Derivatives of naphthalene, the pharmaceutical composition

 

(57) Abstract:

(57) Describes the new derivatives of naphthalene General formula (I) in which R1represents carboxyl or protected carboxyl group, R2represents hydrogen, hydroxyl or protected hydroxyl group, R3represents hydrogen, hydroxyl group, protected hydroxyl group, lower alkyl or halogen, R4represents hydrogen or halogen, AND1represents the lowest alkylen, AND2is a bond or lower alkylene, R5is a group, where R6represents a mono(or di - or tri-)aryl(lower)alkyl, and Z represents N or CH) or-A3-Q (R7) (R8), where values AND3, Q, R7and R8specified in paragraph 1 of the claims. The compounds have pharmacological activity such as inhibitory, anti-hypertensive and are agonists of prostaglandin I2. Also describes pharmaceutical compositions based on them. 2 c. and 4 C. p. F.-ly.

The invention relates to new derivatives of naphthalene and their pharmaceutically acceptable salts which are useful as medicinal sidste 05422032A.

The present invention relates to new derivatives of naphthalene. More specifically, the present invention relates to new derivatives of naphthalene and their pharmaceutically acceptable salts, which possess pharmacological activity, such as inhibiting activity, hypotensive activity or similar activity, and are agonists of prostaglandin I2to processes for their preparation, to pharmaceutical compositions containing the said substances and to their use for the production of medicines.

Accordingly, an object of the present invention are new and useful derivatives of naphthalene and their pharmaceutically acceptable salts.

Another objective of the present invention is a method of obtaining derivatives of naphthalene and their salts.

Another object of the present invention is a pharmaceutical composition containing, as active ingredient, mentioned derivatives of naphthalene or of their pharmaceutically acceptable salts.

Another objective of the present invention is the use of derivatives of naphthalene and their pharmaceutically acceptable salts in the manufacture of pharmaceutical preparations for the treatment and/or prevention of sentenza after percutaneous luminaries coronary angioplasty, hypertension or similar diseases.

Derivatives of naphthalene present invention can be represented by the following formula (I)

< / BR>
in which R1represents carboxyl or protected carboxyl group,

R2represents hydrogen, hydroxyl or protected hydroxyl group,

R3represents hydrogen, hydroxyl group, protected hydroxyl group, lower alkyl or halogen,

R4represents hydrogen or halogen,

A1represents the lowest alkylen,

A2is a bond or lower alkylene,

R5represents a

< / BR>
where R6represents a mono (or di - or tri-) aryl (lower) alkyl and Z represents N or CH, or

< / BR>
where-A3represents or ,

where R9represents hydrogen or lower alkyl,

Q represents N or CH, R7represents aryl, R8represents aryl and is a

In accordance with the present invention, new derivatives of naphthalene (1) can be obtained by methods which are illustrated by schemes (methods 1 - 6), presented at the end SUB>2Q and have installed the above values,

X1represents an acid residue,

Ra1represents a protected carboxyl group,

X2represents halogen,

X3represents halogen,

X4represents a halogen and

R9arepresents lower alkyl.

Some of the source compounds are novel compounds and can be obtained by methods which are illustrated by schemes (methods A-T), presented in the end of the text.

Here R1, R2, R3, R4, R5, R6, R7, R8, R9, A1, A2, Z, Q, X1X3or have installed the above values,

R10represents hydrogen or a group protecting the hydroxyl group,

R11represents useplease group

R12represents carboxyl or protected carboxyl group,

A4is a bond or C1-5-alkylen,

Ra13represents halogen,

R13represents hydrogen or halogen,

X5represents halogen,

R10aperformance>/BR>X7represents halogen,

R14represents lower alkyl, or aryl which may have suitable Deputy (deputies),

R15represents lower alkyl,

X8represents halogen,

Ra4represents a halogen and

R16is a group protecting the amino group.

Suitable pharmaceutically acceptable salt of the target compound (1) are conventional non-toxic salts include metal salts, such as alkali metal salts (e.g. sodium salt, potassium salt, etc. and salts of alkaline earth metals (e.g. calcium salt, magnesium salt, etc.), ammonium salts, salts with organic bases (for example, salts of trimethylamine, salts of triethylamine, pyridine salts, salts picoline, salt dicyclohexylamine, salts of N,N-dibenziletilendiaminom, and etc.), organic acid salts (e.g. acetates, maleate, the tartratami, methansulfonate, bansilalpet, formate, toluensulfonate, triptoreline, etc ), inorganic salts (for example, hydrochloride, hydrobromide, sulfates, phosphates, etc.), salts with amino acids (e.g. arginine, aspartic acid, glutamic acid, etc.,) and Takasago of the invention in the above and subsequent sections of the present description, details are explained next.

The term "lower" is intended to indicate from 1 to 6 carbon atoms, unless otherwise indicated.

Suitable "aryl" and "aryl group" in the term "mono(or di - or tri-) aryl (lower) alkyl" may include phenyl, naphthyl and the like groups.

Suitable "lower alkylene may include linear or branched alkylene containing from 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, or similar groups, preferably alkylene containing from 1 to 3 carbon atoms.

Suitable C1-5-alkylen may include linear or branched alkylene containing from 1 to 5 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, or similar groups.

Suitable "lower alkyl" and "lower alkyl group" in the term "mono (or di - or tri-) aryl (lower) alkyl" may include linear or branched alkyl containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, or similar groups, preferably alkyl, containing from 1 to 4 carbon atoms.

The approach is similar groups.

Suitable examples of the ester groups, esterified carboxyl groups can be groups such as complex lower alkilany ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl methyl ether, pentalogy ester, hexyl ester, etc.,), which may contain at least one suitable Deputy, for example, alkanoyloxy (lower) alkilany ester (for example, acetoxymethyl ether, propionylacetate ether, butyrylacetate ether, veterinarinary ether, pivaloyloxymethyl ether, hexaniacinate ester, 1 (or 2)- ecotoxicology ester, 1 (or 2, or 3)-acetoxypropionyl ester, 1 (or 2, or 3, or 4)-acetoxyvalerenic ester, 1 (or 2)- propionylacetate ester, 1 (or 2, or 3)-propionoxypiperidine ether (1 or 2)-butyrylacetate ester, 1 (or 2)- isobutyrylacetate ester, 1 (or 2)-pivaloyloxymethyl ester, 1 (or 2)-hexanolactone ether, isobutyrylacetate ether, 2-ethylbutyraldehyde ether, 3,3-dimethylbutylamino ester, 1 (or 2)-pentanedinitrile ether, and so on), lower alkylsulfonyl(lower)alkilany ester (for example, 2 - mutilative ether, and so on), mother, and so on), lower alkoxycarbonyl(lower)alkilany ester (for example, methoxycarbonylmethyl ether, ethoxycarbonylmethylene ether, 2-methoxycarbonylmethylene ether, 1 - ethoxycarbonylmethylene ether, 1 - isopropoxycarbonyloxymethyl ether, and so on), thalidomide (lower) alkilany ester or (5-(lower alkyl)-2-oxo-1,3 - dioxol-4-yl) (lower) alkilany ester (for example, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.,),

lower alkenilovyh ester (e.g. vinyl ester, allyl ester, etc.,),

lower alkinilovymi ester (for example, atinlay ether, propenyloxy ether, etc.,),

ar(lower)alkilany ester, which may contain at least one suitable substitute, such as mono(or di or three)-phenyl (lower) alkilany ether, which may contain at least one suitable substituent (for example, benzyl ester, 4-methoxybenzyloxy ether, 4-nitrobenzyloxy ether, finitely ether, trailovic ether, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ether, 4-hydroxy-3,5-di-tert-butylbenzylamine ether, and so on),< / BR>
Caligraphy ester, and similar esters.

Suitable "acid residue" may include halogen (e.g. chlorine, bromine, iodine, etc.,), sulfonyloxy (for example, methylsulfonylamino, phenylsulfonylacetate, coolsolutionsgroup, and so on), and similar groups.

Suitable "protected hydroxy group" can be alloctype and similar groups.

Suitable "acyl group" in the term "alloctype" may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring.

Also, suitable examples of the said acyl group may be lower alkanoyl (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.,),

lowest alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, 1-cyclopropanecarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, hexyloxymethyl, and so on),

lower alkanesulfonyl (e.g. the example, benzazolyl, toil, and so on),

aroyl (for example, benzoyl, toluyl, xyloyl, Naftoli, phthaloyl, endangerment, and so on),

ar(lower) alkanoyl (for example, phenylacetyl, phenylpropionyl, and so on),

ar(lower) alkoxycarbonyl (for example, benzyloxycarbonyl, ventilatsioonil, and so on), and similar groups.

Suitable "halogen" may be a chlorine, bromine, iodine and fluorine.

Suitable "useplease group" may be lower alkoxygroup (for example, methoxy, ethoxy-, propoxy-, isopropoxy, butoxypropan and so on ), and similar groups.

A suitable substituent in the definition of "aryl which may contain suitable Deputy (deputies)" may include lower alkyl, examples of which are given above, and similar groups.

Suitable "group protecting the amino group may be an acyl group, examples of which are given above, mono(or di - or tri-) aryl (lower) alkyl and similar groups.

Suitable "group protecting the hydroxyl group may be a lower alkyl, examples of which are given above, silyl, which may have from one to three suitable substituents, and similar groups.

Suitable is by a lower alkyl, examples of which are given above, aryl, examples of which are given above, and similar groups.

Preferred variants of the target compounds (1) are compounds in which

R1represents carboxyl or protected carboxyl group (preferably esterified carboxyl group, most preferably lower alkoxycarbonyl,

R2represents hydrogen, hydroxyl or protected hydroxyl group (preferably alloctype),

R3represents hydrogen, hydroxyl group, protected hydroxyl group (preferably alloctype), lower alkyl or halogen,

R4represents hydrogen or halogen,

A1represents the lowest alkylene (preferably - C1-3-alkylene, most preferably methylene),

A2is a bond or lower alkylene (preferably C1-3-alkylene, most preferably methylene or ethylene),

R5represents a

(where R6is a diaryl (lower) alkyl (and preferably diphenyl (lower) alkyl, most preferably - diphenylmethyl), and Z is from is a hydrogen or lower alkyl),

Q represents N or CH, R7represents aryl (preferably phenyl), and R8represents aryl (preferably phenyl), and is a

Methods of obtaining the target and source connections of the present invention more are explained next.

Method 1

The compound (I) or its salt can be obtained by reacting the compound (II) or its salt with the compound (III) or its salt.

This reaction is usually carried out in a solvent such as acetonitrile, benzene, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, telengard, chloroform, diethyl ether or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

The reaction is usually carried out in the presence of a base.

A suitable base may be an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), hydroxide of alkaline earth metal (e.g. magnesium hydroxide, calcium hydroxide, and so forth), a carbonate of an alkali metal (on arbonet potassium, and so on), carbonate of alkaline earth metal (e.g. magnesium carbonate, calcium carbonate, etc.,) or a similar compound, and an organic base such as tri (lower) alkylamine (for example, trimethylamine, triethylamine, diisopropylethylamine, and so on ), di(lower)alkilani (for example, dimethylaniline, etc.), pyridine or similar connection.

Method 2

The compound (1B) or its salt can be obtained when the compound (1A) or its salt is subjected to the reactions of elimination group protecting the carboxyl group.

The proper way to implement such a reaction may be a conventional method such as hydrolysis, reduction, and similar methods.

(I) Hydrolysis

The hydrolysis is carried out preferably in the presence of a base or an acid including Lewis acid.

A suitable base may be an inorganic base and organic base, such as alkali metal (e.g. sodium, potassium, etc.), the hydroxide or carbonate or bicarbonate of an alkali metal, trialkylamine (for example, trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo[4.3.0] non-5-ene, 1,4-diazabicyclo[2.2.2] octane, 1,8-diazabicyclo[5.4.0] undec-7-ene, or similar connection.

The reaction is usually carried out in a solvent such as water, alcohol (e.g. methanol, ethanol, etc), methylene chloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, mixtures, or any other solvent which does not exert adverse influence on the reaction. Liquid base or acid can also be used as solvents. The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

(II) rehabilitation

The restoration carried out in the usual way, including chemical recovery and catalyst recovery.

Suitable reducing agents which are used in the practical or inorganic acid (for example, formic acid, p-toluensulfonate acid, hydrochloric acid, Hydrobromic acid, etc.,).

Suitable catalysts, which are used in catalytic reduction are conventional catalysts such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium-on-charcoal, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), Nickel catalysts (e.g., the recovered Nickel, Nickel oxide, Raney Nickel, etc), cobalt catalysts (e.g., the recovered cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.,), copper catalysts (for example, the recovered copper, Raney copper, Ullman copper, etc ), and similar catalysts. Recovery is usually carried out in a conventional solvent which does not exert adverse influence on the reaction, such as water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran or their mixtures. In addition, when Washakie can be used as solvents.

The reaction temperature such recovery is not critical and the reaction is usually carried out under conditions of from cooling to heating.

Method 3

The compound (1B) or its salt can be obtained by reacting compound (IV) or its salt with the compound (V) or its salt.

This reaction is usually carried out in a solvent such as acetonitrile, benzene, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, telengard, chloroform, diethyl ether or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

The reaction is usually carried out in the presence of a base.

Suitable base may be the basis of the number mentioned in method 1. Liquid Foundation can also be used as solvent.

Method 4

The compound (1G) or its salt can be obtained by reacting compound (VI) or its salt with the compound (VII) or its salt.

This reaction is usually carried out in a solvent such as acetonitrile, benzene, N, N-Dimethylol is barely, which has no adverse effect on the reaction.

The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

The reaction is usually carried out in the presence of a base.

Suitable base may be the basis of the number mentioned in method 1.

Method 5

The compound (1D) or its salt can be obtained by reacting compound (VIII) or its salt with the compound (IX) or its reactive derivative at the carboxy group or its salt.

Suitable reactive derivative at a carboxyl group of compound (IX) may be galoyanized, acid anhydride, activated amide, an activated ester and the like compounds. The suitable example may be an acid chloride, acid azide, mixed anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphorous acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, etc.,), dialkylphosphorous acid, sulfurous acid, tisera acid, alkanesulphonic acid (for example, methanesulfonamide (for example, Pavlova acid, pentane acid, isopentane acid, 2-ethylmalonate acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.,), a symmetric acid anhydride, amide, activated imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, or activated ester (for example, cinematology ether, methoxymethyl ether, dimethylaminomethylene ether, vinyl ether, propargilovyh ether, p-nitrophenyloctyl ether, 2,4-dinitrophenoxy ether, trichloranisole ether, pentachlorphenol ether, methylphenylene ether, phenylazophenyl ester, a phenyl thioether, p-nitrophenyloctyl tiefer, p-crazily tiefer, carboxymethoxy tiefer, paranjoy ether, pyridyloxy ether, piperidinyl ether, 8-hinolinovy tiefer, and so on), or an ester with N-hydroxidealuminum (for example, N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridine, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, and so on ) etc. These reactive derivatives can be selected optionally include compounds corresponding to the used compounds of type (IX).

The reaction obychnoi, telengard, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvents which do not render harmful influence on the reaction. These solvents can also be used in mixture with water.

When the compound (IX) used in the reaction in the form of a free acid or in the form of its salt, the reaction is carried out preferably in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl - N'-morpholinobutyrophenone, or similar compounds.

The reaction can also be carried out in the presence of inorganic or organic bases such as bicarbonate of an alkali metal, three (lower) alkylamine, pyridine, N-(lower) alkalifying, N,N-di(lower) alkylbenzenes, or similar connection. The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

Method 6

The compound (1G) or its salt can be obtained by reacting compound (1E) or its salt with a compound (X) or its salt.

This reaction can be carried out in accordance with the method described below in example 20, or similar method.

This reaction can be carried out in accordance with the method described in preparative example 31, or a similar method.

Method B

The compound (XV) or its salt can be obtained when the compound (XIV) or its salt is subjected to reaction recovery.

This reaction can be carried out in accordance with the method described in preparative example 32, or a similar method.

The way IN

The compound (XVII) or its salt can be obtained when the compound (XVI) or its salt is subjected to dehydration reaction.

This reaction can be carried out in accordance with the method described in preparative example 33, or similar method.

Method D

The compound (XIX) or its salt can be obtained when the compound (XVIII) or its salt is subjected to oxidation reaction.

This reaction can be carried out in accordance with the methods described below in preparative examples 34 and 35, or similar method.

Method D

The compound (XX) or its salt can be obtained when the compound (XV) or its salt is subjected to reaction haloiding.

This reaction can be carried out in accordance with spne (XXII) or its salt can be obtained, when the compound (XXI) or its salt is subjected to reaction recovery.

This reaction can be carried out in accordance with the methods described below in preparative examples 1, 11, 13 and 40(2), or similar method.

Way W

The compound (XXV) or its salt can be obtained by reacting the compound (XXIII) or its salt with the compound (XXIV) or its salt.

This reaction can be carried out in accordance with the methods described below in preparative examples 2 and 46, or similar method.

Method 3

The compound (II) or its salt can be obtained when the compound (XXXXIV) or its salt is subjected to the reactions of elimination group protecting the hydroxyl group.

The reagent used in this reaction may include halogenalkyls (for example, attributively, and so on), dialkoxy alkali metal (for example, titoxd sodium, and so on), the sulfide of an alkali metal (for example, the sulphonamide of sodium, and so on), diphenyl alkali metal (e.g. lithium diphenylphosphide, and so on), aluminum halide (e.g., aluminum chloride, aluminum bromide, etc.,), trihalogen boron (for example, trichloride boron, tribromide boron, and so on), the pyridine hydrochloride is legend of tetraalkylammonium (for example, tetrabutylammonium, and so on), the combination of methionine and a sulfonic acid (for example, methanesulfonate acid, and so forth), and similar compounds.

The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, telengard, chloroform, N,N-dimethylformamide, N, N-dimethylacetamide or any other organic solvent which has no adverse effect on the reaction.

The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

Method AND

The compound (XXVIII) or its salt can be obtained by reacting compound (XXVI) or its salt with the compound (XXVII) or its salt.

This reaction can be carried out in accordance with the methods described below in preparative examples 8, 17 and 19, or similar method.

The compound (XXVII) or its salt can be obtained in accordance with the method described in preparative example 7, or similar method.

The way TH

Compound (XXX) or its salt can be obtained from compound (XXIX) or its salt with a
The compound (XXXI) or its salt can be obtained when the compound (XV) or its salt is subjected to reaction recovery.

This reaction can be carried out by the method similar to the method in the above method 2, and therefore the reagents used and the reaction conditions (e.g. solvent, reaction temperature, etc.,) may correspond shown in method 2.

Method L

The compound (XXXIII) or its salt can be obtained by reacting the compound (XXIII) or its salt with the compound (XXXII) or its salt.

This reaction is usually carried out in a solvent such as acetonitrile, benzene, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, telengard, pyridine, chloroform, diethyl ether or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

The reaction is usually carried out in the presence of a base.

A suitable base may be the basis of the number mentioned in method 1.

Method M

Compound (XXXVI) or its salt can be obtained by woudestein in accordance with the method, described in preparative example 38, or similar method.

Method H

The compound (XXXXV) or its salt can be obtained when the compound (XXIII) or its salt is subjected to reaction haloiding.

This reaction can be carried out in accordance with the methods described below in preparative examples 14 and 15, or in a similar way.

How ABOUT

Compound (XXXVIII) or its salt can be obtained when the compound (XXXVII) or its salt is subjected to reaction haloiding.

This reaction can be carried out in accordance with the method described in preparative example 21, or similar method.

Method P

The compound (XXXX) or its salt can be obtained by reacting compound (XXXIX) or its salt with the compound (IX) or its reactive derivative at the carboxy group or its salt.

This reaction can be carried out by the method similar to the method in the above-mentioned method 5, and therefore the reagents used and the reaction conditions (e.g. solvent, reaction temperature, and so on) can correspond given in method 5.

Method P

The compound (IV) or its salt can be reaction can be carried out according to the method, similar to the method in the above-mentioned method 1, and therefore the reagents used and the reaction conditions (e.g. solvent, reaction temperature, etc.,) may correspond to the above in method 1.

Way

The compound (VI) or its salt can be obtained by reacting compound (IV) or its salt with a compound (XXXXII).

This reaction is usually carried out in a solvent such as acetonitrile, benzene, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, telengard, chloroform, diethyl ether or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

The reaction is usually carried out in the presence of a base.

A suitable base may be the basis of the number mentioned in method 1.

Way T

The compound (VIII) or its salt can be obtained when the compound (XXXXIII) or its salt is subjected to the reactions of elimination group protecting the amino group.

This reaction can be carried out by the method similar to the method in the above-mentioned method 2, and so on) may correspond shown in method 2.

The target compound (1) of the present invention and its pharmaceutically acceptable salts possess pharmacological activity such as the activity of inhibiting platelet aggregation, vasodilator, antihypertensive action, or similar activity, and are agonists of prostaglandin I2and , therefore, can be used for the treatment and/or prevention of blockage of the artery (e.g., chronic arterial obstruction, and so on), diseases of the brain vessels, stomach ulcers, hepatitis, liver failure, cirrhosis of the liver, arteriosclerosis, emissionstag heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension, inflammation, heart failure, kidney disease (e.g., renal failure, nephritis, etc.), complications of diabetes (e.g. diabetic nephropathy, diabetic retinopathy, etc.), disorders of peripheral blood circulation, and so on, and can also be used for protection of organs after a transplant.

To show the suitability of the target compound (1), the following are the pharmacological characteristic data of the compounds (1).

I) Inhibition of agrigenetics)-2-hydroxy-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate

(2) 2-[(1,2,3,4-Tetrahydro-5-carboxymethoxy-2-naphthyl)methyl]- 6-diphenylmethyl-C(2H)-pyridazinone

(II) test Method

Get human blood from healthy volunteers and mix it with 1/10 by volume of 3.8% sodium citrate, pH of 7.4. Blood with citrate, centrifuged at 150 x g for 10 minutes and remove platelet-rich plasma (PRP). The remaining blood is centrifuged for 10 minutes at 1500 x g and get the plasma-depleted platelet (PRP), which is used as a standard for platelet aggregation. The study of the aggregation is carried out, using an 8-channel aggregometer HEMATRACER 801 (NBS, Japan). Mix 25 ál of the sample solution and 225 μl of PRP and stirred at 1000 rpm for 2 minutes at 37oC. induce Aggregation solution ADR at final concentration of 2.5 mm.

(III) test Results

Check the connection - Inhibition (%)

(1) (1,010-7M) - 971,2

(2) (1,010-6M) - 100 0,4 - mean STD.

II) Effect on mean arterial blood pressure in rats, in consciousness

(I) Check the connection

Sodium salt [5-(carboxymethoxy)-2-hydroxy - 1,2,3,4-tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate

(II) test Method

Rats Sprage. The Lennie with heparin solution, and measure the average blood pressure. Average blood pressure measured by the blood pressure sensor and recorded on a polygraph. Check the connection, dissolved in ethanol, polyethylene glycol and distilled water (1: 1:1), is injected through a polyethylene catheter inserted in the femoral vein in a volume of 1 ml/kg of Intravenous anti-hypertensive action check the connection is expressed as the maximum reduction (R max). Briefly, R max is expressed as the maximum pressure change, in %, compared with an average blood pressure before the introduction of verifiable connection.

(III) test Results

Check the connection - R max (%)

10 µg/kg 27,5

III) Analysis of receptor binding

(I) Check the connection

Sodium salt of (2R)-[5-(carboxymethoxy)-2-hydroxy-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate

(II) test Method

Clone cDNA of the human IP receptor and Express in COS7 using the vector pCDM8, in a manner similar to the method described in the literature [J. Biol. Chem., Vol. 269, No. 16, pp. 12173-12178 (1994); Circulation, Vol. 90, No. 4, pp. 1643-1647 (1994); FEBS Letters 344 (1994) 74-78].

After transfection cells that Express the human IP receptor, collect scraper for cleto who/SUB>, 1 mm etc and 0.1 mm PMSF. Thaw the frozen cells and aliquots (4,5105cells) incubated for 60 minutes with shaking at 30oC in plastic tubes in 100 μl of buffer for analysis with 10 nm of [3H]-iloprost (iliprost) in the presence or in the absence of verifiable connection (110-6M).

To determine nonspecific binding, add iloprost at a concentration of 10 μm. Each analysis is performed twice. The reaction mixture was filtered through a glass filter Whatman GF/C to stop the reaction. After washing the filter ice buffer for analysis checks count the radioactivity of the filter. The nonspecific binding is subtracted from the total binding and receive specific binding. Action check the connection is expressed as % inhibition of specific binding of [3H]-iloprost.

(III) test Results

Inhibition (%): 96,5

The pharmaceutical composition of the present invention can be applied in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form (for example, tablets, pills, lozenges, capsules, suppositories, creams, ointments, aerosols, powders, solutions, emulsions, suspensions, and so on), which is suitable for rectal administration, introduction through the lungs (primary or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administration, or insufflation.

The pharmaceutical composition of the present invention can contain various organic or inorganic carriers which are generally used for pharmaceutical purposes, such as excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, and so forth), a binder (e.g., cellulose, methylcellulose, hydroxypropylcellulose, polipropilenglicol, gelatin, Arabic gum, polyethylene glycol, sucrose, starch, etc.), a disintegrator (e.g. starch, carboxymethyl cellulose, hydroxypropylmethyl, nitroglycerol, sodium bicarbonate, calcium phosphate, calcium citrate, etc.,), a lubricant (e.g. magnesium stearate, talc, sodium lauryl sulfate, etc.,), corrigent (for example, citric acid, menthol, glycine, orange powder, and etc.), preservatives (e.g. sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), a stabilizer (for example, citric acid, sodium citrate, exust. p.), a dispersant, an aqueous diluent (e.g. water), wax-base (e.g. cocoa butter, polyethylene glycol, white petrolatum, and so on).

Effective ingredient can be administered, as a rule, a standard dose of from 0.01 mg/kg to 50 mg/kg 1-4 times per day. But the above dosage may be increased or decreased in accordance with age, weight and condition of the patient or the method of administration.

The following preparative examples and examples are given only for a more detailed explanation of the present invention.

Preparative example 1

A suspension of ethyl-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)acetate (1,02 g) and lithium aluminum hydride (0.20 g) in tetrahydrofuran (15 ml) stirred at 0oC for 2.5 hours. The solution was poured into cold 1N hydrochloric acid, then the resulting mixture is filtered through celite and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuum will receive 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethanol as a colorless oil (0.85 grams).

NMR (CDCl3, ): 1,66-2,07(7H, m), 2.49 USD was 2.76(2H,m), 2,92-2,99(1H,m), of 3.77(2H, t, J = 6.8 Hz), 3,81(3H,s), to 6.67(1H,d, J= 8.0 Hz,), for 6.81(1H,d, J= 7,7 Hz), 7,11(1H, DD, J = 8.0 a, 7,7 Hz).

(+) APCI M-n-m/z: 207 (Panikarovskaya (348 mg) in pyridine (180 mg) was stirred at 100oC for 2 hours, cooled to room temperature and distributed between ethyl acetate and 1N hydrochloric acid. The organic layer is successively washed with brine, aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuum. The residue is treated with diethyl ether, and receive (1,2,3,4-tetrahydro-5-methoxy - 2-naphthyl)methyl-N,N-diphenylcarbamate (218 mg) as a pale-purple powder.

So pl. 143,5-146oC

IR (Wesel.oil): 1710, 1260 cm-1< / BR>
NMR (CDCl3, ): 1,22 was 1.43(1H, m), 1,8-of 2.05(2H, m), 2,35 of 2.6(2H,m), 2,65 and 2.9(2H, m), of 3.80(3H, s), 4,06-to 4.23(2H, m), of 6.65(1H, d, J = 7.9 Hz), of 6.65(1H, d, J= 7.9 Hz), 7,11(1H,t, J= 7.9 Hz), 7,16-7,38(10H,m).

(+) APCI M-n-m/z: 388 (M++1).

Preparative example 3

According to the method similar to the method of preparative example 2, receive

2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl-N,N-diphenylcarbamate.

So pl. 97oC

IR (Wesel.oil): 1710 cm-1< / BR>
NMR (CDCl3, ): 1,68 is 2.01(6H,m), 2,46-to 2.74(3H,m), with 3.79(3H,s), 4.26 deaths(2H, t, J= 6.4 Hz), to 6.58(1H, d, J= 7,7 Hz), only 6.64(1H, d, J= 8.0 Hz), 7,05(1H,DD, J = 8.0 a, 7,7 Hz), 7,16-7,38 (10H, m).

(+) ARM.-C. m/z: 402 (M++1).

Preparative example 4

A suspension of (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)-methyl-N,N - diphenylcarbamate (1,93 m) and DL-Salem poured into ice water. The resulting mixture is extracted with ethyl acetate. The extract is successively washed with brine (twice), aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuum. The remainder chromatographic on silica gel (toluene - ethyl acetate), and receive (1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl) methyl-N,N-diphenylcarbamate (82 mg) as a yellow solid.

So pl. 96-98oC

IR (Wesel.oil): 3330, 1675, 1585 cm-1< / BR>
NMR (CDCl3, ): a 1.25 to 1.47(1H,m), 1.85 to 2.05 is(2H,m), 2,42 at 2.59(2H,m), 2,66-2,84(2H, m), 4,07-to 4.23(2H,m), of 5.05(1H,s), to 6.58(1H, d, J= 7,7 Hz), 6,62 (1H, d, J= 7,7 Hz), of 6.96 (1H, t, J= 7,7 Hz), 7,15-to 7.68 (10H, m).

(+) APCI m-c. m/z: 374 (M++1) Elemental analysis. For C24H23NO3< / BR>
calculated: C-77,19, H-6,21, N-3,75

found: C 77,31, H-6,29, N-3,67.

Preparative example 5

A suspension of 2- (5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl - N,N-diphenylcarbamate (0,93 g) and DL-methionine (3.50 g) in methanesulfonic acid (15 ml) was stirred at room temperature for 16 hours, and then poured into ice water. The resulting mixture is extracted with ethyl acetate. The extract is successively washed with 5% hydrochloric acid and brine, dried over sodium sulfate, and evaporated in HAC is R>
A suspension of (1,2,3,4-tetrahydro-5-hydroxy-2 - naphthyl)methyl-N, N-diphenylcarbamate (67 mg), ethylbromoacetate (33 mg) and potassium carbonate (37 mg) in N, N-dimethylformamide (1.0 ml) was stirred at room temperature for 5.5 hours, and then the mixture is extracted with ethyl acetate. The extract is washed with water and brine (twice), dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silicagel (toluene - ethyl acetate), and obtain [5-(ethoxycarbonylmethoxy)-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate (61 mg) as oil.

IR (film): 1755, 1710, 1585, 1200 cm-1< / BR>
(+) APCI m-c. m/z: 460 (M++1).

Example 2

According to the method similar to the method of example 1, get 2-[5-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydro-1-naphthyl]ethyl - N,N-diphenylcarbamate.

IR (film): 1760-1700 (wide) cm-1< / BR>
NMR (CDCl3, ): of 1.29(3H, t, J= 7,1 Hz), 1,57 is 2.00(6H,m), 2,48 was 2.76(3H, m), 4,18-or 4.31(4H,m), 4,60(2H,c), of 6.50(1H, d, J= 8.0 Hz), is 6.61(1H, d, J= 7,7 Hz), 7,01(1H, DD, J = 8.0 a, 7,7 Hz),7,05 - 7,38(10H, s).

(+) APCI M-n-m/z: 474 (M++1).

Example 3

A solution of [5-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydro-2-naphthyl] methyl-N, N-diphenylcarbamate (59 mg) and 1N solution of sodium hydroxide (0.15 ml) in ethanol (1.5 ml) was stirred at room temperature for 1 the solution dried over magnesium sulfate and evaporated in vacuum. The residue is converted into a powder of n-hexane, and receive [5-(carboxymethoxy)-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate (47 mg) as colorless powder.

So pl. 137-141,5oC

IR (Wesel.oil): 1740, 1705, 1580, 1250 cm-1< / BR>
NMR (DMSO-d6, ): 1.2 to about 1.35(1H, m), 1,75-2,0(2H,m), 2,27-and 2.83(4H,m) 4,06(2H, sm., J= 5.8 Hz), with 4.64(2H,s), 6,59(1H, d, J= 7.8 Hz), 6,63(1H, d, J= 7.8 Hz), 7,01(1H, t, J= 7.8 Hz), 7.23 percent - the 7.43(10H,m), 12,95(1H,CL).

(+) APCI m-c. m/z: 432 (M++1).

Example 4

A solution of 2-[5-(ethoxycarbonylmethoxy)-1,2,3,4 - tetrahydro-1-naphthyl] ethyl-N, N-diphenylcarbamate (0,83 g) and 1N solution of sodium hydroxide (2.1 ml) in dioxane (5 ml) was stirred at room temperature for 30 minutes and washed with ether. The resulting aqueous layer was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuum. The residue is converted into a powder of 2-propanol, and get 2-[5-(carboxymethoxy)-1,2,3,4-tetrahydro-1-naphthyl] ethyl-N, N-diphenylcarbamate (0,46 g) as colorless powder.

So pl. 145oC

IR (Wesel.oil): 1730, 1695 cm-1< / BR>
NMR (DMSO-d6, ): 1,60 is 1.91(6H,m), 2,42-2,60(3H,m), 3,57(1H, broad), is 4.15(2H, t, J= 6.2 Hz), br4.61(2

Example 5

A solution of 2-[5-(carboxymethoxy)-1,2,3,4-tetrahydro - 1-naphthyl]ethyl-N,N-diphenylcarbamate (0.12 g) and 1N solution of sodium hydroxide (0,265 ml) in ethanol evaporated in vacuo. The residue is converted into a powder from ethanol, and get the sodium salt of 2-[5-(carboxymethoxy)-1,2,3,4-tetrahydro-1 - naphthyl] ethyl-N,N-diphenylcarbamate (0.11 g) as colorless powder.

So pl. 200-215oC

IR (Wesel. oil): 1700, 1610 cm-1< / BR>
NMR (CD3OD, ): 1,67-a 2.01(6H, m), 2.57 m-2,85(3H,m), 4,18-4.26 deaths(2H,m), 4,35(2H, s), of 6.49(1H, d, J = 7,7 Hz), 6,56(1H, d, J = 8.1 Hz), 6,94(1H, DD, J= 8,1, 7,7 Hz), 7,20-7,40(10H,m).

FAB M.-c. m/z: 468 (M+)

Example 6

To a solution of [5-(ethoxycarbonylmethoxy)-2-hydroxy - 1,2,3,4-tetrahydro-2-naphthyl] methyl-N,N-diphenylcarbamate (570 mg) in ethanol (20 ml) is added 1N solution of sodium hydroxide (1.2 ml). After stirring for 4 hours at room temperature to remove the solvent in vacuo, and receive sodium salt [5-(carboxymethoxy)-2-hydroxy-1,2,3,4-tetrahydro-2 - naphthyl] methyl-N,N-diphenylcarbamate (500 mg).

IR (Wesel.oil): 3300-3400, 1700, 1580 cm-1< / BR>
NMR (D2O ): 1,2-1,6(2H,m), and 2.1 to 2.6(4H,m), and 3.72(1H, d, J= 11,0 Hz), 3,85(1H, d, J= 11.0 in Hz) of 4.13(2H,s), of 6.29(2H,m), 6,4-7,0 (12H,m).

FAB M-c. m/z: 470 (M++1).

Preparative example 6

To a solution of (5-methoxy-1, sulphonylchloride (1,15 g). The mixture is stirred for 1 day at room temperature and distributed between ethyl acetate and water. The organic layer was separated, washed with water (twice), 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuum. The residue is purified column chromatography on silica gel (n-hexane : ethyl acetate = 10:1), and receive (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methyl-p-toluensulfonate (1.70 g) as a white powder.

So pl. 81-82oC

IR (Wesel.oil): 1590, 1370, 1260, 1180, 790, 770, 720 cm-1< / BR>
M.-c. (+ APCI): 347 (M++1).

NMR (CDCl3, ): 1,10-1,50(1H,m), 1,80-2,20(2H,m), 2,20 - 2,60(2H,m), of 2.45(3H,c), 2,60-2,95(2H,m), with 3.79(3H,c) to 3.99(2H, d, J= 6.6 Hz), only 6.64(1H, d, J= 7.9 Hz), only 6.64(1H, d, J = 7.9 Hz), 7,07 (1H, DD, J = 7.9 Hz, 7.9 Hz), 7,34(2H, d, J= 8,2 Hz), 7,79(2H, d, J= 8,2 Hz).

Preparative example 7

A solution of 1,1-diphenylacetone (25 mg) and Glyoxylic acid monohydrate (of 41.6 g) in 1,2-dimethoxyethane (75 ml) is refluxed for 3 days. The solution is distributed between ethyl acetate and water. The organic layer was washed with water (twice) and evaporated in vacuo. The residue is treated with ethyl acetate and a solution of ammonia (200 ml) and the aqueous layer was separated. To the aqueous layer add hydrazinehydrate (22,6 g), and the mixture is stirred for 2 hours at 100

So pl. 161-162oC.

IR (Wesel.oil): 3300-2800, 1660, 1600, 760, 740, 700 cm-1< / BR>
NMR (CDCl3, ): 5,44(1H,s), to 6.88(1H, d, J= 9.8 Hz), 7,10-7,40(11H, m), of 11.29(1H, CL).

M.-C. (+ APCI): 263 (M++1).

Elemental analysis. For C17H14N2O

calculated: C 77,84, H is 5.38, N IS 10.68

found: C-77,76, H-5,39, N-10,66.

Preparative example 8

A suspension of 6-diphenylmethyl-3(2H)-pyridazinone (0,58 g) and sodium hydride (60%, 110 mg) in dry N,N-dimethylformamide (7 ml) stirred at 0oC for 30 minutes. To the suspension at room temperature is added dropwise a solution of (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methyl-p-toluensulfonate (0,77 g) in dry N,N-dimethylformamide (5 ml). The mixture is stirred for 6 hours, and poured it into 1N hydrochloric acid with ice, and extracted with ethyl acetate. The extract is separated, washed with water (twice) and brine, dried over magnesium sulfate and evaporated in vacuum. The residue is purified column chromatography on silica gel (n-hexane:ethyl acetate = 5:1 3:1), and obtain 2-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl] -6-diphenylmethyl - 3(2H)-pyridazinone (0,61 g) as pale-yellow,m), of 3.80(3H, c), 4,05-of 4.25(2H,m), the 5.45(1H,c) and 6.1(1H, d, J= 6.9 Hz), only 6.64(1H, d, J= 6.9 Hz), 6.87 in(1H, d, J= 9.5 Hz), 7,00-to 7.35(12H,m).

M.-C. (+ APCI): 437 (M++1).

Preparative example 9

To a solution of 2-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl] -6-diphenylmethyl-3(2H)-pyridazinone (0,60 g) in dry dichloromethane (5 ml) while cooling in an ice bath, is added dropwise 1N solution tribromide boron in dichloromethane (1.5 ml). The mixture is stirred at the same temperature for 2.5 hours. The mixture is then poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract is separated, washed with brine, dried over magnesium sulfate and evaporated in vacuum. The residue is purified column chromatography on silica gel (n - hexane : ethyl acetate = 1:1), and obtain 2-[(1,2,3,4-tetrahydro-5 - hydroxy-2-naphthyl)methyl] -6-diphenylmethyl-3(2H)-pyridazinone (0,44 g) as a pale yellow oil.

IR (film): 3000-3500, 1650, 770, 700 cm-1< / BR>
NMR (CDCl3, ): 1,35-of 1.66(1H,m), 1,80-2,00(1H,m), 2,25 - 2,90(5H,m), 4,00-4, 30(2H,m), vs. 5.47(1H,c), 6,55-of 6.65(2H,m), 6.90 to - to 7.35(14H,m).

M. c.-c. (+ APCI): 423 (M++1).

Example 7

A suspension of 2-[(1,2,3,4-tetrahydro-5-hydroxy-2 - naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (425 mg), ethylbromoacetate (184 mg) and potassium carbonate (152,9 mg) in acetonitrile (15 ml) is refluxed in techouse. The residue is purified column chromatography on silica gel (n-hexane : ethyl acetate = 1:1), and obtain 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy - 2-naphthyl)methyl] -6-diphenylmethyl-3(2H)-pyridazinone (0,43 g) as a pale yellow oil.

IR (film): 1750, 1660, 1580, 760, 720, 700 cm-1< / BR>
NMR (CDCl3, ): 1,35-to 1.60(1H,m) of 1.29(3H, t, J= 7,1 Hz), 1,80-2,00(1H, m), 2,20-3,20(5H, m), 4,15-4,20(2H,m), 4,25(2H, K, J= 7,1 Hz), br4.61(2H,s), the 5.45(1H,s), 6,51(1H, d,J= 7.8 Hz), only 6.64(1H, d, J= 7,8 Hz), 6,86(1H, d,J= 9.5 Hz), was 7.08(1H, DD, J= 7.8 Hz, 7.8 Hz), 7,10-to 7.35(11H,m).

M.-C. (+ APCI): 509 (M++1).

Example 8

A solution of 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy-2-naphthyl) methyl] -6-diphenylmethyl-3(2H)-pyridazinone (0,43 g) in 1,2-dimethoxyethane (9.0 ml) and 1.0 N aqueous sodium hydroxide solution of 0.85 ml) was stirred at room temperature for 5 hours. The solution is evaporated in vacuo, and the residue is extracted with ethyl acetate and 1N hydrochloric acid. The organic layer is separated and washed with water and brine, dried over magnesium sulfate and evaporated in vacuum. The residue is crystallized from n-hexane, ethyl acetate and ether, and get 2-[(1,2,3,4-tetrahydro-5-carboxymethoxy-2-naphthyl)methyl] -6 - diphenylmethyl-3(2H)-pyridazinone (330 mg) as a white powder.

So pl. 176-178oC

IR (Wesel.oil): 2600-2200, 1740, 1640, 770, 700 see<20-7,35(11H,m), 12,96(1H,CL).

M.-C. (+ APCI): 481 (M++1).

Preparative example 10

A mixture of (1R,2S)-methyl-[1-hydroxy-5-methoxy-1,2,3,4-tetrahydro-2 - naphthyl] formate (2,22 g) and 10% palladium-on-coal in methanol (50 ml) is stirred in hydrogen atmosphere (2-3 ATM) at room temperature for 22 hours. The catalyst is filtered off and the filtrate evaporated in vacuum. The residue is purified column chromatography on silica gel (n-hexane:ethyl acetate = 4:1), and obtain (S)-methyl-(5-methoxy-1,2,3,4-tetrahydro-2-naphthyl) formate in the form of a colorless oil (1.66 g).

NMR (CDCl3, ): 1,70-1,90(1H, m), 2,15-of 2.30(1H,m), 2,50-3,00(5H,m), 3,74(3H,c), 3,81(3H,c), 6,60 to 6.75(2H,m), 7,05 - to 7.15(1H,m).

M.-C. (+ APCI): 221 (M++1).

Preparative example 11

To a mixture of lithium aluminum hydride (0.28 g) in dry tetrahydrofuran (THF) (5 ml) at -60oC in nitrogen atmosphere is added dropwise a solution of (S)-methyl-[5-methoxy-1,2,3,4-tetrahydro-2-naphthyl] formate (1.65 g) in THF (7 ml). After 1 hour the reaction mixture at -60oC is added dropwise a mixture of 1N hydrochloric acid (5 ml) and THF (5 ml). The reaction mixture is treated with ethyl acetate and water. The organic layer is separated, washed with 1N hydrochloric acid, sodium hydrogen carbonate solution and brine, dried over magnesium sulfate is>/P>[]3D0= -71,98(C=1,26, CH2Cl2)

NMR (CDCl3, ): 1,25-of 2.20(4H, m), 2.40 a-to 2.65(2H,m), 2,80-3,00(2H,m), 3,62(2H, d, J= 6.3 Hz), 3,81(3H,s), and 6.6(1H, d,J= 7.9 Hz), 6,72(1H, d,J= 7.9 Hz), was 7.08(1H, DD, J = 7.9 Hz, 7.9 Hz).

Preparative example 12

According to the method similar to the method of preparative example 6, receive

(S)-(5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methyl methanesulfonate.

[]2D5= -45,70(C= 1,00, CH2Cl2)

IR (film): 1580, 1340, 1180 cm-1< / BR>
NMR (CDCl3, ): 1,30-1,60(1H, m), 1,90-of 2.30(2H,m), 2,45-2,70(2H,m), 2,80-3,00(2H, m), 3,03(3H, c), 3,81(3H, c), 4,20(2H,d, J= 6.5 Hz), 6,60 to 6.75(2H,m), 7,00 - of 7.25(1H,m).

M.-C. (+ APCl): 271 (M++1).

Preparative example 13

To a solution of methyl-(5-methoxy-3,4-dihydro-2-naphthyl)formate (0.75 g) in toluene (10 ml) at 4oC6oC in nitrogen atmosphere is added dropwise a solution of diisobutylaluminium (1,02 N in toluene (6,7 ml)). The reaction mixture was stirred under these conditions for 2.5 hours. The mixture is then poured into a saturated solution of ammonium chloride, and the organic layer was separated, washed with saline, dried over magnesium sulfate and evaporated in vacuum. Get raw (5-methoxy-3,4-dihydro-2-naphthyl)methanol as a colorless oil (0.66 g).

IR (film)6,60-to 6.80(2H,m), 7,05-to 7.15(1H,m).

M.-C. (+ APCI): 173 (M++1)

Preparative example 14

Chetyrehhloristy carbon (1,00 g x 4) at room temperature is added by portions to a solution of (3,4-dihydro-5-methoxy-2-naphthyl) methanol (2.00 g) and triphenylphosphine (4,14 g) in dichloromethane (40 ml). The reaction mixture is stirred for 2 hours and evaporated in vacuum. To the residue add hexane and diethyl ether, a white powder is filtered, and the filtrate evaporated in vacuum. Obtain crude 3-methyl bromide-1,2-dihydro-8-methoxynaphthalene in the form of a pale yellow oil.

Preparative example 15

To a solution of 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethanol (0.20 g) and triphenylphosphine (0,42 g) in dichloromethane (10 ml) and 5oC add tetrabromomethane (0,90 g). The solution is stirred at 5oC for 1.5 hours and evaporated in vacuum. To the residue is added ethyl acetate, and filtered insoluble substances. The solution in ethyl acetate evaporated in vacuum. The remainder chromatographic on silica gel (n-hexane), and get 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethylbromide (0.18 g) as a colourless oil.

NMR (CDCl3, ): 1,64-of 1.85(4H,m), 2,03 - to 2.29(2H,m), 2.57 m) was 2.76(2H,m), 2,98-to 3.02(1H, m), 3.45 points-of 3.60(2H, m), 3,81(3H, s), of 6.68(1H, d, J= 7.9 Hz), to 6.80(1H, d, J= 7.9 Hz), 7,20(1H, DD,J= 7,9, 7.9 Hz).

M.-C.-6-diphenylmethyl-3(2H)-pyridazinone obtained from (S)-(5-methoxy-1,2, 3,4-tetrahydro-2-naphthyl)methylmethanesulfonate by the method similar to the method of preparative example 8.

[]3D0= -29,76(C=0,86, CH2Cl2)

NMR (CDCl3, ): 1,35-of 1.55(1H, m), 1,80-2,00(1H,m), 2,25-of 3.00(5H,m), 3,80(3H,c), 4,05-of 4.25(2H,m), the 5.45(lH,c), is 6.61(1H, d, J= 6.9 Hz), only 6.64(1H, d, J= 6.9 Hz), 6.87 in(1H, d, J = 9.5 Hz), 7,00-to 7.35(12H,m).

M.-C. (+ APCI): 437 (M++1).

Preparative example 17

To a solution of tert-butoxide potassium (0.39 g) and 18-crown-6 (0.08 g) in dry N, N-dimethylformamide (4 ml) at room temperature add 6-diphenylmethyl-3(2H)-pyridazinone (0,83 g). After 10 minutes the solution was added 3-methyl bromide-1,2-dihydro-8-methoxynaphthalene (0,80 g), and the mixture is stirred at the same temperature throughout the night. The reaction mixture was poured into ethyl acetate and 1N hydrochloric acid, and the organic layer was separated, washed with water, aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and evaporated in vacuum. The residue is purified column chromatography on silica gel (n-hexane: ethyl acetate = 1:1), and obtain 2-[(3,4-dihydro-5-methoxy-2-naphthyl)methyl]-6 - diphenylmethyl-3(2H)-pyridazinone (0.55 g).

IR (CH2Cl2): 1670, 1600 cm-1< / BR>
NMR (CDCl3, ): 2,22(2H, t,J= 8.0 Hz), 2,77(2H, t, J= 8.0 Hz), 3,82(3H, s), 4,84(2H,s), 5,44(1H/P> Preparative example 18

The following connections get in the way, similar to the way preparative example 17.

(1) 1-[(3,4-Dihydro-5-methoxy-2-naphthyl)methyl]-5-diphenylmethyl - 2(1H)-pyridone.

IR (CH2Cl2): 1670, 1600 cm-1< / BR>
NMR (CDCl3, ): of 2.16(2H, t,J=8,2 Hz), a 2.75(2H, t, J=8,2 Hz), 3,83(3H, s), to 4.62(2H, s), 5,23(1H,s), x 6.15(1H,s), 6,55-6,60(2H,m), 6,70-6,85(2H,m), 7,05-to 7.35(12H,m).

M.-C. (+APCI): 434 (M++1).

(2) 1-[(3,4-Dihydro-5-methoxy-2-naphthyl)methyl]-3-diphenylmethyl-2 (1H)-pyridone

IR (CH2Cl2): 1650, 1600 cm-1< / BR>
NMR (CDCl3, ): to 2.18(2H,t, J=8,2 Hz), and 2.79(2H,t, J=8,2 Hz), 3,81(3H,s), 4,71(2H, s), of 5.82(1H,s), 6,11(1H, t, J=6.8 Hz), 6,24(1H,s), 6,60-of 6.90(3H,m), 7,05-to 7.35(12H,m).

M.-C. (+ APCI): 434 (M++1)

Preparative example 19

To a solution of 6-diphenylmethyl-3(2H)-pyridazinone (0,22 g) and tert-butoxide potassium (0.20 g) in N,N-dimethylformamide (2 ml) at room temperature add a solution of 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethylbromide (0.18 g) in N,N-dimethylformamide (3 ml). The reaction mixture is stirred for 2 hours at the same temperature, and treated with water and ethyl acetate. The organic layer was washed with water (3 times) and brine, dried over sodium sulfate and evaporated in vacuum. The remainder chromatographic on silicagel (0.25 g) as oil.

NMR (CDCl3, ): 1,65-of 2.05(4H, m), 2,10-of 2.28(1H,m), 2,50-to 2.85(3H,m), 3,80(3H,c), 4,07-to 4.33(3H,m), 5,46(1H,c), only 6.64(1H, d,J=8.5 Hz), 6,69(1H, d,J= 9.4 Hz), at 6.84(1H,d, J=9.4 Hz), 7,02 and 7.36(12H,m).

M.-C. (APCI) m/z: 451 (M++1).

Preparative example 20

The following connections get in the way, similar to the way preparative example 9.

(1) (S)-2-[(1,2,3,4-Tetrahydro-5-hydroxy-2-naphthyl)methyl]-6 - diphenylmethyl-3(2H)-pyridazinone.

[]2D5= -30,28(C=1.04 MILLION, CH2Cl2)

IR (film): 3500-3000, 1650, 770, 700 cm-1< / BR>
NMR (CDCl3, ): 1,35-to 1.60(1H, m), 1,80-2,00(1H,m), 2,25-2,90(5H,m), 4,00-4,30(2H,m), vs. 5.47(1H,c), 6,55-of 6.65(2H,m), 6.90 to - to 7.35(14H,m).

M.-C. (+APCI): 423 (M++1).

(2) 2-[(3,4-Dihydro-5-hydroxy-2-naphthyl)methyl] -6 - diphenylmethyl-3(2H)-pyridazinone.

So pl. 174-176oC

IR (Wesel.oil): 3200, 1650 cm-1< / BR>
NMR (DMSO-d6, ): 2,09(2H, t, J= 8,2 Hz), 2,62(2H, t, J= 8,2 Hz), 4.72 in(2H, s) to 5.56(1H,s) 6,09(1H,s), of 6.45(1H, d, J= 7,2 Hz), of 6.65(1H, d, J= 7,2 Hz), 6,85 - to 6.95(2H,m), 7,15-7,40(11H,m), 9,23(1H,s).

M.-C. (+ APCI): 421 (M++1).

(3) 1-[(3,4-Dihydro-5-hydroxy-2-naphthyl)methyl] -6 - diphenylmethyl-3(2H)-pyridone.

So pl. 178-180oC.

IR (Wesel.oil): 3150, 1650 cm-1< / BR>
NMR (CDCl3, ): 2,15(2H, t, J=8,2 Hz), 2,70(2H, t, 7= 8.2 Hz), to 4.62(2H, s), of 5.26(1H, s), 6,11(1H, s), is 6.54(1H, d, J= the XI-2-naphthyl)methyl]-3-diphenylmethyl-2 (1H)-pyridone.

So pl. 196-197oC.

IR (Wesel.oil): 3250, 1640 cm-1< / BR>
NMR (DMSO-d6, ): 2,10(2H, t, J= 8,3 Hz) of 2.64(2H, t, J= 8,3 Hz), 4,63(2H, s), the 5.65(1H,s), 5,96(1H,s), 6,24(1H, t, J= 6.8 Hz), 6.42 per (1H, d,J= 7,2 Hz), only 6.64 (1H, d, J = 7.5 Hz), 6,85-to 7.35(12H,m), 7,55-of 7.60(1H,m), 9,24(1H,s).

M.-C. (+APCI): 420 (M++1).

Preparative example 21

A mixture of 1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl-N, N - diphenylcarbamate (100 g) and N-chlorosuccinimide (35,8 mg) in 1,4-dioxane (1.5 ml) was stirred at 100oC for 5 hours, cooled to room temperature, and treated with ethyl acetate and brine. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (toluene - ethyl acetate), and get (6 - or 8-chloro-1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl) methyl-N,N-diphenylcarbamate (62 mg) as a colorless solid.

So pl. 138-144oC.

IR (Wesel.oil): 3320, 1675, 1575, 1220 cm-1< / BR>
NMR (CDCl3, ): 1,20-of 1.41(1H,m), 1.85 to 2.1 a(2H,m), 2,18 of-2.32(1H,m), 2,42 - of 2.56(1H, m), 2,74-to 2.94(2H, m), 4,07-to 4.28(2H,cm), 4,91(1H,s), is 6.54(1H, d, J= 8.5 Hz), 7,05 (1H, d, J= 8.5 Hz), 7,16-7,39(10H,m).

(+) APCI M-n-m/z: 408 (M++1).

Preparative example 22

The solution diethylazodicarboxylate (871 mg) in tetrahydrofuran (4 ml) at premesis the mg), phthalimide (736 mg) and triphenylphosphine (1.31 g) in tetrahydrofuran (10 ml) and the resulting mixture was stirred at the same temperature for 24 hours. The reaction mixture is evaporated in vacuo, and the residue chromatographic on silica gel (toluene). The eluate evaporated in vacuo, and the residue proscout with n-hexane, receive N-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl] phthalimide (888 mg) as colorless powder.

So pl. 143-144oC

IR (Wesel.oil): 1770, 1705, 1580, 1260 cm-1< / BR>
NMR (CDCl3, ): 1,33-of 1.55(1H, m), 1.93 and-2,03(1H,m), 2,15 was 2.25(1H,m), 2,35-2,63(2H, m), 2,75-of 2.97(2H, m), 3,71(2H, d, J= 7,1 Hz), with 3.79(3H,s), 6,62-6,69(2H,m), 7,06(1H, t, J= 7.9 Hz), 7.68 per-to 7.77(2H,m), 7,82-of 7.90(2H,m).

(+) APCI M-n-m/z: 322 (M++1).

Preparative example 23

According to the method similar to the method of preparative example 4, receive

N-[(1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl]phthalimide.

IR (Wesel.oil): 3310, 1765, 1690, 1585 cm-1< / BR>
NMR (DMSO-d6, ): to 1.38(1H,m), at 1.91(1H,m), is 2.05(1H,m), 2,34-2,5(2H,m), 2,69-2,77(2H,m) to 3.58(2H, d,J= 7,0 Hz), 6,47(1H, d,J= 7,4 Hz), 6,56(1H, d,J= 7,4 Hz) 6,86(1H, t,J = 7.4 Hz), 7,81-to 7.93(4H,m), to 9.15(1H,s).

(+) APCI M-n-m/z: 308 (M++1).

Preparative example 24

A solution of N-[(1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl] phthalimide (634 mg) and hydrazine monohydrate (309 mg) in ethanol (14 is IU. The remainder chromatographic on alumina (methylene chloride - methanol), and receive-6-(aminomethyl)-5,6,7,8-tetrahydro-1 - naphthol (281 mg) as colorless powder.

So pl. 183-192oC

IR (Wesel.oil): 3350-3100, 2750-2300, 1580 cm-1< / BR>
NMR (DMSO-d6, ): 1,11-1,32(1H,m), 1,58(1H,m), 1,91 - of 1.97(1H,m), 2,23 at 2.45(2H, m), 2,68 is 2.80(2H,m), 3,1(3H,s), of 6.49(1H,d, J=7,6 Hz), 6,55(1H, d,J= 7.8 Hz), 6,85(1H, t, J=7,7 Hz).

(+) APCI M-n-m/z: 178 (M++1)

Preparative example 25

A solution of 4-nitrophenylphosphate (2,02 g) in dichloromethane (15 ml) under cooling with ice and stirring is added dropwise to a solution of benzhydrol (1.84 g) and pyridine (1.19 g) in dichloromethane (18 ml). The resulting mixture awhile stirred at the same temperature, and leave it to stand at room temperature for 3 days. The reaction mixture was successively washed with water, with ice, 1N hydrochloric acid with ice and salt solution with ice, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (toluene - ethyl acetate), and get benzhydryl(4-nitrophenyl) carbonate (of 3.32 g) as colorless crystals.

So pl. 53-59oC

IR (film): 1770, 1520, 1345, 1260-1180 cm-1< / BR>
NMR (CDCl3, ):for 6.81(1H,s), 7,30-7,47(12H,m), of 8.25(2H, d, J = 9,2 Hz). the Tola (23 mg) and 4-nitrophenyl(benzhydryl) carbonate (45 mg) in N,N-dimethylformamide (0.5 ml) was stirred at 50oC for 2 hours, cooled to room temperature and extracted with ethyl acetate. The extract is successively washed with water, aqueous sodium bicarbonate solution (three times) and brine, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (toluene - ethyl acetate), and get benzhydryl-N-[(1,2,3,4-tetrahydro-5-hydroxy - 2-naphthyl)methyl]carbamate (40 mg) in the form of butter.

IR (film): 3350, 1695 cm-1< / BR>
NMR (CDCl3, ): 1,35-1,45(1H,m),1,94(2H,m), 2,45 of 2.6(2H,m), was 2.76-of 2.86(2H, m), up 3.22(2H, t, J = 6.3 Hz), 5,04(1H,m), to 6.58(1H, d,J=7.9 Hz), only 6.64(1H, d,J=7,6 Hz), for 6.81(1H,s), 6,97(1H,t,J=7,8 Hz), 7,15-to 7.35(11H,m).

(+) APCI M-.m/z: 167.

Preparative example 27

(6RS)-5,6,7,8-Tetrahydro-6-[((1S)-1-phenylethyl)amino] -1-naphthol is obtained from the hydrochloride (2RS)-1,2,3,4-tetrahydro-5-methoxy-N- ((1S)-1-phenylethyl)-2-naphtylamine by the method similar to the method of preparative example 9.

IR (film): 3500-3350, 1585 cm-1< / BR>
NMR (CDCl3, ): to 1.38(3H, d,J=6.6 Hz), 1,5-2,2(3H,m), 2,45-to 2.65(2H,m), of 2,75 2,85(2H,m), of 4.05(1H,, J=6.6 Hz), 6,4-to 7.35(9H,m).

(+) APCI M-n-m/z: 268 (M++1).

Preparative example 28

A solution of (6RS)-5,6,7,8-tetrahydro-6-[((1S)-1-phenylethyl)amino] -1-naphthol (267 mg) in dimethyl sulfoxide (3 ml) at room temperature, under nitrogen atmosphere and at perisurgical (0.5 ml), the mixture was stirred at 50oC for 10 minutes, and cooled to room temperature. Add ethylbromoacetate (167 mg) in dimethyl sulfoxide (1 ml) and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract is washed twice with saline, dried over sodium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (dichloromethane - ethanol), and get ethyl-[(6RS)-5,6,7,8-tetrahydro - 6-[((1S)-phenylethyl)amino] -1-naphthyloxy]acetate (243 mg) as a brown oil.

IR (film): 3320, 1755, 1730 (shoulder), 1585, 1195 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t,J= 7,1 Hz) to 1.37(3H, d, J=6.6 Hz), to 1.48(3H, BL), of 2.09(1H, BL), 2,48-to 3.02(4H,m), Android 4.04(1H,, J=6.6 Hz), 4,25(2H, K,J=7,1 Hz), 4,58(2H,s), of 6.49(1H, d,J= 8.0 Hz), to 6.67(1H, d,J=8.0 Hz), 7,01(1H, t, J= 8.0 Hz), 7,20 - 7,33(5H,m).

(+) APCI M-.with: 354(M++1)

Preparative example 29

Ethyl-[(6RS)-5,6,7,8-tetrahydro-6-[((1S)-1-phenylethyl)amino] - 1-naphthyloxy] acetate (185 mg) was converted into the hydrochloride in the usual way, using a 4N solution of hydrogen chloride in ethyl acetate. A mixture of the hydrochloride, 10% palladium-on-coal (50% wet., 100 mg) and ammonium formate (330 mg) in ethanol (40 ml) is stirred while boiling under reflux in teteatete and aqueous sodium bicarbonate solution. An ethyl acetate layer is dried over sodium sulfate and evaporated in vacuum, get ethyl-[(6RS)-6-amino-5,6,7,8-tetrahydro-1-naphthyloxy] acetate (95 mg) as oil.

IR (film): 3600-3150, 1750, 1730 (shoulder), 1580, 1195 cm-1< / BR>
NMR (CDCl3, ): of 1.30(3H, t, J=7,1 Hz), 1,46 - of 1.66(3H,m), a 2.01(1H,m), 2,48-2,78(2H, m), 2,92-and 3.16(3H, m), 4.26 deaths(2H, K, J= 7,1 Hz), to 4.62(2H,s), 6,53(1H, d,J= 8.0 Hz), 6,74(1H, d,J=7,6 Hz), 7,05 (1H, t, J= 7,8 Hz).

Preparative example 30

A suspension of (5-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)methanol (0.20 g), ethylbromoacetate (0.15 ml), potassium iodide (catalytic amount) and potassium carbonate (0.20 g) in acetonitrile (10 ml) stirred at the boil under reflux for 2.5 hours. Remove the solvent, and the residue is treated with ether and 1N hydrochloric acid. The organic layer is washed with water and brine, dried over sodium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (n - hexane-ethyl acetate), and receive (5-ethoxycarbonylmethoxy - 1,2,3,4-tetrahydro-1-naphthyl)methanol (0.29 grams) in the form of butter.

IR (film): 3400, 1730 cm-1< / BR>
NMR (CDCl3, ): the 1.44(3H, t, J=5.4 Hz), 1,80 - of 1.95(4H,m), 2,63 are 2.98(3H, m), 3,80(2H, DD,J=5,4, 5,4 Hz), 4.26 deaths(2H, K, J =7,1 Hz), to 4.62(2H,s), 6,56(1H, d, J = 7.9 Hz), 6.89 in(1H, d, J=7.9 Hz), to 7.09(1H, DD, J= 7,9, 7,9 Hz).

M.-C. APCI m/z: 265 (M++1), 247 (M++1 - HoC add 5-tert-butyldiphenylsilyl-1-oxo-1,2,3,4-tetrahydronaphthalen (17 g). The mixture is stirred at the same temperature for 4 hours, and then cooled solution was washed with a saturated solution of NaHCO3and a salt solution. The solvent from the dried solution is evaporated in vacuo, and the residue purified by chromatography on silica gel, get 5-tert-butyldiphenylsilyl-2-etoxycarbonyl-1-oxo - 1,2,3,4-tetrahydronaphthalen (20 g).

IR (pure): 1730, 1680 cm-1< / BR>
NMR (CDCl3, ): a 1.11(9H, s), 1,25(3H, t, J= 7 Hz), 2,3-2,7 (2H,m), 2,8-3,4(2H, m), 3,60(1H, DD, J= 5,2, 10.4 Hz), 4,28(2H, K, J= 7 Hz), from 6.4 to 6.8(2H,m), 7,2-7,8(11H,m).

M.-C. m/z: 473 (M++1).

Preparative example 32

To a solution of 5-tert-butyldiphenylsilyl-2-etoxycarbonyl-1-oxo - 1,2,3,4-tetrahydronaphthalene (17 g) in ethanol (100 ml) and tetrahydrofuran (100 ml) at 0oC add NaBH4(1.4 g). After stirring the mixture for 6 hours at room temperature the solvent is removed in vacuum. The residue is dissolved in a mixture of ethyl acetate and water, and the organic solution washed with 1N HCl solution, a saturated solution of NaHCO3and a salt solution. The solvent from the dried solution is removed in vacuo, and the residue purified by chromatography on silica gel, paucity): 3450, 1730 cm-1< / BR>
NMR (CDCl3, ): 1,10(9H, s) of 1.26(3H, t, J= 7 Hz), of 2.2-2.5 (2H,m), 2.5 and 3.4(4H, m) to 4.16(2H, K, J= 7 Hz), 5,02(1H,m), 6,2-6,4(1H,m), 6,7-7,0(2H, m), 7,2-7,8(10H,m).

Preparative example 33

To a solution of 1-hydroxy-2-etoxycarbonyl-5-tert-butyl - diphenylsilane-1,2,3,4-tetrahydronaphthalene (5.9 g) in toluene (100 ml) add KHS04(2.0 g). The mixture is stirred for 1 hour at boiling under reflux, and then cooled solution was washed with a saturated solution of NaHCO3and a salt solution. The solvent from the dried solution is removed in vacuo, and the residue purified by chromatography on silica gel, get 2-etoxycarbonyl-5-tert-butyldiphenylsilyl-3,4-dihydronaphthalene (7,4 g).

IR (pure): 1700 cm-1< / BR>
NMR (CDCl3, ): a 1.11(9H, s) of 1.35(3H, t,J= 7 Hz), 2,5 - 2,7(2H,m), 3,03(2H, t, J= 8,8 Hz), 4,27(2H, K,J= 7 Hz), 6,3-6,5(1H,m), 6,7-6,8(2H,m) and 7.1-7,8(11H,m).

M.-C. m/z: 457 (M++1).

Preparative example 34

A solution of AD-mix - a (trade name Aldrich) (9.2 grams) in a mixture of tert-butyl alcohol (30 ml) and water (30 ml) is stirred for 1 hour, and then to the solution at room temperature add methanesulfonamide (0,62 g) and 2-etoxycarbonyl-5-tert-butyldiphenylsilyl-3,4-dihydronaphthalene (3.0 g). After stirring for 20 hours at ethylacetate and water. The organic layer was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get (1S, 2R)-1,2-dihydroxy-2-etoxycarbonyl-5-tert-butyldiphenylsilyl-

1,2,3,4-tetrahydronaphthalen (3.1 g).

IR (pure): 3450, 1705 cm-1.

NMR (CDCl3, ): 1,09(9H, s), 1,25(3H, t, J= 7 Hz), to 2.1-2.3(2H,m), 2,50(1H, d, J= 10,8 Hz), 2,9 - 3,2(2H,m) to 3.58(1H,s), 4,35(2H, K, J= 7,0 Hz), to 5.03(1H, d, J= 10,8 Hz), 6,32(1H, d, J= 8.0 Hz), to 6.80(1H, t, J= 8.0 Hz), 7,14(1H, d, J= 8.0 Hz), 7.3 to about 7.8(10H, m).

M.-C. m/z: 470 (M+-17).

HPLC: chiralcel AD, 5% isopropanol in hexane, 12.9 ml/min

Preparative example 35

According to the method similar to the method of preparative example 34, instead of using AD-mix - AD-mix - a (trade name Aldrich), get (1R, 2S)-1,2-dihydroxy-2 - etoxycarbonyl-5-tert - butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalen (3.1 g).

HPLC: chiralcel AD, 5% isopropanol in hexane, 11,00 ml/min

Preparative example 36

To a solution of 2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4 - tetrahydronaphthalene (3.9 g) in tetrahydrofuran (50 ml) at 0oC and in an atmosphere of N2add NaH (0.73 g, 60% in oil) and then methyliodide (3 ml). After stirring for 1 hour at to, asystem solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 2-methyl - 2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen (4.0 g).

IR (pure): 1720, 1680 cm-1< / BR>
NMR (CDCl3, ): 1,49(3H,s), 1,9-2,1(1H,m), 2.4 to a 3.0(3H,m), 3,66(3H,m), 3,88(3H, m), 7,01(1H, d,J= 8 Hz), 7,26(1H, t, J= 8.0 Hz), to 7.68(1H, d,J = 8 Hz).

M.-C. m/z: 249 (M++1).

Preparative example 37

To a solution of 2-methyl-2 - methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (2.0 g) in triperoxonane acid (20 ml) at room temperature add triethylsilane (2.0 ml). After stirring for 6 hours at room temperature the solution is poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 2-methyl-2-methoxycarbonyl-5-methoxy-1,2,3,4-tetrahydronaphthalen (4.0 g).

IR (pure): 1720 cm-1< / BR>
NMR (CDCl3, ): 1,25(3H,s), 1,6-2,3(2H,m), of 2.5 - 2.8(3H,m), 3,20(1H, d, J= 16 Hz), 3,66(3H, m), 3,80(3H,m), only 6.64(1H, d, J= 8 Hz), 6,70(1H, d, J=8 Hz), was 7.08(1H, t, J= 8 Hz).

M.-C. m/z: 235 (M++1).

Preparative is in the atmosphere N2add NaH (3.4 g, 60% in oil). After stirring for 30 minutes to a mixture of 5-tert-butyldiphenylsilyl-1-oxo-1,2,3, 4-tetrahydronaphthalen (20 g). After stirring for 12 hours at 80oC the solution is poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is dissolved in a mixture of toluene (100 ml) and 1,8-diazabicyclo[5.4.0]-7-undecene (17 ml) and the mixture stirred for 3 days at 100oC. the Solution was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 5-tert-butyldiphenylsilyl-1-ethoxycarbonylmethyl - 3,4-dihydronaphthalene (20,3 g).

IR (pure): 1740 cm-1< / BR>
NMR (CDCl3, ): 1,10(9H, m), 1,25(3H, t, J= 7 Hz), 2,2-2,4(2H,m) to 2.99(2H, t, J= 8,2 Hz), 3,40(2H,s), 4,17(2H, K, J= 7 Hz), 6,00(1H,m), 6,3 - 6,5(1H,m), 6,6-6,8(2H,m), 7.3 to about 7.8 (10H,m).

M.-C. m/z: 471 (M++1).

Preparative example 39

To a solution of Diisopropylamine (17 ml) in THF (tetrahydrofuran) (210 ml) at -78oC in an atmosphere of N2add n-utility (67 ml of 1.6 N in hexane). The solution is stirred for 30 m is for 30 minutes at the same temperature. Get Li-idolatry solution. Cooled to -78oC solution of 5-tert - butyldiphenylsilyl-1-oxo-1,2,3,4-tetrahydronaphthalene (10 g) in THF (50 ml), add the above solution Li-enolate (35 ml), and the whole is stirred for 1 hour at the same temperature. The mixture is then poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 1 - hydroxy-1-ethoxycarbonylmethyl-5-tert-butyldiphenylsilyl - 1,2,3,4-tetrahydronaphthalen (8.0 g).

IR (pure): 3400, 1705 cm-1< / BR>
NMR (CDCl3, ): 1,10 (9H,c) of 1.27(3H, t, J= 7 Hz), 1,6-2,2 (4H,m), of 2.7-3.0(4H,m), 4,20(2H, K, J = 7 Hz), 6,30(1H, d, J= 8 Hz), 6,77(1H, t, J= 8 Hz), 7,10(1H, d, J= 8 Hz), 7,2-7,8(10H,m).

M.-C. m/z: 471 (M+-17)

Preparative example 40

(1) To a solution of (1S,2R)-1,2-dihydroxy-2-etoxycarbonyl-5-tert - butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalene (1.8 g) in CH2Cl2(20 ml) at room temperature add triphenylphosphine (2.9 g) and CBr4(4.9 g). After stirring for 1 hour the solution was added ethyl acetate (200 ml). After filtration of the mother liquor is washed with water, saturated solution of NaHCO3and salt Rast is use the residue is purified by chromatography on silica gel. The oil obtained is dissolved in tetrahydrofuran (30 ml), at 0oC add LiAlH4(420 mg). The mixture is stirred for 2 hours at the same temperature, quenched with 1N HCl solution and treated with ethyl acetate and water. The organic layer is washed with water, saturated solution of NaHCO3and a salt solution. The drained solvent is evaporated in vacuo, and the residue purified by chromatography on silica gel, get (2R)-2 - hydroxy-2-hydroxymethyl-5-tert-butyldiphenylsilyl-1,2,3,4 - tetrahydronaphthalen (1.8 g).

IR (pure): 3500, 1600 cm-1< / BR>
NMR (CDCl3, ): 1,10(9H,s) of 1.8-2.0(4H,m), 2,85(2H,s) of 3.00(2H, t, J = 7,0 Hz) and 3.59(2H,m), of 6.29(1H, d, J= 8.0 Hz), 6,6 - 6,8(2H,m), 7.3 to about 7.8(10H,m).

M.-C. m/z: 397 (M+-35).

Preparative example 41

According to the method similar to the method of preparative example 40, receive (2S)-2-hydroxy-2-hydroxymethyl-5-tert-butyldiphenylsilyl - 1,2,3,4-tetrahydronaphthalen.

Preparative example 42

According to the method similar to the method of preparative example 40, get 5-tert-butyldiphenylsilyl-1-(2-hydroxyethyl)-3,4 - dihydronaphthalene.

IR (pure): 3400-3300 cm-1< / BR>
NMR (CDCl3, ): of 1.06(3H,s), 2,2-2,4(2H,m), of 2.6-3.0(4H,m), 3,76(2H, t, J= 6.4 Hz), 5,96(1H,m), 6,36(1H, d,J=8.0 Hz), 6,7-6,9(2H,m), 7,2-7,8(10H,m).

M.-C. m/z: 429 (MoC in an atmosphere of N2add diethylzinc (7.2 ml, 1M solution in hexane) and diiodomethane (1.2 ml). After stirring for 4 hours at room temperature the solution is poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 5-tert-butyldiphenylsilyl-1,2-methylene-2-hydroxymethyl-1,2,3,4 - tetrahydronaphthalen.

Preparative example 44

According to the method similar to the method of preparative example 43, receive 1,2-methylene-1-(2-hydroxyethyl) -5-tert-butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3400-3300, 1700 cm-1< / BR>
NMR (CDCl3, ): 0.7 to 0.9(2H,m) a 1.08(9H,c), 1,2 - 1,5(2H,m), 1,7-2,5(3H, m), 2,6-2,9(1H, m), 3,1-3,3(1H, m), of 3.7 - 3.9(2H,m), 6,27(1H, d, J= 8 Hz), 6,72(1H, t, J= 8 Hz), of 6.99(1H, d,J= 8 Hz), a 7.2 to 7.8(10H,m).

M.-C. m/z: 443 (M++1).

Preparative example 45

To a solution of 5-tert-butyldiphenylsilyl-1-(2-hydroxyethyl)-3,4 - dihydronaphthalene (1.0 g) in CH2Cl2(30 ml) at 0oC add Na2CO3(290 g) and m-chloroperbenzoic acid (750 mg). After stirring for 2 hours the solvent is removed in vacuum. The remainder extra over MgSO4and evaporated in vacuum. The residue is dissolved in tetrahydrofuran (20 ml), at 0oC add LiAlH4(200 mg). After stirring for 2 hours the reaction is quenched with a saturated solution salinetreated. After filtration the solvent is removed, and the residue purified by chromatography, get (CIS)-5-tert - butyldiphenylsilyl-1-(2-hydroxyethyl)-1,2,3,4-tetrahydronaphthalen (1.9 grams).

IR (pure): 3300 cm-1< / BR>
NMR (CDCl3, ): 1,10(9H,s), 1.8 to 2.3(4H,m), is 2.8 - 3.2(3H,m), 3,6-4,2(3H, m), 6,2-6,4(1H,m), 6,6-6,8(2H,m), 7,0 - 7,8 (10H,m).

M.-C. m/z: 429 (M+-17).

Preparative example 46

A mixture of (2R) -2-hydroxy-2-hydroxymethyl-5-tert - butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalene (1.4 g) and N,N-diphenylcarbamate (3 g) in pyridine (15 ml) was stirred at 100oC for 12 hours, cooled to room temperature, and treated with ethyl acetate and 1N HCl. The organic layer was washed with 1N HCl solution, a saturated solution of NaHCO3and a salt solution. The drained solvent is evaporated in vacuo, and the residue purified by chromatography on silica gel, get (2R)-2-hydroxy-2-(N, N - diphenylcarbamate)-5-tert-butyldiphenylsilyl-1,2,3,4 - tetrahydronaphthalen (1.3 g).

IR (pure): 3400, 1700 cm-1< / BR>
NMR (CDCl3++1).

HPLC: chiralcel OD, 10% isopropanol in hexane, 12.0 ml/min

Preparative example 47

The following compounds produced by methods such as preparative method of example 46.

(1) (2S)-2-Hydroxy-2-(N, N-diphenylcarbamate)-5 - tert-butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalen.

HPLC: chiralcel OD, 10% isopropanol in hexane, 10.1 ml/min

(2) (CIS)-1-Hydroxy-2-(N,N-diphenylcarbamate) -5-tert-butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalen.

NMR (CDCl3, ): a 1.08(9H,s), 1,6 - 2,1(3H,m), of 2.5 - 3.2(2H,m), 4,0-4,2(1H, m), 4,4-4,8(2H,m), 6,32(1H, d, J = 8 Hz), 6,6-6,9(2H,m) and 7.1-7,8(20H,m).

M.-C. m/z: 610 (M+-1)

(3) (TRANS)-1-Hydroxy-2-(N,N-diphenylcarbamate) -5-tert-butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalen.

NMR (CDCl3, ): a 1.08(9H,s), 1,4-2,1(3H,m), 2,6 - 3,1(2H,m), 4,13(1H, DD, J= 11,2, 5,2 Hz), 4,48(1H, d, J= 8 Hz), to 4.62(1H, DD, J= 11,2, 4,4 Hz), 6,30(1H, d, J= 8 Hz), 6,77(1H, t, J= 8 Hz), was 7.08(1H, d, J= 8 Hz), 7,1-7,8 (20H,m).

M.-C. m/z: 610 (M+-1).

(4) 5-tert-Butyldiphenylsilyl-1,2-methylene-2-(N, N - diphenylcarbamate)-1,2,3,4-tetrahydronaphthalen.

IR (pure): 1700 cm-1< / BR>
NMR (CDCl3, ): 0,8-1,2(2H,m), 1,6-1,9(2H,m), 2,0 - 2,3(1H,m), 3.1 to 3.4(1H, m), 4,20(1H, d,J= 11.2 Hz), 4,30(1H, d, J= 11.2 Hz), and 6.25(1H, d,J=8 Hz), 6,6-7,0(2H,m), jonatton.

IR (pure): 1700 cm-1< / BR>
NMR (CDCl3, ): 0.6 to 0.9(2H,m) a 1.08(9H,s), 1,2-2,5(5H,m), 2,6-3,1(2H, m), of 4.0-4.4(2H,m), 6,24(1H, d, J=8 Hz), of 6.65(1H,t, J= 8 Hz), of 6.96(1H, d, J= 8 Hz), 7,1 - 7,8 (20H,m).

(6) 1-[2-(N, N-Diphenylcarbamate)ethyl]-5 - tert-butyldiphenylsilyl-3,4-dihydronaphthalene.

IR (pure): 1705 cm-1< / BR>
NMR (CDCl3, ): 1,10(9H,s), to 2.1-2.3(2H,m), of 2.72 (2H, t, J= 6.6 Hz), 2,90(2H, t, J= 8.0 Hz), 4,30(2H, t, J= 7.0 Hz), 5,78(1H,t, J= 4.4 Hz), 6,33(1H, d, J= 8 Hz), 6,6 - 6,9(2H,m) and 7.1-7,8(20H,m).

M.-C. m/z 624 (M++1).

(7) (CIS)-5-tert-Butyldiphenylsilyl-1, 2-methylene-[2- (N,N-diphenylcarbamate)ethyl]-2-hydroxy-1,2,3,4 - tetrahydronaphthalen.

IR (pure): 1700 cm-1< / BR>
NMR (CDCl3, ): 1,10(9H,s), 1,6-2,3(4H,m), 2,7-3,2(3H,m), of 4.0-4.4(3H, m), and 6.25(1H, d, J= 8 Hz), of 6.49(1H, d, J= 8 Hz), 6,66 (1H, t, J = 8 Hz), 7,1-7,2(20H,m).

Preparative example 48

Methods similar to the methods of preparative examples 13 and 46, from 2-etoxycarbonyl-5-tert-butyldiphenylsilyl-3,4-dihydronaphthalene get 2-(N, N-diphenylcarbamate)-5-tert - butyldiphenylsilyl-3,4-dihydronaphthalene.

IR (pure): 1710 cm-1< / BR>
NMR (CDCl3, ): 1,10(9H,m), of 2.23(2H, t,J= 8,4 Hz), of 2.97(2H, t, J=8,4 Hz), of 4.77(2H, s), 6,23(1H, s), of 6.31(1H, d, J= 8 Hz), 6, 50 (1H, d, J = 6.8 Hz), of 6.68(1H, t, J = 8 Hz), 7,2-7,8(20H,m).

Preparative example 49

Ways, podobajut 2-(N,N-diphenylcarbamate)-2-methyl-5-methoxy - 1,2,3,4-tetrahydronaphthalen.

IR (pure): 1700 cm-1< / BR>
NMR (CDCl3, ): or 0.83(9H, s), 1,4(2H,m), about 2.2-2.8(4H,m), 3,80(3H,m), 3,90(1H, d, J= 10.4 Hz), 4,00(1H, d, J= 10.4 Hz), 6,59(lH, d, J= 8 Hz), 6,63(1H, d, J= 8 Hz), was 7.08(1H, t, J= 8 Hz), 7,1-7,5(10H,m).

M.-C. m/z: 402 (M++1).

Preparative example 50

Methods similar to the methods of preparative examples 1 and 46, from 1-ethoxycarbonylmethyl-1 - hydroxy-5-tert-butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalene get 1-[2-(N,N-diphenylcarbamate)ethyl]-1-hydroxy-5 - tert-butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3450, 1710 cm-1< / BR>
NMR (CDCl3, ): 1,09(9H,s), 1,6-2,2(6H,m), of 2.7 - 3.0(2H,m) to 4.33(2H, t, J= 6.6 Hz), of 6.26(1H, d, J= 8 Hz), 6,78(1H, t, J= 8 Hz), 6,78(1H, t, J= 8 Hz), of 6.96(1H, d, J= 8 Hz), 7,1-7,8(20H,m).

M.-C. m/z: 626 (M+-17)

Preparative example 51

According to the method similar to the method of example 21, from 5-tert-butyldiphenylsilyl-1-[2-(N, N - diphenylcarbamate)ethyl]- 3,4-dihydronaphthalene get 5-tert-butyldiphenylsilyl-1,2-dihydroxy-1-[2-(N, N-diphenylcarbamate)ethyl]-1,2,3,4-tetrahydronaphthalene.

IR (pure): 3500-3400, 1700 cm-1< / BR>
NMR (CDCl3, ): 1,09(9H,m), 1.7 to 2.2(4H,m), 2,6-3,1(2H,m), 3,8-4,0(1H, m), 4,1-4,4(2H, m), 6,32(1H, d, J= 8 Hz), 6,77(1H, t, J= 8 Hz), 7,01(1H, d, J= 8 Hz), 7,1-7,8 (20H,m).

Preparative example 52

A solution of 5-tert-butylbiphenyl the th acid (20 mg) in toluene (40 ml) is stirred for 30 minutes while boiling under reflux. The mixture was washed with 1N HCl solution, a saturated solution of NaHCO3saline solution, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 5-tert-butyldiphenylsilyl-1-[2-(N, N - diphenylcarbamate) ethyl] -2-oxo-1,2,3,4-tetrahydronaphthalene (1.0 g).

IR (pure):1800, 1705 cm-1< / BR>
NMR (CDCl3, ): of 1.12(9H,s), of 2.0 to 2.6(4H,m), of 2.7 - 3.0(1H,m), 3.1 to 3.4(2H, m), 4,0-4,2(2H,m), 6,40(1H, d, J= 8 Hz), 6.48 in(1H, d, J= 8 Hz), 6,76(1H, t,J= 8 Hz), 7,1-7,8 (20H,m).

M.-C. m/z: 638 (M++1).

Preparative example 53

To a solution of 5-tert - butyldiphenylsilyl-1-[2-(N,N-diphenylcarbamate)ethyl] -2-oxo-1,2,3,4-tetrahydronaphthalene (0.9 g) in THF (tetrahydrofuran) (20 ml) at 0oC in an atmosphere of N2add methylanisole (2.0 ml, 1M solution in THF). After stirring for 1 hour at room temperature the solution is poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 5-tert-butyldiphenylsilyl-1-[2-(N, N-diphenylcarbamate)ethyl] -2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen (0.6 g).

IR (pure): 3400, 1705 cm-1The
20H,m).

M.-C. m/z: 638 (M+-18).

Preparative example 54

To a solution of 1-[2-(N,N-diphenylcarbamate)ethyl]-5-tert - butyldiphenylsilyl-3,4-dihydronaphthalene (2.0 g) in THF (tetrahydrofuran) (20 ml) at 0oC in an atmosphere of N2add NR3(4.8 ml, 1M solution in THF). After stirring for 12 hours at room temperature to the solution was added 2N NaOH solution (1.5 ml) and H2O2(1.0 ml, 35% solution), and stirred for 4 hours. The mixture is then poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get (TRANS)-1-[2-(N, N-diphenylcarbamate)ethyl]-2 - hydroxy-5-tert-butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalen (1.1 g).

IR (pure): 3400, 1700 cm-1< / BR>
NMR (CDCl3, ): 1,10(9H,s), with a 1.7-2.1(4H,m), of 2.7 - 3.0(3H,m), 3,9-4,0(1H, m), 4,1 - 4,3(2H,m), 6,24(1H, d, J= 8 Hz), of 6.49(1H, d,J=8 Hz), to 6.67(1H, t, J= 8 Hz), 7,1-7,8 (20H,m).

M.-C. m/z: 642 (M++1).

Preparative example 55

A solution of methyl-[5-methoxy-1-oxo - 1,2,3,4-tetrahydro-2-naphthyl] formate (2.50 g), D-10-camphorsulfonic acid (124 mg), [RuCl2(S)-binap]2NEt3(90 mg) [see Tetrahedron Lettets, Vol. 35, No. 26, pp. 455940 hours. The reaction mixture is evaporated in vacuo, and the residue is purified column chromatography on silica gel (n-hexane:ethyl acetate = 4:1), receive (1R,2S)-methyl-[1-hydroxy-5-methoxy-1,2,3,4 - tetrahydro-2-naphthyl]formate (2,47 g) as a white powder.

So pl. 87-88oC.

Example 9

The following connections get in the way similar to the method of example 7.

(1) (S)-2-[1,2,3,4-Tetrahydro-5-ethoxycarbonylmethoxy-2-naphthyl) methyl] -6-diphenylmethyl-3(2H)-pyridazinone.

[]2D6= -20,63(C=0.95, AND CH2Cl2)

IR (film): 1750, 1660, 1580, 760, 720, 700 cm-1< / BR>
NMR (CDCl3, ): 1,35-to 1.60(1H,m) of 1.29(3H, t, J= 7,1 Hz), 1,80-2,00(1H, m), 2,20-3,20(5H, m), 4,15-4,20(2H,m), 4,25(2H, K, J= 7,1 Hz), br4.61(2H,s), the 5.45(1H, s), 6,51(1H, d, J= 7.8 Hz), only 6.64(1H, d, J= 7,8 Hz), 6,86(1H, d, J= 9.5 Hz), was 7.08(1H, DD, J= 7.8 Hz, 7.8 Hz), 7,10-to 7.35(11H,m).

(2) 2-[(3,4-Dihydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl] - 6-diphenylmethyl-3(2H)-pyridazinone.

IR (film): 1740, 1660, 1600 cm-1.

NMR (CDCl3, ): of 1.30(3H, t, J=7,1 Hz), of 2.23(2H, t, J= 8,3 Hz), of 2.86(2H, t, J= 8,3 Hz), 4.26 deaths(2H, K, J= 7,1 Hz), to 4.62(2H,s), 4,84(2H,s), 5,44(1H,s), of 6.26(1H,s), 6,50-6,70(2H,m), 6,85-of 6.90(1H,m), 7,00-to 7.35(12H,m).

M.-C. (+ APCI): 507 (M++1).

(3) 1-[(3,4-Dihydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl] - 5-diphenylmethyl-2(1H)-pyridone.

J= 7,1 Hz), to 4.62(2H,s), 5,23(1H,s), 6,14(1H,s), 6,50-6,70(3H,m), 6,80 - 6,85(1H,m), 7,05-to 7.35(12H,m).

M.-C. (+ APCI): 506 (M++1).

(4) 1-[(3,4-Dihydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl] - 3-diphenylmethyl-2(1H)-pyridone.

IR (film): 1750, 1660, 1600 cm-1< / BR>
NMR (CDCl3, ): of 1.29(3H, t, J= 7,1 Hz), measuring 2.20(2H, t, J= 8.6 Hz), 2,89(2H, t, J= 8.6 Hz), 4,25(2H, K, J= 7,1 Hz), br4.61(2H,s), 4,71(2H,s), and 5.30(1H, s), of 5.82(1H, s), 6,12(1H, t, J= 6.8 Hz), 6,60-6,70(3H,m), 7,00-to 7.35(12H,m).

M.-C. (+ APCI): 506 (M++1).

Example 10

The following connections get in the way similar to the method of example 1.

(1) [1,2,3,4-Tetrahydro-5-(ethoxycarbonylmethoxy)-2-naphthyl) methyl]-N, N-diphenylcarbamate.

So pl. to 89.5-91oC

IR (Wesel.oil): 1765, 1710, 1590, 1205 cm-1< / BR>
NMR (CDCl3, ): 1,23-of 1.44(1H,m), 1, 86-2,01(2H,m), 2,35 is 2.75(3H,m), 2,90-2,99(1H,m), with 3.79(3H,c), 4,07-to 4.23(2H,m), to 4.62(2H,s), 6,51(1H, d, J= 8.0 Hz), 6,69(1H, d, J= 7,6 Hz), 7,03(1H, t, J= 7.8 Hz), 7,16-7,38(10H,m).

(+) APCI M-n-m/z: 446 (M++1).

(2) [6 - or 8-Chloro-1,2,3,4-tetrahydro-5-(ethoxycarbonylmethoxy)- 2-naphthyl)methyl]-N,N-diphenylcarbamate.

IR (film): 1755, 1705 cm-1< / BR>
NMR (CDCl3, ): 1,25-of 1.36(1H, m), 1,8-of 2.05(2H,m), 2,18 is 2.33(1H,m), 2.4 to approximately 2.65(1H, m), 2,82-to 3.02(2H, m), with 3.79(3H,c), 4,07-4,27(2H,m), br4.61(2H,s), 6.48 in(1H, d, J= 8.7 Hz), 7,12(1H, d, J= 8.7 Hz), 7,16-7,39(10H,m).

(+) APCl M-n-m/z: 480 (M++1).

(3) Benzo is>IR (Wesel.oil): 3350, 3320, 1765, 1680, 1250, 1215 cm-1< / BR>
NMR (CDCl3, ): 1,35 was 1.43(1H,m), of 1.94(2H,m), 2,36 at 2.59(2H,m), 2,78-3,03(2H, m), up 3.22(2H, t, J= 6.4 Hz), with 3.79(3H,s), 4,63(2H,s), 4,99(1H,m), 6,51(1H, d, J= 8.0 Hz), of 6.71(1H, d, J= 7,6 Hz), for 6.81(1H,s), 7,03(1H, t, J= 7.9 Hz), 7,15-to 7.35(10H,m).

(+) APCI M-n-m/z: 167.

Example 11

To a solution of (2R)-2-hydroxy-2-(N,N-diphenylcarbamate)- 5-tert-butyldiphenylsilyl-1,2,3,4-tetrahydronaphthalene (1.9 g) in THF (tetrahydrofuran) (20 ml) add tetrabutylammonium (5 ml of a 1N solution in THF). After stirring for 1 hour at room temperature the solution is extracted with ethyl acetate. The mixture is washed with water and brine. The solvent from the dried organic layer is evaporated in a vacuum. The oil obtained is dissolved in N,N-dimethylformamide (10 ml), and then at room temperature add K2CO3(1.0 g) and ethylbromoacetate (0.6 ml). The mixture is stirred for 2 hours at the same temperature and treated with ethyl acetate and water. The organic layer is washed with water, saturated solution of NaHCO3and a salt solution. The solvent from the dried solution is evaporated in vacuo, and the residue purified by chromatography on silica gel. Get (2R)-2-hydroxy-2- (N, N-diphenylcarbamate)-5-ethoxycarbonylmethoxy-1,2,3,4 - Tetra to 3.0(4H,m), 4,10(2H, s), 4,14(2H, K, J= 7 Hz), 4,60(2H, s), of 6.52(1H, d, J= 8 Hz), of 6.66(1H, d, J=8 Hz), 7,10(1H, t, J= 8 Hz), 7,2-7,5(10H,m).

M.-C. m/z: 476 (M++1)

HPLC: chiralcel AD, 50% ethanol in hexane, to 12.8 ml/min

Example 12

The following connections get in the way similar to the method of example 11.

(1) (2S)-2-Hydroxy-2-(N, N-diphenylcarbamate) -5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen.

HPLC: chiralcel AD, 50% ethanol in hexane, to 11.7 ml/min

(2) 2-(N, N-Diphenylcarbamate)- 5-ethoxycarbonylmethoxy-3,4-dihydronaphthalene.

IR (pure): 1740, 1705 cm-1< / BR>
NMR (CDCl3, ): of 1.29(3H, t, J= 7 Hz), to 2.18(2H, t, J= 8,4 Hz), 2,87(2H, t, J= 8,4 Hz), 4,25(2H, K, J= 7 Hz), br4.61(2H,s), and 4.75(2H,s), and 6.25(1H,s), 6,5-6,7(2H,m), 7,06(1H, t, J= 8 Hz), 7,2-7,5(10H,m).

(3) (CIS)-2-(N, N-Diphenylcarbamate)-5-ethoxycarbonylmethoxy - 1-hydroxy-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3400, 1740, 1700 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), 1,4-2,1(3H,m), 2,4-3,2(3H,m), 4,25(2H, K, J= 7 Hz), 4,4-4,7(5H,m), 6,63(1H, d, J= 8 Hz), of 6.99(1H, d, J= 8 Hz), to 7.15(1H, t, J = 8 Hz), 7,2-7,5 (10H,m).

M.-C. m/z: 458(M+-17).

(4) (TRANS)-2-(N, N-Diphenylcarbamate)-5 - ethoxycarbonylmethoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3400, 1740, 1695 cm-1< / BR>
NMR (CDCl3

M.-C. m/z: 458 (M+-17).

(5) 1,2-Methylene-2-(N, N-diphenylcarbamate)-5 - ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen.

IR (pure):1700, 1740 cm-1< / BR>
NMR (CDCl3, ): 0,8-1,1(2H,m), 1,25(3H, t, J= 7 Hz), 1,5-2,2(3H,m), 3,1-3,3(1H, m), a 4.1 and 4.4(4H,m), 4,69(2H,s), is 6.54(1H,d, J= 8 Hz), 6,85(1H, d, J= 8 Hz), 7,05(1H, t, J= 8 Hz), 7,1-7,5 (10H, m).

(6) 1,2-Methylene-1-[2-(N, N-diphenylcarbamate)ethyl] -5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen.

IR (pure): 1700, 1740 cm-1< / BR>
NMR (CDCl3, ): 1,6-1,9(2H,m), 1,25(3H, t, J= 8 Hz), 1,2-2,2(5H,m), 2,6-3,1(2H,m), of 4.0-4.4(4H,m), 4,60(2H,s), of 6.50(1H, d, J= 8 Hz), 7,0-7,5(12H, m).

M.-C. m/z: 486 (M++1).

(7) 1-[2-(N, N-Diphenylcarbamate)ethyl]-2-hydroxy-2-methyl-5 - ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3400, 1740, 1690 cm-1< / BR>
NMR (CDCl3, ): of 1.23(3H,s), 1,4-2,0(4H,m), about 2.2 - 2.8(3H,m), 2,9-3,1(1H, m), of 4.0 - 4.4(4H,m), 4,59(2H,m), of 6.52(2H, d, J= 8 Hz),? 7.04 baby mortality(1H, t, J = 8 Hz), and 7.1 to 7.4(10H, m).

M.-C. m/z: 486 (M+-17).

(8) (CIS)-1-[2-(N, N-Diphenylcarbamate)ethyl] -2-hydroxy - 5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3400, 1730, 1680 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), 1,6 - 2,3 (5H,m), of 2.6-3.0(3H,m), 4.0 to 4.5(5H, m), br4.61(2H, s), of 6.52(1H, d, J= 8 Hz), is 6.61(1H, d, J= 8 Hz), 7,03(1H, t, J= 8 Hz), and 7.1 to 7.4 (10H,m).

M.-C. m/z: 4,4-tetrahydronaphthalen.

IR (pure): 3400, 1700-1720 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), 1,7-2,0(4H,m), of 2.6-3.0(3H,m), 3,8-4,0(1H, m), a 4.1 and 4.4(4H,m), 4,60(2H,s), of 6.52(1H, d, J= 8 Hz), is 6.61(1H, d, J= 8 Hz),? 7.04 baby mortality(1H, t, J= 8 Hz), and 7.1 to 7.4(10H,m).

M.-C. m/z: 490 (M++1).

(10) 1-[2-(N,N-Diphenylcarbamate)ethyl]-1-hydroxy-5 - ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3450, 1720, 1705 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), 1,6-2,2(6H,m), 2.8 to 3.0(2H,m), of 3.7-3.9(2H, m), 4,1-4,4(2H, m), 4,60(2H,s), 6,5-6,9(2H,m), of 6.96(1H, d, J= 8 Hz), and 7.1 to 7.4(10H,m).

M.-c. m/z: 472 (M+-17).

(11)-1-[2-(N, N-Diphenylcarbamate)ethyl] -5-ethoxycarbonylmethoxy-3,4-dihydronaphthalene.

IR (pure): 1740, 1705 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), 2,1(2H,m), 2,7-2,9(4H,m), from 4.2 to 4.4(4H, m), br4.61(2H, s), 5,79(1H, t, J= 4.4 Hz), 6,59(1H, d, J= 8 Hz), 6,94(1H, d, J= 8 Hz), 7,01(1H, t, J= 8 Hz), of 7.1 to 7.4(10H,m).

Example 13

To a solution of 2-[2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.25 g) in methylene chloride (10 ml) at -5oC add a solution of tribromide boron in methylene chloride (1N, 0,78 ml) and the solution stirred at the same temperature for 4 hours. The reaction mixture is washed with water and brine, dried over sodium sulfate and evaporated in vacuum. The rest is a crude 2-[2-(5-hydroxy - 1,2,3,4 is trihydro-1-naphthyl)ethyl] -6-diphenylmethyl-3(2H)-pyridazinone (0.34 g), potassium carbonate (0.16 g) and ethylbromoacetate (0.2 ml) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 24 hours. The reaction mixture is treated with ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (n-hexane - ethyl acetate = 3:2), and obtain 2-[2-(5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1 - naphthyl)-ethyl] -6-diphenylmethyl-3(2H)-pyridazinone (0.17 g) as a pale yellow oil.

IR (solution in CH2Cl2): 1750, 1660, 1585 cm-1< / BR>
NMR (CDCl3, ): 1,50-2,02(6H, m), 2,04-of 2.58(1H,m), 2,80-2,95(2H,m), 4,10-or 4.31(4H,m), 4,60(2H,c), the 5.45(1H,c), of 6.50(1H, d, J= 7.9 Hz), 6,72(1H, d, J= 7.9 Hz), at 6.84(1H, d, J= 9.5 Hz), 6,97-7,54(12H,m).

M.-c.(APCI) m/z: 523 (M++1).

Example 14

According to the method similar to the method of example 13, to obtain 2-(N,N-diphenylcarbamate)-2-methyl-5-ethoxycarbonylmethoxy - 1,2,3,4-tetrahydronaphthalen.

IR (pure): 1740, 1700 cm-1< / BR>
NMR (CDCl3, ): or 0.83(3H, s), 1,25(3H, t, J=7 Hz), of 1.52(2H,m), 2,2-2,9(4H, m), 3,92(1H, d, J= 10,2 Hz), 4,00(1H, d, J= 10,2 Hz), 4,24(2H, K, J= 7 Hz), 4,60(2H,s), of 6.50(1H, d, J= 8 Hz), only 6.64(1H, d, J= 8 Hz), 7,06(1H, t, J= 8 Hz), 7, 2-7, 5 (10H, m).

M.-C. m/z: 474 (M++1).

Example 15

To a solution of 2-(N,N-diphenylcarbamate)-5-TeV>2
CO3(290 mg) and m-chloroperbenzoic acid (550 mg). After stirring for 2 hours the solvent is removed in vacuum, the residue is extracted with ethyl acetate. The mixture was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 1,2-epoxy-2-(N,N - diphenylcarbamate)-5-tert-butyldiphenylsilyl-1,2,3,4 - tetrahydronaphthalen. This compound is treated in the same manner as in example 11, and receive a 1,2-epoxy-2-(N, N - diphenylcarbamate)-5-ethoxycarbonylmethoxy-1,2,3,4 - tetrahydronaphthalen (370 mg).

IR (pure): 1720 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), 1,6-1,9(1H,m), to 2.1-2.5(2H,m), to 3.0-3.2(1H, m) and 3.59(1H,m) to 4.23(2H, K, J= 7 Hz), 4,58(2H,s), of 6.73(1H, d, J= 8 Hz), 6,93(1H, d, J= 8 Hz), was 7.08(1H, t, J= 8 Hz), and 7.1 to 7.7(10H,m).

M.-C. m/z: 474 (M++1).

Example 16

To a solution of 5-tert-butyldiphenylsilyl-1-[2-(N,N - diphenylcarbamate)ethyl] -2-hydroxy-2-methyl - 1,2,3,4-tetrahydronaphthalene (800 mg) in toluene (20 ml) is added KHSO4(100 mg). The mixture is stirred for 1 hour at boiling under reflux, and then cooled solution was washed with a saturated solution of NaHCO3and a salt solution. Rastburg add tetrabutylammonium fluoride (2 ml, 1N solution in THF). After stirring for 1 hour at room temperature the solution is extracted with ethyl acetate. The mixture is evaporated in vacuum. The oil obtained is dissolved in N,N-dimethylformamide (5 ml), and to the solution add ethylbromoacetate (0.2 ml) at room temperature. The mixture is stirred for 2 hours at the same temperature and treated with ethyl acetate and water. The organic layer is washed with water, saturated solution of NaHCO3and a salt solution. The solvent from the dried solution is evaporated in vacuo, and the residue purified by chromatography on silica gel, get 1-[2-(N,N-diphenylcarbamate)ethyl]-2-methyl-5-ethoxycarbonylmethoxy - 3,4-dihydronaphthalene (310 mg).

IR (pure): 1740, 1700 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t, J= 8 Hz), 1,89(3H,s), 1,9-2,2(1H,m), 2,8-3,3(3H, m), 3,42(1H,m), of 3.8-4.1(1H,m), a 4.1 and 4.4(4H,m), to 4.62(2H,s), is 6.54(1H, d, J= 8 Hz), 6,62(1H, d, J= 8 Hz), 7,07(1H, t, J= 8 Hz), 7,1-7,5(10H,m).

M.-C. m/z: 486 (M++1).

Example 17

A mixture of ethyl-[5,6,7,8-tetrahydro-6-(2-hydroxyethyl)-1-naphthyloxy] acetate (50 mg), N,N-diphenylcarbamate (50 mg) and pyridine (32 ml) was stirred at 100oC for 1 hour and 40 minutes, cooled to room temperature and treated with ethyl acetate and 1N hydrochloric acid. An ethyl acetate layer serial is pariwat in vacuum. The remainder chromatographic on silica gel (toluene-ethyl acetate), and get 2-[5-(ethoxycarbonylmethoxy)- 1,2,3,4-tetrahydro-2-naphthyl]ethyl-N,N-diphenylcarbamate (31 mg) as a syrup.

IR (foam): 1755, 1705, 1195 cm-1< / BR>
NMR (CDCl3, ): of 1.30(3H, t, J = 7,1 Hz), 1,25-of 1.42(1H,m), 1,61 is 1.70(3H, m), 1,86-of 1.93(1H, m), 2,29-of 2.64(2H, m), 2.71 to of 2.97(2H,m), 4,20-4,32(4H,m), br4.61(2H, s); 6,51(1H, d, J= 8.0 Hz), to 6.67(1H, d, J= 7,6 Hz), 7,03(1H, t, J= 7.9 Hz), 7,13 and 7.36(10H,m).

(+) APCI M-n-m/z: 474 (M+1), 261.

Example 18

To a solution of phosgene dimer (0,027 ml) in methylene chloride (1 ml) at -5oC add a solution of (5-ethoxycarbonylmethoxy-1,2,3,4 - tetrahydro-1-naphthyl) methanol (0.12 g) and pyridine (0.1 ml) in methylene chloride (2 ml) and the solution stirred at room temperature for two hours. To the reaction mixture add a solution of the hydrochloride 1,1-diphenylhydrazine (0.10 g) and pyridine (0.05 ml) in methylene chloride (2 ml). The solution was stirred at room temperature for 3 hours, washed with 5% hydrochloric acid, water and brine, dried over sodium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (n - hexane - ethyl acetate), and get 2-[(5-ethoxycarbonylmethoxy-1, 2,3,4-tetrahydro-1-naphthyl)methoxycarbonyl] -1,1-diphenylhydrazine made (0.13 g) as colorless solids.

M.-C. (APCI) m/z: 475 (M+1).

Example 19

A solution of ethyl-(6-amino-5,6,7,8-tetrahydro-1-naphthyloxy)acetate (83 mg) and 4-nitrophenyl(benzhydryl) carbonate (116 mg) in N,N-dimethylformamide (2 ml) was stirred at 50oC for 1 hour and 30 minutes, cooled to room temperature and extracted with ethyl acetate. The extract is washed five times with an aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (toluene - ethyl acetate), and get benzhydryl-N- [1,2,3,4-tetrahydro - 5-(ethoxycarbonylmethoxy)-2-naphthyl]carbamate (110 mg) as oil.

IR (film): 1750, 1720, 1705, 1210 cm-1< / BR>
NMR (CDCl3, ): of 1.29(3H, t, J= 7,1 Hz) to 1.79(1H,m), 2,04(1H,m), 2,65(1H, DD, J= 16,4, 8.0 Hz), 2,79-2,89(2H,m), 3,11(1H, DD, J= 16,3, and 4.5 Hz), Android 4.04(1H, m), 4.26 deaths(2H, K, J= 7,1 Hz), to 4.62(2H,s), 4,91(1H,sm), is 6.54(1H, d, J= 8.1 Hz), of 6.71(1H, d, J= 7,6 Hz), for 6.81(1H,s), 7,06(1H, t, J= 7.9 Hz), 7,15-to 7.35(10H,m).

(+) APCI M-n-m/z: 167.

Example 20

To a solution of benzhydryl-N-[[1,2,3,4-tetrahydro-5- (ethoxycarbonylmethoxy)-2-naphthyl]methyl]carbamate (117 mg) and under the conditions (36 mg) in N, N-dimethylformamide (1.2 ml) under ice cooling and stirring, 60% sodium hydride (10,2 mg), and the mixture is stirred at the same temperature in thechinese stirred at room temperature for 3 days and extracted with ethyl acetate. The extract is washed twice with saline, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (toluene - ethyl acetate), and get benzhydryl-N-methyl-N-[[1,2,3,4-tetrahydro-5-(ethoxycarbonylmethoxy)- 2-naphthyl]methyl]carbamate (71 mg) as oil.

IR (film): 1755, 1730 (shoulder), 1690, 1200 cm-1< / BR>
NMR (CDCl3, ): 1,25-1,45(1H,m), 1.85 to to 2.15(2H,m), 2,35 is 2.8(3H,m), 2,96 and is 3.08(3H,s), 3,05(1H,m), 3,3-3,5(2H), with 3.79(3H,s), 4,63(2H), 6,51(1H, d, J= 7.9 Hz), 6,66(1H,m), PC 6.82(1H,s), 7,03(1H,m), 7,18-7,33(10H,m).

(+) APCl M-n-m/z: 167.

Example 21

To a solution of 2-(N,N-diphenylcarbamate)- 5-ethoxycarbonylmethoxy-3,4-dihydronaphthalene (270 mg) in a mixture of acetonitrile (10 ml) and water (5 ml) at 0oC add N-oxide 4-methylmorpholine (0,34 ml) and O5O4(1 ml, 2.5% solution in tert-butyl alcohol). After stirring for 4 hours the solution was diluted with ethyl acetate. The mixture was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The residue is purified by chromatography on silica gel, and get 1,2-dihydroxy-2- (N, N-diphenylcarbamate)-5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3400, 1720 cm-1< / BR>
NMR (CDCl3, ): of 1.29(3H, t, J=7 Hz), 1.6 to the emer 22

According to the method similar to the method of example 21, receive 1-[2-(N,N-diphenylcarbamate)ethyl] -1,2-dihydroxy-5 - ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen.

IR (pure): 3450, 1740, 1705 cm-1< / BR>
NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), 1.7 to 2.2(4H,m), 2,68 to 3.0(2H,m), of 2.6-3.0(2H, m), 3,82(1H, m), from 4.2 to 4.4(4H, m), 4,59(2H,s), 6,50(1H,m) and 7.1 to 7.4(12H,m).

M.-C. m/z: 488 (M+-17)

Example 23

To a solution of 1,2-epoxy-2-(N,N-diphenylcarbamate)-5 - ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalene (0.2 g) in CH2Cl2(30 ml) at 0oC added HF-pyridine (0.5 ml). After stirring for 2 hours the solvent is removed in vacuum. The residue is extracted with ethyl acetate. The mixture was washed with 1N HCl solution, a saturated solution of NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The remainder chromatographic on silica gel, and get 1-fluoro-2-hydroxy-2-(N,N-diphenylcarbamate)- 5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen (70 mg).

IR (pure):1700 cm-1< / BR>
NMR (CDCl3, ): of 1.26(3H, t, J= 7 Hz), 1,5 of-2.1(4H,m), of 2.6-3.0(2H,m), 4.0 to 4.5(4H, m), to 4.62(2H,m), 5,20(1H, d, J= 52 Hz), 6,69(1H,m), 7,0-7,5(12H, m).

M.-C. m/z: 494 (M++1)

Example 24

To a solution of 2-hydroxy-2-(N,N-diphenylcarbamate)-5 - ethoxycarbonylmethoxy-1,2,3,4-t is After stirring for 30 minutes, the mixture was washed with saturated NaHCO3and brine, dried over MgSO4and evaporated in vacuum. The remainder chromatographic on silica gel, and get 2-fluoro-2-(N, N-diphenylcarbamate)-5 - ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen (40 mg).

NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), 1,6-2,0(2H,m), of 2.8-3.0(4H,m), 4.26 deaths(2H, K, J= 7 Hz), 4,27(2H, d, J= 22 Hz), was 4.76(2H,s), is 6.54(1H, d, J= 8 Hz), only 6.64(1H, d, J= 8 Hz), 7,06(1H, t, J= 8 Hz), a 7.1 to 7.5(10H,m).

M.-c. m/z: 478 (M++1).

Example 25

According to the method similar to the method of example 24, we get 1-[2-(N,N - diphenylcarbamate)ethyl] -2-fluoro-5-ethoxycarbonylmethoxy - 1,2,3,4-tetrahydronaphthalen.

NMR (CDCl3, ): a 1.25(3H, t, J= 7 Hz), a 1.7-2.1(4H,m), 2,6-2,9(2H,m), a 4.1 and 4.4(4H,m), 4,60(2H,s), 6,5-6,7(2H,m), of 7.0 to 7.4(11H,m).

M.-C. m/z: 492 (M++1).

Example 26

A solution of 2-[(3,4-dihydro-5-ethoxycarbonylmethoxy - 2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.20 g) and 3-chloroperoxybenzoic acid (94 mg) in dichloromethane (5 ml) stand in the refrigerator (about -15oC) during the night. The reaction mixture is evaporated in vacuo, and the residue is treated with ethyl acetate and sodium hydrogen carbonate solution. The organic layer is separated and washed with water, brine, dried over magnesium sulfate and evaporated in vacuum. The residue and 10% palladium-on-coal in atilas temperature for 4 hours. The catalyst is filtered off and the filtrate evaporated in vacuum. The residue is purified column chromatography on silica gel (n-hexane - ethyl acetate = 2:1 1:1), and obtain 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy - 2-hydroxy-2-naphthyl)methyl] -6-diphenylmethyl-3(2H)-pyridazinone (0.08 g) as a pale yellow oil.

IR (CH2Cl2): 3600-3100, 1750, 1660 cm-1< / BR>
NMR (CDCl3, ): of 1.29(3H, t, J= 7,1 Hz), 1,60 - 2,00(2H,m), 2,75-3,00(4H, m), 4,20 is 4.35(4H,m), br4.61(2H,s), 5,43(1H,s), 6,53(1H, d, J= 8 Hz), is 6.61(1H, d, J= 8 Hz), 6.90 to - to 7.35 (13H, m).

M.-C. (+ APCI): 525 (M++1).

Example 27

A solution of 2-[(5-ethoxycarbonylmethoxy-1,2,3,4 - tetrahydro-1-naphthyl)methoxycarbonyl] -1,1-diphenylhydrazine (0.17 g) and 1N aqueous sodium hydroxide solution (1 ml) in dioxane (1.5 ml) was stirred at room temperature for 30 minutes, and treated with a solution of 5% hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuum. The residue is washed with isopropanol, and get 2-[(5-carboxymethoxy-1,2,3,4-tetrahydro-1-naphthyl) methoxycarbonyl]-1,1-diphenylhydrazine (0.08 g) as colorless powder.

IR (Wesel.oil): 3230, 1730, 1700 cm-1< / BR>
NMR (CD3OD, ): 1,49 is 2.01(4H,m), 2,70-3,13(3H,m), 4,10 - 4,47(2H,m), 4,48(2H,s), 6,62-7,30(14H,m).

(1) (S)-2-[(1,2,3,4-Tetrahydro-5-carboxymethoxy-2-naphthyl)methyl]- 6-diphenylmethyl-3(2H)-pyridazinone.

[]2D5= -27,6(C=0.75 IN, CH2Cl2)

So pl. 144-145oC

IR (Wesel.oil): 2600-2200, 1740, 1640, 770, 700 cm-1< / BR>
NMR (DMSO-d6, ): 1,20-of 1.45(1H,m), 1,70-1,90(1H,m), 2,10-2,90(5H,m), 3,90-4,10(2H, m) and 4.65(2H,c), to 5.57(1H,c), 6,55-of 6.65(2H,m), 6.90 to-7,05(2H,m), 7,20-to 7.35(11H,m), 12,96(1H,CL).

M.-C. (+ APCI): 481 (M++1).

(2) 2-[(3,4-Dihydro-5-carboxymethoxy-2-naphthyl)methyl]- 6-diphenylmethyl-3(2H)-pyridazinone.

So pl. 156-158oC.

IR (Wesel.oil): 1710, 1630 cm-1< / BR>
NMR (DMSO-d6, ): 2,12(2H, t, J= 8,9 Hz) to 2.67 (2H, t, J= 8,9 Hz), of 4.66(2H, s), 4,74(2H, s) to 5.56(1H, s), 6,13(1H,s), 6,62(1H, d, J= 7.9 Hz), of 6.71(1H, d, J= 7.9 Hz), to 6.95(1H, d, J = 9.6 Hz), 7,05(1H, d, J= 7.9 Hz), 7,15-7,40(11H,m), 13,0(1H,CL).

M.-C. (+APCI): 479 (M++1).

(3) 2-[(1,2,3,4-Tetrahydro-5-carboxymethoxy-2-hydroxy-2 - naphthyl)methyl] -6-diphenylmethyl-3(2H)-pyridazinone.

So pl. 122-123oC

IR (Wesel.oil): 3600-3200, 1730, 1650 cm-1< / BR>
NMR (CDCl3, ): 1,50-1,90(2H,m), 2,50-3,00(4H,m), 3,82(2H,CL), to 4.23(1H, d, J= a 13.9 Hz), 4,37(1H, d, J= a 13.9 Hz), 4,63(2H,s), 5,44(1H,s), 6,50-of 6.65(2H,m), 6,95-7,40(13H,m).

M.-C. (+APCI): 497 (M++1)

(4) 1-[(3,4-Dihydro-5-carboxymethoxy-2-naphthyl)methyl]-5 - diphenylmethyl-2(1H)-pyridone.

Hz), br4.61(2H, s), 4,69(2H, s) 5,41(1H,s), 6,03(1H,s), to 6.43(1H, d, J= 10,2 Hz), 6,60(1H, d, J= 7,4 Hz), 6,72(1H, d, J= 8.0 Hz), 7,00-to 7.35(13H,m), 12,98(1H, CL).

M.-C. (+APCI): 478 (M++1).

(5) 1-[(3,4-Dihydro-5-carboxymethoxy-2-naphthyl)methyl]-3 - diphenylmethyl-2(1H)-pyridone.

So pl. 186-188oC.

IR (Wesel. oil): 1750, 1640 cm-1< / BR>
NMR (DMSO-d6, ): 2,13(2H, t, J= 8,2 Hz), is 2.74(2H, t, J= 8,2 Hz), of 4.66(2H, s), the 5.65(1H,s), of 5.99(1H,s), and 6.25(1H, t, J= 6.8 Hz), 6,59(1H, d, J= 7,3 Hz), of 6.71(1H, d, J= 8.0 Hz), 6.87 in(1H, J= 6,7 Hz), 7,0-to 7.35 (11H,m), to 7.59(1H, d, J= 6,7 Hz).

(6) 2-[2-(5-Carboxymethoxy-1,2,3,4-tetrahydro-1-naphthyl) ethyl]-6-diphenylmethyl-3(2H)-pyridazinone.

NMR (CD3OD, ): 1,60-to 2.55(6H, m), 2,55-2,90(3H,m), 4,11-the 4.29(2H,m), 4,47(2H,s), of 5.55(1H,s), 6,54-of 6.61(2H,m), 6,88-of 6.90(2H,m), 7,17-to 7.35(11H,m).

M.-C. (APCI) m/z: 495 (M++1).

(7) 2-[5-(Carboxymethoxy-1,2,3,4-tetrahydro - 2-naphthyl]-ethyl-N,N-diphenylcarbamate.

So pl. 175-177,5oC.

IR (Wesel.oil): 2750-2250, 1765, 1675 cm-1< / BR>
NMR (DMSO-d6, ): 1,24(1H,m), of 1.57(3H,m) to 1.79(1H,m), of 2.2-2.5(2H,m), 2,65-to 2.85(2H,m), 4,19(2H,m) and 4.65(2H,s), 6,56 - only 6.64(1H,m), 7,00(1H, t,J= 7.8 Hz), 7.18 in-7,39(10H,m).

(+ APCI) M-C.: 446 (M++1), 233.

(8) [5-(Carboxymethoxy-2-methyl-1,2,3,4-tetrahydro-2-naphthyl] methyl-N, N-diphenylcarbamate.

IR (Wesel.oil): 1700 cm-1< / BR>
NMR (CDCl3, ): or 0.83(3H,s) of 1.44(2H,m), 2,2-2,9(4H,m), 3,92(1H, d, J= 10.6 G THE LASS="ptx2">

Example 29

The solution benzhydryl-N-[[1,2,3,4-tetrahydro-5-(methoxy, carbonyloxy)-2-naphthyl]methyl]carbamate (60 mg) in a mixture of 1N aqueous sodium hydroxide solution (0,20 ml), methanol (1 ml) and 1,2-dimethoxyethane (1 ml) was stirred at room temperature for 30 minutes, neutralized 1N hydrochloric acid and extracted with ethyl acetate. The extract is washed with saline, dried over magnesium sulfate and evaporated in vacuum. The oily residue is converted into a powder of diisopropyl ether, and get benzhydryl-N-[[1,2,3,4-tetrahydro-5-(carboxymethoxy)-2-naphthyl] methyl]carbamate (51 mg) as colorless powder.

So pl. 160-161oC

IR (Wesel.oil): 3350, 2800-2300, 1755, 1685 cm-1< / BR>
NMR (DMSO-d6, ): 1.2 to about 1.35(1H,m) of 1.84(2H,m), 2,25 - 2,5(2H,m), 2,7-to 2.85(2H, m), 3,01(2H, m), with 4.64(2H,s), 6,56 is 6.67(3H,m), 7,00(1H, t, J= 7.8 Hz), 7,30-7,38(10H,m), EUR 7.57(1H,t), and 12.9(1H,sh).

(+ APCI) M-n -: m/z 412.

Example 30

According to the method similar to the method of example 29, receive [6 - or 8-chloro-5-(carboxymethoxy)-1,2,3,4-tetrahydro-2-naphthyl] methyl-N,N-diphenylcarbamate.

So pl. 138-144,5oC

IR (Wesel.oil): 2700-2300, 1740, 1710 cm-1< / BR>
NMR (DMSO-d6, ): 1,23(1H,BL), of 1.84(2H,BL), 2,12 - of 2.27(1H,m), 2,35-2,6(1H, m), 2,7-to 2.85(2H,m), 4,05-to 4.15(2H,m), of 4.66(2H,s), 6,69(1H, d, J = 8,8 Hz), 7,15-7,42(11H,m).

(+ APCI) M-n-m is Boymatov-1,2,3,4-tetrahydronaphthalene (0.9 g) in ethanol (20 ml) is added 1N NaOH solution (1.9 ml). After stirring for 4 hours at the same temperature the solvent is removed in vacuum, and get the sodium salt of (2R)-[5-carboxymethoxy) -2-hydroxy-1,2,3,4-tetrahydro-2-naphthyl]methyl-N,N - diphenylcarbamate (0.9 g).

IR (Wesel.oil): 3400, 1700, 1580 cm-1< / BR>
NMR (D2O ): 1,2-1,6(2H,m), and 2.1 to 2.6(4H,m), and 3.72(1H, d, J= 11,0 Hz), 3,85(1H, d, J= 11.0 in Hz) of 4.13(2H,s), of 6.29(2H,m), 6,4-7,0(11H,m).

FAB M.-C. m/z: 470 (M++1).

HPLC: chiralcel AGP, 8% acetonitrile in 0.02 N phosphate buffer (pH=6,0) of 5.3 ml/min

Example 32

The following compounds obtained by methods similar to the methods of examples 6 and 31.

(1) Sodium salt benzhydryl-N-[5-(carboxymethoxy)-1,2,3,4 - tetrahedral-2-naphthyl]carbamate.

So pl. 209-223oC (decomp.)

IR (Wesel.oil): 3340, 1695, 1615, 1250 cm-1< / BR>
NMR (DMSO-d6, ): of 1.57(1H, m), of 1.94(1H,m), of 2.51 - to 2.67(2H,m), 2,83 of 2.92(2H, m), of 3.60(1H,m), 4,10(2H,s), 6.48 in - 6,56(2H,m), 6,69(1H,s) 6,94(1H, t, J= 7.9 Hz), 7,26-7,38(10H,m), EUR 7.57(1H,d, J= 7,2 Hz).

FAB M.-C. m/z: 454 (M++1), 432.

(2) Sodium salt of (2S)-[5-(carboxymethoxy)-2-hydroxy-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate.

HPLC: chiralcel AGP, 8% acetonitrile in 0.02 N phosphate buffer (pH=6,0), 7,4 ml/min

(3) Sodium salt [5-(carboxymethoxy)-3,4-dihydro - 2-naphthyl] methyl-N, N-diphenyl 6,21(1H,s), of 6.50(1H, d, J=8 Hz), 6,60(1H, d, J= 8 Hz), 6,98(1H, t, J= 8 Hz), 7,2-7,5 (10H, m).

FAB M.-C. m/z: 452 (M++1).

(4) Sodium salt [5-(carboxymethoxy)-1,2-dihydroxy-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 3340, 1650-1600 cm-1< / BR>
NMR (DMSO-d6,) is 1.6-1.8(2H,m), 2,5-2,8(2H,m), 4,0-4,9(5H,s), 6,53(1H, m), the 6.9 to 7.5(12H,m).

FAB M.-C. m/z: 486 (M++1).

(5) Sodium salt [5-(carboxymethoxy)-1,2-epoxy-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 1700, 1590 cm-1< / BR>
NMR (DMSO-d6, ): 1,4-1,7(1H,m), 1,9-2,2(2H,m), 2,8-3,1(1H,m), the 3.65(1H, s) 4,08(2H, s), 4,20(1H, d, J= 12.0 Hz), to 4.52(1H, d, J= 12.0 Hz), of 6.71(1H, d, J= 8.0 Hz), at 6.84(1H, d, J= 8 Hz), 7,05(1H, t, J= 8 Hz), 7,2-7,5(10H,m).

FAB M.-C. m/z: 468 (M++1).

(6) Sodium salt of (TRANS)-[5-(carboxymethoxy)-1-hydroxy-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 3400-3200, 1700, 1590 cm-1< / BR>
NMR (DMSO-d6, ): 1.2 to 1.5(1H, m), 1,6-1,9(2H, m), 2,2 - 2,8(2H,m) 4,06(2H,s), a 4.1 and 4.4(3H,m), of 6.52(1H, d, J= 7 Hz), 6,8-7,1(2H,m) and 7.1 and 7.5(10H, m).

FAB M.-C. m/z: 470 (M++1)

(7) Sodium salt of (CIS)-[5-(carboxymethoxy)-1-hydroxy-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 3400-3200, 1690, 1590 cm-1< / BR>
NMR (DMSO-d6, ): 1,4-2,0(3H,m), 2,2-2,8(2H,ptx2">

(8) Sodium salt [5-(carboxymethoxy)-1-fluoro-2-hydroxy - 1,2,3,4-tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 3400-3300, 1710, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 1,4-2,0(2H, m), of 2.5-3.2(2H, m), 3.9 to 4.5(4H,m) 5,00(1H, d, J= 52 Hz), 6,7-7,5(13H,m).

FAB M.-C. m/z: 488 (M++1).

(9) Sodium salt [5-(carboxymethoxy)-1,2-methylene-1,2,3,4 - tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 0,8-1,4(2H,m), a 1.7-2.1(3H,m), and 3.0(1H,m) 4,06(2H,s), 4,10(1H, d, J= 10,8 Hz), 4,20(1H, d, J= 10,8 Hz), 6,50(1H, d, J= 8 Hz), of 6.71(1H, d, J= 8 Hz), 6,93(1H, t, J= 8 Hz), a 7.2 to 7.6(10H,m).

FAB M.-C. m/z: 466 (M++1).

(10) Sodium salt [5-(carboxymethoxy)-2-fluoro-1,2,3,4-tetrahydro - 2-naphthyl]methyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 1,6-2,0(2H,m), of 2.5-3.0(4H,m), 4,08(2H,s), 4,25(2H, d, J= 20 Hz), 6,47(1H, d, J= 8 Hz), 6,51(1H,d, J= 8 Hz), 6,97(1H, t, J= 8 Hz), 7,1-7,5(10H,m).

FAB M.-C. m/z: 472 (M++1).

(11) Sodium salt of 2-[5-(carboxymethoxy)-1,2-methylene-1,2,3,4 - tetrahydro-1-naphthyl]ethyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 1705, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 0,5-0,8(2H, m), 1.0 to 2.0(5H, m), of 2.5 - 3.0(2H,m), of 4.05(2H,s), 4,0-4,3(2H,m), of 6.49(1H, d, J= 8 Hz), 6,8-7,0(2H,m) and 7.1 and 7.5(10H, m).

FAB M.-C. m/z: 480 (M++1).

IR (Wesel.oil): 3400, 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): of 1.05(3H,s), 1,1-2,0(4H,m), by 2.0 - 2.4(2H,m) of 2.75(1H, m), 4,07(2H, s), 4,0-4,3(2H,m), 6,18(1H, d, J= 8 Hz), 6,46(1H, d, J= 8 Hz), 6,85(1H, t, J= 8 Hz), 7,1 - 7,5(10H,m).

FAB M.-C. m/z: 498 (M++1).

(13) Sodium salt of 2-[5-(carboxymethoxy)-2-methyl-3,4-dihydro - 1-naphthyl]ethyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 1,68(3H,s), of 2.0 to 3.2(4H,m), 3,2 - 4,2(4H,m), of 4.12(2H, s), 6,5-6,7(2H,m), 7,0-7,8(11H,m).

FAB M.-C. m/z: 480 (M++1).

(14) Sodium salt of 2-[5-(carboxymethoxy)-1,2-dihydroxy-1,2,3,4 - tetrahydro-1-naphthyl]ethyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 3300, 1700, 1590 cm-1< / BR>
NMR (DMSO-d6, ): 1.7 to 2.2(4H,m), 2,5-2,7(1H,m), 2.8 to 3.0(1H,m in), 3.75(1H, t, J= 5.4 Hz), 4,0-4,3(2H,m), to 4.38(2H,s), 6,6-6,8(1H,m), 7,0 - 7,4(12H,m).

FAB M.-C. m/z: 500 (M++1)

(15) Sodium salt of (CIS)-2-[5-(carboxymethoxy)-2-hydroxy - 1,2,3,4-tetrahydro-1-naphthyl]ethyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): of 1.5-2.1(4H,m), 2.4 to 2.8(3H,m), 3,83(1H,m) 4,06(2H,s), 4,0-4,3(2H, m), of 6.29(1H, d, J= 8 Hz), 6,46(1H, d, J= 8 Hz), 6.87 in(1H, t, J= 8 Hz), 7,1-7,5 (10H,m).

FAB M.-C. m/z: 484 (M++1)

(16) Sodium salt of (TRANS)-2-[5-(carboxymethoxy)-2-hydroxy - 1,2,3,4-tetrahydro-1-naphthyl]ethyl-N,N-diphenylcarbamate.

IR (Wesel.wt 8 Hz), 6,87(1H, t, J= 8 Hz), 7,1-7,5 (10H,m).

FAB M.-C. m/z: 484 (M++1)

(17) Sodium salt of 2-[5-(carboxymethoxy)-2-fluoro-1,2,3,4 - tetrahydro-1-naphthyl]ethyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): of 1.5-2.0(4H,m), 2,5-2,9(3H,m), of 3.73(1H,m), 4,08(2H,s), 4,0-4,3(2H, m), 6,41(1H, d, J= 8 Hz), of 6.49(1H, d, J= 8 Hz), 6,91(1H, t, J= 8 Hz), 7,1-7,5(10H,m).

FAB M.-C. m/z: 486 (M++1)

(18) Sodium salt of 2-[5-(carboxymethoxy)-1-hydroxy-1,2,3,4 - tetrahydro-1-naphthyl]ethyl-N,N-diphenylcarbamate.

IR (Wesel.oil): 3400, 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 1,4-2,0(6H,m), 2,5-2,6(2H,m), 4,0-4,2(2H,m), 4,37(2H, s), to 6.58(1H, t, J= 5 Hz), 7,02(2H, d, J= 5 Hz), 7,1-7,5(10H,m).

FAB M.-C. m/z: 484 (M++1)

(19) Sodium salt of 2-[5-(carboxymethoxy)-3,4-dihydro-1-naphthyl] ethyl-N, N-diphenylcarbamate.

IR (Wesel.oil): 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): of 2.0-2.2(2H, m), to 2.5-2.7(4H, m), 4,0 - 4,3(4H,m), of 5.75(1H, m), 6,63(1H, d, J= 8 Hz), to 6.80(1H, d, J= 8 Hz), 6,98(1H, t, J= 8 Hz), 7,0-7,4(10H,m).

FAB M.-C. m/z: 466 (M++1)

Example 33

The solution benzhydryl-N-methyl-N-[[1,2,3,4-tetrahydro-5- (ethoxycarbonylmethoxy)-2-naphthyl] methyl] carbamate (60 mg) in 0.1 N sodium hydroxide solution (1,27 ml) and methanol was stirred at room temperature overnight and evaporated in vacuum. The residue is converted into a powder when carbamate (50 mg) as pale yellow powder.

So pl. 100-105oC.

IR (Wesel.oil): 1695, 1605, 1200 cm-1< / BR>
NMR (DMSO-d6, ): 1,2(1H,BL), a 1.75-of 2.05(2H,m), 2,25-3,1(4H,m), 2,87, and is 3.08(3H,s), 3,2-3,4(2H,m) 4,06(2H,s), 6.48 in(2H,sm), 6,70(1H,s) 6,94(1H,PCs), 7,2-7,4(10H,m).

FAB M.-C. m/z: 482 (M++1)

Example 34

A solution of [1,2,3,4-tetrahydro-5-(ethoxycarbonylmethoxy)-2-naphthyl] methyl] -N, N-diphenylcarbamate (600 mg) in 1N aqueous sodium hydroxide solution (2.0 ml), methanol (7 ml) and 1,2-dimethoxyethane (7 ml) was stirred at room temperature for 40 minutes, neutralized 1N hydrochloric acid, evaporated in vacuo, and the residue is treated with ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuum. The residue was washed with n-hexane, and receive a colorless powder (500 mg) which is dissolved in a mixture of ethanol (20 ml), methanol (30 ml) and tetrahydrofuran (10 ml). The solution is mixed with 1N aqueous solution of sodium hydroxide (1,10 ml) and the mixture is evaporated in vacuum. The residue was washed with n-hexane, and receive sodium salt [5- (carboxymethoxy)-1,2,3,4-tetrahydro-2-naphthyl]methyl-N,N - diphenylcarbamate (475 mg) as colorless powder.

IR (Wesel.oil): 1715, 1625, 1600 (shoulder) cm-1< / BR>
NMR (DMSO-d6, ): 1,24(1H, m) and 1.83(2H,m), 2,25 - of 2.81(4H,m), a 4.03-4,08(4H,m), 6,45-of 6.52(2H,m), NNaO5< / BR>
calculated: C-68,87, H-5,33, N-3,09,

found: C-68,59, H-5,31, N is 3.08.

Example 35

A mixture of 1-[(3,4-dihydro-5-carboxymethoxy)-2-naphthyl)methyl] -5 - diphenylmethyl-2(1H)-pyridone (100 mg) and a catalytic amount of 10% palladium-on-coal (50% moist.) stirred at room temperature in a hydrogen atmosphere for 5 hours. The catalyst is filtered off and the filtrate evaporated in vacuum. The residue is purified column chromatography on silica gel (dichloromethane: methanol = 5:1), and obtain 1-[(1,2,3,4-tetrahydro-5-carboxymethoxy-2-naphthyl)methyl] -5-diphenylmethyl-2(1H)-pyridone (94,5 mg) as pale yellow powder.

So pl. 162-163oC

IR (Wesel.oil): 1670, 1610 cm-1< / BR>
NMR (DMSO-d6, ): 1,10-1,40(1H, m), 1.70 to 4,00(8H, m), 4,28(2H,s), of 5.39(1H,s), 6,35-6,55(4H,s), 6.90 to-7,00(1H,m), 7,10-to 7.50 (11H,m).

M.-C. (+ APCI): 480 (M++1)

Example 36

According to the method similar to the method of example 35, receive 1-[(1,2,3,4-tetrahydro-5-carboxymethoxy-2-naphthyl)methyl]-3-diphenylmethyl-2 (1H)-pyridone.

So pl. 185-187oC.

IR (Wesel.oil): 1730, 1640 cm-1< / BR>
NMR (DMSO-d6, ): 1,20-4,00(9H, m), 4,30(2H,s), 5,64(1H,s), x 6.15 and 6.25(1H,s), 6,45-6,60(2H,m), 6,70-7,40(12H,m), 7,55-of 7.70(1H,m).

Example 37

Sodium salt of 2-[5-(carboxymethoxy)-2-methyl-1,2,3,4 - tetrahydro-1-naphthyl] ethyl-N,N-di method, similar to the method of example 31.

IR (Wesel.oil): 1700, 1600 cm-1< / BR>
NMR (DMSO-d6, ): 0,86(3H, d, J= 6.4 Hz), 1,3 and 2.9(4H,m), 4,0-4,2(4H, m), 6,33(1H, d, J= 8 Hz), 6,46(1H, d,J= 8 Hz), 6.87 in(1H, t,J= 8 Hz), 7,1-7,5(10H,m).

FAB M.-C. m/z: 482 (M++1)

Example 38

The solution of sodium salt (0.2 g) (2R)-[5-(carboxymethoxy)-2 - hydroxy-1,2,3,4-tetrahydro-2-naphthyl] methyl-N, N-diphenylcarbamate in a mixture of water and ethyl acetate was washed with 1N HCl solution and brine. The drained solvent is removed in vacuo, and the residue recrystallized from ethyl ether, receive (2R)-[5-(carboxymethoxy)-2-hydroxy-1,2,3,4-tetrahydro-2-naphthyl]methyl-N,N-diphenylcarbamate (150 mg).

NMR (CDCl3, ): 1,6-2,0(2H,m), 2,60 to 3.0(4H,m), is 4.15(2H,s), with 4.64(2H,s), is 6.54(1H, d, J= 8 Hz), 6,69(1H, d, J= 8 Hz), 7,07(1H, t, J= 8 Hz), 7,1-7,5(10H,m).

The powder

The compound of example 38 - 0,2%

Lactose - 99,2%

The stearate polyoxyl 40 - 0,1%

Hydroxypropylcellulose - 0,5%

These components are mixed, ground and dosed into powders by known methods.

The composition tablets

The compound of example 38 - 0.2 mg

Lactose - 95,2 mg

Sodium carboxymethylcellulose - 2.2 mg

Hydroxypropylcellulose - 0.7 mg

The stearate polyoxyl 40 - 0.7 mg

Magnesium stearate 1.0 mg

Vicepresidente the claimed compounds.

The compound of example 38 when tested for toxicity on rats with oral administration (30 mg/kg / day, 13 weeks) showed no toxicity.

Accordingly, the claimed compounds can be classified as compounds with low toxicity.

1. Derivatives of naphthalene General formula I

< / BR>
where R1represents carboxyl or protected carboxyl group;

R2represents hydrogen, hydroxyl or protected hydroxyl group;

R3represents hydrogen, hydroxyl group, protected hydroxyl group, lower alkyl or halogen;

R4represents hydrogen or halogen;

AND1represents the lowest alkylen;

AND2is a bond or lower alkylene;

-R5represents a

< / BR>
where R6represents a mono (or di - or tri-)phenyl-(lower)alkyl;

Z represents N or CH,

or

where-A3represents a

< / BR>
where R9represents hydrogen or lower alkyl;

Q represents N or CH;

R7represents phenyl;

R8represents phenyl;

presceiption carboxyl group, AND1is a (C1- C3-alkylen, AND2represents a bond or (C1- C3-alkylene, and R5represents a

< / BR>
where R6represents a diphenyl mono(lower) alkyl;

Z represents N or CH, or

< / BR>
where-A3represents a

< / BR>
< / BR>
where R9represents hydrogen or lower alkyl;

Q represents N or CH;

R7represents phenyl;

R8represents phenyl.

3. Connection on p. 2, in which R1represents a carboxyl group or a lower alkoxycarbonyl, R2represents hydrogen, a hydroxyl group, or alkoxygroup, R3represents hydrogen, a hydroxyl group, alloctype, lower alkyl or halogen, R4represents hydrogen or halogen, AND1represents methylene, AND2represents a bond, methylene or ethylene, and R5represents a

< / BR>
where R6is diphenylmethyl;

Z represents N or CH,

or

< / BR>
where-A3represents a

< / BR>
< / BR>
where R9represents hydrogen or lower and is a phenyl.

4. Connection on p. 3, representing a compound of formula

< / BR>
where R1represents a carboxyl group or a lower alkoxycarbonyl;

R2represents a hydrogen or hydroxyl group;

R3represents hydrogen, hydroxyl group, lower alkyl or halogen;

R4represents hydrogen or halogen;

AND1represents methylene;

AND2represents methylene or ethylene;

-R5represents a

< / BR>
or

< / BR>
5. Connection on p. 4, selected from the group which consists of (1) sodium salt of (2R)-[5-(carboxymethoxy)-2-hydroxy-1,2,3,4-tetrahydro-2-naphthyl] methyl-N,N-diphenylcarbamate, (2) sodium salt of (TRANS)-[5-(carboxymethoxy)-2-hydroxy-1,2,3,4-tetrahydro-1-naphthyl] ethyl-N, N-diphenylcarbamate and (3) (S)-2-[(1,2,3,4-tetrahydro-5-carboxymethoxy-2-naphthyl)methyl] -6-diphenylmethyl-3-(2H)-pyridazinone.

6. The pharmaceutical composition containing the active ingredient in a mixture with pharmaceutically acceptable carriers, wherein as the active ingredient it contains a connection on p. 1 or its pharmaceutically acceptable salt.

Priority points and features:

10.03.94 under item 1, where the p. 1, where in the General formula I is other specified values.

 

Same patents:

The invention relates to a method for producing derivatives of 2-aryloxy-4-chloropyridine F.-ly (I), where R1- (C1- C4)alkyl, R2is methyl or ethyl, R3, R4and R5- (C1- C4)alkyl or (C1- C4)alkoxy, or their pharmaceutically acceptable salts by the interaction of the compounds f-crystals (II) with a phenol F.-ly (III), where R1- R5have the above meanings, in the presence of a base capable of deprotonation of compounds f-crystals (III), and in the presence of a metal halide and pyridine followed by, if necessary, the compounds obtained into pharmaceutically acceptable salt

The invention relates to a method for producing derivatives of 2-aryloxy-4-chloropyridine F.-ly (I), where R1- (C1- C4)alkyl, R2is methyl or ethyl, R3, R4and R5- (C1- C4)alkyl or (C1- C4)alkoxy, or their pharmaceutically acceptable salts by the interaction of the compounds f-crystals (II) with a phenol F.-ly (III), where R1- R5have the above meanings, in the presence of a base capable of deprotonation of compounds f-crystals (III), and in the presence of a metal halide and pyridine followed by, if necessary, the compounds obtained into pharmaceutically acceptable salt

The invention relates to some 2,6-disubstituted pyridinium and 2,4-disubstituted the pyrimidines, the way they are received, to herbicide compositions on their basis and to a method of combating the growth of unwanted vegetation

The invention relates to derivatives of pyridine-2-or pyridine-2-thione F.-ly (I), where Y Is O, S or NH; R1-C20-alkyl, oxygen or sulfur, provided that R is different from chlorbenzyl, which has an antimicrobial activity

The invention relates to compounds of dehalogenation and to insecticides and acaricides containing compounds dehalogenation as the active ingredient

The invention relates to new chemical substances possessing valuable properties, in particular derived peritoneal General formula (I)

< / BR>
where

R1- carboxypropyl or alkoxycarbonyl with 1 - 8 carbon atoms in the CNS;

R2is unbranched or branched alkyl with 1 to 8 carbon atoms or the group-CH2-O-R5in which R5denotes unbranched or branched alkyl with 1 to 10 carbon atoms;

R3is hydrogen;

R4is hydrogen, halogen, alkyl with 1 to 6 carbon atoms, a hydroxy-group, alkoxygroup with 1 to 8 carbon atoms, trifluoromethyl or tripterocarpa, if R2means the group-CH2-O-R5in which R5have the above significance, or, if R2denotes unbranched or branched alkyl with 1 to 8 carbon atoms, R3and R4the same or different and mean hydrogen, halogen, cyano, hydroxy-group, alkoxygroup with 1 to 6 carbon atoms, unbranched or branched with 1 to 8 carbon atoms, trifluoromethyl, cryptometer, carboxamido, carboxypropyl, alkoxycarbonyl with 1 to 8 carbon atoms

The invention relates to new chemical compounds having valuable properties, particularly to derivatives of biphenylmethane General formula (I)

< / BR>
where R1unbranched alkyl with 1 to 10 carbon atoms, unsubstituted or substituted by cycloalkyl with 3 to 6 carbon atoms, hydroxyl or unbranched or branched alkoxygroup with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, or halogen,

A direct link, an oxygen atom or sulfur, or a group CH2or a group of the formula

-NR6,

where R6hydrogen or an unbranched or branched alkyl with 1 to 6 carbon atoms,

R2hydrogen, halogen, alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by hydroxyl, alkoxyl with 1 to 6 carbon atoms, benzyloxycarbonyl, formyl group CO2R7where R7is hydrogen, alkyl with 1 to 6 carbon atoms, unsubstituted or phenylselenenyl, alkali metal, or

R1and R2together form alkylenes chain with 1 to 5 carbon atoms, provided that A means direct link,

R3hydrogen, alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by hydroxyl, alkoxyl with 1 to 6 atoms уww.fips.ru/fullimg3/rupat2/19976/013.dwl/2100350-7t.gif" ALIGN="ABSMIDDLE">< / BR>
where R7have the above values,

R8and R9hydrogen, alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, benzyl,

R10hydrogen, alkyl with 1 to 6 carbon atoms or triphenylmethyl,

R4hydrogen, cyano, halogen, alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by hydroxyl, alkenyl with 1 to 6 carbon atoms, a group of CO2R7where R7have the above values,

R5hydrogen

D balance formula< / BR>
where R11group of formula-CO-R12where R12is hydrogen, alkyl with 1 to 6 carbon atoms,< / BR>
where R13hydrogen, alkaline metal, an unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted acyl, triphenylmethyl or groupwhere R14unsubstituted or phenylselenenyl alkyl with 1 to 6 carbon atoms

The invention relates to new visakapatnam the tritium substituted the carbamates of the formula R-NH-CO-OR1(I) where R is m-aminoacetophenone, when R1represents isopropyl, or R represents 3-(dimethylamino)-propyl, when R1is propyl

The invention relates to methods of producing alkyl-N-arylcarbamates, which use, for example, as starting materials for the production of isocyanates, pesticides, etc

The invention relates to the production of compounds which are useful as intermediates for obtaining spirotaenia derivatives of glutarimide, especially in connection with a registered brand name candoxatril and systematic name /S/-CIS-4-/1-[2-/5-intenrational/-3-/2-methoxyethoxy/propyl] -1 - cyclopentanecarboxylic/-1 cyclohexanecarbonyl acid

The invention relates to new 3-intellipedia formula I, where R1, R2, R3and R4denote H, A, OH, OA, F, Cl, Br, J, CN, CF3, COOH, CONH2, CONHA, CONA2or COOA, or R1and R2and R3and R4together denote methylenedioxy, R5Is H or OH, R6- H or R5and R6together denote a bond, And represents C1- C6-alkyl, n denotes a number from 2 to 6, and their physiologically acceptable salts

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis

The invention relates to medicine
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