Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies

Definitions

• This invention relates to novel bis-- and mono-quaternary ammonium derivatives of 2 ⁇ , 16 ⁇ -dipiperidino- 5 ⁇ -androstanes, to processes for their preparation and to pharmaceutical preparations. containing one or more of said androstane compounds as active constituent.
• Bis- and mono-quaternary ammonium derivatives of 2 ⁇ , 16 ⁇ -dipiperidino-5 ⁇ -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 (3 ⁇ , 17 ⁇ -diacetoxy-2 ⁇ , 16 ⁇ - dipiperidino-5 ⁇ -androstane dimethobromide), which has proved a clinically useful non-depolarizing muscle relaxant of medium duration of action.
• R 1 H (CK 3 ) 2 (isobutyryl)
• R 2 methyl, ethyl or allyl, preferably allyl;
• R 3 methyl, ethyl or allyl, preferably ethyl, and with the proviso that R 2 and R 3 , are not methyl simultaneously;
• the novel compounds show a high selectively, i.e. have a favorable 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.
• the compounds according to the invention can be prepared by meth ⁇ ds employing steps known or obvio ⁇ s to those skilled in the art.
• Suitable starting substances include 2 ⁇ , 16 ⁇ - dipiperidino-3 ⁇ -hydroxy-5 ⁇ -androstan-17-one and
• a complex metal hydride such as potassium borohydride, lithium aluminum hydride, sodium triethoxy aluminum hydride or sodium trimethoxy borohydride, in a suitable solvent, e.g. t-butanol, whereafter the 3 ⁇ -isobutyroxy- 17 ⁇ -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.
• a complex metal hydride such as potassium borohydride, lithium aluminum hydride, sodium triethoxy aluminum hydride or sodium trimethoxy borohydride
• a suitable solvent e.g. t-butanol
• an aliphatic carbacylic acid having 1-6 carbon atoms e.g. acetic acid, butyric acid, valeric acid, caproic acid,
• the 2 ⁇ , 16 ⁇ -bispiperidino-3 ⁇ -isobutyroxy-17-ketone or -17 ⁇ -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, eg 80 oC, for 6 to 12 hours.
• a suitable solvent such as methylene Chloride or methylcyanide
• the 16-mono-quaternary ammonium compound may be prepared by treating the 2 ⁇ , 16 ⁇ -dipiperidino steroid with a methyl, ethyl or allyl halide in a solvent , eg 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 2 ⁇ , 16 ⁇ -bis-quaternary ammonium compound.
• the anion in the bisquaternary ammonium derivatives of the invention (X-) is halogen, e.g. Cl-, Br- or I-, preferably Br-.
• the present bisquaternary ammonium compounds are intended particularly for use in clinical practice to produce skeletal muscular paralysis during surgical operations.
• 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 ranks of 25 to 75% of that of pancuronium bromide.
• the ratio between onset time and recovery time is in the ranks 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.)
• the present invention also relates to novel 16-mono-quaternary ammonium compounds having the formula II:
• R 1 H (CH 3 ) 2 (isobutyroxy);
• R 3 ethyl or allyl, preferably ethyl
• X a halogen atom, preferably Br.
• Example I a) 2 ⁇ , 16 ⁇ -didiperidino-5 ⁇ -androstane-3 ⁇ , 17 ⁇ -diol-di isobutyrate
• Ethyl bromide (10.0 g) was added to a solution of 2 ⁇ , 16 ⁇ -dipiperidino-5 ⁇ -androstane-3 ⁇ , 17 ⁇ -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.
• Methyl bromide (90 g) was added to a solution of 2 ⁇ , 16 ⁇ -dipiperidino-5 ⁇ -androstane-3 ⁇ , 17 ⁇ -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- (3 ⁇ , 17 ⁇ -di-isobutyroxy-2 ⁇ -piperidino-5 ⁇ -androstan-16 ⁇ -yl) piperidinium bromide was precipitated as a pale yellow solid which was filtered and dried (26.5 g).
• Example III 2 ⁇ , 16 ⁇ -di (l'-allyl-1'-piperidino) -5 ⁇ -androstane-3g, 17 ⁇ -diol di-isobutyrate dibromide
• Example IV a) 3 ⁇ -isobutyroxy-2 ⁇ , 16B-dipiperidino-5 ⁇ -androstan-17-one
• Example V a) 23 16ß-Dipiperidino-5 ⁇ -androstane-3 ⁇ , 176-diol 3-isobutyrate sodium borohydride (16 g) was added to a stirred solution of 3 ⁇ -isobutyroxy-2 ⁇ , 16 ⁇ -dipiperidino-5 ⁇ - 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 2 ⁇ , 16 ⁇ -dipiperidino-5 ⁇ -androstane-3 ⁇ , 17 ⁇ -diol 3-isobutyrate (21 g) which was recrystallized from ether.

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• General Health & Medical Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Hydrogenated Pyridines (AREA)

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• 1980
  • 1980-12-08 IE IE2566/80A patent/IE50675B1/en not_active IP Right Cessation
  • 1980-12-09 AU AU66405/81A patent/AU534992B2/en not_active Ceased
  • 1980-12-09 WO PCT/EP1980/000143 patent/WO1981001710A1/de not_active Ceased
  • 1980-12-09 EP EP80201186A patent/EP0032261B1/en not_active Expired
  • 1980-12-09 HU HU811180A patent/HU185865B/hu unknown
  • 1980-12-09 JP JP56500158A patent/JPH026360B2/ja not_active Expired - Lifetime
  • 1980-12-09 DE DE8080201186T patent/DE3065088D1/de not_active Expired
  • 1980-12-10 US US06/214,650 patent/US4348390A/en not_active Expired - Lifetime
  • 1980-12-11 CA CA000366536A patent/CA1153366A/en not_active Expired
  • 1980-12-12 ES ES497724A patent/ES497724A0/es active Granted
• 1981
  • 1981-06-15 FI FI811857A patent/FI66394C/fi not_active IP Right Cessation
  • 1981-06-15 DK DK260881A patent/DK158741C/da not_active IP Right Cessation

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