• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:

    公开号:SU1144618A3
    申请号:SU833566494
    申请日:1983-03-22
    公开日:1985-03-07
    发明作者:Бангольцер Рольф；Бауер Рудольф
    申请人:Берингер Ингельгейм Кг (Фирма)；
    IPC主号:
    专利说明:

    The invention is attributed to the generation of quadritsus (& 1x salts of esters of esters 6, P-dagidrodiben: th b, e thienin-11 - l-alkyl alkyls of the general formula where R is C., C is Alksh1, K is chlorine, bromine, L5 ethanesulfonate, possessing antispasmodic activity. It is known to prepare npocrnix esters by the action of alcohols of halogen-containing compounds 1. It is also known to prepare four diameters of different M-containing heteroiclicus compounds by the interaction of corresponding bases with alkyl halides of the invention. m The method of obtaining new compounds with valuable pharmacological properties The goal is achieved by obtaining quaternary simple methods with: fi 6,1 bdig drodbenzo b, e1tne.pin-1 lN-alkylnskopin of the general formula (G), , that L-chloro-6, P-didydrotsibenzo 1b, c) hyse gsn formula I H is subjected to interaction with M-alipynscopic general formula where R has the specified value, at 40--80 C in the medium ort-anneesk-th dissolve 82 bodies and the resulting in this case, the ether 6,11-; gigidrodibenzo b, e tiepin-1 lN-alkylnor Pin 1 de general formula R has the meaning indicated, is reacted with a "d neniem general formula CH, XV wherein X is as defined above, at from room temperature / w 40 ° C in a medium orga {cal solvent. The desired product is isolated with known griemi. The starting compound ((p) can be obtained by known methods, for example as follows: EoOH A compound of general form (M1) can be obtained by a known method 3) or by hydrogenolysis of M-alkyd-polactant of the general formula where R has the indicated value or its salt by complex hydriding of the metal in an organic medium solvent at a temperature of from -10 to. Compounds of the general formulas (I) and (IV) in the dibenzothiepin radical have an asymmetric carbon atom, therefore they are prepared in
    as a racemic mixture of two optically active enantiomers.
    Example 1
    , a) Ether 6,11-digilrodibenzo b, e tiepin-11-scopin.
    195.5 g (1.26 mol) of scopine are dissolved in 600 ml of absolute methylene chloride and a solution of 156.5 g (0.63 mol) of 11-chloro-6, added dropwise to the resulting solution, during 3 hours P-Dihydrodibenzo b, tiepina in 200 ml of absolute methtylene chloride. After 3 days at 40 ° C, the reaction is stopped, the precipitated crystals (110 g of scopin hydrochloride) are filtered off with suction and washed with methylene chloride with methylene chloride. The combined methylene chloride solutions are extracted first with water and then 600 mp1 of 1 N hydrochloric acid, the methylene chloride phase is washed with water until neutral and combined 1P) 1e of the aqueous phases are alkalinized with an aqueous solution of sodium carbonate (66 g of sodium carbonate in 200 ml of water) and the chlorine is extracted t1m methylene. Volume; the alkaline methylene chloride phases are dried over sodium sulfate and chloride
    methylene is distilled off under reduced pressure. 189 g of white crystals are obtained, which are recrystallized from a. Etonitrile (over active carbon).
    Yield 159.8 g (69.4% of theoretical yield) of white crystals with mp 74-175 C.
    Found,%: C 71.92; H 6.44; N 4.13; S 8,89
    CziHa NOjS
    Calculated,%: C, 72.30; H 6.34; N 3.83; S 8.77.
    b) Methyl bromide ether 6,11-dihydrobenzo b, e-tyepin-11-scopin.
    2.0 g (0.0055 mol) of 6.11 -dihydro-dibenzo b, prepared according to example 1 a of ether, b, tiepin-11-scopin is reacted with 2.6 g (0.0275 mol) of methyl bromide in a medium of 35 ml of absolute acetonitrile at room temperature. After 24 hours, the quartering process is stopped. The acetonitrile is then distilled off and the precipitate is taken up in. After repeated this operation, the resulting solid is dissolved in water, purified with active charcoal, and the resulting surface solution is freeze-dried.
    Yield 1.2 g (47.4% of theoretical yield) The resulting white substance melts at a temperature of from 140 ° C (with softening).
    Found,%; C 57.94; H 6.70: N 2.99; S 6,62
    С „, Н., - NO.Sr Вг
    Hjo

    Calculated,%: C 57.74; H 5.90; N 2.93 S 6.70
    Example 2. Methyl methanesulfonate simple ether 6,11-digilrodibenzo b, e) -thiipin-11-scopin.
    131.3 (036 mol) obtained according to example 1 (X ether 6,11-dihydrodibenzo b, e tiepin-1-scopin dissolved in 400 ml of absolute methylene chloride, add 47.4 g (0.43 mol) complex methyl ester of methanesulphonic acid and stirred, the mixture is allowed to react at 40 ° C. After 6 hours, another 19 g (0.17 mol of methanesulphonic acid methyl ester is added. After a total reaction time of 24 hours, the quaternization process is stopped. The precipitated crystals are sucked off and washed methylene chloride. According to 1 take into account the first 149.6 g of product in vi de raw white crystals with mp 2, 6-237 ° C (decomposition) .An additional 8.5 g (0, qO mol) of methanesulfonic acid methyl ester is added to the methylene chloride solution and the mixture is allowed to react once more to the same research institute 24 at 40 ° C. To achieve complete conversion, 8.5 g (0.08 mol) of methanesulfonic acid methyl ester are added again and the mixture is left to stand for 24 hours. After washing with methylene chloride, another 18.1 is obtained. g in the form of cheeses of white crystals with m. pl. 236 237 C (depreciation). Both fractions of crude crystals in methanol are purified over active charcoal and, after the addition of acetomethryl, the methanol solution is subjected to a co-reduction under reduced pressure.
    crystals. I
    The yield of 137.7 g (80.4% of theoretical yield).
    The resulting white crystals have so pl. 236-237 C (decomposition).
    Found.%: C 60.50; H 5.48; N 3.05; S 13.37.
    C2.5H2feNOjS CH, 8Oz
    Calculated 7o: C 60.61; And 6.15; N 2.95; S 13.48
    PRI me R 3.
    a) Ether 6,11 - digi.chrodobenzo b, e tiepin-1 l-N-ethylnorskopina.
    5.5 g (0.032 mol) of N-ethylscopicine is dissolved in 50 ml of absolute toluene and a solution of 4.0 g (0.016 mol) of P-chloro-6,11-g of hydrodibenzo b is added dropwise to the resulting solution. , e Tiepina in 30 ml of absolute toluene at 80 ° C for 0 min. After 6 hours, the reaction is stopped. The reaction mixture is processed according to example 1. Yield 5.7 g (93.4% of theoretical yield) The resulting crystals (from acetonitrile) have a mp. 128-130 C. Found;%; C, 72.56; H 6.68; N 3.68; Cj.H jNOgS Infused,%: C 72.79; H 6.64; N 3.69; The initial G4-ethyl-nskopin is obtained in the following way, i 35.4 g (0.1 mol) of the N-ethyl normin polyamine padrochloride are suspended in 350 ml of ethanol and the resulting suspension is mixed with 20 m intervals for 20 min i 78 g v (0.1 mol) of sodium borane at 20 ° C with constant stirring. The reaction mixture is then allowed to stand for J2 hours to complete the reaction. After this time, the process of hydrogenolysis is completed. Then, at a temperature of from -5 to 10 ° C in a nitrogen atmosphere, hydrochloric gas is supplied to the start of the acidic reaction and the solution is washed with 1.5 liters of ether, purifying it from hydrogen chloride. The crystals obtained after drying are suspended in finely divided form in 2 liters of methylene chloride, heated to boiling, and ammonia is distilled off under reduced pressure to form a base in boiling methylene chloride until complete conversion. Get free of charge crystals (ethanol / ether) with t. Pl. 139 b) Mstilbromid iqjocToro ester of 6,11-dihydrodibeiso te, el tiepin-11-M-ethylnorscopin. 2.0 g (0.0053 mol) of 6,11-dihydrodibenzo {b, f) tiepin-15-N-ethyl-nor-scopic ether, prepared according to example 3 a), is reacted with 3.75 g (0.04 mol of methyldi in 14 ml of absolute acetonolol at room temperature. After 48 hours, the quaternization process is preserved; Acetonitrile is distilled off, the residue is absorbed in acetonitrile and supersaturated. After repeatedly repeating this operation, the resulting solid product is dissolved in water, purified with active carbon and the resulting the clear solution is freeze-dried. 1.5 g (60.0% of theoretical yield. The obtained solid melts at a temperature of from 130 ° C (with softening), Found,%: C 59.1 i; H 7.26; N 2.95; S 6 , 69; Br 16.24. (C HjgNO., S Bg 1/2 HjO Calculated,%: C 59.62; H 6.05; N 2.90; S 6.63; Br 16.53. Analogously to examples 1-3, the following compounds are prepared: 6,1 1-dihydrodibe-izo ether (hydrochloride, hydrochloride (T, typene-N-n-propyl-hypoxy). So (isopropanol) 183-185 ° C (decomposition) Found: C, 65.75 ; H 6.87; N 3.11; S 7.11; C1 7.89 Cj HjyNO S HC1. 1/2 Calculated,%: C 65.66; H N 3.19; S 7.30; C1 8.07. Methyl bromide 6,11 -dihydrodibenzo (B, e) tiepi-Mn-propylnorscopin. T. pl. 150-160С (decomposition). Found,%: With 56.47; H 6.06; N 2.76; S 6.16; Br 15.10 CjsH NOjSjBr. 2 1/4 HjfO Calculated,%: C 56.47; H 6.57; N 2.65; S 6.06; Br 15.11. Ester 6,11-digiu diethyl chloride; fOdibenzo (b, el - thiepin-N-isopropylnorskopin. Mp. (Ethanol) 150-151 C (decomposition). Found: C 65.81; H 7.29; N 2.97; C1 7.54 C, HjjNOgS- HC1 3/4 CjHjOH Calculated,%: C 65.93; H 7.05; N 3.02; C1 7.63 Methyl chloride of ether 6,11-digitsybenzo { b, el tiepin-N-isopropylnorskopin f Softening point 148 C (does not crystallize.) Found: C 62.97; H 7.11; N 2.90; C1 6.81 CjyH oNOgS C1 Calculated: C 62.55; H.7.14; N 2.92; C1 7.38 Compounds of general formula (I) possess antispasmodic activity. The closest structural analogue of compounds (I) is methyl ether bromide 6,} 1-dihydrodibenzo b, e tiepin-11-N-propylnortropin (2), which also has antispasmodic activity Example 4. An antispasm on an isolated organ (guinea pig intestine, in a pube). cm suspended in an organ bath containing a Locke-Ringer solution Bath temperature is 35 ° C. Caused by spapemogen - acetylcholine (test aj or histamine (test b) contractions of the longitudinal muscles are recorded with a kymograph. The standard antispasmodic (atropine in experiment a and benadril in experiment b) is introduced into the bath 90 s before giving the spasmogen (a preventive method). This determines the dose of atropine and benadril, at which a 50% inhibition of the effect of the spasmogen (EdDud) is achieved. Then, the dose of the known compound (methyl ether bromide 6,11 -dihydro-dibenzo b, e tbn-1GH-N-propylnortropina) n compound of example 1b is determined in the same way, which is compared with the dose of the standard, i.e. atropine and benadril, in order to determine the percentage increase in antispasmodic activity. The results of the experiments are given in the table. A significant increase in spasms. Compound of prayer activity compared with benadris atropine. Example 1 b. Known toxicity of the compound of example 1 b and the known compound is 1574 and 1550 mg / kg, respectively (orally; rats).
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING QUATERNARY SALTS OF ETHERS 6,11-RHODIBENZO DIHID [b, f] thiepin-1 lN-alkylnorscopin of the general formula with the pin of the general formula where R has the indicated meaning, at 40-80 C in an organic solvent and the ether obtained 6,11-dihydrodibenzo (b.e) thiepin-1 lN-alkylnorscopin of the general formula
    SU "1144618 where R is C l -C e -alkyl;
    X is chlorine, bromine, methanesulfonate, characterized in that 11-chlorine. 6.11 · dibenzo fb, e) thiepin of formula wherein R has the meaning indicated, is reacted with a compound of the general formula • CH z- x wherein X is as defined above, at from room temperature to 40 ° C in an organic solvent followed by isolation of the desired product.
    ΐ
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19823211185|DE3211185A1|1982-03-26|1982-03-26|NEW QUARTAERE 6,11-DIHYDRO-DIBENZO--THIEPIN-11-N-ALKYL-NORSCOPINETHER AND METHOD FOR THE PRODUCTION THEREOF|
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