The method of obtaining (-)- 1-ethyl - 1-(hydroxymethyl)-1,2,3,4, 6,7,12, 12b 1-octahedron(2,3-a)hemolysin (options), 1-ethyl-1 - (hydroxymethyl)-1,2,3,4,6,7-hexahydro-n-indole(2, 3-a)hemolysin and its optically active salt

 

(57) Abstract:

Usage: in medicine, methods of obtaining (-)-1 - ethyl - 1 -(hydroxymethyl) - 1, 2, 3, 4, 5, 6, 7, 12, 12 b a-octahedron (2,3-a) hemolysin by reacting 1 - ethyl 2, 3, 4, 6, 7, 12 - hexahedronal (2,3-a) hemolysin with an equivalent amount of formaldehyde to obtain a racemate of 1 - ethyl - 1 - (hydroxymethyl) - 1, 2, 3, 4, 6, 7 - hexa - N - indole (2,3-a) hemolysin, then adding more or less an equivalent amount of the optically active acid in the environment of the solvent at ambient temperature with Poluchenie of diastereoisomeric salts which may be allocated and from which recovery produce the target product as the base. 7 C. and 2 h. p. F.-ly.

The invention relates to a new process for the preparation of 1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7,12,12 b-octahedrons [2,3-a] hemolysin and new intermediate products, namely the method of production of (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7,12,12 b-octahedron [2,3-a] hemolysin formula I

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(I) and new intermediate products obtained along the way during this process.

The compound of formula (I), having a peripheral vasodilator, it is well known, the method of its production and health the 3-a] chinoline, used as raw material in the process described in [2] can be prepared using the method [1] which consists in carrying out the reaction of 1-ethyl-2,3,4,6,7,12-hexahydrobenzo [2,3-a] hemolysin formula II

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(II) with formaldehyde, the amount of which exceeds considerably necessary. In this case, the obtained compound of formula (I) in racemic form. As described in [2] a therapeutically effective ethylpropane can be obtained by acylation of the specified racemic compounds with subsequent decomposition acylated thus the connection and subsequent diallylammonium allocated-ethyl-form four-step reaction. Output pharmaceutically ineffective-ethylpropane allocated on the stage of decomposition, only 25 per cent estimated for the original hexahedronal [2,3-a] hemolysin formula (II), if we consider the known data on the product yield [1,2]

The purpose of the invention is to develop a rational sequence of synthesis, through which you can convert the original 1-ethylhexanediol [2,3-a] hemolysin formula (II) into the corresponding-ethylpropane more easily, efficiently, and with a possible re-use of waste-ethylpropane about what provedenii reaction 1-ethylhexanediol [2,3-a] hemolysin formula (II) with an almost equivalent amount of formaldehyde or its polymerized form get a new connection, racemic 1-(hydroxymethyl)-1,2,3,4,6,7-hexahydrobenzo [2,3-a] hemolysin formula III

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(III) from which you can simply obtain the target compound in two different ways, restoring new salt indochinoise salt of formula IV

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(IV) where Xrepresents the residue of an optically active acid, and salt get either

a) after processing the corrosive (solvent) substance in an amount which is less than the equivalent quantity, or

b) after treatment of corrosive (solvent substance) in an amount that is greater than an equivalent amount.

Corrosive (solvent) substance is optically active acid. Such acids known in the field of science and technology.

The invention allows to obtain

(-)-1-ethyl-1-(hydroxymethyl)-1, 2,3,4,6,7,12,12 b-octahedron [2,3-a] hemolysin formula (I) in accordance with the scheme. This process differs in that

1) it involves the reaction of 1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] hemolysin formula (II) with an almost equivalent amount of formaldehyde or its polymerized form and, after isolation (if necessary), new racemic 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexa - hydro-N-indole [2,3-a] hyocorou less than an equivalent amount, in the result that are restoring to a new salt of 1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-Yuma formula (IV), or

b) processed corrosive (solvent) substance in a quantity that is greater than an equivalent amount, and then, vapours salts of diastereomers of formula (IV) and (V)

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(V) where Xhas a specified value, and the resulting new salt of 1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indolo[2,3-a]Chi - naizin-5-Yuma restored to obtain the compounds of formula (I) and, if necessary, a new salt of 1-ethyl - 1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole [2.3-a] chinolin-5-Yuma formula (V) is converted into the original compound of formula (II); or

2) it involves the reaction of 1-ethyl-2,3,4,6,7,12-hexahydrobenzo [2,3-a] hemolysin formula (II) with an almost equivalent amount of formaldehyde or its polymerized form and corrosive (solvent) substance in an amount which is less than the equivalent amount, after which a new salt of 1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-in - Dol [2,3-a] chinolin-5-imum restored to obtain the compounds of formula (I) or

3) it involves the reaction of salts of 1-ethyl-1,2,3,4,6,7-hexahydrobenzo [2,3-a] chinolin-5-Yuma formula IIa

has a specified value and, possibly, the binding free base of formula (I).

The invention relates to new compounds of formula III

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(III) i.e., 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indolo [2,3-a] hemolysin.

Also proposed new compound of the formula IV

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(IV) where Xhas the specified value.

Also proposed new compound of the formula V

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(V) where Xhas the specified value

The original compound of formula (II) interacts with an almost equivalent amount, preferably 0.9 to 1.1 moles, of formaldehyde or its polymeric form, such as paraformaldehyde, at a temperature close to the room. Paraformaldehyde is introduced into a solution of starting compound of the formula (II) in the proton or bipolar aprotic solvent, or a mixture thereof. New racemic substance of the formula (III) thus obtained, after separation or mainly without selection interacts with the corrosive (solvent) substance is taken in a quantity greater than the equivalent ethyl)-1,2,3,4,6,6-hexahydro-N-indole- [2,3-a] hemolysin formula (IV), formed by using the specified present and degrades (solvent) substances from which the target compound is obtained by recovery, and then, perhaps, the binding free base.

The above-described reaction with formaldehyde and handling of corrosive (solvent substance) is performed at a temperature close to the room, in a bipolar aprotic solvent type, acetone, methyl ethyl ketone, methylisobutylketone, acetonitrile, dimethylformamide, mainly in acetone, or in proton solvent type, methanol, ethanol, propanol, isopropanol, mainly in isopropanol, or in a solvent mixture of these two types, mainly in acetone containing ethanol or isopropanol.

Dissolution (dissolution) of the new compounds of formula (III) comply with optically active acids, mainly(-)-L-dibenzoyltartaric acid.

The restoration of the new compounds of formula (IV) can be performed in a known manner by means of a chemical reducing agent type sodium borohydride or by catalytic hydrogenation using a catalyst mainly of palladium on charcoal. When the recovery is performed using chemical is) crystallizes from the reaction mixture by adding water. When the recovery is carried out by means of catalytic hydrogenation, the target connection is allocated after the binding of free base. The binding free base performed in a known manner by adding inorganic bases hydroxide of an alkali metal or ammonium hydroxide. When performing the above described method are compound of the formula (IV) of the starting compound of the formula (III) in very good (close to 90%) output from the compounds obtained by the described recovery receive target Etienne derivative compound of formula (I). Thus, it is possible to convert the source compound of formula (II) in the target product of the formula (I) with the release of over 80% (calculated, for example, on the basis of the data of examples 13 and 8), and, if you compare the number of stages of the reaction and the outputs provided by the method [2] what you see is indisputable advantages of the proposed method.

Under option 1b) of the proposed method, a new racemic compound of the formula (III) obtained at the beginning of the reaction, decompose (dissolved) using corrosive (solvent) substance in excess of the equivalent amount. In this case, the decomposition (dissolution) perform the ora L-dibenzoyltartaric acid in bipolar aprotic solvent type acetone at a temperature close to the room. When used last Wednesday, the expensive L-dibenzoyltartaric acid can be replaced mostly cheaper acid, such as acetic acid in an equivalent amount of about 0.5.

The original compound of formula (II) can be recovered from the new salt of 1-ethyl-1 -(hydroxymethyl)-1,2,3,4,5,7-hexahydro-N-indole [2,3-a] chinolin-5-Yuma formula (V) obtained after separation by processing appropriately chosen basis, although you could get a therapeutically ineffective stereoisomer of the target compound by restoring this salt. Primary treatment can be performed by using organic bases triethylamine or dialkylanilines, or with inorganic bases type hydroaxe ammonium or hydroaxe alkali metal, mainly in the heterogeneous phase system containing water base and immiscible with water, an organic solvent type aliphatic or aromatic hydrocarbons, for example dichloromethane, chloroform, dichloroethane and chlorobenzene, or aromatic hydrocarbons such as benzene and xylene; as the aqueous base can be used mainly sodium hydroxide solution. The reaction is carried out by preimushestvenno(II), received and allocated in the form of an acid salt type, perchlorate, oxalate or (-)-L-dibenzoyltartaric, re-used as starting material for the preparation of therapeutically effective L-atilade. The advantage of the method according to option 1b before way, the essence of which opened in the description of [2] is that the waste therapeutically ineffective stereoisomer is not possible at all, because its useless stereoisomer of formula (V) obtained as a by-product of the synthesis, is converted into the parent compound of formula (II).

Thus, the use of the original hexahedronal [2,3-a] hemolysin formula (II) is from about 60 to 70% according to the calculations of the final product.

Under option 2) of the proposed method, the original hexahedronal [2,3-a] hemolysin formula (II) interacts with an almost equivalent number of paraformaldehyde in properly selected solvent or solvent mixture in the presence of present and degrades (solvent) of a substance used in an amount which is less than the equivalent, calculated on the amount of starting compound of the formula (II) and corrosive (solvent) substance mainly I have but one stage of the reaction for several hours at a very good almost 80% of the yield and the optical purity of about 100%

Under option 3) the proposed method, the final product can also be obtained by reaction of the salt of starting compound of the formula (II) prepared in optically active acid, mainly -(1-ethyl-1,2,3,4,6,7-hexahydro-N-indole[2,3-a] chinolin-5-FMD)2(-)-L-dibenzoyltartaric, i.e. the compounds of formula (IIa), in properly selected solvent or solvent mixture with an almost equivalent amount of formaldehyde in the presence of 0.01-0.1) is equivalent to the number of properly selected Foundation type of starting compound of the formula (II), to obtain the compound of formula (IV) in crystalline form after stirring the reaction mixture for several hours at achieving yield and purity at the level described above.

According to this variant of the process according to the invention, corrosive (dissolving) the substance is introduced into the reaction mixture in the form of a salt of starting compound of the formula (II). Solvents or solvent mixtures used in options 2) and 3) the method according to the invention, can be the same as that used in embodiment 1). Described in process variants 1A), 2) and (3) handling corrosive (solvent) substance leads to asymmetric premolded, forms a racemic adduct of formula (III). Racemic adduct of the formula (III) is in dynamic equilibrium with the compound of the formula (II). If this equilibrium mixture is less than the equivalent amount of present and degrades substances that (mostly) one of the stereoisomeric salts racemic adduct of the formula (III) crystallizes, and the other remaining in the solution diastereoisomer salt becomes racemic through the implementation of the described process of dynamic equilibrium. This equilibrium exists only in the form of a base and, therefore, a slight excess of the base with respect to the applicable decomposes the acid.

Summarizing the advantages of options 1), 2) and (3) offer and comparing them with the process [2] it is possible to establish that the receipt of the target compounds is possible in two, not four, stage reaction at a much higher outputs. If you are performing the method according to option 1b), we get a very good output therapeutically effective compound is ethyl, and its therapeutically ineffective antipode, which went to waste, as in the method according to the invention can be used.

The initial compounds of formulas (II) and (IIa) and the s are not limiting the scope of invention.

P R I m e R 1. ( )-1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydrobenzo [2,3-a] hemolysin (III).

of 37.8 grams (0.15 mol) of 1-ethyl-2,3,4,6,7,12-hexahydrobenzo [2,3-a] hemolysin dissolved in 100 ml of acetone, add 5 g of paraformaldehyde and stirred the mixture at room temperature for one and a half hours. After that, the mixture was added 30 ml of distilled water for 15 minutes and continue stirring for one hour at a temperature of 0aboutC. the Precipitated product specified in the header of the sample obtained in the form of orange crystals, is filtered and washed twice in acetone, the total of which amounts to 20 ml at a temperature of 0aboutC.

Weight 34,13 g (80,7%); melting point (III) 113aboutC.

P R I m m e R 2. a) (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-FMD-(+)-D-tartarate (V). 8.6 g (0,0573 mol) of (+)-D-tartaric acid are dissolved in 160 ml of distilled water and add 16,1 g (0,057 mol) ( )-1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro Dol [2.3-a] hemolysin prepared according to example 1. The mixture is stirred for 10 minutes at room temperature to obtain a homogeneous solution. This solution, if necessary, filtered through celite and allow to settle for 2 the Ohe, the total number of which is 10 ml, the Mass of 10.2 g, melting point 103-105aboutS; output 82,7% [D2081,7about(C=1, methanol).

b). (+)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-FMD-(+)-D-tartarate (IV).

The aqueous mother liquor, obtained as described in part a) the sample is cooled at a temperature of 10aboutWith and allow to settle for 24 hours Obtained in the form of crystals precipitated product is filtered off and washed twice in acetone, the total of which amounts to 10 ml Mass of 6.2 g; melting point 136-139oWith the output 58,4% [D20-117about(C=1, methanol).

P R I m e R 3. (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahedronal 2,3-and hemolysin-5-FMD (-)-L-dibenzoyltartaric (IV).

14.1 g (0.05 mol) of ( )-1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydrobenzo [2,3-a] hemolysin prepared according to example 1 are suspended in 50 ml of acetone. Then add a solution of 2 g of acetic acid and 8.5 g (0,0226 mol) monohydrate (-)-L-dibenzoyltartaric acid in 30 ml of methanol, while stirring. The mixture is stirred for 3 h and filtered at 20aboutC, and then washed with acetone. Specified in the header of the example, the product is obtained in the form of a crystal the project 59,3% as determined by titration of HClO4. The yield, calculated on the content of the base is 84,1%

P R I m e R 4. (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydrobenzo [2,3-a] chinolin-5-FMD]2(-)-L-dibenzoyltartaric (IV).

of 37.8 grams (0.15 mol) of 1-ethyl-2,3,4,6,7,12-hexahydrobenzo [2,3-a] hemolysin dissolved in 100 ml of acetone, added to a solution of 5.2 g of paraformaldehyde and mix salt in one and a half hours at room temperature. After that add in a mixture of 50 ml of acetone, and then a solution of 6 g of acetic acid and 28 g (0,0745 mol) monohydrate (-)-L-dibenzoyltartaric acid in 100 ml of methanol. The mixture is stirred for 3 h, and the precipitated crystalline product that is specified in the header of the example, is filtered at a temperature of 20aboutC and washed with acetone.

Weight 28 g; melting point 171-173aboutC.

[D20-82,7about(C=1, dimethylformamide); the content of the base 59,2% as determined by titration of HClO4. The yield, calculated on the content of the base, equal 78,37%

P R I m e R 5. Perchlorate 1-ethyl-1,2,3,4,6,7-hexahydro-N-indolo [2,3-a] chinolin-5-Yuma (II, salt).

of 21.6 g (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indolo [2,3-a] chinolin-5-FMD-(+)-L-tartrate prepared according to example 2A), suspended in smem stirring and continue stirring for 15 minutes Then add 10 ml of 25% aqueous sodium hydroxide solution and continue vigorous stirring for 15 minutes the Organic phase is separated and the aqueous phase is extracted with 30 ml dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered from the drying agent and evaporated.

The residue is dissolved in 40 ml of methanol and acidified to pH 1-2 60% aqueous solution perchloro acid. The precipitated product is specified in the header of this example, is obtained in the form of crystals; it is filtered at a temperature of 0aboutC and washed twice in chilled methanol, the total of which amounts to 10 ml. Mass 14,95 g (85%). Melting point 178-180aboutC.

P R I m e R 6. 1-ethyl-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-FMD-(-)-L-dibenzoyltartaric (II, salt).

The compound prepared as in example 5 with the difference that the residue of the solvent is dissolved in 60 ml of acetone, added to a solution of 9.45 g of the monohydrate of (-)-L-dibenzoyltartaric acid and stirred for 15 min under reflux. Specified in the header of the example, the product obtained in the form of crystals, is filtered at a temperature of 10aboutC and washed twice in acetone, the total number p 7. Perchlorate 1-ethyl-1,2,3,4,6,7-hexahydro-N-indolo [2,3-a] chinolin-5-Yuma (II, salt).

The mother solution containing acetone and methanol obtained in example 2, is evaporated in a vacuum. To the residue add 70 ml of dichloromethane and 100 ml of water and then 10 ml of concentrated ammonia and 8 ml of 25% aqueous sodium hydroxide solution, producing and mixing. After stirring for half an hour, separate the organic phase and the aqueous phase is extracted in two steps, using a total of 30 ml of dichloromethane. The combined extracts are evaporated, the residue is added 20 ml of methanol and acidifying the resulting solution to achieve pH 1-2 by addition of 60% aqueous solution of chloric acid. The precipitated product is specified in the header of this example, is filtered at a temperature of 0aboutC and washed twice in chilled methanol, the total of which amounts to 10 ml Mass of 12.33 (87%); melting point 178-180aboutC.

From the obtained salt can easily obtain the corresponding free base, i.e., 1-ethyl-2,3,4,6,7,12-hexahydrobenzo [2,3-a] hemolysin, in the form of a solution in an organic solvent, carrying out distribution of phases between immiscible with water rastvoritelb also suitable for processing making solutions described in the examples 2,3,4,10 and 12.

P R I m e R 8. (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7,12,12-octahedron [2,3-a] hemolysin (I).

47,63 g (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-FMD]2-(-)-L-dibenzoyltartaric prepared according to example 13 containing the base 59,2% are suspended in 800 ml of methanol. Then, the suspension is admixed in small portions of 6.5 g of sodium borohydride, carrying out mixing up until the suspension becomes colorless. The mixture was concentrated in vacuo to one third its original volume and add 800 ml of water. The precipitated white substance is filtered off, washed neutral substance (water) and dried in a vacuum desiccator. The mass of 27.8 g (98%), melting point 228-230aboutC; [D20-108,4 (C=1, dimethylformamide).

P R I m e R 9. (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7,12,12 b-octahedron [2,3-a] hemolysin (I).

4.3 g (+)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-octahydro-N-indole [2,3-a] chinolin-5-FMD-(+)-b-tartrate prepared according to example 2b), suspended in 70 ml of methanol. In suspension, mixing, add small portions of 0.7 g of sodium borohydride at a temperature of 20aboutWith continuing mixing until until the solution not stonestrom water. Weight is 2.74 g (97%); melting point 228-230aboutC; [D20108,7about(C=1, dimethylformamide).

P R I m e R 10. (-)-1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7,12,12 b - octahedron [2,3-a] hemolysin (I).

10 g of (-)-[1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-FMD]2-(-)-L-dibenzoyltartaric (content base 59.3% ) were suspended in a mixture of 40 ml of dimethylformamide and 40 ml of methanol, then add 0.5 g of 10% palladium charcoal and hydrogenized mixture of elemental hydrogen up until the consumption of hydrogen stops. The catalyst is filtered off and the filtrate is washed twice with methanol, the total of which amounts to 10 ml. Methanol removed from the filtrate by atmospheric distillation, and the residue is slowly poured vigorously stirring, in a mixture of 3 ml of concentrated ammonia and 120 ml of water. Settled the matter, 5.75 g (97% ), filtered and washed neutral substance with water. The product is obtained in the form of crystals precipitated from dimethylformamide. Product parameters: melting point 228-230aboutC; [D20-108,4about(C=1, dimethylformamide).

P R I m e R 11. (-)-[1-ethyl-1 -(gidroksimetil)-1,2,3,4,6,7-hexahydro-N-indole[2,3-a] chinolin-5-FMD]2aboutReceived in the form of crystals deposited compound indicated in the heading of example, and washed it twice in a mixture of acetone and methanol in the ratio of 5:2, the total amount of the mixture of 20 ml, and then dried. Weight of 18.7 g; melting point 170-172aboutC; [ D20-60,4about(C=1, dimethylformamide). The content of the base 59,2% as determined by titration of HClO4. The yield, calculated on the content of the base equal to 78.5% of the

The mother liquor can be processed by a method, the essence of which is disclosed in example 7.

P R I m e R 12. (-)-[1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7 - hexahydro-N-indole [2,3-a] chinolin-5-FMD]2-(-)-L-dibenzoyltartaric (IV).

of 37.8 grams (0.15 mol) of 1-ethyl-2,3,4,6,7,12-hexahydrobenzo [2,3-a] hemolysin dissolved in 100 ml of acetone, and then added to 5.2 g (0,173 mol) of paraformaldehyde is added and stirred the mixture at room temperature for one and a half hours. Then, the resulting solution was added 50 ml of acetone and a solution of 26 g of the monohydrate of (-)-L-dibenzyline is sucked in at a temperature of 20aboutC and washed twice in a mixture of acetone and methanol and proportions 5: 2, the total amount of the mixture (60 ml) and then dried. Weight of 52.5 g; melting point 170-172aboutC; [D20-79,7about(C=1, dimethylformamide). The content of the base is 58% as determined by titration HlCO4. The yield, calculated on the content of the base is 73%

P R I m e p 13. (-)-[1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-FMD]2-(-)-L-dibenzoyltartaric (IV).

of 37.8 grams (0.15 mol) of 1-ethyl-2,3,4,6,7,12-hexahydrobenzo [2,3-a] hemolysin interacts with a 5.4 g (0.18 mol) of paraformaldehyde in 100 ml of acetone at a temperature of 20aboutC for 1 h and then added to the mixture a solution of 26 g (0,069 mol) monohydrate (-)-L-dibenzoyltartaric acid in 100 ml ethanol. The mixture is stirred for 10 hours at a temperature of 20aboutC. the Precipitated product is specified in the header of the example, is filtered and washed twice in ethanol, the total number of 50 ml. Weight 61 g; melting point 170-172aboutC; [D20-74,1about(C=1, dimethylformamide). The content of establishment: 57,6% yield, calculated on the content of the Foundation, is 89%

P R I m e R 14. (-)-[1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7 - hexahydro-N-ind is except that the same number of source 1-ethyl-2,3,4,6,12-hexahydrobenzo [2,3-a] chinoline, paraformaldehyde and (-)-L-dibenzoyltartaric acid are simultaneously added to 150 ml of acetonitrile and stirred the mixture at a temperature of 20aboutC for 24 h According to the procedure described in example 13, indicated in the header of the example product is obtained in the number of 54.8, Yield 80%

P R I m e R 15. (-)-[1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-FMD]2-(-)-L-dibenzoyltartaric (IV).

17.3 g [1-ethyl-1,2,3,4,6,7-hexahydro-N-indole [2,3-a] chinolin-5-FMD]2-(-)-L-dibenzoyltartaric and 1.35 g of paraformaldehyde suspended in a mixture of 160 ml of acetonitrile and 10 ml of methanol, add 0.4 g of triethylamine and stirred the mixture at room temperature for 24 hours Product specified in the header of the example, is filtered at a temperature of 0aboutWith in the form of crystals, washed twice with methanol, the amount of which in total is 10 ml, and dried. Weight of 14.4 g; yield 78%

Scheme for compounds I.

The original connection.

1. The method of obtaining (-)-1 - b-ethyl-1 a-hydroxymethyl-1,2,3,4,6,7,12,12 b a-octahedron (2,3=a) hemolysin formula I

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by vzaimoizgodni in the environment of the solvent followed by the addition of the optically active acid in the environment of the solvent to obtain the corresponding salt, from which emit crystallization of optically active salt, of which we distinguish a target product in the form of a base, characterized in that the formaldehyde or paraformaldehyde is used in almost the equivalent amount and get the racemate 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexa-N-indole (2,3-a)hemolysin formula III

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which is treated with an optically active acid, taken in an amount less than the equivalent quantity, at ambient temperature to obtain the salt of the racemate from which emit optically active salt of (-)-1-ethyl-1 -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole(2,3-a)hemolysin-5-Yuma formula IV

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where Xthe remainder of the optically active acid, which is treated with a reducing agent to obtain the target product as the base.

2. The method of obtaining (-)- 1-ethyl - 1a -(hydroxymethyl)-1,2,3,4,6,7,12,12 b a - octahedron (2,3-a) hemolysin formula I

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by reacting 1-ethyl-2,3,4,6,7,12-hexahedronal(2,3-a) hemolysin formula II

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with formaldehyde or paraformaldehyde in the environment of the solvent followed by the addition of the optically active acid in the environment of the solvent to obtain the corresponding salt, from which crystallization allocate DASD use in almost equivalent to the number of receiving racemate 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexa - N-indole (2,3-a) hemolysin formula III

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which is treated with an optically active acid, taken more than an equivalent amount, at ambient temperature to obtain the salt of the racemate from which emit a pair of diastereomeric salts of the formula IY and Y

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< / BR>
where X- the remainder of the optically active acid,

and the resulting salt of the diastereoisomer of formula IV turn recovery into the base connection of the formula I, a salt of the diastereoisomer of formula V, if necessary, converted into the original compound of formula II by treatment with hydroxide selango metal.

3. The method of obtaining ( - )- 1-ethyl-1a -(hydroxymethyl)-1,2,3,4,6,7, 12,12 b a-octahedron (2,3-a) hemolysin formula I

< / BR>
by reacting 1-Eitel-2,3,4,6,7,12-hexahedronal-(2,3-a) hemolysin formula II

< / BR>
with formaldehyde or paraformaldehyde, including processing optically active acid in the environment of the solvent to obtain the salt of the diastereoisomer with the subsequent turning it at the base, characterized in that the formaldehyde or paraformaldehyde is used in almost equivalent amounts, the process is conducted at ambient temperature, optically active acid is added simultaneously with formaldehyde or paraform is the quality diastereoisomer salts are salt of the diastereoisomer of formula IY

< / BR>
where X- the remainder of the optically active acid,

and the selection of a free base of compounds of formula I - lead by treatment with reducing agent.

4. The method of obtaining ( - )- 1-ethyl-1a -(hydroxymethyl)-1,2,3,4,6,7,12,12 b a - octahedron (2,3-a) hemolysin formula I

< / BR>
by interacting derived 1,2,3,4,6,7-hexahedronal (1,3-(a) hemolysin-5-Yuma with formaldehyde or paraformaldehyde in the environment of a solvent in the presence of a base to obtain the corresponding salt, which produce the target product, characterized in that as a function of 1,2,3,4,6,7-hexahedronal (2,3-a) hemolysin-5-Yuma using salt and 1-ethyl-1,2,3,4,6,7-hexahedronal (2,3-a) hemolysin-5-Yuma with the optically active acid of formula IIa

< / BR>
where X- the remainder of the optically active acid.

formaldehyde or paraformaldehyde is used in almost the equivalent amount of obtaining salts of 1-ethyl-1a (hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole (2,3-a) hemolysin-6-Yuma formula IY

< / BR>
where X- the remainder of the optically active acid,

which is treated with a reducing agent to obtain the target product as the base.

5. The method according to PP. 1 to 4, otlichayushchiesya active acid with formaldehyde in the presence of a maximum of 0.1 equivalent amount of a base at a temperature close to the room, proton or bipolar aprotic solvent or in mixtures of these solvents.

6. The method according to PP. 1 to 4, characterized in that carry out the restoration of salt 1-ethyl-1a -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole (2,3-a) hemolysin-5-Yuma formula IY chemical reducing agent, mainly with sodium borohydride or by catalytic hydrogenation possibly in the presence of palladium charcoal as catalyst.

7. 1-ethyl-1 - (hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole (2,3-a) hemolysin formula III

< / BR>
8. Optically active salt of 1-ethyl-1a -(hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole (2,3-a) hemolysin-5-Yuma formula IV

< / BR>
where Xthe balance in ( - ) - dibenzoyltartaric acid or a residue of (+)-D-tartaric acid.

9. Optically active salt of (-1 - 1b - ethyl - 1a - (hydroxymethyl)-1,2,3,4,6,7-hexahydro-N-indole(2,3-a) hemolysin-5-Yuma formula V

< / BR>
where Xthe balance in ( - ) - dibenzoyltartaric acid or a residue of (+)-D-tartaric acid.

 

Same patents:

The invention relates to a new series of tetracyclic compounds having two or three nitrogen atoms included in the ring, which have significant anti-allergic and anti-asthma activity, provides methods and compositions for their use, as well as technologies of their production

The invention relates to new heterocyclic compounds having valuable biological properties, in particular to derive dipyrido-diazepine General formula (I)

(I) where Z is oxygen, sulfur, group NCN иNOR9where R9lower alkyl;

R1hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkenylacyl, lower alkoxyl, lower alkanoyl, lower dialkylaminoalkyl, lower alkoxyalkyl, lower alkylthiomethyl, benzyl;

R2hydrogen, lower alkyl, lower foralkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, cyano, phenyl, benzyl, lower alkoxybenzyl, methylsulphonyl;

R3hydrogen, hydroxyl, halogen, nitro, lower alkyl, lower alkoxy, amino, lower mono - or dialkylamino, lower alkynylamino, pyrrolidin-1-yl, pyrrolin-1 - yl, tetrahydropyridine-1-yl, morpholine-1-yl, piperidine-1-yl, methoxyphenylethylamine, methoxybenzylamine;

R4hydrogen, halogen, lower alkyl, nitro, amino;

R5hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, trihalomethyl, lower oxyalkyl, cyano;

R8hydrogen, lower alkyl; and when Z is oxygen or sulfur, R2hydrogen, lower alkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, phenyl, benzyl, lower alkoxybenzyl; R3, R4, R5, R6, R7and R8a hydrogen atom or one of the substituents R3, R4, R5, R6, R7and R8the lower alkyl and the other substituents are hydrogen, or one of the substituents R3, R4, R5and R7the halogen and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7nitro, and the remaining substituents R5, R6and R8hydrogen, or one of zamestitelei R3, R5and R6is hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5alkoxy, and the other substituents R4, R6, R7and R8hydrogen, or R5lowest oxyalkyl or cyano, and R3, R4, R6, R7and R8hydrogen, or R7azido, and R3, R4, R5, R6and R83, R4and R5means butyl, and the other substituents R6, R7and R8mean hydrogen, and R6, R7and R8independently of one another denote hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8means butyl, and the other substituents R3, R4and R5mean hydrogen, R1does not mean hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkanoyl, lower alkoxyalkyl and lower alkylthiomethyl, and their hydrates and pharmacologically tolerable salts have valuable biological properties, particularly an inhibitory effect on reverse transcriptase of the virus HIV-1, so that they can be used for prevention or treatment of AIDS

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel derivative of variolin B of the general formula (I) or their pharmaceutically acceptable salts possessing antitumor activity. In the general formula (I) radical R1 means aromatic group representing aromatic group representing phenyl optionally substituted with nitro-group, amino-group or alkyl-substituted amino-group, or aromatic group represents 5-6-membered heterocycle with two nitrogen atoms or sulfur atom as heteroatoms optionally substituted with (C1-C12)-alkyl, -OH, unsubstituted amino-group or amino-group substituted with (C1-C4)-acyl, phenyl-(C1-C4)-alkyl wherein phenyl group can be substituted with -OR1, or (C1-C12)-alkylthio-group, (C1-C12)-alkyl- or phenylsulfonyl, (C1-C12)-alkyl- or phenylsulfinyl or -OR1 wherein R1 is chosen from (C1-C12)-alkyl or phenyl; R2 represents hydrogen atom; R3 represents oxo-group when a dotted line is between nitrogen atom to which R2 is bound and carbon atom to which R3 is absent, or R2 is absent when R3 represents optionally protected amino-group wherein a substitute is chosen from (C1-C4)-acyl, phenylsulfonyl and (C1-C4)-alkylphenylsulfonyl when a dotted line forms a double bond between nitrogen atom to which R2 is bound and carbon atom to which R2 is bound; R4 represent hydrogen atom. Also, invention relates to a method for synthesis of compounds of the invention and to intermediate substances for their realization. Also, invention relates to a pharmaceutical composition based on variolin B derivatives.

EFFECT: improved method of synthesis, valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 5 sch, 1 tbl, 50 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of dihydroimidazo[5,1-a]-β-carboline of the general formula (I): wherein R1 = R3 = R4 mean hydrogen atom (H); R2 means hydrogen, halogen atom, (C1-C6)-alkyl, hydroxyl, (C1-C6)-alkoxyl; R5 means hydrogen atom or (C1-C6)-alkyl; R6 and R7 mean independently hydrogen atom or (C1-C6)-alkyl or phenyl with exception compounds of the general formula (I) wherein R1-R6 mean hydrogen atom, and R7 means group -CH or phenyl, and their isomers and additive salts with pharmaceutically acceptable acid also, and a method for their synthesis and pharmaceutical composition. Novel compounds possess soporific effect and can be used in producing a medicinal agent.

EFFECT: improved method of synthesis and preparing, valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 10 tbl, 25 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of varioline and their pharmaceutically acceptable salts and esters possessing anti-tumor activity. In compound of the formula (I): each among R1 and R2 is chosen independently from group comprising hydrogen atom (H), -OH, -OR', -SH, -SR', -SOR', -SO2R', -NO2, -NH2, -NHR', -N(R')2, -NHCOR'. -N-(COR')2, -NHSO2R', (C1-C12)-alkyl, (C1-C12)-halogenalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaromatic group; R3 is chosen from group comprising -OH and -OMe wherein group R' or each among groups R' is chosen independently from group comprising -OH, (C1-C12)-alkyl, (C1-C12)-halogenalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl and substituted or unsubstituted heteroaromatic group; if group R1 or R2 represents group of the formula -N(R')2 or -N(COR')2 then all groups R' can comprise similar or different values, either groups R' in common with nitrogen atom to which they are added can form 5-7-membered heterocyclic ring. Aryl group or aryl moiety of aralkyl and arylalkenyl group represents a carbocyclic aryl group comprising 6 carbon atoms in carbocyclic ring; aralkyl group represents (C1-C6)-alkyl group substituted with abovementioned aryl group; arylalkenyl group represents (C2-C6)-alkenyl group substituted with abovementioned aryl group; heteroaromatic group represents a heterocyclic aromatic group comprising from 5 to 7 atoms in ring wherein heteroatoms in ring are chosen from nitrogen atom; substituted in aryl and heteroaromatic groups and in aryl moiety of aralkyl and arylalkenyl groups are chosen from group comprising (C1-C12)-alkyl, (C1-C12)-halogenalkyl, (C1-C12)-alkoxy-, (C1-C12)-alkylthio-group, -NH2, (C1-C6)-alkylamino-, di-(C1-C6)-alkyl)-amino-, (C1-C4)-alkanoylamino-, di-(C1-C4)-alkanoylamino-group, -NO2, -CN and halogen atom, its derivatives wherein nitrogen atom is quaternized. Proposed compounds possess anti-tumor activity and can be used in treatment or prophylaxis of cancerous diseases, for example, ovary cancer, prostate cancer, mammary cancer and melanoma.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods of treatment, improved methods of synthesis.

38 cl, 10 sch, 2 tbl, 25 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for synthesis of nitrogen containing heterocyclic compounds, in particular compounds of formula I , wherein 1) R and R1 are H; 2) R is H, R1 is CH3; 3) R and R1 are CH3. Claimed method includes reaction of 2-chloro-3-nitropyridine with 3-R-5-R1-pyridine at 30°C in molar ratio of 1:7 followed by reduction and simultaneous cyclization of produce salt of N-(nitro-2-pyridyl)-3-R-5-R1-pyridinium of general formula II , wherein R and R1 are as defined above, by treatment of alcohol solution of abovementioned salt with SnCl2 solution in hydrochloric acid in molar ratio of N-(nitro-2-pyridyl)-3-R-5-R1-pyridinium salt : SnCl2 = 1:3 at 20°C for 0.12 hours.

EFFECT: reduced synthesis cost, decreased time and temperature of process, target product with increased yield and purity.

2 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel imidazo-condensed compounds of the general formula (I): wherein Z represents nitrogen atom (N); Z1 represents N whein a bond between C5 and Z1 represents a simple bond, and Z1 represents carbon atom (C) when a bond between C5 and Z1 represents a double bond; R1 represents hydrogen atom; R2 represents (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, phenyl-(C1-C4)-alkyl substituted with halogen atom, ((C1-C4)-alkyl)-SO2, (C1-C6)-alkyl, (C5-C6)-cycloalkyl possibly substituted with hydroxy-group, phenyl substituted with halogen atom, heterocyclyl possibly substituted and chosen from group consisting of tetrahydropyranyl, (N-methylsulfonyl)piperidinyl or tetrahydro-1,1-dioxide-2H-thiopyranyl; A is absent or represents -O-; a bond between C5 and Z1 is a simple or double bond; a bond between C8 and C9 is a simple or double bond; Y represents phenyl substituted with halogen atom, or their pharmaceutically acceptable salts possessing inhibitory activity with respect to p38 MAP kinase, and pharmaceutical composition containing thereof. Proposed compounds can be used, for example, in treatment/or prophylaxis of such diseases as rheumatic arthritis, fever and reduced bone resorption.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 2 tbl

FIELD: organic chemistry, pharmacy, veterinary science.

SUBSTANCE: invention relates to compound comprising 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine or pharmaceutically acceptable salt of this compound and pharmaceutical composition used for stimulation of biosynthesis of cytokine based on abovementioned compound Also, invention claims a method for stimulation of biosynthesis of cytokines in animal body involving administration in animal body of above described compound or its salt. Invention provides preparing a novel compound possessing useful biological properties.

EFFECT: valuable biological properties of compound and pharmaceutical composition.

3 cl, 12 tbl, 213 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the common formula III: where, if X is selected from the group containing NH and S, R1, R2, R3, R4, R5, R6, R7, R8 and R9, each independently is selected from the group containing H, OH, OR', substituted or unsubstituted aryl, where substitutes independently correspond to H, OH, C1-C12alkoxy; where, if X means O, R1, R2, R3, R4, R5, R6, R7 and R8, each independently, selected from the group containing H, OH, OR', SH, SR', SOR', SO2R', OSO2R', NHR', N(R') CO2R', OC(=O)R'; and R9 independently selected from the group containing H, OR', unsubstituted or substituted with aminogroup or halogen C2-C12 alkenyl, unsubstituted C2- C12 alkenyl, unsubstituted thienyl and halogen; where each of the R' groups are independently selected from the group containing H, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted aryl; where substitutes are independently selected from the group containing halogen, OH, CN, C1-C12 alkoxy, phenyl; and the dotted line represents the simple or double bind; or its pharmaceutically compatible salt or complex ether. Other novel lamellarin analogs are described.

EFFECT: compounds have antitumor activity.

24 cl, 2 tbl, 3 ex

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