Benzopyranones and benzododecinium compounds, intermediate compounds, pharmaceutical composition and method of inhibiting

 

(57) Abstract:

Benzopyranones and benzododecinium the compounds of formula I and its pharmaceutically acceptable salts, where a' Is Oh or CH2, R3, R4-H or a hydroxy-group, R5- -(CH2)nCNH9X10, -(CH2)nX10, -CH(OH)X10; n=0 or 1; X9- H or phenyl; X10- H, alkyl, phenyl, possibly substituted, R6and R7each H or alkyl, R1- CIS - or TRANS- (CH2)m-CX3X4X5and substituted six-membered aromatic ring, where m = 0, and X3and X4taken together with the carbon atom to which they are attached, form a4-7-cycloalkyl; X5-carboxypropyl, R2- N, are antagonists leukotriene4(FULLY4). 4 C. and 8 C.p. f-crystals, 1 PL.

< / BR>

The present invention relates to new benzopyranones and other benzododecinium antagonists leukotriene B4(FULLY4), to pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions containing such compounds, and to a method of using such compounds as antagonists fully4.

Compounds of this is SNA, induced fully4such as inflammatory diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis and other skin diseases such as eczema, erythema, itching and acne, irritation and other forms of reperfusion diseases, graft rejection, autoimmune diseases, asthma and other conditions where there is a marked infiltration of neutrophils.

Antagonists of leukotriene B4described in the European patent publications 276064 and 292977 that mention diphenyl ethers, benzophenone and other compounds containing two phenyl groups, and 7-(3-alkoxy-4-alkanoyl-phenoxy)alkoxybenzenes derivatives, respectively.

Brief description of the invention

The present invention relates to new benzopyrene and other benzododecinium connections - antagonists leukotriene B4(FULLY4) formula

< / BR>
and their pharmaceutically acceptable salts,

where A1is O, CH2, S, NH or N(C1-C6)alkyl;

R3is hydrogen or hydroxy;

A2does

< / BR>
R4is hydrogen or hydroxy;

R5selected from the group of the and 3; X9is hydrogen, (C1-C6)alkyl or optionally substituted phenyl; where the optionally substituted phenyl optionally substituted by one or two substituents, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl; X10is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl or one of the following optionally substituted rings: phenyl, teinila, pyridium, fullam, naphthyl, chinaillon, ethanolism, pirimidinom or pyrazinium; where the optionally substituted rings are optionally substituted by one or two substituents, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)-alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl, phenylsulfonyl and optionally substituted phenyl; where optional Samedi fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce,

(C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl;

R6and R7are each independently hydrogen or (C1-C4)alkyl, or R6and R7together with the carbon atom to which they are attached, form a (C4-C7)cycloalkyl;

R1selected from the group comprising tetrazolyl, carboxy, CIS - or TRANS - (CH2)m-CX1= CX2-CO2H, -(CH2)m-CX3X4X5, -CO-NG1G2and substituted five - or six-membered aromatic ring, optionally having one or two heteroatoms, where the heteroatoms optionally independently selected from the group comprising O, S and N; where m is 0,1 or 2;

Y is O, CH2, S, NH or N(C1-C6)alkyl;

X1and X2are each independently hydrogen or (C1-C4)alkyl;

X3and X4are each independently hydrogen or (C1-C4)alkyl, or X3and X4are taken together with the carbon atom to which it is om or-CO-NG3G4;

X6is carboxy, tetrazolyl, CH2HE or-CO-NG5G6, G1, G2, G3and G4, G5and G6each independently selected from the group comprising hydrogen, (C1-C6)alkyl, (C1-C4)-perfluoroalkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl,

(C1-C6)alkylsulfonyl, phenylsulfonyl, hydroxy, phenyl and (Q1)a-substituted phenyl; where a is 1 or 2; Q1for each case independently selected from fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl; substituted five - or six-membered aromatic ring, substituted with one Deputy, selected from the group comprising carboxy, tetrazolyl, -CO-N(H)(SO2-X7), -N(H)(SO2-X7), -N(H)(CO-X7and-N(H)(CO-OX7), and one or two substituents, each independently selected from the group comprising fluorine, chlorine, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (Cthe IMT and phenylsulfonyl; where X7is hydrogen, -CH2F, -CHF2, -CF3, (C1-C6)alkyl, (C3-C8)cycloalkyl or one of the following optionally substituted rings: phenyl, teinila, pyridium, fullam, naphthyl, chinaillon, ethanolism, pirimidinom or pyrazinium; where the optionally substituted rings optionally substituted by one or two substituents, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl, phenylsulfonyl and optionally substituted phenyl; where the optionally substituted phenyl optionally substituted by one or two substituents, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C4) alkylsulfonyl and phenylsulfonyl;

R2represents hydrogen, fluorine, chlorine, (C1-C6)alkyl, (C1-C6)ALCO is UB>6
)alkylsulfonyl, phenylsulfonyl, (C1-C6) alkylsulfonyl or phenylsulfonyl;

provided that

G1and G2are not both hydroxy at the same time;

G3and G4are not both hydroxy at the same time;

G5and G6are not both hydroxy at the same time; and

when R3is hydroxy and R4is hydrogen, then R5is-CH(OH)X10.

A preferred group of compounds are those compounds of formula I or their pharmaceutically acceptable salt,

where R3is hydroxy; A2is , and R1, R2, A1, R4and R5are as defined above for formula I.

A more preferred group of compounds are those compounds of formula I or their pharmaceutically acceptable salts, where R3is hydroxy; A1is Oh or CH2; A2is and R1, R2, R4and R5are as defined above for formula I.

Even more preferred group of compounds are those compounds of formula I or their pharmaceutically acceptable salts, where R3is hydroxy; A1I have emenim five - or six-membered aromatic ring, one Deputy, selected from the group comprising carboxy, tetrazolyl, -CO-N(H)(SO2-X7), -N(H)(SO2-X7), -N(H)(CO-X7and-N(H)(CO-OX7), and one or two substituents, each independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl; and m, X3X4X5X7, R2, R4and R5are as defined above for formula I.

Even more preferred group of compounds are those compounds of formula I or their pharmaceutically acceptable salts, where R3is hydroxy; A1is O or CH2; A2is R1is substituted phenyl, substituted by one Deputy, selected from the group comprising carboxy, -N(H)(SO2-X7), -N(H)(CO-X7and-N(H)(CO-OX7), and one or two substituents, each independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)alkylsulfonyl and phenylsulfonyl; and X7, R2, R4and R5are as defined above for formula I.

The most preferred group of compounds are those compounds of formula I or their pharmaceutically acceptable salts, where R3is hydroxy; A1is O or CH2; A2is R1is substituted phenyl with one Deputy, selected from the group comprising carboxy, -N(H)(SO2-X7), -N(H)(CO-X7and-N(H)(CO-OX7), and with one or two substituents, each independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio,

(C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl; R4is hydroxy, and R3hydroxy is either CIS or TRANS with R4hydroxy; and X7, R2and R5are as defined above for formula I. From directly above the group of most preferred compounds are even more preferred group of compounds are those where R3and R4g is th compounds are those compounds of formula I or their pharmaceutically acceptable salts, where R3is hydroxy; R4is hydroxy; A1is O or CH2; A2is R1is substituted phenyl, substituted by one Deputy, selected from the group comprising carboxy, and-N(H)(SO2-X7), and with one or two substituents, each independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6) alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce,

(C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6) alkylsulfonyl and phenylsulfonyl; R3hydroxy and R4hydroxy are CIS with respect to each other; R5is -(CH2)nCHX9X10where X9is hydrogen, and X10is one of the optionally substituted rings as defined above for formula I; and n, X7and R2are as defined above for formula I. Preferred group of compounds of the last of the above group of compounds are those compounds where n is 1; and X10is phenyl, substituted in the para-position by phenyl. And the next group of compounds is most preferred groupvelocity carboxy-N(H)(SO2-X7), and one or two substituents, each independently selected from the group comprising fluorine, chlorine and (C1-C4)perfluoroalkyl.

The present invention also relates to pharmaceutical compositions for the treatment of diseases caused by fully4which contains an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, as described above, and a pharmaceutically acceptable carrier or diluent. The invention also relates to pharmaceutical compositions for the treatment of eczema, erythema, itching, acne, irritation, transplant rejection, autoimmune diseases and asthma, containing such amount of the compounds of formula I, as defined above, or its pharmaceutically acceptable salt, which is sufficient for the treatment of these diseases, and a pharmaceutically acceptable carrier or diluent. Preferred compositions are those compositions where the compound of formula I is the preferred connection.

The present invention also includes a method of inhibiting the binding of receptors, inhibition of the functional activity and inhibition is fully4in vivo by introducing the subject of the complaint salt. The present invention includes a method of treating inflammatory diseases, eczema, erythema, itching, acne, irritation, rejection of the transplant, autoimmune diseases and asthma by introducing to a subject in need of such treatment, the compounds of formula I, as defined above, or its pharmaceutically acceptable salt. Preferred methods of the present invention are those methods where the compound of formula I is preferred compound or its pharmaceutically acceptable salt.

The present invention also relates to an intermediate compound of formula IA

< / BR>
where A is O, CH2, S, NH or N(C1-C6)alkyl;

A2does

< / BR>
R4is hydrogen or hydroxy;

R5selected from the group comprising -(CH2)nCHX9X10, -(CH2)nX10-CH(OH)X10; where n is 0, 1, 2 or 3;

X9is hydrogen, (C1-C6)alkyl or optionally substituted phenyl; where the optionally substituted phenyl optionally substituted by one or two substituents, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alcok the>)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl;

X10is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl or one of the following optionally substituted rings: phenyl, teinila, pyridium, fullam, naphthyl, chinaillon, ethanolism, pirimidinom or pyrazinium; where the optionally substituted rings are optionally substituted by one or two substituents, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl, phenylsulfonyl and optionally substituted phenyl; where the optionally substituted phenyl optionally substituted by one or two substituents, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce,

(C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl;

R6and R4-C7)cycloalkyl;

R1selected from the group comprising tetrazolyl, carboxy, CIS or TRANS -(CH2)m-CX1= CX2-CO2H, -(CH2)m-CX3X4X5, -CO-NG1G2and substituted five - or six-membered aromatic ring, optionally having one or two heteroatoms, where the heteroatoms are optionally independently selected from the group comprising O, S and N; where m is 0,1 or 2;

Y is O, CH2, S, NH or N(C1-C6)alkyl;

X1and X2are each independently hydrogen or N(C1-C6)alkyl;

X3and X4are each independently hydrogen or (C1-C6)alkyl, or X3and X4taken together with the carbon atom to which they are attached, form a (C3-C7) cycloalkyl;

X5is hydroxy, carboxy, tetrazolyl or-CO-NG3G4;

X6is carboxy, tetrazolyl, CH2OH or-CO-NG5G6; G1, G2, G3, G4, G5and G6each, independently, selected from the group comprising hydrogen, (C1-C6)alkyl, (C1-C4)perfluoroalkyl, (C1-C1)a-substituted phenyl; where a is 1 or 2; Q1for each case, independently selected from fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl; substituted five - or six-membered aromatic ring, substituted with one Deputy, selected from the group comprising carboxy, tetrazolyl, -CO-N(H)(SO2-X7), -N(H)(SO2-X7), -N(H)(CO-X7and-N(H)(CO-OX7), and one or two substituents, each independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl; where X7is hydrogen, -CH2F, -CHF2, -CF3, (C1-C6)alkyl, (C3-C8)cycloalkyl or one of the following optionally substituted rings: phenyl, teinila, pyridium, fullam, naphthyl, chinaillon, ethanolism, pirimidinom or parlami, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)-perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl, phenylsulfonyl and optionally substituted phenyl; where the optionally substituted phenyl optionally substituted by one or two substituents, independently selected from the group comprising fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl and phenylsulfonyl;

R2represents hydrogen, fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl or phenylsulfonyl;

provided that G1and G2are not both hydroxy at the same time; G3and G4are not both hydroxy at the same time; G5and G6the min "C1-C6alkyl" whenever it is used in the present description, refers to saturated monovalent aliphatic hydrocarbon radicals with a straight or branched chain, having from one to six carbon atoms, such as methyl, ethyl, propyl, tert-butyl, hexyl, etc. are Also the terms of C3-C7cycloalkyl and C3-C8cycloalkyl indicate cycloalkyl group having from three to seven or eight carbon atoms respectively, such as cyclopropyl, cyclohexyl, cyclooctyl etc.

When A1is oxygen and A2is in the compound of formula I, the compound may be described as 3,4-dihydrobenzofuran or as Roman.

Compounds of the present invention, when R3is HE, have two asymmetric carbon atom marked with an asterisk in the following formula:

< / BR>
Stereoisomers may be designated by specifying R and S rotation in accordance with standard nomenclature. When there is a reference to the S, R or R, S, refers to a single enantiomerically pure compound, and S*, R*and R*S*denote racemic mixture. The invention includes racemic mixtures and the optical Isom is inania the above formula II, which are intermediate compounds of the formula I, where R1is -(CH2)mX3X4X5where m is 0 and X5is carboxy or its esters, obtained by the interaction of the compounds of the above formula III and IV with the formation of the compounds of formula V (not shown) and subsequent reduction with the formation of compounds of formula I.

The interaction of compounds III and IV is usually conducted in a solvent. Suitable solvents are the ether solvents such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and 1,4-dioxane, dipolar aprotic solvents such as dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethylsulfoxide, hexamethylphosphoramide, N,N-dimethylpropyleneurea, non-polar aromatic solvents such as xylene, benzene, chlorobenzene and toluene, and halogenated solvents such as methylene chloride, chloroform and dichloroethane. Particularly suitable solvents are xylene or a mixture of equal volumes of ethylenglycol dimethyl ether and dimethylformamide. The reaction temperature is in the range from -78oC to 200oC, depending on the boiling point of the used races who may be performed in the presence of Lewis acids, such as zinc chloride, aluminium chloride, magnesium bromide, tin chloride and titanium chloride. When it is present, the amount of Lewis acid is in the range from about 0.05 to about 2 equivalents per mole of compound III.

The interaction is usually carried out with a palladium catalyst. Suitable palladievye catalysts are tetranitroaniline palladium chloride bis-benzonitrile palladium dimer allylchloride palladium, palladium chloride, palladium acetate, palladium on coal and chloride biocatalytic palladium. The specific catalyst comprises 5% by weight dimer of allylchloride palladium or 5% of the weight of bicentenaria palladium chloride. As a rule, use from about 0.001 equivalent to one equivalent of catalyst per mole of substrate.

The interaction is usually performed in the presence of a phosphine ligand such as triphenylphosphine, tri-o-tolylphosphino or three 2-furifosmin in the amount of from about 0.1 to about 5, preferably from 1 to 2 molar equivalents per mole of the used substrate.

The recovery of the compounds of formula V is carried out in the usual way with sodium borohydride in an alcohol solvent at ambient temperature with the formation of compound SUP> or -(CH2)mX10can be obtained as follows.

The compound of formula VI interacts with a sulfonic anhydride of triptorelin (also called Trifonova anhydride) in a suitable solvent, such as methylene chloride, in the presence of triethylamine with formation of the corresponding triflates equivalent.

The group R5when it is defined as -(CH2)nX9X10or -(CH2)nX10where n, X9and X10are as defined above for formula I, may be injected into triflates similar by the two-stage method, including interaction with the aldehyde of formula X9X10CH(CH2)q-1CHO or X10(CH2)q-1CHO with the formation of the corresponding alkinoos analogue, where R5represents =CH(CH2)q-1CHX9X10or =CH(CH2)q-1X10where q is 1, 2, 3, or 4, respectively, and then hydrogenation. Interaction with the aldehyde is carried out in the presence of pyrolidine catalyst or catalyst on the basis of hydrochloric acid in acetic acid. The hydrogenation is carried out in the usual way with hydrogen and palladium catalyst.

Connect osobov, well-known specialists in this field. For example, the compounds of formula VI, where A1is oxygen, and A2is can be obtained from R2-substituted 2', 4'-dihydroxy-3-chloropropiophenone (hereinafter compound 1) by cyclization with sodium hydroxide. Compound 1 can be obtained from R2-substituted resorcinol and 3-chloropropionic acid in the presence of acid, preferably triftormetilfullerenov acid. The compounds of formula VI, where A1is grey, and A2is can be similarly obtained from R2-substituted 4' or 5'-hydroxy-2'-sulfhydryl-3-chloro-propiophenone, which, in turn, can be obtained from R2-substituted 3-hydroxythiophenol.

The compounds of formula VI, where A2is A1is O or S, can be obtained by reacting R2-substituted resorcinol or 3-hydroxythiophenol, respectively, and 4-chlorobutanol acid (and its derivatives), and cyclization with sodium hydroxide.

The compounds of formula I, where R1is -(CH2)m-CH2CX1=CX2-CO2H, can be synthesized by reacting the compounds of formula III (CH3)4), in the presence of a phosphine ligand, as described above for the reaction of compounds of formulas III and IV, to obtain the corresponding analog trimethylsilane. Similar trimacinolone turn in the ether-protected compound of the formula Z1O2CX2C=CX1-(CH2)mZ2where Z1is alkyl or cycloalkyl and Z2is iodine, bromine or CF3SO3. The binding reaction occurs in the presence of a palladium catalyst, such as bescription the palladium chloride as described above. Ketone esters are first reduced to the corresponding hydroxyl compounds, and then hydrolized to the corresponding acid of formula I. the Restoration carried out with sodium borohydride. Generally, recovery is carried out in a solvent. Suitable solvents are lower alcohols having from one to six carbon atoms, mixtures of lower alcohols with organic solvents, such as tetrahydrofuran or dioxane, and a mixture of water-soluble lower alcohols or other miscible with water, organic solvents and water. The solvent is preferably a lower alcohol such as methanol or ethanol. The range of values SUP>C to about 25oC.

The recovery phase gives a stereoisomeric mixture of the ether compounds of the formula I having the following structure:

< / BR>
These CIS and TRANS isomers can be separated by using conventional column chromatography.

The separation of enantiomeric mixtures obtained after the separation of CIS and TRANS isomers may be achieved using methods known in this field. In one of the ways connection of the formula I, where R1carboxyl group (COOH), interacts with a chiral base such as d-ephedrine, in a polar solvent such as simple air, with the formation of diastereomeric salts, which divide, and then converted into optically pure acid by treatment with acid, such as aqueous or methanolic solution of hydrogen chloride. In another method, the compound of formula I, where R1contains ester group of carboxylic acid, interacts with an optically active acid, such as R-mandelic acid or N-tert-butoxycarbonyl-D-tryptophan with the formation of diastereomeric esters with hydroxyl group, which after the separation is converted into optically pure acid by treatment with base, such as sodium hydroxide, in >conveniently carried out in an aqueous solution of base, such as alkali metal hydroxide, for example sodium hydroxide, at temperatures ranging from about room temperature to the temperature of reflux distilled or boiling point of the used solvent or mixture of solvents. The reaction can be carried out in the presence of co-solvent, such as methanol, ethanol or tetrahydrofuran.

The compounds of formula I, where R1is carboxy and R2is hydrogen, can be obtained from the intermediate compounds of formula III, first by replacing CF3SO3-group methoxycarbonyl, and then by hydrolysis. The substitution reaction is performed with the carbon monoxide in the presence of palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene (DFFF), methanol and triethylamine. Hydrolysis of produce as described previously.

The compounds of formula I, where R1is -(CH2)mCX3X4X5where m, X3X4and X5are as defined above for formula I, hereinafter referred to as compounds of formula XXI (not shown). Although subsequent further description of chemical reactions describes the formation of compounds of formula XVI, where R1is -(CH2)m
1as defined with reference to formula I, which are inert under the reaction conditions described below.

The compounds of formula XXI, where X5is tetrazolyl, can be obtained from compounds of formula XVI

< / BR>
According to this method, compound XVI is first subjected to interaction with tert-butyldimethylsilyloxy in the presence of imidazole and DMF (dimethylformamide) to protect the hydroxyl group, as is well known in this field. Secure connection interacts with ammonia and triethylaluminium in xylene with the substitution of CO2C2H5group to the cyano. The cyano substituted by trimethylsilylcyanation by interacting with trimethylaniline in toluene. Conversion to tetrazolyl and removal of the silyl protective group is achieved through the interaction with tetrabutylammonium in tetrahydrofuran.

The initial product of the formula XVI is identical to the compound of formula II above, where R1is (CH2)mCX3X4X5where X5is carboxitherapy ether and m is 0. The receipt of this original product described above.

< / BR>
The compound of formula XVII transform POM and (3) cyclization with polyphosphoric acid with the formation of the compounds of formula XVIII. The introduction of the group R5obtaining the compounds of formula XIX is as described for compounds of formula VI. Hydrogenation and hydrolysis of the compounds of formula XIX is as described above.

The compound of formula XVII can be obtained from 3-hydroxyphenylacetic acid by introducing groups X3and X4using known methods.

The original product XVI, when m is 0, 1 or 2, A2is A1is O, S, NH or N(C1-C6)alkyl, can be obtained by reacting the compounds of formula XVII with BrCH2CN or BrCH2CH2CH2CN on stage (1) of scheme I and the subsequent conversion as described with reference to scheme I.

The original product XVI, where A1is CH2, m is 0, 1 or 2 and A2is where R4, R5, R6and R7are as described above for formula I, can be obtained as described below.

Benzene, substituted -(CH2)m-CX3X4CO2C2H5interacts with MONOFILM of monochlorohydrin malonic, succinic or glutaric acid in the presence of a catalyst of the Friedel-such as aluminium chloride. The resulting ketone is converted into soo what their restore using Nickel Rani, and then amyraut. Form a ring with polyphosphoric acid with the formation of bicyclic compounds XIX. The introduction of the group R5occurs as described above.

The compounds of formula XXI, where X5is the CO2H, can be obtained by saponification of compounds of formula I, where R1is -(CH2)mCO2CH3, the receipt of which is described above.

The compounds of formula XXI, where X5HE is, m is 0, 1 or 2, and X3and X4are, each, hydrogen, can be obtained using a conventional hydrogenation of the compounds of formula I, where R1is -(CH2)mCO2CH3where m is 0, 1 or 2, with socialiniai.

The compounds of formula XXI, where X5HE is, m is 0, 1 or 2, and X3and X4are, each, alkyl, can be obtained by reacting the corresponding compounds where X3and X4are hydrogen, one equivalent of a Grignard reagent containing the group X3for example, X3MgCl, and then with one equivalent of a Grignard reagent containing the group X4for example X4MgCl.

The compounds of formula XXI, where X5HE is, m is 0, 1 or 2, and X3and X3and X4are hydrogen, with the Grignard reagent derived C3-C7dihalogenoalkane, for example, ClMg(C3-C7alkenyl)MgCl.

The compounds of formula I, where R1is where X6is carboxy, tetrazolyl, -CONG5G6or CH2OH; Y is O, S, NH or NH(C1-C6by alkyl); and m is 0, 1 or 2, can be obtained by reacting compounds of the formula

< / BR>
with triflate derivative of the formula I, where R1is CF3SO3(CH2)min the presence of a base such as triethylamine or sodium hydride, in a reaction-inert solvent.

Triflate can be obtained by reacting Trifonova anhydride with the compound of the formula XXI, where m is 0, 1 or 2; X3and X4are hydrogen; and X5is hydroxyl, the synthesis of which is described above.

The compounds of formula I, where R1is-CONG1G2can be obtained from the corresponding compounds where R1is carboxy, by reacting with an amine of the formula NHG1G2.

According to a specific method of the present invention are intermediate compounds of the above formula II, where R1avenier formula , where R2is the same as described for formula I. This reaction is usually conducted in a solvent such as an ethereal solvent, for example tetrahydrofuran, diethyl ether, etilenglikolevye ether, 1,4-dioxane, preferably tetrahydrofuran. The reaction is carried out in the presence of catalytic amounts of a catalyst, particularly a palladium catalyst, from any source of palladium, which supplies palladium (Pdo) under the reaction conditions, for example tetranitroaniline palladium. The reaction is usually carried out at a temperature equal to or approximately equal to the temperature of reflux distilled solvent used, preferably at a temperature of about 78oC. the reaction Time is usually from about 1 to 24 hours, for example, about 3 hours.

The compounds of formula IB receive in situ from a compound of the formula where R2is the same as defined above for formula I, by their interaction with n-butyllithium or second-butyllithium in hexane at low temperatures of about -78oC, and then with ZnCl2or ZnBr2usually at temperatures from about 0oC to about 78oC for from about one to two hours.

The ketones of formula II, where A1, A2, R1and RoC to about 100oC, and typically from about 0oC to about 25oC.

< / BR>
The compound of formula XIV is formed by reacting the compounds of formula III (CH3)3SnSn(CH3)3and a palladium catalyst, such as tetranitroaniline palladium (Pd(PPh3)4), or chloride bis-benzonitrile, in the presence of a phosphine ligand such as triphenylphosphine, in an amount of from about 0.1 to about 5 molar equivalents per mole of the used substrate. The compound of formula XIV is converted into the compound of formula XV by reacting with the ester-protected compound of the formula

< / BR>
where X is C, CH, N, O or S;

K1is carboxy, protected(H)(CO-OX7) (this group receive in the form of acid before it is converted into ester);

K2is independently F, Cl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl or phenylsulfonyl;

l is 1 or 2;

Z is iodine, bromine or CF3SO3.

The binding reaction is carried out in the presence of palladium catalyst, such as tetranitroaniline or chloride bis-triphenylphosphine.

Ketone esters of formula XV is first reduced to the corresponding hydroxyl, and then hydrolized to the corresponding acid of formula I. the Restoration is carried out with sodium borohydride, as described above with reference to the restoration of the ketones of formula II. Hydrolysis to the acid can be carried out with a water solution of base, such as alkali metal hydroxide, for example sodium hydroxide, optionally in the presence of co-solvent, such as methanol or ethanol, at temperatures ranging from room temperature to the temperature of reflux distilled or boiling used is Holocene of the esters of formula I by removal of the hydroxyl group with the formation of the olefin. This is carried out by a method well-known to specialists in this field, by treatment with acid, such as hydrochloric, sulfuric, Trifonova or preferably toluensulfonate acid in a solvent such as benzene, acetic acid, dioxane or preferably toluene, at a temperature of approximately 25oC to the boiling temperature under reflux for from about 0.5 to 5 hours.

The resulting alkene can be gidroksilirovanii using catalytic osmium tetroxide and an oxidizing agent, such as morpholine-N-oxide, or the like, in a solvent such as ether, THF or preferably acetone, mixed with water. The mixture is stirred at room temperature until such time as all of the original product is not consumed, that always takes from about 1 to 5 hours.

This gives exclusively the CIS-dihydroxy compounds. Transdigital analogues can be obtained by a longer oxidation, from about 10 to 24 hours, under the same reaction conditions, followed by reduction of 3-hydroxy-4-keto product with hydride regenerating agent such as LiAlH4or LiBH4or preferably NaBH4in a solvent such as THF, but predpochtitel what voditelem, such as lower boiling alcohols, preferably ethanol, to obtain the acid in the food.

Alkene can also be processed by nagkalat, preferably by metacompetencies acid, in a solvent such as THF or preferably dichloromethane, at a temperature of from about 0oC to room temperature, preferably at a temperature of 0oC for 1-5 hours with obtaining epoxide. Epoxide hydrolyzing with H2and 10% Pd/C in an inert solvent, such as acetic acid ethyl ester with 3-hydroxy ester (R3= H, R4= HE).

The compounds of formula I, where R1is

< / BR>
where R10is independently fluorine, chlorine, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)perfluoroalkyl, (C1-C4)perforamce, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, phenylsulfonyl, (C1-C6)alkylsulfonyl or phenylsulfonyl;

r is 1 or 2,

can be obtained by reacting compounds of the formula I, where R1is

< / BR>
where R10and r are as defined above,

with a sulfonamide of the formula X7SO2NH2in the presence of binding agentsoho Foundation, such as pyridine, dimethylaminopyridine, triethylamine, diisopropylethylamine or diazabicyclo[5,4,0] undec-7-ene. The reaction is carried out in a solvent such as tetrahydrofuran, diethyl ether, toluene and chlorobenzene, at a temperature in the range from about room temperature to about the boiling temperature used in the reaction solvent.

The compounds of formula I, where X6of R1or aromatic substitution equal NHCO-X7, NHSO2-X7or NHCO-OX7can be obtained by the interaction of the compounds of formula I, where X5or X6for R1is carboxy or substituted aromatic or heteroaromatic acid, diphenylphosphorylacetate in a solvent such as toluene, DME, THF or dichloromethane, in the presence of benzyl alcohol and amine base, such as pyridine, diisopropylethylamine, pyrrolidin or preferably triethylamine, at the boiling point of the used solvent for 5-48 hours, preferably 16 hours. The product from this reaction hydronaut in a lower alcohol in the presence of a palladium catalyst, preferably Pd(OH)2/C, followed by acylation using the appropriate carboxylic acid, carbamoylated or the events, used and can be used to produce compounds of the present invention.

Where possible, as can be determined by a person skilled in the art using the present description, pharmaceutically acceptable cationic salts of certain compounds of the present invention include, but are not limited to, salts of sodium, potassium, calcium, magnesium, ammonium, N,N'-dibenziletilendiaminom, N-methylglucamine, ethanolamine and diethanolamine. Pharmaceutically acceptable cationic salts of the compounds of formula I can be obtained by mixing the compounds of formula I with one equivalent of amine base or Foundation of the alkali metal.

Compounds of the present invention can be administered to mammals, including humans, for the treatment of diseases induced by fully4various ways, including oral, parenteral and local, including the use of suppositories and enemas. When administered orally, the dose levels from about 0.5 to 1000 mg/day, more preferably about 5-500 mg/day may be administered in a single dose or in divided doses, up to three doses. For intravenous administration, the dose levels are 0.1-500 mg/day, more preferably about 0.1-100 mg/day. Nutritioniste from age, weight and condition of the subject treated and the particular route of administration, which can be understood from this description, the person skilled in the art

Compounds of the present invention can be administered by themselves, but usually will be introduced in a mixture with a pharmaceutical carrier or diluent selected with regard to the intended route of administration and conventional pharmaceutical practice, well known to the person skilled in the art. For example, they can be taken inside in the form of tablets containing such excipients as starch or lactose, or in capsules either by themselves or in a mixture with excipients, or in the form of elixirs or suspensions containing flavouring or tinted agents. They may be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral reception is best used in the form of a sterile aqueous solution which may contain other dissolved substances, for example enough salts or glucose to make the solution isotonic.

The activity of the compounds of the present invention in relation to fully4can be determined by comparing the ability of compounds of this izaberete the zones of spleen cells of the Guinea pig. The cell membrane of Guinea-pig spleen receive, as described by Cheng et al. (J. Pharmacology and Experimental Therapeutics 232:80, 1985). The analysis of binding3H-FULLY4produced in 150 μl containing 50 mm Tris pH 7.3, 10 mm MgCl2, 9% methanol, 0.7 nm3H-FULLY4(NEN, about 200 Ci/mmol) and 0.33 mg/ml membranes of the spleen cells of the Guinea pig. Its fully4add in a concentration of 5 μm for the determination of nonspecific binding. Connections added in various concentrations to assess their impact on binding 3H-FULLY4. The reaction mixture is incubated at a temperature of 4oC for 30 minutes. Membrane binding3H-FULLY4collect by filtration through glass fiber filters, and the associated number is determined by counting scintillate. Value IR50to connect represents the concentration at which inhibited 50% of specific binding3H-FULLY4.

The functional activity of compounds of the present invention can be defined in several ways, using biological tests. Described as high-and noscapine form fully4receptor, which are differently associated with chemotaxis of leukocytes and regulation of ADH is Horvath, L. et al., J. Immunol. , 1987, 139, 3055. Regulation of human neutrophils CDIIb measured as described Marder, P. et al., Prostaglandins, Leukotriene Essent. Fatty Acids, 1991, 46, 265-278.

In addition, the compounds of formula I can be tested in vivo in accordance with the method similar to the method described Pettipler, E. R. et al. , Brit. J. Pharmacology, 1993, 423-427, by injection fully4in the dermis Guinea pigs and measuring the blockade of neutrophil migration into the skin using an acceptable oral compounds of formula I.

The following examples illustrate the formation of compounds of the present invention and may not be used to limit the scope of the present invention in any way.

Example 1

(5S*, 6S*)2-(6-Benzyl-5,6-dihydroxy-5,6,7,8-tetrahydro - naphthalene-2-yl)-4-Formentera acid

A. 2-(4-Forfinal)-4,4-dimethyl-4,5-dihydrooxazolo

To a stirred solution of 2-amino-methylpropanol (0,378 mol, 33,64 g) in 300 ml of methylene chloride at a temperature of about 0oC was added a solution of 4-tormentilla (0,189 mol, 22,36 ml) in 100 ml of methylene chloride for about 0.5 hour. Mixture was allowed to warm to room temperature and stirred for about 3 hours. The mixture was then poured into water and the layers separated. The organic phase is washed with two hours is Italia in vacuum gives colorless solid product which is stirred while adding dropwise SOCl2(0,567 mol, 41 ml) for about 30 minutes the resulting solution is stirred for about 0.5 hours, at this time, add diethyl ether, and the solution is rapidly stirred. In continuation of this procedure is obtained a colorless precipitate. The suspension is filtered and the solid product is washed with three portions of 250 ml of diethyl ether. The solid product is then dissolved in 300 ml of 3n. KOH and the resulting solution was extracted with ethyl acetate. The organic extracts washed with saturated solution of NaCl and dried over MgSO4. Removal of solvent in vacuo gives 32 g specified in the title of this example 1A connection: 1H-NMR (250 MHz, CDCl3) : 8,00-to $ 7.91 (m, 2H), 7,10-7,02 (m, 2H), 4,11 (s, 2H), 1.39 in (s, 6H).

B. 2-Benzylidene-6-methoxy-3,4-dihydro-2H-naphthalene-1-he

To a stirred solution of 6-methoxy-1-tetralone (0,227 mol, 40 g) and benzaldehyde (0,272 mol, 27.5 ml) in 450 ml of methanol is added pyrrolidine (0,272 mol, of 23.6 ml). The mixture is stirred at room temperature for about 4 days before until TLC shows that the source tetralone is missing. The mixture was concentrated in vacuo, then dissolved in EtOAc, washed with four portions of 10% HCl, the two parts of a saturated solution of NaHCO3and one CNAM 38 g specified in the title of this example 1B connection, so pl. 100-102oC. Calculated for C18H16O2: 264, 1146. Found: 264, 1149.

C. 2-Benzyl-6-methoxy-3,4-dihydro-2H-naphthalene-1-he

The apparatus Parradownload chromenones (15 g), ethyl acetate (150 ml) and 1 g of 10% palladium on charcoal. The mixture hydronaut apparatus Parrawith shaking for about 15 hours under hydrogen pressure of 20 pounds per square inch (1406 g/cm2). The resulting mixture was filtered through a layer of Celite and concentrated in vacuo to obtain a red oil, which is purified by flash chromatography (3:1 hexane/diethyl ether) to obtain 14.1 g of the compound of example 1C, so pl. 50-51oC. Calculated for C18H18O2: 266, 1302. Found: 266, 1308.

D. 2-Benzyl-6-hydroxy-3,4-dihydro-2H-naphthalene-1-he

To a stirred solution of compound of example 1C (sensititre) (5 g, 19 mmol) in methylene chloride (40 ml) at a temperature of about -78oC add tiobraid boron (1,95 ml, 21 mmol). The cooling bath removed and the reaction mixture was stirred over night at room temperature, after this time add an additional 1.5 ml of tribromide boron. Stirring is continued at room temperature additionally for more about sysout with sodium chloride and extracted with four portions of methylene chloride. The layers are separated and the organic phase is washed with water and dried over anhydrous sodium sulfate. Filtration and removal of solvent in vacuo giving a brown solid product, which was purified by flash chromatography (3:2 hexane/ether) to give 3 g of the compound of example 1D, so pl. 160-162oC. Calculated for C17H16O2: 252, 1146. Found: 252, 1144.

E. 6-Benzyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid

To a stirred solution of the compound of example 1D (2,75 g, 11 mmol), triethylamine (4,56 ml, 33 mmol) and DMAP (0.05 g) in methylene chloride (100 ml) at a temperature of about -78oC add triftormetilfullerenov anhydride (2 ml, 12 mmol). The cooling bath removed and the reaction mixture is heated to room temperature and stirred over night. The mixture is then poured into ice water and extracted with ethyl acetate. The obtained organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum. The crude product is purified by flash chromatography to obtain 3.9 g of the compound of example 1E, so pl. 52-53,7oC. Calculated for C18H15SF3: 384, 0638. Found: 384, 0602.

F. 2-Benzyl-6-[2-(4,4-dimethyl-4,5-dehydrator in hexane, 9 mmol) in toluene (10 ml) at a temperature of about -40oC add a solution of arelaxation (1,76 g, 9 mmol) in toluene (5 ml) dropwise via pipette. The mixture is stirred at a temperature of about -40oC for about 0.5 hour, then heated to a temperature of about -25oC and stirred for about 1 hour. To this mixture is added zinc chloride (9 ml, 1 M solution in diethyl ether, 0,009 mol). The cooling bath removed and the mixture is heated to room temperature and stirred for about 1 hour. The resulting mixture was added with a pipette to a solution of TETRANITRATE (3.5 g, 9 mmol) and tetranitronaphthalene (0.5 mmol, 0,63 g) in tetrahydrofuran (15 ml). The reaction mixture is heated under reflux for about 2 hours, cooled to room temperature and poured into saturated aqueous solution of ammonium chloride. The aqueous mixture is extracted with three portions of ethyl acetate. The organic phase is washed with three portions of 1M HCl, saturated aqueous sodium bicarbonate and saline. The organic phase is then dried over anhydrous sodium sulfate, filtered and the solvent is removed in vacuum. The crude product is purified by flash chromatography (2:1 diethyl ether/hexane) to obtain the 2,07 g of a compound is nil-6-[2-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)- 5-forfinal]-1,2,3,4-tetrahydro-2H-naphthalene-1-ol

To a stirred solution of compound of example 1F (1.5 g, 3.5 mmol) in methanol (35 ml) is added sodium borohydride (0.20 g, a 5.25 mmol). The obtained brown mixture was stirred at room temperature for about 1 hour, then poured into brine and extracted with three portions of ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuum to obtain 1.20 g of 1:1 mixture of CIS and TRANS alcohols, I. pl. 88-89oC. Calculated for C28H28NO2F: 429, 2087. Found: 429, 2067.

H. 2-(6-Benzyl-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)- 4-Formentera acid

The compound of example 1G (1.0 g, 2.34 mmol) was dissolved in 5 ml of methyliodide and stirred at room temperature for about 2 days, during this time, methyliodide removed in vacuum. The residue is extracted with methylene chloride and concentrated in order to remove traces of remaining methyliodide. Dark red residue is dissolved in methanol (5 ml) and add 2n. NaOH (5 ml). The resulting mixture was heated under reflux with stirring for about 5 hours. The mixture was then cooled to room temperature and acidified with 3n. HCl. The resulting suspension is extracted with three portions of ethyl acetate and the combined organic phase washed with soluction of 0.80 g of the compound of example 1H.1H-NMR (250 MHz, methanol-d4) : 7,83 (DD, 1H, J= 7,0, 7,5), to 7.50 (d, 1H, J=7,0), 7,30-7,00 (m, 9Hx2), 4,50 (d, 1H, J=2,0), to 4.41 (d, 1H, J= 8.0 a) and 3.15 (DD, 1H, J=5,4, 13,9), 3,00-2,57 (m, 4H), 2,42 (DD, 1H, J=11,4 13,5), 2,09-of 1.35 (m, 5Hx2).

I. Ethyl ester of 2-(6-benzyl-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl) -4-fermenting acid

To a stirred solution of compound of example 1H (0,80 g, 2,13 mmol) and ethyliodide (0,34 ml, 4.26 deaths mmol) in acetonitrile (20 ml) is added potassium carbonate (1,03 g, 1,45 mmol). The resulting suspension is heated to a temperature of about 60oC for about 24 hours. The mixture is cooled to room temperature, diluted with diisopropyl ether and filtered through celite. Concentration in vacuo gives to 0.72 g of the compound of example in the form of a 1:1 mixture of CIS/TRANS. Data for a mixture of diastereoisomers are as follows: 1H-NMR (250 MHz, chloroform-d) : 7,88 (DD, 1H, J=7,0, 7,5), 7,53 (d, 1H, J=7,0), 7,39-of 7.70 (m, NH), 4,58-to 4.52 (m, NH), of 4.12 (q, 2H, J=7,0), 4,11 (q, 2H, J= 7,0), of 3.13 (DD, 1H, J=6,1, 14,2), 3,00 (NH, NH), 2,92-2,70 (m, 2H), by 2.55 (DD, 1H, J=9,4, 14,2), 2,11-1,40 (m, NH), a 1.08 (t, 3H, J=7,0), of 1.07 (t, 3H, J=7,0).

J. Ethyl ester of 2-(6-benzyl-7,8-dihydronaphthalene-2-yl)- 4-fermenting acid

In a round bottom flask containing the compound of example 1I (0,70 g) in benzene (50 ml), add n-toluensulfonate acid (0.09 g). The flask is provided with a trap Dina-Starcase, then cooled to room temperature and concentrate under reduced pressure. The residue is extracted with chloroform and washed with saturated aqueous sodium bicarbonate. Chloroformate extracts dried over anhydrous sodium sulfate and the solvent is removed in vacuum to obtain a yellow oil, which was purified by flash chromatography (6:1 hexane/ethyl acetate) to give 0.56 g of the compound of example 1J. Calculated for C26H23O2F: 386, 1676. Found: 386, 1713.

K. Ethyl ester of CIS-(5S*, 6S*)-2-(6-benzyl-5,6 - dihydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-4-fermenting acid

To a stirred solution of compound of example 1J (0.50 g, 1.3 mmol) in 3:1 mixture of acetone/water (6 ml) is added N-methylmorpholine-N-oxide (has 0.168 g, 1.4 mmol), then added osmium tetroxide (0,79 ml, 4% solution in water, 0.1 mmol). The reaction mixture was stirred at room temperature and monitored by TLC for the disappearance of the original product. The mixture was then diluted with chloroform and washed with 10% aqueous solution of NaHSO3. Chloroform extracts dried over anhydrous sodium sulfate and remove the solvent under reduced pressure. The residue is purified by flash chromatography (1:1 hexane/ethylacetate) poleena: 420, 1722.

L. (5S*, 6S*)-2-(6-Benzyl-5,6-dihydroxy-5,6,7,8 - tetrahydronaphthalen-2-yl)-4-Formentera acid

To a stirred solution of compound of example 1K (0,30 g, 0.71 mmol) in a mixture of 3:1 methanol/water (12 ml) add hydrocodonehydroc lithium (0.15 g, 3.6 mmol). The resulting mixture was heated under reflux for about 4 hours. The mixture is cooled to room temperature and acidified with 1N. HCl. The aqueous suspension is extracted with ethyl acetate. The organic phase is washed with saline, dried over anhydrous sodium sulfate and removed under vacuum of the solvent to obtain 0.24 g of the compound of example 1L (specified in the title of the product), so pl. 127-130oC. Calculated for C24H21O4F: 392, 1423. Found: 392, 1948.

Example 2

7-(2-Carboxy-5-triptoreline)-C-phenylmethyl-Z-hydroxy-2,3,4 - dihydrobenzofuran

A. 2', 4' -Dihydroxy-3-chloropropiophenone

To a stirred mixture of resorcinol (200 g, 1.82 mol) and 3-chloropropionic acid (200 g, of 1.84 mol) at a time add triftormetilfullerenov acid (1 kg). The solution is slowly heated for about 45 minutes to a temperature of 80oC, then cooled to room temperature for about 15 minutes and poured into chloroform (4.0 l). Ol). The combined organic layers washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gives an orange semi-solid product (to 244.1 g), which is used crude in the next stage. 1H-NMR (300 MHz, CDCl3: 12,56 (1H, s), 7,63 (1H, d, J=7,6), 6,37-6,46 (2H, m) to 3.92 (2H, t, J=6,3), to 3.41 (2H, t, J=6,3).

B. 7-Hydroxybenzophenone-4-one

To a cooled (about 5oC) a solution of 2 n sodium hydroxide (10.0 l) at a time add the compound of example 2A (to 244.1 g). The solution is heated to room temperature for about 2 hours, using a bath of hot water, then cooled to about 5oC and set pH 2 using 6 M sulfuric acid (1.2 l). The mixture is extracted with 3 x 3,0 l ethyl acetate, washed with brine (1 x 2.0 l), dried over sodium sulfate and filtered. Concentration in vacuo gives a yellowish-brown solid product. Rubbing with hexane and filtering gives 173,7 g (yield 58%) of the compound of example 2B. So pl. 136-137oC.

C. 7-[Tripterocalyx]-benzopyran-4-one

To a stirred solution of the compound of example 2B (173,7 g, 1.05 mol) in methylene chloride (3.0 l) at a temperature of about -78oC add triethylamine (320 g, and 3.16 mol) and dimethylaminopyridine (2.5 g is lo 20 minutes the product is stirred for about 30 minutes at a temperature of about -78oC and then warmed to room temperature for about 2 hours. The reaction mixture was poured into a saturated solution of ammonium chloride (2.5 l) and the layers separated. The aqueous layer was extracted with 2 x 2.0 l of methylene chloride. The combined organic fractions washed with water (1 x 1.0 l), dried over magnesium sulfate and filtered. Concentration in vacuo gives a red oil. Chromatography on silica gel (1 kg) with elution (8:1) hexane: ethyl acetate to give after removal of solvent 211,1 g (yield 69%) indicated in the title of this example 2C of the product. So pl. 43-44oC.

D. 7-[(Trifloromethyl)oxy]-C-phenylmethylene-benzopyran-4-one

To a stirred solution of the product of example 2C (27 g, and 91.2 mmol) in 183 ml of methanol is added benzaldehyde (11,1 ml, 109 mmol), then add pyrrolidine (9.1 ml, 109 mmol). The mixture is stirred at room temperature overnight, cooled to about 0oC and filtered. The solid product is washed once with 50 ml of methanol with ice and then dried in a vacuum; emit of 35.2 g (75% yield) specified in the title of this example 2D product. So pl. 133-135oC. 1H-NMR (300 MHz, CDCl3) : 8,11 (1H, d, J=8,7), to $ 7.91 (1H, user. C), 7,40-7,51 (2H, m), 7.24 to 7,38 (the Piran-4-one

To a stirred solution of the product of example 2D (26,6 g of 69.2 mmol) in 250 ml of ethyl acetate in a 500 ml Parr apparatuswith shaking add a catalyst of 10% palladium on coal (1.3 g). The mixture hydronaut at 40 pounds per square inch (2812 g/cm2) up until after about 3 hours will not stop the release of hydrogen. The mixture is filtered through Celite(brand diatomaceous earth) to remove the palladium catalyst and subjected to chromatography on silica gel (hexane-ether); gain of 25.1 g (yield 94%) indicated in the title of this example 2E product. So pl. 56-58oC.1H-NMR (300 MHz, CDCl3) : 8,01 (1H, d, J=8,5), 7,20-to 7.35 (5H, m), for 6.81-of 6.96 (2H, m), 4,42 (1H, DD, J= 11,6, 4,4), 4,22 (1H, DD, J=11,6, 8,7), 3,26 (1H, DD, J= 14,0, 4,4), 2,90-3,05 (1H, m), 2,70 (1H, DD, J=14,0, 8,7).

F. 7-(2-Carboethoxy-5-triptoreline)-C-phenylmethyl - 3,4-dihydrobenzofuran

Using the method described in examples 1F-1J, but using 2-(4-triptoreline)-4,4-dimethyl-4,5-dihydrooxazolo as a reagent, get the desired product of example 2F.1H-NMR (300 MHz, CDCl3) : 7,87 (1H, d, J=8,0), 7,68-to 7.61 (2H, m), 7,41-7,22 (5H, m), 6,97 (1H, d, J=7,8), 6,85-of 6.73 (2H, m), 6,21 (1H, s), 4,71 (2H, s), 4,20 (2H, q, J=7,2), of 3.48 (2H, s) and 1.15 (4H, t, J=7,2).

G. 7-(2-Carboethoxy-5-triptoreline)-3-phenylmethyl - 3,4-acceralator about 0oC add m-CPDA (89 mg, of 0.53 mmol). After 1 hour the mixture is diluted with ether and washed with 1 N. NaOH solution and brine. The organic layer is dried (MgSO4), filtered and concentrated. Purification with flash chromatography (elution with a mixture of 3:1 hexane-ethyl acetate) to give the corresponding epoxide of example 2G (209 mg, 87%). The product is used directly for the next stage.

H. 7-(2-Carboethoxy-5-triptoreline)-C-phenylmethyl-C - hydroxybenzophenone

To a solution of the epoxide of example 2G (150 mg, 0.33 mmol) in ethyl acetate added 10% palladium on coal (100 mg). The system is connected to a cylinder containing H2, and the flask is rinsed several times. After stirring for about 16 hours the solution is filtered and concentrated. Flash chromatographic elution give the desired alcohol of example 2H (80 mg,53%).1H-NMR (300 MHz, CDCl3) : 7,89 (1H, d, J=8,0), 7,70 to 7.62 (2H, m), 7,42-of 7.25 (5H, m), 7,07 (1H, d, J= 7,8), 6,90-to 6.80 (2H, m), of 3.95 (2H, s), 4,19 (2H, q, J=7,l), 3.04 from-2,72 (4H, m).

I. 7-(2-Carboxy-5-triptoreline)-3-phenylmethyl-3 - hydroxybenzamide

Saponification of the compound of example 2H according to the method described in example 1L, gives the desired product of example 2.1H-NMR (300 MHz, CDCl3) : 7,98 (1H, d, J=7,8), to 7.67-to 7.64 (2H, m), 7,38-7,26 (5H, m), 7,06 (1H, d, J=7,8), 6,88-6,85 (2H, m), 2,99-of 2.72 (4H, ethyl-3,4-dihydrobenzofuran

A. 7-(Carboethoxy-5-triptoreline)-3-phenylmethyl-3 - hydroxybenzophenone-4-one

To a solution of the olefin from example 2F (3.7 g, 8,44 mmol) in a mixture of acetone-water (3:1) add N-methylmorpholin-N-oxide (3.0 g, to 25.3 mmol), then add OsO4. After stirring overnight the solution was diluted with water and extracted with ethyl acetate. The combined extracts are dried and concentrated. Purification of the residue by flash chromatography gives the appropriate hydroxyketone this example 3A (3.0 g, 76%). So pl. 85-87oC.

Century (3S*, 4R*)-7-(2-Carboethoxy-5-triptoreline)-3, 4-dihydroxy-Z-phenylmethylbenzene

To a solution of the ketone of example 3A (3.0 g, 6.4 mmol) in methanol (50 ml) at room temperature add NaBH4(250 mg, 6.4 mmol). After about 30 minutes the reaction mixture is quenched (NH4Cl Rast.), extracted (ethyl acetate), dried (MgSO4), filtered and concentrated. Flash chromatography (elution with a mixture of 2: 1 hexane-ethyl acetate) gives the desired TRANS-diol of example 3B (2.9 g, 97%).1H-NMR (300 MHz, CDCl3) : 7,89 (1H, d, J=8,0), 7,69-of 7.55 (2H, m), 7,42-7,20 (5H, m), 6.90 to-PC 6.82 (2H, m), 4,43 (1H, s), 4,15 (IH, d, J=12,l), 3,90 (1H, d, J=12.1) is, with 3.79 (3H, s), 3,13 (1H, d, J=13,5), 2,85 (1H, d, J=13,5).

C. (3S*, 4R*)-7-(2-Carboxy-5-trifluoromethyl-3,4 - dihydroxy)-3-penile is on example 3. So pl. 100-102oC.

Example 4

(3S*, 4R*)-7-(2-Triftormetilfullerenov-5-forfinal) -3,4-dihydroxy-3-hydroxy-3-phenylmethyl-2H-1-3,4-dihydrobenzofuran

A. 7-[(5-fluoro-(2-(4,4-dimethyl-2-oxazolyl)phenyl] -3-phenylmethylene-1 - benzopyran-4-one

To a stirred solution of 2-(4-forfinal)-4,4-dimethyl-2-oxazoline (1.0 EQ in tetrahydrofuran, concentration 0.5 M) at a temperature of about -78oC in an atmosphere of N2add n-utility in hexane (1.1 equiv, 2.5 M solution). The mixture is stirred at a temperature of about -78oC for about 1 hour, then add ZnCl2(1M solution in ether, 1.1 EQ). The mixture is heated up to about 10oC for about 1 hour to obtain 2-(4-forfinal)-2-hartsink)-4,4-diethyl-2-oxazoline (do not release). To this solution was added 7-[((trifter-methyl)sulfonyl)oxy] -3-phenylmethylene-1-benzopyran-4-one (1.0 EQ) and Pd(PPh3)4(0.02 EQ). The mixture is heated under reflux (about 68oC) for about 3 hours, cooled to room temperature and poured into a solution of NH4Cl. The solution is extracted three times with diethyl ether and the combined organic fraction dried over MgSO4. Filtration followed by removal of solvent in vacuum and column chromatograph is 5%, so pl. 110-112oC. 1H-NMR (300 MHz, CDCl3) : of 8.04 (1H, d), to $ 7.91 (1H, s), 7,78 (1H, DD), 7,41-7,52 (3H, m), 7,31 (2H, d), 7,06-to 7.18 (3H, m), 7,02 (1H, s), of 5.40 (2H, s), 3,86 (2H, s) is 1.31 (6H, s).

Century (3S*, 4R*)-7-[5-fluoro-(2-(4,4-dimethyl-2-oxazolyl)- phenyl]-4-hydroxy-3-phenylmethyl-2H-1-benzopyran

To a stirred solution of the compound from example 4A in THF (0.1 M) at a temperature of about 0oC added dropwise LiAlH4(1M in ether, 2.2 EQ) for about 10 minutes. The mixture is heated to room temperature and stirred for about 12 hours. The mixture is cooled to about 0oC, quenched with Rochelle salt and filtered through diatomaceous earth. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers washed with brine and dried over MgSO4. Filtration and removal of solvent gives a yellow oil. Chromatography on silica gel (ethyl acetate: hexane) gives a 60% yield specified in the title compound of example 4B in the form of a white solid product. So pl. 65-70oC (decomp. ). Calculated for C27H26NO3F: C 75,15; H 6,07; N 3,25. Found: C 74,75; H Of 6.02; N 3,09.1H-NMR (300 MHz, CDCl3) : of 7.70 (1H, DD), 7,02-7,37 (8H, m), of 6.96 (1H, DD), to $ 7.91 (1H, d), 4,51 (1H, d), to 4.23 (1H, DD), 4,39 (1H, DD), a 3.87 (2H, DD), is 2.74 (1H, DD), to 2.55 (1H, DD), 2,18-of 2.28 (1H, m) is 1.31 (6H, d).

C. (3S*,4Rmethyliodide (0.5 M) at room temperature and stirred for about 24 hours. Methyliodide removed in vacuum, the oily solid product was dissolved in CH2Cl2and the solvent is removed in vacuum. This process is repeated to remove traces of methyliodide. The solid product is dissolved in methanol (0.5 M) and added 2 M NaOH (0.5 M). The mixture is heated under reflux for about 5 hours, cooled to room temperature and acidified to pH 2 using 1 M HCl. The mixture is extracted twice with ethyl acetate, washed with brine, dried over MgSO4. Filtration and removal of solvent in vacuo, and then chromatography (silica gel, mixture 10:1 methylene chloride:methanol) to give the desired acid of this example 4C, the yield of 93%.1H-NMR (300 MHz, CD3COCD3) : 7,80 (1H, DD), of 7.48 (1H, d), 7,18 (7H, m), 7,13 (1H, DD), 6,91 (1H, DD), to 6.80 (1H, d), to 4.52 (1H, d), to 4.23 (1H, DD), of 3.96 (1H, DD), 2,89 (1H, DD), of 2.54 (1H, DD), 2,19-of 2.30 (1H, m).

D. (3S*, 4R*)-7-(2-Carboxy-5-forfinal)-3,4-dihydroxy - 3-phenylmethyl-2H-1-benzopyran

Using the methods of examples 1I to 1L, get mentioned in the title compound of example 4D from the compound of example 4C.

That is, (3S*, 4R*)-7-(2-Carbobenzoxy-5-fluoro)-3,4 - dihydroxy-3-phenylmethyl-2H-1-benzopyran

To a solution of the compound obtained in example 4D (1 mmol) in 10 ml of 1,4-dioxane, Dobeles heated under reflux for about 16 hours, the solvent is removed in vacuo and the residue chromatographic on silica gel (1:1 - hexane:EtOAc) to give N-CBZ product of this example 4E.1H-NMR (300 MHz, CDCl3) : 8,02 (1H, s), 7,39-7,22 (1H, m), 7,03 (1H, dt, J=7,2), 6,95-6,87 (2H, m), 6,83 (1H, s), 5,11 (2H, s), 4,48 (1H, s), 3,98 (1H, d, J=10,1), 3,80 (1H, d, J=10,1), 2,89 (2H, s).

F. (3S*, 4R*)-7-(2-Triftormetilfullerenov-5-fluoro) - 3,4-dihydroxy-3-hydroxy-3-phenylmethyl-2H-1-benzopyran

To a solution of the compound obtained in example 4E, in 10 ml of EtOH added to 0.05 equivalent weight of Pd(OH)2and suspension gidrogenit apparatus Parrawith shaking at 1 ATM for 3 hours. The mixture is filtered through Celiteand the filtrate is evaporated. Yellow oil re-dissolved in CH2Cl2(10 ml), cooled to a temperature of about 0oC and add triethylamine (2.2 EQ), and then anhydride triftormetilfullerenov acid (1.1 EQ). After stirring for about 2 hours add 2 equivalent solid NaOMe, the reaction mixture is stirred for about 15 minutes and add H2O (10 ml). Set the pH of the mixture 2 with 0.1 M HCl, then extracted with 3 x 10 ml of EtOAc. The combined organic layers washed with brine, dried over MgSO4filter and remove the solvent in vacuun the product of this example 4F. So pl. 55-57oC.

Example 5

1-(3S, 4S)-((3-(4-phenylphenolate)-3-hydroxy)-4-hydroxy)chroman-7-yl) cyclopentanecarbonyl acid

A. Ethyl 1-(3-(4-phenylphenolate)-4-chromanone-7-yl)cyclopentanecarboxylate

3-(4-Phenylbenzyl)-7-tripterocalyx-4-chromanone (35,0 g, 91,0 mmol), obtained from the product of example 2C biganimalmovies using the methods of example 2D and 2E, dissolved in a mixture of dimethylformamide (230 ml) and dimethoxyethane (230 ml). To this solution is added in the following order: Tris(2-were)phosphine (of 7.48 g, 24.6 mmol), chloride bis(benzonitrile)palladium (II) (2,44 g, 6,37 mmol), trimethylsilylcyanation of ethylcyclopentadienyl (29,26 g to 136.5 mmol) and 1.0 M ethereal solution of zinc chloride (25 ml, 25 mmol). The obtained transparent yellow solution heated under reflux for about 1 hour. At this point, add additional trimethylsilylcyanation (9.75 g, and 45.5 mmol) and continue heating under reflux for a further 1 hour. The cooled mixture is diluted with water (1 l) and extracted with ether. The combined ether extracts washed with water (1 l) and then dried over magnesium sulfate. Filtration and concentration of the extract gives a yellow oil, which chromatographic on silica gel (8:92 product; so pl. 50-56oC.1H-NMR (CDCl3) : of 1.23 (3H, t, J=7,0), a 1.75 (4H, m), 1,9 (2H, m), and 2.6 (2H, m), 2,70 (1H, DD, J=10,5, 13,8), 2,9 (1H, m), 3,26 (1H, DD, J=4,3, 13,8), 4,08 (2H, d, J=7,0), is 4.15 (1H, DD, J=8,2, 11,5), 4,35 (DD, J= 4,3, 11,5), to 6.95 (1H, d, J=1,7), 7,02 (1H, DD, J=1,7, 8,3), 7,2-7,4 (5H, m), to 7.84 (1H, d, J=8,3).

B. Ethyl 2-(4-hydroxy-Z-(4-phenylphenolate)chroman-7-yl) cyclopentanecarboxylate

The compound of example 5A (months amounts to 111.99 g, 295,9 mmol) dissolved in ethanol (2.5 l) and gently heated with sodium borohydride (12.3 g, 325,5 mmol) at room temperature. After about 3 hours the reaction mixture is concentrated to small volume and diluted with ether. The ether was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. The extract was filtered and concentrated to an oil, which chromatographic on silica gel (20:80 ethyl acetate/hexane). This gives and 63.4 g (56%) of the highest Rfproduct 3R*, 4R*in the form of oil:1H-NMR (CDCl3: to 1.15 (t, J=7,1, 3H), 1,7 (m, 1.8 to 1.9 (m, 2H), 2,3 (m, 1H), 2,5-2,6 (m, 2H), 2,66 (DD, J=7,2, 13,6, 1H), 2,86 (DD, J= 8,4, 13,6, 1H), 4,0-4,1 (m, 4H), 4,47 (user. t, 1H), 6,85 (d, J=1,8, 1H,), to 6.88 (DD, J=1,8, 7,9 1H,), 7,12 (d, J=7,9, 1H,), 7,1-to 7.35 (m, 5H); and 43.3 g (38%) lower Rfproduct, that is, 3S*, 4R*in the form of oil:1H-NMR (CDCl3) : of 1.17 (t, J=7,0, 3H), 1,7 (m, 4H), 1,8-1,9 (m, 2H), 2,2 (m, 1H), 2,52 (DD, J= 9,3, 13,7, 1H), and 2.6 (m, 2H), 2,70 (DD, J=6,3, 13,7, 1H), 3,95 (DD, J=3,7, and 11.2, 1 is silvermetal)-3-hydroxy)-4-hydroxy) chroman-7-yl)cyclopentanecarbonyl acid

The desired product is obtained from CIS and TRANS mixture of compound of example 5B by reacting the compound of example 5B is similar to the methods described in the Examples 1J-1L, obtaining specified in the title compound of this example 5. So pl. 185-187oC.

Example 6

(3S, 4S)-7-(Carboxy-5-triptoreline)-3,4-dihydroxy-Z-phenylmethyl - 3,4-dihydrobenzofuran

A. 7-(2-Carbomethoxy-5-triptoreline)-4-L-tert-Boc-tryptophan ester-3-hydroxy-3-phenylmethyl)benzopyran

To a solution of (3S, 4S)-7-(carbomethoxy-5-triptoreline)-3,4-dihydroxy-3-phenylethylenediamine (225 mg; 0.49 mmol) in CH2Cl2(6 ml) is added tert-BOC-L-tryptophan (223 mg; 0,74 mmol), DMAP (120 mg; 0.98 mmol) and EDCI (165 mg, 0.86 mmol). After stirring for about 16 hours the solution was diluted with ethyl acetate and washed with 1N. HCl and brine, dried (MgSO4), filtered and concentrated. Purification of the residue by flash chromatography (elution with a mixture of hexane-ether-methylene chloride 3:1:6) to give 137 mg, 38% coming faster than diastereoisomer, and then 135 mg, 37%, going slower diastereoisomer of example 6A.1H-NMR (300 MHz, (CDCl3) : LP isomer: 8,98 (1H, s), of 8.00 (1H, d, J=8,0), 7,76-to 7.67 (2H, m), 7,68 (1H, d, J=7,5), 7,40 (1H, d, J= 7,6), 7,37-7,09 (9H, m), 6,92-6,86 (2H, m), is 6.61 (1H, s) 5,80 (1H, s), is 4.93 (1H, d, J=6,3), 4 (1H, C) 8,03 (1H, d, J=7,9), 7,78 - 7,71 (2H, m), to 7.59 (1H, d, J=8,0), 7,32-7,05 (9H, m), 6,93 - to 6.80 (2H, m), 6,41 (1H, m), the ceiling of 5.60 (1H, s) to 5.17 (1H, d, J=6,0), 4,68-4,58 (1H, m), of 3.95 (2H, s), the 3.65 (1H, d, J=10,3), 3,43 (1H, d, J=10,2), 3,30 (1H, DD, J=15,1, 5,3), of 3.13 (1H, DD, J=15,0, 7,9), of 2.72 (2H, s), for 1.49 (9H, s).

B. (3S, 4S)-7-(2-Carbomethoxy-5-triptoreline)-3,4-dihydroxy-3 - phenylmethylbenzene

To a solution of higher Rftert-BOC-tryptophan ester of example 6A (130 mg; 0,17 mmol) in methanol-THF (7 ml, such as 5:2) is added 1N. NaOH (175 ml, 1N. ). After about 1 hour the solution is diluted with ethyl acetate, washed with 1N HCl and brine, dried (MgSO4), filtered and concentrated. Purification by flash chromatography (elution hexane-ether-methylene chloride 2: 1:6) gives the corresponding alcohol of example 6B (63 mg, 80%). 1H-NMR (300 MHz, CDCl3) : 7,94 (1H, d, J=7,8), 7,72-of 7.60 (2H, m), 7,46 (1H, d, J=8,0), 7,40-7,22 (4H, m), 6,97-6,85 (3H, m) to 4.52 (1H, s), was 4.02 (1H, d, J= 12,1), 3,86 (IH, d, J=10,1), and 3.72 (3H, s), with 2.93 (2H, s), 2,48 (1H, user. C).

C. (3S, 4S)-7-(Carboxy-5-triptoreline)-3,4-dihydroxy-3 - phenylmethylbenzene

To a solution of the ester of example 6B (60 mg, 0.13 mmol) in methanol (3 ml) is added NaOH (3 ml; 3 N.). After heating at a temperature of about 60oC for about 1 hour the mixture is cooled and acidified using 1N. HCl. The solution is extracted with ether and the combined extracts prom is this example 6 (46 mg, 80%), which is further purified by recrystallization from a mixture of hexane-ethyl acetate. So pl. 90-92oC.

Example 7

7-(2-Carboethoxy-5-fluoro-phenyl)-4-hydroxy-Z-(4-phenyl-phenylmethyl)-3,4 - dihydrobenzofuran

A. 7-(Tributylstannyl)-3-(4-phenylphenolate)benzopyran-4-one

To a stirred solution of the compound obtained in example 2E (10,95 g 25,0 mmol) in 200 ml of dioxane is added lithium chloride (3,20 g, 75,0 mmol), Pd(PPh3)4(to 1.15 g, 1.0 mmol), 3 crystal bottled hydroxytoluene and hexamethyldisilane (9.0 g, 27.5 mmol). The mixture is heated under reflux for about 1.5 hours, cooled to room temperature and poured into 150 ml of a saturated aqueous solution of ammonium chloride. The mixture is extracted with 3 x 150 ml diethyl ether and the combined organic fractions washed with brine, dried over sodium sulfate and filtered. Evaporation in vacuo gives a yellow semi-solid product, which chromatographic on silica gel (5: 1 hexane:ether) to give 9.8 g (yield 89%) specified in the title product of example 7A.1H-NMR (300 MHz, CDCl3) : a 7.85 (1H, d, J=8,7), 7,18-7,37 (9H, m), 7,14 (1H, d, J=8,7), 7,11 (1H, s), to 4.38 (1H, DD, J= 11,6, 4,5), 4,17 (1H, DD, J=11,6, 8,4), or 3.28 (1H, DD, J= 14,0, 4,4), 2,84-2,95 (1H, m), 2,71 (1H, DD, J=14,11), 0,31 (9H, s).

B. 7-(2 the EPA 7A (of 8.28 g, 17.5 mmol) in dimethylformamide (DMF) (35 ml) is added Pd(PPh3)2Cl2(490 mg, 0.7 mmol), 3 crystal EIT and ethyl-2-iodine-5-perbenzoate (5,4 g of 19.1 mmol). The mixture is stirred at reflux for about 1.5 hours, cooled to room temperature and poured into 150 ml of a saturated aqueous solution of ammonium chloride. The mixture is extracted with 3 x 150 ml diethyl ether and the combined extracts washed with 2 x 100 ml of water, and then brine. The solution is dried over sodium sulfate, and evaporated in vacuo to obtain a yellow oil. Chromatography on silica gel (elution with 4:1 hexane:ether) barks 6,51 g specified in the title of this example 7B connection in the form of a viscous oil.1H-NMR (300 MHz, CDCl3) : of 7.95 (2H, m), 7,28-the 7.65 (9H, m), 6,92-7,22 (4H, m), 4,49 (1H, DD, J=11,6, 4,5), the 4.29 (1H, DD, J=11,6, 8,5), is 4.15 (2H, q), and 3.31 (1H, DD, J=14,0, 4,4), 2,91-2,99 (1H, m), 2,73 (1H, DD, J=14,0, 11,1), of 1.20 (3H, t).

C. 7-(2-Carboethoxy-5-fluoro-phenyl)-4-hydroxy-Z-( 4-phenyl-phenylmethyl) benzopyran

To a stirred solution of the compound of example 7B (6.60 g, 17.5 mmol) in 35 ml of methanol at room temperature is added sodium borohydride (940 mg, 26.0 mmol) at once. The dark mixture was stirred at room temperature for about 2 hours, then poured into saturated aqueous races of the solution, dried over sodium sulfate, filtered and concentrated in vacuo to obtain a yellowish oil. Chromatography on silica gel (elution with 4: 1 hexane:ether) gives first 3,26 g CIS ring isomer specified in the title of this example 7 compound, and then 1.98 g of TRANS-isomer specified in the title of this example 7 compound as a viscous oil, the total yield of 81%. CIS ring isomer:1H-NMR (300 MHz, CDCl3) : of 7.95 (1H, dt), 6,8-to 7.61 (14H, m), 4,58 (1H, t, J=7,2), 4,28 (1H, DD, J=9,1, 2,5), a 4.03 (1H, DD, J=9,1, 5,4), is 4.15 (2H, q), 2,78 (1H), 2,77 (1H, DD, J= 13,7, 6,2), 2,58 (1H, DD, J-13,7, 9,1), 2,20-2,29 (1H, m) and 1.83 (1H, d, J= 7,2), 1,1 (3H, t). TRANS ring isomer:1H-NMR (300 MHz, CDCl3) : of 7.95 (1H, dt), 6,8-7,60 (14H, m), 4,56 (1H, dt, J=4,7, 3,8), 4,12-4,19 (2H, m), 4,10 (2H, HF), 2,90 (1H, DD, J=13,6, 8,4), 2,70 (1H, DD, J=13,6, 7,2), 2,36-2,39 (1H, m) 1,75 (1H, d, J=4,7), of 1.12 (3H, t).

Below are the results of the activity in vitro of the compounds according to example 10 of the present application in the analysis of chemotaxis (examples 8 to 16, see table). For comparison, also the results for the compounds that have a structure similar to the structure of the compound from example 10, in the form of activity in the same analysis of chemotaxis. Analysis of chemotaxis is the analysis of the impact of pharmacological compounds on neutrophil chemotaxis person by chemotax is unknowne in the area of inflammation, neutrophils undergo oxidative decomposition with the release of oxygen radicals and matrix metalloprotease that entails the damaged tissue. Thus, inhibition of LTB4 reduces tissue damage. Research results:

Connection example 10:

< / BR>
Analysis of chemotaxis: IC50= 0,003 mm.

As compounds comparison tested the following compounds with the same structure:

< / BR>
IC50= 39 µm

< / BR>
IC50= 6 ám.

The above data demonstrate the difference in activity between the connection according to example 10 of the present application and close the structure of the compounds.

The difference in activity is so great that the compounds of the comparison, in essence, can be considered as inactive in relation to inhibition of LTB4. Significantly lower values IC50show that the compounds of the present invention are much more active antagonists of LTB4, than the connection of the comparison.

1. Benzopyrano or benzododecinium the compounds of formula I

< / BR>
and its pharmaceutically acceptable salt,

where A1is O, CH2;

R3is an atom Vodogray;

R5selected from the group comprising -(CH2)nCHX9X10, -(CH2)nX10and-CH(OH)X10; where n is 0 or 1;

X9is a hydrogen atom or optionally substituted phenol;

X10is a hydrogen atom, a C1-C6-alkyl, optionally substituted by phenyl which may be substituted;

R6and R7are each independently a hydrogen or C1-C4-alkyl;

R1selected from the group consisting of CIS - or TRANS- (CH2)m-CX3X4X5and substituted six-membered aromatic ring, where m is 0, and X3and X4taken together with the carbon atom to which they are attached, form a C4-C7-cycloalkyl;

X5is carboxypropyl,

and substituted six-membered aromatic ring substituted by one Deputy, selected from the group comprising carboxypropyl or-N(H)(SO2-X7and one or two substituents, where each independently selected from the group including a fluorine atom or a chlorine or C1-C4-perfluoroalkyl, where X7is-CF3;

R2represents a hydrogen atom, provided that when R3is hydroxycu is or its pharmaceutically acceptable salt, where R3is a hydroxy-group and A2is

< / BR>
3. Connection on p. 2 or its pharmaceutically acceptable salt, where R1is -(CH2)mCX3X4X5or substituted six-membered aromatic ring, substituted with one Deputy, selected from the group comprising carboxylate, or-CO-N(H)(SO2-X7), and one or two substituents, where each independently selected from the group including a fluorine atom or a chlorine or C1-C4-perfluoroalkyl.

4. Connection on p. 3 or its pharmaceutically acceptable salt, where R1is substituted phenyl, substituted by one Deputy, selected from the group comprising carboxylate, or-N(H)(SO2-X7and one or two substituents, where each independently selected from the group including a fluorine atom or a chlorine or C1-C4-perfluoroalkyl.

5. Connection on p. 4 or its pharmaceutically acceptable salt, where R4is a hydroxy-group, and R3the hydroxy-group is either CIS-or TRANS with respect to R4the hydroxy-group.

6. Connection on p. 5 or its pharmaceutically acceptable salt, where R1is phenyl, substituted by one Deputy, in which gdy independently selected from the group including a fluorine atom or a chlorine or C1-C4-perfluoroalkyl; and R3the hydroxy-group and R4the hydroxy-group are CIS with respect to each other.

7. Connection on p. 6 or its pharmaceutically acceptable salt, where R5is -(CH2)nCHX9X10where X9is a hydrogen atom and X10is optionally substituted by phenyl.

8. Connection on p. 7 or its pharmaceutically acceptable salt, where n = 1; X10is phenyl or phenyl substituted in paraprotein by phenyl.

9. Connection on p. 8 or its pharmaceutically acceptable salt, where R1is substituted phenyl, substituted by one Deputy, selected from the group comprising carboxypropyl and-N(H)(SO2-X7and one or two substituents, where each independently selected from the group including a fluorine atom or a chlorine or C1-C4-perfluoroalkyl.

10. Pharmaceutical composition for the treatment of fully4induced diseases, which contains an effective amount of the compounds under item 1 or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier or diluent.

11. Method of inhibiting the binding of PE is interested, in need of such inhibition, an effective amount of the compounds under item 1 or its pharmaceutically acceptable salt.

12. Benzopyranones and benzododecinium the compounds of formula IA

< / BR>
where A1is O, CH2;

A2does

< / BR>
R4is a hydrogen atom or a hydroxy-group;

R5selected from the group comprising -(CH2)nCHX9X10, -(CH2)nX10and-CH(OH)X10where n is 0 or 1;

X9is a hydrogen atom or optionally substituted phenyl;

X10is a hydrogen atom, a C1-C6-alkyl or optionally substituted phenyl;

R1selected from the group consisting of CIS - or TRANS -(CH2)m-CX3X4X5and substituted six-membered aromatic ring, where m is 0;

X3and X4taken together with the carbon atom to which they are attached, form a C3-C7-cycloalkyl;

X5is hydroxy or carboxypropyl, and substituted six-membered aromatic ring substituted by one Deputy, selected from the group comprising carboxypropyl, -N(H)(SO2-X7), and one or two substituents, where each nesetsja CF3;

R2represents a hydrogen atom,

provided that when R3is a hydroxy-group, and R4is a hydrogen atom, then R5is-CH(OH)X10and the compound of formula IA can not be 2-hydroxy-1-tetralone-8-carboxylic acid.

 

Same patents:

The invention relates to new substituted benzopyranones that have antiatherosclerotic and antithrombotic action

The invention relates to new benzododecinium the compounds containing pharmaceutical compositions, method of production thereof, and to a method for producing an intermediate product

The invention relates to chemical-pharmaceutical industry, namely, to new biologically active substances on the basis of which can be created drugs that have coagulation activity

The invention relates to new chemical compound, namely 3-(4-methyl-2-thiazolyl)-6-proper-7-(1-methyl-1-etoxycarbonyl)metaxia - Mona, of the formula I

< / BR>
which has analepticheskih, hypoglycemic and hypolipidemic effect

The invention relates to chemical-pharmaceutical industry, namely, to new biologically active substances on the basis of which can be created drugs with antimicrobial activity

The invention relates to chemical-pharmaceutical industry, namely to new biologically active substances on the basis of which can be created drugs with hypotensive and analepticheskih activity

The invention relates to chemical-pharmaceutical industry, namely to new biologically active substances on the basis of which can be created drugs that have anti-allergic activity

The invention relates to crystalline salts of the optically active derivative of aminocoumarin with pharmaceutical efficacy in the treatment and prevention of cerebral dysfunction associated with cerebral stroke and cranial trauma

The invention relates to a process for the catalytic methylation of 1-naphthol in the ortho-position with the formation of 2-methyl-1-naphthol and catalysts for this process

The invention relates to the field of organic synthesis, namely to obtain methylated napolov, in particular a mixture of 2-methyl-1-naphthol, 2,6-dimethyl-1-naphthol used as feedstock for the synthesis of 2-methyl-1,4-naphthoquinone - synthetic vitamin K3(menadione)

The invention relates to neuroprotective 3R*, 4S* 3-[4-(4-forfinal)-4-hydroxypiperidine-1-yl] chroman-4,7-djolu, its enantiomers and pharmaceutically acceptable salts, and pharmaceutical compositions based on them, which are effective oral agents for the treatment of diseases or conditions susceptible to treatment with drugs that block NMDA receptors, as well as to a method of blocking sites of NMDA receptors

The invention relates to pharmaceutical compounds, their preparation and use

The invention relates to medicine, refers to medicines and can be used for the treatment of gunshot and infected wounds
Up!