Derivatives 20,21-dinarabaykenova, or their optical isomers, or salts with organic acids

 

(57) Abstract:

Usage: as a substance having affinity to adrenergic receptors. Entity: product: derived 20,21-dinarabaykenova General formula I:

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< / BR>
< / BR>
where R is-C1-C6-alkyl possibly substituted hydroxy-, cyano - or carboxypropyl, possibly esterified WITH2-C4alkenyl,2-C4-quinil or free or esterified carboxypropyl, R1group = CR8R9where R8and R9both hydrogen or one is hydrogen and the other is cyano, or their optical isomers, or salts with organic acids. 3 table.

The invention relates to new derivatives dinarabaykenova formula (I):

(1)

where X1X2and X3identical or different, represent a hydrogen atom, halogen atom, alkyl radical, alkenyl or quinil, and these radicals being linear or branched and contain not more than 18 carbon atoms which may be substituted, linear or branched radical of alkyloxy, which contains not more than 7 carbon atoms which may be substituted, a hydroxyl radical, trifloromethyl or nitro, and radicals of amino, mono - who

where R is:

a) a radical of the alkyl, alkenyl or quinil, linear or branched, contains not more than 7 carbon atoms and is possibly substituted

b) a phenyl radical which may be substituted,

in free carboxypropyl, in the form of a salt or aviaproizvodstvo

B) a group

where R1represents one of two groups

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< / BR>
where:

R8and R9identical or different, are such that one selected from the group formed by: a) hydrogen atom, b) a radical of the alkyl, alkenyl or quinil, linear or branched, containing not more than 6 carbon atoms, possibly substituted, the phenyl radical, possibly substituted, g) radical aviaproizvodstvo of carboxyl, d) cineradiogram, e) the acyl radical containing from 2 to 6 carbon atoms; and the other is selected from the group formed by: a) hydrogen atom, b) a radical of the alkyl, alkenyl or quinil, linear or branched, containing not more than 6 carbon atoms, possibly substituted, the phenyl radical, later substituted, and R10is: a) hydrogen atom, b) a radical of the alkyl, alkenyl or quinil, linear or branched, containing not more than 6 carbon atoms is replaced, in) for the mi in the form of the racemates, and in the form of optically active isomers, and salts of organic or inorganic acids or bases of the products of formula (I).

The subject of this invention are, in particular dengeburtigen formula (1A):

< / BR>
where X1X2and X3listed below and

represents either a group

in which RAhas the value given above for R, in addition to free of carboxyl, in the form of a salt or aviaproizvodstvo or group ,

where R1above.

Products (1) and(1Athe hydrogen atom in position 3 and the hydrogen atom in position 16 can each take a position alpha or beta, which determines the existence of CIS - and TRANS-stereoisomers.

Products (1) and (1Aand in the subsequent:

halogen atom, primarily means a chlorine atom or fluorine, but can also represent a bromine atom, or iodine,

the radical is a linear or branched alkyl, mainly mean the radicals methyl, ethyl, n-propyl or isopropyl, but can also represent a radical n-butyl, isobutyl, Deut.-butyl, t-butyl or n-pentile,

radical, alkyloxy in linear or branched form means, mainly the radicals methoxy Kala,

the radical monoalkyl or dialkylamino means, mostly radicals monoalkyl or dialkylamino, where linear or branched alkali contain from 1 to 5 carbon atoms, and in particular the radicals methyl, ethyl or isopropyl,

the radical is a linear or branched alkenyl means, mainly radical vinyl, allyl, 1-propenyl, butenyl or pentenyl,

the radical is a linear or branched quinil means, mainly the radical ethinyl, propargyl, butynyl or pentenyl,

the acyl radical with 2-6 carbon atoms means, mainly the acetyl radical, propionyl, butyryl or benzoyl, and radical Valerie, hexanoyl, acryloyl, crotonoyl or carbamoyl,

carboksiproizvodnyi means, mainly the lower group allyloxycarbonyl, such as methoxycarbonyl, etoxycarbonyl or benzyloxycarbonyl.

Salts of organic or inorganic acids of the products of formula (I) and (IA) can be, for example salts of such acids as hydrochloric, bromide, iodata, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoic, maleic, shmarinova, amber, tartrate, lemon, axalingua, pixelenemy, aspartic,background, alkylsulfonic acids, as for example methanesulfonate, alpha - or beta-desulfonema, and allanazarovich acids, such as benzenesulfonate and ridiculousy acids.

When R represents a carboxyl group, it may be in the form of a salt or contain the remainder of the base. In this case, you can get sodium, potassium salt, lithium salt, calcium, magnesium or ammonium. In a series of organic bases can be called methylamine, Propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanamine, Tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

The radicals alkyl, alkenyl or quinil can be unsubstituted or to have several alternative groups, as for example the following radicals: hydroxy, aryl, for example phenyl or naphthyl, arylalkyl (benzyl or phenetyl), cycloalkyl, such as cyclopropyl, cyclopentyl or cyclohexyl, alkyloxy, for example methoxy, ethoxy, propoxy or isopropoxy, as for example in groups methoxymethyl or 1-ethoxyethyl, aryloxy(phenoxy), (arylalkyl)hydroxy, for example benzyloxy, mercapto, alkylthio, for example methylthio or ethylthio, aaltio, the Aral sea is thylamino, halogen, for example chlorine or bromine, such as 2-bromacil, nitro, azido, carbarnoyl, substituted carbarnoyl with a group of primary N-monoalkyl carbarnoyl, such as N-methylcarbamoyl, N-ethylcarbazole, primary-dialkylamino as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, primary N-(hydroxyalkyl)carbarnoyl as N-(hydroxymethyl)carbarnoyl, N-(-hydroxyethyl)carbarnoyl, primary alkyl carbarnoyl, as carbamoylmethyl, carbamoylethyl, carboxy, carboxyester, such as methoxycarbonyl or etoxycarbonyl, formyl, acyl, for example acetyl, propionyl or benzoyl, acyloxy, for example acetoxy or propionyloxy, cyano, phthalimido, acylamino, such as acetamido or benzamido, allyloxycarbonyl, for example, methoxycarbonylamino or ethoxycarbonyl, or (arylalkyl) oxycarbonyl, for example, benzyloxycarbonylamino.

The aryl radicals or arylalkyl may be substituted or may contain one or more substitutional groups, as for example the following radicals: hydroxy, halogen, alkyl, for example methyl, ethyl, isopropyl or tertbutyl, alkyloxy, for example methoxy, ethoxy or isopropoxy, alkylaryl, for example methylthio or ethylthio, nitro, amino, substituted amino, as monoalkylamines, dialkylamines, for example m is the alkyl or substituted, alkyloxy, this radical can be substituted, by one or more hydroxyl radicals, carboxy - or karboksimetilproizvodnykh, such as methoxycarbonyl or etoxycarbonyl, and the alkyl radical may also be substituted by a radical of linear or branched alkyloxy containing from 1 to 5 carbon atoms, for example methoxy, ethoxy or isopropoxy.

The object of the present invention is a method for preparing products of formula (I) or (1A) as defined below, where X1X2and X3represent a hydrogen atom, the said products of formula (1) or (1A) are all possible isomers in the form of racemates and in the form of optically active isomers, and salts of organic or inorganic acids or bases named products of formula (I).

In particular, the object of the present invention is a method for preparing products of formula (I) or (IA) as defined above where one or more substituents, which may contain alkyl radicals, alkyloxy, alkenyl or quinil, are selected from the group formed by hydroxyl radical; halogen atoms; halogen atoms, radicals, alkyloxy, sensora; radicals or free carboxyl or carboxyester formed by linear or branched alkyl containing not more than 5 carbon atoms; a cyano radical; a radical of carbamoyl, subsequently substituted; the phenyl radical, later substituted; radical ,

in which R5and R6identical or different, represent:

a hydrogen atom;

linear or branched alkyl radical containing not more than 7 carbon atoms, later substituted by one or more radicals selected from the group formed by hydroxy radical, a linear or branched radicals of alkyloxy containing not more than 5 carbon atoms, and the radicals or free carboxyl or carboxyester formed by linear or branched alkyl containing not more than 5 carbon atoms;

the aryl radical or arylalkyl containing from 7 to 12 carbon atoms, these radicals can be substituted,

or R5and R6form together with the nitrogen atom to which they are bound, a heterocycle of five or six units containing a second heteroatom selected from oxygen, sulfur or nitrogen, possibly substituted on the nitrogen atom not connected with R5and R6:

linear or razwell is halogen or a radical of alkyloxy, containing from 1 to 4 carbon atoms;

the aryl radical or a radical of arylalkyl containing from 7 to 12 carbon atoms, possibly substituted named products of formula (I) or are all the isomers in the form of racemates and in the form of optically active isomers, and salts of organic or inorganic acids or bases named products of the formula (1):

The most interesting products of the formula (I) or (Iand), where one or more substituents, which may contain the radicals phenyl, aryl and arylalkyl, chosen from the group formed by halogen atoms, hydroxy radical, a linear or branched alkyl radicals, alkyloxy containing not more than 5 carbon atoms, radicals methylthio, nitro, amino, monoalkyl and dialkylamino called the products of formula (I) and (Iand) can be in the form of all possible isomers in the form of racemates and in the form of optically active isomers and their salts with organic or inorganic acids or bases.

In the products of formula (I) or (Iandand then:

arylalkyl radical containing from 7 to 12 carbon atoms, denoted by, mainly, the benzyl radical or Venetia and among the possible, the isopropyl and tert-butyl, methoxy, ethoxy and propoxy;

in the case when R5and R6form together with the nitrogen atom to which they are bound, a heterocycle, it is, for example, about the cycles pyrrolidino, piperidino, morpholino, piperazinil, methylpiperazine, ethylpiperazine, propylpiperazine, phenylpiperazines or benzylpiperazine, in the case when R5and R6represents the last two radicals, the radicals phenyl and benzyl can be substituted by the abovementioned substituents, in respect of aryl and arylalkyl.

More specifically we are talking about the following products:

oxalate [16 alpha, ()]-15-(1-PROPYNYL)-20,21-dinarabaykenova;

[16 alpha, ()]-15-methyl-20,21-dinarabaykenova;

malata acid [16 alpha, ()]-14,15-dihydro-15-methylene-20,21-dinarabaykenova;

maleate [16 alpha, ()]-20,21-dinarabaykenova-15-ethyl acetate;

malata acid [16 alpha, ()]-20,21-dinarabaykenova-15-methanol;

malata acid [16 alpha, ()]-N,N-dimethyl-20,21-dinarabaykenova-15-methanamine.

The method of obtaining new compounds is that is injected into the interaction product of the formula (II):

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where X1pX2pand X3prepresent X1X2and X3to the (III)

R' V Hal (III)

where V represents an atom of magnesium or zinc, and Hal represents a halogen atom,

or organometallics compound of formula (IV)

R'- W (IV)

where W represents an atom of lithium, sodium or potassium, and in formulas (III) and (IV) R' represents any of the values specified above for R except the scatter carboxyl, in the form of a salt or aviaproizvodstvo or specified values for R, in which the reaction of a protected group, to obtain compounds of formula (V):

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where R' has the above meaning, which is subjected to dehydration reaction and, if necessary, the reaction of removing the protective groups with reactive groups that can carry X1pX2pand X3pand R', to obtain compounds of the formula (Ia1):

< / BR>
where X1X2and X3and R' above, the resulting product of the formula (Ia1), in which case, when R represents a radical CH2OH oxidizes to obtain a product of formula (Ia2):

< / BR>
where X1X2and X3the above and Z represents a hydrogen atom or the residue of the ether group, which by necessity or desire to expose one of the two following reactions:

hydrolysis of the ether group;

atrificial the and formula (VI):

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or a phosphonate of the formula (VI'):

< / BR>
where R12represents a radical of alkyloxy, and in formulas (VI) and (VI') R8R9above that, in accordance with the working conditions and subsequent removal of the protective groups with reactive groups that can carry X1X2Pand X3results of the substances of the formula (Ib1):

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or substances of the formula (Ia3):

< / BR>
where X1X2X3, R8and R9above,

In) or with an acetylene derivative of the formula (VII):

R10-C CH (VII)

where R10above, to obtain a product of formula (VIII):

< / BR>
where X1X2Pand X3and R10above, which, after activation of the hydroxyl and possible protection of reactive groups, which may have R10, is subjected to reduction reaction of optionally with subsequent removal of the protective groups to obtain the substances of the formula (Ib2):

< / BR>
where X1X2and X3and R10indicated above, and treated with the desired products of formulas (Ia1), (Ia3), (Ib1) and (Ib2organic or inorganic acid to obtain the corresponding salt, the product of the conditions for the implementation of this invention, the described process is as follows:

in the reaction, as described above in paragraph (a), cooking magyarkanizsa or zinc compounds of the formula (III) and their reaction products of the formula (A) can be realized under normal conditions.

The halogen atom of the halide of magnesium or zinc formula (III) may be a bromine atom, such as bromide vinylmania, as well as the atoms of iodine or chlorine.

Obtaining magnesium halide may be carried out, for example by reaction of magnesium with an organic halide in an inert, slightly polarized environment, such as ether in accordance with the method of preparation magyarkanizsa halides or Grignard reagents.

The reaction product of the formula (II) with a halide of magnesium formula (III) to obtain products of formula (V) occurs mostly in organic solvents such as ether or tetrahydrofuran at room temperature or at reflux.

Getting metalloorganicheskikh substances according to formula (IV), where W is represented by a lithium atom, sodium or potassium and the reaction product of the formula (II) occurs in normal conditions.

Getting organolithium substances according to formula (IV) can be implemented, gabrielova ether or tetrahydrofuran at a low temperature.

The reaction product of the formula (II) with organolithium substance of the formula (IV) can be implemented, for example, tetrahydrofuran or ether at a low temperature from -70 to -10oC or dimethoxymethane.

Dehydration product of formula (V) to obtain the product of formula (Ia1) proceeds in an organic solvent, for example toluene or xylene, but this role can perform the tetrahydrofuran in the presence, for example P2O5or salts Burgess. This reaction dehydration may also occur due to the activation of alcohol, mainly dobesilate, chloride methanesulfonyl with subsequent treatment of the strong base, such as databaseconnect or Diisobutylene.

The oxidation product of the formula (Ia1), leading to the product of the formula (Ia2) proceeds in the usual way using, for example, salts of chromium, oxides of selenium or through reaction Swarna.

Hydrolysis of the ether group, the subsequent esterification or salt formation product of formula (Ia2) is carried out in the usual way.

In the reaction described above in points) 1) triphenylphosphorane formula (VI) is obtained by reaction of triphenylphosphine with scale of phosphonium, which reacts with such a Foundation, such as terbutalin potassium or utility, to obtain the desired product of formula (VI). The reaction proceeds in an organic solvent, for example tetrahydrofuran or ether, at a temperature of 0oC and reflux.

The reaction product of the formula (II) with triphenylphosphorane formula (VI) to obtain products of formula (Ib1) proceeds at temperatures from -70 to 0oC.

Preparation of a reagent of formula (VI) and its reaction with the product of formula (II) are carried out by classical methods.

The reaction product of the formula (II) and phosphonate of the formula (VI') to obtain the product of formula (Ib1) proceeds in the presence of sodium hydride or weak base, such as sodium carbonate or potassium hydroxide, in a solvent such as tetrahydrofuran.

When using equimolar mixture of the product of formula (II) and phosphonate of the formula (VI') will be mainly obtained desired substances of the formula (Ib1), whereas excess Elura and alkaline environment will lead to compounds of the formula (Ia3):

In the most favorable reaction conditions as phosphate derivative, is used to obtain compounds of the formula (Ib1), where RP CLASS="ptx2">

In those cases where R8and R9contain one or more ether, cyano or alkyl groups, the phosphate derivative is used primarily phosphonate.

In the reaction, as defined in paragraph (C), the product of formula (II) with an acetylene derivative of the formula (VII) to obtain the substances of the formula (VIII) is an acetylene derivative, such as acetylene or propyne, is activated in the form of anion in alkaline medium, for example a sodium alcoholate or potassium, such as Arbuthnot potassium, or lithium base such as utility. The reaction occurs in such an organic solvent, such as tetrahydrofuran or ether.

In the reaction, as defined in paragraph (B) recovering the product of formula (VIII) with hydride, namely, hydride mixture, as for example the mixture of hydrides hydrides line and aluminum or dieselhybrid sodium and aluminum. Can also be used as a reagent borohydride sodium or potassium or cyanoborohydride sodium in the presence of such an alcohol, such as methanol or ethanol.

Activation of the hydroxyl group of substances of the formula (VIII) can be implemented, for example using a halide such as chloride methanol tetrahydrofuran or dichloromethane.

The reduction of activated substances of the formula (VIII) to obtain the substances of the formula (Ib2occurs mainly in arid environments, such as lithium hydride and aluminum in tetrahydrofuran or ether.

In the case where R10contains one or more carboxyamide groups, the latter can, thanks to the reduction reaction of the substances of the formula (VIII) above, to be transformed in the alcohol group, and in such cases, the obtained alcohol group can again be oxidized to secondary receipt of the initial carboxylating groups: such secondary oxidation can occur, for example with chromium oxide or chromium salts, such as bichromate of pyridine or Harrogate pyridine, in a solvent such as for example dichloromethane or dimethylformamide.

To obtain products of formula (I) as defined above and where

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represents a group

< / BR>
and R7represents a methyl radical, possibly substituted by a hydroxy radical, a halogen atom or radical ,

where R5and R6have the meanings specified above, or R7is a free radical carboxy in the form of a salt or airopro the above, halogen derivatives methyloxazolidine formula (IX):

< / BR>
in an alkaline medium to obtain a reactive epoxide corresponding to the formula (X):

< / BR>
where X1pX2pand X3phave the meanings indicated above, which process:

any reason for obtaining alcohol corresponding to the formula (X'):

< / BR>
where X1pX2pand X3phave the meanings indicated above, and which if necessary is subjected to the reaction of removing the protective groups with reactive groups, which may contain X1pX2pand X3pto obtain the product of formula (Ia4):

< / BR>
where X1pX2pand X3phave the meanings indicated above, and if necessary or desired, the resulting product (Ia4) is treated with an oxidant to obtain a product of formula (Ia2):

< / BR>
where X1pX2pand X3pand Z have the meanings indicated above, and which, if necessary or desired, is subjected to one of the two following reactions: hydrolysis of the ether group, the salt formation or esterification of carboxyl groups, using base

or an amine of the formula (XI):

< / BR>
where R5and R6have the values pointed to by the data above, moreover, these substances of the formula (X') and (XII) are after activation of the hydroxyl radical:

or in the case of a substance (X') reaction with an amine of formula (XV) in a form in which it is described above,

or in the case of substances (XII) dehydration reaction to obtain in both cases, and after removal, if necessary, the protective groups with reactive groups, which may contain X1pX2pand X3psubstances of the formula (Ia5):

< / BR>
where X1X2X3; R5and R6have the meanings indicated above,

or tetrabutylammonium halide to obtain a product of formula (XIII):

< / BR>
where Hal represents a halogen atom, and then subjected to dehydration reaction to obtain (after removal if necessary, the protective groups with reactive groups, which may contain X1pX2pand X3p) substances of the formula (Ia6):

< / BR>
where X1X2X3and Hal have the meanings stated above, and treated with the desired product of formula (Ia3), (Ia5) and (Ia6organic or inorganic acid to obtain the corresponding salt, and named the products of formula (I) are all possible isomers in the form of racemates or enantiomers.

Disclosure of reactive epoxide by the formula (X), leading to the product of formula (X') is implemented for example in a solution of diisopropylamide lithium in tetrahydrofuran at a temperature of about -70oC, which is then increased to room temperature.

The oxidation product of the formula (Ia4), leading to the product of the formula (Ia2) proceeds as outlined above, to oxidation products (Ia1).

The hydrolysis of the ester group, it is possible to esterification or salt formation are the usual well-known ways.

The reaction disclosure epoxide of the formula (X) adding an amine of formula (XI), leading to the substances of the formula (XII), is implemented in such alcoholic solvent like methanol or ethanol under reflux used alcohol.

The hydroxyl compounds of the formula (X') and (VII) may be activated, for example Nia as pyridine or triethylamine.

Dehydration active substances of the formula (XII), leading to the product of the formula (Ia5), takes place in such an organic solvent as, for example toluene, in the presence of such a strong base as databaseconnect or diazabicyclo at reflux.

The product of formula (Ia5) can also be obtained by adding an amine of formula (XI) to an activated substance of the formula (X'): the reaction proceeds in a solvent such as toluene or xylene, or in this alcohol, such as methanol or ethanol, the mixture is brought to reflux.

The halide used to obtain the product of formula (XIII) is, for example tetrabutylammonium fluoride in an organic solvent.

To obtain products of formula (I) in which:

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represents a group

< / BR>
where R11is acetylenyl a radical of the formula:

R10-C C -

where R10has the value specified above, the product of formula (VIII):

< / BR>
where X1pX2pX3pand R10have the meanings indicated above is subjected after activation of the hydroxyl radical reaction dehydration to obtain after removing, if necessary, the protective groups with reactive groups, which/SUB> X2pX3pand R10have the meanings specified above, and treated with the desired product of formula (Ia7organic or inorganic acid, and said products of formula (I) are all possible isomers in the form of racemates or enantiomers.

The dehydration reaction of the substances of the formula (VIII) with an activated hydroxyl group, activated, for example as described above, to nelfinavir or acetate, occurs mainly in such an organic solvent as, for example toluene, in the presence of such bases as, for example, databaseconnect or Diisobutylene.

Various reactive groups, which may contain some of the above substances can be optionally protected, we are talking about, for example, the radicals hydroxyl, acyl, free carboxy - or amino -, monoalkylamines radicals, which may be protected with appropriate protective groups.

Below is an incomplete list of examples of protective groups:

hydroxy-group may be protected, for example radicals of trimethylsilyl, tert-butyldimethylsilyl, dihydropyran or methoxymethyl,

the amino group may be protected, for example radicals of trityl, gasoline is acyl as formyl can for example, to be protected in the form of cyclic or acyclic ketals as dimethyl or diethylacetal or atlanticocean,

carboxypropyl can be, for example, protected in the form of esters formed with easily esters, such as benzyl or tert-butyl esters.

The removal of these protective groups takes place in normal conditions, namely by acid hydrolysis with the participation of such acids as hydrochloric acid, benzolsulfonat or paratoluenesulfonyl, formic or triperoxonane acid.

Group phthalimido removed by hydrazine. In the patent BF N 2499995 given a list of various used protective groups.

Optically active forms of the products of formula (I) can be obtained by separation of racemates in accordance with the applicable methods or using as initial products of optically active products of the formula (II).

Substances of the formula (I) or (IA) as defined above, and their salts with acids exhibit interesting pharmacological properties.

Some products have affinity to the alpha 2 adrenergic receptors.

Some products can also prowl CLASS="ptx2">

New connections are not toxic.

These properties allow the use of products of formula (I) or (IA) in all possible forms of the isomers in the form of racemates or optically active isomers and their salts with acids or bases that are acceptable from a pharmaceutical point of view as medicines.

In a number of medicines in accordance with this invention, special attention is drawn to the substances of the formula (I) or (IA), whose names are listed below: oxalate 16 alpha ()-15-(1-PROPYNYL)-20,21-dengeburtigen; 16 alpha ()-15-methyl-20,21-dengeburtigen; maleic acid 16 alpha ()-14-15-dihydro-15-methylene-20,21-dengeburtigen; maleate 16 alpha ()-15-methyl-20,21-dengeburtigen-15-ethyl acetate; maleic acid 16 alpha, ()-N, N-dimethyl-20,21-dengeburtigen-15-methanamine, and if necessary, their salts with organic and inorganic pharmaceutically acceptable acids.

Medication in accordance with the invention can be used in the treatment of cerebral insufficiency anoxic or ischemic origin, disorders of memory and attention. They can also be used as anti-depressive drugs.

Substances in order to find to obtain pharmaceutical compositions containing them as an active ingredient.

These pharmaceutical compositions can enter the oral, rectal, parenteral or local topical application on the skin and mucous membranes.

These compositions can be in solid or liquid form and can be in any common pharmaceutical forms commonly used in medicine, namely, tablets, coated tablets, pills, granules, suppositories, injectable preparations, ointments, creams, gels and products in aerosols, they are prepared by conventional methods. The active ingredient may be incorporated in excipients commonly used in pharmaceutical compositions, such as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or anhydrous media, animal or vegetable fats, paraffin derivatives, glycols, various moisturizing, dispersion or emulsion agents, preservatives.

The usual dose, depending on the used product from the disease and the patient can be for an adult person of 50 kg per day orally.

The original connection of the formula (IIa), in which three substituent X1X2and X3represent hydrogen atoms, are described in European Pat1X2and X3provided that at least one represents a hydrogen atom, can be obtained according to the method described in the aforementioned patent, with substituted tryptamines as the original substances.

The following are examples which illustrate the invention, without limiting its scope.

Example 1.16 alpha ()}-15-ethinyl-20,21-dengeburtigen.

Stage A: 16 alpha, ()}-14,15-dihydro-16-ethinyl-20,21-dengeburtigen-15-ol.

Acetylene bubbled for 30 min at 0oC 600 cm3molar solution of terbutaline potassium in tetrahydrofuran. Then at a temperature of 0oC add a solution of 6 g alpha ()}-20,21-dengeburtigen-15(14N)-it is 140 cm3tetrahydrofuran (THF). Within 3 hours, it was stirred at room temperature. Poured into water, extracted with methylene chloride, dried and evaporated to dryness under reduced pressure and the gain of 5.4 g of the product, which is used as received on the next stage.

Stage B: 16 alpha, ()}-14,15-dihydro-15-ethinyl-20,21-dengeburtigen-15-methane-sulfonate.

To a solution of 3.1 g of the product obtained at stage A, 125 cm3tetrahydrofuran (THF) add 3,7 cm3of triethylamine. Mix in accordance with the room temperature. Filter and concentrate the filtrate to dryness. Obtained 3.8 g of the product used for the next stage.

RMN: (CDCl3) 250 MHz

N-CH2-C is 5.18 ppm (d, j 11 Hz)

-O-Mes 3,28 (S)

Acetylene 3,06 (S)

Aromatic compounds 7,1 7,5 (m)

Stage b:16 alpha, ()}-15-ethinyl-20,21-dengeburtigen.

To a solution of 3.8 g of the product obtained at stage B, and 125 cm3toluene, add 3.3 cm3diazabicyclo,4,0} undec-7-ene (DBU), stirred for 20 h at room temperature, then for 8 hours at a temperature of 50oC toluene extract is evaporated and the residue 200 cm3ethyl acetate, washed with water, dried and evaporated to dryness. The residue is subjected to chromatography (4,2 g) on silica (eluent of methylene chloride - methanol (98-2) to obtain 2.3 g of the product, which again chromatographic on silica (eluent: hexane ethyl acetate (8-22)). Obtain 1.6 g of the desired product, so pl. 106oC.

The spectrum of IR (l3)

-C C - H 3306 cm-1< / BR>
Range Balmanno

Conjugated system

1654 cm-1< / BR>
1654 cm-1< / BR>
Aromatic compounds

1594 cm-1(F)

1569 cm-1< / BR>
Example 2.16 alpha, -15-(1-PROPYNYL)-20,21-dengeburtigen and its oxalate.

oC, which, after condensation in acetone, used as received on the next stage.

Stage B:16 alpha, ()}-14,15-dihydro-15-(1-PROPYNYL)-20,21-dengeburtigen-15-methane-sulfonate.

The operation proceeds in the same way as in stage B of example 1, but starting material take 0,750 g of the product obtained at stage A, the result is 0.6 g of the desired product and in this form it is used for the next stage.

Stage b: 16 alpha, ()}-15- (1-PROPYNYL)-20,21-dengeburtigen and its oxalate.

To a solution of 0.6 g of the product obtained at stage B, 30 cm3toluene added to 0.22 cm3diazabicyclo{5,4,0}undec-7-ene (DBU), then mixed for 20 h at 50oC. the Toluene is evaporated and chromatographic the residue on silica (eluent: ethyl acetate-hexane (2-8). Get 0,270 g of the desired product in the form of a Foundation. F > 260oC.

The salt formation: to a solution of 0.1 g of the product obtained as described above, in 20 cm3ethyl acetate hot, add 32 g of oxalic acid in 2 cm3 ethyl acetate. Get 0,097 g of the desired product. So pl. 220oC.

Analysis of C20H20N2C2H2O4< / BR>
Designed WITH 69,82; N 5,86; N 7,4

Found, FROM 69.7; H 5,7; N 7,2

The spectrum of IR (l3)

< / BR>
Aromatic compounds 1563 cm-1< / BR>
The ranges of Bolman

Example 3.16 alpha ()}-14,15-dihydro-15-tinylogin-20,21-dengeburtigen and its maleate.

To a suspension of lithium aluminum hydride in 30 cm3of tetrahydrofuran is added slowly, not exceeding 50oC, a solution of 0.44 g of the product obtained in stage B of example 1, 70 cm3tetrahydrofuran (THF). Mix for 20 h at room temperature. The excess hydride destroy with 15 cm3a mixture of tetrahydrofuran-water (2/3 1/3). The tetrahydrofuran is evaporated and extract the residue with 100 cm3ethyl acetate, filtered, the filtrate is washed with water, dried and evaporated to dryness. The residue (0,650 g) chromatographic on silica (eluent: methylene chloride methanol (98 2)). Get 0,210 g of the desired product in the form of a Foundation. F 138oC.

The salt formation: to a solution of 0,210 g of the base obtained above, 100 cm3ethyl acetate, add hot 88 mg of maleic acid dissolved in 5 cm3poluchat the desired product, 0,240 So pl. 196oC.

Analysis19H20N2C4H4O4< / BR>
Designed WITH 70,39; N 6,16; N 7,13

Found, C to 70.2; H 6,1; 7,0 N

The spectrum of IR (l3)

1963 cm-1< / BR>
Example 4.16 alpha ()}-15-phenyl-20,21-dengeburtigen and its maleate.

Stage A:16 alpha, ()}-14,15-dihydro-15-phenyl-20,21-dinarabaykenova.

To a suspension of 5.34 g of magnesium in 50 cm3ether type 21,6 cm3solution of bromine benzol 200 cm3the ether. Stirred at room temperature until complete disappearance of magnesium (approximately 4 hours). Cooled to 10oC and added dropwise over 50 min at +10oC, a solution of 10 g (16 alpha) 20,21-dengeburtigen-15(14N)-it (EP 0013315) 300 cm3tetrahydrofuran (THF). Stirred for 20 h at room temperature, poured into 400 cm3water containing ammonium chloride, extragere etiracetam, dried to dryness, evaporated under reduced pressure, the residue (13 g) chromatographic on silica (eluant: chlormethine-acetone (8 - 2)). Gain of 2.05 g of the desired product (isomer A), so pl. > 260oC.

Stage B:16 alpha, ()}-15-phenyl-20,21-dengeburtigen and its maleate.

To a suspension of 0.8 g of the product obtained at stage A, 30 cm3anhydrous Tolu the odes, alkalinized with concentrated hydroxide ammonium and extracted with ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. The residue (0.8 g) chromatographic on silica (eluant methylene chloride-ethyl acetate (9 1) and get 0,350 g of the product as the base. F 148oC.

The salt formation: 0.6 g obtained above base are dissolved in 20 CC of ethyl acetate hot, add 0,252 g of maleic acid and mixed for 2 h at room temperature. Press and washed with 3 cm of ethyl acetate. Get 0,785 g of the desired product. So pl. 260oC.

Analysis23H22N2C4H4O4< / BR>
Calculated C 73,28; H of 5.92; N 6,33

Found, WITH 73.6; H 5,9, N, 6,1

The spectrum of IR (l3)

C C 1650 cm-1< / BR>
< / BR>
The range of Bolman

Example 5.16 alpha (+)}-15-methyl-20,21-dengeburtigen.

Stage A:16 alpha (+)}-14,15-dihydro-15-methyl-20,21-dengeburtigen-15-ol.

Operating as in stage a of example 4, but using as the starting material 5,33 g (16 alpha), 20,21-dengeburtigen-15(14N)-it (EP 0013315) and applying 40 cm3toluene solution (1.5 M) of methyl magnesium obtain after chromatography on silica (eluent: methylene what">

To a solution of 3.5 g of the product obtained at stage A, 100 cm3tetrahydrofuran (THF) added 4.3 cm3of triethylamine, then, 1.56 g of the chloride of Mesilla. Mix for 3 h at room temperature, filtered nerastvorim part and concentrate the filtrate is dried under reduced pressure. The residue is dissolved in 100 cm3dioxane and add 3,7 cm3diazobicyclo-undecylenic, mixed for 16 h under reflux, then cooled and mixed for 48 h at room temperature. Is evaporated to dryness under reduced pressure and chromatographic on silica (eluent: methylene chloride-acetone (1 1)). Obtain 0.6 g of the desired product. So pl. 110oC.

Operating on the principle of example B and, using the appropriate isomer 20,21-dengeburtigen-15(14N)-she will receive the following products:

Example 6.16 alpha (+)}-15-methyl-20,21-dengeburtigen

F 140oC. alpha}D+ 313o5o(C 0.5% CHCl3)

Example 6.3 alpha ()}-15-methyl-20,21-dengeburtigen. So pl. 140oC. alpha}D-311o5o(C 0.5 CHCl3)

Operating as in example 5, using the appropriate alkyl bromide of magnesium, receive the products described in the following examples.

Example 8.16 alpha ()}-15-atournament. So pl. 200oC.

Example 10.

16 alpha, ()}-14,15-dihydro-15-ethylidene-20,21-dengeburtigen and its oxalate.

To a mixture of 2.51 g of terbutaline potassium and 8,35 g brominecontaining of phosphonium, completely dehydrated, add 40 cm3of tetrahydrofuran and mixed for 30 minutes In a solution of 80 cm3tetrahydrofuran (THF) added 3 g (16 alpha)-2,21-minoribetween-15(14N)-it (EP 0013315). Then for 1 h, mixed, filtered and the filtrate is evaporated to dryness. The residue is extracted with ethyl acetate, the filtrate is brought to a dry state, the residue is concentrated in isopropyl ether, filtered and the filtrate is evaporated to dryness. To the obtained residue add 100 cm3ethyl acetate and 1,008 g of oxalic acid. The resulting oxalate is filtered. It is dissolved in water and alkalinized with ammonia at 0oWith, mix for 15 minutes, wring out and thicken 60 cm3pentane. Obtain 1.8 g of the desired product in the form of a Foundation. So pl. 138oC.

The salt formation: to a solution of 1.8 g obtained as described above Foundation in 120 cm3ethyl acetate added at 45oC 10 cm3ethanol and brought to reflux. Add 0,581 g of oxalic acid in 15 cm3hot ethyl acetate and 5 cm3ethanol, then 3 cm3of ethanol. Get to 1.87 g of the desired product. So pl. 225oC.

Analysis19H22N2C2H2O4.

Calculated C 68,46; H 6,56; N 7,6

Found, C 68,4; H 6,7; N 7,6

NMR CDCl3300 MHz

A mixture of Delta E/Delta Z 35/65

1,79 ppm CH3-CH=

of 1.88 ppm

4,43 ppm (J 14 Hz, d) N-CH2-C= isomer majoritary

equal to 4.97 ppm (J 14 Hz, d) N-CH2-C= isomer Minoritarnii

of 4.44 ppm (system AB)

of 5.53 ppm (9 1)CH-CH3< / BR>
of 5.82 ppm (91)

from 7,06 up to 7.5 ppm(m) 4H: aromatic compounds

Example 11.16 alpha ()}-14,15-dihydro-15-methylene-20,21-dengeburtigen and acid maleate.

Operate in the same manner as in example 10, but based on 2 g alpha ()} -20,21-dengeburtigen-15(14N)-he (EP 0013315) and using are 5.36 g bromomethylpropane. Receive 2 g of the desired product as the base.

The salt formation: 2 g of the product obtained above are dissolved in 100 cm3ethyl acetate and add 872 mg of a solution of maleic acid in 50 cm3boiling ethyl acetate. Stir for 2 h at room temperature, drained, washed in ethyl acetate. Get 2,32 g of the desired product. So pl. 208oC.

Analysis22H24N2O4< / BR>
Settlement, 69,46 p 12. 16 alpha, ()}-20,21-dengeburtigen-15-ethyl acetate and maleate.

Working as in example 10, but take as starting substances 2.5 g (16 alpha)-20,21-dengeburtigen-15(14N)-it (EP 0013315) and using 0.9 g of 50% sodium hydride in liquid oil and 3,72 cm3diethyl phosphonate ethyl acetate. Obtain 1.1 g of the desired product as the base.

The salt formation: to a solution of 1.1 g of the base obtained above, 60 cm3hot ethyl acetate add 0,379 g of a solution of maleic acid in 10 cm3hot ethyl acetate. Mix for 2 h, filtered and washed with ethyl acetate. Receive 1 g of the desired product. So pl. 180oC.

Analysis21H24N2O2C4H4O4< / BR>
Calculated C collected 66.36; H 6,24; N IS 6.19

Found, C to 66.4; H 6,1; N 6,2

The spectrum of IR (l3)

1728 cm-1> 0 unpaired system

1653 cm-1(F) C C

Example 13:16 alpha, ()}-20,21-dengeburtigen-15-methanol and acid maleate.

Stage A: [16 alpha, ()]Spiro-20,21-dengeburtigen-15-(14N)-2' ethylene oxide (isomer A) and its maleate.

To a mixture of 19 g of the iodide trimethyl oxazolone and 9.6 g of terbutaline anhydrous potassium add 100 cm3of tetrahydrofuran and mixed during the 013315) 100 cm3of tetrahydrofuran and mixed for 1 h at room temperature. The precipitate is filtered and the filtrate is evaporated to dryness, the residue is washed with water, then chromatographic on silica (eluent ethyl acetate), get 10,54 g of isomer A (so pl. 182oC) and 2 g of isomer B (So pl. 167oC).

The salt formation: 1.39 g of a solution of the base obtained above (isomer A), 100 cm3ethyl acetate add 575 g of a solution of maleic acid in 50 cm3ethyl acetate. Mix for 4 h, dehydrated and washed with 100 cm3ethyl acetate. Obtain 1.66 g of the desired product. So pl. 200oC.

Stage B:16 alpha, ()}-20,21-dengeburtigen-15-methanol and its maleate.

a) Obtaining diisopropylamide lithium

To a solution of 6 cm3diisopropylamide 100 cm3of tetrahydrofuran stirred at -70oC, is added dropwise to 28.3 cm3utility. Stirred for 20 min at 0oC/+10oC.

b) the Solution is cooled to -70oC and at this temperature, add a solution of 9.9 g of isomer A (16 alpha)-20,21-dengeburtigen-15(14N)-2'-ethylene oxide at 150 cm3of tetrahydrofuran, stirred for 30 min at -70oC, then for 1 h at room temperature. We use the n chloride, washed in water, dried and evaporated to dryness under reduced pressure. The residue is extracted with a mixture of methylene chloride-methanol (2 1), filter the solution on Florisil, the filtrate is evaporated to dryness and receive 9,38 g of the desired product in the form of a Foundation. So pl. 188oC.

The salt formation: g to a solution of 1.38 g of the base obtained above in 200 cm3a mixture of ethyl acetate-methanol (1 1) add a solution of 571 g of maleic acid in 50 cm3boiling ethanol. Mix for 3 h at room temperature. Dehydrated, washed with ethanol, dried and obtain 1.55 g of the desired product, So pl. 220oC.

Analysis of C22H24N2O5< / BR>
Designed WITH 66,65; N 6,10; N 7,07

Found C, with 66.5; H 6,2; N 6,9

The spectrum of IR (l3)

< / BR>
The range of Bolman

Example 14.16 alpha (+)}-N,N-dimethyl-20,21-dengeburtigen-15-methanamine and its maleate.

Stage A: 16 alpha (+)} -14,15-dihydro-N, N-dimethyl-15-methanamine-20,21,15-dengeburtigen -+5-ol.

To a solution of 4 g of the product obtained in stage a in example 14, 80 cm3tetrahydrofuran bubbled methylamine until saturation at 0 - 5oC, heated for 24 h under pressure during reflux, cook until dry, thickened L. 200oC, is used for the next stage.

Stage B:16 alpha (+)}-15-chloro-14,15-dihydro-N,N-dimethyl-20,21-dengeburtigen-15-methanamine.

To a solution of 2.75 g of the product obtained at stage a, 50 cm3of tetrahydrofuran is added slowly at -20oC 6,3 cm3solution of utility 1.5 M and mixed at 0oC for 45 minutes, Add a solution of 0.74 cm3methanesulfonanilide 10 cm3of tetrahydrofuran, mixed for 15 h at room temperature, filtered, washed with tetrahydrofuran and concentrated to dryness of the filtrate. The remainder chromatographic on silica (eluent: methylene chloride-methanol (95-5) and obtain 1.84 g of the desired product. So pl. 140oC.

Stage b: 16 alpha (+)}-N,N-dimethyl-20,21-dengeburtigen-15-methanamine and its maleate.

To a solution of 1.84 g of the product obtained at stage B, 100 cm3toluene add 4 cm3diazabicyclo-undecene (DBU) and mixed for 24 h under reflux. Cooled, washed with water, dried and evaporated to dryness under reduced pressure. The remainder chromatographic on silica (eluent: ethyl acetate with 3% triethylamine) obtain 1.07 g of the desired product in the form of a Foundation. So pl. 111oC.

Salubritas acid in 10 cm3boiling ethanol, mixed for 3 h at room temperature, then at 0oC for 10 minutes, Dehydrated, washed with 2 x 10 cm3of ethanol. After drying under reduced pressure at 60oC obtain 570 mg of the desired product. So pl. 176oC.

< / BR>
The Ranges Of Bamana.

Microanalysis WITH28H33N3O8< / BR>
Calculated C 62,33; H 6,16; N 7,79

Found, C 62,0; H 6,3; N 7,8

Example 15.15 alpha (+)}-N-methyl-20,21-dengeburtigen-15-methanamine and its maleate.

Operating as in example 14, using as the starting material 4 g of the product obtained at stage a, in example 13, and applying monoethylamine get the desired product.

Example 16. 16 alpha (+)}-20,21-dengeburtigen-15-acetonitrile and its maleate.

Dropwise under conditions of inert atmosphere add to 1.35 cm3phosphonate of diethylcarbamyl in suspension 0,396 g of sodium hydride in 25 cm3tetrahydrofuran (THF). Mix for 30 min, add 1 g of the solution (16 alpha)-20,21-dengeburtigen-15(14N)-it (EP 0013315) 20 cm3of tetrahydrofuran and mixed for 3 h at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed in water, h is the product of the base. Dissolve in hot 200 mg of the base 30 cm3ethyl acetate and 5 cm3ethanol, add 80 mg of maleic acid, mixed for 3 h at room temperature, dried at 70oC under reduced pressure and obtain 220 mg of the desired product. So pl. 250oC.

The spectrum of IR (l3):

C=C aromatic substance: 1656, 1633 cm-1< / BR>
C N 2250 cm-1< / BR>
The Ranges Of Bamana.

Microanalysis of C19H19N3C4H4O4405,456

Calculated C 68,13; H 5,72; N 10,36

Found, C 68,3; H 5,7; N 10,4

Example 17. 16 alpha (+)}-14,15-dihydro-15-ethylpropyl-20,21-dengeburtigen-15-ol.

6.4 cm3Diisopropylamine dissolved in 15 cm3of tetrahydrofuran, added at -10oC/-20oC in an inert atmosphere 30 cm3solution of 1.6 M utility in hexane. Mix the solution for 2 h at -20oC, then for 15 min at 0oC. is Cooled to -50oC, slowly add 4.8 cm3ethylpropyl, mixed for 30 min at -50oC add 4 g of the solution (16 alpha) ()-(20,21-dengeburtigen-15(14N)-it (EP 0013315) 60 cm3of tetrahydrofuran and mixed at this temperature for 1 hour, Pour the reaction mixture into ice-cold water is military pressure. Gain of 6.1 g of the product, which is purified by chromatography on silica (eluent methylene chloride-methanol 95-5). Obtain 3.7 g of the desired product. So pl. 228oC.

The spectrum of IR (l3):

OH+ related: 3595 cm-1< / BR>
C C 2444 cm-1< / BR>
>C C 1710 cm-1the conjugated ester

C C aromatic connection: 1630, 1604, 1512 cm-1< / BR>
Stage B:16 alpha, ()}(20,21-dengeburtigen-15-yl) ethylpropane.

3.7 g of the Product obtained at stage A, is dissolved in 30 cm3of tetrahydrofuran, is added dropwise in an inert atmosphere 2.7 cm3of triethylamine, then 0,97 cm3chloride of Mesilla. Stirred for 2 h at room temperature, filtered suspension concentrate the filtrate and get 5.3g nelfinavir. The product is dissolved in 130 cm3toluene, add 1,49 cm3diazabicyclo-undecene, mixed for 4 h at room temperature and concentrate the reaction mixture under reduced pressure. Obtain 6.5 g of product, which is purified by chromatography on silica (eluent: hexane-ethyl acetate 8-2, then methylene chloride-methanol (95-5). Get your desired product. So pl. 100oC.

Microanalysis WITH22H22N2O2< / BR>
Calculated C 76,27tx2">

To 350 mg (16 alpha) () 20,21-dengeburtigen-15-acetonitrile obtained in example 16 dissolved in 10 cm3methanol, add 10 cm35N sodium hydroxide, then 1 cm3the hydrogen peroxide. Stirred at room temperature for 3 hours, then added to the obtained suspension of 50 cm3water, dewatered sludge, washed with water, dried at 70oC under reduced pressure and obtain 190 mg of the desired product in the form of a Foundation. F 160oC.

250 mg of the above base are dissolved in a mixture of 10 cm3ethyl acetate and 10 cm3of ethanol. Add 87 mg of fumaric acid, dissolved in 10 cm3boiling ethanol. The reaction mixture was mixed for 2 h at room temperature and after drying under reduced pressure and recrystallization in ethanol obtain 140 mg of the desired product. So pl. 230oC.

The spectrum of IR (liquid paraffin):

C O: 1672 cm-1< / BR>
< / BR>
Microanalysis WITH19H21N3O, C4H4O4< / BR>
Calculated C 65,24; H 5,59; N 9,92

Found, C 65,3; H 5,9 N 9,9

Example 19. (16 alpha) () (14,15-dihydro-20,21-dengeburtigen-15-ilidene)-acetonitrile and its maleate.

Operating as in example 16, but using as the source Vashon (EP 0013315). Obtain 560 mg of the desired product as a base, then in the form of 245 mg maleate acid. So pl. 222oC.

The spectrum of IR (l3):

C=C, C=N, aromatic connection: 1656, 1631 cm-1< / BR>
C N 2224 cm-1< / BR>
The ranges of Bolman

Microanalysis for C19H19N3C4H4O4< / BR>
Calculated C 68,13; H 5,72; N 10,36

Found, C 68,2; H 5,6; N 10,4

Example 20. (16 alpha) () 20,21-dengeburtigen-15-acetic acid and its hydrochloride.

(16 alpha) () 20,21-dengeburtigen-15-acetate, obtained as described in example 12, emulsified with 55 ml of 2N hydroxyl sodium, heated for 13 hours at 100oC. is Cooled at 0oC, acidified with concentrated hydrochloric acid, dehydrated crystals, washed with ethanol and dried at 50oC. Obtain 0.87 g of the product of gross, which is recrystallized in water. So pl. > 260oC.

The spectrum of IR (liquid paraffin):

O: 1724 (max), 1700 cm-1(eq)

conjugated system

+ 1652, 1630, 1602, 1562 cm-1< / BR>
aromatic substance

Microanalysis WITH19H20N2O2HCl

Calculated C 66,18; H 6,14; N 8,12; Cl 10,28

Found, C 65,9; H 6,0; N, 8,1; Cl 10,1

Example 21. (16 alpha) () 20,21-deerborn is 5 cm3of methylene chloride, mixed for 10 min, added 0.66 g of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

Stirred for 10 min, added 0.28 g of hexanol, mixed for 16 h at room temperature. Suspension bring in water, extracted with methylene chloride, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water, dried and remove the solvents under reduced pressure. After chromatography on silica (eluent: methylene chloride-acetonitrile 9-1) obtain 0.3 g of the desired product in the form of the base, 0.3 g of base is dissolved in hot 10 cm3ethyl acetate and added 70 mg of oxalic acid dissolved in hot 5 cm3ethyl acetate. The resulting suspension is stirred for 1 h, dehydrated crystals, wash them with ethyl acetate and dried. Get 0,240 g of the desired salt. So pl. F 190oC.

Microanalysis: C25H32N2O2C2H2O4< / BR>
Calculated C 67,20; H 7,10; N 5,8

Found, C of 67.4; H 7,1; N 5,5

Example 22. (16 alpha) () 20,21-dengeburtigen-15-Il-2-propanone.

Operating as in example 12, using as starting material (16 alpha) 20,21-dengeburtigen 15+14N-he (EP 0013315) and, accordingly, izvozna 20,21-dengeburtigen-15 + 14N-she and allylbromide magnesium, receive the following products:

Example 23. (16 alpha) () 9-methoxy-15-methyl-20,21-dengeburtigen.

Example 24. (16 alpha) () 15-(trifluoromethyl)-20,21-dengeburtigen.

The products below can also be obtained by the method described above in this invention.

Example 25. (16 alpha) () 15-(permitil)-20,21-dengeburtigen.

Example 26. (16 alpha) () 20,21-dengeburtigen-15-ethylpropane.

Example 27. (16 alpha) () 20,21-dengeburtigen-15-ethylcarboxylate.

Example 28. (3 alpha) 20,21-dengeburtigen-15-ethyl acetate.

Example 29. (16 alpha) 20,21-dengeburtigen-15-ethyl acetate.

Example 30. (16 alpha) () 20,21-dengeburtigen-15-dimethylacetal.

Example 31. (16 alpha) () alpha-methyl-20,21-dengeburtigen-15-ethyl acetate.

Example 32. the pharmaceutical composition. Tablets were prepared according to the following formula:

The product of example 1, 25 mg

The filler for the finished tablets 300 mg (elements excipient: lactose, talc, starch, magnesium stearate).

Example 33. the pharmaceutical composition

Tablets were prepared according to the following formula:

the product of example 12 25 mg

the filler for the finished tablets 300 mg (filler elements: laktasi receptor alpha 2:

The cerebral cortex of 10 male rats of average weight 150 g of homogenized in 90 ml of 0.32 M sucrose. Then, 1000 g of a homogenized mixture was centrifuged for 10 min at 0 +4oC. the Precipitate resuspendable in 240 ml of buffer solution Tris HCl 50 mm pH of 7.7 and centrifuged at 30,000 g for 15 min at 0o4oC. Again the precipitate was resuspendable in 480 ml of buffer solution NaKPO4pH 7.4 50 mm.

Then 2 ml of the suspension were incubated for 45 min at 25oC in the presence of3H rauwolscine, the concentration of which is equal to 0.15 nM:

I) one

II) with increasing concentrations of tested product or

III) to determine nonspecific binding with non-radioactive phentolamine with a concentration of 10-5M.

Incubated suspensions were filtered on Whatman GF/C filters and washed three times with 5 ml of buffer solution NNaKPO4pH 7.4 at 0oC. the Radioactivity of the filters was measured by liquid scintillation.

The affinity of the investigated product to adrenergic receptors alpha 2 is given relative to fentolamina, which is the product of the standard.

C/D concentration fentolamina that inhibits 50% of specific binding3H rauwolscine.

The relative affinity is calculated by the ratio: ARL 100 (see tab. 1)

These products exhibit high means in relation to adrenergic receptors alpha 2.

2) hypobaric Anoxia

Rats-males-type CD1CHARLES RIVER weighing 20 to 25 g, have not eaten for 6 h were placed in 2-liter chamber, which is implemented depression 620 mmHg on the kinetics (see tab. 2)

Survival time is measured starting from the moment THAT the maximum duration is 3 min: (70 sec in control animals).

Rectal temperature was measured directly to determine the survival time. The products are injected intraperitoneally, the dose of 10 mg/kg in a volume of 10 ml/kg at 60 min prior to the start of the experiment. The results are given in percent increase in survival time compared to control animals (see table. 3).

For comparison of activity the applicant has chosen as a reference compound [()(16 alpha)]-11-methyl-20,21-dinarabaykenova]fumarate.

The comparison was done in terms of test "affinity" adrenergic receptors".

The indicator "ARZ" for connection 160.

Thus, the new compounds exhibit a higher affinity for 2-alpha-BR> -a group of radical

< / BR>
or

< / BR>
where R is C1C6-alkyl, possibly substituted by hydroxy, cyano, CONH2or carboxypropyl, possibly esterified, C2- C4alkenyl, C2C4-quinil or free or esterified carboxypropyl;

R1CR8R9where R8and R9both hydrogen or one is hydrogen and the other is cyano,

or their optical isomers, or salts with organic acids.

 

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,

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2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I or its pharmaceutically acceptable salts, which are inhibitors of Trk kinases and are useful for treating pain, malignant oncological disease, inflammation, neurodegenerative diseases and Trypanasoma Crusi infections. Invention also describes versions of methods of producing compound of formula I. In Formula I (I) ring A is selected from A-1, A-2, A-3, having structure , where wavy line marked 1 indicates connection point of ring A to ring B, and wavy line marked 2 indicates point of connection ring A to W; X is N or CH; Y is H or F; R1 is H or halogen; ring B is selected from rings B-1 and B-2, having structure , where wavy line marked 3 indicates point of connection to ring A, and wavy line marked 4 indicates point of connection to pyrazolo[1,5-a]pyrimidine ring of formula I; W is O, NH or CH2, wherein, when ring A is A-2, then W is CH2; m is 0, 1 or 2; D is carbon, R2 and R2a independently represent H, F, (1-3C)alkyl or OH (provided that R2 and R2a are not simultaneously OH), and R3 and R3a are independently H or (1-3C)alkyl, or (D) is carbon or nitrogen, R2 and R3 are absent, and R2a and R3a together with atoms to which they are bonded, form 5-6-member heteroaryl ring containing 1-2 heteroatoms ring; Z is *-NR4aC(=O)-, *-ONHC(=O)-, *-NR4bCH2- or *-OC(=O)-, where asterix indicates connection point of Z to containing carbon R3; R4a is H or (1-6C)alkyl; R4b is H, (1-6C)alkyl, ((1-6C)alkyl)C(O)-, HOCH2C(O)-, ((1-6 C)alkyl) sulfonyl, HO2CCH2- or ((1-6C)alkyl)NH(CO)-; and R-5 and R6 independently represent H, halogen, OH or (1-6C)alkyl.

EFFECT: useful for treating pain, malignant oncological disease, inflammation, neurodegenerative diseases and Trypanasoma Crusi infections.

73 cl, 1 tbl, 45 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to a compound of general formula

or , or pharmaceutically acceptable salts thereof, R is methyl, ethyl, propyl or benzyl; * - X - * is selected from the group consisting of , and ; Y is (-CH2-)3 or (-CH2-)4. The invention also relates to a method for preparation of compounds of general formula 1 or 2.

EFFECT: new compounds are obtained that have the properties of protein-protein interactions inhibitors.

4 cl, 2 tbl, 3 ex

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