Method for synthesis of benzopyrane derivatives or theirs pharmaceutically acceptable additive salts

专利摘要:
The invention relates to the production of substituted benzopyran, in particular the preparation of compounds of the general formula I CH & CR1-CH CH-C C-CR6R5-CHR-CR3R2-0. The invention relates to a process for the preparation of new benzopyran derivatives of the general formula: where RI H, halogen, CPH N02, CN, lower alkyl, alkoxycarbonyl, alkanoyl, benzoyl (it can be substituted with halogen, MO2) or carbamoyl; R2 H, lower alkyl or phenyl; Pz H or lower alkyl; R4 RS H, or R4 - OH and RS H, or R4 and RS (together) carbon-carbon bond; Re-pyrimidinyl, quinolyl, isoquinolyl or pyridyl (they can be substituted with halogen, OH, C 1 -C 4 alkyl, NH 2 amino group, phenyl C 1 -C 4 alkylphenyl, C 1 -C 4 alkoxycarbonyl or phenyl-C- | - C4-alkoxy group and contain in position 2 N-oxide group), or their pharmaceutically acceptable salts (additive), which have a hypotensive effect. The goal is to create new, more active substances of the specified class. Synthesis is carried out by oxidation of the compound f-ly I, where instead of Re there is the group R pyrimidinyl, quinolyl, isoquinolyl or pyridyl and all the radicals indicated for Re, except for oxide nitrogen in position 2. The desired product is isolated in free form or in the form of the desired salt. New substances have a longer than known, hypotensive effect. 2 tab. where RI is a hydrogen or halogen atom, trifluoromethyl, nitro or cyano group, lower alkyl. lower alkoxycarbonyl, lower alkanoyl, benzoyl substituted by a halogen atom or a nitro group. or carbamoyl; R2 is a hydrogen atom, lower alkyl or phenyl; R3 is a hydrogen atom or lower alkyl; R4 and RS is a hydrogen atom or R4 is hydroxyl, and RS is a hydrogen atom, or R4 and RS VJ are X 4 O CO
公开号:SU1757466A3
申请号:SU884356220
申请日:1988-07-05
公开日:1992-08-23
发明作者:Ричард Эттвуд Михаел；Стефен Джоунс Филип；Редшов Сэлли
申请人:Ф.Хоффманн - Ля Рош Аг (Фирма)；
IPC主号:

专利说明:

together they represent a carbon-carbon bond;
. Re is pyrimidyl, quinolyl, isoquinolyl or pyridyl, unsubstituted or substituted by a halogen atom, hydroxy group, amino group, Ci-C4 alkyl, phenyl, Cr O-alkylphenyl, C1-C4-alkoxycarbonyl or phenyl-C1-C4-alkoxy group, or C4-alkoxycarbonyl or phenyl-C1-C4-alkoxy group, or C4-alkoxycarbonyl or phenyl - C1-C4-alkoxyl group, N-oxide group in position 2, or their salts, which have a hypotensive action.
Known derivatives of benzopyran, such as croquolin, have a hypotensive effect.
However, these compounds do not show a sufficiently high duration of action.
The purpose of the invention is to obtain new benzopyran derivatives with hypotensive activity with a longer duration of action.
The compound of formula () is obtained by oxidation of a compound of formula
where RI - RS have the indicated meanings;
Ret pyridyl, quinolyl, isoquinolyl or pyridyl, unsubstituted or substituted by a halogen atom, hydroxy group, amino group, C 1 -C 4 alkyl, phenyl, C 1 -C 4 -a - kilphenyl, C 1 -C 4 -alkoxycarbonyl or phenyl-C 1 -C 4 alkoxy a nitrogen atom in position 2 and the desired product is isolated in free form or in the form of its pharmaceutically acceptable additive salt.
Example 1.130 mg of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl} -2H-1-benzopyran was dissolved in 10 ml of dichloromethane at room temperature and 93 mg of m-chloroperbenzoic acid was added. 2 hours thin layer chromatography indicated the presence of a certain amount of starting material, after which additional (amount) m-chloroperbenzoic acid was added until the reaction was completed. The mixture was sequentially washed with sodium bisulfite solution, sodium bicarbonate solution and water, dried over sodium sulfate and evaporated, giving 105 mg -okisi-2- {3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl-pyridine as an oil.
NMR (300 MHz,): 8.36-8.30 (1 I, m.), 7.21-7.04 (4H, m.) 6.89-6.76 (3N, m). 5.36-5.25 (1H, m.), 2.46 (1H, d.d., 14Hz.6.5 Hz), 1.75 {1H,
broad m., 14 Hz), 1.44 (ЗН, s.), 1.40 (ЗН, с.), МС (EI): 255 (М +, 238 / М + -ОН).
3,4-Dihydro-2,2-dimethyl-4- (2-pyridyl) -2N-1-benzopyran, used as a starting material, was prepared as follows,
A) 43.84 g of 1-bromo-2-methylprop-1-ene in 150 ml of tetrahydrofuran was added dropwise to 9.8 g of magnesium in 50 ml of tetrahydrofuran while heating the mixture under reflux. After 1 h, the mixture was allowed to cool to room temperature, after which 47.7 g of 2-methoxyphenyl-2-pyridyl ketone in 200 ml was slowly added.
5 tetrahydrofuran. After stirring for 2 hours at room temperature, 200 ml of saturated ammonium chloride was added and the mixture was extracted with ethyl acetate. Organic extract dried
0 over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether {1: 6), followed by elution.
5 ethyl acetate / petroleum ether (1: 4), giving 36.6 g of 1- (2-methoxyphenyl) -3-methyl-1- (2-pyridyl) -2-butene-1-ol as an oil.
B) 36.6 g of 1- (2-methoxyphenyl) -3-methyl-1- (2-pyridyl) -2-butene-1-ol was heated at
0 70 ° C in 200 ml of dimethylformamide with 28.6 g of sodium methanethiol. After 10 hours, the mixture was allowed to cool to room temperature, the mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate for
0 elution to give 28.5 g (C2-hydroxyphenyl) -3-methyl-1- (2-pyridyl) -2-butene-1-ol as an oil.
C) 4.42 g of 1- (2-hydroxyphenyl) -3-methyl-1- (2-pyridyl) -2-butene-1-ol dissolved in 70
5 ml of diethylene glycol dimethyl ether and heated at 150 ° C for 2 hours. The mixture was allowed to cool to room temperature, the solvent was removed by evaporation, and the residue was distributed between ethyl acetate and sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of
5 ethyl acetate / petroleum ether (1: 4) for elution, giving 2.4 g of 2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran with mp. 80-82 ° C.
E) 6.95 g of 2,2-dimethyl-4- (2-pyridyl) -2N-1-benzopyran were dissolved in 100 ml of ethanol and shaken at room temperature with 10% palladium on carbon in
hydrogen atmosphere. After the required volume of hydrogen was taken up, the catalyst was filtered off, the filtrate was evaporated, and the residue was recrystallized from n-hexane, to give 5.07 g of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl ) -2H-1-benzopyrast.n.pl. 99-101 ° C.
Example 2. 242 mg of 3,4-dihydro-2,2-dimethyl-6-nitro-4- (2-pyridyl) -2H-1-benzopyran was dissolved in 5 ml of dichloromethane at room temperature and added 149 mg of m-chloroperbenzoic acid. After stirring at room temperature for 3 days, more m-chloro benzene benzoic acid was added until the starting material could no longer be detected by thin layer chromatography. The mixture was washed successively with a solution of sodium bisulfite, a solution of sodium bicarbonate and a solution of sodium chloride, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 4% (v / v) ethanol-dichloromethane mixture for elution, and the resulting foam was triturated with n-hexane, to give 80 mg of 2- (3,4-dihydro-2, 2-dimethyl-6-nitro-2H-1-benzopyran-4-yl) pyridin-N-xydastop. 116-119 ° C.
3,4-Dihydro-2,2-dimethyl-6-nitro-4- (2-pyridyl} -2H-1-benzopyran, used as a starting material, was prepared as follows,
1.32 g of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran was dissolved in 20 ml of acetonitrile and 0.73 g of nitronium tetrafluoroborate was added at room temperature. After 1 h, the mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with sodium chloride solution, dried over sodium sulfate and evaporated to give an oil. This oil was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 4) for elution. It turned out 245 mg of 3,4-dihydro-2,2-dimethyl-b-nitro-4- (2-pyridyl) -2H-1-benzopyran as an oil.
Example 3. 261 mg of 6-zcetyl-3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzoprane were dissolved in 20 ml of dichloromethane at room temperature and added 250 mg of m-chloroperbenzoic acid. After stirring at room temperature for 3 days, the mixture was washed successively with sodium bisulfite solution, sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The residue was chromatographed with silica gel using 2-5% (v / v) for elution methanol / chloroform. The resulting foam was treated with methylcyclohexane and the resulting solid was recrystallized with tert-butyl methyl ether to give 20 mg -2- (6-acetyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4 N-oxide -il) pyridine with so pl. 132-133 ° C.
The 6-acetyl-3.4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran- used as the starting material was prepared as follows.
1.56 g of 3,4-dihydro-2,2-dimethyl 2H-1-benzopyran-4-yl-pyridine dissolved in
5 20 ml of nitromethane at room temperature. 1.67 g of aluminum chloride and 1.11 g of acetyl chloride were added, and the mixture was stirred at 50 ° C for 1 hour. A diluted solution was added to the mixture.
0 sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic extract was washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel.
5 using for elution with a mixture of ethyl acetate / petroleum ether (1: 2) and then ethyl acetate / petroleum ether (1: 1). The residue was treated with n-hexane. giving a solid which after recrystallization
0 from tert-butyl methyl ether yielded 261 mg of 6-a cetias l-3,4-d and hy d-2,2-d-methyl-4- {2-n and riil 2H-1-benzopyran with t. square 102-105 ° C.
Example 4. 101 mg of 6-acetyl-3,4-dihydro-2.2-dimethyl-4- (3-methyl) -2-pyridyl- (2H-15 benzopyran) was dissolved in 5 ml of dichloromethane at room temperature and added 91 mg of m-chloroperbenzoic acid. After 1 h, the mixture was washed successively with a solution of bisulfite (Na 3), sodium bicarbonate solution and water. The organic extract was dried over sodium sulfate and evaporated to give an oil. The oil was treated with tert-butyl methyl ether to give a solid,
5 which, after recrystallization from ethyl acetate / tert-butyl methyl ether, gave 28 mg of 2- (6-acetyl-3,4-di-hydro-2,2-dimethyl-2H-1-benzopyran-4-yl} - N-oxide) 3-methyl pyridine with mp, 154-156 ° C.
0 As a starting material, 6-aietil-3,4-dihydro-2,2-dimethyl-4- (3-methyl-2-pyridyl) -2H-1-benzopyran was prepared as follows. A) 35.5 g of o-bromoanisole were added at
5 drops to 5.71 g of magnesium chips, coated with 50 ml of tetrahydrofuran, while heating under reflux. Fifteen minutes after the addition was complete, 14.93 g of 2-cyano-3-methylpyridine in 150 ml of tetrahydrofuran was added dropwise without
further heating. After 1 hour, diluted hydrochloric acid and ethyl acetate were added at room temperature, followed by dilution with sodium hydroxide solution to pH 14. The mixture was extracted with ethyl acetate, the organic extract was dried over sodium sulfate and then evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 2) for elution. This produced 9.81 g of 2-methoxyphenyl-3-methyl-2-pyridyl ketone in the form of a solid with mp. 98-100 ° C.
B) 9.23 g of 1-bromo-2-methylprop 1-ene was added dropwise while heating to 2.5 g of magnesium shavings, filled with tetrahydrofuran. When heated to reflux, 7.76 g of 2-methoxyphenyl-3-methyl-2-pyridyl ketone was added. After 4 hours, the mixture was allowed to cool to room temperature. A saturated ammonium chloride solution was added, and the resulting mixture was extracted with dmethyl ether. The organic extract was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 4) for the elution. This produced 5.75 g of 1- (2-methoxyphenyl) -3-methyl 1- (3-methyl-2-pyridyl) -2-butene-1-ol as an oil.
C) 7.13 g of 1- (2-methoxyphenyl) -3-methyl-1- (3-methyl-2-pyridyl) -2-butene-1-ol was dissolved in 100 ml of dimethylformamide at room temperature and added 5 , 29 g methanethiol and sodium. After stirring at 120 ° C for 2 hours, the mixture was allowed to cool to room temperature and then evaporated. Water was added to ethyl acetate, the organic phase was separated, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 4) for elution. This gave 4.53 g of 1- (2-hydroxyphenyl) -4-methyl-1- {3-methyl-2-pyridyl) -2-butei-1-ol as an oil.
E) 4.5 g of 1- {2-hydroxyphenyl) -3-methyl-1- (3-methyl-2-pyridyl) -2-butene-1-ol was dissolved in 50 ml of diethylene glycol dimethyl ether and heated at reflux temperature. for 1 hour. The mixture was allowed to cool to room temperature and then evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 2) for elution. this produced 2.97 g of 2,2-dimethyl-4- (3-methyl-2-pyridyl) -2H-1-benzopyran as an oil.
E) 2.97 g of 2,2-dimethyl-4- (3-methyl-2-pyridyl) -2H-1-benzopyran was dissolved in 50 ml of ethanol, and the mixture was shaken at room temperature under a hydrogen atmosphere.
with 10% palladium on carbon in the presence of 0.5 ml of acetic acid. After 24 hours, the catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel using a mixture of elution
ethyl acetate / petroleum ether (1: 4). 3,4-dihydro-2,2-dimethyl-4- (3-methyl-2-pyridyl) -2H-1 benzopyran (1.4 together with mixed fractions containing this substance and starting material was obtained. The described procedure was carried out using the aforementioned mixed fractions, and 675 mg of 3,4-di-hydro-2,2-dimethyl-4- (3-methyl-2-pyridyl) -2H-1-benzopyran were obtained, which was recrystallized from tert-butyl methyl ether and then melted at 100-102 ° C.
F) 712 mg of 3,4-dihydro-2,2-dimethyl-4- (3-methyl-2-pyridyl) 2H-1-benzopyrane was suspended in 100 ml of nitromethane at
room temperature. 750 mg of aluminum chloride and then 500 mg of acetyl chloride were added to the mixture. After 1 hour, sodium hydroxide solution was added at room temperature, and the mixture was extracted with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 1) as eluent. The resulting oil was treated with n-hexane. giving a solid which, after recrystallization from cyclohexane, gave 165 mg 6-acetyl-3,4-dihydro-2,2-dimethyl-4- (3-methyl-2-pyridyl} 2H-1-benzopyran
st.pl.87-88 ° C.
Example 5. 248 mg of 3,4-dihydro-2,2-dimethyl-4- (3-methyl pyridyl) -6-nitro-2H-1-benzopyran was dissolved in 20 ml of dichloromethane at room temperature and 222 mgm chloroperbenzoic acid was added. After stirring at room temperature overnight, the solution was washed successively with sodium bisulfite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate and evaporated. The resulting solid was triturated with diethyl ether, filtered and recrystallized from acetonitrile to give 133 mg 2- (3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-yl) -3-methyl β-pyridine N-oxide with so pl. 218-220 ° C.
3,4-Dihydro-2,2-dimethyl-4- (3-methyl-2-pyridyl) -6-nitro-2H-1-benzopyran. ISSSHJStSjT - 1757466
ten
V
used as a starting material, was prepared as follows.
685 mg of 3,4-dihydro-2,2-dimethyl-4- (3-methyl-2-pyridyl) -2H-1-benzopyran was dissolved in 20 ml of acetonitrile at room temperature, and 360 mg of tetrafate was added. torborat Nitroni. After 30 minutes, the solvent was removed by evaporation and ethyl acetate and water were added. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 4) to elute. 374 mg of 3,4-dihydro-2,2-dimethyl-4- (3-methyl-2-pyridyl) -6-nitro-2H-1-benzopyran was obtained in the form of a solid with m.p. 164-165 ° C after recrystallization from tert-butyl methyl ether.
Example 6. 406 mg of m-chloroperbenzoic acid were added to a solution of 524 mg of 2,2-dimethyl-4- (2-pyridyl) -2I-1-benzopyr-6-carbonitrile in 15 ml of dichloromethane at room temperature. After stirring at room temperature for 17 hours, the solution was washed with sodium bicarbonate solution. The organic phase of sulphate was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of methanol and ethyl acetate (1: 4) for elution. It turned out 240 mg of N-oxide of 2- (6-cyano-2,2-dimethyl-2H-1) benzopyran-4-yl-pyridine with so pl. 187-189 ° C after recrystallization from ethyl acetate.
2,2-Dimethyl-4- (2-p and Ridyl) -2H-1-benzopyran-6-carbonitrile, used as starting material, was prepared in accordance with Method A or B as follows.
A) 53 mg of copper iodide (I), 293 mg of triphenylphosphine and 99 mg of palladium chloride (I) were dissolved in 320 ml of diethylamine. 10.4 g of 4- (1,4-dimethyl-2-propynyloxy) benzonitrile and 11.5 g of 2-iodopyridine were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 days. Water and ethyl acetate were added, and the organic phase was separated, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (1: 3), and then a mixture of ethyl acetate and petroleum ether (1: 2) for elution, giving 12.98 g, 1-dimethyl 3- (2-pyridyl ) -2-Propynoloxy benzonitrile as an oil.
12.98 g, 1-dimethyl-3- (2-pyridyl -2-propynyloxy} benzonitrile was dissolved in 50 ml of 1,2-dichlorobenzene and heated at reflux in
for 5 hours. After cooling, the mixture was evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (1: 2), ethyl acetate and petroleum ether (1: 1), and ethyl acetate for elution. It turned out 6.5 g of 2,2-dimethyl-4- (2-pyridyl) -2N-1-benzopyran-6-kzrbonitrilast.pl. 106-108 ° C after recrystallization from cyclohexane.
C) 280 mg of N-rxide 2- {6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) pyridine was heated at -120 ° С in 3 ml acetic anhydride for 24 hours. After cooling, the mixture was evaporated, and the residue was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated. The residue was recrystallized from cyclohexane to give 181 mg of 2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile, which was used without further purification.
Example 7. 406 mg of m-chloroperbenzoic acid were added to a solution of 528 mg of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane at room temperature. After 2 hours at room temperature, the mixture was washed with sodium bicarbonate solution, and the organic phase was dried over sodium sulfate and evaporated. The residue crystallized from t-butyl methyl ether and recrystallized from toluene to give 360 mg of M-2- (6-cyano-3,4-di-hydro-2,2-dimethyl-2H-1-benzopyran-4-yl) - pioidina with so pl. 158-160 ° C.
The 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2 -2-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows.
2.96 g of 2,2-dimethyl-4- (2-pyridyl 2H-1-benzopyran-6-carbonitrile was dissolved in 100 ml of ethanol and added at room temperature to 100 mg of 10% palladium on charcoal. Shake at room temperature under nitrogen for 2 hours. The catalyst was then removed by filtration, and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 2) for elution. The result was 2.44 g 3 , 4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopran-6-carbonitrile with mp 114-115 ° C.
Example 8. 1.61 g of 2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran was dissolved in 10 ml of dichloromethane at room temperature, and 2.0 g of m-chloroperbenzoic acid was added. After 1 h, the mixture was washed with sodium bisulfite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate, ethanol and formic acid (40: 4: 1) for elution. The product was obtained as an oil, which solidified upon trituration with diethyl ether. Recrystallization from toluene yielded 0.034 g of N-oxide of 2- (2,2-dimethyl-2H-1-benzopyran-4-yl) pyoidine, m.p. 148-150 ° C.
Example 9. 330 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopran and dissolved in 10 ml of dichloromethane at room temperature, and adding Elk 280 mg of m-chloroperbenzoic acid. After stirring at room temperature for 3 days, the mixture was washed with sodium bisulfite solution, then with sodium bicarbonate solution and finally with water. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 4% (v / v) methanol / ethyl acetate for elution, to give 250 mg of N- oxide 2- {6-bromo-3,4-Dihydro-2,2-dimethyl-2H-1-benzopyran -4-yl) pyridine in the form of a foam.
NMR (300 MHz, CDS1): 8.35-8.30 (1H, m.), 7.26-7.15 (ZN, m.), 7.13-7.05 (1H, m.), 6.95 (1H, broad s.), 6.75 (1H, d., 9 Hz), 5.28 (1H, broad s.), 2.42 (1H, dl, 13 Hz. 6 Hz). 1J (1H, broad s.), 1.42 (3N, s). 1.37 PPH, p.), MS (E1): 335 (M + / B8t) ,, 333 (H + / B79), 318 (M + (B81) - OH). 316 (M + (.
6-Bromo-3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran, used as a starting material, was prepared as follows.
0.5 g of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran was dissolved in 10 ml of 3-carbon chloride at room temperature, and 0.25 ml of pi was added. - Ridin and 0.12 ml of bromine. The mixture was stirred at room temperature for 1 hour, then at 35 ° C for 1 hour, and finally at 65 ° C for 1 hour. After cooling, the mixture was washed with sodium bicarbonate solution, the aqueous washes were extracted with dichloromethane, and the combined organic the phases were washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 2% (v / v) methanol / dichloromethane mixture for elution. The product was recrystallized from t-butyl methyl ether to give 230 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-4- {2-pyridyl) -2H-1-benzopyran with mp. 134 -136 ° C.
Example 10. 402 mg of methyl 2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carboxylate were dissolved in 15 ml of dichloromethane at room temperature and 330 mg of m is added. chloroperbenzoic acid. After stirring at room temperature overnight, the mixture was washed with sodium bisulfate solution and sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 10% (v / v) methanol / ethyl acetate for elution. The product was recrystallized from t-butyl methyl ether to give 65 mg of N-oxide.
2- {6- {methoxycarbonyl) -2,2-dimethyl-2H-1-benzopyran-4-yl pyridine with so pl. 155-157 ° C.
Methyl 2,2-dimethyl-4- (2-pyridyl) -2H-1benzopyran-6-carboxylate, used as a starting material, was prepared as follows.
A) 2.2 g of 2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile were suspended in 40 ml of a 0.5 M sodium hydroxide solution and heated to reflux for 18 h. . The mixture was allowed to cool to room temperature, and then it was extracted with ethyl acetate. The aqueous phase was acidified to pH 6 with citric acid, after which a solid crystallized. This solid was filtered, washed.
diethyl ether and recrystallized from ethanol, giving 1.27 g of 2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyrene-6-carbonic acid with m.p. 238-240 ° C.
B) 0.65 g of 2,2-dimethyl-4- (2-pyridyl) -2N-1-benzopyran-b-carboxylic acid was dissolved in 10 ml of thionyl chloride and stirred at room temperature for 1 hour. The mixture was evaporated, added elk 5 ml of methanol, and the mixture again
was evaporated. The residue was partitioned between diethyl ether and an aqueous solution of sodium hydroxide. The organic phase was separated, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) to elute. The product was recrystallized from cyclohexane to give 345 mg of methyl 2,2-dimethyl-4- (2-p and riilyl) -2 H-1-benzop and 6-carboxylate ran with a melting point of 94-95 ° C.
Example 11. 313 mg of methyl 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carboxylate was dissolved in 10 ml of dichloromethane at room temperature,
and 283 mg of m-chloroperbenzoic acid was added. After stirring at room temperature for 2 hours, the mixture was washed with sodium bisulfite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using first 2% (v / v) methanol-ethyl acetate, and at the end 5% (v / v) methanol / ethyl acetate for elution. It was obtained 250 mg of 2- {3,4-dihydro-6- (methoxycarbonyl) -2,2-dimethyl-2H-1-benzopyran-4-yl pyridine N-oxide as an oil, which solidified upon grinding with diethyl alcohol. new air. After recrystallization from toluene, the product was melted at 128-130 ° C.
Methyl 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carboxylate, used as a starting material, was prepared as follows.
A) 2.44 g of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile. suspended in 100 ml of a 0.37 M sodium hydroxide solution and heated at reflux overnight. The resulting solution was extracted with ethyl acetate, and the aqueous phase was acidified with citric acid. The precipitated solid was filtered and washed with water and diethyl ether. 1.6 g of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-b-enzopyran-6-carboxylic acid with a melting point of 207-208 ° C were obtained.
B) 0.8 g3, 4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carboxylic acid was stirred at room temperature in 10 ml of thionyl chloride. The reaction was followed by flash chromatography on silica gel using a mixture of ethyl acetate, ethanol, and formic acid (40: 4: 1) for elution. After completion of the reaction, the mixture was evaporated, toluene was added, the mixture was again evaporated, toluene was added again, and the mixture was evaporated again. The residue was partitioned between dry ethyl acetate and sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated. The reaction mixture was chromatographed on silica gel using ethyl acetate and petroleum ether (1: 1) for elution, to give 430 mg of methyl 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2N-1 -benzopyran-6-k-arboxylate, which after recrystallization from cyclohexane was melted at 113-115 ° C.
Example 12. 564 mg of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carboxamide was dissolved in 20 ml of dichloromethane at room temperature,
and 540 mg of m-chloral benzoic acid was added. After stirring at room temperature overnight, the mixture was washed with sodium bisulfate solution, sodium bicarbonate solution and water. The oro panic phase was dried over sodium sulphate and evaporated to give a solid, which was recrystallized from isopropanol, to give 184 mg of N- oxide 2- (6-carbamoyl-3,4-dihydro-2,2-dimethyl-2H-15 benzopyran-4 -il) pyridine with so pl. 248-250 ° C.
3,4-Dihydro-2,2-dimeti-4- {2-pyridyl) -2H-1-benzopyran-6-carboxammd used as a starting material
0 was prepared as follows.
803 mg of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl} -2H-1-benzopyran-b-carboxylic acid was dissolved in 10 ml of thionyl chloride and stirred at room temperature for 5 hours The mixture was evaporated, the residue was dissolved in toluene, and the solution was evaporated again, the residue was treated with 0.88 ammonia, and the mixture was partitioned between ethyl acetate and sodium bicarbonate solution three. The organic phase was washed with water and sodium chloride solution, dried over sodium sulfate and evaporated The residue was recrystallized from ethanol, to give 400 mg of 3.4-dihydro-2,2-dime 5 Tyl-4- (2-pyridyl) -2N-1-benzopyran-6-carboxyamide with mp 225-227 ° C.
Example 13. Similarly to the method described in example 9, from 6-chloro-3,4-di-hydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-ben-zopyran was obtained M-oxide-2 - (b-chloro-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-y-l) pyridine as a foam.
NMR (ZOOMHz) d; 8.36-8.30 (IH, m.). 7.26-7L8 (2H, m.), 7.14-7.05 (2H, m.), 6.845 6.75 (2H, m.), 5.29 (W, broad s.), 2, 42 (N, dd, 12.5 Hz, 6 Hz), 1.76 (1H, broad s.), 1.44 (ZN.s), 1.39 (ZN, s.).
MS (EI): 289 (M + (C135)), 272 (M + (C135) -OH). 6-Chloro-3,4-dihydro-2,2-dimethyl-4- {2-n0 iridyl) -2H-1-benzopyran, used as the starting material, was prepared as follows,
1 g of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran was dissolved in 20 ml
5 carbon tetrachloride at room temperature, and 0.25 ml of pyridine and 10 ml of a 0.42 M solution of chlorine in carbon tetrachloride are added. After 30 minutes, the mixture was washed with sodium bicarbonate solution, the organic phase was separated, dried
over sodium sulfate and evaporated. The residue was chromatographed on silica gel using a 1% (v / v) mixture of methanol and dichloromethane, and then a 2% (v / v) mixture of methanol and dichloromethane for elution. The product was crystallized from tert-butyl methyl ether, giving 200 mg of b-chloro-3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran with mp. 124-125 ° C.
Example 14. In the same manner as described in the first paragraph of Example 9, 2- (2,2,6-trimethyl-2H) was obtained from 4- (2-pyridyl) -2,2,6-trimethyl-2H-1-benzoprane; -1- benzopyran-4-yl) pyridine N-oxide with so pl. 189-191 ° C after recrystallization from ethyl acetate. .
4- (2-P and rihl) -2,2, b-trimethyl-2H-1-benzopyran, used as a starting material, was prepared from 2-bromo-4-methylanisole and 2-cyanopyridine according to the method similar to that described in example 4A-D.
Example 15. According to the method described in the first paragraph of Example b, from 2,2-dimethyl-4- (2-pyridyl) -6- (trifluoromethyl) -2H-1-benzopyran, N-oxide (trifluoromethyl) was obtained -2,2-dimethyl-2 H-1-benzopyran-4-yl) pyridine with t, pl. 149-152 ° C after recrystallization from cyclohexane.
2,2-Dimethyl-4- (2-pyridyl) -6-trifluoromethyl-2H-1-benzopyran, used as a starting material, was prepared as follows.
A) 1.62 g of 4- (trifluoromethyl) phenol; 11.53 g of 2-chloro-2-methyl-3-butyne and 10 g of potassium carbonate were heated at the boil under reflux in 50 ml of acetone. After 18. 42 and 66 h, additional portions of 1.53 g-chloro-2-methyl-3-butine were added. 72 hours after the last addition, the mixture was allowed to cool to room temperature, and the mixture was partitioned between diester ether and water. The organic phase was washed with an aqueous solution of sodium hydroxide, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 5% (v / v) mixture of ethyl acetate and petroleum ether for elution. It turned out 1,8g4- (1,1-dimethyl-2-propynyloxy) trifluoromethylbenzene as a yellow oil.
B) 4- {1,1-Dimethyl-2-propynyloxy) trifluoromethylbenzene was converted to 2,2-dimethyl 4- {1-pyridyl) -6-trifluoromethyl-2H-1-benzopyran in a manner analogous to that described in Example 6 BUT.
Example 16. By the method similar to that described in the first paragraph of Example 3, from 6- (tert-butyl) -3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1- benzopyran was prepared (tert-butyl) -3,4-di-hydro-2,2-dimethyl-2H-1-benzopyran-4-yl pyridine N-oxide as a white solid with mp. 128-130 ° C after recrystallization from cyclohexane.
b tert-Butyl 3 -dihydro-dimethyl-4- (2-pyridyl) -2H-1-benzopyran, used as the starting material, was prepared in the same way as described in the last paragraph of example 3, but using pivaloyl chloride instead of acetyl chloride.
5 PRI me R 17. 94 mg of 6-benzoyl-3,4-di-g and d-ro-2,2-dimethyl-4- (2-pyr-dyl) -2 H-1-benzopyran and 52 mg of m-chloroperbenzoic acid was stirred in 15 ml of dichloromethane at room temperature until
0 according to the results of thin layer chromatography did not establish the end of the reaction. The mixture was washed successively with a solution of sodium bisulfite and a solution of sodium bicarbonate, then dried over
5 Sodium sulfate and evaporated. The residue was chromatographed on silica gel using methanol / ethyl acetate 10% v / v for elution. After rubbing the residue with diethyl ether
0 received 20 mg of 2- (6-benzoyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) pyridine N-oxide with so pl. 134-136 ° C.
The b-benzoyl-3,4-dihydro-2,2-dime5-tyl-4- (2-pyridyl) -2H-1-benzopyran used as the starting compound was prepared as follows.
264 mg of aluminum chloride were added to an ice-cooled solution of 237 mg of 3,4-dihydro-2,2-dimethyl-4- (2 pyridyl} -2H0 1-benzopyran in 6 ml of nitromethane. The mixture was stirred for 5 minutes, added 349 mg of benzoyl chloride and stirring were continued at 0 ° C for 30 minutes and at room temperature for 16 hours. The reaction mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried with sodium sulfate and evaporated. The residue was passed through a silica gel chromatography. using eluting mixture L of ethyl acetate and petroleum ether (2: 3) to yield 94 mg of 6-beneoil-3,4-dihydro-2,2-dimethyl-4- (2-pyridyl} -2 H-1-benzopyran,
5 PRI me R 18.
134 mg of 3,4-dihydro-2,2-dimethyl-6- (4-nitrobenzoyl) -4- {2-pyridyl) -2H-1-benzopyran was dissolved in 15 ml of dichloromethane and 72 mg of m-chloroperbenzoic acid was added. The mixture was stirred at room temperature.
temperature overnight. After successive washing with sodium bisulfite solution and sodium bicarbonate solution, the organic phase was dried with sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using a mixture of ethyl acetate and methanol (4: 1) for elution. The residue was recrystallized from isopropanol, resulting in 50 mg of 2- {3,4-dihydro-2,2-dime-. Tyl-BCH4-nitobenzoyl) -2H-1-benzopyran-4-yl - pyridine M-oxide with m.p. 209-211 ° C.
3,4-dihydro-2,2-dimethyl-6- (4-nitrobenzoyl) -4- (2-pyridyl) -2H-1-benzopyran, used as the starting compound, was prepared as follows.
200 mg of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-b-benzopyran was dissolved in 10 mg of nitromethane and the solution was cooled to 0 ° C under a nitrogen atmosphere. 240 mg of finely powdered aluminum chloride was added and, after stirring for 5 minutes at 0 ° C, 388 mg of 4-nitrobenzoyl chloride was added. After 16 h at room temperature, 120 mg of aluminum chloride was added and the mixture was stirred at 100 ° C for 45 minutes. After diluting with diethyl ether and washing with sodium hydroxide solution, the organic phase was dried over sodium sulfate and evaporated. The residue was recrystallized vi was treated with diethyl ether, resulting in 150 mg of 3,4-dihydro-2,2-dimethyl-b- (4-nitrobenzoyl) 4- (2-pyridyl) -2H-1-benzopyran.
Example 19. 207 mg of 3,4-dihydro-2,2-dimethyl-6- (2-iodobenzoyl) -4- (2-pyridyl) -2H-1-benzopyran was stirred in 15 ml of dichloromethane with 76 mg of m-chloroperbenzoic acid for 3 h. The mixture was successively washed with sodium bisulfite solution and sodium bicarbonate solution, the organic phase was dried with sodium sulfate and evaporated. The residue was chromatographed on silica gel using 13% (v / o) methanol / ethyl acetate for elution, resulting in recrystallization from diethyl ether gave 15 mg, 4-dihydro-2,2-dimethyl-6- (2-iodobenzene - yl) -2H-1-benzopyran-4-yl-oxy-pyridin M dast.pl. 114-120 ° C.
3,4-dihydro-2,2-dimethyl-6- (2-iodobenzoyl) -4- (2-pyridyl) -2H-1-benzopyrane was used as the starting compound as follows:
25 mg of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran was dissolved in 10 ml of nitromethane and cooled in an ice bath under a nitrogen atmosphere. 280 mg of dispersed powdered aluminum chloride was added, and then after 5 minutes 700 mg of 2-iodo-benzoyl chloride. After stirring for 30 minutes at 0 ° C and for 1 hour at
at room temperature, the mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried over sodium sulfate and evaporated. The residue was subjected to chromatographic purification
0 on silica gel using ethyl acetate / petroleum ether (1: 2) for elution. as a result, 230 mg of 3,4-dihydro-2,2-dimethyl-6- (2-iodobenzoyl) -4- (2-pyridyl) -2H-1-benzopyran was obtained.
5 Example 20. In a similar manner as described in Example 19, from 3,4-dihydro-2,2-dimethyl-6- (3-iodobenzoyl) -4- (2-pyridyl) -2H -1-benzopyran was obtained, 4 -dihydro-2,2-dimethyl-6- (3-iodobenzoyl) -2H-1-benzo 0 uran-4-yl pyridine N-oxide with mp, 128-130 ° С (from a mixture of cyclohexane / ethyl acetate).
3,4-dihydro-2,2-dimethyl-6- (3-iodobenzoyl) -4- (2-pyridyl) -2H-1-benzopyran as the starting compound used
5 was prepared in the same manner as described in the last paragraph of Example 19, using 3-iodobenzoyl chloride instead of 2-iodobenzoyl chloride.
Example 21. In the same way as
0 is described in the first paragraph of Example 19, from 3,4-dihydro-2,2-dimethyl-6- (4-iodobenzoyl) -4- (2-pyridyl) -2H-1-benzopyran was obtained, 4-dihydro-2, 2-dimethyl-6- (4-iodobenzoyl} -2H-1-benzopyran-4-yl pyridine N-oxide with
5 m.p. 171-173 ° C (from these l acetate).
3,4-dihydro-2,2-dimethyl-6- (4-iodo-benzoyl) -4- (2-pyridyl) -2H-1-benzopyran compound used as the starting material was prepared in the same way as described in
0 the last paragraph of Example 19, using 4-iodobenzoyl chloride instead of 2-iodobenzoyl chloride.
Example 22. In the same way as described in the first paragraph of Example 6, from 25 ethyl-2-methyl-4- (2-pyridyl) -2H-1-benzopyr-6-carbonitrile, 2- {6-cyano-2 - ethyl-2-methyl-2H-1-benzopyran-4-yl) pyridine is an N-oxide with a melting point of 129-131 ° C (from ethyl acetate / petroleum ether).
0 2-ethyl-2-methyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile used as the starting compound was prepared as follows.
A) 17.46 g of 2-chloro-2-methylpent-1-ene to 5 Bavili to a mixture of 11.9 g of 4-cyanophenol, 6.0 g of sodium hydroxide, 15 ml of 40% methanol solution of benzyltrimethylammonium hydroxide in 85 ml of water and 85 ml of dichloromethane and stirred for 4 days. The organic phase was separated, washed with 2M sodium hydroxide solution, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 9) for the elution to give 10.1 g of 4- (1-ethyl-1-methyl-2-propynloxy) benzonitrile.
C) 4- (1-ethyl-1-methyl-2-propynyl-si) benzonitrile was converted to 2-ethyl-2-methyl-4- (2-pyridyl) -2H-6 benzopyran-6-carbonitrile, in a similar way as described in example 6 A.
Example 23. In the same way as described in the first paragraph of Example 4, 2- (6-acetyl-2-methyl) was obtained from 6-adethyl-2-methyl-4- (2-pyridyl) -2H-1-beisopirane 2H-1-benzopyran-4-yl) pyridine N-oxide with so pl. 170-172 ° C (istoluene).
The 6-acetyl-2-methyl-4- (2-pyrmdyl) -2H-1-benzopyran used as the starting compound was obtained from 1-bromo-2-methylprop-1-ene and 2-methoxyphenyl-2-pyridyl ketone. in the same way as described in example 1 A - D.
Example 24. 152 mg of 4- (b-chloro-2-pyridyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopran-6-carbonitriles and 136 mg of m-chloroedobenzoic the acids were boiled (in a flask with reflux) in 15 ml of chloroform. After 10 and 20 hours, add co. 80 and 50 mg of m-chloroperbenzoic acid are responsible. After 30 hours, the mixture was cooled to room temperature, successively washed with sodium bisulfite solution and sodium bicarbonate solution, dried with sodium sulfate and evaporated. The residue was purified by chromatography on silica gel, using ethyl acetate to elute, resulting in a solid residue, after trituration with n-hexane, which was recrystallized from acetone. Thus, 33 mg of 2-chloro-6- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) pyridine M-hydroxide was obtained. 195-196 ° C.
The 4- {6-chloro-2-pyridyl} -3,4-dmhydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows.
1 g of 2- {6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) pyridine M-oxide was dissolved in 15 ml of phosphorus oxychloride, heated at 80 ° C for 2 h, and then during nbchi cooled to room temperature. The phosphorus oxychloride was removed under vacuum, and the residue was treated with sodium bicarbonate solution and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate, and the combined ethyl acetate solutions were dried over sulfate.
rub and evaporated. The residue was passed through a silica gel chromatography column. In the elution with ethyl acetate / petroleum ether (1: 4), 271 mg of 4- (6-chloro-2-pyridyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonite- After eluting with ethyl acetate / petroleum ether (1: 2), 170 mg of 4- {4-chloro-2-pyridyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran- 6-carbonitrile.
Example 25. 79 m g of 4- (4-chloro-2-pyrimyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopira-i-6-carbonitrile was dissolved in 10 mm dichloromethane and 70 mg of m-chloroperbenzoic acid. The mixture was stirred at room temperature for three days, then sequentially washed with sodium bisulfite solution, sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using a 1% (v / v) methanol / ethyl acetate mixture for elution, and a residue was obtained after treatment with diethyl ether, which was recrystallized from ethyl acetate / petroleum ether. Thus, 20 mg of 4-chloro-2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyridine-4-yl) pyridine N-oxide was obtained with m. square 173-174 ° C.
Example 26. 406 mg of m-chloroperbenzoic acid were added to a solution of 554 mg of 4- (6-amino-2-pyrmdyl) -2,2-dimethyl-2H-1-5-e nzopyran-b-carbonitrile a in 10 ml chloromethane and the mixture was stirred for 3 hours. The mixture was then washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using for elution, methanol / ethyl acetate (1: 4), resulting in a solid residue, which was treated with dichloromethane and recrystallized from isopropanol. Thus, 130 mg of 2-amino-6- (6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) pyridine N-hydroxide mp. 241-242 ° C.
4- (b-amino-2-pyridyl) -2,2-dimethyl l-2H-1-benzo-pyran-6-carboxy nitrile was used as starting compound 4- (1,1-dimethyl -2-propynyloxy) benzonitrile and 2-amino-6-iodopyridine in the same way as described in Example 6A,
Example 27. In the same way as described in the first paragraph of Example 8, 2- from 4- (6-amino-2-pyridyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitriles was obtained -amino-b- (6-cyano-3,4-dihydro-2.2-dimet
yl-2H-1-benzopyran-4-yl) pyridine N-oxide with t, pl. 210-212 ° C (from isopropanol).
4- (6-amino-2-pyridyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile obtained from 4- (6-amino- 2-pyridyl) - 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile in the same way as described in the last paragraph of example 7.
Example 28.406 mg of m-chloroperbenzoic acid was added to a solution of 552 mg of 2,2-dimethyl-4- (4-methyl-2-pyridyl) -2H-1-b-penzopyran-6-carbonitrile in 20 ml of dichloromethane and the mixture was stirred for 1 hour. Sequentially, the mixture was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using methanol / ethylenedetate (1: 4) for the elution. After recrystallization from ethyl acetate, 140 mg of 2- (6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) -4-methyl pyridine N-oxide was obtained with m.p. 199 - 201 ° C.
The 2,2-dimethyl-4- (4-methyl-2-pyridyl) -2H-1-benzopyran-6-carbonitrile used as the starting compound was obtained from 2-iodo-4-methylpyridine and 4- (1,1 -dimethyl-2-propynyloxy) benzonitrile in the same way as described in example 6 A.
Example 29. In the same way as described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4- (4-methyl-2-pyridyl) 2H-1-benzopyran-6-carbonitrile, 2- ( 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1 -be nzopyran-4-yl) -4-methyl l-pyridine N-oxide with mp, 156-159 ° С (from diethyl ether ).
3,4-dihydro-2,2-dimethyl-4- (4-methyl-2-pyridyl) -2H-1-benzopyran-6-carbonitrile was used as the starting compound from 2,2-dimethyl 4- (4-methyl-2-pyridyl) -2H-1-benzopyran-6-carbonitrile in the same way as described in the last paragraph of Example 7.
Example 30.1 g of 2,2-dimethyl-4- (5-methyl-2-pyridyl) -2H-1-benzopyran-6-carbonitrile and 0.62 g of m-chloroperbenzoic acid were dissolved in 30 ml of dichloromethane and the mixture stirred at room temperature for 3 hours. The mixture was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column; using a 20% (v / v) methanol / ethyl acetate mixture to elute, resulting in 280 mg of 2- (6-cisno-2,2-dimethyl) obtained after recrystallization from ethyl acetate
five
0
five
0
five
0
five
0
five
2H-1-benzopyran-4-yl) -5-methylpyridine N-oxide with so pl. 151-154 ° C.
The 2,2-dimethyl-4- (5-methyl-2-pyridium l) -2H-1-benzopyran-6-carbonitrile used as the starting compound was obtained from 2-iodo-5-methylpyridine and 4- (1,1- dimetl-2-lopinyloxy) benzonitrile in the same way as described in example 6 A,
Example 31. In the same way as described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4- (5-methyl-2-pyridyl) -2H-1-benzopyran-6-carbonitrile, 2 - {6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-be nzopyran-4-yl) -5-methylpyridine N-oxide with so pl. 151-153 ° C (from ethyl acetate and cyclohexane).
3,4-dihydro-2,2-dimethyl-4- (5-methy-l-2-pyridyl) -2H-1-benzopyran-6-carbonitrile used as the starting compound was obtained from 2,2-dimethyl-4-5 -methyl-2-pyridyl) -2H-1-benzopyrene-6-carbonitrile in the same way as described in the last paragraph of Example 7.
Example 32. 237 mg of methyl 6- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-bezopyran-4-yl) -3-pyridinecarboxy-ata was dissolved in 30 ml of dichloromethane and 180 mg was added m - chloroperbenzoic acid. The mixture was stirred at room temperature overnight, and then sequentially washed with a solution of sodium bisulfite, sodium bicarbonate and water, dried over sodium sulfate and evaporated. The resulting oily residue was treated with diethyl ether to give a solid which was recrystallized from t-buty methyl ether. Thus, 60 mg of 2- (6-cyano-3,4-di hydro-2,2-dimethyl-2H-1 -6-enzopyran-4-yl) -5- {methoxycarbonyl) pyridine N-oxide was obtained from m.p. 135 137 ° C.
The 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) -3-pyridinecarboxylate used as starting compound 6 was prepared as follows.
A) 11 g of 2-iodopyridin-5-carboxylic acid was suspended in 300 ml of dichloromethane and 4.8 g of benzyl alcohol, 10 g of dicyclohexylcarbodiimide and 100 mg of 4-dimethylaminopyridine were added. The mixture was stirred at room temperature and filtered after 2 hours. The filtrate was evaporated, and the residue was passed through a silica gel chromatography column, using first an ethyl acetate / petroleum ether (1: 9) mixture for elution, and then an ethyl acetate / petroleum ether mixture (1: 6). Thus, 12.2 g of benzyl 2-iodopyridine-5-carboxylate was obtained, which was used without further purification.
B) 12.2 g of benzyl 2-iodopyridine-5-carboxylate and 5.64 g of 4- {1,1-dimethyl-2-propynyloxy) 6 benzonitrile were mixed with 32 mg of copper (I) iodide, 162 mg of triphenylphosphine and 180 mS of palladium (I) chloride in 280 ml of diethylamine at room temperature for 7 days under a nitrogen atmosphere. The mixture was evaporated and the residue was treated with ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using ethyl acetate / petroleum ether (1: 4) for elution. So got 9.04
g benzyl 2- 3- {4-cyanophenoxy) -3-methyl-1-butyl-1 -yl} pyridine-5-carboxylates, which was used without further purification.
C) 9 g of benzyl (4-cyanophenoxy) -3-methyl-1-butyn-1-yl pyridine-5-carboxylate was dissolved in 300 ml of 1,2-dichlorobenzene and the solution was added dropwise over 5 hours
to 100 ml of boiling 1,2-dichlorobenzene. After another 2 h, the mixture was allowed to cool to room temperature, and then evaporated. The residue was passed through a silica gel chromatography column using ethyl acetate / petroleum ether (1: 9), (1: 6) and (1: 4) for the elution. Thus, 5.5 g of benzyl 6- {6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) -3-pyridine carboxylate was obtained, which was used without further purification.
D) 5.06 g of benzyl b- (6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl} -3-pmridinecarboxylate was heated at 100 ° C with 7.8 ml of tributylamine, 244 mg 10% palladium on activated carbon and 0.9 ml of formic acid. After 12 hours, another 7.8 ml of tributylamine and 10 ml of formic acid were added. After 24 hours, another 2 ml of tributylamine and 3 ml of formic acid were added. another 170 mg of 10% palladium on activated carbon, 2 ml of tributylamine and 3 ml of formic acid. After 28 hours, the mixture was evaporated and filtered. The filtrate was evaporated and the resulting residue was passed through chromatography silica gel column using ethyl acetate / petroleum ether (1: 2) and ethyl acetate for elution. Thus obtained 1.4 g of 6- {6-cyano-2,2-dimethyl-2H-1-benzopyran-4 -yl) -3-pyridinecarboxylic acid, which was used without any additional cleaning.
E) 1.4 g of 6- (6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) -3-pyridinecarboxylic acid was dissolved in 200 ml of ethyl acetate and shaken overnight under a hydrogen atmosphere with 103 mg 10% palladium
activated carbon. The mixture was filtered and the filtrate was evaporated. Thus, 680 mg of 6- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) -3-pyridinecarbonic acid was obtained, which was used without further purification.
F) 300 mg of 6- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) -3-pyridine-arboxylic acid in 10 ml of methanol was treated with ethereal solution of diazomethane until yellow staining appears. The yellow color disappeared when acetic acid was added dropwise, then the mixture was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated, and as a result, after recrystallization from t-butyl methyl ether, 270 mg of methyl 6- (6-cyano-3,4-dihydro-2,2- dimethyl-2H-1-benzopyran-4-yl) -3-p-iridinecarboxylate with so pl. 131-133 ° C.
Example 33.1 g4- {5-amino-2-pyridyl) -2,2-dimet wi-2 H-1-benzopyran-6-carbonitrile was dissolved in 15 ml of dichloromethane and 1 g of m-chloroperbenzoic acid was added. After stirring at room temperature for 1 h, another 0.5 g of m-chloroperbenzoic acid was added. After stirring at room temperature overnight, the mixture was washed successively with sodium bisulfite solution, sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The residue was run through a silica gel column chromatography, using first a 10% (v / v) methanol / ethyl acetate mixture, and then a 20% (o / o) methanol / ethyl acetate 5-amino-2- (6- cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) -pyridine was converted into the hydrochloric acid salt, which was recrystallized from isopropanol. Thus, 238 mg of 5-amino-2- (6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) p iridium N-hydrochloride was obtained with a mp. 235-237 ° C.
The 4- (5-emino-2-pyridyl) -2,2-dime-Tyl-2H-1-benzopyran-6-carbonitrile used as the starting compound was prepared as follows.
A) 2,2-Dimethyl-4- (5-nitro-2-pyridyl) -2M 1-benzopyran-6-carbonitrile was obtained from 4- (1,1-dimethyl-2-propynyloxy) benzonitrile and 2-iodo 5-nitropyridine in the same way as described in example b A.
B) 1.91 g of 2,2-dimethyl-4- (5-nitro-2-pyridyl) -2H-1-benzopyran-b-carbonitrile was dissolved in 25 ml of acetic acid and 25 ml of water and 1.3 were added. g of iron powder After stirring at 100 ° C for 1 h, the mixture was poured into 2 M
The sodium hydroxide solution and the resulting mixture were extracted with ethyl acetate. The organic phase was filtered and the filtrate was dried with sodium sulfate, evaporated and obtained after trituration with diethyl ether600 mg
4- (5-amino-2-pyridyl) -2,2-dmemethyl-2H-1-b-enzopyran-6-carbonitrile, which was used without further purification.
Example 34. In the same way as described in the first paragraph of example 7 from 4- (5-aa but-2-p-iri dil) -3,4-di hydro-2,2-dimethyl-2H-1-benzopyran-6 -carbonitrile, 5-amino-2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) pyridine N-oxide was obtained with m.p. 218-220 ° C (from acetonitrile).
The 4- {5-amino-2-pyridyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile used as the starting compound was prepared from 2,2-dimethyl- 4- (5-nitro-2-pyridyl) -2H-1-benzopyran-b-carbonitrile-yl in the same way as described in the last paragraph of Example 7.
Example 35. 400 mg of 4- (5-hydroxy-2-pyridyl) -2,2-dimethyl-2H-1-benzopyran-b-carbonitrile and 350 mg of m-chloroperbenzoic acid were stirred in 100 ml overnight dichloromethane. The mixture was washed successively with a solution of sodium bisulfite, a solution of sodium bicarbonate and water, dried over sodium sulfate and evaporated. The residue was passed through a silica gel column chromatography using 10% (v / v) methanol / ethyl acetate for aluminization. Thus, 30 mg of 2 (6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) -5-hydroxypyridine N-oxide with a melting point of 260-262 ° C (from ethanol) was obtained
The 4- (5-hydroxy-2-pyridyl) -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile used as the starting compound was prepared as follows.
1.62 g of 4- (5-amino-2-pyridyl) -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile was suspended in 12 ml of concentrated hydrochloric acid, 30 g of ice and 18 ml of N- methyl pyrrolidone. The mixture was cooled to -5 ° C and 0.44 g of sodium nitrite in 5 ml of water was added dropwise while maintaining the temperature below 0 ° C. After the introduction of the reactants was completed, the mixture was allowed to warm to room temperature and then heated at 40 ° C for 1 hour. The mixture was extracted with ethyl acetate and the extract was evaporated, the residue was treated with diethyl ether and water, the organic phase was separated and washed with water, dried with sodium sulfate and boiled over. The residue was passed through a silica gel chromatography column using an elution mixture for eluting.
ethyl acetate / petroleum ether (1: 1) and ethyl acetate, resulting in 270 mg of 4- (5-chl o-p-2-p and ri dyl) -2,2-dimethyl-2 H-1-benzoate. zopyram-5-carbonitrile and 254 mg of 4- (5-hydroxy-2-pyridyl) -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile.
Example 36. In the same way as described in the first paragraph of Example 35, from 4- (5-chloro-2-pyrmdyl) -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile, 5-chloro-2 was obtained (6-cyano-2,2-dimethyl-2 H-1-benzene aira n-4-yl) pyridine N-oxide a in the form of oil.
NMR (300 MHz,) d; 8.30 (IH. Broad s.); 7.35 (N, dd 10 Hz, 2 Hz); 7.29 (IH, dd, 9 Hz, 2 Hz); 7.22 (IH, D .. 10 Hz); 6.8T0N, d, 2 Hz); 6.83 OH, d., 10 Hz); 5.82 (1H, p.); 1.47 (6H, s,).
MS (El): 3.12 (H (C135)).
Example 37. In the same way as described in the first paragraph of Example 35, from 4- (5-chloro 2-pyridyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile was obtained 5-chloro-2- (6-cyano-3,4-dmhydro-2,2-dimethyl-2H-1 -be n-sol and ran-4-and l) n iridium N-oxide with mp . 159-161 ° C (from ethanol).
The 4- (5-chloro-2-pyridyl) -3.4-dihydro-2,2-dimethyl-2H-1-benZopyran-6-carbonitroyl, used as the starting compound, was obtained by catalytic hydrogenation of 2,2-dimethyl-4- ( 5-nitro-2-pyridyl) -2H-1-benzopiran-6-carbonitrile in the same way as described in the last paragraph of example 7, and then by treatment of the resulting 4- {5-amino-2-pyridyl) -3 , 4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile according to the procedure described in the last paragraph of Example 35.
Example 38. In the same way as described in the first paragraph of Example 6, from 2.2-dimethyl-4- (5-phenyl-2-pyridyl) -2H-1-benzopyran-6-carbonitrile, 2- {b-cyano- 2,2-dimethyl-2H-1-benzopyran-4-yl) -5-fen-ylpyridine N-oxide with m.p. 173-175 ° C (from ethyl acetate).
The 2,2-dimethyl-4- (5-phenyl-2-pyridyl) -2H-1-benzopyran-b-carbonitrile used as the starting compound was prepared as follows.
A) 15.98 g of 2-chloro-5-phenylpyridine was dissolved in 150 ml of 55% aqueous hydroiodic acid and the solution was heated for 2 hours. A precipitate formed on cooling, which was filtered and washed with water. The residue was treated with dimethyl ether and 2M sodium hydroxide solution, the organic phase was dried with sodium sulfate and evaporated, resulting in 15.87 g of 2-iodo-5-phenylpyridine, which was used without further purification.
B) In the same way as described in Example 6 A and B, from 2-iodo-5-phenylpyridine and
2,2- dimethyl-4- {5-phenyl-2-pyridyl) -2H-1-benzopyran-b-carbonitrile, 4- (1,1-dimethyl-2-propynyloxy) benzonitr yl,
Example 39 In the same way as described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4- (5-phenyl-2-pyridyl) -2H -1 - benzopyran-6-carbonitrile was prepared
2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-5-enzopyran-4-yl) -5-phenylpyridine N-oxide with m.p. 174-176 ° C (from ethyl acetate).
The 3,4-dihydro-2,2-dimethyl-4- (5-phenyl-2-pyridyl) -2H-1-benzopyran 6-carbonitrile used as the starting compound was obtained by catalytic hydrogenation of 2,2-dimethyl 4- (5-phenyl-2-pyridyl} -2H-1-benzopyran-6-carbonitrile in the same way as described in the last paragraph of Example 7.
Example 40 In the same way as described in the first paragraph of Example 3, 2- (6-acetyl-2, from b-acetyl-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran was obtained from 2-dimethyl- 2H-1-benzopyran-4-yl) pyridine oxide with m.p. 165-167 ° C (from distil ether).
Used as the starting compound, 6-acetyl-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran was prepared as 2,2-dimethyl-4- (2-pyridyl) -2H 1 -benzopyra on the same way as described in the last paragraph of example 3.
Example 41. In the same way as described in the first paragraph of Example b, 2- (6-bromo-2, from 6-bromo-2,2-dimetip-4- (2-pyridyl) -2H-1-benzobarine) 2-dimethyl-2H-1-benzopyran-4-yl) pyridine N-oxide with so pl. 146-148 ° C (from ethyl acetate).
The 6-bromo-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran used as the starting compound was prepared as follows.
A) 69.2 g of p-bromophenol and 33.6 g of 2-methyl-but-3-yn-2-ol were dissolved in 600 ml of dichloromethane and 75 ml of diethyl azodicarboxylate was added. 126 g of triphenylphosphines were added in several steps and the mixture was stirred overnight. The mixture was washed with dilute hydrochloric acid and 2M sodium hydroxide solution dried over sodium sulfate and evaporated. The residue was passed through a chromatographic silica gel column, eluting with ethyl acetate / methyl ether (1:10). Thus, an oily residue was obtained, which was distilled to obtain 14.4 g of 4- (1,1-dimethyl-2-propynyloxy) bromobenzene, mp. 96- 106 ° C / t mmHg
B) In the same way as described in Example 6A, from 4- (1,1-dimethyl-2-propynyloxy) bromobenzene and 2-iodopyridine were obtained
6-bromo-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran.
Example 42. In the same way as described in the first paragraph of Example 6, 2- (6-cyano-2) was obtained from (4-methylphenyl) -2-pyridylZ-2,2-dimethyl-2H--1-benzopyran-6-carbonitrile , 2-dimethyl-2H-1-benzopyran-4-yl) -5- (4-methylphenyl) pyridine N-oxide with so pl. 173-175 ° С with decomposition (from ethyl acetate).
The (4-methylphenyl) -2-pyridine-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile used as the starting compound was prepared as follows.
A) 9.5 g of 4- (5-amino-2-pyridyl) -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile was dissolved in 150 ml of acetic acid and 100 ml of water. 3.16 g of sodium hydrite in 10 ml of water were introduced into the reaction mixture at such a rate that the temperature did not exceed 5 ° C. After 15 min, 23 g of potassium iodide in 0 ml of water were added and the mixture was stirred at room temperature for 1 hour. The mixture was then poured into 1 L of 2M sodium hydroxide solution and extracted with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using ethyl acetate / petroleum ether (1; 4) for elution, to obtain 4.78 g of 4- (5-iodo-2-pyridyl) -2,2-dimethyl-2H- 1-benzopmran-b-carbon ggril, which was used without further purification.
B) 440 mg of 4- (5-iodo-2-pyridyl) -2,2-dimethyl-2H-1-benzopyran-b-carbonitrile, 386 mg of p-tolyltrimethyltin, 114 mg of lithium chloride, and 16 mg of bis (triphenylphosphine ) palladium dichloride in 4 ml of dimethylformamide was heated at 100 ° C for 2 hours. After cooling to room temperature, 10% aqueous ammonia and ethyl acetate were added, the phases were separated and the aqueous phase was again extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using ethyl acetate: petroleum ether (1: 4) for the elution, resulting in 286 mg of (4-methylphenyl) -2-pyridyl -2,2-dimethyl-2H-1-benzo - pyran-b-carbonitrile, which was used without further purification.
Example 43. In the same way as described in the first paragraph of Example 4, 2- {b-acetyl-2-methyl is obtained from 6-acetyl-2-methyl-2-phenyl-4- (2 pyridyl) -2H1-benzopyran -2-phenyl-2H-1-benzopyran-4-yl) pyridine N-oxide with m.p. 192-194 ° C (from acetonitol).
Used as starting compound, 6-acetyl 2-methyl-2-phenyl-4- (2-pyridyl) -2H-1-benzopyran was obtained from 2-methoxyphenyl-2-pyridyl ketone and 1-bromo-2-phenyl-1-propene in the same way as described in example 4 of BD and E.
Example 44. In the same way as described in the first paragraph of Example 7, from (-) - 3,3-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile was obtained ( (-) - 2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-b-benzopyran-4-yl) pyridine N-oxide with m.p. 142-144 C (from diethyl ether).
  -76.8 ° (from 0.997 in ethanol).
The (-} - 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile) used as the starting compound was prepared as follows.
A) 36.15 g of 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carboxylic acid and 41.39 g of quinine were dissolved in 650 ml of ethyl acetate and left to crystallize. 16.5 g of solid precipitate was filtered and dissolved in 250 ml of ethyl acetate and 150 ml of 2M acetic acid. The organic phase is washed with 2M acetic acid. The combined aqueous phases were washed with ethyl acetate, and the organic phase was washed with 25 ml of 2% (w / v) citric acid solution. The organic phases were combined, washed with water, dried with sodium sulfate and evaporated, giving 7.2 g of (-) - 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1 -benzopran-6-carboxylic acid.
B) 7.2 g of (-) - 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzol of ra-6-carboxylic acid was heated at a temperature of 70 ° С in 30 ml of penis chloride for 1 hour and the mixture is then evaporated. The residue was dissolved in toluene and the solution was evaporated to remove traces of thionyl chloride. The residue was dissolved in 100 ml of dichloromethane and 50 ml of concentrated aqueous ammonia was added with stirring. Then, stirring was carried out for 15 minutes. The organic layer was separated, washed with water, dried with sodium sulfate and evaporated, giving 7.1 g of (-) - 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) - 2H-1-benzopyran. -6-carboxamide, which was used without further purification.
C) 7.19 g of (-) - 3,4-dihydro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carboxamide ida was heated at 80 ° for 30 minutes C in 25 ml of phosphorus oxychloride. Then the mixture was cooled and evaporated. The residue was dissolved in dichloromethane and a 2M sodium carbonate solution. The organic layer was separated, dried with sodium sulfate and evaporated, resulting in 6.65 g of obtained
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(-) - 3,4-dihydro-2,2-dimethyl-4- {2-pyridyl) -2H-1-benzopyrene-6-carbonitrile, which was used without further purification. Example 45 In a similar manner as described in the first paragraph of Example 7, from (+) - 3,4-dihydro-2,2-dimethyl-4- {2-pyridyl) -2H-1-benzopyran-6-carbonitrile was prepared ( + V 2- {6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-b-benzopyran-4-yl) pyridine N-oxide with a melting point of 143-144 ° C (from diethyl ether) .
   + 78.8 ° (with 1.001 in ethanol).
The (+) - 3,4-dihydro-2,2-dimethyl-4- {2-pyridyl) -2H-1-benzopyran-6-carbonitfil used as the starting compound was obtained from the quinine stock solutions described in Example A. Free acid was obtained in a similar manner, 4.01 g of this acid was dissolved in 90 ml of acetone and 2.42 g of (S) - (-) - 1- (1-naphthyl) ethylamine was added. A crystalline precipitate formed, which was filtered and recrystallized from dioxane. The crystals were dissolved in ethyl acetate and 2% (w / v) citric acid. The combined aqueous extracts were again extracted with ethyl acetate, the organic phases were combined, washed with water, dried with sodium sulfate and evaporated, resulting in 1.41 g of (+) - 3.4-di-hydro-2,2-dimethyl-4- (2-pyridyl ) -2H-1-benzopyran-6-carboxylic acid. This acid was converted to (+) - 3.4-dihadro-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile in the same way as described in Example 44 B and C .
Example 46 2.24 g of 5-benzyloxy-2- 3- (4-cyanophenoxy) -3-methyl-1-butenyl pyridine N-oxide was heated at 80 ° C with 45 ml of toluene for 12 hours. The solvent was evaporated, and the residue was passed through a silica gel column using an ether / methanol (97.5: 2.5) mixture, and as a result, 0.45 g of 5-benzyloxy-2- (6-cyano) was obtained. - 3,4-dihydro) -2,2-dimethyl-2H-1-benzopyran-4-yl) pyridine N-oxide as a white crystalline substance with a melting point of 224 ° C.
The 5-benzyloxy-2- 3- (4-cyanophenoxy) -3-methyl-1-butenyl pyridine N-oxide used as the starting compound was prepared as follows.
A) 23.8 g of 4-cyanophenol in 150 ml of dimethylformamide are added dropwise with stirring; 6 g of 80% sodium hydride in 100 ml of dimethylformamide are added to the suspension and the mixture is then stirred for another 1 hour. 39 g of ethylbromide isobutyrate and the mixture are added dropwise over 76
h was heated at 100 ° C. The solvents were evaporated, and the residue was treated with diethyl ether and water. The organic layer was successively washed with 2M sodium hydroxide solution and sodium chloride solution, and then evaporated, resulting in 9.4 g of ethyl 2- (4-cyanophenoxy) -2-methylpropionate in the form of a colorless viscous liquid with a dot boiling 115-117 ° C / 0.05 mm Hg.
B) 5 ml of a 1.2 M solution of butyl lithium in n-hexane was added to a solution of 0.6 g of diisopropylamine in 10 ml of tetrahydrofuran with stirring, at a temperature of -78 ° C under a nitrogen atmosphere. The solution was stirred for another 15 minutes, and then 1.07 g of 5-benzyl-coke-2-methylpyridine N-oxide in 10 ml of tetrahydrofuran was added to it. The mixture was allowed to warm to 20 ° C, stirred for 30 minutes, and then cooled to -78 ° C. 1.16 g of ethyl 2- {4-cyanophenoxy} -2-methyl propionate was added, then the mixture was allowed to warm to 20 ° C and stirred for 16 h. The mixture was diluted with 50 ml of ethyl acetate and washed successively with water and sodium chloride solution. . The boundary layer was evaporated and the residue was passed through a silica gel chromatography column using a mixture of dichloromethaneUmethanol (94: 4) to calibrate, resulting in 0.46 g of 5-beisyloxy-2- {3- {4-C-2- phenoxy) -3-methyl-2-oxobutylZpyridine N-oxide as a pale yellow crystalline substance with mp. 134-136 ° C (from diethyl ether),
C) 0.46 g of sodium borohydride was added to a stirred solution of 4.53 g of 5-benzyloxy-2- {3- (4-cyanophenoxy) -3-methyl-2-ox-twisted n-fidine N-oxide in 60 ml ethanol. After 2 h, the solution was diluted with 200 ml of water and extracted with diethyl ether. The organic layer was evaporated and 3.67 g of 5-benzyloxy-2- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl pyridine N-oxide was obtained with a melting point of 125 ° C after recrystallization from ethanol.
D) 0.7 g of methanesulfonyl chloride was added to a stirred solution of 2.3 g of 5-benzyloxy-2- 3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl pyridine N-oxide and 1 ml of 2,6-hydrochloride tidine in 10 ml of dichloromethane. The mixture was stirred for 4.5 hours, and then another 1 ml of 2,6-lutidine and 0.7 g of methanesulfonyl chloride was added and the mixture was stirred for 16 h. Then the mixture was diluted 50
,,
ml of dichloromethane and washed successively with 2 M hydrochloric acid, water and 10% sodium bicarbonate solution. The organic solution was evaporated, and the residue was passed through a silica gel column chromatography, using for elution
,,
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35 40 45
50 55
a mixture of diethyl ether / methanol (9: 1), resulting in 0.89 g of 5-benzyloxy- (4-cyanophenoxy) -3-methyl-2- (methylsulfonyloxy) butyl pyridine N-oxide as a substance cream color with m.p. 142 ° C after recrystallization from ethyl acetate.
E) 1.69 g of 5-benzyloxy-2- 3- (4-cyanophenoxy) -3-methyl-2- (methylsulfonyloxy) butyl pyridine N-oxide was added to a solution of 0.14 g of 80% hydride sodium solution in 15 ml of isopropanol and the solution was stirred at 20 ° C for 16 h. Then the solvent was evaporated and the residue was treated with ethyl acetate and sodium chloride solution. The organic layer was washed with a solution of sodium chloride and then evaporated, resulting in 1.64 g of 5-benzyloxy-2- 3- (4-cyano-phenoxy) -3-methyl-1-butyl pyridine N-oxide as a pale cream. substances with so pl. 125 ° C after recrystallization from ethyl acetate.
Example 47. In a similar manner as described in the first paragraph of Example 7, from rac-trans-3,4-dihydro-3-hydroxy-2.2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-b-carbonitri - la obtained rac-trans-2- (b-cyano-3,4-di-hydro-3-hydroxy-2,2-dimethyl-2H-1-benzolyra-n-4-yl) -pyridine N-oxide with melting point 222-224 ° C (from acetonitrile).
Rac-trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile used as the starting compound was prepared as follows: in a way.
A) 3 g of 2.2-dimethyl-4- (2-pyrmdyl) benzopyran-6-carbonitrile and 420 mg of sodium tungstate were heated in 30 ml of methanol and 30 ml of acetonitrile at 50 ° C; and then 12 ml of 30% (w / v) hydrogen peroxide was added. After heating overnight, the mixture was evaporated, the residue was treated with dichloromethane and water. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using ethyl acetate / petroleum ether (1: 3 and 1: 2) for elution, resulting in 440 mg of la, 7b-dihydro-2,2-dimethyl-7b- (2 -pyridyl) -2H-hydroxyreno (c) (1) benzopyran-6-carbonitrile, which was used without further purification.
B) 646 mg of la, 7b-dihydro-2,2-dimethyl-7b- (2-pyridyl) -2H-oxyreno (c) (I) benzopyran-6-carbonitrile was dissolved in 100 ml of ethanol and 100 mg of 10% - palladium on activated carbon. The mixture was shaken under a hydrogen atmosphere overnight and then filtered. The filtrate was evaporated and the remaining oily substance was passed through a silica gel column twice, eluting first with ethyl acetate / petroleum ether (1: 3), and then with 1-2% (v / o) methanol / dichloromethane. Thus, 66 mg of rac-cis-3,4-dihydro-3-hydroxy-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile with a melting point of 18b was obtained. -188 ° C (from acetonitrile) and 340 mg of rac-trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran-6-carbonitrile from m.p. 175-176 ° C (from t-butyl methyl ether).
Example 48. In the same way as described in the first paragraph of Example 7, from rac-trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4- (2-pyridyl) -2H-1-benzopyran- b-carbonitrile obtained rac-cis-2- (6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4- -yl) pyridium N-oxide from m.p. 215-216 ° C (from acetonitrile).
Example 49. 242 mg of 3,4-dihydro-2,2-dimethyl-4- (2-pyrimidinyl) -2H-1-benzopy-ran-6-k arbonitrile was dissolved in 5 ml of dichloromethane at room temperature and - Bavili 450 mg of m-chloroperbenzoic acid. After stirring overnight, the mixture was washed with sodium bisulfite solution and sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using ethyl acetate / ethanol / formic acid (40: 4: 1) for the elution. The result was a product in the form of an oily substance, which was dissolved in diethyl ether and washed with sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The resulting oily product was recrystallized from tert-butyl methyl ether to obtain 25 mg of 2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) pyrimidine 1-oxide with m.p. 98-100 ° C.
3,4-dihydro-2,2-dimethyl-4- (2-pyrimidilyl) -2H-1-benzopyran-6-carbonitrile was used as the starting compound as follows.
A) 0.63 g of 4- {1,1-dimethyl-2-propynyloxy) benzonitrile, 0.75 g of 2-iodopyrimidine, 18 mg of triphenylphosphine, 12 mg of palladium (II) chloride, and 3.5 mg of copper iodide ( I) stirred overnight in 20 ml of triethylamine under a nitrogen atmosphere. The mixture was evaporated to dryness, and then ethyl acetate and water were added. The organic layer was dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using ethyl acetate / petroleum ether (1: 3) for elution, and then ethyl acetate / petroleum ether (1: 1).

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In this way, 580 mg, 1-dimethyl-3- (2-pyrimidinyl) -2-propynyloxy-Begononitrile, were obtained in the form of an oil,
B) 580 mg of 1-dimethyl-3- (2-pyrimidinyl) -2-propynyloxy-benzonitrile was boiled in 20 ml of dichlorobenzene for 3 hours. The solution was allowed to cool and then evaporated to dryness. The residue was passed through a silica gel chromatography column using ethyl acetate / petroleum ether (1: 2) and then ethyl acetate / petroleum ether (1: 1). Thus, 361 mg of 2,2-dimethyl-4- (2-pyrimidinyl) -2H-1-benzopyran-6-carbonitrile was obtained, which after recrystallization from tert-butyl methyl ether melted at 108-109.5 ° C.
C) 1.0 g of 2,2-dimethyl-4 (2-pyrimidinyl) -2H-1-benzopyran-6-carbonitrile was dissolved in 100 ml of ethanol, poured onto 10% palladium on activated carbon and shaken under an atmosphere of hydrogen. at room temperature. After 2 hours, the catalyst was filtered off and the filtrate was evaporated. The residue was passed through a silica gel column chromatography using ethyl acetate / petroleum ether (1: 1) for the elution. The product was recrystallized from cyclohexane to obtain 0.5 g of 3,4-dihydro-2,2-dimethyl-4- (2-pyrimidinyl) -2H-1-benzopyran-b-carbonitrile with a melting point of 109-111 ° C.
Example 50. 450 mg of m-chloroperbenzoic acid was added at room temperature to a solution of 624 mg of 2,2-dimethyl-4- (2-quinolyl) -2H-1-benzopyran-n-6-carbonitrile in 20 ml of dichloromethane. After stirring at room temperature for 6 hours, the mixture was washed with sodium bicarbonate solution and the organic layer was dried over sodium sulfate and evaporated. The residue was passed through a silica gel column using ethyl acetate / petroleum ether (4: 1) and then again passed through silica gel column using 1: 9 methanol / ethyl acetate for the elution. The product was recrystallized from toluene to obtain 45 mg of 2- {6-cyano-2,2-dimethyl-2H-1-benzopyran-4- or) quinoline 1-oxide mp 177 ° C.
The 2,2-dimethyl-4- (2-quinolyl) -2H-1-benzopyran-6-carbonitrile used as the starting compound was prepared as follows.
A) At room temperature, 5.1 g of 2-iodoquinoline was added to a solution of 18 mg of palladium (II) chloride, 52 mg of triphenyl phosphate and 38 mg of copper (I) iodide in 100 ml of diethylamine.
3.7 g of 4- (1,1-dimvtil-2-propynyloxy) benzonitrile are added. After stirring at room temperature for 18 hours, the mixture was evaporated, and the residue was dissolved in ethyl acetate and water. The organic layer was dried over sodium sulfate and evaporated. The residue was passed through a chromatography column b with silica gel using ethyl acetate / petroleum ether (1: 2) for elution, resulting in 5.8 g of 4-fl, 1-dimethyl-3- (2-quinolyl) -2- propynyloxy-7benzonitrile as a yellow gum.
. C) 5.8 g of 4- {1,1-dimethyl-3- {2-quinolyl) -2-propynyloxy-benzonitrile was boiled for 2 hours in 50 ml of dichlorobenzene. The mixture was allowed to cool to room temperature and then evaporated to dryness. The residue was passed through a silica gel column chromatography using ethyl acetate / petroleum ether (1: 3) for the elution. The product was recrystallized from isopropanol to obtain 2.1 g of 2,2-dimethyl-4- (2-quinolyl) -2H-1-benzopyran-6-carbonitrile with a melting point of 102-104 ° C.
Example 51.205 mg-chloroperbenzoic acid at room temperature was added to a solution of 314 mg of 3,4-dihydro-2,2-dimethyl-4- (2-quinolyl) -2N-1-benzopyran-6-carbonitrile in 10 ml of dichloromethane. After stirring for 2 hours, the mixture was washed with sodium bisulfite solution and sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue is crystallized from diethyl ether to obtain 230 mg of 2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl) -quinoline 1-oxide with m.p. 183-185 ° C.
The 3,4-dihydro-2,2-dimethyl-4- (2-quinolyl) -2H-1-benzopyran-6-carbonitrile used as the starting compound was prepared as follows:
624 mg of 2,2-dimethyl-4- (2-quinolyl) 2H-1-benzpyrene-b-kerbonytryl gfMTShm sodium temperature was shaken under a hydrogen atmosphere in 25 ml of ethanol with 50 mg of 10% palladium on activated carbon. After 4 h, the mixture was filtered and the filtrate was evaporated. The residue was passed through a silica gel chromatography column using ethyl acetate / petroleum ether (1: 2) for the elution. The product was recrystallized from isopropanol to obtain 410 mg of 3,4-dihydro-2,2-dimethyl-4- {2-quinolyl) -2H-1-ben opiran-6-carbonitrile with m.p. 174- 176 ° C}
Example 52. 260 mg of m-chloroperbenzoic acid are added at room temperature to a solution of 400 mg of 4- {3-isoquinolyl) -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile in 5 ml of dichloromethane. After 4 hours, the mixture is washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was passed through a silica gel chromatography column using 5% v / v methanol / ethyl acetate for elution. 69 mg of 3- (6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) isoquinoline 2-oxide with the melting point are obtained. 229-230 ° C (from isopropanol).
The 4- (3-isoquinolyl} -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows.
A) 4.16 g of 3-bromoisoquinoline. 5.55 g of 4- (1,1-dimethyl-2-propynyloxy) -benzonitri, 45 mg of palladium chloride (I), 130 mg of triphenylphosphine and 95 mg of copper (I) iodide are mixed in 150 ml of triethylamine under a nitrogen atmosphere at room temperature. After 5 days, the mixture was evaporated and the residue was added to a mixture of ethyl acetate and water. The organic layer was dried with sodium sulfate and evaporated. The residue is passed through a silica gel column chromatography. using ethyl acetate / petroleum ether (2: 3) for the elution, the result is 810 mg of 4- {5- (3-isoquinolyl) -1,1-Dimethyl-2-propynyloxy / benzonitrile as an oil.
B) 0.8 g of 4- 3- {3 isoquinolyl) 1,1-dimethyl-2-propynyloxy 6-benzonitriles is boiled for 2.5 hours in 40 ml of 1,2-dichlorobenzene. After cooling, the mixture is evaporated. The residue is passed through a: silica gel chromatography column using ethyl acetate / petroleum ether () for the elution, resulting in 510 mg of 4- (3-isoquinolyl 3-dimethyl L-M-benopyran-6-carbonitrile, mp. 143-154 ° C (from isopropanol).
Example 53. 793 mg of 4- (5-iodo-2-pyridyl) -2,2-dimethyl / -2H-1-benzopyran-b-carbonitrile is dissolved in 100 ml of dichloromethane and 612 mg of m- chloroperbenzoic acid. The mixture was stirred at room temperature for 12 hours, and then another 200 mg of m-chloroperbenzoic acid was added. Stir for another 2 hours and then the mixture is washed with sodium bisulfite solution, sodium thiosulfate solution, sodium bicarbonate solution and water. The organic layer is dried over sodium sulfate and evaporated. The residue is passed through a silica gel column chromatography using ethyl acetate / petroleum ether (1: 2) for the elution. whereby 30 mg of 2N 6-cyano-2,2-dimethyl 2H-1-benzopyran-4-yl) -5-iodopyridine N-oxide are obtained in the form of an oil.
NMR (300 MHz, SDS13): 8.53 (IH, d., 2 Hz), 7.56 (IH, d, d, 8 Hz, 2 Hz), 7.35 {IH, dd, 8.5 Hz, 2 Hz), 6.98 (H, d., 8 Hz), 6.87 (IH, d., 2 Hz), 6.81 (IH, d., 8.5 Hz). 5.81 (IH, p.) - 1.49 (6H, p.).
MS (EI): 404 (Ml.
Example 54. 352 mg of 4- 5- {3-methylphenyl) 2-pyridyl} -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile is dissolved in 10 ml of dichloromethane and 243 mg of m -chloro-perbenoic acid. The mixture is stirred at room temperature for 12 hours and then washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. The mixture is passed through a silica gel chromatography column using an ethyl acetate / petroleum ether (1: 1) mixture and ethyl acetate to elute, resulting in a foam that solidifies upon trituration with diethyl ether. The resulting solid is filtered and recrystallized from methyl tert. butyl ester to give 93 mg of 2- (6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl) -5- (3-methylphenyl) pyridine 1-oxide with m.p. 163-165 ° C.
4- 5- {3-Methylphenyl} -2-liridyl -2,2-dimethyl-2H-1-benzopyran-6-carbonitrile, used as the starting compound, is obtained from 4- (5-iodo-2-pyridyl ) -2,2-dimethyl- 2H-1 benzopyran-6-carbonitrile and m-tolyltrimethyltin according to the method described in Example 42 C.
The compounds of formula i and their salts have a pronounced activity of activating the potassium ducts and can be used as medicines, especially in the treatment and prevention of high blood pressure, congestive heart failure, pectoral sore throat, diseases of the peripheral vessels and cerebral vessels and disorders of smooth muscle ( for example, gastrointestinal, respiratory, uterine and urinary tracts, as in the case of peptic ulcers, irritable bowel syndrome (mucous colitis a) diverticular disease, reversible obstruction (obstruction) of the respiratory tract, asthma, premature birth and incontinence.In addition, they can also be used to restore hair with baldness.
The activity of the proposed compounds, expressed in the activation of the potassium channels, can be demonstrated through experience.
In male Sprague-Dawley rats, the hepatic portal veins are removed and suspended in baths from the organ at an initial pressure of 0.5 g for isometric recording of pressure. The veins are incubated in Krebs a solution (consisting of 118 mM sodium chloride, 25 mM sodium bicarbonate, 10.5 mM 6-glucose, 4.7 mM potassium chloride, 0.4 mM magnesium sulfate, 1.2 mM potassium acid phosphate (KH2P04) and 2.5 mM calcium chloride), through which 95% of oxygen and 5% of carbon dioxide are passed, and which is kept at 37 ° C. After incubation for 0.5 h-1 h, another 20 mM potassium chloride is added, followed by an addition after 0.25 h-0.5 h of increasing concentrations of the test substance. The activity of the test substance is expressed as the ICB value, which is the concentration of the test substance, giving half the maximum recovery of the contractions of the heart muscle caused by potassium chloride.
Test data are presented in table I.
The main advantage of the compounds of the formula () is the increase in the duration of the activity.
Presented in table. Figure 2 shows the potassium channel activating effect of the tested compounds B, C, D (1,2,3), but they do not show the duration of their action.
A comparison of the comparative data sufficiently proves that the compounds of the formula (I) are superior to the known compounds, as regards the duration of their action. The indicated data comparison shows a comparison of a representative of compounds of formula (I) with a representative of three known compounds with respect to their blood pressure lowering effect in rats with spontaneous hypertension. The first comparative compound is cromacolin, which is the most important known compound and is very structural in structure to the proposed compounds. This compound also has an activating channel of potassium and has long been used in the treatment of patients. Cromacoline is a compound that corresponds to the formula I, where RI is cyano, RZ and H3 is each methyl; R4 is hydroxy, Rs is hydrogen, and Re is 2-oxo-pyrrolidinyl. Known compounds are dl-a-tocopheryl-5-butyl picolinate, and in addition, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4- {L, L- -dimethyl-2 -acetamido 2H-1-benzopyran-3-ol.

权利要求:
Claims (1)
[1]
Invention Formula
Method for preparing benzopyran derivatives of general formula I
five
-Rt.
° V where Ri is a hydrogen or halogen atom, trif
tormethyl, nitro or cyano, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, benzoyl substituted by halogen atom or nitro group, or carbamoyl;
R2 is a hydrogen atom, a lower alkyl or phenyl;
 - hydrogen atom or lower alkyl; R4 and RS each means a hydrogen atom or R4 is a hydroxy group and RS is a hydrogen atom or R4 and RS together represent a carbon-carbon bond; Re is pyrimidinyl, quinolyl, isoquinolyl or pyridyl, unsubstituted or substituted by a halogen atom, hydroxy group, amino group, C 1 -C 4 alkyl, phenyl, C 1 -C 4 alkylphenyl, C 1 -C 4 alkoxycarbonyl or phenyl-C 1 -C alkoxygroup and containing the N-oxide group in position 2, or their pharmaceutically acceptable additive salts, characterized in that the compound of general formula II
.
chahiz
About R,
where Ri, Ra, RS, R4 and RB have the indicated meanings;
1757466
40
|
5 I
;
I
0
0
five
Rei pyrimidinyl, quinolyl, isoquinolyl or pyridyl, unsubstituted or substituted by a halogen atom, a hydroxy group. the amino group, C1 C4 alkyl, phenyl, Ci-C4 alkylphenyl, C1-C4 alkoxycarbonyl or phenyl C1-C4 alkoxygroup, having a nitrogen atom in position 2, is oxidized and the desired product is liberated or in in the form of its pharmaceutically acceptable additive salt.
Priority featured:
07.06.87 when Ri is a hydrogen or halogen atom, a nitro or cyano group, lower alkyl, lower alkoxycarbonyl or carbamoyl;
R2 and B3 - hydrogen atom or lower alkyl;
R4 and RS are the same - hydrogen atom;
RS is a hydrogen atom or R4 and RS together form a carbon-carbon bond;
Re - pyrimidyl, quinolyl, isoquinolyl or pyridyl, unsubstituted or substituted by halogen, hydroxy, amino, C1-C4 alkyl, phenyl, Ci- d-alkylphenyl, Ci-Cj-alkoksikarboni- scrap or phenyl-C1-C4-elkoksikarbonilom, containing the N-oxide group at position 2.
04.04.88pri
Rt is trifluoromethyl or benzoyl substituted by a halogen atom or a nitro group;
R2 is phenyl; R is a hydroxy group; RS is a hydrogen atom.
41
1757466
42 Table 1
table 2

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同族专利:

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IL86923D0|1988-11-30|

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HU202513B|1991-03-28|

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NO170727C|1992-11-25|

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SK484188A3|1998-05-06|

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CN1030582A|1989-01-25|

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IS1596B|1996-04-12|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB878715839A|GB8715839D0|1987-07-06|1987-07-06|Benzopyran derivatives|

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GB888810212A|GB8810212D0|1987-07-06|1988-04-29|Benzopyran derivatives|

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