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    • 专利摘要:
    Compounds of the formula <IMAGE> (Ia) wherein R1 represents cyano, nitro or C1-C4-alkyl or the 7,8-dihydro derivative thereof or the 5,6,7,8 tetrahydro derivative of the formula <IMAGE> (Ib) wherein R1 is as defined under formula Ia and R2 is hydrogen, C1-C4-alkyl, halogen etherified or esterified hydroxy or mercapto, carboxy-C1-C4-alkyl or C1-C4-alkoxycarbonyl-C1-C4-alkyl or C1-C4-alkanoyl, to stereoisomers, mixtures of these stereoisomers and salts of these compounds are disclosed as well as their preparation, pharmaceutical compositions containing the same and the use thereof as inhibitors of aromatase activity.
    公开号:SU1443802A3
    申请号:SU864027758
    申请日:1986-07-02
    公开日:1988-12-07
    发明作者:Джонстон Браун Ласли
    申请人:Циба-Гейги Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of new heterocyclic compounds, in particular, to a method for producing substituted nitrogen-containing bicyclic compounds of the total form (CHg) „.
    (I)
    where n - 1, 2 or 3;
    R is hydrogen, C, -C-alkyl, cyano, halogen, carbamoyl, C -C-alkylcarbamoyl, or formyl;
    R ,, is hydrogen, phenyl-C-C-alkyl, carboxy-C, -C-alkyl, -alkoxycarbonyl-C-C-alkyl, or C -C-alkylthio group,
    or their stereoisomers, or mixtures of their stereoisomers, or their acid additive salts with the properties of aromatase inhibitors.
    The purpose of the invention is to create, on the basis of known methods, a method of producing new compounds with valuable pharmacological properties.
    Example 1. 5- (pa-cyanophenyl) -5,6,7,8-tetrahydroim hydrochloride
    Dazo S1,5-aJ pyridine.
    A solution of 2.0 g of 4- (4-chloro-4) -para-cyanofeiyl- (n-butyl) -1H-imidazole in 50 ml of chloroform is heated under reflux for 4 hours under nitrogen, cooled, evaporated and get the target connection.
    Getting the original compounds.
    4- (3-formyl-n-propyl) -1-trimethylsilylimidazole.
    A solution of 1.82 g of 4- (3-ethoxycarbonylpropyl) -1H-imidazole in 30 ml of tetrahydrofuran is treated in nitrogen atmosphere with 0.5 g of sodium hydride (50% suspension in oil) for 30 minutes and 1 hour. , 45 ml of trimethyl silyl chloride at 0 ° C for 3 hours. The reaction mixture is washed with cold 0.5 N sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. The oil is redissolved in 100 ml of methylene chloride at -78 ° C under a nitrogen atmosphere and 12.82 ml of diisobuyl aluminum hydride (1., 56 M) are added dropwise. Reak
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    The mixture is stirred for 5 minutes at -78 ° C, 1 ml of methanol is added, then 10 ml of water and filtered
    (S
    via Celite. The organic phase is separated, dried over sodium sulfate, evaporated to give the desired compound.
    4-4-para-tert-butylaminocarbonyl-phenyl) -4-hydroxy-n-butyl J-1-trimethylsilyl-imidazole.
    To a solution of 6.95 g of para- (tert-butyl-aminocarbonyl) -bromobenzene, dissolved in 175 ml of tetrahydrofuran, at -70 ° C under a nitrogen atmosphere, 20.1 ml of n-butyllity ( 2.7 M) in hexane. After reacting for 30 minutes, a solution of 5.69 (3-formyl-n-propyl) -1-trimethylsilylimidazole in 10 ml of tetrahydrofuran is slowly added. The reaction mixture is allowed to slowly warm to room temperature and 20 ml of ammonium chloride are added. The organic layer is separated, dried over sodium sulfate, evaporated and the title compound is obtained.
    4-C4-Chloro-4 - (- para-cyanophenyl) -n-butyl -1 H-imidazole.
    A solution of 4.5 g of (p-tert-butylaminocarbonylphenyl) -4-hydroxy-n-butyl -1-trimethylsilyl imidazole in 50 ml of thionyl chloride is heated under reflux for 1 hour, cooled and evaporated. The residue is extracted with a mixture of methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase is separated, dried over sodium sulfate, evaporated to give the desired compound.
    Example 2. 5- (para-cyanophenyl) -5,6,7,8-tetrahydropyrimidazo tl, 5-a1-pyridine hydrochloride.
    A solution of 1.13 g of 5- (para-carbamoyl-phenyl) -5,6,7, 8-tetrahydro O 11 Midazo tl, 5-a pyridine and 1.0 ml of phosphorus oxychloride in 30 ml of chloroform is heated under reflux for 1 15 h, cooled and evaporated with toluene. The resulting oil is dissolved in 30 ml of methylene chloride, cooled to, and 30 ml of an ice-cooled solution of 50% ammonium hydroxide is added. The organic phase is separated, dried and evaporated to an oil. By filtration through 20 g of silica with ethyl acetate, the desired compound is obtained, which is dissolved in 20 ml of acetone, treated with 1.2 ml of a 3 N ethereal solution of hydrogen chloride and the hydrochloride is obtained, mp 209-210 0.
    Example 3. 5- (para-Cyacophenyl) -5,6,7,8-tetrahydroimidazo C1,5 pyridine.
    A mixture of 85 mg of 5- (para-bromophenyl) -5,6,7,8-tetrahydroimidazo Cl, 5-aJ pyridine and 74 mg of monovalent copper cyanide in 1 ml of N, N-dimethylforma is heated under nitrogen atmosphere for 11 The reaction mixture is cooled, diluted with 10 m of water and extracted with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated. The resulting oil is chromatographed on silica gel with ethyl acetate to give the title compound. M.p. 117 - 118 ° C.
    Example 4. 5- (p-Cyanophenyl) -5,6,7,8-tetrahydroimidazo t, 5-a pyridine.
    A solution of 2.01 g of 5- (para-formylphenyl) -5,6,7,8-tetrahydroimidazo 1,5-a-pyridine and 0.96 g of hydrochloric acid in 30 ml of benzene is incubated with external cooling at room temperature. , added dropwise 0.8 ml of concentrated sulfuric acid. The reaction mixture is stirred for 2 hours and neutralized. The organic phase is separated, dried over sodium sulfate, evaporated to give an oil, which is chromatographed on silica gel with ethyl acetate to give the desired compound.
    Example 5. Hydrochloride 5- (p-ra-cyanophenyl) -5-methylthio-5,6,7,8-tetrahydroimidazo Cl, 5-a pyridine.
    A solution of lithium diisopropylamide is obtained at 0 ° C under a nitrogen atmosphere from 0.6 ml of n-butyl lithium (2.5 M) and 0.15 g of diisopropylamine in 5 ml of dry tetrahydrofuran and transferred to 0.29 g of 5- (p-cyanophenyl ) -5,6,7,8-tetrahydroimidazo tl, 5-a pyridine in 10 ml of tetrahydrofuran at -78 ° C. The reaction mixture is stirred for 30 minutes and 0.14 g of dimethyl disulfide is added dropwise. After 30 minutes, the cooling is stopped, the mixture is allowed to warm to room temperature and 10 ml of a saturated solution of ammonium chloride are added. The layers are separated and the organic phase is washed with cold 1 N CH1. The aqueous phase is neutralized and extracted
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    ethyl acetate. The organic extracts are dried over sodium sulfate and reduced to an oil, which is chromatographed on silica gel with 5% isopropanol in ethyl acetate. The resulting oil is dissolved in acetone,. treated with 0.1 ml of 4 N ethereal solution of HC1 and get the target compound. M.p. 204-205 ° C.
    Example .6. A solution of 3.13 g of (4-tert-butylaminocarbonylphenyl) -3-chloroprop-1-yl -1-trityl imidazole in 150 ml of acetonitrile is refluxed for 15 hours, cooled and 150 ml of methanol are added. The reaction mixture is heated under reflux for an additional 15 hours and evaporated to dryness. The residue is extracted with a mixture of sulfuric ether and water. The ether layer was separated and washed with 1 N HC1 (2 x 15 ml). The combined aqueous extracts were adjusted to pH 8, extracted with methylene chloride, which was dried over sodium sulfate, filtered and evaporated to a white foam. The product is crystallized from ether and 1.30 g of 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrolo 1, 2- -c imidazole are obtained. M.p. 136-139 C.
    The starting compounds are obtained in a slurry manner.
    A solution of 6.0 g of methyl 3- (1H-imidazol-4-yl) propionate and 11 ml of triethyl amine in 31 ml of dimethylformamide is treated with a solution of 9.65 g of triphenyl methyl chloride in 110 ml of dimethylformamide for 2 hours at room temperature. temperature under nitrogen. The reaction mixture is poured into 700 g of ice, the resulting solid is collected by filtration and recrystallized. from ether and get 13,83 g of methyl 3- (1-tritylamide-4-yl) propionate. NMR (CDC1 j): / 2.75 (multiplet, 4H); 3.05 (singlet, ZN); 6.5-7.5 (multiplet, 17H).
    A solution of 44.4 mmol of diisobutyl aluminum hydride in 29 ml of toluene was added to a solution of 8.79 g of methyl 3- (1-tritylimidazol-4-yl) propionate in 175 ml of methyl chloride at -72 ° C under a nitrogen atmosphere. After 5 min, the reaction is terminated by the addition of 14 ml of methanol and then 90 ml of water. The reaction mixture is allowed to warm to room temperature and filtered through zeolite. The organic phase is separated, dried over sodium sulfate, evaporated to yellow.
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    the oil which is chromatographed on 280 g of silica is obtained and 4.13 g of 3- (1-tritylimidazol-4-nl) propionaldehyde will be obtained in the form of an oil, IR (CDCl1): 2830; 2740; 1730 cm
    A solution of 25 mmol of n-butyl lithium in 10 ml of hexane was added dropwise to a solution of 3.19 g of S-tert-butyl-4- -bromobenzamide in 250 ml of tetrahydrofuran at 1Q ° under argon atmosphere. After 30 minutes, a solution of 3.74 g of 3- (1-tritylimidazol-4-yl) propionaldehyde in 100 ml of tetrahydrofuran is slowly added. The reaction mixture was stirred at -70 ° C for 30 minutes, allowed to warm to 25 ° C, stirred at 25 for 2.5 hours, and terminate the reaction with an excess of saturated ammonium chloride solution. The aqueous layer was separated and extracted with methylene chloride (2 x 100 ml). The combined organic extracts are dried over sodium sulfate and evaporated. The residue is chromatographed on 220 g of dioxide, silicon with a mixture of ether and ethyl acetate in the ratio 5: 1 to obtain 4-C3- (4-tert-butylaminocarbonylphenyl) -3-oxyprop-1-yl J-1-tritylamidazole as an oil . IR (CH-j Cl1660 cm-4
    A solution of 3.21 g of (4-tert-butylaminocarbonylphenyl) -3-hydroxyprop-1-yl-1-1-trityl imidazole and 1.5 ml of thiochloride in 50 ml of methylene chloride is refluxed 1 4 is cooled and poured into 50 ml of ice-cold sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate, evaporated, and 4-GB-(4-tert-butyl-aminocarbonylphenyl) -3-chloroprop-1-yl-7-1-trityl imidazole is obtained as a white foam. NMR (CDCl: ,,): c 1.45 (singlet, -9H); 4.30 (triplet, I 6.0 Hz 2H). .
    Example 7. A solution of 1.25 g of 5H-5- (4-tert-butylaminocarbonylphenyl) -6, 7-dihydropyrrolo 1, dazole in 10 lyyi thionyl chloride is heated under reflux for 1 hour, cooled and evaporated. The residue is dissolved in 10 ml of chloroform with and 10 ml of ice-cold concentrated ammonium hydroxide solution are slowly added. The aqueous layer was separated, washed with chloroform (3 x 20 ml) and the combined organic extracts were dried over sodium sulfate. By filtration, evaporation and chromatography on 45 g of silica with 5% solution of ammonium hydroxide in ethyl acetate, an oil is obtained, which is treated with 1 molar equivalent of ethereal HC1 solution and 0.5 g of hydrochloride is obtained. - (4-cyanofenyl) -6,7-dihydropyrrolo G1, 2-cimidazole. M.p. 227-228 s.
    Example 8. A solution of 1.29 g of 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7,8,9-tetrahydroimidazo 1,5-a-azepine in 10 ml of thionyl chloride is refluxed for 1 h. , cool and bulge. The residue is extracted with a mixture of methylene chloride and an ice-cold sodium bicarbonate solution. The aqueous layer was separated and extracted with methylene chloride (3 x 15 ml). The combined organic layers were dried over sodium sulfate and evaporated. The resulting oil is chromatographed on 26 g of silica with 5% methanol in methylene chloride. The product is treated with a molar equivalent of fumaric acid in ethanol to give 5H-5- (4-cyanofekyl) -6,7,8,9-tetrahydroimide 30 1, 5-aj azepin-fumarate, T, ll. 153-155 ° C.
    The starting compound was obtained from ethyl 5- (1-trityl imidazol-4-yl) -1-pentoate, prepared as follows in the same manner as to prepare 5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrol-1,2- сimidazole from ethyl 3- (1-tritylimidazol-4-nl) propionate.
    A solution of 5.6 ml of diisopropylamine in 150 ml of tetrahydrofuran at -70 ° C in a nitrogen atmosphere is treated with 14.5 m 2.5 M n-butyl lithium for 30 minutes and 7.2 ml of triethyl phosphoacetate are added dropwise. After 30 minutes, slowly add a solution of 10.09 g of 3- - (1-tritylimidazol-4-yl) propionose aldehyde in 50 ml of tetrahydrofuran. The reaction mixture is allowed to slowly warm to room temperature, stirred for 15 hours and the reaction is terminated with an excess of saturated ammonium chloride solution. The aqueous layer was separated and extracted with ethyl acetate (2 x 50 ml). The combined organic extracts are dried over sodium sulfate and evaporated to an oil (15.35 g), which is chromatographed on 430 g of silica with ether to give 9.61 g of ethyl 5- (1-tritylimidazol-4-yl) -1- pent-2-enoate.
    m.p. se-ss c.
    A solution of 9.20 g of ethyl 5- (1-tritylamidazol-4-yl) -1-pent-2-enoate in 460 ml of anhydrous ethanol is hydrogenated with 1.88 g of 10% palladium on carbon at atmospheric pressure in hydroimidazoG1, 5-a pyridine, so pl. 253-254 ° C, prepared as in Example 2. Example 12. Racemic hydrochloride of 5- (para-cyanophenyl) -5,6,7,8- -tetrahydroimidazo 1,5-a of pyridine is passed in aliquots of 20 mg through a 4.6 x 250 column mm containing associated with silica gel beta
    20 min. The catalyst was removed by cyclodextrin filter using a mixture of water and methanol in a ratio of 7: 3 as eluent at a flow rate of 0.8 ml / min. Separate fractions are evaporated in vacuo and (-) - 5- (para-cyanophenyl) -5,6,7,8- -tetrahydroimidazo G1,5-a pyridine is obtained. -89,2 and () -5- (para-cyanophenyl) -5,6,7,8-tetrahydroimidation through zeolite. A solid is obtained by evaporation which is recrystallized from hexane to obtain 8.64 g of ethyl 5- (1-trityl imidazol-4-yl) -1-pentanoate. M.p. 84-88 s.
    Example 9. A solution of 0.21 g of 5- (4-cyanophenyl) -6-methoxycarbonylmethyl-5,6,7,8-tetrahydropyrimidazo 1, 5-a pyridine hydrochloride in 1, 2 ml of ethanol and 1.2 ml of IN sodium hydroxide is stirred at room temperature for 15 hours, evaporated and the residue is dissolved in water. The aqueous phase is extracted with ethyl acetate, adjusted to pH 2, extracted again, neutralized and evaporated. The residue is triturated with tetrahydrofuran. The organic phase is treated with an ethereal HC1 solution and 0.12 g of 5- (4-cyanophenyl) -6-carboxymethyl-5,6,7,8-tetrahydroimidazo 1,5-a pyridine is collected. M.p.
    209-211 ° C. I
    Example 10. A solution of 0.80 mmol
    lithium diisopropylamide, obtained from 0.12 ml of diisopropylamine and 0.32 ml of 2.5 M n-butyl lithium, in 6 ml of tetrahydrofuran at 0 ° C is slowly added to a solution of 0.17 g of 5- (4-cyanofenyl) -5,6,7,8-tetrahydroimidazo 1,5-a-pyridine in 2 ml of tetrahydrofuran at -78 ° C. After 0.5 h, 0.1 ml of benzyl bromide is added dropwise. The reaction mixture is stirred for another 1 h, the reaction is terminated with water (5 ml), acidified with HCl IN, diluted with 20 ml of ether, and the layers are separated. The aqueous phase is adjusted to pH 7, extracted with ethyl acetate (3 x 15 ml) and the organic extracts dried over sodium sulfate. Filtration and evaporation give a foam, which is treated with 1 molar equivalent of ethereal HCl solution and 5-benzyl-5- (4-pianophenyl) hydrochloride is obtained 15
    20
    25
    thirty
    35
    40
    45
    50
    30 1, 5-a pyridine, d + 85,02 °. Both compounds are separately dissolved in acetone and treated with a 1 molar equivalent of an ethereal HCl solution, to give the hydrochloride salts, respectively, mp. 82-83 (amorphous) and 218-220 C.
    Example 13: Analogously to Example 1, the following compounds were prepared:
    5-benzyl-5- (4-cyanophenyl) -5,6,7,8-tetrahydroimidazo P, 5-a pyridine, m.p. its hydrochloride 249-251 C;
    7- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo 1,5-a pyridine, m.p. its hydrochloride is 253-254 ° C;
    7- (p-carbamoylphenyl) -5,6,7,8-tetrahydroimidazo 1,5-a} pyridine, m.p. its fumarate is 193-195 ° C;
    5- (para-carbamoylphenyl) -5,6,7,8- -tetrahydroimidazo 1,5-a pyridine, m.p. 181-183 ° C;
    5- (p-tolyl) -5,6,7,8-tetrahydroimidazo 1,5-a pyridine, m.p. its hydrochloride 173-175 C;
    5- (para-bromo; 1 rot) -5,6,7,8-tetrahydroimidazo 1,5-a pyridine, m.p. its hydrochloride
    5- (para-formylphenyl) -5,6,7,8-tetrahydroimidazo 1 5-a1-pyridine, mp, its fumaric acid salt 131 C;
    5- (p-cyanophenyl) -5-methylthio-5,6,7,8-tetrahydroimidazo P, rydin, m.p. its hydrochloride 204-205 ° C;
    5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrolo 1,2-e by them-5 6,7.8-tetrahydroimidazo 11, 55 dazole, m.p. 136-139 ° C;
    ... iy / t
    readin M.p. 249-25GS.
    Example 11. 7- - (p-cyanophenyl) -5,6,7,8-tetrahydrin 5H-5- (4-cyanophenyl) -6,7-dihydropyrrolo 1, 2-nd imidazole hydrochloride, so pl. 227 - 228 ° C;
    Yu
    15
     Cyclodextrin using a mixture of water and methanol in a ratio of 7: 3 as eluent at a flow rate of 0.8 ml / min. Separate fractions are evaporated in vacuo and (-) - 5- (para-cyanophenyl) -5,6,7,8- -tetrahydroimidazo G1,5-a pyridine is obtained. -89,2 and () -5- (para-cyanophenyl) -5,6,7,8-tetrahydroimide0
    five
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    30 1, 5-a pyridine, d + 85,02 °. Both compounds are separately dissolved in acetone and treated with a 1 molar equivalent of an ethereal HCl solution, to give the hydrochloride salts, respectively, mp. 82-83 (amorphous) and 218-220 C.
    Example 13: Analogously to Example 1, the following compounds were prepared:
    5-benzyl-5- (4-cyanophenyl) -5,6,7,8-tetrahydroimidazo P, 5-a pyridine, m.p. its hydrochloride 249-251 C;
    7- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo 1,5-a pyridine, m.p. its hydrochloride is 253-254 ° C;
    7- (p-carbamoylphenyl) -5,6,7,8-tetrahydroimidazo 1,5-a} pyridine, m.p. its fumarate is 193-195 ° C;
    5- (para-carbamoylphenyl) -5,6,7,8- -tetrahydroimidazo 1,5-a pyridine, m.p. 181-183 ° C;
    5- (p-tolyl) -5,6,7,8-tetrahydroimidazo 1,5-a pyridine, m.p. its hydrochloride 173-175 C;
    5- (para-bromo; 1 rot) -5,6,7,8-tetrahydroimidazo 1,5-a pyridine, m.p. its hydrochloride
    5- (para-formylphenyl) -5,6,7,8-tetrahydroimidazo 1 5-a1-pyridine, mp, its fumaric acid salt 131 C;
    5- (p-cyanophenyl) -5-methylthio-5,6,7,8-tetrahydroimidazo P, rydin, m.p. its hydrochloride 204-205 ° C;
    5H-5- (4-tert-butylaminocarbonylphenyl) -6,7-dihydropyrrolo 1,2-e im 5 dazol, so pl. 136-139 ° C;
    Dazole, so pl. 136-139 ° C;
    ... iy / t
    5H-5- (4-cyanophenyl) -6,7-dihydropyrrolo 1, 2-e imidazole, so pl. 227 - 228 ° C;
    9U
    5H-5- (4-cyanophenyl) -6,7,8,9-tetrahydroimidazo 1,5-a azepine, m.p. ISS-ISS C;
    5- (4-cyanophenyl) -6-ethoxycarbonylmethyl-5,6,7,8-tetrahydroimide-, 5-aJ pyridine, m.p. 126-127 ° C;
    5- (4-cyanophenyl) -6-carboxymethyl-5,6,7,8-tetrahydroimidazo 1,5-a pyridine, m.p. 209-211 ° C.
    Toxicity data
    Hydrochloride 5- (para-cyanofenyl) -5,6,7,8-tetrahydroimidazo 1,5-a-pyridine was administered orally to 10 males and 10 female rats for 13 weeks at a dose of 0.2. Mg per kg of body weight. per day and 1.0 mg per kg of body weight per day, respectively. No changes in animal liver
    Pharmacological testing.
    The activity of the compounds according to in vitro inhibition of aromatase is studied as follows.
    A test method for determining aromatase inhibition data.
    The microsomal fraction is made from fresh human Pladant, lyophilized and stored in a desiccator at -40 ° C. The test is performed in a total amount of 1 ml of 0.05 M potassium phosphate buffer (pH 7.4) with the incubation mixture containing 1.135x10 M 4 - Cl-androsten-
    -3,17-dione, 2,4x10-M NADPH (Sigma, type III tetrasodium salt), different - concentrations of 5-para-cyanophenyl-5,6,7,8-tetrahydroimidazo 1,5-aa pyridine in as a representative test compound and 226 µg / ml microsomal enzyme fraction, corresponding to 120 µg / m microsomal protein. After incubation for 20 minutes, the mixture is extracted twice with seven volumes of ethyl acetate and the combined extracts evaporated to dryness. The resulting residue was chromatographed for 65 minutes on thin-layer plates, pre-coated with silica gel 60, using a mixture of ethyl acetate and iso-octane (ratio 70:30 v / v) as a solvent system. The arrangement of the radioactive zones of the plate is determined and pic-estrone is determined by comparison with an authentic standard substance. The corresponding band of silica gel is transferred into counting tubes in chains.
    02
    ten
    detection with liquid scintillation detector. In this system, neither the concentration of the substrate, nor the NADPH does not limit the reaction rate. The number of counted pulses from estrone is calculated in the presence of the test compound and in the presence of each concentration of the test compound. The minimum concentration (MIC), in the presence of which a specifically significant inhibition of aromatase is obtained, is presented in the table.
    The MIC value for the compounds listed in the table is approximately 1000 times lower than that of aminoglutedimide (Merk Index, X, No. 443), a highly active aromatase inhibitor.
    40 f
    formula of invention
    The method of obtaining the substituted nitrogen-containing bicyclic compounds of the general formula
    . (I)
    -fCH2).
    where nk,
    RO 1, 2 or 3;
    hydrogen, C-C-alkyl, cyano, halogen, carbamoyl,
    C-C-alkylcarbamoyl or
    formyl;
    hydrogen, phenyl-C1-C - lkil,
    carboxy-C1-C-alyl, C-C-alkoxycarbonyl-C, -0-alkyl
    or C-C-alkylthio,
    or their stereoisomers, or mixtures of stereoisomers, or their acid-additive salts, characterized in that the compound of the general formula
    144
    (CH2) p
    one
    where R. and R,
    15
    . have the indicated meanings;
    X is halogen;
    R is hydrogen or trityl
    Group,
    subjected to cyclization and the resulting compound of general formula (I) is isolated in free-form or as an acid addition salt, or the compound of general formula (I), where Ra C, -C4-alkoxy-jn carbonyl-C-C-alkyl, is subjected hydrolysis to form compound (I), where Ri is carboxy-C-C-alkyl or a compound of the general formula (I), where R is hydrogen and the group is in js
    ten

    15
    ;
    jn js
    380212
    position 5, is subjected to interaction with C ,. to il-disulfide o to form compound (I), where R is C, -C-alkylthio, or a compound of the general formula (1), where R is hydrogen and C is in position 5, is reacted with phenyl-C, - C.-alkyl halide to form a compound (I), where phenyl-C, -C-alkyl, or to obtain compounds of general formula (I), where R is cyano, dehydrate the compound of general formula (I), where R, - carbamoyl, or a compound of the general formula (1), where R is a halogen, is reacted with CuCN, or the compound (I) is oxidized, where RI is a formula, or dealkanol is izyt of (I), wherein R, - C -C -alkilkarbamoil or a racemate obtained is separated into optical isomers and the resulting title product is isolated in free form or in the form of acid addition salts.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining substituted nitrogen-containing bicyclic compounds of the general formula where η - 1,2 or 3;
    'is hydrogen, C ^ -C ^ -alkyl, cyano, halogen, carbamoyl, C 4 -alkylcarbamoyl or formyl;
    R 2 is hydrogen, phenyl-Cι-C 4 -alkyl, carboxy-Ci-C ^ -alkyl, C, -C 4 -alkoxycarbonyl-C, -C 4 -alkyl or C Ί -C 4 -alkylthio, or their stereoisomers or a mixture of stereoisomers, or their acid addition salts, wherein the compound of general formula (II) wherein R and R ^ have the indicated meanings;
    X is halogen;
    R is hydrogen or a trityl group, j is subjected to cyclization and the obtained compound of the general formula (I) is isolated free or as an acid addition salt, or a compound of the general formula (I), where R 2 is C, -C 4 -alkoxycarbonyl-C 4 -C 4 ~ alkyl, is hydrolyzed to form compound (1), where R 2 is carboxy-C, -C 4 -alkyl or a compound of general formula (I), where R 2 is hydrogen and a group C £ M 4 -R 4 is in position 5, is subjected to interaction with C G ~ C 4 -alkyl disulfide with the formation of compound (I), where R 2 C, -C 4 ~ alkylthio group, or a compound of general formula (1), g de R 2 is hydrogen and the C 6 HR group, at position 5, is reacted with phenyl-C, -C ^-alkyl halide to form compound (I), where R 2 is phenyl-C 1 -C 4 -alkyl, or for for the preparation of compounds of general formula (I), where R ί is a cyano group, a compound of general formula (I) is dehydrated, where R ( carbamoyl, or a compound of general formula (1), where R t is halogen, is reacted with CuCN, or compound ( I), wherein R, - formyl or dealkanoliziruyut compound (I), wherein R, - C 5 -C -alkilkarbamoil 4, or a racemate obtained is separated into optical isomers and Preparation the desired product is isolated in free form or in the form of acid addition salts.
    类似技术:
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    同族专利:
    公开号 | 公开日
    DK170302B1|1995-07-31|
    BG60305B2|1994-05-27|
    IL75546A|1990-01-18|
    ES8802048A1|1988-03-16|
    AU4385785A|1986-01-02|
    ES8800681A1|1987-11-16|
    ES544344A0|1987-01-01|
    SU1482530A3|1989-05-23|
    DK277685D0|1985-06-19|
    MX9203369A|1992-09-01|
    PT80661B|1987-05-04|
    PT80661A|1985-07-01|
    ES555540A0|1987-12-16|
    FI852399A0|1985-06-17|
    BG60307B2|1994-05-27|
    ES555539A0|1988-04-01|
    KR900008566B1|1990-11-24|
    ES555541A0|1987-11-16|
    ES8702406A1|1987-01-01|
    SU1436879A3|1988-11-07|
    ES555542A0|1988-03-16|
    CS268672B2|1990-04-11|
    NO162467B|1989-09-25|
    PL145104B1|1988-08-31|
    NO852474L|1985-12-23|
    ES8802049A1|1988-03-16|
    CA1276633C|1990-11-20|
    NZ212483A|1988-10-28|
    JPH047746B2|1992-02-12|
    IL75546D0|1985-10-31|
    PL145105B1|1988-08-31|
    DD237510A5|1986-07-16|
    HUT37936A|1986-03-28|
    BG60353B2|1994-08-15|
    US4617307A|1986-10-14|
    PL145103B1|1988-08-31|
    EP0165904B1|1991-04-10|
    HK23494A|1994-03-25|
    FI852399L|1985-12-21|
    PL145814B1|1988-11-30|
    PL254099A1|1986-09-09|
    RO92583A|1987-11-30|
    SU1436880A3|1988-11-07|
    BG60402B2|1995-02-28|
    BG60306B2|1994-05-27|
    ES8801262A1|1987-12-16|
    AU589565B2|1989-10-19|
    BG60352B2|1994-08-15|
    FI80694B|1990-03-30|
    CS444985A2|1989-07-12|
    DK277685A|1985-12-21|
    PL145087B1|1988-08-31|
    ZA854615B|1986-02-26|
    BG60262B2|1994-03-31|
    SU1436878A3|1988-11-07|
    FI80694C|1990-07-10|
    DZ799A1|2004-09-13|
    NO162467C|1990-01-10|
    JPS6112688A|1986-01-21|
    IE851520L|1985-12-20|
    MA20459A1|1985-12-31|
    CY1750A|1994-06-03|
    DE3582452D1|1991-05-16|
    AT62415T|1991-04-15|
    KR860000299A|1986-01-27|
    ES8802155A1|1988-04-01|
    EP0165904A3|1987-09-09|
    EP0165904A2|1985-12-27|
    GR851487B|1985-11-25|
    PL145348B1|1988-09-30|
    SU1433413A3|1988-10-23|
    PH23390A|1989-07-26|
    IE58070B1|1993-06-30|
    ES555538A0|1988-03-16|
    HU202529B|1991-03-28|
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    法律状态:
    优先权:
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