19-Nor-steroids

This application is a division of U.S. patent application Ser. No. 08/068,735 filed May 28, 1993, now U.S. Pat. No. 5,707,982, which is a continuation of U.S. patent application Ser. No. 07/745,289 filed Aug. 14, 1991, now abandoned which is a continuation-in-part of U.S. patent application Ser. No. 07/484,424 filed Feb. 23, 1990, now U.S. Pat. No. 5,149,696.

Related prior art are U.S. Pat. No. 4,477,445; No. 4,540,686 and No. 3,922,292 and French Patent No. 2,582,654.

It is an object of the invention to provide the novel compounds of formulae I and IA and a novel process and novel intermediates for their preparation.

It is another object of the invention to provide novel hormonal compositions and novel methods of inducing hormonal reactions in warm-blooded animals.

These and other objects and advantages of the invention will become obvious from the following detailed description.

The novel compounds of the invention are 19-nor-steroids of the formula

wherein the A and B rings have a structure selected from the group consisting of

are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, R 3 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and acyl of an organic carboxylic acid of 1 to 7 carbon atoms, R 17 and R′ 17 together form ═O or R 17 is —OH or acyloxy and R′ 17 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and alkenyl and alkynyl of 2 to 8 carbon atoms, all optionally substituted, X is selected from the group consisting of —CH 2 — or —CH 2 O—, arylene and arylenoxy linked to the C ring through a carbon atom, Y is selected from the group consisting of a simple bond and saturated and unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with at least one member of the group consisting of arylene, —O— and optionally oxidized —S— and optionally terminated with aryl, Z is a simple bond or —CH 2 O— linked to Y by a carbon atom, R A and R A ′ being individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms optionally substituted with at least one member of the group consisting of aryl, alkylamino, dialkylamino, —OH, halogen and esterified carboxyl or R A and R A ′ taken together with the nitrogen to which they are attached form 5 to 6 ring heterocycle optionally containing at least one heteroatom selected from the group consisting of —S—, —O— and —N— optionally substituted with alkyl of 1 to 4 carbon atoms with the proviso 1) that both R A and R A ′ are not hydrogen, and 2) when Z and Y are both simple bonds, X is not —CH 2 — or —CH 2 O—, A) wherein n is 1, K is oxygen, R 18 is —OH or optionally salified

R B ′ is methyl, R B is isopropyl or n-butyl or heptafluorobutyl, X′ is selected from the group consisting of methylene, phenylene and phenoxy attached to the steroid by a carbon atom, Y′ is selected from the group consisting of —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 5 —C≡C—, —(CH 2 ) q —O——CH 2 — and

q is an integer from 5 to 7, n′ is 0, 1 or 2 and Z is a simple bond and B) wherein n is 1 or 2, K is —O— or —S—, R 18 and R′ 18 form ═O or R 18 is —OH or acyloxy, and R′ 18 is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl and alkynyl of up to 8 carbon atoms, X′ is selected from the group consisting of —CH 2 —, —CH 2 O—, arylene and arylenoxy and arylenethio connected to the steroid by a carbon atom, Y′ is selected from the group consisting of a simple bond and optionally unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with arylene or —O— or —S—, —SO— or —SO 2 — and optionally terminated with arylene, Z′ is a simple bond with the proviso that when Y′ and Z′ are both a simple bond, X′ is not —CH 2 — or —CH 2 O— and R B and R′ B are individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms optionally substituted with a member of the group consisting of aryl, alkylamino, dialkylamino, —OH, halogen and esterified carboxy or taken together with the nitrogen to which they are attached form an optionally unsaturated 5- or 6-member heterocycle optionally containing at least one additional heteroatom of —O—, —S— or nitrogen optionally substituted with a member of the group consisting of alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 10 carbon atoms with the proviso that at least one of R B and R′ B is not hydrogen and at least one of the following conditions is met, n is 2 or K is —S— or X′ is arylenethio attached to the steroid by a carbon atom or R B and R′ B with the nitrogen is a 5- or 6-member heterocycle substituted by aryl or aralkyl.

Examples of R 3 , R 2 and/or R′ 2 as alkyl are methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl and isobutyl, preferably methyl. Examples of R 3 as acyl are acetyl, propionyl, butyryl and benzoyl.

When R 17 or R 18 is an acyloxy, it is derivative of an aliphatic or cycloaliphatic carboxylic acid, saturated or unsaturated and especially alkanoic acids such as for example, acetic acid, propionic acid, butyric acid or isobutyric acid, valeric acid or undecylic acid; a hydroxyalkanoic acid such as hydroxyacetic acid; cycloalkylcarboxylic acids or cycloalkylalkanoic acids such as cyclopropylcarboxylic acid, cyclopentylcarboxylic acid or cyclohexyl carboxylic acid, cyclopentyl or cyclohexyl acetic acid or propionic acid, benzoic acid, salicylic acid or a phenylalkanoic acid such as phenylacetic acid or phenylpropionic acid, an amino acid such as diethylaminoacetic acid or aspartic acid or formic acid. It is preferably a derivative of acetic acid, propionic acid, butyric acid or butanedioic acid.

When R 17 or R 18 is alkyl, it is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl and most preferably, methyl.

When R 17 or R 18 is alkenyl, it is preferably vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl and most preferably vinyl or propenyl. When R 17 or R 18 is alkynyl, it is preferably ethynyl, propynyl, propargyl, butynyl or isobutynyl and most preferably ethynyl or propynyl.

The expression optionally substituted applied to the alkyl, alkenyl or alkynyl includes at least one member of the group consisting of halogen, such as fluorine, chlorine, bromine or iodine, alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino or methyl ethylamino, each of the dialkylaminos being optionally in the oxidized form; aminoalkyl such as aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylaminomethyl or ethyl, dialkylaminoalkoxy such as dimethylaminoethoxy, optionally acylated hydroxyl, for example acetoxy or

in which n=2 to 5, such as acetyl, propionyl, butyryl, benzoyl, free or esterified carboxy and alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, cyano, trifluoromethyl, aryl such as phenyl, furyl, thienyl or aralkyl such as benzyl, these being optionally substituted by alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or by alkoxy, alkylthio, alkylamino or di-alkylamino indicated above.

When X or X′ is arylene it is preferably phenylene and when X or X′ is arylenoxy, it is preferably phenylenoxy.

When Y or Y′ is saturated or unsaturated linear or branched aliphatic chain, it can be methylene, ethylene, propylene, isopropylene, butylene, isobutylene or tert.-butylene, n-pentylene, n-hexylene, 2-methyl pentylene, 2,3-dimethyl butylene, n-heptylene, 2-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 3-ethylpentylene, n-octylene, 2,2-dimethylhexylene, 3,3-dimethylhexylene, 3-methyl 3-ethylpentylene, nonylene, 2,4-dimethyl heptylene, n-decylene, n-undecylene, n-dodecylene, n-tridecylene, n-tetradecylene, n-penta-decylene, n-hexadecylene n-heptadecylene or n-octadecylene, preferably n-nonylene or n-decylene. Equally it can be one of the following; vinylene, isopropylene, allylene, 2-methylallylene or isobutenylene, and when the chain is interrupted or terminated by one or more arylenes, it is preferably phenylene, it being understood that terminated relates to anyone of the two extremities of Y or Y′.

When R A or R′ A or R B or R′ B is alkyl, it can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl.

The aforementioned radicals can be substituted by one or more aryl such as phenyl, furyl, thienyl, preferably phenyl; by one or more alkylamino or dialkylamino such as dimethylamino or by one or more esterified carboxyl such as methoxycarbonyl or an ethoxycarbonyl, by one or more halogen atoms for example, fluorine, chlorine or bromine. 2,2,3,3,4,4,4-hepta fluorobutyl or 2-chloro-2-methylpropyl can notably be cited.

When R A and R′ A or R B and R′ B form with the nitrogen atom to which they are linked a heterocycle with 5 to 6 links, it is a saturated heterocycle, preferably pyrrolidine or piperidine optionally substituted by alkyl such as methyl, ethyl, propyl or isopropyl, preferably methyl or ethyl or an unsaturated heterocycle, preferably pyrrole or pyridine optionally substituted by alkyl such as methyl, optionally containing another heteroatom, preferably morpholine, piperazine or pyrimidine, optionally substituted by alkyl, preferably methyl or ethyl.

The preferred compounds of formula I of the invention are those wherein the A and B rings are

and those wherein A and B are

in which R″ 2 or R″′ 2 are hydrogen or methyl, preferably hydrogen, those in which Z is a simple bond and those in which R 17 is hydroxyl, those in which R 17 is hydrogen, ethynyl or propynyl, those in which X is methylene and Y is saturated linear chain of 5 to 10 carbon atoms optionally interrupted by an oxygen atom and those in which X is phenylene and Y is a saturated linear chain of 3 to 10 carbon atoms optionally interrupted by an oxygen atom and those in which X is phenylenoxy and Y is saturated linear chain of 3 to 10 carbon atoms optionally substituted by an oxygen or sulfur atom.

Among the preferred compounds of formula I are those in which either R A and R′ A are both methyl or R A is hydrogen or methyl and R′ A is butyl, or R A is methyl and R′ A is isopropyl, dimethylaminoethyl, benzyl or heptafluorobutyl or R A and R′ A form together a piperazine optionally N-substituted or a pyrrolidine.

Among the specific preferred compounds of formula I are 11 β-N-(2-dimethylaminoethyl)-17 β-hydroxy-N-methyl-3-oxo-δ 4,9 -estradien-undecanamide, N-butyl-4-(3,17 β-dihydroxy-δ 1,3,5(10) -estratrien-11 β-yl)-N-methyl-benzene octanamide, 3,17 β-dihydroxy-N-methyl-N-isopropyl-11β-δ 1,3,5(10) -estratrien-undecanamide, N-butyl-3,17β-dihydroxy-N-methyl-19-nor-11β-(17α-δ 1,3,5(10) -pregnatrien-20-yn)-undecanamide, 3,17 β-dihydroxy-N-methyl-N-isopropyl-19-nor-11β-17 α-δ 1,3,5(10) -pregnatrien-20-yn)-undecanamide; [[8-(3,17β-dihydroxy-δ 1,3,5(10) -estratrien-11 β-yl)-octyl]-oxy]-N-methyl-N-isopropyl-acetamide, N-butyl-8-{4-(3,17β-dihydroxy δ 1,3,5(10) -estratrien-11 β-yl)-phenoxy-N-methyl octanamide, N-butyl-[5-[4-(3,17 β-dihydroxy-δ 1,3,5(10) -estratrien-11β-yl)-phenoxy]-pentoxy]-N-methyl acetamide, 2-[(7-[4-(3,17β-dihydroxy-δ 1,3,5(10) -estratrien-11β-yl)-phenyl]-6-heptyl]-oxy]-N-butyl-N-methyl acetamide, 3,17β-dihydroxy-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-δ 1,3,5(10) -estratrien-11 β-yl]-undecanamide and N-[4-(3,17 β-dihydroxy-δ 1,3,5(10) -estratrien-11β-yl)-phenyl-N-butyl-N-methyl octynamide.

Among the preferred compounds of formula I A are those wherein n is 1 or 2, those wherein K is oxygen or sulfur, those wherein R′ 18 and R 18 form ═O or R 18 is —OH or acyloxy and R′ 18 is hydrogen or optionally substituted alkyl, alkenyl or alkynyl of up to 8 carbon atoms, those wherein X′ is methylene, arylene, —CH 2 O—, arylenoxy or arylenethio attached to the steroid with a carbon atoms, those wherein Y′ is a simple bond or an optionally unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with at least one member of the group consisting of arylene, —O—, —S—, sulfone or sulfoxide and optionally terminated with arylene, those wherein Z′ is a simple bond when Y′ is a single bond but X′ is not —CH 2 — or —CH 2 O—, those wherein R B and R′ B are individually selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms optionally substituted by aryl, alkylamino, dialkylamino, hydroxy, halogen or esterified carboxy or R B and R′ B together with the nitrogen to which they are attached form an optionally unsaturated 5- or 6-member heterocycle optionally containing at least one heteroatom of oxygen, sulfur or nitrogen optionally substituted by alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms or aralkyl of 7 to 10 carbon atoms with the proviso that at least one of R B and R′ B is not hydrogen and at least one of following conditions is met; n=2 or K is sulfur or X′ is arylenethio attached to the steroid by a carbon atoms or R B and R′ B form with the nitrogen or 5- or 6-member heteroatom substituted by aryl or aralkyl.

Examples of specific compounds of Formula I A are

monobutanedioate of 11β-(4-((7-(butylmethylamino)-carbonyl)-heptyl)-oxy-phenyl)-δ 1,3,5(10) -estratrien-3-ol-17β-yl;

butanedioate of 11β-(4-((7-((butylmethylamino)-carbonyl)-heptyl)-oxy)-phenyl)-δ 1,3,5(10) -estratrien-3-ol-17β-yl and its sodium salt; N-butyl-2-(6-(4-( 67 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenoxy)-hexyloxy-N-methyl-acetamide;

N-butyl-8-(4-(δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenoxy)-N-methyl-2-octynamide;

N-butyl-2-((5-(4-(δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenyl)-pentyl)-thio)-N-methylacetamide;N-butyl-4-(δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-N-methyl-benzenenonamide;

N-butyl-2-((5-(4-δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenyl)-pentyl)-oxy)-N-methyl-acetamide; and

2-((8-(δ 1,3,5(10) -19-nor-17α-pregnatrien-3,17β-diol-20-yn-11β-yl)-octyl)-oxy)-N-methyl N-(1-methylethyl)-acetamide.

The novel process of the invention for the preparation of the compounds of formula I comprises reacting a compound of the formula

wherein X, Y, R 17 and R′ 17 have the above definitions with R 17 being other than OH either with an oxidizing agent to obtain a product of the formula

reacting the latter with an agent permitting the activation of the carboxylic function, then with a compound of the formula

wherein RA and RA′ have the above definitions to obtain the product of formula Ia corresponding to the compound of formula I in which Z is a simple bond and the rings A and B are

wherein R 2 and R′ 2 are hydrogen or with a compound capable of introducing

to obtain a compound of formula II′a which is a compound of Formula I wherein Z is —CH 2 O— and A and B rings have the definition of formula I a , the compounds of formulae I a or I′ a optionally being reacted with a reducing agent when R 17 and R′ 17 together form —O, then if appropriate reacting the 17-hydroxylated compound with an acylation agent, or with a saponification agent when R 17 is an acyloxy, to obtain a product of formula Ia or I′ a in which R 17 has the above meaning, then if desired, reacting one of the products of formula Ia or I′ a , either to obtain an alkylation at position 2, when at least one of R 2 and R′ 2 is hydrogen, or reacts with an aromatization agent of ring A, then to a saponification agent to obtain the products of formula Ib, corresponding to product of formula Ia and the products of formula I′ b corresponding to the products of formula I′ a in which the rings A and B are

optionally reacting the products of formula Ib and Ib′ to an alkylation or acylation reaction of the 3-hydroxy, then, if desired, either, when R 17 and R′ 17 together form ═O to a reducing agent or to a metallic complex of the formula

M—R′ 17   V

wherein M is a metallic ion and R′ 17 has the above definition other than hydrogen, or when R 17 is a hydroxy reacting with an acylation agent selective at position 17, then, if desired, with one of the products of formula I obtained above, or when RA or RA′ is hydrogen with an appropriate alkylation agent.

The compounds of formula I are 19-nor steroids having: either a chain at the 11β-position containing a substituted amide function which compounds are then chosen from among the compounds of formulae Ia and Ib, or a chain at the 11β-position containing a substituted carbamate function which compounds are chosen from among the compounds of formulae I′a and I′b.

The compounds of formula I′a are obtained by reacting a compound of formula II either with an activator of the hydroxyl such as phosgene, then with a primary or secondary amine of formula IV in a neutral solvent such as methylene chloride or tetrahydrofuran in the presence of a base such as potassium carbonate or methylamine, or with an isocyanate of the formula RA—N═C═O to obtain a product in which RA′ is hydrogen.

The compounds of formula Ia are obtained by reacting a compound of formula III activated, for example in the form of the mixed anhydride with an agent such as chloroformate, for example, isobutyl chloroformate, in the presence of a base such as a tertiary amine like N-methylmorpholine in an anhydrous solvent such as a chlorinated solvent, i.e., methylene chloride with the amine of formula IV.

The product of formula III is obtained by using an oxidizing agent such as, for example, the mixture CrO 3 -sulfuric acid in a neutral solvent such as acetone.

In a preferred embodiment of the invention:

The compounds of formula II contain a 11β chain terminated by an alcohol function selected from the following Table:

as illustrated in the examples hereafter.

The compounds of formula III contain a 11β-chain terminated by a carboxylic acid corresponding to the oxidation product of a chain chosen from among the 11β-chains terminated by one of the alcohol functions cited above.

The compound of formula IV is chosen from the following amines: butylamine, methylbutylamine, dimethylamine, methylisopropylamine, methyldimethylaminoethylamine, methylbenzylamine, pyrrolidine or N-methylpiperazine which are known products.

When the compound of formulae Ia or I′ a has a 17β-ketone, the corresponding 17β-hydroxyl steroid is obtained by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol or triterbutoxylithium aluminium hydride in tetrahydrofuran.

When the compound of formulae Ia or I′ a has a 17β-hydroxy, the corresponding 17-acyloxylated steroid is obtained by the action of an acylation agent, for example an acetylation agent such as acetic anhydride in pyridine, optionally in the presence of 4-dimethylamino-pyridine.

When the compounds of formulae Ia or I′ a have 17β-acyloxy, the corresponding 17β-ol steroid is obtained with a saponification agent such as potassium hydroxide in an alcoholic medium.

When the compounds of formulae Ia or I′ a has one or two hydrogen atoms at position 2 or/and 2′, the corresponding mono or dialkylated steroid at position 2 and 2′ is obtained by the action of an alkylation agent, preferably a methylation agent such as methyl iodide.

The compounds of formulae Ib and I′ b which are steroid derivatives of estradiol having a 11β-chain containing a substituted amide function or a substituted carbamate function are obtained starting with the compounds of formulae Ia and I′ a respectively, by the action of an aromatization agent such as palladium hydroxide on magnesia in methanol or a mixture of acetyl bromide and acetic anhydride at a temperature not exceeding that of ambient followed by a saponification reaction using, for example, potassium hydroxide in methanol, sodium bicarbonate or methanol in the presence of hydrochloric acid.

When the compounds of formulae Ib or I′ b have a 3-hydroxy, the corresponding alkylated steroids is obtained with an alkylation reagent such as alkyl iodide or an alkyl sulfate, for example, methyl sulfate or the corresponding acylated steroid by the action, of a standard acylation reagent such as an acyl halide like acetyl chloride.

When the compounds of formula Ib or I′ b have a 17 ketone, the corresponding 17β-hydroxyl steroids are obtained under the conditions described above for Ia or I′ a , for example by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol and the corresponding compound of formulae Ib or I′ b wherein R′ 17 is alkyl, alkenyl or alkynyl optionally substituted are obtained by using as a complex, for example, a lithium complex according to the process of EP Patent Application 57,115.

When the compounds of formula Ib or I′ b have a 17β-hydroxy, the acyloxyl steroids can be obtained by the action of a selective acylation agent such as acetic anhydride in pyridine.

When RA or RA′ is hydrogen, the corresponding alkylated product may be obtained by the action of an alkyl halide, for example methyl or ethyl iodide, methyl or ethyl bromide in a solvent such as tetrahydrofuran. It is well understood that if R′ 17 contains an alkyl, alkenyl or alkynyl substituted by a reactive function, this can be provisionally protected by the usual methods.

The novel process of the invention for the preparation of compounds of formula I′ wherein X is arylene and Y is aliphatic optionally linked to arylene by a double or triple bond and having at least 3 carbon atoms or linked to arylene through an oxygen atom comprises reacting a compound of the formula

wherein W is either —OH or —C≡CH, the rings A′ and B′, Ra 17 and Ra′ 17 having the same meanings as indicated above for rings A and B, R 17 and R′ 17 and in which the 3- and 17-reactive functions are optionally protected or, when W is —C≡CH reacted with a halogenation agent of the formula

wherein Hal is halogen, Z, RA, and RA′ have the above definitions and Y′ is aliphatic Y having 2 carbon atoms missing in the presence of a strong base, and optionally to the action of a deprotection agent to obtain a product of the formula

which optionally is reacted with a partial or total reducing agent of the triple bond to obtain a product of the formula

or, in the case where W is —OH to the action of a halogenated derivative of the formula

in which Hal, Y, Z, RA and RA′ have the above definitions in the presence of an alkaline agent, and optionally reacting with a deprotection agent to obtain a product of the formula

which optionally, when Y is an unsaturated aliphatic is reacted with a partial or total reducing agent, and the products of formula I′ A , I′ B or I″ A may be subjected to any one of the reactions indicated above for Ia, Ia′, Ib and Ib′.

In a preferred process of the invention, the optional protection groups of the 3- or 17-hydroxyl are selected from the standard groups such as tetrahydropyranyl and tert.-butyl and the halogen of Hal may be bromine, chlorine or iodine. The strong base used is, for example, butyllithium or sodium hydride and the alkaline agent used is an alkali metal hydroxide such as sodium hydroxide. The deblocking of the protected functions may be effected using of a standard hydrolysis agent such as hydrochloric acid and the optional reduction of the triple bond is effected either using hydrogen in the presence of palladium on activated charcoal, barium sulfate and optionally a base such as pyridine or quinoline in the case of a partial reduction. Palladium hydroxide is used alone in the case of a total reduction. In the compound of formula X used initially, W is in the para position.

In a variation of the processes, the products of formula I wherein Z is a simple bond and Y is a linear aliphatic terminated by vinylene before the amide function, a compound of the formula

corresponding to the product of formula II in which Y″ is the aliphatic chain Y containing 2 carbon atoms missing, is reacted with an oxidation agent to obtain the corresponding aldehyde which is reacted with a phosphorane of the formula

The products of formula I in which Y is a branched aliphatic chain can be prepared by alkylation of the products of formula I in which Y is a linear aliphatic chain after having, if appropriate, blocked the 3- and/or 17-reactive functions. The alkylation is effected by using an alkyl halide such as methyl iodide in the presence of lithium diisopropylamide. The products of formula III can be prepared by alkaline hydrolysis of the corresponding products containing at 11β position a —X—Y—CN chain of ducts obtained starting with products of formula II′ as defined above in which one protects the hydroxyl functions, then is reacted with a halogenation agent such as an alkali metal halide, for example, sodium iodide and then an alkali metal cyanide such as potassium cyanide.

The process of the invention for the preparation of the compounds of formula I A comprises reacting a compound of the formula

wherein X, Y, n, R′ 18 and R 18 have the above definition with the proviso if R 18 is —OH, it is protected, with an oxidation agent to obtain a compound of the formula

subjecting the latter to an agent for activating the carboxyl and then with a compound of the formula

to obtain a compound of the formula

wherein Z is a simple bond and optionally deprotecting the hydroxy and if desired reacting the compound of formula V′ with a reducing agent when R 18 and R′ 18 are ═O and acylating the 17-hydroxy or with a saponification agent when R 18 is acyloxy. The compound of formula V′ may be subjected to an aromatization agent for the A ring and then with a saponification agent to obtain the compounds of formula I A .

The resulting compounds of formula I A may be subjected to at least one of the following reractions: when R 18 and R′ 18 are ═O, they may be reacted with a reducing agent or a metal complex M—R′ 18 wherein M is a metal ion and R′ 18 has the above definition other than hydrogen or when R 18 is —OH, they may be selectively acylated in the 17-position or when R B and R′ B are hydrogen, they may be reacted with an appropriate alkylation agent or when Y′ is an unsaturated aliphatic, they may be subjected to a hydrogenation agent to obtain compounds of formula I A where K′ is oxygen which, if desired, may be reacted with a sulfuration agent to obtain a compound of formula I A where K′ is —S—.

The compounds of formula V′ are obtained by reacting an active compound of formula IV′ in the form of a mixed anhydride by reaction with chloroformate for example isobutyl chloroformate in the presence of a tertiary amine such as N-methyl morpholine in an anhydrous solvent such as methylene chloride with the amine of formula V′.

The products of formula III′ are obtained with an oxidation agent such as a mixture of sulfuric acid and CrO 3 — in a neutral solvent such as acetone. In a preferred mode, the compounds of formula II′ contain a 11 β-group terminated with an alcohol group wherein

As an illustration of some examples, the compounds of formula III′ with a 11β-chain terminated with a carboxyl group are obtained by oxidation of a compound with a 11β-chain terminated with a hydroxy group. The compounds of formula IV′ may be an amine such as butylamine, methylbutylamine, methylisopropylamine or benzylpiperidine which are known or methyl heptafluorobutylamine which is prepared infra.

When the compound of formula V′ was a 17-one group, it may be reacted with a reducing agent such as sodium borohydride in a neutral solvent such as methanol or tritert.-butoxy lithium aluminum hydride in tetrahydrofuran to obtain the corresponding 17β-ol compound. The latter may be reacted with an acylation agent such as acetic anhydride in pyridine in the optional presence of 4-dimethylamino-pyridine to obtain the 17β-acyloxy compound. The latter compounds may be reacted with a saponification agent such as alcoholic potassium hydroxide to obtain the 17β-ol compound.

The compounds of formula I A which are steroid derivatives of estradiol with a 11β-chain containing a substituted amide group are obtained by reacting a compound of formula V′ with an aromatization agent such as palladium hydroxide on magnesia in methanol or a mixture of acetyl bromide and acetic anhydride at a temperature not greater than room temperature followed by a saponification reaction with for example potassium hydroxide in methanol or sodium bicarbonate or methanol in the presence of hydrochloric acid.

When the compounds of formula I A have a 17-one group, the corresponding 17-ol compound can be prepared by the reducing conditions described for the compounds of formula V′ such as sodium borohydride in a neutral solvent such as methanol. The compounds of formula I A wherein R′ 18 is optionally substituted alkyl, alkenyl or alkynyl can be obtained using a complex such as lithium complex as described in EPO Patent No. 57, 115.

When the compounds of formula I A contain a 17-ol group, the 17-acyloxy may be formed by selective acylation with acetic anhydride in pyridine, for example. When R B or R′ B is hydrogen, the corresponding alkyl compound can be obtained by reaction with an alkyl halide such as methyliodide, ethyliodide, methylbromide or ethylbromide in a solvent such as tetrahydrofuran. It is well known that if R′ 18 is alkyl, alkenyl or alkynyl substituted with a reactive group, that it is possible to protect the same by known methods.

When Y′ is an unsaturated aliphatic, the compounds of formula I A can have the triple bond reduced with hydrogen in the presence of palladium on activated carbon or barium sulfate and optionally with a base such as pyridine or quinoline in the case of a partial reduction. One may use palladium hydroxide alone or chlorotris (triphenylphosphine) rhodium for a total reduction.

The compounds of formula I A wherein Y′ is a branched aliphatic chain may be prepared by alkylation of compounds of formula I A wherein Y′ is a linear aliphatic group while blocking any reactive group in the 3- and 17-positions. The alkylation may be effected with methyliodide in the presence of lithium diisopropylamide, for example.

When K′ is oxygen, the corresponding compound of formula I A wherein K′ is sulfur may be obtained by reaction with a sulfurization agent such as [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphenate-2,4-disulfur] or Lawesson reagent after optional blocking of any reactive groups in the 3- and 17-positions.

Another process of the invention for the preparation of compounds of formula I A wherein Y′ is an aliphatic chain optionally containing an arylene attached by a double or triple bond and having at least 3 carbon atoms or an arylene attached by oxygen or sulfur comprises reacing a compound of the formula

wherein W is selected from the group consisting of —OH, optionally activated mercapto and —C═CH and n, R 18A and R′ 18A have the above definitions or if R 18A is —OH, it is optionally protected, the A′ and B′ rings are

and R 3 is hydrogen or a —OH protecting group or when W is —C≡CH with a halogen derivative of the formula

wherein Hal is halogen, Z′, R B and R′ B have the above definitions and Y″ is the aliphatic chain of Y′ having at least 2 carbon atoms in the presence of a strong base and optionally with a deprotection agent for the 3- and/or 17-positions to obtain a compound of the formula

optionally subjecting the latter to a partial or total reduction of the triple bond to obtain a compound of the formula

or when W is —OH or optionally activated mercapto with a halogen derivative of the formula

wherein Hal, Y′, Z′, R B and R′ B have the above definitions in the presence of an alkaline agent and then with a deprotection agent to obtain a compound of the formula

wherein K′ is oxygen or sulfur and the compounds of formulae IX′ A , IX′ B and IX′ C may be reacted as the compounds of formula V above to obtain the compounds of formula I A as individual above.

When W is an activated mercapto, it is formed by reaction with a metal thiolate such as silver thiolate.

In a preferred mode of the process, the 3- and 17-ols are protected by tetrahydropyran or tert.-butyl and Hal is preferably bromine, iodine or chlorine. The strong base is preferably butyllithium or sodium hydride. The optional reduction of the triple bond is effected either with hydrogen in the presence of palladium on activated carbon, barium sulfate and optionally a base such as pyridine or quinoline for a partial reduction or with palladium hydroxide alone or chlorotris (triphenylphosphine) rhodium for a total reduction.

Preferably, the optional activation of mercapto is effected by reaction with a metallic salt such as silver nitrate with the mercapto protected such as a thioether i.e. alkylthio like tert.-butylthio, triphenylmethylthio, isobutoxymethylthio or a derivative of 5- or 6-member ring optionally containing a nitrogen, oxygen or sulfur heteroatom, preferably oxygen. An example of such a protected mercapto is tetrahydropyranylthio.

Preferably, the alkaline agent is an alkali metal hydroxide such as sodium hydroxide and the deblocking of the protected functions is effected with a hydrolysis agent such as hydrochloric acid. The preferred compounds of formula VII′ have W in the para-position.

The novel hormonal compositions of the invention are comprised of an hormonally effective amount of at least one compound of formula I and I A and an inert pharmaceutical carrier or excipient. The compositions may be in the form of tablets, dragees, capsules, granules, suppositories, pessaries, ointment, creams, gels, microspheres, implants, patches and injectable solutions or suspensions.

Examples of suitable excipients are talc, arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants and emulsifiers and preservatives.

The compositions containing compounds of formula I and I A present interesting pharmacological properties. The study of products on the hormonal receptors has brought to the fore that the compounds of formulae Ia and Ib possess glucocoticoid or antiglucocorticoid, progrestomimetic or antiprogestomimetic, androgen or antiandrogen, antimineralocorticoid, estrogen or anti-estrogen activity and the compounds of formulae Ib and I′b possess particularly a remarkable anti-estrogen activity and anti-proliferative properties as shown by the results of tests given intra.

These properties make the compositions containing compounds of formula Ia and I′a useful for combatting the side effects of glucocorticoids and permit the combatting of disorders due to a hypersecretion of glucocorticoids and notably the combatting of aging in general and more particularly the combatting of hypertension, atherosclerosis, osteoporosis, diabetes, obesity as well as the depression of immunity and insomnia. These compositions are equally of interest in the treatment of certain hormonal-dependent tumors.

The compositions containing compounds of formulae Ia and Ib which possess antiprogestomimetic properties can be used for the preparation of original contraceptives or as abortion agents and are useful for inducing (menstrual) periods in women and more generally in warm-blooded female animals. The compositions are administered during the periods where progesterone plays an essential physiological role, i.e., during the luteal phase of the cycle, at the moment of nidation (or implanation of the embryo) and during pregnancy. One method of contraception of the invention consists of administering to the women at least one of the products of formula Ia or I′a over 1 to 5 days, preferably at the end of the cycle. This product is then preferably administered orally or in vagino but it can also be administered parenterally and endonasally.

The compositions containing the compounds of formulae Ia and I′a possessing anti-progestomimetic properties are also useful against hormone irregularities and, are of interest in the treatment of hormone-dependent tumors. Their actions on hypophysial secretions make the products usable in the menopause and these compositions can be used in the synchronization of estrus in farm animals, particularly cattle and sheep and for controlling the fertility of pets such as dogs or cats. Equally the compositions containing compounds of formulae Ia and I′a can have progestomimetic properties and can be used in the treatment of amenorrhea, dysmenorrhea and luteal insufficiencies.

The compositions of compounds of formula Ia and I′a which possess anti-androgenic properties can be used in the treatment of hypertrophia and cancer of the prostate, hyperandrogenia, anemia, hirsutism and acne. Equally they can be used for male contraceptives.

The compositions of compounds of formulae Ia and Ia′ which possess estrogenic properties make them useful in the treatment of disorders linked to a hypofolliculinia for example amenorrhea, dysmenorrhea, repeated miscarriages, premenstrual troubles as well as in the treatment of the menopause and of osteoporosis.

The anti-estrogen and anti-proliferation properties of compositions containing the compounds of formulae Ib and Ib′ and the compounds of formula IA make them useful in the treatment of mammary carcinomas and their metastases and in the treatment of benign tumors of the breast.

Among the preferred compositions of the invention are those containing the compounds of Examples 8, 16, 19, 21, 35, 37, 43, 46, 55, 71, 75, 77, 78, 79, 80, 82, 83, 85, 86 and 89.

The novel method of inducing hormonal activity in warm-blooded animals, including humans, comprises administering to warm-blooded animals an hormonally effective amount of at least one compound of formula I. The compounds may be administered orally, rectally or parenterally and the usual daily dose is 0.013 to 1.33 mg/kg depending upon the method of administration, the condition being treated and the specific compound being administered.

The compounds of formulae II and III are novel intermediates and an object of the invention.

The compounds of formula II may be prepared by reacting a magnesium derivative of a halogenated alcohol of the formula

Hal—X—Y—CH 2 OR   VI

wherein X and Y have the above definitions, Hal is a halogen and R is hydrogen or an alcohol protecting groups such as

in the presence of a copper salt with a compound of the formula

wherein K is a ketone protector group such as a cyclic ketal to obtain a compound of the formula

optionally reacting the latter with a lithium derivative of a compound of the formula

H—R′ 17   IX

wherein R′ 17 has the above definition other than hydrogen or with a reducing agent, then optionally with an acylation agent and then to a dehydration and hydrolysis agent capable of liberating the 3-keto-Δ 4 function and the alcohol function to obtain the compound of formula II.

Certain intermediates of formula II′ and III′ are novel, namely those wherein n is 2.

The products of formula VII′ are known products and their preparation is described, for example, in EP Patent No. 0,057,115. The products of formula X′ are described notably in European Patent Application No. EP 0,245,170 when n is 1 and in EP application No. 0,116,974 when n is 2, and specific examples of the preparation of products of formula X′ are described hereinafter in the examples. Examples of the preparation of products of formulae IX and XII are in the experimental part.

Among the preferred new products of formula II of the invention are 17β-acetyloxy-11β-[(8-hydroxy-octyl)-phenyl]-Δ 4,9 -estradiene-3-one, 11β-(12-hydroxy-dodecyl)-Δ 4,9 -estradiene-3,17-dione and 11β-(8-hydroxyoctyl)-Δ 4,9 -estradien-3,17-dione.

Among the preferred products of formula III of the invention are 17β-acetyloxy-3-oxo-11β-Δ 4,9 -estradiene-undecanoic acid, 3,17-dioxo-11β-Δ 4,9 -estradiene undecanoic acid and 17β-hydroxy-3-oxo-17α-(1-propynyl)-11β-Δ 4,9 -estradiene undecanoic acid.

The following products are products able to be obtained within the scope of the present invention:

The products of formula VII′ wherein n is 1 and W is other then mercapto are described in European Patent application No. 0,245,170 and the products where n is 2 and W is other than mercapto may be prepared by the process for the preparation of compounds of formula XII′ where n is 2.

The compounds of formula VII′ where W is optionally activated mercapto are novel and may be prepared by reaction of a magnesium compound containing a mercapto with a compound of formula VII′. Specific examples are described infra.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

PREPARATION 1

17β-Acetyloxy-11β-[4-(2-hydroxymethyl)-phenyl)-Δ 4,9 -estradiene-3-one

Step A: (5α,11β)-3-(1,2-ethanediyl cyclic acetal) of 5α-hydroxy-11β-[4-[2-[[(1,1-dimethylethyl)-dimethylsilyl]-oxy]-methyl]-phenyl]-Δ 9 -estrene-3,17-dione

Preparation of the Magnesium Reagent:

To a suspension of 1.4 g of magnesium turnings in 20 ml of tetrahydrofuran, 19.9 g of the brominated derivative obtained from preparation 9 in solution in 60 ml of tetrahydrofuran were added dropwise followed by stirring for 1 hour at 50° C. to obtain a solution with a titre=0.85 mole/liter.

Condensation:

For 10 minutes at ambient temperature, a solution of 4.5 g of 3-(1,2-ethanediyl cyclic acetal) of 5α,10α-epoxy-Δ 9,11 -estrene-3,17-dione [EP 0,057,115 (Example 7)] in 45 ml of tetrahydrofuran and 0.4 g of cupric chloride was stirred and over a period of 20 minutes, 50 ml of the magnesium reagent above were added without exceeding 27° C. After 90 minutes of stirring, the mixture was poured into an ice-cooled solution of ammonium chloride. The aqueous phase was extracted once with ethyl acetate and 3 times with methylene chloride to obtain 15.423 g of a product which was chromatographed over silica (eluant:cyclohexane=ethyl acetate (7-3) to obtain 6.29 g of the desired product.

Step B: 3-(1,2-ethanediyl cyclic acetal) of 5α,17β-dihydroxy-11β-[4-2-[[(1-dimethylethyl)-dimethylsilyl]-oxy]-methyl]-phenyl]-Δ 9 -estren-3-one

To a solution of 6.15 g of the product of Step A in 100 ml of methanol, 6 g of sodium boron hydride were added over 13 minutes and the mixture was stirred for two hours and poured into 500 ml of water and extracted with methylene chloride. The organic phase was evaporated to dryness to obtain 6.17 g of the desired product which was used as such in the following step.

a) Acetylation

To a solution of 6.1 g of the product of Step B in 52 ml of pyridine and 1.15 g of 4-dimethylamino-pyridine, 5.2 ml of acetic anhydride were added and the mixture was stirred for 20 minutes and poured into 200 ml of an ice-cooled solution of sodium bicarbonate. The mixture was stirred for 10 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness to obtain 6.828 g of the expected amorphous product.

b) Hydrolysis

The said product was taken up in 40 ml of 2N hydrochloric acid and 50 ml of ethanol and was stirred for 1 hour at ambient temperature and concentrated to half-volume under reduced pressure. The mixture was diluted with 100 ml of water, and extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica (eluant:cyclohexane=ethyl acetate (1-1) to obtain 3.39 g of the desired product.

PREPARATION 2

3,17-dioxo-11β-Δ 4,9 -estradiene-pentanoic Acid

Preparation of the Magnesium Reagent of 1-chloro-5-pentanol

To a solution of 24.6 ml of 1-chloro-5-propanol in 246 ml of tetrahydrofuran, 300 ml of a 0.67 M/liter solution of the magnesium reagent of 2-chloropropane in tetrahydrofuran was added over 20 minutes at −20° C. and the mixture was stirred for 20 minutes at −20° C. 7.3 g of the magnesium reagent in shavings were added followed by 0.5 ml of dibromoethane. The mixture was refluxed for 1 hour, 0.5 ml of dibromoethane were added and then reflux was continued for two hours. The mixture returned to ambient temperature to obtain the solution of the desired magnesium reagent titering 0.18 M/liter.

Condensation:

To a mixture of 12 g of the 5,10 epoxy compound of EP 0,057,115 (Example 7) and 600 mg of cuprous chloride in 150 ml of tetrahydrofuran, 570 ml of the magnesium reagent were added dropwise at −50° C. and the mixture was stirred for a further 30 minutes and poured into a mixture of 250 ml of a saturated solution of ammonium chloride and 250 g of ice. The mixture was extracted with chloroform and the organic phase was washed with a saturated solution of sodium chloride, dried and evaporated to to dryness under reduced pressure. The 35 g of the residue were chromatographed over silica (eluant:methylene chloride−acetone) (85-15)) to obtain 13.5 g of the desired product.

For 90 minutes, a mixture of 5 g of the product of Step A, 110 ml of ethanol and 28 ml of 2N hydrochloric acid was stirred and the mixture was made alkaline to pH of about 9 with concentrated ammonia. The mixture was washed with water, and a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 4.8 g of residue were chromatographed over silica (eluant:methylene chloride−acetone (85-15)) to obtain 3.97 g of the expected product.

To a solution of 2.9 g of the product of Step B in 140 ml of acetone cooled down to −4° C., 1 ml of Heilbron-Jones reagent were added over 25 minutes at 0° to −4° C. and the mixture was stirred for a further 5 minutes at 0° C. The excess reagent was destroyed by the addition of 2.5 ml of methanol and a solution of 22 g of barium carbonate in 220 ml of water was added. The mixture was stirred for 1 hour at ambient temperature and filtered to remove the mineral salts which were washed 5 times with 200 ml of acetone. The acetone was evaporated and the aqueous phase was extracted 4 times with 200 ml of methylene chloride. The organic phase was washed with water, and sodium chloride in saturated solution and evaporated to dryness under reduced pressure to obtain 3.4 g of the desired product used as such in the following step.

PREPARATION 3

3,17-dioxo-11β-Δ 4,9 -estradiene-heptanoic Acid

Using the procedure of Step A of Preparation 2, 14.4 g of 1-chloro-7-heptanol [obtained in Preparation 10 starting from 13.9 g of the 5α,10α-epoxide of EP 0,057,115 Example 7] yield. 26.9 g of crude product which was chromatographed over silica (eluant:methylene chloride-acetone-triethylamine (85-15-0.4)) to obtain 9 g of the desired product. The latter was chromatographed once more (eluant:ethyl acetate-cyclohexane-triethylamine (60-40-0.4)) to obtain 8.17 g of the desired product.

Using the procedure of Step B of Preparation 2, 2.5 g of the product of Step A were reacted and after chromatography over silica (eluant:cyclohexane-diethyl acetate (1-1)), 1.935 g of the desired product were obtained.

Using the procedure of Step C of Preparation 2, 3.2 g of the product of Step B were reacted to obtain 3.04 g of the desired product which was used as such in the following step.

PREPARATION 4

17β-acetyloxy-11β-[4-(8-hydroxy octyl)-phenyl]-Δ 4,9 -estradiene-3-one

Step A: 3-(1,2-ethanediyl cyclic acetal) of 11β-[4-[8-[[(1,1-dimethyl ethyl)-dimethylsilyl]-oxy]-ocytl]-phenyl]-Δ 9 -estrene-5α-ol-3,17-dione

Using the procedure of Step A of Preparation 1, 3.171 g of the epoxide of EP 0,057,115 (Example 7) and 9.9 g of dimethyl tert.-butyl silyl octanyloxy bromobenzene (of Preparation 11) were reacted to obtain after chromatography over silica (eluant:cuyclohexane-ethyl-acetate (6-4)), 4.127 g of the desired product.

Step B: 3-(1,2-ethanediyl cyclic acetal) of 11β-[4-[8-[[(1,1-dimethyl ethyl)-dimethylsilyl]-oxy]-octyl]-phenyl]-Δ 9 -estren-5α,17β-diol-3-one

Using the procedure of Step B of preparation 1, 2.62 g of the product of Step A were reacted to obtain 2.6 g of the desired product for use as is in the following step.

Step C: 3-(1,2-ethanediyl cyclic acetal) of 17β-acetyloxy-11β-[4-[8-[[(1,1-dimethyl ethyl)-dimethylsilyl]-oxy]-octyl]-phenyl]-Δ 9 -estren-5α-ol-3-one

Using the procedure of (a) Step C of preparation 1, the product of Step B was reacted to obtain after chromatography on silica (eluant:cyclohexane-ethyl acetate (6-4)), 2.58 g of the desired product.

Using the procedure of (b) Step C of preparation 1, the product of Step C was reacted to obtained after chromatography on silica (eluant:cyclohexane-ethyl acetate (5-5), 1.2 g of the desired product.

PREPARATION 5

17β-acetyloxy-3-oxo-11β-Δ 4,9 -estradiene undecanoic Acid

Step A: 3-(1,2-ethanediyl cyclic acetal) of 11β-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-Δ 9 -esterene-5-ol-3,17-dione

Using the procedure of Step A of preparation 1, 17.5 g of the epoxide of EP 0,057,115 (Example 7) and 500 ml of a 0.32 M suspension in tetrahydrofuran of 11-(dimethyl-tert-.butylsilyloxy)-undecyl magnesium bromide (prepared by ICI Patent No. 85-100658) were reacted to obtain after chromatography on silica (eluant:cyclohexane-ethyl acetate (95-5 then 5-5)), 15.3 g of the desired product.

Step B: (1,2-ethanediyl cyclic acetal) of 11β-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-Δ 9 -estren-5α,17β-diol-3-one

Using the procedure of Step B of preparation 1, 15.2 g of the product of Step A were reacted to obtain 14.863 g of the desired product, which was used as is for the following step.

Step C: (1,2-ethanediyl cyclic acetal) of 17β-acetyloxy-11β-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-Δ 9 -estren-5α-ol-3-one

A mixture of 13.335 g of the product of Step B, 53 ml of pyridine and 26 ml of acetic anhydride was stirred for 4 hours 30 minutes at ambient temperature and was then cooled and neutralized by adding, over 45 minutes, sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with water, dried and evaporated to dryness under vacuum to obtain 15 g of the desired product which was used as is for the following step.

A mixture of 15 g of the product of Step C, 300 ml of methanol and 75 ml of 2N hydrochloric acid was stirred for 2 hours 45 minutes and then 20 ml of concentrated ammonia were added and the methanol was evaporated under vacuum. The mixture was extracted with ethyl acetate and the organic phase was washed with water saturated with sodium chloride, dried and evaporated to dryness under vacuum to obtain 12.75 g of product which was chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5)) to obtain 8.37 g of the desired product.

Using the procedure of Step C of preparation 1, 8.37 g of the product of Step D were reacted to obtain after chromatography on silica (eluant:cyclohexane-ethyl acetate (5-5)), 6.67 g of the desired product.

PREPARATION 6

3,17-dioxo-11β-Δ 4,9 -estradiene undecanoic Acid

A mixture of 1 g of the product of Step A of preparation 5, 20 ml of methanol and 5 ml of 2N hydrochloric acid was stirred for 75 minutes at ambient temperature and the mixture was made alkaline to pH approx. 9 with concentrated ammonia, then was evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed with a saturated sodium chloride solution, dried and concentrated to dryness under reduced pressure. The dry extract was chromatographed on silica (eluant:cyclohexane-ethyl acetate (6-4)) to obtain 670 mg of the desired product.

Using the procedure of Step C of preparation 2, 10.4 g of the product of Step A were reacted to obtain 12.4 g of the desired product which was used as is for the following step.

PREPARATION 7

17β-hydroxy-3-oxo-17α-(1-propynyl)-11β-Δ 4,9 -esterdiene Undecanoic Acid

To a solution of 5 kg of 3,3-dimethyl ketal-Δ 4,9 -estradien-17-one (French Patent No. 1,514,086) in 25 liters of methylene chloride and 25 ml of pyridine, 430 g of hexachloroacetone and 1.3 liters of 200 volume hydrogen peroxide were added and the mixture was stirred for 24 hours at 16 to 18° C. and poured into a mixture of 1,400 kg of sodium thiosulfate and 50 liters of demineralized water. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure to obtain 7.29 kg of the desired product which was used as is for the following step.

Step B: 3,3-dimethyl ketal of 11β-(11-dimethyl tert-butyl silyloxy undecyl)-Δ 9 -estrene-5β-ol-3,17-dione

To 600 ml of the magnesium derivative of bromo undecyloxy dimethyl tert-butyl silane (ICI Patent No. 85-100658) in 50 ml of tetrahydrofuran cooled to 0° C., there was added 1.58 g of cuprous chloride and the mixture was stirred for 30 minutes and cooled to −30° C. A solution of 18.17 g of the product of Step A in solution in 87 ml of tetrahydrofuran was added and the mixture was stirred for 3 hours and 30 minutes at ambient temperature, then poured into a solution of ammonium chloride at 0° C. The mixture was stirred for 10 minutes and extracted with ethyl acetate followed by methylene chloride. The organic phases were washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The 123 g of residue was chromatographed on silica (eluant:methylene chloride-ethyl acetate (9-1) with 1% of triethylamine) to obtain 5.19 g of the desired product used as is in the following step.

84 ml of butyl lithium in hexane (1.6 mol/liter) were cooled to −70° C. and slowly 84 ml of tetahydrofuran were added. Methyl acetylene was bubbled therethrough while maintaining the temperature at −50° C. and after 10 minutes, the temperature fell to −70° C. The bubbling in was stopped and the mixture was stirred for 30 minutes at −70° C. 4.18 g of the product of Step B in solution in 80 ml of tetrahydrofuran were added and the temperature returned to ambient temperature. The mixture was stirred for 1 hour under these conditions and poured into a solution of ammonium chloride at 0° C. The mixture was extracted with ethyl acetate and then methylene chloride and the organic phases were washed, dried and evaporated to dryness under reduced pressure. The 6 g of residue were redissolved in 50 ml of ethanol and 10 ml of 2N hydrochloric acid and the mixture was stirred for 1 hour at ambient temperature and diluted with 100 ml of water. The mixture was extracted with chloroform and the organic phase was evaporated to dryness. The 4.9 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5) to obtain 2.25 g of the desired product.

a) Diacetylation.

A solution of 5.07 g of the product of Step C of Example 9 in 48 ml of pyridine, 1 g of 4-dimethylamino-pyridine and 17.6 ml of acetic anhydride was stirred for 18 hours at 20° C. and then 200 ml of ice were added all at once. The mixture was neutralized with a saturated sodium bicarbonate solution and stirred for 30 minutes followed by extraction with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 8 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5)) to obtain 2.83 g of the desired product.

b) Mono-saponification.

A solution of 2.8 g of the diacetylated product in 28 ml of methanol with 0.7 g of potassium bicarbonate was heated to 70° C. for 90 minutes and then 100 ml of iced water were added. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness. The 2.6 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5)) to obtain 1.18 g of the desired product used as is for the following step.

To a solution of 460 mg of the product of Step A in 24 ml of acetone, 0.8 ml of a solution prepared from 57 ml of concentrated sulfuric acid, 67 g of chromic oxide and sufficient water to make to 250 ml were added over 1 hour at 0° C.

8 drops of methanol, 28 ml of water and 8 g of barium carbonate were added to the reaction solution at 0° C. and the mixture was stirred for 1 hour at 0° C. and filtered to remove the insoluble material. The filtrate was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure and the 384 mg of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5)) to obtain 198 mg of the desired product.

A solution of 722 mg of the product of Step B in 8 ml of a 1 M solution of methanolic potassium hydroxide was stirred at room temperature for one hour and 10 g of ice, then 10 ml of normal hydrochloric acid were added all at once. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure to obtain 593 mg of the desired product used as is for the following step.

PREPARATION 8

11β-(12-hydroxy dodecyl)-Δ 4,9 -estradiene-3,17-dione

Step A: 3-(1,2-ethanediyl cyclic acetal) of 11β-[12-[[(1,1-dimethylethyl)-dimethylsilyl]-oxy]-dodecyl]-Δ 9 -estrene-5α-ol-3,17-dione

Using the procedure of Step A of preparation 1, 2.97 g of the epoxide of European Patent No. 0,057,115 (Example 7) and 12 g of dodecanoxy dimethyl tert-butyl silane magnesium bromide (preparation 13) were reacted to obtain, after chromatography on silica (eluant:cyclohexane-ethyl acetate (6-4)), 5.24 g of the desired product.

Using the procedure of Step A of Preparation 6, 5.2 g of the product of Step A were reacted and after chromatography on silica (eluant:cyclohexane-ethyl acetate (6-4)), 2.78 g of the desired product were obtained.

PREPARATION 9

Phenethoxy Dimethyl Tert-Butyl Silyl Bromide

To a solution of 15 g of 4-bromophenethyl alcohol in 60 ml of tetrahydrofuran at 0° C. to 5° C., 10.6 g of imidazole were added followed by addition over 30 minutes of a solution of of 14.33 g of dimethyl tert-butyl chlorosilane in 20 ml of tetrahydrofuran at 0°±2° C. The mixture was diluted with 40 ml of tetrahydrofuran and was then stirred for 2 hours at ambient temperature and filtered to remove the insoluble material. The filtrate was evaporated to dryness under reduced pressure and the 32.89 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (95-5)), to obtain 24 g of the desired product.

IR Spectrum: (CHCl 3 ) Absence of OH Presence of

PREPARATION 10

1-chloro-7-heptanol (Used in Step A of Preparation 3)

A mixture of 44 g of heptane diol, 400 ml of concentrated hydrochloric acid, 150 ml of toluene and 50 ml of water was stirred for two and half hours at reflux. The toluene fraction was removed and 200 ml of toluene were added to the aqueous fraction and the mixture was heated for five hours at 85° C. to 90° C. The toluene was removed and 200 ml of toluene and 100 ml of concentrated hydrochloric acid were added to the aqueous phase. The mixture was heated for five hours, then cooled and the organic fraction was combined with the two preceding toluene fractions. The toluene fraction was washed with water, dried and evaporated to dryness under reduced pressure, then distilled at 70° C. under 0.5 mm of mercury to obtain 37 g of the desired product.

PREPARATION 11

Dimethyl Tert-Butyl Silyl Octyloxy Bromobenzene

To a mixture of 40.93 g of 1-chlorohexanol, 42.9 g of imidazole and 102 ml of tetrahydrofuran, a solution of 56.07 g of dimethyl tert-butyl silyl chloride in 114 ml of tetrahydrofuran was added at 15 to 18° C. and the mixture was stirred for 15 hours at ambient temperature and then centrifuged to remove the precipitate. Chromatography on silica (eluant:cyclohexane-ethyl acetate (95-5)) obtained 74.28 g of the desired product.

a) Chlorohexyloxy dimethyl tert-butyl silyl magnesium.

A solution of 74.82 g of the product of Step A in 300 ml of tetrahydrofuran was added to a suspension of 0.871 g of magnesium and 271 ml of tetrahydrofuran and the mixture was refluxed for 4 hours and cooled to obtain the desired magnesium derivative with a titer approximately 0.375 mol/liter

50 g of iodoethyl benzene (Preparation 12) in 500 ml of tetrahydrofuran were added at −70° C. over 15 minutes to 640 ml of the magnesium derivative solution and the mixture was stirred while allowing a return to ambient temperature and the stirring was continued for 15 hours. 500 ml of water saturated with ammonium chloride were added and the mixture was stirred for 15 minutes. The decanted organic phase was washed, dried and evaporated to dryness and the 101.3 g of residue were chromatographed on silica (eluant:cyclohexane) obtain 39.5 g of the desired product.

PREPARATION 12

1-p-bromophenethyl Iodide

To a solution of 95.2 g of 4-bromophenyl acetic acid in 950 ml of tetrahydrofuran, 49 ml of 10 M borane-dimethyl sulfide complex were added over 35 minutes at 15 to 20° C. and the mixture was refluxed over 20 minutes and maintained for 10 minutes, then cooled. 50 ml of water were added and the mixture was extracted with ethyl acetate and evaporated to dryness under reduced pressure. The 102 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (6-4)) to obtain the desired product.

To a solution of 41 g of the alcohol of Step A in 102 ml of pyridine, 77.72 g of tosyl chloride were added over 35 minutes at 5° C.±1° C. and the mixture was stirred for another 30 minutes at 5° C., then allowed to return to ambient temperature. 500 ml of of saturated sodium bicarbonate solution were added and the mixture was extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure to obtain 71.4 g of the desired product melting at 92° C.

To a solution of 71.4 g of the p-toluene sulfonate of Step B in 1,400 ml of acetone, 45.12 g of sodium iodide were added and the mixture was heated to a slight reflux which was maintained for 2 hours, then cooled. The mixture was centrifuged to remove the precipitate which was washed with acetone. The filtrate was evaporated to dryness under reduced pressure and the 80.5 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (8-2)) to obtain 60.54 g of the desired product melting approximately at 40° C.

PREPARATION 13

Bromododecanoxy Dimethyl Tert-Butyl Silane

To a solution of 10 g of 12-bromo-1-decanol in 40 ml of tetrahydrofuran, 5.48 g of imidazole were added and over 10 minutes a solution of 7.058 g of dimethyl tert-butyl chlorosilane in 10 ml of tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble material was filtered off. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed on silica (eluant:cyclohexane-ethyl acetate (95-5)) to obtain 13.57 g of the desired product usable as is for Step A of Example 15.

PREPARATION 14

N-hepta-fluorobutyl N-methylamine Hydrochloride

100 ml of anhydrous ether and 100 ml of anhydrous tetrahydrofuran was cooled down to 0° C. and the methyl amine was bubbled through for 10 minutes. 44.98 g of heptafluorobutyric anhydride were introduced over half an hour, while maintaining a weak bubbling through of methyl amine. The mixture was stirred while allowing the temperature to return to ambient and was then distilled to a small volume under reduced pressure. The mixture was taken up in 200 ml of anhydrous tetrahydrofuran and 30 ml of dioborane-dimethyl sulfide complex were introduced slowly. The mixture was refluxed for 16 hours, cooled down to ambient temperature and then 200 ml of methanol were introduced slowly. Then, gaseous hydrochloric acid was bubbled through for 15 minutes and the reaction medium was refluxed for one hour. The solvents were distilled off under reduced pressure and the residue was taken up in 200 ml of methanol. Gaseous hydrochloric acid was again bubbled through for 10 minutes, followed by refluxing for 2 hours. The solvent was distilled off and the residue was stirred in 100 ml of ice-cooled 6N hydrochloric acid for 10 minutes. After separating, washing with 2N hydrochloric acid and drying, 22.699 g of the expected product were obtained. The hydrochloride was purified by crystallization from 140 ml of ethanol. Then, 140 ml of ether were added and the mixture was stirred for half an hour, followed by separating, washing with ether and drying under reduced pressure to obtain 21.7 g of the desired product (subliming at about 200° C.).

PREPARATION 15

[(5-chloro pentyl)-oxy]-dimethyl (1,1-dimethyl)-silane

13.8 ml of triethylamine and then 200 mg of 4-dimethyl amino-pyridine were added under a nitrogen atmosphere to a solution of 10.2 g of 5-chloropentanol in 80 ml of methylene chloride. The mixture was cooled down to −10° C. and 13.75 g of tertbutyl chloro dimethyl-silane were added. The mixture was stirred for 15 minutes at −10° C. then left to reheat to ambient temperature and diluted with a saturated solution of sodium bicarbonate. The oily crude derivative was separated out and chromatographed on silica (eluant:cyclohexane-ethyl acetate 95-5) to obtain 18 g of the expected product.

PREPARATION 16

[(3-bromopropyloxy)]-dimethyl-(1,1-dimethylethyl)-silane

9.46 g of sodium hydride at 50% in oil were introduced into a spherical flask placed under an argon atmosphere and the oil was eliminated by washing with hexane. 380 ml of tetrahydrofuran and 15 g of 1,3-propanediol were added and the mixture was stirred for one hour at ambient temperature. After cooling the mixture to +5° C., 29.7 g of terbutyl-chlorodimethyl silane were added and the mixture was stirred for one hour at ambient temperature and then poured into 3.5 liters of ethyl ether. It was washed with 1 liter of a 10% aqueous solution of potassium carbonate, then with 1 liter of a saturated aqueous solution of sodium chloride, then dried over sodium sulfate and evaporated to dryness under reduced pressure. The 3.5 g of residue were chromatogrpahed on silica (eluant:ethyl acetate-cyclohexane 4-6) to obtain 30.6 g of the expected product.

5.44 g of tetrabromomethane and 4.30 g of triphenyl-phosphine were added to a solution of 2.5 g of the product of Step A in 27 ml of methylene chloride cooled down to −25° C. The reaction solution was stirred for 90 minutes at 0° C. and then was chromatographed on silica (eluant:ethyl acetate-cyclohexane 1-9) to obtain 2.885 g of the expected product.

PREPARATION 17

4-trimethylsilylethynyl-bromobenzene

150 g of 97% bromo iodo benzene, 500 ml of anhydrous dimethylformamide, 100 ml of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 of copper iodide and 2.22 g of bis-(triphenyl-phosphine)-palladium (II) dichloride were mixed together and stirred for 2 hours. Then, 500 ml of ice-cooled water were added and extraction was carried out 3 times with 500 ml of ethyl acetate. The organic phase was washed with salt water, then dried over sodium sulfate. The solvents were evaporated under reduced pressure to obtain 136.54 g of a brown oil. Purification was carried out by distillation under reduced pressure to obtain 106.97 g of the expected product with a boiling point of 75° C. to 82° C. under 0.2 mbar and a melting point of 62° C.

IR Spectrum: (CHCl 3 ) absence of C═CH C≡C 2160 cm −1

PREPARATION 18

[(8-bromo-octyl)-oxy]-dimethyl-(1,1-dimethylethyl)-silane

1.55 g of imidazole were added to a solution fo 3.97 g of 8-bromo octanol in 19 ml of dimethylformamide, and over 10 minutes, 3.32 g of terbutyl chloro dimethyl silane in solution in 4.7 ml of tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica (eluant:cyclohexane-toluene 8-2) to obtain 5.4 g of the expected product.

Preparation A of Example 78: 11β-(4-hydroxyphenyl)-δ 4,9 -estradien-3,17-dione

a) Preparation of the magnesium compound

50 g of trimethylsilyloxy 4-bromo benzene in 100 ml of tetrahydrofuran were added dropwise at reflux to a suspension of 7.1 g of magnesium turnings in 14.5 ml of tetrahydrofuran. After stiring for 30 minutes at reflux, a solution of about 0.95 M of magnesium compound was obtained.

b) Condensation

10 g of cyclic 3-(1,2-ethanediyl) acetal of 5,10 α-epoxy-δ 9,11 -estradien-3,17 dione [obtained by EP 0,057,115 (Example 7)] in solution in 200 ml of tetrahydrofuran and 0.45 g of copper chloride were stirred for 10 minutes at ambient temperature. 110 ml of the magnesium compound solution were added over 20 minutes, without exceeding 27° C. After 90 minutes of stirring, the mixture was poured into 1300 ml of a saturated ice-cooled solution of ammonium chloride. The aqueous phase was extracted 3 times with ethyl acetate, washed with a saturated solution of dehydrated sodium chloride and evaporated to dryness under reduced pressure to obtain 34.9 g of crude product.

c) Desilylation

The crude product was dissolved in 150 ml of tetrahydrofuran and 130 ml of a 1M solution of tetrabutylammonium fluoride were added. The mixture was stirred for 15 minutes at ambient temperature and then poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and evaporated to dryness under reduced pressure to obtain 26.9 g of crude product which was made into a paste at 40° C. over 30 minutes in 100 ml of an ethyl acetate—methylene chloride mixture (1-1). The insoluble part was filtered off and 5.77 g of the desired product were obtained. The mother liquors were chromatographed on silica (eluant: ethyl acetate—methylene chloride (1-1) and an additional 5.7 g of desired product were collected. The combined two batches of product (11.47 g) were crystallized from ethanol to obtain 8 g of expected product melting at 225° C.

5 g of the product of Step A, 110 ml of ethanol and 28 ml of 2N hydrochloric acid were stirred for 90 minutes and the mixture was alkalized to a pH of about 9 with concentrated liquid ammonia and evaporated to dryness. The residue was taken up in ethyl acetate, washed with water and with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 4.8 g of residue were chromatographed on silica (eluant: methylene chloride—ethyl acetate 7-3) to obtain 3.97 g of the desired product.

Preparation B of Example 78 [(5-Brompentyl)-Oxy]-N-Butyl-N-Bethyl Acetamide

26 g of butylmethylamine in solution in 120 ml of ether were added to a solution, cooled down to −20° C., of 11.9 ml of bromo-acetyl bromide in 180 ml of ether. The temperature was returned to 20° C. and the mixture was stirred for 30 minutes, diluted with water and extracted with ether. The extracts were evaporated to dryness under reduced pressure. The 27.4 g of residue were distilled under reduced pressure (0.05 mbar) at 79° C. to 83° C. to obtain 19.36 g of the desired product.

19.14 g of tertbutyl chlorodimethylsilane were added while cooling to a solution of 10 g of 4-pentanol, 200 ml of methylene chloride, 19.5 ml of triethylamine and 566 mg of 4-dimethylamino-pyridine. The mixture was stirred for one hour at ambient temperature, diluted with water and the organic phase was decanted, washed, dried and evaporated to dryness under vacuum. The 42 g of residue were chromatographed on silica (eluant: essence G—ethyl acetate 95-5) to obtain 23.3 g of silyloxy pentene which was dissolved in 250 ml of tetrahydrofuran. 6 ml of borane-methylsulfide complex were added at 20° C. and the mixture was stirred for 30 minutes at 20° C. to 25° C., then for 30 minutes at 35° C. 18 ml of sodium hydroxide, then 18 ml of hydrogen peroxide were added at +10° C. The mixture was stirred for 30 minutes and was diluted with water and extracted with ethyl acetate. The extracts were washed with a 10% solution of sodium thiosulfate, dried and concentrated to dryness under reduced pressure. The 25.85 g of residue were chromatographed on silica (eluant: cyclohexane—ethyl acetate 8-2) to obtain 22.7 g of product which was distilled under reduced pressure (0.06 mbar) to obtain 18.7 g of the desired compound with a boiling point of 73° C. to 75° C. at 0.06 mbar.

2.16 g of sodium hydride at 50% in oil were added to a solution of 8 g of the alcohol of Step B in 40 ml of tetrahydrofuran and the mixture was stirred for 30 minutes at ambient temperature. A solution of 9.5 g of the brominated product of Step A in 13 ml of tetrahydrofuran were added dropwise over 15 minutes. After stirring for 16 hours at ambient temperature, a saturated aqueous solution of ammonium chloride was added. Extraction was carried out with ethyl acetate and the extracts were washed, dried and evaporated to dryness under vacuum to obtain 14.8 g of intermediate N-butyl-[[5-[[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-pentyl]-oxy]-N-methyl acetamide which was dissolved in 83 ml of tetrahydrofuran and 46 ml of a 1M solution of tetrabutyl ammonium fluoride. The mixture was stirred for 2 hours at ambient temperature and then poured into water and extracted with ethyl acetate. The extract was evaporated to dryness under reduced pressure. The 13.6 g of residue were chromatographed on silica (eluant: methylene chloride—isopropanol 94-6) to obtain 7.28 g of the desired compound.

13 g of tetrabromo-methane and 10.3 g of triphenyl-phosphine were added at −10° C. to a solution of 7.2 g of the product of Step C in 73 ml of methylene chloride. The reaction medium was stirred for one hour at 0° C. and chromatographed on silica (eluant: ethyl acetate—cyclohexane 7-3) to obtain 7.49 g of the desired compound.

4-(17β-Hydroxy-3-Oxo-Δ 4,9 -Estradien-11-yl)-N-Methyl-N-benzene Acetamide

a) Oxidation:

A solution of 3 ml of the product of Step C of Preparation 1 in 200 ml of acetone was cooled to 0° C. and 6.36 ml of a solution prepared from 67 g of chromic oxide, 57 ml of sulfuric acid and demineralized water sufficient for 250 ml were added over 20 minutes at +2-+3° C. and the mixture was stirred for 5 minutes. 4 ml of methanol and 16 g of barium carbonate were added and the mixture was stirred for one hour and permitted to return to ambient temperature. The mixture was filtered, washed with acetone and evaporated to dryness to obtain 3.282 g of residue.

b) Amidification:

To a solution cooled to −10° C. of 3.282 g of the above product in 150 ml of methylene chloride, 3 ml of N-methyl morpholine and 3.3 ml of isobutyl chloroformate were added and the mixture was stirred for 30 minutes at −10° C. 3.3 ml of N-isopropyl methylamine were added and the temperature was allowed to rise. After stirring for 30 minutes, the mixture was poured into an iced sodium bicarbonate solution, stirred for 10 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness and the 7.6 g of residue were chromatographed on silica (eluant: methylene chloride—acetone (9-1)) to obtain 2.15 g of the desired product.

A solution of 0.5 g of the product of Step A, 15 ml of methanol and 336 mg of potassium hydroxide was stirred for one hour and then cooled to 0° C. and neutralized by the addition of 7.4 ml of 2N hydrochloric acid. The mixture was extracted with methylene chloride and evaporated to dryness under reduced pressure. The 459 mg of residue were chromatographed on silica (eluant:ethyl acetate—cyclohexane (9-1)) to obtain 0.288 g of the desired product.

4-(3,17β-Dihydroxy-Δ 1,3,5(10) -Estradien-11β-yl)-N-Methyl-N-Isopropyl-Benzene Acetamide

To a solution of 1.045 g of the product of Step A of Example 1 in 20 ml of methanol, 2 g of palladium hydroxide with 20% magnesium oxide were added and the mixture was refluxed for 30 minutes then filtered off the catalyst. The filtrate was washed with methanol and evaporated to dryness under reduced pressure. The 1.03 g of residue were redissolved in 30 ml of methanol and 980 mg of potassium hydroxide pellets were added. The mixture was stirred for 45 minutes at ambient temperature and 50 g of ice and 20 ml of 2N hydrochloric acid were added. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure. The 1.1 g of residue were chromatographed on silica (eluant: ethyle acteate—cyclohexane (8-2)) to obtain 467 mg of the desired product.

N-Butyl-3,17β-Dihydroxy-11β-Δ 1,3,5(10) -Estratriene-Pentanamide

To a solution of 3.4 g of the product of Step C of Preparation 2 in 64 ml of methylene chloride at −10° to −15° C., 3.25 ml of N-methyl morpholine were added dropwise followed by 3.8 ml of isobutyl chloroformate and the mixture was stirred for 30 minutes at −10° to −15° C. and then at this temperature, 4.1 of N-butylamine were added. The mixture was allowed to return to ambient temperature and after 40 minutes, 100 ml of a saturated sodium bicarbonate solution were added. The mixture was stirred for 10 minutes and the decanted aqueous phase was extracted with methylene chloride. The organic phase was washed with a saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The 7 g of residue were chromatographed on silica (eluant: methylene chloride—acetone (8-2)) and after evaportaion to dryness, 2.3 g of the desired product were obtained.

To a solution of 2.3 g of the product of Step A in 25 ml of methylene chloride at 0° C. to −5° C., 2.5 ml of acetic anhydride and 1.25 ml of acetyl bromide were added and the mixture was stirred for 80 minutes at ambient temperature and then poured into a mixture of 150 ml of saturated sodium bicarbonate solution and 50 g of ice. The mixture was stirred for 15 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and washed twice with toluene to obtain 2.9 g of product which was chromatographed on silica (eluant: methylene chloride—acetone (9-1)) to obtain 2.3 g of the desired product.

To a solution of 1.85 g of the product of Step B in 16 ml of methanol at 0° to 5° C., 192 mg of sodium borohydride were added and the mixture was stirred for 30 minutes. 640 mg of potassium hydroxide pellets were added and after 20 minutes at ambient temperature, 50 g of iced water (1-1) were added and the pH was adjusted to 4-5 with 2N hydrochloric acid. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The organic phase was evaporated to dryness and the residue was chromatographed on silica (eluant: methylene chloride—acetone (75-25)) to obtain 1.56 g of the desired crude product. The latter was dissolved in 5 ml of methanol and 75 ml of methylene chloride were added. The mixture was filtered and concentrated to crystallization. The mixture was refrigerated for 3 hours, and centrifuged to obtain 1.33 g of the desired product melting at ≃ 100° C. (approximately) with a specific rotation of [α] D +117.5±2° (c=1% in EtOH).

N-Butyl-3,17β-Dihydroxy-N-Methyl-11β-Δ 1,3,5(10) -Estradien-Pentanamide

Using the procedure of Step A of Example 3, 3 g of the acid of Step C of Preparation 2 and 4.1 ml of N-methy butylamine instead of the N-butylamine were reacted to obtain 2.82 g of the desired product.

Using the procedure of Step B of Example 3, 2.8 g of the product were reacted to obtain 2.62 g of the desired product.

Using the procedure of Step C of Example 3, 2.5 g of the product of Step B were reacted to obtain 2.026 g of the desired product. An analytical sample was prepared by dissolving 1.8 g of the product in 100 ml of ethyl acetate at 60° C. and after filtration, the filtrate was concentrated to the start of crystallization, then stirred for 3 hours at 0° C., and centrifuged to obtain 1.58 g of the desired product melting at approximately 165° C. and with a specific rotation of [α] D =+113°±2° (c=1% in EtOH).

N-Butyl-3,17β-Dihydroxy-11β-Δ 1,3,5(10) -Estratriene-Heptanamide

Using the procedure of Step A of Example 3, 2.6 g of the acid of Step C of Preparation 3 were reacted to obtain 1.845 g of the desired product.

Using the procedure of Step B of Example 3, 2.025 g of the product of Step A were reacted to obtain 1.95 g of the desired product.

Using the procedure of Step C of Example 3, 1.68 g of the product of Step B were reacted to obtain after chromatography on silica (eluant: methylene chloride—acetone (8-2)), 1.277 g of the desired product. A sample for analysis was prepared by crystallization of 1.2 g of the crude product in ethyl acetate to obtain 1.04 g of the desired product melting at approximately 139° C. and having a specific rotation of [α] D =+113°±2° (c=1% in ethanol).

N-Butyl-3,17β-Dihydroxy-N-Methyl-11β-Δ 1,3,5(10) -Estratriene-Heptanamide

Using the procedure of Step A of Example 5, 3.04 g of the acid of Step C of Preparation 3 and 3.8 ml of N-methyl butylamine was reacted to obtain 3 g of the desired product.

Using the procedure of Step B of Example 5, 2.95 g of the product of Step A were reacted to obtain 2.7 g of the desired product.

Using the procedure of Step C of Example 5, 2.6 g of the product of Step B were reacted to obtain 2.067 g of the desired product. A sample for analysis was prepared by crystallizing 1.8 g of the product from chloroform to obtain 1.697 g of the desired product melting at 110° C. and having a specific rotation of [α] D =106.5°±2° (c=1% in ethanol).

N-Butyl-4-(17β-Hydroxy-3-Oxo-Δ 4,9 -Estradien-11β-yl)-N-Methyl Benzene Octanamide

a) 17β-acetoxy-3-oxo-11β-Δ 4,9 -estradiene-benzene octanoic acid

Using the procedure of Step C of Preparation 2, 970 mg of the product of Step D of Preparation 4 were reacted to obtain 1.219 g of the desired product which was used as is for the amidification.

b) Amidification

Using the procedure of Step A of Example 3, 1.219 g of the above product and 1.1 ml of N-methyl butylamine were reacted to obtain after chromatography on silica (eluant: cyclohexane—ethyl acetate (5-5)), 842 mg of the desired product.

Using the procedure of Step B of Example 1, 716 mg of the product of Step A were reacted to obtain after chromatography on silica (eluant: cyclohexane—ethyl acetate (5-5)), 508 mg of the desired product with a specific rotation of [α] D =+169°±3° (c=0.5% in EtOH).

N-butyl-4-(3,17β-dihydroxy-Δ 1,3,5(10) -estratrien-11yl)-N-methyl benzene octanamide

To a solution of 293 mg of the product of Step A of Example 7 in 3 ml of methylene chloride, there was added at 0° C. to 5° C. 0.15 ml of acetyl bromide and 0.3 ml of acetic anhydride, and the mixture was stirred for 2 hours at ambient temperature and then poured into a saturated sodium bicarbonate solution. The mixture was stirred for 30 minutes and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under vacuum. The 300 mg of residue were chromatographed on silica (eluant: cyclo-hexane—ethyl acetate (7-3)) to obtain 217 mg of the desired product.

At ambient temperature: 471 mg of the product of Step A in solution in 3.65 ml of methanolic potassium hydroxide was stirred for 40 minutes and then ice was added followed by 2.5 ml of 2N hydrochloric acid. The mixture was extracted with ethyl acetate, washed with water, dried and evaporated to dryness under vacuum. The 460 mg of residue were chromatographed on silica (eluant: cyclohexane—ethyl acetate (5-5)) to obtain 264 mg of the desired product with a specific rotation of [α] D =+20°+2° (c=0.5% in EtOH).

N,N-dimethyl-17β-hydroxy-3-oxo-11β-Δ 4,9 -estradiene-undecanamide

Using the procedure of Step A of Example 3, 2.7 g of the product of Step E of Preparation 5 and 2.28 g of dimethylamine in solutino in 20 ml of tetrahydrofuran were reacted to obtain 1.6 g of the desired product.

Using the procedure of Step B of Example 1, 780 mg of the product of Step A were reacted to obtain after chromatography on silica (eluant: methylene chloride—acetone (8-2)), 485 mg of the desired product with a specific rotation of [α] D =−21.5°±2.5° (c=0.35% in EtOH).

N,N-Dimethyl-3,17β-Dihydroxy-11β-Δ 1,3,5(10) -Estratriene-Undecanamide

Using the procedure of Step B of Example 3, 697 mg of the product of Step A of Example 9 were reacted to obtain 660 mg of the desired product.

Using the procedure of Step B of Example 1 and isolating the product by crystallization in isopropanol there were obtained of 369 mg of the desired product melting at 130° C. and a specific rotation of [α] D =+100°±2° (c=0.95% in EtOH).

N-Butyl-17β-Hydroxy-3-Oxo-11β-Δ 4,9 -Estradiene-Undecanamide

Using the procedure of Step A of Example 3, 6.67 mg of the product of Step B of Preparation 5 were reacted to obtain, after chromatography on silica (eluant: cyclohexane—ethyl acetate (1-1)), 6.911 g of the desired product. A second chromatography of 3.443 g of the product with the same eluant yielded 2.898 g of the purified product.

0.5 of the product of Step A, 5 ml of methanol and 280 mg of potassium hydroxide pellets were stirred for 40 minutes at ambient temperture and 20 ml of ice were added. The mixture was neutralized with 2.5 ml of 2N hydrochloric acid and was extracted with ethyl acetate to obtain after evaporation to dryness 509 mg of product. The latter was chromatographed on silica (eluant: cyclohexane—ethyl acetate (1-1)) to obtain 287 mg of the desired product.

N-Butyl-3,17β-Dihydroxy-11β-Δ 1,3,5(10) -Estratriene-Undecanamide

Using the procedure of Step B of Example 3, 3 g of the product of Step A of Example 11 were reacted to obtain 3.66 g of crude product used as is for the following step.

To a solution of 2.96 g of the product of Step A in 74 ml of methanol there was added 8.9 ml of a solution of 6 ml of a 11 g methanolic potassium hydroxide and the mixture was stirred for 2 hours at 60° C. and then was iced, and neutralized with 15 ml of normal hydrochloric acid. The methanol was distilled and the mixture was diluted with aqueous saturated sodium chloride and extracted with ethyl acetate. After evaporation to dryness, the 2.7 g of residue were chromatographed on silica (eluant: cyclohexane—ethyl acetate (5-5)) to obtain 1.841 g of the desired product. A sample for anaylsis was prepared by a second chromatogrphy under the same conditions to obtain 1.547 g of the desired compound with a specific rotation of [α] D =+85°±3° (c=0.5% in ethanol).

N-Butyl-3,17β-Dihydroxy-N-Methyl-11β-Δ 1,3,5(10) -Estratriene-Undecanamide

A solution of 226 mg of the product of Step B of Example 12, 6.7 ml of sulfuric ether 4.7 ml of dihydropyran and 5 mg of p-toluene sulfonic acid was stirred for 90 minutes and 1 ml of triethylamine was added. The mixture was washed with a sodium bicarbonate solution, then with a saturated sodium chloride solution, dried and evaporated to dryness. The 400 mg of residue were chromatographed on silica (eluant: cyclohexane—ethyl acetate (7-3)) to obtain 286 mg of the desired product.

STEP B: N-butyl-3,17β-bis-[(tetrahydro-2H-pyrann-2-yl)-oxy]-N-methyl-11β-Δ 1,3,5(10) -estratriene-undecanamide

920 mg of the product of Step A with 14 ml of tetrahydrofuran, 2.27 g of tetrabutylammonium bromide, 1.9 g of powdered potassium hydroxide and 14 ml of methyl iodide were stirred for 18 hours at 50° C. under pressure. After refrigeration, the insoluble material was filtered off and washed with 5 changes of 50 ml of tetrahydrofuran. The organic phase was evaporated to dryness under reduced pressure and the 3.4 g of residue were chromatographed on silica (eluant: cyclohexane—ethyl acetate triethylamine (70-30-0.2)) to obtain 850 mg of the desired product used as is for the following step.

850 mg of the product of Step B, 35 ml of methanol and 3.5 ml of 2N hydrochloric acid were stirred for 1 hour at ambient temperature and the pH was adjusted to 5-6 with 5 ml of concentrated ammonia. The mixture was extracted with methylene chloride, and the organic phase was washed with water, then with a saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The 638 mg of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate (6-4)) to obtain 520 mg of the desired product. A sample of 618 mg of product (98 mg from an earlier preparation was joined to the 520 mg obtained above) was chromatographed on silica (eluant: methylene chloride—acetone (9-1)) to obtain 527 mg of purified product with a specific rotation of [α] D =90.5°±2° (c=1% in EtOH).

N-Butyl-3,17β-Dihydroxy-N-Methyl-11β-Δ 1,3,5(10) -Estratriene Undecanamide

Using the procedure of Step A of Example 3, 88.5 g of the acid of Step E of Preparation 5 and 88.5 ml of N-methyl butylamine were reacted to obtain after chromatography on silica (eluant: hexane—ethyl acetate (5-5)) 67.3 g of the desired product.

Using the procedure of Step B of Example 3, 67.3 g of the product of Step A were reacted and the dry extract obtained was not chromatographed to obtain 75 g of the desired product used as is for the following step.

74 g of the product of Step B, 1.850 liters of methanol and 222 ml of methanolic potassium hydroxide at 11 g % ml was stirred for 2 hours at 60° C. and cooled to 0° C. to +5° C. The pH was adjusted to 4-5 by the addition of hydrochloric acid and the methanol was distilled under reduced pressure. The mixture was extracted with methylene chloride and the organic extracts were washed with water, dried and evaporated to dryness under reduced pressure to obtain 65.8 g of resin to which was added 1.7 g made in a previous preparation.

Purification

67.5 g of crude product were crystallized from 350 ml of ethyl acetate and the mixture was centrifuged at 0° to +5° C. to obtain 45 g of the desired product to which was added 3 g of once-purified product obtained from the mother liquors.

The 48 g of product were crystallized from 4 volumes of ethyl acetate to obtain 46.1 g of the desired product melting at 127° C. and with a specific rotation of [α] D =+90.1°±2° (c=1% in EtOH).

17β-hydroxy-N-methyl-N-isopropyl 3-oxo- 11β-Δ 4,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 610 mg of the acid of Preparation 6 and 0.73 ml of N-methyl N-isopropylamine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone (9-1)), 455 mg of the desired product.

To a solution of 1.18 g of the product of Step A in 18 ml of tetrahydrofuran, there were added at 0° to −5° C. 707 mg of triterbutoxy aluminum-lithium hydride and the mixture was stirred for 1 hour at 0° to −5° C. and poured into 80 gms of a mixture of equal parts of ice and a saturated ammonium chloride solution. The mixture was stirred for 5 minutes and extracted three times with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The 1.14 g of residue and 256 mg obtained from a preceding preparation were chromatographed on silica (eluant: methylene chloride-acetone (9-1)) to obtain 640 mg of the desired product with a specific rotation of [α] D =−43°±2.5° (c=0.4% in ethanol).

3,17β-dihydroxy-N-methyl-N-isopropyl- 11β-Δ 1,3,5(10) -estratriene undecanamide

Using the procedure of Step B of Example 3, 360 mg of the product of Step A of Example 15 were reacted to obtain after chromatography over silica (eluant: methylene chloride-acetone ( 95-5 )) 310 mg of the expected product.

Using the procedure of Step C of Example 3, 272 mg of the product of Step A were reacted to obtain after chromatography (eluant: methylene chloride-acetone (9-1)), 195 mg of the crude expected product. The said product and 460 mg of product from a previous preparation were purified by passing three times over silica (eluant: acetonitrile) to obtain 460 mg of product which was chromatographed again over silica (eluant: methylene chloride-acetone (9-1)) to obtain 432 mg of the desired product with a specific rotation of [α] D =+85° C.±2° (c=1% in EtOH).

N-benzyl-17β-hydroxy-N-methyl-3-oxo-11β-Δ 4,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 2.1 g of the acid of Step E of Preparation 5 and 2.2 ml of benzyl methylamine were reacted to obtain after chromatography over silica (eluant: cyclohexane-ethyl acetate (1-1)), 1.82 g of the desired product.

Using the procedure of Step B of Example 1, 1 g of the product of Step A were reacted to obtain 670 mg of the desired product.

N-benzyl-3,17β-dihydroxy-N-methyl-11β-Δ 1,3,5(10) estratriene undecanamide

To a solution of 829 mg of the product of Step A of Example 17 in 8 ml of methylene chloride cooled to 0° to +5° C., 0.6 ml of acetic anhydride and 0.3 ml of acetyl bromide were added and the mixture of ice and a saturated solution of sodium bicarbonate (1-1). The mixture was stirred for 30 minutes and the decanted aqueous phase was extracted with methylene chloride. The organic phase was washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure The residue was chromatographed on silica (eluant: cyclo-hexane-AcOEt (75-25)) to obtain 760 mg of the desired product.

630 mg of the product of Step A, 13 ml of methanol and 910 mg of potassium hydroxide pellets were stirred for 1 hour at ambient temperature and the pH was adjusted to 4-5 by the addition of 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride and evaporated to dryness under reduced pressure. The 555 mg of residue were chromatographed over silica (eluant: methylene chloride-acetone (9-1)) to obtain 390 mg of the desired product with a specific rotation of [α] D =+85.5°±2° (c=0.9% in EtOH).

N-[2-(dimethylamino)-ethyl]-17β-hydroxy-N-methyl-3-oxo-11β-Δ 4,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 500 mg of the product of Step E of Preparation 5, 0.5 ml of N-N-N-trimethyl ethylenediamine were reacted to obtain after chromatography over silica (eluant: toluene-triethylamine (8-2)), 380 mg of the desired product.

800 mg of the product of Step A, 8 ml of methanol and 500 mg of potassium hydroxide pellets were stirred for 1 hour at ambient temperature and the mixture was concentrated to half-volume and a water and ice mixture was added. The mixture was extracted with ethyl acetate and the organic phase was washed with water, then with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 645 mg of residue were chromatographed first over silica (eluant: ethyl acetate-isopropanol-ammonia (80-20-2)), then a second time (eluant: ethyl acetate-triethylamine (6-4)) to obtain 526 mg of the desired product with a specific rotation of [α] D =−26°±1.5° (c=0.7% in EtOH).

N-[2-(dimethylamino)-ethyl]-3,17β-dihydroxy-N-methyl-11β-Δ 1,3,5(10) -estradiene undecanamide

STEP A: N-[2-dimethylamino)-ethyl]-3,17β-diacetyloxy-N-methyl-11β-Δ 1,3,5(10) -estradiene undecanamide

Using the procedure of Step B of Example 3, 800 mg of the product of Step A of Example 19 were reacted to obtain after chromatography over silica (eluant: toluene-triethylamine (8-2)), 700 mg of the desired product.

STEP B: N-[2-(dimethylamino)-ethyl]-3,17β-dihydroxy-N-methyl-11β-Δ 1,3,5(10) -estradiene undecanamide

Using the procedure of Step B of Example 10, 800 mg of the product of Step A were reacted to obtain after chromatography over silica (eluant: toluene-triethylamine (8-2)), 550 mg of product which was chromatographed once more (eluant: ethyl acetate-isopropanol-ammonia (80-2-2)) to obtain 527 mg of the desired product with a specific rotation of [α] D =+77.5°±1.5° (c=0.9% in EtOH).

N-butyl-3,17β-dihydroxy-N-methyl-19-nor-11β-Δ 4,9 -estradiene undecanamide

Using the procedure of Step A of Example 3, 7.5 g of the acid of Step B of Preparation 6 of 6.4 ml of N-methyl butyl-amine were reacted to obtain 5.89 g of the desired product.

IR Spectrum: (CHCl 3 )

Tertiary amide

1628 cm −1

Using the procedure of Step B of Example 3, 2.63 g of the product of Step A were reacted to obtain 2.91 g of crude product which was used as is in the following step.

To a solution of 1 g of the product of Step B in 10 ml of ethylenediamine, 1.62 g of lithium acetylide-ethylenediamine complex was added and the mixture was stirred for 4 hours 30 minutes at 50° C., then cooled. 20 g of ice, 10 ml of a saturated solution of ammonium chloride and 30 ml of methylene chloride were added and the mixture was filtered. The aqueous phase was re-extracted with methylene chloride and the combined organic phases were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 0.805 g of residue was chromatographed over silica (eluant: methylene chloride-acetone (9-1)) to obtain 0.58 g of product which was chromatographed again over silica (eluant: methylene chloride-acetone (95-5)) to obtain 0.489 g of the desired product with a specific rotation of [α] D =+40.5°±2.5° (c=0.5% in EtOH).

Using the procedure of Step A of Example 1, 1 g of the alcohol of Step B of Preparation 8 and 1.1 ml of N-methyl-butyl-amine were reacted to obtain after chromatography over silica (eluant: ethyl acetate-cyclohexane (8-2)), 717 mg of the desired product.

To a solution of 837 mg of the product of Step A in 17 ml of tetrahydrofuran at 0° C., 494 mg of aluminium lithium tri-terbutoxy hydride were added for 20 minutes at 0° C. 20 ml of a saturated solution of ammonium chloride were added and the mixture was extracted with ethyl acetate and with methylene chloride. The organic phase was evaporated to dryness under mixture was extracted with ethyl acetate and with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 836 mg of residue were chromatographed over silica (eluant: ethyl acetate-cyclohexane (6-4)) to obtain 604 mg of the expected product.

To a solution cooled to 0° C. of 0.2 g of the product of Step B in 2.6 ml of methylene chloride, 0.26 ml of acetate anhydride and 0.13 ml of acetyl bromide were added at 0° C. and was allowed to recover to ambient temperature. After 1 hour, 20 ml of sodium bicarbonate in saturated solution were added and the mixture was stirred for 30 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 250 mg of residue were taken up in 10 ml of methanol. 150 mg of potassium hydroxide pellets were added to the solution which was heated for 2 hours at 40° C., then cooled to 0° C. The mixture was neutralized with concentrated hydrochloric acid and extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 188 mg of residue were chromatographed over silica (eluant: cyclohexane-ethyl acetate (6-4)) to obtain 131 mg of the expected product with a specific rotation of [ ] D =+89°±3° (c=0.6% in EtOH).

1-[11-(17β-hydroxy-3-oxo-Δ 4,9 -estradien-11β-yl)-1-oxo-undecyl]-pyrrolidine

Using the procedure of Step A of Example 3, 2.76 g of the acid of Step E of Preparation 5 and 2.5 ml of pyrrolidine were reacted to obtain after chromatography over silica (eluant: cyclohexane-ethyl acetate (4-6)), 2.18 g of the desired product.

For 40 minutes, a solution of 1.265 g of the product of Step A in 10 ml of N ethanolic potassium hydroxide was stirred and 12 ml of N hydrochloric acid and then 2 ml of concentrated ammonia were added. The mixture was extracted with ethyl acetate, washed with water, dried and evaporated to dryness. The 1.164 g of residue were chromatographed over silica (eluant: ethyl acetate-cyclohexane (8-2)) to obtain 988 mg of the desired product.

1-[11-(3,17β-dihydroxy-Δ 1,3,5(10) -estratrien-11β-yl)-1-oxo-undecyl]-pyrrolidine

773 mg of the product of Step A of Example 25 dissolved in 8 ml of methylene chloride at 0° C. to +5° C. were admixed with 0.4 ml of acetyl bromide and 0.8 ml of acetic anhydride and the mixture was stirred for 2 hours while allowing the temperature rise to ambient temperature. After adding ice and neutralizing by addition of sodium bicarbonate, the mixture was washed with water, dried and evaporated to dryness under vacuum to obtain 829 mg of the intermediate diacetate.

The 829 mg of product were reacted as in Step B of Example 25 and after chromatography over silica (eluant: ethyl acetate alone, then ethyl acetate with 20% methanol); 545 mg of the expected crude product were obtained which were crystallized from a methylene chloride-isopropyl ether mixture, then from ethyl acetate to obtain 396 mg of the desired product melting at 150° C. and having a specific rotation of [α] D =+70°±2.5° (c=0.5% in CHCl 3 ).

PREPARATION OF EXAMPLE 27

11β-[4-hydroxyoctyl)-phenyl]-Δ 4,9 -estradien-3,17-dione

Using the procedure of Step A of preparation 6, 8.5 g of the product of Step A of preparation 4 were reacted to obtain after chromatography on silica (elution with methylene chloride-acetone 9-1),5.65 g of the desired product.

4-[3-hydroxy-17-oxo-Δ 1,3,5(10) -estratrien-11β-yl-N-methyl-N-isopropyl-benzene]-octanamide

Using the procedure of Example 1, 7.05 g of the product of preparation 14 and 7.9 ml of N-methyl-isopropylamine for the amidification were reacted, and after chromatography on silica (eluant: methylene chloride-acetone 9-1) obtained 5.99 g of the expected product.

STEP B: 4-(3-acetyloxy-17-oxo-Δ 1,3,5(10) -estratrien-11β-yl)-N-methyl-N-isopropyl-benzene octanamide

Using the procedure of Step B of Example 3, 4 g of the product of Step A and 1.9 ml of acetyl bromide and 3.8 ml acetic anhydride were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 4.2 g of the expected product.

Using the procedure of Example 2, 2.3 g of the product of Step B were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1) 2 g of the desired product with a specific rotation of [α] D =−16°±2° (c=0.5% in ethanol).

A suspension of 46.8 g of the product of Step A, 200 ml of ethanol and 8.1 of sodium hydroxide was stirred for 30 minutes and 16.7 ml of concentrated hydrochloric acid were added, The mixture was stirred at ambient temperature and then concentrated to half the volume and extracted with methylene chloride. The organic phase was dried and evaporated under reduced pressure. The 38.23 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 31.06 g of the desired product melting at 184° C.

Acetylation at Position 3

Using the procedure of Step B of Example 3, 31 g of the compound of Step B and 47.1 ml of acetic anhydride and 23.8 ml of acetyl bromide were reacted to obtain 31.2 g of 3-acetate which was saponified by using the procedure of Step B of Example 1. After chromatography on silica (eluant: cyclo-hexane-ethyl acetate 7-3), 27.03 g of crude product were obtained and made into a paste in ether to collect 22.852 g of the desired product melting at 163° C.

a) Reduction of the 17-ketone

Using the procedure of Step B of Example 39, 14 g of the compound of Step C and 10 g of sodium borohydride were reacted.

b) Dihydropyranylation

Using the procedure of Step A of Example 39, 17.3 g of the 17-hydroxy intermediate obtained above and 24.4 ml of dihydropyran and 0.3 g of p-toluene sulfonic acid were reacted to obtain after chromatography on silica, 13.6 g of crude product which was taken up in isopropyl ether to collect 10.23 g of the desired product melting at 213 to 215° C.

PREPARATION C OF EXAMPLE 31

1-oxo-6-bromo hexyl morpholine

Using the procedure of Step A of Example 3, 5 g of 6-bromo-benzylic acid and 3.4 ml of N-methyl morpholine, 3.7 ml of isobutyl chloroformate and 3.35 ml of morpholine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 9-1), 7 g of the desired product which was used as is for the following step.

To a solution of 2.234 g of the product of the Preparation of Example 40 in 20 ml of anhydrous pyridine, there were added 3.36 g of p-toluene sulfonyl chloride and the mixture was stirred for 80 minutes. 30 ml of a saturated solution of sodium bicarbonate were added and the mixture was stirred for 30 minutes and extracted with methylene chloride. The solvents were dried, then evaporated to dryness under reduced pressure. The 2.9 g of residue were chromatographed on silica (eluant: methylene chloride-acetone 9-1) to obtain 2.255 g of the desired product.

2.2 g of the product of Step A in 50 ml of acetone and 0.787 g of sodium iodide were stirred at reflux for one hour and then filtered. The filtrate was evaporated to dryness under reduced pressure and the 3.6 g of residue were taken up in 10 ml of ether and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 1.722 g of the desired product.

3.6 g of the product of Step B in 55 ml of ethanol and 10 ml of water with 0.872 g of potassium cyanide were stirred at reflux for 2 hours and then 50 ml of ice were added. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated under reduced pressure to obtain 1.68 g of the desired product.

Using the procedure of Step B of Example 3, 1.27 g of the product of Step C were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 1.281 g of the desired product.

STEP E: 4-(3-isobutyl-carbonyloxy-17-oxo-Δ 1,3,5,(10) -estratrien-11β-yl)-N-methyl-N-isopropyl-benzene nonamide

a) Hydrolysis of the Nitrile:

1.225 g of the product of Step B, 24 ml of ethanol and 1.5 ml of sodium hydroxide were stirred at reflux for 60 hours and then cooled and poured into a mixture of 73 ml of N hydrochloric acid and 100 ml of ice. The mixture was stirred for 10 minutes and extracted with methylene chloride. The organic phase was dried, filtered and concentrated to dryness under reduced pressure to obtain 1.145 g of the desired product

b) Amidification:

To a solution of 1.145 g of the said product in 50 ml of methylene chloride, there were added 0.3 ml of N-methyl morpholine and 1 ml of isobutyl chloroformate and the mixture was stirred for 10 minutes. 1 ml of isopropyl methylamine was added and the mixture was stirred for 30 minutes at ambient temperature and then poured into 50 ml of a saturated solution of sodium bicarbonate. The mixture was stirred for 10 minutes and then extracted with methylene chloride. The organic phase was dried and evaporated to dryness under reduced pressure. The 2 g of residue were chromatographed on silica (eluant: cyclohexane ethyl acetate 1-1) to obtain 0.778 g of the desired product.

a) Reduction of the 17-keto:

Into a solution of 0.778 g of the product of Step E in 15 ml of tetrahydrofuran, there were introduced by fractions 0.451 g of tritertbutoxy aluminium-lithium hydride. The mixture was stirred for 30 minutes, then poured into ice-cooled solution of monosodium phosphate. The mixture was stirred for 30 minutes and then extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure to obtain 0.9 g of the 17-hydroxy product.

b) Saponification:

Using the procedure of Example 2B, the product obtained above was reacted to obtain after chromatography on silica (eluant: ethyl acetate-cyclohexane 6-4), 613 mg of the expected product with a specific rotation of [α] D =−17°±1° (c=1% in ethanol).

PREPARATION OF EXAMPLE 41

3-(1,2-ethanediyl) cyclic acetal of 5α-hydroxy-11β-[4-((6-hydroxy-hexyl )-oxy)-phenyl]-Δ 9 -estren-3,17-dione

STEP A: 3-(1,2-ethanediyl) cyclic acetal of 11β-(4-hydroxyphenyl )-5 α-hydroxy-Δ 9 -estren-3,17-dione

a) Preparation of the magnesium compound

Using the procedure of Step A of Example 1, 7.1 g of magnesium turnings and 50 g of 4-triethylsilyloxy-bromo-benzene were reacted to obtain an approximately 0.95M solution of magnesium compound in tetrahydrofuran.

b) Condensation

Using the procedure of Step A of Example 1, 10 g 3-(1,2-ethanediyl) cyclic acetal of 5 α, 10α-epoxy-Δ 9 -estren-3,17-dione obtained by EP 0,057,115 (Example 7) and 110 ml of the magnesium compound solution were reacted to obtain 34.9 g of crude product.

c) Desilylation

The crude product was dissolved in 150 ml of tetrahydro furan, and after 130 ml of a 1M solution of tetrabutylammonium fluoride were added, the mixture was stirred for 15 minutes at ambient temperature, then poured into water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 26.9 g of crude product which was triturated at 40° C. for 30 minutes in 100 ml of an ethyl acetate-methylene chloride mixture (1-1). The mixture was filtered to obtain 5.77 g of the desired product. By chromatography on silica of the mother liquors (eluent: ethyl acetate-methylene chloride 1-1), an additional 5.7 g of the desired product were obtained and the combined batches of product (11.47 g) were crystallized from ethanol to obtain 8 g of the expected product melting at 255° C.

STEP B: 3-(1,2-ethanediyl) cyclic acetal of 5α-hydroxy-11β-[4-((6-hydroxy-hexyl )-oxy)-phenyl]-Δ 9 -estren-3,17-dione

To a solution of 3.77 g of the product of Step A in 18 ml of acetone, 13.3 ml of 2N sodium hydroxide and then 3 ml of bromohexanol were added and the mixture was heated at 50° C. for 3 hours, then poured into a saturated solution of ammonium chloride. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure. The 7.7 g of residue were chromatographed on silica (eluant: methylene chloride-ethyl acetate 6-4 then 1-1) to obtain 4.11 g of the desired compound.

7-(4-(3,17β-dihydroxy-Δ 1,3,5,(10) -estratrien-11β-yl)-phenoxy)-N-methyl-N-isopropyl-heptanamide

STEP A: 3-(1,2-ethanediyl) cyclic acetal of 5α-hydroxy-11β-[4-[(6-[(4-methylphenyl)-sulfonyloxy)-hexyl]-oxy]-phenyl]-Δ 9 -estren-3,17-dione

Using the procedure of Step A of Example 40, 4.08 g of the compound of the Preparation of Example 41 and 2.85 g of p-toluene sulfonyl chloride were reacted to obtain after chromatography on silica (eluant: methylene chloride-ethyl acetate 2-1), 4.19 g of the desired product which was used as is for the following step.

STEP B: 3-(1,2-ethanediyl) cyclic acetal of 5α-hydroxy-11β-[4-[(6-iodohexyl )-oxy ]-phenyl ]-Δ 9 -estren-3,17-dione

Using the procedure of Step B of Example 40, 4.19 g of the product of Step A and 1.39 g of sodium iodide were reacted to obtain 3.9 g of the desired product.

STEP C: [4-[3,3-(1,2-ethanediyl)-bis-oxy-5α-hydroxy-17-oxo-Δ 9 -estren-11β-yl )-phenoxy)-heptane nitrile

Using the procedure of Step C of Example 40, 3.75 g of the compound of Step B and 730 mg of potassium cyanide were reacted to obtain after chromatography on silica (eluant: cyclohexane-ethyl acetate 1-1), 2.9 g of the desired product.

A mixture of 2.46 g of the product of Step C, 13 ml of methanol and 4 ml of 2N hydrochloric acid was stirred for 2 hours at ambient temperature and after dilution with water, and extraction with methylene chloride, the organic phase was distilled under reduced pressure to obtain 2.2 g of crude product which was chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 1.875 g of the desired product melting at 176° C.

a) Aromatization

Using the procedure of Step B of Example 3, 1.693 g of the product of Step B and 1.7 ml of acetic anhydride and 0.85 ml of acetyl bromide were reacted to obtain 2.15 g of the desired crude product.

b) Reduction of the Ketone at Position 17

Using the procedure of Step B of Preparation 1, 2.15 g of the product above and 280 mg of sodium borohydride were reacted to obtain after chromatography on silica (eluant: ethyl acetate-cyclohexane 40-60), 1.12 g of the desired product.

Using the procedure of Step B of Example 2, 900 mg of the product of Step E were reacted to obtain after chromatography on silica (eluant: essence G-acetone 65-35 with 1% of acetic acid, then acetone only), 779 mg of the desired product.

STEP G: 7-(4-(3,17β-dihydroxy-Δ 1,3,5 (10) -estratrien-11β-yl)-phenoxy)-N-methyl-N-isopropyl-heptanamide

Using the procedure of Step A of Example 3, 400 mg of the product of Step F and 0.34 ml of isopropyl methylamine were reacted to obtain 511mg of crude product (intermediate carbonate at position 3) which was saponified as in Step A of Example 2. After chromatography on silica (eluant: ethyl acetate then acetone with 1% of acetic acid) 336 mg of the desired product with a specific rotation of [α] D =−39°±2° (c=0.7% in ethanol) were obtained.

N-butyl-4-[3,17[-dihydroxy-19-nor-17α-Δ 1,3,5,(10) -pregnatrien-20-yn-11β-yl]-N-methyl Benzene

Using the procedure of Example 21, the product of Step A of Preparation 4 was reacted to obtained 250 mg of the desired product.

PREPARATION OF EXAMPLE 43

11β-(4-hydroxyphenyl-Δ 4,9 -estradien-3,17-dione

Using the procedure of Step B of Preparation 3, 1 g of the compound of Step A of the Preparation of Example 41 was reacted to obtain after chromatography on silica (eluant: methylene chloride-ethyl acetate 7-3), 703 mg of the sought product.

PREPARATION B OF EXAMPLE 43

[(5-bromopentyl)-oxy]-N-butyl-N-methyl Acetamide

To a solution cooled to −20° C. of 11.9 ml of bromoacetyl bromide in 180 ml of ether there were added 26 g of butylmethyl, amine in solution in 120 ml of ether and then the temperature returned to 20° C. The mixture was stirred for 30 minutes and diluted with water and extracted with ether. The ether phase was evaporated to dryness under reduced pressure and the 27.4 g of residue were distilled under reduced pressure (0.05 mbar) 79/83° C. to obtain 19.36 g of the desired product.

To a solution; of 10 g of 4-pentanol, 200 ml of methylene chloride, 19.5 ml of triethylamine and 566 mg of 4-dimethylamino pyridine, there were added with cooling, 19.14 g of tert-butyl-dimethylsilyl chloride. The mixture was stirred for one hour at ambient temperature, diluted with water and the decanted organic phase was washed, dried and evaporated to dryness under vacuum. The 42 g of residue were chromatographed on silica (eluant: essence G-ethyl acetate 95-5) to obtain 23.3 g of silyloxy pentene that was dissolved in 250 ml of tetrahydrofuran. 6 ml of borane-methylsulfide complex were added at 20° C. and the mixture was stirred for 30 minutes at 20 to 25° C., then for 30 minutes at 35° C. 18 ml of sodium hydroxide and then 18 ml of oxygenated water were added at 10° C. and the mixture was stirred for 30 minutes and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with a 10% sodium thiosulphate solution, dried and concentrated to dryness under reduced pressure. The 25.85 g of the residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 8-2) to obtain 22.7 g of product which was distilled under reduced pressure (0.06 mbar) to obtain 18.7 g of the desired compound with a boiling point of 73 to 75° C. at 0.06 mbar.

To a solution of 8 g of the alcohol of Step B in 40 ml of tetrahydrofuran there were added 2.16 g of 50% sodium hydride in oil. The mixture was stirred for 30 minutes at ambient temperature and then a solution of 9.5 g of the brominated compound of Step A in 13 ml of tetrahydrofuran was added dropwise over 15 minutes. The mixture was stirred for 16 hours at ambient temperature and a saturated aqueous solution of ammonium chloride was added. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to dryness under vacuum to obtain 14.8 g of intermediate N-butyl-[5-[(dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-pentyl)-oxy]-N-methyl acetamide which was dissolved in 83 ml of tetrahydrofuran and 46 ml of a 1M solution of tetrabutyl ammonium fluoride. The mixture was stirred for 2 hours at ambient temperature and then poured into water and extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure and the 13.6 g of residue were chromatographed on silica (eluant: methylene chloride-isopropanol 94-6) to obtain 7.28 g of the desired compound.

To a solution of 7.2 g of the product of Step B in 73 ml of methylene chloride, there were added at −10° C. , 13 of tetrabromoethane and 10.3 g of triphenylphosphine and the solution medium was stirred for one hour at 0° C. and chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 7.49 g of the desired compound.

N-butyl-[5-[4-(3,17β-dihydroxy-Δ 1,3,5,(10) -estradien-11β-yl)-phenoxy)-pentyloxy]-N-methyl Acetamide

To a solution of 2.5 g of the product of Step A of the Preparation of Example 41 in 26 ml of acetone and 6.4 ml of 2N sodium hydroxide, there were added 3.75 g of [(5-bromopentyl)-oxy]-N-butyl-N-methyl acetamide (obtained in the above preparation) in solution in 6 ml of acetone. The mixture was stirred for 5 hours at 50° C., cooled and poured into water. The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. After washing, drying and evaporating to dryness under reduced pressure, the 6.8 g of residue were chromatographed on silica (eluant: ethyl acetate) to obtain 2.63 g of the desired product.

STEP B: N-butyl [5-[4-(3-hydroxy-17-oxo-Δ 1,3,5(10) -estratrien-11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide

Using the procedure of Step A of Example 2, 2.61 g of the product of Step A and 2.61 g of palladium hydroxide over magnesium oxide were reacted to obtain after chromatography on silica (eluant: ethyl acetate-essence G 9-1), 1.83 g of the desired product.

STEP C: N-butyl-[5-[4-(3,17β-dihydroxy-Δ 1,3,5(10) -estratrien-11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide

Using the procedure of Step B of Preparation 1, 500 mg of the product of Step B 66 mg of sodium borohydride were reacted. The 514 mg of residue were chromatographed on silicia (eluant: methylene chloride-isopropanol 95-5), then a second time (eluant: ethyl acetate) to obtain 343 mg of the desired product with a specific rotation of [α] D =−31.1° (C=1% in chloroform).

N-butyl-[5[-4-(3,17β-dihydroxy-19-nor-17α-Δ 1,3,5(10) -pregnatrien-20-yn-11β-yl)-phenoxy]-pentyloxy]-N-methyl Acetamide

To a solution of 500 mg of the product of Example 43 in 4 ml of tetrahydrofuran, there were added 6 ml of a 0.44M solution of potassium acetylene in tetrahydrofuran (prepared by bubbling acetylene through a solution of potassium tert-butylate in tetrahydrofuran) and after stirring for 30 minutes, the mixture was poured into a saturated solution of ammonium chloride. After extraction with ethyl acetate, followed by washing, drying and evaporating to dryness under reduced pressure, the 504 mg of residue were chromatographed on silica (eluant: ethyl acetate-essence G 85-15), then under pressure (eluant: methylene chloride-acetone 90-10) to obtain 264 mg of desired product with a specific rotation of [α] D =−107°±2.50°(c=0.8% in ethanol).

PREPARATION OF EXAMPLE 45

8-[4-(3,17-dioxo-Δ 4,9 -estradien-11β-yl)-phenoxy]-octanoic Acid

STEP A: 3-(1,2-ethanediyl) cyclic acetyl of 11β-[4-[(8-hydroxy-acetyl)-oxy]-phenyl]-5α-hydroxy-Δ 9 -estren-3,17-dione

Using the procedure of Step A of Example 43, 1.5 g of the product of Step A of the Preparation of Example 41 and 2.22 g of 8-bromo octanol were reacted to obtain after chromatography on silica (eluant: ethyl acetate-methylene chloride 6-4), 1.475 g of the desired product.

Using the procedure of Step B of Preparation 2, 1.44 g of the product of Step A were reacted to obtain after chromotography on silica (eluant: ethyl acetate-methylene chloride 1-1), 1.049 g of the expected product.

Using the procedure of Step C of Preparation 2, 1,008 of the product of Step B and 1.25 ml of Heilbron-Jones reagent were reacted to obtain 1.009 g of the desired product.

8-[4-(3,17β-dihydroxy-Δ- 1,3,5,(10) -estratrien-11β-yl)-phenoxy]-N-methyl-N-isopropyl Octanamide

Using the procedure of Step A of Example 3, 1 g of the product of the Preparation and 1.03 ml of N-isopropyl methylamine were reacted to obtain after chromatography on silica (eluant ethyl acetate-methylene chloride 60-40), 722 mg of the desired product.

STEP B: 8-[4-(3,17β-dihydroxy-Δ 1,3,5,(10) -estratrien-11β-yl)-phenoxy]-N-methyl-N-isopropyl octanamide

a) Aromatization

Using the procedure of Step A of Example 2, 695 mg of the product of Step A and 0.7 ml of acetic anhydride and 0.35 ml of acetyl bromide were reacted to obtain 815 mg of the crude intermediate 3-acetoxy compound.

b) Saponification

Using the procedure of Step A of Example 2, 677 mg of crude 3-hydroxy-17-keto product were obtained.

c) Reduction of the Ketone at Position 17

Using the procedure of Example 28, 767 mg of lithium tritertbutoxy alumino hydride were reacted to obtain after chromatography on silica (eluant: ethyl acetate-methylene chloride 6-4), then successively, under pressure, methanol-water (85-15), (75-25) and finally twice with ethyl acetate-methylene chloride (6-4), 211 mg of the desired product with a specific rotation of [α] D =45°±2° (c=0.7% in ethanol).

PREPARATION OF EXAMPLE 46

8-bromo-N-butyl-N-methyl-octanamide

Using the procedure of Step A of Example 3, 5 g of 8-bromo octanoic acid and 13 ml of N-methyl butylamine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 95-5), 6.14 g of the expected product.

IR Spectrum: (CHCl 3 ) C=0 (tertiary amide type): 1627 cm −1

N-butyl-8-[4-(3,17β-dihydroxy-Δ 1,3,5,(10) -estratrien-11β-yl )-phenoxy]-N-methyl Octanamide

Using the procedure of Step A of Example 43, 725 mg of the product of the Preparation of Example 43 and 0.2 ml of 8-bromo-N-butyl-N-methyl octanamide obtained in the above preparation were reacted to obtain after chromatography on silica (eluant: essence G-ethyl acetate 4-6), 540 mg of the expected product.

Using the procedure of Step A of Example 2, 170 mg of the product of Step A and 260 mg of palladium hydroxide over magnesium oxide were reacted to obtain after chromatography on silica (eluant: ethyl acetate-essence G 1-1), 360 mg of the desired compound.

Using the procedure of Step B of Preparation 1, 360 mg of the product of Step B and 72 mg of sodium borohydride were reacted to obtain the desired product.

N-butyl-8-[4-(3,17β-dihydroxy-19-nor-17αa-Δ 1,3,5,(10) -pregnatrien-20-yn-11β-yl)-phenoxy]-N-methyl octanamide

STEP A: N-butyl-8-[4-(17β-hydroxy-3-oxo-19-nor -17αΔ 1,3,5,(10) -pregnatrien-20-yl-11β-yl )-phenoxy]-N-methyl octanamide

Using the procedure of Step A of Example 43, 1.975 g of 17β-hydroxy-11β(4-hydroxyphenyl)-19-nor-17-Δ 4,9 -pregnadien-20-yl-11β-yl)-phenoxy]-N-methyl octanamide

Using the Procedure of Step A of Example 43, 1.1975 g of 17β-hydroxy-11β-(4hydroxyphenyl)-19-nor-17-Δ 4,9 -pregnadien-20-yn-3-one (prepared according to French Patent No. 2,522,328) and 1.9 ml of 8-bromo-N-butyl-N-methyl octanamide (Preparation A of Example 46) were reacted to obtain after chromatography on silica (eluant: ethyl acetate-cyclo, hexane 7-3), 2.45 g of the expected product.

STEP B: N-butyl-N-methyl-8-[4-[3-oxo-17β-(tetrahydro-2H-2-pyranyloxy]-19-nor-17α-Δ 4,9 -pregnadien-11β-yl)-phenoxy]-octanamide

To a solution of 2.45 g of the compound of Step A in 25 ml of anhydrous tetrahydrofuran and 5 ml of dihydropyran, there were added 75 mg of p-toluene sulfonic acid and the mixture was stirred for 2 hours at ambient temperature. 1 ml of triethylamine was added and the mixture was diluted with a sodium bicarbonate solution. Extraction was effected with ethyl acetate and the organic phase was washed, dried, and evaporated to dryness under reduced pressure. The 4.3 g of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 2.61 g of the expected compound.

STEP C: N-butyl-8-[4-(3,17β-dihydroxy-19-nor-17α-Δ 1,3,5(10) -pregnatrien-20-yl-11β-yl)-phenoxy]-N-methyl octanamide

Using the procedure of Example 8, 515 mg of the product of Step B and 0.5 ml of acetic anhydride and 0.25 ml of acetyl bromide were reacted and for the saponification, 1 ml of sodium hydroxide was used. After chromatography on silica (eluant: essence G—ethyl acetate 1=1), 460 mg of the desired product were obtained.

PREPARATION OF EXAMPLE 48

9-Bromo-N-Butyl-N-Methyl-7-Nonynamide

Using the procedure of Step A of Example 3, 4 88 g of 6-bromohexanoic acid and 4.36 ml of N-methylbutylamine were reacted to obtain 7. g of the expected product which was used as is for the following step.

A solution of 1.77 ml of propargyl alcohol, 30 ml of tetrahydrofuran and 7.5 ml of hexamethyl phosphotriamide cooled to −60° C. was admixed with 37.5 ml of a 1.6M solution of butyl-lithium in hexane and after stirring for 45 minutes at −30° C., 7 g of the product of Step A in solution in 7 ml of tetrahydrofuran were added. The mixture was stirred for 16 hours at ambient temperature and then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with 2N hydrochloric acid and with a saturated solution of sodium bicarbonate, dried and evaporated to dryness. The 5.78 g of residue were chromatographed on silica (eluant: methylene chloride—ethyl acetate 70-30, then methylene chloride—isopropanol 95-5) to obtain 1.65 g of the desired product.

To a solution of 1.65 g of the product of Step B in 16.5 ml of methylene chloride cooled to −5° C. there were added 2.85 g of carbon tetrabromide and 2.25 g of triphenylphosphine. The reaction solution was stirred for 30 minutes at 0° C. and chromatographed on silica (eluant: methylene chloride—ethyl acetate 90-10) to obtain 1.82 g of the desired product.

N-Butyl-9-[4-(3,17β-Dihydroxy-Δ 1,3,5(10) -Estratrien-11β-Yl)-Phenoxy]-N-Methyl-7-Nonynamide

Using the procedure of Step A of Example 43, 816 mg of the compound of Preparation of Example 43 and 1.25 g of 9-bromo-N-butyl-N-methyl-7-nonynamide (above preparation) were reacted to obtain 2.2 g of crude product to which was added 270 mg of a previous lot. The mixture was chromatographed on silica (eluant: ethyl acetate—essence G 75-25) to obtain 1.126 g of the expected product.

Using the procedure of Steps B and C of Example 3, 1.1 g of the product of Step A and 1.1 ml of acetic anhydride and 0.55 ml of acetyl bromide were reacted to obtain the 3-acetoxy. 2.8 ml of 2N sodium hydroxide were used for the saponification at the 3-position and 142 mg of sodium borohydride were used for the reduction of the 17-keto. After successive chromatography on silica (eluant: ethyl acetate—essence G 70-30), micro-bondapack C 18 (eluant: methanol—water 80-20), then again on silica (eluant: ethyl acetate—essence G 70-30), 540 mg of desired product with a specific rotation of [α] D =−67°±2° (c=0.83% in chloroform) were obtained.

N-Butyl-9-[4-(3,17β-Dihydroxy-Δ 1,3,5(10) -Estratrien-11β-Yl)-Phenoxy]-N-Methyl Nonanamide

A solution of 212 mg of the product of Example 48 and 42 mg of Wilkinson catalyst in solution in 2 ml of toluene and 2 ml of ethanol were hydrogenated under 1900 mbars for one hour and after filtering, the filtrate was evaporated under reduced pressure. The 265 mg of residue were chromatographed on silica (eluant: ethyl acetate—essence G 70-30) to obtain 168 mg of the desired compound with a specific rotation of [α] D =−32° (c=0.49% in CHCl 3 ).

PREPARATION OF EXAMPLE 50

17β-Acetyloxy-11β-(10-Hydroxy-Decyl)-Δ 4,9 -Estradien-3-One

STEP A: 3-(1,2-ethanediyl cyclic acetal) of 11β-[11-[[(1,1-dimethylethyl)-silyl]-oxy]-decyl]-5α-hydroxy-Δ 9 -estren-3,17-dione

Using the procedure of Step A of Preparation 5, 19.5 g of the epoxide of EP No. 0,057,115 (Example 7) and 113.5 ml (of 0.59M solution of 10-(dimethyl-tert-butylsilyloxy)-decyl magnesium compound were reacted to obtain 43.78 g of crude product to which was added 11.3 g of a previous preparation. The mixture was chromatographed on silica (eluant: cyclohexane—ethyl acetate 7-3) to obtain 23.15 g of the desired product.

STEP B: (1,2-ethanediyl cyclic acetal) of 5α,17β-dihydroxy-11β-[[10-[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-decyl]-Δ 9 -estren-3-one

Using the procedure of Step B of Preparation 5, 23.57 g of the product of Step A and 1.447 g of sodium borohydride were reacted to obtain 22.342 g of the desired product. 103 mg of the product were chromatographed on silica (eluant: cyclohexane—ethyl acetate 1-1) to obtain 96.8 mg of pure product.

STEP C: (1,2-ethanediyl cyclic acetal) of 17β-acetyloxy-11β-[[10-[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-decyl]-5α-hydroxy-Δ 9 -estren-3-one

Using the procedure of Step C of Preparation 5, 22.225 g of the product of Step B and 44.5 ml of pyridine and 22.25 ml of acetic anhydride were reacted to obtain 23.74 g of the expected product.

Using the procedure of Step D of Preparation 5, 23.74 g of the product of Step C and 100 ml of 2N hydrochloric acid were reacted and chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 15.238 g of the expected product.

17β-Hydroxy-N-Methyl-N-Isopropyl-3-Oxo-Δ 4,9 -Estradien-11β-Decanamide

Using the procedure of Step E of Preparation 5, 942 mg of 17β-acetoxy-3-oxo-Δ 4,9 -estradien-11β-decanol (obtained in the above preparation) and 1.1 ml of Heilbron-Jones reagent were reacted to obtain 964 mg of the expected product which was used as is for the next step.

Using the procedure of Step A of Example 3, 940 mg of the product of Step A and 0.41 ml of methylisopropylamine were reacted to obtain after chromatography on silica (eluant: essence G—ethyl acetate 1-1), 705 mg of the desired product.

Using the procedure of Step B of Example 1, 194 mg of the compound of Step B and 0.3 ml of 2N sodium hydroxide were reacted to obtain after chromatography on silica (eluant: ethyl acetate), 165 mg of the expected product.

3,17β-Dihydroxy-N-Methyl-N-Isopropyl-Δ 1,3,5(10) -Estratrien-11β-Decanamide

Using the procedure of Example 2, 0.5 g of the compound of Example 50 and 0.5 ml of acetic anhydride and 0.25 ml of acetyl bromide were reacted during aromatization and 1.6 ml of 2N sodium hydroxide were used for the saponification. After chromatography on silica (eluant: ethyl acetate—essence G 7-3) 357 mg of the expected product were obtained. After crystallization from ethyl acetate, 318 mg of the desired product melting at 150° C. were obtained.

10-(17β-Hydroxy-3-Oxo-Δ 4,9 -Estradien-11β-Yl)-Decyl Methyl Isopropyl Carbamate

To a solution of 470 mg of 17β-acetoxy-3-oxo-Δ 4,9 -estradien-11β-decanol (obtained in the Preparation of Example 50) in 4 ml of toluene and 122 mg of dimethylamino pyridine at 0° C., 118 mg of triphosgene were added and the mixture was stirred for 30 minutes at ambient temperature. 312 ml of methylispropylamine were added and the mixture was stirred for 30 minutes at ambient temperature and then poured into 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to dryness. The 642 mg of residue were chromatographed on silica (eluant: essence G—ethyl acetate 6-4) to obtain 545 mg of the desired product.

Using the procedure of Step B of Example 1, 293 mg of the product of Step A and 1 ml of 2N sodium hydroxide were reacted to obtain after chromatography on silica (eluant: essence G—ethyl acetate 1-1), 244 mg of the desired product.

10-(3,17β-Dihydroxy-Δ 1,3,5(10) -Estratrien-11β-Yl)-Decyl Methyl Isopropyl Carbamate

Using the procedure of Step A of Example 8, 230 mg of the compound of Step a of Example 52 and 230 ml of acetic anhydride and 115 ml of acetyl bromide were reacted to obtain 234 mg of the expected product.

Using the procedure of Step B of Example 8, 260 mg of the product of Step A were reacted to obtain after chromatography on silica (eluent: essence G—ethyl acetate 6-4), 245 mg of the desired product.

3,17β-Dihydroxy-17α-Methyl-N-Methyl-Isopropyl- Δ1,3,5(10) -Estratrien-11β-Undecanamide

One agitated under reflux for 30 minutes 1 g of the product of Step A of Example 15 with 200 ml of methanol as well as 2.2 g of palladium hydroxide on magnesium compound were reflux with stirring for 30 minutes and was then filtered. Evaporation of the solvents under reduced pressure yielded 985 mg of product which was chromatographed on silica (eluant: acetonitrile) to obtain 543 mg of the desired product with a specific rotation of [<] D =+121°±3° (c=0.5% in ethanol).

STEP B: 3,17β-dihydroxy-N-methyl-N-isopropyl-19-nor-17α-Δ 1,3,5(10) -pregnatrien-20-yn-11β-undecanamide

To a solution of 0.5 g of the product of Step A in 10 ml of anhydrous tetrahydrofuran at 20° C., 13.7 ml of 0.6M ethyl magnesium bromide were added and the mixture was stirred for 2 hours then poured into an ammonium chloride solution. The mixture was extracted with methylene chloride, dried and evaporated to dryness under reduced pressure. The 466 mg of residue were chromatographed on silica (eluant: methylene chloride—acetone 9-1) to obtain 225 mg of the expected product melting at 148° C. and with a specific rotation of [α] D =+83°±2.5° (c=0.5% in ethanol).

3,17β-Dihydroxy-N-Methyl-N-Isopropyl-19-Nor-17α-Δ 1,3,5(10) -Pregnatrien-20-Yn-118-Undecanamide

Using the procedure of Step C of Example 21, 0.954 g of the product of Step A of Example 54 and 1.470 g of lithium acetylide—ethylene diamine complex were reacted to obtain after chromatography on silica (eluant: methylene chloride—acetone 9-1), 284 mg of the desired product with a specific rotation of [α] D =+43.5°±3° (c=0.2% in ethanol).

3-Hydroxy-11β-(11-(Methyl-Isopropyl-Amino)-11-Oxo-Undecyl)- Δ1,3,5(10) -Estratrien-17β-Yl Propanoate

To a solution of 0.511 g of the product of Step B of Example 16 in 5.1 ml of pyridine, 0.3 ml of propionyl chloride were added and the mixture was stirred for 105 minutes and 0.1 ml of propionyl chloride was added and the mixture was stirred for 90 minutes, then poured into 30 g of water and ice. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and distilled to dryness under reduced pressure to obtain 0.848 g of the product that was chromatographed on silica (eluant: cyclohexane—ethyl acetate 6-4).

STEP A: 3-hydroxy-11β-(11-(methyl-isopropyl amino)-11-oxo-undecyl)-Δ 1,3,5(10) -estratrien-17β-yl propanoate

To a solution of 0.34 g of the product of Step A in 4 ml of methanol, there were added 55 mg of potassium bicarbonate in solution in 0.4 ml of above. The mixture was stirred for 22 hours at ambient temperature and water was added. The mixture was extracted with methylene chloride and the organic phase was washed, dried and evaporated to dryness under reduced pressure. The 0.304 g g of residue were chromatographed on silica (eluant: cyclohexane—ethyl acetate 6-4) to obtain 0.285 g of the desired product.

N,N-Bis-Isopropyl-17β-Hydroxy-3-Oxo-Δ 4,9 -Estradien-11β-Undecanamide

Using the procedure of Step A of Example 3, 1.44 g of 17β-acetyloxy-3-oxo-11-Δ 4,9 -estradien-undecanoic acid of Step E of Preparation 5 and 2.1 ml of diisopropylamine were reacted to obtain after chromatography on silica (eluant: cyclohexane—ethyl acetate 1-1), 0.533 g of the desired product.

Using the procedure of Step B of Example 1, 248 mg of the compound of Step A were reacted to obtain after chromatography on silica (eluant: cyclohexane—ethyl acetate 1-1), 91 mg of the desired product.

N,N-Bis-Isopropyl-3,17β-Dihydroxy-Δ 1,3,5(10) -Estratrien-11β-Undecanamide

Using the procedure of Example 8, 0.952 g of the product of Step A of Example 57 were reacted to obtain after chromatography on silica (eluant: cyclohexane—ethyl acetate1-1), 302 mg of the desired product.

3,17β-Dihydroxy-α-N-Dimethyl-N-Isopropyl-Δ 1,3,5(10) -estratrien-11β-Undecanamide

STEP A: 3,17β-Bis-(Tetrahydropyranyloxy)-N-Methyl-N-isopropyl-Δ 1,3,5(10) -estratrien-11β-undecanamide

For one hour, a mixture of 1.045 g of the product of Step B of Example 16, 50 ml of ether, 3.75 ml of dihydropyran and 30 mg of p-toluene sulfonic acid was stirred and was then poured into 100 ml of a saturated solution of sodium bicarbonate and was extracted with ether. The ether extract was evaporated to dryness under reduced pressure to obtain 2.216 g of resin which was chromatographed on silica (eluant: methylene chloride—acetone 95-5) to obtain 1.38 g of the desired product.

Using the procedure of Step B of Example 39, 435 mg of the product of Step A were reacted to obtain 430 mg of product, the pyranyls of which were hydrolyzed by stirring in a mixture of 4 ml of ethanol and 4 ml of 2N hydrochloric acid. After concentration to half volume under reduced pressure, and extraction with methylene chloride, and chromatography on silica (eluant: methylene chloride—methanol 95-5), 0.178 g of the desired product having a specific rotation of [α] D =+90°±2° (c=0.15% in ethanol) were obtained.

3,17β-Dihydroxy-α,α-Dimethyl-N-Methyl-N-Isopropyl-Δ 1,3,5(10) -Estratrien-11β-Undecanamide

Using the procedure of Step C of Example 39, 210 mg of product of Step A of Example 59 were reacted to obtain after chromatography on silica (eluant: methylene chloride—acetone 95-5), 103 mg of the desired product with a specific rotation of [α] D =+72°±2.5° (c=0.5% in ethanol).

1-(11-(17β-Hydroxy-3-Oxo-Δ 4,9 -Estradien-11β-Yl)-1-Oxo-Undecyl)-4-Methyl-Piperazine

Using the procedure of Step A of Example 3, 3.886 g of the acid of Step E of Preparation 5 and 4.33 ml of N-methyl piperazine were reacted to obtain after chromatography on silica (eluant: ethyl acetate—methanol 95-5, then 90-10), 3.14 g of the desired product.

Using the procedure of Step B of Example 1, 1.398 g of the product of Step A were reacted to obtain after chromatography on silica (eluant: methylene chloride—methanol 95-5), 1.012 g of the expected product with a specific rotation of [<] D =−36°±2.5° (c=0.5% in ethanol).

4-[11-(3,17β-Dihydroxy-Δ 1,3,5(10) -Estratrien-11β-Yl)-1-Oxo-Undecyl]-4-Methyl Piperazine

Using the procedure of Example 2, 1.619 g of the product of Step A of Example 61 were reacted to obtain after two successive chromatographies on silica (eluant: methylene chloride—methanol 95-5), 466 mg of the desired product with a specific rotation of [α] D =+70.5°±2.5° (c=0.5% in ethanol).

N-(2-Chloro-2-Methylpropyl)-17β-Hydroxy-3-Oxo-Δ 4,9 -Estradien-11β-Undecanamide

Using the procedure of Step A of Example 3, 2.35 g of the compound of Step E of Preparation 5 and 2.5 ml of 2,2-dimethyl-aziridine were reacted to obtain after chromatography on silica (eluant: methylene chloride—acetone 92.5-7.5) 2.08 g of the desired product.

Using the procedure of Step B of Example 1, 720 mg of the product of Step A were reacted to obtain after chromatographed on silica (eluant: cyclohexane—ethyl acetate 1-1), 420mg the desired product with a specific rotation of [α] D =−38°±1°(c=0.7% in ethanol).

3.75 g of [(5-bromopentyl)-oxy]-N-butyl-N-methyl acetamide in solution in 6 ml of acetone were added to a solution of 2.5 g of the product of Step B of Preparation A of Example 78 in 26 ml of acetone and 6.4 ml of 2N sodium hydroxide. The mixture was stirred for 5 hours at 50° C., cooled, poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extracts were washed, dried and evaporated to dryness under reduced pressure. The 6.8 g of residue were chromatographed on silica (eluant: ethyl acetate) to obtain 2.63 g of the desired product.

STEP B: N-butyl-[5-[4-(3-hydroxy-δ 1,3,5(10) -estratrien-17-one-11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide

2.61 g of palladium hydroxide at 20% on magnesium oxide were added to a solution of 2.61 g of the product of Step A in 54 ml of methanol and the mixture was heated at reflux for 30 minutes. The catalyst was filtered off and washed with methanol. The filtrate was evaporated to dryness under reduced pressure and the 2.5 g of residue were taken up in 75 ml of methanol. 2.45 g of potassium hydroxide in pellet form were added and the mixture was stirred for 45 minutes at ambient temperature. 130 g of ice and 50 ml of 2N hydrochloric acid were added and extraction was carried out with methylene chloride. The extracts were evaporated to dryness under reduced pressure. The 2.75 g of residue were chromatographed on silica (eluant: ethyl acetate-essence G 9-1) to obtain 1.83 g of the desired product.

STEP C: N-butyl-[5-[4-(3,17β-dihydroxy-δ 1,3,5(10) -estratrien-11β-yl)-phenoxy]-pentyloxy]-N-methyl acetamide

66 mg of sodium borohydride were introduced over 15 minutes into a solution of 500 mg of the product of Step B in 8 ml of methanol and the mixture was stirred for 2 hours, then poured into 40 ml of water and extracted with methylene chloride. The extracts were evaporated to dryness under reduced pressure. The 514 mg of residue were chromatographed on silica (eluant: ethyl acetate) then a second time with the same eluant to obtain 343 mg of the desired product with a specific rotation of [α] D =−31.1° (c=1% in chloroform).

STEP D: N-butyl-[5-[4-(3,17β-diacetoxy-δ 1,3,5(10) -estratrien-11β-yl)-phenoxy]-pentyloxy]-N-methyl-acetamide

0.9 ml of 98% acetic anhydride and 23 mg of 4-dimethylaminopyridine were added to a solution of 450 mg of the product of Step C in 2.3 ml of pyridine. The mixture was stirred for one hour and 5 ml of water and 5 ml of methanol were added. The mixture was stirred for 10 minutes followed by extraction with ethyl acetate. The extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 580 mg of residue were chromatographed on silica (eluant: ethyl acetate) to obtain the desired product.

STEP E: N-butyl-[5-[4-(3,17β-diacetoxy-δ 1,3,5(10) -estratrien-11β-yl)-phenoxy]-pentoxyl]-N-methyl-ethanethioamide

400 mg of Lawesson reagent were added to a solution of 480 mg of the product of Step D in 10 ml of toluene. The mixture was stirred for one hour at 50° C. After it had cooled down to ambient temperature, it was filtered and the filtrate was evaporated to dryness uner reduced pressure. The 840 mg of residue were chromatograph on silica (eluant: essence G-ethyl acetate 1-1) to obtain 450 mg of the desired product.

STEP F: N-butyl-[5-[4-(3,17β-dihydroxy-δ 1,3,5(10) -estratrien-11β-yl)-phenoxy]-pentyloxy]-N-methyl-ethanethioamide

2.8 ml of 2N sodium hydroxide were added to a solution of 480 mg of the product of Step E in 10 ml of methanol and the mixture was stirred for 4 hours at ambient temperature and then neutralized with 2N hydrochloric acid. Extraction was carried out with ethyl acetate and the extracts wee washed with a saturated solution of sodium chloride, dried and then evaporated to dryness under reduced pressure. The 428 mg of residue were chromatographed on silica (eluant: essence G-ethyl acetate 1-1) to obtain 365 mg of the expected product with a specific rotation of [α D =−22.5°±1.5° (c=1% in CHCl 3 ).

PREPARATION OF EXAMPLE 79

8-bromo-N-butyl-N-methyl octanamide

9.1 ml of N-methylmorpholine and then 10.4 ml of isobutyl chloroformate were added dropwise at −10° C. to −15° C. to a solution of 5 g of 8-bromo octanoic acid in 200 ml of methylene chloride. The mixture was stirred for 30 minutes at −10° C. to −15° C. and then at this temperature, 13 ml of N-methylbutylamine were added. The mixture was allowed to rise ambient temperature and stood for 40 minutes. Then, 150 ml of a saturated solution of sodium bicarbonate were added and the mixture was stirred for 10 minutes. After decanting, extraction was done with methylene chloride and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride-acetone 95-5) to obtain 6.14 g of the expected product.

IR Spectrum: (CHCl 3 )

C═O

1627 cm −1 (amide III)

N-butyl-8-(4-(3,17β-dihydroxy-δ 1,3,5(10) -estratrien-11β-yl)-phenoxy)-N-methyloctanethioamide

Using the procedure of Step A of Example 78, 725 mg of the product of Step B of Preparation A of Example 78 and 0.2 ml of 8-bromo-N-butyl-N-methyl octanamide were reacted to obtain after chromatography on silica (eluant: essence G-ethyl acetate 4-6), 540 mg of the expected product.

Using the procedure of Step B of Example 78, 470 mg of the product of Step A and 260 mg of palladium hydroxide on magnesium oxide were reacted to obtain after chromatography on silica (eluant: ethyl acetate-essence G 1-1), 360 mg of the desired compound.

Using the procedure of Step C of Example 1, 360 mg of the product of Step B and 72 mg of sodium borohydride were reacted to obtain 460 mg of the expected product.

Using the procedure of Step D of Example 78, 460 mg of the product of Step C and 0.9 ml of acetic anhydride and 24 mg of 4-dimethylamino pyridine were reacted. 510 mg of the residue were chromatographed on silica (eluant: essence G-ethyl acetate 1-1) to obtain the desired product.

STEP E: N-butyl-8-[4-(3,17β-acetoxy-δ 1,3,5(10) -estratrien-11β-yl)-phenoxy]-N-methyl octane thioamide

Using the procedure of Step E of Example 1, 510 mg of the product of Step D and 1.54 g of Lawesson reagent were reacted. Heating was carried out at 50° C. for 3 hours 15 minutes and the 1.18 g of residue was chromatographed on silica (eluant: essence G-ethyl acetate 7-3) to obtain 430 mg of the desired product.

Using the procedure of Step F of Example 78, 408 mg of the product of Step E were reacted and the mixture was stirred at ambient temperature for one hour. 370 mg of residue were isolated and after chromatography, 261 mg of the expected product with a specific rotation of [α] D =−31.5°±1.5° (c=1% in CHCl 3 ) were obtained.

Using the procedure of Step A of Preparation 16, 8.12 g of sodium hydride at 50% in oil, 20 g of 1,6-hexane diol and 25.5 g of terbutyl dimethyl chloro silane were reacted to obtain after chromatography, 20.7 g of the expected product.

1.78 g of sodium hydride at 50% in oil were added to a solution of 7 g of the product of Step A in 35 ml of tetrahydrofuran and the mixture was stirred for 40 minutes at ambient temperature. A solution of 7.8 g of bromo N-butyl N-methylacetamide of Step A of Preparation B of Example 78 in 10 ml of tetrahydrofuran was added dropwise over 10 minutes. The mixture was stirred for 16 hours at ambient temperature and a saturated aqueous solution of ammonium chloride was added. Extraction was carried out with ethyl acetate and the extracts were washed, dried and evaporated to dryness under reduced pressure. The 13.4 g of residue were dissolved in 69 ml of tetrahydrofuran and 48 ml of a 1M solution of terabutylammonium fluoride were added. The mixture was stirred for 3 hours at ambient temperature and was then poured into water and extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride, dried and then evaporated under reduced pressure. The 10.8 g of residue were chromatographed on silica (eluant: methylene chloride-isopropanol 94-6) to obtain 5.56 g of the expected product.

9.3 g of tetrabromomethane and 7.4 g of triphenyl phosphine were added at −15° C. to a solution of 5.52 g of the product of Step B in 55 ml of methylene chloride and the reaction mixture was stirred for one hour at 0° C., then chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 6.22 g of the expected product.

N-butyl-2-(6-(δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenoxy)-hexyloxy)-N-methyl-acetamide

Using the procedure of Step A of Example 1, 2 g of the product of Step B of Preparation A of Example 78 and 3.14 g of 2-[(6-bromohexyl)-oxy]-N-butyl-N-methyl acetamide were reacted and the 5.7 g of residue were chromatographed on silica (eluant: ethyl acetate) to obtain 2.68 g of the expected product.

STEP B: N-butyl-2-[6-[4(δ 1,3,5(10) -estratrien-3-ol-17-one-11β-yl)-phenoxy]-hexyloxy]-N-methyl acetamide

Using the procedure of Step B of Example 78, 2.63 g of the product of Step A and 2.63 g of palladium hydroxide on magnesium oxide were reacted and the 2.165 g of residue were chromatographed on silica (eluant: methylene chloride-isopropanol 94-6) to obtain 1.62 g of the expected product.

Using the procedure of Step C of Example 78 450 mg of the product of Step B and 58 mg of sodium borohydride were reacted and the 461 mg of residue were chromatographed on silica (eluant: methylene chloride-isopropanol 94-6), then a second time (eluant: ethyl acetate) to obtain 274 mg of the expected product with a specific rotation of [α] D =−32.5° (c=1% in ethanol)

PREPARATION OF EXAMPLE 84

8-bromo-N-butyl-N-methyl-2-octynamide

1.63 g of lithium acetylide, ethylene diamine complex and 15 ml of dimethyl sulfoxide were introduced into a spherical flask under a nitrogen atmosphere and the mixture was stirred for 30 minutes at ambient temperature. Then, 3.64 g of the product of Preparation 15 were added over 45 minutes. The mixture was stirred for 4 hours and poured into an ice-cooled saturated solution of ammonium chloride, washed with hexane, then with water, dried and evaporated to dryness under reduced pressure to obtain 3.08 g of crude product.

2.4 ml of a solution of 15% butyl lithium in hexane were added at −60° C. to −70° C. under a nitrogen atmosphere to a solution of 630 mg of the crude product of Step A in 4 ml of tetrahydrofuran and the mixture was stirred for 15 minutes at −60° C., then placed under a CO 2 atmosphere. The mixture stood under CO 2 for 15 minutes at −60° C., then was allowed to return to ambient temperature and was diluted with water and ethyl acetate while emulsifying. The aqueous phase was separated out and then the organic phase was extracted with an aqueous solution of sodium bicarbonate. The alkaline aqueous phase was acidified by the addition of monosodium phosphate and was extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure to obtain 540 mg of the expected product.

2.8 ml of methyl morpholine were added to a solution of 4.55 g of Step B in 20 ml of methylene chloride and the mixture was cooled to −30° C. under a nitrogen atmosphere. Then, 3.3 ml of isobutyl chloroformate in solution in 10 ml of methylene chloride were added slowly. After stirring at −5° C. for 35 minutes, 4 ml of methyl butylamine were added at 0° C. over 5 minutes. The reaction medium was allowed to return to ambient temperature and was poured into an aqueous solution of sodium bicarbonate. Extraction was carried out with methylene chloride and the extracts were dried and evaporated to dryness under reduced pressure. The 6.9 g residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 7-3) to obtain 2 g of the expected product.

1 ml of 2N hydrochloric acid was added to a solution of 1.9 g of the product of Step C and the mixture was maintained for one hour at ambient temperature, then extracted with ethyl acetate. The extracts were washed with water, dried and evaporated to dryness under reduced pressure. The 1.79 g of residue were chromatographed on silica (eluant: ethyl acetate) to obtain 870 mg of the expected product.

1.205 g of triphenyl phosphine were added to a solution of 855 mg of the product of Step D in 4 ml of methylene chloride and the mixture was cooled to −10° C. 1.522 g of tetrabromomethane were added, and after stirring for one hour at −5° C., the reaction mixture was chromatographed on silica (eluant: cyclohexane-ethyl acetate 35-65) to obtain 0.98 g of the expected product.

N-butyl-8-(4-(δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenoxy)-N-methyl-2-octynamide

A solution of 970 mg of the product of Step E in 6 ml of acetone was introduced over 40 minutes into a solution of 1.09 g of the product of Step B of Preparation A of Example 78 in 20 ml of acetone and 1.5 ml of 2N sodium hydroxide which was refluxed under a nitrogen atmosphere. The mixture was refluxed for 6 hours, cooled and diluted with an ammonium chloride solution. Extraction was carried out with methylene chloride and the extracts were washed, dried and evaporated to dryness under reduced pressure. The 2.13 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 4-6) to obtain 1.21 g of the expected product.

0.8 ml of acetic anhydride and 0.4 ml of acetyl bromide were added to a solution of 830 mg of the product of Step A in 8 ml of methylene chloride cooled to 0° C. to +5° C. and under a nitrogen atmosphere. The mixture was maintained at this temperature for 10 minutes, then at ambient temperature for one hour. A saturated solution of sodium bicarbonate was added to make an emission and 3.5 ml of methanol were added. Extraction was carried out with methylene chloride and the organic phase was collected, washed with sodium bicarbonate solution, dried and evaporated to dryness under reduced pressure to obtain 950 mg of product which was used as is in solution in 10 ml of methanol cooled to 0° C., +5° C. 0.2 g of sodium borohydride were added and the mixture was stirred for 45 minutes. 2 ml of water and 1 ml of 2N sodium hydroxide were added and the reaction was held for one hour at ambient temperature, diluted with a saturated solution of ammonium chloride and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The 850 mg of residue was chromatographed on silica (eluant: cyclohexane-ethyl acetate 4-6) to obtain 438 mg of the expected product.

PREPARATION OF EXAMPLE 85

2-[(5-bromopentyl)-thio]-N-butyl-N-methyl acetamide

10 ml of 5-chloropentanol were added to a suspension of potassium thioacetate in 100 ml of ethanol and under a nitrogen atmosphere, the mixture was refluxed for one hour. After cooling, 100 ml of ethyl ether were added, followed by filtering and evaporating and filtrate to dryness. 100 ml of ethyl ether were added to the oily residue and the precipitate was filtered. The organic solution was evaporated to dryness and the 12.5 g of oil residue were put in solution in 50 ml of methanol. 10 ml of 10N sodium hydroxide were added and the solution was held for one hour at ambient temperature. A saturated solution of ammonium chloride was added and extracted was carried out with ethyl acetate, then with methylene chloride. The organic phases were dried and evaporated to dryness under reduced pressure to obtain 9.3 g of oily residue which was dissolved in 50 ml of methanol with 10% water, and nitrogen was bubbled through for 15 minutes. 5 ml of n-tributyl-phosphine were added slowly over 2 minutes and the mixture was held for 2 hours 30 minutes at ambient temperature. Extraction was carried out with ethyl acetate and the extracts were dried and evaporated to dryness under reduced pressure. The 13.6 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 6.55 g of the expected product.

1.4 g of sodium hydride at 50% in oil and 6 g of bromo N-butyl-N-methyl acetamide of Step A of Preparation B of Example 78 were added to a solution of 3.36 g of the product of Step A in 45 ml of tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred for 2 hours at ambient temperature and poured into an ammonium chloride solution and extracted with ethyl acetate. The extracts were washed and evaporated to dryness under reduced pressure. The 10 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 2-8) to obtain 5.27 g of the expected product.

6.88 g of triphenyl phosphine were added to a solution of 5.27 g of the product of Step B in 52 ml of methylene chloride and the mixture was cooled to 0° C. to +5° C. under a nitrogen atmosphere. 8.68 g of tetrabromo methane were added with stirring for one hour at 0° C. The reaction mixture was chromatographed on silica (eluant: cyclohexane-ethyl acetate 2-1) to obtain 6.2 g of the expected product.

IR Spectrum: (CHCl 3 )

C═O

1638 cm −1 (amide III)

N-butyl-2-((5-(4-(δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenoxy)-pentyl)-sulfinyl)-N-methyl-acetamide

5.1 ml of 2N sodium hydroxide were added to a solution of 3.09 g of the product of Step B of Preparation A of Example 78 in 45 ml of acetone and the mixture was refluxed under a nitrogen atmosphere. 6.2 g of the product of Step D were added in a 4 fractions over 2 hours and the mixture was refluxed for 80 minutes, cooled and diluted with a saturated solution of ammonium chloride. Extraction was carried out with ethyl acetate and the extracts were washed, dried and evaporated to dryness under reduced pressure. The 10 g of residue were chromatographed on silica (eluant: essence G-ethyl acetate 4-6) to obtain 3.4 g of the expected product.

STEP B: N-butyl-[5-[4-δ 1,3,5(10) -estratrien-3-ol-17-one-11β-yl)-phenoxy]-pentylthio]-N-methylacetamide

Using the procedure of Step B of Example 82, 2.6 g of the product of Step A in 26 ml of methylene chloride under a nitrogen atmosphere and 2.6 ml of acetic anhydride and 1.3 ml of acetyl bromide were reacted. After reaction and chromatography on silica, 1.6 g of the expected product were obtained.

STEP C: N-butyl-[5-[4-(δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenoxy]-pentylthio]-N-methylacetamide

Using the procedure of Step C of Example 82, 600 mg of the product of Step B and 60 mg of sodium borohydride were reacted to obtain the expected product.

STEP D: N-butyl-2-[[5-[4-(δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenoxy]-pentyl]-sulfinyl]-N-methylacetamide

4 ml of a 0.1M solution of sodium periodate were added to a solution of 147 mg of the product of Step C in 10 ml of methanol and the mixture was refluxed for 40 minutes, cooled, diluted with water and extracted with chloroform. The extracts were evaporated to dryness under reduced pressure and the 180 mg of residue were chromatographed on silica (eluant: ethyl acetate-acetone 1-1) to obtain 150 mg of the expected product.

PREPARATION A OF EXAMPLE 86

3,17β-bis-(tetrahydro-2H-2-pyrannyl)-oxy]-(4-ethynyl-phenyl)-δ 1,3,5(10) estratrien-11β-yl

STEP A: (5α,11β-)3-(cyclic 1,2-ethanediyl acetal)-5-hydroxy-11-[[4-(1,1-dimethylethyl)-dimethylsilyl]-ethynyl-phenyl-δ 9 -estren-3,17-dione

Using the procedure of Step A of Preparation A of Example 78, 30 g of 3-(cyclic 1,2-ethanediyl acetal) of 5α,10β-epoxy-δ 9,11 -estradiene-3,17-dione [obtained by EP 0,057,115 (Example 7)] using for the preparation of the magnesium compound 81.254 g of bromine derivative, of 4-trimethylsilylethynyl-bromo benzene obtained in Preparation 17 and 7.96 g of magnesium, then for the condensation, 1.4 g of copper chloride were reacted. The crude product to which was added the product from an operation carried out in an identical way starting with 16.52 g of epoxide was chromatographed on silica (eluant: methylene chloride-acetone 98-2) to obtain 50.8 g of pure product A and 6 g of slightly less pure product B which were used as is for the following step.

A suspension of 46.8 g of the product of Step A, 200 ml of ethanol and 8.1 ml of sodium hydroxide was stirred for 30 minutes and then 16.7 ml of concentrated hydrochloric acid were added. The mixture was stirred at ambient temperature and the mixture was concentrated to half its volume and extracted with methylene chloride. The extracts were dried and evaporated under reduced pressure. The 38.23 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 31.06 g of the desired product melting at 184° C.

47.1 ml of acetic anhydride and 23.8 ml of acetyl bromide were added at 0° C. to −5° C. to a solution of 31 g of the product of Step B in solution in 340 ml of methylene chloride and the mixture was stirred for 90 minutes at ambient temperature, then was poured into a mixture of 2 liters of a saturated solution of sodium bicarbonate and 700 g of ice. The mixture was stirred for 15 minutes followed by extraction with methylene chloride. The extracts were evaporated to dryness under nitrogen at reduced pressure and the residue was chromatographed on silica (eluant: methylene chloride-acetone 9-1) to obtain 31.2 of product with the acetate at position 3, which was stirred for one hour in 930 ml of methanol and 20.96 g of potassium hydroxide. After cooling to 0° C., and neutralizing with 2N hydrochloric acid, extraction was carried out with methylene chloride. The extracts were evaporated to dryness under reduced pressure and chromatographed on silica (eluant: cyclohexane-ethyl acetate 7-3) to obtain 27.03 g of crude product which was made into a paste in ether to collect 22.85 g of the desired product melting at 163° C.

a) Reduction of the ketone in position 17

10 g of sodium borohydride were added at 0° C. to +5° C. to a solution of 14 g of the product of Step C in 120 ml of methanol, and the mixture was stirred for 3 hours at ambient temperature. 380 g of a water-ice (1-1) mixture were added and the pH was adjusted to between 4 and 5 with 2N hydrochloric acid. Sodium chloride was added until saturation was reached and extraction was carried out with ethyl acetate. The residue was evaporated to dryness to obtain 17.3 g of the crude product.

b) Dihydropyranylation

17.3 g of the 17 hydroxy intermediate were stirred for 2 hours 30 minutes in the presence of 700 ml of ether, 34.4 ml of dihydropyran and 0.3 g of p-toluene sulfonic acid and 35 ml of triethylamine were added. The mixture was poured into a (1-1) mixture of ice and a saturated solution of sodium bicarbonate. Extraction was carried out with ether, followed by filtering and evaporating to dryness under nitrogen at reduced pressure. The residue was chromatographed on silica (eluant: cyclohexane-ethyl acetate 1-1) to obtain 13.6 g of crude product which was taken up in isopropyl ether to collect 10.23 g of the desired product melting at 213° C. to 215° C.

PREPARATION B OF EXAMPLE 86

5-[4-[3,17β-bis-[(tetrahydro-2H-2-pyrannyl)-oxy]-δ 1,3,5(10) -estratrien-11β-yl]-phenyl]-4-pentyl-1-ol

STEP A: 3,17β-bis-[(tetrahydro-2H-2-pyrranyl)-oxy]-11β-[4,5-[[dimethyl-11-dimethyl-ethyl)-silyl]-oxy]-1-pentynyl]-phenyl-δ 1,3,5(10) -estratriene

5.9 ml of hexamethyl phosphorotriamide were added to a solution of 714 mg of the product of Step D of Preparation A in 5.9 ml of tetrahydrofuran and 1.5 ml of 1.32M solution of butyl lithium in hexane, then 669 mg of brominated product of Step B of Preparation 16 were added over 5 minutes at −35° C. The mixture was stirred for one hour at ambient temperature and then poured into a saturated aqueous solution of sodium chloride. Extraction was carried out with ethyl acetate and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue was dissolved in water and extracted with ethyl ether. The extracts were washed with water, dried and evaporated to dryness under reduced pressure. The 1.198 g of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane 1-9 with 0.1% triethylamine) to obtain 941 mg of the expected intermediate product.

STEP B: 5-[4-[3,17β-bis-[(tetrahydro-2H-2-pyrannyl)-oxy]-δ 1,3,5(10) -estratrien-11β-yl]-phenyl]-4-pentyn-1-ol

1.4 ml of a 1M solution of tetrabutyl ammonium fluoride were added to a solution of 931 mg of the product of Step A in 10 ml of tetrahydrofuran and the mixture was stirred for 105 minutes at ambient temperature, then poured into water and extracted with ethyl acetate. The extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 755 mg of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane 4-6 with 0.1% triethylamin) to obtain 408 mg of the expected product.

PREPARATION C OF EXAMPLE 86

N-Methyl-N-Butyl-Mercaptoacetamide

4.16 g of bromo-N-butyl-N-methylacetamide of Preparation B of Example 78, Step A in 1.5 ml of methanol were added to a suspension of 2.28 g of potassium thioacetate in 10 ml of methanol and the mixture was heated for one hour at 40° C. under an argon atmosphere. After evaporation to dryness under reduced pressure, the residue was dissolved with ethyl ether, the insoluble part filtered off and the solution was evaporated to dryness to obtain 4.06 g of oily product.

1 ml of hyrazine hydrate was added to a solution of 3.99 g of the product of Step A in 10 ml of tetrahydrofuran and the mixture was stirred for 16 hours at ambient temperature. 0.5 ml of hydrazine hydrate were added and stirring was continued for 16 hours at ambient temperature. The mixture was poured into a mixture of 40 ml of 2 N hydrochloric acid and 40 g of ice. Extraction was carried out with ethyl acetate and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 3.13 g of residue were chromatographed on silica (eluant: ethyl acetate-ethyl ether 7-3) to obtain 79.5 mg of the expected product.

N-Buty-2-((5-(4-δ 1,3,5(10) -Estratrien-3,17β-Diol-11β-yl)-Phenyl)-Pentyl)-Thio)-N-Methyl-Acetamide

STEP A: 2-[[5-[4-(3,17β-bis[(tetrahydro-2H-2-pyrannyl)-δ 1,3,5(10) -estratrien-11β-yl]-phenyl]-4-pentynyl]-thio]-N-butyl-N-methyl acetamide

1.5 ml of pyridine and 259 mg of tosyl chloride were added to a solution of 408 mg of the product of Step B of Preparation B and the mixture was stirred for 4 hours at ambient temperature, then poured into a saturated aqueous solution of potassium bicarbonate and extracted with ethyl acetate. The extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 512 mg of tosylated crude product were dissolved in 4.5 ml of methanol and 165 mg of N-methyl-N-butyl mercapto acetamide of Preparation C and 0.94 ml of a solution of sodium methylate at 58.4 mg/ml in methanol were added. Reflux was maintained until total reaction was achieved, and the methanol was evaporated under reduced pressure. Water was added and extraction was carried out with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 677 mg of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane 4-6 with 0.1% triethylamine) to obtain 315 mg of the expected product.

STEP B: N-butyl-2-[[5-[4-[δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl]-phenyl]-4-pentynyl]-thio]-N-methyl-acetamide

16 ml of methanol, then 3.2 ml of 2 N hydrochloric acid were added to a solution of 315 mg of the product of Step A and the mixture was stirred for one hour at ambient temperature, then poured into a saturated aqueous solution of sodium chloride. Extraction was carried out with methylene chloride and the extracts were washed, dried and evaporated to dryness under reduced pressure to obtain 225 mg of the expected product.

STEP C: N-butyl-2-((5-(4-δ 1,3,5(10) -estratrien-3,17β-diol-11β-yl)-phenyl)-pentyl)-thio)-N-methyl-acetamide

90 mg of chlorotris(triphenyl phosphine) rhodium were added to a solution of 222 mg of the product of Step B in 2.2 ml of methanol and 2.2 ml of toluene and hydrogenation was carried out under 1885 mbars for 18 hours. A further 22.5 mg of chlorotris(triphenyl phosphine) rhodium, 0.7 ml of ethanol and 0.7 ml of toluene were added and hydrogenation was carried out until saturation was obtained. Evaporation to dryness was carried out under reduced pressure. The 333 mg of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 103 mg of the expected product.

PREPARATION OF EXAMPLE 87

7-Bromo-N-Butyl-N-Methyl-Heptanamide

Using the procedure of Example 78, 707 mg of 7-bromoheptanoic acid, obtained by stirring for 3 hours of 3 g of ethyl 7-bromo-heptanoate in 28 ml of 2 N sodium hydroxide and 10 ml of ethanol were reacted and extracted at pH=1 with ethyl ether. Evaporation to dryness under vacuum of 1.4 ml of N-methyl morpholine, 1.69 ml of isobutyl chloroformate, then 2.1 ml of N-methylbutylamine were used to obtain 3.124 g of oily residue which was distilled under reduced pressure to obtain 676 mg of the expected product in the form of an oil.

N-Buty-4-(δ 1,3,5(10) -Estratrien-3,17β-Diol-11βyl)-N-Methyl-Benzenenonamide

STEP A: 9-[4-[3,17β-bis-[(tetrahydro-2H-2-pyrannyl)-oxy]-δ 1,3,5(10) -estratrien-11β-yl]-phenyl]-N-butyl-N-methyl-8-nonyn-amide

5 ml of hexamethylphosphorotriamide and then slowly 1.22 ml of a 1.1 M solution of butyl lithium in hexane were added at −30° C. to a solution of 0.6 g of 3,17β-bis-[(tetrahydro-2H-2-pyrannyl)-oxy]-(4-ethynylphenyl)-δ 1,3,5(10) -estratrien-11β-yl of Step D of Preparation A of Example 86 in 5 ml of tetrahydrofuran and the mixture was stirred at −30° C. for 30 minutes. Then, 0.401 g of brominated product of the above preparation were added and the mixture was stirred for 90 minutes at ambient temperature, then poured into 20 ml of a saturated aqueous solution of monosodium phosphate. Extraction was carried out with methylene chloride and the extracts were dried and evaporated to dryness under reduced pressure. The 5.4 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 1—1) to obtain 0.67 g of the expected product.

10 ml of 2 N hydrochloric acid, then 20 ml of water were added to a solution of 0.640 g of the product of Step A in 20 ml of ethanol and extraction was carried out with methylene chloride. The extracts were dried and evaporated to dryness under reduced pressure to obtain 0.494 mg of residue. 30 mg of palladium on charcoal were added to a solution of 0.26 g of the crude product in 20 ml of ethanol and hydrogenation was carried out under 1120 mbars for 20 minutes. After filtration and washing in ethanol, the solution was evaporated to dryness under reduced pressure. The 0.272 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 1—1) to obtain 0.198 g of the expected product.

IR Spectrum: (CHCl 3 )

C═O

1630 cm −1 (amide III)

PREPARATION OF EXAMPLE 88

[(3-Bromopropyl)-Oxy]-N-Butyl-N-Methylacetamide

Using the procedure of Step B of the preparation of Example 83, 2.5 g of 3-[[(dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-propanol of Step A of Preparation 16, 775 mg of sodium hydride at 50% in oil and 3.42 g of bromo-N-butyl-N-methylacetamide were reacted to obtain 4.92 g of residue which was treated with 16.4 ml of a tetrabutyl ammonium fluoride solution. After chromatography, 1.61 g of the expected product were obtained.

Using the procedure of Step C of the Preparation of Example 83, 1.56 g of the product of Step A, 3.18 g of tetrabromo methane and 2.51 g of triphenyl phosphine were reacted to obtain after chromatography, 1.356 g of the expected product.

1.77 g of the product of Step A, 35 ml of methanol and 8.85 ml of 2 N hydrochloric acid were stirred for 75 minutes at ambient temperature, and the mixture was alkalized to a pH of about 9 with concentrated liquid ammonia, then evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate, washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. After chromatography on silica (eluant: methylene chloride-ethyl acetate 1—1), 1.08 g of the desired compound were obtained.

2-((8-(δ 1,3,5(10) 19-Nor-17β-Pregnatrien-3,17β-Diol-20yn-11β-yl)-Octyl)-Oxy)-N-Methyl-N-(1-Methyl Ethyl)-Acetamide

1.4 ml of bromo-N-methyl-N-(1-methyl ethyl)-acetamide of Preparation A above and 285 mg of sodium iodide, then 140 mg of sodium hydride at 50% in oil were added to a solution of 570 mg of the compound of the above preparation in 10 ml of tetrahydrofuran. The mixture was stirred for one hour, poured into a N hydrochloric acid solution at 0° C. and extracted with methylene chloride. Evaporation to dryness was carried out and the 2 g of residue were chromatographed on silica (eluant: ethyl acetate-ether 8-2) to obtain 350 mg of the desired product.

STEP B: 2-[[8-(δ 1,3,5(10) -estratrien-3-ol-17-one-11β-yl)-octyl]-oxy]-N-methyl-N-(1-methyl ethyl)-acetamide

10 ml of acetic anhydride and 5 ml of acetyl bromide were added at 0° C. to a solution of 9.4 g of the produce of Step A in 195 ml of methylene chloride under a nitrogen atmosphere and the mixture was stirred for 5 minutes at 0° C., then for 2 hours 30 minutes at ambient temperature. The mixture was cooled to 0° C. to +5° C. and water, then methanol were added slowly. The mixture was stirred for 5 minutes and 50 ml of 2 N sodium hydroxide were added. The organic phase was extracted again with methylene chloride and the extracts were dried and evaporated to dryness under reduced pressure. 10 g oxide acetylated residue were dissolved in 100 ml of methanol under a nitrogen atmosphere and 20 ml of 2 N sodium hydroxide were added. The mixture stood for one hour at ambient temperature and the acidification was carried out with 2 N hydrochloric acid. Extraction was done with methylene chloride and the extracts were washed, dried and evaporated to dryness under reduced pressure. The 9 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acette 3-7) to obtain 7.9 g of the expected product.

STEP D: 2-[[8-(δ 1,3,5(10) -19nor-17 β-pregnatrien-3,17β-diol-20-yn-11 β-yl)-octyl]]-oxy]-N-methyl-N-(1-methyl ethyl)-acetamide

A suspension of potassim acetylide was obtained by placing 3 ml of a 0.88 M of potassium terbutylate in tetrahydrofuran in a spherical flask under a nitrogen atmosphere to which 5 ml of tetrahydrofuran were added, then acetylene was bubbled through for 15 minutes. A solution of 520 mg of the product of Step C in 5 ml of tetrahydrofuran was added and after reaction for 30 minutes at ambient temperature, a saturated aqueous solution of ammonium chloride was added. Extraction was carried out with ethyl acetate and the extracts were washed, dried and evaporated to dryness under reduced pressure. The 550 mg of residue were chromatographed on silica (eluant: methanol-water 85-15) to obtain 470 mg of the expected product.

PREPARATION A OF EXAMPLE 92

2-[(4-Bromophenyl-Thio]-Tetrahydro-2H-Pyran

2.3 mg of p-toluene sulfonic acid were added to a solution of 1 g of 4-bromo thiophenol in 1 ml of 3,4-dihydro-[2H]-pyran and 1 ml of tetrahydrofuran and the mixture was stirred for 20 hours at ambient temperature. 0.1 ml of triethylamine were added and the mixture was poured into a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 1.603 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 97.5-2.5) to obtain 1.246 g of the expected product.

PREPARATION B OF EXAMPLE 92

11 β-[4-[(tetrahydro-2H-2-pyrannyl)-Thio]-Phenyl]-δ 4,9 -Estradien-3,17-Dione

a) Preparation of the Magnesium Compound

1.045 g of 2-[(4-bromo phenyl)-thio]-tetrahydro-2-pyran of Preparation A in solution in 2.5 ml of tetrahydrofuran were added over 15 minutes at 60° C. to 65° C. to a suspension of 139 mg of powdered magnesium in 0.65 ml of tetrahydrofuran placed under an argon atmosphere, and stirring was carried out for 30 minutes.

b) Condensation

The suspension was cooled to 0° C. to +5° C. and 29 mg of copper chloride and 1 ml of tetrahydrofuran were added. The mixture was stirred for 15 minutes at 0° C. and after cooling to −20° C., 650 mg of cyclic 3-(1,2-ethanediyl) acetal of 5 α,10β-epoxy-δ 9,11 -estra-dien-3,17-dione [obtained according to EP 0,057,115 (Ex 7) in 4 ml of tetrahydrofuran were added. The mixture was stirred for 30 minutes at −1.5° C., then for 30 minutes at 0° C. The mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extracts were dried and evaporated to dryness under reduced pressure to obtain 1.409 g of crude product.

c) Deketalization

6 ml of 2 N hydrochloric acid were added to a solution of 1.409 g of the product in 30 ml of methanol under an argon atmosphere and the mixture was stirred for one hour at ambient temperature and poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 1.27 g of residue were chromatographed on silica (eluant: ethyl acetate-cyclohexane 1—1) to obtain 647 mg of the expected product which was crystallized from a mixture of methylene chloride and isopropyl ether to obtain 596 mg of crystals.

N-Butyl-8-(4-(δ 1,3,5(10) -Estratrien-3,17β-Diol-11 β-yl)-Phenyl-Thio)-N-Methyl-Octanamide

a) Formation of the Silver Thiolate

4.5 ml of methanol, then 1 ml of a 1 M aqueous solution of silver nitrate were added to a solution of 368 mg of the product of Preparation B in 3.7 ml of chloroform at 40° C. and the mixture was stirred for 10 minutes at 40° C. The mixture was cooled to 0° C. to +5° C. and the precipitate was retained by decanting the supernatant.

b) S-elkylation

A solution of 353 mg of 8-bromo-N-butyl-N-methyl octanamide of the preparation of Example 79 in 7.4 ml of acetone, then 103 mg of potassium bicarbonate and 2.95 ml of hexamethyl phosphorotriamide were added to the precipitate dissolved in 3.7 ml of chloroform. The mixture was heated to 60° C. for 70 hours, cooled to ambient temperature and poured into a 1 M hydrochloric acid solution. After extraction with ethyl acetate and filtering, the organic phase was washed with a saturated solution of sodium chloride, dried, then evaporated to dryness under reduced pressure. 0.74 ml of 2 N sodium hydroxide solution were added to the 1.362 g of oily residue which had been put in solution with 3.7 ml of acetone. The mixture was heated to 60° C. for one hour, then poured into water, acidified with 2 N hydrochloric acid, extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. The 914 mg of residue were chromatographed on silica (eluant: ethyl acetate-methylene chloride 1—1) to obtain 332 mg of the expected product in the form of an oil.

Using the procedure of Step B of Example 84, 333 mg of the product of Step A, 0.34 ml of acetic anhydride and 0.17 ml of acetyl bromide were reacted and then extraction was carried out with ethyl acetate. The 335 mg of residue were treated with 27.5 mg of sodium borohydride, then 0.7 ml of 2 N sodium hydroxide. After extraction with ethyl acetate, the 303 mg of residue were chromatographed on Lichroprep Si 60 (eluant: acetone-methylene chloride 1-9) then on Lichrosorb RP 18 (eluant: methanol-water 9-1) to obtain 134 mg of the expected product with a specific rotation of [α] D =−49.5° (c=1.1% in CHCl 3 ).

PREPARATION OF EXAMPLE 93

3,17aβ-Bis-[(Tetrahydro-2H-2-Pyrannyl)-Oxy]-11β-(4-Ethynyl Phenyl)-D-Homo-δ 1,3,5(10) -Estratriene

STEP A: 5α, 10β-epoxy-17β-[(tetrahydro-2H-2-pyrannyl)-oxy]-D-homo-δ 9(11) -estren-3-one cyclic 1,2-ethanediyl acetal

0.6 ml of pyridine, then at 0° C. 1.7 ml of hexafluoroacetone and over 5 minutes 3.4 ml of 50% hydrogen peroxide were added to a solution of 6 g of 17β-[(tetrahydro-2H-2-pyrannyl)-oxy]-D-homo-δ 5(10),9(11) -estradien-3-one cyclic 1,2-ethanediyl acetal [obtained by French Patent No. 2,594,830 (Example 6—Step A)] in 60 ml of methylene chloride. The mixture was stirred for 6 hours 30 minutes at 0° C., poured into a saturated solution of sodium thiosulfate, and washed until the peroxide had gone. Extraction was carried out with methylene chloride and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 12 g of residue of 2 identical preparations were chromatographed on silica (eluant: cyclohexane-ethyl acetate 9-1 with 0.5% triethylamine) to obtain 7.1 g of the expected α-epoxide.

a) Condensation

Using the procedure of Step A of Preparation A of Example 78, 5.7 g of the epoxide dissolved in 46 ml of tetrahydrofuran, 232 mg of copper chloride and 60 ml of magnesium compound of Step A of Preparation A of Example 86 starting with 4-trimethyl-ethynyl-bromobenzene described in preparation 17, which was introduced slowly under a nitrogen atmosphere at −5° C./0° C. the residue was chromatographed on silica (eluant: cyclohexane-ethyl acetate 7-3 with 0.5% triethylamine) to obtain 6.3 g of product which was desilylated in solution in 100 ml of methanol and 20 ml of methylene chloride by the addition of 2.6 ml of 10 N sodium hydroxide. The 17- and 3-protected functions were liberated by the addition of 7.2 ml of concentrated hydrochloric acid at 0° C. to +5° C., then after dilution with ice, by adjusting the pH to 8-9 with concentrated liquid ammonia. Extraction was carried out with methylene chloride and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 4.3 g of residue were chromatographed on silica (eluant: methylene chloride-acetone 96-4) to obtain 3.36 g of the expected product.

0.09 ml of acetyl bromide, then 0.18 ml of acetic anhydride were added at 20° C./+5° C. to a solution of 200 mg of the product of Step B in 2 ml of methylene chloride and the mixture was stirred for 3 hours at ambient temperature, poured into 20 g of a (1—1) mixture of ice and saturated potassium bicarbonate solution and extracted with methylene chloride. The extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 230 mg of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 9-1) to obtain 147 mg of the expected product.

STEP D: 3,17aβ-bis-[(tetrahydro-2H-2-pyrannyl)-oxy]-11β-(4-ethynylphenyl)-D-homo-δ 1,3,5(10) -estratriene

2.395 g of the product of Step C in a 1 M solution of potassium hydroxide in methanol were stirred under an argon atmosphere and the mixture was heated to 35° C. for 30 minutes, then poured into ice-cooled water. The pH was adjusted to 7 with 2 N hydrochloric acid and extraction was carried out with methylene chloride. The extracts were washed with a saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The 2.14 g were chromatographed on silica (eluant: cyclohexane-ethyl acetate 6-4) to obtain 1.89 g of the intermediate deacylated product. 1.8 g of the product dissolved in 60 ml of ethyl ether were added to 3.2 ml of dihydropyran and 50 mg of p-toluene sulfonic acid and the mixture was stirred for 3 hours at ambient temperature. 30 ml of saturated sodium bicarbonate solution were added, followed by extraction with ethyl acetate. The extracts were washed, dried and evaporated to dryness under reduced pressure. The 2.7 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 9-1 with 0.5% triethylamine) to obtain 2.429 g of the expected product.

A. Activity on Hormonal Receptors

Mineralocorticoid Receptor of the Rats' Kidney:

Male Sprague-Dawley EOPS rats weighing 140 to 160 g were subjected to supraenalectomy 4 to 8 days earlier and were sacrificed and their kidneys were perfused in situ with 50 ml of a 10 mM Tris, 0.25 M saccharose, HCl buffer pH 7.4. The kidneys were then removed, decapsulated and homogenized at 0° C. with the aid of a Potter teflon-glass (1 g of tissue for 3 ml of buffer). The homogenate was centrifuged for 10 minutes at 800 mg and 0° C. and then to eliminate the fixation of the tritiated aldosterone upon the glucocorticoid receptor, 11β-,17β-dihydroxy-21-methyl-Δ 1,4,6 -pregnatrien-20-yn-3-one which was fixed uniquely upon the glucocorticoid receptor was added to the supernatant at a final concentration of 10 −6 M. This supernatant was ultracentrifuged at 105,000 g for 60 minutes at 0° C. and aliquots of the supernatant thus obtained were incubated at 0° C. with a constant concentration (T) of tritiated aldosterone in the presence of increasing concentrations (0-2500.0 −9 M) of the cold aldosterone or the cold product to be studied. After an incubation time (t), the concentration of bound tritiated aldosterone (B) was measured by the adsorption on dextran carbon technique.

Androgen Receptor of Rat's Prostate:

Male Sprague Dawley EPOS rats weighing 160 to 200 g were castrated and 24 hours after the castration, the animals were killed. Their prostates were removed, weighed and homogenized at 0° C. using a Potter teflon-glass in a TS buffered solution (Tris 10 mM, saccharose 0.25 M, HCl pH 7.4) (1 g of tissue for 5 ml of TS). The homogenate was ultracentrifuged (105,000 g for 60 minutes) at 0° C. and aliquots of the supernatant were incubated at 0° C. for an incubation time E with a constant concentration (T) of tritiated testosterone in the presence of increasing concentrations (0-1000.10 −9 M) either of cold testosterone or of the product to be tested. The concentration of bound tritiated testosterone (B) was then measured in each incubate by the adsorption on dextran carbon technique.

Progestogen Receptor of Rabbit's Uterus:

Impuberal rabbits weighing about 1 kg received a cutaneous application of 25 μg of estradiol and 5 days after this treatment, the animals were killed. The uteri were removed, weighed and homogenized at 0° C. using a Potter teflon-glass in a TS buffered solution (Tris 10 mM, Saccharose 0.25 M, HCl pH 7.4) (1 g of tissue for 50 ml of TS). The homogenate was then ultracentrifuged (150,000 g×90 minutes) at 0° C. and aliquots of the supernatant were incubated at 0° C. for a time t, with a constant concentration (T) of the tritiated product R (17,21-dimethyl-19-nor-Δ 4,9 -pregnadiene-3,20-dione in the presence of increasing concentrations (0-2500.10 −9 M) either of cold R or of cold progesterone, or of the cold product to be tested. The concentration (B) of bound tritiated R was subsequently measured in each incubate by the technique of adsorption on dextran charcoal.

Glucocorticoid Receptor of Rat Thymus:

Male Sprague Dawley EOPS rats weighing 160 to 200 g were subjected to suprarenalectomy and 4 to 8 days after this intervention, the animals were killed. The thymuses were removed and homogenized at 0° C. in a 10 mM Tris, 0.25 M saccharose, 2 mM dithiothreitol, HCL pH 7.4 buffer, with the aid of a Potter polytetrafluoroethylene-glass (1 g of tissue for 10 ml of TS). The homogenate was subsequently ultracentrifuged (105,000 g×90 min) at 0° C. and aliquots of the supernatant were incubated at 0° C. for a time (t) with a constant concentration (T) of tritiated dexamethasone in the presence of increasing concentrations (0-2,500.10 −9 M) either of cold dexamethasone, or of cold product to be tested. The concentration (B) of the bound tritiated dexamethasone was measured in each incubate by the adsorption technique on dextran carbon.

Estrogenic Receptor of Mouse Uterus:

Impuberal female mice aged from 18 to 21 days were killed and their uteri were removed, then homogenized at 0° C. with the aid of a Potter teflon-glass in a TS buffered solution (10 mM Tris, 0.25 M saccharose, HCL pH 7.4) (1 g of tissue for 25 ml of TS). The homogenate was ultracentrifuged (105,000 g×90 min) at 0° C. and aliquots of the supernatant were incubated at 0° C. or at 25° C. for a time (t) with a constant concentration (T) of tritiated estradiol in the presence of increasing concentrations (0-1000×10 −9 M) either of cold estradiol, or of the cold product to be tested. The concentration (B) of bound tritiated estradiol was measured in each incubate by the technique of adsorption on dextran carbon.

Calculation of the Relative Affinty of the Bond

The calculation of the Relative Affinity of the Bond (RAB) was identical for all the receptors. The following 2 curves were traced; the percentage of the bound tritiated hormone B T

was a function of the logarithm of the concentration of the cold reference hormone and B T

as a function of the logarithm of the concentration of the cold product tested.

One determined the straight line of the equation I 50 = ( B T     max + B T     min ) / 2. B T     max = percentage  of  the  bound  tritiated  hormone  for  an incubation  of  this  tritiated  hormone  at  the  concentration  (T), B T     min = percentage  of  the  bound  tritiated  hormone  for  an incubation  of  this  tritiated  hormone  at  the  concentration  (T) in  the  presence  of  a  great  express  of  cold  hormone ( 2500 × 10 - 9     M ) .

The intersections of the straight line I 50 and of the curves make it possible to evaluate the concentrations of the cold reference hormone (CH) and of the tested cold product (CX) which inhibit to an extend of 50% the binding of the tritiated hormone upon the receptor. The relative affinity of the bond (RAB) of the tested product is determined by the equation

RAB=100(CH)/(CX)

The results obtained are as follows:

Conclusion:

The products studied, particularly the products of Examples 8, 13, 16, 37, 46, 55, 71 and 92 had a marked affinity for the estrogen receptors at the second time. The product of Example 19 had a moderate affinity for the androgen receptor and the products of Examples 17 and 22 for the pregesterone receptor. Furthermore, the majority of the products are free of uterotrophic activity.

B. Anti-proliferative activity of the products of the invention upon the growth of MCF-7 mammary tumoral cells.

Description of the Test:

a) Cell Culture:

The MCF-7 strains were kept under culture in FCS(1) medium at 37° C. under a humid atmosphere containing 5% CO 2 and the cells at subconfluence were harvested by trypsination (0.05% trypsine, 0.02% EDTA), then rinsed by gentle centrifugation. A sample of the cells in suspension was counted on Malassez cell.

b) Growth Study:

The cells, resuspended in FCS medium, were seeded at a rate of 30,000 cells per pit in multi-pit plates (24 pits of 2.5 cm 2 ) and twenty four hours after seeding (DO), the product to be tested was added to the medium in ethanolic solution (final concentration in ethanol: 0.1%), at a concentration of 10 −12 to 10 −6 M, the control pits receiving the same concentration of ethanol. The media were renewed every 48 hours and at the end of the experiment (D6), the medium was sucked off and the cells were immediately fixed with 150 microliters of methanol to estimate the DNA. The anti-proliferative activity of the products was evaluated by their capacity to inhibit the increase of DNA.

c) Measurement of DNA:

The DNA was measured by a fluorimetric method employing DABA (3,5-diaminobenzoic acid) (2): 150 microliters of DABA were added to each of the pits and the plates were then incubated for 45 minutes at 56° C., then 2 ml of 1 N HCl were added. The fluorescence was measured with the aid of a fluorimeter (length of the exiting wave: 408 nm, length of the emitting wave: 501 nm). The quantity of DNA per pit was evaluated with reference to a standard scale obtained by treating a standard DNA from calf thymus under the same conditions.

Results

The concentration in nM which inhibited the growth of MCF 7 to an extent of 50% (IC 50 ) was determined in the manner indicated below:

Results:

Product of Example 8: IC 50 =0.04 nM

Product of Example 13: IC 50 =0.5 nM

Product of Example 16: IC 50 =0.02 nM

Product of Example 21: IC 50 =0.02 nM

Product of Example 24: IC 50 =0.06 nM

Product of Example 35: IC 50 =0.04 nM

Product of Example 37: IC 50 =0.03 nM

Product of Example 43: IC 50 =0.002 nM

Product of Example 46: IC 50 =0.006 nM

Product of Example 55: IC 50 =0.01 nM

Product of Example 71: IC 50 =0.1 nM

Product of Example 78: IC 50 =0.03 nM

Product of Example 79: IC 50 =0.035 nM

Product of Example 82: IC 50 =0.02 nM

Product of Example 83: IC 50 =0.007 nM

Product of Example 86: IC 50 =0.009 nM

Product of Example 92: IC 50 =0.015 nM

Furthermore, the maximum inhibitor effect of the products reached about 90%.

(1) The fetal calf serum (FCS) culture medium was prepared as follows: MEM medium (minimal essential medium) to which were added:

Non-essential amino acids (GIBCO),

Peni-strepto (100 U/ml penicillin, 0.1 mg/ml streptomycin),

Fungizone 0.1%

Insulin (50 ng/ml),

Fetal calf serum containing no steroids (10% final concentration).

(2) Puzas and Goodman, Analytical Biochemistry, Vol. 86, pp. 50, 1978.

Various modificatons of the products and method of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is intended to be limited only as defined in the appended claims.