PT76307B

New derivatives of 3-keto delta 4,9,19-nor steroids,their preparation,their application as medicaments,the compositions containing them and the new intermediates obtained

Abstract

This record has no abstract on file.

PT76307B, drawing sheet 1 — Sheet 1 of 73

Term

Term ended

Expired 28 February 1998, 28.6 years ago.

1 claim: 1 independent, 0 dependent

1
REIVINDICAÇÕES - 12 Processo para a preparação dos produtos da fórmula geral I na qual ou Rj representa um radical tienilo, eventualmente substituido, um radical furilo, uma radical cicloalquilo tendo de 3 a 6 átomos de carbono, um radical fenilo eventualmente substituido por um ou vários radicais escolhidos entre os radicais hidroxi, halogéneo, trifluormetilo, alquilo, alcoxi, alquiltio eventualmente oxidado sob a forma de sulfóxido ou de sulfona, alqueniloxi tendo no máximo 6 átomos de carbono e feniloxi, ou Rj representa um radical naftilo ou fenil-fenilo ou um radical alquilo, ou alquenilo suportando eventualmente várias insaturações e tendo no máximo 6 átomos de carbono; R 2 representa um radical metilo ou etilo, R 3 representa um átomo de hidrogénio, um radical alquilo, alquenilo ou alquinilo eventualmente substituido, um radical hidroxi, acetilo, hidroxiacetilo, carboxialcoxi tendo dé 2 a 4 átomos de carbono eventualmente esterificado ou salifiçado, hidroxialquilo eventualmente esterificado, R^ representa um átomo de hidrogénio, um radical hidroxi ou um radical alquilo, alquenilo ou alquinilo tendo no máximo 12 átomos de carbono eventualmente substituido por um radical amino, alquilamino, dialquilamino, ou por um halogéneo, um radical alquiltio, alcoxi, trialquilsililo ou ciano, Rg representa um átomo de hidrogénio ou um radical metilo na posição aou β, X representa um átomo de oxigénio ou um radical hidroxiimino ou alcoxiimino tendo de 1 a 4 átomos de carbono, na posição sin ou anti; A e B representam uma função oc-epoxi ou a presença duma segunda ligação entre os carbonos 9 e 10? bem como dos sais destes produtos com os ácidos quando R^ representa um radical compreendendo uma função amino? à excepção dos produtos nos quais A e B representam uma segunda ligação entre os carbonos que os suportam, X representa um átomo de oxigénio, R^ representa um átomo de hidrogénio e:a) R 2 representa um radical metilo e: cc) Rg representa um radical hidroxi e: i) R^ representa um radical etilo ou fenilo e R^ representa um átomo de hidrogénio, ou: ii) R 1 representa um radical etilo, propilo, isopropilo, vinilo, alilo, isopropenilo, fenilo, par afluorofenilo, metoxifenilo ou tienilo e R^ representa um radical etinilo, ou? iii) R 1 representa um radi cal propilo, isopropilo, vinilo, alilo, isopropéiilg p-metoxifenilo ou tienilo e R^ representa um radical metilo, β) Rg representa um radical acetilo e: i) R^ representa um radical etilo, vinilo ou fenilo e R^ representa um radical hidroxilo ou: X J.) R 1 Representa um radical vinilo e R^ representa um radical metilo, b) R 2 representa um radical etilo e R 1 representa um radical vinilo, Rg representa um radical hidroxi e R^ representa um átomo de hidrogénio, caracterizado por se submeter um produto com a fórmula geral (II) K OH na qual K representa um agrupamento cetónico bloqueado sob a forma de cetal, de tiocetal, de oxima ou de metiloxima, R‘g tem os valores de Rg anteriormente indicados e ainda mais o valor acetilo bloqueado, R'j tem o valor de Rj anteriormente indicado ainda mais com o valor fenilo substituido por um radical hidroxi protegido, tendo Rg, R^ e Rg os valores anteriormente indicados, à acção dum agente de desidratação susceptível de libertar a ou as funções protegidas, para obter um produto da fórmula 1^;correspondendo a um produto da fórmula I na qual X representa um átomo de oxigénio e A e B formam em conjunto urna segunda ligação entre os carbonos que os suportam, produto esse da fórmula que se desejado, se submete, por uma ordem qualquer a uma ou várias das reacções seguintes: a) oxidação de maneira a obter os produtos nos quais A e B . formam uma função epóxida e, quando Rj comporta um átomo de enxofre, oxidação em sulfoxido ou sulfona deste átomo;b) à acção da hidroxilamina ou dum derivado alquilado da hidroxilamina de maneira a obter os produtos nos quais X representa um radical hidroxiimino ou alcoxiimino;c) hidrolisar e salificar eventualmente os produtos nos quais Rg representa um radical carboxi-alcoxi esterificado d) salificação dos produtos nos quais R^ representa um radical alquilo, alquenilo ou alquinilo substituido por um radical amino, alquilamino ou dialquilamino. - 2§ Processo de acordo com a reivindicação 1, caracterizado por se utilizarem produtos da fórmula (ll) nos quais R' 3 representa um radical hidroxi, R^ representa propinilo, R 2 representa um radical metilo e R^ representa um átomo de hidrogénio. _ 3â _ Processo de acordo com a reivindicação 1, caracterizado por se utilizarem pradutos âa fórmula (II) na qual R' 3 representa um radical acetilo, representa um radical metilo ou um átomo de hidrogénio e R 1 ^ representa um radical fenilo eventualmente substituido. „ 4â _ Processo de acordo com a reivindicação 1, caracterizado por se utilizarem produtos da fórmula (II) na qual R'^ representa ciclopropilo, um agrupamento fenilo eventualmente substituido por um dos radicais escolhidos no grupo formado pelos radicais cloro, fluor, metiltio, metilsulfonilo, metoxi, hidroxi e aliloxi, ou um agrupamento clorotienilo e R^ representa um radical propinilo. - 5â Processo de acordo com a reivindicação 1, caracterizado por se utilizarem produtos da fórmula . (II) escolhidos de tal maneira que se obtenham qualquer um dos produtos da fórmula (I) tal como definida na reivindicação 1 seguintes: lip-/(4-cloro)-fenil/-17j3-b.idroxi-17 %- (prop-l-inil)-estra-4,9-dien-3-ona;llj3-/(5-cloro)-tienil/-17(3-hidroxi-17a- (prop-l-inil)-estra· -4,9-dien-3-ona;- lip-/(3-cloro)-fenil/-17{3-hidroxi-17a- (prop-l-inil)-estra-4,9-dien-3-ona;- ll£-/(4-metiltio)-fenil/-17p-hidroxi-17cc- (prop-l-inil)-estra-4,9-dien-3-ona;llp-/(3-fluoro)-fenil/-17p-hidroxi-17a- (prop-l-inil)-estra -4,9-dien-3-ona? 11β-/(4-metiltio)-fenil/-17a-metil-19-nor-pregna-4,9-dieno-3,20-diona;llj3-/(4-metiltio)-fenil/-16a-metil-19-nor-pregna-4, 9-dieno-3,20-diona;lip-ciclopropil-17p-hidroxi-17a-(prop-l-inil)-estra-4,9-dien-3-ona? 11β-/3- (2-propeniloxi)-fenil/-17 ( S-hidroxi-17a- (prop-1-inil)-estra-4,9-dien-3-ona;9a, 10a-epoxi-17p-bidroxi-lip~ (4-metoxifenil)-17a- (prop-1-inil)-estr-4-en-3-ona;9a, 10a-epoxi-17$-hidroxi-ll(3-/(4—metil-sulfonil)-fenil/-17a-(prop-l-inil)-estr-4-en-3-ona? 11β-/ (3-fluoro)-fenil/-3-hidroxiimino-17a-(prop-l-inil)-estra-4,9-dien-17p-ol isómero anti;- 17}3-hidroxi-17a- (prop-l-inil)-11β- (4-hidroxifenil)-estra-4,9- dien-3-ona. - 6ã _ P r ocesso de acordo com a reivindicação 1, caracterizado por se utilizar o produto da fórmula (II) escolhido de maneira tal que se obtenha a 11β-/(4-metiltio)-ΐθηϋ/-17β-ΗΐάΓθχϊ-17α- (prop-l-inil)-estra-4,9-dien-3-ona. - 7s P r ocesso para a preparação de composições farmacêuticas, caracterizado por incorporar como principio activo pelo menos um dos produtos da fórmula geral (II) quando preparados de acordo com as reivindicações anteriores, ou pelo menos um dos seus sais de adição com os ácidos farmaceuticamente aceitáveis em combinação com veículos ou substâncias de suporte. - 8® Processo para a preparação de composições farmacêuticas, caracterizado por se incorporar como prin cipio activo pelo menos um dos produtos da fórmula geral (l), quando preparados de acordo com as reivindicações 7 ou 8, em combinação com veículos ou substâncias de suporte. A requerente declara que o primeiro pedido desta patente foi depositado na França em, 1 de Março

1,059 paragraphs in 38 sections, as filed

The present invention is directed to a process for preparing the products of general formula (I):

GSP wherein R1 represents an optionally substituted thienyl radical, a furyl radical, a cycloalkyl radical having from 3 to 6 carbon atoms, a phenyl radical optionally substituted by one or more radicals selected from hydroxy, halogen, trifluaomethyl, alkyl radicals alkoxy, alkylthio optionally oxidized under j. sulfoxide or sulfone, alkenyloxy having a maximum of 6 carbon atoms and phenyloxy.

or represents a naphthyl or phenylphenyl radical or an alkyl or alkenyl radical optionally bearing various unsaturation and having a maximum of 6 carbon atoms;

R2 represents a methyl or ethyl radical;

R g represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical, a hydroxy, acetyl, hydroxyacetyl, carboxyalkoxy radical having from 2 to 4 carbon atoms which may be esterified or salified, optionally esterified hydroxyalkyl;

R4 represents a hydrogen atom, a hydroxy radical or an alkyl, alkenyl or alkynyl radical having a maximum of 12 carbon atoms optionally substituted by an amino, alkylamino, dialkylamino radical or by a halogen, alkylthio, alkoxy, trialkylsilyl or cyano radical;

R 4 represents a hydrogen atom or a methyl radical at the α or β position;

X represents an oxygen atom or a hydroxyimino or alkoxyimino radical having from 1 to 4 carbon atoms, in the sin or anti position;

A and B represent an epoxy function or the presence of a second bond between carbons 9 and 10;

as well as the salts of these products with acids when R2 represents a radical comprising an amino function; With the exception of products in which A and B represent a second bond between the carbons supporting them, X represents an oxygen atom, Rg represents a hydrogen atom and a) R2 represents a methyl radical and;

a) Rg represents a hydroxy radical and:

i) R4 represents an ethyl or phenyl radical and

R4 R 2 represents an ethyl, propyl, isopropyl, vinyl, allyl, isopropenyl, phenyl, parafluorophenyl, methoxyphenyl or thienyl radical and R 2 represents an ethynyl radical, or;

iii) Rj. R1 represents a propyl, isopropyl, vinyl, allyl, isopropenyl, p-methoxyphenyl or thienyl radical and R3 represents a methyl radical;

β) Rg represents an acetyl radical and;

O

i) Rj. represents an ethyl, vinyl or phenyl radical and R3 represents a hydroxyl radical or ii) R3 represents a vinyl radical and R34 represents a methyl radical?

b) R2 represents an ethyl radical and:

Rj. represents a vinyl radical, R2 represents a hydroxy radical and R24 represents a hydrogen atom.

Among the thienyl radical substituents may be mentioned halogen radicals such as fluorine, chlorine, bromine, alkyl radicals such as methyl, ethyl, haloalkyl radicals such as trifluoromethyl. Cycloalkyl radicals may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals. Possible substituents on the phenyl radical which may represent R ^ include alkyl radicals such as methyl, ethyl, propyl isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl. The alkoxy and alkylthio radicals are derived from the aforementioned alkyl radicals. Alkoxy and alkylthio radicals are preferred.

The vinyloxy alkenyloxy radicals are preferably allyloxy.

Among the alkyl radicals which may represent R1 may be mentioned the above alkyl radicals.

Alkenyl radicals include vinyl and allyl radicals. POAlso mentioned are radicals comprising various unsaturation such as the propa-1,2-dienyl radical.

Enter the values of R2 methyl is preferred.

Among the values other than those mentioned above, tert-butoxycarbonylmethoxy, carboxymethoxy optionally salified for example as alkali or alkaline earth metal, ammonium magnesium or organic base radicals are preferred.

POmention may be made, for example, of sodium, potassium, lithium, calcium, magnesium or ammonium salts. Among the organic bases are methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, Ν-dimethylethanolamine, tris- (hydroxymethyl) amino-methane, · ethanolamine, pyridine, picoline. dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

Sodium salt is preferred.

Quand is substituted, R 6 may be substituted by the alkylamino or dialkylamino radical, halogen, alkylthio, alkoxy or trialkylsilyl.

Among the values of R3, particularly mention can be made of methyl, ethyl, ethynyl, prop-1-ynyl. Also mentioned are 3-dimethylamino-prop-1-ynyl or 3-amino-prop-1-ynyl.

ANDnoBetween Rg and R4, radicals having a maximum of 4 carbon atoms, especially ethynyl or propynyl, are preferred.

ANDnoAmong the alkyloximes which X may represent, the methyloxime value is preferred.

As acid addition salts are salts formed with hydrochloric, acetic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, phosphoric, sulfuric, hydrobromic acids.

The present invention is directed in particular to a process for preparing the products of formula (I) as defined above wherein the radical R3 represents the cycloalkyl radical having from 3 to 6 carbon atoms or a substituted thienyl radical, or X represents a hydroxyimino or alkoxyimino radical having from 1 to 4 carbon atoms in the sin or anti position, with letters A and B representing an α epoxy function, or R3 representing a methyl radical.

More particularly, the present invention is directed to a process for preparing the products of formula (I) as defined above, wherein Rg represents a hydroxy radical, represents a propynyl radical,

Rg represents a methyl radical and Rg represents a hydrogen atom and those wherein Rg represents an acetyl radical R4 represents a methyl radical or a hydrogen atom and R1 represents an optionally substituted phenyl radical.

Preferred products obtained according to the present invention include those in which the radical R 1 represents a cyclopropyl, a phenyl group optionally substituted by one of the radicals selected from the group consisting of chloro, fluor, methylthio, methylsulfonyl, methoxy radicals. hydroxy and allyloxy or a chlorothienyl group and R4 represents a propyryl radical.

• A preferred product class is also comprised of the products of formula (i) wherein the letters A and B represent an epoxy group.

Of course, the products described below in the examples are particularly preferred products. This is particularly true of the following products;

11β- / (4-chloro) phenyl / 17β-hydroxy-17α (prop-1-ynyl) -estra-4,9-dien-3-one;

lip - [(5-chloro) thienyl] -17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one;

- H3 / (3-chloro) phenyl / 17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one;

11 '- ((4-methylthio) phenyl / 17-hydroxy-17a) prop-1-ynyl) -estra-4,9-dien-3-one;

- lip / (3-fluoro) phenyl (17 p-hydroxy-17α-) prop-1-ynyl) -estra-4,9-dien-3-one;

11β - / (4-methylthio) phenyl / 17α-methyl-19-nor-pregna-4,9-dien-3,20-dione;

lip - [(4-methylthio) phenyl] -16α-methyl-19-nor-pregna-4,9-dien -3,20-dione;

- 5> 4iB, $ 0 Cte |

13-cyclopropyl-17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one;

- 11β- / 3- (2-propenyloxy) phenyl / 17β-hydroxy-17α- (prop-linyl) -estra-4,9-dien-3-one;

9a, 10a-epoxy-17β-hydroxy-11)Q- (4-methoxyphenyl) -17a- (prop-1-ynyl) -estra-4-en-3-one;

- 9a, 10a-epoxy-17β-hydroxy-11β- (4-methylsulfonyl) phenyl / 17α- (prop-1-ynyl) -estra-4-en-3-one?

- ll<S-//(3-fluoro) phenyl / -3-hydroxyimino-17α- (prop-1-ynyl) -estr-4,9-dien-17β-ol, anti isomer;

17β-hydroxy-17α- (prop-1-ynyl) -11β- (4-hydroxyphenyl) estra-4,9-dien-3-one;

especially for:

- ll;S - / (4-methylthio) phenyl / 17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one;

The process according to the present invention is characterized by submitting a product of the general formula (II):

OH in which K represents a blocked ketone group in the form of ketal, thiocetal, oxime or methyloxime,

Rg1 has the Rg values given above, in addition to the blocked acetyl value, R31 has the value of R4 given above, in addition the phenyl value substituted by a protected hydroxy radical, Rg, R4 and Rg having the values given above to the action of a dehydrating agent capable of releasing the protected function or functions to get a product of formula I

corresponding to a product of formula I wherein X represents an oxygen atom and A and B together form a second bond between the carbons that support them, which product of formula 14, which, if desired, undergoes, in any order , to one or more of the following reactions:

a) oxidation to obtain the products in which A and B form an epoxide function and, when R3 comprises a sulfur atom, sulfoxide or sulfone oxidation of this atom;

b) action of hydroxylamine or an alkylated hydroxylamine derivative to obtain products in which X represents a hydroxyimino or alkoxyimino radical;

c) possible hydrolysis and salification of the products wherein R3 represents an esterified carboxyalkoxy radical;

d) salifying those products in which R3 represents an alkyl, alkenyl or alkynyl radical substituted by an amino, alkylamino or dialkylamino radical.

In a preferred embodiment of the process, the dehydrating agent capable of releasing the protected function (s) which is ketone or hydroxy functions is a sulfonic resin (acid form), for example a polystyrene-supported or commercially-supported sulfonic resin. styrene / divinylbenzene polymer, but a mineral acid such as hydrochloric acid or sulfuric acid in a lower alkanol or perchloric acid in the acetic acid may also be used, or a sulfonic acid such as paratoluenesulfonic acid.

The oxidizing agent is preferably a peracid such as methachloroperbenzoic acid, peracetic acid or perphthalic acid. Hydrogen peroxide may also be used alone or in the presence of hexachlor or hexafluoroacetone.

Of course, depending on the number of functions that can be oxidized, one or more equivalents of oxidizing agent may be used.

Thus for example if the sulfur atom comprising R o in sulfone is to be oxidized and the double bond in epoxide it is well understood to use at least 3 equivalents of oxidizing agent.

The action of hydroxylamine or an alkylated hydroxylamine derivative, preferably methylhydroxylamine, is preferably effected in an alcohol such as ethanol. Preferably a salt, in particular a hydrochloride, is also used.

Possible hydrolysis and salification of the products in which Rg comprises an esterified carboxy alkoxy radical is carried out under usual conditions.

Hydrolysis may be carried out at reflux of an organic solvent such as benzene in the presence of an acid such as paratoluenesulfonic acid.

Basic hydrolysis may also be used in the presence of a base followed by acidification.

Salification is carried out under the usual conditions. It can be operated for example in the presence of ethanolic soda. A sodium salt such as sodium or potassium carbonate or bicarbonate may also be used.

Also salification by an acid is carried out under the usual conditions. It preferably operates with hydrochloric acid, for example in ethereal solution.

NuIn a preferred embodiment, the above process is carried out using products of formula (II) wherein R1 'represents a hydroxy radical, R1'.4 represents a propynyl radical, R2 R3 represents a methyl radical and R4 represents a hydrogen atom or those wherein R4 'represents an acetyl radical, R44 represents a methyl radical or a hydrogen atom and R41 represents an optionally substituted phenyl radical, finally those in which the radical R41 represents a cyclopropyl, a phenyl group optionally substituted by one of the radicals selected from the group consisting of chlorine, fluorine, methylthio, methylsulfonyl, methoxy, hydroxy and allyloxy group, or a chlorine thienyl group and R4 represents a propynyl radical.

The products of formula (1) as well as their pharmaceutically acceptable acid addition salts are particularly pharmaceutically interesting products. They have in particular remarkable antiglucocorticoid activity.

The study of the products on the hormonal receptors allowed by one to show the progestominética or antiprogestominética activities, androgens or antiandrogenas.

The products of formula (1) as well as their pharmaceutically acceptable acid addition salts can therefore be used as medicines to combat mainly the side effects of glutocurticoids, and also to combat the disturbances due to glucocurticoid hypersecretion and in particular against aging in general and more particularly against hypertension, atherosclerosis, osteoporosis, diabetes, obesity as well as immunosuppression and insomnia.

The products of formula (I) as well as their addition salts with pharmaceutically acceptable acids having anti-progestometric properties may be used as contraceptives; may be used against hormonal disorders; they may furthermore be of interest for the treatment of hormone-dependent cancers.

IWI1' 1

Certain products of formula (I) as well as their pharmaceutically acceptable acid addition salts may also have prosgestomimetic properties and thus may be employed in the treatment of amenorrhoea, dysmenorrhoea and luteal insufficiency.

The products of formula (1) as well as their pharmaceutically acceptable acid addition salts having anti-androgenic properties may be used for the treatment of prostate hypertrophy and cancer, hyperandrogenia, anemia, hirsutism and acne. .

Among the medicaments according to the present invention may be cited in particular the following products:

11β - / (4-chloro) phenyl / 17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one;

lip - / (5-chloro) thienyl / 17β-hydroxy-17α- (prop-1-ynyl) -estra -4,9-dien-3-one?

lip - / (3-chloro) phenyl / 17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one;

11β- / (4-methylthio) phenyl / 17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one;

11β- / (3-fluoro) phenyl / 17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one, · lip- / (4-methylthio) phenyl / -17α-methyl-19-nor-pregna-4,9-diene-3,20-dione;

- lip - / (4-methylthio) phenyl / -16α-methyl-19-nor-pregna-4,9-diene-3,20-dione, 'lip-cyclopropyl-17β-hydroxy-17α- (prop-1 -inyl) -estra-4,9-dien-3-one;

- 11β- / 3- (2-propenyloxy) phenyl / 17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one

- 9a, 10a-hepoxy-17β-hydroxy-lip- (4-methoxyphenyl) -17a- (prop-1-ynyl) -estr-4-en-3-one;

- 9a, 10a-hepoxy-17β-hydroxy-lip - [(4-methylsulfonyl) phenyl] -17a- (prop-1-ynyl) estr-4-en-3-one;

- 11β - / (3-fluoro) phenyl / -3-hydroxyimino-17α- (prop-1-ynyl) -estra-4,9-diene-17oc-ol, anti-isomer

17β-hydroxy-17α- (prop-1-ynyl) -1β- (4-hydroxyphenyl) -estra-4,9-diene-3-one;

and more especially the

lip - [(4-methylthio) phenyl] -17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one.

Useful dosage varies in fennel of disease to be treated and route of administration; it may vary for example from 10 mg to 1 g per day in the adult orally.

Novel products of formula (I) and their salts as defined above may be employed to prepare pharmaceutical compositions containing as an active ingredient at least one of said products.

The products of formula (I) and their salts are used digestively, parenterally or locally. POthey may be prescribed in the form of single or drageed tablets, gelules, granules, suppositories, injectable preparations, ointments, creams, gel which are prepared by the usual methods.

or the active ingredients may be incorporated with excipients commonly employed in such pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or plant origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

The process according to the present invention makes it possible to prepare new intermediate products, ie products of the general formula (ϋ&) :

OH in which R '' represents or an optionally substituted thienyl radical, a furyl radical, a cycloalkyl radical containing from 3 to 6 carbon atoms, a phenyl radical optionally substituted by one or more radicals selected from the optionally protected hydroxy radicals; trifluoromethyl, alkyl, alkoxy, alkylthio optionally oxidized to sulfoxide or sulfone, alkenyloxy, having a maximum of 6 carbon atoms and phenyloxy, or R 'represents a naphthyl or phenyl-phenyl radical or an alkyl or alkenyl radical optionally bearing various unsaturation and having a maximum of 6 carbon atoms,

Rg represents a methyl or ethyl radical and or R3 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical, a hydroxy, acetyl radical optionally protected as ketal, hydroxyacetyl, carboxyalkoxy having 2 to 4 esterified carbon atoms or acyloxyalkyl and R '4 represents a hydrogen atom, a hydroxy radical or an alkyl, alkenyl or alkynyl radical having a maximum of 12 carbon atoms, optionally substituted by an aminoalkylamino or dialkylamino or dialkylamino radical, with a halogen, alkylthio, alkoxy trialkylsilyl or cyano radical ?

or R3 represents a cyano radical and R 'is an OH group blocked as an easily cleavable ether?

R4 represents a hydrogen atom or a methyl radical at the position or?

K represents a blocked ketone group in the form of thiocetal, oxime or methyl oxime ketal, except for products in which K represents a (1,2-ethanediyl) acetal radical, Rg represents a hydrogen atom and 1 1 * <4.11 1

a) Rg represents a methyl radical and

y) R3 R 1 represents a trimethylsilyloxy radical and R 4 represents a phenyl, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, allyl, isopropenyl, o- or p-methoxyphenyl, thienyl, methoxyvinyl or p radical -fluoro-phenyl?

β) R3 represents a hydroxy radical, R '4 R1 represents an ethyl, propyl, isopropyl, vinyl, isoprppenyl, allyl, or - or p-methoxyphenyl or thienyl radical;

R3 represents an acetyl radical and s

i) R 2 represents a hydroxy radical and R 2 represents an ethyl, phenyl or vinyl radical or:

ii) R1R4 represents a methyl radical and R4 represents a vinyl radical;

b) Rg represents an ethyl radical and:

R3 R4 represents a hydroxy radical, R2 represents a vinyl radical and R2 represents a hydrogen atom.

Among these products, thienyl radical substituents may be as described above. Equally cycloalkyl radicals and R values1Identical to those of R hidro hydroxy radical may be protected by a classical protecting radical in organic chemistry. For example, acyl radicals such as acetyl, chloroacetyl, trifluoroacetyl, phenoxyacetyl may be mentioned.

Also mentioned are radicals such as tetrahydropyranyl, trityl, benzyl, benzhydryl or trimethylsilyl radicals.

acyloxyalkyl radical which may represent R3 is preferably 1-acetoxyethyl radical.

easily cleavable ether which may represent R '4 is preferably trimethylsilyl.

Ketone grouping is preferably blocked as ethanediyl.

These products of formula (II) are pred.

those wherein R 'represents a hydroxyl radical, represents a propynyl radical, Rg represents a hydrogen atom and R2 represents a methyl radical.

With regard to the value of R 1, the cycloalkyl values, especially cyclopentyl, are preferred, the phenyl optionally substituted by one of the radicals selected from the group consisting of chloro, fluoro, methylthio, methylsulfonyl, hydroxymethyl and aryloxy radicals. and finally the chlorothienyl value.

The products of formula 11 may be prepared by action under the product of formula III:

where K, R2, R4, R '4 and Rg have the above meaning of a product of the formula:

(laughs)2 Culi or R4 Mg Hal or R4 Li having R4 as above and Hal represents a halogen atom, where appropriate in the presence of a catalytic amount of porous halide, to obtain a product of formula II, which product if desired, subject in any order to any of the following reactions: a) action of a lithium ethylene diamine acetylide complex on a product in which R3 represents a cyan radical and R *4 an easily blocked cleavable OH grouping to obtain a product of the formula& where R2 represents a hydroxyl radical and R1R4 represents an ethynyl radical;

or b) action of a methyl magnesium halide on the same product in which Rg represents a cyano radical and R *4 represents an OH-blocked grouping as an easily cleavable ether to obtain a product in which R3 represents an acetyl radical and R '4 represents a hydroxyl radical;

c) deprotection of protected hydroxyl or acetyl groups.

When the compound of the formula is used, it is preferably operated at a temperature of from -100 ° C to 0 ° C.

When using the compound of the formula R 1, Mg Hal, preferably represents a bromine or chlorine atom and operates in the presence of a catalytic amount of chloride or coprous bromide preferably at a temperature of -40 ° C. C and 0 ° C.

When a compound of the formula is used in the presence of a catalytic amount of chloride or coprous bromide; at a temperature of from -40 ° C to 0 ° C.

coprous halide is optionally supplied as a complex with a dialkyl sulfide.

In all cases, it is preferably operated in an organic solvent or a mixture of solvents such as ethyl ether, isopropyl ether or tetrahydrofuran. In a particular embodiment of the process according to the present invention when R1R @ 4 represents a different radical from the allyl radical, is used to introduce the substituent 11β, the compound of the formula R @ 1 MgBr in the presence of a catalytic amount of co-chloride operating at a temperature of from -40 ° C to -20 ° C in ethyl ether and / or tetrahydrofuran, when R 'represents an allyl radical, it is used to introduce the substituent 11.!β is the compound of the formula operating at a temperature of from -90 ° C to -10 ° C.

The products of formula II in which R3 represents a hydroxyl radical and R '4 represents a radical

alkyl, alkenyl or alkynyl having a maximum of 12 carbon atoms may also be obtained by the action of an alkyl, alkenyl or alkynyl magnesium halide on a product of formula IV;

where K, R1^, R2 and R2 has the above meanings. The products of formula IV may be prepared by the action of a product of formula (R).2CuLi, R4 MgHal or R4 Li under the conditions given above for a product of formula V:

The products of Formulas III or V are, for many of them known in the literature or can easily be prepared from literature products.

These products are generally prepared by the action of an oxidant such as hydrogen peroxide in the presence of a catalyst or an organic peracid on a product of the formula:

wherein R 1 and R 4 have the values given above for R 6 and R 6 or R 8 or R 4 together form a keto radical.

Examples of preparation of starting products III or V will be found in the following experimental part.

In addition to the following Examples illustrating the present invention without limitation, the following products are products which may be obtained within the scope of the present invention.

CH.

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C-CIL · -CHO

Z 3 3 O

C-CH- -CH „z 3 3

OH -CH2- <> CH

-CH2-CH = CH2

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OH -CH2-CH = CH2

-ch2- <> ch

-CH2-CH3 -CH CN //

-CH,

Preparation 1; 3,3-ethylene-bis (oxy) -17g- (prop-1-yl) -D-β (21thienyl) es.tr-9-en-5g, 17β- <3ίο1

Ino0.82 g of co-chloride in 162 cm3 of thienyl magnesium bromide in tetrahydrofuran (1.05 M / l) is added at -25 ° C under nitrogen.

Stir for 15 minutes and introduce dropwise so that the temperature does not rise above -20 ° C a solution of 15 g of 3,3-ethylene-bis- (oxy) -5a, 10a epoxy-17a- (prop-1-ynyl) -estr-9- (11) -en-17p-ol at 80 cm

- tetrahydrofuran. Leave under nitrogen, stir at -25 ° C for

1 hour later 2 hours at 0 ° C. Then pour into an ice cold aqueous ammonium chloride solution. Stir, extract with ether, wash the organic phase with water, dry and concentrate under reduced pressure to give 18.8 g of crude product. It is pubicated by chromatography on silica / eluent: chloroform-ethyl acetate (9-1) / and 9.85 g of product Έ = 250 ° C.

Starting Product Preparation

3,3-ethylene-bis- (oxy) -5a, 10a-epoxy-17α- (prop-1-ynyl) -estr-9- (11) -en-17β-ol used from preparation 1 was prepared as follows:

a) 3,3-Bis-methoxy-17a- (prop-1-ynyl) -estra-5- (10) -9- (11) -dien-17β-ol

a) propine magnesium bromide:

Ino35 ° C of a solution of ethyl magnesium bromide in tetrahydrofuran (1.1 M / l) is added under nitrogen. Cool to 0 ° C and bubble the brine for 2 hours while maintaining the temperature at +10 ° C by an ice bath.

The temperature is allowed to rise to 20 ° C by continuing the bubbling of brine, β) Condensation:

To the above solution, a solution of 50 g of 3,3-bis-methoxy-stri-5- (10) -9- (11) -dien-17-one in 40 cm3 of 50 g of the above solution is introduced at 50 ° C for 50 minutes. tetrahydrofuran and two drops of triethylamine, stir for 75 minutes then pour into a cold aqueous ammonium chloride solution.

Stir for 15 minutes then extract with ether and wash with saturated sodium bicarbonate solution in water containing two drops of pyridine. Dry, concentrate under reduced pressure and give 62.4 g of crude product, 974 mg of this product is chromatographed on silica / eluent: ethyl ether-petroleum ether (Eb.60 ° - 80 ° C) 3 -144, yielding 744 mg of purified product which is recrystallized in a mixture containing 5.5 cm3 of isopropyl ether, 0.4 cm3 of methylene chloride-traces of pyridine. Filter, concentrate, bake crystallization, run, wash with isopropyl ether, dry and give 444 mg of pure product F = 138 °.ç.

b) 3,3-ethylene-bis-oxy-17a- (prop-1-ynyl) -estra-5- (10) -9- (11) -dien-17B-ol

88.5 g of the product obtained above in a) are introduced under nitrogen into 442.5 cm3 of glycol. Heat to 60 ° C under stirring and nitrogen and 4.425 g of pyridine hydrochloride are introduced. Stir for 15 minutes at 60 ° C then cool to 20 ° C, while cooling (at 40 ° C) add 17.7 cm @ 3 of triethylamine. The suspension at 20 ° C is poured into 3 l of ice water.

Guburn 1 hour at 0 ° C then drain, wash with water, dry and give 75.4 g of product F = 135-140 ° C.

c) 3,3-ethylene-bis- (oxy) -5α, 10K-epoxy-17α- (prpp-1-ynyl-estr · -9- (11) -en-176-ol

30 g of the product obtained above in b) is cooled to 0 ° C in 150 cm @ 3 of methylene chloride containing 2 drops of pyridine, then 1.8 cm @ 3 of hexafluoro acetone sesquidrate is added, then added dropwise. 4.35 cm @ 3 of 85% hydrogen peroxide is stirred, stirred at 0 ° C for 72 hours then a mixture of 250 g of ice is poured into 500 cm @ 3 of 0.2 N sodium thiosulphonate. with methylene chloride. The organic phase is washed, dried, concentrated under reduced pressure and 31.6 g of the expected product are obtained.

Preparation 2; 3,3-ethylene-bis- (oxy) -1H- (o-fluorophenyl) -17 k- (prop-1-ynyl) -estr-9-ene-5α-17β-diol

Under the same conditions as in preparation 1, p-fluorophenyl magnesium bromide on the same product is 3,3-ethylene-bis- (oxy) -5x, 10a-epoxy-17a ·

- (prop-1-ynyl) -estra-9- (11) -εη-17β-ο1 in the presence of coprous chloride in tetrahydrofuran.

Chromatography gives the desired product / α /D = - 57.5 ° to 1.5 ° (c = 1% CHCl 3)

Preparation 3: 3,3-Ethylene-bis- (oxy) -1H- (p-trifluoromethylphenyl) -17a- (prop-1-vinyl) -estr-9-ene-5g, 17B-diol:

It operates as in preparations 1 and 2 using p-trifluoromethyl phenyl magnesium bromide on the same product.

The desired product is obtained / α /Q = -56 ° to 2.5 ° (c = 0.4% CHCl 3).

P-repair 4: 3,3-bis-methoxy-11S-methyl-17α- (prop-1-ynyl) -estr-9-ene-5oc, 176-diol:

A mixture of 11.4 g of coprous iodide in 120 cm @ 3 of ether is cooled under nitrogen at 0 ° C and 69 cm @ 3 of 1.74 M methyl lithium in ether is added over 30 minutes. Stir further 10 minutes at 0Â ° C then 5.5 g of 3,3-bis-methoxy-5a, 10a-epoxy-17β- (prop-1-ynyl) - estra-9- (ql) -en-17β-ol in 50 cm @ 3 of tetrahydrofuran. Allow two hours to stir at 0 ° C then pour into a cold aqueous ammonium chloride solution. Stir for 1 hour at room temperature. Extract with ether, wash, dry, concentrate dry under reduced pressure and give 5.7 g of crude product.

6.8 g of the product obtained are chromatographed as indicated above on silica / eluent methylene chloride acetone (9-1) and / / triethylamine /. 4.05 g of expected product is obtained F = 155 ° C. [α] D = 80 ° -2 ° (c = 1% CHCl 3).

Starting Product Preparation

3,3-bis-methoxy-5a, 10a-epoxy-17a- (prop-1-ynyl) -estr-9-) 11) -en-17β-ol used at the outset to

Preparation 4 was prepared as follows:

Ino62.4 g of 3,3-bis-methoxy-17α- (prop-1-ynyl) -estra-5- (lo) -S- (11) -diene-17α-ol prepared under nitrogen preparation 1 in 280 cm @ 3 of methylene chloride. Cool to 0 ° C with stirring and add once

8.5 cm @ 3 of hexafluoroacetone followed by dropwise 10.1 cm @ 3 of 85% hydrogen peroxide. After stirring for 41 hours at 0 ° C, pour into a mixture of 1.41 of 0.5 M / l sodium bisulfite solution, 200 g of ice and 5 drops of pyridine. Stir 5 minutes then extract with methylene chloride containing 2 'drops of pyridine. Wash the organic phase with water containing traces of pyridine, dry concentrate under reduced pressure and give 63.8 g of the desired product.

Preparation 5; 3,3-bis-methoxy-116- (propa-1,2-dienyl) -17q- (prop-1-ynyl) -estr-9-ene-5a, 17g, -diol:

a) Alenyl lithium (GHg = G = CHLi)

300 cm @ 3 of dry tetrahydrofuran is cooled to 0 ° C and allene gas is bubbled to about 18 to 20 g. It is then cooled to -70 ° C and 180 cm @ 3 of n-butyllithium in 1.35 N n-hexane is added dropwise over 30 minutes. 1 hour is stirred at -70 ° C.

β) Dialenyl cuprolitian / tCHg = G = CtL, CuLi /

To the above suspension, about 24.66 g of the dimethyl sulfur complex copper bromide is introduced in small fractions over 15 minutes. Stir further 1 hour at 30 to -70 ° C.

) Condensation on epoxide

InoThe solution of 11 g of 3,3-bis-methoxy-5α, 10α-epoxy-17α- (prop-1-ynyl) -estr-9 is dropwise added at -70 ° C for 10 minutes. (11) -en-17β, -ol in 60 cm @ 3 of dry tetrahydrofuran and slowly return to about -5 ° C (-20 ° C) and stir under nitrogen for 18 hours at this temperature.

Then stir with an ice cold aqueous ammonium chloride solution. After 1 hour stirring at room temperature, extract with ether, wash, dry and concentrate dry under reduced pressure.

11.2 g of the desired crude product are obtained.

Chromatograph on silicon (eluent) methylene chloride acetone (9-1 wt.% Triethylamine). 6.6 g of the expected product are obtained.

/ α /D = -25 ° - 1 ° C (c = 1%, CHCl 3)

Preparation 6: 3,3-bis-methoxy-17α, - (prop-1-ynyl) -116-tert-butyl-estr-9-ene-5oc, 17β-diol

Proceed as indicated in preparation 1 starting from 13.8 cm @ 3 of 0.65 M tert-butyl magnesium chloride in tetrahydrofuran and 1.1 g of 3,3-bis-methoxy-5α, 10α-epoxy-17α - (prop-1-ynyl) -estra-9- (11) -en-17β-ol. After stirring for 3 hours at -20 ° C the desired product is obtained P = 148-150 ° C.

Preparation 7: 3,3-Bis-methoxy-116- (2-furyl) -17cc-prop-1-ynyl) -estr-9-ene-5cc, 176-diol:

Process as in preparation 5, difuri] cuprolitian is condensed onto the same product 3,3-bis-methoxy-5a, 10a-epoxy-17cc- (prop-1-ynyl) -estra-9- (11) -en -17'β-οΐ.

The desired product is obtained / α =

--62 ° to 1.5 ° (c = 1% CHG13).

Preparations 8 to 28;

Charging as in preparation 1, the following products are obtained: See Tables on the following pages.

Preparation 29: 3,3-Ethylene-bis- (oxy) -17β-trimethylsilyl-oxy-118- (2'-methyl-prop-1'-enyl) -5-g-hydroxy-estr-g-ene-11fe -carbonitrile

32 cm @ 3 of a 0.95 M solution of 2-methyl-prop-1-enyl lithium in ether are added dropwise at -40øC to 3.1 g of copper dimethyl sulfide-bromide complex in suspension in 30 cc of tetrahydrofuran. 4.16 g of

5 - / (1,2-ethanediyl) acetal / from 5α, 10α-epoxy-17c (α-trimethylsilyl-oxy-17β-cyano-estr-9- (11) -en-3-one) ·

After 30 minutes at -30 ° C, a solution of ammonium chloride is poured out and extracted with ether. The organic phase is dried and the solvent is expelled under reduced pressure. 5.45 g of crude product are collected, 570 mg are collected and purified by silica chromatography (eluent: benzene-ethyl acetate 8-2) and 450 mg of pure product is isolated P = 154 ° C.

THEnoalysis: G28H42°4NSi

Calculated: C ° / ° 69.38 H%: 8.73 N%: 2.89

ANDnocontracted: 69.4 9.0 2.9

Preparation 29 A: 3,3-Ethylene-bis- (oxy) -17a-ethynyl-11B- (2'-methyl-prop-1-enyl) -estr-9-eno-5Î ±, 17B-diol

The 5.45 g of crude product obtained in preparation 29 is dissolved in 50 cm @ 3 of ethylenediamine. Stir under nitrogen at 50 ° C and add 6 g of the lithium acetylide-ethylenediamine complex in small fractions. After 3 hours at the same temperature the reaction mixture is poured into an ice-water mixture and extracted with ether and then chloroform. THEs The organic phases are dried, then the solvent is evaporated under reduced pressure, the crude product is chromatographed over silicon (eluent: benzene-ethyl acetate 7: 3 to 0.1% triethylamine) and 2.763 g of the expected product are obtained. Rf = 0.3 which is recrystallized from isopropyl ether F = 208 ° C. (0.26 g of the 17-keto product are also obtained as a by-product).

THEnoalysis: C26H36O4

Calculated: C% 75.69 H% 8.80

Found: 75.9 8.8

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Preparation 30; 3,3-Ethylene-bis- (oxy) -17α-trimethylethylyloxy-11β- (3-methoxyphenyl) -5α-hydroxy-estr-9-ene-178-carbonitrile

It operates in the same manner as described for preparation 1 from the same starting product as preparation 29 and 3-methoxy-phenyl magnesium bromide. 9.406 g of the expected product were obtained P = 166 ° C. Analyze; G26H36O4

Calculated; C%: 69.23%; 8.06 N%: 2.60

Found; 69.4 8.1 2.6

Preparation 30 A; 3,3-ethylene-bis- (oxy) -5α, 17α-dihydroxy-118- (3-methoxyphenyl) -19-nor-pregn-9-en-20-one;

Concentrate 20 cm3 of a solution of 1.3 M methyl magnesium bromide in tetrahydrofuran to give a solution of 2 M (7 cm3 ':'and tetrahydrofuran are eliminated). 2.79 g of the product obtained in preparation 30 are added and refluxed overnight. 10 cm3 of 1.3 M magnesium solution are added and 5 cm3 of tetrahydrofuran are distilled and heated at 100 ° C for 7 hours. Hydrolize with the aid of a cold aqueous ammonium chloride solution, extract with ether, dry and evaporate the solvent under reduced pressure. Chromatograph on silicon (eluent: benzene-ethyl acetate 6: 4 to 0.1% triethylamine) gives 1.722 g of pure desired product which is recrystallized from a mixture of isopropyl ether-methylene chloride. P - 190 ° C.

THEnoanalysis: C ^ HggOg

Calculated: C%: 72.17 H%; 7.94

Found: 72.5 8.0

Preparation 31; 17α-methyl-116-propyl-5α-hydroxy-19-nor-preken-9-en-3,20-dione 3,220-bis-ethylene ketal;

It operates in a similar manner to that described in preparation 1 from 3,20-bis-ethylene ketal of 17a33.

-methyl-5-α, 10α-epoxy-19-nor-pregna-9- (11) -en-3,20-dione and propylmagnesium bromide (2 hours at -30 ° C).

Preparation of the starting product:

The 17α-methyl-5cc, 10α-epoxy-19-nor-pregna-9 (11) 3,20-bis-ethylene ketal in 3,220-dione used from preparation 31 was prepared as follows:

a) 17α-methyl-19-nor-pregna-5- (10) -9- (11) -diene-3,20-dione 3,20-bis-ethylene ketal

1.5 g of the paratoluenesulfonic acid monohydrate are added to a 21 g solution of 17α-methyl-19-pregna-4,9,9-dene-3,20-dione in a 200 cm @ 3 mixture of methylene chloride. 200 cm @ 3 of ethylene glycol and 100 cm @ 3 of ethyl orthoformate. The reaction mixture is heated at reflux for 7 hours and 2 cm @ 3 of triethylamine is added. Part of the solvent is distilled off, water is added and the precipitate is collected by filtration. Depoid is washed with water, dissolved in methylene chloride and dried. After addition of isopropyl ether and concentration, the desired product crystallizes (22.65 g). An analytical sample is obtained by chromatography then recrystallized from isopropyl ether F = 175 ° C.

THEnoalysis: C25H36O4

Calculated: C%: 74.96 H%: 9.06

Found: 75.0 9.1

b) 17α-methyl-5α, 10-epoxy-19-norpregn-9- (11) -ene-3,20-dione 3,20-bis-ethylene ketal:

100 mg of the product obtained above in a) are dissolved in 2 cm @ 3 of methylene chloride. Sodium bicarbonate (450 mg) is added and stirred at 0 ° C. 0.1 cm3 of chlorine is then added and 0.1 cm3 of hydrogen peroxide (110 volumes). The reaction is terminated after 4 hours. The reaction mixture is poured into sodium thiophate solution, extracted with methylene chloride, dried and the solvent evaporated under reduced pressure. 98 mg of the desired epoxide is isolated.

Preparation 31 A: 17β-Methyl-11β-vinyl-19-nor-pre-9-en-5g-ol 3,20-bis-ethylene ketal

It operates in the same manner as described in preparation 1 from the starting product of preparation 31 and vinylmagnesium bromide (2 hours at -30 ° C).

The expected product is obtained F = 192 ° C

THEnoalysis: G27H40 ° 5

Calculated: C%: 72.94 H%: 9.07

ANDnofound: 72.7 9.2

Preparations 32 to 35: See Table below (page 31)

Preparation 36: /(3,3- Ethylene-bis-oxy-116- (3-methoxyphenyl) -17a.- (prop-1-ynyl) -17B-estr-9-cno-5 (x-hydroxy-17- tert-butyl yloxyoxy acetate.

A solution of 960 mg of 3,3-ethylene-bis-oxy-11β- (3-methoxyphenyl) -17α- (prop-1-ynyl) -estr-9-ene-5a is cooled to -40 ° C. 17β-diol prepared in preparation 13 in 30 cm @ 3 of tetrahydroburan and 3.2 cm @ 3 of butyl lithium in n-hexane (at 1.25 M / l) is added dropwise. Allow to rise to room temperature then add 1.3 cm @ 3 of tert-butyl bromoacetate dropwise.

After 1 hour and 30 minutes, pour into an aqueous ammonium chloride solution, extract with ether, wash, dry, evaporate to dryness and give the desired product.

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W »I 1-1 Preparation: 42: 3,3-Ethylene-bis-oxy-11g-thiene-2-yl-17a-methyl-5α, 21-dibhydro-19-nor-preqn-9-en-20-one

300 mg of 40 cm @ 3 coprous chloride of 0.5 M thienyl magnesium bromide in tetrahydrofuran are added. Cool to -20 ° C and contact 30 minutes. Then 2.02 g of 3,3-ethylene-bis- (oxy) -17a-methyl-5a, 10a, epoxy-21-hydroxy-19-nor-pregn-9- (11) is added dropwise. -en-20-one in solution in 20 cm3 of dry tetrahydrofuran. After 2 hours, contact at -20 ° C-25 ° C, then hydrolyze with an aqueous ammonium chloride solution. Extract with ethyl ether to give 2.218 g of silica chromatographed resin (eluent: benzene-ethyl acetate 1: 1) and give 701 mg of the desired product. Rf = 0.29 P = 204 ° C.

Starting Product Preparation

a) A mixture of 120 cm @ 3 of tetrahydrofuran and 6.6 cm @ 3 of N-cyclohexylisopropylamine is cooled to -50Â ° C and 19.6 cm @ 3 of n-butyllithium in hexane is added over 12 minutes. Stir then add 8.9 g of 3,3-ethylene-bis- (oxy) -17a-methyl-19-nor-pregna-5- (10) -9 (11) -dien-20-one .

Stir for 1 hour at -35 ° C-40 ° C then 17.4 g of oxidation reagent / oxodiperoxy pyridine (hexamethylphosphoramido) molybdenum VI described in Buli.Soc.1481 (1969) is added and stirred. at -30 ° C-35 ° C for 1 hour and 30 minutes. It is then poured into ice water, extracted with ethyl acetate, then washed, dried and concentrated to dryness. The residue is chromatographed on silica (eluent: benzene) to give 4.03 g of product used as follows.

(b) A solution of 1,826 g of 3,3-ethylenedioxy-17α-methyl-21-hydroxy-19-nor-pregna-5- (10) -9- (11) is cooled to 0 ° / + 5 ° C. -diene-20-one obtained above stains 18.3 cm @ 3 of methylene chloride and 7.8 cm @ 3 of a molar solution of hexafluoroacetone hydroperoxide in methylene chloride is added. Leave 75 minutes at 0 ° / + 5 ° C then pour into a solution of 0.5 M sodium thiosulfate. Extract with chloroform, wash, dry and give 2.02 g of the product as used.

20R-acetoxy-3,3-ethylene-bis- (oxy) -1S- (3-methyloxyphenyl) -17cc-methyl-19-nor-pregn-9-en-5es-ol

Preparation 48:

ODwas as indicated above from 80 cm @ 3 of 0.9 M 3-methyloxyphenyl magnesium bromide in tetrarhydrofuran and 7.5 g of 20R-acetoxy-5α, 10α-epoxy-3,3-ethylene-bis-bromide. oxy-17α-methyl-19-nor-pregn-9 (11) -ene. After 18 hours of stirring at -20 ° C, 5.4 g of the expected product are obtained after pressure chromatography and recrystallized from ether. F = 160 ° C.

/ tt / = + 19.5 ° to 1 ° (c = 1%, CHG13).

Starting Product Preparation

(a) Under stirring at 25 ° C 2.7 g of hydrated paratoluenesulfonic acid, then 40 cm @ 3 of methylene chloride are added to a 45 g suspension of 20R-acetoxy-17α-pregna -4,9-dien-3 on 180 cm3 glycol and 180 cm3 ethyl orthoformate.

Stir 45 minutes at room temperature under nitrogen then add 10 cm @ 3 of triethylamine.

The solvent is expelled under reduced pressure. For an hour (500 cm3) of ice water is added, pour into stirring with two liters of ice water containing pyridine.

After stirring at 0 ° C, drain, wash, dry and give 50.5 g of the product which is recrystallized by dissolving at reflux in 10 cm @ 3 of triethylamine isopropyl ether and recrystallization. in the cold. 450 mg of expected product are obtained. F = 148 ° C.

/ CC / = + 121 ° - 3.5 ° (c = 0.5% GHCl3).

(b) A mixture of 40 g of 20R-acetoxy-3,3-ethylene-bis-oxy-17α-methyl-19-nor-pregna-5,9-diene prepared above and 200 cm3 of methylene chloride containing 0.1 cm3 pyridine, and 2.5 cm3 hexafluoroacetone sesquihydrate and 1 cm3 hydrogen peroxide 85% then 0.1 cm3 pyridine are added. Stir for 6 to 7 hours at 0 ° C, pour the mixture into 1.5 l of sodium thiosulfate solution.

a, 2, 500 g ice and 1 cm 3 pyridine.

Stir for 10 minutes at room temperature then decant, extract with methylene chloride, wash with 0.2 M sodium thiosulfate solution, dry, dry concentrate under reduced pressure and obtain 44 g of crude product are obtained. Take up to 40 cm @ 3 of 1 ° / o isopropyl ether of 60 ° C pyridine then allow to return to room temperature. 27.6 g of the expected product are obtained.

F = 166 ° C.

/ The /O = - 4.5 ° to 1 ° (c = 1%, CHG13)

Preparation 55 Cyclic 17g- [3- (dimethyl-amino-prop-1-ynyl) -5g, 17g-dihydroxy-11β- (3-methoxyphenyl) -estr-9-en] -1,2-ethanediyl-acetal 3-one /

a) 3,3-Ethylene-bis-oxy-116- (3-methoxy) phenyl-5g-hydroxy-estr-9-en-17-one

Stir to dissolution at room temperature a mixture of 5 g of 3,3-ethylene-bis-oxy-5a, log-epoxy-estr-9 (11) -en-17-one in 50 cm @ 3 of tetrahydrofuran containing 310 mg of coprous chloride and 195 mg of lithium chloride. Cool to -20 ° C and add 31 cm @ 3 of a 0.75 M solution of 3-methoxyphenyl magnesium bromide in tetrahydrofuran.

Dand1 hour at -20 ° C, reheat to -15 ° C then add the same amount of magnesium.

Pour into a cold aqueous ammonium chloride solution, stir, extract with ether, then methylene chloride, pour the organic phase into saturated aqueous sodium chloride solution, dry and evaporate. if the solvent.

After chromatography the desired product is obtained.

b) 17g- / 3- (dimethylamino-prop-1-ynyl) -5a, 178-dihydroxy-116- (3-methoxyphenyl) -estr-9-en-3-one bicyclo [1,2-ethanediyl-acetal] / 1 o

30 ml of 0.67 M / l lithium diisopropylamide in ether (prepared according to J.rg. Chem. 43, 704 (1978) and 3.9 cm @ 3 of N, N-dimethylaminopropine are slowly added. The temperature is allowed to rise to 0 ° C, then cooled to -40 ° C and then 4 g of 3,3-ethylene-bis-oxy-lip- (3-methoxy) -phenyl is added dropwise. 5uhydroxy-estr-9-en-17-one obtained above in solution on 11 cm @ 3 of tetrahydrofuran.

DandThe temperature is raised to 0 ° C for 1 hour, poured into 500 cm3 of saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, After drying, the solvent is evaporated and 4.9 g of the expected product are obtained. 600 mg of this product is chromatographed on silicon (eluent: methylene chloride-methanol 92: 8) to give 200 mg of pure product.

/ K /D => - 62 ° - 2.5 ° (c = 0.5%, CHCl 3).

A-nálse:

Calculated: C%: 73.6 H%: 8.3

Found: 73.3 8.3

Preparation 57: // 3,3-Ethylene-bis-oxy-118- (4-hydroxyphenyl) 17t-prop-1-ynyl) -estr-9-ene-5a, 178-diol //

a) Preparation of 4-trimethylsilyloxy-phenyl magnesium bromide

7.8 g of p-bromophenyl dissolved in 15 cm @ 3 of tetrahydrofuran is added then 5.75 cm @ 3 of trimethylsilyl chloride at 50 cm @ 3 of a 0.9 M solution of isopropyl magnesium chloride in tetrahydrofuran. Throw the solution over 1, 2 g of magnesium in turns. A little 1,2-dibromethane then 2 cm @ 3 of hexamethyl phosphotriaide is added and then heated 2, and 30 minutes at reflux.

b) // 3,3-ethylene-bis-oxy-11,8- (4-hydroxyphenyl) -17α- (prop-1-yl) -estr-9-ene-5a, 178-diol //

35. mg of coprous chloride is then added 1.45 g of 3,3-ethylene-bis-oxy-5cc, 10cc-epoxy-17α- (prop-1-ynyl) -estr-9- (11) -en 176-ol dissolved in 15 cm3 of tetrahydrofuran at 75 cm3 of the magnesian solution described above.

LTheAn aqueous ammonium chloride solution is extracted, extracted with ether, the organic phase is washed with an N solution of soda. sandThe solvent is then evaporated under reduced pressure. After chromatography on silicon (eluent: benzene-ethyl acetate 7-3), 207 mg of the expected product is isolated.

THEnoalysis: C29H3605

Calculated: C%: 74.97 H%: 7.81

Found: 75.0 7.9 / α /D = - 58.5 ° to 2.5 ° (c = 0.5%, CHCl3)

Example 1: 17B-Hydroxy-17α- (prop-1-ynyl) -11β- (2-thienyl) -estra-4,9-dien-3-one

9.85 g of the product obtained in preparation 1 are introduced into 330 cm @ 3 of 95 ° ethanol. Heat to reflux and add 9.85 g of Redex CF resin in one go. Allow to reflux under stirring and nitrogen for 4 hours. Filter, rinse with ethanol and concentrate under reduced pressure. 9 g of crude product is chromatographed on silicon (eluent: chloroform-ethyl acetate 9-1). 6.5 g of the expected product is recrystallized from isopropyl ether. Drain, rinse with isopropyl ether, dry and give 5.315 g of pure product. F = 192 ° C.

Analyze: Ç25H28°2s

Calculated: C%: 76.5 H%%: 7.18 S%: 8.16

ANDnocontracted: 76.4 7.5 8.0 / α /D = + 83 ° to 2 ° (1%, CHCl3) .

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Example 36: // tert-Butyl 11β- (3-methoxyphenyl) -3-oxo-17Î ± (prop-1-ynyl) -176) -estra-4,9-dienyl / oxy-acetate

Take up to 40 cm @ 3 of methanol and 4 cm @ 3 of 2 N 7α-3,3-ethylene-bis-oxy-lip- (3-methoxyphenyl) -17a-prop-1-ynyl) - (17β) hydrochloric acid. tert-9-en-5α-hydroxy-17-yl tert-butyl acetate-acetate obtained in preparation 36.

After 1 hour stirring at room temperature, pour into 50% aqueous sodium bicarbonate solution, stir 5 minutes, extract with ether, wash with saturated sodium chloride solution, dry and Dry evaporates under reduced pressure.

The residue is chromatographed on silicon (eluent: petroleum ether eb.60-80 ° C - ethyl acetate 7-3). Finally, 720 mg of the expected product are used as used.

Example 37: // 16- (3-Methoxyphenyl) -3-oxo-17cc- (prop-linyl) - (178) -estra-4,9-dien-17-yl / oxy-acetic acid

A mixture of 5 g of the product obtained as in Example 36,500 mg of paratoluenesulfonic acid and 100 cm3 of benzene is refluxed for 5 hours. The obtained resin is evaporated to dryness, chromatographed on silicon (methylene chloride eluent). methanol 92.5-7.5). 886 mg of the expected product are collected / t / d = + 50.5 °, c = 0.3%, CHCl3.

Example 38; // 16- acid sodium salt; (3-methoxyphenyl) -3-oxo-17Î ± - (prop-1-ynyl) - (17S -) - estra-4,9-dien-17-yl / oxy-acetic

A mixture of 305 mg of the acid obtained in Example 37 and 3 cm @ 3 of ethanolic soda (0.2 M / l) is stirred until dissolved, the slight insoluble is filtered off. Evaporate to dryness under reduced pressure, triturate the residue with isopropyl ether to cogloberation. Stir, drain and rinse with isopropyl ether. Dry and give 280 mg of expected product P 270 ° C% Na: 4.63% Found 4.45

Example 44; 9g, 10g-epoxy-178-hydroxy-116- (4-methoxy phenyl) -17g- (prop-1-ynyl) -estr-4-en-3-one

It is joined by stirring in fractions,

700 85% metachloroperbenzoic acid to a 0 ° C solution of 1.3 g of 11β- (4-methoxy) phenyl-17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9- dien-3-one prepared as in Example 14 in 25 cm @ 3 of methylene chloride.

After 1 hour at 0 ° C, return to room temperature, wash with 0.5 N aqueous sodium thiosulfate solution then saturated sodium bicarbonate solution. sandThe solvent is then evaporated. ÇrThe residue is chromatographed on silicon (eluent: 95-5 methylene chloride acetone and 1.075 g of the expected product is recrystallized from a methanol mixture, isopropyl ether F = 185-189 ° C).

Example 45: 9g, 10g-epoxy-176-hydroxy-118- (4-methylsulfonyl) phenyl-17g- (prop-1-ynyl) -estr-4-en-3-one

960 mg of 85% metachloroperbenzoic acid in small portions was added to a solution of 570 mg of 11: (3- (4-methylthio) phenyl) -17β-hydroxy-17α- (prop-1) -inyl) -estra-4,9-dien-3-one as obtained in Example 23 in 13 cm @ 3 of methylene chloride cooled to 0 ° C.

Stir for 1 hour and 30 minutes at 0 ° C under nitrogen then pour into stirring with 100 cm @ 3 of 0.5 M aqueous sodium thiosulfate solution and stir briefly at room temperature.

Extract with methylene chloride, wash with aqueous sodium bicarbonate solution, dry and concentrate to dryness.

The product obtained is chromatographed on silicon (eluent benzene-ethyl acetate 1: 1). 750 mg of the expected product are obtained which is recrystallized from a mixture of isopropyl ether and methylene chloride. F = 20-5-2 ° C / α /D = + 67.5 ° ± 1.5 ° (c = 1%, CHCl 3)

Example 46; 3-Methoxyimino-11S- (4-bromophenyl) -17α- (prop-1-ynyl) -estra-4,9-dien-17β-ol / sin (Z) and anti (E) / isomer:

170 mg of methylhydroxylamine hydrochloride is added to a solution of about 700 mg of 11β- / (4-bromo) phenyl / 17β-hydroxy-17cc- (prop-1-ynyl) -estra-4,9- dien-3-one as obtained in Example 22 in 10 cm @ 3 of ethanol and stir for 2 hours at room temperature. Pour into water, then extract with ether with methylene chloride. The organic phase is dried, the solvent is evaporated and the residue is chromatographed over silicon (eluent: benzene-ethyl acetate 9: 1).

This gives 408 mg of anti-isomer product (produto) P = 185 ° C, then 200 mg of Z-isomer product P = 217 ° C.

THEnoanti product analysis:

Calculated: C%: 68.01, H% ·: 6.52, N%: 2.83, Br%: 16.16 Enocontracted 68.3 6.6 2.9 16.0

Example 47: 11S- (3-fluorophenyl) -3-hydroxyimino-17c (; - (prop-1-ynyl) -estra-4,9-α-176-ol (sin (Z) and anti (Ξ) isomers):

1.27 g of hydroxylamine hydrochloride is added to a solution of 3.7 g of 11β - / (3-fluoro) phenyl / 17β-hydroxy-17a- (prop-1-ynyl) - estra-4,9-dien-3-one as obtained in Example 26 in 44.4 cm3 absolute ethanol and 7.6 cm3 pyridine.

Heat at reflux for 1 hour, cool to 0 ° C and then stir into 450 cm 3 of a water-ice mixture. Extinguish with methylene chloride, wash the organic phases with water, then dry under reduced pressure.

Crude product is chromatographed under pressure (eluent: cyclohexane-ethyl acetate 7-3). Finally, 2.7 g of anti-isomer (e) isomer and 857 mg of isomer (z) isomer are obtained.

The anti product is recrystallized from a mixture of 20 απ3 of isopropyl ether and 10 cm3 of methylene chloride. 2.145 g of pure product are obtained. F = 210 ° C.

/ cc /D = + 35 ° C ± 2.5 ° (c = 0.5%, CHCl 3)

THEnoalysis;

Calculated; C%: 77.3, H%; 7.21, N%; 3.34

ANDnocontracted; 77.3 7.5 3.3

Example 50; 11ft-tert-Butyl-9g, 10oc-epoxy-17B-hydroxy-17cc- (prop-1-ynyl) -estr-4-en-3-one

0Das in Example 44 starting from 2.11 g of lip-tert-butyl-17β-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one as obtained in Example 6 and 2.92 g of metachloroperbenzoic acid gives 0.55 g of the desired product after chromatography F = 186-187 ° C.

THEnoAnalysis: Calculated: C%: 78.49,: 8.96

Found: 78.4 9.0 / α /D = + 38 ° to 1 ° (c = 1%, CHCl3)

Example 51; 118-cyclopentyl-9cc, 10K-epoxy-178-1-hydroxy-17α- (prop-1-ynyl) -estr-4-sn-3-one

It operates as in Example 44 starting from 1.5 g of 11g-cyclopentyl-17β-hydroxy-17cc- (prop-1-ynyl) -estra-4,9-dien-3-one as obtained in Example 43 and 0.8 g methachloroperbenzoic acid. After chromatography, 0.7 g of the expected product is obtained. F = 170 ° C.

THEnoalysis; Calculated: C%: 79.15, H%: 8.68 Found: 79.6 8.7 / α /D = + 6.5 ° - 1 ° (c - 1%, CHCl3)

Example 5 2; 118- (3-methoxyphenyl) -9g, 10g-epoxy-17β-hydroxy-17a- (prop-1-ynyl) -estr-4-en-3-one

It operates as in Example 44 starting from 1.05 g of 11β- (3-methoxyphenyl) -17α-3-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien-3-one such as as obtained in Example 13 and 0.608 g of metachloroperbenzoic acid. After chromatography 0.65 g of the expected product is obtained.

/ α /: + 43 ° to 2.5 ° (c = 0.6% CHCl3).

Example 53: 116-phenyl-9g, 10cc-epoxy-17S-hydroxy-17S- (prop-1-ynyl) -estr-4-en-3-one

It operates as in Example 44 starting from 1.15 g of lip-phenyl-17β-hydroxy-17α- (prop-1-ynyl) -estr-4,9-dien-3-one as obtained in Example 20. and 0.608 g of metachloroperbenzoic acid.

After chromatography, 0.85 g of crystals are obtained. P = 186-187 ° C.

THEnoAnalysis: Calculated: C%: 80.56 H%: 7.51

Found: 80.6 7.3 / α /D = + 47.5 ° to 1.5 ° (c = 1%, CHCl 3)

Example 54: 11B- / 4- (3-methyl) butylsulfonyl / phenyl / -9g, 10a-epoxy-17B-hydroxy-17oc- (prop-1-yl) -estr-4-en-3-one one

It operates as in Example 45 starting from HB- / 4 - / (3-methyl) butylthio / phenyl / 17- (3-hydroxy-17α- (prop-1-ynyl) -estra-4,9-dien). -3-one as obtained in Example 49. The expected product is obtained. E = 147 ° C.

/ α /D = + 62 ° to 2.5 ° (c = 0.6%, CHCl 3)

Example 55: 23-M, E-Dimethylamino-178-hydroxy-11R- (3-methoxyphenyl) -19,21,24-trinor-17cc-cola-4,9-dien-2O-yn-3-one

Stir for 1 hour at room temperature 4.3 g of 17β- / 3-dimethylamino-1-propynyl / -5α, 17β-dihydroxy-11β / 3-methoxyphenyl / -estr-9 cyclic 1,2-ethanediylacetal -en-3-one as obtained in preparation 55 in 100 cm @ 3 of methanol and 3 cm @ 3 of 2N hydrochloric acid.

Pour into a mixture of 300 cm @ 3 of ethyl acetate and 200 cm @ 3 of 0.25 M aqueous sodium bicarbonate solution. Decant, reextract with ethyl acetate, pool the organic phases. Wash with the aid of a saturated aqueous sodium chloride solution, dry, evaporate the solvent, and chromatograph the residue over silicon / eluent: (methylene chloride-methanol 95: 5) (acetone). ethyl acetate 3: 1) /. Is1.7 g of the expected product used are washed as is in the next step.

/ α /D = + 40 ° - 1 ° (c = 1% CHCl3)

Example 56: 23-N, N-Dimethylamino-176-hydroxy-11α- (3-methoxyphenyl) -19,21,22-trinor-17α-cila-4,9-dien-2-yn-3-one hydrochloride

1.5 g of the product obtained in Example 55 are dissolved in 50 cm @ 3 of ether, stirred 10 minutes at room temperature and the slight insoluble is removed. Ino16.5 cm @ 3 of an ethereal solution of gaseous hydrochloric acid is then dropwise added. The suspension is stirred for 10 minutes then drained, rinsed with ether and 1.4 g of the expected product are obtained. F = 190 ° C.

/ CC /D = + 49 ° -2 ° (c = 0.5%, water). Analyze:

Calculated: C%: 72.63%, H%: 7.72 N%: 2.82

Found: 72.5 7.7 2.7

Example 57: 17ft-hydroxy-17α- (prop-1-ynyl) -1H- (4-hydroxyphenyl) -estra-4,9-dien-3-one

A solution of 90 mg of 3,3-ethylene-bis-oxy-11 is stirred at room temperature for 2 hours.t8- (4-hydroxyphenyl) -17oc- (prop-1-ynyl) -estr-9-en-5a, 17β-diol (as obtained in preparation 57) in 2 cm3 of methanol and 0.3 cm3 of hydrochloric acid 2 N. LTheIt is made up in an ice-cold 50% sodium bicarbonate solution, extracted with ether and then methylene chloride. The organic phase is washed with a saturated aqueous solution of dry sodium chloride, concentrated to dryness under reduced pressure and the residue is chromatographed over silicon (eluent: methylene chloride acetone 92.5-7.5). 71 mg of the expected product are obtained.

/ cc /D + 67 ° (c = 0.25%, CHCl3)

Example 58: Ilg- (3-hydroxyphenyl) -17g-hydroxy-17cc- (prop-1-ynyl) -estra-4,9-dien-3-one

Step A: 3,3-Ethylenedioxy-11g- [3- (2-tetrahydropyranyloxy) phenyl] -17cc- (prop-1-ynyl) -estr-9-ene-5c, 17g-diol

a) Preparation of the Machnesian

20.6 g of metabromo-phenol tetrahydropyranyl ether and 150 cc of tetrahydrofuran are mixed under nitrogen. 10 cm @ 3 of the solution is poured into 2.2 g of magnesium coils, then, after the reaction has begun, the remaining solution is slowly released keeping the temperature at 52 ° C.

- 2 ° C. Then reflux for 30 minutes and cool to 20 ° C. b) Addition of magnesian

5.55 g of 3,3-ethylene-dioxy-5cc, 10α-epoxy-17α- (prop-1-ynyl) -estr-9- (11) -en-17β-ol is dissolved in inert gas. 55 cm @ 3 of tetrahydrofuran and 0.36 g of anhydrous cupric chloride and 0.18 g of lithium chloride are added. To the solution is added for 30 minutes at 0 + 3 ° C, 102 cm @ 3 of the magnesian solution obtained above. Stir for 1 hour at 0 ° C, then introduce 50 cm @ 3 of aqueous ammonium chloride solution. It is quenched, extracted with ethyl acetate, the organic phase is washed with water, dried and the solvent is evaporated. The residue is chromatographed on silicon eluting with 1% methylene chloride-acetone (95-5) mixture of triethylamine. 6.3 g of the expected product is crystallized from ethyl ether. F = 216 ° C.

Step B: 118- (3-hydroxyphenyl) -178-hydroxy-17a- (prop-1-ynyl) -estra-4,9-dien-3-one

5.42 g of the product obtained in phase A are suspended at 20 ° C under inert gas in 6 cm3 of 95 ° ethanol. 5.5 g of Redex CF resin are then added to reflux for 1 hour and 30 minutes. Filter, evaporate the solvent and chromatograph the residue on silica eluting with cyclohexane-ethyl acetate (1-1). Get

3.8 g of the expected product which is crystallized from ethyl acetate then acetone. F = 215 ° C.

/ α /D = + 34.5 ° to 1 ° (c = 1% CHCl3)

THEnoalysis: G27H30 ° 3 (402.51)

Calculated: C%: 80.56 H%: 7.51

Found: 80.5 7.5

Contents38

62 members in 34 offices

This recordMember, by publication datePriority claim24 more offices are in the list below

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Priority claims
Document	Office	Kind	Date
8203338	France	A	1982-03-01

Members62

Family members, oldest first
Document	Office	Kind
SE8300308D0	Sweden	D0	1983-01-21
DK89783D0	Denmark	D0	1983-02-25
FI830652A0	Finland	A0	1983-02-28
IT8347820D0	Italy	D0	1983-02-28
PT76307A	Portugal	A	1983-03-01
GB8305558D0	United Kingdom	D0	1983-03-30
IL67920A0	Israel	A0	1983-06-15
IL67920D0	Israel	D0	1983-06-15
BE896042A	Belgium	A	1983-08-29
IE830429L	Ireland	L	1983-09-01
DK89783A	Denmark	A	1983-09-02
FI830652L	Finland	L	1983-09-02
FR2522328A1	France	A1	1983-09-02
SE8300308L	Sweden	L	1983-09-02
AU1191383A	Australia	A	1983-09-08
DE3307143A1	Germany	A1	1983-09-08
LU84667A1	Luxembourg	A1	1983-09-08
WO8303099A1	World Intellectual Property Organization (WIPO)	A1	1983-09-15
MA19716A1	Morocco	A1	1983-10-01
NL8300738A	Netherlands (Kingdom of the)	A	1983-10-03
GB2118186A	United Kingdom	A	1983-10-26
JPS58201800A	Japan	A	1983-11-24
ES520195A0	Spain	A0	1983-12-01
ES8401495A1	Spain	A1	1983-12-01
ZA83982B	South Africa	B	1984-03-28
IT8347820A1	Italy	A1	1984-08-28
KR840003649A	Republic of Korea	A	1984-09-15
GR78465B	Greece	B	1984-09-27
US4477445A	United States of America	A	1984-10-16
OA07567A	African Intellectual Property Organization (OAPI)	A	1985-03-31
US4540686A	United States of America	A	1985-09-10
PT76307BThis record	Portugal	B	1986-01-27
FR2522328B1	France	B1	1986-02-14
GB2118186B	United Kingdom	B	1986-04-23
YU47883A	Yugoslavia, later Serbia and Montenegro (until 2006)	A	1986-04-30
CA1206471A	Canada	A	1986-06-24
CH657368A5	Switzerland	A5	1986-08-29
CA1215353A	Canada	A	1986-12-16
AU562739B2	Australia	B2	1987-06-18
SU1340593A3	Soviet Union (until 1991)	A3	1987-09-23
HU193269B	Hungary	B	1987-09-28
PH21308A	Philippines	A	1987-09-28
MX7199E	Mexico	E	1987-12-23
KR880001870B1	Republic of Korea	B1	1988-09-23
IT1197592B	Italy	B	1988-12-06
IT8347820A0	Italy	A0	1988-12-06
FI80049B	Finland	B	1989-12-29
IE54748B1	Ireland	B1	1990-01-31
FI80049C	Finland	C	1990-04-10
FR2639045A2	France	A2	1990-05-18
EP0369881A1	European Patent Office (EPO)	A1	1990-05-23
JPH02188599A	Japan	A	1990-07-24
JPH02275895A	Japan	A	1990-11-09
EG15881A	Egypt	A	1991-06-30
US5064822A	United States of America	A	1991-11-12
AR241187A1	Argentina	A1	1992-01-31
JPH0443920B2	Japan	B2	1992-07-20
ATA71183A	Austria	A	1992-10-15
JPH054397B2	Japan	B2	1993-01-19
US5182381A	United States of America	A	1993-01-26
AT396109B	Austria	B	1993-06-25
FR2639045B2	France	B2	1994-07-29

Abstract

Term

O

-OH

-OH

OH

-CCH

-C-CH-OH

-OH

-H

-OH

-CH2-CH3 -CH CN //

-CH,

I

I

THE

I

I

I

II

SU

I

I

I

I

G

I

P

CM

I

O

P

G

O

H

C0

THE

I

4J

(D

Priority claims1

Members62

Events

Numbers

Titles2

Classification