CH617710A5 - Process for the preparation of steroids of the pregnane or 19-norpregnane series with anaesthetic activity - Google Patents

Description

617 710

2nd

PATENT CLAIMS 1. Process for the production of anesthetically active steroids of the Pregnan or 19-Norpregnan series of the formula 1

CH "-CN

I 2

CO

R1 represents a hydrogen atom or a methyl group;

R2 has a hydrogen atom or an alkoxy group

1 to 6 carbon atoms, an alkanoyloxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 5 carbon atoms, a thiocyanyt group or a halogen atom;

R3 represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms;

R4 represents a hydrogen atom or a methyl group;

R5 represents a hydrogen atom or a methyl group in the a or β position; and

R6 is an oxo group or two hydrogen atoms;

wherein these steriodes in the 1,2- and or 4,5-position can have a double bond, characterized in that a corresponding steroid, which has an easily removable residue in the 21-position and its oxy group in the 3cx position and / or oxo group is optionally protected in the 20 position, reacted with a compound releasing cyanide ions and, if appropriate, subsequently splitting off the protective group in the 3a and / or 20 position.

2. The method according to claim 1, characterized in that one starts from a 21-bromo or 21-chlorine compound.

3. The method according to claim 1 or 2, characterized in that an alkali metal cyanide is used as the cyanide ion-donating compound.

4. Process for the preparation of salts of compounds of the formula 1, characterized in that compounds of the formula 1 are prepared by the process of claim 1 and treated with a base.

5. Process for the preparation of anesthetically active steroids of the Pregnan or 19-Norpregnan series of the Formet

CH.-N,

I 2 3

CO

in which mean:

R1 represents a hydrogen atom or a methyl group;

R2 represents a hydrogen atom or an alkoxy group having 1 to 6 carbon atoms, an alkanoyloxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 5 carbon atoms, a thiocyanate group or a halogen atom;

R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

R4 represents a hydrogen atom or a methyl group; , "R5 represents a hydrogen atom or a methyl group in the a or β position; and

R6 is an oxo group or two hydrogen atoms;

these steroids in the 1,2- and / or 4,5-position can have a double bond, characterized in that 15 a corresponding steroid, which has an easily removable residue in the 21-position and its oxy group in the Sa position and / or the oxo group in the 20-position is optionally protected, reacted with a compound releasing azide ions and, if appropriate, subsequently splitting off the protective group in the 2o 3a and / or 20-position.

6. The method according to claim 5, characterized in that one starts from a 21-bromo or 21-chloro compound.

7. The method according to claim 5 or 6, characterized

25 characterized in that an alkali metal azide is used as the compound which donates azide ions.

8. Process for the preparation of anesthetically active steroids of the Pregnan or 19-Norpregnan series of the Formet

CO

in which mean:

R1 represents a hydrogen atom or a methyl group;

R2 represents a hydrogen atom or an alkoxy group with 1 to 6 5, i carbon atoms, an alkanoyloxy group with 1 to 6 carbon atoms, an alkyl group with 1 to 5 carbon atoms, a thiocyanate group or a halogen atom;

R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

55 R4 represents a hydrogen atom or a methyl group;

R5 represents a hydrogen atom or a methyl group in the a or β position;

R6 is an oxo group or two hydrogen atoms; and R7 is an amino group in which the nitrogen atom is member 60 of a 3 to 8 atom ring;

these steroids in the 1,2- and / or 4,5-position can have a double bond, characterized in that a corresponding steroid which has an easily cleavable residue in the 21-position and its oxy group in the 3a-position 65 and / or the oxo group in the 20-position is optionally protected, reacted with an appropriate amine and, if appropriate, subsequently the protective group is split off in the 3a and / or 20-position.

40

3rd

617 710

9. The method according to claim 8, characterized in that one starts from a 21-bromine or 21-chlorine compound.

10 The method according to claim 8 or 9, characterized mei 1, that one produces compounds in which R7 represents an amino group in which the nitrogen atom is a member of a corresponding saturated ring containing nitrogen or sulfur as the second heteroatom.

11. The method according to claim 10, characterized in that compounds are prepared in which R7 is a morpholino or thiamorpholino group.

12. The method according to claim 10, characterized in that compounds are prepared in which R7 is a thiazolidino group.

13. The method according to claim 8 or 9, characterized in that compounds are prepared in which R7 is a corresponding cyclic amino group substituted by one or more alkyl radicals.

14. A process for the preparation of salts of compounds of formula 1, characterized in that compounds of formula 3 are prepared by the process of claim 8 and treated with an acid.

15. The method according to claim 14, characterized in that hydrochlorides, hydrobromides, phosphates, sulfates, p-toluenesulfonates, methanesulfonates, citrates, tratrates, acetates, ascorbates, lactates, maleates or succinates of compounds of formula 3 are prepared.

It has long been known that a number of steroids have severe central nervous system depression and pharmacodynamically act as anesthetics or hypnotics. Such compounds have been the subject of much research to find anesthetics to replace compounds such as thiopentone sodium, which is commonly used but is well known to have some disadvantages. The literature shows that many steroid compounds with this aim have been investigated. Summaries and discussions of some of the work carried out can be found, for example, in “Methods in Hormone Research” (edited by Ralph I. Dorfman, Volume III Part A, Academic Press, London and New York, 1964, pages 415-475); H. Witzel, Z. Vitamin hormone fermentation research. 1959, 10.46-74; H. Selye, Endocrinology, 1942,30,437-453; S.K. Figdor et al., J. Pharmacol Exptl.

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

A thorough review of the literature shows that many anesthetic steroids require poor activity and / or long induction times. A variety of undesirable side effects such as paraesthesia and venous damage are also observed.

It has now been found that a new group of steroids, namely steroids of the Pregnan or 19-Norpregnan series of the formulas 1, 2 and 3, in which the radicals R1 to R7 have the meanings given in patent claims 1,5 and 8, respectively , are anesthetically effective.

The compounds mentioned may contain substituents at other positions in the steroid nucleus, for example in the 2, 3β, 11 or 16 positions. They can also be unsaturated, for example in the A1 or off positions. If a hydrogen atom is present in the 5-position, it can be in either the a or the β configuration, preferably it is in the a configuration.

In general, the compounds mentioned are good anesthetics and generally have short induction times. At suitable doses, the anesthetic effect is generally instantaneous. These compounds are thus excellent anesthetics to induce anesthesia, which can be maintained, for example, by an inhalation anesthetic such as ether, halo-5 than, laughing gas or trichlorethylene. However, the compounds are also capable of maintaining anesthesia and analgesia to a sufficient extent that various surgical operations can be carried out without the use of inhalation anesthetics, the level of anesthesia required being maintained, if necessary, by repeated administrations or even by continuous administration. The anesthetics mentioned generally show minimal side effects compared to many of the steroid anesthetics previously described. The basic amino group present in the compounds of formula 3 is preferably a member of a 5- or 6-membered ring. The rings can also contain one or more further heteroatoms, such as nitrogen, oxygen or sulfur. In addition, these rings can be substituted one or more times, the substituents being e.g. Oxo-alkyl (e.g. methyl), aralkyl, alkoxy, alkoxycarbonyl or acyloxy groups can be considered. Preference is given to rings which, in addition to the amino nitrogen atom, have a further hetero atom, an oxygen or sulfur atom. Saturated rings are generally preferred; Examples are morpholine, thiamorpholine and thiazolidine.

The latter rings, in particular the morpholine ring, can in turn be substituted, e.g. by one or more alkyl groups with 1 to 6 carbon atoms, e.g. Methyl, m wherein rings which are substituted in the 3-position, based on the nitrogen atom, are preferred.

Compounds of formula 3 which have a Morpholino group in the 21-position and an oxo group in the 11-position are particularly important.

35 Examples of R2 in the compounds of the formulas 1 to 3 are:

Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and tert-butoxy;

Acetoxy, propionyloxy and butyryloxy; and 4 (1 methyl, ethyl, propyl, butyl, isobutyl and tert-butyl.

Examples of R3 in the compounds of the formulas 1 to 3 are methyl or ethyl.

The substituent R6 in the 11-position is preferably an oxo group.

45 Certain of the compounds mentioned, for example those which contain a basic nitrogen atom, can form acid addition salts, which is advantageous since this 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 acid addition salts of compounds that. contain a basic nitrogen atom, can also solve a further 55 amounts of the free base. These solutions can be meaningful that they are less acidic than the solutions of the acid addition salts, and they can be prepared, for example, by adding the free base or another base to a solution of the acid addition salt. For example, 60 aqueous 3a-hydroxy-21-morpholino-5a-pregnan-11,20-dione citrate can have up to 2 or more equiv. the free base.

Compounds containing a 21-cyano group are capable of forming water soluble salts such as the alkali metal, e.g. 65 sodium, potassium or lithium and the ammonium (including the substituted ammonium) salts.

When used as anesthetics, these salts should be non-toxic, i.e. be physiologically acceptable in dose, in

617 710

4th

of which they are administered. However, other salts can be useful, for example, in isolating the product from the synthesis reaction

The following compounds are particularly preferred because of their excellent anesthetic properties:

1) 21-Cyano-3a-hydroxy-5a-pregnan-l 1,20-dione and the sodium salt

2) 21-Cyano-2ß-ethoxy-3a-hydroxy-5a-pregnan-l 1,20-dione and the sodium salt

3) 21-cyano-2β-methoxy-hydroxy-5a-pregnan-l 1.20-

dion

4) 21-Cyano-2ß-isopropoxy-3a-hydroxy-5a-pregnan-11,20-dione

5) 21-cyano-3a-hydroxy-16a-methyl-5a-pregnan-l 1.20-

dion

6) 3a-Hydroxy-21-morpholino-5a-pregnan-l 1,20-dione and the citrate, mesylate and hydrochloride

7) 2β-ethoxy-3a-hydroxy-21-morpholino-5a-pregnan-11,20-dione and the citrate, phosphate, acetate and ascorbate

8) 3a-Hydroxy-16a-methyl-21-morpholino-5 a-pregnan-11,20-dione

9) 3a-Hydroxy-21- (2'-methylmorpholino) -5a-pregnan-11,20-dione

10) 3a-Hydroxy-21- (cis-2 ', 6'-dimethylmorpholino) -5a-pregnan-11,20-dione

11) 3a-Hydroxy-21-thiamorpholino-5a-pregnan-l 1,20-dione

12) 3a-Hydroxy-21-thiamorpholino-19-nor-5a-pregnan-11,20-dione and the citrate

13) 21-Azido-3a-hydroxy-5a-pregnan-l 1,20-dione

14) 21-Azido-2ß-ethoxy-hydroxy-5a-pregnan-l 1,20-dione

15) 21-Azido-3a-hydroxy-5ß-pregnan-l 1,20-dione

16) 21-Azido-3a-hydroxy-5a-pregnan-20-one

17) 21-Azido-3 a-hydroxy-16a-methyl-5 a-pregnan-11,20-dione

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

19) 21-Azido-3a-hydroxy-19-nor-5 a-pregnan-11,20-dione

20) 21-Azido-3a-hydroxy-5 a-pregn-1-en-11,20-dione

21) 21-Cyano-3a-hydroxy-2ß-methyl-5a-pregnan-l 1,20-dione

22) 3a-Hydroxy-21-thiazolidino-5a-pregnan-l 1,20-dione and

23) 21-Azido-3 a-hydroxy-2ß-methyl-5a-pregnan-l 1,20-dione.

Particularly preferred compounds in the list above are the compounds 1,2,3,6,7, 8,9,10,11 and 12 and their salts, 13,14,16,18,20, 21 and 22.

Pharmaceutical formulations

The anesthetic compounds mentioned can be formulated as needed using generally known pharmaceutical methods (including methods in human and veterinary practice) using one or more pharmaceutical excipients or excipients. For anesthesia purposes, the steroid is administered by injection and the invention relates to anesthetic compositions for parenteral administration which contain one of the mentioned anesthetic compounds with a parenterally acceptable carrier. If the anesthetic compounds are sufficiently soluble in water (for example the salts, in particular the citrates mentioned above), they can be formulated in aqueous solutions (for example in isotonic sterile solutions). Many of the anesthetic steroids mentioned are poorly soluble in water. However, it has been found that they can be formulated for parenteral administration in aqueous solution of a parenterally acceptable, non-ionic surfactant.

These surfactants can also be used if the steroid is sufficiently water soluble as they can reduce the risk of thrombophlebitis.

The nonionic surfactants used in the present invention are generally those which are water soluble and which conveniently have an HLB of at least 9, preferably at least 12, advantageously at least about 13. Preferably, the HLB value of the surfactant m is no greater than about 18. A mixture of the surfactants can be used, in which case the HLB value of the mixture is suitably between the values just mentioned.

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

Surfactants that can be used in the present invention are, for example, those found among the following non-ionic surfactants and classes of surfactants:

Polyoxyethylated derivatives of fat (C12-C2o) glyceride oils, for example castor oil, which contains 35 to 60 oxyethylene groups per 25 moles of fat oil. Polyoxyethylene ethers (which contain from 10 to 30 oxyethylene groups) of long-chain alcohols (which contain, for example, from 12 to 18 carbon atoms).

Polyoxyethylene-polyoxypropylene ethers containing from 5 to 150 or from 15 to 50 oxyethylene or oxypropylene groups m. Polyoxyethylene ethers (containing 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 anis hydrides, e.g. Sorbitan or Mannitan.

Long-chain (for example C10-16) alkanoyl mono- and dialkanolamides (the alkanol parts containing, for example, 1 to 5 carbon atoms), for example lauroyl mono- and diethanolamides. Polyethylene glycol esters (which contain from 6 to 40 ethylene-4 (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 aforementioned types that are useful in the present invention include:

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

Tween 80, polyoxyethylene sorbitan monooleate, which contains about 20 ethylene oxide units;

Tween 60, polyoxyethylene sorbitan monopalmitate containing 55 approximately 20 ethylene oxide units;

Tween 40, polyoxyethylene sorbitan monopalmitate, containing about 20 ethylene oxide units.

The term "solutions" as used herein means liquids which have the appearance of true solutions and which are therefore optically clear and capable, for example, of passing through a microporous filter, regardless of whether such solutions are true solutions in classic chemical Are meaningful, and regardless of whether they are stable or h5 metastable. The steroid can thus be associated with micelles. The solutions according to the invention behave regardless of their true physical nature as true solutions in practical intravenous injection.

5

617 710

The level of surfactant used in the compositions mentioned depends on the type and the desired concentration of the steroid in the final composition. In preferred of the compositions mentioned, the proportion of surface-active agent is preferably at least 5% by weight and advantageously above 10% by weight. A very suitable level of surfactant has been found to be 20% by weight, but 30 and up to 50% by weight can be used. The proportions of surfactant are expressed by weight based on the total volume of the composition.

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

The solutions can also be prepared by shaking the steroid with an aqueous surfactant solution.

In all cases, simple tests allow determination of what relative levels of surfactant are required. It is clear that the amount of steroid dissolved in the aqueous medium in the present invention depends on the water solubility of the steroid and, if present, the nature and amount of the surfactant used. The composition will generally contain at least 1 g / ml steroid! but solutions can be prepared which 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 equal concentrations can also be made in cases where the use of a surfactant 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 if the compounds contain both 21-azide and 11-oxo groups.

The anesthetic solutions mentioned above are generally administered by intravenous injection, although in some specific cases, as is known in the anesthesia 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 the weight of the individual to be anesthetized. In general, a dose of 0.1 to 30 (e.g. 0.2 to 30) mg / kg will be satisfactory in intravenous administration to an average person to induce anesthesia. The preferred dose is in the range of 0.5 to 20 mg / kg. The dose will depend to some extent depending on the physical condition of the patient and the level and time of anesthesia required, all of which are well known in the anesthesia field. By adjusting the dose, it is possible to achieve anesthesia periods that vary from about 10 minutes to 1 hour or longer. If a longer anesthesia is to be maintained, repeated doses of the solutions mentioned above can be used, these repeated doses generally being of the same order of magnitude or less than the original dose. Alternatively, continuous administration can take place, for example at speeds of 0.025 to 2.0 (for example 0.09 to 1.4) mg / kg / min.

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

Establishing the connections

According to the invention, the compounds mentioned are produced in the manner described in the characterizing part of patent claims 1, 5 and 8, respectively.

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

In the preparation of the 21-cyano compounds, the corresponding 21-bromo compound can be reacted with a source of cyanide ions, for example a salt of hydrogen cyanide with an organic or inorganic base, preferably an alkali metal cyanide such as sodium or potassium cyanide. The cyanide is preferably 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 dimethylacetamide, often preferably in the presence of water). The reaction can be carried out at any suitable temperature 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 readily soluble in the reaction mixture and thus it is difficult to isolate it. It is therefore preferred to add acid and to isolate the product as the desired non-ionic nitrii.

In the preparation of the 21-amino compounds, the corresponding 21-bromsteroid can be reacted with an amine, for example an amine in which the amine nitrogen atom is a member of a 3 to 8-membered ring, as described above, or has the formula HNR'R2, in which R1 and R2 have the definitions given above, are implemented. The amine is preferably present in excess and can in fact be used as a reaction solvent. The reaction may alternatively be carried out 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 dimethylacetamide, or an alcohol such as ethanol or methanol) at a suitable temperature up to the reflux temperature . If desired, the reaction can be carried out in a nitrogen atmosphere or in the presence of an agent which binds acid, such as calcium oxide, carbonate or bicarbonate.

In the preparation of the 21-azido compounds, the corresponding 21-bromsteroid can be reacted with a source of azide ions, for example an alkali metal azide such as sodium or lithium azide. The reaction is preferably carried out in a polar solvent medium (e.g. a cyclic ether such as dioxane or tetrahydrofuran, an amide or alcohol solvent as indicated above, or dimethyl sulfoxide, with or without a solvent for the steroid such as a halogenated hydrocarbon such as

S

Jl)

15

2t)

25th

W

35

40

45

50

55

M)

<> 5

617 710 6

Chloroform) at a suitable temperature up to. It has been found that it is generally useful

Reflux temperature carried out. is the bromine elimination at elevated temperatures, for example

In these reactions, as indicated above, the manner can be carried out at 80 to 170 ° C. Lower temperature compounds used as the starting material instead of the ren can be used when a lithium or Cal bromine atom contains other eliminable 21 substituents. 5 cium halide is present.

The 21 -substituted compounds which contain the AMI saturation as starting material compounds can be prepared from materials in the preparation of the compounds according to the invention by A3 steroids by processes which are used in a similar manner to genes and can easily be obtained from known compounds as are used for the preparation of the A 'compounds can be prepared from A2 dung by known methods. A 21 steroids are described. Alternatively, the A4 steroid bromine compound can be obtained, for example, by brominating the mi by methods as described in the Belgian corresponding 21-unsubstituted compound, for example patent 774 988 by the same applicant, with molecular bromine in a solvent such as methanol.

or ethanol. The reaction is preceded by compounds that have a double bond between the 8-

trains carried out at a temperature of -10 to + 30 ° C. and contain 9 positions and an 11-oxo group, if desired, the reaction can be carried out in the presence of a 1 s, for example by methods as described in the Belgian patent catalyst such as hydrogen bromide (in acetic acid) or step 776 786 by the same applicant , her-tylchloride can be carried out. be put. These connections can also be made through

In the preparation of compounds according to the invention, dehydration of the corresponding 9a-hydroxy compound which may contain substituents or a carbon carbon, for example using thionyl chloride in pyridine or a double bond as described above, it is obtained 2.

expedient that this substituent or the unsaturation in The mentioned 5-a-steroids can be present from the corresponding to the 21-substituted starting material. Aging - the 3-oxo compounds by stereospecific reduction, natively these substituents or the unsaturation can, for example, according to the method of Browne and Kirk (J.

then by generally known methods under Chem. Soc. C., 1969, 1653) or by the method of using known compounds as starting materials 2s Swiss Patent No. 606 097 (Glaxo). The following are some procedures. In the latter method, a predetermined

specified to use the desired substituents or the unsaturated iridium catalyst reduction system. Introduce into a 3-oxygenated-20-Oxopregnan. For example, an iridic acid reduction system may be new to these processes. or a salt (e.g. chloro iridium (IV) acid), one

The substitution in the 2β position can be carried out, for example, via a trivalent phosphorus compound such as a phosphorus compound, the corresponding 2a, 3a epoxy compound. The ep acid esters, e.g. trimethyl phosphite, water and oxy compound itself can be made by dehydrating an organic reaction medium (e.g. first dehydrating a 3-hydroxy compound, making the alcohol such as isopropanol). The reduction-corresponding A2 compound is obtained (for example by first tosylating the system with an organic base such as with a hydroxyl group and then sylating the product with secondary or tertiary amine (for example triethylamine)). Then the A2 compound can be neutralized with a peracid (for example to a pH of 6 to 8.5)

treated, forming the 2a, 3a epoxy ring. and then implemented with the steroid. If the catalyst A-2ß substituent can then be introduced according to the procedure described in the Belgian stem by heating at reflux temperature for 16 to 775 239 hours, the reduction can be carried out in 2 to 3 den. This general procedure can be used to finish 40 hours at reflux. At Zimmertem-all 2ß-substituents described above to introduce. Temperature may need longer.

Processes to add substituents in the 2a-, 3ß-, 11- and 16- 5ß-steroids can be similarly reduced by hydride

Introducing positions are made in the Belgian patents 3-oxosteroids.

776 786 (part 13) and 774 988 (part 6) of the same application- In the reparative procedures described above-

described. These or analogous methods may be used, it may be desirable to use a 3a-hydroxy or 20-det to protect all of the above-described substituents on oxo group during the reaction. The protection-to introduce these positions. For example, an 11-SruPPe is then subsequently cleaved off and the hydroxy-alkenyl or 16-alkyl group is introduced by methods or the oxyogroup is regenerated. A 3a-hydroxy group similar to that in the Belgian patent can be protected, for example, in the form of a nitrate ester or a tetra-776 786 for the introduction of an 11-allyl or 16-methyl-5 (1 hydropyranyl ether 20-0xo group substituents can be protected as ketal and, for example, by

Hydrolysis in the presence of an acid (for example chloro-5a steroids which contain A'-unsaturation can also hydrochloric acid or acetic acid), at a temperature of 0 if prepared by known methods. It can be regenerated up to 100 ° C.

however preferred to use a method in which a 2β- 55 The following examples illustrate the invention without restricting it to bromo-3a-hydroxypregnan in the corresponding 2ß, 21-dibromo.

Connection is transferred. If desired, the 3a- All temperatures are given in 0 C. The ultraviolet

Hydroxy groups are protected (for example, as tetrahy spectra (UV spectra) were determined in ethanol. The dropyranyl ethers). Dehydrobromination gives the A'-optical rotations were in chloroform at an approximation and then the protective group is optionally split off, its concentration of 1% w / v, unless otherwise stated, taking into account the desired Give 1,2-dehydro-3a-hydroxy-20-, determined. "Petrol" means a petroleum ether with oxo-21-bromo compound. a boiling point of 60 to 80 ° C. The preparative thin

The dehydrobromination or bromine elimination can be carried out by layer chromatography (preparative t.l.c.) using silica gel, for example using a Lewis base.

Nitrogen contains like a di-lower-alkyl-lower-acylamide, <) 5 Three general processes, processes A, B and, for example, dimethylformamide or dimethylacetamide, c, were used according to the invention to obtain a number of cyano-,

preferably in the presence of an alkali metal or alkaline earth metal azido and amino compounds. These were the metal carbonates, for example calcium carbonate. following procedures:

7

617 710

Procedure A

Production of 21-cyano-3a-hydroxypregnan-20-ones

The corresponding 21-bromo-3a-hydroxypregnan-20-one is treated in ethanol with calcium cyanide and water. The solution is heated to reflux for 30 minutes, cooled, treated with 2N HCl and extracted into ethyl acetate. The organic layer is washed with water, dried (Na2S04) and evaporated. The residue is purified by preparative thin layer chromatography and / or crystallization, whereby the desired product is obtained.

Procedure B

Production of 21-azido-3a-hydroxypregnan-20-ones

A solution of the corresponding 21-bromo-3a-hydroxypre-gnan-20-one in methanol is added to a solution of lithium azide in methanol. The mixture is heated to reflux for 2 hours and then partitioned between water and ether. The organic layer is washed with water, dried (Na2S04) and evaporated. The residue is purified by preparative thin layer chromatography and / or crystallization, whereby the desired product is obtained.

Procedure C

Preparation of 21-amino-3o.-hydroxypregnan-20-ones

A solution of a mixture of the corresponding 21-bromo-3a-hydroxypregnan-20-one and amine in dry tetrahydrofuran is heated to reflux. The resulting solution is distributed between water and ether. 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 prepare the following compounds:

Table 1

21-cyano compounds prepared by Method A

Example No.

1

2nd

3rd

4th

5

9

10th

connection

21-Cyano-3a-hydroxy-5a-pregnan-11,20-dione 21-Cyano-2ß-ethoxy-3a-hydroxy-5a-pregnan-11,20-dione

21-cyano-3a-hydroxy-5ß-pregnan-11,20-dione 21-cyano-3a-hydroxy-5 a-pregnan-20-one 21-cyano-3a-hydroxy-2ß-methoxy-5 a-pregnan- 11.20-dione

21-cyano-3a-hydroxy-2ß-isopropoxy-5a-pregnan * 11,20-dione

21 -Cyano-3a-hydroxy-2ß-n-propoxy-5a-pregnan-11,20-dione

21 -Cyano-3a-hydroxy-16a-methyl-5a-pregnan-11,20-dione

21-cyano-3a-yhdroxy-5a-pregn-1-en-11.20-dione 21-cyano-3a-hacroxy-2ß-methyl-5a-pregnan-11.20-dione

: i] Details of the procedures used in these examples and some properties of the compounds are listed in Table I below.

The column with the heading "Conc." in Table I (and in Tables II and III below) indicates the concentration 25 (% w / v) at which the optical rotations were determined. The following abbreviations were used in Tables I to III:

EA = ethyl acetate

.io MA = methyl acetate

B = benzene

A = acetone

CH = cyclohexane

P = petroleum ether - ■

35 THF = tetrahydrofuran

example

Gew.d.

Gew.d.

Vol.v.

Vol.v.

Elution

Crystalline

Out

Mp

MD

Conc.

No.

21-bromine

KCN (mg)

EtOH (ml)

H20 (ml)

solution

station solution

prey

° C

verb. (mg)

average

(mg)

1

1.0 g

325

60

5

EA / CHC131: 1

B / CH

158

158

+96

1.9

2nd

2.0 g

650

120

10th

EA / P

A / P

600

184

+ 103

0.9

1: 1 u. 2: 1

3rd

1.0 g

325

60

5

A

300

218

+ 101

1.1

4th

1.0 g

325

60

5

A

600

209-211

+ 116

0.5

5

436

130

22

2nd

CAP, 1: 1

A / P

250

210

+ 109

1.2

6

430

130

22

2nd

EA / P, 1: 1

A / P

100

174

+94

1.0

7

1.15 g

325

60

5

EA / P, 2: 1

A / P

300

219

+ 74

1.0

8 (1)

1.0 g

330

60

5

EA / CHC13.1: 1

-

480

-

+96

1.0

9

300

97.5

20th

1.5

EA / CHCI3.1: 1

-

100

-

+58

0.6

10 (2)

240

100

40

2nd

EA / P, 1: 1

-

150

+ 110

1.0

Remarks:

1. The resulting solution, after being heated to reflux, was not treated with 2N HCl

2. The solution was heated to reflux for 1 hour.

Method B was used to make the following compounds:

Example No.

11

12

13

connection

21-Azido-3a-hydroxy-3ß-methyl-5 a-pregnan-11,20-dione

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

21-azido-3a-hydroxy-5a-pregn-l-en-ll, 20-dione

14 21-Azido-3a-hydroxy-5a-pregnan-l 1,20-dione

15 21 - Azido-2ß-ethoxy-3 a-hydroxy-5 a-pregnan-o 11.20-dione

16 21-azido-3 a-hydroxy-5β-pregnan-ll, 20-dione

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

18 21-Azido-3a-hydroxy-2ß-methoxy-5 a-pregnan-20-on s 19 21-Azido-3a-hydroxy-19-nor-5a-pregnan-ll, 20-

dion

20 21-azido-3a-hydroxy-2ß-methyl-5a-pregnan-

11.20-dione.

617 710

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

Tables

21 -azido compounds prepared by method B

example

Gew.d.

Vol.v.

Gew.v.

Vol.v.

Elution

Crystalline

Out

Mp

Md

Conc.

No.

21-bromine

MeOH

LiN3

MeOH

solution

station solution

prey

° C

verb.

(ml)

(mg)

(ml)

medium means

(mg)

(mg)

11 (2)

700

20th

250

100

CHCI3

MA / P

400

176

+ 141

0.8

12 (2)

750

20th

250

100

B / EA, 2.5: 1

-

200

-

+ 98

0.9

13

300

8th

125

40

B / EA, 2.5: 1

-

100

-

+ 81

0.4

14

750

201 '

250

100

EA / P, 1: 2

-

550

-

+ 106

1.0

15

1.0 g

30 '

325

150

EA / P, 1: 1

-

330

-

+ 94.8

1.0

16 (3)

1.0 g

301

325

150

EA / P, 1: 1

-

575

-

+ 120.8

1.0

17 (3)

1.0 g

301

325

150

-

A / P

400

150

+ 126

1.0

18 (2)

1.0 g

-

130

150

EA / CHCI3,

1: 1 MA / P

-

162-164

-

-

19 (4)

794

30 '

260

100

CHCI3

A / P (twice) 195

142-144

+219

1.2

20th

200

-

75

100

EA / P, 1: 1

-

52

-

+ 110

0.4

(2,3,5)

Remarks:

1. The methanol was replaced with chloroform.

2. After refluxing, the solution was evaporated to a small volume before being partitioned between water and ether.

3. The mixture was refluxed for 1½ hours.

4. Ethyl acetate was used as the extraction solvent.

5. The mixture was refluxed for 3 hours.

Method C was used to make the following compounds:

example

No connection

21 3a-Hydroxy-21-morpholino-5ß-pregnan-l 1,20-dione

22 3a-Hydroxy-3ß-methyl-21-morpholino-5 a-pregnan-11,20-dione

23 3a-Hydroxy-21-morpholion-19-nor-5a-pregnan-11,20-dione

24 3a-Hydroxy-16a-methyl-21-morpholino-5a-pre-gnan-11,20-dione

25 3a-Hydroxy-21-morpholino-5a-pregn-l-en-11,20-dione

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

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

28 3a-Hydroxy-21- (2'-methylmorpholino) - 5a-pre-gnan-11,20-dione

29 3a-hydroxy-2β-methoxy-21-morpholino-5a pre-gnan-20-one

30 3x-Hydroxy-21- (3'-pyrrolin-l'-yl) -5a-pregnan-11,20-dione

35 31 3a-hydroxy-21-pyrrolodino-5a-pregnan- 11.20-

dion

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

33 2ß-ethoxy-3a-hydroxy-21 - morpholino-5 a- pre-

40 gnan-11,20-dione

34 3a-Hydroxy-2ß-methyl-21-morpholino-5a-pregnan-11,20-dione

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

45

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

Table III

21-amino compounds according to method C

example

Gew.d. 21-

Vol.d.

Vol. V.

Elution

yield

[a] D

Conc.

React

No.

Bromine verb.

Amines

THF

solvent

(mg)

(Hours.)

(mg)

(ml)

(ml)

21 (1)

1.0 g

4.5

25th

EA / A 1: 1

355

+76.7

1.0

2nd

22

700

4th

40

EA

400

+71

1.1

4th

23 (1.2)

794

870 mg

20th

EA

310

+ 137

1.1

1.25

24th

1.0 g

4.5

42

EA

600

+65

1.1

4th

25th

800

4th

40

EA

400

+43

1.3

4th

26 (2.3)

1.0 g

720 mg

40

EA / P 1: 1

560

+74

1.3

2/3

27 (4)

800

400 mg

40

EA / P 1: 1

391

+ 120

1.75

2nd

28 (5)

1.6 g

0.7

40

CHCI3 / EA 1: 2

900

+75

1.4

2nd

9

617 710

Example Gew.d.21- Vol.d. Vol.v. Elution yield [a] D conc. Reaction time

No. bromverb. Amine THF solvent (mg) (h)

(mg) (ml) (ml)

29

1.0 g

4th

25th

EA

800

+74

1.0

4th

30th

1.0 g

0.5

306

EA / CHC13 1: 1

500

+ 82

1.4

2nd

31 (8)

750

1.5

30th

-

500

+ 77

1.3

3rd

32

750

1.5

30th

-

500

+ 82

1.0

3rd

33

2.0 g

4th

606-7

EA / CHC13 / A 1: 1: 1

169

+ 71

0.7

16

34 (1.2)

240

0.2

40

EA

170

+ 99

0.9

1

35 (2)

1.0 g

0.5

406

EA / P 1: 1

+67

0.42

1.5

Comments for Table III

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

2. Ethyl acetate replaced ether as an extraction solvent.

3. The ethyl acetate extract was washed with 5% NaHC03.

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

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

6. THF was replaced with acetone.

7. The reaction was carried out at room temperature.

8. The product was purified by recrystallization from acetone / petroleum ether.

Example 36

21- Cyano 3 -a-hydroxy-5a -pregnan-11,20-dione sodium salt

A solution of 2 l-cyano-3a-hydroxy-5a-pregnane-l 1,20-dione (80 mg, 0.222 mmol) in ethanol (4.4 ml) was treated with 0.1 l sodium hydroxide solution (2.22 ml, 0.222 mmol) treated. The solvents were then slowly removed under reduced pressure at room temperature and water (8 ml) was added to give an aqueous solution of the title compound at a concentration of 10 mg ml -1 based on the steroid (pH 11.7).

Example 37

21-cyano-2β-ethoxy-3a-hydroxy-5a-pregnan-11,20-dione antrium salt

A solution of 21-cyano-2β-ethoxy-3ct-hydroxy-5ct-pre-r gnan-11,20-dione (80 mg, 0.2 mmol) in ethanol (4.4 ml) was' with 0, ln Sodium hydroxide solution (2.0 ml, 0.2 mmol) treated. The solution is slowly evaporated to constant weight under reduced pressure at room temperature. The residue is dissolved in sufficient water (8 ml) to obtain a concentration of the aqueous solution of 10 mg ml-1 based on the steroid (pH 11.3).

Example 38

3a-Hydroxy-21-morpholino-5a-pregnan-ll, 20-dione

A solution of 21-bromo-3a-hydroxy-5a-pregnan-l 1,20-dione (1.6 g) in tetrahydrofuran (40 ml), which boiled under reflux, was treated with morpholine (0.7 ml ) treated under nitrogen and then poured into ether. The ethereal solution was then washed successively with 5% aqueous sodium bicarbonate solution and water, dried over Na2SÒ4 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 water, dried (Na2SO4) and evaporated to give the title compound (1.5 g) as a white foam, [a] D + 81 ° (cl, l).

Example 39

2ß-ethoxy-3a-hydroxy-21-morpholino-5a-pregnan-11,20-n || dion-citrate

A solution of 2β-ethoxy-3a-hydroxy-21 -niorpholino-5ct-pregnan-l 1.20-dione (0.093 g, 0.2 mmol) in ethanol (1 ml) was treated with 0.1 M citric acid solution (2 ml , 0.2 mmol) treated at room temperature. The clear solution was evaporated directly to dryness at room temperature and redissolved in distilled water (approx. 5 ml). The aqueous solution was stored at 0 ° overnight and then filtered. The solid was collected, washed with distilled water (approx. 1 ml) and the washing solutions and filtrates were combined, (1 min. The residue was dissolved in chloroform and evaporated in vacuo to constant weight (0.0016 g). The filtrate and the washing water was made up to 9.14 ml with distilled water to obtain a solution of the title compound (pH 3.59) at a concentration of 10 mg / ml based on the steroid.

Example 40

21-cyano-3a-hydroxy-19-nor-5a -pregnan-11,20-dione 21-bromo-3a-hydroxy ~ 19-nor-5a-pregnan-11,20-dione 4 || (794 mg) was added to a solution of calcium cyanide (300 mg) in ethanol (60 ml) and water (5 ml) and the mixture was 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 45 and the combined extracts were washed with water, dried (MgSO4) and evaporated to give a yellow foam. Purification by preparative thin layer chromatography (CHC13 / Et OAc 3: 1) gave the most polar component, a yellow foam (400 mg). 5II Further purification by preparative thin layer chromatography (CHC13) as the most polar compound gave the title compound (310 mg) as a colorless foam, [a] D +178 (c 0.9).

Example 41

3a-Hydroxy-21- (eis- and trans-2 ', 6'-dimethylmorpholino) -5a-pregnan-l 1,20-dione

21-Bromo-3a-hydroxy-5a-pregnan-l 1,20-dione (1 g) was dissolved in dry tetrahydrofuran (50 ml) and cis / trans-2,6-6I) dimethylmorpholine (1 ml) was added to the Added solution. The mixture was heated to reflux 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 has been. The faster-running band (R. {~ 0.6) gave the 3a-hydroxy-21- (trans-2 ', 6'-dimethylmorpho-

617 710

10th

Iino) -5a-pregnan-11,20-dione (150 mg, 14%) as a colorless foam, [a] D + 70.5 ° (c0.42).

A slower band (Rf 0.2 to 0.4) was isolated in two parts; products were obtained which were identical spectroscopically. The first foams were recrystallized from ethyl acetate / petroleum ether to give the 3a-hydroxy-21- (cis-2 ', 6'-dimethylmorpholino) -5a-pregnan-l 1,20-dione (500 mg) as almost colorless needles , Mp 134 ° (dec.), [A] D + 73.5 ° (c 1.06).

Example 42

3a-Hydroxy-21-morpholino-5a-pregnane-1, 1.20-dione hydrochloride

A solution of 3a-hydroxy-21-morpholino-5a-pregnan-11,20-dione (104.14 mg, 0.25 mmol) in ethanol (4 ml) was treated with 0.1 in chlorohydric acid (2.5 ml, 0 , 25 mmol) treated. The solution was evaporated in vacuo and then treated with water (5 ml). The undissolved solid (8.4 mg) was removed by filtration and the filtrate was made up to 9.6 ml with distilled water to give a 1% aqueous solution of the title compound.

Example 43

3a-Hydroxy-21-morpholino-5a-pregnan-11,20-dione-mesylate

A solution of 3a-hydroxy-21-morpholino-5a-pregnan-11,20-dione (167 mg, 0.4 mmol) in ethanol (2 ml) was mixed with 0.204N aqueous methanesulfonic acid solution (3.92 ml, 0.8 mmol) treated. The resulting solution was evaporated in vacuo and then treated with 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 water to give a 1% aqueous solution of the title compound.

Example 44

2β-ethoxy-3a-hydroxy-21 -morpholino-5a -pregnan-11,20-dione-dihydrogenphosphate

2ß-ethoxy-3a-hydroxy-21-morpholino-5 a-pregnan-11,20-dione (231.2 mg, 0.5 mmol) in ethanol (3 ml) was treated with 0.095M aqueous o-phosphoric acid (5, 3 ml, 1 eq.) And the resulting solution was evaporated in vacuo. The residue was dissolved in water (5 ml) and made up to a total solution weight of 23.12 g to give a 1% aqueous solution of the title compound.

Example 45

3a-Hydroxy-21-thiamorpholino-19-nor-5a-pregnane-l 1,20-dione-citrate

3a-Hydroxy-21-thiamorpholino-19-nor-5a-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 water clear, 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 w.r.t. steroid base) was obtained, the pH of the solution was 3.2.

Example 46

2β-ethoxy-3a-hydroxy-21-morpholino-5a-pie, gnan-II, 20-dione acetate

A solution of 2β-ethoxy-3a-hydroxy-21-morpholino-5a-pregnan-11,20-dione (116 mg, 0.25 mmol) in ethanol (2 ml) was treated with 0.1 l aqueous acetic acid (2.5 ml, 0.25 mmol) treated. The resulting solution was evaporated in vacuo. The residue was treated with water (approx. 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 1% aqueous solution of the title compound.

5 Example 47

3a-Hydroxy-2-morpholinopregn-4-ene-11,20-dione

21-Bromo-3a-hydroxypregn-4-en-1 1,20-dione (150 mg) in tetrahydrofuran (5 ml) was treated with morpholine (0.1 ml) and the stirred mixture was under nitrogen for 2 hours heated at reflux. A colorless precipitate formed during this time. The mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with additional methylene chloride and the combined organic extracts were washed with water, dried over sodium 15 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 off and the title compound (99 mg) was obtained as a colorless foam, [a] D + 174 °, m (Ç 0.12).

Example 48

3a-Hydroxy-21-morpholino-5a-pregnan-11.2 0-dione-citrate A solution of 3a-hydroxy-21-morpholino-5a-pregnan-25 11.20-dione (83.52 mg, 0.2 mmol) in absolute ethanol (1 ml) was treated with 0.1 M 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 obtained was kept at room temperature for 2 hours. The solution was filtered through a No. 3 sintered filter. The flask was rinsed with water (0.5 ml) and this was also filtered. The filter and the flask were washed with chloroform (10 ml). The chloroform was washed with saturated sodium bicarbonate solution (2X5 ml) and with water (3x5 ml) and evaporated to give a residue which was obtained by azeotropic distillation with benzene (6 X 10 ml) and in vacuo (20.6 mg) was dried. The filtrate was diluted with water (1 ml) to give the title compound as 4o 10 mg / ml aqueous solution based on the steroid. The pH of the solution was 3.45.

Example 49

2β-Ethoxy-3a-hydroxy-21 morpholino-Sa -pregnan-11.2 0-45 dione-ascorbate

A solution of 2β-ethoxy-3a-hydroxy-21-morpholino-5a-pregnan-1 1,20-dione (116 mg, 0.25 mmol) in ethanol (2 ml) was washed with a 0.1 in 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 diluted to 11.6 ml with distilled water to give a 1% aqueous solution of the title compound.

55 Example 50

2ß-ethoxy-3a-hydroxy-21-morpholino-5a-pregnan-l 1,20-dione-citrate (partially saline)

A solution of 2ß-ethoxy-3a-hydroxy-21-morpholino-5a-pregnan-l 1.20-dione (0.93 g) in ethanol (1 ml) is mixed with 6 (0.1M citric acid solution (20 ml) The solution is evaporated to dryness and redissolved in distilled water (5 ml). The resulting solution is filtered and the residue collected is washed with water (1 ml). The ritrate and the washing solutions 65 are diluted to 9 with distilled water , 2 ml filled up, whereby a solution of 2ß-ethoxy-3a-hydroxy-21-morpholino-5a-pregnan-l 1.20-dione-citrate in a concentration of 100 mg / ml, based on the steroid (pH 3 , 5).

11

617 710

A further amount of 2β-ethoxy-3a-hydroxy-21-morpholino-5a-pregnan-l 1,20-dione (0.93 g) is added to this solution and the solution is clarified by filtration, whereby the title solution ( pH 3.9).

The production processes 1 to 13 listed below relate to the production of the starting compounds used in the preceding examples.

Manufacturing process I

21-bromo -3a-hydroxy-5β-pregnan-11,20-dione

A stirred solution of 3a-hydroxy-5β-pregnan-l 1,20-dione (10 g) in dry methanol (700 ml) is at 0 ° C 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 divided between water and chloroform. The organic layer is washed with water, dried (Na2S04) 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 °

(ç 1.1) -

Manufacturing process 2

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

A solution of 3a-hydroxy-19-nor-5a-pregnan-l 1,20-dione (5.0 g) in dry methanol (300 ml) is at 0 to 5 ° C during the dropwise addition of bromine (0, 82 ml) in methanol (20 ml). After 1 hour the conversion was extremely low (indicated by the disappearance of the bromine discoloration before the further addition). External cooling was stopped and 1 drop of hydrobromic acid was added. Further addition of bromine gave a quick discoloration and the reaction was complete in another 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water, washed with water, dried (MgSO4) and evaporated to give a colorless foam (6.2 g). Isolation of the main band after preparative thin layer chromatography (EtOAc) gave 90% pure title compound (5.2 g).

Manufacturing process 3

1 la-Hydroxy-19-norpregna-4,16-diene-3,20-dione

A solution of a mixture of 1 la-17a-dihydroxy-19-norpregn-4-en-3,20-dione (4 g) and semicarbazide hydrochloride (4 g) in methanol (200 ml) was on for 2 hours Reflux heated. The methanol was then removed by distillation under reduced pressure and water was added to the residue. The precipitate which separated out was separated off by filtration, washed with water and dried over P205 in vacuo. 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 carbonate and ethyl acetate. The organic layer was washed with water, dried (Na2SO4) and evaporated to dryness. The residue was subjected to preparative thin layer chromatography (CHC13 / (CH3) 2 CO; 15: 1) and crystallized from acetone / petroleum ether to give the title compound (1.6 g) as colorless needles, mp 149 ° C.

Production method 4 3a-hydroxy-nor-5a-pregnan-l 1.20-dione A) 19-nor-5a-pregna-3, l 1.20-trione over 3 ^, 1 la, 20% trihydroxy-19 -nor-5a -pregnan

A solution of lla-hydroxy-19-nor-pregna-4,16-diene-3,20-dione (2.5 g) in dry tetrahydrofuran (200 ml)

became a solution of lithium over 5 minutes

(5 g) in liquid ammonia (2.5 1). The solution was then left to stand for 30 minutes. Ethanol (approx. 100 ml) was then added until the blue color disappeared and the ammonia was allowed to evaporate. The residue was distributed between water and ether. The organic layer was washed, dried (Na2SO4) and evaporated to give the crude title compound (1.5 g).

B) 19-Nor-5a-pregnan-3,11,20-trione m B) 19-Nor-5a-pregnan-3, l 1,20-trione

A solution of crude 3§, 1 la, 20 ltr-trihydroxy-19-nor-5a-pregnan (4 g) in acetone (280 ml) was treated with a solution of potassium dichromate (8.0 g) in 2N sulfuric acid (38 ml ) treated at room temperature for 1 hour. A further 15 amount of 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 (Na2S04) 2 »and evaporated. The remaining oil was subjected to preparative thin layer chromatography (CHC13) and recrystallized from acetone / petroleum ether to give the title compound (1.04 g) as colorless prisms, mp 151 °, [a] D + 240 °.

25th

3a-Hydroxy-19-nor-5a-pregnan-11,20-dione

A solution of 19-nor-5a-pregnan-3, l 1,20-trione (0.9 g) in "stock" chloriridium (IV) solution (prepared by mixing a mixture of 0.09 g of chloriridium ( IV) acid, 200 ml .io of 90% isopropyl alcohol and 16 ml of trimethyl phosphite were heated for 16 hours. The solution was then neutralized with triethylamine immediately before use) (75 ml) was heated under reflux for 24 hours. The solution was then cooled, partitioned between water and ether and the organic layer was washed well with water, dried (Na2SO4) 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, mp 154 °, [ct] D 4o + 200 °.

Manufacturing process 5

2 l-bromo-3a-hydroxy-3ß-methyl-5a-pregnan-l 1,20-dione A stirred solution of 3a-hydroxy-3ß-methyl-5a-pre-45 gnan-ll, 20-dione (17) (5.0 g, 15.0 mmol) in methanol (300 ml) was treated with a solution of bromine (1.0 ml) in methanol (30 ml) at 0 ° at such a rate that the yellow color of the solution disappeared before adding more bromine solution. The mixture was then poured into water, the precipitated title compound (2.8 g) was collected by filtration and dried over P2Os in vacuo.

Manufacturing process 6

21 -Brom-3a-hydroxy-2ß-methoxy-5a -pregnan-2 0-one 55 A stirred solution of 3a-hydroxy-2ß-methoxy-5a-pregnan-20-one (4.0 g) in dry methanol ( 300 ml) was treated at 0 ° with a solution of bromine (0.65 ml) in methanol (15 ml) at such a rate that the yellow color disappeared before further addition. The M mixture was then poured into water and the precipitated solid was collected by filtration, washed with water and dried in vacuo to give the title compound (4.0 g) as colorless crystals.

65 Manufacturing Process 7 21 -Brom-3a-hydroxy-2ß-methyl-5a-pregnan-11,20-dione A solution of 3a-hydroxy-2ß-methyl-5a-pregnan-11,20-dione (1.04 g) in dry methanol (150 ml)

617 710

0 to 5 ° stirred during the dropwise addition of 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 (MgSO4) 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), mp. 140 ° (dec.), [A] D + 133 ° (c0.95).

Manufacturing process 8

2 l-bromo-2ß-ethoxy-3a-hydroxy-5a-pregnan-l 1,20-dione

Bromine (0.53 g) in methanol (1.45 ml) was added dropwise to a stirred solution of 3a-hydroxy-2ß-ethoxy-5a-pre-gnan-11,20-dione (2.0 g) in methanol ( 15 ml), which contained a trace of acetyl chloride, was added at 0 °. The addition was carried out over 2 hours and the clear solution was then poured into water and collected by filtration, washed with water and dried in vacuo to give the title compound.

Manufacturing process 9

21-bromo-3a-hydroxy-2β-n-propoxy-5a-pregnan-l 1,20-dione

A solution of 3a-hydroxy-2ß-n-propoxy-5a-pregnan-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 treated with a solution containing 0.314 g / ml bromine). The resulting solution was then poured into water and the precipitated solid was collected by filtration, washed with water and dried in vacuo to give the title compound.

Manufacturing process 10

2 l-bromo-3a-hydroxy-5a-pregn-l-en-l 1,20-dione

A stirred solution of 2β-bromo-3 a-hydroxy-5a-pre-gnan-11,20-dione (5.0 g) in methanol (100 ml was at 0 ° with a solution of bromine (1 ml) in methanol (30 ml) treated at such a rate that the yellow color disappeared before further bromine solution was added, the mixture was poured into water and the precipitated solid was collected by filtration, washed with water and dried over P205 in vacuo The resulting solid (5.0 g) was purified by column chromatography (silicon dioxide, EtOAc / C6H61: 2.5), whereby the crude 2β, 21-dibromo-3a-hydroxy-5a-pregnane-l 1,20-dione (3 , 4 g) was obtained.

A solution of the crude 2β, 21-dibromo steroid (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 successively with dilute aqueous sodium bicarbonate and water, dried (Na2SÖ4) and evaporated. The residue was subjected to preparative thin layer chromatography (CHC13)

to obtain crude 2ß-21-dibromo-3a-tetrahydropyranoxy-5a-pregnan-11,20-dione as a colorless foam.

A mixture of this product (0.7 g), dimethylacetamide (20 ml), lithium bromide (2.6 g) and calcium carbonate (4.0 g) was stirred at 100 ° 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 (Na2S04) and evaporated.

A solution of the residue (0.5 g) in ethanol (5 ml)

was at room temperature with 2N hydrochloric acid

12

(0.5 ml) stirred for 2 hours. The mixture was then partitioned between aqueous sodium bicarbonate and ether. The organic layer was washed with water, dried (Na2S04) and evaporated. The residue was subjected to preparative thin layer chromatography (EtOAc / CHCl3.1: 2) to give the title compound (0.15 g) as a colorless foam, [a] D + 85 ° (c0.8).

Production method 11 m N- (2'-hydroxy-2'-phenylethyl) ethanolamine

Styrene oxide (1.2 g), ethanolamine (0.6 g) and water (0.65 g) were heated at 70 ° with stirring for 24 hours. The mixture was cooled, evacuated and the oil formed was triturated with ether to give the title is compound (550 mg), mp 93.5 to 95 °.

Production process 12 2-phenylmorpholine

N- (2'-Hydroxy-2'-phenylethyl) ethanolamine (5.3 g) was: ii dissolved in 6N hydrochloric acid (100 ml) and the solution was heated at 110 ° for 4 hours. The mixture was then mixed with sodium hydroxide solution until basic reaction and extracted into ether. The extract was washed with water, dried over anhydrous sodium sulfate 25 and evaporated to give a crude sample of the title compound (Ig) as an orange-colored oil.

Production process 13 21 -Brom-3a-hydroxypregn-4-en-l 1.20-dione M) A) 4ß, 21 -Dibromo-3a-hydroxy-5a-pregnan-l 1.20-dione

4β-Bromo-3a-hydroxy-5a-pregnan-l 1,20-dione (945 mg) in dry methanol (70 ml) at 0 ° C was added dropwise with a solution of bromine (0.125 ml) in methanol (5 ml) treated at such a rate over 7 hours 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 4ii 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, 45 the title compound (580 mg) as colorless crystals, mp 164 to 166 ° C, [a] D + 76 ° (c 1.35).

B) 21 -Brom-3a-hydroxypregn-4-en-l 1.20-dione s »4ß, 21 -dibromo-3 a-hydroxy-5 a-pregnan-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 ° C for 3'A hours. The reaction mixture was filtered and the solid residue ss was washed with ether and ethyl acetate. The combined filtrate and wash 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 60 1/1. The main band gave the title compound (70 mg) as a colorless foam [a] D + 140 °.

The preparation of the other intermediate products which are required in the production process are described in the examples of DE-OS 2 162 594 and in BE-PS 775 239.

C.