Pharmaceutical composition, derived triterpene

 

(57) Abstract:

The invention relates to pharmaceutical compositions inhibiting necrosis of hepatocytes derived triterpene General formula I, where R1- OH, C1-6alkoxy, C1-6alkylcarboxylic or benzyloxy, R2- C1-6alkyl, CH2OR SIG5where R5- H1-6alkyl, benzyl or1-6alkylsulphonyl, formyl, R6where R6- H, or C1-6alkyl, or-CH2N(R7R8where R7and R8the same or different, is H or C1-6alkyl, or R1and R2together form-O-(CR9(R10)-OCH2- where R9and R10the same or different, is H, or C1-6alkyl, or phenyl; R3and R4the same or different, is H, HE, C1-6alkyl, hydroxy1-6alkyl, formyl, -R11where R11- N or or12where R12- C1-6alkyl, benzyl,1-6alkylsulphonyl, phenylcarbinol,2-6alkenyl,2-6alkenylboronic or phenylacetylcarbinol, or R3and R4together form =CH2or =O-group; means simple or double bond, provided that when is a double bond, R4no. Compounds have a t is, 1 PL.

The invention relates to a derivative of triterpene used as therapeutic agents in the treatment of liver diseases.

The liver is an important organ that performs a variety of functions necessary to maintain the life of the organism, such as detoxification, various types of exchange and accumulation of substances. However, it often suffers from acute or chronic damage caused by viruses, drugs, alcohol, and other various reasons. This causes viral hepatitis induced by drugs hepatopathy, alcohol hepatopathy, fatty infiltration of the liver and, in addition, diseases such as cirrhosis and liver cancer.

So far for the treatment of diseases such applied dietetics, rest cure and other therapies that use drugs glycyrrhizin, adrenal cortical steroids, interferon, and the like. However, these therapies are not effective in the treatment of liver diseases. Glycyrrhizin and interferon applied intravenously, and therefore they are not suitable for long-term administration. In addition to interferon and steroids there is a problem side effect the activity against platelet aggregation. Therefore they are known as preventive and therapeutic agent for immunological diseases and thrombosis (tiled Japan's bid - 85344/1986). In addition, derivative triterpene described, for example, paved the application Japan 37749/1986, Chem. Pharm. Bull., 36, 153 (1988), Chem. Pharm. Bull., 24, 121 (1976), Chem. Pharm. Bull.,,30, 2294 (1982), Chem. Pharm. Bull., 33, 4267 (1985), Chem. Pharm. Bull., 31, 664 (1983), Chem. Pharm. Bull., 31, 674 (1983), Phytochemistry 27, 3563 (1988), Planta Medica 46, 52 (1982), J. Chem. Soc., and Chem. Comm., 785 (1982).

However, as far as is known to the present applicants, there are no reports that derived triterpene effective as therapeutic agents for the treatment of liver diseases.

The present applicants have found that derivatives of triterpene effective in the treatment of liver diseases. In addition, they achieved success in the synthesis of new derivatives of triterpene. This invention is based on these new discoveries.

Thus, one aspect of the present invention, the proposed therapeutic agent for the treatment of liver diseases, including derivative triterpene represented by the formula (I) or its pharmaceutically acceptable salt:

< / BR>
where R1represents a hydroxyl group,

C1-6alkoxy,

C1-6alkyl,

-CH2OR5where R5represents a hydrogen atom, a C1-6alkyl, aralkyl, which may be optionally substituted, or C1-6alkylsulphonyl, formyl,

-COOR6where R6represents a hydrogen atom or a C1-6alkyl, or

-CH2(R7R8where R7and R8that may be the same or different, represent a hydrogen atom or a C1-6alkyl; or

R1and R2can be combined with each other to form-O-CR9(R10)-OCH2- where R9and R10that may be the same or different, represent a hydrogen atom, a C1-6alkyl or aryl;

R3and R4that may be the same or different, represent

a hydrogen atom,

hydroxyl group,

C1-6alkyl,

hydroxy, C1-6alkyl,

formyl,

-COOR11where R11represents a hydrogen atom or a C1-6alkyl, or

-OR12where R12represents C1-6alkyl, aralkyl, which may be optionally substituted C1-6alkylsulphonyl, arylcarbamoyl, which may be optionally substituted C2-6alkenyl, C2-6alkenylboronic or arylalkylamine methylene group;

denotes a single or double bond, provided that when a represents a double bond, R4is missing.

According to another aspect of this invention is new derivatives of triterpene represented by formula (II) or pharmaceutically acceptable salt

< / BR>
where R1represents a hydroxyl group,

C1-6alkoxy,

C1-6alkylcarboxylic, or

aralkylated, which may be optionally substituted;

R2represents C1-6alkyl,

-CH2OR5where R5represents a hydrogen atom, a C1-6alkyl, aralkyl, which may be optionally substituted, or C1-6alkylsulphonyl,

formyl,

-COOR6where R6represents a hydrogen atom or a C1-6alkyl, or

-CH2N(R7R8where R7and R8that may be the same or different, represent a hydrogen atom or a C1-6alkyl; or

R1and R2can be combined with each other to form-O-CR9(R10) -OCH2- where R9and R10that may be the same or different, represent a hydrogen atom, a C1-6alkyl or aryl, which may be optionally substituted;

R31-6alkyl,

formyl,

-COOR11where R11denotes a hydrogen atom or a C1-6alkyl, or

-OR12where R12represents C1-6alkyl, aralkyl, which may be optionally substituted, arylcarbamoyl, which may be optionally substituted WITH2-6alkenyl, C2-6alkenylboronic or arylalkylamines, which may be optionally substituted; or

R3and R4can be combined with each other to form a methylene group;

denotes a single or double bond, provided that when a represents a double bond, R4no;

when R1and R2can be combined with each other to form-O-CR9(R10) -OCH2- where any one of R9and R10denote aryl, R3and R4may also denote a hydrogen atom, a hydroxyl group or aralkylated;

when any one of R3and R4represents C1-6alkyl group, another Deputy may additionally denote a hydroxyl group; and

when R2denotes-CH2OR5, R3and R4can additionally denote hydrogen atom.

In addition, new connections in the optimum group, R2denotes-COO-C1-6alkyl,

R3denotes a hydrogen atom and R4denotes a hydroxyl group;

the compound represented by formula (II), where R1represents C1-6alkoxy, R2denotes-CH2OH, R3denotes a hydrogen atom and R4denotes a hydroxyl group,

the compound represented by formula (II), where R1indicates aralkylated, R2denotes formyl, carboxyl, -COO-C1-6alkyl or-CH2OR5where R5denotes a hydrogen atom, a C1-6alkyl or C1-6alkylsulphonyl, R3represents a hydrogen atom and R4indicates aralkylated, which may be optionally substituted; and

the compound represented by formula (II), where R1denotes a hydroxyl group or a C1-6alkoxy, R2denotes aralkylamines, which may be optionally substituted, R3denotes a hydrogen atom and R4indicates aralkylated, which may be optionally substituted.

Therapeutic agent for the treatment of diseases of the liver/ the compounds of formula (I)

Compounds represented by formula (I) and their salts are effective in the treatment of liver diseases. and chronic viral hepatitis, autoimmune hepatitis and drug-induced, toxic, alcoholic, intrahepatic cholestasis, and congenital metabolic hepatopathy. Used in the description, the term "hepatopathy" refers to inflammatory diseases and, depending on the development of the symptom is used as a concept including fatty infiltration of the liver, cirrhosis and hepatoma.

In particular, derivative triterpene represented by the formula (I), when inkubirane together with cells human hepatoma (ner G2) in the presence of aflatoxin B1(the substance causing hepatopathy) exhibit inhibitory activity against necrosis of these cells.

As used in the description, the term "alkyl" related to the group or part of a group, refers to both linear and branched alkali. Specific examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl. The term "halogen atom" means a fluorine atom, chlorine, bromine or iodine. The term "aryl" as a group or part of a group preferably denotes phenyl, naphthyl, tolyl, methoxyphenyl or the like. The term "aralkyl" as a group or part of a group preferably denotes phenyl C1-4alkyl, more prefer the x atom, "aryl" or "aralkyl" optionally can be substituted, and examples of the substituent include a hydroxyl group, a C1-6alkoxy (preferably C1-4alkoxy, more preferably methoxy), halogen atom, amino, dimethylamino, acetoxy, methylendioxy and nitro. Examples of the substituted aryl or aralkyl include methoxy, phenyl, hydroxyphenyl, dihydroxyphenyl and acid.

In the formula (I) C1-6alkoxy, denoted by R1preferably represents C1-4alkoxy, more preferably methoxy or ethoxy. Specific examples include methoxy, ethoxy, propyloxy, bucalossi, pentyloxy, hexyloxy. C1-6alkylsulphonyl preferably represents C1-4alkylsulphonyl, and its specific examples include acetyl, propionyl, butyryl, pentanoyl and hexanoyl. Aralkylated denoted by R1preferably represents benzyloxy, penetrate, methylbenzylamine, naphthalenyloxy.

In the formula (I), -CH2OR5denoted by R5preferably represents-CH2OH, -CH2O-C1-4alkyl, -CH2O-(phenyl C1-4alkyl), or-CH2O-CO-C1-4alkyl, more preferably hydroxymethyl. The group-COOR61and R2can be combined with each other to form-O-CR9(R10) -OCH2- where R9and R10that may be the same or different, represent a hydrogen atom, a C1-6alkyl or aryl. Their preferred examples include-O-CR9(R10) -OCH2-, where R9and R10denote C1-6alkyl, preferably C1-4alkyl, more preferably methyl or ethyl, and-O-CR9(R10)-OCH2- where any one of R9and R10denotes a hydrogen atom, and the other radical is an aryl, preferably phenyl, tolyl, xylyl, diphenyl, naphthyl, antrel or tenantry.

In the formula (I) C1-6alkyl, denoted by R3or R4preferably represents C1-4alkyl, more preferably methyl or ethyl. Hydroxy, C1-6alkyl, denoted by R3or R4preferably represents hydroxy, C1-4alkyl, more preferably hydroxymethyl.

In the formula (I) -COOR11denoted by R3or R4preferably represents-COOH or-COO-C1-4alkyl.

In addition, in the formula (I) R12in-OR12denoted by RUB>2-6alkenylboronic or arylalkylamine. In addition, C2-6alkenyl preferably represents C2-6alkenyl and its specific examples include vinyl, propenyl, allyl, butenyl, 2-methylpropenyl, pentenyl and hexenyl. Examples of aralkyl include benzyl, phenethyl, methylbenzyl, naphthylmethyl and phenylpropyl. C1-6alkylsulphonyl preferably represents C1-4alkylsulphonyl and its specific examples include acetyl, propionyl, butyryl, pentanoyl and hexanoyl. Preferred examples of arylcarboxylic include benzoyl and afterburner. WITH2-6alkenyl preferably represents C2-4its specific examples include acryloyl, arylcarbamoyl and butanol. C2-6alkenylboronic preferably represents C2-4alkenylboronic. Specific examples of arylalkylamine include cynnamoyl and phenylethanol.

R3and R4can be combined with each other to form a methylene group.

In the formula (I) denotes a single or double bond.

When represents a double bond, preferably R1denotes a hydrogen atom, and R2denotes CH2HE, or R1and R2unite with obrazovanii a hydrogen atom.

Compounds represented by formula (I), isomers, and this invention includes such isomers and mixtures thereof.

According to a preferred variant embodiment of the present invention, preferred compounds have a configuration represented by the following formula (I-1):

< / BR>
In addition, compounds represented by formula (I), can easily give a salt with a pharmaceutically acceptable base. Preferred bases include inorganic bases such as sodium hydroxide, potassium hydroxide, aluminium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate, and organic bases, such as piperazine, morpholine, piperidine, ethylamine and trimethylamine.

Preferred compounds of this invention represented by formula (I) include:

a group of compounds, where R1denotes a hydroxyl group, R2denotes-CH2OR5and R3denotes a hydrogen atom, among them, more preferred group of compounds in which R4denotes a hydroxyl group or-OR12and a group of compounds, where R1represents C1-6alkoxy,

a group of compounds, where R1denotes a hydroxyl group, R a group of compounds, where R1denotes a hydroxyl group or aralkylated, R2means-COOR6, R3denotes a hydrogen atom and R4denotes a hydroxyl group or-OR12,

a group of compounds, where R1denotes a hydroxyl group, a C1-6alkoxy or C1-6alkylcarboxylic, R2denotes-CH2OR5and R3and R4represent a hydrogen atom,

a group of compounds, where R1denotes a hydroxyl group, R2denotes-CH2OR5, R3represents C1-6alkyl, and R4denotes a hydroxyl group, and

a group of compounds, where R1denotes a hydroxyl group, R2denotes-CH2OR5, R3denotes a hydrogen atom and R4denotes hydroxy, C1-6alkyl or carboxyl.

Although the compound represented by formula (I) can be entered as the starting material, preferably it can be put into the form of pharmaceutical compositions. The pharmaceutical composition as a therapeutic tool for the treatment of liver diseases, comprising as active ingredient a compound of the formula (I) or its salt, you can enter either orally or by parenteral) people or animals, in addition to the man.

Therefore, a therapeutic agent for the treatment of hepatic diseases according to this invention can be obtained in the form of a composition (preparation), suitable for the method of administration. In particular, it can be prepared in any of the following medications: injections, such as intravenous or intramuscular injections; oral preparation such as a capsule, tablet, granule, powder, pill, fine powder (powder or pellet; preparation for rectal administration; oily suppository and water suppository. The above variety of drugs can be obtained in the conventional way using excipient, extender, binder, wetting means, dezintegriruetsja tools, surfactants, lubricants, dispersing funds, buffer, preservative, solubilizer, antiseptics, perfumes, sedative, stabilizer and the like. Examples of the above additives, non-toxic and suitable for use in preparations include lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethyl cellulose or its salt, arvey sodium, the sodium sulfate and sodium phosphate.

The dosage of the compounds represented by formula (I) may vary depending on age, weight, condition or disease severity of the patient. However, in General, it is approximately 0.1-1000 mg, preferably 1-100 mg per day for an adult, once or twice a day. You can enter either orally or parenterally.

New derivatives of triterpene/ the compounds of formula (II)

According to another aspect of the present invention, provided new derivative triterpene. New derivatives triterpene in this invention are compounds represented by the formula (II).

In the formula (II) when R1, R2, R3and R4have the above for formula (I) values, the preferred compounds represented by formula (II) can be the same compounds that are described above for formula (I).

Compounds represented by formula (II) are isomers, and the present invention covers these isomers and their mixtures.

According to a preferred variant embodiment of the invention, preferred compounds have a configuration represented by the following formula (II-1):

< / BR>
Also Preferred bases include bases, both examples above for formula (I).

According to a preferred variant embodiment according to this invention, the preferred compounds of this invention represented by formula (II) include:

a group of compounds, where R1denotes a hydroxyl group, R2denotes-CH2OR5and R3denotes a hydrogen atom, especially a group of compounds, where R5denotes a hydrogen atom and R4means-OR12where R12represents C1-6alkyl, aralkyl, arylcarbamoyl, C2-6alkenyl, C2-6alkenylboronic or arylalkylamines,

a group of compounds, where R1and R2are combined with each other to form-O-CR9(R10)-OCH2- especially the group of compounds where R9and R10denote methyl, R3denotes a hydrogen atom and R4means-OR12where R12represents C1-6alkyl, aralkyl, arylcarbamoyl,2-6alkenyl,2-6alkenylboronic or arylalkylamines, a group of compounds, where R9denotes a hydrogen atom and R10denotes aryl, and a group of compounds, where R3and R4represent a hydrogen atom, or R3denotes a hydrogen atom and R4, a hydroxyl group or aralkylated (preferably phenyl C1-4alkyl), R2denotes-CH2OR5and as R3and R4represent a hydrogen atom,

a group of compounds, where R1denotes a hydroxyl group, a C1-6alkoxy or C1-6alkylcarboxylic, R2denotes-CH2OR5(where R5preferably denotes a hydrogen atom or aralkyl, more preferably phenyl C1-4alkyl) and R3and R4represent a hydrogen atom,

a group of compounds, where R1denotes a hydroxyl group, R2denotes-CH2OR SIG5(preferably R5=N), R3represents C1-6alkyl, and R4denotes a hydroxyl group,

a group of compounds, where R1denotes a hydroxyl group, R2denotes-CH2OR5(preferably R5=N), R3denotes a hydrogen atom and R4denotes hydroxy, C1-6alkyl, or-COOR11(preferably R11= N),

a group of compounds, where R1denotes optionally substituted, Arakelots (preferably phenyl C1-4alkyloxy), R2denotes-CH2OR5where R5denotes a hydrogen atom, a C1-6alkyl (preferably C1-4alkyl), or C1-6allylcarbamate, where R1denotes a hydroxyl group, R2denotes-CH2OR5where R5represents C1-6alkyl (preferably C1-4alkyl), or C1-6alkylaryl (preferably C1-4alkylsulphonyl), and R3and R4represent a hydrogen atom,

a group of compounds, where R1denotes a hydroxyl group, a C1-6alkoxy (preferably C1-4alkoxy) or C1-6alkylcarboxylic (preferably C1-4alkylcarboxylic), R2denotes-CH2OR5where R5denotes optionally substituted aralkyl (preferably phenyl C1-4alkyl), and R3and R4represent a hydrogen atom,

a group of compounds, where R1represents C1-6alkoxy (preferably C1-4alkoxy) or C1-6alkylcarboxylic (preferably C1-4alkylcarboxylic), R2denotes-CH2HE and R3and R4represent a hydrogen atom,

a group of compounds, where R1denotes a hydroxyl group, R2denotes-CH2OR SIG5(preferably R5=N), and R3and R4are combined with each other to form a methylene group, and

a group of compounds, where R1and R10=methyl) and represents a double bond.

In addition, the new compounds of this invention represented by formula (II) are:

connection, where R1denotes a hydroxyl group, R2denotes-COO-C1-6alkyl (preferably-COO-C1-4alkyl), R3denotes a hydrogen atom and R4denotes a hydroxyl group;

connection, where R1represents C1-6alkoxy (preferably C1-4alkoxy), R2denotes-CH2OH, R3denotes a hydrogen atom and R4denotes a hydroxyl group,

connection, where R1indicates Arakelots (preferably phenyl C1-4alkyloxy), R2denotes formyl, carboxyl, -COO-C1-6alkyl (preferably-COO-C1-4alkyl), or-CH2OR5where R5denotes a hydrogen atom, a C1-6alkyl (preferably C1-4alkyl or C1-6alkylaryl (preferably C1-4alkylsulphonyl), R3denotes a hydrogen atom and R4indicates Arakelots (preferably C1-4alkoxy), and

connection, where R1denotes a hydroxyl group or a C1-6alkoxy (preferably C1-4alkoxy), R2means and the n Arakelots (preferably phenyl C1-4alkyloxy).

Obtaining compounds

Some of the compounds represented by formula (I), known in the field and can be obtained by previously described methods.

Preferred methods of obtaining will be described. Compounds represented by formula (II) are covered by the compounds represented by formula (I) and, therefore, can be obtained by the methods described below.

Preferably in the following ways any functional group is not involved in the reaction, preferably protected. Specialist with appropriate skills in this area, it is clear that in this case, for this purpose, can serve as a protective group known from the prior art.

Method (A)

Among derivatives triterpene represented by the formula (I), the compound represented by formula (Ia) where R3arepresents C1-6alkyl, can be obtained according to scheme 1 (see the end of the description).

At the stage of (i) the compound (III) is oxidized to the compound (IV). Used for this oxidizing agents include, for example, chromate pyridinium, pyridinium dichromate dioxide magnesium and dimethylsulfoxide (DMSO) okishio based on the compound (III). The reaction can be carried out in an inert solvent (e.g. dichloromethane, chloroform, diethyl ether or tetrahydrofuran (THF) in the temperature range from -78 to 40oC.

At stage (ii), the compound of formula (IV) reacts with the compound of the formula (V), where R3arepresents C1-6alkyl, M represents a metal, X represents halogen or Li, m is an integer from 1 to 4 and n denotes an integer from 1 to 3, giving the compound of formula (Ia). The reaction can be carried out in an inert solvent (e.g. diethyl ether, THF, benzene, toluene, hexane, dimethylformamide (DMF), hexamethylphosphoric triamide or dichloromethane) in the temperature range from -78 to 20oC. Preferably the compound of formula (V) used in the amount of 1-3 equivalents based on the compound of the formula (IV). Preferred examples of metals denoted by M include lithium, magnesium, tin, zinc, boron, silicon, aluminum, and copper.

In reaction scheme 1 is preferably a compound represented by the formula (III), where R1denotes a hydroxyl group, and R2represents hydroxymethyl, reacts, for example, CR9R10(OMe)2to protect the hydroxyl groups present in R1and R2and the organic acid, such as hydrochloric acid or sulfuric acid, or a Lewis acid such as BF3Et2in the solvent (e.g. methanol, ethanol, isopropanol (IPA), water, dichloromethane or chloroform) at a temperature in the range from 0 to 120oC.

Method ()

Among derivatives triterpene represented by the formula (I), the compound represented by formula (Ib) can be obtained according to scheme 2 (see the end of the description).

The compound of formula (VI) can be oxidized with a suitable oxidizing agent to the compounds of formula (Ib). Used oxidants include, for example, chromate pyridinium, pyridinium dichromate, dioxide magnesium and dimethylsulfoxide (DMSO) oxidizing agents, such as DMSO-oxalicacid. Preferably, the oxidant is used in an amount of 1-5 equivalents based on the compound of the formula (VI). The reaction can be carried out in an inert solvent (e.g. dichloromethane, chloroform, diethyl ether or tetrahydrofuran (THF) at a temperature in the range from -78 to 40oC.

Method (C)

Among derivatives triterpene represented by the formula (I), the compound represented by the following formula (IC) can be obtained by oxidation of compounds of formula (Ib)
(e) in the presence of an oxidant (for example, pyridinium dichromate, reagent Jones (Jones), potassium permanganate or sodium chlorite) in the temperature range 0-60oC. In General, the oxidizing agent is preferably used in an amount of from 1 to 30 equivalents based on the compound of formula (Ib).

Method (D)

Of derivatives triterpene represented by the formula (I), the compound represented by formula (Id) can be obtained according to scheme 3 (see end of description).

At stage (i), the compound of formula (IV) reacts with methyltyrosine agent (e.g., PH3R= CH2, reagent Tabbe'a or reagent Nysted'a), giving the compound of formula (VII). Preferably methylanisole agent is used in amount of 1-10 equivalents based on the compound of the formula (IV). The reaction can be carried out in an inert solvent (e.g. dichloromethane, chloroform, diethyl ether, THF, DMF or DMSO) at a temperature in the range from -78 to 40oC. If necessary, to accelerate the reaction to the reaction system may be added Lewis acid such as titanium tetrachloride.

Then, at stage (ii), the compound (VII) can be kataliticheski restored in the presence of a catalyst to obtain the compounds of formula (Id). The reaction can be conducted in earthsphere hydrogen at 1-4 ATM, at room temperature. For example, as a catalyst can be used palladium on carbon, palladium black or palladium hydroxide on carbon in amounts of 0.1 to 0.6 equivalents.

Method (E)

Of derivatives triterpene represented by the formula (I), the compound represented by formula (S), where R4denotes formyl, can be obtained according to scheme 4 (see end of description).

At stage (i), the compound of formula (IV) medienraum according to method (D).

Then at stage (ii), the compound of formula (IV) reacts with hydrobryum reagent, after which the reaction product is subjected to oxidation, receiving compound of formula (IX). Used hydrobiidae reagents include, for example, NR3-THF, axillary, 9-borabicyclo(3,3,1)nonan. Preferably the reagent is used in an amount of 1-10 equivalents based on the compound of the formula (IV). The reaction can be carried out in an inert solvent (e.g. diethyl ether or THF) at a temperature in the range of 0oWith up to room temperature.

In the oxidation reaction to the reaction mixture add the oxidizing agent (for example, sodium hydroxide or 30% hydrogen peroxide) and the reaction is carried out at 0oC.o
C.

Method (F)

Of derivatives triterpene represented by the formula (I), the compound represented by formula (If) can be obtained by oxidation of compounds of formula (Ie)

< / BR>
Used oxidants include pyridinium dichromate, Jones reagent, potassium permanganate and sodium chlorite. The oxidant is used in an amount of from 1 to 30 equivalents based on the compound of formula (Ie). The oxidation reaction is carried out in an inert solvent (such as DMF, tert-butanol, acetone or water) at the temperature range 0-60oC.

Method (G)

Of derivatives triterpene represented by the formula (I), the compound represented by formula (Ig) where denotes a double bond, can be obtained according to scheme 5 (see the end of the description).

On cdnow group or aryl group, giving the compound of formula (XI). Preferred examples of compounds of formula (X) include methanesulfonate, benzosulphochloride and p-toluensulfonate. The reaction is carried out in the presence of a suitable base in an inert solvent (e.g. benzene, toluene, dichloromethane, chloroform, diethyl ether, THF or DMF) in the temperature range 0-60oC. Preferred bases include, for example, triethylamine, pyridine, 4-dimethyl-aminopyridine and preferably the compound of formula (X) and the base are used in amounts of 1-3 equivalents based on the compound of the formula (III).

At stage (ii) thus obtained compound of the formula (XI) can be restored with a suitable regenerating agent with obtaining the compounds of formula (Ig). Used reducing agents include, for example, triethylborohydride. Preferably the reducing agent is used in amount of 1-5 equivalents based on the compound of the formula (XI). The reaction is carried out in an inert solvent (e.g. diethyl ether, THF, benzene, toluene or dichloromethane) at a temperature range of -78 to 80oC.

Way (N)

Of derivatives triterpene represented by the formula (I), the connection is a recovery action can be performed by catalytic reduction of compound (Ig) in the presence of a catalyst. The reaction can be carried out in an inert solvent (e.g. methanol, ethanol, THF, dioxane, dichloromethane, chloroform or water), usually in an atmosphere of hydrogen at 1-4 ATM at room temperature. For example, as a catalyst can be used palladium on carbon, palladium black or palladium hydroxide on carbon in amounts of 0.1 to 0.6 equivalents.

Method (I)

Of derivatives triterpene represented by the formula (I), the compound represented by formula (Ii), where R13has the above meanings, can be obtained according to scheme 6 (see the end of the description).

The compound of formula (III) reacts with the compound of the formula (XII): R12Y, where R12has the above meanings and Y represents a hydrogen atom, in the presence of a base, giving the compound of formula (Ii). The reaction is carried out in an inert solvent (e.g. chloroform, dichloromethane, diethyl ether, THF, benzene, toluene, DMF or DMSO) at temperatures from -78 to 60oC. Used bases include, for example, pyridine, triethylamine, 4-dimethylaminopyridine, sodium hydride, potassium hydride, n-utility, NaCH2SOCH3and tert-BuOk. Preferably, the base and the compound of formula (XII) is used in which the terpene, represented by formula (I), the compound represented by formula (Ij1), where R5has the above significance, and the compound of formula (Ij2), where R1arepresents C1-6alkyl, C1-6alkylsulphonyl or aralkyl, can be obtained according to scheme 7 (see the end of the description).

At stage (i), the compound of formula (VI) reacts with Agcn(OMe)2or AgSnO in the presence of acid, giving the compound of formula (XIV). The reaction can be carried out in an inert solvent (e.g. benzene, toluene, xylene, dichloromethane, chloroform, diethyl ether, THF, DMF or acetone) in the temperature range 0-120oC. Apply the acid include hydrochloric acid, sulfuric acid, p-toluensulfonate and camphorsulfonate. Preferably Agsn(OMe)2or AgSnO used in the amount of 1-30 equivalents based on the compound of the formula (VI).

At stage (ii) thus obtained compound of the formula (XIV) can be restored with a suitable regenerating agent with obtaining the compounds of formula (XV) and the compound of formula (XVI). Used reducing agents include aluminum hydride, the hydride Diisobutyl-aluminum hydride layalina-aluminium chloride. Preferably the reducing agent used is barely (for example, dichloromethane, chloroform, benzene, toluene or diethyl ether) at a temperature of from -30 to 40oC.

Then, in stage (iii) thus obtained compound of the formula (XVI) is reacted with a compound represented by the formula: R5Y, where R5has the above meanings and Y represents a halogen atom, in the presence of a base, giving the compound of formula (XVII). Used bases include, for example, sodium hydride, potassium hydride, n-butyl-lithium, NaCH2SOCH3and tert-BuOk, triethylamine, pyridine and 4-dimethylaminopyridine. Preferably the base and the compound of the formula: R5Y is used in quantities of 1 to 10 equivalents based on the compound of formula (XVI). The reaction is carried out in an inert solvent (e.g. diethyl ether, THF, benzene, toluene, DMF, DMSO or dichloromethane) at -78 to 60oC.

At stage (iv) thus obtained compound of the formula (XVII) can be catalytically restored in the presence of a catalyst to obtain formula (Ij1). The reaction can be carried out in an inert solvent (e.g. methanol, ethanol, THF, dioxane, dichloromethane, chloroform or water), usually in an atmosphere of hydrogen at 1-4 ATM and at room temperature. As catalysts of the kind in an amount of 0.1 to 0.6 equivalent.

At stage (v), the compound of formula (XV) may react with the compound of the formula: R1aY, where R1ahas previously adopted values, a Y indicates a halogen atom, in the presence of a base to obtain the compounds of formula (XVIII). Used bases include, for example, sodium hydride, potassium hydride, n-utility, NaCH2SOCH3and tert-BuOk, triethylamine, pyridine and 4-dimethylaminopyridine. Preferably the base and the compound of the formula: R5Y is used in quantities of 1 to 10 equivalents based on the compound of formula (XVI). The reaction is carried out in an inert solvent (e.g. diethyl ether, THF, benzene, toluene, DMF, DMSO or dichloromethane) at -78 to 60oC.

On stage (vi) thus obtained compound of the formula (XVIII) can be catalytically restored in the presence of a catalyst to obtain the compounds of formula (Ij1). The reaction can be carried out in an inert solvent (e.g. methanol, ethanol, THF, dioxane, dichloromethane, chloroform or water), usually in an atmosphere of hydrogen at 1-4 ATM and at room temperature. As a catalyst can be used, for example, palladium on carbon, palladium black or palladium hydroxide on carbon in an amount of 0.1 to 0.6 equivale, the de R7and R8have the above meanings, can be obtained from compounds of formula (Ib) according to scheme 8 (see end of description).

The compound of formula (Ib) and the compound of formula R7R8NH, where R7and R8have the above values, the catalytically restore in the presence of a catalyst. The reaction can be carried out in an inert solvent (e.g. methanol, ethanol, THF, dioxane, dichloromethane, chloroform or water), usually in an atmosphere of hydrogen at 1-4 ATM and at room temperature. As catalysts may be used, for example, palladium on olurode, palladium black or palladium hydroxide on carbon in an amount of 0.1 to 0.6 equivalent.

Method (L)

Of derivatives triterpene represented by the formula (I), the compound of formula (Il), where R6has the above meanings, can be obtained from compounds of formula (IC) by esterification according to scheme 9 (see at the end of the description).

The etherification is carried out by the compounds of formula (IC) with R6X, where R6represents C1-6alkyl group, and X denotes halogen, in the presence of a base, or R6OH, where R6has the above significance, and condensing Agay the General formula (II). Used bases include sodium bicarbonate, sodium carbonate, sodium hydride, cesium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine and DBU. Used condensing agents include cyclohexylcarbodiimide. Preferably, base, R6X, R6OH and the condensing agent is used in an amount of 1-2 equivalents based on the compound of the formula (Ic). The reaction can be carried out in an inert solvent (e.g. diethyl ether, THF, benzene, toluene, DMF, dichloro-methane or Meon in the temperature range 0-40oC.

Examples

This invention is disclosed in more detail below by examples, but it should be understood that it is not limited to only these examples.

Were septiawan the following compound 1-73 listed in table 1. Compounds 1, 4, 24, 25, 27 and 28 obtained by the method disclosed in Chem. Pharm. Bull., 36, 153 (1988), and compound 9 was obtained by the method described in Chem. Pharm. Bull., 24, 121 (1976), in Chem. Pharm. Bull., 31, 664 (1983) Chem. Pharm. Bull., 31, 674 (1983).

Example 1. 22-Oxolan-12-ene-3, 24(4)-diol (compound 2)

Oxalicacid (0.4 ml) dissolved in 10 ml of dichloromethane and the solution cooled to -78oC. To the cooled solution was added a solution of 0.65 ml of DMSO in 2 ml of 1.5 g of compound 1 in 5 ml of dichloromethane and the mixture is then stirred at -78oWith 15 minutes. To the reaction mixture are added to 2.1 ml of triethylamine and the mixture was stirred at -78oWith 5 minutes. The temperature of the reaction mixture gradually increased to 0oWith, dilute the mixture with water and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate and dried over magnesium sulfate. Then, the inorganic salt is removed by filtration and the filtrate concentrated under reduced pressure. The obtained solid product clean column chromatography on silica gel (n-hexane : ethyl acetate = 10:1). Thus obtained unpainted solid product (1.3 g) dissolved in 30 ml of methanol, add 1 N. hydrochloric acid and the mixture is stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane, washed with water and dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure, obtaining 1.2 g (yield 86%) of compound 2 in the form of unpainted solid.

NMR (l3) memorial plaques 0,86 (3H, s) of 0.90 (3H, s) to 0.94 (3H, s), 0,99 (3H, s), and 1.00 (3H, s) to 1.22 (3H, s) of 1.26 (3H, s), 0.88 to 2,58 (N, m), 3,35, 4,21 (both 1H, both d, J=11,1 Hz), of 3.45 (1H, DD, J=4.4 Hz), and 5.30 (1H, t-like).

MS EI (m/z): 456(M+).

Example 2. 22-Metrolan-12-ene-3, 22, 24(4)-> the 670 μl of solution metallyte (1.8 mol/l) in diethyl ether. The mixture is stirred for one hour, gradually raising the temperature to 0oC. water is Added and the mixture extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (n-hexane : ethyl acetate = 2:1) to give 62 mg (yield 60%) of compound 3.

NMR (CDCl3) memorial plaques 0,86 (3H, s), 0,89 (6N, C) to 0.96 (3H, s) of 1.07 (3H, s), 1,10 (3H, s) of 1.16 (3H, s), 1,25 (3H, s), 0,84-2,86 (24N, m) to 3.35 (1H, t, J=10,2 Hz), 3,44 (1H, m), 4,20 (1H, d, J=11,1 Hz), 5,23 (1H, t-like).

MS EI (m/z): 472 (M+).

Example 3. 3, 22 Dimensions-24(4)-triphenyltetrazolium-12-ene (compound 5)

In 5 ml of anhydrous DMF is dissolved 95 mg of compound 4. To the solution was added 83 mg of 60% sodium hydrate and the mixture is then stirred at room temperature for 1.5 hours thereafter, to the reaction mixture add 75 ál of benzylbromide and the mixture is then stirred at 40oWith 5 hours. The reaction mixture was diluted with ethyl acetate, washed twice with water and dried over magnesium sulfate. Then, the inorganic salt is removed by filtration and the filtrate concentrated under reduced pressure is 1), getting 118 mg (yield 65%) of compound 5 in the form of unpainted solid.

NMR (CDCl3) memorial plaques of 0.33 (3H, s) of 0.82 (3H, s) to 0.88 (3H, s) to 0.92 (3H, s) of 1.03 (3H, s) a 1.08 (3H, s) of 1.34 (3H, s), 0.70 to 2,15 (N, m), 2,93-of 2.97 (1H, m), 3,06-of 3.07 (1H, m), 3,17 (1H, d, J=9,2 Hz), 3,53 (1H, d, J=9,2 Hz), 4,32 (1H, d, J=11,9 Hz), to 4.38 (1H, d, J=11,9 Hz), br4.61 (1H, d, J=11,9 Hz), 4,63 (1H, d, J=11,9 Hz) to 5.17 (1H, t-like), 7,19-7,50 (25N, m).

MS FD (m/z): 881 (M++1).

Example 4. 3, 22-Dibenzalacetone-12-EN-24(4)ol (compound 6)

In a mixed solution of 10 ml of methanol and 2 ml of acetone is dissolved 440 mg of compound 5. Then add concentrated hydrochloric acid (0.4 ml) and the mixture heated under reflux for 30 minutes. Then to the reaction mixture, water is added, the mixture is neutralized 1 N. sodium hydroxide and extracted twice with dichloromethane. The organic layer is dried over magnesium sulfate. After separation of the inorganic salts by filtration, the filtrate is concentrated under reduced pressure. Thus obtained oil clean column chromatography on silica gel (n-hexane : ethyl acetate = 10:1) to give 231 mg (yield 72%) of compound 6 in the form of butter.

NMR (CDCl3) memorial plaques to 0.88 (3H, s) to 0.89 (3H, s) of 0.93 (3H, s) to 0.94 (3H, s) of 1.05 (3H, s) a 1.11 (3H, s) to 1.21 (3H, s), 0,85-2,18 (22N, m), 3,07-is 3.08 (1H, m), 3,18-3,24 (2H, m), 4,16 (1H, d, J=10.5 Hz), 4,32 (1H, d, J=11.7 Hz), 4,39 (1S="ptx2">

Example 5. 3, 22 Dimensions-24(4)-oxolan-12-ene (compound 7)

Oxalicacid (0.15 ml) dissolved in 4 ml of dichloromethane and the solution cooled to -78oC. To the cooled solution was added a solution of 0.23 ml of DMSO in dichloromethane, after which the mixture is stirred for 10 minutes To the reaction mixture add a solution of 128 mg of compound 6 in 2 ml of dichloromethane and the mixture is then stirred at -78oWith 15 minutes. To the reaction mixture add 0.7 ml of triethylamine and the mixture was stirred at -78oWith 5 minutes. The temperature of the reaction mixture gradually increased to 0oWith, dilute the mixture with water and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate and dried over anhydrous magnesium sulfate. Then, the inorganic salt is filtered off and the filtrate is concentrated under reduced pressure. The oil obtained is cleaned column chromatography on silica gel (n-hexane : ethyl acetate = 10: 1) to give 104 mg (yield 82%) of compound 7 as a colorless foamy substance.

NMR (CDCl3) memorial plaques of 0.83 (3H, s) to 0.89 (3H, s) of 0.93 (3H, s) to 0.94 (3H, s), was 1.04 (3H, s), 1,10 (3H, s) to 1.21 (3H, s), 0,85-2,18 (N, m), of 3.07 (1H, DD, J= 3.1 Hz, 3.1 Hz), 3,18 (1H, DD, J=5,1 Hz, 5.1 Hz), 4,20 br4.61 (1H, each, both d, J=11.7 Hz), 5,23 (1H, t-like), 7,22-to 7.35 (10H, m), 10,07 (1H, s).

oraut 30 mg of compound 7 and to the solution was added 30 mg of 20% Pd(OH)2-C. a Mixture of catalytically restore at room temperature under atmospheric pressure for one hour. Then the reaction mixture was filtered through Celite, the filtrate concentrated under reduced pressure, getting 21 mg (yield 100%) of compound 8.

NMR (CDCl3) memorial plaques 0,88 (6N, C) to 0.92 (3H, s), and 1.00 (3H, s), was 1.04 (3H, s) of 1.13 (3H, s) of 1.30 (3H, s), 0,97-2,12 (22N, m), 3,12-3,20 (1H, m), 3,44 (1H, t, J=5,1 Hz), 5,26 (1H, t-like), 9,76 (1H, d, J=2,4 Hz).

MS EI (m/z): 456 (M+).

Example 7. 3, 22-Dibenzalacetone-12-EN-24(4)-Wake acid (compound 10)

In 6 ml of tert-butanol was dissolved 20 mg of compound 7 and add 1.5 ml of 2-methyl-2-butene. To the reaction solution was added a solution of 250 mg of sodium chlorite and 250 mg monopotassium phosphate sodium 2.5 ml of water and then the mixture was stirred at room temperature overnight. Then the reaction mixture was concentrated under reduced pressure, the concentrate is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. Then, the inorganic salt is filtered off, the filtrate is concentrated under reduced pressure. Thus obtained oil clean column chromatography on silica gel (n-hexane : ethyl acetate = 5:1) getting to 6.8 mg (yield 34%) of compound 10 as pokrasheno is) 0,85-2,19 (N, m), 3,05-to 3.09 (1H, m), 3,15-3,19 (1H, m), 4,32 (1H, d, J=11,83 Hz), 4,56 (1H, d, J=11,83 Hz), br4.61 (1H, d, J=11,83 Hz), is 4.85 (1H, d, J=11,83 Hz), 5,23 (1H, t-like), 7.23 percent-7,52 (10H, m).

MS EI (m/z): 652 (M+).

Example 8. 3, 22-Dihydroxytoluene-12-EN-24(4)-Wake acid (compound 11)

Compound 10 (5 mg) was dissolved in a mixed solvent consisting of 0.5 ml of methanol and 0.5 ml of dichloromethane and to the solution was added 5 mg of 20% PD(OH)2-C. the Mixture kataliticheski restore at room temperature and atmospheric pressure for 45 minutes After which the reaction mixture is filtered through Celite, the filtrate concentrated under reduced pressure, obtaining 3,3 mg (yield 92%) of compound (11) in the form of a foamy substance.

NMR (Dl3) memorial plaques of 0.85 (3H, s) to 0.92 (3H, s) of 0.93 (3H, s), and 1.00 (3H, s) of 1.02 (3H, s) a 1.11 (3H, s) of 1.41 (3H, s), 0,87-2,08 (N, m), 3,09-of 3.12 (1H, m), 3,40-of 3.43 (1H, m), 5,27 (1H, t-like).

MS SIMS (m/z): 473(M++1).

Example 9. 22-Medienallee-12-ene-3, 24(4)-diol (compound 12)

In 12 ml of reagent Nysted'a suspended 1.0 g of compound 2 and the suspension cooled to -78oC. To the cooled suspension portions add solution (5 ml) of titanium tetrachloride (1.0 M) in dichloromethane. The temperature of the reaction mixture was raised to room temperature and then the reaction mixture permissibility. The mixture is extracted three times with chloroform, then the organic layer is dried over anhydrous magnesium sulfate. Then, the inorganic salt is removed by filtration and the filtrate concentrated under reduced pressure. The obtained solid product clean column chromatography on silica gel (n-hexane : ethyl acetate = 2:1) to give 518 mg (yield 52%) of compound 12 in the form of unpainted solid.

NMR (Dl3) memorial plaques to 0.78 (3H, s) to 0.89 (3H, s) of 0.90 (3H, s) of 0.95 (3H, s) of 1.03 (3H, s) of 1.17 (3H, s), 1,25 (3H, s), 0,84-2,20 (N, m), 2,39 (1H, usher.), of 2.72 (1H, usher.), 3,32-3,37 (1H, m), 3.43 points-of 3.46 (1H, m), is 4.21 (1H, d, J=11,10 Hz), 5,27 (1H, t-like).

MS El m/z): 454 (M+).

Example 10. 22-Metrolan-12-ene-3, 24(4)-diol (compound 13)

Compound 12 (29 mg) was dissolved in a mixed solvent consisting of 1.0 ml of methanol and 9 ml of dichloromethane and to the solution was added 20 mg of 20% Pd(OH)2-C. a Mixture of catalytically restore at room temperature and atmospheric pressure for one hour. Then the reaction mixture was filtered through Celite, the filtrate concentrated under reduced pressure, getting 27 mg (yield 93%) of compound 13 in the form of unpainted solid.

NMR (Dl3) memorial plaques to 0.80 (3H, s) 0,86 (6N, C) to 0.89 (3H, s) of 0.90 (3H, s) of 0.93 (3H, s) of 1.13 (3H, s), 1,25 (3H, s), 0,64-1,94 P> Example 11. 22-Hydroxymethylation-12-ene-3, 24(4)-diol (compound 14)

In 7 ml of anhydrous THF was dissolved 300 ml of connection 12, and the solution was added 3.3 ml of a solution NR3-THF (1.0 M) in THF. The mixture is then stirred at room temperature overnight. To the reaction mixture under stirring and ice cooling for 5 minutes, add 3 ml of 10% solution hydroxide and 3 ml of 30% hydrogen peroxide. The mixture is stirred under ice cooling for 1.5 hours, add water. The mixture is extracted with ethylacetate. The organic layer was washed with saturated salt solution and then dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (n-hexane : ethyl acetate = 1:1) to give 245 mg (yield 79%) of compound 14.

NMR (Dl3) memorial plaques to 0.70 (3H, s) of 0.90 (3H, s) of 0.91 (3H, s) to 0.92 (3H, s) to 0.96 (3H, s) of 1.05 (3H, s), 1,25 (3H, s), 0,84-1,87 (22N, m), 3,28-to 3.35 (2H, m), 3,42-3,47 (1H, m), 3,65-3,70 (1H, m), 4,20 (1H, d, J=11,10 Hz), the 5.25 (1H, t-like).

MS EI (m/z): 472 (M+).

Example 12. 22-Hydroxymethyl-3, 24(4)-isopropylidenedioxy-12-ene (compound 15)

In 13 ml of acetone is dissolved 200 mg of compound 14 and to the solution add 10 ml of 2,2-dimethoxypropane and 3 mg camphorsulfonic reduced pressure, the residue is dissolved in ethyl acetate and added a small amount of silicagel. Then the mixture is stirred at room temperature for two days. The reaction solution is concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (n-hexane : ethyl acetate = 5:1) to give 105 mg (yield 48%) of compound 15 as unpainted solid.

NMR (l3) memorial plaques to 0.70 (3H, s) of 0.91 (3H, s) of 0.95 (3H, s) to 0.96 (3H, s) of 1.06 (3H, s) of 1.17 (3H, s) to 1.21 (3H, s) to 1.37 (3H, s) of 1.43 (3H, s), 0,87-2,04 (22N, m), 3,21 (1H, d, J=11,54 Hz), 3,32 (1H, t, J=10.5 Hz), of 3.45 (1H, DD, J=4,62 Hz, 9,24 Hz) to 3.67 (1H, DD, J=10,52 Hz, 10,52 Hz), a 4.03 (1H, d, J=11,54 Hz), 5,27 (1H, t-like).

MS EI (m/z): 512 (M+).

Example 13. 22-Formyl-3, 24(4)-isopropylidenedioxy-12-ene (compound 16)

Repeating the method of example 5, except that as the starting compound used 105 mg of compound 15. Thus obtain 91 mg (yield 87%) of compound 16.

NMR (Dl3) memorial plaques of 0.87 (3H, s) of 0.90 (3H, s) to 0.96 (3H, s), 0,99 (3H, s), 1,10 (3H, s) of 1.18 (3H, s) to 1.21 (3H, s) to 1.37 (3H, s) of 1.43 (3H, s), 0.88 to 2,10 (22N, m), up 3.22 (1H, d, J=11,72 Hz), 3.45 points-of 3.48 (1H, m), a 4.03 (1H, d, J=11,72 Hz), and 5.30 (1H, s), 9,80 (1H, s).

MS EI (m/z): M. D. 510 (M+).

Example 14. 22-Formillion-12-ene-3, 24(4)-diol (compound 17)

Compound 16 (10 mg) restoraunts 1 N. of hydrochloric acid. Then the mixture is stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate and then dried over anhydrous magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure. The residue is dissolved in a mixed solvent of 2 ml of acetone and 0.2 ml of water, add a small amount of camphorsulfonate. The mixture is stirred at room temperature overnight. Then the reaction solution is concentrated under reduced pressure, the residue is dissolved in dichloromethane. The solution is washed with water and saturated aqueous sodium bicarbonate and then dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure, receiving 7 mg (yield 78%) of compound 17 as unpainted solid product.

NMR (Dl3) memorial plaques of 0.79 (3H, s), or 0.83 (6N, C) is 0.84 (3H, s) to 0.92 (3H, s) of 1.02 (3H, s) of 1.18 (3H, s), 0.77-a 2,03 (22N, m) to 2.41 (1H, usher.), to 2.67 (1H, user. ), 3,30 (1H, usher.), 3,37 (1H, d, J=11,43 Hz), 4,13 (1H, d, J= 11,43 Hz), to 5.21 (1H, t-like), 9,72 (1H, s).

MS FD (m/z): 471 (M++1).

Example 15. 22-Carboxy-3, 24(4)-isopropylideneglycerol-12-ene (compound 18)

Repeat the method with ucaut 21 mg (yield 99%) of compound 18.

NMR (CDCl3) memorial plaques of 0.83 (3H, s) of 0.90 (3H, s) of 0.95 (3H, s), 0,99 (3H, s) of 1.07 (3H, s) of 1.17 (3H, s) to 1.21 (3H, s) to 1.38 (3H, s) of 1.44 (3H, s), 0,87-2,24 (22N, m), up 3.22 (1H, d, J=11,73 Hz), 3.45 points-of 3.48 (1H, m), a 4.03 (1H, d, J=11,73 Hz), and 5.30 (1H, s).

MS EI (m/z): 526 (M+).

Example 16. 22-Carboxyla-12-ene-3, 24(4)-diol (compound 19)

Compound 18 (20 mg) was dissolved in a mixed solvent of 2 ml of methanol and 1 ml of dichloromethane, to the solution under cooling with ice add 0.2 ml of 1 N. hydrochloric acid. Then the mixture is stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure. The resulting product is cleaned column chromatography on silica gel (n-hexane : methanol = 10:1 ), yield 12 mg (yield 64%) of compound 19 as a colorless foamy substance.

NMR (Dl3) memorial plaques 0,81 (3H, s), 0,90 (N, C), and 0.98 (3H, s) of 1.06 (3H, s) of 1.23 (3H, s), 0,83-2,21 (22N, m), 3,32 (1H, d, J=11,1 Hz), 3,40 (1H, DD, J=4,16 Hz, 11,38 Hz), 4,20 (1H, d, J=11,1 Hz), 5,28 (1H, t-like).

MS FD (m/z): 486 (M+).

Example 17. 3, 24(4), Isopropylidenedioxy-22-toiletsealed-12-ene (compound 20)

Compound 1 (50 mg) is dissolved in pyridine, the solution is added 287 mg p-toluensulfonate during the night. Then to the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. Then, the inorganic salt is filtered off and the filtrate is concentrated under reduced pressure, getting 654 mg (yield 100%) of compound 20 in the form of unpainted solid.

NMR (CDCl3) memorial plaques from 0.76 (3H, s) 0,84 (N, C) to 0.94 (3H, s) to 0.96 (3H, s), 1,10 (3H, s) to 1.14 (3H, s) to 1.21 (3H, s) to 1.37 (3H, s) of 1.44 (3H, s), 0,78-2,10 (N, m), of 2.45 (3H, s), up 3.22 (1H, d, J=11,65 Hz), 3.43 points-of 3.46 (1H, m), a 4.03 (1H, d, J=11,65 Hz), 4,34-4,37 (1H, m), with 5.22 (1H, t-like).

MS FD (m/z): 652 (M+).

Example 18. 3, 24(4)-Isopropylidenedioxy-12,21-diene (compound 21)

To 65 mg of compound 20 added under ice cooling, 2 ml of createlineborder (1.0 M THF solution) and the mixture is then stirred at 65oWith one hour. The temperature of the reaction mixture was raised to room temperature. Then water is added and the mixture extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. Then, the inorganic salt is removed by filtration, the filtrate is concentrated under reduced pressure. The obtained solid product clean column chromatography on silica gel (n-hexane : ethyl acetate = 10:1) to give 38 mg (yield 79%) of compound 21 as unpainted solid.

is, m), 3,23 (1H, d, J=11,54 Hz), 3.45 points-of 3.48 (1H, m), of 4.05 (1H, d, J=11,54 Hz), 5,20-5,32 (3H, m).

MS EI (m/z): 480 (M+).

Example 19. Olean-12,21-diene-3, 24(4)-diol (compound 22)

Compound 21 (48 mg) was dissolved in a mixed solvent of 1 ml of methanol and 1 ml of dichloromethane, to the solution add 0.5 ml of 1 N. hydrochloric acid. Then the mixture is stirred for 1 hour. The reaction mixture was diluted with dichloromethane, washed with water and dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure, obtaining 36 mg (yield 82%) of compound 22 as unpainted solid.

NMR (Dl3) memorial plaques of 0.87 (3H, s) of 0.90 (3H, s) to 0.94 (3H, s) of 0.95 (3H, s), and 0.98 (3H, s), is 1.11 (3H, s), 1,25 (3H, s), 0,84-2,13 (N, m), a 2.36 (1H, d, J= 4,10 Hz), 2,68 (1H, d, J=6,67 Hz), 3,32-3,37 (1H, m), 3.43 points-of 3.48 (1H, m), is 4.21 (1H, d, J=11,28 Hz), 5,20-and 5.30 (3H, m).

MS EI (m/z): 440 (M+).

Example 20. Olean-12-ene-3, 24(4)-diol (compound 23)

Compound 21 (30 mg) dissolved in a mixed solvent of 2 ml methanol and 1 ml of dichloromethane, to the solution was added 5 mg of 20% Pd(OH)2-C. After which the mixture is catalytically restore at atmospheric pressure during the night. Then the reaction mixture is filtered and the filtrate concentrated under reduced pressure, obtaining 26 mg (yield 9, is), of 0.93 (3H, s) of 1.13 (3H, s), 1,25 (3H, s), 1,25 (3H, s), 0,78-2,03 (N, m), is 2.37 (1H, d, J=4,16 Hz), 2,71 (1H, DD, J=2,50 Hz, 8,88 Hz), 3,32-3,37 (1H, m), 3,42-of 3.48 (1H, m), is 4.21 (1H, d, J=10,88 Hz), by 5.18 (1H, t-like).

MS EI (m/z): 442 (M+).

Example 21. 3, 24(4), Isopropylidenedioxy-22-metaxylem-12-ene (compound 26)

Compound 1 (300 mg) is dissolved in 5 ml of THF, added 130 mg of 55% sodium hydride and the mixture is then stirred at room temperature for one hour. Then to the reaction solution additionally add 2 ml of methyliodide. The mixture is stirred over night. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate. After which the inorganic salt is filtered off, the filtrate is concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (n-hexane : ethyl acetate = 10: 1) to give 285 mg (yield 93%) of compound 26 as a colorless foamy substance.

NMR (Dl3) memorial plaques 0,86 (3H, s) of 0.90 (3H, s), 0,99 (3H, s), and 1.00 (3H, s), is 1.11 (3H, s) and 1.15 (3H, s) to 1.22 (3H, s) to 1.37 (3H, s) of 1.44 (3H, s), 0,83-2,10 (N, m), 2,80-and 2.83 (1H, m), 3,23 (1H, d, J=11.8 Hz), or 3.28 (3H, C), 3,44-3,47 (1H, m) 4,06 (1H, d, J=11.8 Hz), 5,23 (1H, t-like).

MS FD (m/z): 512 (M+).

Example 22. 22-Metaxylem-12-ene-3, 24(4)-diol (compound 27)

Compound 26 (280 mg) was dissolved in mperature. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. After removal of inorganic salts by filtration, the solution concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (n-hexane : ethyl acetate = 2:1) to give 203 mg (yield 79%) of compound 27 as unpainted solid.

NMR (Dl3) memorial plaques of 0.85 (3H, s) to 0.89 (3H, s) of 0.90 (3H, s) to 0.94 (3H, s), and 1.00 (3H, s), is 1.11 (3H, s), 1,25 (3H, s), 0,80-2,10 (N, m), 2,80-2,82 (1H, m), or 3.28 (3H, s) to 3.33 (1H, d, J=11,1 Hz), 3,42 is-3.45 (1H, m), with 5.22 (1H, t-like).

MS EI (m/z): 472 (M+).

Example 23. 22-Benzyloxy-3, 24(4)-isopropylideneglycerol-12-ene (compound 30)

Compound 1 (50 mg) dissolved in 2 ml of anhydrous DMF, the solution was added 20 mg of 60% sodium hydrate and the mixture is stirred at room temperature for one hour. Then to the reaction solution add 85 ál of benzylbromide and the mixture is stirred over night. The reaction mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure. The remainder of the cleaning column chromatography on silicagel the tx2">

NMR (Dl3) memorial plaques to 0.89 (3H, s) to 0.94 (3H, s), 0,99 (3H, s), was 1.04 (3H, s) of 1.12 (3H, s) of 1.55 (3H, s) to 1.22 (3H, s) to 1.37 (3H, s) of 1.44 (3H, s), 0,87-2,17 (N, m), of 3.07 (1H, DD, J=3,05 Hz, 6,38 Hz), up 3.22 (1H, d, J=11,65 Hz), of 3.45 (1H, DD, J=of 4.44 Hz, 9,44 Hz), of 4.05 (1H, d, J=11,65 Hz), 4,32 (1H, d, J= 11,65 Hz), br4.61 (1H, d, J=11,65 Hz), of 5.24 (1H, t-like), 7.23 percent-7,37 (5H, m).

MS EI (m/z): 588 (M+).

Example 24. 22-Benzisoxazole-12-ene-3, 24(4)-diol (compound 31)

Compound 30 (34 mg) was dissolved in a mixed solvent of 2 ml of methanol and 1 ml of dichloromethane, to the solution add 0.5 ml of 1 N. hydrochloric acid and the mixture is then stirred at room temperature for 30 minutes After which the reaction mixture is added saturated sodium bicarbonate and the mixture is twice extracted with dichloromethane. The organic layer is dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure, obtaining 28 mg (yield 86%) of compound 31 as unpainted solid.

NMR (l3) memorial plaques 0,89 (6N, C) of 0.93 (3H, s) to 0.94 (3H, s), was 1.04 (3H, s), is 1.11 (3H, s), 1,25 (3H, s), 0,83-2,18 (N, m) of 2.38 (1H, usher.), 2,69 (1H, usher.), of 3.07 (1H, DD, J=is 3.08 Hz, 6,16 Hz), 3,32-to 3.36 (1H, m), 3.43 points-of 3.46 (1H, m), 4,20 (1H, d, J=10,51 Hz), 4,32 (1H, d, J=11,80 Hz), br4.61 (1H, d, J= 11,80 Hz), with 5.22 (1H, t-like), 7.23 percent-7,38 (5H, m).

MS EI (m/z): 548 (M+).

Example 25. 22 Ethoxy-3, 24(4) to the solid fuel source connections using 100 mg of compound 1 and 80 μl of ethyliodide. Thus obtained 61 mg (yield 58 %) of compound 32 as a colorless foamy substance.

NMR (CDCl3) memorial plaques of 0.87 (3H, s) to 0.89 (3H, s), 0,99 (3H, s) a 1.01 (3H, s) of 1.12 (3H, s) of 1.13 (3H, t, J=7.18 in Hz) and 1.15 (3H, s) to 1.22 (3H, s) to 1.37 (3H, s) of 1.44 (3H, s), 0,90-2,11 (N, m), 2,89 (1H, DD, J=2,82 Hz, 6.42 per Hz), 3,23 (1H, d, J=11,28 Hz), 3,22-3,30 (1H, m), of 3.46 (1H, DD, J=4,36 Hz, 9,24 Hz), 3,52-of 3.60 (1H, m), of 4.05 (1H, d, J=11,28 Hz), 5,23 (1H, t-like).

MS EI (m/z): 526 (M+).

Example 26. 22-Amoxilin-12-ene-3, 24(4)-diol (compound 33)

Repeating the method of example 24, except that as the starting compound used 61 mg of compound 32. Thus obtain 49 mg (yield 88%) of compound 33 as a colorless solid.

NMR (CDCl3) memorial plaques 0,86 (3H, s) to 0.89 (3H, s) of 0.90 (3H, s) of 0.95 (3H, s) a 1.01 (3H, s) of 1.12 (3H, s) to 1.14 (3H, t, J=7,22 Hz), 1,25 (3H, s), 0,84-2,13 (N, m), 2.40 a (1H, d, J=4,16 Hz), 2,70 (1H, d, J=8,87 Hz), 2,89 (1H, DD, J= 2,77 Hz, 6,38 Hz), 3,22-3,30 (1H, m) to 3.35 (1H, t, J=9,71 Hz), 3,42-3,47 (1H, m), 3,52-of 3.60 (1H, m), is 4.21 (1H, d, J=9,71 Hz), to 5.21 (1H, t-like).

MS EI (m/z): 486 (M+).

Example 27. 22 Allyloxy-3, 24(4)-isopropylidenedioxy-12-ene (compound 34)

Repeating the method of example 23, except that as the starting compound used 50 mg of compound 1 and 46 μl of Allilueva. Thus obtain 35 mg (yield 65%, is), of 1.12 (3H, s) of 1.16 (3H, s) to 1.22 (3H, s) to 1.37 (3H, s) of 1.44 (3H, s), 0,87-2,15 (N, m), 2,98 (1H, DD, J=2,78 Hz, 6,38 Hz), 3,23 (1H, d, J=11,65 Hz), of 3.45 (1H, d, J=of 4.44 Hz, 9,43 Hz), of 3.77-3,82 (1H, m), as 4.02-4,07 (2H, m), 5.08 to 5,12 (1H, m), 5,22 is 5.28 (2H, m), 5,85-to 5.93 (1H, m).

MS EI (m/z): 538 (M+).

Example 28. 22-Aliakseyeu-12-ene-3, 24(4)-diol (compound 35)

Repeating the method of example 24, except that as the starting compound used 33 mg of compound 34. Thus obtain 27 mg (yield 88%) of compound 35 as unpainted solid.

NMR (Dl3) memorial plaques to 0.88 (3H, s) to 0.89 (3H, s) of 0.90 (3H, s) to 0.94 (3H, s) a 1.01 (3H, s), is 1.11 (3H, s), 1,25 (3H, s), 0,84-2,75 (N, m), 2,97-2,99 (1H, m), 3,32-to 3.38 (1H, m), 3,42-of 3.48 (1H, m), of 3.77-a 3.83 (1H, m), as 4.02-4,08 (1H, m), is 4.21 (1H, d, J=11,09 Hz), 5,09-5,13 (1H, m), to 5.21 is 5.28 (2H, m), 5,86-5,94 (1H, m).

MS EI (m/z): 498 (M+).

Example 29. 22-Benzoyloxy-3, 24(4)-isopropylidenedioxy-12-ene (compound 36)

Compound 1 (50 mg) dissolved in 5 ml of dichloromethane, to the solution was added 18 mg of 4-dimethylaminopyridine and 17 μl of benzoyl chloride and the mixture is heated under reflux during the night. The reaction mixture was diluted with dichloromethane, washed with water and dried over magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure. The balance of cleaning the e unpainted solid.

NMR (CDCl3) memorial plaques of 0.91 (3H, s) of 0.93 (3H, s), and 1.00 (3H, s) of 1.06 (3H, s) of 1.16 (3H, s) of 1.18 (3H, s) of 1.23 (3H, s) to 1.38 (3H, s) of 1.44 (3H, s), 0.88 to 2,37 (N, m), 3,23 (1H, d, J=11,54 Hz), 3,47 (1H, DD, J=of 4.44 Hz, 9,48 Hz), of 4.05 (1H, d, J=11.54 in Hz), is 4.93 (1H, t, J=3,85 Hz), 5,33 (1H, t-like), was 7.45 (2H, t, J=6,70 Hz), 7,55 (1H, t, J=6,70 Hz), with 8.05 (2H, d, J=6,70 Hz).

MS EI (m/z): 602 (M+).

Example 30. 22-Benzoylacetone-12-ene-3, 24(4)-diol (compound 37)

Repeating the method of example 24, except that as the starting compound used 24 mg of compound 36. Thus obtain 19 mg (yield 83%) of compound 37 as unpainted solid.

NMR (Dl3) memorial plaques of 0.83 (3H, s), is 0.84 (3H, s) 0,86 (3H, s) to 0.88 (3H, s), and 0.98 (3H, s), is 1.11 (3H, s) of 1.18 (3H, s), 0,78-2,78 (N, m), or 3.28 (1H, t, J= 10,77 Hz), 3,35 is 3.40 (1H, m), 4,14 (1H, d, J=10,77 Hz), a 4.86 (1H, t-like), a 5.25 (1H, t-like), 7,37 (2H, t, J=7.18 in Hz) of 7.48 (1H, t, J= 7.18 in Hz), 7,98 (2H, d, J=7.18 in Hz).

MS EI (m/z: 562 (M+).

Example 31. 3, 24(4), Isopropylidenedioxy-22-propionyloxy-12-ene (compound 38)

Repeating the method of example 29, except that as the starting compound used 100 mg of compound 1 and 27 μl propionitrile. Thus obtain 73 mg (yield 66%) of compound 38 in the form of unpainted solid.

NMR (CDCl3) memorial plaques of 0.82 (3H, s) of 0.90 (3H, s), 0,99 (3H, THE(1H, d, J=11.54 in Hz}, of 3.46 (1H, DD, J=4,36 Hz, 9,23 Hz), of 4.05 (1H, d, J=11,54 Hz), of 4.66 (1H, t, J=3,59 Hz), 5,27 (1H, t-like).

MS EI (m/z): 554 (M+).

Example 32. 22-Propionyloxy-12-ene-3, 24(4)-diol (compound 39)

Repeating the method of example 24, except that as the starting compound used 73 mg of compound 38. Thus obtained 56 mg (yield 82%) of compound 39 as unpainted solid.

NMR (CDCl3) memorial plaques 0,81 (3H, s), 0,89 (6N, C) of 0.95 (3H, s), and 1.00 (3H, s) to 1.14 (3H, t, J = 7,49 Hz) and 1.15 (3H, s), 1,25 (3H, s), 0,84-2,75 (25N, m), 3,32-3,37 (1H, m), 3.43 points-of 3.46 (1H, m), is 4.21 (1H, d, J = 11,10 Hz), of 4.66 (1H, t, J = 2,89 Hz), 5,26 (1H, t-like).

MS EI (m/z): 514 (M+).

Example 33. 3, 24(4), Isopropylidenedioxy-22-valerolactones-12-ene (compound 40)

Repeating the method of example 29, except that as the starting compound used 50 mg of compound 1 and 36 μl of veterinaria. Thus obtain 32 mg (yield 55%) of compound 40 as an unpainted solid.

NMR (Dl3) memorial plaques of 0.82 (3H, s) of 0.90 (3H, s) to 0.92 (3H, t, J = 7,21 Hz), 0,99 (3H, s), and 1.00 (3H, s) and 1.15 (3H, s) of 1.16 (3H, s) of 1.23 (3H, s) to 1.38 (3H, s) of 1.44 (3H, s), 0,78-2,33 (N, m), 3,23 (1H, d, J = 11,65 Hz), of 3.46 (1H, DD, J = of 4.44 Hz, 9,43 Hz) 4,06 (1H, d, J = 11,65 Hz), of 4.66 (1H, t, J = 3,88 Hz), 5,28 (1H, t-like).

MS EI (m/z): 582 (M+)m exception as source connections using 31 mg of compound 40. Thus obtain 17 mg (yield 59%) of compound 41 in the form of unpainted solid.

NMR (CDCl3) memorial plaques 0,81 (3H, s), 0,89 (6N, C) to 0.92 (3H, t, J = 7,21 Hz) of 0.95 (3H, s) and 1.00 (3H, s) and 1.15 (3H, s), 1,25 (3H, s), 0,84-2,71 (29N, m), 3,31-to 3.38 (1H, m), 3,42-to 3.49 (1H, m), is 4.21 (1H, d, J = 10,82 Hz), of 4.66 (1H, t, J = 3,61 Hz), 5,26 (1H, t-like).

MS EI (m/z): 542 (M+).

Example 35. 22-TRANS-crotonylene-3, 24(4)-isopropylidenedioxy-12-ene (compound 42)

Repeating the method of example 29, except that as the starting compound used 50 mg of compound 1 and 30 μl of transnationalised. Thus obtain 9 mg (yield 16%) of compound 42 in the form of unpainted solid.

NMR (l3) memorial plaques of 0.82 (3H, s) of 0.90 (3H, s), 0,99 (3H, s) and 1.00 (3H, s), 1,15 (6N, C) of 1.23 (3H, s) to 1.38 (3H, s) of 1.44 (3H, s), 0.88 to 2,25 (24N, m), 3,23 (1H, d, J = 11,65 Hz), 3,47 (1H, DD, J = of 4.44 Hz, 9,44 Hz), of 4.05 (1H, D, J = 11,65 Hz), 4,71 (1H, t, J = 3,61 Hz), 5,28 (1H, t-like), of 5.81 and 5.86 (1H, m), 6.90 to-6,99 (1H, m).

MS EI (m/z): 566 (M+).

Example 36. 22-TRANS-cratonisation-12-ene-3, 24(4)-diol (compound 43)

Repeating the method of example 24, except that as the starting compound using 9 mg of compound 42. So get 5 mg (exit 59) 0,99 (3H, C) and 1.15 (3H, s), 1,25 (3H, s), 0,84-2,74 (N, m), 3,31-to 3.38 (1H, m), 3,42-3,47 (1H, m), 4,20 (1H, D, J = 10,77 Hz), 4,71 (1H, t, J = 3,59 Hz), 5,26 (1H, t-like), 5,81-to 5.85 (1H, m), 6.89 in-6,98 (1H, m).

MS EI (m/z): 526 (M+).

Example 37. 22 Cinnamoyloxy-3, 24(4)-isopropylidenedioxy-12-ene (compound 44)

Repeating the method of example 29, except that as the starting compound used 50 mg of compound 1 and 50 mg cinnamoylcocaine. Thus obtain 39 mg (yield 63%) of compound 44 as unpainted solid.

NMR (CDCl3) memorial plaques to 0.88 (3H, s) to 0.92 (3H, s), and 1.00 (3H, s) of 1.05 (3H, s) of 1.16 (3H, s) of 1.17 (3H, s) of 1.23 (3H, s) to 1.38 (3H, s) of 1.44 (3H, s), 0,90-2,32 (N, m), 3,24 (1H, d, J= 11,54 Hz), 3,47 (1H, DD, J = 4,36 Hz, 9,23 Hz), of 4.05 (1H, d, J = 11,54 Hz), 4,80 (1H, t, J = 3,59 Hz), 5,31 (1H, t-like), to 6.43 (1H, d, J = 15,90 Hz), 7,37-7,40 (3H, m), 7,52-of 7.55 (2H, m), 7,66 (1H, d, J = 15,90 Hz).

MS EI (m/z): 628 (M+).

Example 38. 22-Cinnamoyloxy-12-ene-3, 24(4)-diol (compound 45)

Repeating the method of example 24, except that as the starting compound used 30 mg of compound 44. Thus obtain 23 mg (yield 84%) of compound 45 as unpainted solid.

NMR (CDCl3) memorial plaques of 0.87 (3H, s) to 0.89 (3H, s) of 0.91 (3H, s) of 0.95 (3H, s), was 1.04 (3H, s) of 1.16 (3H, s), 1,25 (3H, s), 0,85-2,70 (N, m), 3,31-to 3.38 (1H, m), 3,42-to 3.49 (1H, m), is 4.21 (1H, d,>/P>MS EI (m/z): 588 (M+).

Example 39. 3, 22(4)-Dimensions-24(4)-N-methylamino-Olean-12-ene (compound 46)

Compound 7 (50 mg) was dissolved in a mixed solvent of 2 ml of methanol and 2 ml of dichloromethane, to the solution add 0.1 ml of 40% aqueous solution of methylamine and 10 mg of 20% Pd(OH)2-C. the mixture is Then catalytically restore at atmospheric pressure for 2 hours. Then the reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (dichloromethane : methanol =5:1) to give 13 mg (yield 25%) of compound 46 as unpainted solid.

NMR (CDCl3) memorial plaques to 0.89 (3H, s) of 0.90 (3H, s) of 0.93 (3H, s) to 0.94 (3H, s), was 1.04 (3H, s), 1,10 (3H, s) of 1.42 (3H, s), 0,87-2,19 (22N, m), 2,58 (3H, s) of 3.00 (1H, d, J = 12,20 Hz), 3,06-to 3.09 (1H, m) and 3.15 (1H, d, J = 12,20 Hz), 3,06-to 3.09 (1H, m) and 3.15 (1H, d, J = 12,20 Hz), 3,24 of 3.28 (1H, m), 4,32 (1H, d, J = 11,65 Hz) to 4.41 (1H, d, J = 10,82 Hz), br4.61 (1H, d, J = 11,65 Hz), and 4.68 (1H, d, J = 10,82 Hz), to 5.21 (1H, t-like), 7,28-7,40 (10H, m).

MS TSP (m/z): 652 (M++1).

Example 40. 24(4)-N-Methylamino-Olean-12-ene-3, 22-diol (compound 47)

Compound 46 (13 mg) was dissolved in a mixed solvent of 1 ml of methanol and 1 ml of dichloromethane, to the solution was added 10 mg of 20% Pd(OH)2-C. the mixture is Then catalytically restore and when the reduced pressure, receiving 4 mg (yield 49%) of compound 47 as unpainted solid.

NMR (CDCl3) memorial plaques 0,86 (3H, s) 0,92 (6N, C) of 0.95 (3H, s) of 1.03 (3H, s), 1,10 (3H, s) of 1.33 (3H, s), 0.88 to 2,10 (N, m), 2,68 (3H, s), 2,90 (1H, d, J = 12,57 Hz), 3,18 (1H, d, J = 12,57 Hz), 3,39 is-3.45 (3H, m), 5.25-inch (1H, t-like).

MS TSP (m/z): 472 (M++ 1).

Example 41. -3, 24(4)-Benzylideneacetone-12-ene (compound 48)

Compound 23 (500 mg) is dissolved in 12 ml of anhydrous DMF, and to the solution add 0.2 ml of benzaldehydes and a catalytic amount of camphorsulfonic. The mixture is then stirred at 45oWith during the night. Add benzaldehydes (0.1 ml) and the mixture was stirred at 45oWith 8 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and dried with magnesium sulfate. After removal of inorganic salts by filtration, the filtrate is concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (n-hexane : ethyl acetate =10:1) to give 498 mg (yield 83%) of compound 48 in the form of unpainted solid.

NMR (Dl3) memorial plaques from 0.84 (3H, s), 0.88 to (6N, C) to 0.97 (3H, s) of 1.07 (3H, s) and 1.15 (3H, s) to 1.48 (3H, s), 0.79, which is 2,48 (N, m), 3,60-to 3.67 (2H, m), 4,30 (1H, d, J = 11,54 Hz), 5,19 (1H, t-like), 5,78 (1H, s), 7,30-7,52 (5H, m).

MS is n-3-ol (compound 50)

Compound 48 (200 mg) dissolved in 3 ml of anhydrous toluene and to the solution is added dropwise 1.5 ml of a solution of hydride diisobutylaluminum (1.0 M) in toluene at temperatures from -25 to -20oC. the Mixture is stirred for one hour and then for another 3 hours, during which the temperature of the mixture is gradually raised to room. After adding to the reaction mixture of water the mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. After removal of inorganic salts by filtration, the solution concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (n-hexane : ethyl acetate =10:1), obtaining, in the form of unpainted solids, 61 mg (30% yield) of compound 49 and 96 mg (yield 48%) of compound 50.

Compound 49:

NMR (CDCl3) memorial plaques of 0.82 (3H, s), 0,87 (6N, C) to 0.89 (3H, s) to 0.94 (3H, s) of 1.12 (3H, s) to 1.21 (3H, s), 0,78-2,01 (N, m), 3,17 of 3.28 (3H, m), 4,16 (1H, d, J = 10,34 Hz), and 4.40 (1H, d, J = 11,38 Hz), of 4.67 (1H, d, J = 11,38 Hz), by 5.18 (1H, t-like), 7,25-7,37 (5H, m).

MS FAB (m/z): 533 (M++ 1).

Compound 50:

NMR (CDCl3) memorial plaques of 0.82 (3H, s) of 0.85 (3H, s), 0,86, (3H, s) of 0.87 (3H, s) to 0.92 (3H, s) of 1.12 (3H, s) of 1.28 (3H, s), 0,80-2,01 (N, m), 3,22-and 3.31 (2H, m), of 3.94 (1H, d, J = 7,21 Hz), 4,00 (1H, d, J = 9,16 Hz), 4,48 (2H, d, J = 2,77 Hz) to 5.17 (1H, t-like), 7,26-7,37 (5H, m).

MS EI (m/z): what astonaut in 0.5 ml of dichloromethane, to the solution add 0.5 ml of pyridine and 0.5 ml of acetic anhydride and the mixture is stirred at room temperature overnight. Then to the reaction mixture is added ice water and the mixture extracted with ethyl acetate. The extract is dried over magnesium sulfate. After which the inorganic salt is filtered off and the filtrate is concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (n-hexane : ethyl acetate =5:1) to give 14 mg (yield 81%) of compound 51 as unpainted solid.

NMR (Dl3) memorial plaques of 0.83 (3H, s), 0,87 (6N, C) to 0.96 (3H, s) to 0.97 (3H, s) of 1.12 (3H, s) and 1.15 (3H, s), 0,78-2,00 (N, m) to 1.98 (3H, m), 3,03 (1H, DD, J = 4,16 Hz, 11,65 Hz), 4,19 (1H, d, J = 11,93 Hz), 4,35 (1H, d, J = 11,93 Hz), 4,37 (1H, d, J = 11,65 Hz) and 4.65 (1H, d, J = 11,65 Hz), 5,19 (1H, t-like), 7,27-7,34 (5H, m).

MS EI (m/z): 574 (M+).

Example 44. 24(4)-Acetoxyl-12-EN-3-ol (compound 52)

Repeating the method of example 8, except that as the starting compound used 14 mg of compound 51. Thus receive 8 mg (yield 65%) of compound 52 in the form of unpainted solid.

NMR (CDCl3) memorial plaques of 0.83 (3H, s), 0,87 (6N, C) of 0.93 (3H, s) of 0.95 (3H, s) of 1.13 (3H, s) and 1.15 (3H, s), 0,78-2,08 (24N, m) to 2.06 (3H, s), 3,30 (1H, DD, J = 4,71 Hz, 11,38 Hz), 4,14 (1H, d, J = 11,65 Hz), 4,35 (1H, d, J = 11,65 Hz),the Association 53)

Repeating the method of example 21, except that as the starting compound used 26 mg of compound 49 and 30 μl of methyliodide. Thus obtain 17 mg (yield 61%) of compound 53 in the form of unpainted solid.

NMR (CDCl3) memorial plaques of 0.83 (3H, s), 0,87 (6N, C) to 0.96 (3H, s) a 1.01 (3H, s) of 1.12 (3H, s) and 1.15 (3H, s), 0.75 to 2,00 (N, m), 2,98 (1H, DD, J = 4,10 Hz to 11.79 Hz), 3.27 to (ZN, C), 3,39 (1H, d, J = 9.75 Hz), the 3.65 (1H, d, J = 9.75 Hz), was 4.42 (1H, d, J = 11,80 Hz), 4,63 (1H, d, J = 11,80 Hz), 5,19 (1H, t-like), 7,25 and 7.36 (5H, m).

MS EI (m/z): 546 (M+).

Example 46. 24(4)-Metaxylem-12-EN-3-ol (compound 54)

Repeating the method of example 8, except that as the starting compound used 17 mg of compound 53. Thus receive 12 mg (yield 86%) of compound 54 in the form of unpainted solid.

NMR (Dl3) memorial plaques of 0.82 (3H, s) 0,86 (3H, s) of 0.87 (3H, s) of 0.91 (3H, s) to 0.94 (3H, s) of 1.13 (3H, s) to 1.22 (3H, s), 0,78-2,02 (N, m), 3,21 (1H, d, J = 9,16 Hz), 3,22-3,29 (1H, m), and 3.31 (3H, s) to 3.89 (1H, d, J = 9,16 Hz), 3,91-of 3.95 (1H, m), is 5.18 (1H, t-like).

MS EI (m/z): 456 (M+).

Example 47. 3-Acetoxy-24(4)-benzisoxazole-12-ene (compound 55)

Repeating the method of example 43, except that as the starting compound used 25 mg of compound 50. Thus obtained 21 mg (output(3H, C) 0,95 (6N, C) of 1.07 (3H, s) of 1.12 (3H, s) 2,03 (3H, s), 0,78-2,00 (N, m), 3,49 (1H, d, J = 9,43 Hz), to 3.73 (1H, d, J = 9,43 Hz), 4,48 (2H, s), of 4.57 (1H, DD, J = 4,72 Hz, 11,10 Hz), is 5.18 (1H, t-like), 7,25-to 7.35 (5H, m).

MS EI (m/z): 574 (M+).

Example 48. 3-Acetoxyl-12-EN-24(4)-ol (compound 56)

Repeating the method of example 8, except that as the source connections using 21 mg of compound 55. Thus receive 10 mg (yield 56%) of compound 56 as unpainted solid.

NMR (CDCl3) memorial plaques of 0.82 (3H, s) of 0.87 (3H, s) to 0.88 (3H, s) of 0.91 (3H, s) of 0.95 (3H, s) of 1.09 (3H, s) of 1.13 (3H, s), 0.79, which is 2.00 (24N, m), of 2.08 (3H, s), 3,37-of 3.43 (1H, m), 4,16 (1H, d, J = 12,21 Hz) and 4.65 (1H, t, J = 8,05 Hz)that is 5.18 (1H, t-like).

MS EI (m/z): 484 (M+).

Example 49. 24(4)-Benzyloxy-3-metaxylem-12-ene (compound 57)

Repeating the method of example 23, except that as the starting compound used 26 mg of compound 50 and 30 μl of methyliodide. Thus obtain 19 mg (yield 70%) of compound 57 as unpainted solid.

NMR (CDCl3) memorial plaques of 0.83 (3H, s), 0,87 (6N, C) 0,94 (6N, C) of 1.12 (3H, s) of 1.17 (3H, s), 0.79, which is 2,02 (N, m) of 2.72 (1H, DD, J = 4,14 Hz, 11,93 Hz) to 3.34 (3H, s), 3,39 (1H, d, J = 9,71 Hz), and 3.72 (1H, d, J = 9,71 Hz), of 4.44 (2H, s), by 5.18 (1H, t-like), 7,22-to 7.35 (5H, m).

MS EI (m/z): 546 (M+).

Example 50. the output connections use 19 mg of compound 57. Thus obtain 9 mg (yield 56%) of compound 58 as unpainted solid.

NMR (Dl3) memorial plaques of 0.82 (3H, s), 0,87 (N, C) to 0.94 (3H, s) of 1.13 (3H, s) of 1.20 (3H, s), 0.79, which is 2,02 (N, m), with 2.93 (1H, DD, J = 4,16 Hz, 11,38 Hz), 3,18-of 3.25 (2H, m) to 3.36 (3H, s), 4,10-to 4.14 (1H, m), is 5.18 (1H, t-like).

MS EI (m/z): 456 (M+).

Example 51. 24(4)-Acetoxy-3, 22-benzisoxazole-12-ene (compound 59)

Repeating the method of example 43, except that as the starting compound used 30 mg of compound 6. Thus obtain 24 mg (yield 76%) of compound 59 as unpainted solid.

NMR (CDCl3) memorial plaques to 0.89 (3H, s) to 0.94 (3H, s) to 0.96 (3H, s) to 0.97 (3H, s) of 1.05 (3H, s), is 1.11 (3H, s) and 1.15 (3H, s) to 1.98 (3H, s), 0,84-2,18 (N, m), to 3.02 (1H, DD, J = 4,16 Hz, 11,65 Hz), of 3.07 (1H, DD, J = 2,77 Hz, 6,10 Hz), 4,18 (1H, d, J = 11,93 Hz), 4,32 (1H, d, J = 11,93 Hz), 4,35 (1H, d, J = 11,93 Hz), 4,37 (1H, d, J = 11,93 Hz), to 4.62 (1H, d, J = 11,93 Hz) and 4.65 (1H, d, J = 11,93 Hz), 5,23 (1H, t-like), 7.23 percent and 7.36 (10H, m).

MS EI (m/z): 680 (M+).

Example 52. 24 (4)-Acetoxyl-12-ene-3, 22-diol (compound 60)

Repeating the method of example 8, except that as the starting compound used 24 mg of compound 59. Thus receive 12 mg (yield 69%) of compound 60 in the form of unpainted solid.

NMR (CDCl3) m the C), to 4.14 (1H, d, J = 11,66 Hz), 4,35 (1H, d, J = 11,66 Hz in), 5.25 (1H, t-like).

MS EI (m/z): 500 (M+).

Example 53. 3, 22 Dimensions-24 (4)-propionyloxy-12-ene (compound 61)

Repeating the method of example 29, except that as the starting compound used 32 mg of compound 6 and 6.8 μl propionitrile. Thus obtain 22 mg (yield 62%) of compound 61 in the form of unpainted solid.

NMR (CDCl3) memorial plaques to 0.89 (3H, s) to 0.94 (3H, s) to 0.96 (3H, s) to 0.97 (3H, s) of 1.05 (3H, s) of 1.09 (3H, t, J = 7,49 Hz), 1,11 (3H, s) and 1.15 (3H, s), 0,84-2,30 (N, m), 3.00 and-3,10 (2H, m), 4,20 (1H, d, J = 11.55 m Hz), 4,30-4,39 (3H, C) 4,60-of 4.67 (2H, m), 5,23 (1H, t-like), 7,25-to 7.35 (10H, m).

MS EI (m/z): 694 (M+).

Example 54. 24(4)-Propionyloxy-12-ene-3, 22-diol (compound 62)

Repeating the method of example 8, except that as the source connections using 21 mg of compound 61. Thus obtain 14 mg (yield 88%) of compound 62 in the form of unpainted solid.

NMR (CDCl3) memorial plaques to 0.88 (3H, s) to 0.92 (3H, s) to 0.94 (3H, s) to 0.97 (3H, s) of 1.05 (3H, s) of 1.12 (3H, s) and 1.15 (3H, t, J = 7,49 Hz) of 1.16 (3H, s), 0,89-2,13 (22N, m) to 2.35 (2H, q, J = 7,49 Hz), 3,29 (1H, DD, J = 4,72 Hz, 10,82 Hz), 3,42 is-3.45 (1H, m), 3,49 (1H, s) to 4.16 (1H, d, J =11,66 Hz), 4,37 (1H, d, J = 11,66 Hz), 5,26 (1H, t-like).

MS EI (m/z): 514 (M+).

Welcome, as source connections using 20 mg of compound 6 and 0.3 ml of methyliodide. Thus receive 8 mg (yield 38%) of compound 63 in the form of unpainted solid.

NMR (CDCl3) memorial plaques to 0.89 (3H, s) to 0.94 (3H, s) to 0.97 (3H, s) of 1.02 (3H, s), was 1.04 (3H, s), 1,10 (3H, s) and 1.15 (3H, s), 0,78-2,18 (N, m), 2.95 and 3.00 for (1H, m), 3,05-3,10 (1H, m), with 3.27 (3H, s), 3,39 (1H, d, J = 9.75 Hz), the 3.65 (1H, d, J = 9.75 Hz), 4,32 (1H, d, J = 11,80 Hz), 4,42 (1H, d, J = 11,80 Hz), br4.61 (1H, d, J = 11,80 Hz), 4,63 (1H, d, J = 11,80 Hz), 5,23 (1H, t-like), 7,24-to 7.35 (10H, m).

MS EI (m/z): 652 (M+).

Example 56. 24(4)-Metaxylem-12-ene-3, 22-diol (compound 64)

Repeating the method of example 8, except that as the starting compound used 8 mg of compound 63. Thus receive 6 mg (yield 98%) of compound 64 as unpainted solid.

NMR (CDCl3) memorial plaques of 0.87 (3H, s) of 0.91 (3H, s) to 0.92 (3H, s) of 0.95 (3H, s), was 1.04 (3H, s), is 1.11 (3H, s) to 1.22 (3H, s), 0,84-2,12 (N, m), 3,20 (1H, d, J = 9,15 Hz), 3,23-of 3.27 (1H, m), and 3.31 (3H, s), 3,42-3,44 (1H, m), the 3.89 (1H, d, J = 9,15 Hz), of 5.24 (1H, t-like).

MS EI (m/z): 472 (M+).

Example 57. 3, 4-Benzylideneacetone-12-EN-22-ol (compound 65)

Repeating the method of example 41, except that as the starting compound used to 1.00 g of compound 9. So get 997 mg (yield 83%) soy is (3H, C) a 1.08 (3H, s) to 1.14 (3H, s) to 1.48 (3H, s), 0,90-2,50 (22N, m), 3,44 (1H, q, J = 5 Hz), 3,60-to 3.67 (2H, m), 4,30 (1H, d, J = 11 Hz), 5,26 (1H, t-like), 5,78 (1H, s), 7,30-7,40 (3H, m), 7,45-of 7.55 (2H, m).

MS EI (m/z): 546 (M+).

Example 58. 22 - Benzyloxy-3, 24-benzylideneacetone-12-ene (compound 66)

Repeating the method of example 23, except that as the starting compound used 5,42 mg of compound 65. So get 3.24 mg (51% yield) of compound 66 in the form of unpainted solid.

NMR (Dl3) memorial plaques of 0.90 (3H, s) of 0.95 (3H, s), and 0.98 (3H, s) of 1.05 (3H, s) of 1.07 (3H, s) of 1.13 (3H, s) to 1.48 (3H, s), 0,90-2,50 (N, m) is 3.08 (1H, q, J = 3 Hz), 3,60-3,66 (2H, m), 4,30 (1H, d, J = 11 Hz), 4,32 (1H, d, J = 12 Hz), 4,60 (1H, t, J = 11 Hz), of 5.24 (1H, t-like), 5,78 (1H, s), 7,2-7,6 (10H, m).

MS EI (m/z): 636 (M+).

Example 59. 22, 24(4)-Dibenzalacetone-12-EN-3-ol (compound 67)

Repeating the method of example 42, except that as the starting compound used 400 g of compound 66. So get 275 mg (yield 69%) of compound 67 and 25.1 mg (yield 6%) of compound 6 as unpainted solid.

NMR (CDCl3) memorial plaques of 0.85 (3H, s) to 0.89 (3H, s) 0,93 (6N, (C), was 1.04 (3H, s), is 1.11 (3H, s) of 1.28 (3H, s), 0,80-2,20 (22N, m), 3,05-is 3.08 (1H, m), 3,26-3,30 (2H, m), 3.95 to as 4.02 (1H, m), or 4.31 (1H, d, J = 12 Hz), 4,48 (2H, s), br4.61 (1H, d, J = 12 Hz), to 5.21 (1H, t-like), the Association 68)

Repeating the method of example 43, except that as the starting compound used 100 g of compound 67. Thus obtain 33 mg (30% yield) of compound 68 in the form of unpainted solid.

NMR (CDCl3) memorial plaques to 0.89 (3H, s) of 0.93 (3H, s), 0,95 (6N, (C), was 1.04 (3H, s) of 1.06 (3H, s), 1,10 (3H, s) 2,02 (3H, s), 0,90-2,18 (N, m), 33,05-to 3.09 (1H, m), 3,48 (1H, d, J = 9,71 Hz), to 3.73 (1H, d, J = 9,71 Hz), 4,32 (1H, d, J = 11,65 Hz), 4,47 (2H, s), of 4.57 (1H, DD, J = 4,71 Hz, 11,37 Hz), br4.61 (1H, d, J = 11,65 Hz), with 5.22 (1H, t-like), 7,25 was 7.36 (10H, m).

MS EI (m/z): 680 (M+).

Example 61. 3-Acetoxyl-12-ene -22, 24(4)-diol (compound 69)

Repeating the method of example 8, except that as the starting compound used 32 mg of compound 68. Thus receive 15 mg (yield 64%) of compound 69 in the form of unpainted solid.

NMR (Dl3) memorial plaques of 0.87 (3H, s) of 0.91 (3H, s) to 0.92 (3H, s) to 0.96 (3H, s), was 1.04 (3H, s) of 1.09 (3H, s), is 1.11 (3H, s), of 2.08 (3H, s), 0,90-2,12 (N, m), 3,37-of 3.46 (2H, m), 4,15 (1H, d, J = 11,80 Hz), 4,62-of 4.67 (1H, m), the 5.25 (1H, t-like).

MS EI (m/z): 500 (M+).

Example 62. 22, 24(4), Dibenzylamine-3-metaxylem-12-ene (compound 70)

Repeating the method of example 23, except that as the starting compound used 100 mg of compound 67. Thus obtain 49 mg (yield 47%)), of 0.95 (3H, s), was 1.04 (3H, s), 1,10 (3H, s) of 1.17 (3H, s), 0.75 to 2,17 (N, m), 2,73 (1H, DD, J = 4,11 Hz, 11,80 Hz), 3,05-is 3.08 (1H, m) to 3.34 (3H, s) to 3.38 (1H, d, J = 9.75 Hz), 3,71 (1H, d, J = 9.75 Hz), 4,32 (1H, d, J = 12,05 Hz), of 4.44 (2H, s), br4.61 (1H, d, J = 12,05 Hz), with 5.22 (1H, t-like), 7.23 percent and 7.36 (10H, m).

MS TSP (m/z): 653 (M++ 1).

Example 63. 3-Metaxylem-12-ene -22, 24(4)-diol (compound 71)

Repeating the method of example 8, except that as the starting compound used 48 mg of compound 70. Thus obtained 21 mg (yield 59%) of compound 71 as unpainted solid.

NMR (CDCl3) memorial plaques of 0.87 (3H, s) to 0.88 (3H, s) of 0.91 (3H, s) of 0.95 (3H, s), was 1.04 (3H, s), is 1.11 (3H, s) of 1.20 (3H, s), 0,84-2,14 (22N, m) of 2.92 (1H, DD, J = 4,71 Hz, 11,80 Hz), 3,19-3,24 (2H, m) to 3.36 (3H, s), 3,44 (1H, t-like), 4,10-to 4.15 (1H, m), a 5.25 (1H, t-like).

MS TSP (m/z): 473(M++ 1).

Example 64. Methyl ester 3, 22 - dibenzalacetone-12-EN-24 (4)- eve acid (compound 72)

Compound 10 (15 mg) dissolved in 1 ml of methanol and to the solution add a solution trimethylsilyldiazomethane in hexane to until the yellow color will not fade. Then the reaction mixture was concentrated under reduced pressure and the residue cleaned column chromatography on silica gel (n-hexane : ethyl acetate =4:1) to give 13 mg (yield 83%) of compound 72 in the form of colorless to 1.31 (3H, C) 0,85-2,32 (N, m), 2,96 (1H, DD, J = 4,16 Hz, 11,93 Hz), of 3.07 (1H, DD, J= 3,05 Hz, 6,38 Hz), the 3.65 (3H, s), 4,32 (1H, d, J = 11,93 Hz), 4,48 (1H, d, J = 12,21 Hz), br4.61 (1H, d, J = 11,93 Hz), 4.72 in (1H, d, J = 12,21 Hz), with 5.22 (1H, t-like), 7,26-7,37 (10H, m).

MS FAB (m/z): 667 (M++ 1).

Example 65. Methyl ester 3, 22 - dihydroxytoluene-12-EN-24 (4)-eve acid (compound 73)

Repeating the method of example 8, except that as the starting compound used 12 mg of compound 72. Thus obtain 9 mg (yield 100%) of compound 73 as unpainted solid.

NMR (CDCl3) memorial plaques to 0.80 (3H, s) to 0.88 (3H, s) to 0.92 (3H, s), 0,99 (3H, s), was 1.04 (3H, s) of 1.12 (3H, s) of 1.42 (3H, s), 0,72-2,12 (N, m), 3,07-3,13 (1H, m), 3.43 points-of 3.48 (1H, m), of 3.69 (3H, s), 5,27 (1H, t-like).

MS EI (m/z): 486 (M+).

The substituents in the formula (I-1), corresponding to the structures of the compounds 1-73 are as shown in the table.

In the table below: Tg denotes trail, PG denotes a benzyl, and Ts denotes toil.

In compounds 1-20 and 23-73 indicates a simple relationship. Whereas in compounds 21 and 22 denotes a double bond.

Preparative example 1.

Tablets

The connection according to this invention granularit wet. After addition of magnesium stearate, the mixture is pressed, produces metalcrafter sodium - 20

The hypromellose - 5

Magnesium stearate - 3

Only 278

Preparative example 2

Suppositories

Valappil (Weilapzole) H-15 is heated at 60oTo add the connection 9 and is dispersed in the resulting melt. The variance of making containers for suppository. Then these containers are cooled to room temperature, receiving suppositories. Each suppository has the following composition, mg:

Connection 9 - 200

Valappil N-15 - 1000

Just - 1200

Example test 1

Research hepatocytomegaly inhibitory model (in vitro)

The test compound added at a concentration of 0.1-10 μg/ml to ner G-2 cells in the presence of aflatoxin B1(10-5M). The cells are then incubated in CO2-incubator at 37oWith 48 hours. After incubation of the cells stained with Trianon blue. The ability of the injected dye was measured using Monocellator (manufactured by Olympus Optical Co., Ltd.). Hepatocytomegaly inhibitory activity (%) calculated from the following equation. In the equation the value for the control group represents the optical density (%) in the presence only of aflatoxin B1and the value for the treated group is optical, what hepatocytomegaly inhibitory activity of compounds 1, 3, 8, 9, 10, 11, 14, 19, 23, 25, 27, 35, 37, 43, 45, 52, 54, 60, 64, 71 and 73 is more than 5%.

< / BR>
Acute toxicity

Compound 9 according to this invention is injected SN-male mice at a dose of 4 mg/kg twice a day for 3 days. As a result of the absence of any significant toxicity.

Application

Test connection: 10 µg/ml

Connection - Inhibitory activity (%)

28 - 19

Test connection: 1 µg/ml

Connection - Inhibitory activity (%)

12 - 18

17 - 12

29 - 11

50 - 5

Test connection: 0.1 ág/ml

Connection - Inhibitory activity (%)

13 - 11

31 - 7

33 - 7

56 - 7s

1. The pharmaceutical composition inhibiting necrosis of hepatocytes containing derivative triterpene represented by the formula (I)

,

or its pharmaceutically acceptable salt,

where R1denotes a hydroxyl group, WITH1-6alkoxy, C1-6alkylcarboxylic or benzyloxy;

R2- C1-6alkyl, -CH2OR SIG5where R5is a hydrogen atom, a C1-6alkyl, benzyl or1-6alkylsulphonyl, formyl, -R6, RG may be the same or different, is a hydrogen atom or a C1-6alkyl;

or R1and R2can be combined with each other to form - O-(CR9(R10)-OCH2- where R9and R10that may be the same or different, represent a hydrogen atom or a C1-6alkyl or phenyl;

R3and R4that may be the same or different, represent a hydrogen atom, hydroxyl group, WITH1-6alkyl, hydroxy1-6alkyl, formyl, -R", where R11is a hydrogen atom or or12where R12- C1-6alkyl, benzyl; C1-6alkylsulphonyl, phenylcarbinol,2-6alkenyl,2-6alkenylboronic or phenylacetylcarbinol, or R3and R4are combined with each other to form a methylene group or = O;

means simple or double bond, provided that when a double bond, R4is missing.

2. The pharmaceutical composition according to p. 1, where R1- hydroxyl group, R2- -CH2OR SIG5and R3- the hydrogen atom.

3. The pharmaceutical composition according to p. 2, where R4is a hydroxyl group or-or SIG12.

4. The pharmaceutical composition according to p. 1, where R1- C1-6alkoxy.

5. Pharmaceutical kouklina group.

6. The pharmaceutical composition according to p. 1, where R1means hydroxyine group or benzyloxy which may be optionally substituted, R2- -R6, R3is a hydrogen atom and R4denotes a hydroxyl group or-OR12.

7. The pharmaceutical composition according to p. 1, where R1denotes a hydroxyl group, a C1-6alkoxy, C1-6alkylcarboxylic, R2- -CH2OR5and R3and R4- the hydrogen atom.

8. The pharmaceutical composition according to p. 1, where R1means hydroxyine group, R2- -CH2OR5, R3- C1-6alkyl, and R4- hydroxyl group.

9. The pharmaceutical composition according to p. 1, where R1means hydroxyine group, R2- -CH2OR5, R3is a hydrogen atom and R4- hydroxy C1-6alkyl or carboxyl.

10. The pharmaceutical composition according to any one of paragraphs. 1-9, where a derivative triterpene represented by the formula (I) has a configuration represented by the formula (I-1)

< / BR>
11. Derived triterpene represented by the formula (II)

,

or its pharmaceutically acceptable salt,

where R1denotes a hydroxyl group, WITH1-65
is a hydrogen atom, a C1-6alkyl, benzyl, triphenylmethyl or1-6alkylsulphonyl; formyl, -R6where R6is a hydrogen atom or a C1-6alkyl,

or-CH2N(R7R8where R7and R8that may be the same or different, represent a hydrogen atom or a C1-6alkyl;

or R1and R2can be combined with each other to form-O-(CR9(R10)-OCH2- where R9and R10that may be the same or different, represent a hydrogen atom or a C1-6alkyl or phenyl;

R3and R4that may be the same or different, represent1-6alkyl, hydroxy1-6alkyl, formyl, -R11where R11is a hydrogen atom or or12where R12- C1-6alkyl, benzyl, phenylcarbinol,2-6alkenyl,2-6alkenylboronic or phenylacetylcarbinol, or

R3and R4can be combined with each other to form a methylene group;

means simple or double bond, provided that when a double bond, R4no;

when R1and R2combined with the formation of-O-(CR9(R10)-OCH2- where any one of R9and R10,

when any one of R3and R4stands WITH1-6alkyl group, another Deputy may additionally denote a hydroxyl group.

12. Connection on p. 11, where R1and R2combined with the formation of-O-(CR9(R10)-OCH2.

13. Connection on p. 12, where R9and R10is methyl, R3is a hydrogen atom and R4- -OR12where R12- C1-6alkyl, phenylcarbinol,2-6alkenyl,2-6alkenylboronic or phenylacetylcarbinol.

14. Connection on p. 12, where R9is a hydrogen atom and R10is phenyl.

15. Connection on p. 14, where R3and R4- the hydrogen atom.

16. Connection on p. 12 or 14, where R4is hydroxyl or benzyloxy.

17. Connection on p. 11, where R1denotes a hydroxyl group, R2- - CH2OR SIG5, R3- C1-6alkyl, and R4- hydroxyl group.

18. Connection on p. 17, where R5- the hydrogen atom.

19. Connection on p. 11, where R1denotes a hydroxyl group, R2- -CH2OR SIG5, R3is a hydrogen atom and R4- hydroxy1-6alkyl or-R11.

20. Connection on p. 19, where R5- atom is be optionally substituted,2- -CH2OR SIG5where R5is a hydrogen atom, or1-6alkyl or C1-6alkylsulphonyl.

22. Connection on p. 11, where R1denotes a hydroxyl group, R2- -CH2OR SIG5where R5- C1-6alkyl or C1-6alkylsulphonyl.

23. Connection on p. 11, where R1denotes a hydroxyl group, WITH1-6alkoxy or1-6alkylcarboxylic, R2- -CH2OR SIG5where R5- benzyl.

24. Connection on p. 11, where R1- C1-6alkoxy or1-6alkylcarboxylic, R2- -CH2HE.

25. Connection on p. 11, where R1denotes a hydroxyl group, R2- -CH2OR5and R3and R4are combined with each other to form a methylene group.

26. Connection on p. 25, where R5- the hydrogen atom.

27. Connection on p. 11, where R1and R2are combined with each other to form-O-(CR9(R10)-OCH2and represents a double bond.

28. Connection on p. 27, where R9and R10is methyl.

29. Connection on p. 11, where in the formula (II) R1denotes a hydroxyl group, R2- -COO-C1-6alkyl.

30. The connection is de in the formula (II)R1- benzyloxy, R2- formyl, carboxyl, -COO-C1-6alkyl or-CH2OR SIG5where R5is a hydrogen atom, a C1-6alkyl or C1-6alkylsulphonyl and R4- benzyloxy.

32. Connection on p. 11, where in the formula (II) R1denotes a hydroxyl group or a C1-6alkoxy, R2- benzyloxyethyl and R4- benzyloxy.

33. The compound according to any one of paragraphs. 11-28 having the configuration represented by the formula (II-1)

< / BR>
34. Derived triterpene represented by the formula (II), or its pharmaceutically acceptable salt

< / BR>
where R1represents a hydroxyl group;

R2- -CH2OR5where R5is a hydrogen atom, a C1-6alkyl, or benzyl;

R3is a hydrogen atom;

R4- C1-6alkyl, hydroxy1-6alkyl, formyl, -R11where R11is a hydrogen atom or a C1-6alkyl, or - OR12where R12- C1-6alkyl, aralkyl, which may be optionally substituted, arylcarbamoyl,2-6alkenyl,2-6alkenylboronic, or arylalkylamines, which may be optionally substituted.

35. Connection on p. 34, where R5is a hydrogen atom, R4- -OR SIG12where R12the sludge.

36. Connection on p. 34, representing a 22-metaxylem-12-ene-3, 24(4)-diol or its pharmaceutically acceptable salt.

37. Connection on p. 34, representing a 22-amoxilin-12-ene-3, 24(4)-diol or its pharmaceutically acceptable salt.

Priority points and features:

07.07.1995 on PP. 1-37;

26.02.1996 - clarification of signs.

 

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< / BR>
showing hepatoprotective and anti-HIV activity

The invention relates to the synthesis of allobetulin (19, 28-epoxy-oleana-3-Ola) isomerization of Betulinol(loop-20(29)-EN-3, 28-diol) in the presence of catalysts

-l-rhamnopyranoside methyl ester of glycyrrhetic acid, manifesting hepatoprotective activity" target="_blank">

The invention relates to organic chemistry, to new chemical compound, namely 3-O-[2-deoxy--L-rhamnopyranose]-11-oxo-20-methoxycarbonyl-30-norolean-12-EN-3-Olu formula

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showing hepatoprotective activity

-d-galacto - or-l-rhamnopyranoside methyl ester of glycyrrhetic acid, manifesting antiulcer activity and stimulating reparative regeneration of the skin" target="_blank">

The invention relates to organic chemistry, new chemical compounds, namely 3-O-2-deoxy--D-galacto - and-L-rhamnopyranoside methyl ester of glycyrrhetic acid of General formula

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showing antiulcer activity and stimulating reparative regeneration of the skin

The invention relates to the field of chemical processing of birch bark (outer layer of birch bark)

The invention relates to extraction of valuable chemicals from waste timber, namely the allocation method betulin formula I from birch bark

The invention relates to a steroid compound of General formula I

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whereis = O, -HE, or SIG or ООСR, where R represents an alkyl group having from 1 to 6 carbon atoms; R6represents H or -(CH2)mN, where m = 1 or 2; R7represents H, C1-4-alkyl, C2-4alkenyl or2-4-quinil; R11represents H, C1-4-alkyl, C2-4alkenyl,2-4-quinil; E represents, including the carbon atoms 16 and 17 of the D ring, a 4-7-membered hydrocarbon ring, where the specified ring is in the-position relative to the D-ring, substituted by a group REand optionally contains one endocyclic double bond; RErepresents H, C1-5-alkyl, C2-5alkenyl,2-5-quinil,1-5-alkyliden, -(CH2)n-N3or -(CH2)n-SP, where n = 1 or 2, and where the alkyl group may be substituted by-OR, -OOCR where R is alkyl with 1-6 carbon atoms; R17is-HE-or SIG or ООСR, where R is alkyl with 1-6 carbon atoms, where the aforementioned steroid compound may be, but neeba is either ring may be aromatic

The invention relates to medicine

The invention relates to the field of pharmacy

The invention relates to medicine, namely to dentistry

The invention relates to medicine, namely to dentistry
The invention relates to medicine and can be used in the treatment of concomitant chlamydial herpes infection in women with inflammatory diseases of the pelvic organs (PID)

The invention relates to medicine and can be used to treat a variety of rhinitis: allergic, polynosic, year-round

The invention relates to medicine, in particular to urology and andrology

The invention relates to medicine, in particular to andrology and urology

FIELD: medicine, immunology.

SUBSTANCE: invention proposes an agent enhancing the immunogenic properties of tetanus anatoxin (adjuvant). Invention proposes the vegetable triterpenic compound miliacin as an agent enhancing immunogenic properties of tetanus anatoxin. Agent enhances the immune response value in its applying as a vaccine preparation of tetanus anatoxin. The agent miliacin elicits its stimulating effect for both the first and repeated administration of vaccine that allows suggesting its possible applying for prophylactic vaccinations with tetanus anatoxin. Taking into account the high tolerance of miliacin in the broad range of its doses it is suggested its practical applying as an agent promoting to the enhanced formation of vaccinal immunity in prophylactic vaccinations with tetanus anatoxin.

EFFECT: valuable medicinal properties of agent.

6 tbl

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