DE1938283A1 - 6-substituted-13-polycarbonate-alkyl-18,19-dinorpregn-4-en-3-ones, their delta-dehydro-analogs, intermediates, processes for the preparation of these compounds and their use - Google Patents

Description

DR. BERG DIFL.-ING. STAPF

PATENT AGENT 8MUNCHENa ₁ HIL ₁ BLESTRASSCaO 1938283

Df. BfB Dlpl.-Ina- Stopf, I MOnthw 2, HilbltttroB «20

28.

Our date of arrival

Attorney file 18 694- Βθ / Soh

American Homo Products Corporation, New York / USA

"6-sub3t. -13-Polycarbonalkyl-18,19-dinorpregn-4-en-3-ones, their £ ± -dehydro-analogs, intermediates,. Process for the preparation of these compounds and their use"

This invention relates generally to steroid compounds and methods of making and using them, and further to useful intermediates. in the it relates in particular to steroids of the 6-substituted-1J-polycarbonate-alkyl-18,19-dinorpregnr4-en-3-one series, the Δ -dehydro analogues of the same, intermediates and processes for their preparation «

ÄHP-4764-f -2-

INSPECTED

The steroid compounds of this invention have formula

(I)

wherein the radical R is an alkyl group with from 2 to 6 Carbon atoms, X is C = O or C (H) OR, wherein

R is hydrogen or a (lower) alkanoyl group, Y = H, OH or OCOR ² , where R ^{2 is} a (lower) alkyl group and either rings A and B have the formula P.

(P)

is a divalent radical of the formula

have what

wherein Z is chlorine, bromine or fluorine and Z is chlorine or bromine provided that when X is C = O and Y = H then -C5-

-iet or rings A and B have the formula

(Q)

9Ö9886 / 1667

- 3 in which W is an alkoxy group and V «is CHpOH or GHO.

The term "(lower) alkyl" means straight or branched hydrocarbons with from 1 to Carbon atoms and these include, for example, methyl, ethyl, n-propyl, i-propyl, η-butyl, s-butyl, t-butyl, n-rentyl, laopentyl and hexyl. The designation "Polycarbonalkyl" refers to polycarbon (lower) alkyl with from 2 to 6 carbon atoms and includes the groups explained above but excluding the methyl group, the ethyl group being preferred. The Ber. θ sizing "(lower) alkanoyl" denotes groups of the Formula (lower) alkyl-CO-, wherein "(lower) alkyl" has the meaning given above, acetyl is preferred

Reference is made to a number of particularly valuable preferred compounds of the present invention. , These are i

Compounds of the formula Ia:

(la)

0
where R is alkyl having from 2 to 6 carbon atoms, X is CQ or C (H) OR, where R is hydrogen or (lower)

6/166?

ρ Ο

Alkanoyl. is, Y = H, OH or OGOR, where R (lower) Is alkyl and -Cg-On- is a divalent radical of Formula is

τ ^0Γ τ

ei ^{GH G1}

13β-Ethyl-20 £ -hydroxy-6-methyl-18,19-dinorpregna-4,6-dien-3-one, a compound of the formula Ia in which R is ethyl, X * C (H) OH, Y - H and -0 - C ₀ -

⁰ p.

is.

13ß-Ethyl-17or-iiydroxy-6-methyl-18,19-dinorpregna-4,6-diene-3 | 20-dione and the 17 "-acetate ester thereof, ie compounds of the formula Ia in which R is ethyl, X 0 = 0, Y is QH or OCOCH _x and -0 ^ -0, -, -

OH,

is.

13ß-Ethyl-6aT-chloro-18,19-dinorpregn-4-en-3-one-20-oli ^ acetate, a compound of the formula Ia in which R is ethyl. XC (H) OCOCH _x , Y = H and -Cc-C ₀

egg
909886/1667

13ß-Ethyl-6-chloro-18,19-dinorpregna-4,6-dien-3-one-20-olacetate, a compound of the formula Ia, in which R is ethyl, XG (H) OCOCH ₅ , Y = H and -O ₅ -C ₇ -

Cl is.

13ß-ethyl-6a-chloro-18,19-dinorpregn-4-en-3, 2O-dione-17 <xol acetate, a compound of the formula Ia, in which R is ethyl, XC = O, Y OCOCH ₅ and -O ₆ -O ₇ -

Cl is.

13ß-ethyl-6-chloro-18,19-dinorpregna-4,6-diene-3 »20-dione-17ocM> l-acetate, a compound of the formula Ia in which R is ethyl, XC = Cl ₁ Y OCOCH, and -O ₆ -C ₇ -. "

Cl

-18,19-dinorpregna-4,6-diene- 3,2Q-dione, a compound of the formula Ia, in which R is ethyl, X σ »α, υ oh and -C ₆ -C ₇ -

-6-9Ö9886 / 1667

Cl

Compounds of the formula Ib:

CE,

O ■

(Ib)

where R is alkyl of 2 to 6 carbon atoms and Y = H, OH

ρ ρ

or OCOR where R is (lower) alkyl.

--18,19-dinorpregn-4-en-3-one, a compound of the formula Ib, wherein R is ethyl ^ X C (H) OH and Y = H,

Compounds of the formula Ic:

CE.

--Ϊ ¹

(Ic)

where R is alkyl of 2 to 6 carbon atoms, XC = O or G (H) OH, Y ¹ »is OH or OCOR ² , where R ^{2 is} (lower) alkyl and

9Ö9886 / 1667

-7-

-18,19-dinorpregn-4-en-3,20-dione acetate, a compound of the formula Ic, in which R is ethyl, XC = O and Y ¹ = OGOGH.

The compounds of formula I in which rings A and B have the formula (P) given here are, with the exception of the 6-methylene compounds, valuable hormonally active substances Substances. It has been found that in standard pharmacological studies in laboratory animals, such as mice, rats, rabbits and the like, are progestational and antioestrogenic. They are more effective than many known connections currently with these Efficacies are used and they additionally exhibit a valuable separation of the hormonal properties in to a greater extent than many are currently using them. Activities used connections. Progestationally effective Substances are used in cases of infertility and especially, but without limitation, to delay the Oestrus (menstration cycle) and ovulation in calves, pigs and dogs ”. Anti-estrogen effective Compounds are used as antidotes to the effects of excess estrogen, such as estrone and the like metrotropic agents administered. The present compounds are still in the field of use as Very small dose contraception is known to be effective. They have an anti-fertility effect at a considerable rate administration doses lower than those conventionally

§09886 / 1667 ~ ⁸ ~

used, i.e. 1 mg to 100 mg daily. The 6-methylene compounds of formula I and the compounds of formula I in which rings A and B have the formula P are intermediates.

The compounds of formula I of this invention can be prepared by a general method wherein man

(a) a methylene compound of the formula II

(II)

in which R, X and Y have the meanings given above, for example by exchange hydrogenation with a suitable one organic hydrogen donor, for example cyclohexene, in the presence of a catalyst, for example Palladium-on-carbon, with formation of a compound of the formula Id

(Id)

wherein R, X and Y have the meaning given above, hydrogenated,

9 0 9886/1667

-9-

(b) a 6-methylene compound of the formula given above II, for example by heating with a weak base, for example sodium acetate, and a noble metal catalyst, preferably a Pt or Pd catalyst, for example Pt or Pd / G, in an inert solvent, for example ethanol, to form the corresponding Compound of formula Ie

- Y

(Ie)

wherein R ₁ X and Ϊ have the meaning given above, rearranged,

(c) an enol ester of the formula III

(HI).

R ³ COCi

wherein R, X and Y are as defined above and Br is (lower) alkyl, for example with N-chlorosuccinimide or N-bromosuocinimide to form a compound of the formula If

- Y

(If)

-10-

§Ö§ | 186/1687

- ίο -

in which R, X, Y and Z have the meaning given above, chlorinated or brominated,

(d) a compound of the formula If to form a compound of the formula Ig

(Ig)

wherein R, X, Y and Z have the meanings given above, for example by heating with Ghloranil directly dehydrated or preferably

(e) an epoxide of the formula IV

(IV)

wherein R _1, X and Y have the meaning given above, with a hydrogen halide, namely dry hydrogen chloride, hydrogen bromide or hydrogen fluoride, to form a compound of the formula Ih

-Y

(Ih)

-11-

J509886 / 1667

CD

in which R, X, Y and Z have the meaning given above, implements,

(f) a compound of the formula Dc

- O.COR ^C

. (Ik)

wherein Z is methyl, bromine, chlorine, or "fluorine," in part hydrolyzes to form a compound of the formula

OGOR

(Ij)

wherein R, R and -0, - Gr ₇ * - have the meaning given in formula I.

The Partialhydrolyae can with diluted iü hydroxide, for example 2 # strength methanolic potassium hydroxide. -

The compound of the formula Ik can be prepared by acylating a compound of the formula Ii with a reagent of the formula

2 2

(R CCOgO or R GOOl or preferably a mixture thereof in the presence of an acid-binding agent, for example an organic base such as dimethylaniline, N-methylmorpholine or preferably pyridine can be obtained.

909886/1667

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--OH

(Ii)

(g) a compound of the formula

^CH 3

CHOH J ... Y

selectively oxidized to a compound of the formula

where H and Y- have the meaning given above,

(h) a compound of the formula

selectively hydrolyzed to form a compound of the formula

7 »

JR CHOH
--Y

wherein R, R and X have the meaning given above,

909886/1667

-13-

(i) a compound of the formula

(In the)

select ⁴ - "^ reduced to form a compound of the formula

(In)

Wl

CH ₂ OH
in which R, X, Y and W have the meaning given above,

(j) a compound of the formula Jn as defined above, hydrolyzes to form a compound of the formula

--Y

(II)

wherein the groups E ₉ X, Y, 2, -C ₆ -C ₁ ^ R ¹ , R ² and W have the meaning defined above and Tr is a lower alkyl radical,

(k) a compound of the formula

909886/1667

-14-

- · γ

wherein K is a protected oxo group which in compound with the unsaturation indicated by dotted lines in rings A and / or B by acid to a 4,5-ethylenic 3-ketone is hydrolyzable and X has the meaning given above or a protected Garbonyl- or hydroxymethylene group to form a compound of the formula Id and / or the corresponding 6ß-Methy! Compound, hydrolyzed,

(1) a compound of the formula

■ 8 X

Ko)

wherein Z ^ is methyl, α-chlorine or α-bromine, isomerized with formation of a corresponding gon-4-en-3-one,

(m) a compound of formula 1 (p)

Kp)

9Θ & 886/166 7

wherein W is an alkoxy group, there are also ethylenic bonds in the 2- and 5 (10) -positions or 3- 'and 5-positions, if necessary with conversion of the Y or X group, formylated to form a compound of the formula Im, as explained above, where the groups R _t X »

1-12

Y, Z, Z, -O ₆ -C ₇ -, R, R and V / have the meaning given above and R is a lower alkyl radical.

The process of step (a), i.e., hydrogenating the 6-methylene compound of the formula II. can be carried out by an exchange hydrogenation · In this Process is, for example, a mixture of the 6-methylene compound with about 5 parts by weight of cyclohexene and about 1/5 part by weight of a catalyst, such as a 5 # ig © a Palladium on carbon, in about 1/2 absolute ethanol refluxed for about 1/2 hours. The product of the formula Id is obtained by any standard method. One of the most useful methods is to give ether to, filter the Geraisch, add a trace of mineral acid and evaporate the solvent, creating the product remains as a residue. If desired, it can be purified by recrystallization from ether «

The process of stage Cb) _1, ie the rearrangement of a 6-methylene compound of the formula II, can be carried out by treating it with a weak base in the presence of a catalyst such as palladium-on-carbon

909886/1667 ^

-16 «

and treated in an inert solvent, preferably at a moderately elevated temperature, for example from 75 to 10O ^{0 O.} After a procedure, the compound of formula II in about 300 parts by weight of an alcohol, for example ethanol, suspended and thereto about 0.5 parts by weight of sodium acetate and about 0.15 parts of 5 # ig are palladium-on-charcoal ^there were added . When the mixture is heated and left for about 1 to 5 hours

"Keeping the flow is the rearrangement to the connection of formula Ie essentially ended. This can after obtained by any conventional method, but a simple means is to cool the mixture, dilute it with ether, filter it off, add saturated aqueous sodium bicarbonate solution, then add salt solution wash, dry over anhydrous sodium sulfate and finally evaporate the solvents, the Product remains as a residue. If desired, it can be purified by recrystallization from ether, (■

-S

A useful set of compounds outside the scope of the invention, namely the ^ -Polycarbonalkyl-öa-methyl-18,19-dinorpregn-4— en ~ 3 | 20-dione, can thereby be produced be that the corresponding compounds of the formula Id, where R is polycarbonate alkyl, X = CH (OH) and Y H, with a standard oxidizing agent, for example the Jones reagent, 8N chromic acid, until conversion to a corresponding compound wherein X

909886/1 667 " ¹⁷ ~ ·

0 «is 0, has essentially ended and this® connection, the valuable progestational and anti-estrogens Has properties wins.

Starting materials of the formula II can, for example, according to one of the process routes given below can be obtained.

Well one of the first will be an IJ
18 _t 19-dinorpregna-2,5 (10) -diene (V) subjected to a Vilemeier reaction (POOl, in dimethylformamide), whereby the corresponding 13-alkyl-6-formyl-20-hydroxy-3-ralkoxy- 18,19-dinorpregna-3,5 (6) -diene-20-formate (VI) is obtained · The compound VI is hydrolyzed, as for example with potassium hydroxide in methanol, to the corresponding alcohol (VII), which after treatment with a metal hydride -fieduktions- agent, for example sodium borohydride in methanol mixed with tetrahydrofuran, daa 13-alkyl-20-hydroxy-6-hydroxymethyl-3-alkox3 [-18,19-dinorpregna-3,5 (6) -diene (VIII)) supplies. Treatment of compound VIII with acid, for example a mineral acid such as dilute methanolic H ₂ SO 4, suitably at about 25 ° 0 results in hydrolysis of the enol ether and simultaneous elimination of water to form the 13-alkyl-20-hydroxy-6-methylene -18,19-dinorpregn-4-en-3-one of the formula Ha (where R has the meaning given and X is 0 (H) OH):

90 9 8 86/1667

CHO VII

MeOH / CiLO THF

CH ₂ OH

νίπ

VIII

C (H) OH

909886/1667

wherein "DMP" is dimethylformamide and. "THP" is tetrahydrofuran. In the procedure given above, the 3-alkoxy group suitably a methoxy group, but of course other alkoxy groups can also be used and this process provides access to the 3-alkoxy compounds In (corresponding to the compound VIII of the above scheme).

In the second process, the starting material, 13β-alkyl-17oc-hydroxy-18,19-dinorpregn-4-en-3 »20-dione, treated with an acylation agent, for example acetic anhydride and a trace of perchloric acid in ethyl acetate, whereby the corresponding 13β-alkyl-3 »17-dihydroxy-18,19-dinorpregna-3» 5-dien-20-one diacetate which is then converted to tetrahydrofuran with a base, for example methanolic potassium hydroxide with formation of the corresponding 13β-alkyl-17-hydroxy-18,19-dinorpregn-4— en-3,20-dione acetate, which in turn with methyl orthoformate in dioxane, p-toluenesulfonic acid contains, is reacted to form the corresponding 13β-alkyl-17-hydroxy-3-methoxy-18,19-dinorpregna-3 »5-dien-20-one acetate, which in turn is formylated with phosphorus oxychloride in dimethylformamide and ethylene dichloride to form the corresponding 13ß-alkyl-6-formyl ~ 17a-hydroxy-3-methoxy-18,19-dinorpregna-3,5-dien-2Q-one acetate, which is reduced to that with lithium aluminum tri-t-butoxyhydride in tetrahydrofuran

909886/1667 -20-

corresponding 13β-alkyl-17o (rhydroxy-6-hydroxymetliy.l-3-methoxy-18,19-dinorpregna-3 | 5-dien-20-one acetate, treated with oxalic acid in methanol and water, the desired 13β-Alkyl-17 ((- hydroxy-6-methylene-3-methoxy-18,19-dinorpregna-4-en-3,20-dione-acetate delivers according to the following process sequence:

90 98 86/168 7

Dioxane / θ ' p-TSA

POC

Ethylene dichloride

--OCOCH-

LiAl (O «> tB u) _? H THP CH, 0

- • oooc:

Oxalic acid /

Methanol /

water

- OOOCH ^

909886/1667 -22-

wherein R is as defined above, ¹¹ THF "is tetrahydrofuran," p-TSA "is p-toluenesulfonic acid and" MeOF "is methyl orthoformate. Of course, other alkylating agents can also be used instead of" MeoF ".

The process of step (c), i.e., chlorination of an enol ester of formula III with a reagent such as N-chlorosuccinimide or N-bromosuccinimide can be carried out by adding about 30 parts of the enol ester a (4: 1) mixture of acetone and water is added, this being approximately 0.7 parts sodium acetate and 0.7 parts glacial acetic acid contains per part by weight of enol ester. The mixture is then cooled to about 5 ° C and about 6 to 8 parts N-chlorosuccinimide was added per part by weight of enol ester. the Formation of the product of formula If is in about 1 to Completed about 4 hours and this can be obtained by mixing the reaction mixture with water diluted, then extracted with ether and evaporated to dryness, leaving the compound If as a residue. If, instead of N-glorosuccinimide, N-bromosuccinimide is used, the corresponding 6-bromine compound is used of the formula If.

The starting materials of the formula III given above can be prepared by using an enol ether starting material of the formula Vb

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--Y

(Vb)

(in which R, X and Y have the meaning given above), acid hydrolysis, for example with methanol: concentrated HCl: water 90: 6: 4 or the equivalent subjecting cyclic 20-ethylene ketal to acid hydrolysis, then with an acid anhydride, preferably acetic anhydride acylated in the presence of a trace of perchloric acid and about 40 vol, parts of ethyl acetate. The reaction is very quick and essentially completes in about 15 to 20 minutes. Treatment with enough watery Sodium bicarbonate to destroy the excess acetic anhydride and evaporate the organic ones Layer to dryness gives the compound III as a residue.

The process of step (d), i.e., the dehydration of a Compound of the formula If for the introduction of a double bond between Cg and C-, can be mixed with a reagent such as Chloranil can be carried out. According to one procedure, the compound If can be dissolved in 25 parts by volume of a solvent, like ithylacetat, which contains about 5 parts by volume of acetic acid and about 2 parts by weight of chloranil per weight. Part If contains, be suspended. When the mixture

909886/166 7

refluxed under nitrogen for approximately 24 hours is, the conversion of the compound Ig is essentially complete and it can be, for example, by cooling the mixture, washing with 10 # sodium hydroxide solution, then obtained with brine, drying over anhydrous sodium sulfate and finally evaporation to dryness, with Ig remaining as a residue.

The process of step (e), ie the treatment of the epoxide of the formula IV with a halogen acid to form the 6-halo-4,6-diene of the formula Ih, can be carried out with dry hydrohalic acids. In one procedure, the epoxide (IV) can be suspended in about 30 parts by volume of glacial acetic acid. Sas mixture is cooled to about the freezing point of the acetic acid, 16.6 ⁰ C and a slow stream of gaseous hydrogen chloride, hydrogen bromide or hydrogen iodide is passed. After about 2 to 6 hours, the formation of the compound of the formula Ih is essentially complete and the product can be obtained, for example, by pouring the mixture into ice water and with a water-immiscible solvent such as a mixture of 10: 1 benzene and ether extracted. The organic layer is washed free of acid, for example with dilute sodium bicarbonate, dried and evaporated, leaving the compound Ih as a residue.

909886/1667

-25-

The starting materials of the formula IV given above, the epoxides, can be prepared by splitting off halogen in the 6-chloro or -bromine compound of the formula If with formation of the ^, e-diene (IX) with subsequent epoxidation with formation of the prebond IV naoh the following Procedure:

^ch j

DMi? or
Pyridine

If

IX

l'oraiiure

where, R, X, Y and Z have the ^{definition given above and 11} DMS "means ¹ dimethylformamide. The dehalogenation is carried out, for example, by suspending the compound If in approximately 50 parts by volume of dimethylformamide or pyridine and by adding approximately 3 parts by weight Calcium carbonate, based on parts by weight of If, is maintained under reflux for about 1 hour under nitrogen, filtered

/ ib
the filtrate pours into water, extracted with

903086/1667

-26-

Ether and evaporates the ether and receives the 4,6-diene IX as a residue. This is ^ for example, by suspending in about 50 parts by volume of chloroform and precipitated by treating the mixture with 1 part by weight peracid such as perbenzoic and / or preferably Monoperphthalsaure, per part by weight of Compound IX, during about 48 hours at about 22 ⁰ C j epoxidized. The epoxide IV is then obtained by, for example, washing the organic phase with saturated sodium bicarbonate, then with brine, then drying over sodium sulfate and evaporating the solvent, IV remaining as a residue.

The process of step (f), i.e., selectively hydrolyzing a compound of formula Ii, inclusive the preparation of the diacylate intermediate is preferably carried out in stages, first with an appropriate one Acyl anhydride, for example acetic anhydride, or an acyl halide, for example acetyl chloride or Acetylhromide or preferably with mixtures thereof, in the presence of an acid binder such as an organic base, preferably pyridine, to form the corresponding Enol ester 17 pt »acylate 8. According to a procedure the compound Ii is treated with an excess of acetic anhydride and acetyl chloride in pyridine and heated the mixture to about 50 to 75 ° C for a few minutes and then for about 67 hours at about 23 ° C · ■

909886/1667 " ²⁷ "

held. The enol ester is obtained by pouring the mixture into a large volume of water, extracting the organic layer with ether, washing, drying, evaporating the ether, leaving the enol ester as a residue. This is selectively hydrolyzed with a dilute base. According to one procedure, the enol acetate is suspended in 2 # strength methanolic potassium hydroxide and the mixture is ^{stirred at 0} ° C. until the partial hydrolysis has essentially ended. Cooling and neutralization of the reaction mixture, evaporation to dryness, extraction of the residue with ether and evaporation of the ether yield the compound Ij as a residue.

The selective oxidation of stage (f) can with a

ρ Jones reagent if Y is hydrogen or OCOR, and with dimethyl sulfoxide in acetic acid, provided Y = OH, be performed.

The compounds described can also be carried out by known methods for analogous compounds will.

The starting material for all of the above-mentioned compounds can be prepared by methods applicable to analogous connections in the co-pending patent application of the same applicant, attorney's file $ 18 59 are described. Other starting materials are described in U.K. Patent 1,115,635. You can

909886/1667. -28-

. - 28 -

can be produced by using processes of total synthesis in earlier stages, as described by Douglas, Graves, Hartley, Hughes, McLoughlin, Siddall, and Smith in J.Chem Soc, 1963, 5072-5904 and H Smith, Hughes, Douglas, Wendt, Buzby, Jr., Edgren, Fisher, Foell, Gadsby, Hartley, Fall, Jansen, Ledig, McLoughlin, McMenanim, Pattison, Phillips, Rees, Siddall, Suida, L. Smith, Tokolics, and Wateon in J. Chem. Soc, 1964, 4472-4492 are used. When the starting materials are the product of an overall synthesis which does not involve a suitable step of separation, the compounds of the invention will be racemic Shape to be present. However, if a separate starting material is used (e.g. Separate obtained at an earlier stage in the synthesis Of course, the products of the methods described herein will be separate d-enantiomers. Suitable separate intermediates as starting materials of the invention are in the literature, for example in J. Med. Chem. 1967, 199-204 using a convention as described by Fieser and Fieser, "Steroids", page 356 (1959) are referred to as the d-forms of the compound referred to are the enantiomers in the C-13 configuration corresponding to the natural Hormone oestron considered. The corresponding enantiomorphs are therefore as 1-forms and the racemates referred to as dl forms. The structural formulas only show

-29- 909886/1667

the enantiomorphs of the d-configuration but it is natural it goes without saying that the racemates are also included in the invention.

Those in performing the above procedures The time and temperature ranges used are not particularly critical and it is clear to those skilled in the art that they are selected so that the reaction can be carried out in a minimum of time without undue difficulty can be. It can therefore reaction temperatures below those specified can be used, but then the response time extended. On the other hand, higher reaction temperatures than those specified under simultaneous Reduction of the reaction time can be used, although the purity of the Brodukt thereby somewhat decreases will.

As already mentioned above, the compounds of the formula I in which the rings A and B have the formula P have progestational ones and anti-estrogenic effectiveness and they are furthermore useful for the preparation of compounds with these activities. The progestational effectiveness is illustrated by standard pharmacological studies in lower warm-blooded animals. In such an attempt the Glauberg experiment, undeveloped female rabbits are prepared for 6 days with estradiol-17ß. The prepared rabbits then get tiered

90 9886/1667 " ⁵ °"

5 doses of the tested compound daily Days before the autopsy on the sixth day. The progestational effectiveness is assessed by histological evaluation Uterine gland proliferation according to Elton and Edgren, Endocrinology, 63, 464-4-72 (1958). The antiestrogenic Efficacy is also determined according to standard pharmacological studies in lower warm-blooded animals. In such an attempt, the estrogen counteracting "must" -. Uterus growth attempt 100 / Ug Oestriol- simultaneously with graduated doses of the the compound under test was administered for three days. At autopsy on the fourth day, the uteri are removed and weighed. Effective materials inhibit the metrotropic effects of estriol, such as that of Edgren and Calhoun, Experientia, 16, 188 (1960).

The products of the formula I of this invention, wherein the rings A and B have the formula F given above, can be used in conjunction with a non-toxic carrier for the pharmacological purposes indicated above. They can be in liquid or solid forms, for example as capsules, tablets, suppositories, powders, dispersible granules, troches and the like can be presented, combining them with conventional carriers will. Such conventional carriers include magnesium carbonate or stearate, talc, sugar, lactose, Pectin, dextrin, starch, gelatin, tragacanth, methyl

909886/1667

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- 51 -

cellulose, sodium carboxymethyl cellulose, low melting point Wax and cocoa butter. Thinners or extenders, Flavors, solubilisers, lubricants, suspending agents, Binder or tablet-disintegrating Funds can be used. Powders or tablets preferably contain 5 or 10 to 99 # active ingredient. That effective steroid can be presented with an enveloping material with or without other carriers.

Liquid preparations such as solutions, suspensions or Emulsions can also be used. Such preparations include dispersions in a non-toxic Carriers such as arachis oil or sterile water, preferably containing a non-ionic surfactant Means such as fatty acid esters of polyhydroxy compounds, for example sorbitan, aqueous starch in sodium carboxymethyl cellulose solutions, aqueous propylene glycol or polyethylene glycol. So can a water-propylene glycol solution for parenteral injection and aqueous suspensions suitable for oral use are made by using natural or synthetic gums, resins, methyl cellulose, or others known suspending agents are used.

The preparation can give the lower warm-blooded animals in the form are administered by dosage units, the dosage unit for example from about 0.1 to

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contains approximately 200 mg of the respective active steroid. The dosage unit can be a packaged preparation, for example packaged powder, vial or Ampoules or, for example, in the form of capsules, cachets or tablets, or any number of these Have options in packaged form. The preparations can continue to consist essentially alone the active steroid when it is in unit dosage form. When the connections Used for the above purposes, their dosage may vary with the conditions being treated change, but in general the range given for Progoesteron (Merck Index, 7 »edition, Page 856 (1960)) must be adhered to.

The following examples, which describe preferred embodiments, serve solely to illustrate without limiting the scope of the invention.

example 1

13β-Ethyl-20i-hydroxy-6a-methyl-18,19-dinorpregn- ^/ <-en-3-one (a) dl

dien-20-ol formate

To a solution of distilled dimethylformamide (0.65 s) in distilled ethylene dichloride (1.0 ml) at ⁰ ° O, a solution of distilled phosphorus oxychloride (0.69 ε) in ethylene dichloride (3.0 ml) is added over 30 minutes.

909886/166 7

-53-

After stirring for an additional ^{10 minutes at 0 0} O, pyridine (1 drop) and then a solution of dl-13ß-ethyl-3-methoxy-18,19-dinorpregna-2,5 (10) -diene-20§- ol (0.66 g) in ethylene dichloride (10 ml) containing pyridine (100 mg) was added all at once. After the red solution has been ^{stirred at 0 0} O for 1 hour, a solution of sodium acetate (4-.0 g) in water (40 ml) is added and the mixture is stirred vigorously for 10 minutes. The mixture is poured into water, extracted with ether, the organic layer washed with water until the wash liquors are colorless, then dried over anhydrous sodium sulfate and stripped under vacuum. Trituration dea Rückstandfe with methanol yields 0.34 g of yellow product, melting point 175-182 ⁰ C, (softening 17Q ⁰ C); ^λ m? x ^ ⁸⁴ ' ⁶ ' ° ⁷ * ⁶ » ² V ^J ^ 2 £ ^{H 22} ° Γ ^{(£? 700)} ' 321 mu (£ i4 800).

(b) dl-13β- &thyl-6-formyl-3-methoxy-18,19-dinorprefz; na-

To a solution of dl-13ß-ethyl-6-formyl-3-methoxy-18,19 dinorpregna-3,5-dien-20f-ol-formate (2.65 g) in {tetrahydrofuran (100 ml) under nitrogen a solution of potassium hydroxide (1.35 g) in methanol (100 ml) is added all at once about 23 ^{° C.} Stirring is continued for 30 minutes at room temperature, then the mixture is poured into saturated aqueous sodium bicarbonate and extracted with benzene. The benzene extracts are made with

909886/166 7 -34-

Washed water, dried over anhydrous sodium sulfate and stripped under vacuum. The trituration the residue with ether gives 1.41 g of yellow colored

Product, melting point 185 to 191 ⁰ C ^ ^ 3.03, 6.07,

6.24 / U; λ ^ ^ü 220 mu (£ 9,400), 322 mu (<£ 15,400).

preKna-3 »5-diene-20 ^ -öl

To a solution of dl-13ß-ethyl-6-formyl-3-methoxy-18,19-dinorpregna-3,5-dien-20 ^ -ol (1.0 g) in methanol (20 ml) and tetrahydrofuran (20 ml) sodium borohydride (250 mg) is added all at once at room temperature. The mixture is stirred at about 23 ° C for 15 minutes, poured into water and extracted with benzene. The organic layer is washed with water, brine, dried over anhydrous sodium sulfate and stripped under vacuum. Trituration of the residue with ether yields 0.45 g of colorless alcohol, melting point 128 to 133 ° C; λ Jjj £ 3.04, 6.11, 6.21 / U; λ ξ ^ ^Ά 250 mu

(£ 17 βοά).

(d) dl-13ß-Eth.yl-20 ^ -hydroxy-6-meth.ylen-18.19-dinor pregn-4-en-3-one

To a stirred slurry of dl-13ß-ethyl-6-hydroxymethyl-3-methoxy-18,19-dinorpregna-? _{A trace of 8N sulfuric acid is added to i} 5-dien-20 ^ -ol (100 mg) in methanol (1.0 ml) at room temperature. The solution takes place immediately after the addition of the acid and the renewed precipitation

909886/1667

ORIGINAL BATHROOM -35-

takes place after 2 minutes. After 5 minutes the precipitate is filtered and gives 40 mg of colorless product, melting point 160 to 165 ^° C. and 215 to 222 ^° C.; A jjj ^ £ 2.96, 6.04, 6.18, 6.50 / U; λ ^ H _{265 fflu} (^ _{11 500) #}

(e) dl-13ß-ethyl-20 (-h.ydrox.Y-6a-meth.yl-18.19-dinorpregn- 4-en-3-one

A mixture of dl-15β-ethyl-20 ^ ~ hydroxy-6rmethylene-18,19-dinorpregn-4-en-3-one (650 mg), cyclohexene (1.95 ml) and Pd / C (5SIi, 150 mg ) in absolute ethanol (32.5 ml) is refluxed for 45 minutes. The mixture is diluted with ether and filtered through filter aid. A trace of concentrated hydrochloric acid is added and the solution stripped under vacuum _β Recrystallization of the solid residue from ether provides 0.605 g of colorless product, mp 162-168 ⁰ C; Λ JJ * 2.94, 6.05, 6.23 / U; λ ^ ° ^Η 241 mu (£ 14,800); KMR has 4H at 5.85 ppm, 17H at 3.78 ppm (triplet), 6α. CH- at 1.18 ppm (doublet, J 2 cps) and 21 CEU at 1.0? ppm (doublet, J 2 cps).

Analysis; calculated for Ö22 ^ 34 ⁰ 2 ^ ^: 79.95 ^c > ¹⁰ »37 ^H found (#): 79.58 C, 10.24 H.

Example 2

13ß-ethyl-6a-methyl-18 _% 19-dinorpresn ~ 4-en-3 «20-dione To a solution of dl-13ß-ethyl-20 _< ^ -hydroxy-6a-methyl-18,19-dinorpregn-4 -en-3-one (600 mg) in acetone (30 ml) is added ^{dropwise Jones reagent at 0} ° C. over 5 minutes

90988 6/1667 -36-

(8N chromic acid, 0.50 ml) added. Stirring is continued at ^{0 0 0 for a} further 10 minutes and excess isopropanol is added. The mixture is diluted with ether, filtered through filter aid, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, and stripped under vacuum. The solid residue is recrystallized from ether to give 0.37 g of whitish colored product,

Melting point 143 to 146 ⁰ C; λ jjjr 5.90, 6.00, 6.24 / 1;

QIcLjC /

ϊί £ ^Η 241 mu (£ 15,900); KMR has 4H at 1.09 ppm

UlcLJrC /

(Doublet, J 6 cps).

Analysis: calculated for C ₂ 2 ^H 32 ^Q 2 ^ ^{: 00} ^ ^G »^» 53 H found (JIS): 80.61 C, 9.33 H.

Example 3

13β-Eth.yl-20 ^ -h.Ydrox.y-6-meth.yl-18 «19-dinorpr egn-4.6-dien-3-one

A mixture of dl-13ß-ethyl-20 ^ -hydroxy-6-methylene-18,19 dinorpregn-4-en-3-one (10Q rag), sodium acetate (50 mg) and Pd / C (5 ^, 15 mg ) in absolute ethanol (30 ml) is refluxed for 11/2 hours. The mixture is cooled to about 23 ⁰ C, diluted with ether, filtered through filter aid, washed with saturated aqueous sodium bicarbonate and then brine, stripped over anhydrous sodium sulfate and dried under vacuum ·. The solid residue is recrystallized from ether with the formation of 22 mg of colorless product; Melting point 204 to

909886/1667 ~ ⁵⁷ ~

205 ^° C; λ JjJ * 2, .91, 6.05, 6.18, 6.51 / U; λ f £ ^E 290 mu (£ 22,800) ·, KMR has vinyl protons at 5.93 ppm and 6.03 ppm »17H at 3.75 ppm, 6 OH ₅ at 1.80 ppm and 21 CH ₅ at 1.12 ppm (doublet, J 5 »5 cps).

Example 4

13ß-Ethyl-17 (x-hydroxy-6a-methyl-18 »19-dinorpresn-4-en- 3ι20-dione acetate

(a) dl-13ß-ethyl-3.17-dihydroxy-18 «19-dinorpregna-3.5-dien-20-one diacetate

A solution of dl-13ß-ethyl-17 "-hydroxy-18,19-dinorpregn-4-en-3,20-dione (1.10 g) in ethyl acetate (10 ml) containing acetic anhydride (11, 2 ml) and perchloric acid (0.011 ml) is stirred at room temperature for 5 minutes. The resulting yellow solution is diluted with ether, washed with saturated aqueous bicarbonate solution, then brine, dried over anhydrous sodium sulfate and stripped off under vacuum Resinous residue from methanol gives 1 »Q3 g of colorless product, melting point 182 to 191 ° C | λ J ^ 5.71, 5.80, 5.89, 6.01 and no hydroxyl absorption; λ ^ ¹¹ 245 mu (£ 17 6QQ) ·, KMH. Has vinyl protons at 5.47 ppm and 5.76 ppm, two acetate methyls at 2.11 ppm and O ₂₁ methyl at 2.09 ppm.

(b) dl-13ß-ethyl-17ofc-hydroxy-18.19-dinorpregn-4-en-3.20-dione-acetate

A solution of dl-13ß-ethyl-3,17-dihydroxy ~ 18 _t 19-dinor- 909886/1667 -38-

pregna-3 »5-cLien-20-one diacetate (5» 40 g) in tetrahydrofuran (108 ml) and methanol (108 ml) is mixed under nitrogen at ⁰ ° C. with a 2 solution of potassium hydroxide in methanol (108 ml) are added. Stirring is ^{continued at 0} ° C. for 25 minutes. The scaffold is poured into saturated aqueous sodium bicarbonate, extracted with ether and the organic layer washed with water, then brine, dried over anhydrous sodium sulfate and stripped under vacuum to give a colorless solid. Recrystallization from ethyl acetate / hexane yields 4.22 g of colorless product, mp 194- 192 to ⁰ C; λ ^ 5.80, 5.84, 6.01, 6.22

(c) dl-13ß-Eth.yl-17a-h.ydrox.y-3-methox.y-18.19-dinor pregna-3,5-dien-20-one-acetate

To a suspension of dl-13ß-ethyl-17-hydroxy-18,19-dinorpregn-4-en-3,20-dione acetate (3 * 0 g) in dioxane (15 »9ml) is methyl orthoformate (4.0 ml) and a solution with p-toluene sulfonic acid (0.16 g) and at room temperature Added methanol (0.36 ml) in dioxane (1.75 ml). The steroid dissolves after stirring for 5 minutes and that Stirring is continued for an additional 55 minutes. Pyridine (8.5 ml) is added and the mixture diluted with ether. Then there is washing with water, saline solution, drying over anhydrous sodium sulfate and stripping under vacuum provides a resin. The crystallization from methanol containing a trace of Fyri & in

909886/1667 ~ ³⁹ ~

BATH ORIGINAL

193828?

1.81 g of colorless product, mp 153-166 ⁰ Cj ^{5ϊ79) 5 '83}

(d) dl-13ß-Eth.yl-6-form.yl-17a-h.ydroxyT3-methoxy-> 18 «19- dinorpreKna-3 <3-dien-20-one ~ acetate

A solution of distilled phosphorus oxychloride (1.50 g) in ethylene dichloride (9 »0 ml) is added over 30 minutes ^{at 0} ° C. to a solution of distilled dimethylformamide (7.25 mL) and distilled ethylene dichloride (3 | 0 ml). After stirring for an additional 10 minutes at ⁰ ° C., pyridine (1 drop) is added and then a solution of dl-13β-ethyl-17oc-hydroxy-3-methoxy-18,19-dinorpregna-3,5-diene-20- on acetate (1.70 g) in ethylene dichloride (27 ml) containing pyridine (15 drops) was added all at once. After stirring for 1 hour, the red solution at ^{0 0} O, a solution of sodium acetate (12.0 g) in water (125 ml) is added and the mixture is stirred vigorously for 10 minutes. The mixture is vigorously stirred with ethyl acetate. The organic layer is washed with saturated aqueous sodium bicarbonate, then with water until the wash liquors are colorless, dried over anhydrous sodium sulfate and stripped under vacuum. Trituration of the resulting resin with ether / hexane gives 1.29 g of yellow colored product, melting point 182 to 187 ⁰ O; λ ^ 5 »78, 5.83, 6.02, 6.19 (very strong), 6.28 (shoulder), 6.40 (shoulder); Λ ^ ^H 220 n> u (£ 9 400), 322 mu. (£ i5 800).

-40-909886 / 1667

1938293

(e) dl-13ß ~ ethyl-17a-hycLroxy-6-hyaroxymethyl-3-metho3cy-

18.19-dinorpregna-3.5-dien-2Q-on-ac etat To a solution of dl-43ß-i £ bhyl-6-iormyl-17-bydro3cy-3-methoxy-18 _f 19-dinorpregna-3,5-diene -2Q-on-> acetate (1.0 g) in tetrahydrofuran (20 ml) is added to a solution of lithium tri-t-butoxyaluronium hydride (1.24 g) in tetrahydrofuran (20 ml) under nitrogen at room temperature . The mixture is stirred for 20 hours at room temperature and poured into ice water. Diluting with Ither, washing the organic layer with saturated aqueous sodium bicarbonate, then brine, drying over anhydrous sodium sulfate, and stripping under vacuum provides a resin. Recrystallization from ether / hexane gives 0.78 g Eroduktj melting point 157-162 ⁰ C; λ 5J * 2.90,

Hl el Jt

5.80, 5.88, 6.12 and 6.22 / Uj λ ^ ⁰ ^ 248 bu (£ 18,700).

(f) dl-13ß-ethyl-17 <x * -h.hydroxy-6-meth.ylen-18.19-dinorpregn- 4-en-3 «2Q-dione acetate

To a solution of dl-13ß-ethyl-17-hydroxy-6-hydroxymethyl-3-methoxy-18,19-dinorpr © gna-3,5-aien-20-on ~ ac «did (0.73 g) and oxalic acid dihydrate (0.73 g) in methanol (73 nil) water (30 ml) is added at room temperature. After 5 minutes a precipitation begins form. After 45 minutes at room temperature, d & s Mixture poured into saturated aqueous sodium bicarbonate, extracted with ether, the extract with brine washed, dried over anhydrous sodium sulfate

-41- 90 9886/166 7

and stripped off under vacuum · The residue is triturated with ether / hexane and yields 0.53 g of product, melting point 226 to 252 ⁰ O (turns brown); λ *? * 5.80 »

UJ el A-

5.88, 6.00, 6.19, 6.29, 10.93 / ij λ ^ ^H 266 mu (£ .10,900).

dl-13ß-ethyl-17a-h.ydr oxy-6a-methyl-18,19-dinorpr egn- 4-en-3 «20-dione-ac etat

Using the same conditions as in Example 1, step (e), the compound of this example, step (f) is converted to the title compound which has a melting point of 160 to 163 ° C; ⁵ » ⁸⁰ ' ⁵ ' ⁸⁴ (shoulder), 6.01, 6.22 / U ₅ A ^ 240 mu.

Analyzes calculated for C ₃₄ IW ^ (#): 74- »57 C, 8.7 H found (#): 74.27 O, 8.65 H

Example 5

13ß-Eth.yl-17a-hydroxy-6-met h.yl-18 «19-dinorpregna-4« 6-diene-3 * 20-dione

Following the procedure of Example 3, 13β-ethyl-17α-hydroxy-6-methylene-18,19-dinorpregn-4-en-3,20-dione is obtained converted to the compound indicated in the heading

Example- 6

-18,19-dinorpregn-4-en-3-oii-20 ~ ol-acetate

and 1 gfl ^^ thyl ^ eo ^ -brom-IB »19-dinorpr egn-4-en ~ 3-on-2Q-ol acetate

909886/166 7

(a) 13β-Ethyl-18.19-dinorpreKna-3.5 (6) -diene-5.20-dione- 3 «20-diacetate

13β-Ethyl-3-methoxy-18,19-dinorpregna-2,5 (10) -dien-20-ol is dissolved in a mixture of methanol : concentrated hydrochloric acid: water, 90: 6: 4 (30 ml) for one hour hydrolyzed with stirring. The product is immediately filtered off and washed with water. After drying, the crude 13β-ethyl-18,19-dinorpregn-4-en-3-on-20-ol (0.75 g) has a melting point of 170 to 175 ° C; Λ f * ° ^H 242 (£ 14,400).

IR shows 6.01 / U and 6.19 / U.

This material is dissolved in a mixture of acetic anhydride (4.8 ml), ethyl acetate (45 ml) and 70% perchloric acid (0.01 ml) suspended and stirred for 15 to 20 ^ minutes. The excess acetic anhydride is removed by shaking Destroyed with saturated sodium bicarbonate solution and the organic layer evaporated, giving the title designated product.

acetate

13-ethyl-18,19- <iinorpregna-3,5 (6) -diene-3,20-diol-3,20-diacetate (1 g) is added to a mixture of acetone (23 ml), water (6 ml), sodium acetate (0.7 g) and acetic acid (0.7 Bl) added. The mixture is cooled to 5 ° C, then treated with 8.3 g of N-chlorosuccinimide. After 11/4 Hours water is added and the product with ether

909886/166 7

extracted. The organic layer is evaporated and the product obtained as a residue.

(c) 13β-ethyl-6o> -broine-18. ^< 19-dinorpregn-4-en-3-one'-2Q-Ol "> acetate

The procedure of step (b) is repeated, wherein one N-brorasuccinimide used instead of the chlorine compound, whereby the designated product is obtained

Example 7

13ß-Eth.Yl »6 ~ chloro-18,19-dinorpregna-4« 6 «dien» 3-one-20 ~ olacetate and 20-alcohol

(a) 13β-Ethyl-18.19-dinorpregna-4.6-dien-3-on-2Q ^ ol-acetate

The product of Example 6, Stuf® (o) is in dimethyl- ' formamide (50 ml) with 3 g of potassium carbonate for 1 hour Refluxed nitrogen. The substance is filtered off, the filtrate is poured into water and washed with ether extracted. Evaporation of the solvent gives the compound identified in the heading.

(b) 13β-Ethyl -18.19- dinor-6a, 7a-oxidopregn-4 ~> en-3-one-20r-ol-acetate

13β- £ ethyl-18,19-dinorpregna-i |. ₉ 6-dien ~ 3 ~ on-20-ol acetate (1 g) in chloroform (50 ml) is treated with monoperphthalic acid (24 mr, 0.67 M) for 48 hours at room temperature. The organic phase is washed with saturated sodium bicarbonate

909886/1667

then washed with brine and over sodium sulfate dried · Evaporation of the solvent gives the compound named in the heading.

(c) 13β-ethyl-6-ohlor-18.19-dinorpregna-4,6-dien-3-one- 20-ol-acetate and 20-alcohol

13β-Ithyl-18,19-dinor-6a, 7 <x -oxidopregn-4-en-3-one-2O-ol acetate (1 g) is suspended in glacial acetic acid (30 ml). A slow stream of dry hydrogen chloride is bubbled through the mixture at a temperature near the freezing point of acetic acid (16.6 ⁰ C). After 2 to 6 hours, the mixture is poured into ice water and extracted with benzene ether (10: 1). The organic layer is washed free of the acid, then dried and evaporated to give the compound identified in the title. Treatment of this material with 2% methanolic potassium hydroxide provides the corresponding alcohol at C-20.

An optional method of making the one in the heading The compound referred to consists in the fact that the 13β-fchyl-6cc-chloro-18,19-dinorpregn-4-en-3-one-20-ol acetate from Example 6, step (b) (1 g) in JLfchylacetat (25 oil), acetic acid (5 ml) and used with chloranil (2 g) reflux under nitrogen for 24 hours. That Mixture is cooled, washed with sodium hydroxide solution (10 #, then washed with brine and dried «. Evaporate

909886/1867

supplies 13β-ethyl-: 6-chloro- ^/ 18,19-dinorpregna ~ 4 _t 6-dien-3-one-20-ol acetate.

The procedure of this example, step (c) is repeated, using dry hydrogen bromide and hydrogen fluoride instead of hydrogen chloride. Man In this way, 13β-ethyl-6-bromo-18,19-dinorpregna-4,6-dien-3-one-20-ol acetate is obtained and 20-alcohol and 13ß- Ethyl 6-fluoro-18,19-dinorpregna-4,6-diene - $ - on-20-olacetate and 20 alcohol.

Example 8

13β-Ä ^v thyl-6a-ohlor-18. ^/ 19-dinorpregn-4-en-3> 20-dione-17a-ol acetate

(a) 13β-Eth.yl-18.19-dinorpregna-3,5 (6) -dien-20-one-3 «17 <fcdiol diacetate

Using the same conditions as in Example 6, step (a), IJß-Ethyl-i-methoxy-ie ^ -dinorpregna-2.5 (10 > -dien-20-on-17o »-ol to that indicated in the heading Compound converted.

(b) 13βHfcb h.yl-6tti-chloro - 18 »19-dinorpr erai - ^ - en-3 , 2Q-dione-17oE & -ol - acetate

Using the same conditions as in Example 6, step (b), 13β-Ä ± hyl-18 _l 19-dinorpregna-3,5 (6) -dien-2O-one-3 »17aä-diol diacetate results in the product converted·

-46- 809886/1867

. ■■■; - 46 -

Example 9

13ß "ethyl-6 ~ chloro-18.19-dinorpregna» 4 jp-diene-3 «2Q-dione- 17a-ol-acetate and 17a-alcohol

(a) 13ß-ethyl-18.19-dinorpreg; na-4,6-dione-3 «20-dione-17aol -acetate

The product of Example 8, step (b) is made with dimethyl formamide and calcium carbonate following the procedure of Example 7 »stage (a) heated and obtained the designated compound.

(b) 13β-Eth.yl-18.19-dinor-6a, 7oc-oxidopregn-4-en-3.20-dione-17a ^ ol-acetate

Using the same conditions as in Example 7, step (b), 13β-ethyl-18 _t 19-dinorpregna-4,6-diene-3 »20-dione-17a-ol acetate is converted to the compound designated in the heading .

(c) 13β-Eth.Yl-6-chloro-18 «19-dinorpr egna-4-. 6-diene-3.20-dione-17a ^ ol-acetate and 17a-alcohol

B-using the same conditions as in Example 7, step (c), 13ß-ethyl-18,19-dinor-6a, 7 (X ₅ -OXIdOPrOgHa-4-en-3 »20-dione-17a-ol- acetate converted to the compound designated in the heading. The dl form has a melting point of 198 to 200 ° C; λ J ^ £ 5.78, 5 »85, 5» 99, 6.23 (shoulder) j λ ^^ 283 fx (£ 23 QOO).

Analysis: calculated for CgxHgQClO ^:

Ws 68.23 O, 7.22 H, 8.76 OI found (#) 't 68.60 O, 6.56 H, 8.79 Cl. 909806/1687

Optionally, when using the conditions of the second process of Example 7, step (c) 13β-ethyl-6-chloro-18,19-dinorpregn-4-en-3,20-dione-17a-ol aetate converted to the connection named in the heading "

The 17-acetate group of the compound of this example becomes with 2 # strength methanolic potassium hydroxide according to Example 7 hydrolyzed and obtained the 17a alcohol.

In a similar way, according to the procedure tob Example 7, the corresponding 13β-ethyl-6-bromo ° 18,19-dinorpregna-4,6-diene-3j20-dione-17a-ol-acetate and the 17-alcohol and 13β -Ethyl-6-fluoro-18,19-dinorpregna-4,6-diene-3 ₉ 20-dione-17oc-ol-acetate and 17-alcohol produced.

Example 10

The method of Example 1, step (e) is repeated, instead of IJβ-ethyl ^ O ^ -hydroxy-e-methylene-18j19-dinorpregna-4— en-3-one stoichiometric amounts of the following compounds are used:

-48-909886 / 1687

193828 $

CH ₂ CIL CH ₂ CH CH ₂ CH ₃ CH ₂ CH ₃

X I. C (H) OH E. C (H) OH B. C (H) OH H C (H) OH OCOCB- CsO OH C = O
CO OCOCE ₃
OCOCH ₂ C (H) OCOCH- B.

The following compounds are obtained 1

H ₂ CH ₃

B B B

900886/166

CH ₂ CH ₃ CH ₂ CH ₃

X CO

C = O CeO C (H) OCOCH ₃

Y OH

OCOC

H ₃

Example 11

The procedure of Example 3 is repeated, nan instead of 13 ^ -ethyl ^ 2O-hydroxy-6-methylene-18 _t 19- "dinorpregn-4-en-3-one stoichiometric amounts of the corresponding 6 * -Methylenverbindungen of Example 10 ver turns. There are obtained the following compounds!

R. X I. CH ₂ CH ₂ CH ₃ C (H) OH H CH ₂ (CH ₂ ) ^ CH ₃ C (H) OH H wJl Y ^ f Π » M 0 ± C (H) OH H CH ₂ CH ₃ C (H) OH OCOCH ₃ CH ₂ CH ₃ C-O OH CH ₂ CH ₃ C-O OCOCH ₃ CH ₂ CH ₃ C-O OH ₂ CH ₃ C (H) OCOCH ₃ H 903686/1667

Using the same process, 13β-ethyl-6-methylene-18, 19-dinorpregn-4-en-3-2O-dione is converted into 13β-ethyl-6-ethyl-18 _f 19-dinorpregna-4,6-diene-3 , 20-dione rearranged

Example 12

The process of Example 6 with steps (b) and (o) is repeated, using instead of 13β-ethyl-18,19-dinorpregna-3 »5 (6) -diene-320-diol-3» 20-diaoetate atochio-Bietrisohe amounts of the following compounds used)

CH ₅

H ⁵ OCO

ltd X I. CH ₂ CH ₂ CH ₃ C (H) OCOCiL H CH ₂ (CH ₂ ) ^ Cl i- C (H) OCOCH ₃ H CH ₂ CH ₃ C (H) OCOCH ₂ (CH ₂ ) ^ CH ₃ H CH ₂ CH ₃ C-O « CH ₂ CH ₃ C (H) OH O! CH ₂ CH ₃ C (H) OCOCH- O

R ³

CH ₃

OH,

OCOOH ₃ CH ₃

The following connections are obtained

-51-

.dp

R. χ T Cl CHgCHgCH CH (H) OCOCHj H Br CHgCHgCH C (H) OCOCH ₅ H . Cl CHg (CHg) ^ CHj C (H) OCOCHj H Br CHg (CHg) ^ CHj C (H) OCOCH ₃ H Cl CHgCHj C (H) OCOCHg (CH ^) ₄ CH ₃ H Br CHgCHj C (H) OCOCH ₂ (CH ₂ ) ^ CH, H Cl CHgCIL C-O H CHgCHj C = O Ξ Cl CHgCHj C (H) OH OE Br CHgCHj C (H) OH OH Cl CHgCHj C (H) OCOCHj OCOCHj Br CHgCHj 0 (H) OCOClL OCOCH ₃ Example 13 .

The process of Example 7 »step (c), the chloranil dehydrogenation is repeated, instead of 13ß-ethyl-6a-chloro» 18,19-dinorpregn-4-en-3-one ~ ol-ao etat stoichiometric amounts of Products from Example 12 used. The following compounds are obtained in this way.

CHgC

HgCH ₃

C (H) OCOCIL

C (H) OCOCL

C (H) OCOCH

C (H) OCOCH

C (H) OCOCHg (CHg) ₄ CH ₃

C (H) OCOCHg (CHg) ₄ CH ₃

CHgCH ₃ C (H) OH CH-CH, C (H) OH CHgCH ₃ C (H) OCOCaL ■ WIL VUn C (H) OCOCH ₃ example 1

Y Cl H Br H Cl H Br H Cl H Br H Cl H . Br H Cl OH Br OH Cl OCOCH ₃ Br OCOCB-

The procedure of Example 7 »Step (0), the opening of the 6a, 7oc epoxy ring with hydrogen chloride, hydrogen bromide or hydrogen fluoride is repeated, instead of IJß-ethyl-ISj ^ -dinor-ea ^ a-oxidopregn - ^ - en-3-on-20-ol-acetate used stoichiometric amounts of the following compounds:

- Y

CHgCHgCHj

CHgCHj CHgCHj

X Y C (H) OCOCHj H C (H) OCOCHj H C (H) OCOCHg (CHg) ₄ CHj H C = O H C (H) OH OH C (H) OCOCHj OCOCH ₅

CHgC

The following connections are obtained!

CE

- Y

X γ 7th Z C (H) OCOCHj H Cl C (H) OCOCHj H Br C (H) OCOCHj H Γ C (H) OCOCHj H Eq G (H) OGOCH. H bar §IiÜ6 / 16i

R X Y Z

C (H) OCOCH ₃ HF

C (H) OCOCH ₂ (CH ₂ ) ^ CH ₃ H Cl CH ₂ CH- CCHXXMCtjCCB ^ CHj H Br CH ₂ CH ₃ C (H) ₂ OCOCH (CHG) ₄ CH ₃ HF

CH ₂ CH ₃ C = O ^{H C1}

CH ₂ CH ₃

C = O H Br

CH ₂ CH ₃ • C = O

CH ₂ CH ₅ C (H) OH

CH ₂ CH ₃ C (H) OH -

CH ₂ CH ₃ C (H) OH

CH ₂ CL C (H) OCOCH ₃ CH ₂ CIL C (H) OCOCH ₃ CH ₂ CH ₃ C (H) OCOCH ₃ Example 15

13ß-Äth.yl-17a-h.ydiOx.y-6-met h.yl-18 ₁ 19-dinorpr eKna-4-, 6-

serve-3 120-dione »ac etat

(a) dl ~ 13ß-Eth.yl « ^/ l7a-h.hydroxy-6-hydroxymeth.yl-3-methoxy- 4

OH Cl OH Br OH F. OCOCH ₃ Cl OCOCH ₃ Br OCOCH- Γ

To a solution of dl-13ß-ethyl-6-formyl-17a-hydroxy- ^ -methoxy-ie ^ i ^ dinorpregna ^ j ^ dien ^ O-on-acetate (I ₁ O g) in tetrahydrofuran (freshly distilled, 20 , 0 ml) under nitrogen at room temperature a solution of lithium tri-t-buto.xyaluminium hydride (1.24 g) in tetrahydrofuran (freshly distilled, 20.0 ml) is added all at once.

-55-

given. After 20 minutes at room temperature, the mixture is poured into ice water. Extraction with ether, washing the organic layer with saturated aqueous sodium bicarbonate, then brine, drying over anhydrous sodium sulfate, and stripping under vacuum provides a resin. Crystallization from ether / hexane gives 0.78 g of a slightly yellow solid, melting point 157 to 162 ° 0; λ ™ £ 2 ₅ 9O ₉ 5.80 and 5.88 / U; ^^ _χ ^Η 248 mu (£ 18,700).

Cb) dl-13ß-Ethy1-17a-hydroxy-6-methylene-18.19-dinorpregna- 4- en-3 »20-dione-acetate

To a solution of oxalic acid dihydrate (3.2 g) in methanol (320 τηΐ) is dl- ^ ß-ethyl-e-hydroxymethyl ^ -methoxy- 18,19-dinorpregna-3,5-dien-20- * on acetate (3 »00 g) added. Water (132 ml) is added and the mixture is stirred at room temperature for 45 minutes. The mixture is poured into saturated aqueous sodium bicarbonate, extracted with ether and the extracts washed with brine and dried over anhydrous sodium sulfate. Evaporation in vacuo provides a solid which is triturated with ether to give 2.25 g of slightly yellow product, m.p. 225-246 ° C (decays); Λ J ^ 5.80-5.83, 6.02 / U; λ j ^ £ ^H (with a previously prepared sample) 226 mu (£ 1O 900).

909886/1667

4,6-di en-3 ₁ 20-dione-ac etat

A mixture of dl- ^ ß-ethyl- ^ a-hydroxy-ö-methylene-18,19-dinorpregna-4-en-3,2Q-dione acetate (0.50 g), Pd / G (5 #, 75 mg) and sodium acetate (0.25 g) in absolute Ethanol (15 ml) is refluxed for 45 minutes, after which a sample shows UV absorption at 287 mu and no absorption at 266 rou. After cooling to room temperature the mixture is filtered through filter aid and diluted with ether. Wash with saturated aqueous sodium sulfate and stripping under vacuum yields a resin. Column chromatography over Woelin Neutral alumina grit III using $ 100 benzene as the eluant yields 0.28 g colorless Product after crystallization from ether / hexane,

Melting point 190 to 191 ° C; J ^ £ 5.80-5.90, 6.09,

6.21 (weak), 6.30 Ai (weak); ^ ^H 287 mu (24,200); KMR has methyl singlets at 1.93, 2.10 and 2.14 ppm and vinyl protons at 5-93 and 6.02 ppm.

Analysis: calculated for C24 ^H 32 ° 4 ^ '' ^ * 97 C, 8.39 H found (#): 74.84 C, 8.38 H.

The 6-methyl compounds of this invention can also by hydrolysis of a compound of the formula

Θ09886 / 1667

-57-

wherein K is a protected oxo group which, together with the unsaturation in rings A and / or B indicated by the dotted line, is acid hydrolyzable to a 4-, 5-ethylenic 3-ketone. Protected oxo groups are known in steroid chemistry and suitable starting materials can be prepared from known 6-methyl compounds, for example 6-methylgonatrienes described in British Patent 1,103,205. Preferred starting materials for the above method is 2.5 (1O) dienes, where K is an alkoxy group or 3-acyloxy-3 '5- <, _WO rin K is Ïîèñê an acyloxy group. X can be protected, for example when it is carbonyl, by a ketal group. The product of the above reaction has predominantly the 6oc-methyl group, but can also contain the 6a-methyl compound.

The 3-alkoxy-2,5 (10) -diene starting materials for the above process, wherein X is hydroxymethylene and X is hydrogen, can be prepared from 13β-alkyl-3-alkoxy-6-methylgona-1 _S 3.5 (10 ) -trien-17-ones by the method of British Patent 1,103,205. The 17-one starting material is ethynylated according to a standard process, after which the conversion of the resulting 17cc-ethynyl-17ß-ol is carried out by acylation and treatment with N-bromoacetamide yields a 17a-dibromoacetyl group and then by debroraation

909886/1667

-58-

with zinc and acetic acid a 17cx-acetyl-17 ^ -s ^L getoxy compound is obtained, which in turn is the Birch reduction to form a 17ß- (a-hydroxyeth, yl) -3-alkoxy-13ti-alkyl-6-methylgona-2, 5 (10) -diene compound, which is then hydrolyzed according to the method of the invention given above. The production of the starting material is explained by the following process sequence:

-59-

90 988 0/166?

"Co".

938283

H OH

! "■ -Bromoacetamide

IBOH

(t)

909886/1667

Other starting materials (a) for the hydrolyzing process can for example be prepared by selective oxidation of intermediate (h) prior to hydrolysis to give a compound wherein X is carbonyl. A starting material (a) wherein K is Alkoxy group, accompanied by ethylenic bonds in the 2- and 5 (10) -positions, and Y hydroxyl or acyl can be made by the following process:

-61- 909886/1667 -

(3)

''H

70. ' Porchloric acid; AthyX acetate

KOt-Bu

in t-BuOH

(k)

(1) Eeraic acid (2)

OS

9886/1667 ORIGINAL BATHROOM

A 17-acetyl-3-alkoxy-13β-alkyl-6-methylgona-1,3,5 (1O) -triene (j) which is obtained, for example, by oxidation including A-aromatization of the above-mentioned compound (A) is obtained to the corresponding 17β-acetyl- ^ a-hydroxy compound 1 either by treatment with potassium t-butoxide in t-butanol in the presence of oxygen or by treatment with an acid anhydride (R 00) ^ 0, in which R is a lower alkyl group, in 70 # perchloric acid and ethyl acetate are converted to give compound (K) which, after treatment with a peracid then with potassium hydroxide in methanol, gives compound (1). The compound (1) is coalized according to standard processes, for example with ethylene glycol in benzene with p-toluenesulfonic acid as a catalyst, whereby the ketal (m) is obtained by a Bireh reaction (for example Li in liquid ammonia in now of t-butanol) is reduced imiies? Eir.er forming compound (s), which is a Ausgasiijgc ^ «^ s ¹ IaI for process (a) to (b). After Hycli? C ^ j ax acid, to: Example hydrochloric acid in methanol, ~ fird the obtained V * -> ._ oir, -dung (b), where X is carbonyl and ϊ IJjdroxy (sum part., Ίei a compound o), obtain. The corresponding compound in which Y is acyl can be obtained by acylation by compound (o) to form the corresponding jjiy-bisoyl-jji ^ cLiens, the partial hydrolysis being

-63-909886 / 1667 _B a0 ORtGtNAL

(q) GE ₃

- o.ccsar

the compound (q) yields

A compound of the invention, the 4,5-ethylenic bond in the input A and. Eis © has unsaturation in ring B can be prepared by isomerization using standard procedures of the appropriate compound having a 5 (10) ethylenic bond. This latter compound can be obtained, for example, by treatment with a 3-alkoxy-2,5 ( ^> 10) -diene under mild hydrolyzing conditions, such as, for example, with oxalic acid.

909886/1667

-64-

BATH ORIGINAL

Claims (1)

Pat * -en. tan. Sayings : wherein R © ine alkyl group with from 2 to 6 carbon Λ 1 atoms, X is C «O or G (H) OR, where R is hydrogen or a (lower) alkanoyl group, Y - H, OH or OCOR, where R is a (lower) alkyl group and either rings A and B have the formula wherein -C ^ -C ₉ - is a divalent radical of the formula or OH, k ¹ CH ₃ Z ^CH 2 wherein Z is chlorine, bromine or fluorine and Z is chlorine or bromine, provided that when XC = O and Y »H ₁ -Cg-Cr ₇ -a meaning other than or rings A and B have the formula -65- 909886/1667 BAD ORlGfNAL where W is an alkoxy group and V - GH ₂ OH or OHO « 2. A compound according to claim 1 characterized in that the rings A and B have the formula P and sofe _rn ine 6-methyl group in a saturated ring B is present, it has the α-configuration. 3 «connection according to claim 2, characterized in that that R is an ethyl group .. 4. Compound according to claim 2 or 3 characterized 1
indicates that R is an aoetyl group. 5 · Connection according to one of claims 2 to 4 thereby characterized in that R is a methyl group 6 · Compound of Formula ⁷ ■ '■ wherein R is an alkyl group of 2 to 6 carbon atoms, Λ Λ X is C-O or G (H) OR, where R is hydrogen or a ο is (lower) alkanoyl group, Y is »H, OH or OCOR, where R is a (lower) alkyl group and -Og-On- -66- 909036/1667 divalent remainder of the formulas or Cl Cl is. 7. Characterized connection according to claim 1! that rings A and B correspond to formula Q and W is a methoxy group. 8. Compound of Formula C% where R is an alkyl group having from 2 to 6 carbon atoms and Y «H, OH οι
(lower) alkyl group is atoms and Y ■ is H, OH or OCOR, where R ^{2 is} a 9. Compound of Formula wherein R is an alkyl group of 2 to 6 carbon atoms, X 909886/1667 -67- C = O or G (H) OH and X ¹ '■ is OH or OC0R ² , where R ^{2 is} a (lower) alkyl group © « 10. A compound according to any one of claims 6, 8 or 9 characterized in that R © in © is aetisyl group » 11. 13β-ethyl »20J ^: hydroxy-6-iBethyl-» 18 _f 19-dinorpregaa-4,6-dien-3-one. 12. 13β-Ethyl-6-methyl-18.19 "" dinorpregna-4,6-diene-3 ₁ 20-dione. 4,6-diene ~ 3.20-3100. . The 17-acetate test of the compound g @ aäß iaasp ^ iöh 13 16. 13β-Ithyl-6-chloro = 18 ₉ 19-dinorpregna 20-cI-acetato 17 o 13ß-ethyl-6a-ohlor-18 ₉ 19-dinorpr © gn-4 ~ © n-3 ₈ 20-dione-17a ~ ol «acetate. 18. 13ß-ethyl-6 ~ ehlor- = 18,19-dihorpr egna »4 _s 6 = di" © a-3,20- 901886/1667 - ^ ⁶⁸ " ⁵ BATH ORIGINAL dion-17a-ol acetate. 19th
diene-3,2O-dione. 20. 13β-Ethyl-20 £ - hydroxy-6a-methyl-18,19-dinorpregn - ^ - βη-3-οη. 21. 13β-Ethyl-17a ~ hydroxy-6a-methyl-18, igen- ^ , 20-dione-ac etat 22. 1 3β-Ethyl-17a-hydroxy-6-hydroxynjetliyl - $ - inethoxy-18,19-dinorpregna-3 * 5-diene-2O-on-acetate. 23. 13β-Ethyl-17a-hydroxy-6-methylene-18 _} 19-dinorpregn-4-en-3 j 20-diol acetate. 24 ·. 13β-Ethyl-6-hydroxymetlayl-3-methoxy-18,19-dinorpregna-3,5-dien-2O-ol. 25. 13β-Ethyl-20J ~ hydroxy-6-methylene-18,19-dinorpregn-4-en-3-one. 26. A method for producing a compound according to claim 1 characterized in that one (a) a compound of formula II is hydrogenated -69-SÖ9886 / 1667 with formation of a compound of the formula Id: ₃
(b) a compound of the formula II as defined above, rearranged to form a compound of the formula Ieί · -Y (ο) halogenated a compound of the formula XEI R ⁵ COO to form a compound of the formula If IF, • Y 808886/186? -70- (d) a compound of the formula If, as defined above, dehydrates to form a compound of the formula Ig (e) a compound of formula IV - Y reacts with a hydrogen halide to form a compound of the formula Ih? (f) a compound of the formula Ik - O.COR wherein X has the meaning given in claim 1 and 2
Z is methyl, bromine, chlorine or fluorine, partially hydrolyzed to form a compound of formula 1 * 3 90 & 886/1667 -71-BATH ORIGINAL - O.COB ² (g) selectively oxidizing a compound of formula to a compound of the formula "I. (h) a connection of the selective hydrolysis: formula forming a compound of Cf (i) its compound of formula Im 90988 6/166 7 selectively reduced to form a compound of the formula In a compound of the formula In, as explained above, «■ ρ] -H ₃ hydrolyzed to form a compound d «T · formula II K χ (k) a compound of the formula -pij ^ r _i? Oxogriippe is which together with} i * ö Ιΐΐ dea rings A and / or B, which is aEgeseigt by kLiids'i, du ^ & h acid too 909888/1667 -73- BATH a 4,5-ethylenic 3-ketone is hydrolyzable and X has the meaning given above or can be a protected carbonyl or hydroxymethylene group _} hydrolyzed to form a compound of the formula Id and / or the corresponding 6β-methyl compound, (1) a compound the formula χχ9 *. where 7? Is methyl, α-chlorine or α-bromine, isoerized to form a corresponding gon-4-en-3-one, (m) a compound of formula 1. (p) where W is an alkoxy group which is accompanied by ethylenic bonds in the 2- and 5 (10) -positions or 3- and 5-positions, formylated, if necessary with reconversion of the group Y or X to form a compound of the formula Im, as explained above, where the groups R, X, T., Z. Z, -Cg-Op-, H ₁ H and W have the meaning defined in claim 1 and R is a lower alkyl radical -74- 909886/1667 27. The method according to claim 26, characterized in that that R is an ethyl group, 28 · The method according to claim 26 or 27, characterized in that that a compound of formula II by exchange hydrogenation with an organic hydrogen donor is hydrogenated in the presence of a catalyst to form a compound of Formula Id. 29 «The method according to claim 28, characterized in that that the exchange hydrogenation with cyelohexene is carried out in the presence of a Palladium "" & uf "carbon catalyst. 3Q »method according to claim 26 or 27, characterized in that that a compound of formula II to form a compound of formula Ie by heating with a weak base in the presence of a noble metal catalyst is relocated 31 β method according to claim 30, characterized in that that the weak base is sodium acetate. 32. The method according to claim 30 or 31, characterized in, that the noble metal catalyst is a platinum or palladium catalyst. 33. The method according to claim 26 or 27 characterized -75-909886 / 1667 bad ORiGiMAL . - 75 - shows that a compound of the formula £ 11 with N-Öhlor-? © the N-bromosuccinimide with the formation of a? Connection of Formula If is halogenated. 3 #. Procedure according to A && pruoh 26 © & © r 27 &&& u & * © fo Seichnet that © ine connection of the JForm ©! If duroh Β & - ! strands with ChloraniX, forming © icea * Ve & bis & tia® der Formula is dehydrated «, 53 = method according to claim 26 or 2? da & eat? eüß ^ © ichnet that © in © connection of ¹ JFosiJel 1? with * @ ίε @ ® hydrogen halide under image? Ver & ind & ug ⁶ i @ r gapälB ÄMBOsneh 26 © äös ⁵ S? j © iE. ©? © s? © iadung d®2? # © thin θ s Hkali! 3 © uailfe | ^ © i £ id dung ύ, ΘΤ formula Xj paj & ml 37o procedure g © raäß lasppussli that the Hjdrcsl ^ s © sait ICaliumhydro2d. & is is joined ο 38 ο 7tr £ ahrer; geffiäß üaspni © li 26 or 2? dadm ^ e Reichn-st that θϊηφ ¥ © ^ biffi & isg d © ^ Ιθ ^ θθ! In the sm . m'v; v. "of the formula In dur @ ii © in M Kx-stal; selectively i Ö § Ö 8 6/1 6 6 39 ο Vρ - drive geralß Anspruöli 38 datm * ³ © ^ g © feafäas © i © M @ * _B gAD ORIGINAL that sodium borohydride or lithium tri-t-butoxyaluminum hydride is used as the metal hydride reducing agent. 40. The method according to claim 26 or 27, characterized in that a compound of the formula In with dilute mineral acid or an organic acid is added a compound of formula II is hydrolyzed. 41 _β Method according to claim 40, characterized in that dilute sulfuric acid or oxalic acid is used as the acid » 4-2. Process according to Claim 38 or 59, characterized in that a compound of the formula Im, in which W © ine is Mstaoxygruppe, is used " 43 » Υ · 52? £ ΰύχϊ" 3: ϊί gesäS Assspring 40 oeLsce 41 thereby gskenn- ^ oiaosrs, e.sß siae connection of the fcraiel In, where ¥ ■ ilne -Ms'tsliOSigrgr ^ pp ©; » is used" ;; &, ¥ srfoiii2? Ea. according to Ä.r> spruch- 26 or 2? dadiJi / oli can " L; 3ioImet _D. that the S'mfe (k) is carried out and E i: ia &i; -lk-s5v! f ;; - iipp® Lsi ;, äie durcii äthy2, ©; iisalis bindings ii- d & ü S => ~ <in ^r l 5 (10) * »or 5» »and J ^ StellmngeE feegleitet 009886/1667 BATH 45. The method according to claim 26, characterized in that step (m) is carried out and W © ine methoxy group is. 46. The method according to claim 26 or 27 essentially as described in one of Examples 1 to 14 _o 47 «The method according to claim 26 essentially as in Example 15 described. 48. Steroid compound, provided they are after one. procedure according to one of claims 26 or 27. 49. Steroid compound provided after a procedure according to any one of claims 28 to 35. 50. Steroid compound provided after a procedure according to one of claims 36 or 37. 51 · Steroid compound provided following a procedure according to any one of claims 38 to 41. 52. Steroid compound provided following a procedure was produced according to one of claims 42 or 43 « 53 · Steroid compound provided following a procedure -78-909886 / 1667 according to claim. 44 was made 54 ". UhezaL'iJ ^ ffni- ^ vbr ^ _; ,? £) for it was produced by a method according to claim 41 » 55 «Sterc-iöverftindufcg» provided they are following a procedure in accordance with Address 46 was produced 5Cf St ^ ciidTarl ^ ic ^ m ^ i * provided that it was made according to a procedure according to Au »p3? Uc> i 'Vf h ^ r ^ v» · ¹ ·; «!!"!;. 8, i9-dinorpregna-3,5- xfe-.i.-L'PifTO ^ .t.'is ^ fei! Ziib ^ re.-LtUKg dadiiToh marked, 5-ί.ΐ- ·>: ίπβ - fe ^ oily according to one of claims 2 to 6 Kiil β ILc 21 Ctaiter exclusion of 6-methylene compounds) '«Vid e \ ii ^ a pii & 3? S ¥?, Se-u.tic supports. 909886/166 7 BftD.OniuiiMAL