Derivatives sordaria and possessing antifungal activity of the pharmaceutical composition on the basis of their

 

(57) Abstract:

Describes the new derivatives sordaria General formula I, where Z is tetrahydropyranol selected from formulas (a) and (b). The values of the radicals X, Y, W, R1-R17specified in the claims. They possess antifungal activity. Describes a pharmaceutical composition based on them. 3 C. and 10 C. p. F.-ly, 1 PL.

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The subject of this invention is new derivatives of sordaria possessing this makes it activity, methods for their preparation, containing their pharmaceutical compositions and their use in medicine, in particular for the prevention or treatment of animal diseases, including those caused by fungal infection.

It is known [1] get antibiotic SL2266 by cultivation of the strain NRRL 3196 mushroom species Sordaria araneosa. And it is known that SL2266 named later sordaria has fungistatic activity. This same research group described [2] degradation sordaria to agaricina. It is also known [3] get antibiotic themarina possessing this makes it active.

Sagarin, agaricin and trimaran can be represented by the following formula (A)

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Although cordain and trimaran show anthropou activity, both of these compounds are only moderately active and have a limited range of validity when tested against a set of fungal organisms. We offer a new group fungicidal derivatives sordaria that this makes it have excellent activity and a broad spectrum of action. For example, according to the first aspect of the present invention we provide compounds of formula (I)

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where Z is tetrahydropyranol selected from

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and their pharmaceutically acceptable salt and solvate (e.g. hydrate) or metabolically labile derivatives

where R1represents hydrogen, halogen, hydroxyl, C1-4alkoxyl or acyloxy;

R2and R3can independently represent hydrogen, C1-6alkyl or C1-4alkoxyl1-4alkyl, or R2and R3together with the angle of the native atom to which they are attached, represent C=O, C=S or C3-8cycloalkyl;

R4represents hydrogen or CH2R7(where R7is hydrogen, hydroxyl, C1-4alkoxyl or group OCOR in which R8is C1-4lkyl or C1-4alkoxyl1-4alkyl, or R5and R6may together with the carbon atom to which they are attached, represent C=O, C=S or C3-8cycloalkyl;

n = 0 or 1;

X and Y each independently may represent oxygen, sulfur or CR9R10(where R9and R10each can independently represent hydrogen, C1-6alkyl, C1-4alkoxy or C1-4alkoxyl1-4alkyl, or R9and R10may together with the carbon atom to which they are attached, represent C=O, C=S, C3-8cycloalkyl or C= CHR11where R11is hydrogen or C1-4by alkyl); or, if X and Y are oxygen, and n = 0, then-Y-CR2R3or-X-CR2R3respectively, can also be represented as-N=CR3- or-NR12-CR2R3- (where CR2and R3are C=O, a, R12is C1-4alkylsilane group COR13where R13is C1-6by alkyl), or if Y is oxygen, and n = 0, then X can be represented by a group of CR11(where R11has the above specified values) that is attached to PYRANOVA ring via a double bond;

R15represents hydrogen, halogen, azizli 2 C1-3CNS groups), aryls1-4alkoxy, C3-6alkenylacyl, group OCOR18(where R18is aryl (C1-4alkoxyl or C1-10alkyl group may contain one or two double bonds or C1-6alkoxycarbonyl C1-4alkoxyl, a R16represents hydrogen, or R15and R16may together with the carbon atom to which they are attached, represent C=O or C=CH2;

R17represents CH2R19where R19is hydrogen, hydroxyl, C1-14alkoxyl or group OCOR20in which R20is C1-4by alkyl); and

W represents an oxygen atom or sulfur, or CH2group;

and the dotted line in the group (a) indicates the possible presence of additional relationships.

Suitable pharmaceutically acceptable salts of compounds of formula (I) include salts of inorganic bases, such as alkali metal salts (e.g. sodium and potassium salts) and ammonium salts and salts of organic bases. Suitable salts of organic bases include amine salts such as salts of trialkylamine (e.g., triethylamine), dialkylamino (for example, dicyclohexylamine), possibly substituted bisamine and three(hydroxymethyl)methylamine, and salts of amino acids (for example, salt of lysine and arginine).

References hereinafter to a compound of formula (I) include this compound and its pharmaceutical acceptable salts.

Other salts which are not pharmaceutically acceptable may be used to obtain compounds of formula (I) and form another aspect of the invention.

Metabolically labile derivatives of compounds of formula (I) are compounds that are in the body into compounds of formula (I). Examples of such derivatives include normal metabolically labile esters formed from the free carboxylic acid in the molecule.

It should be understood that the present invention encompasses any of the individual isomers, including optical isomers of the compounds described by formula (I), as well as their mixtures, including their wholly or partially racemic mixtures.

Used herein, the term "alkyl" as a group or part of the C1-4CNS group may be a straight or branched chain. Acceptable examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl, n-hexyl and n-octyl.

Used herein, the term "aryl" as a group or part of a group means phenyl or heteros is hydroxyl, C1-6of alkyl, C1-6alkoxyl or C1-4alkoxycarbonyl. Heteroaryl group may be a 5 - or 6-membered heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Acceptable examples of heteroaryl groups include pyridyl, furyl, thienyl and pyrrolyl.

The term "halogen" denotes here a fluorine, chlorine, bromine or iodine.

If R1is Allexinno group, then it can represent, for example, a group OCOR13where R13defined above.

Examples of C3-8cycloalkyl groups include cyclopeptide and tsiklogeksilnogo group.

Examples of X groups include oxygen, CR9R10where R9and R10each are hydrogen, C1-4alkoxyl or C1-4the alkyl or CR9R10represents a group C=O or C=CHR11for example , C=CH2or X represents CR11.

Examples of acceptable Y groups include oxygen or CR9R10where R9is hydrogen, C1-4alkoxyl or C1-4the alkyl, and R10is hydrogen or C1-4the alkyl.

If R18is unsaturated C1-10alkyl group, the total two double bonds, for example-CH=ZCH-CH=ECHCH3.

If R15is C1-6CNS group substituted by hydroxyl or alkoxyl, it may be, for example, 2,3-dihydroxypropyl and obtained from him acetonitrile or 2,3-dimethoxy-propoxyphenol group.

R16is preferably a hydrogen atom with R15located in the configuration.

R1can represent, for example, a hydrogen atom or a hydroxyl group.

R2can represent, for example, hydrogen or C1-4alkyl (e.g. methyl), and R3can represent, for example, hydrogen, C1-4alkyl (e.g. methyl, ethyl or n-propyl) or C1-4alkoxyl1-4alkyl (for example, methoxyethyl) or CR2R3can represent C=O, C=S or C3-8cycloalkyl (for example, cyclopentyl).

R4can represent, for example, methyl or C1-4alkoxymethyl (for example, methoxymethyl).

R5and R6each can independently represent, for example, hydrogen or C1-4alkyl (e.g. methyl).

Examples of ring systems described

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include

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Examples of otiluke - carbonyloxy, C1-4alkoxycarbonylmethyl and C1-4alkoxyl1-4alkoxy (for example, methoxyethoxy), C1-4alkoxycarbonyl - C1-4alkoxy, C1-4alkylcarboxylic, 2,3-dihydroxypropyl and their acetonyl, 2,3-dimethoxypropane, C3-6alkenones, such as allyloxy or 3-methylacrylates, or R15and R16and the carbon atom to which they are attached represent C=O or C=CH2.

R17can represent, for example, methyl or C1-4alkoxymethyl (in particular, methoxymethyl) or hydroxymethyl.

R15preferably represents C1-4alkoxy, C3-4alkenylacyl, benzyloxy or OCOR4(where R4is C1-4alkyl group), particularly those in the configuration.

R17preferably represents methyl.

W preferably represents oxygen.

A special group of compounds according to the invention are the compounds of formula (I) in which Z is a group

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or

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where one of X and Y is oxygen and the other is oxygen or the group CR9R10. Within this group, more specifically R1is a hydroxyl sludge, C1-4the alkyl, a R10is hydrogen, or CR9R10represents a group C=O or C=CHR11, Y is oxygen or CHR9where R9is H or C1-4the alkyl, R2and R3each independently is hydrogen, C1-4the alkyl, such as stands, propylene or C1-4alkoxyalkyl, in particular methoxymethyl, or R2and R3together with the carbon atom to which they are attached, represent cyclopentyloxy group or the group C=O or C=S; R5and R6each are preferably hydrogen.

If R1represents a hydroxyl or C1-4alkoxyl, R1the part is preferably in axial configuration. However, R1preferably represents a hydrogen atom.

R2and R3can each individually represent hydrogen or C1-4alkyl.

R4preferably represents methyl.

R5and R6each is preferably hydrogen.

n is preferably zero.

Specific ring systems described

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include,

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where R2and R3previously described, and X and is slowiy, that at least either X or Y are oxygen or ring.

Among the ring systems

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preferred rings are those in which one of X or Y is oxygen and the other is a CR9R10(where R9and R10each independently represents hydrogen or C1-4alkyl (e.g. methyl) or CR9R10represent a group C=O or C=CH2), or X and Y both represent oxygen; R2and R3represent hydrogen, C1-4alkyl or a group CO.

It should be understood that the present invention covers all combinations of particular and preferred groups described.

Following a special group of compounds according to the invention are the compounds of formula (I), where Z is a group (a), and where R1is hydrogen, a R4is stands;

n = 0, a R2and R3are hydrogen or C1-4the alkyl, X and Y are oxygen, or Y is oxygen and X is a group CHR9where R9is hydrogen or C1-4the alkyl, C=O, C=CH2or X is CH, Y is oxygen, n is zero and R2and R3are hydrogen.

Following the BR> and their pharmaceutically acceptable salt and solvate (e.g. hydrate), where W is oxygen or sulfur, and R15is as defined above. More specifically, W is oxygen, and R15is a group selected from C1-4alkoxyl, benzyloxy or OCOR4(where R4is C1-4alkyl group such as isopropyl or t-bootrom), or C3-4alkenylacyl, C1-4alkoxycarbonylmethyl.

Specific compounds according to the present invention include:

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,7R,9R]-2,8-Dioxa-9-methyl-4-methylene - CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4,4 a,5,6,7, 7a, 8,3 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin - 3a(1H)-carboxylic acid.

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-dideoxy-3,4-O-isopropylidene- - D-allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid;

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4R,7R,9R]-2,8-dioxa-4,9-dimethyl-CIS-bicyclo [3.4.0] non-7-yl-oxy-methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid;

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8a-[[1S, 4S,6R,8R]-2,7-dioxa-4,6-dimethyl-CIS-bicyclo [3.4.0] non-8-yl-hydroxy-methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-ind the-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-5-Indus-price-3a(1H)-carboxylic acid;

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-anhydrous-6-deoxy-4-O-methyl--D - mannopyranosyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid;

and their pharmaceutically acceptable salt and solvate (e.g. hydrate) or metabolically labile derivatives.

The compounds of formula (I) are highly active fungicides suitable for combating fungal infections in animals, including humans. For example, they can be used for the treatment of fungal infections caused by such organisms as Candida species (e.g., Candida albicans, Candida glabrata, (Torulopsis glabrata), Candida tropicalis, Candida parapsilosis and Candida pseudotropicalis), Cryptococcus neoformans, Pneumocystis carinii, Aspergillus sp. (for example, Aspergillus flavus and Aspergillus fumigatus), Coccidioides (e.g., Coccidioides immitis), Paracoccidioides (e.g., Paracoccidioides brasiliensis), Histoplasma (e.g., Histoplasma capsulatum) or Blastomyces (e.g., Blastomyces dermatitidis). They can also be used to treat other fungal infections caused by species of Candida, Trichophyton, Microsporum or Epidermophyton (e.g., Trichophyton mentographytes, Trichophyton rubrum, Microsporum canis or Epidermophyton floccosum), or infections of the mucous membranes caused by Candida albicans.

The compounds of formula (I) can also be used to treat other infections caused by species of filamentous fungi, such is for example, Sporothrix schenckii), Scedosporium (e.g., Scedosporium apiosperum), Cladosporium (for example, Cladosporium carrionii) and Pityrosporum ovale.

The compounds of formula (I) can also be used to treat infections caused by protozoa such as Toxoplasma, Cryptosporidium, Leishmania, Tripanosoma, Giardia and Trichomonas.

In vitro determination of this makes it the active compounds according to the invention was carried out in liquid or on solid medium using the method antigennogo twofold serial dilution to determine the minimum inhibitory concentration (MIC) antigennogo agent that inhibited the development of growth in 24-48 hours incubation at 37oC. In practice, a series of agar plates or cuvettes for microdesmidae nutrient medium containing a twofold dilution of test antigennogo agent, was inoculable standard culture clinically appropriate pathogen, such as Candida albicans. Cups with agar or cuvette for microdesmidae nutrient medium and then analyzed for the presence or absence of growth of the fungus and recorded the corresponding values MICK.

MIC values (defined as the lowest antigena concentration that kills at least 99.9% of the original inoculum in a liquid medium) can also be defined PU and, which saw an increase, and each transparent holes on agar plates.

In vivo determination of compounds of formula (I) can be carried out on a series of dose levels by injection (e.g. subcutaneously, orally, intraperitoneally or intravenously) to mice or rats, inoculated with strain Candida albicans. Untreated animals die in the interval from 3 to 9 days, while registering the dose level at which the test compound provides 50% protection against the lethal action of infection.

From the point of view of their this makes it activity, the compounds of formula (I) is recommended for the treatment of various fungal infections in humans and animals. Such infections include superficial, cutaneous, subcutaneous and systemic mycotic infections such as respiratory tract infections, gastrointestinal tract, cardiovascular infections, urinary tract infections, infections of the Central nervous system, candidiasis and chronic candidiasis of the mucous membranes (in particular, thrush and vaginal candidiasis), and skin infections caused by fungi, cutaneous and mucocutaneous candidiasis, ringworm, including tinea, athlete's foot, paronychia, bran-a prominent zoster, erythrasma, intertriginoznoy dermatitis, fungal visip ticheskih means to prevent systemic and local fungal infections. Use as prophylactic agents may be useful, for example, as part of the design of selective bowel decontamination to prevent infection in patients with immune disorders (in particular, patients, AIDS patients undergoing anticancer therapy or patients undergoing transplantation of organs and tissues). Preventing excessive development of fungi during antibiotic treatment may also be desirable under some painful syndromes or iatrogenic conditions.

Despite the fact that it is permissible to use in therapy, the compounds according to the invention can be introduced in the form of a crude compound, it is preferable to present the active ingredient as a pharmaceutical preparation. The invention therefore further proposed that the pharmaceutical preparation containing the compounds of formula (I) and their pharmaceutically acceptable salts together with one or more pharmaceutically acceptable carriers and, possibly, other therapeutic and/or prophylactic ingredients. The carrier (s) must be "acceptable" in the sense that it must be compatible with other ingredients of the drug and not be harmful to oral, transbukkalno, parenteral administration, administration in the form of an implant, rectal, local, ophthalmic or genito-urinary introduction, or in a form suitable for administration by inhalation or insufflation.

Tablets or capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, gum Arabic, gelatin, sorbitol, tragakant, starch glue or polyvinylpyrrolidone; fillers, for example lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrant, for example, potato starch or starch glycolate, sodium or croscarmellose sodium; or wetting agents such as sodium lauryl sulfate. Tablets, which include chewing, dissolving, or effervescent tablets may be coated according to methods known from the prior art. Liquid preparations for oral administration can take the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product that can be connected with vodeine supplements such as suspendresume agents, for example sorbitol syrup, methylcellulose, glucose syrup/sugar, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats; emulsifying agents, for example lecithin, monooleate sorbitan or gum Arabic; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example methyl - or propyl-p-hydroxybenzoate or sorbic acid.

Composition for transbukkalno injection can be in the form of tablets or lozenges prepared in the usual way.

The composition according to the invention can be produced in a form for parenteral administration by injection or continuous injection. Preparations for injection can be in the form of single doses in capsules, or in mnogochasovykh containers with added preservatives. The compositions can have such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may include forming agents, such as suspendida, stabilizing and/or dispersing agents. On the other hand, AK is Telem, for example, sterile pyrogen free and no water.

The compositions according to the invention for administration by inhalation, usually in the form of an aerosol spray from packages with high blood pressure with the use of appropriate propellant, for example DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a dispenser. In the case of an aerosol under pressure dosing unit can be determined by setting valve for the introduction of a measured quantity.

On the other hand, the compositions according to the invention for administration by inhalation may be in the form of dry powder formulations, for example a powder mix of the compound and a suitable powder base, such as lactose or starch, or modified physical form of this drug substances without additives. The powder composition may be in the form of a unit dosage forms, such as capsules or containers, in particular, gelatin, or in the form of packets, from which the powder may be introduced using an inhaler or uduwela.

The compositions can be in the form of suppositories, e.g. containing conventional suppozitornyj basis or Vaga is you can also be made for local application in the form of ointments, creams, gels, lotions, shampoos, powders (including sprayable powders), vaginal suppositories, tampons, sprays, liquids wetting, aerosols, drops (e.g. eye, ear or nose drops) or lotions. Ointments and creams may, for example, be made of an aqueous or oily base with the addition of suitable sealing and/or gelling agents. Ointment for introduction into the eye can be manufactured in a sterile manner with the use of sterilized components. Lotions can, for example, be manufactured for veterinary use in oil-containing organic solvents, possibly forming agents, such as stabilizing and solubilizers agents. Vaginal suppositories and vaginal swabs introduction can be manufactured using conventional methods and, if appropriate, may contain foaming media. Such compositions can also contain other active ingredients, such as corticosteroids, antibiotics or anti-parasitic means, as appropriate.

Liquid preparations for intranasal injection can be in the form of solutions or suspensions and may contain conventional excipients, such as regulatory tal, phenethyl alcohol; and other components of the agents, such as suspendida, sautereau, stabilizing, dispersing and/or corrective agents.

Percutaneous introduction may be effected by applying a suitable system, which stimulates the absorption of active compounds through the skin and which usually consists of drug-basics encased in an adhesive patch containing membranes, membranes and emitting layers. Such systems may contain amplifiers absorption, such as alcohols, or act by strengthening ionotophoresis.

The composition according to the invention can be made in the form of a preparation with prolonged action. These drugs for long periods can be introduced by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. For example, the connection according to the invention can be skompanovano with suitable polymeric or hydrophobic materials (for example, emulsion in an acceptable oil) or ion exchange resins, either in the form of slightly soluble derivatives, for example in the form of a slightly soluble salt.

When the compositions contain dosage units, each unit preferably on the invention should be administered orally. The daily dose used for the treatment of an adult, should preferably range from 0.001 mg to 5000 mg of active ingredient, most preferably from 0.01 mg to 2000 mg, which can be entered as 1-4 single doses, for example, depending on route of administration and the condition of the patient and the disease to be treated.

The connection can be entered by intravenous infusion, using, for example, up to 50 mg/kg/day of the active ingredient. The duration of treatment should be determined by the degree of response, and not just a number of days.

Compounds according to the invention can also be used in combination with other therapeutic means, and the invention therefore, in the following aspect provides a combination comprising a compound according to the invention together with another therapeutically active agent.

So, for example, the compounds according to the invention can be used in combination with one or more other antigenic agents such as polyene derivative (Amphotericin B, Nystatin, a lipid preparation of Amphotericin B), derived azole (fluconazole, Itraconazole, Ketoconazole, Miconazole, Clotrimazole, ZD-08070, UK-109496), 5-Fertilizin derived Pneumocandin or Echinocandin - ), interleukin (IL-1, IL-2, IL-3 and IL-8) and the factors, colony stimulating [(G)-CSF (M)-CSF and (GM)-CSF], and defensive.

Most appropriate for use with the compounds according to the invention compounds include Itraconazole, Flucytosine, fluconazole or Amphotericin B.

If the compounds according to the invention is administered in combination with another antifungal agent, the compounds according to the invention and other fungal agent can be introduced at the recommended maximum clinical dosage or at lower doses.

The above combinations may be proposed for use in the form of a pharmaceutical preparation of such pharmaceutical preparations containing the above-described combination, together with their pharmaceutically acceptable carrier, are another aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical preparations.

If the connection according to the invention is used in combination with a second therapeutic agent against the same condition, the dose of each compound may differ from the dose, which is used each connection separately. Appropriate dose Dol is m the compound of formula (I) or a physiologically acceptable salt, a pharmaceutical composition containing the compound of formula (I) or a physiologically acceptable salt, as defined above, for use in therapy, in particular for the treatment of fungal infections in animals (especially humans).

According to further aspect of the present invention we provide the use of compounds of formula (I) or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of fungal infections in humans and animals.

According to further aspect of the present invention, we provide a method of treatment of the human or animal with the aim of combating fungal diseases, this method includes the introduction of the specified organism an effective amount of the compounds of formula (I) or its physiologically acceptable salt.

Professionals should be borne in mind that reference to treatment includes both the prevention and treatment of established conditions or infections.

Compounds according to the invention can be obtained as described below.

Thus, the General method (A) for obtaining the compounds of formula (I), where Z is a group (a) includes the interaction of the compounds of formula (II)

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in which R1and R4set the exception X and/or Y may not be CR9R10,

for the formation of the desired cyclic system with the subsequent removal carboxylamide group.

According to the first implementation of the method (A), the compound of formula (Ia) in which R1-R4defined above in formula (I), n = 0 and X and Y are both oxygen, can be obtained by treating the diol of formula (III)

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in which R1and R4defined above in formula (I), a Rpis carboxylamide group

compound (L)2CR2R3(where L is acceptable leaving group), with the subsequent removal carboxylamide group. If R2and R3are both hydrogen, the reaction rim conveniently be accomplished by treatment of compounds of formula (III) dihalomethane (in particular, dibromethane) in the presence of a strong base, such as alkali metal hydroxide (e.g. sodium hydroxide), preferably in terms of a phase transition, using, for example, tetraalkylammonium salt of (in particular, tetrabutylammonium), at a temperature close to ambient temperature. If at least either R2or R3is C1-6alkyl group ppoi, the reaction rim conveniently be made by treatment of compounds of formula (III) Cetelem (RO)2CR2R3(where R is a C1-6alkyl group, such as stands), preferably in the presence of acceptable acids, such as p-toluensulfonate acid or pyridine-p-toluensulfonate, and in an acceptable solvent such as a ketone (e.g. acetone), a nitrile (e.g. acetonitrile), or halogenosilanes hydrocarbon (e.g. dichloromethane) at about room temperature. The compounds of formula (Ia) in which X and/or Y are sulfur, can be similarly obtained from the intermediate compounds corresponding to the compounds of formula (III), in which one or both of diol hydroxyl group is replaced by a thiol. If CR2R3represents the C=O or C=S, then the reaction rim is conveniently carried out by means of interaction of the compounds of formula (III) with a carbonyl diimidazol or thiocarbonyldiimidazole in an appropriate solvent such as a hydrocarbon (e.g. toluene) or an ether (e.g. tetrahydrofuran), with delegacia. If CR2R3represents the C=S, then the reaction rim is conveniently accomplished by processing the EP, toluene able reflux distilled), followed by the addition of gulatinget (for example, penishealthinformation) in a hydrocarbon solvent (e.g. toluene) at a temperature close to the room.

According to the following implementation method (A), the compound of formula (I) in which R1and R4the same as defined in the above formula (I), or R2or R3represents a C1-6alkyl, and the remaining radical is a hydrogen, C1-6alkyl or C1-4alkoxyl1-4alkyl, (CR5R6)nrepresents CR5R6where R5and R6the same as defined in formula (I) above, and X and Y both represent oxygen, can be obtained by processing diol of formula (III) oxide, tin (for example, oxide dibutylamino) in a hydrocarbon solvent (e.g. toluene able reflux distilled), followed by the addition of allivalite CR5R6CR2=CHR14(where R14is hydrogen or C1-6the alkyl and Gal is halogen, for example bromine and fluorine salts (for example, tetrabutylammonium) in an appropriate solvent, such as ether (e.g. tetrahydrofuran), and progrevanii (IV)

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which can be converted into the desired compound of formula (Ia) via cyclization involving intramolecular electrophilic accession induced mercury salt (for example, trifurcation mercury) with subsequent hydride recovery, for example by using hydride triamcinolone (for example, anti-hydride), and then removing carboxylamide group. The reaction is conveniently carried out at a temperature close to the room temperature, in the presence of a suitable solvent, such as ether (e.g. tetrahydrofuran).

In another implementation of the method (A), the compound of formula (Ia) in which R1-R4the same as defined above in formula (I), n = 0, and X or Y are oxygen, and the remaining residue is CR9R10(where one of R9or R10represents a C1-6alkyl and the other represents hydrogen, C1-6alkyl or C1-4alkoxyl1-4alkyl, or CR9R10represents C=CHR11), can be obtained by treatment of compounds of formula (III) oxide, tin (for example, oxide dibutylamino) in a hydrocarbon solvent (e.g. toluene able reflux distilled), and possibly in the presence of fluoride salts (the>CHR14or generalize CR2R3CCR11(where R11, R14and Gal are the same as defined above), or by adding allelulia or alkylhalides after defending one diol hydroxyl groups with the formation of the compounds of formula (V)

< / BR>
where X1represents OH, a Y1is an OCR2R3CR9=CHR14or OCR2R3CCR11or X is an OCR2R3CR9=CHR14or OCR2R3CCR11a Y1represents a protected hydroxyl group.

Cyclization can be completed through the initial removal hydroxylamino group, if it exists, and then activating the free hydroxyl groups, for example through the formation of S-alkyldithiophosphate (in particular, S-methyldithiocarbamate), then ring closure under radical conditions, for example by treatment of a solution of the activated intermediate compound in a hydrocarbon solvent (e.g. toluene) at reflux distilled donor hydrogen, hydride such as regenerating agent (in particular, the hydride triamcinolone, such as anti-hydride) in the presence of an activating agent [e.g AZ is easily done by processing the compounds of formula (V), in which one of the radicals X1and Y1is OH and the other is OCR2R3CR9=CHR14or OCR2R3CCR11strong base of an alkali metal (e.g. sodium hydride) in the presence of imidazole in an appropriate solvent, such as ether (e.g. tetrahydrofuran) at low temperature (e.g. about 0oC), and then adding carbon disulfide and alkylamide (for example, under the conditions), at a temperature close to the room.

In the following the implementation of the method A compound of formula (I) in which Y is oxygen, n = 0, a R2and R3are hydrogen, X is a group of CR9R10can be obtained by reaction of compounds of formula (V) in which X1is hydroxyl, with triphenylphosphine, iodine and imidazole in an appropriate solvent, such as tetrahydrofuran, to obtain the desired 4-vodoprovodnogo (Va). Then can be obtained the desired ring system radical conditions, such as interaction with hydride triamcinolona in a hydrocarbon solvent by heating.

< / BR>
In the following the implementation of the method A compound of formula (I) in which Y avaiiable connection iodine formula (Va) with sodium hydride and an isocyanate R12NCO in an aprotic solvent such as tetrahydrofuran, followed by removal carboxylamide group.

In the following the implementation of the method (A), the compound of formula (I) in which R1and R4the same as defined in the above formula (I), R2and R3each independently represent hydrogen, C1-6alkyl or C1-4alkoxyl1-4alkyl, or CR2R3represents a C3-8cycloalkyl, n = 0, and one of the radicals X or Y is-NR12- (where R12is the same as defined in the above formula (I)), and the other represents oxygen, can be obtained by N-atsilirovaniya the compounds of formula (VI)

< / BR>
in which one of the radicals X11and Y11is OH and the other is NH2,

or a protected derivative, for example by applying such allvalid as acylchlorides, under appropriate conditions followed by treatment of the amide with an aldehyde or ketone R2R3C=O or dialkylated R2R3C(Alkyl)2in the presence of an appropriate acid, such as p-toluensulfonate acid or p-toluensulfonate pyridinium, and in an appropriate solvent, such as Galenia any present protective groups.

In another implementation of the method (A), the compound of formula (Ia) in which R1and R4also, as defined in the above formula (I), n = 0, -X-CR2R3or-Y-CR2R3represent-N= CR3- (where R3is C1-6the alkyl or C1-4alkoxyl1-4by alkyl), and the remaining X or Y is oxygen, can be obtained by treating the compounds of formula (VI) iminoethyl R3C(=NH)OR (where R is a C1-6alkyl group, such as stands).

According to the General method B, the compounds of formula (I) in which Z is a group (a), a Y is oxygen, n = 0, R2and R3are hydrogen, X is CH, can be obtained by the reaction of compounds of formula (VII)

< / BR>
in which R21is a group CHO or its protected derivative, Rpis a protected carboxyl group, a dialkyl-desmethyltramadol in the presence of a base, such as tert-piperonyl potassium, in an aprotic solvent such as ether (e.g. tetrahydrofuran), followed by removal of carboxyl - protective group, Rpand, if necessary, illegitamite group, 4-kyaterekera derivative (VII) can be obtained by oxidation with>/P>General method (B) obtain the compounds of formula (I) in which Z is a group (b), a W is oxygen, involves the cyclization of the compounds of formula (VIII)

< / BR>
in which R15a, R16aand R17ashall have the same meaning as defined for R15, R16and R17in the preceding formula (I) or are protected derivatives, Rpis hydrogen or carboxylamide group, L is an appropriate leaving group, such as alkyl or arylsulfonyl group, and R22is hydrogen or OR22is the same group as defined for L,

followed, if necessary, removing any present protective groups.

The cyclization reaction is conveniently accomplished by treatment of compounds of formula (VIII) with a strong base, such as alkali metal hydride (e.g. sodium hydride), in an appropriate solvent, such as dimethylformamide or an ether (e.g. tetrahydrofuran) typically at room temperature. You can also use sodium in an alcohol solvent (e.g. methanol), especially if OR22is the same group that is defined for L. In this case, the basic system is a hydrocarbon (for example, dichloromethane), the reaction is carried out usually at a temperature of from room temperature to the temperature of reflux distilled.

Another common way (G) obtaining the compounds of formula (I) in which W is sulfur, enables handling of the compounds of formula (IX)

< / BR>
in which R15, R16and R17are the same values that are defined for them in the above formula (I),

the sulfur donor. For example, the reaction can conveniently be by treating the compounds of formula (IX) 5,5-dimethyl-2-thiolo-2-thioxo-1,2,3 - dioxaphosphorinanes in a solvent such as dimethylformamide, preferably in the presence of an appropriate base, such as trialkylamine (e.g. triethylamine), at elevated temperature (for example, from 80 to 120oC).

The compound of formula (IX) can be easily obtained from the compounds of formula (VIII), in which L is a hydroxyl group, OR a22represents an appropriate leaving group, such as alkyl or arylsulfonyl group, using the conditions described in method (B), followed, if necessary, removing any present protective groups.

Another common way (D) involves the reaction of mutual transformations of isomers when the connection form implement the method (D) carboxyamide derivative compounds of formula (I), in which Z is a group (a) and in which R1is hydroxyl may be converted into the corresponding compound of formula (I) in which R1is hydrogen, by a process that includes (i) the formation of S-alkyldithiophosphate according to the method described previously, and (ii) the removal of this group by treating a solution of intermediate compound in a hydrocarbon solvent (e.g. toluene) at elevated temperature (for example, from 80 to 120oC) hydride regenerating agent (for example, a hydride triamcinolone, such as anti-hydride), and then remove carboxylamide group.

In the following the implementation of the method (D) compound of formula (I) in which Z is a group (a), in which R1is C1-4acyloxymethyl and/or R4is C1-4alkoxymethyl, can be obtained by alkylation of a protected derivative of a compound of formula (I) in which R1is a hydroxyl and/or R4is hydroxymethyl, and all labile groups (e.g. carboxyl and hydroxyl groups are protected, with the subsequent removal of the present protective groups. The alkylation is conveniently done with the help of the original Regionala). The reaction can be carried out in an appropriate solvent, such as ether (e.g. tetrahydrofuran) at a temperature within the range from about 0 to 30oC.

In another implementation of the method (D) compound of formula (I) in which R1is alloxylon and/or R4is CH2OCOR8can be obtained by atsilirovaniya protected derivative compounds of formula (I) in which R1is a hydroxyl and/or R4is CH2OH and all labile groups (e.g. carboxyl and hydroxyl groups are protected, with the subsequent removal of any present protective groups. The reaction atsilirovaniya can be performed by conventional methods, for example by treating the carboxylic acid in the presence of an activating agent, such as dicyclohexylcarbodiimide, and the appropriate base, such as dimethylaminopyridine, or using an acid halide (e.g. acid chloride), possibly in the presence of an appropriate base, such as pyridine or 4-dimethylaminopyridine.

According to the following implementation method (D), the compound of formula (I) in which R1is a hydroxyl group in the Equatorial configuraciones group in axial configuration and all labile group (e.g., carboxyl, hydroxyl and CHO groups) are protected, followed by removal of any present protective groups. The isomerization reaction can be easily done by using the two step method including (i) oxidation of the 2'-axial OH in oxoprop by treatment with a suitable oxidizing system [e.g., chromium oxide in the presence of pyridine in a solvent such as halogenosilanes hydrocarbon (particularly dichloromethane) containing acetic anhydride] and (ii) the recovery of the carbonyl group to the Equatorial Oh groups using a suitable reducing agent, such as barbadoro (for example, barbadoro sodium). Recovery may be easily carried out in a suitable solvent, such as alcohol (e.g. aqueous methanol) at a temperature in the range from about 0 to 10oC.

In another implementation of the method (D) compound of formula (I) in which R1is a halogen atom, can be obtained from a protected derivative compounds of formula (I) in which R1is a hydroxyl group, with the subsequent removal of any present protective groups. In the inversion of configuration is a substitution reaction. So, for example, axial OH gr is the same material in an appropriate solvent, such as a hydrocarbon (e.g. toluene), in the presence of triphenylphosphine and iodine, and then heating the mixture (for example, delegacia).

Similarly, there may be a fluorine atom by treatment with an appropriate fluorinating agent such as TRIFLUORIDE diethylaminoethyl (will GIVE), in a suitable solvent, such as halogenosilanes hydrocarbon (e.g. dichloromethane) or an aromatic hydrocarbon (e.g. toluene) at a temperature close to the room.

In the following the implementation of the method On the compound of formula (I), where Y is oxygen, n = 0, R1and R2are hydrogen, and X is CH, or a protected derivative can be converted into the corresponding compound in which X becomes CH2in the reduction with hydrogen in the presence of an appropriate catalyst, for example palladium on charcoal, in a suitable solvent, followed by removal carboxylamide group.

In another implementation of the method On the compound of formula (I), where Y is oxygen, n = 0, R2and R3are hydrogen, and X is the group C=CH2can be converted into the corresponding compound in which X becomes a group C= O as a result of oxidation na), where Y is oxygen, n = 0, R2and R3are hydrogen, and X is the group C=CH2can be converted into the corresponding compound of formula (I) in which R2and R3and the carbon atom to which they are attached, turn to the group C=O as a result of oxidation, for example with chromium trioxide in pyridine.

According to the following implementation method (D), carboxyamide derivative compounds of formula (I) in which R15is hydroxyl may be converted into the corresponding compound of formula (I) in which R15is halogen by standard substitution reactions with subsequent removal carboxylamide group. For example, the replacement of hydroxyl by fluorine atom can be easily implemented with inversion of configuration by adding the TRIFLUORIDE diethylaminoethyl (will GIVE) to a solution of starting material in a solvent such as halogenosilanes hydrocarbon (e.g. dichloromethane). The reaction readily proceeds at room temperature.

In the following the implementation of the method (D) compound of formula (I) in which R15is C1-6CNS or possibly substituted CNS group and/or R17is C1-415and/or R17contains free hydroxyl group and any labile groups (e.g. carboxyl and hydroxyl groups) are protected, if appropriate, with the subsequent removal of the present protective groups. The alkylation can be carried out in the initial reaction with the Foundation of a strong alkali metal (e.g. sodium hydride), and then alkylhalides (for example, methylbromide). The reaction can be carried out in an appropriate solvent, such as ether (e.g. tetrahydrofuran) at a temperature within the range from about 0oC to 50oC. If appropriate, may be ammonium salt, such as tetraalkylammonium (for example, tetrabutylammonium).

On the other hand, a straight or branched alkyl group can be easily introduced in two stages, the first stage includes alkenylamine using a suitable alkanolamine in the presence of such grounds, as a carbonate (e.g., cesium carbonate) in a solvent such as dimethylformamide, at a temperature close to the room, and the second stage involves the process of halogenization in the presence of a palladium catalyst (for example, 10% of pulled the s (I), in which R15is CH2OCOR20or R1is OCOR18may be obtained by acylation of a protected derivative of a compound of formula (I) in which R17is CH2OH, or R15is hydroxyl, and any labile groups (e.g. carboxyl or hydroxyl groups are protected, with the subsequent removal of any present protective groups. The acylation reaction can be carried out in the usual way, for example by treatment of carboxylic acid in the presence of an activating agent, such as dicyclohexylcarbodiimide, and the appropriate base, such as dimethylaminopyridine, or by using gelegenheid (e.g., carboxylic acid), possibly in the presence of a suitable base, such as pyridine or dimethylaminopyridine.

According to the following implementation method (D), the compound of formula (I), in which CR15R16represents C=O, can be obtained by oxidation of the protected derivative of the compound of formula (I) in which R15is a hydroxyl group, and all labile groups (e.g. carboxyl and hydroxyl groups are protected, with posledovavshemu appropriate oxidizing agent, such as dimethyl sulfoxide, in the presence of triperoxonane anhydride. Oxidation easily passes in the presence of a suitable solvent, such as halogenosilanes hydrocarbon (e.g. dichloromethane), at elevated temperature (for example, from about 40 to 80oC).

The compounds of formula (I), where CR15R16represents the group CH=CH2can be obtained by reaction of the corresponding compounds of formula (I) or its protected derivative, where CR15R16is the group C=O, with alkyldiphenyl-phosphonylation and alkyllithium in an aprotic solvent such as tetrahydrofuran.

The compounds of formula (I), where R15is the azide group can be obtained from the corresponding compounds of formula (I) or its protected derivative, where R15is a hydroxyl group, the reaction with toluensulfonate with subsequent treatment of the formed toluensulfonate derived azide of an alkali metal such as lithium azide, aprenda solvent, for example dichloromethane.

Many of the above methods to obtain the desired compounds of formula (I) require the removal of one or blemishing derivative compounds of formula (I). Suitable for using in it carboxylate group and hydroxylamine groups include any conventional protective groups [4,5]. Examples of acceptable carboxylamide groups include arylalkyl groups, such as diphenylmethylene, p-methoxyaniline and silyl groups (for example, trimethylsilylmethyl or t-butyldimethylsilyl). Examples of acceptable hydroxylamine groups include arylalkyl groups such as p-methoxybenzylidene and ether groups, such as benzyloxycarbonyl. Aldehyde groups can usually be protected in the form of cyclic ketals.

The protective group can be removed by standard methods. So, diphenylmethylene group can be easily removed using triperoxonane acid or by hydrogenolysis in the presence of a palladium catalyst (for example, 10% palladium on coal). Benzyloxycarbonyl group can be easily removed by hydrogenolysis in the presence of a palladium catalyst (for example, 10% palladium on coal). P-methoxybenzyl group can be easily removed by using 2,3-dichloro-5,6-dicea-but-1,4-benzoquinone. Silyl group, such as trimethylsilyl or t-butyldimethylsilyl can be easily removed with the help of fluoride ions. Gracility, such as hydrochloric acid.

The compounds of formula (II) can be easily obtained by reaction of compounds of formula (X)

< / BR>
where Rpis carboxylamide group

with the compound of the formula (XI)

< / BR>
where R1, R4X and Y are the same as defined in the above formula (II) or its protected derivative with subsequent removal, if necessary, any present protective groups. This reaction can be easily carried out by heating (X) and (XI) at a temperature in the range from about 40oC to 80oC in an appropriate solvent such as a hydrocarbon (e.g. toluene) in the presence of acid, such as Hydrobromic acid is triphenylphosphine.

If XH and YH in the formula (XI) are hydroxyl groups, they can be easily protected as Allexinno (for example, acetoxyl) group, with the removal of the protective group after the reaction with the compound of the formula (X). Remove acetoxysilane groups can be easily implemented by adding a suitable base, such as alkoxide (e.g. sodium methoxide) in an appropriate solvent, such as alcohol (e.g. methanol) at a temperature close to that on the/SUP> not a methyl group. If R4is a methyl group, it may be more appropriate to obtain the compounds of formula (II) from 4'- dimethyl-sordaria, the compounds of formula (XII)

< / BR>
For example, the compounds of formula (III) in which R4represents methyl, can be obtained by protecting the carboxyl group in (XII) appropriate methods, followed, if necessary, the conversion of 2'-axial hydroxyl group to another R1the group by way of mutual transformation described above. It may be necessary to protect the 3' and 4' hydroxyl group of the manipulation of a 2-axial hydroxyl group. Protection can be easily done through education isopropylidenebis group through a process described in the first implementation of the method (A). Subsequent removal of this group to ensure diol functions can be achieved by treatment with acid such as an inorganic acid (e.g. hydrochloric acid).

If the carboxyl group in the compound of formula (XII) are protected diphenylmethylene group, the reaction of protection can easily be carried out by treating a solution of the compounds of formula (XII) in ethanol restorefactory conveniently added as a solution in halogenosilanes hydrocarbon solvent (for example, dichloromethane).

The compounds of formula (II), where X and Y represent oxygen or sulfur, can also be obtained by decarboxylation of the corresponding protected derivative compounds of formula (I), in which CR2R3represents the C= O and n is zero. The decarboxylation can be easily implemented by adding CNS compounds (for example, CH3ONa) in an appropriate solvent, such as alcohol (e.g. methanol).

The compounds of formula (X) can be easily obtained from agaricina, using the normal way of protecting the carboxyl group. For example, if Rpin the compound of formula (X) represents trimethylsilylmethyl, this group can be introduced by processing agaricina O-[2-(trimethylsilyl)ethyl] -N,N'- diisopropylamino, usually in an appropriate solvent, such as ether (e.g. tetrahydrofuran) at elevated temperature (for example, delegacia). If Rpis diphenylmethyl, this group may be introduced by the method described above.

If the hydroxyl group in carboxylamide derived sordaria or the compound of formula (XII) protected p-methoxybenzyloxy group, Ogorodnik solvent (for example, toluene able reflux distilled) and then adding p-methoxybenzaldehyde in the presence of fluoride salts (for example, tetrabutylammonium). If this group is protected benzyloxycarbonyloxy group, it may be introduced by reaction with benzylmaleimide in the presence of an appropriate amine base, such as 4-dimethylaminopyridine, in such a solvent as halogenosilanes hydrocarbon (e.g. dichloromethane or acetonitrile.

Education group L in formula (VIII), where L is alkyl or arylsulfonyl group and/or the group R22O, where R22O is alkyl or arylsulfonyl group, can be carried out by the reaction of the corresponding protected derivative sordaria or the compounds of formula (XII) with alkyl - or arylsulfonamides in the presence of an appropriate solvent, such as pyridine, and possibly also containing amine base (for example, 4-dimethylaminopyridine), or in halogenosilanes hydrocarbon solvent (e.g. dichloromethane) in the presence of an appropriate amine base (for example, 4-dimethylaminopyridine). The reaction can be easily carried out at room temperature. The other is that it may be appropriate transformation of the hydroxyl group in the desired R15the group before the cyclization according to process (B). So, suitably protected derivative of 4'-dimethylarginine or the compound of formula (II) in which R15ais hydroxyl, by conventional methods, can be processed, which resulted in the 4'-hydroxyl group is converted into the desired group R1. For example, the transformation in C1-6CNS, C1-4alkoxyl1-4CNS or arils1-4CNS group can be achieved by conventional alkylation, for example according to various methods described herein above. The removal of the hydroxyl group to obtain compounds in which R15is hydrogen, can be easily carried out in two stages, including (i) the formation of S-alkyldithiophosphate by processing the basis of a strong alkali metal (e.g. sodium hydride) in the presence of imidazole, in an appropriate solvent, such as ether (e.g. tetrahydrofuran) at low temperature (e.g. about 0oC), and then adding carbon disulfide and alkylamide (for example, under the conditions) at a temperature close to the room, and (ii) the removal of this group through processing solution proer, approximately 80 to 120oC) with hydride regenerating agent (for example, a hydride triamcinolone, such as hydride three-butyanova), possibly in the presence of an activating agent [for example, azobis(isobutyronitrile)] . The transformation in C2-6the alkyl group can easily be done through (i) education S-alkyldithiophosphate as previously described, (ii) substitution of this group alkenylphenol group in the reaction with the compound dialkylacrylamide under the conditions described above for the removal of s-alkyldithiophosphate group and (iii) recovery alkenylphenol group in the alkyl group, for example by hydrogenation in the presence of a suitable palladium catalyst (for example, 10% palladium on coal).

Basic salts of compounds of formula (I) can be easily formed by processing the compounds of formula (I) corresponding salt or base. For example, salt can be easily obtained by treating the compounds of formula (I) salt or a base selected from a hydroxide, bicarbonate, carbonate or potassium acetate or sodium (for example, potassium hydroxide, potassium bicarbonate, sodium bicarbonate or potassium acetate, ammonium acetate, acetate calculi or Foundation (if necessary in an aqueous solution) to the solution or suspension of the compounds of formula (1) in a suitable solvent, such as alcohol (e.g. methanol) or dioxane at a temperature of, for example, from 0oC to 80oC, and usually at room temperature.

Pharmaceutically acceptable salts can also be obtained by standard methods from other salts, including other pharmaceutically acceptable salts of compounds of formula (I).

Metabolically labile esters of compounds of formula (I) can be formed with present in these compounds a carboxyl group, and they can be obtained by standard methods. Similarly metabolically labile esters may also be formed with any free hydroxyl group present in the molecule.

The new compound of the formula (XII) can be easily obtained as described below fermentation process or by demethylation sordaria in the process of biotransformation.

The fermentation process involves culturing a microorganism capable of producing the compound of the formula (XII), followed by separation of the compounds of formula (XII) of the culture.

Microorganisms capable of producing the compound of the formula (XII) are generally mutant strains of Sordaria araneosa, kotorov by analyzing a test sample, obtained after fermentation of the microorganism using standard methodology. In particular, microrganismos suitable for use, is a mutant strain of Sordaria araneosa, deposited in the collection of type culture of the CAB International Mycological Institute, Genetic Resource Reference Collection, Bakeham Lane, Egham, Surrey TW20 9TY, England. This strain was obtained by the Institute on 10 June 1994 and he was subsequently assigned catalogue number IMI 362184 and the date of acceptance and confirmation of the viability - June 13 and June 21, 1994, respectively. This Institute is an International Authority on Deposit according to the Budapest Treaty. Characteristics, have been identified to date for IMI 362184 shown in Example 74.

In his next aspect the present invention provides microrganism IMI 362184 as such and its mutants.

Mutants IMI 362184 can occur spontaneously or can be produced in various known ways [6] . Such methods include ionizing radiation, chemical methods, for example, processing of N-methyl-N'-nitro-N-nitrosoguanidine (IGT), heating, genetic methods, such as recombination and transformation, and selective methods for spontaneous mutants.

Getting connection formulated.the organism in the presence of assimilated carbon sources nitrogen and mineral salts, followed by separation of the desired product.

Assimilated sources of carbon, nitrogen and minerals can be entered as either simple or complex power sources. The carbon sources typically include glucose, maltose, starch, glycerol, molasses, dextrin, lactose, sucrose, fructose, galactose, meso-Inositol, D-mannitol, soybean oil, carboxylic acids, amino acids, glycerides, alcohols, alkanes and vegetable oil. The carbon sources are usually from 0.5 to 10% by weight of the fermentation medium. Fructose, glucose and sucrose are the preferred carbon sources.

The nitrogen sources typically include waste (pomace) beans, corn extract, grains, yeast extracts, waste cotton seeds, gelatin, cake ground peanuts, malt extract, molasses, casein, a mixture of amino acids, ammonia (gas or solution), ammonium salts or nitrates. Can also be used urea and other amides. The nitrogen sources are usually from 0.1 to 10% by weight of the fermentation medium.

Nutrient mineral salts, which can be introduced into the culture medium include commonly used salts that can form ions natrona, phosphate, sulfate, chloride and carbonate ions.

Cultivation of the microorganism is usually carried out at a temperature from 20 to 40oC, preferably from 20 to 35oC, especially when the 25oC, preferably with aeration and agitation, such as shaking and stirring with a stirrer. The environment may initially be inoculated with a small amount of mycelium and/or spores. Received vegetative AMF inoculum can be transferred in a fermentation medium or in one or more of cultivated plants, if you will have further growth before moving into the main fermentation medium. The fermentation is usually conducted in the range of pH from 3.5 to 9.5, preferably from 4.5 to 7.5. It may be necessary to add in a fermentation medium base or acid to maintain the pH within the required range. Acceptable grounds which can be added include hydroxides of alkali metals, such as aqueous sodium hydroxide or aqueous potassium hydroxide. Acceptable acids include mineral acids such as hydrochloric, sulphuric or phosphoric acid.

Fermentation can last for 4-30 days, preferably about 5-15 days. To control excessive foam is nitrogen can also be added to the fermentation medium as needed.

The compound of formula (XII) is associated mainly with cells and can be translated into the solution or by adding acid and miscible with water, organic solvent or, preferably, by adding a base (e.g. sodium hydroxide). Cells can be separated from these solutions either by centrifugation followed by filtration, or by membrane filtration. The liquid can then be subjected to treatment with acid, such as sulfuric acid, up until the pH is below 6 (for example, about 4.5).

The compound of formula (XII) can be isolated and purified using different fractionation techniques, such as absorption-elution, precipitation, crystallization, solvent extraction and fractionation of liquid-liquid, which can be combined in different ways.

It was found that the absorption on a solid substrate with subsequent elution is most appropriate for the isolation and purification of the compounds of formula (IX).

Acceptable solid substrates include silicon; nonfunctional macrostate adsorption resin, such crosslinking styrene-divinyl-benzene of polim the Il-benzene polymer, such as Diaion SP207 (Mitsubishi); aminoalkenes [e.g. IRA-958 or MacroPrep High Q (BioRad)] , compatible with the organic solvent crosslinking dextran such as Sephadex LH20 (Pharmacia UK Limited), or the substrate with reversed phase, such as cross-linked with hydrocarbon silicon, for example, C18-custom made silicon.

The compound of formula (XII) can be isolated and purified through the use of these anion-exchanger, as LA 2.

The selection of suitable solvents for the elution of the compounds of formula (XII) will of course depend on the nature of the adsorbent. When using a polymer resin such as XAD-16, the most appropriate can be mixed with water solvents, such as methanol, acetone, isopropanol or acetonitrile in different proportions in water.

The presence of the compounds of formula (XII) during the processes of extraction/separation can be monitored by conventional methods such as liquid chromatography high resolution (IHVR) or UV spectroscopy, or through the use of optical rotation or other connection properties.

If the compound of formula (XII) is obtained in the form of a solution in an organic solvent, for example, after purification by absorption/elution, rastvorite. If required, the connection can be further purified chromatographic methods, such as countercurrent chromatography with the use of the extractor in the form of a coil, such as a multilayer coil extractor or liquid chromatography high resolution or supercritical liquid chromatography on such adsorbents, such as carbon, aluminum, vanadium, polymer resin or silicon, with related phases or without them. The selection of suitable solvents and eluents for chromatographic purification/separation of the compounds of formula (XII) will of course depend on the nature of the adsorbent. When using C8 linked silicon the most appropriate mixture of acetonitrile and water. On the other hand, the connection can be further purified by solvent extraction, for example using an appropriate organic solvent such as a ketone (in particular, acetone, or methyl ethyl ketone), halogenosilanes hydrocarbon, an alcohol (e.g. methanol), diol (for example, propane-1,2-diol or butane-1,3-diol) or an ester (such as methyl acetate or ethyl acetate). In addition, solutions of the compounds (XII) can be further purified by treatment with adsorbents that selectively remove impurities while adding in with the of lonitrile and water), or by using a combination of these processes.

Biotransformation sordaria 4'-dimethylarginine, the compound of formula (XII) may be carried out by incubation sordaria in the culture containing the appropriate body and the sources of carbon and nitrogen, including the sources described previously, followed by separation of the compounds of formula (XII) of the culture.

Microorganisms capable of demetilirovanie sagarin 4'-position can be easily identified by applying small-scale test and analyzing the obtained test sample, using standard methodology, for example, applying GHUR. Examples of microorganisms that have been identified as dimethylether sordaria include Streptomyces capreolus ATCC 31963, Streptomyces avermitilis ATCC 31272, Streptomyces armentosus NRRL.3176, Streptomyces antibioticus ATCC 31771,

Streptomyces rimosus ATCC 23955, Streptomyces platensis ATCC 29778, Streptomyces mashuensis ATCC 23934, Streptomyces eurythermus ATCC 14975, Nocardia orientalis ATCC 43491 and Cunninghamella echinulata var elegans 36112.

Cultivation of the organism is usually carried out at a temperature of from 20 to 40oC, preferably from 20 to 35oC, especially around 28oC, and is usually preferably with aeration and stirring, for example by shaking or stirring using a stirrer. Environment the loom can be transferred in a fermentation medium, or in one or more of cultivated plants, where further growth (e.g., within 1-3 days) before transferring to the main enzymatic environment. The main enzymatic environment will also contain sagarin, and the fermentation is usually conducted at a pH in the range from 3.5 to 9.5, preferably from 4.5 to 7.5. It may be necessary to add in a fermentation medium base or acid to maintain the pH within the required range. Acceptable grounds which can be added include hydroxides of alkali metals, such as aqueous sodium hydroxide or potassium hydroxide. Suitable acids include mineral acids such as hydrochloric, sulfuric or phosphoric. Fermentation can last for a period of from 2 to 5 days, preferably about 3 days. To control excessive foaming can be a defoamer, which is added as necessary. Sources of carbon and nitrogen can also be added to the fermentation medium as needed.

Separation and isolation of the compounds of formula (XII) from the fermentation of a nutrient medium can be carried out by traditional methods, as described earlier. If you want to lower the pH of the fluid below pH 6 (for example the PTA.

It should be noted that the biotransformation can be carried out in several different ways. For example, cells can be grown and harvested before adding a solution sordaria, for example, in the buffer, depleted fermentation medium or water. It is also likely that can be selected and used appropriate enzymes (with the appropriate coenzymes) or these enzymes can be cloned and preexpansion.

As previously noted, sagarin and agaricin are known compounds which can be obtained by methods described in the literature. So, for example, is described in [1] obtaining agaricina by cultivation Sordaria araneosa NRRL 3196 (also deposited in the ATCC as ATCC 36386). Specific examples of the preparation sordaria using similar methods described below.

Agaricin can be easily obtained in a fermentation conditions similar to conditions described for obtaining sordaria using Sordaria araneosa NRRL 3196 or a suitable mutant, with separation of the desired compounds corresponding chromatographic means. One such mutant was deposited in the collection of type culture of the CAB International Mycological Institute, Genetic Resource Reference Collection, Bakehem Lane, Egham, Surrey TW20 9TY, Engla with the date of confirming the viability of 19 August 1994. This Institute is an International Authority on Deposit according to the Budapest Treaty. Characteristics identified for IMI 362947 shown in Example 75.

The present invention provides in a further aspect, the microorganism IMI 362947 as such and its mutants.

Methods of obtaining mutants IMI 362947 and their genetic material is usually similar to the methods described above for processing IMI 362184.

Agaricin can also be obtained from sordaria through biotransformation. Biotransformation can be easily carried out by incubation cordarone in culture, containing a suitable organism and sources of carbon and nitrogen, including the above-mentioned sources, followed by separation of agaricina of culture.

Microorganisms capable of transforming cordain in agaricin, can be easily identified using small-scale test and analyzing a test sample obtained in the standard way, for example using GHUR. We identified one such microorganism and deposited it in the National Collections of Industrial and Marine Bacterial Limited (NCIMB), 23 St. Machar Drive, Aberdeen AB2 IRY, Scotland. The strain was obtained NCIMB 4 August 1994 and in the same day would be the organizmu, which is a form of Coryneform having the characteristics shown in Example 76 was assigned catalogue number NCIMB 40675. NCIMB is an International Authority on Deposit under the Budapest Treaty.

The invention thus provides, in still another aspect, the microorganism NCIMB 40675 as such and its mutants.

According to further aspect of the present invention, we provide genetic material NCIMB 40675 and its mutants involved in the bioconversion cordarone in agaricin.

Methods of obtaining mutants NCIMB 40675 and their genetic material similar to the methods described above to work with IMI 362184.

Cultivation NCIMB 40675 usually carried out at a temperature of from 20 to 40oC, preferably from 20 to 35oC, especially around 28oC, and preferably with aeration and stirring, for example, by shaking or stirring using a stirrer. The environment may initially be inoculated with a small amount of mycelium and/or spores. Received vegetative mycelium can be transferred in a fermentation medium or in one or more of cultivated plants, if there is further growth (e.g., about 1-3 days) before the case is usually in the range of pH from 3.5 to 9.5, preferably about 7.5. It may be necessary to add in a fermentation medium base or acid to maintain the pH within a specific range. Acceptable grounds which can be added include hydroxides of alkali metals, such as aqueous sodium hydroxide or potassium hydroxide. Acceptable acids include mineral acids such as hydrochloric, sulfuric or phosphoric. The fermentation can be carried out in the period from 4 to 8 days, preferably about 6 days. To control excessive foaming can be antifoam added as needed. Sources of carbon and nitrogen can also be added to the fermentation medium as needed.

It should be noted that the biotransformation can be done in several different ways. For example, cells can be grown and collected before adding a solution sordaria, for example in the buffer depleted fermentation medium or water. It is also likely that can be selected and used appropriate enzymes or the enzymes can be cloned and preexpansion.

Division and allocation of agaricina of the fermentation medium can be done which can be easily achieved by adding acid such as orthophosphoric.

It should be understood that described above to obtain agaricina the processes of fermentation and bioconversion are the following aspects of the present invention.

The following examples illustrate aspects of the present invention, but in no way limit it.

THE DRUG 1

Getting sordaria

Culture Sordaria araneosa NRRL 3196 (ATCC36386) were grown on agar medium until then, until you be Mature height. Agar blocks with a diameter of 6 mm, containing the culture was transferred into a sterile water or the environment on the basis of cardio-cerebral extract (Oxoid) + 10% glycerol and kept at ambient temperature or at -140oC, respectively. A suspension containing 2 such agar block was used for inoculation of the Erlenmyer flask with a capacity of 250 ml containing 50 ml of medium FS.

Wednesday FS - g/l

Peptone (Oxoid L34) - 10

Malt extract (Oxoid L39 are effective) - 21

Glycerol (Glycerine CP) - 40

Junlon 110 (Honeywell & Stein) - 1

Distilled water

The culture was incubated at 25oC for 5 days on a rotary shaker working at a speed of 250 rpm and a diameter of orbital movement of 50 mm Aliquots (2 ml) developed inoculum was used for inoculation of the flasks Erienmyer capacity flasks with stirring, was used for inoculation of two 7-liter fermenters containing 5 l of FS environment. Fermentation was carried out at a temperature of 25oC. the Culture was stirred at a speed of 400 rpm and aeronavali at a flow rate of 2 l/min After 3 days of fermentation, 10 l of the culture was used for inoculation 780 - liter fermenter containing 500 l environment SM55VAR.

SM55VAR - g/l

Glucidex 32D (Roqette Frere) - 74

Peptone (Oxoid L37) - 10

Proflo (Traders & Protein - 30

Beet molasses - 15

MgSO47H2O (BDH) - 5

CaCO3(BDH) - 5

FeSO47H2O (Sigma) - 2

ZnSO47H2O (BDH) - 0.04

L-tryptophan (Sigma) - 2

PPG2000 (K & K Greef) - 0,5

The 1520 silicone (Dow Corning) - 0.04

Distilled water

Fermentation was carried out at a temperature of 25oC. culture medium was stirred at 300-350 rpm and aeronavali at 200 l/min To maintain a positive residual concentration of glucose to the culture was added 70% (V/V) Meritose (Tunnel Refineries) solution. Distilled water was added to maintain the culture volume of 500 L. For foam control was added antifoam PPG2000. All extracts nutrient medium (aqueous acetonitrile + 1% triperoxonane acid) were analyzed for the presence of sordaria with the aid of the shaft titer sordaria 0.6 g/L. Fermentation medium was made 0.1 M relative to sodium hydroxide and after incubation over night at ambient temperature was filtered through Dicallite on a rotary vacuum filter (1% Dicallite added to the environment to facilitate filtering). The filtrate is brought to pH 6-7 with concentrated sulfuric acid and the solution was applied on XAD16 resin (10 volumes of filtrate/volume of resin). The adsorbent was washed with water and with a mixture of acetone: water (1:3), obtaining in both cases, transparent eluent before elution sordaria a mixture of acetone: water (3:1; collected 2 volume of the column). The flow rate during the process averaged 1-2 column volume/hour. The eluate was concentrated to small volume (8.5 l). The concentrate was brought to pH 3 with phosphoric acid and left overnight at ambient temperature to drop sordaria in the sediment. The supernatant decantation, then centrifuged, and the supernatant was discarded. Precipitation after centrifugation and sedimentation transferred in 75% aqueous acetonitrile, resulting in the 3.9 l dark brown solution. Thereto under stirring was added 1.0 l of 0.2 M NH4H2PO4the solution was brought to pH to 4.0 with phosphoric acid, receiving the final volume of 5.0 l with an approximate composition of 60% acetonitrile - 0.1 M NH4
H2PO4pH 4 (50 ml of acetonitrile was brought to 100 l of water containing 575 g NH4H2PO4and 40 ml of H3PO4), a flow rate of 600 ml/min, monitoring by UV absorption ( 210 mm).

Collected fraction, elyuirovaniya between 15.4 to 19.2 minutes combined fractions from 10 injections (23 l) was diluted with water to 50 l, and the solution was again put on Kromasil column with a speed of 28 l/h. The column was washed with water (25 l), and then suirable 90% acetonitrile (10 l). The eluate was evaporated to balance the volume of 1300 ml, which was dried by freezing, receiving the result of the connection specified in the header, in the form of a light yellow powder (105,6 g). MS and NMR analyses of the product showed its equivalence with authentic sample sordaria.

DRUG 2

Obtaining potassium salt cordarone

Sordaria araneosa NRRL3196 (ANCC36386) were grown in medium on the basis of cardio-cerebral extract (Oxoid) + 10% glycerol at -140oC as described in Preparation 1. A suspension containing 2 agar cutting, used for inoculation Erlenmyer flask with a capacity of 250 ml containing 50 ml of medium FS. The culture was incubated at 25oC for 5 days on a rotary shaker working at a speed of 250 rpm and the diameter of the orbital motion of 50 mm All), which were incubated as described above. 80 ml developed inoculum grown in flasks with stirring, was used for inoculation of each of the two digesters with a capacity of 7 liters, containing 5 l of FS environment. Fermentation was carried out at a temperature of 25oC. the Culture was stirred at 400 rpm and aeronavali at 2 l/min After 3 days fermentation 10 l of the culture was used for inoculation of the fermenter with a capacity of 780 l, containing 500 l environment SD1.

SDI - g/l

Meritose (Tunnel refineries) - 22

Lactose - 20

Glucidex 32D (Roquette Frere) - 30

Arkasoy (The British Arkady Co) - 20

CSL - 20

FeCl36H2O - 0,05

NH4H2PO4- 5

ZnSO47H2O (BDH) - 0,1

PPG2000 - 0,5

Distilled water

Fermentation was carried out at a temperature of 25oC. the Culture medium was stirred with a speed of 350 rpm and aeronavali at 200 l/min To maintain the volume of culture 500 ml) was added water. Extracts of the nutrient medium was tested for the presence of sordaria using GHUR with reversed phase. The culture was harvested after 6 days, when the title sordaria in the extract of the sample environment was 1.3 g/l Sample collected environment volume of 50 l was made 0.1 M relative to sodium hydroxide and kept at 4oC during the night. Cells icallite. The filtrate is brought to pH 6 with concentrated sulfuric acid. Extract the nutrient medium was pumped through the layer of Amberchrom CG161 resin with a speed of 320 ml/min (0.64 layer volumes per minute). Effluent was analyzed using GHUR. After about 45 minutes (the equivalent of the pumped volume of 14.4 l) sagarin began to pass and the pumping stopped. The adsorbent was washed with water (2 l), then 25% V/V acetone in water (2 l). Cordain was suirable 75% V/V acetone in water (1.5 l). 75% V/V acetone eluate was evaporated to approximately 200 ml using a rotary evaporator at 40oC. was Added 200 ml of butane-1-ol and evaporation was continued to obtain a viscous oil (containing some amount of butane-1-ol). The oily residue was extracted with hot methanol (2x500 ml). The extracts were combined, filtered (Whatman paper number 1) and then evaporated at 40-45oC, receiving the viscous oil. It was extracted with hot acetone (2x500 ml). The acetone extracts were combined, filtered and evaporated to a viscous oil. Added propan-2-ol (350 ml) and the oil was dissolved at 45oC, getting a clear brown solution. In a conical flask with a capacity of 500 ml was poured a solution of potassium-2-etilenmocevina (39% in/in solution in propan-2-Ola, 54 g). Cord 4 hours at room temperature. The solution was made of the seed of potassium salt sordaria (about 5 mg) and plugged flask were incubated for 3 days at 4oC. the Resulting whitish substance was filtered under vacuum (slag hopper N 4) and obtained the Packed sediment was washed with propan-2-I (about 20-30 ml). The substance was transferred to a crystallization Cup and dried under vacuum over P2O5for 16 hours, resulting in the connection specified in the header (10.5 g).

DRUG 3

Obtaining potassium salt cordarone

500 liters of culture medium was obtained as in Preparation 1. Nutrient medium was made 0.1 M relative to sodium hydroxide and after four days at 0oC was filtered through a layer of Dicalite on a rotary vacuum filter. To the medium was added 1% Dicalite to facilitate filtering. the pH of the filtrate was brought from pH 9.6 to pH 7.5 with concentrated sulfuric acid. The filtrate (10 l) was brought to pH 6 with H3PO4and put on a layer (200 ml) XAD-16 resin in the water when the velocity of the flow 1-1 .5 volumes/layer including the resin was washed with water (1 volume of the layer), and then 25% aqueous isopropanol (2.5 displacement layer) before elution of pure isopropanol. After duct 50 ml isopropanol eluate was collected in output volume. Added isopropanol, bringing the volume back up to 500 ml, and then evaporation to half the original volume was repeated to remove residual water by azeotropic distillation. After the third evaporation to half of the volume of the residue was filtered, and the filter was rinsed with isopropanol. To the combined filtrate and proryvnym water (400 ml) was added a solution of 2-etilenmocevina (8 g) in isopropanol (100 ml). The mixture was made a seed crystal of the potassium salt sordaria and left for several days at 4oC as long, until he started slow crystallization. The crystals were filtered on slag filter N 3, washed with a small amount of chilled on ice isopropanol and dried under vacuum, resulting in the connection specified in the header, in the form of a pale brown powder (4,85 g).

THE DRUG 4

Obtain 4'-dimethylarginine

(i) IMI 362184 maintained in a nutrient medium on the basis of cardio-cerebral extract (Oxoid) + 10% glycerol at -140oC as described in Preparation 1. A suspension containing 2 agarwood carving, was used for inoculation of the Erlenmyer flask of 250 ml, siderably 50 ml of medium FS. The culture was incubated at 25oC for 5 days on a rotary shaker, who worked with the speed CII following Erlenmyer flasks with a capacity of 250 ml, coderush Wednesday FS (50 ml), and incubated them as described above. 80 ml developed inoculum grown in flasks with stirring, was used for inoculation of each of the two digesters with a capacity of 7 liters, coderush 5 l FS environment. Fermentation was carried out at a temperature of 25oC. the Culture was stirred at a speed of 400 rpm and aeronavali with a flow rate of 2 l/min After 3 days fermentation 10 l of the culture was used for inoculation of the fermenter with a capacity of 780 l, containing 500 l environment SM55VAR (as described in Preparation 1). Fermentation was carried out at a temperature of 25oC. culture medium was stirred with a speed of 350 rpm and aeronavali with a flow rate of 500 l/min To maintain a positive residual concentration of glucose to the culture was added 70% in the/about the solution Meritose (Tunnel Refineries). To maintain the volume of culture at the level of 500 l of distilled water was added. Extracts of the nutrient medium was tested for the presence of 4'-dimethylarginine using GHUR with reversed phase. The culture was harvested after 10 days, when the extract of a sample of the nutrient medium showed a titer of 4'-dimethylarginine equal to 0.8 g/l of Fermentation medium was brought to 0.1 M relative to sodium hydroxide and after incubation for 1 hour at a temperature of Oka to facilitate filtering). The filtrate is brought to pH 4.5 with concentrated sulfuric acid and put the solution on XAD16 resin (20 g/l of resin). The adsorbent was washed with 0.1% phosphoric acid (10 column volumes) and a mixture of acetonitrile:water 1:4 (6 column volumes) before elution of the product with a mixture of acetonitrile:water (1:1; 2 volume of the column). The flow rate during the process was 1-2 column volumes/hour. The eluate was concentrated until dry with the addition of butane-1-ol, the solid phase was extracted at 60oC methanol (12 l), then acetone (10 l). Insoluble material was separated at each stage by filtering through a glass slag N 3, and the extracts were concentrated until dry, as before. Substance led from a mixture of acetonitrile:water (3:7) before recrystallization from the same solvent and dried to constant weight over the P2O5receiving the result of the connection specified in the header (244,0 g) that, when proton NMR analysis showed the equivalence with an authentic sample of 4'-dimethylarginine.

(ii) Repeating the process fermentati described in (i), and after the nutrient medium was brought to 0.1 M relative to sodium hydroxide, she was subjected to ultrafiltration through ETNA 10A membrane (10 ctor. After adjusting to pH 5.2 with concentrated sulfuric acid, the filtrate was applied on the column with XAD16 resin with a flow rate of 2 column per hour, resulting in the ultimate load 32 g of 4'-dimethylarginine per liter of resin. The column was washed with 2 column volume per hour, first of 0.1% V/V phosphoric acid, and then with 20% V/V mixture of acetonitrile/water (10 column volumes of each component). The column was suirable 65% mixture of acetonitrile:water with flow rate 2 column volume per hour. Head wrap value 0.75 volume of the column was discarded. 85% damage 4'-dimethylarginine retrieve the next portion of the eluate volume of 1.6 volumes of the column. Enriched eluate was treated under stirring for 5 minutes 2%/about DE52 cellulose, which was removed by filtration. An aliquot DE52 processed eluate was concentrated to 62% of the original volume (43% acetonitrile) using a rotary evaporator. The concentrated eluate was kept for 15 hours at 4oC for crystallization, and the resulting solids were collected by filtering through a glass slag. The crystals were washed with a volume of 30% V/V mixture of acetonitrile:water equal to four volumes of the layer, and dried at 30oC the first substance.

THE DRUG 5

Screening of microorganisms capable of demetilirovanie sagarin 4' position

Microorganisms capable of demetilirovanie sagarin 4' position, can be identified by culturing them in the 28oC (bacteria) or 25oC (mushrooms) in 10 ml volumes SB1 (bacteria) or FB1 (mushrooms) in conical flasks of 50 ml volume, peremalyvavshaya at a speed of 250 rpm After 2 days added cordain to a final concentration of 0.5 mg/ml (200 mg/ml stock solution in 80% ethanol), and the flask is then incubated for a further 3 days. A sample of the culture volume of 500 µl was mixed in an Eppendorf tube with 500 ál of a mixture of 80% acetonitrile/2% triperoxonane acid and left for extraction at room temperature for 30 minutes. Extractive supernatant obtained after centrifugation of the samples in microcentrifuge analyzed by isocratic GHWR the presence of 4'-dimethylarginine. 4'-dimethylarginine was suirable for the 3.35 min using a 35% acetonitrile in water as mobile phase, flow rate 2 ml/min, using a column of Spherisorb C6(5 μm, 15 cm x 4.6 mm). Using this method were identified as demethylation sordaria the following microorganism

Streptomyces rimosus - ATCC 23955;

Streptomyces platensis - ATCC 29778;

Streptomyces mashuensis - ATCC 23934;

Streptomyces eurythermus - ATCC 14975;

Nocardia orientalis - ATCC 43491;

Cunninghamella echinulata var elegans - ATCC 36112.

Wednesday SB1 - g/l

Arkasoy - 25

Yeast extract - 5

KH2PO4- 5

Glucose - 20

Distilled water

pH 7

Wednesday FB1 - g/l

Soybean oil - 30

Arkasoy - 10

Yeast extract - 5

K2HPO4- 5

Glucose - 20

Distilled water

pH 5,5

THE DRUG 6

Obtain 4'-dimethylarginine through biotransformation cordarone

0.3 ml of the spore suspension Strepcomyces capreolus ATCC 31963 (15% V/V glycerol, stored at -20oC) inoculable in 30 ml SB1 environment in Erlenmyer flask with a capacity of 250 ml to obtain a seed culture, which was incubated at 28oC and 250 rpm on a rotary shaker. After 4 days in 0.5 ml of culture was used for inoculation of 35 ml SB1 in the flask with a capacity of 250 ml, which were grown for 48 hours at 28oC, 250 rpm At this stage of culture in the form of an aliquot of 10 ml was transferred into a Erlenmyer flask with a capacity of 50 ml, which was added 5 mg cordarone (200 mg/ml stock solution in ethanol). Incubation was continued for another 3 days. The entire volume of medium was added to the offering. After 30 minutes the cells were removed by centrifugation. The acetonitrile was removed by evaporation and the pH of the aqueous solution was brought to 2.5 with orthophosphoric acid. The solution was passed through a column containing Amberlite XAD-16 resin (layer volume 5 ml). The adsorbent was washed successively with water (10 ml), 10% V/V acetonitrile in water (20 ml), 30% V/V acetonitrile in water (10 ml), 50% V/V acetonitrile in water (20 ml) and 90% V/V acetonitrile in water (10 ml). Fractions were analyzed by GHWR; 4'-dimethylarginine was localized in the eluate of 50% V/V acetonitrile in water. The fraction containing 4'-dimethylarginine, was evaporated until dry under vacuum at room temperature, and the residue pererestorani in 35% acetonitrile in water (15 ml), 4'-dimethylarginine was purified by GHWR:

Column Spherisorb 5 µm C625 cm x 2.5 cm;

The flow rate is 25 ml/min;

Detection UV at 210 nm;

The mobile phase is 350 ml of acetonitrile was brought to 1000 ml of 0.05 M ammonium dihydrophosphate in water, the pH was brought to 2.5 with phosphoric acid;

Injected volume of 4.5 ml

4'-dimethylarginine was suirable after 10 minutes under these conditions. Combined fractions from four cycles GHUR was diluted 1:1 with water, and seatbelt washed with water (200 ml), and the adsorbed product was suirable 95% V/V acetonitrile in water (200 ml). Acetonitrile/water eluate was evaporated to remove organic solvent, and the aqueous solution was freeze dried, resulting in the 4'-dimethylarginine (1.5 mg), as white powder.

(1H, CDCl3); 9,74 (s,1H); between 6.08 (W, H 3,1); 4,70 (d, 1,5, 1H); 4.16 the (d, 9,5, 1H); 4,08 (dd, 4,5, 3,5, 1H); 3,88 (dd, 4,5, and 1.5, 1H, in), 3.75 (dq, 8,5, 6,1, 1H); 3,62 (d, 9,5, 1H); 3,68 (dd, 8,5, 3,5, 1H); to 2.65 (m, 1H); of 2.34 (m,1H); 1.32 to (d, 6, 3H); 1.30 on (d, 12,5, 1H); of 1.23 (m, 1H); 1,04 (d, 7, 3H); 0,99 (d, 7, 3H); 0,81 (d, 7, 3H)

PREPARATION 7

Getting agaricina

Conducted process as described for Preparation 1 up to and including phase preparative GHUR. Collected fraction, elyuirovaniya between 21,4 and 25 minutes combined fractions from 10 injections (22 l) was diluted with an equal volume of water and this solution was again pumped through a Kromasil column when the velocity of the flow 28 l/h Column was washed with water (20 l), and then suirable 90% acetonitrile (4.5 l). This eluate was combined with the corresponding fraction of the eluate (4.5 l) of similar fermentation, which was carried out in the same way. United eluate in 90% acetonitrile was concentrated using a rotary evaporator until then, until he started crystallization product (volume of about 1.6 l). The residue was heated the solution. The solution was cooled and kept at 4oC. the Crystals were filtered on slag filter No. 3 and dried under vacuum, resulting in the brown stuff. He was subjected to re-crystallization from a mixture of acetonitrile:water (40:60), and the product was filtered, washed with 25% acetonitrile and dried under vacuum, resulting in the connection specified in the header (10.7 g). MS and NMR analyses of the product showed its equivalence to the authentic sample agaricina.

PREPARATION 8

Biotransformation cordarone in agaricin

0.2 ml of the suspension NCIMB 40675 used for inoculation Erlenmyer flask with a capacity of 250 ml containing 50 ml of culture medium (Oxoid), enriched with 0.2% yeast extract. The culture was incubated at 28oC for 29 hours on a rotary shaker working at a speed of 250 rpm in an orbital movement 50 mm Aliquots (1 ml) developed inoculum used for inoculation of the following Erlenmyer flasks of 250 ml containing 50 ml of culture medium at twice the concentration (Oxoid), enriched with 0.1% yeast extract. They were incubated for approximately 24 hours. 62 such flasks were combined, getting to 2.65 liters of advanced culture, which was added to 30 liters of fermentation fil is the commutator with a capacity of 70 litres at 30oC, under stirring speed of 200 rpm and aeration of 0.5 Rev/min. pH was maintained at 7.5 by adding 1N hydrochloric acid. After 6 days approximately 16 g sordaria turned into agaricin. Wednesday after biotransformation was filtered through Dicalite on a vacuum filter, the filtration layer was washed with water, getting 31.5 l of filtrate, pH of 8.2. It was brought to a pH of 6.0 using H3PO4and was pumped through the layer (25 cm x 25 cm) Amberchrom CG161 resin at a speed of duct 290 ml/min. Layer Amberchrom washed with 0.1% H3PO4(2 l) and 25% acetonitrile (4 l), and then suirable 60% CH3CN (2 l). The eluate was concentrated on a rotary evaporator until the onset of crystallization, then the residue was heated on a water bath at 60oC, adding a minimum amount of acetonitrile and deliver a clear solution. It was cooled and kept at 4oC during the night. The crystals were filtered off, washed with 25% acetonitrile and dried under vacuum, obtaining a brown powder. The crude product was subjected to recrystallization from a mixture of 1 liter acetonitrile:water (40:60), was filtered, washed and dried as previously described, to deliver agaricin in the form of a pale brown needle Cristallo filmed grown culture NCIMB 40675, and inoculable it Erlenmyer flask with a volume of 250 ml containing 50 ml of culture medium (Oxoid), enriched with 0.2% yeast extract. The cultures were incubated for 26 hours at 25oC on a rotary shaker working at a speed of 250 rpm and a diameter of movement 50 mm Aliquots developed culture volume of 1 ml was used for inoculation Erlenmyer flasks with a capacity of 250 ml, as described above. To the flask was added pure cordain in 80% ethanol to a final concentration of 1.25 mg/ml Flasks were incubated for 8 days, then their contents are combined, getting 365 ml of culture medium containing agaricin. The mixture after the bioconversion was centrifuged to remove NCIMB 40675 cells, and the supernatant (350 ml) decantation. To the supernatant was added Whatman Partisil P40 DS-3 (5 ml, pre-moistened acetonitrile), the pH of the mixture was brought to 4.0 using H3PO4. Partisil was filtered on a Buchner funnel and was suirable first acetonitrile (100 ml), and then 75% acetonitrile (100 ml). United eluate was evaporated to an aqueous residue volume of 10-15 ml was heated on a water bath at a temperature of 60oC was added in acetonitrile to obtain a clear solution, and then heating was continued and added water up until the solution does not NAA slag filter N 3, washed with water and dried under vacuum over P2O5receiving the result of agaricin in the form of white needle crystals (92 mg).

THE DRUG 10

Getting agaricina

Frozen ampoule IMI 362947 used for inoculation of 50 ml of seed medium FS in Erlenmyer flask with a capacity of 250 ml of the flask were incubated at 25oC for 6 days on a rotary shaker working at a speed of 250 rpm and a diameter of orbital movement of 50 mm Aliquots (1 ml) developed inoculum used for inoculation Erlenmyer flasks with a capacity of 250 ml containing 50 ml of medium SM55/A for cultivation in katalozhnyh flasks.

SM55/A - g/l

Maltodextrin MD30E (Roquette Frere) - 120

Beet molasses - 15

Peptone (Oxoid L37) - 10

Proflo (Traders Protein) - 30

L-Tryptophan (Sigma) - 2

ZnSO47H2O (BDH) - 0.04

FeSO47H2O (Sigma) - 2

CaCO3(BDH) - 5

MgSO47H2O (BDH) - 5

Prepared with distilled water and autoclave at 121oC for 120 minutes.

These cultures were incubated as described above for 7 days. The contents of the flasks were combined and a portion of a volume of 40 ml was treated with 1N sodium hydroxide (4 ml) at periodic stirring at room temperature for 45 mi and brought its pH to 3 with 1N hydrochloric acid. The solution was passed through a Bond Elut column (size 1 g; C18), the adsorbent was washed with water (20 ml), then was suirable 90% V/V acetonitrile in water (15 ml). The eluate was evaporated to the dry state at room temperature and the residue was transferred into a 50% V/V acetonitrile in water (9 ml). Agaricin was purified by preparative GHUR:

Column Spherisorb 5 µm ODS-2 (25 cm x 2.1 cm);

The flow rate is 25 ml/min;

The mobile phase - 550 ml of acetonitrile is brought to 1000 ml water, 1 ml triperoxonane acid per liter of mobile phase;

Detection of 210 nm;

Injected volume of 4.5 ml

Agaricin was suirable in these conditions, after 6 minutes the Fractions containing agaricin were combined, the acetonitrile was removed with a rotary evaporator at room temperature, and the aqueous solution was freeze dried, resulting in the connection specified in the header (8,9 mg) as a white powder.

THE INTERMEDIATE CONNECTION 1

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy- - atropinelike)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of 4'-dimethylarginine (10 g) in methanol (200 ml) at room temperature dropwise add the ü evaporated until dry, and the residue was chromatographically on a column of fast separation with silica gel, using as eluent a mixture of hexane:ethyl acetate (3: 1), receiving the result of the connection specified in the header (12,6 g), as pale yellow foam.,

(1H, CDCl3): 9,73 (s, 1H, CHO), 6,98 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J= 1.5 and 3.6 Hz) and 4.65 (d, 1H, H-1, J=1.5 Hz), 4.09 to, 3,76 (2d, 2H, 8a - J= 9 Hz), 4,01 (m, 1H, H-2'), a-3.84 (m, 1H, H-3' in), 3.75 (m, 1H, H-5'), of 3.69 (m, 1H, H-4'), 2,73 (t, 1H, H-1, J=4, 2 Hz).

INTERMEDIATE COMPOUND 2

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a-[(6-deoxy-3,4-O-isopropylidene- - D-atropinelike) methyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a-octahydro-7-methyl-3-(1-methylethyl)- (1H)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate compound 1 (650 mg) in 15 ml of a mixture of dimethoxypropane: acetone (1:2) was added p-toluensulfonate acid (10 mg). The solution was stirred at room temperature for 1.5 hours, then was added potassium carbonate (1.0 g), stirring was continued for another 30 minutes and the solvent evaporated until dry. The crude mixture was fractionally between ethyl acetate (50 ml) and water (25 ml), the aqueous phase was extracted with ethyl acetate (2 × 50 ml), the organic phase was washed with brine, dried over magnesium sulfate and evaporated until dry. The residue was subjected credentia, specified in the header (600 mg) as a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-of 7.24 (m, 10H, 2Ph), 6,98 (s, 1H, CHPh2), the 6.06 (dd, 1H, H-2, J=1.5 and 3.3 Hz), of 4.57 (d, 1H, H-1', J=3.0 Hz), 4,30 (dd, 1H, H-3', J=3.6 and 5.7 Hz), 4,07 (d, 1H, 8aCH2, J=9.0 Hz), 3.95 to 3,93 (m, 1H, H-2'), 3,85 (dd, 1H, H-4', J=5.7 and 9.3 Hz in), 3.75 (d, 1H, 8aCH2, J=9.0 Hz), 3,44 (dq, 1H, H-5', Jd=6.3 Hz), 2,73 (t, 1H, H-1, J=3.6 Hz).

INTERMEDIATE COMPOUND 3

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a-[(6-deoxy-3,4-O-(2-pentylidene)- - D - atropinelike)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a suspension of Intermediate 1 (500 mg) and p-toluensulfonate acid (5 mg) in dichloromethane (5 ml) was added 2,2-dimethoxyethane (2 ml). The mixture was stirred at room temperature for 2 hours. Was added potassium carbonate (150 mg) and continued stirring for 30 minutes. The solvent is evaporated until dry and the residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of ethyl acetate:hexane (15: 85) and (30:70), receiving the result of the connection specified in the header (474 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-7,24 (m, 1H, 2Ph), 6,98 (s,1H, ), the 6.06 (dd, 1H, H-2, J=1.5 and 3.3 Hz), of 4.57 (d, 1H, H-1', J=2.1 Hz), 4,30 (dd, 1H, H-3', J=3.9 and 6.0 Hz), Android 4.04 (d,1H, 8aCH2, 2 (t, 1H, H-1, J=3.6 Hz).

INTERMEDIATE COMPOUND 4

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a-[(6-deoxy-3,4-O-(4-methoxy-2-butylidene) - - D-atropinelike)methyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

To a suspension of Intermediate 1 (350 mg) and p-toluensulfonate acid (5 mg) in dichloromethane (4 ml) was added 2,2,4-trimethoxymethane (1 ml). The mixture was stirred at room temperature for 1 hour. Was added potassium carbonate (150 mg) and continued stirring for 30 minutes. The solvent is evaporated until dry and the residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of ethyl acetate:hexane (3: 7) and (4:6), receiving the result of the connection specified in the header (290 mg) in epimeres a ratio of 3:1.

(1H, CDCl3signals for the main component: 9,73 (s, 1H, CHO), 7,45-7,20 (m, 10H, 2Ph), 6,98 (s, 1H, ), the 6.06 (dd, 1H, H-2, J=1,5 H and 3.6 Hz), of 4.57 (d, 1H, H-1', J=2.1 Hz), or 4.31 (dd, 1H, H-3', J=3.9 and 6.0 Hz), of 4.05 (d, 1H, 8aCH2, J=9.0 Hz), 3.95 to 3,90 (m, 1H, H-2'), 3,88 (dd, 1H, H-4', J=6.0 and 9.3 Hz), to 3.73 (d, 1H, 8aCH2, J=9.0 Hz), 3,51 (t, 2H, CH2, J=7,2 Hz), 3,50 is-3.45 (m, 1H, H-5'), to 3.33 (s, 3H, CH3O) of 2.72 (t, 1H, H-1, J=3.6 Hz).

THE INTERMEDIATE COMPOUND 5

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a-[(6-deoxy-3,4-O-cyclopentolate-- D-slots diphenylmethylene ether

To a suspension of Intermediate 1 (160 mg) in a mixture of dichloromethane: 1,1-dimethoxysilane (3: 1, 4 ml) was added p-toluensulfonate acid (5 mg) and the resulting mixture was stirred at room temperature for 2 hours. Was added potassium carbonate and continued the stirring for 30 minutes. The solvent is evaporated until dry and the residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of ethyl acetate:hexane (1:4), receiving the result of the connection specified in the header (142 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-7,25 (m, 10H, 2Ph), 6,98 (s, 1H, CHPh2), the 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,55 (d, 1H, H-1', J=1.8 Hz), 4,17 (dd, 1H, H-3', J=3.0 and 5.1 Hz), 4,08 (d, 1H, 8aCH2, J=9.0 Hz), 3,95 (dt, 1H, H-2', Jd=1.8 Hz, Jt=3.0 Hz), 3,81 (dd, 1H, H-4', J= 5.1 and 9.3 Hz), 3,76 (d, 1H, 8aCH2, J=9.0 Hz), 3,42 (dq, 1H, H-5', Jd= 9,3 Hz, Jq=6.3 Hz), 2,73 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE COMPOUND 6

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a[(6-deoxy-3,4-O-isopropylidene-2-O-(methylthio) thiocarbonyl- - D-atropinelike)methyl] -4-formyl-4, 4a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane - s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

Intermediate compound 2 (100 mg) and imidazole (1 mg) was dissolved in dry tetrahydrofuran (4 ml) under nitrogen atmosphere. EXT is obavljale carbon disulphide (27 μl), continued stirring for another 20 minutes and added methyliodide (18 μl). After 2 hours the reaction was stopped by adding 1N ammonium chloride (20 µl). The mixture was extracted with ethyl acetate (3x25 ml), the organic phase was washed with brine, dried over magnesium sulfate and the solvent evaporated until dry. The residue was purified by column chromatography rapid separation on silica gel, elwira a mixture of ethyl acetate: hexane (1:9), receiving the result of the connection specified in the header (110 mg).

(1H, CDCl3: 9,71 (s, 1H, CHO), 7,44-7,25 (m, 10H, 2Ph), of 6.96 (s, 1H, CHPh2), 6,01 (dd, 1H, H-2, J=1.2 and 3.6 Hz), 6.90 to (dd, 1H, H-2', J=2.4 and 5.4 Hz), is 4.85 (d, 1H, H-1', J=2.4 Hz), a 4.53 (dd, 1H, H-3', J=5.4 and 6.3 Hz), 4,00 (dd, 1H, H-4', J=6.3 and 8.7 Hz), 3,93 (d, 1H, 8aCH2, J=9,3 Hz), 3,65 (dq, 1H, H-5', Jd=8,7, Jq=6.3 Hz), 2,68( t, 1H, H-1, J=3,9 Hz) at 2.59 (s, 3H, CH3S).

INTERMEDIATE COMPOUND 7

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a-[(2,6-Dideoxy-3,4-O-isopropylidene- - D - allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

(i) the Intermediate compound 6 (95 mg) was dissolved in dry toluene (5 ml) under nitrogen atmosphere and warmed up at 110oC. After 1.5 hours under stirring was added dropwise Rast is balali methanol (2 ml) and the solvent evaporated until dry. After chromatography rapid separation on silica gel of the residue by elution with a mixture of ethyl acetate:hexane (1:9) received the connection specified in the header (42 mg).

(1H, CDCl3: 9,73 (s, 1H, CHO), 7,44 - 7,25 (m, 10H, 2Ph), 6,98 (1H, s, CHPh2), equal to 6.05 (dd, 1H, H-2, J=1.2 and 3.3 Hz), of 4.54 (dd, 1H, H-1', J=2.7 and 9.3 Hz), 4,39 (dt, 1H, H-3', Jd=2.7 Hz, Jt=3.6 Hz), Android 4.04 (d, 1H, 8aCH2, J=9.0 Hz), to 3.67 (d, 1H, 8aCH2, J=9.0 Hz), the 3.65 (dd, 1H, H-4', J=3.6 and 8.7 Hz), 3,44 (dq, 1H, H-5', Jd= 6.3 Hz, Jq=8,7 Hz) of 2.75 (t, 1H, J=3,9 Hz).

(ii) a Solution of anti-hydride (5.5 ml) in dry toluene (150 ml) was degirolami current of argon for 1 hour and heated with delegacia. Then after 2 hours was added to a solution of intermediate compound 6 (6 g) in dry toluene (50 ml). Heating was continued until completion of the reaction (1.5 hours). After removal of the solvent under reduced pressure was obtained the crude product, which was subjected to chromatography rapid separation on silica gel, elwira hexane and hexane:ethyl acetate (20:1 to 15:1), receiving the result of the connection specified in the header (4 g).

INTERMEDIATE COMPOUND 8

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a[(2,6-Dideoxy-3,4-O-(4-methoxy-2-butylidene)- - -D-allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-coffrane (10 ml) at 0oC in an atmosphere of nitrogen was added sodium hydride (30 mg) and imidazole (5 mg). The solution was stirred for 10 minutes and was added carbon disulfide (147 μl). After 20 minutes was added methyliodide (127 ml) was kept stirring for another 30 minutes. Added 1N ammonium chloride (20 ml) and was extracted with a mixture of ethyl acetate (3x25 ml), the organic phase was washed with brine, dried over magnesium sulfate and the solvent evaporated until dry. The residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of ethyl acetate: hexane (15:85), resulting in the white foam. This foam was dissolved in dry toluene (10 ml) under nitrogen atmosphere and after 2 hours at 115oC was added dropwise a solution of anti-hydride ones (0.46 ml) in toluene (10 ml). Heating was continued for 2 hours. The solvent is evaporated until dry and the residue was purified by chromatography rapid separation on silica gel, elwira a mixture of ethyl acetate:hexane (15:85), receiving the result of the connection specified in the header (260 mg) in epimeres the ratio of 4:1.

(1H, CDCl3): 9,63 (s, 1H, CHO), 7,44-7,20 (m, 10H, 2Ph), of 6.99 (s, 1H, CHPh2), the 6.06 (dd, 1H, H-2, J=1.2 and 3.3 Hz), a 4.53 (dd, 1H, H-1', J=2.7 and 8.7 Hz), 4,42 (dt, 1H, H-3', Jd=3.0 Hz, Jf=4,2 Hz), a 4.03 (d, 1H, J=9.0 Hz), 3,68 (3
O) to 2.74 (t, 1H, H-1, J=4, 2 Hz).

INTERMEDIATE COMPOUND 9

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a[(6-deoxy-3,4-O-thiocarbonyl- - D - atropinelike)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A mixture of intermediate compound 1 (0,500 g) and thiocarbonyldiimidazole (0,270 g) in tetrahydrofuran (10 ml) warmed up with delegacia within 6 hours. The solvent is evaporated under vacuum, obtaining the resulting yellow residue, which was chromatographically on the column for fast separation with silica gel, elwira a mixture of hexane:ethyl acetate (3:1), receiving the result of the connection specified in the header (to 0.263 g).

(1H, CDCl3): 9,71 (s, 1H, CHO), 7,44-7,26 (m, 10H, 2XPh), 6,97 (s, 1H, ), the 6.06 (dd, 1H, H-2, J=1.5 and 3.3 Hz), is 4.93 (dd, 1H, H-3', J=3.9 and 7.2 Hz), 4,63 (d, 1H, H-1', J=2.1 Hz), br4.61 (dd, 1H, H-4', J=7.2 and 9.3 Hz), of 4.12 (m, 1H, H-2'), 4,08 (d, 1H, 8aCH2I , JAB=9,3 Hz), 3,74 (d, 1H, 8aCH2I , JAB=9,3 Hz) to 3.64 (m, 1H, H-5'), 2,69 (m, 1H, H-1).

INTERMEDIATE COMPOUND 10

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a[(2,6-Dideoxy- - D-allopregnanolone)methyl] -4 - formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of intermediate compound 7 (1.5 g) in a mixture of tetrahydrofuran (30 Eoliano acid (15 ml). Immediately upon completion of the reaction (TLC control) was added saturated sodium bicarbonate (50 ml) and ethyl acetate (200 ml) and the mixture was separated. The organic layer was washed with water (2x100 ml) and dried over magnesium sulfate. After removal of the solvent was obtained residue, which was subjected to chromatography rapid separation on silica gel with elution by the mixture hexane: ethyl acetate (5:1) and (2:1), receiving the result of the connection specified in the header (1.1 g) in the form of a white foam.

(1H, CDCl3: 9,73 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), of 6.99 (s, 1H, CHPh2), equal to 6.05 (dd, 1H, H-2, J=1.2 and 3.3 Hz), with 4.64 (dd, 1H, H-1', J=2.1 and 9.6 Hz), 4,11 (m, 1H, H-3'), 4,06 (d, 1H, 8aCH2I , JAB=9,3 Hz), 3,70 (m, 2H, H-5' and 8aCH2), to 3.34 (m, 1H, H-4'), a 2.75 (t, 1H, H-1, J=3.6 Hz).

INTERMEDIATE COMPOUND 11

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a[(2,6-Dideoxy-3,4-O-thiocarbonyl- - D - allopregnanolone)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid diphenylmethylene ether

A suspension of Intermediate 10 (160 mg) and oxide dibutyrate (124,5 mg) in dry toluene (15 ml) warmed up with delegacia for 2 hours in a flask equipped with a condenser, Dean-Stark, and then left at room temperature in a nitrogen atmosphere. To the resulting solution was added phenyl-chlorothionoformate (alali under reduced pressure, the crude mixture was subjected to chromatography rapid separation on silica gel with elution by the mixture hexane:ethyl acetate (20:1 and 15:1), receiving the result of the connection specified in the header (150 mg) as a colourless oil.

(1H, CDCl3): 9,72 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), 6,97 (s,1H, CHPh2), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 5,10 (m, 1H, H-3'), br4.61 (dd, 1H, H-1', J=2.4 and 8.4 Hz), of 4.44 (dd, 1H, H-4', J=6.6 and 9.0 Hz), Android 4.04 and 3.67 (2d, 2H, 8aCH2I , JAB=9 Hz), 3,62 (m, 1H, H-5'), 2,70 (t, 1H, H-1, J=2.0 Hz).

INTERMEDIATE COMPOUND 12

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Allyl-2,6-dideoxy- - D - allopregnanolone)methyl] -4-formyl-4-4a,5,6,7,7 a,8 a,8 a-octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A suspension of Intermediate 10 (400 mg) and oxide of anti - (240 mg) in dry toluene (50 ml) warmed up with delegacia in a flask equipped with a condenser, Dean-Stark, and then left at room temperature in a nitrogen atmosphere (approximately 10 ml azeotropic mixture was removed). Sequentially added allylbromide (71 μl) and tetrabutylammonium (1M solution in tetrahydrofuran, of 0.95 ml) and warming the mixture at 50oC for 24 hours. After removal of the solvent was obtained residue, which was subjected to chromatography rapid separation of the e (300 mg), in the form of a colorless oil.

(1H, CDCl3): 9,72 (s, 1H, CHO), 7,52 to 7.2 (m, 1H, 2Ph), 6,98 (s, H, CHPh2), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz), of 5.89 (m, 1H, ), and 5.30-5,20 (m, 2H, ), with 4.64 (dd, 1H, H-1', J=2.1 and 9.6 Hz), 4,19 (m, 1H, H-3'), 4,15-3,95 (m, 3H ), 3,80-of 3.60 (m, 2H, H5'+8aCH2), 3,06 (dd, 1H, H-4', J=3.3 and 9.3 Hz), a 2.75 (t, 1H, H-1, J=3,9 Hz), 2,38 (bd, 1H, OH).

INTERMEDIATE COMPOUND 13

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2,6-Dideoxy-4-O-(2-methyl-2-propenyl)- - D-allopregnanolone)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin - 3a(1H)-carboxylic acid diphenylmethylene ether

A suspension of Intermediate compound 10 (500 mg) and oxide anti (300 mg) in dry toluene (50 ml) warmed up with delegacia in a flask equipped with a condenser and Dean-Stafk, and then left at room temperature in a nitrogen atmosphere (approximately 10 ml azeotropic mixture was removed). Successively added 3-Bromo-2-methyl-propene (202 μl) and tetrabutylammonium (1M solution in tetrahydrofuran, of 0.90 ml), the mixture was let warm up at 50oC for 24 hours. After removal of the solvent was obtained residue, which was subjected to chromatography rapid separation on silica gel with elution with a mixture of acetone: hexane (1:20) and (1:15), receiving the result of the connection specified in the header (340 mg) as a colourless oil.

INTERMEDIATE COMPOUND 14

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,7R,9R]-2,5,8-Trioxa-3,7-dimethyl-CIS - bicyclo[4,4,0] -Dec-9-yl-hydroxy-methyl] -4-Fort-mil-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl 1,4-methane-s-indocin - 3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of intermediate 12 (200 mg) in aqueous tetrahydrofuran (10 ml) at room temperature in a nitrogen atmosphere in small portions was added solid triptorelin mercury (213 mg). The reaction mixture was left for 30 minutes at room temperature, and then under vigorous stirring was added the anti-hydride (135 μl). After 30 minutes, was added ethyl acetate (50 ml) and the suspension was filtered through brownmillerite, receiving the colorless solution, which was washed with water (3x100 ml) and dried over magnesium sulfate. After removal of the solvent was obtained an oil which was subjected to chromatography rapid separation on silica gel with elution with a mixture of acetone:hexane (1:15), which received the connection specified in the header (120 mg) in a 1:1 mixture EP

INTERMEDIATE COMPOUND 15

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,7R,9S]-2,5,8-Trioxa - 3,3,7-trimethyl-CIS-bicyclo[4,4,0] -Dec-9-yl-oxy-IU-Tyl] -4 - formyl-4,4 a,5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3A(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate compound 13 (325 mg) in anhydrous tetrahydrofuran (10 ml) at room temperature under nitrogen atmosphere was added in small portions solid triptorelin mercury (303 mg). The reaction mixture was left at room temperature for 30 minutes and then under vigorous stirring was added the anti-hydride (192 μl). After 30 minutes, was added ethyl acetate (50 ml) and filtered the resulting suspension through brownmillerite, thus obtaining a colorless solution, which was washed with water (3x100 ml) and dried over magnesium sulfate. After removal of the solvent was obtained an oil which was subjected to chromatography rapid separation on silica gel with elution with a mixture of acetone: hexane (1:20) and (1:15), receiving the result of the connection specified in the header (210 mg) as a colourless oil.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,50-7,20 (m, 1H, 1Ph), 6,98 (s, 1H, CHPh2), 6,03 (dd, 1H, H-2, J=1.2 Hz, J=3.3 Hz), of 4.54 (dd, 1H, H-9', J= 2.1 and 9.6 Hz), 4,25 (m, 2H, H-7' and H-1'), 4,05 and 3,66 (2d, 2H, 8aCH2I , JAB=9 G

THE INTERMEDIATE CONNECTION 16

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2,6-Dideoxy-4-O-p-methoxybenzyl- - D-allopregnanolone)methyl] -4-formyl-4,4 a,5,6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid diphenylmethylene ether

A suspension of Intermediate compound 10 (500 mg) and oxide of anti - (374 mg) in dry toluene (50 ml) warmed up with delegacia in a flask equipped with a condenser and Dean Stark, and then left at room temperature in a nitrogen atmosphere (approximately 10 ml azeotropic mixture was removed). Sequentially added n-Methoxybenzylamine (135 μl) and tetrabutylammonium (1M solution in tetrahydrofuran, 1.5 ml) and warming the mixture at 60oC for 24 hours. After removal of the solvent was obtained residue, which was subjected to chromatography rapid separation on silica gel with elution with a mixture of acetone:hexane (1:20) and (1:15), receiving the result of the connection specified in the header (300 mg) as a colourless oil.

(1H, CDCl3): 9,72 (s, 1H, CHO), 7.5 to about 7.2 (m, 12H, 2Ph and 2H ortho), 6,97 (s, H, CHPh2), to 6.88 (m, 2H, 2H meta), 6,04 (dd, 1H, H-2, J=1.5 Hz, J=3.6 Hz), with 4.64 (dd, 1H, H-1', J=2.4 and 9.9 Hz), 4,55 and 4.50 (2d, 2H, CH2Ph, JAB= 11.2 Hz), 4,18 (m, 1H, H-3'), Android 4.04 and 3,66 (2d, 2H, 8aCH2I , JAB=9 Hz), 3,80 (s, 3H, CH3O), 3,74 (m, 1H, H-5'), 3,12 (d is desoxy-4-O-p - methoxybenzyl- - D-allopregnanolone)methyl]-4-formyl-4,4 and 5, 6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3A(1H)-carboxylic acid diphenylmethylene ether

To intensively peremalyvavshaya a solution of Intermediate 16 (400 mg) in anhydrous tetrahydrofuran (10 ml) under nitrogen atmosphere at 0oC) was added in small portions sodium hydride (48 mg). After complete addition, the mixture was left at room temperature for 1 hour and then added allylbromide (191 μl). After 24 hours the reaction was suppressed by the addition of ammonium chloride (1N solution in water, 100 ml) and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water (1x100 ml), dried over magnesium sulfate and concentrated until dry, getting in the oil, which was subjected to chromatography rapid separation on silica gel with elution with a mixture of ethyl acetate:hexane (1:20) and (1:15), receiving the result of the connection specified in the header (400 mg) as a colourless oil.

(1H, CDCl3): 9,74 (s, 1H, CHO), 7.5 to about 7.2 (m, 12H, 2Ph and 2H ortho), 6,98 (s, H, CHPh2), 6,86 (m, 1H, 2H, meta), 6,04 (dd, 1H, H2, J=1.2 and 3.3 Hz), 5,95 (m, 1H, ), 5,28 and 5,15 (2m, 2H, ), 4,60 (m, 2H, H-1' and CH2Ph), was 4.42 (d, 1H, CH2Ph, JAB=to 11.4 Hz), 4,13 (m, 2H ), 4.02 and 3,68 (2d, 2H, 8aCH2I , JAB=9.6 Hz), with 3.89 (m, 2H, H-5' and H-3'), 3,80 ,7a,8a) ] 8a-[(3-O-Allyl-2,6-dideoxy- - D - allopregnanolone)methyl-4-formyl-4,4 a, 5,6,7,7 and, 8,8 - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

A solution of Intermediate 17 (2.3 g) in dichloromethane (200 ml) was stirred with water (20 ml) was added 2,3-dichloro-5,6 - dicyanamide (0,79 g). After stirring over night at room temperature the mixture was filtered through a layer of brownmillerite with additional quantities of dichloromethane. The dichloromethane phase was washed aqueous sodium bicarbonate, and then with a solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated until dry. The residue was chromatographically on silica gel using a mixture of dichloromethane: methanol (49:1) as eluent, to deliver the connection specified in the header (1,95 g) as a white foam.

(1H, CDCl3): of 9.75 (s, 1H, CHO), 7,45-7,24 (m, 1H, Ph2), of 6.99 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.3 Hz), 5,95 (m, 1H, ), of 5.26 (m, 2H ), 4.53-in (dd, 1H, H-1', J=1.8 and 9.6 Hz), 4,19 and 3,96 (2m, 2H, ), and 4,03 of 3.69 (2d, 2H, 8a-CH2, J=9,3 Hz), 3,80 (q, 1H, H-3', J= 3.3 Hz), 3,60 (dq, 1H, H-5', J=9.6 and 6.3 Hz), 3,23 (ddd, 1H, H-4', J=10,8, a 9.6 and 3.3 Hz), is 2.74 (t, 1H, H-1, J=3,6 Hz in), 2.25 (d,1H, OH, J=10,8 Hz).

INTERMEDIATE COMPOUND 19

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(3-O-Allyl-2,6-dideoxy-4-O- (methylthio)thiocarbonyl- - D-and the second acid diphenylmethylene ether

To a chilled solution of Intermediate 18 (1.9 g) in anhydrous tetrahydrofuran (50 ml) under nitrogen atmosphere was added in small portions (240 mg) sodium hydride and a catalytic amount of imidazole. Then ice bath was removed and the reaction mixture is left at room temperature with stirring for 1 hour. Then was added carbon disulfide (1.5 ml) and methyliodide (1.25 ml). After completion of the reaction (TLC control), the crude mixture was poured into ethyl acetate (500 ml) and was suppressed in 0.1 N aqueous ammonium chloride (250 ml). The organic layer was then washed with brine (1x500 ml) and water (1x500 ml), dried over anhydrous sodium sulfate and concentrated until dry. The oily residue was subjected to chromatography rapid separation on silica gel, using as eluent a mixture of hexane:dichloromethane (3:5), and receiving the result of the connection specified in the header (1.85 g) in the form of a white foam.

(1H, CDCl3):

9,74 (s, 1H, CHO), 7,45-7,24 (m, 1H, Ph2), of 6.99 (s,1H, ), the 6.06 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 5,88 (m, 1H, ), 5,41 (dd, 1H, H-4', J= 2.7 and 9.6 Hz), with 5.22 (m, 2H ), 4,70 (dd, 1H, H1', J=2.1 and 9.3 Hz), 4,20-was 4.02 (m, 5H, H-5', H-3' and 8aCH2(1H)), 3,71 (d, 1H, 8a-CH2, J=9,3 Hz) of 2.75 (t, 1H, H-1, J=3,9 Hz), 2,58 (s, 3H, 3CH3).

INTERMEDIATE COMPOUND 20

(a) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4S,6R) - Rev.)-1,4-methane-s - indocin-3a(1H)-carboxylic acid diphenylmethylene ether and

(b) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S, 4R,6R,8R]-2,7-Dioxa - 4,6-dimethyl-CIS-bicyclo[3.4.0] non-8-yl-hydroxy-methyl]-4-formyl-4, 4a,5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane - s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A solution of Intermediate 19 (1.8 g) in dry toluene (250 ml) was degirolami current of argon for 1 hour and then heated with delegacia. For about 2 hours until the continued heating and blowing with argon, with a syringe was added a catalytic amount of azobis(isobutyronitrile)and anti-hydride (0.95 ml), dissolved in dry toluene (50 ml). After the addition was completed, the reaction mixture is warmed up with delegacia for 1 hour and then cooled, concentrated until dry and subjected to chromatography rapid separation on silica gel, using as eluents hexane and then hexane: ethyl acetate (9: 1). Intermediate compound 20 (a) (680 mg; Rf=0.31 in a mixture of hexane:ethyl acetate 4:1) was obtained as a white foam, and the Intermediate compound 20(b) (180 mg; Rf=0,35 in a mixture of hexane:ethyl acetate 4:1) was isolated as white matter.

(a) (1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-7,28 (m, 1H, Ph2), of 6.99 (s, 1H, CHPh2), equal to 6.05 (dd, 1H, H-2, J=1.2 to 6' and CH2-3'(1H)), 2,77 (t, 1H, H-1, J= 3,9 Hz) of 1.05 (d, 3H, 4'-CH3, J=6,9 Hz).

(b) (1H, CDCl3): 9,72 (s, 1H, CHO), 7,45-7,24 (m, 1H, Ph2), of 6.99 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1,50 and 3.6 Hz), 4,42 (dd, 1H, H-8', J= 2.1 and 9.6 Hz), 4,20 (m, 1H, H-1'), 4,07 and 3.67 (2d, 2H, 8a-CH2, J=9,3 Hz), of 3.97 (t, 1H, CH2-3', J=8,4 Hz), of 3.54 (m, 1H, H-6'), of 3.46 (dd, 1H, CH2-3', J=10.5 Hz), 2,77 (t, 1H, H-1, J=3,9 Hz), 2,53 (m, 1H, H-4'), of 1.02 (d, 3H, 6-CH3).

THE INTERMEDIATE CONNECTION 21

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Allyl-2,6-dideoxy-3-O-(methylthio) thiocarbonyl- - D-allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7, 7a,8,8A-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin - 3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate compound 12 (380 mg) in anhydrous tetrahydrofuran (10 ml) under nitrogen atmosphere at 0oC) was added in small portions of solid sodium hydride (48 mg) and a catalytic amount of imidazole. After complete addition, the cooling bath was removed and the reaction continued for 1 hour at room temperature. Sequentially added carbon disulfide (300 μl) and methyliodide (250 μl). After 4 hours the mixture was poured into ethyl acetate (100 ml) and extinguished 1N aqueous ammonium chloride (50 ml). The organic layer was washed with brine (1x100 ml) and water (1x100 ml), dried over magnesium sulfate and concentrated to a dry status is barely, using as eluent a mixture of ethyl acetate:hexane (1:25) and (1:20) and receiving the result of the connection specified in the header (350 mg) as a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,50 - 7,20 (m, 1H, 2Ph), 6,98 (s, H, CHPh2), 6,24 (m, 1H, H-3'), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz), to 5.85 (m, 1H, ), and 5.30 - 5,20 (m, 2H ), 4,56 (dd, 1H, H-1', J=1.8 and 9.3 Hz), 4,15 - of 3.75 (m, 4H, =CH2+8aCH2+H-5'), of 3.69 (d, 1H, 8aCH2, J=9,3 Hz), 3,21 (dd, 1H, H-4', J=3.3 and 9.3 Hz), of 2.72 (t, 1H, H-1, J= 3,89 Hz) at 2.59 (s, 3H, SCH3).

INTERMEDIATE COMPOUND 22

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-Dideoxy-3-O- (methylthio)thiocarbonyl-4-O-(2-methyl-2-propenyl)- - D - allopregnanolone)methyl] -4-formyl-4,4 a,5,6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methyl ethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

To a chilled solution of Intermediate compound 13 (700 mg) in anhydrous tetrahydrofuran (30 ml) under nitrogen atmosphere was added in small portions sodium hydride (85 mg) and a catalytic amount of imidazole. Then the ice bath was removed, and the reaction mixture was left at room temperature under stirring with a magnetic stirrer for 1 hour. Sequentially added carbon disulfide (0.54 ml) and methyliodide (0.45 ml). After completion of reaction (TLC control), the crude mixture was poured into ethyl acetate (200 ml) and extinguished a 0.1 N aqueous chloride the sodium atom and concentrated until dry. Thus obtained oily residue was chromatographically on silica gel, using as eluent a mixture of hexane: ethyl acetate (19: 1) to deliver the connection specified in the header (600 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-7,26 (m, 1H, Ph2), 6,98 (s, 1H, ), 6,24 (m, 1H, H-3'), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4.92 in and 4,88 (2m, 2H, ), 4,55 (dd, 1H, H-1', J=2.1 and 9.6 Hz), and 4,03 of 3.69 (2d, 2H, 8a-CH2, J=9,3 Hz), 3,95, and is 3.82 (2d, 2H, J=12.3 Hz), 3,86 (m, 1H, H-5'), 3,19 (dd, 1H, H-4', J=3 and 9.3 Hz), of 2.72 (t, 1H, H-1, J=3,9 Hz), 2,58 (s,3H, 3CH3), to 1.70 (s, 3H ).

INTERMEDIATE COMPOUND 23

(a) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4R,7R,9R]-2,8-Dioxa-4,9 - dimethyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4, 4a,5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether and

(b) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4S,7R,9R]-2,8-Dioxa-4,9-dimethyl - CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

METHOD AND

A solution of Intermediate 21 (1.5 g) in dry toluene (150 ml) was degirolami argon for 90 minutes and then was heated with delegacia. To this boiling solution was added to the anti-hydride (847 μl) and azobis(isobutyronitrile) (33 mg). Heating was continued in t is a strict separation on silica gel, using as eluent a mixture of hexane:ethyl acetate (20:1) to deliver the connection specified in the header (a) (15,0 mg; Rf=0.6 V mixture of hexane:ethyl acetate 4;1) and the compound indicated in heading (b) (260 mg; Rf=0.4 V mixture of hexane:ethyl acetate 4: 1) as colourless oils.

(a) (1H, CDCl3): of 9.75 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), of 6.99 (s, 1H, CHPh2), the 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,46 (dd, 1H, H-7', J=3 and 7.5 Hz), 4,06-3,95 (m, 2H, H-3' and 8aCH2), 3,78-of 3.60 (m, 2H, H-1' and 8aCH2), 3,38-3,26 (m, 2H, H-9' and H-3'), a 2.75 (t, 1H, H-1, J=3.6 Hz), and 0.98 (d, 3H, CH, J=6,9 Hz).

(b) (1H, CDCl3): 9,74 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), of 6.99 (s, 1H, CHPh2), 6,04 (dd, 1H, H-1, J=1.5 and 3.6 Hz), 4,74 (t, 1H, H-7', J=3 Hz), 3,94, and 3,61 (2d, 2H, 8aCH2I , JAB=9,3 Hz), 3,88 and 3.76 (2d, 2H, H-3'), 3,66 (m, 1H, H-9'), of 3.43 (t, 1H, H-1', J=7,8 Hz), of 2.72 (t, 1H, H-1, J=3.6 Hz), 2,46 (2m, 2H, H-5'), of 0.97 (d, 3H, J=6.9 Hz).

METHOD B

A solution of Intermediate 98 (685 mg) in o-xylene (15 ml) was degirolami argon for 60 minutes and then was heated with delegacia. Added anti-hydride (379 μl) and continued heating for another 15 minutes. After cooling, the mixture was distributed between diethyl ether (150 ml) and water (100 ml). The organic layer was washed with a saturated aqueous solution of potassium fluoride until then, until he stopped precipitation of the fluoride tribute chromatography rapid separation on silica gel, elwira a mixture of hexane:ethyl acetate (20:1) to deliver the connection specified in the header (a) (103 mg) and the compound indicated in heading (b) (235 mg).

METHOD IN

A solution of anti-hydride (684 μl) in dry toluene (25 ml) was degirolami current of argon for 1 hour with delegacia, and then after 2 hours with a syringe was added a solution of intermediate 98 (610 mg) in dry toluene (30 ml). Heating was continued for 3.5 hours. After removal of the solvent under reduced pressure was obtained the crude product, which was subjected to chromatography rapid separation on silica gel, elwira hexane and hexane:ethyl acetate (10:1) to (8:1), resulting in the compound indicated in heading (a) (357 mg).

INTERMEDIATE COMPOUND 24

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,7R,9R]-2,8-Dioxa-4,4,8 - trimethyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4, 4a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A solution of Intermediate 22 (580 mg) in dry toluene (150 ml) was degirolami current of argon for 1 hour and then heated with delegacia. Within 2 hours, while continued heating and blowing with argon, using a Luer silp is in dry toluene (20 ml). After complete addition, the reaction mixture was heated for another 3 hours, then cooled, concentrated and chromatographically on silica gel, using as eluents first with hexane and then hexane: ethyl acetate (4:1) to deliver the connection specified in the header (100 mg) as a white foam.

(1H, CDCl3): 9,74 9,74 (s, 1H, ), 7,45-7,26 (m, 1H, Ph2), of 6.99 (s, 1H, ), 6,04 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,71 (t, 1H, H-7', J=3.3 Hz), 3,93 and 3,61 (2d, 2H, 8a-CH2, J=9,3 Hz), 3,85 (t, 1H, H-1', J=8.7 Hz), of 3.56 (m, 1H, H-9'), 3,55 and 3,43 (2d, 2H, CH2-3', J=8,4 Hz), 2,73 (m, 1H, H-1), of 1.08 and 0.99 (2s, 6H, 4'-CH3).

INTERMEDIATE COMPOUND 25

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[(6-deoxy- - D-atropinelike) methyl] -4-(1,3-dioxolane-2-yl)-4,4 and,5,6,7,7 and 8,8 and octahydro-7-methyl - 3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a stirred solution of Intermediate 1 (2.5 g) in dry acetonitrile (100 ml) at room temperature was added ethylene glycol (30 ml), triethylorthoformate (2 ml) and a catalytic amount of p-toluensulfonate acid. The reaction mixture was stirred for 3 hours, then was diluted with ethyl acetate (300 ml) and carefully washed with 5% aqueous sodium bicarbonate and brine. Organicheskaja, using as eluent a mixture of hexane:ethyl acetate (3:1) to deliver the connection specified in the header (2.6 g).

(1H, CDCl3): 7,46-7,24 (m, 1H, Ph2), 6,94 (s, 1H, ), of 5.83 (dd, 1H, H-2, J=1.2 and 3.6 Hz), 5,07 (s, 1H, beta) and 4.65 (d,1 H, H-1', J= 1.8 Hz), 4,07-Android 4.04 (m, 2H, 8a-CH2(1H) and H-3'), 3,88 at 3.69 (m, 8h, 8a-CH2(1H), H-2', H-4' and H-5'), of 2.51 (t, 1H, H-1, J=4.5 Hz), is 2.37 (d, 1H, OH, J=2.7 Hz), 2,28 (d, 1H, OH, J=3.6 Hz), 2,04 (d, 1H, OH, J= 5.7 Hz).

THE INTERMEDIATE CONNECTION 26

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3,4-O-isopropylidene- - D - atropinelike)methyl]-4-(1,3-dioxolane-2-yl)-4,4-a, 5,6,7,7 a,8,8 and octahydro-7-methyl-3- (1-methylethyl) -1,4-methane-s - indocin-3A(1H)-carboxylic acid diphenylmethylene ether

A solution of Intermediate 25 (200 mg) in dry acetonitrile (6 ml) under nitrogen atmosphere was treated with 2,2-dimethoxypropane (0.6 ml) and a catalytic amount of p-toluensulfonate pyridine. After 4 hours at room temperature the mixture was treated with saturated aqueous one-deputizing sodium carbonate (20 ml) and was extracted twice with ethyl acetate (20 ml). The combined organic phases are washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography rapid separation on silica gel, elwira a mixture of hexane:this is the head (205 mg), in the form of a white foam.

(1H, CDCl3: 7,47 to 7.2 (m, 1H, 2Ph), 6,93 (s, 1H, ), of 5.83 (dd, 1H, H-2, J=1.2 and 3.6 Hz), to 5.08 (s, 1H, 1,3-dioxolane), 4,56 (d, 1H ,H-1', J=2.1 Hz), 4,3 (dd, 1H, H-3', J=3.6 and 5.7 Hz), Android 4.04 (d, 1H, A part of 8aCH2I , JAB= 9 Hz), 3.95 to a 3.75 (m, 7H, H - 2', H-4', and part B from 8aCH2), 3,44 (dq, 1H, H-5', J=6 and 9 Hz), 2,65 (m, 1H, ), of 2.51 (bt, 1H, H-1, J=3.6 Hz), 2,35 (d, 1H, OH2'), 1,47, of 1.36 (2s, 6H, 2CH3ketal of isopropylidene).

INTERMEDIATE COMPOUND 27

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3,4-O-isopropylidene- - D - allopregnanolone)methyl]-4-(1,3-dioxolane-2-yl)-4,4 and,5,6,7,7 a,8,3 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

Pyridine (of 0.67 ml) was added to a mixture of chromium oxide (CrO3) (412 mg) in dichloromethane (25 ml) at 0oC. After 15 minutes was added acetic anhydride (0,40 ml), and another 10 minutes at the same temperature was added a solution of Intermediate 26 (750 mg) in dichloromethane (25 ml). The mixture was stirred for 2 hours, filtered through a column of silica gel with a top layer of magnesium sulfate, the filtrate is evaporated until dry under reduced pressure, resulting in a received syrup. It was dissolved in a mixture of methanol: water (10:1, 11 ml), and then at 0oC was added sodium borohydride (40 mg). The mixture was stirred at 0o the ri reduced pressure, getting in the white substance, which was purified twice by column chromatography rapid separation on silica gel, elwira successively with a mixture of hexane:ethyl acetate (6:1), and then with a mixture (2: 1). Fractions containing desired product were combined and evaporated under vacuum, resulting in the connection specified in the header (585 mg).

1H, CDCl3): 7,24-7,46 (m, 1H, 2Ph), 6,92 (s, 1H, ), by 5.87 (dd, 1H, H-2, J=3.9 and 1.5 Hz), 5,09 (s, 1H, ), to 4.52 (t, 1H, H3', J= 4.5 Hz), of 4.45 (d, 1H, H-1', J=7,8 Hz), 4,07 (d, 1H, 8aCH2, J=9 Hz), 3,74-3,86 (m, 6H, 2CH2-dioxolane, H-4', 8aCH2), to 3.67 (m, 1H, H-2'), to 2.65 (m, 1H, H-14), 2,58 (t, 1H, H-11).

THE INTERMEDIATE CONNECTION 28

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 4-Formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-8a - hydroxymethyl-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin - 3a(1H)-carboxylic acid 2-(trimethylsilyl) ethyl ester

The solution agaricina (6.6 g) and O-[2-(trimethylsilyl)ethyl]- N,N'-diisopropylethylamine (9.3 g) in anhydrous tetrahydrofuran (150 ml) was heated with delegacia for 3 hours. Then the mixture was cooled to room temperature, filtered and concentrated until dry. The residue was dissolved in ethyl acetate (750 ml) and intensively washed with 1N hydrochloric acid, 5% aqueous bicarbonate and brine. The organic layer was dried over anhydrous slania on silica gel, using as eluent solution (10%) ethyl acetate in hexane to deliver the connection specified in the header (6.8 g) as a white foam.

(1H, CDCl3): 9,67 (s, 1H, CHO), 6,07 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,27 (m, 2H ), 3,93 and 3,49 (2m, 2H, 8a-CH2), a 2.75 (bs, 1H, OH), to 2.54 (t, 1H, H-1), of 1.05 (m, 2H, ), of 0.07 (s, 9H, (CH3)3Si);

(13C, CDCl3): 204,9 173,6 148,2 , to 130.6 66,9 (8a-CH2O), 64,0 177,7 1,6 (CH3)3Si).1[7].

INTERMEDIATE COMPOUND 29

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(3,4,6-Tri-O-acetyl-2-deoxy- - D - allopregnanolone)methyl] -4-formyl-4,4 a, 5,6,7,7 and, 8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid trimethylsilylethynyl ether

To a solution of Intermediate 28 (63 mg) and 3,4,6-tri - O-acetyl-D-allal1(20 mg) in dry toluene (1 ml) was added Hydrobromic triphenylphosphine (9 mg). The reaction mixture was warmed up at 60oC for 2 hours and was poured into 1M sodium bicarbonate solution (100 ml). Added ethyl acetate (100 ml), the organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated until dry and the residue was purified by column chromatography rapid separation on silica gel, elwira a mixture of hexane:ethyl acetate (10:1), UB>): 9,73 (s, 1H, CHO), 6,03 (dd, 1H, H-2, J=1.5 and 3.6 Hz), of 5.48 (m, 1H, H-3'), 4,89 (dd, 1H, H-4', J=3.3 and 9.6 Hz) and 4.65 (dd, 1H, H-1', J=2.4 and 8.7 Hz), to 4.23 (m, 4H, H-6', ), was 4.02 (ddd, 1H, H-5', J=3, 5.4 and 9.6 Hz), 3,92 and of 3.69 (2d, 2H, 8aCH2, J=9.6 Hz), a 2.75 (t, 1H, H-1), of 2.28 (m, 1H, ).1[8].

THE INTERMEDIATE CONNECTION 30

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2-deoxy-3,4-O-isopropylidene-6 - O-methyl - D-allopregnanolone)methyl] -4-formyl-4,4 a,5,6, 7,7 a,8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane - s-indocin-3a(H)-carboxylic acid 2-(trimethylsilyl)ethyl ester

To peremalyvavshaya solution of Intermediate 29 (275 mg) in absolute methanol (10 ml) was added 2 or 3 drops of 1M solution of sodium methoxide in methanol. After stirring for 1.5 hours the reaction mixture was concentrated, diluted with toluene (10 ml) and concentrated to obtain a yellow syrup. It was dissolved in acetone (5 ml) and 2,2-dimethoxypropane (60 μl) was added monohydrate p-toluensulfonate acid (75 mg). The reaction mixture was stirred at room temperature for 1 hour, neutralized with sodium carbonate, filtered and the filtrate concentrated until dry. The oily residue was dissolved in ethyl acetate (20 ml), washed with water and brine, dried and concentrated, resulting in the oil. The solution of this oil in dry tetrahedral under the conditions (100 μl). The reaction mixture for 3 hours was gradually heated to room temperature. The reaction was suppressed by methanol (1 ml), the mixture was then concentrated, the residue was purified three times by column chromatography rapid separation, applying successively a mixture of hexane:ethyl acetate(10: 1), (6: 1) and (4:1), the appropriate fractions were combined and the solvents evaporated, resulting in the received connection specified in the header (50 mg) as a colourless oil.

(1H, CDCl3): 9,73 (s, 1H, CHO), 6,04 (dd, 1H, H-2, J=1.2 and 3.6 Hz), br4.61 (dd, 1H, H-1', J=2.4 and 8.4 Hz), 4,43 (m, 1H, H-3'), 4,34-4,10 (m, 2H, CH2SEM protective group), 3,66 and the 3.89 (2d, 2H, 8aCH2, J=9,3 Hz), a 3.87 (m, 1H, H-4'), 3,48-to 3.64 (m, 3H, 2H-6' and H-5'), 3,24 (s, 3H, 6'OMe), 2,73 (t, 1H, H-1, J=3.6 Hz), of 1.34 and 1.35 (2s, 6H, methyl group, isopropylidene).

THE INTERMEDIATE CONNECTION 31

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-((E)-2-Butenyl)-2,6-dideoxy- - D-allopregnanolone)methyl] -4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A suspension of intermediate 10 (1.5 g) and nitric oxide diotisalvi (0.9 g) in dry toluene (150 ml) was heated with delegacia for 2 hours in a flask equipped with Dean-Stark condenser, and then left at room temperature in nitrogen atmosphere the ANS, of 0.37 ml), tetrabutylammonium (3.6 ml of 1M solution in tetrahydrofuran)

and 4 A molecular sieves (activated powder), and the mixture was let warm up at 60oC for 24 hours. Molecular sieves were filtered off. After removal of the solvent was obtained residue, which was subjected to chromatography rapid separation on silica gel with elution by the mixture hexane: acetone (95:5), receiving the result of the connection specified in the header (1 g) as a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,44-of 7.23 (m, 10H, 2Ph), 6,98 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 5,75-5,52 (m,2H, ), with 4.64 (dd, 1H, H-1', J= 2.1 and 9.6 Hz), 4,16 (m, 1H, H-3'), to 4.98 (m, 3H, 8a-CH2, (1H), 3,74 (m, 1H, H-5'), to 3.67 (d, 1H, 8a-CH2(1H), J=9,3 Hz), 3,05 (dd, 1H, H-4', J=3.0 and 9.6 Hz), a 2.75 (t, 1H, H-1, J=3.6 Hz), 2.40 a (d, 1H, OH, J=2.1 Hz), 1,72 (m, 3H ).

THE INTERMEDIATE CONNECTION 32

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-Dideoxy-4-O-propargyl- - D - allopregnanolone)methyl] -4-formyl-4,4 a, 5,6,7,7 and, 8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid diphenylmethylene ether

A suspension of intermediate 10 (2 g) and oxide dibutyrate (1.2 g) in dry toluene (150 ml) was heated with delegacia in a flask equipped with Dean-Stark condenser, and then left at room temperature in a nitrogen atmosphere (approximately 20 ml of azeotropic mixtures in which fluoride (4.8 ml 1M solution in tetrahydrofuran) and 4A molecular sieves (activated powder), the resulting mixture was warmed up at 60oC for 24 hours. Molecular sieves were filtered off. After removal of the solvent was obtained residue, which was twice subjected to chromatography rapid separation on silica gel with elution by the mixture hexane: acetone (96:4), receiving the result of the connection specified in the header (to 1.25 g) as a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,44-7,26 (m, 10H, 2Ph), 6,98 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.2 and 3.3 Hz) and 4.65 (dd, 1H, H-1', J=2.1 and 9.6 Hz), 4,29 (10, 1H, H-3'), 4,24 4,22 and (2d, 2H, J=2.4 Hz), 4,05 and 3,68 (2d, 2H, 8a-CH2, J=9,3 Hz in), 3.75 (m, 1H, H-5'), of 3.25 (dd, 1H, H-4', J= 3.0 and 9.3 Hz), a 2.75 (t, 1H, H-1, J=3,9 Hz), 2,46 (t,1H, J=2.4 Hz).

THE INTERMEDIATE CONNECTION 33

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-(3-methyl-2-butenyl)-2,6-dideoxy- - D-allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid diphenylmethylene ether

A suspension of intermediate 10 (1 g) and tributyltinoxide (600 mg) in 150 ml dry toluene was heated with delegacia for 2 hours in a flask equipped with Dean-Stark condenser (25 ml azeotropic mixture was removed), and then cooled to room temperature. Then were added 2-Methyl-4-bromo-2-butene (276 μl) and tetrabutylammonium (1M solution in tetrahydrofuran, 2.4 ml) and the mixture was heated to 50o

1H, CDCl3): 9,73 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), 6,98 (s, 1H, CHPh2), equal to 6.05 (dd, 1H, H2, J=1.5 and 3.3 Hz), 5,33 (m, 1H, ), with 4.64 (dd, 1H, H1', J=2.1 and 9.6 Hz), 4,20 (m, 1H, H3'), 4.25 in-3,95 (m, 3H ), 3.75 to the 3.65 (m, 2H, H5'+8aCH2), 3,03 (dd, 1H, H4', J=3.3 and 9.6 Hz), a 2.75 ( t, 1H, H1, J=3,9 Hz), 2,44 (d, 1H, OH, J=2.1 Hz).

THE INTERMEDIATE CONNECTION 34

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a-[(4-O-((E)-2-Butenyl)-2,6-dideoxy-3-O - methylthio)thiocarbonyl- - D-allopregnanolone)methyl]-4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methyl-ethyl)-1,4-methane-s - indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a chilled solution of intermediate 31 (1 g) in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere was added in small portions sodium hydride (0.156 g) and a catalytic amount of imidazole. Then the ice bath was removed and the reaction mixture was left at room temperature under stirring for 1 hour. Sequentially added carbon disulfide (0,58 ml) and methyliodide (0.8 ml). After completion of the reaction (TLC control), the crude mixture was poured into ethyl acetate (400 ml) and put it 1N aqueous ammonium chloride (500 ml). The organic layer is then thoroughly washed with 1N hydrochloric acid (200 ml), 5% aqueous sodium bicarbonate (200 m the od vacuum. Thus obtained residue was subjected to chromatography rapid separation on silica gel with elution with a mixture of dichloromethane: hexane (6: 4), receiving the result of the connection specified in the header (1.04 g) as a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,45 - 7,26 (m, 10H, 2Ph), 6,98 (s, 1H, ), 6,23 (dd, 1H, H-3', J=3.0 and 6.3 Hz), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.3 Hz), 5,75 - of 5.40 (m, 2H ), 4,55 (dd, 1H, H-1', J=1.8 and 9.3 Hz), 4,05 - of 3.80 (m, 4H, 8a-CH2(1H), and H-5'), of 3.75 (d, 1H, 8a - CH2(1H), J= 9,3 Hz), 3,20 (dd, 1H, H-4',J=3.0 and 9.3 Hz), of 2.72 (t, 1H, H-1, J=3,9 Hz), 2,58 (s, 3H, CH3S), by 1.68 (m, 3H ).

THE INTERMEDIATE CONNECTION 35

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-Dideoxy-3-O-(methylthio) thiocarbonyl-4-O-propyl- - D-allopregnanolone)methyl] -4 - formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3A(1H)-carboxylic acid diphenylmethylene ether

It had been cooled solution of intermediate 32 (1.25 g) in anhydrous tetrahydrofuran (25 ml) under nitrogen atmosphere was added in small portions sodium hydride (0.2 g) and a catalytic amount of imidazole. Then the ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. Sequentially added carbon disulfide (0.6 ml) and methyliodide (0.75 ml). After completion of the reaction (TLC control), the crude mixture was poured into ethyl acetate (the Oh (200 ml), 5% aqueous sodium bicarbonate (200 ml) and brine (200 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to chromatography rapid separation on silica gel with elution by the mixture hexane:ethyl acetate 97:3 and 95:5, receiving the result of the connection specified in the header (1.2 g) as a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-7,26 (m, 10H, 2Ph), of 6.99 (s, 1H, ), 6,28 (q, 1H, H-3', J=3.3 Hz), the 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), of 4.57 (dd, 1H, H-1', J=1.8 and 9.3 Hz), 4,19 and 4.17 (2d, 2H , J=2.4 Hz), 4,03 and 3.70 (2d, 2H, 8a-CH2, J=9,3 Hz), 3,86 (dq, 1H, H-5', J=6.3 and 9.3 Hz), 3,50 (dd, 1H, H-4', J=3.0 and 9.3 Hz), 2,73 (t, 1H, H-1, J=3,9 Hz), 2,58 (s, 3H, CH3S), 2,42 (t, 1H, ).

INTERMEDIATE COMPOUND 36

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-(3-methyl-2 - butenyl)-2,6-dideoxy-3-O-(methylthio)thiocarbonyl- - D - allopregnanolone)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid defininately ether

To a solution of intermediate 33 (770 mg) in dry tetrahydrofuran (15 ml) was added at 0oC in nitrogen atmosphere sodium hydride (105 mg) and imidazole (30 mg). The mixture was stirred for 1 hour at room temperature, then was added carbon disulfide (300 μl) and methyliodide (311 μl). After stirring for 1 chili over magnesium sulfate and concentrated, getting in the oil, which was subjected to chromatography rapid separation (silica gel, ethyl acetate: hexane 1: 25 and 1:20), receiving the 780 mg of the connection specified in head (90%), in the form of a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), 6,98 (s, 1H, CHPh2), of 6.26 (m, 1H, H-3'), the 6.06 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 5,26 (m, 1H, ), of 4.54 (dd, 1H, H1', J=1.8 and 9.6 Hz), 4,10-of 3.75 (m, 4H, ), of 3.69 (d, 1H, 8aCH2, J=9.6 Hz), 3,18 (dd, 1H, H4', J=3 and 9.3 Hz), of 2.72 (t, 1H, H1, J=3,9 Hz), 2,58 (s, 3H, SCH3).

INTERMEDIATE COMPOUNDS 37 and 38

a) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[1S,4R,7R,9R]-2,8-Dioxa - 4-ethyl-9-methyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl]]-4 - formyl-4,4 a,5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

b) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[1S,4S,7R,9R]-2,8 - Dioxa-4-ethyl-9-methyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] ] -4 - formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A solution of intermediate 34 (1.04 g) in dry toluene (50 ml) was degirolami current of argon for 1 hour at reflux distilled. Added anti-hydride (0,55 ml) and a catalytic amount of azobis(isobutyronitrile). The reaction mixture was then subjected to reflux distilled within 20 minutes and the follower is Lucia hexane and hexane:ethyl acetate (94:6). The result obtained Intermediate compound 37 (220 mg, Rf=0.32 in a mixture of hexane:ethyl acetate 4:1) as a white foam and intermediate compound 38 (444 mg, Rf=0.27 in a mixture of hexane:ethyl acetate 4:1) as white matter.

THE INTERMEDIATE CONNECTION 37

(1H, CDCl3): of 9.75 (s, 1H, CHO, 7,45-7,26 (m, 10H, 2Ph), of 6.99 (s, 1H, ), the 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,50 (dd, 1H, H-7, J=2.7 and 6.9 Hz), 4.06 and 3,38 (2dd, 2H, CH2-3', J=8.4 and 7.5 Hz), 4,01 and the 3.65 (2d, 2H, 8a-CH2, J=9.0 Hz), 3,71 (dd, 1H, H-1', J=7.5 and 9.0 Hz), to 3.34 (m, 1H, H-9'), a 2.75 (t, 1H, H-1), of 0.93 (t, 3H, J=7.5 Hz).

INTERMEDIATE COMPOUND 38

(1H, CDCl3): 9,74 (s, 1H, CHO), 7,45-7,26 (m, 10H, 2Ph), of 6.99 (s, 1H, ), 6,04 (dd, 1H, H-2, J=1.2 and 3.6 Hz), to 4.73 (t, 1H, H-7', J=3.0 Hz), 3,92 (m, 2H, 8a-CH3(1H) and CH3-3'(1H) in), 3.75 (m, 1H, H-9' and H-1'), 3,62 (d, 1H, 8a-CH2, J= 9,3 Hz), 3,48 (m, 1H, CH2-3'(1H)), 2,71 (t, 1H, H-1, J=3.6 Hz), 2,55 and 2,23 (2m, 3H, H-4', H-5' and 3-CH), is 0.96 (m, 3H, CH2).

INTERMEDIATE COMPOUNDS 39 and 40

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S,4R,7R,9R)-2,8-Dioxa-4-(1-methylethyl)- 9-methyl-CIS-bicyclo[3.4.0] non-7-yl-oxymethyl)]-4-formyl-4, 4a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ester and [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S,4S,7R,9R)-2,8-Dioxa-4-(1-methylethyl)-9-methyl - CIS-bicyclo[3.4.0] non-7-yl-oxymethyl)]-4-formyl-4,4 a,5,6,7,7 a,8, 8a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- Carbo who was aziraphale argon for 1 hour, and then was heated with delegacia. Added anti-hydride (367 μl) and a catalytic amount of a,a'-azoisobutyronitrile (20 mg) and the mixture was subjected to reflux distilled for 2 hours, then cooled to room temperature. After removal of the solvent was obtained residue, which was subjected to chromatography rapid separation (silica gel, hexane:ethyl acetate 25:1, 20:1, 18:1 and 15:1), resulting in the 280 mg of intermediate 39 (yield 41%) and 300 mg of intermediate 40 (yield 44%) as oils (Rfof 0.5 and 0.3 in a mixture of hexane:ethyl acetate/3:1, respectively).

THE INTERMEDIATE CONNECTION 39

(1H, CDCl3): of 9.75 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 1Ph), of 6.99 (s,1H, CHPh2), equal to 6.05 (dd, 1H, H2, J=1.2 and 3.6 Hz), of 4.57 (dd, 1H, H7', J=2.7 and 5.7 Hz), 4,05-3,90 (m, 2H, H3'+8aCH2), to 3.73 (dd, 1H, H1', J=8.1 and 9.3 Hz), 3,62 (d, 1H, 8aCH2, J=9 Hz), 3,50 is-3.45 (m, 2H, H3'+H9'), is 2.74 (t, 1H, H1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 40

(1H, CDCl3): 9,74 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), of 6.99 (s, 1H, CHPh2), 6,03 (dd, 1H, H2, J=1.5 and 3.3 Hz), 4,74 (t, 1H, H7', J=3 Hz), of 4.0 to 3.8 (m, 8aCH2+H9'+H3'), to 3.73 (dd, 1H, H1', J=3,3 H 4.5 Hz), 3,63 (d, 1H, 8aCH2, J= 9.6 Hz), 3,52 (dd, 1H, H3', J=8.1 and 10.5 Hz), 2,70 (t, 1H, H1, J= 3,9 Hz).

THE INTERMEDIATE CONNECTION 41

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[1S,7R,9R]-2,8-Dioxa-4-methylene,9 - methyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4,4 a/BR> A solution of intermediate 35 (1,02 g) in dry toluene (50 ml) was degirolami current of argon for 1 hour at reflux distilled. Added anti-hydride (0,55 ml) and a catalytic amount of azobis(isobutyronitrile). Then the reaction mixture was subjected to reflux distilled for 1 hour, then cooled, concentrated, and then was twice subjected to chromatography rapid separation on silica gel with elution with hexane and hexane:ethyl acetate (94: 6). Thus received net connection specified in the header (380 mg), and was isolated as a white foam.

(1H, CDCl3): of 9.75 (s, 1H, CHO), 7,44-7,28 (m, 10H, 2Ph), of 6.99 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 5,07 and 5,02 (2dd, 2H, J= 2.4 and 4.8 Hz), 4,49-or 4.31 (m, 3H, H-7' and CH2-3'), 3,95 and 3,66 (2d, 2H, 8a-CH2, J= 9,3 Hz), 3,80 (dd, 1H, H-1', J=7.5 and 9.3 Hz), 3,26 (m, 1H, H-9'), to 3.02 (m, 1H, H-5'), was 2.76 (t, 1H, H-1, J=3,9 Hz);

(13C, CDCl3): 204,4 171,0 148, 8 persons and 148,3 (C-3 and C-4'), 139,5 and 139,4 (CIV 2 Ph), 130,7 (C-2), 128,6, 128,5, 128,2, 128,0, 127,7 and 127,0 103,9 of 98.3 (C-7'), 80,4 and 69.5 (C-1' and C-9'), 78.5 per (CHPh2), 73,9 and 70.6 and C-3').

THE INTERMEDIATE CONNECTION 42

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,7R,9R]-2,8-Dioxa-9-methyl-4-methylene-3 - oxo-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl]-4-formyl-4,4 a,5,6,7, 7a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To peremeci ulali intermediate connection 41 (0.15 g) in dry dichloromethane (3 ml). Stirring at room temperature was continued for 6 hours, then the reaction mixture was directly subjected to chromatography rapid separation on silica gel using dichloromethane as eluent to deliver the connection specified in the header (65 mg) as a white foam.

(1H, CDCl3): 9,74 (s, 1H, ), 7,44-7,25 (m, 10H, 2Ph), 6,98 (s,1H, ), 6,37 and 5,64 (2d, 2H, ), 6,04 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 4,47 (dd, 1H, H-7', J=3.6 and 6.0 Hz), the 4.29 (m, 1H, H-1'), 4.00 and of 3.64 (2d, 2H, 8a-CH2, J=9,3 Hz), 3,40 (m, 1H, H-5'), 3,30 (m, 1H, H-9'), 2,73 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 43

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,7R,9R]-2,8-dioxa-9-methyl-4-oxo-CIS - bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methyl-ethyl)-1,4-methane - s-indocin-3A(1H)-carboxylic acid diphenylmethylene ether

METHOD AND

It had been cooled on ice, a mixture of Intermediate 41 (105 mg) and N-methylmorpholine N-oxide (43 mg) in acetone: water (8:1.9 ml) was added cityregional osmium (a 2.5% weight. a solution of 2-methyl-2-propanol, 0.075 ml). Then the ice bath was removed, and the mixture was stirred at room temperature for 24 hours. The reaction was suppressed by sodium bisulfite, was stirred for 1 hour and the solvent evaporated. The crude residue was diluted with ethyl acetate (100 ml) and posledovatelei and evaporated. The crude product was dissolved in a mixture of dioxane:water (2:1, 6 ml) and cooled to 0oC. in Small portions was added periodate sodium (0,13 g) and the mixture was stirred for 6 hours at room temperature, then concentrated and fractionally the crude product between water (60 ml) and ethyl acetate (60 ml). The organic phase was dried and concentrated, and the thus obtained residue was purified by chromatography rapid separation on silica gel (hexane:ethyl acetate 85:15), receiving the result of the connection specified in the header (0,045 g).

METHOD B

To a solution of triperoxonane anhydride (0,43 ml) in dry dichloromethane (2.5 ml) was added dimethyl sulfoxide (0,22 ml) at -60oC in nitrogen atmosphere with vigorous stirring. After 10 minutes was added a solution of Intermediate 79 (470 mg) in dry dichloromethane (2.5 ml) and stirred the mixture at -60oC for 2 hours. Within 10 minutes dropwise added triethylamine (1.4 ml) and brought the temperature up to -20oC. Then was added water (20 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was separated and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layers are washed with 1N hydrochloric acid (100 ml), asymetria, getting in the oil, which was dissolved in dichloromethane and treated with triethylamine (1 ml) overnight. The solvent was removed and the resulting oil was subjected to chromatography rapid separation (silica gel, ethyl acetate:hexane 1:25, 1:20 and 1:15) to give 400 mg of the compound indicated in heading (yield 86%).

(1H, CDCl3): 9,71 (s, 1H, ), 7,44-7,26 (m, 10H, 2Ph), 6,97 (s, 1H, ), the 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,18-4,11 (m, 3H, H-7', H-1' and H-3' (1H), 4.00 and 3,62 (2d, 1H, 8a-CH2, J=9,3 Hz), 3,91 (d, 1H, H-3', J=18 Hz), 3,30 (m, 1H, H-9'), 2,85 (bt, 1H, H-5', J=7,8 Hz) of 2.75 (t, 1H, H-1, J= 3,9 Hz).

THE INTERMEDIATE CONNECTION 44

[R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-{[4-O- (TRANS-2 - butenyl)-6-deoxy- - D-atropinelike] methyl}-4-formyl - 4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A suspension of intermediate compound 1 (5 g) and oxide dibutyrate (2.3 g) in dry toluene (300 ml) was subjected to reflux distilled for 3 hours in a flask equipped with Dean-Stark condenser, under nitrogen atmosphere, and then cooled to 60oC. was Sequentially added molecular sieves (4A, powder), brothelbased (2.4 ml) and a 1M solution in tetrahydrofuran of tetrabutylammonium (23 ml), the mixture was let warm up for 1 hour at 60oC and kept at komnatnaya on a column of fast separation with silica gel by elution with hexane and hexane: acetone (9:1), receiving a result of the connection specified in the header (3.2 g) in the form of a white foam.

(1H, CDCl3); 9,73 (s, 1H, CHO), 7,45 to 7.2 (m, 10H, 2Ph), 6,98 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 5,8-the 5.65 (m, 1H, ), 5,65 to 5.5 (m, 1H, ), 4,63 (d, 1H, H-1', J=0.9 Hz), from 4.2 to 3.8 (m, 5H, H-2', H-3', 8aCHa ), 3,8-the 3.65 (m, 2H, H-5', 8aCHb), and 3.6 (dd, 1H, H-4', J=3 and 9.3 Hz), is 2.74 (t, 1H, H-1, J=3,9 Hz), 1,71 (dd, 3H, CH3-C=C, J= 1,2 and 6.3 Hz).

INTERMEDIATE CONNECTIONS 45, 46 and 47

a) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-{[2,3-Anhydrous-4-O-(TRANS - 2-butenyl)-6-deoxy- - D-mannopyranosyl] methyl} -4-formyl - 4,4 a,5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

b) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S,4S,6S,7R,9R)-2,8 - Dioxa-4-ethyl-6-hydroxy-9-methyl-CIS-bicyclo[3.4.0] non-7-yl - oxymethyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1 - methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

b) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S,4R,6S,7R,9R)-2,8 - Dioxa-4-ethyl-6-hydroxy-9-methyl-CIS-bicyclo[3.4.0] non-7 - yl-oxymethyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

Intermediate compound 44 (1,225 g), triphenylphosphine (1,38 g) and imidazole (0.36 g) was subjected to reflux distilled toluene (35 Il) under stirring, and then added dropwise within 2 hours

added races of the sa. The reaction mixture was cooled and was fractionally between ethyl acetate (100 ml) and 1N aqueous hydrochloric acid (50 ml). The organic layer is successively washed with 1N aqueous hydrochloric acid, water, aqueous solution of sodium metabisulfite, water, and brine, then dried (Na2SO4), filtered and concentrated under vacuum. The residue was subjected to chromatography rapid separation on silica gel with elution by the mixture hexane:atidaryta (7:1), resulting in the 2:1 mixture of two compounds with very close values of Rfin the system hexane:ethyl acetate (1.08 g) (Rf= 0,4 in the system hexane:ethyl acetate 4:1). The mixture was dissolved in dry toluene (25 ml), the solution was degirolami current of argon for 1 hour and then heated with delegacia. Added anti-hydride (0,36 ml) and continued dephlegmation for 20 minutes. After cooling, was added carbon tetrachloride (2 ml) and stirred solution at room temperature for 1 hour. Then was added a dilute solution of iodine in the air as long as he remained weak staining. Then the solvent was removed under vacuum and the residue was transferred into diethyl ether and washed several times with saturated aqueous solution of sodium fluoride until then, until the termination shall STATCOM, which was twice subjected to chromatography rapid separation on silica gel, elwira a mixture of dichloromethane:ethyl acetate (95: 5) to deliver the compound indicated in heading (a) of the Intermediate compound 47 (230 mg, Rf=0.8 in the system of dichloromethane: ethyl acetate 9:1) specified in the header (b) of the intermediate compound 45 (275 mg, Rf= 0.5 V system dichloromethane: ethyl acetate 9:1) and specified in the header (in) intermediate compound 46 (200 mg, Rf=0,4 in the system of dichloromethane: ethyl acetate

9:1).

THE INTERMEDIATE CONNECTION 45

(1H, CDCl3): 9,72 (s, 1H, CHO), 7,46-of 7.23 (m, 10H, 2Ph), 6,98 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.2 and 3.3 Hz), br4.61 (d, 1H, H-7', J=3.3 Hz), a 4.03 (d, 1H, 8a-CHa, J= 9.3 Hz), 3,90 (dd, 1H, Ha-3', J=6.9 and 8.7 Hz), 3,82 at 3.69 (m, 3H, H-6', H-1' and H-9'), 3,66 (d, 1H, 8a-CHb, J=9.6 Hz), 3,61 (dd, 1H, Hb-3', J=6,6 and 8.4 Hz), 2,69 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 46

(1H, CDCl3): 9,74 (s, 1H, CHO), 7,45-7,22 (m, 10H, 2Ph), of 6.99 (s, 1H, ), the 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,50 (d, 1H, H-7', J=2.1 Hz), 4.1 and was 4.02 (m, 2H, 8aCHa and Ha-3'), of 3.84 (dd, 1H, H-1', J=7.5 and 8.7 Hz), 3,76-3,66 (m, 2H, 8aCHb and H-6'), a 3.5-to 3.38 (m, 2H, H-9' and Hb-3'), of 2.72 (t, 1H, H-1, J=3,9 Hz) to 0.94 (t, 3H, J=7.5 Hz).

THE INTERMEDIATE CONNECTION 47.

(1H, CDCl3): of 9.75 (s, 1H, CHO), 7,45 to 7.2 (m, 10H, 2Ph), of 6.99 (s, 1H, ), between 6.08 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 5,85-5,7 (m, 1H, ), 5,65 to 5.5 (m, 1H, ), of 4.67 (s, 1H, H-1'), 4,2-of 4.05 (m, 2H, OCHa-C=C and 8aCHa), of 4.05 to-3.9 (m, 1H, OCHb-C=C), of 3.78 (d, 1H, 8aCHb, J=9 the,4,4 a,7,7 a,8a) ] 8a-[(6 - deoxy-4-O-methyl- - D-atropinelike) methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

In the solution sordaria (10.0 g) in dichloromethane (150 Il) was added dropwise a solution of diphenyldiazomethane in dichlormethane (0.35 M, 85 ml). The resulting solution was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography rapid separation on silica gel, elwira a mixture of hexane:ethyl acetate (4: 1) and (2:1). Fractions were combined and evaporated, resulting in the connection specified in the header (to 11.8 g) as a white foam.

(1H, CDCl3): 10,00 (s, 1H, CHO), 7,63 (m, 10H, 2Ph), 7,26 (s, 1H, ), 6,30 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 4.92 in (d, 1H, H-1', J=0.9 Hz), 4,84 (t, 1H, H-3', J=3.3 Hz), 4,03 and 4.35 (2d, 2H, 8aCH2, J=9 Hz), 3,88 (m, 1H, H-2'), 3,70 (dq, 1H, H-5', J=6.3 and 9.3 Hz), to 3.41 (s, 3H, 4'-OMe), 3,20 (dd, 1H, H-4', J=3.3 and 9 Hz), a 2.75 (t, 1H, H-1).

THE INTERMEDIATE CONNECTION 49

a) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-4-O-methyl-2,3 - di-O-tosyl- - D-atropinelike)methyl] -4-formyl-4,4 a,5, 6,7,7-a,8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane - s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether and

b) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-4-O-methyl-2-O-tosyl- - D - ultrapornstars)methyl]4-vore

Intermediate compound 48 (2 g) and 4-dimethylaminopyridine (500 mg) was dissolved in dry pyridine (30 ml). Was added dropwise a solution of tosylchloramide (960 mg) in dry pyridine (20 ml). The reaction mixture was stirred at room temperature for 4 days. The solvent is evaporated under vacuum, obtaining the resulting yellow residue, which was chromatographically on a column of silica gel, elwira a mixture of hexane:ethyl acetate (4:1) and (1:1), resulting in the compound indicated in heading (a), with a large value of Rfin the form of a white foam (1.65 g) and the compound indicated in heading (b), with a smaller value of Rfand also in the form of a white foam (1,17 g).

(a) (1H, CDCl3): 9,71 (s, 1H, CHO), a 7.85 to $ 7.91 (m, 4H, ortho-Ts), 7,26-7,41 (m, 14H, meta Ts and 2Ph), to 6.95 (s, 1H, ), by 5.87 (dd, 1H, H-2, J= 1.2 and 3.3 Hz), to 4.92 (dd, 1H, H-3', J=3.3 and 4,2 Hz) and 4.65 (dd, 1H, H-2', J= 1.2 and 4.5 Hz), br4.61 (d, 1H, H-1', J=1.2 Hz), 3,50 and of 3.94 (2d, 2H, 8aCH2, J=9 Hz), 3,68 (dq, 1H, H-5', J=6.6 and 9 Hz), and 3.16 (dd, 1H, H-4', J=3 and 9 Hz), 2,78 (s, 3H, 4'-OMe), 2,45 and 2,47 (2s, 6H, 2Ts).

(b) (1H, CDCl3): 9,71 (s, 1H, CHO), a 7.85 (m, 2H, ortho-Ts), 7,26-7,41 (m, 12H, meta Ts and 2Ph), to 6.95 (s, 1H, ), by 5.87 (dd, 1H, H-2, J=1.5 and 3.3 Hz), br4.61 (d, 1H, H-1', J=1.5 Hz), 4,55 (dd, 1H, H-2', J=1,2 and 4.2 Hz), 4,37 (m, 1H, H-3'), 3,50, and 3.95 (2d, 2H, 8aCH2, J=9 Hz), 3,70 (dq, 1H, H-5', J=8.4 and 6.3 Hz), 3,23 (dd, 1H, H-4', J=3.3 and 8.7 Hz), 2,42 (s, 3H, Ts).

THE INTERMEDIATE CONNECTION 50

Upon cooling to 0oC in anhydrous methanol was added sodium (0.5 g), then the Intermediate compound 49 (670 mg) in dry dichloromethane (20 ml). The mixture was stirred for 5 days at room temperature, and 4 days with delegacia. The mixture was filtered and the solvent evaporated. The residue was purified by chromatography rapid separation elution by the mixture hexane:ethyl acetate (3: 1), receiving the result of the connection specified in the header (330 mg).

(1H, CDCl3): of 9.75 (s, 1H, CHO), 7,26-7,44 (m, 10H, 2Ph), of 6.99 (s, 1H, ), between 6.08 (dd, 1H, H-2, J=1.5 and 3 Hz), and 4.68 (s, 1H, H-1'), 3,78, and 4,11 (2d, 2H, 8aCH2, J=9 Hz), 3,49 (s, 3H, 4'-OMe), 3,26 (d, 1H, H-2', J=3.9 Hz), 3,18 (m, 1H, H-5'), of 3.12 (d, 1H, H-3', J=3.6 Hz), is 3.08 (m, 1H, H-4'), of 2.86 (m, 1H, H-1').

THE INTERMEDIATE CONNECTION 51

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-6-deoxy-4-O-methyl - D - allopregnanolone)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

A solution of sodium hydride (25,9 mg) suspended in dry dimethylformamide (5 ml). Was added dropwise Intermediate compound 49 (b) (470 mg) in dry dimethylformamide and the mixture was stirred at room temperature for 40 minutes. The reaction mixture under stirring was poured into had been cooled with ice water (20 ml), and Polat magnesium. The resinous residue obtained after evaporation of the solvents was purified by column chromatography rapid separation elution by the mixture hexane:ethyl acetate (5: 1), receiving the result of the connection specified in the header, in the form of a white foam (332 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,26-7,44 (m, 10H, 2Ph), 6,98 (s, 1H, CO2CHPh2), between 6.08 (dd, 1H, H-2, J=1.5 and 3 Hz), 4,60 (s, 1H, H-1'), 3,76, and a 4.03 (2d, 2H, 8aCH2, J=9,3 Hz), 3,51 (m, 4H, H-4' and 4'-OMe), to 3.33 (m, 3H, H-2', H-3' and H-5'), 2,80 (m, 1H, H-1).

THE INTERMEDIATE CONNECTION 52

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-6-deoxy-4-O-methyl - D - atropinelike)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid

To a solution of Intermediate 51 (100 mg) in ethyl acetate (15 ml) was added in a nitrogen atmosphere of 10% palladium on coal (100 mg). The mixture was shaken in a Parr apparatus under 15 psi of hydrogen for 1 hour at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was purified by chromatography rapid separation on silica gel, elwira a mixture of hexane:ethyl acetate (3:1) and dichloromethane: methanol (15: 1). The appropriate fractions were combined, the solvent was removed and resulted connection, MC H-1', J=0.9 Hz), 3.58 and 4,17 (2d, 2H, 8aCH2, J=9.6 Hz), 3,51 (m, 4H, H-3', and 4'-OMe), to 3.38 (m, 1H, H-5'), 3,34 (d, 1H, H-2', J= 4, 2 Hz), 3,30 (dd, 1H, H-4',J=9 and 1.5 Hz), 2,65 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 53

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Allyl-6-deoxy- - D-atropinelike) methyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A suspension of Intermediate 1 (2 g) and oxide dibutyrate (870 mg) in dry toluene (25 ml) was subjected in an atmosphere of nitrogen reflux distilled for 2 hours in a flask equipped with Dean-Stark condenser, and then left at room temperature. Sequentially added allylbromide (0.3 ml) and 1M solution of tetrabutylammonium (3.5 ml), the mixture warmed up in the atmosphere of nitrogen at 40oC for 24 hours. The solvent was evaporated until dry and the residue was chromatographically on a column of fast separation with silica gel, elwira a mixture of hexane: acetone (10:1) and (9:1), receiving the result of the connection specified in the header (1.7 g) in the form of a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 6,98 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz), of 5.89 (m, 1H, in ), 5.25 (m, 2H, ), with 4.64 (d, 1H, 1H, H-1', J= 1.5 Hz), 4,15 (t, 1H, H-3', J=3.3 Hz), 4.09 to (m, 3H,),), a 3.87 (m , 1H, H-2'), 3,74 (m, 2H, H-5'), to 3.38 (dd, 1H, H-4', J=3.3 and 9 Hz), is 2.74 (t, 1H, H-1, J=3,9 Hz).

(1H, CDCl3): 9,73 (s, 1H, CHO), 7.24 to 7,44 (m, 15H, 3Ph), 6,98 (s, 1H, CO2CHPh2), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz) and 4.65 (d, 1H, H-1', J=1.2 Hz), 4,57 (AB system, 4'OCH2Ph, J=11,1 Hz), is 4.21 (m, 1H, H-3'), and 3,76 4,07 (2d, 2H, 8aCH2, J= 9 Hz), a 3.87 (m, 1H, H-2'), 3,76 (m, 1H, H-5'), 3,49 (dd, 1H, H-4', J=3.3 and 9 Hz), is 2.74 (t, 1H, H-1, J=3.6 Hz).

THE INTERMEDIATE CONNECTION 55

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2-O-Benzyloxycarbonyl-6 - deso is)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 48 (3 mmol) in dry dichloromethane (15 ml) at 0oC in an atmosphere of nitrogen was added 4-dimethylaminopyridine (6.3 mmol). After stirring for 15 minutes the mixture was cooled to -20oC and was added dropwise a solution of benzylbromide (3.6 mmol) in dry dichloromethane (15 ml). After 2 hours the solvent is evaporated and the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate (3:1) to deliver the connection specified in the header (1.2 g).

(1H, CDCl3): to 9.70 (s, 1H, CHO), 7,35 (m, 15H, 3xPh), of 6.96 (s, 1H, ), of 5.99 (dd, 1H, H-2, J=1.5 and 3.6 Hz), is 5.18 (AB system, 2H, J= 12 Hz), 5,00 (dd, 1H, H-2', J=1,5 and 4.2 Hz), 4,70 (d, 1H, H-1', J=1.8 Hz), 4,13 (m, 1H, H-3'), 4,01 and 3,66 (dd, 1H, 8a-CH2, J=9 Hz), of 3.75 (m, 1H, H-5'), 3,40 (s, 3H, OMe), 3,17 (dd, 1H, H-4', J=3.3 and an 8.4 Hz), 2,62 (t, 1H, H-1, J=3.6 Hz), 2,43 (d, 1H, OH, J=2.4 Hz), of 2.21 (m, 1H, ).

THE INTERMEDIATE CONNECTION 56

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Allyl-2-O-benzyloxy-carbonyl-6-deoxy- - D-atropinelike)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

To a solution of Intermediate 53 (1.4 g) in dry methylene chloride (30 ml) at 0oC was added dimethylaminopyridine (513 mg) and stirred is loride (15 ml) and the mixture was stirred for 4 hours. Then the mixture was diluted with methanol (1 ml) and methylene chloride (20 ml) and washed with water, 1N hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated until dry. The residue was purified by column chromatography rapid separation, elwira a mixture of hexane:ethyl acetate (7:1) and (5:1) to deliver the connection specified in the header (1.1 g).

(1H, CDCl3): to 9.70 (s, 1H, CHO), of 6.96 (s, 1H, ), of 5.99 (dd, 1H, H-2, J= 1.5 and 3.6 Hz), 5,88 (m, 1H, ), 5,20 (m, 4H, ), 4,99 (dd, 1H, H-2', J=1,5 and 4.2 Hz), 4,70 (d, 1H, H-1', J=1.5 Hz), of 4.12 (m, 1H, H-3')that is 4.03 (m, 3H), 3,76 (m, 1H, H-3'), to 3.64 (d, 1H, 8.7 Hz), to 3.34 (dd, 1H, H-4', J=3.3 and 8.7 Hz), 2,61 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 57

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Benzyl-2-O-benzyloxycarbonyl-6-deoxy- - D-atropinelike)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

To a solution of Intermediate 54 (3.7 g) in dry dichloromethane (25 ml) at 0oC in an atmosphere of nitrogen was added 4-dimethylaminopyridine (1.85 g). After stirring for 15 minutes the mixture was cooled to -20oC and was added dropwise a solution of benzylbromide (0.68 ml) in dry dichloromethane (10 ml) until such time as the product is not the current was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate (6:1) to deliver the connection specified in the header (3.6 g) in the form of a white foam.

(1H, CDCl3); to 9.70 (s, 1H, CHO), 7,26 - 7,42 (m, 20H, 4Ph), of 6.96 (s, 1H, ), of 5.99 (dd, 1H, H-2, J=1.2 and 3.3 Hz), is 5.18 (AB system, 2-OCO2CH2Ph, J=12.3 Hz), 5,00 (dd, 1H, H-2', J=1,5 and 4.2 Hz), 4,71 (d, 1H, H-1', J=1.5 Hz), 4,56 (AB system, 4 - J=11, 1 Hz), is 4.15 (m, 1H, H-3'), 3,66 and 4,00 (2d, 2H, 8aCH2, J=9 Hz), 3,81 (dq, 1H, H-5', J= 6.6 and 9 Hz), 3.43 points (dd, 1H, H-4', J=3.3 and 9 Hz), 2,60 (t, 1H, H-1, J=3.6 Hz).

THE INTERMEDIATE CONNECTION 58

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2-O-Benzyloxycarbonyl-6 - deoxy-4-O-methyl-3-O-tosyl- - D-atropinelike)methyl]-4 - formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A solution of Intermediate 55 (3 mmol) and 4-dimethylaminopyridine (5.1 mmol) in dry dichloromethane (60 ml) was treated dropwise with a solution of tosylchloramide (4.5 mmol) in dry dichloromethane (20 ml). After 24 hours, the solvent evaporated and the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate (5:1) and receiving

as a result, the connection specified in the header (1.8 g).

(1H, CDCl3): to 9.70 (s, 1H, CHO), 7,84 and to 7.32 (d, m, 2H, 17H, Ar) of 6.96 (s, 1H, ), 5,94 (dd, 1H, H-2, J=1,, ,76 (dd, 1H, H-5', J=6.3 and 8.1 Hz), 3,18 (dd, 1H, H-4', J=3 and 8.1 Hz), 3,05 (s, 3H, OMe), of 2.51 (t, 1H, H-1, J=3.6 Hz), 2,43 (s, 3H, ), a 2.01 (m, 1H, ).

THE INTERMEDIATE CONNECTION 59

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Allyl-2-O-benzyloxy-carbonyl-6-deoxy - 3-O-tosyl- - D-atropinelike)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid diphenylmethylene

To a solution of Intermediate 56 (1.1 g) and dimethylaminopyridine (300 mg) in dry methylene chloride (40 ml) was added dropwise a solution of tosylchloramide (400 mg) in dry methylene chloride (20 ml) and stirred the reaction mixture for 3 days at room temperature. The solvent was evaporated until dry and the residue was Chromatographically on a column of fast separation with silica gel, elwira a mixture of hexane:ethyl acetate (9:1) and (6:1) to deliver the connection specified in the header (820 mg).

(1H, CDCl3): to 9.70 (s, 1H, CHO), to 6.95 (s, 1H, ), 5,94 (dd, 1H, H-2, J= 1.5 and 3.9 Hz), 5,61 (m, 1H, ), 5,12 (m, 4H, ), 4,84 (dd, 1H, H-2', J=3 and 5.1 Hz), 4,69 (d, 1H, H-1, J=1,8 Hz), 3.96 points and 3,63 (2d, 2H, J= 9.0 Hz), 3,76 (m, 4H, H-3', H5', ), to 3.38 (dd, 1H, H-4', J=3 and 8.1 Hz), 2,50 (t, 1H, H-1, J=3,9 Hz), 2,42 (s, 3H ).

THE INTERMEDIATE CONNECTION 60

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Benzyl-2-O-benzyloxycarbonyl - 6-deoxy-3-O-tosyl- - D-atropinelike)methyl]-4-formyl - 4,4-a, 5,6 Toru Intermediate 57 (3.5 g) and dimethylaminopyridine (1.3 g) in dry methylene chloride (80 ml) was added dropwise a solution of tosylchloramide (2 g) in dry methylene chloride (50 ml) and the mixture was stirred for 3 days at room temperature. The solvent is evaporated and the residue was chromatographically on a column of fast separation with silica gel, using as eluent a mixture of hexane:ethyl acetate (9:1) to deliver the connection specified in the header (3,14 g).

(1H, CDCl3): to 9.70 (s, 1H, CHO), to 6.95 (s, 1H, ), 5,95 (dd, 1H, H-2, J is 1.2 and 3.3 Hz), 5,16 (m, 3H, H-2'), is 4.93 (dd, 1H, H-3', J-3 and 4.8 Hz), 4,71 (d, 1H, H-1', J=1.8 Hz), 4,25 (AB system, 2H, O-CH2Ph, J= 11.5 Hz), 3.96 points, 3,63 (2d, 2H, J 9.0 Hz), 3,83 (m, 1H, H-5'), of 3.45 (dd, 1H, H-4', J= 3 and 8.4 Hz), of 2.51 (t, 1H, H-1, J-3,9 Hz) to 2.35 (s, 3H, CH3-Ph).

THE INTERMEDIATE CONNECTION 61

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-4-O-methyl-3-O-tosyl- - D - atropinelike)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 58 (1.9 mmol) in ethyl acetate (60 ml) under nitrogen atmosphere was added 10% palladium on coal (100 mg). The mixture was shaken in a Parr apparatus under 15 psi of hydrogen for 1 hour at room temperature. The catalyst was filtered, and the solution was treated with 0.35 M solution diphenyldiazomethane (20 ml). After 2 hours the solvent is evaporated and the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate (3:1), and receiving in re the), 6,98 (s, 1H, ), the 6.06 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 4,84 (dd, 1H, H-3', J=3 and 4.2 Hz), with 4.64 (d, 1H, H-1', J 1.5 Hz), 4.06 and a 3.75 (2d, 2H, 8a-CH2, J=9,3 Hz), was 4.02 (m, 1H, H-2'), 3,70 (m, 1H, H-5'), and 3.16 (dd, 1H, H-4', J=3 and 9 Hz), with 2.93 (s, 3H, OMe), 2,69 (t, 1H, H-1, J=3,9 Hz), a 2.45 (s, 3H ), 2,30 (d, 1H, OH, J=3 Hz), of 2.23 (m, 1H, ).

THE INTERMEDIATE CONNECTION 62

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-4-O-propyl-3-O-tosyl- - D-atropinelike)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 59 (800 mg) in ethyl acetate (200 ml) under nitrogen atmosphere was added 10% palladium on coal (300 mg). The mixture was shaken in a Parr apparatus under 20 psi of hydrogen for 1 hour at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was dissolved in methylene chloride (50 ml) and was added dropwise 0.35 M solution diphenyldiazomethane (6 ml). The mixture was stirred at room temperature for 3 hours. The solvent is evaporated and the residue was chromatographically on a column of fast separation with silica gel, elwira a mixture of hexane: ethyl acetate (8:1) and (3:1) to deliver the connection specified in the header (630 mg).

(1H, CDCl3): 9,72 (s, 1H, CHO), 6,98 (s, 1H, ), the 6.06 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 4,84 (dd, 1H, H-2', J=3 and 4s).

THE INTERMEDIATE CONNECTION 63

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Benzyl-6-deoxy-3-O-tosyl- - D - atropinelike)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate 60 (1.0 g) in ethyl acetate (70 ml) under nitrogen atmosphere was added 10% palladium on coal. The mixture was shaken in a Parr apparatus under 15 psi of hydrogen for 4 hours at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was purified by Chromatography rapid separation on silica gel, elwira a mixture of hexane:ethyl acetate (3:1) and (1:1). The appropriate fractions were combined and the solvent is evaporated, resulting in the connection specified in the header (530 mg).

(1H, CDCl3): to 9.70 (s, 1H, CHO), 7,81 and 7.10-7,30 (2m, 9H, Ts and Ph), between 6.08 (dd, 1H, H-2, J is 1.5 and 3.3 Hz), 4,91 (dd, 1H, H-3', J=3.3 and 4.5 Hz), and 4.68 (d, 1H, H-1', J 1.5 Hz), 4,12 (m, 3H, H-2'), 4.06 and to 3.64 (2d, 2H, J= 9,3 Hz), 3.46 in (m, 1H, H-4'), to 2.65 (m, 1H, H-1), a 2.36 (s, 3H, Ts).

THE INTERMEDIATE CONNECTION 64

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2.3-Anhydrous-6-deoxy-4-O - methyl - D-mannopyranoside)methyl] -4-formyl-4,4 a, 5,6,7,7 a 8.8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

The suspension of the hydride naenia 61 (1.6 mmol) in dry dimethylformamide (6 ml). After 40 minutes was added a mixture of water: acetic acid ethyl ester (III, 60 ml). The organic phase is evaporated and the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate (4:1) to deliver the connection specified in the header (960 mg), having a proton NMR spectrum identical to the spectrum of the Intermediate 50.

THE INTERMEDIATE CONNECTION 65,

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-6-deoxy-4-O-propyl - D-mannopyranoside)methyl] -4-formyl-4,4 a, 5,6,7,7 and,8,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a suspension of sodium hydride (35 mg) in dry dimethylformamide (10 ml) was added dropwise a solution of Intermediate 63 (600 mg) in dry dimethylformamide (15 ml). The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour, and then was treated with 1N ammonium chloride (50 ml) and ethyl acetate (70 ml). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated until dry. The residue was chromatographically on a column of fast separation with silica gel, elwira a mixture of hexane: ethyl acetate (8:1) and (6:1) to deliver the connection specified in the header (450 m is 3,79 (2d, 2H, 8a-CH2, J=9.0 Hz), 3,68 (m, 1H, H-5'), of 3.45 (m, 1H, H-4'), 3,24 and 3.12 (2d, 2H, H-2', H-3', J= 3.9 Hz), 3,19 (t, 2H, J=7 Hz), 2,86 (t, 1H, H-1, J=3,9 Hz).

INTERMEDIATE COMPOUND 66

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3-O-tosyl- - D - atropinelike)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid

To a suspension of 10% palladium on coal (800 mg) in ethyl acetate (60 ml) in a hydrogenation flask under nitrogen atmosphere was added a solution of Intermediate 60 (1.0 g) in ethyl acetate (30 ml) and the mixture methanol; 1N hydrochloric acid (3:1; 4 ml). The flask was shaken in a Parr apparatus for hydrogenation under hydrogen pressure of 30 psi for 18 hours. The reaction mixture was filtered, and the filtrate was evaporated until dry. The residue was purified by column chromatography rapid separation on silica gel, elwira a mixture of dichloromethane: methanol (20:1). The appropriate fractions were combined and the solvent is evaporated, resulting in the connection specified in the header (380 mg).

(1H, CDCl3): to 9.70 (s, 1H, CHO), 7,84 and 7,38 (2d, 4H, Ts), the 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), and 4.75 (dd, 1H, H-3', J=3.3 and 4.5 Hz), br4.61 (d, 1H, H-1', J=1.2 Hz), of 4.05 (d, 1H, H-8aCH2a, J=9,3 Hz) to 3.92 (dd, 1H, H-2', J=1.2 and 4.5 Hz), the 3.65 (m, 3H, H-5', H-4' and H-8aCH2b) 2,63 (m, 1H, H-1), the 2.46 (s, 3H, Ts).

Promezhutochnaya-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid diphenylmethylene ether

A solution of Example 55 (585 mg) in dry dichloromethane (20 ml) was treated dropwise with a purple solution diphenyldiazomethane in dichloromethane (0.35 M, 8 ml). The resulting solution was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography rapid separation on silica gel, elwira a mixture of hexane: ethyl acetate (6: 1) and (4:1). The appropriate fractions were combined and evaporated, resulting in the connection specified in the header (764 mg) as a white foam.

(1H, CDCl3): of 9.75 (s, 1H, CHO), 7,26-7,44 (m, 10H, 2Ph), 7,00 (s, 1H, ), 6,09 (dd, 1H, H-2, J=1.2 and 3.6 Hz), 4,71 (s, 1H, H-1'), 3,79 and 4.12 (2d, 2H, 8aCH2, J=9,3 Hz), 3,63 (dd, 1H, H-4', J=5.7 and 8.7 Hz), 3,21 (m, 1H, H-5') and 3.15 and 3.24 in (2d, 2H, H-2' and H-3', J=3.6 Hz), 2,86 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 68

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-4,6-dideoxy-4-fluorescent- - D - teleperedachi)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A solution of Intermediate 67 (300 mg) in dichloromethane (25 ml) was treated with the TRIFLUORIDE diethylaminoethyl (0.16 ml), the mixture was stirred over night at room temperature. The mixture was cooled to 0o

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-7,26 (m, 10H, 2Ph), 6,98 (s, 1H, ), 6,09 (dd, 1H, H-2, J=1.5 and 3.9 Hz), 5,09 (d, 1H, H-1', J=1.5 Hz), 4.75 V and 4,58 (2dq, 1H, H-5', J5'F=48.6 Hz; J=6,6 Hz, J=3,9 Hz), 4,18 and 4,11 (2d, 1H, H-4', J4'F=23.1 Hz, J=3,9 Hz), 3,97 and 3,81 (2d, 2H, 8aCH2, J=9,3 Hz) of 3.75 and 3.70 (2m, 2H, H-2' and H-3'), 2,84 (t, 1H, H-1).

THE INTERMEDIATE CONNECTION 69

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-6-deoxy-4-O-(2-methoxyethyl)- - D-mannopyranoside)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a suspension of sodium hydride (24 mg) in dry tetrahydrofuran (20 ml) at 0oC in an atmosphere of nitrogen was added Intermediate compound 67 (300 mg) and the resulting mixture was stirred for 30 minutes. Was added 2-Bromatology ester (300 mg) and 1N tetrabutylammonium (2 ml) and warmed up the mixture for 2 days at 40oC. the Reaction was suppressed 1N ammonium chloride (10 ml) and the mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated until dry. The residue was chromatographically on a column of fast separation with silica gel, elwira a mixture of hexane:ethyl acetate (5:1) to deliver the compound H-2, J=1.2 and 3.3 Hz), 4,67 (s, 1H, H-1'), 4,10 and of 3.78 (2d, 2H, 8a-CH2, J=9.0 Hz), 4.09 to 4,00 (m, 2H, H-4', H-5'), 3,90-of 3.53 (m, 4H, ), 3,40 (s, 3H ), 3,29 and 3,11 (2d, 2H, H-3' and H-2', J=3.9 and 3.9 Hz), 2,86 (t, 1H, H-1, J=3,7 Hz).

THE INTERMEDIATE CONNECTION 70

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2. 3-Anhydrous-6-deoxy-4-O-(2-methylprop-2-enyl)- - D-mannopyranoside)methyl] -4-formyl-4,4 a,5,6,7,7 a, 8,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A mixture of intermediate 67 (0.3 mmol), cesium carbonate (0.3 mmol) and 3-bromo-2-methyl-propene (0.5 mmol) in dry dimethylformamide (1.5 ml) was stirred for 3 days at room temperature. After dilution with diethyl ether (30 ml) and the mixture was washed with water. The solvent is evaporated and the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate (4:1) to deliver the connection specified in the header (62 mg).

(1H, CDCl3): of 9.75 (s, 1H, CHO), 7,35 (m, 10H, 2xPh), of 6.99 (s, 1H, ), between 6.08 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 5.00 and is 4.93 (m,m, 1H, 1H, CH2= C), 4,70 (s, 1H, H-1'), 4,12 and with 3.79 (2d, 2H, 8a-CH2, J=9,3 Hz), 4,12 vs. 3.96 (d, d, 1H, 1H, CH2O, J=12 Hz), 3,26 (m, 3H, H-3', H-4' and H-5'), 3,13 (d, 1H, H-2', J=3.9 Hz), 2,86 (t, 1H, H-1, J=3,9 Hz), of 2.23 (m, 1H, ).

THE INTERMEDIATE CONNECTION 71

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-6-deoxy-4-O-(1-meth is ndacan-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 67 (160 mg) in dry

dichloromethane (5 ml) was added 4-dimethylaminopyridine (70 mg) and isobutyrate (60 μl). The mixture was stirred over night at room temperature, and then concentrated to obtain yellow oil, which was chromatographically on a column of fast separation with silica gel using as solvent a mixture of hexane:ethyl acetate (5:1) to deliver the connection specified in the header (162 mg) as a white foam.

(1H, CDCl3): 9,75 (5, 1H, CHO), 7,26-7,44 (m, 10H, 2Ph), of 6.99 (s, 1H, ), between 6.08 (dd, 1H, H-2), of 5.75 (s, 1H, H-1'), and 4.68 (d, 1H, H-4', J=9 Hz), 4,12 and of 3.80 (2d, 2H, J=9 Hz), 3.43 points (dq, 1H, H-5', J=6.6 and 9 Hz), 3.15 in (s, 2H, H-2' and H-3'), of 2.86 (m, 1H, H-11), at 2.59 (m, 1H, 4'- ).

THE INTERMEDIATE CONNECTION 72

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-6 - deoxy-4-O-(2,2-dimethylpropionic)- - D-mannopyranoside) methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1 - methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A mixture of Intermediate 67 (0.3 mmol) and 4-dimethylaminopyridine (0.6 mmol) in dry dichloromethane (15 ml) was treated with the acid chloride trimethylhexanoic acid (0.45 mmol). After 2.5 hours the mixture was washed with water. The organic phase is evaporated and the residue was purified by a colon is the result of the connection, specified in the header (190 mg).

(1H, CDCl3): 9,76 (s, 1H, CHO), 7,83 (m, 10H, 2xPh), 7,00 (s, 1H, ), between 6.08 (dd, 1H, H-2, J=1.5 and 3.3 Hz), of 4.77 (s, 1H, H-1'), of 4.67 (d, 1H, H4', J= 9 Hz), 4,13 and 3,81 (d,d, 1H, 1H, 8a-CH2, J=9 Hz), 3.43 points (m, 1H, H5'), of 3.13 (m, 2H, H-2' and H-3'), of 2.86 (t, 1H, H-1, J=3,9 Hz), 2,24 (m, 1H, ).

THE INTERMEDIATE CONNECTION 73

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-4-O-benzyloxy-carbonyl-6 - deoxy- - D-mannopyranose)methyl]-4-hornil-4,4 a,5,6,7,7 a,8, 8A-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid diphenylmethylene ether

A solution of Intermediate 67 (0.3 mmol) and 4-diethylaminopentane (0.8 mmol) in dry dichloromethane (15 ml) was treated dropwise with benzyloxycarbonylamino (0.7 mmol) and was stirred for 3 hours. After washing with water and brine, the solvent evaporated and the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane: ethyl acetate (5:1) to deliver the connection specified in the header (185 mg).

(1H, CDCl3): of 9.75 (s, 1H, CHO), 7,32 (m, 15H, 3xPh), of 6.99 (s, 1H, ), between 6.08 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 5,20 (m, 2H ), 4.72 in (s, 1H, H-1'), of 4.57 (d, 1H, H-4', J=8,4 Hz), 4,11 and with 3.79 (2d, 2H, 8a-CH2, J=9 Hz), 3.43 points (m, 1H, H-5'), 3.27 and 3.15 in (2d, 2H, H-2' and H-3', J=3.6 Hz), 2,85 (t, 1H, H-1, J=3,9 Hz), 2,24 (m, 1H, ).

THE INTERMEDIATE CONNECTION 74

[1R- (1,3 a,4,4 a, is later)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

The solution triperoxonane anhydride (0.1 ml) in dry dichloromethane (5 ml) at -60oC was treated dropwise dimethylsulfoxide (0.06 ml) and a solution of Intermediate 67 (0,39 mmol) in dry dichloromethane (5 ml). After 60 minutes was added triethylamine (0,24 ml) and the mixture was stirred at -20oC for 2 hours. The mixture was diluted with dichloromethane (20 ml) and washed with water. After removal of solvent the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate (4:1) to deliver the connection specified in the header (171 mg).

(1H,CDCl3): 9,76 (s, 1H, CHO), was 7.36 (m, 10H, 2xPh), 6,59 (s, 1H, ), 6,09 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,84 (s, 1H, H-1'), 4,11 and 3,84 (2d, 2H, 8a-CH2, J=9 Hz), 3,92 (q, 1H, H-5', J=6.9 Hz), 3,59, and 3,37 (2d, H-2' and H-3', J=4, 2 Hz), 2,86 (t, 1H, H-1, J=3,9 Hz), and 2.26 (m, 1H, ).

THE INTERMEDIATE CONNECTION 75

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2-O-Benzoyl-6-deoxy-4-O-methyl - D - atropinelike)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 48 (15,88 g) and dimethylaminopyridine (8,83 g) in dry dichloromethane (200 ml) at - 20oC in an atmosphere of nitrogen was added dropwise a benzoyl chloride (2 ml) in dry d is Yanou acid (10 ml). The two phases were separated and the organic layer was diluted with dichloromethane (600 ml) and washed with 1N hydrochloric acid (500 ml), 10% sodium bicarbonate (500 ml) and brine (500 ml). The solvent was removed to dry condition and was received in the oil, which was subjected to chromatography rapid separation (silica gel, ethyl acetate:hexane/1:20 and 1: 7), receiving the result of 8.75 g of compound indicated in the heading output 48%), in the form of foam.

1H, CDCl3): to 9.66 (s, 1H, CHO), 8,15-8,05, 7,60- 7,2 (dd, 15H, 3Ph), to 6.95 (s, 1H, CHPh2), 5,93 (bd, 1H, H2, J=2.1 Hz), to 5.35 (dd, 1H, H2', J=1.5 and 4.8 Hz), 4,82 (d, 1H, H1', J=1.8 Hz), 4,25 (m, 1H, H3'), 3,99 (d, 1H, 8aCH2, J= 9 Hz), 3,86 (dq, 1H, H5', J=6.3 and 8.1 Hz), 3,68 (d, 1H, 8aCH2, J=9 Hz), 3.43 points (s, 3H, OCH3), up 3.22 (dd, 1H, H4', J=3 and 8.1 Hz), 2,62 (t, 1H, H1, J=3,9 Hz), a 2.45 (d, 1H, OH, J=2.4 Hz), 2,19 (m, 1H, CH(CH3)2).

THE INTERMEDIATE CONNECTION 76

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2-O-Benzoyl-3,6-dideoxy-4-O-methyl-3-oxo - D-allopregnanolone)methyl] -4-foriel-4,4 a, 5,6,7,7 a,8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid diphenylmethylene ether

To a solution of triperoxonane anhydride (1,29 ml) in dry dichloromethane (15 ml) for 10 minutes in a nitrogen atmosphere at -60oC was added DMSO (0,66 ml). To the resulting suspension was added a solution of Intermediate d the triethylamine (5,76 ml), brought the temperature to -20oC, and then the formed yellow solution was added water (6 ml) and the mixture was stirred at room temperature for 1 hour. Added dichloromethane (200 ml) and water (200 ml) and separated phases. The organic layer was dried over magnesium sulfate and concentrated until dry, give crude product, which was dissolved in Dichloromethane (10 ml) and treated with triethylamine (2 ml) overnight. After removal of the solvent was obtained an oil which was subjected to chromatography rapid separation (silica gel, ethyl acetate:hexane/1:15 and 1:10), receiving the result of 2.6 g of compound indicated in heading (yield 76%) as a foam.

(1H, CDCl3): 9,68 (s, 1H, CHO), 8,2-8,0, 7,6- 7,2 (2m, 15H, 3Ph), of 6.96 (s, 1H, CHPh2), USD 5.76 (dd, 1H, H2, J=1.2 and 3.3 Hz), 5,77 (dd, 1H, H2, J=1.2 and 3.3 Hz), of 5.39 (dd, 1H, H2', J=1.2 and 8.1 Hz), a 4.53 (d, 1H, H1', J= 8.1 Hz), 4.09 to (d, 1H, 8aCH2, J=9 Hz in), 3.75 (d, 1H, 8aCH2, J=9 Hz), 3,7-3,4 (m, 5H, H4'+OCH3+H5'), 2,63 (t, 1H, H1, J=4,2 Hz).

THE INTERMEDIATE CONNECTION 77

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3,6-Trideoxy-4-O-methyl-3-oxo - D-allopregnanolone)methyl] -4-formyl-4,4 a,5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin - 3a(1H)-carboxylic acid diphenylmethylene ether

The well-degassed solution (Ar, 15 minutes) hydride t Intermediate 76 (5.7 g) and a,a'-azoisobutyronitrile (420 mg) in dry toluene. Heating was continued until completion of the reaction, and then the mixture was cooled to room temperature. Was added water (40 ml) and potassium fluoride (1.5 g) and stirred the mixture overnight. The crude product obtained after removal of solvent, was mixed with diethyl ether for 1 hour, the solid phase was removed by filtration. The ether solution was concentrated until dry, and the resulting oil was subjected to chromatography rapid separation (silica gel, ethyl acetate:hexane 1:15 and 1;10), receiving the 2,22 g of compound indicated in heading (yield 61%), in the form of a foam after vacuum drying.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), 6,98 (s, 1H, CHPh2), 6,04 (dd, 1H, H2, J=1.5 and 3.6 Hz), of 4.45 (dd, 1H, H1', J=2.7 and 8.7 Hz), 4,06 (d, 1H, 8aCH2, J=9 Hz), 3,70 (d, 1H, 8aCH2, J=9 Hz), 3,52 (s, 3H, OCH3), 3,5-3,3 (m, 2H, H4'+H5'), 2,7-2,5 (m, 3H, H1+H2'), 2,24 (m, 1H, CH(CH3)2)

THE INTERMEDIATE CONNECTION 78

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S, 7R,9R)-2,8-Dioxa-9-methyl - bicyclo[3.4.0] non-4-EN-7-yl-oxymethyl] -4-formyl-4,4 a,5,6,7, 7a,8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To intensively peremalyvavshaya solution of Intermediate 77 (260 mg) and diethyldithiophosphate (110 mg) in dry tetrahydrofuran at 0

(1H, CDCl3); of 9.75 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), of 6.99 (s, 1H, CHPh2), equal to 6.05 (dd, 1H, H2, J=1.2 and 3.3 Hz), the 5.45 (m, 1H, H4') and 4.65 (m, 2H, H3'), 4,25-to 4.15 (m, 2H, H7'+H1'), 4,07 (d, 1H, 8aCH2, J=9 Hz), 3,71 (d, 1H, 8aCH2, J= 9 Hz), 3,19 (dq, 1H, H9', J=6 and 8.4 Hz), 2,77 (t, 1H, H1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 79

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S,4R,7R,9R)-2,8-Dioxa-4-hydroxy - 9-methyl-CIS-bicyclo[3.4.0] non-7-yl-oxymethyl]-4-hydroxymethyl - 4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 78 (620 mg) in anhydrous tetrahydrofuran (5 ml) under nitrogen atmosphere was added 9-borabicyclo [3,3,1]nonan (0.5 M solution in tetrahydrofuran, 6 ml). The mixture was let warm up at 50oC for 1 hour. Then at the 50oC for 3 hours was added solution volume 9 berbisik is. storage was added ethanol (2 ml) (gas evolution) and the stirred solution over 1 hour. Then at 0oC was added 3N sodium hydroxide (5 ml) and hydrogen peroxide (35% V/V, 5 ml) and stirred the mixture at room temperature, at 0oC and at 70oC during the night. The resulting solution was cooled to room temperature and concentrated to half of its original volume, then diluted with 1N hydrochloric acid (100 ml) and was extracted twice with ethyl acetate (2x200 ml). The organic layer is washed with 1N hydrochloric acid (100 ml), sodium bicarbonate (2x100 ml) and brine (100 ml), dried over sodium sulfate and concentrated until dry, resulting in the syrup, which was subjected to chromatography rapid separation (acetone:hexane 1: 10 and 1:5), receiving the result of 475 mg of the compound indicated in heading (yield 74%), in the form of foam.

(1H, CDCl3): of 7.5 to 7.2 (m, 10H, 2Ph),? 7.04 baby mortality (s, 1H, CHPh2), 5,90 (dd, 1H, H2, J=1.5 and 3.6 Hz), and 4.75 (d,1H, J=10.5 Hz), to 4.62 (dd, 1H, H7', J=2.7 and 5.1 Hz), 4,27 (m, 1H, H4'), 4,16 (d, 1H, 8aCH2, J=9 Hz), 4.09 to (dd, 1H, H3', J=6 and 9.6 Hz), 3,91 (t, 1H, H3', J=6.9 Hz), 3,7-3,5 (m, 3H, 8aCH2+H1'+H9'), to 3.35 (d, 1H, HOCH2, J=11.5 Hz), up 3.22 (dd, 1H, HOCH2, J=11.1 and 12 Hz), 2.57 m (t, 1H, H1, J=4.5 Hz), 2,48 (m, 1H, H5'), is 2.30 (m, 1H, CH(CH3)2).

The INTERMEDIATE CONNECTION is oxymethyl] - 4,4 a, 5,6,7,7 a,8,8 and octahydro-7-methyl-3-(1-methyl-ethyl)-1,4-methane - s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 78 (200 mg) in tetrahydrofuran (5 ml) was added solid Brewtality sodium (18,9 mg) and water (1 ml), the mixture was stirred at 0oC for 30 minutes and then 1 hour at room temperature. The mixture was carefully suppressed by the addition of water (2 ml) at 0oC and fractionally between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over magnesium sulfate and concentrated until dry, resulting in the syrup, which was dissolved in dry dimethylformamide (5 ml) and treated overnight at room temperature in a nitrogen atmosphere by imidazole (204 mg) and tert-butyl - dimethyl-silingardi (316 mg). The solution was poured into 100 ml of a mixture of 1N ammonium chloride and ethyl acetate (1:1) and was stirred for 1 hour. The organic layer is washed with 1N ammonium chloride (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated until dry, resulting in the foam, which was subjected to chromatography rapid separation (silica gel, ethyl acetate:hexane/1:20), receiving a result of 215 mg of the compound indicated in heading (total yield 92%).

2+H7'+H1'), 4,1 (d, 1H, 8aCH2, J=9,3 Hz), 3,69 (d, 1H, SiOCH2, J=9 Hz), 3,30 (d, 1H, 8aCH2, J=9,3 Hz), 3,19 (dq, 1H, H9', J=6 and 9 Hz), 2,68 (dd, 1H, H6', J=2 and 13.2 Hz), 2.57 m (t, 1H, H1, J=4,2), 2,3 (m, 2H, CH(CH3)2+H6'), -0,017 and -0,03]. (2s, 6H, (CH3)2Si).

THE INTERMEDIATE CONNECTION 81

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S, 4R, 7R, 9R)-2,8-Dioxa-hydroxy - 9-methyl-CIS-bicyclo[3.4.0] non-7-yl-oxymethyl] -4-[tert-butyl dimethylsilane-oxymethyl] -4,4 a, 5,6,7,7 a,8,8 and octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 80 (700 mg) in dry tetrahydrofuran (5 ml) under nitrogen atmosphere was added 9-borabicyclo [3,3,1] nonan (0.5 M solution in tetrahydrofuran, 6 ml). The mixture was heated to 50oC for 1 hour. Within 3 hours to complete the reaction at 50oC added additional volume 9 - borabicyclo[3,3,1] nonane, and then the mixture was cooled to room temperature and carefully added ethanol (2 ml). After 1 hour at 0oC was sequentially added 3N sodium hydroxide (5 ml) and hydrogen peroxide (35% V/V, 5 ml), the mixture was stirred at room temperature for 1 hour and overnight at 70oC. the Solution was cooled to room temperature and concentrated to half the original volume, staminali 1N hydrochloric acid (100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated until dry, resulting in the syrup, which was subjected to chromatography rapid separation (acetone:hexane 1:20 and 1:15), to deliver 550 mg (yield 77%) of the compound indicated in the title, in the form of a white foam.

(1H, CDCl3): of 7.5 to 7.2 (m, 10H, 2Ph), 6,94 (s, 1H, CHPh2), 5,95 (m, 1H, H2), of 4.57 (dd, 1H, H7', J= 3 and 5.1 Hz), 4,30-to 4.15 (m, 2H, H4'+CH2OSi), 4,10-3,95 (m, 2H, H3'+8aCH2), a 3.87 (t, 1H, H3', J=6.9 Hz), 3,7 - 3,5 (m, 3H, H1+8aCH2+H9'), 3,30 (d, 1H, CH2OSi, J=9,3 Hz), 2,53 (t, 1H, H1, J= 3,9 Hz), 2,46 (m, 1H, H5'), 2,32 (m, 1H, CH(CH3)2), -0,016 and -0,029 (2s, 6H, (CH3)2Si).

THE INTERMEDIATE CONNECTION 82

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S, 4R,7R,9R)-2,8-Dioxa-4-methoxy-9-methyl - CIS-bicyclo[3.4.0] non-7-yl-oxymethyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 81 (537 mg) in anhydrous tetrahydrofuran (5 ml) in small portions under nitrogen atmosphere at 0oC was added sodium hydride (75 mg). After stirring for 10 minutes was added matroidal (374 μl) and leaving the mixture at room temperature until completion of the reaction. The mixture was suppressed by addition of water (100 MLA dry condition, getting in the foam, which was dissolved in anhydrous THF (5 ml) and 4 0oC for 24 hours were treated with tetrabutylammonium (1.1 M solution in tetrahydrofuran, 2 ml). The resulting solution was concentrated until dry and the residue was dissolved in Acoet and washed with water (2x100 ml), dried over magnesium sulfate and concentrated, resulting in the syrup, which was dissolved in dry dichloromethane 85 ml). Added chloromethylpyridine (215 mg) and the mixture was stirred at room temperature until completion of the reaction. The suspension was poured into a well peremalyvavshaya a mixture of dichloromethane and sodium metabisulfite (10% aqueous solution). The organic layer is washed with 1N hydrochloric acid (200 ml) and 1N sodium hydroxide (200 ml), dried over magnesium sulfate and con centered until dry, getting in the oil, which was subjected to chromatography rapid separation on silica gel (ethyl acetate:hexane 1:15, 1:10 and 1:8), receiving the result of 255 mg of the compound indicated in the title, in the form of oil (total yield 57%).

(1H, CDCl3): 9,74 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), of 6.99 (s, 1H, CHPh2), 6,04 (dd, 1H, H2, J=1.2 and 3.6 Hz), 4,60 (m, 1H, H7'), 4,10-3,95 (m, 2H, H4'+8aCH2), 3,90-the 3.65 (m, 3H, H3'+H1'), 3,65-3,55 (m, 2H, 8aCH2+H9'), 3,35 (5, 3H,OCH3), 2,73 (t, 1H, H1, J=3,6 who hydroxy-4-O-methyl- - D-atropinelike) methyl] -4-(1,3-dioxolane-2-yl)-4,4-a, 5,6,7,7 a, 8, 8a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid diphenylmethylene ether

A solution of Intermediate 48 (9.7 mmol) in dry methanol (40 ml) was treated with ethylene glycol (110 ml), triethylorthoformate (3,25 ml) and a catalytic amount of p-toluensulfonate acid. The mixture was let warm up at 40oC for 3 hours. After cooling, the mixture was poured into a mixture of ethyl acetate: water sodium bicarbonate (1:1; 500 ml), the aqueous layer was thoroughly extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried. After removal of solvent the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane: ethyl acetate (6: 1) to deliver the connection specified in the header (6,1 g).

(1H, CDCl3): 7,43 and 7,30 (m,m, 4H, 6H, 2xPh), 6,94 (s, 1H, ), of 5.83 (dd, 1H, H-2, J=1.2 and 3.6 Hz), 5,07 (s, 1H, 4-CH), 4,63 (d, 1H, H1', J= 1.5 Hz), 4,20 (t, 1H, H-3, J=3.3 Hz), 4,07 (d, 1H, 8a-CHa, J=9.3 Hz), a-3.84 (m, 6H, H-2', 8a-CHb and OCh2CH2O), 3,71 (m, 1H, H-5'), 3,42 (s, 3H, OCH3), 3,21 (dd, 1H, H-4', J=3 and 9 Hz), 2.63 in (m, 1H, ), of 2.54 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 84

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2-O-Benzoyl-6-deoxy-4-O-methyl - D-ultraparadoxical diphenylmethylene ether

To a solution of Intermediate 83 (12,12 g) and dimethylaminopyridine (6.3 g) in dry dichloromethane (155 ml) dropwise at -20oC in an atmosphere of nitrogen was added benzoyl chloride (1,40 ml) in 50 ml of dry dichloromethane. After stirring for 2 hours the mixture was left to warm to room temperature, the solution was washed with 0.1 N hydrochloric acid (500 ml), saturated sodium bicarbonate (500 ml) and brine (500 ml). After removal of the solvent was obtained residue, which was subjected to chromatography rapid separation (silica gel, ethyl acetate:hexane/1:4), receiving the result of 5.89 g of compound specified in head (42%), in the form of foam.

(1H, CDCl3): 8,14-8,05, 7,6-7,2 (2m, 15H, 3Ph), 6,91 (s, 1H, CHPh2), 5,70 (bd, 1H, H2, J=2.1 Hz), of 5.34 (dd, 1H, H2', J=2.1 and 5.1 Hz), free 5.01 (s, 1H, OCHO), 4,82 (d, 1H, H1', J=1.8 Hz), 4.26 deaths (m, 1H, H3'), 3,98 (d, 1H, 8aCH2, J=9,3 Hz), 3,92-3,74 (m, 5H, H5'+OCH2CH2O), and 3.72 (d, 1H, 8aCH2, J=9,3 Hz), 3,42 (s, 3H, OCH3), 3,23 (dd, 1H, H4', J=3.3 and 8.1 Hz), 2.57 m (m, 1H, CH(CH3)2), 2,44-of 2.38 (m, 2H, OH+H1).

THE INTERMEDIATE CONNECTION 85

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2-O-Benzoyl-3,6-dideoxy - 4-O-methyl-3-oxo - D-allopregnanolone)methyl] -4-[1,3 - dioxolane-2-yl)-4,4-a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1 - methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene

To a solution of the three is balali DMSO (0,23 ml). To the thus obtained suspension was added a solution of Intermediate 84 (1.2 g) in dry dichloromethane (5 ml), the mixture was stirred at -60oC for 1 hour. Added by drop wise addition of triethylamine (1,24 ml), brought the temperature to -20oC, then to the resulting yellow solution was added water (2 ml) and the resulting mixture was stirred at room temperature for 1 hour. Added dichloromethane (200 ml) and water (250 ml) and separated phases. The organic layer was dried over magnesium sulfate and concentrated until dry, resulting in the crude product, which was dissolved in dichloromethane (10 ml) and treated with triethylamine (2 ml) overnight. After removal of the solvent was obtained an oil which was subjected to chromatography rapid separation (silica gel, ethyl acetate:hexane/1:15 and 1:10), resulting in the 1.1 g of the compound indicated in heading (yield 92%), in the form of a foam, which was then dried under vacuum.

1H, CDCl3): 8,2-8,0, 7,6-7,2 (2m, 15H, 3Ph), of 6.90 (s, 1H, CHPh2), to 5.57 (dd, 1H, H2, J=1.2 and 3.6 Hz), lower than the 5.37 (dd, 1H, H2', J=1.5 and 8.1 Hz), of 5.05 (s, 1H, OCHO) to 4.52 (d, 1H, H1', J=8.1 Hz), 4,08 (d, 1H, 8aCH2, J= 8.7 Hz), from 3.9 to 3.7 (m, 5H, OCH2CH2O+8aCh2), 3,6-3,4 (m, 5H, H4'+OCH3+H5'), 2,62 (m, 1H, CH(CH3)2), 2,43 (t, 1H, H1, J=3,9 Hz).

Prolixly-2 - yl)-4,4-a,5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1 - methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

The well-degassed solution (Ar, 15 minutes) anti-hydride (263 μl) in dry toluene (10 ml) at 90oC for 1 hour by means of a syringe was added a solution of Intermediate 85 (250 mg) and a,a'-azoisobutyronitrile (16 mg) in dry toluene (5 ml). Heating was continued until completion of the reaction, the mixture is then cooled to room temperature. Was added water (5 ml) and potassium fluoride (100 mg) and stirred the mixture overnight. The crude product obtained after removal of solvent, was mixed with diethyl ether for 1 hour, the solid phase was removed by filtration. The ether solution was concentrated until dry, and the resulting oil was subjected to chromatography rapid separation (silica gel, ethyl acetate: hexane 1: 15 and 1:10), to deliver 168 mg of the compound indicated in heading (yield 80%), in the form of foam during vacuum drying.

(1H, CDCl3): of 7.6 and 7.1 (m, 10H, 2Ph), 6,92 (s, 1H, CHPh2), 5,80 (dd, 1H, H2, J=0.9 and 3.6 Hz), to 5.08 (s, 1H, OCHO), of 4.44 (dd, 1H, H1', J=2.7 and 8.7 Hz), of 4.05 (d, 1H, 8aCH2, J=9,3 Hz), from 3.9 to 3.7 (m, 5H, OCH2CH2O+8aCH2), 3,50-3,30 (m, 2H, H5'+H4'), 2,5-2,1 (m, 3H, H2'+CH(CH3)2), 2,50 (t, 1H, H1, J=4.5 Hz).

P is[1,3-dioxolane-2 - yl] -4,4-a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To intensively peremalyvavshaya solution of Intermediate 86 (160 mg) and diethyl-diazomethyl-phosphonate (63 mg) in dry tetrahydrofuran was slowly added at 0oC in nitrogen atmosphere, the suspension of tert-butoxide potassium (100 mg) in dry tetrahydrofuran (2.3 ml) (watched immediate evolution of gas). After 10 minutes, the mixture was diluted with dichloromethane (100 ml) and washed with 1N hydrochloric acid (2x100 ml), saturated sodium bicarbonate (2x100 ml), brine (2x100 ml) and immediately dried over magnesium sulfate. After removal of the solvent was obtained an oil which was subjected to chromatography rapid separation (silica gel, ethyl acetate:hexane/1:15 and 1:12), resulting in the 110 mg of the compound indicated in heading (yield 70%), in the form of foam.

1H, CDCl3): of 7.5 to 7.2 (m, 10H, 2Ph), 6,94 (s, 1H, CHPh2), of 5.83 (dd, 1H, H2, J= 1.2 and 3.3 Hz), of 5.53 (m, 1H, H4'), is 5.06 (s, 1H, OCHO) and 4.65 (m, 2H, H3'), 4.25 in-4,10 (m, 2H, H7'+H1'), of 4.05 (d, 1H, 8aCH2, J=9,3 Hz), 3,90 - 3,70 (m, 5H, OCH2CH2O+8aCH2), 3,18 (dq, 1H, H9', J=6 and 8.7 Hz), of 2,75 2,50 (m, 3H, H6'+CH(CH3)2+H1)

THE INTERMEDIATE CONNECTION 88

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-(4-O-Allyl-3,6-dideoxy-3-iodo - D-mannopyranoside)methyl] -4-formyl-4,4-a, 5,6,7, is Astor Intermediate 53 (GM 2008) (103 mg), triphenylphosphine (197 mg) and imidazole (51 mg) in dry tetrahydrofuran (5 ml) was treated with portions of iodine (95 mg). After stirring for 1 hour at room temperature the solution was subjected to reflux distilled until then, until he was consumed all the source material (TLC analysis of hexane:ethyl acetate 4:1). The reaction mixture was cooled and was fractionally between ethyl acetate (50 ml) and 1N aqueous hydrochloric acid (30 ml). The organic layer was washed successively 1N aqueous hydrochloric acid, water, aqueous solution of sodium metabisulfite, water, and brine, then dried (Na2SO4), filtered and concentrated. The residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of hexane: ethyl acetate (9:1) to deliver the connection specified in the header (70 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,46-7,22 (m, 10H, 2Ph), 6,98 (s, 1H, ), 6,03 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 6,02-5,9 (m, 1H, ), 5,35-of 5.15 (m, 2H ), 4,4-4,32 (m, 1H, O-CHa-C=C), 4,35 (d, 1H, H-1', J= 0.6 Hz), 4,18-of 3.96 (m, 4H, O-CHb-C=C, H-2', H-3', 8aCHa in), 3.75 (d, 1H, 8a-CHb, J=9 Hz), of 3.45 (dd, 1H, H-4', J=9 and 10.2 Hz), to 3.34 (dq, 1H, H-5', J to 5.7 and 8.7 Hz), of 2.72 (t, 1H, H-1, J=3,9 Hz).

INTERMEDIATE COMPOUND 89a and b

a) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S,4S,6S,7R,9R)-2,8-Dioxa-4,9-dimethyl-6 - hydroxy-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl]-4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(,9R)-2,8-Dioxa-4,9-dimethyl - 6-hydroxy-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl]-4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin - 3a(1H)-carboxylic acid diphenylmethylene ether

A solution of intermediate 88 (80 mg) in dry toluene (2 ml) was degirolami current of argon for 60 minutes and then was heated with delegacia. Added anti-hydride (41 μl) and continued dephlegmation for 15 more minutes. The solvent was removed under vacuum and the residue was transferred into diethyl ether (50 ml) and washed with saturated aqueous solution of potassium fluoride until then, until he stopped precipitation of the anti-fluoride. The organic layer was dried and evaporated, obtaining a residue that was purified by preparative TLC (silica gel, dichloromethane:ethyl acetate 95:5), resulting in the compound indicated in heading (a) of the Intermediate compound 89a (35 mg, Rf=0,4 dichloromethane:ethyl acetate 9:1) and the compound indicated in heading (b) Intermediate connection b (24 mg, Rf=0,3 dichloromethane:ethyl acetate 9:1).

INTERMEDIATE COMPOUND 89a

1H, CDCl3): 9,73 (s, 1H, CHO), 7,46-7,22 (m, 10H, 2Ph), of 6.99 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 4,63 (d, 1H, H-7', J=3.3 Hz), was 4.02 (d, 1H, 8aCHa, J=9 Hz), 3,86 (dd,1H, Ha-3', J=6.6 and 8.7 Hz), 3,83-3,6 (m, 4H, H-6', H-1', H-9' and 8a-CHb), 3,52 (dd, 1H, Hb-3', J=5.7 and 8.7 Hz), 2,69 (t, 1H, H-1, J=3,9 Hz).

INTERMEDIATE the TS) of 4.1 to 4.0 (m, 2H, 8a-CHa and Ha-3'), 3,85 (dd, 1H, H-1', J=7,8 and 9 Hz), 3,76-3,68 (m, 1H, 8a-CHb and H-6'), 3.46 in-3,3 (m, 2H, H-9' and Hb-3'), 2,73 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 90

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy- - D-atropinelike)methyl] - 4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of 4'-dimethylarginine (10 g) in methanol (20 ml) was added dropwise at room temperature a solution of diphenyldiazomethane (90 ml) in methylene chloride and the mixture was stirred for 6 hours. The solvent was evaporated until dry and the residue was chromatographically on the column for fast separation on silica gel, elwira a mixture of n-hexane:ethyl acetate (3:1) to deliver the connection specified in the header (12,6 g), in the form of foam pale yellow color.

(1H, CDCl3): 9,73 (s, 1H, CHO), 6,98 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=1.5 and 3.6 Hz) and 4.65 (d, 1H, H-1', J=1.5 Hz), 4.09 to, 3,76 (2d, 2H, 8a - J= 9 Hz), 4,01 (m, 1H, H-2'), a-3.84 (m, 1H, H-3' in), 3.75 (m, 1H, H-5'), of 3.69 (m, 1H, H-4'), 2,73 (t, 1H, H-1, J=4, 2 Hz).

THE INTERMEDIATE CONNECTION 91

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3,4-O-isopropylidene- - D - atropinelike)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro - 7-methyl-3-(1-methylethyl)-(1H)-1,4-methane-s-indocin-3a (1H)-carboxylic acid diphenylmethylene ether

To a solution of Preotu (10 mg). The solution was stirred at room temperature for 1.5 hours, then was added potassium carbonate (1.0 g) and continued stirring for another 30 minutes and the solvent was evaporated until dry. The crude mixture was fractionally between ethyl acetate (50 ml) and water (25 ml), the aqueous phase was extracted with ethyl acetate (2 × 50 ml), the organic phase was washed with brine, dried over magnesium sulfate and evaporated until dry, the residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of ethyl acetate: hexane (1: 3) and receiving the result of the connection specified in the header (600 mg), in the form of a white foam.

1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-of 7.24 (m, 10H, 2Ph), 6,98 (s, 1H,

CHPh2), the 6.06 (dd, 1H, H-2, J=1.5 and 3.3 Hz), of 4.57 (d, 1H, H-1', J=3.0 Hz), 4,30 (dd, 1H, H-3', J=3.6 and 5.7 Hz), 4,07 (d,1H, 8aCH2, J=9.0 Hz), 3.95 to 3,93 (m, 1H, H-2'), 3,85 (dd, 1H, H-4', J=5.7 and 9.3 Hz in), 3.75 (d, 1H, 8aCH2, J= 9.0 Hz), 3,44 (dq, 1H, H-5', Jd=9,3 Hz, Jq=6.3 Hz), 2,73 (t, 1H, H-1, J=3.6 Hz).

THE INTERMEDIATE COMPOUND 92

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3,4-O-isopropylidene-2-O-(methylthio) thiocarbonyl- - D-atropinelike)methyl)-4-formyl-4,4 a,5, 6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin - 3a(1H)-carboxylic acid diphenylmethylene ether

Intermediate compound 91 (100 mg) and amasyali suspension at room temperature for 0.5 hours. Added carbon disulfide (2.7 ml), stirring was continued for another 20 minutes and added methyliodide (18 ml). After 2 hours the reaction was stopped by addition of 1N ammonium chloride (20 ml). The mixture was extracted with ethyl acetate (3x25 ml), the organic phase was washed with brine, dried over magnesium sulfate and the solvent was evaporated until dry. The residue was purified by column chromatography rapid separation on silica gel, elwira a mixture of ethyl acetate: hexane (1:9) and receiving the result of the connection specified in the header (110 mg).

1H, CDCl3): 9,71 (s, 1H, CHO), 7,44-7,25 (m, 10H, 2Ph), of 6.96 (s, 1H, CHPh2), 6,01 (dd, 1H, H-2, J=1.2 and 3.6 Hz), 6.90 to (dd, 1H, H-2', J=2.4 and 5.4 Hz), is 4.85 (d, 1H, H-1', J=2.4 Hz), a 4.53 (dd, 1H, H-3', J=5.4 and 6.3 Hz), 4,00 (dd, 1H, H-4', J=6.3 and 8.7 Hz), 3,93 (d, 1H, 8aCH2, J=9,3 Hz), 3,65 (dq, 1H, H-5', Jd=8,7, Jq=6.3 Hz), 2,68 (t, 1H, H-1, J=3,9 Hz), 2,59 (8, 3H, CH3S).

THE INTERMEDIATE CONNECTION 93

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-Dideoxy-3,4-O-isopropylidene- - D - allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

The intermediate compound 92 (95 mg) was dissolved in dry toluene (5 ml) under nitrogen atmosphere and warmed up at 110oC. Over 1.5 hours with stirring dropwise EOW, was added methanol (2 ml) and the solvent was evaporated until dry. After chromatography rapid separation of the residue on silica gel with elution with a mixture of ethyl acetate:hexane (1:9) received the connection specified in the header (42 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), 7,44-7,25 (m, 10H, 2Ph), 6,98 (1H, s, CHPh2), equal to 6.05 (dd, 1H, H-2, J=1.2 and 3.3 Hz), of 4.54 (dd, 1H, H-1', J=2.7 and 9.3 Hz), 4,39 (dt, 1H, H-3', Jd=2.7 Hz, Jt=3.6 Hz), Android 4.04 (d, 1H, 8aCH2, J=9.0 Hz), to 3.67 (d, 1H, 8aCH2, J=9.0 Hz), the 3.65 (dd, 1H, H-4', J=3.6 and 8.7 Hz), 3,44 (dq, 1H, H-5', Jd=6.3 Hz, Jq=8,7 Hz) of 2.75 (t, 1H, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 94

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-Dideoxy- - D-allopregnanolone)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

To a solution of Intermediate 93 (1.5 g) in a mixture of tetrahydrofuran (30 ml) and methanol (15 ml) at room temperature with intensive stirring was added dropwise 1N hydrochloric acid (15 ml). Immediately after completion of the reaction (TLC control) was added saturated sodium bicarbonate (50 ml) and ethyl acetate (200 ml) and was fractionally mixture. The organic layer was washed with water (2x100 ml) and dried over magnesium sulfate. After removal of the solvent was obtained residue that under the resulting compound, specified in the header (1.1 g) in the form of a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), 7.5 to about 7.2 (m, 10H, 2Ph), of 6.99 (s, 1H, CHPh2), equal to 6.05 (dd, 1H, H-2, J=1.2 and 3.3 Hz), with 4.64 (dd, 1H, H-1', J is 2.1 and 9.6 Hz), 4,11 (m, 1H, H-3'), 4,06 (d, 1H, 8aCH2I , JAB=9,3 Hz), 3,70 (m, 2H, H-5' and 8aCH2), to 3.34 (m, 1H, H-4'), a 2.75 (t, 1H, H-1, J=3.6 Hz).

THE INTERMEDIATE CONNECTION 95

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3,6-Trideoxy-3-iodine- - D-glucopyranosyloxy) methyl]-4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro-7-methyl-3-(1 - methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

Intermediate compound 94 (2.0 g), triphenylphosphine (3.4 g) and imidazole (186 mg) was subjected to reflux distilled toluene (50 ml) under stirring, and then was treated with iodine, adding it in small portions. Dephlegmation continued for 4 hours. The reaction mixture was cooled and through a separate funnel decantation in excess aqueous sodium bicarbonate and sodium thiosulfate. The mixture was shaken until complete consumption of iodine. Toluene phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography rapid separation, elwira a mixture of hexane: ethyl acetate (15: 1) and (5:1) to deliver the connection specified in the header (1.65 g).

(1H, CDCl3)> J=9 Hz), 3,40 (m, 1H, H-3'), of 3.32 (m, 1H, H-5'), is 2.74 (t, 1H, H-1, J=4, 2 Hz), 2,32 2,53 and (2m, 2H, 2H-2').

THE INTERMEDIATE CONNECTION 96

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3,6-Trideoxy-3-ethylamino-3-N, 4 - O-carbonyl - D-allopurinol)oxy)methyl] -4-formyl - 4,4 a, 5,6,7,7 and, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A solution of intermediate 95 (200 mg) in dry tetrahydrofuran (15 ml) was treated with sodium hydride (24 mg, 1.0 mol). After 15 minutes, was added utilizationa (0.04 ml) and the reaction mixture was stirred with delegacia within 6 hours. After repayment of water (3 ml) the mixture was extracted with ethyl acetate (3x5 ml), the combined organic solutions were treated with brine (1x5 ml) and dried over magnesium sulfate, filtered and concentrated under vacuum to obtain a syrup. It was purified by column chromatography rapid separation on silica gel, elwira a mixture of hexane:ethyl acetate 3: 1, resulting in the net connection specified in the header (75 mg).

(1H, CDCl3): 9,74 (s, 1H, ), 7,44-7,26 (m, 10H, 2Ph), 6,98 (s, 1H, -CHPh2), 6,03 (dd, 1H, H-2, J=3.3 and 1.2 Hz), 4,60 (dd, 1H, H-1', J=5.1 and 3.9 Hz), of 4.12 (m, 2H, H-3', H-4'), 4,01 (d, 1H, H-8a, J=9.3 Hz), to 3.64 (d, 1H, H-8a, J= 9.3 Hz), 3,61 (dq, 1H, H-5', J=8.7 and 6.3 Hz), 3,49 (m, 1H, ), of 3.13 (m, 1H, ), 2,70 (t, 1H, H-1, J=3,9 Hz), 2,24 (m, 1H), what tilty)-thiocarbonyldi-CIS-bicyclo[3.4.0] non-7-yl-oxy - methyl] -4-formyl-4,4 a,5,6,7,7 a,8,8 a-octahydro-7-methyl-3-(1 - methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid defermation ether

The intermediate connection b (250 mg) and imidazole (catalytic amount) under nitrogen atmosphere was dissolved in dry tetrahydrofuran (10 ml). Was added sodium hydride (45 mg) and was stirred suspension at room temperature for 20 minutes. Added carbon disulfide (140 ml), stirring was continued for 20 minutes and added methyliodide (150 ál). After 2 hours the reaction was suppressed by adding dropwise ethyl acetate (10 ml) and then water (5 ml). The mixture was fractionally between ethyl acetate (50 ml) and water (50 ml), the organic layer was washed with water and brine, and then dried and evaporated. The residue was purified by chromatography rapid separation on silica gel, elwira a mixture of hexane: ethyl acetate (10:1) to (8:1), receiving the result of the connection specified in the header (211 mg).

(1H, CDCl3): 9,72 (s, 1H, CHO), 7,46-7,22 (m, 10H, 2Ph), 6,97 (s, 1H, ), of 6.02 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 5,80 (dd, 1H, H-6', J=2.1 and J= 6.3 Hz), 4.72 in (d, 1H, H-7', J=2.1 Hz), of 4.05 (dd, 1H, Ha-3', J=a 7.2 and 8.4 Hz), 3,98-3,86 (m, 2H, 8aCHa and H1'), 3,66-3,55 (m, 2H, 8aCHb and H-9'), to 3.34 (t, 1H, Hb-3', J=8,4 Hz), 2,73 (t, 1H, H1, J 3.9 Hz), at 2.59 (s, 3H, SCH3).

THE INTERMEDIATE CONNECTION 98

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Allyl-3-iodo-2,3,6-trideoxy- - D - glucopyranosyloxy)methyl]-4-formyl-4,4 a,5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic kila (28 mg) in dry tetrahydrofuran (5 ml) was treated with small portions of iodine (51 mg). The mixture was stirred at room temperature for 1.5 hours and was fractionally between ethyl acetate (30 ml) and 1N aqueous hydrochloric acid (30 ml). The organic layer was washed successively 1N aqueous hydrochloric acid, water, aqueous solution of sodium metabisulfite, water, and brine, then dried, filtered and concentrated. The residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of hexane:ethyl acetate (9: 1) to deliver the connection specified in the header (68 mg).

1H, CDCl3): 9,73 (s, 1H, CHO), 7,45-7,22 (m, 10H, 2Ph), 6,97 (s, 1H, ), 6,07-5,9 (m, 2H, H-2 ), lower than the 5.37-5,14 (m, 2H ), 4,45 is 4.35 (m, 1H, ), 4,25 to 4.1 (m, 2H, H-1'), 4,1-3,95 (m, 2H, H-3' and 8a-CHa), 3,66 (d, 1H, 8a-CHb, J=9 Hz), 3,29 (dq, 1H, H-5', J= 6 and 8.7 Hz) and 3.15 (dd, 1H, H-4', J=8.7 and 9.9 Hz), 2,73 (t, 1H, H-1, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 99

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-(2,3-Anhydrous-6-deoxy- - D-mannopyranoside)methyl-4-(1,3-dioxolane-2-yl)-4,4-a, 5,6,7,7 a,8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A solution of intermediate 67 (3.2 mmol) in dry acetonitrile (40 ml) was treated with ethylene glycol (39 ml), triethylorthoformate (1.1 ml) and p-toluensulfonate acid (30 mg). After 5 hours the mixture is thoroughly extracted with ethyl acetate. After Adalia hexane: ethyl acetate 3:1, and receiving the result of the connection, specified in the header (2,08 g).

(1H, CDCl3): 7,43 and 7,29 (m,m, 4H, 6H, 2xPh), to 6.95 (s, 1H, ), 5,86 (d, 1H, H-2, J=3.3 Hz), to 5.08 (s, 1H, 4-CH), 4,69 (s, 1H, H-1'), 4,11 (d, 1H, 8a-CHa, J=9.3 Hz), 3,81 (m, 5H, 8a-CHb ), 3,63 (m, 1H, H-5'), 3,23 and 3.15 (d,d, 1H, 1H, H-2' and H-3', J=3.6 Hz), 3,20 (m, 1H, H-4'), 2,63 (m, 2H, H-1 ).

THE INTERMEDIATE CONNECTION 100

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-(2,3-Anhydrous-4-oxo-6-deoxy- - D-mannopyranoside)methyl-4-(1,3-dioxolane-2-yl)- 4,4 a,5,6,7,7 a,8,8 and octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

The solution triperoxonane anhydride (230 μl) in dry dichloromethane (10 ml) at -60oC was treated dropwise dimethylsulfoxide (138 μl) and a solution of Intermediate 99 (0.9 mmol) in dry dichloromethane (10 ml). After 60 minutes was added triethylamine (554 μl) and the mixture was stirred at -20oC for 2 hours. Then it was diluted with dichloromethane and washed with water. After removal of solvent the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate 4:1, and receiving the result of the connection specified in the header (214 mg).

(1H, CDCl3): 7,44 and 7,30 (m,m, 4H, 6H, 2xPh), 6,94 (s, 1H, ), by 5.87 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 5,10 (s, 1H, 4-CH), to 4.81 (s, 1H, H-1'), 4.09 to (d, 1H, 8a-CHa, J=8.7 Hz), 3,88 (m, 5H, 8a-CHb ), 3.58 and to 3.36 (d,d, 1H is ethoxy-4 - methylene- - D-mannopyranoside)methyl-4-(1,3-dioxolane-2 - yl)-4,4-a,5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1, 4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

The solution methyltriphenylphosphonium (0.3 mmol) in dry tetrahydrofuran (10 ml) in a nitrogen atmosphere at -78oC was treated with n-Butyllithium 2.44 M (0.15 ml). After 15 minutes, was slowly added a solution of Intermediate 100 (0.21 mmol) in dry tetrahydrofuran (5 ml), the mixture is then slowly heated to room temperature. The mixture was diluted with ethyl acetate and washed with ammonium chloride (IN) and brine. After removal of solvent the residue was purified By chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate 4:1, and receiving the result of the connection specified in the header (91 mg).

(1H, CDCl3): 7,45 and 7,29 (m,m,4 H,6 H, 2xPh), to 6.95 (s, 1H, ), by 5.87 (m, 1H, H-2), 5.35 and with 5.22 (d,d, 1H, 1H, CH2=C, J=2.4 Hz), to 5.08 (s, 1H, 4-CH), and 4.68 (s, 1H, H-1'), 4,10 (m, 2H, 8a-CHa, and H-5'), 3,82 (m, 5H, 8a-CHb ), 3.57 and the 3.35 (d,d, 1H, 1H, H-2' and H-3', J=3.9 Hz), 2.63 in (m, 2H, H-1 ).

THE INTERMEDIATE CONNECTION 102

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-(2,3-Anhydrous-6-deoxy- - D-teleperedachi) methyl-4-(1,3-dioxolane-2-yl)-4,4-a, 5,6,7,7 a,8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid diphenylmethylene ether<-78oC was slowly added L-selectride 1N (2 ml). After 1 hour the mixture was diluted with ethyl acetate (100 ml) was heated to room temperature and washed with ammonium chloride (1N), water and brine. After removal of solvent the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane:ethyl acetate 3:1, and receiving the result of the connection specified in the header (431 mg).

(1H, CDCl3): 7,44 and 7,31 (m,m, 4H, 6H, 2xPh), to 6.95 (s, 1H, ), to 5.85 (dd, 1H, H-2, J=1.2 and 3.6 Hz), to 5.08 (s, 1H, 4-CH), 4.92 in (s, 1H, H-1'), 4,11 (d, 1H, 8a-CHa, J=9.3 Hz), 3,83 (m, 5H, 8a-CHb ), 3,62 (m, 1H, H-4'), of 3.54 (dd, 1H, H-3', J=3.6 and 5.1 Hz), 3,40 (m, 1H, H-5'), 3,24 (d, 1H, H-2, J=3,9 Hz).

THE INTERMEDIATE CONNECTION 103

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-(2,3-Anhydrous-4-O-tertbutyl-carbonyl-6 - deoxy- - D-teleperedachi)methyl-4-(1,3-dioxolane - 2-yl)-4,4-a, 5,6,4,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3a(1H)-carboxylic acid diphenylmethylene ether

A mixture of Intermediate compound 102 (0.2 mmol) and 4-dimethylaminopyridine (0.4 mmol) in dry dichloromethane (15 ml) was treated with the acid chloride trimethylhexanoic acid (0.3 mmol). After 30 minutes, washed with water and purified by chromatography rapid separation, using as eluent a mixture of hexane: ethyl acetate 5:1 and receiving the connection is and 3.6 Hz), to 5.08 (s, 1H, 4-CH), 4,82 (t, 1H, H4', J= 3.9 Hz), 4,60 (s, 1H, H-1'), of 4.12 (d, 1H, 8a-CHa, J=9.6 Hz), 3,83 (m, 5H, 8a-CHb ), the 3.65 (m, 1H, H-5'), 3,53 (t, 1H, H-3', J = 4, 2 Hz), 3,17 (d, 1H, H-2", J=4, 2 Hz), 2.63 in (m, 2H, H-1 ).

THE INTERMEDIATE CONNECTION 104

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8a-(4-O-Allyl-2,3-anhydrous-6-deoxy- - D-teleperedachi)methyl-4-(1,3-dioxolane-2-yl)-4,4-a, 5,6,7,7 a, 8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid diphenylmethylene ether

To a solution of Intermediate 102 (0.3 mmol) in dry tetrahydrofuran (10 ml) under nitrogen atmosphere was added sodium hydride (0.6 mmol) and a catalytic amount of tetrabutylammonium. After 30 minutes, was added allylbromide (0.9 mmol) and stirred the mixture overnight at room temperature. Then it was diluted with ethyl acetate (10 ml) and washed with ammonium chloride (1N) and brine. After removal of solvent the residue was purified by chromatography rapid separation, using as eluent a mixture of hexane: ethyl acetate 4:1, and receiving the result of the connection specified in the header (163 mg).

(1H, CDCl3): 7,44 and 7,29 (m, m, 4H, 6H, 2x Ph), to 6.95 (s, 1H, ), 5,96 (m, 1H, H-2"), to 5.85 (dd, 1H, H-2, J = 1, 2 and 3.6 Hz), 5,30 and 5.12 (m, m, 1H, 1H, CH2-3"), is 5.06 (s, 1H, 4-CH), 4,58 (s, 1H, H-1'), or 4.31 (m, 1H, H-4'), 4,10 (m, 2H, H-5' and 8a-CHa), 3,83 (m, 5H, 8a-CHb ), 3,53 (m, 2H, CH2O) to 4.23 (t, 1H, H-3', J=4, 2 Hz), 3-Anhydrous-6-deoxy-4-O-tosyl - D-teleperedachi)methyl-4-(1,3-dioxolane-2-yl)-4,4-a,5,6,7,7 a,8 a,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)

-carboxylic acid diphenylmethylene ether

A solution of the obtained compound 102 (0.45 mol) in dry dichloromethane (7 ml) was treated with 4-dimethylaminopyridine (1,32 mmol) and taillored (0.9 mmol) and was stirred over night at room temperature. Then it was washed with water and brine. After removal of solvent the residue was purified by chromatography, using as eluent a mixture of hexane:ethyl acetate 3: 1. The appropriate fractions are evaporated, resulting in the connection specified in the header (277 mg).

(1H CDCl3) : 7,86, 7,42 and 7,29 (m, m, 10H, Ar), 6,93 (s, 1H, ), of 5.82 (m, 1H, H-2), is 5.06 (s, 1H, 4-CH), and 4.68 (t, 1H, H-3', J = 4, 2 Hz), 4,55 (s, 1H, H-1'), 4,07 (d, 1H, 8a-CH2, J = 8.7 Hz), 3,81 (m, 5H, 8a-CHb ), 3,62 (m, 1H, H-5'), 3,30 (t, 1H, H-2', J = 4, 2 Hz), 3.15 in (d, 1H, H-4', J = 3.9 Hz), 2,61 (m, 2H, H-1 ).

THE INTERMEDIATE CONNECTION 106

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8a-(2,3-Anhydrous-6-deoxy-4-azido-4,6-dideoxy- - D-mannopyranoside)methyl-4-(1,3-dioxolane-2-yl)-4,4-a, 5,6,7,7 a,8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid diphenylmethylene ether

A solution of Intermediate 105 (0.15 mmol) and lithium azide (0.45 mmol) in dry dimethylformamide water and brine. After removal of solvent the residue was purified by chromatography, using as eluent a mixture of hexane:ethyl acetate. The appropriate fractions were evaporated, resulting in the connection specified in the header (53 mg).

(1H CDCl3): 7,46 - of 7.23 (m, 10H, Ph2), 6,94 (s, 1H, ), 5,86 (dd, 1H, H-2, J=1.2 and 3.6 Hz), to 5.08 (s, 1H, 4-CH), 4,67 (s, 1H, H-1'), 4,10 (d, 1H, 8a-CHa, J = 8.7 Hz), 3,83 (m, 4H, 8a-CHb ), 3,40 (d, 1H, H-4', J = 9.3 Hz), 3,31 and 3.15 (d,d,H-2' and h-3', J = 3.6 Hz), 3,23 (m, 1H, H-5'), to 2.65 (m, 2H, H -).

PROMEZHUTOCHNOE CONNECTION 107

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8a-[(4-O-Allyl,2,3-anhydrous-6-deoxy- - D-mannopyranosyl)oxymethyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid diphenylmethylene ether

METHOD AND

To a solution of Intermediate 21 (650 mg) in 50 ml dry THF at 0oC was added 90 ml of sodium hydride. The mixture was stirred in the atmosphere at 0oC for 30 minutes. Then added 875 mg allylbromide and a catalytic amount of tetrabutylammonium (50 mg). The reaction was ended after 5 hours stirring at room temperature. The crude product was treated with 1N ammonium chloride and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4and was evaporated to dry soott 7:1, and receiving the result of 590 mg of the compound, specified in the header, in the form of a white foam.

METHOD B

To a solution of Intermediate 53 (3 g) in dry methylene chloride (200 ml) at room temperature was added 2.35 g dimethylaminopyridine. Then, stirring was slowly added to the solution 3,66 g taillored in 100 ml of methylene chloride. The mixture was stirred for 3 days at room temperature until completion of the reaction. The crude product is washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and treated with 20 ml of metaxya in methanol (25 wt.%). This mixture was stirred at room temperature for 1 day. The crude product was treated with 1N hydrochloric acid and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by chromatography rapid separation, using as eluent a mixture of n-hexane:ethyl acetate 8:1, and receiving the result of the connection specified in the header, in the form of a white foam (total yield 45%).

(1H, CDCl3): of 9.75 (s, 1H, CHO), of 6.99 (s, 1H, ), between 6.08 (dd, 1H, H-12), J = 1.2 and 3.3 Hz), 5,90 (m, 1H, ), 5,28 (m, 2H ), 4,69 (d, 1H, H-1, J = 1.2 Hz), to 4.23 (m, 1H, H-5'), 4,11 (d, 1H, H-19a, J = 9 Hz), 4,06 (m, 1H, H-4'), with 3.79 (d, 1H, H-19b, 108

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8a-[2,3-anhydrous-6-deoxy-4-O-(2,3-dihydroxypropyl) - D-mannopyranosyl)oxymethyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid diphenylmethylene ether

To a solution of Intermediate 107 (2 g) in 50 ml of acetone and 5 ml at 0oC was added N-oxide-N-methylmorpholine. To this mixture was slowly added 0.2 ml of chetyrehokisi osmium (2.5 wt.% in Isobutanol). Hydroxylation GM 218045 was completed after stirring for 3 days at room temperature. The crude product was treated with sodium hydrosulfide, filtered through brownmillerite and evaporated until dry. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, was evaporated until dry and chromatographically on a column of silica gel in the system n-hexane:ethyl acetate, 1: 1 methylene chloride:methanol, 50:1. The connection specified in the header (mixture of enantiomers of 50:50) was obtained as a white foam (1.75 g).

1H CDCl3): of 9.75 (s, 1H, CHO), of 6.99 (s, 1H, ), between 6.08 (dd, 1H, H-12, J = 1.5 and 3.6 Hz), 4,69 (s, 1H, H-1'), 4,10 (d, 1H, H-19a, J = 9,3 Hz), 3,90 - to 3.58 (m, 5H, 4'), with 3.79 (d, 1H, H-19d, J = 9,3 Hz), 3,27, 3,13 (d,d 1H, 1H, H-2' and H-3', J = 3.9 Hz), 3,28 - up 3.22 (m, 2H, H-4' and H-5'), 2,85 (t, 1H, H-11, J = 3.6 Hz).

propyl] - - D-mannopyranosyl)oxymethyl]-4-formyl-4,4 a, 5,6,7,7 a,8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid diphenylmethylene ether

To a solution of intermediate 108 (350 mg) in dry acetone (20 ml) was added 250 μl of 2,2-dimethoxypropane and a catalytic amount of p-toluensulfonate acid (30 mg). The mixture was stirred at room temperature for 2 hours in nitrogen atmosphere. The crude product was evaporated until dry and the residue was again dissolved in ethyl acetate (70 ml) and washed with water and brine. The organic layer was concentrated and was purified on a column of silica gel in the system n-hexane:ethyl acetate 6:1, resulting in the connection specified in the header (mixture of isomers (50:50), in the form of a white foam (290 mg, yield 80%).

(1H, CDCl3): 9,74 (s, 1H, CHO), of 6.99 (s, 1H, ), between 6.08 (dd, 1H, H-12, J = 0.9 and 3.3 Hz), of 4.67 (d, 1H, H-1', J = 2.1 Hz), 4,32 - 4,22 (m, 1H, 4'), 4,12 - a 4.03 (m, 2H, H-19a and 4'), 3,82 - 3,51 (m, 4H, H-19b, ), 3,29 and 3.12 (d,d, 1H, 1H, H-2' and H-3', J = 3.9 Hz), 3,26 - 3,20 (m, 2H, H-4' and H-5'), 2,85 (t, 1H, H-11, J = 3,9 Hz), 1,42, and 4,36 (d,d, 3H, 3H isopropylidene).

EXAMPLE 1

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8a-[(6-deoxy-3,4-O-isopropylidene) - D-mannopyranosyl)methyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H) -carboxylic acid

To a suspension of 10% palliata (10 ml) and the mixture was hydrogenosomal at room temperature under hydrogen pressure of 30 psi for 1 hour. The catalyst was filtered, the solvent was evaporated until dry. After chromatography rapid separation on silica gel of the residue by elution with a mixture of dichloromethane:methanol (20:1) received the connection specified in the header (128 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J = 1.5 and 3.3 Hz), br4.61 (d, 1H, H-1', J = 2.1 Hz), 4,30 (dd, 1H, H-3', J = 3.6 and 5.4 Hz), Android 4.04 (d, 1H, 8aCH2, J = 9,3 Hz), 3,95 (dd, 1H, H-2', J = 2.1 and 3.6 Hz), 3,85 (dd, 1H, H-4', J = 5.4 and 9.0 Hz), 3,66 (d, 1H, J = 9.3 Hz), 3,49 (dg, 1H, H-5', Jd= 9,0 Hz, Jq= 6.3 Hz), 2,69 (t, 1H, H-1, J=3.6 Hz); (13C, CDCl3): 204,8(CHO), 175,4 (CO2H), 148,3 (C-3), 130,7 (C-2), 109,3 (Cq.ESOP), which accounted for 98.9(C-1'), 76,9(C-4'), to 75.8(C-2'), 74,2 (8aCH2), of 71.7(C-3'), only 68.6(C-5'), 65,6(C-8a), of 58.9(C-4).

EXAMPLE 2

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3,4-O-isopropylidene- - D-atropinelike)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid sodium salt

The compound of example 1 (246 mg) was dissolved in dioxane (2 ml) was added 0.5 M sodium bicarbonate (0,99 ml). The solution was stirred for 15 minutes and dried by freezing, receiving the result of the connection specified in the header (256 mg).

(1H, CDCl3): 9,88 (s, 1H, CHO), 5,95 (dd, 1H, H-2, J=1.5 and 3.3 Hz), 4,51 (d, 1H, H-1', J=1.8 Hz), 4.26 deaths (dd, 1H, H-3', J=4.8 and 6.0 Hz), 4,01 (d, 1H, 8aCH2, J=9.6 Hz), a 3.87-of 3.80 (m, 2H, H-2', NXI-3,4-O-(2-pentylidene)- - D-atropinelike)methyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a suspension of 10% palladium on coal (30 mg) in ethyl acetate (10 ml) under nitrogen atmosphere was added a solution of Intermediate compound 3 (140 mg) in ethyl acetate and was hydrogenosomal the mixture under hydrogen pressure of 30 psi for 45 minutes. The catalyst was filtered, and the solution was evaporated until dry. After chromatography rapid separation on silica gel using as eluent a mixture of dichloromethane:methanol (30:1) received the connection specified in the header (75 mg), epimeres ratio of 26:74.

(1H, CDCl3), 9,82 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J is 1.5 and 3.3 Hz), 4,60 (d, 1H, H-1', J=1.8 Hz), 4,30 (dd, 1H, H-3', J = 4.2 and 6.0 Hz), 3,98 (d, 1H, 8aCH2, J= 9,3 Hz), of 3.94 (dd, 1H, H-2', J=1,8 and 4.2 Hz), a 3.87 (dd, 1H, H-4', J=6.0 and 9.3 Hz), the 3.65 (d, 1H, 8aCH2, J=9,3 Hz), 3,47 (dq, 1H, H-5', Jd= 9,3 Hz, Jq= 6.3 Hz), 2,70 (t, 1H, H-1, J=3,9 Hz); (13C, CDCl3); 204,5 (CHO), 176,5 (CO2H), 148,2 (C-3), to 130.6 (C-2) and 110.8 (Cq acetal), 98,8 (C-1'), to 76.6 (C-4'), 75,6 (C-2'), 73,9 (8aCH2), From 71.3 (C-3'), For 68.9 (C-5'), 65,5 (C8a), 58,8 (C-4).

EXAMPLE 4

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3,4-O-(4-methoxy-2-butylidene)- - -D-atropinelike)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(nominating connection 4 (260 mg) in ethylacetate (10 ml) and was hydrogenosomal the resulting mixture under nitrogen pressure of 30 psi for 45 minutes at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of dichloromethane:methanol (30:1) to deliver the connection specified in the header (172 mg).

(1H CDCl3): 9,71 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,60 (d, 1H', J = 2.4 Hz), or 4.31 (dd, 1H, H-3', J = 4.2 and 6.0 Hz), 3,98 (d, 1H, 8aCH2, J= 9.3 Hz), of 3.94 (dd, 1H, H-2', J=2,4 and 4.2 Hz), 3,88 (dd, 1H, H-4', J=6.0 and 9.3 Hz), the 3.65 (d, 1H, 8aCH2, J=9,3 Hz), 3,50 (t, 1H, CH2O, J= 7,2 Hz), 3,50 is 3.40 (m, 1H, H-5'), 2,69 (t, 1H, H-1, J=3,9 Hz); (13C, CDCl3): 204,5 (CHO), 176,2 (CO2H), 148,2 (C-3), to 130.6 (C-2), 109,8 (C-2'), 98,8 (C-1'), to 76.7 (C-4'), to 75.7 (C-2'), 73,8 (8aCH2), 71,2 (C-2'), TO 68.8 (C-5') AND 68.4 (CH2O), 65,6 (C8a), of 58.9 (C-4), 58,5 (CH3O).

EXAMPLE 5

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-Deoxy-3,4-O-cyclopentadien- - D-atropinelike)methyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methyl-3-(1-methylethyl)-1,4-methane-s-methane-s-indocin-3a(1H)- carboxylic acid

To a suspension of 10% palladium on coal (50 mg) in ethyl acetate (10 ml) was added a solution of Intermediate compound 5 (232 mg) in ethyl acetate and the resulting mixture was hydrogenosomal at room temperature under hydrogen pressure of 35 psi for 1.5 hours. The catalyst was filtered, and the solvent was evaporated to dry the ethanol (30:1) to deliver the connection, specified in the header (67 mg).

(1H, CDCl3): 9,71 (s, 1H, CHO), 6,07 (dd, 1H, H-2, J=1.5 and 3.3 Hz), 4,59 (d, 1H, H-1', J=2.1 Hz), 4,17 (dd, 1H, H-3', J=3.6 and 5.4 Hz), of 4.54 (d, 1H, 8aCH2, J= 9,3 Hz), of 3.97 (dd, 1H, H-2', J=2.1 and 3.6 Hz), 3,81 (dd, 1H, H-4', J=5.4 and 9.0 Hz), 3,70 (d, 1H, 8aCH2, J=9,3 Hz), 3,44 (dq, 1H, H-5', Jd= 9,0 Hz, Jq= 6.3 Hz), 2,69 (t, 1H, H-1, J=3.3 Hz).

EXAMPLE 6

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1,6-Dideoxy-3,4-O-isopropylidene- - D-allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate compound 7 (1.2 g) in ethyl acetate (60 ml) under nitrogen atmosphere portions was added 10% palladium on coal (600 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 40 psi at room temperature. The catalyst was filtered and washed with additional ethyl acetate. The solvent was evaporated until dry and the residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of dichloromethane: methanol (25:1) to deliver the connection specified in the header (0,79 g).

(1H, CDCl3): 9,81 (s, 1H, CHO), equal to 6.05 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 4,63 (dd, 1H, H-1', J=2.4 and 8.4 Hz), to 4.38 (dt, 1H, H-3', Jd=3.0 Hz, Jt= 5,1 Hz), the 4.29 (d, 1H, 8aCH2, J=9,3 Hz) to 3.64 (dd, 1H, H-4', J=5.1 and 9.3 Hz), 4,43 (dq, 1H, H-5', Jd2)2), of 98.3 (C-1'), to 76.6 (C-4'), 73,7 (8aCH2), To 72.5 (C-3'), Of 71.7 (C-5'), 67,0 (C8a), 65,2, Or 59.0 (C-4).

EXAMPLE 7

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-Dideoxy-3,4-O-(4-methoxy-2-butylidene)- - D-allopregnanolone)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a suspension of 10% palladium on coal (300 mg) in ethyl acetate (10 ml) was added a solution of Intermediate compound 8 (246 mg) in ethyl acetate (10 ml) and was hydrogenosomal the resulting mixture at room temperature under hydrogen pressure of 45 psi for 1 hour. The catalyst was filtered, and the solvent was evaporated until dry. The residue was purified by chromatography rapid separation on silica gel, elwira dichloromethane and a mixture of dichloromethane: methanol (30:1) to deliver the connection specified in the header (182 mg), in the form of foam, epimeres the ratio of 4:1.

(1H, CDCl3signals of the main component: 9,81 (s, 1H, CHO), the 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), to 4.62 (dd, 1H, H-1', J=2.7 and 8.1 Hz), to 4.41 (dt, 1H, H-3', Jd=3.3 Hz, Jt= 2,5 Hz), 4,24 (d, 1H, 8aCH2, J=9.0 Hz), 3,68 (dd, 1H, H-4', J=5.7 and 9.0 Hz), 3,50 (t, 2H, CH2, J=7.5 Hz), 3.46 - to 3.38 (m, 1H, H-5'), to 3.33 (s, 3H, CH2O) to 2.54 (t, 1H, H-1, J= 4, 2 Hz); (13C, CDCl3): 204,5 (CHO), 175,1 (CO2H), 148,2 (C-3), 130,7 (C-2), 109,4 (C-2 ' /BR> [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-Dideoxy-3,4-O-isopropylidene- - D-allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid sodium salt

The compound from Example 6 (376 mg) was dissolved in dioxane (3 ml) was added 0.5 N sodium bicarbonate (1.50 ml). The resulting solution was stirred for 30 minutes at room temperature, and then dried by freezing, receiving the result of the connection specified in the header (392 mg).

(1H, CDCl3): 9,84 (s, 1H, CHO), 5,94 (dd, 1H, H-2, J=1.5 and 3.6 Hz), to 4.52 (dd, 1H, H-1', J=2.4 and 9.0 Hz), to 4.41 - 4,37 (m, 1H, H-3'), was 4.02 (d, 1H, 8aCH2CH, J=9.6 Hz), 3,74 (d, 1H, 8aCH2, J=9.6 Hz), 3,57 (dd, 1H, H-4', J=5.4 and 10.0 Hz), 3,42 (dq, 1H, H-5', Jd=6.3 Hz, Jq=6.3 Hz), of 2.56 (t, 1H, H-1, J= 3.6 Hz).

EXAMPLE 9

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3,4-O-thionocarbonate- - D-atropinelike)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a (1H)-carboxylic acid

2% solution triperoxonane acid in dichloromethane (20 ml) was added to a solution of Intermediate compound 9 (0,220 g) in dichloromethane (5 ml) at 0oC. the Reaction mixture was stirred at 0oC for 1 hour and then washed with water (2x20 ml) and dried (magnesium sulfate). The solvent is evaporated, resulting in Rasool (from 40:1 to 20:1) and receiving the connection specified in the header (0.1 g).

(1H, CDCl3): 9,68 (s, 1H, CHO), 6,09 (dd, 1H, H-2, J = 1.5 and 3.6 Hz), 4,94 (dd, 1H, H-3', J=3.9 and 7.2 Hz), to 4.62 (m, 2H, H-1'), 4,14 (dd, 1H, H-2', J= 2.1 and 3.9 Hz), 4.00 points (d, 1H, 8aCH2I , JAB=9.3 Hz), and 3.72 (d, 1H, 8aCH2I , JAB= 9.3 Hz), 3,68 (m, 1H, H-5'), a 2.71 (m, 1H, H-1); (13C, CDCl3): 204,4 (CHO), 190,2 (CS), 176,4 (CO2H), of 148.4 (C-3), to 130.6 (C-2), of 98.2 (C-1'), 82,3 and to 80.1 (C-3' and C-4'), 74,5 (8aCH2), of 71.7 (C-3a), 69.2 and to 66.4 (C-2' and C-5'), 65,5 (C-8a), 58,8 (C-4), 46,0 (C-1)

EXAMPLE 10

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,6-Dideoxy-3,4-O-carbonyl- - -D-allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate compound 10 (125 mg) in delegateuser dry toluene (15 ml) was added under nitrogen atmosphere in small portions excess carbonyldiimidazole. Immediately after completion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude mixture was dissolved in dichloromethane (200 ml), washed with 1N hydrochloric acid (g ml), brine (1x100

ml) and water (I ml), then dried over magnesium sulfate and concentrated until dry, getting in the oil, which was used without further purification. The oil was dissolved in ethyl acetate (15 ml) and shaked (15 ml) was shaken in a Parr apparatus at a pressure of nitrogen ke filtering off the catalyst and removal of solvent received syrup, which was purified by preparative TLC (silica gel, methanol: dichloromethane 1: 15), receiving the result of the connection specified in the header (50 mg), isolated from the fraction with Rf0,5.

(1H, CDCl3): to 9.70 (s, 1H, CHO), 6,07 (ss, 1H, H-2, J = 1.2 and 3.3 Hz), is 4.93 (m, 1H, H-3'), 4,63 (dd, 1H, H-1', J = 2.4 and 7.8 Hz), 4,24 (dd, 1H, H4', J = 6.6 and 9.3 Hz), 4,05 and 3.57 (2d, 2H, 8aCH2I , JAB= 9 Hz), 3,63 (m, 1H, H-5'), of 2.66 (t, 1H, H-1, J = 3,9 Hz); (13C,CDCl3): 204,6 17,6 154,0 148,2 130,7 97,5 76,6 74,7 69,9 31,7

EXAMPLE 11

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2,6-Dideoxy-3,4-O-thiocarbonyl- - D-allopregnanolone)methyl]-4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl - 3(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate 11 (130 mg) in dry dichloromethane (5 ml) at 0oC was added triperoxonane acid (250 μl). After 2 hours the solution was diluted with dichloromethane (50 ml), washed with water (I ml), dried over magnesium sulfate and concentrated until dry, getting in the oil, which was purified by preparative TLC (silica gel, methanol: dichloromethane 1:15), receiving the result of the connection specified in the header (68 mg), isolated from the fraction with Rf0,6.

(1H, CDCl3): to 9.70 (s, 1H, CHO), 6,07 (dd, 1H, H-2, J=1.2 and 3.3 Hz), to 5.08 (m, 1H, H-3'), 4,63 (dd, 1H, H-1', J = 2.7 and 8.4 Hz), 4,45 (d90,9 176,3 148,2 130,7 97,5 80,3 of 79.6 (C-3'), FOR 69.5(C-5'), 31,3(C-2').

EXAMPLE 12

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2,6-Dideoxy-3,4-O-methylene - D-allopregnanolone)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl - 3(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate compound 10 (450 mg) in dibromomethane (10 ml) under vigorous stirring was added tetrabutylammonium (40 mg) and 50% aqueous sodium hydroxide (100 ml). After 12 hours the mixture was suppressed by the addition of 1N hydrochloric acid (100 ml) and was extracted with dichloromethane (100 ml). The organic layer is washed with 1N hydrochloric acid (g ml), dried on magnesium sulfate and concentrated until dry, resulting in the white substance, which was used without further purification. This substance was repeated in ethyl acetate (15 ml) was shaken in a Parr apparatus under hydrogen pressure of 20 psi in the presence of 10% palladium on charcoal (50 mg) for 1 hour at room temperature. After filtering off the catalyst and removing the solvent the oily residue was subjected to chromatography rapid separation on silica gel with elution with a mixture of acetone:hexane (1:10) and (1: 5), receiving the result of the connection specified in the header (130 mg), in the form of oil).

(1H, CDCl3): 9,80 (s, 1H, CHO), equal to 6.05 (dd, 1H, ), to 3.67 (dd, 1H, H-4'), J = 5.1 and 8.7 Hz), to 3.38 (m, 1H, H-5'), 2,58 (t, 1H, H-1, J = 3,9 Hz); (13C, CDCl3): 204,6 174,8 148,3 130,6 98,1 94,9 75,4 73,9 70,3 32,3

EXAMPLE 13

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2,6-Dideoxy-3,4-O-methylene - D-allopregnanolone)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl - 3(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 12 (200 mg) in methanol (5 ml) was added dropwise 1,106 N sodium hydroxide solution in water (3.98 ml). After 30 minutes the solvent was removed under reduced pressure, and the residue was dissolved in dioxane (5 ml) and liofilizirovanny, receiving the connection specified in the header (209 mg).

(1H, CDCl3): 9,87 (s, 1H, CHO), is 6.54 (dd, 1H, H-2, J = 1.5 and 3.6 Hz), 5,10 and 4,82 (2m, 2H, OCH2O) 4,51 (dd, 1H, H-1', J = 2.4 and 8.7 Hz), of 4.12 (m, 1H, H-3'), and 4,03 of 3.73 (2d, 2H, 8aCH2I , JAB= 9.9 Hz), 3,61 (m, 1H, H-4'), at 3.35 (m, 1H, H-5'), of 2.56 (t, 1H, H-1); (13C CD3OD): 200,2 169,0 142,9 120,6 90,3 86,4 67,5 66,2 61,8

EXAMPLE 14

(a) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,3R,7R, 9R]-2,5,8-Trioxa-3,7-dimethyl-CIS-bicyclo[4.4.0] -Dec-9-yl-hydroxy-methyl] - 4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl - 3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

(b) [1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S, 3R, 7R, 9R]-2,5,8-Trioxa-3,7-dimethyl-CIS-bicyclo[4.4.0] -Dec-9-yl-hydroxy-methyl] - 4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl - 3-(1-methylethyl)-1,4-methane-s-inductee at a pressure of 20 psi hydrogen in the presence of 10% palladium on coal (50 mg) for 1 hour at room temperature. After filtering off the catalyst and evaporating the solvent under reduced pressure was obtained a syrup which was subjected to chromatography rapid separation on silica gel, using as eluent a mixture of acetone:hexane(1:10), (1:7) and (1:5), resulting in the compound indicated in heading (a) (35 mg; Rf= 0.5 V system of hexane:acetone 4:1) and the compound indicated in heading (b) (40 mg; Rf= 0,4 in the system hexane:acetone 4:1), in the form of colourless oils.

(a) (1H, CDCl3): 9,80 (s, 1H, CHO), 6,04 (dd, 1H, H-2, J = 1.2 and 3.3 Hz), to 4.62 (dd, 1H, H-9', J = 2.1 and 9.9 Hz), 4,20 (m, 2H, 8aCH2+ H-7'), of 3.97 (m, 1H, H-1'), to 3.73 (m, 1H, ), 3,40 (m, 2H, 8aCH2+ OCH2), with 3.27 (d, 1H, OCH2I , JAB= to 10.8 Hz), 3,18 (dd, 1H, H-6', J = 3.3 and a 10.2 Hz); (13C, CDCl3): 204,6 , 174,6 148,3 130,6 97,9 , 73,5 73,2 72,1 71,9 65,4 31,9 23,7

(b) (1H, CDCl3): 9,79 (s, 1H, CHO), equal to 6.05 (dd, 1H, H-2, J = 1.5 and 3.6 Hz), to 4.73 (dd, 1H, H-9', J = 3.0 and 6.3 Hz), 4.26 deaths (m, 1H, H-1'(1), to 4.15 (m, 2H, 8aCH2+ H-7'), 3,98 (m, 1H, ), with 3.79 (dd, 1H, OCH2, J = 3,1 and 11.4 Hz), 3,41 (d, 1H, 8aCH2, J = 9.6 Hz), the 3.35 (m, 1H, OCH2, J = 3.1 and 6.3 Hz), with 3.27 (dd, 1H, H-6', J = 5.7 and 11.7 Hz), to 2.55 (t, 1H, H-1); (13C, CDCl3): 204,6 174,6 148,3 130,6 99,2 74,7 73,6 69,3 66,3 65,4 31,9 22,6

EXAMPLE 15

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S, 3R,7R, 9R]-2,5,8-Trioxa-3,3,7-trimethyl-CIS-bicyclo[4.4.0] -Dec-9-yl-hydroxy-methyl] - 4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl - 3-(1-methylethyl)-1,4-methane in the atmosphere of nitrogen was added 10%hydrated palladium on coal (50 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 20 psi for 1 hour at room temperature. After filtering off the catalyst and evaporation of the solvent was obtained residue, which was subjected to chromatography rapid separation on silica gel, elwira a mixture of acetone: hexane (1:10) and (1:15) and receiving the result of the connection specified in the header (140 mg) as a white foam.

(1H, CDCl3): 9,81 (s, 1H, CHO), 6,03 (dd, 1H, H-2, J = 1.5 Hz), to 4.62 (dd, 1H, H-1', J = 2.1 Hz, J = 9.6 Hz), 4,35 - to 4.15 (m, 3H, 8aCH2, H-7' and H-1'), 3,40 (m, 2H, 8aCH2and OCH2) at 3.25 - 3.15 in (m, 2H, H-6' and OCH2), 2,52 (t, 1H, H-1), 1.33 and of 1.13 (2s, 2CH3); (13C, CDCl3): 204,7 174,1 148,3 130,6 98,0 73,4 73,3 65,1 64,7 31,9 21,1

EXAMPLE 16

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4S,6R, 8R]-2,7-Dioxa-4,6-dimethyl-CIS-bicyclo[3.4.0] non-9-yl-hydroxy-methyl] - 4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl - 3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate 20(a) (680 mg) in ethyl acetate (100 ml) under nitrogen atmosphere was added 10% palladium on coal (200 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 25 psi for 2 hours at room temperature. The residue was purified by chromatography rapid separation, elwira a mixture of dichloromethane: methanol (49:1) and receiving the result from the, or = 1.5 and 3.6 Hz), of 4.57 (dd, 1H, H-8', J = 2.4 and 9.3 Hz), Android 4.04 (d, 1H, 8a-H2, J = 9.6 Hz), 4,08 (m, 2H, H-1' and CH2-3'(1H)), with 3.27 (m, 3H, H-6', CH2-3' (1H), 8a-CH2(1H)), 2,47 (t, 1H, H-1, J= 3,9 Hz) of 1.02 (d, 3H, 4'-CH3, J = 6.6 Hz); (13C, CDCl): 204,7 173,8 (COOH), of 148.4(C-3), 130,5(C-2), to 98.5 (C-8'), and 75.2(C-1'), 74,3 73,3(C-3'), to 71.9 (C-6'), a 51.2 (C-5'), 36,0 (C-4'), 32,9(C-9'), 19,4 (4'-CH3).

EXAMPLE 17

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4S,6R, 8R]-2,7-Dioxa-4,6-dimethyl-CIS-bicyclo[3.4.0] non-8-yl-hydroxy-methyl] - 4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl - 3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 16 (450 mg) in methanol (100 ml) was added dropwise aqueous sodium hydroxide (0,099 N, and 9.5 ml). The solvent was removed under reduced pressure, and the residue was dissolved in water (80 ml) and liofilizirovanny, receiving the result of the connection specified in the header (470 mg).

(1H CD3OD): 9,86 (s, 1H, CHO), 5,94 (dd, 1H, H-2, J = 1.5 and 3.6 Hz), 4,43 (dd, 1H, H-8', J = 2.1 and 9.3 Hz), 4,13 - was 4.02 (m, 3H, 8a-CH2(1H), H-1', CH2-3'(1H), 3,74 (d, 1H, 8a-CH2, J = 9.9 Hz), 3,34 is 3.23 (m, 2H, CH2-3'(1H), H-6'), of 2.56 (t, 1H, H-1, J = 3,9 Hz), 2,34 (m, 1H, H-4'), 0,99 (d, 3H, 4'-CH3, J = 6.9 Hz); (13C CD3OD): 209,7 TO 178.4 (COO-Na+), 152,4 (C-3), to 130.1 (C-2), 100,1 (C-8'), for 77.2 (C-1'), 77,0 (C-3'), 75,3 (8a-CH2), 73,0 (C-6'), OF 52.8 (C-5'), 37,2 (C-4'), 34,5 (C-9'), 19,6 (4'-CH3).

EXAMPLE 18

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[is ethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate 23(a) (150 mg) in ethyl acetate (15 ml) under nitrogen atmosphere was added 10% palladium on coal (50 mg). The suspension was shaken in a Parr apparatus under hydrogen pressure of 25 psi for 2 hours at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was twice subjected to chromatography rapid separation on silica gel, using as eluents consistently mixture of dichloromethane : methanol (49 : 1) and hexane : acetone (4 : 1) to deliver the connection specified in the header (90 mg) as a white foam.

(1H CDCl3) : of 11.5 (bs, 1H, ), 9,87 (s, 1H, ), 6,04 (dd, 1H, H-2, J = 1.2 and 3.3 Hz), a 4.53 (dd, 1H, H-8', J = 2.4 and 9.9 Hz), 4,45 and 3.26 (2d, 2H, 8a-CH2, J = 9,3 Hz), 4,19 (q, 1H, H-1', J = 3.3 Hz), 3.96 points (t, 1H, CH2-3, J = 8,4 Hz) to 3.58 (m, 1H, H-6'), of 3.43 (dd, 1H, CH2-3', J = 10,2 Hz) to 2.55 (m, 1H, H04'); (13C, CDCl3) : 204,6 (CHO), OF 174.4 (COOH), 148,3 (C-3), TO 130.6 (C-2), IS 97.9 (C-8'), TO 78.7 (C-1'), 73,3 (C-3'), 72,9 OF 68.7 (C-6'), 46,1 (C-5'), 36,6 (C-4'), 34,02 (C-9'), 21,8 (6'-CH3), 13,6 (4'-CH3).

EXAMPLE 19

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4R,7R,9R]-2,8-Dioxa - 4,9-dimethyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4, 4a5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane - s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate 23(a) (150 mg) in ethyl acetate (15 Orada 20 psi for 1 hour at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. Thus obtained residue was purified by chromatography rapid separation, elwira a mixture of acetone : hexane (1 : 3), receiving the result of the connection specified in the header (100 mg) in the form of a crystalline substance.

(1H, CDCl3) : 9,86 (s, 1H, CHO), equal to 6.05 (dd, 1H, H-2, J = 1.2 and 3.3 Hz), 4,63 (dd, 1H, H-7', J = 3.3 and 6.6 Hz), 4,37 (d, 1H, 8aCH2I , JAB= 9.6 Hz), 3,98 and 3.67 (2dd, 2H, H-3', J = 6.6 and 8.1 Hz), 3,40 - 3,20 (m, 3H, 8aCH2, H-9' and H-1'), 2,46 (t, 1H, H-1, J = 3,9 Hz), was 1.04 (d, 3H ).

EXAMPLE 20

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4R,7R,9R]-2,8-Dioxa-4,9-dimethyl-CIS - bicyclo[3.4.0] -7-yl-oxy-methyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3a(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 19 (100 mg) in methanol (5 ml) was added dropwise hydroxy sodium (0,16 N solution in water, of 1.88 ml). After 30 minutes the solvent was removed under reduced pressure, and the residue was dissolved in water (3 ml) and liofilizirovanny, receiving the result of the connection specified in the header (104 mg).

(1H CD3OD) : 9,88 (s, 1H, CHO), to 5.93 (dd, 1H, H-2, J = 1.2 and 3.3 Hz),

of 4.49 (m, 1H, H-7'), was 4.02 (m, 2H, H-3' and 8aCH2), and 3.72 (d, 1H, 8aCH2I , JAB= 9,3 Hz), of 2.56 (t, 1H, H-1, J = 3.6 Hz); (13C CD3OD): the KSA-4,9-dimethyl-CIS-bicyclo[3.4.0] non-7 - yl-oxy-methyl] -4-formyl-4, 4a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate sections 23(b) (260 mg) in ethyl acetate was added 10% palladium on coal (50 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 20 psi for 1 hour at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. Then the residue was purified by preparative TCX (silica gel, methanol : dichloromethane 1 : 20), receiving the result of the connection specified in the header (185 mg), in the form of oil with Ff= 0,6.

(1H, CDCl3) : 9,85 (s, 1H, CHO), 6,04 (dd, 1H, H-2, J = 1.5 t and 3.6 Hz), 4,88 (t, 1H, H-7', 2.7 Hz), 4,27 and 3,28 (2d, 2H, 8aCH2I , JAB= 9.9 Hz), 3,85, and to 3.73 (2m, 2H, OCH2), of 3.60 (m, 1H, H-9'), 3,37 (dd, 1H, H-1', J = 7,2 and 8.4 Hz), 2,47 (m, 3H, ); (13C,CDCl3): 204,4 173,7 148,2 (C-3), 130,5 (C-2), BY 98.7 (C-7'), 81,2 (C-1'), 72,8 TO 69.9 (C-9'), AND 25.4 (C-6'), 12,4

EXAMPLE 22

[1R-(1,3 a,4,4 a,7,7 a,8a) 8a-[[1S, 7R,9R]-2,8-Dioxo-4,4, 9-trimethyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4, 4a,5,6,7,7a8,8a-octahydro-7-methyl-3-(1-methylethyl)-(1,4-methane-s - indocin-3a(1H)-carboxylic acid

To a solution of Intermediate compound 24 (100 mg) in ethyl acetate (40 ml) under nitrogen atmosphere was added 10% palladium on coal (50 mg). The mixture was shaken in a Parr was shaken in a Parr apparatus at a pressure of water is up to dry. The residue was twice subjected to chromatography rapid separation, using as eluents sequentially with 1.5% methanol in dichloromethane and 15% acetone in hexane to deliver the connection specified in the header (40 mg) as a white foam.

(1H, CDCl3) : 9,85 (s, 1H, CHO), equal to 6.05 (dd, 1H, H-2, J = 1.2 and 3.6 Hz), 4,84 (t, 1H, H-7', J = 3 Hz), 4,23 and 3,29 (2d, 2H, 8a-CH2, J = 9.6 Hz), 3,81 (t, 1H, H-1', J = 8.7 Hz), 3,52 (dq, 1H, H-9', J = 9.3 and 6.3 Hz), 3,50 and 3,42 (2d, 2H, CH2-3', J = 8,4 Hz), 2,48 (t, 1H, H-1, J = 4, 2 Hz), 1,09 and 0.98 (2s, 6H, 4'-CH3); (13C, CDCl3): 204,5 174,0 148,2 130,5 (C-2), BY 98.7 (C-7'), 81,01 (C-1'), OF 78.8 (C-3'), 72,7 TO 70.2 (C-9'), A 41.3 (C-4'), 40,4 (C-5'), 27,3 (4'-CH3), 26,5 (C-6'), 22,8 (4'-CH3).

EXAMPLE 23

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(6-deoxy-3,4-o-isopropylidene--D-allopregnanolone)-methyl] -4-formyl-4,4 a, 5,6,7,7 a,8,8 a - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid

To a solution of Intermediate 27 (125 mg) in methanol (25 ml) under nitrogen atmosphere was added 10% palladium on coal (100 mg). The mixture was shaken for 1.5 hours at room temperature. The catalyst was filtered and to the filtrate at 0oC was added 1N hydrochloric acid (0.5 ml). After stirring for 1 hour the mixture was neutralizable 10% hydroxycarbonate sodium. The solvent was evaporated to dry with the Yu hexane : ethyl acetate (4 : 1) and dichloromethane : methanol (20 : 1) to deliver the connection, specified in the header (62 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), 6,10 (dd, 1H, H-2, J = 1.2 and 3.3 Hz), 4,51 (t, 1H, H-2', J = 4.5 Hz), 4,48 (d, 1H, H-1', J = 7.5 Hz), 3,65, and 4,07 (2d, 2H, 8aCH2, J = 9,3 Hz), of 3.78 (dd, 1H, H-4', J = 9 and 5.1 Hz), of 3.69 (dd, 1H, H-3', J = 7,5 and 5.1 Hz), 3,50 (m, 1H, H-5', J = 6 and 9 Hz), 2,59 (t, 1H, H-1, J = 3,9 Hz), 2,32 (m, 1H, CHMe2);13C, CDCl3): 204,6 (CHO), 176,1 (CO2H), 148,2 (C-3), 130, 8mm (C-2), 110,4 (Quaternary C Isopropylidene), to 100.9 (C-1'), 78,34 (C-4'), a 75.1 (C-2'), 74,7 (ASN2), to 72.5 (C-4a), of 71.7 (C-3') and 69.3 (C-5'), 65,6 (C-8a), of 58.9 (C-4), and 46.3 (C-1).

EXAMPLE 24

[1R- (1,3 a,4,4 a,7,7 a,8a) 8a-[(2-deoxy-3,4-o-isopropylidene-6-O-methyl-a-D-allopregnanolone)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

A solution of Intermediate 30 (50 mg) in tetrahydrofuran (5 ml) at room temperature was treated with tetrabutylammonium (a 1.0 M solution in tetrahydrofuran, 200 ml). After 24 hours the reaction mixture was concentrated until dry, and the resulting yellow oil was purified by column chromatography rapid separation, elwira a mixture of dichloromethane : methanol (15 : 1) to deliver the connection specified in the header (18 mg).

(1H, CDCl3): 9,80 ('s. 1H, CHO), 5,98 (dd, 1H, H-2, J = 1.2 and 3.3 Hz), with 4.64 (dd, 1H, H-1', J = 2.7 and 8.1 Hz), 4,42 (m, 1H, H-3'), 3.68 and 4,01 (2d, s of isopropylidene); (13C, CDCl3): 206,3 (CHO), 175,7 (CO2H), 149,7 (C-3), 129,7 (C-2), 108,9 (C-Quaternary isopropylidene), of 98.2 (C-1'), 74,8 (C-3a), 74,8 (C-4), 74,4 (8aCH2), to 72.6 (C-3'), which accounted for 71.3 (C-5'), a total of 65.1 (C-8a), with 61.1 (C-6'), 58,4 (C-4), 48,4 (6'-OMe), 46,1 (C-1), is 32.8 (C-2').

EXAMPLE 25

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4R,7R,9R]-2,8-Dioxa-4-ethyl-9-methyl-CIS-bicyclo[3.4.0] non-7-yl - oxy-methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1 - methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of intermediate 37 (200 mg) in ethylacetate (40 ml) under nitrogen atmosphere was added 10% palladium on coal (50 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 30 psi at room temperature for 2 hours. The catalyst was filtered and the solvent evaporated until dry. Thus obtained residue was subjected to chromatography rapid separation on silica gel, using as eluent a mixture of dichloromethane : methanol (98 : 2) to deliver the connection specified in brackets (125 mg).

(1H, CDCl3): 9,86 (s, 1H, CHO), equal to 6.05 (dd, 1H, H-2, J = 1.5 and 3.3 Hz), of 4.66 (dd, 1H, H-7', J = 3.0 and 6.0 Hz), 4,32 and 3,29 (2d, 2H, 8a-CH2, J = 9.6 Hz), was 4.02 (dd, 1H, CH2-3', (1H), J = 7,2 and 8.4 Hz), to 3.67 (dd, 1H, H-1', J = 7,8 and 9.3 Hz), 3,41 - up 3.22 (m, 2H, H-9' and CH2-3' (1H)), 2,48 (t, 1H, H-1, J = 3,9 Hz) to 0.92 (t, 3H, J = 7.5 Hz); (13C, CDCl3): 204,5 (CHO), 174,2 (COOH), 148,3 (C-is Il-9-methyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl -4,4 a,5,6,7,7 a, 8, 8A-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 25 (88 mg) in methanol (10 ml) was added dropwise 0,099 N aqueous sodium hydroxide (1.8 ml). The solvent was removed under reduced pressure, and the residue was dissolved in water (50 ml) and liofilizirovanny, receiving the connection specified in the header (92 mg).

(1H DMSO-d6): 9,77 (s, 1H, CHO), 5,78 (m, 1H, H-2), and 4.40 (brdd, 1H, H-7'), 3,92 (m, 1H, H-3'), a 3.87 (d, 1H, 8a-CH2(1H), J=9.6 Hz), 3,50 (m, 2H, 8a-CH2(1H) and H-1'), 3,38-is 3.21 (m, 2H, H-3' and H-9').

EXAMPLE 27

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S,4S,7R,9R]-2,8-Dioxa-4-ethyl-9-methyl-CIS-bicyclo [3.4.0] non-7-yl-oxy-methyl] -4-formyl -4,4 a,5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1 - methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of intermediate 38 (420 mg) in ethyl acetate (80 ml) under nitrogen atmosphere was added 10% palladium on coal (100 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 30 psi at room temperature for 1.5 hours. The catalyst was filtered, the solvent is evaporated to the dry state, thus obtained residue was purified by chromatography rapid separation on silica gel, using as eluent a mixture of dichloromethane: methanol (98:2) and getting in and 3.6 Hz), 4,89 (m, 1H, H-7'), 4,29 and 3,29 (2d, 2H, 8a-CH2, J=9.9 Hz), 3,90 (dd, 1H, H-3', J=7.5 and 8.7 Hz), of 3.75 (m, 1H, H-1'), to 3.64 (m, 1H, H-9'), of 3.43 (t, 1H, H-3', J= 8.7 Hz), 2,46 (t, 1H, H-1, J=3.6 Hz), of 0.93 (t, 3H, J=7.2 Hz); (13C, CDCl3): 204,4 (CHO), 173,7 (COOH), 148,2 (C-3), 130,5 (C-2), 98,8 (C-7'), 81,3 (C-1'), 72,8 and 70.9 ((8A-C) and C-3'), 69,8 (C-9').

EXAMPLE 28

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8A- [[1S, 4S,7R, 9R]-2,8-Dioxa-4-ethyl-9-methyl-CIS-bicyclo[3.4.0] non-7-yl-hydroxy-methyl [4-formyl -4,4 and,5,6,7,7 a, 8,8-octahydro-7-methyl - 3- (1-methylethyl) -1,4-methane-s-indocin-3A(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 27 (262 mg) in methanol (20 ml) was added dropwise 0,099 N aqueous sodium hydroxide (5.3 ml). The solvent was removed under reduced pressure, and the residue was dissolved in water (100 ml) and liofilizirovanny, receiving the result of the connection specified in the header (272 mg).

(1H, DMSO-d6: 9,77 (s, 1H, ), 5,79 (dd, 1H, H-2, J=1.2 and 3.6 Hz), of 4.57 (m, 1H, H-7'), 3,83 and 3.45 (2d, 2H, 8a-CH2, J=9.6 Hz), 3,76 and 3.33 (2m, 2H, CH2-3'), 3,52 (m, 2H, H-1' and H-9').

EXAMPLE 29

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[[1S,4R,7R,9R]-2,8-Dioxa - 4-(1-methylethyl)-9-methyl-CIS-bicyclo [3.4.0] non-7-yl - oxymethyl) 1-4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3a(1H)carboxylic acid

To a solution of intermediate 39 (280 mg) in ethyl acetate (15 ml) under nitrogen atmosphere was added palladium (10%) n the filtration of the catalyst and evaporation of the solvent was obtained residue, which was purified by chromatography rapid separation (silica gel, hexane: acetone/10: 1 and 5:1), resulting in the 180 mg of the compound indicated in the title, in the form of an oil (yield 84%).

(1H, CDCl3): 12-11 (b, 1H, COOH), 9,88 (s, 1H, CHO), 6,053 (dd, 1H, H2, J=1.5 and 3.6 Hz), of 4.77 (m, 1H, H7'), 4,37 (d, 1H, 8aCH2, J=9,3 Hz), 3,95 (dd, 1H, H3', J=7.2 and 8.7 Hz), to 3.67 (dd, 1H, H1', J=8.7 and 9 Hz), 3,5-on 3.36 (m, 2H, H3'+H9'), 3,23 (d, 1H, 8aCH2J=9,3 Hz), 2,43 (t, 1H, H1, J=3,9 Hz).

EXAMPLE 30

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[[1S,4R,7R,9R]-2,8-Dioxa-4-(1-methylethyl)-9-methyl-CIS-bicyclo [3.4.0] non-7-yl-oxymethyl)]-4-formyl-4,4 a, 5,6,7,7 and, 8, 8A-octahydro-7-methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3a(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 29 (170 mg) in methanol (15 ml) was added 0,0956 N sodium hydroxide solution (3,45 ml). After stirring for 1 hour the solvent was removed until dry, receiving the substance, which was dissolved in 3 ml of water and dried by freezing.

(1H, CDCl6): 9,78 (s, 1H, CHO), 5,80 (dd, 1H, H2, J=1.2 and 3.6 Hz), 4,46 (dd, 1H, H7', J=2.7 and 5.1 Hz), from 3.9 to 3.8 (m, 2H, H3'+8aCH2), of 3.54 (dd, 1H, H1', J= 8.1 and 9 Hz), 3,47 (d, 1H,8aCH2, J=9,3 Hz); (13C, DMSO-d6): 206,4 174,3 (COO-), 151, 3mm Uniforms, 127.6 97,1 (C7'), 80,7 (C1').

EXAMPLE 31

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S,4S,7R,9R)-2,8-Dioxa-4-(1-methylethyl) -9-methyl-CIS-bicyclo [3.4. the slot

To a solution of compound from Example 40 (280 mg) in ethyl acetate (15 ml) under nitrogen atmosphere was added palladium (10%) coal (50 mg). The mixture was shaken in a Parr apparatus (PH2= 20 psi) for 1 hour at room temperature. After filtration of the catalyst and evaporation of the solvent was obtained residue, which was subjected to chromatography rapid separation (silica gel, hexane: acetone/10:1 and 5:1), to deliver 190 mg of the compound indicated in the title, in the form of a crystalline substance (yield 89%).

(1H, CDCl3): 9,88 (s, 1H, CHO), equal to 6.05 (dd, 1H, H2, J=1.5 and 3.3 Hz), 4.92 in (1,1 H, H7', J=2.7 Hz), 4,33 (d, 1H,8aCH2, J=10,2 Hz), of 3.94 (t, 1H, H3', J= 8,1 Hz), and 3.8 to 3.7 (m, 2H, H1'+H9'), 3,47 (dd, 1H, H3', J=8,4 and 10.8 Hz), 3,29 (d, 1H, 8aCH2, J=10.5 Hz).

EXAMPLE 32

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[1S,4S,7R,9R)-2,8-Dioxa-4-(1-methylethyl) -9-methyl-CIS-bicyclo [3.4.0] non-7-yl-oxymethyl)]-4-formyl-4, 4a, 5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin - 3A(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 31 (165 mg) in methanol (15 ml) was added 0,0956 N sodium hydroxide solution (3,35 ml). After stirring for 1 hour the solvent was removed until dry, receiving the substance, which was dissolved in 3 ml of water and dried by freezing.

(1H, CDC, =9.9 Hz); (13C, CDCl3): 206,3 174,3(COO-), 151,4 127,5 96,7 (C7'), 80,8 (C1').

EXAMPLE 33

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[[1S,7R,9R]-2,8-Dioxa-9-methyl-4-methylene-CIS-bicyclo [3.4.0] non-7-yl-hydroxy-methyl) 1-4-formyl-4,4 a,5,6,7,7 a, 8,8-octahydro - 7-methyl-3-(1-methylethyl)-1.4-methane-5-indocin-3A(1H)-carboxylic acid

To a cooled with ice to a solution of intermediate 41 (330 mg) in dichloromethane (4 ml) was added triperoxonane acid (0.2 ml). The mixture was stirred for 20 minutes at 0oC and then was diluted with dichloromethane (150 ml), washed three times with water (100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated until dry, getting in the oil, which was subjected to chromatography rapid separation on silica gel, using as eluent a mixture of dichloromethane: methanol (98:2). The appropriate fractions were then collected and subjected to RP-18 under medium pressure (10 bar), using a linear gradient of acetonitrile (60 to 75%) in water and receiving the result of the connection specified in the header.

(1H, CDCl3): 9,87 (s, 1H ), 6,04 (d, 1H, H-2, J=3.3 Hz), 5.08 to and 5,02 (2m, 2H, ), 4,50 (dd, 1H, H-7', J=2.7 and 8.4 Hz), 4,48 - the 4.29 (m, 3H, 8A-CH2(1H)), 3,76 (dd, 1H, H-1', J-7.2 and 9.3 Hz), with 3.27 (m, 1H, H-9'), to 3.02 (m, 1H, H-5'), of 2.45 (m, 1H, H-1); (13C, CDCl3): 205,1 176,0 of 148.6 ( methyl-4-methylene-dis-bicyclo [3.4.0] non-7-yl-hydroxy-methyl) 1 - 4-formyl-4,4 a, 5, 6,7,7-a, 8,8-octahydro-7-methyl-3- (1 - methylethyl) -1,4-methane-s-indocin-3A(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 33 (140 mg) in methanol (15 Il) was added dropwise 0,945 N aqueous sodium hydroxide (3,06 ml). The solvent was removed under reduced pressure, and the residue was dissolved in water (60 ml) and liofilizirovanny, receiving the result of the connection specified in the header (145 mg).

(1H, DMSO-d6): 9,76 (5,1 H ), USD 5.76 (d, 1H, H-2, J=3.3 Hz), 5,04 (m, 2H ), 4,34-4,20 (m, 3H, H-7' and CH2-3'), 3,84, and a 3.50 (2d, 2H, 8a-CH2, J= 9.9 Hz), 3,62 (dd, 1H, H-1', J=7.5 and 9.3 Hz), 3.15 in (m, 1H, H-9'), 2,89 (m, 1H, H-5').

EXAMPLE 35

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[[1S,7R,9R]-2,8-Dioxa - 9-methyl-4-methylene-3-oxo-CIS-bicyclo [3.4.0] non-7-yl - hydroxy-methyl)] 4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of intermediate 42 (62 Mg) in dry dichloromethane (1.1 ml) was added triperoxonane acid (0.05 ml). The mixture was stirred at 0oC for 20 minutes, then was diluted with dichloromethane (50 ml) and washed with water (I ml). The organic layer was dried over anhydrous sodium sulfate and concentrated, resulting in the oil, which was twice subjected to chromatography rapid separation on silica gel, using kachestva pale yellow (25 mg).

(1H, CDCl3): of 9.75 (s, 1H, CHO), 6.35mm and 5.63 (2d, 2H, H2C=C, J=3.3 Hz),

6,04 (dd, 1H, H-2, J=1.2 and 3.3 Hz), to 4.52 (t, 1H, H-7', J=4,8 Hz), 4,24 (t, 1H, H-4', J=8.7 Hz), 4.09 to and 3.46 (2d, 2H, 8a-CH2, J=9,3 Hz) to 3.38 (m, 1H, H-5'), 3,30 (m, 1H, H-9'), 2,59 (t, 1H, H-1, J=3,9 Hz); (13C, CDCl3): 204,5 (CHO), 175,3 (COOH), 169,7(C-3'), 148,2 (C-3), 136,8 (C-4'), to 130.6 (C-2), 122,4 of 97.7(C-7'), 77,8(C-1') and 71, 2 (C-9').

EXAMPLE 36

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[[1S, 7R,9R]-2,8-Dioxa-9-methyl-4-methylene-3-oxo - CIS-bicyclo[3.4.0] non-7-yl-hydroxy-methyl)] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a - octahydro-7-methyl-3-(1-methyl-ethyl)-1,4-methane-s-indocin-3a(1H)- carboxylic acid sodium salt

To a solution of the compound from example 35 (25 mg) in methanol (10 ml) was added dropwise 0,0945 N aqueous sodium hydroxide (0,53 ml). The solvent was removed under reduced pressure, and the residue was dissolved in water (25 ml) and liofilizirovanny, receiving the result of the connection specified in the header (26 mg).

(1H, DMSO-d6): of 9.75 (s, 1H, CHO), 6,15 and 5.82 (2d, 2H, J=3.3 Hz), 5,76 (brd, 1H, H-2), or 4.31 (dd, 1H, H-7', J=2.4 and 7.8 Hz), 4,24 (t, 1H, H-1', J=8.7 Hz), 3,84, and 3,52 (2d, 2H, 8a-CH2, J=9.9 Hz), to 3.38 (m, 1H, H-5'), 3,21 (m, 1H, H-9').

EXAMPLE 37

[1R- (1,3 a,4,4 a,7,7 a,8a) ]8a-[(1S,7R, 9R]-2,8-Dioxa-9-methyl-4-oxo-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl]- 4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3-(1-methyl-ethyl)-1,4 - methane-s-indocin-3a(1H)-carboxylic acid

To a solution of intermediate connection in a Parr apparatus under hydrogen pressure of 25 psi for 1 hour at room temperature. The catalyst was filtered and the solvent evaporated until dry. Thus obtained residue was purified by chromatography rapid separation on silica gel, using as eluent a mixture of hexane:ethyl acetate (65:35) and was received as a result of the connection specified in the header (25 mg).

(1H, CDCl3): 9,77 (s, 1H, CHO), equal to 6.05(dd, 1H, H-2, J=2, J=1.5 and 3.6 Hz), 4,17 (m, 4H, H-3'(1H), 8a-CH2(1H), H-7' and H-1'), 3,90 (d, 1H, H-3'(1H), J= 17,7 Hz), 3,42 (d, 1H, 8a-CH2(1H), J=9 Hz) and 3.31 (m, 1H, H-9'), 2,85 (m, 1H, H-5'), 2,58 (t, 1H,H-3, J=3,9 Hz); (13C, CDCl3): 214,4(C-4), 204,8 148,3 (C-3), to 130.6(C-2), the 98.9(C-7'), 78,6 and is 70.3 (C-1' and C-9'), 73,6 69.1 and C-3').

EXAMPLE 38

[1R- (1,3 a,4,4 a,7,7 a,8a) ]-8a-[[1S,4S,6S,7R, 9R]-2,8-Dioxa-4-ethyl-6-hydroxy-9-methyl-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4,4-a, 5,6,7 a, 8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of Intermediate 45 (123 mg) in ethyl acetate (50 ml) under nitrogen atmosphere was added 10% palladium on coal (65 mg) and hydrogenosomal the mixture under hydrogen pressure of 15 psi for 1 hour at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of dichloromethane: IU): 9,67(s, 1H, CHO), 6,07 (d,1H,H-2, J=3.3 Hz), with 4.64 (d, 1H, h-7', J=3.6 Hz), was 4.02 (d,1H, 8aCHa, J=9.9 Hz), with 3.89 (dd, 1H, Ha-3', J=6.9 and 9 Hz), 3,85 to 3.7 (m, 3H, H-6', H-1' and H-9'), 3,68 to 3.5 (m, 2H, Hb-3' and 8a-CHb), 2,65 (t, 1H, h-1, J= 3.6 Hz); (13C, CDCl3): 204,9 (CHO), 176,3 (CO2H), 148,9(C-3), to 130.1 (C-2), and 99.2 (C-7'), 80,5, 70,1 and 65.5 (C-6', C-9'), 73,7 and 71.0 ( C-3'), 13,4

EXAMPLE 39

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a[(1S, 4R, 6S, 7R, 9R]-2,8-Dioxa-4-ethyl-6-hydroxy-9-methyl-CIS-bicyclo [3.4.0] non-7-yl-oxymethyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3a(1H)-carboxylic acid

To a solution of intermediate 46 (102 mg) in ethyl acetate (25 ml) under nitrogen atmosphere was added 10% palladium on coal (60 mg), the mixture was hydrogenosomal when the hydrogen pressure of 15 psi for 1 hour at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of dichloromethane:methanol (25:1), receiving the result of the connection specified in the header (75 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1,2, J=1.2 and 3.6 Hz), a 4.53 (d,1H, H-7', J=1.8 Hz), of 4.05 (dd, 1H, Ha-3',J=7,2 and 8.4 Hz), was 4.02 (d, 1H, 8a-CHa, J=9.3 Hz), 3,83 (dd, 1H,H-1', J=7.2 and 8.7 Hz), and 3.72 (dd, 1H, H-6', J= 2.1 and 4.8 Hz), to 3.64 (d, 1H, 8a-CHb, J=9,3 Hz), 3,54-to 3.36 (m, 2H, H-9' and Hb-3'), 2,68 (t, 1H, H-1, J=3,9 Hz) to 0.96 (t, 3H, J=7,5);13C, CDCl3): 204,7 (CHO), 176,1 S, 4R, 6S, 7R, 9R]-2,8-Dioxa- -4-ethyl-6-hydroxy-9-methyl-CIS-bicyclo [3.4. O] 1-non - 7-yl-oxy-methyl]-4-formyl-4,4 a, 5,6,7,7 and 8,8 and octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid sodium salt

To a solution of the compound from Example 39 (490 mg) in methanol (50 ml) was added dropwise 0,095 N aqueous sodium hydroxide solution (10 ml). After 30 minutes the solvent was removed under reduced pressure, and the residue was dissolved in water (10 ml) and liofilizirovanny, receiving the result of the connection specified in the header (475 mg).

(1H, (CD3)2)SO): 9,77 (s, 1H, CHO), and 5.8 (d, 1H, H-2, J=2,4 Hz) to 4.41 (bs, 1H, -OH), or 4.31 (d,1 H, H-7', J=2.1 Hz), 3,94-3,82 (m, 2H, 8aCHa and Ha-3'), 3,66 (t, 1H, H-1', J=8.1 Hz), 3,54-to 3.34 (m, 3H, 8aCHb, H-6' and H-9'), 3,24 (t, 1H, Hb-3, J=8.1 Hz), to 2.55 (t, 1H, H-1, J=3.6 Hz).

EXAMPLE 40

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[1S,4R,6S,7R,9R]-2,8 - Dioxa-4-ethyl-6-hydroxy-9-methyl-dis-bicyclo [3.4.O]-non-7 - yl-oxy-methyl]-4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7 - methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3A (1H)-carboxylic acid sodium salt

To a solution of the compound from Example 39 (490 mg) in methanol (50 ml) was added dropwise 0,095 N aqueous sodium hydroxide solution (10 ml). After 30 minutes the solvent was removed under reduced pressure, and the residue was dissolved in water (10 ml) and liofilizirovanny, receiving the connection, decree, H, H-7', J=2.1 Hz), 3,94-3,82 (m, 2H, 8aCHa and Ha-3'), 3,66 (t, 1H, H-1', J-8.1 Hz), 3,54-to 3.34 (m, 3H, 8aCHb, H - 6' and H-9'), 3,24 (t, 1H, Hb-3',J=8.1 Hz), to 2.55 (t, 1H, H-1, J=3.6 Hz).

EXAMPLE 41

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[[1S,7R,9R]2,8-Dioxa-9-methyl-4-oxo-CIS-bicyclo [3.4.0] non-7-yl-oxymethyl] 1-4-formyl-4, 4A, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3A(1H)-carboxylic acid sodium salt

To a solution of intermediate 43 (350 mg) in ethyl acetate (15 ml) under nitrogen atmosphere was added palladium (10%) coal (50 mg). The mixture was shaken in a Parr apparatus (PH2=25 psi) for 1 hour at room temperature. After filtration of the catalyst and evaporation of the solvent was obtained residue, which was subjected to chromatography rapid separation (silica gel, dichloromethane: methanol/100:1, 70:1 and 50:1), to deliver 200 mg of a foam which was dissolved in methanol (10 ml) and treated 0,0947 M sodium hydroxide (4,54 ml). The solvent was removed under vacuum, and the resulting substance was dissolved in water (15 ml) and dried by freezing.

(1H, DMSO-d6): 9,76 (s, 1H, CHO), 5,80 (dd, 1H, H2, J=0.9 and 3.3 Hz), 4,20-3, 95(m, 4H, H7'+H1+H3'), to 3.89 (d, 1H, 8aCH2, J=9.6 Hz), 3,47(d, 1H, 8aCH2=9.6 Hz), of 2.92(m, 1H, H5').

EXAMPLE 42

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8a-[(1S,4R,7R,9R)-2,8-Dioxa-4-methoxy-9-methyl-dis-bicyclo [3.4.0] non-7-yl-oxymethyl the l

To a solution of intermediate 82 (250 mg) in ethyl acetate (15 ml) under nitrogen atmosphere was added palladium (10%) coal (50 mg). The mixture was shaken in a Parr apparatus (PH2=25 psi) for 1 hour at room temperature. After filtration of the catalyst and evaporation of the solvent was obtained residue, which was subjected to chromatography rapid separation (silica gel, dichloromethane: methanol 100: 1, 70:1, 50:1 and 40:1), receiving the 120 mg syrup, which was dissolved in methanol (15 ml) and treated 0,0947 M sodium hydroxide (of 2.51 ml). After removal of solvent received semi-solid substance, which was dissolved in water (15 ml) and dried by cooling.

(1H, DMSO-d6): 9,77 (s, 1H, CHO), 5,80 (dd, 1H, H2,J=1.2 and 3.3 Hz), 4,47 (t, 1H ,H7', J=3.9 Hz), 3.96 points-a-3.84 (m, 2H,H3'+ASN2), of 3.80 (m, 1H, H4'), 3,65 is 3.40 (m, 4H, H9'+8aCH2+H3'+H1'), 3,23 (s, 3H, OCH3), 2,46-2,2 (m,4H, H1+h6'+H5'+CH(CH3)2; (13C,DMSO-d6): 206,4 of 174.4 151, 3mm uniforms, 127.6 96,9 84,1 (C4'), 56,6

EXAMPLE 43

[1R- (1,3 a,4,4 a,7,7 a,8a)] 8A-[[1S,7R,9R)-2,8-Dioxa-9-methyl-bicyclo [3.4.0] non-4-EN-7-yl-oxymethyl]-4-formyl-4,4 a,5,6,7,7 a, 8, 8A-octahydro-7-methyl-3- (1-methylethyl) -1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of intermediate 87 (120 mg) in dry dichloromethane (20 ml) at 0oC in an atmosphere of nitrogen was added to trifero the m (100 ml), then was dried over magnesium sulfate and concentrated, to give crude product, which was dissolved in a mixture of tetrahydrofuran: methanol (2:1, 15 ml) and was treated with 1N hydrochloric acid (5 ml). After completion of the reaction, it was diluted with water (100 ml) and was extracted twice with dichloromethane. The organic layer was dried over magnesium sulfate, getting an oil, which was purified by preparative TLC (silica gel; acetone: hexane 1: 3), resulting in the 62 mg compounds; specified in the header (yield 73%) as white foam.

(1H, CDCl3): 9,79 (s, 1H, CHO), the 6.06 (dd, 1H, H2, J=1.2 and 3.3 Hz), 5.56mm (m, 1H, H4'), 4,65 with 4.65 (m, 2H, H3'), a 4.3 to 4.0 (m, 3H, H7+8aCH2+ H1'), 3,50 (d, 1H, 8aCH2, J=9 Hz), 3,18 (dq, 1H, H9', J=6.3 and 9 Hz), of 2.72 (m, 1H, H6'), 2,62 (t, 1H, H1, J=3 Hz); (13C, CDCl3): 204,6 175,2 148,3 136,3 (C5'), To 130.6 (C2), 119,15 (C4'), 101,5 (C7'), 86,5 (C1').

EXAMPLE 44

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(1S,7R,9R)-2,8-Dioxa-9-methyl-bicyclo[3.4.0] non - 4-ene-yl-oxymethyl-4-(formyl-4,4 a, 5,6,7,7 a,8,8 and octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid sodium salt

To a solution of compound from Example 43 (50 mg) in methanol (5 ml) was added 0,0966 N sodium hydroxide (1,09 ml). The mixture was stirred for 15 minutes and the solvent was removed to dry. The residue was dissolved in water (1 ml) and dried of Zamaraev is C), 4,05-3,90 (m, 2H, H1'+8aCH2), of 3.56 (d, 1H, 8aCH2, J=9.6 Hz), 3,06( dq, 1H, H9', J= 6.3 and 8.7 Hz); (13C, DMSO-d6): 215,9 183,9 160,9 146,1(C5', 137,2(C2), 128,3(C4'), 110,9 (C7'), 95,7(C1').

EXAMPLE 45

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(1S,7R,9R)-Dioxa-9-methyl-CIS-bicyclo[3.4.0] non-7-yl-oxymethyl]-4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro-7-methyl - 3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of intermediate 87 (100 mg) in ethyl acetate (15 ml) under nitrogen atmosphere was added palladium (10%) coal (50 mg). The mixture was shaken in a Parr apparatus (PH2=20 psi) for 1 hour at room temperature. After filtration of the catalyst and evaporation of the solvent was obtained residue, which was dissolved in a mixture of tetrahydrofuran: methanol (2:1, 15 ml) and was treated with 1N hydrochloric acid (5 ml). After the reaction was added dichloromethane (100 ml) and water (100 ml) and separated the two layers. The organic layer was dried over magnesium sulfate and concentrated, obtaining oil, which was purified by preparative TLC (hexane: acetone/3:1) to give 20 mg of the compound indicated in the title, in the form of a clear oil (total yield 30%).

(1H, CDCl3): 9,86 (s, 1H, CHO), equal to 6.05 (dd, 1H, H2, J=1.5 and 3.6 Hz), 4,07 (dd, 1H, H7', J=3 and 5.4 Hz), 4,33 (d, 1H, 8aCH2, J=9.6 Hz), 3,90 (m, 1H, H3'), of 3.69 (m, 1H, H3'), 3="ptx2">

EXAMPLE 46

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(1S,7R,9R)-2,8-Dioxa-4,9-dimethyl-6-hydroxy-CIS - bicyclo[3.4.0] non-4-EN-7-yl-oxymethyl]-4-formyl-4,4 a, 5,6,7,7 a, 8,8 - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indacene(1H)-carboxylic acid sodium salt

To a solution of Intermediate compound b (90 mg) in ethyl acetate (25 ml) under nitrogen atmosphere was added 10% palladium on coal (50 mg) and the resulting mixture was hydrogenosomal when the hydrogen pressure of 40 psi for 45 minutes at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was subjected to chromatography rapid separation on silica gel, elwira a mixture of dichloromethane: ethyl acetate (10:1), receiving the result of the connection specified in the header (60 mg).

(1H, CDCl3): 9,74 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.5 and 3.6 Hz), a 4.53 (d, 1H, H-7', J=2.1 Hz), 4.09 to (d, 1H, 8a-CHa, J=9.6 Hz), was 4.02 (dd, 1H, Ha-3', J= 7,5 and 8.4 Hz), of 3.84 (dd, 1H, H-1', J=7,8 and 9 Hz), 3,74 (dd, 1H, H-6', J= 2.1 and 5.1 Hz), 3,60 (d, 1H, 8a-CHb, J=9,3 Hz), 3,42 (dq, 1H, H-9', J=6 and 9 Hz), 3,34 (t, 1H, Hb-3', J=8.7 Hz), 2,66 (t, 1H, J=3,9 Hz).

EXAMPLE 47

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(1S,4R,6S,7R,9R)-2,8-Dioxa-4,9-dimethyl-6-hydroxy-CIS-bicyclo [3.4.0] non-7-yl-oxy-methyl]-4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A (1H)-carboxylic acid sodium salt

To a solution of coedine 15 minutes the solvent was removed under reduced pressure, and the residue was dissolved in water (10 ml) and liofilizirovanny, receiving the result of the connection specified in the header (250 mg).

(1H, (CD3)2SO): 9,77 (5, 1H, CHO), 5,79 (d, 1H, H-2, J=3.6 Hz), the 4.29 (d, 1H, H-7', J=1.8 Hz), 3,94 to 3.8 (m, 2H, 8a-CHa and Ha-3'), to 3.67 (t, 1H, H-1', J=8,4 Hz), 3, 55-3, 25(m, 3H, 8a-CHb, H-6',H-9'), 3,14 (t, 1H, Hb-3', J= 8,4 Hz) to 2.54 (t, 1H, H-1, J=3.6 Hz).

EXAMPLE 48

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-(((2,3,6-Trideoxy-3 - ethylamino-3-N, 4-O-carbonyl - D-allopurinol)oxy)methyl) - 4-formyl-4,4 a,5,6,7,7 a, 8,8-octahydro-7-methyl-3-(1-methylethyl)- 1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of intermediate 96 (180 mg) in ethyl acetate (15 ml) under nitrogen atmosphere was added palladium (10%) coal (30 mg). The mixture was shaken in a Parr apparatus (PH2=20 psi) for 2 hours at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was purified by column chromatography rapid separation on silica gel, elwira a mixture of hexane: ethyl acetate 1:1, resulting in the pure GM H (70 mg).

(1H, CDCl3): 9,76 (s, 1H, ), equal to 6.05 (dd, 1H, H-2, J=3.0 and 1.2 Hz), with 4.64 (dd, 1H, H-1', J=5.7 and 3.3 Hz), 4,11 (m, 2H, H-3',H-4'), Android 4.04 (d, 1H, H-8a, J=9.3 Hz), 3,62 (dq, 1H, H-5', J=8.4 and 6.0 Hz), 3,51 (d, 1H, H-8a, J= 9.3 Hz), 3,49 (m, 1H, ), of 3.13 (m, 1H, ), 2,62 (t, 1H, H-1, J= 3.6 Hz), 2,32 (m, 1H,) and 1.15 (t, 3H, J=7.2 Hz); (13With, CDCl3
To a solution of Intermediate 50 (140 mg) in ethyl acetate (20 ml) under nitrogen atmosphere was added 10% palladium on coal (100 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 15 psi for 1 hour at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was purified by chromatography rapid separation on silica gel, elwira a mixture of hexane: ethyl acetate (5:1) and dichloromethane: methanol (20:1). The appropriate fractions were combined and the solvent was removed, resulting in the connection specified in the header (85 mg), in the form of foam.

(1H, CDCl3): 9,76 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 4,74 (s, 1H, H-1'), 3,63 and 4.13 (2d, 2H, 8aCH2, J=9,3 Hz), 3,48 (m, 4H, H-4' and 4'-OMe), and 2.26 (d, 1H, H-2', J=3.9 Hz), 3,19 (m, 1H, H-5'), 3,13 (d, 1H, H-3', J=3.9 Hz), 3,06 (d, 1H, H-4', J=8, 7 Hz), is 2.74 (t, 1H, H-1, J=3.6 Hz); (13C, CDCl3): 204,8 (CHO), COVERS 175.6 (CO2H), 148,2 (C-3), 130, 8mm (C-2), 98,0 (C-1'), a 76.5 (C-4'), 74,3 (8aCH2), for 74.4 (C-3a), to 72.5 (C-5'), 65,6 (C-8a), or 59.0 (C-4), 58,2 (4'-OMe), 53,6 (C-2') and 50.3 (C-3'), 46,4 (C-1).

EXAMPLE 50

[1R- (1,3 a,4,4 a,7,7 a,8a) 8A-[(2,3-Anhydrous-6-deoxy-4-O-methyl - D-mannopyranoside)methyl] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3-(1-m is oral in methanol (10 ml) was added an aqueous solution of sodium hydroxide (0,0976 N, 6,69 ml). The mixture was stirred for 2 hours at room temperature. The solvent was removed, and the residue was dissolved in water (2 ml) and was dried by freezing, receiving the result of the connection specified in the header (324 mg) in the form of a white foam.

(1H, CDCl3): 9,87 (s, 1H, CHO), 5,98 (dd, 1H-2, J=1.5 and 3.6 Hz), 4,69 (s, 1H, H-1'), 3,85, and 4,07 (2d, 2H, 8aCH2, J=9.6 Hz), 3,47 (s, 3H, 4'-OMe), 3,26 (d, 1H, H-2', J=3.9 Hz), 3,19 (dq, 1H, H-5', J=5,7 and 9 Hz), 3,12 (d, 1H, H-3', J=3.9 Hz), 2,97 (dd, 1H, H-4', J=0.6 and 8.7 Hz), 2,66 (t, 1H, H-1, J= 3.6 Hz); (13C, CDCl3): 209,6 (CHO), 178,6 (CO2H, 152,4 (C-3), is 130.2 (C-2), 100,1 (C-1'), to 78.2 (C-4'), 77,9 (8aCH2), of 73.8 (C-3a), 73,9 (C-5'), 65,6 (C-8A), a 59.2 (C-4), 58,2 (4'-OMe), 54,6 (C-2'), with 51.9 (C-3'), 46,4 (C-1).

EXAMPLE 51

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Epithio-4-O-methyl-2,3,6-trideoxy- - D-mannopyranoside)methyl]-4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)- carboxylic acid

A mixture of Intermediate 52 (0.67 mmol), 5,5-dimethyl - 2-thiolo-2-thioxo-1,3,2-dioxaphosphorinanes1(3,37 mmol) and triethylamine (4.02 mmol) in dry dimethylformamide (5 ml) warmed up for 48 hours at 100oC. After cooling, the mixture was poured into water ether. The organic phase is evaporated and the residue was purified by chromatography rapid separation, using as eluent a mixture of dihormati the 9,77 (5, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.2 and 3.3 Hz), of 4.95 (d, 1H, H-1', J=1.8 Hz), 4,15 and the 3.65 (d,d, 1H, 1H, 8a-CH2), J=9,3 Hz), 3.33 and (d, 1H, H-4', J=8.7 Hz), 3,18 (m, 1H, H-5'), 3,14 (m, 2H, H-2' and H-3'), 2,70 (m, 1H, H-1), is 2.30 (m, 1H, ); (13C, CDCl3); 204,7 (CHO), COVERS 175.6 (CO2H), 148,3 (C-3), 130,7 (C-2), to 98.5 (C-1'), 79,1 (C-4'), 74,1 (8A-CH2), 73,5 (C-5') AND 46.6 (C-1), WITH 35.6 (C-2'), 35,2 (C-3'), 27,51[9]

EXAMPLE 52

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a- [(2,3-Anhydrous-6-deoxy-4-O - propyl- - -D-mannopyranoside)methyl]-4-formyl-4,4 a, 5,6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3A(1H)-carboxylic acid

To a solution of Intermediate 65 (400 mg) in ethyl acetate (100 ml) under nitrogen atmosphere was added 10% palladium on coal. The mixture was shaken in a Parr apparatus under hydrogen pressure of 20 psi for 1 hour at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was purified on a column of silica gel, elwira with methylene chloride and a mixture of methylene chloride: methanol (25:1), receiving the result of the connection specified in the header (300 mg), in the form of a white foam.

(1H, CDCl3): 9,76 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4.72 in (s, 1H, H-1'), 4,13 and the 3.65 (2d, 2H, 8a-CH2, J=9 Hz), to 3.67 (m, 1H, H-5'), 3,44 (m, 1H, H-4'), 3,25 and 3.12 (2d, 2H, H-2', H-3', J=4, 2 Hz), 3,20 (m, 2H, ), is 2.74 (t, 1H, H-1, J=3,9 Hz); (13C, CDCl3): 204,8 (CHO), 175,8 (CO2H), 130, 8mm (C-2), 148,2 (C-3), 98,0 (C-1'), the o-6-deoxy-4-O - propyl- - -D-mannopyranoside)methyl] 4-formyl-4,4 a,5,6,7,7 a,8, 8A-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A (1H)-carboxylic acid sodium salt

To a solution of the compound from Example 52 (400 mg) in dry methanol (30 ml) at room temperature was added dropwise 0,0976 N sodium hydroxide solution (8,15 Il), and the mixture was stirred for 1 hour. The solvent was evaporated until dry, and the solid residue was dissolved in minimum volume of water (10-15 ml). This solution is then liofilizirovanny, receiving the result of the connection specified in the header (417 mg), as white matter.

(1H, CDCl3): of 9.89 (s, 1H, CHO), 5,97 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,70 (s, 1H, H-1'), and 4.09 to 3,86 (2d, 2H, 8a-CH2, J=9.7 Hz), 3,70 (m, 1H, H-5'), 3,44 (m, 1H, H-4'), 3,24 and 3.12 (2d, 2H, H-2' and H-3', J=4 Hz), 3,20 (m, 2H ), 2,65 (t, 1H, H-1, J=3,9 Hz); (13C, CDCl3): 209,6 (CHO), 178,38 (CO2Na), 152,4 (C-3), To 130.1 (C-2), 100,1 (C-1'), 77,9 To 76.6 (C-4'), 73,5 (C-5'), 73,1 Of 66.6 (C-3'), To 18.9 (C-6').

EXAMPLE 54

[1R (1.3 a,4,4 a,7,7 a,8a) ] 8A-[(2,3-Anhydrous-4-O-benzyl-6-deoxy- - D-mannopyranoside)methyl]-4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a suspension of sodium hydride (22 mg) in dry dimethylformamide (5 ml) was added dropwise a solution of Intermediate 63 (200 mg) in dry dimethylformamide of ovali 1N hydrochloric acid was added ethyl acetate (30 ml). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to the dry state. The residue was subjected to chromatography on a column of fast separation with silica gel, using as eluents mixture of methylene chloride: methanol (50: 1) and (35:1) and receiving the result of the connection specified in the header, in the form of a white foam (150 mg).

(1H, CDCl3): 9,86 (s, 1H, CHO), 7,31 (m, 5H, ), between 6.08 (dd, 1H, H-2, J= 1.2 and 3.3 Hz), and 4.75 (d, 1H, J=11,4 Hz), to 4.73 (s, 1H, H-1'), 4,56 (d, 1H, J=11,4 Hz), 4,17 and 3,62 (2d, 2H, J=9.0 Hz), 3,32 3.14 (2d, 2H, H-3' and H-2', J=3,7 Hz), 3,30 (m, 2H, H-4', H-5), a 2.71 (t, 1H, H-1); (13C, CDCl3): 204,9 (CHO), 175,8 (COOH), 137,2, 128,14, 128,11 (6C-Ph), 148,3 (C-3), 130, 8mm (C-2), 98,0 (C-1'), 74,4 of 74.3 (C-4'), 72,6 of 72.5 (C-5'), 65,5 (C-8a), 54,0 (C-2') and 50.3 (C-3'), and 18.6 (C-6').

EXAMPLE 55

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(2,3-Anhydrous-6-deoxy - - D-mannopyranoside) methyl] -4-formyl-4,4 a,5,6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a suspension of dry sodium hydride (75 mg) in dry dimethylformamide (5 ml) under nitrogen atmosphere was added a solution of Intermediate 66 (500 mg) in dry dimethylformamide (5 ml). The reaction mixture was stirred in nitrogen atmosphere for 3 hours, and then extinguished the reaction by adding water and neutralized to pH 6.5-7 using 0.5 H water solza were extracted with ethyl acetate (2x20 ml), the organic phases were combined and treated with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a syrup. It was purified by chromatography rapid separation on silica gel, elwira a mixture of dichloromethane: methanol (40: 1), receiving the result of the connection specified in the header (172 mg) as white foam.

(1H, CDCl3): 9,76 (s, 1H, CHO), 6,09 (dd, 1H, H-12, J=1.5 and 3.6 Hz), of 4.77 (s, 1H, H-1'), 3,61 and 4,21 (2d, 2H, 8aCH2, J=9 Hz), 3,60 (d, 1H, H-4', J=8.7 Hz), 3,21 (dq, 1H, H-5', J=9 and 6 Hz), and 3.16 3.27 (2d, 2H, H-2'and H-3', J= 3.6 Hz), 2,70 (t, 1H, H-1), (13C, CDCl3); 205,5 (CHO), 174,6 (CO2H), of 148.4 (C-3), 130, 8mm (C-2), and 97.8 (C-1'), 74,1 (8aCH2), 73,9 (C-4'), at 73.7 (C-3a), and 67.2 (C-Ba) 65,5 (C-8a), or 59.0 (C-4), of 56.5 (C-2'), and 50.4 (C-3'), which is 46.5 (C-1).

EXAMPLE 56

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[2,3-Anhydrous-4,6-dideoxy-4-fluoro- - D-teleperedachi)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A (1H)-carboxylic acid

To a solution of Intermediate 68 (130 mg) in ethyl acetate (30 Il) under nitrogen atmosphere was added 10% palladium on coal (100 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 15 psi for 1 hour at room temperature. The catalyst hotelroyal, and the solvent was evaporated until dry. The residue was chromatographically on to orotan: methanol (20:1) to deliver the connection, specified in the header, in the form of a white foam (82 mg).

(1H, CDCl3): 9,79 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.2 and 3.6 Hz), 5,13 (s, 1H, H-1'), 4,75 and 4,58 (2dq, 1H, H-5', J5'F=48,3 Hz, J=6,6 Hz, J= 3,9 Hz), 4,18 and 4,11 (2d, 1H, H-4', J=3,9 Hz and J4'F=23.1 Hz), 4,07 and 3,61 (2d, 2H, 8aCH2, J=9,3 Hz), of 3.77 (m, 2H, H-2' and H-3'), to 2.67 (t, 1H, H-1); (13C, CDCl3): 204,6 (CHO), 175,3 (CO2H), 148,2 (C-3), 130,7 (C-2), of 101.7 (C-1'), 90,2 (d, C-4', JC4'-F=157 Hz), 80,3 (d, C-5', JC5'-F=21,4 Hz), of 74.3 (C-8aCH2), 73,4 (C-3a), and 65.4 (C-8a), of 58.9 (C-4), of 55.9 (C-2'), with 55.1 (d, C-3', JC3'-F=6.3 Hz), and 16.4 (d, C-6', JC6'-F=21 Hz).

EXAMPLE 57

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[2,3-Anhydrous-6-deoxy-4-O-(2-methoxyethyl)- - D - mannopyranoside)methyl]-4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of Intermediate 69 (140 ml) in ethyl acetate (50 ml) under nitrogen atmosphere was added 10% palladium on coal (70 mg). The mixture was shaken Parr apparatus under hydrogen pressure of 20 psi for 1 hour at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was purified on column for fast separation with silica gel, elwira dichloromethane and a mixture of dichloromethane: methanol (40:1), receiving the result of the connection specified in the header (74 mg) as white foam.to 3.50 (m, 4H, , to 3.38 (s, 3H, 3.30, and 3,13 (2d, 2H, H-2' and H-3', J= 3.9 Hz), 3,26-up 3.22 (m, 2H, H-4' and H-5'), 2,68 (t, 1H, H-1, J=3,7 Hz); (13C, CDCl3): 204,8 (CHO), 175,2 (COOH), 148,3 (C-3), 130, 8mm (C-2), is 97.9 (C-1'), 74,2 to 72.4 (C-5'), 71,7 and 69,9 of 54.1 (C-2') and 50.3 (C-3'), 46,5 of 18.5 (C-6').

EXAMPLE 58

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(2,3-Anhydrous-6-deoxy-4-O-(2-methylpropyl)- - -D-mannopyranoside)methyl]-4-formyl-4,4 a,5,6,7,7 and 8,8 and octahydro - 7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of Intermediate 70 (0.14 nmol) in ethyl acetate (30 ml) under nitrogen atmosphere was added 10% palladium on coal*50 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 25 psi for 30 minutes at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was purified by chromatography rapid separation, using as eluent a mixture of dichloromethane: methanol to deliver the connection specified in the header (49 mg).

(1H, CDCl3): 9,76 (s, 1H, CHO), 6,09 (dd, 1H, H-2, J=1.2 and 3.3 Hz), to 4.73 (s, 1H, H-1'), 4,12 & 3.65 (2d, 2H, 8A-CH2J=9,3 Hz), 3,49 (m, 1H, H-5'), up 3.22 (m, 3H, H-2' and CH2-Oh) of 3.13 (m, 2H, H-3' and H - 4'), a 2.75 (t, 1H, H-1, J=3,9 Hz), 2,33 (m, 1H, ); (13C, CDCl3): 204,8 (CHO), 176,0 (CO2H), 148,2 (C-3), 130, 8mm (C-2), 98,0 (C-1'), and 77.6 (C-1'), and 75.2 (C-4'), 74,3 (8a-CH2), with 72.9 (C-3a), to 72.6 (C-5'), 65,6 (C-8a), or 59.0 (C-4), 54,1 (C-2'), and 50.4 (C-3'), 4 D-mannopyranoside)methyl]-4-formyl-4,4 a, 5,6,7,7 a, 8,8 - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of Intermediate 71 (140 mg) in ethyl acetate (20 ml) under nitrogen atmosphere was added 10% palladium on coal (120 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 20 psi for 1 hour at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was purified by column chromatography rapid separation on silica gel, elwira mixtures of hexane:ethyl acetate (4:1) and dichloromethane: methanol (20: 1) to deliver the connection specified in the header (103 mg), in the form of a white foam.

(1H, CDCl3): 9,74 (s, 1H, CHO), 6,09 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 4,78 (s, 1H, H-1'), of 4.66 (d, 1H, H-4', J=9 Hz), 4,10 and of 3.60 (2d, 2H, 8aCH2, J= 9 Hz), 3,42 (dq, 1H, H-5', J=9 and 3 Hz) and 3.15 (s, 2H, H-2' and H-3'), 2,78 (m, 1H, H-1), 2,58 (m, 1H, ); (13C, CDCl3): 204,9 (CHO), 176,1, 175,9 (CO2and 4'OCOR), 148,2 (C-3), 130,9 (C-2), is 97.9 (C-1'), to 74.5 (C-8aCH2), to 72.6 (C-3a),71,4 (C-4'), and 67.8 (C - 5'), 66,0 (C-8A), or 59.0 (C-4), of 18.5 and 18.8

EXAMPLE 60

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(2,3-Anhydrous-6-deoxy-4-O-(2,2-dimethylpropionic)- - D - mannopyranoside)methyl]-4-formyl-4,4 a,5,6,7,7 a, 8,8 - octahydro-7-methyl-3-(1-methylethyl) -1,4-methane-s-indocin-3A(1H) - carboxylic acid

To a solution of Intermediate compound urate when the hydrogen pressure of 20 psi for 30 minutes at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was purified by chromatography rapid separation, using as eluent a mixture of dichloromethane: methanol (40:1) to deliver the connection specified in the header (101 mg).

(1H, CDCl3): of 9.75 (s, 1H, CHO), 6,10 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 4,80 (s, 1H, H-1'), with 4.64 (d, 1H, H-4', J=9 Hz), 4,11 and 3.70 (2d, 2H, 8a-CH2, J= 9,3 Hz), 3.43 points (m, 1H, H-5'), of 3.13 (m, 2H, H-2' and H-3'), 2,78 (t, 1H, H-1, J= 3,9 Hz), 2,34 (m, 1H, ); (13C,CDCl3): 204,9 (CHO), 177,3 and 176,5 (2CO2), 148,2 (C-3), 130,9 (C-2), 98,0 (C-1'), 74,5 (8A-CH2), to 72.6 (C-2), from 71.3 (C-5'), with 67.9 (C-4'), and 65.7 (C-8a), or 59.0 (C-4), 54,3 (C-2'), 50,1 (C-3'), and 46.3 (C-1), compared with 41.8 (C-4a), a 41.3 (C-8), 38,8 (CtBu) 32,0 (C-5), of 30.9 (C-7), and 18.5 (tBu).

EXAMPLE 61

[R- (1,3 a,4,4 a,7,7 a,8a) 8a[(2,3-Anhydrous-4-O-benzyloxycarbonyl-6-deoxy- - D-mannopyranoside)methyl]-4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

A solution of Intermediate 73 (0.22 mmol) in dichloromethane (10 ml) at 0oC was treated triperoxonane acid (0.1 ml). After two hours the mixture was washed with water, and the organic phase evaporated. The residue was purified by chromatography rapid separation, using as eluent a mixture of dichloromethane: methanol (40:1) and receiving the connection is m,2H, ), and 4.75 (s,1H,H-1'), 4,55 (d,1H,H-4', J=9 Hz), 4,08 and 3.70 (2d,2H,8A-CH2, J=9 Hz), 3,47 (m,1H,H-5'), 3.28 and to 3.16 (d,d,1H, 1H, H-2' and H-3' Hz), and 2.79 (t,1H,H-1, J=3,9 Hz), 2,33 (m,1H, ); (13C, CDCl3): 204,8 (CHO), 176,4 (CO2H), (154,1 (CO3), 148,1 (C-3), 134,6 (Cipso), 130,9 (C-2), 128,8, 128,7, 128,5, 128,4 (Ph), and 97.8 (C-1'), 74,5 (8A-CH2), to 72.5 (C-3a), 71,6 (C-5'), 71,1 (8C-4'), 70,3, and 65.7 (C-8a), of 58.9 (C-4), 53,9 (C-2'), 50,0 (C-3') and 46.2 (C-1), and 41.7 (C-4a), a 41.3 (C-7a).

EXAMPLE 62

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(2,3-Anhydrous-6-deoxy - 4-oxo- - D-mannopyranoside)methyl] -4-formyl-4,4 a, 5,6,7,7 and, 8,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s - indocin-3A(1H)-

carboxylic acid

To a solution of Intermediate 74 (0.26 mmol) in ethyl acetate (30 ml) under nitrogen atmosphere was added 10% palladium on coal (50 mg). The mixture was shaken in a Parr apparatus under hydrogen pressure of 25 psi for 1.5 hours at room temperature. The catalyst was filtered, and the solvent was evaporated until dry. The residue was purified by chromatography rapid separation, using as eluent a mixture of dichloromethane: methanol (40: 1), the appropriate fractions were collected and evaporated, resulting in the connection specified in the header (38 mg).

(1H, CDCl3), 9,72 (s, 1H, CHO), 6,12 (dd, 1H, H-2, J=1.5 and 3.6 Hz), to 4.87 (s, 1H, H-1'), 4,10 and 3.76 (2d, 2H, 8aCH2, J=9 Hz), 3,83 (q, 1H, H-5', J=6.6 Hz), 3,60, and 3.38 (d,d, 1H, 1H,3' and 26.6 (C-5'), 74,7 (8aCH2), for 72.1 (C-3a), and 65.7 (C-8a), of 58.9 (C-4), 54,2 and 53.5 (C-2' and C-3'), 46,1 (C-1), compared with 41.8 (C-4a), a 41.3 (C-7a).

EXAMPLE 63

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous-4,6-dideoxy- -4-methylene - D-mannopyranoside)methyl] -4-formyl-4,4 a,5,6,7,7 and 8,8 and octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

A solution of intermediate compound 101 (0,17 mmol) in dichloromethane (15 ml) at 0oC was treated triperoxonane acid (0.15 ml). After 2 hours it was treated with water (10 ml). The organic phase is evaporated, and the residue was dissolved in ethanol (15 ml) and 1N hydrochloric acid (1.5 ml) and stirred at 0oC for a further 2 hours. The solvent was removed and the residue was purified, using as eluent a mixture of dichloromethane: methanol 20:1. The appropriate fractions were evaporated, resulting in the connection specified in the header (24 mg).

(1H, CDCl3): of 9.75 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.2 and 3.3 Hz), 5,20 and 5,10 (s,s, 1H, 1H, CH2=C), 4,82 (d, 1H, H-1, J=2.1 Hz), 4,42 (m, 2H, H-5' and H-3'), 4,19 and of 3.56 (d,d, 1H,1H, 8a-CH2, J=9.6 Hz), the 3.65 (m,1H,H-2'), 2,63 (t, 1H, H-1, J= 3,9 Hz), a 2.36 (m,1H, ); (13C, CDCl3): 204,7 (CHO), 175,0 (CO2H), 148,5 (C-3), 145,6 (C-4'), 130,5 (C-2), 112,1 of 99.5 (C-1'), 74,0 (8a-CH2), 73,0 (C-5'), for 72.8 (C-3a), 72,2 and 71,6 (C-2' and C-3').

EXAMPLE 64

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(2,3-Anhydrous-4-O-tertbutyloxycarbonyl-6-deoxy - - D-telapi the PTA

A mixture of intermediate compound 103 (0.1 mmol) and water (2 ml) at 0oC was treated triperoxonane acid (3 ml). After 90 minutes the mixture was poured into a mixture of ethyl ether: water 1:1 (30 ml). The organic phase was evaporated and the residue was purified chromatography, using as eluent a mixture of dichloromethane: methanol 40: 1, receiving the result of the connection specified in the header (32 mg).

(1H, CDCl3): 9,77 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.5 and 3.6 Hz), and 4.75 (dd, 1H, H-4', J=3.6 and 4.8 Hz), 4,68 (3, 1H, H-1'), 4,17 (d, 1H, 8a-CHa, J= 9.3 Hz), 3,66 (m, 2H, 8a-CHb and H-5'), of 3.57 (t, 1H, H-3', J=4, 2 Hz), 3,17 (d, 1H, H-2', J= 3.6 Hz), 2,73 (t, 1H, H-1, J=3,9 Hz), 2,33 (m, 1H, ); (13C, CDCl3): 204,8 (CHO), 178,5 and 175,7 (2CO2), 148,3 (C-3), 130, 8mm (C-2), is 97.9 (C-1'), 74,1 (8a-CH2), 73,0 (C-3A), for 71.5 (C-5'), 66,0 (C-4'), 65,6 (C-8a), or 59.0 (C-4), or 51.3 (C-2'), at 50.7 (C-3').

EXAMPLE 65

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[2,3-Anhydrous-4-O-(TRANS-2-butenyl) -6-deoxy - -D-mannopyranosyl]methyl]-4-formyl-4,4 a,5,6,7,7 and 8,8 and octahydro - 7-methyl] -3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

A solution of intermediate 47 (103 mg) in dry dichloromethane (5 ml) at 0oC was treated triperoxonane acid (100 μl). After 1 hour the mixture was fractionally between ethyl acetate (50 ml) and saturated aqueous sodium sulfate (50 ml). The organic layer was washed with saturated aq on silica gel, elwira a mixture of hexane: ethyl acetate (2:1) to (1:1), receiving the result of the connection specified in the header (50 mg).

(1H, CDCl3): 9,76 (s, 1H, CHO), between 6.08 (dd, 1H, H-2, J=1.5 and 3.6 Hz), of 5.82-of 5.68 (m, 1H, ), 5,62 - of 5.48 (m, 1H, ), 4,72 (s, 1H, H-1'), from 4.2 to 4.1 (m, 2H, O-Dream-C=C and 8A-CHa), was 4.02-to 3.92 (m, 1H, OCHb-C=C), 3,63 (d, 1H, 8a-CHb, J= 9,3 Hz), 3,3-3,15 (m, 3H, H-3', H-4' and H-5'), of 3.12 (d, 1H, H-2', J= 3.9 Hz), 2,73 (t, 1H, H-1, J=3,9 Hz), 1,72 (dd, 3H, H3C=C, J=1,2 and 6.6 Hz); (13C, CDCl3): 204,8 (CHO), COVERS 175.6 (CO2H), 148,2 (C-3), 130, 8mm (C-2), RB 131.1 and 126,6 , is 97.9 (C-1'), 74,2 71,2 73,5 and 72,5 (C-4' and C-5')

EXAMPLE 66

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-(2,3-Anhydrous-6-deoxy-4-O-propyl - D-teleperedachi)methyl] -4-formyl-4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A (1H)carboxylic acid

To a solution of intermediate 104 (150 mg, 0.21 mmol) in ethanol (50 ml), ethyl acetate (10 ml) and 1N hydrochloric acid (1 ml) under nitrogen atmosphere was added palladium (10%) coal (30 mg). The mixture was shaken in a Parr apparatus (PH2=35 psi) for 3.5 hours at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was purified by chromatography, using as eluent a mixture of dichloromethane: methanol 30:1, and receiving the connection specified in the header (60 mg).

(12H, CDCl3): 9,83 (s, 1H, CHO), the 6.06 (dd, 1H, H-2, J=1.2 and 3.6 Hz), 4.75 in (s2,51 (t, 1H, H-1, J=3.6 Hz); (13C, CDCl3): 204,7 (CHO), 174,9 (CO2H), of 148.6 (C-3), 130,4 (C-2), is 97.9 (C-1'), to 78.7 (C-4'), 73,9 (8a-CH2), 73,3 (CH2O) 69,8 (C-5') and 69.3 (C-3'), was 65.3 (C-8A), or 59.0 (C-4), the 54.6 (C-2'), and 47.0 (C-1).

EXAMPLE 67

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A (2,3-Anhydrous-4-azido-4,6-dideoxy- - D-mannopyranoside)methyl-4-formyl-4,4 a, 5,6,7,7 a, 8,8 a-octahydro-7-methyl-3- (1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

A solution of intermediate 106 (0.06 mmol) in dry dichloromethane (5 ml) at 0oC was treated triperoxonane acid (70 μl). After 2 hours, it was washed with water and brine. The solvent is evaporated and the residue was purified chromatography, using as eluent a mixture of dichloromethane:methanol 30: 1, and receiving the result of the connection specified in the header (12 mg).

(1H, CDCl3): 9,73 (s, 1H, CHO), 6,09 (d, 1H, H-2, J=3.6 Hz), to 4.73 (s, 1H, H-1'), 4,12 and 3.67 (d,d, 1H, 1H, 8a-CH2, J=9 Hz), 3,39 (d, 1H, H-4', J=9 Hz), 3.33 and and 3,17 (d,d, 1H, 1H, H-2' and H-3', J=3.6 Hz), up 3.22 (m, 1H, H-5'), was 2.76 (t, 1H, H-1, J=3.6 Hz), 2,34 (m, 1H, ); (13C, CDCl3): 205,1 (CHO), 175,3 (CO2H), of 148.4 (C-3), 130, 8mm (C-2), and 97.8 (C-1'), 74,6 (8a-CH2), 72,7 (C-5'), to 68.0 (C-3A), and 65.7 (C-8A), or 59.0 (C-4), of 58.7 (C-4), 54,4 (C-2'), 50,1 (C-3'), and 46.3 (C-1).

EXAMPLE 68

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(4-O-Allyl, 2,3-anhydrous, 6-deoxy - a-D-mannopyranosyl)oxymethyl] -4-formyl-4,4 a,5,6,7,7 a,8,8 and octahydro-7 - methyl-3-(1-methylethyl)-1, is chloride and 0.2 ml triperoxonane acid was stirred at 0oC for 4 hours. The crude product is evaporated until dry and the residue was purified by chromatography rapid separation in the system methylene chloride: methanol 50:1, resulting in the 140 mg of the compound indicated in the title, in the form of a white foam.

(1H, CDCl3): 9,77 (s, 1H, CHO), between 6.08 (dd, 1H, H-12, J=1.2 and 3.3 Hz), 5,90 (m, 1H, ), 5,28 (m, 2H, ), and 4.75 (s, 1H, H-1'), 4,28 (m, 1H, H-5'), is 4.21 (d, 1H, H-19a, J=9.6 Hz), of 4.05 (m, 1H, H-4'), of 4.05 (m, 1H, H-4'), 3,60 (d, 1H, H-19b, J=9.6 Hz), 3,27, 3,14 (d,d, 1H, 1H, H-2', H-3', J= 3,9 Hz) at 3.25 (m, 2H ), 2,68 (t, 1H, H-11, J=4,2 Hz); (13C, CDCl3): 205,07 (CHO), 174,6 (CO2H), OF 148.4 (C-13), 133,7 129,7 (C-12), 118,0 , AND 97.8 (C-1'), 74,17 (C-19), 74,04 (C-4'), TO 72.5 (C-5'), 71,0 OF 54.1 (C-2'), 50,2 (C-3'), 27,5 (C-14), 22,7 (0-20), 21,2 (C-15), AND 18.6 (C-6'), 17,4 (C-17).

EXAMPLE 69

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous,6-deoxy, 4-O-tertbutoxycarbonyl- - D-mannopyranosyl)oxymethyl] -4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3A(1H)-carboxylic acid

To a solution of Intermediate 21 (200 mg) in 15 ml of dry THF at 0oC was added 30 mg of sodium hydride. The mixture was stirred at 0oC in nitrogen atmosphere for 30 minutes. Then was added 260 μl tert-butyl-bromoacetate and the mixture was stirred at room temperature for 3 days. The crude product was treated with 1N ammonium chloride and ethyl acetate. Artnum way the crude product was purified by chromatography rapid separation in the system methylene chloride:methanol 50:1, resulting in the 140 mg of the compound indicated in the title, in the form of a white foam.

(1H, CDCl3): 9,74 (s, 1H, CHO), between 6.08 (dd, 1H, H-12, J is 1.5 and 3.9 Hz), 4,74 (s, 1H, H-1'), is 4.21 (dd, 1H, H-4', J=3.6 and 6.0 Hz), 4,16 (d, 1H, H-19a, J= 9 Hz), of 4.12 (s, 2H, -CO2C(CH3)3), 3,63 (d, 1H, H-19b, J=9 Hz), 3,36, 3,14 (d, d, 1H, 1H, H-2', H-3', J=3.9 Hz), 3,30 (m, 1H, H-5'), 2,71 (t, 1H, H-11, J= 3,9 Hz); (13C, CDCl3): KZT 205.7 (CHO), 174,9 (CO2C(CH3)3), 168, 8MM OF 148.4 (C-13), 130, 8MM (C-12), AND 97.8 (C-1'), AND 82.2 75,6 (C-4'), TO 72.4 (C-5'), 68,2, OR 59.0 (C-3), 53,9 (C-2') AND 50.3 (C-3'), 27,5 (C-14), AN INCREASE OF 22.7 (C-20) AND 21.2 (C-15), AND 18.6 (C-6'), 17,4 (C-17).

EXAMPLE 70

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8A-[(2,3-Anhydrous-6-deoxy-4-O-ethyl - D-mannopyranosyl)oxymethyl] -4-formyl - 4,4 a,5,6,7,7 a,8 a,8 a-octahydro-7-methyl-3-(1-methylethyl)-1,4 - methane-s-indocin-3A(1H)-carboxylic acid

To a solution of Intermediate 21 (290 mg) in 5 ml of dry dimethylformamide at 0oC in an atmosphere of nitrogen was added 25 mg of sodium hydride. The mixture was stirred for 30 minutes at 0oC, and then added 1 mmol of ethyliodide. The reaction was terminated after 16 hours stirring at room temperature. The crude product was treated with 1N ammonium chloride and ethyl acetate. The organic layer was washed with water and brine, suspesion, the crude product was purified by chromatography rapid separation in the system methylene chloride: methanol, 50:1, resulting in the 180 mg of the compound indicated in the title, in the form of a white foam.

(1H, CDCl3): 9,73 (s, 1H, CHO), between 6.08 (d, 1H, H-12, J=3.3 Hz), to 4.73 (s, 1H, H-1'), 4,16 (d, 1H, H-19a, J=9,3 Hz), 3,78, of 3.54 (m,m, 1H, 1H, ), 3,63 (s, 1H, H-19b, J=9,3 Hz), 3,25, 3,13 (d,d, 1H, 1H, H-2', H-3', J=3.9 Hz), 3,19 (m, 2H, H-4', H-5'), 2,71 (t, 1H, H-11, J=3.3 Hz); (13C,CDCl3): 201,8 THOUSAND CUB. (CHO), 175,0 (CO2H), 148,2 (C-13), 130,7 (C-12), IS 97.9 (C-1') SHOWS THAT 74.6 (C-4'), OF 74.3 (C-19), FROM 72.5 (C-5'), 54,3 (C-2') AND 50.3 (C-3'), 27,5 (C-14), AN INCREASE OF 22.7 (C-20) AND 21.2 (C-15), AND 18.6 (C-6'), 17,4 (C-17).

EXAMPLE 71

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous, 6-deoxy-4-O- (2,3-dihydroxypropyl) - -D-mannopyranosyl)oxymethyl] ] -4-formyl-4,4 a, 5,6,7,7 a, 8,8 - octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H) -carboxylic acid

To a solution of Intermediate 108 (700 mg) in ethanol (100 ml) under nitrogen atmosphere was added palladium (10%) coal (350 mg). The mixture was shaken in a Parr apparatus (PH2=20 psi) for 1 hour at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was purified on a column of silica gel, elwira with methylene chloride and a mixture of methylene chloride: methanol 25:1, resulting in the 425 mg of the compound indicated in heading (a mixture of isomero is (d, 1H, H-19a, J=9.6 Hz), 3,81 (d, 1H, H-19b, J= 9.6 Hz), 3,81-3,68 (m, 2H, C-4'), 3,55-of 3.31 (m, 3H, C-4'), 3,30-3,11 (m, 4H, H-2', H-3', H-4', H-5'), was 2.76 (t, 1H, H-11, J=3.6 Hz); (13C, CDCl3): 207,70 (CHO), 178,2 (CO2H), 150,49 (C-13), 131,44 (C-12), 99,81 (C-1'), 77,07 and 76,96 ( C-4'), 76,57 (C-19), to 73.55 (C-4'), 72,86 and 72,69 ( C-4'), 72,24 (C-5'), 55,01 (C-3'), 51.89ˆ (C-2'), 23,2 (C-20), to 21.6 (C-15), TO 19.4 (C-6'), AND 17.9 (C-17).

EXAMPLE 72

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a-[(2,3-Anhydrous, 6-deoxy-4-O-(2,3-dimethoxyphenyl)- -D - mannopyranosyl)oxymethyl] -4-Formyl-4,4 a, 5,6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H) - carboxylic acid

To a solution of Intermediate 108 (350 mg) in dry THF (20 ml) under nitrogen atmosphere was added sodium hydride (40 mg), the mixture was stirred for 30 minutes, then added methyliodide (0.5 ml) and the reaction was conducted with stirring at room temperature for two days under nitrogen atmosphere. The crude product was treated with 1N ammonium chloride and ethyl acetate. The organic layer was washed with water and brine and evaporated until dry. The residue was hydrogenosomal standard way without pre-treatment, receiving the result of the connection specified in the header (mixture of isomers (50: 50), in the form of a white foam (225 mg).

(1H, CDCl3): of 9.75 (s, 1H, CHO), between 6.08 (d, 1H, H-12, J=3.3 Hz), to 4.73 (d, 1H, H-1', J= 1.5 Hz), 4,18 (d, 1H, H-19b, J=9 Hz), 3,62 (d, 1H, H-48,4 (C-11), 130,7 (C-12), is 97.9 (C-1'), 79,0 in C-4'), 75,6, and to 75.7 (C-4'), to 72.4 (C-5'), 71,6 and 71,5 in C-4'), 70,1 and 69.8 ( C-4'), 59,2, 57.9, 57,8 ( and C-4'), 53,9 and 50.2 (C-2' and C-3'), an increase of 22.7 (C-20), OF 21.2 (C-15), AND 18.6 (C-6'), 17,4 (C-17).

EXAMPLE 73

[1R- (1,3 a,4,4 a,7,7 a,8a) ] 8a- [(2,3-Anhydrous, 6-deoxy-4-O-[(2,3-O-isopropylidene) -2,3-dihydroxypropyl]- -D-mannopyranosyl)oxymethyl] -4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7 - methyl-3-(1-methylethyl)-1,4-methane-s-indocin-3A(1H)-carboxylic acid

To a solution of Intermediate compound 109 (250 mg) in ethyl acetate (50 ml) under nitrogen atmosphere was added palladium (10%) coal (100 mg). The mixture was shaken in the apparatus (PH2=20 psi) for 1 hour at room temperature. The catalyst was filtered and the solvent evaporated until dry. The residue was purified by chromatography rapid separation in systems of n-hexane: ethyl acetate 1:1 methylene chloride: methanol 50:1, receiving the result of the connection specified in the header (blend

isomers (50:50), in the form of a white foam.

(1H, CDCl3): of 9.75 (s, 1H, CHO), between 6.08 (dd, 1H, H-12, J=1.5 and 3.6 Hz), 4,71 (d, 1H, H-1', J=0.9 Hz), 4,29-4,24 (m, 1H, 4'), 4,15-4,01 (m, 3H, H-19a and 3,82-to 3.49 (m, 4H, H-19b, 3,29, and of 3.13 (d, d, 1H, 1H, H-2' and H-3', J=3.9 Hz), 3.27 to 3,18 (m, 2H, H-4'and H-5'), is 2.74 (t, 1H, H-11, J= 3.6 Hz), 1,41, and 1.35 (d,d, 3H, 3H, ; (13C, CDCl3): 204,8 (CHO), 165,7 (CO2H, 148,2 (C-11), 130, 8mm (C-12), is 97.9 (C-1'), 75,7 and 75.6 ( C-4'), 74,4 (C-4'), 72,8 and to 72.4 (C-5'), 72,0 and 7IMI 362184 is a mutant Sordaria araneosa (ATCC 36386, NRRL 3196), isolated after treatment with the mutagen N-methyl-N'- nitro-N-nitrosoguanidine ascospores of this strain. Characteristics IMI 362184 basically similar to the characteristics described [1] to NRRL 3196, with the exception that IMI 362184 produces 4' -dimethylarginine as the main product in the same conditions, which are used for producing sordaria strain NRRL 3196.

EXAMPLE 75

Description IMI 362947

IMI 362947 is a mutant Sordaria araneosa (ATCC 36386, NRRL 3196), isolated after treatment with the mutagen N-methyl-N'-nitro - N-nitrosoguanidine ascospores of this strain. Characteristics IMI362947 basically similar to the characteristics described [1] to NRRL 3196, with the exception that IMI 362947 are not able to quickly produce ascospores under cultivation on arape. This stamp is also different from the NRRL 3196 what he produces agaricin as the main product in the same conditions, which are used for producing sordaria strain NRRL 3196.

EXAMPLE 76

Description NCIMB 40675

NCIMB 40675 is aerobic. Gram-positive stationary single-ended wand that produces lemon-yellow, translucent, round, clean, convex colonies with a diameter of between 0.5 to 1 mm and growth within 48 hours and temperatures up to 37oC but not at 45oC. Metachromatic granules were not observed, the strain is catalase-positive, oxidase-negative and not utilizes enzymatic glucose. This strain may dispose of the following carbon sources: D-glucose, D-fructose, p-hydroxyphenyl-acetic acid, D-mannitol, methylpiruvate, lactamide, D-trehalose and sucrose. The specified body can only poorly be disposed of D-gluconic acid, pyruvic acid and salicin as the sole carbon sources. Colony morphology and microscopic morphology corresponds to the morphology of the club-shaped bacteria. Genus Corynebacteriym was excluded on the grounds that peptidoglycan from NCIMB 40675 contains ornithine instead of the meso-isomer of 2,6-diaminopimelic acid or diamino-butyric acid. Also this organism contains a complex mixture of fatty acids with branched chains, atypical for the species Corynebacterium, namely 12-methyltetrazolyl, 14-methylhexadecanoic and 14 methylpentadiene acid. The presence of branched - hydroxylated fatty acids has not been determined. Based on these results NCIMB 40675 most closely resembling one of the following genera of actinobacteria: Aureo-bacterium, Curtobacterium or Cellulomonas.Pharmaceutical Examples

1. Standard oral tablet

Drug 100 mg

Microcrystalline cellulose - 160 mg

Sodium-crosscarmelose 20 mg

Magnesium stearate 5 mg

The medicinal substance is mixed with microcrystalline cellulose, sodium crosscarmellose and magnesium stearate and then compressed into tablets.

Chewable oral tablet

Drug 100 mg

Xylitol - 865 mg

Extract of peppermint (peppermint) 5 mg

Aspartame 10 mg

Polyvinylpyrrolidone 15 mg

Magnesium stearate 5 mg

The medicinal substance, xylitol, aspartame and polyvinylpyrrolidone are mixed together and granularit with water, and then dried. This granule is mixed with extrac the introduction

Drug 100 mg

The hypromellose 150 mg

Propylhydroxybenzoate sodium - 1 mg

Methylhydroxybenzoate sodium 2 mg

Orange flavor 10 mg

Saccharin sodium 5 mg

Sucrose - 800 mg

Appropriate buffers - as required

Purified water to 5 ml

Dissolve the drug substance and all excipients in most parts of purified water and mix. Bring to volume, and mix. To maintain the pH in the region of maximum stability can be added to the corresponding buffers.

Non-aqueous suspension for oral administration

Drug 100 mg

Aspartame is 50 mg

Grapefruit flavouring 25 mg

Mannitol - 800 mg

Colloidal silica 10 mg

Fractionated coconut oil - 5 ml

Dispersed drug and mannitol in the amount of fractionated coconut oil by high-speed mixing. Add remaining ingredients and pereshivayut. Bring the volume of fractionated coconut oil and mix.

5. Ointment

Drug 200 mg

Soft white paraffin - 9800 mg

Melted soft white paraffin, the tx2">

6. Injection

Drug 40 mg

Appropriate buffers - as required

Appropriate antioxidants - as required

Appropriate chelating agents as you want

Water for injection up to 2 ml

Dissolve the drug in most of the water for injection. To maintain the pH within the optimal stability can be added to the appropriate tabularasa agents. To improve the stability of the injection can be added to the appropriate antioxidants and chelating agents. Bring to the mark with water for injection. Fill ampoules or vials, and then sterilized by autoclaving. Can be sterilized by filtration and filled the tank filled.

Antigena activity

The compounds of formula (I) were tested on anthropou activity by standard in vitro screening and determined for each connection, the minimum inhibitory concentration (MIC; μg/ml) against a set of clinically relevant pathogens. Below are the results obtained for some compounds according to the invention.

Compounds according to the invention is generally non-toxic in therapeutically used doses. Napravnik C. albicans 4711E. The value of LD50for compounds of example 8 on the male mice was more than 1000 mg/kg orally.

1. Derivatives sordaria formula I

< / BR>
where Z is tetrahydro-pornography selected from

< / BR>
< / BR>
and its pharmaceutically acceptable salt and solvate (e.g. hydrate) or metabolically labile derivatives

where R1represents hydrogen, hydroxyl;

R2and R3each can independently represent hydrogen, C1-6alkyl or C1-4alkoxy WITH1-4alkyl, or R2and R3may together with the carbon atom to which they are attached, represent C=O, C=S or C3-8cycloalkyl;

R4represents hydrogen or CH2R7(where R7is hydrogen, C1-4alkoxy);

R5and R6each can independently represent hydrogen;

n = 0 or 1;

X and Y each can independently represent an oxygen or CR9R10(where R9and R10each can independently represent hydrogen, C1-6alkyl, C1-4alkoxy, or R9and R10may together with the carbon atom to which they are attached, represent C=O, C=R1P> or-X-CR2R3-, respectively, can also be a-NR12where R12is1-4by alkyl; or when Y is oxygen, and n = 0, then X may represent a group of CR11that is attached to PYRANOVA ring double bond;

R15represents hydrogen, halogen, asiagraph,1-6alkoxy (possibly substituted by one or two hydroxy or Cetelem or one or two C1-3CNS groups), aryl WITH1-4alkoxy, C3-6alkenylacyl, group R18where R18is aryl WITH1-4CNS or C1-10alkyl group; or C1-6alkoxycarbonyl1-4alkoxy;

R16represents hydrogen, or

R15and R16may together with the carbon atom to which they are attached, represent a C=O or C=CH2;

R17represents CH2R19where R19is hydrogen;

W represents an oxygen atom or sulfur;

the dashed line in group (a) indicates the possible presence of additional relationships.

2. Connection on p. 1, where Z is a group

< / BR>
or

< / BR>
where one of X or Y is oxygen, and others whom/P> 4. The compound according to any one of paragraphs.1 to 3, where X and Y are both oxygen, and R2and R3independently represent hydrogen or C1-4alkyl.

5. The compound according to any one of paragraphs.1 to 3, where one of X or Y is oxygen and the other is a group of CR9R10.

6. Connection on p. 5, where R9represents hydrogen or C1-4alkyl, and R10represents hydrogen or the group CR9R10is a group WITH or=R11.

7. Connection on p. 5 or 6, where X is oxygen.

8. The compound according to any one of paragraphs.1 to 7, where R1is hydrogen or hydroxyl, and R4is stands.

9. Connection on p. 1, where

< / BR>
where W is oxygen.

10. Connection on p. 1, selected from among the following: [1R-(1,3 a,4,7,7 a,8a)] 8A-[(2,6-dideoxy-3,4-O-isopropylidene--D-allopregnanolone)methyl] -4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-S-indocin-3A(1H)-carboxylic acid; [1R-(1,3 a,4,4,7,7 a,8a)] 8A-[[1S, 4R, 7R,9R]-2,8-dioxa-4,9-dimethyl-Cabello[3.4.0] non-7-yl-oxy-methyl]-4-formyl-4,4 a,5,6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-S-indocin-3A(1H)-carboxylic acid; [1R-(1,3 a,4,4,7,7 a,8a)] 8A-[[1S,4S,6R,8R]]-2,7-dioxa-4,6-dimethyl-Cabello [the traveler acid; [1R-(1,3 a,4,4,7,7 a,8a)] 8A-[(2,3-anhydrous-6-deoxy-4-O-propyl-D-mannopyranoside)methyl] -4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-S-indocin-3A(1H)-carboxylic acid; [1R-(1,3 a,4,4,7,7 a,8a)] 8A-[(2,3-anhydrous-6-deoxy-4-O-methyl-a-D - mannopyranoside)methyl] -4-formyl-4,4 a,5,6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-S-indocin-3A(1H)-carboxylic acid; and their pharmaceutically acceptable salts.

11. Connection on p. 1 representing [1R-(1,3 a,4,4,7,7 a,8a)] 8A[(6-deoxy-3,4-O-isopropylidene--D-atropinelike)methyl] -4-formyl-4,4 a, 5,6,7,7 and 8,8 and octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-S-indocin-3A(1H)-carboxylic acid and its pharmaceutically acceptable salts.

12. [1R-(1,3 a,4,4,7,7 a,8a)] 8A[[1S,7R,9R]-2,8-dioxa-9-methyl-4-methylene-CIS-bicyclo[3.4.0] non-7-yl-oxy-methyl] -4-formyl-4,4 a, 5,6,7,7 and, 8,8-octahydro-7-methyl-3-(1-methylethyl)-1,4-methane-S-indocin-3A(1H)-carboxylic acid and its pharmaceutically acceptable salts.

13. Pharmaceutical composition having anti-fungal activity and containing the compound as defined in any of paragraphs.1 - 12, in a mixture with one or more than one physiologically acceptable carrier or excipient.

 

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< / BR>
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