The method of obtaining derivatives benzocycloheptene acids

 

(57) Abstract:

Usage: in medicine, as hypercholesterolemics, antithrombotic and anti-fungal drugs. The inventive product: derived benzocycloheptene acids f-crystals I mentioned in the description of the invention in which X = CH2O or O, or S; R1and R2identical or different, represent H, alkyl C1-C3or they form together a chain - (CH2)n- (n = 4 or 5), necessary in the case of symmetrically substituted by one or two alkyl radicals in C1-C3. R3and R4identical or different H, CF3, halogen (Cl, F, Br), N, N-dialkylamino in C1-C5, alkyl C1-C4, alkoxy, C1-C5alkylthio in C1-C3or phenyl, where appropriate substituted by not more than two substituents, which may be identical or different and represent alkyl radicals in C1-C3, alkoxy, C1-C3or halogen (F, Cl), it is understood that when one of R3, R4represents the radicals: CF3N, N-dialkylamino, C6H5or substituted phenyl, it is in positions 3', 4' or 5' is) represent H, halogen (F, Cl, Br, CF3, alkyl C1-C3, alkoxy, C1-C3C6H5if necessary substituted by not more than two substituents, which may be different or the same and represent radicals: alkyl C1-C3, alkoxy, C1-C3or halogen atoms (F, Cl), provided that when one of R5, R6is CF3C6H5or substituted phenyl, it is in position 6 or 7, and the other denotes a hydrogen atom. The substituents R3and R4and, accordingly, R5and R6can also form together, when two adjacent positions, the diradicals of the formula - CH = CH - CH = CH, (CH2)m- , - O(CH2)pwhere m = 3 or 4, p = 1 or 2, it is understood that, when R5and R6form a chain O(CH2)pO , it is associated with the vertices of the 3', 4' or 4', 5' and 6 and 7 in accordance with formula I. R7and R8= H or they form together with the existing bond C - C double bond geometry TRANS; R9and R10= H or form together dialkylamino group C1-C3/. In the form of free acids, salts, esters, amides or-latanov. Reagent 1: ketoester f-crystals II, the decree is exousia agent of the type derived boron, such as trialkylborane or discocellulars. Reaction conditions: low temperature with subsequent treatment with alkali metal borohydride for 5 to 8 h followed by conversion of one of the target product to another target product. The compound I in a dose of 0.23 mg/kg reduces cholesterolemic 50% and exceeds the drug lovastatin LD503200 mg/kg

The invention relates to a method for producing new derivatives benzocycloheptene acids.

It is known that certain derivatives of 3,5-dihydroxy-3-methylpentanoic acid, known under the name "mevalonovoy acids are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is responsible for the biosynthesis of cholesterol (see Singer et coll. Proc. Sc. .. Biol. Med. 102, 275, 1959).

It has recently been suggested connection - derived mevalonovoy acid, called "lovastatin", previously called "mevinolin", as the active component of the drug compositions used in the treatment of hypercholesterolemia (see patent US 423938 on behalf of the firm Merck).

Currently, it was found that new derivatives benzocycloheptene-dihydroxyheptanoic acids have hypercholesterol and, refers to compounds of the formula I, which are numbered for better understanding of the invention and only as an example below:

In this formula, X represents a methylene group,- CH2-, an oxygen atom or a sulfur atom;

R1and R2which may be identical or different, represent hydrogen atoms or alkyl radicals with 1 to 3 carbon atoms;

R1and R2can also together form alkylenes chain -(CH2)n- in necessary cases symmetrically substituted by one or two alkyl radicals with 1 to 3 carbon atoms, and the number n in the chain to have values of 4 or 5.

R3and R4which may be identical or different, represent hydrogen atoms, halogen atoms (fluorine, chlorine or bromine), radicals: trifluoromethyl, N, N-dialkylamino with 1-3 carbon atoms, alkyl with 1-4 carbon atoms, alkoxy with 1-5 carbon atoms, alkylthio with 1-3 carbon atoms or phenyl, if necessary substituted by not more than two substituents, which may be identical or different and represent radicals; alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms or the halogen atoms (fluorine or chlorine), provided what if one of the substituents is located at the vertices of a 3', 4' or 5' (meta or para) in the formula I, and the other Deputy is a hydrogen atom.

R5and R6which may be identical or different, represent hydrogen atoms, halogen atoms (fluorine, chlorine or bromine), radicals: trifluoromethyl, alkyl with 1-3 carbon atoms, alkoxy WITH1-C3or a phenyl radical, if necessary substituted by not more than two substituents, which may be identical or different and represent radicals: alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms, or a halogen (chlorine or fluorine), provided that if one of the substituents R5or R6represents the radicals: trifluoromethyl, phenyl or substituted phenyl, it is in the tops 6 and 7 in the formula I, and the other Deputy denotes a hydrogen atom.

The substituents R3and R4and, accordingly, R5and R6can also form together, when on adjacent vertices, diradicals: dietilen, alkylen or alkylenedioxy formula : -CH= CH-CH= CH-, -(CH2)m-, -O(CH2)pO-, in which m can have values of 3 or 4 and p values 1 or 2, provided that, if R3and R4and, accordingly, R5and R6form of bird the SNO formula I.

The substituents R7and R8each represents a hydrogen atom or form together with the existing relationship With-With a double bond to a TRANS-geometry (E).

Each of the substituents R9and R10represents a hydrogen atom or together they form dialkylamino group with 1-3 carbon atoms.

R11may be a hydroxyl radical, in this case, the compounds of formula I are carboxylic acids in the free state.

The compounds of formula I can be obtained in the form of esters or amides, which are also part of the invention.

Especially preferred are the esters and amides, which are physiologically acceptable for the formula I, in which the substituent R11is alkoxyalkyl with 1-4 carbon atoms, a benzyloxy radical, alkylamino or N, N-dialkylamino with 1-3 carbon atoms, imino, with 4-6 carbon atoms, cycloalkylation with 3-6 carbon atoms or radicals of amino, or benzylamino.

The compounds of formula I in the form of salts, i.e., in the formula which the substituent R11represents a group of formula-O-M+in which M+denotes a pharmaceutically acceptable cation, is also part of the invention, The compounds of formula I can exist in the form of lactones, when the substituent R11forms with substituent R9a simple link, the compounds of formula I in the form of lactones are also part of the invention.

In accordance with the preferred form of the invention, the subject invention are the compounds of formula I in which the substituents R1and R2are identical or form an unsubstituted alkylenes chain -(CH2)n- in which the number of links n is 4 or 5.

The preferred value of the substituents R1and R2,when they denote alkyl radicals with 1 to 3 carbon atoms is, for example, methyl.

The preferred value of n, when the substituents R1and R2form alkylenes chain -(CH2)nis for example 4.

Particular values for one or the other substituent R3and R4are, only as an example,

if this Deputy is halogen: fluorine or chlorine,

if he is an alkyl radical with 1-4 carbon atoms: methyl or ethyl,

if he represents an alkoxy radical with 1-5 carbon atoms: methoxy or ethoxy,

if he represents the radical of alkylthio with 1-3 carbon atoms: methylthio,

if he PREDSTAVITEL size m, when the substituents R5and R4form biradical -(CH2)m- that is, for example, 4.

The specific value of p, when the substituents R3and R4form biradical alkylenedioxy-O(CH2)pO-is, for example, 1.

Preferred meanings of the radicals R3and R4are, when R3and R4denote alkyl radicals with 1-4 carbon atoms and/or halogen atoms, or a halogen atom and an alkoxy radical with 1-5 carbon atoms; when one of the substituents R3or R4is a halogen atom or an alkyl radical with 1-4 carbon atoms, or alkoxy radical with 1-5 carbon atoms, or a radical of alkylthio with 1-3 carbon atoms and the other represents a hydrogen atom.

The specific combination of the radicals R3and R4are, for example, when they represent methyl radicals in positions 3' and 5' fluorine atom in position 4' and methyl at position 3', the fluorine atoms in positions 3' and 4', the fluorine atom at position 3' or 4' and a hydrogen atom, a methyl or ethyl radical in position 4' and a hydrogen atom, a methoxy radical in position 3' or 4', and the hydrogen atom, the chlorine atom at position 3' or 4' and the hydrogen atom or hydrogen atoms.

lagena: fluorine or chlorine;

alkyl radical with 1-3 carbon atoms: methyl;

the alkoxy radical with 1-3 carbon atoms: methoxy;

substituted phenyl radicals: phenyl radical substituted in paraprotein fluorine atom or chlorine, or methoxy radical.

When the substituents R5and R6form together alkylenes chain -(CH2)m- the number m is, in particular, 4.

When the substituents R5and R6form together a chain of alkylenedioxy-O(CH2)pO-, then the value of p is, in particular, 1.

The preferred meanings of the radicals R5and R6are, for example, halogen atoms (fluorine, chlorine, bromine), alkyl radicals with 1 to 3 carbon atoms or alkoxy radicals with 1 to 3 carbon atoms, or when one of the substituents R5or R6represents a halogen atom, which may be fluorine, chlorine or bromine, or represents an alkyl radical with 1 to 3 carbon atoms, or an alkoxy radical with 1-3 carbon atoms, and the other Deputy is a hydrogen atom.

Specific combinations of values of the radicals R5and R6are, for example, methyl radicals in positions 5 and 7, the chlorine atom in position 6 and a hydrogen atom, a methoxy radical in paloom hydrogen; radical 4-forfinal in position 6 or 7 and a hydrogen atom, or two hydrogen atoms.

The value of the substituents R9and R10when they form a group of dialkylamino is, for example, dimethylmethylene. Specific values of the substituent R11are, as an example:

the alkoxy radical with 1-4 carbon atoms: methoxy or ethoxy;

the of the alkylamine radical with 1-3 carbon atoms: methylamine, ethylamine or isopropylamino;

the radical of N, N-dialkylamino with 1-3 carbon atoms: diethylamino, imino radical, with 4-6 carbon atoms: pyrrolidino.

The compounds of formula I in which the substituents R7and R8form together a bond, are preferred with respect to the corresponding compounds of the formula I, in which each of the substituents R7and R8is a hydrogen atom.

All other things being equal the radicals of the compounds of formula I, in which each substituent R9and R10means a hydrogen atom, are preferred, compared to compounds in which the substituents R9and R10form dialkylamino group.

When all identical radicals of the compounds of formula I galactosemia are preferred and are preferred, compared with the free acid.

All the same radicals, retrosternally are preferred with respect to createrootpane (terms of Erythro and threo refer to the relative orientation of groups OR9and OR10).

From Viktorovich compounds of formula I, TRANS stereoisomers are preferred in relation to the stereoisomers of CIS (the terms CIS and TRANS refer to the relative radical or Equatorial positions of the two substituents lactoovo cycle).

Especially preferred group of compounds in accordance with the invention include the compounds of formula I, in which

A) X represents the atoms of oxygen or sulfur, or a methylene group, R1and R2each represents a methyl radical, or together they form tetramethylene chain -(CH2)4and only one of the radicals R3or R4and, accordingly, R5or R6is hydrogen, R7and R8form together a bond and each of R9and R10is a hydrogen atom.

B) X, R1, R2, R7, R8, R9and R10have the meanings given above in A), one of the substituents R3and R4means the atom is odorata.

C) X, R1, R2, R7,R8, R9and R10have the meanings given above in A), one of the substituents R3and R4is a hydrogen atom and the other is a fluorine atom or chlorine, and each of the substituents R5and R6is a hydrogen atom.

D) X, R1, R2, R7, R8, R9and R10have special meanings given above in (A), two Deputy R3and R4are hydrogen atoms, and one of the radicals R5and R6is a hydrogen atom.

E) X, R3, R4,R5, R6, R7, R8, R9, R10have the meanings given above in (C), and R1and R2form together tetramethylene chain -(CH2)4-.

F) X, R1, R2, R7,R8, R9, R10have the meanings given above in (E), and each of the substituents R3, R4, R5, R6is a hydrogen atom.

In each of the compounds of the formula I with at least two centers of asymmetry, which are two carbon atoms, media groups OR9or or10when the substituents R9and R10each is a hydrogen atom or together form dialkylamino graphicscom oxygen atom, when the substituents R9and R10together form a bond.

From this it follows that each connection, free acid, ester, amide, salt or lactone corresponding to the formula I can exist in at least four stereoisomers, two by two diastereoisomers, which are indicated using conventional configuration symbols R and S, i.e., RR, SS, RS and SR, or diastereoisomeric racemate mixtures, RR-SS and RS-SR.

All of these stereoisomers are also part of the invention. In the compounds of formula I can be more than two centers of asymmetry, in particular, when the substituents R1and R2different, due to this there are additional stereoisomers that are also part of the invention.

Selection or synthesis of optically active forms of compounds of formula I by prominent specialist methods, for example by dividing the racemate or by getting in early synthesis of optically active compounds, and then determine the biological properties of the obtained isomers in accordance with the following tests.

The term "physiologically acceptable ester or amide" refers to an ester or amide compounds, in compliance is acceptable alcohol or amine, i.e., not toxic in desired doses.

The term "alkyl" refers to saturated hydrocarbon chain, linear or branched, derived from the corresponding alkane, when the removal of a hydrogen atom.

The term "alkoxy" means an alkyl radical as defined above, associated with the parent molecule, the oxygen atom.

The term "alkylamino" imply a nitrogen atom substituted with hydrogen atom or an alkyl radical, as defined above, with the free valence is used to create a relationship with the parent molecule.

The term "N, N-dialkylamino" mean alkylamino radical, as defined above in which a hydrogen atom is substituted by an alkyl radical, as defined above.

The term "imino" refers to a radical of dialkylamino, as defined above, in which the two alkyl radicals together form alkylenes chain.

The term "dialkyl. . . 1 x carbon atoms" means that each of the two alkyl radicals, forming dialkylphenol group may independently contain from 1 to x carbon atoms. As typical compounds in accordance with the invention only in cadinene 1: (+, -)-6E-Erythro-7-(4-(4-forfinal)-Spiro-3(2H-benzopyran-1,2,1'- cyclopentyl))-3,5-dihydroxy-6-heptanoate ethyl.

Compound 2: (+, -)-6E-Erythro-7-(1,2-dihydro-2,2-dimethyl-4-phenyl-3-naphthyl)-3,5 - dihydroxy-6-hepten-oat bromide.

Compound 3: (+, -)-6E-Erythro-7-(4-(4-chlorophenyl)-2,2-dimethyl-2H-3-benzothia-RAS-yl)- 3,5-dihydroxy-6-hepten-oat bromide.

Compound 4: (+, -)-Erythro-7-[4-(4-forfinal)-Spiro-3-(2H-benzopyran-1,2,1'-CEC - lipantil)] -3,5-dihydroxyheptanoic ethyl.

Compound 5: (+, -)-6E-Erythro-7-[4-(4-forfinal)-Spiro-3-(2H-benzopyran-1,2,1'-cyclopentyl )] -3,5-dihydroxy-6-hepten-oat sodium.

Compound 6: (+, -)-6E-Erythro-7-(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1,2,1'-cyclopentyl ))-3,5-dihydroxy-6-hepten-oat of benzil.

Compound 7: (+, -)-6E-Erythro-7-(4-(4-forfinal)-Spiro-3-(2H-benzopyran - 1,2,1'-cyclopentyl))-3/5-dihydroxy-N-methyl-6-heptenoic. Compound 8: (+, -)-TRANS-6-6-{ 1E-2-[4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-Cyclops ntil)] -ethynyl} -4-hydroxy-3/4/5/6-tetrahydro-2-pirano.

Compound 9: (+, -)-TRANS-4-hydroxy-3,4,5,6-tetrahydro-6(2-(4-(4-forfinal)-SPI - ro-3-(2H-benzopyran-1-2,1'-cyclopentyl)- ethyl)-2-pirano.

Compound 10: (+, -)-Erythro-7-(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-cyclopentyl)) -3,5-dihydroxyheptanoic-1,3-dioxane-4-yl)-ethyl acetate.

Compound 12: (+, -)-6E-Erythro-3,5-dihydroxy-7-(4-perspira-3-(2H-benzodi-RAS-1-2,1'- cyclopentyl))-6-heptanoate ethyl.

Compound 13: (+, -)-6E-Erythro-7-[4-(4-ethylphenyl)-Spiro-3-(2H-benzopyran-1-2,1'-cyclopentyl )] -3,5-dihydroxy-6-heptanoate ethyl.

Compound 14: (+, -)-6E-Erythro-3,5-dihydroxy-7[6-methyl-4-perspira-3(2H-Ben - superan-1-2,1'- cyclopentyl)] -6-hepten-oat ethyl.

Compound 15: (+, -)-6E-Erythro-7-[7-fluoro-4-phenyl-Spiro-3-(2H-benzopyran-1-2.1 - cyclopentyl)] -3,5-dihydroxy-6-hepten-oat bromide.

Compound 16: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(4-were)-3-Spiro(2H-benzopyran-1-2 , 1'-cyclopentyl)] -6-hepten-oat ethyl.

Compound 17: (+, -)-6E-Erythro-7-[4-(3-forfinal)-3-Spiro-(2H-benzopyran-1,2,1'-cyclopentyl )] -3/5-dihydroxy-6-hepten-oat ethyl.

Compound 18: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(4-methoxyphenyl)-3-Spiro (2H-benzopyran-1-2,1'-cyclopentyl)] -6-hepten-oat ethyl.

Compound 19: (+, -)-6E-Erythro-7-[4-(4-chlorophenyl)-3-Spiro(2H-benzopyran-1-2,1'-CEC - lipantil)] -3,5-dihydroxy-6-hepten-oat ethyl.

Compound 20: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(1-naphthyl)-3-Spiro(2H-benzo - Piran-1-2,1'-cyclopentyl)] -6-hepten-oat ethyl.

Compound 21: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(3, 5dimethylphenyl)-3-Spiro- (2H-the Il-3-Spiro(2H-benzo - Piran-1-2,1'-cyclopentyl)] -3,5-dihydroxy-6-hepten-oat ethyl.

Compound 23: (+, -)-6E-Erythro-7-[4-(4-ethoxy-phenyl-3-Spiro-(2H-benzopyran-1-2, 1'-cyclopentyl)] -3,5-dihydroxy-6-hepten-oat bromide.

Compound 24: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(4-isopropoxyphenyl)-3 - Spiro(2H-benzopyran-1-2,1'-cyclopentyl)] -6-hepten-oat bromide.

Compound 25: (+, -)-6E-Erythro-7-[4-(4-forfinal)-6-methoxy-3-Spiro(2H-benzopyran-1-2,1'-qi clopotel)] -3/5-dihydroxy-6-hepten-oat bromide.

Compound 26: (+, -)-6E-Erythro-7-(4-(4-triptoreline)-3-Spiro(2H-benzodi - RAS-1-2,1'-cyclopentyl))-3,5-dihydroxy-6-hepten-oat ethyl.

Compound 27: (+, -)-6E-Erythro-3,5-dihydroxy-7[4-(4-n-pentyloxide)-3-SPI - ro(2N-benzopyran-1-2,1'-cyclopentyl)] -6 - hepten-oat bromide.

Compound 28: (+, -)-6E-Erythro-7-[4-(4-forfinal)-3-Spiro(2H-oil(b)Piran-1-2, 1'-cyclopentyl)] -3,5-dihydroxy-6-hepten-oat bromide.

Compound 29: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(4-methylthiophenyl)-3-Spiro- (2H-benzopyran-1-2,1'-cyclopentyl)] -6-hepten-oat bromide.

Compound 30: (+, -)-6E-Erythro-7-(4-(4-tert-butylphenyl)-3-Spiro(2H-benzopyran-1-2,1'-Cyclops Intel)-3/5-dihydroxy-6-hepten-oat ethyl.

Compound 31: (+, -)-6E-Erythro-7-((4-(4-forfinal)-3-Spiro(2H-benzopyran-1-2,1'-cyclohexyl ))-3/5-DigiTrace-6-hepten-oat ethyl.

Soedinenii bromide.

Compound 33: (+, -)-6E-Erythro-7-[(4-forfinal)-3-Spiro(2H-benzopyran-1-2,1'-cyclopentyl)] - 3,5-dihydroxy-6-heptenoic.

Compound 34: (+, -)-6E-Erythro-7-[4-(4-forfinal)-3-Spiro(2H-benzopyran-1-2,1'-cyclopentyl) ] -3,5-dihydroxy-N-isopropyl-6-heptenoic.

Compound 35: (+, -)-6E-Erythro-7-[4-(1,1-biphenyl-4-yl)-3-Spiro(2H-benzopyran-1-2, 1'-cyclopentyl)] -3,5-dihydroxy-N, N-tetramethylene 6-heptenoic.

Compound 36: (+, -)-6E-Erythro-7-[4-(4-forfinal)-3-Spiro(2H-benzopyran-1-2,1'-cyclopentyl) ] -3/5-dihydroxy-N-cyclohexyl-6-heptenoic.

Compound 37: (+, -)-6E-Erythro-N-benzyl-7-[4-(4-forfinal)-3-Spiro(2H-benzopyran-1-2,1'-CEC lipantil)] -3/5-dihydroxy-6-heptenoic.

Compound 38: (+, -)-6E-Erythro-7-[4-(4-ethylphenyl)-3-Spiro(2H-benzopyran-1-2,1'-cyclopentyl) ] -6-hepten-oat sodium.

Compound 39: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(6-were)-3-Spiro(2H-benzopyran-1-2 , 1'-6-hepten-oat sodium.

Compound 40: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(4-isopropylphenyl-3-Spiro- (2H-benzopyran-1-2,1'-cyclopentyl)] -6-hepten-oat sodium.

Compound 41: (+, -)-6E-Erythro-3,5-dihydroxy-7-[(4-phenyl-3-Spiro(2H-benzodi-RAS-1-2,1'-CEC lipantil)] -6-hepten-oat sodium.

Compound 42: (+/-)-6E-Erythro-7-[4-(4-chlorophenyl)-3-Spiro(2H-benzopyran-1-2,1'-2H-1-benzopyran-3 - yl) -6-hepten-oat ethyl.

Compound 44: (+, -)-6E-Erythro-7-[4-(4-forfinal)-2,2-dimethyl-2H-11-benzodi - ran-3-yl)-3,5-dihydroxy-6-hepten-oat bromide.

Compound 45: (+, -)-6E-Erythro-7-(4-(4-forfinal)-2-isopropyl-2H-1-benzopyran-3-yl)-3,5-dihydroxy-6-hepten-oat ethyl.

Compound 46: (+, -)-TRANS-4-hydroxy-3,4,5,6-tetrahydro-2-[1E-4-phenyl-3-Spiro- (2H-benzopyran-1-2,1'-cyclopentyl)-ethynyl] - 6-2N-2-pirano.

Compound 47: (+, -)-TRANS-6{ 1E-2[4-(4-forfinal)-6-methoxy-3-Spiro(2H-benzodi - RAS-1-2,1'-cyclopentyl)] -etanol} -4-hydro - XI-3,4,5,6-tetrahydro-2H-2-pirano.

Compound 48: (+, -)-TRANS-6-[1E-2-(1,2-dihydro-2,2-dimethyl-4-phenyl-3-naphthyl)- ethynyl] -4-hydroxy-3,4,5,6-tetrahydro-2H-2-pirano.

Compound 49: (+, -)-TRANS-4-hydroxy-3,4,5,6-tetrahydro-6-[1E-2-(2H-2,2-dimethyl-4-phenyl-3 - benzothiophenes)-ethynyl] -2H-2-pirano.

Compound 50: (+/-)-6E-Erythro-3,5-dihydroxy-7-[(4-phenyl-3-Spiro(1,2-dihydro-2,1'-naphthalen cyclopentyl)] -6-hepten-oat bromide.

Compound 51: (+, -)-6E-Erythro-7-[4-(4-forfinal)-1,2-dihydro-2,2-dimethyl-3-on - ftil)] -3,5-dihydroxy-6-heptenoic bromide.

Compound 52: (+, -)-6E-Erythro-7-(1,2-dihydro-2,2-dimethyl-4-phenyl-3-naphthyl)-3,5-dihydroxy - 6-hepten-oat bromide.

Compound 53: (+, -)-6E-Erythro-7-[4-(4-fluoro-phenyl)-3-Spiro(1,2-dihydro-2,1'-nafta - Lenz who dihydro-2,1'-nafta - encyclopedic)] -3,5-dihydroxy-6-hepten-oat bromide.

Compound 55: (+, -)-6E-Erythro-7-(4-chlorophenyl)-1,2-dihydro-2,2-dimethyl-3-naphthyl) -3,5-dihydroxy-6-hepten-oat bromide.

The connection 56: (+, -)-6E-Erythro-7-(4-(3-forfinal)-3-Spiro(1,2-dihydro-2,1'-nafta - encyclopedic))-3,5-dihydroxy-6-hepten-oat bromide.

Compound 57: (+, -)-6E-Erythro-7-(4-(4-forfinal)-1,2-dihydro-3-naphthyl)-3,5-dihydroxy-6-hepten-oat sodium.

The connection 58: (+, -)-6E-Erythro-7-(1,2-dihydro-2-isopropyl-4-phenyl-3-naphthyl)-3, 5-dihydroxy-6-hepten-oat bromide.

Compound 59: (+, -)-6E-Erythro-7-(1,2-dihydro-2-methyl-4-phenyl-3-naphthyl)-3,5-di - hydroxy-6-hepten-oat bromide.

Compound 60: (+, -)-6E-Erythro-3,5-dihydroxy-7-(8-methyl-4-(4-were)-3 - Spiro(1,2-dihydro-2,1'-naphtalanskaya - Teal))-6-hepten-oat bromide.

Compound 61: (+, -)-6E-Erythro-7-[6-chloro-4-(4-chlorophenyl)-3-Spiro(1,2-dihydro-2,1'-naphtalen clopotel)] -3/5-dihydroxy-6-hepten-oat bromide.

Compound 62: (+/-)-6E-Erythro-3,5-dihydroxy-7-[(8-methyl-4-(4-methoxyphenyl)-3-Spiro(1,2-di hydro-2/1'-naphthalenesulfonyl)] -6-hepten-oat bromide.

Compound 63: (+, -)-6E-Erythro-7-[6-chloro-4-(4-forfinal)-3-Spiro(1,2-dihydro-2,1'- naphthalen-cyclopentyl)] -3,5-dihydroxy-6-hepten-oat bromide.

Compound 64: (+, -)-6E-Erythro-7-(1,2-dihydro-2,2-dimethyl-7-methoxy-3-naphthyl) -3,ia - Piran-1-2,1'-cyclopentyl))-6-hepten-oat sodium.

Compound 66: (+, -)-6E-Erythro-3,5-dihydroxy-7-[4-(4-were)-3-Spiro(2H-benzothiophen - 1 - 2,1'-cyclopentyl)] -6-hepten-oat bromide.

Compound 67: (+, -)-6E-Erythro-3,5-dihydroxy-7-(4-phenyl-2,2-dimethyl-2H-3-Ben - soupirant)-67-hepten-oat bromide.

Compound 68: (+, -)-6E-Erythro-3,5-dihydroxy-7-(4-phenyl-2,2-dimethyl-2H-3-Ben - soupirant)-6-hepten-oat sodium.

The invention relates to methods for producing compounds according to the invention, characterized in that they include at least:

a) restore keeeper General formula 4, in which X, R1, R2, R3, R4, R5, R6, R7, R8and R11have the above values,

COR11(4) if necessary:

(b) transesterification of compounds of formula 1 or alcoholysis of the compounds of formula 1 in the form of lactones, or alkylation of compounds of formula I in the form of salts,

C) hydrolysis of compounds of formula 1 in the form of an ester or lactone,

d) when R7and R8and, accordingly, R9and R11form a simple link, then treated with the appropriate compounds of formula I in the form of salts of tertiary bleach

e) when R7, R8and R10denote a hydrogen atom and R7and R8form a bond, or are lactonization corresponding acidic compounds of formula 1 in which R7, R8and R10represent a hydrogen atom,

f) aminals compounds of formula 1 in the form of ester or lactone,

g) if R9and R10together form dialkylamino group, perform the cyclization of the corresponding compounds of formula 1 in which R9and R10each denotes a hydrogen atom, with alkoxyalkane.

The compounds of formula 1 in which X, R1, R2, R3, R4, R5, R6, R7, R8have the above specified values, and in which the substituents R9and R10each denotes a hydrogen atom, can be obtained in the form of esters by below in scheme I, the sequence of reactions.

SCHEME I

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As shown in Scheme I, aldehyde compounds of formula 2, in which the substituents R1, R2, R3, R4, R5, R6, R7and R8have the above specified values, is subjected to aldol condensation with the appropriate acetoacetate in the form of a mixed double salt of sodium and lithium of the formula 3, in which F11matter that prepology 7 5-hydroxy-3-oxo-6-hepten-oaty General formula 4.

Esters of 4, in the form of a solution in an inert solvent, such as THF or ether, treated with alkaline borohydride, preferably sodium borohydride (method A), which leads to the compounds 1 in the form of mixtures of isomers of threo and Erythro, which can then be separated by conventional physico-chemical methods, such as chromatography.

Method B is preferable to method A and allows you to get a connection in accordance with the invention in the form of eritro. Method B is that, before the restoration of alkaline borohydride handle esters 4 in an appropriate solvent, such as THF, complexing agent, preferably trialkylborane, such as tributylamine (see Narasaka, Chem. letters, 1415-1418, 1980) or alkoxycarbonyl, such as methoxymethanol see Chenet Coll. Tetrahed. Lett. , 28(2), 155-158, 1987).

The compounds of formula 2, in which the substituents R7and R8form together a bond, can be obtained in accordance with the sequence of reactions shown in the scheme II.

SCHEME II

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As shown in scheme II, compounds of formula 5, in which X, R1, R2, R3, R4, R5and R6have preveden is in an inert solvent, for example acetonitrile, at a temperature of 20aboutTo return temperature refrigerator/ and receive connections 2 geometry TRANS/ how this is confirmed by the Yarm-spectroscopy.

Another method of producing aldehydes of formula 2/ in which R7and R8form together the connection is illustrated in the following scheme III.

SCHEME III

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As shown in scheme III, compounds of formula 5 is subjected to the reaction of synthesized using N-bromosuccinimide (NBS) in a solvent of N, N-dimethylformamide (DMF) or in a chlorinated solvent, for example, carbon tetrachloride or methylene chloride, and obtain the corresponding 3-brominated compound 6, which consistently treated with butyllithium in an appropriate solvent, preferably ether, for example in diethylether, then 3-amoxiciolin or N, N-dimethylamino-3-acrolein, and receive aldehydes 2 in the TRANS-form, as indicated by NMR spectroscopy.

The following scheme IV illustrates an alternative obtaining aldehyde intermediates of formula 2 in which R7and R8form together the link:

As shown in scheme IV, compounds of formula 5 is subjected to the reaction of Vilsmeier with N, N-dimethylformamidine Wittig reaction with ethoxy or methoxycarbonylmethylene or phosphonate methyl or ethyl (see Organic Reactions 14, 273, 1965), and get 3-substituted proteinemia esters 8, in which the TRANS-geometry, which is confirmed by NMR spectroscopy.

When X represents sulfur, to obtain the intermediate compounds of formula 8 is particularly preferred is an alternative reaction, which consists in carrying out the reaction of the bromide compound of formula 6 with alkylacrylate, preferably methyl acrylate or acrylate, in the presence of a base, such as triethylamine or sodium bicarbonate, dispersed coal palladium or a derivative of palladium, such as palladium dichloride or its acetate and a ligand, preferably of triarylphosphine, such as trichotillomania, in a suitable solvent, such as N, N-dimethylformamide.

Esters 8 restore using hydride diisobutylaluminum (DIBAL) in a solvent, usually in diethyl ether or THF, in the corresponding 3-substituted TRANS-propanol, which is then oxidised using oxalicacid in DMSO (see Swern et coll. , J. Org. Chem. 43, 2480, 1978), or with manganese dioxide in an appropriate solvent, for example THF, and get the aldehydes of the formula 2-TRANS-geometry.

Aldehydes of formula 2, in which the substituents R7and R8SS="ptx2">

SCHEME V

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In accordance with the reaction sequence of scheme V, the aldehydes of formula 2 in which R7and R8form a double bond, is subjected to reaction acetalization, for example, using orthoformiate formula HC(OR12)3in which R12represents an alkyl radical with 1-4 carbon atoms, preferably methyl or ethyl, in the presence of an acidic resin, or spend colocataires reaction with the alcohol of formula R12OH, in which R12has the above values, or may represent a radical of the formula -(CH2)qOH, where q = 2 or 3, and receive connections 10, with methylene radical R12. . . R12- forms with the oxygen atoms to which it is attached, a series of 5 or 6 links.

Then carry out the hydrogenation of compounds 10, preferably at reduced pressure and in the presence of a metal catalyst, for example dispersed palladium on coal, in an appropriate solvent, such as THF or alcohol, for example methanol, to the corresponding 3-substituted acetals of propanimidamide 11, which can then be deacetylation in propanimidamide 2 using conventional methods desecularization, such as processing AI in a mixture of appropriate solvents.

Alternative to obtain the aldehyde compounds of formula 2, in which each substituent R7and R8denotes a hydrogen atom, consists in the reaction of methyl compounds of formula 6 with allyl alcohol in the presence of a base, such as triethylamine or sodium bicarbonate, dispersed coal palladium or a derivative of palladium, for example douglasthe palladium or its acetate and a ligand, preferably of triarylphosphine, for example, triorthocresyl, in a suitable solvent, for example N, N-dimethylformamide.

The compounds of formula 5 can be obtained by using the sequence of reactions shown in scheme VI,

SCHEME VI

in accordance with which the ketone compounds of formula 12, in which X, R1, R2, R5and R6have the above values, process the corresponding lithium or magnesium compound of the formula 13, in which R3and R4have the above specified value, and is obtained by combining 1-2 corresponding alcohols 14, which dehydration in the required connections 5 by the action of dehydrating substances, such as acidic potassium sulfate or paratoluenesulfonyl acid.

The compounds of formula 12/ to the deposits/ receive method of the Kaba (Kabbe et coll. , Synthesis, 12, 886, 1978).

The compounds of formula 12/ in which X represents a methylene group and R1/ R2/ R5and R6have the above values/ receive, according to the sequence of reaction/ shown in scheme VII.

SCHEME VII

As shown by scheme VII, cyanoethyl formula 15 in which R1, R2, R5and R6have the above values, hydrolyzing and decarboxylase using glycolate, potassium into the corresponding acid 16, which cyclist in connection 12 by heating in an acidic environment. The compounds of formula 15 get method Prout et coll Org. Synth. , Coll. Vol. IV, 93, 1963).

The compounds of formula 1 in the form of esters can also be obtained by transesterification of compounds of formula 1, the distinguished Deputy R11or by alcoholysis of the compounds of formula 1 in the form of lactones, or by O-alkylation of compounds of formula 1 in the form of salts, preferably sodium salts, using a bromide or iodide of the formula R11-Br(1), in which R11has the above specified values.

The esters corresponding to formula 1, in which each of the substituents R7and R8represents a hydrogen atom, can be obtained by hydrogenation according to the leaders introduce pressure, in the presence of a metal catalyst, for example palladium or platinum oxide, in an appropriate solvent, for example THF.

The compounds of formula 1 in the form of salts can be obtained by alkaline hydrolysis, for example with alkali sodium or potassium alkali, in an appropriate solvent, preferably alcohol, the corresponding compounds of formula 1 in the form of esters, preferably the methyl or ethyl esters, or in the form of lactones.

-lactonase the compounds of formula 1, in which the substituents R7and R8together form a bond, can be obtained by the reaction of the corresponding compounds of formula 1 in the form of salts, preferably sodium salts, bleach, preferably with 2-chloroethyl-N, N-diethylamino, in an appropriate solvent, preferably in carbonella, for example, acetone or butanone. -lactonase the compounds of formula 1 in which R7, R8and R10each represents a hydrogen atom, is obtained by lactonization corresponding acids of formula 1, i.e., formulas where R11represents a hydroxyl radical: the reaction of lactonization carried out preferably by heating the acid in an inert aromatic solvent, the emer, paratoluenesulfonyl acid; the other, a specific method of obtaining-Viktorovych compounds of formula 1 in which R7, R8and R10means a hydrogen atom, is to hydrogenation in a heterogeneous phase, the corresponding unsaturated compounds of formula 1, i.e., compounds of the formula where R7and R8and, accordingly, R9and R11form together a bond, in the presence of a metal catalyst, preferably, dispersed coal palladium or platinum oxide, in an appropriate solvent, preferably in an ether, such as THF, or in alcohol, such as methanol or ethanol.

Acidic compounds of formula 1 in which R9and R10each denotes a hydrogen atom, can be obtained by acidification of the corresponding compounds of formula 1 in the form of salts, or by hydrogenolysis in the presence of dispersed palladium on coal, the corresponding benzyl esters, i.e. compounds of formula 1 in which R11represents a benzyloxy group.

The compounds of formula 1 in the form of amides obtained by aminolysis, with an excess of amine in a polar solvent, preferably methanol or ethanol, the corresponding esters of formula 1, predpochtitelney formula 1, in which the substituents R9and R10form together dialkylamino group with C1-3, obtained by the reaction of the corresponding compounds of formula 1 in which R9and R10denote each a hydrogen atom, with the corresponding alkoxyalkane (the term alkoxyalkyl means alkene having 3-7 carbon atoms, substituted on the double bond alkoxy radical, as defined above, preferably methoxy), in an appropriate solvent, for example, N, N-dimethylformamide, in the presence of an acid catalyst, for example, paratoluenesulfonyl acid.

It should be noted that the compounds in accordance with the invention in different forms: acids, salts, esters, amides or lactones, can be converted in accordance with the above-described ways, therefore, these different forms are also intermediate for the synthesis of compounds in accordance with the invention.

A mixture of stereoisomers (CIS-, TRANS-, three-, Erythro-, enantiomer) can be separated by conventional methods, stages of synthesis, which are the most suitable.

Under conventional methods involve a combination of methods known to the expert, for example, recrystallization, chromatography or the expectation by equation 2, 4, 5, 6, 7, 8, 9, 10, 11, 14, are also part of the invention, except for products of formula 5, in which R1and R2are H and X is S or CH2some of these compounds are well known through his work, Dehghani (Degani, Ann. Chem. (Rome) 1971, 61(2), 793-813) and Foam (Penn, J. Magn. Res. 1975, 18(1), 6-11).

The present invention relates also to methods of producing these intermediates synthesis.

The compounds of formula 1 have the ability to inhibit 3-hydroxy-3-methylglutaryl, coenzyme A, reductase, and therefore they have a strong hypocholesterolemic action.

The compounds of formula 1 can also be receptor antagonists of thromboxane A2this property manifests itself in integriruyuschim action on platelets.

Such properties of the compounds in accordance with this invention makes them particularly interesting for use as drugs in the treatment of various diseases of the heart muscle, such as thrombotic manifestations of diabetes, atherosclerosis, hyperlipoproteinemias.

In addition, the compounds according to the invention have antifungal properties, which is of great interest for use as protivogribkoe the Ana by conducting the following studies.

Test A: measurement of the hepatic14C-cholesterolemia in vivo in rats according to the method described by Boucheron (Bucher et coll. , J. Biol. Chem. , 222, 1-15, 1956) and Albertson (Albets et coll. , Proc. Natl. Acad. Sci. USA, 77(7), 3957-3961, 1980).

Test B: measure the total cholesterolemia "in vivo in rats at intravenous treatment with Triton WR 1339 according to the method described Endo (Endo et coll. Biochem. Biophys. Acta, 575, 226, 1979).

Test: measure the aggregation of platelets induced by agonist receptors THA2in Guinea pigs, by the following method: platelet-rich plasma (PRP) get aortas puncture from shot animals, blood (9 vol. ) collected in 106 mm solution traintravel citrate (1 vol. ) to prevent coagulation. PRP isolated by slow centrifugation (10 min, 380 g) and incubated for at least 3 min (37aboutWith slow stirring), aggregometry type CHRONOLOG-400. Aggregation of platelets is called by adding a direct agonist of receptors THA2for example, compounds known under the code U46619(at a concentration of 20nM), in accordance with the method of Malmstein (Malmstein, Life Sci. , 18, 169-178, 1976); compounds in accordance with the invention was investigated in-vitro.

For example, for compounds 1, 2, 19 and 65 were receiving the DE 50 was equal to 0.39 mg/kg

For the same compounds in test B were obtained DE values 25, respectively, 29, 100, 110 and 74 mg/kg, and for Lovastatin under the same conditions DE 25-130 mg/kg

To test for compounds 1 and 19 received value Cl 50: 91 28.10-6mol/L.

The present invention also relates to medicaments comprising compounds of General formula I, taken as they are in pure form or in combination with any other substance, acceptable from a pharmaceutical point of view, which may be inert or physiologically active.

These medicines can be entered in any patologicheskoi form, in the form of tablets, pills, capsules, powders, granules, etc. In these compositions the active ingredient is mixed with one or more inert diluents, such as lactose or starch, in addition, in these compositions, in addition to diluents may include lubricants, as talc or magnesium stearate; if you want to obtain aqueous suspensions, elixirs or syrups for oral administration, the active ingredient may be combined with various sweetening or flavouring substances, in necessary cases with emulsifiers and/or with substances that creates a suspension, while dilute the accordance with the invention for oral administration to a single dose contains 1-500 mg of active substance.

The following example is given as a non-limiting, illustrates a composition of this type.

P R I m m e R. the Composition, mg Active substance 10 Lactose 104 corn starch 30 Talc 2.5 Polyvidone linking 3 magnesium Stearate 0.5 to

This invention is illustrated by the following non-limiting examples, in which:

stage evaporation is carried out, unless otherwise stated, in a rotary evaporator under reduced pressure;

temperatures are indicated in degrees centigrade (aboutC);

if you specify "room temperature" is the temperature from 18 to 25aboutC;

unless otherwise indicated, the reaction is controlled by thin-layer chromatography (TLC).

The new compounds are characterized by necessary physical constants; the melting point and boiling point, in necessary cases, the pressure is expressed in millibars.

The output is indicated only as an illustration and is not the highest possible output.

The spectra of nuclear magnetic resonance, if not otherwise indicated, are proton spectra and was shot at 60 MHz, as an internal standard tetramethylsilane was used, chemical add DD - double doublet, Tr - triplet, q - Quartet, m - multiplet.

Infrared spectra of compounds were recorded on samples dispersed in potassium bromide in the case of solids, or in films - in the case of liquid samples.

P R I m e R 1. (+, -)-6E-Erythro-7-[4-(4-forfinal)-3-Spiro(2H-benzopyran-1-2,1'- cyclopentyl)] -3,5-dihydroxy-6-hepten-oat ethyl (compound 1) - formula 1: X = O; R1-R2= -(CH2)4-; R3= 4'F, R4= R5= R6= R9= R10= H, R7-R8= communication, R11= OC2H5.

Stage I

4-(4-Forfinal)-3,4-dihydro-4-hydro-xepera(2N-benzopyran-1-2,1'- cyclopentane) (Scheme VI - formula 14).

Work in a nitrogen atmosphere in a place protected from moisture reactor. To 6,07 g (0.25 g x atom) of magnesium shavings, suspended in 130 cm3diethylether add so as to maintain a small flow of air in the reflux, 43,75 g (0.25 mol) of 1-bromo-4-fervently dissolved in 200 cm3diethylether.

The mixture was kept at the reflux for 4 h, then cooled to room temperature and at this temperature, add a solution of 20 g (0.1 mol) of Spiro(2H-benzopyran-1-2,1'-4-cyclopent - Nona) (produced by the method Kabbe (Kabbe et coll. , Synthesis, 12 is lnike.

Stir the mixture for 2 h at room temperature, then poured into ice-cold aqueous solution of ammonium chloride in a large excess relative to the stoichiometry, add hydrochloric acid in a quantity sufficient for complete dissolution suspension, then decanted organic phase, this phase is washed with water until neutral pH, then dried over sodium sulfate, filtered and the solvent is evaporated; get 30 g of oil, which is used as it is in subsequent syntheses.

Stage II.

4-(4-Forfinal)-Spiro(2H-benzopyran - 1-2,1'-cyclopentane) (scheme VI, formula 5).

Under reduced pressure (16 mm RT. Art. ), at a temperature of 120aboutWith over 30 min, heat the mixture of 30 g (0.1 mol) of the product of stage 1 and 3 g KHSO4(0,1 weight of the work connection). The residue is dissolved in sufficient quantity of dichloromethane, then the solution is washed with water, then dried over sodium sulfate, filtered and evaporated the solvent, the obtained solid was dispersed in methyl alcohol.

So pl. = 76-78about(Diisopropylamino). A yield of 75% .

(Thin layer chromatography: ethyl acetate (AcOEt)-hexane: 5-95 (spot).

Elemental analysis: C

NMR (CDCl3): 1,25-2,70 (m, 8H), 5,73 (s, 1H), 6,50-7,87 (m, 8H).

Stage III. 2E-3-(4-(4-forfinal)-3-Spiro(2H-Ben-superan-1-2,1'-cyclopentyl))-2-propenal ü (scheme II - formula 2).

Work in an atmosphere of nitrogen in a reactor protected from moisture. Unless otherwise indicated, during subsequent operations the temperature of the reaction mixture support equal to -20aboutC. To a solution of 20.9 g (0.2 mol) of N, N-3-dimethylaminopyridine 200 cm3the acetonitrile is added dropwise within 30 min, with stirring, of 29.1 g (to 0.19 mol) of phosphorus oxychloride, stirring is carried out for 10 min, then added within 15 min and 11.2 g (0.04 mol) of the compound stage II in solution in 100 cm3acetonitrile. Then the temperature of the mixture is brought to room temperature, then heated under reflux until the disappearance of the original product, which is monitored by thin-layer chromatography, in the present case, the required heating time 40 PM

The mixture is evaporated, then the residue is poured into 1000 cm3ice water, neutralized (pH = 9) by adding a sufficient amount of concentrated caustic sodium solution is stirred for 15 min, then extracted with cm3of methylene chloride (2 x 500 cm3). The organic layer PR is outstay 100 g of silica gel. After filtration and evaporation receive oil, which crystallized in solid yellow substance by dispersion in hexane.

So pl. 108-111about(Diisopropylamino). The output of 8.4 g (63% ).

TLC: AcOEt - hexane 1: 9: 1 (spot).

Elemental analysis: C22H19FO2. Mol. weight 334,37.

Calculated, % : C 79,02; N 5,73; F 5,68.

Received, % : 78,82; N. Of 5.75; F 5,65.

IR, SNO: 1670 cm-1.

NMR (CDCl3) 1,25-2,87 (m, 8H), 5,98 (DD, 1H, J = 17 Hz and 7 Hz), 6,37-7.5 (m, N), a 9.25 (d, 1H, J = 7 Hz).

Stage IV. (+, -)-6E-7[4-(4-forfinal)-3-Spiro(2H-benzopyran-1-2,1'- cyclopentyl)] -5-hydroxy-3-oxo-6-hepten-oat ethyl (scheme I, formula 4).

Work in a nitrogen atmosphere, in the absence of moisture, unless otherwise indicated, the temperature of the mixture is equal to -20aboutC.

To a suspension of 1.2 g (0.05 mol) of sodium hydride in 300 cm3 of tetrahydrofuran (THF) is added 5.6 g (0,043 mol) of ethylacetoacetate in solution in 25 cm3THF, the mixture is stirred for 20 min, then added to it over time 15-20 min 27 cm3a 1.6 n solution of utility in hexane (i.e. 0,043 mol BuLi), stirring is continued for 20 minutes, then drops add a solution of 8.7 g (0,026 mol) of the aldehyde stage 3 140 cm3THF. A mixture of AC is Jana acid. Extracted with ethyl acetate, the organic phase is washed with water until pH 7, dried over sodium sulfate, evaporated to dryness, get the oil, which crystallizes upon dispersion in hexane.

So pl. 87-90aboutWith (ethyl acetate). The output 110 g (90,9% ).

(TLC: silica gel, AcOEt-hexane: 1-2: 1 spot).

Elemental analysis: C28H29FO5. Mol. weight 464,51.

Calculated, % : C 72,40; N 6,29; F 4.09 To.

Received, % : 72,33; N. Of 6.31; F 4,05.

IR, HE: 3420 cm-1; WITH: 1740 and 1710 cm-1.

NMR (CDCl3): 1,326 (t, 3H), of 1.5 to 2.35 (m, 8H), 2,52 (d, 2H), 3,92 with 4.65 (m, 3H), and 5.30 (DD, 1H, J = 15,8 Hz and 5.5 Hz), 6,00 (d, 1H, J = 15,8 Hz), from 6.25 to 7.50 (m, 8H). FIA, in the present case, the required heating time 40 PM

The mixture is evaporated, then the residue is poured into 1000 cm3ice water, neutralized (pH = 9) by adding a sufficient amount of concentrated caustic sodium solution is stirred for 15 min, then extracted with 1000 cm3of methylene chloride (2 x 500 cm3). The organic layer is washed with water, dried over sodium sulfate, filtered, add 1000 cm3hexane and stirred in the presence of 100 g of silica gel. After filtration and evaporation receive oil that crystallizer). The output of 8.4 g (63% ).

TLC: AcOEt - hexane 1: 9: 1 (spot).

Elemental analysis: C22H19FO2. Mol. weight 334,37.

Calculated, % : C 79,02; N 5,73; F 5,68.

Received, % : 78,82; N. Of 5.75; F 5,65.

IR, SNO: 1670 cm-1.

NMR (CDCl3) 1,25-2,87 (m, 8H), 5,98 (DD, 1H, J = 17 Hz and 7 Hz), 6,37-7.5 (m, N), a 9.25 (d, 1H, J = 7 Hz).

Stage IV.

(+, -)-6E-7[4-(4-forfinal)-3-Spiro(2H-Ben - superan-1-2,1'- cyclopentyl)] -5-hydroxy-3-oxo-6-hepten-oat ethyl (scheme I, formula 4).

Work in a nitrogen atmosphere, in the absence of moisture, unless otherwise indicated, the temperature of the mixture is equal to -20aboutC.

To a suspension of 1.2 g (0.05 mol) of sodium hydride in 300 cm3tetrahydrofuran (THF) is added 5.6 g (0,043 mol) of ethylacetoacetate in solution in 25 cm3THF, the mixture is stirred for 20 min, then added to it over time 15-20 min 27 cm3a 1.6 n solution of utility in hexane (i.e. 0,043 mol BuLi), stirring is continued for 20 minutes, then drops add a solution of 8.7 g (0,026 mol) of the aldehyde stage 3 140 cm3THF. The mixture is stirred for 3 hours, then add drops to her, at a temperature of from -20 to 10aboutWith 40 ml of 3 n hydrochloric acid. Extracted with ethyl acetate, washed with AutoRAE crystallizes when the dispersion in hexane.

So pl. 87-90aboutWith (ethyl acetate). The output 110 g (90,9% ).

(TLC: silica gel, AcOEt-hexane: 1-2: 1 spot).

Elemental analysis: C28H29FO5. Mol. weight 464,51.

Calculated, % : C 72,40; N 6,29; F 4.09 To.

Received, % : 72,33; N. Of 6.31; F 4,05.

IR, HE: 3420 cm-1; WITH: 1740 and 1710 cm-1.

NMR (CDCl3): 1,326 (t, 3H), of 1.5 to 2.35 (m, 8H), 2,52 (d, 2H), 3,92 with 4.65 (m, 3H), and 5.30 (DD, 1H, J = 15,8 Hz and 5.5 Hz), 6,00 (d, 1H, J = 15,8 Hz), from 6.25 to 7.50 (m, 8H).

Stage V

(+, -)-6E-Erythro-7-[4-(4-forfinal)-3-SPI - ro(2N-benzopyran-1,2,1'-cyclopentyl)] -3, 5-dihydroxy-6-hepten-oat ethyl (compound 1).

Work in an atmosphere of nitrogen, protected from moisture reactor. If there are no other instructions, then the following operations, the temperature of the reaction mixture support -70aboutC.

To a solution of 3.25 g (to 0.007 mol) of keeeper stage IV in a mixture of 65 cm3THF and 15 cm3methanol added during 5 min, with stirring, 7.7 cm31 N. of a solution of diethylmethoxyborane in THF (i.e. to 0.007 mol + 10% of borane). Stirring is continued for 40 min, then add to 0.29 g (0,007 mol + 10% ) sodium borohydride. The mixture is stirred for 5 h, then acidified by adding 6.5 cm3acetic acid, then add 80 cm3M solution of sodium bicarbonate (2x200 cm3), then with water, the organic phase is decanted, dried over sodium sulfate, then the solvent is evaporated. The oil obtained is dissolved in 60 cm3methanol, the solution was stirred at 35aboutC for 20 min, then evaporated to dryness. This operation is repeated until then, until you get a constant weight, in this case, the operation was repeated 4 times.

In this way we obtain 3.1 g of a solid substance, which is dispersed in Diisopropylamine.

So pl. 112-114aboutWith (ethyl acetate). Output 2,48 g (76% ).

(TLC: silica gel: AcOEt-hexane 1-1: 1 spot).

Elemental analysis: C28H31FO5. Mol. weight 466,55.

Calculated, % : C 72,08; N 6,70; F 4,07.

Received, % : 71,82; H 6,83; F 3,90.

IR: OH: 3390 cm-1; FROM: 1715 cm-1.

NMR (CDCl3)-(200 MHz): of 1.27 (t, 3H), 1,20 is 1.58 (m, 2H), 1.60-to 2.29 (m, 8H), 2,36 is 2.44 (m, 2H), 4,17 (kV, 2H), 4,00-the 4.29 (m, 2H), of 5.34 (DD, 1H, J = 16.1 Hz and J = 6.3 Hz), 5,94 (DD, 1H, J = 16,1 and 1.2 Hz), is 6.54 (DD, 1H,40J = 7,7 Hz and 1.5 Hz), 6,70-6,85 (m, 2H), 7,00-7,20 (m, 5H).

Ghvd (liquid chromatography high pressure):

column oxide silicon 5 and Starosel 25 cm;

detector UV 254 nm (nanometers);

mobile phase: AcOEt: hexane: AcOH 35: 65: 0,01.

1 peak (11,1 min).

2, R1= R2= CH3, R3= R4= R5= R6= R9= R10= H, R7and R8connection R11= OCH3).

Stage I

2-(2,2-Dimethyl-3-phenylpropyl)-CYANOGEN - zitat ethyl (scheme VII, formula 15).

To a suspension of 19.2 g (0,79 g at) magnesium in the form of shavings 100 cm3ether type so that was a weak flow in the reflux, a solution of 100 g (0,79 mol) benzylchloride 400 cm3the ether. The mixture is heated under reflux for 15 min, then add to the weak flow in the reflux, the solution to 101.1 g (0.66 mol) isopropylbenzene ethyl 130 cm3simple ether. The mixture is heated under reflux for 2 h, then cooled and added slowly to 400 cm3water, then 100 cm320% H2SO4.

The mixture is stirred for 30 min, then the organic phase is decanted. The aqueous phase is extracted with ether, dried ethereal collected phase over sodium sulfate, filter and distil.

Ebfor 0.3= 115-121aboutC. the Yield 147 g (90% ).

IR: C= O: 1740 cm-1CN: 2250 cm-1.

NMR (CDCl3): 1-1,5 (m, N), a 2.75 (s, 2H), 3,25 (s, 1H) and 4.2 (q, 2H), between 6.7 to 7.6 (m, 5H).

stage I add, not cooling, a solution of 70 g of potassium alkali 230 cm3of ethylene glycol. The mixture is heated under reflux (140aboutC) for 3 h 15 min Volatile solvent is evaporated at 15 mm RT. Art. , then heated at the reflux (197aboutC) for 6 hours the Mixture is cooled, add it to 500 cm3water and extracted with ether.

The aqueous phase is acidified by adding concentrated hydrochloric acid and extracted with benzene.

Besolova phase is washed with water, dried over sodium sulfate, filtered and evaporated to dryness.

So allot of 48.7 g of oil, which is used as it is in subsequent syntheses. Yield 89% .

IR: C= O: 1700 cm-1.

NMR (CDCl3): 1 (C, 6N), 2,2 (s, 2H), 2,65 (s, 2H), 6,8-7,5 (m, 5H).

Stage III

1,2,3,4-Tetrahydro-3,3-dimethyl-1-oxo-naphthalene (scheme VII - formula 12).

Heated at a temperature of from 70 to 80aboutWith a mixture of 292 g of polyphosphoric acid and 860 cm3xylene was added when the temperature of 48.7 g (0,253 mol) of the compound of stage 2 in a solution of 550 cm3xylene. The mixture is heated under reflux for 6 h 30 min, then cooled, decanted kelloway phase, the remaining mineral phase add the om alkali sodium, then water, dried over sodium sulfate. Filtered, evaporated the solvent and distil the residual oil.

Ebof 0.2= 72-90aboutC. The Yield Of 87.5% .

IR, C= O: 1680 cm-1.

NMR (CDCl3): 0,8-1,8 (m, 1H), 2,5 (s, 2H), 7-7,7 (m, 3H), 8 (DD, 1H).

Stage IV

1,2,3,4-Tetrahydro-1-hydroxy-3,3-dimethyl-1-phenylnaphthalene (scheme VI - formula 14).

To 8,07 g (1,16 g.al) lithium in suspension in 200 cm3ether type so that was a weak flow of air in the reflux, the solution 86,95 g (0.55 mol) of bromine benzol 150 cm3the ether. The mixture is heated at the reflux for 45 min, then to it was added at a temperature of 5-10aboutFrom 38.6 g (to 0.19 mol) of the compound stage III in solution in 150 cm3the ether.

The mixture is stirred at room temperature for 4 h, then add 150 cm3water, maintaining a temperature of 5-10aboutC. Stirred for 15 min, then the organic phase is decanted, washed with water, dried over sodium sulfate, filtered, the solvent is evaporated.

Get a solid yellow substance, which is dispersed in hexane, dehydrated and dried.

So pl. 107-110aboutC. Exit to 47.4 g (85% ).

Stage V.

Eba 0.1= 103-105aboutS. T. pl. 82-84aboutC. The Yield Of 89% .

Elemental analysis: C18H18. Mol. weight 234,34.

Calculated, % : C 92,26; N 7,74.

Received, % : 92,42; N. Of 7.64.

NMR (CDCl3): 1,05 (C, 6N), and 2.7 (s, 2H), 5,7 (s, 1H), 6.75 in to 7.4 (m, N).

Stage VI

3-Bromo-1,2-dihydro-2,2-dimethyl-4-Fe-ninetales (scheme III - formula 6).

To a stirred suspension of 27.3 g (0,117 mol) of the compound stage 5 120 cm3DMF add, when the flow rate such that the temperature of the mixture did not exceed 30aboutWith 25 g (0.14 mol) of N-bromosuccinimide in solution in 120 cm3DMF.

Stirring was performed at room temperature for another 24 h, and then left for 48 h, then the mixture was poured onto 800 cm3ice water, carry out the extraction of 400 cm3ether (2 x 200 cm3collected extracts washed with water, dried over sodium sulfate, the ether is evaporated and carry out the chromatography was carried out residual oil on silica gel, using as eluent hexane. After evaporation of the hexane receive the oil which is used as it is, for the further synthesis.

Output 32,4 g (89% ).

NMR (CDCl3): 1,2 (c, 6H), 2.95 and (c, 2H), 6.3 to 7.5 (m, N).

Stage VII

3E-3-(1,2-Dihydro-2,2-dime is then carried out at a temperature of -50aboutC.

To a solution of 6.26 g (0.02 mol) of the compound phase 6 100 cm3ether, cooled to -50aboutWith and, respectively, stir, add 13.8 g of 1.6 n solution of utility in hexane (i.e. 0,022 mol BuLi). Then the temperature is increased to room temperature and the solution heated under reflux for 1 h 20 min, then cooled to a temperature of from -50 to -60aboutWith and add 2 g of 3-N, N-dimethylaminopropane in solution in 30 cm3the ether. Continue to stir the mixture at -50aboutC for 1 h 30 min, then the temperature rises to room, continue stirring for 30 minutes, then all poured on 300 cm310% hydrochloric acid under stirring. The organic phase is decanted and then washed with water, the aqueous phase is extracted with chloromethylene, the extract washed with water; collect all of the organic phase, dried over sodium sulfate, evaporated the solvent and the residual oil crystallized in pentane.

So pl. 105-108aboutC. the Yield 2.6 g (45% ).

IR, C = 0: 1680 cm-1.

NMR (CDCl3): 1,2 (C, 6N), and 2.8 (s, 2H), equal to 6.05 (DD: J = 16.5 and a 7.5, 1H), of 6.4-7.5 (m, 10H), and 9.5 (d: J = 7,5, 1H).

Stage VIII. (+, -)-6E-7-(1,2-Dihydro-2,2-dimethyl-4-phenyl-3-naphthyl)-5-hydroxy - 3-oxo-6-hepten-oat bromide (scheme I - forms is of asle. Yield 87% .

NMR (CDCl3): 1,1 (C, 6N), 1,9-2,6 (m, 3H), of 2.72 (s, 2H), 3,3 (s, 2H), the 3.65 (s, 3H), 3.45 points to 4.5 (m, 2H), 4,8-to 5.35 (m, 1H), 6 (d, J = of 15.75, 1H), 6,35-7.5 (m, 5H).

Stage IX.

(+, -)-6E-Erythro-7-(1,2-dihydro-2,2-dime - Tyl-4-phenyl-3-naphthyl)-3,5 - dihydroxy-6-hepten-oat bromide (compound 2).

Produced from compound stage VIII by the method of phase V of example 1. Solid yellow color.

So pl. 101-103aboutC. the Yield 2.2 g (67% ).

Elemental analysis: C26H30O4. Mol. weight 406,52.

Calculated, % : C 76,82; N 7,44.

Received, % : 76,57; N 7,43.

P R I m e R 3. (+, -)-6E-Erythro-7-[4-(4-chlorophenyl)-2,2-dimethyl-2H-benzothia-3-PIR - nil)] -3,5 - dihydroxy-6-hepten-oat bromide (compound 3, formula 1: X = S, R2= CH3, R3= 4'Cl, R4= R5= R6= R9= R10= H, R7and R8= = bond, R11= OCH3).

Stage I

4-(4-Chlorophenyl)-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-benzopyran (scheme VI - formula 14) is obtained from 2,3-dihydro-2,2-dimethyl-4H-4-benzothiadiazine according to the method of stage 4 of example 2, is used without purification in the subsequent syntheses.

Stage II

4-(4-Chlorophenyl)-2,2-dimethyl-2H-benzo - Piran (scheme VI, formula 5) is produced from compound stage I according to the methods one hundred 17
H15The ClS. Mol. weight 286,81.

Calculated, % : C 71,19; N 5,27; Cl 12,36; S 11,18.

Received, % : Is 70.94; H 5,42; Cl 12,60; S 10,90.

NMR (CDCl3): 2 (C, 6N), of 5.75 (s, 1H), 's 6.75-7.5 (m, 8H).

Stage III

3-Bromo-4-(4-chlorophenyl)-2,2-dimethyl-2H-benzopyran (scheme III - formula 6) is produced from compound stage II by the method of phase VI of example 2; after evaporation of the ether get a solid substance, which is dispersed in sufficient quantity cooled to -20aboutWith methanol, and the resulting solid is dewatered and dried.

So pl. 150-156aboutC. The Yield Of 88% .

NMR (CDCl3): 1,6 (C, 6N), 6,2-7,8 (m, 8H).

Stage IV.

2E-3-(4-chlorophenyl)-2,2-dimethyl-2H-3-benzopyranyl)-2-propen-oat ethyl (scheme IV - formula 8).

The operation is carried out in nitrogen atmosphere, protected from moisture reactor. Within 4 h heated under reflux a mixture of 20.1 g (by 0.055 mol) of the compound stage III, 27.5 cm3(0,254 mol) acrylate, 130 cm3N, N-dimethylformamide, 130 cm3of triethylamine, 1 g trichotillomania and 0.25 g of palladium diacetate, the mixture was poured into a mixture of ice - water and extracted with a sufficient quantity of ether, the extract alternately washed with hydrochloric acid and water to obtain the hexane, dehydrating the obtained solid and dry.

So pl. 97-99aboutC. The Yield 91% .

Elemental analysis: C22H21ClO2S. Mol. weight 384,91.

Calculated, % : C 68,65; N. Of 5.50; Cl Of 9.21; S 8,33.

Received, % : 68,58; N 5,79; Cl 9,45; S 8,30.

NMR (CDCl3): 1-1,75 (m, N), 3.75 TO 4.5 M (9, 2H), 5,3-of 5.75 (d, 1H), 6,5-7,5 (m, N).

Stage V

2E-3-[4-(4-Chlorophenyl)-2,2-dimethyl-2H, 3-benzothiophenes)] -2-propanol (scheme IV - formula 9).

The operation is carried out in nitrogen atmosphere in a place protected from moisture reactor. To a solution of 18.9 g (0,049 mol) of the compound of stage 4 180 cm3cooled to -20aboutFrom tetrahydrofuran add 196 cm31 N. of a solution of hydride diisobutylaluminum in tetrahydrofuran (i.e. 0,049 x 4 mol DIBAL), the mixture is stirred at room temperature for 1 h, then added to the mixture of 200 cm3water, adding exothermic, therefore, the flow rate is adjusted so that the temperature of the mixture was less than the 30aboutC, then the mixture is acidified to pH 1 by adding a sufficient amount of concentrated hydrochloric acid, then conduct extraction with ether. The ether phase is washed with water until neutral, then dried over sodium sulfate, and after filtration is UP>aboutWith hexane, and the obtained solid is dewatered and dried.

So pl. 105-108aboutC (hexane). Yield 87% .

Elemental analysis: C20H19ClOS. Mol. weight 342,87.

Calculated, % : C 70,06; N 5,59; Cl 10,34; S 9,35.

Received, % : 69,91; N 5,78; Cl 10,52; S 9: 30 A.m.

Stage VI 2E-3-[4-(4-chlorophenyl)-2,2-dimethyl-2H-3-benzothiophenes)] -2-propenal (scheme IV - formula 2).

The operation is carried out in protected from moisture reactor. At room temperature, stirred for 48 h the mixture 14,63 g (0,0427 mol) of the compound stage 5, 22,26 g (0,0427 x 6 mol) of manganese dioxide and 300 cm3dichloromethane, the mixture is then filtered, evaporated dichloromethane filtrate, and the obtained solid residue was dispersed in a sufficient number of Diisopropylamine, dehydrated and dried.

So pl. = 132-134aboutC (CH3CO2C2H5). Yield 82% .

Elemental analysis: C20H17ClOS. Mol. weight 340,86.

Calculated, % : C 70,47; N 5,03; Cl From The 10.40; S 9,41.

Received, % : 70,27; N 4,98; Cl 10,51; S 9,85.

NMR (CDCl3): 1,5 (C, 6N), OF 5.75 AND 6.25 (9, 1H), 's 6.75-7.5 (m, N), 9,25 to 9.5 (d, 1H).

Stage VII (+, -)-6E-7-(4-(4-chlorophenyl)-2,2-dimethyl-2H-3-benzothiophenes)-5-hydroxy - 3-oxo-6-heptenoic bromide (scheme I - shape is OH). Yield 94% .

IR: C = O: 1740 and 1700 cm-1.

NMR (CDCl3): 1,5 (C, 6N), 2,25-2,75 (m, 3H), 3,3 (s, 2H), of 3.75 (s, 3H), 4,25 to 4.5 (m, 1H), 5-5,55 (DD, 1H), of 5.75 and 6.25 (d, 1H), 6.5 to 7.5 (m, 8H).

Stage VIII (+, -)-6E-Erythro-7-(4-chlorophenyl)-2,2-dimethyl-2H-3-benzothiophenes))-3,5-dihyd-Roxy-6-heptenoic bromide (scheme I - formula 1) is produced from compound stage VII by the method of phase V of example 1.

So pl. = 115-117about(Diisopropylamino). Yield 58% .

Elemental analysis: C25H27ClO4S. Mol. weight 458,99.

Calculated, % : C 65.42 Per; N 5,93; Cl 7,72; S 6,98.

Received% 65,52; N 6,02; Cl 7,80; S 7,09.

IR: CO = 1720 cm-1, OH = 3400 cm-1.

NMR (CDCl3): 1,5 (C, 6N), and 2.5 (d, 2H), 3-3,75 (m, 2H), of 3.75 (s, 3H), 4-4,5 (m, 2H), 5-5,5 (DD, 1H), of 5.75 and 6.25 (d, 1H), 6.5 to 7.5 (m, 8H).

P R I m e R 4. (+, -)-Erythro-7-(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-cyclo - pentyl))-3,5-dihydroxy-heptanoate ethyl (compound 4 - formula 1: X = O, R1-R2= (CH2)4-, R3= 4'F, R4= R5= R6= R7= R8= R9= R10= H, R11= OC2H5).

Stage I 3E-3(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1, of-2.1'-cyclopentyl))-2-propenal ü, dimethylacetal (scheme V the formula 10).

The operation is carried out in nitrogen atmosphere, 4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-cyclopentyl))-2-propenal ü, which was derived from Spiro (2H-benzopyran-1-2,1'-4-cyclopenten) by the method of stages I, II, III of example 1, 2.25 resin Amberlyst 15, 625 cm3meteorophobia.

Again add 2.25 g of resin Amberlyst and the mixture is stirred at room temperature for 12 h Such processing is repeated 4 times consecutively, one after the other, is evaporated excess meteorophobia, emit a white solid, which was dispersed in hexane, dehydrated and dried.

So pl. 112-114aboutC. the Yield 16.3 g (88% ).

NMR (CDCl3): 2,1-2,2 (m, 8H), of 3.07 (s, 6N), equal to 6.05 (d, 1H, J = 5 Hz), 5,3 (DD, 1H, J = 5 and 16 Hz), equal to 6.05 (d, 1H, J = 16 Hz), 6,3-7,2 (m, 8H).

Stage II

3-[4-(4-Forfinal)-Spiro-3-(2H-benzo - Piran-1-2,1'-cyclopentyl)] -propanal, dimethylacetal (scheme V the formula 11).

Produce hydrogenation under normal pressure and at room temperature 3.8 g (0.01 mol) of the compound stage I in solution in 100 cm3THF, in the presence of 0.5 g of dispersed palladium on coal. When it reaches theoretical amount of absorbed hydrogen, the mixture is filtered and the THF is evaporated, get the oil, which crystallizes over time, the thus obtained solid substance was dispersed in hexane, then dehydrate and what - hexane-1-9: 1 spot).

NMR (CDCl3): 1,9-2,5 (m, N), 3,2 (s, 6N), is 4.15 (t, 1H, J = 5 Hz), 6,3-7,25 (m, 8H).

Stage III

3-[4-(4-Forfinal)-Spiro-3-(2H-benzo - Piran-1-2,1'-cyclopentyl))-propanal (scheme V - formula 2).

At room temperature for 96 h, stirred mixture of 2 g (0,0052 mol) of the compound of stage 2 and 2 g of resin Amberlyst 15 the resin is filtered off, the filtrate is evaporated to dryness, absorb the balance of 40 cm3of methylene chloride, washed with water and dried over sodium sulfate, filtered and evaporated to dryness, in this way we obtain 0.9 g of oil.

So pl. = 118-120about(Diisopropylamino).

IR: C = O: 1720 cm-1.

NMR (CDCl3): 1-2,5 (m, 10H), 6,2-7,2 (m, 8H), of 9.55 (s, 1H).

Elemental analysis: C22H21FO2. Mol. weight 336,39.

Calculated, % : C 78,55; N 6,29; F 5,65.

Received% 78,33; N 6,04; F 5,57.

Stage IV

(+, -)-4-(4-Forfinal)-7-Spiro-3-(2H - benzopyran-1-2,1'-cyclopentyl)-5 - hydroxy-3-oxogedunin ethyl (scheme I, formula 4, R7= R8= H).

Produced from compound stage 3 and according to the method of stage 4 of example 1.

The compound obtained as oil (yield 51% ), it is used as it is, for the further synthesis.

Stage V (+, -)-Erythro-7-(4-(4-formanilide connection stage 4 according to the method stage 5 of example 1.

Connection white.

So pl. = 103-105about(Diisopropylamino). Yield 65% .

Elemental analysis: C28H33FO5. Mol. weight 468,54.

Calculated, % : C 71,77; N 7,10; F 4,05.

Received, % : 71,63; N 7,11; F 3,98.

NMR (CDCl3): from 0.9 to 2.25 (m, 17H), 2,35 (d, 2H, J = 6 Hz), 3-3,5 (m, 2H), of 3.5-3.9 (m, 1H), 3,9-4,4 (m, 3H), 6,2-7,2 (m, 8H).

P R I m e R 5. (+, -)-6E-Erythro-7-[4-(4-forfinal)-Spiro-3-(2H-benzopyran-1,2,1'-CEC - lipantil)] -3,5-dihydroxy-6-heptenoic sodium (compound 5, the formula 1: X = O, R1-R2= (CH2)4-, R3= 4'F, R4= R5= R6= R9= R10= H, R7and R8= communication, R11= -O-Na+).

At 60aboutWith the heat so you have a clear solution, 2.14 g (0,0046 mol) of the compound 4 in 30 cm3ethanol, then this solution is cooled to room temperature and add to it an aqueous solution of alkali sodium, prepared by dissolving 0.18 g (0,0046 mol) of alkali sodium pellets in 100 cm3water. The mixture is stirred for 30 min, filtered and evaporated to dryness, the residue is dried by heating at 60aboutWith under reduced pressure (0.5 mm RT. Art. ) within 1 h

So pl. is not defined. Output 2,04 g (96% ).

the C = 460,47

Calculated, % : C 67,82; N 5,69; F 4,13; Na 4,99.

Received, % : 67,44, N 5,71; F 3,91; Na 5,11.

P R I m e R 6. (+, -) 6E-Erythro-7-(4-(4-forfinal)Spiro-3-(2H-benzopyran-1-2,1'-cyclopentyl))-3/5 - dihydroxy-6-heptenoic-benzene (compound 6 - formula 1: X = O, R1-R2= -(CH2)-, R3= 4'F, R4= R5= R6= R9= R10= H, R7and R8= communication, R11= C6H5CH2O-).

To a solution of 1.55 g (0,00337 mol) of the compound 5 in 40 cm3methyl ethyl ketone add 0,638 g (0,00337 mol + 10% ) bromide benzene, the mixture is then heated under reflux for 3 hours Again add 0,638 g of bromide benzene and heat the mixture under reflux for 8 hours

The mixture is filtered, the filtrate is evaporated, dissolved the residue in sufficient quantity of ethyl acetate, the solution washed with water, dried over sodium sulfate, filtered and evaporated to dryness.

Spend chromatography of the residual oil on 15 g of silica gel using a mixture of ethyl acetate: hexane: 30-70% .

Collected II fraction after evaporation of the solvent gives a solid substance, which is dispersed in Diisopropylamine. Solid dewatered and dried.

So pl. = 81-83aboutC. Output% 74,98; N 6,29; F 3,59.

Received, % : 74,91; N 6,23; F 3,55.

NMR (CDCl3): 1,1-2,3 (m, 10H), of 2.45 (d, 2H, J = 6,7 Hz), 2,7-3,2 (m, 1H, D2O), 3,3-3,6 (m, 1H D2O), 3.8 to 4.5 (m, 2H), 5,0-5,6 (+d, 3H) and 5.9 (d, 1H, J = 15.7 Hz), and 6.3 to 7.7 (m, 13H).

P R I m e R 7. (+, -)-6E-Erythro-7-(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-CEC - lipantil))-3,5-dihydroxy-N-methyl-6-hepten-amide (compound 7 - formula 1: X = O; R1-R2= -(CH2)4-; R3= 4'F; R4= R5= R6= R9= R10= H; R7and R8= link; R11= CH3NH-).

At room temperature, for 24 hours stirred solution of 0.67 g (0,00165 mol) of the compound 1 in 25 cm333% solution of methylamine in ethanol. The solvent is evaporated and the residue was dispersed in 8 cm3ethyl acetate, dehydrated and dried.

So pl. 150-152aboutC. the Yield 0.52 g (70% ).

Elemental analysis: C27H30FNO4. Mol. weight 451,54.

Calculated, % : C 71,66; H 6,90; N 3,10; F 4,20.

Received, % : 71,47; N 6,76; N 2,93; F 4,08.

P R I m e R 8. (+, -)-TRANS-6-(1E-2-(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-cyclopent yl)-ethynyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-2-pirano (compound 8 - formula 1: X = O; R1-R2= -(CH2)4-, R3= 4'F; R4= R5= R6is the guy the atmosphere.

Within 3 hours, heated under reflux a mixture of 6 g (0,0135 mol) of the compound 4 and of 1.94 g (0,0135 mol) of 2-chloroethyl-diethylamino 120 cm3of acetone. Evaporate the acetone and the residue is dissolved in sufficient quantity of ethyl acetate. The solution is washed with water to pH 7, and then dried over sodium sulfate. Filter and evaporate the ethyl acetate.

Get a solid substance directly recrystallized from 120 cm3ethyl acetate.

So pl. = 188-191aboutC. Output 4,27 g (79% ).

Elemental analysis: C26H25FO4. Mol. weight 420,49.

Calculated, % : C 74,27; H 5,99; F To 4.52.

Received% 74,07; N 6,04; F 4,49.

NMR (DMSO d6) - 200 MHz: 1,45-of 2.20 (m, 10H), was 2.34 (DD, 1H, J = 16 Hz and 3.45 Hz), 3,93-4,10 (m, 1H), 4,85-5,0 (m, 1H), 5,11 (d, 1H, J = 3.3 Hz), 4,42 (DD, 1H, J = 16.3 and of 6.7 Hz), of 6.02 (d, 1H, J= 16,3 Hz). 6.42 per-6,54 (m, 1H), 6,72-6,83 (m, 2H), 7,07-7,34 (m, 5H).

P R I m e R 9. (+, -)-TRANS-4-hydroxy-3,4,5,6-tetrahydro-6-{ 2-[4-(4-forfinal)-SPI - ro-3-(2H-benzopyran-1-2,1'-cyclopentyl)] -ethyl} -2-pirano (compound 9 of formula 1: X = O; R1-R2= -(CH2)4-; R3= 4'F; R4= R5= R6= R7= R8= R10= H; R9and R11= link).

At normal pressure and at room temperature hydronaut 1,72 g (0,00409 mo is practical amount of absorbed hydrogen, the mixture is filtered, the filtrate is evaporated and the resulting residue is dispersed in Diisopropylamine. The obtained solid is dewatered and dried.

So pl. = 156-157about(Diisopropylamino). Yield 0.7 g (41% ).

Elemental analysis: C26H27FO4. Mol. weight 422,50.

Calculated, % : C 73,91; N 6,44; F 4,50.

Received, % : 75,83; H 6,32; F 4,40.

NMR (DMSOd6)-200 MHz: 1,38-of 2.21 (m, 14N), 2,39 (DD, 1H, J = 17.2 in Hz and 2.8 Hz), to 2.57 (DD, 1H, J = 17.2 in and 4.6 Hz), 3.96 points-of 4.11 (m, 1H), 4,25-to 4.46 (m, 1H), 5,04 (d, 1H, J = 3.2 Hz), of 6.31-6,41 (m, 1H), 6,69-6,85 (m, 2H), 7,02-7,34 (m, 5H).

P R I m e R 10. (+, -)-Erythro-7-(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-CEC - lipantil))-3,5-dihydroxyheptanoic sodium (compound 10 - formula 1: X = O, R1-R2= -(CH2)4-, R3= 4'F, R4= R5= R6= R7= R8= R9= R10= H, R11= -ONa+).

At room temperature, stirred mixture 0,22 g (0,00052 mol) of compound (9) and 0.52 cm3(0,00052 mol - 5% ) 1 N aqueous alkali of sodium in 25 cm3of ethanol. The ethanol is evaporated, the residue was dispersed in ether, dehydrated and dried obtained tveraa substance.

(TLC: silica gel, AcOEt-hexane: 1-1 + 3% AcOH: 1 spot).

So pl. is not defined, the yield 0.12 g (50% ).

Received% 67,30; H Of 5.92; F 3,90; Na 5,00.

P R I m e R 11. (+, -)-Erythro-7-(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-CEC - lipantil))-3,5-dihydroxyheptanoic ethyl (compound 4).

Hydronaut at normal pressure of 1.4 g (of 0.003 mol) of the compound 1 dissolved in 100 cm3THF in the presence of 0.6 g of dispersed palladium on coal. When it reaches theoretical amount of absorbed hydrogen, the mixture is filtered, evaporated to dryness and dispersed the residue in hexane, and then dehydrated and dried.

So pl. = 103-105about(Diisopropylamino). Output 1 g (71% ).

P R I m e R 12. (+, -)-TRANS-6-(1E-2-(4-(4-forfinal)-Spiro-3-(2H-benzopyran-1-2,1'-cyclopent yl)-ethynyl)-2/2-dimethyl-1-3-dioxane-4-yl) ethyl acetate (compound 11 - formula 1: X = O, R1-R2= -(CH2)4-, R3= 4'F, R4= R5= R6= H, R7and R8= communication, R9-R10= (CH3)2C-, R11= OC2H5).

At room temperature, for 48 h stirred mixture of 2 g (0,0043 mol) of the compound 1, 0.7 g of 2-methoxypropene and 8 mg managerfinance n-toluensulfonate acid in 25 cm3DMF. Add 125 cm3simple ether, washed with aqueous saturated sodium bicarbonate solution, then water. Organizujut in hexane. Dewatered, dried and spend chromatography on 20 g of silica gel using a mixture of hexane-ethyl acetate: 1-1 as solvent and eluent. The collected fractions I and II is evaporated, the residue is crystallized in hexane, dehydrated and dried.

So pl. = 103-105aboutC. the Yield of 0.95 g (44% ).

Elemental analysis: C31H35FO5. Mol. weight = 506,61.

Calculated, % : C 73,50; N. Of 6.96; F 3,75.

Received% 73,64; H 6,98; F To 3.73.

NMR (CDCl3): 0,9-2,5 (m, N), 3.9 to 4.5 (m, 2H), of 4.05 (q, 2H), 5,95 (d, 1H), 6,2-7,25 (m, 8H).

The following examples of compounds in accordance with the invention, the following abbreviations are used: Me is methyl, Et is ethyl, Pr is propyl, Bz is benzyl, Pe - pentyl, tBu is tert-butyl, iPr is isopropyl, Phe - phenyl, Pyr - pyrolidine.

P R I m e p 13. Using the techniques described in examples 1-12, receive connections (PL. below), in the formula 1 where X = O; R1and R2form chain -(CH2)n-, R7and R8form together a simple link, R9and R10each denotes hydrogen (PL. 1).

P R I m e R 14. Using described in examples 1-12 techniques, receive connections (table below) of formula 1 in which X = O, R4= R5= R9= R10= H, R7and R84= R6= R10= H, R7and R8accordingly, R9and R11form together a simple link (see tab. 3).

P R I m e R 16. Using the described in examples 1-12 techniques, receive connections (table below) of formula 1 where X = CH2or S, R4= R6= R9= R10= H, R7and R8form a simple link (see tab. 4).

P R I m e R 16 (continued). Using techniques for intermediate stages in the examples 1 to 4, receive intermediate compounds, which are listed below (see tab. 5).

P R I m e R 17. Intermediate compounds of General formula 4, in which X = O, R1and R2form a chain: -(CH2)n-, R7and R8form together a bond, R9denotes a hydrogen atom (see tab. 6).

P R I m e R 18. Intermediate compounds of General formula 4, in which X = O, R4= R5= R6= R9= H, R7and R8form a relationship (see tab. 7).

P R I m e R 19. Intermediate compounds of General formula 4, in which X = CH2or S, R4= R6= R9= H, R7and R8form a bond, R11- methoxy (see tab. 8).

P R I m e R 20. Intermediate compounds of General formula 2 in which X = >/P>P R I m e R 21. Intermediate compounds of General formula 2 in which X = CH2or O, S, R4= R6= H and R7and R8form together a bond (see tab. 10).

P R I m e R 22. Intermediate compounds of General formula 6 in which X = CH2or S, R4= R6= H (see table. 11).

P R I m e R 23. Intermediate compounds of General formula 5, in which X = O, R1and R2form tetramethylene chain -(CH2)4- (see tab. 12).

P R I m e R 24. Intermediate compounds of General formula 5, in which R4= R6= H (see tab. 13).

P R I m e R 25. Intermediate compounds of General formula 9, in which X = S and R4= R6= H (see tab. 14).

P R I m e R 26. Intermediate compounds of General formula 8, in which X = S, R4= = R6= H, R = C2H5(see tab. 15).

Elemental analysis are presented in table. 16.

Lovastin meets the following formula:

< / BR>
It can be stated that, if lovastatin is a connection that, according to the applicant, structurally closest to the compounds in accordance with the invention, however, ultimately, its structure is far from the structure of the compounds according to the invention.

Balemi (test B), than the connection in accordance with the invention NN 1,2,19, and 65.

In addition, the compounds NN 5, 9, 41 and 42 were also tested in accordance with tests A and B. the Results of these tests are presented in table. 17, below.

Value DE50in each case, less (in tests A and B) for compounds in accordance with the invention in relation to DE50for lovastatin.

On the other hand, all connections in accordance with the invention are antiagregatini platelets, which, according to the U.S. patent 4231938 not inherent to lovastatin, which is a positive effect of all compounds in accordance with the present invention.

All connections in accordance with the invention is extremely low toxicity. This applies in particular to the case of compounds of the type of esters, lactones and amides. Acid salts usually have DL50a little weaker, but their therapeutic action remains excellent.

As an example, below are some of the values DL50obtained for rats at oral introduction (see tab. ).

A new example.

Using appropriate methods of examples 1-12, got a connection (as shown in the table below), in which the form of the communication, and X, R3, R5and R11have the following meanings, are presented in table. 18.

Getting acid salt of (+, -)-6E-Erythro-7-[4-(4-forfinal)-3-Spiro-(2H-benzo (a) pyrene-1,2,1'-cyclopentyl )] -3,5-dihydroxy-6-heptenophos acid (formula I: X = O, R1-R2= -(CH2)4-, R3= 4'-F, R4= H, R5= R6= R9= R10= H; R7and R8= communication, R11= OH).

To a suspension of 2.30 g (0,005 mol) (+, -)-6E-7-[4-(4-forfinal)-3-Spiro(2H-benzopyran-1, 2,1'-cyclopentyl)] -3,5-dihydroxy-6-heptanoate in 20 ml of tetrahydrofuran was added dropwise at room temperature and 5 ml (0,00535 mol) of an aqueous solution of 1.07 N. chlorotalonil acid.

The resulting solution was stirred for 10 min at room temperature, then extracted with 200 ml of ethyl acetate, wash the organic extract with water until neutralization. Dried over sodium sulfate and then the solvent is distilled off. Allocate the target product in the form of oil. Yield 1.8 g (82% ).

Physico-chemical characteristics:

Chromatography in thin layer:

gel silica, AcOEt-hexane 1: 1, one spot,

Rf= 0,05.

IR, = 1712 cm-1WITH = 3411 cm-1.

Elementary analysis: C26H27FO5.


According to test A, the resulting product has a dose DL50(dose required to reduce cholesterolemia 50%) component of 0.23 mg/kg (56) U.S. Patent N 4231938, class C 07 D 309/30, 1980.

The method of obtaining derivatives benzocycloheptene acids of General formula I

1

< / BR>
where X is CH2, oxygen, or sulfur;

R1and R2identical or different, is hydrogen or an alkyl radical containing 1 to 3 carbon atoms, R1and R2can also together form alkylenes chain - (CH2)n- in which the number of links n may be equal to 4 or 5;

R3and R4identical or different, is hydrogen or halogen, such as chlorine, fluorine and bromine radicals: CF3N, N-dialkylamino-containing 1 to 3 carbon atoms, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 5 carbon atoms, phenyl, and when one of the substituents R3or R4represent the radical CF3N, N-dialkylamino and phenyl, it is in positions 3', 4' or 5', and the other Deputy is hydrogen;

R5or R6identical or different, is hydrogen or halogen, such as chlorine, fluorine or bromine radicals: alkyl, C1- C3, alkoxy - C1<, is that when one of the substituents R5or R6represents a radical, phenyl or substituted phenyl, it is in position 6 or 7, and the other Deputy is hydrogen, the substituents R3and R4and, accordingly, R5and R6can also together form, provided that they are in adjacent positions, diradicals with the formula-CH= CH-CH= CH-;

R7and R8each hydrogen or form together with the existing bond C-C double bond geometry of TRANS-form (E);

R9and R10each hydrogen or together form dialkylaminoalkyl the residue containing 1 to 3 carbon atoms;

R11together with a group of CO., with which it is linked, forms a feature of the free acid, of ester, amide, acid or salt forms with radical R9cycle-lactone,

wherein ketoester General formula II

2

< / BR>
where X, R1- R8and R11have the specified values,

subject to recovery in a solution of inert solvent in the processing for 40 min - 1 h complexes agent of the type derived boron, such as trialkylborane or discocellulars, at low temperature, then when processing the alkali borohydride is SUB>11
together with a group of CO., with which it is linked, forms a complex function of the ether, alcoholysis compounds of General formula I, where R9and R11form a relationship that is dissolved in the excess alcohol at a temperature between room temperature and the temperature phlegmy specified alcohol, and optionally in the presence of catalytic amounts of base type alcoholate of an alkali metal such as sodium methylate, or tertiary amine, alkylation of compounds of General formula I, where R11together with a group of CO., with which it is linked, forms a function of the salt of the acid, in a solution of solvent a ketone such as methyl ethyl ketone, in the presence of iodide or bromide, such as benzylbromide at a temperature of phlegmy specified solvent is a ketone, or with the aim of obtaining compounds of General formula I in the form of salts hydrolysis of compounds of General formula I in the form of ester or, in which R9and R11form a relationship, in a solution of inert solvent, preferably alcohol, under the action of a basic agent, such as sodium hydroxide or potassium hydroxide, at temperatures between room temperature and the temperature phlegmy specified solvent; or with the purpose of obtaining compounds of General formula I, where R9and R11form a function of the free acid, when processing in an inert solvent type carbonyl solvents, such as acetone or butanone, or aromatic hydrocarbon type solvents such as benzene, toluene or xylene, with the help of agent lactonization type tertiary bleach, such as chloroethylamine, or agent of dehydration type paratoluenesulfonyl; or with the purpose of obtaining compounds of General formula I, where R7and R8is hydrogen, and R9and R11form a bond, hydrogenation of compounds of General formula I, where R7and R8respectively, with R9and R11form a relationship, in a solution of inert solvent type tetrahydrofuran or in a solution of alcohol with a low boiling point such as methanol or ethanol, in the presence of a metal catalyst, such as palladium, at room temperature; or with the purpose of obtaining compounds of General formula I in the form of an amide, aminals compounds of General formula I in the form of ester or in which R9and R11form a relationship, in a solution of inert solvent, mainly gidrauxilirovannogo, type of alcohol in the presence of excess amine and at room temperature; or with the purpose of obtaining compounds of General formula I, in which R9and R10form along the th hydrogen, alkene, containing 3 to 7 carbon atoms, substituted at the double bond by alkoxylation, mainly methoxy-, solvent type of dimethylformamide in the presence of an acid catalyst type paratoluenesulfonyl at room temperature.

 

Same patents:

The invention relates to pharmaceutical industry and relates to a method of obtaining a crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

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

4 cl, 2 tbl, 568 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compositions eliciting an antilipidemic effect and comprising inhibitor of bile acid transport in jejunum of the general formula (I): and inhibitor of HMG-CoA-reductase. Also, invention relates to a method for carrying out the combined therapy.

EFFECT: improved treatment method, valuable medicinal properties of compositions.

15 cl, 9 tbl, 1401 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 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: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new lipoic acid derivatives of general formula Ia

1, wherein n = 0-4, integer; -X-Y represents -O(CH2)r-, -CO-N(R3)-(CH2)r-, -N(R4)-CO-(CH2)r; -X'-Y' represents -(CH2)r-, -(CH2)r-N(R3)-(CH2)r-, -(CH2)r-CO-N(R3)-(CH2)2-; R3 and R4 are the same or different and represent hydrogen or alkoxycarbonyl; r = 0-4, integer; Ω represents piperazinyl, piperidyl or phenyl. Also disclosed are method for production the claimed derivatives and pharmaceutical composition, containing the same. Compounds are useful as NO-syntase inhibitors and/or reagents mediating redox state of thiol groups.

EFFECT: new lipoic acid derivatives.

7 cl, 17 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in stomatology in the topical anesthesia. The pharmaceutical composition comprising articaine hydrochloride and epinephrine hydrochloride and accessory substances, such as sodium metabisulfite, sodium chloride and water for injection involves additionally glycine and pH-regulating substance taken in the definite ratio of components. Invention provides preparing the preparation that is stable, non-toxic and doesn't cause allergic response reactions and elicits highly expressed infiltration and conducting anesthetic activity, good tissue tolerance and activity promoting to accelerated wound-healing in the post-operative period.

EFFECT: improved and valuable medicinal properties of composition.

3 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using compounds of (R,S)-2-arylpropionic acids of the formula (Ia) , and their (R)- and (S)-isomers as inhibitors of neutrophile (PMN leukocytes) chemotaxis induced by IL-8. These compounds elicit unexpected ability to inhibit effectively IL-8-induced chemotaxis and degranulation of neutrophiles being without significant effect on activity of cyclooxygenases. These compounds can be used in treatment of such diseases as psoriasis, ulcerated colitis, melanoma, chronic obstructive pulmonary disease, bulla pemphigus, rheumatic arthritis, idiopathic fibrosis, glomerulonephritis, and for prophylaxis and treatment of damages induced by ischemia and reperfusion.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

9 cl, 3 tbl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention concerns to applying RARγ agonist for preparing a medicinal agent comprising one or some such agonists and designated for treatment of emphysema wherein RARγ agonist is taken among compounds of the formula (I):

wherein R1 means residue of the formula:

or , or , or ; R2 means (C2-C8)-alkanoyl, (C2-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or group -OCH2R3 wherein R3 means hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl; each among R4-R9 means independently of one another hydrogen atom or (C1-C6)-alkyl; or R8 and R9 mean in common (CRaRb)n wherein Ra and Rb mean independently of one another hydrogen atom or (C1-C6)-alkyl; n = 1, 2 or 3; R4-R7 have above given values; R10 means carboxyl, (C1-C6)-alkoxycarbonyl or mono- or di-(C1-C6)-alkylcarbamoyl; and their pharmaceutically acceptable salts; or among compounds of the formula (VI):

wherein R1 means C(O)R6 or CH2OH (wherein R6 means hydroxy-group or (C1-C6)-alkoxy-group); R2 means hydrogen atom, (C1-C15)-alkyl, (C1-C6)-alkoxy-group or cycloaliphatic group; R3 means hydrogen atom, hydroxy-group, (C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, (C1-C10)-alkoxy-group or cycloaliphatic group; R4 and R5 mean independently of one another hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; or among compound of the formula (VIII):

. Invention provides applying agonists eliciting the selective effect with respect to RARγ, for preparing a medicinal agent comprising one or some such agonists designated for emphysema treatment.

EFFECT: valuable medicinal properties of compounds.

4 cl, 5 tbl, 3 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

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

28 cl, 10 tbl, 16 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivative of aminobenzopyrane of the formula (2): Method involves reduction of nitro-group in derivative of 2,2-dimethyl-2H-1-benzopyrane of the formula (1): with hydrazine in the presence of a metallic catalyst. Invention provides high selectivity of the process with respect to olefin bonds and simple treatment that results to small waste and doesn't effect on reactor.

EFFECT: improved method of synthesis.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2H-1-benzopyran-2-methanol-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], i.e. a nebivolol base of formula (IX), or its hydrochloride salt

as well as to a method of producing an intermediate compound - benzylated nebivolol of formula (VIII),

EFFECT: invention also relates to a pharmaceutical composition with antihypertensive action without using a wetting agent, and to a tablet containing this pharmaceutical composition.

21 cl, 20 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel aminoalkyl-and amodialkylbenzopyran derivatives of the general formula (I): (a), where (a) group is a substitute in 6 or 7 position, where R is mono- or bicyclic (C6-C10)-aryl radical optionally substituted with one or two substitutes selected out of linear or ramified (C1-C5)-alkyls, linear or ramified (C1-C5)-alkoxy, hydroxy, halogen and trifluoromethyl; m is zero or integer 1-3; n, p, R1 and R2 are as indicated in the description, and both R3 and R4 are hydrogen or both are oxygen: and to pharmaceutically acceptable salts thereof.

EFFECT: selective reversible MAO-B inhibitors in vitro and in vivo, applicable as medicines for prevention and treatment of degenerative central nervous system disorders.

13 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel chromane derivatives of formula I: or their pharmaceutically acceptable salts, where: m equals 0 or 1; p equals 2; q equals 2; Ar is phenyl which is possibly substituted with a halogen atom; each R1 is independently a halogen; R2 is ; n equals 1 or 2; each of R3 and R4 is independently hydrogen or C1-12-alkyl; each of R5 and R6 is independently hydrogen or C1-12-alkyl; and each of R7 and R8 is independently hydrogen or C1-12-alkyl; or one of R7 and R8 is hydrogen and the other is a 5- or 6-member heterocyclyl containing one nitrogen atom, or R7 and R8 together with the nitrogen atom with which they are bonded can form an amidinyl group, a urea group, a guanidinyl group or a pyrrolidine ring which is possibly substituted with an amine group.

EFFECT: obtaining novel chromane derivatives and pharmaceutical compositions having 5-HT6 and/or 5-HT2a receptor modulator activity.

22 cl, 11 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the given invention, there is offered a method for preparing a compound of formula , where Y is specified of CH3, CH2OH, CH2CH2OH, CH2Br and Br; involving the stages: (1) reaction of the compound of formula where OX represents hydroxy or O-M+ where M+ represents cation chosen of Li+, Na+ and K+ and Y is such as specified above; with trans-cynnamaldehyde , with a secondary amine compound added; then (2) acid treatment of a product from the previous stage to prepare a compound of formula (I). The aforesaid method can be used for preparing tolterodine and fezoterodine which are effective in treating the hyperactive urinary bladder. There are also declared compounds of formulae V, VI and VII.

EFFECT: development of the effective method for preparing the compound.

25 cl, 19 ex

FIELD: medicine.

SUBSTANCE: invention relates to condensed bicyclic compounds, having affinity with mineralocorticoid receptor (VR) of formula [I] and formula [ii], as well as to pharmaceutical compositions on their basis. In general formula [I[ and [ii] ring A represents benzene ring, which has substituent R1, condensed with adjacent 6-membered heterocyclic ring, and said benzene ring additionally optionally is substituted with one or two substituent(s), selected from halogen atom and C1-8-alkyl group, R1 represents C1-8-alkylsulfonyl amino group or C1-8-alkyl aminosulfonyl group, R2 and R3 (a) are similar or different and represent group, selected from hydrogen atom, C1-8-alkyl group, and from 6- to 10-membered monocyclic or bicyclic aryl group (said aryl group is optionally substituted with halogen atom), (b) are combined with each other with formation of oxogroup or (c) are combined with each other on their ends together with adjacent carbon atom with formation of C3-10-cycloalkyl group, X represents the following group =N-, =C(R4)- or -CH(R4)-, R4 represents hydrogen atom, cyanogroup, halogen atom, C1-6-alkyl group, C2-6-alkenyl group, C3-10-dicloalkyl group, C1-7-alkanoyl group, carbamoyl group or C3-8cycloalkenyl group, Ar represents from 6- to 10-membered monocyclic or bicyclic aryl group, optionally containing one or several heteroatom(s), selected from sulphur atom, oxygen atom and nitrogen atom (said aryl group is optionally substituted with similar or different, one or two substituent(s), selected from halogen atom, cyanogroup, C1-8-alkyl group, trihalogen- C1-8-alkyl group and C1-8alkoxygroup), and dotted line represents presence or absence of double bond, Xa represents the following group =N- or =C(CN)-, RZ represents hydrogen atom or halogen atom, R25 and R35 represent alkyl group, and Ar3 represents phenyl group, optionally substituted with one or two group(s), which is(are) selected from halogen atom and trihalogenalkyl group.

EFFECT: compounds can be applied as antihypertensive medication.

15 cl, 18 tbl, 8 dwg, 71 ex

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