Hexahydronaphthalen ester compounds and pharmaceutical composition

 

(57) Abstract:

Proposed hexahydronaphthalen ester compounds of formula (I) in which R1represents a group of formula (II) (III), R5represents a hydrogen atom; Rarepresents a hydroxy-group; R6arepresents a hydrogen atom or hydroxyamino group; and either: (a) R2represents ethyl group, R3represents an alkyl group having from 1 to 4 carbon atoms, or alkenylphenol group having from 2 to 6 carbon atoms, and R4represents an alkyl group having from 2 to 4 carbon atoms, or alkenylphenol group having from 2 to 6 carbon atoms; or (b) R2is sawn group, R3represents a hydrogen atom and R4is through the group; or (c) R2is boutelou group, R3represents a methyl group and R4represents a methyl group; and its pharmaceutically acceptable salts. The proposed pharmaceutical composition inhibiting cholesterol biosynthesis comprising as active ingredient the compounds of formula (I) and a pharmaceutically acceptable carrier. 2 C. and 7 C.p. f-crystals, 10 PL.

The invention relates to certain new hexahedronal to inhibit the synthesis of cholesterol and can be used for the treatment and prevention of hypercholesterolemia and various cardiac disorders. The invention also relates to methods and compositions based on these compounds, and methods for their preparation.

Excessive levels of cholesterol in the blood are the cause of many vitally threatening disorders and, therefore, a need for drugs that lowering effect on levels of cholesterol in the blood. One possible way of achieving this through the use of a medicinal product is reduced to the inhibition of the biosynthesis of cholesterol.

The number of known compounds, which in General case can be described as 7-[(substituted)-1,2,3,5,6,7,8,8 and octahydro-1-naphthyl] -3,5-dihydroxyheptanoic, and such compounds are disclosed in European patent publication N 314435, in which more detail the development and precursors of these types of compounds. However, I believe that the closest connection to the compounds of the present invention are the compounds disclosed in the description of the invention the UK N 2077264 and in Japanese patent application N 59-175450, which can be represented correspondingly by the formulae (A) and (B):

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These known compounds and compounds of the present izobreteny and prevention of various diseases, caused by hypercholesterolemia, such as atherosclerosis and various cardiac disorders.

The purpose of the present invention is to provide a range of new hexahydronaphthalen derivatives.

Next, and more precisely the aim of the present invention is to provide compounds which have the ability to inhibit the biosynthesis of cholesterol.

Other objectives and advantages of the present invention will become apparent from the subsequent description.

Thus, the present invention relates to compounds of formula (I)

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in which R1represents a group of formula (II) or (III)

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R2represents an alkyl group with carbon atoms of 1 to 6, alkenylphenol group with the number of carbon atoms from 2 to 6 or alkylamino group with the number of carbon atoms from 2 to 6;

R3and R4independently selected from the group comprising a hydrogen atom, alkyl group with carbon atoms of 1 to 6, alkeline group with the number of carbon atoms from 2 to 6 and alkyline group with the number of carbon atoms from 2 to 6;

R5represents a hydrogen atom or carboxyamide group;

Rais the ATA is composed of hydrogen atoms, hydroxyamide group, alkyl group with carbon atoms of 1 to 6, alkanesulfonyl group with the number of carbon atoms from 1 to 6, a halogenated alkanesulfonyl group with the number of carbon atoms from 1 to 6 and arylsulfonyl group in which the aryl part is an aromatic hydrocarbon ring which contains from 6 to 14 carbon atoms and is unsubstituted or substituted by at least one Deputy, selected from the group which consists of the Deputy , defined below;

the mentioned substituents selected from the group which includes halogen atoms, alkyl groups with carbon atoms of 1 to 6, alkoxygroup with the number of carbon atoms from 1 to 6, carboxypropyl, nitro, ceanography, alkylenedioxy with the number of carbon atoms from 1 to 4, alluminare, alkoxycarbonyl group with the number of carbon atoms from 2 to 7 and aryl groups;

Provided that when R2represents an ethyl group, and R3represents a hydrogen atom, R4not a methyl group, and when R2represents an ethyl group, and R3represents an alkyl group, R4also not an alkyl group;

The invention also relates to a method of treatment of a mammal suffering from a disorder caused by an imbalance of cholesterol in the blood, which includes the introduction of the said mammal an effective amount of a substance that inhibits the biosynthesis of cholesterol and selected from the group consisting of the compounds of formula (I) defined above, and their pharmaceutically acceptable salts and esters.

The invention also relates to methods of preparing compounds of formula (I) and their pharmaceutically acceptable salts and esters, which are described in more detail below.

The compounds of the present invention include compounds of formulas (Ia) and (Ib) that resembles the following:

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in which groups R1, R2, R3, R4and R6have the meanings previously defined. To eliminate any doubt in the above two formulas also shows the system of partial numericaxis of the invention, in which R2, R3, R4, R6, R6aor R6brepresents an alkyl group, this group may be an alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms; preferably the number of carbon atoms comprised of 1 to 4. Examples of such groups are methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina, tert-bucilina, pentilla, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexeline, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl group, of which preference should be given to methyl, ethyl, sawn, ISO-propyl, butilkoi and tert-butilkoi groups. In the case of a group R2more preferred are methyl and ethyl group, and ethyl group is most preferable. In the case of a group R3more preferred groups are methyl, ethyl, sawn and ISO-propyl group, and most preferred groups are ethylenimine, ISO-propyl, bucilina and tert-bucilina group, and most preferred are ethyl and isopropyl group.

When R2, R3or R4represents alkenylphenol group, it may be alkenylphenol group with a straight or branched chain, containing from 2 to 6 carbon atoms; preferably, it contains from 2 to 4 carbon atoms. Examples of such groups are vinyl, 1-protanilla, allyl (i.e., 2-protanilla), 1-methyl-2-protanilla, 2-methyl-1-protanilla, 2-methyl-2-protanilla, 2-ethyl-2-protanilla, 1-bucinellina, 2-bucinellina, 1-methyl-2-bucinellina, 2-methyl-2-bucinellina, 3-methyl-2-bucinellina, 1-ethyl-2-bucinellina, 3-bucinellina, 1-methyl-3-bucinellina, 2-methyl-3-bucinellina, 1-ethyl-3-bucinellina, 1-pencilina, 2-penttila, 1-methyl-2-penttila, 2-methyl-2-penttila, 3-penttila, 1-methyl-3-penttila, 2-methyl-3-penttila, 4-penttila, 1-methyl-4-penttila, 2-methyl-4-penttila, 1-examilia, 2-examilia, 3-examilia, 4-examilia and 5-examilia group, of which preferred are the vinyl, allyl and 3-bucinellina group, and most preferred is allyl group.

If the group is th alkylamino group with a straight or branched chain, containing from 2 to 6 carbon atoms, preferably it contains from 2 to 4 carbon atoms. Examples of such groups are ethyl, 2-through, 1-methyl-2-proponila, 2-methyl-2-proponila, 2-ethyl-2-proponila, 2-bucilla, 1-methyl-2-Butyrina, 2-methyl-2-Butyrina, 1-ethyl-2-Butyrina, 3-Butyrina, 1-methyl-3-Butyrina, 2-methyl-3-Butyrina, 1-ethyl-3-Butyrina, 2-penicilina, 1-methyl-2-penicilina, 3-penttila, 1-methyl-3-penicilina, 2-methyl-3-penicilina, 4-penicilina, 1-methyl-4-penicilina, 2-methyl-4-penicilina, 2-hexylamine, 3-hexylamine, 4-hexylamine and 5-hexylamine group, of which preferred is 2-proponila group.

The term "carboxyamide group", as used in the definition of the group R5covers protecting group which can be removed by chemical methods (such as hydrogenolysis, hydrolysis, electrolysis or photolysis) with the formation of free carboxypropyl, or cover protecting group which can be removed in vivo by biological methods, such as hydrolysis.

Examples carboxyamide groups, which can be removed by chemical methods, are lonefire the number of carbon atoms comprised of 1 to 6, such as the groups described as examples above in connection with the consideration of the group R2and so on, and tertiary alkyl groups, such as groups, are well known in this technical field, for example Reptilia, anjilina, Danilina, decile, Godzilla, redecilla, pentadactyla, octadecyl, Donatella and Casilina group, but the most preferred are methyl, ethyl and tert-bucilina group;

halogenated alkyl groups with carbon atoms of 1 to 6, preferably the number of carbon atoms from 1 to 4, in which the alkyl part is as defined and illustrated by examples in connection with the above consideration alkyl groups, and in which the halogen atom is chlorine, fluorine, bromine or iodine, such as 2,2,2-trichlorethylene, 2-Galatina (for example, 2-chloraniline, 2-florachilena, 2-brometalia or 2-idalina group), 2,2-dibromoethylene and 2,2,2-tribromaniline group;< / BR>
cycloalkyl group with the number of carbon atoms from 3 to 7, for example cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo and cycloheptyl group;

kalkilya groups in which the alkyl part contains from 1 to 3 carbon atoms, and aryl is 14, which may be substituted or unsubstituted and, if it is substituted, contains at least one of the substituents defined and illustrated by the examples below; the alkyl group may contain 1, 2 or 3 such aryl substituent; examples of such Uralkalij groups are benzyl, fenetylline, 1-phenylethylene, 3-phenylpropionate, 2-phenylpropionate, -naphthylethylene, -naphthylmethyl, 2-(-naphthyl)ethyl, 2-(2-naphthyl)ethyl, benzydamine (i.e. diphenylmethylene), triphenylethylene (i.e. triticina), -afterdirectly, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylethylamine, 2-nitroaniline, 4-nitroaniline, 3-nitroaniline, 4-chloraniline, 4-brombenzene, 4-cyanoaniline, 4-cyanopyrrolidine, bis-(o-nitrophenyl)methyl, 9-intellilink and piperella group;

alkeneamine group with the number of carbon atoms from 2 to 6, such as vinyl, allyl, 2-methylaniline, 1-protanilla, isopropylene, 1-bucinellina, 2-bucinellina, 3-bucinellina, 1-penttila, 2-penttila, 3-penttila, 4-penttila, 1-examilia, 2-examilia, 3-examilia, 4-examilia, and 5-hexene proponila and bucinellina group, the most preferred are allyl and 2-methylaniline group;

substituted serialkiller groups in which the alkyl part has the values defined and illustrated by examples earlier, and silyl group contains up to three substituents selected from alkyl groups with carbon atoms of 1 to 6 and the phenyl groups which are unsubstituted or have at least one Deputy, selected from the substituents defined and illustrated by examples below, for example 2-trimethylsilylethynyl group;

aryl group with the number of carbon atoms from 6 to 14, and optionally substituted by one or more substituents , defined and illustrated by examples below, for example phenyl, -naftalina, -naftalina, indayla and andrenaline group, it is desirable that they phenyl or indayla group, and more preferably, it was a phenyl group; any of these aryl groups may be unsubstituted or substituted and, if they are substituted, it is desirable to have attended at least one alkyl group with carbon atoms of 1 to 4 or aceraminophen; examples of the substituted groups are tolylene the ü one of the deputies , defined and illustrated by examples below, e.g itself penicilina group or p-brompheniramine group; and

cyclic and acyclic terpinolene group, for example geronilla, nerilka, linella, matchlock, Mantilla (especially m - and p-Mantilla), Tugela, Carolina, pinnella, bornilla, naccarella, nobinonly, norbornylene, montanella, Campanella and norbornylene group.

Examples carboxyamide groups, which can be removed in vivo by biological methods, such as hydrolysis, are ester groups and others, such as

alkoxyalkyl group in which the alkoxy and alkyl parts each containing from 1 to 5 carbon atoms, preferably contained from 1 to 4 carbon atoms, especially alkoxymethyl groups and such groups which contain at least one Deputy, preferably from one to five substituents, preferably from one to three substituents, but the best one Deputy, selected preferably from the lower alkoxymethyl groups and other alkoxyalkyl groups (such as methoxymethyl, ethoxymethylene, propoxymethyl, isopropoxyaniline, butoxymethyl and tert-butoxyl the group), halogenated lower alkoxymethyl groups (such as 2,2,2-trichloroethylene and bis-(2-chloroethoxy)methyl group and a lower alkoxy-substituted ethyl and higher alkyl groups (such as 1-amoxicilina, 1-methyl-1-methoxyaniline and 1-isopropoxyaniline group);

other substituted ethyl group, preferably selected from halogenated ethyl groups (such as 2,2,2-trichlorethylene group), and arilsulfonilglitsiny ethyl group, in which the aryl component is as defined previously, it is desirable that it was a phenyl group (such as 2-(phenylseleno)ethyl group);

aliphatic aryloxyalkyl group, in which the acyl group is mainly alkanoyloxy group (which may be substituted or may have at least one Deputy, selected from the group comprising amino, alkylamino and dialkylamino) and, more preferably, alkanoyloxy group with the number of carbon atoms from 2 to 6 and in which the alkyl component is characterized by the presence of from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as acetoxymethyl, dimethylaminoacetonitrile, propionylthiocholine, Buena, 1-isobutyrylacetate, 1-pivaloyloxymethyl, 2-methyl-1-pivaloyloxymethyl, 2-pivaloyloxymethyl, 1-isobutyrylacetate, 1-isobutylacetophenone, 1-acetoxypropionyl, 1-acetoxy-2-methylpropyl, 1-propionylcarnitine, 1-propionoxypiperidine, 2-acetoxypropionyl and 1-butyrolacetone group;

alkoxycarbonylmethyl groups, especially 1-(alkoxycarbonyl)ethyl group, whose alkoxysilanes contains from 1 to 10, preferably from 1 to 6 and, better still from 1 to 4 carbon atoms and whose alkyl constituent contains from 1 to 6, preferably from 1 to 4, carbon atoms, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxyimino, msobuttoniconandcaption, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyloxymethyl, 1-butoxycarbonyloxyimino, 1-msobuttoniconandcaption, 1-second-butoxycarbonyloxyimino, 1-tert-butoxycarbonyloxyimino, 1-(1-ethylpropylamine)ethyl and 1-(1,1-dipropylenetriamine)ethyl group, and other aldoxycarb is 4, carbon atoms, such as 2-methyl-1-(isopropoxycarbonyl)through 2-(isopropoxycarbonyl)through isopropoxycarbonyloxymethyl, tert-butoxycarbonyloxyimino, methoxycarbonylmethylene and ethoxycarbonylmethylene group;

cycloalkylcarbonyl and cycloalkylcarbonyl group who cycloalkyl group contains from 3 to 10, preferably from 3 to 7 carbon atoms is mono - or polycyclic and is arbitrarily substituted, at least one (and preferably only one) substituent in the form of alkyl groups with carbon atoms of 1 to 4 (for example, a group selected from those alkyl groups in which an example was previously known), and in which the alkyl constituent contains from 1 to 6, but more preferably from 1 to 4, carbon atoms (e.g., group selected from those alkyl groups in which an example was previously known) and, most preferably, represented a methyl, ethyl or through a group, for example, they can be cyclohexyloxycarbonyloxy, 1-methylcyclohexanecarboxylic, 1-methylcyclohexanecarboxylic, cyclopentanecarboxaldehyde, C, 1-cyclopentanecarbonitrile, 1-cyclopentanecarbonitrile, 1-cyclohexyloxycarbonyloxy, 1-cyclohexylcarbodiimide, 1-methylcyclohexanecarboxylic, 1-methylcyclohexanecarboxylic, 2-methyl-1-(1-methylcyclohexanecarboxylic)through 1-(1-methylcyclohexanecarboxylic)through 2-(1-methylcyclohexanecarboxylic)through 1-(cyclohexyloxycarbonyloxy)through 2-(cyclohexyloxycarbonyloxy)through 2-methyl-1-(1-methylcyclopentadienyl)through 1-(1-methylcyclopentadienyl)through 2-(1-methylcyclopentadienyl)through 1-(cyclopentanecarbonyl)-through 2-(cyclopentanecarbonyl)through 1-(1-methylcyclopentadienyl)ethyl, 1-(1-methylcyclopentadienyl)through adamantanecarboxylic, adamantankarboksilato, 1-adamantanecarboxylic, 1-adamantankarboksilato, cyclohexyloxycarbonyloxy)cyclohexyl)methyl group;

cycloalkylation aliphatic aryloxyalkyl group, in which the acyl group is preferably alkanoyloxy group and, more preferably, alkanoyloxy group with the number of carbon atoms from 2 preferably from 1 to 4, carbon atoms, such as (cyclohexylmethoxy)methyl, 1-(cyclohexyloxy)ethyl, 1-(cyclohexylmethoxy)through 2-methyl-1-(cyclohexylmethoxy)through (cyclopentyloxy)methyl, 1-(cyclopentyloxy)ethyl, 1-(cyclopentyloxy), sawn and 2-methyl-1-(cyclopentyloxy), sawn group;

cycloalkylcarbonyl group, whose alkoxygroup contains only cycloalkenyl Deputy, and cycloalkenyl Deputy contains from 3 to 10, preferably from 3 to 7, carbon atoms and is a mono - or polycyclic, for example, they can be cyclopropanecarboxylate, cyclobutanedicarboxylate, cyclopentanetetracarboxylic, cyclohexyloxycarbonyloxy, 1-(cyclopropylmethoxy)ethyl, 1-(cyclobutanedicarboxylate)ethyl, 1-(cyclopentanecarbonyl)ethyl and 1-(cyclohexyloxycarbonyloxy)ethyl group;

technicianlocation and technilogically group who terpinolene group is similar to those in the example cited previously, and it is desirable that it was circular terpinolene group,cimetidina, methylcarbamoylmethyl, 1-(3-pennicornis)ethyl, 1-(3-pennicornis)ethyl, 3-pinaysexscandaldownload and 3-finanisirovaniya group;

5-alkyl or 5-phenyl (which may be substituted by at least one Deputy , defined and illustrated by examples below) (2-oxo-1-,3-dioxolan-4-yl)alkyl groups in which each alkyl group (which may be the same or different) have from 1 to 6, preferably from 1 to 4, carbon atoms, such as (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-tert-butyl-2-oxo-1,3-dioxolan-4-yl)methyl and 1-(5-methyl-2-oxo-1,3-dioxolan-4-yl)ethyl group; and

phthalidyl group that may be unsubstituted or may be substituted by at least one Deputy, selected from the group of substituents defined and illustrated by examples below, preferably they alkyl group or alkoxygroup, such as felicilda, dimethylpyridine and dimethoxytrityl group;

any of the alkyl groups is illustrated prepupa; and

ameloblastoma amino acid residues, such as phenylalanine.

Examples of the substituents mentioned above are

the halogen atoms such as fluorine atoms, chlorine, bromine and iodine;

alkyl groups with carbon atoms of 1 to 6, such as group shown in the example earlier, especially methyl, ethyl and tert-bucilina group;

alkoxygroup with the number of carbon atoms from 1 to 6, such as methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy-, tert-butoxy-, pentyloxy, isopentylamine, neopentylene, hexyloxy and isohexadecane, which contain from 1 to 4 carbon atoms, preferably they methoxy-, ethoxy-, propoxy-, isopropoxy, butoxy and isobutoxy, and most preferred is a methoxy group;

carboxypropyl, nitro and cyanopropyl;

alkylenedioxy with the number of carbon atoms from 1 to 4, such as methylendioxy;

alluminare containing alluminare corresponding aliphatic and aromatic acyl groups, examples of which will be given below in connection with the consideration of hydroxyamides groups, preferably they had acetamido to 5, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, solutionline and tert-butoxycarbonyl group; and

aryl groups, such as the one shown in the example earlier, provided that any such aryl group, which is contained in the substituents , is optionally substituted aryl group.

To identify the possible removal of protecting groups by biological means a compound containing such a group or its pharmaceutically acceptable salt, is administered by intravenous injection test animal, such as rat or mouse, and the products of metabolism, subsequently extracted from body fluids used animal examined for the presence of a split-off group. From the above protecting groups, preference should be given to those groups that can be derived in vivo by biological methods, such as hydrolysis. It should, of course, be understood that at least some of these groups, which can be chipped off in vivo by biological methods, can also be split and chemical methods.

The term "hydroxyamide the attending group, able to be chipped off when exposed to chemical methods (such as hydrogenolysis, hydrolysis, electrolysis or photolysis) to form a free hydroxy-group, or a protecting group capable of chipped off in vivo when exposed to biological methods, such as hydrolysis.

Examples hydroxyamides groups that can be split by chemical methods, are

aliphatic acyl group, preferably alcoholnye group with the number of carbon atoms from 1 to 25, more preferably that they were with the number of carbon atoms from 1 to 20, even more preferably, they were with the number of carbon atoms from 1 to 6, and it is best that they were with the number of carbon atoms from 1 to 4 (such as formyl, acetyl, propylaniline, Butyrina, isobutylene, bialoleka, valerina, isovaleryl, hexanoyl, heptanoyl, actinaria, Laurila, Mirandolina, tridecanol, palmifolia, and caarolina group, from which the acetyl group is most preferred); halogenated alcoholnye group with the number of carbon atoms from 2 to 6, especially halogenated acetyl groups (such as chlorocichla, dichloroacetylene, trichlo is from 1 to 6, preferably from 1 to 3, carbon atoms and alcoolica portion contains from 2 to 6 carbon atoms, and preferably represents an acetyl group (such as methoxyacetyl group); and unsaturated analogs of such groups, especially alkenols or alkylarene group with the number of carbon atoms from 3 to 6 (such as calolina, methacryloyl, Propylamine, crotonoideae, isotretinoina and (E)-2-methyl-2-butenolide group);

aromatic acyl group, preferably arylcarbamoyl group, in which the aryl component contains from 6 to 14, more preferably from 6 to 10, more preferably 6 or 10, and most preferably 6, ring carbon atoms and is a carbocyclic group which is unsubstituted or contains from 1 to 5, preferably from 1 to 3, substituents selected from the group consisting of the substituents defined and illustrated by examples previously, such as the unsubstituted group (such as benzoline, -napolina and-napolina group); halogenated arylcarbamoyl group (such as 2-bromobenzoyl and 4-chlorbenzoyl groups); lower alkyl substituted arylcarbamoyl groups in which the alkyl or each alkyl substituent contains about alkoxysilane arylcarbamoyl group, in which the alkoxy or each alkoxylation mainly contains from 1 to 6, and even better from 1 to 4, carbon atoms (such as 4-ansorena group); carboxyaldehyde arylcarbamoyl group (such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl group); nitrosamine arylcarbamoyl group (such as 4-nitrobenzoyl and 2-nitrobenzoyl groups); lower alkoxycarbonylmethyl arylcarbamoyl groups in which alkoxycarbonyl or each alkoxycarbonyl Deputy mainly contains from 2 to 6 carbon atoms (such as 2-(methoxycarbonyl)benzoline group); and aryl-substituted arylcarbamoyl groups in which the aryl Deputy is the way it has been defined previously, except that if it is replaced by the additional aryl group, that aryl group is not itself substituted by an aryl group (such as 4-phenylbenzophenone group);

heterocyclic group including a ring of 5 or 6 atoms of which 1 or 2 atoms are heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, preferably oxygen atoms or sulfur, and such groups can be unsubstituted ohms of oxygen, preferably, the chalcogen atoms and alkoxygroup; examples are tetrahydropyranyl group which may be substituted or unsubstituted, such as tetrahydropyran-2-ilen, 3-bromotetradecane-2-ilen and 4-methoxyacridine-4-ilen group; tetrahydropyranyl group which may be substituted or unsubstituted, such as tetrahydrothiopyran-2-ilen and 4-methoxytryptamine-4-ilen group; tetrahydropyranyl group which may be substituted or unsubstituted, such as tetrahydrofuran-2-ilen group; and tetrahydroquinoline group which may be substituted or unsubstituted, such as tetrahydrothieno-2-ilen group;

tizanidine silyl group, in which all three or two or one of the substituents are alkyl groups with carbon atoms of 1 to 5, preferably from 1 to 4, and none or one or two of the substituents are aryl groups defined above, preferably phenyl or substituted phenyl groups, preferably three(lower alkyl) silyl groups such as trimethylsilyl, triethylsilyl, isopropylideneuridine, tert-butyldimethylsilyl, methyldiisopropanolamine, IU is a or two alkyl groups, substituted aryl groups, such as diphenylmethylsilane, diphenylmethylsilane, diphenyl-tert-butylstyrene, diphenylmethylsilane and phenyldimethylsilane group;

alkoxyalkyl groups in which the alkoxy and alkyl parts each containing from 1 to 6, preferably from 1 to 4, carbon atoms, especially alkoxymethyl groups and such groups which contain at least one, preferably from 1 to 6, more preferably from 1 to 3 and most preferably 1, Deputy, preferably lower alkoxymethyl groups and other alkoxyalkyl groups (such as methoxymethyl, ethoxymethylene, propoxymethyl, isopropoxyaniline, butoxymethyl and tert-butoxymethyl groups); lower alkoxy-substituted lower alkoxymethyl group (such as 2-methoxyethoxymethyl group); halogenated lower alkoxymethyl groups such as 2,2,2-trichloroethylene and bis-(2-chloroethoxy)methyl group and a lower alkoxy-substituted ethyl groups (such as 1-amoxicilina, 1-methyl-1-methoxyaniline and 1-isopropoxyaniline group);

other substituted ethyl group, preferably a halogenated ethyl group such as 2,2,2-trichlorethylene group); and arylsulfonamides)ethyl group);

kalkilya groups, preferably alkyl groups containing from 1 to 4, more preferably from 1 to 3 and most preferably 1 or 2, carbon atoms, which are substituted one to three aryl groups, defined and illustrated by examples previously, which may be unsubstituted (such as benzyl, fenetylline, 1-phenylethylene, 3-phenylpropionate, -naphthylethylene, -naphthylethylene, diphenylmethylene, triphenylethylene, -afterdirectly and 9-intellilink group) or substituted in the aryl part of the lower alkyl group, lower alkoxygroup, a nitro-group, a halogen atom, by cyano or alkylenedioxy with the number of carbon atoms from 1 to 3, preferably by methylendioxyphenyl, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylethylamine, 2-nitroaniline, 4-nitroaniline, 4-chlorbenzoyl, 4-brombenzene, 4-cyanoaniline, 4-cyanobenzeneboronic, bis-(2-nitrophenyl)methyl and piperella group;

alkoxycarbonyl groups, especially those groups that contain from 2 to 7, preferably from 2 to 5, carbon atoms and which can be nezametnymi) or substituted by a halogen atom or tizamidine silyl group, for example, three(lower alkylsilanes) group (such as 2,2,2-trichlorocarbanilide and 2-trimethylsilylethynyl group);

altneratively groups in which Alchemilla portion contains from 2 to 6, preferably from 2 to 4, carbon atoms (such as vinyloxycarbonyl and allyloxycarbonyl group);

sulfopropyl and

aracelikarsaalyna groups in which kalkilya part is as defined and illustrated by examples earlier, and in which the aryl ring, if it is substituted, is substituted by at least one Deputy, selected from the group consisting of the substituents defined and illustrated by examples earlier, one or two lower alkoxy or microsatellites, such as benzyloxycarbonyl, 4-methoxybenzylideneamino, 3,4-dimethoxybenzonitrile, 2-nitrobenzisoxazole and 4-nitrobenzisoxazole group.

Examples hydroxyamides groups that have the ability to be chipped off in vivo when exposed to biological methods, such as hydrolysis, are

doxologically group, aliphatic acyl group and an aromatic acyl group, such atok, which forms a salt Palmyra dicarboxylic acid such as succinic acid;

the residue, which forms a salt in the form of phosphate;

the remainder of ester amino acids and

carbonylcontaining groups, such as pivaloyloxymethyl group. In that case, the code group R1represents a group of formula (II), two groups represented by the groups R6aand R6bcan together form one of the following bidentate protecting groups:

lower alkylidene group with the number of carbon atoms from 1 to 46 such as mathildenhohe, utilizinga or isopropylidene group;

aralkylamines group in which the aryl part may be as defined above, and alkylidene portion contains from 1 to 4 carbon atoms, such as benzylidene group;

alkoxyethanol group, in which alkoxides contains from 1 to 6, preferably from 1 to 4, carbon atoms, such as methoxyacridine or amoxicillinbuy group;

exomethylene group and

trioxymethylene group.

The ability of the protecting groups described above, be chipped off when exposed to biological methods can be defined in the same way, kateli preferred silyl group and protecting groups, capable chipped off in vivo by biological methods.

When the group R6, R6aor R6brepresent an alkyl group, it can be any of the alkyl groups, illustrated by examples in relation to the group R2and other

When the group R6, R6aor R6brepresent alkanesulfonyl, it can be a group with a straight or branched chain, containing from 1 to 6 carbon atoms, such as methanesulfonamido, econsultancy and propanesulfonate.

When the group R6, R6aor R6bare the halogenated alkanesulfonyl, it may be either unsubstituted alkanesulfonyl listed above, and preferably it is a fluorinated alkanesulfonyl, such as triftormetilfullerenov or pentafluoroethanesulfonyl.

When the group R6, R6aor R6brepresent arylsulfonate, aryl part may be as defined and illustrated with examples above, and examples of such groups are benzolsulfonate and p-toluensulfonate.

1represents a group of formula (II) and R5represents a hydrogen atom, may form a salt. Examples of such salts are salts with alkali metal such as sodium, potassium or lithium salt with alkaline earth metal such as barium or calcium; salts with another metal, such as magnesium, aluminum, iron, zinc, copper, Nickel or cobalt, ammonium salts, salts of organic bases, in particular salts with organic amines, such as salt with triethylamine, Diisopropylamine, cyclohexylamine, tert-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycinonitrile esters, Ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N'-dibenziletilendiaminom, chloroprocaine, procaine, diethanolamine, N-benzilpenitsillinom, piperazine, Tetramethylammonium or Tris(hydroxymethyl)aminomethane, and salts with basic amino acid such as histidine ,-diaminobutane acid, lysine, arginine, ornithine, glutamic acid or aspartic acid.

In addition, when the compound of the present invention Soi are salts with mineral acids, especially kaleidostone acids (such as hydrofluoric acid, Hydrobromic acid, itestosterone acid or hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonyl acids such as methanesulfonate acid, triftormetilfullerenov acid or econsultancy acid, salts with arylsulfonic acids, such as benzolsulfonat acid or p-toluensulfonate acid, salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid, and salts with amino acids such as glutamic acid or aspartic acid.

Compounds of the present invention may contain one or more asymmetric carbon atoms in their molecules and, thus, can form optical isomers. Although all of these compounds are presented in the present description only the molecular formula, the present invention races is by stereospecific synthesis or as starting substances are used optically active compounds, can be received directly by the individual isomers; on the other hand, if you get a mixture of isomers, the individual isomers can be obtained by ordinary methods of allocation.

Preferred classes of compounds of the present invention are compounds of formula (I), (Ia) or (Ib) and their pharmaceutically acceptable salts and esters, in which

(A) R2represents an alkyl group with carbon atoms of 1 to 4, alkenylphenol group with the number of carbon atoms from 2 to 4 or alkylamino group with the number of carbon atoms from 2 to 4 and

R3and R4are the same or different and each represents a hydrogen atom, alkyl group with carbon atoms of 1 to 4, alkenylphenol group with the number of carbon atoms from 2 to 4 or alkylamino group with the number of carbon atoms from 2 to 4;

or

(B) R2represents an alkyl group with carbon atoms of 1 to 4, alkenylphenol group with the number of carbon atoms from 2 to 4 or alkylamino group with the number of carbon atoms from 2 to 4;

R3represents an alkyl group with carbon atoms of 1 to 4, alkenylphenol group with the number of carbon atoms from 2 to 4 or alkylamino group with the number of the carbon from 1 to 4, alkenylphenol group with the number of carbon atoms from 2 to 4 or alkylamino group with the number of carbon atoms from 2 to 4;

(C) R2represents an alkyl group with carbon atoms of 1 to 4 or alkenylphenol group with the number of carbon atoms from 2 to 4;

R3represents an alkyl group with carbon atoms of 1 to 4 or alkenylphenol group with the number of carbon atoms from 2 to 4 and

R4represents a hydrogen atom, alkyl group with carbon atoms of 1 to 4 or alkenylphenol group with the number of carbon atoms from 2 to 4;

(D) R2represents an ethyl group;

R3represents an alkyl group with carbon atoms of 1 to 4 and

R4represents an alkyl group with the number of carbon atoms from 2 to 4;

(E) R2represents an ethyl group;

R3represents an alkyl group with carbon atoms of 1 to 3 and

R4represents an alkyl group with carbon atoms is 2 or 3;

(F) R1represents a group of formula (II) and, more preferably, R2, R3and R4have the meanings given in one of the above paragraphs (A) to (E);

(G) R1more preferably R2, R3and R4have the meanings given above one of the paragraphs (A) to (E);

(H) pharmaceutically acceptable salts of the compounds defined above under item (G);

(I) R5represents a hydrogen atom or a protecting group capable of chipped off in vivo by biological methods;

(J) R6, R6aand R6beach represents a hydrogen atom or a protecting group capable of chipped off in vivo by biological methods, such as hydrolysis; and

(K) R5represents a hydrogen atom.

Specific examples of individual compounds of the present invention are given by the following formulas (I-1), (I-1a), (I-2) and (I-2a), in which the various symbols have the meanings defined in the corresponding one of the table. 1 and 2, i.e., PL.1 relates to formula (I-1) and (I-1a), and table.2 relates to formula (I-2) and (I-2a). In these tables for some groups used the following abbreviations:

All - allyl group,

Bu - bucilina group,

iBu - isobutylene group,

tBu is tert-bucilina group,

Me is a methyl group,

Pr - through the group,

iPr is isopropyl group,

Et is ethyl group.

Of the compounds listed above, -38, 1-39, 1-41, 1-45, 1-48, 1-49, 1-52, 1-54, 1-56, 1-57, 1-60, 1-63, 1-65, 1-66, 1-70, 1-71, 1-73, 1-74, 1-75, 1-79, 1-82, 1-86, 1-87, 1-90, 1-93, 1-94, 1-96, 1-97, 1-99, 1-100, 1-101, 1-102, 1-103, 1-105, 1-106, 1-108, 1-109, 1-112, 1-115, 1-116, 1-118, 1-120, 1-123, 1-125, 1-128, 1-129, 1-130, 1-135, 1-137, 1-139, 1-140, 1-141, 1-142, 1-146, 1-147, 1-151, 1-154, 1-155, 1-157, 2-4, 2-5, 2-6, 2-7, 2-9, 2-10, 2-13, 2-19, 2-20, 2-21, 2-22, 2-23, 2-25, 2-29, 2-30, 2-32, 2-33, 2-38, 2-39, 2-41, 2-45, 2-48, 2-49, 2-52, 2-54, 2-56, 2-57, 2-60, 2-63, 2-65, 2-66, 2-70, 2-71, 2-73, 2-74, 2-75, 2-79, 2-82, 2-86, 2-87, 2-90, 2-93, 2-94, 2-96, 2-97, 2-99, 2-100, 2-101, 2-102, 2-103, 2-105, 2-106, 2-108, 2-109, 2-112, 2-115, 2-116, 2-118, 2-120, 2-123, 2-125, 2-128, 2-129, 2-130, 2-135, 2-137, 2-139, 2-140, 2-141, 2-142, 2-146, 2-147, 2-151, 2-154, 2-155 and 2-157.

More preferred compounds are compounds NN: 1-5, 1-7, 1-13, 1-19, 1-22, 1-23, 1-25, 1-29, 1-32, 1-33, 1-38, 1-41, 1-45, 1-49, 1-52, 1-54, 1-56, 1-57, 1-60, 1-63, 1-65, 1-66, 1-70, 1-73, 1-74, 1-75, 1-79, 1-82, 1-87, 1-90, 1-93, 1-94, 1-96, 1-99, 1-100, 1-101, 1-102, 1-103, 1-105, 1-109, 1-112, 1-120, 1-155, 2-4, 2-5, 2-7, 2-13, 2-19, 2-22, 2-23, 2-25, 2-29, 2-32, 2-33, 2-38, 2-41, 2-45, 2-49, 2-52, 2-54, 2-56, 2-57, 2-60, 2-63, 2-65, 2-66, 2-70, 2-73, 2-74, 2-75, 2-79, 2-82, 2-87, 2-90, 2-93, 2-94, 2-96, 2-99, 2-100, 2-101, 2-102, 2-103, 2-105, 2-109, 2-112, 2-120 and 2-155.

The most preferred compounds are compounds with the following numbers.

1-4. 3,5-Dihydroxy-7-(6-hydroxy-2-methyl-8-isovalerianic - 1,2,6,8,8 and hexahydro-1-naphthyl)heptane acid.

1-5. 3,5-Dihydroxy-7-(6-hydroxy-2-methyl-8-hexanoate - 1,2,6,7,8,8 and hexahydro-1-naphthyl)heptane acid.

1-7. 3,5-Dihydroxy-7-[6-hydroxy-2-hydroxy-2-methyl-8-(2-methyl-pentanoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-22 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2-ethylbutyrate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-32. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2-propyl-pentanoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-33. 3,5-Dihydroxy-7-[(6-hydroxy-2-methyl-8-(2-isopropyl-3 - metabolizable)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-41. 3,5-Dihydroxy-7-[6-hikkoshi-2-methyl-8-(2-butylphenoxy)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-49. 3,5-Dihydroxy-7-[6-hikkoshi-2-methyl-8(2-allyl-4-pentenoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-52. 3,5-Dihydroxy-7-(6-hydroxy-2-methyl-8-pivaloyloxy - 1,2,6,7,8,8 and hexahydro-1-naphthyl)heptane acid.

1-54. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2,2-dimethylbutanoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-56. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2,2, -dimethylhexanoic)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-60. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2,2-dimethyl - 4-pentenoate)-1,2,6,7,8,8 and hexahydro-naphtyl]heptane acid.

1-63. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2-ethyl-2 - methylpentanoate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane sour tanova acid.

1-73. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2-methyl-2 - propylpentanoate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-90. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2-allyl-2-methyl-4 - pentenoate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-93. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2,2-diethylbutyl)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-94. 3,5-Dihydroxy-7-[6-hydroxy-2-metal-8-(2,2-diethylphenyl)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-100. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2,2-diethyl-4 - pentenoate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-120. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2-allyl-2-ethyl-4 - pentenoate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

1-155. 3,5-Dihydroxy-7-[6-hydroxy-2-methyl-8-(2,2-diallyl-4 - pentenoate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-4. 3,5-Dihydroxy-7-(2-methyl-8-isovalerate-1,2,6,7,8-8A-hexahydro - 1-naphthyl)heptane acid.

2-5. 3,5-Dihydroxy-7-(2-methyl-8-hexanoate-1,2,6,7,8,8 and hexahydro - 1-naphthyl)heptane acid.

2-7. 3,5-Dihydroxy-7-[2-methyl-8-(3,3-dimethylbutyryl)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-13. 3,5-Dihydroxy-7-[2-methyl-8-(2-ethylbutyrate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-32. 3,5-Dihydroxy-7-[2-methyl-8-(2-propylpentanoate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-33. 3,5-Dihydroxy-7-[2-methyl-8-(2-isopropyl-3-metabolicrare)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-41. 3,5-Dihydroxy-7-[2-methyl-8-(2-butylacrylate)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-49. 3,5-Dihydroxy-7-[2-methyl-8-(2-allyl-4-pentenoate)- 1,2,6,7,8,7 and hexahydro-1-naphthyl]heptane acid.

2-52. 3,5-Dehydrase-7-(2-methyl-8-pivaloyloxy-1,2,6,7,8,8 and hexahydro-1-naphthyl)heptane acid.

2-54. 3,5-Dihydroxy-7-[2-methyl-8-(2,2-dimethylbutanoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-56. 3,5-Dihydroxy-7-[2-methyl-8-(2,2-dimethylhexanoic)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-60. 3,5-Dihydroxy-7-[2-methyl-8-(2,2-dimethyl-4-pentenoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-63. 3,5-Dihydroxy-7-[2-methyl-8-(2-ethyl-2-methylpentanoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-65. 3,5-Dihydroxy-7-[2-methyl-8-(2-ethyl-2-methylbutyrate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-73. 3,5-Dihydroxy-7-[2-methyl-8-(2-methyl-2-propylpentanoate)- 1,2,6,7,8,8 and hexahydro-1-NAF is DRO-1-naphthyl]heptane acid.

2-93. 3,5-Dihydroxy-7-[2-methyl-8-(2,2-diethylbutyl)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-94. 3,5-Dihydroxy-7-[2-methyl-8-(2,2-diethylphthalate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-100. 3,5-Dihydroxy-7-[2-methyl-8-(2,2-diethyl-4-pentenoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-120. 3,5-Dihydroxy-7-[2-methyl-8-(2-alkyl-2-ethyl-4-pentenoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid.

2-155. 3,5-Dihydroxy-7-[2-methyl-8-(2,2-dialkyl-4-pentenoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid;

and lactones with a closed ring, corresponding to the hydroxy acids listed above;

and their pharmaceutically acceptable salts and esters.

Compounds of the present invention can be obtained in a variety of ways well known in obtaining compounds of this type. For example, in the General case they can be obtained by the coupling of compounds of formula (IV)

< / BR>
(in which Rarepresents a hydrogen atom or a group with the formula, R6O - and the symbols R6each represents any of groups represented by R6but cannot be a hydrogen atom) with reactions the compounds of the formula (V)

< / BR>
in which groups R2, R3, R4and R6have the meanings previously defined, and, if necessary, removing the protecting groups, and, if necessary, exposure of the compounds of formula (V) hydrolysis or solvolysis with ring opening and, if desired, when Rarepresents a hydrogen atom, with the introduction of a group of the formula R6O - instead of Ra.

In more detail, the compounds of the present invention can be obtained as illustrated in the following reaction schemes A, B, C, and D.

Reaction scheme A

The compounds of formula (Ia) can be obtained as illustrated by the following reaction scheme A (PL.3).

In this method, the starting material of the formula (VI) may be known connection pravastatin in which the hydroxy-group in position 6 is in the configuration. Throughout the reaction scheme corresponding group in 6-position, stereochemical are considered to be in configuration. Alternatively, as the source of matter at the stage of AI can be used epimeric isomer 6-position of pravastatin, in which case you can get the required compound of formula (X), (XI) and (XII) in which the substituents in the 6-pologea formulas, in the present invention assumes the use of selected individual isomers, such as pravastatin or its epimeres, and mixtures of these isomers.

In the above formulas (PL.3):

R5represents a hydrogen atom, carboxyamide group defined for R5or cationic portion of the salt;

R6is hydroxyamides group, alkyl group, alkanesulfonyl group, halogenated alkanesulfonyl group or arylsulfonyl group, all of which are defined and illustrated by examples in the relation R6and so on;

R7represents a group of the formula

-CO-C(R2)(R3)(R4)

in which R2, R3and R4have the same meaning as before, and

M represents a hydrogen atom or a cation portion of the salt.

If R5'or M is a cation portion of the salt, it can be any of the cations listed in the example earlier in connection with pharmaceutically acceptable salts.

Stage AI

At the stage of AI this reaction scheme, the compound of formula (VII) is obtained by hydrolysis of compounds of formula (VI) or its pharmaceutically acceptable salt. Hydroly onefinal side chain, in the position 8 in the hydroxy-group.

The reaction is normally and preferably carried out in the presence of a solvent. There are no particular limitations concerning the nature of the solvent, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of acceptable solvents include water and organic solvents, such as ethers, such as tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol and dimethyl simple ether; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol or etilenglikolevye onomatology simple ether; and mixtures of water with one or more of these organic solvents.

There are no particular limitations concerning the nature of the used grounds, and any base commonly used as a base in conventional reactions may be equally applied here. Examples of preferred bases are inorganic bases, such as carbonates of Molochny the s metals (for example, sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium), hydroxides of alkali metals (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide and alkoxides of alkali metals (such as sodium methoxide, ethoxide sodium, potassium methoxide, ethoxide potassium tert-piperonyl potassium and lithium methoxide).

When using as the base of the carbonate of alkali metals, carbonates of alkali metal or alkali metal hydroxide, it is desirable to conduct the reaction using one or more equivalents of base per mole of compound with formula (VI). When using as the base of the alkali metal alkoxide reaction is carried out at such a number of reasons, which exceeds the catalytically required number of reasons.

The reaction may proceed in a wide range of temperatures and the precise temperature is not critical magnitude in the invention. In the General case, the inventors found that the reaction is conveniently lead or at temperatures in the -20oC to 150oC, more preferably from 80oC to 120oC, or at the boiling point of the used solvent. Time, the mu is built on the temperature of the reaction and the nature of the reacting substances the base and the solvent used for the reaction. However, if the reaction is carried out at the preferred conditions outlined above, are usually a sufficient period of from 3 to 100 hours, more preferably from 24 to 60 hours

Upon completion of the reaction, the desired product of formula (VII) can be isolated from the reaction mixture by conventional means. For example, if one of the acceptable methods for extracting the reaction mixture is adequately neutralized in the presence of insoluble substances are removed by filtration, the reaction mixture or to the filtrate add water and immiscible with water, an organic solvent, such as ethyl acetate, and the final product is extracted with a solvent, the extract washed with water and dried, for example over anhydrous magnesium sulfate, and the solvent is then distilled off, getting in as residue the desired product.

The compound of formula (VII) obtained in this way is a salt of a hydroxy acid, and, if necessary, it can be cleaned in the usual way, for example by recrystallization, presidenial or various chromatographic methods. Examples of chromatographic techniques are the distribution chromatography using synthetic grass is P>TMXAD-11 (trade name material company "Rohm and Haas co.) or diaionTMHP-20 (trade name material company "Mitsubishi Kasei Corporation"); column chromatography by passing the substance through regularly-phase or reversed-phase column with a nozzle made of silica gel or alkylated silica gel (preferably high performance liquid chromatography) or a combination of these methods with subsequent elution using a suitable eluting solvent.

Stage A2

At this stage lactoovo compound of formula (VIII) is produced by interaction of salt gidrokshikislota the compounds of formula (VII) with one or more equivalents of acid to obtain the free carboxylic acid, and then subjected to the reaction product of the cyclization.

The reaction is normally and preferably carried out in the presence of a solvent. There are no particular limitations concerning the nature of the solvent, provided that it does not detrimentally impact on the course of the reaction or reactive substances involved in it, and that it can dissolve the reacting substances, at least to some extent. Examples of suitable solvents I have an, dimethoxyethane and diethyleneglycol dimethyl simple ether); alcohols (such as methanol, ethanol, propanol, isopropanol, butanol, Isobutanol, tert-butanol, diethylene glycol and cyclohexanol) and a mixture of water with one or more of these organic solvents.

There are also no specific limitations regarding the nature of the acid used in the first part of this stage; and there can be used any catalyst commonly used when carrying out reactions of this type. Examples of preferred acids are inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid or phosphoric acid.

The reaction may proceed in a wide range of temperatures and the precise temperature interaction is not critical for the invention. In the General case it is established that it is convenient to conduct the reaction at a temperature in the range -20oC and up to 50oC, more preferably in the range of 0oC and approximately to room temperature. The time required for the reaction may also vary widely, depending on many factors, namely temperature interaction, and p is s, agreed, it can be completed immediately after adding the acid, or the reaction of conduct during the period of time up to 2 hours, more preferably for a period of up to 30 minutes

After completion of the reaction the desired product of this reaction can be recovered from the reaction mixture by conventional means. For example, in the case of one of the acceptable methods of extraction of the reaction mixture is adequately neutralized in the presence of insoluble substances are removed by filtration, the reaction mixture or to the filtrate add water and immiscible with water, an organic solvent, such as ethyl acetate, and the product is extracted with a solvent, the extract washed with water and dried, for example over anhydrous magnesium sulfate and the solvent is distilled off, getting in the remainder of the desired product. Alternative after completion of the reaction, the desired compound can be recovered by distillation of the solvent from the reaction mixture, mixing the residue with an organic solvent, filtering the insoluble solids and distillation of the solvent. Examples of organic solvents that can be used in this method of extraction, are aliphatic hydrocarbons, such as g is generowanie hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethyl simple ether; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, Isobutanol, tert-butanol, diethylene glycol or cyclohexanol; ketones such as acetone and metaliteracy ketone.

The desired compound thus obtained can be, if necessary, subjected to cleaning by conventional means, such as recrystallization, presidenial or chromatographic methods. Examples of acceptable chromatographic techniques are the distribution chromatography by passing the purified substance through a synthetic absorbent such as SephadexTMLH-20 (trade name material company "pharmacy, Inc."), amberlitTMXAD-11 (trade name material company "Rohm and Haas co.) or diaionTMHP-20 (Mitsubishi Kasei Corporation"); column chromatography by passing the purified substances through regularly-falsafat high performance liquid chromatography), or a combination of these methods with subsequent elution using a suitable eluting solvent.

Holding cyclessa lactonization in the second part of the stage gidrokshikislotu make in connection with Laktionova cycle. The reaction can be conducted in different ways, for example, by the following methods:

method 1 involves simply heating the corresponding hydroxy acid in a solvent;

method 2 involves processing the corresponding hydroxyacids sonoelasticity agent in a solvent.

Method 1.

The interaction is carried out in the presence of a solvent. There are no particular limitations concerning the nature of the employed solvent, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents are aliphatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran the tone, methylisobutyl ketone, isophorone or cyclohexanone; NITRILES, such as acetonitrile or isobutyronitrile.

Interaction can take place in a wide range of temperatures and the precise temperature is not critical. In General it is established that the reaction is conveniently carried out at a temperature in the range of 0oC to the temperature of reflux distilled solvent used, more preferably in the range of from about room temperature up to 100oC. the Time required for communication, can also vary widely, depending on many factors, especially by temperature interaction, and the nature of the reagents and solvent used in the reaction. If the reaction is carried out at the preferred conditions outlined above, are usually a sufficient period of from 10 min to 6 h, more preferably from 30 minutes to 3 hours

The reaction can be accelerated by the use of acid as a catalyst. There is no particular restriction concerning the nature of the acid used, and here in equal measure can be used any acid which is acceptable for use as an acid catalyst in conventional reactions. Examples of such acids are organic acids, the OIC acid, triperoxonane acid or triftormetilfullerenov acid; a Lewis acid such as boron trichloride, boron TRIFLUORIDE and trichromacy Bor. Of these compounds, preference should be given to organic acids, and more preferably, they have a strong organic acid.

Method 2.

The interaction method 2 usually necessary and desirable to maintain in the presence of a solvent. There is no particular restriction concerning the nature of the solvent, which must be applied provided that it does not detrimentally impact on the course of the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. The solvent should be anhydrous. Examples of suitable solvents are aliphatic hydrocarbons, such as hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethyleneglycol dimethyl ether; ketones, home to the thrill or isobutyronitrile; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyridone, N-methylpyrrolidinone or hexamethylphosphoric triamide.

Examples tarifitsiruemih agent, which can be used in method 2 are condensing agents, examples of which are given below; alkylhalogenide, such as methylchloroform or ethylchloride; and complex diesters cyanophosphonate acid, such as diethylthiophosphate. Examples of condensing agents are N-hydroxy, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-hydroxy-5-norbornene-2,3-dicarboximide; disulfide compounds such as 2,2'-piperidinedione; compounds, succinic acid, such as N,N'-disuccinimidyl; phosphinic chloride compounds such as N,N'-bis-(2-oxo-3-oxazolidinyl)fatfingered; oxalate derivatives, such as N,N'-disuccinimidyl, N,N'-debtelimination, N,N'-bis-(norbornanamine)oxalate, 1,1'-bis-(benzotriazolyl)oxalate, 1,1'-bis-(6-chlorobenzotriazole)oxalate or 1,1'-bis-(6-triftormetilfosfinov)oxalate; triarylphosphine, such as triphenylphosphine; the combination of di(lower alkyl)azodicarboxylate and triarylphosphine, such as a combination of diethylazodicarboxylate ffont; carbodiimide derivatives, including N',N'-dicyclohexylcarbodiimide, such as N',N'-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; digitalairlines diselenide, such as di-2-pyridylmethylene; arylsulfonyl thiazolidine, such as p-nitrobenzenesulfonamide; 2-halogen-1-(lower alkyl)pyridinium halides, such as 2-chloro-1-methylpyridinium iodide; directorrelated, such as diphenylphosphoryl; imidazole derivatives such as 1,1'-oxalylamino or N, N'-carbonyldiimidazole; benzotriazine derivatives, such as 1-hydroxybenzotriazole; and dicarboximide derivatives, such as N-hydroxy-5-norbornene-2,3-dicarboximide. Of these compounds, the inventors prefer diarylphosphino azides.

Interaction can take place in a wide range of temperatures and the precise temperature is not critical for the invention. In the General case it is established that it is convenient to conduct the reaction at a temperature in the range from -20oC to 100oC, more preferably in a range of 0oC and approximately to room temperature. The time required for communication, can also vary widely depending on many factors, especially on occhialini conditions, as stated above, generally a sufficient period of from 10 min to 8 h, preferably 30 min to 4 h

After completion of the reaction, the desired compound with the formula (VIII) can be extracted from the reaction mixture by conventional means. For example, in the case of one acceptable method of extraction of the reaction mixture is subjected to neutralization, in the presence of insoluble substances are removed by filtration, the filtrate or the neutralized reaction mixture are added water and immiscible with water, an organic solvent, such as ethyl acetate, and the product is extracted with a solvent, the extract washed with water and dried, for example over anhydrous magnesium sulfate, and the solvent is then distilled off, getting in the remainder of the desired product.

The desired product obtained in this way may be, if necessary, subjected to further purification by conventional means such as recrystallization, presidenial or various chromatographic methods. Examples of suitable chromatographic methods are absorption chromatography by passing the purified substances through the media, such as silica gel, alumina or Florisil (trade name material representing the forces of the political absorbent, such as SephadexTMLH-20 (trade name material company "pharmacy, Inc. "), amberliteTMXAD-11 (trade name material company "Rohm and Haas co.) or diaionTMHP-20 (trade name material company "Mitsubishi Kasei Corporation"); column chromatography by passing the purified substances through regularly-phase or reversed-phase column with a nozzle made of silica gel or alkylated silica gel (preferably high performance liquid chromatography); or a combination of these methods, followed by elution with an appropriate solvent.

Stage A3

At this stage, the compound of formula (IX) are obtained by selective protection of the two hydroxy groups other than the hydroxy-group in position 8, the compound of formula (VIII), R6.

Protection can be done in various ways, which partly depends on the nature of the selected protecting groups, as, for example, is illustrated by the following methods 1 to 3.

Method 1.

In this case, is the interaction of the compounds of formula (VIII) with a suitable number, for example with 1 to 4 equivalents (more preferably to use two to Tr the values previously defined, preferably it represents an acyl group, and X represents tsepliaeva group) in a solvent in the presence or absence of a base. In the above formulas, R6matter previously defined, and preferably is hydroxyamides group, more preferably a silyl group, and most preferably tert-butyldimethylsilyloxy group.

There is no particular restriction concerning the nature tsepliaeva group, provided that it represents a group capable of chipped off in the form of a nucleophilic residue, such as those that are well-known in this technical field. Examples of preferred tseplyaesh groups are halogen atoms such as chlorine atoms, bromine and iodine; lower alkoxycarbonylmethyl, such as methoxycarbonylamino and ethoxycarbonylethyl; halogenated alkylcarboxylic, such as chloroacetoxy, dichloracetate, trichloroacetoxy and triftoratsetofenona; low alkanesulfonyl, such as methanesulfonamido and econsultancy; low guidancearticle such as Tr is solarponics, p-toluensulfonate and p-nitrobenzenesulfonamide. Of these groups, the inventors prefer atoms of halogen, lower haloalkaliphilic and arylsulfonamides.

The reaction is normally and preferably carried out in the presence of a solvent. There is no restriction concerning the nature of the solvent, which must be applied, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved and that it can dissolve them, at least to some extent. Examples of acceptable solvents are aliphatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylethylenediamine simple ether; NITRILES, such as acetonitrile and isobutyronitrile; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidine the establishment, used in method 1, and any base that can be used in a well-known reactions of this type may be equally applied here. Examples of preferred bases are organic bases, such as N-methylmorpholine, triethylamine, tributylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-(1-pyrrolidinyl)pyridine, picoline, 4-(N, N-dimethylamino)pyridine, 2,6-di-tert-butyl-4-methylpyridine, quinoline, N, N-dimethylaniline and N,N-diethylaniline. At desire it is possible to use catalytic amounts of 9-(N,N-dimethylamino)pyridine, 4-(1-pyrrolidinyl)pyridine, or a combination of the other grounds. In order to facilitate a more efficient reaction in the reaction system may be added Quaternary ammonium salt such as the chloride benzyltriethylammonium or tetrabutylammonium chloride) or crown ethers such as dibenzo-18-crown-6).

The interaction can occur in a wide range of temperatures and the precise temperature is not critical in the invention. In the General case it is established that the reaction is conveniently carried out at a temperature in the range from -20oC to the temperature of reflux distilled solvent used, more preferably in the range from e can vary widely depending on many factors, namely, the temperature of the interaction and the nature of the reagents, bases and solvents. If the reaction of lead in the preferred conditions outlined above, then usually sufficient in duration from 10 minutes to 3 days, more preferably from 1 to 6 o'clock

Method 2.

This method involves reacting the compounds of formula (VIII) with the compound of the formula R6-OH in which R6matter previously defined, and preferably represents an acyl group) in a solvent in the presence of tarifitsiruemih agent, such as those illustrated by examples earlier in method 2 at stage A2, and catalytic amounts of base.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the solvent, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents are aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and the COP is ethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylethylenediamine ether; NITRILES, such as acetonitrile and isobutyronitrile; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide.

Examples of bases that may be used in method 2 are the same reasons described in the preceding method 1.

Interaction can take place in a wide range of temperatures and the precise temperature is not critical in the invention. In the General case it is established that the reaction is conveniently carried out at a temperature in the range from -20 to 80oC, more preferably from 0oC to about room temperature. The time required for the flow of interaction, may also vary widely, depending on many factors, namely the temperature of the interaction and the nature of the reagents and solvent. If the reaction of lead in the preferred conditions set forth above, is usually sufficient PI> This method involves reacting the compounds of formula (VIII) with the compound of the formula R6-OH in which R6is as previously defined, and preferably represents an acyl group) in a solvent in the presence of halogenated dealkiller of ester of phosphoric acid, such as diethylphosphate, and reason.

Communication is usually and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the employed solvent, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents are aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxin; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide.

Examples of bases that may be used in method 3 are the same as those described for use in the foregoing method 1.

Interaction can take place in a wide range of temperatures and the precise temperature is not critical in the invention. In the General case it is established that the reaction is conveniently carried out at a temperature in the range of 0oC to the temperature of reflux distilled solvent used, more preferably from about room temperature to 50oC. the Time required for the flow of interaction, can also vary widely depending on many factors, especially by temperature interaction, and the nature of the reagents and solvent. If the reaction of lead in the preferred conditions outlined above, then the duration of the interaction is usually from 10 minutes and up to three days, preferably from 30 minutes to one day.

If the group R6represents a lower alkyl group, it may be introduced into the compound of the formula (VIII) in the usual way, that. The use of protecting reagents with different reactivity can be obtained compound with two hydroxyl groups, protected by various groups of R6.

After completion of the reaction, the desired compound of formula (IX) can be extracted from the reaction mixture by conventional means. For example, in the case of one acceptable method of extracting the reaction mixture was subjected to neutralization, in the presence of insoluble substances are removed by filtration, the reaction mixture or to the neutralized reaction mixture are added water and immiscible with water, the solvent, such as ethyl acetate, and the product is extracted with a solvent, the extract washed with water and dried, for example over anhydrous magnesium sulfate and then the solvent is distilled, obtaining the desired product.

The connection obtained in this way may be, if necessary, purified by using common methods, such as recrystallization, presidenial or various chromatographic methods. Examples of acceptable chromatographic methods are absorption column chromatography by passing the purified substances through the media, such as silica gel, alumina or Florisil (silicacontaining absorbent, such as SephadexTMLH-20 (trade name material company "pharmacy, Inc.) amberlitTMXAD-11 (trade name material company "Rohm and Haas co. "or diaionTMHP-20 (trade name material manufactured by Mitsubishi Kasei Corporation"); column chromatography by passing the purified substances through regularly-phase or reversed-phase column with a nozzle made of silica gel or alkylated silica gel (preferably high performance liquid chromatography); or a combination of these methods with subsequent elution appropriate eluting solvent.

Stage A4

At this stage, the ester compound of formula (X) obtained by acylation of the hydroxy-group in position 8 in the compound of formula (IX), R7. The reaction is carried out according to the method described in the consideration stage A3, using any of the methods described below.

Method 1.

This method involves reacting the compounds of formula (IX) with an appropriate number, for example with 1 to 4 equivalents (more preferably, with two or three equivalents) of the compound of formula R7-X or R7-O-R7(in which R7and X are ptx2">

This method involves reacting the compounds of formula (IX) with the compound of the formula R7-OH in which R7is the same as defined earlier) in a solvent in the presence of tarifitsiruemih substances, such as illustrated by the examples earlier in method 2 at stage A2, and catalytic amounts of base.

Method 3.

This method involves reacting the compounds of formula (IX) with the compound of the formula R7-OH (in which the group R7is the same as defined earlier) in a solvent in the presence of halogenated diethyl ether complex of phosphoric acid, such as diethylphosphate, and reason.

Stage A5

At this stage, the compound of formula (XI) is obtained by removing hydroxyamide groups represented by the group R6of the compounds of formula (X) and then, if necessary, blocking some or all of the resulting free hydroxy groups using the same or different protecting groups, preferably those that can be derived in vivo by biological methods, such as hydrolysis.

The reaction conditions used to remove hydroxyamide groups represented by the group R

Remove using a fluoride anion or organic acids. In those cases, when hydroxyamides group is a silyl group, it can usually be removed by treatment of the protected connection connection, able to give a fluoride anion, such as tetrabutylammonium fluoride or hydrofluoric acid, or treatment with an organic acid, such as methanesulfonate acid, p-toluensulfonate acid, triperoxonane acid or triftormetilfullerenov acid. In the case of fluoride anion as deblokiruyuschee substance reaction can sometimes be accelerated by the addition of organic acids, such as formic acid, acetic acid or propionic acid. This reaction removal is characterized by the advantage that it suppresses side reactions.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the solvent, which must be applied, provided that it does not detrimentally impact on the course of the reaction or reamers of suitable solvents are ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylethylenediamine ether; and NITRILES, such as acetonitrile and isobutyronitrile.

The interaction can occur in a wide range of temperatures and the precise temperature is not critical in the invention. In the General case it is established that the reaction is conveniently carried out at a temperature in the range of 0oC to 50oC, more preferably at a temperature close to the room. The time required for interoperability may also vary widely, depending on many factors, especially by temperature interaction, and the nature of the reagents and solvent. If the reaction of lead in the preferred conditions outlined above, then the duration of the interaction is usually from 2 to 24 hours

Removal by reduction or oxidation. In the case when hydroxyamides group is aracelio or aracelikarsaalyna group, she in a preferred embodiment, can be removed by contacting the protected compound with reducing substances (preferably by catalytic vosstanovlennoi temperature) in a solvent or by use of oxidizing agents.

Response recovery usually and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the solvent, which must be applied, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved in the reaction and that it can dissolve them, at least to some extent. Examples of suitable solvents are alcohols, such as ethanol and isopropanol, ethers, such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as toluene, benzene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; esters such as ethyl acetate and propyl; amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyridine and hexamethylphosphoric triamide; aliphatic acids such as formic acid and acetic acid; or water. Can be used any one of these solvents or can be used a mixture consisting of two or more solvents. Of these compounds, the inventors preference is given to alcohols, aliphatic acids, mixtures of alcohol with simple ether, a mixture of alcohol and water or a mixture of elevationsatellite, and any catalyst commonly used when conducting catalytic reduction, equally can be used here. Examples of preferred catalysts are palladium deposited on activated carbon, palladium black, Raney Nickel, platinum oxide, platinum black, rhodium-aluminum oxide, a combination of triphenylphosphine and rhodium chloride and palladium on barium sulphate.

The pressure of hydrogen used in the reaction is not critical value; however, the reaction is usually carried out at a pressure in the range from ambient pressure to 10 at.

Interaction can take place in a wide range of temperatures and the precise temperature is not critical in the invention, although the preferred temperature may vary depending on such factors as the nature of the reagents and catalyst. In the General case it is established that the reaction is conveniently carried out at a temperature in the range of 0oC to 100oC, more preferably from 20oC to 70oC. the Time required for the flow of interaction, may also vary widely, depending on many factors, namely the temperature of the interaction and the nature of the applied reaganfoundation typically ranges from 5 min to 48 h, more preferably from 1 to 24 hours

In the case of reaction of the oxidation reaction is usually preferably carried out in the presence of a solvent. There is also no particular restriction concerning the nature of the solvent, which should be used provided that it does not detrimentally impact on the course of the reaction or on the reagents involved in the reaction and that it can dissolve them, at least to some extent. Examples of acceptable solvents are water, organic solvents. Examples of such organic solvents are ketones, such as acetone; halogenated hydrocarbons, such as methylene chloride, chloroform and carbon tetrachloride; NITRILES, such as acetonitrile; ethers, such as diethyl ether, tetrahydrofuran and dioxane; amides, such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and sulfoxidov, such as dimethylsulfoxide.

There is no particular restriction concerning the nature of the used oxidizing agents, and any oxidizing substance, usually used to carry out the oxidation reactions of this type, are equally suitable for use here. Note the series and 2,3-dichloro-5,6-dicyano-p-benzoquinone.

Interaction can take place in a wide range of temperatures and the precise temperature is not critical in the invention. In the General case it is established that the reaction is conveniently carried out at a temperature in the range of 0oC and up to 150oC. the Time required for the flow of interaction, can also vary widely depending on many factors, namely the temperature of the interaction and the nature of the reagents and solvent. If the reaction of lead in the preferred conditions outlined above, then the duration of the interaction is usually from 10 minutes to 24 hours

Removal by treatment with an alkaline metal. Protecting group can be removed by treatment with an alkaline metal such as lithium or sodium, in liquid ammonia or alcohol, such as methanol or ethanol, at a proper temperature, for example in the range from -78oC to -20oC.

Removal by treatment with aluminium chloride. You can also remove the protecting group by contacting the protected compound with a mixture of aluminium chloride with sodium iodide or alkylsilanes a halide, such as modesty trimethylsilyl.

The reaction is normally and preferably carried out what that should be applied, provided that he has not had a negative impact on the course of the reaction or on the reagents involved and that it can dissolve them, at least to some extent. Examples of suitable solvents are NITRILES, such as acetonitrile; halogenated hydrocarbons, such as methylene chloride and chloroform. Can be used any one of these solvents or can be used a mixture of two or more solvents.

Interaction can take place in a wide range of temperatures and the precise temperature is not critical in the invention. In the General case it is established that the reaction is conveniently carried out at a temperature in the range of 0oC to 50oC. the Time required for the flow of interaction, can also vary widely depending on many factors, namely the temperature of the interaction and the nature of the application of the reagents and solvent. However, if the reaction of lead in the preferred conditions outlined above, the duration of interaction is usually in the range from 5 minutes and up to three days.

If the reaction substrate contains a sulfur atom, it is preferable to use a mixture of aluminium chloride with sodium iodide.

There is no particular restriction concerning the nature of the used grounds, provided that other parts of the connection are not affected when removing the protecting group. Examples of preferred bases are alkoxides of metals such as sodium methoxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate and lithium carbonate; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide; and ammonia, for example, in the form of an aqueous solution of ammonia or in the form of a mixture of concentrated ammonia with methanol.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the solvent, which must be applied, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents are water; org is n and dioxane; or a mixture of water with any one or more of these organic solvents.

Interaction can take place in a wide range of temperatures and the precise temperature is not critical for the invention. In the General case it is established that the reaction is conveniently carried out at temperatures from 0oC and up to 150oC. the Time required for the flow of interaction, may also vary widely, depending on many factors, especially by temperature interaction, and the nature of the reagents and solvent. If the reaction of lead in the preferred conditions outlined above, then the duration of the interaction is usually from 1 to 10 hours

In the case when hydroxyamide group is altneratively group, the release can also be achieved by treatment with base, and the reaction conditions are the same as when hydroxyamide group is an aliphatic acyl, aromatic acyl or alkoxycarbonyl group.

Removal by treatment with acid. In those cases, when hydroxyamides group is alkoxymethyl, tetrahydropyrane, it can usually be removed by treatment of the protected compound with an acid.

There is no particular restriction concerning the nature of the acid and any acid commonly used for this purpose, including acid Bronsted and the Lewis acid, there can be equally used. Examples of preferred acids are inorganic acids such as hydrogen chloride, hydrochloric acid, sulfuric acid and nitric acid; acid Bronsted, including organic acids such as acetic acid, triperoxonane acid, methanesulfonate acid or p-toluensulfonate acid; a Lewis acid such as boron trichloride; and strongly acidic cation exchange resin, such as Dowex-50WTM(trade name of the material).

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the employed solvent, provided that it does not detrimentally impact on the course of the reaction on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents are aliphatic hydrocarbons, todoroki, such as methylene chloride; chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylethylenediamine ether; alcohols, such as ethanol, propanol, isopropanol, butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol and cyclohexanol; ketones such as acetone, metaliteracy ketone, methylisobutyl ketone, isophorone and cyclohexanone; or water. Can be used any one of these solvents or a mixture of two or more solvents. Of these compounds, the inventors preferred halogenated hydrocarbons, esters and simple esters.

The interaction can occur in a wide range of temperatures and the precise temperature is not critical for the invention. In the General case it is established that the reaction is conveniently carried out at temperatures from -10oC and up to 100oC, more preferably from -5oC to 50oC. the Time required for the flow of interaction, may also vary within wide limits in dependence is Italia. If the reaction of lead in the preferred conditions outlined above, then the duration of the interaction is usually from 5 minutes to 48 hours, more preferably from 30 minutes to 10 hours.

Removing the influence of palladium and triphenylphosphine or tetracarbonyl Nickel. In that case, the code hydroxyamides group is aryloxyalkyl group, it can be simply removed by using a combination of palladium and triphenylphosphine or tetracarbonyl Nickel, which has the advantage of being suppressed side reactions.

Introduction hydroxyamide group. If desired, the resulting free hydroxy-group may be further protected by a protecting group, especially protecting group capable of chipped off in vivo by biological methods, such as hydrolysis. The above can also be implemented by using an appropriate reagent containing the desired protecting group that conducted by the method described in the consideration stage A3.

In the case when the number of protected hydroxy groups is more than one group, they can be protected the same protecting group or different Conn is different protecting groups, presents R6each of these groups can be selectively removed and the resulting free hydroxy-group can then be protected with an appropriate protecting reagents, to obtain compounds with hydroxy groups protected by various groups of R6or

2) two of the hydroxy-group is protected various protecting groups represented by R6using differences in reaction abilities protecting reagents, as is well known in the art.

After the interaction the desired compound of formula (XI) can be extracted from the reaction mixture by conventional methods. For example, if one of the acceptable methods for extracting the reaction mixture was subjected to neutralization, in the presence of insoluble substances are removed by filtration, the filtrate or the neutralized reaction mixture are added water and immiscible with water, the solvent, such as ethyl acetate, and the product is extracted with a solvent, the extract washed with water and dried, for example over anhydrous magnesium sulfate; and the solvent is then distilled off from the extract, resulting in the balance of the desired product.

The desired compound obtained that the deposition or various chromatographic methods. Examples of suitable chromatographic methods are absorption column chromatography by passing the purified substances through the media, such as silica gel, alumina or Florisil containing magnesium and silica gel; distribution column chromatography by passing the purified substance through an absorbent such as SephadexTMLH-20 (company "pharmacy, Inc."), amberlitTMXAD-11 (Rohm and Haas co.) or diaionTM(Mitsubishi Kasei Corporation); liquid chromatography by passing the purified substances through regularly-phase or reversed-phase column with a nozzle made of silica gel or alkylated silica gel (preferably high performance liquid chromatography); or a combination of these methods with subsequent elution using appropriate eluting solvent.

Stage A6

At this stage, the compound of formula (XII), which is a compound of the present invention, receive, carry out the hydrolysis or solvolysis lactoovo ring compounds of the formula (XI), getting a salt of carboxylic acid or ester of carboxylic acid. This reaction can be optionally carried out by

1) is received from the personal protecting groups, preferably able to be chipped off in vivo by biological methods, such as hydrolysis;

3) the protection resulting carboxypropyl protecting group, preferably able to be chipped off in vivo by biological methods, such as hydrolysis, or another salt of carboxylic acid and/or

4) if desired, carrying out the cyclization of compounds of carboxylic acids with obtaining again lactoovo connection.

Obtaining salts of carboxylic acids can be made by conventional hydrolysis using a base, preferably from 1 to 2 mol of base.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the employed solvent, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of acceptable solvents are water or mixtures of water with one or more organic solvents, such as ethers, such as tetrahydrofuran, dioxane or diethylethylenediamine simple ether; alcohols, such ctrlY, such as acetonitrile or isobutyronitrile; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide).

There is no any specific limitation regarding the nature of the used grounds, and any base commonly used in conventional reactions may equally well applied here. Examples of preferred bases are carbonates of alkali metals such as sodium carbonate, potassium carbonate or lithium carbonate; hydrogen carbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; oxides of alkali metals, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide or lithium hydroxide; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium, potassium methoxide, ethoxide potassium tert-piperonyl potassium or lithium methoxide.

The interaction occurs in a wide range of temperatures and the precise temperature is not critical. In General it is established that the reaction is conveniently carried out at temperatures from -10oC and up to 100oC, more preferably from 0oC and about to whom the x depending on many factors, namely, the temperature of the interaction, the basis and nature of the reagents. However, in most cases, the duration of interaction ranges from 30 min to 10 h, preferably from 1 to 5 o'clock

The reaction of receipt of ester carboxylic acid can be carried out by conducting solvolysis in the presence of an acid catalyst and a solvent containing alcohol.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the employed solvent, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of acceptable solvents are aliphatic hydrocarbons, such as hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylethylenediamine ether; catoe as acetonitrile or isobutyronitrile; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide. However, the inventors prefer to use as the solvent alcohol, which corresponds to the ester residue that needs to be entered.

There is no any special restriction concerning the nature of the used acid catalyst, and any acid commonly used as a catalyst when carrying out well-known reactions can be equally applied here. Examples of preferred acid catalysts are inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid or phosphoric acid; acid Bronsted, such as organic acids, including carboxylic acids (such as acetic acid, oxalic acid, formic acid and triperoxonane acid) and sulphonic acids (such as methanesulfonate acid, p-toluensulfonate acid and triftormetilfullerenov acid; a Lewis acid such as boron trichloride, boron TRIFLUORIDE or trichromacy boron; and acidic ion-exchange resin. And the acids.

Interaction takes place in a wide range of temperatures and the precise temperature is not critical. Usually the reaction is conveniently carried out at temperatures from 0oC and the boiling point of the used solvent, more preferably from 50oC and the boiling point of the used solvent. The time required for the flow of interaction, can also vary widely depending on many factors, namely the temperature of the interaction and the nature of the reagents and solvent. However, in most cases, the duration is usually from 10 minutes and up to 6 days, more preferably from 30 min to 3 days.

Upon completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional means. For example, if the reaction is carried out using acidic ion-exchange resin as an acid catalyst, then acceptable retrieval technique includes filtering the reaction mixture and removal by distillation of the solvent from the filter with the receipt of the balance of the desired product. If the reaction is carried out using another acid as the acid catalyst, then acceptable retrieval technique vklyuchyony and immiscible with water solvent, such as ethyl acetate to the neutralized reaction mixture or to the filtrate and extraction of the product with a solvent, washing the extract with water and drying it over anhydrous magnesium sulfate, and then removing the solvent by distillation from the receipt of the balance of the required product.

The desired product, thus obtained, is subjected, if necessary, clean using conventional methods such as recrystallization, pereosazhdeniya or various chromatographic techniques. Examples of such chromatographic methods are the distribution of column chromatography by passing the purified substance through a synthetic absorbent such as SephadexTMLH-20 (Pharmacia, Inc.), amberlitTMXAD-11 ("Rohm and Haas co.) or diaionTMHP-20 (Mitsubishi Kasei Corporation); liquid chromatography by passing the purified substances through regularly-phase or reversed-phase column with a nozzle made of silica gel or alkylated silica gel (preferably high performance liquid chromatography), or a proper combination of these techniques with subsequent elution using appropriate eluting solvent.

Free the slots, obtained above, to the value less than 5, preferably to pH 3 to 4 by adding a suitable acid.

There is no particular limitation regarding the type of acid used, and any organic or mineral acid may be used provided that it does not adversely affect the desired connection. Examples of preferred acids are inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid or phosphoric acid; acid Bronsted, including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, triperoxonane acid or triftormetilfullerenov acid; and acidic ion-exchange resin.

The connection in the form of the free carboxylic acid obtained in this way can be extracted and purified by conventional means, such as extraction, washing, drying, and similar ways, and then it can be used in subsequent interactions.

The hydroxy-group in the resulting compound (which contains in its molecule a salt of a group of carbonhouse preferably a protective group, capable chipped off in vivo by biological methods, such as hydrolysis. The reaction conditions used in the introduction of this protective group, similar to those used on stage A5.

If the product is a compound of formula (II) containing two free hydroxy-group, hydroxy-group can be protected simultaneously diol-protecting group, such as isopropylidene, benzylidene or utilizinga group, by reacting the compound with a suitable reagent in the presence of an acid catalyst.

There is no particular restriction concerning the nature of the reagent used to introduce disamistade group, and any agent that is normally used for protection of diol groups, equally can be used here. Examples of preferred reagents are aldehyde derivatives such as benzaldehyde; ketone derivatives, such as acetone; and dimethoxysilane, such as 2,2-dimethoxypropane or dimethoxybenzyl.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the solvent, provided that it does not atrio least in some degree. Examples of acceptable solvents are halogenated hydrocarbons, such as methylene chloride or chloroform; ethers, such as dioxane or tetrahydrofuran; hydrocarbons, such as hexane or pentane; aromatic hydrocarbons, such as benzene or toluene; esters such as ethyl acetate; and polar solvents such as dimethylformamide or acetone.

There is no particular restriction concerning the nature of the used acid catalyst, and any acid commonly used as a catalyst when carrying out reactions of this type may be equally used. Examples of preferred acid catalysts are organic acids such as p-toluensulfonate acid, camphorsulfonic acid and p-toluensulfonate pyridinium; and inorganic acids such as hydrochloric acid.

The interaction occurs in a wide range of temperatures and the precise temperature is not critical, although the preferred temperature varies depending on the nature of the used acid catalyst and source connections. But usually the reaction is conveniently carried out at a temperature from which the limits of depending on many factors, especially on temperature and the nature of the reagents. However, in most cases, the duration of reaction is usually from 0.1 to 24 hours

If protecting group capable of chipped off in vivo by biological methods used in carboxyamide group represents an alkyl group or a similar compound containing carbonation salt group or a free carbonisation group can be protected by the following methods.

Method 1.

In this method, the connection is to be protected, enter into interaction with the compound of the formula R5-X' (in which R5represents a protecting group capable of chipped off in vivo by biological methods, included in the definition of R5and X' represents a group or atom capable of chipped off in the form of a nucleophilic residue). Examples of groups and atoms capable chipped off in the form of a nucleophilic residue, is the atoms of halogen, such as chlorine atoms, bromine and iodine; lower alkanesulfonyl, such as methanesulfonamido and econsultancy; haloalkaliphilic, such as triftormetilfullerenov, pentafluoroethanesulfonyl the p-nitrobenzenesulfonamide. Examples of such compounds are aliphatic acyloxymethyl, such as acetoxymethyl, pivaloyloxymethyl and pivaloyloxymethyl; lower alkoxycarbonylmethyl halides, such as ethoxycarbonylmethylene, isopropoxycarbonyloxymethyl, 1-(ethoxy-carbonyloxy)ethylchloride and 1-(ethoxycarbonyl)ethyliodide; teledildonic and (5-methyl-2-oxo-5-methyl-1,3-dioxolan-4-yl)methylglucamide.

The reaction is usually preferably carried out in the presence of a solvent. There is no particular restriction concerning the nature of the employed solvent, provided that it does not adversely affect the reaction and the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents are aliphatic hydrocarbons, such as hexane or heptane; aromatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylethylenediamine ether; ketones, such as acetone, mutilation; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide.

The reaction in the presence of a base. There are no particular limitations concerning the nature of the used grounds, and any base commonly used in reactions of this type may be used. Examples of preferred bases are carbonates of alkali metals such as sodium carbonate, potassium carbonate and lithium carbonate; hydrogen carbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; alkali metal fluorides such as sodium fluoride and potassium fluoride; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium, potassium methoxide, ethoxide potassium, tert-piperonyl potassium and lithium methoxide; alkylthiols alkali metals, such as mertiolate sodium and editionat sodium; organic bases, such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine is tert-butyl)-4-methylpyridin, the quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0] Nona-5-ene, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]undec-7-ene; ORGANOMETALLIC bases, such as utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium.

Interaction takes place in a wide range of temperatures and the precise temperature is not critical. Usually the reaction is conveniently carried out at temperatures from -20oC and up to 120oC, more preferably from 0oC to 80oC. the Time required for communication, can also vary widely depending on many factors, namely temperature and the nature of the reagents. However, in most cases, the duration of the interaction is usually from 0.5 to 10 hours.

Method 2.

This method involves reacting the unprotected compound of formula R5-OH in which R5is the same as defined earlier) in a solvent in the presence of tarifitsiruemih agent and a catalytic amount of base. The reaction is carried out according to the method described in the consideration stage A3 of method 2.

Method 3.

This method involves reacting the unprotected compound R5'-OH in which R5

Method 4.

This method can be used when the protecting group is an alkyl group, and includes the interaction of the unprotected compound with an appropriate alcohol, used as a reagent, such as methanol, ethanol, propanol and butanol, in a solvent. There are no particular restrictions on the nature of the solvent, provided that it does not adversely affect the reaction and that it can dissolve the starting material, at least to some extent. Examples of preferred solvents are the same as those alcohols that are used as reagents; aliphatic hydrocarbons, such hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylethylenediamine simple ether; ketones, such as acetone, mutilat is; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide. Of these substances, the inventors prefer the same alcohol that is used as reagents. The reaction is carried out in the presence of an acid catalyst. There are no particular limitations concerning the nature of the used acid catalyst, and any acid commonly used as a catalyst in conventional reactions of this type may be equally used. Examples of preferred acid catalyst are inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid and phosphoric acid; acid Bronsted, including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, triperoxonane acid and triftormetilfullerenov acid; a Lewis acid such as boron trichloride, boron TRIFLUORIDE and trichromacy boron; and acidic ion-exchange resin.

Interaction takes place in a wide range of temperatures, and the precise reaction temperature is not CR is>
C to 60oC. the Time required for the flow of interaction, can also vary widely depending on many factors, namely the temperature of the interaction and the nature of the reagents. However, in most cases, the duration of the interaction is usually from 1 to 24 hours.

Method 5.

This method involves reacting the unprotected carbonbearing connection with either

I) palodiruyut agent, such as pentachloride phosphorus, chloride tiomila or chloride accelerom, at a suitable temperature, for example at room temperature, over a period of time, for example, from 30 min to 5 h to obtain the corresponding galodamadruga acid, or

II) CHLOROFORMATES, such as methylchloroform or ethylchloride, in the presence of organic amine (such as triethylamine), which may be done at the same temperature and for the same period of time as in case 1 above, to obtain the corresponding anhydride acid; followed by treatment of the resulting acid anhydride or galodamadruga acid with a suitable alcohol or alkoxide of an alkali metal to obtain the desired complex ester. For the floor is predpochtitelno are in the presence of a solvent. There are no particular restrictions on the nature of the solvent, provided that it does not detrimentally impact on the course of the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents are aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and propyl; ethers, such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; and NITRILES, such as acetonitrile. The reaction can also be maintained in the presence of a base, the nature of which is not critical, for example in the presence of triethylamine. Interaction can take place in a wide range of temperatures and the precise temperature is not critical. Usually the reaction is conveniently carried out at temperatures from -10oC and up to 150oC, more preferably at about room temperature. The time required for communication may also vary widely, depending on many factors, namely the temperature of the interaction and on the nature of the reagents and solvent. Datacine from 10 min to 15 h, preferably from 30 minutes to 10 o'clock

Method 6.

This method involves reacting the unprotected free carbonbearing connection with diazoalkane, such as diazomethane or diazoethane (usually in the ether solution of the diazoalkane) when suitable temperature, for example approximately at room temperature; however, if necessary, the reaction is carried out at heating.

Or as a starting compound can be used ether carboxylic acid, while the desired compound can be obtained by conventional means, i.e. by carrying out the transesterification compound of formula R5-OH, in which R5is the same as defined above.

If carboxyamide group capable chipped off in vivo by biological methods, represents a group of the amide type, the reaction may be carried out according to the following method.

Method 7.

This method involves the conversion of salts of carboxylic acids or free carboxylic acid, which can be obtained according to the method described above, in galoyanized acid or acid anhydride according to the method described in method 5, and then includes the interaction golodner what Ilumina.

Method 8.

This method involves the exposure of ether carboxylic acids, which can be obtained by the above methods 1 to 6, a conventional Piramides exchange reactions.

Obtaining salts.

Reactions that lead to salts of carboxylic acids can be carried out as follows.

1. Metal salts of carboxylic acids. The desired salt can be obtained by contacting the free carboxylic acid with the appropriate compound of the metal, for example with a metal hydroxide or metal carbonate, in an aqueous solvent.

Examples of preferred aqueous solvents are water itself and a mixture of water with an organic solvent such as an alcohol, for example methanol or ethanol, or a ketone, for example acetone. Special preference inventors give a mixture of water with a hydrophilic organic solvent.

Usually the reaction is preferably maintain at about room temperature or, if necessary, it can lead when heated.

2. Amine salts of carboxylic acids. The desired salt can be obtained by contacting the free carboxylic acid with the appropriate amine in the presence of water dissolve the civil solvent, such as alcohol, for example methanol or ethanol; a simple ether, for example tetrahydrofuran; or a nitrile, for example acetonitrile. Of these substances, the inventors prefer aqueous solution of acetone.

Usually the reaction is preferably carried out at a pH of from 7.0 to 8.5 and at a temperature below room temperature, in particular at temperatures from 5oC and up to 10oC. the Reaction proceeds immediately to completion.

Or the desired salt can be obtained by conducting salt-amine vzaimootno reaction, i.e., by dissolving the metal salt of carboxylic acid, which can be obtained by the above p. 1, in an aqueous solvent and then adding a salt of the mineral acid of the desired amine (for example, salt halogenation acid, such as hydrochloric acid). The reaction can be conducted under the same conditions as described above.

3. Amino acid salts of carboxylic acids. The desired salt can be obtained by contacting the free carboxylic acid with the desired amino acid in an aqueous solvent.

Examples of preferred aqueous solvents are water itself and a mixture of water with an organic solvent such as an alcohol, for example methanol or ethanol; or question the temperature from 50oC to 60oC.

Getting lactone.

Required lactoovo connection can be obtained by contacting compounds of carboxylic acid, obtained as described above, with a catalytic amount of acid.

The reaction is usually preferably carried out in the presence of a solvent. There are no particular limitations concerning the nature of the employed solvent, provided that it does not detrimentally impact on the course of the reaction and the reagents involved and can dissolve the reagents, at least to some extent. Examples of suitable solvents include water, ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diethylethylenediamine simple ether; ketones, such as acetone and metaliteracy ketone; NITRILES, such as acetonitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoric triamide; sulfoxidov, such as dimethyl sulfoxide and sulfone; or mixtures of one or more of such solvents with water.

There are no restrictions concerning the nature of the used acid catalyst, and any acid catalyst, usually ispatih catalysts are inorganic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid and phosphoric acid; acid Bronsted, including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, triperoxonane acid and triftormetilfullerenov acid; a Lewis acid such as zinc chloride, tin tetrachloride, boron trichloride, boron TRIFLUORIDE and trichromacy boron; and acidic ion-exchange resin. Of these substances, the inventors preferred inorganic acids.

The reaction may proceed in a wide range of temperatures and the precise temperature is not critical. Usually the reaction is conducted at temperatures from -20oC to 170oC, preferably from 0oC to 50oC. the Time required for the flow of interaction, can also vary widely depending on many factors, namely temperature and the nature of the reagents and solvent. However, if the reaction of lead in the preferred conditions outlined above, then the duration of the interaction is usually from 10 minutes to one day.

Upon completion of the reaction recip what's kinds of methods of extraction and purification, such as described and illustrated by the examples above, especially the various chromatographic techniques. Examples of such techniques are the distribution of column chromatography by passing the purified substance through a synthetic absorbent such as SephadexTMLH-20 (Pharmacia, Inc.), amberlitTMXAD-11 ("Rohm and Haas co.) or diaionTMHP-20 (Mitsubishi Kasei Corporation"); ion exchange chromatography; gel filtration by passing the purified substance through a column of Sephadex; liquid chromatography by passing the purified substances through regularly-phase or reversed-phase column with a nozzle made of silica gel or alkylated silica gel (preferably high performance liquid chromatography); or any combination of these chromatographic techniques; requested connection can then be allerban the use of appropriate eluting solvent. In another embodiment, the product can be effectively extracted with an organic solvent, such as diethyl simple ether, ethyl acetate or chloroform.

If the desired compound is obtained by carrying out the above-described stages, is formed in the form of a mixture of stereoisomers and neobhodimo ways, as described above, at the end of each reaction or at any reasonable time upon completion of each reaction.

The reaction scheme B.

Another possible way to obtain connection that meets the present invention, shown in reaction scheme B (PL.4).

In the above formulas, R5, R6, R6a, R6b, R6and R7are as defined previously.

Reaction scheme B gives a method of obtaining compounds of formula (XVIII) and (XIX) of the present invention, and an alternative method of preparing compounds of formulas (XI) and (XII), which are also compounds of the present invention.

Stage B1.

At this stage, the compound of formula (XIV) is obtained by hydrolysis of the ester side chain located at the position 8 in the initial compound of the formula (XIII), which use a base in a solvent. This reaction is essentially the same as the reaction described in the consideration stage A1 of reaction scheme A, and it can be carried out using the same reagents and under the same reaction conditions.

Stage B2.

At this stage lactoovo compound of formula (XV) is obtained by neutralization of the salt hydrosilicate the resulting free acid. This reaction is essentially the same as described in the consideration stage A2 of the reaction scheme A, and can be carried out using the same reagents and under the same reaction conditions.

Stage B3.

At this stage compound with the formula (XVI) is obtained by selective protection of the hydroxy-group, different from the hydroxy-group in position 8 in the compound of formula (XV), R6. This reaction is essentially the same as described in the consideration stage A3 of the reaction scheme A, and can be carried out using the same reagents and under the same reaction conditions.

Stage B4.

At this stage, the compound of formula (XVII) is obtained by acylation of the hydroxy-group in position 8 in the compound of formula (XVI) the group R7. The reaction is essentially the same as described in the consideration stage A4 reaction scheme A, and can be carried out using the same reagents and under the same reaction conditions.

Stage B5.

At this stage, the compound of formula (XVIII), which is a compound of the present invention, is obtained by removing hydroxyamide group represented by R6in the compounds of formula (XVII) and seeu be chipped off in vivo by biological methods, such as hydrolysis. This reaction is essentially the same as described in the consideration stage A5 reaction scheme A, and can be carried out using the same reagents and under the same reaction conditions.

Stage B6.

At this stage, the compound of formula (XIX) is obtained by hydrolysis or solvolysis lactoovo ring compounds of the formula (XVIII) with a salt of carboxylic acids or ether carboxylic acid, and then, if necessary, the interaction product is subjected to one of the following reactions:

1) get a free carboxylic acid;

2) the protection of some or all of the free hydroxy groups protecting groups, preferably groups capable chipped off in vivo by biological methods, such as hydrolysis;

3) protection of the resulting carboxypropyl protecting group, preferably a group capable of chipped off in vivo by biological methods, such as hydrolysis, or other salts of carboxylic acids and/or

4) if necessary, obtain alloy lactoovo connection circuit rings. The reaction is carried out by following the procedure described in the consideration stage 6.

Stage B7, B8 and B9.

At these stages of the compounds of formula (XI) is the formula (XIX), its pharmaceutically acceptable salt or a complex ester, or lactoovo the compounds of formula (XVIII) of the enzymatic hydrolysis. This can be done using the procedure described below in the section "obtaining a biological methods". After that, if necessary, can be the following reactions:

1) hydrolysis or solvolysis;

2) get a free carboxylic acid;

3) protect some or all of the free hydroxy groups protecting groups, preferably groups capable chipped off in vivo by biological methods, such as hydrolysis, groups can be the same or different from each other.

4) protection of the resulting carboxypropyl protecting group, which is preferably capable of chipped off in vivo by biological methods, such as hydrolysis, or other salts of carboxylic acids and/or

5) ring closure to obtain a composition lactoovo connection.

These reactions are essentially the same as the reaction described in the consideration stage A6 reaction scheme A, and can be carried out using the same reagents and under the same reaction conditions.

The reaction scheme C.

This scheme gives al actionnow scheme A, and the compounds of formula (XVIII) is used as intermediate compounds in the reaction scheme B (PL.5).

In the above formulas (PL. 5) R6, R6aand R7are the same as defined previously.

The compound of formula (XI) and (XVIII) used as intermediates can be obtained by acylation of all hydroxy groups of the compounds of formula (VIII) or (XV) a group R7obtaining the compounds of formula (XX) or (XXI). This reaction is essentially the same as described in the consideration stage A4 reaction scheme A, and can be carried out using the same reagents and under the same reaction conditions. One or two protecting groups, non-acylated hydroxy-group in position 8 then selectively removed by following the method described in UK patent N 2255974 A, and then, if necessary, any or both of the released group protect-protecting group, preferably a group capable of chipped off in vivo by biological methods, such as hydrolysis, and groups can be the same or different from each other. This reaction is essentially the same as described in the consideration stage A5 reaction shanna scheme D.

This scheme provides an alternative method of preparing compounds of the formula (I') and (XXII) fermentation (table.6)

In the above formulas (PL.6) R5, R6, R6aand R6bare the same as defined above.

On stage D1 compound of formula (I'), which is the compound of the present invention, is produced by inequilibrium microorganism capable of producing the aforementioned compound, which belongs to the genus Penicillium. This can be done using the techniques described below in the section "obtaining a biological methods".

Then, if desired, perform one or more of the following reactions:

1) hydrolysis or solvolysis;

2) get a free carboxylic acid;

3) protection of some or all of the hydroxy groups protecting groups, preferably groups capable chipped off in vivo by biological methods, such as hydrolysis, which may be the same or different from each other;

4) protection of the resulting hydroxy-group-protecting group, which, preferably, is capable of chipped off in vivo by biological methods, such as hydrolysis, or obtain other salts of carboxylic acids and/or

5) if necessary, again R the ve original substance according to scheme B, can be obtained chemically by the following method, described in any of the following literature sources:

(1) D. J. Clive et al., J. Am. Chem. Soc., 112, 3018 (1990);

(2) C. T. Hsu et al., J. Am. Chem. Soc., 105, 593 (1983);

(3) n. n. Jirotra et al., Tetrahedron Lett., 23 5501 (1982); ibid., 24, 3687 (1983) and ibid., 25 5371 (1983);

(4) M. Hirama te al., J. Am. Chem. Soc., 104, 4252 (1982);

(5) P. A. Jrieco et al., J. Am. Chem. Soc., 108, 5908 (1986);

(6) T. Rosen et al., J. Am. Chem. Soc., 107, 3731 (1985);

(7) J. E. Keck et al., J. Am. Chem. 51, 2487 (1986);

(8) A. P. Kozikowski et al., J. Am. Chem., 52, 3541 (1987).

(9) S. J. Danishefsky et al., J. Am. Chem. Soc., 111, 2599 (1989).

According to the methods described in Japanese patent application N Sho 56-12114 and in Japanese patent application Sho 51-136885, the parent compound of formula (XII) and (XV) used in the reaction schemes B and C, can be obtained microbiologically. At the stage of the D1 reaction scheme D both compounds can be prepared simultaneously.

Pravastatin, which can be used as starting substances can be obtained by enzymatic holding stereospeakers hydroxylation of compounds of formula (XIII) in position 6 with obtaining compounds with 6-hydroxy-group according to the technique disclosed in Japanese patent publication N 61-13699 or in stages B7, B8 and B9.

The epimer at position 6 of pravastatin, i.e. shoedini A1. This is the initial connection can be obtained using stereospeakers hydroxylation at position 6 of the compounds of formula (XIII), similar to the synthesis of pravastatin, following the method disclosed in Japanese patent publication N Sho 61-13699 or in the consideration stages B7, B8 and B9.

Carboxylic acid of formula R7-OH, which is used as the starting material in the method of the present invention, can be easily obtained with known methods, for example by the method described by the author P. E. Pfeffer, J. Org. Chem., 37,451 (1972)).

Obtaining biological methods.

Some compounds of the present invention can be also obtained by biological methods, as described in more detail below.

Obtaining compounds of formula (I')

For example, those compounds of formula (IV), which have 2-methylpentanoate in position 8, i.e. the compounds of formula (I')

< / BR>
where R1represents a group of formula (II') or (III')

< / BR>
can be obtained by culturing a microorganism of the genus Penicillium in a nourishing environment for him and the Department mentioned the compounds of formula (I') from the nutrient medium. This method also forms part of the present invention.

Microbiological properties of strain SANK 13380 are as follows.

Colonies grown on the medium čapek (Czapek) from yeast autolysate agar ranged in diameter 1.8 cm after cultivation for 7 days at 25oC. the Colors were white (1 A 1) to light yellow (2 A 4), and the surface was covered with a white flocculent aerial hyphae. The reverse side is colored from white (1 A 1) to light yellow (2 A 4), and was observed radial folds. Didn't found any exudates or soluble pigments.

Colonies grown on the medium of the hangar with malt extract, ranged in diameter 1.3 cm (after growing at 25

Colonies grown on the medium of 25% (weight per volume) glycerol nitrate agar, ranged in diameter 1.6 cm (after growing at 25oC for 7 days). The color of the surface was changed from white (1 A 1) to yellowish white (1 A 2), and the surface is covered with chlopheniramine gifoi. The reverse side is a pale yellow color (2 A 3).

Not seen any growth in any of these environments at the 5oC or 37oC.

The surface of conidiophore were smooth and bebutovskie. Metulla cylindrical with a small puzyrchatogo and have a size 9 to 15 3 to 4 μm. Fieldy ampoule-shaped and have a size 8 - 10 on 3 - 4 μm. Conidia sarcopenia and their surfaces are smooth with the manifestation of small roughness values of diameter from 2.5 to 4 μm.

From the comparison of these properties with the properties observed in known species, it follows that the properties of this strain is consistent with the properties of strain Thom species Penicillium citrinum, described by pitt (J. I. Pitt in "The genus Penicillium and its teleomorpholic states Eupenicillium and Falaromyces", p.634, Academic Press (1979)). In accordance with the foregoing, this strain is identified as Penicillium citrinum Thom.

When describing CEE="ptx2">

It should be noted that the strain SANK 13380 or any other strain, capable of producing the compound of the formula (I') may be subcultivation or biotechnological changed or modified with the formation of the microorganism with other characteristics. The only requirement is that the resulting microorganism has the ability to produce the desired connection. Changes can occur naturally or artificially influenced, for example, ultraviolet radiation, high-frequency waves, radiation, chemical exposure with the formation of mutagens.

Such changes and modification may take any desired form, and they can be a consequence of factors such as, for example, the growing conditions. Strains can be modified by cultivation and subjected to selection with the manifestation of characteristics such as increased growth or growth at low/high temperatures.

Biotechnological modification usually are focused and they can be given the specified characteristics, such as biostatics resistance or susceptibility, or a combination of such characteristics, which ensures tx2">

Other characteristics that can be attributed to genetic manipulation, are any characteristics, valid at the species of the genus Penicillium. For example, can be removed any plasmids of natural origin. For your preferred plasmids are those that give auxotrophy. Plasmids can be obtained from any suitable source or they can be designed by selection of naturally occurring plasmids of the genus Penicillium and inserting the desired gene or genes derived from another source. Natural plasmids can also be modified in any other way, which may seem desirable.

Any such modified strain can be applied in the method of the present invention, provided that the strain has the ability to produce the compound of formula (VI), which can be easily installed by conducting a simple and plain experiment.

To obtain the compounds of formula (VI) from the culture of an appropriate microorganism such microorganism should be subjected to fermentation in a suitable environment. Such environments usually are well-known in this technical field, and often they are widely COI the environment consisted of a combination of a source of carbon, source of nitrogen and one or more inorganic salts, acceptable to the appropriate microorganism. The minimum requirement for the environment is that it should contain such ingredients, which are essential to the growth of the microorganism.

Acceptable sources of carbon are all sorts of carbon-containing substances that can be assimilated by the microorganism, such as carbohydrates (carbohydrates) such as glucose, fructose, maltose, lactose, sucrose, starch, mannitol, dextrin, glycerin, thick malt syrup, molasses, molasses, oat flour, rye flour, corn starch, potato starch, corn flour, soy flour or malt extract; oils and fats such as soybean oil, cottonseed oil, olive oil, fish oil or pork fat; organic acids such as citric acid, sodium ascorbate, malic acid, acetic acid, fumaric acid, tartaric acid, succinic acid or gluconic acid; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, Isobutanol or tert-butanol; and amino acids such as glutamic acid. These substances can be used individually or may be used a mixture preggo 10% (weight per volume) of the number of environment although the number may vary as desired and in accordance with the desired result.

Acceptable sources of nitrogen are any nitrogen-containing substances that can be assimilated by the microorganism, for example compounds containing protein, or other easily assimilable source of nitrogen. Representative examples of the source of nitrogen is organic nitrogen sources of animal and vegetable origin, and they may be extracts derived from such natural sources as soybean flour, wheat bran, wheat germ, peanut flour, flour from cotton seed, cotton oil, isolated soy protein, Casinocity (casein amino acid), casein hydrolysate, feramin, fish meal, corn extract, peptone, meat extract, yeast, yeast autolysate, yeast extract, malt extract and urea; amino acids such as aspartic acid, glutamine, cystine, or alanine; ammonium salt, such as ammonium sulfate, ammonium nitrate, ammonium chloride or ammonium phosphate; and inorganic nitrogen compounds such as sodium nitrate or potassium nitrate. As in the case of a carbon source, they can be used individually or in any combination. In tipichnata environment.

Acceptable nutrient inorganic salts are salts, which give some trace elements, but also the main component of salt. It is desirable that salt was the source of such ions as sodium, potassium, magnesium, ammonium, calcium, phosphate, sulfate, chloride or carbonate, in digestible form, and preferably in trace quantities contained metals such as molybdenum, boron, copper, cobalt, manganese and iron. Examples of suitable compounds are sodium chloride, manganese chloride, cobalt chloride, potassium chloride, calcium chloride, calcium carbonate, aluminiumalloy sulfate, manganese sulfate, copper sulfate (2), cobalt sulphate, zinc sulfate, ferrous sulfate (2), magnesium sulfate, monopotassium phosphate, potassium secondary acid potassium phosphate, secondary, acidic sodium phosphate or aluminum molybdate. In addition, in any acceptable combination can be used all sorts of other additives necessary for growth of the microorganism and contributing to the formation of compound with formula (I').

The addition of compounds of sulfur absorbed by the microorganism from the environment, can sometimes enhance the production of desired compounds. Suitable sulfur compounds are inorganic compounds with the Oia; thiosulfate, such as ammonium thiosulfate; and sulfites such as ammonium sulfite; or organic sulfur compounds which include sulfur-containing amino acids such as cystine, cysteine or L-thiazolin-4-carboxylic acid; sulfate compounds of heavy metals such as iron sulfate (2) or copper sulfate (2); vitamins such as vitamin b1or Biotin; and the factors responsible for the growth of bacteria, such as thiamin.

To the environment can be added defoaming agent, such as silicone oil, polyalkylene glycol ether, vegetable oil, or an appropriate surfactant. This Supplement may be particularly relevant when a microorganism is subjected to enzymes in the form of liquid culture.

It is desirable that the pH value of the environment with the culture, intended for the cultivation of a strain of Penicillium citrinum Thom SANK 13380, when it is used for producing the compounds of formula (I'), was maintained in the region of from 5.0 to 8.0, and more preferably, the pH value was in the region of from 6.0 to 7.0, although the only requirement is that the pH value should not interfere with the growth of the microorganism or adversely and irreversibly affect the quality of the students from the 15oC to 35oC, and grow well at temperatures between 22oC to 30oC. Other temperature that does not fall within these ranges may be applicable when developing a strain that can grow at low or elevated temperatures, or for other special purposes, as is well known in the art. For producing the compounds of formula (I') are preferred temperature is from 15oC to 35oC, more preferably from 22oC to 26oC and preferably at around 24oC.

There is no particular limitation regarding the methods of cultivation used to obtain the compounds of formula (I'), and there may be used any method of dealing with culture, usually used to conduct bacterial growth. However, the compound of formula (I') is obtained by aerobic cultivation and can be applied to all acceptable methods of aerobic cultivation, such as the way of solid-phase growing method with mixed culture method with stationary culture, cultivation with shaking or growing with stirring by aeration.

If the cultivation is carried out in small scale, t is ri temperatures from 20oC to 30oC for several days, and more preferably cultivation carried out approximately at the 24oC.

To start the enzymatic cultivation in the preferred embodiment, applied to the original AMF inoculum prepared in one or two stages, for example, in the Erlenmeyer flask, which is preferably equipped with an air baffles (stekoll, directing the flow of water). For the culture medium, the carbon source and the nitrogen source can be used in combination. The flask with the seed is shaken in a thermostatic incubator at the appropriate temperature, for example, from 20 to 30oC, more preferably from 22oC to 26oC, most preferably about 24oC, for a suitable period of time, typically from 2 to 7 days or until until seen enough growth, preferably from 3 to 5 days. The resulting seed culture can be then used for inoculation of the second seed culture or corporate culture. If you hold the second seed, this can be done similarly and it can be partially used for insulinopenia producing environment. The flask in which inoculated seed culture, built kimalee production, if the temperature is suitable, for example, when 24oC. After incubation the contents of the flask may be collected by centrifugation or filtration.

If culture should be obtained on a large scale, then cultivation is desirable to maintain in the fermenter with agitation with aeration. In this embodiment, the culture medium can be prepared in the fermenter. The environment is first subjected to sterilization at an acceptable high temperature, for example at about 120oC, after which it is cooled and tatrallyay the AMF inoculum, grown previously in an environment subjected to sterilization. Cultivation is desirable to maintain at a temperature of 20oC to 26oC, most preferably from 22oC to 24oC, with stirring and aeration. This method is suitable for obtaining a large number of connections.

The amount of the compounds of formula (I'), produced by the culture with the passage of time, can be controlled by sampling and evaluating the content of the compounds of formula (I') through, for example, high performance liquid chromatography. The compound of formula (I') can exist in lactoovo form, still in hydroxypurine, and it usually is produced in in the time. In General produced a number of compounds of formula (I') reaches its maximum after a period of time between 72 and 300 hours.

The compound of formula (I'), produced by culture, is the culture filtrate and in bacterial cells. It can exist either in hydroxycitrate form or in lactoovo form, each of which can move from one to the other. In addition, gidroksikislotny form can form the corresponding salt, will be sustainable.

Therefore, the compound of formula (I') can be extracted and collected direct use of this property in combination with other properties, for example, as illustrated below.

Method 1.

Bacterial cells and other solid materials found in the environment, is separated by centrifugation or by filtration using a filter material, such as diatomaceous earth, separating the supernatant and bacterial cells.

1. The supernatant. Lactoovo ring in lactoovo form the compounds of formula (I') that exists in the supernatant liquid is subjected to hydrolysis under alkaline conditions (preferably at a pH of 12 or more), the result is converted into the corresponding free gidrokshikislotu by careful acidification; then the compound of formula (I') is obtained from this mixture in the form of the free hydroxy acid, extraction immiscible with water, an organic solvent, such as aliphatic hydrocarbons, such as hexane or heptane; an aromatic hydrocarbon such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether or diisopropyl ether; or a complex ester such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylcarbamyl. These solvents can be used individually or as a mixture of two or more solvents.

2. Bacterial cells. Bacterial cells are mixed with mixed with water, an organic solvent, for example an alcohol, such as methanol or ethanol; a ketone, such as acetone; NITRILES, such as acetonitrile or diisobutyrate; amidon, such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide. The final concentration of bacterial cells in the resulting mixture is preferably from 50% to 90%. The resulting mixture predpechatnoy gidrokshikislotu.

Method 2.

Environment culture is treated under alkaline conditions (preferably at a pH of 12 or more) when heated or at room temperature for cell disruption and hydrolyzing disclosure lactoovo ring molecules. In this case, all the compound of formula (I') is transferred in the form hydroxycitrate salt. The compound of formula (I'), in free hydroxycitrate form, obtained after conversion of the salt form into its corresponding free hydroxycitrate form, using processing similar to that described above when considering the supernatant liquid in method 1.

Received free gidroksikislotny form can be dissolved as a salt in an aqueous solution of alkali metal base, such as hydroxide of alkali metal such as sodium hydroxide. In addition, free gidroksikislotny form can be converted into the salt form, which is easily obtained and most stable.

Or the resulting free gidroksikislotny form can be turned into lactoovo form by dehydration under heating or by cyclization in an organic solvent.

Isolation and purification of free hydroxycitrate form, hydroxycitrate the eye used for separation and purification of organic compounds. Examples of such methods include a method using a synthetic adsorbent, such as distribution chromatography using a carrier such as Sephadex LH-20 (trade mark material company "pharmacy"), amberlite XAD-11 (trade mark material "Rohm and Haas") or diaion HP-20 (trademark material "Mitsubishi chemical industry"). Alternatively, they may stand out and be cleaned using normally-phase or reverse-phase column chromatography using silica gel or alkylated silica gel (preferably high performance liquid chromatography, followed by elution with a suitable solvent.

Laktionova the form can also be purified by the use of adsorption column chromatography using a carrier such as silica gel, alumina or Florisil (brand media magnesiothermic type).

Examples of solvents that can be used as elution solvent are aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons, such as florystyka ethyl formate, the ethyl acetate, propyl, butyl acetate or diethylmalonate; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylethylenediamine simple ether.

Or the same compound can be obtained by passing the extracted solution through a column of adsorbent to remove impurities or adsorption free hydroxycitrate form on this column and subsequent elution of aqueous alcohol such as aqueous methanol, aqueous ethanol, aqueous butanol or aqueous isopropanol; ketone or water, such as aqueous acetone. Acceptable adsorbing substance that can be used is activated carbon or adsorbent resin such as amberlite XASD-2 or XAD-4 (trade name of product of the company "Rohm and Haas") or diaion HP-10; HP-20, CHP-20, HP-50 (trademark, product of Mitsubishi chemical industry").

Free hydroxycitrate and salt of the hydroxy acid can be transformed into each other by conventional means and subjected to cleaning in any desired form.

Hydroxylation of compounds of formula (Ib) in the compound of formula (Ia)

The compound of formula (Ib)

< / BR>
in which R1is the same as the definition is prohibited in compound of formula (Ia)

< / BR>
in which R1is the same as defined previously, or a corresponding compound in which the reactive group is protected with hydralicious enzyme.

Gidrolizatami the enzyme can be obtained by using a microorganism of a genus selected from the group consisting of Amycolata, Nocardia, Syncephalastrum, Mucor, Rhizopus, Zygorynchus, Circinella, Actinomucor, Jongronella, Phycomyces, Absidia, Cunninghamella, Mortierella, Pychpoporus (old generic name: Trametes), Streptomyces and Rhizoctonio.

This hydrolysis can be carried out by any of the following method:

method 1 - includes the addition of the compounds of formula (Ib) to the liquid medium during the cultivation converting microorganisms and then continued cultivation;

method 2 - includes contacting the compounds of formula (Ib) with grown cells collected from the liquid medium with the culture of the above-mentioned microorganism; or

method 2 - includes contacting the compounds of formula (Ib) with a free from the cell extract obtained from the above-mentioned microorganism.

In any of these methods, the microorganism is cultivated under conditions suitable to achieve maximum production and maximum efficiency of the enzyme in a suitable medium in the genus Penicillium.

There are no particular restrictions on the type of microorganism, provided that he is able to enter the hydroxy-group in position 6 of the compounds of formula (Ib). Examples of such microorganisms are:

fungi of the class Zygomycetes: birth Syncephalastrum, Mucor, Rhezopus, Zygorynchus, Circinella, Actinomucor, Jongronella, Phycomyces, Absidia, Cunninghamella and Mortierella;

mushrooms other classes other than Zygomycetes: birth Pychnoporus (old generic name: Frametes) and Rhizoctonia;

actinobacteria: genera Amycolata, Nocardia and Streptomyces; preferably,

strains belonging to the genus Syncephalastrum, including:

Cyncephalastrum racemosum (Cohn) Schroeter SANK 91872 (FERM BP-4107); Syncephalastrum nigricans Vuillemin SANK 42372 IFO 4814 (FERM BP-4106); Syncephalastrum nigricans SANK 42172 (FERM P-6041); Syncephalastrum nigricans SANK 42272 (FERM P-6042); and Syncephalastrum racemosum IFO 4828;

strains belonging to the genus Mucor, including:

Mucor hiemalis Wehmer SANK 36372, IFO 5834 (FERM BP-4108); Mucor hiemalis f. hiemalis IFO 5303; Mucor hiemalis f. hiemalis IFO 8567; Mucor hiemalis f. hiemalis IFO 8449; Mucor hiemalis f. hiemalis IFO 8448; Mucor hiemalis f. hiemalis IFO 8565; Mucor hiemalis f. hiemalis CBS 117.08; Mucor hiemalis f. hiemalisCBS 109.19; Mucor hiemalis f. hiemalis CBS 200.28; Mucor hiemalis f. hiemalis CBS 242.35; Mucor hiemalis f. hiemalis CBS 110.19; Mucor hiemalis f. hiemalis CBS 201.65; Mucor bacilliformis NRRL 2346; Mucor circinelloides f. circenelloides IFO 4554; Mucor circinelloides f. circenelloides IFO 5775; Mucor hiemalis f. corticolus SANK 34572 (FERM P-5913); Mucor dimorphosporus IFO 4556; Mucor fragillis CBS 23635; Mucor genevesis IFO 4584; Mucor globosus SANK 35472 (FERM P-5915); and Mucor circinelloides f. griseocyanusR> strains belonging to the genus Zygorynchus, including: Zygorynchus moelleri IFO 4833;

strains belonging to the genus Circinella, including: Circinella muscae IFO 4457; Circinella umbellata IFO 4452; and Circinella umbellata IFO 5842;

strains belonging to the genus Actinomucor, including: Actinomucor elegans ATCC 6476;

strains belonging to the genus Jongronella, including: Jongronella butleri IFO 8080;

strains belonging to the genus Phycomyces, including: Phycomyces blakesleeanus SANK 45172 (FERM P-5914);

strains belonging to the genus Absidia, including Absidia coerulea IFO 4423; and Absidia glauca var.paradoxa IFO 4431;

strains belonging to the genus Cunninghamella, including Cunninghamella echinulata IFO 4445; Cunninghamella echinulata IFO 4444; and Cunninghamella echinulata ATCC 9244;

strains belonging to the genus Mortierella, including: Mortierella isabellina IFO 6739;

strains belonging to the genus Amycolata, including: Amycolata autotropica SANK 62981 (FERM BP-4105); Amycolata autotropica SANS 62781 (FERM P-6181); Amycolata autotropica subsp. canberrica subsp. nov. SANK 62881 (FERM P-6182); and Amycolata autotropica IFO 12743;

strains belonging to the genus Nocardia, including: Nocardia asteroides IFO 3424; Nocardia farcinica ATCC 3318; and Nocardia coeliaca ATCC 17040;

strains belonging to the genus Pychnoporus, including: Pychnoporus coccineus SANK 11280 (FERM P-5916);

strains belonging to the genus Streptomyces, including: Streptomyces carbophilus SANK 62585 (FERM BP-4128); Streptomyces roseochromogenus IFO 3363; Streptomyces roseochromogenus IFO 3411; and Streptomyces halstedii IFO 3199;

strains belonging to the genus Rhizoctonia, including: Rhizoctonia solani SANK 22972 (FERM P-591;

Syncephalastrum racemosum (Cohn) Schroeter SANK 41872 (FERM BP-4107);

Syncephalastrum nigricans Vuillemin SANK 42372 (FERM BP-4106);

Mucor hiemalis wehmer SANK 36372 (FERM BP-4108) and

Streptomyces carbophilus SANK 62585 (FERM BP-4128).

The microorganisms described above, deposited in culture collections research Institute of fermentation, Agency of industrial science and technology, the Ministry of foreign trade and industry, or they can be obtained from official agencies (IFO, CBS, NRRL and ATCC (American type culture collection of microorganisms) without availability restrictions. The following examples, which use the above mushrooms given to the present invention could be better understood.

It should be noted that the strains mentioned above, or any other strains that are able to show the same activity can be subculturally, or biotechnological changed or modified to obtain the body with different characteristics. The only requirement is that the resulting microorganism was capable of producing the desired connection. Changes can occur naturally or by artificial means.

Such changes and modification may take any desired formdatasource, cultivation and subjected to selection, which contributes to the manifestation of characteristics such as increased growth or growth at low/high temperatures.

Biotechnological modification usually are focused and they can be entered selectivity characteristics, such as bacteriostatic resistance or susceptibility, or a combination thereof for the purity of the culture, or for the purification of cultures, especially seed crops from time to time.

Other characteristics that can be introduced by genetic manipulation, are all characteristics that are valid for the species, which includes the above strains. For example, can be integrated plasmids, kotoroya resistance, or can be deleted plasmids of natural origin. Preferred plasmids are plasmids, which are auxotrophy. Plasmids can be obtained from any suitable source or they can be constructed by natural selection occurring plasmids and embedding into the desired gene or genes taken from another source. Natural plasmids can also be modified otherwise sposobu of the present invention, if the strain is able to show the desired activity that can easily be assessed by conducting a simple and plain experiment.

Mycological properties of these strains is shown below.

Mycological properties of the strain.

Amycolata autotrophica SANK 62981

According to the methods of Shirling and Jottlieb (International Journal of Systematic Bacteriology, 16. 313-340 (1968) and S. A. Waksman (The Actinomyces) observation of strain led within 14 days.

1. Microbiological characteristics.

Form the top of the aerial hyphae - Rectus-flexibilis

View branching hypha - Simple branching

Hypha division - you Can see

The surface structure of arthropod - Smooth

Other bodies - No

2. Properties obtained on media of different types, for classification.

The strain grows well on any tested environment.

Strain SANK 62981 grows, detecting a color from light brownish-white to pale-yellowish-orange. As the duration of cultivation is observed stains from light brown to purple.

In other environments other than yeast extract, such as agar medium with malt extract, observed the formation of light-brownish-serice 7 denote G, AM, R and SP mean growth, aerial mycelium, reverse side and soluble pigment, respectively.

Hue is specified in the table above according to the non-color (Color Tip Numbers) shown in the manual (Standard Color Table) published by Japanese publisher (Nihon Shikisai kenkyujo).

3. Physiological properties.

The reduction in the content of nitrate - Positive result

Hydrolysis of starch Negative result

Education melanoides pigment - Negative result

Determination was carried out on the following three environments:

Wednesday 1: tripton-liquid medium with yeast extract (ISP (I)

Wednesday 2: peptone-yeast extract-agar with iron (ISP 6)

Wednesday 3: the tyrosine agar (ISP 7).

4. Digestibility of different types of carbon sources.

The use of agar medium Pridham-Jottlieb (ISP 9) studied the digestibility of different carbon sources and judged after cultivation for 14 days at 28oC.

The following table indicate mean:

+ assimilation,

weak assimilation and

the absence of absorption.

D-Glucose - +

L-Arabinose - +

D-Xylose - +

D-Fructose - +

5. Intracellular components. According to the methods B. Becker and others (Applied Microbiology 12, 236 (1965)) and (M. P. Lechevalier and others (The Actinomycetales by H. Prauser p. 311 91970)) of the acid hydrolysates of the cells of these strains were analyzed by the method of paper chromatography. In cell walls was discovered meso-2,6-diaminopimelic acid and were seen arabinose and galactose as the sugar components of bacterial cells, which confirmed that bacterial components are of type IV-A.

Nikolova acid is not detected.

On the basis of these results, the strain SANK 62981 was determined belonging to the mind Amycolata autotrophica.

However, as the vegetative growth of strain SANK 62981 detects the color tone similar to amethyst, concluded that the species is a subspecies of the species Amycolata autotrophica.

This strain is deposited on the terms of the Budapest Treaty in the permanent collection of the crops research Institute of fermentation, the Agency of industrial science and technology. The Ministry of foreign trade and industry, Japan, under FERM-BP-4105.

This strain is identified according to the standard International streptomycine project (International Streptomyces Project) (Bergey''s Manual of Determinative Bacteriology, 8th Ed., the Actinomycetes, Vol.2 by S. A. Waksmaia. However, due to differences in the components of bacterial cells now suppose that the genus Amycolata is different from the genus Nocardia and each of them forms a new genus (International Journal of Systematic 36, 29 (1986)).

Mycological properties of the strain Syncephalastrum racemosum (Cohn) Schroeter SANK 41872

This strain was obtained by subculture of the strain deposited at the IFO number IFO 4814. He re-deposited at the research Institute of fermentation, the Agency of industrial science and technology, Ministry of international trade and industry, and assigned a number FERM BP-4197.

Mycological properties of the strain Syncephalastrum nigricans Vuillemin SANK 42372.

Vegetative hyphae develop well and grow quickly. Sporangiophore go vertically from hyphae, are characterized by a pale-brown color in the presence of ritalni and napravilnyh branches and form a partition.

Lateral branches sometimes strongly curved.

At the apex of the main axis and lateral branches bubbles. Bubbles are characterized by subspherical or oval shape, sometimes elliptical shape, and the bubbles that are formed on top of the main axis, have a diameter of from 28 to 50 μm, and bubbles, which are formed on the top side branches are single or finger shape and often is formed from 5 to 10 spores per line.

Disputes almost colorless with smooth surfaces, unicellular and are characterized by a form of subspherical to oval with a diameter of from 3.5 μm to 6.5 μm.

Zygospore not observed.

From the comparison of these properties with the properties of known strains, it follows that the properties of this strain are in good agreement with the properties of Syncephalastrum species nigricans described Vuillemin ("An Illustrated Book of Funji" Ed. by Keisuke Tsubaki and Shun ichi Udagawa, Kodansha, pp. 303-304 (1978)).

This strain is deposited on the terms of the Budapest Treaty at the research Institute of fermentation, Agency of industrial science and technology, Ministry of international trade and industry, under inventory number FERM BP-4106.

Mycological properties of the strain Mucolhiemalis Wehmer SANK 36372.

This strain was obtained by subculture of the strain deposited at the IFO under inventory number IFO 5834. He re-deposited at the research Institute of fermentation, Agency of industrial science and technology, the Ministry of foreign trade and industry under the number FERM BP-4108.

Mycological properties of the strain Streptomyces carbophilus SANK 62585.

1. Morphological characteristics. The morphology of the strain was observed under a microscope after 14 days nternational Streptomyces Project (ISP).

Substrate hyphae rather elongated and branched aerial mycelium simply branched. Sporogenes are either straight or curved, or sometimes form a spiral, and the surface of the spores is smooth.

Not watched any special organs, such as curls, sclerotia, fragmentation of substrate hyphae or sporangium.

2. Properties obtained on different types of environments for classification. Properties of strain SANK 62585 was determined on various media after 14 days incubation at 28oC. the Results are shown in table.8.

In the following table 8 used the same abbreviations as in table.7.

The color tones are listed in the table above correspond to the numbers color (Color Tip Numbers) shown in the manual (Standard Color Table) published by Japanese publisher (Nihon Shikisai Kenkyujo).

Physiological properties.

Hydrolysis of starch Positive

Liquefaction of gelatin - Negative

The decrease in the content of nitrate - Positive

Coagulation of milk - Positive

Pentanisia milk - Positive

Temperature range for growth

(medium 1) - 4-45oC

The temperature interval is catalinae

(environment 3) - Pseudobiological.

(Melanoides pigment sometimes produced in the last period of incubation.)

(environment 4) - Negative

The medium used in the above tests were as follows:

Wednesday 1 - agar containing yeast and malt (ISP 2);

Wednesday 2 - liquid medium with triptan-yeast extract (ISP 1);

Wednesday 3 - agar peptone-yeast extract and iron (ISP 6);

Wednesday 4 - the tyrosine agar (ISP 7).

4. Assimilation of carbon sources. Assimilation of carbon source, which was used in agar base (ISP 9) medium (Pridham-Jottlieb), studied the addition of D-glucose, L-arabinose, D-xylose, Inositol, D-mannitol, D-fructose, L-ramnose, sucrose, raffinose, cellobiose or trehalose. Fermentation with the use of this microorganism was carried out at a temperature of 28oC for 14 days. As the strain grows well in the test environment, and without adding any carbon source assimilation of carbon sources yet to be defined. However, vegetative growth of this strain in media containing D-glucose, D-xylose, Inositol, raffinose, cellobiose or trehalose, much better than in the control environment.

5. Intracellular component, 21-423 (1964)). Were detected L,L-diaminopimelic acid and glycine. Thus was confirmed that the cell wall of this strain are the cell wall of the first type. Components of sugar all cells were analyzed following the method described by M. B. Lechevalier and others (Journal of Laboratory and Clinical Medicine, 71, 934 (1968)), but found no characteristic features.

Based on the above data it is evident that the strain SANK 62585 belongs to the genus Streptomyces, one of the genera of actinomycetes.

Identification of strain SANK were performed according to the standard ISP (The International Streptomyces Project (international streptomycine project); Bergey''s Manual of Determinative Bacteriology (the 8th edition), S. A. Waksman: The Actinomycetes and recent literature on Actinomycetes).

From a careful comparison of the above data with the published descriptions of the known microorganisms follows a significant difference, implying that the strain SANK 62585 should be classified as a new species belonging to the genus Streptomyces. Based on the aforementioned, it is designated as Streptomyces carbophilus. This strain is deposited in the permanent collection of the crops research Institute of fermentation. Agency of industrial science and technology, Ministry of international trade and industry, and his privae is growing, used for the cultivation of converting microorganism, and any method commonly used for cultivation of microorganisms, can be equally well applied here. Examples of such methods include solid-phase cultivation, cultivation in stationary conditions, cultivation with shaking, growing under stirring and cultivation with aeration. Of these methods, the preferred method of cultivation with aeration, i.e., out of the way with stirring, shaking or aeration, more preferred is a method with shaking.

Fermentation on an industrial level is desirable to maintain in terms of mixing culture with forced aeration.

The pH value of the nutrient medium used for the cultivation of converting microorganism is typically in the range from 5.0 to 8.0, preferably from 6.0 to 7.0.

Fermentation using the converting microorganism is preferably carried out at a temperature in the range from 15 to 35oC, more preferably from 26 to 30oC and most preferably in the 28oC.

Method 1.

This method of enzymatic hydrolysis is carried out by incubation of the strain of the/P> The time at which to add the connection may vary depending on the conditions of optimal cultivation used for converting microorganism, in particular, on the type of equipment used for growing, medium composition, temperature, cultivation and other conditions; it is preferable to add the compound of formula (Ib), when hydroxyurea ability converting microorganism begins to increase. In General, preference should be given time, comprising from 1 to 3 days from the start of incubation converting microorganism.

The amount of the compounds of formula (Ib), which should be added is usually in the range from 0.01 to 5.0%, more preferably in the range from 0.025 to 2.0% based volume environment.

The time required for incubation can vary widely depending on many factors, including the cultivation conditions and the nature of the organism, but normally sufficient period of time from 3 to 5 days after addition of the compounds of formula (Ib).

Method 2.

This method is carried out at incubation converting microorganism in the presence of a small amount of the substrate, by the method of method 1 up until gerousia ability varies depending on the type of growing environment, the fermentation temperature and other conditions, but it usually reaches a maximum after 4 to 5 days after the start of cultivation. Cultivation is usually complete at this time.

Cells are then harvested, subjecting the culture broth to centrifugation, filtration or similar influences. It is desirable that the funds thus collected cells were washed before using physiological saline or an appropriate buffer solution.

The compound of formula (Ib) is usually in contact with the cells obtained in this way, in an aqueous solvent, for example in a phosphate buffer with a pH from 5 to 9.

The hydrolysis reaction is preferably carried out at a temperature of 20o45oC, more preferably from 25o35oC.

The concentration of the compounds of formula (Ib) is preferably in the range from 0.01 to 5.0% per volume environment.

The time required for interaction varies depending on many factors such as the concentration of the compounds of formula (Ib), temperature interaction and other conditions, however, the interaction is usually completed over a period of from 1 to 5 days.

Method 3.

In this case, m is chemical methods, for example by grinding or ultrasonic treatment, resulting receive a suspension containing cellular components, including the enzyme. Or this can be achieved by treating the cells with an organic solvent, a surface-active substance or an enzyme is able to give free cell extract. Cells can be obtained as described in method 2. The extract is then brought into contact with the compound of the formula (Ib).

Terms used in contact-free cell extract with a compound of formula (Ib) are similar to the condition described in method 2.

According to the methods described above, a suitable substrate (hydroxycitrate or lactonase connection) enter into interaction with the conversion of the microorganism or its free of cells containing the enzyme extract for stereospeakers the introduction of the hydroxy-group in position 6 of the substrate. The desired compound 6-hydroxy-group, can be selectively obtained by using the appropriate combinations, for example:

1) lactoovo connection and strain of Mucor hiemalis Wehmer;

2) hydroxycitrate connection and strain of Streptomyces carbophilus; or

3) hydroxycitrate connection and strain Amycol combination, for example:

1) lactoovo connection and strain Syncephalastrum nigricans Vuillemin or

2) lactoovo connection and strain Syncephalastrum racemosum (Cohn) Schroete.

The products obtained by the methods described above, the present invention is found in the filtrate obtained from the liquid medium, and in the micelles at the end of the fermentation period. The compound of the present invention exists in the form of either a hydroxy acid or lactone, and these forms can be converted one into the other. An important advantage gidrokshikislota connection is that it can form a stable Sol.

Accordingly, the extraction and removing the desired product from the whole fermentation liquid medium can be carried out, for example, the following method 1 or method 2.

Method 1.

All fermentation fluid centrifuged or filtered in the filter, such as diatomaceous earth, to separate the supernatant from the mycelium and other hard materials. They are then processed as follows.

1. The supernatant. If the supernatant contains lactoovo connection, then it is subjected to hydrolysis under alkaline conditions (preferably pH 12 or more) for the s. This acidified hydrolyzate or the supernatant, containing free gidrokshikislotu then extracted with an immiscible with water, an organic solvent, and the solvent is removed from the extract, for example, by distillation under reduced pressure. Examples of suitable immiscible with water, organic solvents are aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether or diisopropyl ether; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylmalonate; and mixtures of any two or more of the above solvents.

2. The mycelium. Cake of mycelium is mixed with an immiscible with water, an organic solvent so that the final concentration at the pellet ranged from 50 to 90%, considering the volume of the mixture. The resulting mixture is then treated similarly as above, in the case of treatment of the supernatant liquid. Examples of suitable immiscible with water, organic solvents I had utionary; and amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide.

Method 2.

Fermentation liquid medium is subjected to hydrolysis under alkaline conditions (preferably at a pH of 12 or more) or under heating or at room temperature, for disclosure lactoovo rings, at the same time destroyed the mycelium. All active compounds in the liquid medium, turn in salt gidrokshikislota connections, and required free hydroxycitrate can be extracted from a mixture of the same processing as the processing described above with reference to the supernatant.

Free hydroxycitrate connection obtained in this way may be, if necessary, dissolved in an aqueous salt solution of an alkali metal or alkali metal hydroxide such as sodium hydroxide, with the formation of the corresponding salt by the method described in the consideration stage 6. Hydroxycitrate can then be extracted conveniently in the form of its most stable salt.

Alternative to extract the desired connection free hydroxycitrate connection, receiving the with Laktionova ring, according to the method described in the consideration stage 6.

The mixture of compounds comprising free gidrokshikislotu one or more salts of hydroxy acids and lactonase connection, can be separated by conventional methods used in organic chemistry. For example, they can be separated and extracted various chromatographic methods, including the distribution of column chromatography by passing the substance through a synthetic absorbent such as Sephadex LH-20 (Pharmacia, Inc. "), amberliteTMXAD-11 ("Rohm and Haas co.) or diaionTMHP-20 (Mitsubishi Kasei Corporation); liquid chromatography with transmission of matter through regularly-phase or reversed-phase column with a nozzle made of silica gel or alkylated silica gel (preferably high-speed liquid chromatography; or using a suitable combination of techniques; after which the connection can be obtained by elution with a suitable eluting solvent.

Lactoovo connection can also be cleaned absorption column chromatography with the transmission of matter through the media, such as silica gel, alumina or Florisil (containing sinikalliontie hydrocarbons, such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene, or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylmalonate; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylethylenediamine simple ether.

Or the extract can be purified absorption column chromatography, used to remove impurities. Required hydroxycitrate connection can be obtained by its absorption in the absorption column and then the elution his eluting solvent, such as aqueous alcohol such as aqueous methanol, aqueous ethanol, aqueous propanol and water or isopropanol; a ketone or water, such as aqueous acetone. Examples of such absorbents are activated carbon or absorption resin, such as amberliteTMXAD-2 or XAD-4 ("Rohm and Haas co.) or diaionTMHP-10, HP-20, CHP-20 or HP-50 (Mitsubishi Kasei Corporation").

For purification of the desired compound b is caresource vzaimoprevrascheny, according to the method described in the consideration stage 6.

Biological activity.

Compounds of the present invention have a remarkable ability to understand the levels of serum cholesterol. In particular, the compounds inhibit the biosynthesis of cholesterol in the enzyme system or in a cell culture system, separated from the experimental animal by inhibition of 3-hydroxy-3-methylglutaryl-CoA-reductase (HMGGCo'A) enzyme, limiting the rate Teroldego biosynthesis, due to competition with HMG-CoA. From this it follows that the compounds exhibit a strong effect on lowering the content of serum cholesterol when used in the treatment of humans and other animals.

Experiment 1.

Determination of inhibitory activity of 3-hydroxy-3-methylglutaryl-KoA-reductase.

The preferred ability of test compounds to inhibit the activity of 3-hydroxy-3-methylglutaryl-KoA-reductase was determined following the method (Koga) and other (Eur. J. Biochem. 209, 315-319 (1992)), an improved method (Kuroda) and others (Biochem. Biophys. Acta, 485, 70-81 (1977)), which is a modification of the method of Shapiro and others (Anal. Biochem. 31, 383-390,(1969)).

A solution of 5 ml, preferably under test soedinenii the form of a buffer solution (pH 7,4), 0.2 mm (14C)3-hydroxy-3-methylglutaryl-KoA-reductase, 10 mm disodium salt of ethylenediaminetetraacetic acid, 10 mm dithiothreitol, 10 mm recovered adenine dinucleotide phosphate and the enzyme solution (microsomal fraction from rat liver). The content of substances are based on the final volume of the analyzed mixture the size of 50 microns. The resulting mixture was incubated for 15 min at 37oC. the Reaction was then completed by adding 10 μl of 2 n hydrochloric acid to lactonization formed (14C)mevalonata. After 15 min incubation was added 1 ml of 1:1 by volume aqueous suspension of biorex-5, and the vial was vigorously mixed using the mixer "Vortex". The mixture was then centrifuged at 3000 rpm for 1 min for 10 min at 4oC. the Supernatant (400 MCI) was mixed with 4.5 ml of a substance optiflowTMin acquired scintillation vials, and activity (14C)mevalonate was determined by liquid scintillation counter.

The results are shown in table.9.

Experiment 2.

Determination of inhibitory activity against suppression Teroldego synthesis in mouse liver.

Sterelny synthesis in the liver m and 15 μl (14C)acetate. After one hour the animal was killed by decapitation and cut out the liver. Sterelny synthesis in the liver was evaluated by the introduction of active carbon-14 of the drug deposited in digitonin sterols. The preferred test compounds, dissolved in 1% tween 80 was administered to mice orally 2 hours before injection (14C)acetate.

Activity against Teroldego synthesis of control animal that received only 1% solution of tween 80, was taken as 100%. Determined relative inhibition Teroldego synthesis in the liver in mice that received various doses of test compounds, and the expected value ED50(mg/kg, the dose required to inhibit Teroldego synthesis in the liver by 50%).

The results are shown in table.9.

Applied well-known compound has the formula (XXIII) and is a compound of example 4 described in Japanese patent publication N Hei 3-33696.

< / BR>
It is clear from the test results above, the compounds of the present invention compete with 3-hydroxy-3-methylglutaryl-CoA, which is responsible for the progress of limiting the speed stages of the biosynthesis of cholesterol in the Fermi-3-methylglutaryl-CoA-reductase is inhibited and the biosynthesis of cholesterol is prevented.

Compounds of the present invention detect a strong activity against lowering cholesterol in the serum of animals. In addition, their toxicity is very low. Therefore, they are applicable as a medical drug in the treatment of hyperlipemia and to prevent ateriosclerosis, as well as antifungal and anticancer agents.

To this end, the compounds of formulas (I) and (IV) may be administered orally in the form of tablets, capsules, granules, powders or syrups, or parenterally, by intravenous injection, suppositories and the like ways. These pharmaceutical formulations can be prepared by mixing the compound of the present invention, with one or more adjuvants such as fillers (for example, organic fillers, including derivatives of sugars, such as lactose, sucrose, glucose, mannitol, or sorbitol; starch derivatives such as corn starch, potato puree, starch, dextrin or carboxymethoxy starch; cellulose derivatives such as crystalline cellulose, low molecular weight hydroxypropylmethyl cellulose, hypromellose, carboxymethylcellulose, cal; dextran & pullulan (trade name material); inorganic fillers, including silicates, such as light silicic acid anhydride, synthetic aluminum silicate or magnesium meta-craniofacially aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate); lubricating agents (e.g., metallic stearates, such as stearic acid, calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of aliphatic acids; laurilsulfate, such as sodium lauryl sulfate or lauryl sulfate, magnesium; silicates such as silicic acid anhydride or silicic acid hydrate; and the above-mentioned starch derivatives), binders (for example, polyvinylpyridine, macrogol (trade name of material and compounds similar to the above-described fillers); loosening substances (for example, joints, similar to those described above fillers; and chemically modified starch-cellulose, such as crosscarmellose sodium, on entity, such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenethyl alcohol; chloride benzalconi; phenols, such as phenol or creasol; thimerosal; digitoxose acid and sorbic acid); corrigentov (for example, podslushivala, vinegar or odorants, such as commonly used); thinners and similar.

The dose may be different depending on the condition and age of the patient and from the path and nature of the introduction; for example, the compounds of the present invention can be administered orally with a daily dose of from 0.01 to 1000 mg per 1 kg body weight (preferably from 0.05 to 200 mg per 1 kg body weight), as one or separate doses.

Getting some of the compounds of the present invention is illustrated further by the following examples. Further syntheses, as well as examples A and B illustrate the obtaining of some of the starting compounds used in these examples.

These examples include obtaining representative compounds of the present invention a direct allocation of microorganisms. The methods described in these examples are purely illustrative and may be modified based on, for example, the properties of the desired connection. Prov.Roxy-2H-Piran-2-he

< / BR>
A-(1) Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S, 2S,6S,8S,8aR)-6,8 - dihydroxy-2-methyl-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic.

A solution of sodium methoxide with a concentration of 28% (weight per volume) in an amount of 50 ml (0.24 mol) was added to a solution of 100 g (0.31 mol) of (3R, 5R)-3,5-dihydroxy-7-[(1S, 2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- [(S)-2-methylbutyrate] -1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoate (pravastatin; prepared according to the method, described in U.S. patent No. 4 346 227) in 900 ml of methanol, and the resulting mixture was heated in a vessel under reflux for 60 hours At the end of this time the mixture was cooled to room temperature, and methanol was then removed from the reaction mixture by distillation under reduced pressure. The obtained residue was washed with 200 ml of hexane and then dried under vacuum, resulting in a received 120 g of the named compound.

A-(2) (3R, 5R)-3,5-Dihydroxy-7-[(1S, 2S,8S,8S,8aR)-6,8-dihydroxy - 2-methyl-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptane acid.

All sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)- 6,8-dihydroxy-2-methyl-1,2,6,7,8,8 a-hexahydro-1-naphthyl)heptanoate obtained in stage 1 above, was dissolved without additional purification in 300 ml of water. The pH value of the solution was maintained at a level of about 4.0 by adding 35% (by weight in raccontato was dried in vacuum, then the dried residue was dissolved in 300 ml of ethanol. The sodium chloride formed during the interaction was then removed by filtration, and then the resulting filtrate was concentrated by evaporation under reduced pressure. The obtained residue was dried, receiving 94 g of the named compound.

A-(3) (4R, 6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6,8 - dihydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H-Piran-2-it.

All crude (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,3S,8aR)-6,8-dihydroxy - 2-methyl-1,2,6,7,8,8 a-hexahydro-1-naphthyl] heptane acid, obtained in stage 2 above, was mixed with 1000 ml of tetrahydrofuran. 3 Quiroga to the mixture was added 38 ml (9,27 mol) of triethylamine, after which was added 38 ml (0.25 mol) diethylthiophosphate while cooling with ice and stirring. The resulting mixture was then stirred at room temperature for 1.5 hours At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure, and the residue was ground in a simple mixture of diethyl ether from ethanol than stimulated crystallization. The obtained crystals were collected by filtration, receiving of 47.7 g of the named compound. This compound is then recrystallized from a mixture of ethyl acetate with ethanol, getting colourless resonance (270 MHz, hexadeuterated dimethyl sulfoxide) , mln.

of 0.82 (3H, doublet, J = 6.3 Hz);

4,07-to 4.15 (2H, multiplet);

the 4.29 (1H, doublet, J = 4.4 Hz, interchangeable with D2O);

4,23 is 4.35 (1H, multiplet);

to 4.52 (1H, doublet, J = 6,4 Hz, interchangeable with D2O);

4,51-to 4.62 (1H, multiplet);

further 5.15 (1H, doublet, J = 2,9 Hz, interchangeable with D2O);

of 5.40 (1H, broad singlet);

of 5.84 (1H, doublet of doublets, J = 6.2 and 9.3 Hz);

5,90 (1H, doublet, J = 9.8 Hz).

Elemental analysis for C18H26O5:

Calculated: C - 67,06%, H - 8,13%

Found: C - 66,31%, H - 3,37%.

Infrared absorption spectrum (KBr)ax(cm-1) - 3436, 3339, 3222, 1730, 1260, 1217, 1042.

Mass spectrum (m/e): 322 (M+), 304, 286, 268.

[]2D5+RUR 188.6< / BR>
The solution 9,04 g (60,0 mmol) tert-butyldimethylsilyloxy in 35 ml of dimethylformamide, was added dropwise to a solution 9,65 g (30.0 mmol) of (4R, 6R)-6-{ 2-[(1S, 2S, 6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6,8-dihydroxy - 2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H-Piran-2-it (obtained as described above in example A), and 6,12 g (90,0 mmol) imidazole in 45 ml of dimethylformamide under ice cooling and stirring. The resulting mixture was then stirred at room temperature for 5 h, after che is ATA, and the solution is then washed first with water and then saturated aqueous sodium chloride. The solution is then dried over anhydrous magnesium sulfate, and then filtered. The resulting filtrate was then concentrated by evaporation under reduced pressure. The concentrate was purified flash (instant) by chromatography on a column passing through silica gel using the method of gradient elution with a mixture of hexane with ethyl acetate as eluent, with a volume ratio of from 2:1 to 1:1, receiving 13.3 g of the named compound as a colourless solid. This compound is then recrystallized from simple diisopropyl ether, receiving colorless needle-like crystals with a melting point of 132 to 134oC.

Elemental analysis for C30H54O5Si2:

Calculated: C - 65,40%, H - 9,88%,

Found: C - 65,29% H - 9,96%.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) , in ppm,

of 0.79 to 0.92 (M, multiplet);

4,07-to 4.15 (1H, multiplet);

4,27-4,34 (1H, multiplet);

to 4.38 (1H, doublet, J = 3,9 Hz, interchangeable with D2O);

4,48-4,60 (2H, multiplet);

5,33 (1H, broad singlet);

of 5.82 (1H, doublet of doublets, J = 6.2 and 9.8 G is 7, 1736, 1711, 1361, 1257, 1071, 837.

Mass spectrum (m/e): 550 (M+), 532, 493, 475, 343, 275.

[]2D5+89,7< / BR>
i.e., compounds of formula (I) in which R1represents a group of formula (III) and R6represents a tert-butyldimethylsilyloxy group. Each group W as defined in the following examples, attached to the formula shown above, through the connection indicated by Z.

Example 1. (4R, 6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-(3,3-dimethylbutyryl)-2-methyl - 1-naphthyl] ethyl}tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-he

< / BR>
3,3-Dimethyloctane acid and 0.46 ml (3.6 mmol), 741 mg (3.6 mmol) of dicyclohexylcarbodiimide and 13 mg (0.09 mmol) of 4-(1-pyrrolidinyl)of pyridine was added to a solution of 1.00 g (1.8 mmol) of (4R,6R)-6-{2-[1S,2S,6S,8S,8aR)-1,2,6,7,3,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro - 4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) in 15 ml of methylene chloride under cooling with ice. The resulting mixture was stirred at the same temperature for 30 min and then stirred at room temperature for 19 hours At the end of this time the solvent drove by distillation when ponygallery filtering and then twice washed simple diethyl ether using each washing 5 ml of the Filtrate and washing solutions are then combined, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified flash chromatography, passing through silica gel using as eluent a mixture of hexane and ethyl acetate 4:1, by volume receiving 555 mg (yield 47%) of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 2.20 (2H, singlet);

4,24-4,32 (1H, multiplet);

4,39-to 4.46 (1H, multiplet);

4,53 with 4.65 (1H, multiplet);

lower than the 5.37 (1H, broad singlet);

the 5.45 (1H, broad singlet);

of 5.84 (1H, doublet of doublets, J = 9,8 and 5.8 Hz);

of 5.99 (1H, doublet, J = 9.6 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1800, 1250, 1080, 840.

Mass spectrum (m/e): 648 (M+), 633, 591, 532, 475.

[]2D5+87,5< / BR>
of 1.26 ml (9.1 mmol of triethylamine, 15 mg (0.1 mmol) of 4-(1-pyrrolidinyl)pyridine and 0.63 ml (2,73 mmol) of anhydride 2-ethylmalonic acid was added to a solution of 1.00 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2-6,7,8,8 a-hexahydro-6-tert-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-tert-butyltin and ice. The resulting mixture was stirred at room temperature for three days. At the end of this time the reaction mixture was diluted with 50 ml of ethyl acetate, and the diluted mixture was washed with 20 ml water, 10% (weight per volume) aqueous solution of citric acid, 20 ml of a saturated aqueous solution of sodium bicarbonate and 20 ml of a saturated aqueous solution of sodium chloride, in that order. The washed mixture is then dried over anhydrous magnesium sulfate, after which the mixture was filtered. The filtrate obtained was concentrated by evaporation under reduced pressure, and the obtained concentrate was purified flash chromatography, passing through silica gel using as eluent a mixture of hexane with ethyl acetate in a volume ratio of 5:1, receiving 1.04 g (yield 88%) of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,24-4,32 (1H, multiplet);

4,37 figure-4.49 (1H, multiplet);

4,51-to 4.62 (1H, multiplet);

5,42 (1H, broad singlet);

vs. 5.47 (1H, broad singlet);

of 5.84 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

5,98 (1H, doublet, J = 9.9 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 840.

Mass SP is tiramina and 713 mg (4.1 mmol) of diethylphosphate was added to a solution of 400 mg (3.4 mmol) of (S)-2-methylalanine acid in 15 ml of dry benzene, and the resulting mixture was stirred at room temperature for one hour. To the mixture were then added 1,58 g (2.9 mmol) of (4R,6R)-6-{2- [(1S, 2S, 6S, 8S, 8aR)-1,2,6,7,8,8 a-hexahydro-6-tert-butyldimethylsilyloxy - 8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy - 2H-Piran-2-it (obtained as described above in example B) and 250 mg (1.7 mmol) of 4-(1-pyrrolidinyl)pyridine. The mixture was then stirred at room temperature for 24 h, after which the mixture was diluted with 20 ml of benzene. The diluted mixture was then washed with 20 ml water, 20 ml of 10% (weight per volume) aqueous citric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride in that order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent drove by distillation under reduced pressure. The obtained residue was purified column flash chromatography, passing through silica gel, using as eluent a mixture of hexane with ethyl acetate in a volume ratio of 6:1, receiving of 1.36 g (yield 74%) of the named compound.

Spectrum of nuclear magnetic resonance: (400 MHz, CDCl3) , in ppm,

a 1.11 (3H, doublet, J = 7,1 Hz);

4,27-4,30 (1H, multiplet);

to 5.85 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

of 5.99 (1H, doublet, J = 9.7 Hz),

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 840.

Mass spectrum (m/e): 648 (M+), 591, 532, 475.

[]2D5+88,3< / BR>
The substance 4-(1-pyrrolidinyl)pyridine (15 mg, 0.01 mmol) and 592 mg (3.6 mmol) chloride 2-propylvaleric was added to a solution of 1.0 g (1.8 mmol) of (4R, 6R)-6{ 2-[1S, 2S, 6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} -tetrahydro - 4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) in 5 ml dry pyridine under ice cooling, and the mixture was stirred at 70oC for three hours. At the end of this time the reaction mixture was diluted with 100 ml of ethyl acetate, and the diluted mixture was then washed with 100 ml water, 100 ml of 10% (weight per volume) aqueous solution of hydrogen chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride in that order. The organic layer was then dried over anhydrous magnesium sulfate, after which this layer was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and poluceni hexane with ethyl acetate in a volume ratio of 5:1, getting to 1.15 g (yield 93%) of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,25-or 4.31 (1H, multiplet);

4,36-4,48 (1H, multiplet);

4,51-to 4.62 (1H, multiplet);

of 5.40 (1H, broad singlet);

vs. 5.47 (1H, broad singlet);

to 5.85 (1H, doublet of doublets, J = 9,3 and 5.9 Hz);

of 5.99 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 295, 1720, 1250, 840.

Mass spectrum (m/e):

676 (M+), 621, 549, 532, 475.

[]2D5+97,5< / BR>
The triethylamine (from 0.76 ml, 5.4 mmol), 807 mg (5.4 mmol) of 4-(1-pyrrolidinyl)pyridine and 674 mg (4.5 mmol) of 2-ethyl-2-methylbutyraldehyde was added to a solution of 500 mg (of 0.91 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) in 10 ml of benzene, and the mixture was heated under reflux for 5 hours At the end of this time the reaction mixture was diluted with 50 ml ethyl acetate. The diluted mixture was then washed with 30 ml water, 30 ml of 10% (weight per volume) aqueous citric acid, saturated aqueous bicarbonate natidnal magnesium sulfate and was filtered. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was purified evaporative column chromatography by passing through silica gel using as eluent a mixture of hexane with ethyl acetate in a volume ratio of 5:1, getting 601 mg (yield 100%) of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 1.07 (3H, singlet);

4,23-4,32 (1H, multiplet);

4,37-4,48 (1H, multiplet);

4,51 with 4.64 (1H, multiplet);

to 5.35 (1H, broad singlet);

5,46 (1H, broad singlet);

of 5.84 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

5,98 (1H, doublet, J = 9,3 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1180, 840.

Mass spectrum (m/e): 662 (M+), 647, 605, 549, 532.

[]2D5+93,7< / BR>
2.2-deliveryrelated (1.48 g, 9.1 mmol) was added to a solution of 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B), 1,67 g (11.3 mmol) 4-(1-pyrrolidinyl)of pyridine and 1.0 ml (7.1 mmol) of triethylamine in 10 ml of toluene, and the mixture was heated with reverse Ho is Anna above in example 5, getting 1,09 g (yield 89%) of the named compound.

Spectrum of nuclear magnetic resonance: (360 MHz, CDCl3) , in ppm,

0,96 (N, triplet, J = 7,7 Hz);

1,22-of 1.29 (1H, multiplet);

of 1.42 to 1.47 (2H, multiplet);

4.26 deaths-the 4.29 (1H, multiplet);

4,42 is 4.45 (1H, multiplet);

4,53-4,60 (1H, multiplet);

of 5.39 (1H, broad singlet);

5,46 (1H, broad singlet);

to 5.35 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

of 5.99 (1H, doublet, J = 9.7 Hz),

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1715, 1260, 340.

Mass spectrum (m/e): 676 (M+), 661, 619, 532, 475, 400.

[]2D5+an 80.2< / BR>
Followed a methodology similar to that described above in example 3, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert-butyl - dimethylsiloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 466 mg (3.6 mmol) of 2,2-dimethyl-4-pentenol acid, getting 231 mg of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

1,41 (6N, singlet);

of 2.26 (2H, doublet, J = 7,3 Hz);

4,25-to 4.33 (1H, multiplet);

to 4.38-4,47 (1H, multiplet);

of 5.83 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

5,97 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1180, 840.

Mass spectrum (m/e): 645 (M+-15), 603, 535, 517, 475.

[]2D5+87,2< / BR>
Followed a methodology similar to that described above in example 3, but used 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4 - tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 560 mg (4.0 mmol) 2-allyl-4-pentenol acid, receiving of 1.02 g of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4.26 deaths-or 4.31 (1H, multiplet);

4,40-4,48 (1H, multiplet);

to 4.52-to 4.62 (1H, multiplet);

to 4.98-5,11 (4H, multiplet);

of 5.40 (1H, broad singlet);

vs. 5.47 (1H, broad singlet);

5,63-5,80 (2H, multiplet);

to 5.85 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

of 5.99 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 840.

Mass spectrum (m/e): 672 (M+), 615, 532, 475.

[]2D5+to 85.2< / BR>

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 4.25-4.26 deaths (1H, multiplet);

4,39-4,48 (1H, multiplet);

to 4.52-4.63 to (1H, multiplet);

5,42 (1H, broad singlet);

of 5.48 (1H, broad singlet);

5,86 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

6,00 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1850, 1720, 1460, 1250.

Mass spectrum (m/e): 689 (M+-15), 647, 549, 532.

[]2D5+64,8< / BR>
Followed a methodology similar to that described above in example 3, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 423 mg (3.6 mmol) hexanoic acid, received 364 mg of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,25-4,32 (1H, multiplet);

4,39-to 4.46 (1H, multiplet);

4,55 with 4.65 (1H, multiplet);

5,38 (1H, broad singlet);

of 5.48 (1H, broad singlet);

to 5.85 (1H, doublet of doublets, J =9,8, and 5.9 Hz);

6,00 (1H, doublet, J = 9.8 Hz),
range (m/e): 591 (M+-57), 532, 517, 475.

[]2D5+76,5< / BR>
Followed a methodology similar to that described in example 4, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 361 mg (3.0 mmol) of isovaleraldehyde, getting to 1.14 g of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm, were

0,94 (6N, doublet, J = 6.4 Hz);

4,27-the 4.29 (1H, multiplet);

4,40-4,50 (1H, multiplet);

4,55 with 4.65 (1H, multiplet);

of 5.39 (1H, broad singlet);

of 5.48 (1H, broad singlet);

the 5.65 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

5,98 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2875, 1725, 1225, 1080, 840.

Mass spectrum (m/e): 634 (M+), 577, 532, 475.

[]2D5+100,0< / BR>
Followed a methodology similar to that described in example 4, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8 a-hexahydro-6-tert-butyl - dimethylsiloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (Pola.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

1,17 (N, singlet);

4,27-or 4.31 (1H, multiplet);

4,40-of 4.44 (1H, multiplet);

4,56-4,63 (1H, multiplet);

5,32 (1H, broad singlet);

of 5.48 (1H, broad singlet);

of 5.84 (1H, doublet of doublets, J = 9.7 and a 5.3 Hz);

5,98 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1255, 1080, 340.

Mass spectrum (m/e): 634 (M+), 577, 532, 475, 343.

[]2D5+89,1< / BR>
Followed a methodology similar to that described in example 4, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,3S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 2.16 g (14.5 mmol) of 2,2-dimethylpentanenitrile, getting 1,31 g of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

1,13 (6N, singlet);

4,25-4,32 (1H, multiplet);

4,36-to 4.46 (1H, multiplet);

to 4.52 with 4.64 (1H, multiplet);

5,32 (1H, broad singlet);

the 5.45 (1H, broad singlet);

of 5.83 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

5,98 (1H, doublet, J = 9.8 Hz).

[]2D5+93,6< / BR>
Followed a methodology similar to that described in example 4, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 1.26 g (7.3 mmol) chloride 2-allyl-2-methyl-4-pentenol, getting to 2.13 g of the named compound.

Spectrum of nuclear magnetic resonance: (mg, CDCl3) , in ppm,

a 1.08 (3H, singlet);

4,28-or 4.31 (1H, multiplet);

to 4.41 is 4.45 (1H, multiplet);

4,56-4,60 (1H, multiplet);

5,04-to 5.03 (4H, multiplet);

5,38 (1H, broad singlet);

5,46 (1H, broad singlet);

5,62-5,72 (2H, multiplet);

to 5.85 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

5,98 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 835.

Mass spectrum (m/e):

686 (M+), 629, 532, 475.

[]2D5+105,0< / BR>
Followed a methodology similar to that described in example 4, but using 2.0 g (3.3 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro - 6-tert-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl}Tetra is Teal-2-Propellerhead, receiving of 1.05 g of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

a 1.08 (3H, singlet);

4.26 deaths-4,32 (1H, multiplet);

of 4.38 is 4.45 (1H, multiplet);

4,53-4,60 (1H, multiplet);

the 5.45 (1H, broad singlet);

vs. 5.47 (1H, broad singlet);

to 5.85 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

5,98 (1H, J = 9.7 Hz),

max(cm-1infrared absorption spectrum (CHCl3); 2950, 1720, 1250, 1180, 840.

Mass spectrum (m/e): 690 (M+), 675, 633, 549, 532.

[]2D5+97,5< / BR>
Followed a methodology similar to that described in example 4, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6 - tert-butyl-dimethylsiloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4 - tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 1.29 g (7.3 mmol) chloride 2,2-diethylmaleate getting 188 mg of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,20-of 4.25 (1H, multiplet);

4,33-4,37 (1H, multiplet);

4,46-a 4.53 (1H, multiplet);

5,32 (1H, broad singlet);

of 5.39 (1H, broad singlet);

5,79 (1H, doublet of doublets, J = 9.7 and 5.8 Hz);

of 5.92 (1H, S="ptx2">

Mass spectrum (m/e): 690 (M+), 675, 633, 568, 532.

[]2D5+95,7< / BR>
Followed a methodology similar to that described in example 4, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsiloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 888 mg (5.5 mmol) chloride 2-isopropyl-3-methylbutyryl getting 198 mg of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4.26 deaths-4,32 (1H, multiplet);

4,45-4,60 (2H, multiplet);

the 5.45(2H, broad singlet);

to 5.85 (1H, doublet of doublets, J = 9.7 and 6.0 Hz);

of 5.99 (1H, doublet, J = 9.7 Hz).

max(cm-1) spectrum infrared absorption absorption (CHCl3): 2950, 1720, 1250, 1180, 840.

Mass spectrum (m/e): 676 (M+), 661, 619, 568, 532.

[]2D5+95,0< / BR>
Followed a methodology similar to that described in example 6, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 3.1 of magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,22-to 4.23 (1H, multiplet);

to 4.38-4,47 (1H, multiplet);

to 4.52-to 4.62 (1H, multiplet);

5,00-5,14 (2H, multiplet);

5,41 (1H, broad singlet);

5,46 (1H, broad singlet);

5,54-5,72 (1H, multiplet);

to 5.85 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

of 5.99 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 840.

Mass spectrum (m/e): 688(M+), 631, 623, 568, 532.

[]2D5+79,3< / BR>
Followed a methodology similar to that described in example 6, but used of 1.65 g (3.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 2.30 g (15.0 mmol) chloride 2-allyl-2-ethyl-4-pentenol getting 1.63 g of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

0,81 (3H, triplet, J = 7.4 Hz),

4,17-the 4.29 (1H, multiplet);

to 4.41 is 4.45 (1H, multiplet);

4,54-4,60 (1H, multiplet);

5,04-5,12 (4H, multiplet);

5,42-(1H, broad singlet);

5,46 (1H, broad singlet);

the ceiling of 5.60-5,69-(2H, multiplet);

to 5.85 (1H, take the tion spectrum (CHCl3): 2950, 1720, 1255, 1030, 840.

Mass spectrum (m/e): 700 (M+), 643, 532, 475, 400.

[]2D5+89,3< / BR>
Followed a methodology similar to that described in example 6, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert-butyl - dimethylsiloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 584 mg (2.9 mmol chloride 2,2-diallyl-4-pentenol getting 585 mg of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

to 2.29 (3H, doublet, J = 7,2 Hz);

to 3.38 (3H, doublet, J = 7,2 Hz);

4,28-4,30 (1H, multiplet);

to 4.41 is 4.45 (1H, multiplet);

4,54-br4.61 (1H, multiplet);

5,03-5,16 (6N, multiplet);

5,43 (1H, broad singlet);

the 5.45 (1H, broad singlet);

of 5.53-5,80 (3H, multiplet);

to 5.85 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

5,98 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 835.

Mass spectrum (m/e): 712 (M+), 555, 532, 475, 343.

Example 21. (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsiloxy-8-(2-ethyl-2-methylvalerate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-Ispolzovali 1.0 g (1.8 mmol) of (4R,6R)-6{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example B) and 1.18 g (7.3 mmol) chloride with 2-ethyl-2-methylalanine, getting 956 mg of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,27-4,30 (1H, multiplet);

4,40-of 4.44 (1H, multiplet);

4,54 - a 4.53 (1H, multiplet);

are 5.36 (1H, broad singlet);

5,46 (1H, broad singlet);

to 5.85 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

5,98 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 840.

Mass spectrum (m/e): 676 (M+), 619, 591, 532, 475.

[]2D5+93,2< / BR>
Chloride thionyl (121 μl (of 1.66 mmol) was added to 60 mg (0.42 mmol) of (-)-(2S)-2-ethyl-2-methylpentanoic acid (obtained as described in the synthesis of 16), and the mixture was heated at 100oC for one hour. At the end of this time the mixture was concentrated by evaporation under reduced pressure. All the obtained chloride (-)-(2S)-2-ethyl-2-methylmalonyl added without purification to a solution of 453 mg (0.83 mmol) of (4R,6R)-6- {2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert-butyldimethylsilyloxy - 8-hydroxy-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy - 2H-Piran-2-it (obtained as described in example B), 203 mg (from 1.66 mmol) of 4-(N,N-dimethylamino)pyridine, a catalytic amount (20 mg), 4-dimethylaminopyridine is the end of this time the reaction mixture was cooled to room temperature and then mixed with 10 ml of 10% (weight per volume) aqueous solution of hydrogen chloride. The aqueous mixture was extracted three times, using each time with 20 ml of ethyl acetate. The United extracts are then washed with a saturated aqueous solution of sodium chloride, after which the washed solution was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the obtained pale-yellow oily residue was purified column flash chromatography, passing through silica gel, using as eluent a mixture of hexane with ethyl acetate in a volume ratio of 5:1, receiving 88 mg (yield 31%) of the named compound in the form of a foamy substance.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,27-4,30 (1H, multiplet);

4,40-of 4.44 (1H, multiplet);

4,54-4,58 (1H, multiplet);

are 5.36 (1H, broad singlet);

5,46 (1H, broad singlet);

to 5.85 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

5,98 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 840.

Mass spectrum (m/e): 676 (M+).

[]2D5+to 85.2< / BR>
Followed a methodology similar to that described in example 6, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-tert - BU is received as described above in example B) and of 1.33 g (10.0 mmol) of 2,2-diethylhexanoate, getting 1.22 g of the named compound.

Spectrum of nuclear magnetic resonance: (400 MHz, CDCl3) , in ppm,

1,20 (6N, singlet);

4,27-4,30 (1H, multiplet);

4,40-of 4.44 (1H, multiplet);

4,55-br4.61 (1H, multiplet);

of 5.34 (1H, broad singlet);

vs. 5.47 (1H, broad singlet);

of 5.84 (1H, doublet of doublets, J = a 9.6 and 5.9 Hz);

5,98 (1H, doublet, J = 9.6 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 835.

Mass spectrum (m/e): 676 (M+), 619, 532, 475, 343.

[]2D5+89,9< / BR>
i.e., obtaining the compound of formula (I) in which R1represents a group of formula (III) and R6represents a hydrogen atom. Each group W as defined in the following examples, joins the formula shown above, through the connection indicated by Z.

Example 24. (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-8- (2-ethyl-2-methylbutyrate)-2-methyl-1-naphthyl)ethyl} tetrahydro-4-hydroxy - 2H-Piran-2-he

< / BR>
A solution of 600 mg (0.9 mmol) of (4R,6R)-6-{2-[1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a - hexahydro-6-tert-butyldimethylsilyloxy-8-(2-ethyl-2-methylbutyrate)-2 - methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described Oia in tetrahydrofuran and of 1.27 ml of acetic acid, and the mixture was stirred at room temperature for 15 hours At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure. The residue was then diluted with 50 ml of ethyl acetate, and the diluted solution was twice washed with water (60 ml), washed three times with saturated aqueous sodium bicarbonate solution each time, 30 ml, and once washed with a saturated aqueous solution of sodium chloride, in that order. The organic layer was then dried over anhydrous magnesium sulfate and removed from the mixture by filtration, then the solvent was removed by distillation under reduced pressure. The residue was purified evaporative column chromatography, passing through silica gel using as eluent ethyl acetate, getting 387 mg (yield 98%) of the named compound as a colourless solid. This compound is recrystallized from a mixture of hexane with ethyl acetate, getting a named connection in the form of colorless prismatic crystals, melting at temperatures ranging from 152 to 154oC.

Elemental analysis for C25H38O6:

Calculated: C - 69,10%, H - 8,81%;

Found: C - 68,83%, H - 8,70%

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl
of 1.03 (3H, singlet);

4,33-of 4.44 (2H, multiplet);

4,54-is 4.85 (1H, multiplet);

5,04 (1H, broad singlet);

lower than the 5.37 (1H, broad singlet);

of 5.89 (1H, doublet of doublets, J = 5.9 and 9.8 Hz);

6,00 (1H, doublet, J = 9.8 Hz).

max(cm-1infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1150.

Mass spectrum (m/e): 434 (M+), 416, 304, 286.

[]2D5+175,4< / BR>
Followed a methodology similar to that described in example 24, but using 1.0 g (1.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,6S,8aR)-1,2,6,7,8,6 and hexahydro - 6-tert-butyldimethylsilyloxy-8-(2-ethylbutyrate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 2), getting 649 mg of the named compound, melting at 158oC.

Elemental analysis for C24H36O6:

Calculated: C - 68,55%, H - 8,63%;

Found: C - 68,33%, H - 8,71%,

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,32-to 4.46 (2H, multiplet);

4,54 - of 4.66 (1H, multiplet);

the 5.45 (1H, broad singlet);

to 5.58 (1H, broad singlet);

5,90 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

of 6.02 (1H, doublet, J = 9.8 Hz).

Valuesmax(cm-1) infrared is]2D5+184,2< / BR>
Followed a methodology similar to that described in example 24, but used to 1.38 g (2.1 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro - 6-tert-butyldimethylsilyloxy-8-[(S)-2-methylvalerate] -2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 3), getting 674 mg of the named compound, melting at 134oC.

Elemental analysis for C24H36O6:

Calculated: C - 68,55%, H - 8,63%,

Found: C - 68,36%, H - 8,77%.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

to 0.89 (3H, triplet, J = 7,3 Hz);

of 0.91 (3H, doublet, J = 7,3 Hz);

a 1.11 (3H, doublet, J = 7,3 Hz);

2,32 (1H, broad singlet, interchangeable with D2O);

by 2.73 (1H, doublet of doublets, J = 17.7 and and 5.1 Hz);

4,33-4,43 (2H, multiplet);

4,57 with 4.64 (1H, multiplet);

5,41 (1H, singlet);

to 5.57 (1H, singlet);

5,90 (1H, doublet of doublets, J = 9.5 and 5,9 Hz);

6,00 (1H, doublet, J = 9.5 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3501, 3453, 2964, 1724, 1699, 1132, 1044, 861.

Mass spectrum (m/e): 420 (M+), 403, 304.

[]2D5+189,5< / BR>
Followed the technique similar to about what siloxy-8-(2-propylvaleric)-2-methyl-1-naphthyl] - ethyl}tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 4), getting 668 g of the named compound, melting at temperatures from 165 to 166oC.

Elemental analysis for C26H40O6:

Calculated: C - to 69.61%, H - 8,99%:

Found: C - 69,67%, H - 6,95%.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,33 is 4.45 (2H, multiplet);

4,54 with 4.65 (1H, multiplet);

5,43 (1H, broad singlet);

to 5.56 (1H, broad singlet);

5,90 (1H, doublet of doublets, J = 9,3 and 5.9 Hz);

6,01 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720.

Mass spectrum (m/e): 448 (M+), 430, 304, 286.

[]2D5+176,1< / BR>
Followed a methodology similar to that described in example 24, but using 1.45 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro - 6-tert-butyldimethylsilyloxy-8-(3,3-dimethylbutyryl)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 1), receiving 640 mg of the named compound, melting at 155oC.

Elemental analysis for C24H36O6:

The calc is , in ppm,

to 0.80 (3H, doublet, J = 6,8 Hz);

1,02 (N, singlet);

is 2.05 (1H, multiplet, interchangeable with D2O);

of 2.20 (2H, singlet);

4,32-4,48 (2H, multiplet);

4,56-of 4.67 (1H, multiplet);

of 5.40 (1H, broad singlet);

of 5.55 (1H, broad singlet);

5,88 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

6,00 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3400, 2950, 1720.

Mass spectrum (m/e): 420 (M+), 402, 384, 346, 321.

[]2D5+189,1< / BR>
Followed a methodology similar to that described in example 24, but used 2,52 g (3.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 and hexahydro - 6-tert-butyldimethylsilyloxy-3-(2,2-diethylbutyl)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 6), receiving of 1.05 g of the named compound, melting at temperatures of from 146 to 148oC with decomposition.

Elemental analysis for C26H40O6:

Calculated: C - to 69.61%, H - 8,99%;

Found: C - 69,53%, H - 9,10%.

Spectrum of nuclear magnetic resonance: (360 MHz, CDCl3) , in ppm,

0,76 (N, triplet, J = 7.5 Hz);

of 0.91 (3H, doublet, J = 7.0 Hz);

4,35-to 4.41 (2H, mu is uplet of doublets, J = a 9.7 and 5.9 Hz);

6,01 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (KBr): 3428, 2967, 1717, 1255, 1142, 1041.

Mass spectrum (m/e): 448 (M+), 430, 304, 286.

[]2D5+167,8< / BR>
Followed a methodology similar to that described in example 24, but used 227 mg (0.3 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-(2,2-dimethyl-4-pentenoate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 7), getting 127 mg of the named compound, melting at temperatures ranging from 141 to 142oC.

Elemental analysis for C25H36O6;

Calculated: C - 69,42%, H - 8,39%;

Found: C - 69,15%, H - 8.34 Per Cent.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 0.90 (3H, doublet, J = 7,3 Hz);

1.14 in (6N, singlet);

of 2.25 (2H, doublet, J = 7,3 Hz);

4,33 is 4.45 (2H, multiplet);

4,55 is 4.36 (1H, multiplet);

5,01-5,10 (2H, multiplet);

lower than the 5.37 (1H, broad singlet);

to 5.57 (1H, broad singlet);

5,61-USD 5.76 (1H, multiplet);

5,79 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

6,00 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorbs is SUP>D5+188,0< / BR>
Followed a methodology similar to that described in example 24, but used 966 mg (1.4 mmol) of (4R,6R)-6{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,6 and hexahydro-6-tert - butyldimethylsilyloxy-8-(2-allyl-4-pentenoate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 8), getting 555 mg of the named compound, melting at temperatures ranging from 159 to 160oC.

Elemental analysis for C26H36O61/2H2O:

Calculated: C - 66,85%, H is 8.22%;

Found: C - 68,85%, H - 8,10%.

Spectrum of nuclear magnetic resonance: (270 MHz, hexadeuterated dimethyl sulfoxide) , in ppm,

from 0.84 (3H, doublet, J = 6,8 Hz);

4,08-of 4.25 (2H, multiplet);

to 4.41-to 4.52 (1H, multiplet);

was 4.76 (1H, doublet, J = 5,9 Hz, interchangeable with D2O);

4,99 is 5.07 (4H, multiplet);

of 5.17 (1H, doublet, J = 2,9 Hz, interchangeable with D2O);

of 5.26 (1H, broad singlet);

5,49 (1H, broad singlet);

5,61-5,78 (2H, multiplet);

of 5.84 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

5,96 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3400, 2950, 1720, 1240.

Mass spectrum (m/e): 444 (M+), 427, 304, 161.

what does 785 mg (1.1 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-(2-butylphenoxy)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-she (received as described above in example 9) to give 520 mg of the named compound, melting at temperatures ranging from 143 to 145oC.

Elemental analysis for C28H44O6:

Calculated: C - 70,56%, H - of 9.30%;

Found: C - 70,27%, H - 9,36%.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,34 is 4.45 (2H, multiplet);

4,55 with 4.65 (1H, multiplet);

vs. 5.47 (1H, broad singlet);

5,59 (1H, broad singlet);

of 5.89 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

6,01 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720.

Mass spectrum (m/e): 476 (M+), 459, 356, 321.

[]2D5+157,8< / BR>
Followed a methodology similar to that described in example 24, but used the 338 mg (0.5 mmol) of (4R,6R)-6{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,6 and Hexahydro - 6-tert-butyldimethylsilyloxy-8 hexanoate-2-methyl-1-naphthyl] ethyl} tetrahydro - 4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 10), getting a named connection, melting at a temperature of from 138 to 139oC.

Elemental analysis for C24H36O6:

Calculated: C - 68,55%, H - 8,63%;

Found: C - 68,34%, H - 8,67%.

Spec - and 4.68 (1H, multiplet);

5,42 (1H, broad singlet);

to 5.57 (1H, broad singlet);

5,90 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

6,00 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1250.

Mass spectrum (m/e): 420 (M+), 403, 321, 304.

[]2D5+189,6< / BR>
Followed a methodology similar to that described in example 24, but using 1.1 g (1.7 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8 isovalerianic-2-methyl-1-naphthyl] ethyl}-tetrahydro - 4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 11) to give 488 mg of the named compound, melting at temperatures ranging from 153 to 155oC.

Elemental analysis for C23H34O61/2H2O:

Calculated: C - 67,96%, H - 8.43 per cent,

Found: C - 67,31%, H - 8,30%.

Spectrum of nuclear magnetic resonance: (270 MHz, hexadeuterated dimethyl sulfoxide) , in ppm,

from 0.84 (3H, doublet, J = 6,9 Hz);

0,88 (6N, doublet, J = 6.3 Hz);

Android 4.04-4,10 (1H, multiplet);

4,10-4,16 (1H, multiplet);

4,43-4,50 (1H, multiplet);

of 4.77 (1H, doublet, J = 6.3 Hz, interchangeable with D2O);

5,16 (1H, doublet, J = 2,9 Hz, switching universal notebook J = 9,3 and 5.9 Hz);

5,96 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3350, 2880, 1725, 1250.

Mass spectrum (m/e): 406 (M+), 322, 304.

[]2D5+184,0< / BR>
Followed a methodology similar to that described in example 24, but used 571 mg (0,0 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8 pivaloyloxy-2-methyl-1-naphthyl] ethyl}tetrahydro - 4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 12), receiving 354 mg of the named compound, melting at temperatures ranging from 132 to 133oC.

Elemental analysis for C23H34O6:

Calculated: C - 67,96%, H - 8.43 per cent;

Found: C - 37,87%, H - 8,53%.

Spectrum of nuclear magnetic resonance: (270 MHz, hexadeuterated dimethyl sulfoxide) , in ppm,

of 0.85 (3H, doublet, J = 7.0 Hz);

1,10 (N, singlet);

4,08-to 4.15 (2H, multiplet);

4,46-4,50 (1H, multiplet);

4,78 (1H, doublet, J = 6.3 Hz, interchangeable with D2O);

of 5.17 (1H, broad singlet);

of 5.17 (1H, doublet, J = 3.3 Hz, interchangeable with D2O);

the 5.51 (1H, broad singlet);

of 5.84 (1H, doublet of doublets, J = 9.7 and 5.8 Hz);

5,97 (1H, doublet, J = 9.7 Hz).

max(with the/SUP>), 321, 304, 286.

[]2D5+179,0< / BR>
Followed a methodology similar to that described in example 24, but using 1.29 g (1.9 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,65,8, aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-(2,2-dimethylvaleric)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 13), getting 817 mg of the named compound, melting at temperatures ranging from 143 to 144oC.

Elemental analysis for C25H38O6:

Calculated: C - 69,10%, H - 8,81%;

Found: C - 68,86%, H - 8,91%.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

1,13 (6N, singlet);

4,32-4,43 (2H, multiplet);

4,54-of 4.66 (1H, multiplet);

to 5.35 (1H, broad singlet);

to 5.56 (1H, broad singlet);

5,90 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

6,01 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1160.

Mass spectrum (m/e): 434 (M+) 321, 304, 286.

[]2D5+170,5< / BR>
Followed a methodology similar to that described in example 24, but used 2,07 g (3.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyl is a (received as described above in example 14) to give 1.29 g of the named compound, melting at temperatures from 115 to 116oC.

Elemental analysis for C27H38O6:

Calculated: C - 70,72%, H - 8,35%;

Found: C - 70,48%, H - 8,46%.

Spectrum of nuclear magnetic resonance: (270 MHz, hexadeuterated dimethyl sulfoxide) , in ppm,

from 0.84 (3H, doublet, J = 6,9 Hz);

a 1.01 (3H, singlet);

4.09 to-4,11 (1H, multiplet);

4,15-4,18 (1H, multiplet);

4,45-4,50 (1H, multiplet);

rate 4.79 (1H, doublet, J = 6.0 Hz, interchangeable: D2O);

5,04-5,08 (4H, multiplet);

5,19 (1H, doublet, J = 3.2 Hz, interchangeable with D2O);

the 5.25 (1H, broad singlet);

of 5.50 (1H, broad singlet);

5,59-5,70 (2H, multiplet);

of 5.84 (1H, doublet of doublets, J = 9.5 and 5,9 Hz);

5,97 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1250.

Mass spectrum (m/e): 458 (M+), 422, 304, 286.

[]2D5+182,0< / BR>
Followed a methodology similar to that described in example 24, but used 956 mg (1.4 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-(2-methyl-2-propylvaleric)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-trainee, melting at temperatures of from 109 to 111oC.

Elemental analysis for C27H42O6H2O

Calculated: C - 67,61%, H - 8,83%;

Found: C - 67,65%, H - 8,79%.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) ppm;

4,35-and 4.40 (2H, multiplet);

4,57-4,63 (1H, multiplet);

of 5.40 (1H, broad singlet);

to 5.58 (1H, broad singlet);

5,90(1H, doublet of doublets, J = 9.7 and 5,9 Hz);

of 6.02 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1150.

Mass spectrum (m/e): 462 (M+), 444, 321, 304.

[]2D5+142,2< / BR>
Followed a methodology similar to that described in example 24, but used 184 mg (0.3 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro - 6-tert-butyldimethylsilyloxy-8-(2,2-diethylmaleate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 16), getting 97 mg of the named compound, melting at a temperature of from 130 to 131oC.

Elemental analysis for C27H42O6CH3COOC2H5:

Calculated: C - 67,60%, H is 9.15%,

Found: C - 67,32%, H - 9,10%.

Range of nuclear mA the doublets, J = 17,6 and 5.1 Hz);

4,35 was 4.42 (2H, multiplet);

4,56-4,63 (1H, multiplet);

5,44 (1H, broad singlet);

to 5.57 (1H, broad singlet);

of 5.89 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

6,01 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (KBr): 3350, 2950, 1720, 1700.

Mass spectrum (m/e): 462 (M+), 444, 321, 304.

[]2D5+140,4< / BR>
Followed a method similar to example 24, but using 190 mg (0.3 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 and Hexahydro-6-tert - butyldimethylsilyloxy-8-(2-isopropyl-3-methylbutoxy)-2-methyl-1-naphthyl] ethyl}tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 17), receiving 100 mg of the named compound, melting at temperatures from 210 to 211oC.

Elemental analysis for C26H40O6:

Calculated: C - to 69.61%, H - 8,99%;

Found: C - 69,35%, H - 9,04%.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

2,32 is 2.44 (2H, multiplet);

2,56-of 2.66 (2H, multiplet);

of 2.75 (1H, doublet of doublets, J = 17,6 and 5.1 Hz);

4,34-and 4.40 (1H, multiplet);

4,43-4,50 (1H, multiplet);

4,56 with 4.64 (1H, multiplet);

of 5.50 (1H, broad singlet);

to 5.57 (1H, broad) infrared absorption spectrum (CHCl3): 3450, 2950, 1720.

Mass spectrum (m/e): 448 (M+), 418, 321, 304.

[]2D5+172,6< / BR>
Followed a methodology similar to that described in example 24, but used 1,95 g (2.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-(2,2-diethyl-4-pentenoate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 18), receiving 1.04 g of the named compound, melting at temperatures ranging from 107 to 108oC.

Elemental analysis for C27H40O6CH2Cl2:

Calculated: C - 61,64%, H - 7,76%;

Found: C - 61,63%, H - 7,95%;

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in parts per million,

of 0.90 (3H, doublet, J = 7,1 Hz);

of 2.30 (2H, doublet, J = 7,3 Hz);

of 2.75 (1H, doublet of doublets, J = 17,6 and 5.1 Hz);

4,35 is 4.45 (2H, multiplet);

4,55 with 4.64 (H, multiplet);

5,03-5,12 (2H, multiplet);

the 5.45 (1H, broad singlet);

to 5.57 (1H, broad singlet);

5,57-5,69 (1H, multiplet);

5,90 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

6,01 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (KBr): 3340, 2970, 1720, 1690.

Mass spectrum (m/e): 460 (M+), 442, 321, 304.

Elemental analysis for C28H40O61/2H2O:

Calculated: C - 69,82%, H - 8,58%;

Found: C - 69,33%, H - 8,62%.

Spectrum of nuclear magnetic resonance: (270 MHz, hexadeuterated dimethyl sulfoxide), in ppm,

of 0.75 (3H, triplet, J = 7.4 Hz);

from 0.84 (3H, doublet, J = 6,8 Hz);

4.09 to-4,10 (1H, multiplet);

4,14-4,17 (1H, multiplet);

of 4.44-4,48 (1H, multiplet);

to 4.81 (1H, doublet, J = 6.2 Hz, interchangeable with D2O);

5,06-5,10 (4H, multiplet);

5,19 (1H, doublet, J = 3.1 Hz, interchangeable with D2O);

of 5.29 (1H, broad singlet);

of 5.50 (1H, broad singlet);

5,56-to 5.66 (2H, multiplet);

of 5.84 (1H, doublet of doublets, J = 9.7 and 5.8 Hz);

5,98 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (KBr): 3350, 2950, 1710, 1255, 1040.

Mass spectrum (m/e):

472 (M+), 321, 304, 286.

[]2D5+176,0< / BR>
Followed a methodology similar to that described in example 24, but used 267 mg (0.4 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR))-1,2,6,7,8,8 a-Hexahydro-6-tert - butyldimethylsilyloxy-8-(2,2-diallyl-4-pentenoate)-2-methyl-1-naphthyl] I 180 mg of the named compound, melting at temperatures of from 118 to 119oC.

Elemental analysis for C29H40O6:

Calculated: C - 71,87%, H - 8,32%;

Found: C - 71,84%, H - 8,29%.

Spectrum of nuclear magnetic resonance: (270 MHz, hexadeuterated dimethyl sulfoxide) , in ppm,

from 0.84 (3H, doublet, J = 7.0 Hz);

2,21 (6N, doublet, J = 7,3 Hz);

4,08-4,12 (1H, multiplet);

4,16-4,19 (1H, multiplet);

4,45 figure-4.49 (1H, multiplet);

4,80 (1H, doublet, J = 6.3 Hz, interchangeable with D2O);

5,06-5,10 (6N, multiplet);

5,20 (1H, doublet, J = 3.3 Hz, interchangeable D2O);

and 5.30 (1H, broad singlet);

the 5.51 (1H, broad singlet);

5,59-5,71 (3H, multiplet);

of 5.84 (1H, doublet of doublets, J = 9.7 and 5.8 Hz);

5,98 (1H, doublet, J = 9.7 Hz),

max(cm-1infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1220.

Mass spectrum (m/e): 484 (M+), 438, 304, 286.

[]2D5+204,0< / BR>
Followed a methodology similar to that described in example 24, but used 899 mg (2.0 mmol) of (4R,6R)-8-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro - 6-tert-butyldimethylsilyloxy-8-(2-ethyl-2-methylvalerate)-2-methyl-1 - naphthyl]ethyl}tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-she (received as described above in elementry analysis for C26H40O6:

Calculated: C - to 69.61%, H - 8,99%;

Found: C - 69,33%, H - Which 9.22%.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 1.07 (3H, singlet);

4,37-4,39 (2H, multiplet);

4,57-4,63 (1H, multiplet);

5,41 (1H, broad singlet);

to 5.57 (1H, broad singlet);

of 5.89 (1H, doublet of doublets, J = 9.7 and 5,9 Hz);

6,00 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3):

3400, 2950, 1720, 1150.

Mass spectrum (m/e):

448 (M+), 304, 286, 268,

[]2D5+171,2< / BR>
Followed a methodology similar to that described in example 28, but using 80 mg (0.12 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 and hexahydro-6-tert - butyldimethylsilyloxy-8-[(2S)-2-ethyl-2-methylvalerate-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 22)receiving 50 mg of the named compound, melting at 127oC.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 1.07 (3H, singlet);

4,37-4,39 (2H, multiplet);

4,57-4,63 (1H, multiplet);

5,41 (1H, broad singlet);

to 5.57 (1H, broad singlet);

of 5.89 (1H, doublet of doublets, J = (CHCl3): 3400, 2950, 1720, 1150.

Mass spectrum (m/e): 448 (M+).

[]2D5+167,0< / BR>
Followed a methodology similar to that described in example 24, but used to 1.16 g (1,72 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 and hexahydro-6-tert - butyldimethylsilyloxy-8-(2,2-dimethylhexanoic)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described above in example 23), getting 660 mg of the named compound.

Elemental analysis for C26H40O61/4H2O:

Calculated: C - 68,91%, H - 9,01%;

Found: C - 69,05%, H - 8,96%.

Spectrum of nuclear magnetic resonance: (400 MHz, hexadeuterated dimethyl sulfoxide) , in ppm,

from 0.84 (3H, doublet, J = 7.0 Hz);

of 0.85 (3H, triplet, J = 7.0 Hz);

1,06 (6N, singlet);

4,08-to 4.15 (2H, multiplet);

4,45 figure-4.49 (1H, multiplet);

rate 4.79 (1H, doublet, J = 6.0 Hz);

by 5.18 (1H, doublet, J = 3.6 Hz);

5,20 (1H, broad singlet);

of 5.50 (1H, broad singlet);

of 5.84 (1H, doublet of doublets, J = 9.7 and 6.0 Hz);

5,97 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1160.

Mass spectrum (m/e): 448 (M+), 304, 286, 268.

[]2D5+171,0 represents a sodium atom and R6represents a hydrogen atom. Each group W as defined in the following examples, joins the formula shown above, through the connection indicated by the letter Z.

Example 47. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy - 2-methyl-8-(3,3-dimethylbutyryl)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptanoic

< / BR>
Water (0.5 ml) was added to a solution of 32 mg (0,076 mmol) (4R,6R)-6-{2-[(1S, 2S, 6S,8S,8aR)-1,2,6,7,8,8 and hexahydro-6-hydroxy-8- (3,3-dimethylbutyryl)-2-methyl-1-naphthyl] ethyl} tetrahydro-4 - hydroxy-2H-Piran-2-it (obtained as described above in example 28) in 1 ml dioxane, then to the mixture was added 0.8 ml (0.08 mmol) of 0.1 G. of an aqueous solution of sodium hydroxide. The resulting mixture was stirred at room temperature for 30 minutes At the end of this time the reaction mixture was subjected to lyophilization, receiving 35 ml of these compounds in the form of colorless powder.

Example 48. Sodium (3R, 5R)-3,5-dihydroxy-7-{(1S,2S,6S,8S,8aR)-6-hydroxy - 2-methyl-8-(2-ethylbutyrate)-1,2,6,7,8,8 and hexahydro-1-naphthyl] heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 31 mg (0,074 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy - 8-(2-ethylbutyrate)-2-methyl who spent connection in the form of colorless powder.

Example 49. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy - 2-methyl-8-[(S)-2-methylvalerate] -1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 537 mg (1.28 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro - 6-hydroxy-8[(S)-2-methylvalerate-2-methyl-1-naphthyl] ethyl} tetrahydro-4 - hydroxy-2H-Piran-2-it (obtained as described above in example 26), getting 587 g of the named compound as a colorless powder.

Example 50. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy - 2-methyl-8-(2-propylvaleric)-1,2,6,7,8,8 a-hexahydro-1-naphthyl] heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 23 mg (0,051 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 and hexahydro-6-hydroxy-8- {2-propylvaleric)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H - Piran-2-it (obtained as described in example 27), receiving 25 mg of the named compound as a colorless powder.

Example 51. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy - 2-methyl-8-(2-ethyl-2-methylbutyrate)-1,2,6,7,8,8 a-hexahydro - 1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 22 mg (0,051 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexa is wow, as described in example 24), receiving 24 mg of the named compound as a colorless powder.

Example 52. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-3-(2,2 - diethylbutyl)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but used 215 mg (0.46 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2,2-diethylbutyl)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy - 2H-Piran-2-it (obtained as described in example 29), getting 234 mg of the named compound as a colorless powder.

Example 53. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-(2,2 - dimethyl-4-pentenoate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 23 mg (0,053 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2,2, -dimethyl-4-pentenoate)-2-methyl-1-naphthyl)ethyl}tetrahydro-4 - hydroxy-2H-Piran-2-it (obtained as described in example 30), receiving 26 mg of the named compound as a colorless powder.

Example 54. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2 - methyl-8-[2-allyl-4-pentenoate] -1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed mo-6-hydroxy - 8-(2-allyl-4-pentenoate)-2-methyl-1-naphthyl] ethyl}tetrahydro-4 - hydroxy-2H-Piran-2-she (received as described in example 31) to give 29 mg of the named compound as a colorless powder.

Example 55. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,85,8, aR)-7-hydroxy-2-methyl-3-(2 - butylacrylate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl] heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 22 mg (0.046 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8-(2 - butylphenoxy)-2-methyl-1-naphthyl] ethyl}tetrahydro-4-hydroxy-2H-Piran-2-it (obtained as described in example 32), receiving 24 mg of the named compound as a colorless powder.

Example 56. Sodium (3S, 5S)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2 - methyl-8-hexanoate-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 21 mg (0.50 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8 - hexanoate-2-methyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy-2H-Piran-2-it (obtained as described in example 33) to give 23 mg of the titled compound as a colorless powder.

Example 57. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-3 - isovalerianic-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in if a 1-naphthyl] ethyl}tetrahydro-4-hydroxy-Piran-2-she (received as described in example 34) and received 29 mg of the named compound as a colorless powder.

Example 58. Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S, 6S,8S,8aR)-6-hydroxy-2-methyl-8-pivaloyloxy-1,2,6,7,8,8 a-hexahydro-1 - naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 24 mg (to 0.060 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8 - pivaloyloxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H-Piran-2-it (obtained as described in example 35) to give 29 mg of the named compound as a colorless powder.

Example 59. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- (2,2-dimethylvaleric)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 27 mg (0,062 mmol) (4R,6R))-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2,2-dimethylvaleric)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy-2H - Piran-2-it (obtained as described in example 36), received 29 mg of the named compound as a colorless powder.

Example 60. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-(2 - allyl-2-methyl-4-pentenoate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed the methodology analogion(2-allyl-2-methyl-4-pentenoate)-2-methyl-1-naphthyl] ethyl} -tetrahydro-4 - hydroxy-2H-Piran-2-she received and, as described in example 37), received 30 mg of the named compound as a colorless powder.

Example 61. Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- (2-methyl-2-propylvaleric)-1,2,6,7,8,8 a-hexahydro-1-naphthyl heptanoate

< / BR>
Followed a methodology similar to that described in example 47, but using 22 mg (0,048 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2-methyl-2-propylvaleric)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy - 2H-Piran-2-it (obtained as described in example 38), received 24 mg of the named compound as a colorless powder.

Example 62. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- (2,2-diethylmaleate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 19 mg level (0.041 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2,2-diethylmaleate)-2-methyl-1-naphthyl]ethyl}tetrahydro-4 - hydroxy-2H-Piran-2-it (obtained as described in example 39), received 21 mg of the named compound as a colorless powder.

Example 63. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy - 2-methyl-8-(2-isopropyl-3-methylbutyrate)-1,2,6,7,8,8 a-hexahydro-1 - naphthyl]heptanoic

< / BR>
SL is hexahydro-6-hydroxy-8- (2-isopropyl-3-methylbutoxy)-2-methyl-1-naphthyl] ethyl}-tetrahydro-4 - hydroxy-2H-Piran-2-she (received as described in example 40), received 19 mg of the named compound as a colorless powder.

Example 64. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- (2,2-diethyl-4-pentenoate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 12 mg (0,026 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2,2-diethyl-4-pentenoate)-2-methyl-1-naphthyl} ethyl}tetrahydro-4 - hydroxy-2H-Piran-2-it (obtained as described in example 41), received 13 mg of the named compound as a colorless powder.

Example 65. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2 - methyl-8-(2-allyl-2-ethyl-4-pentenoate)-1,2,6,7,8,8 a-hexahydro-1 - naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 24 mg (0,051 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2-allyl-2-ethyl-4-pentenoate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4 - hydroxy-2H-Piran-2-it (obtained as described in example 42), received 25 mg of the named compound as a colorless powder.

Example 66. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- (2,2-diallyl-4-pentenoate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

<-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2,2-diallyl-4-pentenoate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4 - hydroxy-2H-Piran-2-she (received as described in example 43), received 25 mg of the named compound as a colorless powder.

Example 67. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- (2-ethyl-2-methylvalerate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 18 mg (0.040 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- (2-ethyl-2-methylvalerate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4 - hydroxy-2H-Piran-2-it (obtained as described in example 44), received 20 mg of the named compound as a colorless powder.

The method of example 67 may be applied using one of the stereoisomers obtained in example 44, as the starting material, to obtain the corresponding stereoisomer of the compound of example 67, as illustrated in example 68.

Example 68. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- [(2S)-2-ethyl-2-methylvalerate-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but used to 5.8 mg (0.012 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-8- [(2S)-2-ethyl-2-methylvalerate]-2-methyl-1-naphthyl}ethyl} -tetrahydro-4 - hydroxy-2H-Piran-2-it (p>/P>Example 69. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2 - methyl-8-[2,2-dimethylhexanoic)-1,2,6,7,8,8 a-hexahydro-1-naphthyl] heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 28 mg (0,062 mmol) (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-hydroxy-3- (2,2-dimethylhexanoic)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy - 2H-Piran-2-it (obtained as described in example 46), received 32 mg of the named compound as a colorless powder.

In each of the following examples 70 - 74 describes how to obtain the compounds of formula:

< / BR>
i.e. obtaining the compounds of formula (IV) in which R1represents a group of formula (III) and R6represents a hydrogen atom. Each group W as defined in the following examples, joins the formula shown above, through the connection indicated by the letter Z.

Example 70. (4R, 6R)-6-{ 2-[(1S, 2S,8S,8aR)-1,2,6,7,8,8 a-Hexahydro-8-[(S)-2 - methylvalerate] -2-methyl-1-naphthyl]ethyl}-tetrahydro-4-hydroxy-2H - Piran-2-he

< / BR>
70-(1) (4R, 6R)-6-{2-(1S,2S,8S,8aR)-1,2,6,7,8,8 a-Hexahydro-8- [(S)-2-methylvalerate] -2-methyl-1-naphthyl] ethyl} -tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it.

Followed a methodology similar to that described in example 4, but IP is utilimetrics-2H-Piran-2-she (received as described in Japanese patent application N Sho 59-175450) and 4.0 g (29.7 mmol) chloride (S)-2-methylvalerate, and obtained 12.2 g of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 1.12 (3H, doublet, J = 7,3 Hz);

4,27-4,30 (1H, multiplet);

4,54 with 4.64 (1H, multiplet);

5,32 (1H, broad singlet);

to 5.56 (1H, broad singlet);

of 5.75 (1H, doublet of doublets, J = 9,2 and 5.9 Hz);

5,98 (1H, doublet, J = 9,2 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080.

Mass spectrum (m/e): 519 (M++1), 477, 435, 387.

[]2D5+110,6in ppm;

of 1.12 (3H, doublet, J = 6,8 Hz);

4,35-and 4.40 (1H, multiplet);

4,56-of 4.66 (1H, multiplet);

5,33 (1H, broad singlet);

of 5.55 (1H, broad singlet);

5,74 (1H, doublet of doublets, J = 9,3 and 5.9 Hz);

5,98 (1H, doublet, J = 9,3 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1250, 1080.

Mass spectrum (m/e): 404 (M+), 270, 255, 229.

[]2D5+of 267.8< / BR>
71- (1) (4R, 6R)-6-{ 2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-Hexahydro-8-(2-ethyl-2 - methylbutyrate)-2-methyl-1-naphthyl] ethyl} -tetrahydro-4-tert - butyldimethylsilyloxy-2H-PI is{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-hydroxy-2 - methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-she (received as described in Japanese patent application N Sho 59-175450) and 1.4 g (9.4 mmol) chloride with 2-ethyl-2-methylbutyryl received 951 mg of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4.26 deaths-the 4.29 (1H, multiplet);

4,54-br4.61 (1H, multiplet);

5,31 (1H, broad singlet);

5,54 (1H, broad singlet);

5,73 (1H, doublet of doublets, J = 9.7 and 6.0 Hz);

5,98 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1150, 1080, 840.

Mass spectrum (m/e): 532 (M+), 402, 345, 327.

[]2D5+to 163.1in ppm,

0,81 (3H, triplet, J = 7.4 Hz);

of 0.83 (3H, triplet, J = 7.4 Hz);

of 0.90 (3H, doublet, J = 7,1 Hz);

of 1.06 (3H, singlet);

4,37 (1H, broad singlet);

4,57 with 4.64 (1H, multiplet);

of 5.34 (1H, broad singlet);

of 5.55 (1H, broad singlet);

5,74 (1H, doublet of doublets, J = 9.7 and 6.0 Hz);

of 5.99 (1H, doublet, J = 9.7 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 3450, 2950, 1720, 1250, 1150, 1080, 840.

Mass spectrum (m/e): 418 (M+), 400, 369, 288.

Elemental analysis for C25H38O5:

Calculated: C - 71,74%, H is 9.15%;

Found: C - 71,19%, H - 9,29%.

Followed a methodology similar to that described in example 3, but using 1.0 G (2.4 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-hydroxy-2 - methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described in Japanese patent application N Sho 59-175450) and 686 mg (4.8 mmol) of 2-propilvalerianovoy acid, was obtained 1.3 g of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,25-or 4.31 (1H, multiplet);

4,53-br4.61 (1H, multiplet);

to 5.35 (1H, broad singlet);

of 5.55 (1H, broad singlet);

5,74 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

5,96 (1H, doublet, J = 9.8 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2950, 1720, 1250, 1080, 838.

Mass spectrum (m/e): 546 (M+), 402, 345, 327.

[]2D5+116,3in ppm,

4,37 (1H, broad singlet);

4,57 with 4.64 (1H, multiplet);

5,38 (1H, broad singlet);

to 5.56 (1H, broad singlet);

of 5.75 (1H, doublet of doublets, J = 9.6 and 6.0 Hz);

5,97 (1H, doublet, J = 9.6 Hz).

max(cm-1) infrared absorption spectrum (KBr): 3450, 2950, 1720.

Mass spectrum (m/e): 432 (M+), 414, 368, 357.

Elemental analysis for CD5+223,3< / BR>
73- (1) (4R, 6R)-6-{ 2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-Hexahydro-8-(2,2 - diethylbutyl)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-he

Followed a method similar to example 8, but using 1.26 g (3.0 mmol) of (4R, 6R)-6-{ 2-[(1S,2S,8S,8aR)-1,2,6-7,8,8 a-hexahydro-8-hydroxy-2 - methyl-1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described in Japanese patent application N Sho 59-175450) and 2,22 g (to 13.6 mmol) chloride 2,2-diethylbutyl, received 800 mg of the named compound.

Spectrum of nuclear magnetic resonance: (400 MHz, CDCl3) , in ppm,

0,75 (N, triplet, J = 7.5 Hz);

1,56 (6N, Quartet, J = 7.5 Hz);

4.26 deaths-4,30 (1H, multiplet);

4,54-br4.61 (1H, multiplet);

of 5.34 (1H, broad singlet);

of 5.55 (1H, broad singlet);

5,74 (1H, doublet of doublets, J = 9.6 and 6.0 Hz);

5,98 (1H, doublet, J = 9.6 Hz).

max(cm-1) infrared absorption spectrum (CHCl3): 2875, 1715, 1255, 1080, 840.

Mass spectrum (m/e): 546 (M+), 489, 387, 345, 327.

[]2D5+to 185.0in ppm,

0,71 (N, triplet, J = 7.4 Hz);

from 0.84 (3H, doublet, J = 6,9 Hz);

1,48 (6N, Quartet, J = 7.4 Hz);

4,08-4,10 (1H, multiplet);

4,42-4,48 (1H, musyoki singlet);

5,74 (1H, doublet of doublets, J = 9.6 and 6.0 Hz);

5,95 (1H, doublet, J = 9.6 Hz);

max(cm-1) infrared absorption spectrum (CHCl3): 3350, 2880, 1710, 1220.

Mass spectrum (m/e): 432 (M+), 353, 288, 270, 210.

[]2D5+252,5< / BR>
74- (1) (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-Hexahydro-8- (2,2-diethyl-4-pentenoate)-2-methyl-1-naphthyl] ethyl} -tetrahydro-4-tert - butyldimethylsilyloxy-2H-Piran-2-it.

Followed a methodology similar to that described in example 6, but using 1.26 g (3.0 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-hydroxy-2-methyl - 1-naphthyl] ethyl} tetrahydro-4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described in Japanese patent application N Sho 59-175450) and 2,09 g chloride 2,2-diethyl-4-pentenol, received of 1.30 g of the named compound.

Spectrum of nuclear magnetic resonance: (400 MHz, CDCl3) , in ppm,

0,778 (3H, triplet, J = 7.4 Hz);

0,784 (3H, triplet, J = 7.4 Hz);

2,31 (2H, doublet, J = 7,2 Hz);

4,27-4,30 (1H, multiplet);

4,55-br4.61 (1H, multiplet);

5,01 - 5,09 (2H, multiplet);

are 5.36 (1H, broad singlet);

5,54 (1H, broad singlet);

5,59-5,69 (1H, multiplet);

5,74 (1H, doublet of doublets, J = 9.7 and 6.0 Hz);

5,98 (1H, doublet, J = 9.7 Hz),

max(see), 501, 387, 345, 327.

[]2D5+209,0in millions of shares

0,74 (6N, triplet, J = 7,3 Hz);

from 0.84 (3H, doublet, J = 7.0 Hz);

of 2.23 (2H, doublet, J = 7,3 Hz);

4,08-4,12 (1H, multiplet);

4,43-of 4.49 (1H, multiplet);

5,04-5,11 (2H, multiplet);

by 5.18 (1H, doublet, J = 3,4 Hz, interchangeable with D2O);

of 5.24 (1H, broad singlet);

5,54 (1H, broad singlet);

5,55-the 5.65 (1H, multiplet);

5,73 (1H, doublet of doublets, J = 9.6 and 6.0 Hz);

5,95 (1H, doublet, J = 9.6 Hz),

max(cm-1) infrared absorption spectrum (CHCl3): 3350, 2880, 1710, 1220.

Mass spectrum (m/e): 445 (M+), 427, 288, 270, 210.

[]2D5+259,0< / BR>
i.e. compounds of the formula (IV) in which R1represents a group of formula (II), R5represents a sodium atom and R6represents a hydrogen atom. Each group W as defined in the following examples, joins the formula shown above, through the connection indicated by the letter Z.

Example 75. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,8S,8aR,)-2-methyl-8-[(S)-2 - methylvalerate]-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 1.01 g (2.5 mmol) of (4R,6R)-6-{2-[(1S,2S,8S, as described in example 70) was obtained 1.12 g of the named compound as a colorless powder.

Example 76. Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,8S,8aR)-2-methyl-8-(2-ethyl-2 - methylbutyrate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 210 mg (0.50 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-(2-ethyl-2 - methylbutyrate)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy-2H-Piran-2-it (obtained as described in example 71), received 227 mg of the named compound as a colorless powder.

Example 77. Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,8S,8aR)-2-methyl-8-(2 - propylvaleric)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]-heptanoate.

< / BR>
Followed a methodology similar to that described in example 47, but using 200 mg (0.45 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-(2 - propylvaleric)-2-methyl-1-naphthyl] ethyl}tetrahydro-4-hydroxy - 2H-Piran-2-it (obtained as described in example 72), received 223 mg of the named compound as a colorless powder.

Example 78. Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,8S,8aR)-2-methyl-8-(2,2-diethylbutyl)- 1,2,6,7,8,8 a-hexahydro-1-naphthyl]-heptanoate

< / BR>
Followed a methodology similar to that described in example 47, but used is droxi-2H-Piran - 2-she (received as described in example 73) and received 22 mg of the named compound as a colorless powder.

Example 79. Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,8S,8aR)-2-methyl-8-(2,2-diethyl-4 - pentenoate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Followed a methodology similar to that described in example 47, but using 22 mg (0,043 mmol) (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-(2,2-diethyl-4 - pentenoate)-2-methyl-1-naphthyl] ethyl}tetrahydro-4-hydroxy-2H-Piran-2-it (obtained as described in example 74), received 23 mg of the titled compound as a colorless powder.

In each of the following examples 80 - 84 describes the formation of compounds of the following formula:

< / BR>
i.e., compounds of formula (I) in which R1represents a group of formula (II), R5represents a sodium atom and R6represents a hydrogen atom. Each group W as defined in the following examples, joins the formula shown above, through the connection indicated by the letter Z.

Example 80. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)- 2-methylvalerate] -1,2,6,7,8,8 a-hexahydro-1-naphthyl]heptanoic

< / BR>
Method 1. Each of the twenty Erlenmeyer flasks 500 ml, containing 100 ml per flask environments is melirovanie flasks were incubated for three days at 26oC on a rotating stirrer rotating at 200 rpm

Growing medium TS-C % (weight per volume):

Glucose - 1

Polypath (firm "Dago nutrition chemicals co.) - 0,2

Meat extract - 0,1

Yeast extract (Difco) - 0,1

Tap water up to 100

The pH was not regulated.

At the end of this time, 0.1 ml of a solution of (4R,6R)-6-{2-[(1S,2S,8S,8aR)- 1,2,6,7,8,8 a-hexahydro-8-[(S)-2-methylvalerate] -2-methyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy-2H-Piran-2-it (obtained as described in example 70) and dimethyl sulfoxide was added to each flask, resulting in a final concentration of compounds in the culture medium was 0.01% of (weight to volume). Cultivation was then continued for another 3 days in the above conditions.

At the end of this additional period of culture fermentation liquid was filtered, and the filtrate was adsorbing on a column containing 200 ml of resin diaion HP-20 (Mitsubishi Kasei Corporation"). The resin was then washed with 500 ml of distilled water, after which the fractions containing the titled compound was suirable column with 600 ml of 50% (by volume) aqueous solution of acetone. Eluate connected, and the resulting solution was concentrated until rouskas via preparative ODS column (ODS-H-5251 - This trade name material company "Sensu the scientific co. Ltd.) using as eluent a mixture of acetonitrile, water and acetic acid in a volume ratio 450:550:1. The chromatography was monitored by carrying out ultraviolet absorption at a wavelength of 237 nm. The pH value of the eluate was brought to 8.0 with an aqueous solution of sodium hydroxide, and the resulting mixture was concentrated until dry evaporation under reduced pressure. The residue then was dissolved in 20 ml of water, and the solution was adsorbing on a column containing 20 ml diaion HP-20TM. The resin was washed with 50 ml water, after which the resin was suirable 60 ml of 50% (by volume) aqueous solution of acetone, receiving 8 mg of essentially pure titled compound.

Method 2. One platinum loop of inoculum of Streptomyces carbophilus SANK 62585 (FERM BP-4128) was injected into the flask Erlenmeyer, 500 ml, containing 100 ml of medium SC, the composition of which is specified below. Inoculated flask was then incubated at 28oC on a rotary stirrer rotating at 200 rpm

Environment SC, %(weight per volume):

Yeast extract (firm "Difco") - 0,1

Polypath (firm "Dago nutrition chemicals co.) - 1,0

Glucose - 2,0

Tap water up to 100

The pH value was 7.0 (before sterilely in each of the twenty Erlenmeyer flasks 500 ml, containing 100 ml of medium SC in each flask, resulting in the concentration of the inoculated seed medium in fresh medium were 5.0% (weight to volume). This sizeincrement environment then incubated for three days under the conditions specified above.

At the end of the incubation period a certain amount of an aqueous solution of sodium (3R, 5R)-3,5-dihydroxy-7-[(1S, 2S,8S,8aR)-2-methyl-8-[(S)-2 - methylvalerate] -1,2,6,7,8,8 a-hexahydro-1-naphthyl] heptanoate (obtained as described in example 75) was added to the medium to final concentrations of the compounds in the solution of 0.01% (weight to volume). Cultivation then continued for three days under the conditions specified above.

At the end of the cultivation period of fermentation liquid was filtered, and the filtrate was adsorbing on a column containing 200 ml of resin diaion HP-20TM. The resin was washed with 300 ml of distilled water, after which the fractions containing the titled compound was suirable 400 ml of 50% (by volume) aqueous solution of acetone. The fractions obtained were combined, and the eluate was concentrated to dry by evaporation under reduced pressure. The residue is then purified by chromatography, passing the substance through a preparative ODS column (ODS-H-5251 "Selbyana ratio 450: 550: 1. The chromatography was monitored by carrying out ultraviolet absorbance at 237 mm

The pH value of the combined fractions containing the purified compound was then brought to 8.0 by addition of an aqueous sodium hydroxide solution, and the resulting mixture was concentrated to dry by evaporation under reduced pressure. The obtained residue was dissolved in 20 ml of water, after which the solution was adsorbing on a column containing 20 ml diaion HP-20. The resin was washed with 30 ml water and then suirable 100 ml of 50% (by volume) aqueous solution of acetone to give 10 mg of essentially pure titled compound.

It was shown that the physico-chemical properties of the compounds obtained in this way are identical to those of the compound obtained in the above example 49.

Example 81. Sodium (3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2 - methyl-8-(2-ethyl-2-methylbutyrate)-1,2,6,7,8,8 a-hexahydro - 1-naphthyl]heptanoic

< / BR>
One platinum loop of inoculum Amycolata autotrophica SANK 62981 (FERM BP-4105) was inoculable in an Erlenmeyer flask of 500 ml containing 100 ml of yeast medium MU, the composition of which is given below. Inoculated flask is incubated at 28oC on a rotating stirrer, bradauskas with a speed of 200 rpm

Dropko") - 0,3

Polypath (firm "Dago nutrition chemicals to.") - 0,5

Glucose - 1,0

Tap water up to 100

The value of pH of the environment is not regulated.

After incubation inoculated seed medium for three days, the seeding medium was divided and transferred in twenty Erlenmeyer flasks 500 ml, containing 100 ml of yeast medium MU in each flask, resulting in the concentration of the seed medium in fresh yeast medium MU was 0.5% (weight per volume). The flask is then incubated for two days under the conditions specified above.

At the end of the incubation period, a certain amount of an aqueous solution of sodium (3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 8S,8aR)-2-methyl-8-(2-ethyl-2 - methylbutyrate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl] heptanoate (obtained as described in example 76) was added to the liquid medium of cultivation, so that the final concentration of the compounds in solution was to 0.01% (weight to volume). Cultivation was then continued for a further five days under the conditions specified above.

At the end of the cultivation period of fermentation liquid was filtered, and the filtrate was subjected to adsorption on a column containing 200 ml diaion HP-20TM. Resin spray-what about the volume) aqueous solution of acetone.

The eluate was concentrated to dry by evaporation under reduced pressure, and the residue was then purified by chromatography, passing the substance through a preparative ODS column (ODS-H-5251 "Sensu the scientific co., Ltd.) using as eluent a mixture of acetonitrile, water and acetic acid in a volume ratio 450: 550:1. The chromatography was monitored by carrying out ultraviolet absorption at 237 nm. The pH value of the eluate obtained after chromatography was then brought to 8.0 with an aqueous solution of sodium hydroxide, after which the solution was concentrated until dry by evaporation under reduced pressure. The concentrate was dissolved in 20 ml of water, and the solution is then subjected to adsorption on a column containing 20 ml diaion HP-20TM. The resin was washed with 30 ml water and then suirable 100 ml of 50% (by volume) aqueous solution of acetone, getting 5.1 mg of essentially pure titled compound.

Method 2. One platinum loop of inoculum Mucor hiemalis Wehmer SANK 36372 (FERM BP-4108) was inoculable in each of the twenty Erlenmeyer flasks 500 ml, containing in each flask 100 ml of medium TS-C, and inoculated flasks were incubated at 26oC on a rotating stirrer speed of 200 rpm

After three days incubation at } tetrahydro-4-hydroxy-2H-Piran-2-she (received as described in example 70) in dimethyl sulfoxide was added to the medium, resulting in the final concentration of the compounds in the environment has become of 0.01% (weight to volume). Incubation was then continued for three days under the conditions specified above.

At the end of the incubation period, the fermentation liquid was filtered, and the filtrate was subjected to adsorption column containing 200 ml diaion HP-20TM. The resin was washed with 300 ml of distilled water, after which the fractions containing the named compound was suirable 400 ml of 50% (by volume) aqueous solution of acetone. The eluate was then concentrated to dry by evaporation under reduced pressure, and the concentrate was purified by chromatography, passing the substance through a preparative ODS column (ODS-H-5251TM"Sensu the scientific co. , "Ltd") using as eluent a mixture of acetonitrile, water and acetic acid in a volume ratio 450:550:1. The chromatography was monitored by carrying out ultraviolet absorbance at 237 nm. The pH value of the eluate is then brought up to a 3.0 by the addition of an aqueous sodium hydroxide solution, after which the solution was concentrated until dry by evaporation under reduced pressure. The concentrate was then dissolved in 20 ml of water, and the solution is believed to 100 ml of 50% (by volume) aqueous solution of acetone, receiving 48 mg of essentially pure titled compound.

Physico-chemical properties of these compounds are obtained in this way were identical to those of the compound obtained in example 51.

Method 3. One platinum loop of inoculum Syncephalastrum nigricans SANK 42372 (FERM BP-4106) used for insulinopenia 100 ml of medium TS-C in Erlenmeyer flask 500 ml of Inoculated medium is then incubated at 26oC on a rotating stirrer rotating at 200 rpm

After incubation under these conditions for a period of three days 0.1 ml of a solution of (4R, 6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8 and hexahydro-8-(2-ethyl-2 - methylbutyrate)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H - Piran-2-it (obtained as described in example 71) in dimethyl sulfoxide was added to the medium, resulting in the final concentration of the compounds in the environment has become equal to 0.01% (weight to volume). The cultivation was continued for 9 days under the conditions specified above.

At the end of this period of culture fermentation liquid was filtered, and the filtrate was subjected to adsorption on a column containing 200 ml diaion HP-20TM. The resin is then washed with 300 ml of distilled water, after which fractinal and then concentrated to dry by evaporation under reduced pressure. The obtained residue was purified by chromatography, passing the substance through a preparative ODS column (ODS-H-5251TM"Sensu the scientific co. , Ltd.) using as eluent a mixture of acetonitrile, water and acetic acid in a volume ratio 450: 550: 1. The chromatography was monitored by carrying out ultraviolet absorbance at 237 nm. The eluate obtained after carrying out chromatography, and then neutralized by mixing the eluate, without further purification, with 0.1 M aqueous solution (pH 8.0) sodium bicarbonate and sodium hydroxide. The pH of the fractions containing the titled compound, then drove up to 8.0 and the mixture was concentrated to dry by evaporation under reduced pressure. The obtained residue was dissolved in 20 ml of water, after which the solution was subjected to adsorption on a column containing 20 ml diaion HP-20TM. The resin was then washed with 30 ml of distilled water and was suirable 100 ml of 50% (by volume) aqueous solution of acetone, receiving and 24.1 mg of essentially pure titled compound.

Spectrum of nuclear magnetic resonance: (360 MHz, CD3OD) , in ppm,

of 0.35 to 0.92 (6N, multiplet);

to 0.92 (3H, doublet, J = 7,1 Hz);

1,15-1,74 (14N, multiplet);

of 1.76 (1H, multiplet);

of 1.92 (1H, double doublet of doublets, J plet);

5,33 (1H, multiplet);

the 5.65 (1H multiplet);

5,95 (1H, doublet of doublets, J = 9.7 and 6,1 Hz);

of 6.02 (1H, doublet, 1 = 9.7 Hz).

Molecular weight of 438 (according to mass spectrometry high-resolution fast atom bombardment defined as C26H41O7Na).

[]2D5+201,1< / BR>
Method 1. One platinum loop of inoculum Mucor hiemalis Wehmer SANK 36372 (FERM BP-4103) used for insulinopenia 100 ml of medium TS-C composition specified in example 30, in each of the twenty flasks Erlenmeyer, 500 ml Inoculated flasks were then incubated at 26oC on a rotating stirrer speed of 200 rpm

At the end of the third day of incubation, 0.1 ml of a solution of (4R,6R)-6-{2-[(1S,2S, 8S, 8aR)-1,2,6,7,8,8 a-hexahydro-8-(2 - propylvaleric)-2-methyl-1-naphthyl)ethyl} tetrahydro-4-hydroxy - 2H-Piran-2-it (obtained as described in example 72) in dimethyl sulfoxide was added to the medium to final concentrations of the compounds in the environment of 0.01% (weight to volume). Cultivation was then continued for three days under the conditions specified above.

At the end of this additional period of culture fermentation liquid was filtered, and the filtrate was subjected to adsorption on the column, with the s the name of the connection, was suirable 600 ml of 50% aqueous acetone solution (indicated volume concentration). The required fractions were then combined, then the combined eluate was concentrated to dry by evaporation under reduced pressure. The resulting residue was then purified by chromatography, passing the substance through a preparative ODS column (ODS-H-5251TM"Sensu the scientific co. , Ltd.) when used as an eluate mixture of acetonitrile, water and acetic acid in the ratio 450:550:1. The progress of the chromatography was monitored by ultraviolet absorption at 237 mm the pH of the eluate is then brought to 8.0 by addition of an aqueous sodium hydroxide solution, after which the mixture was concentrated to dryness by evaporation under reduced pressure. The residue was dissolved in 20 ml of water, and the resulting solution was subjected to adsorption on a column containing 20 ml diaion HP-20TM. The resin was washed with 50 ml water, after which the resin was suirable 60 ml of 50% (by volume) aqueous solution of acetone, receiving 48 mg of essentially pure titled compound.

Physico-chemical properties of the compounds obtained in this way are identical to the properties of the compounds synthesized in example 50.

Method 2. One platinum loop of inoculum Syncephalastrum racemosum (Cohn) Schroeter SANK hat flasks Erlenmeyer, 500 ml Inoculated flasks were then incubated at 26oC on a rotating stirrer speed of 200 rpm

After three days of incubation, 0.1 ml of a solution of (4R,6R)-6-{2- [(1S, 2S, 8S, 8aR)-1,2,6,7,8,8 a-hexahydro-8-(2-propylvaleric)-2 - methyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy-2H-Piran-2-it (obtained as described in example 72) in dimethyl sulfoxide was added to the medium to concentrations of specified compounds in the environment of 0.01% (weight to volume). Cultivation was then continued for another 7 days at 26oC on a rotating stirrer rotating at 200 rpm

At the end of this additional period of culture fermentation liquid was filtered, and the filtrate was subjected to adsorption on a column containing 200 ml diaion HP-20TM. The resin was washed with 300 ml of distilled water, after which the fractions containing the titled compound was suirable 600 ml of 50% (by volume) aqueous solution of acetone. Received eluate were combined and then concentrated to dryness by evaporation under reduced pressure. The obtained residue was purified by chromatography, passing the substance through the column preparative purposes with padding of ODS (ODS-H-5251TM"Sensu the scientific co., Ltd."), when used as ale the military conduct of the UV absorbance at 237 nm. The obtained eluate was neutralized by mixing without additional purification with 0.1 M aqueous solution of the secondary acid phosphate (pH 8), and sodium hydroxide. The pH of the fractions containing the titled compound was made according to 8.0, after which the mixture was concentrated to dryness by evaporation under reduced pressure. The obtained residue was dissolved in 20 ml of water, and the solution is then subjected to adsorption on a column containing 20 ml diaion HP-20TM. The resin was washed with 50 ml water and then suirable 100 ml of 50% (by volume) aqueous acetone, receiving 33 mg of essentially pure compounds.

Spectrum of nuclear magnetic resonance: (360 MHz, CD3OD) , in ppm,

0,83 (6N, triplet, J = 7.4 Hz);

of 0.91 (3H, doublet, J = 7,2 Hz):

of 1.07 (3H, singlet);

1,2-1,9 (11N, multiplet);

of 1.92 (1H, doubled doublet of doublets, J = 15,4, to 6.1 and 2.1 Hz).

of 2.2-2.5 (5H, multiplet):

of 3.69 (1H, multiplet);

4,10 (1H, multiplet);

to 4.28 (1H, multiplet);

at 5.27 (1H, multiplet);

5,64 (1H, multiplet);

5,94 (1H, doublet of doublets, J = 9.7 and 6,1 Hz);

of 6.02 (1H, doublet, J = 9.7 Hz).

Molecular weight 474 (C25H39O7Na according to mass spectrometry high-resolution fast atom bombardment).

[]2oC on a rotating stirrer speed of 200 rpm

At the end of the 3-day incubation period, 0.1 ml of a solution of (4R,6R)-6-{ 2-[(1S, 2S, 8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-(2,2 - diethylbutyl)-2-methyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy - 2H-Piran-2-it (obtained as described in example 73) in dimethyl sulfoxide was added to the medium to final concentrations of the compounds of 0.01% (weight to volume). Cultivation was then continued for another three days at 26oC on a rotating stirrer speed of 200 rpm

At the end of this time, the fermentation liquid was filtered, and the filtrate was subjected to adsorption on a column containing 200 ml diaion HP-20TM. The resin was washed with 500 ml of distilled water, and fractions containing the titled compound was suirable 800 ml of 50% (by volume) aqueous solution of acetone. The required fractions were combined and the resulting solution was concentrated to dryness by evaporation under reduced pressure. The residue was purified by chromatography, passing the substance through a preparative ODS column (ODS-H-5251TM"Sensu the scientific co., Ltd.) when using as eluent a mixture of acetonitrile, wodzie at 237 nm. The pH value of the eluate was then brought to 8.0 by addition of an aqueous sodium hydroxide solution, and the mixture is then concentrated to dryness by evaporation under reduced pressure. The residue was dissolved in 20 ml of water, and the solution was subjected to adsorption on a column containing 20 ml diaion HP-20TM, after which the resin was washed with 80 ml of water and then suirable 100 ml of 50% (by volume) aqueous solution of acetone, receiving 78 mg of essentially pure titled compound.

It was shown that the physico-chemical properties of the product are identical with those of the compound synthesized in example 52.

Method 2. One platinum loop of inoculum Syncephalastrum nigricans Vuillemin SANK 42372 (FERM BP-4106) used for insulinopenia 100 ml of medium TS-C (composition given in example 80), in each of the twenty flasks Erlenmeyer, 500 ml Inoculated flasks were then incubated at 26oC on a rotating stirrer rotating at 200 rpm

After three days of incubation under these conditions, 0.1 ml of a solution of (4R, 6R)-6-{ 2-[(1S, 2S, 8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-(2,2 - diethylbutyl)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H - Piran-2-it (obtained as described in example 73) in dimethyl sulfoxide was added to the medium so that the final concentration for a further five days.

At the end of this additional period of culture fermentation fluid were analyzed using high-speed liquid chromatography by passing the substance through the cartridge C18with padding of Nova-PakTM(Waters Inc.", Chuck size 8 to 100 mm). The column was suirable using a mixture of acetonitrile and 0.1% (weight per volume) of triethylamine (aqueous solution of phosphoric acid pH brought to 3.2), a flow rate of 1.5 ml/min a Named connection was suirable in the form of a fraction with a retention time of 6,38 minutes (the same compound obtained according to method 1 described above, erwerbende with a column in the form of a fraction with a retention time 5,13 min).

The fermentation broth was filtered, and the filtrate was subjected to adsorption on a column containing 200 ml diaion HP-20TM. The resin was washed with 300 ml of distilled water, and fractions containing the titled compound was suirable 800 ml of 50% (by volume) aqueous solution of acetone. The eluate was concentrated to dryness by evaporation under reduced pressure, and the concentrate was purified by chromatography with the transmission of matter through an ODS column (ODS-H-5251TM"Sensu the scientific co., Ltd. "when using as eluent a mixture of acetonitrile, water and the UKS the AI at 237 nm. The eluate was neutralized immediately mixing with 0.1 M aqueous solution of the secondary acid phosphate and sodium hydroxide (pH 8.0). The pH of the fractions containing the titled compound, then drove to 8.0, and then the fractions were concentrated to dryness by evaporation under reduced pressure. The resulting concentrate was then dissolved in 20 ml of water, and the solution was subjected to adsorption on a column containing 20 ml diaion HP-20TM. The resin was washed with 30 ml water and then suirable 100 ml of 50% (by volume) aqueous solution of acetone, receiving 68 mg of essentially pure form cleared field connection.

Spectrum of nuclear magnetic resonance: (270 MHz, CD3OD) , in ppm,

0,78 (N, triplet, J = 7.4 Hz);

of 0.91 (3H, doublet, J = 7.0 Hz);

1,2-1,9 (13H, multiplet);

of 1.94 (1H, doubled doublet of doublets, J = 15,5, 6,2 and 2.0 Hz);

of 2.2-2.5 (5H, multiplet);

3,68 (1H, multiplet);

4,07 (1H, multiplet);

to 4.28 (1H, multiplet);

and 5.30 (1H, multiplet);

5,63 (1H, multiplet);

5,94 (1H, doublet of doublets, J = 9.7 and 6,1 Hz);

of 6.02 (1H, doublet, J = 9.7 Hz).

Molecular weight 488 (C27H41O7Na, installed by the method of mass spectrometry high-resolution fast atom bombardment).

isovale for insulinopenia 100 ml yeast medium MU (the composition of which is specified above in example 81) in an Erlenmeyer flask of 500 ml. Inoculated flask was then incubated at 28oC on a rotating stirrer speed of 200 rpm

After three days of incubation under these conditions, part of the inoculated seed medium was transferred into each of the twenty Erlenmeyer flasks 500 ml, containing fresh yeast Wednesday MU, so that the final concentration of the seed medium in fresh medium was 0.5% (weight to volume). The flask is then further incubated at 28oC on a rotating stirrer rotating at 200 rpm

After two days of incubation under these conditions, the medium was added an aqueous solution of sodium (3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 8S,8aR)-2-methyl-8-(2,2-diethyl-4 - pentenoate)-1,2,6,7,8,8 a-hexahydro-1-naphthyl] heptanoate (obtained as described in example 79) so that the final concentration of the compounds in the environment amounted to 0.01% (weight to volume). Cultivation was then continued for 5 days under the conditions specified previously.

At the end of this period of culture fermentation liquid was filtered, and the filtrate was subjected to adsorption on a column containing 200 ml diaion HP-20TM. The resin was washed with 300 ml of distilled water, after which the fractions containing named the Yali, and the combined eluate was concentrated, dryness by evaporation under reduced pressure. The obtained residue was purified by chromatography, passing the substance through a preparative ODS column (ODS-H-5251TM"Sensu the scientific co., Ltd.) when using as eluent a mixture of acetonitrile, water and acetic acid in a volume ratio 450:550:1. The progress of the chromatography was monitored by ultraviolet absorption at 237 nm. The pH value of the eluate was brought to 8.0, was added aqueous sodium hydroxide solution, and the resulting mixture was concentrated to dryness by evaporation under reduced pressure. The obtained residue was dissolved in 50 ml of water, and the solution is then subjected to adsorption on a column containing 20 ml diaion HP-20TM. The resin was washed with 100 ml of distilled water and then was suirable 300 ml of 50% (by volume) aqueous solution of acetone, receiving 28 mg of essentially pure titled compound.

It was shown that the physico-chemical properties of the compounds obtained in this way are identical to those of the compound synthesized in example 64.

Example 85. (4R, 6R)-6-{ 2-[(1S, 2S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-8-[(S)-2 - methylvalerate] -2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H-Piran-2-he

< / BR>
Acetonitrile prowess of the th chromatography on stage 2 synthesis of 1, below) by evaporation under reduced pressure using a rotary evaporator. The resulting concentrate was extracted twice with ethyl acetate each in the amount of half the volume of the concentrate. The extracts were combined and then concentrated by evaporation under reduced pressure, obtaining of 5.2 g of oily substance. This substance is then processed in one of two ways.

1. The oily substance obtained in this way was dissolved in 20 ml of acetonitrile. The resulting solution of 2 ml was then injected in ODS-a column (inner diameter 30 mm and length 300 mm; firm "Wye-Em-es, Inc. "with the gasket on the UMC-S-346-15 S-15TM. The column was then subjected to elution and elution was effected in the form of mobile phase using 70% (weight per volume) aqueous acetonitrile at a flow rate of 10 ml/min, and the progress of the elution was monitored using a Refractometer. Eluate with a retention time ranging from 51 to 54 min was collected.

Part of the eluate, obtained above, was purified liquid chromatography high performance, passing the substance through the Chuck with radial-PakTM(8 NVC 184, inner diameter 8 mm 10 is at a flow rate of 2.0 ml/min The required fractions were characterized by UV absorbance at 236 nm. The required fraction had a retention time of 4.7 minutes

Under the conditions specified above, the retention time of the compound obtained in synthesis 1, was 3.6 minutes

The above-described chromatographic purification process was then repeated ten times to obtain fractions with a retention time of 3.6 minutes Eluate obtained in the course of conducting this additional purification were combined and the mixture is then concentrated to dryness by evaporation under reduced pressure using a rotary evaporator, receiving 30 mg of the named compound as a crude product.

II. Alternative metol oily substance obtained above was dissolved in 1.5 ml of acetonitrile, and the solution was then injected into preparative column (ODS-5251-STM, inner diameter 20 mm, 250 mm, Sensu the scientific co., Ltd."). The column was suirable using as mobile phase of 70% (weight to volume) of an aqueous solution of acetonitrile at a flow rate of 5 ml/min Eluate with a retention time of from 33 to 37 min was collected, and the progress of the elution was monitored via Refractometer.

Received eluate collected and provided add is 0 minutes The mixture is then filtered through filter paper, and bleached the filtrate was concentrated to dryness by evaporation under reduced pressure using a rotary evaporator, receiving 13 mg of essentially pure titled compound.

Mass spectrum (m/e 404 (M+).

Molecular formula: C24H36O5.

max(nm) (E1%1ultraviolet spectrum (ethanol): 236,5 (576).

Range nuclear (carbon-13 magnetic resonance (90 MHz, CDCl3) , ppm (as internal standard tetramethylsilane was used; the signal from the deuterated chloroform was detected at 70,0 million shares): 170,3; 176,9; 132,6; 133,6; 128,1; 123,6; 76,2; 67,6; 62,61; 20,90; 38,61; 36,20; 39,94; 37,51; 36,89; 26,19; 33,03; 35,92; 30,9; 24,0; 20,6; 17,4; 13,9; 13,9.

In the spectrum of nuclear magnetic resonance in nuclei of carbon-13 signal was watched 24 carbon atoms in accordance with the data of mass-spectral analysis.

Range nuclear (hydrogen-1) magnetic resonance (360 MHz, CDCl3) , in ppm: 5,88; 5,98; 5,51; 3,68; 5,36; 4,10; 4,29; 2,34; 2,24; 1,53; 1,57; 2,45; 2,37; 1,67; 1,59; 2,48; 1,35; 1,54; 1,22; 1,55; 2,42; 1,32 (each, 1H); 1,12; 0,92; 0,91 (each, 3H).

max(cm-1infrared spectrum (KBr): 3513, 1741, 1700, 1234, 1180.

oC for 30 minutes At the end of this time was added to a mixture of 10 ml of water and the pH of the mixture was brought to 8.5 by the addition of 0.1 G. of an aqueous solution of sodium chloride. The resulting mixture was then adsorbing on a column containing 5 ml diaion HP-20TM. The resin was washed with 20 ml water and then suirable 60% (weight to volume) aqueous solution of acetone. The obtained eluate was concentrated by evaporation under reduced pressure using a rotary evaporator and the concentrate was subjected to lyophilization, receiving of 9.8 mg of the named compound.

Molecular weight: 444 (according to mass spectrometry with fast atom bombardment).

Molecular formula: C24H37O6. Na (installed by the method of mass spectrometry high-resolution fast atom bombardment).

max(nm) UV spectrum (H2O): 237,4.

Range nuclear (carbon-13 magnetic resonance (90 MHz, CD3OD) ppm (as internal standard tetramethylsilane was used; sihouette with the molecular formula), 180,5; 178,5; 135,4; 133,9; 129,3; 124,1; 71,8; 69,4; 69,4; 45,4; 45,2; 41,2; 38,8; 38,5; 37,2; 35,8; 32,1; 27,1; 25,6; 21,9; 21,6; 17,9; 14,4; 14,1.

Range nuclear (hydrogen-1) magnetic resonance (360 MHz, CD3OD) ppm, 5,9; 5,7; 5,5; 5,3; 4,1; 3,7; 3,3 (each, 1H); 1,1 (3H); 0,9 (6N).

max(cm-1infrared spectrum (KBr): 3385, 2936, 1728, 1578, 1409, 1085, 836.

[]2D5+180< / BR>
One platinum loop of inoculum of Streptomyces carbophilus SANK 62585 (FERM BP-4128) used for insulinopenia 100 ml of medium SC (the composition of which is specified in the above example 80) in an Erlenmeyer flask of 500 ml, and inoculated flask is incubated at 28oC on a rotating stirrer rotating at 200 rpm

After a three-day incubation period, a portion of the inoculated seed medium was transferred to each of the five Erlenmeyer flasks 500 ml, containing 100 ml of fresh medium SC, so that the concentration of the seed medium in fresh medium were 5.0% (weight per volume). The flasks are then incubated at 28oC on a rotating stirrer rotating at 200 rpm

After three days incubation aqueous solution of 100 mg of sodium (3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 8S, 8aR)-2-methyl-8-[(S)-2-methylvalerate] - 1,2,6,7,8,8 a-hexahydro-1-naphthas is the acidity of the compounds in the environment were 0.02% (weight per volume). Cultivation was then continued for three days under the conditions specified above.

At the end of this additional period of culture fermentation liquid was subjected to centrifugation for 10 min at a speed of 3000 rpm for separating a mixture of mycelium and supernatant. 400 ml of the supernatant liquid was removed, and the pH of the liquid was brought to 6 by addition of an appropriate quantity 2 N. aqueous sodium hydroxide solution. The mixture was subjected to adsorption on a column containing 20 ml diaion HP-20TM(Mitsubishi Kasei Corporation"). The resin was washed with 200 ml of distilled water and then was suirable 20 ml of 20% (by volume) aqueous solution of methanol, 20 ml of 40% (by volume) aqueous solution of methanol, and 40 ml of 80% (by volume) aqueous solution of methanol in this order.

Fractions that were loirevalley 40% (by volume) aqueous solution of methanol and 60% (by volume) aqueous solution of methanol were combined and then concentrated to dryness by evaporation under reduced pressure using a rotary evaporator, receiving 50 mg of the named compound as a crude product.

The crude product was purified by chromatography, passing the substance through a column of microbond is anola, water and acetic acid in a volume ratio 550:450:1 at a feed rate of eluent 3 ml/min Over the course of the elution was monitored using a differential Refractometer. The fraction with a retention time of the 13 min was collected.

the pH of the collected fractions was brought to 9 by adding the appropriate 2 N. aqueous sodium hydroxide solution, and the methanol was removed from the mixture by distillation under reduced pressure using a rotary evaporator. The pH of the residue was brought to 8, and the mixture was subjected to adsorption on a column containing 2 ml diaion HP-20TM. The resin was washed with 10 ml of distilled water and then was suirable 20 ml of 60% (weight to volume) of an aqueous solution of methanol.

The obtained eluate was concentrated by evaporation under reduced pressure, and then subjected to lyophilization, gaining 3.4 mg of essentially pure titled compound.

Molecular weight according to mass spectrometry with fast atom bombardment) (M+H)+:

Found: 461,2524;

Calculated: 461,2515.

Molecular formula: C24H37O7Na (determined by the method of mass spectrometry with fast atom bombardment).

max(nm) (E1%1ultraviolet spectrum (H2

Range nuclear (hydrogen-1) magnetic resonance (360 MHz, CD3OD) ppm: 5,88; 5,98; 5,51; 3,68; 5,36; 4,10; 4,29; 2,34; 2,24; 1,53; 1,57; 2,45; 2,37; 1,67; 1,58; 2,48; 1,35; 1,54; 1,22; 1,55; 2,42 (each, 1H); 1.32 TO (2H); 1,12; 0,92; 0,91 (each, 3H).

max(cm-1) infrared spectrum (KBr): 3391, 2960, 2935; 1728, 1400, 1181, 1043, 855.

[]2D5+130< / BR>
1. Growing

Medium for seed culture:

The glycerol to 30 grams

Glucose - 30 grams

Soy flour - 20 g

Mikuni town-peptone - 8 g ("Mikuni town chemical industries co., Ltd.)

Sodium nitrate 2 g

Magnesium sulfate 1 g

Tap water (pH 6,0 - 6,5) - up to 1000 ml

The medium for growing the seed culture in a quantity of 50 ml (composition described above) were loaded into the flask Erlenmeyer, 500 ml and was kept in an autoclave at 120oC for 30 min before inequilibrium microorganism. One platinum loop of the original culture of Penicillium citrinum Thom SANK 13380 (FERM BP-4129) on the sloped agar aseptically transferred into the flask containing the medium. Inoculated flask is incubated at 24oC for three days at rotec the water for growing seed crops, was then placed in an autoclave and kept at 120oC for 30 min, after which he inoculable all quantity (about 50 ml) of fermentation liquid obtained as described above. The flask is incubated for two days at 24oC on a rotating stirrer rotating at a speed of 210 rpm, receiving a second generation of culture.

The following environment was used in the subsequent production of these compounds.

Producing environment with culture (I).

Sufficient water was added to 150 g of glycerol and 600 g of liquid Sanmalt "Sanwa cornstarch industry, Ltd.) to bring the total solution volume to 5 L. the Environment (I) then sterilized in the autoclave for 30 min at 120oC.

Producing environment with culture (2). Mixing the following components.

Soy flour - 300 g

Mikuni town-peptone (firm "Mikuni town chemical industries co., Ltd.) - 150 grams

As CS (firm "Ment Corporation) 300 g

Gluten (the firm "Nihon shokuhin cocoa co., Ltd.) - 150 grams

Magnesium sulfate - 15 g

the pH was set from 6.0 to 6.5 by adding 10% (weight by volume) aqueous solution of sodium hydroxide, and then the total volume was brought to 10 liters by adding vodoprivredu A.

Tap water was added to a mixture of 1600 g of glycerin and 6400 g sanmati S (firm Sanwa cornstarch industry, Ltd.) and then the mixture was heated to a temperature above 90oC. After complete dissolution of sanmati S to the solution was added water, bringing the volume up to 10 litres of the Solution is then treated in an autoclave at 120oC for 30 minutes

Recharge environment Century.

Wednesday sunnix PP 2000 ("the Dignity chemical industries Ltd.) in the amount of 600 ml was treated in an autoclave at 120oC for 30 minutes

5 l medium and 10 l medium 2 was treated in the autoclave and then loaded into a cylindrical fermenter stainless steel 30 l to obtain a culture of the second generation.

All contents of the Erlenmeyer flask (approximately 700 ml) containing culture of the second generation, obtained as described above was then used to insulinopenia processed in the autoclave environment intended for use with the producing culture and located in the cylindrical fermenter. The fermenter was incubated at 24oC in terms of mixing with automatically maintaining the speed within the range from 260 to 500 rpm; aeration produced by air flow with a flow rate of 7.5 l/min and pressure modillion.

In the period from the third to the sixth day after completion of incubation 150 ml fueling environment B was added to the medium cultivation once a day (just added 4 times). After the sugar concentration was less than 1%, started to continuously add fueling environment to maintain A pH of liquid medium is about 4.

After 14 days produced a collection of cells obtained liquid medium.

2. Selection.

The pH of a liquid medium grown (40 l), and drove up to 12, was added 800 ml of 6 N. aqueous sodium hydroxide solution, and the resulting mixture was stirred for 60 min at room temperature. At the end of this time the liquid medium was mixed with 1.5 kg SelidovUgol filter material (Celite 545 N; trade name of product of the company "Jonze-Manville products Corp."), and the mixture was stirred. The resulting mixture was filtered by passing through a filter press, receiving the filtrate.

850 ml of 6 N. aqueous hydrochloric acid was carefully added to the filtrate, and the pH of the mixture was brought to 5.0. 80 l of ethyl acetate was added to the obtained solution, and the mixture was stirred for extraction of the desired product. The organic layer was separated, and the aqueous layer was treated with 40 l of ethyl acetate and stirred, extrai is) aqueous solution of sodium bicarbonate. The aqueous layer was separated, and the organic layer was again extracted with 3% (weight to volume) aqueous solution of sodium bicarbonate.

1600 ml N. aqueous hydrochloric acid was carefully added to the combined aqueous extracts, and the pH of the mixture was brought to 5.0. Ethyl acetate (20 l) was added to the obtained mixture, and the mixture was stirred extragere the desired product. The organic layer was separated and the aqueous layer was treated with 10 l of ethyl acetate and stirred for extraction of the desired product. United an ethyl acetate extracts washed with 15 l of 10% (weight by volume) aqueous solution of sodium chloride. The extract is then dried over 3000 g of anhydrous sodium sulfate, and the solvent was removed by evaporation to dryness under reduced pressure using a rotary evaporator, to receive oily residue.

This oily residue was dissolved in 1000 ml of ethyl acetate. To the solution was added 0.5 ml triperoxonane acid, and the mixture was heated under conditions of reflux distilled for 30 min under reflux. The contents were cooled to 10oC and then washed twice with 500 ml portions of 3% (weight to volume) aqueous solution of sodium bicarbonate, and once washed with 800 ml of 10% (weight by volume) water restoy and filtered. The filtrate was freed from solvent by evaporation to dryness under reduced pressure using a rotary evaporator, receiving 50 g of oily residue.

All oily residue was dissolved in 500 ml of acetonitrile and the resulting solution was divided into five parts. Each portion was purified by chromatography, passing the substance through ODS-reverse-phase column (ODS-1050-20SR; 10 cm inner diameter), 50 cm, 15-30 μm (particle size); ("Kurita, Kogyo co., Ltd. "). The column was suirable 70% (by volume) aqueous solution of acetonitrile used as mobile phase, at a flow rate of 200 ml/min Fraction, extracted from the column was monitored by UV absorption, and on the basis of the detected peaks were collected fractions, retention time which was between 30 and 36 minutes

The purity of these fractions was evaluated by carrying out liquid chromatography high resolution, passing the substance through a column (ODS-262; "Sensu the scientific co., Ltd.) when using as mobile phase of 70% (by volume) aqueous solution of methanol at a flow rate of 1.0 ml/min; fractions was monitored by ultraviolet absorbance at 236 nm. The fraction with a retention time of 11 min was characterized by the presence of only have poboltali to retrieve connection synthesized in example 85.

Faction, the retention time of which chromatography with reversed-phase column was in the range from 30 to 36 min, was subjected to concentration by distillation under reduced pressure using a rotary evaporator for distillation of acetonitrile. The concentrate was extracted twice half the volume (the volume of concentrate) of ethyl acetate. An ethyl acetate extracts were combined and concentrated by evaporation to dryness under reduced pressure, obtaining 30 g of oily residue.

The oily substance was rubbed with a mixture of ethanol with water to initiate crystallization. Received 17 g of the named compound as colorless crystals.

Physico-chemical properties of this compound are known and are identical to the properties described in Japanese patent publication N Sho-56-12114 (patent UK N 1453425) and in other literature.

Synthesis of 2. Obtaining the sodium salt of pravastatin.

Flask Erlenmeyer, 500 ml, containing 100 ml of yeast medium MU, intended for cultivation, the composition of which is given in example 61 was inoculable platinum loop of the original culture Amycolota autotrophica SANK 62981 (FERM BP-4105) with beveled agar. Kolb is day twenty Erlenmeyer flasks 500 ml, containing 100 ml of yeast medium MU for growing crops, the composition specified in example 81 was inoculable seed culture, in the amount of 0.5% of the content of the flask. The culture is then incubated at 28oC on a rotating stirrer speed of 200 rpm after two days aqueous solution of sodium salt of compound ML-236B was added to a final concentration of 0.1% sodium salt and the mixture is incubated at 28oC on a rotating stirrer rotating at 200 rpm for 5 days.

At the end of this time, the fermentation liquid was filtered, and the filtrate was subjected to absorption of 200 ml of non-ionic resin diaion HP-20. The resin was washed with 300 ml of distilled water, and fractions containing the titled compound was suirable 800 ml of 50% (by volume) aqueous solution of acetone.

The eluate was concentrated by evaporation to dryness under reduced pressure, and the concentrate was purified by chromatography, passing the substance through a preparative ODS column (ODS-H-5251) using as eluent a mixture of acetonitrile, water and acetic acid in a volume ratio 460:520:1; fractions were monitored by measuring the UV absorbance at 237 nm. The desired fractions were collected, and the pH brought on the pressure. The concentrate was dissolved in 50 ml of water, and the resulting aqueous solution was treated with 50 ml diaion HP-20. The resin was washed with 100 ml of distilled water and then was suirable 200 ml of 50% (by volume) aqueous solution of acetone, getting 618 mg of the named compound.

Physico-chemical properties are known and are identical to the properties described in Japanese patent publication N Sho 61-13699 (patent UK N 2077264) and in other literature.

Synthesis of 3. (4R, 6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-Hexahydro-6-tert - butyldimethylsilyloxy-8-(2,2,3,3-tetramethylcyclopropanecarboxylate)- 2-methyl-1-naphthyl]ethyl}tetrahydro-4-threedimensionally-2H-Piran-2-it.

Followed a methodology similar to that described in example 4, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-6-tert - butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl] ethyl}tetrahydro - 4-tert-butyldimethylsilyloxy-2H-Piran-2-it (obtained as described in example B) and (1,17 g chloride, 2,2,3,3,-tetramethylcyclopropanecarboxylate, getting 833 mg of the named compound.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

4,24-the 4.29 (1H, multiplet);

4,30-of 4.49 (1H, multiplet);

4,56-4,63 (1H, multiplet);

5,41 (1H, broad singlet);

CSOs spectrum (CHCl3): 2950, 1720, 1250, 1080, 840.

Mass spectrum (m/e): 674 (M+), 659, 617, 532.

[]2D5+104,81/2H2O:

Calculated: C - 68,54%, H - to 8.41%;

Found: C - 68,65%, H At 8.60%.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 0.91 (3H, doublet, J = 7,3 Hz);

to 1.15 (3H, singlet);

of 1.17 (3H, singlet);

to 1.22 (3H, singlet);

to 1.24 (3H, singlet);

2,93-3,03 (1H, multiplet);

4,35-4,50 (1H, multiplet);

4,56-and 4.68 (1H, multiplet);

of 5.39 (1H, broad singlet);

5,59 (1H, broad singlet);

5,90 (1H, doublet of doublets, J = 9,8 and 5.9 Hz);

6,01 (1H , doublet, J = 9,3 Hz).

max(cm-1) infrared spectrum (CHCl3): 3450, 2950, 1720, 1180.

Mass spectrum (m/e): 446 (M+), 423, 321, 304.

[]2D5+EUR 188.4in ppm,

5,9 (1H, doublet);

of 5.75 (1H, doublet of doublets);

of 5.55 (1H, broad singlet);

the 4.7 (1H, multiplet);

of 4.35 (1H, multiplet);

of 4.25 (1H, multiplet);

0,9 (2H, doublet).

Range nuclear (carbon-13 magnetic resonance (90 MHz, CDCl3) , in ppm: 171,3; 133,4; 128,4; 123,7; 76,4; 64,4; 62,5; 38,8; 38,5; 36,4; 36,1; 32,7; 30,8; 29,2; 23,8; 20,4; 13,9.

In the following syntheses of 6 - 18 described for various Stere is according to the following reaction scheme (PL.10).

Synthesis of 6. (+)-(2S)-1,2-Dimethyl-2-phenyl-1-Cyclopentanol (compound 2).

A catalytic amount of iodine was added to a suspension of 5.24 g (216 mmol) of magnesium in 30 ml of dry diethyl simple ether with stirring in a stream of nitrogen. Then dropwise within one hour to a mixture solution was added 13.4 ml (216 mmol) iodotope bromide in 180 ml of diethyl ether. The mixture then was stirred for 20 minutes At the end of this time, to the mixture was added dropwise a solution 3,76 g (21.6 mmol) of (+)-(2S)-2-methyl-2-vinylcyclopentane (compound 1) (optical enantiomeric purity was 95%), synthesized by the method of Koga (Koga) and other (Chemical and Pharmaceutical Bulletin (Japan) 27, 2760 (1979)), in 30 ml of diethyl ether for 10 minutes the resulting mixture was then heated under reflux for 2 hours At the end of this time the reaction mixture was cooled with ice, and then to the mixture for 20 min was added dropwise to 250 ml of a saturated aqueous solution of ammonium chloride. The mixture was then diluted with 100 ml of water and the resulting aqueous mixture was extracted twice with 100 ml of ethyl acetate. The extracts were combined, washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation p is x diastereoisomers. The product, consisting of two diastereoisomers, can be used directly in subsequent reactions, i.e., without separation of stereoisomers. Pale yellow oily liquid was purified flash column-chromatography by passing through silica gel using as eluent a mixture of hexane and ethyl acetate in a volume ratio of 5:1 and received 863 mg (yield 21%) of product as a pale yellow oil from the less polar fractions.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 1.26 (3H, singlet);

of 1.32 (3H, singlet);

1,60-2,10 (6N, multiplet; 1H able to share with D2O);

2,69 is 2.80 (1H, multiplet);

7,22-7,53 (5H, multiplet).

max(cm-1) infrared spectrum (CHCl3): 3350, 2950, 1730, 1500, 1440, 1380, 1140, 700.

Mass spectrum (m/e): 190 (M+).

[]2D5+39,5in ppm,

of 0.93 (3H, singlet);

to 1.38 (3H, singlet);

1,70-1,97 (6N, multiplet, 1H able to share with D2O);

2,25-of 2.36 (1H, multiplet);

7,17-7,46 (5H, multiplet);

max(cm-1) infrared spectrum (CHCl3): 3350, 2950, 1730, 1600, 1500, 1370, 1100, 1050, 700.

Mass spectrum (m/e): 190 (M+).

[]2D
2,30-2,39 (2H, multiplet);

of 5.53 (1H, singlet);

7,16-7,34 (5H, multiplet);

max(cm-1) infrared spectrum (CHCl3): 2950, 1600, 1490, 1440, 1370, 1020, 700.

Mass spectrum (m/e): 172 (M+).

[]2D5+95,8in ppm,

1,26 to 1.47 (2H, multiplet);

of 1.50 (3H, singlet);

of 1.92 (3H, singlet);

1,92 is 2.00 (2H, multiplet);

3,24 (3H, singlet);

3,30 (3H, singlet);

4,32 (1H, triplet, J = 5,9 Hz);

7,20-7,39 (5H, multiplet).

max(cm-1) infrared spectrum (CHCl3): 2950, 1700, 1440, 1350, 1120.

Mass spectrum (m/e): 249 (M+-1).

[]2D5+61,1in ppm,

is 1.51 (3H, singlet);

of 1.93 (3H, singlet);

2,15 is 2.33 (4H, multiplet);

7,20-7,41 (5H, multiplet);

to 9.66 (1H, singlet).

max(cm-1) infrared spectrum (CHCl3): 1720, 1600, 1350.

Mass spectrum (m/e): 203 (M+-1).

[]2D5+61,1in ppm,

1,08-1,19 (1H, multiplet);

of 1.12 (3H, doublet, J = 6.5 Hz);

of 1.31 (3H, singlet);

1,34-1,49 (1H, multiplet);

1,54-of 1.62 (3H, multiplet; 2H able to share with D2O);

1,90 of 1.99 (1H, multiplet);

of 3.56 (2H, triplet, J = 6.5 Hz);

a 3.87 (1H, kvar is 0, 2950, 1380, 1260, 1150, 1130, 1100, 700.

Mass spectrum (m/e): 209 (M++ 1).

Elemental analysis for C13H20O2:

Calculated: C - 74,96%, H - 9,68%;

Found: C - 74,75%, H - 9,65%.

[]2D5-4,1in ppm,

of 0.96 (3H, doublet, J = 6.4 Hz);

1,16-of 1.27 (1H, multiplet);

of 1.32 (3H, singlet);

1,38-of 1.55 (3H, multiplet; 2H can share with D2O);

1,71 - to 1.79 (1H, multiplet);

1,82-2,02 (1H, multiplet);

to 3.58 (2H, triplet, J = 6.5 Hz);

a 3.87 (1H, Quartet, J = 6.4 Hz);

7,19-7,38 (5H, multiplet).

max(cm-1) infrared spectrum (CHCl3): 3650, 3450, 2950, 1380, 1150, 700.

Mass spectrum (m/e 209 (M++ 1).

Elemental analysis for C13H20O2:

Calculated: C - 74,96%, H - 9,66%.

Found: C - 74,70%, H - 9,63%.

[]2D5-10,9in ppm,

0,97 (1,2 H, doublet, J = 6.6 Hz);

1,12 (1,8 H, doublet, J = 6.6 Hz);

1,30-of 1.52 (1H, multiplet);

1,34 (1,6 H, singlet);

1,35 (1,2 H, singlet);

1,54 is 1.75 (2H, multiplet; 1H able to share with D2O);

1,80 is 1.91 (1H, multiplet);

2,03-2,12 (1H, multiplet);

3,82-3,91 (1H, multiplet);

4,21-4,27 (2H, multiplet);

7,22-to 7.59 (8H, multiplet);

8,02 (2H, doublet, J = 7.9 Hz).

++ 1).

Synthesis of 12. (-)-(4S)-5-tert-Butyldimethylsilyloxy-4-phenyl-4-methyl-1-hexanol (compound 8).

The imidazole (4,88 g (70,8 mmol), and then 8,02 g (53,1 mmol) chloride tert-butyldimethylsilyl was added in a stream of nitrogen to a solution 5,54 g (about 17.7 mmol) of a mixture of two diastereoisomeric compounds (-)-(8S)-6-benzyloxy-3-phenyl-3-methyl-2-hexanol (obtained as described in synthesis 11) in 20 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 15 hours At the end of this time the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate is diluted with 400 ml of water. The diluted solution was extracted twice, each time with 300 ml of ethyl acetate. The extracts were combined, washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure and obtained a colorless oil. This substance consists of two diastereoisomers originating from the source connection. 53 ml of 1 N. aqueous sodium hydroxide solution was added to a solution of 3.03 g of the above diastereoisomeric mixture in 250 ml of ethanol, and the resulting mixture was stirred at 60oC for 2.5 hours At the end of this time the reaction sstor was extracted twice, each time with 300 ml of ethyl acetate, the extracts were combined, washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, obtaining a colorless oily residue. This residue was purified instant column chromatography, passing through silica gel using as eluent a mixture of hexane with ethylacetate, in the ratio of 4:1 and received lower than the 5.37 g (yield 94%) of the named compound, consisting of two diastereoisomers in the form of a colorless oil.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

0,00-0,10 (6H, multiplet);

0,80 (1,8 H, doublet, J = 6.4 Hz);

of 0.90 (9H, singlet);

0,97 (1,2 H, doublet, J = 6.5 Hz);

of 1.03-1.14 in (1H, multiplet);

1.26 in (1,2 H, singlet);

1,28 (1,8 H, singlet);

1,32-of 1.55 (2H, multiplet; 1H able to share with D2O);

1,72-of 1.84 (2H, multiplet);

3,49 is 3.57 (2H, multiplet);

3,79 (0,4 H, Quartet, J = 6.4 Hz);

3,90 (0,6 H, Quartet, J = 6.4 Hz);

7,14-7,33 (5H, multiplet).

max(cm-1) infrared spectrum (CHCl3): 3650, 2950, 1250, 1150, 1090, 640.

Mass spectrum (m/e) was as follows: 321 (M+-1).

Synthesis of 13. (-)-(3S)-2-tert-butyldimethylsilyloxy,8 mmol) iodotope bromide was added to the solution lower than the 5.37 g (of 16.6 mmol) of a mixture of two diastereoisomers (-)-(4S)-5-tert-butyldimethylsilyloxy-4-phenyl-4-methyl-1-hexanol (received as described above in the synthesis of 12) and 8,73 g (a 33.2 mmol) of triphenylphosphine in 70 ml of dry tetrahydrofuran under ice cooling in a stream of nitrogen, and the resulting mixture was stirred at room temperature for one hour. At the end of this time of 2.18 g (8.3 mmol) of triphenylphosphine was added to the mixture, and the mixture was cooled with ice. Diethylazodicarboxylate (2,62 ml of 16.6 mmol) and 1.55 ml (range 43.8 mmol) iodotope bromide was then added to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes At the end of this time the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was purified instant chromatography, passing through silica gel, using as eluent hexane, receiving of 6.29 g (yield 67%) of the named compound, consisting of two diastereoisomers, in the form of a colorless oil.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

-0,22 (1,8 H, singlet);

-0,04 (1,3 H, singlet);

0,04 (1,2 H, singlet);

0,05 (1,2 H, singlet);

0,79 (1,2 H, doublet, J = 5,9 Hz);

0,82 (5,4 H, singlet);

0,92 (3,6 H, singlet);

0,95 (1,8 H, doublet, J = 5,9 Hz);

1,25 (1,2 H, singlet);

1,28 (1,8 H, singlet);

1,28-1,40 (1H, multiplet);

1,54 - of 1.65 (1H, multiplet);

1,74 - 2,10,16 - to 7.32 (5H, multiplet).

max(cm-1) infrared spectrum (CHCl3): 2950, 1250, 1100, 980, 840, 700.

Mass spectrum (m/e): 431 (M+-1).

Synthesis of 14. (-)-(3S)-2-Hydroxy-3-phenyl-3-methylhexan (compound 10).

The anti-hydride (19.2 ml, 71,0 mmol) and 3.51 g (21,3 mmol) azobisisobutyronitrile was added in a stream of nitrogen to a solution 6,16 g (of 14.2 mmol) of a mixture of two diastereoisomers(-)-(35)-2-tert-butyldimethylsilyloxy-3-phenyl-3-methyl-6-hodgekin (obtained as described in synthesis (13) in 80 ml of toluene, and the resulting mixture was stirred at 80oC for one hour. At the end of this time the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was purified instant column chromatography, passing through silica gel, using as eluent hexane. The product, thus obtained, was dissolved in 200 ml of acetonitrile, after which 20 ml of 46% (weight to volume) aqueous solution of hydrogen fluoride was added to the mixture, which was then stirred at room temperature for 4 h In the end of this time the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was mixed with 300 ml of water. The aqueous mixture then was extracted twice, then dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and colorless oily residue was purified instant column chromatography, passing through silica gel using as eluent a mixture of hexane with ethyl acetate at a volume ratio of 4: 1, receiving 2,84 g (yield 65%) of the named compound (consisting of two diastereoisomers) as a colourless oil.

Spectrum of nuclear magnetic resonance: (270 MHz, CDCl3) , in ppm,

of 0.82 to 0.97 (6N, multiplet);

1,10-1,21 (1H, multiplet);

1,29 (1,6 H, singlet);

1,31 (1,2 H, singlet);

1,35-of 1.93 (4H, multiplet; 1H can share with D2O);

3,83-to 3.92 (1H, multiplet);

7,22-7,41 (5H, multiplet).

max(cm-1) infrared spectrum (CHCl3):

3600, 2950, 1100, 700.

Mass spectrum (m/e) 177 (M+-15).

Synthesis of 15. (+)-(3S)-3-phenyl-3-methyl-2-hexanol (compound 11).

A solution of 1.86 ml (26,2 mmol) of dimethyl sulfoxide in 5 ml of methylene chloride was added dropwise over 5 min in a stream of nitrogen and at a temperature of -78oC to a solution of 1.43 ml (16.4 mmol) of chloride oxalyl in 25 ml of dry methylene chloride, and the resulting mixture was stirred at -78oC for 10 minutes At the end of this time rasna in the synthesis of 14) in 10 ml of dry methylene chloride was added to the mixture dropwise over 5 minutes The mixture obtained in this way was stirred at -78oC for 15 min, and then to the mixture dropwise over 5 min was added to 7.0 ml (50 mmol) of triethylamine. The mixture was then stirred at -78oC for 20 min, after which the mixture was stirred at 0oC for one hour and then mixed with 50 ml of water. The aqueous mixture was extracted three times, each time with 100 ml of ethyl acetate. The extracts were combined, washed first with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained colorless oily residue was purified instant column chromatography, passing through silica gel using as eluent a mixture of hexane with ethyl acetate in a volume ratio of 20:1 and received at 1.91 g (yield 92%) of the named compound as a colourless oil.

Spectrum of nuclear magnetic resonance:

(270 MHz, CDCl3) , in ppm,

of 0.91 (3H, triplet, J = 7,3 Hz);

1,03-of 1.93 (2H, multiplet);

of 1.46 (3H, singlet);

1,87-of 1.93 (2H, multiplet);

1,89 (3H, singlet);

7,22-7,34 (5H, multiplet).

max(cm-1) infer the>
5+49,8in ppm,

from 0.88 to 0.94 (4H, multiplet);

1,12-of 1.28 (1H, multiplet);

of 1.66 (3H, singlet);

of 1.74 (3H, singlet);

1,76-1,82 (1H, multiplet);

1,95 e 2.06 (1H, multiplet);

2,41-2,50 (1H, multiplet);

2,58-to 2.67 (2H, multiplet);

2,86-of 3.00 (2H, multiplet);

of 7.23-7,33 (3H, multiplet);

7,46 (2H, doublet, J = 7,3 Hz).

max(cm-1) infrared spectrum (CHCl3): 2950, 1450, 1270, 700.

Mass spectrum (m/e): 280 (M+).

[]2D5-7,4in ppm,

of 0.66 (3H, triplet, J = 7,3 Hz);

0,81 (3H, triplet, J = 7,3 Hz);

0,85-1,05 (2H, multiplet);

1,09-1,22 (1H, multiplet);

of 1.26 (3H, singlet);

1,43-of 1.78 (3H, multiplet);

7,15-to 7.18 (1H, multiplet);

7,28-7,33 (4H, multiplet),

max(cm-1IR spectrum (CHCl3): 2950, 1600, 1500, 1460, 1380, 700.

Mass spectrum (m/e): 176 (M+).

[]2D5-7,5in ppm,

0,87 - (3H, triplet, J = 7,3 Hz);

of 0.91 (3H, triplet, J = 7,3 Hz);

of 1.12 (3H, singlet);

1,16-1,78 (6N, multiplet);

3,40-4,20 (1H, multiplet, able to communicate with D2O).

max(cm-1) infrared spectrum (CHCl3): 3000, 2950, 1700, 1440, 1120.

Mass spectrum (m/ = 6.9 Hz),

1,23 1,35 (2H, m)

1,37 1,49 (1H, m),

4,07 to 4.14 (1H, m),

4,49 4,43 (1H, m),

the 5.45 (1H, broad singlet),

5,59 (1H, broad singlet),

6,04 (1H, doublet of doublets, J = 9.7 Hz and 5.7 Hz),

6,10 (1H, d, J = 9.7 Hz).

1. Hexahydronaphthalen ester compounds of formula I

< / BR>
in which R1a group of the formula II or III

< / BR>
R5a hydrogen atom;

Rathe hydroxy-group;

R6aa hydrogen atom or hidroxizina group

and/or

(a) R2ethyl group;

R3an alkyl group having from 1 to 4 carbon atoms, or Alchemilla group having from 2 to 6 carbon atoms;

R4an alkyl group having from 2 to 4 carbon atoms;

(b) R2Alchemilla group having from 2 to 6 carbon atoms, or

R1through the group;

R3a hydrogen atom;

R4through the group, or

(C) R2bucilina group;

R3methyl group;

R4methyl group,

and its pharmaceutically acceptable salts.

2. Connection on p. 1, in which

R2ethyl group;

R3an alkyl group having from 1 to 4 carbon atoms, or allyl group;

R4an alkyl group a group of the formula II.

4. Connection on p. 3 in which R6athe hydrogen atom.

5. Connection on p. 1, in which

R2ethyl group;

R3an alkyl group having from 1 to 3 carbon atoms;

R4an alkyl group having 2 or 3 carbon atoms.

6. Connection on p. 5, in which R1a group of the formula II.

7. Connection on p. 6, in which R6athe hydrogen atom.

8. Connection on p. 1, selected from

(3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR)- 6-hydroxy-2-methyl-8-(2-propylpentanoate)-1,2,6,7,8,8 and hexahydro-1-naphthyl] heptane acid;

(3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR)-6-hydroxy-2-methyl-8-(2,2-dimethylhexanoic)-1,2,6,7,8,8 and hexahydro-1-naphthyl] heptane acid;

(3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR)-6-hydroxy-2-methyl-8-(2-ethyl-2-methylpentanoate)- 1,2,6,7,8,8 and hexahydro-1-naphthyl] heptane acid;

(3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR)-6-hydroxy-2-methyl-8- (2-ethyl-2-methylbutyrate)-1,2,6,7,8 and hexahydro-1-naphthyl] heptane acid;

(3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR)-6-hydroxy-2-methyl-8-(2,2-diethylbutyl)- 1,2,6,7,8,8 and hexahydro-1-naphthyl] heptane acid;

(3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR)-6-hydroxy-2-methyl-8- (2,2-diethyl-4-pentenoate)-1,2,6,7,8,8 and hexahydroxy)-1,2,6,7,8,8 and hexahydro-1-naphthyl]heptane acid,

and its pharmaceutically acceptable salts.

9. The pharmaceutical composition inhibiting cholesterol biosynthesis comprising the active ingredient and pharmaceutically acceptable carrier or diluent, wherein the active ingredient is used as a compound of formula I under item 1 or its pharmaceutically acceptable salt in an effective amount.

 

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The invention relates to derivatives of 2,4-dichlorophenoxyacetic (2,4-D) and 4-chlorophenoxyacetic (4-chlorthal) acids, in particular fatty esters and alkoxy-substituted alcohols, as herbicides and plant growth regulators

The invention relates to a derivative propanoic acid, exhibiting fungicidal activity and to methods for their preparation

The invention relates to the field of acids, in particular to a method for producing derivatives of propanolol acid of General formula

and their stereoisomers, where A is hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, phenoxy or1-C4-alkylsulphonyl; It represents oxygen or sulfur; X IS O, S(O)n, NH, NR1: CH2, CHR2, CO, CH2CH2CH = CH, OCH2, (CH2)mO, CHR1O, OCH2O, S(O)nCH2, S(O)CH2O, NR1CH2, COO, OOC, SO2O COCH2O, COCHR1O, CONH, NHCO, NHSO2COS, SCO, N = N, CH2OCO, CH2SCO, CH2NHCO, CH2ON = CH2, OCH2CH2O, NR1N = CH, CH2OCON, CH = CHCH2O, (R2)2P+CH2Q-, N(COR1), N = CH, CH(OH), CO2CH2, SCH2O, NR1CO, S(O)2NH or CONR1; R1- C1-C4-alkyl; R2is phenyl; n is 0,1 or 2; m - 1,2,3,4, or 5; Q is a halide anion; Z is phenyl (possibly monosubstituted WITH1-C6-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, phenoxy,

by phenyl, amino, hydroxy, 1-(C1-C4-alkoxycarbonyl is, or mono - or disubstituted by halogen, nitro, C1-C4-alkyl or cyano; naphthyl, chinoline, pyridinyl (possibly monosubstituted WITH1-C4-alkyl, C1-C4-alkoxycarbonyl, amino, halogen, nitro, C1-C4-alkylcarboxylic, di-(C1-C4-alkylsulfonyl)amino, or CH(O)NH, or mono - or disubstituted WITH1-C4-haloalkyl or cyano, or a disubstituted amino group and one from cyano, halogen or1-C4-alkoxygroup or disubstituted by nitro-group and one of cyano, halogen, di-(C1-C4-alkyl)amino or1-C4-alkoxygroup or substituted by cyano and two WITH1-C4-alkyl groups); pyrimidinyl (possibly: monosubstituted WITH1-C4-alkyl, C1-C4-haloalkyl,1-C4-alkylthio, cyano, nitro, phenyl, HO2C1-C4-alkoxycarbonyl or1-C4-alkylsulfonyl, or mono - or disubstituted WITH1-C4-alkoxy, or mono-, di - or tizamidine halogen, or disubstituted by halogen and one from C1-4alkyl or C1-4alkylthio, or disubstituted WITH1-4alkyl and C1-4haloalkyl), pyrazinyl (possibly mannose is hydrated WITH1-C4-alkoxy, phenyl or aminocarbonyl, or mono - or disubstituted by halogen, or disubstituted by halogen and C1-C4-alkyl), benzothiazolyl, thienyl (possibly monosubstituted by pyrazolyl), which itself Disaese1-C4the alkyl and C1-C4-haloalkyl (or pyridinyl), which itself may monogamist nitro (or disubstituted by halogen), 1,2,4-triazolyl, honokalani (monosubstituted by halogen), 1,3,5-triazinyl (disubstituted by halogen, or disubstituted by halogen and C1-C4-alkoxy), thiazolyl (possibly monosubstituted nitro or mono-or disubstituted WITH1-C4-alkyl), benzoxazolyl, pyridinyl-N-oxide, thieno[2,3-d] pyrimidinyl, pyrrolyl (possibly monosubstituted WITH1-C4-alkyl), isoxazolyl (monosubstituted WITH1-C4-alkyl), 1,3,4,-thiadiazole, pyrazolyl (substituted with halogen and two WITH1-C4-alkyl groups) or 1,2,4-triazinyl (monosubstituted with phenyl); provided that, when Z represents unsubstituted phenyl, and X and both represent oxygen, then A is not hydrogen; which possess fungicidal activity

FIELD: veterinary.

SUBSTANCE: medication includes the following components, wt %: Sulfadimezinum 11.5-15; Trimethoprim 2.0-3.6; Colistin 2.0-3.5; glucose up to 100. Before application the medication is dissolved in warm water or colostrums at 35-37°C or fed with forage. The medication is applied daily twice in the dosage of 100 mg/kg of body weight for 3-5 days, or for 5-7 days under severe course of disease.

EFFECT: enhanced efficiency of colibacteriosis treatment for form animals.

12 tbl, 4 ex

FIELD: medicine, cosmetology.

SUBSTANCE: one should apply acid composition onto patient's skin scar, moreover, this composition consists of the following ratio of components, weight%: alpha-hydroacid 0.1-70; gamma-lactone of 2,3-dehydro-L-gulonic acid 0.1-10; 1,2,3-propanetriol 1-10; strontium nitrate 0.5-10, water - the rest. Moreover, for steady penetration of this composition for desired depth against scars and surrounding skin one should treat them with alcoholic solution of beta-hydroxyacid for 3-7 d, and for improved regeneration one should lubricate it with an ointment supplemented with hydroxyacid for 7 d.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to compositions used for treatment and/or prophylaxis of chlamydium infections caused by C. pheumoniae. Pharmaceutical composition used for treatment and/or prophylaxis of chlamydium infection caused by C. pneumoniae comprises the taken phenolic compound, or extract, or fraction, or incomplete fraction comprising the taken phenolic compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction obtained from plants and comprising indicated compound or corresponding synthetic compound on C. pneumoniae represents the definite percent of inhibition for formation of inclusions. The composition useful for health eliciting an anti-chlamydium effect with respect to C. pneumoniae comprises the taken phenolic compound or extract, or fraction, or incomplete fraction containing indicated compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent for inhibition in formation of inclusions. Also, invention relates to applying the composition useful for health in preparing foodstuffs or as supplements for nutrition for every day. Also, invention relates to applying phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound or mixture of indicated compounds obtained from plants in manufacturing a medicinal agent used for treatment and/or prophylaxis of chlamydium infections caused by C. pneumoniae. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent in inhibition in formation of inclusions. Compositions promote to effective prophylaxis and treatment of chlamydium infections caused by C. pneumoniae.

EFFECT: valuable medicinal properties of compounds.

21 cl, 1 dwg, 1 tbl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises a medicine orlistat and sucrose fatty acid ester wherein fatty acid moiety in fatty acid di-, tri- or tetra-ester means a mixture of two or some fatty acids. Also, invention relates to a method for treatment of obesity by using the claimed composition. Invention provides enhancing effectiveness of treatment.

EFFECT: enhanced and valuable properties of composition.

36 cl, 5 dwg, 7 tbl, 19 ex

FIELD: pharmacy, chemical technology.

SUBSTANCE: invention relates to methods for preparing simvastatin of high purity degree from lovastatin by the following stages: (a) opening lactone ring in addition of lovastatin in reaction with amine for formation of amide; (b) protection of 1,3-diol moiety by a protecting group; (c) removal of 2-methylbutyryl group joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining of 2,2-dimethylbutyrate group by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and lactone ring closure resulting to formation of simvastatin. Semi-synthetic statin is prepared from statin by carrying out the following steps: (a) opening lactone ring by reaction of statin with amine resulting to formation of amide; (b) protection of 1,3-diol moiety by using the protecting group; (c) removal of group R1 joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining group R2 by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and (g) lactone ring closure with formation of semi-synthetic statin. Invention provides enhancing purity degree of the product.

EFFECT: improved preparing methods of statins.

17 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of discodermolid and its analogs of the formula (V): At the first step method involves the coupling reaction of ketone compound of the formula (I): with aldehyde compound of the formula (II): in the presence of dialkylboron halide or triphlate, amine base and polar organic solvent to yield β-hydroxyketone of the formula (III): at the second step method involves reduction of ketone compound synthesized at the first step by its treatment with boron hydride reagent in polar organic solvent medium and proton solvent to yield 1,3-diol of the formula (IV): at the third step method involves lactonization and removal of free acid-labile hydroxyl protective group of 1,3-diol synthesized at the second step by its treatment with hydrogen halide dissolved in polar solvent or mixture of solvents to yield the end compound of the formula (V) wherein R1 means (C1-C6)-alkyl; R2 means (C1-C6)-alkyl; R3 means hydrogen atom or acid-labile hydroxyl protective group; R3'' means acid-labile hydroxyl protective group; R4 means hydrogen atom or methyl group; X means oxygen atom (O) under condition that when X means O and R3 means acid-labile hydroxyl protective group of compound of the formula (I) then residue -X-R3 in compound of the formula (V) represents hydroxyl group (-OH). Also, invention relates to novel intermediate compounds of formulae (I), (III) and (IV) and to a method for synthesis of compound of the formula (I). Invention provides a new method for synthesis of the valuable compound discodermolid and its analogs with the satisfied yields.

EFFECT: improved method of synthesis.

16 cl, 4 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

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

8 cl, 1 tbl, 18 ex

FIELD: pharmacology, in particular composition and methods for obesity treatment.

SUBSTANCE: claimed composition contains lipase inhibitor, namely orlistat and koniac or glucomannan and pharmaceutically acceptable excipients.

EFFECT: composition preventing gastrointestinal disturbances associated with administration of lipase inhibitor orlistat.

35 cl, 10 ex, 3 dwg

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the general formula (I) wherein R1 and R2 mean independently of on another hydrogen atom (H) or fluorine atom (F); R3 means -CH3 or -CF3 ; Ar means structural formulae (a) or (b) Invention relates also to a pharmaceutical composition possessing the modulating activity with respect to progesterone receptor and containing compound of the formula (I), adjuvants, carriers and excipents. Compounds of the formula (I) are used in preparing a medicinal agent designated for selective modulation of processes in organ-targets mediated by progesterone receptor, such as uterus/breast and for selective activation of transcription of progesterone receptor isoform A as compared with transcription of progesterone receptor isoform B, selective enhancing processes mediated by progesterone receptor isoform A as compared with processes mediated by progesterone receptor isoform B and as a contraceptive. Invention provides a compound using as a medicinal agent in hormone-substitution therapy and for control of reproductive function.

EFFECT: valuable medicinal and biological properties of compound and pharmaceutical composition.

45 cl, 4 dwg, 5 tbl, 6 ex

FIELD: medicine, experimental cardiology.

SUBSTANCE: the present innovation deals with restricting the necrosis area in the course of experimental coronary occlusion myocardial infarction due to intragastric introduction of roxytromycin at the dosage of 30 mg/kg 15 min before coronary occlusion. The innovation provides significant decrease of the necrosis area due to cardioprotector action of roxytromycin.

EFFECT: higher efficiency.

1 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

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