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    • 专利摘要:
    Novel 2-azaergolines, 2-aza-8(or 9)-ergolenes, which are neuroleptic agents, are described herein. These compounds are prepared by reacting a 7-amino-6-ketobenzo[f]quinoline with a diazotization agent. e.g. sodium nitrite and a strong mineral acid, to yield the 6-keto-7-diazonium salt intermediate, followed by reduction to yield the final product.
    公开号:SU1005662A3
    申请号:SU792786204
    申请日:1979-06-28
    公开日:1983-03-15
    发明作者:Карл Корнфельд Эдмунд；Джеймс Бах Николас
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    where R and the dotted line have the above meaning, and R takes the values R, except where X is methylthio groups, is reacted with alkali metal nitrite in the presence of a strong inorganic acid followed by oxidation with sulfur dioxide and, if necessary, the compound of formula I obtained, where R the group —CH2. X, where X is mesyl, is treated with methyl mercaptide sodium to produce a compound of general formula i, where CH2X, where X is a methylthio group, followed by isolation of the target product in free form or as a salt, Coe Dinene of the general formula I or their salts exhibit neuroleptic activity. Example 1. Getting D-6-n1-propyl-8-beta-methoxymethyl-2-azaergoline. 1.9 g of the methanesulfonate salt 0-6-n-propyl-8-beta-methoxymethyl ergoline is dissolved in 50 ml of methanol and 50 ml of water. This solution is added to a solution containing 2.14 g of sodium periodate in 200 ml of water. The reaction mixture is stirred for 2 1/4 h, then diluted with an aqueous solution of sodium bicarbonate and the resulting basic solution is thoroughly extracted with chloroform. The chloroform extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the chloroform in vacuo, a residue containing N-t1,2 a, 3,4,4a, 5,6,10 a and a: 1-octahydro-2 beta- (methoxymethyl) -6-oxo-4-n-propylbenzo-benzo C-) quinolin-7-ylSformamide. This compound is purified by chromatography on 35 g of phlorisyl, using chloroform as an eluent, containing increasing amounts of (1-2) methanol. The fractions in which the content of the target compound was established by thin layer chromatography were combined, and the solvent was evaporated from the combined fractions in vacuo. The benzoquinoline obtained is converted to maleate by dissolving the free base in ether and adding a solution of maleic acid in the ether to it. After recrystallization of the salt from methanol-ether, 1.1 g of maleate (-p. -A, 3.4, 4a, 5.6.10) o6-octahydro-2-beta (meth. Oxymethyc) -6-oxo-4 are obtained. -n-propyl-benzo-10 2 - (f) -quinolin-7 yl} formamide with m.p. 172-173 ° C. mg of maleate is dissolved in a mixture of 100 ml of methanol and 100 ml of a 1O aqueous sodium hydroxide solution. The hydrolysis mixture is stirred at room temperature for 1/2 hour and then diluted with water. The healing solution is extracted with several portions of chloroform and the chloroform extracts are combined. The combined extracts are washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the chloroform, 0.62 g of 2-beta-, (methoxymethyl) -n-propyl is obtained. b-oxo-y-amino-1 2a ,, 5,6,1 Ov o (goctahydro-benzo-) quinoline as a residue, which is recrystallized from methanol. M.p. 81-88 C. The crystalline amino ketone {2 mmol) is dissolved in a mixture of 10 ml of water and 10 ml of 12N. an aqueous solution of hydrogen chloride. The mixture is cooled to a temperature. A solution containing 150 mg of sodium nitrite and 5 ml of water was added dropwise to the mixture. Then this diazotizing solution was added dropwise to 50 ml of sulfuric acid saturated with sulfur dioxide, while maintaining the temperature of the reaction mixture in the range of 0-5 ° C. Sulfur dioxide gas is bubbled through the reaction mixture during the entire reaction. The reaction mixture is left at room temperature for 16 1/2 hours, after which it is alkalinized with a concentrated aqueous solution of sodium hydroxide. The solution is extracted in several portions of a mixture of chloroform with isopropanol. The organic extracts are isolated, combined, washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the solvent, a residue is obtained containing 1) -6-n-propyl-8-beta-methoxymethyl-2-azaergoline. The chloroform solution of the residue is chromatographed on 30 g of florisil using chloroform containing increasing amounts of (2-3) methanol as eluent. The fractions in which the content of the desired 2-azaergoline was determined by thin-layer chromatography were combined and 5bO mg) -6-n-propyl-8-beta-methoxymethyl-2-azaergoline was obtained, mp. 25b-258c (with decomposition. The corresponding mesilate 510 salt is melted at 257-259 ° C (with decomposition) after recrystallization from ether-methanol. In the manner described above, lysergic acid methyl ester is oxidized with sodium periodate to obtain the corresponding 2- beta-methoxycarbonyl- -methyl-6-oxo-7-formamido-2 ,,, 6-hexahydrobenzo- (|) -quinoline, which melts at a temperature higher than EPA after recrystallization from methanol. After carrying out hydrolysis to remove the formyl group, followed by dyavo tirovaniye and vos I-6-methyl-8-beta-methoxycarbonyl-.2-azag-9-ergolen is obtained by the formation of the diazonium salt with sulfuric acid. Similarly, by oxidation of the ergopovine maleate, M-C2-hydroxy-1-methylethyl) -2.3, , 5,6-g-xsagydro-t-n-propyl-6-oxo-1-burmamidobenzo- (U quinoline-2-beta-k.arboxamide. Removal of formyls: group 1 followed by diazotization of the resulting amine and reduction of the diazonium salt using sulfuric acid results in yl- (2-hydroxy-1-methylethyl) -6-n-propyl-2-aza-9-ergrhenyl-8-beta-yl-carboxamide. I ...... Example 2. Preparation of 2-azaelimoclavine (1 -6-methyl-8-beta-hydroxy methyl-2-aza-8-ergolene. In accordance with the method described in examples 1 and 2, 1 g of elimoclavine methanesulfonate and 50 ml of water are added to a solution of 2.6 g of sodium periodate in 200 ml of water. The product is isolated and purified by the method described in Example 1. Chromatograph the separated crude product on florisil,. Chloroform containing increasing amounts (2-S%) of methanol as eloent. Chromatographic fractions containing 3, a, 5,6,10a-hexahyd (p) O-3-ximethyl-4-methyl-6-ok-7 formamido benzo- (f) -quinoline, evaporated in vacuo. After recrystallization, a 3,, a, 5,6, 10c «-hexahydro-2-hydroxymethyl-methyl-6-oxo-7-formamidobenzo- (f) -quinoline melts at ikZ-Vk C (with decomposition) after recrystallization from a mixture of ether with a small amount of methanol. 1 g of the formamide derivative is dissolved in 50 ml of methanol, to which 50 ml of a 10% aqueous solution of sodium hydroxide is added. 7-LMI626 noso-compound formed during hydrolysis was isolated according to the method described in Example 1, yield 0.7 g, 3 O ,, 1 Ov o1 hexahydro-2-hydroxymethyl-b-oxo-y-amino-C-methylbenzo- (f) -quinoline is dissolved in 20 ml of 6N. an aqueous solution of hydrogen chloride. The acidic solution is cooled in an ice-water bath, pactBOp 190 mg of sodium nitrite in 5 ml of water is added dropwise to pactBOp. The resulting solution, containing 7-diazonium chloride, is slowly added to the solution with 50 ml of 7N. sulfuric acid saturated with sulfur dioxide at. Sulfur dioxide is bubbled through the reaction mixture during the period of addition, and another 15 min after its completion4 The reaction mixture is kept at room temperature overnight and then basified with Cn. aqueous solution of the hydrate of ammonium oxide. The resulting 2-azaelimoclavine is extracted with several portions of a mixture of solvents, chloroform and isopropanol. The extracts are combined, washed with saturated sodium chloride solution and dried. After evaporation of the solvents, a residue containing 2-aza-elimoclavine is obtained, which is purified by chromatography on 30 g of phlorisil, using chloroform containing increasing amounts (2-10) of methanol as eluent. Fractions containing 2-azaelimoclavine are combined. Hydrochloride is prepared by dissolving the free base. in ethanol and adding an equivalent amount of ethanolic hydrogen chloride solution. The resulting 2-azaelimoclavine hydrochloride melts at temperature U by decomposition), Example 3- Preparation of D-6-methyl-8-beta-methylthi methyl-2-azaergoline. 1 g of 0-6-methyl-8-mesyloxymethyl ergoline and 0.2 ml of methanesulfonic acid are dissolved in 50 ml of methanol. This solution was added to a solution containing 1.3 g of sodium periodate in 100 ml of water, stirred at ambient temperature for 2.75 hours, after which the mixture was diluted with a saturated aqueous solution of sodium bicarbonate. The alkaline mixture is extracted with several portions of chloroform, the chloroform extracts are washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the solvent
    In vacuo, a residue containing ND 2, 5,6,10 in a.-octahydro-2-beta- (mesyloxymethyl) -6-oxo-α-methylbenzo-(f) -quinolin-7 or formamide is obtained, which is purified by chromatography 5 35 florizil using as eluent chloroform containing increasing amounts of () methanol. The fractions containing the desired product are combined and the solvent is removed to remove them in vacuo. The obtained N-ll, 2,, 3, a, 5,6,, ktahydro-2-beta- (mesyloxymethyl) -4-methyl-6-oxo-benzo- (f) -quinolin-7-yl jCHOrmamide crystallizes from ether, m.p. 145 is 1tt6 ° C ...
    815 mg, 2,3, 4a, 5,6,1.0 volo.-octagidro-2-beta (mesyl oximethyl) - | -methyl-b-oxo-benzo- (f) -quinolin-7 or formamide is suspended in 50 ml of methanol . To the suspension was added .50 ml of 1 One aqueous solution of sodium hydroxide. The hydrolysis mixture is stirred at room temperature under a nitrogen atmosphere for jj 1.75 hours. The reaction mixture is diluted with water and extracted with several portions of chloroform. The chloroform extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. After kyparivanie chloroform receive the residue 650 mg of 2-beta-mesyloxymethyl-methyl-6-oxo-7-amino-1, 2,3, 9,5,6,10 in a-octahydro-benzo-SOHINOLINA, which is recrystallized from ether Bp.139 BUT ° C.
    2, C g 2-beta- (mesyloxymethyl-α-methyl-6-oxo-7 amino-1, 2, 5, 6.10 thio1-octahydro-benzo - ({} - quinoline) is dissolved in a mixture of 25 ml of water and 12 n, ° aqueous solution of hydrogen chloride,
    cooled in an ice water bath. A solution of 570 mg of sodium nitrite in 15 ml of water is added dropwise, after which the resulting solution is quickly added 45 p. P. Portion to 125 ml of a 7% aqueous solution of sulfurous acid saturated with sulfur dioxide at. Sulfur dioxide is bubbled through the reaction mixture, for an addition and a d-50 for an additional 15 minutes. The reaction mixture is kept at room temperature for 2k h, and then poured onto ice. The acidic solution is made alkaline by adding a 10% aqueous solution of sodium hydroxide js. The mixture was extracted with several portions of a mixture of chloroform and isopropano. The organic extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the solvent, a residue is obtained containing 0-6-methyl-8-bta-mesyloxymethyl-2-azaergoline, melting at 183-with decomposition after recrystallization from methanol.
    1.5 g of methyl mercaptan is dissolved in 100 ml of dimethylformamide and the solution is cooled in a bath of ice water. In portions, add 1, 5 g of Yttrium hydride in the form of a 50 ° oh suspension in mineral oil. After the addition of sodium hydride is complete. A solution of 1 g of 1) -b-methyl-8-beta-Meter is added dropwise. Zyloxymethyl-2-azaergoline in 50 ml of dimethylformamide. The cooling bath is removed and the reaction mixture is stirred for 1.75 hours at room temperature. The reaction mixture is then diluted with water and extracted with several portions of ethyl acetate. The ethyl acetate extracts are separated and the combined extracts are washed with a saturated aqueous solution of sodium chloride and sushi. After evaporation of the solvent, a residue is obtained containing 3) -6-methyl-8-beta- (methylthiomethyl) -2-azaergoline. The compound was purified by chromatography on florisil using chloroform containing increasing amounts of (O-J) methanol as eluent. The fractions containing the desired compound were combined and the solvent was evaporated. The resulting residue, containing purified 0-6-methyl-8-beta- (methylthio. Methyl -2-azaergoline, m.p. 218: 221 C (with decomposition). The free base is suspended in 10 ml of hot methanol and added 0.15 ml of methanesulfonic acid and 5 ml of methanol. The mixture is heated to dissolve. After that, the solution is cooled to an ambient temperature. The methanesulfonate salt of 0-6-meth-8-beta- (methylthiomethyl -2-azaergoline melts at a temperature of about ( with decomposition), 90% yield
    权利要求:
    Claims (1)
    [1]
    Claim Method Half-Body Derivatives of 2-azergoline of General Formula I
    /
    B-3
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    同族专利:
    公开号 | 公开日
    EG14250A|1983-12-31|
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    FI66381B|1984-06-29|
    BE877263A|1979-12-27|
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    IE48360B1|1984-12-26|
    CA1107275A|1981-08-18|
    AU528075B2|1983-04-14|
    FR2451375B1|1982-02-19|
    GB2044247A|1980-10-15|
    ATA452379A|1982-11-15|
    HU181678B|1983-11-28|
    AT371465B|1983-06-27|
    FI792044A|1980-09-17|
    IL57667A|1983-06-15|
    EP0016274B1|1983-02-16|
    DK268379A|1980-09-17|
    JPS6228794B2|1987-06-23|
    PL128622B1|1984-02-29|
    JPS55124782A|1980-09-26|
    US4201862A|1980-05-06|
    GB2044247B|1983-08-17|
    GR72397B|1983-11-01|
    ZA793246B|1981-02-25|
    ES482092A0|1980-08-01|
    AU4841379A|1980-09-18|
    LU81437A1|1979-09-12|
    AR222178A1|1981-04-30|
    NZ190832A|1983-07-15|
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    IE791212L|1980-09-16|
    CS213380B2|1982-04-09|
    ES8202341A1|1980-08-01|
    DD144671A5|1980-10-29|
    CH641803A5|1984-03-15|
    YU154679A|1983-10-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    IL65269D0|1981-03-24|1982-05-31|Lilly Co Eli|6-substituted hexahydroindazolo or hexahydroisoindolo isoquinolines|
    GB2112382B|1981-11-06|1985-03-06|Erba Farmitalia|Ergoline derivatives|
    GB8419278D0|1984-07-27|1984-08-30|Lilly Industries Ltd|Pharmaceutical compounds|
    US4798834A|1987-08-31|1989-01-17|Eli Lilly And Company|Optionally substituted (3β-9,10-didehydro-2,3-dihydro ergoline as serotonergic function enhancement|
    JPH02111285U|1989-02-27|1990-09-05|
    JPH0625197U|1992-01-14|1994-04-05|森下株式会社|Net transport bag|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/021,055|US4201862A|1979-03-16|1979-03-16|2-Azaergolines and 2-aza-8-ergolenes|
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