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    • 专利摘要:
    Short acting reversible neuromuscular blocking agents of the formula: <IMAGE> where B and C are para or preferably meta, and each is <IMAGE> where m is 2, 3 or 4 and is preferably 2, R1, R2, R3, R4, R5, R6 and R7 are the same or different and are hydrogen or alkoxy of 1 to 4 carbon atoms, Y is alkyl of 1 to 4 carbon atoms, n is 2, 3 or 4, most preferably 3, provided that at least one of R1 to R4 and one of R5 to R7 is lower alkoxy, and X is a pharmaceutically acceptable anion are useful upon administration to a patient in providing muscular relaxation in the patient during surgery and are normally intravenously administered in a pharmaceutically acceptable carrier.
    公开号:SU862820A3
    申请号:SU782646252
    申请日:1978-07-31
    公开日:1981-09-07
    发明作者:Дж. Савариз Джон；Дж.Китз Ричард；Джинберг Сара
    申请人:Дзе Массачусетс Дженерал Хоспитал (Фирма)；
    IPC主号:
    专利说明:

    is reacted with a compound of the general formula a (CHg)) mQ where n, t, Y and each of the radicals RI -Rj have the above meanings, Q and Q t; functional atoms or groups that react to form an ether bond, preferably in an inert solvent medium. Example. Preparation of bis-3-N-methyl-1- (3,4,5-trimethoxybenzyl) -6,7, -dimethoxy-1,2,3, 4-tetrahydroisoquinoline-propyl-m-phenklen-3, 3-dshloride dshlorido (HH110).:. 1 Production of m-phenylenedipropinate silver. A mixture of m-phenylene dipropionic acid 4.4 g (40 mEq), HjO 60 ml, KOH 1 n. 40 ml is heated to boiling and, if necessary, the pH is adjusted to 7.0 using the same acid. AdO3. 6.8 g (40 mmol) is added to the yellow, hot solution. An abundant precipitate forms. The mixture is cooled and filtered, and the filter cake is washed with water, filtered again and dried. The output is quantitative. The product is a slightly amorphous powder. Its ground powder is powdered for use in the next step. 2. Getting U-methoxylaudanosine. 3,4-Dimethoxy shshethylamide and 3,4,5-trimetoxyphenylacetic acid are heated at 165-190 ° C in a flask until the allotment of water ceases. The product N- (3,4,5-trimethoxy trichloride TRl) -homoveratrylamine is recrystallized from methanol. Output 80%, so pl. 94 ° C. 3.9 g (10 mmol) of N- (3,4,5-trimethoxyphenyl acetyl) -homoveratrylamine is heated with a reverse cold in 15 ml of toluene with 5 ml of POC1 for 2 hours. Precipitated semi-solid substances are sharp. but separated (excess POCtj), the free base was removed by adding excess NaOH and extracted with benzene. The resulting product. - 6,7-dimethoxy-1 - (3, 4, 5 -trimeto xibenzsh1) -3,4-dihydroisoquinoline is heated under reflux in acetone or benzene with an excess of methyl iodide. The yutvertic salt of 6,7-dimethoxy-1- (3, 4, 5-trimethoxybenzyl) -2-methyl-3,4-dihydrosoquinoline iodcc precipitates. Melting point 224 C. 1 g (10 mmop) of 6,7-dimethoxy-1- (3, 4,5-tr 1 Shvtoxybenzyl) -2-methyl-3,4-dihydroisoquinol 1 your iodide is dissolved in 80 ml of O and 16 ml of concentrated HCI. Zinc dust (1.1 g) is added to the boiling stirred solution in small portions. Yellow color disappears (reaction time 15-20 min). The mixture is filtered hot from some unreacted zinc and made alkaline with concentrated NaOH. It is not necessary to filter out the partially precipitated zinc hydroxide, and to avoid emulsification, the whole mixture is gently shaken with chloroform. The residue in the chloroform solution is dissolved in ether and the insoluble matter is filtered off in ether. The ether residue does not crystallize upon standing. This amine is a viscous material that solidifies at 100 ° C. The crude amine is used in the next step. 3. Preparation of M- (3-chloropropyl) 5-methoxyl udanosine bromide. 1.4 g (4 mmol) of 5-methoxy laudanosine is dissolved in 8 ml of dimethylformamide with slight heating. 1.2 g (100% excess) of 1-bromo-3-chloropropanes is added and the mixture is left at room temperature for 5 days (some of the unreacted 5-toxyl udanosine sometimes crystallizes, but ultimately dissolves). The reddish-orange solution is treated with a large amount of ether, the precipitated resinous quaternary salt is drunk: suspended in fresh ether. After one hundred hours in ether for one day, low melting point solids are obtained. Yield 1.6 g (80% of theoretical). 4. Preparation of m-phenylene dipropionate ester of dibasic acid N-npomoi-S-methoxyyl udanosine (HH 110). A mixture of M- (3-chloropropyl) -5 - labels of Siluydanozi1b bromide 2.1 g (4 mmol), silver m-pekeylene dipropionate 0.85 g (4 mmol), and HjO 150 ml boiled in an open teapot for 10- 15 min from time to time moving. At the boiling point, the silver salt dissolves and reacts with quaternary bromide. The mixture is cooled to room temperature, filtered, and the aqueous solution is scrubbed to dryness in a large tea-pot on a steam Gata. After heating for 2 hours on a steam bath (90 ° C), neperpjrmrapoBEca ester is terminated. The amorphous residue is boiled with isopropyl (40 ml) and filtered hot from traces of mechanical impurities. The resin precipitates from the filtrate at room temperature, and ends with precipitation at -3 ° C overnight. The surface layer is collated and the material is suspended twice in ethyl acetate. At the same time, the resin is semi-solid and can be filtered out. After careful drying at 75 ° C, the resin becomes solid. At this stage, the substances still hold water. Output 1.0 g (40%). Outputs are distinguished; from piston to serving. T. pl. 80-90 ° C. (with different). AnalysisCalculated,% Found,% C52.9953.22 H6.46 N1.99 J18.06 When calculations were made, 2 HjO per quaternary group. PRI mme R 2. Preparation of bis-3-N-methyl-1- (3,4,5-trimethoxybrcsyl) -6,7-1-dimethoxy-1,2, 3,4-tetrazdroisohananolium — propyl p-phenylene 3, Dichloride 3-dichloride (HH 177). 1. Preparation of silver p-phenylene dipropionate. A mixture of p-phenylene dipropionic acid, 4.4 g (40 mSq), HjO 60 MP, and KOH 1. 40, ml is heated to boiling and, if necessary, the pH is adjusted to 7.0 with this acid. To the yellow mountain solution, add: ЯА10Т AgNOj 6.8 g (40 mmol). Immediately, a heavy precipitate is formed. The mixture is cooled and filtered, and the filter residue is washed with water, re-filtered and dried. Vyghod quantitative. The product is an amorphous, slightly colored powder. It is ground for use in the next step. 2. Preparation of 5-methoxylaudanosine. The 3,4-dimethoxyphenylstilamine and 3,4,5-trimethoxyfenzyacetic acid are heated at 165-190 in the flask until the evolution of water ceases. The resulting product is N- (3,4,5-triplet of syphenylacetyl) -homoveratrylamine, recrystallized from methanol. Yield 80%, etc. 94 ° C. 3.9 g (10 mmol) of M- (3,4,5-trimethoxyphenylacetyl) -home tririamine is refluxed in 15 ml of toluene with 5 ml of ROS1 3 h. The precipitated solids are carefully separated (excess POGIj), liberate the free base by adding an excess of NaOH to extract it with benzene. The resulting product, 6,7-dimethoxy-1- (3, 4, 5-trimetrx benzyl) -3,4-dihydroisoquinoline, is refluxed in acetone or in benzene with an excess of methyl iodide. The quaternary salt precipitates - 6,7-Dimethoxy-1- (3, 4,5-trimethoxybenzyl) -2-metsh1-3,4-dihydroisoicicoline iodide, m.p. 224 ° C .. 1 g of 10 mmol) 6,7-dimethoxyg-1- (3, 4, 5-trimethoxybenzyl) -2-methyl-3,4-dnlDropizoxiko lshod iodide is dissolved in 80 ml of HjO I 16 ml of concentrated NSC Small ones up to Add zinc dust (1.1 g) to boiling g and stirred solution. Yellow color ische5, 94 2.00 19.38 sets (reaction time 15-20 min). The mixture is filtered hot from a quantity of unreacted zinc and alkalinized with concentrated NaOH. It is not necessary to filter out the partially precipitated hydroxide of 1 rshka, and to avoid emulsification, the entire mixture should be carefully mixed with chloroform. The remainder of the chloroform solution is redissolved in ether and the ether-insoluble matter is filtered off. The ether residue does not crystallize upon standing. This amine is a resinous material that hardens upon standing. The crude amine is used in the following steps. 3. Preparation of M- (3-chloropropyl) 5-methoxylduaosini bromide. 1.4 g (4 mmol) of 5-methoxyyl udanosine are dissolved in 8 ml of dimethylformamide with gentle heating. 1-Bromo-3. Chloropropane, 1.2 g (-100% excess) is added and the mixture is left at room temperature. For 5 days (some of the unreacted laudanosine sometimes crystallizes, but eventually dissolves). The reddish-orange solution is treated with a large amount of ether and the precipitated, viscous quaternary salt is drained and suspended in fresh ether. After standing in ether for one day, low-boiling solids are obtained. Output 1.6 g, (80% of theoretical). 4. Preparation of p-phenylene dipropionate dibasic acid ester of N-propyl 5-methoxyyl udanosine (HH 177). A mixture of M- (3-chloropropyl) -5-methoxy-laudanosine bromide 2.1 g, p-fenshgen diprosyun silver 0.85 g (4 mmol) and HjO 150 ml is boiled in an open glass beaker 10-15, from time to time mixing. At the boiling point, the silver salt dissolves and reacts with quaternary bromide. The mixture is cooled to room temperature, filtered and the aqueous solution is scorched to dryness in a large dish on a steam bath. The subsequent heating of the residue on the steam bath (90 ° C) is continued for 2 hours, after which the FALSE ether overloads are completed. The amorphous residue is boiled with izschropanol (40 ml) and filtered off hot from mechanical impurities. The resin is precipitated from the filtrate at a constant temperature, and precipitation at -3 ° C is enacted in the flow (the night surface surface is removed and the material is twice dissolved in ethyl acetate. At the same time, the resin is semi-solid. At this stage, it retains water even more. Exit 1.0 g (40%). The yields vary from portion to portion, f, mp, 80-90 ° C (per dec.). EXAMPLE 3. Preparation of p-phenylene dipropionate dibasic acid ester of N-napropyl udanosine (HH 121). A mixture of M- (3-chloropropyl) laudanosini bromide, 2.1 g (4 mmol) of silver p-feshendipropionate 0.85 g (4 mmol) and HjO 150 ml is boiled in Open a glass beaker for 10–15 minutes, stirring 9 times. At the boiling point, the silver melt dissolves and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered, and the solution is heated to dryness in a large cup on a steam bath. continue for 2 hours, after which the rearrangement to the complex ester is completed. The amorphous residue is boiled in isopropanol (approximately 40 ml) and filtered hot from some traces of mechanical impurities. The resin is precipitated from the filtrate at room temperature., And the precipitation ends at, overnight. The surface layer is applied and the material is suspended twice in ethyl acetate. After careful drying at 75 ° C, the resin becomes solid. At this stage, it still holds water. Yield 1 g (40%). The feeds vary from portion to portion, mp. 80-90 ° C (with decomp.). AnalysisCalculated,% Found,% C53.5753.62 H6.446.06 N2.082.10 J18.8718.87 For calculations, 2 HI O per quaternary group is assumed. PRI me R 4. Obtaining m-phenylene dipropionate ester of dibasic acid N-plopiludanoeina (HH 35). A mixture of L- (3-chloroprosh) -laudanosini bromide 2.1 g (4 mmol), m-phenylene dipropionate silver 0.85 g (4 mmol). and 150 ml boil in an open chemical stack of 10-15 missions. . from time to time mixing. At the boiling point, the silver salt solution is e.ts and enters the reaction with a quarter bromide. The mixture is cooled to room temperature, filtered. Thoroughly dry and evaporate the solution to dryness in a large cup on a steam bath. Subsequent heating of the residue is continued for 2 hours at 90 ° C, after which the rearrangement to the ester is completed. The amorphous residue is boiled with isopropyl (40 ml) and filtered hot from traces of mechanical impurities. The resin precipitates from the filtrate at room temperature and the precipitation ends approximately at overnight. The surface layer was decanted and the material was suspended twice in ethyl acetate. With this, the resin becomes semi-solid and can be filtered out. After careful drying at 75 ° C, the resin becomes hard. At this stage, it still holds the amount of water. Yield 1.0 g (about 40%); The outputs vary from portion to portion, m.p. 80-90 ° C (c.,)., EXAMPLE 5. Preparation of p-phenylene dipropionate ester of dibasic acid Nnr shch 5-me1-oxylaudanosine (LL 37). A mixture of N- (3-chloropropyl) 5-methoxy-Uudanosini 6poNfflaa 2.1 g (4 mmol), silver p-phenylendpropyl 0.85 i (4 mmol) and HjO 150 ml boiled in an open beaker for 10-15 minutes, time from the time of mixing. At the boiling point, the silver salt is slightly soluble and reacts with quaternary bromide. The mixture is cooled to room temperature, filtered and the aqueous solution is evaporated to dryness in a large bowl on a steam bath. The residue is heated for 2 hours on the steam bath (), after which the rearrangement into the ester is completed. The amorphous residue is boiled with isopropyl (40 ml) and filtered off with hot traces of mechanical impurities. The resin is precipitated from the filtrate at room temperature and precipitation is complete with overnight. The surface layer was decanted and the material was suspended twice in ethyl acetate. The resin is semi-solid and can be filtered. After careful drying at 75 ° C, the resin becomes hard. At this stage, it still contains water. Yield 1.0 g (40%). The outputs vary from portion to portion. T. pl. 80-90 C (with decomp.). PRI me R 6. Obtaining p-phenylene dipropionate ester of dibasic acid N-propyl 5-methoxylaudosine (CC 194). A mixture of N (3-chloropropyl) -5.5 g dimethoxyl udanadini bromide 2.1 g (4 mmol), p-phenyl l. f f lp silver lendipropionate 0.85 g (4 mmol) and HI O 150 ml boil in an open beaker for 10-15 minutes, stirring occasionally. At the boiling point, the silver salt dissolves and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered and the aqueous solution is evaporated to dryness in a large dish on a steam bath. The residue is heated for 2 hours at 90 ° C, after which the rearrangement to the ester is completed. PRI me R 7. Bis-3-CH-methyl- - (3,4,5-trimethoxybenzyl) -6,7-dimethoxy-l, 2,3,4-tetrahydroisoquinoline-prop l m-phenyl-3 z-dipropi
    权利要求:
    Claims (2)
    [1]
    Claim
    1. The method of obtaining derivatives yazokhino- 40 line of the general formula
    HF O 2x-
    45
    where B and C are the same or different, and B is in para- or meta, is reacted with a compound of the general formula,
    where n, t, Υ and each of the radicals
    has the above meanings;
    O and O * are functional atoms or groups that react to form an ether bond.
    [2]
    2. The method according to π. 1, 'characterized by frost in that the process is carried out in an inert solvent.
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    同族专利:
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    IE47014B1|1983-11-30|
    SE7808267L|1979-02-02|
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    引用文献:
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    JPS5156762U|1974-10-28|1976-05-04|CA1125287A|1978-07-21|1982-06-08|John J. Savarese|Bis isoquinolinium compositions and methods of use|
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    JPH0144711B2|1979-09-20|1989-09-29|Otsuka Pharma Co Ltd|
    JPS5899465A|1981-11-23|1983-06-13|Wellcome Found|Isoquinoline derivative|
    GB8418303D0|1984-07-18|1984-08-22|Wellcome Found|Compounds|
    JPH0555438A|1991-08-26|1993-03-05|Rohm Co Ltd|Lead terminal structure of electronic component|
    AU6730598A|1997-03-25|1998-10-20|Cornell Research Foundation Inc.|Substituted isoquinolines as ultra short acting neuromuscular block ers|
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    WO2010107488A1|2009-03-17|2010-09-23|Cornell University|Reversible nondepolarizing neuromuscular blockade agents and methods for their use|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US82079477A| true| 1977-08-01|1977-08-01|
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