• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    New triamino-androstanes with curare-type properties and a process for the preparation thereof are disclosed.
    公开号:SU967276A3
    申请号:SU762386220
    申请日:1976-07-30
    公开日:1982-10-15
    发明作者:Туба Золтан；Маршаи Мария；Биро Каталин；Спорнь Ласло；Карпати Эгон；Себереньи Саболч
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    The invention relates to methods for producing new derivatives of triaminoandrostane of the General formula
    where Ac is an alkylcarbonyl group with 1-4 carbon atoms in the alkyl part, the substituents R have the same meanings and denote a methylene group or a group of the formula xN-R ^ in which “alkyl, η · = 1 or 2 and that 1,2,3 or 4. The invention also encompasses salts of these compounds and quaternary ammonium. It is known that, when the halogen derivative epoxyandrostane is reacted with an amine, the corresponding amine derivatives of androstane £ 1J are formed.
    5 The reduction of the carbonyl group and subsequent acig are also known. ligation of the hydroxyl group [2]. V The proposed method, based on well-known reactions, leads to , 0 the production of new derivatives of aminoandrostane having valuable pharmacological properties.
    Proposed method of preparation of compounds of formula 5 is Ϊ that epo'ksiandrosta- derivatives. n-2 << 3 </, 16 <£, 17 s / -diepoxy-5c1-hydroxy-br>-chloro-17p> -bromandrostan 'or' 2 <£, 3 <£, 16 <i, 17o1-diepoxy -5 <£ , N 17 / *) - diacetoxy-br> -bromandrostane or 2οζ 3οζ 5οι, 6 <S 16oL, 17а £ -triepoxy-17) 5-bromoindrostane are reacted with a compound of the formula salts.
    The compounds of formula T possess a kura- 25 repository non-depolarizing neuromuscular-blocking action, i.e. they prevent the transition of nervous irritation to the transverse muscles.
    where R, η and m have the indicated meanings, in the presence of a base and from a compound of the formula y, obtained in this
    (SNG) p
    Where is r
    k < (sn ^
    BUT compound of the formula
    form indicated are stop hydride month to obtain the compound
    of which they are indicated, they are subjected once again with a compound in excess, at 70-160 σ € where R, reading, and the reaction of Y taken in and the resulting compound of the formula have the indicated aliphatic carbohydrate containing 1-5 atoms where R, n and m are acylated with a new acid, carbon, or its reactive derivative in the presence of Llisa acid ^ and the resulting product is isolated in the form of a free compound, salt or quaternary ammonium salt. _
    The starting compounds of formula Y are cyclic amines with 5-8 members in the ring containing one or two ayot atoms. Preferably, these are N-alkyl piperazines, N-alkyl pyrimidines or N-alkylimidazolidines having ’1-3 carbon atoms in the alkyl part. The reaction is usually carried out at room temperature to the boiling point of the reaction mixture, in the presence of water or an inert organic solvent, for example acetonitrile, or in the absence of a solvent. Sodium borohydride is preferably used as the reducing agent, usually in a solvent, such as lower alcohol or chlorinated hydrocarbons. As the acylating agent, it is preferable to use acetic anhydride or propionic acid anhydride. The compounds of formula I can be converted into salts in the usual manner. Most preferred are salts obtained by the addition of hydrohalic acids, while from salts formed by the addition of organic acids, acetates and gluconates should be mentioned first. As materials giving the Quaternary salts, alkyl halides with 1-5 carbon atoms are used, for example methyl propyl ethyl or isobutyl halides, preferably the corresponding bromine compounds or allyl bromide.
    Example 1. 2 ^ 3 <Y ( 5 bob-diepoxy-17-oxo-16 ^ -piperidinoandrostane.
    a) 13.5 g (0.032 mol) 2 <Y, Cs (_, '16 ° /, 17s / -epieoxy-5c (-oxy-br-chloro-17r-bromo-androstane is dissolved in J 100 ml of acetonitrile and added to the solution 11 mp (0.111 mol) of piperidine. The reaction mixture is refluxed for 1 h and then evaporated under reduced pressure. The residue is dissolved in chloroform, the solution is washed with saturated sodium chloride solution and then with water (pH = 7-7.51, then separated phase. The organic phase is dried over sodium sulfate, filtered and the filtrate is evaporated to dryness. The crystalline residue is treated with q, ether, then It is dried and dried to give 10.3 g (82%) of 2sb, Zeb, 5s (-6o (-dipoxy-17-oxo-16/5 ~ piperidinoandrostane, which melts at 187-190 ° C, Wg = +31.7 ° (c = 1, chloroform).
    b) 6.0 g (0.0157 mol) 2sb, Zeb, 5s6 bean, 16ob, 17o6-triepoxy-17 /) - bromo-drostane is dissolved in 45 ml of acetonitrile and 6.4 ml (0.0647 mol) of piperidine are added to the solution . The reaction mixture was refluxed for 1 hour and then evaporated under reduced pressure. The evaporation residue is dissolved in ether and the ether solution is washed first with. a saturated solution of sodium chloride, and then with water. The separated ether phase is dried over sodium sulfate, then filtered off and evaporated to dryness. The residue is mixed with ether, the precipitated product is filtered off and. dried; The physical constants of the products coincide with the constants of the product obtained according to example 1a.
    c) 26.2 g (0.06 mol) of 2αζ 3oL, 16 s of 17 s of diepoxy-5oL-17J3-di-acetoxy-6p> -chlorandrostane are dissolved in a mixture of 221 ml (2.6 mol) of piperidine 35 ml of water. The reaction mixture was kept at 94-96 ° C for 2 hours and then evaporated under reduced pressure and a temperature of 50 ° C. The residue is dissolved in a solution (2 g of sodium hydroxide in 200 ml of methanol) and the solution is refluxed for 20 minutes, after which it is evaporated under reduced pressure, the residue after evaporation is dissolved in 600 ml of ether and the solution is washed with saturated sodium chloride solution to neutral reaction (pH = 7-8). The phases are separated from each other and the ether phase is treated as described in Example 16. The physical constants of the product coincide with the constants of the product obtained in Example 1a.
    Example 2. 2c /, 3c /, 5c /, 6d-diepoxy-17c / -oxo-1br> -M-methylpiperazinoandrostane.
    A compound of 2 </, 3d, 16 s /, 176-diepoxy-5c / -oxy-6 ^> - chloro-17-bromo-androstane and N-methylpiperazine is prepared according to the method described in example 1c, in 75% yield. Mp 149.151 ° С, (d = + 32, 8 6 '(с = 1, chloroform).
    Example 3. 2 <k, 3d, 5c /, 6 (/ - diepoxy-17p> -oxy-1br> -piperidino-androstane.
    g 0.0208 (mol) 2d, 3d, 5c /, 6oL-diepoxy-17-οκοο-16β> -πΗπβρΗΛΗΗοandrostane is dissolved in a mixture of 36 ml of tetrahydrofuran and 15 ml of methanol and 5 g is added at 15-20 ° С ( 0.132 mol) of sodium borohydride suspended in 9 ml of water. The reaction mixture was stirred for 8 hours and then at 40 C p 35 vayut evaporation to dryness. The evaporation residue is combined with water, the precipitate was filtered off, treated with: ether, filtered off and 1 A direct venno thereafter dried. 40 g are obtained, 64 g (79.5 mol) of the indicated product, which melts at 184185 ° C, (</) ^ g = -42.7 '(c = 1, chloroform;
    Example 4. 2οί, 3 «5, 5d-, 6d-diepoxy-17p> -oxy-16p> -M-methylpipe- 45 rasinoandrostane.
    11.4 g (0.2 85 mol) of 2d, 3d, 5 / _, 6s1-diepoxy-17-oxo-1br> -M-methylpiperainoandrostane is reduced with sodium borohydride according to the method described in Example 3. Raw product cleaned as follows. The precipitate was dissolved in methanol and the solution, together with 0.5 g of sodium hydroxide, was boiled for 0_.5 hours under reflux. Then the solvent is distilled off, the residue is washed with saturated sodium chloride solution, then with water, then it is filtered off and dried over phosphorus pentoxide. 10.2 g (88%) of the title product are obtained, which melts at 177-179 ° C. Z (ot) p = -47.5 ° (c = 1, chloroform).
    . Poimer 5. 2p>, 6β>, 16/3-to-> piperidino-3 /, 5 /, 17/1-trioxyandrrstan. 65 g (0.0155 mol) of 2d, 3d, 5d, Sd-diepoxy-17 / L-hydroxy-1br-piperidinoandrostane are dissolved in a mixture of 60 ml (0.606 mol) of piperidine and 10 ml of water. The reaction mixture was heated at 140 ° C for 72 hours in an autoclave. After completion of the reaction, the reaction mixture was evaporated to dryness and the residue was treated with ether. The precipitated crystalline product is filtered off 10 and refluxed with acetonitrile. The purified product is filtered off and dried. 6.7 g (78.5%) of the expected product are obtained, which melts at 22615 228 ^ 0, ((/) ^ / = + 19.3 ^ (0 = 1, chloroform),.
    PRI me R 6. 2d, 6P>, 16 ^ -tri- (M-methylpiperidino) -Zoc-5d, Χ7βtrioxyandrostane.
    A compound of 2 </, Cs /. ',' Is obtained.
    2q 5d, 6o £.-Diepoxy-17p> -oxy-1 br> -I-methylpiperazinoandrostane according to the method described in example 5. The yield is 6 g (80.0%). 207-210'C, (d) j / = 10.6 0 (c = 1, chloroform).
    Example 7. 2 ft, 6p, 16/3-tri- (N-methylpiperaino) - 3d, 17 | 3-diacetoxy-5o (- hydroxyandrostane.
    g (0.0029 mol) 2 β, 6β, 1 br> -tri- (N-methylpiperazino) -3d, 5d, 17/3-trioxyandrostane are dissolved in a mixture of 9 ml of acetic anhydride and 0.6 ml of glacial acetic acid and 0.3 g of zinc chloride is added to the solution; The reaction mixture was stirred at room temperature for 12 hours, then mixed with water. (30 ml) and continue to stir for 2 hours. The aqueous solution is cooled to 0-5 ° C and the pH value is set to 8-10 by adding an aqueous 10% sodium hydroxide solution. The precipitated flocculent precipitate was extracted with ether. The ether extract is washed with an aqueous solution of sodium chloride, and then with water until neutral. The phases are separated and the organic phase is dried over sodium sulfate. After filtration, evaporate to dryness. The residue was dissolved in ether, the solution was clarified with 3 g of silica gel, filtered and then evaporated to dryness. Obtain 1.7 g of the target compound. Mp 150-155 ° C, ('. </.) = -3, 3 ° (C = 1, chloroform).
    Example 8. 2β, 6β, Ιδβ-τρ ип piperidino-Z /., 17 / ’> - diacetoxy-5oC-hydroxyandrostane. ‘
    The compound is obtained from 2β, 6β, 16/5-tripiperidino-3C /, 5d, .17 / 3 ~ trioxyandrostane according to the method described in example 7. Yield 77.0%, mp 104 104 ° C at. decomposition, (o!) ^ 5 - = -7.3 ° (c = 1, chloroform).
    Example 9.2p>, br>, 1br-tri- (4-dimethylpiperazino). -3 <χ, 1 7/3-diacetrxi-5 <£ -oxyandrostane, tribromide.
    0.5 g (0.73 mol) 2/3, 6/3, 1 br-tri- (Ngmethylpiperazino) -Ze !, 17/5-diacetoxI-5 <£ -oxyandrostane is dissolved in 50 ml of acetone and 5 are added to the solution ml of an 8% solution of methyl bromide in acetone (4.2 mol). The reaction mixture was kept at room temperature for 16 hours, then the precipitated crystalline product was filtered off. 0.6 g (.95.5% TT of the left product are obtained. mp 247250 ° C, (d) if = 0 (c = 1, chloroform).
    Example 10 2p j 6β, ~ 16β-tri- (4-propyl-4-methylpipe .razino) -3oL, 17 | L-diacetoxy-5-hydroxyandrostane, tribromide.
    0.5 g (0.73 mol) 2β> 6β, Ϊ6β-tri- (M-methylpiperaino) -Zo (, 17β-diacetoxy-5o (-oxyandrostane is dissolved in 10 ml of acetonitrile, and 4 ml (0, 0442 mol) ed 'propyl bromide The reaction mixture is boiled for 2 hours with refluxing, then cooled to room temperature and diluted with ether to five times the volume of the mixture, the precipitated quaternary salt is filtered off, washed with ether and dried under reduced pressure. 0.65 g (84.5%) of the compound are obtained ... mp 245-248 < C (with decomposition).
    Example 11. 2β, 16β-6Ησ- (Ν-methylpiperidino) -6 / 5-piperidino-Za /, 17p> -diacetoxy-5-hydroxyandrostano-dibro-mid.
    0.3 g (0.785 mol) 2p>, 6β, 16β-tripiperidino-Zyk, 17β-diacetoxy-5c £ -oxyandrostane are dissolved in 20 ml of acetone and 20 ml of an 8% solution of methyl bromide in acetone are added to the solution (16.9 mole). The reaction mixture was allowed to stand at room tem- perature for 1 week and then the product is precipitated with ether. The precipitated quaternary soda is filtered off, washed with acetone, and dried. 0,6.g obtained (92%) of the compound koto-, Roe melts at 187 C (with decomposition), (οά) May 2 = 2 + 9 ° (c = 1, chloroform) ..
    As indicated, the synthesized compounds have a curariform effect, they do not precipitate histamine, do not lower blood pressure, and do not have a hormonal effect. To establish the strength and duration of action, experiments were performed on cats anesthetized with artificial respiration. The peroneusal nerve was electrically irritated and the resulting contraction of the tibial muscle was recorded. As a result of intravenous administration of blocking substances in various doses, the dose (ED 400 ) was determined, which completely stopped muscle contraction. This dose is 6.8 7.1 mcg / kg, i.e. 2.5 times less than known drugs of the same
    35 k action. The time between the onset of action and the full restoration of the normal muscular reaction was also determined - it is approximately 9 to 10 times longer than with known drugs, therefore, the synthesized compounds are especially advantageous for prolonged surgical operations.
    权利要求:
    Claims (1)
    [1]
    The invention relates to methods for producing new triacdanoandrostane derivatives of the general formula QAC (Cig rt9 No. lm ° l NP / ° ° KHiirtr where Ac means an alkylcarbonyl group with 1-4 carbon atoms in the alkyl portion, the substituents R have the same values and denote a methylene group or a group of the form sN-R .. in which R2 is alkyl Q, .. nsl or 2 and ta1,2,3 or 4. The invention also encompasses salts of these compounds and quaternary ammonium salts. Compounds of formula 1 possess a reputable non-depolarizing neuron muscular blocking action, i.e. they interfere with the transfer of nerve irritation to the transverse muscles. It is known that the corresponding amino derivatives of androstane 1 are formed by the interaction of the halogenic epoxy androstane with the amine. The reduction of the carbonyl group and the subsequent acylation of the hydroxyl group 2j are also known. to obtain new derivatives of aminoandrostan. Possessing valuable pharmacological properties. The proposed method for the preparation of compounds of formula 1 is that epoxy-androst derivatives. Na-2o, 3of, 16, 17ai-diepoxy-5 (l-oxy-6fb-hlop-17p) -promandectane or-2d, 3s, 16o, 17o .-diepoxy-5a, 17 / L-diacetoxy-6p) -bromoandrostan or 2dL, So1 5oi, 6 "C 16oL, 17o &amp; triepox-I-171b-bromandrostan are reacted with the compound Y NO, where R, n and m have the in the presence of a base and an excess of the compound of the formula, the compound of the formula (CHg) thus obtained. NNW-IV ICKOaT. Where R, n and m have the indicated values, in its tan the ELI is hydrated with a metal hydride to form a compound of the formula -y - cff V where R, n and m have the indicated values, which is subjected again interaction with a compound of the formula V, taken in excess, at 70-160 and the resulting compound of the formula. Tj-x-lW / (cn) g) p where R, p and m have the indicated meanings, are acylated with an aliphatic carboxylic acid containing 1-5 carbon atoms, or its reactive derivative in the presence of Lys acid, and the resulting product is isolated as a free compound, salt, or quaternary ammonium salt. The starting compounds of the formula Y are cyclic amines with 5-8 members in the ring containing one or two a: nitrous atoms. These are preferably N-alkyl piperazines, N-alkyl pyrimidines, or N-alkyl imidazolidines having from 1 to 3 carbon atoms in the alkyl portion. The reaction is usually carried out at a temperature from room temperature to the boiling point of the reaction mixture, in the presence of an inert or inert organic solvent, for example acetonitrile, or in the absence of a solvent. Sodium borohydride is preferably used as a reducing agent, usually in a solvent, such as lower alcohol or chlorinated hydrocarbons. Acetic anhydride or propionic anhydride is preferably used as the acylating agent. The compounds of formula 1 can be converted into salts in a conventional manner. The most preferred salts are those added by the addition of hydrohalic acids, while the salts formed by the addition of organic acids primarily include acetates and gluconates. Alkyl halides with 1-5 carbon atoms, for example, methylpropyl ethyl or isobutylhalosyl genides, preferably the corresponding bromine compounds or allbromide, are used as quaternary salts. Example 1. 20 /, Sji, 5o 6ofr-diapoxy-17-ohco-lbJ | ) -piperidine endocstan. a) 13.5 g (0.032 mol) of 2c (, Cc, ISo), 17o-diapoxy-5c6-hydroxy-bub-chloro-17 () -bromoandrostane is dissolved in J100 ml of acetonitrile and 11 ml (0.111 mole) of piperidine. The reaction mixture is boiled under reflux for 1 hour and then evaporated under reduced pressure. The residue is dissolved in chloroform, the solution is washed with a saturated solution of common salt and then with water of CHR 7-7.5), after which phase separated. The organic phase is dried over sodium sulfate, filtered and the filtrate is evaporated to dryness. The crystalline residue is treated with zfir, then filtered and dried | UT. 10.3 g (82%) of 2ct, Zo, (1-diepoxy-17-oxo-16 / -piperidinoandrostane, which melts at 187-190 ° C (6L) + 31.7 ° (c 1, chloroform) are obtained. b) 6.0 g (0.0157 mol) of 2oL, 2oi, 5c6 6od., 16ot, 17o6-tri-epoxy-17p-bromoandrostane are dissolved in 45 ml of acetonitrile and added. To solution b, 4 ml (0.0647 mole) piperidine. The reaction mixture is heated under reflux for 1 hour and then evaporated under reduced pressure. The residue after evaporation is dissolved in ether and the ether solution is washed first with an. saturated salt solution, and then water. The separated ether phase is dried over sodium sulfate, then-filtered and evaporated to dryness. The residue is mixed with ether, the precipitated product is filtered and. dried; The physical constants of the products coincide with the constants of the product obtained according to example 1a. c) 26.2 g (0.06 mol) 20 3oi., l6ciy 17c diepoxy-5o1-17 | The α-diacetoxy-6 | h-chlorandrostan is dissolved in a mixture consisting of 221 ml (2.6 mol) of piperidine and 35 ml of water. The reaction mixture was kept at 94–96 ° for 2 hours and then evaporated under reduced pressure and temperature. The residue was dissolved in a solution (2 g of sodium hydroxide in 200 ml of methanol and the solution was heated for 20 minutes under reflux, after The evaporated residue is evaporated under reduced pressure in 600 ml of ether and the solution is washed with a saturated sodium chloride solution until neutral (pH 7-8). The faeses are separated from each other and the ether phase is treated as described in the example 16. The physical constants of the product coincide with tantas of the product obtained according to example 1a Example 2. 2oL, 3oi, Soi, 64, -diepoxy-17c6-oxo-16g -M-methylpiperazinoandrostan. A compound is obtained from 2oL, 3o (.16oi. 6 | -chloro-17-bromandrostane and N-methylpiperaz according to the method described in Example 1c, in 75% yield. Mp 149.15lc, (oi} | S +32.8 (, chloroform) P p i. M e, p 3. 2d., Sot, 5c., 6oi-diepoxy-17P) -oxy-16 | L-piperidinoandrostane 8 g 0.0208 (mol) 2o 3bL, 5c 6o1.-diepoxy-17-oxo The -16p-piperidinoandrostane is dissolved in a mixture consisting of 36 ml of tetrahydrofuran and 15 ml of methanol and at 15-20c, 5 g (0.132 mol) of borohydride per liter is added, with soaked in 9 ml of water. The reaction mixture is stirred for 8 hours and then evaporated to dryness at 40 ° C. The residue after evaporation is combined with water, the precipitated precipitate is filtered, treated:, filtered and dried immediately after that. 64 g (79.5 mol) of the above product are obtained, which melt at 184185 C, (ot) -42, 7 (chloroform; Example 4. 2ot, 5Л, 6db and epoxy-17p-oxy-16p-m-methyl-peptide-azino-androstan. D 11.4 g (0.285 mol) 2oi, 3S Sot, bo1-diepoxy-17-oxo-1bR) -M-methylpi-perazinoandrostan is reduced by sodium borohydride according to the method described by O, GGy. About 7 g „go nr onvvHT oim,„ lk tomu in example 3. The raw product is purified as follows. The precipitate is dissolved in methanol and the solution together with 0, 5 g of sodium hydroxide is boiled for 0, 5 hours under reflux. Then the solvent is distilled off, the residue is washed with a saturated solution of sodium chloride, then with water, then filtered and dried with phosphorus pentoxide. 10.2 g (88%) of the title product are obtained, which melts at 177-179 ° C. (QL) -47.5 (, chloroform). IM-e R 5. 2, 6, 16D-tripiperidino-3: 75, 1ЛЗ-trioxyandrstanine 6 g (0.0155 mol) 2o (, 3, 6ot-diepoxy-17 / b-hydroxy-16b-piperidinoandrostanan solution in a mixture of 60 MP (0.606 mol) piperidine and 10 ml of water. The reaction mixture is heated at 14 ° C for 72 hours in an autoclave. After completion of the reaction, the reaction mixture is evaporated to dryness and the residue is taken up in ether. The precipitated crystalline product is filtered and boiled. the acetonitrile cooler. The purified product is filtered off and dried. 6.7 g (78.5%) of the expected product is obtained which melts and 22P228c, (ot) +19.3 (, chloroform),. PRI me R 6. 2ot, BR, 16 -tri- (M-ketilpiperidino) -Zos 5o., D7 / 3trioxyandrostane. A compound is obtained from 2oi , ZssG 5oi, 6oi.-diapoxy-17 / -ox-16p -N-methyl piperazino androstane according to the method described in Example 5. The yield is 6 g (80.0%). Mp. 207-210 ° C (ct ; If 10, 6 (, chloroform). EXAMPLE 7. 2ft, 6p, 16 / -tri- (N -methylpiperazino) - 3 ot, 17p-diacetoxy-5o (- oxyandrostan. 2 g (0.0029 mol) 2p, 6 /, 16 | -tri- (N-methylpiperazino) -sl, 5-1, 17 / -trioxyandrostane is dissolved in a mixture of 9 ml of acetic anhydride and 0.6 ml of glacial acetic acid and 0.3 g of zinc chloride is added to the solution; The reaction mixture was stirred at room temperature for 12 hours, mixed with water (G30 ml) and continued to stir for 2 hours. The aqueous solution was cooled to and set the value by adding aqueous 10% sodium hydroxide solution. The flocculated precipitate is extracted with ether. The ether extract is washed with an aqueous solution of sodium chloride, and then with water until neutral. The phases are separated and the organics are dried over sodium sulfate. After filtration, evaporated to dryness. The residue was dissolved in ether, the solution was clarified with 3 g of silica gel, filtered and then evaporated to dryness. 1.7 G of the title compound are obtained. M.p. 150-155 ° C, -3 ,, chloroform). Example 8. 2fb, 6 / L, 16 / -ripiperidino-3O1, 17 / -diacetoxy-5 ° C-hydroxyandrostane. It is obtained, a compound from 2UY, 6 /, 16 tripyperidino-ZOC, SoL, .17 / -trioxyandrostane according to the procedure described in Example 7. Exit 77, 0%. M.p. 104106 C at. decomposition, (o-7, 3 (, chloroform). Example 9. 2 | b, 6f),) -tri (4-dimethyl.piperazino), -3do; 1 7/1, -diacetoxy-LOC-oxyandrostane, tribromide. 0.5 g (0.73 mol) of 27, 6, 16p-tri- (M of gmethylpiperazino-Zob, 17L-diacetoxy-5L-oxyandrostane is dissolved in 50 ml of acetone and 5 ml of 8% is added to the solution acetone methyl bromide solution (4.2 mol). The reaction mixture is kept at room temperature for 16 hours, then the precipitated crystalline product is filtered off, W) t. This gives 0.6 g (.95 5% of the G1l of the first product. Mp. 247250 C / (") | 0 (, chloroform). Example 10. 2p 1br -tri- (4-propyl-4-methyl-piperazino) - So1, 17 | b-diacetoxy-5-hydroxyandrostan, tribromide. 0.5 g 0.73 mol) 2, 6 / i, le / J-tri- (H-methylpiperazino) -3of., L7 / i-diacetoxy- 5 ° (-oxyandrostane is dissolved in 10 MP of acetonitrile, and 4 ml (0.0442 mol) of propylbrole is added to the solution. The reaction mixture is boiled for 2 hours under reflux, then cooled to room temperature and diluted with ether to five times the volume of the mixture. You are filtering the fallen quaternary salt, washing it with Dry under reduced pressure and under reduced pressure to obtain 0.65 g (84.5%) of the compound, mp 245-248 ° C (with decomposition). Example 11. 2 | ,, 16р-bis- (M-methylpiperidino) - b b-piperidino-3c, 17a-diacetoxy-5-oxyandrostan-dibrO mid 0.3 g (0.785 moles) 2p ,, 6) ,, 16p, -tripiperidino-3g, 17f -diacetoxy-5c-oxy-ostrostan is dissolved in 20 ml of acetone and 20 ml of a 8% solution of methyl bromide in acetone (16.9 mol) are added to the solution. The reaction mixture is left to stand at room temperature for a week and then the product is precipitated with ether. Dictvertichnuyu sod; filtered off, washed with acetone, dried. This gives 0.6 g (92%) of the compound which is. swarm melts at (during decomposition), (about) +2, 9 (, chloroform) As mentioned, the synthesized compounds have a curare-like effect, they do not induce histamine, do not decrease blood pressure, and do not have hormonal action. In order to establish the strength and duration of the operation, the experiments were conducted on cats that were narcotized with artificial respiration. The perilous nerve was annoyed and the resulting contraction of the tibial muscle was recorded. As a result of intravenous administration of blocking substances in various doses, the dose () was determined, completely stopping the contraction of the muscle. This dose is 6.8 7, 1 µg / kg, i.e. 2.5 times less than the known drugs of an angshogic effect. The time between the onset of action and the complete restoration of the normal muscular response is also determined - it is approximately 9–10 times longer compared with the known preparations, therefore, the synthesized compounds are especially beneficial for prolonged surgical procedures. Claims of Invention A method for producing derivatives of triamino-androstane of general formula I. (CftiW.,.:,. V ar) /,, (cis) ASO 1 io. No.H1 where -AC denotes an alkylcarbonyl group with 1-4 carbon atoms in the alkyl part, R has the same meaning and denotes methylene groups or a group of the general formula sN-Rj, where R denotes alkyl C., n 1 or 2, m 1, 2,3 or 4, of their salts or quaternary ammonium salts, of which they are derived from epoxy androstal, 2oL, 3ot, 16oLf 17c -diepoxy-5 "C-ok-. si-6p) -chloro 7p-brbromandrostan il. and 2d, zo 16c, 17o1.-diepoxy-5 (V, 17 / -diacetoxy-6 / -bromandrostan or 2oL, 3ot, 5ol-, 6ol, 16cl, 17o1-triepoxy -17-bromoandrostan; subjected to interaction with the compound of the formula Y y, 1CHN .. where .R, p and m have the indicated meanings; and the presence of a base AND excess of the compound of the formula Y, obtained by this connection, of the formula 1L PL iV. ГЧЛЛо: TTj, where R, p, and T1 have the indicated values, are reduced by metal hydride to give a compound of the formula P # U Y 1 0-rV, - --QCr
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    GB1533454A|1978-11-22|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    HU165600B|1972-07-27|1974-09-28|
    GB1454749A|1972-11-29|1976-11-03|Akzo Nv|2beta, 16beta-diamino-androstanes and their preparation|HU171661B|1975-07-15|1978-02-28|Richter Gedeon Vegyeszet|Process for producing new 5-alpha-17-beta-diacetoxy-6-beta-chloro-2-alpha-3-alpha-16-alpha-17-alpha-diepoxy-androstane|
    NL175223C|1979-01-09|1984-10-01|Wavin Bv|PLASTIC TUBE PART WITH LINES DIRECTLY CHANNELS WITH A SLEEVE.|
    JPS5939729U|1982-09-06|1984-03-14|
    HU195972B|1985-07-01|1988-08-29|Richter Gedeon Vegyeszet|Process for producing new diamino-androstane derivatives and pharmaceutical compositions containing them|
    IT1277700B1|1995-12-22|1997-11-11|Poli Ind Chimica Spa|PREPARATION PROCESS OF 2-BETA, 16-BETA-DIAMINO 3-ALPHA, 17-BETA- DIACYLOSSES 5-ALPHANDROSTANI, STRUCTURAL NEUROMUSCULAR BLOCKS|
    CN102558276B|2011-12-23|2013-10-30|成都科瑞德医药投资有限责任公司|Non-sizing pipecuronium and preparation method and purpose thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU75RI00000574A|HU172521B|1975-08-01|1975-08-01|Process for producing new triamino-androstane derivatives and quaternary salts thereof|
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