US3880896A - Chemical compounds - Google Patents

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US3880896A
US3880896A US356096A US35609673A US3880896A US 3880896 A US3880896 A US 3880896A US 356096 A US356096 A US 356096A US 35609673 A US35609673 A US 35609673A US 3880896 A US3880896 A US 3880896A
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group
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pregnane
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groups
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Gordon Hanley Phillipps
Robin Lawrence
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond

Definitions

  • the invention provides steroids of the pregnane or l9-nor-pregnane series possessing a Sat-hydrogen atom or a 4,5-double bond, a 3oz-hydroxy group, a 170:- hydrogen atom, a 20-oxo group, and a 2l-fluorine atom, and, where the steroids carry basic groups, the acid addition salts thereof.
  • the invention also provides pharmaceutical compositions comprising an anaesthetic steroid in accordance with the invention and processes for the preparation of the compounds of the invention.
  • the compounds of the invention may possess substituents at other positions of the steroid nucleus, for example at the 2, 3B, 1 l or 16 positions. They may also be unsaturated, for example at the A and/or A or A position.
  • the compounds of the invention are good anaesthetics with generally short induction periods, the anaesthetic action at suitable doses being in general instantaneous; these compounds are thus excellent anaesthetics for inducing anaesthesia which is to be maintained e.g. by an inhalation anaesthetic such as ether, halothane, nitrous oxide. or trichloroethylene.
  • an inhalation anaesthetic such as ether, halothane, nitrous oxide. or trichloroethylene.
  • the compounds are however capable of maintaining anaesthesia 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).
  • the said anaesthetics in accordance with the invention in general give rise to minimal side-effects as compared to many previously described steroidal anaesthetics.
  • substituents which may be present at the ZB-position include an acyloxy group having for example l to 9 carbon atoms, an ether or thioether group (i.e. the residue of an alcohol, a phenol or a thiol) containing for example 1-9 carbon atoms (e.g. methoxy), an alkyl or cycloalkyl group for example containing up to 9 carbon atoms, an aryl group (e.g. a phenyl group), an aralkyl group (e.g. a benzyl group), a hydroxy group, a thiocyanato group, a nitro-oxy group, or a halogen atom.
  • an acyloxy group having for example l to 9 carbon atoms an ether or thioether group (i.e. the residue of an alcohol, a phenol or a thiol) containing for example 1-9 carbon atoms (e.g. methoxy), an alkyl or
  • Acyloxy substitutents (which may be saturated or unsaturated) include lower (C -C alkanoyloxy groups, (substituted if desired, for example, with one or more halogen, e.g. chlorine atoms, lower alkoxy, amino or substituted amino groups), aroyloxy groups (e.g. a benzoyloxy group), or aralkanoyloxy groups (e.g. a phenylacetoxy group).
  • halogen e.g. chlorine atoms, lower alkoxy, amino or substituted amino groups
  • aroyloxy groups e.g. a benzoyloxy group
  • aralkanoyloxy groups e.g. a phenylacetoxy group
  • Ether substituents which may be saturated or unsaturated, include lower (C -C alkoxy groups, lower alkenyloxy groups (e.g. an allyloxy group), cycloalkoxy groups (e.g. a cyclohexyloxy group), aryloxy groups (e.g. a phenoxy group) an aralkoxy groups (e.g. a benzyloxy group).
  • Thioether groups corresponding to the above-mentioned ether groups are representative of ZB-thioether substituents.
  • the 2B-substituent may alternatively be an azido, sulphonyloxy (e.g. tosyloxy) group or an acylthio group.
  • ZB-alkyl groups include especially lower alkyl groups containing l-5 carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl and t-butyl groups.
  • An example of a cycloalkyl group is a cyclohexyl group
  • Examples of lower alkanoyloxy ZB-substituents include acetoxy, propionyloxy, butyryloxy, piperidinoacetoxy, morpholinoacetoxy, diethylaminoacetoxy and chloroacetoxy groups.
  • lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and t-butoxy groups, and the corresponding thio compounds exemplify lower alkyl thio substituents.
  • Lower alkoxy and lower alkylthio substituents at the ZB-position may themselves be substituted for example by one or more halogen (e.g. chlorine) atoms, lower alkoxy, esterified carboxyl (e.g. ethoxycarbonyl), hydroxy, amino or substituted amino (e.g. morpholino) groups, or substituted or unsubstituted acyloxy (e.g. morpholinoacetoxy, chloroacetoxy or diethylaminoacetoxy), or heterocylcic groups, e.g. a tetrahydrofuranyl group.
  • Alkyl, cycloalkyl and aryl groups may also be substituted.
  • the ZB-position may also carry amino substituents, e.g. amino or substituted amino groups, for example monoor dialkylamino or saturated, unsaturated or aromatic heterocyclic amino groups, e.g. a morpholino group.
  • amino substituents e.g. amino or substituted amino groups, for example monoor dialkylamino or saturated, unsaturated or aromatic heterocyclic amino groups, e.g. a morpholino group.
  • a particularly important ZB-Substituent is an ethoxy group.
  • substituents which may be present at the Za-position are alkyl groups, e.g. having 1 to 6 carbon atoms such as methyl or ethyl, or halogen atoms, e.g. chlorine or bromine.
  • substituents which may be present at the 3B-position are alkyl groups, e.g. having 1 to 6 carbon atoms such as methyl, ethyl or pentyl.
  • An oxo group may be present at the l l-position and compounds having this substituent are particularly important.
  • a hydroxy group may be present at the ll-position, in either the a configuration or, in the presence of absence of an -alkyl or alkenyl (C group e.g. methyl or allyl, in the 62 configuration.
  • Another possible grouping is an epoxy group linked also to the 9-position.
  • the l6-position may be substituted by one or more alkyl or alkoxy groups having 1 to 6 carbon atoms (e.g. methyl, ethyl, methoxy, or gemdiemthyl) or by a halogen atom (e.g. fluorine or chlorine).
  • a single 16- substituent may be in the a or ,8 configuration.
  • Certain of the compounds of the invention are capable of forming acid addition salts and this has the advantage of tending to improve the water solubility of the compounds.
  • Such salts include, in the case of aminosubstituted compounds, hydrochlorides, hydrobromides, phosphates, sulphates, p-toluenesulphonates, methanesulphonates, citrates, tartrates, acetates, ascorbates, lactates. maleates and succinates.
  • salts When these salts are used as anaesthetics they should be non-toxic, i.e. physiologically acceptable in the dosage at which they are administered. Other salts may, however, be of use in for example, isolation of the product from a synthetic reaction.
  • Particularly preferred compounds in accordance with the invention by virtue of their excellent anaesthetic properties are 2l-fluoro-3a-hydroxy-5ozpregnane-l 1,20-dione and 2B-ethoxy-21-fluoro-3ahydroxy-Sa-pregnane-l 1,20 -dione.
  • anaesthetic compound of the invention may be formulated as convenient, following generally known pharmaceutical practices, (including both human and veterinary medical practices), with the aid of one or more pharmaceutical carriers or excipients.
  • the steroids will be given by injection and thus one aspect of this invention comprises an anaesthetic composition for parenteral administration comprising an anaesthetic compound in accordance with the invention in a parenterally acceptable vehicle.
  • anaesthetic compounds When the anaesthetic compounds are sufficiently soluble in water (e.g. the salts, particularly the citrates referred to above) they may be formulated in aqueous solutions (e.g. isotonic sterile solutions). Many of the anaesthetic steroids of the invention are poorly soluble in water. We have found however that they may be formulated for parenteral administration in an aqueous solution of a parenterally acceptable non-ionic surface active agent. These surface active agents may also be used even where the steroid is sufficiently water soluble as they may reduce the risk of thrombophlebitis.
  • aqueous solutions e.g. isotonic sterile solutions.
  • Many of the anaesthetic steroids of the invention are poorly soluble in water. We have found however that they may be formulated for parenteral administration in an aqueous solution of a parenterally acceptable non-ionic surface active agent. These surface active agents may also be used even where the steroid is sufficiently water soluble as
  • the non-ionic surface active agents used for the purpose of this invention are generally those of the watersoluble type, conveniently having an HLB value of at least 9, preferably at least about 12, advantageously at least about 13.
  • HLB value of the surface active agent is not greater than about 18.
  • a mixture of surface agents may be used. in which case it is the HLB value of the mixture which is conveniently between the values just mentioned.
  • the surface active agent must naturally be one which is physiologically compatible, i.e. of itself give rise to no physiologically 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 fol lowing non-ionic surfactants and classes of surfactants:
  • Polyoxyethylated derivatives of fatty (Cl2-C20) glyceride oils e.g. castor oil, containing from 35 to 60 oxyethylene groups per mole of fatty oil.
  • Polyoxyethylene ethers containing from 10 to 30 oxyethylene groups of long chain alcohols (containing for example from 12-28 carbon atoms).
  • Polyoxyethylene-polyoxypropylene ethers containing from 5 to 150 and from 15 to 50 oxyethylene and oxypropylene groups respectively.
  • fatty acid e.g. C12-l8
  • esters of sugar alcohol anhydrides e.g. sorbitan or mannitan.
  • Long-chain alkanoyl monoand dialkanolamides (the alkanol portions of which for example contain 1-5 carbon atoms) for example lauroyl monoand di-ethanolamides.
  • Polyethylene glycol esters (containing from 6 to 40 ethylene oxide units) of long chain fatty acids (containing for exammple 12-18 carbon atoms) e.g. polyethyleneglycol monooleate (containing for example 8 ethylene oxide units).
  • phospholipids such as lecithins, e.g. egg or soyabean lecithins.
  • Cremophor EL a polyoxyethlated castor oil containing about 40 ethylene oxide units per triglyceride unit;
  • Tween 80 polyoxyethylene sorbitan monooleate containing about 20 ethylene oxide units
  • Tween 60 polyoxyethylene sorbitan monostearate containing about 20 ethylene oxide units
  • Tween 40 polyoxyethylene sorbitan monopalmitate containing about 20 ethylene oxide units.
  • solutions is used herein to denote liquids which have the appearance of true solutions and are thus optically clear and capable of passage, for example, through a micro-porous filter, irrespective 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 the practical purpose of intravenous injection.
  • the proportion of surface active agent to be used in the compositions of this invention depends upon its nature and upon the concentration of steroid desired in the final composition.
  • the proportion of surfactant is preferably at least 5 percent by weight and advantageously above 10 percent by weight.
  • a very convenient proportion of surfactant has been found to be 20 percent by weight but 30 percent and up to 50 percent may be used.
  • the proportions of surfactant are expressed by weight in relation to the total volume of the composition.
  • the steroid is first dissolved in the selected surfactant, for example with heating, and the resulting solution dissolved in water.
  • the steroid may be dissolved in a volatile organic solvent advantageously having a boiling point of less than about C which is miscible with the surface active agent such as a volatile lower aliphatic ketone e.g. acetone or methyl ethyl ketone or a volatile halogenated hydrocarbon e.g. chloroform or methylene choride.
  • 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 steroid in surfactant is mixed with water.
  • the solutions may also be prepared by shaking the steroid with an aqueous solution of the surface active agent.
  • the proportion of steroid which is dissolved in the aqueous medium according to the invention depends upon the water-solubility of the steroid and, where present, the nature and amount of surface active agent used.
  • the composition will generally contain at least 1 mg/ml of steroid but solutions can be made containing for example up to 6 mg/ml of steroid or even 10 mg/ml.
  • the anaesthetic solutions according to the invention are generally administered by intravenous injection although as is known in the anaesthetic art in certain cases, e.g. with young children, intramuscular injection might be preferred.
  • the quantity of steroid used to induce anaesthesia depends upon the weight of the individual to be anaesthetised.
  • a dose of from 0.2 to 5 mg/kg will in general be found to be satisfactory to induce anaesthesia, the preferred dose being within the range of from 0.5 to 3.5 mg/kg.
  • 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.
  • 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.
  • continuous administration may be undertaken at for example a rate of 0025- (e.g. 0.09-l.4) mg/kg/min.
  • the compounds of the invention may in general be prepared by the nucleophilic displacement of a readily eliminatable substituent at the 2l-position of a corresponding steroid whereby the desired 2l-fluoro substituent is introduced.
  • the starting 2l-substituted steroid is preferably the corresponding 2l-iodo steroid, but other compounds may be used, for example a corresponding 2l-chloro, 2l-bromo or 2l-sulphonyloxy (e.g. methanesulphonyloxy) compound.
  • the starting compound may be reacted with a source of fluoride ions e.g. silver fluoride or an alkali metal fluoride such as sodium fluoride or potassium hydrogen fluoride.
  • a source of fluoride ions e.g. silver fluoride or an alkali metal fluoride such as sodium fluoride or potassium hydrogen fluoride.
  • the reaction may be carried out in any suitable inert and preferably polar solvent (e.g.
  • reaction may be effected at any suitable temperature up to reflux, and may be catalysed by the addition of iodide ions when the starting compound is other than a 2l-iodo compound.
  • the 2 l -substituted compounds used as starting materials in the preparation of the compounds of the invention may readily be prepared from known compounds by conventional methods.
  • a 21-iodo compound for use as a starting material may be prepared by reacting the corresponding 21- bromo or 2 l chloro (preferably the bromo compound) with a source of iodide ions e.g. an alkali metal iodide such as sodium iodide.
  • a source of iodide ions e.g. an alkali metal iodide such as sodium iodide.
  • the reaction may be carried out in solvents such as those referred to above regarding the preparation of the 2l-fluoro compounds, at any suitable temperature up to reflux.
  • the 21-bromo compounds required in the latter preparation may be prepared by bromination of the corresponding 2l-unsubstituted compound, for example with molecular bromine in a solvent such as methanol or ethanol.
  • the reaction is preferably effected at a temperature of l0 to 30C. If desired the reaction may be accelerated by a catalyst such as hydrogen bromide (in acetic acid) or acetyl chloride.
  • Substitution at the 2B-position can be effected for example by way of the corresponding 2a, 3a, -epoxy compound.
  • the epoxy compound itself may be prepared by first dehydrating a 3-hydroxy compound to give the corresponding A compound (e.g. by first tosylating the hydroxy group and then detosylating the product), and then treating the A compound with a peracid to form the 2a, 3a epoxide ring.
  • a 2B-substituent may then be introduced by the method described in pending U.S. patent application Ser. No. 197,915 of Phillipps et al., filed Nov. 11, 197 1. This general method may be used to introduce all the 2/3-substituents described above.
  • Compounds possessing A unsaturation may also be prepared by known methods, but we prefer to use a method which comprises converting a 2B-bromo-3ahydroxy pregnane into its corresponding 23., 21- dibromo compound, if desired protecting the 3ahydroxy group (e.g. as its tetrahydropyranyl ether). dehydrobrominating to give the A compound. and then deprotecting the product where necessary to give the desired l,2-dehydro-3a-hydroxy-20-oxo-2 l -bromo compound.
  • the dehydrobromination may be effected. for example, using a nitrogen containing Lewis base such as a di-lower alkyl lower acylamide e.g. dimethylformamide or dimethylacetamide advantageously in the presence of an alkali metal or alkaline earth metal carbonate, for example calcium carbonate.
  • a nitrogen containing Lewis base such as a di-lower alkyl lower acylamide e.g. dimethylformamide or dimethylacetamide advantageously in the presence of an alkali metal or alkaline earth metal carbonate, for example calcium carbonate.
  • a -steroids may be prepared from A -steroids by methods analogous to those described for obtaining A compounds from A steroids.
  • a -steroids may be obtained by the methods described in U.S. patent application Ser. No. 194.918.
  • Sa-Steroids of the invention may also be prepared from the corresponding 3-oxo compound by stereospecific reduction. e.g. by the method of Browne and Kirk (J. Chem. Soc. C., 1969, 1653) or by the method of U.S. patent application Ser. No. 305,246 of Clayton et al., filed Nov. 10. 1972 and to issue as U.S. Pat. No. 3,822,298 on July 2. 1974.
  • the latter method preferably uses a pre-formed iridium catalyst reduction system.
  • a reduction system may be prepared from an iridium acid or salt (e.g. chloroiridic acid).
  • a trivalent phosphorus compound such as a phosphorous acid ester (e.g.
  • trimethyl phosphite water and an organic reaction medium (e.g. an alcohol such as isopropanol).
  • the reduction system is then neutralised (e.g. to a pH of 6 to 8.5) with an organic base such as a secondary or tertiary amine (e.g. triethylamine) and reacted with the steroid.
  • an organic base such as a secondary or tertiary amine (e.g. triethylamine) and reacted with the steroid.
  • the catalyst system is preformed by heating at reflux for 16 to 72 hours, the reduction can be accomplished in 2-3 hours; longer times may be necessary at room temperature.
  • a 3a-hydroxy group may be for example be protected in the form of a nitrate ester or tetrahydropyranyl ether.
  • a 20-oxo group may be protected as a ketal and regenerated for example by hydrolysis in the presence of an aicd (e.g. hydrochloric or acetic) at a temperature of 100C.
  • PREPARATION 2 21-Bromo-2B-ethoxy-3a-hydroxy-5a-pregnane-l 1,20 -dione 2a, 3a-Epoxy-5a-pregnane-11.20 -dione (500 mg) was dissolved in dry ethanol (30 ml), and concentrated sulphuric acid (0.15 ml) was added. The solution was stirred at 2530 for 15 minutes, then water (100 ml) was added to give a fine crystalline precipitate which was filtered off.
  • Jones reagent is a solution of chromium trioxide (267 g) in a mixture of concentrated sulphuric acid (230 ml) and water (400 ml) made up to 1 litre with water (8N w.r.t. oxygen).
  • EXAMPLE 3 0.058 g of 2l-fluoro-3a-hydroxy-5a-pregnane-l l,20 -dione were dissolved in 2 ml of acetone at 20C. The resulting solution was added to 2 g of Cremophor EL at 20C and stirred until homogeneous. The acetone was removed by a vigorous stream of nitrogen. The solution was diluted with sterile distilled water containing 0.05 gof sodium chloride to give a final volume of l0 ml.
  • the chloroirdic acid reagent was prepared by refluxing a mixture of chloroiridic acid (0.9 g). percent isopropanol (200 ml) and trimethylphosphite (16 ml) for 16 hours. The solution was neutralised with triethylamiine immediately before use.
  • a steroid selected from the group consisting of a compound of the formula III where R is H or CH and R is H or C -C alkoxy. 2. A compound as claimed in formula I in claim 1 wherein R is ethoxy.

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  • Health & Medical Sciences (AREA)
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US356096A 1972-05-05 1973-05-01 Chemical compounds Expired - Lifetime US3880896A (en)

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GB2114472A GB1430932A (en) 1972-05-05 1972-05-05 21-fluoro-pregnanes

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JP (1) JPS4961151A (enrdf_load_stackoverflow)
AU (1) AU475105B2 (enrdf_load_stackoverflow)
BE (1) BE799101A (enrdf_load_stackoverflow)
CA (1) CA996100A (enrdf_load_stackoverflow)
CH (1) CH606098A5 (enrdf_load_stackoverflow)
DE (1) DE2322550A1 (enrdf_load_stackoverflow)
DK (1) DK133785B (enrdf_load_stackoverflow)
FR (1) FR2183793B1 (enrdf_load_stackoverflow)
GB (1) GB1430932A (enrdf_load_stackoverflow)
IE (1) IE37597B1 (enrdf_load_stackoverflow)
LU (1) LU67547A1 (enrdf_load_stackoverflow)
NL (1) NL7306232A (enrdf_load_stackoverflow)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4812413A (en) * 1987-03-17 1989-03-14 Erez Forensic Technology, Ltd. Reagent, process and kit for drug detection

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ300694A3 (en) * 1993-12-02 1996-05-15 Akzo Nobel Nv Substituted 2beta-morpholinandrostane derivatives, process of their preparation, their use for preparing pharmaceutical preparations and pharmaceutical compositions containing thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2884421A (en) * 1958-06-09 1959-04-28 Upjohn Co 6-fluoro-17alpha, 21-epoxy-4-pregnenes
US3050536A (en) * 1961-05-08 1962-08-21 Olin Mathieson 21-fluoro-delta-pregnene-17alpha-ol-3, 20-dione

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1317184A (en) * 1969-06-20 1973-05-16 Glaxo Lab Ltd Steroid-containing pharmaceutical preparations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2884421A (en) * 1958-06-09 1959-04-28 Upjohn Co 6-fluoro-17alpha, 21-epoxy-4-pregnenes
US3050536A (en) * 1961-05-08 1962-08-21 Olin Mathieson 21-fluoro-delta-pregnene-17alpha-ol-3, 20-dione

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4812413A (en) * 1987-03-17 1989-03-14 Erez Forensic Technology, Ltd. Reagent, process and kit for drug detection

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CH606098A5 (enrdf_load_stackoverflow) 1978-10-13
NL7306232A (enrdf_load_stackoverflow) 1973-11-07
FR2183793B1 (enrdf_load_stackoverflow) 1976-10-22
IE37597L (en) 1973-11-05
FR2183793A1 (enrdf_load_stackoverflow) 1973-12-21
DE2322550A1 (de) 1973-11-22
ZA733037B (en) 1974-04-24
CA996100A (en) 1976-08-31
JPS4961151A (enrdf_load_stackoverflow) 1974-06-13
AU5528673A (en) 1974-11-07
DK133785C (enrdf_load_stackoverflow) 1976-12-06
LU67547A1 (enrdf_load_stackoverflow) 1973-07-13
GB1430932A (en) 1976-04-07
BE799101A (fr) 1973-11-05
DK133785B (da) 1976-07-19
AU475105B2 (en) 1976-08-12

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