• 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:WO1981001710A1
    申请号:PCT/EP1980/000143
    申请日:1980-12-09
    公开日:1981-06-25
    发明作者:J Kelder
    申请人:Akzo Nv；
    IPC主号:C07J43-00
    专利说明:
    [0001] MONO AND BIS PIPERIDINIUM ANDROSTANES DERIVATIVES
    [0002] This invention relates to novel bis-- and mono- quaternary ammonium derivatives of 2β, 16β-dipiperidino- 5α-androstanes, to processes for their preparation and to pharmaceutical preparations. containing one or more of said androstane compounds as active constituent.
    [0003] Bis- and mono-quaternary ammonium derivatives of 2β, 16β-dipiperidino-5α-androstanes are known from e.g. Eritish Patent Specifications 1 138 605 and 1 454 749. See also Journal of Medicinal Chemistry 16, 1116-1124, (1973). These compounds have neuromuscular blocking activity. A well-known compound of this type is pancuronium bromide (3α, 17β-diacetoxy-2β, 16β- dipiperidino-5α-androstane dimethobromide), which has proved a clinically useful non-depolarising muscle relaxant of medium duration of action.
    [0004] Surprisingly, it was found that novel bis- quaternary ammonium derivatives of 23, 16ß-dipiperidino- 5α-androstanes, having the formula I:
    wherein
    [0005] R1 =
    H(CK3)2 (isobutyryl)
    [0006] R2 = methyl, ethyl or allyl, preferably allyl;
    [0007] R3 = methyl, ethyl or allyl, preferably ethyl, and with the proviso that R2 and R3, are not methyl simultaneously; R4 = 0 or H(βORc), wherein R5 = H or aliphatic carbacyl
    [0008] (1-6 C), preferably acetyl; and X = a halogen atom, preferably Br, are very potent neuromuscular blocking agents with a quick onset of action, a relatively short duration of action and a quick recovery time. Very remarkable is the short duration and the high ratio between onset time and recovery time. Moreover the novel compounds show a high selectively, i.e. have a favourable ratio of neuromuscular activity and unwanted vagolytic activity, and neither affect the cardiovascular system, nor release histamine to the same extent as the muscle— relaxant d-tubocurarine. Therefore, the present invention relates to the novel compound having the above formula and also extend to processes for their preparation. The invention also relates to pharmaceutical compositions containing a pharrnaceutically effective amount of one or more of the novel compounds having the above formula.
    [0009] The compounds according to the invention can be prepared by methσds employing steps known or obvioυs to those skilled in the art.
    [0010] Suitable starting substances include 2β,16β- dipiperidino-3α-hydroxy-5α-androstan-17-one and
    [0011] 2ß , 16ß-dipiperidino-5α-androstane-3o:, 17β-diol which can be prepared according to the methods described in British Patent Specification 1 138 605.
    [0012] These starting substances are esterified in Position 3 with isobutyric acid, preferably with a functional derivative thereof, such as the anhydride or the acid Chloride, and if desired in a suitable solvent, such as methylene Chloride or pyridine. Esterification of the 3α-hydroxy-17-ketone gives the 3α-isobutyrate, whereas esterification of the 3α,17β-diol results in the 3α, 17β-di-isobutyrate. For obtaining the 3α-isobutyrate with a different ester group in 17β-position the 3α-isobutyroxy- 17-ketone is reduced e.g. with a complex metal hydride such as potassium borohydride, lithium aluminium hydride, sodium triethoxy aluminium hydride or sodium trimethoxy borohydride, in a suitable solvent, e.g. t-butanol, whereafter the 3α-isobutyroxy- 17β-ol is esterified with an aliphatic carbacylic acid having 1-6 carbon atoms, e.g. acetic acid, butyric acid, valeric acid, caproic acid, trimethyl acetic acid, or a functional derivative thereof, such as the anhydride or the acid Chloride.
    [0013] The 2β, 16β-bispiperidino-3α-isobutyroxy-17-ketone or -17β-acylates are then reacted with a methyl, ethyl or allyl halide in a suitable solvent, such as methylene Chloride or methylcyanide, at room temperature for several days or at an elevated temperature, e.g. 80 ºC, for 6 to 12 hours. Since the 16-piperidino group is more reactive to quaternarisation than is the 2-piperidino group, the 16-mono- quaternary ammonium compound may be prepared by treating the 2β, 16β-dipiperidino steroid with a methyl, ethyl or allyl halide in a solvent, e.g. ether, in which the formed 16-monoquaternary ammonium steroid is sparingly soluble. The 16-monoquaternary ammonium compound can then be further treated with a different alkyl halide to give the corresponding 2β,16β-bis- quaternary ammonium compound.
    [0014] The anion in the bisquaternary ammonium derivatives of the invention (X-) is halogen, e.g. Cl-, Br- or I-, preferably Br-.
    [0015] The present bisquaternary ammonium compounds are intended particularly for use in clinical practice to produce skeletal muscular paralysis during surgical operations.
    [0016] The compounds are usually administered by intravenous injection, in initial dosages between 10 and 50 mg (bolus injection), followed if necessary by smaller supplementary dosages. The compounds have a very short duration of action, which is in the ränge of 25 to 75% of that of pancuronium bromide. The ratio between onset time and recovery time is in the ränge of 1 to 10, i.e. recovery times are equal or even shorter than onset times. (For pancuronium bromide the recovery time is lonqer than the onset time. )
    [0017] In the preparation of the bisquaternary ammonium compounds of the present invention the 16-mono- quaternary ammonium compounds are valuable intermediates Therefore, the present invention also relates to novel 16-mono-quaternary ammonium compounds having the formula II:
    [0018]
    wherein
    [0019] R1 =
    H(CH3)2 (isobutyroxy);
    [0020] R3 = ethyl or allyl, preferably ethyl;
    [0021] R4 = 0 or H(βOR5), wherein R5 = H or aliphatic carbacyl (1-6 C) , preferably- acetyl; and
    [0022] X = a halogen atom, preferably Br.
    [0023] These compounds are not only important intermediates for preparing bisquaternary ammonium compounds having the formula I, but possess themselves also interesting neuromuscular blocking activities.
    [0024] The following examples illustrate the invention.
    [0025] Example I a) 2β, 16β-didiperidino-5α-androstane-3α,17β-diol-di isobutyrate
    [0026] Isobutyryl Chloride (40 ml) was added over 10 minutes to a stirred solution of 2β, 16β-dipiperidino- 5α-androstane-3α, 17β-diol (40 g) in methylene dichloride (200 ml), keeping the reaction temperature at 5 ºC + 5º. After 16 hours, saturated potassium bicarbonate solution (250 ml) was added, ensuring the final pH was above 7. The methylene dichloride layer was given a further potassium bicarbonate wash followed by water to pH = 7. The dried extract after evaporation to dryness in vacuo, afforded a brown gum (52.4 g), which was filtered through a column of acid-washed alumina (2 wt.) in ether to give a pale yellow eluate, which when concentrated (ether evaporation) gave 48.1 g of non-crystalline 3, 17-di-isobutyrate. b) 2β , 16β-Dipiperidino-5α-androstane-3α, 17β-diol di-isobutyrate di-ethobromide
    [0027] Ethyl bromide (10.0 g) was added to a solution of 2β, 16β-dipiperidino-5α-androstane-3α, 17β-diol di-isobutyrate (4.8 g) in freshly distilled methylene Chloride (15 ml). The solution was stored at room temperature and further portions (10.0 g) were added after 7 "days and 14 days. The solvents were removed under reduced pressure after a total of 17 days, the residue dissolved in 3:1 ethyl acetate/isopropanol and chromatographed in acid-washed alumina. Elution with isopropanol gave a colourless gum (6.3 g) which was crystallised twice from isopropanol/acetone to give 3.5 g 2β, 16β—dipiperidino-5α—androstane- 3α,17β-diol di-isobutyrate di-ethobromide.
    [0028] Using ethyl iodide in place of ethyl bromide the corresponding di—etho-iodide was obtained.
    [0029] Example II a) N-methyl-N-(3α, 17β-di-isobutyroxy-2β-piperidino- 5α-androstan-16β-yl)piperidinium bromide
    [0030] Methylbromide (90 g) was added to a solution of 2β, 16β-dipiperidino-5α-androstane-3α, 17β-diol di-isobutyrate (30 g) in methylene dichloride (600 ml) in a pressure bottle at 20 ºC. After 5 hours the reaction mixture was evaporated to dryness in vacuo, taken up in the minimum of methylene dichloride and on addition of ether N-methyl-N-(3α, 17β-di-isobutyroxy-2β- piperidino-5α-androstan-16β-yl)piperidinium bromide was precipitated as a pale yellow solid which was filtered and dried (26.5 g).
    [0031] The filtrate which contained the unquaternised free base, was recycled to afford a further crop (5.4 g) of the title compound. The two crops were combi-ned and crystallised from methylene dichloride/ acetone to yield the 16-mono-metho-bromide as an off-white solid (25.4 g).
    [0032] The following compounds were prepared in a similar manner:
    [0033] N-ethy1-N- ( 3 α, 17β-di-isobutyroxy-2β-piperidino- 5α-androstan-16β-yl)piperidinium bromide;
    [0034] N-allyl-N-(3α, 17β-di-isobutyroxy-2β-piperidino- 5α-androstan-16β-yl)piperidinium bromide. b) 3α, 17β-Di-isobutyroxy-2β-(1'-allyl-1'-piperidino)- 16β-(1''-methyl-1''-piperidino)-5α-androstane dibromide
    [0035] Freshly distilled allyl bromide (4.0 ml) was added to a solution of N-methyl-N-(3α, 17β-di-iso- butyroxy-2β-piperidino-5α-androstan-16β-yl)piperidinium bromide (8.0 g) in methylene dichloride (80 ml) in a pressure bottle at 20 ºC. After 70 hours the reaction mixture was filtrated and the filtrate evaporated to dryness in vacuo. Chromatography and crystallisation from isöpropanol/acetone gave 3.8 g 3α, 17β-di-iso- butyroxy-2β-(1'-allyl-1'-piperidino)-16β-(1''-methyl- 1''-piperidino)-5α-androstane dibromide.
    [0036] The following compounds were prepared in a similar manner:
    [0037] 3α, 17β-di-isobutyroxy-2β-(l'-allyl-1'-piperidino)- 16β-(1 '-ethyl-1''-piperidino)-5α-androstane dibromide; 3α, 17β-di-isobutyroxy-2β-(1'-methyl-1'-piperidino)- 16β-(1''-ethyl-1''-piperidino)-5α-androstane dibromide.
    [0038] Example III 2β, 16β-Di(l'-allyl-1'-piperidino)-5α-androstane-3g, 17β- diol di-isobutyrate dibromide
    [0039] In a similar way as described in Example I b) but using allyl bromide in place of ethyl bromide 2β, 16β-dipiperidino-5α-androstane-3α, 17β-dioi was converted into the title compound. Example IV a) 3α-Isobutyroxy-2β, 16B-dipiperidino-5α-androstan-17-on
    [0040] Isobütyrylchloride (55 ml) was added over 20 minutes to a stirred solution of 3α-hydroxy-2β, 16β- dipiperidino-5α-androstan-17-one (150 g) in methylene dichloride (750 ml), keeping the reaction temperature at 5 °C (± 5°).
    [0041] After 16 hours saturated potassium bicarbonate solution (1.000 ml) was added, ensuring that the final pH was >7. The methylene dichloride layer was given a further potassium bicarbonate wash, followed by water to pH = 7. The dried extract after evaporation to dryness in vacuo afforded a brown gum, which was crystallised from ether to give 3α—isobutyroxy— 2β, 16β-dipiperidino-5α-androstan-17-one (115 g).
    [0042] Recrystallisation from ether yielded the isobutyroxy- 17-ketone (103.2 g). b) Quaternarisation of 3α-isobutyroxy-2β, 16β- dipiperidino-5α-androstan-17-one in a similar way as described in Example I b) gave the corresponding di-ethobromide, the di-ethochloride and the di-allylo- iodide, respectively. c) Quaternarisation of 3α-isobutyroxy-2β, 16β- dipiperidino-5α-androstan—17-one in a similar way as described in Example II gave the corresponding 2β-(1'-allyl-1'-piperidino)-16β-(1''-methyl-1''- piperidino)-dibromide, 2β-(l'-allyl-1'-piperidino)- 162-(1''-ethyl-1''-piperidino)-dibromide and 23-(1'-methyl-1'-piperidino)-16β-(1''-ethyl-1''- piperidino)-dibromide, respectively.
    [0043] Example V a) 23 , 16ß-Dipiperidino-5α-androstane-3α, 176-diol 3-isobutyrate Sodium borohydride (16 g) was added to a stirred solution of 3α-isobutyroxy-2β, 16β-dipiperidino-5α- androstan-17-one (51.6 g) in methylene dichloride (150 ml) and methanol (150 ml) and the reaction mixture was stirred for a further hour. Water was added, the product extracted with ether, and the extract washed well with water and dried. Concentration of the ether solution yielded 2β, 16β-dipiperidino- 5α-androstan-3α,17β-diol 3-isobutyrate (21 g) which was recrystallised from ether.
    [0044] By quaternarisation the di-ethobromide and the 2β-(1'-allyl-1'-piperidino)-16β-(1''-methyl-1''- piperidino)-di-iodide, respectively, were obtained.
    [0045] Example VI a) 28, 16β-Dipiperidino-5α-androstane-3α, 17β-diol 3-isobutyrate 17-acetate
    [0046] A solution of 2β, 16β-diρiperidino-5α-androstane- 3α,17β-diol 3-isobutyrate (10 g) in methylene dichloride (35 ml) was treated with acetic anhydride (20 ml) at about 20 C for 1 hour. Water was added and the methylene dichloride solution washed with sodium bicarbonate solution and water and dried. Evaporation to dryness and crystallisation from ether- methanol gave the title compound (6.2 g).
    [0047] Using propionic anhydride instead of acetic anhydride the corresponding 3-isobutyrate 17-propionate was obtained. b) Quaternarisation of 2β, 16β-dipiperidino-5α- androstane-3α, 17β-diol 3-isobutyrate 17-acetate in a similar way as described in Example II gave the following compounds:
    [0048] 2β, 16β-dipiperidino-5α-androstane-3α, 17β-diol 3-isobutyrate 17-acetate di-ethobromide; 2β, 16β-dipiperidino-5α-androstane-3α, 17β-diol 3-isobutyrate 17-acetate di-allylobromide. c) Quaternarisation of 2β, 16β-dipiperidino-5α- androstane-3α, 17β-diol 3-isobutyrate 17-acetate and the corresponding 17-propionate in a similar way as described in Example II gave the following 16-mono- quaternary compounds:
    [0049] N-methyl-N-(3α-isobutyroxy-17β-acetoxy-2β-piperidino- 5α-androstan-16β-yl) piperidinium bromide; N-ethyl-N-(3α-isobutyroxy-17β-acetoxy-2β-piperidino- 5α-androstan-16β-yl) piperidinium bromide; N-allyl-N-(3α-isobutyroxy-17β-acetoxy-2β-piperidino- 5α-androstan-16β-yl) piperidinium bromide; and the corresponding 17β-propionates; and the following 2, 16-bis-quaternary compounds: 2β-(1'-methyl-1'-piperidino)-16β-(l''-ethyl-1''- piperidino)-5α-androstane-3α, 17β-diol 3 isobutyrate 17-acetate dibromide;
    [0050] 2β-(1'-methyl-1'-piperidino)-16β-(1''-allyl-1''- piperidino)-5α-androstane-3α, 17β-diol 3-isobutyrate 17-acetate dibromide; 2β-(1'-allyl-1'-piperidino)-16β-(1''-ethyl-1''- piperidino)-5α-'androstane-3α, 17β-diol 3-isobutyrate 17-acetate dibromide;
    [0051] 2β-(1'-allyl-l'-piperidino)-16β-(l''-methyl-1''- piperidino)-5α-androstane-3α, 17β-diol 3-isobutyrate 17-propionate dibromide;
    [0052] 2β-(1'-ethyl-1'-piperidino)-16β-(1''-methyl-1''- piperidino)-5α-androstane-3α, 17β-diol 3-isobutyrate 17-propionate di-iodide.

    权利要求:
    Claims

    1. Novel bisquaternary ammonium derivatives of 2β,16β-dipiperidino-5α-androstanes having the formula I:
    wherein
    R1 = H(CH3)2;
    R2 = CH- C2H5 or CH2CH=CH2;
    R3 = CH3 , C2H5 or CH2CH=CH2, with the proviso that R2 and R3 are not CH3 simultaneously;
    R4 = O or H(βOR5), wherein R5 = H or aliphatic carbacyl (1-6 C); and
    X = a halogen atom.
    The compounds according to claim 1, wherein
    R2 = CH2CH=CH2.
    3. The compounds according to claim 1 or 2, in R3 = C2H5.
    4. The compounds according to Claims 1-3 wherein
    R4 = H(β-acetoxy).
    The compounds according to Claims 1-4, wherein X = Br.
    Process for preparing the compounds of Claims 1-5, wherein a 2β , 16β-dipiperidino-3α-hydroxy-5α- androstane compound having a 17-oxo or a 17β-hydroxy group is esterified with isobutyric acid or a functional derivative thereof, such as the anhydride or the acid Chloride, so as to obtain the 3α-iso- butyrate or the 3α, 17β-di-isobutyrate, a possibly present 17-oxo-group is reduced, if desired, to a 17β-hydroxy group, a 17β-hydroxy group, if present, is esterified if desired, and the piperidino groups in 2- and 16-position are quaternarised by reaction with a methyl, ethyl or allyl halide, wherein use is made of the difference in reactivity to quaternarisation between the 16-piperidino group and the 2-piperidino group for obtaining bisquaternary compounds having different quaternary ammonium groups in 2- and 16-position.
    7. Novel monoquaternary ammonium derivatives of 2β, 16β-dipiperidino-5a-androstanes having the formula II:
    wherein
    R1 = CH(CH3)2;
    R3 = C H5 or CH2CH=CH2;
    R4 = 0 or H(βOR5), wherein Rr = H or aliphatic carbacyl (1-6 C); and X = a halogen atom.
    8. The compounds according to claim 7, wherein R3 = C2H5, R4 = H(β-acetoxy) and X = Br.
    9. Process for preparing the compounds of claim
    7 or 8, wherein a 2β, 16β-dipiperidino-3α-hydroxy-5α- androstane compound having a 17-όxo or a 17β-hydroxy group is esterified with isobutyric acid or a functional derivative thereof, such as the anhydride or the acid Chloride, so as to obtain the 3α-iso- butyrate or the 3α, 17β-di-isobutyrate, a possibly present 17-oxo group is reduced, if desired, to a 17β-hydroxy group, a 17β-hydroxy group, if present, is esterified if desired, and the piperidino group in 16—position is quaternarised by reaction with an ethyl or allyl halide in a solvent, in which the formed 16-monoquaternary ammonium compound is sparingly soluble. 10. Pharmaceutical preparations having neuromuscular blocking activity comprising a pharmaceutically effective amount of one or more compounds of Claims 1-5, 7 or 8.
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    同族专利:
    公开号 | 公开日
    FI811857L|1981-06-15|
    IE802566L|1981-06-12|
    CA1153366A|1983-09-06|
    ES497724D0||
    DK260881A|1981-06-25|
    JPH026360B2|1990-02-08|
    AU534992B2|1984-02-23|
    AU6640581A|1981-07-06|
    JPS56501761A|1981-12-03|
    CA1153366A1||
    EP0032261B1|1983-09-28|
    DE3065088D1|1983-11-03|
    FI66394B|1984-06-29|
    ES8204443A1|1982-05-01|
    DK158741C|1990-11-26|
    FI66394C|1984-10-10|
    EP0032261A1|1981-07-22|
    DK158741B|1990-07-09|
    FI811857A||
    ES497724A0|1982-05-01|
    IE50675B1|1986-06-11|
    US4348390A|1982-09-07|
    HU185865B|1985-04-28|
    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|
    FR2319370A1|1975-08-01|1977-02-25|Richter Gedeon Vegyeszet|Nouveaux derives de diaminoandrostane et leurs sels d'addition d'acides et sels quaternaires doues d'activite curarisante et leur procede de preparation|
    EP0008824A1|1978-09-05|1980-03-19|Akzo N.V.|Säureadditionssalze von 2-beta, 16-beta-bis-Piperidino-androstan-16-beta-monoquaternären Ammoniumderivaten und diese enthaltende pharmazeutische Zusammensetzungen|WO1999021854A1|1997-10-24|1999-05-06|Newlaxant Llc|Bis-quaternary ammonium derivatives as neuromuscular relaxants|GB1454749A|1972-11-29|1976-11-03|Akzo Nv|2beta, 16beta-diamino-androstanes and their preparation|IE53463B1|1981-06-15|1988-11-23|Akzo Nv|Mono-and bisquaternary ammonium derivatives of 2 beta,16 beta-d-amino-5 alpha-androstane derivatives and pharmaceutical preparations containing same|
    US4726275A|1983-05-10|1988-02-23|Synthaxe Limited|Electronic musical instrument|
    US5418226A|1992-04-22|1995-05-23|Akzo N.V.|Monoquaternary 2,16-bispiperidinylandrostane derivatives|
    US5926516A|1995-05-24|1999-07-20|Siemens Aktiengesellschaft|Absorption structure for absorbing neutrons and method for producing an absorption structure|
    IT1277700B1|1995-12-22|1997-11-11|Poli Ind Chimica Spa|Processo di preparazione di 2-beta, 16-beta-diamino 3-alfa, 17-beta-diacilossi 5-alfaandrostani, bloccanti neuromuscolari a struttura|
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    优先权:
    申请号 | 申请日 | 专利标题
    GB7942883||1979-12-12||
    GB7942883||1979-12-12||AU66405/81A| AU534992B2|1979-12-12|1980-12-09|Novel bis-and mono-quaternary ammonium derivatives of 2beta, 16beta-dipiperidino-5alpha-androstanes, processes for their preparation and pharmaceutical preparations|
    DK260881A| DK158741C|1979-12-12|1981-06-15|Analogifremgangsmaade til fremstilling af biskvaternaere ammoniumderivater af 2beta,16beta-dipiperidino-5alfa-androstaner|
    FI811857A| FI66394C|1979-12-12|1981-06-15|Foerfarande foer framstaellning av nya biskvaternaera ammoniumderivat av 2beta 16beta-dipiperidino-5alfa-androstaner|
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