Benzododecinium compounds, pharmaceutical compositions on their basis, the method of production thereof and method for producing the intermediate product

 

(57) Abstract:

Benzopyran and other benzododecinium antagonists leukotriene4have the formula (I) in which R1is phenyl or substituted phenyl group, and A, n, and R3are as defined in the description. The invention includes a pharmaceutical composition based on compounds of the formula I, the method of obtaining compounds of formula I and a method of obtaining an intermediate product of the formula II. 4 C. and 8 C.p. f-crystals, 3 tables.

The invention relates to new benzododecinium the compounds containing pharmaceutical compositions, method of production thereof, and to a method for producing an intermediate product. Compounds of the invention inhibit the effects of leukotriene B4(FULLY4) and therefore can be used in the treatment of diseases caused fully4for example, inflammatory diseases, including rheumatoid arthritis, osteoarthritis, inflammatory diseases of the digestive tract, psoriasis and other skin diseases, such as eczema, erythema, pruritus, acne, sudden seizures (fits) and other forms of reperfusion disorders, graft rejection, autoimmune diseases, asthma and other conditions, cog patent publications N 276064 and 292977 and treat diphenyl ethers, the benzophenone and other compounds containing two phenyl groups, and derivatives of 7-(3-alkoxy-4-alkanoyloxy)alkoxybenzenes, respectively.

In accordance with the invention it was found that the compounds of formula I possess antagonistic properties against fully4< / BR>
,

where

A denotes an oxygen atom or a group-CH2-;

R1refers to the substituent in position "b" or "c" and has the formula

,

where

R4is carboxypropyl, tetrazolyl or oxazolyl;

R10denotes a hydrogen atom or one or any two substituent selected from a fluorine atom or chlorine, C1-C6-alkyl, C1-C6-alkoxygroup or C1-C4-perfluoroalkyl;

R3is a group -(CH2)q-CHR11R12or -(CH2)q-R12,

where

q is 0, 1, 2 or 3;

R11represents a hydrogen atom, a C1-C6-alkyl, or R8- substituted phenyl, where R8denotes a hydrogen atom or one, or any two substituent selected from a fluorine atom or chlorine, C1-C6-alkyl, C1C6-alkoxygroup or C1-C4-perfluoroalkyl;

R12presented is displaced by phenyl, where R9matter listed for R8above,

or their salts or esters of such compounds of General formula I, which contain carboxypropyl, while the ester group is selected from groups containing C1-C6-alkyl, phenyl-C1-C6-alkyl, C3-C7-cycloalkyl, or phenyl or benzyl substituted by fluorine atom or chlorine, C1-C6-alkyl or C1-C6-alkoxygroup.

Inhibition of receptor binding is fully4can be done by introducing the subject in case of need of such inhibiting compounds of formula I, which is defined above.

The invention also includes a method of producing intermediates of formula II

,

where

A denotes an oxygen atom or a group-CH2-;

R1refers to the substituent in position "b" or "c" and has the formula

,

where

R10denotes a hydrogen atom or one, or any two substituent selected from a fluorine atom or chlorine, C1-C6-alkyl, C1-C6-alkoxygroup or C1-C4-perfluoroalkyl;

R3is a group -(CH2)q-CHR11R12or -(CH2)q-R12,

where

q is 0, e R8denotes a hydrogen atom or one, or any two substituent selected from a fluorine atom or chlorine, C1-C6-alkyl, C1-C6-alkoxygroup or C1-C4-perfluoroalkyl;

R12represents phenyl or naphthyl, where the specified phenyl may be substituted by phenyl, R9or R9-substituted phenyl, where R9matter listed for R8above,

or their salts,

by reacting the compounds of formula IV

,

where

R3and A described above, and a group of CF3SO3is in position "b" or "c", with the compound of the formula V

,

where

X is a chlorine atom, bromine or iodine, and R10above,

which is obtained by reacting the compounds of formula VI

,

with n-butyllithium and then ZnX2where X is specified above.

The term "C1-C6-alkyl" whenever it is used here in the description, such as definitions from R1to R14means saturated monovalent straight or branched aliphatic hydrocarbon radicals having from one to six carbon atoms, for example methyl, ethyl, propyl, tert-butyl, hexyl, etc.

Like terms C3-C7- CEC, the example accordingly cyclopropyl, cyclooctyl etc.

When in the compound of formula I, A is oxygen, the compound may be described either as 3,4-dihydrobenzofuran, or as Roman.

Compounds of the invention have two asymmetric carbon atoms marked with asterisks in the following formula

.

Stereoisomers can be described referring to R and S in accordance with standard nomenclature. When referring here to the S, R or R, S, this means one enantiomerically pure compound, while S*, R*and R*S*mean racemic mixtures and the optical isomers of the formula I.

In accordance with a specific form of the invention, intermediates of the above formula II, where R1Deputy formula III is produced by the interaction of the compounds of formula IV, which is defined above, with a compound of formula V, which is defined above. The reaction usually takes place in a solvent such as an ethereal solvent, such as tetrahydrofuran, diethyl ether, etilenglikolevye ether, 1,4-dioxane, preferably tetrahydrofuran. The reaction is carried out in the presence of a catalyst, particularly a palladium catalyst, katerynopilsky. The reaction is usually carried out at a distillation temperature of the used solvent, preferably at 78oC. the reaction Time is usually from 1 to 24 hours, for example about 3 o'clock

The compounds of formula V receive in situ from a compound of the above formula VI by reacting with n-butyllithium or second-butyllithium in hexane at temperatures below -78oC and then with ZnX2, where X is iodine, bromine or chlorine, usually at a temperature of from 0 to 78oC for 1 to 4 h

Ketones of the formula II, in which A, R4and R3are as defined with reference to formula I, can be restored to the corresponding hydroxyl compounds of the formula I by reacting with sodium borohydride. Usually the 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 the mixture vodosmeshivayuschego lower alcohols or other vodosmeshivayuschego organic solvents with water. The solvent is preferably a lower alcohol, for example methanol or ethanol. The reaction temperature is usually from -78 to 100othe crystals I, having the following structure:

.

These CIS - and TRANS-isomers can be divided conventional column chromatography.

Re-dissolution of the enantiomeric mixture, after separation of CIS - and TRANS-isomers, can be performed by methods known in this field. One of the ways the compound of formula 1, where R1carboxyl group (COOH), interacts with a chiral base such as methylbenzylamine in a polar solvent, for example ether, with the formation of diastereomeric salts, which are separated and then converted into optically pure acid by treatment with acid, for example aqueous or methanolic hydrogen chloride. According to another method, the compound of formula 1, where R1contains ether group, interacts with an optically active acid, for example, R-almond acid or N-tert-butoxycarbonyl-D-tryptophan with the formation of diastereomeric esters, which are divided into optically pure esters, for example by chromatography.

Destruction of separating the ester group and hydrolysis of the ester group of carboxylic acid in R1usually spend aqueous base, such as alkali metal hydroxide, for example sodium hydroxide, in Tampa. The reaction can be carried out in the presence of co-solvent, for example methanol, ethanol or tetrahydrofuran.

The compounds of formula 1, where R4is oxazolium, converted into the corresponding compounds of formula 1, where R4is carboxy, first by interacting with methyliodide when possible presence of dimethyl sulfoxide and then with a base, for example aqueous sodium hydroxide solution.

The compounds of formula IV, where R3is (CH2)qCHR11R12or (CH2)qR12may be obtained in accordance with reaction scheme 1 from compounds of formula VIII, where a is as defined with reference to formula 1.

The compound of formula VIII interacts with triftormetilfullerenov anhydride in a suitable solvent, such as methylene chloride, in the presence of triethylamine to form compounds of formula IX.

The group R3when it is defined as -(CH2)qCHR11R12or -(CH2)qR12you can enter in the compound of formula IX two-stage method, including interaction with the aldehyde of formula R11R12CH (CH2)qCHO or R12(CH2)q-1CHO with oblasti pyrolidine catalyst or hydrochloric acid in acetic acid. The hydrogenation is conducted with hydrogen in the presence of palladium catalyst in the usual way (scheme 1).

.

The compounds of formula VIII are generally commercially available. If not, they can be obtained by methods known in the previous field. For example, the compounds of formula VIII, where a is oxygen, can be obtained from substituted 2', 4' -dihydroxy-3-chloropropiophenone (hereinafter referred to as compound 1) by cyclization with sodium hydroxide. Compound 1 can be obtained from substituted resorcinol and 3-chloropropionic acid in the presence of acid, preferably triftormetilfullerenov acid. The compounds of formula VIII, in which a is sulfur, can similarly be obtained from substituted 4'-hydroxy-2'-sulfhydryl-3-chloropropiophenone, which can be obtained from substituted 3-hydroxythiophenol.

Group 3, when it is defined as-O(CH2)pCHR11R12or-O(CH2R12you can enter into compounds of the formula VIII according to the method outlined in scheme 11.

The compounds of formula XI can be obtained from the compounds of formula II in which R3is hydrogen, by mixing them with 20% potassium hydroxide solution and add phenyldiazoniumpR12form compounds of formula XII, which are converted into the compounds of formula XIII by hydrolysis with acid, such as hydrochloric acid. The compounds of formula XIII when recovering form the compounds of formula 1. The restoration carried out in the usual manner with sodium borohydride in an alcohol solvent at ambient temperature. The above compounds of formula IV can be converted into compounds of formula 1 in which R1is the same as defined with reference to formula 1, and R4is carboxy in accordance with reaction scheme III.

.

The compound of formula XIV is formed by reacting the compounds of formula IV with (CH3)3Sn Sn(CH3)3and a palladium catalyst, such as tetrahetarenoporphyrazines (Pd(PPd3)4or bisbenzimidazole, in the presence of a phosphine ligand such as triphenylphosphine, in an amount of from 0.5 to 5 molar equivalents per mole of the used framework. The compound of formula XIV is converted into a compound of formula XV by reacting with firosemide compound of the formula

,

in which

R10is the same as defined with reference to formula 1, R14is the result in the presence of a palladium catalyst, for example tetranitroaniline or bestretailphpi.blog palladium.

Esters of ketone of formula XV is first reduced to the corresponding hydroxyl compounds XVI (formula not shown) and then hydrolized to the corresponding acid of formula 1. In the reaction participates sodium borohydride, which was previously described when referring to the restoration of the ketones of formula II. Hydrolysis to the formation of the acid can be an aqueous solution of base, such as alkali metal hydroxide, for example sodium hydroxide, in the optional presence of co-solvent, such as methanol or ethanol at temperatures from room temperature up to the temperature of the distillation or boiling point of the used solvent.

The compounds of formula 1 in which R1is:

,

where

R10and R13are as defined above with reference to formula 1, can be obtained by reacting compounds of formula 1 in which R1is:

,

with a sulfonamide of formula R13SO2NH2in the presence of binders, for example 1,3-dicyclohexylcarbodiimide or 1-/3-(dimethylamino)propyl/-3-ethylcarbodiimide, and in the presence of an organic base, naccio carried out in a solvent, for example, tetrahydrofuran, diethyl ether, toluene and chlorobenzene at a temperature of from room temperature up to the boiling temperature used in the reaction solvent.

The compounds of formula 1 in which R4is tetrazolium can be obtained from the corresponding ether compounds of formula 1 in which R4is carboxyl-C1-C4alkylamino group (-CO2/C1-C4/alkyl). Essential connection first interacts with tributyltinchloride in the presence of an organic base such as triethylamine or pyridine, or preferably imidazole in a polar aprotic solvent, preferably dimethylformamide, to protect the hydroxyl group, which is known in this field. Protected volatile compound reacts with ammonia and three (C1-C8)alkylamines in xylene to replace carboxylating cyano group. Cyano interacts with trimethylaniline in toluene at 110oC. Transformations in tetrazolyl and removal of the silyl protective group reach through reaction with tetrabutylammonium in tetrahydrofuran to obtain the compounds of formula 1 in which R4assetcategory interaction with base such as alkali metal hydroxide, for example sodium hydroxide, or alkali earth metal hydroxide such as magnesium hydroxide. Esters of compounds 1, containing carboxypropyl, can be obtained in the usual way by reacting the acid group with a C1-C6alcohol, for example ethanol, phenyl (C1-C6) alcohol, (C3-C7-cycloalkanones, phenol, substituted by one to three groups selected from fluorine, chlorine, C1-C6-alkyl or C1-C6-alkyl or C1-C6- alkoxy.

Compounds of the invention can be assigned to a person for treatment of diseases caused by fully4various ways: orally, parenterally or locally, as well as with the use of suppositories and enemas.

In oral administration, the dose level is from 0.5 to 1000 mg/day, mostly about 5-500 mg/day, which can be given as a single dose or as three small doses, repeated at intervals of time. When administered intravenously, the dose level is about 1-500 mg/day, mostly about 1.0-100 mg/day. Intravenous administration may include continuous drip infusion. Depending on age, webest specialists in this field.

Compounds of the invention can be entered separately, but they are usually injected in a mixture with a pharmaceutical carrier selected depending on the method of administration of the medicine and standard pharmaceutical practice. For example, they can be taken orally in form of tablets containing such excipients as starch or lactose, or in separate capsules or in a mixture with excipients, or in the form of elixirs or suspensions containing tools for flavor or coloring tools. They can be administered parenterally, for example intramuscularly, intravenously or subcutaneously. When parenteral they are 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 was isotonic.

The activity of compounds of the invention in relation to fully4can be determined by comparing the ability of compounds of the invention to compete with radiolabelled fully4for competitive cell receptors fully4on the membranes of the Guinea-pig spleen. Shell spleen Guinea pigs were obtained as described by Cheng et. al. (J. Pharmacology and Experimental Therapeutics, 232:80, 1985). 0.7 nm3H - FULLY4(NEN, approximately 200 Ci (mmol) and 0.33 mg/ml membrane of Guinea-pig spleen. Added unlabeled radioactive isotope is fully4at a concentration of 5 μm in order to determine the nonspecific binding. Test compounds were added at various concentrations to evaluate their effect on binding3H IS FULLY4. The reaction was performed in a thermostat at 4oC for 30 minutes3H-FULLY4associated shell, collected by filtration through glass fiber filter, and the associated number was determined by counting the scintillations. The 1C50 value for the test compound is the concentration at which inhibit 50% of specific binding3H - FULLY4. Test data are given in table. 3. The following examples illustrate the formation of compounds of the invention.

Example 1. A. 2',4-dihydroxy-3-chloropropiophenone.

To a stirred mixture of resorcinol (200 g, 1.82 mmol) and 3-chloropropionic acid (200 g, of 1.84 mol) was added triftormetilfullerenov acid ( 1 kg) in one portion. The solution was slowly heated for 45 min up to 80oC, then cooled to room temperature for 15 min and poured into chloroform (4 l). The organic portion was slowly poured into voli brine, was dried over sodium sulfate and filtered. Upon concentration in vacuo got an orange semi-solid substance (244, 1 g) which was used crude in the next stage.

1H-NMR (300 MHz, CDCl3): 12,56 (1H, s), 7,63 (1H, d, J = 7,6 Hz), 6,37 - 6,46 (2H, m) to 3.92 (2H, t), J = 6,3 Hz), to 3.41 (2H, t, J = 6,3 Hz).

Century 7 - Hydroxybenzophenone-4.

To a cooled solution (5oC/2N sodium hydroxide (10 l) was added compound A stage (244, 1 g) in one portion. The solution was heated to room temperature over 2 h using a bath with warm water, then re-cooled to 5oC and set a pH of 2.6 M sulfuric acid (1.2 l). The mixture was extracted with 3x3,0 l ethyl acetate, washed with brine (1x2,0 l), dried over magnesium sulfate and filtered. Upon concentration in vacuo got reddish-brown solid. After grinding to a powder in hexane and filtering received 173,7 g (yield 58%) of the main product. Melting point - 136 - 137oC.

C. 7-//Trifloromethyl/hydroxy/benzopyrane-4.

To a stirred solution of compound stage B (173,7 g, 1.05 mol) in methylene chloride (3.0 l) at -78oC was added triethylamine (320 g, and 3.16 mol) and dimethylaminopyridine (2.5 g). The settlement of the offer was stirred for 30 min at -78oC, and then heated to room temperature within 2 hours, the Reaction mixture was poured into a saturated solution of ammonium chloride (2.5 l) and the layers were separated. The aqueous layer was extracted with 2x2,0 l of methylene chloride. The combined organic fractions were washed with water (1x1,0 l), dried over magnesium sulfate and filtered. Upon concentration in vacuo got a red oil. Chromatography on silica gel ( 1 kg) for elution with a mixture of hexane and ethyl acetate (8: 1) provided upon removal of solvent 211,1 g (yield 69%) of the main product. Melting point 43 - 44oC.

D. 7-//Trifloromethyl/oxy/-3-phenylethylenediamine-4.

To a stirred solution of the product of stage C (27 g, and 91.2 mmol) in 183 ml of methanol was added benzaldehyde (11,1 ml, 109 mmol), and then pyrrolidine (9.1 ml, 109 mmol).

The mixture was stirred at room temperature overnight, cooled to 0oC and filtered. The solid product once washed with 50 ml of methanol, cooled with ice, and dried in a vacuum; allocated of 35.2 g (75% yield) of the main product. The melting point of 133 to 135oC.

1H NMR (300 MHz, CDCl3):8,11 (1H, d, J = 8,7 Hz), to $ 7.91/1H,bs/, 7,40 - 7,51 (2H, m), 7.24 to 7,38 (3H, m), 6,97 (1H, dd, J = 8,7 Hz, 2,4 Hz), 6,91 (1H, d, J = 2,4 Hz2) before the termination of the absorption of hydrogen for 3 hours the Mixture was filtered through brownmillerite (trade name diatomaceous earth) to remove the palladium catalyst and subjected to chromatography on silica gel (hexane-ether); obtained 25,1 g (yield 94%) of the main product. Melting point 56 - 58oC.

1H NMR (300 MHz, CDCl3): 8,01 (1H, d, J = 8,5 Hz), 7,20 - to 7.35 (5H, m), 6,981 - of 6.96 (2H, m), 4,42 (1H, dd, J=11,6, 4,4 Hz), 4,22 (1H, dd, J=11,6 Hz, 8,7 Hz), 3,26 (1H, dd, J=14,0, 4,4 Hz), 2,90 was 3.05 (1H, dd, J=8,7 14,0 Hz.

F. 7-(Tributylstannyl)-3-phenylmethylbenzene-4-one.

To a stirred solution of compound stage E (9,20 g 25,0 mmol) in 200 ml of dioxane was added lithium chloride (3,20, 75,0 mmol), Pd(PPd3)4(to 1.15 g, 1.0 mmol), 3 crystal bottled hydroxytoluene and hexamethylditin (9.0 g, 27.5 mmol). The mixture was heated under reflux for 1.5 h, cooled to room temperature and poured into 150 ml of a saturated aqueous solution of ammonium chloride. The mixture was extracted with CH ml of diethyl ether and consolidation in vacuum led to a yellow semi-solid substances, which was subjected to chromatography on silica gel (ratio of hexane to ether 5:1) to obtain 8.90 g (yield 89%) of the main product. The melting point of 84-86oC.

1H YARM (300 MNz, CDCl3): a 7.85 (1H, d, J=8,7 Hz), 7,18-7,37 (5H, m), 7,14 (1H, d, J= 8,7 Hz), 7,11 (1H, S), to 4.38 (1H, dd, J=11,6, 4,5 Hz), 4,17 (1H, dd, J= 11,6 Hz, 8,4 Hz), or 3.28 (1H, dd, J=14,0, 4,4 Hz), 2,84-2,95 (1H, m), 2,71 (1H, dd, J=14 Hz, J=11,0 Hz), 0,31 (9H, ).

G. 7-(3-carbomethoxybiphenyl)-3-phenylmethylbenzene-4-one.

To a stirred solution of compound stage F (7.0 g, 17.5 mmol) in dimethylformamide (DMF) (35 ml) was added Pd(PPh3)2Cl2(490 ml, 0.7 mmol), 3 crystal BHT and methyl-3-iodobenzoate (5.0 g, of 19.1 mmol). The mixture was stirred at reflux distilled for 1.5 h, cooled to room temperature and poured into 150 ml of a saturated aqueous solution of ammonium chloride. The mixture was extracted with CH ml of diethyl ether, the combined extracts washed h ml of water, and then brine. The solution was dried over sodium sulfate, filtered and evaporated in vacuo to obtain a yellow oil. Chromatography on silica gel (elution with a mixture of hexane and ether in the ratio 4:1) received 6,51 g main product in the form of a viscous mass z
), 7,79 (1H, dd, J=7,6 Hz, 1,6 Hz), 7,53 (1H, t, J= 7,6 Hz), 7,22 and 7.36 (7H, m) to 4.41 (1H, dd, J=11,6, 4,5 Hz), is 4.21 (1H, dd, J=11,6, 8,5 Hz), of 3.94 (3H, S), and 3.31 (1H, dd, J=14,0, 4,4 Hz), 2,91-2,99 (1H, m), 2,73 (1H, m), 2,73 (1H, dd, J=14,0, 11,1 Hz).

H. 7-(3-carbomethoxybiphenyl)-4-hydroxy-3-phenylmethyl benzopyran.

To a stirred solution of compound stage G (6.50 g, 17.5 mmol) in 35 ml of methanol at room temperature was added sodium borohydride (940 mg, 26.0 mmol) in one portion. The mixture of dark color was stirred at room temperature for 2 h, then poured into a saturated aqueous solution of ammonium chloride (75 ml) and was extracted with CH ml of diethyl ether. The combined extracts were washed with brine, dried over sodium sulfate and concentrated in vacuum to obtain low-grade yellow oil. Chromatography on silica gel with elution with a mixture of hexane and ether with the ratio of components in the mixture 4:1 received first 3,26 g of CIS-cyclic isomer primary connection, and then 1.98 g, TRANS isomer of the compound in the form of a viscous oil, the total yield of 81%.

CIS-cyclic isomer:

1H YARM (300 MHz, CDCl3): compared to 8.26 (1H, t, J=1,7, Hz), 8,02 (1H, dt, J=7,8, 1,7 Hz), 7,76 (1H, dt, J=7,8, 1,7 Hz), 7,50 (H,t, D=7,8 Hz), 7,41 (1H, d, J= 7,9 Hz), 2,58 (1H, dd, J=13,7, 9,1 Hz), 2,20-to 2.29 (1H, m) and 1.83 (1H, d, J=7,2 Hz).

TRANS-cyclic isomer:

1H NMR (300 MHz, CDCl3): 8,23 (1H, t, J=1,7 Hz), 7,98 (1H, dt, J=7,8 Hz), 7,74 (1H, t, J=7.8 for Hz, 1,7 Hz), of 7.48 (1H, t, J=7.8 for Hz), 7,20 was 7.36 (6H, m), to 7.15 (1H, dd, J=8.0 a, 1,8 Hz) to 7.09 (1H, d, J=1,8 Hz), 4,56 (1H, dt, J= 4,7, 3,8 Hz), 4,12-4,19 (2H, m) to 3.92 (3H, S), 2,90 (1H, dd, J=13,6, 8,4 Hz), 2,70 (1H, dd, J=13,6, 7,2 Hz), a 2.36-2,39 (1H, m) 1,75 (1H, d, J=4,7 Hz).

J. N - tert-butoxycarbonyl-L-tryptophan-7-[(3-carbomethoxybiphenyl)-3-phenylmethyl]chromanol-4 ether.

To a stirred solution of compound stage H (2.5 g, 6.7 mmol) in 70 ml of CH2Cl2added DMAP (897 mg, 7,34 mmol, 1.1 equivalent) and N-tert-BOC- -tryptophan (2.4 g, 8,01 g mmol, 1.2 equivalent). The mixture was stirred at room temperature for 12 h, filtered and washed with 1M HCl and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuum. Chromatography (on silica gel with a ratio of cyclohexane to ether 3:1) has obtained 860 mg of the less polar diastereoisomer (Rf=0.3) and 700 mg of the more polar diastereoisomer (Rf=0,2).

The less polar product (3 S, 4R):

1H-YARM (300 MHz, CDCl3); 8,29 (1H, S), 8,03 (2H, d,73-3,85 (2H, m), 3,18 of 3.28 (2H, m), 2,45-2,61 (2H, m), 2,09-to 2.15 (1H, brds), 1,39 (H, S).

The more polar product (3R, 4S):

1H-NMR (300 MHz, CDCl3): of 8.25 (1H, S), 8,01 (1H, d, J = 7,8 Hz), 7,94 (1H, brds), 7,74 (1H, d, J = 8,2 Hz), 7,54 (1H, d, J = 11,9 Hz), of 7.48 (1H, t, J = 7.8 for Hz), 7,09-7,38 (H, m), to 6.95 (1H, S), 5,61 (1H, S), to 5.08 (1H, d, J = 8,2 H), 4,55-4,60 (1H, m), of 3.94 (3H, S), of 3.73 is 3.76 (2H, m), 3,22-to 3.35 (2H, m), 2,42-2,60 (2H, m), 1,90 is 1.96 (1H, m) of 1.39 (9H, S).

K. 3S,4R-7-(3-carboxyphenyl)-4-hydroxy-3-phenylmethyl-2H-1-benzopyran.

To a stirred solution of the less polar 4R, 3S-tryptophan ester stage J (840 mg, of 1.08 mmol) in 10 ml of methanol was added 10 ml of 2 M NaOH. The mixture was heated under reflux for 8 h, cooled and acidified to pH 4 with IM HCl. Turbid emulsion was extracted with 3h20 ml of ethyl acetate, then the combined organic fractions were washed with brine and dried over MgSO4. After filtration and removal of solvent in vacuo received a yellow foam. Chromatography on silica gel (ratio of ethyl acetate:hexane:acetic acid 35:75:1) received 210 mg of product.

1H NMR (300 MHzCD3CN): by 8.22 (1H, t, 1,7 Hz), of 7.97 (1H, dt, J = 7,8, 1,7 Hz), 7,87(1H, dt, J=7,8, 1,7 Hz), at 7.55 (1H, t, J = 7.8 for Hz), 7,42 (1H, d, J= 7,9 Hz),7,15-7,36 (6H, m), 7,10 (1H, d, J = 1,8 Hz), of 4.44 (1H, d, J = 4,9 Hz), 4,19 (1H, dd, J = 9,1, 2,5 Hzin methanol, melting point 210-212oC.

When the saponification is more polar 3R, 4S tryptophan ester (700 mg) obtained 3R, 4S enantiomer.

1H-NMR (300 MHzCD3CN): by 8.22 (1H, t, 1,7 Hz), of 7.97 (1H, dt, J = 7,8, 1,7 Hz), 7,87 (1H, dt, J = 7,8, 1,7 Hz), at 7.55 (1H, t, J = 7.8 for Hz), 7,42 (1H, d, J = 7,9 Hz), 7,15 and 7.36 (6H, m), 7,10 (1H, d, J = 1,8 Hz), of 4.44 (1H, d, J= 4,9 Hz), 4,19 (1H, dd, J=9,1, 2,5 Hz), of 3.97 (1H, dd, J = 9,1, 5,4 Hz), of 2.72 (1H, dd, J = 13,7, 6,2 Hz), of 2.51 (1H, dd, J = 13,7, 9,1 Hz), 2,04-of 2.20 (3H, m), []D= 11,0 when c=1.01 in methanol; melting point 209-211oC.

L. TRANS 3-phenylmethyl-4-hydroxy-7-(3-carboxyphenyl)-2H-I-benzopyran.

The saponification, both at the stage K, the TRANS-cyclic isomer stage H, received the appropriate acid.

1H-NMR (300 MHzCD3CN): by 8.22 (1H, t, 1,7 Hz), of 7.97 (1H, dt, J= 7,8, 1,7 Hz), 7,87 (1H, dt, J = 7,8, 1,7 Hz), at 7.55 (1H, t, J= 7.8 for Hz), 7,42 (1H, d, J = 7,9 Hz), 7,15 and 7.36 (6H, m), 7,10 (1H, d, J = 1,8 Hz), of 4.44 (1H, d, J = 4,9 Hz, 4,19 (1H, dd, J= 9,1, 2,5 Hz), of 3.97 (1H, dd, J= 9,1; 5,4 Hz), of 2.72 (1H, dd, J= 13,7, 6,2 Hz), of 2.51 (1H, dd, J = 13,7, 9,1 Hz), 2,04-of 2.20 (3H, m). Melting point 210-212oC.

Example 2. The following compounds in table. 1 were obtained by saponification according to example 1J. The melting point of the above is m 1J, formed 7-(4-hydroxy-3-carboxyphenyl)-4-hydroxy-3-phenylmethyl-2H-1-benzopyran having a melting point of 158-160oC (Cys) and 173-175oC (TRANS).

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

To a stirred solution of 2-(4-forfinal)-4,4-dimethyl-2-oxazoline (1.0 equivalent in tetrahydrofuran, concentration 0.5 m) at -78oC in nitrogen atmosphere was added n-utility in hexane (1.1 equivalent of 2.2 M solution). The mixture was stirred at -78oC for 1 h, then added ZnCl2(IM solution in ether, 1.1 equivalent). The mixture was heated to 10oC for 1 h to obtain 2-(4-forfinal-2-hartsink)-4,4-diethyl-2-oxazoline (not separated).

To this solution was added 7-[((trifluoromethyl)sulfonyl-oxy] 3-phenylmethylene-1-benzopyrane-4-(1.0 equivalent) and Pd(PPh3)4(0.2 equivalent). The mixture was heated under reflux (68oC) for 3 h, cooled to room temperature and poured into a solution of NH4OH. The solution was extracted 3 times with diethyl ether and the combined organic fraction was dried over magnesium sulfate. Then was carried out by filtration, removal of solvent in vacuo and column chromatography on silica gel (sootnosheniaC.

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).

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

To a stirred solution of compound from step a in THF (tetrahydrofuran) (0.1 M) at 0oC was added dropwise LiAlH4(1M in ether, 2.2 equivalents) for 10 minutes the Mixture was heated to room temperature and was stirred for 12 hours the Mixture was cooled to 0oC, extinguished Rochelle salt and filtered through infusorial earth (kieselguhr). The aqueous layer was twice extracted with ethyl acetate, the combined organic layers were washed with saline and dried over MgSO4. After filtration and removal of solvent received a yellow oil. Chromatography on silica gel obtained white solid, yield 60%. The melting temperature of 65 - 70oC (decomposition).

Calculated, %: C 75,15; H 6,07; N 3,25.

C27H26NO3F

Found: C 74,75; H Of 6.02; N 3,09.

1H-NMR (300 MNz, 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*, 4R*)methyliodide (0.5 M) at room temperature and was stirred for 24 h Methyliodide removed in vacuum, the oily solid was dissolved in CH2Cl2and the solvent was removed in vacuum. The operation was repeated to remove traces under the conditions. The solid product was dissolved in methanol (0.5 M) and added 2M NaOH (0.5 M). The mixture was heated under reflux for 5 h, cooled to room temperature and acidified to pH 1 1M HCl. The mixture was twice extracted with ethyl acetate, washed with brine and dried over MgSO4. Was carried out by filtering and removing the solvent in vacuum, and then chromatography on silica gel (ratio of methyl chloride to methanol 10:1), resulting in a received desired acid, the yield of 93%.

1H-NMR (300 MNzCD3COCD3): 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).

D1. (3S, 4R)-7/carboxy-5-forfinal/-4-hydroxy-3-phenylmethyl - 2H-1-benzopyran.

The compound from step C was dissolved in diethyl ether (0.1 M) and heated under reflux. To the solution was added dropwise S(-)methylbenzylamine (1 equivalent) in diethyl ether (0.1 M) for 10 minutes the Mixture was cooled to room temperature and was stirred for 48 hours the Precipitated salt was filtered, then the UP>oC) were placed in methylene chloride and washed 3 times with 1M HCl, then once with brine, dried over MgSO4and filtered. After removal of the solvent in vacuo and recrystallization (hexane:ether = 1:1) got white small crystals with more than 99,8% enantiomeric excess by HPLC analysis (high performance liquid chromatography).

[]2D5= +23,8, c=0.6 CHCl3, melting point 119 - 121oC.

Calculated, %:C 73,01; H Is 5.06.

C23H19O4F

Found, %: C 72,88; H 4,76.

D2. (3R, 4S/7-/2-carboxy-5-forfinal/-4-hydroxy-3-phenyl methyl-3H-1-benzopyran.

The filtrate is combined suspensions of salt stage D1 three times washed 1M HCl, once with brine and dried over MgSO4. After filtration and removal of solvent received a yellow solid. By using a similar procedure described in stage D1, and the use of R(+) methylbenzylamine obtained the desired product.

[]2D5= -23,4 (c=0.6, in CHCl3), melting point 118 - 120oC

Calculated,%: C 73,01; H Is 5.06.

C23H19O4F

Found,%: C 73,03; H 4,84.

Example 5. 2-(6-Benzyl-5-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-yl)- 4-fluoro-benzoic acid is 6-methoxy-12-tetralone (227 mmol, 40 g) and benzaldehyde (272 mmol, 27.5 ml) in 450 ml of methanol add pyrrolidine (272 mmol, 23,6 ml). The mixture is stirred at room temperature for 2 days before until TLC shows that in the mixture there is no source tetralone. The mixture was concentrated in vacuo, then dissolved in ethyl acetate, washed with four portions (parts) 10% HCl, the two portions (parts) of a saturated solution of NaHCO3and one portion (part) of the brine. The solvent is removed in vacuum and the crude oil proscout with diethyl ether, receiving 38 g of target compound of this example obtaining 1A; so pl. 100-102oC.

Analysis for C18H16O2:

calculated: 264.1146,

found: 264.1149.

B. 2-Benzyl-6-methoxy-3,4-dihydro-2H-naphthalene-1-it.

Flask for Parr hydrogenationdownload naphthalene-1-one (15 g), ethyl acetate (150 ml) and 1 g of 10% palladium-on-charcoal grill. The mixture hydronaut apparatus for shaking Parrfor 15 h under hydrogen pressure 1,406 kg/cm3. The resulting mixture was filtered through a layer (lining) of celite (Celite) and concentrated in vacuo to obtain a red oil, which was purified using flash chromatography (hexane/diethyl ether = 3:1), itano: 266.1302,

found: 266.1308.

C. 2-Benzyl-6-hydroxy-3,4-dihydro-2H-naphthalene-1-it.

To mix the solution benzylacetone (5 g, 19 mmol) in methylene chloride (40 ml) at a temperature of about -78oC add tribromide boron (1,95 ml, 21 mmol). The cooling bath removed and the reaction mixture was stirred over night at room temperature, then add an additional 1.5 ml of tribromide boron. Stirring is continued at room temperature for the next 4 hours, then poured into ice water and stirred for about 0.5 hours Water mixture is saturated 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 the vacuum lead to hard brown substance, which is purified by flash chromatography (hexane/ether = 3:2) to give 3 g of phenol; so pl. 160-162oC.

Analysis for C17H18O2:

calculated: 252.1146,

found: 252.1144.

D. 6-Benzyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-silt broadcast triftoratsetata.

To a stirred solution of phenol (2,75 g, 11 mmol), triethylamine (4,56 ml, 33 mmol) and DMAP (2 ml, 12 mmol). The cooling bath removed and the reaction mixture is heated to room temperature and stirred over night. The mixture was 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 using flash chromatography, receiving of 3.9 g of the triflate; so pl. 52-53,7oC.

Analysis for C18H15O4SF3:

calculated: 384.0638,

found: 384.0602.

E. 2-Benzyl-6-/2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5 - forfinal/-3,4 dihydro-2H-naphthalene-1-it.

To a stirred solution of n-utility (3.6 ml, 2.5 M solution 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) by addition of the pipette. The mixture is stirred at about -40oC for about 0.5 h, then heated to about -25oC and stirred for the next approximately 1 h To this mixture is added zinc chloride (9 ml, 1 M solution in diethyl ether, 9 mmol). The cooling bath removed and the mixture is heated to room temperature and stirred for about 1 h the mixture with the ol, 0,63 g) in tetrahydrofuran (15 ml). The reaction mixture is refluxed for about 22 hours, cooled to room temperature and poured onto a 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 0.1 M HCl solution saturated aqueous sodium bicarbonate and brine. 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 (diethyl ether/hexane = 2:1), receiving 2,07 g of the reaction product combinations; so pl. 114-115oC.

Analysis for C28H26NO2F:

calculated: 427,1948,

found: 427,1956.

F. 2-Benzyl-6-/2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)- 5-forfinal/-1,2,3,4-tetrahydro-naphthalene-1-ol.

To a stirred solution of tetracosactrin (1.5 g, 3.5 mmol) in methanol (35 ml) is added sodium borohydride (0.20 g, a 5.25 mmol). The mixture brown was stirred at room temperature for about 1 h, 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 HAC is/SUB>D:

calculated: 429.2087,

found: 429.2067.

G. 2-(6-Benzyl-5-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-yl)- 4-Formentera acid.

The oxazoline (1.0 g, 2.34 mmol) was dissolved in 5 ml under the conditions and stirred at room temperature for about 5 days, after which methyliodide removed in vacuum. The residue is treated with methylene chloride and concentrated to remove residual traces under the conditions. Dark red residue was dissolved in methanol (5 ml) and added 2n NaOH solution (5 ml). The resulting mixture was refluxed under stirring for about 5 hours the Mixture was then cooled to room temperature and acidified with 3n HCl solution. The resulting suspension is extracted with three portions of ethyl acetate and the combined organic phase washed with brine. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuum, obtaining 0,80 g carboxylic spartakiadi.

1H-NMR (250 MHz, methanol-d4) : 7,83 (dd, 1H, J = 7,0, 7,5); 7,50 (d, 1H, J = 7,0); 7,30-to 7.00 (m, 9H x 2); 4,50 (d, 1H, J = 2,0); to 4.41 (d, 1H, J = 8,0); 3.15 in (dd, 1H, J= 5,4, 13,9); 3,00-2,57 (m, 4H); 2,42 (dd, 1H, J= 11,4, 13,5); 2,09-1,35 (m, 5H x 2).

1. Benzododecinium compounds of General formula I

< / BR>
where A is an oxygen atom or carboxypropyl, tetrazolyl or oxazolyl;

R10is a hydrogen atom or one or any two substituent selected from a fluorine atom or chlorine, C1-C6-alkyl, C1-C6-alkoxygroup or C1-C4-perfluoroalkyl;

R3group -(CH2)q-CHR11R12or -(CH2)q-R12,

where q is 0, 1, 2 or 3;

R11is a hydrogen atom, a C1-C6-alkyl, or R8- substituted phenyl, where R8is a hydrogen atom or one, or any two substituent selected from a fluorine atom or chlorine, C1-C6-alkyl, C1-C6-alkoxygroup or C1-C4-perfluoroalkyl;

R12is a hydrogen atom, phenyl or naphthyl, where the specified phenyl may be substituted by phenyl, R9or R9-substituted phenyl, where R9matter listed for R8above,

or their salts, or esters of such compounds of General formula I, which contain carboxypropyl, while the ester group is selected from groups containing C1-C6-alkyl, phenyl-C1-C6-alkyl, C3-C7-cycloalkyl, or phenyl or benzyl substituted by fluorine atom or chlorine, C1-C6-alkyl or C1-C6-alkoxygroup.

2. Connection of on p. 1 or 2, where R1is in position "c" and denotes 2-carboxyphenyl, 2-carboxy-5-chlorophenyl, 2-carboxy-4-chlorophenyl, 2-carboxy-3-forfinal, 2-carboxy-5-forfinal, 2-carboxy-5-triptoreline, 2-carboxy-4-forfinal, 2-carboxy-6-forfinal, 2-tetrazolyl-5-forfinal or 3-carboxyphenyl.

4. The compound according to any one of paragraphs. 1 to 3, where R3and adjacent to the hydroxy-group are TransGroup.

5. Connection on p. 4, where R1- 2-carboxy-5-forfinal, and R3- benzyl.

6. Connection on p. 5, where the absolute configuration at position attached to R3there S a in position, attached to the hydroxy-group, is R.

7. Connection on p. 5, where the absolute configuration at position attached to R3there R a in position, attached to the hydroxy-group, there is s

8. Connection on p. 4, where R1- 2-carboxy-5-forfinal or 2-carboxy-4-chlorophenyl, and R3- 4-phenylbenzyl.

9. Connection on p. 1, where A is-CH2-, R1- 2-carboxy-5-forfinal and R3- 4-phenylphenoxide.

10. Pharmaceutical composition having the property of antagonist of leukotriene B4comprising the active ingredient and what it contains an effective amount of the compounds of formula I according to any one of paragraphs. 1 to 9.

11. The method of obtaining the compounds of formula I

< / BR>
where the values of A, R1and R3listed in paragraph 1,

characterized in that the restoring compound of formula XIII

< / BR>
where the values of A, R1and R3above.

12. The method of obtaining the compounds of formula II

< / BR>
where A is an oxygen atom or the group-CH2-;

R1the substituent in position "b" or "c" and has the formula

< / BR>
where R10is a hydrogen atom or one, or any two substituent selected from a fluorine atom or chlorine, C1-C6-alkyl, C1-C6-alkoxygroup or C1-C4-perfluoroalkyl;

R3group -(CH2)q-CHR11R12or -(CH2)q-R12,

where q is 0, 1, 2 or 3;

R11is a hydrogen atom, a C1-C6-alkyl, or R8- substituted phenyl, where R8is a hydrogen atom or one, or any two substituent selected from a fluorine atom or chlorine, C1-C6-alkyl, C1-C6-alkoxygroup or C1-C4-perfluoroalkyl;

R12is phenyl or naphthyl, where the specified phenyl may be substituted by phenyl, R9or R9-substituted phenyl, where R9matter listed for R8new R3and A described above, and a group of CF3SO3is in position "b" or "c,"

with the compound of the formula V

< / BR>
where

X is a chlorine atom, bromine or iodine, and R10above,

which is obtained by reacting the compounds of formula VI

< / BR>
with n-butyllithium and then ZnX2where X is specified above.

 

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