• 专利附录
  • 专利说明
  • 权利要求
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  • 优先权
    • 专利摘要:
    Curare-type salts of the formula <IMAGE> (1a) or <IMAGE> (1b) WHEREIN Ac is an alkyl carbonyl group containing 1 to 4 carbon atoms in the alkyl moiety and one of R1 and R2, is a methylene group and the other is a group of the formula >N-R2 wherein R2 is an alkyl group containing 1 to 3 carbon atoms, A is halogen and R3 is an alkyl group containing 1 to 4 carbon atoms, or an alkyl group; and A PROCESS FOR THE PREPARATION THEREOF ARE DISCLOSED.
    公开号:SU1001859A3
    申请号:SU762386214
    申请日:1976-07-30
    公开日:1983-02-28
    发明作者:Туба Золтан；Маршай 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 a method for producing new 2 P ", 1 br-diaminoand * rostan derivatives of the general form
    >.
    if R | = “CHr L T,
    Yu R r = c i-4 ~ alkyl;
    0 = 0,1,2;
    A is the anion of a monobasic acid, or their salts.
    Compounds of the specified general formula 1 have a strong curariform effect.
    It is known that compounds containing cyclic systems with two quaternary (or tertiary) nitrogen atoms (for example, tubocurarine chloride, diplacin, qualified pancuronium bromide) in their structure have a pronounced curare-like action of £ 1 ^.
    However, the known compounds are not high enough and if R ^ C ^ - ^ or R $ x * = , then
    SNE
    R ^ = N =, R ~ = No. or Rj-NS, +
    R4 ““ CH a -, and if R ^ R ^ —№, then V'f'lN. CH ( · ♦ if N =, then R ^ = Rj cn / ty, as well as the presence of side effects in some cases. The alkylation reaction of 20 amines with epoxy compounds is known, which occurs at room temperature or when heated in an inert organic solvent or water and leads to the formation of of the corresponding 2-hydroxyalkylamines Q2], as well as re3 100, the reduction of ketones with sodium borohydride in an inert organic solvent, leading to the formation of the corresponding alcohols £ zZ. nizm.
    This goal is achieved by the fact that according to the method for producing new 2 | 3, Ι6β-diaminoandrostane derivatives of the specified general formula I, the compound of the general formula
    where x is bromine or iodine, treated with a compound of the general formula
    where Ν = or —CH ^ -, hydrochloric acid, such as hydrochloric acid, is added to the obtained compound, if necessary, and the intermediate obtained is reduced with alkali metal borohydride such as sodium borohydride, the obtained compound of the general formula
    where R ^ - has the indicated value;
    - a halogen atom, for example chlorine; Y, 2_ is an oxy group, or U / j. form an epoxy group, react with a compound of the specified general formula III, in which P. has the opposite value of R & in the compound of formula IV, acetylate, for example, with acetic anhydride and isolate the desired product in free form or in the form of a salt or, if necessary, process by a compound of the general formula to 5 -W-v about where Ry is C ^ -alkyl and the desired product is isolated in the form of a salt.
    859 4
    As a rule, the acetylation of the intermediate in the preparation of the target products of the general formula 1 is carried out with a mixture of acetic anhydride ί and acetic acid in the presence of catalytic amounts of zinc chloride.
    The isolation of the target products is carried out by well-known methods — extraction and crystallization using inert organic solvents. Example 1 2p / Epoxy SPR _ 17 ~ -okSo- 1br> - (N -methyl pi per azine) -5ct androstane.
    g (0.069 mol) 2q /, Goiter 16c /, 17ot diepoxy-1 7 “6poM-5dt androstane is dissolved in 170 ml of acetonitrile and 20.5 ml (.0.190 mol) of N-methylpiperidine are added to the solution. The reaction mixture is left at room temperature for 24 hours, then refluxed for 15 minutes. After that, the reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in methylene chloride. The solution is washed with water to a neutral pH and the phases are separated. The organic phase was dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by extraction with ether, the crystalline product was filtered off and dried. 20.1 g of (76.5¾) 2a (,
    Zosgepoxy-1 7-hydroxy-Ι6β> - (N-methylpiperazine) ~ 5 s (.- androstane with mp 132-134 ° С, (ct) 2 = + 121.2 ° (с = 1, chloroform )
    Found,%: C
    N, 7.12
    Calculated
    N, 7.24.
    74.39; H 9.97, *
    C 74.60 *. H 9.85, ’
    The initial 2o (, 3ct, 16qL, 17θί ~ diepoc si -17p-bromo-5 (£ -androstane is prepared as follows.
    200 g (0.735 mol) of 17-oxo-5c (.- androst-2-ene is dissolved in 2000 ml of ethanol and to the solution, 3BO ml of triethylamine and 880 ml of 98% hydrazine hydrate (14.7 ml) are added. refluxed for 2 hours, then cooled to room temperature and poured into 20 L of ice-water with vigorous stirring. 185 g (91%) of “17-hydrazone-5a6” androst-2-ene are obtained, mp 124 132 ° C.
    4 /) ^ 5 = -98 ° (c = 1, chloroform).
    Found,%: C 79.42; H, 10.60; N, 9.60.
    calculated,%: C 79.60; H 10.50; ’
    N 9.70 * g (0.100 mol) 17 ~ hydrazone-5c £ - androst-2-ene is dissolved in 200 ml of anhydrous pyridine, the solution is cooled to -10 ° C. At a temperature of from 0 to -10 ° C, a solution of 30 g (0.18 mol) of N-bromosuccinimide in 330 ml of pyridine- 15 on is added. The reaction mixture is stirred until nitrogen evolution ceases, then 3 L of 5% cooled hydrochloric acid is added. product was extracted with 300-400 ml leroda tetrachloride ^. The combined extracts were first washed to neutral (pH 7) reaction, 5% · * ηορι aqueous hydrochloric acid, then with water. The washed solution was dried over sodium sulfate, filtru- 35 dissolved, the filtrate is evaporated to dryness. The oily the residue is triturated with 100 ml of hexane released at et m byproduct was filtered off, the filtrate was evaporated to dryness, and the residue was triturated with a mixture of 30 of ethanol and acetone 9:. 1 (50 ml) After filtration and drying, 23.4 g (66%) of 17-bromo-androsta-5sS _ 2.16 -diene (αί)% ε = + 71, 2 ° C, mp 7b ~ 77 r C. (c = 1, chloroform).
    71.21; H, 8.15;
    C 71.35) H 8.07;
    (c = 1, chloroform). 59.52; H 6.90 ’, □
    Found,%: С Вг 23.57
    W r
    Calculated; %:
    Vg 23.80
    In the same way, the corresponding iodine compound is obtained from 17tidrazone-5 (£ -androst-2-ene and N-iodosuccinimide. The yield of 66% 17 is iodine-5 (H.androsta-2,16-diene, mp 71-71 ° C.
    (00 ^ = + 56.3 °
    Found,%: C
    32.9
    0ph N ! 17 J
    Calculated,%:
    33.13 g (0.2 7 "mol) 17 - bromo-5 ° (- androsta-2,16-diene is dissolved in 1100 ml of chloroform. A 7.2% solution of 0.81 ml of M is added at room temperature chloroperbenzoic acid (1600 ml) in chloroform The reaction mixture was kept at room temperature in
    C 59.70; H 7.07; □
    1001859 * for 24 hours, then cooled to 0 ° C and washed first with ice-cooling, with 10% aqueous sodium hydroxide, then with acid-free water (pH 7). The phases are separated, the organic phase is dried with sodium sulfate, filtered, the filtrate is evaporated to dryness. The oily residue was triturated with 100 ml of ether, filtered and filtered ^: the crude product was crystallized from aceto-nitrile. 85.7 g of C 87% are obtained) 2 <£, 3άζ 16οό 17 ^ -Diepoxy-17p-bromo ~ 5 ° (-andro ’mill with melting point 1bO-1b2 ° С.
    Vg
    Br (c = 1, chloroform).
    79 ’, H 7.20;
    С 62.00, Н 7.35, (оО £ Б = + 73.5 ° Found,%: С 21.7 С Л Вг0 -2 Calculated,%: 21.80
    In the same way, from 17-iodo-5a (“androsta-2,16-diene is obtained in 81% 2q /, Za !, 16oZ, 11 / -dip ep-si-17/3-iodine 5 _ with £ _ androstane.
    PRI me R 2. 2p-Chloro-3 </ “Oxy-17-oxo-16/3-piperidin-5 (t-androsta- t on hydrochloride.
    12.5 g (0.034 mol) 2a !, For (_, 16 ^, 1X / -DIEPOXY-17-bromo-5a Androstane, dissolve in 85 ml of acetonitrile and add 10 ml (0.1 mol) of piperidine. refluxed for 1 h, then evaporated under reduced pressure.The residue after evaporation is dissolved in diethyl ether and the solution washed with water until neutral (pH 7). The phases are separated, the product is precipitated from the organic phase with a 6% hydrochloric acid solution in the form of a hydrochloride salt, it is filtered off, washed with ether and dried at 6 ° C in vacuo to give 10.3 g (70.0%) g drohlorida 2/3-chloro-Zo0 _ hydroxy-17-oxo-1b | 3-piperidin-5s07androstana st.pl. 237-239 ° C (dec.).
    Found,%: C 64.6 "H 9.0, * C1 15.7
    Calculated,%: C 64.8, *, H 8.7G C1 16.0
    Example 3. 2 /, 3c £ -3poxy-1 ^ 3-hydroxy-1b | 5 -. (H-methylpiperazine ~ 5οίτandrostane. 'G (0.038 mol) 2з (, Zo (-epoxy-17-oxo-16 / & - (Ν -methylpiperazine) -5 ^ -androstane is dissolved in a mixture of 45 ml of methylene chloride and 120 ml of methanol and 12 g (0.31 mol) of borohydri are added to the solution at a temperature below 30 ° C.
    100 yes sodium. At the end of the addition, the reduction product crystallizes. The crystallization mixture is stirred vigorously for 12 hours, then the solvent is distilled off under reduced pressure at a temperature below 40 ° C. The residue is treated with water, the crystals are filtered off, dissolved in chloroform, the solution is first washed with 5% sodium hydroxide solution , 0 ra, then with water until neutral. The separated organic phase was dried with sodium sulfate, filtered and the filtrate was evaporated to dryness. After recrystallization of the residue from aceto -5 nitrile, 11.7 g (77.5%) of 24., 3O (epoxy-17'-hydroxy-1b | G (N-methylpiperazine -5oL ~ androstane with mp. -149) are obtained. -153 ° C.
    (4.) i 5 = + 27.1 ° (c = 1, chloroform). 20 'Found,%: C 74.01; H 10.41 *
    N, 7.07.
    Calculated,%: C 74.20; H 10.30;
    N, 7.22 25
    Example ^. 2 | UHlor-Zo (, 17β “-dioxo-1br-pipepazin-5o £ _ androstan, g (ϋ, 056 mol) of hydrochloride 2β-χπορ- 3 (£ -oxy-1 7-oxo-16 | 3-pipe ~ Ridin-5c -androstane 30 is dissolved in a mixture of 52 mp methylene chloride and 125 ml of methanol 2.75 g (0.09 mol) of sodium hydroxide powder are added to the solution with vigorous stirring, then at 15-20 ° C 12.5 g 35 (0.33 mol) sodium borohydride. Product precipitation begins immediately. The solution containing crystals is stirred for 5 hours, then the product is filtered off and washed with water. The mother liquor is evaporated under reduced pressure at a temperature at a temperature below 30 ° C, the residue was triturated with water. After filtration, the remaining fraction of the product 45 remaining on the filter was washed with water. The two fractions were combined, dried in vacuo at 50 ° C and crystallized from acetone. 20.2 g (88.0 %) 2 ^ -chloro-3c /, 17 | 3 ~ dioxi-1b / 3-piperidin-5 £ ^ -androstane with -d mp mp 232-234 ° C.
    Found,%: C 70.0 *, H 3.95 CI 8.8.
    Calculated,%: C 70.3 H 9.7, * C1 8.6 Example 5. 2 [3- g 'iperidin-Ι6β- s5 - (N-methylpiperazine) - 3ΰί, 17 ^ ~ dioxi-54-androstane.
    14.8 g (0, 038 mol) X4, 34-epoxy-1 7g-hydroxy-1br- (Ν-methylpiperazine) 859 z 8
    54 - androstan is dissolved in a mixture
    168 mp (1, 65 mol) of piperidine and 24 ml of water. The solution was heated at 140 r C in an autoclave for 72 hours, then evaporated under reduced pressure. The evaporation residue is extracted with acetonitrile and filtered. The solid suspended in acetonitrile is heated under reflux. Then the crystalline product is filtered off and dried. Receive 12.4 g ·: (69.0%) 2 [ - piperidin-16 / 5- (Ν-methylpiperazine) -34 ^ 1 7 ^ - DIOxy-54-androstane with so pl. 154 ~ 15b ° C.
    (4) ^ = + 81.5 ° (c = 1, chloroform).
    Found,%: C 70.8; H 10.97, *
    N 9, Yu
    WA · n 2 ° ' o
    Calculated,%: C 71.0; H 10.80, '
    N, 9.26
    PRI me R 6. 2p> - (L1-methylpiperazine n) -16 β-piperidin-34, 17p-dioxi5 ° C _an DRostan.
    This compound was prepared according to the procedure described in Example 5 from 2βτχπορ-, For £, 1 7β ~ dioxi-1b) 3-piperidin-5oC ~ an D “Rostan and N-methylpiperazine with a yield of 67%. Mp 230-234 ° C.
    = + 81.7 ° (c = 1, chloroform).
    Found,%: C 70.8, ’H 10.70)
    N 9.05
    C D
    Calculated,% ·. C 71.0, H 10.80,
    N, 9.26
    PRI me R 7. 2gPiperidin-Ι6β- (Ν-methylpiperazine) - 3d, 17β-diacetoxy-54.-androstane.
    g (0.00b3 mol) 2p> -piperidine-Ι6β- (9-methylpiperazine) -Зо4, 1 7/3 - dioxi-54 - androstane is dissolved in a mixture of 13 ml of acetic anhydride and 1 ml of acetic acid, and 0 is added to the solution 3 g of zinc chloride. The reaction mixture was stirred for 12 hours, then the excess of acetic anhydride was decomposed by adding 40 ml of water. The solution was cooled to 0-5 ° C and at this temperature a 15% aqueous solution of sodium hydroxide was added to a pH of 9 “Yu. The flocculent precipitate is immediately extracted with ether. The ether extract is washed with saturated sodium chloride solution until neutral. After phase separation, the organic phase is dried with sodium sulfate, filtered, the filtrate is made transparent with 3 g of silica gel, filtered again and evaporated to dryness. Of
    100 of the obtained residue, the product is crystallized by trituration with hexane, filtered and dried. 2.6 g (73.3%) of 2] 3-piperidin-16 / 3- (N-methylpiperazine) -3o /, 17p-diacetoxy-5z /.-Andro-stan are obtained with mp. 95 “98 ° C.
    (o ') 2 * = + 33.9 ° (c = 1, chloroform) Found,%: С 71, 01 Н 8.87,' N 7.36
    UU-L '
    Calculated,%: C 71.20, 'H 9.0, ’,
    N, 7.34
    P II and Example 8 2 / 3- (N-Metilpiperazin- 1b / 3-piperidin-ZA4, 17s6 '5 £ Diacetoxy androstane c'
    This compound was prepared according to the procedure described in Example 7 by acylation of 2p> - (N-methyl piperazine) 16/3-piperidine-3CC, 1 / ^ - Dioxo-B ^ Landrostane “Yield 72.0%.
    (s () ^ = + 29.4 ° (c = 1, chloroform). 21 о Found,%: С 70.9, 'Н 8.8, * N 7.3
    Calculated,.%: С 71, 20 Н 9, 00 · ^ N 7.54
    Example · Dibromide 2 / 3- (N- 2
    -methylpiperidinium) Bb / 3- (4,4-dimethylpiperazinium ~ 3s /, 17/3 “Diacetoxy-5o / g -androstane.
    1 g (0.0018 mol) of 2p> -piperidine -16 / 3- (Y-methylpiperazine) -Cc7, 17/3-DI- »acetoxy-5c0 _ androstane is dissolved in 20 ml of acetone. To the solution was added 10 ml of a 5% acetone methyl bromide solution. The reaction mixture was kept at room temperature for 48 hours. The quaternary salt was evaporated, filtered off, triturated first with acetone, then with ether and filtered. The filter cake is refluxed refrigeration <(nick in acetone, then the solution containing crystals was cooled to room temperature, the product was filtered off and dried to yield 1.2 g (87.2%) dibromide 2p.> - (N-methylpiperidinium) - 1br > - (4,4-dimethylpiperazinium) ~ 3o1, 1 7P> -diacetoxy-5o (, - androstane with melting point 260-264 ° С (decomp.)
    Found,%: C 54.81; H, 8.10; Vg 20.51; N, 5.40
    W 4 3 Br0 4 ^ °
    Calculated,%: C 55.0; H, 8.24, ’
    Vg 20.90; N 9, 50 "
    Example 10. Dibromide 2p> - (4,4-dimethylpiperazinium) - 1b | 3 -, (M-methylpiperidinium) -ZOL 17/3 “Diacetoxy-5cE · and- 5: rostan.
    1.3 g (2.34 mol) 2 / 3- (N-methylpiperazine) - 1b / - piperidin-3c (., 1 7p> -di
    859 10 acetoxy-5a £ -androstane is dissolved in a mixture of 10 ml of acetone and 20 ml of acetonitrile, and 32 ml of an 8.4% solution of methyl bromide (28 mmol) are added to the solution. The reaction mixture was kept at room temperature for 9 hours, then the quaternary salt was isolated according to the procedure described in Example 9. 1.4 g (78.5%) of 2/3-4,4-dimethylpiperazinium dibromide + .16 / 3 were obtained. - (M-methylpiperidinium) -Zo £, 17/3 “-diacetoxy-5o Androstane st. Pl. 248252 ° С (decomp.) (= ^) - ^ = -14.3 е (с = 1, ethanol), Found. %: C 54.75, 'H.7.96,'
    N 5.42; ' V g 20 g 6 <0, 'H-0
    Calculated,%: С 55.00, ’Н 8.24;
    N 5.5, ’Vg 20.9
    Example 11. 2 g (3.6 mol) 2 / ¼ - (N-methylpiperazine) 16 / ¼ piperidin-3θί “17 [3-diacetoxy-5c / tandrostane is dissolved in 20 ml of acetone and 12 ml of 8.4 is added to the solution % acetone solution and methyl bromide (.10.6 mol). The reaction mixture was kept at room temperature for 1 hour, then the precipitated Quaternary salt was filtered off, washed first with acetone, then with ether, extracted with acetone, filtered off and dried. Obtain 1.5 g (62.5%) of 2p- (4,4-dimethylpiperazinium) -1br-piperidine -3q / bromide, 17/3-diacetoxy-5o £ -androstane with mp. 234-237 C (decomp.).
    (ol) ^ = + 12.8 (c = 1, chloroform)
    Found,%: C 61.1; H, 8.9; 'N, 5.9;
    Wh 11.3.
    Calculated! % T C 61, 4; H 8.7, * N 6.1 Vg 11.7
    The compounds of general formula 1 have a curariform, non-depolarizing neuromuscular blocking effect, i.e. they inhibit the passage of nerve stimuli in the muscles. These compounds do not release histamine, do not lower blood pressure, do not affect hormones, their effect can be neutralized by the action of neostigmine.
    To determine the strength of action and duration, artificial respiration tests are performed on anesthetized cats. The perennial nerve is irritated by electricity and the induced mutual attraction of the tibial muscles is recorded. Using intravenous administration of blocking substances in different doses, the dose of complete binding of mutual attraction of muscles (ED ^) is determined. The time between the onset of action and the complete cessation of normal muscle response is determined.
    The data in the table refer to doses of complete suppression 0. Pancuronium bromide is used as a comparative compound.
    Compound mgk / kg Duration of action, min L_______ 2p- 4,4-Dimethylpiperazinium -ΐ6β> - (Ν ~ ΜβτΗΠpiperidinium) .- 3 (£, 1 7β ~ -diacetoxy-5a (- androstane dibromide 4,5 16 2p> - (N-Methylpiperidinium) - 1br> - (4,4-dimethyl piperazinium) -ZdC1 7 ^> - di-acet oxy-androstane dibromide 7.2 18 Pancuronium bromide 18.0 23.
    The table shows that the proposed compounds in doses of 2.5 "4 times smaller act the same as pancuronium bromide, and the duration of their action is only 30-40% less.
    权利要求:
    Claims (3)
    [1]
    3100 shares of the reduction of ketones with sodium borohydride in an inert organic solvent, resulting in the formation of the corresponding 3K alcohols. The purpose of the invention is the expansion of the field of means of influence on a living organism. This goal is achieved by the fact that according to the method of obtaining new, 1b (L-diamino-androstane derivatives of the indicated general formula {compound of the general formula where, - N or, to the resulting compound, if necessary, add a hydrogen halide to the slot, such as salt, the resulting intermediate product is reduced with an alkali metal borohydride, as well as sodium borohydride, the resulting total Formulas Yn, where R - has the indicated value jy / j is a halogen atom, for example, chlorine y / j is a hydroxy group, or Y and y / j form an epoxy group, are brought into interaction with the compound of the indicated general formula III, in which R. / has the opposite meaning to K in a compound of formula IV, acetylized, for example, with acetic anhydride and the desired product is isolated in free form or as a salt or, if necessary, treated with a compound of general formula Rj-Br / de K5-C 4-alkyl , and the target product is isolated as a salt 9. As a rule, acetylation of the intermediate with Compounds in the preparation of the desired products of the general formula 1 are carried out with a mixture of acetic anhydride and acetic acid in the presence of catalytic amounts of zinc chloride. The selection of the desired products is carried out by known methods - extraction and crystallization using inert organic solvents,. Example K ZQ /, CcSepoxy-17-ox; o-1b) - (N-methyl pi perzin) androstane, 25 g (0.069 mol) 2Q /, Goiter 1bo, 1 Wrodiepoxy-1 7 6poM-5ot androstane are dissolved in 170 ml of acetonitrile and 20.5 ml of C0.190 mol) N-methylpiperidinoo are added to the solution. The reaction mixture is left at room temperature for an hour, then heated to reflux for 15 minutes. After that, the reaction mixture is evaporated to dryness in vacuo and the residue is dissolved in methylene chloride. The solution is washed with water to a neutral pH and the phases are separated. The organic phase is dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by extraction with ether, the crystalline product is filtered and dried. This is 20.1 g. (7b, 5%) 2af, Za1hepoxy-1 7-hydroxy- (N-methylpiperazine): xs6 androstane with ToPL 132-13 + c. , (o (,) + 121.2 (, chloroform). Found,%: C 7.39; H 9.97, N 7.12 Calculated,% C 7.60; H 9.85, N 7.2i The initial 2 (, Craw, I6ct, 17a -diepoxy-17p-bro-5o1-androstane was prepared as follows, 200 g (0.735 mol) of 17-oxo-5y1-androst-2-ene are dissolved in 2000 ml of ethanol and to the solution, add 3 ml of triethylamine and 880 ml of 98% hydrazine hydrate (1.7 ml). The reaction mixture is heated under reflux for 2 hours, then cooled to room temperature and poured into 20 l with strong stirring. the precipitated product is filtered off, the triethylamine is washed with water and the product is dried over phosphorus pentoxide at room temperature under vacuum.The crude product crystallizes 5 1 from hexane to give 185 g (91%) of 1 -hydrazone-5c3-androst-2-ene, mp 12 132 ° C. U} -98 ° (, chloroform).,%: C 7E, 2; H 10.60, N 9.61,. Calculated, -%: C 79.60; H 10.50; N 9.70 30 g (0.100 mol) 17-rMflpa30H-5d-androst-2-enea is dissolved in 200 ml of anhydrous pyridine, the solution is cooled to, At a temperature from 0 to -10 ° C, a solution of 30 g is added (0, 1b8mol M - bromosuccinimide in 330 ml of pyridine . The reaction mixture is stirred until the evolution of nitrogen ceases, then 3 L of 5% chilled hydrochloric acid is added. The precipitated product is extracted with 300-i 00 ml of four-trichloride (lerod. The United extracts are first washed to neutral (pH 7) with aqueous hydrochloric acid, then with water. The washed solution is dried over sodium sulfate, filtered, the filtrate is evaporated to dryness. The oily residue is triturated with 100 ml of hexa The filtrate is evaporated to dryness, and the residue is triturated with a mixture of ethanol and acetone 9: 1 (50 ml). After filtration and drying, 23, g (66%) of 17-bromo-5c6-androsta-2 are obtained , 1b-diene with m.p. 7b-77 S. (oL) +7, 2 ° (, ch roform) Found:% C 71.21; H 8.15, Br 23.57 calculated;%: C 71.35; H 8.07, Br 23.80 In the same way, out of 17 Thidrazon-5 (-androst 2-ene and N-iodosuccinimide receive a corresponding and homogeneous compound. Yield 66% 17 iodine-5c-androst-2, 16-diene with m „pl, 71-71 C. (oL) +56.3 (, chloroform). Found,%: C 59.52; H 6.90; C 32.9 0, .7 Calculated,%: C 59.70; H 7.07; D 33.13. 90 g (0.27 mol) 17 -bromo-5Ob-androsta-2, 1b-diene was dissolved in 1100 ml of chloroform. At room temperature, a 7.2% solution of 0.81 ml of M-chloroperbenzoic acid (1600 ml) in chloroform is added. The reaction mixture is kept at room temperature for 59 "for 2C h, then cooled to and washed first with ice, 10% aqueous sodium hydroxide, and then with acid-free water (pH 7). The phases are separated, the organic phase is dried with sodium sulfate, filtered, and the filtrate is evaporated to dryness. The oily residue is triturated with 100 ml of ether, filtered and the filtered crude product is crystallized from acetonitrile. 85.7 g of C 87% - 2oL, 3d 1bo 1H -Diepoxy-17p-bromo-5 ° C androstane are obtained with m, pl. 1bO-1b2S (o :) +73.5 (, chloroform). Found,%: C 61.79, H 7.20; Br 21.7 C HnBrO Calculated,%: C 62.00, H 7.35, Br 21.80 In the same way, from 17-iodine-5a androsta-2, 1b-diene is obtained with the output 8U 20 /, Y, 1b ; 1 b-diapoxy-17p-iodine 5-c-androstane, Example 2, 2 / -Chlor-Zl Oxy-17-oxo-16 () - piperidine-5c-androst per hydrochloride, 12, 5 g (0.03 mol) 2a :, Zy, 1baG, 17c -diepoxy-17-bromo-5c-androstane are dissolved in 85 ml of acetonitrile and 10 ml (0.1 mol) of piperidine is added. . The reaction mixture is heated under reflux for 1 hour, then evaporated under reduced pressure. The residue after evaporation is dissolved in diethyl ether and the solution is washed with water until neutral reaction (pH 7). The phases are separated, the product in the form of hydrochloride is precipitated from the organic phase with a 6% ethereal solution of hydrochloric acid. It is filtered off, sampled with ether and dried under vacuum. 10.3 g (70.0%) of hydrochloride 2 | 5 chloro-Zo-oxy-17-oxo-1b3-piperidine-5ob7 androstane are obtained, pLo 237-239 ° C (decomp.). Found,%: C 6i, 6 H 9.0, C1 15.7 C Hj O NCIjz. It is calculated,%: C 6.8, H 8.7, C 16.0 frost. 2csL, So-Epoxy-1; 3-hydroxy-1b | b-. (N-methylpiperazine-5b androstane. 15 g (C}, 038 mol) 2: 3, 3-epoxy-17-oxo-166- (n-methyl-piperazine) -androstane is dissolved in mixtures of 45 ml of methylene chloride and 120 ml of methanol and to the solution are added at a temperature below 12 g (0.31 mol) of sodium borohydride. At the end of the addition, the product of recovery is cured. The crystallization mixture is intensively stirred for 12 hours, then the solvent is distilled off at under reduced pressure at a temperature below. The residue is taken up in water, the crystals are filtered, dissolved in chloroform, the sleep solution The solution is washed with a 5-ml solution of sodium hydroxide and then with water until neutral. The separated organic phase is dried with sodium sulfate, filtered and the filtrate is evaporated to dryness. After recrystallization of the residue from acetonitrile, half-add 11.7 g (77.5%) 2 o L, 3-epoxy. -17 | goxy-I6pr (N-methylpiperazine -Lc-androstane with mp. Ui9-153 ° C, (ci) +27.1 (, chloroform). ° - C 7.01; H 10.1; Found ,%: N 7.07. С 7,2о; H 10,30; Calculated, N 7,22 Example 4, 2 | U Chlor-Zo 6 7p-diox-1b | pipepazin-5o-androstan. 25 g (1), 05b mol) of 2J-chlorop-3 hydrochloride (t-ox-1 7-0 x 16- 16) 5-piperidine-5c6 androstane is dissolved in a mixture of 52 ml of methylene chloride and 125 m of methanol to a solution at 2.75 g (0.0–9 mol) of powdered sodium hydroxide is added to vigorous stirring, then at 15–20 12.5.5 g (0.33 mol) of sodium borohydride. Product starts precipitating immediately. The solution containing crystals is stirred for 5 m, then the product is filtered off and washed with water. The mother liquor is evaporated under reduced pressure at a lower temperature, the residue is triturated with water. After filtering, the second fraction of product is washed with water. Both fractions are combined, dried under vacuum at 50 ° C, and crystallized from acetone. I get 20.2 g (88.0) 2 Vxlop-3Q, 17p-dioc sy-1b | 3-piperidine-5c-androstan with so pl. 232-23 4 s. C 70, o; and uh, 9; o 8, Found, AW C 70.3, H 9.7, C1 8 Calculated, Example 5. 2p | -peridine 1bri - (1 -methylpiperazine) -M, 17 Dioxy-5. with gandrostan " 1i |, 8 g (0.038 mol) S, Zo (gopoxy-1 7p -oxy-1br (N-methyl piperazine) 5 CС-androstane is dissolved in a mixture of 168 ml (1, b5 mol) piperidine and 2A ml of water. The solution is heated during the autoclave for 72 hours, then evaporated under reduced pressure. The residue after evaporation is extracted with acetonitrile and filtered. The solid suspended in acetonitrile is heated under reflux. Then the crystalline product is filtered and su Receive 12, G: (69,0) 2 -piperidine-1b | - (N-methylpiperazine) -ScA 1 7 3-dioxy-5 - androstane with t „pl. (oL) | +81, 5 (, chloroform). Found, |: C 70.8; H 10.97, N 9.10 .0-Calculated, I: C 71.0; H 10.80; N 9.26. 6o 2) - (M-methylpiperazine) Nb (piperidine-Cs1, 17 | b-dioxy-5o6-androstane) This compound is prepared according to the procedure described in example 5 from 2pr tnop-. 3fl, 1 7p-dioxy-1b b-piperidine -5 ° C of androstane and N-methylpiperazine with a yield of 671 mp: 230-23t ° Co (cL) + 81.7 ° (chloroform), C 70.8, H 10.70: Found, 9.05 A.jOa : C, 71.0; H, 10.80; Calculated; 2 Piperidine- I6fii mep 7. - (N-methylpiperazine) - 3d, 1 7 | | -diatsvtoksi-5ci.-en drost en, 3 g (0, ОБЗЗ mole). -piperidine-1brg- (N-methylpiperazine) -3с1, 1 7/5-dioxy- | heandrostane dissolved in a mixture of 13 ml of acetic anhydride and 1 ml of acetic acid and 0.3 g of zinc chloride are added to the solution. The reaction mixture is stirred for 12 hours, then the excess of acetic anhydride is decomposed by adding -0.0 ml of water. The solution is cooled before and at this temperature an aqueous solution of sodium hydroxide is added up to -PH 9-10 °. The flocculent precipitate is immediately extracted with ether. The ether extract is washed with a saturated solution of sodium salt until neutral. After separation of the C-az, the organic phase is dried with sodium sulfate, filtered, the filtrate is made transparent with 3 g of silica gel, filtered again and evaporated to dryness. From 9 of the obtained residue, the product is crystallized by trituration with hexane, filtered and dried. Obtain 2.6 (73.3) 2 | -piperidine-1br1- (N-methylpyraein) -3 () /, 17p-diacetoxy-5 -androstane with TaPL. 95-98 C. N.} + 33.9 ° (chloroform) Found,%: C 71, 01, H 8.87, N 7.36 (hUA04 Calculated,%: C 71.20, H 9.0, N 7: EXAMPLE 8. 2p {N-Methylpiper zin-161-piperidine-Za, 17c6-Diacetoxy iAPQCTaH, Et J compound is prepared according to the procedure of Example 7 by acylation of 2 | i- (N-methyl piperazine) 1b | -piperidine-3c (,, 17 / -dioxy 5handrostan, Exit 72, W) +29.4 (, chloroform). o- Found,%: C 70.9, H 8.8; N 7.3 Calculated, %: C 71, 20, N9.00, N7, PRI me R 9o Dibromide 2j3- (N-methylpiperidinium) 46 | V (4, -dimethyl perazinium-3 (/, 17p-diacetoxy-5o g -androstane 1-g (0.0018 mol) 2p-piperidine -1br- (S-methylpiperzine) -Cc, 1-diacetoxy-5o-androstane is dissolved in 2 0 ml of acetone. 10 ml of a 5% acetone solution of methyl bromide are added to the solution. The reaction mixture is kept at room temperature for 48 hours. A quarter salt is evaporated, filtered, wiped first with acetone, then with ether, and filtered. reflux in acetone, then the solution containing the crystals is cooled to room temperature, the product is filtered and dried. Obtains 1.2 g (87.2) of dibromide 2fi) - (L-methylpiperidine) (4, -dimethylpiperidine) -3oL, 1,1b-diaaethoxy-5o1-androstane with a temperature of 260-26 C (decomp.) Found ,%: C 5.81; H 8.10; Br 20.51, N 5.0 N3Br04HiO UI is numerical o,%: C 55.0, H 8.2V Bg 20.90, N 5.500 Example 10, Dibromide 2pi- {i (, i | -dimethyl piperazium) - Tbrgr- DM-Methyl. Peridinium) -3o /, 17 &amp; -Diacetoxy-5c (Gandar rostan, 1.3 g (2.3 mol) (N-methylphenazine) - 1br-piperidine-3o (., 7p) -di5910 acetoxy -5a (; - androstane was dissolved in a mixture of 10 ml of acetone and 20 ml of acetonitrile, and 32 ml of 8.4% methyl bromide solution (28 mmol) was added to the solution. The reaction mixture was kept at room temperature for 9 hours, then isolated Quaternary salt is prepared according to the procedure described in Example 9. 4,4-dimethylpipazine d (78.5) dibromide is obtained. (M- methylpiperidinium) -Zo1, 17 / -diacetoxy-5a-hydrostatic with S.t.p.1, 2 + 8252С (decomp.) (d.), 3 (, ethanol), Found.% i С 5.75, H, 7.9b; N 5.2; V g 20.6 Calculated: C 55.00; H 8.24; N 5.5, V g 20.9 Example 11, 2g (3.6 mol) 2 / V - (N-methylpiperazine) 16 Upiperidin-30 (.17p-diacetoxy-5oandrostane is dissolved in 20 ml of acetone and 12 ml of 8.4% acetone solution and methyl bromide C are added to the solution), the reaction mixture incubated at room temperature for 1 h, then the precipitated quaternary salt is filtered, washed first with acetone, then ether, extracted with acetone, filters vayut and dried. 1.5 g (62.5) bromide of 2JJ- (4-dimethyl piperazinium) -1br-piperidine-So, 17fb-diacetoxy-5cli-andpropanol with t, pl., 234-231 C (decomp.) Are obtained. (o) +12.8 (, chloroform) Found: C, 61.1; H 8.9, N 5.9; Вг 11,3. (L, hLBrN ,, 0 / H, 0 Numbers;%: C 61.4, H 8.7, N6, G Bg 11.7 Compounds of general formula 1 have a curare-like, non-depolarizing neuro-muscular blocking effect, i.e. they inhibit passage of nerve stimuli in muscles. These compounds do not release histamine, do not reduce blood pressure, do not affect hormones, their action can be neutralized by the action of the commune. To determine the strength and duration of the test, artificial respiration is carried out on anesthetized cats. annoyed by electricity and recorded in Called mutual attraction of the tibial muscles. By intravenous injection of blocking substances in different doses, the dose of complete binding of the mutual attraction of the muscles (EDurd) is determined. The time between the onset of action and the complete cessation of the normal muscle response is determined. cs to doses of complete suppression "Pancuronium bromide is used as a comparative compound. 2p-, -Dimethylpiperazinium - (N-methylpiperidinium), -3Q, 17p-diacetoxy-Zo-androstane dibromide (N-Methylpiperidinium) - 16p- (4,4- dimethyl piper zi NII) 7 | b-diacetoxy-5o1-androstanadibromide Pankuroniumbromide From the table it can be seen that the compounds in doses of 2 less act the same as kuroniumbromide, and the duration is only less. The claims of the method for producing 2p, 1br androstane derivatives are 1 p and A, which have the following traces: -, then R, NS if R NS, R.CH, -N or Rj - CHj / if R. CH.jN or Rj - - jj R, or Ry-N, g -cn / 2., moreover, CH, / then R4 if -M, then R. Rc Cf -4, 1,2, A is the anion of monobasic acid, or their salts differing in that the compound of the general formula P to, f -: ChChKh, where X is bromine or iodine, is treated with the compound of the general formula III and O, where R (, CK, jN or -CH, -, to the resulting compound, if necessary, add hydrohalic acid, such as salt, the resulting intermediate product alkali metal borohydride is reduced, such as sodium borohydride, the obtained compound of general formula IV where R has the indicated value, y / f is halo, for example chlorine, hydroxy group, and the VO forms an epoxy group, is reacted with a compound of formula 1 in which R has the opposite meaning of R in the compound of formula IV, is acetylated, for example, with acetic anhydride and the desired product is isolated in free form or as a salt or, if necessary, treated with the compound of the general formula Rg-Br, where R (G - al l, and target out oh salt product.
    131001859I
    Information sources,
    [2]
    2. Bühler, K., Pearson, D, Organically Accepted Attention in Expertise Syntheses, p. K Mir, 1973, p.
    1, Mashkovsky M, D. Medicinal with .299.
    means, h. 1, M., Medicine, 1972, p. .
    [3]
    3. Ibid, p. 222.
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    同族专利:
    公开号 | 公开日
    AT359218B|1980-10-27|
    DK340976A|1977-02-02|
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    DE2634336B2|1978-03-23|
    IL50099A|1980-02-29|
    PL101306B1|1978-12-30|
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    IL50099D0|1976-09-30|
    DK138460C|1979-02-12|
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    DD126820A5|1977-08-17|
    NL185079C|1990-01-16|
    SE7608608L|1977-02-02|
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    CS189782B2|1979-04-30|
    RO75980A|1981-08-17|
    FR2319370A1|1977-02-25|
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    GB1540405A|1979-02-14|
    DE2634336C3|1978-11-23|
    AU1612576A|1978-01-26|
    DE2634336A1|1977-02-03|
    YU187776A|1982-05-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1138605A|1965-02-19|1969-01-01|Organon Labor Ltd|Improvements in or relating to new 2-ß,16-ß-diamino-androstanes|
    HU168431B|1972-07-27|1976-04-28|EP0008824B1|1978-09-05|1982-04-28|Akzo N.V.|Acid addition salts of 16-beta-monoquaternary ammonium derivatives of 2-beta, 16-beta-bis-piperidino-androstanes and pharmaceutical preparations containing same|
    DE7930964U1|1978-11-03|1984-10-04|Papst-Motoren GmbH & Co KG, 7742 St Georgen|MAGNETIC DISK DRIVE|
    IE50675B1|1979-12-12|1986-06-11|Akzo Nv|Bis-and mono-quaternary ammonium derivatives of 2beta,16beta-dipiperidino-5alpha-androstanes,processes for their preparation and pharmaceutical preparations|
    HU195972B|1985-07-01|1988-08-29|Richter Gedeon Vegyeszet|Process for producing new diamino-androstane derivatives and pharmaceutical compositions containing them|
    USRE35053E|1985-09-12|1995-10-10|The Upjohn Company|Amines useful in producing pharmaceutically active CNS compounds|
    US5099019A|1985-09-12|1992-03-24|Upjohn Company|Amines useful in producing pharmaceutically active CNS compounds|
    US5380839A|1985-09-12|1995-01-10|The Upjohn Company|Phenylpiperazinyl steroids|
    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|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU75RI00000575A|HU172522B|1975-08-01|1975-08-01|Process for preparing new derivatives of 2beta-16beta-diamino-androstane and derivatives / quaternary salts / thereof|
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