CA1037026A - Pharmaceutical preparations - Google Patents
Pharmaceutical preparationsInfo
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- CA1037026A CA1037026A CA217,940A CA217940A CA1037026A CA 1037026 A CA1037026 A CA 1037026A CA 217940 A CA217940 A CA 217940A CA 1037026 A CA1037026 A CA 1037026A
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Abstract
ABSTRACT
This invention is concerned with improvements in or relating to pharmaceutical preparations having anaesthetic activity, and more particularly aqueous preparations suitable for intravenous injection. The preparations comprise solutions of the known anaesthetic steroid 3.alpha.-hydroxy-5.alpha.-pregnane-11,20-dione in aqueous solutions of parenterally acceptable non-ionic surface active agents. The preparations also contain certain new 21-acyloxy-3.alpha.-hydroxy-5.alpha.-pregnane-11,20-diones which act as solubility promoters and constitute a further feature of the invention. Preferred classes of surface active agent are described and the useful materials fall within the class having an HLB
value of at least 9, preferably from 9 to 18. Processes for preparing the preparations are described and claimed. A process for the preparation of the 21-acyloxy-3.alpha.-hydroxy-5.alpha.-pregnane-11,20-diones is described.
This invention is concerned with improvements in or relating to pharmaceutical preparations having anaesthetic activity, and more particularly aqueous preparations suitable for intravenous injection. The preparations comprise solutions of the known anaesthetic steroid 3.alpha.-hydroxy-5.alpha.-pregnane-11,20-dione in aqueous solutions of parenterally acceptable non-ionic surface active agents. The preparations also contain certain new 21-acyloxy-3.alpha.-hydroxy-5.alpha.-pregnane-11,20-diones which act as solubility promoters and constitute a further feature of the invention. Preferred classes of surface active agent are described and the useful materials fall within the class having an HLB
value of at least 9, preferably from 9 to 18. Processes for preparing the preparations are described and claimed. A process for the preparation of the 21-acyloxy-3.alpha.-hydroxy-5.alpha.-pregnane-11,20-diones is described.
Description
~37~26 I~lis application is a divisional of our copending Canadian Paten~
Application Serial No. 085,973 filed June 19, 1970.
This invention is ~oncerned with improvements in relation to pharmaceutical preparations having anaesthetic activi~y, and more particular-ly aqueous preparations suitable for intravenous injection.
It has long been known that a number of steroids giY0 rise to profound depression of the central nervous system and act pharmacodynamically as anaesthetics or hypnotics. Such compounds have been the subject of con-siderable study in an attemp~ to find anaesthe~ics to replace such substances as thiopentone sodium normally used but well known to be accompanied by some degree of hazard or disadvantage. The literature shows that very many steroid compounds have been studied in this regard. Reviews and discussions of some of the work carried out are to be found> for example, in "Methods in Hormone Research" (~dited by Ralph I. Dorfman, Vol. III, Part A, Academic Press London and New York 1964, pages 415-475); }1. Witzel, Z. Vitamin Hormon-Ferment~orsch 1959, 10, 46-74; H. Selye, Endocrinology, 1942, 30, 437-453; S.K. Figdor et al,, J. Pharmacol. Exptl. ~lerap., 1957, 119 299-309 and Atkinson et al., J. Med. Chem. 1965, 8, 426-432.
A thorough review of the literature indicates that anaesthetic steroids generally possess poor activity and/or long induction periods. With such compounds a variety of undesired side effects such as paraesthesia and thrombophlebitis and vein damage have been noted. Many steroid compounds having anaesthetic action are also of poor solubility and thus much research has hitherto been directed to the introduction of solubilising groups into such steroids, e.g. by the formation of partial esters with di- or polybasic acids; such work has hitherto not resulted in ~he discovery of a satisfactory anaesthetic steroid compound. Anaesthetic steroids are generally relatively -simple pregnane derivatives, often hydroxylated in the 3-position, the general trend having been in the latter case to study 3~-hydroxy compounds in pre- :
ference to 3d-hydroxy compounds. ~ -~'~ ' '"' '' : ... .
C~ .' ~'' ~, .
,. . .
~. ~, . . . , - ~ . . . . ... . .. . . . . .. .
~LCI 37~Z6 As a result of prolonged study of numerous steroids exhibiting anaesthetic activity we have found that 3~-hydroxy-5c-pregnane-11,20-dione (hereinafter called "steroid I") has quite remarkable properties as an anaesthetic. This substance has but poor solubility in water and although ~ , ~era~re referred to in the above cited i~ t~ as having anaesthetic properties, has apparently been rejected by reason of its poor solubility and the difficulty to be anticipated in its use by intravenous administration arising therefrom.
We have found however that steroid I can be brought into aqueous solution with the aid of certain non-ionic surface active agents to yield solutions of a sufficient concentration for injection, the resulting solutions when injected showing excellent anaesthetic properties. These solutions also ~
contain one or more 21-acyloxy-3~-hydroxy-5a-pregnane-11,20-diones whic'h act ' ' as solubility promoters for steroid I.
Thus the aqueous solutions of steroid I according to the invention induce anaesthesia and possess short induction periods, the anaesthetic action at suitable doses being indeed instantaneous; the solutions are thus excellent anaesthetics or inducing anaesthesia which is to be maintained e.g. by an inhalation anaesthetic such as ether, halothane, nitrous oxide, trichloro-ethylene etc. The solutions are however capable of maintaining anaesthesia ; and analgesia to a sufficient degree to enable various surgical operations to be conducted without the aid of an inhalation anaesthetic, the required degree of anaesthesia being maintained if necessary by repeated administration ~or even continuous administration). Recovery from anaesthesia (where this is induced only by the solutions of this invention) is excellent, the patient ~ ' exhibiting a feeling of well-being in distinction to the unpleasant after effects generally associated with conventional anaesthetics. Moreover, anaesthetic solutions in accordance with the invention in general give rise ~" ' to none o the undesired side-effects hither to associated with steroidal , ~
. ,:
- 30 anaesthetics.
, ~ ' .
~)37~26 ~ ccording to the invention therefore we provide an anaesthekic com-position suitable for use by parenteral administration of 3~hydroxy-5c~rpreg-nane-11,20-dione in solution in an aqueous medium in an amount of at least 1 mg/ml of said medium, said medium also con~aining at least one further steroid of the formula ~
CH20R , ~
C = O
O ~ ' "
I l (II) "~ I ' , ~ ~,, ' ,. -'~", .. ..... ..
wherein R is selected from the group consisting of lower alkanoyl groups, the hemisuccinyl group and the benzoyl group, said further steroid increasing the solubility of 3~-hydroxy-5~-pregnane-11,20-dione in said medium; and said medium also containing at least 1% by weight of a parenterally acceptable non-ionic surface active agent having an HLB value of at least 9.
The non-ionic surface active agents used for the purpose pf this invention are generally those of the water soluble type, preferably having an HLB value of from 9 to 18, ~ore preferably at least about 12, and advantageous-ly at least about 13. Preferably the HLB value of the surface active agent is not greater than about 15. The surface active agent must naturally be one which is physiologically compatible, i.e of itself give rise to no physiolog-ically unacceptable side effects in the dosages employed in the intended species to be treated (man or animal). Surface active agents for use in ~ : -.
accordance with the invention are for example to be found among the following non-ionic surfactants and classes of surfactants:- Polyoxyethylated derivat-ives of fatty ~C12-C20) glyceride oils, e.g. castor oil, containing from 35 to 45 oxyethylene groups, per mole of fatty oil. Polyoxyethylene ethers ~containing from 10 to 30 polyoxyethylene groups) of long chain alcohols ~con-~: .",' ' .i ' ' 3 _ ~--,: ., . :
; -:
~037~G
taining for example from 12-18 carbon atoms).
Polyoxyathylene-polyoxypropylene ethers containing from 15 to 35 and from 15 to 30 oxyethylene and oxypropylene groups respectively. Polyoxy-ethylene ethers (containing from 6 to 12 oxyethylene groups) of alkyl phenols the alkyl groups of which preferably contain 6-lO carbon atoms.
Polyoxyethylated ~containing from 15 to 30 oxyethylene groups) fatty acid (e.g. C12-18) esters of sugar alcohol anhydrides e.g. sorbitan or mannitan. Long-chain (e.g. Cl0-16) alkanoyl mono- and di-alkanolamides (the alkanol portions of which for example contain l 5 C atoms) for example lauroyl mono- and di-ethanolamides~ Polyethylene glycol esters (containing from 6 to 40 ethylene oxide units) of long chain fatty acids (containing for example 12-22 C atoms) e.g. polyethyleneglycol mono-oleate (containing for example 8 ethylene oxide units).
Examples of non-ionic surface active agents, of the foregoing types, useful in accordance with the invention include:-Cremophor (trade mark) EL, a polyoxyethylated castor oil containingabout 40 ethyleneoxide units per triglyceride unit;
Tween (trade mark) 80, polyoxyethylene sorbitan monooleate containing about 20 ethylene oxide units.
~0 Tween (trade mark) 60, polyoxyethylene sorbitan monostearate contain-ing abo~t 20 ethylene oxide units; and ~
Tween ~trade mark) 40, polyoxyethylene sorbitan monopalmitate con- ~ -taining about 20 ethyleneoxide units. -The expression "solutions" is used herein to denote liquids which -; have the appearance of true solutions and are thus optically clear and cap- --~able of passage, or example, through a micro-porous filter, irrespectlve of whether such solutions are true solutions in the classical chemical sense and irrespective of whether they are stable or metastable. Thus it may be that the steroid is associated with micelles. The solutions of this invention, irrespective of their precise physical nature, behave as true solutions for j . , ' ~ ' , - :
~37~DZ6 the practical purpose of intravenous injection.
As stated above, we have found that the total amount of anaesthetic steroid which may be dissolved in accordance with the invention may be sub-stantially increased by the presence of a steroid of general formula:
C - O .... ..
II
I J
",~
wherein R is a lower alkanoyl group having a straight or branched chain (con-taining for example 2-4 carbon atoms) 9 the hemisuccinyl group or the benzoyl group. Such steroids of formula II thus act as solubility promoters for the steroid I and are capable of substantially increasing the amount of the latter which may be dissolved in the compositions of this invention. Solutions con-taining steroid I together with a steroid of formula II may thus be prepared ~ :
having a substantially greater anaesthetic potency than a solution of steroid -I alone, due to the increased amount of steroid I which can be dissolved and the anaesthetic action of the steroid of formula II per se. -Compounds of formula II above are new compounds, and constitute a further feature of the invention. :' Preferred co~pounds of formula II are those in which R is an acetyl, hen~;suc c~/
propionyl, isobutyryll, or benzoyl group.
The proportion of surface active agent to be used in the compositions of this invention depends upon its nature and upon the concentration of ster-: , oid deslred in the final composition.
In preferred compositions according to the invention the proportion of surfactant is preferably at least 5% by weight and advantageously above ;
10% by weight. A very convenient proportion of surfactant has been found to ~ ;
, ~(137~6 be 20% by weight but 30% and up to 50% may be used. The proportions of sur-factant are expressed by weight in relation to the total volume of the composi-tion in metric units.
The compositions according to this invention may contain up to 40 or even 50% by weight of the total steroid of a compound of formula II; as little as 5% of the total steroid present of a compound of formula II provides useful solubility promotion. For practical purposes it is preferred that of the total steroid at least 10% by weight, and preferably not more than 30%
by weight of the total steroid consists of a compound of formula II. Very satisfactory results have been achieved with a mixture of steroid I with a steroid of formula II in which the proportion ~the steroid of formula II is about 25%, As will be clear, the proportion of steroid I in the aqueous solut-ion according to the invention deperdsupon the nature and amount of surface active agent used and also upon the amount of steroid o formula II present (if used). The composition will contain at least l mg/ml of steroid I and solutions can be made containing for example 2 and ~ mg/ml; using a steroid of formula II as solubilisar the amounts of total steroid can be increased up to 50 mg/ml although less than 30 mg/ml total steroid and generally less than 20 mg/ml will usually be satisfactory. A composition comprising 9 mg/ml of steroid I to 3 mg/ml of a compound of formula II in which R is acetyl has been found to be very satisfactory.
In all cases, as stated above the relative proportion of the various `~
components are adjusted to give a clear solution.
~ ~ According to a ~urther feature of the invention, the anaesthetic :~
solutlons are prepared by mixing steroid I with one or more steroids of ',.~ :
formula II and then dissolving the steroid mixture in the selected surfactant for example, with heating and mechanical agitation and the resulting solution dissolved in water. Alternatively the steroid mixture may be dissolved in a volatile organic solvent advantageously having a boiling point o less than :
' ; ~,.,', '' -~;37~Z6 about 80C which is miscible wi~h the surface active agent such as a volatilelower aliphatic ketone e.g. acetone or methyl ethyl ketone or a volatile halo-genated hydrocarbon e.g. chloroform or methylene chloride. Acetone is particularly preferred for this purpose. The surface active agent is then added to this solution, the organic solvent removed by evaporation, for example by passing a stream of an inert gas through the solution e.g. nitrogen~ and the resulting solution of steroids in surfactant is mixed with water. By these procedures in general it is possible to dissolve increased amoun~s of steroid I as compared with other methods.
Thus according to ano~her feature of this invention there is provided:
a process for preparing an anaesthetic composition suitable for use by parenteral administration in the form of a solution in an aqueous medium con-taining at least 1 mg/ml of 3~-hydroxy-5~-pregnane-11,20-dione wherein the solubility of this substance in water has been increased by the presence of one or more steroids of the formula:
C=O
~b wherein R is selected from the group consisting of lower alkanoyl groups, th0 ;hemisuccinyl group and the benzoyl group and wherein said medium also co~ains ~ at least 1% by weight of a parenterally acceptable non-ionic surface active
Application Serial No. 085,973 filed June 19, 1970.
This invention is ~oncerned with improvements in relation to pharmaceutical preparations having anaesthetic activi~y, and more particular-ly aqueous preparations suitable for intravenous injection.
It has long been known that a number of steroids giY0 rise to profound depression of the central nervous system and act pharmacodynamically as anaesthetics or hypnotics. Such compounds have been the subject of con-siderable study in an attemp~ to find anaesthe~ics to replace such substances as thiopentone sodium normally used but well known to be accompanied by some degree of hazard or disadvantage. The literature shows that very many steroid compounds have been studied in this regard. Reviews and discussions of some of the work carried out are to be found> for example, in "Methods in Hormone Research" (~dited by Ralph I. Dorfman, Vol. III, Part A, Academic Press London and New York 1964, pages 415-475); }1. Witzel, Z. Vitamin Hormon-Ferment~orsch 1959, 10, 46-74; H. Selye, Endocrinology, 1942, 30, 437-453; S.K. Figdor et al,, J. Pharmacol. Exptl. ~lerap., 1957, 119 299-309 and Atkinson et al., J. Med. Chem. 1965, 8, 426-432.
A thorough review of the literature indicates that anaesthetic steroids generally possess poor activity and/or long induction periods. With such compounds a variety of undesired side effects such as paraesthesia and thrombophlebitis and vein damage have been noted. Many steroid compounds having anaesthetic action are also of poor solubility and thus much research has hitherto been directed to the introduction of solubilising groups into such steroids, e.g. by the formation of partial esters with di- or polybasic acids; such work has hitherto not resulted in ~he discovery of a satisfactory anaesthetic steroid compound. Anaesthetic steroids are generally relatively -simple pregnane derivatives, often hydroxylated in the 3-position, the general trend having been in the latter case to study 3~-hydroxy compounds in pre- :
ference to 3d-hydroxy compounds. ~ -~'~ ' '"' '' : ... .
C~ .' ~'' ~, .
,. . .
~. ~, . . . , - ~ . . . . ... . .. . . . . .. .
~LCI 37~Z6 As a result of prolonged study of numerous steroids exhibiting anaesthetic activity we have found that 3~-hydroxy-5c-pregnane-11,20-dione (hereinafter called "steroid I") has quite remarkable properties as an anaesthetic. This substance has but poor solubility in water and although ~ , ~era~re referred to in the above cited i~ t~ as having anaesthetic properties, has apparently been rejected by reason of its poor solubility and the difficulty to be anticipated in its use by intravenous administration arising therefrom.
We have found however that steroid I can be brought into aqueous solution with the aid of certain non-ionic surface active agents to yield solutions of a sufficient concentration for injection, the resulting solutions when injected showing excellent anaesthetic properties. These solutions also ~
contain one or more 21-acyloxy-3~-hydroxy-5a-pregnane-11,20-diones whic'h act ' ' as solubility promoters for steroid I.
Thus the aqueous solutions of steroid I according to the invention induce anaesthesia and possess short induction periods, the anaesthetic action at suitable doses being indeed instantaneous; the solutions are thus excellent anaesthetics or inducing anaesthesia which is to be maintained e.g. by an inhalation anaesthetic such as ether, halothane, nitrous oxide, trichloro-ethylene etc. The solutions are however capable of maintaining anaesthesia ; and analgesia to a sufficient degree to enable various surgical operations to be conducted without the aid of an inhalation anaesthetic, the required degree of anaesthesia being maintained if necessary by repeated administration ~or even continuous administration). Recovery from anaesthesia (where this is induced only by the solutions of this invention) is excellent, the patient ~ ' exhibiting a feeling of well-being in distinction to the unpleasant after effects generally associated with conventional anaesthetics. Moreover, anaesthetic solutions in accordance with the invention in general give rise ~" ' to none o the undesired side-effects hither to associated with steroidal , ~
. ,:
- 30 anaesthetics.
, ~ ' .
~)37~26 ~ ccording to the invention therefore we provide an anaesthekic com-position suitable for use by parenteral administration of 3~hydroxy-5c~rpreg-nane-11,20-dione in solution in an aqueous medium in an amount of at least 1 mg/ml of said medium, said medium also con~aining at least one further steroid of the formula ~
CH20R , ~
C = O
O ~ ' "
I l (II) "~ I ' , ~ ~,, ' ,. -'~", .. ..... ..
wherein R is selected from the group consisting of lower alkanoyl groups, the hemisuccinyl group and the benzoyl group, said further steroid increasing the solubility of 3~-hydroxy-5~-pregnane-11,20-dione in said medium; and said medium also containing at least 1% by weight of a parenterally acceptable non-ionic surface active agent having an HLB value of at least 9.
The non-ionic surface active agents used for the purpose pf this invention are generally those of the water soluble type, preferably having an HLB value of from 9 to 18, ~ore preferably at least about 12, and advantageous-ly at least about 13. Preferably the HLB value of the surface active agent is not greater than about 15. The surface active agent must naturally be one which is physiologically compatible, i.e of itself give rise to no physiolog-ically unacceptable side effects in the dosages employed in the intended species to be treated (man or animal). Surface active agents for use in ~ : -.
accordance with the invention are for example to be found among the following non-ionic surfactants and classes of surfactants:- Polyoxyethylated derivat-ives of fatty ~C12-C20) glyceride oils, e.g. castor oil, containing from 35 to 45 oxyethylene groups, per mole of fatty oil. Polyoxyethylene ethers ~containing from 10 to 30 polyoxyethylene groups) of long chain alcohols ~con-~: .",' ' .i ' ' 3 _ ~--,: ., . :
; -:
~037~G
taining for example from 12-18 carbon atoms).
Polyoxyathylene-polyoxypropylene ethers containing from 15 to 35 and from 15 to 30 oxyethylene and oxypropylene groups respectively. Polyoxy-ethylene ethers (containing from 6 to 12 oxyethylene groups) of alkyl phenols the alkyl groups of which preferably contain 6-lO carbon atoms.
Polyoxyethylated ~containing from 15 to 30 oxyethylene groups) fatty acid (e.g. C12-18) esters of sugar alcohol anhydrides e.g. sorbitan or mannitan. Long-chain (e.g. Cl0-16) alkanoyl mono- and di-alkanolamides (the alkanol portions of which for example contain l 5 C atoms) for example lauroyl mono- and di-ethanolamides~ Polyethylene glycol esters (containing from 6 to 40 ethylene oxide units) of long chain fatty acids (containing for example 12-22 C atoms) e.g. polyethyleneglycol mono-oleate (containing for example 8 ethylene oxide units).
Examples of non-ionic surface active agents, of the foregoing types, useful in accordance with the invention include:-Cremophor (trade mark) EL, a polyoxyethylated castor oil containingabout 40 ethyleneoxide units per triglyceride unit;
Tween (trade mark) 80, polyoxyethylene sorbitan monooleate containing about 20 ethylene oxide units.
~0 Tween (trade mark) 60, polyoxyethylene sorbitan monostearate contain-ing abo~t 20 ethylene oxide units; and ~
Tween ~trade mark) 40, polyoxyethylene sorbitan monopalmitate con- ~ -taining about 20 ethyleneoxide units. -The expression "solutions" is used herein to denote liquids which -; have the appearance of true solutions and are thus optically clear and cap- --~able of passage, or example, through a micro-porous filter, irrespectlve of whether such solutions are true solutions in the classical chemical sense and irrespective of whether they are stable or metastable. Thus it may be that the steroid is associated with micelles. The solutions of this invention, irrespective of their precise physical nature, behave as true solutions for j . , ' ~ ' , - :
~37~DZ6 the practical purpose of intravenous injection.
As stated above, we have found that the total amount of anaesthetic steroid which may be dissolved in accordance with the invention may be sub-stantially increased by the presence of a steroid of general formula:
C - O .... ..
II
I J
",~
wherein R is a lower alkanoyl group having a straight or branched chain (con-taining for example 2-4 carbon atoms) 9 the hemisuccinyl group or the benzoyl group. Such steroids of formula II thus act as solubility promoters for the steroid I and are capable of substantially increasing the amount of the latter which may be dissolved in the compositions of this invention. Solutions con-taining steroid I together with a steroid of formula II may thus be prepared ~ :
having a substantially greater anaesthetic potency than a solution of steroid -I alone, due to the increased amount of steroid I which can be dissolved and the anaesthetic action of the steroid of formula II per se. -Compounds of formula II above are new compounds, and constitute a further feature of the invention. :' Preferred co~pounds of formula II are those in which R is an acetyl, hen~;suc c~/
propionyl, isobutyryll, or benzoyl group.
The proportion of surface active agent to be used in the compositions of this invention depends upon its nature and upon the concentration of ster-: , oid deslred in the final composition.
In preferred compositions according to the invention the proportion of surfactant is preferably at least 5% by weight and advantageously above ;
10% by weight. A very convenient proportion of surfactant has been found to ~ ;
, ~(137~6 be 20% by weight but 30% and up to 50% may be used. The proportions of sur-factant are expressed by weight in relation to the total volume of the composi-tion in metric units.
The compositions according to this invention may contain up to 40 or even 50% by weight of the total steroid of a compound of formula II; as little as 5% of the total steroid present of a compound of formula II provides useful solubility promotion. For practical purposes it is preferred that of the total steroid at least 10% by weight, and preferably not more than 30%
by weight of the total steroid consists of a compound of formula II. Very satisfactory results have been achieved with a mixture of steroid I with a steroid of formula II in which the proportion ~the steroid of formula II is about 25%, As will be clear, the proportion of steroid I in the aqueous solut-ion according to the invention deperdsupon the nature and amount of surface active agent used and also upon the amount of steroid o formula II present (if used). The composition will contain at least l mg/ml of steroid I and solutions can be made containing for example 2 and ~ mg/ml; using a steroid of formula II as solubilisar the amounts of total steroid can be increased up to 50 mg/ml although less than 30 mg/ml total steroid and generally less than 20 mg/ml will usually be satisfactory. A composition comprising 9 mg/ml of steroid I to 3 mg/ml of a compound of formula II in which R is acetyl has been found to be very satisfactory.
In all cases, as stated above the relative proportion of the various `~
components are adjusted to give a clear solution.
~ ~ According to a ~urther feature of the invention, the anaesthetic :~
solutlons are prepared by mixing steroid I with one or more steroids of ',.~ :
formula II and then dissolving the steroid mixture in the selected surfactant for example, with heating and mechanical agitation and the resulting solution dissolved in water. Alternatively the steroid mixture may be dissolved in a volatile organic solvent advantageously having a boiling point o less than :
' ; ~,.,', '' -~;37~Z6 about 80C which is miscible wi~h the surface active agent such as a volatilelower aliphatic ketone e.g. acetone or methyl ethyl ketone or a volatile halo-genated hydrocarbon e.g. chloroform or methylene chloride. Acetone is particularly preferred for this purpose. The surface active agent is then added to this solution, the organic solvent removed by evaporation, for example by passing a stream of an inert gas through the solution e.g. nitrogen~ and the resulting solution of steroids in surfactant is mixed with water. By these procedures in general it is possible to dissolve increased amoun~s of steroid I as compared with other methods.
Thus according to ano~her feature of this invention there is provided:
a process for preparing an anaesthetic composition suitable for use by parenteral administration in the form of a solution in an aqueous medium con-taining at least 1 mg/ml of 3~-hydroxy-5~-pregnane-11,20-dione wherein the solubility of this substance in water has been increased by the presence of one or more steroids of the formula:
C=O
~b wherein R is selected from the group consisting of lower alkanoyl groups, th0 ;hemisuccinyl group and the benzoyl group and wherein said medium also co~ains ~ at least 1% by weight of a parenterally acceptable non-ionic surface active
2~ agent having an ~ILB value of at least 9. -The solutions may aIso be prepared by shaking the steroid mixture with an aqueous solution of the surface active agent.
, ~ .
In all cases simple tests enable one to determine the reIative pro-portions of surface active agent required.
The anaesthetic solutions accorcling to the invention are generally ' .:.- :
:~ ~ '.'''' ~L~37~26 administered by intravenous injection although as is ~nown in the anaesthetic art in certain cases, e.g. with young children intramuscular injection might be preferred.
As is usual in the case of anaesthetics, the quantity of steroid I
used to induce anaesthesia depends upon the weight of the individual to be anaesthetised. For intravenous administration in the average man a dose of from 0.45 to 3.S mg/Kg will in general be found to be satisfactory to induce anaesthesia9 the preferred dose being within the range of from 0.7 to 2.5 mg/Kg.Generally a dose of about 1.35 mg/Kg is very satisfactory. The dose will naturally vary to some extent dependent upon the physical condition of the patient, and the degree and period of anaesthesia required, all as is well known in the art. It is thus possible by adjustment of the dose to achieve durations of anaesthesia varying from about 10 minutes to up to an hour or more. If it is desired to maintain prolonged anaesthesia, repeated doses of the solutions of this invention may be used, such repeated doses being -generally either of the same order or lower than the original dose. Alternat~
ively continuous administralion may be undertaken at for example a rate of 0.09-1.8 mg/Kg/Min.
Where the anaesthetic solutions are administered intramuscularly, naturally higher doses are generally necessary.
, ~ .
In all cases simple tests enable one to determine the reIative pro-portions of surface active agent required.
The anaesthetic solutions accorcling to the invention are generally ' .:.- :
:~ ~ '.'''' ~L~37~26 administered by intravenous injection although as is ~nown in the anaesthetic art in certain cases, e.g. with young children intramuscular injection might be preferred.
As is usual in the case of anaesthetics, the quantity of steroid I
used to induce anaesthesia depends upon the weight of the individual to be anaesthetised. For intravenous administration in the average man a dose of from 0.45 to 3.S mg/Kg will in general be found to be satisfactory to induce anaesthesia9 the preferred dose being within the range of from 0.7 to 2.5 mg/Kg.Generally a dose of about 1.35 mg/Kg is very satisfactory. The dose will naturally vary to some extent dependent upon the physical condition of the patient, and the degree and period of anaesthesia required, all as is well known in the art. It is thus possible by adjustment of the dose to achieve durations of anaesthesia varying from about 10 minutes to up to an hour or more. If it is desired to maintain prolonged anaesthesia, repeated doses of the solutions of this invention may be used, such repeated doses being -generally either of the same order or lower than the original dose. Alternat~
ively continuous administralion may be undertaken at for example a rate of 0.09-1.8 mg/Kg/Min.
Where the anaesthetic solutions are administered intramuscularly, naturally higher doses are generally necessary.
3~-Hydroxy-5-pregnane-11,20-dione (steroid I) can be prepared in any con~enient manner for example as described by Camerino et al, Helv. Chim. Acta.,1953, 36, 1945 or by Nagata et al., Helv. Chim. Acta 1959, 42, 1399. In apply-ing the last-mentioned process we have encountered various difficulties at several stages due to side reactions, which we have found ~o be due to epimer-; isation at position 17. As a result of further work we have developed a new .
synthesis of steroid I based essentially upon the synthesis of Nagata et al but working essentially with intermediates having ~16-unsaturation. Our new synthe-.: .
sis provides generally better yields and affords greater ease of working and purity of product, due essentially to the impossibility of epimerisation at position 17 in compounds of the Q16 series.
' ~a~;37~z~
Thus in accordance with the new synthesis 3~-hydroxy-5a-pregnane-11~20~dione is prepared by hydrogenation of 3~-hydroxy-5~-pregn-16-ene-11,20-dione.
The hydrogenation may be conveniently effected in an organic solvent, for example an alkanol or an ether e.g. methanol, ethanol, propanol, diethyl ether or tetrahydrofuran. A catalyst is preferably used to effect the hydro-genation for example palladised charcoal, Raney nickel, platinum catalysts and the like.
3~-Hydroxy-5~-pregn-16-ene-11,20-dione may, for example,.be prepared , by solvolysis of the 3~-acyloxy group of a 3~-acyloxy-5~-pregn-16-ene-11,20-dione. The acyloxy group at the 3-position may, for example, be a formyloxy, . . . .
acetoxy, propionyloxy, butyryloxy or benzoyloxy group.
The new synthesis of 3~-hydroxy-5~-pregnane-11,20-dione is described in more detail in our copending Canadian Application Serial No. 085,973 filed June 19, 1970.
As stated above, s~eroids of general formula II above are new com-pounds and constitute another feature of.the invention. The preferred com-pounds of formula II for use as solubilising agents in pharmaceutical pre-parations are those in which the 21-acyloxy group is a 21-acetoxy, 21-propionyloxy, 21-isobutryloxy or 21-benzoyloxy group.
This invention also r01ates~ to a process for increasing the solubility in an aqueous medium of 3~-hydroxy-5~-pregnane-11,20-dione and thereby preparing therefrom as anaesthetic composition suitable for use by parenteral administration which comprises incorporating in a suitable aqueous ;
medium at least 1 mg/ml of 3~-hydroxy-5~-pregnane-11,20-dione toge~her with one or more steroids of the formula ll20R
C=O ., O ~ , ''~''' '. ' ., ,~ ,.. .
' ' H
'~~9~
~al3~2~
wherein R is selected from the group consisting of low0r alkanoyl groups, the hemisuccinyl group and the benzoyl group, the said steroid being prepared by a process as defined below or by an obvious chemical equivalent thereof, and including at least 1% by weight of a parenterally acceptable non-ionic surface active agent having an HLB value of at least 9.
The 21-acyloxy compounds of formula II above are prepared according to known processes for the preparation of analogous compounds. Thus this invention relates to a process for preparing a steroi.d of the formula (IIJ:-CH20R ,... ..
C = O : .~
J~,,, '' ' ~i0 1 ~ '' H ' .
wherein R is selected from the group consisting of lower alkanoyl groups~ the -hemisuccinyl group and the benzoyl group, which comprises ~a) reacting a compound of the formula ,, , . ::
C = O , :.
O I ',',, ,'' " .
:~ H - :
~ -9a ~L03~ 6 in which Rl represents a hydroxy or protected hydroxy group with a lead te~ra-acylate of the formula:
Pb(OR)4 wherein R is as defined above and when Rl is a protected hydroxy group con-verting it into a hydroxy group; or (b) reducing a corresponding 21-acyloxy-5~- pregnane-3,11,20-trione of the formula:
C~120R
C = O
J~
~ ' ,'.
wherein R is as defined above; or (c) reacting a 21-halide of the formula:
FH2X ~ :
C= O ' ' '. .
' ~ ':.
~10' , " ' , whereln X is chlorine, bromine or iodine, with a salt of an acid of the formula: -R.OH
wherein R is as defined above or td) acylating a compound of the formula:
. IH2~ ; .
CO
o~J~ ' '' ' 2' ~ -R
.. ;, . . :
~, - '10 -1~37~
wherein R represents a protected hydroxy group so as to replace the hydroxy group by the group RO- and converting the group R2 into a hydroxy group. In process variant (a) a compound of formula:
\ ~III) H
(in which Rl represents a hydroxy or protected hydroxy group e.g. a nitrate, trimethylsilyloxy or trichloroethoxycarbonyloxy group~ with a lead tetraacylate, preferably in the presence of a Lewis acid, and, where Rl represents a protec-ted hydroxy group, subsequent conversion of said group to a hydroxy group. :
Protection of the 3a-hydroxy group of the compound of formula III however, is not essential before the acyloxylation reaction. `
.
The lead tetra-acylate used may be for example lead tetraacetate. The Lewis acid may for example be boron trifluoride, conveniently used as its ;
etherate. We have found, for example that the presence of boron trifluoride :
improves the rate of reaction and can enable lower temperatures of reaction to be employed, thus~ in many cases, the reaction proceeds satisfactorily at :: l ambient temperature, i.e. in the absence of applied heat.
The yield obtained by this process is frequently better than that .
obtained at an elevated temperature in the absence of boron trifluoride and the fact that the reaction rate is faster and thus lower temperatures can often be : ~
~used means that this process possesses economic advantages on the large s~e.
~ The ability to operate at lower temperatures also means that there may be less , .
; likellhood oP undesired side reactions taking place. - ;
The acyloxylation of compounds of the formula III may be carried out ~ ~
in a solvent medium comprising a mixture of a hydrocarbon solvent and an ~ -alcohol. Suitable hydrocarbon solvents are, for example, benzene or toluene ' ~ ~ .
~37~2~i and the alcohol may, for example, be methanol. Advantageously the solvent comprises a mixture of benzene and methanol in the ratio of 19:1.
The acyloxylation is especially suitable for acetoxylation using lead tetraacetate but other lead acylates, e.g. lead ~etrapropionate may, of course, be used with the formation of the corresponding 21-propionyloxy com-pound.
The 3~-trimethylsilyloxy compounds of formula III (Rl representing a trimethylsilyloxy group) may, for example, be prepared by the reaction of the parent 3u-hydroxy compound of formula III tR' representing a hydroxy group) with a trimdhylsilyl halide e.g. trimethylchlorosilane or hexamethyl disilazane in the presence of a tertiary base e.g. pyridine and, if desired, in the pre-sence of a solvent e.g. a halogenated hydrocarbon such as methylene chloride or tetrahydrofuran. The reaction may conveniently be effected at room tempera-ture or i desired, at lower tamperatures e.g. 0C. The trimethylsilyloxy pro- :-~ tecting group is generally automatically removed during the acyloxylation.
j The 3~-trichloroethoxycarbonyloxy compound of formula III may be pre-.
pared by reaction of the parent 3~-hydroxy compound with an alkylchloroformate, e.g. trichloroethyl chloroformate, preferably in the presence of an acid bind-ing agent e.g. a tertiary amine such as pyridine, conveniently in a solvent such as dioxan or t~trahydrofuran. The trichloroethoxy carbonyl protective group may subsequently be removed by reduction for example using a metal/acid system such as zinc and acetic acid.
The 3~-nitrate of formula III may be prepared by reaction of the 1 . - .
parent 3-hydroxy compound with fuming nitric acid and acetic anhydride pre-ferably in the presence of a solvent e.g. chloroform. The nitrate protection group may subsequently be remoyed by reduction, for example, using a metal acid system such as zinc and acetic acid or catalytic hydrogenation using for example, palladium on charcoal as catalyst.
~; Other methods for the preparation of the 21-acyloxy compounds of , ~ 30 ormula II above can also be used. Thus according to process variant (b) a 1:~ .
~ - 12 -~037~26 21-acyloxy-5~-pregnane-3,11,20-trione is reduced, for example, using an enzymatic method such as reduction with brewers yeast (Saccharomyces cerevis-l ). This method is convenient for the preparation of 21-alkanoyloxy com-pounds such as the 21-acetoxy compound.
According to process variant (c) compounds of formula II are also prepared via the corresponding 21-chloro, 21-bromo or 21-iodo compounds. We prefer to proceed via the 21-bromo intermediate which may be prepared from 5~-pregnan-3~-ol-11,20-dione. The bromination is effected for example using molecular bromine, in a solvent such as methanol or ethanol advantageously at a temperature of from -10 to +30C. The reaction is preferably conducted in the presence of a catalyst such as acetyl chloride or hydrogen bromide in acetic acid. The 21-halogeno compound may then be converted into the desired 21-acyloxy compound by reac~ion with the salt of corresponding carboxylic acid, such as an alkali metal salt e.g. the potassium salt or a tertiary amine salt conveniently N-methylmorpholine or N-ethylpiperadine or a trialkyl-ammonium salt e.g. the triethylammonium salt. The reaction is preferably carried out in a solvent for example acetone or methanol, advantageously under anhydrous conditions. -An alternative method is process variant (d), which particularly con-venient for the preparation of compounds of the formula II in which R is other than an acetyl group, comprises acylating a compound of ~ormula~
COCH2OH ;
~ ~ IV
2 "' R
(wherein R represents a protected hydroxy group) and deprotecting the 3~-.
hydroxy group of the 21-acyloxy derivative of the compound of formula IV
produced. The compound of formula IV is conveniently prepared by the deacyla-tion of a 21-acyloxy derivative of a compound of formula IV, for example a ,: ,' :' ~ ' ' ~0~3l7~ 2~i 21-acetoxy derivative thereof, and provides a method for converting one com-pound of formula II for example in which R is acetyl to another compound of formula II in which R is a different acyl group. The 21-acetyl compound of formula II may thus, for example, be converted into another 21-acyl compound of formula II by firstly protecting ~he 3~-hydroxy group with a protecting sub-stituent which may be rernoved under acidic, reductive or other conditions but is stable under alkaline conditions, such as a 3~-ether substituent e.g. a tetrahydropyranyl or triphenylmethyl substituent or preferably a 3~-nitrate ester, hydrolysing the 3a-protected compound to yield the corresponding 21-hydroxy compound, under basic conditionsJ preferably in the presence of potassium or sodium hydrogen carbonate, conveniently in the presence of a solvent e.g. methanol, ethanol or tetrahydrofuran, reesterifying the resultant product and removing the 3~-protecting substituent.
The reesterification is preferably effected using the anhydride or chloride of the desired acid preferably in the presence of a tertiary amine (e.g. pyridine, collidine, or dimethylaniline) which may also serve as solvent for the reaction.
The protecting group at position 3 may be removed in conventional manner, conditions may be chosen which will not effect the rest of the molecule. -Thus for example when the 3~-hydroxy group of the compound of ~ormula II is protected by the formation of a nitrate ester, the nitrate group may be removed by acid hydrolysis of the compound for example using aqueous mineral acid, or by reduction using, for example zinc and acetic acid or by catalytic hydrogena-tion using, for example, ~lladium on charcoal as catalyst. ~
The following Examples are given by way of illustration only, all temperatures being in degrees Centigrade.
21-Acetoxy-3~-hydroxy-5~-pregnane-11,20-dione Boron trifluoride etherate (37.~ ml.) was added to a stirred solution of 3~-hydroxy-5~-pregnane-11,20-dione (6.64 g., 20 mmole) and lead tetraacetate (10.1 g., 22 xmole) in dry benzene (280 ml.) and methanol (15.1 ml.) at room .~: .
~37~26 temperature. After 2 hours the mixture was poured into water (2 1.) and extracted with ether (1 1.). The combined ether extracts were washed successively with sodium bic~rbonate solution and water, dried over magnesium sulphate, and concentrated in vacuo to ~ive a white crystalline mass. Four recrystallisations from acetone-petroleum ~bp. 40-60) gave 21-acetoxy-3~ -hydroxy-S~ -pregnane-11,20-dione as fine needles (4.22 g., 54%) m.p. 172-173, ~]D
~ 104 (c 1-0- CHC13) (Found: C,70.8; ~, 8.9; C23H3405 requires C, ~ -70.8; ~, 8.8%).
~ ' ' , 21-Acetoxy-3~ -hydroxy So~-yreg~ane-11,20-dione via a trimethyl-silyl derivative ,, , Trimethylchlorosilane (0.33 ml, 1.5 equiv) and pyridine C0~485 mlJ 2 equiv) were added to a solution of ac~-hydroxy-5~ - - ;
pregnane~ 20-dione (l.Og.,) in methylene chloride (16.6 ml) at room temperature. After 16 hours at 0 more trimethylchlorosilane (0.33 ml~ 1 equiv) was added and after a further 1 1/2 hour the solvent was removed in vacuo. Ether was added to the residue and the white solid was filtered off. The ether was removed in vacuo and the residue triturated with a little petroleum (bp 40-60) to give 3~ -trimethyl-siloxy-S~ -pregnane-11,20-dione (0.2 g.,) m.p. 95-96. This compound was also prepared ' , , .
, , ~)37026 by the use of hexamethyldisilazane and trimethylchlorosilane in tetrahydro-furan.
?~ The 21-acetoxylation was carried out as described in Example ~ one crystallisation from acetone-petroleum (bp 40-60) afforded the 21-acetate m.p. 170-173.
Example 3 21-Acetoxy-3 ~hydroxy-5~-pregnane-11,20-dione via a trichloroethoxycarbonyl derivative.
, 2,2,2-Trichloroethylchloroformate (1.1 ml.) was added to a cooled, stirred, solution of 3~-hydroxy-5~-pregnane-11,20-dione in pyridine (0.74 ml.) and dioxan (5.6 ml.). After 10 minutes dilute hydrochloric acid (14.5 ml.) was added and the solution was heatedat 100 for 30 minutes. The resulting oil crystallised on cooling to give 3~-(2,2,2-trichloroethoxycarbonyloxy)-5x pregnane-11,20-dione (1.45 g.,) m.p. 130-131, [~]D + 56 (c 1.0, CHC13) (Found: C, 56.0; H, 6.5; Cl, 21.1; C23H33C1305 requires C, 55.6; H, 6.6;
Cl. 20.7%).
21-Acetoxylation of this compound (0.5 g.,) using the procedure described in Example 1 gave a syrupy residue that crystallised on the addit-ion of ether and petroleum. Recrystallisation from ether-petroleum (bp 40-60) gave 21-acetoxy-3~- ~2,2,2-trichloroethoxycarbonyloxy)-5~-pregnane 11,20-dione ~0.325 g.,) m.p. 143-146 (decomp), [~]D ~ 75.2 (c 1.0, CHC13) (Found:
C, 55.1; H, 6.0; Cl, 18.6. C25H35C1307 requires C, 54.3; H, 6.4; Cl, 19.2%).
Removal of the 2,2,2-trichloroethoxycarbonyl group was effected by -stirr m g a solution of the steroid ~0.10 g.,) in ethanol (2 ml.~ and glacial acetic acid (2.5 ml.) for 5 hours with addition of zinc dust ~0.3 g.) during ~`~ this period. The solids were filtered off, washed with ethanol and the combin-ed fi]trate was reduced in volume in vacuo. Addition of water to the residual solution gave 21-acetoxy-3~-h~oxy-5~-pregnane-11,20-dione (0.036 g.,) m.p.
168-172.
,; : .
Example 4 21-Acetoxy-5o~-Eegnan=3a-ol-ll~2o-dione .,,.,~
Dried yeast (Sa_charomyces cerevisiae 60 g.) was stirred at room - , .:
7~Z6 temperature with tap water (2 1.) containing sucrose (200 g.) and di~ammonium hydrogen phosphate (4 g.). After two hours 21-acetoxy-5a-pregnane-3,11,20-trione (1 g.) (Mancara et al., J. Amer. Chem. Soc., 1955, 77 5669) in ethanol (100 ml.) was added. The fermentation was stirred at room temperature for a further 24 hours, the yeast was removed by fil~ration, partially dried at the pump and extracted with hot chloroform ~4 x 250 ml.). The extracts were shaken with the filtrate, washed with water, dried (Na2SO4) and evaporated to a brown gum (634 mg.). This was subjected to preparative thin-layer chromatography which yielded two pure substances. Of these the less polar was the starting material 21-acetoxy-5~-pregnane-3,11,20-trione, (68 mg.); which was recrystallised from acetone/hexane as colourless needles, m.p. 169-172;
[~]D + 127.5, (c 0.87 CHC13). Gas-liquid chromatography confirmed ~hat this was identical with the starting material.
The more polar substance (70 mg.) was recrystallised from acetone/
hexane to afford 21-acetoxy-5~-pregnan-3~-ol-11,20-dione (57 mg.) as colourless needles, m.p. 179-182; [~]D + 107, (c, 109 CHC13). Gas-liquid chromatography confirmed the identity of this material.
Examp~e_5 21-Acetoxy-5u-pregnan-3~-ol-11~20-dione (a) ?1-Bromo-5~-pregnan-3a-ol-11,20-dione 5~-Pregnan-3~-ol-11,20-dione (1 g., 3 mmoles) in stirred methanol (7 ml.) at 30 was treated with acetyl chloride ~1 drop). After two minutes ~
bromine (0.19 ml., 3.52 mmoles) in me~hanol (4.5 ml.) was added dropwise, the ; ;
solution being allowed to decolourise between the addition of each drop. The resu~ing clear solution was poured into chloroform (100 ml.), washed with water ~3 x S0 ml), dried (Na2SO4) and evaporated to a white froth ~1.40 g.).
Preparative thin-layer chromatography afforded 21-bromo-5~-pregnan-3~-ol-11,20- ;
dione (715 mg.) which crystallised from chloroform/ether as clusters of colour-less needles, m.p. 160-163; [~D + 109 (c 0.82, CHC13); (Found: C, 61.0;
H, 7.9; Br, 19.7; C21H31BrO3 requires C, 61.3; H, 7.6; Br, 19.45%).
, ...
- . -1 . ~
~370;~ ~
A second, unstable substance (415 mg.) isolated from this reaction was examined spectroscopically and iden~ified as 17 ~bromo-5 ~pregnan-3 ~ol-11,20-dione.
(b) 21-Acetoxy-5~-pregnan-3~-ol-11,20-dione 5~-Pregnan-3-ol-llJ20-dione (lg. 3 mmoles) was brominated in the manner described above. The total product from the reaction (1.38 g.) was refluxed with stiring with dry acetone (25 ml.) and anhydrous potassium acetate (2 g). After four hours the reaction mixture was poured into chloro-form (100 ml.), washed with water (3 x 50 ml) dried (Na~S0~) and evaporated to a white froth (1.19 g). Preparative thin-layer chromatography afforded 21-acetoxy-5~-pregnan-3~-ol-11,20-dione (634 mg) as a white froth which on cry-stallisation from acetone/ether gave colourless needles, m.p. 177-180;
[~]D + 102.5, (c 0.95, CHC13). Gas-liquid chromatography confirmed the identity of this material.
Example 6 21-Acetoxy-5a-pregnan-3a-ol-11,20-dione 5a-Pregnan-3a-ol-11,20-dione (5 g., 15.0 mmoles) in stirred methanol (35 ml) at 0 was treated with 5 drops of a 50% w/v solution of hydrogen bromide in glacial acetic acid. After several minutes, bromine (0.95 ml., 2.815 g 17.6 mmoles) in methanol (22.5 ml) was added portionwise over ca.
10 minutes. The solution was left stirring until the colour disappeared and ;
then poured into water. The product was isolated by filtration, washed with water and dried in vacuo at 40 for five hours. Final drying was over phos-~phorus pentoxide in a desiccator tovernight). Yield: approximately quantita-; tive.
The crude bromo-intermediate was dissolved in acetone (100 ml, dried ovir~potassium carbonate) and refluxed in the presence of potassium acetate (10 g) for four hours.
~ ,. , ~ The reaction mixture was poured into water ~1 1.) and extracted with ~-ether ~300 ml and 250 ml). The ether was dried over anhydrous magnesium sul-, ~ :
.' . . . ": -~, ' ',, ' ~370;26 phate, filtered and evaporated under reduced pressure.
The residual foam was recrystallised from acetone-petroleum ether to give 21-acetoxy-5a-pregnan-3a-ol-11,20-diolle as white needles. Yield, 63%;
m.p. 173-175; [a]D + 109, (c 1.0, CHC13)-Example 7 21-Propionyloxy-5a-pregnan-3a-ol-11,20-dione 5a-Pregnan-3~_ol-11,20-dione (2 g., 6 mmoles) in methanol (14 ml.) at 30 was ~reated with acetyl chloride t 2 drops). The solution was stirred for two minutes and was treated dropwise with bromine (0.38 ml., 7 mmoles) in methanol (9 ml.) in the manner described above. The reac~ion mixture was poured into stirred water (250 ml.). The product was isolated, washed and dried at the pump and redried over phosphorus pentoxide in vacuo to afford a white powder ~2.49 g.). This was refluxed with propionic acid (11.1 ml., 0.15 mmoles) and triethylamine (7.25 ml., 0.1 moles) in dry acetone (60 ml.). -After five hours the solution was poured into chloroform (300 ml.)~ washed with aqueous potassium hydrogen carbonate (2 x 200 ml.) and with water ~2 x 200 ml.) dried (Na2S0~) and evaporated to a white froth (2.59 g.). Preparat-ive thin-layer chromatography afforded material which on recrystallisation ~;
from chloroform/ether/hexane gave 21-propionyloxy-5a-pregnan-3a-ol-11,20-dione ~589 mg.) as colourless irregular prisms, m.p. 159-170; [~D + 99' (c 0-92, CHC13); (Found: C, 70.5; H, 8.9. C24H3605.1/4 H20 requires C, ~ -70.45; H, 9.0%) Example 8 21-Isobutyryloxy-5a-pregnan-3a-ol-11,20-dione a-Pregnan-3~-ol-11,20-dione ~2 g., 6 mmoles) in methanol (14 ml.) at .
;; ~ 30 was treated with acetyl chloride (2 drops). The solution was stirred for ~two minutes before being treated dropwise with bromine (0.38 ml., 7 mmoles) in methanol (9 ml.) in the manner described above. When the reaction was com-plete the solution was poured into stirred water (250 ml.). The product was isolated, washed and dried at the pump. A final drying over phosphorus pent-oxide~in vacuo afforded a white powder (2.5 g.). This was re~luxed with iso-z~
butyric acid (14.1 ml., 0.15 moles) and triethylamine (7.25 ml., 0.10 moles) in dry acetone (60 ml.). After four hours the solution was poured into chloro-form (300 ml.), washed with aqueous potassium hydrogen carbonate ~2 x 200 ml.), wi~h water (2 x 200 ml.), dried (Na2S04) and evaporated to a white froth (2.54 g.). Preparative thin-layer chromatography afforded 21-isobutyryloxy-5a-pregnan-3a-ol-11,20-dione (1.45 g.) as a white froth, [a]D * 93.5, (c 0.66, CHC13), (Found: C, 70.4; H, 8.8.C25H3805, 1/2 H20 requires C, 70.25; ~l, 9.2%).
Example 9 21-Benzoyloxy-5~-pregnan-3a-ol-11,20-dione 5a-Pregnan-3a-ol-11,20-dione (2 g., 6 mmoles) in methanol (14 ml.) was treated with acetyl chloride (2 drops) and bromine (0.38 ml., 7 mmoles) as described above. Isolation of the crude bromination product in the usual manner afforded a white powder (2.498 g.). This was refluxed with benzoic acid (18.3g., 0.15 moles) and triethylamine (7.25 ml., 0.1 moles) in dry ace-tone (100 ml.). After five hours the solution was poured into chloroform (500 ml.), washed with aqueous sodium hydrogen carbonate (2 x 200 ml.) and with water (3 x 200 ml.), dried (Na2S04) and evaporated to a white froth.
Preparative thin-layer chromatography afforded 21-benzoyloxy-5a-pregnan-3a-ol-11,20-dione (1.27 g.) as a white froth, [a]D + 104, (c 0.65, CHC13), (Found:
C~ 72'6; H~ 7-7- C28H3605 l/2 H20 requires C, 72.85; H, 8.05%).
Example 10 21-Isobutyryloxy-5a-pregnan-3~-ol-ll~2o-dione 3-nitrate i) Fuming nitric acid (1.3 ml.) was added to stirred acetic ~ -~
anhydride (5 ml.). The solution was cooled to -5 and 21-acetoxy-5a-pregnan-3-ol-11,20-dione (500 mg. 1.28 mmoles) in chloroform (2.5 ml.) was added.
The resulting solution was stirred at 5 for an hour before being poured into - ;
dilute aqueous sodium hydroxide tlO0 ml.), extracted with chloroform ~2 x 75 ~-ml.) and the extract washed with aqueous sodium bicarbonate (50 ml.), with water (3 x 50 ml.), dried (Na2S04) and evaporated to a gum (527 mg.). Crystàl-lisation from ether/acetone afforded 21-acetoxy-5~-pregnan-3a-ol-11,20-dione ,~."' :, ,:
".., ~.., -1~371a~Z6 3-nitrate (386 mg.) as colourless needles, m.p. 1~7~ ; [a]D + 103 ~c 1.06 CHC13); (Found: C, 63.6; H, 7.5; N, 3.1. C23H33NO7 requires C, 63-45;
H, 7.65; N, 3.2%).
ii) 5~-Pregna-3a,21-diol-11,20-dione 3-nitrate ~a) 21-Acetoxy-5~-pregnan-3~-ol-11,20-dione 3-nitrate ~837 mg~, 2 mmoles) in ethanol ~42 mg.) and tetrahydrofuran ~42 ml.) was stirred with 10% aqueous potassium hydrogen carbonate ~4 ml.) and 2N aqueous sodium hydroxide ~2 ml.).
After three hours glacial acetic acid ~1 ml.) was added, the solution was poured into water ~400 ml.) and extracted with chloro~orm ~3 x 120 ml.). The extracts were washed with water ~2 x 50 ml.), dried ~MgSO4) and evaporated to a froth. Preparative thin-layer chromatography afforded pure material which on recrystallisation from ether/acetone gave 5~-pregna-3~?2l-diol-ll~2o-dione 3-nitrate ~219 mg.) as colourless irregular prisms, m.p. 172-176; [~]D ~ 91 ~c 0.97, CHC13) ~Found: C, 63.9; H, 7.8; N, 3.5. C21H31NO6 requires C, 64.1; H, 7.95; N, 3.55%).
~b) 21-Acetoxy-5~-pregnan-3~-ol-11,20-dione ~5 g., 13.3 moles) in chloroform ~25 ml.) was added to a stirred solution of fuming nitric acid ~13 ml.) in acetic anhydride ~50 ml.) at -5. The reaction mixture was stirred at -5 for an hour, poured into sarred aqueous sodium hydroxide ~ 1 l.) and extracted with chloroform ~2 x 200 ml.). The extract was washed with aqueous sodium hydrogen carbDnate ~100 ml.) and with water ~2 x 100 ml.), dried ~Na2S04) and evaporat-ed to a white froth. This was dissolved in methanol ~500 ml.), the solution flushed with nitrogen and stirred with 10% aqueous potassium hydrogen carbon-ate (17.5 ml.) for Eour hours, Glacial acetic acid (3 ml.) was added, the solution evaporated to small bulk, poured into water ~1 1.) and extracted with chloroform ~2 x 200 ml.). The extract was washed with water ~2 x 100 ml.), dried ~Na2SO4) and evaporated to a white froth. Crystallisation from acetone/
ether gave 5~-pregna-3~,21-diol-11,20-dione 3-nitrate ~4.31 g.) as colourless irregular~prisms, m.p. 174-181.
iii) 21-Isobutyryloxy-5~-pregnan-3~-ol-11,20-dione 3-nitrate :' ' , ' - . . - .. ~ . . , ~ . . . ., . . -, ~ . . ; . . . . . .
37~2~;
S~-Pregna-3a,21-diol-11,20-dione 3-nitrate (2.0 g., 5.08 mmoles~ in dry pyridine (20 ml.) was treated with isobu~yryl chloride (2 ml.). The pink solution was allowed to stand at room temperature for 20 hours before being poured into stirred water and acidified with dilute hydrochloric acid. The product was isolated, washed thoroughly with water and dried at the pump.
Recrystallisation from acetone/hexane afforded 21-isobutyryloxy-5a-pregnan-3a-ol-11,20-dione 3-nitrate (1.01 g.) as colourless needles, m.p. 167-169;
[a]D + 97 5~ (c 1.48, CHC13), (Found: C, 64.5; H, 7.8; N, 3.2. C25H37NO7 requires C, 64.8; H, 8.05; N, 3.0%).
iv) 21-Isobutyryloxy-5a-pregnan-3a-ol-11,20-dione 21-Isobutyryloxy-5a-pregnan-3a-ol-11,20-dione 3-nitrate (1.35 g., 2.91 mmoles) in glacial acetic acid (35 ml.) was stirred for an hour at room temperature with zinc powder (4 g.). The zinc was removed, washed with hot chloroform (200 ml.) and the combined washings and filtrates were washed with water ~4 x 100 ml.) dried (Na2SO4) and evaporated to a white froth. Preparat-ive thin-layer chromatography afforded 21-isobutyryloxy-5a-pregnan-3a-ol-11,20-dione as a white froth, [a]D t 97.5 (c 1.05, CHC13). Analytical thin-layer chromatography and gas-liquid chromatography indicated that this material was ;
identical with a sample prepared by the method described in Example 12.
xample 11 5~-Pregna-3a,21-diol-11,20-dione 21-hemisuccinate :
. . .
5a-Pregna-3a,21-diol-11,20-dione 3-nitrate 21-hemisuccinate (1.03 g,, 2.09 mmoles) and zinc powder (3 g.) were stirred with acetic acid (25 ml.) for 90 minutes. The zinc was removed, washed with chloroform (100 ml.), 2N -aqueous hydrochloric acid (200 ml.) and chloroform (100 ml.). The combined filtrates were equilibrated and the organic phase was washed with water (3 x 100 ml), dried (Na2SO4) and evaporated to a white froth. Crystallisation from benzene/hexane/chloroform gave 5~-pregna-3a,21-diol-11,20-dione 21-hemisuccin-ate (8C0 mg.) as colourless needles, m.p. 166-168; [a]D + 90.5, (c 1.32 in CHC13~; (Found: C, 66.9; H, 8Ø C25H36O7 requires C, 66.95; H, 8.1%).
The starting material for this preparation was obtained from 5a- ~;
~ ~'''"',' ~0370Z~i ., ~oii C pregna-3a,21-diol-11,20-dione 3-nitrate (see Example ~t~) as described below:-5~-Pregna-3~,21-diol-11,20-dione 3-nitrate (2g., 5.0~ mmoles) and succinic anhydride (2g. 20 mmoles) in dry pyridine (20 ml.) were allowed to stand at room temperature for 18 hours. The solution was poured into stirred water (300 ml.) which was then acidified. After two hours, the precipitate was collected, washed well with water and dried. Recrystallisa~ion from benzene/hexane gave 5~-pregna-3~,21-diol-11,20-dione 3-nitrate 21-hemisuccinate (1.51 g.) as colourless micro-needles,; m.p. 160-163; [~]D ' 89.5, (c 1.14, CHC13), (Found C, 60.8; H, 7.3; N, 2.6. C25H35NOg requires C, 60.8;
H, 7~15; N, 2.85%).
Example 12 0.035 g of steroid I, finely divided in an air-attrition mill and having an approximate mean particle diameter o~ 5~, was mixed with 0.035 g of steroid II tR = CH3CO-) reduced in size as for steroid I. The steroids are added to 10 ml of a 20% w/v solution of Cremophor EL containing 0.025 g of ;
sodium chloride and the mixture mechanically stirred for at least 24 hours.
Any traces of insoluble residue are filtered off using a sintered glass filter.
Example 13 13.5 g of ground steroid I and 4.5 g of steroid II ~R = CH3CO-) are mixed by mechanical agitation with 300.0 g of Cremophor EL at 70C. in an atmosphere of nitrogen. Heating and agitation are continued until the steroids have completely dissolved. The mixture is diluted with sterile distilled water containing 3.75 g of sodium chloride to give a final volume of 1500 ml.
Stirring is continued until the solution is homogeneous.
Example 14 0.045 g of steroid I and 0.015 g of steroid II ~R = CH3CO-) are dissolved in 2 ml of acetone at 20C. The resultant solution is added to 1 g of Cremophor EL at 20C, and stirred until homogeneous. The acetone is remov-ed by a vigorous stream of nitrogen. The solution is diluted with sterile distilled water containing 0.0125 g of sodium chloride to give a final volume :.
of 5 ml. Similar solutions were prepared using chloroform or methylene chloride in place o~ acetone.
Example 15 0.09 g of ground steroid I are mixed with 0.03 g of ground steroid II (R = CH3CO-) and this added to 2.0 g of Tween 80. As in Example 14, the mixture is mechanically agitated at 70C. in a stream of nitrogen until the steroids have dissolved. The mixture is diluted with sterile distilled water containing 0.025 g of sodium chloride to give a final volume of 10 ml.
Example 16 0.045 g of steroid I and 0.015 g of steroid II (R = (CH3)2CHCO-) are formulated as in Example 14. Similar solutions are obtained using steroid II wherein R = C6H5CO-J HO2CCH2CH2CO or C2H5-CO-.
Example 17 0.045 g of steroid I and 0.015 g of steroid II (R = CH3CO) are dis- ~ ;
solved in 2 ml of acetone at 20C. The resulting solution is added to 1 g of Tween 40 at 20C and stirred until homogeneous. The acetone is removed by a vigorous stream of nitrogen. The solution is diluted with sterile distilled -water containing 0.025 g of sodium chloride ~o give a final volume of 10 ml.
Exam~le 18 0.036 g of ground steroid I are mixed with 0.012 g of ground steroid II (R = CH3C0). This is added to 0.8 g of Tween 60. The mixture is mechanically agitated at 70C in a stream of nitrogen until the steroids are dissolved. The mixture is diluted with sterile distilled water containing -0,025 g of sodium chloride to give a final volume of 10 ml. ;~
Example 19 16 mg of steroid I and 4 mg of steroid II (R = CH3CO) were dissolv-ed in 0.2 ml of acetone, and 0.2 ml of Cremophor EL was mixed with this solu- -tion. The acetone was removed by passing a stream of nitrogen through the mixture. The resulting solution was mixed with 0.8 ml of sterile water.
', ~
` .
:..................................................................... ".
~137~26 Example 20 0.135 grams Steroid I and 0.045 grams of Steroid II, (R=CH3C0), are dissolved in 2 mls of acetone at 20C. The resulting solution is added to 3 grams of Cremophor EL at 20C and s~irred until homogeneous. The acetone is removed by a vigorous stream of nitrogen. The solution is diluted with sterile distilled water containing 0.02S grams of sodium chloride to give a final volume of 10 mls.
Example 21 0.045 grams of ground Steroid I are mixed with 0.012 grams of ground Steroid II, (R=CH3C0)~ and the mixture added to 1 gram of Cremophor EL. The mixture is mechanically agitated a~ 70C in a stream of nitrogen until the steroids have dissolved. The mixture is diluted with sterile distilled water containing 0.025 grams of sodium chloride to give a final volume of 10 mls.
- 25 - ~
~ :.- .'
synthesis of steroid I based essentially upon the synthesis of Nagata et al but working essentially with intermediates having ~16-unsaturation. Our new synthe-.: .
sis provides generally better yields and affords greater ease of working and purity of product, due essentially to the impossibility of epimerisation at position 17 in compounds of the Q16 series.
' ~a~;37~z~
Thus in accordance with the new synthesis 3~-hydroxy-5a-pregnane-11~20~dione is prepared by hydrogenation of 3~-hydroxy-5~-pregn-16-ene-11,20-dione.
The hydrogenation may be conveniently effected in an organic solvent, for example an alkanol or an ether e.g. methanol, ethanol, propanol, diethyl ether or tetrahydrofuran. A catalyst is preferably used to effect the hydro-genation for example palladised charcoal, Raney nickel, platinum catalysts and the like.
3~-Hydroxy-5~-pregn-16-ene-11,20-dione may, for example,.be prepared , by solvolysis of the 3~-acyloxy group of a 3~-acyloxy-5~-pregn-16-ene-11,20-dione. The acyloxy group at the 3-position may, for example, be a formyloxy, . . . .
acetoxy, propionyloxy, butyryloxy or benzoyloxy group.
The new synthesis of 3~-hydroxy-5~-pregnane-11,20-dione is described in more detail in our copending Canadian Application Serial No. 085,973 filed June 19, 1970.
As stated above, s~eroids of general formula II above are new com-pounds and constitute another feature of.the invention. The preferred com-pounds of formula II for use as solubilising agents in pharmaceutical pre-parations are those in which the 21-acyloxy group is a 21-acetoxy, 21-propionyloxy, 21-isobutryloxy or 21-benzoyloxy group.
This invention also r01ates~ to a process for increasing the solubility in an aqueous medium of 3~-hydroxy-5~-pregnane-11,20-dione and thereby preparing therefrom as anaesthetic composition suitable for use by parenteral administration which comprises incorporating in a suitable aqueous ;
medium at least 1 mg/ml of 3~-hydroxy-5~-pregnane-11,20-dione toge~her with one or more steroids of the formula ll20R
C=O ., O ~ , ''~''' '. ' ., ,~ ,.. .
' ' H
'~~9~
~al3~2~
wherein R is selected from the group consisting of low0r alkanoyl groups, the hemisuccinyl group and the benzoyl group, the said steroid being prepared by a process as defined below or by an obvious chemical equivalent thereof, and including at least 1% by weight of a parenterally acceptable non-ionic surface active agent having an HLB value of at least 9.
The 21-acyloxy compounds of formula II above are prepared according to known processes for the preparation of analogous compounds. Thus this invention relates to a process for preparing a steroi.d of the formula (IIJ:-CH20R ,... ..
C = O : .~
J~,,, '' ' ~i0 1 ~ '' H ' .
wherein R is selected from the group consisting of lower alkanoyl groups~ the -hemisuccinyl group and the benzoyl group, which comprises ~a) reacting a compound of the formula ,, , . ::
C = O , :.
O I ',',, ,'' " .
:~ H - :
~ -9a ~L03~ 6 in which Rl represents a hydroxy or protected hydroxy group with a lead te~ra-acylate of the formula:
Pb(OR)4 wherein R is as defined above and when Rl is a protected hydroxy group con-verting it into a hydroxy group; or (b) reducing a corresponding 21-acyloxy-5~- pregnane-3,11,20-trione of the formula:
C~120R
C = O
J~
~ ' ,'.
wherein R is as defined above; or (c) reacting a 21-halide of the formula:
FH2X ~ :
C= O ' ' '. .
' ~ ':.
~10' , " ' , whereln X is chlorine, bromine or iodine, with a salt of an acid of the formula: -R.OH
wherein R is as defined above or td) acylating a compound of the formula:
. IH2~ ; .
CO
o~J~ ' '' ' 2' ~ -R
.. ;, . . :
~, - '10 -1~37~
wherein R represents a protected hydroxy group so as to replace the hydroxy group by the group RO- and converting the group R2 into a hydroxy group. In process variant (a) a compound of formula:
\ ~III) H
(in which Rl represents a hydroxy or protected hydroxy group e.g. a nitrate, trimethylsilyloxy or trichloroethoxycarbonyloxy group~ with a lead tetraacylate, preferably in the presence of a Lewis acid, and, where Rl represents a protec-ted hydroxy group, subsequent conversion of said group to a hydroxy group. :
Protection of the 3a-hydroxy group of the compound of formula III however, is not essential before the acyloxylation reaction. `
.
The lead tetra-acylate used may be for example lead tetraacetate. The Lewis acid may for example be boron trifluoride, conveniently used as its ;
etherate. We have found, for example that the presence of boron trifluoride :
improves the rate of reaction and can enable lower temperatures of reaction to be employed, thus~ in many cases, the reaction proceeds satisfactorily at :: l ambient temperature, i.e. in the absence of applied heat.
The yield obtained by this process is frequently better than that .
obtained at an elevated temperature in the absence of boron trifluoride and the fact that the reaction rate is faster and thus lower temperatures can often be : ~
~used means that this process possesses economic advantages on the large s~e.
~ The ability to operate at lower temperatures also means that there may be less , .
; likellhood oP undesired side reactions taking place. - ;
The acyloxylation of compounds of the formula III may be carried out ~ ~
in a solvent medium comprising a mixture of a hydrocarbon solvent and an ~ -alcohol. Suitable hydrocarbon solvents are, for example, benzene or toluene ' ~ ~ .
~37~2~i and the alcohol may, for example, be methanol. Advantageously the solvent comprises a mixture of benzene and methanol in the ratio of 19:1.
The acyloxylation is especially suitable for acetoxylation using lead tetraacetate but other lead acylates, e.g. lead ~etrapropionate may, of course, be used with the formation of the corresponding 21-propionyloxy com-pound.
The 3~-trimethylsilyloxy compounds of formula III (Rl representing a trimethylsilyloxy group) may, for example, be prepared by the reaction of the parent 3u-hydroxy compound of formula III tR' representing a hydroxy group) with a trimdhylsilyl halide e.g. trimethylchlorosilane or hexamethyl disilazane in the presence of a tertiary base e.g. pyridine and, if desired, in the pre-sence of a solvent e.g. a halogenated hydrocarbon such as methylene chloride or tetrahydrofuran. The reaction may conveniently be effected at room tempera-ture or i desired, at lower tamperatures e.g. 0C. The trimethylsilyloxy pro- :-~ tecting group is generally automatically removed during the acyloxylation.
j The 3~-trichloroethoxycarbonyloxy compound of formula III may be pre-.
pared by reaction of the parent 3~-hydroxy compound with an alkylchloroformate, e.g. trichloroethyl chloroformate, preferably in the presence of an acid bind-ing agent e.g. a tertiary amine such as pyridine, conveniently in a solvent such as dioxan or t~trahydrofuran. The trichloroethoxy carbonyl protective group may subsequently be removed by reduction for example using a metal/acid system such as zinc and acetic acid.
The 3~-nitrate of formula III may be prepared by reaction of the 1 . - .
parent 3-hydroxy compound with fuming nitric acid and acetic anhydride pre-ferably in the presence of a solvent e.g. chloroform. The nitrate protection group may subsequently be remoyed by reduction, for example, using a metal acid system such as zinc and acetic acid or catalytic hydrogenation using for example, palladium on charcoal as catalyst.
~; Other methods for the preparation of the 21-acyloxy compounds of , ~ 30 ormula II above can also be used. Thus according to process variant (b) a 1:~ .
~ - 12 -~037~26 21-acyloxy-5~-pregnane-3,11,20-trione is reduced, for example, using an enzymatic method such as reduction with brewers yeast (Saccharomyces cerevis-l ). This method is convenient for the preparation of 21-alkanoyloxy com-pounds such as the 21-acetoxy compound.
According to process variant (c) compounds of formula II are also prepared via the corresponding 21-chloro, 21-bromo or 21-iodo compounds. We prefer to proceed via the 21-bromo intermediate which may be prepared from 5~-pregnan-3~-ol-11,20-dione. The bromination is effected for example using molecular bromine, in a solvent such as methanol or ethanol advantageously at a temperature of from -10 to +30C. The reaction is preferably conducted in the presence of a catalyst such as acetyl chloride or hydrogen bromide in acetic acid. The 21-halogeno compound may then be converted into the desired 21-acyloxy compound by reac~ion with the salt of corresponding carboxylic acid, such as an alkali metal salt e.g. the potassium salt or a tertiary amine salt conveniently N-methylmorpholine or N-ethylpiperadine or a trialkyl-ammonium salt e.g. the triethylammonium salt. The reaction is preferably carried out in a solvent for example acetone or methanol, advantageously under anhydrous conditions. -An alternative method is process variant (d), which particularly con-venient for the preparation of compounds of the formula II in which R is other than an acetyl group, comprises acylating a compound of ~ormula~
COCH2OH ;
~ ~ IV
2 "' R
(wherein R represents a protected hydroxy group) and deprotecting the 3~-.
hydroxy group of the 21-acyloxy derivative of the compound of formula IV
produced. The compound of formula IV is conveniently prepared by the deacyla-tion of a 21-acyloxy derivative of a compound of formula IV, for example a ,: ,' :' ~ ' ' ~0~3l7~ 2~i 21-acetoxy derivative thereof, and provides a method for converting one com-pound of formula II for example in which R is acetyl to another compound of formula II in which R is a different acyl group. The 21-acetyl compound of formula II may thus, for example, be converted into another 21-acyl compound of formula II by firstly protecting ~he 3~-hydroxy group with a protecting sub-stituent which may be rernoved under acidic, reductive or other conditions but is stable under alkaline conditions, such as a 3~-ether substituent e.g. a tetrahydropyranyl or triphenylmethyl substituent or preferably a 3~-nitrate ester, hydrolysing the 3a-protected compound to yield the corresponding 21-hydroxy compound, under basic conditionsJ preferably in the presence of potassium or sodium hydrogen carbonate, conveniently in the presence of a solvent e.g. methanol, ethanol or tetrahydrofuran, reesterifying the resultant product and removing the 3~-protecting substituent.
The reesterification is preferably effected using the anhydride or chloride of the desired acid preferably in the presence of a tertiary amine (e.g. pyridine, collidine, or dimethylaniline) which may also serve as solvent for the reaction.
The protecting group at position 3 may be removed in conventional manner, conditions may be chosen which will not effect the rest of the molecule. -Thus for example when the 3~-hydroxy group of the compound of ~ormula II is protected by the formation of a nitrate ester, the nitrate group may be removed by acid hydrolysis of the compound for example using aqueous mineral acid, or by reduction using, for example zinc and acetic acid or by catalytic hydrogena-tion using, for example, ~lladium on charcoal as catalyst. ~
The following Examples are given by way of illustration only, all temperatures being in degrees Centigrade.
21-Acetoxy-3~-hydroxy-5~-pregnane-11,20-dione Boron trifluoride etherate (37.~ ml.) was added to a stirred solution of 3~-hydroxy-5~-pregnane-11,20-dione (6.64 g., 20 mmole) and lead tetraacetate (10.1 g., 22 xmole) in dry benzene (280 ml.) and methanol (15.1 ml.) at room .~: .
~37~26 temperature. After 2 hours the mixture was poured into water (2 1.) and extracted with ether (1 1.). The combined ether extracts were washed successively with sodium bic~rbonate solution and water, dried over magnesium sulphate, and concentrated in vacuo to ~ive a white crystalline mass. Four recrystallisations from acetone-petroleum ~bp. 40-60) gave 21-acetoxy-3~ -hydroxy-S~ -pregnane-11,20-dione as fine needles (4.22 g., 54%) m.p. 172-173, ~]D
~ 104 (c 1-0- CHC13) (Found: C,70.8; ~, 8.9; C23H3405 requires C, ~ -70.8; ~, 8.8%).
~ ' ' , 21-Acetoxy-3~ -hydroxy So~-yreg~ane-11,20-dione via a trimethyl-silyl derivative ,, , Trimethylchlorosilane (0.33 ml, 1.5 equiv) and pyridine C0~485 mlJ 2 equiv) were added to a solution of ac~-hydroxy-5~ - - ;
pregnane~ 20-dione (l.Og.,) in methylene chloride (16.6 ml) at room temperature. After 16 hours at 0 more trimethylchlorosilane (0.33 ml~ 1 equiv) was added and after a further 1 1/2 hour the solvent was removed in vacuo. Ether was added to the residue and the white solid was filtered off. The ether was removed in vacuo and the residue triturated with a little petroleum (bp 40-60) to give 3~ -trimethyl-siloxy-S~ -pregnane-11,20-dione (0.2 g.,) m.p. 95-96. This compound was also prepared ' , , .
, , ~)37026 by the use of hexamethyldisilazane and trimethylchlorosilane in tetrahydro-furan.
?~ The 21-acetoxylation was carried out as described in Example ~ one crystallisation from acetone-petroleum (bp 40-60) afforded the 21-acetate m.p. 170-173.
Example 3 21-Acetoxy-3 ~hydroxy-5~-pregnane-11,20-dione via a trichloroethoxycarbonyl derivative.
, 2,2,2-Trichloroethylchloroformate (1.1 ml.) was added to a cooled, stirred, solution of 3~-hydroxy-5~-pregnane-11,20-dione in pyridine (0.74 ml.) and dioxan (5.6 ml.). After 10 minutes dilute hydrochloric acid (14.5 ml.) was added and the solution was heatedat 100 for 30 minutes. The resulting oil crystallised on cooling to give 3~-(2,2,2-trichloroethoxycarbonyloxy)-5x pregnane-11,20-dione (1.45 g.,) m.p. 130-131, [~]D + 56 (c 1.0, CHC13) (Found: C, 56.0; H, 6.5; Cl, 21.1; C23H33C1305 requires C, 55.6; H, 6.6;
Cl. 20.7%).
21-Acetoxylation of this compound (0.5 g.,) using the procedure described in Example 1 gave a syrupy residue that crystallised on the addit-ion of ether and petroleum. Recrystallisation from ether-petroleum (bp 40-60) gave 21-acetoxy-3~- ~2,2,2-trichloroethoxycarbonyloxy)-5~-pregnane 11,20-dione ~0.325 g.,) m.p. 143-146 (decomp), [~]D ~ 75.2 (c 1.0, CHC13) (Found:
C, 55.1; H, 6.0; Cl, 18.6. C25H35C1307 requires C, 54.3; H, 6.4; Cl, 19.2%).
Removal of the 2,2,2-trichloroethoxycarbonyl group was effected by -stirr m g a solution of the steroid ~0.10 g.,) in ethanol (2 ml.~ and glacial acetic acid (2.5 ml.) for 5 hours with addition of zinc dust ~0.3 g.) during ~`~ this period. The solids were filtered off, washed with ethanol and the combin-ed fi]trate was reduced in volume in vacuo. Addition of water to the residual solution gave 21-acetoxy-3~-h~oxy-5~-pregnane-11,20-dione (0.036 g.,) m.p.
168-172.
,; : .
Example 4 21-Acetoxy-5o~-Eegnan=3a-ol-ll~2o-dione .,,.,~
Dried yeast (Sa_charomyces cerevisiae 60 g.) was stirred at room - , .:
7~Z6 temperature with tap water (2 1.) containing sucrose (200 g.) and di~ammonium hydrogen phosphate (4 g.). After two hours 21-acetoxy-5a-pregnane-3,11,20-trione (1 g.) (Mancara et al., J. Amer. Chem. Soc., 1955, 77 5669) in ethanol (100 ml.) was added. The fermentation was stirred at room temperature for a further 24 hours, the yeast was removed by fil~ration, partially dried at the pump and extracted with hot chloroform ~4 x 250 ml.). The extracts were shaken with the filtrate, washed with water, dried (Na2SO4) and evaporated to a brown gum (634 mg.). This was subjected to preparative thin-layer chromatography which yielded two pure substances. Of these the less polar was the starting material 21-acetoxy-5~-pregnane-3,11,20-trione, (68 mg.); which was recrystallised from acetone/hexane as colourless needles, m.p. 169-172;
[~]D + 127.5, (c 0.87 CHC13). Gas-liquid chromatography confirmed ~hat this was identical with the starting material.
The more polar substance (70 mg.) was recrystallised from acetone/
hexane to afford 21-acetoxy-5~-pregnan-3~-ol-11,20-dione (57 mg.) as colourless needles, m.p. 179-182; [~]D + 107, (c, 109 CHC13). Gas-liquid chromatography confirmed the identity of this material.
Examp~e_5 21-Acetoxy-5u-pregnan-3~-ol-11~20-dione (a) ?1-Bromo-5~-pregnan-3a-ol-11,20-dione 5~-Pregnan-3~-ol-11,20-dione (1 g., 3 mmoles) in stirred methanol (7 ml.) at 30 was treated with acetyl chloride ~1 drop). After two minutes ~
bromine (0.19 ml., 3.52 mmoles) in me~hanol (4.5 ml.) was added dropwise, the ; ;
solution being allowed to decolourise between the addition of each drop. The resu~ing clear solution was poured into chloroform (100 ml.), washed with water ~3 x S0 ml), dried (Na2SO4) and evaporated to a white froth ~1.40 g.).
Preparative thin-layer chromatography afforded 21-bromo-5~-pregnan-3~-ol-11,20- ;
dione (715 mg.) which crystallised from chloroform/ether as clusters of colour-less needles, m.p. 160-163; [~D + 109 (c 0.82, CHC13); (Found: C, 61.0;
H, 7.9; Br, 19.7; C21H31BrO3 requires C, 61.3; H, 7.6; Br, 19.45%).
, ...
- . -1 . ~
~370;~ ~
A second, unstable substance (415 mg.) isolated from this reaction was examined spectroscopically and iden~ified as 17 ~bromo-5 ~pregnan-3 ~ol-11,20-dione.
(b) 21-Acetoxy-5~-pregnan-3~-ol-11,20-dione 5~-Pregnan-3-ol-llJ20-dione (lg. 3 mmoles) was brominated in the manner described above. The total product from the reaction (1.38 g.) was refluxed with stiring with dry acetone (25 ml.) and anhydrous potassium acetate (2 g). After four hours the reaction mixture was poured into chloro-form (100 ml.), washed with water (3 x 50 ml) dried (Na~S0~) and evaporated to a white froth (1.19 g). Preparative thin-layer chromatography afforded 21-acetoxy-5~-pregnan-3~-ol-11,20-dione (634 mg) as a white froth which on cry-stallisation from acetone/ether gave colourless needles, m.p. 177-180;
[~]D + 102.5, (c 0.95, CHC13). Gas-liquid chromatography confirmed the identity of this material.
Example 6 21-Acetoxy-5a-pregnan-3a-ol-11,20-dione 5a-Pregnan-3a-ol-11,20-dione (5 g., 15.0 mmoles) in stirred methanol (35 ml) at 0 was treated with 5 drops of a 50% w/v solution of hydrogen bromide in glacial acetic acid. After several minutes, bromine (0.95 ml., 2.815 g 17.6 mmoles) in methanol (22.5 ml) was added portionwise over ca.
10 minutes. The solution was left stirring until the colour disappeared and ;
then poured into water. The product was isolated by filtration, washed with water and dried in vacuo at 40 for five hours. Final drying was over phos-~phorus pentoxide in a desiccator tovernight). Yield: approximately quantita-; tive.
The crude bromo-intermediate was dissolved in acetone (100 ml, dried ovir~potassium carbonate) and refluxed in the presence of potassium acetate (10 g) for four hours.
~ ,. , ~ The reaction mixture was poured into water ~1 1.) and extracted with ~-ether ~300 ml and 250 ml). The ether was dried over anhydrous magnesium sul-, ~ :
.' . . . ": -~, ' ',, ' ~370;26 phate, filtered and evaporated under reduced pressure.
The residual foam was recrystallised from acetone-petroleum ether to give 21-acetoxy-5a-pregnan-3a-ol-11,20-diolle as white needles. Yield, 63%;
m.p. 173-175; [a]D + 109, (c 1.0, CHC13)-Example 7 21-Propionyloxy-5a-pregnan-3a-ol-11,20-dione 5a-Pregnan-3~_ol-11,20-dione (2 g., 6 mmoles) in methanol (14 ml.) at 30 was ~reated with acetyl chloride t 2 drops). The solution was stirred for two minutes and was treated dropwise with bromine (0.38 ml., 7 mmoles) in methanol (9 ml.) in the manner described above. The reac~ion mixture was poured into stirred water (250 ml.). The product was isolated, washed and dried at the pump and redried over phosphorus pentoxide in vacuo to afford a white powder ~2.49 g.). This was refluxed with propionic acid (11.1 ml., 0.15 mmoles) and triethylamine (7.25 ml., 0.1 moles) in dry acetone (60 ml.). -After five hours the solution was poured into chloroform (300 ml.)~ washed with aqueous potassium hydrogen carbonate (2 x 200 ml.) and with water ~2 x 200 ml.) dried (Na2S0~) and evaporated to a white froth (2.59 g.). Preparat-ive thin-layer chromatography afforded material which on recrystallisation ~;
from chloroform/ether/hexane gave 21-propionyloxy-5a-pregnan-3a-ol-11,20-dione ~589 mg.) as colourless irregular prisms, m.p. 159-170; [~D + 99' (c 0-92, CHC13); (Found: C, 70.5; H, 8.9. C24H3605.1/4 H20 requires C, ~ -70.45; H, 9.0%) Example 8 21-Isobutyryloxy-5a-pregnan-3a-ol-11,20-dione a-Pregnan-3~-ol-11,20-dione ~2 g., 6 mmoles) in methanol (14 ml.) at .
;; ~ 30 was treated with acetyl chloride (2 drops). The solution was stirred for ~two minutes before being treated dropwise with bromine (0.38 ml., 7 mmoles) in methanol (9 ml.) in the manner described above. When the reaction was com-plete the solution was poured into stirred water (250 ml.). The product was isolated, washed and dried at the pump. A final drying over phosphorus pent-oxide~in vacuo afforded a white powder (2.5 g.). This was re~luxed with iso-z~
butyric acid (14.1 ml., 0.15 moles) and triethylamine (7.25 ml., 0.10 moles) in dry acetone (60 ml.). After four hours the solution was poured into chloro-form (300 ml.), washed with aqueous potassium hydrogen carbonate ~2 x 200 ml.), wi~h water (2 x 200 ml.), dried (Na2S04) and evaporated to a white froth (2.54 g.). Preparative thin-layer chromatography afforded 21-isobutyryloxy-5a-pregnan-3a-ol-11,20-dione (1.45 g.) as a white froth, [a]D * 93.5, (c 0.66, CHC13), (Found: C, 70.4; H, 8.8.C25H3805, 1/2 H20 requires C, 70.25; ~l, 9.2%).
Example 9 21-Benzoyloxy-5~-pregnan-3a-ol-11,20-dione 5a-Pregnan-3a-ol-11,20-dione (2 g., 6 mmoles) in methanol (14 ml.) was treated with acetyl chloride (2 drops) and bromine (0.38 ml., 7 mmoles) as described above. Isolation of the crude bromination product in the usual manner afforded a white powder (2.498 g.). This was refluxed with benzoic acid (18.3g., 0.15 moles) and triethylamine (7.25 ml., 0.1 moles) in dry ace-tone (100 ml.). After five hours the solution was poured into chloroform (500 ml.), washed with aqueous sodium hydrogen carbonate (2 x 200 ml.) and with water (3 x 200 ml.), dried (Na2S04) and evaporated to a white froth.
Preparative thin-layer chromatography afforded 21-benzoyloxy-5a-pregnan-3a-ol-11,20-dione (1.27 g.) as a white froth, [a]D + 104, (c 0.65, CHC13), (Found:
C~ 72'6; H~ 7-7- C28H3605 l/2 H20 requires C, 72.85; H, 8.05%).
Example 10 21-Isobutyryloxy-5a-pregnan-3~-ol-ll~2o-dione 3-nitrate i) Fuming nitric acid (1.3 ml.) was added to stirred acetic ~ -~
anhydride (5 ml.). The solution was cooled to -5 and 21-acetoxy-5a-pregnan-3-ol-11,20-dione (500 mg. 1.28 mmoles) in chloroform (2.5 ml.) was added.
The resulting solution was stirred at 5 for an hour before being poured into - ;
dilute aqueous sodium hydroxide tlO0 ml.), extracted with chloroform ~2 x 75 ~-ml.) and the extract washed with aqueous sodium bicarbonate (50 ml.), with water (3 x 50 ml.), dried (Na2S04) and evaporated to a gum (527 mg.). Crystàl-lisation from ether/acetone afforded 21-acetoxy-5~-pregnan-3a-ol-11,20-dione ,~."' :, ,:
".., ~.., -1~371a~Z6 3-nitrate (386 mg.) as colourless needles, m.p. 1~7~ ; [a]D + 103 ~c 1.06 CHC13); (Found: C, 63.6; H, 7.5; N, 3.1. C23H33NO7 requires C, 63-45;
H, 7.65; N, 3.2%).
ii) 5~-Pregna-3a,21-diol-11,20-dione 3-nitrate ~a) 21-Acetoxy-5~-pregnan-3~-ol-11,20-dione 3-nitrate ~837 mg~, 2 mmoles) in ethanol ~42 mg.) and tetrahydrofuran ~42 ml.) was stirred with 10% aqueous potassium hydrogen carbonate ~4 ml.) and 2N aqueous sodium hydroxide ~2 ml.).
After three hours glacial acetic acid ~1 ml.) was added, the solution was poured into water ~400 ml.) and extracted with chloro~orm ~3 x 120 ml.). The extracts were washed with water ~2 x 50 ml.), dried ~MgSO4) and evaporated to a froth. Preparative thin-layer chromatography afforded pure material which on recrystallisation from ether/acetone gave 5~-pregna-3~?2l-diol-ll~2o-dione 3-nitrate ~219 mg.) as colourless irregular prisms, m.p. 172-176; [~]D ~ 91 ~c 0.97, CHC13) ~Found: C, 63.9; H, 7.8; N, 3.5. C21H31NO6 requires C, 64.1; H, 7.95; N, 3.55%).
~b) 21-Acetoxy-5~-pregnan-3~-ol-11,20-dione ~5 g., 13.3 moles) in chloroform ~25 ml.) was added to a stirred solution of fuming nitric acid ~13 ml.) in acetic anhydride ~50 ml.) at -5. The reaction mixture was stirred at -5 for an hour, poured into sarred aqueous sodium hydroxide ~ 1 l.) and extracted with chloroform ~2 x 200 ml.). The extract was washed with aqueous sodium hydrogen carbDnate ~100 ml.) and with water ~2 x 100 ml.), dried ~Na2S04) and evaporat-ed to a white froth. This was dissolved in methanol ~500 ml.), the solution flushed with nitrogen and stirred with 10% aqueous potassium hydrogen carbon-ate (17.5 ml.) for Eour hours, Glacial acetic acid (3 ml.) was added, the solution evaporated to small bulk, poured into water ~1 1.) and extracted with chloroform ~2 x 200 ml.). The extract was washed with water ~2 x 100 ml.), dried ~Na2SO4) and evaporated to a white froth. Crystallisation from acetone/
ether gave 5~-pregna-3~,21-diol-11,20-dione 3-nitrate ~4.31 g.) as colourless irregular~prisms, m.p. 174-181.
iii) 21-Isobutyryloxy-5~-pregnan-3~-ol-11,20-dione 3-nitrate :' ' , ' - . . - .. ~ . . , ~ . . . ., . . -, ~ . . ; . . . . . .
37~2~;
S~-Pregna-3a,21-diol-11,20-dione 3-nitrate (2.0 g., 5.08 mmoles~ in dry pyridine (20 ml.) was treated with isobu~yryl chloride (2 ml.). The pink solution was allowed to stand at room temperature for 20 hours before being poured into stirred water and acidified with dilute hydrochloric acid. The product was isolated, washed thoroughly with water and dried at the pump.
Recrystallisation from acetone/hexane afforded 21-isobutyryloxy-5a-pregnan-3a-ol-11,20-dione 3-nitrate (1.01 g.) as colourless needles, m.p. 167-169;
[a]D + 97 5~ (c 1.48, CHC13), (Found: C, 64.5; H, 7.8; N, 3.2. C25H37NO7 requires C, 64.8; H, 8.05; N, 3.0%).
iv) 21-Isobutyryloxy-5a-pregnan-3a-ol-11,20-dione 21-Isobutyryloxy-5a-pregnan-3a-ol-11,20-dione 3-nitrate (1.35 g., 2.91 mmoles) in glacial acetic acid (35 ml.) was stirred for an hour at room temperature with zinc powder (4 g.). The zinc was removed, washed with hot chloroform (200 ml.) and the combined washings and filtrates were washed with water ~4 x 100 ml.) dried (Na2SO4) and evaporated to a white froth. Preparat-ive thin-layer chromatography afforded 21-isobutyryloxy-5a-pregnan-3a-ol-11,20-dione as a white froth, [a]D t 97.5 (c 1.05, CHC13). Analytical thin-layer chromatography and gas-liquid chromatography indicated that this material was ;
identical with a sample prepared by the method described in Example 12.
xample 11 5~-Pregna-3a,21-diol-11,20-dione 21-hemisuccinate :
. . .
5a-Pregna-3a,21-diol-11,20-dione 3-nitrate 21-hemisuccinate (1.03 g,, 2.09 mmoles) and zinc powder (3 g.) were stirred with acetic acid (25 ml.) for 90 minutes. The zinc was removed, washed with chloroform (100 ml.), 2N -aqueous hydrochloric acid (200 ml.) and chloroform (100 ml.). The combined filtrates were equilibrated and the organic phase was washed with water (3 x 100 ml), dried (Na2SO4) and evaporated to a white froth. Crystallisation from benzene/hexane/chloroform gave 5~-pregna-3a,21-diol-11,20-dione 21-hemisuccin-ate (8C0 mg.) as colourless needles, m.p. 166-168; [a]D + 90.5, (c 1.32 in CHC13~; (Found: C, 66.9; H, 8Ø C25H36O7 requires C, 66.95; H, 8.1%).
The starting material for this preparation was obtained from 5a- ~;
~ ~'''"',' ~0370Z~i ., ~oii C pregna-3a,21-diol-11,20-dione 3-nitrate (see Example ~t~) as described below:-5~-Pregna-3~,21-diol-11,20-dione 3-nitrate (2g., 5.0~ mmoles) and succinic anhydride (2g. 20 mmoles) in dry pyridine (20 ml.) were allowed to stand at room temperature for 18 hours. The solution was poured into stirred water (300 ml.) which was then acidified. After two hours, the precipitate was collected, washed well with water and dried. Recrystallisa~ion from benzene/hexane gave 5~-pregna-3~,21-diol-11,20-dione 3-nitrate 21-hemisuccinate (1.51 g.) as colourless micro-needles,; m.p. 160-163; [~]D ' 89.5, (c 1.14, CHC13), (Found C, 60.8; H, 7.3; N, 2.6. C25H35NOg requires C, 60.8;
H, 7~15; N, 2.85%).
Example 12 0.035 g of steroid I, finely divided in an air-attrition mill and having an approximate mean particle diameter o~ 5~, was mixed with 0.035 g of steroid II tR = CH3CO-) reduced in size as for steroid I. The steroids are added to 10 ml of a 20% w/v solution of Cremophor EL containing 0.025 g of ;
sodium chloride and the mixture mechanically stirred for at least 24 hours.
Any traces of insoluble residue are filtered off using a sintered glass filter.
Example 13 13.5 g of ground steroid I and 4.5 g of steroid II ~R = CH3CO-) are mixed by mechanical agitation with 300.0 g of Cremophor EL at 70C. in an atmosphere of nitrogen. Heating and agitation are continued until the steroids have completely dissolved. The mixture is diluted with sterile distilled water containing 3.75 g of sodium chloride to give a final volume of 1500 ml.
Stirring is continued until the solution is homogeneous.
Example 14 0.045 g of steroid I and 0.015 g of steroid II ~R = CH3CO-) are dissolved in 2 ml of acetone at 20C. The resultant solution is added to 1 g of Cremophor EL at 20C, and stirred until homogeneous. The acetone is remov-ed by a vigorous stream of nitrogen. The solution is diluted with sterile distilled water containing 0.0125 g of sodium chloride to give a final volume :.
of 5 ml. Similar solutions were prepared using chloroform or methylene chloride in place o~ acetone.
Example 15 0.09 g of ground steroid I are mixed with 0.03 g of ground steroid II (R = CH3CO-) and this added to 2.0 g of Tween 80. As in Example 14, the mixture is mechanically agitated at 70C. in a stream of nitrogen until the steroids have dissolved. The mixture is diluted with sterile distilled water containing 0.025 g of sodium chloride to give a final volume of 10 ml.
Example 16 0.045 g of steroid I and 0.015 g of steroid II (R = (CH3)2CHCO-) are formulated as in Example 14. Similar solutions are obtained using steroid II wherein R = C6H5CO-J HO2CCH2CH2CO or C2H5-CO-.
Example 17 0.045 g of steroid I and 0.015 g of steroid II (R = CH3CO) are dis- ~ ;
solved in 2 ml of acetone at 20C. The resulting solution is added to 1 g of Tween 40 at 20C and stirred until homogeneous. The acetone is removed by a vigorous stream of nitrogen. The solution is diluted with sterile distilled -water containing 0.025 g of sodium chloride ~o give a final volume of 10 ml.
Exam~le 18 0.036 g of ground steroid I are mixed with 0.012 g of ground steroid II (R = CH3C0). This is added to 0.8 g of Tween 60. The mixture is mechanically agitated at 70C in a stream of nitrogen until the steroids are dissolved. The mixture is diluted with sterile distilled water containing -0,025 g of sodium chloride to give a final volume of 10 ml. ;~
Example 19 16 mg of steroid I and 4 mg of steroid II (R = CH3CO) were dissolv-ed in 0.2 ml of acetone, and 0.2 ml of Cremophor EL was mixed with this solu- -tion. The acetone was removed by passing a stream of nitrogen through the mixture. The resulting solution was mixed with 0.8 ml of sterile water.
', ~
` .
:..................................................................... ".
~137~26 Example 20 0.135 grams Steroid I and 0.045 grams of Steroid II, (R=CH3C0), are dissolved in 2 mls of acetone at 20C. The resulting solution is added to 3 grams of Cremophor EL at 20C and s~irred until homogeneous. The acetone is removed by a vigorous stream of nitrogen. The solution is diluted with sterile distilled water containing 0.02S grams of sodium chloride to give a final volume of 10 mls.
Example 21 0.045 grams of ground Steroid I are mixed with 0.012 grams of ground Steroid II, (R=CH3C0)~ and the mixture added to 1 gram of Cremophor EL. The mixture is mechanically agitated a~ 70C in a stream of nitrogen until the steroids have dissolved. The mixture is diluted with sterile distilled water containing 0.025 grams of sodium chloride to give a final volume of 10 mls.
- 25 - ~
~ :.- .'
Claims (37)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a steroid of the formula (II):- (II) wherein R is selected from the group consisting of lower alkanoyl groups, the hemisuccinyl group and the benzoyl group, which comprises (a) reacting a compound of the formula:
(III) in which R1 represents a hydroxy or protected hydroxy group with a lead tetra-acylate of the formula:
Pb(OR)4 wherein R is as defined above, and when R1 is a protected hydroxy group converting it into a hydroxy group; or (b) reducing a corresponding 21-acyloxy-5.alpha.-pregnane-3,11,20-trione of the formula:
wherein R is as defined above; or (c) reacting a 21-halide of the formula:
wherein X is chlorine, bromine or iodine, with a salt of an acid of the formula R.OH
wherein R is as defined above; or (d) acylating a compound of the formula (IV) wherein R2 represents a protected hydroxy group so as to replace the hydroxy group by the group RO- and converting the group R2 into a hydroxy group.
(III) in which R1 represents a hydroxy or protected hydroxy group with a lead tetra-acylate of the formula:
Pb(OR)4 wherein R is as defined above, and when R1 is a protected hydroxy group converting it into a hydroxy group; or (b) reducing a corresponding 21-acyloxy-5.alpha.-pregnane-3,11,20-trione of the formula:
wherein R is as defined above; or (c) reacting a 21-halide of the formula:
wherein X is chlorine, bromine or iodine, with a salt of an acid of the formula R.OH
wherein R is as defined above; or (d) acylating a compound of the formula (IV) wherein R2 represents a protected hydroxy group so as to replace the hydroxy group by the group RO- and converting the group R2 into a hydroxy group.
2. A process for the preparation of compounds of formula II, as de-fined in claim 1, wherein a compound of formula:
(III) (wherein R1 represents a hydroxy or protected hydroxy group) is reacted with a lead tetraacylate and when R1 represents a protected hydroxy group, subsequent conversion of said group to a hydroxy group is effected.
(III) (wherein R1 represents a hydroxy or protected hydroxy group) is reacted with a lead tetraacylate and when R1 represents a protected hydroxy group, subsequent conversion of said group to a hydroxy group is effected.
3. A process as claimed in claim 2 wherein R1 in the compound of formula III represents a nitrate, trimethylsilyloxy or trichloroethoxycarbonyl-oxy group.
4. A process as claimed in claim 2 wherein the reaction is effected in the presence of a Lewis acid.
5. A process as claimed in any of claims 2, 3 and 4 wherein the reaction is effected in solution in a mixture of benzene or toluene with methanol.
6. A process for the preparation of compounds of the formula II, as defined in claim 1, wherein a compound of the formula:
VI
(wherein R is as defined in claim 1) is reduced.
VI
(wherein R is as defined in claim 1) is reduced.
7. A process as claimed in claim 6 wherein the reduction is effected enzymatically using Saccharomyces cerevisiae.
8. A process for the preparation of compounds of the formula II, as defined in claim 1, wherein a compound of formula:
V
(wherein X represents a chlorine, bromine or iodine atom) is reacted with a salt of a carboxylic acid of formula R.OH (wherein R is as defined in claim 1).
V
(wherein X represents a chlorine, bromine or iodine atom) is reacted with a salt of a carboxylic acid of formula R.OH (wherein R is as defined in claim 1).
9. A process as claimed in claim 8 wherein the salt of the carboxylic acid is an alkali metal salt or a tertiary amine salt thereof.
10. A process as claimed in claim 8 or claim 9 wherein the reaction is effected in a solvent.
11. A process for the preparation of compounds of the formula II, as defined in claim 1, wherein a compound of formula:
IV
(wherein R2 represents a protected hydroxy group) is reacted with an acylating agent and the protecting group R2 is converted into a 3.alpha.-hydroxy group.
IV
(wherein R2 represents a protected hydroxy group) is reacted with an acylating agent and the protecting group R2 is converted into a 3.alpha.-hydroxy group.
12. A process as claimed in claim 11 wherein when the group R2 is con-vertible into a 3.alpha.-hydroxy group by treatment with an acid or by reduction, the 21-acyl derivative of the compound of formula IV produced is treated with an acid or is reduced whereby a compound of formula II is produced.
13. A process as claimed in claim 11 wherein R2 in the compound of formula IV represents an etherified hydroxy substituent or a nitrato group.
14. A process as claimed in claim 13 wherein R2 in the compound of formula IV represents a nitrato group which is replaced by a hydroxy group by reduction.
15. A process as claimed in claim 14 wherein the reduction is effected using zinc and acetic acid or catalytically activated hydrogen.
16. A process as claimed in any of claims 11 to 13 wherein replacement of R2 in the compound of formula IV is effected in a solvent.
17. A process as claimed in claim 11 wherein the acylation is effected using a functional derivative of a carboxylic acid of formula ROH (wherein R
is as defined in claim 1).
is as defined in claim 1).
18. A process as claimed in claim 17 wherein the functional derivative of the carboxylic acid is an anhydride or chloride thereof.
19. A process as claimed in claim 17 or claim 18 wherein reaction with a functional derivative of the carboxylic acid is effected in the presence of a tertiary amine.
20. A process as claimed in claim 11 wherein the compound of formula IV
is prepared by hydrolysing a 21-acyloxy derivative of a compound of formula IV
in the presence of a base.
is prepared by hydrolysing a 21-acyloxy derivative of a compound of formula IV
in the presence of a base.
21. A process as claimed in claim 20 wherein the 21-acyloxy derivative of the compound of formula IV which is hydrolysed is the 21-acetoxy derivative thereof.
22. A process as claimed in claim 1, 2 or 6 wherein in the starting materials R is a lower alkanoyl group of 2 to 4 carbon atoms.
23. A process as claimed in claim 1, 2 or 6 wherein in the starting materials R is the acetyl group.
24. A process as claimed in claim 1, 2 or 6 wherein in the starting materials R is the propionyl group.
25. A process as claimed in claim 1, 2 or 6 wherein in the starting materials R is the iso-butyryl group.
26. A process as claimed in claim 1, 2 or 6 wherein in the starting materials R is the hemisuccinyl group.
27. A process as claimed in claim 1, 2 or 6 wherein in the starting materials R is the benzoyl group.
28. A process as claimed in claim 8 or 11 wherein in the starting materials R is a lower alkanoyl group of 2 to 4 carbon atoms.
29. A process as claimed in claim 8 or 11 wherein in the starting materials R is the acetyl group.
30. A process as claimed in claim 8 or 11 wherein in the starting materials R is the propionyl group.
31. A process as claimed in claim 8 or 11 wherein in the starting materials R is the iso-butyryl group.
32. A process as claimed in claim 8 or 11 wherein in the starting materials R is the hemisuccinyl group.
33. A process as claimed in claim 8 or 11 wherein the starting materials R is the benzoyl group.
34. A steroid of formula (II) defined in claim 1, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof,
35. A process for increasing the solubility in an aqueous medium of 3.alpha.-hydroxy-5.alpha.-pregnane-11,20-dione and thereby pre-paring therefrom as anaesthetic composition suitable for use by parenteral administration which comprises incorporating in a suitable aqueous medium at least 1 mg/ml of 3.alpha.-hydroxy-5.alpha.-pregnane-11,20-dione together with one or more steroids of the formula (II) wherein R is selected from the group consisting of lower alkanoyl groups, the hemisuccinyl group and the benzoyl group, the said steroid of formula II being .
prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof, and including at least 1%
by weight of a parenterally acceptable non-ionic surface active agent having an HLB value of at least 9.
prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof, and including at least 1%
by weight of a parenterally acceptable non-ionic surface active agent having an HLB value of at least 9.
36. A process according to claim 35 in which the anaesthetic composition has been prepared by (a) mixing the 3.alpha.-hydroxy-5.alpha.-pregnane-11,20-dione and one or more steroids of formula (II), (b) the resulting steroid mixture is dissolved in the non-ionic surface active agent or an aqueous solution thereof, with heating, and (c) the resulting solution diluted with water to the desired concentration.
37. A process according to claim 35 in which the anaesthetic composition has been prepared by (a) mixing the 3.alpha.-hydroxy-5.alpha.-pregnane-11,20-dione and one or more steroids of formula (II), (b) the resulting steroid mixture is dissolved in a volatile organic solvent having a boiling point less than 80°C and which is miscible with the non-ionic surface active agent or an aqueous solution thereof, (c) adding the non-ionic surface active agent to this solution, (d) the organic solvent is removed by evaporation and (e) the resulting solution of steroids and the surface active agent is diluted with water to the desired concentration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3137169 | 1969-06-20 | ||
| CA085,973A CA1001073A (en) | 1969-06-20 | 1970-06-19 | Anaesthetic compositions containing an anaesthetic steroid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1037026A true CA1037026A (en) | 1978-08-22 |
Family
ID=25666450
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA217,940A Expired CA1037026A (en) | 1969-06-20 | 1975-01-15 | Pharmaceutical preparations |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1037026A (en) |
-
1975
- 1975-01-15 CA CA217,940A patent/CA1037026A/en not_active Expired
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