Polycyclic macrolactam and pharmaceutical composition based on them

 

(57) Abstract:

Proposed polycyclic macrolactone formulas I-III, which means a simple link or when R2athere is a double bond; optionally protected hydroxyl group, and R1a-Hor R1and R1atogether represent oxo, R2represents optionally protected hydroxyl group, or together with R4forms-OC(=O)O-, and R2a-H or absent; when the symbol represents a simple bond, R2together with R2Arepresent oxo; R3is methyl, ethyl, n-propyl or allyl; R4represents optionally protected hydroxyl group, or together with R2forms-OC(=O)O-, and R4a-H or R4together with R4Arepresent oxo; R5is alkoxycarbonylmethyl, halogen, optionally protected hydroxyl, lower alkoxyl, acyloxy or group-OC(X)N(R10R11or R5together with R6Aform a group-OC(X)N(R'10)-, or R5together with R8Ameans oxygraph, then R8represents a hydroxyl; R6is hydroxyl and R6Aor together with R5form a group-OC(=X)N(R'10)-, or R6and R6Atogether form predstavljaet hydroxyl or R'5and R'6together form-OC(=O)O-, R5is hydroxyl or lower alkoxy, and R6represents hydroxyl, or R5and R6together form a group-OC(=O)O-, R7is methoxyl or hydroxyl, R8represents an optionally protected hydroxyl group, acyloxy, imidazoledicarbonitrile or alkoxycarbonylmethyl, and R8Arepresents hydrogen, or R8represents hydroxyl and R8Atogether with R5represent oxygraph, or R8together with R8Arepresent oxo, n = 1 or 2, in free or in salt form. These compounds possess pharmacological activity and can be used in a pharmaceutical composition having anti-inflammatory, immunosuppressive and antiproliferative activity. 3 S. and 3 C.p. f-crystals, 14 PL.

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The invention relates to the field of macrolides. It concerns compounds of formulas

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which symbol represents a simple bond or, when R2ais absent, the double bond;

R1represents optionally protected hydroxyl group, and R1arepresents hydrogen; or R14forms a group-OC(=O)O-, and R2arepresents hydrogen, or is absent;

when the symbol represents a simple bond, R2together with R2aalso represents oxo;

R3represents methyl, ethyl, n-propyl or allyl;

R4represents optionally protected hydroxyl group, or together with R2forms a group-OC(= O)O-, and R4arepresents hydrogen, or R4together with R4arepresent oxo;

R5depicts alkoxycarbonyl, halogen, optionally protected hydroxyl, lower alkoxyl, acyloxy or group-OC(=X)N(R10R11or R5together with R6aform a group-OC(=X)N(R'10is connected through the nitrogen atom with a carbon atom bearing an R6awhere X represents oxygen or sulfur, R10and R11independently represent hydrogen or lower alkyl, or together with the nitrogen atom form a five - or six-membered ring, optionally containing a second heteroatom, such as nitrogen or oxygen, and R'10is hydrogen or lower alkyl, or R5together with R8aform oxygraph, when R8represents a hydroxyl;

R6represents hydroxyl, and R6a6and R6atogether represent oxo;

R'5represents optionally protected hydroxyl, lower alkoxyl or acyloxy, and R'6represents a hydroxyl or R'5and R'6together form a group-OC(=O)O-;

R5represents a hydroxyl or a lower alkoxy, and R6represents hydroxyl, or R5and R6together form a group-OC(=O)O-;

R7is methoxyl or hydroxyl;

R8represents optionally protected hydroxyl group, acyloxy, imidazoledicarbonitrile or alkoxycarbonylmethyl, and R8arepresents hydrogen, or R8represents hydroxyl, and R8atogether with R5represent oxygraph, or R8together with R8arepresent oxo; n = 1 or 2

in free form or in salt form, and which hereinafter for brevity referred to as the "compounds of the invention".

Preferably, when R1and R2represent an optionally protected hydroxyl. Preferably, when R4together with R4arepresent oxo. Preferably, when R5is hydroxyl or together with R8aforms oxygraph. Preferably, when R'5and R5are Hydra is and R6together with R6ais oxo. Preferably, when R7is methoxyl. Preferably, when the symbol depicts a simple link. Preferably, when n = 2. Preferably, when X represents oxygen. Preferably, R10and R11was hydrogens or methyl groups or together with the nitrogen atom - 1 - imidazolium especially when they are methyl groups. Preferably, when R'10represents hydrogen or methyl.

Preferably, the acyl and acyloxy was alkylsulphonyl or respectively alkylcarboxylic with the total number of carbon atoms from 2 to 5, preferably acetyloxy, or formyloxy, or benzoyloxy. Halogen preferably represents chlorine or bromine, mainly it represents chlorine. Lower alkyl and lower alkoxy preferably contains from 1 to 4 carbon atoms, they are mainly methyl and accordingly methoxyl. Protected hydroxyl preferably represents hydroxyl, protected normal hydroxyzinesee group, preferably it represents a hydroxyl-protected tert-butoxycarbonyl or try to 5 carbon atoms and represents mainly methoxycarbonylethyl.

The compound of the invention in free form may be converted into the salt form, where such forms exist, for example, in the form of a salt with an attached acid in the usual way and Vice versa.

A subgroup of compounds of the invention (compounds I p1) includes the compounds of the above formulas I - III, provided that R2and R4are different than when they together form the group-OC(=O)O-; R4is a different group than the protected hydroxyl; R5is different than alkoxycarbonyl, halogen, a protected hydroxyl mentioned above, the group-OC(=X)N (R10R11or above the group-OC(= X)N (R'10) is formed together with R6a; R'5is other than a protected hydroxyl; and R8is other than a protected hydroxyl or alkoxycarbonyl with the total content of carbon atoms of more than 2.

Another subgroup of compounds of the invention (compounds I p2include compounds of the above formulas I - III, provided that R4, R5and R'5are other than a protected hydroxyl, and R8is different than alkoxycarbonylmethyl with the total content of carbon atoms of more than 2.

Another group of compounds izobretatel, optional protected tert-butyldimethylsilyl or methylsulfonyl, and R1aqrepresents hydrogen, or R1qand R1aqtogether represent oxo;

R2qmeans hydroxyl, optionally protected by tert-butyldimethylsilyl or together with R4qform a group-OC(=O)O-;

R3qrepresents ethyl or allyl;

R4qmeans hydroxyl, optionally protected by tert-butyldimethylsilyl, or together with R2qforms a group-CO(=O)O-, and R4aqrepresents hydrogen, or R4qtogether with R4aqrepresents oxo;

R5qmeans methoxycarbonylethyl; chlorine, hydroxyl, optionally protected by tert-butyldimethylsilyl, tert-butoxycarbonyl or methylsulfonyl; methoxy; formyloxy, acetoxy or benzoyloxy; or the group-OC(=O)N(R10qR11qin which R10qand R11qindependently represent hydrogen or methyl, or together with the nitrogen atom form a 4-morpholinyl; or R5qtogether with R6aqform a group-OC(=X)N(R'10q)-, in which X is installed above significance, and R'10qrepresents hydrogen or methyl, or R5qwith R8aqis oxygraph, when R8qpredstavlyaet group-OC(= X)N(R'10q)- mentioned above, or R6qand R6aqtogether represent oxo;

R'5qmeans hydroxyl, optionally protected with a benzoyl or acetyl, and R'6qrepresents hydroxyl, or R'5qand R'6qtogether form a group-OC(=O)O)-;

R5qmeans hydroxyl or methoxy, and R6qrepresents hydroxyl, or R5qand R6qtogether form a group-OC (O)O-;

R8qmeans hydroxyl, optionally protected by tert-butyldimethylsilyl or methylsulfonyl, acetoxy or benzoyloxy, or 1-imidazoledicarbonitrile, and R8aqrepresents hydrogen, or R8qrepresents hydroxyl, and R8aqtogether with R5qis oxygraph, or R8qtogether with R8aqrepresent oxo,

in free form or in salt form.

The preferred stereochemical configuration of the compounds of formula Iq - IIIq is what is given below for formulas Is - Vs.

The invention also provides a method of producing compounds of formulas I - III, which includes

a) obtaining compounds of formulas Ia, IIa and IIIa

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in which the substituents are the foregoing values, pripodnatami base or an organic or inorganic salt, optionally in the presence of a phase transfer catalyst, or

b) obtaining compounds of formula Ia or IIa in the interaction of the compounds of formula V

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in which R9means alkyl and the other substituents have the meanings specified above, with a suitable base or an organic or inorganic salt, optionally in the presence of a phase transfer catalyst,

or c) obtaining the compounds of formulas I - III, in which R2and R4and/or R'5and R'6accordingly, R5and R6together form a group-OC(=O)O-, the interaction of compounds of formula I, II or III, in which R2and R4and/or R'5and R'6accordingly, R5and R6mean hydroxyl, with phosgene, diphosgene or triphosgene in the presence of compounds that bind acid,

or (d) obtaining the compounds of formulas I - III, in which at least one of the substituents R1, R2, R4, R6or R8represents hydroxyl, restoring accordingly, the compound of formula I, II or III, in which at least one of the substituents R1, R2, R4, R6or R8together with R1a, R2a, R6aor, respectively, R8aare soboi lower alkoxyl, alkylating accordingly, the compound of formula I, II or III, in which R5, R'5and R5represent hydroxyl,

or f) obtaining the compounds of formulas I or II, in which at least one of the substituents R5, R'5or R8is acyloxy, alkoxycarbonyl or-OC(=X)N(R10R11, allira accordingly, the compound of formula I or II in which at least one of the substituents R5, R'5or R8represents hydroxyl, and after adding NH3or a suitable amine,

or (g) obtaining the compounds of formula I in which R8together with R8arepresents oxo, oxidizing accordingly, the compound of formula I, in which R8represents hydroxyl, and R8arepresents hydrogen,

or h) obtaining compounds of the formula I, in which R5means halogen, halogenide accordingly, the compound of formula I, in which R5is a hydroxyl, and/or the optional removal of the release(s) of the group (-) of the resultant compounds of formula I - III, when there is(are) protected(s) - hydroxyl(s) group(s), and/or optional introduction formed in the result(s)

and removing the resulting compounds in free form or in salt form.

The method of the invention can be carried out in the usual way.

In variants of the method (a) and (b) the reaction preferably takes place in an inert solvent, such as a simple ether, for example tetrahydrofuran, dioxane or diethyl ether, aromatic hydrocarbon, e.g. benzene or toluene, alcohol such as methanol or ethanol, dimethyl sulfoxide or acetonitrile. Base or metal salts are preferably CsF, Cs2CO3, K2CO3, LiOH, NaOH, KOH, Mg(OR)2where R means a lower alkyl group, KH, NaH, tertiary amine, such as triethylamine, or amidin, for example 1,8-diazabicyclo[5,4,0]-undec-7-EN /DBU/. As phase transfer catalyst may be used salts of Quaternary ammonium bases or preferably the crown ethers such as crown [18,6]. The reaction is preferably carried out at a temperature from -30o50oC, mainly at room temperature. Depending on the reaction conditions (reagents, temperature, reaction time and so on) get specific Regio - and/or diastereoisomerism shape soedineniya in position 9 in the original substance of the formula V. The reaction mixture can be formed in the usual way, for example chromatography.

In a variant of the method c) obtaining carbonates preferably takes place in an inert solvent, such as a simple ether, such as tetrahydrofuran, diethyl ether or dioxane, a chlorinated hydrocarbon, such as 1,2-dichloroethane or methylene chloride, or acetonitrile, at temperatures from -20oC to the boiling temperature of the reaction mixture, preferably at room temperature. As binders acid may be used tertiary amine, such as triethylamine, 4-dimethylaminopyridine or pyridine.

Recovery is a variant of method (d) can be performed in the usual way. Reducing agent is usually a hydride compound, such as NaBH4diisobutylaluminium or tetramethylenedisulfotetramine. The method can be carried out in an inert solvent, such as a simple ether or cyclic simple ether, for example tetrahydrofuran, dioxane or diethyl ether, aromatic hydrocarbon, for example toluene, or in the case of use as a reducing agent Tetramethylammonium the 50oC, mainly at room temperature.

Variant of the method (a) is an alkylation. It is preferably carried out in aprotonin solvent, for example in a simple ether, cyclic simple ether, aromatic hydrocarbons, dimethylformamide or dimethylsulfoxide, in the presence of a base, such as dinucleophiles nitrogenous base, for example DBU, or alkali metal hydride such as sodium hydride or potassium, or a metal salt, such as carbonate or fluoride of potassium, sodium or cesium, optionally in the presence of crown ether. Alkylating agent preferably is a halide, tosylate or mesilate, for example modestie alkyl, mainly methyliodide. The reaction is carried out at room temperature or at elevated temperature, preferably at room temperature.

The acylation in accordance with a variant of the method (f) can be carried out in the usual manner, for example in an inert solvent, such as acetonitrile or dichloromethane, for example, with the acid chloride of the acid or acid anhydride, in the presence of binders acid, such as 4-dimethylaminopyridine, or with acid in the presence of substances as dicyclohexylcarbodiimide. The acylation can be carried out with diphosgene or thiophosgene, followed by the addition of ammonia or a suitable amine to obtain the corresponding carbamates in which R5represents a group of formula-OC(=X)B(R10R11mentioned above. When the reaction is carried out in the presence of NH3or the primary amine, the end products in which R6and R6atogether denote oxo, can undergo cyclization to form the compounds of formula Ib

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in which the substituents are the foregoing values, and which also form part of the invention.

Variant of method (g) represents the oxidation. It can be carried out in the usual manner, for example in an inert solvent such as an aromatic hydrocarbon, such as toluene, or in such as a halogenated hydrocarbon, such as dichloromethane or dichloroethane, at temperatures from 0oC to room temperature, preferably at room temperature. The reaction is carried out, for example, using N-methylmorpholin-N-oxide in the presence of catalytic amounts of perruthenate of tetrapropylammonium, or I, 1,1-Tris(acetoxy)-1,1-dihydrobenzofuran-3(1H) - Rev. and R5represents hydroxyl, can exist in equilibrium with the corresponding compounds of the formula I, in which R8represents hydroxyl, and R5together with R8aare hydroxy-, i.e. compounds of formula Ic

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in which the substituents are the foregoing values, and which also form part of the invention.

Variant of method (g) gives a mixture of these compounds, which can be separated by conventional techniques such as chromatography. Depending on the source substances and conditions for performing the reaction, especially from oxidizing reagent, oxidation can occur at position 10, 14, 22, 24 and/or 33. Different reactivity and/or selective protection of hydroxyl groups can give at the output of the final products, which are oxidized only in the selected positions.

Option h) of the method can be carried out normal to the halogenation method, for example by interacting with a halogenation agent such as thionyl chloride, in a suitable solvent, such as pyridine or tetrahydrofuran, at temperatures, for example between 0oC and room temperature, preferably at room temperature.

Options with what Ktsia in one pot" with variants a) or b) way. A mixture of final products can be separated by conventional means, for example chromatography.

The compounds of formula Ia can be in equilibrium with the compounds of the formula IIa. In many cases, these tautomeric forms can be selected.

Options a) and b) of the method usually means:

a) when it enters the reaction of the compound of formula IV to obtain the compounds of formulas Ia and IIa - rearrangement and cyclization;

b) when it enters the reaction of the compound of formula IV to obtain the compounds of formula III - cyclization;

c) when it enters the reaction of the compound of formula V to obtain the compounds of formula Ia and IIa - cyclization.

When the compounds obtained in accordance with variant (a) - (h) methods have one or more protected hydroxyl groups that protect(s) group(s) may(may) be removed(ies) in the usual way, to obtain the corresponding compounds without the protective group. Removing, for example, tert-butyldimethylsilyl or tert-butoxycarbonyl can be carried out by treating hydrofluoric acid in a solvent such as acetonitrile. Depending on the selected reaction conditions (e.g., length or temperature) removing you can manage that is obtained in accordance with variant a) h) have one or more hydroxyl groups, hydroxyl(s) group(s) may(may) be protected(s) in the usual ways to get the appropriate connections with protective groups. Depending on the selected reaction conditions, the reaction can be controlled so that was protected either all or only some of the hydroxyl group. Suitable protective groups are the groups that are typically used to protect hydroxyl groups, such as tert-butoxycarbonyl or trialkylsilyl, preferably tert-butyldimethylsilyl.

Partial removal or introduction of protective groups is particularly indicated in the case when, at a subsequent stage of the reaction in the reaction must enter a specific hydroxyl group.

Compounds of formulas I - V have multiple chiral centers and may exist in the form of a series of stereoisomers. Variants of the method of the invention generally result in a mixture of such isomers. Depending on conditions and type of reaction method can be controlled so that was mainly out a specific isomer. The invention provides all optical and geometrical isomers as well as racemic mixtures. The isomers can be separated or withperiod shown by the formula Is - Vs

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In the above formula Is - Vs, when R1is other than oxo, together with R1athen R1preferably binds to the carbon atom in position 33 - configuration; R3preferably binds to the carbon atom at position 21 in the configuration; and when R4is other than oxo, together with R4athen R4preferably binds to the carbon atom in position 22 in the configuration.

The compound of the invention can be isolated from the reaction mixture and purified by conventional means.

Starting material of formula V, preferably in the form of diastereoisomers, which further indicated diastereoisomer C", can be obtained by introducing into the reaction of compounds of formula IV, similarly to variant a) method, with subsequent reaction of the resulting product with diazoalkanes. The first stage of this process may be performed as described above, for example, with KOH/crown-ether in tetrahydrofurane. The reaction product is treated in the usual manner, the residue is again dissolved in an inert solvent, such as dichloromethane, and proscout with a solution of the diazoalkane, preferably, diazomethane or diazoethane, in an inert solution is SS="ptx2">

Starting material of formula V, preferably in the form of diastereoisomers, which hereinafter are referred to as "diastereoisomer A", can be obtained by the coupling of compounds of formula IV with a base, followed by reaction of the resulting product with diazoalkanes. This stage of the process can be performed in the usual way. Preferably, it is carried out in a mixture of solvents, for example in a mixture of tetrahydrofuran and water, using as a base LiOH or Ca(OH)2. The reaction product is treated in the usual manner, the residue is again dissolved in an inert solvent, such as dichloromethane, and proscout with a solution of the diazoalkane, preferably diazomethane or diazoethane, in an inert solvent, for example in a simple ether. The resulting reaction mixture can be processed in the usual way.

Insofar (insofar as his getting here is not specifically described, for example, in the examples used as starting substances are known or can be obtained by conventional methods from known compounds, for example, based on the appropriate lines of Streptomyces, such as Streptomyces tsukubaensis N 9993 described, for example, in Fujisawa, Europatent 184162. Samples can be obtained from the first number on April 27, 1989 Agricultural Research Culture Collection International Depository, Peoria, Illinois 61604, USA, provision of the Budapest Treaty, the N Deposit NRRL 18488.

The invention is illustrated by the following examples. They are not limiting the invention. All temperatures are given in degrees Celsius. In NMR spectra all values of the chemical shift are given in ppm; samples are measured in CDCl3if there are no other instructions. Use the following abbreviatory:

O - tert-BDMS - tert-butyldimethylsilyloxy

LW.St. - double bond

other Holy - simple link Im - 1-imidazolidinyl

Br - benzoyl

DBU is 1,8-diazabicyclo[5,4,0]undec-7-ene

Ac - acetyl

BOC - tert-butoxycarbonyl

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Formula Ik ( Rk3= allyl) = FK 506

Formula Ik ( Rk3= ethyl) = FK 520.

Example 1: R1= R2= o-tert-BDMS, R3= C2H5, R7= OCH3= prospect St. , n = 2 (process a)

R1a= R2a= R4a= H

Ia: compound of formula IIIa;

Ib: compound of formula IIa (diastereoisomer A-);

Ic: the compound of formula Ia (diastereoisomer A);

Id: compound of formula Ia (diastereoisomer B);

Ie: compound of formula Ia (diastereoisomer C).

Add 4 g crown[18,6] ether and 12.7 g of cesium carbonate (or 5 g of cesium fluoride) to a solution of anatoy temperature, distributed between ethyl acetate and 1N hydrochloric acid, the phases are separated, the organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated in vacuum. Chromatography of the residue (n-hexane/ethyl acetate = 3/1 -> 1/2) gives named in the title substance as a colorless foam.

Example 2. R1= R2= O-tert-BD MS, R3= C2H5, R4+ R4a= 0 R7= OCH3, = prospect St., n = 2 R1a= R2a= H; diastereoisomer A (b)

2a: compound of formula IIa;

2b: compound of formula Ia.

Add 1 ml of diazabicyclo to a solution of 5.2 g of compound of formula V (R1= R2= O-tert-BDMS, R1a= R2a= H, R3= C2H5, R4+ R4a= 0, R7= OCH3, R9= CH3n = 2, = prospect St., diastereoisomer A) in 250 ml of acetonitrile. The reaction mixture is stirred for 70 minutes at room temperature and then treated as described in example 1 (n-hexane/ethyl acetate = 3/2) to obtain named the title compound as a colourless foam.

In a similar manner as described in examples 1 and 2 obtained as a colorless foam compounds of formulas Ia, IIa and IIIa (R7= OCH3n = 2, = prospect St., R1a= R2a= Nanoline this connection gives compound of example 6c /=example 73 and/ or the compound of example 28.

Example 13. The compound of formula III (R1= R2= O-tert-BDMS, R3= C2H6, R4+ R4a= O, R5+ R6= O-CO-O, R7= OCH3, = prospect St., n = 2, R1a= R2a= H (process c).

To a solution of 0.8 g of the compound of formula III (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= O, R1a= R2a= H, R5= R6= OH, R7= OCH3Ave St., n = 2) in 40 ml of acetonitrile was added queue 0.2 ml of diphosgene and 1.75 g of dimethylaminopyridine. The reaction mixture was stirred for 1.5 hours at room temperature and then treated as described in example 1 (n-hexane/ethyl acetate = 9/1) to obtain named the title compound as a colourless foam.

In a similar manner as described in example 13, obtained as a colorless foam compounds of formulas I - III (R3= C2H5, R7= OCH3, = prospect St. , n = 2, R1a= R2a= R4a= R8a= H) in the following the following table 2.

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Example 19. The compound of formula I (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= 0, R5= R6= R8= CH, R7= OCH3, = prospect St., n = 2, R1Atriacetoxyborohydride to a solution of 1 g of compound of formula I (R1= R2= O-tert-BDMS, R1a= R2a= R8a= H, R3= C2H5, R4+ R4a= R6+ R6a= 0, R5= R8= OH, R7= OCH3, = prospect St., n = 2, diastereoisomer C) in 30 ml of acetonitrile and 5 ml of acetic acid. The reaction mixture was stirred for 3.5 hours at room temperature and then partitioned between saturated aqueous NaHCO3and ethyl acetate. The organic phase is separated, washed in turn with brine, 1N hydrochloric acid and again with brine, dried over Na2SO4, filtered and evaporated in vacuum. Chromatography of the residue (ethyl acetate) gives named the title compound as a colourless foam.

In a similar manner as described in example 19, obtained as a colorless foam compounds of formulas I, II and III (R3= C2H5, R7= OCH3, R8= OH, = prospect St., n = 2, R1a= R2a= H), are listed in the following next table.

a) removing the protective group gives compound of example 118

Example 29. The compound of formula I (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= O R5= R7= OCH3, R8= OH, = prospect St., n = 2, (R1a= R2a= R8a= R8athe ROS 100 g of the compounds of formula I (R1= R2= O-tert-BDMS, R3= C2H5, R1a+ R2a= R8a= H, R4= R4a= R6+ R6a= O, R5= R8= OH, R7= OCH3, = prospect St., n = 2, diastereoisomer A) and stirred for 1.5 hours at room temperature. The reaction mixture is treated as described in example 1 (n-hexane/ethyl acetate = 2/1 to get named in the title compound as a colourless foam.

In a similar manner as described in example 29 are in the form of a colorless foam compounds of formulas I and III (R3= C2H5, R4+ R4a= O, R7= OCH3, R8= OH, = prospect St., n = 2, R1a= R2a= R8a= H) listed in table 4.

Example 32. R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= O, R7= OCH3, = prospect St., n = 2; diastereoisomer A, (process f) (R1a= R2a= H)

32a: compound of formula I (R5= OH, R6+ R6a= O, R8= O-Bz, R8a= H);

32b: -"- I (R5= O-Bz, R6+ R6a= O, R8= O-Br, R8a= H);

32c: -"- I (R5= O-Bz, R6+ R6a= O, R8= OH, R8a= H);

32d: -"- II (R'5= O-Bz, R'6= OH).

Add 5 mol. equivalents of 4-dimethylaminopyridine/SUB> = C2H5, R1a= R2a= R8a= H, R4+ R4a= R6+ R6a= 0, R5= R8= OH, R7= OCH3, = prospect St., n = 2, diastereoisomer A) or the compounds of formula II (R1= R2= O-tert-BDMS, R3= C2H5, R4= R4a= O, R'5= OH, R'6= OH, R7= OCH3, = prospect St., R1a= R2an = H, n = 2). The reaction mixture is stirred for 45 minutes and then treated as described in example 1 (n-hexane/ethyl acetate = 4/1 --> 2/1), and get named in the title substance as a colorless foam.

In a similar manner as described in example 32, obtained as a colorless foam compounds of formulas I and II (R1= R2= O-tert-BDMS, R3= C2H5, R4= R4a= O, R7= OCH3, = prospect St., n = 2, R1a= R2a= H) in the following the following table 5.

1a) removing the protective group gives compound of example 6c (= example 73)

Example 44. The compound of formula I (R1= R2= R8= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= O, R5= O CO (4-morpholinyl), R7= OCH3Ave St., n = 2, diastereoisomer A) (R1a= R2a= R8a= H) (process f)

Add 10 EQ. 4-Dima is-BDMS, R1a= R2a= R8a= H, R3= C2H5, R4+ R4a+ R6+ R6a= O, R5= OH, R7= OCH3Ave St., n = 2, diastereoisomer A) in 50 ml of acetonitrile, the reaction mixture is stirred for 20 minutes at room temperature, then poured into 500 ml of ethyl acetate and 20 ml of the research, vigorously stirred for 10 minutes and then treated as described in example 1 (n-hexane/ethyl acetate = 7/1) to obtain the substance as a colorless foam.

In a similar manner as described in example 44, obtained as a colorless foam compounds of formula I and Ib (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= O, R7= OCH3Ave St., n = 2, R6= OH, R1a= R2a= R6a= H) in the following the following table 6.

Example 50. The compound of formula I (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= R8+ R8a= O, R5= OH, R7= OCH3Ave St., n = 2, diastereoisomer a (g) (R1a= R2a= H)

Add 0.5 g of 1,1,1-Tris(acetoxy)-1,1-dihydrobenzofuran-3 (1H)it to a solution of 0.5 g of the compounds of formula I (R1= R2= O-tert-BDMS, R3= C2H5, RB>3Ave St. , n = 2, diastereoisomer A) in 50 ml of methylene chloride. The reaction mixture is stirred for 3 hours at room temperature, then filtered through silica gel, washed with a mixture of n-hexane with ethyl acetate (1/1) and the filtrate evaporated in vacuum. Chromatography of the residue (n/a hexane/ethyl acetate = 3/1) gives named in the title substance as a colorless foam.

In a similar manner as described in example 50, obtained as colorless foams of the compounds of formula I (R3= C2H5, R4+ R4a= R6+ R6a= R8+ R8a= O, R7= OCH3, = prospect St., n = 2, K2A= H), which are listed in the following next table 7.

Example 55. The compound of formula I (R1= R2= R8= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= O, R5= Cl, R7= OCH3Ave St., n = 2, diastereoisomer EPI-(A) (process h) (R1a= R2a= R8a= H)

Add 0.3 ml of thionyl chloride in 5 ml of pyridine to a solution of 1 g of compound of formula I (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= O, R5= OH, R7= OCH3, R8= O-tert-BDMS, = prospect St., n = 2, R1a= R2a= R8a= H, diastereoisomer A) bespredela between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase is separated, washed twice IN HCl and water, dried over Na2SO4and the solvents removed in vacuo. Column chromatography (n-hexane/ethyl acetate = 9/1) gives named the workpiece compound as a colourless foam.

In a similar manner as described in example 55, obtained as colorless foams of the compounds of formula I (R3= C2H5, R4+ R4a= R6+ R6a= O, R7= OCH3, R8= O-tert-BDMS = prospect St., n = 2, R1a= R2a= R8a= H), in the following the following table 8.

Example 58. The compound of formula I (R1= R2= R8= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= O, R7= OCH3, = prospect St., n = 2, diastereoisomer A (protection). (R1a= R2a= R8a= H)

a) R5= O-tert-BDMS;

b) R5= OH.

Add 5 EQ. 2,6-lutidine and 2 EQ. tert-butyldimethylsilyl to a solution of the compounds of formula I (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= O, R5= R8= OH, R7= OCH3, R1a= R2a= R8a= H = Ave St., n = 2, diastereoisomer A) in 50 ml of acetonitrile, the reaction mixture was stirred for 1.5 ol) gives named the title compound as a colourless foam.

In a similar manner as described in example 58, obtained as colorless foams of the compounds of formula I (R1= R2= R8= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= O, R7= OCH3Ave St., n = 2, R1a= R2a= R8a= H) in the following the following table 9.

Example 61. The compound of formula III (R1= OH, R2= O-tert-BDMS, R3= C2H5, R4+ R4a= O, R5= R6= OH, R7= OCH3Ave St., n = 2, (partial protection) R1a= R2a= R8a= H)

Add 3 ml of 40% hydrofluoric acid to a solution of 0.5 g of the compound of formula III (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= O, R5= R6= OH, R7= OCH3Ave Saint, R1a= R2a= H, n = 2) in 30 ml of acetonitrile. The reaction mixture is stirred for 5 minutes at room temperature, then partitioned between saturated aqueous NaHCO3and ethyl acetate, the organic phase is separated, washed with saturated aqueous NaHCO3and several times with water, dried over Na2SO4, filtered and evaporated in vacuum. Chromatography of the residue (n-hexane/ethyl acetate = 1/2) gives named zagalo colorless foam compounds (R1= OH, R4+ R4a= O, R7= OCH3, = prospect St., n = 2, R1a= R2a= H) in the following the following table 10.

a) removing the protective group gives compound of example 6c (=example 73)

Example 71. The compound of formula I (R1= R2= R5= R8= OH, R3= C2H5, R4+ R4a= R6+ R6a= O, R7= OCH3, = prospect St., n = 2, R1a= R2a= R8a = H, diastereoisomer B) (removing the protective groups).

Add 3 ml of 40% aqueous hydrofluoric acid to a solution of 0.5 g of the compounds of formula I (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= R6+ R6a= O, R5= OH, R7= OCH3Ave St., n = 2, R1a= R2a= R8a = H, R8= . .. diastereoisomer B) in 30 ml of acetonitrile. The reaction mixture is stirred for 4 hours at room temperature, then partitioned between saturated aqueous NaHCO3and ethyl acetate, the organic phase is separated, washed with saturated aqueous NaHCO3and several times with water, dried over Na2SO4, filtered and evaporated in vacuum. Chromatography of the residue (n-hexane/ethyl acetate = 1/2) gives named in the title compound in the form of b is in (R7= OCH3, = prospect St., n = 2, R2a= H) listed in table 11.

Source materials can be obtained as below.

A) 33-O-Methanesulfonyl-24-O-tert-BDMS-FR 520

Add 3 g of 4-dimethylaminopyridine and 0.3 ml of the acid chloride methanesulfonic acid to a solution of 1 g 24-O-tert-BDMS-FR 520 in 40 ml of acetonitrile and stirred at room temperature for 2 hours. Then the reaction mixture was partitioned between saturated aqueous NaHCO3and ethyl acetate, the phases are separated, the organic phase is washed with 1N hydrochloric acid and brine, dried over sodium sulfate, filtered and evaporated in vacuum. Chromatography of the residue (n-hexane-ethyl acetate = 1/1) gives named the title compound as a colourless foam.

B) 33-O-Methanesulfonyl-24-O-tert-BDMS-FR 506

Using as the starting material 24-O-tert-BDMS and acting in the same way as described in (A), get named in the title compound as a colourless foam.

C) the Compound of formula V (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= O, R7= OCH3, R9= CH3, = prospect St., n = 2, diastereoisomer C) (R1a= R2a= H)

Add 0.5 g crown [18,6] ether and 0.7 g 24,33-bis-Ocenia 20 minutes at room temperature, then partitioned between 1N hydrochloric acid and ethyl acetate, the phases are separated, the organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuum. The residue is again dissolved in 30 ml of dichloromethane and proscout with 1 M solution of diazomethane in the air up until the solution is light yellow. After evaporation of the solvent, chromatography of the residue (n-hexane/ethyl acetate = 2/1) gives named the title compound as a colourless foam.

H1NMR (CDCl3): 5,14 (D., J = 7.5 Hz, H-26); 4,99 (D., J = 10 Hz, H-20); 3,97 (D. W., J = 14 Hz, H-6E); 3,81 (C., COOCH3); 2,70 (m, H-11).

D) Compound of formula V (R1= R2= O-tert-BDMS, R3= CH2CH = CH2, R4+ R4a= O, R7= OCH3, R9= CH3, = prospect St., n = 2, diastereoisomer C) (R1a= R2a= H)

Using as the starting material 24,33-bis-O-tert-BDMS-FK 506 and acting in the same way as described in C) get named in the title compound as a colourless foam.

E) Compound of formula V (R1= R2= O-tert-BDMS, R3= C2H5, R4+ R4a= O, R7= OCH3, R9= CH3, = prospect St., n = 2, diastereoisomer A) (R1a= R2a= H)

Add 2 g of calcium hydroxide to the wound temperature. Then the reaction mixture was partitioned between 0.5 N hydrochloric acid and ethyl acetate, the phases are separated, the organic phase is dried and evaporated in vacuum. The residue is again dissolved in 30 ml of dichloromethane and proscout with 1 M solution of diazomethane in the air up until the solution is light yellow. After evaporation of the solvent, chromatography of the residue (n-hexane/ethyl acetate = 2/1) gives named the title compound as a colourless foam.

H1NMR (CDCl3): (mixture of rotamers = 58/42)

main isomer: 5,20 (D., J = 7.5 Hz, H-26); 4,93 (D., J = 10 Hz, H-20); 4.04 the (D. W., J = 13 Hz, H-6e); 3,83 (C., COOCH3);

secondary number: 5,13 (D., J = 10 Hz, H-26); 4,70 (D., J = 10 Hz, H-20); 4,57 (D. W., J = 13 Hz, H-6e); 3,63 (C., COOCH3).

F) the Compound of formula V (R1= R2= O-tert-BDMS, R3= CH2-CH=CH2R4+ R4a= O, R7= OCH3, R9= CH3, = prospect St., n = 2, diastereoisomer A) (R1a= R2a= H)

Using as the starting material 24,33-bis-O-tert-BDMS-FK 506 and acting in the same way as described in section E) will be named the title compound as a colourless foam.

G) the Compound of formula IV (R1= O-tert-BDMS, R2+ R4= O-CO-O, R3= C2H5, = prospect St., n = 2, (R1a= R2a = R4= OH, R3= C2H5n = 2, = prospect St., (R1a= R2a= R4a= H) and acting in the same way as described in example 13, get named in the title compound as a colourless foam.

H1- NMR spectra (500 MHz) (see the end of the description)

In NMR spectra, the following notation: d - doublet; s, singlet; t - triplet; q, Quartet; b - broad; db - broad doublet; dd, double doublet; ddt - doublet-doublet-triplet; m - multiplet.

Compounds of the invention in free form or in the form of pharmaceutically acceptable salts, which are hereinafter for brevity referred to as "substances of the invention have pharmacological activity. Thus, they can be indicated for use as pharmaceuticals. In particular, they possess anti-inflammatory, immunosuppressive and antiproliferative activity.

Anti-inflammatory activity, for example, can be determined following further methods, the description of which used the following abbreviations:

DNP is 2,4-dinitrophenol

DNEB - 2,4-dinitrophenol

TPA - 12-O-tetradecanoylphorbol-13-acetate

1. Inhibition of degranulation of murine mast cells (mast cll) in vitro

the antigen (DNP) and is measured as the activity of hexosaminidase in the supernatant of cells after 60 minutes colorimetric analysis. Inhibiting substances injected 30 minutes prior to the introduction of the DNP.

Substances of the invention in this test cause mast cell degranulation (IC50) at the dose of 1 ng/ml to 50 ng/ml

2. Induced oxazolone allergic contact dermatitis (in mice) [test method described in F. M Dietrich and R. Hess, Int. Arch. Allergy 38 (1970) 246-259]

The active substances of the invention in this test (inhibition of inflammatory swelling) of up to 58% for the single local application in the form of a 0.01% solution. Hydrocortisone (1,2%) inactive under these conditions, on this model, and indomethacin (3,6%) inhibits the swelling of only 22%.

3. Induced by DNFB allergic contact dermatitis (pigs) [test method is what is described, for example, in European patent 315978]

Two-time topical application of compositions containing 0.13% of the substances of the invention, results in inhibition of the inflammatory response to 44%.

4. Inhibition of contact dermatitis induced by irritant complex phorbol ester (TPA) in mice [test method is what is described, for example, in European patent 315978]

In this test, with a single application of the formulation, provided the licensing of contact dermatitis, induced irritant effect of arachidonic acid (in mice)

Conduct local treatment of both external and internal side of the right ear of female mice NMRU 10 ál DAE 244 (DMSO / acetone/ethanol = 2/4/4) containing the test compound (usually 1.2 and 3.6%). After 30 minutes, the right ear is treated locally (inside and outside) 10 μl of acetone containing 1 mg of arachidonic acid. After another 90 minutes, the mice are killed, cut off the ears along the lines of cartilage and weighed. Determine the difference in weight between the left and right ears and calculate the % inhibition relative to the group treated only one arachidonic acid.

In this test, with a single application of the terms of from 0.4 to 3.6% of the substances of the invention have the inhibition reactions of inflammation up to 30% (table. 14).

6. Inhibition of contact dermatitis induced by the irritant effect of ionophore (A 23187) (in mice)

Conduct local treatment of both external and internal side of the right ear of female NMRI mice with 15 μl of a mixture of acetone with 10% DMSO containing 15 mg A 23187 (normal 0.4 and 1.2 percent) or without test compounds. After 7.5 hours, the mice are killed, cut off the ears along the lines of cartilage and weighed. Determine the difference in weight between the left and right">

In this test, with a single application of the terms from 0.4 - 1.2% of the substances of the invention have the inhibition of the inflammatory response to 72%. Indometacin used for comparison, inhibits inflammation by 44% at a concentration of 1.2%.

Immunodepressants and antiproliferative activity can be determined, for example, in accordance with the following further test methods.

7. Proliferative response of lymphocytes to allogeneic stimulation in the reaction of mixed lymphocytes (MLR) in vitro [test method is a method described, for example, in the literature So MEO, "The MLR in the Mouse", Immunological Methods, L. Lefkovits and B. Pernis, Eds., Academic Press, N. Y. (1979) 227-239]

With this test set the suppression of mixed lymphocyte (IC50) substances of the invention at a dose of 10 ng/ml to 100 ng/ml

8. Inhibition of the primary humoral immune response to sheep erythrocytes in vitro [test method is a method described, for example, in the literature R. I. Mishell and R. W. Dutton, Science 153 (1966() 1004-1006; R. I. Mishell and R. W. Dottn, J. Exp. Med. 126 (1967) 423-442]

In this test, the substances of the invention are active with IC50the dose from 0,0024 μg/ml to 0.32 µg/ml.

9. The inhibition of proliferation of keratinocytes h is the test substances of the invention are active at concentrations of 3 μm/ml to 10 μm/ml, resulting in inhibition of 20% to 50%.

10. Inhibition of epidermal hyperproliferation induced by phorbol ester (TPA) (in mice)

For the induction of epidermal hyperproliferative on the outer ear cause TRA (0,005%) in 1 and 3 day. The test substance is applied on the same place daily at 1, 2, 3 and 4 day. Similarly to control animals treated with TPA, cause the media. Evaluation of antiproliferative activity of the test compounds is carried out in 4 day, 6 hours after the last application, by immunohistological studies of the incidence of keratinocytes stained BrdU (BrdU-Staining) (one hour before sacrifice of the animals irectory BrdU labeled cells in S-phase), and by measuring epidermal space plot of the cutoff for the test and control animals.

With this test, with 4 applications of formulations with 0.4 - 1.2% of the substances of the invention detect the inhibition of BrdU labeling 60-70% inhibition of hyperplasia on 17-42%.

The substance of examples 71 (and 6d) and the substance of example 93, in particular the substance of example 71 (6d), are the preferred substances in the above-mentioned conditions. It is noted, for example, that in the above-mentioned experience of 6 these substances in the form 1, the La of the above-mentioned use of compounds of examples 71 (6d) and 93 can be larger mammal, for example a person in the same ways and for the same or lower doses than those typically used in the case of indomethacin. The compounds are used as anti-inflammatory substances and as an immunosuppressant and antiproliferative substances for local and General application for the prevention and treatment of inflammatory and hyperproliferative conditions and conditions requiring immunomodulary, in cases such as

a) the treatment of inflammatory and hyperproliferative skin diseases such as atopic dermatitis, contact dermatitis and other eczematous skin diseases, seborrheic eczema, flat lichen planus, utricularia vulgaris and reminiscent of the disease, congenital bullous bullosa, vasculitis, erythema, cutaneous eosinophilia, systemic lupus erythematosus, acne, psoriasis and skin tumors;

b) prevention and treatment of allergic diseases, such as acquired bronchial asthma, rhinitis, conjunctivitis, endogenous eczema, urticaria (giant hives, food and drug Allergy and anaphylaxis;

c) prevention and treatment

resilience in situations of transplantation of organs or tissues such as heart, kidney, liver, bone is on the brain,

autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, thyroiditis Hashimoto (Hachimoto); multiple sclerosis, severe myasthenia gravis, type 1 diabetes and uveitis,

cutaneous manifestations of immunologically intermediate disorders and

alopecia areata.

The compounds can be administered systemically or topically. For the above indications, the appropriate dosage will of course vary depending, for example, from the host, the route of administration and the nature and severity of the disease treated. However, in General it is shown that the overall therapeutic results are obtained with a daily dosage of 1.0 mg/kg to 10 mg/kg body weight of the animal. The required daily intake for larger mammals lies in the range of 10 mg to 100 mg, administered in the usual manner, for example single doses up to four times per day, or in the form of delay (retard form. The local application therapeutic results were obtained when the local appointment at a concentration of active compound is from 1% to 3% several times a day, for example 2 to 5 times a day.

Substances of the invention can be administered by any conventional route, in particular, enterline, for example, orally, such as tablets or capsules, or topically, e.g. in the form of lotions, the Olga for local treatment of skin and mucous membranes, for example, eyes, respiratory tract, vagina, mouth and nasal cavity.

Pharmaceutical compositions, for example, for local use, including the claimed compounds in combination with at least one pharmaceutically acceptable carrier or diluent may be manufactured in the usual way by mixing. Unit dosage forms contain, for example, from 0,0025 mg to 50 mg of active substance.

The local application may, for example, to the skin. Another type of local application - application for the treatment of the eye, for example for the treatment of immunoprotection (immune - mediated) conditions of the eye such as autoimmune diseases, such as Revit, keratoplasty and chronic keratitis; allergic conditions, such as vernal conjunctivitis; inflammatory conditions and for the transplant of the cornea by local application to the eye surface of the substance of the invention in pharmaceutically acceptable targeted drugs for the eyes of the media.

Designed for ophthalmic drug carrier is a carrier that supports the contact of the substance with the surface of the eyes sufficient time to allow the compound to penetrate the corneal and votran liquid, in the liquid part of the vitreous body, the cornea, the iris and ciliary, in the crystalline lens in the vascular membrane and the retina and the sclera.

Pharmaceutically acceptable suitable for ocular drug carrier can be, for example, ointment, vegetable oil, or encapsulating material.

Although protivovospalitelnoe, immunosuppressive and antiproliferative activity are the main active properties of the substances of the invention, they are also to some extent active the ability to increase the sensitivity or efficiency of chemotherapeutic drugs.

This activity can be determined, for example, in accordance with the test methods described in the European patent 360760.

Compounds of the invention are therefore indicated for use to remove resistance of different types of action of chemotherapeutic drugs, for example, congenital or acquired, or to increase the sensitivity to the treatment of scheduled drugs, for example, as a means of reducing dose level with regular use of chemotherapeutic drugs, for example, in the case of anticancer treatment and the CTB and often, as a means to reduce the overall level of drug toxicity, and, most often, as a tool that can reverse or reduce the resistance, including both congenital and acquired resistance to chemotherapy.

Thus, the invention also concerns the use of substances of the invention as a pharmaceutical preparation, in particular as anti-inflammatory, and immunosuppressive and antiproliferative substances, the substances of the invention for use as a pharmaceutical preparation, application of substances of the invention for preparing a pharmaceutical composition, which consists in mixing at least one pharmaceutically acceptable carrier or diluent; and a method of preparing a pharmaceutical composition that includes a mixture of substances of the invention together with at least one pharmaceutically acceptable carrier or diluent. It also provides a pharmaceutical composition comprising the substance of the invention in combination with at least one pharmaceutical carrier or diluent. It also provides a method of treatment of inflammatory and hyperproliferative States and States, requiring the plants to the patient, who needs such treatment.

Inhibition of contact dermatitis induced complex with phorbol ester (TPA) in mice.

Induced oxazolone allergic contact dermatitis (in mice). The method described above.

2. Examples of pharmaceutical compositions

Example 1. Cream

Component Number, wt.%

The compound of example 6d - 0,3

Hexyleneglycol - 10

Milovy alcohol - 10

Miglyol 812 - 10

Methylparaben - 0,07

Propylparaben - 0,03

Cetyl alcohol - 5

The glycerol monostearate - 10

Water Up to 100

Preparing oil emulsion in water in the form of a cream, using the Compound of Example 601 as the active agent.

The cream is stable, component separation is not observed.

Example 2. Suspension

Component - the Amount of weight.h.

The compound of Example 6d - 0,10

Vaseline is 99.9

The composition is prepared by mixing the components.

1. Polycyclic micromaterial General formula I

< / BR>
General formula II

< / BR>
and the General formula III

< / BR>
in which symbol indicates a simple relationship or when R2Athere is a double bond;

R1is an optional samisen the BR>R2represents an optionally protected hydroxyl group, or together with R4forms a group-OC(=O)O-;

R2Arepresents hydrogen or absent;

when the symbol represents a simple bond,

R2together with R2Aalso represent oxo;

R3is methyl, ethyl, n-propyl or allyl;

R4represents an optionally protected hydroxyl group, or together with R2forms a group-OC(=O)O-;

R4Ais hydrogen or R4represent oxo;

R5is alkoxycarbonylmethyl, halogen, optionally protected hydroxyl, lower alkoxyl, acyloxy or group-OC(X) N (R10R11or R5together with R6Adenote a group attached through a nitrogen atom to the carbon atom bearing R6Aand in these groups, X represents oxygen or sulfur, R10and R11independently is hydrogen or lower alkyl or together with the nitrogen atom form a five - or six-membered ring, optionally containing a second heteroatom, such as nitrogen or oxygen, and is hydrogen or lower alkyl;

or R5together R8Arepresent oxygraph, then R8is hydroxyl;

R6
and R6Atogether form oxo;

represents an optionally protected hydroxyl, lower alkoxyl or acyloxy;

is hydroxyl or together form a group-OC(=O)O-;

is hydroxyl or lower alkoxyl;

is hydroxyl or together form a group-OC(=O)O-;

R7- methoxyl or hydroxyl;

R8represents an optionally protected hydroxyl group, acyloxy, imidazoledicarbonitrile or alkoxycarbonyl;

R8Ais hydrogen or R8is hydroxyl, R8atogether with R5represent oxygraph, or R8together with R8Arepresent oxo;

n = 1 or 2

in free or in salt form.

2. The compound of formulas I - III p. 1, where R2and R4other than educated them together the group-OC(=O)O-, R4- other than the protected hydroxyl, R5- other than alkoxycarbonyl, halogen, a protected hydroxyl group - OC(= X) N(R10R11mentioned above, or formed together with R6Athe group mentioned above, is other than a protected hydroxyl, and R8- other than the protected hydroxyl or alkoxycarbonyl with the total content of carbon atoms of more than 2, free soapsuds other than protective hydroxyl, and R8- other than alkoxycarbonylmethyl with the total content of carbon atoms of more than 2 in free or in salt form.

4. Connection on p. 1 of General formula Iq - IIIq

< / BR>
with the General formula IIq

< / BR>
and the General formula IIIq

< / BR>
where R1qis hydroxyl, optionally protected by tert-butyldimethylsilyl or methylsulfonyl;

R1qis hydrogen or R1qand R1qtogether represent oxo;

R2qis hydroxyl, optionally protected by tert-butyldimethylsilyl or R4qform a group-OC(=O)O-;

R3qis ethyl or allyl;

R4qis hydroxyl, optionally protected by tert-butyldimethylsilyl, or together with R2qforms a group-OC(=O)O-;

R4qis hydrogen or R4qtogether with R4qis oxo;

R5q- methoxycarbonylethyl, chlorine, hydroxyl, optionally protected by tert-butyldimethylsilyl, tert - butoxycarbonyl or methylsulfonyl, methoxy, formyloxy, acetoxy or benzoyloxy or the group-OC(=O) N (R10qR11qin which R10qand R11qindependently is hydrogen or methyl or together with the nitrogen atom form a 4-morpholinyl;

or R5qtogether R6qform a group in which R8qis hydroxyl;

R6qis hydroxyl;

R6qis hydrogen or together with R5qform a group referred to above, or 4 R6qand R6qtogether represent oxo;

is hydroxyl, optionally sexysandy a benzyl or acetyl;

is hydroxyl or together form a group-OC(=O)O-;

is hydroxyl or methoxyl;

hydroxyl, or together form a group-OC(=O)O-;

R8qis hydroxyl, optionally protected by tert-butyldimethylsilyl or methylsulfonyl, acetoxyl or benzoyloxy, or 1-imidazoledicarbonitrile;

R8qis hydrogen or hydroxyl and R8qtogether with R5qrepresent oxygraph, or R8qtogether with R8qrepresent oxo;

in free or in salt form.

5. Polycyclic macrolactam formula I, where R1A, R2Aand R8A- hydrogen atoms, R1, R2, R5and R8- hydroxyl group, R3is ethyl, R4and R4Atogether and R6and R6Atogether represent oxo; symbol means a simple link, R7- methoxy, and n = 2 (diastereoisomer).

6. Pharmaceutical composition having anti-inflammatory, immunogenes the ski acceptable carrier or diluent, characterized in that the active substance it contains a compound of formulas I - III under item 1 in free form or in the form of pharmaceutically acceptable salts.

Priority points

10.03.93 under item 1;

07.05.92 on p. 2.

 

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