCH3SO2HH2
376HHEtOOC-MS3-CH3H2-PyrHH2
377HHEtOOC-MS3-CH3H3-PyrHH2
378HHEtOOC-MS3-CH3H4-PyrHH2
379HHEtOOC-MS3-CH3H2-PyrmHH2
380HHEtOOC-MS3-CH3HPyr-3-CH 2HH2
381HHEtOOC-MS3-CH3HPyr-4-CH2HH2
382HHEtOOC-MS3-CH3HPyr-2-(CH2)2HH2
383HHEtOOC-MS3-CH3HcPnHH2
384HHEtOOC-MS3-CH3HCH32-CH3H2
385HHEtOOC-MS3-CH3H-(CH2)3-(5)-H2
386HHEtOOC-MS3-CH3HH(NH)CHH2
387HHEtOOC-MS3-CH3HCH3CH2(NH)CHH 2
388HHEtOOC-MS3-CH3HPh(NH)CHH2
389HHEtOOC-MS3-CH3HC4H6NHH2
390HHEtOOC-MS3-CH3HC5H8NHH2
391HHEtOOC-MS3-CH3HC6H10NHH2
392HHEtOOC-MS3-CH3HC4H6NSHH2
393HHEtOOC-MSHHCH3HH2
394HHEtOOC-MSHHCH3CH2HH2
395HH EtOOC-MSHHCH3(CH3)CHHH2
396HHEtOOC-MSHHCH3(CH2)2CH2HH2
397HHEtOOC-MSHHPhCH2HH2
398HHEtOOC-MSHHPh(CH2)2HH2
399HHEtOOC-MSHHPhHH2
400HHEtOOC-MSHHCH3OCOCH2HH2
401HHEtOOC-MSHHCH3COHH2
402HHEtOOC-MSHHH2NCOHH 2
403HHEtOOC-MSHHCH3SO2HH2
404HHEtOOC-MSHH2-PyrHH2
405HHEtOOC-MSHH3-PyrHH2
406HHEtOOC-MSHH4-PyrHH2
407HHEtOOC-MSHH2-PyrmHH2
408HHEtOOC-MSHHPyr-3-CH2HH2
409HHEtOOC-MSHHPyr-4-CH2HH2
410HHEtOOC-MSHHPyr-2-(CH2)2H2
411HHEtOOC-MSHHcPnHH2
412HHEtOOC-MSHHCH32-CH3H2
413HHEtOOC-MSHH-(CH2)3-(5)-H2
414HHEtOOC-MSHHH(NH)CHH2
415HHEtOOC-MSHHCH3CH2(NH)CHH2
416HHEtOOC-MSHHPh(NH)CHH2
417HHEtOOC-MSHHC4H6NHH2
418HHEtOOC-MSHH C5H8NHH2
419HHEtOOC-MSHHC6H10NHH2
420HHEtOOC-MSHHC4H6NSHH2
421HHEtOOC-MS3-CF3HCH3HH2
422HHEtOOC-MS3-CF3HCH3CH2HH2
423HHEtOOC-MS3-CF3HCH3(CH3)CHHH2
424HHEtOOC-MS3-CF3HCH3(CH2)2CH2HH2
425HHEtOOC-MS3-CF3HPhCH2H2
426HHEtOOC-MS3-CF3HPh(CH2)2HH2
427HHEtOOC-MS3-CF3HPhHH2
428HHEtOOC-MS3-CF3HCH3OCOCH2HH2
429HHEtOOC-MS3-CF3HCH3COHH2
430HHEtOOC-MS3-CF3HH2NCOHH2
431HHEtOOC-MS3-CF3HCH3SO2HH2
432HHEtOOC-MS3-CF3H2-PyrHH2
433H HEtOOC-MS3-CF3H3-PyrHH2
434HHEtOOC-MS3-CF3H4-PyrHH2
435HHEtOOC-MS3-CF3H2-PyrmHH2
436HHEtOOC-MS3-CF3HPyr-3-CH2HH2
437HHEtOOC-MS3-CF3HPyr-4-CH2HH2
438HHEtOOC-MS3-CF3HPyr-2-(CH2)2HH2
439HHEtOOC-MS3-CF3HcPnHH2
440HHEtOOC-MS3-CF3HCH3H2
441HHEtOOC-MS3-CF3H-(CH2)3-(5)-H2
442HHEtOOC-MS3-CF3HH(NH)CHH2
443HHEtOOC-MS3-CF3HCH3CH2(NH)CHH2
444HHEtOOC-MS3-CF3HPh(NH)CHH2
445HHEtOOC-MS3-CF3HC4H6NHH2
446HHEtOOC-MS3-CF3HC5H8NHH2
447HHEtOOC-MS3-CF3HC6H10NHH2
448HHEtOOC-MS3-CF3HC4H6NSHH2
449HHEtOOC-MS3-H2NCOHCH3HH2
450HHEtOOC-MS3-H2NCOHCH3CH2HH2
451HHEtOOC-MS3-H2NCOHCH3(CH3)CHHH2
452HHEtOOC-MS3-H2NCOHCH3(CH2)2CH2HH2
453HHEtOOC-MS3-H2NCOHPhCH2HH2
454HHEtOOC-MS3-H2NCOHPh(CH2)2HH2
455HHEtOOC-MS3-H2NCOHPhHH2
456HHEtOOC-MS3-H2NCOHCH3OCOCH2HH2
457HHEtOOC-MS3-H2NCOHCH3COHH2
458HHEtOOC-MS3-H2NCOHH2NCOHH2
459HHEtOOC-MS3-H2NCOHCH3SO2HH2
460HHEtOOC-MS3-H2NCOH2-PyrHH2
461HHEtOOC-MS3-H2NCOH3-PyrHH2
462HHEtOOC-MS3-H2 NCOH4-PyrHH2
463HHEtOOC-MS3-H2NCOH2-PyrmHH2
464HHEtOOC-MS3-H2NCOHPyr-3-CH2HH2
465HHEtOOC-MS3-H2NCOHPyr-4-CH2HH2
466HHEtOOC-MS3-H2NCOHPyr-2-(CH2)2HH2
467HHEtOOC-MS3-H2NCOHcPnHH2
468HHEtOOC-MS3-H2NCOHCH32-CH3H2
469HHEtOOC-MS3-H2NCOH-(CH2)3-(5) -H2
470HHEtOOC-MS3-H2NCOHH(NH)CHH2
471HHEtOOC-MS3-H2NCOHCH3CH2(NH)CHH2
472HHEtOOC-MS3-H2NCOHPh(NH)CHH2
473HHEtOOC-MS3-H2NCOHC4H6NHH2
474HHEtOOC-MS3-H2NCOHC5H8NHH2
475HHEtOOC-MS3-H2NCOHC6H10NHH2
476HHEtOOC-MS3-H2NCOHC4H6NSHH2
477HHEtOOC-MS3-FHCH3HH2
478HHEtOOC-MS3-FHCH3CH2HH2
479HHEtOOC-MS3-FHCH3(CH3)CHHH2
480HHEtOOC-MS3-FHCH3(CH2)2CH2HH2
481HHEtOOC-MS3-FHPhCH2HH2
482HHEtOOC-MS3-FHPh(CH2)2HH2
483HHEtOOC-MS3-FHPhHH2
484HHEtOOC-MS3-F HCH3OCOCH2HH2
485HHEtOOC-MS3-FHCH3COHH2
486HHEtOOC-MS3-FHH2NCOHH2
487HHEtOOC-MS3-FHCH3SO2HH2
488HHEtOOC-MS3-FH2-PyrHH2
489HHEtOOC-MS3-FH3-PyrHH2
490HHEtOOC-MS3-FH4-PyrHH2
491HHEtOOC-MS3-FH2-PyrmHH2
492HHEtOOC-MS 3-FHPyr-3-CH2HH2
493HHEtOOC-MS3-FHPyr-4-CH2HH2
494HHEtOOC-MS3-FHPyr-2-(CH2)2HH2
495HHEtOOC-MS3-FHcPnHH2
496HHEtOOC-MS3-FHCH32-CH3H2
497HHEtOOC-MS3-FH-(CH2)3-(5)-H2
498HHEtOOC-MS3-FHH(NH)CHH2
499HHEtOOC-MS3-FHCH3CH2(NH)CHH2
500HHEtOOC-MS3-FHPh(NH)CHH2
501HHEtOOC-MS3-FHC4H6NHH2
502HHEtOOC-MS3-FHC5H8NHH2
503HHEtOOC-MS3-FHC6H10NHH2
504HHEtOOC-MS3-FHC4H6NSHH2
505HHHOOC-MS3-ClHCH3HH1
506HHHOOC-MS3-ClHCH3CH2HH1
507HHHOOC-MS3-ClH CH3(CH3)CHHH1
508HHHOOC-MS3-ClHCH3(CH2)2CH2HH1
509HHHOOC-MS3-ClHPhCH2HH1
510HHHOOC-MS3-ClHPh(CH2)2HH1
511HHHOOC-MS3-ClHPhHH1
512HHHOOC-MS3-ClHCH3OCOCH2HH1
513HHHOOC-MS3-ClHCH3COHH1
514HHHOOC-MS3-ClHH2NCOHH1
515 HHHOOC-MS3-ClHCH3SO2HH1
516HHHOOC-MS3-ClH2-PyrHH1
517HHHOOC-MS3-ClH3-PyrHH1
518HHHOOC-MS3-ClH4-PyrHH1
519HHHOOC-MS3-ClH2-PyrmHH1
520HHHOOC-MS3-ClHPyr-3-CH2HH1
521HHHOOC-MS3-ClHPyr-4-CH2HH1
522HHHOOC-MS3-ClHPyr-2-(CH2)2HH1
523HHHOOC-MS3-ClHcPnHH1
524HHHOOC-MS3-ClHCH32-CH3H1
525HHHOOC-MS3-ClH-(CH2)3-(5)-H1
526HHHOOC-MS3-ClHH(NH)CHH1
527HHHOOC-MS3-ClHCH3CH2(NH)CHH1
528HHHOOC-MS3-ClHPh(NH)CHH1
529HHHOOC-MS3-ClHC4H6NHH1
530HHHOOC-MS3-ClHC H8NHH1
531HHHOOC-MS3-ClHC6H10NHH1
532HHHOOC-MS3-ClHC4H6NSHH1
533HHHOOC-MS3-CH3HCH3HH1
534HHHOOC-MS3-CH3HCH3CH2HH1
535HHHOOC-MS3-CH3HCH3(CH3)CHHH1
536HHHOOC-MS3-CH3HCH3(CH2)2CH2HH1
537HHHOOC-MS3-CH3HPhCH2H H1
538HHHOOC-MS3-CH3HPh(CH2)2HH1
539HHHOOC-MS3-CH3HPhHH1
540HHHOOC-MS3-CH3HCH3OCOCH2HH1
541HHHOOC-MS3-CH3HCH3COHH1
542HHHOOC-MS3-CH3HH2NCOHH1
543HHHOOC-MS3-CH3HCH3SO2HH1
544HHHOOC-MS3-CH3H2-PyrHH1
545H HOOC-MS3-CH3H3-PyrHH1
546HHHOOC-MS3-CH3H4-PyrHH1
547HHHOOC-MS3-CH3H2-PyrmHH1
548HHHOOC-MS3-CH3HPyr-3-CH2HH1
549HHHOOC-MS3-CH3HPyr-4-CH2HH1
550HHHOOC-MS3-CH3HPyr-2-(CH2)2HH1
551HHHOOC-MS3-CH3HcPnHH1
552HHHOOC-MS3-CH3HCH3H1
553HHHOOC-MS3-CH3H-(CH2)3-(5)-H1
554HHHOOC-MS3-CH3HH(NH)CHH1
555HHHOOC-MS3-CH3HCH3CH2(NH)CHH1
556HHHOOC-MS3-CH3HPh(NH)CHH1
557HHHOOC-MS3-CH3HC4H6NHH1
558HHHOOC-MS3-CH3HC5H8NHH1
559HHHOOC-MS3-CH3HC6H10NHH1
560HHHOOC-MS3-CH3HC4H6NSHH1
561HHHOOC-MSHHCH3HH1
562HHHOOC-MSHHCH3CH2HH1
563HHHOOC-MSHHCH3(CH3)CHHH1
564HHHOOC-MSHHCH3(CH2)2CH2HH1
565HHHOOC-MSHHPhCH2HH1
566HHHOOC-MSHHPh(CH2)2HH1
567HHHOOC-MSH HPhHH1
568HHHOOC-MSHHCH3OCOCH2HH1
569HHHOOC-MSHHCH3COHH1
570HHHOOC-MSHHH2NCOHH1
571HHHOOC-MSHHCH3SO2HH1
572HHHOOC-MSHH2-PyrHH1
573HHHOOC-MSHH3-PyrHH1
574HHHOOC-MSHH4-PyrHH1
575HHHOOC-MSH2-PyrmHH1
576HHHOOC-MSHHPyr-3-CH2HH1
577HHHOOC-MSHHPyr-4-CH2HH1
578HHHOOC-MSHHPyr-2-(CH2)2HH1
579HHHOOC-MSHHcPnHH1
580HHHOOC-MSHHCH32-CH3H1
581HHHOOC-MSHH-(CH2)3-(5)-H1
582HHHOOC-MSHHH(NH)CHH1
583H HHOOC-MSHHCH3CH2(NH)CHH1
584HHHOOC-MSHHPh(NH)CHH1
585HHHOOC-MSHHC4H6NHH1
586HHHOOC-MSHHC5H8NHH1
587HHHOOC-MSHHC6H10NHH1
588HHHOOC-MSHHC4H6NSHH1
589HHHOOC-MS3-CF3HCH3HH1
590HHHOOC-MS3-CF3HCH3CH2 HH1
591HHHOOC-MS3-CF3HCH3(CH3)CHHH1
592HHHOOC-MS3-CF3HCH3(CH2)2CH2HH1
593HHHOOC-MS3-CF3HPhCH2HH1
594HHHOOC-MS3-CF3HPh(CH2)2HH1
595HHHOOC-MS3-CF3HPhHH1
596HHHOOC-MS3-CF3HCH3OCOCH2HH1
597HHHOOC-MS3-CF3HCH3COHH1
598HHHOOC-MS3-CF3HH2NCOHH1
599HHHOOC-MS3-CF3HCH3SO2HH1
600HHHOOC-MS3-CF3H2-PyrHH1
601HHHOOC-MS3-CF3H3-PyrHH1
602HHHOOC-MS3-CF3H4-PyrHH1
603HHHOOC-MS3-CF3H2-PyrmHH1
604HHHOOC-MS3-CF3HPyr-3-CH2HH1
605HHHOOC-MS3-CF3Pyr-4-CH2HH1
606HHHOOC-MS3-CF3HPyr-2-(CH2)2HH1
607HHHOOC-MS3-CF3HcPnHH1
608HHHOOC-MS3-CF3HCH32-CH3H1
609HHHOOC-MS3-CF3H-(CH2)3-(5)-H1
610HHHOOC-MS3-CF3HH(NH)CHH1
611HHHOOC-MS3-CF3HCH3CH2(NH)CHH1
612HHHOOC-MS3-CF3HPh(NH)CHH 1
613HHHOOC-MS3-CF3HC4H6NHH1
614HHHOOC-MS3-CF3HC5H8NHH1
615HHHOOC-MS3-CF3HC6H10NHH1
616HHHOOC-MS3-CF3HC4H6NSHH1
617HHHOOC-MS3-H2NCOHCH3HH1
618HHHOOC-MS3-H2NCOHCH3CH2HH1
619HHHOOC-MS3-H2NCOHCH3(CH3)CHHH1
620HHHOOC-MS3-H2NCOHCH3(CH2)2CH2HH1
621HHHOOC-MS3-H2NCOHPhCH2HH1
622HHHOOC-MS3-H2NCOHPh(CH2)2HH1
623HHHOOC-MS3-H2NCOHPhHH1
624HHHOOC-MS3-H2NCOHCH3OCOCH2HH1
625HHHOOC-MS3-H2NCOHCH3COHH1
626HHHOOC-MS3-H2NCOHH2NCOHH1
627HH HOOC-MS3-H2NCOHCH3SO2HH1
628HHHOOC-MS3-H2NCOH2-PyrHH1
629HHHOOC-MS3-H2NCOH3-PyrHH1
630HHHOOC-MS3-H2NCOH4-PyrHH1
631HHHOOC-MS3-H2NCOH2-PyrmHH1
632HHHOOC-MS3-H2NCOHPyr-3-CH2HH1
633HHHOOC-MS3-H2NCOHPyr-4-CH2HH1
634HHHOOC-MS3-H2NCOHPyr-2-(CH2)2 HH1
635HHHOOC-MS3-H2NCOHcPnHH1
636HHHOOC-MS3-H2NCOHCH32-CH3H1
637HHHOOC-MS3-H2NCOH-(CH2)3-(5)-H1
638HHHOOC-MS3-H2NCOHH(NH)CHH1
639HHHOOC-MS3-H2NCOHCH3CH2(NH)CHH1
640HHHOOC-MS3-H2NCOHPh(NH)CHH1
641HHHOOC-MS3-H2NCOHC4H6NHH1
642 HHHOOC-MS3-H2NCOHC5H8NHH1
643HHHOOC-MS3-H2NCOHC6H10NHH1
644HHHOOC-MS3-H2NCOHC4H6NSHH1
645HHHOOC-MS3-FHCH3HH1
646HHHOOC-MS3-FHCH3CH2HH1
647HHHOOC-MS3-FHCH3(CH3)CHHH1
648HHHOOC-MS3-FHCH3(CH2)2CH2HH1
649HHHOC-MS 3-FHPhCH2HH1
650HHHOOC-MS3-FHPh(CH2)2HH1
651HHHOOC-MS3-FHPhHH1
652HHHOOC-MS3-FHCH3OCOCH2HH1
653HHHOOC-MS3-FHCH3COHH1
654HHHOOC-MS3-FHH2NCOHH1
655HHHOOC-MS3-FHCH3SO2HH1
656HHHOOC-MS3-FH2-PyrHH1
657 HHHOOC-MS3-FH3-PyrHH1
658HHHOOC-MS3-FH4-PyrHH1
659HHHOOC-MS3-FH2-PyrmHH1
660HHHOOC-MS3-FHPyr-3-CH2HH1
661HHHOOC-MS3-FHPyr-4-CH2HH1
662HHHOOC-MS3-FHPyr-2-(CH2)2HH1
663HHHOOC-MS3-FHcPnHH1
664HHHOOC-MS3-FHCH32-CH3H1
665HHHOOC-MS3-FH-(CH2)3-(5)-H1
666HHHOOC-MS3-FHH(NH)CHH1
667HHHOOC-MS3-FHCH3CH2(NH)CHH1
668HHHOOC-MS3-FHPh(NH)CHH1
669HHHOOC-MS3-FHC4H6NHH1
670HHHOOC-MS3-FHC5H8NHH1
671HHHOOC-MS3-FHC6H10NHH1
672HHHOOC-MS3-FHHH1
673HHHOOC-MS3-ClHCH3HH0
674HHHOOC-MS3-ClHCH3CH2HH0
675HHHOOC-MS3-ClHCH3(CH3)CHHH0
676HHHOOC-MS3-ClHCH3(CH2)2CH2HH0
677HHHOOC-MS3-ClHPhCH2HH0
678HHHOOC-MS3-ClHPh(CH2)2HH0
679HHHOOC-MS3-ClHPhHH0
680HHOOC-MS3-ClHCH3OCOCH2HH0
681HHHOOC-MS3-ClHCH3COHH0
682HHHOOC-MS3-ClHH2NCOHH0
683HHHOOC-MS3-ClHCH3SO2HH0
684HHHOOC-MS3-ClH2-PyrHH0
685HHHOOC-MS3-ClH3-PyrHH0
686HHHOOC-MS3-ClH4-PyrHH0
687HHHOOC-MS3-ClH2-PyrmHH0
688HHHOOC-MS3-ClHPyr-3-CH2HH0
689HHHOOC-MS3-ClHPyr-4-CH2HH0
690HHHOOC-MS3-ClHPyr-2-(CH2)2HH0
691HHHOOC-MS3-ClHcPnHH0
692HHHOOC-MS3-ClHCH32-CH3H0
693HHHOOC-MS3-ClH-(CH2)3-(5)-H0
694HHHOOC-MS3-ClHH(NH)CHH0
695HHHOOC-MS3-ClHCH3/sub> CH2(NH)CHH0
696HHHOOC-MS3-ClHPh(NH)CHH0
697HHHOOC-MS3-ClHC4H6NHH0
698HHHOOC-MS3-ClHC5H8NHH0
699HHHOOC-MS3-ClHC6H10NHH0
700HHHOOC-MS3-ClHC4H6NSHH0
701HHHOOC-MS3-CH3HCH3HH0
702HHHOOC-MS3-CH3HCH3CH2HH0
703 HHHOOC-MS3-CH3HCH3(CH3)CHHH0
704HHHOOC-MS3-CH3HCH3(CH2)2CH2HH0
705HHHOOC-MS3-CH3HPhCH2HH0
706HHHOOC-MS3-CH3HPh(CH2)2HH0
707HHHOOC-MS3-CH3HPhHH0
708HHHOOC-MS3-CH3HCH3OCOCH2HH0
709HHHOOC-MS3-CH3HCH3COHH0
710HHHOOCMS 3-CH3HH2NCOHH0
711HHHOOC-MS3-CH3HCH3SO2HH0
712HHHOOC-MS3-CH3H2-PyrHH0
713HHHOOC-MS3-CH3H3-PyrHH0
714HHHOOC-MS3-CH3H4-PyrHH0
715HHHOOC-MS3-CH3H2-PyrmHH0
716HHHOOC-MS3-CH3HPyr-3-CH2HH0
717HHHOOC-MS3-CH3HPyr-4-CH2HH
718HHHOOC-MS3-CH3HPyr-2-(CH2)2HH0
719HHHOOC-MS3-CH3HcPnHH0
720HHHOOC-MS3-CH3HCH32-CH3H0
721HHHOOC-MS3-CH3H-(CH2)3-(5)-H0
722HHHOOC-MS3-CH3HH(NH)CHH0
723HHHOOC-MS3-CH3HCH3CH2(NH)CHH0
724HHHOOC-MS3-CH3HPh(NH)CHH0
725HH3-CH3HC4H6NHH0
726HHHOOC-MS3-CH3HC5H8NHH0
727HHHOOC-MS3-CH3HC6H10NHH0
728HHHOOC-MS3-CH3HC4H6NSHH0
729HHHOOC-MSHHCH3HH0
730HHHOOC-MSHHCH3CH2HH0
731HHHOOC-MSHHCH3(CH3)CHHH0
732HHHOOC-MSHHCH3(CHsub> 2)2CH2HH0
733HHHOOC-MSHHPhCH2HH0
734HHHOOC-MSHHPh(CH2)2HH0
735HHHOOC-MSHHPhHH0
736HHHOOC-MSHHCH3OCOCH2HH0
737HHHOOC-MSHHCH3COHH0
738HHHOOC-MSHHH2NCOHH0
739HHHOOC-MSHHCH3SO2HH0
740HH HOOC-MSHH2-PyrHH0
741HHHOOC-MSHH3-PyrHH0
742HHHOOC-MSHH4-PyrHH0
743HHHOOC-MSHH2-PyrmHH0
744HHHOOC-MSHHPyr-3-CH2HH0
745HHHOOC-MSHHPyr-4-CH2HH0
746HHHOOC-MSHHPyr-2-(CH2)2HH0
747HHHOOC-MSHHcPnHH0
748HH HOOC-MSHHCH32-CH3H0
749HHHOOC-MSHH-(CH2)3-(5)-H0
750HHHOOC-MSHHH(NH)CHH0
751HHHOOC-MSHHCH3CH2(NH)CHH0
752HHHOOC-MSHHPh(NH)CHH0
753HHHOOC-MSHHC4H6NHH0
754HHHOOC-MSHHC5H8NHH0
755HHHOOC-MSHHC6H10NHH0
756HHHOOC-MSHHC4H6NSHH0
757HHHOOC-MS3-CF3HCH3HH0
758HHHOOC-MS3-CF3HCH3CH2HH0
759HHHOOC-MS3-CF3HCH3(CH3)CHHH0
760HHHOOC-MS3-CF3HCH3(CH2)2CH2HH0
761HHHOOC-MS3-CF3HPhCH2HH0
762HHHOOC-MS3-CF3HPh(CH2)2HH0
763 HHHOOC-MS3-CF3HPhHH0
764HHHOOC-MS3-CF3HCH3OCOCH2HH0
765HHHOOC-MS3-CF3HCH3COHH0
766HHHOOC-MS3-CF3HH2NCOHH0
767HHHOOC-MS3-CF3HCH3SO2HH0
768HHHOOC-MS3-CF3H2-PyrHH0
769HHHOOC-MS3-CF3H3-PyrHH0
770HHHOOC-MS3-CF3H 4-PyrHH0
771HHHOOC-MS3-CF3H2-PyrmHH0
772HHHOOC-MS3-CF3HPyr-3-CH2HH0
773HHHOOC-MS3-CF3HPyr-4-CH2HH0
774HHHOOC-MS3-CF3HPyr-2-(CH2)2HH0
775HHHOOC-MS3-CF3HcPnHH0
776HHHOOC-MS3-CF3HCH32-CH3H0
777HHHOOC-MS3-CF3H-(CH2)3-(5)-H0
HHHOOC-MS3-CF3HH(NH)CHH0
779HHHOOC-MS3-CF3HCH3CH2(NH)CHH0
780HHHOOC-MS3-CF3HPh(NH)CHH0
781HHHOOC-MS3-CF3HC4H6NHH0
782HHHOOC-MS3-CF3HC5H8NHH0
783HHHOOC-MS3-CF3HC6H10NHH0
784HHHOOC-MS3-CF3HC4H6NSHH0
785HHHOOC-M 3-H2NCOHCH3HH0
786HHHOOC-MS3-H2NCOHCH3CH2HH0
787HHHOOC-MS3-H2NCOHCH3(CH3)CHHH0
788HHHOOC-MS3-H2NCOHCH3(CH2)2CH2HH0
789HHHOOC-MS3-H2NCOHPhCH2HH0
790HHHOOC-MS3-H2NCOHPh(CH2)2HH0
791HHHOOC-MS3-H2NCOHPhHH0
792HHHOOC-MS3-H2NCOCH3OCOCH2HH0
793HHHOOC-MS3-H2NCOHCH3COHH0
794HHHOOC-MS3-H2NCOHH2NCOHH0
795HHHOOC-MS3-H2NCOHCH3SO2HH0
796HHHOOC-MS3-H2NCOH2-PyrHH0
797HHHOOC-MS3-H2NCOH3-PyrHH0
798HHHOOC-MS3-H2NCOH4-PyrHH0
799HHHOOC-MS3-H2NCOH2-PyrmHH0
HHHOOC-MS3-H2NCOHPyr-3-CH2HH0
801HHHOOC-MS3-H2NCOHPyr-4-CH2HH0
802HHHOOC-MS3-H2NCOHPyr-2-(CH2)2HH0
803HHHOOC-MS3-H2NCOHcPnHH0
804HHHOOC-MS3-H2NCOHCH32-CH3H0
805HHHOOC-MS3-H2NCOH-(CH2)3-(5)-H0
806HHHOOC-MS3-H2NCOHH(NH)CHH0
807HHHOOC-MS/td> 3-H2NCOHCH3CH2(NH)CHH0
808HHHOOC-MS3-H2NCOHPh(NH)CHH0
809HHHOOC-MS3-H2NCOHC4H6NHH0
810HHHOOC-MS3-H2NCOHC5H8NHH0
811HHHOOC-MS3-H2NCOHC6H10NHH0
812HHHOOC-MS3-H2NCOHC4H6NSHH0
813HHHOOC-MS3-FHCH3HH0
814HHHOOC-MS3-FHCH CH2HH0
815HHHOOC-MS3-FHCH3(CH3)CHHH0
816HHHOOC-MS3-FHCH3(CH2)2CH2HH0
817HHHOOC-MS3-FHPhCH2HH0
818HHHOOC-MS3-FHPh(CH2)2HH0
819HHHOOC-MS3-FHPhHH0
820HHHOOC-MS3-FHCH3OCOCH2HH0
821HHHOOC-MS3-FHCH3COHH0
822 HHOOC-MS3-FHH2NCOHH0
823HHHOOC-MS3-FHCH3SO2HH0
824HHHOOC-MS3-FH2-PyrHH0
825HHHOOC-MS3-FH3-PyrHH0
826HHHOOC-MS3-FH4-PyrHH0
827HHHOOC-MS3-FH2-PyrmHH0
828HHHOOC-MS3-FHPyr-3-CH2HH0
829HHHOOC-MS3-FHPyr-4-CH2HH0
30 HHHOOC-MS3-FHPyr-2-(CH2)2HH0
831HHHOOC-MS3-FHcPnHH0
832HHHOOC-MS3-FHCH32-CH3H0
833HHHOOC-MS3-FH-(CH2)3-(5)-H0
834HHHOOC-MS3-FHH(NH)CHH0
835HHHOOC-MS3-FHCH3CH2(NH)CHH0
836HHHOOC-MS3-FHPh(NH)CHH0
837HHHOOC-MS3-FHC4H6N HH0
838HHHOOC-MS3-FHC5H8NHH0
839HHHOOC-MS3-FHC6H10NHH0
840HHHOOC-MS3-FHC4H6NSHH0
841HHHOOC-MS3-ClHCH3HH2
842HHHOOC-MS3-ClHCH3CH2HH2
843HHHOOC-MS3-ClHCH3(CH3)CHHH2
844HHHOOC-MS3-ClHCH3(CH2)2CH2HH2
845H HHOOC-MS3-ClHPhCH2HH2
846HHHOOC-MS3-ClHPh(CH2)2HH2
847HHHOOC-MS3-ClHPhHH2
848HHHOOC-MS3-ClHCH3OCOCH2HH2
849HHHOOC-MS3-ClHCH3COHH2
850HHHOOC-MS3-ClHH2NCOHH2
851HHHOOC-MS3-ClHCH3SO2HH2
852HHHOOC-MS3-ClH2-PyrHH 2
853HHHOOC-MS3-ClH3-PyrHH2
854HHHOOC-MS3-ClH4-PyrHH2
855HHHOOC-MS3-ClH2-PyrmHH2
856HHHOOC-MS3-ClHPyr-3-CH2HH2
857HHHOOC-MS3-ClHPyr-4-CH2HH2
858HHHOOC-MS3-ClHPyr-2-(CH2)2HH2
859HHHOOC-MS3-ClHcPnHH2
860HHHOOC-MS3-ClHCH32-CH3 H2
861HHHOOC-MS3-ClH-(CH2)3-(5)-H2
862HHHOOC-MS3-ClHH(NH)CHH2
863HHHOOC-MS3-ClHCH3CH2(NH)CHH2
864HHHOOC-MS3-ClHPh(NH)CHH2
865HHHOOC-MS3-ClHC4H6NHH2
866HHHOOC-MS3-ClHC5H8NHH2
867HHHOOC-MS3-ClHC6H10NHH2
868HHHOOC-MS 3-ClHC4H6NSHH2
869HHHOOC-MS3-CH3HCH3HH2
870HHHOOC-MS3-CH3HCH3CH2HH2
871HHHOOC-MS3-CH3HCH3(CH3)CHHH2
872HHHOOC-MS3-CH3HCH3(CH2)2CH2HH2
873HHHOOC-MS3-CH3HPhCH2HH2
874HHHOOC-MS3-CH3HPh(CH2)2HH2
875HHHOOC-MS3-CH3PhHH2
876HHHOOC-MS3-CH3HCH3OCOCH2HH2
877HHHOOC-MS3-CH3HCH3COHH2
878HHHOOC-MS3-CH3HH2NCOHH2
879HHHOOC-MS3-CH3HCH3SO2HH2
880HHHOOC-MS3-CH3H2-PyrHH2
881HHHOOC-MS3-CH3H3-PyrHH2
882HHHOOC-MS3-CH3H4-PyrHH2
83 HHHOOC-MS3-CH3H2-PyrmHH2
884HHHOOC-MS3-CH3HPyr-3-CH2HH2
885HHHOOC-MS3-CH3HPyr-4-CH2HH2
886HHHOOC-MS3-CH3HPyr-2-(CH2)2HH2
887HHHOOC-MS3-CH3HcPnHH2
888HHHOOC-MS3-CH3HCH32-CH3H2
889HHHOOC-MS3-CH3H-(CH2)3-(5)-H2
890HHHOOC-MS 3-CH3HH(NH)CHH2
891HHHOOC-MS3-CH3HCH3CH2(NH)CHH2
892HHHOOC-MS3-CH3HPh(NH)CHH2
893HHHOOC-MS3-CH3HC4H6NHH2
894HHHOOC-MS3-CH3HC5H8NHH2
895HHHOOC-MS3-CH3HC6H10NHH2
896HHHOOC-MS3-CH3HC4H6NSHH2
897HHHOOC-MSHHCH3 HH2
898HHHOOC-MSHHCH3CH2HH2
899HHHOOC-MSHHCH3(CH3)CHHH2
900HHHOOC-MSHHCH3(CH2)2CH2HH2
901HHHOOC-MSHHPhCH2HH2
902HHHOOC-MSHHPh(CH2)2HH2
903HHHOOC-MSHHPhHH2
904HHHOOC-MSHHCH3OCOCH2HH2
905HH HOOC-MSHHCH3COHH2
906HHHOOC-MSHHH2NCOHH2
907HHHOOC-MSHHCH3SO2HH2
908HHHOOC-MSHH2-PyrHH2
909HHHOOC-MSHH3-PyrHH2
910HHHOOC-MSHH4-PyrHH2
911HHHOOC-MSHH2-PyrmHH2
912HHHOOC-MSHHPyr-3-CH2HH2
913HH HOOC-MSHHPyr-4-CH2HH2
914HHHOOC-MSHHPyr-2-(CH2)2HH2
915HHHOOC-MSHHcPnHH2
916HHHOOC-MSHHCH32-CH3H2
917HHHOOC-MSHH-(CH2)3-(5)-H2
918HHHOOC-MSHHH(NH)CHH2
919HHHOOC-MSHHCH3CH2(NH)CHH2
920HHHOOC-MSHHPh(NH)CHH2
921HHHOOC-MSHHC4H6NHH2
922HHHOOC-MSHHC5H8NHH2
923HHHOOC-MSHHC6H10NHH2
924HHHOOC-MSHHC4H6NSHH2
925HHHOOC-MS3-CF3HCH3HH2
926HHHOOC-MS3-CF3HCH3CH2HH2
927HHHOOC-MS3-CF3HCH3(CH3)CHHH2
928HHHOOC-MS3-CF 3HCH3(CH2)2CH2HH2
929HHHOOC-MS3-CF3HPhCH2HH2
930HHHOOC-MS3-CF3HPh(CH2)2HH2
931HHHOOC-MS3-CF3HPhHH2
932HHHOOC-MS3-CF3HCH3OCOCH2HH2
933HHHOOC-MS3-CF3HCH3COHH2
934HHHOOC-MS3-CF3HH2NCOHH2
935HHHOOC-MS3-CF3HCH3SO 2HH2
936HHHOOC-MS3-CF3H2-PyrHH2
937HHHOOC-MS3-CF3H3-PyrHH2
938HHHOOC-MS3-CF3H4-PyrHH2
939HHHOOC-MS3-CF3H2-PyrmHH2
940HHHOOC-MS3-CF3HPyr-3-CH2HH2
941HHHOOC-MS3-CF3HPyr-4-CH2HH2
942HHHOOC-MS3-CF3HPyr-2-(CH2)2HH2
943HHOOC-MS3-CF3HcPnHH2
944HHHOOC-MS3-CF3HCH32-CH3H2
945HHHOOC-MS3-CF3H-(CH2)3-(5)-H2
946HHHOOC-MS3-CF3HH(NH)CHH2
947HHHOOC-MS3-CF3HCH3CH2(NH)CHH2
948HHHOOC-MS3-CF3HPh(NH)CHH2
949HHHOOC-MS3-CF3HC4H6NHH2
950HHHOOC-MS3-CF3HHH2
951HHHOOC-MS3-CF3HC6H10NHH2
952HHHOOC-MS3-CF3HC4H6NSHH2
953HHHOOC-MS3-H2NCOHCH3HH2
954HHHOOC-MS3-H2NCOHCH3CH2HH2
955HHHOOC-MS3-H2NCOHCH3(CH3)CHHH2
956HHHOOC-MS3-H2NCOHCH3(CH2)2CH2HH2
957HHHOOC-MS3-H2NCOHPhCH2 HH2
958HHHOOC-MS3-H2NCOHPh(CH2)2HH2
959HHHOOC-MS3-H2NCOHPhHH2
960HHHOOC-MS3-H2NCOHCH3OCOCH2HH2
961HHHOOC-MS3-H2NCOHCH3COHH2
962HHHOOC-MS3-H2NCOHH2NCOHH2
963HHHOOC-MS3-H2NCOHCH3SO2HH2
964HHHOOC-MS3-H2NCOH2-PyrHH2
965HHHOOC-MS3-H2NCOH3-PyrHH2
966HHHOOC-MS3-H2NCOH4-PyrHH2
967HHHOOC-MS3-H2NCOH2-PyrmHH2
968HHHOOC-MS3-H2NCOHPyr-3-CH2HH2
969HHHOOC-MS3-H2NCOHPyr-4-CH2HH2
970HHHOOC-MS3-H2NCOHPyr-2-(CH2)2HH2
971HHHOOC-MS3-H2NCOHcPnHH2
972HHHOOC-MS3-H2NCO HCH32-CH3H2
973HHHOOC-MS3-H2NCOH-(CH2)3-(5)-H2
974HHHOOC-MS3-H2NCOHH(NH)CHH2
975HHHOOC-MS3-H2NCOHCH3CH2(NH)CHH2
976HHHOOC-MS3-H2NCOHPh(NH)CHH2
977HHHOOC-MS3-H2NCOHC4H6NHH2
978HHHOOC-MS3-H2NCOHC5H8NHH2
979HHHOOC-MS3-H2NCOHC6H10N HH2
980HHHOOC-MS3-H2NCOHC4H6NSHH2
981HHHOOC-MS3-FHCH3HH2
982HHHOOC-MS3-FHCH3CH2HH2
983HHHOOC-MS3-FHCH3(CH3)CHHH2
984HHHOOC-MS3-FHCH3(CH2)2CH2HH2
985HHHOOC-MS3-FHPhCH2HH2
986HHHOOC-MS3-FHPh(CH2)2HH2
987 HHOOC-MS3-FHPhHH2
988HHHOOC-MS3-FHCH3OCOCH2HH2
989HHHOOC-MS3-FHCH3COHH2
990HHHOOC-MS3-FHH2NCOHH2
991HHHOOC-MS3-FHCH3SO2HH2
992HHHOOC-MS3-FH2-PyrHH2
993HHHOOC-MS3-FH3-PyrHH2
994HHHOOC-MS3-FH4-PyrHH2
995HHHOOC-MS3-FH2-PyrmHH2
996HHHOOC-MS3-FHPyr-3-CH2HH2
997HHHOOC-MS3-FHPyr-4-CH2HH2
998HHHOOC-MS3-FHPyr-2-(CH2)2HH2
999HHHOOC-MS3-FHcPnHH2
1000HHHOOC-MS3-FHCH32-CH3H2
1001HHHOOC-MS3-FH-(CH2)3-(5)-H2
1002HHHOOC-MS3-FHH(NH)CH H2
1003HHHOOC-MS3-FHCH3CH2(NH)CHH2
1004HHHOOC-MS3-FHPh(NH)CHH2
1005HHHOOC-MS3-FHC4H6NHH2
1006HHHOOC-MS3-FHC5H8NHH2
1007HHHOOC-MS3-FHC6H10NHH2
1008HHHOOC-MS3-FHC4H6NSHH2
1009HHEtOOC-MS3-ClHC3H4NOHH1
1010HH EtOOC-MS3-CH3HC3H4NOHH1
1011HHEtOOC-MSHHC3H4NOHH1
1012HHEtOOC-MS3-CF3HC3H4NOHH1
1013HHEtOOC-MS3-H2NCOHC3H4NOHH1
1014HHEtOOC-MS3-FHC3H4NOHH1
1015HHEtOOC-MS3-ClHC3H4NOHH0
1016HHEtOOC-MS3-CH3HC3H4NOHH0
1017HHEtOOC-MSHHHH0
1018HHEtOOC-MS3-CF3HC3H4NOHH0
1019HHEtOOC-MS3-H2NCOHC3H4NOHH0
1020HHEtOOC-MS3-FHC3H4NOHH0
1021HHEtOOC-MS3-ClHC3H4NOHH2
1022HHEtOOC-MS3-CH3HC3H4NOHH2
1023HHEtOOC-MSHHC3H4NOHH2
1024HHEtOOC-MS3-CF3HC3H4NOH H2
1025HHEtOOC-MS3-H2NCOHC3H4NOHH2
1026HHEtOOC-MS3-FHC3H4NOHH2
1027HHHOOC-MS3-ClHC3H4NOHH1
1028HHHOOC-MS3-CH3HC3H4NOHH1
1029HHHOOC-MSHHC3H4NOHH1
1030HHHOOC-MS3-CF3HC3H4NOHH1
1031HHHOOC-MS3-H2NCOHC3H4NOHH1
1032 HHHOOC-MS3-FHC3H4NOHH1
1033HHHOOC-MS3-ClHC3H4NOHH0
1034HHHOOC-MS3-CH3HC3H4NOHH0
1035HHHOOC-MSHHC3H4NOHH0
1036HHHOOC-MS3-CF3HC3H4NOHH0
1037HHHOOC-MS3-H2NCOHC3H4NOHH0
1038HHHOOC-MS3-FHC3H4NOHH0
1039HHHOOC-MS3-Cl HC3H4NOHH2
1040HHHOOC-MS3-CH3HC3H4NOHH2
1041HHHOOC-MSHHC3H4NOHH2
1042HHHOOC-MS3-CF3HC3H4NOHH2
1043HHHOOC-MS3-H2NCOHC3H4NOHH2
1044HHHOOC-MS3-FHC3H4NOHH2
1045HHEtOOC-MS3-ClHC5F4NHH1
1046HHEtOOC-MS3-CH3HC5F4 HH1
1047HHEtOOC-MSHHC5F4NHH1
1048HHEtOOC-MS3-CF3HC5F4NHH1
1049HHEtOOC-MS3-H2NCOHC5F4NHH1
1050HHEtOOC-MS3-FHC5F4NHH1
1051HHEtOOC-MS3-ClHC5F4NHH0
1052HHEtOOC-MS3-CH3HC5F4NHH0
1053HHEtOOC-MSHHC5F4NHH0
HHEtOOC-MS3-CF3HC5F4NHH0
1055HHEtOOC-MS3-H2NCOHC5F4NHH0
1056HHEtOOC-MS3-FHC5F4NHH0
1057HHEtOOC-MS3-ClHC5F4NHH2
1058HHEtOOC-MS3-CH3HC5F4NHH2
1059HHEtOOC-MSHHC5F4NHH2
1060HHEtOOC-MS3-CF3HC5F4NHH2
1061HH EtOOC-MS3-H2NCOHC5F4NHH2
1062HHEtOOC-MS3-FHC5F4NHH2
1063HHHOOC-MS3-ClHC5F4NHH1
1064HHHOOC-MS3-CH3HC5F4NHH1
1065HHHOOC-MSHHC5F4NHH1
1066HHHOOC-MS3-CF3HC5F4NHH1
1067HHHOOC-MS3-H2NCOHC5F4NHH1
1068HHHOOC-MS3-FH C5F4NHH1
1069HHHOOC-MS3-ClHC5F4NHH0
1070HHHOOC-MS3-CH3HC5F4NHH0
1071HHHOOC-MSHHC5F4NHH0
1072HHHOOC-MS3-CF3HC5F4NHH0
1073HHHOOC-MS3-H2NCOHC5F4NHH0
1074HHHOOC-MS3-FHC5F4NHH0
1075HHHOOC-MS3-ClHC5F4NHH 2
1076HHHOOC-MS3-CH3HC5F4NHH2
1077HHHOOC-MSHHC5F4NHH2
1078HHHOOC-MS3-CF3HC5F4NHH2
1079HHHOOC-MS3-H2NCOHC5F4NHH2
1080HHHOOC-MS3-FHC5F4NHH2
1081HHEtOOC-MS3-ClHH(CH3CH2N)CHH1
1082HHEtOOC-MS3-CH3HH(CH3CH2N)CHH1
1083H HEtOOC-MSHHH(CH3CH2N)CHH1
1084HHEtOOC-MS3-CF3HH(CH3CH2N)CHH1
1085HHEtOOC-MS3-H2NCOHH(CH3CH2N)CHH1
1086HHEtOOC-MS3-FHH(CH3CH2N)CHH1
1087HHEtOOC-MS3-ClHH(CH3CH2N)CHH0
1088HHEtOOC-MS3-CH3HH(CH3CH2N)CHH0
1089HHEtOOC-MSHHH(CH3CH2N)CHH0
1090HHEtOOC-S 3-CF3HH(CH3CH2N)CHH0
1091HHEtOOC-MS3-H2NCOHH(CH3CH2N)CHH0
1092HHEtOOC-MS3-FHH(CH3CH2N)CHH0
1093HHEtOOC-MS3-ClHH(CH3CH2N)CHH2
1094HHEtOOC-MS3-CH3HH(CH3CH2N)CHH2
1095HHEtOOC-MSHHH(CH3CH2N)CHH2
1096HHEtOOC-MS3-CF3HH(CH3CH2N)CHH2
1097HHEtOOC-MS3-H2 HH(CH3CH2N)CHH2
1098HHEtOOC-MS3-FHH(CH3CH2N)CHH2
1099HHHOOC-MS3-ClHH(CH3CH2N)CHH1
1100HHHOOC-MS3-CH3HH(CH3CH2N)CHH1
1101HHHOOC-MSHHH(CH3CH2N)CHH1
1102HHHOOC-MS3-CF3HH(CH3CH2N)CHH1
1103HHHOOC-MS3-H2NCOHH(CH3CH2N)CHH1
1104HHHOOC-MS3-FHH(CH3 CH2N)CHH1
1105HHHOOC-MS3-ClHH(CH3CH2N)CHH0
1106HHHOOC-MS3-CH3HH(CH3CH2N)CHH0
1107HHHOOC-MSHHH(CH3CH2N)CHH0
1108HHHOOC-MS3-CF3HH(CH3CH2N)CHH0
1109HHHOOC-MS3-H2NCOHH(CH3CH2N)CHH0
1110HHHOOC-MS3-FHH(CH3CH2N)CHH0
1111HHHOOC-MS3-ClHH(CH3CH2N)CH H2
1112HHHOOC-MS3-CH3HH(CH3CH2N)CHH2
1113HHHOOC-MSHHH(CH3CH2N)CHH2
1114HHHOOC-MS3-CF3HH(CH3CH2N)CHH2
1115HHHOOC-MS3-H2NCOHH(CH3CH2N)CHH2
1116HHHOOC-MS3-FHH(CH3CH2N)CHH2
1117HHEtOOC-MS3-ClHCH3-(CH2)2--1
1118HHEtOOC-MS3-CH3HCH3-(CH2)2-- 1
1119HHEtOOC-MSHHCH3-(CH2)2--1
1120HHEtOOC-MS3-CF3HCH3-(CH2)2--1
1121HHEtOOC-MS3-H2NCOHCH3-(CH2)2--1
1122HHEtOOC-MS3-FHCH3-(CH2)2--1
1123HHEtOOC-MS3-ClHCH3-(CH2)2--0
1124HHEtOOC-MS3-CH3HCH3-(CH2)2--0
1125HHEtOOC-MSHHCH3-(CH2)2- -0
1126HHEtOOC-MS3-CF3HCH3-(CH2)2--0
1127HHEtOOC-MS3-H2NCOHCH3-(CH2)2--0
1128HHEtOOC-MS3-FHCH3-(CH2)2--0
1129HHEtOOC-MS3-ClHCH3-(CH2)2--2
1130HHEtOOC-MS3-CH3HCH3-(CH2)2--2
1131HHEtOOC-MSHHCH3-(CH2)2--2
1132HHEtOOC-MS3-CF3HCH3-(CH2 )2--2
1133HHEtOOC-MS3-H2NCOHCH3-(CH2)2--2
1134HHEtOOC-MS3-FHCH3-(CH2)2--2
1135HHHOOC-MS3-ClHCH3-(CH2)2--1
1136HHHOOC-MS3-CH3HCH3-(CH2)2--1
1137HHHOOC-MSHHCH3-(CH2)2--1
1138HHHOOC-MS3-CF3HCH3-(CH2)2--1
1139HHHOOC-MS3-H2NCOHCH3 -(CH2)2--1
1140HHHOOC-MS3-FHCH3-(CH2)2--1
1141HHHOOC-MS3-ClHCH3-(CH2)2--0
1142HHHOOC-MS3-CH3HCH3-(CH2)2--0
1143HHHOOC-MSHHCH3-(CH2)2--0
1144HHHOOC-MS3-CF3HCH3-(CH2)2--0
1145HHHOOC-MS3-H2NCOHCH3-(CH2)2--0
1146HHHOOC-MS3-FH CH3-(CH2)2--0
1147HHHOOC-MS3-ClHCH3-(CH2)2--2
1148HHHOOC-MS3-CH3HCH3-(CH2)2--2
1149HHHOOC-MSHHCH3-(CH2)2--2
1150HHHOOC-MS3-CF3HCH3-(CH2)2--2
1151HHHOOC-MS3-H2NCOHCH3-(CH2)2--2
1152HHHOOC-MS3-FHCH3-(CH2)2--2
1153HHEtOOC-MS3-ClH C8H14NHH1
1154HHEtOOC-MS3-CH3HC8H14NHH1
1155HHEtOOC-MSHHC8H14NHH1
1156HHEtOOC-MS3-CF3HC8H14NHH1
1157HHEtOOC-MS3-H2NCOHC8H14NHH1
1158HHEtOOC-MS3-FHC8H14NHH1
1159HHEtOOC-MS3-ClHC8H14NHH0
1160HHEtOOC-MS3-CH3HC8H14N HH0
1161HHEtOOC-MSHHC8H14NHH0
1162HHEtOOC-MS3-CF3HC8H14NHH0
1163HHEtOOC-MS3-H2NCOHC8H14NHH0
1164HHEtOOC-MS3-FHC8H14NHH0
1165HHEtOOC-MS3-ClHC8H14NHH2
1166HHEtOOC-MS3-CH3HC8H14NHH2
1167HHEtOOC-MSHHC8H14NHH2
1168HHEtOOC-MS3-CF3HC8H14NHH2
1169HHEtOOC-MS3-H2NCOHC8H14NHH2
1170HHEtOOC-MS3-FHC8H14NHH2
1171HHHOOC-MS3-ClHC8H14NHH1
1172HHHOOC-MS3-CH3HC8H14NHH1
1173HHHOOC-MSHHC8H14NHH1
1174HHHOOC-MS3-CF3HC8H14NHH1
1175HH HOOC-MS3-H2NCOHC8H14NHH1
1176HHHOOC-MS3-FHC8H14NHH1
1177HHHOOC-MS3-ClHC8H14NHH0
1178HHHOOC-MS3-CH3HC8H14NHH0
1179HHHOOC-MSHHC8H14NHH0
1180HHHOOC-MS3-CF3HC8H14NHH0
1181HHHOOC-MS3-H2NCOHC8H14NHH0
1182HHHOOC-MS3-FH C8H14NHH0
1183HHHOOC-MS3-ClHC8H14NHH2
1184HHHOOC-MS3-CH3HC8H14NHH2
1185HHHOOC-MSHHC8H14NHH2
1186HHHOOC-MS3-CF3HC8H14NHH2
1187HHHOOC-MS3-H2NCOHC8H14NHH2
1188HHHOOC-MS3-FHC8H14NHH2
1189HHH3CSO2HHC3H4NOH H0
1190HHH3CSO23-FHC3H4NOHH0
1191HHH3CSO23-ClHC3H4NOHH0
1192HHH3CSO23-CH3HC3H4NOHH0
1193HHH3CSO23-CF3HC3H4NOHH0
1194HHH3CSO23-H2NCOHC3H4NOHH0
1195HFH3CSO2HHC3H4NOHH0
1196HFH3CSO23-FHC 3H4NOHH0
1197HFH3CSO23-ClHC3H4NOHH0
1198HFH3CSO23-CH3HC3H4NOHH0
1199HFH3CSO23-CF3HC3H4NOHH0
1200HFH3CSO23-H2NCOHC3H4NOHH0
1201HHH3CSO2HHC3H4NOHH1
1202HHH3CSO22-FHC3H4NOHH1
1203HHH3CSO2HC3H4NOHH1
1204HHH3CSO22-CH3HC3H4NOHH1
1205HHH3CSO22-CF3HC3H4NOHH1
1206HHH3CSO22-H2NCOHC3H4NOHH1
1207HHH3CSO23-FHC3H4NOHH1
1208HHH3CSO23-ClHC3H4NOHH1
1209HHH3CSO23-CH3HC3H4NOHH1
1210H HH3CSO23-CF3HC3H4NOHH1
1211HHH3CSO23-H2NCOHC3H4NOHH1
1212HFH3CSO2HHC3H4NOHH1
1213HFH3CSO23-FHC3H4NOHH1
1214HFH3CSO23-ClHC3H4NOHH1
1215HFH3CSO23-CH3HC3H4NOHH1
1216HFH3CSO23-CF3HC3H4NOHH
1217HFH3CSO23-H2NCOHC3H4NOHH1
1218HHEtSO2HHC3H4NOHH0
1219HHEtSO23-FHC3H4NOHH0
1220HHEtSO23-ClHC3H4NOHH0
1221HHEtSO23-CH3HC3H4NOHH0
1222HHEtSO23-CF3HC3H4NOHH0
1223HHEtSO23-H2NCOHC3H4NOHH 0
1224HFEtSO2HHC3H4NOHH0
1225HFEtSO23-FHC3H4NOHH0
1226HFEtSO23-ClHC3H4NOHH0
1227HFEtSO23-CH3HC3H4NOHH0
1228HFEtSO23-CF3HC3H4NOHH0
1229HFEtSO23-H2NCOHC3H4NOHH0
1230HHEtSO2HHC3H4NOHH1
HHEtSO22-FHC3H4NOHH1
1232HHEtSO22-ClHC3H4NOHH1
1233HHEtSO22-CH3HC3H4NOHH1
1234HHEtSO22-CF3HC3H4NOHH1
1235HHEtSO22-H2NCOHC3H4NOHH1
1236HHEtSO23-FHC3H4NOHH1
1237HHEtSO23-ClHC3H4NOHH1
1238HEtSO23-CH3HC3H4NOHH1
1239HHEtSO23-CF3HC3H4NOHH1
1240HHEtSO23-H2NCOHC3H4NOHH1
1241HFEtSO2HHC3H4NOHH1
1242HFEtSO23-FHC3H4NOHH1
1243HFEtSO23-ClHC3H4NOHH1
1244HFEtSO23-CH3HC3H4NOHH1
1245H/td> FEtSO23-CF3HC3H4NOHH1
1246HFEtSO23-H2NCOHC3H4NOHH1
1247HHH3CSO2HHC3H4NSHH0
1248HHH3CSO23-FHC3H4NSHH0
1249HHH3CSO23-ClHC3H4NSHH0
1250HHH3CSO23-CH3HC3H4NSHH0
1251HHH3CSO23-CF3HC3H4NSHH0
1252HHH3CSO23-H2NCOHC3H4NSHH0
1253HFH3CSO2HHC3H4NSHH0
1254HFH3CSO23-FHC3H4NSHH0
1255HFH3CSO23-ClHC3H4NSHH0
1256HFH3CSO23-CH3HC3H4NSHH0
1257HFH3CSO23-CF3HC3H4NSHH0
1258HFH3CSO23-H2NCOHC3H4 NSHH0
1259HHH3CSO2HHC3H4NSHH1
1260HHH3CSO22-FHC3H4NSHH1
1261HHH3CSO22-ClHC3H4NSHH1
1262HHH3CSO22-CH3HC3H4NSHH1
1263HHH3CSO22-CF3HC3H4NSHH1
1264HHH3CSO22-H2NCOHC3H4NSHH1
1265HHH3CSO23-F HC3H4NSHH1
1266HHH3CSO23-ClHC3H4NSHH1
1267HHH3CSO23-CH3HC3H4NSHH1
1268HHH3CSO23-CF3HC3H4NSHH1
1269HHH3CSO23-H2NCOHC3H4NSHH1
1270HFH3CSO2HHC3H4NSHH1
1271HFH3CSO23-FHC3H4NSHH1
1272HF H3CSO23-ClHC3H4NSHH1
1273HFH3CSO23-CH3HC3H4NSHH1
1274HFH3CSO23-CF3HC3H4NSHH1
1275HFH3CSO23-H2NCOHC3H4NSHH1
1276HHEtSO2HHC3H4NSHH0
1277HHEtSO23-FHC3H4NSHH0
1278HHEtSO23-ClHC3H4NSHH0
1279H HEtSO23-CH3HC3H4NSHH0
1280HHEtSO23-CF3HC3H4NSHH0
1281HHEtSO23-H2NCOHC3H4NSHH0
1282HFEtSO2HHC3H4NSHH0
1283HFEtSO23-FHC3H4NSHH0
1284HFEtSO23-ClHC3H4NSHH0
1285HFEtSO23-CH3HC3H4NSHH0
1286HF/td> EtSO23-CF3HC3H4NSHH0
1287HFEtSO23-H2NCOHC3H4NSHH0
1288HHEtSO2HHC3H4NSHH1
1289HHEtSO22-FHC3H4NSHH1
1290HHEtSO22-ClHC3H4NSHH1
1291HHEtSO22-CH3HC3H4NSHH1
1292HHEtSO22-CF3HC3H4NSHH1
1293HH2-H2NCOHC3H4NSHH1
1294HHEtSO23-FHC3H4NSHH1
1295HHEtSO23-ClHC3H4NSHH1
1296HHEtSO23-CH3HC3H4NSHH1
1297HHEtSO23-CF3HC3H4NSHH1
1298HHEtSO23-H2NCOHC3H4NSHH1
1299HFEtSO2HHC3H4NSHH1
1300HFEtSO 23-FHC3H4NSHH1
1301HFEtSO23-ClHC3H4NSHH1
1302HFEtSO23-CH3HC3H4NSHH1
1303HFEtSO23-CF3HC3H4NSHH1
1304HFEtSO23-H2NCOHC3H4NSHH1
1305HHEtOOC-MSHHC3H4NSHH0
1306HHEtOOC-MS3-FHC3H4NSHH0
1307HHEtOOC-MS3-ClC3H4NSHH0
1308HHEtOOC-MS3-CH3HC3H4NSHH0
1309HHEtOOC-MS3-CF3HC3H4NSHH0
1310HHEtOOC-MS3-H2NCOHC3H4NSHH0
1311HFEtOOC-MSHHC3H4NSHH0
1312HFEtOOC-MS3-FHC3H4NSHH0
1313HFEtOOC-MS3-ClHC3H4NSHH0
1314HFEtOOC-MS3-CH3HC3H4NS HH0
1315HFEtOOC-MS3-CF3HC3H4NSHH0
1316HFEtOOC-MS3-H2NCOHC3H4NSHH0
1317HHEtOOC-MSHHC3H4NSHH1
1318HHEtOOC-MS2-FHC3H4NSHH1
1319HHEtOOC-MS2-ClHC3H4NSHH1
1320HHEtOOC-MS2-CH3HC3H4NSHH1
1321HHEtOOC-MS2-CF3HC3H4NSHH1
1322HHEtOOC-MS2-H2NCOHC3H4NSHH1
1323HHEtOOC-MS3-FHC3H4NSHH1
1324HHEtOOC-MS3-ClHC3H4NSHH1
1325HHEtOOC-MS3-CH3HC3H4NSHH1
1326HHEtOOC-MS3-CF3HC3H4NSHH1
1327HHEtOOC-MS3-H2NCOHC3H4NSHH1
1328HFEtOOC-MSHHC3H4NSHH1
1329HF EtOOC-MS3-FHC3H4NSHH1
1330HFEtOOC-MS3-ClHC3H4NSHH1
1331HFEtOOC-MS3-CH3HC3H4NSHH1
1332HFEtOOC-MS3-CF3HC3H4NSHH1
1333HFEtOOC-MS3-H2NCOHC3H4NSHH1
1334HHHOOC-MSHHC3H4NSHH0
1335HHHOOC-MS3-FHC3H4NSHH0
1336HHHOOC-MS3-ClH 3H4NSHH0
1337HHHOOC-MS3-CH3HC3H4NSHH0
1338HHHOOC-MS3-CF3HC3H4NSHH0
1339HHHOOC-MS3-H2NCOHC3H4NSHH0
1340HFHOOC-MSHHC3H4NSHH0
1341HFHOOC-MS3-FHC3H4NSHH0
1342HFHOOC-MS3-ClHC3H4NSHH0
1343HFHOOC-MS3-CH3HC3H4NSH 0
1344HFHOOC-MS3-CF3HC3H4NSHH0
1345HFHOOC-MS3-H2NCOHC3H4NSHH0
1346HHHOOC-MSHHC3H4NSHH1
1347HHHOOC-MS2-FHC3H4NSHH1
1348HHHOOC-MS2-ClHC3H4NSHH1
1349HHHOOC-MS2-CH3HC3H4NSHH1
1350HHHOOC-MS2-CF3HC3H4NSHH1
1351 HHHOOC-MS2-H2NCOHC3H4NSHH1
1352HHHOOC-MS3-FHC3H4NSHH1
1353HHHOOC-MS3-ClHC3H4NSHH1
1354HHHOOC-MS3-CH3HC3H4NSHH1
1355HHHOOC-MS3-CF3HC3H4NSHH1
1356HHHOOC-MS3-H2NCOHC3H4NSHH1
1357HFHOOC-MSHHC3H4NSHH1
1358HFHOOC-MS 3-FHC3H4NSHH1
1359HFHOOC-MS3-ClHC3H4NSHH1
1360HFHOOC-MS3-CH3HC3H4NSHH1
1361HFHOOC-MS3-CF3HC3H4NSHH1
1362HFHOOC-MS3-H2NCOHC3H4NSHH1
1363HHH3CSO2HHC4H6NHH0
1364HHH3CSO22-FHC4H6NHH0
1365HHH3CSO22-Cl HC4H6NHH0
1366HHH3CSO22-CH3HC4H6NHH0
1367HHH3CSO22-CF3HC4H6NHH0
1368HHH3CSO22-H2NCOHC4H6NHH0
1369HHH3CSO23-FHC4H6NHH0
1370HHH3CSO23-ClHC4H6NHH0
1371HHH3CSO23-CH3HC4H6NHH0
1372HH H3CSO23-CF3HC4H6NHH0
1373HHH3CSO23-H2NCOHC4H6NHH0
1374HHH3CSO2HHC4H6NHH1
1375HHH3CSO22-FHC4H6NHH1
1376HHH3CSO22-ClHC4H6NHH1
1377HHH3CSO22-CH3HC4H6NHH1
1378HHH3CSO22-CF3HC4H6NHH1
1379HHH3CSO22-H2NCOHC4H6NHH1
1380HHH3CSO23-FHC4H6NHH1
1381HHH3CSO23-ClHC4H6NHH1
1382HHH3CSO23-CH3HC4H6NHH1
1383HHH3CSO23-CF3HC4H6NHH1
1384HHH3CSO23-H2NCOHC4H6NHH1
1385HHEtSO2HHC4H6NH H0
1386HHEtSO22-FHC4H6NHH0
1387HHEtSO22-ClHC4H6NHH0
1388HHEtSO22-CH3HC4H6NHH0
1389HHEtSO22-CF3HC4H6NHH0
1390HHEtSO22-H2NCOHC4H6NHH0
1391HHEtSO23-FHC4H6NHH0
1392HHEtSO23-ClHC4H6NHH 0
1393HHEtSO23-CH3HC4H6NHH0
1394HHEtSO23-CF3HC4H6NHH0
1395HHEtSO23-H2NCOHC4H6NHH0
1396HHEtSO2HHC4H6NHH1
1397HHEtSO22-FHC4H6NHH1
1398HHEtSO22-ClHC4H6NHH1
1399HHEtSO22-CH3HC4H6NHH1
1400HHEtSO22-CF3HC4H6NHH1
1401HHEtSO22-H2NCOHC4H6NHH1
1402HHEtSO23-FHC4H6NHH1
1403HHEtSO23-ClHC4H6NHH1
1404HHEtSO23-CH3HC4H6NHH1
1405HHEtSO23-CF3HC4H6NHH1
1406HHEtSO23-H2NCOHC4H6NHH1
1407HFH3CSO2HHC4H6NHH0
1408HFH3CSO22-FHC4H6NHH0
1409HFH3CSO22-ClHC4H6NHH0
1410HFH3CSO22-CH3HC4H6NHH0
1411HFH3CSO22-CF3HC4H6NHH0
1412HFH3CSO22-H2NCOHC4H6NHH0
1413HFH3CSO23-FHC4H6N HH0
1414HFH3CSO23-ClHC4H6NHH0
1415HFH3CSO23-CH3HC4H6NHH0
1416HFH3CSO23-CF3HC4H6NHH0
1417HFH3CSO23-H2NCOHC4H6NHH0
1418HFH3CSO2HHC4H6NHH1
1419HFH3CSO22-FHC4H6NHH1
1420HFH3CSO22-ClHHH1
1421HFH3CSO22-CH3HC4H6NHH1
1422HFH3CSO22-CF3HC4H6NHH1
1423HFH3CSO22-H2NCOHC4H6NHH1
1424HFH3CSO23-FHC4H6NHH1
1425HFH3CSO23-ClHC4H6NHH1
1426HFH3CSO23-CH3HC4H6NHH1
1427HFH3CSO 3-CF3HC4H6NHH1
1428HFH3CSO23-H2NCOHC4H6NHH1
1429HFEtSO2HHC4H6NHH0
1430HFEtSO22-FHC4H6NHH0
1431HFEtSO22-ClHC4H6NHH0
1432HFEtSO22-CH3HC4H6NHH0
1433HFEtSO22-CF3HC4H6NHH0
1434HFEtSO2 2-H2NCOHC4H6NHH0
1435HFEtSO23-FHC4H6NHH0
1436HFEtSO23-ClHC4H6NHH0
1437HFEtSO23-CH3HC4H6NHH0
1438HFEtSO23-CF3HC4H6NHH0
1439HFEtSO23-H2NCOHC4H6NHH0
1440HFEtSO2HHC4H6NHH1
1441HFEtSO2HC4H6NHH1
1442HFEtSO22-ClHC4H6NHH1
1443HFEtSO22-CH3HC4H6NHH1
1444HFEtSO22-CF3HC4H6NHH1
1445HFEtSO22-H2NCOHC4H6NHH1
1446HFEtSO23-FHC4H6NHH1
1447HFEtSO23-ClHC4H6NHH1
1448HFEtSO23-CH3 HC4H6NHH1
1449HFEtSO23-CF3HC4H6NHH1
1450HFEtSO23-H2NCOHC4H6NHH1
1451HFEtOOC-MSHHC4H6NHH0
1452HFEtOOC-MS2-FHC4H6NHH0
1453HFEtOOC-MS2-ClHC4H6NHH0
1454HFEtOOC-MS2-CH3HC4H6NHH0
1455HFEtOOC-MS2-CF3HC4 H6NHH0
1456HFEtOOC-MS2-H2NCOHC4H6NHH0
1457HFEtOOC-MS3-FHC4H6NHH0
1458HFEtOOC-MS3-ClHC4H6NHH0
1459HFEtOOC-MS3-CH3HC4H6NHH0
1460HFEtOOC-MS3-CF3HC4H6NHH0
1461HFEtOOC-MS3-H2NCOHC4H6NHH0
1462HFEtOOC-MSHHC4H6NHH
1463HFEtOOC-MS2-FHC4H6NHH1
1464HFEtOOC-MS2-ClHC4H6NHH1
1465HFEtOOC-MS2-CH3HC4H6NHH1
1466HFEtOOC-MS2-CF3HC4H6NHH1
1467HFEtOOC-MS2-H2NCOHC4H6NHH1
1468HFEtOOC-MS3-FHC4H6NHH1
1469HFEtOOC-MS3-ClHC4H6NHH1
1470H FEtOOC-MS3-CH3HC4H6NHH1
1471HFEtOOC-MS3-CF3HC4H6NHH1
1472HFEtOOC-MS3-H2NCOHC4H6NHH1
1473HFHOOC-MSHHC4H6NHH0
1474HFHOOC-MS2-FHC4H6NHH0
1475HFHOOC-MS2-ClHC4H6NHH0
1476HFHOOC-MS2-CH3HC4H6NHH0
1477HFHOOC-MS2-CF3C4H6NHH0
1478HFHOOC-MS2-H2NCOHC4H6NHH0
1479HFHOOC-MS3-FHC4H6NHH0
1480HFHOOC-MS3-ClHC4H6NHH0
1481HFHOOC-MS3-CH3HC4H6NHH0
1482HFHOOC-MS3-CF3HC4H6NHH0
1483HFHOOC-MS3-H2NCOHC4H6NHH0
1484HFHOOC-MSHHC4H6NH H1
1485HFHOOC-MS2-FHC4H6NHH1
1486HFHOOC-MS2-ClHC4H6NHH1
1487HFHOOC-MS2-CH3HC4H6NHH1
1488HFHOOC-MS2-CF3HC4H6NHH1
1489HFHOOC-MS2-H2NCOHC4H6NHH1
1490HFHOOC-MS3-FHC4H6NHH1
1491HFHOOC-MS3-ClHC4H6NHH1
1492FHOOC-MS3-CH3HC4H6NHH1
1493HFHOOC-MS3-CF3HC4H6NHH1
1494HFHOOC-MS3-H2NCOHC4H6NHH1

The preferred compounds among the compounds mentioned above as examples are compounds represented by numbered 14 (example 27), 21 (example 41), 22 (example 47), 23 (example 49), 25 (example 53), 26 (example 55), 53 (example 65), 54 (example 67), 81 (example 59), 82 (example 61), 85 (example 45), 109 (example 77), 110 (example 79), 137 (example 71), 138 (example 73), 507 (example 6), 518 (example 28), 523 (example 38), 525 (example 42), 526 (example 48), 527 (example 50), 529 (example 54), 530 (example 56), 557 (example 66), 558 (example 68), 585 (example 60), 586 (example 62), 589 (example 46), 613 (example 78), 614 (example 80), 641 (example 72), 642 (example 74), 1027 (example 89), 1029 (example 94), 1081 (example 86) and 1099 (example 87),

especially preferred are compounds

the dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (example connected to the I No. 14, example

27),

the dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-formamidopyrimidine-4-yloxy)phenyl]sulfamerazine (example compound No. 22, example 47),

the dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(1-aminopropyl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 23, example 49),

the dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 25, example 53),

the dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-were]sulfamerazine (example compound No. 53, example 65),

the dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-triptoreline]sulfamerazine (example compound No. 109, example 77),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-isopropylpiperazine-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 507, example 6),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 518, example 28),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-cyclopentenopyridine-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 523, etc which measures 38),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(indolin-7-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 525, example 42),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-formamidopyrimidine-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 526, example 48),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(1-aminopropyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 527, example 50),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 529, example 54),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-were]sulfamoylbenzoic acid (example compound No. 557, example 66),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 585, example 60),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)-3-triptoreline]sulfamoylbenzoic acid (example compound No. 589, example 46),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-triptoreline]sulfamoylbenzoic acid (example compound No. 613, example 78),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 641, example 72),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1027, example 89),

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1029, example 94)

the dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(N-atinformation)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1099, example 87).

Connection (1) according to the present invention can be obtained in the following ways :

In the above reaction schemes, R1, R2, R3, R4, R5, R6, R7, R8and n have the meanings specified above. R1ais a protected group, R1or a group containing a protected Deputy in R1; R3ais a protected group, R3or a group containing a protected Deputy in R3; R4ais a protected group, R 4or a group containing a protected Deputy in R4; R5ais a protected group, R5or a group containing a protected Deputy in R5; and R6ais a protected group, R6or a group containing a protected Deputy in R6. R6bis an R6aor a protective group for amino. Pro represents a protective group for hydroxyl group. X represents a halogen atom or a hydroxyl group.

Method a is a method of obtaining compound (1) according to the present invention.

(Stage 1)

This stage is a method of obtaining compounds of General formula (4), which is carried out by reaction of a combination of compounds of General formula (2) with the compound of General formula (3) in the presence of phosphine and azo compounds in an inert solvent.

There is no specific limitations to the solvent used in stage 1, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. This solvent is an aliphatic hydrocarbon, such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, chetyrekh the East carbon dichloroethane, chlorobenzene or dichlorobenzene; or an ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; preferably halogenated hydrocarbons (dichloromethane) or an ether (particularly diethyl ether or tetrahydrofuran).

The phosphine used in stage 1 represents, for example, three-(C1-C6-alkylphosphine, such as trimethylphosphine, triethylphosphine, tripropyltin, tributylphosphine, triphenylphosphine, trihexalon or similar phosphine; tri-(C6-C10-arylphosphine, such as triphenylphosphine, TryEngineering, trination or similar phosphine; or three-(C6-C10-arylphosphine, where this aryl group may be optionally substituted (C1-C4)-alkyl group, such as maildefinition, trailerforum, trimethyltin, tributylphosphine, three-6-ethyl-2-natterposted or similar phosphine; preferably three-(C1-C6-alkylphosphine (in particular, trimethylphosphine, triethylphosphine, tripropyltin or tributylphosphine) or three-(C6-C10-arylphosphine (particularly triphenylphosphine, TryEngineering or trination), and preferably tributylphosphine or triphenylphosphine.

Uzasadnienie used in stage 1 is, e.g the measures azodicarbonamide or di-(C1-C4-alkylenedioxy, such as diethylazodicarboxylate, diethylazodicarboxylate, dipropylthiocarbamate or dibutyldithiocarbamate; preferably azodicarbonamide, diethylazodicarboxylate or diethylazodicarboxylate.

The reaction temperature in stage 1 changes depending on the starting compounds and reagents. As a rule, it is in the range from -50 to 100°and preferably, ranges from 0 to 60°C.

The reaction time in stage 1 changes depending on the starting compounds, reagents and the reaction temperature. Typically, it ranges from 5 minutes to 24 hours and preferably ranges from 10 minutes to 6 hours.

At the end of the interaction the desired compound obtained in stage 1, can be isolated from the reaction mixture in the usual way. For example, if the reaction mixture has an insoluble substance, the reaction mixture is filtered and the filtrate is concentrated and receive the remainder. Or at the end of the interaction, the reaction mixture was concentrated and then the residue is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent. The organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the outdoor product. If necessary, the product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

(Stage 2)

This stage is a method of obtaining compounds of General formula (1), which is carried out by using the required reaction:

reaction (a) transformation of ceanography in amidinopropane,

and, if necessary, using the appropriate combination of the following optional reactions:

reaction (b) - delete a group protecting the amino group,

reaction (C) introducing the desired substituent in the amino group,

reaction (d) hydrolysis of ester, and

the reaction of (e) - delete a group protecting the hydroxyl group.

Binding reaction (a), consisting in the transformation of ceanography in amidinopropane, can be done in the usual way known to experts in the art, for example,

(1) the interaction of the original substance with alcohol in the presence of acid in the presence or absence of an inert solvent (preferably in the presence of an inert solvent) followed by ammonolysis product interaction (simple aminoether), or

(2) the interaction of the original substance with hydroxylamine in the presence or in the absence of a base in an inert solvent, followed by hydrolysis of the product interaction is (amidoxime).

Reaction (a)(1) is a two-stage reaction, the first stage is the interaction of the nitrile group with an alcohol in the presence of acid with the formation of simple aminoether.

There is no specific limitations to the solvent used in the first reaction stage (a)(1), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone or methyl ethyl ketone; esters such as methyl acetate or ethyl acetate; nitrosoaniline, such as nitromethane; amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxide such as dimethylsulfoxide or sulfolane; or a mixture thereof; preferably an aromatic hydrocarbon (particularly benzene) or halogenated hydrocarbons (for instance the and, dichloromethane), and preferably a halogenated hydrocarbon (particularly dichloromethane).

The interaction can also be carried out in an excess of alcohol (e.g. methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; preferably methanol or ethanol) as the solvent, and the interaction, as a rule, is carried out in alcohol, provided that the obstacles are not available.

The acid used in the first reaction stage (a)(1)represents, for example, mineral acid such as hydrogen chloride, hydrochloric acid, Hydrobromic acid, uudistoodetena acid, nitric acid, Perlina acid, sulfuric acid or phosphoric acid; sulfonic acid such as methanesulfonate acid, triftormetilfullerenov acid, econsultancy acid, benzolsulfonat acid or p-toluensulfonate acid; or a Lewis acid such as boron TRIFLUORIDE, aluminum chloride, ferric chloride, zinc chloride, or chloride of mercury (II); preferably mineral acid or a Lewis acid, preferably hydrogen chloride.

The reaction temperature in the first reaction stage (a)(1) varies depending on the starting compounds and reagents. As a rule, it is in the range from -10 to 100°S, and is preferably from 0 to 50°C.

The reaction time for the first hundred and the AI reaction (a)(1) varies depending on the starting compounds, the reagents and the reaction temperature. As a rule, it is in the range from 10 minutes to 48 hours and preferably ranges from 1 hour to 15 hours.

At the end of the interaction the desired compound obtained in the first reaction stage (a)(1), can be isolated from the reaction mixture in the usual way (for example, the concentration of the reaction mixture). The reaction product (a)(1) can be used in the subsequent reaction without isolation or purification.

The second reaction stage (a)(1) represents the ammonolysis reaction of simple aminoether obtained in the first stage, which is usually carried out in the presence of ammonium ions in an inert solvent.

There is no specific limitations to the solvent used in the second reaction stage (a)(1), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, alcohol such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; water or mixture of alcohol and water. Preferred solvents are methanol, ethanol, water, aqueous methanol or aqueous ethanol, and particularly preferred solvents are aqueous methanol or aqueous ethanol.

The source of ammonium ions in the second reaction stage (a)(1) is, for example, water ammonia is containing a series of solution, ammonium chloride, ammonium carbonate, or mixtures thereof, preferably ammonium chloride.

In the second reaction stage (a)(1) pH ranges from neutral to slightly alkaline. Preferably adjusted to 7-9 using water ammoniagenesis solution and hydrochloric acid.

The reaction temperature in the second reaction stage (a)(1) varies depending on the starting compounds and reagents. As a rule, it is in the range from -10 to 100°and preferably, ranges from 0 to 50°C.

The reaction time in the second reaction stage (a)(1) varies depending on the starting compounds, reagents and the reaction temperature. As a rule, it is in the range from 10 minutes to 48 hours and preferably ranges from 1 hour to 15 hours.

At the end of the interaction of the desired compound are obtained in the second reaction stage (a)(1), can be isolated from the reaction mixture in the usual way. For example, the reaction mixture was concentrated and get the desired connection or the reaction mixture is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent; the organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate, and get the right product. If necessary, the product can be cleaned additionally conventional methods is AMI, such as recrystallization, pereosazhdeniya, chromatography or the like

The reaction in stage (a)(2) is a two-step reaction, the first reaction is the interaction of nitrile groups with hydroxylamine in inetnum solvent, optionally in the presence of a base, with the formation of amidoxime.

There is no specific limitations to the solvent used in the first reaction stage (a)(2), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone or methyl ethyl ketone; nitrosoaniline, such as nitromethane; a nitrile such as acetonitrile or isobutyronitrile; alcohol, such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; an amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-is ethyl-2-pyrrolidinone; sulfoxide, such as dimethylsulfoxide or sulfolane; or water; preferably an alcohol (particularly methanol or ethanol).

Source of hydroxylamine used in the first reaction stage (a)(2)is an aqueous solution or organic solution of hydroxylamine or additive salt of the acid and hydroxylamine.

There is no special restrictions on the base used in the first reaction stage (a)(2), provided that when using the additive salt of the acid and hydroxylamine, it can neutralize the specified additive salt of the acid (when use solution of hydroxylamine, the base used is not always), and so the base is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal acetate such as sodium acetate; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium or lithium methoxide; or an organic base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1.5-disabi is yclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably a carbonate of an alkali metal (particularly sodium carbonate or alkoxide of the alkali metal (in particular, tert-piperonyl potassium).

The reaction temperature in the first reaction stage (a)(2) varies depending on the starting compounds and reagents. Typically, it ranges from 0 to 150°and preferably, ranges from 50 to 100°C.

The reaction time in the first reaction stage (a)(2) varies depending on the starting compounds, reagents and the reaction temperature. Typically, it ranges from 1 hour to 24 hours and preferably ranges from 5 hours to 12 hours.

At the end of the interaction the desired compound obtained in the first reaction stage (a)(2), can be isolated from the reaction mixture in the usual way (for example, the concentration of the reaction mixture). The reaction product can be used in the subsequent reaction without isolation and purification.

The second stage of the reaction (a)(2) is the hydrogenation amidoxime obtained in the first reaction stage (a)(2).

Before hydrogenation of the hydroxyl group modify the accession of the deleted group, which, as a rule, is acetyl group, and the acetylation reaction carried out using acetic anhydride in acetic acid, if necessary, to dissolve the barely.

There is no specific limitations to the solvent for the acetylation reaction, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone or methyl ethyl ketone; nitrosoaniline, such as nitromethane; or a nitrile such as acetonitrile or isobutyronitrile; preferably halogenated hydrocarbon (particularly dichloromethane) or an ether (particularly tetrahydrofuran).

The temperature of the acetylation reaction varies depending on the starting compounds and reagents. Typically, it ranges from 0 to 150°S, and preferably is from 10 to 50°C.

Time acetylation reaction varies depending on the starting compounds, reagents and the reaction temperature. As a rule, it is in the interval is from 1 hour to 24 hours and preferably ranges from 5 hours to 12 hours.

At the end of the interaction the desired compound obtained by acetylation, can be isolated from the reaction mixture in the usual way (for example, the concentration of the reaction mixture). The reaction product can be used in the subsequent reaction without isolation or purification.

Hydrogenation amidoxime (diacetoxyscirpenol acetylated hydroxyl group), as a rule, carried out in the same solvent in which carry out the first step of the reaction (a)(2) (acetylation). However, if necessary the solvent from the first reaction stage (a)(2) (acetylation) is distilled off, the residue is dissolved in another solvent and then carry out the hydrogenation (diacetoxyscirpenol).

There is no specific limitations to the solvent for the hydrogenation provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or the methyl ether of diethylene glycol; ketone, such as acetone or methyl ethyl ketone; nitrosoaniline, such as nitromethane; a nitrile such as acetonitrile or isobutyronitrile; alcohol, such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; an amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxide such as dimethylsulfoxide or sulfolane; carboxylic acid such as formic acid or acetic acid; water; or mixtures thereof; preferably an alcohol (particularly methanol or ethanol), acetic acid or their mixture.

There is no special limitation as the catalyst for catalytic reduction, provided that it is usually used in the catalytic reduction. This catalyst is, for example, palladium black, palladium-on-charcoal, palladium hydroxide, palladium hydroxide-on-charcoal, Raney Nickel, rhodium-alumina, palladium-barium sulfate, platinum oxide or platinum black; preferably palladium-on-charcoal grill.

The reaction temperature in the second reaction stage (a)(2) varies depending on the starting compounds and reagents. As a rule, it is in the range from -10 to 100°and preferably, ranges from 0 to 80°C.

The reaction time in the second reaction stage (a)(2) varies depending on the starting compounds, reagents and the reaction temperature. As p is Avila, it is in the interval from 1 hour to 24 hours and preferably ranges from 5 hours to 12 hours.

At the end of the interaction of the desired compound are obtained in the second reaction stage (a)(2), can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is filtered to remove the catalyst, then concentrate the filtrate and get the desired connection or the filtrate is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent; the organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate, and get the right product. If necessary, the resulting product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

“Deleting a group protecting the amino group” as an optional reaction (b) stage 2, carried out according to a conventional method known to specialists in this field of technology, as follows.

When a group protecting the amino group is formyl, acetyl, benzyl, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, 2-trimethylsilylethynyl, 2-bromo-tert-butoxycarbonyl, 2,2-dibromo-tert-butoxycarbonyl, vinyloxycarbonyl, benzyloxycarbonyl, (1-phenyl)benzyloxy boil, 9-antimetastasis, p-methoxybenzenesulfonyl or p-nitrobenzisoxazole group specified protective group can be removed by treating compound that contains the specified protective group, an acid in an inert solvent or in an aqueous solvent. This interaction the desired product can be obtained in the form of additive salts of the acid.

The acid used in this method is, for example, hydrochloric acid, sulfuric acid, phosphoric acid, Hydrobromic acid or triperoxonane acid; preferably hydrochloric acid, sulfuric acid, Hydrobromic acid or triperoxonane acid.

There is no specific limitations to the solvent for this reaction is the removal of the protective group, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Dima is oxetan or dimethyl ether of diethylene glycol; ester such as methyl acetate or ethyl acetate; an alcohol such as methanol, ethanol, propanol, 2-propanol or butanol; an amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorotriamide; sulfoxide such as dimethylsulfoxide or sulfolane; aliphatic acid such as formic acid or acetic acid; water; or mixtures thereof; preferably a halogenated hydrocarbon, a simple ether, alcohol, aliphatic acid or a mixture thereof, and preferably a halogenated hydrocarbon (particularly dichloromethane), a simple ether (in particular, tetrahydrofuran or dioxane), aliphatic acid (particularly acetic acid) or an alcohol (particularly methanol or ethanol), water or a mixture.

The reaction temperature for the removal of the protective group varies depending on the starting compounds, solvent and acid used. As a rule, it is in the range from -10 to 150°and preferably, ranges from 0 to 100°C.

The response time of the removal of the protective group varies depending on the starting compounds, solvent and acid used. As a rule, it is in the interval from 5 minutes to 48 hours, and preferably is from 10 minutes to 15 hours.

At the end of the interaction the desired compound obtained by the method (b) stage 2, you can select from the reaction specialicing way. For example, the reaction mixture is filtered, and receive the desired compound in the form of a precipitate; optionally, the reaction mixture is neutralized and the neutralized mixture is concentrated to dryness, and get the desired connection; or to the reaction mixture, water is added, if necessary, the aqueous mixture is neutralized, water or neutralized mixture is extracted with a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or the like substance, concentrate, and get the right product. If necessary, the resulting product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

When a group protecting the amino group is alkanoyl, arylcarbamoyl, alkoxycarbonyl, alkenylacyl, aprildecember aralkyl or aracelikarsaalyna group specified protective group can be removed by treating compound that contains the specified protective group, a base in an inert solvent or in an aqueous solvent.

The basis used at this stage is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal, such as hydroca beat sodium, hydrogen potassium or lithium bicarbonate; alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium or lithium methoxide; alkali metal mercaptan, such as methylmercaptan sodium or ethyl mercaptan sodium, or an organic base such as hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably a carbonate of an alkali metal (particularly sodium carbonate or potassium carbonate), hydroxide of alkaline metal (in particular sodium hydroxide or potassium hydroxide), alkali metal alkoxide (in particular, sodium methoxide, ethoxide or sodium tert-piperonyl potassium) or an organic base (in particular, hydrazine or methylamine).

There is no specific limitations to the solvent for this reaction is the removal of the protective group, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. One is them is the solvent, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohol, such as methanol, ethanol, propanol, 2-propanol or butanol; an amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorotriamide; sulfoxide such as dimethylsulfoxide or sulfolane; water or a mixture of water and an organic solvent, specified previously; preferably a halogenated hydrocarbon, a simple ester, alcohol or a mixture of water and an organic solvent, specified previously, and preferably a simple ether (particularly tetrahydrofuran or dioxane), an alcohol (particularly methanol or ethanol)or a mixture of water and a solvent indicated previously.

The reaction temperature for the removal of the protective group varies depending on the starting compounds, solvent, and used grounds. As a rule, it is in the range from -10 to 50°and is preferably from -5 to 10°C.

The response time of the removal of the protective group is changed for the threaded depending on starting compounds, the solvent and the base. Typically, it ranges from 5 minutes to 20 hours and preferably ranges from 10 minutes to 3 hours.

At the end of the interaction the desired compound obtained by the reaction of removing the protective group, can be isolated from the reaction mixture in the usual way. For example, the sludge precipitated from the reaction mixture, is filtered off and get the desired connection; if necessary, after the interaction, the reaction mixture is neutralized with acid, neutralized mixture of concentrate and get the desired connection; to the reaction mixture, water is added, set the pH of the mixture and obtain the desired compound in the form of loose sediment; or water with adjusted pH is extracted with a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent, the organic layer washed with water, the organic layer is dried over anhydrous magnesium sulfate or the like substance, and then the organic layer is concentrated and get the desired connection. If necessary, the resulting product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

When a group protecting the amino group is tert-butoxycarbonyl group specified protective group can be removed is by treating compound, containing the specified protective group, siliconebased compound or a Lewis acid in an inert solvent.

Silicomanganese connection used this interaction represents, for example, trimethylsilyloxy, trimethylsilylmethyl or trimethylsilyltrifluoromethane. The Lewis acid used in this interaction represents, for example, aluminum chloride or similar connection.

There is no specific limitations to the solvent for this reaction is the removal of the protective group, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; or a nitrile, such as acetonitrile, preferably a halogenated hydrocarbon (particularly dichloromethane or chloroform) or a nitrile (particularly acetonitrile).

The reaction temperature for the removal of the protective group varies depending on the starting compounds, reagents and solvent used. As a rule, it is in the range from -20 to 100°and is preferably from 0 to 50°C.

The response time of the removal of the protective GRU the dust varies depending on the starting compounds, reagents and solvent used. As a rule, it is in the range from 10 minutes to 10 hours and preferably from 30 minutes to 3 hours.

At the end of the interaction the desired compound obtained by the reaction of removing the protective group, can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is concentrated and to the residue is added water, the mixture is alkalinized, then filtered and receive the right product or aqueous mixture is extracted with a solvent immiscible with water such as benzene, ether, ethyl acetate, or similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or the like substance, concentrate, and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

When a group protecting the amino group is allyloxycarbonyl group, the protective group can be removed in the same way as for Uralkaliy group or the like, for example, by catalytic regeneration, i.e. by treating compound with the specified protective group palladium and triphenylphosphine or tetracarbonyl Nickel.

When a group protecting the amino group is kalkilya or (C7-C 11)-aracelikarsaalyna group specified protective group can be removed by treating compound with the specified protective group of a reducing agent (preferably by catalytic reduction in the presence of a catalyst or oxidizing agent in an inert solvent.

There is no specific limitations to the solvent for catalytic reduction, provided that it has no adverse effect on the reaction. Such a solvent is, for example, aliphatic hydrocarbons such as hexane or cyclohexane; an aromatic hydrocarbon such as benzene, toluene or xylene; a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; an ester such as ethyl acetate or propyl; an alcohol, such as methanol, ethanol or 2-propanol; aliphatic acid such as formic acid or acetic acid; or a mixture of water and a solvent indicated previously, preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a simple ether, ester, alcohol, aliphatic acid or a mixture of water and solvent indicated previously, and preferably an alcohol (particularly methanol or ethanol), aliphatic acid (in particular formic acid or acetic acid) or a mixture of water and a solvent indicated previously.

There is no special limitations related and catalyst for catalytic reduction provided what it is usually used in the catalytic reduction. This catalyst is, for example, palladium-on-charcoal, Raney Nickel, rhodium-aluminum oxide or palladium-barium sulfate; preferably palladium-on-coal or Raney Nickel.

There is no special limitation on the hydrogen pressure in the catalytic reduction. The pressure generally is in the range from 1 to 10 atmospheric pressure, preferably is 1 atmospheric pressure.

The reaction temperature catalytic reduction varies depending on the starting compounds, solvent, used reducing agent, etc. and usually ranges from 0 to 100°and is preferably from 10 to 50°C.

The reaction time of the catalyst bed varies depending on the starting compounds, solvent, used reducing agent, the reaction temperature, etc. and usually ranges from 15 minutes to 24 hours and preferably from 30 minutes to 12 hours.

At the end of the interaction the desired compound is obtained by catalytic regeneration, can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is filtered to remove the catalyst from the reaction mixture, the filtrate is concentrated and get the desired connection; to the reaction cosiderable water, the aqueous mixture is alkalinized and then the alkaline mixture is filtered and receive the desired compound in the form of precipitated precipitated substance; or the mixture is extracted with a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the resulting product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

There is no specific limitations to the solvent for the reaction of removing the protective group by means of an oxidising agent, provided that it has no adverse effect on the reaction. Such a solvent is, for example, a ketone such as acetone; halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; NITRILES, such as acetonitrile; a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorotriamide; sulfoxide such as dimethylsulfoxide; or a mixture of water and an organic solvent indicated previously, preferably a ketone, a halogenated hydrocarbon, a nitrile, a simple ester, amide, sulfoxide a mixture of water and an organic solvent, specified previously, and preferably the ketone (particularly acetone), halogenated hydrocarbon (particularly dichloromethane), a nitrile (particularly acetonitrile), amide (in particular, hexamethylphosphorotriamide), sulfoxide (in particular, dimethyl sulfoxide or a mixture of water and an organic solvent, specified previously.

The oxidizing agent used in the reaction of removing the protective group is, for example, potassium persulfate, sodium persulfate, suryamaninagar (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and preferably CAN or DDQ.

The reaction temperature oxidative removal of the protective group varies depending on the source of the substance, solvent and used as oxidant. Typically, it ranges from 0 to 150°and is preferably from 10 to 50°C.

The reaction time of the oxidative removal of the protective group varies depending on the source of the substance, solvent and used as oxidant. Typically, it ranges from 15 minutes to 24 hours and preferably from 30 minutes to 12 hours.

At the end of the interaction the desired compound obtained by oxidative removal of the protective group, can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is filtered to remove the oxidant from the reaction mixture, the filtrate to the will centerour and get the desired product; to the reaction mixture are added water, the mixture is alkalinized and then the alkaline mixture is filtered and receive the desired compound in the form of precipitated precipitated substance; or the mixture is extracted with a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

Optional reaction (C) is a way of introducing the desired substituent in the amino group, which carried out the recovery of the original substance reagent of formula R6-Xa where XA represents a halogen atom (particularly, fluorine atom or chlorine) or alkoxygroup (in particular, methoxy - or ethoxypropan)) in an inert solvent in the presence or in the absence of base.

There is no specific limitations to the solvent used for the reaction (C), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbon, Taco is as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone or methyl ethyl ketone; nitrosoaniline, such as nitromethane; a nitrile such as acetonitrile or isobutyronitrile; alcohol, such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone; or a sulfoxide such as dimethylsulfoxide or sulfolane; preferably an alcohol (particularly ethanol).

The base used in the reaction (C)is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; or an organic base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylene is in, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably a carbonate of an alkali metal (particularly sodium carbonate or potassium carbonate) or an organic base (in particular, triethylamine).

The reaction temperature (C) varies depending on the starting compounds, reagents, etc. As a rule, it is in the range from 10 to 100°and is preferably from 0 to 50°C.

Reaction time (s) varies depending on the starting compounds, reagents and the reaction temperature. Typically, it ranges from 1 hour to 48 hours and preferably ranges from 5 hours to 15 hours.

At the end of the interaction the desired compound obtained by the reaction of (C), can be isolated from the reaction mixture in the usual way. For example, the reaction mixture was concentrated and get the desired connection or the reaction mixture is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the resulting product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography is whether other

Optional reaction (d) is a method of hydrolysis of the ether”, which is carried out by hydrolysis of the original substance with acid or base in the presence or in the absence of a solvent according to the traditional method, known to experts in the art, preferably by hydrolysis of the compounds with acid.

There is no specific limitations to the solvent used for the reaction (d), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, alcohol such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol, or a mixture of water and alcohol, specified previously; preferably aqueous methanol or aqueous ethanol.

The acid used in the reaction (d)is, for example, mineral acid such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, nitric acid, Perlina acid, sulfuric acid or phosphoric acid; sulfonic acid such as methanesulfonate acid, triftormetilfullerenov acid, econsultancy acid, benzolsulfonat acid or p-toluensulfonate acid; or a carboxylic acid such as fumaric acid, succinic acid, lim is fair acid, tartaric acid, oxalic acid, maleic acid or a similar acid, preferably a mineral acid, in particular hydrochloric acid).

The base used in the reaction (d)is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; preferably sodium hydroxide.

The reaction temperature (d) varies depending on the starting compounds used reagents, etc. When using acid, as a rule, the temperature is in the range from 0 to 150°and is preferably from 50 to 100°C. When using a base, as a rule, the temperature is in the range from -10 to 50°and is preferably from -5 to 10°C.

Reaction time (d) varies depending on the starting compounds used reagents and temperature. When using acid, as a rule, it is in the range from 30 minutes to 48 hours and preferably ranges from 3 hours to 10 hours. When using the base, usually it is in the interval from 5 minutes to 10 hours and is preferably from 10 minutes to 3 hours.

Optional reaction (e) is a way of removing the protective group of the protected hydroxyl group”, which is carried out according to the method described by T.W. Greene &P.G.M. Wuts in “Protective Groups in Organic Synthesis”, 3rdedition, John Wiley & Sons, Inc.

When a group protecting the hydroxyl group is F. Ramil, acetyl, benzoyl, tetrahydropyran-2-yl, 3-bromotetradecane-2-yl, 4-methoxyacridine-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytryptamine-4-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroacetyl, bis(2-chloroethoxy)methyl, 1-ethoxyethyl, 1-(isopropoxy)ethyl methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, 2-trimethylsilylethynyl, 2-bromo-tert-butoxycarbonyl, 2,2-dibromo-tert-butoxycarbonyl, vinyloxycarbonyl, benzyloxycarbonyl, (1-phenyl)benzyloxycarbonyl, 9-antimetastasis, p-methoxybenzenesulfonyl or p-nitrobenzenesulfonyl group, such a protective group can be removed by treating compound that contains the specified protective group, an acid in an inert solvent or aqueous solvent.

The acid used in the reaction (e)is, for example, hydrochloric acid, sulfuric acid, phosphoric acid, Hydrobromic acid or triperoxonane acid, preferably hydrochloric acid, sulfuric acid, Hydrobromic acid or triperoxonane acid.

There is no specific limitations to the solvent used for the reaction (e), provided that is has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; esters such as methyl acetate or ethyl acetate; an alcohol such as methanol, ethanol, propanol, 2-propanol or butanol; an amide such as formamide N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorotriamide; sulfoxide such as dimethylsulfoxide or sulfolane; aliphatic acid such as formic acid or acetic acid; water; or a mixture of water and an organic solvent indicated previously, preferably halogenated hydrocarbons, simple, ether, ester, alcohol, aliphatic acid or a mixture of water and an organic solvent, specified previously, and preferably a halogenated hydrocarbon (particularly dichloromethane), a simple ether (particularly tetrahydrofuran or dioxane), esters (in particular, the ethyl acetate), aliphatic acid (particularly acetic acid), water or a mixture of water and organic Rast is orites, specified previously.

The reaction temperature in the reaction (e) varies depending on the starting compounds, solvent and acid used. As a rule, it is in the range from -10 to 150°and is preferably from 0 to 60°C.

The reaction time in the reaction (e) varies depending on the source of the substance, solvent and acid used. Typically, it ranges from 5 minutes to 20 hours and preferably ranges from 10 minutes to 12 hours.

At the end of the interaction the desired compound obtained by the reaction of (e), can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is optionally neutralized, concentrated and get the desired connection or the reaction mixture is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate, and get the right product. If necessary, the resulting product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

When a group protecting the hydroxyl group is alkanoyl, carboxypropanoyl alkanoyl, halogenoalkanes, alkoxyalkanols, nenasi the military alkanoyl, arylcarbamoyl, halogenoalkanes, alkilirovanny arylcarbamoyl, carboxypropanoyl arylcarbamoyl, nitride arylcarbamoyl, alkoxycarbonylmethyl arylcarbamoyl or areleaving arylcarbamoyl, such a protective group can be removed by treating compound that contains the specified protective group, a base in an inert solvent or aqueous solvent.

The base used in the reaction (e)is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium or lithium methoxide; alkali metal mercaptan, such as methylmercaptan sodium or ethyl mercaptan sodium, or an organic base such as hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene DBU), preferably the carbonate of an alkali metal (particularly sodium carbonate or potassium carbonate), hydroxide of alkaline metal (in particular sodium hydroxide or potassium hydroxide), alkali metal alkoxide (in particular, sodium methoxide, ethoxide or sodium tert-piperonyl potassium) or an organic base (in particular, hydrazine or methylamine).

There is no specific limitations to the solvent for the reaction (e), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohol, such as methanol, ethanol, propanol, 2-propanol or butanol; an amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorotriamide; sulfoxide such as dimethylsulfoxide or sulfolane; or a mixture of water and a solvent indicated previously, preferably halogenated who hydrocarbon, simple ether, alcohol or a mixture of water and a solvent indicated previously, and preferably a simple ether (particularly tetrahydrofuran or dioxane), an alcohol (particularly methanol or ethanol) or a mixture of water and a solvent indicated previously.

The reaction temperature in the reaction (e) varies depending on the starting compounds, solvent and base. As a rule, it is in the range from -10 to 150°and is preferably from 0 to 50°C.

The reaction time in the reaction (e) varies depending on the source of the substance, the solvent and the base. Typically, it ranges from 5 minutes to 20 hours and preferably ranges from 10 minutes to 5 hours.

At the end of the interaction the desired compound obtained by the reaction of (e), can be isolated from the reaction mixture in the usual way. For example, the reaction mixture was concentrated and get the desired connection; then the reaction mixture is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate, or similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally conventional methods, such as per the crystallization, pereosazhdeniya, chromatography or the like

When a group protecting the hydroxyl group, is kalkilya or aracelikarsaalyna group, such a protective group can preferably be removed by treating compound that contains the specified protective group, a reducing agent (preferably by catalytic reduction in the presence of a catalyst or oxidizing agent in an inert solvent.

There is no specific limitations to the solvent for the reaction of removing the protective group by catalytic regeneration, provided that it has no adverse effect on the reaction. Such a solvent is, for example, aliphatic hydrocarbons such as hexane or cyclohexane; an aromatic hydrocarbon such as benzene, toluene or xylene; a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; an ester such as ethyl acetate or propyl; an alcohol, such as methanol, ethanol or 2-propanol; aliphatic acid such as formic acid or acetic acid; or a mixture of water and an organic solvent indicated previously, preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a simple ether, ester, alcohol, aliphatic acid or a mixture water and organic solvent, as specified previously, and preferably the alcohol (the company and, methanol or ethanol), aliphatic acid (in particular formic acid or acetic acid) or a mixture of water and an organic solvent, specified previously.

There is no special limitation as the catalyst for catalytic reduction, provided that it can generally be used in the catalytic reduction. This catalyst is, for example, palladium-on-charcoal, Raney Nickel, rhodium-aluminum oxide or palladium-barium sulfate, and preferably palladium-on-coal or Raney Nickel.

There is no special limitation on the hydrogen pressure in the catalytic reduction. The pressure generally is in the range from 1 to 10 atmospheric pressure, preferably is 1 atmospheric pressure.

The reaction temperature catalytic reduction varies depending on the starting compounds, solvent, used reducing agent, etc. As a rule, it is in the range from 0 to 100°and is preferably from 10 to 50°C.

The reaction time of the catalyst bed varies depending on the starting compounds, solvent, used reducing agent, the reaction temperature, etc. As a rule, it is in the interval from 15 minutes to 10 hours and preferably from 30 minutes to 3 hours.

At the end of shimodate the desired connection, obtained by catalytic regeneration, can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is filtered to remove the catalyst from the reaction mixture, the filtrate is concentrated and the residue is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

There is no specific limitations to the solvent for the reaction of removing the protective group by means of an oxidising agent, provided that it has no adverse effect on the reaction. Such a solvent is, for example, a ketone such as acetone; halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; NITRILES, such as acetonitrile; a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorotriamide; sulfoxide such as dimethylsulfoxide; or a mixture of water and an organic solvent indicated previously, the provision of the equipment - ketone, halogenated hydrocarbon, a nitrile, a simple ester, amide, sulfoxide, or a mixture of water and an organic solvent, specified previously, and preferably the ketone (particularly acetone), halogenated hydrocarbon (particularly dichloromethane), a nitrile (particularly acetonitrile), amide (in particular, hexamethylphosphorotriamide), sulfoxide (in particular, dimethyl sulfoxide or a mixture of water and an organic solvent, specified previously.

The oxidizing agent used in the reaction of removing the protective group is, for example, potassium persulfate, sodium persulfate, suryamaninagar (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and preferably CAN or DDQ.

The reaction temperature when the reaction of oxidative removal of the protective group varies depending on the starting compounds, solvent, and used as oxidant, etc. As a rule, it is in the range from 0 to 150°and is preferably from 10 to 50°C.

The reaction time in the reaction of oxidative removal of the protective group varies depending on the starting compounds, solvent, and used as oxidant, etc. As a rule, it is in the interval from 15 minutes to 24 hours and preferably from 30 minutes to 5 hours.

At the end of the interaction the desired compound obtained by oxidative removal of the protective group, is possible the shape of the reaction mixture in the usual way. For example, the reaction mixture is filtered to remove the oxidant from the reaction mixture, the filtrate is concentrated and the residue is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent, the organic layer washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

When a group protecting the hydroxyl group is a silyl group, such a protective group can be removed by interaction of compounds containing the specified protective group, with a compound which forms a fluoride ion, in an inert solvent.

There is no specific limitations to the solvent to remove protective silyl group, provided that it has no adverse effect on the reaction and dissolves the starting material at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons, such to the to dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, preferably a simple ether (particularly tetrahydrofuran).

The connection forming the fluoride anion and used in the reaction, removal of the protective group is, for example, tetrabutylammonium fluoride, hydrofluoric acid in pyridine or potassium fluoride, and preferably of forinternational.

The reaction temperature during the removal of the protective group varies depending on the starting compounds used reagents, etc. As a rule, it is in the range from -50 to 100°and is preferably from -10 to 50°C.

The response time for the removal of the protective group varies depending on the starting compounds used reagents and temperature. As a rule, it is in the interval from 5 minutes to 12 hours and preferably ranges from 10 minutes to 1 hour.

At the end of the interaction the desired compound obtained by the reaction of removing the protective silyl group, can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or beneath the hydrated solvent, the organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

The method is a method of obtaining compounds of General formula (4).

(Stage 3)

Stage 3 is the method of obtaining compounds of General formula (6), which can be accomplished with the help of combination reaction between the compound of General formula (2) and the compound of General formula (5) in the presence of phosphine and azo compounds in an inert solvent.

Stage 3 can be done using the same method described in stage 1.

(Stage 4)

Stage 4 is the method of obtaining compounds of General formula (4), which can be achieved by removal of the protective group protecting the hydroxyl group [reaction (a)], and with the help of combination reaction between the reaction product (a) and the compound of General formula (7)

[where R6a, R7, R8and n have the meanings indicated previously, the reaction (b)].

Reaction (a) can be done using the same method described for the reaction of (e) in stage 2, and the reaction (b) can be performed using the same method described the La stage 1.

The method is a method of obtaining compounds of General formula (2).

(Stage 5)

Stage 5 is the method of obtaining compounds of General formula (9), which can be done with the cooperation of the compounds of General formula (8) with the compound of the formula (Ph)3PCR2CHO (where Ph represents a phenyl group, and R2matter listed above) in an inert solvent.

There is no specific limitations to the solvent used in stage 5, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or a nitrile, such as acetonitrile, propionitrile or butyronitrile and preferably an aromatic hydrocarbon (particularly benzene or toluene).

The reaction temperature in stage 5 varies depending on the source of vases is in, the used reagents, etc. As a rule, it is in the range from 0 to 150°and is preferably from 30 to 100°C.

Reaction time on stage 5 varies depending on the starting compounds used reagents and temperature. As a rule, it is in the range from 10 minutes to 10 hours and preferably from 30 minutes to 5 hours.

At the end of the interaction the desired compound obtained in stage 5, you can select from the reaction mixture in the usual way. For example, the reaction mixture was concentrated and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya, chromatography or the like

(Stage 6)

Stage 6 is the method of obtaining the compounds of formula (2), which carry out the restoration of the compounds of formula (9) a reducing agent in an inert solvent.

There is no specific limitations to the solvent used in stage 6, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons, such as be the angry toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohol, such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; or their mixture.

When the reducing agent is an aluminum hydride or DIBORANE, the solvent used in stage 6, is an aliphatic hydrocarbon (in particular, hexane or cyclohexane), an aromatic hydrocarbon (particularly benzene, toluene or xylene) or a simple ether (particularly diethyl ether, tetrahydrofuran or dioxane). When the reducing agent is a borohydride, in a solvent used in stage 6, is an alcohol (particularly methanol or ethanol) or a mixture of alcohol and halogenated hydrocarbon (in particular, a mixture of ethanol and dichloromethane).

The reducing agent used in stage 6, is an aluminum hydride, such as alumalite lithium, diisobutylaluminum or similar connection; sodium borohydride or DIBORANE, preferably sodium borohydride. In addition, when the reductant used sodium borohydride can be used cerium chloride as a catalyst.

Temperature reacts and on stage 6 varies depending on the starting compounds, the used reagents, etc. As a rule, it is in the range from -78 to 100°and is preferably from 0 to 50°C.

Reaction time on stage 6 varies depending on the starting compounds used reagents and temperature. As a rule, it is in the range from 10 minutes to 12 hours and preferably from 30 minutes to 5 hours.

At the end of the interaction the desired compound obtained in stage 6, you can select from the reaction mixture in the usual way. For example, the reaction mixture was concentrated, the residue is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent. The organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya or chromatography.

(Stage 7 and stage 8)

Stage 7 and stage 8 are method of obtaining compounds of General formula (11), which can be accomplished by reacting the compounds of formula NSSN2O-Pro (where Pro is the value specified previously) catecholborane in the presence or absence of an inert solvent (preferably, in the absence of a trade the aqueous solvent (stage 7)and by interacting compounds received at stage 7, with the compound of General formula (10) in the presence of a base and a palladium catalyst in an inert solvent (stage 8).

There is no specific limitations to the solvent used in stage 7, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; or an ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, and preferably aliphatic hydrocarbon (in particular, hexane or petroleum ether or an aromatic hydrocarbon (particularly toluene).

The reaction temperature in stage 7 varies depending on the starting compounds used reagents, etc. As a rule, it is in the range from 10 to 100°and is preferably from 30 to 80°C.

Reaction time on stage 7 varies depending on the starting substances of reagents used and the temperature is s. As a rule, it is in the range from 10 minutes to 10 hours and preferably from 30 minutes to 5 hours.

After the interaction, the desired compound obtained in stage 7, you can select from the reaction mixture in the usual way. For example, the reaction mixture was concentrated and get the right product. In addition, the crude reaction product obtained in stage 7, you can use on stage 8 without purification.

There is no specific limitations to the solvent used in stage 8, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohol, such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; or a mixture thereof; and preferably aromatic hydrocarbon (particularly toluene).

Palladium catalyst used is Tadei 8, is, for example, a complex of palladium and phosphine, such as tetrakis(triphenylphosphine)palladium, a complex of palladium chloride and bis(triphenylphosphine), a complex of palladium chloride and bis(diphenylphosphinite), a complex of palladium acetate and bis(triphenylphosphine), and similar compounds; or a complex of Tris(dibenzylideneacetone)diplodia and chloroform, bis(dibenzylideneacetone)palladium, palladium acetate or chloride dimer-diallylmalonate; preferably tetrakis(triphenylphosphine)palladium, a complex of palladium chloride and bis(triphenylphosphine) or complex of palladium chloride and bis(diphenylphosphinite), and preferably tetrakis(triphenylphosphine)palladium.

The basis used at the stage 8 is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium or lithium methoxide; or an organic base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-e is (DBU), and preferably an alkoxide of an alkali metal (in particular, ethoxide sodium).

The reaction temperature in stage 8 varies depending on the starting compounds, reagents, etc. As a rule, it is in the range from 0 to 150°and is preferably from 50 to 120°C.

Reaction time on stage 8 varies depending on the starting substances of reagents used and the reaction temperature. As a rule, it is in the range from 10 minutes to 10 hours and preferably from 30 minutes to 5 hours.

At the end of the interaction the desired compound obtained in stage 8, can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent. The organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya or chromatography.

(Stage 9)

Stage 9 is the method of obtaining the compounds of formula (2), which can be accomplished by removal of the group protecting the hydroxyl group in the compound of formula (11). Stage 9 can be done is to leave the same way described for the reaction of (e) in stage 2.

(Stage 10)

Stage 10 is the method of obtaining compounds of General formula (14).

When X in the General formula (12) represents a removable group, the stage 10 can be accomplished by reacting the compounds of formula (12) with the compound of General formula (13)

(where R6b, R7, R8and n have the meanings given above) in the presence of a base in an inert solvent [reaction (a)], or when X in the General formula (12) represents a hydroxyl group, the stage 10 can be implemented with the help of combination reaction with elimination of water of the compounds of formula (12) with the compound of General formula (13) in the presence of phosphine and azo compounds in an inert solvent [reaction (b)]. In addition, reaction (b) can be done in the same procedure, which is described for stage 1.

Reaction (a)

There is no specific limitations to the solvent used in stage (a), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons, such as dihormati is, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; nitrosoaniline, such as nitromethane; a nitrile such as acetonitrile or isobutyronitrile; amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxide such as dimethylsulfoxide or sulfolane; and preferably amide (particularly N,N-dimethylformamide or N,N-dimethylacetamide).

The base used in the reaction (a)is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal acetate such as sodium acetate; alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium methoxide or lithium; or an organic base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diately the Lin, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); alkyllithium connection, such as motility, utility or utility; lithium amide, such as diisopropylamide lithium or dicyclohexylamine lithium; and preferably a hydride of an alkali metal (in particular, lithium hydride or sodium hydride), alkali metal alkoxide (in particular, sodium methoxide) or alkyllithium connection (in particular, utility).

The reaction temperature in the reaction (a) varies depending on the starting compounds used reagents etc.

As a rule, it is in the range from -10 to 100°and is preferably from -5 to 50°C.

The reaction time in the reaction (a) varies depending on the starting compounds used reagents and temperature. Typically, it ranges from 5 minutes to 24 hours and preferably ranges from 10 minutes to 12 hours.

At the end of the interaction the desired compound obtained by the reaction of (a), can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is treated with water and a solvent immiscible with water such as benzene, ether, ethyl acetate or a similar solvent. The organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate, and get the desired p is oduct. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya or chromatography.

(Stage 11)

Stage 11 is the method of obtaining compounds of General formula (15), which is carried out when R6bin the compound of General formula (17) differs from R6a. Deleting a group protecting the amino group can be carried out in a manner similar to the method described for reaction (b) in stage 2. In addition, when R6band R6ain the compound of General formula (17) are the same, the stage 11 can be omitted.

(Stage 12)

Stage 12 is the method of obtaining compounds of General formula (16), which is carried out through the following reactions (1), (2) or (3).

Reaction (1), the interaction of the compounds of General formula (15) with a reagent of formula R6-Xa [where Ha represents a halogen atom (particularly chlorine atom or bromine atom) or alkoxygroup (in particular, methoxy group or ethoxypropan)] in the presence of a base in an inert solvent.

Reaction (2), the interaction of the compounds of General formula (15) with a reagent of formula R6-Xa where XA represents a halogen atom (particularly chlorine atom or bromine atom) or triftormetilfullerenov) in the presence of a palladium catalyst, phosphine and a base in a trade is " a solvent.

Reaction (3), the interaction of the compounds of General formula (15) with acyclic ketone containing from 1 to 6 carbon atoms, or a cyclic ketone containing from 3 to 8 carbon atoms, in the presence of acetic acid and cyanoborohydride sodium or triacetoxyborohydride sodium in an inert solvent.

In addition, when miss stage 11, it is also possible to skip the stage 12.

Reaction (1) can be done using a method similar to the method described for reaction (C) in stage 2.

There is no specific limitations to the solvent used in the reaction (2), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohol, such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; or a mixture thereof; and preferably aromatic coal is adored (in particular, toluene).

Palladium catalyst used in the reaction (2)is, for example, a complex of palladium and phosphine, such as tetrakis(triphenylphosphine)palladium, a complex of palladium chloride and bis(triphenylphosphine), a complex of palladium chloride and bis(diphenylphosphinite), a complex of palladium acetate and bis(triphenylphosphine), and similar compounds; or Tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, palladium acetate or chloride dimer-allylpalladium; and preferably palladium acetate or Tris(dibenzylideneacetone)palladium.

The phosphine used in the reaction (2)represents, for example, three-(C1-C6-alkylphosphine, such as trimethylphosphine, triethylphosphine, tripropyltin, tributylphosphine, three-tert-butylphosphine, triphenylphosphine, trihexalon etc.; three-(C6-C10-arylphosphine, such as triphenylphosphine, TryEngineering, trination and the like; or three-(C6-C10-arylphosphine, where this aryl group may be optionally substituted (C1-C4)-alkyl group, such as maildefinition, trailerforum, trimethyltin, tributylphosphine, three-6-ethyl-2-natterposted, and the like; 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2-(dicyclohexylphosphino)-2’-(N,N-dimethylamino)biphenyl and the like; and the site is preferably - three-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl or 2-(dicyclohexylphosphino)-2’-(N,N-dimethylamino)biphenyl.

The base used in the reaction (2)is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl sodium tert-piperonyl potassium or lithium methoxide; or an organic base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably an alkoxide of an alkali metal (in particular, tert-piperonyl sodium).

The reaction temperature in the reaction (2) varies depending on the starting compounds used reagents, etc. As a rule, it is in the range from 0 to 150°and is preferably from 50 to 100°C.

The reaction time in the reaction (2) varies depending on the starting compounds used reagents and temperature. Typically, it ranges from 30 minutes to 24 hours and is preferably 1 to 5 hours.

At the end of the interaction the desired compound obtained by the reaction of (2), can be isolated from the reaction mixture in the usual way. For example, the reaction mixture was concentrated and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya or chromatography.

Acyclic ketone containing from 1 to 6 carbon atoms, used in reaction (3)represents formaldehyde, acetaldehyde, propane-1-he, propane-2-he (acetone), butane-2-it, pentane-2-it, hexane-2-it, etc. and preferably represents acetone. Cyclic ketone containing from 3 to 8 carbon atoms, used in reaction (3)represents cyclopropane, CYCLOBUTANE, Cyclopentanone, cyclohexanone, cycloheptanone and cyclooctanone and preferably represents a Cyclopentanone.

There is no specific limitations to the solvent used in the reaction (3), provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated at levothroid, such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohol, such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; an amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxide such as dimethylsulfoxide or sulfolane; or their mixture, and preferably halogenated hydrocarbons (in particular, dichloromethane), alcohols (particularly methanol or ethanol) or a mixture (in particular, a mixture of dichloromethane and methanol).

The reaction temperature in the reaction (3) varies depending on the starting compounds used reagents, etc. As a rule, it is in the range from -10 to 150°and preferably, ranges from 0 to 100°C.

The reaction time in the reaction (3) varies depending on the starting compounds used reagents and temperature. Typically, it ranges from 10 minutes to 24 hours and preferably ranges from 1 hour to 12 hours.

At the end of the interaction the desired compound obtained by the reaction (3), can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is treated with water and the solvent, necesidades the water, such as benzene, ether, ethyl acetate or a similar solvent. The organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate, and get the right product. If necessary, the resulting product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya or chromatography.

In addition, when miss stage 11, it is also possible to skip the stage 12.

(Stage 13)

Stage 13 is the method of obtaining the compounds of formula (17), which can be done by restoring the compounds of formula (14) or (16) as follows:

according to reaction (1) reaction of recovery carried out using a catalytic reduction in a hydrogen atmosphere at a pressure equal to 1-5 atmospheric pressure (preferably, at a pressure equal to atmospheric) in an inert solvent; or

according to reaction (2) reaction of the restoration carried out in the usual way nitrogroup reduction to the amino group, known to experts in the art, for example, stirring the compound in acetic acid in the presence of metal powder.

There is no specific limitations to the solvent used in the catalytic reduction, provided that it has no adverse effect on reaktsii dissolves source materials at least to some extent. Such a solvent is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohol, such as methanol, ethanol, propanol, 2-propanol, butanol or Isobutanol; or their mixture, and preferably the alcohol (in particular, methanol) or a simple mixture of ether and alcohol (in particular, a mixture of tetrahydrofuran and methanol or ethanol).

There is no special limitation as the catalyst for catalytic reduction, provided that it usually is used in the catalytic reduction. This catalyst is, for example, palladium black, palladium-on-charcoal, palladium hydroxide, palladium hydroxide-on-charcoal, Raney Nickel, rhodium-alumina, palladium-barium sulfate, platinum oxide or platinum black; preferably palladium-on-charcoal grill.

The reaction temperature in the catalytic reduction varies depending on the starting compounds used reagents, etc. As a rule, it is located is in the range from -10 to 100° With and is preferably from 0 to 50°C.

The response time for the catalytic reduction varies depending on the starting compounds used reagents and temperature. As a rule, it is in the range from 10 minutes to 10 hours and preferably from 30 minutes to 6 hours.

At the end of the interaction the desired compound is obtained by catalytic regeneration, can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is filtered and the filtrate is concentrated and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya or chromatography.

The solvent used for the recovery of metal powder is acetic acid, hydrochloric acid, water, alcohol or a mixture of water and an organic solvent, and preferably acetic acid.

The metal powder used in the restoration, represents, for example, zinc dust, powder tin or iron powder, and preferably zinc dust or powder of tin.

The reaction temperature recovery varies depending on the starting compounds used reagents, etc. As a rule, it is in the range from -10 to 100 With and is preferably from 0 to 50°C.

The reaction time of recovery varies depending on the starting compounds used reagents and temperature. As a rule, it is in the range from 10 minutes to 10 hours and preferably from 30 minutes to 3 hours.

At the end of the interaction the desired compound obtained by reduction can be isolated from the reaction mixture in the usual way. For example, the reaction mixture is filtered and the filtrate is concentrated and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya or chromatography.

(Stage 14)

Stage 14 is the method of obtaining compounds of General formula (3), which can be accomplished by reacting the compounds of formula (17) with the compound of General formula R3aHa (where R3ahas the values given above, and XA represents a group to delete) in the presence or in the absence of a base (preferably in the presence of a base) in an inert solvent.

There is no specific limitations to the solvent used in stage 14, provided that it has no adverse effect on the reaction and dissolves the original matter at least to some extent. This will dissolve the LEM is, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone or methyl ethyl ketone; nitrosoaniline, such as nitromethane; a nitrile such as acetonitrile or isobutyronitrile; amide such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidinone; or a sulfoxide such as dimethylsulfoxide or sulfolane; and preferably a halogenated hydrocarbon (particularly dichloromethane), a simple ether (particularly diethyl ether or tetrahydrofuran) or an amide (particularly N,N-dimethylformamide).

The basis used at the stage 14 is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; an alkali metal hydroxide, such as hydroxide n is sodium, the potassium hydroxide or lithium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium or lithium methoxide; or an organic base such as methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably a carbonate of an alkali metal (particularly sodium carbonate or potassium carbonate, bicarbonate of an alkali metal (in particular sodium bicarbonate or potassium bicarbonate) or hydride of an alkali metal (in particular, lithium hydride or sodium hydride).

The reaction temperature in stage 14 varies depending on the starting compounds used reagents, etc. As a rule, it is in the range from 10 to 100°and is preferably from 0 to 50°C.

Reaction time on stage 14 varies depending on the starting compounds used reagents and temperature. Typically, it ranges from 10 minutes to 24 hours and preferably ranges from 1 hour to 12 hours.

At the end of the interaction the desired compound obtained in stage 14, can be isolated from the reaction mixture in the usual way. For example, the reaction mixture formation is anywayt water and solvent, immiscible with water such as benzene, ether, ethyl acetate or a similar solvent. The organic layer is washed with water, dried over anhydrous magnesium sulfate or a similar substance and concentrate and get the right product. If necessary, the thus obtained reaction product can be cleaned additionally, conventional methods such as recrystallization, pereosazhdeniya or chromatography.

The original substance of the formula(5), (7), (8) and (12) are known compounds or can be easily obtained by methods known to experts in the art [see, for example, Bioorg. Med. Chem. Lett., 8, 277 (1998); Tetrahedron letters, 37, 6439 (1996), etc].

The best ways of carrying out the invention

The present invention will be further explained by examples and examples of the compositions, however, the scope of the present invention is not limited to the given examples.

In addition, determine the NMR spectra using tetramethylsilane as an internal standard. Values δ are given in ppm, and constant interaction represented in Hz and evaluated with the approach of 0.5 Hz. The characteristics of interaction used the following abbreviations:

d - doublet,

DD - doublet of doublets,

DDD - double doublet of doublets,

dt - doublet of triplets,

t - triplet,

K - Quartet

m - multiplet,

s - singlet,

<> Ushs broadened or collapsibly singlecompany the observed signal.

Example 1

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (example compound No. 1)

Through a solution of ethyl N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (938 mg)obtained in reference example 7, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 189 mg of the substance in 10 ml of water) and 28% ammonia solution (0.35 ml) and the resulting mixture was stirred at room temperature overnight. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 22% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid, and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and receive specified in the header connect the tion (841 mg, yield 77%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,90-of 2.08 (2H, m), 2,14-of 2.26 (2H, m), is 2.74 (3H, m), 3.00 and-3,10 (2H, m), 3,32 (1H, m), 3,40-3,50 (1H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (2H, d, J=6,0), 4.62, and 4,87 (total 1H, each m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,31 (1H, t, J=9,0), 7,41 (1H, m), 7,55 (1H, t, J=8,0), 7,60 (1H, m), of 7.69 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1737, 1675, 1352, 1156.

Example 2

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 505)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (435 mg)obtained in example 1, is dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 6.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 13% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (1,00 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized, and get mentioned in the title compound (243 mg, yield 59%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,94 and 2.03 (just H, each m), 2,19 (2H, m), is 2.74 (3H, m), 3.00 and-3,10 (2H, m), 3,30-3,50 (2H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), br4.61 and 4,87 (total 1H, each m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,31 (1H, m), 7,41 (1H, m)of 7.55 (1H, t, J=8,0), 7,60 (1H, m), of 7.69 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,88 (1H, s);

IR (KBr, cm-1): 1732, 1676, 1348, 1155.

Example 3

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-ethylpiperazin-4-yloxy)phenyl]sulfamerazine (example compound No. 2)

Through a solution of ethyl N-[3-chloro-4-(1-ethylpiperazin-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1240 mg)obtained in reference example 13, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 7 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 243 mg of the substance in 10 ml of water) and 28% ammonia solution (0,41 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane, and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 22% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture UE is involve in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (807 mg, yield 56%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), of 1.26 (3H, t, J=7,0), 1,92-of 2.08 (2H, m), of 2.21 (2H, m), 2,99 (2H, m)to 3.09 (2H, m), 3,36, and a 3.50 (total 2H, each m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (2H, d, J=6,0), with 4.64 and the 4.90 (total 1H, each m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,31 (1H, m), 7,41 (1H, m), 7,55 (1H, t, J=8,0), 7,60 (1H, m), 7,68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,88 (1H, s);

IR (KBr, cm-1): 1738, 1675, 1353, 1155.

Example 4

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-ethylpiperazin-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 506)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-ethylpiperazin-4-yloxy)phenyl]sulfamerazine (400 mg)obtained in example 3, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 4 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (1,00 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and receive specified in the header of the connection

(324 mg, Vyhod%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,24 (3H, t, J=7,5), to 1.98 (2H, m)to 2.18 (2H, m), 3,05 (2H, m)3,00-3,50 (4H, m), is 4.15 (2H, s), 4,48 (2H, d, J=6,0), and 4.75 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,29 (1H, d, J=9,0), the 7.43 (1H, DD, J=9,0, 2,5), 7,54 (1H, t, J=8,0), a 7.62 (1H, d, J=2,5), to 7.68 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,88 (1H, s);

IR (KBr, cm-1): 1731, 1676, 1348, 1154.

Example 5

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-isopropylpiperazine-4-yloxy)phenyl]sulfamerazine (example compound No. 3)

Through a solution of ethyl N-[3-chloro-4-(1-isopropylpiperazine-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1171 mg)obtained in reference example 17, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 7 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 224 mg in 10 ml water) and 28% ammonia solution (0,42 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack

ODS-A; YMC, eluent 25% acetonitrile/water). The obtained amorphous solid in the society is dissolved in 1 N. hydrochloric acid, and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (904 mg, yield 67%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), of 1.28 (6H, m), 2.00 in a 2.12 (2H, m), 2,18-of 2.36 (2H, m), of 3.07 (2H, m), 3,22-to 3.52 (3H, m), 4,19 (2H, square, J=7,0), 4,42 (2H, m), 4,47 (2H, d, J=6,0), 4,66 and 4.95 (total 1H, each m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,31 (1H, m), 7,41 (1H, m), 7,55 (1H, t, J=8,0), 7,60 (1H, m), 7,68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,88 (1H, s);

IR (KBr, cm-1): 1738, 1675, 1353, 1156.

Example 6

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-isopropylpiperazine-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 507)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-isopropylpiperazine-4-yloxy)phenyl]sulfamerazine (615 mg)obtained in example 5, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 4 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 17% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (1,00 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and receive what is listed in the title compound (433 mg, yield 74%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (6H, d, J=6,5), of 1.97 (2H, m)to 2.18 (2H, m), 2,90 is 3.40 (5H, m)to 3.99 (2H, s), 4,48 (2H, d, J=6,0), and 4.75 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0), 7,27 (1H, d, J=9,0), 7,46 (1H, DD, J=9,0, 2,5), 7,54 (1H, t, J=8.0 a), the 7.65 (1H, d, J=2,5), to 7.67 (1H, d, J=8,0), 7,71 (1H, d, J=8,0), 7,87 (1H, s);

IR (KBr, cm-1): 1677, 1344, 1151.

Example 7

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-butylpiperazine-4-yloxy)-3-chlorophenyl]sulfamerazine (example compound No. 4)

Through a solution of ethyl N-[4-(1-butylpiperazine-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1177 mg)obtained in reference example 21, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 219 mg of the substance in 10 ml of water) and 28% ammonia solution (0,41 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 27% acetonitrile/is Yes). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized, and get mentioned in the title compound (742 mg, yield 55%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 0.93 (3H, t, J=7,5), of 1.23 (3H, t, J=7,0), 1,32 (2H, m)to 1.67 (2H, m), 1,90-of 2.08 (2H, m), 2,15-of 2.28 (2H, m), 2.95 and-3,10 (4H, m), 3,35-to 3.58 (2H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (2H,, d, J=6,0), 4,63 and 4,88 (total 1H, each m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,31 (1H, m), 7,41 (1H, m), 7,55 (1H, t, J=8,0), 7,60 (1H, m), to 7.67 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,87 (1H with);

IR (KBr, cm-1): 1738, 1675, 1353, 1156.

Example 8

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-butylpiperazine-4-yloxy)-3-chlorophenyl]sulfamoylbenzoic acid (example compound No. 508)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-butylpiperazine-4-yloxy)-3-chlorophenyl]sulfamerazine (600 mg)obtained in example 7, is dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 4.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (1,00 ml) and the resulting mixture was evaporated in vacuum dash is. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (450 mg, yield 78%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 0.90 (3H, t, J=7,5), is 1.31 (2H, m)to 1.61 (2H, m), with 1.92 (2H, m)to 2.13 (2H, m), 2,87 (2H, m), 2,90-3,20 (4H, m), a 4.03 (2H, s), 4,48 (2H, d, J=6,0), 4,70 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0), 7,27 (1H, d, J=9,0), was 7.45 (1H, DD, J=9,0, 2,5), 7,54 (1H, t, J=8,0), to 7.64 (1H, d, J=2,5), to 7.67 (1H, d, J=8,0), 7,71 (1H, d, J=8,0), 7,86 (1H, s);

IR (KBr, cm-1): 1676, 1347, 1153.

Example 9

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-benzylpiperidine-4-yloxy)-3-chlorophenyl]sulfamerazine (example compound No. 5)

Through a solution of ethyl N-[4-(1-benzylpiperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1531 mg)obtained in reference example 25, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 233 mg of the substance in 10 ml of water) and 28% ammonia solution (0,40 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride is in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 30% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid, and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (931 mg, yield 53%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,94-of 2.05 (2H, m), 2,16-of 2.28 (2H, m), 3,01 (2H, m), 3,24-3,44 (2H, m), 4,18 (2H, square, J=7,0), or 4.31 (2H, m), and 4.40 (2H, s), to 4.46 (2H, d, J=6,0), 4,59 and 4,88 (total 1H, each m), 6.42 per (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,27 (1H, d, J=9,0), 7,31 (1H, d, J=9,0), 7,38 (1H, m), 7,43-7,51 (3H, m), 7,52-to 7.59 (2H, m), 7,60-7,66 (2H, m), to 7.67 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,87 (1H, s);

IR (KBr, cm-1): 1738, 1675, 1353, 1155.

Example 10

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-benzylpiperidine-4-yloxy)-3-chlorophenyl]sulfamoylbenzoic acid (example compound No. 509)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-benzylpiperidine-4-yloxy)-3-chlorophenyl]sulfamerazine (731 mg)obtained in example 9, was dissolved in 3 N. hydrochloric acid (30 ml) and the resulting mixture was stirred at 60°C for 6.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The amorphous solid is e substance dissolved in 1 N. hydrochloric acid (1,00 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (547 mg, yield 87%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,90-of 2.08 (2H, m), 2,12-of 2.26 (2H, m), 2,92-to 3.02 (2H, m), 3,20-3,50 (2H, m), 4,20-to 4.38 (2H, m), 4,25 (2H, s), to 4.46 (2H, d, J=6,0), br4.61 and a 4.83 (total 1H, each m), 6.42 per (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0), 7,27 (1H, d, J=9,0), 7,39 (1H, DD, J=9,0, 2,5), 7,40-7,50 (3H, m), 7,54 (1H, t, J=8,0), 7,55-the 7.65 (3H, m), 7,66 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), a 7.85 (1H, s);

IR (KBr, cm-1): 1732, 1675, 1349, 1154.

Example 11

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-finetipped-4-yloxy)phenyl]sulfamerazine (example compound No. 6)

Through a solution of ethyl N-[3-chloro-4-(1-finetipped-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1013 mg)obtained in reference example 29, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 174 mg of the substance in 10 ml of water) and 28% ammonia solution (0.33 ml) and the resulting mixture was stirred at the room for the Noah temperature during the night. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 30% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid, and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized, and get mentioned in the title compound (788 mg, yield 68%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,96-2,12 (2H, m), 2,19 of-2.32 (2H, m), 3,02-3,18 (4H, m), 3,24 is 3.40 (2H, m), 3.49 and 3,62 (total 2H, each m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,47 (2H, d, J=6,0), 4,65 and 4,91 (total 1H each m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,22-7,38 (6H, m), 7,41 (1H, m), 7,55 (1H, t, J=8,0), 7,60 (1H, m), 7,68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,88 (1H, s);

IR (KBr, cm-1): 1738, 1675, 1353, 1156.

Example 12

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-finetipped-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 510)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-finetipped-4-yloxy)phenyl]sulfamerazine (588 mg)obtained in example 11, was dissolved in 3 N. hydrochloric acid (30 ml) and the resulting mixture was stirred at 60°C for 6.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. According to the scientists the residue purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (1,00 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (405 mg, yield 72%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 2,02 (2H, m), 2,18-of 2.28 (2H, m), of 3.07 (4H, m), 3,20-to 3.50 (4H, m), 4.26 deaths (2H, s), 4,47 (2H, d, J=6,0), 4,84 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,22-7,39 (6H, m), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), 7,60 (1H, d, J=2,5), to 7.67 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,87 (1H, s);

IR (KBr, cm-1): 1732, 1675, 1349, 1154.

Example 13

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-phenylpiperidine-4-yloxy)phenyl]sulfamerazine (example compound No. 7)

Through a solution of ethyl N-[3-chloro-4-(1-phenylpiperidine-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1440 mg)obtained in reference example 33, in a mixture of dichloromethane (18 ml) and ethanol (18 ml) under ice cooling bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (30 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 233 mg of the substance in 10 ml of water) and 28% ammonia solution (0,49 ml) and the floor is obtained, the mixture is stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 60% acetonitrile/water) and receive an amorphous solid (924 mg). Then to a solution of the obtained solid (254 mg) in ethanol (6 ml) is added 4 n solution of hydrogen chloride in dioxane (0,31 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is dissolved in water and then lyophilized, and get mentioned in the title compound (278 mg, yield 61%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,93 with 2.14 (2H, m), 2,16-is 2.37 (2H, m), 3,17-of 3.94 (4H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,48 (2H, d, J=6,0), is 4.85 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), 7,21 (1H, m), 7,28-to 7.64 (4H, m), 7,34 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.61 (1H, d, J=2,5), of 7.69 (1H, d, J=8,0), 7,74 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1738, 1675, 1353, 1156.

Example 14

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-phenylpiperidine-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 511)

Ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-phenylpiperidine-4-yloxy)phenyl]sulfamerazine (676 mg)obtained in example 13, was dissolved in a mixture of 3 N. hydrochloric acid (9 ml) and dioxane (3 ml) and the resulting mixture was stirred at 80°C for 6 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative In the LC (YMC-Pack ODS-A; YMC, eluent 40% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (10 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (385 mg, yield 53%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,88-of 2.08 (2H, m), 2,10 of-2.32 (2H, m), 3.04 from-3,91 (4H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), 4,82 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,11 (1H, m), 7,26-7,49 (4H, m), 7,32 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), 7,60 (1H, d, J=2,5), to 7.68 (1H, d, J=8,0), 7,74 (1H, d, J=8,0), 7,88 (1H, s);

IR (KBr, cm-1): 1733, 1676, 1349, 1155.

Example 15

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methoxycarbonylmethylene-4-yloxy)phenyl]sulfamerazine (example compound No. 8)

Through a solution of ethyl N-[3-chloro-4-(1-methoxycarbonylmethylene-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1700 mg)obtained in reference example 37, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 7 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 227 mg washes the VA in 10 ml of water) and 28% ammonia solution (0,42 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 35% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid, and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (950 mg, yield 48%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,84 of-2.32 (4H, m), 2,90-3,68 (4H, m), 3,76 (3H, s), 4,19 (2H, square, J=7,0), 4,30 (2H, m)to 4.41 (2H, s), 4,47 (2H, d, J=6,0), 4,63 and 4,84 (total 1H, each m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,30 (1H, m), 7,40 (1H, m), 7,55 (1H, t, J=8,0), to 7.59 (1H, m), 7,68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,87 (1H, s);

IR (KBr, cm-1): 1742, 1675, 1353, 1156.

Example 16

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-carboxyethylidene-4-yloxy)-3-chlorophenyl]sulfamoylbenzoic acid (example compound No. 512)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methoxycarbonylmethylene-4-yloxy)phenyl]sulfamerazine (810 mg)obtained in example 15, was dissolved in 3 N. hydrochloric acid (30 ml) and the resulting mixture was stirred at 60°C for 15 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. Received mod is to cleanse preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (581 mg, yield 76%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,91-2,07 (2H, m), 2,14-of 2.28 (2H, m), 3.00 and-are 3.90 (4H, m)to 4.16 (2H, s), 4,28 (2H, s), 4,47 (2H, d, J=6,0), 4,65 and 4,84 (total 1H, each m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,32 (1H, m), 7,42 (1H, DD, J=9,0, 2,5), 7,54 (1H, t, J=8,0), 7,60 (1H, d, J=2,5), 7,72 (2H, m), to $ 7.91 (1H, s);

IR (KBr, cm-1): 1737, 1676, 1348, 1155.

Example 17

Hydrochloride ethyl N-[4-(1-acetylpiperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-amidinophenoxy)-2-(E)-propenyl]sulfamerazine (example compound No. 9)

Through a solution of ethyl N-[4-(1-acetylpiperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (733 mg)obtained in reference example 39, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 175 mg of the substance in 10 ml of water) and 28% ammonia solution (0,22 ml) and polucen the second mixture is stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 35% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (488 mg, yield 64%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), of 1.55 (1H, m), of 1.65 (1H, m)of 1.84 (1H, m)of 1.93 (1H, m), a 2.01 (3H, s), 3,28-3,44 (2H, m), 3,56-and 3.72 (2H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), to 4.46 (2H, d, J=6,0), of 4.75 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,29 (1H, d, J=9,0), 7,38 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), EUR 7.57 (1H, d, J=2,5), to 7.67 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,86 (1H, s);

IR (KBr, cm-1): 1739, 1677, 1354, 1157.

Example 18

The hydrochloride of N-[4-(1-acetylpiperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-amidinophenoxy)-2-(E)-propenyl]sulfamoylbenzoic acid (example compound No. 513)

Hydrochloride ethyl N-[4-(1-acetylpiperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-amidinophenoxy)-2-(E)-propenyl]sulfamerazine (352 mg)obtained in example 17, was dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 6 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The obtained residue eyes which indicate preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (0,50 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (109 mg, yield 32%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,54 (1H, m), of 1.65 (1H, m)and 1.83 (1H, m), with 1.92 (1H, m), from 2.00 (3H, s), 3,30-3,70 (4H, m), 3,83 (2H, s), 4,48 (2H, d, J=6,0), 4,71 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,53 (1H, d, J=16,0), 7,26 (1H, d, J=9,0), of 7.48 (1H, DD, J=9,0, 2,5), 7,52 (1H, t, J=8,0), 7,66 (1H, d, J=8,0), to 7.68 (1H, d, J=2,5), 7,71 (1H, d, J=8,0), a 7.85 (1H, s);

IR (KBr, cm-1): 1682, 1345, 1152.

Example 19

Hydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-carbamoylbiphenyl-4-yloxy)-3-chlorophenyl]sulfamerazine (example compound No. 10)

Through a solution of ethyl N-[4-(1-carbamoylbiphenyl-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1015 mg)obtained in reference example 43, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 194 mg of the substance in 10 ml of water) and 28% ammonia solution (0,36 ml) and the resulting mixture was stirred at room the temperature during the night. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 30% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (737 mg, yield 66%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,46 is 1.58 (2H, m), 1,80-1,89 (2H, m), 3,15-3,24 (2H, m), 3,49-of 3.60 (2H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), to 4.46 (2H, d, J=6,0), and 4.68 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,28 (1H, d, J=9,0), 7,38 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), EUR 7.57 (1H, d, J=2,5), to 7.68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,87 (1H, s);

IR (KBr, cm-1): 1738, 1675, 1352, 1156.

Example 20

The hydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-carbamoylbiphenyl-4-yloxy)-3-chlorophenyl]sulfamoylbenzoic acid (example compound No. 514)

Hydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-carbamoylbiphenyl-4-yloxy)-3-chlorophenyl]sulfamerazine (600 mg)obtained in example 19 was dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparations the active HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is suspended in water containing dioxane (one drop) and then lyophilized and get listed in the title compound (466 mg, yield 81%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,48 is 1.58 (2H, m), 1,80-1,90 (2H, m), 3,14-3,24 (2H, m), 3,50-3,60 (2H, m), 4,27 (2H, s), to 4.46 (2H, d, J=6,0), of 4.67 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,27 (1H, d, J=9,0), 7,38 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), EUR 7.57 (1H, d, J=2,5), to 7.67 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,86 (1H, s);

IR (KBr, cm-1): 1676, 1348, 1155.

Example 21

Hydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methanesulfonamido-4-yloxy)phenyl]sulfamerazine (example compound No. 11)

Through a solution of ethyl N-[3-chloro-4-(1-methanesulfonamido-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (835 mg)obtained in reference example 47, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 150 mg of prophetic is TBA in 10 ml of water) and 28% ammonia solution (0,19 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane, and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 40% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (685 mg, 75%yield) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,72-to 1.82 (2H, m), 1.93 and-2,03 (2H, m), 2,89 (3H, s), 3,12-up 3.22 (2H, m), 3,24 is 3.40 (2H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (2H, d, J=6,0), 4,70 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,28 (1H, d, J=9,0), 7,39 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), 7,58 (1H, d, J=2,5), to 7.67 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), a 7.85 (1H, s);

IR (KBr, cm-1): 1739, 1677, 1346, 1156.

Example 22

The hydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methanesulfonamido-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 515)

Hydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methanesulfonamido-4-yloxy)phenyl]sulfamerazine (502 mg)obtained in example 21 were dissolved in 3 G. hydrochloric acid (20 ml) and dioxane (5 ml) and the resulting mixture was stirred at 60°C for 5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. the received residue purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25~50% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (346 mg, yield 72%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,72-to 1.82 (2H, m), 1.93 and-2,03 (2H, m), 2,89 (3H, s), 3,12-3,20 (2H, m), 3,23 is 3.40 (2H, m), Android 4.04 (2H, s), 4,48 (2H, d, J=6,0), and 4.68 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0), 7,26 (1H, d, J=9,0), 7,44 (1H, DD, J=9,0, 2,5), 7,54 (1H, t, J=8,0), 7,63 (1H, d, J=2,5), to 7.67 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,86 (1H, s);

IR (KBr, cm-1): 1679, 1344, 1155.

Example 23

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 12)

Through a solution of ethyl N-[3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1095 mg)obtained in reference example 51, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 197 mg of the substance in 10 ml of water) and 28% ammonia solution (0,37 ml) and the resulting mixture was stirred at room t is mperature during the night. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 50% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (533 mg, yield 42%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,72-of 1.84 (2H, m), 2,01 and 2.13 (2H, m), 3,68-with 3.79 (2H, m), 3,88-3,99 (2H, m), 4,20 (2H, square, J=7,0), 4,43 (2H, s), 4,48 (2H, d, J=6,0), is 4.85 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), 6,92 (1H, m), 7,35 (1H, d, J=9,0), 7,32-7,44 (1H, m), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), of 7.70 (1H, d, J=8,0), 7,74 (1H, d, J=8.0 a), of 7.90 (1H, s), of 7.96 (1H, m), 8,02 (1H, d, J=4,5);

IR (KBr, cm-1): 1738, 1674, 1353, 1155.

Example 24

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 516)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (533 mg)obtained in example 23, dissolved in 3 N. hydrochloric acid (30 ml) and the resulting mixture was stirred at 60°C for 6 hours. After cooling to room temperature the reaction mixture is evaporated in is the Aquum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 30~50% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (427 mg, yield 84%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,71-to 1.82 (2H, m), 2,01-2,12 (2H, m), 3,63 of 3.75 (2H, m), 3,85-of 3.97 (2H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), 4,84 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 6,89 (1H, m), 7,33 (1H, d, J=9,0), 7,30-7,40 (1H, m), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), to 7.68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,88 (1H, s), to 7.93 (1H, m), 8,02 (1H, J=6,0);

IR (KBr, cm-1): 1733, 1676, 1349, 1155.

Example 25

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 13)

Through a solution of ethyl N-[3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (490 mg)obtained in reference example 55, in a mixture of dichloromethane (15 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature overnight in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (9 ml) are added successively water dissolve the ammonium chloride obtained by dissolving 79 mg in 3 ml water) and 28% ammonia solution (0.17 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 40% acetonitrile/water), and receive an amorphous solid (306 mg). Then to a solution of the obtained solid (44 mg) in ethanol (4 ml) is added 4 n solution of hydrogen chloride in dioxane (0.05 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (47 mg, yield 58%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,69-to 1.82 (2H, m), 1,96-of 2.08 (2H, m), 3,42 (2H, m), 3,66 (2H, m), 4,19 (2H, square, J=7,0), 4,43 (2H, s), 4,47 (2H, d, J=6,0), 4,80 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), 7,33 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), of 7.69 (1H, d, J=8,0), 7,74 (1H, d, J=8.0 a), of 7.75 (1H, DD, J=9,0, 5,0), 7,89 (1H, s), 8,03 (1H, DD, J=9,0, 2,5), of 8.15 (1H, d, J=5,0), 8,48 (1H, d, J=2,5);

IR (KBr, cm-1): 1737, 1675, 1352, 1155.

Example 26

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 517)

Ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (247 mg)obtained in example 25, dissolved in 3 N. hydrochloric acid (12 ml) and the resulting mixture was stirred at 60°C for 4 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. Obtained OST the current clean preparative HPLC (YMC-Pack ODS-A; YMC, eluent 27% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (10 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (427 mg, yield 84%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,69-of 1.81 (2H, m), 1,97-of 2.08 (2H, m), 3,42 (2H, m)to 3.67 (2H, m), the 4.29 (2H, s), 4,47 (2H, d, J=6,0), 4,80 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,33 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), of 7.69 (1H, d, J=8,0), 7,74 (1H, d, J=8,0), to 7.77 (1H, DD, J=9,0, 5,5), 7,89 (1H, s), of 8.04 (1H, DD, J=9,0, 2,0), of 8.15 (1H, d, J=5.5), the 8,48 (1H, d, J=2,0);

IR (KBr, cm-1): 1731, 1675, 1348, 1154.

Example 27

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 14)

Through a solution of ethyl N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (637 mg)obtained in reference example 59, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 5.5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively water rest the R of ammonium chloride (obtained by dissolving 115 mg of the substance in 10 ml of water) and 28% ammonia solution (of 0.21 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 27% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (456 mg, yield 62%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,72-to 1.82 (2H, m), 2.00 in of 2.10 (2H, m), 3,71 (2H, m), 3,86 (2H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,48 (2H, d, J=6,0), to 4.87 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), of 7.23 (2H, J=7,5), 7,34 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), to 7.68 (1H, d, J=8,0), 7,74 (1H, d, J=8,0), 7,88 (1H, s), 8,24 (2H, d, J=7,5);

IR (KBr, cm-1): 1738, 1675, 1352, 1155.

Example 28

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 518)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (315 mg)obtained in example 27, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 8 hours. After cooling to room temperature the reaction mixture is pariwat in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (0,50 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (286 mg, yield 95%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,70-1,80 (2H, m), 1,99-of 2.09 (2H, m), of 3.69 (2H, m), 3,85 (2H, m), 4.26 deaths (2H, s), 4,47 (2H, d, J=6,0), a 4.86 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,22 (2H, d, J=7,5), 7,33 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), of 7.69 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,89 (1H, s), 8,24 (2H, d, J=7,5);

IR (KBr, cm-1): 1731, 1675, 1347, 1154.

Example 29

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 15)

Through a solution of ethyl N-[3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1590 mg)obtained in reference example 63, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 7 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of chlorine is Yes ammonium (obtained by dissolving 285 mg of the substance in 10 ml of water) and 28% ammonia solution (of 0.53 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 27% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (1280 mg, yield 70%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,58 by 1.68 (2H, m), 1,89 of 1.99 (2H, m), 3,68 (2H, m), Android 4.04 (2H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (2H, d, J=6,0), 4,80 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), 6,63 (1H, t, J=4,5), 7,31 (1H, d, J=9,0), 7,39 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), EUR 7.57 (1H, d, J=2,5), to 7.67 (1H, d, J=8,0), 7,74 (1H, d, J=8,0), 7,86 (1H, s), at 8.36 (2H, d, J=4,5);

IR (KBr, cm-1): 1740, 1676, 1348, 1151.

Example 30

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 519)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]phenyl]sulfamerazine (800 mg)obtained in example 29, dissolved in 3 N. hydrochloric acid (40 ml) and the resulting mixture was stirred at 60°C for 9 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. Received the first residue purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 35~50% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (673 mg, yield 88%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,60-1,70 (2H, m), 1,90-2,00 (2H, m), 3,60-of 3.80 (2H, m), 4,00-4,10 (2H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), to 4.81 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), of 6.68 (1H, t, J=5,0), 7,31 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), 7,58 (1H, d, J=2,5), of 7.69 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,89 (1H, s), 8,40 (2H, J=5,0);

IR (KBr, cm-1): 1732, 1675, 1345, 1154.

Example 31

Trihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 16)

Through a solution of ethyl N-[3-chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (945 mg)obtained in reference example 67, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6.5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 166 mg substances which in 10 ml of water) and 28% ammonia solution (0,31 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (328 mg, yield 29%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,96-of 2.09 (2H, m), 2,18-2,31 (2H, m), of 3.07 (2H, m), of 3.33 and 3.46 (total 2H, each m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,42-to 4.52 (2H, m), 4,46 (2H, d, J=6,0), 4.62, and 4,89 (total 1H, each m)to 6.43 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,30 (1H, m), 7,40 (1H, m), 7,55 (1H, t, J=8,0), 7,58 (1H, s), to 7.68 (1H, d, J=8,0), 7,72 (1H, d, J=8.0 a), of 7.75 (1H, m), 7,87 (1H, s), at 8.36-8,48 (1H, m), 8,79 (1H, d, J=4,5), 8,96 (1H, m);

IR (KBr, cm-1): 1736, 1674, 1350, 1154.

Example 32

Trihydrochloride N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 520)

Trihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]phenyl]sulfamerazine (175 mg)obtained in example 31, dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 60°C for 8 hours. After cooling to room rate is atory the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15~20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (74 mg, yield 44%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,97-2,12 (2H, m), 2,17-of 2.34 (2H, m), 3.00 and-3,17 (2H, m), of 3.33 and 3.46 (total 2H, each m), 4,27 (2H, s), 4,47 (2H, d, J=6,0), 4,48-4,56 (2H, m), 4.62, and the 4.90 (total 1H, each m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,30 (1H, m), of 7.36 was 7.45 (1H, m), 7,54 (1H, t, J=8,0), 7,58 (1H, s), of 7.69 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,83-to 7.93 (2H, m), at 8.60 (1H, m), 8,86 (1H, d, J=5.0)and 9,06 (1H, m);

IR (KBr, cm-1): 1731, 1675, 1347, 1155.

Example 33

Trihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4-pyridylmethyl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 17)

Through a solution of ethyl N-[3-chloro-4-[1-(4-pyridylmethyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (971 mg)obtained in reference example 72, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 7 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) to ablaut consistently aqueous solution of ammonium chloride (obtained by dissolving 171 mg of the substance in 10 ml of water) and 28% ammonia solution (0,32 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 10~35% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (580 mg, yield 49%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,98-of 2.16 (2H, m), 2,16-to 2.40 (2H, m), of 3.07 (2H, m), 3,32 and 3,44 (total 2H, each m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), to 4.46 (2H, d, J=6,0), of 4.44-4,56 (2H, m), 4.62, and the 4.90 (total 1H, each m)to 6.43 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,30 (1H, m), 7,40 (1H, m), 7,54 (1H, t, J=8,0), 7,58 (1H, s), to 7.68 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,88 (1H, s), 8,00 (2H, m), 8,82 (2H, m,);

IR (KBr, cm-1): 1737, 1675, 1351, 1155.

Example 34

Trihydrochloride N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4-pyridylmethyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 521)

Trihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4-pyridylmethyl)piperidine-4-yloxy]phenyl]sulfamerazine (440 mg)obtained in example 33, dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 60°C for 2 hours. After cooling to room temperature the reaction with the ect evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 10~20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized, and get mentioned in the title compound (155 mg, yield 37%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,97-of 2.16 (2H, m), 2,16-to 2.40 (2H, m), 3,10 (2H, m), 3,32 and 3,44 (total 2H, each m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), 4,56 (2H, m), br4.61 and 4,90 (total 1H, each m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,31 (1H, m), 7,41 (1H, m), 7,54 (1H, t, J=8,0), to 7.59 (1H, s), 7,71 (2H, m), of 7.90 (1H, s), 8,18 (2H, m), 8,91 (2H, m);

IR (KBr, cm-1): 1731, 1675, 1347, 1154.

Example 35

Trihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 18)

Through a solution of ethyl N-[3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1727 mg)obtained in reference example 77, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6.5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively water RA is solution of ammonium chloride (obtained by dissolving 296 mg of the substance in 10 ml of water) and 28% ammonia solution (to 0.72 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25~30% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (944 mg, yield 45%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 2,00-2,12 (2H, m), 2.21 are of 2.33 (2H, m), 3,10-3,70 (4H, m), 3,48-of 3.60 (4H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,48 (2H, d, J=6,0), 4,82 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,33 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), 7,60 (1H, d, J=2,5), to 7.67 to 7.75 (1H, m), of 7.70 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,80 (1H, m), of 7.90 (1H, s), compared to 8.26 (1H, m), 8,73 (1H, d, J=5,0);

IR (KBr, cm-1): 1736, 1674, 1350, 1154.

Example 36

Trihydrochloride N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 522)

Trihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]phenyl]sulfamerazine (400 mg)obtained in example 35, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 4.5 hours. After cooling to room temperature the reaction is mesh evaporated in vacuum.

The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 17% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (201 mg, yield 52%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 2,00-2,12 (2H, m), 2,20 of-2.32 (2H, m), 3,20-of 3.60 (4H, m), 3,39-of 3.48 (2H, m), 3,50-3,59 (2H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), to 4.81 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), to 7.32 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), 7,50-7,58 (1H, m), 7,55 (1H, t, J=8,0), 7,58-7,66 (1H, m), 7,60 (1H, d, J=2,5), of 7.69 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,89 (1H, s), 8,07 (1H, m), 8,65 (1H, d, J=4,5);

IR (KBr, cm-1): 1730, 1675, 1347, 1154.

Example 37

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-cyclopentenopyridine-4-yloxy)phenyl]sulfamerazine (example compound No. 19)

Through a solution of ethyl N-[3-chloro-4-(1-cyclopentenopyridine-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (of 1.30 g)obtained in reference example 81, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) add members is consequently an aqueous solution of ammonium chloride (obtained by dissolving 0.24 g of the substance in 10 ml of water) and 28% ammonia solution (0.45 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (1.20 g, yield 80%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,47 is 1.60 (2H, m), 1,64 to 1.76 (2H, m), 1,76-1,90 (2H, m), 1,94-2,12 (4H, m), 2,16-of 2.36 (2H, m), to 3.02 (2H, m), 3,32-3,55 (3H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,48 (2H,, d, J=6,0), 4,68, and to 4.92 (total 1H, each m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,32 (1H, m), 7,42 (1H, m), 7,55 (1H, t, J=8,0), 7,60 (1H, m), 7.68 per-7,76 (2H, m), 7,92 (1H, s);

IR (KBr, cm-1): 1739, 1674, 1354, 1156.

Example 38

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-cyclopentenopyridine-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 523)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-cyclopentenopyridine-4-yloxy)phenyl]sulfamerazine (790 mg)obtained in example 37, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 4.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. Receiving the hydrated residue purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (522 mg, yield 69%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,48-to 1.63 (2H, m), and 1.63 to 1.76 (2H, m), 1,76-of 1.88 (2H, m), 1.93 and is 2.10 (4H, m), of 2.15 to 2.35 (2H, m), 2.91 in-3,13 (2H, m), 3,20-3,59 (3H, m), 4.26 deaths (2H, s), 4,47 (2H, d, J=6,0), 4,66, and 4,91 (total 1H, each m), 6,45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,31 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.61 (1H, d, J=2,5), of 7.69 (1H, d, J=8,0), 7,73 (1H, d, J=8.0 a), of 7.90 (1H, s);

IR (KBr, cm-1): 1732, 1676, 1348, 1155.

Example 39

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)phenyl]sulfamerazine (example compound No. 20)

Through a solution of ethyl N-[3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1100 mg)obtained in reference example 89, in a mixture of dichloromethane (20 ml) and ethanol (20 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 4 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (25 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 20 mg of the substance in 5 ml of water) and 28% ammonia solution (0.54 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (0,40 ml) and the resulting mixture was evaporated in vacuum, and get mentioned in the title compound (420 mg, yield 33%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), of 1.33 (3H, d, J=6,5), 1,70-of 1.85 (1H, m), 1.85 to a 2.00 (1H, m), of 2.20 to 2.35 (2H, m)of 2.75 (3H, s), 3,05 is 3.15 (1H, m), of 3.25 to 3.35 (1H, m), 3,45-3,55 (1H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (2H, d, J=6,0)and 4.65 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,33 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), to 7.68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,87 (1H, s);

IR (KBr, cm-1): 1738, 1675.

Example 40

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 524)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)phenyl]sulfamerazine (260 mg)obtained in example 39, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 4 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The amorphous solid is e substance dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (220 mg, yield 89%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.33 (3H, d, J=6,5), 1,70-1,80 (1H, m), 1.85 to 1,95 (1H, m), of 2.20 to 2.35 (2H, m), was 2.76 (3H, s), 3,05 is 3.15 (1H, m), 3,20-to 3.35 (1H, m), 3.45 points-of 3.60 (1H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), with 4.64 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,33 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), to 7.68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,86 (1H, C);

IR (KBr, cm-1): 1733, 1676.

Example 41

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(indolin-7-yloxy)phenyl]sulfamerazine (example compound No. 21)

Through a solution of ethyl N-[3-chloro-4-(indolin-7-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (600 mg)obtained in reference example 95, in a mixture of dichloromethane (20 ml) and ethanol (20 ml) under cooling with ice bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 3 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (25 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 130 mg of the substance in 5 ml of water) and 28% ammonia solution (0,29 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The obtained residue cleaned the Ute preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). To a solution of the amorphous solid in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (0,20 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (140 mg, yield 20%) as a yellow amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,60 TO 2.35 (8H, m), 3.00 and-3,10 (2H, m), of 3.25 to 3.35 (1H, m), 3,45-3,55 (2H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (2H, d, J=6,0), to 4.98 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,30-to 7.35 (1H, m), 7,40 was 7.45 (1H, m), 7,55 (1H, t, J=8,0), 7,55-the 7.65 (1H, m), 7,68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,87 (1H, s);

IR (KBr, cm-1): 1738, 1675.

Example 42

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(indolin-7-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 525)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(indolin-7-yloxy)phenyl]sulfamerazine (130 mg)obtained in example 41, dissolved in 3 N. hydrochloric acid (15 ml) and the resulting mixture was stirred at 60°C for 3 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness, and which are square-specified in the title compound (110 mg, yield 88%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,60 to 2.35 (8H, m), 2.95 and-3,10 (2H, m), 3,15-3,50 (3H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), 4,99 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,30-to 7.35 (1H, m), 7,40 was 7.45 (1H, m), at 7.55 (1H, t, J=8,0), 7,55-the 7.65 (1H, m), of 7.69 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1734, 1675.

Example 43

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (example compound No. 57)

Through a solution of ethyl N-[3-(3-cyanophenyl)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (570 mg)obtained in reference example 99, in a mixture of dichloromethane (20 ml) and ethanol (20 ml) under cooling with ice bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 4 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 140 mg of the substance in 5 ml of water) and 28% ammonia solution (0,31 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent to 17.5% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (10 ml) is added 4 n solution of chloride in Dorada in dioxane (0,22 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (150 mg, yield 22%) as a pale yellow amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1.85 to 2.05 is (2H, m), 2.05 is was 2.25 (2H, m), by 2.73 (3H, s), 3.00 and is 3.15 (2H, m), 3,20-3,30 (1H, m), 3,40-3,50 (1H, m), 4,20 (2H, square, J=7,0), 4,34 (2H, s), of 4.44 (2H, d, J=6,0), 4,50-4,60 and 4,70-4,80 (total 1H, each m), to 6.43 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0), 7,00-7,10 (2H, m), 7,35-7,45 (2H, m), 7,54 (1H, t, J=8,0), to 7.68 (1H, d, J=8,0), 7,71 (1H, d, J=8,0), 7,88 (1H, s);

IR (KBr, cm-1): 1738, 1674.

Example 44

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 561)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (250 mg)obtained in example 43, dissolved in 3 N. hydrochloric acid (30 ml) and the resulting mixture was stirred at 60°C for 3 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 10% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (160 mg, yield 58%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,80-of 1.95 (1H, m), 1,95-2,05 (1H, m), 2.05 is was 2.25 (2H, m), 2.70 height is 2.80 (3H, m), 3.00 and is 3.15 (2H, m), 3,20-3,30 (1H, m), 3,40-3,50 (1H, m), 4,20 (2H, s), of 4.45 (2H, d, J=,0), 4,53 and 4,74 (total 1H, each m), 6,44 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0), 7,02 (1H, d, J=9,0), 7,05 (1H, d, J=9,0), 7,39 (1H, d, J=9,0), 7,41 (1H, d, J=9,0), 7,54 (1H, t, J=8,0), to 7.68 (1H, d, J=8,0), 7,71 (1H, d, J=8,0), 7,87 (1H, s);

IR (KBr, cm-1) 1733, 1676.

Example 45

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)-3-triptoreline]sulfamerazine (example compound No. 85)

Through a solution of ethyl N-[3-(3-cyanophenyl)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)-3-triptoreline]sulfamerazine (1298 mg)obtained in reference example 104, in a mixture of dichloromethane (30 ml) and ethanol (15 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6.5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 246 mg of the substance in 10 ml of water) and 28% ammonia solution (0,32 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness and the floor shall indicate the specified header connection (1115 mg, yield 74%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,91, and to 2.06 (total 2H, each m), 2,17-of 2.27 (2H, m), 2,73 (3H, m), 2,87, and a 3.50 (total 2H, each m), 3,37 and 3,44 (total 2H, each m), 4,19 (2H, square, J=7,0), of 4.45 (2H, m), 4,50 (2H, d, J=6,0), 4,74 and 5,00 (total 1H, each m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,39 and 7,45 (total 1H, each d, J=10,0), at 7.55 (1H, t, J=8,0), 7,65-7,74 (4H, m), 7,89 (1H, s);

IR (KBr, cm-1): 1739, 1676, 1353, 1155.

Example 46

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)-3-triptoreline]sulfamoylbenzoic acid (example compound No. 589)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)-3-triptoreline]sulfamerazine (803 mg)obtained in example 45, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 8 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 17% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (607 mg, yield 79%) as a colorless amorphous solid.

1H NMR (500 MHz, CD 3OD) δ ppm: 1,93 and 2.17 (total 2H, each m), 2,28 and 2,39 (total 2H, each m), 2,90 (3H, m), 3,10-of 3.25 (2H, m), 3,47, and of 3.60 (total 2H, each m), of 4.12 (2H, s)4,55 (2H, d, J=6,5), 5,00 (1H, m), to 6.43 (1H, dt, J=16,0, 6,5), to 6.57 (1H, d, J=16,0), 7.30 and was 7.36 (total 1H, each m), 7,54 (1H, t, J=8.0 a), the 7.65 (1H, d, J=8,0), 7,71 (1H, d, J=8,0), 7,72-7,80 (2H, m), 7,80 (1H, s);

IR (KBr, cm-1): 1733, 1676, 1350, 1154.

Example 47

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-formamidopyrimidine-4-yloxy)phenyl]sulfamerazine (example compound No. 22)

a) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine

Through a solution of ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1200 mg)obtained in reference example 70, in a mixture of dichloromethane (30 ml) and ethanol (20 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 208 mg of the substance in 10 ml of water) and 28% ammonia solution (0,40 ml) and the resulting mixture was stirred at room temperature overnight. To the reaction mixture is added 4 n solution of hydrogen chloride is dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). Then to the solution obtained amorphous solid was dissolved in methanol (20 ml) is added 4 n solution of hydrogen chloride in dioxane (0,50 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (662 mg, yield 56%) as a pale yellow amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), a 1.88 (2H, m), 2,10 (2H, m), is 3.08 (2H, m), 3,17 (2H, m), 4,19 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (2H, d, J=6,5), 4,78 (1H, m), 6,44 (1H, dt, J=16,0, 6,5), to 6.57 (1H, d, J=16,0), 7,30 (1H, d, J=9.5)is, 7,41 (1H, DD, J=9,5, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), of 7.69 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,88 (1H, s);

IR (KBr, cm-1): 1737, 1675.

(b) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-formamidopyrimidine-4-yloxy)phenyl]sulfamerazine

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0,79 g)obtained in example 47(a), in ethanol (25 ml) at room temperature successively added the hydrochloride of ethylphenidate (0.29 grams) and triethylamine (0,72 ml) and the resulting mixture left at room temperature for 16 hours. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (10 ml) and the resulting mixture is evaporated is in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (10 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.50 g, yield 61%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,73-to 1.87 (2H, m), 1,99 is 2.10 (2H, m), 3,57-3,68 (2H, m), 3,71-of 3.78 (2H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,47 (2H, d, J=6,0), 4,81-a 4.86 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,33 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), 7,60 (1H, d, J=2,5), 7,69 to 7.75 (2H, m), of 7.90 (1H, s), to 7.99 (1H, DD, J=15,0, 7,0);

IR (KBr, cm-1): 1737, 1702, 1675, 1351, 1155.

Example 48

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-formamidopyrimidine-4-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 526)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-formamidopyrimidine-4-yloxy)phenyl]sulfamerazine (0.35 g)obtained in example 47(b), dissolved in 3 N. hydrochloric acid (15 ml) and the resulting mixture was stirred at 60°C for 4.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified prep the operational HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (3 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.17 g, yield 52%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,73-to 1.87 (2H, m), 1,98-2,11 (2H, m), 3,57-with 3.79 (4H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), 4,79-a 4.86 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,32 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), of 7.70 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,89 (1H, s), to 7.99 (1H, DD, J=15,0, 7,0);

IR (KBr, cm-1): 1731, 1703, 1675, 1347, 1154.

Example 49

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(1-aminopropyl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 23)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0,77 g)obtained in example 47(a), in ethanol (25 ml) at room temperature successively added the hydrochloride of ethylpropylamine (0.54 g), which is produced from propionitrile according to the method described in J. Amer. Chem. Soc., 98, 567 (1976), and triethylamine (0,88 ml) and the resulting mixture left at room temperature for 22 hours. Since the reaction proceeds slowly, yet consistently add g is drochloric of ethylpropylamine (0.18 g) and triethylamine (0.35 ml) and the resulting mixture was stirred at room temperature for 4.5 hours. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (10 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (10 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and receive specified in the header of the connection (or 0.57 g, yield 67%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: to 1.15 (3H, t, J=7,5), of 1.23 (3H, t, J=7,0), 1,74 of-1.83 (2H, m), 2,01 is 2.10 (2H, m), 2,61 (2H, square, J=7,5), to 3.58-of 3.77 (4H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,47 (2H, d, J=5.5), the 4,80-4,89 (1H, m), of 6.45 (1H, dt, J=15,5, 5,5), to 6.58 (1H, d, J=15,5), 7,33 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), 7,69-7,74 (2H, m), of 7.90 (1H, s);

IR (KBr, cm-1): 1738, 1671, 1619, 1352, 1157.

Example 50

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(1-aminopropyl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 527)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(1-aminopropyl)piperidine-4-yloxy]phenyl]sulfamerazine (0,42 g)obtained in example 49, dissolved in 3 N. hydrochloric acid (15 ml) and the resulting mixture of paramashiva the t at 60° C for 6.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 18% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (3 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized, and get mentioned in the title compound (0,37 g, yield 93%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: to 1.15 (3H, t, J=7,5), 1,71-to 1.87 (2H, m), 2.00 in a 2.12 (2H, m), 2.63 in (2H, square, J=7,5), 3,59-3,81 (4H, m), 4,30 (2H, s), 4,48 (2H, d, J=5.5), the 4,81-4,88 (1H, m), 6,46 (1H, dt, J=16,0, 5,5), to 6.58 (1H, d, J=16,0), 7,34 (1H, d, J=9,0), the 7.43 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), 7,60 (1H, d, J=2,5), 7,70-7,76 (2H, m), 7,94 (1H, s);

IR (KBr, cm-1): 1734, 1671, 1620, 1349, 1156.

Example 51

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-aminophenylacetamido-4-yloxy)-3-chlorophenyl]sulfamerazine (example compound No. 24)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0,69 g)obtained in example 47(a), in ethanol (20 ml) at room temperature successively added the hydrochloride of ethylbenzamide (0,63 g) and triethylamine (0,94 ml) and the resulting mixture was stirred at 60°C for 2.5 hours and then left at room temperature the 16.5 hours. Then the obtained mixture is still stirred at 60°C for 11.5 hours and then left at room temperature of 60.5 hours. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (5 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (0.36 g, yield 45%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,73-of 1.81 (1H, m), 1,90-2,03 (2H, m), 2,17-of 2.24 (1H, m), 3,30-3,51 (2H, m), 3,78-3,86 (1H, m), 3,89-of 3.95 (1H, m), 4,18 (2H, square, J=7,0), to 4.41 (2H, s), 4,47 (1H, d, J=6,0)of 4.83-4,88 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,33 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), 7,53-7,73 (9H, m), 7,88 (1H, s);

IR (KBr, cm-1): 1738, 1671, 1605, 1353, 1156.

Example 52

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-aminophenylacetamido-4-yloxy)-3-chlorophenyl]sulfamoylbenzoic acid (example compound No. 528)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(1-aminophenylacetamido-4-yloxy)-3-chlorophenyl]sulfamerazine (0.25 g)obtained in example 51, dissolved in 3 N. hydrochloric acid (12 ml) and the resulting mixture was stirred at 60#x000B0; C for 3 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (3 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.21 g, yield 89%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1.70 to of 1.78 (1H, m), 1,88-2,02 (2H, m), 2,14-2,22 (1H, m), 3,28-3,50 (2H, m), 3,83-are 3.90 (1H, m), 3,91-4,01 (1H, m), 4,27 (2H, s), of 4.45 (2H, d, J=5,0), 4,82-4,89 (1H, m), 6,44 (1H, dt, J=16,0, 5,0), 6,56 (1H, d, J=16,0), 7,32 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), 7,51-7,71 (9H, m), of 7.90 (1H, s);

IR (KBr, cm-1): 1733, 1673, 1605, 1349, 1155.

Example 53

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 25)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0.75 g)obtained in example 47(a), in ethanol (25 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (0.25 g), which is obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine(0,69 ml) and the resulting mixture was stirred at room temperature for 10 hours and then left at room temperature for 84 hours. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (10 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (10 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.52 g, yield 62%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), a 1.75-to 1.86 (2H, m), 2,02 with 2.14 (4H, m), of 2.97 (2H, t, J=8,0), 3,50-3,91 (6H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,47 (2H, d, J=6,0), 4,81-to 4.87 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,34 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), 7,70-7,74 (2H, m), to $ 7.91 (1H, s);

IR (KBr, cm-1): 1738, 1672, 1352, 1156.

Example 54

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 529)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (0.36 g)obtained in example 53, dissolved in 3 N. hydrochloric acid (15 ml) and the resulting mixture was stirred at 60°C for 6 the aces. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15~18% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (3 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.32 g, yield 90%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,73-of 1.88 (2H, m), 2.00 in and 2.14 (4H, m), of 2.97 (2H, t, J=8,0), 3,50-3,88 (6H, m), 4,30 (2H, s), 4,47 (2H, d, J=5.5), the 4,81-4,88 (1H, m), 6,46 (1H, dt, J=16,0, 5,5), to 6.58 (1H, d, J=16,0), 7,34 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), 7,71-7,76 (2H, m), to 7.93 (1H, s);

IR (KBr, cm-1): 1734, 1672, 1350, 1155.

Example 55

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 26)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0,81 g)obtained in example 47(a), in ethanol (20 ml) at room temperature sequentially added 6-ethoxy-2,3,4,5-tetrahydropyridine (0.33 g), which is derived from piperidine-2-it according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,74 ml) and the resulting mixture was sequentially per mesilat at 35° With over 3.5 hours, leave at room temperature for 11 hours and still stirred at 45°C for 24 hours. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (5 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 23% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (1 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.21 g, yield 23%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), of 1.65 and 1.80 (6H, m), 2,00-2,09 (2H, m), 2,66-of 2.72 (2H, m), 3,30-to 3.36 (2H, m), 3.49 points of 3.75 (4H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,47 (2H, d, J=5.5), the 4,81-to 4.87 (1H, m), 6,44 (1H, dt, J=16,0, 5,5), to 6.58 (1H, d, J=16,0), 7,33 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), 7,53-7,59 (2H, m), 7,69-7,74 (2H, m), of 7.90 (1H, s);

IR (KBr, cm-1): 1738, 1674, 1637, 1354, 1155.

Example 56

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 530)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamerazine (0.28 g), the scientists in example 55, dissolve 3 N. hydrochloric acid (12 ml) and the resulting mixture was stirred at 60°C for 5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 18% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (3 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0,19 g, 71%yield) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,64-of 1.81 (6H, m), 1,99-of 2.08 (2H, m), 2,67-of 2.72 (2H, m), 3,30-3,37 (2H, m), 3,55-of 3.78 (4H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), 4,80-to 4.87 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,32 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), 7,53-7,59 (2H, m), to 7.67-7,74 (2H, m), 7,88 (1H, s);

IR (KBr, cm-1): 1734, 1675, 1637, 1352, 1156.

Example 57

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 27)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0.75 g)obtained in example 47(a), in ethanol (25 ml) at room temperature successively added 7-methoxy-3,4,5,6-tetrahydro-2H-azepin (0.39 g) and triethylamine (0,85 ml) and the resulting mixture paramesh what happens at room temperature for 7 hours and then left at room temperature for 15 hours. Since the reaction proceeds slowly add more consistently 7-methoxy-3,4,5,6-tetrahydro-2H-azepin (0,22 g) and triethylamine (0.51 ml) and the resulting mixture was stirred at 45°within 12 hours, leave at room temperature for 11 hours and then stirred at 45°C for 10 hours. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (5 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0,30 g, yield 35%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: to 1.21 (3H, t, J=7,0), 1,52-to 1.63 (4H, m), 1,68-of 1.81 (4H, m), 2,04 is 2.10 (2H, m), 2,84-is 2.88 (2H, m), 3,36-of 3.42 (2H, m), 3,62-3,91 (4H, m), 4,18 (2H, square, J=7,0), to 4.41 (2H, s), to 4.46 (2H, d, J=6,0), 4,81-to 4.87 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,32 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), 7,52-7,59 (2H, m), 7,66-7,74 (2H, m), 7,88 (1H, s);

IR (KBr, cm-1): 1738, 1674, 1628, 1353, 1156.

Example 58

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulf moroccanoil acid (example compound No. 531)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamerazine (0.24 g)obtained in example 57, dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 60°C for 6 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 18% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (3 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.18 g, yield 76%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,52-of 1.62 (4H, m), 1,67-to 1.82 (4H, m), 2,00-2,09 (2H, m), 2,84-is 2.88 (2H, m), 3.43 points-to 3.49 (2H, m), 3,63-3,91 (4H, m), 4,27 (2H, s), to 4.46 (2H, d, J=5.5), the 4,80-a 4.86 (1H, m), 6,44 (1H, dt, J=16,0, 5,5), to 6.57 (1H, d, J=16,0), 7,32 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), 7,51-7,61 (2H, m), 7.68 per to 7.75 (2H, m), 7,89 (1H, s);

IR (KBr, cm-1): 1734, 1675, 1628, 1351, 1156.

Example 59

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 81)

a) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(piperidine-4-yloxy)phenyl]sulfamerazine

Through a solution of ethyl N-[4-(1-tert-butok carbonitriding-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1,46 g), obtained in reference example 108, in a mixture of dichloromethane (50 ml) and ethanol (25 ml) under cooling with ice for 1 hour bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 8 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (40 ml) are added successively an aqueous solution of ammonium chloride (obtained by the dissolution of 0.30 g of substance in 15 ml of water) and 28% ammonia solution (of 0.58 ml) and the resulting mixture left at room temperature for 12 hours. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water) and get listed in the title compound (0,98 g, yield 68%) as a pale yellow amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0)and 1.83 (2H, m), 2,10 (2H, m), 3,05 (2H, m), 3,19 (2H, m), 4,20 (2H, square, J=7,0), 4,34 (2H, s), of 4.45 (2H, d, J=6,0), of 4.66 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0),? 7.04 baby mortality (2H, d, J=8,5), 7,39 (2H, d, J=8,5), at 7.55 (1H, t, J=8.0 a), of 7.69 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1737, 1675.

(b) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(Pipa is one-4-yloxy)phenyl]sulfamerazine (0.52 g), obtained in example 59(a), in ethanol (5 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (0.26 g), which is obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,60 ml) and the resulting mixture was stirred at room temperature for 29 hours and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (40 ml) is added 4 n solution of hydrogen chloride in dioxane (0.75 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and receive specified in the header of the connection (of 0.43 g, yield 77%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,68 and 1.80 (2H, m), 2.00 in and 2.14 (4H, m), 2,96 (2H, t, J=8,0), 3.46 in-a 3.87 (6H, m), 4,20 (2H, square, J=7,0), 4,34 (2H, s), of 4.45 (2H, d, J=6,0), 4,67-to 4.73 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0),? 7.04 baby mortality (2H, d, J=9,0), 7,39 (2H, d, J=9,0), at 7.55 (1H, t, J=8,0), 7.68 per-7,73 (2H, m), 7,88 (1H, s);

IR (KBr, cm-1): 1738, 1671, 1349, 1157.

Example 60

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 585)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-about enyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (0,38 g), obtained in example 59(b), dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 60°C for 4 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (3 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.21 g, yield 59%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,68-of 1.80 (2H, m), 2.00 in to 2.13 (4H, m), 2,96 (2H, t, J=8,0), 3.46 in-and 3.72 (5H, m), 3,83-to 3.92 (1H, m), 4,20 (2H, s), of 4.45 (2H, d, J=5.5), the 4,67-to 4.73 (1H, m), of 6.45 (1H, dt, J=16,0, 5,5), is 6.54 (1H, d, J=16,0),? 7.04 baby mortality (2H, d, J=9,0), 7,39 (2H, d, J=9,0), 7,54 (1H, t, J=8,0), 7,71(2H, d, J=8.0 a), of 7.90 (1H, s);

IR (KBr, cm-1): 1733, 1672, 1347, 1155.

Example 61

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 82)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(piperidine-4-yloxy)phenyl]sulfamerazine (0.50 g)obtained in example 59(a), in ethanol (5 ml) at room temperature sequentially added 6-ethoxy-2,3,4,5-tetrahydropyridine (0.31 g), which is derived from piperidine-2-it according to the on the way described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,60 ml) and the resulting mixture was stirred at room temperature for 4 days and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (25 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.27 g, yield 47%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,65-of 1.78 (6H, m), 1,99-2,07 (2H, m), 2,68-of 2.72 (2H, m), 3,29-to 3.36 (2H, m), 3,44-3,55 (2H, m), 3,70-are 3.90 (2H, m), 4,20 (2H, square, J=7,0), 4,34 (2H, s), of 4.44 (2H, d, J=5,5), 4,68-4,74 (1H, m), 6,44 (1H, dt, J=16,0, 5,5), 6,55 (1H, d, J=16,0), 7,03 (2H, d, J=9,0), 7,39 (2H, d, J=9,0), at 7.55 (1H, t, J=7,7), 7.68 per-7,73 (2H, m), 7,88 (1H, s);

IR (KBr, cm-1): 1738, 1674, 1637, 1351, 1157.

Example 62

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 586)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamerazine (0,76 g)obtained in example 61, dissolved in 3 N. hydrochloric acid (15 ml) and the resulting mixture was stirred at 60°With the 6 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (5 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0,60 g, yield 83%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,65-of 1.78 (6H, m), 2.00 in 2,07 (2H, m), 2,68-a 2.71 (2H, m), 3,30-3,55 (4H, m), 3,70-a 3.87 (2H, m), is 4.21 (2H, s), of 4.45 (2H, d, J=5.5), the 4,67-to 4.73 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0), 7,03 (2H, d, J=9,0), 7,39 (2H, d, J=9,0), 7,54 (1H, t, J=8,0), to 7.67-7,73 (2H, m), 7,87 (1H, s);

IR (KBr, cm-1): 1734, 1674, 1637, 1348, 1156.

Example 63

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 83)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(piperidine-4-yloxy)phenyl]sulfamerazine (0.51 g)obtained in example 59(a), in ethanol (5 ml) at room temperature successively added 7-methoxy-3,4,5,6-tetrahydro-2H-azepin (0.34 g) and triethylamine (0,60 ml) and the resulting mixture was stirred at room temperature for 18 hours and then evaporated in vacuum. The resulting residue is purified preparation the main HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (1 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.14 g, yield 24%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,46 TO 1.76 (8H, m), 2,01 is 2.10 (2H, m), 2,86-2,89 (2H, m), 3.45 points-of 3.50 (2H, m), 3,57-3,70 (2H, m), 3,85-of 3.97 (2H, m), 4,20 (2H, square, J=7,0), 4,34 (2H, s), of 4.45 (2H, d, J=6,0), 4,70 was 4.76 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0), 7,39 (2H, d, J=9,0), 7,54 (2H, d, J=9,0), 7,54 (1H, t, J=8.0 Hz), 7,69-7,73 (2H, m), of 7.90 (1H, s);

IR (KBr, cm-1): 1737, 1674, 1629, 1351, 1158.

Example 64

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 587)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamerazine (0.96 g)obtained in example 63, dissolved in 3 N. hydrochloric acid (25 ml) and the resulting mixture was stirred at 60°C for 6 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The amorphous solid is the second substance is dissolved in 1 N. hydrochloric acid (5 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.54 g, yield 59%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,53-of 1.64 (4H, m), 1,68-to 1.77 (4H, m), 2,02 is 2.10 (2H, m), 2,86-is 2.88 (2H, m), 3.45 points-of 3.50 (2H, m), 3,56-3,70 (2H, m), 3,78-of 3.97 (2H, m), is 4.21 (2H, s), of 4.45 (2H, d, J=6,0), 4,69-of 4.75 (1H, m), 6,45 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0),? 7.04 baby mortality (2H, d, J=9,0), 7,40 (2H, d, J=9,0), 7,54 (1H, t, J=7,5), 7,69-7,72 (2H, m), of 7.90 (1H, s);

IR (KBr, cm-1): 1733, 1677, 1629, 1344, 1154.

Example 65

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-were]sulfamerazine (example compound No. 53)

a) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-(piperidine-4-yloxy)phenyl]sulfamerazine

Through a solution of ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-were]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1,90 g)obtained in reference example 112, in a mixture of dichloromethane (40 ml) and ethanol (40 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (45 ml) are added sequentially in the hydrated solution of ammonium chloride (obtained by dissolving 0.34 g of the substance in 15 ml of water) and 28% ammonia solution (of 0.64 ml) and the resulting mixture left at room temperature for 13 hours. After settling to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). Then the solution of the amorphous solid in methanol (20 ml) is added 4 n solution of hydrogen chloride in ethyl acetate (1 ml), the mixture was evaporated in vacuum to dryness and receive specified in the header connection (1,36 g, yield 73%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), to 1.87 (2H, m), 2,10 (2H, m), 2,17 (3H, s), of 3.07 (2H, m), 3,17 (2H, m), 4,20 (2H, square, J=7,0), to 4.33 (2H, s), of 4.44 (2H, d, J=6,0)and 4.65 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0), 7,05 (1H, d, J=9,0), from 7.24 (1H, DD, J=9,0, 2,5), 7,29 (1H, d, J=2,5), 7,54 (1H, t, J=8,0), 7,71 (2H, m), of 7.90 (1H, s);

IR (KBr, cm-1): 1738, 1675.

(b) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-were]sulfamerazine

To a solution of ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-(piperidine-4-yloxy)phenyl]sulfamerazine (700 mg)obtained in example 65(a), in ethanol (15 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (405 mg), which is obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,57 ml) and the resulting mixture is stirred p. and room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 22% acetonitrile/water) and receive an amorphous solid (565 mg). Then the solution of the amorphous solid (151 mg) in ethanol (4 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (157 mg, yield 66%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,72-of 1.85 (2H, m), 1,98 with 2.14 (4H, m)of 2.16 (3H, s), 2,96 (2H, t, J=8,0), 3.46 in-3,81 (6H, m), 4,20 (2H, square, J=7,0), to 4.33 (2H, s), of 4.44 (2H, d, J=6,0), to 4.73 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,07 (1H, d, J=9,0), from 7.24 (1H, DD, J=9,0, 2,5), 7,29 (1H, d, J=2,5), at 7.55 (1H, t, J=8.0 a), of 7.69 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1738, 1671, 1350, 1157.

Example 66

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-were]sulfamoylbenzoic acid (example compound No. 557)

Ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-were]sulfamerazine (409 mg)obtained in example 65(b), dissolved in 4 N. hydrochloric acid (12 ml) and the resulting mixture was stirred at 70°C for 2 hours. After cooling to room temperature, reacciona the mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 17% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (10 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (266 mg, yield 60%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,72-to 1.86 (2H, m), 1,97 with 2.14 (4H, m)of 2.16 (3H, s), 2,96 (2H, m), 3,47-of 3.80 (5H, m), 3.72 points-is 3.82 (1H, m), 4,19 (2H, s), of 4.44 (2H, d, J=6,0), 4,72 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0), 7,06 (1H, d, J=8,5), 7,25 (1H, DD, J=8,5, 2,5), 7,29 (1H, d, J=2,5), at 7.55 (1H, t, J=8.0 a), of 7.69 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1733, 1672, 1347, 1155.

Example 67

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 54)

To a solution of ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-(piperidine-4-yloxy)phenyl]sulfamerazine (730 mg)obtained in example 65(a), in ethanol (15 ml) at room temperature sequentially added 6-ethoxy-2,3,4,5-tetrahydropyridine (482 mg), which is derived from piperidine-2-it according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,59 ml) and the resulting mixture was stirred at room temperature for 2 days and then evaporated in vacuum. The floor is built the residue purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 28% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (6 ml) is added 4 n solution of hydrogen chloride in dioxane (0,39 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (331 mg, yield 36%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,64 is 1.70 (6H, m), 1,96-of 2.08 (2H, m)of 2.16 (3H, s), 2,70 (2H, t, J=6,0), 3,25-3,37 (2H, m), 3.46 in-a 3.83 (4H, m), 4,20 (2H, square, J=7,0), to 4.33 (2H, s), of 4.44 (2H, d, J=6,0), to 4.73 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,06 (1H, d, J=9,0), from 7.24 (1H, DD, J=9,0, 2,5), 7,29 (1H, d, J=2,5), at 7.55 (1H, t, J=8.0 a), of 7.70 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), of 7.90 (1H, s);

IR (KBr, cm-1): 1738, 1674, 1637, 1351, 1157.

Example 68

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 558)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamerazine (265 mg)obtained in example 67, dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 60°C for 5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetone the Rhyl/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (8 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (236 mg, yield 93%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,64-to 1.82 (6H, m), 1,96-of 2.08 (2H, m)of 2.16 (3H, s), 2,70 (2H, m)to 3.33 (2H, m), 3.46 in-a 3.83 (4H, m), is 4.21 (2H, s), of 4.44 (2H, d, J=6,0), to 4.73 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0), 7,05 (1H, d, J=8,5), 7,25 (1H, DD, J=8,5, 2,5), 7,29 (1H, d, J=2,5), at 7.55 (1H, t, J=8.0 a), of 7.69 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1733, 1676, 1637, 1347, 1156.

Example 69

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 55)

To a solution of ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-(piperidine-4-yloxy)phenyl]sulfamerazine (640 mg)obtained in example 65(a), in ethanol (12 ml) at room temperature successively added 7-methoxy-3,4,5,6-tetrahydro-2H-azepin (348 mg) and triethylamine (0,26 ml) and the resulting mixture was stirred at room temperature for 2.5 days and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 N. RA is solution of hydrogen chloride in dioxane (0,42 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (336 mg, yield 40%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,52-of 1.64 (4H, m), 1,68-to 1.82 (4H, m), 1,98-of 2.09 (2H, m), 2,17 (3H, s), 2,87 (2H, m), of 3.48 (2H, m), 3,65 of 3.75 (2H, m), of 3.77-3,88 (2H, m), 4,19 (2H, square, J=7,0), to 4.33 (2H, ), of 4.44 (2H, d, J=6,0), 4,74 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,06 (1H, d, J=8,5), 7,25 (1H, DD, J=8,5, 2,5), 7,28 (1H, d, J=2,5), at 7.55 (1H, t, J=8.0 a), of 7.69 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1738, 1675, 1628, 1351, 1157.

Example 70

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 559)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-methyl-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamerazine (335 mg)obtained in example 69, dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 60°C for 5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (10 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized andget specified in the title compound (258 mg, yield 80%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,53-of 1.65 (4H, m), 1,68-of 1.84 (4H, m), 1,98 is 2.10 (2H, m)of 2.16 (3H, s), is 2.88 (2H, m), 3,44-of 3.53 (2H, m), 3,62-3,93 (4H, m), 4,19 (2H, s), and 4.40 (2H, d, J=6,0), 4,74 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0), 7,05 (1H, d, J=9,0), 7,26 (1H, DD, J=9,0, 2,5), 7,29 (1H, d, J=2,5), at 7.55 (1H, t, J=8.0 a), of 7.69 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,89 (1H, s);

IR (KBr, cm-1): 1732, 1676, 1628, 1348, 1156.

Example 71

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 137)

a) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]sulfamerazine

Through a solution of ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (2,40 g)obtained in reference example 119, in a mixture of dichloromethane (20 ml) and ethanol (20 ml) with ice cooling for 2.5 hours bubbled hydrogen chloride, and the resulting mixture was stirred at room temperature for 6 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (20 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 0.50 g of the substance in 5 ml of water) and 28% ammonia solution (1,10 ml) and the resulting mixture left at room temperature the re for 13 hours and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (20 ml) is added 4 n solution of hydrogen chloride in ethyl acetate (0,90 ml) and the resulting mixture was evaporated in vacuum to dryness and receive specified in the header connection (0,60 g, yield 25%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1.85 to a 2.00 (2H, m), 2.05 is-of 2.20 (2H, m), 3.00 and-3,10 (2H, m), 3.15 and is 3.25 (2H, m), 4,20 (2H, square, J=7,0), to 4.38 (2H, s), 4,47 (2H, d, J=6,0), 4,80 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), from 7.24 (1H, m)to 7.50 (1H, m), 7,54 (1H, m), the 7.65 to 7.75 (3H, m), of 7.90 (1H, m);

IR (KBr, cm-1): 1736, 1671, 1658.

(b) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine

To a solution of ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]sulfamerazine (500 mg)obtained in example 71(a), in ethanol (15 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (340 mg), which is obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,57 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% AC is control/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (0,50 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (420 mg, yield 67%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,80-of 1.95 (2H, m), 2.00 in to 2.15 (4H, m), 2,96 (2H, m), 3,45-3,55 (1H, m), 3,55-the 3.65 (1H, m), 3,61 (2H, m), 3,65 of 3.75 (1H, m), 3.75 to of 3.85 (1H, m), 4,20 (2H, square, J=7,0), 4,37 (2H,with), 4,47 (2H, d, J=6,0), a 4.86 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,28 (1H, d, J=9,0), 7,51 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.68 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), to 7.77 (1H, d, J=2,5), 7,87 (1H, s);

IR (KBr, cm-1): 1737, 1670.

Example 72

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 641)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (380 mg)obtained in example 71(b), dissolved in 3 N. hydrochloric acid (12 ml) and the resulting mixture was stirred at 60°C for 3 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 13% acetonitrile/water). The obtained amorphous solid substances the CTB dissolved in a mixture of 1 N. hydrochloric acid (1.2 ml) and water (5 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (240 mg, yield 65%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,80-of 1.95 (2H, m), 2.00 in to 2.15 (4H, m), 2,96 (2H, m), 3,45-3,55 (1H, m), 3,55-the 3.65 (1H, m), 3,61 (2H, m), 3,65 of 3.75 (1H, m), 3.75 to of 3.85 (1H, m), 4,24 (2H, s), 4,47 (2H, d, J=6,0), is 4.85 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,28 (1H, d, J=9,0), 7,52 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.67 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), to 7.77 (1H, d, J=2,5), 7,86 (1H, s);

IR (KBr, cm-1): 1731, 1670.

Example 73

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 138)

To a solution of ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]sulfamerazine (500 mg)obtained in example 71(a), in ethanol (15 ml) at room temperature sequentially added 6-ethoxy-2,3,4,5-tetrahydropyridine (360 mg), which is derived from piperidine-2-it according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,77 ml) and the resulting mixture was stirred at room temperature overnight. Since the reaction proceeds slowly, consistently add 6 ethoxy-2,3,4,5-tetrahydropyridine (630 mg) and triethylamine (0,77 ml) and the resulting mixture was stirred at room temperature for od is their day and at the end of a specified period of time has consistently add 6 ethoxy-2,3,4,5-tetrahydropyridine (320 mg) and triethylamine (0.35 ml) and the resulting mixture was stirred at room temperature for one day and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (6 ml) is added 4 n solution of hydrogen chloride in dioxane (0.25 ml) and the resulting mixture was evaporated in vacuum to dryness, and get mentioned in the title compound (200 mg, yield 31%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,24 (3H, t, J=7,0), 1,65-1,90 (6H, m), 2.00 in of 2.10 (2H, m), 2,70 (2H, m)to 3.34 (2H, m), 3,40-of 3.60 (2H, m), 3,70-of 3.85 (2H, m), is 4.21 (2H, square, J=7,0), 4,37 (2H, s), 4,48 (2H, d, J=6,0), to 4.87 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), 7,28 (1H, d, J=9,0), 7,52 (1H, DD, J=9,0, 3,0), 7,56 (1H, t, J=8,0), to 7.68 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,78 (1H, d, J=3,0), 7,86 (1H, C);

IR (KBr, cm-1): 1737, 1673.

Example 74

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 642)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]phenyl]sulfamerazine (200 mg)obtained in example 73, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 3 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, Elya is NT 13% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (0.9 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (137 mg, 71%yield) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,65-1,90 (6H, m), 2.00 in of 2.10 (2H, m), 2,69 (2H, m)to 3.34 (2H, m), 3,40-of 3.60 (2H, m), 3,70-of 3.85 (2H, m), 4,24 (2H, s), 4,47 (2H, d, J=6,0), a 4.86 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,27 (1H, d, J=9,0), 7,52 (1H, DD, J=9,0, 3,0), at 7.55 (1H, t, J=8,0), to 7.67 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), to 7.77 (1H, d, J=3,0), 7,86 (1H, s);

IR (KBr, cm-1): 1731, 1674.

Example 75

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 139)

To a solution of ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]sulfamerazine (400 mg)obtained in example 71(a), in ethanol (10 ml) at room temperature successively added 7-methoxy-3,4,5,6-tetrahydro-2H-azepin (280 mg) and triethylamine (0.31 in ml) and the resulting mixture was stirred at room temperature overnight. Since the reaction proceeds slowly, yet consistently, add 7-methoxy-3,4,5,6-tetrahydro-2H-azepin (280 mg) and triethylamine (0.31 in ml) and the resulting mixture was stirred at 40°C for 12 hours and leave at room temperature overnight. Then the reaction see the camping evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (0,20 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (140 mg, yield 26%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,24 (3H, t, J=7,0), 1,50-of 1.65 (4H, m), 1.70 to about 1.75 (2H, m), 1,80-1,90 (2H, m), 2.05 is-of 2.15 (2H, m), 2,85-2,90 (2H, m), 3.45 points-of 3.50 (2H, m), 3,55-the 3.65 (1H, m), 3,65 of 3.75 (1H, m), 3.75 to of 3.85 (1H, m), 3,85-of 3.95 (1H, m), 4,20 (2H, square, J=7,0), 4,37 (2H, s), 4,47 (2H, d, J=6,0), a 4.86 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,28 (1H, d, J=9,0), 7,51 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.67 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), 7,78 (1H, d, J=2,5), 7,86 (1H, s);

IR (KBr, cm-1): 1737, 1672.

Example 76

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 643)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]phenyl]sulfamerazine (130 mg)obtained in example 75, dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 60°C for 2 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified pre is arational HPLC (YMC-Pack ODS-A; YMC, eluent 12% acetonitrile/water). The obtained amorphous solid was dissolved in a mixture of 1 N. hydrochloric acid (0.25 ml) and water (5 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (50 mg, yield 40%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,55-1,65 (4H, m), 1.70 to about 1.75 (2H, m), 1,80-1,90 (2H, m), 2.05 is-of 2.15 (2H, m), 2,85-2,90 (2H, m), 3.45 points-of 3.50 (2H, m), 3,55-the 3.65 (1H, m), 3,65 of 3.75 (1H, m), 3,80-are 3.90 (1H, m), 3,90-4,00 (1H, m), 4,24 (2H,with), 4,47 (2H, d, J=6,0), a 4.86 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,27 (1H, d, J=9,0), 7,51 (1H, DD, J=9,0, 2,5), 7,54 (1H, t, J=8,0), to 7.68 (1H, d, J=8,0), 7,72 (1H, d, J=8,0), to 7.77 (1H, d, J=2,5), 7,88 (1H, s);

IR (KBr, cm-1): 1732, 1674.

Example 77

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-triptoreline]sulfamerazine (example compound No. 109)

a) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(piperidine-4-yloxy)-3-triptoreline]sulfamerazine

Through a solution of ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-triptoreline]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine from 2.06 g)obtained in reference example 122, in a mixture of dichloromethane (50 ml) and ethanol (25 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 6 hours in a closed re store and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (45 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 0.34 g of the substance in 15 ml of water) and 28% ammonia solution (0.63 ml) and the resulting mixture left at room temperature for 12 hours. After settling to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (2.5 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). Then the solution of the amorphous solid in methanol (20 ml) is added 4 n solution of hydrogen chloride in dioxane (0.5 ml) and the resulting mixture was evaporated in vacuum to dryness and receive specified in the header connection (1,21 g, yield 60%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), to 1.87 (2H, m), of 2.08 (2H, m), 3,11 (2H, m)to 3.33 (2H, m), 4,18 (2H, square, J=7,0), of 4.44 (2H, s), 4,50 (2H, d, J=6,5), 4,89 (1H, m), 6,44 (1H, dt, J=16,0, 6,5), to 6.57 (1H, d, J=16,0), 7,39 (1H, d, J=9,0), at 7.55 (1H, t, J=8,0), 7,66-7,73 (4H, m), a 7.85 (1H, s);

IR (KBr, cm-1): 1738, 1676.

(b) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-triptoreline]sulfamerazine

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(piperidine-4-yloxy)-3-triptoreline]sulfamerazine (800 mg)obtained in PR is a measure 77(a), in ethanol (20 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (370 mg), which is obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,87 ml) and the resulting mixture was stirred at room temperature overnight. Since the reaction proceeds slowly, yet consistently add 5-methoxy-3,4-dihydro-2H-pyrrole (120 mg) and triethylamine (0,26 ml) and the resulting mixture was stirred at room temperature for 4 hours. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 26% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (622 mg, yield 70%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), is 1.82 (2H, m), 2.00 in to 2.15 (4H, m), of 2.97 (2H, t, J=8,0), 3,53-of 3.64 (4H, m), and 3.72 (2H, m), 4,19 (2H, square, J=7,0), of 4.45 (2H, s), 4,50 (2H, d, J=6,0), 4,96 (1H, m), 6,46 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,44 (1H, d, J=10,0), at 7.55 (1H, t, J=8,0), to 7.67 to 7.75 (4H, m), of 7.90 (1H, s);

IR (KBr, cm-1): 1739, 1672, 1353, 1144.

Example 78

The dihydrochloride of N-[3-(3-and lidinopril)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-triptoreline]sulfamoylbenzoic acid (example compound No. 613)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]-3-triptoreline]sulfamerazine (471 mg)obtained in example 77(b), dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 5.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (404 mg, yield 89%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,82 (2H, m), 2.00 in to 2.15 (4H, m), 2,96 (2H, t, J=8,0), 3,49-of 3.64 (4H, m), 3,70 (2H, m), 4,19 (2H, s), 4,50 (2H, d, J=6,0), of 4.95 (1H, m), 6,46 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,43 (1H, d, J=9,5), 7,54 (1H, t, J=8,0), 7,66-to 7.77 (4H, m), 7,89 (1H, s);

IR (KBr, cm-1): 1739, 1672, 1353, 1144.

Example 79

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]-3-triptoreline]sulfamerazine (example compound No. 110)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(piperidine-4-yloxy)-3-triptoreline]sulfamoyl is the Etat (900 mg), obtained in example 77(a), in ethanol (20 ml) at room temperature sequentially added 6-methoxy-2,3,4,5-tetrahydropyridine (480 mg), which is derived from piperidine-2-it according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,98 ml) and the resulting mixture was stirred at room temperature overnight. Since the reaction proceeds slowly, yet consistently add 6 ethoxy-2,3,4,5-tetrahydropyridine (480 mg) and triethylamine (0,98 ml) and the resulting mixture was stirred at room temperature for one day and then at 40°C for one day. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (2.5 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 25% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (429 mg, yield 42%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,64-of 1.85 (6H, m), 1,99 is 2.10 (2H, m), 2,70 (2H, m), 3.27 to 3,39 (2H, m), 3,53-to 3.73 (4H, m), 4,19 (2H, square, J=7,0), of 4.45 (2H, s), 4,50 (2H, d, J=6,0), of 4.95 (1H, m), 6,45 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), the 7.43 (1H, d, J=10,0), at 7.55 (1H, t, J=8.0 a), the 7.65 to 7.75(4H, m), 7,88 (1H, s);

IR (KBr, cm-1): 1739, 1675, 1355, 1141.

Example 80

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]-3-triptoreline]sulfamoylbenzoic acid (example compound No. 614)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(2,3,4,5-tetrahydropyridine-6-yl)piperidine-4-yloxy]-3-triptoreline]sulfamerazine (291 mg)obtained in example 79, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 5.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 22% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (240 mg, yield 86%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,63-of 1.85 (6H, m), 2,03 (2H, m), 2,70 (2H, m), 3,20-of 3.48 (2H, m), 3,52 is 3.76 (4H, m), of 4.12 (2H, s), 4,50 (2H, d, J=6,0), 4,94 (1H, m), 6,46 (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0), 7,42 (1H, d, J=9,0), 7,54 (1H, t, J=8.0 a), of 7.69 (1H, d, J=8,0), 7,71 (1H, d, J=8,0), 7,73 for 7.78 (2H, m), 7,89 (1H, s);

IR (KBr, cm-1): 1732, 1675, 1352, 1143.

Example 81

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(3,4,5,6-those whom rehydro-2H-azepin-7-yl)piperidine-4-yloxy]-3-triptoreline]sulfamerazine (example compound No. 111)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(piperidine-4-yloxy)-3-triptoreline]sulfamerazine (900 mg)obtained in example 77(a), in ethanol (20 ml) at room temperature successively added 7-methoxy-3,4,5,6-tetrahydro-2H-azepin (540 mg) and triethylamine (0,98 ml) and the resulting mixture was stirred at room temperature overnight. Since the reaction proceeds slowly, yet consistently add 7-methoxy-3,4,5,6-tetrahydro-2H-azepin (540 mg) and triethylamine (0,98 ml) and the resulting mixture was stirred at room temperature for 5 hours and then at 40°C for one day. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 30% acetonitrile/water).

The obtained amorphous solid was dissolved in 1 N. hydrochloric acid, and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (340 mg, yield 33%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), 1,52-to 1.67 (4H, m), 1,67-of 1.85 (4H, m)to 2.06 (2H, m), 2,87 (2H, m), of 3.48 (2H, m), 3,67-a 3.83 (4H, m), 4,19 (2H, square, J=7,0), to 4.46 (2H, s), 4,50 (2H, d, J=6,0), equal to 4.97 (1H, m,), 6,46 (1H, dt, J16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,44 (1H, d, J=9.5)is, of 7.55 (1H, t, J=8,0), to 7.67 to 7.75 (4H, m), of 7.90 (1H, s);

IR (KBr, cm-1): 1739, 1675, 1354, 1142.

Example 82

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]-3-triptoreline]sulfamoylbenzoic acid (example compound No. 615)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidine-4-yloxy]-3-triptoreline]sulfamerazine (307 mg)obtained in example 81, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 6.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 23% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness.

The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (218 mg, yield 74%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,46-to 1.67 (4H, m), 1,67-to 1.87 (4H, m)2,07 (2H, m), 2,87 (2H, m), 3,42-to 3.52 (2H, m), 3,64-of 3.85 (4H, m), 4,27 (2H, s), 4,50 (2H, d, J=6,0), 4,96 (1H, m), 6,46 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), the 7.43 (1H, d, J=10,0), at 7.55 (1H, t, J=8,0), 7,66-7,76 (4H, m), 7,89 (1H, s);

IR (KBr, cm-1): 1733, 1676, 1351, 1144.

Example 83

The dihydrochloride ethyl N - [3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(5,6-dihydro-2H-[1,4]thiazin-3-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 28)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0.25 g)obtained in example 47(a), in ethanol (10 ml) at room temperature successively added 5-ethoxy-3,6-dihydro-2H-[1,4]thiazin (0.24 g)was obtained from 3-thiomorpholine, according to the method described in Indian J. Chem., 10, 323 (1972), and triethylamine (0,23 ml) and the resulting mixture was stirred at room temperature for 4 hours and then at 45°C for 3 hours and then aged at room temperature for 11 hours. After keeping to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). Then to the resulting solution of amorphous solids in ethanol (4 ml) is added 4 n solution of hydrogen chloride in dioxane (1 ml) and the resulting mixture was evaporated in vacuum to dryness and get listed in the title compound (0.07 g, yield 24%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,73-to 1.82 (2H, m), 2,02 is 2.10 (2H, m), 2.91 in-2,96 (2H, m), 3,59-3,91 (8H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,47 (2H, d, J=6,0), 4,81-4,88 (1H, m), 6,44 (1H, dt, J=15,5, 6,0), to 6.58 (1H, d, J=15,5), 7,33 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), 7,51- 7,60 (2H, m), of 7.64 to 7.75 (2H, m), 7,87 (1H, s);

IR (KBr, cm-1): 737, 1674, 1633, 1350, 1155.

Example 84

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2,3,5,6-tetrafluoropyridine-4-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 1045)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (930 mg)obtained in example 47(a), in ethanol (20 ml) at room temperature successively added 2,3,5,6-tetrafluoropyridine (0.16 ml) and triethylamine (0,64 ml) and the resulting mixture was stirred at room temperature for 5 hours. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 55% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (893 mg, yield 81%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 1,73-of 1.84 (2H, m), 2,01-2,12 (2H, m), 3,38-of 3.48 (2H, m), 3,59 at 3.69 (2H, m), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,47 (2H, d, J=6,0), 4,80 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), 7,31 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), to 7.59 (1H, d, J=2,5), 7,66 (1H, d, J=8,0), 7,74 (1H, d, J=8,0), 7,86 1H, C);

IR (KBr, cm-1); 1739, 1677, 1351, 1147.

Example 85

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2,3,5,6-tetrafluoropyridine-4-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1063)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(2,3,5,6-tetrafluoropyridine-4-yl)piperidine-4-yloxy]phenyl]sulfamerazine (356 mg)obtained in example 84, dissolved in a mixture of 3 N. hydrochloric acid (20 ml) and 4 n solution of hydrogen chloride in dioxane (20 ml) and the resulting mixture was stirred at 60°C for 8.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 40% acetonitrile/water - only acetonitrile). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (322 mg, yield 94%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,72-of 1.84 (2H, m), 2.00 in a 2.12 (2H, m), 3,38-of 3.48 (2H, m), 3,59 at 3.69 (2H, m), is 4.21 (2H, s), 4,47 (2H, d, J=6,0), 4,79 (1H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,31 (1H, d, J=9,0), 7,42 (1H, DD, J=9,0, 2,5), at 7.55 (1H, t, J=8,0), 7,60 (1H, d, J=2,5), 7,66 (1H, d, J=8,0), 7,73 (1H, d, J=8,0), 7,86 (1H, s);

IR (KBr, cm-1): 1678, 1346, 1147.

Example 86

Digi rochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(N-atinformation)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 1081)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0,38 g)obtained in example 47(a), in ethanol (20 ml) at room temperature successively added methyl N-ethylphenidate (0.09 g), which is obtained from N-ethylformate according to the method described in Angew. Chem., 75, 790 (1963), and triethylamine (0,30 ml) and the resulting mixture was stirred at room temperature for 46 hours. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (1 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (0.14 g, yield 35%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,16-of 1.27 (6H, m), 1,72-of 1.88 (2H, m), 1,99 is 2.10 (2H, m), 3,40-of 3.48 (2H, m), 3,51-to 3.73 (4H, m), 4,19 (2H, square, J=7,5), was 4.42 (2H, s), 4,47 (2H, d, J=5.5), the 4,79-is 4.85 (1H, m), of 6.45 (1H, dt, J=16,0, 5.5), the return of 6.58 (1H, d, J=16,0), 7,32 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), 7,52- 7,59 (2H, m), the 7.65 to 7.75 (2H, m), 7,87 (1H, s), 8,11 (1H, d, J=13,5);

IR (KBr, cm-1): 1738, 1697, 1675, 1350, 1156.

Example 87

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-the ENT-4-[1-(N-atinformation)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1099)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(N-atinformation)piperidine-4-yloxy]phenyl]sulfamerazine (0,38 g)obtained in example 86, dissolved in 3 N. hydrochloric acid (14 ml) and the resulting mixture was stirred at 60°C for 6 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 18% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.25 g, yield 67%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,19 (3H, t, J=7,0), 1,72-of 1.88 (2H, m), 1,98-of 2.09 (2H, m), 3,51-with 3.79 (6H, m), 4,28 (2H, s), 4,47 (2H, d, J=6,0), 4,80-to 4.87 (1H, m), 6,44(1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,32 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,0), 7,52-7,60 (2H, m), 7.68 per to 7.75 (2H, m), 7,89 (1H, s), 8,13 (1H, d, J=13,5);

IR (KBr, cm-1): 1731, 1698, 1677, 1347, 1155.

Example 88

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 1009)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (075 g), obtained in example 47(a), in ethanol (25 ml) at room temperature successively added 2-ethoxy-4,5-dihydrooxazolo (0.28 g), which is obtained from 2-oxazolidone according to the method described in Eur. J. Org. Chem., 10, 2645 (1999), and triethylamine (0.68 ml) and the resulting mixture was stirred at room temperature for 22 hours. After stirring to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (5 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 23% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (10 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (0.56 g, yield 67%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,22 (3H, t, J=7,0), a 1.75-to 1.86 (2H, m), 1,98 is 2.10 (2H, m), 3,51-of 3.78 (4H, m), 3,85 (2H, t, J=8,5), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,47 (2H, d, J=6,0), 4,76-4,85 (3H, m), 6,44 (1H, dt, J=16,0, 6,0), to 6.58 (1H, d, J=16,0), 7,32 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), 7,52-7,60 (2H, m), of 7.69 (1H, d, J=7,5), 7,73 (1H, d, J=7,5), 7,87 (1H, s);

MS (FAB, M+-2HCl): 604.

Example 89

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1027)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (0,29 g)obtained in example 88, dissolved in 3 N. hydrochloric acid (12 ml) and the resulting mixture was stirred at 60°C for 10 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 17% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (2 ml), the mixture was evaporated in vacuum to dryness and receive specified in the header connection (0,23 g, yield 82%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,76-to 1.87 (2H, m), 1,98 is 2.10 (2H, m), 3,51-of 3.78 (4H, m), 3,85 (2H, t, J=8,5), 4,28 (2H, s), 4,47 (2H, d, J=5.5), the 4,77-4,84 (3H, m), 6,44 (1H, dt, J=16,0, 5,5), to 6.58 (1H, d, J=16,0), 7,31 (1H, d, J=9,0), 7,41 (1H, DD, J=9,0, 2,5), 7,52-7,61 (2H, m), 7,68 (1H, d, J=7,5), 7,73 (1H, d, J=7,5), 7,88 (1H, s);

IR (KBr, cm-1): 1733, 1685, 1349, 1155.

Example 90

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(tropan-3-yloxy)phenyl]sulfamerazine (example compound No. 1117)

Through a solution of ethyl N-[3-chloro-4-(tropan-3-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (of 1.30 g)obtained in reference example 126, in a mixture of dichloromethane (25 ml) and ethanol (35 ml) under ice cooling chloride bubbled water is ml and the resulting mixture was stirred at room temperature for 3.5 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (25 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 0.40 g of the substance in 5 ml of water) and 28% ammonia solution (0,90 ml) and the resulting mixture was stirred at room temperature overnight and evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 22% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (15 ml) is added 4 n solution of hydrogen chloride in dioxane (1,40 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (1.07 g, yield 70%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), 2,05-OF 2.30 (8H, m)to 2.66 (3H, s), of 3.94 (2H, m), 4,19 (2H, square, J=7,0), and 4.40 (2H, s), 4,47 (2H, d, J=6,0), 4,84 (1H, m), to 6.43 (1H, dt, J=6,0, 16,0), to 6.57 (1H, d, J=16,0), 7,35-7,45 (2H, m), 7,50-of 7.60 (2H, m), 7,69 (1H, m), 7,73 (1H, m), 7,88 (1H, m);

IR (KBr, cm-1): 1737, 1675.

Example 91

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(tropan-3-yloxy)phenyl]sulfamoylbenzoic acid (example compound No. 1135)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(tropan-3-yloxy)phenyl]sulfamerazine (700 mg)obtained in example 90, dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 60°C for 4 hours. After cooling to room the second temperature, the reaction mixture was evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The obtained amorphous solid was dissolved in a mixture of 1 N. hydrochloric acid (3.3 ml) and water (10 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (580 mg, yield 86%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 2,05-of 2.30 (8H, m)to 2.66 (3H, s), 3,93 (2H, m), 4,27 (2H, s), 4,47 (2H, d, J=6,0), a 4.83 (1H, m), 6,44 (1H, dt, J=6,0, 16,0), to 6.57 (1H, d, J=16,0), 7,35-7,45 (2H, m), 7,50-of 7.60 (2H, m), 7,68 (1H, m), 7,73 (1H, m), 7,87 (1H, m);

IR (KBr, cm-1): 1732, 1675.

Example 92

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3,4,5,6,7,8-hexahydro-2H-asanin-9-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1171)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(piperidine-4-yloxy)phenyl]sulfamerazine (0,78 g)obtained in example 47(a), in ethanol (20 ml) at room temperature successively added 9-methoxy-3,4,5,6,7,8-hexahydro-2H-atonin (0,80 g), which is obtained from ASEAN-2-it according to the method described in Org. Prep. Proceed. Int., 24, 147 (1992), and triethylamine (0,71 ml) and the resulting mixture was stirred at room temperature for 18 hours. Since the reaction proceeds slowly, yet consistently add 9-methoxy-3,4,5,6,7,8-hexahydro-2H-atonin (0.29 grams) and tritium is n (0,53 ml) and the resulting mixture was stirred at room temperature for 72 hours. To the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (5 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 30% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get a mixture of 0.28 g of the dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3,4,5,6,7,8-hexahydro-2H-asanin-9-yl)piperidine-4-yloxy]phenyl]sulfamerazine and impurities in the form of colorless amorphous solid.

Then the mixture obtained above, dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 50°C for 6 hours, leave at room temperature for 61 hours and then stirred at 50°C for 7 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 23% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (2 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (0.09 g, yield 58%) as a colorless amorphous solid.

16) δ ppm: 1,38-of 1.81 (12H, m), 2,00-2,09 (2H, m), 2,78-to 2.85 (2H, m), 3,48 is 3.57 (2H, m), 3,59-and 3.72 (2H, m), of 3.73-3,86 (2H, m), 4,27 (2H, s), to 4.46 (2H, d, J=5.5), the 4,80-4,88 (1H, m), 6,44 (1H, dt, J=16,0, 5,5), to 6.57 (1H, d, J=16,0), 7,31 (1H, d, J=9,0), 7,40 (1H, DD, J=9,0, 2,5), 7,51-7,60 (2H, m), of 7.64 to 7.75 (2H, m), 7,87 (1H, s);

IR (KBr, cm-1): 1733, 1675, 1627, 1352, 1156.

Example 93

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 1011)

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-(piperidine-4-yloxy)phenyl]sulfamerazine (533 mg)obtained in example 59(a), in ethanol (10 ml) at room temperature successively added 2-ethoxy-4,5-dihydrooxazolo (235 mg), which is obtained from 2-oxazolidone according to the method described in Eur. J. Org. Chem., 10, 2645 (1999), and triethylamine (0,43 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 22% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (0,36 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (278 mg, yield 47%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0) of 1.66 and 1.80 (2H, m), 1,94 is 2.10 (2H, m), 3,62-3,82 (4H, m), 3,85 (2H, t, J=8,5), 4,20 (2H, square, J=7,0), 4,34 (2H, s), of 4.44 (2H, d, J=6,0), and 4.68 (1H, m), 4,79 (2H, t, J=8,5), 6,44 (1H, dt, J=16,0, 6,0), 6,56 (1H, d, J=16,0),? 7.04 baby mortality (2H, d, J=9,0), 7,39 (2H, d, J=9,0), 7,54 (1H, t, J=8.0 a), of 7.70 (2H, m), 7,88 (1H, s);

MS (FAB, M+-2HCl): 570.

Example 94

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1029)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (272 mg)obtained in example 93, dissolved in 3 N. hydrochloric acid (10 ml) and the resulting mixture was stirred at 60°C for 5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (4 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (209 mg, yield 80%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,65-of 1.81 (2H, m), 1,97 is 2.10 (2H, m), 3,43-3,62 (4H, m), 3,85 (2H, t, J=8,5), is 4.21 (2H, s), of 4.44 (2H, d, J=6,0), and 4.68 (1H, m), 4,79 (2H, t, J=8,5), 6,44 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0), 7,03 (2H, d, J=9,0), 7,39 (2H, d, J=9,0), 7,54 (1H, t, J=8.0 a), of 7.70 (2H, m), 7,88 (1H, s);

IR (KBr, cm-1): 1687, 1346, 1156.

Example 97

The dihydrochloride of these is N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 1462)

a) Ethyl N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[4-(piperidine-4-yloxy)phenyl]sulfanilate

Through a solution of ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-fluoro-2-(Z)-propenyl]sulfamerazine (1,41 g)obtained in reference example 131, in a mixture of dichloromethane (25 ml) and ethanol (25 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 10 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (30 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 0.25 g of the substance in 10 ml of water) and 28% ammonia solution (0,47 ml) and the resulting mixture left at room temperature for 8 hours. After settling to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (1 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water) and get listed in the title compound (1,00 g, 75%yield) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,24 (3H, t, J=7,0), is 1.81 (2H, m), of 2.08 (2H, m), 3,06 (2H, m), up 3.22 (2H, m), 4,20 (2H, square, J=7,0), 4,36 (2H, s), 4,56 (2H, d, J=16.5 in)and 4.65 (1H, m)5,94 (1H, d, J=39,0), 7,05 (2H, d, J=9,5), 7,40 (2H, d, J=9,5), 7,56 (1H, d, J=8,0), 7,74 (2H, m), 7,81 (1H, s).

(b) Dihydrochloride ethyl N-[3-(3-AMI is inopril)-2-fluoro-2-(Z)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine

To a solution of ethyl N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[4-(piperidine-4-yloxy)phenyl]sulfamerazine (1.27 g)obtained in example 97(a), in ethanol (50 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (0.73 g), which is obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (2.10 ml) and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time the reaction mixture still successively added 5-methoxy-3,4-dihydro-2H-pyrrole (0.73 g) and triethylamine (2.10 ml) and the resulting mixture left at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 20% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (0,80 ml), the mixture was evaporated in vacuum to dryness and receive specified in the header connection (0,60 g, yield 37%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,24 (3H, t, J=7,0), 1,68-to 1.82 (2H, m), 2,02 and 2.13 (4H, m), of 2.97 (2H, t, J=8,0), 3,47-of 3.53 (1H, m), to 3.58-to 3.73 (4H, m), 3,85-to 3.92 (1H, m), is 4.21 (2H, square, J=7,0), 4,37 (2H, s), 4,60 (2H, d, J=16,0), 4,71 (1H, m), 5,95 (1H, d, J=39,0), 7,07 (2H, d, J=9,0), 7,41 (2H, d, J=9,0), to 7.59 (1H, t, J=8.0 a), of 7.70 (1H, d, J=8,0), 7,76 (1H, d, J=8.0 a), of 7.82 (1H, s);

IR (KBr, cm-1):1672, 1354, 1161.

Example 98

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1484)

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (of 0.47 g)obtained in example 97(b), dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 70°C for 2.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (2.5 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (0.39 g, yield 86%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,68-of 1.81 (2H, m), 2,02 with 2.14 (4H, m), 2,96 (2H, t, J=8,0), 3,44-3,74 (6H, m)to 4.23 (2H, s), 4,59 (2H, d, J=16,0), 4,71 (1H, m), 5,95 (1H, d, J=39,0), 7,06 (2H, d, J=9,0), 7,42 (2H, d, J=9,0), to 7.59 (1H, t, J=8,0), to 7.68 (1H, d, J=8,0), 7,76 (1H, d, J=8,0), 7,81 (1H, s);

IR (KBr, cm-1): 1672, 1352, 1158.

Example 99

The dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine (example compound No. 1472)

a) Ethyl N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)propenyl]-N-[3-carbarnoyl-4-piperidine-4-yloxy)phenyl]sulfanilate

Through a solution of ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]-N-[3-(3-cyanophenyl)-2-fluoro-2-(Z)-propenyl]sulfamerazine (4,30 g)obtained in reference example 132, in a mixture of dichloromethane (35 ml) and ethanol (35 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 3 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (30 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 0,80 g of substance in 5 ml of water) and 28% ammonia solution (1.80 ml) and the resulting mixture left at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water) and get listed in the title compound (2.20 g, yield 58%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,24 (3H, t, J=7,0), 1,88 is 1.96 (2H, m), 2,09-2,17 (2H, m), 3,02-to 3.09 (2H, m), 3,17-3,24 (2H, m), is 4.21 (2H, square, J=7,0), and 4.40 (2H, s), to 4.62 (2H, d, J=16,0), to 4.81 (1H, m), 5,98 (1H, d, J=38,0), 7,26 (1H, d, J=9,0), 7,51 (1H, DD, J=9,0, 3,0), 7,57-7,71 (2H, m), 7,73 for 7.78 (2H, m), 7,81 (1H, s).

(b) Dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamerazine

To a solution of ethyl N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[3-carb is oil-4-(piperidine-4-yloxy)phenyl]sulfamerazine (1.20 g), obtained according to example 99(a), in ethanol (40 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (0.64 g), which is obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (1.80 ml) and the resulting mixture was stirred at room temperature for 1 hour, leave at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 15% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (5 ml) is added 4 n solution of hydrogen chloride in dioxane (1.60 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (0.40 g, yield 26%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,24 (3H, t, J=7,0), 1,81-of 1.92 (2H, m), 2,02 with 2.14 (4H, m), 2,96 (2H, t, J=8,0), 3,48-3,88 (6H, m), is 4.21 (2H, square, J=7,0), and 4.40 (2H, s), to 4.62 (2H, d, J=16,0), to 4.87 (1H, m), 5,98 (1H, d, J=39,0), 7,30 (1H, d, J=9,0), 7,49-7,63 (2H, m), 7,68 (1H, d, J=8,0), 7,74-of 7.82 (3H, m);

IR (KBr, cm-1): 1669, 1354, 1156.

Example 100

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]sulfamoylbenzoic acid (example compound No. 1494)

Ethyl N-[3-(3-amidinophenoxy)-2-fluoro-2-(Z)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]Sul is tamaraceite (0.27 g), obtained according to example 99(b), dissolved in 3 N. hydrochloric acid (20 ml) and the resulting mixture was stirred at 70°C for 2.5 hours. After cooling to room temperature the reaction mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 10% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (1.2 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (0.20 g, yield 77%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,82-of 1.93 (2H, m), 2,02-of 2.15 (4H, m), 2,96 (2H, t, J=8,0), 3,48-to 3.73 (5H, m), 3,78-3,88 (1H, m), 4,27 (2H, s), to 4.62 (2H, d, J=16,0), to 4.87 (1H, m), 5,98 (1H, d, J=39,0), 7,30 (1H, d, J=9,0), 7,49-7,71 (3H, m), 7,73-7,83 (3H, m);

IR (KBr, cm-1): 1670, 1352, 1156.

Example 101

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide (example compound No. 1384)

a) the Dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]methanesulfonamide

Through a solution of N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]methanesulfonamide (1.01 g)obtained in reference example 134, in a mixture of dichloromethane (7.5 ml) and ethanol (7.5 ml) under cooling with ice bubbled hydrogen chloride and the resulting cm is camping stirred at room temperature for 4 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (15 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 0.24 g of the substance in 3 ml of water) and 28% ammonia solution (0,43 ml) and the resulting mixture left at room temperature overnight and then evaporated in vacuum. To the obtained residue successively added ethanol (10 ml) and 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 10% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (10 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.95 g, yield 98%) as a pale yellow amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,87-of 1.97 (2H, m), 2,08-to 2.18 (2H, m), 3,06 (3H, s), 3,14-of 3.25 (2H, m), 3,65-3,74 (2H, m), of 4.45 (2H, d, J=6,0), 4,80 (1H, m), 6,46 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), of 7.23 (1H, d, J=9,0), of 7.48-to 7.59 (2H, m), 7.68 per to 7.75 (3H, m), of 7.90 (1H, s);

(b) the Dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide

To a solution of dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]means is lonarid (0.95 g), obtained in example 101(a), in ethanol (15 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (0.52 g)obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (1.20 ml), the mixture was left at room temperature overnight and at the end of a specified period of time has added successively 5-methoxy-3,4-dihydro-2H-pyrrole (0.17 g) and triethylamine (0,24 ml) and the resulting mixture was stirred at room temperature for 6 hours and then evaporated in vacuum. Then to the resulting residue successively added ethanol (10 ml) and 4 n solution of hydrogen chloride in dioxane (4 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 10% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (5 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and receive specified in the header of the connection (of 0.67 g, yield 63%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1,79-of 1.92 (2H, m), 2,02 with 2.14 (4H, m)to 2.99 (2H, t, J=8,0), 3,37 (3H, s), 3,41-to 3.58 (4H, m), 3,82-are 3.90 (2H, m), 4,46 (2H, d, J=6,0), a 4.86 (1H, m), 6,47 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), 7,26 (1H, d, J=9,0), 7,49-7,58 (2H, m), to 7.67-to 7.77 (3H, m), to $ 7.91 (1H, s);

IR (KBr, cm-1): 1669, 1334, 1151.

P the emer 102

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl)acanaloniidae (example compound No. 1406)

a) the Dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]acanalonia

Through a solution of N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]acanaloniidae (1.08 g)obtained in reference example 135, in a mixture of dichloromethane (8 ml) and ethanol (8 ml) under cooling with ice bubbled hydrogen chloride and the resulting mixture was stirred at room temperature for 4 hours in a closed reactor and then evaporated in vacuum. Then to a solution of the obtained residue in ethanol (16 ml) are added successively an aqueous solution of ammonium chloride (obtained by dissolving 0.26 g of the substance in 3 ml of water) and 28% ammonia solution (0,46 ml), the mixture was left at room temperature overnight and then evaporated in vacuum. To the obtained residue successively added ethanol (10 ml) and 4 n solution of hydrogen chloride in dioxane (2 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 10% acetonitrile/water). Then to the solution obtained amorphous solids in ethanol (10 ml) is added 4 n solution of hydrogen chloride in dioxane (2 ml) and p is obtained mixture is evaporated in vacuum to dryness and get listed in the title compound (0.68 g, yield 64%) as a pale yellow amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 1.26 in (3H, t, J=7,5), 1,86-of 1.94 (2H, m), 2,07 with 2.14 (2H, m), 3,01-to 3.09 (2H, m), 3,13 is 3.23 (4H, m), of 4.45 (2H, d, J=6,0), of 4.77 (1H, m), to 6.43 (1H, dt, J=16,0, 6,0), 6,55 (1H, d, J=16,0), 7,20 (1H, d, J=9,0), 7,46 to 7.75 (5H, m), 7,87 (1H, s).

(b) the Dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]acanalonia

To a solution of dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]acanaloniidae (0.68 g)obtained in example 102(a), in ethanol (15 ml) at room temperature successively added 5-methoxy-3,4-dihydro-2H-pyrrole (0.36 g), which is obtained from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (0,85 ml) and the resulting mixture left at room temperature overnight. At the end of this time the reaction mixture at room temperature is added successively 5-methoxy-3,4-dihydro-2H-pyrrole (0,19 g) and triethylamine (0,34 ml) and the resulting mixture was stirred at room temperature for 5 hours and then evaporated in vacuum. Then to the resulting residue successively added ethanol (10 ml) and 4 n solution of hydrogen chloride in dioxane (4 ml) and the resulting mixture is evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, Elya is NT 10% acetonitrile/water). To the obtained amorphous solid substance was added 1 N. hydrochloric acid (8 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.56 g, yield 73%) as a pale brown amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.27 (3H, t, J=7,5), 1,79 is 1.91 (2H, m), 2,02 with 2.14 (4H, m), of 2.97 (2H, t, J=7,0), 3,21 (2H, square, J=7,5), 3,47-to 3.73 (5H, m), 3,90 (1H, m), 4,47 (2H, d, J=6,0), a 4.86 (1H, m), 6,46 (1H, dt, J=16,0, 6,0), to 6.57 (1H, d, J=16,0), 7,26 (1H, d, J=9,0), 7,49-7,58 (2H, m), 7,69-7,76 (3H, m), 7,92 (1H, s);

IR (KBr, cm-1): 1671, 1331, 1146.

Example 103

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydrooxazolo-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide (example compound No. 1211)

To a solution of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]methanesulfonamide (0.32 g)obtained in example 101(a), in methanol (15 ml) at room temperature successively added 2-ethoxy-4,5-dihydrooxazolo (0.21 g), which is obtained from 2-oxazolidone according to the method described in Eur. J. Org. Chem., 10, 2645 (1999), and triethylamine (of 0.56 ml) and the resulting mixture was stirred at room temperature for 2 hours, leave at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 12% acetonitrile/water) Obtained amorphous solid was dissolved in 1 N. hydrochloric acid (2.0 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (0.11 g, yield 26%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,78-of 1.92 (2H, m), 1,98-2,11 (2H, m), 3,06 (3H, s), 3,47-3,88 (6H, m), of 4.45 (2H, d, J=5.5), the value of 4.76-4,85 (3H, m), 6,47 (1H, dt, J=16,0, 5,5), 6,59 (1H, d, J=16,0), 7,25 (1H, d, J=9,0), 7,49-7,58 (2H, m), to 7.67-7,76 (3H, m), to $ 7.91 (1H, s);

IR (KBr, cm-1): 1686, 1334, 1151.

Example 104

The dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydrothiazolo-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide (example compound No. 1269)

To a solution of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-(piperidine-4-yloxy)phenyl]methanesulfonamide (0.32 g)obtained in example 101(a), in a mixture of tetrahydrofuran (3 ml), 1,4-dioxane (3 ml) and water (3 ml) under ice cooling successively added 2-chlorozotocin (0.05 ml) and triethylamine (0,07 ml) and the resulting mixture was stirred at room temperature within 1.5 hours, leave at room temperature overnight and then evaporated in vacuum. The resulting residue is purified preparative HPLC (YMC-Pack ODS-A; YMC, eluent 12% acetonitrile/water). The obtained amorphous solid was dissolved in 1 N. hydrochloric acid (1.2 ml), the mixture was evaporated in vacuum to dryness and get listed in the title compound (0.15 g, yield 59%) as a colorless amorphous t is ejogo substances.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,82-of 1.93 (2H, m), 2,02-2,12 (2H, m), 3,06 (3H, s), 3,52-3,63 (3H, m), 3,68-3,82 (2H, m), 3,91-was 4.02 (3H, m), of 4.45 (2H, d, J=6,0), is 4.85 (1H, m), 6,47 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), to 7.25 (1H, d, J=9,0), 7,49-7,58 (2H, m), 7.68 per-7,76 (3H, m), to $ 7.91 (1H, s);

IR (KBr, cm-1): 1673, 1632, 1333, 1151.

Example 105

The dihydrochloride ethyl N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]-N-[3-[3-(ethoxycarbonyl)(imino)were]-2-(E)-propenyl]sulfamerazine

To a solution of 4-NITROPHENOL (1,00 g) in dichloromethane (20 ml) under ice cooling is added dropwise ethylchloride (0,70 ml) and pyridine (0,70 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. To the obtained residue is added ethyl acetate and the organic layer is successively washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous potassium bicarbonate and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum. Received the remaining solid is collected by filtration using hexane and obtain ethyl 4-nitrophenylarsonic (1.44 g, yield 95%) as a white solid. Then to a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (0,42 g), the scientists in example 1, in water (5 ml) was successively added a solution of the above ethyl 4-nitrophenylarsonic in dichloromethane (obtained by dissolving 0.14 g of the substance in 5 ml of dichloromethane and sodium bicarbonate (0.11 g) and the resulting mixture was stirred at room temperature for 3 hours. After stirring saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and ethanol (1:1). Then to the solution obtained amorphous solids in ethanol (5 ml) was added 1 N. hydrochloric acid (1.4 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.36 g, yield 78%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0), of 1.33 (3H, t, J=7,0), 1,90-2,07 (2H, m), 2,15 was 2.25 (2H, m), is 2.74 (3H, m), 3.00 and-3,10 (2H, m)to 3.33 (1H, m), 3,40-3,50 (1H, m), 4,19 (2H, square, J=7,0), 4,35 (2H, square, J=7,0)that was 4.42 (2H, s), 4,47 (2H, d, J=6,0), 4.62, and 4,87 (total 1H, each m), 6.42 per (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), 7,31 (1H, m), 7,40 (1H, m), 7,54 (1H, t, J=8,0), to 7.59 (1H, m), 7,66 (1H, d, J=8.0 a), of 7.75 (1H that is, J=8,0), 7,86 (1H, s);

IR (KBr, cm-1): 1742, 1674, 1354, 1157.

Example 106

The dihydrochloride ethyl N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]-N-[3-[3-(imino)(4 methoxyphenethylamine)were]-2-(E)-propenyl]sulfamerazine

To a solution of 4-methoxyphenol (1,00 g) in dichloromethane (20 ml) under ice cooling successively added dropwise 4-methoxyphenylalanine (1.25 ml) and pyridine (0,72 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum to dryness and receive bis(4-methoxyphenyl)dicarbonate (2.37 g, yield quantitative) as a white solid.

Then to a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (0.50 g)obtained in example 1, in water (10 ml) is successively added to the solution obtained above bis(4-methoxyphenyl)dicarbonate in dichloromethane (obtained by dissolving 0,22 g of sample in 10 ml of dichloromethane and sodium hydrogen carbonate (0.14 g) and the resulting mixture was stirred at room the temperature during the night. After stirring to the reaction mixture, water is added and hydrogen on the model and the resulting mixture extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and ethanol (5:2). Then to the solution obtained amorphous solids in ethanol (5 ml) was added 1 N. hydrochloric acid (1.6 ml) and the resulting mixture was evaporated in vacuum to dryness. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0,42 g, yield 67%) as a colorless amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ ppm: of 1.23 (3H, t, J=7,0)and 1.83-of 1.93 (1H, m), 2.00 in to 2.18 (2H, m), 2,20-of 2.27 (1H, m), was 2.76 (3H, m), 3.00 and-3,10 (2H, m), 3,30-3,50 (2H, m), of 3.77 (3H, s), 4,19 (2H, square, J=7,0), was 4.42 (2H, s), 4,48 (2H, d, J=6,0), 4,60 and 4,85 (total 1H, each m), to 6.39 (1H, dt, J=16,0, 6,0), 6,59 (1H, d, J=16,0), of 6.99 (2H, d, J=9,0), 7,17 (2H, d, J=9,0), 7,31 (1H, m), 7,41 (1H, m), 7,51 (1H, t, J=7,5), 7,60 (1H, m), of 7.69 (1H, d, J=7,5), 7,80 (1H, d, J=7,5), of 7.97 (1H, s);

IR (KBr, cm-1): 1740, 1671, 1354, 1161.

Example 107

Ethyl N-[3-[3-(tert-butoxycarbonylamino)(imino)were]-2-(E)-propenyl]-N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfanilate

To a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (0,43 g)obtained in example 1, in water (10 ml) was successively added a solution of d is-tert-BUTYLCARBAMATE in dichloromethane (obtained by dissolving 0.15 g of the substance in 10 ml of dichloromethane and sodium hydrogen carbonate (0.12 g) and the resulting mixture was stirred at room temperature for 5 hours. After stirring to the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and the resulting mixture extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and ethanol (5:1), and get mentioned in the title compound (0.36 g, yield 81%) as a colorless amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.35 (3H, t, J=7,0), AND 1.54 (9H, s), 1,87 is 1.96 (2H, m), 1,97-to 2.06 (2H, m), 2,32 (3H, s), 2,39 (2H, m), 2,68 (2H, m)to 3.99 (2H, s), 4,30 (2H, square, J=7,0), to 4.41 (1H, m), of 4.44 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6.42 per (1H, d, J=16,0), 6,91 (1H, d, J=9,0), 7,29 (1H, m), 7,34 (1H, t, J=8,0), was 7.45 (1H, d, J=8,0), 7,52 (1H, d, J=2,5), 7,66 (1H, d, J=8,0), 7,78 (1H, s);

IR (KBr, cm-1): 1740, 1655, 1365, 1163.

Example 108

Ethyl N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]-N-[3-[3-(4-perfunctionary)(imino)were]-2-(E)-propenyl]sulfanilate

To a solution of 4-terfenol (2.00 g) in dichloromethane (40 ml) under stirring and ice cooling successively added dropwise a solution of 4-ftorhinolonami in dichloromethane (obtained by dissolution of 2.35 ml of the substance in 5 ml of dichloromethane and pyridine (1,59 ml) and the resulting mixture was stirred at room temperature during the course the e 1.5 hours and then evaporated in vacuum. To the obtained residue is added saturated aqueous solution of sodium chloride and the resulting mixture extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The obtained white solid is collected by filtration using hexane and receive bis(4-forfinal)dicarbonate (4,25 g, yield 95%) as a white solid.

Then to a solution of dihydrochloride ethyl N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (0.50 g)obtained in example 1, in water (10 ml) is successively added to the solution obtained above bis(4-forfinal)dicarbonate in dichloromethane (obtained by dissolving 0.20 g of the substance in 10 ml of dichloromethane and sodium hydrogen carbonate (0.20 g) and the resulting mixture was stirred at room the temperature during the night. After stirring saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and ethanol (1:1), and receive specified in the header connection (0,47 g, output is 85%) as a colorless amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,86-of 1.95 (2H, m), 1,95-2,04 (2H, m), 2,31 (3H, s)to 2.35 (2H, m)to 2.66 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), and 4.40 (1H, m), 4,46 (2H, d, J=6,5), of 6.26 (1H, dt, J=16,0, 6,5), 6,47 (1H, d, J=16,0), 6,91 (1H, d, J=9,0), was 7.08 (2H, m), 7,17 (2H, m), 7,31 (1H, DD, J=9,0, 2,5), 7,42 (1H, t, J=8,0), 7,53 (1H, d, J=2,5), 7,54 (1H, d, J=8.0 a), of 7.75 (1H, d, J=8,0), 7,86 (1H, s);

IR (KBr, cm-1): 1739, 1668, 1355, 1162.

Example 109

The dihydrochloride of N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]-N-[3-[3-(ethoxycarbonyl)(imino)were]-2-(E)-propenyl]methanesulfonamide

To a solution of dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide (0,23 g)obtained in example 101(b), in a mixture of dichloromethane (4.5 ml) and N,N-dimethylformamide (1.5 ml) at room temperature successively added ethyl 4-nitrophenylarsonic (0.10 g)obtained according to example 105, and triethylamine (0.16 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and methanol(50:0~47:3). Then to a solution of the obtained oily product in ethanol (2 ml) is added 4 n solution of hydrogen chloride in dioxane (0.5 ml) and the resulting mixture was evaporated in vacuum to dryness. The amorphous TV is Joe substance is dissolved in dichloromethane, the resulting mixture was extracted with 1 N. hydrochloric acid and the collected aqueous layer was evaporated in vacuum. The resulting residue is dissolved in water and then lyophilized and get listed in the title compound (0.20 g, yield 84%) as a colorless amorphous solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: of 1.33 (3H, t, J=7,0), 1,80-of 1.92 (2H, m), 2,02 with 2.14 (4H, m), 2,96 (2H, t, J=7,5), 3,06 (3H, s), 3,47-to 3.73 (4H, m), 3,83-3,91 (2H, m), 4,35 (2H, square, J=7,0), to 4.46 (2H, d, J=6,0), to 4.87 (1H, m), of 6.45 (1H, dt, J=16,0, 6,0), 6,60 (1H, d, J=16,0), 7,28 (1H, d, J=9,0), 7,49-of 7.69 (3H, m), 7,73 for 7.78 (2H, m), 7,88 (1H, s);

IR (KBr, cm-1): 1754, 1667, 1334, 1151.

Example 110

N-[3-Carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]-N-[3-[3-(imino)(paulolino)were]-2-(E)-propenyl]methanesulfonamide

To a solution of dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide (0.20 g)obtained in example 101(b), in a mixture of dichloromethane (2.5 ml) and acetonitrile (2.5 ml) under stirring and ice cooling successively added 4-nitrophenylacetate (0.09 g) and triethylamine (0,23 ml) and the resulting mixture was stirred at room temperature for 4 hours. After stirring to the reaction mixture was added dichloromethane and the organic layer is successively washed with 1 N. aqueous sodium hydroxide solution and saturated aqueous sodium chloride, drying the over anhydrous sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and methanol (50:0~47:3) and get listed in the title compound (0.17 g, yield 86%) as a colorless amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.28 (9H, s), 1,78-of 1.88 (2H, m), 1,96-of 2.05 (2H, m), 2,07 with 2.14 (2H, m), of 2.51 (2H, t, J=8,0), 2,96 (3H, s), 3,22-and 3.31 (2H, m), 3,67 is 3.76 (4H, m), of 4.44 (2H, d, J=6,5), of 4.67 (1H, m), 6,23 (1H, dt, J=16,0, 6,5), of 6.52 (1H, d, J=16,0), 7,01 (1H, d, J=9,0), 7,38 (1H, t, J=8,0), was 7.45 (1H, d, J=8,0), 7,52 (1H, DD, J=9,0, 2,5), 7,82-7,88 (2H, m), 8,19 (1H, d, J=2,5);

IR (KBr, cm-1): 1670, 1339, 1153.

Example 111

N-[3-[3-(Benzoylamine)(imino)were]-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide

To a solution of dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide (0,30 g)obtained in example 101(b), in a mixture of dichloromethane (4 ml) and acetonitrile (4 ml) under stirring and ice cooling successively added 4-nitrophenylacetate (0.15 g) and triethylamine (of 0.28 ml) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is diluted with dichloromethane and the organic layer washed sequentially with 0.5 N. aqueous sodium hydroxide solution and saturated aqueous chlorine is Yes sodium, dried over anhydrous sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and methanol (50:0-47:3). A purified solid was dissolved in water and then lyophilized and get listed in the title compound (0.24 g, 75%yield) as a pale yellow amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,77-to 1.87 (2H, m), 1,94-2,12 (4H, m)of 2.50 (2H, t, J=8.0 a), of 2.97 (3H, s), 3,20 of 3.28 (2H, m), 3,65-3,74 (4H, m), of 4.45 (2H, d, J=6,5), of 4.66 (1H, m), 6,27 (1H, dt, J=15,5, 6,5), 6,56 (1H, d, J=15,5), 7,01 (1H, d, J=9,0), 7,42-7,56 (6H, m), 7,94-8,02 (2H, m), to 8.20 (1H, d, J=2,5), at 8.36 (2H, d, J=7,5);

IR (KBr, cm-1): 1670, 1339, 1153.

Example 112

N-[3-[3-(Acetylamino)(imino)were]-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide

To a solution of dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide (0,29 g)obtained in example 101(b), in a mixture of dichloromethane (3 ml) and acetonitrile (3 ml) under stirring and ice cooling successively added 4-nitrophenylacetate (0.09 g) and triethylamine (of 0.26 ml) and the resulting mixture was stirred at room temperature for 4 hours. After stirring to the reaction mixture was added dichloromethane and the organic clipsremovable washed with 0.5 N. aqueous solution of sodium hydroxide and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and methanol (50:0-47:3). The obtained solid substance is dissolved in water and then lyophilized and get listed in the title compound (0.16 g, yield 58%) as a pale yellow amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,78-of 1.88 (2H, m), 1,97-of 2.15 (4H, m), is 2.30 (3H, s), 2,52 (2H, t, J=8,0), 2,96 (3H, s), 3,22-and 3.31 (2H, m), 3,66-of 3.77 (4H, m), of 4.44 (2H, d, J=6,5), and 4.68 (1H, m), of 6.26 (1H, dt, J=15,5, 6,5), 6,50 (1H, d, J=15,5), 7,01 (1H, d, J=9,0), 7,37-7,53 (3H, m), 7,72 for 7.78 (2H, m), 8,18 (1H, d, J=3,0);

IR (KBr, cm-1): 1668, 1338, 1152.

Example 113

N-[3-Carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]-N-[3-[3-(imino)(4 methoxyphenethylamine)were]-2-(E)-propenyl]methanesulfonamide

To a solution of 4-NITROPHENOL (1,00 g) in dichloromethane (30 ml) under stirring and ice cooling is added dropwise 4-methoxyphenylalanine (1,10 ml) and pyridine (0,64 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. To the obtained residue is added ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sulfate on the rija and evaporated in vacuum. The obtained white solid is collected by filtration using hexane and receive (4-methoxyphenyl)(4-nitrophenyl)carbonate (1,72 g, yield 83%) as a white solid.

Then to a solution of dihydrochloride of N-[3-(3-amidinophenoxy)-2-(E)-propenyl]-N-[3-carbarnoyl-4-[1-(4,5-dihydro-3H-pyrrol-2-yl)piperidine-4-yloxy]phenyl]methanesulfonamide (0,29 g)obtained in example 101(b), in a mixture of dichloromethane (3.5 ml) and acetonitrile (3.5 ml) are successively added (4-methoxyphenyl)(4-nitrophenyl)carbonate (0.15 g)obtained above and triethylamine (0,27 ml) and the resulting mixture was stirred at room temperature for 1.5 hours. After stirring the reaction mixture is diluted with dichloromethane and the organic layer washed sequentially with 0.5 N. aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using a mixed solvent containing dichloromethane and methanol(20:0~19:1). The obtained purified reaction product is dissolved in water and then lyophilized and get listed in the title compound (0,23 g, yield 69%) as a colorless amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,77-of 1.88 (2H, m), 1,94 and 2.13 (4H, m), of 2.51 (2H, t, J=8.0 a), of 2.97 (3H, s), 3,21-and 3.31 (2H, m), 3,643,84 (7H, m), 4,43 (2H, d, J=6,5), and 4.68 (1H, m), 6,27 (1H, dt, J=15,5, 6,5), 6,51 (1H, d, J=15,5), 6,91 (2H, d, J=8,5), 7,01 (1H, d, J=9,0), 7,13 (2H, d, J=8,5), 7,40 (1H, t, J=7,5), 7,47-rate of 7.54 (2H, m), 7,80-of 7.90 (2H, m), 8,18 (1H, d, J=2,5);

IR (KBr, cm-1): 1668, 1338, 1152.

Reference example 1

3-Cyanocinnamate

To a solution of 3-cyanobenzaldehyde (4.5 g) in toluene (200 ml) add (triphenylphosphorane)acetaldehyde (13,6 g) and the resulting mixture was stirred at 70°C for 4 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using dichloromethane as eluent. The resulting crude reaction product is recrystallized from a mixture of toluene and hexane and get listed in the title compound (3,09 g, yield 57%) as pale yellow needle crystals.

1H NMR (500 MHz, CDCl3) δ ppm: 6,76 (1H, DD, J=16,0, 7,5), 7,46 (1H, d, J=16,0), 7,58 (1H, t, J=8,0), 7,73 (1H, d, J=8,0), 7,80 (1H, d, J=8,0), to 7.84 (1H, s), of 9.75 (1H, d, J=7,5).

Reference example 2

3-(3-Cyanophenyl)-2-(E)-propen-1-ol

To a solution of 3-cyanocinnamate (3.00 g)obtained in reference example 1 in a mixture of dichloromethane (30 ml) and ethanol (70 ml) under ice cooling successively added sodium borohydride (1,32 g) and cerium chloride (2,49 g) and the resulting mixture was stirred at the same temperature for 1.5 hours. After stirring to the reaction mixture is added saturated aqueous solution of ammonium chloride and the floor is obtained mixture is extracted three times with dichloromethane. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (3,27 g, yield quantitative) as a pale yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: 4,37 (2H, m), to 6.43 (1H, dt, J=16,0, 5,0), 6,62 (1H, d, J=16,0), the 7.43 (1H, t, J=8,0), 7,52 (1H, d, J=8,0), 7,60 (1H, d, J=8.0 a), the 7.65 (1H, s).

Reference example 3

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-chloronitrobenzene

To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (3,32 g), 2-chloro-4-NITROPHENOL (2,36 g) and triphenylphosphine (5,11 g) in dichloromethane (60 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (3,10 ml) and the resulting mixture was stirred at room temperature for 18 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (5:2), and get mentioned in the title compound (3,90 g, yield 76%) as a pale yellow solid.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.48 (9H, s), 1,84-to 1.98 (4H, m), of 3.54 (2H, m), 3,62 (2H, m), to 4.73 (1H, m), 7,00 (1H, is, J=9,0), 8,14 (1H, DD, J=9,0, 3,0), 8,31 (1H, d, J=3,0).

Reference example 4

3-Chloro-4-(1-methylpiperidin-4-yloxy)nitrobenzene

To a suspension of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-chloronitrobenzene (1.50 g)obtained in reference example 3 in 90% formic acid (4,00 g) added 37% formaldehyde (2.50 g) and the resulting mixture was stirred at 100°C for 2 hours. After cooling to room temperature the reaction mixture was neutralized with an aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (1.12 g, yield 98%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,90-2,10 (4H, m), of 2.33 (3H, s), 2,35 at 2.45 (2H, m), 2,60-2,70 (2H, m), 4,58 (1H, m), 6,98 (1H, d, J=9,0), 8,13 (1H, DD, J=9,0, 3,0), 8,30 (1H, d, J=3,0).

Reference example 5

3-Chloro-4-(1-methylpiperidin-4-yloxy)aniline

To a solution of 3-chloro-4-(1-methylpiperidin-4-yloxy)nitrobenzene (8,48 g)obtained in reference example 4 in acetic acid (200 ml) at room temperature add powder tin (18,59 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with an aqueous solution CT is onata potassium and extracted five times with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (3:1) and receive specified in the header of the connection (of 6.95 g, yield 92%) as a reddish brown solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,82-2,02 (4H, m), 2,20-of 2.30 (2H, m), is 2.30 (3H, s), 2,68-2,78 (2H, m), of 4.12 (1H, m), 6,51 (1H, DD, J=8,5, 3,0), 6,72 (1H, d, J=3,0), for 6.81 (1H, d, J=8,5).

Reference example 6

Ethyl N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfanilate

To a solution of 3-chloro-4-(1-methylpiperidin-4-yloxy)aniline (6,95 g)obtained in reference example 5, in dichloromethane (150 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (3,88 ml) and pyridine (4,67 ml) and the resulting mixture was stirred at room temperature for 5 hours. After stirring to the reaction mixture, water is added and the resulting mixture is extracted three times with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(4:1~1:1), and get listed in the title compound (9,12 g, o is d 81%) as a brown solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 1,90-2,00 (2H, m), 2.00 in of 2.10 (2H, m), is 2.37 (3H, s), 2.40 a-2,50 (2H, m), 2.70 height is 2.80 (2H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), to 4.41 (1H, m), 6,93 (1H, d, J=9,0), 7,21 (1H, DD, J=9,0, 2,5), 7,40 (1H, d, J=2,5).

Reference example 7

Ethyl N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (3,30 g)obtained in reference example 2, ethyl N-[3-chloro-4-(1-methylpiperidin-4-yloxy)phenyl]sulfamerazine (7,37 g)obtained in reference example 6, and triphenylphosphine (5,93 g) in dichloromethane (200 ml) under cooling with ice and stirring is added dropwise diethylazodicarboxylate (3,49 ml) and the resulting mixture was stirred at room temperature over night and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing methanol and ethyl acetate(1:3~2:1), and get listed in the title compound (7,29 g, yield 73%) as an orange amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,85-of 1.95 (2H, m), 1,95-of 2.05 (2H, m), 2,31 (3H, s), 2,30-to 2.40 (2H, m), 2,60-2,70 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), and 4.40 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,92 (1H, d, J=9,0), 7,31 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=8,0), 7,46-7,58 (4H, m).

Reference example 8

3-Chloro-4-(piperidine-4-yloxy)nitrobenzene

To a solution of 4-(1-tert-butoxycarbonylamino-4-ilxi)-3-chloronitrobenzene (to $ 7.91 g)obtained in reference example 3 in dioxane (80 ml) at room temperature is added 4 n solution of hydrogen chloride in dioxane (70 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is dissolved in water and neutralized with sodium bicarbonate. The separated crystalline substance is collected by filtration and receive specified in the header connection (8.06 g, yield quantitative) as pale yellow needle crystals.

1H NMR (500 MHz, DMSO-d6) δ ppm: 1,50-1,60 (2H, m), 1,90-2,00 (2H, m), 2.57 m) of 2.68 (2H, m), 2,90-of 3.00 (2H, m), of 3.96 (1H, m), 7,45 (1H, d, J=9,0), 8,18 (1H, DD, J=9,0, 3,0), 8,31 (1H, d, J=3,0).

Reference example 9

4-(1-Acetylpiperidine-4-yloxy)-3-chloronitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (1,00 g)obtained in reference example 8, in pyridine (20 ml) under stirring and ice cooling is added dropwise acetic anhydride (0,55 ml) and the resulting mixture was stirred at room temperature for 3 hours. After stirring to the reaction mixture, water is added and the resulting mixture extracted with ethyl acetate. The extract is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride and the tub over anhydrous magnesium sulfate. The organic layer is evaporated in vacuum and receive specified in the header of the connection (of 1.05 g, yield 90%) as a pale yellow solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,88-2,03 (4H, m), and 2.14 (3H, s), 3,50-3,63 (2H, m), 3,71 (1H, m), of 3.94 (1H, m), to 4.81 (1H, m), 7,01 (1H, d, J=9,0), 8,15 (1H, DD, J=9,0, 2,5), 8,32 (1H, d, J=2,5).

Reference example 10

4-(1-Acetylpiperidine-4-yloxy)-3-Chloroaniline

To a solution of 4-(1-acetylpiperidine-4-yloxy)-3-chloronitrobenzene (of 1.05 g)obtained in reference example 9, in acetic acid (30 ml) at room temperature add powder tin (2,09 g) and the resulting mixture was stirred at room temperature for 10 hours. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with an aqueous solution of potassium carbonate and extracted five times with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol (15:1), and receive specified in the header connection (0,82 g, yield 86%) as an orange oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,78-of 1.94 (4H, m), 2,11 (3H, s), 3.33 and-of 3.43 (1H, m), 3,60-3,70 (1H, m), 3,70-3,82 (2H, m), 4,35 (1H, m), 6,53 (1H, DD, J=8,5, 3,0), 6,74 (1H, d, J=3,0), for 6.81 (1H, d, J=8,5).

Reference primer

3-Chloro-4-(1-ethylpiperazin-4-yloxy)aniline

To a suspension of lithium aluminum hydride (230 mg) in tetrahydrofuran (5 ml) under stirring and ice cooling in a nitrogen atmosphere is added dropwise a solution of 4-(1-acetylpiperidine-4-yloxy)-3-Chloroaniline, obtained in reference example 10, in tetrahydrofuran (10 ml) and the resulting mixture is refluxed for 3.5 hours. After boiling to the reaction mixture add alumoweld lithium (115 mg) and the resulting mixture is refluxed for 2 hours. After cooling to room temperature, to the reaction mixture add decahydrate sodium sulfate and the resulting mixture is still stirred at room temperature overnight. After removal by filtration of insoluble matters, the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(3:1~1:2), and get listed in the title compound (448 mg, yield 58%) as a brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,11 (3H, t, J=7,0), 1,82-of 1.93 (2H, m), 1.93 and-2,04 (2H, m)to 2.29 (2H, m), of 2.45 (2H, square, J=7,0), 2,78 (2H, m), is 4.15 (1H, m), 6,51 (1H, DD, J=8,5, 3,0), was 6.73 (1H, d, J=3,0), for 6.81 (1H, d, J=8,5).

Reference example 12

Ethyl N-[3-chloro-4-(1-ethylpiperazin-4-yloxy)phenyl]sulfanilate

To a solution of 3-the ENT-4-(1-ethylpiperazin-4-yloxy)aniline (853 mg), obtained in reference example 11, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0.45 ml) and pyridine (0.54 ml) and the resulting mixture was stirred at room temperature for 4 hours. After stirring to the reaction mixture, water is added and the resulting mixture was extracted twice with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(3:1~1:1), and get listed in the title compound (1113 mg, yield 82%) as a yellowish brown amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: to 1.15 (3H, t, J=7,0), of 1.34 (3H, t, J=7,0), 1,87 is 2.00 (2H, m), 2.00 in to 2.13 (2H, m), 2,40-2,60 (4H, m), 2,70-and 2.83 (2H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), 4,43 (1H, m), 6,93 (1H, d, J=9,0), 7,21 (1H, DD, J=9,0, 2,5), 7,40 (1H, d, J=2,5).

Reference example 13

Ethyl N-[3-chloro-4-(1-ethylpiperazin-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0,48 g)obtained in reference example 2, ethyl N-[3-chloro-4-(1-ethylpiperazin-4-yloxy)phenyl]sulfamerazine (1,11 g)obtained in reference example 12, and triphenylphosphine (0.87 g) in dichloromethane (20 ml) under cooling with ice and premesis the NII is added dropwise diethylazodicarboxylate (0.51 ml) and the resulting mixture was stirred at room temperature over night and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing methanol and ethyl acetate(1:3~1:1), and get listed in the title compound (1.24 g, yield 83%) as an orange amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.12 (3H, t, J=7,0), of 1.36 (3H, t, J=7,0), 1,86-to 1.98 (2H, m), 1,98 is 2.10 (2H, m), 2,35-of 2.50 (2H, m), 2,48 (2H, square, J=7,0), by 2.73 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,43 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,93 (1H, d, J=9,0), 7,31 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=7,5), of 7.48-7,58 (4H, m).

Reference example 14

3-Chloro-4-(isopropylpiperazine-4-yloxy)nitrobenzene

To a suspension of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (1.50 g)obtained in reference example 8, in acetone (20 ml) under ice cooling successively added acetic acid (0.33 ml) and cyanoborohydride sodium (0.18 g) and the resulting mixture was stirred at room temperature for 4.5 hours. After stirring to the reaction mixture add cyanoborohydride sodium (0.18 g) and the resulting mixture was stirred at room temperature for 3 hours. After stirring to the reaction mixture still successively added acetic acid (0.33 ml) and cyanoborohydride sodium (0.18 g) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. Received OS is atok neutralized with an aqueous solution of potassium carbonate and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (1,36 g, yield 78%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,09 (6H, d, J=6,5), 1,90-2,00 (2H, m), 2.00 in to 2.15 (2H, m), 2,45-2,60 (2H, m), 2,75-2,90 (3H, m), 4,59 (1H, m), 6,98 (1H, d, J=9,0), 8,13 (1H, DD, J=9,0, 3,0), 8,30 (1H, d, J=3,0).

Reference example 15

3-Chloro-4-(1-isopropylpiperazine-4-yloxy)aniline

To a solution of 3-chloro-4-(1-isopropylpiperazine-4-yloxy)nitrobenzene (1,36 g)obtained in reference example 14, in acetic acid (30 ml) at room temperature add powder tin (2.70 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with an aqueous solution of potassium carbonate and extracted three times with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(5:1~1:1), and get listed in the title compound (0,99 g, yield 81%) as a brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.15 (6H, d, J=6,5), 1,80-2,20 (4H, m)to 2.66 (2H, m), of 2.97 (2H, m), 3,03 (1H, m), 4,27 (1H, m), of 6.52 (1H, DD, J=8,5, 3,0), ,73 (1H, d, J=3,0), to 6.80 (1H, d, J=8,5).

Reference example 16

Ethyl N-[3-chloro-4-(1-isopropylpiperazine-4-yloxy)phenyl]sulfanilate

To a solution of 3-chloro-4-(1-isopropylpiperazine-4-yloxy)aniline (985 mg)obtained in reference example 15, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,49 ml) and pyridine (0,59 ml) and the resulting mixture was stirred at room temperature for 4 hours. After stirring to the reaction mixture, water is added and the resulting mixture was extracted twice with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(10:1~3:1), and get listed in the title compound (1094 mg, 71%yield) as an orange amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,10 (6H, d, J=6,5), of 1.33 (3H, t, J=7,0), 1,84-to 1.98 (2H, m), 1,98-2,12 (2H, m)of 2.50 (2H, m), was 2.76-2,90 (3H, m)to 3.92 (2H, s), the 4.29 (2H, square, J=7,0), 4,39 (1H, m), 6,93 (1H, d, J=9,0), 7,20 (1H, DD, J=9,0, 2,5), 7,39 (1H, d, J=2,5).

Reference example 17

Ethyl N-[3-chloro-4-(1-isopropylpiperazine-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0,46 g)obtained in reference example 2, the Teal, N-[3-chloro-4-(1-isopropylpiperazine-4-yloxy)phenyl]sulfamerazine (1,09 g), obtained in reference example 16, and triphenylphosphine (0,82 g) in dichloromethane (30 ml) under cooling with ice and stirring is added dropwise diethylazodicarboxylate (0,48 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing methanol and ethyl acetate(1:2~1:1), and get listed in the title compound (1,17 g, yield 80%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,08 (6H, d, J=6,5), of 1.36 (3H, t, J=7,0), 1,84-of 1.95 (2H, m), 1,95-of 2.09 (2H, m), 2,47 (2H, m), 2,72-is 2.88 (3H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), to 4.41 (1H, m), 4,46 (2H, d, J=6,5), 6,22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,92 (1H, d, J=9,0), 7,31 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=8.0 a), of 7.48-7,58 (4H, m).

Reference example 18

4-(1-Butylpiperazine-4-yloxy)-3-chloronitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (1.50 g)obtained in reference example 8, and butylaldehyde (1,04 ml) in dichloromethane (30 ml) under stirring and ice cooling successively added acetic acid (0.33 ml) and cyanoborohydride sodium (0.18 g) and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time the reaction mixture even add cyanoborohydride sodium (0.18 g) and the resulting mixture was stirred at room is temperature overnight and then evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the solution washed sequentially with water, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing methanol and dichloromethane (1:20), and get mentioned in the title compound (0.88 g, yield 48%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 0.94 (3H, t, J=7,5), of 1.35 (2H, m)of 1.53 (2H, m), 1,92-2,04 (2H, m), 2,04-of 2.15 (2H, m)2,44 (2H, m), 2,53 (2H, m)of 2.75 (2H, m), to 4.62 (1H, m), of 6.99 (1H, d, J=9,0), 8,13 (1H, DD, J=9,0, 2,5), 8,30 (1H, d, J=2,5).

Reference example 19

4-(1-Butylpiperazine-4-yloxy)-3-Chloroaniline

To a solution of 4-(1-butylpiperazine-4-yloxy)-3-chloronitrobenzene (1.48 g)obtained in reference example 18, in acetic acid (30 ml) at room temperature add powder tin (2,81 g) and the resulting mixture was stirred at the same temperature throughout the night. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with an aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatograph is she on silica gel using as eluent a mixed solvent, containing dichloromethane and methanol(5:1~3:1), and get listed in the title compound (1,09 g, yield 82%) as a brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 0.93 (3H, t, J=7,5), of 1.34 (2H, m)to 1.60 (2H, m), 1,92-2,02 (2H, m), 2,08-to 2.18 (2H, m), 2,62 (2H, m), and 2.79 (2H, m)to 2.94 (2H, m), or 4.31 (1H, m), of 6.52 (1H, DD, J=8,5, 3,0), was 6.73 (1H, d, J=3,0), 6,79 (1H, d, J=8,5).

Reference example 20

Ethyl N-[4-(1-butylpiperazine-4-yloxy)-3-chlorophenyl]sulfanilate

To a solution of 4-(1-butylpiperazine-4-yloxy)-3-Chloroaniline (1,09 g)obtained in reference example 19, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,52 ml) and pyridine (of 0.62 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(20:1~9:1), and get listed in the title compound (1,41 g, yield 84%) as a brown amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 0.93 (3H, t, J=7,5), of 1.34 (3H, t, J=7,0), 1,28-to 1.38 (2H, m), and 1.54 (2H, m), 1,86 of 1.99 (2H, m), 2,02-of 2.15 (2H, m), 2,40-2,60 4H, m), and 2.79 (2H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), to 4.41 (1H, m), 6,93 (1H, d, J=9,0), 7,21 (1H, DD, J=9,0, 2,5), 7,40 (1H, d, J=2,5).

Reference example 21

Ethyl N-[4-(1-butylpiperazine-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0,57 g)obtained in reference example 2, ethyl N-[4-(1-butylpiperazine-4-yloxy)-3-chlorophenyl]sulfamerazine (1,41 g)obtained in reference example 20, and triphenylphosphine (1,02 g) in dichloromethane (30 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,60 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing methanol and ethyl acetate(1:20~1:10), and get listed in the title compound (1,17 g, yield 63%) as a yellowish brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 0.93 (3H, t, J=7,5), of 1.36 (3H, t, J=7,0), 1,28-of 1.40 (2H, m), 1,48 is 1.60 (2H, m), 1.85 to a 2.00 (2H, m), 2.00 in to 2.15 (2H, m), 2,38-of 2.58 (4H, m), 2,77 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), to 4.38-to 4.52 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,93 (1H, d, J=9,0), 7,31 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=8.0 a), of 7.48-7,58 (4H, m).

Reference example 22

4-(1-Benzylpiperidine-4-yloxy)-3-chloronitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (1,00 g)obtained in the SS is Lochem example 8, in N,N-dimethylformamide (20 ml) under stirring and ice cooling consistently add benzylbromide high (0.56 ml) and potassium carbonate (0,81 g) and the resulting mixture was stirred at room temperature for 5 hours. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (2:5~only ethyl acetate), and get mentioned in the title compound (1,02 g, 75%yield) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm: 1,88-to 1.98 (2H, m), 1,98-of 2.08 (2H, m), 2,42 (2H, m), of 2.72 (2H, m), 3,55 (2H, s), 4,58 (1H, m), 6,97 (1H, d, J=9,0), 7.23 percent-7,37 (5H, m)to 8.12 (1H, DD, J=9,0, 2,5), 8,30 (1H, d, J=2,5).

Reference example 23

4-(1-Benzylpiperidine-4-yloxy)-3-Chloroaniline

To a solution of 4-(1-benzylpiperidine-4-yloxy)-3-chloronitrobenzene (1,02 g)obtained in reference example 22, in acetic acid (40 ml) at room temperature add powder tin (1.75 g) and the resulting mixture was stirred at the same temperature throughout the night. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with an aqueous solution of hydro is of carbonate sodium and extracted twice with ethyl acetate. The extract is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol (10:1), and receive specified in the header connection (0,78 g, yield 84%) as a brown oil.

1H NMR (400 MHz, CDCl3) δ ppm: 1,80-1,90 (2H, m), 1,90-2,00 (2H, m), and 2.26 (2H, m), was 2.76 (2H, m), 3,52 (2H, s), of 4.12 (1H, m), 6,50 (1H, DD, J=8,5, 3,0), 6,72 (1H, d, J=3,0), to 6.80 (1H, d, J=8,5), 7,25 (1H, m), 7,28 and 7.36 (4H, m).

Reference example 24

Ethyl N-[4-(1-benzylpiperidine-4-yloxy)-3-chlorophenyl]sulfanilate

To a solution of 4-(1-benzylpiperidine-4-yloxy)-3-Chloroaniline (780 mg)obtained in reference example 23, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0.35 ml) and pyridine (0,40 ml) and the resulting mixture was stirred at room temperature for 2.5 hours and then evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified to lodochnoy chromatography on silica gel using as eluent a mixed solvent, containing ethyl acetate and methanol (25:2), and get mentioned in the title compound (1018 mg, yield 89%) as a yellowish brown amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.33 (3H, t, J=7,0), 1,84-of 1.93 (2H, m), 1.93 and-2,02 (2H, m), a 2.36 (2H, m), 2,73 (2H, m), of 3.54 (2H, s), 3,91 (2H, s), the 4.29 (2H, square, J=7,0), 4,37 (1H, m), 6,92 (1H, d, J=9,0), 7,19 (1H, DD, J=9,0, 2,5), 7,27 (1H, m), 7,29-7,37 (4H, m), 7,38 (1H, d, J=2,5).

Reference example 25

Ethyl N-[4-(1-benzylpiperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0.36 g)obtained in reference example 2, ethyl N-[4-(1-benzylpiperidine-4-yloxy)-3-chlorophenyl]sulfamerazine (1,02 g)obtained in reference example 24, and triphenylphosphine (0,69 g) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,40 ml) and the resulting mixture was stirred at room temperature for 2 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent ethyl acetate and get listed in the title compound (1,53 g, yield quantitative) as a yellow-brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.35 (3H, t, J=7,0), 1,84-of 1.93 (2H, m), 1.93 and-2,02 (2H, m), a 2.36 (2H, m), 2,71 (2H, m), 3,53 (2H, s), 3,98 (2H, s), 4,30 (2H, square, J=7,0), and 4.40 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=6,0), 6,91 (1H, d, J=9,0), 7.23 percent-7,37 (6H, m), 7,40 (1H, t, J=8,0), 7,44-7,58 (4H, m).

Reference example 26

3-Chloro-4-(1-finetipped-4-yloxy)nitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (957 mg)obtained in reference example 8, N,N-dimethylformamide (20 ml) under stirring and ice cooling consistently add geneticbased (0,61 ml) and potassium carbonate (770 mg) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (1:5~only ethyl acetate), and get mentioned in the title compound (936 mg, yield 70%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,93-2,03 (2H, m), 2,03 and 2.13 (2H, m), 2,46 at 2.59 (2H, m), 2,61-a 2.71 (2H, m), 2,73-is 2.88 (4H, m), br4.61 (1H, m), of 6.99 (1H, d, J=9,0), 7,17-7,24 (3H, m), 7.24 to 7,34 (2H, m), 8,13 (1H, DD, J=9,0, 3,0), 8,31 (1H, d, J=3,0).

Reference example 27

3-Chloro-4-(1-finetipped-4-yloxy)aniline

To a solution of 3-chloro-4-(1-finetipped-4-yloxy)nitrobenzene (936 mg)obtained in reference example 26, in acetic acid (40 ml) at ControlTemplate add powder tin (1540 mg) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with an aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate. The extract is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol (10:1), and get mentioned in the title compound (720 mg, yield 84%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,83-of 1.95 (2H, m), 1,95 e 2.06 (2H, m), is 2.37 (2H, m), 2,58-to 2.67 (2H, m), 2.77-to only 2.91 (4H, m)to 4.16 (1H, m), of 6.52 (1H, DD, J=8,5, 3,0), was 6.73 (1H, d, J=3,0), PC 6.82 (1H, d, J=8,5), 7,17-7,24 (3H, m), from 7.24 to 7.32 (2H, m).

Reference example 28

Ethyl N-[3-chloro-4-(1-finetipped-4-yloxy)phenyl]sulfanilate

To a solution of 3-chloro-4-(1-finetipped-4-yloxy)aniline (720 mg)obtained in reference example 27, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,31 ml) and pyridine (0.35 ml) and the resulting mixture was stirred at room temperature for 3 hours and then evaporated in vacuum. The resulting residue is diluted with ethylacetate the organic layer is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol (25:2), and get mentioned in the title compound (936 mg, yield 89%) as a yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 1,88-to 1.98 (2H, m), 1,98-of 2.08 (2H, m), 2,48 (2H, m), 2,60-2,70 (2H, m), was 2.76-2,89 (4H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), to 4.41 (1H, m), 6,93 (1H, d, J=9,0), 7,18-7,24 (4H, m), 7.24 to 7,33 (2H, m), 7,39 (1H, d, J=2,5).

Reference example 29

Ethyl N-[3-chloro-4-(1-finetipped-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (325 mg)obtained in reference example 2, ethyl N-[3-chloro-4-(1-finetipped-4-yloxy)phenyl]sulfamerazine (936 mg)obtained in reference example 28, and triphenylphosphine (610 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,36 ml) and the resulting mixture was stirred at room temperature for 4 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and dichloromethane (1:2~only ethyl acetate), and receive specified in the header connect the out (1013 mg, yield 84%) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,87-to 1.98 (2H, m), 1,98-of 2.09 (2H, m), 2,47 (2H, m), 2,60 of 2.68 (2H, m), was 2.76-2,87 (4H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,43 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,93 (1H, d, J=9,0), 7,17-of 7.23 (3H, m), 7.23 percent-7,34 (3H, m), 7,40 (1H, t, J=8.0 a), of 7.48-7,58 (4H, m).

Reference example 30

3-Chloro-4-(1-phenylpiperidine-4-yloxy)nitrobenzene

3-Chloro-4-(piperidine-4-yloxy)nitrobenzene (2,68 g)obtained in reference example 8, brobinson (1.97 g), 2-(di-tert-butylphosphino)biphenyl (0,62 g), Tris(dibenzylideneacetone)dipalladium (0.95 g) and tert-piperonyl sodium (1.20 g) suspended in toluene (30 ml) and the resulting mixture was stirred at 80°C for 2 hours. After cooling to room temperature, insoluble matter is filtered off and the filtrate evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (4:1), and get mentioned in the title compound (1.86 g, yield 54%) as a yellow solid.

1H NMR 400 MHz, CDCl3) δ ppm: 2,00-2,10 (2H, m), 2,11-of 2.21 (2H, m), 3,24 (2H, m), of 3.48 (2H, m), to 4.73 (1H, m), to 6.88 (1H, t, J=7,5), 6,95-7,00 (2H, m), 7,03 (1H, d, J=9,0), 7,25-to 7.32 (2H, m), 8,15 (1H, DD, J=9,0, 3,0), 8,31 (1H, d, J=3,0).

Reference example 31

3-Chloro-4-(1-phenylpiperidine-4-yloxy)aniline

To a solution of 3-chloro-4-(1-phenylpiperidine-4-yloxy)nitrobenzene (1.86 g)obtained in reference example 30, in acetic acid (35 ml) at room temperature add powder tin (of 3.32 g) and the resulting mixture was stirred at room temperature for 1 hour. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (1,69 g, yield quantitative) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,90 for 2.01 (2H, m), 2,03-2,12 (2H, m), of 3.07 (2H, m), 3,55 (2H, m), 4,27 (1H, m), 6,53 (1H, DD, J=8,5, 3,0), 6,74 (1H, d, J=3,0), for 6.81-6.87 in (1H, m), at 6.84 (1H, d, J=8,5), of 6.96 (2H, d, J=8,0), of 7.23-7.29 trend (2H, m).

Reference example 32

Ethyl N-[3-chloro-4-(1-phenylpiperidine-4-yloxy)phenyl]sulfanilate

To a solution of 3-chloro-4-(1-phenylpiperidine-4-yloxy)aniline (1,69 g)obtained in reference example 31, in dichloromethane (25 ml) under which remesiana and ice cooling successively added dropwise a solution of ethylchlorothioformate (1,15 g) in dichloromethane (5 ml) and pyridine (0,50 ml) and the resulting mixture was stirred at room temperature for 2 hours. After stirring to the reaction mixture is added saturated aqueous solution of sodium chloride and the resulting mixture extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and hexane (2:3), and receive specified in the header of the connection (of 2.23 g, yield 88%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 1,95-of 2.05 (2H, m), 2.06 to to 2.15 (2H, m), 3,17 (2H, m), 3,50 (2H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), to 4.52 (1H, m)6,86 (1H, t, J=7,5), 6,94-7,00 (2H, m), 6,97 (1H, d, J=9,0), of 7.23 (1H, DD, J=9,0, 2,5), 7,25-7,30 (2H, m), 7,40 (1H, d, J=2,5).

Reference example 33

Ethyl N-[3-chloro-4-(1-phenylpiperidine-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0,41 g)obtained in reference example 2, ethyl N-[3-chloro-4-(1-phenylpiperidine-4-yloxy)phenyl]sulfamerazine (1,16 g)obtained in reference example 32, and triphenylphosphine (0.87 g) in dichloromethane (25 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,52 ml) and the resulting mixture was stirred at room temperature for 1 hours and then evaporated in vacuum. The resulting residue is purified count the night chromatography on silica gel using as eluent a mixed solvent, containing ethyl acetate and dichloromethane (1:12), and get mentioned in the title compound (1.45 g, yield 95%) as a colorless amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,95-of 2.05 (2H, m), 2.06 to of 2.16 (2H, m), 3,18 (2H, m), 3,49 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,0), 4,55 (1H, m), 6,23 (1H, dt, J=16,0, 6,0), 6.42 per (1H, d, J=16,0), 6,86 (1H, t, J=7,5), 6,93-6,99 (2H, m), 6,97 (1H, d, J=9,0), 7,24-7,30 (2H, m), 7,33 (1H, DD, J=9,0, 2,5), 7,41 (1H, t, J=7,5), 7,49-7,58 (4H, m).

Reference example 34

3-Chloro-4-(1-methoxycarbonylmethylene-4-yloxy)nitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (1,00 g)obtained in reference example 8, N,N-dimethylformamide (20 ml) under stirring and ice cooling consistently add methylbromide (0,43 ml) and potassium carbonate (0,81 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent ethyl acetate and get listed in the title compound (1,16 g, yield 90%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm: 1,93-2,04 (2H, m), 2,04-of 2.15 (2H, m), 2,59-2,69 (2H, m), 2,73-and 2.83 (2H, m), 3,29 (2H, s),3,74 (3H, C)to 4.62 (1H, m), 6,98 (1H, d, J=9,0), 8,13 (1H, DD, J=9,0, 2,5), 8,31 (1H, d, J=2,5).

Reference example 35

3-Chloro-4-(1-methoxycarbonylmethylene-4-yloxy)aniline

To a solution of 3-chloro-4-(1-methoxycarbonylmethylene-4-yloxy)nitrobenzene (1,16 g)obtained in reference example 34, in acetic acid (30 ml) at room temperature add powder tin (2,09 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol (25:1), and receive specified in the header connection (0,79 g, 75%yield) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,87-of 1.95 (2H, m), 1,95-2,03 (2H, m), 2,43 of $ 2.53 (2H, m), 2.77-to of 2.86 (2H, m)of 3.25 (2H, s), of 3.73 (3H, s), 4,17 (1H, m), 6,51 (1H, DD, J=8,5, 3,0), was 6.73 (1H, d, J=3,0), to 6.80 (1H, d, J=8,5).

Reference example 36

Ethyl N-[3-chloro-4-(1-methoxycarbonylmethylene-4-yloxy)phenyl]sulfanilate

To a solution of 3-chloro-4-(1-methoxycarbonylmethylene-4-is lexi)aniline (0,79 g), obtained in reference example 35, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,37 ml) and pyridine (0,43 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent ethyl acetate and get listed in the title compound (1.06 g, yield 89%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 1,90 of 1.99 (2H, m), 1,99-of 2.08 (2H, m), 2,53-2,62 (2H, m), 2,75-2,84 (2H, m), with 3.27 (2H, s), 3,74 (3H, s), 3,91 (2H, s), 4,30 (2H, square, J=7,0), to 4.41 (1H, m), 6,92 (1H, d, J=9,0), 7,20 (1H, DD, J=9,0, 2,5), 7,39 (1H, d, J=2,5).

Reference example 37

Ethyl N-[3-chloro-4-(1-methoxycarbonylmethylene-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0.39 g)obtained in reference example 2, ethyl N-[3-chloro-4-(1-methoxycarbonylmethylene-4-yloxy)phenyl]sulfamerazine (1.06 g)obtained in reference example 36, and triphenylphosphine (0.74 g) in dichloromethane (30 ml) under stirring and ice cooling is added dropwise di is celestialbody (of 0.44 ml) and the resulting mixture was stirred at room temperature over night and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent ethyl acetate and get listed in the title compound (1.70 g, yield quantitative) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,90 of 1.99 (2H, m), 1,99-of 2.08 (2H, m), of 2.54 2.63 in (2H, m), 2,75-2,84 (2H, m), with 3.27 (2H, s), of 3.73 (3H, s), 3,98 (2H, s), or 4.31 (2H, square, J=7,0), of 4.45 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,92 (1H, d, J=9,0), 7,31 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=8,0), 7,44-7,58 (4H, m).

Reference example 38

Ethyl N-[4-(1-acetylpiperidine-4-yloxy)-3-chlorophenyl]sulfanilate

To a solution of 4-(1-acetylpiperidine-4-yloxy)-3-Chloroaniline (650 mg)obtained in referential example 10, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0.33 ml) and pyridine (0,39 ml) and the resulting mixture was stirred at room temperature for 3.5 hours and then evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel (eluent only the ethyl acetate ~ mixed solvent containing ethyl acetate and methanol (10:1)), and ucaut specified in the title compound (773 mg, yield 76%) as an orange oil.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 1,82-to 1.98 (4H, m)to 2.13 (3H, s), 3,47 (1H, m), 3,63 (1H, m), and 3.72 (1H, m), a-3.84 (1H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), 4,60 (1H, m)6,94 (1H, d, J=9,0), 7.23 percent (1H, DD, J=9,0, 2,5), 7,41 (1H, d, J=2,5).

Reference example 39

Ethyl N-[4-(1-acetylpiperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (323 mg)obtained in reference example 2, ethyl N-[4-(1-acetylpiperidine-4-yloxy)-3-chlorophenyl]sulfamerazine (773 mg)obtained in reference example 38, and triphenylphosphine (581 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,34 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel (eluent only the ethyl acetate mixed solvent containing ethyl acetate and methanol (9:1)) and get listed in the title compound (733 mg, 71%yield) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,82-to 1.98 (4H, m), 2,12 (3H, s), of 3.48 (1H, m), 3,61 (1H, m), 3,70 (1H, m), 3,85 (1H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5), 4,63 (1H, m), 6.22 per (1H, dt, J=16,0, 6,5), 6.42 per (1H, d, J=16,0), 6,94 (1H, d, J=9,0), 7,34 (1H, DD, J=9,0, 2,5), 7,41 (1H, t, J=8.0 a), of 7.48-7,58 (4H, m).

Reference example 40

4-(1-carb is oilpipeline-4-yloxy)-3-chloronitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (500 mg)obtained in reference example 8, N,N-dimethylformamide (10 ml) under stirring and cooling with ice add potassium cyanate (790 mg) and the resulting mixture was stirred at room temperature overnight. At the end of this time the reaction mixture even added potassium cyanate (790 mg) and the mixture was stirred at 40°With during the night. Then to the reaction mixture is added 4 n solution of hydrogen chloride in dioxane (1.0 ml) and the resulting mixture was stirred at room temperature for 1 hour. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, evaporated in vacuum and get listed in the title compound (523 mg, yield 88%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,53-to 1.67 (2H, m), 1,86 is 2.00 (2H, m), 3,18-and 3.31 (2H, m), 3,51-of 3.64 (2H, m)to 4.92 (1H, m), 7,49 (1H, d, J=9,0), to 8.20 (1H, DD, J=9,0, 2,5), with 8.33 (1H, d, J=2,5).

Reference example 41

4-(1-Carbamoylbiphenyl-4-yloxy)-3-Chloroaniline

To a solution of 4-(1-carbamoylbiphenyl-4-yloxy)-3-chloronitrobenzene (1.25 g)obtained in reference example 40, in acetic acid (30 ml) at room temperature add powder tin (2,47 g) and polucen the second mixture is stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (20:1), and receive specified in the header of the connection (of 0.91 g, yield 81%) as a pale orange amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,80 is 1.96 (4H, m), 3,30 is 3.40 (2H, m), 3,62-and 3.72 (2H, m)to 4.33 (1H, m), of 6.52 (1H, DD, J=8,5, 3,0), 6,74 (1H, d, J=3,0), for 6.81 (1H, d, J=8,5).

Reference example 42

Ethyl N-[4-(1-carbamoylbiphenyl-4-yloxy)-3-chlorophenyl]sulfanilate

To a solution of 4-(1-carbamoylbiphenyl-4-yloxy)-3-Chloroaniline (907 mg)obtained in reference example 41, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0.45 ml) and diisopropylethylamine (0,88 ml) and the resulting mixture was stirred at room temperature overnight. After stirring for another ethylchloroformiate (0.05 ml) and the resulting mixture was stirred at room temperature for 2 hours and then evaporated in vacuum. The obtained residue RA is billaut with ethyl acetate and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(30:1~20:1), and get listed in the title compound (809 mg, yield 57%) as a pale yellow amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 1,83 of 1.99 (4H, m), 3,47 (2H, m), 3,61 (2H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), 4,58 (1H, m)6,94 (1H, d, J=9,0), of 7.23 (1H, DD, J=9,0, 2,5), 7,41 (1H, d, J=2,5).

Reference example 43

Ethyl N-[4-(1-carbamoylbiphenyl-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (322 mg)obtained in reference example 2, ethyl N-[4-(1-carbamoylbiphenyl-4-yloxy)-3-chlorophenyl]sulfamerazine (809 mg)obtained in reference example 42, and triphenylphosphine (610 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,36 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol (10:1), and receive specified in the header connection (1015 mg, yield 94%) as pale-yellow the CSOs amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,84 of 1.99 (4H, m), of 3.48 (2H, m)and 3.59 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5), to 4.62 (1H, m), from 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,94 (1H, d, J=9,0), 7,33 (1H, DD, J=9,0, 2,5), 7,41 (1H, t, J=8,0), 7,49-EUR 7.57 (4H, m).

Reference example 44

3-Chloro-4-(1-methanesulfonamido-4-yloxy)nitrobenzene

To a suspension of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (1,00 g)obtained in reference example 8, in dichloromethane (20 ml) under stirring and ice cooling consistently add methanesulfonanilide (0.33 ml) and triethylamine (1,09 ml) and the resulting mixture was stirred at room temperature for 2 hours. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and hexane (1:1), and get mentioned in the title compound (0.96 g, yield 73%) as a colorless amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: 2.06 to and 2.14 (4H, m), 2,84 (3H, s), 3,29 (2H, m), 3,55 (2H, m), 4,82 (1H, m), 7,00 (1H, d, J=9,0), 8,16 (1H, DD, J=9,0, 2,5), with 8.33 (1H, d, J=2,5).

Reference example 45

3-Chloro-4-(1-methanesulfonamido-4-yloxy)aniline

To a solution of chlor-4-(1-methanesulfonamido-4-yloxy)nitrobenzene (955 mg), obtained in reference example 44, in acetic acid (30 ml) at room temperature add powder tin (1690 mg) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and hexane (5:3), and get mentioned in the title compound (737 mg, yield 85%) as a yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,92-of 2.08 (4H, m), of 2.81 (3H, s), 3.33 and is-3.45 (4H, m), to 4.38 (1H, m), is 6.54 (1H, DD, J=8,5, 3,0), 6,74 (1H, d, J=3,0), to 6.80 (1H, d, J=8,5).

Reference example 46

Ethyl N-[3-chloro-4-(1-methanesulfonamido-4-yloxy)phenyl]sulfanilate

To a solution of 3-chloro-4-(1-methanesulfonamido-4-yloxy)aniline (737 mg)obtained in reference example 45, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0.33 ml) and pyridine (0,39 ml) and the resulting mixture was stirred at room temperature for 1 hour. At the end of paramasivan is I, the reaction mixture was diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and hexane (3:2) and get listed in the title compound (805 mg, yield 73%) as a pink amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1.26 in (3H, t, J=7,0), 1,96 is 2.10 (4H, m), 2,82 (3H, s), and 3.31 (2H, m), 3,47 (2H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), to 4.62 (1H, m), 6,93 (1H, d, J=9,0), of 7.23 (1H, DD, J=9,0, 2,5), 7,42 (1H, d, J=2,5).

Reference example 47

Ethyl N-[4-(1-carbamoylbiphenyl-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (296 mg)obtained in reference example 2, ethyl N-[3-chloro-4-(1-methanesulfonamido-4-yloxy)phenyl]sulfamerazine (805 mg)obtained in reference example 46, and triphenylphosphine (560 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0.33 ml) and the resulting mixture was stirred at room temperature for 5 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate(20:1~10:1), and get listed in the title compound (835 mg, yield 79%) as escitalo amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,96-of 2.09 (4H, m), 2,82 (3H, s), 3,30 (2H, m), of 3.48 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5)and 4.65 (1H, m), from 6.22 (1H, dt, J=16,0, 6,5), 6.42 per (1H, d, J=16,0), 6,94 (1H, d, J=9,0), 7,35 (1H, DD, J=9,0, 2,5), 7,41 (1H, t, J=7,5), 7,50-of 7.55 (2H, m), 7,56 (1H, s), 7,56 (1H, d, J=2,5).

Reference example 48

3-Chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]nitrobenzene

To a suspension of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (3.00 g)obtained in reference example 8, in pyridine (30 ml) at room temperature, add 2-bromopyridin (1.25 ml) and the resulting mixture was stirred at 150°C for 16 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and hexane (1:2), and get mentioned in the title compound (0,80 g, yield 20%) as a yellow solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,93-to 2.06 (2H, m), 2.06 to 2,17 (2H, m), 3,60-and 3.72 (2H, m), 3,79-are 3.90 (2H, m), 4,79 (1H, m), only 6.64 (1H, DD, J=7,0, 5,0), of 6.71 (1H, d, J=8,5),? 7.04 baby mortality (1H, d, J=9,0), to 7.50 (1H, m), 8,16 (1H, DD, J=9,0, 3,0), to 8.20 (1H, DD, J=5,0, 2,0), 8,32 (1H, d, J=3,0).

Reference example 49

3-Chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]aniline

To a solution of the 3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]nitrobenzene (796 mg), obtained in reference example 48, in acetic acid (40 ml) at room temperature add powder tin (1420 mg) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and hexane (1:1), and get mentioned in the title compound (680 mg, yield 94%) as a bright reddish-purple oil.

1H NMR (400 MHz, CDCl3) δ ppm: 1,83-of 1.95 (2H, m), 1,97-2,07 (2H, m)to 3.41 (2H, m), of 3.95 (2H, m), 4,34 (1H, m), 6,53 (1H, DD, J=8,5, 3,0), 6,59 (1H, DD, J=7,0, 5,5), 6,69 (1H, d, J=8,5), 6,74 (1H, d, J=3,0), 6,85 (1H, d, J=8,5), 7,47 (1H, m), 8,19 (1H, m).

Reference example 50

Ethyl N-[3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]phenyl]sulfanilate

To a solution of 3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]aniline (680 mg)obtained in reference example 49, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,32 ml) and pyridine (0,36 ml) and the resulting mixture was stirred at room temperature is f during the night. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and hexane (1:1), and get mentioned in the title compound (858 mg, yield 85%) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 1,88-to 1.98 (2H, m), 1,98-of 2.08 (2H, m), of 3.56 (2H, m), 3,86 (2H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), 4,58 (1H, m), is 6.61 (1H, m), 6,70 (1H, d, J=8,5), 6,97 (1H, d, J=9,0), of 7.23 (1H, DD, J=9,0, 2,5), 7,40 (1H, d, J=2,5), of 7.48 (1H, m), 8,19 (1H, m).

Reference example 51

Ethyl N-[3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (316 mg)obtained in reference example 2, ethyl N-[3-chloro-4-[1-(2-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (858 mg)obtained in reference example 50, and triphenylphosphine (590 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0.35 ml) and the resulting mixture stirred at room temperature overnight and then evaporated is in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate (10:1), and receive specified in the header connection (1100 mg, yield 98%) as a colorless amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,88-to 1.98 (2H, m), 1,98-of 2.08 (2H, m), of 3.57 (2H, m), a-3.84 (2H, m)4,00 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5), br4.61 (1H, m), 6,23 (1H, dt, J=16,0, 6,5), 6.42 per (1H, d, J=16,0), is 6.61 (1H, DD, J=7,0, 5,0), 6,69 (1H, d, J=8,5), 6,97 (1H, d, J=9,0), 7,33 (1H, DD, J=9,0, 2,5), 7,41 (1H, t, J=8.0 a), of 7.48 (1H, m), 7,50-7,58 (4H, m), 8,19 (1H, m).

Reference example 52

3-Chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]nitrobenzene

3-Chloro-4-(piperidine-4-yloxy)nitrobenzene (2,72 g)obtained in reference example 8, 3-bromopyridine (2,01 g), 2-(di-tert-butylphosphino)biphenyl (0.32 g), Tris(dibenzylideneacetone)dipalladium (0,49 g) and tert-piperonyl sodium (1.22 g) suspended in toluene (30 ml) and stirred at 70°C for 2 hours. After cooling to room temperature, insoluble matter is filtered off and the filtrate evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromate what graphy on silica gel using as eluent a mixed solvent, containing dichloromethane and methanol (9:1), and get mentioned in the title compound (1.56 g, yield 44%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: 2,03-2,22 (4H, m), and 3.31 (2H, m), 3,49 (2H, m), of 4.77 (1H, m), 7,03 (1H, d, J=9,0), 7,18 (1H, DD, J=8.5 a, 4,5), from 7.24 (1H, m)to 8.12 (1H, DD, J=4,5, 1,5), 8,16 (1H, DD, J=9,0, 3,0), 8,32 (1H, d, J=3,0), at 8.36 (1H, d, J=3,0).

Reference example 53

3-Chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]aniline

To a solution of 3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]nitrobenzene (1.54 g)obtained in reference example 52, in acetic acid (30 ml) at room temperature add powder tin (2,74 g) and the resulting mixture was stirred at room temperature for 1 hour. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (9:1), and get mentioned in the title compound (1.39 g, yield 99%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm: 1,92-2,11 (4H, m), 3,14 (2H, m), of 3.56 (2H, m) or 4.31 (1H, m), 6,53 (1H, DD, J=9,0, 2,0), 6,74 (1H, d, J=2,0), at 6.84 (1H, d, J=9,0), 7,16 (1H, DD, J=8.5 a, 4,5), 7,21 (1H, m), 8,08 (1H, d, J=4,5), to 8.34 (1H, d, J=2,5).

Reference example 54

Ethyl N-[3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]phenyl]sulfanilate

To a solution of 3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]aniline (1,38 g)obtained in reference example 53, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise a solution of ethylchlorothioformate (0,93 g) in dichloromethane (5 ml) and pyridine (0,37 ml) and the resulting mixture was stirred at room temperature for 2 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (9:1), and receive specified in the header of the connection (of 1.61 g, yield 78%) as a pale brown amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.33 (3H, t, J=7,0), 1,97-of 2.15 (4H, m), 3,24 (2H, m), 3,51 (2H, m), 3,93 (2H, s), the 4.29 (2H, square, J=7,0), 4,56 (1H, m), 6,97 (1H, d, J=9,0), 7,18 (1H, DD, J=8,5, 4,0), 7,21-7,28 (2H, m), 7,42 (1H, d, J=2,5), 8,10 (1H, d, J=4,0), 8,35 (1H, s).

Reference example 55

Ethyl N-[3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (294 mg)obtained in reference example 2, ethyl N-[3-chloro-4-[1-(3-pyridyl)piperidine-4-yloxy]phenyl]the sylphs is racette (840 mg), obtained in reference example 54, and triphenylphosphine (630 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,38 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (97:3), and receive specified in the header connection (2060 mg, yield quantitative) as a yellow amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,97-of 2.16 (4H, m)of 3.25 (2H, m), 3,49 (2H, m)4,00 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5), 4,60 (1H, m), 6,23 (1H, dt, J=16,0, 6,5), 6.42 per (1H, d, J=16,0), 6,97 (1H, d, J=9,0), 7,34 (1H, DD, J=9,0, 2,5), 7,41 (1H, t, J=8,0), 7,44-7,71 (6H, m), 8,10 (1H, m), 8,35 (1H, m).

Reference example 56

3-Chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]nitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (3.00 g)obtained in reference example 8, N,N-dimethylformamide (30 ml) under stirring at room temperature successively added 4-bromopyridine (2.50 g) and N-methylmorpholin (5,14 ml) and the resulting mixture was stirred at 150°C for 7 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated aqueous solution of the m sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(30:1~10:1), and get listed in the title compound (1.27 g, yield 33%) as a dark yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,98-2,14 (4H, m), 3.46 in-3,55 (2H, m), to 3.58-to 3.67 (2H, m), a 4.83 (1H, m), 6,72 (2H, d, J=6,5), 7,03 (1H, d, J=9,0), 8,16 (1H, DD, J=9,0, 3,0), of 8.28 (2H, d, J=6,5), 8,32 (1H, d, J=3,0).

Reference example 57

3-Chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]aniline

To a solution of 3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]nitrobenzene (1.26 g)obtained in reference example 56, in acetic acid (50 ml) at room temperature add powder tin (2.24 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with an aqueous solution of potassium carbonate and extracted three times with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(10:1~1:1), and receive specified in the header is the connection of 0.85 g, yield 74%) as a pale yellow solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,85-of 2.05 (4H, m), 3,30-to 3.38 (2H, m), 3,65-to 3.73 (2H, m), 4,37 (1H, m), is 6.54 (1H, DD, J=8,5, 3,0), 6,69 (2H, DD, J=5,0, 1,5), 6,74 (1H, d, J=3,0), 6,83 (1H, d, J=8,5), to 8.25 (2H, DD, J=5.0 and 1.5 to).

Reference example 58

Ethyl N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]sulfanilate

To a solution of 3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]aniline (854 mg)obtained in reference example 57, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,40 ml) and pyridine (0.45 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is neutralized with an aqueous solution of potassium carbonate and extracted twice with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(5:1~2:1), and get listed in the title compound (888 mg, yield 70%) as a yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.33 (3H, t, J=7,0), 1,94-2,07 (4H, m), 3,47 (2H, m), the 3.65 (2H, m), 3,93 (2H, s), the 4.29 (2H, square, J=7,0), 4,63 (1H, m), 6,72 (2H, DD, J=5,0, 1,5), of 6.96 (1H, d,J=9,0), of 7.25 (1H, DD, J=9,0, 2,5), the 7.43 (1H, d, J=2,5), compared to 8.26 (2H, DD, J=5,0, 1,5).

Reference example 59

Ethyl N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (327 mg)obtained in reference example 2, ethyl N-[3-chloro-4-[1-(4-pyridyl)piperidine-4-yloxy]phenyl]sulfamerazine (887 mg)obtained in reference example 58, and triphenylphosphine (620 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,36 ml) and the resulting mixture stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(20:1~10:1), and get listed in the title compound (637 mg, yield 55%) as a colorless amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,97-2,07 (4H, m), of 3.45 (2H, m), 3,62 (2H, m)4,00 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,0)and 4.65 (1H, m), from 6.22 (1H, dt, J=16,0, 6,0), 6.42 per (1H, d, J=16,0), 6,70 (2H, d, J=6,5), of 6.96 (1H, d, J=9,0), 7,34 (1H, DD, J=9,0, 2,5), 7,41 (1H, t, J=7,5), 7,53 (2H, m), 7,56 (1H, s), 7,56 (1H, d, J=2,5), of 8.27 (2H, d, J=6,5).

Reference example 60

3-Chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]nitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (2.50 g)obtained in reference Primera, in ethanol (30 ml) at room temperature, add 2-chloropyrimidine (1.12 g) and the resulting mixture was stirred at 30°C for 8 hours. After cooling to room temperature, separated crystalline substance is collected by filtration and receive the mixture mentioned in the title compound and 2-chloropyrimidine. Then to this mixture, add dichloromethane and the insoluble matter is filtered off. The filtrate is evaporated in vacuum and get listed in the title compound (1.29 g, yield 39%) as a pale yellow solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,90-2,00 (2H, m), 2.00 in of 2.10 (2H, m), 3,92-4,00 (2H, m), 4,00-4,08 (2H, m), 4,82 (1H, m), 6,51 (1H, t, J=5.0)and? 7.04 baby mortality (1H, d, J=9,0), 8,16 (1H, DD, J=9,0, 3,0), 8,32 (1H, d, J=3,0), with 8.33 (2H, d, J=5,0).

Reference example 61

3-Chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]aniline

To a solution of 3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]nitrobenzene (1.29 g)obtained in reference example 60, in acetic acid (40 ml) at room temperature add powder tin (2.28 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dry the t over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and hexane (2:1), and get mentioned in the title compound (1.01 g, yield 86%) as a brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,80-1,90 (2H, m), 1,92-2,02 (2H, m)to 3.67 (2H, m), 4,20 (2H, m), 4,37 (1H, m), 6,46 (1H, t, J=4,5), 6,53 (1H, DD, J=8,5, 3,0), 6,74 (1H, d, J=3,0), 6,85 (1H, d, J=8,5), 8,30 (2H, d, J=4,5).

Reference example 62

Ethyl N-[3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]phenyl]sulfanilate

To a solution of 3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]aniline (1.01 g)obtained in reference example 61, in dichloromethane (30 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,47 ml) and pyridine (0,53 ml) and the resulting mixture was stirred at room temperature for 1 hour and then evaporated in vacuum. The resulting residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate(2:1~1:1), and receive specified in the header of the giving (1.29 g, yield 85%) as a pale brown amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 1,85-of 1.95 (2H, m), 1,95-of 2.05 (2H, m), 3,85 (2H, m), 3,93 (2H, s), 4.09 to (2H, m), 4,30 (2H, square, J=7,0), br4.61 (1H, m), 6.48 in (1H, t, J=4,5), 6,98 (1H, d, J=9,0), of 7.23 (1H, DD, J=9,0, 2,5), 7,41 (1H, d, J=2,5), 8,32 (2H, d, J=4,5).

Reference example 63

Ethyl N-[3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0,47 g)obtained in reference example 2, ethyl N-[3-chloro-4-[1-(2-pyrimidyl)piperidine-4-yloxy]phenyl]sulfamerazine (1.29 g)obtained in reference example 62, and triphenylphosphine (0,89 g) in dichloromethane (30 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,52 ml) and the resulting mixture stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate (9:1), and receive specified in the header connection (1,59 g, yield 94%) as a colorless amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,85-of 1.95 (2H, m), 1,95-of 2.05 (2H, m), a 3.87 (2H, m)4,00 (2H, s)4,06 (2H, m), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5), with 4.64 (1H, m), 6,23 (1H, dt, J=16,0, 6,5), to 6.43 (1H, d, J=16,0), 6,48 (1H, t, J=4,5), 6,98 (1H, d, J=9,0), 7,34 (1H, DD, J=9,0, 2,), 7,41 (1H, t, J=8,0), 7,50-of 7.55 (2H, m), 7,55 (1H, d, J=2,5), EUR 7.57 (1H, s), 8,31 (2H, d, J=4,5).

Reference example 64

3-Chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]nitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (1,00 g)obtained in reference example 8, N,N-dimethylformamide (20 ml) at room temperature successively added hydrogen bromide 3-(methyl bromide)pyridine (1.08 g) and potassium carbonate (1.08 g) and the resulting mixture was stirred at room temperature for 2 hours. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (25:1), and receive specified in the header connection (0,98 g, yield 72%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,88-to 1.98 (2H, m), 1,98-of 2.08 (2H, m), 2,39-2,49 (2H, m), 2,65 is 2.75 (2H, m), of 3.56 (2H, s), 4,60 (1H, m), 6,97 (1H, d, J=9,0), 7,27 (1H, DD, J=8.0 a, 5,0), to 7.68 (1H, d, J=8,0), to 8.12 (1H, DD, J=9,0, 3,0), 8,30 (1H, d, J=3,0), charged 8.52 (1H, DD, J=5,0, 1,5), 8,56 (1H, d, J=1,5).

Reference example 65

3-Chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]aniline

To a solution of 3-chloro-4-[1-(3-pyridylmethyl)Pieper is DIN-4-yloxy]nitrobenzene (980 mg), obtained in reference example 64, in acetic acid (50 ml) at room temperature add powder tin (1670 mg) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(10:1~5:1), and get listed in the title compound (874 mg, yield 98%) as a pale yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,80-1,90 (2H, m), 1,90-2,00 (2H, m), 2,32 (2H, m), was 2.76 (2H, m), 3,55 (2H, s)to 4.16 (1H, m), 6,51 (1H, DD, J=8,5, 3,0), 6,72 (1H, d, J=3,0), to 6.80 (1H, d, J=8,5), 7,27 (1H, m), of 7.70 (1H, d, J=7,5), 8,51 (1H, d, J=6,5), 8,55 (1H, s).

Reference example 66

Ethyl N-[3-chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]phenyl]sulfanilate

To a solution of 3-chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]aniline (874 mg)obtained in reference example 65, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,39 ml) is pyridine (of 0.44 ml) and the resulting mixture was stirred at room temperature for 3 hours and evaporated in vacuum. The resulting residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(20:1~10:1), and get listed in the title compound (770 mg, yield 60%) as a yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.33 (3H, t, J=7,0), 1,84-of 1.93 (2H, m), 1.93 and-2,02 (2H, m), of 2.38 (2H, m), of 2.72 (2H, m), 3,55 (2H, s), 3,91 (2H, s), the 4.29 (2H, square, J=7,0), 4,39 (1H, m), 6,92 (1H, d, J=9,0), 7,20 (1H, DD, J=9,0, 2,5), 7,27 (1H, m), 7,39 (1H, d, J=2,5), of 7.69 (1H, d, J=7,5), 8,51 (1H, d, J=3,5), 8,56 (1H, s).

Reference example 67

Ethyl N-[3-chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (275 mg)obtained in reference example 2, ethyl N-[3-chloro-4-[1-(3-pyridylmethyl)piperidine-4-yloxy]phenyl]sulfamerazine (770 mg)obtained in reference example 66, and triphenylphosphine (520 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,30 ml) and the resulting mixture stirred at room temperature overnight and then evaporated in vacuum. The floor is built the residue purified column chromatography on silica gel using as eluent a mixed solvent, containing ethyl acetate and methanol(10:1~5:1), and get listed in the title compound (949 mg, yield 95%) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,84-of 1.93 (2H, m), 1.93 and-2,02 (2H, m), of 2.38 (2H, m), 2,70 (2H, m), of 3.54 (2H, s), 3,98 (2H, s), or 4.31 (2H, square, J=7,0), was 4.42 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,92 (1H, d, J=9,0), 7,26 (1H, DD, J=7,5, 5,0), 7,30 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=7,5), of 7.48-rate of 7.54 (3H, m), 7,55 (1H, s), to 7.68 (1H, d, J=7,5), 8,51 (1H, DD, J=5,0, 1,5), 8,55 (1H, d, J=1,5).

Reference example 68

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-Chloroaniline

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-chloronitrobenzene (2,40 g)obtained in reference example 3, acetic acid (50 ml) under stirring at room temperature add four reception zinc dust (ceiling of 5.60 g) and the resulting mixture was stirred at room temperature for 2 hours. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (1:1), and get mentioned in the title compound (1,99 g, yield 87%) as an orange oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.47 (9H, s), is 1.77 (2H, m)to 1.87 (2H, m), and 3.31 (2H, m), and 3.72 (2H, m), 4.26 deaths (1H, m), of 6.52 (1H, DD, J=9,0, 3,0), was 6.73 (1H, d, J=3,0), to 6.80 (1H, d, J=9,0).

Reference example 69

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-chlorophenyl]sulfanilate

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-Chloroaniline (1.50 g)obtained in reference example 68, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,74 ml) and pyridine (of 0.56 ml) and the resulting mixture was stirred at room temperature for 5 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (1.19 g, yield 54%) as a yellow light red oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), OF 1.47 (9H, s), 1,79-of 1.92 (4H, m), of 3.46 (2H, m)to 3.64 (2H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), to 4.52 (1H, m)6,94 (1H, d, J=9,0), 7,22 (1H, DD, J=9,0, 2,5), 7,40 (1H, d, J=2,5).

Reference example 70

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0.40 g)obtained in reference example 2, ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-chlorophenyl]sulfamerazine (1.19 g)obtained in reference example 69, and triphenylphosphine (0.79 in) in dichloromethane (20 ml) at paramasivan and and ice cooling is added dropwise diethylazodicarboxylate (0,50 ml) and the resulting mixture was stirred at room temperature during the night and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate (10:1), and get mentioned in the title compound (1.20 g, yield 78%) as a pale red amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), OF 1.47 (9H, s), 1,79-of 1.92 (4H, m), 3,47 (2H, m), 3,62 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5), 4,55 (1H, m), 6,23 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,94 (1H, d, J=9,0), 7,32 (1H, DD, J=9,0, 3,0), 7,41 (1H, t, J=7,5), 7,50-7,58 (4H, m).

Reference example 71

Ethyl N-[4-(piperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1.25 g)obtained in reference example 70, in ethanol (15 ml) at room temperature is added 4 n solution of hydrogen chloride in dioxane (15 ml) and the resulting mixture was stirred at room temperature for 4 hours and then evaporated in vacuum. Then the obtained residue was diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound(1.10 g, yield quantitative) as a pale yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,76-of 1.88 (2H, m), 2.00 in of 2.10 (2H, m), 2,85 (2H, m), 3,20 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), to 4.46 (2H, d, J=6,5), 4,50 (1H, m), from 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,93 (1H, d, J=9,0), 7,32 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=8,0), 7,49-to 7.59 (4H, m).

Reference example 72

Ethyl N-[3-chloro-4-[1-(4-pyridylmethyl)piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of ethyl N-[4-(piperidine-4-yloxy)-3-chlorophenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (1.10 g)obtained in reference example 71, N,N-dimethylformamide (30 ml) under stirring at room temperature sequentially add the hydrobromide of 4-(methyl bromide)pyridine (0,59 g) and potassium carbonate (0,59 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol (10:1), and get mentioned in the title compound (0.97 g, yield 75%) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3)δ ppm: of 1.36 (3H, t, J=7,0), 1,86-of 1.95 (2H, m), 1,95-2,04 (2H, m), of 2.38 (2H, m), 2,70 (2H, m), 3,53 (2H, s), 3,98 (2H, s), or 4.31 (2H, square, J=7,0), 4,43 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,92 (1H, d, J=9,0), 7,28 (2H, d, J=6,0), 7,31 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=8,0), 7,49-rate of 7.54 (2H, m), 7,53 (1H, d, J=2,5), 7,55 (1H, s), 8,54 (2H, d, J=6,0).

Reference example 73

2-(2-Bromacil)pyridine

To a solution of 2-pyridinethiol (1,00 ml) in tetrahydrofuran (20 ml) under stirring at room temperature successively added triphenylphosphine (3.51 g) and chetyrehhloristy carbon (4.44 g) and the resulting mixture was stirred at room temperature overnight. After stirring to the reaction mixture is added diethyl ether, the insoluble matter is filtered off and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (1:3), and receive specified in the header of the connection (of 1.30 g, yield 78%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm: to 3.34 (2H, t, J=7,0), of 3.78 (2H, t, J=7,0), 7,15-of 7.23 (2H, m), of 7.64 (1H, m), to 8.57 (1H, m).

Reference example 74

3-Chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]nitrobenzene

To rest the ru 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (1.50 g), obtained in reference example 8, N,N-dimethylformamide (30 ml) at room temperature successively added 2-(2-bromacil)pyridine (of 1.30 g)obtained in reference example 73, and potassium carbonate (1,21 g) and the resulting mixture was stirred at the same temperature throughout the night. After stirring the reaction mixture is diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (10:1~5:1) and receive specified in the header of the connection (of 1.57 g, yield 74%) as a yellow solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,89 is 2.00 (2H, m), 2,00-2,11 (2H, m), 2,52 (2H, m), of 2,75 2,85 (2H, m), and 2.83 (2H, m), 3,01 (2H, m), 4,59 (1H, m), of 6.99 (1H, d, J=9,0), 7,13 (1H, DD, J=7,5, 5,0), 7,20 (1H, d, J=8,0), to 7.61 (1H, m), 8,13 (1H, DD, J=9,0, 3,0), 8,30 (1H, d, J=3,0), 8,53 (1H, d, J=5,0).

Reference example 75

3-Chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]aniline

To a solution of 3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]nitrobenzene (1,57 g)obtained in reference example 74, in acetic acid (50 ml) at room temperature add powder tin (2.58 g) and the resulting mixture was stirred at room temperature overnight. After re is eshiwani the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(5:1~1:1), and get listed in the title compound (1.26 g, yield 87%) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,82-of 1.94 (2H, m), 1,94 e 2.06 (2H, m), 2.40 a (2H, m), of 2.81 (2H, m), 2,89 (2H, m), to 3.02 (2H, m), is 4.15 (1H, m), 6,51 (1H, DD, J=8,5, 3,0), was 6.73 (1H, d, J=3,0), for 6.81 (1H, d, J=8,5), 7,12 (1H, DD, J=7,5, 5,0), 7,20 (1H, d, J=8,0), 7,60 (1H, m), charged 8.52 (1H, d, J=5,0).

Reference example 76

Ethyl N-[3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]phenyl]sulfanilate

To a solution of 3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]aniline (1.26 g)obtained in reference example 75, in dichloromethane (30 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0.54 ml) and pyridine (0,61 ml) and the resulting mixture was stirred at room temperature for 2 hours and evaporated in vacuum. The resulting residue is neutralized with saturated aqueous sodium hydrogen carbonate solution, extracted three times with ethyl acetate, and ek is the tract dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(10:1~5:1), and get listed in the title compound (1.50 g, yield 82%) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.33 (3H, t, J=7,0), 1,86-of 1.97 (2H, m), 1,97-of 2.08 (2H, m)of 2.50 (2H, m), 2.77-to of 2.92 (4H, m), 3,03 (2H, m)to 3.92 (2H, s), the 4.29 (2H, square, J=7,0), and 4.40 (1H, m), 6,93 (1H, d, J=9,0), 7,13 (1H, m,), 7,21 (1H, DD, J=9,0, 2,5), 7,17-7,24 (1H, m), 7,40 (1H, d, J=2,5), to 7.61 (1H, m), 8,53

(1H, d, J=5,0).

Reference example 77

Ethyl N-[3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0.52 g)obtained in reference example 2, ethyl N-[3-chloro-4-[1-[2-(2-pyridyl)ethyl]piperidine-4-yloxy]phenyl]sulfamerazine (1.50 g)obtained in reference example 76, and triphenylphosphine (0,98 g) in dichloromethane (40 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,57 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(30:1~10:1), and get listed in the title compound (1.73 g, yield 89% in the form of a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,86-to 1.98 (2H, m), 1,98 is 2.10 (2H, m), of 2.51 (2H, m), 2,78 of 2.92 (4H, m), 3,03 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,43 (1H, m), 4,46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,93 (1H, d, J=9,0), 7,12 (1H, m), 7,20 (1H, d, J=8,0), 7,31 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=8,0), 7,49-of 7.55 (3H, m), 7,56 (1H, s), 7,60 (1H, m), 8,53 (1H, d, J=4,5).

Reference example 78

3-Chloro-4-(1-cyclopentenopyridine-4-yloxy)nitrobenzene

To a solution of 3-chloro-4-(piperidine-4-yloxy)nitrobenzene (of 4.00 g)obtained in reference example 8, N,N-dimethylformamide (70 ml) at room temperature sequentially add cyclopentylamine (1,96 ml) and potassium carbonate (3,23 g) and the resulting mixture was stirred at 100°C for 7 hours. Since the reaction proceeds slowly add cyclopentylamine (0,70 ml) and the resulting mixture is stirred for further at 100°C for 2 hours and then at 120°C for 5 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(30:1~10:1), and get listed in the title compound (2.35 g, yield 46%) as a brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,37 is 1.48 (2H, m), 1,50-to 1.61 (2H, m)of 1.65 to 1.76 (2H, m), 1.85 to a 2.00 (4H, m), 2.00 in of 2.10 (2H, m)of 2.50 (2H, m), to 2.57 (1H, m)of 2.75 (2H, m), 4,59 (1H, m), 6,98 (1H, d, J=9,0), 8,13 (1H, DD, J=9,0, 3,0), 8,30 (1H, d, J=3,0).

Reference example 79

3-Chloro-4-(1-cyclopentenopyridine-4-yloxy)aniline

To a solution of 3-chloro-4-(1-cyclopentenopyridine-4-yloxy)nitrobenzene (2.35 g)obtained in reference example 78, in acetic acid (50 ml) at room temperature add powder tin (4,29 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. Then to the resulting residue is added saturated aqueous sodium hydrogen carbonate solution and the resulting mixture is extracted five times with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(5:1~1:1), and get listed in the title compound (1.97 g, yield 92%) as a pale brown amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,48-to 1.61 (2H, m), 1,61-of 1.78 (4H, m), 1,86-2,02 (4H, m), 2.06 to 2,19 (2H, m), was 2.76 (2H, m), 2,85 (1H, m)to 2.94 (2H, m), the 4.29 (1H, m), of 6.52 (1H, DD, J=8,5, 2,5), was 6.73 (1H, d, J=2,5), 6,79 (1H,d, J=8,5).

Reference example 80

Ethyl N-[3-chloro-4-(1-cyclopentenopyridine-4-yloxy)phenyl]sulfanilate

To a solution of 3-chloro-4-(1-cyclopentenopyridine-4-yloxy)aniline (1.97 g)obtained in reference example 79, in dichloromethane (40 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,94 ml) and pyridine (1.08 ml) and the resulting mixture was stirred at room temperature for 3 hours and evaporated in vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(25:1~10:1), and get listed in the title compound (1,09 g, yield 37%) as a pale brown amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.33 (3H, t, J=7,0), 1,38-of 1.62 (4H, m), 1,62-to 1.77 (2H, m), 1,80 is 1.96 (4H, m), 1,96-of 2.09 (2H, m), 2,47 (2H, m), 2,59 (1H, m), and 2.79 (2H, m)to 3.92 (2H, s), the 4.29 (2H, square, J=7,0), 4,39 (1H, m), 6,92 (1H, d, J=9,0), 7,20 (1H, DD, J=9,0, 2,5), 7,39 (1H, d, J=2,5).

Reference example 81

Ethyl N-[3-chloro-4-(1-cyclopentenopyridine-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamoyl is tat

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0.39 g)obtained in reference example 2, ethyl N-[3-chloro-4-(1-cyclopentenopyridine-4-yloxy)phenyl]sulfamerazine (1,09 g)obtained in reference example 80, and triphenylphosphine (of 0.77 g) in dichloromethane (30 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0.45 ml) and the resulting mixture was stirred at room temperature over night and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol(10:1~5:1), and get listed in the title compound (1.30 grams, yield 91%) as a yellowish brown amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,40-to 1.61 (4H, m), 1,64 and 1.80 (2H, m), 1,83 of 1.99 (4H, m), 1,99 with 2.14 (2H, m), 2.40 a of 2.68 (3H, m), 2,68-2,87 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), to 4.46 (1H, m), 4,46 (2H,, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,92 (1H, d, J=9,0), 7,31 (1H, DD, J=9,0, 2,5), 7,40 (1H, t, J=8.0 a), of 7.48-of 7.55 (3H, m), 7,56 (1H, s).

Reference example 82

1-tert-Butoxycarbonyl-2-methyl-4-piperidinylmethyl

To a solution of 4-piperidineacetate (9.6 g) in acetone (100 ml) under stirring and cooling with ice add di-tert-BUTYLCARBAMATE (16.0 g) and the resulting mixture was stirred at room temperature for 1 hour and then evaporated in vacuum. Receive the config residue diluted with ethyl acetate and the organic layer is successively washed with water and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum and get 1-tert-butoxycarbonyl-4-piperidinylmethyl a (17.4 g) as a pale yellow solid.

Then to the solution obtained above 1-tert-butoxycarbonyl-4-piperidineacetate in diethyl ether (200 ml) under stirring at -78°sequentially added dropwise N,N,N’,N’-tetramethylenebis (13,0 ml) and 1 n solution of second-utility in a mixture of cyclohexane and hexane (88,0 ml) and the resulting mixture was stirred at -30°C for 30 minutes. After cooling again to -78°to the reaction mixture with stirring, add methyliodide and the resulting mixture was stirred at room temperature for 3 hours. After stirring the reaction mixture gradually pour in water and the resulting mixture extracted with diethyl ether. The extract is successively washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (9:1), and get mentioned in the title compound (6.0 g, yield 34%) as a colourless oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.23 (3H, d, J=7,0), OF 1.46 (9H, s), 1,55-1,70 (4H, m), 1,85-1,90 1H, m), 3,05 is 3.15 (1H, m), 3,90-of 4.05 (4H, m), 4,47 (1H, m).

Reference example 83

1-tert-Butoxycarbonyl-2-methyl-4-piperidone

To a solution of 1-tert-butoxycarbonyl-2-methyl-4-piperidineacetate (6,00 g)obtained in reference example 82, in acetone (150 ml) under stirring and cooling with ice add monohydrate p-toluensulfonate acid (4,40 g) and the resulting mixture was stirred at room temperature overnight. After stirring the resulting mixture was diluted with ethyl acetate and the organic layer is successively washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (2,40 g, yield 48%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.18 (3H, d, J=7,0), FOR 1.49 (9H, s), 2,20-of 2.30 (1H, m), 2,30-to 2.40 (1H, m), 2,45 is 2.55 (1H, m), 2,65-2,70 (1H, m), of 3.25 to 3.35 (1H, m), 3,90-of 4.05 (1H, m), 4,20-4,30 (1H, m).

Reference example 84

1-tert-Butoxycarbonyl-4-hydroxy-2-methylpiperidin

To a suspension of lithium aluminum hydride (1.30 grams) in tetrahydrofuran (50 ml) under stirring and ice cooling in a nitrogen atmosphere is added dropwise 1-tert-butoxycarbonyl-2-methyl-4-piperidone (2,40 g)obtained in reference example 83, and the resulting mixture was stirred at room temperature for 1 hour in an atmosphere of AZ is the same. After stirring to the reaction mixture add decahydrate sodium sulfate and the resulting mixture is stirred for further at room temperature for 1 hour. After removal by filtration of insoluble matters, the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (1:1), and receive, separately, polar compound (0.95 g, yield 39%) and high-polar compound (1,02 g, yield 42%) named the title compound as a yellow oily product.

High-polar compound:1H NMR (500 MHz, CDCl3) δ ppm: 1.14 in (3H, d, J=7,0), 1,30-1,40 (1H, m), 1,45-1,55 (1H, m)of 1.46 (9H, s), 1,80-1,85 (1H, m), 1,90-1,95 (1H, m), 2,85-2,95 (1H, m), 3,90-4,00 (1H, m), 4,00-4,10 (1H, m), 4,45-4,55 (1H, m).

Polar connection:1H NMR (500 MHz, CDCl3) δ ppm: of 1.33 (3H, d, J=7,0), OF 1.46 (9H, s), 1,60-1,75 (3H, m), 1,80-1,90 (1H, m), 3,20-3,30 (1H, m), 3,80-of 3.85 (1H, m), 4,15-4,20 (1H, m), 4,25 is 4.35 (1H, m).

Reference example 85

4-(1-tert-Butoxycarbonyl-2-methylpiperidin-4-yloxy)-3-chloronitrobenzene

To a solution of highly polar 1-tert-butoxycarbonyl-4-hydroxy-2-methylpiperidine (1,02 g)obtained in reference example 84, 2-chloro-4-NITROPHENOL (0,83 g) and triphenylphosphine (1,62 g) in dichloromethane (60 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (097 ml) and the resulting mixture was stirred at room temperature for 8 hours. As the reaction progresses slowly to the reaction mixture successively added triphenylphosphine (1,62 g) and diethylazodicarboxylate (0,97 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (4:1), and receive specified in the header connection (1,15 g, yield 76%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.35 (3H, d, J=7,0), TO 1.48 (9H, s), 1,75-of 1.85 (1H, m), 1,95-2,05 (3H, m), of 3.25 to 3.35 (1H, m), 3,90-4,00 (1H, m), 4,35 is 4.45 (1H, m), to 4.87 (1H, m), 6,97 (1H, d, J=9,0), 8,15 (1H, DD, J=9,0, 2,5), 8,32 (1H, d, J=2,5).

Reference example 86

3-Chloro-4-(1,2-dimethylpiperidin-4-yloxy)nitrobenzene

To a suspension of 4-(1-tert-butoxycarbonyl-2-methylpiperidin-4-yloxy)-3-chloronitrobenzene (1,15 g)obtained in reference example 85, 90% formic acid (3,10 g) added 37% formaldehyde (2.50 g) and the resulting mixture was stirred at 100°C for 2 hours. After cooling to room temperature the reaction mixture was neutralized with an aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography is as silica gel using as eluent a mixed solvent, containing dichloromethane and methanol (9:1), and receive specified in the header connection (0,80 g, yield 90%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.18 (3H, d, J=6,0), of 1.64 (1H, m), 1.85 to 1,95 (1H, m), 2.05 is was 2.25 (4H, m), 2,32 (3H, s)of 3.00 (1H, m), 4,39 (1H, m), of 6.99 (1H, d, J=9,0), to 8.12 (1H, DD, J=9,0, 2,5), 8,30 (1H, d, J=2,5).

Reference example 87

3-Chloro-4-(1,2-dimethylpiperidin-4-yloxy)aniline

To a solution of 3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)nitrobenzene (800 mg)obtained in reference example 86, in acetic acid (20 ml) under stirring at room temperature add powder tin (1700 mg) and the resulting mixture was stirred at room temperature for 4 hours. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum. Then to the resulting residue is added saturated aqueous potassium carbonate solution and the resulting mixture extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (690 mg, yield 96%) as a reddish brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.13 (3H, d, J=6,0), of 1.52 (1H, m), 1,75-of 1.85 (1H, m), 1,90-of 2.15 (4H, m), and 2.27 (3H, s), with 2.93 (1H, m), of 3.95 (1H, m), 6,50 (1H, DD, J=8,5, 3,0), 6,72 (1H, d, J=3,0), 6,83 (1H, d, J=8,5).

Reference example 88

Ethyl N-[3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)phenyl]sulfame laatat

To a solution of 3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)aniline (690 mg)obtained in reference example 87, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,40 ml) and pyridine (0.25 ml) and the resulting mixture was stirred at room temperature for 1 hour and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(9:1~3:1), and get listed in the title compound (800 mg, yield 73%) as a yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.18 (3H, t, J=7,0), of 1.26 (3H, m), 1,55-1,70 (1H, m), 1,75-1,90 (1H, m), 2,15-of 2.30 (2H, m), 2,55 is 2.75 (3H, m), 2,80-3,30 (3H, m), 4,11 (2H, square, J=7,0), 4,20 (2H, s), 4,45-4,55 (1H, m), 7,17 (1H, DD, J=9,0, 2,5), 7,27 (1H, d, J=9,0), 7,29 (1H, d, J=2,5).

Reference example 89

Ethyl N-[3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (320 mg)obtained in reference example 2, ethyl N-[3-chloro-4-(1,2-dimethylpiperidin-4-yloxy)phenyl]sulfamerazine (800 mg)obtained in reference example 88, and triphenylphosphine (680 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,40 ml) and the resulting mixture was stirred at room is based temperature for 4 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel (eluent mixed solvent containing dichloromethane and ethyl acetate (4:1) mixed solvent containing dichloromethane and methanol (9:1)), and get mentioned in the title compound (1100 mg, yield quantitative) as a yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1.14 in (3H, d, J=6,0), of 1.36 (3H, t, J=7,0), 1,50-of 1.65 (1H, m), 1,75-1,90 (1H, m), 1,95-of 2.20 (4H, m)to 2.29 (3H, s), 2,95 (1H, m), 3,98 (2H, s), is 4.21 (1H, m), or 4.31 (2H, square, J=7,0), to 4.46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,94 (1H, m), 7,31 (1H, m), 7,40 (1H, m), 7,45 is 7.50 (1H, m), 7,50-of 7.60 (2H, m), 7,65-of 7.70 (1H, m).

Reference example 90

Indolizine-7-ol

To a suspension of lithium aluminum hydride (2.30 g) in tetrahydrofuran (50 ml) under stirring and ice cooling in a nitrogen atmosphere is added dropwise indolizine-7-he (2,80 g), which is derived from 4,4-diethoxybutane and diethyl-1,3-diacetonitrile according to the method described in Heterocycles, 43, 1391 (1996), and the mixture was stirred at the same temperature for 1 hour. After stirring to the reaction mixture add decahydrate sodium sulfate and the resulting mixture is stirred for further at room temperature for 1 hour. After removal by filtration of insoluble matters, the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel with use is as a solvent of the mixed solvent, containing dichloromethane and methanol (4:1), and get mentioned in the title compound (1.70 g, yield 59%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,24 (1H, m), of 1.40-1.50 (1H, m), 1.55V and 1.80 (2H, m), 1,80-2,00 (4H, m), 2.00 in to 2.15 (3H, m), 3.00 and is 3.15 (2H, m), the 3.65 (1H, m).

Reference example 91

3-Chloro-4-methoxyethoxymethyl

To a solution of 2-chloro-4-NITROPHENOL (5,2 g) in N,N-dimethylformamide (50 ml) under stirring and ice cooling consistently add methoxyethoxymethyl (2.7 ml) and triethylamine (5.0 ml) and the resulting mixture was stirred at room temperature for 1 hour. After stirring to the reaction mixture, water is added and the resulting mixture extracted with ethyl acetate. The extract is successively washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum and get 3-chloro-4-methoxyethoxymethyl (8,1) as a yellow oil.

Then to the solution obtained above, 3-chloro-4-methoxybutyrophenone in a mixed solvent containing acetone (100 ml) and water (100 ml), under stirring at room temperature successively added zinc dust (9,8 g) and ammonium chloride (8.0 g) and the resulting mixture was stirred at 60°C for 40 minutes. After stirring the reaction mixture is filtered and the filtrate evaporated in vacuum and then the mod is to further extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (5.4 g, yield 96%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 3.53 (3H, s), 5,11 (2H, s), of 6.52 (1H, DD, J=8,5, 3,0), was 6.73 (1H, d, J=3,0), 6,98 (1H, d, J=8,5).

Reference example 92

Ethyl N-(3-chloro-4-methoxyethoxymethyl)sulfamerazine

To a solution of 3-chloro-4-ethoxymethylene (5,4 g)obtained in referential example 91, in dichloromethane (50 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (4,7 ml) and pyridine (2.9 ml) and the resulting mixture was stirred at room temperature for 30 minutes. After stirring to the reaction mixture, water is added and the resulting mixture extracted with ethyl acetate. The extract is successively washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (19:1), and get mentioned in the title compound (8.0 g, yield 82%) as a reddish brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 3,52 (3H, s)to 3.92 (2H, s), 4,30 (2H, square, =7,0), of 5.24 (2H, s), 7,15-of 7.25 (2H, m), 7,41 (1H, m).

Reference example 93

Ethyl N-[3-chloro-4-methoxyethoxymethyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (1.6 g)obtained in reference example 2, ethyl N-(3-chloro-4-methoxyethoxymethyl)sulfamerazine (3.4 g)obtained in reference example 92, and triphenylphosphine (3.2 g) in dichloromethane (50 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (1.9 ml) and the resulting mixture was stirred at room temperature for 40 minutes and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate (19:1), and get mentioned in the title compound (3.9 g, yield 81%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 3,51 (3H, s)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5 in), 5.25 (2H, s), from 6.22 (1H, dt, J=15,5, 6,5), 6.42 per (1H, d, J=15,5), 7,20 (1H, m), 7,34 (1H, m), 7,41 (1H, m), 7,50-of 7.60 (4H, m).

Reference example 94

Ethyl N-[3-chloro-4-hydroxyphenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of ethyl N-[3-chloro-4-methoxyethoxymethyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (3.9 g)obtained in reference example 93, in a mixed solvent containing ethyl acetate (50 ml) and dioxane (50 ml), AC is shivani and cooling with ice, add 4 N. a solution of hydrogen chloride in dioxane (25 ml) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is neutralized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract is successively washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (3.6 g, yield quantitative) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 3,98 (2H, s), or 4.31 (2H, square, J=7,0), to 4.46 (2H, d, J=6,5), to 6.22 (1H, dt, J=16,0, 6,5), 6,40 (1H, d, J=16,0), 7,03 (1H, m), 7,32 (1H, m), 7,41 (1H, m), 7,50-of 7.60 (4H, m).

Reference example 95

Ethyl N-[3-chloro-4-(indolin-7-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of ethyl N-[3-chloro-4-hydroxyphenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamerazine (2.0 g)obtained in reference example 94, indolizine-7-ol (1.7 g)obtained in reference example 90, and triphenylphosphine (3.2 g) in dichloromethane (60 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (1.9 ml) and the resulting mixture was stirred at room temperature for 6 hours. As the reaction progresses slowly to the reaction mixture still successively added triphenylphosphine (3.2 g) and diethylazodicarboxylate (1.9 ml) the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol (2:1), and receive containing impurities named the title compound (0.6 g) as an orange oil.

Reference example 96

Ethyl N-(4-methoxyethoxymethyl)sulfamerazine

To a solution of 4-ethoxymethylene (20,9 g) in dichloromethane (400 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate in (18.0 ml) and pyridine (33 ml) and the resulting mixture was stirred at room temperature overnight. After stirring to the reaction mixture, water is added and the resulting mixture extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (28,0 g, yield 67%) as a brown oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.33 (3H, t, J=7,0), of 3.48 (3H, s), 3,90 (2H, s), the 4.29 (2H, square, J=7,0), 5,16 (2H, s), 7,03 (2H, d, J=9,0), 7,28 (2H, d, J=9,0).

Reference example 97

Ethyl N-[3-(3-cyanophenyl)-2-(E)-propenyl]-N-(4-methoxyethoxymethyl)sulfamoyl the acetate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0,53 g)obtained in reference example 2, ethyl N-(4-methoxyethoxymethyl)sulfamerazine (1,00 g)obtained in reference example 96, and triphenylphosphine (1.12 g) in dichloromethane (30 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,66 ml) and the resulting mixture was stirred at room temperature for 3.5 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (1,38 g, yield 94%) as a yellow oil.

1H NMR (270 MHz, CDCl3) δ ppm: to 1.37 (3H, t, J=7,0), of 3.48 (3H, s)to 3.99 (2H, s), 4,32 (2H, square, J=7,0), of 4.49 (2H, d, J=6,0), is 5.18 (2H, s), and 6.25 (1H, dt, J=16,0, 6,0), 6.42 per (1H, d, J=16,0), 7,06 (2H, d, J=9,0), 7,40 (1H, t, J=7,0), 7,41 (2H, d, J=9,0), 7,52 (1H, d, J=7,0), 7,54 (1H, d, J=7,0), 7,56 (1H, s).

Reference example 98

Ethyl N-[3-(3-cyanophenyl)-2-(E)-propenyl]-N-(4-hydroxyphenyl)sulfamerazine

To a solution of ethyl N-[3-(3-cyanophenyl)-2-(E)-propenyl]-N-(4-methoxyethoxymethyl)sulfamerazine (10.7 g)obtained in reference example 97, in ethyl acetate (120 ml) under stirring and cooling with ice, add 4 n solution of hydrogen chloride in ethyl acetate (80 ml) and the resulting mixture was stirred at room temperature for 4 hours and then pack the mandate in a vacuum. The obtained residue was diluted with ethyl acetate and the organic layer is successively washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (1:1), and get mentioned in the title compound (9.1 g, yield 95%) as a yellow oil.

1H NMR (270 MHz, CDCl3) δ ppm: to 1.35 (3H, t, J=7,0), 3,98 (2H, s), 4,30 (2H, square, J=7,0), to 4.46 (2H, d, J=6,0), 6,23 (1H, dt, J=16,0, 6,0), to 6.39 (1H, d, J=16,0), at 6.84 (2H, d, J=9,0), 7,34 (2H, d, J=9,0), 7,39 (1H, t, J=7,5), to 7.50 (2H, m), 7,54 (1H, s).

Reference example 99

Ethyl N-[3-(3-cyanophenyl)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)phenyl]sulfanilate

To a solution of ethyl N-[3-(3-cyanophenyl)-2-(E)-propenyl]-N-[4-hydroxyphenyl]sulfamerazine (700 mg)obtained in reference example 98, 4-hydroxy-1-methylpiperidine (410 mg) and triphenylphosphine (920 mg) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,55 ml) and the resulting mixture was stirred at room temperature overnight. Since the reaction proceeds slowly, add another 4-hydroxy-1-methylpiperidin (410 mg), triphenylphosphine (920 mg) and diethylazodicarboxylate (0,55 ml) and the resulting mixture was stirred at the same temperature the round for 4 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing ethyl acetate and methanol(2:1~1:1), and get listed in the title compound (690 mg, yield 79%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm: to 1.35 (3H, t, J=7,0), 1,70-1,90 (2H, m), 1,95-of 2.05 (2H, m), 2,31 (3H, s), 2,65 is 2.75 (2H, m), 2,85-2,95 (2H, m), 3,98 (2H, s), 4,25 is 4.35 (1H, m), 4,30 (2H, square, J=7,0), 4,47 (2H, d, J=6,5), 6,23 (1H, dt, J=16,0, 6,5), 6,40 (1H, d, J=16,0), of 6.90 (2H, d, J=9,0), 7,35-7,45 (1H, m), 7,38 (2H, d, J=9,0), 7,45-of 7.55 (3H, m).

Reference example 100

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-triftormetilfosfinov

To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.45 g), 2-trifluoromethyl-4-NITROPHENOL (1,38 g), which is obtained from 3-triftormetilfosfinov according to the method described in J. Org. Chem., 63, 4199 (1998), and triphenylphosphine (2,27 g) in dichloromethane (65 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (1,4 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent dichloromethane and get listed in the title compound (2.28 g, yield 88%) as a pale yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: for 1.49 (9H, s), 1,88 of 1.99 (4H, m), 3,51 (2H, m)to 3.64 (2H, m), a 4.83(1H, m)to 7.09 (1H, d, J=9,0), to 8.41 (1H, DD, J=9,0, 3,0), 8,53 (1H, d, J=3,0).

Reference example 101

4-(1-Methylpiperidin-4-yloxy)-3-triftormetilfosfinov

To a suspension of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-triftormetilfosfinov (2,45 g)obtained in reference example 100, in 90% formic acid (8,80 g) added 37% formaldehyde (5.50 g) and the resulting mixture was stirred at 100°C for 6 hours. After cooling to room temperature the reaction mixture was neutralized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (10:1), and receive specified in the header connection (1,82 g, yield 95%) as a yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: 1,94-2,02 (2H, m), 2,02 is 2.10 (2H, m), of 2.33 (3H, s), 2,40 of $ 2.53 (2H, m), 2,53-to 2.65 (2H, m), and 4.68 (1H, m), 7,07 (1H, d, J=9,0), 8,39 (1H, DD, J=9,0, 3,0), 8,51 (1H, d, J=3,0).

Reference example 102

4-(1-Methylpiperidin-4-yloxy)-3-triptorelin

To a solution of 4-(1-methylpiperidin-4-yloxy)-3-triftormetilfosfinov (1,82 g)obtained in reference example 101, in ethanol (30 ml) is added palladium-on-coal (0.18 g) and the resulting mixture is displaced is more at room temperature in a hydrogen atmosphere for 4.5 hours. At the end of this time the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(10:1~1:1), and get listed in the title compound (1.55 g, yield 95%) as a light brown solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,85 is 2.00 (4H, m)to 2.29 (3H, in), 2.25-2.40 a (2H, m), 2,55-2,70 (2H, m), or 4.31 (1H, m), is 6.78 (1H, DD, J=8,5, 3,0), 6,83 (1H, d, J=8,5), 6,91 (1H, d, J=3,0).

Reference example 103

Ethyl N-[4-(1-methylpiperidin-4-yloxy)-3-triptoreline]sulfanilate

To a solution of 4-(1-methylpiperidin-4-yloxy)-3-triptorelin (1.55 g)obtained in reference example 102, in dichloromethane (30 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,76 ml) and pyridine (0,91 ml) and the resulting mixture was stirred at room temperature for 1 hour. After stirring to the reaction mixture, water is added and the resulting mixture is extracted three times with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(10:1~5:1), and get listed in the title compound (2,39 g, yield quantitative) as a pale brown amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), 2,00-of 2.15 (2H, m), 2,35-of 2.50 (2H, m), 2,62 (3H, s), 2,80-3,15 (4H, m)to 3.92 (2H, s), 4,30 (2H, square, J=7,0), 4,72 (1H, m), 6,98 (1H, d, J=9,0), 7,55 (1H, DD, J=9,0, 2,5), a 7.62 (1H, d, J=2,5).

Reference example 104

Ethyl N-[3-(3-cyanophenyl)-2-(E)-propenyl]-N-[4-(1-methylpiperidin-4-yloxy)-3-triptoreline]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (500 mg)obtained in reference example 2, ethyl N-[4-(1-methylpiperidin-4-yloxy)-3-triptoreline]sulfamerazine (1333 mg)obtained in reference example 103, and triphenylphosphine (990 mg) in dichloromethane (30 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,58 ml) and the resulting mixture was stirred at room temperature for 4 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (15:1), and get mentioned in the title compound (755 mg, yield 43%) as a pale yellow amorphous solid.

1H NMR (400 MHz, CDCl3) δ ppm: to 1.35 (3H, t, J=7,0), 1,90-2,10 (4H, m), 2,33 (3H, m), 2.40 a-2,50 (2H, m), 2,55-to 2.65 (2H, m), 3,98 (2H, s), or 4.31 (2H, square, J=7,0), 4,47 (2H, d, J=6,5), a 4.53 (1H, m), 6,23 (1H, dt, J=160, 6,5), 6,41 (1H, d, J=16,0), 6,98 (1H, d, J=9,0), 7,41 (1H, t, J=7,5), 7,50-of 7.60 (4H, m), 7,71 (1H, d, J=2,5).

Reference example 105

4-(1-tert-Butoxycarbonylamino-4-yloxy)nitrobenzene

To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (50,1 g) in N,N-dimethylacetamide (550 ml) under stirring and cooling with ice add sodium hydride (10.5 g) and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time the reaction mixture under stirring at the same temperature is added dropwise a solution of 4-pernitrate (42.2 g) in N,N-dimethylacetamide (100 ml) and the resulting mixture is stirred for further at room temperature overnight. After stirring to the reaction mixture, water is added and the resulting mixture extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (13:7), and get mentioned in the title compound, a 75.1 g, yield 93%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: USD 1.43 (9H, s)of 1.76 (2H, m), at 1.91 (2H, m)to 3.34 (2H, m), the 3.65 (2H, m), 4,56 (1H, m)6,91 (2H, d, J=9,0), of 8.15 (2H, d, J=9,0).

Reference example 106

4-(1-tert-Butylcarbamoyl piperidin-4-yloxy)aniline

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)nitrobenzene (11.9 g)obtained in reference example 105, in methanol (100 ml) is added palladium-on-coal (1.9 grams) and the resulting mixture was stirred at room temperature in hydrogen atmosphere for 4 hours. At the end of this time the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (1:1), and get mentioned in the title compound (10.7 g, yield 99%) as a pale red solid.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.46 (9H, s), 1,71 (2H, m)to 1.87 (2H, m), with 3.27 (2H, m), 3,71 (2H, m), 4.26 deaths (1H, m), 6,63 (2H, d, J=8,5), 6,76 (2H, d, J=8,5).

Reference example 107

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)phenyl]sulfanilate

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)aniline (4,39 g)obtained in reference example 106, in dichloromethane (30 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (2.4 ml) and pyridine (2.4 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent smiling the aqueous solvent, containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (4,96 g, 75%yield) as a pale red oil.

1H NMR (400 MHz, CDCl3) δ ppm: of 1.33 (3H, t, J=7,0), OF 1.47 (9H, s)of 1.75 (2H, m), 1,90 (2H, m)to 3.34 (2H, m), of 3.69 (2H, m)to 3.89 (2H, s), the 4.29 (2H, square, J=7,0), of 4.44 (1H, m), 6.89 in (2H, d, J=8,5), 7,27 (2H, d, J=8,5).

Reference example 108

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0,80 g)obtained in reference example 2, ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)phenyl]sulfamerazine (2,21 g)obtained in reference example 107, and triphenylphosphine (1.70 g) in dichloromethane (40 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (1.0 ml) and the resulting mixture was stirred at the same temperature for 2 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate (10:1), and get mentioned in the title compound (2.15 g, yield 74%) as a colourless oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.35 (3H, t, J=7,0), OF 1.47 (9H, s)of 1.75 (2H, m), 1,90 (2H, m)to 3.34 (2H, m), 3,68 (2H, m), 3,98 (2H, s), 4,30 (2H, square, J=7,0), of 4.45 (1H, m), 4,47 (2H, d, J=6,0), 6,24 (1H, dt, J=15,5, 6,0), 6,40 (1H, d, J=15,5), of 6.90 (2H, d, J=8,5), 7,39 (3H, m), 7,51 (2H, m), 55 (1H, C).

Reference example 109

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-methylnitrobenzene

To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (3,62 g), 2-methyl-4-NITROPHENOL (2.55 g) and triphenylphosphine (the 5.25 g) in dichloromethane (100 ml) under stirring and cooling with ice add diethylazodicarboxylate (3.2 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent dichloromethane and receive containing impurities named the title compound (4,07 g) as a pale yellow oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.48 (9H, s)of 1.84 (2H, m), of 1.95 (2H, m)to 2.29 (3H, s), 3,49 (2H, m), 3,62 (2H, m), of 4.66 (1H, m)6,86 (1H, d, J=8,5), 8,07 (2H, m).

Reference example 110

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-methylaniline

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-methylnitrobenzene (4,07 g)obtained in reference example 109, in methanol (40 ml) is added palladium-on-coal (0,41 g) and the resulting mixture was stirred at room temperature in hydrogen atmosphere for 4 hours. At the end of this time the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent with Sanogo solvent, containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (2,73 g, total yield in two stages - reference example 109, and reference example 110 53%) as a pale red oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.47 (9H, s), of 1.74 (2H, m)to 1.87 (2H, m), 2,17 (3H, s), 3,30 (2H, m), 3,68 (2H, m), 4,25 (1H, m), 6,47 (1H, DD, J=8,5, 2,5), 6,53 (1H, d, J=2,5), of 6.68 (1H, d, J=8,5).

Reference example 111

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-were]sulfanilate

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-methylaniline (1.63 g)obtained in reference example 110, in dichloromethane (30 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,86 ml) and pyridine (0,81 ml) and the resulting mixture was stirred at room temperature for 5 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:2) and get listed in the title compound (1.84 g, yield 76%) as a pale brown amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), OF 1.47 (9H, s)of 1.78 (2H, m), 1,89 (2H, m), 2,22 (3H, s), of 3.43 (2H, m), 3,62 (2H, m), 3,90 (2H, s), the 4.29 (2H, square, J=7,0), 4,48 (1H, m), 6,79 (1H, d, J=8,0), 7,12 (2H, m).

Reference example 112

Ethyl N-[4-(1-tert-butoxycarbonyl the piperidine-4-yloxy)-3-were]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0.64 g)obtained in reference example 2, ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-were]sulfamerazine (1.84 g)obtained in reference example 111, and triphenylphosphine (1.26 g) in dichloromethane (40 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,76 ml) and the resulting mixture was stirred at the same temperature in for 1 hour and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate (12:1), and get mentioned in the title compound (1.90 g, yield 79%) as a colorless amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), OF 1.47 (9H, s)of 1.78 (2H, m), 1,89 (2H, m), of 2.21 (3H, s), 3,44 (2H, m), of 3.60 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), to 4.46 (2H, d, J=6,5), 4,50 (1H, m), 6,24 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), to 6.80 (1H, d, J=8,0), from 7.24 (2H, m), 7,40 (1H, t, J=8,0), to 7.50 (1H, d, J=7,5), 7,52 (1H, d, J=8,0), 7,56 (1H, s).

Reference example 113

Ethyl 5-nitrosalicylic

To a solution of 5-nitrosalicylic acid (10.8 g) in ethanol (100 ml) under stirring at room temperature add concentrated sulfuric acid (92.0 g) and the mixture was refluxed for 7.5 hours. After cooling to room temperature the reaction mixture is neutralized with an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was sequentially washed with saturated aqueous sodium hydrogen carbonate and 0.5 G. hydrochloric acid and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (10.7 g, yield 85%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1,47 (3H, t, J=7,0), of 4.49 (2H, square, J=7,0), to 7.09 (1H, d, J=9,0), with 8.33 (1H, DD, J=9,0, 3,0), 8,79 (1H, d, J=3,0).

Reference example 114

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-ethoxycarbonylmethylene

To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (10.2 g), ethyl 5-nitrosalicylic (10.7 g)obtained in reference example 113, and triphenylphosphine (17.3 g) in dichloromethane (200 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (10.4 ml) and the resulting mixture was stirred at room temperature for 4 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:1), resulting yellow solid is collected by filtration using hexane and get listed in the title compound (12.3 g, yield 61%) as a white solid.

1H NMR (400 MHz, CDCl3) δ m is.: of 1.40 (3H, t, J=7,0), OF 1.47 (9H, s), at 1.91 (4H, m)to 3.58 (4H, m), 4,39 (2H, square, J=7,0), 4,79 (1H, m),? 7.04 baby mortality (1H, d, J=9,0), 8,32 (1H, DD, J=9,0, 3,0), 8,69 (1H, d, J=3,0).

Reference example 115

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-carboxyterminal

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-ethoxycarbonylmethylene (1.0 g)obtained in reference example 114, in ethanol (10 ml) at room temperature, add aqueous potassium hydroxide solution (obtained by dissolving 0.2 g of the substance in 0.5 ml water) and the resulting mixture is refluxed for 2 hours. After cooling to room temperature the reaction mixture is neutralized 1 N. hydrochloric acid and extracted with ethyl acetate. The extract is successively washed with water and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuum and get listed in the title compound (0.9 g, yield 96%) as a pale yellow solid.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.48 (9H, s), 1.85 to 1,95 (2H, m), 2.00 in of 2.10 (2H, m), 3,45-3,55 (2H, m), 3,65 of 3.75 (2H, m), to 4.87 (1H, m), 7,13 (1H, d, J=9,0), 8,39 (1H, DD, J=9,0, 3,0), 8,93 (1H, d, J=3,0).

Reference example 116

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-carbamodithioato

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carboxyterminal (0.9 g)obtained in reference example 115, in dichloromethane (20 ml) at lane is mesheanii and ice cooling consistently add isobutylparaben (0.3 ml) and triethylamine (0.4 ml) and the resulting mixture was stirred at the same temperature for 1 hour. Then to the reaction mixture was added 28% ammonia solution (0.2 ml) and the resulting mixture was stirred at room temperature for 1 hour and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (19:1), and get mentioned in the title compound (0.9 g, yield 98%) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.48 (9H, s), 1,80-1,90 (2H, m), 2.05 is-of 2.20 (2H, m), 3,30 is 3.40 (2H, m), 3.75 to 3,90 (2H, m), to 4.81 (1H, m), 7,11 (1H, d, J=9,0), with 8.33 (1H, DD, J=9,0, 3,0), which is 9.09 (1H, d, J=3,0).

Reference example 117

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-carbamoylation

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamodithioate (5.7 g)obtained in reference example 116, in methanol (80 ml) is added palladium-on-coal (0.6 g) and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 2.5 hours. At the end of this time the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (19:1), and get mentioned in the title compound (4.8 g, yield 91%) as a pale yellow avrprog is solid.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.47 (9H, s)of 1.65 and 1.80 (2H, m), 1,95-of 2.05 (2H, m), 3,19 (2H, m), 3.75 to of 3.85 (2H, m), of 4.44 (1H, m), is 6.78 (1H, DD, J=9,0, 3,0), at 6.84 (1H, d, J=9,0), to 7.50 (1H, d, J=3,0).

Reference example 118

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]sulfanilate

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylation (4.8 g)obtained in reference example 117, in dichloromethane (80 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (2.5 ml) and pyridine (2.3 ml) and the resulting mixture was stirred at room temperature for 6 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (19:1). The obtained orange solid is collected by filtration using diethyl ether, and get mentioned in the title compound (3.7 g, yield 53%) as a pale yellow solid.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.32 (3H, t, J=7,0), OF 1.47 (9H, s), 1.70 to of 1.85 (2H, m), 2.00 in to 2.15 (2H, m), with 3.27 (2H, m), 3.75 to of 3.85 (2H, m), of 3.94 (2H, s), 4,28 (2H, square, J=7,0)and 4.65 (1H, m), 7,02 (1H, d, J=9,0), to 7.59 (1H, DD, J=9,0, 3,0), to 8.12 (1H, d, J=3,0).

Reference example 119

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfamoyl the Etat

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0.7 g)obtained in reference example 2, ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]sulfamerazine (2.0 g)obtained in reference example 118, and triphenylphosphine (1.5 g) in dichloromethane (30 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0.9 ml) and the resulting mixture was stirred at room temperature for 8 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (1:2), and get mentioned in the title compound (2.5 g, yield 94%) as a yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), OF 1.47 (9H, s), 1,75-of 1.85 (2H, m), 2.00 in of 2.10 (2H, m), with 3.27 (2H, m), 3.75 to of 3.85 (2H, m)to 3.99 (2H, s), or 4.31 (2H, square, J=7,0), a 4.53 (2H, d, J=7,0), of 4.66 (1H, m), from 6.22 (1H, dt, J=16,0, 7,0), 6.42 per (1H, d, J=16,0), 7,01 (1H, m), 7,39 (1H, m), 7,45-of 7.60 (2H, m), the 7.65 to 7.75 (2H, m), 8,32 (1H, m).

Reference example 120

4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-triptorelin

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-triftormetilfosfinov (2.28 g)obtained in reference example 100, in methanol (50 ml) is added palladium-on-coal (0.20 g) and the resulting mixture was stirred at room temperature in hydrogen atmosphere for 5 h the owls. At the end of this time the reaction mixture is filtered and the filtrate evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (1,69 g, yield 80%) as a pale red oil.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.47 (9H, s), 1,76-of 1.88 (4H, m), 3.43 points (2H, m)and 3.59 (2H, m), 4,46 (1H, m), is 6.78 (1H, DD, J=9,0, 3,0), 6,83 (1H, d, J=9,0), 6,91 (1H, d, J=3,0).

Reference example 121

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-triptoreline]sulfanilate

To a solution of 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-triptorelin (1,69 g)obtained in reference example 120, in dichloromethane (20 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (0,76 ml) and pyridine (0,49 ml) and the resulting mixture was stirred at room temperature for 3 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (1,74 g, yield 73%) as a pale red oil.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.34 (3H, t, J=7,0), TO 1.48 (9H, s), 1,83-of 1.94 (4H, m), 3,483,60 (4H, m), 3,91 (2H, s), or 4.31 (2H, square, J=7,0)and 4.65 (1H, m), of 6.99 (1H, d, J=9,0), 7,52 (1H, DD, J=9,0, 2,5), 7,56 (1H, d, J=2,5).

Reference example 122

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-triptoreline]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (0,57 g)obtained in reference example 2, ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-triptoreline]sulfamerazine (1,74 g)obtained in reference example 121, and triphenylphosphine (1.07 g) in dichloromethane (27 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,65 ml) and the resulting mixture was stirred at room temperature for 3 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate (12:1), and receive specified in the header of the connection (of 2.06 g, yield 93%) as a colorless amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.35 (3H, t, J=7,0), OF 1.47 (9H, s), 1,82-of 1.92 (4H, m), 3.46 in-3,62 (4H, m), 3,98 (2H, s), or 4.31 (2H, square, J=7,0), 4,48 (2H, d, J=6,5), of 4.66 (1H, m), from 6.22 (1H, dt, J=16,0, 6,5), 6,41 (1H, d, J=16,0), 6,98 (1H, d, J=7,5), 7,41 (1H, DD, J=8.0 a, 7,5), 7,52 (2H, m), EUR 7.57 (1H, s), 7,58 (1H, DD, J=9,0, 2,0), 7,72 (1H, d, J=2,0).

Reference example 123

3-Chloro-4-(tropan-3-yloxy)nitrobenzene

To a solution of 3-tropanol (6.7 g), 2-chloro-4-NITROPHENOL (8,2 g) and triphenylphosphine (16.1 g) in a mixture of dichloromethane (200 ml) and tetrahydrofuran (50 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (9.7 ml) and the resulting mixture was stirred at room temperature during the night and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (19:1), and get mentioned in the title compound (8.5 g, yield 60%) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: 1,65-of 1.75 (2H, m), 2.00 in of 2.10 (4H, m), 2,15 was 2.25 (2H, m), the 2.46 (3H, s), 3,35 is-3.45 (2H, m), and 4.68 (1H, m), 6,98 (1H, d, J=9,0), 8,11 (1H, DD, J=3,0, 9,0), of 8.28 (1H, d, J=3,0).

Reference example 124

3-Chloro-4-(tropan-3-yloxy)aniline

To a solution of 3-chloro-4-(tropan-3-yloxy)nitrobenzene (8.5 g)obtained in reference example 123, in acetic acid (500 ml) at room temperature add powder tin (17.0 g) and the resulting mixture was stirred at room temperature overnight. After stirring the reaction mixture is filtered and the filtrate is neutralized with an aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (3:1), and get mentioned in the title compound (2.5 g, yield 32%) as a colourless solid ve is esta.

1H NMR (500 MHz, CDCl3) δ ppm: 1,50-1,60 (2H, m), 1.85 to 1,95 (4H, m), 2.00 in of 2.10 (2H, m), of 2.38 (3H, s), 3,20-3,30 (2H, m)to 4.23 (1H, m), of 6.49 (1H, DD, J=3,0, 8,5), of 6.71 (1H, d, J=3.0) is for 6.81 (1H, d, J=8,5).

Reference example 125

Ethyl N-[3-chloro-4-(tropan-3-yloxy)phenyl]sulfanilate

To a solution of 3-chloro-4-(tropan-3-yloxy)aniline (2.5 g)obtained in reference example 124, in dichloromethane (50 ml) under stirring and ice cooling successively added dropwise ethylchloroformiate (1.5 ml) and pyridine (0.9 ml) and the resulting mixture was stirred at room temperature for 3.5 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol (4:1), and get mentioned in the title compound (3.5 g, yield 89%) as a pale brown amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: to 1.32 (3H, t, J=7,0), 1,95-of 2.05 (2H, m), 2,20-of 2.25 (2H, m), 2,30-of 2.75 (4H, m), 2,84 (3H, s)to 3.89 (2H, m), 3,98 (2H, s), 4,28 (2H, square, J=7,0), of 4.49 (1H, m), to 6.95 (1H, d, J=8,5), 7,25 (1H, DD, J=2,5, 8,5), was 7.45 (1H, d, J=2,5).

Reference example 126

Ethyl N-[3-chloro-4-(tropan-3-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-(E)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-(E)-propen-1-ol (1.4 g)obtained in reference example 2, ethyl N-[3-chloro-4-(tropan-3-yloxy)phenyl]sulfamerazine (3.5 g)obtained in saloon the m example 125, and triphenylphosphine (2.9 g) in dichloromethane (50 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (1.8 ml) and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and methanol(19:1~9:1), and get listed in the title compound (1.3 g, yield 27%) as a yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), 1,55-1,65 (2H, m), 1,90-2,00 (4H, m), 2.05 is-of 2.15 (2H, m), is 2.37 (3H, s), with 3.27 (2H, m), 3,98 (2H, s), or 4.31 (2H, square, J=7,0), to 4.46 (2H, d, J=6,5), 4,50 (1H, m), 6,21 (1H, dt, J=6,5, 16,0), 6,41 (1H, d, J=16,0), 6,94 (1H, m), 7,29 (1H, m), 7,40 (1H, m), 7,50-of 7.60 (4H, m).

Reference example 130

3-(3-Cyanophenyl)-2-fluoro-2-(Z)-propen-1-ol

To a solution of 2-diethylphosphino-2-forexpros acid (4.35 g), which is obtained according to the method described in J. were obtained. Chem., 332, 1 (1987), in tetrahydrofuran (90 ml) under stirring at -78°With added dropwise a 1.6 n solution of utility in hexane (28 ml) and the resulting mixture was stirred at the same temperature for 1 hour. After stirring to the reaction mixture within 10 minutes is added dropwise a solution of 3-cyanobenzaldehyde (2.66 g) in tetrahydrofuran (10 ml) and the resulting mixture was stirred at the same temperature in ECENA 3 hours. Then the temperature of the reaction mixture was raised to 0°and after adding water, the water layer is separated, the separated parts. The organic layer after separation twice extracted with saturated aqueous sodium bicarbonate. The extract is combined with the aqueous layer separated earlier, bring the pH to 4 with concentrated hydrochloric acid and then extracted five times tert-butylmethylamine ether. The extract is dried over anhydrous sodium sulfate and evaporated in vacuum and receive the intermediate compound (3,47 g) as a white solid.

Then to the solution obtained above intermediate compound (1,15 g) and triethylamine (0,92 ml) in dichloromethane (10 ml) under cooling with ice add ethylchloride (0.63 ml) and the resulting mixture was stirred at room temperature for 15 minutes and evaporated in vacuum. To the obtained residue is added ethyl acetate, the insoluble matter is filtered off and the filtrate evaporated in vacuum. Then to a solution of the obtained residue in tetrahydrofuran (10 ml) under stirring and cooling with ice add an aqueous solution of sodium borohydride (obtained by dissolving 0.45 g of the substance in 5 ml of water) and the resulting mixture was stirred at room temperature for 18 hours. After stirring to the reaction mixture is added a saturated solution of chloride of ammo the Oia and the resulting mixture was three times extracted with tert-butylmethylamine ether. The extract was washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate (3:2), and get mentioned in the title compound (0.33 g, yield 31%) as a colourless solid.

1H NMR (500 MHz, CDCl3) δ ppm: 4,32 (2H, DD, J=12,5, 5,5), of 5.82 (1H, d, J=37,5), was 7.45 (1H, t, J=8,0), 7,53 (1H, d, J=8.0 a), of 7.70 (1H, d, J=8,0), 7,81 (1H, s).

Reference example 131

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)phenyl]-N-[3-(3-cyanophenyl)-2-fluoro-2-(Z)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-fluoro-2-(Z)-propen-1-ol (0.45 g)obtained in reference example 130 ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)phenyl]sulfamerazine (1.12 g)obtained in reference example 107, and triphenylphosphine (0,80 g) in dichloromethane (20 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,48 ml) and the resulting mixture was stirred at the same temperature for 2 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing dichloromethane and ethyl acetate (15:1), and get mentioned in the title compound (1.40 g, Ihad 92%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm: to 1.35 (3H, t, J=7,0), OF 1.47 (9H, s), of 1.74 (2H, m), 1,90 (2H, m)to 3.34 (2H, m), 3,68 (2H, m)4,00 (2H, s), 4,30 (2H, square, J=7,0), to 4.46 (1H, m), of 4.54 (2H, d, J=15,0), 5,62 (1H, d, J=36,5), 6,92 (2H, d, J=9,5), 7,42 (3H, m), 7,51 (1H, d, J=7,0), 7,63 (1H, d, J=8,0), 7,71 (1H, s).

Reference example 132

Ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]-N-[3-(3-cyanophenyl)-2-fluoro-2-(Z)-propenyl]sulfanilate

To a solution of 3-(3-cyanophenyl)-2-fluoro-2-(Z)-propen-1-ol (0,80 g)obtained in reference example 130 ethyl N-[4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]sulfamerazine (2.20 g)obtained in reference example 118, and triphenylphosphine (1.50 g) in dichloromethane (50 ml) under stirring and ice cooling is added dropwise diethylazodicarboxylate (0,86 ml) and the resulting mixture stirred at room temperature for 2.5 hours and then evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent containing hexane and ethyl acetate(1:4~1:2), and get listed in the title compound (3,40 g, yield quantitative) as a pale yellow amorphous solid.

1H NMR (500 MHz, CDCl3) δ ppm: of 1.36 (3H, t, J=7,0), OF 1.47 (9H, s), 1,75-of 1.84 (2H, m), 2,02 is 2.10 (2H, m), 3,23-3,30 (2H, m), 3,76-a-3.84 (2H, m)to 4.01 (2H, s), or 4.31 (2H, square, J=7,0), 4,57-4,70 (3H, m), the 5.65 (1H, d, J=36,5), 7,03 (1H, d, J=9,0), 7,38-7,74 (5H, m), 8,35 (1H, d, J=3,0).

With Ilony example 133

3-[3-[N-[4-(1-tert-Butoxycarbonylamino-4-yloxy)-3-carbamoylmethyl]amino]-1-(E)-propenyl]benzonitrile

3-Cyanocinnamate (0.64 g)obtained in reference example 1 4-(1-tert-butoxycarbonylamino-4-yloxy)-3-carbamoylation (1,36 g)obtained in reference example 117, and crushed molecular sieves of 5.06 g) suspended in toluene (30 ml) and refluxed for 2.5 hours. After cooling to room temperature the reaction mixture was filtered through celite, and the filtrate is evaporated in vacuum and get imino-derivatives.

Then to the suspension obtained above imino-derivatives in ethanol (30 ml) under ice cooling successively added sodium borohydride (0.31 g) and caesium chloride (0.32 g) and the resulting mixture was stirred at room temperature overnight. After stirring to the reaction mixture add sodium borohydride (0.16 g) and the resulting mixture was stirred at room temperature for 30 minutes. After stirring to the reaction mixture is added saturated aqueous solution of ammonium chloride and the resulting mixture extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography on silica gel using as eluent a mixed solvent that contains Amigo hexane and ethyl acetate(7:3~0:10), and get listed in the title compound (1.77 g, yield 92%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm: to 1.47 (9H, s), 1,68-to 1.79 (2H, m), 1,98-2,17 (2H, m), 3,14-up 3.22 (2H, m), 3,78-3,88 (2H, m), 3,99 (2H, d, J=5.5), the of 4.45 (1H, m), 6,38 (1H, dt, J=16,0, 5,5), 6,60 (1H, d, J=16,0