DE1793608C - 17alpha-alkyl-, -alkenyl- or -alkynyl-13beta-alkylgon-4- or -5 (10) -en-17betaol-3-ones. Eliminated from: 1468604 - Google Patents

Description

The invention relates to 17'-alkyl-, -alkenyl- or -alkynyl-13 / J-aIkylgon-4- or -5 (10) -en-17/9-ol-3-ones of the general formula (I)

OH

60

. wherein the dotted ^T "nien in the ring A is an ethylenic bond in the 4 (5) - or mean 5 (10) -position, R ^J is a saturated alkyl group miit and preferably * ursubstituierte at least not more than 6 carbon atoms and R is a substituted or Alkyl, alkenyl or alkynyl group of preferably

wherein the group X is a protected 3-oxo group, which is an organic radical formed by one or two heteroatoms, especially O, S and N with is connected to the carbon atom in the 3-position. and especially a 3-alkoxy-, -acyloxy-, -alky! - thio or dialkylamino group and the nucleus has two double bonds in the 2 (3), 4 (5) -, 2 (3), 5 (6) -; 2 (3), 5 (10) -; 3 (4), 5 (6) or 3 (4), 5 (10) positions contains or X is a 3,3-ketal, master thioketal or thioketal group and is the nucleus a double bond in the 4 (5) -, 5 (6) - or 5 (10) position contains, hydrolyze with an acid or base and, if necessary, with a Isomerize acid or base or

(b) a 5 (10) -unsaturated compound of the general formula (I) with. an acid or base isomerize to a 4 (5) -unsaturated compound of the general formula (I) or

(c) a compound of the general formula (I), in which R ^{a is} an optionally substituted alkenyl or alkynyl group, is partially or completely selectively hydrogenated or

(d) a compound of the general formula (HI]

R ¹ OH

55 HO -

R »

wherein R ¹ and R * have the meaning defined above, e.g. B. oxidize with CrO ₃ or according to Oppenaue and, if necessary, isomerize with acid or base.

R ¹ can be, for example, an ethyl, n-propyl-isopropyl, η-butyl or isobutyl group. Examples for R 'groups are methyl, ethyl, vinyl-athenyl, n-propyl, isopropyl, allyl-1-propynyl-η-butyl or 1- or 2-methallyl groups. The invention includes the 13/9 enantiomers in the presence or in the absence of the corresponding 13 «enantiomer

3 4

mers, i.e. both the separated generally sodium or potassium hydroxide at room temperature

pharmacologically active 13 / f enantiomers as well as the door or with a sodium alcoholate in an alcohol

130-enantiomer in a mixture with the inactive are carried out at 60 ⁰ C. More acidic conditions

13a enantiomers, especially racemic mixtures. such as heating in methanol with concentrated

The compounds according to the invention can preferably be used. The isomerization is in progress

gen the separated 13 /? - enantiomers, which from ab with the appearance of the hydrogen atom in the 10-position

Cleaved starting materials are obtained in the anticonfiguration to the hydrogen in the 9-position.

be able. rjj _e compounds of the general formula (I) with

Compounds in which R ^{1 is} an ethyl group, an ethynyl or an allyl group in the 17-position

(i.e. the 18-homo compounds according to the steroid ίο can be converted to the corresponding 17 «-vinyl, -ethyl-

nomenclature) are of particular importance, be-or -n-propyl compound according to the process

especially those in which R * is also an ethyl, vinyl, variant (c) are hydrogenated. The hydrogenation can be carried out in

Athynyl or n-propyl group. a solvent by shaking the reaction

The group X can be in the compounds of the mixture with hydrogen in the presence of a Palla

general formula (II), for example a methoxy, 15 dium or Raney nickel catalyst are effected,

Athoxy, methoxymethoxy or dihydroxypropyl to the appropriate amount of hydrogen for the selective

oxy group, an alkylthio group (for example a conversion of the R * group is absorbed

Ethylthio or benzylthio group), an acyloxy group fertilize the general formula (III) can under

(e.g. an acetoxy group), a dialkyl use of an Oppenauer reagent, e.g.

amino group (e.g. an N-pyrrolidyl group), 10 oxidized by aluminum isopropoxide or chromic acid

an alkylenedioxy group (for example an ethylene. Starting materials for such an oxy-

dioxy group), an alkylenedithio or alkylenethio- dation process can be achieved by the alkylation of the

be oxy group. corresponding 17-ketones with suitable organo-

Starting materials for the hydrolysis process metal compounds are obtained. This method

according to variant (a) given above, Ge »5 is in detail in British patent specification 1046,850

Mix of 3-AIkOXy-S ₅ S- and -3,5 (10) -dienes (the described.

Enol ethers of zl ⁴ -3-ketones), 3-alkoxy-2,5 (10) -diene Preferred compounds according to the invention are: (the enol ethers of / t ^e < ¹⁰ > -3-ketones), 3-acyloxy

3,5-dienes (enol esters of / l «-3-ketones), mixtures., .., _ .. _t ,, ..... ,," ..

of 3,3-alkylenedioxy-S- and -5 (10) -enes (the alkylene-30 130,17 * -Diathylgon-5 (10) -en-17 /? - ol-3-one,

ketal of / 1 ⁴ -3-ketones), 3,3-alkylenedioxy-5 (10) -ene 13/3-ethyl-17 "-äthinyIgon-5 (10) -en-17 /? - ol-3-one ,

(the alkylene ketal of / l ⁵ < ¹⁰ > -3-ketones) and 3-tert-13 / S-ethyl-17 «-methylgon-4-en-17/3-ol-3-one,

Alkylamino-3,5 (6) -dienes (the tertiary enamines of 130 17ix-diethyl-gon-4-en-17j9-ol-3-one,

^ -3-ketones). Particularly useful are hydrolysis 13 /? - ethyl-17 _a -vinyl-gon-4-en-17 / S-ol-3-one,

process that uses 3-alkoxy 35 ,, ο · _Λ ·. ,,. ..., _Λ -, _α ,,

2,5 (10) -dienes (for example the 3-methoxy-13 ^ -ethyl-17 «-athynyl-gon-4 ^ n-170-ol-3-one,

fertilize), 3,3-alkylenedioxy-5- and -5 (10) -enes (for example 13) S-ethyl-17 "-n-propyl-gon-4-en-17 /? - ol-3-one ,

the 3,3-ethylenedioxy compounds) and 3-A1- 17it-methyl-13/3-n-propyl-gon-4-en-17/9-ol-3-one,

koxy-3,5 (6) - or 3,5 (10) -dienes (for example the 17a-ethyl-13 /? - n-propyl-gon-4-en-17 /? - ol-3-one,

3-ethoxy compounds). 40 n ^ Ethynyl-IS / S-n-propyl-gon ^ -en-n / J-olO-on

The hydrolysis can be carried out by reacting the starting material. .. ". '? ,. . . . ,.

materials with an acid and water for one with connection to the German interpretation

suitable temperature. Where the * ²⁹ ° ³ ₇ ⁹ connection established as well as 13 /? - n-

The starting material is an ethylenic bond in the butyl-17 "-athynyl-gon-4-en-170-ol-3-one.

5 (10) position, according to the invention the 45

) ?, γ-unsaturated ketones (1) with mild hydrolysis- The compounds according to the invention are as

Bonds are obtained, as can be used with aqueous alcoholic pharmaceuticals, the anabolic, the progestational

Lischer oxalic acid at 30 ⁰ C and below; under or other valuable steroid-hormonal properties

have stronger acidic conditions, such as aqueous with 6N, and are also orally effective. It was

Hydrochloric acid at 8O ⁰ C, the isomerization to the 50 is found that it is generally opposite to the

α, / 9-unsaturated ketones (II) facilitated. Where the properties of the corresponding, a 13-methyl-

Starting material no ethylenic bond in the group-bearing compounds superior or

5 (1O) -position contains, the hydrolysis proceeds of which have different properties. Except-

with formation of the «, / 3-unsaturated ketone. In some of these is the difference in properties between

Cases, for example, where the 3-substituent is a 55 according to the invention and the corresponding

Is acyloxy group, hydrolysis by Ver13-methyl compounds can not only be quantitative, but also

can be carried out using a base, for example of a qualitative nature.

wise on sodium hydroxide in aqueous methanol. In particular, it was found that a In many cases hydrolysis with water is not required homologation with an additional carbon, and there is only one hydroxyl group 60 atom at C-18 (which makes a 13-ethyl group) containing medium, for example an alcohol or in general to a retention and increase of a carboxylic acid required. (The latter reaction has valuable properties of the corresponding 13-mostly Strictly speaking, no actual hydrolysis, thyl compounds result. Verbs according to the invention, however can for the purposes of the present invention fertilize with n-propyl or η-butyl at C-13 show im In general, the presence of a hydrolytic reaction 65 is less effective; however, they are can be accepted.) nevertheless valuable, since it separates the activities

The isomerization can show, for example, under ba-, which differs from that of the corresponding 13-methyl-

sic conditions, as differs with aqueous-alcoholic compounds. The thought of gay

1

logging of the angular group with 17-alkyl-19-nortestosterones, which forms the basis of the present invention in its most general meaning, is therefore important, as he "describes the ways in which a particular individual hormonal effect can be achieved." increased without causing an undesirable side effect, which is the case if a corresponding 13-methyl steroid would be used under similar conditions. This is especially true for the anabolic properties and a separation of anabolic and androgenic properties, as is known to be the anabolic activity is closely dependent on the chemical structure.

Anabolic and androgenic activity

The anabolic (myotropic) activity of some compounds according to the invention was determined after the test by H e r s h b e r g e r et al., Proc. Soc. Exp. Biol. Med., 1953, 83, p. 175, examined in the weaned Rats of 45 to 50 g body weight were castrated and treated daily for 7 days. At the the eighth day the rats are sacrificed, the levator muscles removed and weighed, the weight gain being increased taken as a measure of anabolic activity. A series of experiments was made with the help of the Least squares method a dose-response curve calculated, the line obtained is plotted graphically and the dose of the compound graphically estimated that it is necessary to obtain a doubling of muscle weight. In this way the effectiveness in relation to the effectiveness of the anabolic standard substance, testosterone propionate, determined, the relative effectiveness being one hundred times the dose testosterone propionate which is required to double the weight divided by the dose

ίο the connection used for the test that is required is to get the same result. Simultaneously with the determination of the anabolic effectiveness In the Hershberger tests, the androgenic properties of the substances were determined by growth of the ventral prostate gland. As above, a dose-response curve was calculated and the Efficacies determined in relation to testosterone propionate. From the obtained anabolic and androgenic The ratio of anabolic to androgenic efficacies was calculated. Based on this, the anabolic and androgenic potencies as well as the ratios of the anabolic to the androgenic activities of various compounds according to the invention as follows definitely. For the well-known anabolic steroid, (+) - 17a-Äthyi-19-nortestosteron- (17a-ethyl-13- / 3-methylgon-4-en-17 /? - ol-3-one), Similar potencies and ratios were found.

Gon-4-ene of Formet 1 R ² QH ₅ -CH = CH ₂ Anabolic Androgens ratio R ¹ CH ₃ - CH - CH ₂ effectiveness effectiveness V Cl Ilttllilld (+) CH ₃ C ₂ H, 85 12th 7th (±) QH ₅ n-QH ₇ 110 89 1 (±) QH ₅ ■ CH ₂ CH = CH. 340 17th 20th (±) QH ₅ (±) n-QH ₇ CH ₃ 13th 0.7 19th (±) QH ₅ - (±) n-QH ₇ C ₂ H _r , 20th 0.4 50 (±) n-QH ₇ C s CH 270 34 8th (±) n -QH ₇ ; n-QH ₇ 54 11th 5 (. ±) n -QH, - CH ₂ CH = CH ₂ 5 to 10 1 5 to 10 (±) QH ₆ 5 to 10 1 5 to 10 (±) n-QH, 10 1 10 100 10 10 70 6th 66

To enable a direct comparison with the well-known (+) - 17 <x -ethyl-19-nortestosterone, must the activities of the racemic according to the invention listed in the table above Compounds are doubled because the 13 »enantiomers are inactive. It can be seen that the Compounds according to the invention listed in the table above have a greater absolute anabolic effectiveness than the known compound and / or a greater ratio of anabolic to androgenic potency exhibit.

When assessing the anabolic and androgenic efficacies, it is often found in practice that that the dose-response curves are not parallel to the curve for the standard substance teslosteronepropional run and that the method described above for estimating the efficacies this not taken into account. In order to take this factor into account, oosis-effect curves were based on the following Way analyzed: [it is assumed that (a) all Doses of the compound above the point at which the levator ani dose-response curve exceeds the control level cuts, anabolic, and (b) all doses above the point at 'which the ventral prostate dose-response curve the control level cuts, are androgenic. Is with a certain connection the point of intersection on the Levator-Ani curve at a lower dose than the point of intersection on the ventral Prostate curve, so the compound is more anabolic than androgenic, and the weight of the levator ani am The intersection on the ventral prostate curve gives the maximum possible with non-androgenic doses Growth amount.

In the following table are these intersection points (VP and LA), the weight of the musculiis levator ani (W) at the intersection of the ventral prostate as well as the myotropic active wedge listed as the possible Percentage (%) increase in the musculi levator ani at non-androgenic doses of the compounds is.

7th VP 8th LA W. ⁰ A, 3.5
17th
2.3
20th
290
12th
25th 15.5
8.6
2.1
7.7
250
7.5
39 <33
42.2
34
48
36
40
<33 28
3
46
9
21 Testosterone propionate (±) -17a-Ethyl-13/9-methyl-gon-4-en-17 /? - ol-3-one
(±) -13j9-ethyl-17 "-methyI-gon-4-en-17 /? - ol-3-one
(±) -13 / 9.17 "-Diethyl-gon-4-en-17/9-ol-3-one (±) -13 / 9-Ethyl-17 "-n-propyl-gon-4-en-3-one
(±) -17a-Methyl-13-n-propyl-gon-4-en-170-ol-3-one.
(■ £) -17a-ethyl-13-n-propyl-gon-4-en-17 /? - ol-3-one

The excellent properties of the (±) -13 / 3,17a Endrocrinology, 1958, 63, p. 464 gave the following Diethyl-gon-4-en-17 / J-ol-3-one can be seen again. 15 results: Further experiments on the effect of this 13-ethyl compound on the growth of the seminal vesicles of male rats revealed that they were about 15% of the exhibited androgenic activity of the testosterone propionate measured in this way.

estrogen antagonistic activity

The estrogen-antagonistic activity of a compound can be determined with the help of the vaginal smear test in mice according to Edgren, Proc. Soc. Exp. Biol. Med., 1960, 105, p. 252, measured, in which the test material with a total dose of 2 μg of estrone is mixed and the mixture is given in four equal daily injections. The effectiveness is measured as the activity of the progesterone. In the table below are the Results of this experiment using different compounds are listed.

Gon-4-ene of formula I. R ¹ R ^! effectiveness
(Progesterone CH ₃ - C s CH = 100) 20th
(+) C ₂ H, CH ₃ 10 (±) C ₂ H ₈ , C ₂ H ₆ 100 (±) C ₂ H ₁ , -Cs CH 500 25 (±) C, H. -CH ₂ -C (CH ₃ ) = CH ₂ 700 (±) C ₃ H ₁ , -Cs CH 1000 (±) C ₄ H ₁ , - C s CH 250 (±) 25th

Gon-4-ene of formula I. R ² CH ₃ effectiveness R ¹ CH ₃ (Progesterone = 100) (+) CH ₃ C ₂ H ₆ 1800 <±) C ₂ H ₅ C ₂ H ₆ 5000 (+) CH ₃ - C ξ CH 2100 (±) C ₂ H ₆ -Cs CH 3000 ' (+) CH ₃ - CH = CH2 910 (±) C ₂ H ₆ - CH = CH ₂ 5000 (+) CH ₃ 910 (±) C ₂ H ₅ 7000

The table above shows that in each pair of compounds the 13-ethyl compound is more active than the corresponding known 13-methyl compound. The 13-ethyl compounds are racemates, which is why The potencies of these compounds must be doubled for a head-to-head comparison with the (+) - 13-methyl compounds is possible.

In addition, the estrogen-antagonistic activity of the (±) -13 / ?, 17 «-Diälhylgon-5 (10) -en-17 / S-ol-3-one 5 times that of (+) - 17 "-ethyl-13/9-methylgon-5 (10) -en-17/9-ol-3-one.

Progestational activity

Measurement of progestational activity - im called English progestational activity - after the Clauberg method of Elton and Edgren, The above number of effects of the compounds according to the invention must be doubled, thus a direct comparison with the (+) - 13-methyl compound to the known commercially available progestational compound Means noräthisteron is possible.

It was also found that the (±) -17 «-ethynyl-13/9-ethyl- and (±) -17 «-ethynyl-13 /? - n-propyI compounds while obtaining pregnancy in female rats with ovaries removed this through the (-}) - 17 "-ethynyl-13-methyl compound not happening.

(+) - 17a-Ethynyl-13 /? - methylgon-5 (10) -en-17/9-ol-3-one is an important commercial progestational agent, but it has the disadvantage that it accounts for 7% of the estrogenic activity of the esirons. It has been found that the valuable progestational agent (±) -13 /? - Älhyl-17 "-ethynyl-gon-5 (10) -en-17 /? - ol-3-ori only 0.3 ° / ₀ estrogen-metrotropic activity of estrone, but has a greater progestational activity than (+) - l 7 ^ -ethynyl-13-methylgon-5 (10) -en-l 7j8-ol-3-one.

Cholesterol lowering activity

Injecting groups of adult male rats daily for 9 days with Doser of 100, 300 and 1000 μg (±) -13 / ?, 17 «-Diethylgon-

4-en-17/9-oI-3-one and a subsequent blood analysis on the tenth day resulted in cholesterol levels of 44, 39.6 and 42 mg /%, which are compared with the controls a lowering of the cholesterol levels in BIuI

meant by 87, 78 and 83%, respectively.

Investigations with (±) -13 / 9.17 «-Diethylgon-4-en-17 /? -Ol-3-one have shown that this compound shows a remarkably low toxicity when administered to animals. In this respect it is superior to the important commercially available anabolic steroid (±> 17ä ethyl-13 £ -methylgon-4-en-17 /? - ol-3-one, which has an LD ₅₀ of 430 mg / kg, while the 18- homo-

9 10

Compound in amounts up to 5 g / kg either on B ice ρ ie 1 3
administered orally or intraperetoneally to mice without killing any animal (±) -17 * -allyl-1Sβ-ethyl. The administration of the 13-ethyl compound Πβ-οΙ (1.5 g) was suspended in methanol (50 ecm) and water to rats for a period of eight men- 5 (5 ecm). Oxalic acid (1 g), subsequent structural cycles gave no adverse effects. Dioxane (20 ecm) was added and the mixture on reproductive ability (fertility and was stirred until the solution was complete and then fertility of the rats). another 20 minutes. Water became gradually

In this way it was shown that (±) -13β, 17 "-Di- was added, the precipitated material was filtered, with water

äthylgon-4-en-17 /? - ol-3-one washed an excellent anaio and dried. Recrystallize from a

Bolikum with a very high anabolic effectiveness, mixture of ethyl acetate and η-hexane resulted

high anti-estrogenic effect, low androgenic (±) -17Ύ-Α1 ^ 1-13 /! Μί ^^ οη-5 (10) -εη-17/9-ο1-3-οη (1 g);

Activity, strong progestational. Activity, the UV: No separate absorption beyond 220;

Lipid lowering properties in the blood and by IR: 3400, 1640, 1610.

is very low in toxicity. It was also found> 5 _R. . . .

that it shows no appreciable estrogenic activity. _ »Egg game 4

The steroid ketones of this invention are also (±) - 13 /? - Ethy! -3-methoxy-17 <v - propynylgona-

as chemical intermediates for the production of an- 2,5 (10) -dien-17 /? - ol (4 g) was in methanol (200 ecm)

whose sterroids are useful. For example, the and water (20 ecm) can be suspended. Oxalic acid (4 g),

zJ * < ¹⁰ > -En-3-ones to the corresponding d ⁴ -En-3-ones ao below dioxane (100 ecm) was added and

of formula (I) are isomerized. This procedure stirred the mixture until completely dissolved

is in the German patent application P 14 68 604.5 and then still 20 minutes. Water became

described. The / l ⁶ < ¹⁰ > -En-3-ones of the formula (I) are added, the precipitated product is filtered with

further washed and dried as intermediates for the preparation of the water. Recrystallize

corresponding 4,9 (10) -dien-3-ones can be used. »5 from a mixture of ethyl acetate and n-hexane

The invention is resulted from the following Bei- (±) -13 /? - ethyl-17a-propynylgon-5 (10) -en-17 /? - ol-

games explained in which the temperatures in "C 3-one, melting point 156 to 159 °; UV: No separate

indicated, the infrared absorption data (IR) is absorption beyond 220; IR: 2200, 1710.

on the positions of the maxima, ^{indicated in cm "1} , and. ic

the ultraviolet absorption (UV) data to the 3rd place > _ Example

lungs of the maxima, given in μ , relate with (±) -13 / 9-EthyI-17a- (2-methallyl) -3-methoxygona-

Numbers in brackets indicating the molecular absorbance 2.5 (10) -dien-17 /? -Ol (1.5 g) was dissolved in methanol (50 ecm)

specify coefficients at these wavelengths. and water (5 ecm) suspended. Oxalic acid (1 g),

then dioxane (20 ecm) was added and then the mixture was completely dissolved and then

Example 1 stirred for a further 30 minutes. Water became

added, the product extracted with ether that

(±) -13 / ?, 17a-diethyl-3-methoxygona-2,5 (10) -diene ether solution washed, dried and

17/3-ol was stirred in methanol (430 ecm), which evaporates, the residue from a mixture of

Water (87 ecm) and oxalic acid dihydrate (6.6 g) 40 ethyl acetate and η-hexane recrystallized and the

until the solid was completely dissolved. Product (±) -13 / 3- ethyl-17λ- (2-methallyl) -gon-

The separation by means of ether gave a crystalline 5 (10) -en-17 /? - ol-3-one obtained; UV: No separate

Product (4.55 g), melting point 126-134 °, which has absorption beyond 220; IR: 3450.1710.1640.970.

after repeated crystallization from ethyl acetate ". . , _c

(±) -13 / 9.17 «-Diethylgon-5 (10) -en-170-ol-3-one gave 45 ^peiSpie ' ^u

Melting point 142 to 143.5 °; IR: 3450.1710 (found: To (±) -3-methoxy-17, x-methyl-13 / i-n-propyI-

79.6% C, 10.1% H; the gross formula C ₂₁ H ₃₂ O ₂ gona-2,5 (10) -dien-17/3-ol (0.3 g) in methanol (30 ecm)

requires 79.9% C, 10.2% H). a solution of oxalic acid dihydrate (0.46 g)

added in water (6 ecm). After 20 minutes

^{As far as} 1 2 ⁵ ° Rünren *>"room temperature was the solution

^p did not end, and isopropanol (30 ecm) was added

Added to (±) -13 / S-ethyl-17 «-äthinyl-3-methoxygona- and stirring continued for 80 minutes;

2.5 (10) -diene 17 /? - ol (0.6 g) in methanol (30 ecm) the product was then worked up using ether and

a solution of oxalic acid dihydrate (0.46 g) was recrystallized from a mixture of ether and hexane

Water (6 ecm) added. After 45 minutes of standing, (±) -17ix-methyl-13/3-n-propylgon-

Leaving at room temperature gave ether (60 ecm) 5 (10) -en-17 / i-ol-3-one (0.2 g), melting point 158

added, the ether solution washed, dried and up to 163 °; UV: No selective absorption over

evaporates. The residual resin was added to benzene 220; IR: 1695 (carbonyl group).

(5 ecm) dissolved and over activated FuUerde (50 g). . .

chromatographed; Elute with light kerosene, 60 _

which first a small, then a gradual zu (±) -17a-ethynyl-3-methoxy-13 /? - n-propylgona-

contained an increasing proportion of benzene, resulted in a 2,5 (10) -dien-17/9-ol (0.24 g) in methanol (40 ecm)

crystalline by-product to which the desired was a solution of oxalic acid dihydrate (0.58 g)

(±) -130-Äthyl-17a-äthinylgon-5 (10) -en-17 /? - ol-3-one in water (7.6 ecm) was added and the (remisch

followed as a pure compound (0.15 g), crystallized out for 90 minutes at room temperature under: .ckstoff

from a mixture of light petroleum and ethyl g_erickt. Water was added with the product

acetate; the product had a melting point of ether, the residue obtained through

169 to 173 °; IR: 3351, 3241, 1706. Purified chromatography on earth and off

Il 12

Cyclohexane, subsequently ethyl acetate crystallized out, yielded a crystalline residue (0.255g),

gave (±) -17 «-ethynyl-13/3-n-propylgon-5 (10) -en- which from a mixture of ethyl acetate and

17 /? - ol-3-one (0.037 g), melting point 201 to 205 °, light petroleum was crystallized and (±) -13ß,

IR: 3440, 3250, 1710 (found: 80.5% C, 8.6% H; 17 "-Diethylgon-4-en-17 /? - ol-3-one (0.196 g), melting

the gross formula C ₂₂ B ₃₀ C ₂ requires 80.9% C, 5 point 139 to 141 °; UV: 240 (15,000); IR:

9.3% H). 3500.1665.

Examples Example 12

(±) -3-Methoxy-13) 3-n-propyl-17ix-propynylgona- To (±) - 13 /? - Ethyl- 17 * -äthinyl-3-methoxygona-2,5 (10) -diene-17 /? - ol (2.5 g) was stirred for 2 hours in meth- io 2,5 (10) -dien-17 /? - ol (obtained by ethynylation of anol (80 ecm), the methanol being water (t) -13 / 3-Ethyl-3-methoxygona-2,5 (10) -dien-17-one) (10 ecm), oxalic acid dihydrate (1.75 g) and tetrahydro- (0.7 g) in methanol (36 ecm ) contained water (1.6 ecm) furan (60 ecm). The mixture was added to and concentrated hydrochloric acid (2.4 ecm). Brine added and the product extracted with ether. After standing for 2 hours at room temperature. The washed and dried extracts were added to ether and the washed and evaporated extracts to obtain a residue, dried ethereal solution evaporated. It was obtained from a mixture of ethyl acetate and η-hexane resin, which was dissolved in benzene (5 ecm) and recrystallized as a solution to (±) -13 /? - n-propyl-17 «-pro- via activated filling earth was absorbed (50 g). to obtain pinylgon-5 (10) -en-17/3-ol-3-one; Melt elution with light petroleum, which rising point 147 to 150 ° (found: 80.8% C, 9.4% H; also contained part benzene, resulted in a crystalline addition to the gross formula C ₂₃ H ₃₂ O ₂ requires 81.1% C , product; further elution with benzene, which has a 9.5% H). Containing a small amount of ether resulted in a crystalline one

R ρ i ς η i ρ I Q Product which recrystallizes from ethyl acetal

^p das (i) -13 /? - ethyl-17 "-ethynylgon-4-en-17 /? - ol-3-one

(i) -13 /? - n-Butyl-17 "-äthinyl-3-methoxygona-" 5 (0.11 g), melting point 203-206 °; IR: 3370, 2,5 (10) -dien-17 /? - ol (2 g) was in methanol (50 ecm) 3300, 1660.
stirred, which oxalic acid dihydrate (0.9 g) and water Example 13

(12 ecm), with stirring under nitrogen

2 hours took place. The mixture was dissolved in water. A solution of (±) -13 / 3-ethyl-3-methoxy-17ii-n-

poured and extracted with ether. The washed 30 propylgona-2,5 (10) -dien-17 /? - ol (0.53 g) in a powder and dried extracts were mixed with methanol (22.5 ecm) of 12N hydrochloric acid ( 1.5 ecm] was evaporated, the water (1.5 ecm) was ^{purified by chromatography for 2 l} / ₂ hours at room activated fusing earth and kept from a mixture temperature under nitrogen; then it was recrystallized from ethyl acetate and η-hexane ice water (75 ecm) added, the precipitated solid and (i) -13 / 3-n-butyl-17 «-äthinylgon-5 (10) -en-17/3-ol-35 substance filtered off and in ether (50 cm) Di «3-one (0.75 g) gave, melting point 160 to 164 °; ether solution was washed, dried and evaporated.

. . fetches was recrystallized from ethyl acetate and

Example 10 (±) -130-ethyl-17a-n-propylgon-4-en-17 /? - ol-3-one,

A solution of (±) -13-ethyl-3-methoxy-17a-me-40, melting point 132 to 134.5 °, gave: UV: 240 (15,900); thylgona-2,5 (10) -dien-17 /? - ol (0.5 g) in methanol IR: 3425, 1660, 1618 (found: 79.8% C, 10.2% H; (55 ecm) was heated to boiling under nitrogen, the gross formula C ₂₂ H ₃₄ O ₂ requires 79.5% C and 3N hydrochloric acid (0.6 ecm) was added. The 10.4% H).

Solution was allowed to cool to room temperature Example 14

left and kept under nitrogen for 3 hours. Then 45

water was added and the mixture with ether (±) -17a-allyl-13 /? - äthyI-3-methoxygona-2,5 (10) -di

extracted. The washed and dried extracts en-17/3-ol (2 g) was dissolved in a mixture of methanol were evaporated, the residue from a mixture (72 ecm), concentrated hydrochloric acid (4.8 ecm) and from ether and Ηεχε.η and subsequently from benzene water (3.2 ecm) crystallized out in a suspension in a nitrogen atmosphere, gave (±) -13 / 3-ethyl-17a-methylgon- 50 dated. Dioxane (20 ecm) was added and that 4-en-17ß-ol-3-one as a benzene solvate, which is stirred by the mixture until the solution ends Benzene was drying at 100 ° for 7 hours and an additional 20 minutes after which was released; this gave the free compound (0.2 g), water added and the mixture with ether extra melting point 128 to 129 °; UV: 240 (16,200); was here. The ethereal solution was ge-IR: 3390, 1663. 55 saturated sodium bicarbonate solution and with Wassei

Example 11 washed and dried. By evaporating the

Solvent resulted in (±) -17 <x-AllyI-13 / f-ethylgon-

(±) -13 / ?, 17 <x-diethyl-3-methoxygona-2,5 (10) -dien-4-en-170-ol-3-one; UV: 240 (15,600); IR: 3400, Πβ-ol (obtained by ethylation of (±) -13 /? - ethyl-1660, 1610.
3-methoxy-2,5 (10) -dien-17-one) (0.29 g) became 15 ecm 60 Beisni 1 15

a solution trains.-jben obtained by mixing

concentrated Ss »2? acid (2.4 ecm), water (1.6 ecm) (±) - I3ß - ethyl - 3 - methoxy -17 «- propynylgona-

and methanol I So ecm) was produced. The gel 2,5 (10) -dien-17 /? - ol (1.5 g) was mixed in methanol (36 ecm) was shaken for 10 minutes, the suspended and with concentrated hydrochloric acid '2.4 ecm) , Solid was dissolved during this time. After 65 water (1.6 cc) and dioxane (10ecm)> long stirring for 2 hours the solution in water (50 cc) until the solution was finished uad darübei poured and the mixture extracted with ether addition, a further 20 minutes. The product was precipitated through the washed, dried and evaporated ex- the addition of water, filtered, washed

and dried. Recrystallization from a mixture of ethyl acetate and η-hexane gave (±) -130-ethyl-17'-propynylgon-4-en-17 / S-ol-3-one, Melting point 124 to 125 °; UV: 240 (15,600); IR: 3300, 2190, 1660.

Example 16

(±) -13 / I-ethyl-3-methoxy-17 "- (2-methallyl) -gona-2,5 (10) -dien-17 /? - ol (1.5 g) was in a mixture of methanol (36 ecm), concentrated hydrochloric acid (2.4 ecm), water (1.6 ecm) and dioxane (10 ecm) suspended. After the material dissolved, water was added, the precipitate filtered and again stirred with methanol (36 ecm), concentrated hydrochloric acid (2.4 ecm) and water (1.6 ecm) for 20 minutes. Water was then gradually added, the precipitate filtered, washed with water, dried and recrystallized from a mixture of ethyl acetate and n-hexane and then from acetonitrile (i) -13 /? - ethyl-17rt- (2-methallyl) -gon-4-en-17 /? - ol-3-one (2 g). UV: 240 (16,800); IR: 3450, 1670, 1610, 880.

Example 17

(±) -3-Methoxy-17a-methyl-13/3-η-propylgona-2,5 (10) -dier.-17 /? - ol (l, Og) was with 44ccm of an aqueous methanolic hydrochloric acid solution, corresponding to that of Example 2, shaken and 2 hours touched. The mixture was then poured into water and the product separated using ether. To clean by chromatography over silica gel (eluting with ether) and recrystallization from a mixture of ethyl acetate and hexane gave (±) -17 <x -methyl-13/3-n-propylgon-4-cn-17 /? - ol-3-one (0.35 g), melting point 134-135.5 °; UV: 240 (18,100); IR: 1660.

Example 18

A mixture of (±) -17 «-ethyl-3-melhoxy-13 /? -NpropyIgona-2,5 (10) -dier-17/3-ol (0.8 g) in tetrahydrofuran (20 ecm). Methanol (50 cc), 12n-hydrochloric acid (3.3 cc) and water (2.2 cc) was kept under stirring for 2 ¹ / »hours at room temperature and then poured into a sodium chloride solution. The mixture was extracted with ether and the extracts washed, dried and evaporated. The crystalline residue obtained (0.8 g) was dissolved in a mixture (25 ecm) of equal parts by volume of benzene and hexane and chromatographed on silica gel. Eluting with a mixture of equal parts by volume of benzene and chloroform gave a crystalline material which was recrystallized from a mixture of benzene and light petroleum and gave a benzene solvate with a boiling point of 93 to 95 °; Recrystallization of this material from a mixture of hexane and ethyl acetate gave the solvent-free product (±) -17a-ethyl-13 / S-propylgon-4-en-l 7 / S-oi-3-one (0.2 g), melting point 98 to ^100c ; TJV: 240 (15,700), IR. 3415, 1660, 1619.

Example 19

(±) -17 «-Athiny1-3-methoxy-13y? -N-propylgona-2,5 (10) -dien-17 /? - ol (0.31 g) was shaken with a solution obtained by mixing concentrated hydrochloric acid (0.81 ecm), water (0.54 ecm) and methanol (12.15 ecm) was prepared until the solid was dissolved. After the addition of "water, separation with ether, purification by Chromatography over neutral aluminum oxide and recrystallization from cyclohexane gave (±) -17a-ethynyl-13/3-n-propylgon-4-en-17/3-ol-3-one (0.1 g), melting point 149 bis 150.5 °; UV: 240 (15 700); IR: 3345, 3265, 1623 (found: 81.0% C, 9.3% H; the butto formula C ₂₂ H ₃₀ O ₂ requires 80.9% C, 9.3% H).

Example 20

ο (±) -3-methoxy-13j8,17 «-di-n-propylgona-2,5 (10) -dien-17/3-ol (1.07 g) was dissolved under nitrogen in methanol (50 ecm), which was water (2.5 ecm) and 1N hydrochloric acid (3.8 ecm) contained, stirred at room temperature for 2 hours. Then water was added and that

Product extracted with ether. Evaporation of the washed and dried extracts gave one The residue, which was purified by chromatography on aluminum oxide, then repeated was recrystallized from ethyl acetate, below

ao sublimes at 14,570.003 mm to (±) -13 / 3.17a-din-propylgon-4-en-17/3-ol-3-one (0.34 g) to give "melting point 147-149 °;" UV: 241 (16,600); IR: 3440, 1660, 1610.

Example 21

( ± ) -1 7λ - allyl - 3 - methoxy -13/3 - η - propylgona-2,5 (10) -dien-17 / S-ol (0.77 g) was under nitrogen for ₂ hours in isopropyl alcohol ( 25 ecm), which contained 1N hydrochloric acid (2.4 ecm) and water (1.6 ecm), stirred. The mixture was filtered, added to brine and the product then extracted with ether. The washed and dried extracts were evaporated to a residue which was purified by chromatography over activated fuller's earth

and then by recrystallization from ethyl acetate the (±) -17 «-AlIyl-13/3-n-propylgon-4-en-17/3-ol-3-one, melting point 135 ° to 137 °; UV: 241 (17,500); IR: 3390, 1660, 1620 (found: 80.4% C. 9.8% H; the gross formula C ₂₃ H ₃₄ O ₂ requires 80.65% C, 10.0% H).

Example 22

(4-) -3-Methoxy-D / J-n-propyl-Ha-propynylgona-2,5 (10) -dien-17/3-ol (2.5 g) was added under nitrogen with methanol (135 ecm) containing 1N hydrochloric acid (9 ecm) and water (6 ecm) contained, stirred. After 2 hours isopropyl alcohol (35 ecm) was added and that Stirring continued for an additional 30 minutes. The mixture was added to a saline solution and the product

extracted with ether. The washed and getrock designated extracts were evaporated to a glassy residue which was taken up in benzene and chromatographed over activated fuller's earth. Elution in benzene, which contained 5% ether, gave a product which, after recrystallization from a mixture of ethyl acetate and n-hexane, (±) -13 / 3-n propyl-17a-propynyl-gon-4-en-17 / ? -ol-3-one, melting point 182-184 °; UV: 240 (16,700) (found 80.95% C, 9.4% H; gross formula Q ₃ H ₃₂ C requires 81.1% C, 9.5% H).

Example 23

Using the procedure> Example 2 (

became (±) -17a- (2-methylyl) -3-mc! l. y-13/3-n-pro

■ pylgona-2,5 (10) -dien-17 /? - ol hydrolyzed with hydrochloric acid

chromatographed over activated fuller's earth and recrystallized from ethyl acetate to obtain (±) -17 «- (2-methällyl)

IS 16

O / S-n-propylgon- ^ en-n / S-ol-S-one, m.p. 141.5. . ,

to give up to 143.5 °; UV: 241 (16,700); IR: 3480, example io

1660.1620 (found: 80.8% C, 9.9% H; the gross (±) -130 - η - butyl -17 «- ethinyl - 3 - methoxygona-

formula C ₂₁ H ₃₁₁ O ₂ requires 80.85% C, 10.2% H). 2,5 (10) -dien-17 / J-ol (2 g) was added using the

5 method of Example 24 hydrolyzed, and the pro

Example 24 was activated by chromatography over

Fuller's earth purified and then from a mixture of

(±) -17 «- (l-methallyl) -3-methoxy-13 | 9-n-propyl ether and η-hexane recrystallized; it gave (±) -13 / 3-

gona-2,5 (10) -dien-17/9-ol (1.5 g) was n-Butyl-17 «-äthinylgon-4-en-17/3-ol-3-one (0, 71 g),

with methanol (90 ecm), which in hydrochloric acid (9 ecm) ίο melting point 159 to 163 °; UV: 240 (15,900); IR:

and water (6 ecm) contained, stirred. The mixture 1670 (found: 80.8% C, 9.3% H; the gross formula

was added to a saline solution and the product C ₂₃ H ₃₂ Oi requires 81.1% C, 9.5% H).

extracted with ether. The washed and dried- _R. . , .-

Neth extracts were evaporated to give Example 11

(±) -l 7 «- (l -methallyl) -13 £ -n-propylgon-4-en-17; S-ol- 15 (±) -13>? - Ethyl - 17a - äthinylgon-4-en- 17/3-ol-3-one

3-one; UV: 240 (13,500); IR: 910 (0.5 g) in pyridine (20 ecm), which is a 2%

. . Palladium on Calcium Carbonate Catalyst (0.15 g)

Example 25 contained was hydrogen at atmospheric

A solution of (±) -13 /? - n-Butyl-17 «-ethyl- pressure is shaken until one molecular equivalent of water-

3-methoxygona-2,5 (10) -dien-17/3-ol (1.05 g) was absorbed in an ao fabric. The separation with ether

Mixture of tetrahydrofuran (15 ecm), methanol gave a product which was obtained from a mixture of ether

(54 ecm), 12N hydrochloric acid (3.6 ecm) and water (2.4 ecm) and n-hexane recrystallized and 4 hours at 65 ° /

was kept for 2 hours at room temperature 0.005 mm was dried and the (±) -13 /? - ethyl

and then poured into a saline solution (350 ecm). The 17 * -vinylgon-4-en-17 /? - ol-3-one, melting point 108 bis

Work-up with ether gave a resin (1.0 g), which gave 25 111 °; UV: 240 (15,200); IR: 920 (found

in a mixture of light petroleum and benzene 80.4% C, 9.7% H; the gross formula C ₂ IH ₃₀ O ₂ =

(25 ecm) added and over silica gel requires 80.2% C, 9.6% H).

was chromatographed. Elute with benzene, wel- _R. · 1 28

ches contained a small amount of ether, resulted in an e 1 s ρ 1

crystalline by-product (0.1 g); The following EIu- 30 (±) -17 «-ethynyl-13/3-n-propylgon-4-en-17/3-ol-3-one ieren with a mixture of ether, benzene and (0.5 g) was using the procedure of chloroform (in parts by volume 5: 4: 1) gave Example 27 hydrogenated and the product in the same way crystalline product, which was separated and recrystallized from hexane and post- gave (±) -130-n-pro from the following Hexane, which contained a little ethyl acetate pyl-17a-vinylgon-4-en-17/3-ol-3-one (0.425 g), melt, recrystallized (±) -13 / 9-n-butyl-17 <x -ethyl - 35 point 94 to 97 °; UV: 240 (15,600); IR: 920 (found gon-4-en-17/3-ol-3-one (0.23 g), melting point 78 to 80 °, 81.1% C, 9.9% H; the gross formula C ₂₂ H ₃₂ O ₂ required, UV: 240 (14,700); IR: 3470, 1668, 1619. dert 80.4% C, 9.8% HI.

Claims (6)

ί 793 claims: 1.17 «-alkyl-, -alkenyl- or -alkynyl-13 / i-alkylgon-4- or -5 (10) -en-17 / S-ol-3-ones of the general ones Formula I. in which the dotted lines in ring A denote an ethylenic bond in the 4 (S) or 5 (10) position, R ^{1 is} a saturated alkyl group with at least 2 and preferably not more than 6 carbon atoms and R * is a substituted » o represents tuted or unsubstituted alkyl, alkenyl or alkynyl group of preferably not more than 6 carbon atoms, with the exception of 17'-ethynyl-13 /? -n- '5-propylgon-4-ene prepared according to the process according to German Auslegeschrift 1 290 139 -l 7 / J-ol-3-one. 2. Compounds of the general formula I in which R ^{1 is} an alkyl group with 2 to 4 carbon atoms and R * is an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 3 »4 carbon atoms or an alkynyl group with 2 to 4 carbon atoms, with the exception of that 17 <x -ethynyl-13/9-n-propylgon-4-en-17/9-ol-3-one produced by the process according to German Auslegeschrift 1290139. 3. Compounds according to any one of claims 1 and 2, in which R ^{1 is} an ethyl group. 4. 130.17 "-Diethylgon-4-en-170-ol-3-one. 5. 13/9 Ethyl-17 "-äthinylgon-4-en-17 ^ -ol-3-one. 6. Medicines consisting of compounds of general formula I, except that according to the procedure in accordance with the German interpretative document 17 "-ethynyl-13/3-n-propylgon-4-cn-17 /? - oI-3-one produced 1,290,139 and customary pharmacologically acceptable carriers and / or diluents. is not more than 6 carbon atoms, with the exception of the 17'-ethynyl-13 / jn-propylgon-4-en-17 /? -ol-3-one produced by the process according to German Auslegeschrift 1 290 139. In particular, the present invention relates to those compounds of the aforementioned formula (I) in which R ^{1 is} an alkyl group with up to 4 carbon atoms and R * is an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 4 carbon atoms or an alkynyl group with 2 to 4 carbon atoms . The compounds of the invention can be prepared according to the method of patent 1468604. For example, the method known per se can be used
(a) a compound of the general formula (II)