Derived 4-deoxy-4-epipodophyllotoxin or its pharmaceutically acceptable salt or pharmaceutical composition based on it

 

(57) Abstract:

Usage: in medicine as an anticancer agent. The inventive product-derived 4-deoxy-4-epipodophyllotoxin formula (I), where R1is N, stands, benzyloxycarbonyl, lower alkanoyl, which may have one or more halogen atoms or a group of the formula Si(Rx)(Ry)(Rz), where the radicals are the same or different and each represents lower alkyl, or phenyl, R is lower alkenyl, lower alkyl having at least one hydroxyl group, a group of the formula -(CH2)mSNO, where m is an integer from 0 to 4, lower alkyl having ketoaldehyde group, or a group of the formula (CH2)nNHR2R3where n is an integer from 1 to 6, and the radicals are the same or different and each is an atom of N, cycloalkyl, group f-ly-N(Ra)(Rb), where the radicals Ra and Rb are the same or different and each is lower alkyl or phenyl, or the radicals can be combined with the formation of the substituted lower alkyl piperazino group; or lower alkyl which may be substituted by hydroxyl, lower alkoxy, phenyl, 6-membered nitrogen-containing, heterocyclic the tsya lower alkyl, R2and R3can be combined with the formation of a cyclic structure, which may optionally include additional atoms of oxygen and/or nitrogen and may in addition have a lower alkyl which may be substituted by hydroxyl, or piperidino group as a substituent, provided, however, that when R1is H, R-group, f-crystals (CH2mCHO or a group of f-crystals (CH2nNH2R3or their pharmaceutically acceptable salts, and pharmaceutical composition based on it. Compound 1 possesses antitumor activity ED 50 is 1,210 in power minus 7oC6,310 in power minus 9. The pharmaceutical composition comprises a carrier and an active ingredient connection f-crystals 1 or its pharmaceutically acceptable salt at a dose of 0.1 to 5000 mg/day. Connection structure of f-crystals 1

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2 C. and 7 C.p. f-crystals, 2 tab.

The invention relates to new derivatives of 4-deoxy-4-epipodophyllotoxin and their pharmaceutically acceptable salts, which possess antitumor activity and can be used as antitumor agents.

Has long been known derivatives podofillotoksina with antitumor activity, and among them etoposide and opelu, nausea and vomiting, so they cannot be admitted into the clinic with guaranteed security. So, still not been found satisfactory connection.

Noting these problems of the prior art, the author of the invention is enthusiastically developed this technology area and found that a new derivative of 4-deoxy-4-epipodophyllotoxin following General formula (I) or its pharmaceutically acceptable salt have a very high antitumor activity and are useful as an antitumor agent. This discovery formed the basis of the invention.

Thus, the present invention provides 4-deoxy-4-epipodophyllotoxin derivative of General formula (I)

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where R1is a hydrogen atom, stands, benzoyloxymethyl, lower alkanoyl, which may have one or more halogen atoms, or a group of the formula Si(Rx)(Ry)(Rzwhere Rx, Ryand Rzare the same or different and each is lower alkyl or phenyl; R is lower alkenyl, lower alkyl having at least one hydroxyl group, a group of the formula -(CH2)mCHO, where m t is nNR2R3where n is an integer from 1 to 6; R2and R3are the same or different and each is a hydrogen atom, cycloalkyl, a group of the formula N(Ra)(Rb) where Raand Rbis the same or different and each is lower alkyl or phenyl, or Raand Rbcan be combined with the formation of the lower alkyl substituted piperazino group), or lower alkyl which may be substituted by hydroxyl, lower alkoxy, phenyl, 6-ticleni nitrogen-containing heterocyclic group or a group of formula - N(Rc)(Rd), where Rcand Rdare the same or different and each is lower alkyl; R2and R3can be combined with the formation of a cyclic structure, which may not necessarily include additional oxygen atoms and/or nitrogen and may optionally have a lower alkyl which may be substituted by hydroxyl, or piperidino group as a substituent, provided, however, that when R1is a hydrogen atom, R is (CH2)mCHO or (CH2)nN R2R3or its pharmaceutically acceptable salt.

The compound of General formula (I) according to the tumor.

Therefore, the invention provides an anticancer composition comprising an effective amount of the compound of the above formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

In addition, the invention provides a method of treating tumors in mammals, which consists in introducing the compound of the above formula (I) or its pharmaceutically acceptable salt mammal.

Referring to the above General formula (I), the lower alcoolica group R1include2-5-alkanoyloxy group with a straight or branched chain, such as acetyl propionyl, butyryl isobutyryl, valeryl, isovaleryl, pivaloyl, etc., and the halogen atom may be, for example, fluorine, choir, bromine or iodine. Lower alkyl group, as indicated by the Rx, Ry, Rz, R2, R3, Ra, Rb, Rcand Rdinclude1-16-alkyl straight or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert. butyl, pentyl, neopentyl, hexyl, etc., Lower Alchemilla group R include2-6alkenyl straight or branched chain, such as vinyl, 1-propenyl, isopr is, include1-6is alkyl having 1 or 2 hydroxyl groups, such as oximeter, 2-oxyethyl, 2-oksipropil, 3-oksipropil, 2,3-DIXIPAY, 2,3-dioksimaty, 2,3-dioxyphenyl, 2,3-doxyhexal, etc., Lower alkyl having ketoaldehyde group include1-6is alkyl having alpha - or beta-ketoaldehyde group, such as 2-hydroxy-2-formyl-1-ethyl, 2-oxo-3-formyl-1-propyl, 3-oxo-3-formyl-1-propyl, 3-oxo-4-formyl-1-butyl, etc.

In addition, referring to the above General formula (1), the lowest alkoxygroup, in the definition of R2and R3includes WITH1-6-alkoxygroup straight or branched chain, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Deut.butoxy, tert.butoxy, pentyloxy, hexyloxy etc. Cycloalkyl group includes WITH3-6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., nitrogen-Containing 6-Chiclana heterocyclic group include aromatic heterocyclic groups, such as pyridyl, piperidino, morpholino, etc., a Cyclic structure, which may jointly form R2and R3and which, furthermore, may contain additional atom of oxygen and/or nitrogen, includes pyrrolidine, piperidine, morpholine, piano invention includes the salts of various organic acids, such as formic, acetic, propionic, triperoxonane, tartaric, lactic, maleic, fumaric, succinic, oxalic and other acids and various inorganic acids such as hydrochloric, Hydrobromic, sulfuric, phosphoric, etc., acids.

Preferred compounds of General formula (I) are compounds in which R1is a hydrogen atom or benzyloxycarbonyloxy group, and R is a group of the formula -(CH2)nNR2R3.

The most desirable are those compounds in which R1is a hydrogen atom and R is a group of the formula -(CH2)nNR2R3where n is 2 or 3, R2and R3are the same or different and each is a hydrogen atom, a group of the formula N (Ra) (Rb)), where Raand Rbare the same or different and each is lower alkyl or Raand Ratogether can form a substituted lower alkyl pieperazinove group (or a lower alkyl which may be substituted 6-ticleni nitrogen-containing group or a group of formula-N(Rc)(Rd) where Rcand Rdare the same or different and each is lower alkyl, or Rthe global oxygen atoms and/or nitrogen and may be substituted by lower alkyl or piperidino group.

The compound of General formula (I) according to the invention can be obtained in accordance with the following reaction scheme 1, is given at the end of the description (in the above formulas, R4is stands, benzyloxycarbonyl, lower alkanoyl, which may have one or more halogen atoms or by a group of the formula-Si(Rx)(Ry)(Rz), where Rx, Ryand Rzhave the above values) R5is the lowest alkenyl; R6is a hydroxyl-containing alkyl; R7is a group of formula-CH2)mCHO, where m has the above value or lower alkyl having ketoaldehyde group; R8is a group of the formula -(CH2)mCHO; R9is stands, benzyloxycarbonyl, lower alkanoyl, which may be an atom, halogen or a group of the formula-Si(Rx)(Ry)(Rz), where Rx, Ryand Rzhave these values); R2, R3and n respectively have the values previously provided that, however, R4and R9are not the same.

Now explain each of the processes shown above.

Process A.

Known 4-epipodophyllotoxin appropriate solvent, to obtain the desired derivative of General formula (Ia) which corresponds to General formula (I), where R is the lowest alkenyl. The solvent is not specifically limited because it does not participate in the reaction. Useful solvents include, for example, aprotic solvents such as halogenated hydrocarbons, e.g. dichloromethane, chloroform, 1,2-dichloroethane, etc., and ethers, such as tetrahydrofuran, dioxane, etc. May be used Lewis acid such as titanium tetrachloride, trimethylsilyltrifluoromethane, zinc bromide, athirat (ethyl ether) of boron TRIFLUORIDE, etc., For this reaction, the compound of General formula (III) is preferably used in a proportion of 1-5 molar equivalents, considering the connection of General formula (II), and the Lewis acid is preferably used in proportions of 0.5 to 3-molar equivalent, considering the compound of General formula (II). The reaction temperature is usually from -100 to 100oC, and preferably between -20 and 20oC.

The process Century.

Derivative of General formula (Ia) obtained in the Process And oxidized in an inert solvent to obtain the target derivative of General formula (IB), which corresponds to General formula (I), wristy carbon, acetonitrile, acetic acid, water, pyridine, etc., alone or in combination. The oxidizing agent may be, for example, ruthenium oxide, periodate sodium or osmium tetroxide. For this reaction, the oxidizing agent is preferably used in a proportion of 0.1 to 2 molar equivalents relative to the compound of General formula (Ia). The reaction temperature is from -10 to 80oC, preferably 0 to 20oC.

The process With.

Derivative of General formula (Ia) obtained in the Process And, simultaneously subjected to oxidation and reduction in an inert solvent to obtain the target compounds of General formula (Ic), which corresponds to the specified formula (I) in which R is a group of the formula -(CH2)mCHO or a lower alkyl group having ketoaldehyde group. The solvent can be used carbon tetrachloride, methylene chloride, acetic acid, water, tetrahydrofuran, pyridine, etc. individually or in combination. Regenerating agent can be, for example, borane-dimethyl sulfide, tamilporn-dimethyl sulfide or the like, while as the oxidizing agent can be, for example, used chromic acid or pyridineboronic. For this reaction barrel and 1 3-molar equivalent, both counting on compounds of General formula (Ia). The reaction temperature is from -10 to 50oC, preferably 0 to 20oC.

Process D.

Target derivative of General formula (Ic) corresponding to General formula (I) in which R is a group of the formula -(CH2)mCHO or a lower alkyl having ketoaldehyde group, can also be obtained by oxidation in an inert solvent derivative of General formula (IB) obtained in the process C. the solvent can be used carbon tetrachloride, methylene chloride, acetic acid, tetrahydrofuran, diethyl ether, benzene, etc. individually or in combination. The oxidizing agent may be, for example, potassium permanganate, leads to compounds, which lead pyridineboronic, etc. For this reaction, the oxidizing agent is preferably used in a proportion of 0.8

a 3 molar equivalents to the compound of General formula (Ib). The reaction temperature is 0 to 50oC, and preferably 0 to 20oC.

The process that is

Derivative of General formula (Ic) obtained in the Process With a or D, catalytically restore in the presence of a catalyst in an inert solvent to obtain the target compound of General formula (Id), which sootvetsvenno, because he is not involved in the reaction. As a solvent, for example, can be used ethyl acetate, methanol, tetrahydrofuran, etc. individually or in combination. The catalyst may be, for example, palladium black, platinum, etc., the hydrogen Pressure may be 1 of 3 ATM, and preferably 1 to 2 ATM. The reaction temperature is 0 to 40oC, preferably room temperature.

Process F.

Derivative of General formula (I-d) obtained in process E, is introduced into reaction with allermuir agent or silylium agent in the presence of a base in an inert solvent to obtain the target compound of General formula (Ie). The solvent is not specifically limited because it does not participate in the reaction, there can be used carbon tetrachloride, methylene chloride, tetrahydrofuran, benzene, dimethylformamide, dimethylacetamide, etc., individually or in combination). The base can be, for example, pyridine, dimethylaminopyridine, imidazole, etc., Allerease agent includes, for example, acid anhydrides such as acetic anhydride, somerley anhydride, propionic anhydride, butyric anhydride, the anhydride valerianic acid, Chloroacetic anhydride, etc. and galodamadruga acids, ethylchloride, benzyloxycarbonylamino etc. Similarbuy agent includes tert.butyldimethylsilyloxy, triisopropylsilane, tert. butyldiphenylsilyl, etc. For this reaction, the base is preferably used in proportions of 0.01 to 7 molar equivalents, and allerease agent or similitude agent is preferably used in a ratio of 1 to 5-molar equivalents, both considering the connection of General formula (Id). The reaction temperature is 0 to 50oC, preferably 0 to 20oC.

The process G.

Derivative of General formula (Ic) obtained in the Process With a or D, is subjected to reductive aminating aminoguanidinium General formula (IV) in an inert solvent to obtain the target compound of General formula (If), which corresponds to General formula (I) in which R is a group of the formula (CH2)nNR2R3. The solvent is not specifically limited because it does not participate in the reaction. So, for example, can be used alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, dioxane, etc., organic acids such as acetic acid, formic acid, etc., water, etc. individually or in combination. Regenerating agent can be the IV) is preferably used in a proportion of 0.9 3-molar equivalent, and the reducing agent is preferably used in a ratio of 1 3-molar equivalent, both considering the connection of General formula (Ic). The reaction temperature is 0 to 50oC, preferably 0 to 20oC.

The Process N.

Derivative of General formula (If) obtained in Process G, catalytically restore in the presence of a catalyst in an inert solvent to obtain the desired derivative of General formula (Ig). The solvent is not specifically limited because it does not participate in the reaction. So may be, for example, used the ethyl acetate, methanol, tetrahydrofuran, acetonitrile, individually or in combination. The catalyst may be, for example, palladium black, platinum, etc., the hydrogen Pressure may be 1-3 atmospheres, preferably 1-2 atmospheres. The reaction temperature is equal 0-40oC, preferably room.

The compound of the invention obtained by any of the above reactions can be converted into salts by known methods, for example, when interacting with a specified organic acid or inorganic acid in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, etc. at a temperature of about room temperature.

For use as therapeutic drugs for the treatment of tumors in mammals, including man, a compound of the present invention may be provided in various pharmaceutical preparations, such as oral medications, injections, suppositories, etc. each of which can be prepared by the established pharmaceutical procedure.

In the formulation of solid preparations for oral administration of the compound of the invention is formulated with excipients and (optionally) a binder, disintegrator, lubricant, coloring agent, a modifier for pharmaceutical substances, perfume, etc. and processed into tablets, coated tablets, granules, powders, capsules, etc. in the usual way. Supplements are those normally used in this field. For example, excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, etc., Binder includes water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, CT is calcium, polyvinylpyrrolidone, etc., the Disintegrator include dry starch, sodium alginate, agar powder, acid sodium carbonate, calcium carbonate, sodium lauryl sulfate, stallonezone, lactose, etc., Lubricating substance include purified talc, if stearic acid, borax, polyethylene glycol, etc., the Modifier includes sucrose, orange peel, citric acid, tartaric acid, etc.

For the formulation of liquid preparations for oral administration of the compound of the invention may be formulated with a modifier, buffer, stabilizer, flavoring, and/or etc., and the resulting composition can be processed in solution for oral administration, syrups, elixirs, etc. in the usual way. The modifier for this purpose may be any of those mentioned above. The buffer may be, for example, sodium citrate, and the stabilizer may be, for example, tragakant, gum Arabic, gelatin, or etc.

For the formulation of drugs for injection, the compound of the invention can be formulated with regulating pH agent, buffer, stabilizer, isotonic agent, a local anesthetic, etc., and processed for subcutaneous, intramuscular and intravenous injection. Adjusting p. The stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, timelocal acid, etc., Local anesthetic includes procaine hydrochloride, lidocaine hydrochloride, etc.

For the formulation of suppositories compound of the invention may be formulated with a pharmaceutical carrier, are well known in the prior art, such as polyethylene glycol, lanolin, cocoa butter, triglycerides of fatty acids, Literal (trade name), etc. and, if necessary, with such surface-active substance, such as tween (trade name); the resulting composition is processed into suppositories usual.

A number of compounds of the invention in any of the above forms of the dose depends on clinical condition of the patient is assigned to treatment, and from specifically selected shape of the dose. However, it is usually preferred quantity per unit dose is about 1 to 1000 mg for oral preparations, about 0.1 to 500 mg for preparations for injection and about 5 to 1000 mg for suppositories. Daily dosage of any pharmaceutical product mentioned above also depends on the patient's condition, body weight, age, sex and other factors, none dose or 2 4 separate doses.

The following examples, pharmacological test examples and preparations further illustrate the invention.

Example 1. Synthesis of 4-deoxy-4'-dimethyl-4'-0-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin (Compound I).

To a solution of 1 g (1,87 mmol) 4'-demethyl-4'-0-benzyloxycarbonyl-4-epipodophyllotoxin in 15 ml dichloromethane was added 426 mg (3.73 mmol) of trimethylsilane and the mixture is cooled to -10o0oC. To this solution was added 0.6 ml of epirate ethyl ether, boron TRIFLUORIDE and the mixture is stirred for 1 h After the reaction was added 0.6 ml of pyridine and the mixture was poured into cold diluted hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and distilled, the residue is purified by chromatography on a column (silica 50 g, eluent-chloroform). The eluate concentrated and crystallized from ether, get 1 g (yield 95,7) 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin - xing (Compound I).

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Example 2. Synthesis of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4- (2,3-dioxy-1-propyl)- 4 - epipodophyllotoxin (Compound 2).

To a solution of 1 g (1,79 mmol) of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin room temperature for 1 h Upon completion of the reaction was added a solution of 0.8 g of acidic sodium sulfite in aqueous pyridine and the mixture is stirred for further 30 minutes the Reaction mixture was extracted with ethyl acetate and the extract was washed with diluted hydrochloric acid and water and dried. The organic layer, concentrate and purify the residue by chromatography on a column (50 g silica, eluent chloroform methanol 20:1). The eluate concentrated and the residue is crystallized from ether, to obtain 1.0 g (yield was 94.2) 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4 -(2,3-dioxy-1-propyl) 4-epipodophyllotoxin (Compound 2).

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Example 3. Synthesis of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin (Compound 3).

To a solution of 1 g (1,69 mmol) of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-(2,3-dihydroxy-1-propyl)4-epipodophyllotoxin obtained in example 2 in 80 ml of benzene is added 795 mg (1,79 mmol) leads to compounds, which lead and stirred the mixture for 30 minutes at room temperature. Then the reaction mixture was filtered and concentrated the filtrate. The residue is purified by chromatography on a column (70 g of silica, eluent chloroform-methanol 20:1) and crystallized from ether, get 934 mg (yield 98,7) 4 deteksi-4'-demethyl-4'-0-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin who yl)-4-epipodophyllotoxin (Compound 4)

To a solution of 4 g (7,17 mmol) of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin - xing, obtained in example 1 in 40 ml of tetrahydrofuran was added 4.3 ml (8.6 mmol) of a 2 M solution of borane-dimethyl sulfide in tetrahydrofuran dropwise under ice cooling and then the mixture is left to react at room temperature for 1 h, the Reaction mixture was concentrated and the residue is dissolved in 80 ml of methylene chloride, then add 3.0 g (a 13.9 mmol) pyridinylamino. The mixture is stirred at room temperature. After the reaction was added 100 ml of ethyl acetate and the insoluble material is filtered off with Florisil. The filtrate is concentrated and the residue purified by chromatography on a column (50 g silica, eluent hexanitrate 1:1) and crystallized from ether, obtain 1.85 g (yield of 44.9) 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-(2-formyl-1-ethyl)- -4-epipodophyllotoxin (Compound 4)

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Example 5. Synthesis of 4-deoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin (Compound 5)

To a solution of 100 mg (0,178 mmol) of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin obtained in example 3 in 10 ml of ethyl acetate-methanol (1: 1) was added 30 mg of 5-aqueous palladium on coal and conduct catalytic coal and concentrate the filtrate under reduced pressure. The residue is crystallized from ether, to obtain 75 mg (yield 98,9) 4-deoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin (Compound 5).

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Example 6

Synthesis of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4- (-2-oxo-2-formyl-1-ethyl)-4-epipodophyllotoxin (Compound 6).

To a solution of 100 mg (0,17 mmol) of 4-deoxy-4' -demethyl-4'-0-benzyloxycarbonyl-4-(2,3-dihydroxy-1-propyl)- -4-epipodophyllotoxin obtained in example 2 in 5 ml of methylene chloride was added 73 mg (0.34 mmol) pyridinediamine and the mixture is stirred at room temperature for 1 h After the reaction was added ethyl acetate, and the organic layer washed with cold diluted hydrochloric acid and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off and the residue is purified by chromatography on a column (20 g silica, eluent chloroform-methanol 20:1) and crystallized from ether, receive 45 mg (yield of 45.0) 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4- (2-oxo-2-formyl-1-ethyl(-4-epipodophyllotoxin (Compound 6).

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Example 7. Synthesis of 4-deoxy-4'-demethyl-4'-0-chloroacetyl-4 - formylmethyl-4-epipodophyllotoxin (Compound 7).

To a solution of 50 mg (0,117 mmole) 4-deoxy-4'-demethyl-4-formyl-4-epipodophyllotoxin, poluchennogo is inoperative and the mixture is stirred at room temperature overnight. After the reaction the solvent is distilled and purified the residue preparative thin-layer chromatography (eluent chloroform-methanol 30:1). The residue obtained by extraction, crystallized from ethyl acetate-N-hexane and filtered off the crystals obtain 50 mg (yield of 90.0) 4-deoxy-4'-demethyl-4'-0-chloroacetyl-4-formylmethyl-4-epipodophyllotoxin (Compound 7).

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Example 8. Synthesis of 4-deoxy-4'-demethyl-4'-0-trichloroacetyl-4-formyl-4 - epipodophyllotoxin (Compound 8)

To a solution of 4.26 deaths g (10 mmol) of 4-deoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin obtained in example 5 in 50 ml of methylene chloride is added at 2.36 g (13 mmol) of trichloroacetic anhydride and 1.58 g (13 mmol) of dimethylaminopyridine and stirred the mixture at room temperature overnight. After the reaction is distilled off the solvent and purify the residue by chromatography on a column (eluent ethyl acetate-n-hexane 1:1). The eluate is crystallized from methanol and collect the crystals by filtration, get 4,10 g (yield of 71.7) 4-deoxy-4'-demethyl-4'-0-trichloroacetyl-4-formylmethyl-4-epipodophyllotoxin - oxine (Compound 8).

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Example 9. Synthesis of 4-deoxy-4'-demethyl-4'-0-acetyl-4 - formylmethyl - 4-epipodophyllotoxin (Compound 9).

To a solution of 50 mg (0,117 mmol) of 4-deoxy-4'-demethyl-is) of acetic anhydride and 10 mg (of 0.081 mmol) dimethylaminopyridine and stirred the mixture overnight at room temperature. After the reaction is distilled off the solvent and purify the residue preparative thin-layer chromatography (eluent chloroform-methanol 30:1). The residue obtained by extraction, crystallized from n-hexane and collect the crystals by filtration, to obtain 40 mg (yield 73,0) 4-deoxy-4'-demethyl-4'-0-acetyl-4 - formylmethyl-4-epipodophyllotoxin (Compound 9)

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Example 10. Synthesis of 4-deoxy-4'-demethyl-4'-0-tert - butyldiphenylsilyl-4-formylmethyl-4-epipodophyllotoxin (Compound 10).

To a solution of 50 mg (0,117 mmol) of 4-deoxy-4'-demethyl-4 - formyl-methyl-4-epipodophyllotoxin obtained in example 5 in 5 ml of dimethylformamide was added 33 mg (0.12 mmol) of tert-butyldiphenylsilyl and 79 mg (0.64 mmol) of dimethylaminopyridine and stirred the mixture at room temperature overnight. Then the reaction mixture was extracted with ethyl acetate - water and dried. Then the solvent is distilled off and the residue is purified preparative thin-layer chromatography (eluent chloroform-methanol 30:1). The residue obtained by extraction, dried under reduced pressure to obtain 35 mg (yield 37,4) 4-deoxy-4'-demethyl-4'-0 - tert. butyldiphenylsilyl-4-formylmethyl-4-epipodophyllotoxin (Compound 10).

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Example 11. Synthesis of 4-deoxy-4-formylmethyl-4-epipodophyllotoxin is(2.4 mmol) of trimethylchlorosilane and cooling the mixture to -10o0oC. To this solution was added 0.35 ml of ethyl epirate boron TRIFLUORIDE and stirred mixture of 4 hours After the addition of 0.35 ml of pyridine extracted the reaction mixture with ethyl acetate. Dried organic layer is distilled, the residue is purified by chromatography on a column (50 g silica, eluent ethyl acetate: hexane 1:2). The eluate is crystallized from ether-hexane and collect the crystals by filtration, to obtain 450 mg (yield 81,1) 4-deoxy-4-allyl-4-epipodophyllotoxin. Then to a solution of 200 mg (0.46 mmol) of this compound in 4 ml of pyridine was added 116 mg (0.46 mmol) of osmium tetroxide and stirred the mixture at room temperature for 1 h After the reaction was added a solution of 0.1 g of acidic sodium sulfite in aqueous pyridine and the mixture is stirred for 30 minutes This reaction mixture is extracted with ethyl acetate and washed extract diluted hydrochloric acid and water and dried. The organic layer is concentrated and the residue purified by chromatography on a column (50 g silica, eluent chloroform-methanol 20: 1). The eluate concentrated and then crystallized from ether-hexane, to obtain 194 mg (yield 89,3) 4-deoxy-4-(2,3-dihydroxy-1-propyl)-4-epipodophyllotoxin.

so al. 144-145oC (()2D073,42o(C 0,52 CHCl3).

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Example 12. Synthesis of 4-deoxy-4'-demethyl-4'-0 - benzyloxycarbonyl-4-(3-dimethylamino-1-propyl)-4-epipodophyllotoxin (Compound 12).

To a mixture of 0.1 ml of 50 aqueous solution of dimethylamine and 3 ml of methanol was added 0.1 ml of acetic acid and 35 mg (0,56 mmol) laborgerate sodium, then added 300 mg (0.52 mmol) of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-(2-formyl-1-ethyl)- -4-epipodophyllotoxin obtained in example 4. The mixture reacts at room temperature for 1 h Then after adding 30 ml of chloroform, the reaction mixture was washed with saturated aqueous acidic sodium carbonate and dried over magnesium sulfate. Then the solution is distilled in the residue purified by chromatography on a column (20 g silica, eluent chloroform-methanol 20:1) obtain 245 mg (yield 78) 4-deoxy - 4'-demethyl-4'-0-benzyloxycarbonyl-4-(3-N, N-dimethylamino-1-propyl)-4-- epipodophyllotoxin (Compound 12).

Example 13. Synthesis of 4-deoxy-4'-demethyl-4 (0,167 mmol) of 50 aqueous solution of dimethylamine and 5 ml of methanol was added 0.1 ml of acetic acid and 10 mg (0,19 mmol) cyanoborohydride sodium, then add 100 mg (0,178 mmol) of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin obtained in example 3, the mixture is left to interact at room temperature for 1 h after addition of 100 ml of ethyl acetate, the reaction mixture was washed with a saturated solution of acid sodium carbonate and water and dried over magnesium sulfate. Then the solvent is distilled off and the residue is purified by thin-layer chromatography (eluent chloroform-methanol 5:1 receive 60 mg (yield 57,2) 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4- -(3-N, N-dimethylamino-1-ethyl)-4-epipodophyllotoxin (Compound 13).

Example 14. Synthesis of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4- (2-N-methyl-N-cyclohexylamino-1-ethyl)-4-epipodophyllotoxin (Compound 14).

To a solution of 180 mg (1,81 mmol) cyclohexylamine in 10 ml of methanol was added 0.1 ml of acetic acid and 85 mg (1.35 mmol) of cyanoborohydride sodium, then added 500 mg (0.9 mmol) of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-formylmethyl - 4-epipodophyllotoxin obtained in example 3, the mixture is left to react for 1 h at room temperature. To this reaction mixture was added 0.1 ml of a 37-aqueous formaldehyde and the reaction mixture is then left at room temperature for the rija and water and dried over magnesium sulfate. Then distilled off the solvent and purify the residue by chromatography on a column (20 g silica, eluent chloroform-methanol 20: 1) obtain 470 mg (yield 79) 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-(2-N-methyl-N-cyclohexylamino-1-ethyl)-4-epipodophyllotoxin (Compound 14).

Example 15. Synthesis of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4- -(2-N, N-diethylamino-1-ethyl)-4-epipodophyllotoxin (Compound 15).

To a mixture of 38 mg (0,53 mmol) diethylamine and 10 ml of methanol was added 0.1 ml of acetic acid and 52 mg (0.82 mmol) of cyanoborohydride sodium, then added 300 mg (of 0.53 mmol) of 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin obtained in example 3, the mixture is left to react at room temperature for 1 h, the Reaction mixture was diluted with chloroform, washed with saturated aqueous acidic sodium carbonate and water and dried over magnesium sulfate. Then distilled off the solvent and purify the residue by chromatography on a column (20 g silica, chloroform-methanol 20:1) obtain 175 mg (yield of 53.5) 4-deoxy-4-demethyl-4'-0-benzyloxycarbonyl-4-(2-N,N-diethylamino-1-et - yl)- -4-epipodophyllotoxin (Compound 15).

Examples 16 to 27. Compounds 16 and 27, are shown in table. 1, were synthesized by m is epipodophyllotoxin (Compound 28)

To a solution of 230 mg (0.38 mmol) of 4-deoxy-4'-demethyl-4'-0 - benzyloxycarbonyl-4-(3-N,N-dimethylamino-1-propyl)-4 - epipodophyllotoxin obtained in example 12 in 4 ml of ethyl acetate-methanol (1 1) was added 50 mg of 10-aqueous palladium on coal and the mixture hydronaut in a stream of hydrogen at atmospheric pressure for 4 hours After filtered off the catalyst, the solvent is distilled off and the residue is purified by chromatography on a column (5 g silica, eluent:chloroform-methanol 20 1). The eluate was dissolved in 2 ml of dichloroethane, and then add 0.2 ml of 4N-Hcl-ethyl acetate. The mixture is concentrated under reduced pressure and the residue is crystallized from diethyl ether, to obtain 110 mg (yield 61,5 4-deoxy-4'-demethyl-4-(3-N,N-dimethylamino-1-propyl)-4-epipodophyllotoxin - xing (Compound 28).

Example 29.

Synthesis of 4-deoxy-4'-demethyl-4-(2-N,N-diethylamino-1-ethyl)-4-epipodophyllotoxin - on (Compound 31).

To a solution of 160 mg (0.25 mmol) 4-deoxy-4'-demethyl-4'-0-benzyloxycarbonyl-4-(2-N, N-diethylamino-1-e - Tyl)-4-epipodophyllotoxin obtained in example 15, in 20 ml of ethyl acetate: methanol (1 1) was added 20 mg of 10-aqueous palladium on coal and the mixture hydronaut at room temperature in a stream of hydrogen at atmospheric pressure for 10 hours. Filtered rolled 102 mg (yield of 84.3) 4-deoxy-4'-demethyl-4-(2-N, N-diethylamino-1-ethyl)-4-epipodophyllotoxin - on (Compound 31).

Examples 30-53. Compounds 29, 30, 32 and 53, shown in table. 2, were synthesized according to the method of examples 28 and 29.

Pharmacological test 1.

Fee with 96 cells inoculant cell line R murine leukaemia 1 103cells/cell. The test compound is dissolved in dimethylformamide and the solution was diluted with medium to various concentrations and added to the appropriate wells. Then charge incubated for 3 days. then it is fixed with glutaraldehyde and stained crystal violet for cytometry. Cytocine the effect of each compound was expressed as the concentration that causes 50 cent cell death (U50compared with the control. The results are as follows:

Connection N ED50(M)

3 4,5 10-7< / BR>
5 1,2 10-7< / BR>
28 1,2 10-8< / BR>
33 2,0 10-8< / BR>
34 3,0 10-9< / BR>
35 1,0 10-9< / BR>
38 1,9 10-8< / BR>
43 4,1 10-9< / BR>
44 1,2 10-8< / BR>
45 3,3 10-10< / BR>
47 6,3 10-9< / BR>
52 4,0 10-8< / BR>
53 4,3 10-9< / BR>
Pharmacological test 2

Cell line murine leukaemia L1210 1 105cells/mouse, administered intraperitoneally transplanted to male mice CDF

Examples of drugs with the use of compounds of the invention are presented below.

Example of preparation 1. Tablets.

In accordance with the following formula were prepared tablets of the established pharmaceutical procedure:

Connection 34 100 mg

Lactose 47 mg

Corn starch 50 mg

Crystalline cellulose 50 mg

Oxypropylation 15 mg

Talc 2 mg

Magnesium stearate 2 mg

Ethylcellulose 30 mg

The glycerides of unsaturated fatty acid 2 mg

Titanium dioxide 2 mg

The 300 mg tablet

Example of preparation 2. Granules.

In accordance with the following formula is prepared granules according to the established pharmaceutical procedure:

The compound N 35 200 mg

Mannitol 540 mg

Corn starch 100 mg

Crystalline cellulose 100 mg

Oxypropylation 50 mg

The connection 43 200 mg

Mannitol 520 mg

Corn starch 1000 mg

Oxypropylation 70 mg

Talc 1000 mg

Sample preparation 4. The capsule.

In accordance with the following formula is prepared capsules of the established pharmaceutical procedure.

The connection 45 to 100 mg

Lactose 50 mg

Cornstarch 47 mg

Crystalline cellulose 50 mg

Talc 2 mg

Magnesium stearate 1 mg

The 250 mg capsule

Example of preparation 5. The injection.

In accordance with the following formula is prepared, the preparation for injection according to the established pharmaceutical procedure:

Connection 47 100 mg

Distilled water for injection to

For 2 ml vials

Example of preparation 6. Suppositories.

In accordance with the following formula is prepared suppositories on the established pharmaceutical procedure.

The connection 53 100 mg

Witepsol 5-55 1400 mg

(a mixture of mono-, di - and triglycerides of saturated fatty acids from laurinovoj acid to stearic acid, the product Dynamit Nobel).

At 1500 mg suppository

Test method.

Lung cancer cells Lewis (3,2 105cells/mouse) were transplantability in costofliving was administered the test composition once a day for 5 days. The control group of mice transplanted the same cancer cells, but they were not injected into the tail vein of the test compounds. The results were evaluated by the number of mice surviving after 60 days or longer, the ratio of life expectancy of mice and reduction of weight on the 6th day after transplantation of lung cancer cells.

The ratio of life expectancy of mice was determined using the following equation:

< / BR>
where a number of days, during which remained alive mice that were administered the test compounds, and the number of days during which remained alive mouse from the control group. Indicator life expectancy of mice was determined as equal to 60 days. in cases where the number of days during which remained alive mouse of the group that was administered the test compounds was equal to 60 days. and more. The life expectancy of the control group is 18 days.

Below table. 4 shows the results

The results show that the compounds of the invention demonstrated a pronounced high performance as the number of mice surviving for 60 days. and longer, and about the plants have a higher antitumor activity and clinically more useful than etoposide. The results also show that the compounds of the present invention, although slightly and affect the reduction of body weight, but to a lesser extent compared with etoposide, thereby demonstrating less toxicity.

In the known ER N 366122 opsyn way to obtain derivatives of epipodophyllotoxin having the substituent in the 4-position, attached via an oxygen atom or a sulfur atom. Compounds of the invention possess significantly high anti-tumor activity compared with that type of connection.

Known connections to this references worse compared to etoposide test results for anticancer activity in vivo using cell line murine leukemia R, i.e. have a lower anti-cancer activity. Compounds of the invention demonstrated outstanding results in the comparative testing described in EP N 226202, and proved higher anticancer activity than etoposide, and therefore, they have excellent anti-cancer activity compared to known compounds.

The values of the ED50determined in respect of the two compounds in the same manner as it was conducted in the pharmacologist is Oh in the claims, in which the substituent R (R-CH2CH2CH2OH) 4-position is attached through the carbon atom and the bonding links, in which R (R=-OCH2CH2CH2OH) attached via an oxygen atom.

The value of the ED50connection And 6.7 times lower than this value connection C. This means that the connection of the present invention is markedly superior in its anti-cancer activity of the compound of reference (PL. 5).

Derived epipodophyllotoxin with the substituent in the 4-position via a carbon atom in the case of compounds of the present invention differs significantly higher anticancer activity than the connection link having a substituent in the 4-position via an oxygen atom or a sulfur atom. This fact was not obvious at the time of filing of the proposed application.

1. Derived 4-deoxy-4-epipodophyllotoxin General formula

< / BR>
where R1hydrogen, a methyl group, benzyloxycarbonyl group, lower alcoolica group which may have one or more halogen atoms, or a group of the formula

-Si(Rx)(Ry)(Rz)

where Rx, Ryand Rzthe same or different, each lower alkyl or phenyl group;

R lower ALK is CH2)mCHO, where m 0 4, a lower alkyl group having ketoaldehyde group, or a group of the formula -(CH2)nNR2R3where n is 1 to 6;

R2and R3the same or different, are each hydrogen, cycloalkyl group, a group of the formula

-N(Ra)(Rb)

where Raand Rbthe same or different, each lower alkyl group or phenyl group, or Raand Rbcan be combined with the formation of the substituted lower alkyl of piperazinone, or a lower alkyl group which may be substituted by a hydroxy-group, lower alkoxy, phenyl, 6-membered nitrogen-containing heterocyclic group or a group of the formula

-N(Rc)(Rd)

where Rcand Rdthe same or different, each lower alkyl group;

R2and R3can be combined with the formation of a cyclic structure, which may optionally include additional atoms of oxygen and/or nitrogen and may optionally have a lower alkyl which may be substituted by a hydroxy-group, or piperidinium as Deputy;

provided, however, that when R1hydrogen R group of formula -(CH2)mCHO or a group of the formula -(CH2)nNRToxina by p. 1, in which R1a hydrogen atom or benzyloxycarbonyl group, or its pharmaceutically acceptable salt.

3. Derived 4-deoxy-4-epipodophyllotoxin under item 1, in which R1a hydrogen atom, or its pharmaceutically acceptable salt.

4. Derived 4-deoxy-4-epipodophyllotoxin under item 1, in which R is a group of the formula

-(CH2)nNR2R3,

or its pharmaceutically acceptable salt.

5. Derived 4-deoxy-4-epipodophyllotoxin under item 1, in which R is a group of the formula

-(CH2)nNR2R3,

where n is 2 or 3,

or its pharmaceutically acceptable salt.

6. Derived 4-deoxy-4-epipodophyllotoxin under item 1, in which R is a group of the formula

-(CH2)nNR2R3,

where R2and R3the same or different, each a hydrogen atom, a group of the formula

-N(Ra)(Rb)

where Raand Rbthe same or different, each lower alkyl group, Raand Rbcan be combined with the formation of the substituted lower alkyl of piperazinone,

or a lower alkyl group which may be substituted 6-membered nitrogen-containing heterocyclic group or a group of the other group;

or R2and R3combined with the formation of a cyclic structure, which may optionally include additional atoms of oxygen and/or nitrogen and may optionally have a lower alkyl or piperidinium,

or its pharmaceutically acceptable salt.

7. Derived 4-deoxy-4-epipodophyllotoxin under item 1, in which R is a group of the formula

-(CH2)nNR2R3,

where R2and R3the same or different, each a hydrogen atom, a group of the formula

-N(Ra)(Rb)

where Raand Rbthe same or different, each lower alkyl group, Raand Rbcan be combined with the formation of the substituted lower alkyl of piperazinone;

or a lower alkyl group which may be substituted 6-membered nitrogen-containing heterocyclic group or a group of the formula

-N(Rc)(Rd)

where Rcand Rdthe same or different, each lower alkyl group,

or its pharmaceutically acceptable salt.

8. Derived 4-deoxy-4-epipodophyllotoxin under item 1, in which R is a group of the formula

-(CH2)nNR2R3,

where R2and R3together represent the CEC optionally have a lower alkyl or piperidinium,

or its pharmaceutically acceptable salt.

9. Pharmaceutical composition having antitumor activity, comprising an active substance and a pharmaceutically acceptable carrier, characterized in that the active substance composition comprises a derivative of 4-deoxy-4-epipodophyllotoxin on p. 1. appropriate dose of 0.1 to 5000 mg/day.

Priority signs:

25.01.91 when R1a hydrogen atom, benzyloxycarbonyl group, lower alcoolica group which may have one or more halogen atoms, or a group of the formula-Si(Rx)(Ry)(Rz), where Rx, Ryand Rzthe same or different, each lower alkyl or phenyl group, R is lower alkenyl, lower alkyl having at least one hydroxyl group, a group of the formula -(CH2)mCHO, where m is a whole number equal to from 0 to 4, provided that when R1the hydrogen atom, the R group of formula -(CH2)mCHO.

26.03.91 when the R group of formula -(CH2)nNR2R3where n is an integer equal to from 1 to 6, R2and R3the same or different, each a hydrogen atom, zeloallenny group, or a group of formula-N(Ra)(Rb), where Rais ut to unite with the formation of the substituted lower alkyl of piperazinone, or a lower alkyl group which may be substituted by hydroxy, lower alkoxygroup, phenyl group, 6-membered nitrogen-containing heterocyclic group or a group of formula-N(Rc)(Rd), where Rcand Rdthe same or different, are lower alkyl, R2and R3can be combined with the formation of a cyclic structure, which may optionally include additional atoms of oxygen and/or nitrogen and may optionally have a lower alkyl which may be substituted by a hydroxy-group, or piperidino.

22.04.91 when R1methyl.

 

Same patents:

The invention relates to new derivatives of thiourea, and containing antimicrobial agent against Helicobacter pylori and anti-ulcer agent

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new method for preparing phthalanes of the formula (III): wherein R2 represents halogen atom, trifluoromethyl, cyano-group or group -R-CO- wherein R represents alkyl radical comprising 1-4 carbon atoms, and its acid-additive salts. Method involves reaction of compound of salt of the general formula (II): wherein R1 represents halogen atom, and R2 has the above given values with copper cyanide.

EFFECT: simplified process, enhanced yield.

14 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceutical chemistry and specifically 2-methoxy-4-[(3aR,7aS8)-3,3,6-trimethyl-1,3,3a,4,5,7a-hexahydro-2-benzofuran-1-yl]phenol of formula 1, , having anti-Parkinson activity and can be used in medicine.

EFFECT: agent has low toxicity and can be obtained from common natural compounds 2- and 3-carenes.

5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of 1,3-dihydro-5-isobenzofurancarbonyl of formula 1, or their pharmaceutically acceptable salts, where R1 represents phenyl, phenyl substituted with C1-C6-alkyloxy, phenyl, substituted with C1-C6-alkyl, phenyl, substituted with C1-C6-dialkylamine, phenyl, substituted with halogen or thienyl; R2 is selected from group consisting of C1-C6-dialkylamino, pyrazolyl and imidazolyl, excluding C1-C6-dialkylamino, if R1 represents phenyl, phenyl substituted with halogen; n represents integer number from 1 to 3, and method of their obtaining.

EFFECT: invention also relates to pharmaceutical compositions, which include formula 1 compound, and method of treatment and prevention of premature ejaculation.

18 cl, 8 tbl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a compound of general formula VIII of enantiomeric purity min. 80% by a reaction of the compound according to general formula IV with enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid to produce a compound of general formula II to be reduced to prepare a compound for general formula I to be oxidated to form an aldehyde which then reacts with an aromatic amine of formula H2N-Ar to produce a respective imine which is then reduced to prepare a compound described by formula VIII in the enantiomeric pure form. Also, it refers to methods for preparing the compound of formula I, as well as to the compounds of formula I. In general formulas

, ,

, , X1, X2, X3 is specified in fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, trifluoromethyl, amino whereas the other groups X1, X2, X3 represent a hydrogen atom.

EFFECT: preparing the non-steroid anti-inflammatory drugs.

12 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining compound of formula

1,

including condensation of carboxylic acid of formula

2

with aniline of formula

3 in presence of TZR®, where each R2 and R4 independently represents C1-6 alkyl with linear or branched chain, and each C1-6 alkyl with linear or branched chain is independently and optionally substituted with -OR'; each R5 represents OC(O)OR' or R4 and R5, taken together, form group , y represents 0, each R' represents C1-4 alkyl group, optionally substituted with one or more groups, selected from oxo and -O-C1-4-alkyl group. Invention also relates to intermediate compounds and methods of their obtaining.

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52 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula [1] or its pharmaceutically acceptable salt, wherein R1 are R2 identical or different, and each of them represents a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group or C1-6alkoxy group (C1-6alkyl group, C1-6alkoxy group and C3-8cycloalkyl group can be substituted by 1-3 substitutes, which are identical or different from a halogen atom, C1-6alkoxy group); R3 represents a hydrogen atom or C1-6alkyl group; R4 represents a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group (which can be substituted by substitutes specified in the patent claim), a heterocyclic group specified in pyridine; A1 represents a bivalent aryl group, a bivalent heterocyclic group specified in pyridyl, pyrazinyl, thiophenyl, or C3-8cycloalkylene group (bivalent aryl group can be substituted by 1-4 substitutes, which are identical or different from the following group of substitutes Ra, which are specified in the patent claim); L represents -C≡C-, -C≡C-C≡C-, -C≡C-(CH2)m-O-, CH=CH-, -CH=CH-C≡C-, -C≡C-CH=CH-, -O-, -(CH2)m-O-, -O-(CH2)m-, C1-4alkylene group or a bond; m means 1, 2 or 3; A2 represents a bivalent aryl group, a bivalent heterocyclic group (presented in the patent claim), C3-8cycloalkylene group, C3-8cycloalkenylene group, C1-4alkylene group or C2-4alkenylene group (which can be substituted by 1-4 substitutes, which are identical or different and specified in a group of substitutes Rb, which is specified in the patent claim); W represents R6-X1-, R6-X2-Y1-X1-, R6-X4-Y1-X2-Y3-X3-, Q-X1-Y2-X3- or Q-X1-Y1-X2-Y3-X3-; Y2, Y1, Y3, n, X1, X3, X2, X4, Q, R6, R7, R8 and R9 are presented in the patent claim. The compounds of formula [1] possess antimicrobial activity on gram-negative bacteria by LpxC inhibition.

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25 cl, 107 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I)

or to pharmaceutically acceptable salts thereof.

EFFECT: new compounds are obtained, which can be used as oestrogen receptors ligands.

24 dwg, 360 ex, 21 cl

FIELD: chemistry.

SUBSTANCE: invention relates to the individual compounds selected from the group: 4-(1,3-benzoxazole-2-yl)]-N-[(1R,3S)-3-(ethylcarbamate)cyclopentyl]-N-methylbenzamide, N-((1R,3S)-3-ethylcarbamoylcyclopentyl)-N-methyl-4-(1-methyl-1H-benzoimidazol-2-yl)-benzamide, 4-benzothiazol-2-yl-N-((1R,3S)-3-ethylcarbamoylcyclopentyl)-N-methylbenzamide, ((1R,3S)-3-ethylcarbamoylcyclopentyl)-methylamide4'-[(R)-(tetrahydrofuran-3-yl)oxy]-biphenyl-4-carbon acid, 4-benzoxazole-2-yl-N-((1R,3S)-3-isopropylcyclopentadienyl)-N-methylbenzamide, and other compounds that are specified in the claims. The invention also relates to medicinal means having an inhibiting activity against fatty acid synthase (FAS) containing therapeutically effective amount of the compound of the invention.

EFFECT: new compounds are obtained that have an inhibiting activity against the synthesis of fatty acids.

2 cl, 2 tbl, 12 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: chemistry.

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or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I), including any stereochemical isomer forms thereof, or a pharmaceutically acceptable salt thereof, , wherein A is phenyl or 6-member aromatic heterocycle containing 1 or 2 nitrogen atom; wherein said phenyl or 6-member aromatic heterocycle may be optionally condensed with phenyl; Z is CH2 or O; R1 is halogen, hydroxyl, C1-4alkyl, C1-4alkyloxy, or provided A is phenyl, then two neighbour substitutes R1 may be taken together to produce a radical of formula: -O-CH2-O- (a-1) or -O-CH2-CH2-O- (a-2); R2 is hydrogen or C1-4alkyl; each R3 and R4 independently is hydrogen, C1-6alkyl, C1-4alklyloxyC1-6alkyl or phenylC1-4alkyl; or R3 and R4 taken together with a nitrogen atom whereto attached form a radical of formula or , wherein X1 is CH2 or CHOH; and X2 is CH2, O or NR6; R5 is hydrogen, halogen, C1-4alkyl or C1-4alkyloxy; R6 is hydrogen, C1-4alkyl, C1-4alkylcarbonyl; n is equal to an integer 0, 1 or 2; provided the compound is other than , or a pharmaceutically acceptable salt thereof.

EFFECT: compounds are used to treat the diseases the treatment of which is affected, mediated or promoted by GHSlA-r receptor activation The present invention also refers to pharmaceutical compositions and an intermediate compound of formula II: .

22 cl, 10 tbl, 11 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-tetrahydrofuranbenzodioxolyl sulfonamide compounds of the formula (I): , its salts, stereoisomers and racemates that are effective inhibitors of protease activity. Also, invention relates to pharmaceutical preparations, methods for inhibition of retrovirus proteases, in particular, to resistant retrovirus proteases, to many drugs, methods for treatment and prophylaxis of infection or disease associated with retrovirus infection in mammals and to methods for inhibition of retrovirus replication. Invention provides preparing new derivatives of bis-tetrahydrofuranbenzodioxalyl sulfonamides eliciting the valuable pharmaceutical properties.

EFFECT: valuable medicinal properties of compound and composition, improved treatment method.

16 cl, 2 dwg, 3 tbl

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a novel method for preparing 14β-hydroxy-1,4-carbonate-desacetylbaccatin III and intermediate substances used in preparing new derivatives of taxane and possessing an antitumor activity. Method involves the following stages: a) protection of hydroxyls at positions 7 and 10 in 10-desacetylbaccatin III wherein R and R1 are taken among hydrogen atom, (C1-C10)-alkyl or aryl, (C1-C10)-alkyl- or aryl-carbonyl, trichloroacetyl, (C1-C4)-trialkylsilyl; preferably, when R and R1 are similar then they represent trichloroacetyl; when they are different then, preferably, R represents trichloroacetyl and R1 represents acetyl; or R represents triethyl or trimethylsilyl and R1 represents acetyl; b) two-stage oxidation to yield a derivative oxidized to carbonyl at position 13 and hydroxylated at position 14; c) carboxylation of vicinal hydroxyls at positions 1 and 14 to yield 1,14-carbonate derivative; d) reduction of carbonyl at position 13; e) removal of protective groups at positions 7 and 10. Also, invention relates to intermediate substances. Invention provides preparing intermediate substances used in synthesis of taxane.

EFFECT: improved preparing method.

8 cl, 8 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for synthesis of new compounds, namely, 1,11-dialkyl-3,5-dihydrofuro-[2',3':3,4]-cyclohepta[c]isochromens of the formula: (Ia-f): wherein (Ia): R means hydrogen atom (H); R1 means hydrogen atom (H); (Ib): R means bromine atom (Br); R1 means hydrogen atom (H); (Ic): R means chlorine atom (Cl); R1 means hydrogen atom (H); (Id): R means hydrogen atom (H); R1 means bromine atom (Br): (Ie): R means hydrogen atom (H); R1 means chlorine atom (Cl); (If): R means methoxy-group (-OCH3); R1 means hydrogen atom. Method involves formation of condensed tetracyclic system as result of the successive recyclization reactions of furan ring of derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol and the secondary cyclization of formed isochromen ketone in boiling of solution containing derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol of the formula: in ethanol medium in the presence of hydrogen chloride alcoholic solution for 15-40 min. Invention provides synthesis of new derivatives of isochromens possessing the potential anti-inflammatory activity.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

1 cl, 2 tbl, 5 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to a novel crystalline form of (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)ethylideneoxy]-5,20-epoxy-1-hydroxytax-11-ene-13-yl-(2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate that shows the diffraction picture of roentgen rays in powder with characteristic peaks at diffraction angles (θ)= 6.2o, 10.3o, 10.7, 11.4o and 12.0, and a method for its preparing. Method involves carrying out the crystallization step by using organic solvent chosen from group consisting of ketone type solvent, nitrile solvent type and their mixture, or mixture of said solvent and water. Also, invention relates to an antitumor agent based on the prepared crystalline form. Invention provides the stable quality of a medicinal agent based on its lower hygroscopicity.

EFFECT: improved and valuable properties of compounds.

8 cl, 5 ex

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

SUBSTANCE: invention relates to a method for isolation of epotilons used in medicine in treatment of cancer diseases. Method for desorption of epotilons A, B, D and/or E from synthetic resin is based on using low-polar or nonpolar solvent chosen from the group comprising (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Used aromatic solvent is chosen from the group including naphthalene, benzene or naphthalene and benzene substituted with one or some substitutes chosen from the following group: (lower)-alkyl, (lower)-alkoxy-group, halogen atom, nitro-group and (lower)-alkoxy-(lower)-alkyl wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Solvent is removed to the required level but up to preparing a dry residue preferably. If necessary, residue is dissolved in mixture alcohol/hydrocarbon in the corresponding volume ratio. Alcoholic phase is evaporated until dry and then alcoholic extract is crystallized from mixture alcohol and hydrocarbon. Then formed crystallized product is dissolved in mixture nitrile/water but preferably in mixture acetonitrile/water taken in the ratio = 2:3 (vol./vol.). Formed solution is applied on column (if necessary, after separation for some distillates) for preparative chromatography in reversed phase followed by elution with mixture nitrile/water, removing nitrile and extraction of an aqueous phase with ester. Ester extract is evaporated and formed product is subjected for crystallization. Method for preparing epotilons A, B, D and/or E from resin or reaction mixture involves the following steps: (a) desorption of epotilons with low-polar or nonpolar solvent chosen from the group including (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents being the desorption step can be repeated up to achievement of the more complete desorption; (b) removal of solvent used in desorption from formed solutions by evaporation; (c) optional crystallization of epotilon(s) after desorption and first of all for crystallization of epotilon B by addition of mixture of alcohol with hydrocarbon and the following evaporation of alcoholic phase until dry and crystallization of epotilon B from the corresponding mixture of solvents; (d) (obligatory step) separation of epotilons by method of chromatography in reversed phase and the following dissolving a residue obtained in previous step in suitable solvent, elution with mixture nitrile/water and removing nitrile from epotilon-containing fractions by evaporation. If necessary, water remained with epotilon is extracted with ester followed by evaporation of epotilon-containing ester phase until dry; (e) optional purification by adsorption chromatography method, and final recrystallization of purified epotilon from corresponding solvents or mixture of solvents. If necessary, in this process between each step formed solutions or suspensions are concentrated, and/or liquid or solid components are separated of one another. Separation of epotilons A and B is carried out by chromatography method based on a mobile layer modeling. Invention provides simplifying methods for preparing large amounts of epotilons for satisfying requirement in these agents.

EFFECT: improved isolating method.

12 cl, 2 ex

FIELD: organic chemistry, medicine, gynecology.

SUBSTANCE: invention relates to novel tetracyclic heterocompounds of the formula (I): wherein X, Y, Z, R1 - R4, n and m has values given in the invention description and used as selective modulating agents for estrogen receptors. Also, invention relates to a method for synthesis of these compounds and pharmaceutical compositions comprising thereof, and their using in treatment and/or prophylaxis of disorders mediated by one or more estrogen receptors. Proposed compounds are useful in treatment and/or prophylaxis of disorders associated with depleting estrogen and comprising such disorders as rush of blood, vaginal dryness, osteopenia and osteoporosis, hormone-dependent cancer and hyperplasia of breast, endometrium, uterus cervix and prostate, endometriosis, uterus fibroma, osteoarthritis that can be used as contraceptive agents both separately and in combination with progestogen or progestogenous antagonist.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

25 cl, 7 tbl, 171 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

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