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    • 专利摘要:
    Isoquinoline compounds of the following formula are described: wherein the moiety A-B represents a group of formula: -CH2-NR3- or -NR3-CH2-; wherein R3 represents hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, optionally substituted benzyl, C3-6 alkenyl or C1-4 alkanoyl; wherein R represents hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or optionally substituted benzyl; wherein R' and R2 each represent hydrogen or taken together represent a chemical bond; and wherein X is hydrogen or halogen; or an acid-addition salt thereof. The compounds are pharmaceutically and especially useful in the treatment of disorders of the central nervous system.
    公开号:SU1072808A3
    申请号:SU792765898
    申请日:1979-05-22
    公开日:1984-02-07
    发明作者:Кристофер Хорвелл Дэвид；Эдвард Таппер Дэвид
    申请人:Лилли Индастриз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    The proposed compounds are effective over a wide dose range, with the required dose required depending on the compound used. the disease to be treated. and the type and size of the mammal; 11 of them. In treatment, doses of 0.05, 10, 0 mg / kg per day are used, including in the treatment of adults - b, 2.5, O mg / kg.
    Example 1, Preparation of 1-0 benzoyl-4-acetonyl-1,2,2a, 3-tetrahydrobene (cc}) indole-5 (4H) -one.
    Methyl lithium (4 ml; 0.052 M) in tetrahydrofuran 20 ml), distilled from lithium aluminum hydride, 15 is cooled to -25 ° C. Diisopropylamine (O, 8 ml; 0.006 M) is added and stirred until the gas evolution is pre-crycene. The solution is cooled to -70 ° C and 1-20 benzene-1, 2, 2a, 3-tetrahydrobenzene () indol-5 {4H) -one (1.4 g, 0.004 I) is added in one portion, heated to -20 ° C and the pepper over until a clear brown solution is formed within 45 minutes. 25 Cool to -70 ° C and add 2-nitropropene (0.5 g; 0.006 M) dropwise, heat to -30 ° C and stirred for 2 hours. Perchloric acid (1 ml) is added and the reaction mixture is stirred for 18 h, after which it is poured into water (100 ml), extracted into ethyl acetate, washed with water, magnesium sulphate bromine and evaporated to dryness. ChromatograL-1, on silica gel 30 (50% mixture of ethyl acetate and hexane) and crystallization from methanol, give the title compound in a yield of 0.6 g (47%). M.p. 117-119 ° C. Example 2. 1-Benzoyl-4- (2-10xobutyl) -1,2,2a, 3-tetrahydrobenzene () indol-5 (4H) -one is obtained in a manner similar to npm-iiepy 1 id benzoyl-1, 2, 2a 3-tetrahydrobenz C {)) indol5 (4H) -6 on and 2-nitrobutene in the form45
    non-crystalline ointment oil with a yield of 66%, T.p. 120s with a tube diameter of 0.05 mm.
    Example 3 1-Benzoyl-4 (2-oxopentyl) -1,2,2a, 3-tetrahydride-50 robene- () indol-514H) -one is obtained in analogy to example 2 as
    oils.
    I
    Example 4. Preparation of 1 acetyl-2, 3,4,5-tetrahydro-1H-yn-55
    dale (3.4-1§) indan-7 {6H) -one
    1-benzoyl-4-acetonyl-1,2,2a, W
    tetrahydrobenz () -indole-5 (4H) -one, (1.3 rf 0.004 M) in ethanol (100 ml) under nitrogen atmosphere is treated with hydrochloride potassium hydroxide (2.0 g) and heated under reflux for 2 h. The reaction mixture is poured into a mixture of ice and in fact, extracted with chloroform and dried sulfa- 5
    tom magni Acetic anhydride (1 ml) is added to dry the extract and stirred for 1 hour. The extract is evaporated to dryness and the desired product is obtained by crystallization from a mixture of ethyl acetate and hexane in a yield of 0.6 g (64%) and T, III. 180-182 ° C.
    Example 5. 1-Acetyl-8-methyl2, 3,4,5-tetrahydro-1H-indole (3,4-ig) indan-7 (bn) -one is obtained in a similar way from 1-benzoyl-4- (2- oxobutyl) -, 2,2a, -3-tetrahydrobenz (cj) indol-L-5 (6H) -one with a yield of 57%, So pl .; 223-225C.
    Example 6. 1-Acetyl-6-etsh12, 3,4,5-tetrahydro-1H-indole (3,4-fg) indan-7 (6H) -one is similarly prepared from 1-benzoyl-4- (2-oxopentyl ) -1,2, 2a, 3-tetrahydrobenzene (ss}) - indole-5 (6H) it with a yield of 38% and melting point .. 168-169 ° С.
    PR and ME 7. Preparation of 1-acetyl-2,3,4,5-tetrahydro-1H-inddl (3,4-ig) indan-7 (BS) -one oxime.
    1-Acetyl-2,3,4,5-tetrahydro-1Nindole (3-, 4-itf) -indan-7 (bN) -one (200 mg of hydrochloro1 (sislida hydroxylamine (100 mg) and sodium acetate (50 mg ) in methanol (10 ml), heated under reflux for 2 hours. The reaction mixture is cooled, the target product is isolated by filtration and washed with water. 200 mg (95%). The structure is confirmed by mass and NMR spectroscopy.
    Example 8 Oxime-1-acetyl8-methyl-2,3,4,5-tetrahydro-1H-INDOL (3,4-ig) -indane 7 (6H) -one is prepared analogously from 1-acetyl-; 8-methyl-2 , 3,4, 5-tetrahydro-1H-indole (3,4-ig) indan-7 (6H) -one with a yield of 95%. T; pl, viye 320 ° C (with decomposition).
    Example 9. 1-Acetyl-1,2, 3,4, 5,6-hexahydroindole (4,3-lg) indan-7 (bN) -one hydroxy (200 mg) in polyphosphoric acid (2 ml) is stirred and heated up within 2h The reaction mixture is diluted with cold water, extracted with chloroform, washed with water, magnesium sulfate and evaporated to dryness. Crystallization of methanol gives the desired product in a yield of 160 mg (90% I: mp. 300–305 ° C (with decomposition).
    Example 10. 1-Acetyl-9-methyl1, 2,3,4,5,6-hexagndroindole (4,3-ig) isoquinolin-8 (7U-one is obtained according to the similar method from 1-acetyl-8methyl-2, 3, 4,5-tetrahydro-1H-indole (3,4-ig) indan-7 (6H) -one With a yield of 180 mg (90%). Mp.214-216 ° C.
    Approximately 11. 1-Acetyl-2,3,4, 5-tetragite) O-1H-indole (3,4-) indan-7 (6H) -one (2.2 g; 0.0087 M) in. glacial acetic acid (20 ml) was stirred and heated to 60 ° C. Sodium amide (0.6 g; O, 0087 M) was added.
    with post-php added dropwise concentrated sulfuric acid (2 ml) for 5 minutes. The reaction mixture is stirred at -65 ° C until the rapid evolution of gas ceases. Two other additions of sodium amide and concentrated sulfuric acid are carried out to completely convert the starting material. The reaction mixture is then poured into a mixture of ice and a saturated sodium bicarbonate solution, extracted into chloroform, washed with water, dried with magnesium sulfate and evaporated to dryness. Crystallization from methanol gives the desired product with a yield of 1.7 g (73%) and m.p. 300-305 ° С (with decomposition).
    Example 12, 1-Acetyl-9-methyl-1, 2, 3, 4, 5, b-hex sahydroindole. (4, 3-id) - and SOX and NOL and n-8 (7H) -one are obtained in the same way as described from 1 acetyl-8-methyl-2, 3,4,5-tetrahydro-1H-indole (3, 4-ig) indan-7 (bH) -one (75%), m.p. 214-21b ° C.
    Example 13. 1-Acetyl-9-methyl-1, 2,3,4,5,6-hexa hydroindole (4, 3-fg) isoquinoline-8 (7H) -one- is prepared analogously from 1-acetyl-8 -ethyl2, 3,4,5-tetrahydro-1H-indole (3,4-i) indan-7 (bN) -one with a yield of 85%. M.p. 213-215 ° C.
    Example 14. Preparation of Gacetyl-1, 2,3,4,5,6-hexahydroindole (4,3- ± g) -isoquinoline-8 (7H) -one.
    1-Atstsh1-1, 2,3,4,5, 6-hectare sagidroindole- (4.3-1) isoquinoline-8 (7H) -one (140 mg; 0.0005 M) is added to a stirred suspension of sodium hydride (dispersion 50%; 30 mg; 0.0006 M) in dimethylformamide (10 tin) at 60 ° C. Reaction: the mixture is stirred for 30 minutes, cooled down and methyl iodide (100 mg; 0.0007 I) is added. Stirring is continued for 30 minutes, the reaction mixture is diluted with water, extracted with chloroform, washed with water, cyiuaT magnesium sulfate and BI Tpariyvu to dryness. The geleic product is crystallized from ethyl acetate, yield 60 mg (37%). The structure is confirmed by mass spectrometry data.
    Example 15. 1-Acetyl-7,9 dimethyl-1, 2,3,4,5, b-hectare sahidroindole (3,) the isoquinoline-8 (7H) -one is obtained analogously from 1-acetyl-9-methyl-1 , 2,3,4,5, b-sag sagilroindol (4, 3-ig) isoquinoline-8 (7 #) -one, in 75% yield, m.p. 210-212 0.
    Example 16. Preparation of 1 acetyl-7-met yl-1,2,3,4,5, 6-hexahydroindole (4,3-f) isoquinolin-8 (7H).
     1-Acetyl-1, 2, 3,4, 5, b-hex sahydroindole (4.3-1) isoquinoline-8 (7H) -one (2.7; 0.01 M) and acetyltrimethylammonium bromide (3.7 g, -0.01 N) is suspended in tetrahydrofuran (50 ml) and stirred at room temperature. Methyl iodide (3 g; 0.02 M) and 50% NaOH (50 ml) are added and the mixture is stirred.; The reaction mass is poured into ice water, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography
    0 on silica gel 30 with elution with 10% methanol in chloroform and crystallization from ethyl acetate to give the title compound in a yield of 1.3 g (48%), and so forth. 250-255 ° C.
    5-, Example 17. 1-Acetyl-7-9dImethyl-1, 2,3,4,5, b-hexahydroindole (4,3-1) isoquinoline-8 (7H) -one is obtained analogously from 1-acetyl-9methyl -1, 2,3,4,5,6-hexahydroindole
    0 (4, 3-ig) nzokhinolin-8 (7H) -one with a yield of 58%, So pl. 210-212c.
    PRI mera 18. 1-Acetyl-9ethyl-7-methyl-1, 2,3,4,5,6-hexahydroindole (4, 3-fg) isoquinoline-8 (7H) -one
    5 in a similar way, from 1-acetyl-9-ethyl-1,2,3,4,5,6-hexahydroindole (4, 3-i) isoquinoline-8 (7I) it is obtained in 61% yield, m.p. 179-180s. Example 19. 1-Acetyl-9Q methyl-7K-PROPIL-1,2,3,4,5,6-hexahydroindole (4, 3-fg) the isoquinoline-8 (7H) -one is obtained analogously from 1-aethyl-9 -methyl-1,2,3,4,5,6-hexa-. gilroindole (4,3-fg) isoquinoline-8 (7H) -one with a yield of 91%. M.p. 75-78 ° C
    Example 20. 1-Acetyl-7-Chhexyl-9-methyl-1, 2,3,4,5,6-hexahydroindole (4, 3-) isoquinoline-8 (7H) -one is obtained from 1-acetyl-9- methyl-1,2,3, 4,5,6-hexahydroindole- (4,3-f) from 0 quinoline-8 (7H) -one with a yield of 81%, m.p. 82-84 ° C.
    Example 21 1-Acetyl-7allyl-methyl-1, 2,3,4,5,6-hexahydroindole (4,) isoquinoline-8 (7H) -one
    5 is prepared from 1-acetyl-methyl-1,2,3,
    4,5,6-hexahydroindole (4,3-i} isoquinoline-8 (7H) -one with a yield of 40%, So pl.
    Example 22. 1-Acetyl-7- (3,
    0 3-dimethylpropan-2-yl) -9-methyl-1,2, 3, 4, b, 6-hectare sahidroindole (4, 3-fg) isoquinoline-8 (7H) -one is obtained from 1-acetyl-9 -methyl-1, 2,3,4,5,6-hexahydroindole (4, 3-16) -isoquinoline-8 (7H) -one with.
    5 yield 71%, m.p. 89-9O C.
    Example 23. 1-ACetyl-7-cyclopropylmethyl-9-acetyl-1, 2,3,4,5,6 hexahydroindole (4,3-ig) isoquinolin8 (7H) -one is obtained from 1-acetyl-90 methyl-1, 2,3,4,5,6-hexahydroindole (4,3-f) isoquinoline-8 (7H) -one with a yield of 42%, m.p. 177-180 ° C.
    PRI and MER 24. 1-Acetyl-7-ben5 zil-1,2,3,4,5, b-hexahydroindole
    (4,3-fg) eoquinolin-8 (7H) -one is obtained analogously from 1-acetyl-E-Ethyl1, 2,3,4,5,6-hexahydroindole (4, 3-i) isoquinolin-8 (7H) - it has a yield of 30% and 1;. 215-218®C.
    Example 25. 1-Acetyl-7,9DI lethyl-lr 2,3,4,5,9,10-hexahydro-5 indole (4, 3-ig) isoquinoline-8 (7H) -one is obtained analogously to Example 14 by except that the reaction mixture was stirred at for 3 h, So pl. 233-235 ° C
    Example 26. Preparation of 1 acetyl-7-9-dimethyl-1, 2,3,4,5,6,9, Yu-octahydroindole (4,3-1) isoquinoline-8 (7H) -one.
    1-Acetyl-7,9-dimethyl-1,2,3,4,9, 10-hexahydroindole (4,3- {g) isoquinoline-8 (7H) -one (100 mg), in ethanol (20 ml) hydrogenated at 4.21 kg / cm over platinum oxide (10 mg) for 4 hours. The catalyst was removed by filtration and the solvent was removed in vacuo. Crystallization from a mixture of acetonitrile and diethyl ether gives the title compound with m.p. 204-20bs.
    Example 27 Obtaining 7methyl-1, 4,5,6-tetrahydroindole (4, 3-) isoquinoline-B- (7H) -one ..
    1-Lethyl-7-methyl-1,2,3,4,5,6 hexahydroindole (4,) isoquinoline8 (7H) -one (100 mg) in ethanol (20 ml) is treated with 50% sodium hydroxide solution (5 ml ) and stirred at 60 ° C for 18 h. The reaction mixture is poured into water: with ice, extracted into chloroform, washed with water, dried with magnesium sulfate and evaporated to dryness. The crude 7-methyl1, 2,3,4,5) 6-hexahydroindole (4,3-irf) isoquinoline-8 (7H) -one is dissolved in acetone and stirred for 18 hours. manganese dioxide on activated carbon (1 g). Manganese dioxide is removed by filtration, and the solution is evaporated to dryness. Crystallization from ethyl acetate gives the desired product in the form of crystals, the structure of which is confirmed by Maye spectroscopy data.
    Example 28 7,9-Dimethyl1, 4, b, 6-tetrahydroindole (4,3-itf) isoquinoline-8 (H) -one is obtained similarly from 1-acetyl-7,9-dimethyl- 1,2,3,4,5 , 6-gek sagidroindol (4.3-1y) isoquinoline-8 (7H) -one with. 237-239 ° C.
    PRI me R 29. 9-ethyl-7-methyl-1, 4, 5, b-tetrahydroindole (4,3-fg) and eoquinolin-8 (7H) -one are obtained in a similar way from 1-a "ethyl" -9-ethyl-7-methyl-1, 2,3,4,5,6-hexahydro (4.310) isoquinoline-8 (7H) -one with a yield of 51%, m.p. 246-249 ° C.
    Example 30 9-Ketil-7-Ng propyl-1,4,5,6-tetrahydroindole
    (4,3-itf) isoquinolin-8 (7H) -one is obtained analogously from 1-acetyl-9-methyl-7-H-PROPIL-1, 2,3,4,5,6-hexahydroindole (4,) isoquinoline -8 (7I) -one with the release of 36%, So pl. 192-195 ° C.
    Example 31 7-N-hexyl9-methylt-1, 4,5,6-tetrahydroindole 44, a) isoquinoline-817H) -one is obtained analogously from 1-acetyl-7-nhexyl-9-methyl-1, 2,3,4,5 , 6-hexa hydroxyphenol (4,3-ftf) isoquinoline-8 (7H) it with a yield of 35%, m.p. 139-141 ° C.
    Example 32 7-Allyl-9-methyl-1, 4.5, b-tetrahydroindole (4, 3-fg) isoquinoline-8 (7H) -one is obtained ana5 logically from 1-acetyl-7-allyl-9-methyl-1, 2,3, 4, 5,6-hexahydroindole (4, 3-itf) isoquinoline-8 (7H) -one with a yield of 55% ..
    Example 33. 7- (3,3-dimethylprrpen-2-IL) -9-methyl-1,4,5,6-tetra0 hydroindole (4,) isoquinoline-8 (7H) it is prepared analogously from 1-acetyl7- ( 3, 3-dimethylpropen-2-yl) -9-methyl-1, 2, 3,4, 5, 6-hexahydroindole (4, 3-f) 5 isoquinoline-8 (7H) -one with a yield of 48% and T .pl. 225-230 ° C.
    PRI me R 34. 7-CycloLopropylmethyl-9-ethyl-1, 4,5, b-tetrahydroindole (4,3-ig) isoquinolin-8 (7H) -one is obtained similarly from 1-acetyl-7-cyclo0 propylmethyl-9-ethyl-1, 2,3,4,5,6-hexahydroindole (4, 3-ig) isoquinoline-8 7H) -one with m.p. 213-215 C.
    Example 35 7-Renzyl-1,4, -6,5-tetrahydroindole (4,3-i) isoquinoline-8 (7H) -one is obtained analogously from 1-acetyl-7 benzyl-1,2,3,4,5,6hexahydroindole (4, 3-isoquinolin8 (7H) -one with a yield of 47%, mp. 207 208 ° C.
    0
    Example 36 .7,9-Dimethyl1, 4,5,6,9,10-hexahydroindole (4,) the isoquinoline-8 (7H) -one is obtained, analogously to III, 1-acetyl-7, 9-dimethyl 1,2,3, 4,5,6,9,10-octahydroindole (4, 5 3-i) isoquinoline-8 (7H) -one with T pl. 217-219s.
    JI p and m r 37. Preparation of 7-methyl-1, 4,5,6,7,8-hexahydroindole (4,) of isoquinoline maleate.
    07-Methyl-1,4,5,6-tetrahydroindole
    (4,) isoquinoline-8 (7H) -one (600 mg) is dissolved in dry benzene (10 ml) and stirred at room temperature. Sodium 5 bis (methoxyethoxy) aluminum (ReJ-aE) is then added as a 70% solution in benzene (0.5 mi) and the mixture is stirred for 2 hours. The reaction mixture is diluted with cold water, extracted
    0 in ethyl acetate, washed and dried with magnesium sulfate. Maleic acid (0.1 g) in ethyladetate (t5 ml) is added and the salt is crystallized to give 220 mg (79%) of the product with mp 5-20 ° -202 ° C. Example 38. 7,9-Dimvtil-1, 4,5,6,7,8-hect sagidroindole (4,3-frf) and eoquinoline are prepared analogously from 7,9-d and 1-methyl, 4, 5,6-tetrahydroindole . (4,) iaoquinolin-8 (7H) -one. M.p. 1bb-1b9 ° C. Example 39. Malein-9-ethyl 7-methyl-1,4,5,6, 7,8-hexahydroindole (4,3-) and eoquinolik receive similarly from 9-methyl-7-methyl-1, 4, b, 5 tetra Idol swarms (4, 3-fg) isoquinolin 8. (7H) -one with Y0% yield and m.p. 175-177 C. Example 40. 9-Methyl-7 I-prodyl-1,4,5,6,7,8-hexahydroindole (4.3 g) of isoquinoline maleate is prepared in a manner similar to that described from 9-methyl-7-Ü1 -propyl-1, 4,5, 6-tetrahydroindole (4,3-i) isoquinoline-8- (7H) -one with a yield of 76% and m.p. 130-132 ° C. Example 41. 7-H-hexyl-9-m thyl-1,4,5,6,7,8-hectare saohydroindole (4, .3-1) isoquinoline maleate is prepared analogously from 7-n- hexyl-9-methyl-1, 4,5, 6-tetrahydroindole (4,) isoquinoline-8 (7H) -one with a yield of 75%, and so pl. 149-151 ° C. Example 42 Maleinate-7-allyl-9-methyl-1, 4,5,6,7,8-hexahydroindole (4, 3-id) isoquinoline is prepared analogously from 7-allyl-9-methyl-1,4, 5 , 6-tetrahydrocndol (4,3-f) isohiiolin-8 (7H) -one with a yield of 80%, and so pl. 153-155 ° C. Example43. 7- (3,3-Dimethyl prop.en-2-yl) -9-methyl-1,4,5,6,7,8 hexahydroindole (4, 3 ig) isoquinoline maleate is obtained similarly from 7- (3, 3 -dimethylpropan-2-yl) -9-methyl1, 4, 5, b-tetrahydroindole (4,) isoquinoline-8 (7H) -one with yield 80 and so pl. 105-106 ° C. Example 44. Naleinate-7-cycpropylmethyl-9-ethyl-1,4,5,6,7, 8-hexahydroindole (4,3-f) isoquinoline is prepared analogously from 7-cyclopropylmethyl-9-ethyl-1, 4, 5,6-tetrahydroindole (4, 3-ig) isoquinoline-8 (7H) -one. Example 45. Malein-7-6en zyl-1,4,5,6,7,8-hexahydroindole (4,3- {gj isoquinoline is prepared analogously from 7-benzyl-1,4,5,6-tetrahydroindole 4,3- 4) isoquinoline-8 (7H) -one with a yield of 61% and So pl. 206-208 ° C. Example 46 Maleinate-7,9 dimethyl-1, 4,5,6,7,8,9,1O-octagiroin LOL (4,3-ig) isoquinoline is obtained similarly from 7,9-dimethyl-1,4,5,6, 9 , 10-hexahydroindole (4, 3-1) isoquinoline-8 (7H) -one. Example 47. 1,4,5,6-tetrahydroindole (4, -ig) isoquinoline-8 {7H) it. 1-Acetyl-1,2,3,4,5,6-hexahydroindole (4,3-ig) isoquinoline-8 {7H) -one (100 mg) in ethanol (5 ml) and stirred for 18 hours. The reaction mixture is ne The mixture is cooled to ice water, extracted into chloroform, washed with water, dried over magnesium sulfate and evaporated to dryness. The crude 1,2,3,4,5,6-hexahydroindole (4, 3-ig) isoquinoline 8 (7H) -one is dissolved in acetone and stirred for 18 hours with manganese dioxide on activated carbon (1 g). Manganese dioxide is removed by filtration and the solution is evaporated to dryness. Crystallization from ethyl acetate gives the desired product with m.p. 142-144®C. The structure of the compound is confirmed by the combined data obtained from the analysis of IR-UV and mass spectra. . Example 48. 9-P1ethyl-1,4, 5,6-tetrahydroindole (4.3-1) the isoquinoline-8 (7H) -one is obtained similarly from 1-acetyl-9-methyl-1,2,3,4, 5,6 Hexahydroindole (4,) isoquinolin8 (7H) -one with m.p. 198 ° C (ethyl acetate). . Example 49. Preparation of 7-cyclopropylacetamido-9-methyl-1,4, 5, 6-tetra idroindole (4, 3-fg) isoquinoline-8 (7H) -one. To a solution of 9-methyl-1,4,5,6-tetrahydroindole (4, 3-fg) isoquinoline-8 (7H) it (40 mg) in methylene chloride (10 ml) are added triethylamine (5 drops) and cyclopropanecarboxylic chloride acid (4 drops). The reaction mixture was stirred for 4 hours, diluted with methylene chloride, washed with water, dried with magnesium sulfate and "ocyxa" evaporated. Crystallization from ethyl acetate gives the desired product. Example 50 1,4,5,6,7,8. Tetrahydroindole (4, 3-fg) isoquinolin8 (7H) -one (20 mg) is dissolved in dry benzene (10 ml) and stirred at room temperature. A 70% solution was added, in benzene (0.1 ml) and stirred for 2 hours. The reaction mixture was diluted with water, extracted into chloroform, washed with SODA, dried with magnesium sulfate and evaporated to dryness. The crude amide was dissolved in ethyl acetate (5 ml) and maleic acid (10 mg) in ethyl acetate (1 ml) was added. The crystalline product is collected by filtration. Example 51 G1 aleinate-9methyl-1, 4,5,6,7,8-hexahydroindole (4, 3-1) isoquinoline is prepared analogously from 9-methyl-1,4,5,6-tetrahydroindole (4,3-) isoquinoline-8 (7H) she with T. pl. 198-200s. Example 52 Maleinate-7-cyclopropylmethyl-9-methyl-1, 4,5,6,7,8 hexahydroindole (4,3-f) isoquinoline is obtained similarly from 7-cyclopropylacetamide-9-methyl-1, 4,5,6 -tetrahydroindole (4, 3-fg) isoquinoline-8 (7H) - it. Example 53 Preparation of 4.5 DIGIDRO-1H-INDOL (3.4-) indan-7 (bN). 1-BenZIL-4-acetonyl-1,2,3,4-tetr hydrobene (C (j) indole- (4H) -one (1.3, g; 0.004 M) in ethanol (100 ml) under nitrogen atmosphere is treated caustic potassium (2 g) and heated under reflux for 2 h. The reaction mixture is poured over ice and water, extracted with chloroform, dried with magnesium sulfate and evaporated to dryness. Crude 2,3,4,5-tetrahydr-1N indole ( 4)) indan-7 (6H) -one is dissolved in acetone (50 ml) and reduced to manganese dioxide on activated charcoal for 36 hours. Manganese dioxide is removed by filtration and the solution is evaporated to dryness. chloro form and ethyl acetate get the target product as a crystalline solid. Example 54. 8-Methyl-4,5-dihydro-1 JH-indole (3,4-ig) indan-7 (BN) it is prepared analogously from 1-baseoyl 4 ( 2-oxobutyl) -1,2,2a, 3-tetragamide (c) indol-5 (4H) -one with a yield of 30% and T. pl. 257-259 C. PRI me R 55. Oksim-4 , 5-dihydro-1H-indole (3,4-ig) indan-7 (6H), it (200 mg), hydroxyl hydroxylic acid (100 mg) and sodium acetate (50 m in n-propanol (10 ml) are heated under reflux for 18 s. The reaction mixture is diluted with chloroform, filtered through an alumina pack and evaporated to dryness. Crystallization from carbon tetrachloride gives the desired compound in a yield of 150 mg (75%). Example 56. Oxime-8-metsh-4, 5-DIHYDRO-1H-INDOL (3,) indan-7 (bN) -one is obtained similarly from 8-methyl-4, 5-DIHYDRO-1H-INDOL (3,4-ig) indane- 7 (6H) -one with T. pl. 190-200С. Example 57 Obtaining 11 acetyl-7-hydroxy-8-methyl-, 3,4,5,6,7,8, 9-octahydro-1H-indole (3,4-) indane, 1-Acetyl-8-methyl-2,3 , 4,5-tetraHYDRO-1H-INDOL (3,4-ig) indan-7 (bN) it (100 mg) in 31 thanol (100 ml) with platinum oxide (10 mg) is hydrogenated at a pressure of 4.219 kg / cm to a pre-cool hydrogen absorption. The catalyst is removed by filtration, and the solvent is evaporated to dryness. Crystallization from ethanol gave the title compound in a yield of 80 mg (80%), m.p. 223-224 ° C. Example 58 Getting 1- ,, acetyl-8-methyl-2,3,4,5,8,9-hexaHYDRO-1H-INDOL (3,4-ig) indan-7 (6H) it. 1-Acetyl-7t.io si-8-methyl-2,3,4, 5,6,7,8,9-octahydro-1H-INDOL. (3.4-4 |) Yidan- (50 mg) in acetone (10 ml) is stirred and treated with Jones reagent (1 ml). Re-batching is continued for 18 hours and excess methanol is added to decompose excess reagent. The reaction mixture is then evaporated to dryness. And distributed in water and chloroform, the solvent is separated, washed with water, dried over magnesium sulfate and evaporated to dryness. The expected product is obtained which is crystallized from ethyl acetate in 68% yield, m.p. 171-172 ° C. For example, 59. Preparation of I-acetyl-9-methyl-1,2,3,4,5,6,9,10-octahydroindole (3,4-gh) isoquinolin7 (bH) -one, 1-Acetyl-8-methyl-2, 3,4,5,8-hexahydro-1H-indole (3,4-ig) indan-7 (bN) -one (100 mg) in glacial acetic acid (5 ml) is measured and heated to. Sodium azide (40 ml) is then added, followed by the addition of concentrated sulfuric acid (0.1 ml). Stirring is continued until cessation of gas generation at 50-55 ° C. Further addition of sodium azide and concentrated sulfuric acid ensures complete conversion of the starting material. The reaction mixture was poured into a mixture of ice and a saturated sodium bicarbonate solution, extracted into chloroform, washed with water, dried with magnesium sulfate and evaporated to dryness. Crystallization from ethyl acetate gives the desired product, m.p. 224-2ab ° C. PRI me R 60. Getting 9methyl-1, 4,5,6,9,20-hexahydroindole (3,) isoquinone-7 (8H) -one. 1-Acetyl-9-methyl-1,2,3,4,5,6,9, 10-octahydroindole (3,) isoquinoline-7 (bN) -one (100 mg) in ethanol (10 ml), perm; It is eaten at room temperature. A 50% sodium hydroxide solution (5 ml) is added and stirring is continued for 18 hours. The reaction mixture is then poured onto ice; extracted with chloroform, washed with water, dried over magnesium sulfate and evaporated to dryness. Get the target product, the structure of which is confirmed by NMR and mass spectra. . Example 61 Preparation of 1-acetyl-8, 9-dimethyl-1,2,3,4,5,9,10-octahydroindole (3,) and oxo1 nolin7 (8H) -one. A solution of 1-acetyl-9-methyl-1,2,3 4,5,9,1,0-octahydroindole (3,) isoquino jn-7 (8H) -one (100 mg) and sodium hydride (20 mg) in Suksad dimethylformamide (20 ml) is transferred under nitrogen and heated to 60 ° C. within 30 min. The reaction mass is cooled before and methyl iodide (0.1 ml) is added. The mixture was stirred for 30 minutes and diluted with water. Extraction with chloroform, washing with water, drying with magnesium sulfate and evaporation to dryness gave the title compound, which was crystallized from ethyl acetate. M.p. 184-186 ° C. Example 62 nojiyjteHiafif 8 9Dimethyl-1, 4,5,6,9,10-gyok sagidroindole (3,) isoquinoline-7 (8H) -one. 1-Acetyl-8, 9-dimethyl-1, 2, 3,4., 5, 6,9,10-octahydroindole (3,4-h) and zoquinalin 7 (8H) -one (0.3 g) in acetic acid (10 ml) and concentrated hydrochloric acid (10 ml) is heated under reflux for 5 hours. The reaction mixture is poured into ice-water, made alkaline with sodium hydroxide, extracted into chloroform, washed, dried with magnesium sulfate and evaporated. The white solid obtained was redissolved in acetone (20 ml) and manganese dioxide was added on activated carbon (3 g). The mixture was stirred for 10 hours, the catalyst was filtered off, the solution was evaporated in vacuo and crystallization from ethyl acetate gave the desired product. Mp 250-252 ° C., Example 63. Preparation of 8.9 dimethyl-1, 4,5,9,10-hexahydroindole (3,) ieoquinoline. 8,9-Dimethyl-1,4,5,6,9,10-hexahydroindole (3,) isoquinoline-7 (8H) it (50 mg) is dissolved in dry benzene (GO ml) and stirred at room temperature. Add RecJ-Ae (0, l ml). The solution is stirred for 2 hours, poured into cold water, extracted with chloroform, washed with water, dried with magnesium sulfate and evaporated to dryness. Obtain the desired product, the structure of which subtyers (shed by mass spectral analysis. Example 64. 7,9-Dimethyl-1, 4,5,6,7,8-hexahydroindole (4.3-1) isoquinoline (700 ml) is dissolved Phenyltrimethylammonium tribromide (1.1 g) was added to tetragndrofuran (50 ml) and the mixture was outweighed for 2 hours at room temperature, diluted with water, basified with sodium hydroxide solution, extracted with ethyl acetate, washed, dried and evaporated to dryness. and after evaporation 500 mg of a white solid is obtained. the solution is dissolved in ethanol and maleic acid (0.3 g) is added. The solution is boiled with ether until the appearance of crystals, 2-bromo-7,9-dimethyl-1,4,5,6,7,8 hexahydroindole ( 4,3-f) isoquinoline (maleic acid salt) is filtered off, mp 194-19 bs.
    权利要求:
    Claims (1)
    [1]
    . METHOD OF OBTAINING ARRANGEMENT- 1 OF ITSOCHYNOLINE OR THEIR SALTS. , A method for producing derivatives of ioquinoline of the general formula “1 where A B - —CHg — NR ^ or KR ^ —CH ^; R ^ is hydrogen, methyl, ethyl or benzyl; R <u is hydrogen or R <and together is a chemical bond, provided that when AB-NR · "-CH then th Ά ~ not a chemical agent;
    R} is hydrogen, C ^ -C ^ -alkyl, cyclopropyl, cyclopropylmethyl, benzyl, C ^ C-alkenyl or acetyl; X is hydrogen or bromine, or their salts ’, with the fact that the compound of the general formula
    L has gder —E — CO — NR-j or K ″ 3 —CO; the indicated values are reduced with sodium bis- (methoxyethoxy) -aluminate or lithium aluminum hydride at 0 - 50 ° С and the target product, where X-hydrogen. the target product, where X is bromine, in the free entry or in the form of a salt. *
    Feature priority:
    05/23/78 at X - hydrogen; 04/12/79 at X - bromine.
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    同族专利:
    公开号 | 公开日
    DE2962784D1|1982-07-01|
    EP0005646A1|1979-11-28|
    FR2453860A1|1980-11-07|
    NZ190513A|1982-03-30|
    CH641802A5|1984-03-15|
    GB2031409B|1982-12-08|
    FI64595C|1983-12-12|
    DD143776A5|1980-09-10|
    AU4728879A|1979-11-29|
    PT69645A|1979-06-01|
    MX5565E|1983-10-14|
    EG14314A|1983-12-31|
    YU120079A|1983-06-30|
    RO77552A|1982-02-01|
    PL121298B1|1982-04-30|
    FR2453860B1|1982-02-19|
    FI791615A|1979-11-24|
    US4277480A|1981-07-07|
    CA1118423A|1982-02-16|
    IL57344A|1982-05-31|
    EP0005646B1|1982-05-12|
    GB2031409A|1980-04-23|
    US4245095A|1981-01-13|
    USRE31194E|1983-03-29|
    IL57344D0|1979-09-30|
    PL215772A1|1980-07-14|
    FI64595B|1983-08-31|
    BG30326A3|1981-05-15|
    DK209279A|1979-11-24|
    AU525554B2|1982-11-11|
    HU180494B|1983-03-28|
    ES480849A1|1980-02-01|
    AR223177A1|1981-07-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE3207775A1|1981-03-13|1982-09-23|Sandoz-Patent-GmbH, 7850 Lörrach|METHOD FOR PRODUCING MOTHER-CORNAL CALOIDS|
    DE3402392A1|1984-01-25|1985-08-01|Sandoz-Patent-GmbH, 7850 Lörrach|NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND THEIR USE|
    GB8419278D0|1984-07-27|1984-08-30|Lilly Industries Ltd|Pharmaceutical compounds|
    DE4033496A1|1990-10-20|1992-04-23|Sandoz Ag|NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND USE|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB2135578|1978-05-23|
    GB7912970|1979-04-12|
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