FI110688B - New 11-beta-aryl-4-estrene(s) - exhibiting anti-glucocorticoidal activity and useful for treatment of glaucoma and cushings syndrome - Google Patents

Abstract

Estrenes of formula (I) are new: X = O, hydroxyimino greater than N-OH, or two H's; R1 = H or Ch3; R2 = OH, 1-10C alkoxy, or 1-10C acyloxy; R3 = H, -(CH2)nCH2Z, -(CH2)m-CC-Y, or -(CH2)p-CH=CH-(CH2)k-CH2-R6; Z = H, CN or OR5; n = 0-5; R5 = H, 1-10C alkyl, 1-10C acyl; m = 0-2; Y = H, F, Cl, Br, 1-10C hydroxyalkyl, 1-10C alkoxyalkyl or 1-10C acyloxyalkyl. p = 0-1; k = 0-2; R6 = H, Oh, 1-4C alkoxy, or 1-4C acyloxy; R2 and R3 = may form (II), (III) or (IV) R4 = H, cyano, Cl, F, Br, I, trialkylsilyl, trialkylstannyl, 1-8C (un)saturated 1-8C alkyl, acyl or alkoxyl, NR7R8, amine oxide of formula -N+(-O-)R7R8, OR9 or S(O)i-R9; R7, R8 = H, 1-4C alkyl i = 0-2; R9 = H, methyl, ethyl, propyl, isopropyl, methoxyphenyl, allyl, or 2-dimethylaminoethyl; Or R4 = heteroaryl of formula (VII) A = N, O S; -B-D-E- = -C-C-C-, -N-C-C-, -C-N-C-; R10 = H, cyano, Cl, F, Br, I, trialkylsilyl, trialkylstannyl, 1-8C (un)saturated alkyl, acyl, alkoxyalkyl, or amino (-N(R7)R8); Or R4 = heteroaryl of formula (VIII) A = N; -B-D-E- = -C-C-C-, -N-C-C-, -C-N-C-, -C-C-N-; R10 = as given; Or R4 = phenyl monosubstituted by 1 R10;.$ USE/ADVANTAGE : (I) exhibit antiglucocorticoidal activity and can be used for therapy of glaucoma as well as long-term treatment of Cushing's Syndrome.

Description

Mw 11β-aryl-4-esters and a process for their preparation

Separated from patent application 903153.

The present invention relates to liparyl-4-estrenes having general formula Ia

ys ..

Wherein X represents an oxygen atom, a hydroxyimino group> N ~ OH or two hydrogen atoms, R1 represents a hydrogen atom or a methyl group, R2 represents a hydroxyl group or a methoxy group, R3 represents a hydrogen atom, a group - (CH2) nCH2Z, where n is 0, 1 or 2, Z represents a hydrogen atom, a cyano group or a group -OR5 where R5 represents H or methyl, or Z represents a group -C = CY, wherein Y represents a methyl group; or a hydroxymethyl group, or Z represents a group: ··· 25 -CH = CH-CH 2 OH or an allyl group -CH 2 -CH = CH 2, or R 2 and R 3 · · · together form a group of formula f j f i ta ± Ί f · o II oo · · · · 17 17X 17: R 4 represents a straight-chained, saturated or unsaturated C 1 or C 2 alkyl chain or acetyl group, 35 2 110688 R 7 amino groups -N 4 where R 7 and R 8 independently represent hydrogen atom or a methyl group, or the corresponding R 7 amine oxide or -OR 9 or -S (O) i R 9, 10

Q

wherein i is 0, 1 or 2, wherein R is a methyl group, or a heteroaryl group of formula Ia, (Aa) wherein A is an oxygen or sulfur atom, R10 is a hydrogen atom, a cyano group, a fluorine atom, a straight chain , saturated C1 - C2. 20,. R7 is an alkyl group, an acetyl group, an amino group or: R8 · '*: a group of -S (0) ± R9 wherein i, R7, R8, R9 are the same as above, or a heteroaryl group of the formula Ιβ-R10 ΓI ™ 30 N · /. ·· where -BD- represents an element of the group -CC- or -CN- and '' · R10 has the meaning given above, or a phenyl group of the formula Ιγ 35 - (Ιγ) S / 3 11068b wherein R10 has the meaning given above as well as their pharmacologically tolerable acid addition salts.

The invention further relates to a novel process for the preparation of the compounds of formula I as defined above and their acid addition salts as defined in claim 8.

The invention particularly relates to compounds wherein X is an oxygen atom.

The following compounds are particularly preferred according to the invention: 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one, 11β- [4 -cyanophenyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-15-oxy-1Z-propenyl) -4-estren-3-one, 11β- [4- (4-cyanophenyl) phenyl] -17β-hydroxy- 17α- (1-prop-ynyl) -4-estren-3-one, (11β, 17β) -4 ', 5'-dihydro-11- [4- (dimethylamino) phenyl] -spiro [estr-4- en-17,2 '(3 R) -furan] -3-one, 20 (11β, 17β) -3', 4'-dihydro-11- [4- (dimethylamino) phenyl] spiro [estr-4- en-17,2 '(3' H) -furan] -3,5 '-dione, (11β, 17β) -11- [4-dimethylamino) phenyl] spiro [estr-4-en-'. 17,2 '(5R) -furan] -3-one.

; ··; In the case of the compounds of the general formula I · * ·:: 25 are competing progesterone antagonists ·. · '(Antigestagens). In all cases of steroidal antigen antigens known to date, in addition to the Δ4 A9-3 oxochromophore, there is preferably a substituted β-phenyl group (A. Belanger, D. Philibert and G. Teutsch. 30 Steroids 37 (1981) 2742; D. Philibert, T. Ojasoo. and JP

. ··· Raynand, Endocrinology 10 (1977) 1850, EP-A-057 115; G: '*. Teutsch, T. Ojasoo and J.P. Raynand, J. Steroid Biochem. 31, 549 (1988).

More recently, antigenic antigens of steroidal origin 35 have also been found in which the 9,10 double bond is located between a methylene bridge and a 110,688 4 ortho position C atom of the Ιΐβ-aryl ring (EP-A-0 283 428). .

Apparently, the incorporation of the Ιΐβ-aryl group contributes to the conversion of the gestagenic effect to the antigenic one. However, so far no antigen progestogen closest to 5 progesterone has been produced, one would say "antiprogesterone" which would not have a 9,10 double bond but would have a "free" 10β substituent, for example a hydrogen atom, in addition to the ,β-aryl group. Attempts to isomerize 11β- [4- (substituent) aryl] -17β-hydroxy-5 (10) -estren-3-10-one by transiently treating with dilute inorganic acids the corresponding compound having a 4 (5) double bond under conditions wherein In the 11-unsubstituted set, the transfer of the double bond from 5 (10) to 4 (5) without further success failed 15 (G. Neef, G. Sauer and R. Weichert, Tet. Let. 24, 5205 (1983)).

However, conditions have now been found for surprisingly successful transfer of a 5 (10) double bond to a 4 (5) position.

20 A compound of general formula II

r · VN, *.

: R1 V8 25 (II) 30 ° wherein: · R1 and R4 have the meanings given in formula I, A is a β-hydroxyl group or R2 and '· B is an a-hydrogen atom, a group R3 at position α and j B together form a keto-oxygen atom, 5,106,680 is treated with an acid in an inert solvent to give compounds of general formula Ia

5 V ^ I V

depth

I_ (Ia)

10 I T

wherein R 1, A and B have the meanings given in Formula II and R 4 'has the same meaning as R 4 in Formula I so that R 4 is stable under said high potency conditions.

Preferably, isomerization is heated to 80-120 ° C in an inert solvent, for example toluene. The reaction lasts at least 45 minutes, but may, if necessary, last for 24 hours or more.

· “Both inorganic and organic acids are suitable as acids; of the latter, p-toluenesulfonic acid is preferred.

In the case of compounds of general formula Ia, the final compound of general formula I may already be present if the substituents R 4, A and B in the starting compound of general formula II contain substituents which are capable of withstanding the highly active reaction conditions necessary for isomerization. In particular, the free radicals present on the tertiary carbon atom, in particular, are removed under these reaction conditions.

However, * it may be meaningful to attach the substituents R 2 and R 3 to the C-17 atom and to attach the R 4 β-phenyl ring to the 4-position only after isomerization.

6

11068B

Depending on the final desired substituents of the compound of general formula I after isomerization of R 2, R 3 and R 4, optionally either a) in the compound of general formula Ia where A is a β-hydroxyl group and B is an a-hydrogen atom b) converting the 3-keto group into a dithioketal, whereupon any other keto groups present may be ketalized or first carried out b) and then a) and then c) if R4 in the 3-thioketalized compound has a methoxy or hydroxyl group and R4 is finally desired does not have a methoxy or hydroxyl group, the hydroxy compound, optionally after cleavage of the methoxy compound, is converted to the corresponding perfluoroalkylsulfonic acid compound wherein -alkyl-

A C 1 -C 4 alkyl group, and from this either directly by reacting the correspondingly substituted tin (trialkyl) compound R 4 "-Sn (alkyl) 3, or the corresponding boron substituted R 4" -BL 2 (L = hydroxy or alkyl), wherein R 4 is is the same as R 4 of the compound of general formula I or is a tautomeric precursor of R 4 and represents a C 1 -C 4 alkyl group or indirectly a tin (trialkyl) in the 4-position of the phenyl group with a · 25 (alkyl = C1-C4) via a substituted compound V obtained from a perfluoroalkyl sulfonate compound

reaction with Sn 2 alkyl 6, and further treating the 11β- (4-trialkylstanyl) phenyl compound with R 4 -Y, wherein R 4 is the same as R 4 of the general formula I or is a tautomeric precursor of R 4 and Y

·· * is a leaving group, preferably a halogen atom, and * · especially a bromine atom, is prepared in the presence of a transition metal catalyst, a compound of general formula III 35 7 110688 X'Vvs 5 (III) 10 wherein Z is a protected keto group in dithioketal form and ) where R 2 and R 3 in the final desired compound of general formula I do not represent a hydroxy group or hydrogen atom or R 2 and R 3 together do not form a keto acid atom, the desired substituents R 2 and R 3 are attached to the C-17 atom of the steroid backbone; and thereafter c), protecting groups are cleaved, if desired, free hydroxyl groups are alkylated or acylated and, if desired, the 3-keto group is converted into 3-X "hydroxyimino group> N ~ O or the 3-keto group is converted into with some acid.

· 25 The implementation of process steps a), b), c) and d) v is carried out by methods known per se. The oxidation of the hydroxyl group a) to the keto group can be carried out, for example, according to Oppenauer or using chromic acid reagents (Jones reagent) or chromic acid-pyridine. The protecting group for the 3-keto group is an ethane-1,2-. · * · Diylbis (thio) group which can be attached to the 3-keto compound.

* I

·· Reaction with ethane-1,2-dithiol, for example in the presence of p-toluenesulfonic acid, on the 3-C atom of the steroid. Alternatively, oxidation may be carried out first, followed by the attachment of a protecting group, or first the addition of a protecting group,, followed by oxidation. In reaction step c), the substituent R 4 or R 4 'of the 1106Sli 8 is attached to the p-position of the ring. This procedure is necessary when R 4 is a substituent that does not withstand strong isomerization conditions, for example an allyl or vinyl group.

The starting point for this coupling is the 11β- (4-hydroxyphenyl) compound obtained from the corresponding methoxy compound using ether cleavage, for example with sodium methane thiolate in a solvent such as dimethylformamide.

Reaction of the hydroxy compound with perfluoro (C 1 -C 4) alkylsulfonic anhydride or halide in the presence of a base such as pyridine or 4- (dimethylamino) pyridine affords the corresponding 11β- [4- (perfluoroalkylsulfonyloxy) phenyl] compound (J.

15 Stang, M. Hanack, and L.R. Subramanian, Synthesis 85 (1982).

When coupling the Ιΐβ-aryl compound with R4 -Sn (alkyl) 3 or R4-BL2, either the perfluoroalkylsulfonate leaving group in the transition metal catalyzed (preferably Pd) reaction is substantially quenched with the desired substituent or »» with substantially desired simultaneous substitution. [Arylic coupling with tin compound: JE McMurry. and S. Mohanraj, Tetrahedron Letters 24 (1983) no. 27, 2723-2726; X. Lu and J. Zhu, Communications 1987, 726-727; Q.-Y.

• · · ”25 Chen and Z.-Y. Yang, Tetrahedron Letters 27 (1986) no. 10, 1171-1174; S. Cacchi, P.G. Giattini, E. Morera and G. Ortar, Tetrahedron Letters 27 (1986) no. 33, 3931-3934; A.M.

Echavarren and J.K. Stille, J. Am. Chem. Soc. 1987, 109, 5478-5486, with boron compound: Synthesis 936 (1984); Chem.

30 Pharm. Bull. 33: 4755-4763 (1985); J. Org. Chem. 49, 5237-4 (1984); Bull. Chem. Soc. Jpn. 61, 3008-3010 (1988)], * or prepared from a perfluoroalkyl sulfonate compound

• I I

indirectly and transition metal catalyzed, the corresponding * organic tristannyl, preferably tri-n-alkyl * * 35 stannyl compound [J.K. Stille, Angew. Chem. 98: 504-5199 (1986)]. This is then reacted in a one-step reaction of 9-10680 with a halogen, preferably bromo or iodo substituted carbocyclic or heterocyclic aromatic compound [Y. Yamamoto, Y. Azuma, H. Mitoh,

Communications 1986, 564-565; T.J. Bailey, Tetrahedron 5 Letters 27 (1986) no. 37, 4407-4410], which may additionally have other substituents; The Ιΐβ substituent then has the desired substitution or is a precursor having the desired substitution.

Numerous reactions with steroids having a trifluoromethanesulfonate group at the 4-position of the β-phenyl ring are described in EP-A-0 283 428. Free hydroxyl groups can be alkylated or acylated in a manner known per se. Dialkylamines can be converted to the desired N-oxides using suitable oxidizing agents (e.g., hydrogen peroxide 15 or peracids) [see, e.g. Contact (Darmstadt) 1986, 3, p.12].

Compounds having dialkylamine substituents on the Ιΐβ-phenyl ring can be modified by reacting with bromocyano in aprotic solvents such as dioxane, benzene or toluene at elevated temperature (Braun amine cleavage) in the reference Org. Reactions 7 (1953) 198, K.W. Bentley, Techniques of 't', Organic Chemistry 11, 773 (1963) and Houben-Weyl, 5/4 (1960) 151, as described in Yield 4-1. The compounds of the present invention are useful as the corresponding (N-cyano-N-alkylamino-N-aryl) derivatives.

These are always reduced, according to the final meaning of the group of the final product, R 7 -N, to the dialkyl amine * 1, in a manner known per se. Ni compounds (e.g., diisobutylaluminum hydride in toluene as N-formyl-N-alkylaminophenyl intermediates followed by lithium aluminum hydride) or N-H-N-; ·, · 35 alkyl compounds (for example, lithium aluminum hydride or lithium in liquid ammonia). The latter 10 110680 are then acylated as desired in the literature, if desired, and optionally subsequently reduced, for example, with lithium aluminum hydride to a new dialkylamine derivative (cf.

5 DE 36 23 038).

Finally, in process step d), the desired substituents R 2 and R 3 of the 17-C atom are finally attached, unless it is a methoxy or hydroxyl group previously obtained as R 2, or a hydrogen atom as R 3 or a keto oxygen formed together by R 2 and R 3. This coupling is carried out according to methods known in the literature (e.g. J. Fried, J. Edwards, Organic Reactions in Steroid Chemistry, van Nostrand Reinhold Company, vol. 1 and 2, 1972; Terpenoids and 15 Steroids, Specialist Periodical Report, The Chemical Society, vol. 1-2, London) using nucleophilic coupling to the C-17 ketone.

, o

Attachment of the substituent -C = C-Y to R, wherein Y has the meaning given above, occurs; 20 with a metal compound of the general formula MC = C-Y ', wherein Y' is an alkyl protecting group such as trimethylsilyl or tert-butyldimethylsilyl.

The organometallic compound may also be formed in situ and reacted with the 17-ketone. Thus, for example, 17 · ketone in a suitable solvent may be reacted with acetylene and an alkali metal, particularly potassium, sodium or lithium, in the presence of alcohol or ammonia. The alkali metal may also act, for example, as methyl or butyllithium. Particularly suitable solvents are dialkyl ethers, tetrahydrofuran, dioxane, benzene and toluene.

•; The coupling of 3-hydroxypropylene, propylene, or propane to the 17-position is accomplished by reacting the 17-ketone with the dianion 35 of propargyl alcohol (3-hydroxypropylene), for example, the in-situ dipotassium salt of propargyl, - 11 1106813 ynyl) -17β-hydroxy derivative or with metal derivatives of 3-hydroxypropyn, for example 1-lithium-3- (tetrahydropyran-2'-yloxy) prop-1-yn-1-id 17- [3- (tetrahydropyran- 2'-yloxy) prop-1-ynyl] -17? -Hydroxy-5, which can then be hydrogenated to 17- (3-hydroxypropyl or hydroxypropenyl) -17? -Hydroxy compounds. This is accomplished, for example, by hydrogenation at room temperature and pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate by the addition of noble metal catalysts such as platinum or palladium.

Coupling of homologous hydroxyalkyne, hydroxyalkene, and hydroxyalkane groups is accomplished in a similar manner using propargyl alcohol homologs.

A compound having a Z-configuration double bond in the hydroxypropenyl group is formed by hydrogenation of an acetylene triple bond with a deactivated noble metal catalyst (J. Fried, J. Edwards, Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold 20 Company 1972, p. 134; and HO House, Modern; Synthetic t ·.:. Reactions 1972, p. 19). When deactivated with precious metal: ·. catalysts include, for example, a 10% palladium-barium sulfate catalyst in the presence of an amine or a 5% palladium-on-carbon catalyst using a lead (II) - '· *' acetate addition. Hydrogenation is stopped when one equivalent of hydrogen is consumed.

The compound having the E-configuration double bond in the hydroxypropenyl group is formed by reduction of the acetylene triple bond in a manner known per se. A large body of literature has been described in the literature. methods for converting alkynes to trans-olefins, for example, reduction with sodium in liquid ammonia (J. Am. Chem. Soc. 63 (1941) 216), sodium amide · 35 in liquid ammonia (J. Chem. Soc. 1955, 3558). , ____ lithium in small molecule amines (J. Am. Chem.

12 110680

Soc. 77 (1955) 3378), boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1972) 6560), diisobutylaluminum hydride and methyl lithium (J. Am. Chem. Soc. 89 (1967)). 5085) and especially with lithium aluminum hydride / alcoholate (J. Am. Chem. Soc. 89, 4245 (1967)). Another possibility is the reduction of the triple bond with chromium (II) sulfate in the presence of water or dimethylformamide under mildly acidic conditions (J. Am. Chem. Soc. 86, 4358 (1984)), and generally reduction by allowing the transition metal compounds to effect oxidation.

The coupling of hydroxyalkenes can be accomplished directly by the addition of a corresponding hydroxyalkenyl metal compound such as 1-lithium-3- (tetrahydropyran-2'-yl-15-oxy) prop-1 (E) -ene (J. Org. Chem. 40, 2265) or 1- lithium 3- (tetrahydropyran-2'-yloxy) prop-1 (Z) -ene (Synthesis 1981, 999). Homologs can also be linked in this way.

The coupling of 3-hydroxypropane to the 17-position can also be accomplished directly by reacting the 17-ketone with metal derivatives of 3-20 halo-propanols - wherein the 1 »hydroxyl group is in the metal treatment step as an alcohol, tin (Tetrahedron Letters 1978, 3013) or protected. (J. Org. Chem. 37, 1947) as a 17- (3-hydroxypropyl) -17β-hydroxy compound or as a protected compound from a terminal hydroxyl group. Protective groups V include, for example, ethoxyethyl, tetrahydropyranyl and methoxymethyl groups.

If the final products of formula I, in which R2 / R3 is of interest, are desired, 30 · .. o · j-1 o

Vcα 35 Π 13 11068b The 17- (3-hydroxypropyl) or 17- (4-hydroxybutyl) compound is oxidized in a manner known per se, for example Jones reagent, brownstone, pyridinium dichromate, pyridinium chlorochromate, chromic acid pyridine or Fetizonarbona reagent / selite (Compt. rend. 267 (1968) 900).

Preparation of final products of formula I in which R2 / R3 is of significance

10 Ϊ J

The ω1 17 is carried out by the corresponding ring closure reaction of the corresponding 17- (3-hydroxyprop-1- (Z) -enyl or 17-15 (4-hydroxybut-1- (Z) -enyl-17β-hydroxy duct). Hydrogenation of the 6-ring spiroether by contact with palladium on activated carbon leads to saturated spiro ethers.

; Synthesis of the 17-cyanomethyl side chain is carried out in a manner known per se from the 17-ketone, for example, through 17-spiroepoxide and by cleavage of the spiroepoxide; HCN to five Z. Chem. 18: 259-260 (1978).

Also, the 17-hydroxyacetyl side-chain linkage is performed by methods known per se, for example, in J. Org. Chem. 47: 2993-2995 (1982), Chem. Ber.

113 (1984), 1184 or according to the methods described in U.S. Patent 4,600,538.

The free hydroxyl groups may be alkylated or acylated in a manner known per se.

Optionally, the substituent R 1 and R 2 R * may also be coupled first as described in d) and then c) the substituent R 4 will always be synthesized according to the reaction conditions of the second reaction step. first linked and synthesized .... substituents.

14 11068ο

The protecting groups present are further cleaved using conventional methods.

The resulting compounds of general formula I wherein X represents an oxygen atom may, if desired, be reacted with hydroxylamine hydrochloride in the presence of tertiary amines at -20 to +40 ° C to oximes (formula I wherein X represents a hydroxyimino group> N-). 0H, whereby the hydroxyl group may be in the syn or anti position). Suitable tertiary bases include, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7. -ene (DBU), with pyridine being preferred.

Removal of the 3-oxo group to give the final product of general formula I, wherein X represents two hydrogen atoms, can be effected, for example, according to the instructions set forth in DE-A-28 05 490 using thioketal reducing cleavage.

The novel compounds of general formula I together with their pharmacologically tolerated acids form Addition salts are valuable substances. They have ;; 'has a potent effect on gestagenic receptors and surprisingly •' 'strong antigenestagenic and antiglucocorticoid, ··' antimeric corticoidal and antiandrogenic properties.

These substances, which have excellent anti-gestagenic activity, are suitable for abortion because they remove progesterone from the receptor required for maintenance of pregnancy. They are therefore valuable and interesting; 30 others for use in post-partum fertility control.

*; *. Compositions may be prepared based on the compounds of general formula I and their addition salts with pharmacologically acceptable acids, optionally in the presence of conventional excipients and carriers.

is 11068b

The compounds of the formula I and their salts may be further processed by methods known per se for enteral, percutaneous, parenteral or topical use. They can be administered as tablets, granules, jelly capsules, granules, suppositories, transplants, injectable sterile aqueous or oleaginous solutions, suspensions or emulsions, ointments, creams and jellies.

The active ingredient or agents may then be mixed with standard excipients such as, for example, gum arabic, talc, starch, mannitol, methylcellulose, lactose, surfactants such as Tweens'R or Myrj'R, magnesium stearate, aqueous or non-aqueous carriers, dispersants, emulsifiers, preservatives and flavoring agents (for example, essential oils).

As the addition salts of the compounds of the invention with acids, in particular hyd. . 20 hydrochlorides and methanesulfonates.

'; The unit dose contains from about 1 mg to about 100 mg of active ingredient (s).

The dosage of the compounds of the invention is about 1 to 1000 mg per day in man.

In order to characterize the antigenic effect, the abortifacient effect was determined.

The experiments were performed using female rats weighing about 200 g. Following mating, the onset of pregnancy was confirmed by detecting sperm by sweeping the extracted 30 vaginal specimens. Sperm date is 1 day of pregnancy (dl p.c.).

The animals were treated with the respective test substance or solvent after immersion (d5 p.c. -,? 35 d7 p.c.) in the uterine mucosa. Animals were sacrificed on the 9th day of pregnancy (d9 p.c.) and implanted and resorption sites of uterus were examined.

110 ^ 16

Photographs were taken of all wombs. Absence of implants, pathal, bleeding, or otherwise abnormal sites of nidation were interpreted to terminate pregnancy.

The test substances were dissolved in a benzyl benzoate-castor oil mixture (1: 4 ratio). The amount of solvent per single dose was 0.2 ml. The treatment was subcutaneous.

The superiority of the compounds of the invention is clearly demonstrated in the individual by comparing the effect of Compounds A to E on the effect of contraception on Compound F described in EP 0 057115; reference compound F (RU 486) differs from compound A only in respect of the additional 9 (10) double bond.

The following compounds were studied as antigestagens: A: 11β- [4- (dimethylamino) phenyl] -173-hydroxy-17α- (1-propynyl) -4-estren-3-one B: (Z) -11β- [4- ( dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one. 20 C: (Z) -11β- (4-Acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one D: (Z) -173-Hydroxy-17α - (3-Hydroxy-1-propenyl) -? 11? - [4- (3-pyridinyl) phenyl] -4-estren-3-one E: (Z) -4 '- [17? -Hydroxy-17? - ( 3-hydroxy-1-propene: 25 yl) -3-oxo-4-estren-11B-yl] [1,1'-biphenyl] -4-; carbonitrile F: 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -4,9 (10) -estradien-3-one 1710681 '

Abortion test in pregnant rats. Time of treatment d5 p.c. - d7 p.c., autopsy d9 p.c.

Compound Dose Interruption Level 5 te mg / animal / day s.c. n abortions / n total% A 3.0 4/4 (100) 1.0 4/4 (100) 0.3 3/4 (75) 10 - B 3.0 4/4 (100) 1.0 4/4 (100 ) 0.3 4/4 (100) 15 C 3, 0 4/4 (100) 1.0 4/4 (100) 0.3 4/4 (100) 0.1 4/4 (100) 20 D 3, 0 4/4 (100) 1.0 4/4 (100). . 0.3 4/4 (100) E 3, 0 4/4 (100) 25 i, and 4/4 (100) 0, 3 4/4 (100); ··; o, i 4/4 (100) · F 3, 0 4/4 (100) 30 1.0 2/4 (50) 0.3 0/4 (0)

Solvent as reference: 35 0.2 ml benzylbenzene! . soate / ... · castor oil (1: 4) - 0/5 (0) ·: * '40 ---— n = 4 rats 18 1 10681;

Preparation of the required intermediates of general formula II

The starting compound A (3,3- [2,2-dimethyl-1,3-propanediylbis-5 (oxy)] -5a, 10a-epoxyestr-9 (11) -βη-17β-β1ϊ) required for all syntheses is described in EP-A-0 110 434 and 0 127 864.

For the case where R 4 = -N (CH 3) 2, 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -5 (10) -estren-3-one ( 1 M) preparation to represent all compounds of general formula II.

By using a nucleophilic reagent other than propylene in the synthesis step IL, other R 2 / R 3 groups of the invention can also be attached under the conditions described above.

Example 2 illustrates the preparation of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 10β, 11β- (5-methoxy-o-phenylene-thio) -estran-5α, 17β-4β-1βη.

As described in Example 1, optionally using a nucleophilic reagent other than t · · · · · · · · · · · · · · · · Propyne and proceeding in a similar manner to step IL affords compounds of general formula II wherein R 4 '' is a methoxy group.

• 'Other starting materials of general formula II may be prepared as shown in the following scheme' (the substituents R1, R2, R3, R4 'and R4 have the same meaning' as in the general formulas).

Compounds D, E and L are compounds of general formula II.

Reaction Step F - I is carried out using compounds F where R 4 'is a hydroxyl group. This is coupled, if appropriate, by cleavage of the corresponding methyl ether.

; . Steps F _> I and I _> K are carried out in the same manner as the triflate ·; ·· 'formation and subsequent coupling of the Ιΐβ-aryl group at 4-35 positions after isomerization.

19 i i l C ^

C I

<U Λ _ «> 1 (¾, .-- <U fl" «X * .s / —V- ^ + J (Ö / / \« λ; ^ \ / -V> 3 ") - (> 0 ε

m / C = 141 141 H

m. s / rS) / \ «m s>. -n cn \ v -V () · π c −π

«-I W> P

α *. m NX. 3 «H U o. O n y rn • H 0) QJ CN '* U ^ T3 CQ 1¾ £ If) 1

* H · Η H 4J «3 C

, _ ^ * H

k / I v o O - / n Q cn

H «\ - ~~ \ I \ OK

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20 1 10688

The column chromatography purification steps are carried out in the following examples, unless otherwise stated, on silica gel using a mixture of hexane and ethyl acetate as the eluent, optionally with a mixture of increasing polarity.

Example 1 Preparation of 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (1N) A. 10β - [(3-Aminophenyl) thio] - 3,3- [2,2-Dimethyl-1,3-10-propanediylbis (oxy)] - 9 (11) -estren-5a, 17? -Diol (IA) 750 mg of 3-mercaptoaniline are dissolved in 5 ml of absolute THF and is stirred at -40 ° C with 3.73 ml of a 1.6 M solution of n-butyllithium in hexane.

Remove the cooling and stir for 30 min. Then 500 mg of 3,3- [2,2-dimethyl-1,3-propanediyl-bis (oxy)] - 5a, 10a-epoxyestr-9 (11) θη-17β-ο1Ϊ3 is dissolved in 4 ml of absolute THF, whereby the temperature is maintained at 0 ° C. Stirring is then continued for 2 hours at room temperature. The reaction mixture is stirred with 15 ml '; saturated NH 4 Cl solution and extracted with ethyl acetate, the solvent is removed under reduced pressure. Column chromatography gives 484 mg of Compound IA as a foam.

B. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11. 10B - [[3- (Formylamino) phenyl] thio] -9 (11) -estrene-? 5a, 17? -Diol (IB) 0.4 mL of acetic anhydride and 0.17 mL of formic acid are combined and stirred for 15 min under argon at room temperature . To this solution is added 1.0 g of compound 30 IA dissolved in 5 ml of pyridine p.a. and stirred at room temperature under argon for 2 hours. The reaction mixture is then taken up in ethyl acetate, ··· shaken with saturated NaHCO 3 solution until · · · reached a pH of about 8, washed with water, dried with V 35 Na 2 SO 4 and evaporated in a rotary evaporator.

21 11068ο

Yield after column chromatography: 935 mg of compound IB as a foam C. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 10β - [[3- (methylamino) phenyl] thio] -9 (11) -estren-5α, 17β-diol (1C) 9.4 g of compound IB and 2.5 g of lithium aluminum hydride are heated in 400 ml of absolute THF at 80 ° C under argon for 1 hour under reflux. The excess lithium aluminum hydride is then hydrolyzed with water, diluted with ethyl acetate, separated with the organic phase and washed with water, dried over Na 2 SO 4 and the solvent removed in a rotary evaporator.

Yield after column chromatography: 8.4 g of 1C as a 15D foam. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 10β - [[3- (N-formyl-N-methylamino) phenyl] thio] -9 (11) -estren-5α, 17β-diol (ID)

Execution and processing as in Example IB.

Amounts used: 8.6 g of 1C, 3.39 ml of 20-acetic anhydride, 1.4 ml of formic acid, 45 ml of pyridine 1 p.a.

Yield after column chromatography: 6.0 g of compound ID as a foam «E. 10β - [[3-dimethylamino) phenyl] thio] -3,3- [2,2-di-, · 25 methyl-1, 3-Propanediylbis (oxy)] -9 (11) -estrene-? 5a, 17? -Diol (IE) 3.95 g of ID are dissolved in 150 ml of absolute THF and stirred at 0 ° C under argon atmosphere: 1.46 ml: with 10 M borane, 30 dimethylsulfide complex solution in THF. Stirring is continued at room temperature for 2.5 hours. Reaction mixture. Slowly stir in 4 ml of methanol at 0 ° C and leave to stand overnight with air ·; ··. It is then diluted with water and ethyl acetate. The organic phase is separated, washed with water, dried over Na2SO4 and evaporated under reduced pressure. Yield after column chromatography: 3.6 g of IE as a foam.

F. 10β - [[2-Bromo-5- (dimethylamino) phenyl] thio] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 9 (11) -5-estren-5a , 17β-diol (1F) 5 g of IE are dissolved in 200 ml of CCl4, stirred at 0 ° C with 1.65 g of N-bromosuccinimide and stirred at 0 ° C under argon for 2 hours. The reaction mixture is diluted with CH 2 Cl 2 and stirred with saturated NaHCO 3 solution, the organic phase is washed with water and dried over Na 2 SO 4 and the solvent is removed in a rotary evaporator.

Yield after column chromatography: 2.7 g of 1F as 15G foam. 10β, 11β- [5- (dimethylamino) -o-phenylenethio] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] estran-5a, 17β-diol (1G) 1.7 g of 1F, 1.15 ml of tri-n-butyltin anhydride and 30 mg of azobisisobutyronitrile. The mixture is stirred in 115 ml of toluene p.a. under argon and J 1 is refluxed for 1 hour under a 300 W light bulb.

;; * · Column chromatography gives 675 mg of «» * 'as a 1G foam.

H. 11β- [4- (Dimethylamino) -2- (methylthio) phenyl] -3,3'-trans, 25 [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5 (10 ) -; θ3ΐηθη-17β-ο1ί (1H) 300 ml of liquid ammonia are condensed in a beaker cooled to -70 ° C. 7.23 g of compound 1G in 50 ml of absolute THF 30 are added dropwise at -70 ° C. Add 521 mg of lithium in portions, then stir at the same temperature for 3 hours, using a shielding gas. 1.5 ml of t-butanol are then added dropwise and stirred for a further 2 hours. After adding 1.5 ml of iodomethane, warm to room temperature and dilute with water. The mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography of the residue gives 4.34 g of 1H as a white foam.

1. 11β- [4- (Dimethylamino) phenyl] -3,3- [2,2-dimethyl-5,3-propanediylbis (oxy)] - 5 (10) -estren-17? -Ol

(ID

The four spatula spiked Raney nickels are washed five times with methanol and mixed with a solution of 4.30 g of 1H in 200 ml of methanol.

The reaction mixture is stirred for 16 hours using shielding gas at room temperature. The solution is decanted, the residue is washed twice with methanol and three times with dichloromethane. The combined solutions are suction filtered through a filter crucible and evaporated under reduced pressure. Column-15 chromatography of the residue gives 2.35 g of compound 11 as a white foam.

K. 11β- [4- (Dimethylamino) phenyl] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5 (10) -estren-ννβ-οηχ (1K) 20 containing 2.3 g of compound 11, 2.45 ml of i *! of cyclohexane and 350 mg of aluminum triisopropylate in 50 ml of toluene are boiled in a water separator for 14 hours using a shielding gas. After cooling, the reaction mixture is stirred with water and extracted with ethyl acetate.

The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on alumina (neutral, step III) using a mixture of hexane and ethyl acetate as eluent.

2.16 g of 1K are obtained as a white foam.

L. 11β- [4- (dimethylamino) phenyl] -3,3- [2,2-dimethyl *; , 1,3-propanediylbis (oxy)] - 17α- (1-propynyl) - ”· 5 (10) -β3ΐηβη-17β-ο1ϊ (IL) · · 75 ml of absolute tetrahydrofuran are saturated by passing propylene at a temperature of 1 hour. 0 ° C. Subsequently, at 0 ° C, 16 ml of a 15-24 110686% butyl lithium hexane solution are added dropwise and the mixture is stirred for 1 hour under a protective gas. After a solution of 2.1 g of 1K is added dropwise, the mixture is stirred for an additional 20 hours at room temperature. The reaction mixture is stirred with water and extracted with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on alumina (neutral, step III) using a mixture of 10 hexane and ethyl acetate as eluent. 2.13 g of IL are obtained in the form of a white foam.

M. 11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -5 (10) -estren-3-one (1 M) 2.11 g of compound IL are dissolved in 100 ml of acetone , Is mixed with 17 ml of 4 M hydrochloric acid and stirred at room temperature for 30 min. The reaction solution is neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, and dried. evaporated under reduced pressure. Residual column ;; · Chromatography yields 1.59 g of IM as a white foam.

N. 11β- [4- (Dimethylamino) phenyl] -173-hydroxy-17α-: 25 (1-propynyl) -4-estren-3-one (IN):: 509 mg of p-toluenesulfonic acid is heated to 95 of toluene under boiling gas to the boiling point. 1.05 g of compound IM in 5 ml of toluene are added rapidly. Stir at 110 ° C for 45 min and add. After 30 drops of triethylamine. After cooling, it is washed with sodium bicarbonate solution.

; . The organic phase is dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 223 mg of the title compound IN 35 as a white foam.

1106ο-, 1 H NMR (CDCl 3) δ: 7.27 ppm (2Η, d, J = 8 Hz, aromatic); 6.67 ppm (2H, d, J = 8 Hz, aromatic); 5.85 ppm (1H, s, broad, H-4); 3.33 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.5 Hz, H-11); 2.94 ppm (6H, s, H-NCH 3); 1.89 ppm (3H, 5 s, H-CH 3 - (> C-); 0.67 ppm (3H, s, H-18)) [α] 20 D = 17.0 ° (CHCl 3; c = 0.505). ).

Compound 11 may also be prepared according to the following protocol:

To a solution of 2.5 g of 1115- [4- (10-dimethylamino) phenyl] -173-hydroxy-5 (10) -estren-3-one (prepared in Tet. Let. 24, 5205 (1983)): dichloromethane, 1.66 g of 2,2-dimethyl-1,3-propanediol, 0.87 ml of trimethoxymethane and 150 mg of p-toluenesulfonic acid are added. The reaction mixture is stirred for 14 hours under shielding gas at room temperature, diluted with dichloromethane and washed with sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane.

The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. Column chromatography of the residue, 20, gives 2.32 g of compound 11.

Example 2 Preparation of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] -?,? - (5-methoxy-o-phenylenethio) estran-5?, 17? -Diol (2B): 25 A. 10β - [(2-Bromo-5-methoxyphenyl) thio] -3,3- [2,2-di ', 2'-methyl-1,3-propanediylbis (oxy)] -9 (11) - ester- 5α, 17β-diol (2A)

Execution and processing are as described in Example IA.

, ·,; Amounts used: 12.73 g of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] -5a, 10a-epoxyestr-9 (11) -εη-17β- *; . ol in 100 ml absolute tetrahydrofuran, 22.3 g 2-bromo-5-methoxythiophenol in 182 ml absolute *: ··: tetrahydrofuran, 40 ml 2.5 M butyllithium solution in n-35 hexane.

26 11068,

Column chromatography gives 17.99 g of 2A. Mp: 117-119 ° C.

B. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 10β, 11β- (5-methoxy-o-phenylenethio) estran-5α, 17β-5 diol (2B)

Execution and processing are as in Example 1G.

Yield: 1.09 g of 2B, m.p. 95-97 ° C.

Example 3 Preparation of 11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (3E) A. 11β- [4- (Dimethylamino) ) Phenyl] -17β-hydroxy-4-estren-3-one A solution of 2.7 g of 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-5 (10) -estren-3-one (Preparation in Tet. Let. 24, 5205 (1983)) In 270 ml of dichloromethane, heat with 3.91 g of p-toluenesulfonic acid under reflux for one day, then add a few drops of triethyl! amine. After cooling, wash with sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 1.85 g of 3A as a white foam.

* · · / · · Β. 11β- [4- (dimethylamino) phenyl] -3,3- [1,2-ethanediylbis (thio)] -4-estren-17β-ol (3B)

To a solution of 500 mg of 3A in 5 ml of glacial acetic acid is added 0.11 ml of 1,2-ethanedithiol and 3.62 mg of p-toluenesulfonic acid. The reaction mixture is stirred for 1 hour at room temperature under a shielding gas and then Ί. make basic with 2 M sodium hydroxide. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure; pressure. Column chromatography gives 399 mg of 3B.

C. 11β- [4- (Dimethylamino) phenyl] -3,3- [1,2-ethane-diyl-bis (thio)] - 4-estren-17-one (3C) 5 Solution containing 390 mg of the compound 3B, 0.42 ml of cyclohexanone and 76 mg of aluminum triisopropylate in 10 ml of toluene are refluxed for 30 hours in a water separator. After cooling, the reaction mixture is stirred with water and extracted with ethyl acetate, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 330 mg of 3C as a white foam.

D. 11β- [4- (Dimethylamino) phenyl] -3,3- [1,2-ethanediyl] bis (thio)] - 17α - [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-propynyl] -4-63 ^ οη-17β-ο1ϊ (3D)

A solution of 0.89 ml of 2- (2-propynyloxy) tetrahydro-2H-pyran in 30 ml of tetrahydrofuran is stirred at 0 ° C with a solution of 3.66 ml of 15% butyllithium in hexane, · , · 20 sleigh solutions, and stir for 30 min at 0 ° C under a protective gas. A solution of 280 mg of 3C in 10 ml of tetrahydrofuran is then added dropwise at the same temperature. It is then stirred for two hours at a temperature of <»· · <; 0 ° C. The reaction mixture is stirred with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 328 mg of 3D as a white foam.

, ·, 30 E. 11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propynyl) -4-estren-3-one (3E) '1. 300 mg of 3D and 2.21 g of glycolic acid hydrate are dissolved in 18 ml of glacial acetic acid. The reaction mixture is stirred for 1.5 min under shielding gas at room temperature, stirred with 2.1 ml of 4 M aqueous hydrochloric acid and stirred for a further 10 min. The reaction mixture is then neutralized with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography of column 5 gives 135 mg of 3E.

Crystallization from a mixture of ethyl acetate and hexane affords 112 mg of the title compound. Mp: 142-145 ° C; [α] 20 D = + 4.0 ° (CHCl 3; c = 1.000) F. 11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4- estren-3-one (3F)

A solution of 78 mg of 3E in 2 ml of pyridine is hydrogenated for 3 hours to give 13 mg of 10% Pd / BaSCh catalyst. The reaction mixture is suction filtered with celite and then washed with ethanol-15a and dichloromethane. The filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel using a mixture of dichloromethane and methanol as eluent. 63 mg of 3F is isolated as a white foam.

1 H-NMR (CD 2 Cl 2) δ: 7.27 ppm (2H, d, J = 9 Hz, Aromatic H); 6.67 ppm (2H, d, J = 9 Hz, aromatic H); 5.78 * · ** ppm (1H, s, broad, H-4); 5.68 ppm (1H, ddd, J = 12.5 Hz and J = 5.0 Hz and J = 4.5 Hz, H-CH =); 5.63 ppm (1H, d, J = 12.5 Hz, * H-CH =); 4.32 ppm (1H, dd, J = 13.0 Hz and J = 5.0 Hz); 3.28 ppm? · (1H, dd broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.92 ppm (6H, i: 25 s, H-NCH 3); 0.71 ppm (3H, s, H-18).

Y Example 4t-lip- (4-acetylphenyl) -17β-hydroxy-17α- (1-prop-ynyl) -4-estren-3-one (4K) Δ17β-hydroxy-lip- (4-hydroxyphenyl) -5 (10) -estren-, 30 3-one (4A) 11

To a solution of 5 g of 17β-hydroxy-lip- (4-methoxyphenyl) -5 (10) -estren-3-one (prepared by reference to Tet. Let. 24, 5205 (1983)) in 50 ml of absolute N, N- Dimethylformamide, 3.27 g of sodium methanethiolate are added and the reaction mixture is stirred for 90 min at r%: 160 ° C. After cooling, the mixture is diluted with water and extracted with ethyl acetate 110.b. column evaporation under reduced pressure gives 4.29 g of 4A as a white foam.

B. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- (4-hydroxyphenyl) -5 (10) -estren-17β-ol (4B) A solution containing 4, 2 g of compound 4A, 1.72 g of 2,2-dimethyl-1,3-propanediol, 1.5 ml of trimethoxymethane 10 and 250 mg of p-toluenesulfonic acid in 40 ml of dichloromethane are stirred for 14 hours at room temperature under inert gas. A saturated sodium hydrogen carbonate solution is then added. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. 3.25 g of 4B as a white foam are obtained from Pyl flash chromatography.

C. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β - [4 - [[(trifluoromethyl) sulfonyl] oxy] phenyl] -5 (10) -estren- 17β-ol (4C)! To a solution of 3.2 g of 4B and 4.75 g of 4- (dimethylamino) pyridine in 100 ml of dichloromethane is added dropwise a solution of 1.86 ml of trifluoromethane sulphide in a -78 ° C shield: formic acid anhydride in 10 ml of dichloromethane. reaction

The mixture is further stirred for 2 hours at -78 ° C

and then poured into a saturated sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water, ·; 30 ml, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 2.9 g '! . 4C as a white foam.

D. 11β- (4-Acetylphenyl) -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] -5 (10) -β3 ^ οη-17β-ο1ϊ (4D) 35 contains 2.84 g of 4C in 35 ml of N, N-dimethylformamide, mixed with 393 mg of lithium-30 Π 0688 um chloride and stirred for 15 min at room temperature under a protective gas. 277 mg of tetra-cis (triphenylphosphine) palladium (0) and 1.7 ml of (1-ethoxyethenyl) tributyl stannane are then added. The reaction mixture is stirred for 3 hours at 110 ° C, after cooling, diluted with 120 ml of ethyl acetate and subjected to suction filtration with celite. The filtrate is washed four times with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Chromatography of column chromatography-10 gives 1.79 g of 4D as a white foam.

E. 11β- (4-Acetylphenyl) -17β-hydroxy-5 (10) -estren-3-one (4E) 1.7 g of 4D dissolved in 100 ml of acetone are mixed with 5.4 ml of 4 M aqueous hydrochloric acid and stir for 1 hour at room temperature under a protective gas. The reaction solution is neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over sodium hydroxide solution. sulfate and evaporate under reduced pressure,

h "Column chromatography gives 1.31 g of 4E

• 'as white foam.

··: 4F. 11β- (4-Acetylphenyl) -17β-hydroxy-4-estren-3-: 25 one (4F) • 485 mg of p-toluenesulfonic acid in 100 ml of toluene is heated to 90 ° C under a protective gas. 500 mg of compound 4E dissolved in 5 ml of toluene are added rapidly. The reaction mixture is stirred for 1 hour at 90 ° C, and after cooling, stirred with saturated sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate. account. The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and hexane. 239 mg of the title compound 4F are obtained in the form of a white foam.

110686 1 H NMR (CDCl 3) δ: 7.90 ppm (2H, d, J = 8 Hz, aromatic H); 7.54 ppm (2H, d, J = 8 Hz, aromatic H); 5.87 ppm (1H, s, H-4); 3.61 ppm (1H, dd, broad, J = 9.0 Hz and J = 7.5 Hz, H-17); 3.42 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.5 Hz, H-11); 2.61 ppm (3H, s, H-Ac); 0.52 ppm (3H, s, H-18).

G. 3,3- [1,2-Ethanediyl-bis (thio)] - 11β- [4- (2-methyl-1,3-dithiolan-2-yl) -phenyl] -4-η 3 -β-β-17β-η 1 ( 4G) To a solution of 2.12 g of 4F in 40 ml of glacial acetic acid is added 0.90 ml of 1,2-ethanediol and 1.18 g of p-toluenesulfonic acid. The reaction mixture is stirred for 5 hours at room temperature under a protective gas and then made basic with 2M sodium hydroxide. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The crude product is dissolved in 80 ml of dichloromethane and 160 ml of ethanol and heated under reflux for 6 hours with 1.49 g of solid potassium carbonate. The cooled solution is filtered and evaporated. Column mapping, · 20 mapping gives 2.02 g of 4G as a white foam.

'' H. 3,3- [1,2-Ethanediylbis (thio)] - 11β- [4- (2-methyl- '1,3-dithiolan-2-yl) phenyl] -4-estren-17-one (4H) G In the same manner as in Example 3C, 1.95: 25 g of 4G are prepared using an additional 2.42 ml of cyclohexanone · · · · · n and 438 mg of aluminum triisopropylate in 35 ml of toluene. 4H.

IR (KBr): 1740 cm -1 (C = O) 1. 3,3- [1,2-Ethanediylbis (thio)] - 11β- [4- (2-methyl-1,3-dithiolan-2-one). yl) phenyl] -17α- (1-propynyl) -4- [t] ... θ3 → βη-17β-η1 (41) '. In the manner described in Example IL, 769 mg of 4H and 5.8 ml of a 15% solution of butyllithium in hexane in 50 ml of propylene-saturated tetrahydrofuran are prepared 779 mg of 41.

'] IR (KBr): 2240 cm -1 (C = C) 11068 ° 32 K. 11β- (4-Acetylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one 1 , 28 g of N-chlorosuccinimide and 1.83 g of silver (I) nitrate are placed in 50 ml of a mixture of acetonitrile and water (8: 2). At room temperature, a solution of 700 mg of compound 41 in 3 ml of acetone and 2 ml of acetonitrile is rapidly added dropwise under a shielding gas. After 15 min, saturated sodium sulfite solution, saturated sodium carbonate solution and 10 saturated sodium chloride solution, and dichloromethane are successively stirred. The mixture is filtered with celite, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 238 mg of the title compound as a 4K pale yellow foam.

IR (KBr): 2235 cm -1 (≤ C), 1678 cm -1 (C = O), 1664 cm -1 (C = O) 1 H-NMR (CDCl 3) δ: 7.90 ppm (2H, d, J = 9 Hz, aromatic H); 7.54 ppm (2H, d, J = 9 Hz, aromatic H); 5.88 ppm (1H, s, broad, H-4); 3.48 ppm ( 1 H, dd, broad, J = 6.5 Hz. 20 and J = 6.0 Hz, H-11); 2.80 ppm (1H, m, H-10); 2.60 ppm (3H, 1 H). s, H-ac), 1.8 9 ppm (3H, s, H-CH 3 -C = C-), 0.59 ppm (3H, s, H-18).

* 'Example 5 ...: (Z) - 11 β - (4-Acetylphenyl) -17? -Hydroxy-17? - (3- ?: hydroxy-1-propenyl) -4-estren-3-one (5C) Preparation A. 3,3- [1,2-Ethanediylbis (thio)] - 11β- [4- (2-methyl-1,3-dithiolan-2-yl) phenyl] -17α- [ 3 - [(Tetrahydro-2H-pyran-2-yl) oxy] -1-propynyl] -4-θ3 ^ βη-17β-30 ol (5A)

1.0 is prepared as described in Example 3D. g of 4H and 2.74 ml of 2- (2-propynyloxy) tetrahydro-2H-pyran and 11.3 ml of a 15% solution of butyl lithium in 120 ml of tetrahydrofuran- 35 nia 1.19 g of 5A.

11068b 33 B. lip- (4-Acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propynyl) -4-estren-3-one (5B) 1.73 g of compound 5A is reacted With 2.71 g of N-chlorosuccinimide and 3.87 g of silver (I) -5 nitrate in 10 ml of acetone, 24 ml of water and 96 ml of acetonitrile as described in Example 4K. The crude product is mixed with 127 mg of pyridinium p-toluenesulfonate in 15 ml of aqueous ethanol for two hours at 60 ° C. The solvent is evaporated to half volume, diluted with ethyl acetate, washed with half-saturated sodium chloride solution and water, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 265 mg of 5B as a pale yellow foam.

IR (KBr): 2235 cm-1 (C? C), 1678 cm-1 (C = O), 1665 cm-1 (C = O) 1 H-NMR (CDCl 3) δ: 7.91 ppm (2H, d, J = 9 Hz, aromatic H); 7.54 ppm (2H, d, J = 9Hz, aromatic H); 5.88 ppm (1H, s, broad, H-4); 4.37 ppm (2H, s, broad, H-CH 2 OH); 2.48 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.81 I ppm (1H, m, H-10); 2.61 ppm (3H, s, H-Ac); 0.62 ppm (3H, s, H-18).

* [C. (Z) -11β- (4-Acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (5C), 255 mg as described in Example 3F. hydrogenation of V 5B using 60 mg of 10% Pd / BaSO 4, in 4 mL of pyridine and 4 mL of ethanol. After silica gel chromatography, 170 mg of the title compound 5C are obtained. Crystallization from a mixture of dichloromethane, 30 methane and diisopropyl ether yields 146 mg ... of 5C as pale yellow crystals.

E. Mp: 225-230 ° C; [α] D 20 = + 76.4 ° (CHCl 3; c = 0.500).

IR (KBr): 1680 cm -1 (C = 0), 1665 cm -1 (C = 0).

34 110681,

Example 6 Preparation of 11β- [4- (dimethylamino) phenyl] -17α- (1-propynyl) -4-estren-17β-ol (6C) A. 11 (3- [4- (Dimethylamino) phenyl] -4-ester -176-ol 5 (6A) 120 ml of liquid ammonia are condensed in a beaker cooled to -75 ° C. Add 91 mg of lithium After 20 min, a solution of 770 mg of compound 3B in 4 ml of tetrahydrofuran is added dropwise. of lithium and then stirred for two hours at -75 [deg.] C. Then, 9 ml of ethanol are added dropwise, the batch is allowed to stand at room temperature overnight and then diluted with water. The mixture is extracted with Chromatography of the residue on silica gel gives 350 mg of 6A as a white foam.

1 H-NMR (CD 2 Cl 2) δ: 7.27 ppm (2H, d, J = 9 Hz, aromatic-t, δ 20 t H); 6.63 ppm (2H, d, J = 9 Hz, aromatic H); 5.40! ppm (1H, s, broad, H-4); 3.51 ppm (1H, ss, broad, J = 9 Hz and "* J = 6 Hz, H-17); 3.22 ppm (1H, dd, broad, J = 6 Hz and J = 5 Hz, : * H-11); 2.91 ppm (6H, s, H-NCH 3); 2.46 ppm (1H, m, H-10); 0.50 ppm (3H, s, H-18).

»T. B. 11β- [4- (Dimethylamino) phenyl] -4-estren-17-one 0 '(6B)

As described in Example 3C, 327 mg of compound 6A is prepared using 400 μΐ of cyclohexanone and 409 mg of aluminum triisopropylate in 10 ml of toluene 225 30 mg of compound 6B.

h. IR (KBr): 1740 cm -1 (C = O) 1 H-NMR (CD 2 Cl 2) δ: 7.28 ppm (2H, d, J = 9 Hz, aromatic H); 6.64 ppm ( 2H, d, J =) Hz, aromatic H); 5.43 ppm (1H, s, broad, H-4); 3.29 ppm (1H, dd, broad, J = 5.5 Hz; V 35 and J = 5 Hz, H-11); 2.91 ppm (6H, s, H-NCH 3); 2.50 ppm (1H, m, H-10); 0.63 ppm (3H, s) , H-18).

35 1 10680 C. 11β- [4- (Dimethylamino) phenyl] -17α- (1-propynyl) -4-estren-17β-ol (6C)

As described in Example IL, 215 mg of compound 6B is prepared using 2.1 ml of a 15% butyl-5-lithium hexane solution in 20 ml of propylene-saturated tetahydrofuran 207 mg of compound 6C. Crystallization from a mixture of pentane and ethyl acetate gives 168 mg of the title compound.

Mp: 187 ° C; [.alpha.] D @ 20 = -28.3 DEG (CHCl3; c = 0.505).

IR (KBr): 2240 cm -1 (C = C)

Example 7 Preparation of (Z) -17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (71) , 3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- [4- (3-pyridinyl) phenyl] -5 (10) -θ3βΓΓη-17β-α1α (7A) and B. 3 , 3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- (4-ethylphenyl) -5 (10) -θ3ίηθη-17β-ο1χ (7B), ·, · 20 Under a shielding gas into the solution, which contains 2.71 g * *! compound 4C in 40 ml of toluene and 18 ml of ethanol, * '' * add 747 mg of diethyl (3-pyridinyl) borane (Aldrich), »· '392 mg of lithium chloride, 6 ml of 2 M sodium carbonate solution * ·». .! and 267 mg of tetrakis (triphenylphosphine) palladium (0). The mixture is heated at 95 ° C for two hours and then, after cooling, transferred to ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 1.94 g of 7A and 171 mg of 7B.

t ♦ C. 17β-Hydroxy-11β- [4- (3-pyridinyl) phenyl] -5 (10) -. estren-3-one (7C)

As described in Example 4E, 1.9 g of compound 7A is prepared using 7 ml of a 4M aqueous hydrochloric acid solution in 150 ml of acetone 1.07 g of compound 7C.

17x-Hydroxy-113- [4- (3-pyridinyl) phenyl] -4-estren-3-one (7D) 1.06 g of compound 7C is dissolved in 20 ml of trichloro methane, is stirred under a shielding gas with 944 mg of p-5 toluenesulfonic acid and heated at reflux for 3 hours. A few drops of triethylamine are added to the cooled solution, diluted with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Silica-10 gel chromatography gives 644 mg of 7D.

IR (KBr): 1667 cm -1 (C = O) 1 H-NMR (CDCl 3) δ: 8.87 ppm (1H, d, broad, J = 2 Hz, H-Py 2); 8.58 ppm (1H, dd, broad, J = 5.0 Hz and J = 2 Hz, H-

Py6); 7.89 ppm (1H, ddd, J = 8 Hz and J = 2 Hz, H-Py4); 7.54 ppm δ (4H, m, aromatic H); 7.37 ppm (1H, dd, broad, J = 8 Hz and J = 5.0 Hz, H-Py5); 5.88 ppm (1H, s, broad, H-4); 3.61 ppm (1H, dd, broad, J = 9.0 Hz and J = 7.0 Hz, H-17); 3.40 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.86 ppm (1H, m, H-10); 0.58 ppm (3H, s, H-18).

, ·, · 20 E. 3,3- [1,2-Ethanediylbis (thio)] - 11β- [4- (3-pyridinyl) phenyl] -4-β3 → θη-17β-η 1 (7E) t "" "As described in Example 4G, 629 mg of compound * 7D is prepared using 123 μΐ 1,2-ethanedithiol and * → ... E 419 mg p-toluenesulfonic acid in 6 ml glacial acetic acid and · 25 using 203 mg of potassium carbonate in 8 ml of dichloromethane. and 45 ml of methanol, 569 mg of compound 7E.

F. 3,3- [1,2-Ethanediylbis (thio)] - 11β- [4- (3-pyridinyl) phenyl] -4-estren-17-one (7F)

In the manner described in Example 3C, 550 30 mg of 7E are prepared using 510 μ 5 of cyclohexanone and 100 µl of aluminum triisopropylate in 17 ml of toluene, 460 mg of compound 7F.

IR (KBr): 1736 cm @ -1 (C = O)> 1 .times.times.110.sub.31068o g. 3.3- [1,2-Ethanediylbis (thio)] - 11β- [4- (3- pyridin-yl) phenyl] -17α- [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-propynyl] -4-β3ΡΓθη-17β-ο1ί (7G) As described in Example 3D, from 442 mg Compound 7F is prepared using 1.30 mL of 2- (2-propynyloxy) tetrahydro-2H-pyran and 5.36 mL of a 15% solution of butyllithium in hexane in 70 mL of tetrahydrofuran 460 mg of 7G.

H. 17β-Hydroxy-17α- (3-hydroxy-1-propynyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (7H)

As described in Example 3E, 453 mg of the compound of Example 7 G is prepared using 3.27 g of glycolic acid and 2.98 ml of 4M aqueous hydrochloric acid in 8 ml of acetone and 8 ml of glacial acetic acid, 234 mg of 15H.

1 H-NMR (CDCl 3) δ: 8.88 ppm (1H, d, broad J = 2 Hz, H-Py 2); 8.59 ppm (1H, dd, broad, J = 4.5 Hz and J = 2 Hz, H-Py6); 7.90 ppm (1H, ddd, J = 8 Hz and J = 2 Hz, H-Py4); 7.53 ppm (4H, m, aromatic H); 7.38 ppm (1H, dd, broad, J = 8 Hz and G 1. 2 J = 4.5 Hz, H-Py 5); 5.89 ppm (1H, s, broad, H-4); 4.38 ppm: (2H, m, H-CH 2 OH); 3.48 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.88 ppm (1H, m, H-10); 0.68 ppm (3H, s, 'H-18) -; L. (Z) -17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β-; ·; 25 [4- (3-Pyridinyl) phenyl] -4-estren-3-one (71) f · As described in Example 3F, 225 mg of 7H is hydrogenated using 45 mg of 10% Pd / BaSCh catalyst in 2 ml of pyridine and 4 ml of ethanol. Silica gel chromatography gives 160 mg of the title compound 71.

IR (KBr): 1663 cm -1 (C = O) 1 H-NMR (CDCl 3) δ: 8.88 ppm (1H, d, broad J = 2 Hz, H-Py 2); 8.59 ppm (1H, dd, broad, J = 4.5 Hz and J = 2 Hz, H-Py6); 7.91 ppm (1H, ddd, J = 8 Hz and J = 2 Hz, H-Py4); 7.52 ppm (4H, 35 m, aromatic H); 7.40 ppm (1H, dd, broad, J = 8 Hz and J = 4.5 Hz, H-Py5); 5.88 ppm (1H, s, broad, H-4); 5.72 ppm 38 110681 (1H, ddd, J = 11, 5 Hz and J = 5.5 Hz and J = 5.5 Hz, H-CH =); 5.65 ppm (1H, d, broad, J = 11, 5 Hz, H-CH =); 4.28 ppm (2H, m, H-CH 2 OH); 3.42 ppm (1H, dd, broad, J = 6.0 Hz and J = 4.5 Hz, H-11); 2.87 ppm (1H, m, H-10); 0.73 ppm (3H, s, H-18).

Example 8 Preparation of 17? -Hydroxy-3-oxo-11? - [4- (3-pyridinyl) phenyl] -4-estren-17? -Acetonitrile (8B) A. 3,3- [1,2-Ethanediylbis (thio) ] -17? -Hydroxy-lip- [4- (3-pyridinyl) phenyl] -4-estren-17α-acetonitrile 10 (8A)

To a solution of 3.31 ml of diisopropylamine in 100 ml of tetrahydrofuran is added dropwise at -78 ° C an aliquot of 13.7 ml of 15% butyl lithium hexane solution. After 30 min, 1.13 ml of acetonitrile are added at the same temperature. 15 min later at the same temperature, 1.00 g of 7F in 90 ml of tetrahydrofuran are added dropwise and stirring is continued for a further 2 hours. It is then mixed with saturated ammonium chloride solution and extracted with ethyl acetate; Sat. The combined organic phases are washed with water, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 1.05 g of 8A.

. B. 17β-Hydroxy-3-oxo-lipo [4- (3-pyridinyl) phenyl] -; 4-Estrene-17α-acetonitrile (8B) As described in Example 3E, 1.04 g of Compound 8A is prepared using 7.51 g of glycolic acid and 6.85 ml of 4 M aqueous hydrochloric acid in 18 ml of acetone and 18 ml of of glacial acetic acid 644 mg of 8B. Crystallization from a mixture of ethyl acetate and hexane gives 597 mg of the title compound.

m.p. 173-174 ° C; [.alpha.] D @ 20 = + 131.8 DEG (CHCl3; c = *; 0.500).

IR (KBr): 2245 cm-1 (C> N), 1664 cm-1 (C = 0).

39 τηοεει

Example 9 (E) -17β-Hydroxy-3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (9A) and 5 (Z) -17β-hydroxy Preparation of -3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-estren-17a-acetonitrile (9B) A. (E) -17β-Hydroxy-3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-ester-17α-acetonitrile 10 (9A) and B. (Z) -17β-Hydroxy-3- (hydroxyimino) -11β- [4- (3-Pyridinyl) phenyl] -4-ester-17-ol-acetonitrile (9B) 219 mg of compound 8B are stirred for 90 min with 50 mg of hydroxylammonium chloride in 5 ml of pyridine under suction gas at 50 ° C. The reaction mixture is taken up in water and extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography and direct crystallization from dichloromethane / diisopropyl ether gives 97 mg of 9A.

', 1 [m.p. 227-229 ° C; [α] D 20 = 192.4 ° (CHCl 3 / MeOH; c = 0.500); IR (KBr): 2250 cm-1 (C = N), 1635 cm-1 (C = NOH)] and 61 mg of 9B [m.p. Mp: 198-200 ° C; [cx] 2d = +230, 4 °> ·; (CHCl 3; c = 0.500); IR (KBr): 2250 cm-1 (C = N), 1635 cm-1: 25 (ONOH)].

Example 10 Preparation of 17β-hydroxy-17α- (2-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (10B) [1,2-Ethanediylbis (thio)] - 17α- (2-propenyl) - 11β- [4- (3-pyridinyl) phenyl] -4-estren-17β-ol (10A). Under the shielding gas is placed 414 mg of magnesium turnings in 5 ml of diethyl ether. Add 150 μΐ of 3-bromo-1-'b 'propene and a few crystals of iodine, then drop by drop: · 35 Slowly add a solution of 2.00 g of 7F and 1.32 g of 3-bromo-1-propene in 40 ml diethyl ether and 10 40 11068c; ml of tetrahydrofuran and reflux for 3 hours. After treatment, a saturated solution of ammonium chloride is added and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 1.63 g of 10A.

B. 17β-Hydroxy-17α- (2-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (10B) 1.44 g as described in Example 3E: From 10A and 10.35 g of glyoxylic acid and 9.40 ml of a 4M aqueous hydrochloric acid solution in 25 ml of acetone in 25 ml of glacial acetic acid are prepared 592 mg of 10B. Crystallization from a mixture of ethyl acetate and hexane yields 15,483 mg of the title compound.

Mp: 127-128 ° C; [α] D 20 = + 128.7 ° (CHCl 3; c = 0.470).

IR (KBr): 1668 cm <-1> (C = 0).

Example 11 Preparation of 17? -Hydroxy-17? - (methoxymethyl) -11? - [4- (3-pyrid-1'-1-ynyl) phenyl] -4-estren-3-one (11C) A. (11β, 17β) -3,3- [1,2-ethanediylbis (thio)] - 11- [4- (3-pyridinyl) phenyl] spiro [estr-4-en-17,2'-oxy] -1H ryan] (HA) '' / / 2.5 g of 7F are mixed with 4.12 g of trimethylsulfonium iodide and 2.75 g of potassium tert-butylate in 100 ml of dimethylformamide under a shielding gas at room temperature. min. Water is then added under cooling in the same ice bath and extracted with ethyl acetate; ·, 30 with acetate. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 866 mg of 11A.

! i I.

* »41 1 10680 B. 3,3- [1,2-Ethanediylbis (thio)] - 17α- (methoxymethyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-17β- (11B) 1.20 g of sodium are dissolved in 15 ml of methanol. A solution of 842 mg of compound 11A in 20 ml of methanol is dropped on Ti-5. The reaction mixture is heated at reflux for 5 hours. Thereafter, most of the methanol is evaporated. The residue is taken up in water and extracted with dichloromethane. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 486 mg of 11B.

C. 17β-Hydroxy-17α- (methoxymethyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (11C) As described in Example 3E, from 470 mg of 11B and 3, From 38 g of glycolic acid and 3.00 ml of a 4M aqueous hydrochloric acid solution in 8 ml of acetone and 8 ml of glacial acetic acid are prepared 252 mg of compound 11C. Crystallization from a mixture of ethyl acetate and hexane gives 20-204 mg of the title compound.

Mp: 145-146 ° C; [.alpha.] D @ 20 = + 120.8 DEG (CHCl3; c = 0.465). IR (KBr): 1665 cm -1 (C = O).

Example 12: Preparation of 11β- (4-ethylphenyl) -17β-hydroxy-17α- (1-propyn: 25-yl) -4-estren-3-one (12F) v; A. 11β- (4-Ethylphenyl) -17β-hydroxy-5 (10) -estren-3-one (12A)

As described in Example 4E, 576 mg of compound 12A are obtained from 863 mg of compound 7B and 3 ml of a 4M aqueous hydrochloric acid solution in 70: 30 ml of acetone.

Β. 11β- (4-Ethylphenyl) -17β-hydroxy-4-estren-3-one. (12B)

As described in Example 7D, 568 mg of compound 12A and 500 mg of p-toluenesulfonic acid 10 in 35 ml of trichloromethane give 443 mg of compound 12B · 42 110681 IR (KBr): 1665 cm @ -1 (C = 0).

1 H-NMR (CDCl 3 + Py-d 5) δ: 7.31 ppm (2H, d, J = 9 Hz, aromatic H); 7.10 ppm (2H, d, J = 9 Hz, aromatic H); 5.84 ppm (1H, s, broad, H-4); 3.59 ppm (1H, dd, broad, 5 J = 9.0 Hz and J = 7.5 Hz, H-17); 3.33 ppm (1H, dd, broad, J = 6.0

Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 2.62 ppm (2H, q, J = 7.5 Hz, H-Et); 1.23 ppm (2H, t, J = 7.5 Hz, H-Et); 0.55 ppm (3H, s, H-18).

C. 3,3- [1,2-Ethanediylbis (thio)] - 11β- (4-ethylphenyl) -4-estren-17β-ol (12C)

As described in Example 4G, 433 mg of 12B and 85 crude 1,2-ethanedithiol and 285 mg of p-toluenesulfonic acid in 5 ml of glacial acetic acid and 140 mg of potassium carbonate in 6 ml of dichloromethane and 30 ml of 15 methanol are prepared. 399 mg of 12C.

D. 3,3- [1,2-Ethanediylbis (thio)] - 11β- (4-ethylphenyl) -4-estren-17-one (12D)

As described in Example 3C, 390 mg of 12C and 360 of cyclohexanone and 70 mg of aluminum, 20 ml of triisopropylate in 15 ml of toluene are prepared! 347 mg of 12D.

IR (KBr): 1740 cm <-1> (C = 0).

E. 3,3- [1,2-Ethanediylbis (thio)] - 11β- (4-ethylphenyl) -17α- (1-propynyl) -4-estren-17β-ol (12E) ): 25 As described in Example IL, 100 mg of 12V and 800 of 15% butyl lithium hexane in 10 ml of propylene-saturated tetrahydrofuran are prepared in 99 mg of 12E.

IR (KBr) δ 2235 cm -1 (C = C).

, ·,; F. 11β- (4-Ethylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (12F). As described in Example 3E, 89 mg of 12E, 64 mg of glyoxylic acid and 600 of 4M aqueous hydrochloric acid in 2 ml of acetone and 2 ml of glacial acetic acid afforded 34 mg of 12F after crystallization from a mixture of dichloromethane and hexane.

43 110686

Mp: 195-196 ° C; [.alpha.] D @ 20 = -17.9 DEG (CHCl3; c = 0.485).

IR (KBr): 2240 cm -1 (C = C), 1655 cm -1 (O).

Example 13 Preparation of (Z) -11β- (4-ethylphenyl) -17β-hydroxy-17α- (3-hydroxy-5-oxy-1-propenyl) -4-estren-3-one (13C). [1,2-ethanediylbis (thio)] - 11β- (4-ethylphenyl-yl) -17? [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-propynyl] -4-θ35Γθη- 17β-ο1ί (13A)

As described in Example 3D, 235 mg of compound 10D and 0.70 ml of 2- (2-propynyloxy) tetrahydro-2H-pyran and 2.90 ml of 15% butyl lithium hexane solution are prepared in 40 ml of tetrahydrofuran 241 mg of 13A.

B. 11β- (4-Ethylphenyl) -17β-hydroxy-17α- (3-hydroxy-15-propynyl) -4-estren-3-one (13B)

As described in Example 3E, from 124 mg of 13A, 1.60 g of glyoxylic acid and 1.50 ml of a 4M aqueous hydrochloric acid solution in 5 ml of acetone and 5 ml of glacial acetic acid are prepared 124 mg of 13B.

IR (KBr): 2230 cm -1 (C = C), 1660 cm -1 (C = 0).

! C. (Z) -11β- (4-Ethylphenyl) -17β-hydroxy-17α- (3-hydroxy- (1,1-oxy-1-propenyl) -4-estren-3-one (13C). In a manner 115 mg of Compound 13B is hydrogenated with 25 mg of 10% Pd / BaSO 4 in 1 ml of pyridine and 4 ml of ethanol.

(I

After chromatography on silica gel and crystallization from dichloromethane / hexane, 76 mg of 13C is obtained.

Mp 98-101 ° C; [?] D25 = +76.6 (CHCl3, c = 0.500).

. IR (KBr): 1665 cm -1 (C = O).

* i • 1 t »i t t 11« 44 110630

Example 14 Preparation of (Z) -11β- [4- (3-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (14D) , 3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- [4- (3-furanyl) phenyl] -5 (10) -estren-17β-17ΐί (14A)

Under a shielding gas is added to a solution of 3.50 g of 4C in 25 ml of dioxane and 0.46 ml of 10 pyridine, 6.43 g of (3-furanyl) tributylstannane (preparation instruction in Synthesis 1985, 898), 510 mg of lithium chloride and 693 mg of tetrakis (triphenylphosphine) palladium (0). The mixture is heated at reflux for 2 hours, transferred to ethyl acetate after cooling and filtered through celite. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. Purification by Pyl flash chromatography gives 2.79 g of 14A.

B. 11β- [4- (3-Furanyl) phenyl] -17β-hydroxy-4-estren-3-one (14B) · · · · 2.70 g of 14A are prepared according to the procedures of Examples J 4E and 7D. ketal hydrolysis and isomerisation using * 1.03 g of 14B.

1 H NMR (CDCl 3) δ: 7.74 ppm (1H, dd, J = 1.3 Hz and J = 0.8 Hz, H-Fu 2); 7.48 ppm (1H, dd, J = 1.8 Hz and J = 1.3 Hz, 25 H-Fu5); 7.42 ppm (4H, m, aromatic H); 6.71 ppm (1H, dd, V * J = 1.8 Hz and J = 0.8 Hz, H-Fu4); 5.87 ppm (1H, s, broad, H-4); 3.60 ppm (1H, dd, J = 9.0 Hz and J = 7.0 Hz, H-17); 3.36 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 0.57 ppm (3H, s, H-18).

30 C. 11β- [4- (3-Furanyl) phenyl] -173-hydroxy-17α- (3- [4-hydroxy-1-propynyl) -4-estren-3-one (14C) '! . 1.00 g of Compound 14B is prepared according to the instructions of Examples 4G, 3C, 3D and 3E, 358 mg of Compound ': ** 14C.

35 IR (KBr): 2230 cm -1 (C = C), 1660 cm -1 (C = 0).

11068ο 45 D. (β) -11β- [4- (3-Furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (14D) As described in Example 3F. 344 mg of 14C is hydrogenated using 70 mg of 10% Pd / BaSC> 4-5 in 3 ml of pyridine and 6 ml of ethanol. After silica gel chromatography and crystallization from ethyl acetate and hexane, 180 mg of the title compound 14D are obtained.

Mp: 164-166 ° C; [.alpha.] D @ 20 = + 99.0 DEG (CHCl3; c = 0.200).

IR (KBr): 1662 cm -1 (C = O).

Example 15 Preparation of (β) -11β- [4- (2-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (15D) , 3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- [4- (2-furanyl) phenyl] -5 (10) -estren-17β-οΐί (15A)

Under a shielding gas is added to a solution of 4.00 g of 4C in 65 ml of toluene and 25 ml of ethanol, 1.52 g of (2-furanyl) boronic acid (Preparation • in J. Heterocycl. Chem. 1975, 195), 580 mg of lithium chloride, 8.5 ml of 2 M sodium carbonate solution and 340 mg of tetrakis (triphenylphosphine) palladium (O). The mixture is heated at reflux for 4 hours and transferred: after cooling to ethyl acetate. The organic phase is washed with 1M sodium hydroxide and saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 2.57 g of 15A.

. ·,; B. 11β- [4- (2-Furanyl) phenyl] -170-hydroxy-4-estren-3-one (15B) 2.52 g of compound 15A are prepared according to the procedures of Examples 4E and 7D by ketal hydrolysis and isomerization. : using 1.10 g of 15B.

IR (KBr): 1664 cm -1 (C = O).

46 1106οι.

1 H-NMR (CDCl 3 + Py-d 5)) δ: 7.60 ppm (2H, d, J = 9 Hz, aromatic H); 7.47 ppm (1H, dd, J = 1.8 Hz and J = 0.8 Hz, H-Fu5); 7.44 ppm (2H, d, J = 9 Hz, aromatic H); 6.62 ppm (1H, dd, J = 3.5 Hz and J = 1.8 Hz, H-Fu3); 6.48 ppm (1H, dd, J = 3.5 Hz and J = 0.8 Hz, H-Fu4); 5.85 ppm (1H, s, broad, H-4); 3.61 ppm (1H, dd, J = 9.0 Hz and J = 7.0 Hz, H-17); 3.38 ppm (1H, dd, broad, J = 5.5 Hz and J = 5.0 Hz, H-11); 2.84 ppm (1H, m, H-10); 0.56 ppm (3H, s, H-18).

C. 11β- [4- (2-Furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (15C) from 1.07 g of 15B according to the instructions of Examples 4G, 3C, 3D and 3E, 313 mg of 15C is prepared. IR (KBr): 2235 cm <-1> (C = C), 1665 cm <-1> (C = 0).

D. (Z) -11β- [4- (2-Furanyl) phenyl] -17β-hydroxy-17α-15 (3-hydroxy-1-propenyl) -4-estren-3-one (15D)

In the manner described in Example 3F, 299 mg of 15C is hydrogenated using 61 mg of 10% Pd / BaSO 4 in 3 ml of pyridine and 5 ml of ethanol. After silica gel chromatography and crystallization from a mixture of ethyl acetate and hexane-20 n, 205 mg of the title compound 15 D is obtained.

Mp: 148-149 ° C; a] 2D 2 = + 126.5 ° (CHCl 3; c = 0.350).

IR (KBr): 1660 cm -1 (C = 0).

• Example 16: 25 (Z) -4- [17β-1β, 3β-17α- (3-Hydroxy-1-propenyl) -3-oxo-4-estrophenyl] [1,1′-biphenyl] Preparation of 4-carbonitrile (16D) A. 4 '- [3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] -17β-hydroxy-5 (10) -estren-1 N-yl] [1,1 '-, ·,; 30 Biphenyl] -4-carbonitrile (16A)

A solution containing 5.00 g of 4C 170 '! . ml of dioxane, stir with 1.09 g of lithium chloride for 15 minutes at room temperature under a shielding gas. Add 13 ml of hexabutylditin and 494 mg of V 35 to tetrakis (triphenylphosphine) palladium (0). The reaction mixture is heated at reflux for 2 hours. Then 47.61068ϋ of 15.6 g of 4-bromobenzonitrile are added and the batch is heated at boiling point for a further 24 hours. After cooling, the solution is filtered through celite, washed with ethyl acetate and evaporated under reduced pressure. After column chromatography, 3.16 g of 16A is obtained.

B. 4 '- [17β-Hydroxy-3-oxo-4-ester-lipyl] [1,1'-biphenyl] -4-carbonitrile (16B) From 3.10 g of 16A is prepared according to Examples 4E and According to 7D, 1.36 g of compound 16B was used for ketal hydrolysis and isomerization.

IR (KBr): 2233 cm-1 ((> N); 1660 cm-1) (C = 0).

1 H-NMR (CDCl 3 + Py-d 5) δ: 7.73 ppm (2H, d, J = 9 Hz, aromatic H); 7.70 ppm (2H, d, J = 9 Hz, aromatic H); 7.53 ppm (4H, m, aromatic H); 5.87 ppm (1H, s, broad, 15H-4); 3.60 ppm (1H, dd, J = 9.0 Hz and J = 7.5 Hz, H-17); 3.43 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 0.57 ppm (3H, s, H-18).

C. 4 '- [17β-Hydroxy-17α- (3-hydroxy-1-propynyl) -3-oxo-4-estren-11β-yl] [1,1'-biphenyl] -4-carbonyl triyl ( 16C) X 1.32 g of compound 16B is prepared according to the procedures of Examples 4G, 3C, 3D and 3E, 405 mg of 16C. IR (KBr): 2230 cm -1 (C = N and C = C); 1658 cm -1 (C = 0).

D. (Z) -4'- [17β-Hydroxy-17α- (3-hydroxy-1-propenyl) - :: 25-3-oxo-4-estren-1 H -yl] [1,1'-biphenyl] -4-Carbonitrile (16D)

386 mg of 16C is hydrogenated using the catalyst described in Example 3F using 77 mg of 10% Pd / BaSO 4 catalyst in 4 ml of pyridine and 6 ml of ethanol.

After chromatography on silica gel and concentration on a mixture of ethyl acetate and hexane, 242 are obtained. mg of the title compound 16D.

Mp: 259-260 ° C; [.alpha.] D @ 20 = + 135.2 DEG (CHCl3; c = 0.510).

IR (KBr): 2230 cm -1 (C = N); 1664 cm -1 (C = 0).

X 35 48 -ca ·

Example 17 Preparation of 11β- (4-Ethenylphenyl) -17β-hydroxy-17α-methyl-4-estren-3-one (17E) A. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy) ] -? 11β- (4-Ethenylphenyl) -5 (10) -estren-17? -Ol (17A)

Under a shielding gas, a solution of 4.00 g of 4C in 50 ml of dimethylformamide, 2.40 ml of ethenyltributylstannane, 554 mg of lithium chloride and 378 mg of tetrakis (triphenylphosphine) palladium (O) is added. The mixture is blown for 150 min at 110 ° C, transferred to ethyl acetate after cooling and filtered through celite. The filtrate is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Column chromatography gives 3.11 g of compound 15 17A.

B. 3.08 g of 11β- (4-ethenylphenyl) -17β-hydroxy-4-estren-3-one (17B) is prepared according to the procedures of Examples 4E and 7D using ketal hydrolysis and isomerization of 1.09 g. 17B.

IR (KBr): 1663 cm -1 (C = O).

C. 3,3- [1,2-Ethanediylbis (thio)] - 11β- (4-ethenylphenyl) -4-estren-17-one (17C) ··· 1.06 g of 17B is prepared by the following procedures: and 3C by thioketalization and oxidation V 'using 805 mg of 17C.

IR (KBr): 1736 cm <-1> (C = 0).

D. 3,3- [1,2-Ethanediylbis (thio)] - 11β- (4-ethenylphenyl) -17a-methyl-4-estren-173-ol (17D) At 0 ° C, dropwise dropwise a solution of 780 mg of 17C in 20 ml of tetrahydrofuran,. under a shielding gas, 11.9 ml of a 1.6 M solution of methyl lithium in 1.6 M diethyl ether. The reaction mixture is stirred for another 30 min and then poured into a saturated solution of ammonium chloride. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated 4 9 λ '1068; under reduced pressure. Column chromatography gives 629 mg of 17D.

E. 11β- (4-Ethenylphenyl) -17β-hydroxy-17α-methyl-4-estren-3-one (17E) 5 As described in Example 3E, 605 mg of 17D and 4.23 g of glyoxylic acid and 3 , From 70 ml of a 4M aqueous hydrochloric acid solution in 10 ml of acetone and 10 ml of glacial acetic acid are prepared 216 mg of the title compound 17E.

[Α] 20 D = + 151.8 ° (CHCl 3; c = 0.505).

IR (KBr): 1666 cm -1 (C = 0).

1 H-NMR (CDCl 3) δ: 7.39 ppm (2H, d, J = 9 Hz, aromatic H); 7.33 ppm (2H, d, J = 9.0 Hz, aromatic H); 6.70 ppm (1H, dd, J = 17.0 Hz and J = 10.5 Hz, H-vinyl); 5.86 ppm 15 (1H, s, broad, H-4); 5.73 ppm (1H, d, J = 17.0 Hz, H-vinyl); 5.22 ppm (1H, d, J = 10.5 Hz, H-vinyl); 3.39 ppm (1H, dd, broad, J = 9.5 Hz and J = 4.5 Hz, H-11); 2.87 ppm (1H, m, H-10); 1.22 ppm (3H, s, H-CH 3); 0.66 ppm (3H, s, H-18). Example 18 Preparation of (Z) -3H-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β- (4-methylphenyl) -4-estren-3-one (18D) A. 3,3- [ 2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- (4-methylphenyl) -5 (10) -estren-17β-ol (18A) ** To a suspension of 2.10 g of copper (I ) cyanide • in 40 ml of diethyl ether and 10 ml of tetrahydrofuran, *, dropwise 27.8 ml of a 1.6 M solution of methyl lithium in diethyl ether at -78 ° C. The reaction solution is warmed to -20 ° C and cooled again to -78 ° C after 15 min. At this temperature, a solution of 4.00 g of 4C in 25 ml of diethyl ether is added dropwise. The reaction mixture is slowly warmed to -20 ° C and stirred at this temperature for 2 days.

After treatment, a saturated solution of ammonium chloride · ”is added and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, dried over 50 l of 1068c sodium sulfate and evaporated under reduced pressure. Column chromatography gives 1.65 g of 18A.

B. 17β-Hydroxy-1- (4-methylphenyl) -4-estren-3-one (18B) δ 1.61 g of compound 18A are prepared according to the procedures of Examples 4E and 7D using ketal hydrolysis and isomerization of 920 mg of 18B.

IR (KBr): 1662 cm -1 (C = O).

C. 17β-Hydroxy-17α- (3-hydroxy-1-propynyl) -11β- (4-10 methylphenyl) -4-estren-3-one (18C) 895 mg of 18B are prepared according to Examples 4G, 3C, 3D. and 3E, 294 mg of 18C. [.alpha.] D @ 20 = -26.6 DEG (CHCl3; c = 0.500).

IR (KBr): 2230 cm -1 (C = C), 1659 cm -1 (C = 0).

1 H-NMR (CDCl 3) δ: 7.29 ppm (2H, d, J = 8.0 Hz, aromatic H); 7.09 ppm (2H, d, J = 8.0 Hz, aromatic H); 5.86 ppm (1H, s, broad, H-4); 4.37 ppm (2H, m, 5-CH 2 OH); 3.39 ppm (1H, dd, broad, J = 6.5 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 2.32 ppm (3H, s, H-CH 3); 0.76 ppm (3H, 20 s, H-18).

· 'D. (Z) -173-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β- (4-methylphenyl) -4-estren-3-one (18D)

265 mg of I * are hydrogenated as described in Example 3F.

·; of 18C using 53 mg of 10% Pd / BaSO 4 -3: 25 in 3 mL of pyridine and 6 mL of ethanol.

V After silica gel chromatography, 193 mg of the title compound 18D is obtained.

[α] 20 D = + 75.8 ° (CHCl 3; c = 0.510).

IR (KBr): 1664 cm -1 (C = O).

1 H-NMR (CDCl 3) δ: 7.29 ppm (2H, d, J = 8.0 Hz, ar. ··· mathematical H); 7.09 ppm (2H, d, J = 8.0 Hz, aromatic H); - 5.85 ppm (1H, s, broad, H-4); 5.71 ppm (1H, ddd, J = 12.0 Hz and J = 5.5 Hz and J = 5.5 Hz, H-CH =); 5.62 ppm (1H, d, broad, 3 J = 12.0 Hz, H-CH =); 4.24 ppm (2H, m, H-CH 2 OH); 3.33 ppm (1H, 35 dd, broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.84 ppm (1H, m, H-110); 2.32 ppm (3H, s, H-CH 3); 0.71 ppm (3H, s, H-18).

110681

Example 19 (Z) -17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β- [4- (5-pyrimidinyl) phenyl] -4-estren-3-one (19D) A. 3.3 - [2,2-dimethyl-1,3-propanediylbis (oxy)] -? 11 - [4- (5-pyrimidinyl) phenyl] -5 (10) -estren-17β-ol (19A)

A solution of 4.40 g of 4C in 300 ml of dioxane is stirred with 1.35 g of lithium chloride for 15 min at room temperature under a protective atmosphere of al-10a. 8.3 ml of hexabutyltin and 735 mg of tetra-cis (triphenylphosphine) palladium (0) are added. The reaction mixture is heated at 100 ° C for 90 min. 2.3 g of 5-bromopyrimidine are then added and the batch is heated at reflux for a further 7 hours. After cooling, it is filtered through see-15 Hit, washed again with ethyl acetate and evaporated under reduced pressure. After column chromatography, 2.37 g of 19A are obtained.

B. 17β-Hydroxy-lipo [4- (5-pyrimidinyl) phenyl] -4-estren-3-one (19B), · 2.31 g of compound 19A are prepared according to the procedures of Examples jE and ED by ketal hydrolysis and by isomerisation, 991 mg of 19B.

IR (KBr): 1660 cm -1 (C = 0).

1 H-NMR (CDCl 3 + Py-d 5) δ: 9.19 ppm (1H, s, broad, H ?: 25 Py 2); 8.99 ppm (2H, s, broad, H-Py4 and Py6); 7.60 ppm (2H, t V d, J = 9 Hz, aromatic H); 7.53 ppm (2H, d, J = 9 Hz, aromatic H); 5.87 ppm (1H, s, broad, H-4); 3.60 ppm (1H, dd, J = 8.5 Hz and J = 7.0 Hz, H-17); 3.43 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.84 ppm (1H, m, H-10); 0.57 30 ppm (3H, s, H-18).

t »1

52 1 106SG

C. 17β-Hydroxy-17α- (3-hydroxy-1-propynyl) -11β- [4- (5-pyrimidinyl) phenyl] -4-estren-3-one (19C) 955 mg of compound 19B are prepared according to Example 4G. , 3C, 3D, and 3E, 203 mg of 19C. IR (KBr): 2235 cm -1 ((> C), 1665 cm -1 (C = 0).

D. (Z) -17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β- [4- (5-pyrimidinyl) phenyl] -4-estren-3-one (19D) As described in Example 3F. mg of 19C is hydrogenated using 37 mg of 10% Pd / BaSC> 4 to 10 in 2 ml of pyridine and 4 ml of ethanol. After silica gel chromatography, 112 mg of the title compound 19D are obtained.

IR (KBr): 1664 cm -1 (C = O).

1 H-NMR (CDCl 3) δ: 9.20 ppm (1H, s, broad, H-Py 2); 8.98 ppm (2H, s, broad, H-Py4 and Py6); 7.59 ppm (2H, d, J = 9

Hz, aromatic H); 7.52 ppm (2H, d, J = 9Hz, aromatic H); 5.88 ppm (1H, s, broad, H-4); 5.72 ppm (1H, ddd, J = 11, 5 Hz and J = 5.5 Hz and J = 5.5 Hz, H-CH =); 5.65 ppm (1H, d, broad, J = 11, 5 Hz, H-CH =); 4.29 ppm (1H, dd, broad, J = 14 Hz and λ 20 J = 5.5 Hz, H-CH 2 OH); 4.26 ppm (1H, dd, broad, J = 14 Hz and. J = 5.5 Hz, H-CH 2 OH); 3.44 ppm (1H, dd, broad, J = 6.0 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 0.72 ppm (3H, s, 1H H-18).

• 1 1 · Example 20 '25 (11B, 17B) -11- [4- (5-Pyrimidinyl) phenyl] spiro [estr-4-en-17,2' (3H) -furan] -3-one ( 20A) A. (11β, 17β) -11- [4- (5-Pyrimidinyl) phenyl] spiro [estr-4-en-17,2 '(3 H) -furan] -3-one (20A) 320 mg of the compound described in Example 19D at 400 ° C in 400 mg of p-toluene - >>> sulfonic acid chloride and 1 ml of triethylamine. Reaction! . the thiomide mixture is stirred for 12 hours at room temperature and then stirred with saturated sodium bicarbonate solution and extracted with methylene chloride.

·, · 35 The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and dried over magnesium sulfate.

1106CB

evaporate in vacuo. Column chromatography affords 140 mg of 20A.

1 H-NMR (CDCl 3) δ: 9.20 ppm (1H, s broad, H-Py 2); 8.98 ppm (2H, s broad, H-Py4 and Py6); 7.57 ppm (2H, d J = 95 Hz, H-aromatic); 7.52 ppm (2H, d J = 9 Hz, H-aromatic); 5.88 ppm (1H, s broad, H-4); 5.86 ppm (1H, m, H-CH =); 5.81 ppm (1H, m, H-CH =); 4.52 ppm (1H, d broad J = 14 Hz, H-CH2OC); 4.49 ppm (1H, d broad J = 14H2, H-CH2OC); 3.39 ppm (1H, dd broad J = 9.0 Hz and J = 4.0 Hz, H-11); 2.84 δ ppm (1H, m, H-10); 0.71 ppm (3H, s, H-18).

Claims (24)

54 11068c 1. Liparyl-4-esters known to have the general formula I YC · '′ -' 10 - (i) wherein X represents an oxygen atom, a hydroxyimino group> N-OH, or two hydrogen atoms, R1 represents a hydrogen atom or a methyl group, R2 represents a hydroxyl group or a methoxy group, R3 represents a hydrogen atom, a group - (CH2) nCH2Z1! wherein n is 0, 1 or 2, Z represents a hydrogen atom, a cyano group or a group -OR 5 where R 5 represents H or methyl, or Z represents a group -C = CY, wherein Y represents a methyl group or a hydroxymethyl group, or Z represents a group i: -CH = CH-CH 2 OH or an allyl group -CH 2 -CH = CH 2, or R 2 and R 3; together form a group of formula Γ ~ | ΓΠ- 1 1 *. · C 17 π w R 4 represents a straight, saturated or unsaturated C 1 or C 2 alkyl chain or acetyl group, 55 110 6 8 55 R? an amino group wherein R7 and R8 independently of one another are hydrogen or methyl, or the corresponding amine oxide "R. or -O R 9 or -S (O) i R 9, 0- ^ R 8 wherein i is 0, 1 or 2, wherein R 9 is a methyl group, or a heteroaryl group of the formula Ia \ / \ '/ R Av / "\ 15. da) wherein A is an oxygen or sulfur atom, R 10 is a hydrogen atom, a cyano group, a fluorine atom, a straight-chain, saturated C 1 -C 2 alkyl group, an acetyl group, an amino group -nY or a group -S (O) ± R 9 i, R7, R8, R9 denote the same as above, or a heteroaryl group of the formula Ιβ0 ′ R10 Γ L (I ^30 where -BD-strikes the group -CC or -CN-, · * · R10 has the meaning given above, or a phenyl group having the formula Ιγ1: YY / °: ·. 35 I (Ιγ) V 11068 ί wherein R10 has the meaning given above, and their pharmacologically tolerated acids addition salts. The compound of claim 1 which is 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one. The compound of claim 1, which is 11β- [4-cyanophenyl) phenyl] -17β-hydroxy-17 (x- (3-hydroxy-1Z-propenyl) -4-estren-3-one. The compound of claim 1, which is 11β- [4- (4-cyanophenyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one. The compound of claim 1 which is (11β, 17β) -4 ', 5'-dihydro-11- [4- (dimethylamino) phenyl] spiro [estr-4-en-17,2' ( 3'H) -furan] -3-one. The compound of claim 1 which is (11β, 17β) -3 ', 4'-dihydro-11- [4- (dimethylamino) phenyl] spiro [estr-4-en-17,2' (3 ') -furan] -3,5'-dione. The compound of claim 1 which is 20 (11β, 17β) -11- [4-dimethylamino) phenyl] spiro [estr-4-en-17,2 '(5' H) -furan] -3-one . "** 8. A process for the preparation of non-drug 11β- *] aryl-4-esters of the general formula * ··: IL; · 25 Tl« 'fU _ (i) wherein X represents an oxygen atom, hydroxy- imino group- ": ** amount> N-OH or two hydrogen atoms, R 1 represents a hydrogen atom or a methyl group, R 2 represents a hydroxyl group or a methoxy group, 1063; R 3 represents a hydrogen atom, a group - (CH 2) n CH 2 Z where n is 0, 1 or 2, Z represents a hydrogen atom, a cyano group or a group -OR 5 R 5 is H or methyl, or Z represents -C = cY, wherein Y represents a methyl group 5 or a hydroxymethyl group, or Z represents -CH = CH-CH 2 OH, or an allyl group -CH 2 -CH = CH 2, or R 2 and R 3 form together of the formula 0 f il r or Ί ϊ 10. I o o j β \ / '' α e'y · - 'a 17 17 17 R 4 represents a straight-chain, saturated or unsaturated C 1 or C 2 -alkyl chain or acetyl group R 7, an amino group -N where R 7 and R 8 independently of each other represent a hydrogen atom or a methyl group, or R 7 represents a corresponding amine oxide. or -OR 9 :: 25 or -S (O) i R 9, 0- ^ R 8 wherein i is 0, 1 or 2, wherein R 9 is a methyl group, or a heteroaryl group of formula Ia, v 30 S / A ' y (Ia) 35 where A is an oxygen or sulfur atom, R 10 is a hydrogen atom, a cyano group, a fluorine atom, a straight-chain, saturated C 1 -C 2 - 11068 ° R 7 alkyl group, an acetyl group, an amino group or a 0) iR 9 wherein i, R 7, R 8, R 9 have the same meanings as defined above, or a heteroaryl group of the formula Ιβ R 10 dp) V "wherein -BD- represents the group -CC- or -CN- and R 10 has the meaning given above, or a phenyl group of the formula Ιγ 15 —f— (Ιγ) ·, * 20 wherein R 10 has the above moiety meaning, t; and for the preparation of their pharmacologically tolerable acid addition salts, characterized in that, the compound of general formula II: wherein R 1 and R 4 have the meaning shown in formula I, 35 is a β-hydroxyl group or a group R 2 and B is an a-hydrogen atom, the R group at the α-position or 110681 A and B together represent an oxygen atom, is converted by heating in the presence of an acid to a compound of general formula Ia 5-Ia) wherein R1, A and B And R4 has the same meaning as R4 in formula I, so that R4 is stable under said vigorous conditions, and then either a) in the compound of general formula Ia, if A has a β-hydroxyl group and B is an hydrogen atom, an oxidant -> V 20 if desired, the 17-hydroxy group is converted to the 17-keto group and »· b) the 3-keto group is converted to the dithioketal, including all other possible keto groups * · ketal or (b) then (a) followed by · ·; ”* after · 25 c) if the R4 '3-thioketalized compound has a methoxy or hydroxyl group and R 4 in the desired compound of the general formula I is not methoxy or hydroxyl group, the hydroxy compound optionally after cleavage of the methoxy compound is converted to the corresponding per-fluoroalkylsulfonic acid compound wherein -alkyl is. "A C 1 -C 4 alkyl group, and from this, either directly by reaction with an appropriately substituted tin (trialkyl) compound R 4" -Sn (alkyl) 3 or a correspondingly substituted boron compound R 4 -BL 2 (L = hydroxy or alkyl), ( Wherein R is the same as R 4 of the general formula I or is a tautomeric precursor of R 4 and alkyl Ί "1068 b represents a C 1 -C 4 alkyl group or indirectly a tin (trialkyl) in the 4-position of the Ιΐ 2 -phenyl group. via a compound substituted with (alkyl-C1-C4) obtained by reaction of a perfluoroalkylsulfonate compound with 5 Sn2alkyl6, and further treating the 11β- (4-trialkylstanyl) phenyl compound with R4-Y, wherein R4 "is the same as or Y is a tautomeric precursor of R4 and Y is a leaving group, preferably a halogen atom and especially a bromine atom, is prepared in the presence of a transition metal catalyst wherein Z is a protected keto group in the form of a dithioketal; and: d) when R 2 and R 3 in the final desired compound of formula I do not represent a hydroxyl group or a hydrogen atom or R 2 and R 3 together do not form a keto acid atom, the desired substituents R 2 are attached to the C-17 atom of the steroid backbone. and R3 are known per se * or d) and then c), ···, the protecting groups are cleaved, if desired, the free hydroxyl groups are alkylated or acylated and, if desired, the 3-keto group is converted with hydroxylamine hydrochloride 3-hydroxy: the simino group> N-OH or the 3-keto group is converted to the dihydro compound and optionally a pharmaceutically acceptable addition salt is prepared with an acid. 11 ϋ 6 o c Process according to Claim 8, characterized in that the heating is carried out at a temperature of 80 to 120 ° C. Process according to Claim 8 or 9, characterized in that the heating takes place in the presence of an inorganic acid or in the presence of an organic acid, which is preferably p-toluenesulfonic acid. 11068b 1. lpp-aryl-4-estrener, a n-butyl ester derivative of formula I <x, Xn a- · (I) 10 - 15 d x X a necklet, hydroxyimino-grouping> N-OH elleric acid atom, R1 betecknar en väteatom eller en methylgroup, R2 betecknar en hydroxylgrupp eller methoxygroup,! 20 R3 betecknar en groupering - (CH2) 11CH2Z, colors 0, 1 eller 2, Z betecknar group, -OR5, R5 group H eller: methyl, eller Z betecknar group, - C = CY, colors Y is: en methyl-methyl hydroxymethyl group, eller Z betecknar en * · · 25 grouping -CH = CH-CH 2 OH eller en-allyl group -CH 2 -CH = CH 2, eller R 2 and R 3 picture of the group med formeln ΓΊ ! ϊ 1 \ —s • 30 β \. ··· ά a \ .a eller \ As. i \ / a 17 17 17 R4 betecknar en celled, dull eller doped C1-C11 alkyl2and eller acetyl group, 35 63 110681 R7 en amino group -N ^, d R7 and R8 oberoende av r8 5-membered betecknar en methyl group, eller en motif stock R7 aminoxid eller en grouping -OR9 eller -S (O) i R9, 0- ^ R8 10 derivatives 0, 1 eller 2, colors R9 en methyl group, eller en heteroaryl group med formeln /α / AV B10 S / \ XX (Ia) derivative C, C, C, C, C, C, C, C, C, C, C, C, C, C; eller en gruppering -S (O) i R 9 ,; R8 25 colors, R7, R8, R9 betecknar samma som ovan, eller en heteroarylgroup med formeln °β v 30 (Ιβ) 1 / o d -BD- betecknar en grundämnesgrupp -CC- eller -CN-och Gruppen R10 betecknar samma som ovan, eller en phenyl-35 group med formeln Ιγ 64 110661: / γ "-f- (IY> d. Gruppen RIO betecknar samma som ovan, samt med syror bildade pharmacologically tolerated additions. 2. Feningen enligt patent crav 1, som and 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one. 3. Förening enligt patent crav 1, som and 11β- [4-cyanophenyl) phenyl] -17? -Hydroxy-17? - (3-hydroxy-1Z-propenyl) -4-estren-3-one. 4. Enricht patent crav 1, som and 11β- [4- (4-15 cyanophenyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one. 5. Feningen enligt patent name 1, som (11β, 17β) -4 ', 5'-dihydro-11- [4- (dimethylamino) phenyl] spiro [estr-4-en-17,2' (3 ') - furan] -3-on. 6. Förening enligt patent name 1, som (11β, 17β) -,: 3 ', 4'-dihydro-11- [4- (dimethylamino) phenyl] spiro [estr-4-en-17,2' (3 'H) -furan] -3,5' -dione. . 7. Förening enligt patent crav 1, som (11β, 17β) - (11- [4-dimethylamino) phenyl] spiro [estr-4-en-17,2 '(5' H) -furan] -25 3-one . 8. Förfarande för framställning av llp-aryl-4-estrener, som inte används som läkemedel, med den allmänna formeIn I: '. där 65. W6ii X betecknar en syreatom, hydroxyimino-grouppering> N-OH elleridyl, R1 betecknar en sylmethyl eller en methyl, 5 R 2 is a hydroxy-methyl methoxy group, R 3 is a substituent, en grouppering - (CH 2) 11 CH 2 Z, the colors are 0, 1 eller 2, Z is a methyl group, OR 5, R 5 is H eller methyl. , eller Z betecknar en grouppering -CH = CY, shades Y 10 methyl methyl eller hydroxymethyl group, eller Z betecknar en grouppering -CH = CH-CH20H eller en allyl group -CH2-CH = CH2, eller R och R bildar tillsammans en group med formeln r ~ i [r \ —t 15 \, · - \, - eller <. β ^ χ "α βΝ ^ α Κ / α π π π R4 betecknar en celled, dull eller doped C1-eller C2-alkylkedja eller acetyl, 20 en amino-N ^, d R7 and R8 oberoende av r8 varandra betecknar en väteatom eller en, methyl, eller »amino acids 25 aminoxid eller en grouping -OR9 eller -S (O) i R9, 30 mo 0, 1 eller 2, colors R9 en methyl group, eller * en heteroaryl med formeln Ia / AV B10. / N Λ (I} 35) / 11068b derivative of the aryl group, R 10 is an unsubstituted atom, en cyclo group, en fluoro atom, en cellular, unsaturated C 1 -C 2 alkyl group, acetyl group, N 5 -C 7 R 7 amino group. eller en grouppering -S (O) iR9, colors ^ \ R8 i, R7, R8, R9 betecknar samma som ovan, eller en hetero-arylgroup med formeln Ιβ R10 (Ipl där -BD- betecknar en grundämnesgrupp -CC- eller - CN-och Gruppen R10 betecknar samma som ovan, eller en phenyl-group med formeln Ιγ; * 20 i; xy · ί L (ΐγ): V 25 »d Gruppen R10 betecknar samma som ovan, samt för fram-ställning av pharmacologiskt tolererbara syraadditionssalt därav, kännetecknat av att en förening med den all pine formeln II: 30 V \ r1 V8; VyyS ™ 67 11068ο for R1 and R4 betecknar det som anförts i formeln I, A β-hydroxyl group eller en group R2 and 5 B en a-position, en R3 i a-positionen el ler A och B tillsammans betecknar en syreatom, omvandlas genom upphettning i närvaro av en syra account en förening med den allmänna formeln Ia 10 VN 15 - (la). . 20 där gruppna R1, A and B betecknar det som anförts i sam-! band med formeln II och Gruppen R4 'betecknar samma som; ··· group R4 i formeln I, ¤ att R4 i nd Starka förhällan-: "den is stable and därefter antingen a) i föreningen med den allmänna formeln Ia, ifall · 25 A-en-β-hydroxylgroup och B-a-väteatom däri, oxideras ::: om sa isskas 17-hydroxigruppen account en 17-ketogrupp och (b) 3-ketogruppen omvandlas account dithioketal, colored by andra eventuellt nerve end ketogrupper keta-liseras eller b) och sedan a) och därefter, · _ · 30 c) ifall R41 i en 3-thioketalizerad förening å methoxy-eller hydroxylgro and R4 i den slutliga föreningen med den allmänna formeln I inte-methoxy-eller hydroxylgroup , omvandlas hydroxiföreningen even-tuellt efter spjälkningen av metoxiföreningen account en mot- 35 svande perfluoroalkylsulf onsyraf aging, där-alkylen en C1-C4-alkylg, och härur vidare antingen direct ge 110 6 8 ϋ genom omsättning med en motsvaran de substituent tenn- (trialkyl) substitution R4 '' -Sn (alkyl) 3 eller med en motovvarande substituent boron substituent R4 '' - BL2 (L = hydroxy eller alkyl), bonded R4 '' betecknar samma som R4 i föreningen 5 med den allmänna formeln I eller en tautomerisk förform av Group R4 and alkyl beteckenar C1-C4-alkyl, eller indirectly via the enantiomeric trialkyl (alkyl = C1-C4) 4-positionen i up- phenyl group, coupling reaction with perfluoroalkyl-10 sulfonate transfer reaction with Sn2alkyl6, and genomic attenuation reaction with 11β- (4-trialkylstannyl) phenylfureningen med en förening R4, '- Y, d &lt; 4 &gt; allmänna formeln I eller en tautomerisk förformen Gruppen R4 och Y är en avgäende Group 15, förmänligt en halogenatom och roesstrom bromine, framställs i närvaro av en övergängsmetallkatalysator en förening med den allmänna formeln III 20 R1 \ / B:: 25 derivatives of the ketogroup i form av dithioketal och d) compounds R2 and R3 i den slutliga self-synthesizing, \ - 30 med denomannna formeln, in hydroxyl group, ··· eller en väteatom eller R2 and R3 Tillsammans inte bildar en ketosyreatom, bindas de selfsubstance substituenterna R2 och R3 account steroidstommens C-17-Atom genome i och för sig kän-da förfaranden eller först utförs d) och därefter c),:,>] 35 skydds spjälks, om ssyl alkyleras eller asyleras de fria hydroxylgrupperna och om såsskas omvandlas 11060b 3-ketogroupen med hjälp av hydroxylamin hydrochloride till N-OH eller 3-ketogroupen om-vandlas till en dihydrof eventuellt framställs et farmaceutiskt tolererbart additionssalt med hjälp av 5 en syra. 9. Förfarande enligt patentkrav 8, tilt-tecknat av att upphettningen Utfors till en tempur av 80-120 ° c. 10. Förfarande enligt patent krav 8 eller 9, kän-10 netecknat av att upphettningen sker i nerve n avero o organisk syra, som förmänligt är p-toluensulfonsyra. «I» <· * · »• · 1 I »ft *