WO1998023634A1

WO1998023634A1 - Cycloalkyl steroids, method for the production thereof, pharmaceutical preparations containing same cycloalkyl steroids and the use thereof as medicaments

Info

Publication number: WO1998023634A1
Application number: PCT/EP1997/006542
Authority: WO
Inventors: Helmut Kasch; Klaus Schöllkopf; Karl-Heinrich Fritzemeier; Rolf Krattenmacher; Hans-Peter Muhn
Original assignee: Schering Aktiengesellschaft
Priority date: 1996-11-22
Filing date: 1997-11-24
Publication date: 1998-06-04
Also published as: AU5555198A; DE19649984A1

Abstract

Novel 16α, 17α carbocylic steroids of general formula (I), wherein R17=C2-C5 alcanoyl, but not acetyl, when R?2' and R3'¿ both mean a hydrogen atom, C¿2?-C5-(1-hydroxy)-alkyl, C2-C5 -(1-aroyloxy)-alkyl, C2-C5-(1-C1-C5-alkanoyloxy)-alkyl, C2-C5-1(aroyloxy)-alkyl, C2-C5-(1-aroyloxy)-alkyl, C2-C5-(2-hydroxy)-alcanoyl, cyano, (hydroxyamino)-carbonyl, (C1-C5-alcoxyamino)-carbonyl, C1-C5-(1 hydroxyimino)-alkyl, C1-C5-(1-C1-C5-alcoxyimino)-alkyl, C1-C5-(1-C1-C5- alkylimino)-alkyl, C1-C5-(1-C1-C5-alkanoyloximino)-alkyl, C1-C5-(1-alkylaminocarbonyloxy)-alkyl, C2-C5-(1-arylaminocarbonyloxy)-alkyl, R?13¿=methyl or ethyl, R?2', R3', R4'¿ mean individually a hydrogen atom or a methyl group, C2'-C3' mean a C-C- single or double bond, X means 2 hydrogen atoms, a hydrogen atom and a hydroxy group, a radical of formula -S-(CH¿2?)n-S- with n=2,3,4 or 5, an oxygen atom, a hydroxyimino-, C1-C6-alcoxy-, C1-C6-alcanoyl, C1-C6 alcoxycarbonylimino, C1-C6-alcoxyimimino, C1-C6-alcoxycarbonyloximino- or a C1-C6 alkanoyloximino group. The invention also describes a method for the production thereof. The compounds of formula (I) exhibit high progestogenic efficiency, and are suitable for the production of medicaments.

Description

Cycloalkyl steroids, process for their preparation, pharmaceutical preparations containing these cycloalkyl steroids and their use for the production of medicaments

The present invention relates to 16α, 17 -cycloalkyl steroids of the general formula L,

wherein

R ¹⁷ = C, -C ₅ alkanoyl, but not acetyl if R ² 'and R ³ ' each represent a hydrogen atom, C ₂ -C ₅ - (l-hydroxy) alkyl, C ₂ -C ₅ - ( IC ₁ -C ₅ alkoxy) alkyl, CC ₅ - (IC _r C ₅ - alkanoyloxy) alkyl, C ₂ -C ₅ - (1-aroyloxy) alkyl, C, -C ₅ - (2-hydroxy) -alkanoyl, cyano, (hydroxyamino) carbonyl, (-C-C ₅ -alkoxyamino) -carbonyl, CC ₅ - (l-hydroxyimino) -alkyl, C _r C ₃ - (1 -CC ₅ -alkoxyimmo) alkyl, CC ₃ - (l -C Cs-alkylimino ^ alkyl, CC ₅ - (l -CC ₅ - ^ kanoyloximino) alkyl, C ₁ -C ₅ - (l-alkylaminocarbonyloxy) alkyl, CC ₅ - (l-arylaminocarbonyloxy) - alkyl,

R ¹³ = methyl or ethyl,

R-, R ^{3 '} , R ⁴ ' independently of one another represent a hydrogen atom or a methyl group,

C ₂ -C ' _{3 is} a CC single or double bond,

X two hydrogen atoms, a hydrogen atom and a hydroxy group, a radical of the formula -S- (CH2) "- S- with n = 2, 3, 4 or 5, an oxygen atom, a hydroxyimino, -C-C ₆ - alkoxy-, means Alkoxycarbonyloximino- or CC _ö -Alkanovlαximinogruppe - Ci-C _ä alkanoyl, C _x -C ₆ -Alkoxycarbonylimino-, Ci-C _ö -Alkoximino-, CC. ₆

Ci-Cj-Alkanoyl stands for a straight or branched chain alkanoyl group with up to 5 carbon atoms, such as acetyl, propionyl, butyryl. Aroyloxy means an arylcarbonyloxy group, the aryl radical preferably being one

Is phenyl radical, or can also be a 1- or 2-naphthyl radical.

C ₁ -C ₅ alkyl substituted in the 1 position includes all possible radicals such as methyl, ethyl,

Propyl, i-propyl, butyl, i-butyl, pentyl, i-pentyl etc. which do not contain a tertiary 1-

Have carbon atom.

In the event that the alkyl group in the 1-position with a hydroxy, alkanoyloximino or

Alkoxyimino group is substituted, residues such as ethyl, propyl and branched residues such as t-propyl or t-pentyi come into question.

The C _r Cs alkoxy substituents mentioned are residues such as methoxy, ethoxy,

Propoxy, ∑ ^' propoxy, butoxy, r-butoxy.

Preferably means

R ¹⁷ = C ₂ -Cs-alkanoyl, in particular acetyl or propionyl, -C-C _$ - (V-hydroxy) alkyl,

R ^{13 is} equally methyl or ethyl,

X two hydrogen atoms, a hydrogen atom and a hydroxy group, or an oxygen atom.

A C-C double bond is particularly preferred for Ci-C'z.

The compounds mentioned below are particularly preferred according to the invention:

16α, 17-Cyclohexano-13ß-ethyl-17ß- [l'-oχo-] propyl-3-oxo-4,9-gonadiene

16α, 17α-Cyclohex-2 ', 3'-eno-13ß-methyl-17ß- [-oxo-] propyI-3-oxo-4,9-gonadiene

16α, 17α-Cyclohex-2 ', 3'-eno-13ß-ethyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gonadiene

16α, 17α-Cyclohexano-13ß-methyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gonadiene

17β-acetyl-16, 17 -cyclohex-2 ', 3 ^, -eno-13-methyl-3-oxo-4,9-goπadiene,

17β-Acetyl-16α, 17α-cyclohex-2 ', 3'-eno-13-ethyl-3-oxo-4,9-gonadiene. 16α, 17α-carbocyclic steroids with a 16α, 17α-cyclohexano and 16, 17α-cyclohex-3 ', 4'-eno ring are already known.

Kamemitzki et al. (J.Steroid Biochem. 16 (1982) 61-67) describe i.a. 16α, 17α-Cyclohex-3'-eno-pregn-4-en-3.20-dione and 16α, 17α-Cyclohexano-pregn-4-en-3.20-dione, which have proven to be effective gestagens in various test models . With the introduction of the double bond in the D'-ring, the gestagen activity decreases. The cyclohexeno compound has a low contraceptive effect, while the cyclohexano compound exhibits about two thirds of the contraceptive effectiveness of megestrol acetate.

DD 251 142 AI (Ponsold et al.) Shows 16α, 17ct-cyclohexano-17ß-acetyi-gona-4,9-dien-3-one. The corresponding 13-ethyl compound is also covered by the claim. The compounds have a high gestagenic activity. In the McPhail test, they are much more effective than progesterone. They are potential contraceptives.

17ß-substituted 16, 17-cyclohexano-estr-4-en-3-one (hydroxymethyl, formyl, hydroxycarbonyl, methoxycarbonyl and acetoxymethyl as 17ß substituents) are the subject of DD 277 684 AI. The compounds are characterized by a high level of binding to the progesterone receptor and have proven to be effective gestagens in the McPhail test on rabbits.

Finally, the DD 277 685 AI 16, 17α-cyclohexano-estra-4,9-dien-3-one, which as a 17ß substituent, a formyl, carboxyl, hydroxymethyl, alkoxymethyl, alkoxycarbonyl, aroyloxycarbonyl, acyloxymethyl - or wear aroyloxymethyl group. The 3 'and 4' positions in the D 'ring can be unsubstituted or methyl-substituted. Only 16α, 17α-cyclohexano-17β-hydroxymethyl-estra-4,9-dien-3-one is mentioned as an example. The compounds are distinguished by a high level of binding to the progesterone receptor and have been shown to be more effective in the McPhail test on rabbits compared to progesterone.

In contrast, 16α, 17-cyclohex-2 ', 3'-eno-steroids as such and new 16α, 17α-cyclohexano-steroids with additional combinations of substituents are not known.

It has now been found that 16α, 17α-cyclohex-3 ', 4'-eno-steroids can surprisingly be rearranged in a targeted manner into 16, 17α-cyclohex-2', 3'-eno-steroids. It was further found that the compounds of general formula I according to the invention with the new structural features (double bond in the D'-ring and / or extended 17β side chain) have a strong affinity for the progesterone receptor. They are clearly superior to the closest compounds known from the prior art with regard to gestagen activity in vivo. The compounds according to the invention are extremely effective gestagens which are suitable for maintaining pregnancies in both parenteral and oral administration. In combination with an estrogen, combination products are available that can be used for contraception and for menopausal symptoms. In addition, the compounds of general formula I according to the invention have an antiandrogenic partial action. Such a spectrum of action has not yet been described for the upcoming compounds of the prior art.

Because of their high gestagenπen effectiveness, the new compounds of general formula () can be used, for example, alone or in combination with estrogens in contraceptive preparations. But all other possible uses known today for progestins are also open to the new compounds.

Suitable dosages can be routinely determined, e.g. B. by determining the bioequivalence to a known progestogen for a particular use, for example an amount that is bioequivalent to 30 to 150 μg levonorgestrel for contraception.

The dosage of the compounds according to the invention in contraceptive preparations should preferably be 0.01 to 2 mg per day.

The gestagenic and estrogenic active ingredient components are preferably administered orally together in contraceptive preparations. The daily dose is preferably administered once.

All natural and synthetic compounds known to be active as estrogens are suitable as estrogens.

As natural estrogens, these are in particular estradiol and also its longer-acting esters such as valerate etc. or estriol.

However, preference is given to synthetic estrogens such as ethinyl estradiol, 14α, 17α-ethano-1,3,5 (10) -estratrien-3,17ß-diol (WO 88/01275), 14α, 17α-ethano-1,3,5 (10 ) -estratrien-3, 16α, 17ß-triol (WO 91/08219) or the 15,15-dialkyl derivatives of estradiol, and of these in particular 15,15-dimethyltradiol. Ethinyl estradiol is preferred as the synthetic estrogen.

The recently known estratriene-3-amidosulfonates (WO 96/05216 and WO 96/05217), derived from estradiol or ethinyl estradiol, which are characterized by small amounts hapatic estrogenicity are suitable as estrogens for common use with the compounds of general formula I.

Finally, the 14α, 15α-methyl steroids from the estrane series, in particular the 14α, 15α-methyl-17α-estradiol, and the corresponding 3-amidosulfonate derivatives should be mentioned.

The estrogen is administered in an amount equal to that of 0.01 to 0.05 mg of ethinyl estradiol.

The new compounds of the general formula (I) can also be used in preparations for the treatment of gynecological disorders and for substitution therapy. Because of their favorable activity profile, the compounds according to the invention are particularly well suited for the treatment of premenstrual complaints, such as headache, depressive mood, water retention and mastody ie. The daily dose for the treatment of premenstrual complaints is about 1 to 20 mg.

Finally, the new compounds can also be used as a gestagen component in the recently known compositions for female fertility control, which are characterized by the additional use of a competitive progesterone antagonist (HB Croxatto and AM Salvatierra in Female Contraception and Male Fertility Regulation, ed. by Runnebaum, Rabe & Kiesel - Vol. 2, Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group - 1991, page 245).

The dosage is in the range already specified, the formulation can be carried out as with conventional OC preparations. The additional, competitive progesterone antagonist can also be applied sequentially.

The pharmaceutical preparations based on the new compounds are formulated in a manner known per se by adding the active ingredient, optionally in

Combination with an estrogen, with those used in galenics

Carrier substances, diluents, possibly flavoring agents, etc., processed and converted into the desired application form.

For the preferred oral application, tablets, coated tablets,

Capsules, pills, suspensions or solutions in question.

Oily solutions such as, for example, are particularly suitable for parenteral administration

Solutions in sesame oil, castor oil and cottonseed oil, suitable. To increase the Solubilizers can be solubilizers, such as benzyl benzoate or

Benzyl alcohol can be added.

The compounds of general formula (I) can also be administered continuously by an intrauterine release system (IUD); the release rate of the active compound (s) is chosen so that the daily dose is within the dose ranges already specified.

It is also possible to incorporate the substances according to the invention into a transdermal system and thus to apply them transdermally.

The compounds of the general formula I are prepared according to the invention by 16α, 17α-cyclohex-3 ', 4'-eno-steroids of the general formula IL

woπn

R ¹⁷ '= acetyl, 1-hydroxyethyl, (ICC ₅ alkoxy) ethyl, (IC, -C ₅ alkanoyloxy) ethyl,

(2-hydroxy) acetyl,

R ¹³ , R-, R ^{3 '} and R ⁴ ' and alkanoyl and aroyl have the meanings given above under formula I,

are implemented according to scheme 1.

Scheme 1

ß Bromination 'd ehydrobromization

g) Oxidaύon derivatization

For the synthesis of the starting products to be used according to the general

Formula H, which ultimately leads to the end products of general formula I with the substituents mentioned there, is followed by synthesis routes A and B shown in Scheme 2 (Ponsold et al. DD 218369 and 218368; Kasch et al. DD 240545; Z. Chem. 26 (1986) 375-376, J. Practical Chem. 328 (1986) 903-905).

Scheme 2

a ') Cyansüylether synthesis (Ie3SiCN) b') POCl ₃ pyridine c ¹ ) MeMgBr d ¹ ) DLBAH reduction e ') Diels-Alder reaction

The compounds of the general formula I are prepared according to the invention by 16, 17-cyclohex-3 ', 4'-eno-steroids of the general formula II with the meaning given above (see scheme 1)

in step a) by catalytic hydrogenation of the 3 ', 4'-double bond in the condensed D'-ring in an alcohol-ether mixture using Pd / C as a catalyst in 16α, 17α-cyclohexano-steroids, in which the D'-ring none Contains double bond, and otherwise the radicals R ¹³ , R-, R ^{3 '} and R ⁴ ' have the same meaning as in formula II,

in step b)

Cyclohexano-steroids of the general formula (1) or Cyclohex-3 ', 4'-eno-steroids of the general formula H, which contain a 17β-acetyl group as a common structural feature, with equivalent amounts of a base, such as lithium butyl or lithium diisopropylamide, in an inert solvent treated and the resulting enolates at the C ₂ 'end of the 17ß-

Side chain alkylated with an alkyl halide, being compounds of general formulas 1 and 2 are formed in which the radicals R ¹³ , R-, R ^{3 '} and R ⁴ ' have the same meaning as in formula π and R ^{1T can} additionally be a C2-C5-alkanoyl,

in step c)

17β-alkanoyl-16α, 17α-cyciohex-3 ', 4'-eno-steroids of the general formula H or 2, if necessary by reducing the 17ß-Cι'-carbonyi group with a complex metal hydride to the corresponding 17ß [l'-hydroxy] - transferred alkyl steroids and the isomerization of compounds with a 3 ', 4'-double bond of the general formula II or 2 by means of a base in a solvent in the heat, whereby 17ß- alkanoyl- or 17ß- [l'-hydroxy] -alkyI -16α, 17α-cycIohex-2 ', 3'-eno-steroids of the general formula 3 arise in which the radicals R ¹³ , R ² ", R ³ ' and R ⁴ 'have the same meaning as in formula LI and R ^ιr additionally Can mean C2-C5-alkanoyl, C2-C5- (-hydroxy) -alkyl and the carbon atoms 2 'and 3' are connected by a double bond,

in step d)

16α, 17 -carbocyclic compounds of the general formula 1, 2 or 3 according to Birch are converted into the enol ethers of the general formula 4 by means of an alkali metal in ammonia / alcohol in the presence of a solubilizer, and in addition to the aromatic A ring also πβ-Ci'- Carbonyl compounds are reduced, and wherein R ¹⁷ '= C2-C5- (l'-hydroxy) -alkyl or C2-C5- (l'-CC ₅ -alkoxy) -alkyl, and the carbon atoms 2' and 3 'by one Double bond can be linked and the other radicals R ¹³ , R-, R ³ 'and R ⁴ ' have the same meaning as in formula II,

in step e) the 16, 17α-carbocyclic compounds of the general formula 4 are converted into 3-keto-5 (10) -en steroids of the general formula 5 by enol ether cleavage using mineral acid in a suitable solvent / water mixture,

in step f) the 3 -oxo-5 (10) -enes of the general formula 5 are selectively brominated in the cold with bromine in pyridine or with pyridinium perbromide in pyridine and at room temperature to 3-0x0-4.9- serve the general formula 6 dehydrobrominated,

in step g) the 3-oxo-4,9-dienes of the general formula 6 obtained are converted into 20-keto, 20-formyl or 20-carboxy-steroids, if appropriate by Jones oxidation, and / or etherified in a manner known per se , esterified, acetalized, thioketalized or oximated, oximes optionally dehydrated to nitriles and the carboxy compounds converted into the corresponding hydroxamic acid derivatives of the general formula I. Process step a) is preferably carried out in the hydrogenation in ethanolic THF solution, in process step b) the alkylation is carried out using methyl iodide in THF, in process step c) the isomerization of the 3 ', 4'-double bond with potassium tert-butoxide or KOH in absolute

Dimethyl sulfoxide at 70 ° C, the reduction of 17-alkanoyl steroids with sodium borohydride in Ethanoi carried out in process step d) in the Birch reduction of cyclohexano compounds saturated in the D'-ring and of cyclohexeno compounds unsaturated in the D'-ring with lithium or Sodium in ammonia / tert.

Butanol worked at -50 ° C, in process step e) the enol ether cleavage in aqueous acetone in the presence of dilute mineral acid, preferably sulfuric acid, in process step f) immediately after the bromination excess bromination agent by adding a

Removed reducing agent, carried out in step g) the oxidation using chromic acid or pyridine * S0 ₃ and at

Derivatization (ketalization, oximation, thioketalization) primarily selective conversion in 3-

Position realized.

In a particularly preferred embodiment of the process, the alkylation (extension of the side chain) is carried out before the isomerization.

The invention also relates to the new intermediates of formulas 5 and 6,

wherein

R ¹⁷ '= C ₂ -C ₅ - (1-hydroxy) -alkyl, C ₂ -C ₃ - (1C ₁ -C ₅ -alkoxy) -alkyl, C ₂ -C ₃ - (1C-C ₃ -alkanoyloxy) - alkyl, C ₂ -C ₅ - (l-aroyloxy) -alkyl, C ₂ -C ₅ - (2-hydroxy) -alkanoyI,

R ¹³ = methyl or ethyl,

R, R ^{3 '} and R ⁴ ' independently of one another are H or methyl and in which there is possibly an additional double bond between the carbon atoms 2 'and 3'.

The invention further relates to the process for the preparation of compounds of the general form in L 5 and 6 and intermediates for their preparation, the individual steps a to g according to the invention according to Scheme 1, including derivatization, medicament containing at least one compound of the formula L and the use of the compounds of the formula L 5 and 6 for the manufacture of medicinal products.

The following examples serve to explain the invention in more detail without restricting it in any way.

example 1

16α, 17 -CycIohexano-13ß-ethyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gonadiene

a)

17β-acetyl-16α, 17α-cyclohexano-13ß-ethyl-3-methoxy-1,3,5 (10) -gonatriene

50 mg of 5% Pd / C are suspended in 15 ml of ethanol (f.UV) and 15 ml of THF in a hydrogenation vessel and loaded with hydrogen. Subsequently Fuegi g I7ß-acetyl-I6 1, 17α- ^cyclohex-3, 4'eno-13ß-ethyl-3-methoxy-l, 3,5 (10) -gonatrien (2.65 mmol) are added and hydrogenated so long at a hydrogen pressure of 1 atmosphere until the theoretical amount of hydrogen is absorbed (59.3 ml). After this amount of hydrogen has been taken up, the hydrogenation comes to virtually a standstill. The catalyst is filtered off, the mixture is concentrated and the residue is recrystallized from ethanol.

F .: 155 to 159 ° C

LR [cm ^"1 ]: 1683 (20-on); 1604, 1568, 1496 (Aromat)

b)

16α, 17α-Cyclohexano-13ß-ethyl-3-methoxy-17ß- [-oxo-] propyl-l, 3,5 (10) -goπatrien

Option A

0.85 g 17ß-AcetyI-16α, 17 -cyclohexano-13ß-ethyi-3-methoxy-l, 3,5 (10) -gonatrien (2.23 mmol) are in nitrogen in 10 ml abs. THF dissolved and 1.875 ml of a 1.6 m solution of lithium butyl in hexane (3 mmol) were added with stirring, with the exclusion of water and cooling. The solution, which has been warmed to room temperature, is stirred for about 20 minutes and then 0.311 ml (5 mmol) of methyl iodide is added. The reaction mixture is stirred for about 20 minutes, then poured into water and the steroid extracted with ether. After concentrating the extracts, it is recrystallized from methanol. Chromatography on silica gel for fine purification. Toluene is used as the eluent. F .: 149 to 152 ° C

Variant b

To a solution of 0.85 g of 17ß-acetyl-16α, 17 -cyclohex-3 ', 4'-eno-13ß-ethyl-3-methoxy-1,3,5 (10) -gonatrien (2.23 mmol) 0.22 ml (3 mmol) of diisopropylamine are added to 10 ml of absolute tetrahydrofuran, the solution is cooled to -10 ° C. and then 1.87 ml of a 1.6 M lithium butyl solution in hexane (3 mmol) are added under inert gas and the mixture is stirred the reaction mixture for 10 minutes at this temperature. Thereafter, 0.31 ml (5 mmol) of methyl iodide is added and the mixture is gradually warmed to room temperature. You stir about 20 Minutes at room temperature, then pour into ice water and extract the steroid with ether. After concentrating the extracts, it is recrystallized from methanol. F .: 149 to 152 ° C

c)

16α, 17-Cyclohexano-13ß-ethyl-17ß- [-hydroxy-] propyl-3-methoxy-2,5 (10) -gonadiene

1 g (2.5 mmol) of 16α, 17α-cyclohexano-13ß-ethyl-3-methoxy-17ß- [l'-oxo] propyl-l, 3.5 (10 gonatrien are dissolved in 20 ml of THF and made into a prepared Birch solution consisting of 5 ml of THF, 50 ml of ammonia, 5 ml of tert-butanol and 250 mg of lithium (35.7 mmol) is slowly added dropwise and after the addition has ended, the mixture is stirred under argon at about -33 ° C. for 2.5 hours. Excess reducing agent is then destroyed by adding methanol, the ammonia is evaporated off, water is added in the cold and the steroid is extracted with methylene chloride. After the extracts have been concentrated, flash chromatographies are carried out on silica gel. Toluene is used as the eluent 20 alcohols (690 mg) are concentrated and used in the next step without further purification

LR [cm ^"1 ]: 3625 (20-OH); 1690 and 1660 [2.5 (10) -diene]

MS: [M + H] 399.1

e)

16α, 17α-Cyclohexano-13ß-ethyl-17ß- [l'-hydroxy-] propyl-3-oxo-5 (10) -gons

0.69 g of 16, 17α-cyclohexano-13ß-ethyl-17ß- [l'-hydroxy-] ρropyl-3-methoxy-2,5 (10) - gonadiene (1.73 mmol) becomes 80 percent in 20 ml dissolved aqueous acetone and mixed with vigorous stirring with 20 ul 25 percent sulfuric acid. The mixture is then stirred for about 5 hours at room temperature, neutralized with sodium bicarbonate solution and, after further dilution with water, the steroid is extracted with methylene chloride. The crude product resulting after the concentration is chromatographed on silica gel (elution with toluene). The mixture of the isomeric 20 alcohols is used in the next step without crystallization.

IR [cm ^"1 ]: 3625 (20-OH)

)

16,17-Cyclohexano-13β-ethyl-17ß- [r-hydroxyethyl] -3-oxo-4,9-gonadiene

0.4 g of 16α, 17 -cyclohexano-13ß-ethyl-17ß- [r-hydroxyethyl] -3-oxo-5 (10) -gons (1.09 mmol) are dissolved in 10 ml of pyridine and at -5 ° C 0.418 g (1.31 mmol) of pyridine hydrobromide perbromide were added within 5 minutes. After 15 minutes Excess perbromide is decomposed by adding dihydropyran. Then 4 to 5

Stirred for hours at room temperature and then stirred into ice water. After this

Storage in the refrigerator for 16 hours crystallizes the 4,9-diene. The crude product is chromatographed on silica gel (elution with toluene / ethyl acetate 4: 1) and the fractions containing the isomeric 20-hydroxy compounds are narrowly concentrated and used in the next stage without recrystallization

LR [cm ^{* 1} ]: 3620 (OH); 1645 u. 1601 (4,9-diene)

G)

16α, 17α-Cyclohexano-13ß-ethyl-17ß- [l-oxo] prαpyl-3-oxo-4,9-gona-diene

0.35 g l6, 17α-cyciohexano-13ß-ethyl-17ß- [l'-hydroxy-] propyI-3-oxo-4,9-gonadiene (0.91 mmol) are dissolved in 30 ml acetone (ü. KMnθ4 dist .) dissolved and 0.8 ml Jones reagent was added within 5 minutes at 0 to 10 ° C. After a reaction time of 15 minutes, excess reagent was reduced by adding isopropanol, the solution was mixed with water and the steroid was extracted with methylene chloride. After concentrating the extracts, the residue is flash chromatographed on silica gel (or aluminum oxide neutral). Toluene / ethyl acetate (4: 1) is used as the eluent. After concentrating the corresponding eluates, the residue is crystallized from ether / n-hexane.

F .: 134 to 138 ° C

TR [cm ^'1 ]: 1684 (20-one); 1648 u. 1599 (Dienon)

MS: found 380.27261 dev. -1.1 must. C ₂ 6H ₃ 6θ ₂

¹³ C NMR: 3C 199.67; 4C 122.17; 5C 157.21; 8C 39.63; 9C 146.11; IOC 125.6; 13C

50.83; 14C 52.13; 16C 34.37; 17C 62.69; 18C 18.51; 19'C 8.71; 20C 214.4; 21C

21.13; 22C 8.18

1H NMR: 5.7 s (4-H); . 0.64 tr (18-CH _3); 1.09 tr. (21-CH ₃ )

Example 2

16α 17α-cyclohex-2 3'-eno-13ß-methyl-17ß- [l'-oxo-] ^{propyl-3-oxo-4,9-gonadien,,}

b)

16α, 17 -CycIohex-3 ', 4'-eno-13ß-methyl-3-methoxy-17ß- [l'-oxo] propyl-l, 3,5 (10) - gonatriene

To a solution of 0.83 g of 17β-acetyl-16, 17 -cyclohex-3 ', 4'-eno-13ß-methyl-3-methoxy-l, 3.5 (10) -gonatriene (2.3 mmol) 0.22 ml (3 mmol) of diisopropylamine are added to 10 ml of absolute tetrahydrofuran, the solution is cooled to -10 ° C. and then 1.87 ml of a 1.6 M lithium butyl solution in hexane (3 mmol) are added under inert gas and the mixture is stirred the reaction mixture for 10 minutes at this temperature. Subsequently with 0.31 ml WO 98/23634 _ _{χ 5} _ PCT / EP97 / 06542

(mmol) of methyl iodide are added and the mixture is gradually warmed to room temperature. The mixture is stirred at room temperature for about 20 minutes, then stirred into ice water and the steroid is extracted with ether. After concentrating the extracts, the product is crystallized from methylene chloride / methanol

F .: 87 to 90 ° C

LR [cm ^{* 1} ]: 1687 (20-one); 1638 (3 ', 4'-eno); 1638, 1604 u. 1497 (aromatic)

c)

16α, 17-Cyclohex-2 ', 3'-eno-13ß-methyl-3-methoxy-17ß- [l'-oxo] propyl-l, 3,5 (10) - gonatriene

5 g of 17β-acetyl-16α, 17 -cyclohex-3 ', 4 ^" eno-13ß-methyl-3-methoxy-l, 3,5 (10) -gonatrien (13.2 mmol) are heated in 50 ml of DMSO ( dissolved molecular sieve dried) and mixed with 5 g of potassium tert-butoxide (addition of the KtB only after the temperature has reached 70 ° C.) under nitrogen, followed by stirring for 30 minutes at 70 ° C. After the reaction has taken place (in TLC silica gel / AgNOß T: ethyl acetate 20: 1 or AHO- / AgNθ3 toluene) is stirred into ice water acidified with a little hydrochloric acid and the suspension is kept in the refrigerator overnight for the purpose of complete precipitation After concentration of the appropriate fractions, the product is crystallized from methanol / methylene chloride, giving 4 g of the target product, F .: 98 to 102 ° C.

d)

16, 17α-Cyclohex-2 ', 3'-eno-17ß- [l'-hydroxy-] propyl-13ß-methyl-3-methoxy-2,5 (10) - gonadiene

1.1 g (2.9 mmol) 16, 17-cyciohex-2 ', 3'-eno-13ß-methyl-3-methoxy-17ß- [l'-oxo] propyl-l, 3.5 (10 ) -Gonatrien are dissolved in 25 ml THF and slowly added dropwise at - 50 ° C to a prepared Birch solution consisting of 5 ml THF, 100 ml ammonia, 5 ml tert-butanol and 450 mg lithium (64.3 mmol). After the addition has ended, the mixture is stirred under argon at about -33 ° C. for 2.5 hours. Excess reducing agent is then destroyed by adding methanol, the ammonia is evaporated, water is added in the cold and the steroid is extracted with methylene chloride. After concentrating the extracts, it is chromatographed on silica gel. Toluene is used as the eluent. The dc-pure enol ether eluates of the isomeric 20 alcohols are concentrated and used in the next step without further purification.

LR [cm ^'1 ]: 3620 or 3615 (OH pol. Or unp.Prod.); 1690 u. 1660 [2.5 (10) -diene]

MS [M + H]: 383 e) 16α, 17 -cyclohex-2 ', 3'-eno-17ß- [l'-hydroxy-] propyl-13ß-methyl-3-oxo - 5 (10) -gons

0.6 g (1.57 mmol) 16α, 17α-cyclohex-2 ^" , 3'-eno-17ß- [l'-hydroxy-] propyl-13ß-methyl-3-methoxy-2,5 (10) - Gonadiene (concentrated eluates) are treated as in Example 1, stage 4. After extraction with methylene chloride, flash chromatography is carried out on silica gel using toluene as the eluent, and the concentrated eluates are used in the next stage without crystallization.

IR [cm ^"1 ]: 3624 (OH); 1706 (3-one)

)

16α, 17α-Cyclohex-2 ', 3'-eno-17ß- [l'-hydroxy-] propyl-13ß-methyl-3-oxo-4,9-gonadiene

0.45g l6α, 17 -cyclohexano-13ß-ethyl-17ß- [l'-hydroxyethyl] -3-oxo-5 (10) -gons (1.2 mmol) are dissolved in 10 ml pyridine and at - 10 to - 5'C with 0.46 g (1.44 mmol) of pyridehydrobromide perbromide added within 5 minutes. After 5 minutes, excess perbromide is decomposed by adding dihydropyran. The mixture is then stirred for 4 to 5 hours at room temperature and then stirred into ice water. After storage in the refrigerator for 16 hours, the 4,9-diene crystallizes out. The crude product is chromatographed on silica gel (elution with toluene / ethyl acetate, 4: 1) and the fractions which contain the isomeric 20-hydroxy compounds are concentrated and used in the next stage without recrystallization.

IR [cm ^"1 ]: 3620 and 3560 (unp. And pol. 20-OH); 1645 and 1599 (4,9-diene)

G)

16α, 17-Cyclohex-2 ', 3'-eno-13β-methyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gonadiene

0.38 g of 16, 17α-cyclohexano-13ß-ethyl-17ß- [l'-hydroxy-] propyl-3-oxo-4,9-gonadiene (1 mmol) are dissolved in 30 ml acetone (over KMnθ4 dist. ) dissolved and 0.8 ml of Jones reagent was added within 5 minutes at 0 to 10 ° C. After a reaction time of 15 minutes, excess reagent was reduced by adding isopropanol, the solution was mixed with water and the steroid was extracted with methylene chloride. For the purpose of fine cleaning, the residue is flash chromatographed on silica gel. A toluene / ethyl acetate mixture (4: 1) is used as the eluent. After concentrating the corresponding eluates, the residue is crystallized from ether / n-hexane.

F .: 146 to 148 ° C

LR [cm ^{* 1} ]: 1688 (20-one); 1650 u.1603 (Dienon)

MS: found 378.25549 Dev. + 0.4 mmu f. C ₂₆ H ₃₄ 0 _: ¹³ C NMR: 3C 199.67; 4C 122.13; 5C 157.2; 8C 39.65; 9C 145.6; IOC 125.2; 13C

46.66; 14C 51.6 16C 33.07; 17C 65.01; 18C 14.952; 20C 211.02; 21C 20.0; 22C

8.16; CV 126.32; C ₂ '133.45. ¹ H NMR: 5.67 s (4-H); 5.87 d (2'H); 6.02 qu. (3'H); 0.855 (13-CH _3); 1.05 tr. (21-

CH ₃ )

Example 3 16α, 17-Cyclohex-2 ', 3'-eno-13ß-ethyl-17ß- [l'-oxo] propyl-3-oxo-4 _} 9-gonadiene

b)

16α, 17-Cyclohex-3 ', 4'-eno-13ß-ethyl-3-methoxy-17ß- [l'-oxo] propyl-l, 3,5 (10) -gonatriene

1 g of 17β-acetyl-16α, 17α-cyclohex-3 ', 4'-eno-13ß-ethyl-3-methoxy-l, 3,5 (10) -gonatriene is alkylated according to Example 2 stage 1. After the reaction, add a little methanol and concentrate in vacuo. The steroid crystallizes out.

F .: 139 to 142 ° C

LR [cm ^'1 ]: 1685 (20-one); 1604, 1568 and 1457 (Aromat)

c) l6α, 17-cyciohex-2 ', 3'-eno-13ß-ethyl-3-methoxy-17ß- [l'-oxo] propyi-l, 3,5 (10) -gonatriene

2 g 16α, 17α-CycIohex-3 ', 4'-eno-13ß-ethyl-3-methoxy-17ß- [l'-oxo] propyl-l, 3,5 (10) - gonatrien in 20 ml DMSO (dried molecular sieve) and mixed with 2 g of potassium tert-butoxide (addition of the KtB only after the temperature has reached 70 °) under nitrogen. Then the mixture is stirred at 70 ° C. for 30 minutes. After the reaction is complete, the mixture is stirred into water acidified with a little hydrochloric acid and the suspension is kept overnight in the refrigerator for the purpose of complete precipitation. The crude product obtainable after frying is chromatographed on silica gel. The elution is carried out with toluene. After the appropriate fractions have been concentrated, the product is crystallized from methanol / methylene chloride.

F _Me0H -: 105 to 107 ° C

LR [cm ^'1 ]: 1687 (20-one); 1639 (2 ', 3'-eno); 1604, 1569 and 1496 (Aromat)

d)

16α, 17α-Cyclohex-2 ', 3'-eno-13ß-ethyl -17ß- [l'-hydroxy-] propyl-3-methoxy-2,5 (10) - gonadiene

0.99 g of 16α, l7 -cyclohex-2 ', 3'-eno-13ß-ethyl-3-methoxy-17ß- [l'-oxo] propyl-l, 3,5 (10) - gonatriene are according to example 1 Birch level 3 reduced. After extraction, flash chromatography is carried out on silica gel. The corresponding

Fractions are concentrated and used in the next stage without further manipulation

IR [cm ^{* 1} ]: 3620 u. 3567 (OH unp. U. Pol .. component); 1690 u. 1660 [2.5 (10) -diene]

MS: [M + H] 397

e)

16α, 17α-Cyclohex-2 ', 3'-eno-13ß-ethyl-17ß- [l'-hydroxy-] propyi-3-oxo - 5 (10) -gons

0.52 g of 16α, 17α-cyclohex-2 ^" , 3'-eno-13ß-ethyl -17ß- [l'-hydroxy-] propyl-3-methoxy-2,5 (10) -gonadiene become 80 in 20 ml -% aqueous acetone dissolved and 20 μ \ 25% sulfuric acid was added with vigorous stirring, followed by stirring for about 5 hours at room temperature, neutralized with sodium bicarbonate solution and, after further dilution with water, the steroid was extracted with methylene chloride Chromatographed on Kieseigel (elution with toluene) The mixture of the isomeric 20 alcohols is used in the next step without crystallization.

LR [cm ^{* 1} ]: 3624 (OH); 1706 (3-oxo)

f)

16α, 17-Cyclohex-2 ', 3'-eno-13ß-ethyl -17ß- [l'-hydroxy-] propyl-3-oxo - 4,9-gonadiene

0.38 g of 16α, 17 -cyclohex-2 ', 3'-eno-13ß-ethyi-17ß- [l'-hydroxy-] propyl-3-oxo - 5 (10) -gons are brominated according to Example 1 stage 5 and dehydrobrominated. The precipitated semicrystalline crude product is used in the next stage without purification LR [cm ^"1 ]: 3624 (20-OH); 1645 and 1602 (4,9-diene)

G)

16α, 17-Cyclohex-2 ', 3'-eno-13ß-ethyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gonadiene

0.34 g of 16α, 17α-cyclohex-2 ', 3'-eno-13ß-ethyl -17ß- [l'-hydroxy-] propyl-3-oxo - 4,9-gonadiene are according to Example 1 stage 6 with Jones Reagent oxidized The resulting crude product is purified by flash chromatography on silica gel. A toluene / ethyl acetate mixture (4: 1) is used as the eluent. The recrystallization is carried out with ether / n-hexane.

F .: 144 to 148 ° C

L LRR [[ccmm ^''11 ]] :: 11668877 ((22C0-on); 1648 and 1602 (Dienon)

MS: found 378.25650 dev. O.δ mmu f. C26H34O2 ¹³ C NMR: 3C 199.64; 4C 122.13; 5C 157.22; 8C 39.55; 9C 145.62; IOC 125.23; 13C 50.17; 14C 53.6; 16C 33.32; 17C 63.93; 18C 18.43; 19'C 8.735; 20C 211.04; 21C 19.81; 22C 8,095; Cy 127.12; C ₃ '132.83. ¹ H NMR: 5.66 s (4-H); 5.96 m (2'-H and 3'-H); 0.65 tr. (18-CH ₃ ); 1.047 tr. (21-CH ₃ )

Example 4 16α, 17α-Cyclohexano-13ß-methyl-17ß- [l'-oxo] propyI-3-oxo, 9-gona-diene

a)

17β-acetyl-16α, 17 -cyclohexano-3-methoxy-13ß-methyl-l, 3,5 (10) -gonatriene

lg 17β-acetyl-16α, 17α-cyclohex-3 ', 4'eno-3-methoxy-13ß-methyl-l, 3,5 (10) -gonatriene are hydrogenated according to Example 1 stage 1. F _Me oH »139.5 to 142 ° C

b)

16, 17-Cyclohexano-3-methoxy-13ß-methyl-17ß- [-oxo] propyl-1,3,5 (10) -gonatriene

1.1 g of 17β-acetyl-16, 17α-cycIohexano-3-methoxy-13ß-methyl-1,3,5 (10) -gonatriene are reacted according to Example 1 variant a

F-Meθa Me-hylenciιiorid. ^: 28 to 131 ° C

ER [cm ^{* 1} ]: 1684 (20-one); 1604, 1569 and 1496 (Aromat)

d)

16α, 17-Cyclohexano-17ß- [l'-hydroxy-] propyl-3-methoxy-13ß-methyl-2,5 (10) -gonadiene

0.7 g of 16, 17-cyciohexano-3-methoxy-13β-methyl-17β- [l'-oxo] propyl-l, 3,5 (10) -gonatriene are subjected to Birch reduction according to Example 1 stage 3 . The crude product is flash chromatographed on 13 g of silica gel. Toluene serves as the mobile phase. The concentrated eluates (0.52 g) are used in the next step without further purification steps.

LR [cm ^{* 1 *} ]: 3625 (OH); 1690 u. 1660 [2.5 (10) -diene]

MS [M + Li]: 390.8

e)

16α, 17α-Cyclohexano-17ß- [l'-hydroxy-] propyI-13ß-methyl-3-oxo-5 (10) -gons

0.52 g of 16, 17-cyclohexano-17β- [l'-hydroxy-] propyl-3-methoxy-13β-methyl-2,5 (10) - gonadiene are subjected to an enol ether cleavage in accordance with Example 1 stage 4. The Crude product is flash chromatographed on silica gel for purification. Toluene is used as the eluent. The concentrated eluates containing the 3-keto 5 (10) product are used directly in the next step

LR [cm ^{* 1} ]: 3625 (20-OH)

0

16α, 17α-Cyclohexano-17ß- [l'-hydroxy-] propyl-13ß-methyl-3-oxo-4,9-gonadiene

0.4 g of 16α, 17α-cyclohexano-17ß- [l'-hydroxy-] propyl-13ß-methyl-3-oxo-5 (10) -gons are brominated and dehydrobrominated according to Example 1 stage 5. The semi-crystalline crude product is used in the next stage without special purification IR [cm ^{* 1} ]: 3620 (20-OH); 1645 u. 1599 (4,9-diene)

G)

16α, 17α-Cyclohexano-13ß-methyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gona-diene

0.35 g of 16, 17α-cyclohexaπo-17ß- [l'-hydroxy-] propyl-13ß-methyl-3-oxo-4,9-gonadiene are oxidized according to Example 1 stage 6 with Jones reagent. The crude product obtainable after extraction is flash chromatographed on silica gel. Elution is carried out with a toluene / ethyl acetate mixture (4: 1). The concentrated target fractions are crystallized from ether / n-hexane

F _{E (fro} .: 145 - 148 ° C

IR [cm ^{* 1} ]: 1685 (20-on); 1647 u. 1600 (Dienon)

MS: found 366.25470 dev. 1.2 mmu f. C25H34O2

¹³ C NMR: 3C 199.57; 4C 122.13; 5C 157.01; 8C 39.45; 9C 145.94; IOC 125.49; 13C

46.8; 14C 50.34; 16C 34.18; 17C 63.71; 18C 15.38; 20C 214.6; 22C 8.32

^X H NMR: 6.0 s (4-H); 0.81 s (13-CH _3); 1.086 tr. (21-CH ₃ )

Claims

Claims:

1. 16α, 17 -carbocyclic steroids of the general formula L,

woπn

R ¹⁷ = C ₂ -C ₅ alkanoyl, but not acetyl if R and R ³ 'each represent a hydrogen atom, C ₂ -C ₅ - (l-hydroxy) alkyl, C ₂ -C ₅ - (lC ₁ -C ₅ alkoxy) -alk 1, C ₂ -C ₅ - (1-C ₁ -C ₅ -alkanoyloxy) -alkyl, C ₂ -C ₅ - (1-AroyIoxy) -alkyl, C ₂ -C ₅ - (2-Hydroxy) alkanoyi, cyano, (hydroxyamino) carbonyl, (C ₁ -C ₅ alkoxyamino) carbonyl, Cχ-C ₅ - (l-hydroxyimino) alkyl, C _r Cs- (l-Cι -C ₅ -alkoxyimino) alkyl, CC ₅ - (lC ₁ -C ₅ alkylimino) alkyl, CC ₅ - (lC _r C ₅ - alkanoyloximino) alkyl, C ₁ -C ₅ - (l-alkylaminocarbonyloxy) - alkyI, Ci-C ₅ - (1-arylaminocarbonyloxy) alkyl,

R ¹³ = methyl or ethyl,

^? , R ³ ', R ⁴ ' independently of one another denote a hydrogen atom or a methyl group,

C ₂ - _{2 is} a CC single or double bond,

X two hydrogen atoms, a hydrogen atom and a hydroxy group, a radical of the formula -S- (CH2) _n -S- with n = 2, 3, 4 or 5, an oxygen atom, a hydroxyimino, CC ₆ - alkoxy, Ci C _ä alkanoyl, CC _ä -Alkoxycarbonylimino-, CC ₆ -Alkoximino-, Cχ-C ₆ - or C Alkoxycarbonyloximino- means _ö -Alkanoyloximinogruppe

2. 16α, 17α-carbocyclic steroids according to claim 1, nämüch

16α, 17α-Cyclohexano-13ß-ethyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gonadiene

16α, 17 -cyclohex-2 ', 3 ^, -eno-13ß-methyl-17ß- [-oxo] propyl-3-oxo-4,9-gonadiene

16α, 17-Cyclohex-2 ', 3 ^, -eno-13ß-ethyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gonadiene

16α, 17-Cyclohexano-13ß-methyl-17ß- [l'-oxo] propyl-3-oxo-4,9-gonadiene

17β-acetyl-16α, 17α-cyclohex-2 ', 3'-eno-13-methyl-3-oxo-4,9-gonadiene,

17β-acetyl-16α, 17 -cyclohex-2 *, 3'-eno-13-ethyl-3-oxo-4,9-gonadiene.

3. 16α, 17α-carbocyclic steroids according to claim 1, wherein R ^{17 is} C _j . -C ₅ -alkanoyl

4. 16α, 17α-carbocyclic steroids according to claim 3, wherein R ^{17 is} acetyl or propionyi

5. 16α, 17-carbocyclic steroids according to claim 1, wherein R ^{17 is} -C ^ l'-hydroxy ^ alkyi.

6. 16α, 17α-carbocyclic steroids according to claim 1, wherein X stands for two hydrogen atoms.

7. 16α, 17α-carbocyclic steroids according to claim 1, wherein X represents a hydrogen atom and a hydroxy group

8. 16α, 17 carbocyclic steroids according to claim 1, wherein X is an oxygen atom

9. 16α, 17-carbocyclic steroids according to claim 1, wherein C ' ₂ -C _{3 is} a CC double bond.

10. 16α, l7α-carbocyclic steroids of the formulas

woπn

R ^{17 "} = CC ₃ - (1-hydroxy) alkyl, C ₂ -C ₅ - (1C ₁ -C ₃ alkoxy) alkyl, Ca-Cs-Cl-d-Cs-alkanoyloxy) - aikyl, C ₂ -C ₃ - (l-aroyloxy) alkyl, C ₂ -C ₃ - (2-hydroxy) alkanoyl,

R ¹³ = methyl or ethyl, R ^{2 *} , R ³ 'and R ⁴ ' independently of one another are H or methyl

and in which there is possibly an additional double bond between the carbon atoms 2 'and 3'

11. Pharmaceutical preparations containing at least one compound of general formula I according to claim 1 and a pharmaceutically acceptable carrier.

12. Use of compounds of formula I according to claim 1 for the manufacture of medicaments.