DE2322532A1 - PREGNANDERIVATES AND THE PROCESS FOR THEIR MANUFACTURING - Google Patents

Description

Dr. F. Zumsteln sen. - Dr. E. Assmann Dr. R. Koenigsberger - Dipl.-Phys. R. Holzbauer- Dr. F. Zumsteln | un.

PATENT LAWYERS

TELEPHONE: COLLECTIVE NO. 225341 TELEGRAMS: ZUMPAT CHECK ACCOUNT: MUNICH 91139

BANK ACCOUNT: BANK H. AUFHAUSER

8 MUNICH 2,

Wt / My
Anesthetics 17

GLAXO LABORATORIES LIMITED, Greenford, Middlesex / England Pregnan derivatives and processes for their production

The invention relates to compounds of the pregnane series having anesthetic activity.

It has long been known that a number of steroids can cause severe depression on the central nervous system has and pharmacodynamically as anesthetics or hypnotics works. Such compounds have been the subject of much research to find anesthetics to help one such compounds as thiopentone sodium, which is commonly is used, but which is well known to have some disadvantages to replace. The literature shows that many steroid compounds have been studied with this aim. Summaries and discussions of some of the work carried out can be found, for example, in "Methods in Hormone Research" (published by Ralph I. Dorfman, Volume III, Part A, Academic Press, London and New York, 1964, pp. 415-475); H. Witzel, Z. Vitamin Hormon-Fermentforsch. 1959, Ij), 46-74; H. Selye, Endocrinology, 1942, 50, 437-453; S.K. Figdor et al., J. Pharmacol Exptl.

3 0 9 8 A 7/1 1 3 2

QRfOlNAL INSPECTED

Therap., 1957, 119 , 299-309 and Atkinson et al., J. Med. Chem. 1965, 8, 426-432.

A close review of the literature reveals that many are anesthetic Steroids require poor activity and / or long induction times. A multitude of undesirable side effects such as paresthesia and venous damage is also observed.

It has now been found that a new group of pregnanseroids has potent anesthetic activity.

The invention relates to steroids of the pregnant or 19-norpregnan series, which have a 3 ″ -hydroxy group, a 17α-hydrogen atom, a 20-oxo group and one in the 21-position Contain cyano, basic amino or azido groups, and their salts.

The compounds according to the invention can contain substituents at other positions on the steroid nucleus, for example in the 2-, 3-, 11- or 16-divisions. They can also be unsaturated, for example in the Λ ^ö ^ ^y 'and / or / y or / \ positions. If a hydrogen atom is present in the 5-position, it can be in either the α- or β-configuration, preferably it is in the α-configuration.

In general, the compounds of the invention are good anesthetics and generally have short induction times. The anesthetic effect is generally momentary at appropriate doses. These compounds are thus excellent anesthetics for inducing anesthesia, which can be sustained, for example, by an inhalation anesthetic such as ether, halo than, nitrous oxide or trichlorethylene. However, the compounds are also capable of anesthesia and analgesia to a sufficient extent _s maintain so you different surgical operations without the use of anesthetic agents can perform, the required

3 0.9 S · ■ 7 -M 1 3 2

Degree of anesthesia, possibly through repeated administrations or even maintained by continuous administration. The anesthetics according to the invention show generally minimal side effects compared to many previously described steroid anesthetics.

The basic amino group present in the 21-position is preferably one in which the amino nitrogen atom is a member of a saturated or unsaturated, substituted one or unsubstituted 3- to 8-, preferably 5- or 6-membered ring, the one or more further May contain heteroatoms such as nitrogen, oxygen or sulfur. The rings can be substituted, for example by one or more oxo, alkyl (e.g. methyl), aralkyl, alkoxy, alkoxycarbonyl or acyloxy groups. The ring contains preferably two heteroatoms (including the amino nitrogen atom), wherein the second heteroatom is oxygen or sulfur. Saturated rings are generally preferred; Examples are morpholine, thiamorpholine and thiazolidine.

These latter rings, in particular morpholine, can themselves contain substituents, for example one or more Alkyl groups with 1 to 6 carbon atoms such as a methyl group, especially in the 3-position, based on the Nitrogen atom.

Compounds with a morpholino group in the 21-position are particularly important, especially when an oxo group is also present in the 11-position.

Examples of substituents which may be present in the 2β-position are, for example, an acyloxy group with, for example 1 to 9 carbon atoms, an ether or thioether group (for example the remainder of an alcohol, a phenol or a thiol) containing, for example, 1 to carbon atoms (e.g. methoxy), an alkyl or

Cycloalkyl group, for example one containing up to 9 carbon atoms contains, an aryl group (e.g. a phenyl group), an aralkyl group (e.g. a benzyl group), a hydroxyl group, a thiocyanato group, a nitro-oxy group or a halogen atom.

Acyloxy substituents (which can be saturated or unsaturated) are, for example, lower (Cj-Cg) alkanoyloxy groups (if necessary substituted, for example with one or more halogen, for example chlorine atoms, lower alkoxy, amino or substituted amino groups), Aroyloxy groups (e.g. a benzoyloxy group) or Aralkanoyloxy groups (e.g. a phenylacetoxy group).

Ether substituents, which can be saturated or unsaturated, are for example lower (C.-Cg) alkoxy groups, lower ones Alkenyloxy groups (e.g. an allyloxy group), cycloalkoxy groups (e.g. a cyclohexyloxy group), Aryloxy groups (e.g. a phenoxy group) and aralkoxy groups (e.g. a benzyloxy group). Thioether groups, corresponding to the above-mentioned ether groups are examples of 2β-thioether substituents.

The 2β substituent can alternatively be an azido, sulfonyloxy (e.g. Tosyloxy) group or an acylthio group be.

Examples of 2β-alkyl groups particularly include lower alkyl groups containing 1 to 5 carbon atoms such as Methyl, ethyl, propyl, butyl, isobutyl and tert-butyl groups. An example of a cycloalkyl group is a cyclohexyl group.

Examples of lower alkanoyloxy-2ß-substituents are for example acetoxy, propionyloxy, butyryloxy, Piperidinoacetoxy, morpholinoacetoxy, diethylaminoacetoxy

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and chloroacetoxy groups. Examples of lower alkoxy groups are, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and tert-butoxy groups, and the corresponding thio compounds are examples of lower alkylthio substituents.

Lower alkoxy and lower alkylthio substituents in the 2β-position can themselves be substituted, for example by one or more halogen (for example chlorine) atoms, lower alkoxy, esterified carboxyl (for example ethoxycarbonyl), Hydroxy, amino or substituted amino (e.g. morpholino) groups, or substituted or unsubstituted acyloxy (for example morpholinoacetoxy, Chloroacetoxy or diethylaminoacetoxy) or heterocyclic groups, for example a tetrahydrofuranyl group. The alkyl, cycloalkyl and aryl groups can also be substituted.

The 2β-position can contain amino substituents, for example amino or substituted amino groups, for example Mono- or di-alkylamino groups or saturated, unsaturated or aromatic heterocyclic amino groups, for example a morpholino group.

A particularly important 2β-substituent is an ethoxy group.

Examples of substituents present in the 2 <x position are alkyl groups, for example with 1 to 6 carbon atoms such as methyl or ethyl groups or Halogen atoms, for example chlorine or bromine atoms.

Examples of substituents which may be present in the 3β-position are alkyl groups, for example with 1 to 6 carbon atoms such as methyl, ethyl or pentyl.

An oxo group may be present in the 11-position, and compounds which contain these substituents are special

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important. Alternatively, there can be a hydroxyl group in the 11-position either in the α configuration or in the presence or absence of a (C ^^ α-alkyl or alkenyl group (for example a methyl or allyl group) be present in the ß-configuration. Another possible group is an epoxy group attached at the 9-position.

The 16-position can be replaced by one or more alkyl or alkoxy groups with 1 to 6 carbon atoms (for example methyl, ethyl, methoxy or gem-dimethyl) or by a halogen atom (e.g. fluorine or chlorine atom) may be substituted. A single 16-substituent can be used in α- or ß-configuration be present.

Certain compounds according to the invention, for example those which contain a basic nitrogen atom can acid addition salts form, which is advantageous because it increases the water solubility of the compounds. Such salts include, for example, in the case of amino-substituted compounds, the hydrochlorides, hydrobromides, phosphates, Sulfates, p-toluenesulfonates, methanesulfonates, citrates, tartrates, Acetates, ascorbates, lactates, maleates and succinates.

Solutions of the acid addition salts of compounds which contain a basic nitrogen atom can also contain further Dissolve amounts of the free base. Significantly, these solutions can be less acidic than the solutions the acid addition salts, and they can be produced 'by for example the free base or another base to a solution of the acid addition salt. For example, aqueous 3α: -hydroxy-21-morpholino-5α-pregnane-11,20-dione citrate up to 2 or more equiv. dissolve the free base.

Compounds containing a 21-cyano group are capable of water-soluble salts such as the alkali metal, for example sodium, potassium or lithium and the ammonium (including

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borrowed the substituted ammonium) salts to form.

If these salts are used as anesthetics, they should be non-toxic, i.e. physiologically acceptable in the Dose in which they are administered. However, other salts can be used, for example when isolating the product the synthesis reaction, be useful.

Particularly preferred compounds according to the invention are because of their excellent anesthetic properties:

1) 21-cyano-3a-hydroxy-5a-pregnane-11,20-dione and the sodium salt

2) 21 -Cyano-2ß-ethoxy-3a-hydroxy-5 <x-pregnane-11,20-dione and the sodium salt

3) 21 -Cyano ^ ß-methoxy-jJcc-hydroxy-Sa-pregnan-1 »20-dione

4) 21-cyano-2β-isopropoxy-3oc-hydroxy-5a-pregnane-11,20-dione

5) 21 -Cyano-3a-hydroxy-16oc-methyl-5a-pregnane-11,20-dione

6) 3 "-Hydroxy-21-morpholino-Soc-pregnan-i 1,20-dione and the citrate, mesylate and hydrochloride

7) 2β-Ethoxy-3cc-hydroxy-21-morpholino-Soc-pregnan-i 1,20-dione and the citrate, phosphate, acetate and ascorbate

8) Sa-Hydroxy-iea-methyl ^ i-morpholino-Sa-pregnan-ii, 20-dione

9) 3oc-Hydroxy-21 - (2 ^f -methylmorpholino) -5 "-pregnane-11,2-dione

10) 3a-Hydroxy-21- (cis-2 ', 6'-dimethylmorpholino) - ^ oc-pregnane-11,20-dione

11) 3 "-Hydroxy-21-thiamorpholino-5a-pregnane-11,20-dione

12) 3tt-Hydroxy-21-thiamorpholino-19-nor-5cc-pregnane-11,20-dione and the citrate

13) 21-azido-3oc-hydroxy-5a-pregnane-11,20-dione

14) 21-Azido-2β-ethoxy-3oc-hydroxy-5cx-pregnane-11,20-dione

15) 21-azido-3cc-hydroxy-5ß-pregnane-11,20-dio ₍ n

16) 21-azido-3a-hydroxy-5oc-pregnan-20-one

17) 21-azido-3α-hydroxy-16α-methyl-5cc-pregnane-11,20-dione

18) 21-Azido-3oc-hydroxy-2β-methoxy-5oc-pregnan-20-one

19) 21 -Azido ^ a-hydroxy-ig-nor-Sa-pregnan-ii, 20-dione

20) 21 -azido-3a-hydroxy-5cc-pregn-1-ene-11,20-dione

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21) 21 -Cyano-3oc-hydroxy-2'ß-methyl-5a-pregnane-11,20-dione

22) 3α-Hydroxy.-21-thiazolidino-5α-pregnane-11,20-dione and

23) 21-Azido-3oc-hydroxy-2β-methyl-5a-pregnane-11,20-dione.

Particularly preferred compounds in the above list are compounds 1, 2, 3, 6, 7, S, 9, 10, 11 and 12 and their salts, 13, 14, 16, 18, 20, 21 and 22.

Pharmaceutical formulations

The anesthetic compounds according to the invention can be formulated as required, generally known ones uses pharmaceutical procedures (including procedures in human and veterinary practice), using one or more pharmaceutical carriers or drug carriers. For anesthetic purposes the steroid is administered by injection and the invention relates to anesthetic compositions for parenteral administration comprising an anesthetic compound of the invention with a parenteral contain an acceptable carrier. Are the anesthetic compounds sufficiently soluble in water (for example the salts, especially the citrates, which have been mentioned above), they can be in aqueous solutions (for example in isotonic sterile solutions). Many of the anesthetic steroids of the invention are poor in water soluble. However, it has been found that they are suitable for parenteral administration in aqueous solution of a parenterally acceptable, nonionic surfactants can be formulated. These surfactants can also should be used when the steroid is sufficiently soluble in water as it will reduce the risk of thrombophlebitis can.

The nonionic surfactants used in the present invention are general those which are water-soluble and which expediently have an HLB value of at least 9, preferably of at least 12,

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advantageously of at least about 13. Preferably is the HLB value of the surfactant no greater than about 18. A mixture of the surfactants Medium can be used, in which case the HLB value of the mixture is suitably between the straight mentioned values.

The surfactant must of course be one which is physiologically acceptable, i.e. not itself physiologically unacceptable side effects at the doses used in the species to be treated (humans or animals).

Surfactants which can be used in the present invention are, for example, those which among the following nonionic surfactants and classes of surfactants can be found:

Polyoxyethylated derivatives of fatty (C ₁₂ -C ₂₀ ) glyceride oils, for example castor oil, which contains 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 to 18 carbon atoms).

Polyoxyethylene-polyoacypropylene ethers, which range from 5 to 150 resp. contain from 15 to 50 oxyethylene or oxypropylene groups. Polyoxyethylene ethers (containing from 6 to 12 oxyethylene groups) of alkylphenols, the alkyl groups preferably containing 6 to 10 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. C10-16) alkanoyl mono- and dialkanolamides (where the alkanol parts are, for example, 1 to

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5 carbon atoms), for example lauroyl mono- and diethanolamides. Polyethylene glycol esters (those from 6 to 40 ethylene oxide units) of long-chain fatty acids (which contain, for example, 12 to 18 carbon atoms), for example polyethylene glycol monooleate (which contains, for example, 8 ethylene oxide units).

Other valuable surface-active agents are, for example, phospholipids such as lecithins, for example egg or soybean lecithins.

Examples of nonionic surfactants of the the aforementioned types useful in the present invention are, for example:

Cremophor EL, a polyoxyethylated castor oil containing approximately 40 ethylene oxide units per triglyceride unit;

Tween 80, polyoxyethylene sorbitan monoolelate, which is approximately Contains 20 ethylene oxide units;

Tween 60, polyoxyethylene sorbitan monostearate, which contains approximately 20 ethylene oxide units;

Tween 40, polyoxyethylene sorbitan monopalmitate, which contains approximately 20 ethylene oxide units.

The term "solutions" as used herein means liquids that have the appearance of true solutions and which are thus optically clear and are able to pass through a microporous filter, for example, independently on whether such solutions are true solutions in the classical chemical sense, and regardless of whether they are are stable or metastable. The steroid can thus be associated with micelles. The solutions according to the invention behave as true solutions in practical intravenous regardless of their true physical nature Injection.

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The proportion of surfactant in the inventive Compositions used depends on their type and on the desired concentration of the steroid in the finished composition. In preferred compositions according to the invention, the proportion of surface-active Medium preferably at least 5% by weight and advantageously above 10% by weight. It was found that a A very suitable level of surfactant is 20% by weight, but 30 and up to 50% by weight can be used. the Surfactant proportions are expressed by weight based on the total volume of the composition.

In one method of preparing solutions containing a surfactant, the steroid is first dissolved in the selected surfactant, such as by heating, and then the resulting solution is dissolved in water. Alternatively, the steroid can be in a volatile organic solvent, advantageously with a boiling point that is less than about 80 ⁰ C, which is miscible with the surfactant, such as in a volatile lower aliphatic ketone, for example acetone or methyl ethyl ketone, or a volatile one halogenated hydrocarbon, for example chloroform or methylene chloride, are dissolved. The surfactant is then added to this solution, the organic solvent is removed by evaporation, for example by passing a stream of inert gas, e.g. nitrogen, through the solution, and the resulting steroid solution in the surfactant is then mixed with water.

The solutions can also be prepared by mixing the steroid with an aqueous solution of the surfactant Means shakes.

In all cases, simple tests enable a determination to be made which relative proportions of surfactant required-

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are. It is clear that the proportion of steroid which is dissolved in the aqueous medium in the present invention, on the water solubility of the steroid and, if available, the nature and amount of surfactant used Means depends. The composition will generally contain at least 1 mg / ml steroid, but solutions can be used produce that contain, for example, up to 300 mg / ml steroid or even up to 400 mg / ml. The more concentrated Solutions can generally only be made with water-soluble steroids, but solutions of the same concentration can also be made in cases where the use of a surfactant Means is required. Surprisingly, it has been found in particular that solutions can be prepared which contain up to 30 mg / ml of water-insoluble compounds when the compounds contain both 21-azide and 11-oxo groups contain.

The anesthetic solutions of the invention are generally administered by intravenous injection, although in some specific cases, as is known in the anesthetic field, for example in young children, intramuscular Injections may be preferred.

As is common in the anesthetic field, the amount of steroid used to induce anesthesia depends on on the weight of the individual to be anesthetized. It is generally used intravenously When administered to an average person, a dose of 0.1 to 30 (e.g. 0.2 to 30) mg / kg is satisfactory be to induce the anesthesia. The preferred dose is in the range of 0.5 to 20 mg / kg. The dose is in to some extent depending on the physical condition of the patient and the required degree and the required Dependent on the time of anesthesia, all of this is well known in the anesthetic field. By adjusting the dose, it is possible

3 0 9 8 A 7/1 1 3 2

Achieve periods of anesthesia that vary from approximately 10 minutes to 1 hour or longer. Should one If longer anesthesia is maintained, repeated doses of the solutions according to the invention can be used, whereby these repeat doses are generally of the same order of magnitude or lower than the original Dose. Alternatively, continuous administration, for example at rates of 0.025 to 2.0 (e.g. 0.09 to 1.4) mg / kg / min.

When the anesthetic solutions are administered intramuscularly, higher doses are generally required.

Making the connections

The compounds according to the invention can generally by nucleophilic replacement of an easily eliminable substituent in the 21-position of the corresponding steroid, whereby the desired 21-substituent is introduced will.

The 21-substituted steroid used as starting material is preferably the corresponding 21-bromo steroid, but other compounds can be used, for example the corresponding 21-chloro, 21-iodine or 21-sulfonyloxy (for example Methanesulfonyloxy) compound.

In the preparation of the 21-cyano compounds, the corresponding 21-bromine compound with a source of cyanide ions, for example a salt of hydrogen cyanide with an organic one or inorganic base, preferably an alkali metal cyanide such as sodium or potassium cyanide. Preferred the cyanide is present in excess. The reaction can be carried out in any suitable inert solvent (e.g. an alkanol such as ethanol or methanol, a ketone such as acetone or methyl ethyl ketone, nitrile solvents such as acetonitrile or amide solvents such as dimethylformamide or dimethyl acetamide, often preferably in the presence of water),

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be performed. The implementation can be at any suitable Temperature can be carried out up to the reflux temperature. The first reaction product is usually a Salt of the desired nitrile with cations from the cyanide reactant and this is in the reaction mixture easily soluble and thus difficult to isolate. It is therefore preferred to add acid and the product than to isolate the desired non-ionic nitrile.

In the preparation of the 21-amino compounds, the corresponding 21-bromo steroid with an amine, for example an amine in which the amine nitrogen atom is a member of a 3- to 8-membered ring is, as described above, or

12 12

has the formula HNR R wherein R and R are as given above Have definitions, are implemented. Preferably the amine is present in excess and, in fact, it can act as a reaction solvent be used. The. Alternatively, reaction can take place in a suitable inert solvent (e.g. a cyclic ether such as tetrahydrofuran or dioxane, a ketone such as acetone or cyclohexanone, an amide such as Dimethylformamide or dirnethylacetamide, or an alcohol such as ethanol or methanol) at a suitable temperature up to the reflux temperature - be carried out. The implementation can if desired in a nitrogen atmosphere or in the presence an agent that binds acid such as calcium oxide, carbonate or bicarbonate.

In the preparation of the 21-azido compounds, this can occur. Speaking 21-bromine steroid with a source of azide ions, for example an alkali metal azide such as sodium or Lithium azide. The implementation is preferred in a polar solvent medium (for example, a cyclic ether such as dioxane or tetrahydrofuran, a Amide or alcohol solvents as indicated above, or dimethyl sulfoxide, with or without a solvent for the steroid such as a halogenated hydrocarbon such as chloroform) at a suitable temperature up to the return

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carried out at the river temperature.

In these reactions, as indicated above, the compounds used as starting material can be used instead of the bromine atom contain other eliminable 21-substituents.

The 21-substituted compounds used as starting materials in the preparation of the compounds of the present invention can be easily prepared from known compounds by known methods. A 21-bromine compound can be prepared, for example, by bromination of the corresponding 21-unsubstituted compound, for example with molecular bromine in a solvent such as methanol or ethanol. The reaction is preferably carried out at a temperature of -10 to +30 ⁰ C. If desired, the reaction can be carried out in the presence of a catalyst such as hydrogen bromide (in acetic acid) or acetyl chloride.

In the preparation according to the invention of compounds which optionally have substituents or a carbon-carbon double bond contained as described above, it is appropriate that this substituent or the unsaturation in the 21-substituted starting material is present. Alternatively, these substituents or the unsaturation can subsequently by well-known methods using known compounds as starting materials. Im The following are some methods given to convert the desired substituents or unsaturation into a 3-oxygenated-20-oxopregnane to introduce. Some of these procedures are new.

The substitution in the 2β-position can take place, for example, via the corresponding 2cc, 3cc-epoxy compound. The epoxy compound itself can be prepared by first dehydrating a 3-hydroxy compound, using the corresponding ^ Compound is obtained (for example by first tosylating the hydroxyl group and then de-

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tpsylated). Then the Δ, compound can be treated with a peracid to form the 2 oc, 3 ct epoxy hydration.

A 2ß-substituent can then according to the Belgian Patent 775,239 described methods are introduced. This general procedure can be used to to introduce all of the 2β-substituents described above.

Method to replace substituents in the 2a, 3β, 11- and 16-positions are to be introduced in Belgian patents 776 786 (part 13) and 774 988 (part 6) of the same applicant described. These or analogous methods can be used for all of the substituents described above to be introduced at these positions. For example, an 11-alkenyl or 16-alkyl group can be introduced by methods are analogous to those described in Belgian patent 776 786 for the introduction of an 11-allyl or 16-methyl substituents are described.

5a steroids containing A 1 unsaturation can also be prepared by known methods. However, it is preferred to use a method in which a 2β-bromo-3cc-hydroxypregnane is converted into the corresponding 2β, 21-dibromo compound. If desired, the 3cc-hydroxy group can be protected (for example as tetrahydropyranyl ether). Dehydrobromination gives the A compound and then, if necessary, the protective group is split off, giving the desired 1,2-dehydro-3ct-hydroxy-20-oxo-21-bromine compound.

The dehydrobromination or elimination of bromine can be carried out, for example, by using a Lewis base, the nitrogen contains like a di-lower-alkyl-lower-acylamide, for example dimethylformamide or dimethylacetamide, preferably in the presence of an alkali metal or alkaline earth metal carbonate, for example calcium carbonate.

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It has been found that it is convenient, in general, up to 170 ⁰ C to carry out the removal of bromine at elevated temperatures, for example at the 80th Lower temperatures can be used when a lithium or calcium halide is present.

Compounds containing Δ, unsaturation can be prepared from A- steroids by methods which are analogous

1 2

as they are described for the production of the £ -compounds from / \ _ -steroids. Alternatively, the A steroids can be obtained by methods such as those described in Belgian patent 774,988 owned by the same applicant.

Compounds containing a double bond between the 8- and 9-positions and an 11-oxo group can, for example by processes as described in Belgian patent specification 776 786 by the same applicant will. These compounds can also by dehydrating the corresponding 9oc-hydroxy compound, for example using thionyl chloride in pyridine.

The 5 <x steroids according to the invention can be obtained from the corresponding 3-oxo compounds by stereospecific reduction, for example according to the method of Browne and Kirk (J. Chem. Soc. C, 1969, I653) or according to the method of the German

Patent specification (patent application P 22 55 108.2

according to British application no. 52465/71, A I4,) will. In the latter process, a pre-formed iridium catalyst reduction system is preferably used. For example, a reduction system composed of an iridic acid or a salt (for example chloride of iridium (IV) acid), a trivalent phosphorus compound such as a phosphorous acid ester, for example trimethyl phosphite, Water and an organic reaction medium (for example an alcohol v / ie isopropanol) are produced. The reduction system is then with an organic base v / ie with a secondary or tertiary amine (for example triethyl

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amine) neutralized (for example to a pH of 6 to 8.5) and then reacted with the steroid while heating the catalyst system at reflux temperature If preformed 16 to 72 hours, the reduction can be finished in 2 to 3 hours at reflux temperature. at Longer times may be required at room temperature.

5ß-steroids can be produced similarly by hydride reduction of 3-0xosteroids getting produced.

In the preparative procedures described above, it may be desirable to protect a 3a-hydroxy or 20-oxo group during the reaction. The protective group is then split off and the hydroxy or oxy group is regenerated. A 3cc-hydroxy group can be protected, for example, in the form of a nitrate ester or a tetrahydropyranyl ether. A 20-oxo group can be protected as a ketal v / ground and, for example, by hydrolysis in the presence of an acid (for example hydrochloric acid or acetic acid), at a temperature of 0 to 100 ⁰ C are regenerated.

The following examples illustrate the invention without restricting it.

All temperatures are in ⁰ C. The ultraviolet spectra (UV spectra) were determined in ethanol. Optical rotations were determined in chloroform at an approximate concentration of 1% w / v unless otherwise specified. "Petrol" refers to a petroleum ether having a boiling point of 60 to 80 ⁰ C. The preparative thin layer chromatography (prep TLC) was performed on silica gel.

Three general methods, Method A, 'B and C, were used in the present invention to identify a number of cyano, azido and to make amino compounds. These were the following procedures:

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Procedure A Production of 21-cyano-3fl-hydroxypregnan-20-ones

The corresponding 21-bromo-3a-hydroxypregnan-20-one is in Ethanol treated with potassium cyanide and water. The solution is refluxed for 30 minutes, cooled and treated with 2N HCl and extracted into ethyl acetate. The organic layer is washed with water, dried (NapSO ^,) and evaporated. The residue is purified by preparative thin-layer chromatography and / or crystallization purified to obtain the desired product.

Procedure B Preparation of 21-azido-3a-hydroxypregnan-20-ones

A solution of the corresponding 21-bromo-3a-hydroxypregnan-20-one in methanol is added to a solution of lithium azide in methanol. The mixture is refluxed for 2 hours heated and then distributed between water and ether. The organic layer is washed with water, dried (NapSO,) and evaporated. The residue is processed by preparative Purified thin layer chromatography and / or crystallization to give the desired product.

Procedure C

Production of 21-amino-3a-hydroxypre, q; nan-20-ones

A solution of a mixture of the corresponding 21-bromo-3cchydroxypregnan-20-one and amine in dry tetrahydrofuran is heated to reflux. The resulting solution is between Water and ether distributed. The organic layer is washed with water, dried and evaporated. The residue is subjected to preparative thin layer chromatography to give the desired product.

Method A was used to make the following compounds:

3 0 9 3 A 7/1 1 3 2

example

No connection

1 21 -Cyano- ^ a-hydroxy ^ a-pregnan-i 1 »20-dione

2 21 -Cyano-2β-ethoxy-3cc-hydroxy-5oc-pregnane-11,20-dione

3 21 -Cyano-3a-hydroxy-5β-pregnane-11,20-dione

4 21-cyano-3a-hydroxy-5a-pregnan-20-one

5 21-Cyano ^ a-hydroxy ^ ß-methoxy ^ a-pregnan-i 1,20-dione

6 21 -Cyano ^ oc-hydroxy ^ ß-isopropoxy-Scc-pregnan-i 1120-dione

7 21-cyano-3a-hydroxy-2β-n-propoxy-5 "-pregnane-11,20-dione

8 21-cyano-3oc-hydroxy-16a-raethyl-5oc-pregnane-11,20-dione

9 21-cyano-3a-hydroxy-5a-pregn-1-ene-11,20-dione

10 21 -Cyano-3oc-hydroxy-2β-methyl-5cc-pregnane-11,20-dione

Details of the procedures used in these examples and some properties of the compounds are set out in US Pat Table I below.

The column with the heading "Conc." in Table I (and in
Tables II and III below) indicates the concentration (% w / v) at which the optical rotations are determined
became. The following abbreviations have been used in Tables I to III:

EA = ethyl acetate CH = cyclohexane

MA = methyl acetate P = petroleum ether

B = benzene THF = tetrahydrofuran

A = acetone

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Table I 21-cyano compounds, prepared according to method A

Example weight d. Weight d. Vol.v. Vol.v. Eluting crystalline no. 21-bromo-KCN (rag) EtOH (ml.) HpO (ml) solution solution (mg) averaging with.

Aus Fp

prey

(mg)

⁰ C

1 1.0 G 325 60 2 2.0 G 650 120 3 1.0 G 325 60 4th 1.0 G 325 60 5 436 130 22nd 6th 430 130 22nd 7th 1.1 5 g 325 60 8 (1) 1.0 G 330 60 9 300 97.5 20th 10 (2) 240 100 40

5
10

EA / CHC1 ₃ 1: 1 B / CH

EA / P A / P 1: 1 and 2: 1

1.5

EA / P, 1: 1 EA / P, 1: 1 EA / P, 2: 1 EA / CHC1 ₃ , 1: 1 EA / CHC1 ₃ , 1: 1 EA / P, 1: 1

A / P

A / P

A / P 158 600

300 600 250 100 300 480 100 150

158 184

+96 +103

218 +101 209-211 +116

210 174 219

+109

+94

+74

+96

+58

+110

Conc.

Remarks:

1. The resulting solution, after being refluxed, was not treated with 2N

2. The solution was refluxed for 1 hour.

1.0 0.9

1.1 0.5 1.2 1.0 1.0

1, -0 0.6 1.0

Treated HCl

Method B was used to make the following compounds:

Example No. link

11 21-Azido-3oc-hydroxy-3ß-ynethyl-5a-pregnane-11,20-dione

12 21-Azido-3a-hydroxy-16a-methyl-5a-pregnane-11,20-dione

13 21-Azido-3a-hydroxy-5a-pregn-1-ene-11,20-dione

14 21-azido-3a-hydroxy-5cx-pregnane-11,20-dione

15 21-azido-2β-ethoxy-3cc-hydroxy-5cc-pregnane-11,20-dione

16 21 -azido-3a-hydroxy-5β-pregnane-11,20-dione

17 21-azido-3a-hydroxy-5a-pregnan-20-one

18 21-Azido-3a-hydroxy-2ß-methoxy-5a-pregnan-20-one

19 21 -Azido ^ a-hydroxy-ig-nor ^ a-pregnan-ii, 20-dione

20 21-Azido-3a-hydroxy-2ß-methyl-5a-pregnane-11,20-dione.

Details of the procedures used in these examples and some of the properties of the compounds are listed in Table II below.

Π Q π ' ^r - / 1 1 "i

Weight 21-
Bromverb.
(mg) G Vol.v.
MeOH
(ml) Table II . Vol.v.
MeOH
(ml) . Eluting crystallization
solvent solvent
middle A / P the end
prey
(mg) 1 Fp.
⁰ C +141 Conc. ro 700 G 20th produced according to method B 100 CHCl ₃ "MA / P EA / CHC1 ₃ , 1: 1 MA / P 400 195 1 176 +98 0.8 I. 750 G 20th Weight v,
(mgj 100 B / EA, 2.5: 1 CHCl ₃ A / P (twice) 200 52 - +81 0.9 300 G 8th 250 40 B / EA, 2.5: 1 EA / P, 1: 1 100 - +106 0.4 21-azido compounds, 750 20 ¹ ' 250 100 EA / P, 1: 2 550 - +94.8 1.0 E.g.
No. 1.0 30 ¹ 125 150 EA / P, 1: 1 330 - +120.8 1.0 11 (2) 1.0 250 150 EA / P, 1: 1 575 - +126 1.0 12 (2) 1.0 325 150 400 150 __ 1.0 13th 1.0 - 325 150 62-164 +219 _ 14th 794 30 ¹ 325 100 42-144 +110 1.2 15th 200
5) - 130 100 - 0.4 16 (3) 260 17 (3) 75 18 (2) 19 (4) 20th
(2.3,

Remarks:

1. The methanol was replaced with chloroform.

2. After heating at reflux for _t the solution was evaporated to low volume, partitioned between water and ether.

3 x The mixture was refluxed for 11/2 hours.

4. Ethyl acetate was used as the extraction solvent.

5. The mixture was refluxed for 3 hours.

before You

GJ

cm CJ

Method C was used to prepare the following compounds _s:

No connection

21 3 "-Hydroxy-21-morpholino-Sβ-pregnan-i1,20-dione

22 3a-Hydroxy-3ß-methyl-21-morpholino ^ a-pregnan-i1,20-dione

23 3 "-Hydroxy-21-morpholino-19-nor-5a-pregnane-11,20-dione

24 3a-Hydroxy-16a-methyl-21-morpholino-Sa-pregnan-i 1,20-dione

25 3α-Hydroxy-21-morpholino-5α-pregn-1-ene-11,20-dione

26 3a-Hydroxy-21-thiamorpholino-5a-pregnane-11,20-dione

27 3 "-Hydroxy-21 -thiamorpholino-19-nor-5oc-pregnane-11,20-dione

28 3a-Hydroxy-21- (2 ^! -Methylmorpholino) -5a-pregnane-11,20-dione

29 3a-Hydroxy-2ß-methoxy-21-morpholino-5cx-pregnan-20-one

30 3a-Hydroxy-21- (3'-pyrrolin-1 ^! -Yl) -5 "-pregnan-11,20-dione

31 3cc-Hydroxy-21-pyrrolidino-5oc-pregnane-11,20-dione

32 3a-Hydroxy-21-piperidino-5cc-pregnane-11,20-dione

33 2β-Ethoxy-3cc-hydroxy-21 -rao rpho lino-5 "-pregnan-11,20-dione

34 3oc-Hydroxy-2β-raethyl-21-morpholino-Scc-pregnan-i 1,20-dione

35 3 "-Hydroxy-21-thiazolidino-5a-pregnane-11,20-dione.

Details of the procedures used in these examples and some properties of the compounds are given in US Pat listed below in Table III.

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O ID CO

Weight d. 21- Vol. Tabel according to procedure C (ml) III (mg) [cc] _n Conc. reaction time I. Bromverb. d. Vol. Ν 25th (Hours.) ν η (mg) Amine THF 40 . Elution yield 355 I. 21-amino compounds 1.0 g (ml) '" mg 20 solvent 400 +76.7 1.0 2 E.g. 700 4.5 42 310 +71 1.1 4th No. 2) 794 4th 40 EA / A 1: 1 600 +137 1.1 1.25 1.0 g 870 mg 40 EA 400 +65 1.1 4th 21 (1) 800 4.5 mg 40 EA 560 +43 1.3 4th 22nd 3) 1.0 g 4th 40 EA 391 +74 1.3 2/3 23 (1, 800 720 25th EA 900 +120 1.75 2 NJ 24 1.6 g 400 30 ⁶ EA / P 1: 1 800 +75 1.4 2 CJ 25th 1.0 g 0.7 30th EA / P 1: 1 +74 1.0 4th NJ 26 (2, 1.0 g 4th 30th CHC1 ₃ / EA 1: 2 500 +82 1.4 2 NJ 27 (4) 750 0.5 60 ⁶ ' ⁷ EA 500 +77 1.3 3 CJJ 28 (5) 750 1.5 40 EA / CHC1, 1: 1 500 +82 1.0 3 CO 29 2.0 g 1.5 40 ⁶ 169 +71 0.7 16 NJ 30th 2) 240 4th - 170 +99 0.9 1 31 (8) 1.0 g 0.2 EA / CHCWA 1: 1: 1 +67 0.42 1.5 32 0.5 EA 33 EA / P 1: 1 34 (1, 35 (2)

Notes for Table III

1. The reaction mixture was _{treated with 5% NaHCO 3} before extraction.

2. Ethyl acetate replaced ether as extraction solvent,

3. The ethyl acetate extract was washed with 5% NaHCCU.

4. After refluxing for 2 hours, an additional 0.1 ml of the thiamorpholine was added and the reaction was continued for another hour.

5. After refluxing, the reaction solution became left overnight at room temperature.

6. THF was replaced with acetone.

7. The reaction was carried out at room temperature.

8. The product was made by recrystallization Acetone / petroleum ether purified.

Example 36

21-cyano ^ ft-hydroxy-ga-pregnan-i1,20-dione-sodium salt

A solution of 21-cyano-3cc-hydroxy-5cc-pregnane-11,20-dione (80 mg, 0.222 mmol) in ethanol (4.4 ml) was mixed with 0.1N sodium hydroxide solution (2.22 ml, 0.222 mmol). The solvents then became under reduced pressure at room temperature slowly removed and water (8 ml) was added to give an aqueous solution of the title compound with a concentration of 10 mg ml based on the steroid (pH 11.7).

Example 37

21 -Cyano-2ß-ethoxy-3cx-hvdroxv-5cc-oregnan-11,20-dione-sodium salt

A solution of 21-cyano-2ß-ethoxy-3ct-hydroxy-5a-pregnane-11,20-dione (80 rag, 0.2 ml-Iol) in ethanol (4.4 ml) was mixed with 0.1N sodium hydroxide solution (2.0 ml, 0.2 mmol). The solution is slowly released under reduced pressure at room temperature evaporated to constant weight. The residue is in Sufficient water (8 ml) dissolved to, based on the steroid (pH 11.3), a concentration of the aqueous solution of 10 mg ml "

. 309847/1132

to obtain.

Example 38

^ oc-Hydroxy-21-morpholino- ^ oc-pregnan-i1,20-dione

A solution of 21-bromo-3a-hydroxy-5ct-pregnane-11,20-dione (1.6 g) in refluxing tetrahydrofuran (40 ml) was treated with morpholine (0.7 ml) for 3 hours. Treated under nitrogen and then poured into ether. The ethereal solution was washed successively with 5% aqueous sodium bicarbonate solution and water, over ITapSO. dried and evaporated. The residue was partitioned between a mixture of 2N hydrochloric acid (6 ml), water (200 ml), acetone (20 ml) and methylene chloride (120 ml). The aqueous phase was treated with 2N sodium hydroxide (6 ml) and sodium chloride (20 g) and the resulting mixture was extracted with methylene chloride. The extracts were washed with v / water, dried (ITapSO.) And evaporated to give the title compound (1.5 g) as a white foam, [Cc] ₃₃ + 81 ° (c 1.1).

' Example 39

2β-Ethoxy-3Q> hydroxy-21-morpholino-5tt-pregnan-11 «20-dione-citrate

A solution of 2β-ethoxy-3a-hydroxy-21-morpholino-5a-pregnane-11,20-dione (0.093 g, 0.2 mmol) in ethanol (1 ml) was mixed with 0.1 M citric acid solution (2 ml, 0.2 mmol) at room temperature treated. The clear solution was immediately evaporated to dryness at room temperature and poured into distilled water (approx. 5 ml) redissolved. The aqueous solution was stored at 0 ° overnight and then filtered. The solid became collected, washed with distilled water (approx. 1 ml) and the washing solutions and filtrates were combined. The residue was dissolved in chloroform and evaporated in vacuo to constant weight (0.0016 g). The filtrate and the wash water were made up to 9.14 ml with distilled water, a solution of the title compound (pH 3.59) having a concentration of 10 mg / ml based on the steroid.

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Example 4P

21 -Cyano-3tx-hydroxy-19-nor-5a-pregnan-11,20-dione

21-bromo-3a-hydroxy-19-nor-5a-pregnan-11,20-dione (794 mg) was added to a solution of potassium cyanide (300 mg) in ethanol (60 ml) and water (5 ml) and the mixture became Heated to reflux for 1.5 hours. 2N sulfuric acid (5 ml) was added and the suspension was poured into water. The product was extracted with ethyl acetate and the combined extracts were washed with water, dried (MgSO,) and evaporated to give a yellow foam, purification by preparative thin layer chromatography (CHCl ^ / Et OAc 3: 1) gave the ingredient as the most was polar, a yellow foam (400 mg).

Further purification by preparative thin-layer chromatography (CHCl,) gave the title compound (310 mg) as the most polar compound as a colorless foam, [aJ _D +178 (£ 0.9).

Example 41

3oc-Hydroxy-21- (cis- and trans-2 ¹ , 6'-dimethylmorpholino) -5oc pregnane-11,20-dione

21-Bromo-3a-hydroxy-5 "-pregnane-11,20-dione (1 g) was dissolved in dry tetrahydrofuran (50 ml) and cis / trans-2,6-dimethylmorpholine (1 ml) was added to the solution . The mixture was refluxed for 4 hours. The mixture was poured into water, the emulsion was extracted into ether and the combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to give a pale yellow foam (1.07 g) which was purified by preparative thin layer chromatography in ethyl acetate . The faster running band (R _f ^ 0.6) gave the 3a-hydroxy-21 - (trans-2 ¹ , 6'-dimethylmorpholino) -5a-pregnane-11,20-dione (150 mg, 14%) as a colorless foam , [a] _D + 70.5 ° (c 0.42).

309847/1 132

A slower moving band (R-0.2-0.4) was isolated in two parts; products were obtained which were spectroscopically identical. The first foams were recrystallized from ethyl acetate / petroleum ether, giving the 3cc-hydroxy-21- (cis-2 ^l , 6 ^l -dimethylmorpholino) -5cc-pregnane-11,20-dione (500 mg) as almost colorless needles, M.p. 134 ° (dec.), [A] _D + 73.5 ° (c 1.06).

Example 42

3a-Hydroxy-21-morpholino ^ a-pregnan-i1,20-dione hydrochloride

A solution of 3a-hydroxy-21-morpholino-5a-pregnane-11,20-dione (104.14 mg, 0.25 mmol) in ethanol (4 ml) was mixed with 0.1N Hydrochloric acid (2.5 ml, 0.25 mmol). the Solution was evaporated in vacuo and then treated with v / water (5 ml). The undissolved solid (8.4 mg) was through Filtration was removed and the filtrate was made up to 9.6 ml with distilled water, using a 1–6% aqueous Solution of the title compound was obtained.

Example 43

3 <x -hydroxy-21-morpholino ^ ft-pregnan-i 1,20-dione-mesylate

A solution of 3oc-hydroxy-21-morpholino-5cc-pregnane-11,20-dione (167 mg, 0.4 mmol) in ethanol (2 ml) became more aqueous with 0.204N Methanesulfonic acid solution (3.92 ml, 0.8 mmol). The resulting solution was evaporated in vacuo and then treated with v / water (5 ml). The undissolved solid (14.7 mg) was removed by filtration and the filtrate was made up to 15.23 ml with distilled Y / water, whereby a 1 / o aqueous solution of the title compound was obtained.

Example 44

2ß-ethoxy-3a-hydroxy-21-morpholino-Soc-pregnan-i 1,20-dione dihydr oprenoho sphat -

2β-ethoxy-3cc-hydroxy-21-morpholino-5oc-pregnane-11,20-dione (231.2 mg, 0.5 mmol) in ethanol (3 ml) was treated with 0.095M v / ßri-

309847/1132,

ger o-phosphoric acid (5.3 ml, 1 eq.) Treated and the resulting Solution was evaporated in vacuo. The residue was dissolved in water (5 ml) and brought to a total solution weight of 23.12 g made up, whereby a 10% aqueous solution of the Title compound received.

Example 45

3a-Hydroxy-21-thiamorpholino-19-nor-5 "-pregnane-11,20-dione citrate

3a-Hydroxy-21 -thiamorpholino-19-nor-5 <x-pregnan-11,20-dione (83.922 mg, 0.2 mmol) was dissolved in ethanol (2 ml) and a solution of citric acid (2 ml; 0 , 1M 10.507 g / 500 ml; 0.2 mmol) was added. The solution was evaporated to dryness, dissolved in water (5 ml) and filtered. Insoluble material weighed 7 mg. The filtrate, which was clear as water, contained the steroid base (76.9 mg). The volume was adjusted to 7.69 ml, whereby a solution of the title compound (10 mg / ml wrt steroid base) was obtained, the pH of the solution was 3.2.

Example 46

2ß-Ethoxy-3tt-hydroxy-21 ~ morpholino-5g-pregnan-11 «20-dione-acetate

A solution of 2β-ethoxy-3oc-hydroxy-21-morpholino-5a-pregnane-11,20-dione (116 mg, 0.25 mmol) in ethanol (2 ml) was treated with 0.1N aqueous acetic acid (2.5 ml, 0.25 mmol). The resulting solution was evaporated in vacuo. The residue was treated with v / water (ca 1 ml) and the undissolved solid (66 mg) was removed by filtration. The filtrate was diluted to 5 ml with distilled water to give a volume aqueous solution of the title compound.

Example 47

3a-Hydroxy-2-morpholinoT) reffn-4-ene-11,20-dione

21 -Brom ^ a-hydroxypregn ^ -en-H, 20-dione (150 mg) in tetra-

309847/1132

hydrofuran (5 ml) was treated with morpholine (0.1 ml) and the stirred mixture was refluxed under nitrogen for 2 hours. During this time a colorless precipitate formed. The mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with more methylene chloride and the combined organic extracts washed with water, dried over sodium sulfate and evaporated to give a foam (152 mg) which was purified by preparative thin layer chromatography in acetone / petroleum ether 1/1. The main band Rf 0.3 to 0.45 was separated and the title compound (99 mg) was obtained as a colorless foam, [α] _β + 174 °, (c 0.12).

Example 48

3a-Hydroxy-21-morpholino.-5oc-pregnane-11,20-dione-citrate

A solution of 3a-hydroxy-21-morpholino-5cc-pregnane-11,20-dione (83.52 mg, 0.2 mmol) in absolute ethanol (1 ml) treated with 0.1M aqueous citric acid (2 ml, 0.2 mmol). The ethanol was removed by evaporation and the resulting Solution was freeze dried. Water (5 ml) was added and the cloudy solution that was obtained became at 2 hours Stored at room temperature. The solution was filtered through a No. sintered filter. The flask was filled with water (0.5 ml) rinsed and this was also filtered. The filter and the flask were washed with chloroform (10 ml). That Chloroform was washed with saturated sodium bicarbonate solution (2x5 ml) and with water (3x5 ml) and evaporated, whereby a residue was obtained, which by azeotropic distillation with benzene (6 χ 10 ml) and in vacuo (20.6 mg) was dried. The filtrate was diluted with water (1 ml) to give the title compound as 10 mg / ml aqueous Solution based on the steroid received. The pH of the solution was 3.45.

3 0 9 8 Λ 7/1 1 32

Example 49

2ß-Ethoxy-3ct-hydroxy-21-morpholino- ^ a-pregnan-i 1,20-dione ascorbate

A solution of 2β-ethoxy-3a-hydroxy-21-morpholino-5oc-pregnane-11,20-dione (116 mg, 0.25 mmol) in ethanol (2 ml) was treated with a 0.1N aqueous solution of ascorbic acid (2.5 ml, 0.25 mmol) and the resulting solution was evaporated in vacuo. The residue was dissolved in water (approx. 5 ml) and clarified by filtration. The filtrate was made up to 11.6 ml diluted with distilled water, a 1 ^ strength aqueous solution of the title compound being obtained.

Example 50

3ct-Hydroxy-21-morpholino-5 "-pregnan-11" 20-dione

A solution of 21-morpholino-5a-pregnane-3,11,20-trione (100 mg) in "stick" chloriridium (IV) solution- (see Preparation Method 6 below) (10 ml) was added for 14 hours on Heated to reflux. The cooled mixture was poured into water and just made alkaline. The slightly oily precipitate was extracted into ethyl acetate and the extracts were washed with water, dried (Na ₂ SO ^) and evaporated, essentially giving the title compound, as determined by NMR spectroscopy and thin layer chromatography (Rf 0.16) on silica in ethyl acetate and which was identical to the product of Example 38.

Example 51 3cc-Hydroxy-21-morpholino-5cc-pregnan- "1-1,20-dione

21-chloro-Sa-pregnan ^, 11,20-trione (200 mg) in dry tetrahydrofuran (4 ml) was treated with morpholine (0.20 ml). The solution is refluxed for 2 1/2 hours and then at room temperature left for 3 days. The solution is diluted with water and extracted with chloroform. the organic solution is washed with water, dried over sodium sulfate and evaporated to give a colorless

309847/1132

Foam (210 mg) is obtained, which is purified by preparative thin-layer chromatography in ethyl acetate, 21-morpholino-5a-pregnane-3,11,20-trione (88 mg) being obtained as a colorless foam, [a] _D + 99 ° (£ 0.59). Treatment of this product in a manner similar to that described in Example 50 gives the title compound.

Example 52

2ß-ethoxy-3a-hydroxy-21-morpholino- ^ oc-pregnan-i 1,20-dione citrate (partly saline)

A solution of 2β-ethoxy-3a-hydroxy-21-morpholino-5a-pregnane-11,20-dione (0.93 g) in ethanol (1 ml) is treated with 0.1M citric acid solution (20 ml) at room temperature. The solution is evaporated to dryness and redissolved in distilled water (5 ml). The resulting solution is filtered and the The collected residue is washed with water (1 ml). The piltrate and the washing solutions are washed with distilled water made up to 9/2 ml, a solution of 2ß-ethoxy-3ahydroxy-21-morpholino-5a-pregnane-11,20-dione citrate in a concentration of 100 mg / ml, based on the steroid (pH 3.5).

A further amount of 2β-ethoxy-3ahydroxy-21-morpholino-5oc-pregnane-11,20-dione is added to this solution (0.93 g) and the solution is clarified by filtration to give the title solution (pH 3.9).

Example 53

3oc-Hydroxy-21-morpholino-Sa-pregnan-i 1.20-dione-citrate

3a-Hydroxy-21-morpholino-5cc-pregnan-11,20-dione (500 mg) in Ethanol (60 ml) is treated with n / 10 aqueous citric acid (12 ml) and the mixture is evaporated to dryness. Of the The residue is dried to constant weight in vacuo and the resulting solid is dissolved in water (30 ml). The solution is filtered and the solid is collected

309847/1132

and discarded. Water is added to the piltrate until a concentration of 10 mg / ml on the steroid is obtained will. The pH of the solution is 3.4. 2N aqueous sodium hydroxide solution is added dropwise until a pH value of 4.7 is achieved.

Formulations Example A

0.139 g of 3a-hydroxy-21-azido-5cc-pregnane-11,20-dione dissolved in 2 ml of acetone at 20 ° C. The resulting solution is added to 1 g of Cremophor EL at 20 ^° C. and stirred until it is homogeneous. The acetone is removed by a strong stream of nitrogen. The solution is diluted with sterile, distilled water containing 0.025 g of sodium chloride to make a final volume of 5 ml.

Example B.

0.025 g 2ß-ethoxy-3a-hydroxy-21-azido-5a-pregnan-11,20-dione are dissolved in 2 ml acetone at 20 ⁰ C. The resulting solution is added to 1 g of Cremophor EL at 20 ^° C. and stirred until it is homogeneous. The acetone is removed by a strong stream of nitrogen. The solution is diluted with sterile, distilled water containing 0.15 g of sodium chloride, a final volume of 5 ml.

Example C

0.009 g of 3a-hydroxy-21-azido-5a-pregnan-20-one are dissolved in 2 ml acetone at 20 ⁰ C. The resulting solution is added to 2 g of Cremophor EL at 20 ^° C. and stirred until it is homogeneous. The acetone is removed by a strong stream of nitrogen. The solution is diluted with sterile, distilled water containing 0.05 g of sodium chloride to give a final volume of 10 ml.

309847/1132

Manufacturing process 1

21 -Bromo-5g-hydroxy - 5β-pre & nan-11,20-dione

A stirred solution of 3oc-hydroxy-5β-pregnan ~ 11,20-dione (10 g) in dry methanol (700 ml) is made up at 0 ° with a solution of bromine (1.9 ml) in methanol (45 ml) treated in such a way that the yellow color disappears before further addition. The solution is then partitioned between water and chloroform. The organic layer is washed with water, dried (NapSOi) and evaporated. Chromatography of the residue (with benzene / ethyl acetate, 2.5: 1) gives the title compound as a colorless foam (7.2 g), [a] _D + 100 ° (c_ 1.1).

Preparation process 2 21-Bromo-3a-hydroxy-19-nor-5a-preffnan-11 «20-dione

A solution of 3cc-hydroxy ~ 19-nor-5oc-pregnan-11,20-dione (5.0 g) in dry methanol (300 ml) is added at 0 to 5 ° during the dropwise addition of bromine (0.82 ml) in methanol (20 ml) touched. After 1 hour the conversion was extremely low (indicated by the disappearance of the bromine discoloration before the further addition). The external cooling was stopped and

I drop of hydrobromic acid was added. Another encore of bromine gave a rapid discoloration and implementation was finished in another 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, washed with water, dried (HgSO ^) and evaporated, whereby one colorless foam was obtained (6.2 g). Isolation of the main band after preparative thin-layer chromatography (EtOAc) gave 90% pure title compound (5.2 g).

Manufacturing process ^ I1 oc-Hvdroxv-19-norpreg; na-4.16-dien-3.20-dione

A solution of a mixture of 11a-17a-dihydroxy-19-norpren-4-en-3,20-dione (4 g) and semicarbazide hydrochloride (4 g) in methanol (200 ml) was refluxed for 2 hours. That Methanol was then removed by distillation under reduced pressure

309847/1132

removed and water was added to the residue. The deposited precipitate was separated off by filtration, washed with water and _{dried over Ρ 2} ^ 5 ^ ^m vacuum. A solution of this solid in a mixture of glacial acetic acid (80 ml), water (28 ml) and pyruvic acid (4 ml) was heated on a steam bath for 1 hour. The resulting solution was concentrated under reduced pressure and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with water, dried (Na ₂ SCh) and evaporated to dryness. The residue was subjected to preparative thin-layer chromatography (CHCl, / (CH *) ₂ CO; 15: 1) and crystallized from acetone / petroleum ether, the title compound (1.6 g) being obtained as colorless needles, melting point 149 °.

Manufacturing process 4

19-nor-5cc-pregna-3,11,20-trione over 3? ", Hoc, 20 j-trihydroxy- 19-nor-5a-pregnan

A solution of 11a-hydroxy-19-nor-pregna-4, i6-diene-3,20-dione (2.5 g) in dry tetrahydrofuran (200 ml) was converted into a solution of lithium (5 g) given in liquid ammonia (2.5 l). The solution was then left to stand for 30 minutes. Ethanol (approx. 100 ml) was added to it until the blue color disappeared and the ammonia was allowed to evaporate. The residue was partitioned between water and ether. The organic layer was washed, dried (Na ₂ SO 4) and evaporated to give the crude title compound (1 »5 g).

Manufacturing process 5

19-nor-5a-pregnan-3111.20-trion

A solution of raw 3 £, 11 α, 20 ^ -
Pregnane (4 g) in acetone (280 ml) was treated with a solution of potassium dichromate (8.0 g) in 2N sulfuric acid (38 ml) at room temperature for 1 hour. Another amount of '

309847/1132

Potassium dichromate (8 g) in 2N sulfuric acid (38 ml) was then added and then the reaction mixture was allowed to stand at room temperature for 15 minutes. The solution was then partitioned between water and ether and the organic layer was washed with water, dried (NapSO ^) and evaporated. The remaining oil was subjected to preparative thin layer chromatography (CHCl-,) and recrystallized from acetone / petroleum ether to give the title compound (1.04 g) as colorless prisms, m.p. 151 °, [a] _D + 240 °.

Manufacturing process 6

3a-Hydroxy-19-nor-5 "-pregnane-11,20-dione

A solution of 19-nor-5 "-pregnan-3,11,20-trione (0.9 g) in ^M Stock" chloriridium (IV) solution (prepared by adding a mixture of 0.09 g of chloriridium ( IV) acid, 200 ml of 90% isopropyl alcohol and 16 ml of trimethyl phosphite for 16 hours. The solution was then neutralized with triethylamine immediately before use) (75 ml) was refluxed for 24 hours. The solution was then cooled between Water and ether partitioned and the organic layer washed well with water, dried (Na ₂ SO 4) and evaporated The residue was subjected to preparative thin layer chromatography (EtOH) and recrystallized from acetone to give the title compound (0.6 g) as colorless needles obtained, melting point 154 °, [a] _D + 200 °.

Manufacturing process 7 21-bromo-3g-hydroxy-3ß-methyl-5oc-prep; nan-11,20-dione

A stirred solution of 3cc-hydroxy-3ß-methyl-5a-pregnane-11,20-dione (17) (5.0 g, 15.0 mmol) in methanol (300 ml) was mixed with a solution of bromine (1.0 ml) in methanol (30 ml) at 0 ° in treated at such a rate that the yellow color of the solution disappeared before the addition of more bromine solution took place. The mixture was then poured into water, the precipitated title compound (2.8 g) was collected by filtration

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collected and dried over Pp ^ 5 * - ^m vacuum.

Preparation Method 8 21-Bromo-ga-hydroxy-2ß-methoxy-5a-pregnan-20-one

A stirred solution of 3tt-Hydroxy-2ß-methoxy-5 "-pregnan-20-one (4.0 g) in dry methanol (300 ml) was mixed with a solution of bromine (0.65 ml) in methanol (15 ml) at 0 ° with such Speed treated so that the yellow color disappeared before another addition was made. The mixture was then poured into water and the precipitated pesticide was collected by filtration, washed with water and dried in vacuo, whereby the title compound (4.0 g) was obtained as colorless crystals.

Manufacturing process 9

21 -Bromo-3 a-hydroxy ^ ß-methyl-5 "-pregnane-11.20-dione

A solution of 3'-hydroxy-2ß-methyl-5a-pregnane-11,20-dione (1.04 g) in dry methanol (150 ml) was stirred at 0 to 5 ° while a solution of bromine ( 0.16 ml) in dry methanol (20 ml) over 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water, dried (MgSO.) And evaporated to give a colorless foam. Purification by preparative thin-layer chromatography (ethyl acetate: benzene 1: 2.5) gave the title compound (510 mg), melting point 140 ° (dec.), [A] _D + 133 ° (c 0.95).

Manufacturing process 10

21-Bromo-2β-ethoxy-3a-bydroxy-5 "-pregnane-11.20-dione

Bromine (0.53 g) in methanol (1.45 ml) was added dropwise to a stirred solution of 3a-hydroxy-2ß-ethoxy-5a-pregnane-11,20-dione (2.0 g) in methanol (15 ml) containing a trace of acetyl chloride. contained, added at 0 °. The addition was made during 2 hours and the clear solution was then in water

309847/1 1 32

poured and collected by filtration, washed with water and dried in vacuo to give the title compound. -

Manufacturing process 11

21 -Bromo-3cx-hydroxy-2β-n -propoxv-5o: -pregnan-11,20-dione

A solution of 3ct-hydroxy-2ß-n-propoxy-5oc-pregnane-11,20-dione (2.0 g) in methanol (15 ml) was added dropwise over 2 hours with a solution of bromine in methanol (2.5 ml of a solution, containing 0.314 g / ml bromine) treated. The resulting solution was then poured into water and the precipitated one Solid was collected by filtration, washed with water and dried in vacuo to give the title compound received.

Manufacturing process 12 21-bromo-5a-pregnane-3 »11 _t 20-trione

21-Bromo-3a-hydroxy-5a-pregnane-11,20-dione (412 mg) in acetone (20 ml) was stirred with the dropwise addition of Jones reagent (0.4 ml) at room temperature. After 10 minutes the reaction mixture was poured into water / water, extracted with chloroform and the combined chloroform extracts were washed with water / water, dried (MgSO ^) and evaporated. The residue was recrystallized from ether / petroleum ether, giving the title compound (350 mg) as colorless microcrystals, melting point 170 ° _D + 132 ° (61.1).

Jones reagent is a solution of chromium trioxide (267 g) in a mixture of concentrated sulfuric acid (230 ml) and water (400 ml), made up to 1 l with water (8n w.r.t. Oxygen). "Stock" -Chloriridium (IV) solution was prepared, by adding a mixture of chloriridium (IV) acid (0.09 g), 90% isopropanol (200 ml) and trimethyl phosphite (16 ml) refluxed for 16 hours. The solution was neutralized with triethylamine immediately before use.

309847/1132

Manufacturing process 13

21 -Morpholine- ^ g-preffnan-3111 »20-trion

A solution of 21-bromo-5cc-pregnane-3,11,20-trione (500 mg) in dry tetrahydrofuran was treated at reflux temperature with morpholine (0.5 ml) for half an hour and then poured into water. The oily precipitate was extracted into ether and the extracts were washed with water, dried (Na ₂ SO,) and evaporated, whereby a. The crude product was obtained which was purified by preparative thin-layer chromatography in ethyl acetate and crystallization from ether to give the title compound (220 mg), melting point 159 to 164 °, [ct] _D + 98 ° (c = 1.1? I).

Manufacturing process 14

21-bromo-ga-hydroxy- ^ a-pregn-i-en-11,20-dione

A stirred solution of 2β-bromo-3oc-hydroxy-5a-pregnane-11,20-dione (5.0 g) in methanol (100 ml) was mixed at 0 ° with a solution of bromine (1 ml) in methanol (30 ml) at such a rate that the yellow color disappeared before further addition of bromine solution was made. The mixture was then poured into water and the precipitated solid was collected by filtration, washed with water and _{dried over P 2} O ₅ in vacuo. The resulting solid (5.0 g) was purified by column chromatography (silica, EtOAc / CgHg 1: 2.5), whereby the crude 2β, 21-dibromo-3a-hydroxy-5oc-pregnane-11,20-dione ( 3.4 g).

A solution of the crude 2β, 21-dibromosteroid (2.0 g) - in benzene (100 ml) was treated with dihydropyran (2 ml) and p-toluenesulfonic acid (40 mg) for 20 minutes. The reaction mixture was then washed sequentially with dilute aqueous sodium bicarbonate and water, dried (Na ₂ SO,) and evaporated. The residue was subjected to preparative thin layer chromatography (CHCl,) to give crude 2β-21-dibromo-3a-tetrahydropyranoxy-5oc-pregnane-11,20-dione as a colorless foam.

309847/1132

A mixture of this product (0.7 g), Dirnethylacetainid (20 ml), Lithiunibromid (2.6 g) and calcium carbonate (4.0 g) was stirred at 100 ⁰ C for 2 hours. The calcium carbonate was then removed by filtration and the filtrate was partitioned between ether and water. The organic layer was washed with water, dried (Na ₂ SO ^) and evaporated.

A solution of the residue (0.5 g) in ethanol (5 ml) was stirred at room temperature with 2N hydrochloric acid (0.5 ml) for 2 hours. The mixture was then partitioned between aqueous sodium bicarbonate and ether. The organic layer was washed with water, dried (Na ₂ SOi) and evaporated. The residue was subjected to preparative thin layer chromatography (EtOAc / CHCl ^, 1: 2), whereby the title compound (0.15 g) was obtained as a colorless foam, [a] _β + 85 ° (c 0.8).

Manufacturing process 15

N- (2'-hydroxy-2'-phenylethyl) -ethanolamine .

Styrene oxide (1.2 g), ethanolamine (0.6 g) and water / water (0.05 g) were heated at 70 ° with stirring for 2 ½ hours. the The mixture was cooled, evacuated and the oil formed was triturated with ether to give the title compound (550 mg) obtained, m.p. 93.5-95 °.

Manufacturing process 16 2-phenylr morpholine

N- (2 ¹ -hydroxy-2'-phenylethyl) ethanolamine (5.3 g) was dissolved in 6N hydrochloric acid (100 ml) and the solution was heated at 110 for 4 hours. Sodium hydroxide solution was then added to the mixture until it was basic and extracted into ether. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give a crude sample of the title compound (1 g) as an orange colored oil.

3098A7 / 1132

Production process 17 4β, 21-dibromo-3 "-hydroxv-5oi: -pregnan-11 _t 20-dione

4β-Bromo-3a-hydroxy-5cc-pregnane-11,20-dione (945 mg) in dry methanol (70 ml) at 0 ° was mixed with a solution of bromine (0.125 ml) in methanol (5 ml) dropwise over the course from . Treated for 7 hours at such a rate that the bromine color disappeared during the addition. The reaction solution was then stirred at room temperature for 30 minutes until it became colorless, and was then diluted with water (300 ml). The colorless precipitate was extracted into methylene chloride. The organic solution was washed with water, dried over sodium sulfate and evaporated to a colorless foam (1.2 g) which was purified by preparative thin layer chromatography in ethyl acetate / benzene. 1/3 of the upper (main) band gave 660 mg of a colorless solid, which was triturated with ether, whereby the title compound (580 mg) was obtained as colorless crystals, bp 164 to 166 °, [a] _D + 76 ° ( c. 1 »35).

Method of manufacture 18 21-Bromo-3 ^ -hydro.xypre / yn-4-en-11 _t 20-dione

4β, 21-dibromo-3cc-hydroxy-5a-pregnane-11,20-dione (200 mg) in dry dimethylacetamide (10 ml) was treated with calofort U (1.5 g) and lithium bromide (0.9 g). The mixture was stirred at 85 for 3 1/2 hours. The reaction mixture was filtered and the solid residue was washed with ether and ethyl acetate. The combined filtrates and washing water were washed well with water (5 times), dried over sodium sulfate and evaporated to give a brown oil which was purified by preparative thin layer chromatography in ethyl acetate / petroleum ether 1/1. The main band gave the title compound (70 mg) as a colorless foam [ocJ _D + 140 °.

The manufacture of the other intermediates involved in the manufacturing process are required, are in the examples of DT-OS 2 162 594 and in BE-PS 775 239 of the same Israel-

309847/1132

described in it.

Manufacturing process 19

21-Hydroxv-ga-pregnan-g * 11120-trion

21-acetoxy-5 "-pregnane-3,11,20-trione (4.85 g) in hot Methanol (200 ml) is mixed with potassium bicarbonate solution (10%, 20 ml) and the stirred solution is refluxed under nitrogen for 15 minutes. The cooled reaction mixture is diluted with water, the oily precipitate is extracted into methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated to a foam (4.3 g) which is triturated with ether, whereby one the title compound (3.07 g) is obtained as colorless crystals, melting point 164 ° to 170 °.

Manufacturing process 20

21 -Chlor-5cc-pregnane-3,11,20-trione

21-Hydroxy-5a-pregnane-3,11,20-trione (3.0 g) in anhydrous pyridine (15 ml) is treated with toluene-4-sulfonyl chloride (3.0 g) and the pale orange solution is kept at room temperature during Stirred for 3 hours. The cold solution is stirred vigorously during the slow addition of ice-cold water (200 ml) and hydrochloric acid (2N, 50 ml). The yellow crystalline precipitate is filtered off, washed well with water and dried in vacuo at 60 °. The resulting crude product (2.4 g) is recrystallized from acetone / petroleum ether, the crude title compound (1.13 g) being obtained as an almost colorless crystalline solid, melting point 168 ° to 172 °, [a] _D + 137 ° (c 1.13).

309847/1 13

Claims (34)

Claims ,1. Pregnan or 19-norpregnan pure steroids, i a 3oc-hydroxy group, a 17a-hydrogen atom, a. 20-oxo group and in the 21-position a cyano, azido or contain basic amino group, and their salts. 2. Steroids according to claim 1, which have a 5cc hydrogen atom contain. 3. Steroids according to claim 1 or 2, which have a 11-oxo group contain. 4. Steroids according to one of the preceding claims, which have a I6a-methyl group and / or a double bond in 1 L of the Δ or Δ. group included. 1 4
the Δ or Δ position or a 2β-alkyl or alkoxy 5. Steroids according to any one of the preceding claims, in which the group present in the 21-position is a basic amino group, where the amino nitrogen atom is a member of a 3- to 8-membered ring. 6. Steroids according to claim 5, wherein the ring contains 5 or 6 members. 7. Steroids according to claim 5 or 6, in which the Ring is saturated. 8. Steroids according to one of claims 5 to 7 _f, in which the ring contains 2 heteroatoms, v / obei the second heteroatom is an oxygen or sulfur atom. 9. Steroids according to claim 5, in which the basic amino group is a morpholino or thiamorpholino group. 309847/1132 10. ■ steroids according to any one of claims 5 to 9, "in which the ring contains one or more alkyl substituents. 11. Steroids according to claim 5, in which the basic amino group is a thiazolidino group. 12. Steroids according to one of the preceding claims, which contain a basic nitrogen atom, wherein the steroids in the form of their hydrochlorides, hydrobromides, phosphates, sulfates, p-toluenesulfonates, methanesulfonates, citrates, tartrates, acetates, Ascorbates, lactates, maleates or succinates are present, or which contain a 21-cyano group and where the steroids are in the form of salts with bases. 13. 21-cyano-3a-hydroxy-5cc-pregnane-11,20-dione and the sodium salt; 21 -Cyano-2ß-ethoxy-3oc-hydroxy-5a-pregnane-11,20-dione and the sodium salt; 21-cyano-2β-methoxy-3cc-hydroxy-5apregnan-11,20-dione; 21-cyano-2β-isopropoxy-3a-hydroxy-5apregnane-11,20-dione; 21-cyano-3'-hydroxy-16a-methyl-5a-pregnane-11,20-dione; 3cc-Hydroxy-21-morpholino-Soc-pregnan-i 1,20-dione and the citrate, mesylate and hydrochloride; 2β-ethoxy-3-hydroxy-21-morpholino-5 "-pregnan-11,20-dione and the citrate, phosphate, acetate and ascorbate; 3a-hydroxy-16oc-methyl-21-morpholino-5a-pregnan-11,20-dione; 3cc-hydroxy-21 - (2'-methylmorpholino) -5cc-pregnane-11,20-dione; 3a-Hydroxy-21- (cis ~ 2 ^!, 6 ¹ -dimethylKiorpholino) -5oc-pregnane-11,20-dione; 3cc-hydroxy-21-thiamorpholino-5ct-pregnan-11,20-dione; 3oc-hydroxy-21-thiamorpholino-19-nor-5tt-pregnan-11,20-dione and the citrate; 21-azido-3ahydroxy-5a-pregnane-11,20-dione; 21-A? .Ido-2ß-ethoxy-3o: -hydroxy-5a-pregnane-11,20-dione; 21-azido-3oc-hydroxy-5β-pregnane-11,20-dione; 21-azido-3cc-hydroxy-5a-pregnan-20-one; 21-azido-3ahydroxy-16a-methyl-5oc-pregnan-11,20-dione; 21-azido-3a-hydroxy-2ß-methoxy-5a-pregnan-20-one; 21-azido-3a-hydroxy-19-nor-5apregnan-11,20-dione and 21-azido-3a-hydroxy-5a-pregn-1-en- 11,20-dione. 309847/113 2 14. 21-cyano-3cc-hydroxy-2β-methyl-5cc-pregnane-11,20-dione; 3a-hydroxy-21-thiazolidino-5oc-pregnane-11,20-dione; and 21-azido-3a-hydroxy-2ß-methyl-5cc-pregnane-11,20-dione. 15. Steroids according to claim 1, prepared as described in one of Examples 1 to 9, 11 to 19, 21 to 33 and 36 to 49. 16. Steroids according to claim 1, prepared according to Examples 10, 20, 34, 35 and 50. 17. A pharmaceutical composition containing a steroid according to claim 1 together with a pharmaceutical Carrier or diluent. 18. Anesthetic composition for parenteral administration, containing an anesthetic steroid according to Claim 1 in a parenterally acceptable carrier. 19. Composition according to claim 17 or 18, containing a parenterally acceptable, nonionic surfactant. 20. The composition according to any one of claims 17 to 19, containing a steroid according to claim 1, which is a basic Has amino group, the steroid being solubilized by the presence of an acid addition salt thereof. 21. Pharmaceutical composition prepared according to Examples A to C. 22. A method for producing a steroid according to claim 1, characterized in that in the 21-position of the corresponding Steroid replaces an easily eliminable substituent nucleophilically, with the desired 21-substituent is introduced. 309847/1132 -47-? 32? 532 23. The method according to claim 22, characterized in that the corresponding steroid is a 21-bromine or chlorine compound used. 24. The method according to claims 22 or 23, characterized in that the corresponding steroid with a Source of cyanide ions is converted, wherein a 21-cyano group is introduced. 25. The method according to claim 24, characterized in that the source of cyanide ions is an alkali metal cyanide used. 26. The method according to claim 22 or 23, characterized in that the corresponding steroid is reacted with an amine where the basic 21-amino group is introduced. 27. The method according to claim 26, characterized in that the reaction is carried out in the presence of an agent that binds acid. 28. The method according to claim 22 or 23, characterized in that the corresponding steroid with a source of Azide ions is reacted, whereby a 21-azido group is introduced. 29. The method according to claim 28, characterized in that an alkali metal azide is used as the source for azide ions . 30. A method for producing a steroid according to claim 1, characterized in that a corresponding 3-oxo compound is reduced stereospecifically. 31. The method according to claim 30 for producing a A steroid containing a 5oc hydrogen atom, characterized in that that the reduction with a catalyst reduction 309847/1 132 system that contains iridium; is carried out" 32. A method for producing a steroid according to claim 1, carried out as in Examples 1 to 9, 11 to 19 »21 to 33 and 36 to 49 are described. 33. A method for producing a steroid according to claim 1, as described in Examples 10, 20, 34, 35 and 50. 34. Steroid, produced by a method according to one of claims 22 to 33. calibrated .. "Long walk" n am 309847/1132