NO131412B - - Google Patents

Description

Process for the production of therapeutically active

steroids of the 913 ,10a-androstane or pregnane series.

A large number of steroids are known which have a methyl group in the 10 and 13 positions of the steroid molecule. There are also known steroid-like compounds which have no methyl group in the 10-position. In the past, no attention has been paid to the influence of the α or β configuration of the 10-methyl group on the pharmacological properties of the steroids. In this connection, it should be noted that in the above-mentioned 10-methyl compounds the methyl group has g-configuration. However, relatively many other steroid-like compounds are also known in which the 10-methyl group has the ot configuration, but no pharmacological activity has been mentioned for any of these compounds. This essentially concerns compounds which are discussed in the Journal of Chemical Society 1955, pages 2176 to 2190; Berichte 69, page 1123 (1936) and Journal of the Chemical Society,

1938, page 869. All these known 10(a)-methylsteroids have in the 17-position of the steroid skeleton a hydrocarbon residue with 8 or 9 carbon atoms which is close to the 17-positioned residues of cholesterol or ergosterol.

It has now been found that steroids which at the carbon atom

8, 9, 10, 13 and 14 have the same configuration as dihydroisolumisterone,

has surprising and special pharmacological properties. Thus, the new compounds show an increased specific intrinsic effect and in particular have a missing or reduced androgenic side effect.

Castells and co-workers have demonstrated (Proceedings of the Chemical Society, January 1958, page 7) that dihydroisolumisterone has the configuration 96,10a-methyl, 8g,133-methyl, 14a-. This configuration differs at carbon atoms 9 and 10 from the configuration of normal steroids. While dihydroisolumisterone and thus the new compounds that can be prepared according to the invention at these two atoms have a 9B,10a structure, the normal steroids, on the other hand, have a 9a,10g configuration. The compounds that can be produced according to the invention are designated in the following with the prefix "9$,10a", to clearly express this difference in relation to the normal steroids.

The new compounds have the general formula

in which formula FL means a hydrogen atom or the methyl group, R2

can be a double bond in at least one of the positions 1,2,3,4,5,6,

15 and/or 16, R 1 is a hydrogen atom. methyl, ethyl or a

hydroxy or etherified or, esterified hydroxy group, R^ is a j keto or a hydroxy or an etherified or esterified hydroxy group, R(j is a hydrogen atom or a halogen atom, Rg is a hydrogen | atom, the methyl group, a halogen atom or a hydroxy or a for-

ether or esterified hydroxy group, is a halogen atom or in a hydrogen atom,. Rg is a hydrogen atom, a hydroxy or a keto group, R^ is a hydrogen atom or a saturated or unsaturated hydro- i

■

carbon residue with 1 to 6 carbon atoms or such a hydrocarbon residue where at least one hydrogen atom is replaced by at least one hydroxy or etherified or esterified hydroxyl group and/or at least one double-bonded oxygen atom, R-^q is a hydrogen atom, a hydroxy or an etherified or esterified hydroxy group, with the condition that Rq °S R]_Q °Sso. together can form a keto group, however, both are not a hydrogen atom, and R-^ is a hydrogen atom or a hydroxy or an etherified or esterified hydroxy group.

In this formula, the dashed line at carbon atoms 10 and 14 means the a-configuration and the unbroken line at atoms 8, 9 and 11* the $-configuration. The substituents R 1 and R 1 to R 11 can be attached a- or g-positioned to the steroid skeleton.

The method according to the invention for the production of steroids of the 93,10a-androstane or pregnane series with an increased specific intrinsic effect, in particular with a lack or reduced androgenic side effect, which corresponds to the general formula stated above, is characterized in that according to methods known in and of themselves

a) a compound with the general formula

wherein X means the 17-position linked 90,10a-steroid residue with

the general formula

in that the configuration of the steroid skeleton in positions 8, 9> 10, 13 and 14 is the same as in dihydroisolumisterone and in which R^ can be a hydrogen atom or the methyl group, R 2 a double bond in one or more of the positions 1, 2, 3, 4, 5 > 6, 15 or 16, R-j means a hydrogen atom, the methyl or ethyl group or an optionally etherified or esterified hydroxy group, R^ means keto- or an optionally etherified

or esterified hydroxy group, means a hydrogen atom•or a halogen atom, Rg means a hydrogen atom, the methyl group, a halogen atom or an optionally etherified or esterified hydroxy group, R^ means a hydrogen atom or a halogen atom, Rg means a hydrogen atom, a hydroxy or keto group, R ,, means a hydrogen atom or an even-IV

tually esterified or etherified hydroxy group, Q means a hydrogen atom, a secondary amino group, an O-acyl group, the phenyl group or a lower aliphatic hydrocarbon group and means a hydrogen atom, the phenyl group or an aliphatic hydrocarbon group, provided however that not both groups Q<IV> and Q<V> are hydrogen atoms, are broken down oxidatively to the corresponding 20-keto-pregnane compound or b^) a 20-keto-21-halogen compound of the 93,10a-pregnane series with the general formula

in which X has the above meaning, and since R-^ can also be the methyl group, and since further R^q means a hydrogen atom or an optionally etherified or esterified hydroxy group at carbon atom 17 and Hig means an iodine or bromine atom, acyloxylated in the 21-position, optionally followed by saponification of the formed 21-ester group, or b2) a 20-keto compound of the 9$>10a-preghan series with the general formula is acyloxylated or hydroxylated with lead tetraacetate or by microbiological hydroxylation at carbon atom 21, or c) a 17,20- Epoxy formate of the 93,10a^pregnan series with the general formula in which X has the meaning mentioned above, is hydrolyzed to form the corresponding 17a-hydroxy-20-ketopregnan compound, optionally followed by esterification of the 17-hydroxy group, or in 1 ■ ! • - ■ 1

d) a 9B,10a-17(20)-bisnorcholen-22-al, a 93,10a-17(20)-pregnen-20-ol-20-acylate or a 9B,10a-17(20)-bisnorcholenic acid with it

general formula

in which X has the above meaning and in which Q<VI> is a hydrogen atom or the methyl group and Q is one of the groups HCN or bisulphite addition product thereof, -0-acyl or an optionally esterified -COOH group, is oxidized to form the corresponding 17_keto-93,10a-androstane compound or e) a 17-keto compound of the 93,10a-androstane series with the general formula in which X has the above meaning, is reacted with an optionally unsaturated metal aliphatic compound to form the corresponding 17ct-alkyl-(or alkenyl - or alkynyl-) 173-hydroxy compound or is reduced at the 17-keto group to form the corresponding 17-hydroxy compound, possibly followed by esterification of the 17-hydroxy group, or f) a 1,2-dihydro compound of 93,10a-androstane- or 98510a -the pregnane series with the general formula in which the configuration of the steroid skeleton in positions 8, 9, 10, 13 and 14 is the same as in dihydroisolumisterone and in which R-^j R-j, R^ to Rg and R^-^ have the above un where point a) mentioned meaning, R2 can be a double bond at one or more of the carbon atoms 4, 5j 6, 15 or 16, Rg means a hydrogen atom, a saturated or unsaturated hydrocarbon residue with 1 to 6 carbon atoms or such a hydrocarbon residue, where at least one of the hydrogen atoms are replaced by at least one hydroxy group and/or double-bonded oxygen atom, R^q is a hydrogen atom or an optionally etherified or esterified hydroxy group, so that R^ and R^q can also together form the keto group, but not both are a hydrogen atom, is dehydrated in l(2)- position, or g) a 6,7-dihydro compound of the 9B,10a-androstane or 98,10a-pregnane series with the general formula in which Rj, Rj, R^ to R^ have the meaning mentioned above under point a) and R2 can be a double bond at one or more of positions 1, 15 or 16, is dehydrated in the 6(7) position, or h) a 93jlOa-androstane or 93,10a-pregnane compound of the general formula

in which R1, R^ to R^ have the meaning mentioned above under point a), R2 can be a double bond at one or more of the positions 4, 5,

6, 15 and/or 16, and R 12 is an alkyl group,

is reacted with a methyl or ethyl halide and then with an alkali alcoholate to form the corresponding 2-methyl or ethyl compounds.

In process steps a) or d), the starting compounds are preferably substituted in the 1-, 2-, 4-, 6-, 9~, 11- and 16-position with hydrogen, it occurs at carbon atom 3 of these keto- or an optionally etherified or esterified hydroxy group,

and they contain one or more double bonds in the 4-, 4,6-, or 3,5-position. In particular, one starts from a 3~keto-, 3-keto-4-dehydro-, 3-keto-4,6-bisdehydro-, 3-keto-1,4-bis-dehydro-, 3_hydroxy-3,5- bisdehydro or 3-hydroxy-4-dehydro compound or their 3-ether or 3-esters.

The 20-enamines or 20-enolacylates used as starting compounds are preferably a 20-piperidylenamine or a 20-enol acetate.

The oxidation of a 20-enamine or 20-enolacylate allows

advantageously carried out with ozone in the presence of a nitrogen base,

since the ozonide formed is relatively easy to reduce with an aliphatic or aromatic aldehyde.

For the method according to steps b-^) and b2), the starting compounds preferably have no other substituents than hydrogen in the 1-position, hydrogen or methyl as substituents in the 2-position,

in the 3-position the keto group or an optionally etherified or esterified hydroxy group, in the 4-position hydrogen, in the 6-position hydrogen.,, fluorine, chlorine or an optionally etherified or esterified hydroxy group,

in the 9-position hydrogen or fluorine, in the 11-position hydrogen, keto or (H, 0H), in the 17-position hydrogen or an optionally etherified or esterified hydroxy group and in the 16-position hydrogen*, methyl or an optionally etherified or esterified hydroxy group as substituents, with a double bond occurring in at least one of positions 1, 4, 6 or 16.

In particular, the starting compounds in methods b-^)

and b2) in the 1-, 2-, 4-, 6- and 16-position only hydrogen, in the 3-position keto- or an optionally etherified or esterified hydroxy group, in the 11-position a hydrogen atom, keto- or (H-, 0H-) group as substituents and further one or more double bonds in the positions 1 > 3j 4, 5 or 6. Preferably, one starts from 3-keto-, 3-keto-4-dehydro-, 3-keto-4,6 -bisdehydro-, 3-keto-1,4-bisdehydro-, 3-hydroxy-3,5-bisdehydro- or 3-hydroxy-4-dehydro compounds or their 3-esters or 3-ethers.

For the method according to step c) it comes in particular

considering output connections as in 1-, 2-, 4-, 6-, 9-, 11- and

16-position only has hydrogen as substituents and which further has a 3-positioned keto or possibly etherified or esterified 3-hydroxy group and one or more double bonds in the 1-, 3-> 4-, 5- or 6-position. Of these starting compounds, 3-keto-, 3-keto-4-dehydro-, 3-keto-4,6-bisdehydro-, 3-keto-1,4-bisdehydro-, 3-hydroxy-3,5-bisdehydro are particularly preferred - or 3_hydroxy-4-dehydro compounds or their 3-esters or 3-ethers.

In the method according to step d), work is preferably done with a starting material in which Q<VI> means the methyl group and Q<VI1> a group with the formula

For the method according to step e), a starting compound is preferably selected which is substituted with hydrogen in the 1-, 2-, 4-, 6-, 9-, 11- and 16-position, which has a 3-positioned keto- or an optionally etherified or esterified 3-hydroxy group and which contains one or more double bonds in the 1-, 3-, 4-, 5- or 6-position, in particular the corresponding 3-keto, 3-keto-4-dehydro-, 3-keto- 4,6-bisdehydro-, 3-keto-1,4-bisdehydro-, 3-hydroxy-3,5-bisdehydro- or 3-hydroxy4-dehydro compound or their 3-esters or 3-ethers as starting material.

According to a preferred embodiment of step f), a substance selected as starting compound contains a 17-positioned -CO-CH-j-, a -C0-CH2-0-acyl-, a -C0-CH"2OH- or a saturated or unsaturated alkyl group with 1 to 2 carbon atoms and further at carbon atom 17

a hydrogen atom, a hydroxy group or an etherified or esterified hydroxy group, since both substituents at carbon atom 17 can also form a keto group; they are further substituted with hydrogen in positions 1, 2, 4, 6, 9> 11 and 16 and have 4- and/or 6-positioned double bonds.

According to a preferred embodiment of step g) has

the compounds used as starting material a 17-positioned -CO-CH3-, a -CO-CH2-C~acyl-, a -C0-CH20H- or a saturated or unsaturated alkyl group with 1 to 2 carbon atoms, in 1-, 2- , 4-, 6-, 9-, 11- and 16-position hydrogen as substituents and optionally a 1-positioned double bond; in particular, the method according to step g) is carried out by halogenation in the allyl position to the 4-positioned double bond and subsequent dehydrohalogenation or with chloranil.

According to a preferred method according to step h), a compound used as starting material contains in the 17-position a -CO-CH3-, a -CO-CH2-0-acyl, a -CO-CH2OH- or a saturated or unsaturated alkyl group with 1 to 2 carbon atoms, further in the 1-, 4-, 6-, 9-, 11- and 16-position hydrogen and in the 4- and/or 6-position a

double bond.

When the above-mentioned compounds contain etherified hydroxy groups, these groups can consist of lower aliphatic alcohols, e.g. methanol, ethanol, propanol, propanol-2, butanol or mixed aliphatic-aromatic alcohols, e.g. benzyl alcohol, etherified hydroxy groups.

In the event that these groups are esterified, this can take place with one of the following acids:

formic acid,

acetic acid,

propionic acid,

butyric acid,

α-methylpropionic acid,

valerian acid,

α-methylbutyric acid,

B-methylbutyric acid,

caproic acid,

t-butyl acetic acid,

trimethylacetic acid,

cyclopentylcarboxylic acid,

cyclohexylacetic acid,

cyclohexyl carboxylic acid,

o-toluic acid,

glutaric acid,

glycolic acid,

g-methylglutaric acid,

succinic acid,

adipic acid,

acrylic acid,

crotonic acid,

undecylenic acid,

maleic acid,

citraconic acid,

benzoic acid,

phenylacetic acid,

phenylpropionic acid,

(o-, m-, p-)toluic acid,

palmitic acid,

stearic acid,

oil acetic acid.

When the compounds contain at least one halogen atom, these are preferably fluorine or chlorine atoms.

The compounds that can be prepared according to the invention show a partially progestative effect, namely both when administered parenterally and also when administered orally. As a further peculiarity, it should be mentioned that these compounds do not have an antiestrogenic effect. They correspond to the general formula

in which Rh means the keto group, a hydroxy or an etherified or esterified hydroxy group, R2 means a double bond in the 4-position or two double bonds in the 4- and 6-position, or two double bonds in the 3- and 5-position, in which latter case R ^ means an etherified or esterified hydroxy group, R^ is a hydrogen atom, a saturated or unsaturated alkyl group with 1 to 3 carbon atoms, which optionally contains a double-bonded oxygen atom and/or a hydroxy or an etherified or esterified hydroxy group, and R1Q is a hydrogen atom ( with the precaution that B. g and R1Q cannot both be a hydrogen atom) or a hydroxy group or an etherified or esterified hydroxy group or R^ and R1Q together form the keto group.

In particular, this group of substances includes a class

for which R 1 , R 2 and R 1 Q have the above-mentioned meaning and R 2

is a hydrogen atom or a -CO.CHj-, -CHg-CHj-, -CH=CH2-C=CH- or

in which last group the hydroxy group may be etherified or esterified, with the precaution that Rg and R^q indeed together form a keto group, but cannot both be a hydrogen atom. It should be noted that the progestative action of the above compounds,

insofar as these contain a -CO-CH^ group and a hydroxy group, both at carbon atom 17, compared to the corresponding compounds, whose 17-hydroxy group is esterified, is low.

Of the ether groups, mention must be made of ethers of lower aliphatic alcohols, aliphatic-aromatic alcohols, e.g. methanol, ethanol, propyl alcohol, butanol or benzyl alcohol.

Compounds with the general formula that can be prepared according to the invention

wherein Rjj is the keto group, a hydroxy or an etherified or esterified hydroxy group, R2 is a double bond in the 4-position or two double bonds in the 4- and 6-position or two double bonds in the 3- and 5-position, in which latter case R^ is an esterified or esterified hydroxy group, and R^ is a keto group or a hydroxy group or an esterified or esterified hydroxy group, has an anabolic action in addition to a usually progestati<y> action and a lack of androgenic, estrogenic or antiandrogenic action.

Of the ether groups, mention must be made of ethers of lower aliphatic alcohols, aliphatic-aromatic alcohols, e.g. methanol, ethanol, propyl alcohol, butanol or benzyl alcohol.

The different biological effects were determined

in the following experiment:

1. Androgenic and antiandrogenic effect.

These effects were measured on the weight of the seminal vesicles, the weight of the ventral prostate both in infantile and castrated male rats, which were possibly pre-treated with an androgenic substance.

2.. Estrogenic and anti-estrogenic effect.

These effects were measured on the uterine weight of infantile and castrated female rats as determined by a vaginal swab of adult female rats and the vaginal opening of infantile female rats, the rats possibly .

was pretreated with an androgenic substance.

3. Progestative effect.

This effect was assessed after subcutaneous, intramuscular or oral administration on infantile female rabbits with a weight of 600 to 800 g on uterine aspect and according to the technique of Clauberg. 4. Anabolic effect.

This effect was assessed on the impact in renotropic experiments

(kidney weight gain) in castrated adult male mice. This is conditioned by the fact that the experiment is kin dependent with the help of the Musculus levator ani, which means that the Musculus levator ani does not increase in weight, when there is no male effect present.

5. Antiovulatory effect.

This effect was measured on adult female rats which, after previous administration and during this administration of the substance in question during two sexual cycles, were brought into contact with male partners, after which occurrence of a fertilization was assessed 14 days after the male partner had been removed.

6. Anti-inflammatory effect.

This effect is measured by the adult male rats being housed

cotton balls subcutaneously, which results in the body reacting to this with an inflammatory effect. Under the influence of various substances (hydrocortisone), this inflammatory effect is removed.

Listed below are some properties of a number of compounds produced according to the invention.

9B,10a-pregn-4-ene-3,20-dione has no androgenic and no estrogenic effects. It is orally progestative and not antiestrogenic. In this connection, it should be noted that progesterone is androgenic and not orally active and that the progestatiiye effect is five times weaker than that of lumiprogesterone (93,10a-pregn-4-en-3,20-dione). Furthermore, the 9$,10a compounds have a strong inhibitory effect on ovulation, a property lacking in progesterone.

93,10a-pregna-4,6-diene-3j20-dione is parenteral

progestatively active, namely 5.4 times stronger than 93,10a-pregn-4-ene,3,20-dione. The oral progestative activity of 93,10α-pregna-4,6-diene-3,20-dione is more than 20 times that of 93,10α-pregn-4,6-diene-3,20-dione. 93,10a-pregna-4,6-dien-3,20-dione has no androgenic and no estrogenic effects. Nor is it anti-■ ... j

estrogenically active. Furthermore, the compound is not anabolically active and it has a stronger, antiovulatory effect than lumiprogesterone.

96,10a-androsta-4,6-dien-17B-ol-3-one has no

androgenic and no estrogenic effect. It is orally progestative and not antiestrogenic. Very interesting is the antiandrogenic effect of this compound and furthermore its ability to provide an anabolic effect.

17a-ethynyl-98>10a-androst-4-en-17-ol-3-one' has no androgenic and no estrogenic effects. It is orally progestative and not antiestrogenic. The progestative effect exceeds that of progesterone.

96jlOa-androst-4-ene-3,17-dione is not androgenic and

not estrogenically active. Furthermore, it is not antiestrogenic. The compound has an orally progestative effect and has an anabolic effect.

96,10a-androst-4-en-178-ol-3-one is, with regard to the properties, little similar to the corresponding testosterone from the normal range.

It has no androgenic effect and is not estrogenically active. The

is orally progestative and not antiestrogenic. Furthermore, it shows an anabolic effect.

The 17-acetate of 17a-hydroxy-96,10a-pregn-4-ene-3j20-dione

is not androgenic and not estrogenic active. The connection is 25

to 30 times more progestatively active than 96,10a-pregn-4-ene-3,20-dione. It is orally active and, compared to the duration of action of progesterone, has a longer lasting effect. The compound has no antiestrogenic effect.

17-caproate of 17α-hydroxy-98,10α-pregn-4-ene-3,20-dione

has no androgenic and no estrogenic effects. The compounds are progestatively active, namely twice as strong as 96,10ot-pregn-4-ene-3,20-dione. The compound is orally active and has a strong prolonged action that surpasses that of 17-acetate. The compound has no antiestrogenic effect.

The 3,17-diacetate of 17ct-hydroxy-96,10a-pregn-4-ene-3,20-dione has no androgenic and no estrogenic action. It is several times more progestatively active than 96,10a-pregn-4-en-3,20-

dion. It has approximately the same effect as the 17-monoacetate of 17c6-hydroxy-96,10a-pregn-4-ene-3,20-dione, as far as the latter effect is concerned. It is also orally active and has a prolonged effect, which exceeds that of monoacetate. Furthermore, it is

not antiestrogenically active.

The 17-acetate of 9B,10a-pregn-4,6-dien-3,20-dione has no androgenic and no estrogenic effects. It is several times more progestatively active than 9B,10a-pregna-4,6-diene-3,20-dione. It is orally active and, with respect to progesterone, has a longer-lasting effect. Furthermore, it has no antiestrogenic effect.

98,10a-androst-4-en-3>178-diol has no androgen and

no estrogenic effect. It is orally progestatively active and has no antiestrogenic effect. Furthermore, the compound shows an anabolic effect.

9£,10ct-androst-4-ene-17$-ol-3-one-17$-(3-phenylpropionate)

has no androgenic and no estrogenic effects. Furthermore, it is orally progestatively active and has no antiestrogenic properties. The compound is actively anabolic and has an antiandrogenic effect.

93,10a-androsta-4,6-diene-17$-ol-3-one-17$-propionate

has no androgenic and no estrogenic effects. It is orally progestative and not antiestrogenic. Furthermore, it has an anabolic effect and provides an antiandrogenic effect.

9&jlOa-pregn-4-en-21-ol-3,20-dione-21-acetate has no androgenic and no estrogenic effects. It is an oral progesta-

as and has no antiestrogenic effect. Furthermore, the compound produces an inflammatory effect in anti-inflammatory tests.

The precautions used for carrying out the method according to the invention are the same as those also used in steroid-

the chemistry (9a,108). They are sufficiently well known.

The biologically active compounds that can be produced by the method according to the invention can be processed in the usual way into pharmaceutical preparations. When the compounds are orally active,

can they be processed into tablets or dragees in the usual way, e.g.

with a carrier material such as lactose or starch, a lubricant,

e.g. talc and/or magnesium stearate, and possibly with flavor

or dyes.

For the production of injectable liquids, the active compounds can be dissolved or dispersed in water, possibly with the addition of a buffer, a solvent carrier or a dispersant.

The method according to the invention shall be explained in more detail by means of the following examples. The production of the starting materials does not fall within the scope of the present invention.

Example 1.

Examples 1 a) to f) refer to the preparation of the starting material used for this example.

a) With very good stirring, 125 g of lumista-4,7,22-trien-3~one was dissolved at +10°C in 2.2 liters of dry propanol-2, as previously

had been saturated with dry hydrochloric acid gas. After that yet in | hour had been passed through a slow stream of hydrochloric acid gas, it was

as quickly as possible, completely with stirring in a mixture of solid sodium bicarbonate and a saturated bicarbonate solution, which solution had been formed by stirring 4 kg of sodium carbonate in 8 liters of water. After some time, the yellow isopropanol layer was separated and the salt layer was extracted with 2 . 1 liter of petroleum ether. The combined layers were

then washed with sodium bicarbonate solution and water (3 times), then dried over sodium sulfate and evaporated to dryness after filtration. Ultraviolet absorption spectra had a maximum at 287 my, ie

1?

the value E:r<*> amounted to 562 (content of pure substance approx. 85%).

-L cm

The residue formed was dissolved in 250 ml of boiling petroleum ether (40 to 60°C), crystallized for a few hours at -5°C and finally overnight at -25°C. By filtration, 80.5 g of lumista-4,6,22-trien-3-one with a m.p. from 99 to 100.5°C (yield good 64?). A quantity of the substance was recrystallized a few more times from petroleum ether for analysis, the melting point being increased from 101 to 102°C. /<->a7p<5>° = -632° (CHCl3); X = 287 mu, E = 26,200.

<C>28<H>4<20:>

Found C 85.67? R10.65?

85.68? H 10.77?

calculated C 85.22? H 10.63?.

In the infrared spectrum, next to the 964 cm<->'<*>' band for the side chain of the transethylene bond, three characteristic bands at 1586, 1622 and 1661 cm"<1> were found.

b) With good stirring, a solution of 3.0 g of lumista-4,6,22-trien-3-one in 300 ml of dry diethyl ether was added in an amount of

450 ml of liquid ammonia. When the first part of the solution was added, the substance crystallized, but it later dissolved again after a larger amount had been added. Then, with good stirring, a solution of 420 mg of lithium in 100 ml of ammonia was very carefully added dropwise, until no more appeared

L

spontaneous discoloration. After adding 90 ml of dry ethanol drop by drop, it was also stirred for 30 min., diluted with water and the reduction product

was taken up in diethyl ether. The ethereal extracts were washed well with water, dried over Na 2 SCL, filtered and evaporated to dryness, forming a pale yellow resin. E^<*>m (X = 242 = 196.

The resin was dissolved in 100 ml of boiling ethanol and, after adding 6 ml of 2-n NaOH, also boiled for 5 min., after which it was rapidly cooled. By diluting with water, taking up in diethyl ether, washing the ether layers with water, drying, filtering and evaporating, a light brown, completely solid residue was finally formed, E<1>^ ( X^ = 242 my) = 420.

This substance was chromatographed in 25 ml of pure benzene over 30 g of A120^ (activity III) and eluted with the same solvent (total 75 ml), with a dark brown ring remaining at the top of the column. The eluate evaporated to dryness was recrystallized from 45 ml of methanol at +5°C, after which the filtered product was washed with 20 ml of methanol at -25°C. Long, light brown needles (1.5 to 2 cm length), weight 2.43 g, m.p. 122 to 124°C.

500 mg of the substance was recrystallized twice from

3 ml of acetone at -5°C, finally forming 313 mg of colorless crystals of lumista-4,22-dien-3-one, ax = 242 my.

E = 16,800, m.p. 122 to 124°C /~a7p° = -125 (CHCl^.

<C>28<H> 44<0:>

Found: C 84.98? H 10.96?

84.89? 11.03?

Calculated: C 84.79? H 11.17?.

In the infrared spectrum, a strong band was found at 1665 cm<-1>, a somewhat weaker band at 1620 cm<1>, a weak band at 962 cm<-1> and a somewhat stronger band at 978 cm<-1 >. In a mixture of 750 ml of freshly distilled methylene chloride and 5.75 ml of dry pyridine, 20 g of the 4,22-dien-3-one formed above were then dissolved and the mixture was ozonized under magnetic stirring at -80°C (carbonic acid -ice-acetone) for 41 hours (0.205 mmol per minute). The oxygen flow rate (= VO2.) was 9 to 10 l/hour. The ozonide formed was then decomposed during one hour at 0° stirring with a suspension of 20 g of zinc dust after the addition of 105 ml of acetic acid. The reaction mixture was then heated for 5 min at 35°C, and the solid was then separated by filtration. After the addition of ice, the filtrate was successively washed with 75 ml and 50 ml of ice-cold 10 µg Na^O-j solution, 50 ml of 10 µg NaOH solution at 0°C and 4.300 ml of ice water.

The methylene chloride layer was then dried over Na 2 SO 1 {, filtered, and the filtrate was dry distilled, the last part thereby in vacuo. The colorless practically completely crystalline residue was recrystallized from 50 ml of diethyl ether at -25°C, with 10.1 g of 3-oxo-96,10a-bisnorchol-4-en-22-al being formed as the first crystallisate with a m.p. . of 119 to 121°C. Several times of recrystallization from petroleum ether (boiling range 40 to 60°C), to which a few drops of alcohol had been added and from diethyl ether increased the melting point to 122 to -123°C.

The further analytical data of the pure substance were:

<X>max = 242.5 my, E = 16,700, /~a72.3 = -144° (CHC1 ).

<C>22<H>32°2<:>

Found C 79.87? H 9.73?

80.06? 9.81?

Calculated C 80.42? H 9.82?

The infrared spectrum had characteristic bands at

1712, 1662 and 1610 cm"<1>.

c) A solution of 450 mg of the aldehyde formed above (according to example lb)) in 15 ml of chloroform and 25 ml of acetic acid, in which

200 mg of chromic acid and 0.2 ml of water had been dissolved, was subjected for 16 hours to an oxidation reaction at approx. 30°C.

After the excess of chromic acid had been decomposed

at 30 min. continuous stirring with 1.5 ml of methanol, it was diluted with water and the substance was taken up in benzene. The benzene extract was washed with water to a neutral reaction, dried over Na-^SO^ and filtered. After evaporation to dryness, a crystalline residue appeared, which on recrystallization from diethyl ether gave 340 mg of 3~oxo-9B,10a-bisnorchol-4-ene-20-carboxylic acid. Temp. 194 to 198°C. Some recrystallizations increased the melting point to 202 to 204°C,

Xmax = 242 m»> E = 16-800'

<C>22<H>32°3<:>

Calculated: C 76.70? H 9.36?

Found: C 76.39? H 9.45?

76.92? 9.48?.

d) A solution of 450 mg of ozonide in 25 ml of methylene chloride which was formed in the manner described in example lb) by ozonation

of lumista-4,22-dien-3_one, was oxidized with a solution of 200 mg of chromic acid in 25 ml of acetic acid overnight at 30°G. The excess of chromic acid was then cleaved by stirring with 2 ml of methanol for 30 min.

After dilution with water, the substance was taken up in diethyl ether and the ether-methylene chloride extract was washed three times with 50 ml of 2? NaOH. These layers were combined and again extracted with diethyl ether for

to remove residues of neutral components. The organic acid was released by acidification with concentrated hydrochloric acid and absorption in diethyl ether. After washing with water to a neutral reaction, it was dried over Na^O^, filtered and finally evaporated to dryness, forming 240 mg of a crystalline residue. A recrystallization from methanol at -5°C gave 150 mg of 3-oxo-9$,10a-bisnorchol-4-ene-20-carboxylic acid with m.p. 200 to 203°C.

The substance formed shows no melting point depression when mixed with the substance formed according to example 1 c), e) A solution of 300 mg of the aldehyde (prepared according to example 1 b), which was formed by ozonization of lumista-4,22-diene-3 -on was heated in 5 ml dry. benzene after addition of 0}11 ml of dry, freshly distilled piperidine and 1 to 5 mg of p-toluenesulfonic acid for 3 hours under N 2 on a reflux condenser, the refluxing benzene to remove formed water being dripped through powdered BaO in an extraction column.

After cooling, the reaction mixture was poured into water, taken up in diethyl ether and then washed four times thoroughly with water. The ether-benzene layers dried over Na 2 SO 4 and filtered were completely evaporated to dryness in vacuo. The resin-like residue was stirred at -15°C with 3 ml of methanol and, after crystallization, also cooled for 2 hours at -25°C. Purification gave 285 mg of the 22-piperidine-enamine of 3-oxo-9B,10a-bisnorchol-4-en-22-al with a m.p. from 88 to 93°C. Twice recrystallization from methanol increased the melting point to 94 to 96°C.

Xmax <2>41.5 my, E = 21,800, /"a7<2>° = 139° (CHC13).

<C>27<H>4l<N0:>

The skin C 81.7236 H 10.64? N 3.60?

81.78? 10.67? 3.66?

Calculated: C 8l.97? H 10.45? N 3.54?.

The infrared spectrum showed a strong band at 1660 cm1 1 which visibly overlapped a band with a lower extinction value at 1650 cm-1. Besides a band at l6l0 cm""<*>" it also gave a weaker band at 874 cm-1. After a smaller amount of this enamine had been prepared in a similar manner, a final substance was constantly being formed with m.p. from 94 to 96°C, production was switched to on a larger scale. Thereby, an amine with a different m.p. (114 to 115°C) was formed in high yield. This is probably attributable to cistrans- isomerism.

A solution of 10 g of 3-oxo-98,10a-bisnorchol-4-en-22-al was boiled in 180 ml of dry benzene with 3.8 ml of piperidine and 30 mg of p-toluenesulfonic acid for 3 hours under nitrogen and reflux . The condensed liquid was dried using powdered barium oxide. The reaction mixture was then completely evaporated to dryness in vacuo, forming a crystalline residue of 12.3 g which, after recrystallization from 10 ml of methanol, gave 9.3 g of 22-enamine of 3-oxo-9B,10ct-bisnorchol-4-en- 22-al with a m.p. from 98 to 107 to 111°C. A quantity of the substance which then had a sufficient purity for further processing was recrystallized for analytical purposes a few more times from acetone, whereupon a constant melting point of 114 to 115°C was obtained. The other analytical values found were: A.max = 241.5 mp, E 22,000 /"W<23> = -123° (CHC13>.

Found: C 81.87? H 10.49? N 3.52?

81.98? 10, H7% 3.63?.

The infrared spectrum of this substance differs only in details from the spectrum of the preparation with a m.p. from 94 to 96°C.

The characteristic bands mentioned for this substance were also found here,

f) A solution of 300 mg of 22-piperidine-enamine of 3-oxo-96,10a-bisnorchol-4-en-22-al in 4.5 ml of dry, thiophene-free benzene

was at -5 to +5°C with good stirring during 45 min. added dropwise a solution of 453 mg of sodium bicarbonate (2 . H^O) in 4.5 ml of acetic acid and 3 ml of benzene. After a further 2 hours of stirring at 0°C, 0.75 ml of methanol was added to the dark colored solution,

and it was stirred for 30 min. at the same temperature.

The reaction mixture was worked up by pouring into

25 ml of water and by extraction with benzene. The combined benzene extracts were then successively washed with water, 3 ml cold 10 µg NaOH solution (2 times), water, 3 ml cold 10 µg hydrochloric acid solution and water (4 times). A completely crystalline residue was finally formed from the solution dried over Na 2 SO 4 , filtered and then evaporated to dryness.

This was dissolved in 1 ml of methylene chloride, to which solution 4 ml of petroleum ether was added at boiling temperature. It knows

-25°C completed crystallization gave 150 mg of pale yellow, hard crystals

blocks with a m.p. from l6l to l63°C. A repeated recrystallization gave 130 mg of 98,10a-pregn-4-ene-3,20-dione with a m.p. of 163 to 164°C. <X>max= 241.5 my, E = 16,800, /"a/<20> = -62° (CHCl3).

<C>21<H>30°2<:>

Found: C 79.90? H 9.75?

79.89? 9.75?

Calculated: C 80.20? H 9.62?.

The infrared spectrum shows strong bands at 1690 and

1662 cm-1 and a weaker band at 1615 cm-1.

Example 2.

a) For the preparation of the starting material, a solution of 1 g of 3-oxo-98,10a-bisnorchol-4-en-22-al in 50 ml

freshly distilled acetic anhydride added 0.5 g of freshly melted Na acetate and the mixture was boiled for 16 hours in a nitrogen atmosphere under reflux.

The solvent was then distilled off as best as possible

under reduced pressure (about 10 mm Hg), and the residue formed was dissolved in 25 ml of chloroform. The undissolved Na-acetate was filtered off, the filter was washed with some chloroform and the filtrate supplemented with the same solvent up to 125 ml. Thereby a solution of 22-enol acetate of 3_oxo-98,10a-bisnorchol-4-en-22-al was formed. b) During ice water cooling, the thus formed solution of the starting compound was ozonized for 14 minutes, as per

my. 10.5 mg ozone was absorbed. Then, after adding 15 ml of acetic acid and 2 g of zinc dust, it was shaken for 10 minutes. and after filtering

was the solution washed with 10? NaOH solution and water (until neutral reaction). The solution dried over NaSO 4 , filtered and evaporated to dryness was then boiled for 45 min to hydrolyse any 3-enol acetate present. under reflux in 45 ml of methanol and 25 ml of 2-n HgSO^. After concentration in vacuo to

Half the volume of the organic matter was dissolved in diethyl ether and the ether extract was washed with 10? NaOH solution and water to neutral reaction, dried over NagSO^, evaporated to dryness and finally recrystallized from 4 ml of diethyl ether. The formed crystallisate was recrystallized with a mixture of methylene chloride + n-hexane, forming 113 mg of the substance with a m.p. from l60 to l63°C. The substance gave no melting point depression with the 98,10a-pregn-4-ene-3,20-dione formed according to example 1, /~a7p° = - 6l,5° (CHClj)

(average value of -62.1 and -60.9°)•

Example 3-

5.55 g of 21-iodo-93,10a-pregn-4-ene-3,20-dione (prepared by reaction of 98,10a-pregn-4-ene-3520-dione with diethyl oxalate and subsequent reaction of the formed 21 -ethoxy-oxalyl compound with iodine) was in 200 ml purified, dried acetone (KMnO^

and I^CO-j) boiled for 18 hours with 12 g of freshly melted potassium acetate under reflux. After evaporation of the acetone, 300 ml of water was added and the separated oil was dissolved in methylene chloride. After drying over Na2S<0>lj, the extract was evaporated to dryness (weight 1.4g) and chromatographed in benzene over 10 g of neutralized A^O^. Elution with benzene gave 700 mg of residue, from which, after recrystallization from acetone, 150 mg of the substance with a m.p. of 159 to 164°C.

By recrystallization from acetone, 425 mg of substance with a m.p. from 164 to 167°C, after which 335 mg of 21-hydroxy-9$,10a-pregn-4-ene-3,20-dione-21-acetate was finally formed by recrystallization from ethanol with a m.p. of 165 to 168°C. E<1*>

(Xmax = 242 my) = 457 and 462, E (242 my) 2 17,100.

<C>23<H>32°4 (372.49):

Calculated: C 74.15? H 8.66?

Found: C 74.03? H 8.55?

74.27? 8.77?.

The infrared spectrum gave i.a. bond at 1226, 1609,

I663, 1724 and 1751 cm"1.

Example 4.

a) For the preparation of the starting compound, a solution of 9.6 g of enamine (prepared according to example 1 e)) in

475 ml of methylene dichloride with stirring at -55°C in a nitrogen atmosphere is added dropwise to a solution of 4.08 g of bromine in 50 ml of methylene chloride. After the addition of 47 ml of solution, the mixture became light brown, after which the dropwise addition was terminated. This results in 20,22-dibromide of 22-piperidinenamine of 3-oxo-9B,10a-bisnorchol-4-en-22-al. After the reaction mixture had been cooled to 0°C, 60 ml of water was added, after which it was stirred vigorously for 2 hours at 20°C. The then separated methylene dichloride layer was, after washing twice with 100 ml of water, dried over Na^SO^. The residue contained 3-oxo-9B,10a-20-bromo-bisnorchol-4-ene-22-aldehyde.

70 ml of dry pyridine was added to the filtered solution and the methylene chloride was distilled off in vacuo, after which it was dehydrobrominated under N2 for 60 min. at 70°C and then for 30 min. at 100°C. Distillation of the pyridine in vacuo gave a residue which was dissolved in methylene chloride and then washed successively with 2-n HOI, water (3 times), 5 µg Na2CO.j solution °S water (3 times), after which it was dried over Na2S0^, filtered and evaporated to dryness. Yield: a light brown crystalline residue with a m.p. of 150 (decomposition) to 153°C to 155°C and E<**>m (*max = 248 my) = 865.

Recrystallization from 30 ml of acetone at -5°C gave 6 g of 3-oxo-96,10a-bisnorchola-4,17(20)-dien-22-al with a m.p. on

154 (dec) to 155 to 158°C. A small amount was also recrystallized three times with acetone and once with ethanol for analysis of a pure preparation. The analytical values were as follows: m.p. 151 (s) to 155 to 159°C, /<_>a7<23> = -138° (CHC13), E^°m Umax = 248 my) = 945, 930 and 956.

<C>22<H>30 °2<:>

Calculated C 80.98? H 9.20?

, Found C 80.95? H 9,10?

80.93? 9.26?.

The infrared spectrum gave a strong band at 1665 cm<-1>, a shoulder at 1710 em-1 and a weak band at 1620 cm<-1>. With regard to the not sharply defined mp. is it not entirely impossible that a mixture of cis-trans isomers was formed.

b) With good stirring, 5 g of powdered 3-oxo-9S,10ct-bisnorchola-4,17(20)-dien-22-al were suspended at -20°C

(according to example 4 a))' in a solution of 8 g of NaCN in 50 ml of absolute methanol. For this suspension, at -20°C during approx.

45 min. added 7.1 ml of glacial acetic acid, after which in the course of approx. 2 hours

the reaction temperature was increased from -20°C to +5°C. The resulting white porridge was then stored for a further 40 hours at +5°C, after which the mixture was worked up by pouring into 150 ml. methylene dichloride of 0°C and subsequent washing with 75 and 3 times 25 ml of ice water and post-drying over Na-^SO^ overnight at -5°C.

A small amount of the filtered solution was evaporated to dryness. Of the practically colorless residue, the N content found was 4.20? (theoretical value 3.96?) and E:r* (X o = '

$ XCIu ni cl KS

244 my) = 535 (methanol); Ej<*>m Umak3 <=2>33 my) = 516 (diethyl ether).

The compound thus formed is the cyanohydrin of 3-oxo-93,10a-bisnorchola-4,17(20)-dien-22al.

The remainder of the filtrate was ozonized at -80°C with stirring after 1.5 ml of dry pyridine had been added. The duration of the ozonization was 75 min. (pto 10 min. 2.16 mmol 0^), while the speed of the gas was approx. 10 l/hour.

The reaction mixture was then cleaved, stirring for 2 hours with 5 g of zinc dust and 15 ml of glacial acetic acid, the temperature gradually rising to 20°C. The filtered solution was then washed with water (150 ml and 2.100 ml), 10 µg NaOH solution (2.50 ml), water (2 times), 10 µg HCl solution (50 ml) and water (3 times), dried over Na2S0^ and after filtration evaporated to dryness. Several times of recrystallization from ethanol gave 1.48 g of 98,10a-androst-4-ene-3,17-dione, m.p. 153 to 155°C.

A part of this crystallisate was recrystallized for analysis from 90?-ig resp. 96?-ig ethanol. Temp. 154 to 156°C, <E>lcm (<X>max<=> 24°^ <my>) <=><569.>

<C>19<H>26°2<:>

Calculated: C 79.68? H 9.15?

Found: C 78.63? H 9.24?

79.20? 9.22?.

The infrared spectrum had a strong band at 1735 and 1665 cm 1 . Besides a shoulder at 1655 cm 1 , it also gave a <n>aver peak at 1608 om"<1>.

Example 5•

To a solution of 1.13 g of 9β,10α-androst-4-ene-3,17_dione, which was derived from lumisterol, in 20 ml of dry tetrahydrofuran, a solution of 550 mg LiAlH^ in 55 ml tetrahydrofuran.

The resulting thick mush was also boiled for 1 hour under a reflux condenser and after cooling, excess LiAlHjj was carefully cleaved with ethyl acetate. After dilution with diethyl ether, the reaction mixture was washed with water (3 times), dried over Na 2 SO 4 and evaporated to dryness.

The reaction product was crystallized from a mixture of acetone-hexane at -5°C, forming 0.6 g of the substance with a m.p. of 108 to 112°C. During melting, gas evolution occurred probably due to the crystal solvent.

After two recrystallizations from dry petroleum ether at -5°C, the melting point increased from 117 to 118°C, while no gas evolution occurred during melting. Repeated recrystallizations did not further change the melting point.

In the ultrafine range, the substance (9£,10a-androst-4-ene-3S,17B-diol) has no absorption.

<C>19<H>30°2<:>

Calculated: C 78.55? H 10.41?

Found: C 78.60? H 10.93?

78,78? 11,17?.

The infrared spectrum had more or less strong bands

of 863, 1048, 1059, 1077, 1236, 1421, 1468 and 1663 cm<-1>.

Example 6.

To a solution of 500 mg of 90,10a-androst-4-en-176-ol-3-one in 10 ml of dry, freshly distilled pyridine, a solution of 0.5 ml of g-phenylpropionyl chloride was added at 0°C with good stirring in 5 ml of dry, anhydrous benzene, whereupon the reaction mixture was stirred for 16 hours at room temperature.

By pouring into a mixture of 80 g of ice and 20 ml of concentrated sulfuric acid, excess acid chloride was decomposed. The ester was dissolved in benzene (3.20 ml), and the combined extracts were successively washed with a sodium carbonate solution (10?) and water until neutral, dried over sodium sulfate, filtration and evaporation to dryness gave 700 ml of an oily product, of which the after filtering the benzene solution through a column with 10 g of neutralized alumina, 590 mg of a resin appeared which crystallized after some time. The crystal fraction formed by stirring with petroleum ether gave, after 2 times recrystallization from methanol at -5°C, 197 mg of 9$,1Oct-androst-4-en-17e-ol-3-one-17B-phenylpropionate with a m.p. from 73 to 74°C. Recrystallization otherwise no m.p. more. E<1*> (xmax = 242 m ^) = ^ 21> E = 17--700. C28H36°3 (420>6);

Calculated: C 79.97? H 8.63?

Found: C 80.00? H 8.58?

79.52? 8.38?.

The infrared spectrum had bands at 1725, 1663 cm 1 (strong), 1610 cm"<1> (moderately strong) and 1173 cm<-1.>

Example 7.

A solution of 5 g of 93,10a-androst-4-ene-17$-ol-

3~one was boiled in 330 ml of freshly distilled tertiary butanol in a nitrogen

atmosphere with stirring and reflux with 8.5 g of chloranil in 5

hours. After cooling, it was diluted with 2 liters of water and extracted with 3 times 200 ml of methylene chloride. After dilution with 750 ml of petroleum ether (40 to 60°C), the extract was washed with 100 ml of 5% NaSO solution with 4 . 50 ml 1-n NaOH and water to neutral reaction. After drying over ^ 2^ 0^, filtration through some magnesium aluminum silicate and evaporation to dryness, 2.3 g of a brown crystalline residue was formed which in benzol was filtered through 25 g of alumina (Broekmann, strength II). Slurry with 300 ml of benzene gave 2.0 g of crystalline substance, Eix " cm (A niaK, S= 284 my) = 815.

Recrystallization from acetone-hexane at -5°C fa

1.43 g with a m.p. of 170 to 172°C. Repeated recrystallization gave 1.05 g of 9B,10ct-androsta-4,6-dien-178-ol-3-one, m.p. 173 to 174.5°C. From the filtrates, 240 mg were also obtained with a m.p. from

167 to 170°C.

Finally, for the production of analytically pure substance, it was recrystallized from diethyl ether. Temp. 174 to 175°C, Elcm (<X>max = 284 my) = 903 °e 893 > E 284 my = 25-7°°-

C19H26°2 <28M):

Calculated: C 79.68? H 9.15?

Found: C 79.86? H 9.27?

79.58? 9.09?.

Infrared spectrum had characteristic bands at

3441 cm<-1> (strong, OH frequency), l64l cm<-1> (strong, conjugated keto group), l6l5 cm"<1> (strong, double bond) and 1571 cm 1 (weak, double bond).

Example 8.

A solution of 360 mg of 93,10a-androsta-4,6-dien-170-ol-3-one in 8 ml of dry freshly distilled pyridine was added at e°C to a solution of 0.14 ml of distilled propionyl chloride in 4 ml of dry , thiophene-free benzene. After stirring for 20 hours at room temperature, it was poured onto a mixture of 50 g of ice and 16 ml of concentrated sulfuric acid. The ester solution formed by extraction with benzene (3.15 ml) was successively washed with a sodium carbonate solution (10?) and water to a neutral reaction. Drying, filtration and evaporation to dryness gave 435 mg of residue, which was crystallized with methanol at -5°C. Recrystallization with the same solvent gave 233 mg of 9S,10a-androsta-4,6-dien-17B-ol-3-one-17-propionate with a m.p. of 113 (slight sintering) to 115 to 117°C. Recrystallization of a portion of this material for analytical purposes increased the melting point to 114 to 115 to 117°C. E^m amax = 285 my) = 739, E = 25-400.

C22H32°3 ^44.5):

Calculated C 77.14? H 8.83?

Found: C 77.27? H 8.82?

77.27? 8.68?.

The infrared spectrum had bands at 1731, 1650, 1618. cm-1 (strong) and 1571 cm 1 (relatively strong).

Example 9 -

In a three-necked flask, 50 ml of ammonia was condensed from 250 ml at -80°C. The ammonia gas was previously dried as it was passed through three drying columns, which contain solid KOH, soda lime or KOH. 1.61 g of potassium was then dissolved in the condensate, after which ethylene gas was introduced into the dark blue solution until complete decolorization had been achieved. This gas was cleaned and dried using solid KOH, soda lime or KOH, concentrated HgSO^ and solid KOH.

1.06 ml of dry acetone was then quickly added to the acetylide while stirring and cooling at -80°C and immediately afterwards a solution of 3.03 g of 98.10ct-androst-4-ene-3,17-dione in a mixture of 25 ml of dry thiophene-free benzene and 25 ml of dry peroxide-free diethyl ether.

Passing a slow, dry stream of nitrogen, the reaction mixture remained without further cooling for another 16 hours, after which it was quenched with 175 ml of water. The thus separated clear benzene layer was worked up after washing with water, drying over NaSO 2 , filtration and dry evaporation. The residue of 3.25 g of Z_Eicm (<X>max <=> 2^ 2 mu) = 28-^ was chromatographed 1 benzene through 50 g of A^O^ (strength according to Brockmann, strength II).

Slurry with benzene (800 ml) and diethyl ether

(200 mL) gave crystalline fractions, which were collected and recrystallized from n-hexane to give 1.95 g needles of 17o-ethynyl-9e,10a-androst-4-en-173-ol-3-one with a m.p. of 195 to 196°C.

A small amount was recrystallized a few more times from n-hexane for analytical purposes, finally the constant melting point was 195 to]96°C /"W<20> = -219° (CHC13), E\% cm (<X>max <=><2>42 my) <=> 524.

<C>21<H>28°2<:>

Found C 80.88? H 8.98?

80.83? 9.11?

Calculated C 80.73? H 9.03?.

The substance's infrared spectrum had, among other things, bands at 877, 1063, 1128, 1222, 1604 and 1648 cm"<1> (more or less strong). Example 10.

To a solution of 1 g of 9B,10a-androst-4-en-17$-ol-3-one in 35 ml of benzene was added 1 g of selenium dioxide and 0.6 ml of water, after which the whole was boiled in a nitrogen atmosphere under to-back race for 48 hours.

After filtering off and washing the solids with benzene, the filtrate was successively washed with a bicarbonate solution and water. The dried, filtered solution was evaporated to dryness in vacuo to give 625 mg of a resin. E1^ (Xmax 243 my) = 358.

During an additional treatment of the solid components after the reaction (selenium dioxide, etc.) with carbon tetrachloride, a further 50 mg of resin was also obtained after work-up. The total amount was then dissolved in benzene and chromatographed on 40 g of aluminum oxide.

Fractions 3 and 4 were crystallized from n-hexane

(2 times), forming 150 mg of the substance with a m.p. of 164 (slight sintering) to 172-173°C Recrystallization with a mixture of n-hexane and methylene chloride gave 98 mg of 9B,10ct-androsta-1,4-dien-17$-ol-3-one, m.p. 171-175-177°C, E<1>^ (Xmakg = 243.5 my) = 538,

E = 15,300.

C19H26°2 (286.4):

Calculated C 79.68? H 9.15?

Found C 79.44? H 9.07?

79.07? 9.15?

The infrared spectrum had, among other things, bands at 3364, 1650 cm 1 (strong), 1609 cm<-1> (fairly strong), 1592 cm<-1> (weak) and 884 cm<-1>. Example 11.

A solution of 1.3 g of 2-ethoxyethyl-9B,10a-androst-4-ene-173-ol-3-one enolate in 25 ml of dry, purified acetone was boiled with 2 ml of methyl iodide for 18 h in the presence of 1 g dry potassium carbonate under reflux. After cooling, it was diluted with water and dissolved in diethyl ether, after which the extract was washed with 1-n caustic soda and water to a neutral reaction, dried over NagSO 4 . and after filtration evaporated to dryness.

The residue of 1.05 g was boiled for 3 hours with a solution which had been formed by the reaction of 0.5 g of sodium in 10 ml of anhydrous ethanol. After cooling, it was poured into water and the separated substance was dissolved in diethyl ether, washed with water, dried over sodium sulfate, filtered and evaporated to dryness, forming 0.515 g of a resinous substance which could not be easily brought to crystallization. Chromatography of a solution of the substance in benzene on 25 g of aluminum oxide gave the following fractions:

Twice as crystallization of fractions 2 to 4 from a mixture of diethyl ether and n-hexane gave 207 mg of 2-methyl-9$,10a-androst-4-en-17$-ol-3-one with a m.p. of 175 to 179°C.

For analysis purposes, a portion was recrystallized again, the melting point being 177 to 179*5°C, E^m Umax = 241.5 my) = 508, E = 15,400.

C20<H>30°2 (302.46):

Calculated C 79.41? H 10.00?

Found C 79.50? H 9.98?

79.81?9.84?.

Example 12.

A solution of 7.5 g of 93,10a-pregn--4-ene-3,20-dione

in 500 ml of freshly distilled tert.-butyl alcohol was heated with 12.75 g of finely powdered chloranil with stirring for 5 hours under nitrogen and reflux. After cooling, 2 liters of water were added and it was extracted 3 times with 200 ml of methylene chloride. The combined extracts were then diluted with 1 liter of petroleum ether (40 to 60°C)

successively washed with dilute NagSO^ (100 ml), 4 . 75 ml 1-n NaOH and water to neutral reaction.

Drying over Na 2 SO 4 and evaporation to dryness (last part in vacuum) gave 3.7 g of crystalline residue.

Filtration of the benzene solution through 35 g of alumina (according to Brockmann, strength II) and slurrying with benzene gave, after evaporation of the solvent, 3.11 g of crystalline residue. From this, 900 mg of crystallisate with a melting point of 165 to 170°C was obtained by recrystallization from 15 ml of acetone at room temperature (a by-product crystallized at a lower temperature).

Passing the mother liquor into a mixture of ethanol and hexane gave 1.7 g of the substance with a m.p. from 135 to 145°C. This fraction was then recrystallized from acetone (room temperature) to give 600 mg with a m.p. from 166 to 171°C. The two already fairly pure fractions, after recrystallization from a mixture of acetone and hexane, finally gave 1.0 g of 93, 10a-pregna-4,6-diene-3,20-dione with a m.p. from 169 to 170°C. From the mother liquor, a secondary fraction of 0.44 g is obtained with a m.p. from 168 to 169°C.

A small part was again recrystallized from acetone for analysis purposes, whereby the melting point was increased to 169 to 170°C.

EIL (<X>max = 286>5 my> = 842 °S 848><E>286.5<my><=>26'4°°-

C21H28°2 (312.43):

Calculated C 80.73? H 9.03?

Found C 81.11? H 9.20?

81.25? 9.07?.

The infrared spectrum had, among other things, band at 1695 cm 1

(strong, unconjugated keto group), 1656 cm 1 (strong, conjugated keto group), l6l7 cm<-1> (strong, double bond in conjugation)

1573 cm<-1> (moderately strong, double bond) and 888 cm"<1> (strong). Example 13.

Examples 13 a) and 13 b) refer to the production of the starting material.

a) 3.95 g of isolumisterone according to example 1 a) was dissolved in 150 ml of dry methylene chloride. To this resolution it was set

0.81 ml of dry pyridine. The solution thus formed was cooled to -80°C and then for 26 min. passed through 14 mmmol of ozone (ie 140% of the theoretical amount). The reaction mixture was then skilfully stirred, after which 15 g of paraformaldehyde was added. With continuous stirring, the temperature increased over the course of 4 hours to approximately room temperature. After overnight storage, the solid was suctioned off, washed with petroleum ether and ether. The solution was then washed with water, cold NaOH and water. After drying over Na-SOj, the solution was evaporated. Yield: 3.08 g residue. E:j: _ cm(286 my) 2,770. This residue was crystallized from acetone and then further recrystallized twice. The thus formed pure 3_oxo-93,10a-bisnorchola-4,6-dien-22-al had a m.p. of 153 to 155°C. The UV absorption spectrum had a maximum at 286 my, E1^ = 780, E = 25,400.

C22H30°2 (326.48): Calculated C 80.94? H 9.26? 0 9.80?

Found C 81.07? H 9,l6? 0 9.94?

80.87? 9.05? 10.00?

It was, among other things, found the following bands in the infrared spectrum: 1410 cm"<1> (weak), 1654, 1717, 1584 cm<-1> (strong) and 1621 cm 1 (fairly strong).

b) 3.5 g of the aldehyde formed according to example 13 a) (crude, crystalline, m.p. 146-151°C) was dissolved in 50 ml absolute

. benzene, to this solution was added 1.27 ml of piperidine and

20 mg of p-toluenesulfonic acid. This reaction mixture was refluxed (over BaO) for 2 hours. The solvent was then distilled off in vacuo. This gave 4.4 g of residue (105?). It was brought to crystallization with 30 ml of methanol at -25°C. Yield: 2.1 g of 22-(N-piperidino)-9β,10α-bisnorchola-4,6,20(22)-trien-3-one with one m.p. of 127 to 135°C. After 2 recrystallizations from acetone, the substance was pure. Temp. (in vacuum) 135 to 136°C.

The UV absorption spectrum had a maximum at 287 my, E*J_ = 661 and 657, E = 26,000 and 25,800.

C27H39NO (393.62): Calculated C 82.39? H 9.99? 0 4.06? N 3.56?

Found: C 82.40? H 9.86? 0 4.35? N 4.13?.

In the infrared spectrum, a band was found at 870,

1622, 1656 cm"<1> (strong), 1410 cm"<1> (weak).

c) 16.7 g of the thus formed 3-oxo-93,10a-bisnorchola-4,6-dien-22-al-22-piperidine-enamine in 250 ml of dry, thiophene-free benzene

was within 45 min. added to a well-stirred, to approx. 0°C cooled solution of 25.2 g sodium bichromate in 250 ml acetic acid + 170 ml benzene. After stirring for 2 hours at 6°C, 42 ml of methanol was added and it was again stirred for 1 hour at 0°C. The reaction mixture was then poured into water and extracted with ether. The extract was washed with water, dilute sodium hydroxide solution and water. After drying over Na 2 SO 4 , the solvent was distilled off. Yield: 12.24 g = 92? residue. This was crystallized from acetone-hexane (6.6 g) and then purified by recrystallization twice with acetone. The melting point of the 93,10α-pregna-4,6-diene-3,20-dione thus formed was 168 to 169°C.

Example 14.

a) For the preparation of the starting material, a solution of 0.987 g (3 mmol) of 3-oxo-93,10a-bisnorchola-4,17(20)-dien-22-ol (prepared according to example 4 a)) in 10 ml of dry, thiophene-free benzene under ice water cooling added a solution of 1.2 g of monoperphthalic acid (6.6 mmol) in 25.5 ml of ethyl acetate.

From the remaining amount of the reaction mixt

the phthalic acid formed was filtered off, and the filtrate formed was washed with a 10 µg solution of sodium bicarbonate in water,

dried over Na2S0^.and after filtration evaporated to dryness. This gave 0.88 g of an approximately colorless resin, which could not be brought to crystallization.

b) 0.88 g of 17(20)-epbksy-A4-3-keto-9B,10a-pregnen-20-ol-20-formate was dissolved in 150 ml of ethanol (95?), heated to 30°0

and mixed with 35 ml of aqueous 2.0 N sodium hydroxide solution at room temperature, the reaction mixture turning pale yellow. After standing for 2 hours at room temperature without cooling and without heating, the mixture was neutralized with 6 ml of acetic acid. The light yellow solution thus formed was then concentrated at the lowest possible temperature to a water jet vacuum to approx. 60 ml,

and then 100 ml of water was added. The thus separated oil was dissolved by two extractions in ether and the solution was, after washing with dilute carbonate solution and water and after drying, filtered over Na2S0i}. By dry evaporation, 580 mg of crystalline residue is obtained. E1^ (xmax = 242,504.

After recrystallization three times from ethanol at -5°C, 118 mg of hard crystals of 17α-hydroxy-9β,10α-pregn-4-ene-3β2O-dione are obtained with a -m.p. from 222 to 225°C,

Elcm (Xmax 242 my) = 5°0' E (242 my) = l6' 5°°-

C21H30°3 (330.45):

Calculated: C 76.32? H 9.15?

Found: C 76.07? H 9.14?

75.84? 9,10?

The infrared spectrum had, among other things, band ,at 3369 cm 1 (strong, hydroxyl band), l697 cm<-1> (strong, unconjugated keto group), 1643 cm'<1> (strong, conjugated keto group), l6l0 cm<-1 >(fairly strong, double bond ), 1354, 1232, 928 and 858 cm"<1>.

Example 15»

A solution of 220 mg of 17a-hydroxy-9B,10ct-pregn-4-ene-3,20-dione and 220 mg of p-toluenesulfonic acid in 15 ml of distilled acetic anhydride was kept for 18 hours at room temperature, crystallizing a small amount of small needles from the very dark reaction mixture. By pouring into ice water and after adding some pyridine, it was stirred and thus the excess of acetic anhydride was decomposed. The ester was dissolved in ether (3.30 mL) and methylene chloride (1.30 mL). The combined extracts were successively washed with water, 2-n sulfuric acid (until the mixture was pyridine-free), water, 5 µg bicarbonate solution and water, dried over Na2S0^ and after filtration evaporated to dryness whereupon it was formed

a completely crystalline residue. Crystallization from a mixture of methylene chloride and methanol at -5°C gave 130 mg of crystals of the 3-enolacetate-17-acetate of 17o-hydroxy-98,10a-pregn-4-ene-3,20-dione, m.p. 207 (sintering)' to 213-216°C. After recrystallization twice with the same mixture, it gave constant melting point 207 (sintering) to 213 to 217°C. In high vacuum, the melting point was 217-218°C. E<1>^ (Xmax = 236.5 my) = 44.5 and 439, E 236.5 my 18,300.

<C>25<H>34°5<: >Calculated: C 72.43? H 8.27? Found: C 71.71? H 8.21?

71.78? 8,12?. / The infrared spectrum had, among other things, band at 1744 cm-1 (broad, strong band, acetate group (2 times)}, 1707 cm 1 (strong, unconjugated keto group), l66l cm<-1> (weak), 1624 cm 1 (very weak),

1248 and 900 cm"<1> (strong).

Example 16.

• A solution of 500 mg of 17a-hydroxy-93,10a-pregn-4-ene-3,20-dione and 500 mg of p-toluenesulfonic acid in a mixture of 5 ml of freshly distilled acetic anhydride and 25 ml of acetic acid was

preserved 15 hours at room temperature. The acetic acid had previously been made anhydrous during reflux cooling with acetic anhydride and by subsequent fractionation.

The dark colored reaction mixture was poured into

200 ml of water, and the reaction product was dissolved in methylene chloride. After addition of ether, the extract was successively washed with

water, 5% bicarbonate solution (3 times) and water. Drying over sodium sulfate and evaporation to dryness gave a crystalline residue which was dissolved in methanol. Grafting with diacetate according to example 15 allows some of this ester to crystallize at room temperature. 3 hours of suction gave 75 mg of diacetate with a m.p. of 205 (sintering) to 211-2l4°C. The filtrate was concentrated and brought to crystallization at -5°C. Yield: 260 mg of 17ct-hydroxy-98,10a-pregn-4-ene-3,20-dione-17-acetate with a m.p. of 162 (sintering) to l67-172°C. After recrystallization twice, the melting point increased to a constant value from 171 to 173°C (sintering at 169°C). E<1>^ = (*max <=>

241.4 my) 444 and 452, E = 24l.4 my = 16,700.

<C>23<H>32°4<:>

Calculated: C 74.16? H 8.66?

Found: C 73.8l? H 8.69?

73.88? 8.68?.

The infrared spectrum had, among other things, band at 1724 cm 1

(strong, acetate keto group), 1707 cm<-1> (fairly strong, not conju-

gert keto group), 1657 cm<-1> (strong, conjugated keto group), l6ll cm 1 (rather strong, double bond), 1256 and 871 cm<-1.>

Example 17»

900 mg of 17α-hydroxy-9B,10α-pregn-4-ene-3,20-dione was shaken for 15 hours in 20 ml of caproic anhydride under nitrogen with 1.1 g of toluenesulfonic acid. After adding 20 ml of ethanol and 0.3 ml of concentrated hydrochloric acid, the dark-coloured reaction mixture was boiled for 1 hour under reflux, after which 40 ml of pyridine was added. It was then evaporated to dryness in vacuo and the residue was dissolved in methylene chloride. The resulting solution was washed with water to a neutral reaction, dried over Na2SO4 and finally evaporated to dryness, forming 1.25 g of a resin-like product. The substance could not be brought to crystallization, even after filtering the benzene solution through 18 g of neutral alumina. The neutral alumina was prepared by suspending the commercial product (Merck) for 6 hours in boiling ethyl acetate and after filtration dried at 100°C, whereupon elution with benzene and dry evaporation of the eluate gave 1.1 g of resin with ia (xmax = 21 +1 etc.)

<=> 310.

The residue was therefore, after careful drying (for 2 hours at 60°C at 0.1 mm Hg), chromatographed in petroleum ether containing 5% diethyl ether on 25 g of neutral alumina, after which it was eluted with the same Manding.

The crystalline fractions 3 and 4 had, after recrystallization twice, a m.p. of 50 to 53°C (weight 67 mg). The thus formed 17-caproate of 17a-hydroxy-93310a-pregn-11-ien-3,20-dione had a value E*Jm (Xmakg = 242 my) of 388.

<C>27<H>43°4<:>

Calculated C 75.66? H 9.4l?

Found C 75.15? H 9.22?

75.40? 9.30?

The infrared spectrum had, among other things, band at 1721 cm 1

(strong, ketocaproxy), 1709 cm<-1> (strong, unconjugated keto group), 1664 cm<-1> (strong, conjugated keto group) and l6l3 cm<-1 >(fairly strong, double bond).

Example 18.

A solution of 0.495 g (1.5 mol) of 17ct-hydroxy-93,10a-pregn-4-ene-3,20-dione in 60 ml of tert.-butanol was boiled under nitrogen and refluxed with 0.74 g (3 mmol) chloranil. After 2 hours and after 4 hours, samples were taken and worked up by pouring into water, dissolving in methylene chloride-ether and washing with 2-n caustic soda and water. The residue formed by drying over Na2S0^ and after filtration and dry evaporation had an absorption maximum at X = 286 my with a value e}^ ° of 203 resp. 462.

limb ^

After a total of 7 hours of boiling under reflux

the reaction mixture as a whole was worked up in the above-mentioned manner and filtered through neutral aluminum oxide in benzene solution, 180 mg of raw material being formed. Crystallization from a mixture of ethanol-hexane at -5°C gave 97 mg with a m.p. of 229 (sintering) to 239-244°C. Two recrystallizations finally gave 50 mg of 17α-hydroxy-93,10α-pregn-4,6-diene-3,20-dione with a m.p. of 242 to 245°C (high vacuum, 243 to 245°C). E^m Umax = 286 my) = 776 and 756,

E 286 my = 25,100.

C21H28°3 (328.45):

Calculated C 76.79? H 8.59?

Found C 76.38? H 8.61?

76.64? 8.50?

The infrared spectrum had, among other things, band at 3344 cm 1 (strong, hydroxyl group)j 1697 cm 1 (strong, non-conjugated group), 1641 cm<-1> (strong, conjugated keto group), l6l2 cm<-1> (strong, double bond), 1576 cm" 1- (fairly strong, double bond) and 873 cm 1 (fairly strong, conjugated keto group).

Example 19.

A solution of 372 mg (1 mmol) of 17α-hydroxy-93,10α-pregn-4-ene-3,20-dione-17-acetate in 40 ml of tert.-butanol was boiled under nitrogen and refluxed with 490 mg (2 mmol) chloranil. After different reaction times, samples were taken and processed as above. The UV spectra of the crude dehydration products formed were determined, as it turned out that after 11 hours of boiling the value E, x cm at 286 my had risen to 585" The reaction mixture's up-

working as a whole after the mentioned time gave 152 mg of residue which was crystallized from acetone and then recrystallized from a mixture of acetone and hexane at -5°C, finally forming 32 mg of crystals of 17a-hydroxy-93,10a-pregn- 4,6-diene-3,20-dione-17-

acetate with a m.p. of l8l to 183°C. E<1>^ ( X , = 286 my) = 622

^ limb max

and 633, E 286 my = 23,200.

°23<H>30°4 (370.49):

Calculated C 74.54^ H 8.16%

Found C 73.85? H 8.13?

73.75? 8.16?.

The infrared spectrum had a band at 1724 cm <1> (strong,

ketoacetate group), 1704 cm 1 (strong, non-conjugated keto group),

1653 cm-1 (strong, conjugated keto group), 1625 cm <1> (fairly large,

double bond), 1585 cm <1> (rather weak, double bond),

1258 cm-1 (strong, acetate group) and 878 cm <1> (strong, conjugated keto-

group).

The compound was also formed when 17α-hydroxy-93,10α-pregn-4,6-diene-3,20-dione was esterified with acetic anhydride on

the manner described in example 16.

Claims (13)

1. Process for the production of therapeutically active steroids of the 90,10a-androstane or pregnane series with increased specific intrinsic effect, in particular with no and reduced androgenic side effect, which corresponds to the general formula and in which R^ is a hydrogen atom or the methyl group, R2 can be a double bond in at least one of the positions 1, 2, 3> 4, 5, 6, 15 and/or 16, FU is a hydrogen atom, methyl or ethyl or a hydroxy or etherified or esterified hydroxy group, R^ is a keto- or a hydroxy or an etherified or esterified hydroxy group, R^ is a hydrogen atom, or a halogen atom, Rg is a hydrogen atom, the methyl group, a halogen atom or a hydroxy or an etherified or esterified hydroxy group, Ry is a halogen atom or a hydrogen atom, Rg is a hydrogen atom, a hydroxy or a keto group, Rg is a hydrogen atom or a saturated or unsaturated hydrocarbon residue with 1 to 6 carbon atoms or such a hydrocarbon residue where at least one hydrogen atom is replaced by at least one hydroxy or etherified or esterified hydroxy group and/or at least one doubly bonded oxygen atom, R^Q is a hydrogen atom, a hydroxy or an etherified or esterified hydroxy group, with the precaution that R^ and R.^ also together can form a keto group, however, not both are a hydrogen atom and R-^ is a hydrogen atom or a hydroxy- or an etherified or esterified hydroxy group, the substituents R^ and R^ to R^^ can be bonded a- or g- placed to the steroid skeleton, characterized in that according to methods known per se a) a compound with the general formula wherein X means the 17-positioned linked 935 10ot steroid residue of the general formula since the configuration of the steroid skeleton in positions 8, 9, 10, 13 and 14 is the same as in dihydroisolumisterone and in which R-^ can be a hydrogen atom or the methyl group, R2 can be a double bond at one or more of the positions 1, 2,'3- 4, 5, 6, 15 or 16, R-, means a hydrogen atom, the methyl or ethyl group or an optionally etherified or esterified hydroxy group, R^ means keto- or an optionally etherified or esterified hydroxy group, R^ means a hydrogen atom or a halogen atom, Rg means a hydrogen atom, the methyl group, a halogen atom or an optionally esterified or esterified hydroxy group, Rj means a hydrogen atom or a halogen atom, Rg means a hydrogen atom, a hydroxyl or the keto group, R.., means a hydrogen atom or an optionally esterified or esterified hydroxy group, Q<IV > means a hydrogen atom, a secondary amino group, an O-acyl group, the phenyl group or a lower aliphatic hydrocarbon group and Q means a hydrogen atom, the phenyl group or an aliphatic hydrocarbon group, under the condition, however, that not both groups Q<1>^ and Q are hydrogen atoms, oxidatively to a corresponding 20-keto-pregnane compound, or b^) a 20-keto-21-halo compound of the 93, 10a-pregnane series with the general formula in which j }, has the meaning mentioned above, and where R^ can also be the methyl group and where further R^q means a hydrogen atom or an optionally etherified or esterified hydroxy group at carbon atom 17 and Hig means an iodine or bromine atom, acyloxylated in the 21-position, optionally followed of saponification of the formed 21-ester group, or b2) a 20-keto compound of the 93,10a-pregnane series with the general formula is acyloxylated or hydroxylated with lead tetraacetate or by microbiological hydroxylation at carbon atom 21, or c) a 17,20-epoxy formate of the 93jlOa pregnane series with the general formula wherein X has the above-mentioned meaning, is hydrolyzed below formation of the corresponding 17ot-hydroxy-20-ketopregna compound and optionally esterified at the 17-hydroxy group, or d) a 9B,10ct-17(20)-bisnorcholen-22-al, -17 (20)-pregnen-20-ol- 20-acylate or a 93,10a-17(20)-bisnorcholenic acid of the general formula wherein X has the above meaning, and wherein Q^<1> is a hydrogen atom or a methyl group and oT11 is one of the groups its HCN or bisulphite addition product -O-acyl or an optionally esterified -COOH group, is oxidized to form the corresponding 17-keto-93,10a-androstane compound, or e) a 17-keto compound of the 93,10ct-androstane series with the general formula where-in X has the meaning mentioned above, is reacted with an optionally unsaturated metalaliphatic compound to form the corresponding 17a-alkyl-(or -alkenyl)- or -alkynyl-17g-hydroxy compound or is reduced by the 17-keto group to form the corresponding 17-hydroxy compound and optionally the 17-hydroxy group is esterified, or f) a 1,2-dihydro compound of the 93,10*a-androstane or -pregnan series with the general formula in which the configuration of the steroid skeleton in positions 8, 9, 10, 13 and 14 is the same as in dihydroisolumisterone and in which R^, R^, R^ to Rg and R^ have the meaning mentioned above under point a) R2 can be a double bond at one or more of the carbon atoms 4, 55 6, 15 or 16, R^ means a hydrogen atom, a saturated or unsaturated hydrocarbon residue with 1 to 6 carbon atoms, or such a hydrocarbon residue where at least one of the hydrogen atoms is replaced by at least a hydroxy or etherified or esterified hydroxy group and/or doubly bonded oxygen atom, R-^q is a hydrogen atom or an optionally etherified or esterified hydroxy group, so that Rg and R^0 can also together form the keto group, but not both be a hydrogen atom, is dehydrated in the 1(2) position, or g) a 6,7-dihydro compound of the 9g,10ct-androstane or 93,10a-pregnane series with the general formula in which R15 R^j R^ to R^ has the meaning mentioned above under point a), and R2 can be a double bond at one or more of positions 1, 15 or 16, is dehydrated in the 6(7) position, or h) a 93,10a-androstane or -pregnane compound of the general formula in which R^, R^ to R^ 1 have the meaning mentioned above under point a), R2 can be a double bond at one or more of the positions 4, 5, 6, 15 and/or 16, and R12 is an alkyl group, is reacted with a methyl or ethyl halide and then with an alkali alcoholate to form the corresponding 2-methyl or -ethyl compounds. 2. Method according to claim 1 a) or ld), characterized in that the compounds used as starting material in the 1-, 2-, 4-, 6-, 9-, 11- and 16-positions are substituted with hydrogen, in the 3- position has a keto- or an optionally etherified or esterified hydroxy group, as they may contain one or more double bonds in the 4-, 4,6- or 3j5-position and that one especially uses a corresponding 3-keto-, 3-keto-4- dehydro-, 3-keto-4,6-bisdehydro-, 3-keto-1,4-bisdehydro-, 3-hydroxy-3,5-bisdehydro- or 3-hydroxy-4-dehydro compound or their 3-ether or -ester as starting compound. 3. Process according to claim 1 a) or 2, characterized in that a corresponding 20-enamine or 20-enolacylate of the 93,10a-pregnan series is used, in particular a 20-piperidylenamine or 20-enol acetate as starting compound. 4. Method according to claim 3, characterized in that the oxidation is carried out with ozone in the presence of eh nitrogen base. and that the ozonide formed is reduced with an aliphatic or aromatic aldehyde. 5. Method according to claims 1 b-^ and 1 b2), characterized in that the compounds used as starting material are substituted in the 1-position with hydrogen, in the 2-position with hydrogen or methyl, in the 3-position are substituted with the keto group or a optionally esterified or etherified hydroxy group, in the 4-position is substituted with hydrogen, in the 6-position with hydrogen or a chlorine or fluorine atom or an optionally esterified or etherified hydroxy group, in the 9-position is substituted with hydrogen or fluorine, i-11- position is substituted with hydrogen, the keto or (H, OH) group, in the 17-position is substituted with hydrogen or an optionally etherified or esterified hydroxy group and in the 16-fefcLlling is substituted with hydrogen, the methyl group or an optionally etherified or esterified hydroxy group and in at least one of positions 1, 4, 6 or 16 has a double bond. 6. Process according to claims 1 b^) and 1 b^), characterized in that the compounds used as starting materials in the 1-, 2-, 4-, 6- and 16-positions are substituted with hydrogen, in the 3-position they have keto - or an optionally etherified or esterified hydroxy group, contains one or more double bonds in the 1-, 3-, 4-, 5- or 6-position and in the 11-position is substituted with a hydrogen, keto or (H, OH) group , and that a corresponding 3-keto-4-dehydro, 3~keto-, 3-keto-4, 6-bisdehydro-, 3-keto-1, 4-bisdehydro-, 3-hydroxy- 3,5-bisdehydro or 3-hydroxy-4-dehydro compound or their 3-ester or ether. 7. Process according to claim lc), characterized in that the compounds used as starting material in the 1-, 2-, 4-, 6-, 9-, 11" and 16-positions are substituted with hydrogen, contain the 3-positioned keto- or an optionally etherified or esterified hydroxy group and contains one or more double bonds in the 1-, 3-j 4-, 5- or 6-position and that in particular a corresponding 3-keto, 3-keto-4-dehydro- , 3-keto-4,6-bisdehydro-, 3-keto-1,4-bisdehydro-, 3-hydroxy-3,5-bisdehydro- or 3-hydroxy-4-dehydro compound or their 3-esters or -ethers. 8. Method according to claim ld), 2 and 3, characterized in that in the compounds used as starting material, QVI means the methyl group and Q a group with the formula 9. Method according to claim le), characterized in that the compounds used as starting material in the 1-, 2-, 4-, 6-, 9-, 11- and 16-positions are substituted with hydrogen, contain a 3-positioned keto - or an optionally etherified or esterified hydroxy group and contains one or more double bonds in the 1-, 3-, 4-, 5- or 6-position and that one especially uses as starting compounds a corresponding 3-keto-, 3-keto-4- dehydro-, 3-keto-4,6-bisdehydro-, 3-keto-1,4-bisdehydro-, 3-hydroxy-3,5-bisdehydro- elbr 3-hydroxy-4-dehydro compound or their 3-esters or -ethers. 10. Process according to claim 1 f), characterized in that the compounds used as starting material have a 17-positioned COCH2-, COCH2-0-acyl-, COCH2OH group or a saturated or unsaturated alkyl group with 1 to 2 carbon atoms and R^q is a hydrogen atom, a hydroxy group or an etherified or esterified hydroxy group or R^ and R^q together form a keto group and that these are substituted in 1-, 2-, 4-, 6-, 9-, 11- and 16-position with hydrogen and has a H- and/or 6-positioned double bond. 11. Method according to claim 1g), characterized in that the compounds used as starting material contain a 17-positioned COCH-j-, COCH2-0-acyl-, COCH"2OH group or a saturated or unsaturated alkyl group with 1 to 2 carbon atoms, is substituted with hydrogen in the 1-, 2-, 4-, 6-, 9-, 11- and 16-position and optionally contains a 1-positioned double bond. 12. Process according to claims 1 g) and 10, characterized in that the 6-dehydrogenation is carried out by halogenation in the allyl position to A<4-> double bond and subsequent dehydrohalogenation or with chloranil. 13. Method according to claim lh), characterized in that they used as starting material compounds inside holds a 17-positioned COCH^-, C0CH2-0-acyl-, COCHgOH group or a saturated or unsaturated alkyl group with 1 to 2 carbon atoms, is substituted with hydrogen 1-, 4-, 6-, 9~, 11- and l6 position o and contains a double bond in the 4- and/or 6-position.