HU205077B - Process for produicng hydroquinone derivatives and pharmaceutical compositions comprising such compounds - Google Patents

Abstract

The present invention relates to a compound of formula I wherein R1, R2 and R3 are methyl, R4 is pyridyl, R5 is hydrogen or carboxyl, n is an integer from 0 to 5. The compounds of the present invention are prepared by: a) deprotecting a compound of formula II wherein R1, R2, R3, R4 and R5 are as defined above and R8 is methyl; ) the hydroquinone derivative of formula IV wherein R1 is as defined above for the compound of formula V wherein n is R, as defined above and X is hydroxy or acetoxy, is condensed, or c. ) reduction of the quinone derivative of formula (III) wherein R ', R2, R3, R4, R5 are n is given. The compounds of the present invention have thromboxane A2 synthase inhibitor, thromboxane A2 receptor antagonist, 5-lipoxygenase inhibiting or active oxygen strain elimination. EN 205 077 Qf-CH- (CH2) n-R5 (V) Scope of the description: 10 pages (including 2 sheets)

Description

The present invention relates to novel hydroquinone derivatives and to pharmaceutical compositions containing them. The compounds of the present invention possess at least two of thromboxane A ₁ synthetase inhibitors, thromboxane A ₂ receptor antagonists, 5-lipoxygenase inhibitors, and active oxygen strain elimination. The compounds of the present invention are thus useful in the treatment of diseases resulting from cardiac, brain, lung and kidney disorders.

A number of publications have appeared on the thromboxane _A2 synthetase (denoted TXA ₂ marking the thromboxane _A2 still another aspect herein), inhibiting the TXA ₂ receptor, the 5-lipoxygenase and active oxygen species of antagonizing, or eliminating active compounds . To compounds or compositions, however, it has not been described, of which the TXA ₂ synthetase inhibitor, a TXA ₂ -receptor antagonists of the 5-lipoxygenase inhibitor and an active oxygen species eliminating effect of two or more vasodilator.

The novel hydroquinone derivatives of the present invention exhibit two or more of the effects listed above.

The novel hydroquinone derivatives of the present invention are represented by formula (I) wherein R ¹ , R ² and R ³ are methyl,

R ⁴ is pyridyl,

^R5 is hydrogen or carboxyl, n is an integer from 0 to 5

The compounds of the invention are prepared by:

a) a compound of formula (Π): wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings given above, and

R ⁸ is a methyl group is deprotected, or

b) a hydroquinone derivative of formula IV

- wherein R ¹ is as defined above, with the compound of formula (V): wherein n is, R ⁵ is as defined above and X is a hydroxyl or acetoxy group, or

(c) a quinone derivative of formula (III)

- in the formula R ¹ , R ² , R ³ , R ⁴ , R ⁵ are as defined above, n is reduced.

The present invention further encompasses the preparation of a pharmaceutical composition comprising the hydroquinone derivatives of formula (I).

The hydroquinone derivatives of formula (I) may also exist in the form of their salts with inorganic acids such as hydrochloric acid, nitric acid or phosphoric acid and organic acids such as methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid or succinic acid.

The hydroquinone derivatives of formula (I) may be prepared from the compounds of formula (Π) by deprotection reaction (acid hydrolysis). R ⁸ is a methyl group in the formula II, the acidic catalyst is preferably hydrobromic acid and the solvent is preferably acetic acid or water. The reaction temperature is 60 ° C to 120 ° C, preferably about 80 ° C.

The foregoing compounds of formula (I) may be prepared from a hydroquinone derivative of formula (IV) wherein R ¹ is as defined above, and a compound of formula (V) wherein n is as defined above, R ⁵ is as defined above, and X represents by condensation in the presence of a hydroxyl or acetoxy group in the presence of a catalyst. The acidic condensation reaction can be carried out in the absence of a solvent or in an organic solvent in the presence of concentrated sulfuric acid, trifluoromethylsulfonic acid or fluorosulfonic acid under nitrogen or argon. The reaction solvent may be, for example, methylene chloride, 1,2-dichloroethane, benzene or toluene. The reaction temperature is 30-100 ° C, preferably 60-90 ° C. The amount of catalyst is 1.2 to 5 molar equivalents, preferably 2 to 3 times molar.

Hydroquinone derivatives of Formula I can also be readily prepared from quinone derivatives of Formula III by known methods with mild reducing agents such as sodium hydrosulfite, sodium bisulfite or sodium borohydride, or by catalytic reduction with platinum oxide or palladium. carbon in the presence of a catalyst.

The hydroquinone derivatives of formula (I) are isolated and purified in a known manner (e.g., by chromatography or crystallization).

The hydroquinone derivatives of formula (I) and the quinone derivatives of formula (III) may be converted into one another by chemical or biochemical oxidation or reduction of the hydroquinone core or quinone core. The compounds of formula (I) are generally sensitive to oxidation by oxygen or air and are thus generally converted to the corresponding stable quinone derivatives of formula (III).

Certain hydroquinone derivatives of formula (I) have an asymmetric center at the carbon atom of the side chain of the hydroquinone nucleus and are thus optically active. Accordingly, the process of the present invention includes the preparation of optically active forms and racemates of the compounds of formula (I).

The compounds of formula I improve the metabolism of polyunsaturated fatty acids (linolenic, γ-linolenic, α-linolenic, arachidonic, dihomoyl-linolenic, eicosapentaenoic) and have two or more effects on the production of fatty acid peroxides. inhibition (antioxidation), metabolites of 5-lipoxygenase system (e.g. leucotrienes, 5-hidroxieikoza-tetraenoic acid, 5-peroxy-eicosatetraenoic acid, lipoxidok) would submarket inhibition, inhibition of thromboxane synthetase _2, thromboxanes ₂ receptor antagonizing, the active elimination of oxygen strains, in addition they have very low toxicity and hardly any side effects. Thus, the compounds of formula I are useful in the treatment and prevention of diseases in mammals (mice, rats, rabbits, dogs, monkeys and humans). Such be2

EN 205,077 Β diseases such as thrombosis, ischemic diseases due to thrombosis, heart, lung, brain and kidney contraction or convulsion, stroke, nephritis, lung failure, trachea, psoriasis, inflammation, direct allergy, arteriosclerosis, hepatitis, pneumonia, immune deficiency, cardiovascular diseases (myocardial infarction, stroke, nephritis) caused by disorders of the active oxygen species in tissues, enzymes and cells, and cancer. Accordingly, the compounds are useful as antithrombotic, vasoconstrictor, anti-asthmatic, antiallergic, psoriasis, cardiac, brain and cardiovascular, nephritis, active oxygen eliminating, anticancer and arachidonate cascade control agents.

Because the compounds of this invention are less toxic, the compounds may be used alone or in pharmaceutical compositions in admixture with pharmaceutically acceptable carriers and diluents known per se (e.g., tablets, capsules (soft and microcapsules), liquid preparations, injections, or suppositories). The dosage used will depend on the route of administration, the symptoms, for example, for an adult suffering from thrombosis, the oral dosage will usually be 0.1 mg / kg to 20 mg / kg body weight, preferably about 0.2 to 10 mg / kg body weight per day. Add 3 times.

The novel hydroquinone derivatives of the present invention promote the metabolism of multifunctional unsaturated fatty acids, in particular by regulating the biosynthesis of arachidonate cascade products (inhibition of 5-lipoxygenase, inhibition of TXA ₂ synthetase, antagonization of TXA ₂ receptors, and effective drugs for the treatment of cardiac, brain, lung and kidney dysfunctions and circulatory disorders, as well as asthma and allergic diseases.

Example 1

A solution of 3-bromopyridine (10.0 g, 63.3 mmol) in ether (100 mL) was cooled to -78 ° C and a solution of n-butyllithium (40 mL, 64 mmol) in hexane (1.6 mL) was added dropwise with stirring. . After the addition was complete, the reaction mixture was stirred for 15 minutes and a solution of γ-butyrolactone (5.45 g, 63.3 mmol) in ether (15 ml) was added dropwise and the reaction mixture was stirred for an additional hour at -78 ° C to room temperature. To the reaction mixture was added aqueous ammonium chloride solution, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) and recrystallized from ethyl acetate / isopropyl ether. There was thus obtained 8.0 g (77%) of 4- (3-pyridyl) -4-oxobutanol, m.p. 36-37 ° C.

Similarly, 5- (3-pyridyl) -5-oxopentanol (71%) and 6- (3-pyridyl) -6-oxohexanol (57%) were prepared from δ-valerolactone and ε-caprolactone.

Example 2

A solution of 12.5 g (69.8 mmol) of the alcohol of Example 1 and 12.6 mL (90.7 mmol) of triethylamine in 100 mL of dimethylformamide is cooled with ice and 9.1 g (83.8 mmol) is slowly added dropwise with stirring. mmol) trimethylchlorosilane. After stirring for 30 minutes, the reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated. The residue was distilled under reduced pressure to give 13.4 g (76.4%) of 1- (3-pyridyl) -4-trimethylsilyloxybutan-1-one, mp 126-130 ° C. C.

Similarly, 1- (3-pyridyl) -5-trimethylsilyloxy-pentan-1-one, m.p. (1 mm) 134-138 ° C, and 1- (3-pyridyl) - were prepared. 6-Trimethylsilyloxyhexan-1-one, b.p. (1 mm) 140-143 ° C.

Example 3

Grignard reagent was prepared from 7.73 g (29.8 mmol) of 1-bromo-2,5-dimethoxy-3,4,6-trimethoxybenzene, 700 mg (28.8 mmol) of magnesium and 50 mL of tetrahydrofuran at 65 ° C. The resulting solution was cooled to 0 ° C and a solution of 6.0 g (23.9 mmol) of the silyl ether derivative of Reference Example 2 in 10 ml of tetrahydrofuran was added dropwise with stirring. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (magnesium sulfate) and the solvent was evaporated. To the residue was added ethanol (50 mL) and 2N hydrochloric acid (10 mL), and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and neutralized with sodium bicarbonate, and the resulting product was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was dissolved in acetic acid (80 ml), sulfuric acid (15 ml) was added and the mixture was stirred at 80 ° C for 30 minutes. After cooling, 60 g of sodium bicarbonate was carefully added, diluted with water, and the product was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution and water, dried (magnesium sulfate) and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) to give 4.09 g (43.8%) of 1-acetoxy-4- (2,5-dimethoxy-3,4,6-trimethylphenyl) ) -4- (3-pyridyl) -3-butene is obtained as an oil.

In a similar manner, 1-acetoxy-5- (2,5-dimethoxy-3,4,6-trimethylphenyl) -5- (3-pyridyl) -4-pentene and 1-acetoxy-6- (2 , 5-dimethoxy-3,4,6-trimethylphenyl) -6- (3-pyridyl) -5-hexene.

HU 205 077 B

Example 4

A solution of the butene prepared in Example 3 (1.0 g, 2.7 mmol) in acetic acid (10 ml) was catalytically reduced at 80 ° C in the presence of 0.4 g of 5% palladium / C catalyst. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, water, dried and the solvent was evaporated. The residue was purified on a silica gel column (ethyl acetate) to give 750 mg (74.6%) of 1-acetoxy-4- (2,5-dimethoxy-3,4,6-trimethylphenyl) -4- (3- pyridyl) -butane is obtained as an oil.

In a similar manner, 1-acetoxy-6- (2,5-dimethoxy-3,4,6-trimethylphenyl) -6- (3-pyridyl) hexane and 1-acetoxy-5- (2,5 -dimethoxy-3,4,6-trimethylphenyl) -5- (3-pyridyl) pentane.

Example 5

To a solution of the butane derivative of Example 4 (0.7 g, 1.88 mmol) in methanol (3 mL) was added a solution of sodium hydroxide (0.3 g, 7.50 mmol) in water (3 mL) at room temperature and the reaction stirred for 30 minutes. at room temperature and then water. The product was extracted with ethyl acetate and the extract was washed with water, dried and evaporated. The residue was purified on a silica gel short column (ethyl acetate) to give 4- (2,5-dimethoxy-3,4,6-trimethylphenyl) 4- (3-pyridyl) 0.5 g (80.5%). -1-butanol is obtained as an oil.

In a similar manner, 5- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) -5- (3-pyridyl) -1-pentanol was prepared, m.p. -dimethoxy-3,4,6-trimethylphenyl) -6- (3-pyridyl) -1-hexanol, m.p. 90-91 ° C.

Example 6

A solution of 3-bromopyridine (10.0 g, 63.3 mmol) in ether (100 mL) was cooled to -78 ° C and a solution of n-butyllithium in hexane (40 mL, 1.6 m, 64 mmol) was added dropwise. The reaction mixture was stirred for 15 minutes after the addition was complete, and a solution of 7.52 g (67.7 mmol) of heptanoic acid nitrile in 15 ml of ether was added dropwise and the reaction mixture was stirred at -78 ° C to room temperature for 1 hour. chloride solution was added and the product was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: isopropyl ether) to give 3.9 g (36%) of 3-heptanoylpyridine as an oil.

Similarly, 3-propionylpyridine and 3-pentanoylpyridine-propionitrile and valeronitrile are prepared.

Example 7

Grignard reagent was prepared from 693 mg (28.3 g atom) of magnesium, 7.6 g (29.3 mmole) of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene and tetrahydrofuran at 65 ° C. then cooled to 0 ° C and a solution of 3.75 g (21.9 mmol) of 3-heptanoylpyridine in 10 mL of tetrahydrofuran was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography (isopropyl ether) and recrystallized from hexane. 3.2 g (39%) of 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -1- (3-pyridyl) -heptanol are obtained as a suppository, m.p. 109-110 ° C.

In a similar way, 1- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) -1- (3-pyridyl) -propanol and 1- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) were prepared. -l- (3-pyridyl) pentanol.

Example 8

To a solution of the alcohol of Example 7 (2.5 g, 6.74 mmol) in acetic acid (20 mL) was added concentrated sulfuric acid (2.5 mL) and the reaction mixture was heated at 80 ° C for 1 h. After cooling, cautious potassium carbonate (6.8 g) was added, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and aqueous sodium bicarbonate, dried and the solvent was evaporated. After purification on a short silica gel column (isopropyl ether), 2.2 g (92.5%) of 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -1- (3-pyridyl) -1 -heptene.

Example 9

1.2 g (3.4 mmol) of the heptene derivative of Reference Example 8 are hydrogenated in 12 ml of acetic acid in the presence of 0.6 g of 5% Pd / C at 80 ° C. The reaction mixture was monitored by TLC. After completion of the reaction, the catalyst was filtered off, the filtrate was evaporated, ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium bicarbonate. The organic phase is dried and the solvent is evaporated. The residue was purified by silica gel column chromatography (isopropyl ether / hexane 2: 1) to give 1.1 g (91.2%) of 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -1 - ( 3-pyridyl) -heptane was obtained as an oil.

Similarly, 1- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) -1- (3-pyridyl) -propane and 1- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) - were prepared. l- (3-pyridyl) pentane.

Example 10

A solution of the butanol derivative of Example 5 (525 mg, 1.6 mmol) and triethylamine (0.33 mL, 2.4 mmol) in dichloromethane (3.5 mL) was cooled to 0 ° C and added with stirring. 15 mL (1.94 mmol) of methanesulfonyl chloride. The reaction mixture is stirred at the indicated temperature for 30 minutes, water is added and the organic phase is separated off, and the aqueous phase is extracted with dichloromethane and the extract is combined with the organic phase.

The resulting organic layer was washed with water, dried and evaporated. The residue was dissolved in dimethyl sulfoxide (5 mL), and sodium cyanide (148 mg, 2.9 mmol) was added to the resulting solution.

The mixture was stirred at 80 ° C for 2 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give 445 mg (82.5%) of 4-cyano-1- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) -1- (3-pyridyl) - butane is obtained as an oil.

Similarly, 5-cyano-1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -1- (3-pyridyl) pentane was prepared as an oil, 6-cyano-1- (2 5-dimethoxy-3,4,6-trimethyl-phenyl) -1 (3-pyridyl) -hexane as an oil and 7-cyano-1- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) - 1- (3-pyridyl) heptane as an oil.

Example 11

To a solution of the cyano derivative of Example 10 (445 mg, 1.32 mmol) in methanol (3 mL) was added a solution of sodium hydroxide (1.5 g, 37.5 mmol) in water (5 mL), and the reaction mixture was refluxed for 3 hours. The resulting reaction mixture was cooled, diluted with water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give 400 mg (85.1%) of 5- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) -5- (3-pyridyl). pentanoic acid, m.p. 82-84 ° C.

In a similar manner, 6- (2,5-dimethoxy-3,4,6-trimethyl-phenyl) -6- (3-pyridyl) -hexanoic acid was prepared, m.p. 183184 ° C. 3,4,6-trimethylphenyl) -7- (3-pyridyl) heptanoic acid as an oil and 8- (2,5-dimethyl-3,4,6-trimethylphenyl) -8- (3-pyridyl) octanoic acid as an oil.

Example 12

A solution of 1.0 g (2.82 mmol) of the heptene derivative of Example 8 in 20 mL of acetonitrile / water (1: 1) was cooled in ice and 4.1 g (7.48 mmol) of cerium ammonium was added dropwise with stirring. nitrate in 15 ml of acetonitrile / water (1: 1). The reaction mixture was stirred at the indicated temperature for 30 minutes after the addition was complete, then basified slightly with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated. The residue was chromatographed on a silica gel column (isopropyl ether) to elute 313 mg of (E) -1- (3,5,6-trimethylbenzquinon-2-yl) -1- (3-pyridyl) heptene at the top of the column. , and 395 mg of (Z) -1- (3,5,6-trimethyl-benzoquinon-2-yl) -1- (3-pyridyl) -heptene is subsequently eluted.

In a similar manner, (E), (Z) -7- (3,5,6-trimethyl-benzoquinon-2-yl) -7- (3-pyridyl) -heptanoic acid is prepared.

The physical properties of the compounds are shown in Table 12:

Table 12

The formula Formula and physical characteristic Nuclear Magnetic Resonance Spectrum, δ-values (ppm) in CDCl ₃ , TMS Internal Standard Compound of Formula (1) ^ 21 ^ 25 ^ θ2 0.83 (3H, t, J = 6.0 Hz), 1.30 (6H, m), 1.93 (3H, s), 2.00 (3H, s), 2.10 (3H, s) ), 2.20 (2H, m), 5.67 (1H, t, J = 6.0 Hz), 7.21 (1H, ddd = 7.5 and 4.5 Hz), 7.53 (1H , dt, J = 7.5 and 1.5 Hz), 8.47 (2H, m) Compound (2) C21H25 NO2 oil 0.87 (3H, t, J = 6.0 Hz), 1.30 (6H, m), 1.93 (3H, s), 2.00 (3H, s), 2.10 (3H, s) ), 2.20 (2H, s), 6.23 (1H, t, J = 6.0 Hz), 7.20 (1H, dd, J = 7.5 and 4.5 Hz), 7.52 (1H, dt, J = 7.5 and 1.5 Hz), 8.40 (1H, dd, J = 4.5 and 1.5 Hz), 8.47 (1H, d, J = 1.5 Hz) Compound of Formula (3) C21H23 NO2 oil 1.60 (4H, m), 1.97 (3H, s), 2.03 (3H, s), 2.13 (3H, s), 2.0-2.50 (4H, m), δ , 70 (0.5H, t, J = 7.5Hz), 6.27 (0.5H, t, J = 7.5Hz), 7.25 (1H, m), 7.55 (1H, m), 8.50 (3H, m)

* E denotes the isomer where the pyridine core on one carbon atom and the hydrogen atom on the other carbon on the triple substituted olefinic bond are facing in the same direction, ** Z is the isomer where said substituents are in the opposite direction, *** E + Z represents Designates a mixture of E and Z isomers.

Example 13

1,4-Dimethoxy-2,3,5-trimethyl-benzene (9.00 g, 50 mmol) was dissolved in dichloromethane (60 mL) and the solution was stirred under ice-cooling. To the resulting solution was added dichloromethylether (14.4 g, 50 x 2.5 mmol), titanium tetrachloride (13.8 mL, 50 x 2.5 mmol) dissolved in dichloromethane (30 mL) dropwise over 15 minutes. The reaction mixture was stirred for 60 minutes under ice-cooling, the ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. The resulting reaction mixture was poured onto crushed ice (about 200 g) and stirred vigorously for 30 minutes. The dichloromethane layer was washed with water (three times) and dried (magnesium sulfate), and the dichloromethane was evaporated. The residue was isopropyl ether / hex

Recrystallization from xylan (1: 1) gave 6.18 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. The mother liquor was evaporated and the residue was chromatographed on a silica gel column (60 g) (eluent isopropyl ether) to give 3.70 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde.

Yield: 9.88 g (95%), m.p. 85-86 ° C.

To a solution of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (96 g) (96 mmol) in ethanol (200 mL) was added sodium borohydride (1.8 g, 47.6 mmol) and the mixture was stirred for 30 minutes. To the reaction mixture was added salt and the product was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl ether to give 18.6 g (92.1%) of 2,5-dimethoxy-3,4,6-trimethylbenzyl alcohol, m.p. 121-122 ° C.

A solution of 16.5 g (78.5 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl alcohol in 90 ml of tetrahydrofuran was cooled to 0 ° C and 14.2 g (52.5 mmol) was added with stirring. PBr. The reaction mixture was stirred at the indicated temperature for 30 minutes, diluted with water and extracted with isopropyl ether. The extract was washed with a saturated aqueous sodium bicarbonate solution and dried, and the solvent was evaporated. The residue was crystallized from methanol to give 17.2 g (80.0%) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide, m.p. 71-72 ° C.

A solution of 15.5 g (98.1 mmol) of 3-bromopyridine in 200 mL of ethyl ether was cooled to -78 ° C and 61.3 mL (98.1 mmol) of n-butyllithium solution (1.6 mL) was added dropwise. m solution in hexane). After the addition was complete, the reaction mixture was stirred at the indicated temperature for 20 minutes and a solution of 26.8 g (98.1 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide in 100 ml of ethyl ether was added dropwise. The reaction mixture was stirred at -8 ° C to room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The extract was back-extracted with 2N hydrochloric acid and the aqueous phase was made slightly basic with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate) to give 22.8 g (85.8%) of 3- (2,5-dimethoxy-3,4,6-trimethylbenzyl) pyridine.

In a similar manner, 3 - [(2- [1,4-dimethoxy-3-methyl-naphthyl] methyl) -pyridine [2- (2-formyl-1,4-dimethoxy-3-methyl-naphthalene)] is prepared. 1,4-dimethoxy-3-methyl-naphthyl) -methanolone (m.p. 122-123 ° C) and [2- (1,4-dimethoxy-3-methyl-naphthyl)] methyl bromidone (m.p. 79-80 ° C).

Example 14 2- (3-Pyridylmethyl) -3,5,6-trimethyl-benzoquinone (1 g) was dissolved in ethyl acetate. To the resulting solution was added 10% aqueous sodium dithionite solution and the reaction mixture was shaken. The organic phase is removed and the reaction mixture is washed with water, dried and evaporated. The product was crystallized from isopropyl ether to give 2- (3-pyridylmethyl) -3,5,6-trimethylhydroquinone (0.92 g) as a crystalline material. Yield: 91.3%, m.p. 180-185 ° C.

The resulting crystals were dissolved in ethanol and a calculated amount of concentrated hydrochloric acid was added to the resulting solution. The resulting solution was evaporated to give crystals of the hydrochloride salt of 2- (3-pyridylmethyl) -3,5,6-trimethylhydroquinone, m.p. 244-247 ° C.

Example 75 A mixture of 1- (3-pyridyl) ethanol (4.0 g, 32.5 mmol), 2,3,5-trimethylhydroquinone and trifluoromethanesulfonic acid in dichloromethane (25 mL) was stirred for 20 hours under argon. -boil under reflux and then cooled. The reaction mixture was poured into ice water, washed with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was washed with water, dried and evaporated. The residue was crystallized from isopropyl ether / ethyl acetate to give 2,3,5-trimethyl-6- [1- (3-pyridyl) ethyl] -1,4-hydroquinone (4.8 g, 57.7). %). Melting point: 238-241 ° C.

NMR δ ppm (d ₆ -DMSO): 1.68 (3H, d, J = 7.0Hz), 1.98 (3H, s), 2.07 (3H, s), 2.16 (3H, s) ), 4.67 (1H, q, J = 7.0 Hz), 7.40 (2H, broad s), 7.67 (1H, dd, J = 7.8 and 5.4 Hz), 8, 30 (1H, d, J = 7.8Hz), 8.56 (1H, s), 8.72 (1H, d, J = 5.4Hz).

Example 16

7- (2,5-Dimethoxy-3,4,6-trimethyl-phenyl) -7- (3-pyridyl) -heptanoic acid (1 g, 2.6 mol) in 47% hydrobromic acid (20 ml) 12 reflux for an hour under argon. The cooled solution was neutralized with saturated aqueous sodium bicarbonate solution and the product was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was chromatographed rapidly on silica gel (ethyl acetate / ethanol 9: 1) to give 7- (2,5-dihydroxy-3,4,6-trimethyl-phenyl) -7- (3-pyridyl) -heptanoic acid (570 mg). , 61.4%) as a colorless oil.

NMR δ ppm (CDCl ₃ ): 1.10-1.45 (6H, m), 1.57 (2H, m), 2.05 (3H, s), 2.28 (2H, t, J = 7 , 6 Hz), 3.50 (3H, bs), 4.45 (1H, m), 7.15 (1H, dd, J = 7.8 and 5.0 Hz), 7.62 (1H, d, J = 7.8 Hz), 8.24 (1H, broad s), 8.33 (1H, d, J = 5.0 Hz).

Claims (2)

PATENT CLAIMS A process for the preparation of a compound of formula (I): wherein R ^1, R ² and R ³ is methyl; R ⁴ is pyridyl, ^R5 is hydrogen or carboxyl, n is an integer from 0 to 5 for the preparation, characterized in that (a) a compound of formula (II): wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings defined in the preceding paragraph; HU 205 077 Β R ⁸ is a methyl group the protecting group is removed, or b) a hydroquinone derivative of formula IV - wherein R ¹ is as defined in the parent compound with the compound of formula (V) - wherein n is 5, R ⁵ is as defined in the parent ring and X is a hydroxy or acetoxy group, or (c) a quinone derivative of formula (III) - wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ are as defined above, n is reduced to 10. 2. A process for the preparation of a thromboxane A ₂ synthetase inhibitor, a thromboxane A ₂ receptor antagonizing agent, a 5-lipoxygenase inhibitor, and an active oxygen strain eliminator comprising the steps of: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined above, converted into pharmaceutical compositions using customary pharmaceutical excipients. '.