Derivatives of 4-phenylmethyl-1h-indole in the form of enantiomers, racemates or diastereoisomers or in the form of an acid additive salts with antiarrhythmic or anticalcium activity

 

(57) Abstract:

Usage: in medicine as a drug having anti-arrhythmic and anticalcium activity. The inventive products-derivatives of 4-phenylmethyl-1H-indole f-crystals of l, where R and R1same or different: hydrogen, lower alkyl or cycloalkyl to 6 carbon atoms, or R and R1together with the nitrogen atom form a piperazinil, substituted lower alkyl, And-(CH2)nwhere n is an integer 2 or 3, or CH2CH(OH)CH2-, Z is hydrogen, lower alkyl or aminoalkyl-R2NH2where R2lowest alkylene, X and Y are hydrogen atoms, or one of them is hydrogen and the other WITH1-C4alkyl or hydroxy-group, a, b, c and d such that either b and C form a double bond, and d-hydrogens, or a and b form oxoprop, C and d-hydrogens. Reagent 1: compound f-ly ll. Reagent 2: compound f-lll ly, where M is lithium or magnesium Hal is halogen. Reaction conditions: in a medium of an organic solvent at 0-5oC. Structure of compounds f-l l-lll presented in the description. table 4.

The invention relates to indole derivative of General formula (l):

(I)

where R and R1such that:

or R and R1the same or different hydrogen atom, a straight or rorym they are connected, form piperazinil, substituted lower alkyl,

A -:

or chain /CH2/n, where n can take the values 2 or 3,

either chain

X and Y or each a hydrogen atom,

or one hydrogen atom and the other is a hydroxy radical or1-C4-alkyl,

or X and Y together form an oxo radical, a radical alkyltin with 1-4 carbon atoms or a radical N-OR5where R5a hydrogen atom or an alkyl radical with 1-4 carbon atoms, the substituents a, b, c, d such that:

either each hydrogen atom,

or a and b together form a function oxo and C and d are each a hydrogen atom;

Z -:

or a hydrogen atom,

or a moiety of the lower alkyl or the group aminoalkyl formula:

R2NH2,

where R2lowest alkylen;

moreover, these compounds of formula I can exist in all possible enantiomeric, racemic or diastereoisomeric types and additive salts with mineral or organic acids.

Additive salts with mineral or organic acids can be, for example, salts formed with hydrochloric acid, hydrogen bromide, nitric, sulfuric, phosphoric, acetic, formic, propionic, malonic, maleic, fumaric, succinic, tartaric, lithocholate, arenesulfonates such as benzene or paratoluenesulfonyl and arylcarboxylic acids such as benzoic acid.

Among the products of formula (I) can lead, in particular, the following products in the examples and especially derivatives of the formula /I/, such as defined above, the names of which are given below:

/2-/3-//1,1-dimethyl ethyl/amino/2-hydroxypropoxy/phenyl//1H-indol-4-yl/metano,

/2-/3-//1,1-dimethyl ethyl/amino/propoxy/phenyl//1H-indol-4-yl/metamon.

1-//1,1-dimethyl ethyl/amino/3-/2-//1H-indol-4-yl/methyl/phenoxy/2-propanol,

///2-/3-//1,1-dimethylethyl/amino/2-hydroxypropoxy/phenyl//1-methyl-1H-indol-4-yl/metano,

1,3-dihydro 4-/2-/3-//1,1-dimethylethyl/amino/2-hydroxypropoxy/benzoyl/2H-indol-2-it,

- //3-//1,1-dimethylethyl/amino/1-//2-/1H-indol-4-yl/ethynyl/phenoxy/2-propanol,

N-31,1-dimethylethyl/3-/2-/1-/1H-indol-4-yl/ethynyl/phenoxy/propanamine,

alpha/2-/3-//1,1-dimethylethyl/amino/2-hydroxypropoxy/phenyl/1H-indole-4-methanol,

as well as their additive salts with mineral or organic acids.

The method of obtaining new compounds of the formula I is that the product of formula (II):

(II)

where Z' IS:

any values specified above for the radical Z, iskluchenuya;

subjected to the condensation reaction with the ORGANOMETALLIC compound of the formula (III:

(III)

where the protective group of the hydroxy radical, M is a lithium atom or a magnesium l halogen atom, to obtain a product formula /IV/:

< / BR>
which is subjected to oxidation reaction to obtain a product formula /V/:

< / BR>
the hydroxy group of which is selectively released to obtain the product formula /VI/:

< / BR>
that or subjected to a reduction reaction of a function oxo to obtain the product formula /VII/:

(VII)

or process ORGANOMETALLIC reagent, and then dehydrated to obtain a product formula /VIII/:

(VIII)

where YAthe radical alkyliden with 1-4 carbon atoms, which is optionally subjected to hydrogenation to obtain the product formula /VIII'/:

(VIII')

YBthe alkyl radical with 1-4 carbon atoms, or make the product formula /VI/ in the corresponding oxime of formula IX/:

(IX)

where R5has the above value,

then the products of formula /VI/, /V/, /VIII/, /VIII'/ or /IX/ is subjected to the condensation reaction at the hydroxyl group,

either the product formula /X/:

(X)

to obtain the product formula /XI/

(XI)

where X' and Y' is a hydrogen atom was iligal alkyl with 1-4 carbon atoms,

either the product formula /XII/:

Hal-A'-Hal (XII)

where a' /CH2/n, to obtain the product formula /XIII/:

(XIII)

where a', Z', X' and Y' are above this value and subjected to the products of formula /XI/, or /XIII/ additive reaction with the amine of the formula /XIV/

NH /R//R1/ (XIV)

where R and R1have given above is, to obtain the product formula /XV/:

(XV)

which emit or optionally subjected to one of the following reactions in any order:

and/ removing the protective groups, which are at Z' to obtain Z,

b/ restore functions oxo formed by X' and Y', to the functions of the spirit,

in/ halogenoalkane in the position beta to the nitrogen atom on adere of the pyrrole moiety of the indole, followed by hydrolysis in an acidic medium to obtain products of formula /l/, where a and b form a function oxo,

e/ bisect racemic products by classical methods for obtaining optically active ingredients and optionally converted into a salt products formulas /l/ to obtain salt.

In the product of formula (II), Z' may represent a protective group of a nitrogen atom, obtained by the introduction of halide in the presence of alkali: in this case, it is preferable that the protective group is a radical Toil /4-meter and vodoodonate tetrabutylammonium in the presence of benzene at room temperature for about 1 hour and 30 minutes

In the product formula /III/, which can be organolithium compound, the radical hydroxy protected group may be a group of alkyloxy, such as methoxy, benzyloxy or trimethylsilyloxy.

A halogen atom, which is represented l may be a chlorine atom or bromine.

The reaction of the condensation product of the formula (II) or a derivative of indole-4-carboxaldehyde with the ORGANOMETALLIC compound of the formula (III, is carried out, for example, in a solvent, which may be THF /tetrahydrofuran/ at the temperature at 0-5oC for 1 h

Alcohol formula /IV/ is subjected to oxidation reaction, for example, in Harrogate pyridinium or preferably pyridinium dichromate in an inert solvent, such as halogeno or POLYHALOGENATED and preferably methylene chloride /dichloromethane/ for about 20 h with compact temperature.

A protected hydroxy group of the product formula /V/ may be released in a selective manner, to keep the protective group, as defined above, the removal of the protective group, to obtain the product formula /VI/ for example, in the presence of Lewis acid: which can be tribromide boron or dimethylsulfide boron in dichloromethane pocolo 180oC.

The product formula /VI/ may be subjected to a reduction reaction of a function oxo in order to obtain the product formula /VII/, for example, using lithium in liquid ammonia or preferably with hydrazine hydrate in diethylene glycol in the presence of caustic coli at a temperature of about 130oC for about 1 h 30 min

To obtain the product formula /VIII/ expose the product formula /VI/ action ORGANOMETALLIC reagent, such as a halide Metalmania in the environment of an organic solvent, for example when working with reflux of the solvent, and then dehydrated, for example, heating the reaction medium at 50oAnd podkisst.

The product formula /VIII'/ can be obtained by catalytic hydrogenation in the presence of palladium product formula /VIII/.

The product formula /VI/ can be converted into the oxime of formula IX/ classic ways, by condensation with hydroxylamine or a derivative of this product formula H2N-OR5.

The products of formula /VI/, /V/, /VIII/, /VIII'/ or /XI/ can be subjected to reaction joining the group hydroxyphenol using a halogenated derivative of the formula /X/ or /XII/, where the atom or atoms of halogen can achlorhydric in the presence of alkaline agents, such as caustic soda, caustic potash, sodium carbonate or preferably potassium carbonate with reflux organic solvent, such as acetone or dialkylated, for example, methyl ethyl ketone or methyl isobutyl ketone, approximately 24 h to obtain the products of formula /XI/, or a substitution reaction using dehalogenating derived formula /XII/, such as 1-bromo-3-chloropropane with reflux polar solvent, which may be an alcohol, such as ethanol derived oxo, such as acetone or DMF /dimethylformamide in the presence of alkali, such as sodium carbonate or potassium hydroxide, to obtain the product formula /XIII/.

Attaching an amine of the formula /XIV/, such as, for example, tributyl amine, the compound of the formula /XI/, or /XIII/ is reflux for about 2 h polar solvent, for example alcohol, such as ethanol or DMF) in the presence or absence of a base, such as sodium carbonate or potassium.

The resulting products of formula /XV/ form part of the compounds of the formula /I/. These products formula /XV/ represent formula (I), when Z' represents a protective group, or does not carry a protective group. These products are optionally subjected to one or more follow the tis reaction saponification using, for example, sodium cyanide in the presence of DMSO/ dimethyl sulfoxide at a temperature of about 100oWith or preferably an alcoholic solution of caustic potash;

b/ restoration of the carbonyl group to an alcohol, for example, using alkaline hydroborate, for example, tetrahydroborate potassium or preferably sodium, in an alcoholic medium such as methanol or preferably butanol, reflux or with aluminum hydride and lithium in THF or ether;

in/ halogenoalkane in the position beta to the nitrogen atom on the nucleus of the pyrrole moiety of the indole in the classical way, followed by hydrolysis in an acidic medium to obtain the products of formula (I), where a and b form a function oxo, halogenoalkane can be carried out in N-haloacrylates, such as N-chlorosuccinimide /NCHS/ or N-bromosuccinimide in an organic solvent, such as dioxane or acetic acid, and the hydrolysis may be effected in aqueous hydrochloric and phosphoric acids;

g/ splitting of racemic products by classical methods for obtaining optically active products and turning into salt, if desired, the products of formula I to obtain the corresponding salt.

Among the ways of turning into salt, can be given, naprimer salt derivatives of the formula /I/, acting in approximately stoichiometric ratios, mineral or organic acid in this derived formula /I/. Salts can be obtained without providing the appropriate reason.

The products of formula (II), such as defined above, are known products or they can be obtained as described, in particular, in J. Org. Chem. /1980/, 45, 3350 S. and following yet or are new and can be obtained by the addition of halide of the formula /XVI/:

Hal Z' /XVI/

where Z' is the preceding definition,

Hal preferably an iodine atom, a well-known product formula /XVIII/ or /IH/-indol-4-carboxaldehyde:

(XVII)

in the two-phase environment of the alkyl halide such as dichloromethane, and alkaline environment, for example, aqueous sodium hydroxide, and salts of Quaternary ammonium compounds, such as hydrogensulfate tetrabutylammonium. An example of such a preparation is given in the experimental part.

ORGANOMETALLIC products formula /III/, are known products and can be obtained, for example, on the basis of 1-bromo-4-methoxybenzoyl or 4-bromoanisole, in trade, to which are added atom of magnesium in the presence of THF.

Derivatives obtained by the method of the invention, obladayuschie properties and blocking properties slow calcination channels (protivokashlevoe property). Some have, in addition, anisopliae trombocitnim and betablockers properties.

These properties are illustrated in the experimental part.

These properties allow the use of derivatives of 4-phenylmethyl-1H-indole of the formula I and their pharmaceutically acceptable salts as medicaments in the treatment of heart failure and arrhythmias, Migranian pain and angina pectoris in all forms, also in the case of spastic and unstable angina. Drugs according to the invention also apply in the case of antithrombotic treatment.

The usual dose, changing depending on the use of the derivative, the patient and the disease may be, for example, 50 mg 1 g / day. Through the mouth, for men, a derivative of example 4 can be entered on the day of 300-600 mg, for example, in the case of stoppage of the heart, i.e., about 5-10 mg per kg of body weight.

The compounds of formula I, as well as their additive salts with pharmaceutically acceptable mineral or organic acids may be used to prepare pharmaceutical compositions containing as an active start these compounds and salts.

As medicines derivatives corresponding to the formula /I/, and their additive salt SEMA digestive tract or parenteral way.

For example, these pharmaceutical compositions can be liquid or solid and is available in the forms used in medicine, for example, in the form of tablets, pills, gelatin capsules, granules, suppositories, preparations for injection. One or more active principles can be put into the excipients usually used in these pharmaceutical compositions, such as tal, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous media, animal or vegetable fats, paraffin derivatives, glycols, various wetting, dispersant emulsifiers, preservatives.

The following examples illustrate the invention but do not restrict it.

Example 1. The neutral fumarate[4-[3-[(1,1-dimethylethyl)amino]propoxy] phenyl]-(1H-indol-4-yl)-methanone.

Stage A: 1-[(4-were)sulfenyl)]sulfonyl 1H-indol-4-carboxaldehyde.

To a suspension of 20 g of 4-carboxaldehyde 600 cm3benzene was added to 150 cm350%-aqueous sodium hydroxide solution, and 4.75 g of hydrogensulfate tetrabutylammonium and 30,24 g chloride paratoluenesulfonyl. Stirred for 1 h 30 min at room temperature. Decanted, extracted with benzene, washed with water, dried and evaporated to dryness under reduced on the tour and sucked off. Get 23,96 g of the target product. So pl. 144-146oC.

The product is used in this form in the next stage.

The IR spectrum /CHCl3/

The absence of NH

C=0 aldehyde 1691 cm-1< / BR>
C-H aldehyde 2740 cm-1< / BR>
Stage B: alpha-(4-methoxyphenyl)-1-[(4-were)sulfonyl]-1H-indole-4-methanol.

To 226 cm3solution magyarkanizsa connections 4-bromoanisole in tetrahydrofuran, the title 1,77 M/L, is slowly added at 0/5oWith a solution of 60 g of the product obtained in the previous phase, 600 cm3tetrahydrofuran (THF). Stirred for 1 h at 0/5oC, add 250 cm3a saturated solution of ammonium chloride, maintaining the temperature at 5oC, extracted with methylene chloride and brought to dryness under reduced pressure. Obtain 114 g of product, which is thickened in 150 cm3isopropyl ether and collected to 78.2 g of the target product, So pl. 90oC.

An analytical sample was obtained paracrystalline 1 g of the product obtained above from 10 cm3isopropanol and got 0,93 g of the product. So pl. 90oC.

The IR spectrum

The absence of C=0

HE at 3601 cm-1< / BR>
C=C aromatic compounds: 1612, 1599, 1586, 1528, 1511, 1495 cm-1< / BR>
One hundred of the stage B of alcohol in 1500 cm3chloride methylene added 15.6 g of siliporite NK 30 and 105,4 g of pyridinium dichromate. Stirred at room temperature for 20 h, filtered and concentrated to dryness under reduced pressure. The remainder chromatographic on silicon dioxide /eluant methylene chloride/ and get to 71.9 g of the target product, which is used in this form in the next stage. So pl. 135oC.

The IR spectrum

C=0 1646 cm-1< / BR>
C=C and aromatic connection: 1600, 1573, 1510, 1495 cm-1.

Stage G: (1H-indol-4-yl)-(4-hydroxyphenyl)-methanon.

Heated 16 h at 140oWith the solution containing 56,1 g obtained at the previous stage of the product, 66,16 g DANIDA sodium and 370 cm3dimethyl sulfoxide. Allow the temperature to drop to room temperature and add 1500 cm32-n solution of hydrochloric acid, extracted with ethyl ether and concentrated to dryness under reduced pressure. The remainder chromatographic /70,4 g/ silicon dioxide /eluant: methylene chloride ethyl ester of acetic acid /85-15//. Get to 20.1 g of the target product. So pl. 177oC. This product is used in this form in the next stage.

After chromatography on silica obtained 5.5 g of the above product /eluant ethyl epirot of 3.96 g of pure product. So pl. 177oC.

Analysis for C15H11NO2,

Calculated: 75,94 N 4,67 N 5,9

Found: C 75,7 H 4,6 N 5,8

Stage D: [4-(3-chloropropoxy)phenyl]-(1H-indol-4-yl)-methanon.

Stirred with reflux 4 h 30 min the mixture to 5.93 g obtained at the previous stage of the product 6,91 g of potassium carbonate, 150 cm3acetone and 9,84 g of 1-bromo-3-chloropropane. Allow the temperature to drop to room temperature, filtered, washed with acetone and concentrated to dryness under reduced pressure. The remainder chromatographic /14.2 g/ silicon dioxide /eluant: methylene chloride/ and get the 7.8 g of the target product, which is used in this form in the next stage. So pl. 86oC.

The IR spectrum

No, HE

NH indole 3479 cm-1< / BR>
1640 cm-1aromatic connection: 1601, 1575, 1509 cm-1.

Stage E: [4-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl]-(1H-indol-4-yl)methanon.

48 h at 140oWith heated in the autoclave a mixture of 7.75 g obtained at the previous stage of the product 6,83 g of potassium carbonate, 25,8 cm3tertbutylamine and 150 cm3of ethanol. Filtered, brought to dryness under reduced pressure and chromatographic balance /11,7 g/ silicon dioxide /eluant: ethyl ester of acetic acid is yl)amino]propoxy] phenyl](1H-indol-4-yl)methanone.

the 5.45 g of the product obtained above are dissolved in 60 cm3ethanol, filter the solution, and then add a solution of 1.8 g of fumaric acid in 40 cm3of ethanol. Ledent, suck 4,24 g of crystalline product, which is purified by recrystallization in hot and cold 600 cm3ethanol, filtered, concentrated to half volume, ledent, sucked off, rinsed with ether, dried at 80oC under reduced pressure and get 3,62 g of pure product. So pl. 210oC.

Analysis 2/S22H26N2O2/C4H4O4,

Calculated: C 70,56 N 6,91 N 6,86

Found: C 70,50 H 6,90 N 6,90

Example 2. The neutral fumarate[4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]phenyl](1H-indol-4-yl)methanone.

Stage A: (1H-indol-4-yl)[4-[(2-oxiranyl)methoxy]phenyl]metano.

3 h with reflusso stirred mixture of 2.37 g of the product obtained in stage G of example 1, with 2.76 g of potassium carbonate, 1,18 cm3of epichlorohydrin and 40 cm3of acetone. Then add 1,18 cm3of epichlorohydrin and stirred with reflux for another 5 hours Then add 1,18 cm3of epichlorohydrin and stirred with reflux. After reflux for 24 h, filtered and brought to dryness under intelligent is /1-1// and get 2,82 the target product. So pl. 96oC.

The IR spectrum

NH indole 3480 cm-1< / BR>
Ketone 1640 cm-1< / BR>
Aromatic compounds: 1600, 1576, 1509, 1497 cm-1< / BR>
Stage B: [4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]phenyl](1H-indol-4-yl)methanon.

Reflux is stirred for 2 h, the solution 4,65 g obtained at the previous stage of the epoxide, 100 cm3ethanol and 9,94 cm3tertbutylamine. Distilled to dryness and chromatographic balance /6,83 g/ silicon dioxide /eluant: ethyl ester of acetic acid triethylamine /9-1// get 4.77 g of the target product.

Stage b: neutral fumarate[4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]phenyl](1H-indol-4-yl)methanone.

Act as in stage G of example 1, but from 4.6 g obtained above product and of 1.46 g of fumaric acid. Obtain 3.4 g of the target product. So pl. 210oC.

Analysis 2/S22H26N2O3/ C4H4O4,

Calculated: FROM 67.9 N 6,65 N 6,6

Found: C, 67.2 per H 6,6 6,2 N

Example 3. Benzoate[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl](1H-indol-4-yl)methanone.

Stage A: 4-[hydroxy(2-methoxyphenyl)methyl]1-[(4-were)sulfonyl] 1H-indole.

Act as in stage B of example 1, but based on 80 g PR is monisola in tetrahydrofuran, title 2.28 M/L. Collected 109 g of the target product used in this form in the next stage.

The IR spectrum

No

HE at 3600 cm-1< / BR>
Aromatic compounds: 1600, 1589, 1529, 1491, 1484 cm-1< / BR>
SO21773, 1178 cm-1< / BR>
Stage B: 4-(2-methoxybenzoyl) 1-[(4-were)sulfonyl]1H-indole.

Act as on stage In example 1, but from 108,9 g, obtained at the stage And alcohol 150,8 g of pyridinium dichromate. Get 101,4 g of the target product used in this form in the next stage. So pl. 154oC

The IR spectrum

No, HE

1657 cm-1< / BR>
C=C and aromatic compounds: 1599, 1580, 1521, 1488 cm-1< / BR>
Stage b: 4-(2-hydroxybenzoyl) 1-[(4-were)sulfonyl]1H-indole.

Heated 4 h at 180oWith a mixture of 85 g obtained at the previous stage of the product and 600 g of pyridine hydrochloride. Cooled to 80oWith and add 700 cm3a saturated solution of sodium carbonate, extracted with ethyl ether, acetic acid, washed twice with 300 cm3n-th solution of hydrochloric acid and then water, dried and evaporated to dryness under reduced pressure. The remainder chromatographic /100,3 g/ silicon dioxide /eluant: methylene chloride hexane /8LASS="ptx2">

The IR spectrum

The total absorption type HE chelate

1626 cm-1< / BR>
C=C + aromatic compounds: 1606, 1594, 1583, 1524, 1485 cm-1< / BR>
Stage G: (2-hydroxyphenyl)(1H-indol-4-yl)methanon.

Reflux 1 h, stirred solution 84,2 g obtained at the previous stage of the product and 850 cm310% ethanol solution of sodium hydroxide. Distilled ethanol and absorb the residue of a saturated aqueous solution of sodium chloride; extracted with ethyl ether, acetic acid, washed with water, dried and evaporated to dryness. Balance /63,8 g/ chromatografic on silicon dioxide and gathering of 49.6 g of product, which is thickened in 150 cm3ethyl ether. Gain of 40.9 g of the target product. So pl. 165oC.

The IR spectrum

NH indole 3479 cm-1< / BR>
The total absorption type HE chelate

1626 cm-1< / BR>
aromatic compounds: 1613, 1598, 1575, 1503, 1425 cm-1< / BR>
Stage D: [2-[3-chloropropoxy)phenyl](1H-indol-4-yl)methanon.

Act as in stage D of example 1, but according to 10.9 g of the product obtained in the previous phase, using 18,17 cm31-bromo-3-chloropropane.

Chromatographic on silicon dioxide /eluant: chloride metalang.exe /75-25// and get to 14.4 g of the target product to the R>
NH indole 3479 cm-1< / BR>
aromatic compounds: 1609, 1599, 1581, 1571, 1489 cm-1< / BR>
Stage E: [2-[3-[(1,1-dimethylethyl)amino] propoxy]phenyl](1H-indol-4-yl)methanon.

Act as in stage E of example 1, but on the basis of 14.3 g of the product obtained in the previous phase. Get of 12.12 g of the target product. So pl. 130oC.

The IR spectrum

NH indole 3479 cm-1< / BR>
1649 cm-1< / BR>
aromatic compounds and conjugated: 1609, 1599, 1581, 1572, 1488 cm-1< / BR>
Stage G: benzoate[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl](1H-indol-4-yl)methanone.

Act as in stage G of example 1, but from 3.0 g obtained at the previous stage of the product and use of 1.05 g of benzoic acid. Get of 3.42 g of product, which is recrystallized in isopropanol. So pl. 162oC. Get 2,73 g of pure desired product. So pl. 162oC.

Analysis for C22H26N2O2WITH7H6O2,

Calculated: 73,71 N 6,82 N 5,93

Found: C 73,7 H 6,9 N 5,9

Example 4. The neutral fumarate[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl](1H-indol-4-yl)methanone.

Stage A: (1H-indol-4-yl)[2-(2-oxiranyl)methoxy]phenyl]metano.

Act as in stage a of example 2 IUT 12.3 g of the target product, used in this form in the next stage.

The IR spectrum

NH indole 3479 cm-1< / BR>
1649 cm-1< / BR>
aromatic compounds: 1609, 1600, 1581, 1571 cm-1< / BR>
Stage B: 2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl](1H-indol-4-yl)methanon.

Act as in stage B of example 2, on the basis of 12.3 g obtained at the previous stage of the product. Get 12,45 g of the target product (I.e pl. 130oC), which is used in this form in the next stage.

Stage b: neutral fumarate[2-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]phenyl](1H-indol-4-yl)methanon.

Act as in stage G of example 1, from 3.0 g product obtained above and 1.19 g of fumaric acid, acting in ethanol. Gain of 2.05 g of the desired product. So pl. 245oC.

Analysis for C22H26N2O3/2C4H4O4,

Calculated: C 67,91 N 6,65 N 6,6

Found: C 67,8 H 6,5 6,4 N

Example 5. Benzoate 1-[(1,1-dimethylethyl)amino]3-[2-[(1H-indol-4-yl)methyl] phenoxy]-2-propanol.

Stage A: 2-[(1H-indol-4-yl)methyl]phenol.

At 140oWith stirred for 30 min the mixture 22,74 g of the product obtained in stage G of example 3 with 49,4 cm3monochlorohydrin hydrazine, 96 cmoC. Allow to cool to room temperature and poured into 300 cm3saturated aqueous solution of sodium chloride, extracted with ethyl ether, acetic acid and evaporated to dryness under reduced pressure. The remainder chromatographic on silicon dioxide /eluant: methylene chloride/ get a 20.55 g of the target product, So pl. 139oC, which is used in this form in the next stage.

The IR spectrum

NH indole 3480 cm-1< / BR>
HE + assosiated 3598 cm-1< / BR>
bands of aromatic compounds of the type: 1617, 1585, 1489 cm-1< / BR>
2 alkylphenol

other aromatic connection: 1501 cm-1< / BR>
Stage B: 4-[[2-[(2-oxiranyl)methoxy]phenyl]methyl]1H-indole.

Act as in stage a of example 2, on the basis of 10.0 g product obtained above, using 3 times 17,56 cm3of epichlorohydrin. Get 12.5 g of the target product (I.e pl. 78oC), which is used in this form in the next stage.

The IR spectrum

No HE C-NH - 3482 cm-1< / BR>
aromatic compounds: 1611, 1600, 1587, 1492 cm-1< / BR>
Stage b: 1-[(1,1-dimethylethyl)amino]3-[2-[(1H-indol-4-yl)methyl]phenoxy] -2-propanol.

Act as in stage B of example 2, on the basis of 13,06 g obtained above products[(1,1-dimethylethyl)amino]-3-[2-[(1H-indol-4-yl)methyl] phenoxy]-2-propanol.

Act as in stage G of example 3, on the basis of 16,3 product obtained above, using the 5.65 g of benzoic acid. Get 8,29 g of the target product. So pl. 195oWith /ethanol/.

Analysis for C22H28N2O2C7O2H6.

Calculated: 73, 39 N 7, 22 N 5,9

Found: C 73,0 H 7,3 N 5,8

Example 6. Benzoate N-(1,1-dimethylethyl)-3-[2-[1H-indol-4-yl-methyl]phenoxy] propanamine.

STAGE AND: 4-[[2-(3-chloropropoxy)phenyl]methyl]1H-indole.

Act as in stage D of example 1, on the basis of 0.8 g of the product obtained in stage a of example 5. After chromatography on silica /eluant: methylene chloride hexane /1-1//, obtain 10.8 g of the target product (I.e pl. 75oC), which is used in this form in the next stage.

The IR spectrum

No HE-NH-type indole 3483 cm-1< / BR>
C=C and aromatic compounds: 1612, 1600, 1588, 1492 cm-1< / BR>
Stage B: N-(1,1-dimethylethyl)-3-[2-[(1H-indol-4-yl)methyl]phenoxy]propanamine.

Act as in stage E of example 1, based on 10,55 g of product obtained above. Get 8.65 g of the target product (I.e pl. 96oC), which is used in this form in the next stage.

Stage: benzoate N-(1,1-dimethylethyl)-3-[(1H-indol the e product using 2,95 g of benzoic acid. Get 7,42 g of the target product (I.e pl. 183oC), after recrystallization in ethanol.

Analysis for C22H28N2O, C7H6O2,

Calculated: 75,95 H 7,47 N 6,11

Found: C 76,1 H 7,5 N 5,8

Example 7. Benzoate alpha-[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl] 1H-indole-4-methanol.

Stage A: alpha-[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl]1H-indole-4-methanol.

Reflux is stirred for 1 hour a mixture of 5.25 g of the product obtained in stage E of example 3, 70 cm3normal butanol and 1.7 g of hydrobomide sodium. Cool and add 200 cm3a saturated solution of sodium carbonate, extracted with a mixture of ethyl ester of acetic acid, tetrahydrofuran and brought to dryness under reduced pressure. Chromatographic on silicon dioxide /eluant: ethyl ester of acetic acid triethylamine /95-05/ receive 5.0 g of product. So pl. 205oC.

4.3 g of this product is recrystallized at 580 cm3acetonitrile. Get of 3.78 g of the target product. So pl. 205oC.

The IR spectrum

No

integrated absorption region NH/OH

C=C and aromatic compounds: 1602, 1590, 1496 cm-1< / BR>
Analysis for C22and-[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl] 1H-indole-4-methanol.

To the mixture, heated to 70oWith, 2.15 g obtained in stage a product and 400 cm3ethyl ester of acetic acid, was added a solution of 0,745 g of benzoic acid in 11 cm3ethyl ester of acetic acid, the resulting solution is filtered while hot, cooled and receive 2,62 g of the target product. So pl. 185oC.

Analysis for C22H28N2O2C7H6O2,

Calculated: 73,39 N 7,22 N 5,90

Found: C 73,1 H 7,3 N 5,8

Example 8. Benzoate alpha-[2[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl]1H-indole-4-methanol (Isomer A).

Stage A: alpha-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl] 1H-indole-4-methanol.

Act as in stage a of example 7, according to 6.9 g of the product obtained in stage B of example 4. After extraction with ethyl ether, acetic acid and concentration to dryness chromatografic the residue on silica /eluant: ethyl ester of acetic acid triethylamine /95-05// get 1,71 g of isomer a and 4.4 g of a mixture of isomers AB. The mixture chromatographic on silicon dioxide /eluant: ethyl ester of acetic acid triethylamine-methanol /80-15-5// and get all 3,29 g of isomer A (So pl. 205oC) and 2.51 g of isomer B, which again chromatographical alpha-[2-[3-[1,1-dimethylethyl)amino]2-hydroxypropoxy] phenyl]1H-indole-4-methanol (Isomer A).

3,29 g of isomer a, obtained in stage a will recrystallized 400 cm3acetonitrile and obtain 2.66 g of product. So pl. 205oC. 2.6 g of recrystallized isomer And dissolved in 300 cm3ethyl ester of acetic acid and add 0,86 g of benzoic acid in solution in 30 cm3ethyl ester of acetic acid, filtered, cooled in an ice bath for 12 h, and get sucked off 3 g of the target product. So pl. 191oC.

Analysis for C22H22N2O3C7H6O2,

Calculated: 71,00 N 6,98 N 5,71

Found: C 70,9 H 7,1 N 5,6

Example 9. Benzoate alpha-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl]1H-indole-4-methanol /Isomer/.

To a solution of 1.25 g of the isomer In /obtained in stage a of example 8/ 50 cm3ethyl ester of acetic acid was added a solution of 0.41 g of benzoic acid in 10 cm3ethyl ester of acetic acid. Obtain 1.1 g of the target product, which is recrystallized in 200 cm3acetonitrile. Obtain 0.95 g of the target product. So pl. 196oC.

Analysis for C22H28N2O3WITH7H62,

Calculated: 71,00 N 6,98 N 5,71

Found: C 70,9 H 7,1 N 5,9

Example 10. [2-[3-[(1,1-dimethylethyl)amino]2-gelecegin.

At room temperature, stirred for 4 h 34 g of indole 4-carboxaldehyde 800 cm3chloride methylene from 79.5 g hydrogensulfate tetrabutylammonium and 16,04 cm3of methyl iodide in 400 cm35 n solution of sodium hydroxide. Add 300 cm3chloride methylene, decanted, extracted with methylene chloride, washed the organic layer with a saturated aqueous solution of sodium chloride, dried, concentrated to dryness, chromatografic the residue on silica (eluant: methylene chloride) and get to 36.8 g of the target product. So pl. <40C.

Stage B: alpha /2-methoxyphenyl/-1-methyl-1H-indole/-4-methanol.

Act as in stage B of example 1, according to 36.8 g obtained at the stage And product, using 104 cm3magyarkanizsa solution of 2-bromoanisole in tetrahydrofuran, the title of 1.9 N. Extracted with ethyl ether, acetic acid, washed with salt water, heat, bring to a dry state, chromatografic the residue on silica /eluant: methylene chloride/ and get a 46.5 g of the target product. So pl. 95oC.

Stage b: (2-methoxyphenyl) (1-methyl-1H-indol-4-yl)methanon.

Act as in stage b of example 1, based on 43,7 g obtained in stage B JV is at the next stage.

Stage G: (2-hydroxyphenyl) (1-methyl-1H-indol-4-yl)methanon.

Act as on stage In example 3, but using as the source of 29.9 g obtained at the stage In the product, 300 g of the hydrochloride of pyridine and methylene chloride as eluant chromatography. Get to 17.2 g of the target product (I.e pl. 80o(C) used in this form in the next stage.

Stage D: (1-methyl-1H-indol-4-yl) [2-(2-oxiranylmethyl)phenyl]metano.

Act as in stage a of example 2, but using 3 g obtained in stage G of the product, 6.6 g of potassium carbonate and adding 5 times 4.7 cm3of epichlorohydrin. After 48 h of reflux, filtered, concentrated to dryness under reduced pressure and chromatographic residue as described in example 2. Obtain 3.7 g of the target product.

The IR spectrum

About: 1650 cm-1< / BR>
aromatic compounds: 1599, 1581, 1567, 1508, 1481 cm-1< / BR>
Stage E: // [2-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]phenyl] (1-methyl-1H-indol-4-yl)methanon and benzoate.

Stirred for 3 hours and 30 minutes with reflux a solution of 3.7 g obtained above epoxide, 80 cm3ethanol and 7.5 cm3tertbutylamine. Distilled to dryness and chromatographic the residue on silica (eluant: ethyl the obtained product is dissolved in 50 cm3ethanol, and then added a solution of 1.22 g of benzoic acid in 12 cm3of ethanol. Cooled in an ice bath for 12 h, sucked off, washed with ethanol, dried at 80oWith under reduced pressure, get of 4.05 g of the benzoate, which is recrystallized in ethanol. So pl. 166oC.

Analysis for C23H28N2O3C7H16O2,

Calculated: 71,69 N 6,82 N 5,57

Found: C 71,7 H 6,8 N 5,5

Example 11. // 1-[(1,1-dimethyl)amino] -3-[2-[(1-methyl-1H-indol-4-yl)methyl]phenoxy]2-propanol and its benzoate.

Stage A: 2-[(1-methyl-1H-indol-4-yl)methyl]phenol.

Act as in stage a of example 5, but using 2.6 g of the product obtained in stage G of example 10, 5,33 cm3of hydrazine hydrate, 10 cm3diethylene glycol and 4 cm338%-aqueous sodium hydroxide solution and a mixture of ethyl ester of acetic acid hexane 5-5, as eluant chromatography. Obtain 2.5 g of the target product used in this form in the next stage.

Stage B: 1-methyl-4-[[2-oxiranylmethyl)phenyl]methyl]1H-indole.

Act as in stage a of example 2 on the basis of 2,45 g obtained in the previous stage of the product using 3 times of 4.05 cm3of epichlorohydrin. After chromatography on dioxide nom in the next stage.

The IR spectrum

no, HE

aromatic compounds: 1601, 1587, 1514, 1494 cm-1< / BR>
Stage b: /$E+-/ 1-[(1,1-dimethyl)amino] -3-[2-[(1-methyl-1H-indol-4-yl)methyl]phenoxy]-2-propanol and its benzoate.

Act as in stage E of example 10, but using 2,95 g obtained in stage B epoxide, 65 cm3ethanol and 6.3 cm3tertbutylamine. Obtain 3.6 g of the desired product in the form of a Foundation. 3.80 g of the base obtained as described above, is dissolved in 70 cm3isopropanol and added to 1.33 g of benzoic acid in solution in 15 cm3isopropanol. Cooled with ice 12 h, sucked off, washed with isopropanol and then ether, and dried at 80oWith under reduced pressure and collect 2,61 g of the target product. So pl. 136oC.

Analysis for C23H30N2O2C7H6O2,

Calculated: 73,74 N 7,43 N 5,73

Found: C 73,6 H 7,4 N 5,7

Example 12. [2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl](1-methyl-1H-indol-4-yl)methanon.

Stage A: [2-(3-chloropropoxy)phenyl](1-methyl-1H-indol-4-yl)methanon.

Reflux is stirred for 24 h in a mixture of 8 g obtained at the previous stage of the product 8,80 g of potassium carbonate, 215 cm3acetone and 12,53 cm31-bromo-3-chloropropane. Give emeniem. The remainder chromatographic on silicon dioxide /eluant: methylene chloride hexane 7-3/ and get 10,4 target product (So pl. 60oC), which is used in this form in the next stage.

The IR spectrum

No, HE

C=O: 1649 cm-1< / BR>
conjugated system: 1599, 1582, 1568, 1508 cm-1< / BR>
aromatic compound

Stage B: [2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl](1-methyl-1H-indol-4-yl)methanon.

Heated in an autoclave at 150oC for 24 h the mixture 10.30 g obtained at the previous stage of the product 8,68 g of potassium carbonate, 13,13 cm3tertbutylamine and 180 cm3of ethanol. Filtered, brought to dryness under reduced pressure and chromatographic the residue on silica /eluant: ethyl ester of acetic acid triethylamine 95-05/. Get 11,06 g of the target product as the base. Then act on stage In example 11 using 3 g of the above base and 1 g of benzoic acid. Get 3,15 g of the benzoate. So pl. 172oC.

Analysis for C23H28N2O2WITH7H62,

Calculated: C 74,05 N? 7.04 baby mortality N 5,76

Found: C 74,0 H 7,0 N 5,8

Example 13. // alpha-[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl]1-methyl-1H-indole-4-methanol and its fuuma is

At room temperature, stirred for 5 h 0.4 g[2-[3-[(1,1-dimethylethyl)amino] propoxy] phenyl] (1H-indol-4-yl)methanone obtained in stage E of example 3, 8 cm3of methylene chloride, 0,07 cm3iodide of methyl, 4 cm35 n-th caustic soda and 0.39 g of hydrogensulfate tetrabutylammonium. Diluted with water, extracted with methylene chloride, washed the organic layer with salt water, dried and bringing that to dryness under reduced pressure. The remainder chromatographic on silicon dioxide /eluant: ethyl ester of acetic acid triethylamine 95-5/: obtain 0.4 g of the target product. So pl. 60oC.

Stage B: // alpha[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl]1-methyl-1H-indole-4-methanol and its fumarate.

Heated to reflux 1 h 3,30 g of the product prepared as on stage And in 33 cm3butanol, in the presence of 1.027 g of sodium borohydride. Cooled to room temperature, poured into 100 cm3saturated aqueous solution of sodium carbonate and extracted with ethyl ester of acetic acid. Concentrate to dryness under reduced pressure, chromatografic the residue on silica /eluant: ethyl ester of acetic acid - triethylamine 95-5/ and get totaling 3.04 g of the target product as the base. So Y, obtained, as indicated above, and 1.07 g of fumaric acid. Get 3,48 g target fumarata. So pl. 208oC.

Analysis for C23H30N2O2C4H4O4,

Calculated: 67,2 N 7,10 N 5,80

Found: C 67,5 H 7,2 N 5,8

Example 14. 1,3-dihydro-4-[2-[3-(1,1-dimethylethyl)amino]propoxymethyl] 2H-indol-2-he and his fumarate.

Stage And: [2-[3-[(1,1-dimethylethyl)amino] propoxy]phenyl](3-chloro 1H-indol-4-yl)methanon.

At room temperature, stirred for 2 h 6.3 g of [2-[3-(1,1-dimethylethyl)amino] propoxy] phenyl] (1H-indol-4-yl)methanone obtained in stage E of example 3, 50 cm3acetic acid in the presence of 2.64 g of N-chlorosuccinimide. The mixture is then poured into 300 cm3saturated aqueous solution of sodium carbonate, extracted with ethyl ether, acetic acid, washed the organic layer with salt water, dried and concentrated to dryness. After chromatography of the residue on silica /eluant: ethyl ester of acetic acid triethylamine 95-5/ receive 5,52 g of the target product used in this form in the next stage.

Stage B: 1,3-dihydro-4-[2-[3-(1,1-dimethylethyl)amino]propoxy]benzoyl] 2H-indol-2-he and his fumarate.

With reflux heated 1 h 30 min 5.50 g obtained Allow the temperature to drop to room, pour 170 cm3normal sodium hydroxide solution and extracted with ethyl ester of acetic acid. Washed organic layer is dried and concentrated to dryness. Obtain 5.7 g of crude product, which chromatographic on silicon dioxide /eluant: ethyl ester of acetic acid methanol triethylamine 8-1-1/. After thickening, isopropyl ether and drying under reduced pressure to obtain 3.80 g of the target product. So pl. 132oC. the Fumarate get as indicated in stage F of example 1, using 2.5 g of the base obtained above and 0.79 g of fumaric acid, acting in ethanol. After recrystallization obtain 1.51 g of the target fumarata. So pl. 258oC.

Analysis for C22H26N2O3WITH4H4O4,

Calculated: 67,91 N 6,65 N 6,60

Found: C 67,9 H 6,6 N 6,3

Example 15. 1,3-dihydro-4-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]benzoyl]2H-indol-2-he and his fumarate (neutral).

Heated 1 h with reflux solution containing 4 g of neutral fumarata obtained as indicated in stage b of example 4, 160 cm3ethanol and 1.57 g of N-chlorosuccinimide. Cooled to room temperature and add 50 cm3n-solution of caustic soda and 100 cm3water. Extras which are square-3.6 g of the intermediate product (chlorinated), to which is added 57,6 cm3ethanol and 113 cm3of hydrochloric acid. Stirred for 24 h at room temperature, and then 45 minutes with reflux. Allow to cool to room temperature, add 150 cm3normal sodium hydroxide solution, extracted with ethyl ether, acetic acid, dried, concentrated to dryness, chromatografic the residue on silica /eluant: ethyl ester of acetic acid metanarration 80-10-10). Obtain 2.37 g of the target product as the base. So pl. 158oC. Then act as in stage G of example 1 from 2,3 g of product obtained above and of 1.46 g of fumaric acid. Obtain 1.78 g of the target product. So pl. 236oC.

Example 16. [2-[2-[(1,1-dimethylethyl)amino] ethoxy] phenyl](1H-indol-4-yl)methanon and its fumarate.

Stage A: [2-(2-chloroethoxy)phenyl](1H-indol-4-yl)methanon.

At the 50oWith stirred 72 h 6 g of the product obtained as in stage G of example 3, 192 cm3toluene, 90 cm3acetonitrile, 2.16 g of hydrogensulfate tetrabutylammonium, 9,18 cm3tosilata 2-chloroethanol and 90 cm35 n solution of sodium hydroxide. Diluted with water, extracted with ethyl ether, acetic acid, washed organic layer is dried, concentrated to dryness PT of 5.39 g of the target product, used in this form in the next stage.

STAGE B: [2-[2-[(1,1-dimethylethyl)amino] ethoxy] phenyl] (1H-indol-4-yl)methanon and its fumarate.

Act as in stage E of example 1, based on 5,46 g of the chlorinated derivative, obtained as described above, of 5.03 g of potassium carbonate, to 7.61 cm3tertbutylamine 70 cm3of ethanol. Gain of 4.95 g of the target product as the base. So pl. 140oC. the Fumarate receive according to 4.73 g of the base and 1.63 g of fumaric acid, acting as a stage G of example 1. Get 3,34 g target fumarata, after recrystallization in ethanol. So pl. 180oC.

Analysis for C21H24N2O2THAT 1/24H4O4,

Calculated: 70,03 H 6,64 N 7,10

Found: C 70,3 H 6,7 N 7,1

Example 17. // [2-[2-hydroxy-3-[(1-methylethyl)amino] propoxy] phenyl] (1H-indol-4-yl)methanon and its fumarate.

Act as in stage B of example 2, but using 3.7 epoxide obtained in stage a of example 4 and of 6.45 cm3Isopropylamine 45 cm3of ethanol. Get 3,26 g of the target product as the base. Proceeding as in stage G of example 1, based on 3,19 g obtained above grounds and 1.05 g of fumaric acid, and gain of 1.62 g of the target fumarata. So pl. 193oC.


Found: C 67,4 H 6,6 6,7 N

Example 18. // [2-[3-[bis-(1-methylethyl)amino]2-hydroxypropoxy]phenyl] (1H-indol-4-yl)methanon and his chlorhydrate.

Within 4 h, heated to reflux 1 g of the epoxide obtained in stage a of example 4, 40 cm3ethanol and added 2.4 cm3Diisopropylamine. The solvent is distilled off under reduced pressure, cooled to 4oWith, thicken with ether and collected 880 mg of the target product as the base. So pl. 100oC. 2.1 g of base are dissolved in 100 cm3ethyl ester of acetic acid at room temperature, add 3 cm3the solution of the ethyl ester of acetic acid saturated with hydrochloric acid, cooled in an ice bath for 1 h, sucked off and dried under a reduced pressure of 2.25 g of the target hydrochloride. So pl. 210-212oC.

Analysis for C24H30N2O3, HCl,

Calculated: 66,89 N 7,25 CL 8,23 N 6,5

Found: C 66,6 H 7,4 Cl 8 N 6,2

Example 19. // [2-[2-hydroxy-3-(4-methyl-1-piperazinyl)propoxy]phenyl] (1H-indol-4-yl)methanon and its fumarate.

Act as in stage B of example 2, using 2.5 g of the epoxide obtained in stage a of example 4, and 4.73 cm3N-methylpiperazine. After chromatography on silica /eluant: chloroform-methanol-three is obtained above the base and 0.97 fumaric acid, receive, after recrystallization in ethanol, 3.25 g of the target fumarata. So pl. 186oC.

Analysis for C23H27N3O3, 1/2 C4H4O4,

Calculated: 66,5 N 6,47 N 9,31

Found: C 66,4 H 6,5 N 9,3

Example 20. // [2-[2-hydroxy-3-(propylamino)propoxy]phenyl](1H-indol-4-yl)methanon and its fumarate.

Act as in example 19 using 3 g of the epoxide obtained in stage a of example 4, and 5,22 cm3N-Propylamine. Obtain 2.4 g of the desired product in the form of a substrate that is subjected to interaction with 0,79 g of fumaric acid to obtain a rate of 1.67 g of the target fumarata. So pl. 175oC.

Analysis for C21H24N2O3, 1/2 C4H4O4,

Calculated: 67,3 N 6,38 N 6,82

Found: C, 67.2 per H 6,3 N 6,8

Example 21. // [2-[(3-cyclohexylamino)2 hydroxypropoxy]phenyl](1H-indol-4-yl)methanon.

Act as in example 19 using 3 g of the epoxide obtained in stage a of example 4, and 5.8 cm3cyclohexylamine. Receive 2 g of the target product in the form of a Foundation, which is recrystallized in acetonitrile. Obtain 1.6 g of the pure product. So pl. 136-138oC.

Analysis for C24H28N2O3,

Calculated: 73,44 N 7,19 N 7,14

N is orgeret.

Stage A: 2-[1-(1H-indol-4-yl)ethynyl]phenol.

Getting metalmilitia.

To 20 g of magnesium shavings in 70 cm3ether is slowly added 52 cm3under the conditions of 400 cm3the ether. Heated 1 h with reflux and get the target magyarkanizsa connection, the title of 1.48 M/L.

The condensation.

To 236 cm3solution magyarkanizsa compound, obtained above, at room temperature was added 20 g /2-hydroxyphenyl//1H-indol-4-yl/methanone, obtained as described in stage G of example 3 in solution in 400 cm3tetrahydrofuran (THF). Remove the ether, replace it with tetrahydrofuran, heated 1 h with reflux, cooled, destroy the excess magyarkanizsa compounds by the addition of saturated aqueous ammonium chloride, diluted with water and extracted with ethyl ester of acetic acid. Dried the organic layer, remove the solvents under reduced pressure at 50oWith and get to 21.9 g of crude product, which chromatographic on silicon dioxide /eluant: methylene chloride ethyl ester of acetic acid 98-2/ and obtain 17.8 g of the target product, which is crystallized in isopropyl ether. Receive 2 admission of 17.4 g of pure product. So pl. 117-118o3of epichlorohydrin. After 44 h with reflux, filtered, concentrated to dryness under reduced pressure at 50oAnd chromatographic the residue on silica /eluant: methylene chloride ethyl ester of acetic acid 98-2/ collect fractions, which rf 0.35 and after crystallization in isopropyl ether get to 7.35 g of the target product. So pl. 87-88oC.

Stage: // 3-[(1,1-dimethylethyl)amino] 1-[2-[1-(1H-indol-4-yl/ethynyl] phenoxy]2-propanol and its hydrochloride.

Act as in stage B of example 2, from 7 g obtained in stage B of product, 70 cm3ethanol and 35 cm3tertbutylamine. Gain of 7.7 g of the desired product in the form of a Foundation. So pl. 127-128oC.

IR spectrum: /CHCl3/

HE: 3535 cm-1C-NH: 3490 cm-1< / BR>
C=C + aromatic compound: 1620, 1600, 1580, 1490 cm-1< / BR>
When the room temperature is dissolved 3.7 g obtained above the base 200 cm3ethyl ester of acetic acid to form the hydrochloride by the addition of a solution of hydrochloric acid in ethyl ether acetic acid. After recrystallization in ethanol obtain 2.7 g of the target hydrochloride. So pl. 204-2,5oC.

Analysis for C23H1-dimethylethyl)amino]-1-[2-[1-(1H-indol-4-yl)ethyl] phenoxy]-2-propanol and its hydrochloride.

At the 50oWith, hydrogenizing 30 min 4.1 g of the base obtained as described in stage b of example 22 in 400 cm3ethanol, in the presence of 1.3 g of activated charcoal containing 10% of palladium. The catalyst is filtered off, the solvent is distilled at 50oWith under reduced pressure and obtain 4.6 g of crude product which is recrystallized in isopropyl ether. Gain of 3.3 g of the desired product in the form of a Foundation. So pl. 135-137oC.

The IR spectrum /CHCl3/

OH 3630 cm-1C-NH 3486 cm-1< / BR>
C=C + aromatic compound 1610, 1599, 1586, 1492 cm-< / BR>
3,3 g of the above base are dissolved in 400 cm3isopropyl ether to form the hydrochloride by addition of a saturated solution of hydrochloric acid in ethyl ether acetic acid. After recrystallization in acetonitrile obtain 2.6 g of the target hydrochloride. So pl. 208-209oC.

Analysis for C23H30N2O2, HCl,

Calculated: 68,56 N 7,75 Cl 8,80 N 6,95

Found: C 68,3 H 7,9 Cl 8,8 7,0 N

Example 24. N-(1,1-dimethylethyl)-3-[2-[1-(1H-indol-4-yl)ethynyl]phenoxy] propanamide and its hydrochloride.

Stage And: 4-[-1-[2-(3-chloropropoxy)phenyl]ethynyl]-1H-indole.

Act as indicated in stage D of example 1, KJV the Nata potassium and 11.5 cm31-chloro-3-bromopropane and heating with reflux for 20 hours After chromatography and crystallization in petroleum ether (So Kip. 40-70oC) get 7,05 g of the target product. So pl. 70-72oC.

Stage B: N-(1,1-dimethylethyl)-3-[1-(1H-indol-4-yl)ethynyl]phenoxy]propanamide and its hydrochloride.

Act as in stage E of example 1, by heating for 6 h at 120oWith 7 g obtained at the stage And product, 50 cm3tertbutylamine, 2.9 g of potassium carbonate in 50 cm3of ethanol. After chromatography and crystallization in isopropyl ether to obtain 7.4 g of the desired product in the form of a Foundation. So pl. 112oC.

The IR spectrum /liquid paraffin/

NH indole: 3630 cm-1< / BR>
C=C, C=N, and an aromatic compound 1615, 1597, 1578 cm-1< / BR>
Hydrochloride get as indicated in stage b of example 22 from 4.6 g obtained above reasons. Get at 3.35 g of the target hydrochloride. So pl. 238-240oC.

Analysis for C23H28N2O, Hcl,

Calculated: 71,76 N To 7.59 CL Of 9.21 N 7,28

Found: C 71,8 H 7,6 Cl 9,4 7,0 N

Example 25. // 0-methyloxime[2-[3-[(2,2-dimethylethyl)amino]-2-hydroxypropoxy]phenyl](1H-indol-4-yl)methanone and its hydrochloride.

Stage A: // 0-methyloxime(2-hydroxyphenyl)(1H-indol-4-yl)methanone.

With the Ref 3, 100 cm3methanol from 8.5 g of the hydrochloride of methylhydroxylamine, 4.8 g of sodium acetate in 40 cm3of distilled water. Remove methanol under reduced pressure, diluted with water and extracted with ethyl ester of acetic acid. Concentrate to dryness, chromatografic the residue on silica /eluant: methylene chloride ethyl ester of acetic acid 98-2/ and get on the one hand 4,08 g of isomer A (So pl. 228oC) /corresponding to the crystallized product in a mixture of chromatography, and the fraction of rf= 0.50 in/ and on the other hand, 900 mg of the isomer In /corresponding fraction rf=0.25 in).

Analysis for C16H12O2,

Calculated: 72,17 N 5,30 N 10,52

Found:

Isomer A: C 72,2 H 5,1 N 10,4

Isomer B: C 72,4 H 5,3 N 10,3

Stage B: 0-methyloxime[2-(2-oxiranylmethyl)phenyl] (1H-indol-4-yl)methanone.

Act as in stage a of example 2, using 3.57 g obtained at the stage And product, 7.5 g of potassium carbonate and adding 4 times 5.4 cm3of epichlorohydrin. After 96 h of heating under reflux was filtered and concentrated to dryness under reduced pressure and chromatographic the residue on silica /eluent: hexane ethyl ester acetic acid 7-3/. Obtain 2.7 g of the target product. So pl. 140oC.

With reflux heated 5 h 2.7 g obtained at the stage And product 270 cm3ethanol in the presence 4,42 cm3tertbutylamine. Cooled to room temperature, concentrated to dryness, chromatografic the residue on silica /eluant: chloroform methanol-triethylamine 90-5-5/. Receive 2 g of crude product, which is thickened in the air and collect 1,67 g of the target product as the base. So pl. 153 to 155oC.

The IR spectrum /CHCl3/

HE 3542 cm-1C-NH 3480 cm-1+< / BR>
C=N + aromatic compound 1610, 1600, 1589 cm-1< / BR>
Hydrochloride get as indicated in stage b of example 22, using 1.7 g obtained above reasons. After crystallization in isopropanol obtain 1.4 g of the target hydrochloride. So pl. 246-248oC.

Analysis for C23H29N3O3, HCl,

Calculated: C 63,95 N 7,00 Cl 8,21 N 9,73

Found: C 63,7 H 7,1 Cl 8,1 N 9,6

Example 26. There were prepared tablets corresponding to the formula:

the product of example 4 (100 mg

excipient sufficient for one complete tablets 150 mg

/detail excipient: lactose, starch, talc, magnesium stearate/.

Pharmacological research.

2/ anti-Arrhythmic effect in rats.

Introduced under the skin of the needle, so to record the electrocardiogram rats on signal branch DII.

Investigational products administered intravenously or by mouth.

In the case of the introduction of injection after 5 min in the case of insertion through the mouth after 1 h, produce perfusion jugular vein of rats with 10 micrograms /min at 0.2 ml of aconitine and note the time the first of ventricular ekstrasistola. The number perfoirmance Aconite is calculated and then expressed depending on the body weight of the animal.

The increase in percentage dose of Aconite required for actuation of ventricular ekstrasistola after treatment is calculated relative to the control animals.

The results are on table. 1 and show that the products of this application have great antiarrhythmic properties.

Note: the CR by mouth, IV intravenous.

To confirm the effectiveness of the proposed connection, the applicant has compared them with the connection from European application 0.213.984: benzoate 2-[3-[(1,1-dimethylethyl)-amino] -2-hydroxypropoxy] -N-(1H-indol-4-yl)-benzamide. (A) in the conditions of the test protiwaritmical the way the percentage protection was 33. This comparison indicates a significantly higher effectiveness of the proposed connections.

2/ Sample anticalcium activity in vitro.

Selected caudal artery of the rat.

Ring caudal artery of Wistar rats were hanged people in the solution of Krebs-bicarbonate /NaCl: 120,8 mm, KCl: 5,9 mm MgCl2: 1,2 mm, NaH2PO4: 1,2 mm NaHCO3: 15,5 mm, glucose: 12.6 mm/ without calcium in the presence of fentolamina 10-5M, which oxygenlive a gas mixture containing 5% CO2in oxygen and maintained at 37oC.

After 30 min of equilibrium drugs were reduced every 15 min using depolarizing solution /NaCl: 26,7 mm, KCl: 100 mm MgCl2: 1,2 mm, NaH2PO4: 1,2 mm NaHCO3: 15,5 mm glucose: 12.6 mm/ containing 2.5 mm l2.

When contractile reactions are reproducible, then add the studied product with increasing concentrations 15 min before each contraction.

The concentration that inhibits 50% of the contraction induced calcium chloride, calculated /CL50/.

The results are in the table. 2, establish that the products of this application have strong antigene in vitro in plasma, rich records /bbs/.

Measurement of lamellar clusters is conducted by the turbidimetric method of Born G. V. and Croos M. J. 1963, J. Physiol. 168 178. The blood of the rabbit is taken by 3.2% NA citrate cardiac puncture. Rich in platelets plasma is obtained by centrifugation and fitting number plates to 300 000 ml.

Congestion is caused by collagen /40 micrograms/ml PTB/ or PAF, acheter/ - 0.05 micromol/l bbs/.

The investigated molecules are placed for incubation at different concentrations in DBS 2 min to a means of accumulation.

The results are expressed in CL50(concentration, the inhibitory concentration at 50% relative to the control curve) (table. 3).

4/ Study of acute toxicity.

Were estimated lethal dose DLovarious of the compounds studied after insertion through the mouth of the mouse.

DLois called the maximum dose that does not cause mortality in 8 days.

The following results are obtained (table. 4).

Derivatives of 4-phenylmethyl-1H-indole of General formula

< / BR>
where R and R1the same or different, hydrogen, a normal or branched lower alkyl or cycloalkyl to 6 carbon atoms, or R and R1together with the nitrogen atom s>-

Z is hydrogen, lower alkyl or aminoalkyl R2NH2where R2lowest alkylen,

x and y are hydrogen atoms, or one of them is hydrogen and the other WITH1- C4alkyl or hydroxy-group, or x and y together form oxoprop, alkyliden with 1 to 4 carbon atoms or N-OR3where R3is hydrogen or C1WITH4alkyl,

a, b, c and d such that either b and c form a double bond, a and d - hydrogens, or a and b form oxoprop, c and d hydrogens,

in the form of enantiomers, racemates or diastereoisomers, or in the form of an acid additive salts with antiarrhythmic and anticalcium activity.

 

Same patents:

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to new imidazole derivative of General formula I

where R1-COOH or the group< / BR>
R2=H-C3H7or n-C4H9;

R3-Cl, CF3C2F5C6H5or COOH;

R4-COOH, CHO, or CH2HE, provided that

a) when R4-CH2OH, R3-C2F5and R2-n-C3H7,

b) when R3-COOH, R4also is COOH,

b) when R2-n-C3H7, R3-C2F5and R4-COOH, R1is the groupwhich inhibit the action of the hormone angiotensin and can be used in medicine

The invention relates to a new method of getting some 3-substituted indoles and to certain intermediates that are useful in this way

The invention relates to new biologically active compounds 2-pyrrolone, namely 4-acetyl-5-p-itfeel-1-carboxymethyl-3-hydroxy-2,5-dihydropyrrol-2-ONU formula

< / BR>
possessing analgesic activity, suggesting the possibility of its use in medicine as an anaesthetic

The invention relates to heteroalicyclic alkanoyl derivatives, which have a biocidal effect, and more particularly to aminoalcohols derived molecules containing heteroalicyclic ring system, to methods of their synthesis, their new intermediates, containing pharmaceutical compositions and to their use as biocidal agents, in particular anticancer agents

The invention relates to new derivatives dihydroxyphenylpropionic General formula

where R is H; R1-NO2or R-NO2, R1-H, which possess antihypoxic and coagulation action

The invention relates to pharmaceutical industry and relates to a method of obtaining purpurine-18, used in medicine for treatment of cancer

The invention relates to polycyclic compounds, their pharmaceutical compositions and methods of their use in human diseases associated with impaired memory processes, diseases of the nervous system and/or depression, such as, but not limited to, degenerative changes in the nervous system

FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: method involves making incision in conjunctiva and Tenon's capsule of 3-4 mm in size in choroid hemangioma projection to sclera 3-4 mm far from limb. Tunnel is built between sclera and Tenon's capsule to extrasclerally introduce flexible polymer magnetolaser implant through the tunnel to the place, the choroid hemangioma is localized, after performing transscleral diaphanoscopic adjustment of choroid hemangioma localization and size, under visual control using guidance beam. The implant has permanent ring-shaped magnet in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 2-3 mTesla units intensity. It is arranged with its north pole turned towards the choroid hemangioma so that extrascleral implant laser radiator disposition. The other end of the implant is sutured to sclera 5-6 mm far from the limb with two interrupted sutures through prefabricated openings. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. 0.1-1% khlorin solution is injected in intravenous bolus dose of 0.8-1.1 mg/kg as photosensitizer and visual control of choroid hemangioma cells fluorescence and fluorescent diagnosis methods are applied. After saturating choroid hemangioma with the photosensitizer to maximum level, transscleral choroid hemangioma laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm with total radiation dose being equal to 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the intraocular neoplasm, repeated laser irradiation of the choroid hemangioma is carried out with radiation dose of 30-60 J/cm2.

EFFECT: enhanced effectiveness of treatment.

4 cl

FIELD: medicine.

SUBSTANCE: method involves creating tunnel between sclera and Tenon's capsule in intraocular neoplasm projection. Intraocular neoplasm localization and size is adjusted by applying transscleral diaphanoscopic examination method. 0.1-0.3 ml of photosensitizing gel based on viscoelastic of hyaluronic acid, selected from group containing chealon, viscoate or hyatulon, is transsclerally introduced into intraocular neoplasm structure using special purpose needle in dosed manner. The photosensitizing gel contains khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-1% by mass. Flexible polymer magnetolaser implant is extrasclerally introduced into the built tunnel in intraocular neoplasm projection zone under visual control using guidance beam. The implant has permanent ring-shaped magnet axially magnetized and producing permanent magnetic field of 3-4 mTesla units intensity, in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The implant is arranged with its north pole turned towards the intraocular neoplasm so that implant laser radiator lens is extrasclerally arranged in intraocular neoplasm projection zone. The implant light guide is sutured to sclera 5-6 mm far from the limb with single interrupted suture. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transscleral intraocular neoplasm laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm. The treatment course being over, the flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, neodymium-iron-boron or samarium-iron-nitrogen. 0.1-1% khlorin solution as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is additionally intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg and repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2 15-20 min later during 30-90 s.

EFFECT: complete destruction of neoplasm; excluded its further growth.

4 cl

FIELD: medicine.

SUBSTANCE: method involves applying transscleral diaphanoscopic examination method for adjusting intraocular neoplasm localization and size. Rectangular scleral pocket is built 2/3 times as large as sclera thickness which base is turned from the limb. Several electrodes manufactured from a metal of platinum group are introduced into intraocular neoplasm structure via the built scleral pocket. Next to it, intraocular neoplasm electrochemical destruction is carried out in changing electrodes polarity with current intensity of 100 mA during 1-10 min, and the electrodes are removed. Superficial scleral flap is returned to its place and fixed with interrupted sutures. 0.1-2% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transpupillary laser radiation of 661-666 nm large wavelength is applied at a dose of 30-120 J/cm2. the operation is ended with placing sutures on conjunctiva. Platinum, iridium or rhodium are used as the metals of platinum group. The number of electrodes is equal to 4-8. 0.1-1% khlorin solution, selected from group containing photolon, radachlorine or photoditazine, is additionally repeatedly intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2.

EFFECT: complete destruction of neoplasm; excluded tumor recurrence; reduced risk of tumor cells dissemination.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine.

SUBSTANCE: method involves intravitreously introducing two electrodes into intraocular neoplasm after carrying out vitrectomy and retinotomy to expose the intraocular neoplasm. The electrodes are manufactured from platinum group metal. Electrochemical destruction is carried out with current intensity of 100 mA during 1-10 min or 10 mA during 10 min in changing electrodes polarity and their position in the intraocular neoplasm space, and the electrodes are removed. 0.1-1% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, intravitreous laser radiation is carried out in parallel light beam of wavelength equal to 661-666 nm is applied at a dose of 30-120 J/cm2.The transformed retina and tumor destruction products are intravitreally removed. Boundary-making endolasercoagulation of retinotomy area is carried out after having smoothed and compressed retina with perfluororganic compound. The operation is finished with placing sutures on sclerotomy and conjunctiva. Platinum, iridium or rhodium are used as the platinum group metals. Another embodiment of the invention involves adjusting position and size of the intraocular neoplasm in trans-scleral diaphanoscopic way. Rectangular scleral pocket is built above the intraocular neoplasm to 2/3 of sclera thickness with its base turned away from limb. Several electrodes are introduced into intraocular neoplasm structure via the built bed. The electrodes are manufactured from platinum group metal. Electrochemical destruction is carried out with the same current intensity in changing electrodes polarity and their position in the intraocular neoplasm space, and the electrodes are removed. Superficial scleral flat is returned to its place and fixed with interrupted sutures. 0.1-1% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg after having carried out vitrectomy and retinotomy. Visual control of intraocular neoplasm cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, intravitreous laser radiation is carried out in parallel light beam of wavelength equal to 661-666 nm is applied at a dose of 30-120 J/cm2. The transformed retina and tumor destruction products are intravitreally removed using vitreotome. Boundary-making endolasercoagulation of retinotomy area is carried out after having smoothed and compressed retina with perfluororganic compound. The operation is finished with placing sutures on sclerotomy and conjunctiva. Platinum, iridium or rhodium are used as the platinum group metals. The number of electrodes is equal to 4-8.

EFFECT: reduced risk of metastasizing.

4 cl, 13 dwg

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