NO771197L - PROCEDURE FOR THE MANUFACTURE OF PHYSICALLY ACTIVE STEROIDS - Google Patents

Description

The present invention relates to steroids with an anesthetic effect.

Many steroids are known to have an anesthetic effect, these are usually 3a-hydroxy-5a- or A 4-compounds in the 17a-unsubstituted 20-oxo-pregnan and androstane series, the best compounds often have an 11-oxo- group. These compounds are usually insufficiently soluble in water, and it is necessary to formulate these for administration in aqueous solutions of parenterally acceptable non-ionic surfactants such as e.g. described in British Patent No. 1,317,184 with respect

to the important 3α-hydroxy-5α-pregnan-11,20-dione with anesthetic effect. There are also known steroids with anesthetic effects such as

have water-solubilizing groups in different positions in the steroid nucleus, e.g. in the 23- or 3a-position or the 21-position in a pregnane or the 173-position in an androstane, but introduction of the water-solubilizing group often results in a drop in potency or stability.

We have now found a very interesting anesthetic effect in 4 5

a group of 3α-hydroxy-5α-,. 53 or A or A pregnanes and

-androstanes and D-homo-analogues thereof which have an amino group, disubstituted with aliphatic or araliphatic groups, or a heterocyclic amino group in the lla position, especially in water-

soluble salts of these compounds with acids.

The present invention thus relates to steroids

with formula:

where

R"*" is a group -NRaRb, where Ra and R*3 (which may be the same or different) are C1-6-alkyl, C1-6-alkenyl or cycloalkyl (provided that Ra and R*3 together contain 2- 7 carbon atoms and that, when R a and/or R is an alkenyl group, the carbon atom or atoms are adjacent to the nitrogen atom in the group

-NRaR^ saturated); or where one of Ra and K° is a benzyl or phenethyl group and the other a methyl group; or where R and R (together with the nitrogen atom) mean an azetidino, pyrrolidino, piperidino, hexamethyleneimino or morpholino group, and these groups may optionally be substituted with

one or two methyl groups;

R 1 is a hydrogen atom or a C 1 -C 1 -alkyl group;

4

R is a hydrogen atom or a C^_^-alkyl-, C^_^-alkyl-

(which may optionally be substituted with a halogen atom, e.g. chlorine), benzyloxy, C 2 -alkanoyloxy or thiocyanato group or a halogen atom,

R is a hydrogen atom or a methyl group;

R g is a hydrogen atom or a methyl group;

7 8

R means a hydrogen atom or (except when R is a group (c) as indicated below) a chlorine atom; and

8

R is (a) a cyano group;

(b) a group -COR<9>wherein R<9>is a methyl group or

such a group substituted with a fluorine atom, a C^_^-Alkoxy-, hydroxy-, C-^^^-alkyl-, methoxymethyl-, ethoxymethyl-, C2-5~

alkanoyloxy-, benzoyloxy- or C0_ ,--alkoxycarbonyloxy group,

g or R is a C^_^-alkyl or cyclopropyl group; or R is the group -NR R-* where R and Ry (which may be the same or different) are methyl or ethyl; or

(c) a vinyl group or together with R^° a Z-substituted

methylene group where the substituent is a methyl or cyano group;

R<10> is a hydrogen atom (except when R^ and R together mean

a substituted methylene group);

the dashed lines indicate the possible presence of double bonds in the positions shown;

provided that at least one of R<3> and R<4> is a hydrogen atom;

and R 3 and R 4 together mean a hydrogen atom when the 1,2-double bond is present; and that the 2-position is saturated when a 4.5-double-3 4

bonding is present; and that R is a hydrogen atom, R is a

5

hydrogen atom or a methyl group and R is a hydrogen atom or optionally (when R 4 is a hydrogen atom) a methyl group when a 53~ hydrogen atom is present; 8 10 and D-homo-analogues thereof having R in the 17a3 position, R in the 17aa position and R 7 in the 17 position; and acid addition salts thereof.

In tests carried out, the compounds prepared according to the invention have generally been shown to be good anesthetics which usually give rapid induction of anesthesia when administered intravenously. Water-soluble salts are particularly important in that they can be formulated in aqueous solution, and by common comparison

with known water-soluble steroids with anesthetic action, they are superior in terms of strength and/or quality of anesthesia and/or by being free of side effects such as thrombophlebitis.

The aqueous solutions of water-soluble salts have also generally been found to be very stable. The compounds produced according to the invention are useful for inducing anesthesia which is to be maintained e.g. by means of an inhalation anesthetic such as ether, halothane, nitrous oxide or trichlorethylene. The compounds also have the ability to maintain anesthesia to a sufficient extent to enable surgical operations to be performed without the aid of an inhalation anesthetic, anesthesia being maintained if necessary by repeated or continuous administration. The compounds may have other useful sedative effects on the central nervous system, e.g. they can be used as sedatives.

As indicated above, the R ci - and R b groups may be C 1-6 alkyl groups which may be linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl or 1,3-dimethylbutyl ; or C 1 -alkenyl groups such as allyl.

ci b ~*

When R or R is a cycloalkyl group, it can e.g. be one

cyclopentyl or cyclohexy1 group.

When one of R a and R b is a C3_g alkenyl group, there is preferably only one double bond present, e.g. as in an allyl group, and the second group is preferably an alkyl group, e.g. methyl.

When -NR<a>R^ signifies a heterocyclic group, it is preferably pyrrolidino.

a b

Preferably, one of R and R is a methyl group, and the other group is a methyl, ethyl, propyl, isopropyl or butyl group. Compounds in which both R ci and R b are methyl are particularly preferred.

When a 2a(R 3 ) substituent is present, it is preferably a methyl group.

When R 6 is a methyl group, the 6-position is preferably saturated.

Compounds that have a 23(R4.)-substituent are particularly important in the 5a series, examples of such substituents are a methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, acetoxy or thiocyanato group, or a chlorine, bromine or fluorine atom.

Compounds in the 5a- and 53~ hydrogen series are usually preferred, as well as compounds in which the tetracyclic steroid-6 7

the system is saturated and where R and R are both hydrogen atoms;

R is also preferably a hydrogen atom. When the steroid rings are unsaturated, the A^ compounds are preferred."

A group of compounds prepared according to the invention are compounds where Ra and R^ are different from benzyl or

8 9 9

phenethyl; R is different from the group -COR where R is a methyl-3 4 5 group substituted with a C 1-2 -alkyl group; and wherein R , R , and R are all hydrogen atoms when a 53 hydrogen atom is present.

A preferred group of compounds are those of formula (II):

where

R"*" is a group -NRaR^ where one of Ra and R^ is a methyl group and the other group is a methyl, ethyl, propyl, isopropyl, butyl or allyl group, or where both R and R

a "b

are ethyl groups, or where R and R (together with the nitrogen atom) mean a pyrrolidino group; .

R 3 is a hydrogen atom or a methyl group;

4

R is a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, acetoxy or thiocyanato group or a fluorine, chlorine or bromine atom;

8 9

R is (a) a cyano group; (b) a group -COR where

R 9 is a methyl group or such a group substituted by one

9

methyl, hydroxy or acetoxy group, or R is a cyclopropyl group; or (c) a vinyl group, or, together with R'

a Z-ethylidene group; and

.R^ is a hydrogen atom (except when R and R^ together mean an ethylidene group); the dashed lines indicate the possible presence of a double bond in the 1,2 position;

3 4

provided that at least one of R and R is et

3 4

hydrogen atom; that R and R together mean a hydrogen atom when a 1,2-double bond is present; and that R 3 is a hydrogen atom and R 4 is a hydrogen atom or a methyl group when a 53 hydrogen atom is present;

and D-homo-analogs having R 8 in the 17a3_position and R<10>

in the 17aa position;

and acid addition salts thereof.

8 9 R is preferably a cyano group or a group -COR

9

where R is a methyl group (which is optionally substituted with a hydroxy, methyl or acetoxy group) or a cyclopropyl group. The 1,2 position is preferably saturated.

In the compounds of formulas (I) and (II), R 8 is preferably an acetyl or cyano group; R 4 is preferably a hydrogen atom when a 53-hydrogen atom is present, or is a hydrogen atom or an alkoxy group, advantageously an ethoxy group, when a 5a-hydrogen atom is present; and R 3 is preferably a hydrogen atom. It is particularly preferred that R<8> is an acetyl group,

cl laughed

ring D is a 5-ring and that -NR R is a dimethylamino group. 5a compounds are particularly preferred.

As indicated above, the ability of the bases prepared according to the invention to form soluble acid addition salts is particularly important. The compounds produced according to the invention in the form of their bases can thus be formulated in a simple way in aqueous acidic solution.

Examples of suitable salts are hydrogen chlorides, hydrogen bromides, phosphates, sulfates, p-toluenesulfonates, methanesulfonates, citrates, tartrates, acetates, ascorbates, lactates, maleates, succinates, tricarballylates, glutarate, aconitates, citraconates, mesaconates, salicylates and glutaconates. The citrate and hydrogen chloride salts are particularly preferred for use as anesthetics.

When these salts are used as anesthetics, they should be physiologically acceptable in the doses that are administered.

However, other salts can be used, for example in isolating the product from a synthesis.

Preferred compounds are:

1. 11a-N,N-dimethylamino-3a-hydroxy-5a-pregnan-20-one; 2. lla-N,N-dimethylamino-23-ethoxy-3a-hydroxy-5a-pregnan-20-one;. 3. 11a-N,N-dimethylamino-3α-hydroxy-23-methyl-5α-pregnan-20-one; 4. 11a-N,N-dimethylamino-3a-hydroxy-2a-methyl-5a-pregnan-20-one; 5. 11a-N,N-dimethylamino-3α-hydroxy-53-pregnan-20-one; 6. 11a-N,N-dimethylamino-3α-hydroxy-5α-androstane-173-carbonitrile; 7. 11a-N-butyl-N-methylamino-3a-hydroxy-5a-pregnan-20-one; 8. 23-chloro-lla-N,N-dimethylamino-3a-hydroxy-5a-pregnan-20-one; 9. 11a-N,N-dimethylamino-23-fluoro-3a-hydroxy-5a-pregnan-20-one; 10. 11a-N,N-dimethylamino-3α-hydroxy-23-methoxy-5α-pregnan-20-one; 11. 23-Ethoxy-11a-N-ethyl-N-methylamino-3a-hydroxy-5a-pregnan-20-one; 12. 11a-N-ethyl-N-methylamino-3a-hydroxy-5a-pregnan-20-one;

13. 3α-hydroxy-lla-N-methyl-N-propylamino-5α-pregnan-20-one;.

14. 11a-N-ethyl-N-methylamino-3a-hydroxy-23-methoxy-5a-pregnan-20-one; 15. 3α-hydroxy-lla-N-isopropyl-N-methylamino-23-methoxy-5α-pregnan-20-one; 16. 11a-N-allyl-N-methylamino-23-ethoxy-3a-hydroxy-5a-pregnan-20-one; 17. 23_ethoxy-3α-hydroxy-lla-pyrrolidino-5α-pregnan-20-one; 18. 11a-N,N-diiraethylamino-3a-hydroxy-23-propoxy-5a-pregnan-20-one; 19. 11a-N,N-dimethylamino-3a-hydroxy-23-isopropoxy-5a-pregnan-20-one; 20. 23-acetoxy-11a-N,N-dimethylamino-3a-hydroxy-5a-pregnan-20-one; 21. 23-acetoxy-11a-N-ethyl-N-methylamino-3a-hydroxy-5a-pregnan-20-one; 22. 23-acetoxy-3α-hydroxy-lla-N-isopropyl-N-methylaraino-5α-pregnan-20-one; 2 3. 11a-N-ethyl-N-methylamino-23-fluoro-3a-hydroxy-5a-pregnane-20-one; 24. 23-fluoro-3a-hydroxy-11a-N-isopropyl-N-methylamino-5a-pregnan-20-one; 25. 23-chloro-lla-N-ethyl-N-methylamino-3a-hydroxy-5a-pregnan-20-one; 26. 23-Chloro-3a-hydroxy-lla-N-isopropyl-N-methylamino-5a-pregnan-20-one; 27. 23-bromo-lla-N,N-dimethylamino-3a-hydroxy-5a-pregnan-20-one; 28. 11a-N,N-dimethylamino-3α-hydroxy-23-thiocyanato-5α-pregnan-20-one; 29. 11a-N,N-dimethylamino-3α-α-hydroxy-5α-pregn-1-en-20-one; 30. 11a-N,N-dimethylamino-3α-hydroxy-D-homo-5α-pregnan-20-one; 31. 11a-N,N-dimethylamino-23-ethoxy-3a-hydroxy-D-homo-5a-pregnan-20-one; 32. 11a-N,N-dimethylamino-21,21-ethylene-3a-hydroxy-5a-pregnan-20-one; 3 3. 11a-N,N-dimethylamino-3a-hydroxy-21-methyl-5a-pregnan-20-one; 34. 11a-N,N-dimethylamino-23-ethoxy-3a-hydroxy-21-methyl-5a-pregnan-20-one; 35. 21-acetoxy-11a-N,N-dimethylamino-23-ethoxy-3a-hydroxy-5a-pregnan-20-one; 36. 11a-N,N-diethylamino-3a-hydroxy-53-pregnan-20-one; 37. 3α-hydroxy-lla-N-isopropyl-N-methylamino-53-pregnan-20-one; 38. 11a-N-ethyl-N-methylamino-3a-hydroxy-53-pregnan-20-one; 39. 3a,21-dihydroxy-lla-N,N-dimethylamino-53-pregnan-20-one; 40. 21-acetoxy-11a-N,N-dimethylamino-3a-hydroxy-53-pregnan-20-one; 41. lla-N,N-dimethylamino-3a-hydroxy-5(3-androstane-173-carbonitrile; 42. lla-N,N-dimethylamino-2|3-ethoxy-3a-hydroxy-5a-androstane-173- carbonitrile; 43. (Z)-lla-N,N-dimethylamino-3a-hydroxy-5a-pregn-17(20)-ene; 44. methyl-lla-N,N-dimethylamino-23-ethoxy-3a-hydroxy -5a-androstane-173-carboxylate y 45. lla-N,N-dimethylamino-3a-hydroxy-5a-pregn-20(21)-ene; 46. 23-butoxy-lla-N,N-dimethylamino-3a- hydroxy-5α-pregnan-20-one 47. 11a-N,N-dimethylamino-23-ethoxy-3α-hydroxy-21-propyl-5α-pregnan-20-one;

and the physiologically acceptable water-soluble salts of these compounds.

All of the above compounds have shown good efficacy in . our tests in the form of citrate salts in aqueous solutions (sometimes in the presence of sodium and chloride ions). Good action has also been shown in our tests for the tricarballylate, hydrogen chloride, phosphate and methanesulfonate of Compound No. 1; the acetate, methanesulfonate, lactate, phosphate, tartrate, tricarballylate, hydrogen chloride, succinate, citraconate, aconitate and mesaconate of Compound No. 2; the acetate, hydrogen chloride, tartrate, lactate, tricarballylate, phosphate, methanesulfonate and succinate of Compound No. 5 and the acetate salt of Compound No. 10.

Of the above-mentioned compounds, compounds No. 1, 2, 5, 6, 8, 9, 31, 36-38, 41 and 42 and their salts are particularly preferred.

Compound No. 5 and physiologically acceptable water-soluble salts thereof (especially the hydrogen chloride and the citrate)

are particularly preferred. Compound No. 2 and physiologically acceptable water-soluble salts thereof (especially the hydrogen chloride and the citrate) are particularly preferred.

Pharmaceutical preparations

The compounds produced according to the invention can be suitably formulated by following known pharmaceutical practice (including both human and veterinary medical practice), using one or more pharmaceutical carriers or excipients. For anesthetic purposes, the steroids are given by injection dg a feature of the present invention thus comprises a preparation for parenteral administration and consists of one or more compounds produced according to the invention in a parenterally acceptable solvent.

When the compounds (e.g. the salts) are sufficiently soluble in water, they can be used in aqueous solvents for injection. Preparation of suitable solutions by bringing the free bases into solution in aqueous acid is described below. For induction of anesthesia these solutions will usually contain 0.1-4.0% (suitably 0.2-2%) w/v of the active compound, but stronger solutions can be prepared with more soluble salts. If desired, the free base and acid required for salt formation can be packaged separately in a two-part package for formulation as needed. Alternatively, the steroid salt and it can. the aqueous solvent for injection is packed separately in a two-part pack.

Although the compounds of the invention are preferably formulated as simple aqueous solutions of their salts, the free bases or salts may also be formulated in an aqueous solution of a parenterally acceptable nonionic surfactant in the same manner (and using the same amounts of substances) as described in British Patent No. 1,317,184 for 3ct-hydroxy-5cx-pregnari-ll, 20-dione. The simple aqueous solutions have the advantage that one e.g. avoids anaphylactoid responses in people hypersensitive to surfactants.

The aqueous solutions can be adjusted in tonicity,

e.g. with sodium chloride.

The solutions of anesthetics produced according to the invention are usually administered by intravenous injection,

although in certain cases (eg with children or animals) intramuscular injection may be preferable.

The simple aqueous solutions of the salts can also be administered subcutaneously. For intramuscular injection, hydrogen chloride salts are particularly suitable.

As usual with anesthetics, the amount of steroid used to induce anesthesia depends on the weight of the subject. be anesthetized. For intravenous administration to the average man, it will be found that a dose of 0.1-8.0 mg/kg will usually be sufficient to induce anesthesia, the preferred doses being in the range of 0.2-4.0 mg/kg. The dose will usually vary to some extent, depending on the physical condition of the patient and the degree and duration of the anaesthesia.

If it is desired to maintain prolonged anesthesia, repeated doses of the above solutions can be used, such repeated doses are usually either of the same size or less than the original dose. Alternatively, continuous administration can be used using solutions containing 0.01-0.4% (preferably 0.02-0.2%) weight/volume of the active compound, e.g. at an addition rate of 0.0125-0.2 (eg 0.025-0.1) mg/kg/min. Continuous administration can also be used to provide a calming effect for longer periods of time.

When the anesthetic solutions are administered intramuscularly or subcutaneously, higher doses are usually required.

Preparation of the compounds

The new compounds can be prepared according to a number of different methods using known techniques. Suitable methods are discussed below. 1. Transfer of an unsubstituted or monosubstituted lla-amine to a disubstituted amine.

This reaction can be carried out by reacting a corresponding compound of formula (I) where either one of or both

Elto ci

R and R are hydrogen, with a compound of formula R X where

X is a readily replaceable group such as halide (eg, iodide), a hydrocarbylsulfonyloxy group (eg, toluene-p-sulfonyloxy), hydrocarbyloxysulfonyloxy (eg, methoxysulfonyloxy), or a dimethoxyphosphonyloxy group (eg, dimethoxyphosphonyloxy). The reaction is preferably carried out in the presence of a base (eg potassium carbonate or silver oxide) in solution at a suitable temperature, from ambient temperature to reflux temperature, suitably at ambient temperature. An excess of the compound R<a>X, e.g. Methyl iodide can be used as a solvent in the reaction, but there are many other alternative solvents, such as halogenated hydrocarbon solvents (e.g. methylene chloride), alkanols (e.g. ethanol or methanol) or acetonitrile.

When an N-mono-substituted starting material is used

ci b, the reaction can give N,N-disubstituted compounds where R and R

are either similar or different groups.

The N-mono-substituted starting materials can be prepared in a similar manner by reacting a compound with

a b

formula I where both R and R are hydrogen, with a compound of formula R<a>X as discussed above.

a b

Compounds where -NR R is a heterocyclic amino group can also be prepared according to this method by using as reagent X-R a -R b-X where X is as stated above (e.g. a 2,2'-dihaloethyl ether or a dihaloalkane, such such as 1,4-diiodobutane).

When a 20-oxo group is present in the starting material, this can be protected as discussed below, as a 20-ketal group;

Such protection is not necessary in the N-substitution reaction, but a 20-ketal group is often present as a result of the earlier steps in the preparation sequence. Isolation of the product from the N-substitution reaction often involves acidic conditions that also serve to regenerate the desired 20-oxo group.

The necessary lla-amino starting materials for this reaction can e.g. is produced by stereo-selective reduction of the corresponding 11-oxime. This reduction can be carried out with an alkali or alkaline earth metal as reducing agent in an alcohol and/or an amine and/or ammonia, e.g. sodium in n-propanol, if desired in the presence of a suitable solvent, e.g. tetrahydrofuran, at a suitable temperature up to,

and preferably at, reflux temperature.

The 11-oximes can themselves be prepared from the corresponding . The 11-oxo compounds where the 20-oxo group (if present) is protected as a ketal group. The 11-oxo compound can e.g. is reacted with hydroxylamine under strongly alkaline conditions in aqueous alcohol (e.g. ethanol), preferably at reflux. When other oxo groups are not present, the reaction can be carried out under acidic conditions (approx. pH 4), e.g. in buffered pyridine.

The strict conditions applied to the reduction

of the 11-oxime makes it necessary or desirable that certain of the optional substituents are introduced after the formation of the lla-amino group, examples of such are 173-cyano and -alkoxycarbonyl, 21-alkanoyloxy and -halo, 23-halo, -alkanoyloxy and

-thiocyanate and 16a-chloro. When introducing certain of these substituents (according to methods described below, e.g. by acylation or esterification) it may be desirable to

protect the lla-amino group. Conventional methods for protecting the amino group can be used, e.g. acylation (eg with trifluoroacetic acid or formic acid or a reactive derivative thereof) or silylation.

2. A corresponding lla-acyl aminosteroid (ie where one of R and R is as defined above and the other is an acyl group)

can be reduced, e.g. with lithium aluminum hydride in an ether solution (eg tetrahydrofuran or dimethoxyethane) at any suitable temperature up to reflux temperature. The starting material may have a 20-ketal group which is then transferred to a 20-oxo group or a 3a-esterified hydroxy group, which is transferred to a 3ct-hydroxy group during the reaction.

The acylamino starting materials can be prepared by acylation of a suitable 11a-mono-substituted amino compound (or a 20-ketal or 20-hydroxy derivative thereof), e.g. with the appropriate carboxylic acid (or a reactive derivative thereof,

e.g. an acid halide, ester or anhydride), if desired in the presence of an acid binding agent (eg pyridine). The 3a-hydroxy group and any other hydroxy group present will be acylated during the reaction and can, if desired, be regenerated by treatment with a base before the reduction; if a 20-hydroxy group is present, the acylamino intermediate can first be oxidized and ketalized to form the desired protected 20-oxo group. If the 11-acylamino compound has a 3-oxo group, this can then be reduced to produce the desired 3a-hydroxy group.

3. Opening of a corresponding 2a, 3a-epoxide.

This reaction can be used to prepare ring-A-saturated-23-substituted-5a compounds, and it is the preferred way to prepare 23-halo, alkoxy, alkanoyloxy and thiocyanate compounds. The usual method for preparing the compounds 23 in this way is described in our British patent 1376892. Usually the reaction consists in treating the corresponding 2a,3a-epoxide with a compound HR 4 under acidic conditions (if necessary in the presence of an added acid catalyst, eg sulfuric acid, perchloric acid or boron trifluoride) or a

4-4

compound giving the anion.(R ) (where R is as indicated above, different from hydrogen), and then (when the starting material

has a deprotonated 3a-hydroxy group) treat the product with a source of protons (e.g. aqueous ammonium chloride) to produce the 3a-hydroxy group. Examples of HR 4 reagents are alcohols, carboxylic acids, thiocyanic acid and hydrogen halides (HF can be used in the form of HF-urea complex, suitably in the absence of a solvent); examples of reagents that give (R 4 )--anions are metal-alkyl, such as lithium dimethyl cuprate, alkali metal or ammonium salts of HR 4 acids and alkali metal alkoxides. The reaction is preferably carried out under anhydrous conditions in a suitable solvent (e.g. a hydrocarbon or an ether) at a suitable temperature up to reflux temperature. The 23-halogen and thiocyanate compounds can also be prepared in aqueous media.

The necessary starting materials for this turnover can e.g. is prepared by first introducing the desired 11a-substituted amino group (e.g. by the method in reaction 1 above)

2

by using an A starting material, then forming a salt (eg with toluene-p-sulfonic acid) and then epoxidizing the A 2 compound with a peracid, and finally regenerating the free base. The A 2 compounds can be prepared by forming 3-methanesulfonate and then eliminating the methanesulfonic acid. 4. A corresponding lla-amino- or lla-mono-substituted amino compound (or a 20-ketal thereof) is reductively alkylated with a suitable mono- or dicarbonyl compound in the presence of a reducing agent. E.g. in the case of the lla-amino compounds, the use of mono-carbonyl compounds, such as formaldehyde or acetaldehyde, can give lla-dimethyl- or -diethylamines, while a dicarbonyl compound can give a compound where -NR R is a heterocyclic amino group (e.g. glutardialdehyde can used to produce a piperidino group). When an 11a-N-mono-substituted starting material is used, a mono-carbonyl compound should be used. The reducing agents which can be used are those which are generally known to reduce imines, e.g. formic acid (e.g. at a suitable temperature up to 100-120°C, e.g. from room temperature and up to 100° and using the carbonyl compound as solvent in the reaction, in the presence or absence of water), an alkali metal borohydride or cyanoborohydride (eg sodium borohydride or cyanoborohydride using an alcohol such as ethanol as solvent, suitable at room temperature), iron pentacarbonyl or an alkali metal hydrogen iron carbonylate (eg Fe(CO)5 or MHFe(CO)^

where M is sodium or potassium, at a suitable temperature up

to reflux temperature using an ether such as tetrahydrofuran or an alcohol or aqueous alcohol as solvent), hydrogen in the presence of a metal catalyst (using an alcohol, e.g. ethanol, an ether, e.g. dioxane or an ester , eg ethyl acetate, as the reaction solvent, suitably at room temperature) or aluminum amalgam in the presence of water (suitably at room temperature, and in the presence of an ether solvent, eg tetrahydrofuran).

The metal catalyst can e.g. be a noble metal catalyst, such as platinum, platinum oxide, palladium or rhodium. The catalyst can be present on a carrier, e.g. on

charcoal or diatomaceous earth. A homogeneous catalyst such as tristripheny.lf or inrhodium chloride can also be used. If desired, the intermediate product, the imino compound, can be isolated.

The 11a-N-monosubstituted amino starting materials can be prepared in a similar manner by reacting the corresponding 11a-amino compound with a suitable aldehyde or ketone in the presence of a reducing agent as described above. The use of formaldehyde, acetaldehyde or acetone can thus e.g. give lla-N-methyl-, N-ethyl or N-isopropylamines, respectively.

Whether one obtains an lla-N-mono- or N,N-disubstituted for-

bond is partly dependent on the amount of ketone or aldehyde

which is used.

5. Ring-A-saturated-23-unsubstituted 5a-steroids

can be prepared from suitable 3^oxo compounds by stereospecific reduction, e.g. by the method of Browne and Kirk (J. Chem. Soc. C,

1969, 1653) or by the method in our UK patent 1409239.

The latter method preferably uses a previously prepared reduction system of iridium catalyst. A reduction system can e.g. is prepared from an iridium acid or salt (e.g. chloroiridium acid), a trivalent phosphorus compound, such as an ester of phosphoric acid (e.g. trimethylphosphite), water and an organic reaction medium (e.g. an alcohol such as isopropanol ). The reducing system is then neutralized (eg to a pH of

6-8.5) with an organic base such as a secondary or tertiary amine (eg triethylamine) and reacted with the steroid. When

When the catalyst system is formed in advance by heating at reflux, e.g. for 16-72 hours, the reduction can be achieved e.g.

in 2-3 hours under reflux, longer time may be required at room temperature.

6. Reduction of a corresponding 3-oxo-53 compound. 3a-hydroxy-53-steroids can be prepared by hydride reduction of the corresponding 3-oxo compound (where a 20-oxo group, if present, is optionally protected), e.g. with sodium borohydride using an alcohol (eg ethanol) or pyridine as solvent. 7. Inversion of the derivatives of the corresponding 33_hydroxy compounds.

This preparation method is suitable for the preparation of compounds which are unsubstituted in the 33-position and which do not have a 5,6-double bond. The starting material may be a corresponding compound having an easily replaceable 33 group,

such as a hydrocarbylsulfonyloxy group (eg p-toluenesulfonyloxy or mesyloxy), and the 33 group can be replaced by hydrolysis (eg under acidic conditions) to produce the desired 3α-hydroxy compounds. Methods for producing the A 4 compounds in this way are described in our British patent 1,372,175.

16

8. Reduction of the corresponding A compound.

8

Compounds where R is a group (a) or (b) as indicated above can be prepared by hydrogenation of the corresponding A₂ compound in the presence of a hydrogenation catalyst (e.g. a palladium catalyst) in a suitable solvent (f .eg an alcohol, ether or ester). The reaction may conveniently be carried out at or around room temperature and atmospheric pressure in the presence of a tertiary base, e.g. triethylamine

(except when an easily replaceable substituent (e.g. bromine) is in the 23-position) and/or an acid, e.g. acetic acid. 9.. Hydrochlorination of the corresponding A 16 compound.

The 16a-chloro compounds can be prepared by reacting

the corresponding A 16 compound with hydrogen chloride in an anhydrous solvent (e.g. an ether) at a temperature of e.g. 15-40°C, as described in our British patent 1,380,248 10. Dehydration of a corresponding 173-carbamoyl compound or the oxime of a corresponding 17(3-formyl compound.

173-cyano compounds can be prepared by dehydration of the appropriate oxime, e.g. with acetic anhydride under reflux. The 3a-hydroxy group will usually be esterified during the reaction and must be regenerated by deesterification. The oxime used as starting material for this reaction can be prepared from the corresponding 173-formyl compound (with NH2OH) which itself is prepared by periodate cleavage of the corresponding 20,21-dihydroxypregnane.

Alternatively, the corresponding 173~ (unsubstituted carbamoyl) compound can be dehydrated, e.g. using polyphosphate ethyl ester, as described in our British Patent No. 1,380,246. 11. Esterification of a corresponding 173-carboxylic acid.

173-Alkoxycarbonyl compounds can be prepared by

to react the corresponding 173-carboxylic acid or a reactive derivative thereof (eg an acid halide or anhydride or a salt) with the appropriate alcohol or alkyl halide. The reaction is preferably carried out at temperatures of -20°C to 110°C, as ■ discussed e.g. in our British patent 1,380,246.

The 173-carboxylic acid can conveniently be prepared by oxidizing the corresponding 173-acetyl compound, using e.g. NaOBr in an aqueous, inert solvent (eg dioxane). The acids can conveniently be obtained in the form of their triethylammonium salts by neutralization and addition of triethylamine, followed by extraction in a suitable solvent (eg chloroform). These salts can be converted to alkali metal salts by treatment with an alkali metal alkoxide (eg lithium methoxide).

12. Reaction of the corresponding 173_carboxylic acid with an amine. 173-(Substituted carbamoyl) compounds can be prepared by reacting the corresponding 173-carboxylic acid or a reactive derivative thereof (e.g. an acid halide or ester) with an amine HNR x RJ y , where R x and R 4 are as indicated above. The reaction is again preferably carried out in the presence of an acid-binding agent, as indicated in our British Patent No. 1,380,246. 13. Acyloxylation of a corresponding 21-unsubstituted compound.

21-alkanoyloxy and benzoyloxy compounds can be prepared by treating the corresponding 21-unsubstituted compound (where the 3α-hydroxy group is optionally protected) with the appropriate lead tetraacylate, preferably in the presence of a Lewis acid (e.g. boron trifluoride) in a hydrocarbon/alcohol solvent. This turnover is carried out as described

in our British patent no. 1,317,185.

14. Substitution of a 21-iodine atom mqd fluoride.

21-fluorides can be prepared from the corresponding 21-iodo compounds by treatment with a source of fluoride ions (eg an alkali metal or silver fluoride), as described in our British Patent No. 1,430,932.

15. Deacylation of a corresponding 21-acyloxy compound. The 21-hydroxy compounds can be prepared by hydrolysis of a corresponding 21-acyloxy compound (eg a 21-acetoxy compound) under basic conditions, as described in our British Patent No. 1,377,608. 16. Etherification of a corresponding 21-hydroxy or 21-halogen compound. 21-Alkdoxy compounds can be prepared by etherification of a corresponding compound having a 21-hydroxy group or a replaceable substituent in the 21-position (e.g. a 21-halo, e.g. a 21-bromo compound) with e.g. a suitable alkanol, diazoalkane or alkali metal alkoxide; these methods are again described in our British patent no. 1,377,608. The 3a-hydroxy group is protected if desired in these reactions. 17. Acyloxylation of a corresponding 21-substituted compound.

The 21-alkanoyloxy and benzoyloxy compounds can be prepared by reacting a corresponding compound having an easily replaceable substituent in the 21-position (e.g. a bromine, chlorine or iodine atom, or a hydrocarbyl-sulfonyloxy group), with a salt of the appropriate carboxylic acid. This reaction is described in our British Patent No. 1,317,185.

18. Acylation of the corresponding 21-alcohol.

21-alkanoyloxy and benzoyloxy compounds can also be prepared by acylating the corresponding 21-alcohol, again as described in our British Patent No. 1,317,185. 21-carbonate-

esters can be prepared in a similar way by using e.g.

the appropriate alkyl chloroformate.

19. Dehydrohalogenation of a corresponding 23-halogen compound. A^-5<x compounds can be prepared by dehydro-. halogenation of a corresponding 2|3-halogen compound (preferably a 23-bromo compound) using e.g. of a nitrogen-containing Lewis base, e.g. dimethylformamide or dimethylacetamide. The starting material may contain a protected 3a-hydroxy group, and the reaction is advantageously carried out in the presence of an alkali metal or alkaline earth metal carbonate or halide (e.g. a mixture of calcium carbonate and lithium bromide) at a temperature of 80-170°C. This reaction is described in our British Patent No. 1,380,248. 20. A 173-vinyl group can e.g. is introduced by partial hydrogenation of a suitable 173-ethynyl compound.

The required 173-ethynyl compounds can themselves be prepared from a 173-acetyl steroid by first preparing the corresponding 20-hydrazone, iodination of the hydrazone (e.g. with iodine and triethylamine), and then dehydroiodination of the iodide (e.g. with ethanolic potassium hydroxide).

The 173-ethynyl compounds can also be prepared by treating a suitable 21-methanesulfonyloxy-20-oxo steroid with toluene-p-sulfonylhydrazide and then a base. 21. A 173-vinyl group can also be introduced by treating a

suitable 20,21-epoxide with an alkali metal (e.g. potassium) selenocyanate, e.g. in an alcoholic solvent. The epoxies can be prepared as indicated in our British Patent No. 1,377,608.

22. A Z-ethylidene or Z-cyanomethylene group may be introduced

by a Wittig reaction, by reacting a 17-oxo-steroid with e.g. a suitable organophosphorus reagent, such as (i) a substituted or unsubstituted methylenephosphorane (e.g. ethylidenetriphenylphosphorane);

suitably prepared in situ using a base (e.g., sodium hydride) in a solvent (such as dimethyl

sulfoxide or tetrahydrofuran) and a substituted or unsubstituted methylphosphonium salt (eg, an ethyltriphenylphosphonium halide, eg, bromide or chloride), or (ii) a substituted methyldialkylphosphonate (eg, diethylcyanomethylphosphonate). 23. Compounds where Ra is a methyl or cyclopropyl group or a methyl group substituted with a C^_^-alkyl group can be prepared by reacting the 173-carboxylic acid or preferably a salt (e.g. lithium or triethylamine salt) with the appropriate lithium alkyl (e.g. when using 2-4 mol of lithium alkyl per

moles of carboxylic acid or salt). Examples of suitable solvents for the reaction include ethers and hydrocarbons (eg diethyl ether and hexane); the reaction is suitably carried out at room temperature and is followed by protonation (eg by addition of water).

24. Decetalization of a corresponding 20-ketal.

As stated above, it is often necessary or desirable to protect a 20-oxo group during the preparation of pregnanes according to the invention, e.g. by ketalization. The 20-oxo group can then be regenerated as the last step in the preparation. The ketal is preferably the corresponding 20,20-ethylenedioxy compound, and the 20-oxo group can be calculated e.g. by hydrolysis in the presence of an acid (e.g. hydrochloric, sulfuric or acetic acid), or by yield reaction with a ketone, e.g. acetone, in the presence of an acid catalyst, e.g. p-toluenesulfonic acid, at a temperature of 0-100°C. 25. Deprotection of a corresponding compound having a protected 3a-hydroxy group.

This method is sometimes a necessary last step in the preparation of the compounds according to the invention in that the 3a-hydroxy group is often intentionally protected or is formed

in the esterified state by inversion from a 33-hydroxy compound (e.g. by treating 33-alcohol with diethyl azodicarboxylate in the presence of an acid such as formic or benzoic acid and a phosphine such as triphenylphosphine). The group that is present in the 3a position in the starting materials in this reaction can thus be an ester group, e.g. an alkanoyloxy group, and such esters can be hydrolyzed to give the desired 3α-hydroxy compounds under slightly acidic or basic conditions. Weak

basic conditions are usually most suitable (use e.g.

of an alkali metal bicarbonate in aqueous methanol at a suitable temperature up to reflux temperature). Diluted mineral acids (eg perchloric acid in aqueous methanol) can also be used. Strong bases (eg alkali metal hydroxides) can be used

if the turnover is carried out in a short time.

Alternatively, the starting material in this reaction can be a protected 3α-hydroxy compound such as a 3α-ether (eg 3α-tetrahydropyranyl ether) or a 3α-nitrooxy compound. Such ether protecting groups can be removed by treatment with an aqueous acid, and such nitro-oxy groups can be removed by reduction, e.g. using zinc and acetic acid.

26. Salt spray

The compounds produced according to the invention can, if desired, be used in the form of a salt, and salt formation by reaction of a base with an acid is thus particularly important.

A suitable method for the formation of the salts is usually

mixing suitable amounts of the free base and the acid in a mixture of water and a solvent for the base (e.g. an alcohol such as ethanol), removing the solvent (e.g. by evaporation) and then, if desired, dissolving the residue in water .

In some cases, solid salts can be prepared by treating the free base with acid (eg, citric acid, HCl) in an anhydrous solvent, such as diethyl ether. In most cases, it is possible to prepare an aqueous solution of the salt by simply mixing the free base with an aqueous acid. If desired, one or more steroid bases and/or one or more acids can be used.

In these preparations, the base and the acid are not necessarily used in equal amounts. When the acid is a weak acid, it is sometimes desirable to use an excess of acid.

When producing aqueous solutions, it has been found in some cases that e.g. can use an excess of the base, which causes the free base to dissolve to a certain extent in the salt solution.

If desired, the pH of the salt solution can then be adjusted by adding a base, e.g. sodium hydroxide and/or disodium hydrogen citrate..

The methods indicated above for the preparation of the new compounds can be used as the last, main step in the preparation sequence. The same general methods can be used for introducing the desired groups or unsaturated bonds in an intermediate step in the stepwise formation of the desired product, and it will be understood that these methods can be combined in many different ways in such multi-step processes, which will appear from the following examples. Thus, e.g. the desired 11a-substituted amino group is formed either before or after the reduction of a 3-oxo group or 16,17-double bond, and either before or after the introduction

of a possible substituent at the 16, 173 or 21 equivalents

or the formation of a double bond in the 1,2 position.. The sequence of the reactions in the multi-step processes should of course be chosen

so that the reaction conditions used do not affect the groups in the molecule that are desired in the final product.

Other structural features which may be present in the compounds produced according to the invention can be introduced by means of the following methods.

Methods which are generally suitable for introducing substituents into the 2a and 33 positions are described in our British Patent No. 1,380,248.

A 4 steroids can be obtained by methods described in our British Patent No. 1,372,175,

Compounds having an alkyl or substituted alkyl group in the 21-position or a cyclopropyl group in the 20-position. can be produced by methods generally described in our British Patent No. 1,436,324.

Compounds having a 63-methyl group can be prepared by hydrogenation of a corresponding 6-methyl-3-oxo-4,6-diene, followed by reduction of the 63-methyl-3-oxo compound prepared, for example, using chloriridium acid in the 5a series as discussed above.

The D-homo-, A^-f orcompound and the A"1", 5 3~ f orcompounds can

is produced by choosing starting materials of a single structure.

The following examples illustrate the invention. Temperatures are indicated in °C.

Melting points were determined on a Kofler block and are uncorrected. Optical rotations were determined at room temperature on solutions in chloroform (approx. 1% weight/volume) if nothing else is stated.

Preparative TLC (thin layer chromatography) and CC

(column chromatography) was performed on silica.

Hydrochloric acid reagent was prepared by refluxing a mixture of hydrochloric acid (50 mg, isopropanol (94 ml), water (6 ml) and trimethylphosphite (8 ml) for 24 hours and adjusted to pH 7 by adding triethylamine immediately before use .

Methylene chloride (dichloromethane) was redistilled and dried.

The solutions were dried either azeotropically or using magnesium or sodium sulfate.

In the following examples and preparations, abbreviations are used for reagents and solvents. Thus is:

EA = ethyl acetate,

PE = petroleum ether (b.p. 60-80°C)

AN = acetonitrile,

CH = chloroform

DM = dichloromethane,

DE = diethyl ether,

DMS0= dimethylsulfoxide,

PY = pyridine

THF = tetrahydrofuran,

W = water

B = benzene

PTSA= toluene-4-sulfonic acid,

MA = methyl acetate

ET = ethanol,

IMS = industrial denatured alcohol

PR = propan-l-ol,

DC = 1,2-dichloroethane,

D = dioxane PT = petroleum ether (b.p. 40-60°C)

DMF = dimethylformamide

AC = acetone,

ME = methanol and

RT- = room temperature.

In the preparations and examples, 98-100% formic acid was used and formaldehyde was used as a 37-40% weight/volume aqueous solution.

The following known starting materials were used in the production:

(I) 20,20-ethylenedioxy-3α-hydroxy-5α-pregnan-11-one

(II) 3α-Hydroxy-2(3-methoxy-5α-pregnan-11,20-dione

(III) 23-butoxy-3a-hydroxy-5a-pregnan-ll, 20-dione

(IV) 20,20-ethylenedioxy-2α,3α-epoxy-5α-pregnan-11-one

(V) 3|3-hydroxy-20,20-ethylenedioxy-5a-pregnan-11-one-oxime

(VI) 20,20-ethylenedioxy-5a-pregn-2-en-11-one

(VII) 23-ethoxy-3α-hydroxy-5α-pregnan-11,20-dione

(VIII) 20,20-ethylenedioxy-3a-hydroxy-2a-methy1-5a-pregnan-11-one (IX) 20,2O-ethylenedioxy-3a-hydroxy-33-methy1-5a-pregnan-11-one (X ) 6-methylpregna-4,6-diene-3,11,20-trione

(XI) 3a-hydroxy-21-methyl-5a-pregnan-11,20-dibn (XII) 21, 2.1-ethylene-3a-hydroxy-5a-pregnan-11,20-dione (XIII) 3a-hydroxy-21 -methoxy-5a-pregnan-11,20-dione (XIV) 23-ethoxy-3a-hydroxy-5a-pregnan-11,20-dione (XV) 3a-hydroxy-D-hbmo-5a-pregnan-11,20 -dione (XVI) 23-ethoxy-3a-hydroxy-D-homo-5a-pregnan-11,20-dione (XVII) 203,21-epoxy-3a-hydroxy-5a-pregnan-11-one (XVIII) 5a -pregna-2,16-diene-11,20-dione (XIX) 3a-hydroxy-5a-androstane-11,17-dione

(XX) 3α,203,21-trihydroxy-5α-pregnan-11-one

(XXI) 20,30-ethylenedioxy-3a-hydroxy-53-pregnan-ll-one (XXII) 3a,203,21-trihydroxy-53-pregnan-ll-one

Many compounds which are dealt with further have been given numbers to avoid repetition of their full names. So that connections sbm correspond to these numbers can be easily identified using the following index:

Production 1

( Z)^ lla- amino- 5a- pregn- 17( 20)- en- 3a-ol (XLI)

A solution of (Z)-3α-hydroxy-5α-pregn-17(20)-en-11-one-.oxime (9.638 g) in PR (200 mL) was heated under reflux under ^ while Na (9.6 g) was added in portions. When all the Na had been converted, approx. 90 ml PR and then the rest was poured on. W, ice was added and the crystalline solid (9.19 g) was collected by filtration. One serving (6.17 g)

was crystallized from ET-W to give the final product (3.6 g), m.p. 118-125°, [a] + 5.4°.

Preparation 2

6 p- methyl- 5a- pregnan- 3, 11, 20- trione (XXIII)

X (1.7 g) in EA (100 mL) was hydrogenated at atmospheric pressure using 10% palladium on charcoal (Pd-C) (500 mg) as catalyst. The catalyst was filtered off and the filtrate evaporated. Crystallization of the residue from AC-PE gives the final product (720 mg), m.p. 174-176°, [α]D+106°.

Manufacturing 3

3a- hydroxy- 63~ niethyl- 5a- pregnan- ll, 20- dione

XXIII (600 mg) was heated under reflux with chloriridium acid reagent (35 mL) for a total of 8.5 hours. The reaction mixture was diluted with W and extracted with EA. Evaporation of the extract gave a foam which was purified by preparative TLC in EA-PE (1:1), and the final product (440 mg) is obtained as a foam, [ot]D+88°.

Manufacturing 4

21- N, N- dimethylaminomethyl- 23- ethoxy- 3a- hydroxy- 5a- pregnane- 11, 20-dione

(XXIV)

XIV (10.0 g) was dissolved in dry AN (50 mL) and N,N-dimethyl(methylene)ammonium chloride (5.0 g) was added. The mixture was heated under reflux for 2 hours, cooled

and partitioned between 2N hydrochloric acid and EA and the acidic extract was basified with NaOH solution and extracted with CH (2x). The extract was dried -(Na-SO4) and evaporated, and the final product (10.7 g) is obtained as a foam.

Manufacturing. 5

23- ethoxy- 3a- hydroxy- 21- methylene- 5a- pregnane- 11, 20-dione (XXV)

XXIV (10.5 g) was dissolved in ME (105 mL) and iodomethane (10.5 mL) was added. The mixture was kept at 20° for 20 hours

and was then evaporated under reduced pressure. The residue was dissolved in DM (200 mL) and vigorously stirred with 5% NaHCO 3 solution

(100 ml) for 1.5 hours. The layers were separated and the organic base was dried (Na 2 SO 4 ) and evaporated to give a foam.

CC using EA-PE (1:1) gives the final product (3.48 g), m.p. 181-184°, [a] +112°.

Manufacturing 6

23- ethoxy- 3a- hydroxy- 21- methyl1- 5a- pregnane- 11, 20-dione

XXV (.3.37 g) was hydrogenated at atmospheric pressure and 23° in EA (150 mL) over 5% Pd-C. The catalyst was removed by filtration and the filtrate evaporated to give the final product as a foam (3.27 g), m.p. 147.149°, [a] +92°.

Manufacturing 7

3a- hydroxy- 5a- pregn- 2O- en- 11- one

XVII (330 mg) in W-ME (1:10, 11 mL) was treated with potassium selenocyanate and the solution was heated at 60°C for 20 h. The solution was filtered through diatomaceous earth and the filtrate evaporated to dryness under reduced pressure. The residue was dissolved in DM and purified by CC by elution with EA-PE (1:1), and a foam was obtained which was crystallized from DE-PE, and the final product was obtained as a pale yellow solid (80 mg), sm.p. 137.5-139.5°.

Manufacturing 8

( Z)- 3a- hydroxy- 5a- pregn- 17( 20)- en- ll- one

Sodium hydride (80% dispersion in oil, 1.0 g) was washed with PE and heated with dry DMSO at 70-80° until a green solution was obtained. The solution was cooled to RT and treated with ethyltriphenylphosphonium iodide (13.3 g) in DMSO (50 mL). XIX

(2.0 g) in distilled DMSO (40 mL) was added in one portion and the mixture was heated to 40-60°. After 6 hours, the reaction mixture was poured into W and extracted with DE. Evaporation of the washed and dried extract gives an oil which bee purified by CC

using EA-PE (1:1) and crystallized from EA-PE, and the final product (824 mg) is obtained, [a]D +29.0°.

Production 9

20- oximino- 5a- pregna- 2, 16- diene- 11- one (XXVI)

A mixture of XVIII (60 g), hydroxylammonium chloride

(21 g) and anhydrous PY (240 ml) were allowed to stand at RT overnight before dilution with ice and W. The resulting precipitate was collected by filtration, washed with W and dried in vacuo at 80°, (62 g). Crystallization from EA gives the final product, m.p. 168-182°.

[a]D+137°.

Production 10

5a- androst- 2- en- ll, 17- dione (XXVII)

A solution of XXVI (60 g) in anhydrous PY (250 ml)

was treated with 225 mL of a solution prepared from phosphorus oxychloride (55 mL) in anhydrous PY (250 mL) while maintaining the reaction temperature at < 5° during addition of the reagent.

The reaction mixture was then added to a solution of concentrated HCl (350 mL) in W (3 L). The mixture was stirred for 60 hours before the precipitate was collected by filtration. The precipitate was washed with W, dissolved in hot IMS and treated with 2N HCl

(50 mL) at RT. After 1 hour, the reaction mixture was diluted

with W and the precipitate obtained was collected by filtration,

washed with W and dried (38.4 g). Crystallization from ME gave the final product, m.p. 188-192°, [α]D+207°.

Production 11

lia- amino- 2ft- ethoxy- 3a- hydroxy- 21- methy1- 5a- pregnan- 20- one (LXII)

23-ethoxy-20,20-ethylenedioxy-3α-hydroxy-21-methyl-5α-pregnan-11-one-oxime (2.8 g) was dissolved in PR (150 mL) and heated to reflux temperature. Na (12.6 g) was added and refluxing was continued until all Na was dissolved. PR was removed by distillation with simultaneous addition of W. The resulting mixture was extracted with EA (2x) and the washed organic layer was again extracted with 2N HCl. The sour one

extract was basified to pH 11 with 40% NaOH solution, extracted with EA (2x), dried (Na 2 SO 4 ) and evaporated to give the final product as a foam (1.94 g).

Production 12

21- bromo-lla- N, N- dimethylamino- 23- ethoxy- 3a- hydroxy- 5a- pregnan-20- one (XXVIII)

A solution of 11a-N,N-dimethylamino-23-ethoxy-3α-hydroxy-5α-pregnan-20-one hydrogen chloride (450 mg) in dry ME (50 mL) was treated dropwise with a solution of bromine (0, 1 mL) in ME (5 mL) at 0°C with stirring. Each subsequent drop of the reagent solution was added when the color from previous additions had disappeared. When the addition was complete, 10% K-jCO 3 solution (150 mL) was added and the mixture was stirred for 15 minutes. The precipitate was filtered off and washed with W and dried. Cleaning

by preparative TLC in EA-PE (1:1) gave the final product (230 mg).

Production 13

lla- N, N- dimethylamino- 23- ethoxy- 3a- hydroxy- 5a- androstane- 173- carboxylic acid lithium alt (LXXV)

Bromine (4.3 mL) was added to a stirred solution of NaOH (12.1 g) in W (90 mL) at -5 to 0°. D (42 ml) was added and this mixture became. added to a stirred solution of 11a-N,N-dimethylamino-23-ethoxy-"3a-hydroxy-5a-pregnan-20-one (10.0 g)

in D (316 mL) and W (90 mL) at 8°. The mixture was stirred at 5-10° for 3.5 hours. A solution of sodium sulfate heptahydrate (4.66 g) in W (20 mL) was added and the mixture was boiled for 15 minutes. The solution was filtered hot and the cooled filtrate was extracted with CH. The CH extract was washed with W and the combined aqueous fractions were acidified with concentrated HCl to pH 3. Triethylamine (50 mL) was added and the solution was extracted with CH. The extract was dried (MgSO 4 ) and evaporated to dryness to give the crude triethylammonium salt,

which was dissolved in ME (20 mL) and treated with a solution of lithium methoxide (20.4 mmol) in ME (35.7 mL). The resulting solution was evaporated to dryness and the residue was crystallized from a mixture of ME (36 ml), PT (36 ml) and DE (354 ml) to give the final product (7.03 g), m.p. > 300°, [α]D+ 9.1°.

Production 14

3a, 2l-. dihy droxy- lla- N, N- dime ty lamino- 2 g- e toxy- 5 q- pregnan-

20- on (XXX)

A solution of XXIX (2.8 g) in ME (100 mL) was treated at RT with 10% K 2 CO 3 solution (15 mL) for 15 min. The mixture was diluted with W to 700 mL and the oily residue was extracted into DE (3x). The extracts were washed with W, dried (Na 2 SO 4 ) and. evaporated to a foam (2.5 g). A sample (300 mg) was purified by preparative TLC in EA-PE (1:1),

and the final product (160 mg) is obtained as a foam, [a]D+ 65°.

Production 15

lla- N, N- dimethylamjno- 2P- ethoxy- 5a- pregnan- 3a, 203, 21- triol (XXXI)

A solution of XXX (2.2 g) in ME (50 mL) was treated with sodium borohydride (230 mg). After 10 minutes, the mixture was diluted with 10% K 2 CO 3 solution (80 mL) and W to 300 mL. The mixture was extracted with DE (3x) and the extracts were washed with W, dried (Na 2 SO 4 ) and evaporated to a foam which was purified by CC and eluting with DM-AC (1:1) to give the final product (700 mg) as a foam, [ot] D -5°.

Production 16

20, 20- ethylene- dioxy- 3a- hydroxy- 2p- me. tyl-5a-pregnan-11-one

A stirred suspension of dried copper(I) iodide (19.6 g) in dry xylene (350 mL) under nitrogen was cooled to -10° and 1.9 M methyllithium in DE (108 mL) was added until the original yellow precipitate was .dissolved again to give an almost clear,, f heirless liquid. A solution of IV (12.9 g) in xylene (430 mL) was added dropwise at -10 to -5°. After the addition, the mixture was stirred overnight at RT, and then poured into 25% NH 2 Cl solution (1200 ml). The mixture was extracted with DE and the extract was washed with 25% NH 2 Cl solution and W. Evaporation of DE left an oily solid which by TLC was a 2:1 mixture of starting material and final product. This solid material was recycled using the same amounts of reagents, temperatures and times. The resulting solid was crystallized from EA-PE to give the final product (7.22 g), m.p. 167-168°, [α]D+68.1°.

Production 17

20, 20- ethylenedioxy- 2p- ethoxy- 3a- hydroxy- 5a- pregnan- 11- one (XXXII)

A solution of VII (8.2 g) in B (300 mL) and ethylene glycol (40 mL) was treated with PTSA (200 mg) by heating under reflux in a Dean&Stark water trap using vigorous stirring. After 6 hours, solid NaHCO 3 (500 mg) was added to the cooled mixture. Aqueous saturated NaHCO-j solution (100 ml) and W (50 ml) were added and the organic phase

was washed with W (3x), dried (Na 2 SO 4 ) and evaporated to a foam' which was purified by CC and elution with EA-PE (1:2) to give 6 g of the product, of which 500 mg was crystallized from MA-PE,

to give the final product (210 mg), m.p. 124-127°C, [a]D +53°.

Presentations 18-26

Table 1 summarizes the preparation of 20-ketals according to

the following method.'

A solution of the appropriate 20-ketone in B and ethylene glycol was heated under reflux under a Dean and Stark water trap in the presence of PTSA for the indicated time.

The cooled mixture was then worked up after

one of the following methods:

A. The mixture was treated with solid NaHCO^ and

diluted with (i) DE-W or (ii) W. The organic phase was separated, washed, dried and evaporated.

B. The mixture was diluted with aqueous NaHCO^-

solution and extracted with (i) EA or (ii) DM. The extract was washed, dried and evaporated. C. The mixture was poured into aqueous NaHCO 3 solution, the layers separated and the aqueous layer extracted with B.

The combined organic extracts were washed, dried and evaporated.

The material obtained by one of these methods

was purified by chromatography (CC or TLC) and/or crystallization.

Production 2 7

2 0, 20- ethylenedioxy- 5a- pregn- 2- en- 11- one- ll- oxime (XXXIII)

A solution of VI (5 g) in ET (150 ml) was treated with

a mixture of hydroxylamine hydrogen chloride (10 g) and 50% NaOH solution (40 ml) at pH 11. The mixture was refluxed for 3 days, diluted with W and the precipitate was filtered off,

washed with W and dried. The residue (5.5 g) was crystallized from MA-PE (2 x), and the product (2.2 g) is obtained. One serving (200 mg)

was further crystallized, and the final product (150 mg) is obtained, m.p. 174-179°C, [a] +144°.

Production 28

20, 2 O- e ty lendiok sy- 2 | 3- e toxy- 3 a- hy dr oxy- 5 a- pregnan- 11- one- 11-

oxime (XXXIV)

A solution of XXXII (5 g) in ET (200 ml) bee treated with

a mixture of hydroxylamine hydrogen chloride (15 g) and 40% NaOH solution (60 ml) under reflux for 18 hours at approx. pH 11. The mixture was diluted with W to 2 L and the precipitate was filtered off, washed with W and dried in vacuo to give 4.5 g of the product, of which a sample (500 mg) was crystallized from MA-PE, and gives the final product (150 mg), m.p. softens > 170°C, [a]D+83.3°.

Production 29

20, 20- ethylenedioxy- 3a- hydroxy- 5g- pregnan- 11- one- ll- oxime (XXXV)

A solution of XXI (11 g) in ET (150 ml) was treated with

a mixture of hydroxylamine hydrogen chloride (15 g) and 50% NaOH

(50 ml). The mixture was refluxed for 24 hours at pH 11, then diluted to 2 L with W. The precipitate (11 g) was filtered off, washed with water and dried. A portion (500 mg) was purified by preparative TLC and crystallized from DE-PE to give the final product (100 mg), m.p. 224-228°C, [a]D +100°..

Presentations 30-46

Table 2 summarizes the preparation of 11-oxime after

the following method.

A solution of the corresponding 11-ketone in ET was refluxed with a mixture of hydroxylamine hydrogen chloride and aqueous NaOH at pH 11 for the indicated time. The cooled mixture was diluted with W and the precipitate was filtered off, washed and dried. The material obtained was purified by chromatography (CC or TLC) and/or crystallization.

Production 47

lla- amino- 23- ethoxy- 3a- hydroxy- D- homo- 5a- pregnan- 20- one (LXIV)

Na (8 g) was added portionwise to a solution of 23-ethoxy-20,20-ethylenedioxy-3a-hydroxy-D-homo-5a-pregnan-11-one-ll-oxime (4.0 g) in PR ( 200 ml) under reflux. The reflux treatment was continued for 4 hours and then ME (10 ml) was added. The alcoholic solvents were removed by distillation with the addition of W. The cooled aqueous suspension was extracted with EA (3x) and the combined extracts were washed with brine (2x), dried and evaporated to a foam. This was dissolved in EA and extracted with 2N HCl (3x). The pooled aqueous extracts were basified with 0.88 ammonia solution and extracted with EA. The combined EA extracts were washed with saturated saline, dried and evaporated, and the final product is obtained as a foam (2.43 g), [<*]D +40°.

Production 48

3a, 203, 21- trihydroxy- 53- pregnan-ri- one- l, l- oxime (XXXVI)

50% KOH solution (32 mL) was added to a solution of hydroxylamine hydrochloride (16 g) in W (32 mL) with cooling and the resulting mixture was added to a solution of XXII (8 g) in ET (256 mL ). The reaction mixture was refluxed for 4 days, from which ET was distilled off and the mixture was poured into ice-cooled 2N HCl. The steroid was extracted with EA and crystallized from EA to give the final product (6.7 g), m.p. 226-229°, [α]D+82° (c 0.7 D).

Production 49

20, 20- ethylenedioxy- 5a- pregn- 2-en- lla- amine (XXXVII)

A solution of XXXIII (1.85 g) in PR (250 mL) was treated by heating under reflux with Na (20 g) added over 1.5 h. When Na was consumed ME (20 mL) was added and the mixture was diluted to 2 L with W. The mixture was extracted with DE and the extract was washed with W, dried (Na 2 SO 4 ) and evaporated to give the final product as an oil (2 g ).

Production 50

lia- amino- 20, 20- ethylenedioxy.- 2 g- e toxy- 5 a- pregnan- 3 a- ol (XXXVIII)

A solution of XXXIV (4 g) in PR (500 mL) was treated by heating under reflux with Na (40 g) for 1 h. When all the Na had dissolved, ME (20 ml) was added. The mixture was

■ then distilled under constant addition of W until all

PR had been removed. The product was extracted into DE (2 x) and the extract was washed with W (2 x), dried (Na 2 SO 4 ) and evaporated to a foam (3.7 g), which was purified by CC, eluted with ME,

and the final product was obtained as a foam (2.5 g), t ot ] D +13.7°.

Production 51

lia- amino- 20, 20- ethylenedioxy- 5g- pregnan- 3a-ol (XXXIX)

A solution of XXXV (2 g) in PR (250 mL) heated under reflux was treated with Na (20 g) for 1 h. When all the Na had dissolved, ME was added. PR was removed by distillation with careful addition of W. The residue was extracted with DE and the extract was washed with W, dried (Na 2 SO 4 ) and evaporated to give a solid which was purified by CC, eluted with ME and crystallized from MA , and the final product (220 mg) was obtained.

153-155°C, [a]D+5° (c 0.65)

Presentations 52-63

Table 3 summarizes the preparation of lla-amines according to

the following method:

A solution of the corresponding 11-oxime in PR was heated under reflux with sodium. When all the sodium had been converted, PR was distilled and at the same time replaced with W.

The remaining mixture was worked up after one of those

the following methods:

A. The mixture was extracted with (i) DE or (ii) EA, and

the extract was washed, dried and evaporated.

B. The resulting slurry was filtered off, washed and

dried.

The material obtained was purified by crystallization.

Manufacturing. 64

( Z)- lla- amino- 2g- ethoxy- 5a- pregn- 17( 20)- en- 3a-ol (LXV)

A solution heated under reflux (under nitrogen) of (Z)-2g-ethoxy-3a-hydroxy-5a-pregn-17(20)-en-ll-one-11-oxime (450 mg) in PR (15 ml ) were treated with pieces of Na (450 mg). When there were no traces of Na left, the mixture was added to cooled W, and a precipitate of small particles was obtained which was collected by filtration.

The solid was dissolved in EA, dried (Na 2 SO 4 ) and evaporated to a foam which was partitioned between 2N HCl and DE. The insoluble material that separated was collected by filtration and partitioned between EA and 2N NaOH solution. The organic phase was isolated, washed with W, dried (Na 2 SO 4 ) and evaporated to give a foam which was crystallized from PE,

and the final product (110 mg) was obtained, m.p. 65-70°. ^ a^ Q +10°.

Production 65

lla- dimethylamino- 5g- pregnane- 3a, 20g, 21- triol (LIII)

XXXVI (5.75 g) was dissolved in PR (500 mL) and Na (6 g)

was added portionwise under nitrogen. Excess PR was removed in vacuo and EA (1 L) was added to the cooled reaction mixture. The solution was washed with W (4x), dried (MgSO 4 ) and evaporated. The crude amine was dissolved in HCHO (60 mL) and HCOOH (1.2 mL). The solution was heated to 100° for 6 minutes and poured onto ice, basified with 50% NaOH solution and the steroid was extracted with EA. The resulting gum was redissolved in ME (80 mL) and 25% aqueous NaOH (20 mL) was added. The solution was allowed to stand at RT for 45 minutes and then acidified with HCl. The solution was washed with EA and basified with 50% NaOH solution. Extraction with EA gives the material which was triturated with pentane and crystallized from MA-pentane to give the final product (1.8 g), 124-128°.

Production 66

lia- amino- 3a- hydroxy- D- homo- 5a- pregnan- 20- one (LXIII)

20,20-Ethylenedioxy-3α-hydroxy-D-homo-5α-pregnan-11-one-11-oxime (1.87 g) in PR (200 mL) was treated with Na (10 g) and worked up as described in Preparation 47. Crystallization from

EA-PE gave the final product (128 mg), m.p. 154-157°, [α]D +36.1°.

Production 67

Lla- amino- 33- hydroxy- 5a- pregnan- 20- one (XLIV)

To a solution (under nitrogen) of V (7.0 g) in PR

(700 ml) under reflux were added small pieces of Na metal

(14g). When all the Na metal had been consumed, the reaction mixture was evaporated to approx. 200 ml and added cold W. Cooling overnight gave a precipitate which was collected by filtration and then partitioned between 2N HCl and DE. The aqueous phase was basified with 2N-NaOH solution and extracted with DE. The organic extract was washed with W and evaporated to a small volume. The crystalline material that precipitated was collected by filtration and crystallized from DE to give the final product, m.p. 140-152°, [α]D+ 58.3°.

Presentation 68

lla- N- ethylamino- 3a- hydroxy- 53- pregnan- 20- one

XXXIX (1 g) was dissolved in ET (30 mL) and K 2 CO 3 (1 g) and ethyl iodide (3 mL) were added. The reaction mixture was stirred at reflux for 2.5 hours and then evaporated to dryness. The residue was redissolved in ET (10 mL) and 2N HCl (10 mL) at RT,

and after 15 minutes made basic with aqueous KOH. The steroid was extracted with EA and purified by preparative thick layer chromatography using EA-ME (3:1) as eluent to give the final product (201 mg) as a foam, mp +43°.

Production 69

lla- N- butylamino- 3a- hydroxy- 5a- pregnan- 20- one (LXVII)

A solution of 11a-amino-20,20-ethylenedioxy-5a-pregnan-3a-ol (XL) (1.5 g) in 1-iodobutane (20 ml) was treated at 80°C

with K-^CO^(3 g) and stirred for 3 hours. The mixture was partitioned between DE and W and the organic layer was extracted with 2N HCl. The extract was basified with 4N NaOH solution and the oily precipitate was extracted into DE. The extract was washed with W, dried (Na 2 SO 4 ) and evaporated to give a foam (1.5 g).

A portion (500 mg) was purified by preparative TLC in AC to give the final product (350 mg) as an oil. [alD+60°.

Production 70

3a- hydroxy- lia- N- propylamino- 5a- pregnan- 20- one (LXVI)

A solution of XL (1 g) in 1-iodoprpane (10 mL) was stirred under reflux with I^CO^ (3 g) for 40 min, and the mixture was worked up as indicated under Preparation 69.

CC using Me and removing the solvent from

the last fractions gave a residue which was crystallized from PE, and. the final product (450 mg) was obtained, m.p. 138-141°. [ot]D+32°.

Production 71

lla- N- methylamino- 3a- hydroxy- 5a- pregnan- 20- one (LXVIII)

A solution of XL (4 g) in ethyl iodide was stirred with Ag 2 O (12 g) at RT for 2 h. Ag2° was removed by filtration and the filtrate worked up as in Preparation 69. CC and TLC gave the final product (400 mg).

Production 72

llg- N- alylamino- 2 ( 3- e toxy- 3 a- hy droxy- 5 a- pregnan- 20- one

A solution of XXXVIII (750 mg) in ET (10 mL) was treated with allyl bromide (2 mL) and I 2 CO 2 (1 g) at 80° for 3 h. After filtration, the reaction mixture was evaporated to dryness and the residue distributed between EA and salt solution (adjusted to approx. pH 9 by addition of 2N Na2CO3). The aqueous layer was extracted with additional EA and the combined extracts washed with brine, dried (Na 2 SO 4 ) and evaporated. Preparative TLC gave the final product as a gum (107 mg).

Production 73

lla- ethylamino- 5g- pregn- 2- en- 20- one (XLII)

XXXVII (1 g) was mixed with acetaldehyde (0.4 ml) i

ET (20 mL) at 21° and sodium cyanoborohydride (400 mg) were added. After 15 minutes, the clear solution was made alkaline with NaHCO 3 solution. Brine was added and the mixture was extracted with EA (3x). The combined organic solutions were washed with saline (3x) and then shaken with 2N HCl. Excess of 40% aqueous NaOH solution was added and the layers separated. The organic solution was washed with brine (2x) and evaporated to dryness. The resulting oil was chromatographed on EA-PE to give the final product as a crystalline solid (774 mg). A sample was recrystallized from ET-W. and showed m.p. 105-108°. [a]^ + 89.6°.

Production 74

lla- N- cyclohexylamino- 2p- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one

XXXVIII (0.5 g) was mixed with cyclohexanone (2 mL) in ET (20 mL) at RT and NaBH 2 CN (250 mg) and acetic acid (0.1 mL) were added. After 20 hours, the mixture was worked up as indicated in Preparation 73 and purified by TLC to give the final product (268 mg) as a foam, [a] + 26.6°.

Production 75

lla- N- benzylamino- 2P- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one

XXXVIII (0.5 g) was mixed with benzaldehyde (1 ml) i

ET (10 mL) at RT and NaBH 2 CN (250 mg) and acetic acid (0.1 mL) were added. After 1 hour, the mixture was worked up as in Preparation 73 and purified by CC and TLC, and the final product (205 mg) was obtained as a foam, ta]D+34.1°.

Production 76

lla- isopropy. lamino- 5a- pregn- 2- en- 20- one (XLIII)

XXXVII (200 mg) was mixed with AC (0.2 mL) in ET (5 mL) containing NaBH 2 .CN (200 mg); After 3.5 hours, the mixture was worked up as in Preparation 73 and purified by CC in EA-PE, followed by recrystallization from ET-W, and the final product (55 mg) was obtained, m.p. 99-101°, [α]D +80.6° (c 0.5.2).

Production 77

3a-hydroxy-N-isopropylamino-5P-pregnan-20-one

XXXIX (920 mg) was dissolved in ET (40 mL) and added to NaBH 3 CN (450 mg). AC (4 mL) was added, followed by acetic acid (0.2 mL) and the reaction mixture was kept at RT for 17 h. The reaction mixture was divided into two parts for extraction.

(a) The solution was partitioned between EA and Na 2 CO 3 ~ solution and the organic layer was washed well with W., dried (MgSO 4 ) and evaporated to dryness. The residue was dissolved in ME (10 mL) and 2N HCl (10 mL) was added. The mixture was allowed to stand at RT for 30 minutes and then basified with Na^CO^ solution and

the steroid extracted with EA.

(b) The second portion of the reaction mixture was partitioned between EA and Na-jCO 3 solution as in (a) above and the organic layer was then shaken with 2N HCl. and allowed to stand for 30 minutes. The reaction mixture was then basified with NaHCO 3 and extracted with EA. The combined EA extracts were washed with water, dried (MgSO 4 ) and evaporated. (a)<p>g (b) was collected and subjected to thick plate chromatography using EA as solvent and the steroid was eluted with EA-ME to give the final product

(590 mg) , [<x]D+38°.

Production 78

( Z)- lla- N- ethylamino- 5a- pregn- 17( 20)- en- 3a-ol

NaBH 2 CN (398 mg) was added to a solution of XLI (1.027 g) in ET (30 mL) and when the solution was complete, acetaldehyde (9 mL) was added. After 35 minutes the solution was diluted with 2N HCl and W and washed with EA, basified with 2N NaOH and the precipitate was extracted into EA. The washed organic extract was evaporated in vacuo to give an oil. Purification by preparative TLC (Me-EA 1:1) gave an oil, which crystallized on trituration with a little AN. Recrystallization from. W-AN gave the final product (287 mg), m.p. 106-109°, [α] -19.9°.

Production 79

(Z)-lla-isopropylamino-5a-pregn-17(20)-en-3a-ol

A solution of XLI (422 mg) in IMS (6 mL) containing AC (1 mL) was treated with NaBH^CN and the resulting mixture was worked up as described in Preparation 78. Purification by TLC (Et-CH 1:1) gave the final product (180 mg) as a foam.

Production 80

23- ethoxy- 20, 20- ethylenedioxy- lla-(4- methylpent- 2- ylamino)- 5 a-pregnan- 3a-ol, isomers A ( L) & B. ( LI)

XXXVIII (1.06 g) was refluxed with 4-methyl-pentan-2-one (2 mL) in PR (40 mL) under nitrogen for 20 h. Refluxing under nitrogen was maintained and Na (4 g) was added for 3 hours. W (ca. 50 ml) was added and . PR was evaporated at reduced pressure. The aqueous residue was extracted with EA. The combined extracts were washed with brine, dried (N 2 SO 4 ) and evaporated to a gum. This was purified by preparative TLC developed in ME-EA (1:9) to separate isomers of the final product, and isomer A (333 mg) (gum) and isomer B (322 mg) (gum) were obtained.

Production 81

lla- N- ethyl- N- methylamino- 5a-pregn- 2- en- 20- one (XLVI)

XLII (658 mg) was heated at 100° for 5 min with formic acid (0.32 mL) in aqueous HCHO solution (37% solution,

2.5 ml). The mixture was cooled to 21° and an excess of aqueous Na 2 CO 3 solution was added. The mixture was extracted with EA and the combined organic layers were washed with brine, dried and evaporated to dryness. The remaining gum was filtered through silica gel in EA-PE (1:9). Evaporation of the eluate gave the final product (477 mg), [a]D+ 111°.

Production 82

lla-N-isopropyl-N-methylamino-5a-pregn-2-en-20-one (XLVII)

Reaction of XLIII (838 mg) with 37% aqueous HCHO (3.3 mL) containing formic acid (0.43 mL) in a similar manner as described in Preparation 81 and recrystallization from ET-W gave the final product (643 mg), sm. p. 88-99°, [α]D+113.5°.

Production 83

lla-N,N-dimethylamino-5α-pregn-2-en-20-one (XLV)

XXXVII (8.2 g) was heated at 95° to 110° in HCHO

(37% aqueous solution, 32 mL) and formic acid (4 mL) for 6 min. The mixture was rapidly cooled and partitioned between EA and 2N Na 2 CQ 3 solution. The aqueous layer was extracted with EA and the combined organic solutions were washed with brine before evaporation to give a solid which was dissolved in EA and filtered through silica gel. The eluate was evaporated and the residue was crystallized from ME, and the final product was obtained - (4.0 g),

sm.p. 123-126°, [a] + 110°.

Production 84

lla- N, N- dimethylamino- 5a- pregnane- 3a, 203, 21- triol (LII)

11a-amino-5α-pregnan-3α,203f21-triol (950 mg) was dissolved in ME (20 mL) and methyl iodide (10 mL) and stirred at RT with K 2 GO 3 (3 g) for 4 h. Workup as in Preparation 69 and purification by TLC in AC and recrystallization from DE gave the final product (160 mL), m.p. 121-125°, [α] -16.7°.

Presentation 85

lla- N, N- dimethylamino- 23- ethoxy- 20, 20- ethylenedioxy- 5a- pregnan- 3a-ol

(LXI)

XXXVIII (5.0 g) was dissolved in a mixture of 40% aqueous HCHO (60 mL) and 98-100% formic acid (2.1 mL) and the resulting solution was heated on a steam bath for 15 minutes. The solution was cooled, diluted with W (190 mL) and saturated aqueous NaHCO 3

(25 ml) and pH brought to 11 by addition of NaOH (0.3 g) dissolved in W (30 ml). The resulting precipitate was collected by filtration, washed with W and dried to give the final product (5.41 g), [α]D+ 57.5°, m.p. 70°.

Production 86

11g- dimethylamino- 33- hydroxy- 5a- pregnan- 20- one (LVII)

A mixture of XLIV (0.5 g), 37% HCHO solution (3 ml). and 98% formic acid (0.3 ml) was held at 100° for 3 minutes before pouring into aqueous NaHCO 3 solution. The precipitate was collected by filtration and partitioned between EA and 2N HCl.

The acid phase was basified with 2N NaOH solution, extracted with EA, washed with W and evaporated to a foam.

CC (EA-PE 1:2) and crystallization from EA-PE gave the final product (300 mg), m.p. 119-121°, [a] + 68.0°.

Production 87

lla- N, N- dimethylamino- 2a, 3a- epoxy- 5a- pregnan- 20- one (LXIX)

XLV (1.9 g) and PTSA (1.0 g) were dissolved in DC (150 mL)

and added m-chloroperbenzoic acid (1.24 g). After stirring the mixture at 20° for 15 hours, the organic solution was washed successively with dilute aqueous Na 2 S 2 O 3 solution, NaHCO 3 solution and W. Each time the organic layer was extracted

back with DC. The combined organic solutions were dried (MgSO 4 ) and evaporated. The residue was filtered through silica gel

in 1:3 EA-PE and the eluate evaporated, and crystals were obtained which on recrystallization from PE gave the final product (0.51 g), m.p. 154-157°, [α]D+80.0°.

Production 88

2a, 3a- epoxy-lla- N- ethyl- N- methylamino- 5a- pregnan- 20- one

XLVI (6.0 g) and PTSA (3.21 g) were dissolved in DC (300 mL)

and added m-chloroperbenzoic acid (4.4 g). After 1 hour, the mixture was worked up as in Preparation 87 (except that DM was used instead of DC). Cleaning by CC upon application

of EA-PE gave the final product (4.49 g), [α]D+79.5°.

Production 89

2a, 3a- epoxylla- N- isopropy1- N- methylamino- 5a- pregnan- 20- one

XLVII (300 mg) and PGSA (154 mg) were dissolved in DC (30 mL) and m-chloroperbenzoic acid (210 mg) was added. After 30 minutes

additional oxidizing agent (60 mg) was added. After a further 30 minutes, the mixture was worked up as for Preparation 87. Purification by preparative TLC (EA-PE) and recrystallization from W-ET gave the final product (114 mg), m.p. 114-116°, [α]D + 84.5°.

Preparation 90

2a, 3a- epoxy- 5a- androstane- ll, 17-dione (XLVIII)

A mixture of XXVII (37.2 g), m-chloroperbenzoic acid

(30 g) and CH (600 ml) were allowed to stand for 0.5 h at RT before partitioning between CH and saturated aqueous NaHCO 3 solution. The organic phase was isolated and washed with W, dried and evaporated to a small volume. Addition of PE, followed by cooling overnight gave a crystalline material (27.5 g). Recrystallization from EA-PE gave the final product, m.p. 166-167° [a]D+126°.

Production 91

2( 3- ethoxy- 3a- hydroxy- 5a- androstane- ll, 17-dione (XLIX)

A solution of XLVIII (5.0 g) in absolute ET (250 mL) was treated with 8 drops of fuming H 2 SO 4 at RT. After 45 minutes, the reaction mixture was treated with aqueous NaHCO 3 and evaporated

to low volume. W was added to the mixture which was then cooled overnight. The precipitate was collected by filtration, washed with W and dried. Recrystallization from W-ET gave the final product (2.1 g), m.p. 164-167°, [a] +114°.

Production 92

( Z) "- 2p- ethoxy- 3a- hydroxy- 5a- pregn- 17 ( 20) - en- ll- one

A mixture of XLIX (1.742 g), ethyltriphenylphosphonium iodide (6.27 g), sodium hydride (360 mg) and Na-dried tetrahydrofuran (100 mL) was stirred and refluxed under nitrogen. After 4.5 hours, the reaction mixture was partitioned between EA and W. The organic phase was isolated, washed with W, dried (Na 2 SO 4 ) and evaporated to give an oil (4.0 g). CC (EA-PE 1:2) followed by preparative TLC (EA-PE 1:1 x 2) and crystallization from EA-PE gave the final product (110 mg), m.p. 172-178°, [a] +25°.

Production 9 3

lia- amino- 2g- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one (LIX)

XXXVIII (10 g) was suspended in W (38 mL) and treated with concentrated HCl (12 mL). The insoluble material remained

removed by filtration and washed with a small portion of W. This . material was resuspended in W (50 ml) and treated with 2N NaOH to pH 9. The mixture was stirred at 0° for 10 minutes and the solid was filtered off, washed with W to give the final product, m.p. 160-164°, [α]D+79.2°.

Production 9 4

lia- amino- 3a- hydroxy- 5p- pregnan- 20- one (LX)

XXXIX (2 g) was dissolved in ME (20 mL) and added

2N HCl (20 mL)..The reaction mixture was kept at RT for 15 min, basified with ice-cold NaOH solution, and the

The white solid was filtered off. Crystallization from ME-W gave the final product (1.13 g), m.p. 128-130°.

Production 95

2p- ethoxy- 3a- hydroxy- lla-(4- methylpent- 2- ylamino)- 5a- pregnan-20- one, isomer A

L (330 mg) was dissolved in ME (20 mL) and 2N HCl (0.5 mL) was added. After 15 minutes at 21°, the mixture was neutralized with 2N Na 2 CO 3 solution and evaporated to a small volume. The residue was partitioned between EA and saline. The aqueous layer was extracted with additional EA and the combined organic solutions were washed with brine (2x), dried (Na2SO4) and evaporated to dryness (310 mg). Purification by preparative TLC developed in 5% ME in EA and EA gave the final product as a white foam, [Q]D"1°

Preposition 96

23- ethoxy- 3a- hydroxylia-( 4- methylpent- 2- ylamino)- 5a- pregnan-20- one, isomer B

LI (322 mg) was treated as described in Preparation 95 to give the final product (170 mg) as a white foam,

[a]D+2.1° (c 0.36).

Production 97

lla- N, N- dimethylamino- 3a- hydroxy- 5a- androstane- 173~ carbaldehyde oxime (LV)

A solution of LI-I (250 mg) in D (15 ml) and W (3 ml) was treated with periodic acid (1 g) for 30 min. Aqueous NaOH-. solution (2N, 10 mL) and W (200 mL) were added and the oily precipitate was extracted into DE. The extract was washed with W, dried (Na 2 SO 4 ) and evaporated to give 11a-N,N-dimethylamino-3α-hydroxy-5α-androstane-173-carbaldehyde as a foam (185 mg).

The aldehyde was dissolved in ET (50 mL) and a mixture of NH 2 OH.HCl (300 mg) and NaOH solution (2N, 5 mL) was added to pH 11. After 15 min the mixture was diluted with W and the precipitate was extracted into DE. The extract was washed with W, dried (Na 2 SO 4 ) and evaporated to give a foam which was crystallized from PE-DE to give the final product (130 mg), m.p. 107.5-110°C, [α]D+4°.

Production 98

lla- N, N- dimethylamino- 23~ ethoxy- 3a- hydroxy- 5a- androstane- 173~ carbaldehyde oxime (LVI)

XXXI (650 mg) was treated as indicated under Preparation 97 and crystallized from hexane-DE to give the final product (380 mg), m.p. 99-102°, [α]Q+12°.

Preparation 99

lla- dimethylamino- 3a- hydroxy- 53- androstane- 173- carbaldehyde (LIV)

LIII (1.3 g) was dissolved in D (65 mL) and added

periodic acid (1.3 g) in W (6.5 mL). The reaction mixture was kept at RT for 15 min, poured into aqueous NaHCO 3 and the steroid was extracted with EA. A portion of the steroid (300 mg) was subjected to preparative thick plate chromatography using EA-PT

1:3. Elution with ME gave the final product as a foam (150 mg), [α]D +24° (c 0.5).

Production 100

3a- acetoxy- lla- dimethylamino- 5( 3- androstane- 173- carbonitrile (LXXI I)

50% aqueous KOH (4 mL) was added to a solution of NH 2 OH.HCl (2 g) in W (4 mL) with cooling. This resolution

was then added to LIV (860 mg) in ET (32 mL) and the mixture was held at RT for 10 min. Dilution with W and

extraction with EA gave the 173-oxime (890 mg).

This material was dissolved in acetic anhydride (20 mL)

and refluxed for 15 minutes. After dilution with ice-cold aqueous NaHCO 3 solution, the mixture was stirred for an additional 30 minutes. The steroid was extracted with EA and subjected to preparative TLC using EA-PT 1:3 as. solvent. Elution with ME and crystallization from EA-ME

gave the final product (560 mg), m.p. 148-152°.

Manufacturing 101

3a- acetoxy- lla- N, N- dimethylamino- 5a- androstane- 173~ carbonitrile

(LXX)

A solution of LV (1.30 g) in acetic anhydride (20 mL) was refluxed for 1 hour. The mixture was poured onto ice-cooled, saturated NaHCO 3 solution (300 mL) and the precipitate was extracted into DE. The extract was washed with W, dried (Na 2 SO 4 )

and evaporated to give a foam which was purified by preparative TLC

in EA-PE (1:5) and crystallized from DE to give the final product (300 mg), m.p. 167-171°C, [α]D+53°.

Manufacturing 102

3a- acetoxy- lla- N, N- dimethylamino- 2g- ethoxy- 5a- androstane- 17g- carbonitrile (LXXI)

LVI (500 mg) was treated as described in Preparation 101 and purified by preparative TLC in AC-PE to give the final product (380 mg), [<x]D+57°.

Production 103

lla- N, N- dimethylamino- 5a- pregnane- 3, 20-dione (LVIII)

A cold solution of LVII (181 mg) in AC (10 mL) was treated dropwise with Jones reagent (0.25 mL) (prepared from CrO 3 (66.7 g) in W and conc. H 2 SO 4 (53.3 mL) dil. to 250 ml with W). The reaction mixture was partitioned between EA and aqueous NaHCO 3 solution, the organic phase was isolated, washed with W, dried (Na 2 SO 4 ) and evaporated to a solid (170 mg). Crystallization from DE-PE gave the final product (158 mg), m.p. 146-152° [α]D+ 62.5°.

Production 104

17, 17- ethylenedioxy- 2g- ethoxy- 3a- hydroxy- 5a- androstane- ll-one

(LXXVI)

A mixture of XLIX (8.0 g), PTSA (160 mg), ethylene glycol (13 mL), triethyl orthoformate (8.3 mL), and CH (80 mL) was kept at RT overnight before partitioning between CH and saturated NaHCO^ -resolution. The organic phase was isolated, washed with W and dried (Na^O^). Evaporation of this solution gave a foam which was purified by preparative TLC (AC-PE) and crystallization from EA-PE to give the final product (60 mg), m.p. 142-145°, [α]D+18.2°.

Preparation 105

17, 17- ethylenedioxy- 2g- ethoxy- 3a- hydroxy- 5a- androstane- 11-one- ll-oxime (LXXVII)

A mixture of LXXVI (8.2 g), NH 2 OH.HCl (15 g), 44% aqueous NaOH (90 mL) and ET (500 mL) was stirred and refluxed for 2 4 h before evaporation to ca. half volume. Addition of W followed by cooling overnight gave a precipitate which was collected by filtration, washed with water and dried (6.4 g). Crystallization from EA-PE gave the final product, m.p. 136-140°, [α] +41.1°.

Production 106

lia- amino- 23- ethoxy- 3a- hydroxy- 5a- androstane- 17- one (LXXVIII)

LXXVII (5.7 g) in PR (400 mL) under reflux was treated with small pieces of Na metal (7.5 g) under N 2 . The reaction mixture was evaporated to a small volume and partitioned

between EA and W. The organic phase was washed with W, dried (Na-^SO^) and evaporated to a foam. This foam was partitioned between 2N HCl and PE. The acid layer was basified with 2N NaOH and extracted with EA. The EA phase was washed with W,

dried (Na2SO4) and evaporated to a foam. Crystallization with DE gave the final product (2.43 g), m.p. 144-148° [α]D+61.5°.

Production 107

lla- dimethylamino- 2g- ethoxy- 3a- hydroxy- 5a- androstane- 17- one (LXXIX)

A solution of LXXVIII (2.2 g), HC0 2 H (1.2 ml) and

HCHO (12 mL) was maintained at ca. 100° for 3 minutes before it was poured into saturated NaHCO 3 solution. Vigorous stirring gave a precipitate which was collected by filtration, washed with W and dried. CC (EA-PE) followed by PTLC (EA-PE) and crystallization from ET-W gave the final product, m.p. 65-68°, [α]D+41.7°

Production 108

Ila- aminotigogenin

11-oxotigogenin-11-oxime (2.0 g) in PR (140 mL) was heated to reflux and Na (10 g) added.

When the Na was reacted, the PR was distilled from and the volume was maintained by the addition of W. The aqueous liquids were extracted with EA

and the extract was washed with W, dried (Na 2 SO 4 ) and evaporated. The solid residue was crystallized from EA-PE to give the final product (450 mg), m.p. 180-182°, [α] -72.5°.

Production 109

33, 26- diacetoxy- lla- N, N- dimethylamino- 5a- furost- 20( 22)- ene (LXXX)

11a-dimethylaminotigogenin (2.0 g) in acetic anhydride

(6 ml) and PY (3 ml) were heated on a steam bath for 30 minutes. The mixture was evaporated and a solid was obtained. This was

dissolved in octanoic acid (10 mL) and acetic anhydride (1 mL), and the mixture was distilled under N 2 until the temperature of the mixture reached 240°. This temperature was maintained for 2 hours after which the mixture was allowed to cool and was extracted into EA. The extracts were washed with dilute NaHCO 3 solution and W and evaporated to give a gum. This was dissolved in ME (20 mL), treated with KOH (2.0 g) and heated on a steam bath for 2 hours. The product was precipitated by addition of hot W and isolated by filtration. This was dissolved in acetic anhydride (6 mL) and PY

(3 ml) and heated on a steam bath for 30 minutes. The unclean. the product was isolated by evaporation and was then purified by CC and crystallized from DE to give the final product (500 mg), m.p. 131-134°, [ct]D +4.2°.

Production 110

33~ acetoxy- lla- N, N- dimethylamino- 5a-pregn- 16- en- 20- one (LXXXI)

LXXX (2.0 g) in acetic acid (21 mL) was cooled to 10° in

a water bath and treated with CrO^ (800 mg) in W (7 ml). The reaction mixture was stirred for 30 minutes and poured into B and W. The B liquids were separated and the aqueous liquids were extracted with B. The combined B extracts were washed with dilute NaHCO 3 solution and W, filtered and evaporated to give crude 33-acetoxy-lla-N,N-dimethylamino-163-(5-acetoxy-4-pentanoyloxy)-5a-pregnan-20-one

(1.9 g) as a foam.

The foam (1.9 g) in acetic acid (5 ml) as contained traces

of PY was heated under reflux for 30 min. The mixture was allowed to cool and was evaporated, and an oil was obtained. This was dissolved in EA, washed with 5% NaHCO^ solution and W. The EA liquids were dried (Na-^SO^) and evaporated, and a foam was obtained. This was purified by preparative TLC to give the final product (250 mg), [a]D+9.3 .

Production 111

lla- N, N- dimethylamino- 33~ hydroxy- 5a- pregn- 16- en- 20- one (LXXXII)

LXXXI (6.0 g) in D (100 mL) was treated with KOH

(2.0 g) in W (20 mL) and stirred at RT for 72 h. The solution was concentrated by evaporation, diluted with W and extracted with EA. The extracts were washed with W, dried (Na-2SO4) and evaporated to give a foam. This was purified by CC and crystallized from EA to give the final product (466 mg), m.p. 135-140°,

[a] +12.9°.

Production 112

lla- N, N- dimethylamino- 3a- hydroxy- 5a- pregn- 16- en- 20- one (LXXXIII)

LXXXI I (900 mg) in THF (35 mL) was treated with HCQ 2 H (0.27 mL) and triphenylphosphine (1.96 g) and stirred at RT for 15 min. Diethyl azodicarboxylate (865 mg) in THF (8 mL) was slowly added to the reaction mixture and the solution was stirred at RT for 6 h. The reaction mixture was concentrated by evaporation and the residue was dissolved in EA and washed with NaHCO 3 solution and W. The EA liquids were dried (Na 2 SO 4 ) and evaporated to give a solid. This was purified by CC and impure 3a-formate was obtained. This

was dissolved in ME (10 mL), treated with 60% HC104 (12 drops)

and stirred at RT for 3 h. The reaction mixture was concentrated by evaporation, diluted with 5% NaHCO 3 solution (10 mL) and W (20 mL) and extracted with EA. The EA extracts were washed with W, dried (Na 2 SO 4 ) and evaporated to give a foam. This was purified by preparative TLC to give the final product as a foam (300 mg), [ a] D +16°.

Production 113

lla-N,N-dimethylaminotigogenin

11a-aminotigogenin (1.1 g) in HCHO (25 ml) and HCO 2 H

(0.25 ml) was heated to approx. 100° for 15 minutes. The solution was allowed to cool, diluted with saturated NaHCO 3 (50 mL) and W

(150ml). The precipitated product was isolated by filtration and crystallized from ME-W to give the final product (256 mg),

sm.p. 103-105°, [α]D-78.1°.

Preparation 114

lla- aminopregn- 4- en- 3, 20-dione (LXXXIV)

40% aqueous NaOH (60 mL), and then NF^OH.HCl (15 g) was added to a suspension of 3,3;20,20-bisethylenedioxypregn-5-en-11-one (5.0 g ) in ET (200 mL). The mixture was heated under reflux for a total of 107 hours, then cooled and diluted with W (2 L) with stirring. The precipitate (5.01 g) was collected, washed with W (2 L) and dried in vacuo at 60° over P2°5'PMR~spectrum (CDCl^) showed that the material contained 3,3;20,20-bisethylene- dioxypregn-5-en-11-one-ll-oxime.

Na (4.5 g) was added portionwise over 30 minutes to a stirred, refluxing solution of the oxime (4.50 g) in

PR (225 ral). The mixture was heated under reflux i

2 h, and then ME (10 mL) was carefully added. The alcohol solvents were then removed by distillation adding W (225 mL) to maintain volume. It. resulting aqueous suspension was cooled and extracted with EA

and the extract was washed with saturated saline, dried and

evaporated to a solid. This was partitioned between 2N HCl and EA. The aqueous portion was washed with EA, then overlayed

with EA, made basic with 0.88 ammonia solution and the layers separated. The aqueous layer was extracted with additional EA,

and then the combined extracts were washed with saturated saline, dried and evaporated to a solid. This was crystallized from EA-PE, and the final product (1.12 g) was obtained,

sm.p. 146-148°, [<x]D+180°.

Production 115

lla-dimethylaminopregn-4-ene-3,20-dione (LXXXV)

H 2 H (0.29 mL) was added to a suspension of

LXXXIV (1.00 g) in HCHO (8 mL) and the mixture was heated to

about. 100° for 15 minutes, then cooled and partitioned between 5% aqueous NaHCO 3 and EA. The organic extract was washed with saturated saline, dried and evaporated. The rest became crystal-

lysed from AN, and the final product (0.67 g) was obtained, m.p. 159-

162°, [a]D+174°.

Example 1

l la- N, N- dimethylamino- 23- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one

A solution of XXXVIII (500 mg) in methyl iodide (5 ml)

was stirred with K 2 CO 3 (1.5 g) for 2 h. The mixture was partitioned between DE and W, and the organic phase was extracted with 2N HCl.

The pooled extracts were washed with DE and basified with

6N NaOH. The oily residue was extracted into DE and the extract was washed with W, dried (Na 2 SO 4 ) and evaporated to give a

foam which was purified by preparative TLC in AC-PE (1:3) and crystallization from PE-DE to give the final product (180 mg),

sm.p. 139-143°C, [a] +84°.

Example 2

lla- N, N- dimethylamino- 23- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one

XXXVIII (10 g) was stirred in a mixture of HCHO-. solution (120 mL) and formic acid (4.3 mL) at RT for 6.5 h.

DM (40 mL) was added to the mixture as follows

was adjusted to pH 11 with NaOH solution. The organic phase was separated, washed with W and extracted first with a solution of concentrated H 2 SO 4 (4.0 mL) in W (70 mL) and then with W.

The acidic extracts were collected and adjusted to pH 11 with NaOH solution and again extracted with DM. The organic extracts were washed with W and evaporated under reduced pressure to give a solid which was purified by filtration through silica gel in DM-MA (9:1) and crystallization from AC-W which gave the final product (6.43 g) , [a] +84.1°, m.p. 123-131°.

Example 3

lla- dimethylamino- 3a- hydroxy- 53- pregnan- 20- one

XXXIX (500 mg) was partially dissolved in HCHO (10 mL) and formic acid (0.2 mL) and the reaction mixture was heated to ca. 100° under nitrogen for 5 minutes. The reaction mixture was poured into NaHCO 3 solution and the steroid was extracted into EA and the extract was washed with VJ. The organic layer was extracted with 2N HCl and the extract was basified with NaOH solution and extracted with EA. Removal of the solvent from the extract left a foam which was dissolved in a small amount of CH and added to a column of silica in PT. Elution with EA-PT (1:1) and removal of the solvent from the eluate gave the final product as a white foam (370 mg), [α]Q+ 83° (c, 1.5).

Example 4

lia- dimethylamino- 3a- hydroxy- 53- pregnan- 20- one

XXXIX (2.8 g) was dissolved in methyl iodide (30 mL) and K 2 CO 3 (3 g) was added. The reaction mixture was stirred for 17 hours, methyl iodide was evaporated and the solid residue was partitioned between EA and W. The organic layer was washed with W, dried (MgSO 4 ) and evaporated. The residue was dissolved in a small volume of CH and added to a column of basic aluminum oxide (60 g) in PT. The column was washed with EA and the eluate was evaporated, and a foam was obtained.

The foam was dissolved in ME (20 mL), 2N HCl (5 mL) was added and the solution was allowed to stand at RT for 15 min and was poured into ice-cold NaHCO 3 solution. The solid was filtered off and purified by preparative TLC using AC-PT (1:3)

as a solvent. Elution with EA gave the final product (800 mg), [ a] Q +85°.

Example 5

lla- dimethylamino- 3a- hydroxy- 53- pregnan- 20- one

XXXIX (200 mg) was stirred at RT with HCHO (4 mL) and formic acid (0.08 mL) for 23 h. The solution was poured into 2N HCl

(20 mL) and held at RT for an additional 15 min. Dilution

with aqueous NaHCO 3 solution and extraction with EA gave the final product, which gave similar TLC and gas chromatography to the product of Example 3.

Examples 6- 2 3

A. The llct-amine was heated to approx. 100° with formic acid in aqueous HCHO, the mixture was cooled and partitioned between EA and 5% aqueous NaHCO 3 solution. The EA extract was extracted with 2N HCl and the aqueous extract was basified with 40% NaOH solution, extracted again with EA, washed with W, dried and evaporated.

B. The lla amine was stirred at R.T. (unless otherwise stated) with an alkyl halide and P^CO^. The reaction mixture was then worked up by one of the following methods: (i) K 2 CO 3 was filtered off and the alkyl halide removed under reduced pressure. The mixture was partitioned between EA and W and the organic phase extracted with 2N HCl. The aqueous layer was basified with aqueous NaOH solution and extracted with EA. The EA layer was washed, dried and evaporated.

(ii) The mixture was partitioned between (a) DE or (b) CH and W

and the organic phase extracted with 2N HCl. There the acid phase was made basic with aqueous NaOH solution and extracted again with DE. The extracts were washed, dried and evaporated.

(iii) As stated under Exhibit 72.

(iv) The mixture was diluted with DE and W and the organic layer was washed with W, dried and evaporated.

The material obtained by one of these methods

was purified by CC and/or preparative TLC and/or crystallization.

Example 2 4

11a- diethylamino- 3a- hydroxy- 53~ pregnan- 20- one

XXXIX (0.5 g) was dissolved in ET (25 mL) and acetaldehyde (5 mL) and NaBH 2 CN (250 mg) were added. The reaction mixture

was kept at RT for 15 min and then acidified with

2N HCl. After a further 15 minutes, the solution was basified with KOH and extracted with EA. Crystallization from Me-W gave the final product (354 mg), m.p. 123-125°, [α]D+ 36°.

Example 25

11a-diethylamino-3a-hydroxy-53-pregnan-20-one

XXXIX (50 mg) was dissolved in ET (2.5 mL) and acetaldehyde (0.25 mL) and NaBH 2 (25 mg) were added. The reaction mixture was kept at RT for 30 minutes and then worked up as in Example 24, and the final product was obtained, which by gas chromatography was identical to the product in Example 24.

Example 2 6

2g- ethoxy- 3a- hydroxyl- lla- piperidino- 5a- pregnan- 20- one

XXXVIII (0.5 g) was mixed with 25% aqueous glutardialdehyde solution (2 mL) in ET (10 mL) at RT and added NaBH 2 CN (250 mg) and acetic acid (0.1 mL). After 6 hours, the mixture was worked up as in Preparation 73 and purified by CC

and TLC and the final product (211 mg) was obtained as a foam.

[a]D+ 35.2°.■

Example 2 7

3a-hydroxyl-lla-piperidino-5g-pregnan-2Q-one

XXXIX (1 g) was mixed with NaBH^CN (500 mg) and added a 25% aqueous solution of glutardialdehyde (5 mL) in ET (10 mL) at RT and acetic acid (0.2 mL). After 3 hours, the mixture was partitioned between EA and NaHCO 3 solution. The organic solution was washed with 2N HCl and the combined acid extract was washed with EA, basified using 50% NaOH solution, extracted with EA, washed with W, dried (MgSO 4 ) and evaporated to give a foam .

This material was purified by preparative TLC by elution with ME containing approx. 1% W and the solution was evaporated.

The product was then dissolved in DE, filtered and evaporated to give the final product (318 mg), [ct]D + 58.5°.

Example 2 8

lia- dimethylamino- 2p- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one (a) LIX (200 mg) heated to approx. 100° with HCHO (4 ml) and formic acid (0.08 ml) for 10 minutes.

The reaction mixture was then poured into NaHCO 3 solution and the steroid was extracted with EA. Preparative TLC using AC-PT (3:7) and crystallization from DE-PT gave the final product (50 mg), m.p. 140-143°. (b) LIX (250 mg) was dissolved in EA (25 mL) and 37% aqueous HCHO (0.5 mL). 10% palladium-on-charcoal (250 mg) was added and the solution was hydrogenated for 17 hours. The catalyst was removed by filtration through diatomaceous earth and the solution was washed with W, dried (MgSO 4 ) and evaporated to dryness. Preparative TLC using CH-MA-ME (49:49:2), followed by crystallization from AC-W, gave the final product (100 mg), m.p. 129-134°. (c) LIX (100 mg) was dissolved in EA (10 mL) and HCHO (0.2 mL). Tris(triphenylphosphine)chlororhodium (50 mg) was added and the solution was hydrogenated for 17 hours. It was then washed with W and the organic layer was dried (MgSO 4 ) and evaporated to dryness. Thick plate chromatography using MA-PT-ME (33:65:2) as solvent gave the final product

(30 mg) which by TLC and gas phase chromatography is identical to the product in part (a).

Example 29

lla- N, N- dimethylamino- 3a- hydroxy- 5g- pregnan- 20- one (LXXIII)

(a) LX (50 mg) was stirred at RT with HCHO (1 mL) and formic acid (0.02 mol) for 23 h to give the final product corresponding to the product of Example 3 by TLC. (b) LX (50 mg) was dissolved in EA (10 mL) and paraformaldehyde (100 mg) and 10% platinum-on-carbon (50 mg) were added. The reaction mixture was stirred for 17 hours under hydrogen, and the final product was obtained which was identical to the product in example 3 by TLC.

(c) LX (100 mg) was dissolved in EA (10 mL) and HCHO was added

(1 ml) and 10% Pd/C (100 mg). The reaction mixture was hydrogenated

for 17 hours and the catalyst removed by filtration through diatomaceous earth. The solution was washed with W, dried (MgSO 4 ) and evaporated to dryness to give the final product (110 mg)

which by TLC and PMR spectroscopy resembled the product of Example 3.

(d) A solution of HCHO in EA (20 mL; prepared by heating paraformaldehyde at 200° and bubbling HCHO gas in EA for 5 min) was added to LX (100 mg) and 10% Pd/C (100 mg )

in EA (5 ml). The reaction mixture was stirred with hydrogen

30 minutes, and the end product was obtained which was identical by TLC

with the product in example 3.

Example 30

lla- N, N- dimethylamino- 2g- ethoxy- 3a- hydroxy- 21- methy1- 5a- pregnan- 20- one

LXII (1.00 g) was heated for 10 minutes at approx. 100°

in a mixture of HCHO solution (20 ml) and formic acid (0.4 ml).

The cooled reaction mixture was diluted with 5% NaHCO 3 solution (50 mL) and extracted with EA. The organic extracts

was extracted with 2N HCl, basified with 40% NaOH solution

to pH 11 and re-extracted with DM. The extract was dried (Na 2 SO 4 ) and evaporated to give a foam which was purified by CC using EA as eluent to give the final product as a foam (828 mg), [a]D +72°.

Example 31

lla- dimethylamino- 3a- hydroxy- D- homo- 5a- pregnan- 20- one

A suspension of LXIII (656 mg) in HCHO (5 ml) was

treated with formic acid (0.21 mg) and the mixture heated to

about. 100° for 5 minutes. The cooled solution was partitioned between EA and 2N Na 2 CO 3 . The organic portion was washed with brine, dried and evaporated to give a foam (704 mg).

This was purified by preparative TLC (ME) and crystallization from

ME, and the final product was obtained, m.p. 116-118°, [α]D+41.5°.

Example 32

lla- dimethylamino- 2g- ethoxy- 3a- hydroxy- D- homo- 5a- pregnan- 20- one

Formic acid (0.29 mL) was added to a suspension of LXIV

(1 g) in HCHO. The mixture was heated on a steam bath for 20 minutes,

cooled and partitioned between EA and 5% aqueous NaHCO^. The organic extract was washed with brine, dried and evaporated to a foam. This was purified by preparative TLC (ME) and crystallization from AN, and the final product (469mg) was obtained,

sm.p. 132.5-133.5°, [a] + 46.8°.

Example 3 3

( Z)- lla- dimethylamino- 23- ethoxy- 5a- pregn- 17( 20)- en- 3a-ol

A mixture of LXV (1.8 g), HCHO (12 ml) and formic acid

(1.2 ml) was maintained at approx. 100° for 5 minutes before pouring it

into aqueous NaHCO^ solution. The precipitated solid was collected by filtration, washed with W and dissolved in EA. Evaporation gave a foam which was filtered through a plug of silica in EA-PE 1:1. Recrystallization from Me-W then gave the final product, m.p. 63-78°, [α]D-2°.

Example 34

( Z)- lla- dimethylamino- 5a- pregn- 17( 20)- en- 3a-ol

A suspension of XLI (550 mg) in HCHO (4 mL) was treated with formic acid (0.3 mL) and the mixture was stirred until the steroid was dissolved. The solution was heated to approx. 100° for 10 minutes, cooled<p>g diluted with excess NaOH solution. The precipitated material was extracted into EA, the extract was washed with W and then with 2N HCl. The acidic extract was washed with EA, basified with NaOH and re-extracted with EA. Evaporation of the washed organic extract gave a crystalline material which was purified by preparative TLC (5% Me-CH) and crystallization from Me-W to give the final product (309 mg), m.p. 59-61°,

[<x]D- 8.1°.

Example 35

( Z )- lla- diethylamino- 5a- pregn- 17( 20)- en- 3a-ol

A solution of XLI (608 mg) in ET (20 mL) was treated with acetic acid (0.1 mL) and NaBH 2 CN (2 31 mg). The mixture was kept at RT for 27 minutes and then acetaldehyde (3 mL) was added. After a further 15 minutes, the mixture was worked up as in Example 24 and purified by preparative TLC (EA) and crystallization from AN-W, and the final product (333 mg) was obtained, m.p. 89-90°,

[a]D-38.1°.

Example 36

(Z)-lla-piperidino-5a-pregn-17(20)-en-3ct-ol

A solution of XLI (795 mg) in IMS (10 mL) was treated with NaBH 2 CN (395 mg), 25% aqueous glutardialdehyde (2 mL) and acetic acid (0.1 mL). The mixture was kept at RT for 1 hour and then worked up as in Example 24. Purification by preparative TLC using 10% ME-EA gave the final product as a foam (410 mg), [α]D-15.3°.

Example 3 7

lla-dimethylamino-5a-pregn-2O-ene-3a-ol

lla-amino-5a-pregn-20-en-3a-ol (650 mg) in methyl iodide

(15 mL) was stirred with f^CO^ for 6 hrs. The reaction mixture was evaporated to dryness under reduced pressure and the residue was partitioned between EA and W. The organic layer was washed with W and then extracted with dilute HCl. The acidic extract was washed with EA, basified with concentrated ammonia solution and extracted with EA. The organic extract was washed with W, dried (MgSO 4 ) and evaporated to give a foam. This was purified by preparative TLC (EA-PE 1:1) and the final product was obtained as a crystalline solid (270 mg), m.p. 131-133°.

Examples 3 8- 46

Table 5 summarizes the preparation of lla-N,N-disubstituted amines from the suitable lla-N-monosubstituted amines by the following method: The amine was dissolved in HCHO solution containing formic acid and the mixture was heated to approx. 100°.

The mixture was then worked up by one of the following methods: A. The mixture was partitioned between EA and aqueous NaHCO 3 and the EA extract was washed with brine, dried and evaporated. B. The mixture was diluted with W and extracted into EA. The aqueous layer was basified with NaOH, extracted with EA and evaporated. The original EA washes were washed with NaOH and W and evaporated. The remains were collected. C. The mixture was neutralized with NaOH and extracted with EA. The washed extract was evaporated. D. The mixture was diluted with saturated NaHCO 3 solution and the precipitate collected.

The material from one of these methods was purified by CC or preparative TLC and/or crystallization.

The following compounds were prepared:

38. lla-N-cyclohexyl-N-methylamino-23-ethoxy-3a-hydroxy-5a-pregnan-20-one 39. 2(3-ethoxy-3a-hydroxy-lla-(N-methyl-N-4- methylpent-2-ylamino)-5a-pregnan-20-one, isomer A 40. 23-ethoxy-3a-hydroxy-lla-(N-methyl-N-4-methylpent-2-ylamino)-5a-pregnan-20 -one, isomer B 41. lla-N-benzyl-N-methylamino-23-ethoxy-3a-hydroxy-5a-pregnan-20-one 42. lla-N-allyl-N-methylamino-23-ethoxy-3a- hydroxy-5α-pregnan-20-one

43. (Z)-lla-N-ethyl-N-methylamino-5a-pregn-17(20)-en-3a-ol

44. (Z)-lla-N-isopropyl-N-methylamino-5a-pregn-17(20)-en-3a-ol

45. lla-N-ethyl-N-methylamino-3a-hydroxy-53-pregnan-20-one

46. 3a-hydroxy-lla-N-isopropy1-N-methylamino-53-pregnan-20-one

Example 47

3a- hydroxy- lla- N- methyl 1- N- propylamino- 5a- pregnan- 20- one

A solution of LXVI (380 mg) in methyl iodide (10 mL)

was stirred with I^CO^(lg) for 4 hrs. The mixture was diluted with DE and W and the organic phase was extracted into 2N HCl. The extract was basified with 6N NaOH and the oily precipitate was extracted into DE. The extracts were washed with W, dried (Na 2 SO 4 ) and evaporated to give a foam which was purified by preparative TLC and crystallization from PE to give the final product (210 mg), m.p. 149-152°C, [α]D+90°.

Example 48

lla- N- buty1- N- methylamino- 3a- hydroxy- 5a- pregnan- 20- one

A solution of LXVII (1 g) in methyl iodide (40 mL) was stirred with f₂CO₂ (3 g) for 3 h. Workup as in Example 47 and purification by preparative TLC in AC-PE (1:3) gave the final product (680 mg), [a] +83°.

Example 49

lla- N- ety1- N- methylamino- 3a- hydroxy- 5a- pregnan- 20- one

A solution of LXVIII (370 mg) in methyl iodide (2 mL) and DM (40 mL) was stirred with K 2 CO 3 (1 g) for 3 h. DE and W were added and the organic phase was washed with W, dried (Na-SO4) and evaporated to a foam which was purified by preparative TLC in AC-PE (1:3) to give the final product (350 mg) as a foam, [a]D+83.7°.

Example 50

lla- N, N- dimethylamino- 23- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one

LXIX (560 mg) was stirred with boron trifluoride etherate (0.5 mL) in ET (25 mL) at 20° for 4 days. The mixture was concentrated by evaporation and partitioned between EA and 2N Na-jCO 2 solution. The aqueous layer was extracted with additional EA and the combined organic solutions were washed with brine, dried (MgSO 4 ) and evaporated to an oil. This oil was purified by preparative TLC and recrystallization from PE to give the final product (46 mg), m.p. 131-137.5° [α]D+83.3°.

Example 51

lla- N, N- dimethylamino- 2g- ethoxy- 3a- hydroxy- 5g- pregnan- 20- one

60% aqueous perchloric acid (2 mL) was added to a stirred solution of LXIX (1 g) in ET (100 mL) at 20°. After 2 hours, Na 2 CO 3 ~ solution was added to raise the mixture to pH 9 and most of the ET was evaporated. The residue was partitioned between EA and W. The aqueous layer was extracted with further EA

and the combined organic solutions were washed with saturated saline, dried (Na 2 SO 4 ) and evaporated to a gum. This gum was purified by preparative TLC and recrystallization from ET-W to give the final product (504 mg), m.p. 119-123°, [<*]D +83°.

Examples 52-70

Table 6 summarizes the preparation of 23-substituted-11a-disubstituted amines from the corresponding 2a,3a-epoxide by the following method: the 2a,3a-epoxide was treated with the appropriate alcohol or acid in the presence of a catalyst (if necessary) at RT ( or 100°C in the case of 23-acetoxy compounds) for the indicated time. The mixture was diluted with aqueous Na 2 CO 3 solution (or aqueous NaOH in the case of 23-fluoro compounds) and worked up by one of the following methods: A. The mixture was extracted with EA and the extract was washed with brine, dried and evaporated.

B. The solid that precipitated was collected by filtration, washed and dried. C. The alcohol was evaporated and the aqueous residue was extracted as in A above.

The material from one of these methods was further purified by CC and/or preparative TLC and/or crystallization.

The following 23-substituted derivatives of 3a-hydroxy-lla-N,N-dimethylamino-5a-pregnan-20-one were prepared (Example No. is given in parentheses): 23-fluoro (66), -chloro (61) , -bromo (65), -thiocyanate (64), -acetoxy (69), -propoxy (54), -benzyloxy (59), -chloroethoxy (60) and -isopropoxy (52); of lla-N-ethyl-N-methylamino-3g<->hydroxy-5a-pregnan-20-one: 23-fluoro (68), -chloro (62), -methoxy- (55), -ethoxy (53) and -acetoxy (70); and of 3α-hydroxy-llct-N-isopropyl 1-N-methyl-5α-pregnan-20-one: 23-fluoro (67), -chloro (63), -methoxy (56), -ethoxy (57) and

-acetoxy (58).

HCIO was used as a 60% aqueous solution.

Example 71

lla- N, N- dimethylamino- 3a- hydroxy- 5a- androstane- 173~ carbonitri1

A solution of LXX (500 mg) in ME (150 mL) was treated with saturated NaHCO 3 solution (20 mL) at reflux for 24 h. The mixture was diluted with W to 1 L and the precipitate was filtered off, washed with W and dried. The solid (340 mg) was purified by preparative TLC in EA-PE (1:2) and crystallization from DE-PE to give the final product (170 mg), m.p. 183-186°C, [α]D +47.5°.

Example 72

lla- N, N- dimethylamino- 2[ 3- ethoxy- 3a- hydroxy- 5a- androstane- 17P-carbonitrile

A solution of LXXI (320 mg) in ME (80 mL) was refluxed with saturated NaHCO 3 solution (8 mL). After 5 hours the mixture was diluted to 600 ml with W and the precipitate was extracted into DE. The extracts were washed with W, dried (Na 2 SO 4 )

and evaporated to a foam (300 mg) which was purified by preparative TLC in AC-PE (1:3) to give the final product (250 mg) as a foam, [ci]D + 46°.

Example 73

lla- dimethylamino- 3a- hydroxy- 5g- androstane- 173- carbonitrile

KHCO 3 (1 g) in W (20 mL) was added to a solution of LXXII (500 mg) in ME (50 mL) and the mixture was refluxed under nitrogen for 2 h. Dilution with W and extraction with

EA gave impure product, which was crystallized from DE-PE and ME-W to give the final product (170 mg), m.p. 137-139°, [α]'D+67°.

Example 7 4

21- acetoxy- 1la- N, N- dimethylamino- 3a- hydroxy- 53- pregnan- 20- one

(LXXIV)

.Lead tetraacetate (1.0 g) was added to a solution of LXXIII (0.5 g) in benzene (18 mL) and ME (1.15 mL). The solution was cooled to 10° and boron trifluoride etherate (2.85 mL) was added, the reaction mixture was stirred at 10° for 5 h and then poured into aqueous NaHCO 3 solution. The steroid was extracted in DE and subjected to preparative TLC in 2:1 EA-PT. Elution with EA, followed by crystallization from DE gave the final product (100 mg), m.p. 150-152°.

Example 75

3a, 21-dihydroxy-lla-dimethylamino-5( 3-pregnan-20-one

LXXIV (500 mg) was dissolved in ME (20 mL) and added

aqueous KHCO^(5 mL, 20%). The solution was refluxed under nitrogen for 2 hours, then poured into W and the steroid extracted with EA. Preparative TLC using AC-PT 1:2 as solvent and eluting with AC gave the final product as a white foam (310 mg), tcx"] D<+>47°.

Example 76

lla-dimethylamino-3a-hydroxy-5a-pregnan-20-one

LVIIII (110 mg) was treated with a solution of chloridric acid reagent (3 mL) under reflux for 1 h before partitioning between EA and aqueous NaHCO 3 solution. The organic phase was isolated, washed with W and evaporated to a foam. Crystallization from PE gave the final product (78 mg), m.p. 119-122°, [α]D+76.0°.

Example 77

lla-dimethylamino-3a-hydroxy-5a-pregnan-20-one

To a mixture of LVII (362 mg), formic acid (0.11 ml), triphenylphosphine (787 mg) and tetrahydrofuran (15 ml) was added a solution of diethyl azodicarboxylate (348 mg) in tetrahydrofuran (3 ml). The reaction mixture was allowed to stand at RT overnight

before partitioning between EA and aqueous NaHCO^ solution. The organic phase was isolated, washed with W, dried (Na 2 SO 4 ) and evaporated

to a foam. CC (elution with DM) gave a foam which was dissolved in ME (10 mL) and treated with 10 drops of perchloric acid. After

0.5 h, the reaction mixture was worked up as in Example 76. Crystallization from PE gave the final product (106 mg), m.p. 119-123°, [α]D+76.7°.

Example 7 8

lla- dimethylamino- 2p- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one

XLV (100 mg) was stirred with PTSA (61 mg) in DC (10 mL)

and ET (5 ml) for 5 minutes. m-chloroperbenzoic acid (75 mg) was added and after 24 hours at 20° TLC showed formation of the final product.

Example 79

lla- N, N- dimethylamino- 2p- ethoxy- 3g- hydroxy- 5a- pregnan- 20- one

LXI (3.0 g) was dissolved in DM (20 mL) and the soln

was extracted with a solution of conc. F^SO^(1.8 mL) in W

(25 ml) and then with W (15 ml). The combined aqueous extracts were kept at RT for 10 minutes and then brought to pH 11 by addition of NaOH solution. The precipitate was extracted in DM

and the extracts were washed with W. The dried (MgSO 4 ) solution was subjected to CC and eluted with DM-MA (9:1). The eluate was evaporated to a foam which was crystallized from AC-W (4:1) to give the final product (1.66 g), [α]D+74°, m.p. 135-143°.

Example 80

Methyl- lla- N, N- dimethylamino- 2p- ethoxy- 3a- hydroxy- 5a- androstane-17P- carboxylate

Iodomethane (8.4 mL) was added to a solution of LXXV

(3.5 g) in dimethylformamide (30 ml) and triethylamine (25 ml).

After stirring for 20 hours, the mixture was poured into 5% NaHCO 3 solution (50 mL) and extracted with CH. The combined extracts were dried (MgSO 4 ) and evaporated. The residue was purified by CC

using 1:4 EA-PE as eluent, and the final product was obtained as a foam (965 mg), [α]D+35°.

Example 81

lla- N, N- dimethylamino- 2p- ethoxy- 3a- hydroxy- 21- propy1- 5a- pregnan-2 0- one

Butyllithium in hexane (8.6 mL, 1.7M) was added to a suspension of LXXV (2.0 g) in DE (12 mL) under nitrogen while cooling in ice-W. The mixture was stirred vigorously at 20° for 31 h and then diluted with W (25 mL). The mixture was extracted with EA and the combined extracts were washed with 0.1N NaOH. The dried (MgSO 4 ) extract was evaporated to a foam which was purified by preparative TLC on alumina using 1:2 EA-PE as eluent to give the final product (146 mg) as a foam, [ot] D +75° .

Example 82

lla- dimethylamino- 3a- hydroxy- 5a- pregn- 1- en- 20- one

2 (3-bromo-l la-N, N-dime ty lamino- 3 a-hydroxy-^ 5 a-pregnan-

20-one (2.76 g) was stirred with dihydropyran (7 mL) and PTSA (1.30 g)

in B (150 ml) at 21°. After 1 hour, the clear solution was washed with an excess of 2N Na 2 CO 3 solution, brine and dried (Na 2 SO 3 ). B was evaporated to an oil which was then dissolved in DMF (75 mL) and heated at 105°-115° with CaCO 3

(7.5 g) and LiBr (10 g) for 19 hours. The mixture was diluted

with ME and insoluble solids were separated by filtration. The residue was washed with further ME and the combined ME solutions were diluted to approx. 300 ml.

This solution was adjusted to pH 1 with 2N HCl

and after 1 hour at 21°, 2N Na 2 CO 3 solution was added to raise the pH of the mixture to 9.0 and the ME was evaporated under reduced pressure. The residue was extracted twice with EA and the combined extracts were washed with saline, dried (Na2SO4) and evaporated to an oil. Remaining DMF was evaporated using an oil pump leaving behind a gum. This was dissolved in 1:1, EA-PE

and filtered through silica gel (30 g),. and the impure product was obtained. This was purified by preparative TLC (EA-PE) to give the final product (611 mg), [α]D+1.5°.

Examples 83-157

Manufacture of salts

Table 7 summarizes the properties and preparation of aqueous solutions of salts prepared according to the invention according to one of the following methods: A. The lla-amine was added to a solution of the acid in W and the mixture was stirred or shaken until a clear solution was obtained. The solution was added with W to the indicated weight, filtered through a membrane and the pH was determined.

B. As A above, except that before adding W, the solution was filtered and treated dropwise with 0.1M NaOH solution until the - initially formed slurry does not completely redissolve upon stirring.

C. A solution of the lla-amine in ET was treated with a solution of the acid in W. The mixture was evaporated in vacuo and dried to constant weight. The residue was dissolved in a little W and any material which then remained undissolved was collected in a weighed funnel, and the weight of the dissolved free base was calculated. The solution was added W to the indicated weight and the pH measured.

D. The lla-amine was added to a solution of acid in W

and the mixture was stirred or shaken. As free base remained undissolved, additional acid was added and the mixture was stirred again. W was added to the solution and any material that then remained undissolved was collected in a weighed funnel and the weight of dissolved free base was calculated and the pH of the solution was determined.

The E. lla amine was added to a solution of the acid in W and the mixture was stirred or shaken. The solution was added W to the indicated weight. Remaining undissolved material was collected

in a weighed funnel and the weight of dissolved free base was calculated and the pH of the solution was measured. The solid citric acid was used as its monohydrate.

Examples 158-171

Preparation of salts of lla-N,N-dimethylamino-2[3-ethoxy-5a-pregnan-20-one (Table 8)

The amine was added to a solution of the acid in W and the mixture was stirred or shaken until a clear solution was obtained. The solution was then either: (A) treated dropwise with 0.1M NaOH until the initially formed precipitate was just redissolved, added W to the indicated weight, filtered through a membrane and pH determined; or (B) added W to indicated weight, filtered through eh membrane and pH determined.

Examples 172-180

Preparation of salts of lla-N,N-dimethylamino-3a-hydroxy-5| 3-pregnan-20-one (Table 9)

The amine was added to a solution of the acid in W, and the mixture was stirred or shaken until a clear solution was obtained. The solution was added with W to the indicated weight, filtered through a membrane and the pH was determined.

Example 181

lla- N, N- dimethylamino- 2g- ethoxy- 3a- hydroxy- 5a- pregnan- 20- one, hydrogen chloride salt

A solution of lla-N,N-dimethylamino-2β-ethoxy-3α-•hydroxy-5α-pregnan-20-one (10.5 g) in dry DE (80 mL) was stirred while a stream of HCl was passed through . The precipitated solid was collected by filtration under the pressure of a nitrogen atmosphere and washed well with dry DE to give the final product (11.5 g), m.p. split 200°C [a]D +35° (ME)

Example, 182

lla- N, N- dimethylamino- 2p- ethoxy- 3a- hydroxy- 5a- pregnane- 20-one citrate salt

A solution of 11a-N,N-dimethylamino-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one (1 g) in DE (20 mL) was added to a stirred

solution of citric acid monohydrate (1.05 g) in DE (60 ml).

A precipitate immediately formed which was collected by filtration under a nitrogen atmosphere, and the final product containing 1 mole of citric acid in excess was obtained.

The filtrate was evaporated to half volume and the precipitate. filtered from and a further end product was obtained which contained 1 mol of citric acid in excess.

T values (D20) include 9.35 (s, 18-H), 8.87 (s, 19-H), 8.84

(t, J 7 Hz, -OCH2_CH3) , 7.78 (s, 21-H) , 7.67 (triplet of doublet, J 12 and 5 Hz, 113-H), 7.02 and 7.24 (ABq , J 16 Hz, -CH2~of citric acid), 6.97 and 7.09 (2 singlets, lla-<+>NH(CH3)2), 6.2-6.6 (m, -OCH2CH3, 2a- H and 13-H) and 6.05 (m, 33-H).

Example 183

21- acetoxy- 1la- N, N- dimethylamino- 23~ ethoxy- 3a- hydroxy- 5a- pregnan-20- one (XXIX)

A solution of XXVIII (200 mg) in AC (10 ml) was stirred at RT with anhydrous potassium acetate (200 mg) for 4 h. The mixture was diluted with W to 100 ml and the precipitate was extracted into DE. The extract was washed with W, dried (Na 2 SO 4 ) and evaporated to a foam (180 mg) which was purified by preparative TLC in EA-PE (1:1) to give the final product (114 mg) as a foam, [a]D +90.5°.

Example 184

lla- dimethylamino- 3a- hydroxy- 53~ pregnan- 20- one

11a-amino-53-pregnan-3α,203-diol (44 mg) in 37% aqueous HCHO (1 mL) and HCO 2 H (0.01 mL) was heated on a steam bath for 5 min. The cooled solution was diluted with NaHCO 3 -

solution and extracted with EA. Evaporation of the washed and dried (MgSO 4 ) organic extract gave a gum which was purified by preparative TLC in AC-PE (2:3) to give 11a-dimethylamino-53-pregnan-3a,203-diol.

The latter compound (40 mg) in AC (4 mL) was treated at 0° with Jones reagent (0.24 mL). After 15 minutes, the mixture was poured into ice-cold NaHCO 3 solution and extracted with EA. The washed and dried (MgSO 4 ) extract was evaporated to give a solid which was purified by filtration through silica gel in AC-PE (1.:10) and crystallization from ME-W,

and 11x-dimethylamino-5(3-pregnan-3,20-dione (10 mg) was obtained.

A solution of the latter compound (250 mg) in ET

(17 mL) was stirred at RT for 15 min with NaBH^ (125 mg). Excess NaBH^ was decomposed by the addition of a little acetic acid.

and the mixture was then diluted with NaHCO 3 solution and extracted with EA. Evaporation of the washed and dried (MgSO 4 ) extract gave a foam which was purified by preparative TLC using AC-PE (1:5) to give the final product, [α] +66.2°.

Example 185'

lla- N , N- dimety lamino- 2 ( 3- e toxy- 3 a- hy dr oxy- 5 a- pregnan- 20- one

LXXV triethylammonium salt (500 mg) was dissolved in dry

THF (5 mL). Methyllithium (7.2 mL, 1.7M solution in DE) was added and the mixture stirred at 20° under nitrogen for 28 hours.

W (25 mL) was added and the mixture was extracted with EA (3x). The combined extracts were dried (MgSO 4 ) and evaporated to give the final product (372 mg) corresponding to the product of Example 1 by chromatography.

Example 186

( Z)- 17- cyanorethylene- lla- dimethylamino- 23- ethoxy- 5 a- androstane- 3 a-ol

To a mixture of NaH (500 mg), diethyl cyanomethyl-' phosphonate. (4 mL) and dry THF (16 mL) was added a solution of LXXIX (1.2 g) in dry THF (12 mL). The reaction mixture was stirred at RT overnight before partitioning between EA and W. The organic phase was washed with W, dried (Na 2 SO 4 ) and evaporated to an oil. Purification by CC (EA-PE) and crystallization from ME-W gave the final product (833 mg), m.p. 128-146°, [α]D-10.8°, shown by N.M.R.

to contain the corresponding E-isomer.

Example 187

lla-dimethylamino-3a-hydroxy-5a-pregnan-20-one

LXXXIII (100 mg) in EA (10 mL) containing a few drops of acetic acid was hydrogenated at atmospheric pressure using 5% Pd-C as catalyst. After 24 hours, the catalyst was removed by filtration through diatomaceous earth, the filtrate evaporated,

and the final product (70 mg) corresponding to the product in Example 6 was obtained by P.M.R., G.L.C. and T.L.C.

Example 188

lla-dimethylamino-3a-hydroxypregn-4-en-20-one

A solution of NaBH 2 (117 mg) in W (5 mL) was added

a stirred solution of LXXXV (500 mg) in THF (20 mL). The solution was stirred for 5 1/4 hours at approx. +21°,.and then glacial acetic acid was added drop by drop until the effervescence ceased. The solution was partitioned between W and EA and the organic extract was washed with saturated saline and dried. Evaporation gave 11a-dimethylamino-pregn-4-ene-3(3,20£-diol (510 mg).

A solution of diethyl azodicarboxylate (348 mg) in dry

THF (2 ml) was added dropwise over approx. 5 more minutes

a stirred solution of the above diol (361 mg) in dry THF (12 mL) containing triphenylphosphine (787 mg) and chloroacetic acid (283 mg). The solution was stirred at approx. +21° for 1 hour and then distributed between 5% aqueous NaHCO^ and EA. The organic extract was washed with brine, dried and evaporated to give a solid (1.58 g). This was purified by preparative TLC (EA-PE),

to give 3α-chloroacetoxy-lla-dimethylaminopregn-4-en-20?-ol.

A solution of the above compound (438 mg) in AC (10 ml) was cooled to 0-5° with stirring and Jones reagent (0.3 ml)

was added dropwise over 3 minutes. After a further 20 minutes at 0-5°, the mixture was partitioned between 2.5% aqueous NaHCO 3 and EA. The organic extract was washed with brine, dried and evaporated to give a foam. This was purified by preparative TLC (EA-PE), and 3α-chloroacetpxyl-lla-dimethylaminopregn-4-en-20-one was obtained.

A solution of this compound (469 mg) in ME (15 mL) was refluxed and a solution of NaHCO 3 was added

(181 mg) in W (2.5 mL). The mixture was refluxed for 30 minutes, then cooled and partitioned between W and EA. It

The organic extract was washed with brine (100 ml), dried and evaporated to give a liquid. This was purified by preparative TLC (EA-PE) and a liquid (123 mg) was obtained. The PMR spectrum showed that the material contained the end product and 11a-dimethyl lamino-33-hydroxyregn-4-en-20-one.

The above epimeric mixture (121 mg) was mixed with corresponding derivative material (158 mg) and again subjected to TLC purification (EA-PE). The more polar band was eluted with AC

and evaporated to give the final product as a foam (123 mg), [a]Q+170°.

Example 189

lla- dimethylamino- 23- ethoxy- 21- fluoro- 3a- hydroxy- 5a- pregnan- 20- one and. the citrate salt thereof

A mixture of XXVIII (4.9 g), sodium iodide (5 g) and

AC (300 mL) was refluxed for 30 min before evaporation to low volume and partitioning between DE and W. The organic phase was washed with W, dried and evaporated to a foam. This foam was dissolved in AN (350 mL) and treated with a solution of silver fluoride (3 g) in W (15 mL) at 45° for 24 h. The reaction mixture was partitioned between DE and potassium carbonate solution. The organic phase was washed with W, dried and evaporated to a foam. Purification by preparative TLC (EA-PE 1:1) gave the final product as a foam (240 mg), [<*]D + 69.8°.

The latter free base (85 mg) was stirred with a solution of citric acid (82 mg) in W (8 mL). The solution was added W to 8.5 g and an insoluble residue removed by filtration to give a solution of concentration 8.2 mg/ml and pH 2.9.

The above compound and its salt is a preferred compound. Addition of preferred groups of compounds are those having the formula (I) or (II) where R<9> is a fluoromethyl group.

Claims (29)

1. Steroids with the formula: where 1 ci b ci Id R is a group -NR R , where R and R (which can be equal or different) are C 1 -g-alkyl, C 3 -g-alkenyl or cycloalkyl groups (provided that Ra and R 2 together contain 2-7 carbon a b atoms and that, when R and/or R is an alkenyl group, the carbon atom or atoms adjacent to the nitrogen atom in the group -NRaR^ is saturated); or wherein one of Ra and R is a benzyl or phenethyl group and the other group is a methyl group; or where Ra and R*3 (together with the nitrogen atom) mean an azetidino, pyrrolidino, piperidino, hexamethyleneimino or morpholino group, and the groups may optionally be substituted with one or two methyl groups; R 1 is a hydrogen atom or a C 1 -alkyl group; R 4 is a hydrogen atom or a C 1 -alkyl-, C 1 -alkyl- (which may optionally be substituted with a halogen atom), benzyloxy, C 3 -alkanoyloxy or thiocyanate group or a halogen atom; 5 R is a hydrogen atom or a methyl group; R<6> is a hydrogen atom or a methyl group; R 7 means a hydrogen atom or (except when R 8 is a group (c) as indicated below) a chlorine atom; and 8 9 9 R is (a) a cyano group; (b) a group -COR where R is one methyl group or such group substituted with a fluorine atom, a C 1 -4 - alkoxy, hydroxy, C 3 -alkyl methoxymethyl, ethoxymethyl, C 2 -alkanoyloxy, benzoyloxy or 3 - 5 - 5 - 6 alkoxycarbonyloxy group; or where R 1 is a C 1 - 1 - alkyloxy or cyclopropyl group; or where R is the group -NR RJ wherein Rx and bX (which may be the same or different) are methyl or ethyl groups; or (c) a phenyl group or together with R"*"0 a Z-substituted methylene group where the substituent is a methyl or cyano group; R"^ is a hydrogen atom (except when R^ and R"*"0 together mean a substituted methylene group); the dashed lines indicate the possible presence of double bonds in the positions shown; provided that one of R 3 and R 4 is a hydrogen atom; and R 3 and R 4 together mean a hydrogen atom when a 1,2-double bond is present; and that the 2-position is saturated when a 4,5-3 4 double bond is present; and that R is a hydrogen atom, R is a hydrogen atom or a methyl group and R 5 is a hydrogen atom or optionally (when R 4 is a hydrogen atom) a methyl group when a 53 hydrogen atom is present; 8 10 and D-homo-analogs thereof having R in the 17a3 position, Ri 7 the 17aa position and R in the 17 position, and acid addition salts thereof. 2. Compounds as set forth in claim 1, wherein Ra and K° are different from benzyl or phenethyl groups; R 8 is different 9 9 from the group -COR where R is a methyl group substituted with a 3 4 5 C2_4~alkyl group; and wherein R , R , and R are all hydrogen atoms when a 53 hydrogen atom is present. 3. Compounds as stated in claim 2, characterized in that they have a 5a- or 53-hydrogen atom. 4. Compounds as stated in claim 2 or claim 3, characterized in that the tetracyclic steroid 5 6 7 system is saturated and R , R , and R are all hydrogen atoms. 5. Compounds as stated in any of claims 2-4, characterized in that R is a hydrogen atom or a methyl group. 6. Compounds as stated in any of claims 2-5, characterized in that the ring D is a 5-ring. 7. Compounds as stated in any of claims 2-6, characterized in that they have a 5a-hydrogen atom. 8. Compounds as set forth in any of claims 2-7, 8 characterized in that R is (a) a cyano group 9 9 or (b) a group -COR where R is a methyl group or such a group substituted with a hydroxy-, methyl- or acetoxy- .group, or where R 9 is a cyclopropyl group. 9. Connections as stated in claim 8, 8 characterized in that R is an acetyl group. 10. Compounds as stated in claim 8, characterized in that R g is a cyano group. 11. 5a compounds as stated in any of the 4 preceding claims, characterized in that R' is a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, acetoxy or thiocyanato group or a chlorine, bromine or fluorine atom. 12. Compounds as stated in claim 11, characterized in that R 4 is a hydrogen atom or an ethoxy group. 13. Compounds as stated in any of claims 2-12, characterized in that R a and R b are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 1, 3-dimethylbutyl, allyl, cyclopentyl or cyclohexyl groups and that -NRaR- means a pyrrolidino group. 14. Compounds as stated in claim 13, characterized in that one of R a and R b is a methyl group and the other is a methyl, ethyl, propyl, isopropyl, butyl or allyl group. 15. Compounds as stated in claim 13, characterized in that both Ra and R*3 are methyl groups. 16. Compounds as stated in claim 1 with the formula: where R is a group -NRaR, where one of Ra and R is a methyl group, the second group is a methyl, ethyl, propyl, isopropyl, butyl or allyl group, or where both Ra and R are ethyl-Sl b groups, or where R and R (together with the nitrogen atom) means a pyrrolidino group; R<3> is a hydrogen atom or a methyl group; R <4> is a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, acetoxy or thiocyanato group or a fluorine, chlorine or bromine atom; 8 9 9 R is (a) a cyano group; (b) a group -COR where R is one methyl group or such a group substituted by a methyl, hydroxy or acetoxy group, or R 9 is a cyclopropyl group; or (c) a vinyl group or, together with R"^, a Z-ethylidene group; and R is a hydrogen atom (except when R and R"1"0 together mean an ethylidene group); the dashed line indicates the possible presence of one double bond in the 1,2 position; provided that one of R and R 4 is a hydrogen atom; that R and R 4 together means a hydrogen atom when 1,2-double bond is present; and that 3 4 R is a hydrogen atom and R is a hydrogen atom or a methyl group when a 53-hydrogen atom is present; 8 10 and D-homo-analogs having R in the 17a3_position and R in the 17aa position; and acid addition salts thereof. 17. Compounds as stated in claim 16, characterized in that R is a dimethylamino group, 3 4 R is a hydrogen atom, R is a hydrogen atom or an alkoxy group, R g is an acetyl or cyano group and ring D is a 5-ring. 18. Compounds as stated in claim 2, characterized in that they are in the form of their hydrogen chloride, hydrogen bromide, phosphate, sulfate, p-toluene sulfonate, methanesulfonate, citrate, tartrate, acetate, ascorbate -, lactate, maleate, succinate, tricarballylate, glutarate or glutaconate salts. 19. Compounds as set forth in any of claims 1-17, characterized in that they are in the form of their aconitate, citraconate, mesaconate or salicylate salts. 20. Compounds as stated in claim 2, characterized in that they are in the form of their citrate or hydrogen chloride salts. 21. Compounds as stated in claim 2, characterized in that the compounds are 11a-N,N-dimethylamino-23-ethoxy-3a-hydroxy-5a-pregnan-20-one and physiologically acceptable acid addition salts thereof. 22. Compounds as stated in claim 2, characterized in that the compounds are 11a-N,N-dimethylamino-3a-hydroxy-53-pregnan-20-one and physiologically acceptable acid addition salts thereof. 23. Pharmaceutical preparation consisting of one or more compounds as set forth in any of the preceding claims, together with one or more pharmaceutical carriers or excipients. 24. Preparation as stated in claim 2 3 in the form of a solution of the compound(s) in a parenterally acceptable solvent. 25. Preparation as stated in claim 24 in the form of a. simple aqueous, acidic solution of the compound(s). 26. Preparation as set forth in any of claims 23-25, wherein the compound is a compound as set forth in claim 2. 27. - Preparation as stated in claim 25, characterized in that the compound is a compound as stated in any one of claims 21 or 22. 28. Process for producing a compound as stated in claim 1, characterized in that one: (a) ' converts a corresponding steroid where one or both SL b cl R and R is a hydrogen atom, with a compound of the formula R X or (when preparing a compound where R^" is one heterocyclic amino group) with a compound of the formula 3. b X-R-R-X (where X is a readily replaceable substituent); (b) reduces a corresponding 11a-acylaminosteroid; (c) in the preparation of ring A-saturated 23-substituted 5α-steroids, opens the epoxide ring of a corresponding 2α,3α-epoxide; (d) reductively alkylates a corresponding 11a-amino- or 11a-mono-substituted aminosteroid; (e) for the production of 53-steroids or ring A-saturated-23-unsubstituted 5α-steroids, it reduces the corresponding 3-oxo-steroid; (f) for the preparation of 33-unsubstituted compounds which do not have a 5,6-double bond, invert the 3-hydroxy group of a derivative of a corresponding 33-hydroxy compound; (g) for the preparation of compounds where R 8 is a group (a) or (b) as set forth in claim 1, reduces the corresponding A"^-f compound; (h) for the production of 16a-chloro compounds, 16 hydrochlorinates the corresponding A compound; (i) for the preparation of 173-cyano compounds, dehydrate the corresponding 173-carbamoyl compound or the oxime of the corresponding 173~ formyl compound; (j) for the preparation of 173-Alkoxycarbonyl compounds, esterifies the corresponding 173-carboxylic acid; (k) for the preparation of 173-(substituted carbamoyl) compounds, reacting the corresponding 173-carboxylic acid with an amine; (1) for the preparation of 21-alkanoyloxy or 21-benzoyloxy compounds, acyloxylate the corresponding 21-unsubstituted compound; (m) for the preparation of 21-fluorine compounds, replacing the iodine atom in the corresponding 21-iodo compound with fluoride; (n) for the production of 21-hydroxy compounds, deacylates a corresponding 21-acyloxy compound; (o) for the preparation of 2l- alkoxy compounds, ether is a corresponding compound having a 21-hydroxy group or a replaceable 21-substituent; (p) for the preparation of 21-alkanoyloxy or 21-benzoyloxy compounds, acyloxylate a corresponding compound having a readily replaceable 21-substituent; (q) for the preparation of 21-alkanoyloxy or 21-benzoyloxy compounds, acylates the corresponding 21-alcohol; (r) for the preparation of A" <*> "-5a compounds, dehydrohalogenate a corresponding 23-halogen compound; (s) for the preparation of 20-oxo compounds, deketalizes a corresponding 20-ketal; (t) deprotecting the corresponding compound having a protected 3α-hydroxy group; (u). to prepare a salt, treat the appropriate free base with an acid; (v) for the preparation of 173-vinyl compounds, partially hydrogenate the corresponding 173-ethynyl compound; (w) for the preparation of 173-vinyl compounds, treating the corresponding 20,21-epoxide with an alkali metal selenium cyanate; (x) for the preparation of 17-(Z)-ethylidene or 17-(Z)-cyanomethylene compounds, reacts the corresponding 17->oxo-steroid with an organophosphorus reagent; or (y) for the preparation of compounds where R 9 is a methyl or cyclopropyl group or a methyl group substituted with a C 1 -4 alkyl group, react a 173-carboxylic acid or a salt thereof with the appropriate lithium alkyl. 29. Method as stated in claim 28 for the production of a. compound as stated in claim 2, characterized in that the method is as stated in any of paragraphs (a) - (x) in claim 28.