HU211865A9 - Novel steroids substituted in the 11-beta position with thiocarbonate containing chain, process to prepare them, their intermediates and us as medicament - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to 19-norsteroids containing a sulfur and carbon chain at the 11-position, to the preparation of these compounds, to intermediates in the process, to their use in medicine, and to pharmaceutical compositions containing them.

The invention compound (I) and their addition salts of formula, wherein R ₁₇ and R 'together represent a ketone _l7, or R ₇ is a hydroxyl group or up to 12 carbon atoms, an acyloxy group, and

R ₁₇ is hydrogen or alkyl, alkenyl or alkynyl optionally substituted with up to 8 carbon atoms, m is 0 or 1,

X is methylene, an arylene or allyloxy group containing up to 10 carbon atoms attached to the steroid ring via a carbon atom,

Y is a C 1 -C 18 saturated or unsaturated, linear or branched aliphatic chain, and

Z is C 1 -C 8 optionally substituted straight or branched alkyl, or optionally substituted aryl or arylalkyl. wherein the alkyl group may have up to 6 carbon atoms and the aryl group may be a 5- or 6-membered monocyclic ring or an 8-10 membered fused ring group, where these groups may optionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur, wherein the alkyl groups represented by R _'17 and Z, the alkenyl or alkynyl groups represented by R' ₇ and the aryl or arylalkyl groups represented by Z may be optionally substituted with one or more of the following:

- halogen,

- an amino group, an alkylamino group or a dialkylamino group, wherein the alkyl group (s) may contain from 1 to 4 carbon atoms,

- a hydroxyl group.

- free carboxyl group converted into an ester or a salt,

- C 1 -C 8 alkyl, optionally mono- or polysubstituted by halogen,

- oxo-. cyano, nitro or formyl,

- acyl or acyloxy having up to 12 carbon atoms.

- C 1-4 alkoxy or alkylthio,

- carbamolyl.

- an alkenyl or alkynyl group containing up to 4 carbon atoms. and

- an aryl group as defined above.

As used herein, acyloxy-saturated or unsaturated aliphatic or cycloaliphatic acids, in particular alkanoic acids such as acetic acid, propionic acid, butyric or isobutyric acid, valeric acid or undecanoic acid; hydroxyalkanoic acid. thus, hydroxyacetic acid; cycloalkylcarboxylic acid or cycloalkylalkanoic acid such as cyclopropyl. cyclopentyl or cyclohexylcarboxylic acid, cyclopentyl or cyclohexylacetic acid or propionic acid, benzoic acid, salicylic acid or phenylalkanoic acid such as phenylacetic acid or phenylpropionic acid; an amino acid such as diethylaminoacetic acid or aspartic acid, formic acid or a divalent acid optionally converted into an acid salt such as butanedioic acid or its monosodium salt. Acetic acid, propionic acid or butyric acid derivatives are preferred.

By acyl is meant those corresponding to the acyloxy groups discussed above.

Alkoxy includes methoxy, ethoxy, propyloxy and alkylthio includes, inter alia, methylthio, ethylthio.

Alkyl means one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl, η-hexyl, 2-methylpentyl, 2,3-dimethylbutyl- . η-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, η-octyl, 2,2-dimethylhexyl- .

3,3-dimethylhexyl and 3-methyl-3-ethylpentyl. A preferred embodiment of alkyl groups is methyl.

Alkenyl may be vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl. Vinyl or propenyl is preferred.

Alkynyl includes, but is not limited to, ethynyl, propynyl, propargyl, butynyl or isobutynyl. Ethynyl or propynyl are preferred.

Preferably, X in the meaning of X is phenylene.

When X is an aryleneoxy group, it is preferably a phenyleneoxy group.

In Y, saturated or unsaturated, straight or branched aliphatic groups may be methylene, ethylene, propylene, isopropylene, butylene, isobutylene or tert-butylene, n-pentylene, η-hexylene, 2-methyl- pentylene. 2,3-butylene. n-heptylene. 2-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 3-ethylpentylene, η-octylene, 2,2-dimethylhexylene. 3.3-dimethylhexylene, 3-methyl-3-ethylpentylene, nonylene. 2,4-dimethyl-heptylene, η-decylene, n-undecylene, η-dodecylene, n-tridecylene, η-tetradecylene, n-pentadecylene, η-hexadecylene, n-heptadecylene or n octadecylene, preferably n-pentylene, η-hexylene, nheptylene, n-octylene or n-nonylene.

Y is vinylene. it may also be isopropenylene, allylene, 2-methylallylylene, isobutenylene, butenylene, pentenylene, hexenylene, heptenylene or octenylene, with hexenylene being preferred.

Y is ethynylene, propynylene. propargenilén-. butynylene, isobutynylene, pentynylene, hexynylene, heptinylene or octynylene, the preferred variants of which are propynylene, hexinylene and octynylene.

Z may be a straight or branched alkyl group as defined above, preferably propyl, butyl, or n-pentyl.

When Z is an arylalkyl group, the alkyl group may be as defined above, including methyl, ethyl, propyl, isopropyl. butyl, isobutyl, n-pentyl or n-hexyl, preferably methyl or ethyl.

The aryl group in the arylalkyl group may be:

- a single ring carbocyclic group such as phenyl,

HU 211 865 A9

- a single ring heterocyclic group such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl or tetrazolyl, and isomers resulting from the position of the heteroatom (s) in these groups,

- a group formed by carbocyclic fused rings, such as naphthyl or phenanthrenyl,

- a group formed of heterocyclic fused rings such as benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho [2,3-b] thienyl, thiantrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, indolizinyl, -, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl. quinolinyl, phthalazinyl, naphthydrinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl-indolinyl, isoindolinyl, imidazidine, imidazidine, imidazidine or fused polycyclic systems formed by a single ring heterocyclic group, such as furo [2,3, -b] pyrrole or thieno [2,3-b] furan.

Examples of aryl or arylalkyl groups in the meaning of Z include phenyl, furyl such as 2-furyl, imidazolyl such as 2-imidazolyl, pyridyl such as 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrimidinyl, such as pyrimidin-2-yl, thiazolyl. such as thiazol-2-yl, thiazolinyl such as thiazolin-2-yl, triazolyl such as triazol-2-yl, tetrazolyl such as tetrazol-2-yl, benzothiazolyl such as benzothiazol-2-yl , a purinyl group such as a purin-7-yl group or a quinolinyl group such as 4-quinolinyl group, in particular methyl or ethyl groups substituted by one of the above aryl groups.

The term "substituted" as used herein with respect to the alkyl groups represented by R 'ρ and Z, the alkenyl or alkynyl groups represented by R', ₇ , and the aryl or arylalkyl groups represented by Z means that they may optionally be taken together with the aforementioned groups. they may be polysubstituted wherein the substituents are in particular halogen such as fluoro, chloro, bromo or iodo, amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethyl; amino, diethylamino or methylethylamino, optionally acylated hydroxy, such as acetoxy, or a group -O-CO- (CH ₂ ) _n -COOH wherein n is 1-5, free or esterified a carboxyl group such as an alkoxycarbonyl group which may be, inter alia, a methoxycarbonyl or ethoxycarbonyl group or a salt thereof. such as, for example, a carboxy group containing sodium or potassium,

C 1 -C 4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, which may be optionally substituted one or more times by halogen such as fluorine or trifluoromethyl; , oxo, cyano, nitro or formyl, allyl such as acetyl, propionyl, butyryl or benzoyl, acyloxy such as acetoxy, alkoxy such as methoxy, ethoxy, propyloxy, isopropyl oxy or butyloxy, alkylthio such as methylthio, ethylthio, propylthio.

isopropylthio or butylthio, carbamoyl, alkenyl such as vinyl or propenyl, alkynyl such as ethynyl or propynyl, and aryl such as phenyl, furyl or thienyl.

Examples of such substituted groups include alkyl or singly or multiply substituted alkyl groups such as halogen, such as fluorine, such as trifluorobutyl, pentafluoropropyl, pentafluorobutyl, pentafluoropentyl, heptafluorobutyl.

Examples include substituted aryl groups substituted with one or more halogen atoms, such as chlorine, exemplified by 2,3,5,6-tetrachloro-4-pyridyl; an amino group such as 4,6-diamino-2-pyrimidinyl; a hydroxyl group such as 2,6-dihydroxy-4-pyrimidinyl; esterified carboxyl group including methoxycarbonyl group such as 2-methoxycarbonylphenyl; alkyl, including methyl, such as η-methylimidazolyl, n-methyltriazolyl or n-methyltetrazolyl; which alkyl group is optionally substituted by halogen such as fluorine, such as 7-trifluoromethyl-4-quinolinyl, or oxo and alkyl, including methyl, such as 1,3-dimethyl-2,6-dioxopurin-7-yl .

Preferred compounds of the present invention are those compounds of formula (I) containing a sulfoxide group, wherein m is 1, and sulfones wherein m is 2. Preferred values of Z include - (CH ₂ ) _p -CF ₂ -. CF ₃ wherein p is 1, 2 or 3.

Naturally, the present invention also encompasses salts of the compounds of formula (I), including, when the compounds of formula (I) contain an amino group, salts with the following acids: hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acid such as methane or ethanesulfonic acid, aromatic sulfonic acid such as benzene or p-toluenesulfonic acid or aromatic The compounds of formula I contain an acidic group - salts with alkaline or alkaline earth metals or with optionally substituted ammonia.

Of the compounds of the present invention, those of formula I in which R ₁₇ is hydroxy and R 17 is hydrogen are _noteworthy .

HU 211 865 A9

Particularly preferred compounds of the present invention are those compounds of formula I wherein X is methylene and Y is a C7-C9 saturated straight chain, and compounds wherein X is phenylene and Y is C3-C8, saturated or unsaturated, straight chain, with the proviso that when the chain is unsaturated, it contains a vinylene or ethynylene group directly attached to the phenylene group, and compounds wherein X is phenyleneoxy and Y is C 5-6 saturated, straight-chain group. When X is phenylene, Y preferably has 5 or 6 carbon atoms.

Particular compounds of the invention include those compounds of formula I wherein:

Z is a pentafluoroalkyl group having 3 to 5 carbon atoms.

-COO-alkyl, wherein alkyl is C1-C4 alkyl;

(e), (f). (g), (h). a 5-membered heterocyclic ring of formula (i) or <j), of formula (k), (1), (m), (n), (o) or (p). A group containing a 6-membered heterocycle, or (q). a heterocyclic group of the formula (r), (s) or (t) having two fused rings.

Preferred values for the substituent Z include pentafluoroalkyl, especially pentafluoropropyl, pentafluorobutyl, or pentafluorophenyl.

Preferred compounds of the present invention, the preparation of which is described in more detail below.

β- {8- [2-Pyridinylmethyl) thio] octyl} -estra-1,3,5 (10) -triene-3.17 β-diol, β- [4- {3 - [(1-methyl-1H) -imidazol-2-yl) thio] -1-propynyl} phenyl] -estra-1,3,5 (10) -triene-3.17 β-diol.

β- [4- (5 - [(2-Furanylmethyl) thio] pentyloxy} phenyl] estra-1,3,5 (10) -triene-3,17 β-diol, β- [4- {5 - [(2-ρΪΓί0ϊηϊΙ-ΓηεΐίΙ) -8ζυ1ίϊηί1] -ρ € ηπ1oxy] -phenyl] -estra-1,3,5 (10) -triene-3,17 β-diol, β- [4 - {5 - [(3-Pyridinylmethyl) sulfinyl] pentyloxy} phenyl] -estra-1,3,5 (10) -triene-3,17 β-diol, β- [4- {6 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl] hexyloxy) phenyl] estra-1,3,5 (10) -triene-3,17 β-diol.

The invention further provides a process for the preparation of compounds of formula (I). In the process, a compound of formula II, wherein R _17a and R _{17a are as} defined above for R ₁₇ and R ₁₇ , where the reactive groups optionally present are optionally protected,

X and Y have the meanings above,

R ₃ is hydrogen or a hydroxyl protecting group and fish is a reactive group. Thus, a halogen or pseudo-halo such as tosylate is reacted with a mercaptan of formula (III) or a salt thereof

Za-SH (ΠΙ)

wherein Za has the same meaning as Z above, wherein the optionally present reactive groups are optionally protected from the hydroxy groups 3 and 17 and optionally from other reactive groups by removal of the protecting groups by a suitable reagent of formula (I). to give a compound of formula (IA), wherein m is 0, which is a narrower group of compounds of formula (IIa) and subjecting the resulting compound of formula (IA) as desired or optionally (in any order) to the following reaction (s):

R _n and R '| ₇ , the metal complex of formula (IV) is added by addition to the ketone group of R ₁₇ and R ' _n .

M-R _l7a (IV) wherein M is a metal atom and R _7a are as defined above with the proviso that, other than hydrogen, the 17-position, _- when R ₇ is hydroxy - is conducted on a selective acylation reaction, when Y represents an unsaturated chain the ethynylene group is partially or completely reduced, the sulfur atom is oxidized to a sulfoxide or sulfone and optionally salted with an acid or a base.

Compounds of formula (I), wherein m is 0, which form a narrower group of compounds of formula (I), are prepared by reacting a compound of formula (II) wherein hal is, inter alia, chlorine or tosylate; optionally protected with an acetyl, tetriobutyl or tetrahydropyranyl group and the R _(7a , R ' _7a) substituents optionally having conventionally protected reactive groups, - reacting with a compound of formula (III), the latter preferably being sodium carbonate, hydroxide. sodium methylate or ethylate, and the like use a salt obtained by addition of the form, as well as the reaction inert solvent such as methanol, dimethylformamide, hexamethylphosphoramide (HMPT), acetonitrile is carried out. during which the solvents _(CH? CN) in pure or mixed form with each other if The reaction may be carried out at about 50 ° C or under reflux conditions, if necessary in the presence of sodium iodide or similar reagents, and if desired, the resulting compound is exposed to deprotecting reagents.

Reactive groups. Thus, the amino or hydroxyl groups may be protected with protecting groups customary in organic chemistry, particularly peptide chemistry. A non-exhaustive list of these groups, as well as appropriate removal procedures, can be found in French Patent No. 2,499,995, the contents of which are incorporated herein by reference. including

Examples of tetrahydropyranyl or trityl include A9.

In a preferred embodiment of the invention, compounds of formula (III) which have a β-terminal halogen atom or a pseudo-halogen at the 11-position may be used, such as the group selected from the following table:

-X -Υ -fish -CH ₂ - <CH ₂ ) ₇ -O-SO ₂ - φ-CH, -ch ₂ - (CH ₂ ) ₉ -O-SO ₂ - φ-CH, -Φ -C sC- (CH ₂ ) Cl - Φ -C sC- (CH ₂ ) ₄ Cl -Φ -C = C- (CH ₂ ) ₆ Cl -φθ - (CH ₂ ) j Cl -φθ - <ch ₂ ) ₆ -1

in which φ represents a phenylene group, as exemplified in the following examples, the compounds of formula (III) discussed in the experimental section below may also be used. Illustrative listings include methyl ester of 2-mercaptobenzoic acid, furfuryl mercaptan, 2-thiazolin-2-thiol, 2-mercaptothiazole, 2-mercapto-1-methylimidazole, 1-methyl-5-mercapto1, 3,4-thiazole. 1-methyl-5-mercapto-1,2,3,4-tetrazole,

2-pyridine-methanethiol, 4,6-diaminopyrimidine-3-thiol. 2,3,5,6-tetrachloropyridine-4-thiol, 2-mercaptobenzothiazole, 7-trifluoromethyl-4-quinolinothiol and

4.4.5,5,5 pentafluoro-pentane-thiol.

When the compound of formula (IA) contains protected reactive groups, the corresponding unsaturated compound is conventional, such as reagents used for saponification, including potassium hydroxide or an hydrolyzing agent in an alcoholic medium. This is obtained by the use of hydrochloric acid. French Patent No. 2,499,995 also discloses processes for deprotection.

If the compound of formula (LA) contains a keto group at position 17,

- the corresponding hydroxylated 17 β-compound can be prepared using a reducing agent, including sodium borohydride, in an inert solvent such as methanol,

- the corresponding alkyl, alkenyl or alkynyl group optionally substituted with R _{'17 is} prepared by the addition of a compound of formula IV, such as a lithium complex, as described in EP 57,115.

When the compound of formula IA contains a hydroxy group at the 17-position, the corresponding acyloxylated 17-position is prepared with a selective acylating agent such as acetic anhydride in pyridine.

When the compound of formula (IA) contains an ethynylene group, the corresponding vinyl group compound or the corresponding saturated compound is prepared by using a partial or total reduction reagent. In the case of partial reduction, hydrogen is used in the presence of palladium on activated charcoal or barium sulfate and optionally in the presence of a base such as pyridine or quinoline, while in the case of complete reduction palladium hydroxide is used.

For the preparation of compounds of formula I wherein m is 1, the compounds of formula IA may be reacted with a sulfoxidizing agent such as sodium metaperiodate, but for the preparation of compounds of formula I wherein m is 2 a sulfonating agent such as perphthalic acid or m reaction with -chloroperbenzoic acid.

The invention further provides a process for the preparation of compounds of formula I. In the process, a compound of formula (V) - wherein R _17a and R ' _17a have the same meaning as R ₁₇ and R' ₁₇ above, where the reactive groups optionally present are optionally protected,

X and Y have the meanings above,

R'is a hydrogen atom or a hydroxyl protecting group, and

W is a hydrogen atom or an acyl group of the formula -COR wherein R is a C 1 -C 5 group

- reacting a compound of formula VI or a salt thereof

wherein Za is as defined above for Z, where the optionally present reactive groups are optionally protected and hal 'is a reactive group such as a halogen or pseudo-halogen such as mesylate or tosylate in the presence of a base and optionally Removal of the protecting groups from the hydroxyl groups at the 3- and 17-positions and optionally other protected reactive groups affords the compound of formula (IA) which may be reacted as desired or optionally described above for the compound of formula (IA).

According to this embodiment of the invention, compounds of formula IA which are the same as compounds of formula I wherein m is 0 are prepared by reacting a compound of formula V wherein W is acyl - can be, for example, acetyl, propionyl or butyryl; OR ₃ is an optionally protected hydroxyl group wherein the protecting group may be, for example, acetyl, tert-butyl or tetrahydropyranyl; _! reactive groups which are optionally the R _17a and R _7a are optionally substituted with optionally protected by conventional means - a compound (VI) or a salt thereof, such as reaction with a hydrochloride, wherein the reaction is carried out in a solvent such as methanol or dimethylformamide, where optionally heating the solvent to about 50 ° C or refluxing the reaction with a base,

Thus, it is carried out in the presence of sodium methylate or concentrated sodium hydroxide.

In a preferred embodiment of the invention, the compounds of formula (V) containing a chain containing a thiol or thioacetyl group at the 11-position are selected from the following table.

-X -Υ, -S-W -ch ₂ - (CH ₂ ) g -S-CO-CH -Φ - <CH ₂ ) ₆ -S-CO-CH -Φ -C = C- (CH 2) 4 -s-co-ch, -φθ - (CH ₂ ) ₅ -s-co-ch, -φθ - (CH ₂ ) ₅ SH -φθ - (CH ₂ ) ₆ -s-co-ch, -φθ - (CH ₂ ) ₅ -S-CO-CH

wherein φ is phenyl and the compounds of formula VI mentioned in the experimental part are used.

Examples of compounds of formula VI include: 3-chloromethylpyridine, 4-chloromethylpyridine, 6- (chloromethyl) uracil, 2-chloromethylbenzimidazole, 7- (2-chloroethyl) - theophylline and its addition salts such as its hydrochloride. or pentafluoropentyl halide mesylate or tosylate, preferably 4,4,5,5,5-pentafluoroiodo-pentane, as exemplified in the following examples.

4,4,5,5,5-pentafluoroiodo-pentane, the preparation of which is described in the experimental part, is obtained by iodination of the corresponding alcohol, 4, 5, 5, 5, 5-fluoropentanol, which can be prepared, inter alia, in the literature. from the corresponding partially unsaturated 4,4,5,5.5-pentafluoro-2-penten-1-ol [T. Kitazume et al. (1985) J. Am. Chem. Soc. 107, 5186-5191], such as hydrogenation in the presence of Raney nickel in methanol or platinum oxide in ethanol.

The above saturated alcohol intermediate is prepared according to a method known in the art [N.O. Brace, Journal of Fluorine Chemistry 20, 313-327 (1982)], in which the starting iodopentafluoroethane is condensed under pressure with allyl alcohol. Thus, aza-isobutyronitrile (AIBN). in the presence of Raney nickel in ethanol, tetrakis (triphenylphosphino) palladium in hexane or tin and silver acetate in methanol, in the presence of:

2-Iodo-4,4,5,5,5-pentafluoro-pentanol is obtained, inter alia, with hydride in methanol. Hydrogenated by reaction with tributyltin hydride in the presence of 10% by weight of magnesium oxide in the presence of palladium or Raney nickel in ethanol or in the presence of azoisobutyronitrile.

The compounds of formula (IA) obtained by the process variant of the present invention may be subjected to one of the reactions described above, if necessary, to prepare compounds of formula (I).

the compounds of the formula I have useful therapeutic properties. By studying the effect of the products on hormone receptors, we have discovered that they exhibit particularly remarkable anti-estrogenic activity and antiproliferative properties, as confirmed by the test results described below.

These properties make the compounds of formula I useful in the treatment of hormone-dependent cancers, such as breast cancer and metastases thereof, and in the treatment of benign breast tumors.

Therefore, the invention further provides compounds of formula I as medicaments.

Among the compounds of formula (I), the following compounds are particularly suitable as medicaments according to the invention:

β - {[(2-pyridinylmethyl) thio] octyl] -estra-1,3,5 (10) -triene-3,17 β-diol, β- [4-; 3 - [(1-methyl- 1H-imidazol-2-yl) thio] -1-propynyl] phenyl]-total-1,3,5 (10) -triene-3,17 β-diol, β- [4- [5 - [( 2-ίυΓ3ηίΙ-ιη6ύ1) -ύο] -ρ € ηΰ1-οχί} -ί6nil] -estra-1,3,5 (10) -triene-3,17 β-diol, β- [4- {5 - [( 2-Pyridinylmethyl) sulfinyl J-pentyloxy) phenyl] estra-1,3,5 (10) -triene-3,17 β-diol, β- [4- {5 - [(3-pyridinyl) methyl) sulfinyl] pentyloxy) phenyl] estra-1,3,5 (10) -triene-3,17 β-diol.

β- [4- {6 - ((4,4,5,5,5-ρεηΐ3ί1υοΓ-ρ € ηύ1) -5ζυ1ίίηί1] hexyloxy} phenyl] estra-l, 3,5 (10) -trien 3.17 β-diol.

The useful dose may vary with the disease being treated and the route of administration; in adults, the daily dose for oral administration may range from 1 to 100 mg.

The present invention includes within its scope pharmaceutical compositions containing at least one of the above medicaments as an active ingredient.

The compounds of formula (I) may be administered via the digestive tract, parenterally or topically, such as by percutaneous route. These active ingredients are available in the form of tablets or sugar-coated dragees, capsules, granules, suppositories, pessaries. injectables, ointments, creams, gels, microspheres, implants and impregnated patches. which can be prepared in a conventional manner.

The active ingredient (s) may be incorporated into excipients commonly used in pharmaceutical compositions of this type, which may be talc, gum arabic, lactose. hardening agents, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols, various wetting, dispersing, emulsifying or preserving agents.

Some of the intermediates of formula (II) or (V) are novel compounds. therefore, the invention also relates to the compounds of formulas II and V as defined above.

The novel intermediates of formula (II) above may be prepared according to the procedure described below.

In general, the compounds of formula (II) may be prepared by the following process:

a compound of Formula VII wherein R 1 is _7a and R '| _7a is as defined above, K is methyl6

EN 211 865 Connected to the steroid ring through the A9 bran group

C2-C19 aliphatic chain or arylene group (a) when K is an aliphatic chain, contacting the alcohol hydroxyl activating genes such as tosyl chloride in pyridine or in the presence of triphenylphosphine in a halogen-releasing gene such as carbon tetrachloride;

b) contacting a halogenated compound of formula VIII in the presence of a base when K is an arylene group,

Br-Y fish fVIII)

- in which Y is as defined above and hal is halogen - and in the preparation of compounds of formula II wherein X is methylene or arylene oxysopone, the compound obtained in steps a) and b) may be prepared with a flavoring agent such as methanol or acetyl; or by reacting palladium hydroxide on magnesium oxide in a mixture of bromide and acetic anhydride, or subjecting the compound (VII) as defined above to the aromatization reaction described above. followed by the reaction of steps a) or b) above, or to a compound of formula II wherein X is arylene and Y is directly linked to X via an ethynylene group, a compound of formula IX wherein R ₃ . R ₁₇ and R ' _{t 7a} are as defined above, X' is arylene, and Y 'is as defined above for Y. wherein it contains less than 2 carbon atoms attached to the arylene group represented by X - an alcoholic hydroxyl activating agent, such as in the presence of triphenylphosphine in an ophthalmic solvent, subject to carbon tetrachloride or tosyl chloride in pyridine, and optionally partially or we react completely.

Some of the compounds of formula (VII) required for carrying out the invention are known compounds. Their preparation is described in Examples 43 and 50 of EP-A-384 842, the disclosure of which is incorporated herein by reference. The novel compounds of formula (VII) may be prepared in a similar manner, as described in the above-mentioned publication.

Applying the procedure of the invention, (IX) Compounds of formula I are prepared according to known methods (X) from compounds of formula, wherein R ₃ and _{R] 7,} R _17a and X'jelentése above.

Starting from compounds of formula (X), compounds of formula (IX) are prepared by reacting Y 'with methylene, with paraformaldehyde in the presence of butyl and lithium chloride in a neutral solvent, or, when Y' is an aliphatic chain containing at least 2 carbon atoms, in the presence of a strong base with a halide of the formula Rp-OY-Hal. in which Fish | is halogen. and Rp is a protecting group for an alcoholic hydroxy group. These production methods are illustrated by examples.

Certain compounds of Formula II wherein hal is halogen. or directly in the presence of a strong base by reacting a halide of formula Hal ₂ -Y'-Hal wherein Hal 1 and Hal ₂ are halogen.

Compounds of formula (X) are disclosed, inter alia, in European Patent Publication No. 384,842, and other compounds of formula (X) may be prepared in a similar manner, following the procedure described in Example 31 of the above-mentioned disclosure.

The novel intermediate of formula (V) as defined above is prepared as described below.

Compounds of formula (V) may be prepared in general by the following process:

a compound of formula (II), which is a narrower group of compounds of formula II, wherein hal is chlorine or bromine to produce a compound of formula V wherein W is acyl, with an iodinating reagent such as acetone or treatment with sodium iodide in methyl ethyl ketone, optionally refluxing, and reacting the product with a thiocarboxylic acid salt of formula XI,

R-CO-SH (XI) wherein R is for the preparation of the above compound or V.

wherein W is hydrogen is reacted with the aforementioned compound of formula XI and the disulfide of formula XII is obtained wherein R ₃ , X, Y, R 1 are hydrogen; _7a and R ' _{) 7a} are as defined above, with a reducing agent such as tri-n-butylphosphine in an inert solvent, including an aqueous organic solvent.

In addition to the following non-limiting examples, the present invention provides within the scope of the invention compounds of formula I wherein R ₁₇ is hydroxy, R ₁₇ is hydrogen, m is 0, 1 or 2, and X, Y and Z has the meaning given in the table below, where φ has the meaning given above.

-X | -Y -z - <t> o - (CH ₂ ) ₅ ςχΛ ' -Φ -C sC- (CH 2) 4 - (CH ₂ ) ₃ -CF ₂ -CF ₃ -Φ -ích ₂ ) ₆ - (CH ₂ ) ₃ -CF ₂ -CF ₃ -ch ₂ - (CH ₂ ) g - (CH ₂ ) ₃ -CF ₂ -CF ₃ -φθ - (CH ₂ ) ₄ -ch ₂ -cf ₂ -cf ₂ -cf ₃ -φθ - (CH ₂ ) ₅ -ch ₂ -cf ₂ -cf ₂ -cf ₃ -φθ - (CH ₂ ) ₇ -ch ₂ -cf ₂ -cf ₂ -cf ₃ -φθ - <ch ₂ ) ₆ - (CH ₂ ) ₃ -CF ₃

HU 211 865 A9

Example 1 Preparation of β- {8 - [(2-Pyridinylmethyl) thio] octyl [-estra-1,3,5 (10) -triene-3, 17? -Diol

Step A: Preparation of 17? -Acetyloxy-11? - [8- (acetyloxy) octyl] estra-4,9-dien-3-one

1.4 g (European Patent Publication No. 384,842)

To a solution of 17? - (acetyloxy) -1? - (8-hydroxyoctyl) estra-4,9-dien-3-one in 10 cm ^{3 of} pyridine prepared by a procedure similar to that described in Example 50, Step D 3.6. cm ^{3 of} acetic anhydride and 95 mg of 4- (dimethylamino) pyridine were added. After stirring for 1 hour at room temperature, water (5 cm ³ ) and methanol (5 cm ^{3) were} added, the resulting mixture was stirred for 10 minutes at 0-5 ° C, then poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and washed with saturated sodium chloride solution, then dried and, after pyridine extraction with toluene, concentrated under reduced pressure to dryness. The resulting crude product (1.61 g) was chromatographed on silica gel with ethyl acetate / cyclohexane (3: 7) to yield 1.28 g of the desired product.

IR (CHC1 _medium?):

C = O 1735 cm ^{-1 on} diene 1660-1605 cm ^-1

Step B: Preparation of $ 11 - [8- (Acetyloxy) octyl] -estra-1,3,5 (10) -triene-3,17-diol diacetate 1.273 g of the product obtained in the previous step are obtained.

Dissolve in 13 cm ^{3 of} methylene chloride containing 1.3 cm ^{3 of} acetic anhydride and 0.65 cm ^{3 of} acetyl bromide, stir at 0 ° C for 10 minutes, then at room temperature for 1 hour 30 minutes, then add 2 drops of water and cm ^{3 of} methanol was added. The reaction mixture was poured into a saturated sodium bicarbonate solution, extracted with methylene chloride, washed with water, dried and concentrated under reduced pressure to dryness to give 1.387 g of the desired product.

IR spectrum:

C = O 1740-1730 cm ^-1 aromas 1610-1590-1500 cm ^-1

Step C: Preparation of $ 11 - (8-hydroxyoctyl) -estra-1.3.5 (10) -triene-$ 3.17-diol

To a solution of 1.377 g of the product obtained in the previous step in cm ^{3 of} methanol is slowly added 20 cm ^{3 of a} 2 M sodium hydroxide solution, and the mixture is stirred for 2.5 hours at room temperature. Subsequently, 21.5 cm <^{3> of a} 2M hydrochloric acid solution was added, the whole was poured into a saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, dried and dried under reduced pressure. until concentrated. The resulting 1.119 g of the desired product is used in the next step without further processing.

Step D: Preparation of $ 11 - (8-Bromooctyl) -estra-1,3,5 (10) -triene-$ 3.17-diol

1.107 g of product obtained in the previous step

To a solution of 8.1 cm ^{3 of} tetrahydrofuran and 2.561 g of carbon tetrabromide in 32.5 cm ^{3 of} acetonitrile is added dropwise a solution of 2.88 g of triphenylphosphine in 8.1 cm ^{3 of} methylene chloride at 40 ° C. The reaction mixture was stirred for 1 hour at room temperature and then concentrated under reduced pressure to dryness. The resulting product (6.05 g) was chromatographed on silica gel with ethyl acetate / cyclohexane (3: 7) to give 283 mg of the desired product.

IR spectrum:

OH 3605 cm ^-1 aromas 1615-1600-1590-1500 cm ' ¹

Step E: Preparation of $ 11 - (8 - [(2-Pyridinylmethyl) thio] octyl) estra-1,3,5 (10) -triene-3,17 $ -diol 125 mg of 2-pyridine methane thiol and sodium methylate

A mixture of 0.98 cm ³ of a solution of 51.3 mg / cm ^{3 in} methanol is stirred for 5 minutes and then a solution of 150 mg of the product obtained in the previous step in 4 cm ^{3 of} methanol is added at room temperature. followed by the addition of 60 mg of sodium iodide, and the resulting mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution and concentrated under reduced pressure to dryness. Chromatography on silica gel with methylene chloride / methanol (97.5: 2.5) followed by ethyl acetate / cyclohexane (40:60) afforded 224 mg of product.

IR spectrum:

OH 3604-1616 cm ^-1 aromas 1598-1584 cm ^-1 heterocyclic 1571-1498 cm ^-1

Example 2 β- [4- {3 - [(1-methyl-1H-imidazol-2-yl) thio] -1-propionyl} phenyl] estra-1,3,5 (10) -triene-3 , 17 β-diol

Step A: Preparation of $ 3.17-bis (tetrahydro-2H-2-pyranyloxy) -11- (4-ethynylphenyl) estra-1,3,5 (10) -triene

0.1 cm ^{3 of} chlorobutane, 14 mg of powdered lithium, 540 mg (prepared according to Example 31, Step D, variant B of EP-A-384 842) 3- {4 [3,17 β-bis (tetrahydro-2H) A mixture of -2-pyranyloxy) -estra-1,3,5 (10) -triene-17β-ί1] -ίεηί1} -ρΓορ-2-ίη-1-ο1 and 2 cm ^{3 of} tetrahydrofuran was stirred in an ultrasonic vessel It was continued at 30-35 ° C for 30 minutes, and after the addition of 29 mg paraformaldehyde, stirring was continued at 30-35 ° C for several minutes. The reaction mixture was diluted with water, acidified with monosodium phosphate, extracted with methylene chloride, dried and concentrated under reduced pressure to dryness.

EN 211 865 A9. The resulting product (613 mg) was chromatographed on silica gel with cyclohexane / ethyl acetate (1: 1) to give 400 mg of the desired product (m.p. 214 ° C).

IR spectrum:

C = CHOH 3609 cm -1 1607-1572-1555-1492 cm ^-1

Step B: $ 3.17-Bis (Tetrahydro-2H-2-pyranyloxy) -β- [4- (3-chloro-1-propynyl) phenyl] estra-1,3,5 (10) triene production

A solution of 570 mg of the product obtained in the previous step, 14 cm ^{3 of} carbon tetrachloride, 2 cm ^{3 of} tetrahydrofuran and 4 cm ^{3 of} acetonitrile, was added in portions to 530 mg of triphenylphosphine for 1 hour at room temperature and then refluxed for 2 hours. boil. After addition of 5 g of silica gel, the mixture was concentrated under reduced pressure to dryness. The resulting residue was chromatographed on silica gel with cyclohexane / ethyl acetate (8: 2) to give 370 mg of the desired product.

IR spectrum (CHCl _{3 in} medium nickel-prism):

OH 3598 cm ^-1

C = C 2268 (f) -2220 cm ^-1 aromas 1606-1560-1531-1506 cm ^-1

Step C: $ 3.17-Bis (Tetrahydro-2H-2-pyranyloxy) $ 11- {4- [3- (1-methyl-1H-imidazol-2-yl) thio] -1-propynyl} Preparation of -phenyl] -estra-1,3,5 (10) -triene 38 mg of a solution of 2-mercapto-1-methylimidazole in 2 cm ^{3 of} tetrahydrofuran cooled to 0 ° C in the form of a 50% oil dispersion sodium hydride was added. After stirring for 1 hour at 0 ° C, a solution of 2 g of the product obtained in the preceding step in 2 cm ^{3 of} tetrahydrofuran is added. After stirring for 3 hours, the reaction mixture was poured into an aqueous solution of ammonium chloride, extracted with ethyl acetate, then dried and concentrated under reduced pressure to dryness. The product was chromatographed on silica gel with ethyl acetate / cyclohexane (2: 8) to give 180 mg of the desired product.

IR spectrum (CHCl _{3 in} medium nickel-prism):

OH 3600 cmC = C 2218aromatic + heterocycles 1608-1582-1506 cm ^-1 (complex)

Step D: $ 11 -4- {3 - [(Methyl-1H-imidazol-2-yl) -thio] 1-propionyl-phenyl] -estra-1,3,5 (10) -triene-3.17 Preparation of βdiol

143 mg of product obtained in the previous step. A mixture of 2 cm ^{3 of} ethanol and 2 cm ^{3 of} 2 mol / L hydrochloric acid was stirred for 2 hours at room temperature. After partial concentration, the mixture was extracted with ethyl acetate and concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel with cyclohexane: ethyl acetate (1: 1) to give 96 mg of the desired product.

IR spectrum (CHCl _{3 in} nicolytic prism):

OH 3608 cm ^-1 + secondary values C = C2210cm ^-1 aromatic heterocycles 1583-1554-1505 cm ^-1

Example 3 β- [4- {5 - [(2-ΡυΓΗηί1-πιεΐί1) -ΐίο] -ρεηϋ1-οχί} -ίβnyl] -estra-1,3,5 (10) -triene-3,17 β-diol production

Step A: Preparation of $ 11 - {4 - [(5-Chloro-pentyl) -oxy] -phenyl-estra-4,9-diene-3,17-dione

28.2 g (European Patent Publication No. 384,842)

Example 43) 11 β- (4-1ιίύΓθχί-ίεηϊ1) estra-4,9-diene-3,17-dione, 450 cm ^{3 of} acetone, 45 cm ^{3 of} 2 M sodium carbonate and

A mixture of 18.5 cm ^{3 of} 1-bromo-5-chloropentane was heated with stirring for 6 hours. The acetone was evaporated and the residue was taken up in 200 cm ^{3 of} methylene chloride, washed with water, dried and then concentrated to 100 cm ³ by addition of 10 cm ^{3 of} isopropyl ether, followed by concentration to crystallization, followed by separation and drying 26.3 g. Chromatography on silica gel (G: ethyl acetate = 1: 1) gave 4.2 g of the desired product (m.p. 220 ° C).

IR (CHC1 ₃ medium):

17-keto 1735 ^cm-1

3-keto group 1658 cm ^-1

C = C and aromatics 1609-1580-1509 cm ^-1

Step B: Preparation of 3-Acetyloxy-11β - [4 - [(5-chloropentyl) oxy] phenyl] -estra-1,3,5 (10) -triene-17-one 30 g

Prepared in 300 cm ^{3 of} methylene chloride. To the solution cooled to + 4 ° C was added 30 cm ^{3 of} acetic anhydride and 15 cm ^{3 of} acetyl bromide. The reaction was allowed to warm to room temperature and stirred for 1 hour and then 30 cm ³ of methanol and 500 cm ³ of saturated sodium bicarbonate was added while cooling. Stirring was continued at room temperature for 45 minutes, then the mixture was decanted, washed with water and then concentrated to dryness. 37 g of product are obtained, which product is used as is in the following stage.

Step C: Preparation of 3-Hydroxy-N- (4- (1- (5-chloropentyl) oxy) phenyl-distra-1,3,5 (10) -trien-17-one) adjusted to 200 cm ³ of tetrahydrofuran and the solution was 64 cm ³ of 2 mol / 1 concentration sodium carbonate were stirred at room temperature for 40 minutes. then, 64 cm ³ of 2 mol / 1 hydrochloric acid was added thereto, and the solvents were evaporated under reduced pressure, then extraction with methylene chloride, followed by washing with water and drying, followed by

The residue is concentrated under reduced pressure to dryness. 32 g of the expected product are obtained, which product is used as is in the following stage without further processing.

Step D: Preparation of $ 11 - / 4 - [(5-chloropentyl) oxy] phenyl} oestral, 3,5 (10) -triene-$ 3.17 diol

Solution of the product from the previous step was 32 g of tetrahydrofuran containing 150 ^cm-1 to 150 cm ³ of methanol and - during at 0-5 ° C over 10 minutes - 2.56 g, and skin (95%) of sodium borohydride. After stirring for 1 hour at 0-5 ° C, 10 cm ^{3 of} acetone was added, the solvents were evaporated and the residue was taken up in methylene chloride, washed with water, dried and concentrated to dryness. The product (34 g) was chromatographed on silica gel with toluene / ethyl acetate (8: 2).

15.15 g of the expected product are obtained (m.p. 165 DEG C. after recrystallization from ethyl acetate).

IR spectrum (nujol):

absorption in the NH / OH range of aromatics 1618-1608-1582-1512-1492 cm ^-1

Step E: Preparation of $ 11- [4- (5- (2-furanylmethyl) thio] pentyloxy) phenyl] estra-1,3,5 (10) -triene-5.17 p-diol

A mixture of 0.15 cm ³ (90-95% by weight) of furfuryl mercaptan, mg of sodium methylate, 90 mg of sodium iodide, 4 cm ^{3 of} methanol and 234 mg of the product obtained in the preceding step is refluxed for 4 hours. The methanol was evaporated under reduced pressure, the residue was taken up in ethyl acetate, washed with water, dried and concentrated under reduced pressure to dryness. 340 mg of product are obtained, which is chromatographed on silica gel with a 6: 4 solution of G solution in ethyl acetate to give 260 mg of product. The resulting product was chromatographed on a Lichrosorb RP18 cartridge with 9: 1 methanol: water to afford 140 mg of the desired product.

IR (CHC1 ₃ medium):

OH 3602 cm ' ¹ aromatics + conjugated systems 1610—1581—

1512-1504 cm 4. Preparation of β- [4- {5 - [(2-pyridinylmethyl) thio] pentyloxy} phenyl] estra-1,3,5 (10) -triene-3,17 β-diol

0.17 cm ^{3 of} 2-pyridine methanethiol, 81 mg of sodium methylate, 234 mg. Example 3 A solution of the product prepared in Step D and 4 cm ^{3 of} methanol was refluxed for 3 hours. The methanol was evaporated. the residue was taken up in ethyl acetate, washed with water, dried and concentrated to dryness under reduced pressure. The resulting 360 mg residue was chromatographed on silica gel with 8: 2 ethyl acetate: G to give 280 mg of the desired product.

IR (CHC1 ₃ medium):

OH 3605 cm @ ^-1 aromatics 1610-1581-1511 cm ^-1 pyridin 1594-1571 cm ^-1

Example 5 Preparation of β- [4- {5 - [(2-Pyridinylmethyl) sulfinyl] -pentyloxy} phenyl] estra-1,3,5 (10) -triene-3,17 β-diol

To a solution of the product obtained in Example 4 (172 mg) in 12 cm ^{3 of} methanol was added 3.7 cm ^{3 of a} 0.1 M aqueous solution of sodium metaperiodate. The reaction mixture was stirred for 1.5 hours, 3.4 cm ³ of methanol and 0.6 cm ³ of sodium metaperiodate was added, and after stirring for 3.5 h the reaction mixture was poured into water, extracted with ethyl acetate, followed by brine wash and concentrate under reduced pressure to dryness. The resulting residue (176 mg) was chromatographed twice on silica gel with methylene chloride / methanol (92.5: 7.5) to afford 107 mg of the desired product.

Spectrum IR (CHC1 medium _{nikolprizmán?):}

OH 3606 cm @ ^-1 aromatics and heterocycle sulfoxide 1610-1596-1583- 1572-1512 cm ^-1 1031 cm ^-1

Example 6

Preparation of P - [(3-Pyridinylmethyl) thio] pentyloxy) phenyl] estra-1,3,5 (10) -triene-3,17 β-diol

Step A: <11 β, 7 'β) - / 7,7' - {dithiobistyl-5,1-pentyloxy- (4,1-phenylene)] -? - diestra-1,3.5 (10) - preparation of triene-3,17 βdiol

11 β- {4 - [(5-chloropentyl) oxy] phenyl} estra-1,3,5 (10) -triene-3,17 β-diol obtained in Example 3, Step D

1.9 g and 910 mg of potassium thioacetate in 20 cm ^{3 of} ethanol are heated under reflux for 17 hours. After addition of 910 mg of potassium thioacetate, refluxing was continued for 10 hours with stirring. The ethanol was evaporated, the residue was taken up in ethyl acetate, washed with brine, dried and concentrated to dryness under reduced pressure. The residue (2.1 g) was chromatographed on silica gel with ethyl acetate / G (6: 4) to give 1.72 g of the desired product.

IR spectrum (nujol):

absorption in the NH / OH range of aromatics 1609-1580-1510 cm ^-1

Step B: Preparation of 11β- [4- (5- (3-Pyridinyl) -thio] -pentyloxy] -phenyl] -estra-1.3.5 (10) -triene-3,17-$ diol

a) reduction of disulfide

465 mg of the product obtained in the previous step and 0.25 cm ^{3 of} tributylphosphine are added to a previously degassed solution of 5 cm ^{3 of} tetrahydrofuran. The reaction medium is 2

After stirring at ambient temperature for 9 hours, the mixture was extracted with ethyl acetate, washed with water, dried and concentrated to dryness under reduced pressure to give 640 mg of mercaptan.

b) alkylation

The resulting mercaptan was dissolved in 5 cm ^{3 of} methanol and 160 mg of sodium methylate and 342 mg (96% by weight) of 3-chloromethyl-pyridine hydrochloride were added.

The resulting slurry was heated under reflux for 55 minutes with stirring, cooled to room temperature, acidified with 2 cm ^{3 of} 2N hydrochloric acid, basified with sodium bicarbonate, extracted with ethyl acetate, washed with brine, and then dried to dryness. until concentrated. The resulting product (650 mg) was chromatographed on silica gel with ethyl acetate / G (8: 2) to give 370 mg of the desired product.

IR (CHC1 ₃ medium):

OH 3607 cm 'aromas 1610-1580-1512 cm ^-1

Example 7

Preparation of P- [4- {5 - [(3-Pyridinylmethyl) sulfinyl] pentyloxy} phenyl] estra-1,3,5 (10) -triene-3,17 β-diol

The procedure was carried out as described in Example 5 except that 177 mg of the product of Example 6 were used as starting material. 185 mg of crude product are added to which is added 24 mg of an additional portion and the combined product is chromatographed on silica gel twice with 9: 1 CH 2 Cl 2 to give 138 mg of the desired product.

IR (CHCl ₃ nikolprizmán medium):

OH 3606 cm ' ¹ + general absorption heterocycles and aromas 1610-1580-1515 cm' ¹ sulfoxide -1030-1040 cm ^_i

Example 8 β- [4- (6 - [(4,4,5,5,5-Ρβηΐ3ί1υοΓ-ρβηύ1) -ύο] -ΗεχίΙoxy} -phenyl] -estra-1,3,5 (10) -triene- Preparation of 3.17 β-diol

Step A: Preparation of 11 β- {4 - [(6-100Γ-Ηεχί1) -οχϊ] -ίεηί1} -05ζΐΓ34,9-diene-3,17-dione

362 mg of 11 (4-hydroxyphenyl) -estra-4,9-diene-3,17-dione, 5 cm ^{3 of} acetone (obtained by the procedure described in Example 43 of European Patent Application 384 842),

A mixture of 1.5 cm <^{3> of} 6-bromo-chlorohexane and 138 mg of potassium carbonate was heated under reflux for 5 hours with stirring. Subsequently, 1 cm ^{3 of} 6-bromochlorohexane was added and stirring was continued for 16 hours while allowing the reaction mixture to cool to room temperature. The reaction mixture was then acidified with 2M hydrochloric acid, extracted with ethyl acetate, washed with water, dried and concentrated under reduced pressure to dryness. The received

The product (3.48 g) was chromatographed on silica gel with ethyl acetate / solution G (6: 4) and the residue was crystallized from methylene chloride / isopropyl ether to give 290 mg of the desired product (m.p. 221 ° C).

Step B: Preparation of 3-hydroxy-11 - {4 - [(6-chloro-hexyl) -oxy] -phenyl] -estra-1,3,5 (10) -trien-17-one Example 3 B Steps A and C are repeated, except that 481 mg of the product obtained in Step A above are used as starting material, followed by 0.5 cm ^{3 of} acetic anhydride and 0.25 cm ^{3 of} acetyl bromide. 483 mg of the expected product are obtained.

Step C: Preparation of $ 11 - (4 - [(6-chloro-hexyl) -oxy] -phenyl] -estra], 3,5 (10) -triene-3,17-β-diol As described in Example 3, Step D. except that 465 mg of the above product, 60 mg of boron and sodium hydride are used as starting material, 300 mg of the title product are chromatographed on silica gel with a 6: 4 solution of G and ethyl acetate and crystallized from methylene chloride. m.p. 176 ° C.

Step D: Preparation of $ 11 - (4 - [(6-iodohexyl) oxy] phenyl} oestral, 3,5 (10) -triene-3,7,17-diol To a solution of 6 cm <^{3> in} methyl ethyl ketone was added 150 mg of sodium iodide and the solution was stirred at reflux for 24 hours, then 100 mg of sodium iodide was added and the mixture was stirred at reflux for 2 hours. stirring was continued for 16 hours while allowing the reaction mixture to cool to room temperature, then taken up in ethyl acetate, washed, dried and concentrated under reduced pressure to dryness to give 470 mg of product which was used in the next step.

Step E: Preparation of $ 11 - (4 - ((6- (thioacetyl) hexyl] oxy / phenyl / estra-1,3,5 (10) -triene-3,17-β-diol) To a solution of 470 mg of product (470 mg) in 6 cm <^{3> of} ethanol was added 150 mg of potassium thioacetate, and the reaction mixture was stirred for 1 hour 50 minutes at 50 [deg.] C. The ethanol was evaporated. The resulting residue (400 mg) was chromatographed on silica gel with ethyl acetate / G (6: 4 then 8: 2) to give 265 mg of the desired product (m.p. 90 ° C).

IR spectrum (CHCl _{3 in} nicolytic prism):

OH 3602 cm ^-1 C = O 1686 cm ^-1 aromas 1610-1581-1512 cm ^-1

Step F: $ 11 - (4- (6 - ((4,4,5,5,5-pentafluoropentyl) thio] hexyloxy} phenyl] estra-1,3,5 (10) -triene- 3, Preparation of J7 βdiol

200 mg of the above product and 127 mg of 4,4,5,5,5-pentafluoroiodine (prepared as described below)

GB 211 865 A9 pentane was added in 5 cm ³ of methanol, 0.1 cm ³ of sodium hydroxide solution. The reaction mixture was stirred at 50 ° C for 1 hour and then the solvent was evaporated under reduced pressure. The residue was taken up in a mixture of methylene chloride and 2M hydrochloric acid, extracted with methylene chloride, washed with water, dried and concentrated under reduced pressure to dryness. The resulting residue was subjected to silica gel chromatography (65:35 v / v ethyl acetate) to obtain 149 mg of the desired product.

IR (CHC1 ₃ medium):

OH 3600 cm ¹ aromas 1620-1580-1512 cm ^-1

Example 9 β- [4- {6 - ((4,4,5,5,5-Pentafluoropentyl) sulfinyl] hexyloxy} phenyl] estra-1,3,5 (10) -triene -3.17 Preparation of β-diol

To a solution of 110 mg of the product of Example 8 in 5.5 cm ^{3 of} methanol was added 0.61 cm ³ of a 0.5 M aqueous solution of sodium metaperiodate. After stirring for 1 hour at room temperature, the methanol was evaporated under reduced pressure. The residue was taken up in 2N hydrochloric acid and extracted with methylene chloride. After drying and concentration to dryness, the resulting residue is chromatographed on silica gel (methylene chloride: methanol = 95: 5, v / v) to give 96 mg of the desired product.

IR spectrum (in CHClben medium):

OH 3605 cnr ¹ + secondary values aromatic 1610-1580-1512 cm ^-1 sulfoxide 1031 cm ¹

Example 9a β- [4- {6 - ((4,4,5,5,5-Pentafluoropentyl) sulfinyl] hexyloxy} phenyl] -estra-1,3,5 (10) -triene- Preparation of 3,17-diol

To a solution of 150 mg of the product of Example 8 in 2 cm ^{3 of} methylene chloride is added 150 mg (70% by weight) of perphthalic acid. After stirring for 1 hour and 15 minutes, aqueous sodium thiosulfate solution was added followed by aqueous sodium bicarbonate solution. After extraction with methylene chloride, the mixture was dried and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel (eluting solvent: G: 6: 4) to give 130 mg of the desired product.

IR (CHC1 ₃ medium):

OH 3603 cm ¹ + secondary values aromatic 1622-1610-1570-1511 -1505 cm 'sulfone 1305-1132 cm ^-1

Preparation of reagent used in Example 9

4,4,5,5,5-pentafluoro-iodopentane

Step A: Preparation of 4,4,5,5,5-pentafluoropentanol g prepared in known manner [T. Kitazume and N.

Ishikawa, J. Am Chem. Soc., 107, 5186-5191 (1985)].

4,4,5,5,5-Pentafluoro-2-penten-1-ol is dissolved in 100 cm ^{3 of} methanol and hydrogenated in the presence of 0.5 g of Raney nickel. The catalyst was removed by filtration, washed with ethanol, and after distillation at ambient pressure, the desired alcohol was collected (b.p. 133 ° C, _D ²³ : 1.3305):

Step B: Preparation of 4,4,5,5,5-pentafluoroiodo-pentane

To a solution of 2.65 g of triphenylphosphine and 0.69 g of imidazole in 20 cm ^{3 of} methylene chloride, keeping 2.54 g of iodine and keeping the temperature below 25 ° C - 1.78 g of the product obtained in Step A A solution of 3 cm ^{3 of} methylene chloride was added. The reaction mixture was stirred for 3 hours, then filtered, the methylene chloride was evaporated and the residue was taken up several times with pentane. Evaporation of the pentane gives 3.45 g of product, which product is obtained by distillation (b.p. - 42-45 ° C at 40 mbar; n _D ²³ : 1.4054):

10-13. examples

By following the procedure of Example 1 and starting from the product of Example 1, Step D, the compound of Example 10 is prepared. 11-13. The following compounds were prepared according to the procedure described in Example 1 except that the corresponding compounds of formula II were used as starting materials.

10-13. Examples 1 to 9 are compounds of formula I wherein R ₁₇ is hydroxy, R ₁₇ , ₇ are hydrogen, m is 0, and X, Y and Z are as defined in Table I below. In each example, mercaptan of formula (III) is used where Za is as defined in Table I for Z.

10-13. The IR spectra of the compounds of Examples 1 to 4 are also shown in Table 1.

10-13. The compounds of formula (I) wherein m is 1 are prepared according to the procedure of Example 5.

Table 1

Examples X Y z IR cm ^-1 10 ch ₂ (CH ₂ ) ₇ 3602 (OH), 1609, 1585, 1501 11 ch ₂ (CH ₂ ) ₉ 3603 (OH), 1609, 1561, 1498 12 ch ₂ (CH ₂ ) ₉ 3602 (OH), 1615, 1609. 1583, 1498

HU 211 865 A9

13 ch ₂ (CH ₂ ) ₉ CH 1 Y i Μ H 3603 (OH), 1609, 1580, 1500

14-24. examples

14-21. Examples 22-24 are prepared according to the procedure described in Example 2, Examples 22-24. The compounds of Examples 1 to 8 are also prepared according to the procedure of Example 2, but using the corresponding compounds of formula II as starting materials. These compounds are compounds of formula (I). wherein R ₁₇ is hydroxy, R ₁₇ is hydrogen, m is 0, X, Y and Z are the following II. given in table. Any of the above compounds is prepared using mercaptan (III) wherein Za is as defined in ZII. table.

14-24. The IR spectra of the compounds of Examples 1 to 4 are also shown in Table II. Table.

14-24. The compounds of formula (I) wherein m is 1 are prepared according to the method of example 5.

Π. spreadsheet

i Examples nr Ϋ- z IR cm ^-1 ! 14 1 ί φ C eC- (CH ₂ ) OH, NH, 2218 (C 1 C), 1612,, 1575, 1508, 1499 i • 15 φ C = C- (CH ₂ ) nh ₂ -0 nh ₂ OH.NH. 1614, 1580, 1543, 1500 16 φ C sC- (CH ₂ ) : ¼ ¹ 3601 (OH), 1605, 1583, 1555, 1504 17 φ C = C- (CH ₂ ) F _p 3601 (OH), 2212 (CsC), 1609, 1571, 1505 18 φ C = C- (CH ₂ ) O-t y ο-CH, 3600, 3330 (OH), 1705 (C = 0), 1617, 1603, 1585, 1575. 1560,, 1505 19 φ C = C- (CH ₂ ) xo 3601 (OH), 2212 (CsC). 1610. 11584, 1555, 1505 20 φ ChC- (CH ₂ ) 3602 (OH), 1607,1593, 1571, 1554, 1505

HU 211 865 A9

21 Φ C = C- (CH ₂ ) OH, NH, 1601. 1504 22 Φ C s C - (CH ₂ ) ₄ 3604 (OH), 1613, 1571, 1505 23 Φ C s C - (CH ₂ ) ₆ 3605 (OH), 1615, 1610,, 1571, 1505 24 _ Φ C C- (CH ₂ ) ₆ 3600 (OH), 1609. 1596, 1571, 1505

25-29. examples

25-27. The compounds of Examples 1 to 8 were prepared according to the procedure of Example 6 and the compound of Example 28 was prepared according to the procedure of Example 8. These compounds are compounds of the formula I. wherein R ₇ is hydroxy. R'n is hydrogen and m is 0. X. Y and Z are as defined in formula III. given in table. The above compounds are prepared using a compound of formula VI wherein Za is as defined in ZIII. table.

25-28. The compounds of formula (I) wherein m is 1 are prepared according to the procedure of Example 5. The compound of Example 29 was also prepared by this procedure using the compound of Example 25 as starting material.

25-29. The IR spectra of the compounds of Examples 1 to 4 are also shown in Table III. Table.

III. spreadsheet

Examples X γ z IR cm ¹ 25 φθ (CH ₂ ), OH E.g OH, NH. 1708, 1660 (C = 0), 1608, 1578, 1510 26 φθ (CH ₂ ) ₅ OH. NH. 1610, 1580, 1530, 1510 27 φθ (CH ₂ ) ₅ V ^{/ Hs} V-11 ^X CH, 3608 (OH), 1705, 1658 (C = 0), 1609, 1578, 1551, 1512. 1503 28 φθ (CH ₂ ), 3606 (OH), 1609, 1581, 1565, 1512, 1609, 1585, 1501 29 φθ (CH ₂ ) ₅ OH OH, NH, 1708, 1660 (C = O), 1608. 1578, 1510, 1015 (SO)

HU 211 865 A9

Example 30

3- [4- {6 - [(4,4,5,5,5-Pentafluoropentyl) thio] pentyloxy} phenyl] estra-1,3,5 (10) -triene-3 , l7 β-diol

The desired product was prepared according to the procedure of Example 8 except that 5-bromo-chloropentane was reacted with 11 β- (4-1ιί0Γθχί-ίεηί1) -05ζΐΓ3-4,9-0ίene-3,17-dione. .

IR spectrum (CHCl _{3 in} nicolytic prism):

C = 0OH 3600 cm * aromas 1625-1613-1570-1511-1500 cm31. Example β- [4- {6 - [(4,4,5,5,5-Pentafluoropentyl) sulfinyl] pentyloxy} phenyl] -estra-1,3,5 (10) -triene-3 , 17 β-diol

The title compound was prepared according to the procedure of Example 9 using the product of Example 30 as starting material.

IR spectrum (CHCl _{3 in} nicolytic prism):

OH 3606 cm ^-1 + secondary maturity aromas 1622-1610-1570-1511-1505 cm ¹ sulfoxide 1030 cm ¹

Medicinal preparations

Tablets were prepared as follows:

The compound of Example 5 was 50 mg to 50 mg

- binder (talc, hardener, magnesium stearate) for a total weight of 120 mg required.

Pharmacological Testing of Compounds of the Invention

1. To study the activity of the compounds of the invention on the estrogen receptor in the mouse uterus

18-21 days old, sexually immature female mice are dissected, removed from the uterus, and potter's Teflon Teflon / homogenize using a glass vessel (1 g tissue per 25 ml TS solution). The homogenate (209,000 g for 30 minutes) was ultracetrifuged at 0 ° C. Aliquots of the supernatant thus obtained at constant concentrations of tritium-labeled estradiol (T), with increasing concentrations (0-1000 χ 10 ^-9 mol / L) of unlabelled estradiol or (1-25000 χ 10 ^-9 mol / L) unlabeled test compound in the presence of 25 ° C for 5 hours. The concentration of bound tritium-labeled estradiol (B) in each incubated sample was determined by the carbon / dextran adsorption method.

Calculation of Realistic Binding Affinity (RKA)

The following two curves are plotted: the percentage of B / BO bound tritiated hormone as a function of the logarithm of the concentration of unlabeled reference hormone or of the concentration of unlabeled test compound.

Determine the following equation for a straight line:

Ijo = 100 (B / BO + B ^ n / BO) ^, ie

I ₅₀ = 100 (1 + 6 ^ 0) / 2 = 10 (1 -ι-Β, ηίη / ΒΟ).

In the equation above

BO means:% bound of bound tritiated hormone without labeled compound,

B is the% binding of bound tritiated hormone in the presence of unlabeled compound X, and

B _mn :% binding of bound tritiated hormone in the presence of a large excess (500 nmol / L) of unlabelled reference hormone.

Determine the unlabelled reference hormone (CH) and unlabeled test compound (CX) of the concentrations corresponding to I ₅₀ and a linear equation of the curves intersect at points that are binding to 50% to inhibit tritiated hormone receptor.

The relative binding affinity (RKA) of the test compound was calculated using the following equation:

RKA = 100 (CH) / (CX).

The following values are provided as an illustration:

EXAMPLE 1 Compound incubation of the estrogen receptor for 5h at 25 ° C 5th 21.2 _ 26.3

2. Antiproliferative Activity of the Compounds of the Invention on Growth of MFC-7 Type Mammary Tumor Cells

Description of the test

(a) Cell culture

Cells belonging to the MCF-7 cell line were cultured on SVF medium [1] at 37 ° C in a humidified atmosphere of 5% CO ₂ . The confluent cells were harvested by trypsinization (0.05 wt% tnpsin, 0.02 wt% EDTA) and rinsed by gentle centrifugation. The sample containing cells in suspension is assayed with a Maltz-type cell counter.

(b) Growth assays

Cells resuspended in DSE medium according to [1] are transferred to a microtiter plate at 50,000 cells / well (25 wells / 2.5 cm ² ). Twenty-four hours after inoculation (JO), the test compound is added to the medium in an ethanol solution (final concentration of ethanol is 0.1% v / v, with a concentration ranging from 10 ~ ^H to 10 ^-6 mol / l). The medium is renewed every 48 hours At the end of the experiment (J7-J9) the medium is extracted and the cells are immediately fixed with 150 μΐ of methanol to add DNA.

The antiproliferative activity of the compounds is determined by their ability to inhibit the growth of DNA.

C) Addition of DNA

DNA is added by fluorimetry [2]

Using DABA (3,5-Diaminobenzoic Acid) according to EN 211 865 A9: Add 150 μAB DABA to each well, then incubate the plates at 56 ° C for 45 minutes and add 2 ml of 1 M hydrochloric acid. . Fluorescence was measured with a fluorimeter (excitation wavelength: 408 nm, emission wavelength: 510 nm).

The amount of BNS per well is determined by reference to a scale obtained by treatment with calf thymus DNA under the same conditions.

Results

The concentration in nmol / l which inhibits the growth of MCF7 cells by 50% (IC ₅₀ ) was determined as discussed above.

Example 1 Compound: IC ₅₀ = 0.024 nmol / L

Example 5 Chemical: IC ₅₀ = 0.012 nmol / L

Example 7 Compound: ICγ = 0.026 nmol / L [1] The stock medium was prepared as follows:

NOT medium (Minimum Essential Medium) to which we add the following:

- 1% by weight of non-essential amino acids (GIBCO),

- 100 U / ml penicillin and 0.1 mg / ml streptomycin,

0.1% by weight of fungizone.

- 2 mmol / l glutamine and

- 2.25 mg / ml sodium bicarbonate.

The SVF medium consists of 95% v / v stock and 5 volumes of bovine embryo serum.

The DSE 95 volumetric fluid alapközegből, 5 volumetric steroid free carbon-dextran the supported borjúernbrió from serum and a 10 ^IU mol / 1 estradiol.

[2] Puzas and Goodman, Analytical Biochemistry.

Claims (13)

PATENT CLAIMS Compounds of formula (I) and addition salts thereof, wherein: R ₁₇ and R 'together represent a ketone _I7, or R ₇ is a hydroxyl group or up to 12 carbon atoms, an acyloxy group, and R'i is hydrogen or up to 8 carbon atoms. optionally substituted alkyl. alkenyl or alkynyl. m is 0, 1 or 2, X is a methylene group having up to 10 carbon atoms attached to the steroid ring via a carbon atom, or an aryleneoxy group, Y is a C 1 -C 18 saturated or unsaturated, linear or branched aliphatic chain, and Z is C 1 -C 8 optionally substituted straight-chain or branched alkyl or optionally substituted aryl or arylalkyl wherein the alkyl group can be up to 6 carbon atoms and the aryl group is a 5- or 6-membered monocyclic ring or —Is a group of 10-membered fused rings wherein these groups may optionally contain one or more heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the alkyl groups of R _'17 and Z, the alkenyl or alkynyl of R' ₁₇ and the aryl or arylalkyl groups in Z are optionally substituted one or more times with: - halogen, - an amino group, an alkylamino group or a dialkylamino group, wherein the alkyl group (s) may have from 1 to 4 carbon atoms, - hydroxy, - free carboxyl group converted to an ester or a salt. - C 1 -C 8 alkyl, optionally mono- or polysubstituted by halogen, - oxo, cyano, nitro or formyl, - acyl or acyloxy having up to 12 carbon atoms, - C 1-4 alkoxy or alkylthio. - carbamoyl, - an alkenyl or alkynyl group containing up to 4 carbon atoms, and - an aryl group as defined above. 2. A compound according to claim 1 (I) is hydrogen, wherein _{R] 7} jelenétse hydroxyl group, and R 'is _l7. Compounds of formula (I) according to claim 1 or 2, in which X is a methylene group and Y is a C7-C9 saturated straight chain group. The process according to claim 1 or 2. Compounds of formula (I) wherein X is phenylene and Y is a C 3-8 saturated or unsaturated straight chain moiety, provided that the unsaturated moiety contains a vinylene or ethynylene group directly attached to the phenylene group. A compound of formula (I) according to claim 1 or 2, wherein X is phenyleneoxy. and Y is a C4-C7 saturated straight chain group. 6. A compound of formula (I) according to any one of claims 1 to 3. in which formula Z is a pentafluoroalkyl group having 3 to 5 carbon atoms, O-COO-alkyl, wherein alkyl is C 1-4 alkyl; a 5-membered heterocyclic group of formula (e), (f), (g), (h), (i) or (j), (k), (1), (m), (n), (o). ) or a 6-membered heterocycle having the formula (p) or a heterocyclic group having two fused rings of the formula (q), (r), (s) or (t). 7. A process according to any one of claims 1 to 4. It is a compound of general formula (1) 11 3 - [(2-pyridinylmethyl) thio] octyl} -estra-1,3,5 (10) -triene-3,17-β-diol, HU 211 865 A9 11 β- [4- {3 - [(1-methyl-1H-imidazol-2-yl) thio] -1-propynyl} phenyl] -estra-1,3,5 (10) -triene-3, 17 β-diol, 11 β- [4- {5 - [(2-furanylmethyl) thio] pentyloxy} phenyl] estra-1,3,5 (10) -triene-3,17 β-diol, 11 β- [4- {5 - [(2-pyridinylmethyl) sulfinyl] pentyloxy} phenyl] estra-1,3,5 (10) -triene-3,17 β-diol, 11 β- [4- {5 - [(3-pyridinylmethyl) sulfinyl] pentyloxy} phenyl] estra-1,3,5 (10) -triene-3,17 β-diol, 11 β- [4- {6 - [(4,4,5,5,5-ρεηΐ8ί1ιΐ0Γ-ρεηΙϊ1) -5Ζΐι1ίϊηί1] hexyloxy} -phenyl] -estra-1,3,5 (10) -triene-3 , 17 β-diol. Process according to claim 1 of formula (I): characterized in that a compound of formula (II) wherein R _17a and R ' _{) 7a} has the same meaning as in R ₁₇ and R' _{7 is as} claimed in claim 1, wherein the reactive groups optionally present are optionally protected . X and Y are as defined in claim 1, R ₃ is hydrogen or a hydroxyl protecting group and fish is a reactive group such as a halogen or a pseudo-halo group such as a tosylate is reacted with a mercaptan of formula (III) or a salt thereof. Za-SH (III) wherein Za has the same meaning as Z according to claim 1, wherein the optionally present reactive groups are optionally protected, then optionally removing the protecting groups from the 3- and 17-position hydroxyl groups and optionally other reactive groups with a suitable rag. A compound of formula I, which is a narrower group of compounds of formula I, is obtained. wherein m is 0 - and the resulting compound of formula IA is then subjected to the following reaction (s) as desired or optionally (in any order): reducing the ketone moiety formed by R ₁₇ and R ₁₇ to form a metal complex of formula (IV) by addition to the ketone moiety R ₁₇ and ed ₁₇ ' M-R _l7a (IV) wherein M is a metal atom and R _'7 are as defined above with the proviso that, other than hydrogen, the 17-position - is conducted on a selective acylation reaction, when Y is unsaturated - when R ₁₇ is hydroxy the ethynylane group is partially or completely reduced, the sulfur atom is oxidized to a sulfoxide or sulfone and optionally salted with an acid or a base. A process for the preparation of a compound of formula (I) according to claim 1, wherein a compound of formula (V) wherein R _17a and R 'have the same meaning as R ₁₇ and R' ₁₇ according to claim 1, where the reactive groups present in the protected exet are optionally protected, X and Y are as defined in claim 1, R ₃ is hydrogen or hydroxy protecting group, and W is a hydrogen atom or an acyl group of the formula -COR wherein R is a C 1 -C 5 group - is reacted with a compound of the formula VI or a salt thereof. Zahal '(VI) wherein Za is as defined for Z in claim 1, wherein the optionally present readable groups are optionally protected and hal 'is a reactive group such as a halogen or pseudp-halogen such as mesylate or tosylate in the presence of a base, optionally removing the protecting groups from the hydroxy groups at the 3- and 17-positions and optionally other protected reactive groups to give the hydrogen compound of formula (IA) according to claim 8, which is desired or optionally for the compounds of formula (IA) . 10. Compounds of formula (I) according to any one of claims 1 to 6 as medicaments. Compounds of formula (I) according to claim 7, as medicaments. Pharmaceutical compositions containing as active ingredient at least one medicament according to claim 10 or 11. 13. Compounds of formula (II) and (V) wherein the substituents are as defined in claim 8 or claim 9 as novel intermediates, except for compounds of formula (II) wherein X and Y are methylene, R _7a is an optionally protected hydroxyl group, and R'I? _a is hydrogen.