FR2582654A1 - 11 beta -Substituted steroids useful especially in the treatment of hormone-dependent tumours and process for producing them - Google Patents

Abstract

THE 11B-SUBSTITUTED STEROIDS ACCORDING TO THE INVENTION ARE 3-OXO- OR 3-METHYLENE-4 (5), 9 (10) -ESTRADIENES OF GENERAL FORMULA I: (CF DRAWING IN BOPI) APPLICATIONS: PHARMACEUTICAL COMPOSITIONS IN HUMAN MEDICINE OR VETERINARY, ESPECIALLY AS ANTIPROGESTERONE AND ANTIGLUCOCORTICOID AGENTS AND IN THE TREATMENT OF HORMONO-DEPENDENT TUMORS.

Description

The present invention relates to novel 11P-substituted steroids, a

  process for making and compositions

  pharmaceutical or veterinary medicines containing them.

  The compounds of the invention have the following general formula: R <zR7 (I)

1 41

R 6

R2 R3

  wherein R1 and R2 are both hydrogen or R1 and R2 taken together represent an oxo residue or = CH2; R3 is a substituent at the 6 or 7 position selected from C1-C6 alkyl, C2-C5 alkenyl and C2-C5 alkynyl radicals; R4 is a group of the formula - (CH2) n-A-Z-, in which n is

  equal to 0 or an integer of 1 to 3 ;.

  A is a bond or represents a C4-C7 cycloalkyl ring, a phenyl ring or a saturated or unsaturated heteromonocyclic ring containing one or more heteroatoms selected from O, S and N; and R Z represents: (a) hydrogen; (b) a group of the formula -N8R wherein R8 and R9 each independently represent hydrogen or a C1-C6 alkyl or phenyl group, or R8 and R9 taken together with the nitrogen atom to which they are attached form a saturated heteromonocyclic ring containing one or more heteroatoms selected from O, S and N; (c) a R 10 group of the formula -Si R 11 wherein R 10, R 11 and R 12 R 12 are the same or different and each represents a C 1 -C 6 alkyl or phenyl group; (d) a group of formula -O- (CH2) D-R13 wherein p is 0 or an integer R of 1 to 5 and R13 is a hydrogen atom or a NR group in which R8 and R9 are defined as above; or (e) a halogen atom or a halo-C 1-6 alkyl group; R5 is a C1-C6 alkyl group; R6 is hydroxy and R7 is hydrogen, C1-C6alkyl, C2-C5alkenyl or C2-C5alkynyl, or

  R6 and R7 together represent The group = CH2.

  The invention also comprises the pharmaceutically acceptable salts of the compounds of formula (I)

  as well as the possible isomers of formula (I) and mixtures thereof.

  In the present description, the alkyl groups,

  alkenyls and alkynyls can be straight-chain or branched.

  A C 1 -C 6 alkyl group is preferably a group

  C1-C3 alkyl, in particular methyl or ethyl.

  A C2-C5 alkenyl group is preferably a group

vinyl or allyl.

  A C2-C5 alkynyl group is preferably a group

  ethynyl, 1-propynyl or 2-propynyl.

  A halogen atom is preferably a chlorine atom

or fluoren particular fluorine.

  A C1-C6 haloalkyl group is preferably a

  di- or trihalo-C 1 -C 6 alkyl group, in particular difluoro-

methyl or trifluoromethyl.

  When, in the definition of R4 above, A represents

  a C4-C7 cycloalkyl ring, it is preferably a ring:

cyclopentyl or cyclohexyl.

  When A represents a saturated or unsaturated heteromonocyclic ring as indicated above, it is preferably a group

piperidyl or pyridyl.

  In the case where A is a cycloalkyl, phenyl or heteromonocyclic ring as defined above with reference to formula (I), Z indicates a substituent at any position of said ring. R 7/8 When Z represents a group -N <R, wherein R8 9'0

  and R9 are each independently C1-C6alkyl, preferably

  C1-C4alkyl, especially methyl or ethyl.

  When Z is -N: R or a and R9 taken together with the nitrogen atom to which they are attached form a heteromonocyclic ring as previously indicated, it is preferably a piperazinyl, imidazolidinyl, morpholino or piperidino group. -

  The same applies to the definition of R13 when

/ 8

  that it represents a group -N mR.

  / 10 When Z represents a -Si-Ril group defined as

R12

  above, R10, R11 and R12 are preferably identical and

  each have a C1-C6 alkyl group, in particular methyl.

  Preferably, R 3 is a C 1 -C 6 alkyl group,

especially methyl or ethyl.

  Preferably, R4 is a - (CH2) n-A-Z- group in which, either 1) n is 1 or 2 or preferably 3, A is a bond and Z

  is a group -NtR8, where R and R are as defined above.

  above; or else 2) n is zero, A is phenyl and Z is (i) a group -N, R8, wherein R8 and R are as defined above, group -R 9 R sotcmedfnsc-ess or ii) a group -O- (CH 2) p R 13, wherein p is 1 or 2 and R 13 is hydrogen or a group -N, wherein R 8 and

13 9 9

  R9 are as defined above, or (lii) a halogen atom

  or a C1-C6 haloalkyl group.

  Preferred -N 4 R 8 groups are amino and dimethylamino groups Preferred groups -O- (CH 2) p-R 13 are

  methoxy, aminoethoxy and dimethylaminoethoxy.

  The preferred halogen is fluorine and halogeno groups.

  Preferred C1-C6 alkyls are difluoromethyl and more particularly

trifluoromethyl.

  Specific examples of preferred R 4 substituents are dimethylaminopropyl, dimethylaminophenyl,

  dimethylaminoethoxyphenyl, methoxyphenyl and trifluoromethylphenyl.

  A preferred R 5 residue is methyl or ethyl, in particular

bind methyl.

  Preferably, R 7 is C 1 -C 6 alkyl or C 2 -C 5 alkenyl, or more preferably C 2 -C 5 alkynyl, particularly 1-propynyl. As already mentioned, the invention also encompasses the pharmaceutically acceptable salts of compounds

of formula (I).

  These salts may be salts formed with acids that are either inorganic or organic that are acceptable in human or veterinary pharmacy. Examples of inorganic acids are hydrochloric, hydrobromic, nitric and sulfuric acid and phosphoric acid; examples of organic acids are acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, malic acid, fumaric acid, succinic acid,

  tartaric, citric, oxalic, methanesulfonic and ethanesulfonic.

  In formula (I) above and the following formulas,

  a dashed line (. ,, '') indicates a substitute in the configuration.

  a, that is to say, below the plane of the nucleus; a trait in

  tip (-) indicates a substituent in the To configuration, that is,

  say above the plane of the nucleus; a wavy line (rx.J) indicates that a substituent may be in configuration a or in configuration 1 or both. Accordingly, when a formula has a substituent with a wavy bond, the formula may represent a compound having the substituent only in the α configuration or only in the A configuration, or it may represent a mixture of both the compounds having the substituent in the configuration a and compounds having the

  substituent in configuration 1.

  A preferred class of compounds of the invention comprises those compounds of formula (I) wherein R 1 and R 2 taken together form an oxo residue; R3 is a C1-C6 alkyl group; R4 is - (CH2) nAZ wherein n is an integer MR8 of 1 to 3, A is a bond and Z is -N 'R8 wherein R8 and R9 are each independently hydrogen or an alkyl group C1-C6 alkyl; R5 is a C1-C2 alkyl group; R6 is hydroxy and R7 is C1-C6 alkyl, C2-C5 alkenyl or alkynyl

  C2-C5, and their acceptable salts in human or veterinary pharmacy.

nary.

  Another preferred class of compounds of the invention

  takes the compounds of formula (I) in which R1 and R2 taken together form an oxo residue or = CH2; R3 is a C1-C6 alkyl group; R4 is - (CH2) -AZ wherein n is zero, A is phenyl and Z is (i) -N-R8, wherein R9 R8 and R9 are each hydrogen or an alkyl group; C1-C6 or (ii) a -O- (CH2) p-R13 group in which p is 1 or 2 and R13 is a hydrogen atom or a group -N 8 in

13 - R9.

  wherein R8 and R9 are defined as above or (iii) a halogen atom or a C1-C6 haloalkyl group; R5 is a C1-C2 alkyl group; R6 is hydroxy and R7 is C1-C6 alkyl, C2-C5 alkenyl or C2-C5 alkynyl, and

  acceptable salts in human or veterinary pharmacy.

  As specific examples of preferred compounds of the invention, mention may be made of the following compounds:

  methyl-17β-hydroxy-17- (1-propynyl) -11- (4-dimethylaminophenyl) -

4 (5), 9 (10) -estradiène-3-one;

  1-methyl-70-hydroxy-17? - (1-propynyl) -11- (3-N, N-dimethylamino)

  propyl) -4 (5) 9 (10) -estradiène-3-one;

  -methyl-17D-hydroxy-17? (1l-propynyl) -11P- (4-trifluoromethylphenyl) -

4 (5), 9 (10) -estradiène-3-one;

  6β-methyl-17α-hydroxy-17α- (1-propynyl) -11- (4-N, N-dimethylamino);

  ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one;

  7a-methyl-17-hydroxy-17? (1-propynyl) -110- (4-dimethylaminophenyl) -

4 (5), 9 (10) -estradiène-3-one;

  7α-methyl-170-hydroxy-17α- (1-propynyl) -11- (3-N, N-dimethylamino);

  propyl) -4 (5), 9 (10) -estradiene-3-one;

  7a-methyl-170-hydroxy-17- (1l-propynyl) -1103- (4-trifluoromethyl

  phenyl) -4 (5) 9 (10) -estradiène-3-one;

  7a-methyl-17D-hydroxy-17? (1-propynytl-11D- (4-N, N-dimethylamino

  ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one;

  6p-methyl-170-hydroxy-17? (1-propynyl) -110- (4-methoxyphenyl) -

4 (5), 9 (10) -estradiène-3-one;

  6i-ethyl-17-hydroxy-17? (1-propynyl) -110- (4-dimethylaminophenyl)? -

4 (5), 9 (10) -estradiène-3-one;

  -ethyl-170-hydroxy-17a-C1-propynyl) -110- (3-N, N-dimethylamino

  propyl) -4C5), 9 (10) -estradiène-3-one; 6α-ethyl-17α-hydroxy-17α- (1-propynyl) -110- (4-trifluoromethylphenyl) -4 (5), 9 (10) -estradien-3-one;

  613-ethyl-17? -Hydroxy-17? (1-propynyl) -11- (4-N, N-dimethylamino

  ethoxyphenyl) -4 (5) 9 (C10) -estradiène-3-one;

  7a-ethyl-17l-hydroxy-17a) - (1-propynyl) -113- (4-dimethylaminophenyl) -

4 (5), 9 (10) -estradiène-3-one;

  7a-ethyl-170-hydroxy-17? (1-propynyl) -110- (3-N, N-dimethylamino

  propyl) -4 (5) 9 (10) -estradiène-3-one;

  7a-ethyl-170-hydroxy-17? (1-propynyl) -111- (4-trifluoromethyl

  phenyl) -4 (5) 9 (10) -estradiène-3-one;

  7a-ethyl-17? -Hydroxy-17? (1-propynyl) -11- (4-N, N-dimethylamino

  ethoxyphenyl) -4C (5), 9 (10) -estradien-3-one;

  7a-ethyl-17-hydroxy-17cl- (1-propynyl) -11t- (4-methoxyphenyl)? -

4 (5), 9 (10) -estradiène-3-one;

  6α-methyl-3-methyl-17α-hydroxy-17α- (1-propynyl) -110- (4-dimethyl) -1-

  aminophenyl) -4 (5), 9 (10) -estradien-3-one;

  7a-methyl-3-methylene-17i-hydroxy-17o- (1-propynyl) -11- (4-dimethyl-

  aminophenyl) -4 (5), 9 (10) -estradien-3-one; and when they agree, their acceptable selections in human pharmacy

or veterinary.

  Compounds of Formula (C1) are prepared by a process of dehydrating a compound of Formula (II) R

R 7

R! 1

R '2

  where R3, R4, R5, R6 and R7 are defined as above, R'1 and R'2 are R'1 and R1 are both hydrogen or taken together form

1 R2

  a protected oxo residue or = CH 2 and if desired to convert a compound of formula (I) into another compound of formula (I) and / or if desired to convert a compound of formula (I) into one of its salts (acceptable in human or veterinary pharmacy) or to obtain a free compound from a salt and / or if desired to separate

  a mixture of isomers of formula (I) to the isolated isomers.

  When, in a compound of formula (II) above, R '1 and R' taken together form a protected oxo residue, the R2 oxo residue may be protected in the acetal or thioacetal form, for example dimethoxyacetal, diethoxyacetal ,. dimethylthioacetal, diethylthioacetal, or in the form of ketal or thioketal, for example ethylenedioxyketal, or ethylenedithioketal, preferably ethylenedioxycetal. The dehydration of a compound of formula (II) can be carried out with a suitable dehydrating agent which can be for example a mineral acid, preferably concentrated, for example hydrochloric or sulfuric acid, or also with a sulfonic resin. The reaction may be carried out in an inert organic solvent, preferably an anhydrous, for example methanol, ethanol, benzene, toluene, n-hexane or cyclohexane, at a temperature which varies slightly

  about 0.degree. C. to about 500.degree. C., preferably at room temperature.

ambient temperature.

  When the reaction is carried out on a compound of formula (II) in which R'1 and R'2 taken together form a

  protected oxo as defined above, the elimination of the

  protection occurs at the same time as dehydration.

  The optional conversion of a compound of formula (I) into another compound of formula (I) may be carried out according to

known techniques.

  An optional conversion may be for example the conversion of a compound of formula (I) in which R1 and R2 taken

  together form an oxo residue in the corresponding compound of

  mule (I) in which R1 and R2 are both hydrogen: this transformation can be carried out for example by reacting first the 3-oxo derivative (compound of formula (I) in which R1 and R2 taken together form an oxo residue) with ethanedithiol

  in methanol and in the presence of boron trifluoride as a catalyst

  to obtain the 3,3-ethylene-dithio-ketal corresponding to

  and then reducing the latter by known techniques to obtain the corresponding compound of formula (I) wherein R1 and R2 are both hydrogen. In particular, for example, the selective reduction can be achieved by using the known techniques described in organic chemistry for the reduction of thioketals; for example, an alkali metal such as Li, Na or K in liquid ammonia can be used according to the procedure indicated for example by R.E. Ireland et al. in J. Amer. Chem. Soc. 1958, page 4604, or Raney nickel according to

  the procedure described for example by L. F. Fieser in J. Amer.

Chem. Soc. 70 1945, 1954.

  According to another optional conversion, one can trans-

  forming a compound of formula (I) in which R1 and R2 taken together form an oxo residue, in the corresponding compound of formula (I) in

  which R1 and R2 taken together form the remainder = CH2. This conversion

  The reaction may be carried out, for example, by treatment with a Wittig reagent of formula (O) 3 P) -CH 3 H 3 (-) in which O is a phenyl residue or a C 1 -C 6 alkyl group and Hal is bromine. or chlorine, following conventional procedures, for example the reaction can be carried out using a

  Slight excess of Wittig's reagent, using an organic solvent

  inert ether such as, for example, ethyl ether, tetrahydrofuran,

  n-hexane, dimethylsulfoxide, dimethylformamide or hexamethylphosphorine

  amide, and in the presence of a base which may be for example hydride

  of sodium or potassium tert-butoxide at a

  taken between about 0 C and the reflux temperature of the solvent

  used, preferably at room temperature.

  Also, the optional conversion of a compound of formula (I) into one of its salts and the preparation of a free compound from one of its salts can be carried out

according to known techniques.

  It is possible to operate according to conventional techniques such as, for example, fractional crystallization or chromatography for

  separate a mixture of isomers into the isolated isomers.

  A compound of formula (II) can be prepared by a process consisting of: 1) reacting a compound of formula (III)

R 6

He 1 RO. in which

R 'R'R

  R'1, R'2, R3 and R5 are defined as above, R 'is hydroxy and R'7 is hydrogen or C1-C6 alkyl, C2-C5 alkenyl or C2 alkynyl -C 5, with an organometallic compound carrying the radical R 4 as defined above, so as to obtain a compound of formula (II) in which R 6 is a hydroxy group and R 7 is hydrogen or a C 1 -C 6 alkyl group , C2-C5 alkenyl or C2-C5 alkynyl, and if desired, 2) to oxidize a compound of formula (II) wherein R6 is hydroxy and R7 is hydrogen so as to obtain a compound of formula (IV) wherein R'I1, R'2, R3, R4 and RS are defined as above, and then 3) by reacting a compound of formula (IV) with a Wittig reagent of formula (O) 3 P-CH 3 .alpha. in which 0 and Hal are defined as above, so as to obtain a compound of formula (II) in which R 6 and R 7 taken together form the

group = CH2.

  The organometallic compound carrying the radical R4 used for the reaction with a compound of formula (III) can be for example (R4) 2CuLi or R4Li or R4MgX, where X is a halogen, preferably

chlorine, bromine or iodine.

  The reaction is carried out preferably in the presence of a cuprous salt according to known techniques, as described for example by G. Teutsh in Tetr. Lett. 22, p. 2021 (1979). The optional oxidation of a compound of formula (II), wherein R 6 is hydroxy and R 7 is hydrogen, to obtain a compound of formula (IV) may be carried out according to

  known oxidation techniques, for example with dicyclohexyl-

  carbodiimide and pyridine in the presence of trifluoroacetic acid at room temperature. For the reaction between a compound of formula (IV) and a Wittig reagent of formula (0) 3 P H3.Hal (,

  conditions similar to those described above can be used

  above for the analogous reaction on a compound of formula (I),

  in which R1 and R2 form an oxo residue.

  The compounds of formula (III) can be prepared by epoxy-

  dation of a compound of formula (V): R '

^ 'R 17

R 'I (V)

R 3

  in which R'1, R'2, R3 and R5, R'6 and R'7 are defined as above. The epoxidation reaction may be carried out according to known techniques as described for example by L. Nedetec in Bull. Soc.

Chim. France 7, page 2548, 1970.

  The compounds of formula (V) can in turn be obtained by a multistep process comprising 1) bromination and dehydrobromination of a compound of formula (VI): R5 (VI)

0

  R3 in which R3 and R5 are as defined above, R "6 is a free or esterified hydroxy group and R" 7 is hydrogen so as to obtain a compound of formula (VII): R "

R 6 R'R

  (VII) wherein R3, R5, R6 and R7 are defined as above; 2) protecting the free carbonyl group in a compound of formula (VII) so as to obtain a compound of formula (VIII): ## STR5 ## wherein R 3, R 5, R 6 and R "7 are defined as above and R" 1 and R "2 taken together form a protected oxo residue; and 3) the optional conversion of a compound of formula (VIII) into a

compound of formula (V).

  When R "6 is an esterified hydroxy group, it may be, for example, esterified with a C 2 -C 7 aliphatic carboxylic acid or aromatic, for example acetic acid or benzoic acid, and the bromination and dehydrobromination of a compound of formula (VI) can be implemented by known techniques, for example by reaction with bromine, the perbromide of

  pyridine hydrobromide or pyrrobromide hydrobromide perbromide

  lidine in pyridine and subsequent treatment with an appropriate base

  asked. Protection of the free carbonyl group in a compound of formula (VII) can be implemented according to known techniques; preferably, the protection by ketalization is carried out under conventional conditions such as for example reaction with ethylene glycol in the presence of catalytic amounts of acid

  p-toluenesulfonic and optionally ethyl orthoformate.

  Optional conversion of a compound of formula (VIII)

  in a compound of formula (V) for example comprises

  which can be carried out in any preferred order: a) saponification of a compound of formula (VIII), wherein R "6 is an esterified hydroxy group, to obtain a compound of formula (V), wherein R 'is a free hydroxy group, R'7 is hydrogen and R' and R2 taken together form a

7 R1 R'2

  remains protected oxo; b) oxidation of a compound of formula (V) obtained under a) above to obtain the corresponding 17-oxo derivative, followed by nucleophilic addition to the 17-oxo group with an organometallic reagent carrying a residue R "'7, R 7 is C 1 -C 6 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl, so as to obtain a compound of formula (V) in which R 'is hydroxy and R' 7 is C1-C6alkyl, C2-C5alkenyl or C2-C5alkynyl and R'1 and R'2 taken together form a protected oxo residue; c) reduction on the protected oxo residue represented by R "1 and R" 2, or by R'1 and R'2, so as to obtain a compound of formula (V), in which R'1 and R'2 are both hydrogen; or d) removing a protecting group from the oxo residue represented by R "1 and R" or by R 'and R' and Wittig reaction with a

1 R2 1

  a compound of formula (O) 3 P CH 3 .alpha. in which O and Hal are defined as above, so as to obtain a compound of formula (V) in which R 'and R' taken together form

the group = CH2.

  The transformations indicated above can be

  performed according to known techniques by following

classical ways.

  In particular, for example, the saponification reaction a) can be carried out for example with an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, in an alcoholic medium, for example methanol, according to known techniques, while for the reactions indicated under b), c) and d), conditions similar to those described above for similar reactions can be followed. In particular, for example, the oxidation of a compound of formula CV), in which R 'is a free hydroxyl group and R' 7 is hydrogen, to give the corresponding 17-oxo derivative, may be used in a manner analogous to that described above for the preparation of a compound of formula (IV). Similarly, the nucleophilic addition to said 17-oxo group may be carried out for example with an organometallic reagent of formula (R "'7) 2CuLi or R"' 7Li or R "'7MgX, wherein R"' 7 and X are as defined above, operating in a manner analogous to that indicated above for the reaction between a compound

  of formula (III) and analogous organometallic compounds.

  The compounds of formula (VI) can be obtained by protecting, for example by ketalization as indicated above, a compound of formula (IX), R "6

RR "7

CIX) in which

  R3, R5, R6 and R7 are defined as above.

  A mixture of isomers A5 (10) and A5 (6) of formulas (Xa) and (Xb), respectively:

R "R 6

R 6X7

  Ri1 1., R R RR3 2 Ca (Xa) (Xb) in which

  R "1, R" 2, R 3, R 5, R "6 and R" 7 are defined as above.

  The isomer A5 (10) is separated from the mixture, for example by

  fractional crystallization or chromatography and then

  mine the protective groups of the rest oxo in a conventional manner.

  According to another mode of implementation, it is also possible

  The compounds of the formula (VI) can be obtained by dehydration of a compound of the formula (XI) R 6 (XI) R 'a OH R 3 in which R "1, R" 2, R 3, R 5, R "6 and R" 7 are defined as above, and

  then removing the protecting group from the oxo function.

  Dehydration can be carried out for example

  with a desiccant selected from SOCL2, P205 and Dicycolo

  hexylcarbodiimide by operating in an inert anhydrous solvent such as for example pyridine, tetrahydrofuran, methylene chloride

or benzene.

  The removal of the protective group of the oxo function can be carried out in a conventional manner, preferably under mild conditions, for example with acetic or formic acid.

  or oxalic acid in aqueous acetone.

  The compounds of formula (IX) are known IR. VilLotti, J. Am. Chem. Soc. 81, p. 4566 (1959) and J. F. Grunwell, Steroids 27, 6, 599 (1965)] or can be prepared by known techniques. The compounds of formula (XI) are also known compounds or can be prepared according to known techniques from

of known compounds.

  The compounds of the invention exhibit an activity

  anti-progesterone and anti-glucocorticoid.

  Although the compounds of the invention have been found to have in vitro affinity for rabbit uterine progesterone receptors and for rat thymus glucocorticoid receptors, however, after in vivo administration, it has been found that they are antagonists of progesterone and antagonists

  glucocorticoid without agonist effect.

  The progestomimetic and anti-

  progestomimetic in rabbits by measuring the proliferation of

  the uterine lining according to McPhail (J. Physiol 8, page 145, 1934).

  The compounds were administered for four consecutive days

  at various doses, alone and with a standard dose of progesterone.

  Glucocorticoid and antiglucocorticoid activities were evaluated in the liver glycogen accumulation test in rats according to G. P. Guthrie (Endocrinology 107, p. 1393, 1980). Played rats were treated for 14 h with various doses of the compounds alone (glucocorticoid activity) and with a standard dose of a glucocorticoid, dexamethasone (anti-glucocorticoid activity) and liver glycogen was estimated in animals sacrificed after 7 h . Progesterone is a key hormone in establishing and maintaining pregnancy in women and is involved in several hormone-dependent tumors. Because of their antiprogesterone activity, therefore, the compounds of the present invention may be useful for inducing menses when administered in the luteal phase of the menstrual cycle by preventing implantation during administration to implantation and causing abortion

  during administration in early pregnancy.

  The compounds of the invention can therefore be interesting

  in the regulation of hormonal imbalances and as anti-

  tumors for the treatment of hormone-dependent tumors

  than breast cancer and endometrial cancer.

  Because of their anti-glucocorticoid activity, the compounds of the invention are also of interest for treating, for example, the hypersecretion of glucocorticoids, the aging

in general and hypertension.

The compounds of the invention may be administered in any suitable manner, for example orally or parenterally, for example by injection or intravenous infusion.

  or by intramuscular, intravaginal or local injection. Oral administration is particularly suitable for compounds

  of the invention because the presence of the substituent R3 on the C6 or C7 carbon in the compounds of formula (I)

  an improved oral activity.

  Doses are highly dependent on the weight of the condition and

the history of the patient to be treated.

  For oral administration, the dose may be for example between 10 and 400 mg, one or more times per day for

some days.

  The pharmaceutical compositions of the invention are

  ordinarily prepared according to conventional techniques and

  in a form acceptable in pharmacy.

  For example, the solid forms for the oral route, for example tablets and capsules, may contain, in addition to the active compound, diluents, for example lactose, dextrose, sucrose,

  cellulose, corn starch and potato starch; lubricants

  such as silica, talc, stearic acid, magnesium stearate

  sium or calcium and / or polyethylene glycol; binding agents, for example starches, gum arabic, gelatin, methylcellulose,

  carboxymethylcellulose, polyvinylpyrrolidone; disorganized agents

  giants, for example a starch, alginic acid or alginates, starch glycolate sodium; effervescent mixtures; dyes; sweeteners; wetting agents, for example lecithin, polysorbates, lauryl sulphates; and in general, non-toxic and pharmacologically inactive substances used

  in pharmaceutical formulations.

  Said pharmaceutical preparations may be manufactured in known manner for example by mixing processes,

  granulation, pelletizing, coating or lacquering.

  Liquid dispersions for oral administration

  can be for example syrups, emulsions and suspensions.

  The syrups may contain as carriers or carriers, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol; in particular, a syrup to be administered to diabetic patients can only contain supports that are not metabolizable in glucose or metabolizable in very small amounts of glucose, such as sorbitol. The suspensions and emulsions may contain as support, for example a natural gum, agar, ialginate

  sodium, pectin, methylcellulose, carbox-

  methylcellulose or polyvinyl alcohol.

  Suspensions or solutions for intra-

  may contain, in conjunction with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol, and, if it is desired, a suitable amount of lidocaine hydrochloride. Solutions for intravenous infusions or infusions may contain as support, for example water

  sterile or preferably they may be in the form of

  sterile aqueous isotonic saline solutions.

  The gynecological tablets may contain, with the active compound, a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, acid surfactant ester

  polyoxyethylene sorbitan fat or lecithin.

  Compositions for local application, such as

  for example creams, lotions or pasta, can be prepared by -

  example by mixing the active ingredient with an oleaginous excipient

or classic emulsifier.

  The invention is illustrated, but not limited to, by the following examples, in which the abbreviations THF, DMSO and TLC refer to tetrahydrofuran, dimethylsulfoxide,

  and "thin layer chromatography".

Example 1

  A suspension of 12.69 g is cooled by an external bath.

  19-nor-5α-hydroxy-6α-methyl-3,3-ethylenedioxy-17 17-acetate

  17-hydroxyandrostane in 190 ml of pyridine and then dropwise into the vessel with stirring 12.7 ml of SOCI2 and keep the temperature below 5 C. When the addition is complete, the mixture is stirred for 5 minutes. 10 min then 200 ml of water are added and the aqueous layer is extracted a number of times with ethyl acetate. The organic phase is washed with water, dried over Na 2 SO 4 and the solvent is removed to give 14.2 g of crude 17-ethyl-17-hydroxy-3,3-ethylenedioxy-5 (10) estrene-17-acetate. NMR (CDCl 3) 6: 0.81 (3H, s); 1, 05 (3H, d); 2.03 (3H, s);

3.98 (4H, s); 4.66 (1H, dd)].

  The crude product is dissolved in 130 ml of ethyl ether and the solution is treated with 640 ml of 65% aqueous acetic acid and stirred for 24 hours at room temperature (20 ° C.). The reaction mixture is diluted with 1.3 l of water and extracted several times.

by ethyl acetate.

  The organic phase is dried, the solvent is removed in vacuo and the acetic acid is distilled azeotropically with cyclohexane. The crude product is purified on silica gel using ethyl ether: n-hexane 1: 1 as eluent.

  to give 7.85 g of 17-acetate of 6f-methyl-17-hydroxy-5 (10) -

  pure oily estrene-3-one [NMR Spectrum (CDCl3) 6: 0.84 (3H, s, C18); 1, 04 (3H, d, C6); 2.04 (3H, s); 2.63 (1H, d, C4); 2.98 (1H, d, C4);

4.65 (1H, dd, C17)].

  Using the same method, the following compounds are prepared: 60-ethyl-17α-hydroxy-5 (10) -estren-3-one acetate; 17-n-propyl-17? -5 (10) -estren-3-one 17-acetate;

  17-acetate 6f-isopropyl-170-hydroxy-5 (10) -estren-3-one.

  When dissolving 7.15 g of 17-acetate of 60-methyl-17?

  Hydroxy-5 (10) -estren-3-one in 500 ml of anhydrous benzene and 50 g of basic Al 2 O 3 are added, the mixture is refluxed for 1 h, Al 2 O 3 is filtered off and the solvent is removed. 1 g of crude 6O-methyl-17-hydroxy-5 (10) -estren-3-one acetate; chromatographic purification on silica gel using ethyl acetate: n-hexane 1: 1 gives 4 g of 17-acetate

  pure 6x-methyl-170-hydroxy-5 (10) -estren-3-one (oil).

Example 2

  To a solution of 7.85 g of 17-acetate of 60-methyl-17?

  5-hydroxy-5 (10) -estren-3-one in 380 ml of anhydrous pyridine is added in portions 9.9 g of pyridine hydrobromide perbromide, operating in a dry nitrogen atmosphere and cooling with an external bath. The mixture is stirred for 15 minutes and then warmed to 50 ° C. and stirred for 1 hour. The reaction is stopped by diluting the mixture in 500 ml of water, acidified to pH 2 with 98% H 2 SO 4 and extracted with ethyl acetate. The organic phase is dried and then the solvent is removed

  under vacuum and chromatographed 17-acetate-6-methyl-17g-

  Crude 4-hydroxy (5), 9 (10) -estradien-3-one on silica gel using the 6: 4 ethyl ether: n-hexane mixture so that

  obtain 6.12 g of 17-acetate 65-methyl-173-hydroxy-4 (5), 9 (10) -

  pure estradiene-3-one in the form of white crystals, F 97-99 C; UV spectrum (EtOH) max = 304, = 19429; [t] D = -215 (c = 1, CHCl3); NMR spectrum (CDCl3) δ: 0.92 (3H, s); 1.04 (3H, d); 2.02 (3H, s);

4.64 (1H, dd); 5.70 (1H, s).

  Following a similar procedure, the following estradiene derivatives are prepared: 17-acetate 63-ethyl-173-hydroxy-4 (5), 9 (10) estradien-3-one; 17-acetate of 6α-methyl-173-hydroxy-4 (5), 9 (10) estradien-3-one; 17α-methyl-17α-hydroxy-4 (5), 9 (10) -stradien-3-one 17-acetate; 17α-ethyl-17α-hydroxy-4 (5), 9 (10) -stradien-3-one 17-acetate;

Example 3

  To a solution of 9.2 g of 17-acetate of 69-methyl-17?

  4-hydroxy (5), 9 (10) -estradien-3-one in 100 ml of anhydrous CH 2 Cl 2, 6.3 ml of ethylene glycol, 7.5 ml of ethyl orthoformate and 0.24 g of ethyl acetate are added. p-toluenesulfonic acid, then the mixture is heated to 40 ° C. and stirred for 1.5 h. The reaction mixture is neutralized with triethylamine, diluted with 100 ml of ethyl acetate and washed with saturated potassium carbonate solution and dried; we then eliminate

  the solvent to give 10 g of 17-acetate of 60-methyl-170-hydroxy-3,3-

  crude ethylenedioxy-5 (10), 9 (11) -estradiene. The crude product is dissolved in 150 ml of methanol and treated with 6 g of lithium hydroxide and 50 ml of water. The solution is stirred for 1.5 h at room temperature and then neutralized with 2N HCl; the methanol is removed by

  distillation and the residue is extracted with ethyl acetate.

  The organic phase is dried and evaporated in vacuo to give 9.7 g of 60-methyl-17e-hydroxy-3,3-ethylenedioxy-5 (10),

  9 (11) -estradiène. To a solution of 6.44 g of 60-methyl-17e-

  5,3-hydroxy-3,3-ethylenedioxy-5 (10), crude 9 (11) -estradiene in 60 ml

  of the DMSO / benzene mixture 1: 1 sec, 12.1 g of dicyclohexyl-

  carbodiimide, 1.57 ml of pyridine and 0.77 ml of trifluoro-

  acetic acid and then the mixture is stirred at 20 ° C. for 5 hours. When the oxidation is complete (reaction controlled by TLC), the mixture is diluted with 90 ml of benzene, the solid is filtered off with suction and the organic phase is evaporated under vacuum. The crude product obtained is chromatographed on silica gel (ethyl ether mixture: n-hexane: triethylamine 50: 50: 0.2 as eluent) to give 5.74 g of 60-methyl-3,3-ethylenedioxy (10), 9 (11) -estradien-17-one pure Eal] D = + 267 ° C (c = 1, CHCl3); NMR (CDCL3) δ: 0.88 (3H, s); 1.12

(3H, d); 3.98 (4H, s); 5.56 (1H, m).

  Following a similar procedure, the compounds listed below are prepared: ethyl-3,3-ethylenedioxy-5 (10), 9 (11) -estradien-17-one; 63propyl-3,3-ethylenedioxy-5 (10), 9 (11) -estradiène-17-one; 6t-methyl-3,3éthylènedioxy-5 (10), 9 (11) -estradiène-17-one; 6a-ethyl-3,3-éthylènedioxy5 (10), 9 (11) -estradiène-17-one; 7a-methyl-3,3-ethylenedioxy-5 (10), 9 (11) estradiene-17-one; 7a-ethyl-3,3-ethylenedioxy-5 (10), 9 (11) -estradiène-17one.

Example 4

  In a 2.2M solution of ethylmagnesium bromide

  in 120 ml of anhydrous THF, the mixture is bubbled for 2 hours

  acetylene dried over calcium chloride, cooled to 30 C by an external thermostatic bath. Subsequently, a solution of 8.6 g of 60-methyl-3,3-ethylenedioxy-5 (10), 9 (11) -estradien-17-one in ml of a solution of Anhydrous THF. The reaction mixture is stirred for 1 h and then the reaction is stopped by 500 ml of ice-water / NH 4 Cl mixture.

  and extracted several times with ethyl ether.

  The organic phase is washed with water, dried and

  removes the solvent; the crude residue is purified on At 2 O 3 using

  ethyl acetate: n-hexane 10:90 as the solvent for

  give 8.7 g of 60-methyl-170-hydroxy-17α-1-propynyl-3,3-ethylene-

  dioxy-5 (10), 9 (-11) -estradiene, [a] D = + 161 (c = 1, CHCl 3); NMR (CDCL3) 6:

  0.84 (3H, s); 1.09 (3H, d); 1.83 (3H, s); 3.98 (4H, s); 5.55 (1H, m).

  Following a similar procedure, the following compounds are prepared:

  6j-ethyl-17-hydroxy-17? (1-propynyl) -3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  6α-propyl-17-hydroxy-17α- (1-propynyl) -3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  6a-methyl-171-hydroxy-17? (1-propynyl) -3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  6o-ethyl-173-hydroxy-17o- (1-propynyl) -3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  7a-methyl-17f-hydroxy-17a-t (1-propynyl) -3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  7 "-ethyl-17α-hydroxy-17α- (1-propynyl) -3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene.

  Following a similar procedure but using acetylene instead of methylacetylene, the corresponding 17a-ethynyl compounds are listed below:

  63-methyl-17f-hydroxy-17m-ethynyl-3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  -ethyl-17f-hydroxy-17a-ethynyl-3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  -propyl-17-hydroxy-17a-ethynyl-3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  6α-methyl-17-hydroxy-17α-ethynyl-3,3-ethylenedioxy-5 (10), 9 (11l) -

estradiene;

  6α-ethyl-170-hydroxy-17α-ethynyl-3,3-ethylenedioxy-5 (10), 9 (11) -

estradiene;

  7m-methyl-170-hydroxy-17a-ethynyl-3,3-ethylenedioxy-5 (10), 9 (11) -

  estradiene; 7m-ethyl-170α-hydroxy-17α-ethynyl-3,3-ethylenedioxy-5 (10), 9 (11), estradiene.

258? 654

ExempLe 5

  A solution of 7.78 g of 6-methyl-170-hydroxy-17α- (1-propynyl) -3,3-ethylenedioxy-5 (10), 9 (11) -estradiene in 100 ml is cooled to -5 ° to -10 ° C. of CH 2 Cl 2 and treated portionwise with 4.78 g of mchloroperbenzoic acid and stirred for 45 minutes, then 4.62 g of K 2 CO 3 are added with stirring and the suspension is allowed to warm to room temperature over 30 minutes. The solid is filtered and the organic phase is diluted with ethyl acetate, washed with an aqueous solution of NaHCO.sub.3.

  5%, then dried and the solvent removed.

  The crude product is chromatographed on silica gel using the mixture n-hexane: ethyl acetate: triethylamine

  : 30: 0.2 as eluent to obtain 3.85 g of 60-methyl-5,10 "-

  epoxy-173-hydroxy-17α-α-propynyl-3,3-ethylenedioxy-9 (11) -estrene, [C] D = 1.1 (c = 1, CHCl3); NMR (CDCL3) δ: 0.83 (3H, s); 1.14

  (3H, d); 1.85 (3H, s); 3.92 (4H, m); 6.04 (1H, m).

  Using a similar procedure, one prepares

  5,10-epoxy derivatives of the compounds listed in Example 4.

Example 6

  A 1M solution of p-dimethylaminophenylmagnesium bromide in 240 ml of THF is cooled to -30 ° C. under a dry nitrogen atmosphere and then 1.20 g of CuCl is then added. The mixture is stirred for 20 minutes and then a solution of 15 g is added dropwise while cooling to -30 ° C. with an external bath.

  60-methyl-5,10-t-epoxy-171-hydroxy-17α-C1-propynyl) -3,3-

  Ethylenedioxy-9 (11) -estrene in 80 mL of THF.

  The temperature is maintained at -30 ° C. for 1 h and then allowed to rise to room temperature. The reaction is then quenched with 500 ml of ice-cold NH 4 Cl solution and extracted with ethyl acetate, the organic phase is washed with saturated aqueous NaCl solution, dried and the solvent is removed. The crude product is purified on a column of

  silica using the mixture n-hexane: ethyl acetate: triethyl-

  60: 40: 0.2 amine as eluent to obtain 14.1 g of 60-methyl-5a,

  17i-dihydroxy-17? (1-propynyl) -11- (4-dimethylaminophenyl) -3,3-

  9-ethylenedioxy (10estrene, e [] D = -13 (c = 1, CHCl 3); NMR (CDCL 3) 6: 0.44 (3H, s); 1.05 (3H, d); 1.96 (3H); 2.90 (6H, s) 4.00 (4H, m);

  4.16 (1H, m); 6.70 (2H, d); 7.10 (2H, d).

Example 7

  To a cooled solution of 3- (N, N-dimethyl) bromide

  1M amino) -propylmagnesium in 80 ml of THF is added under a dry nitrogen atmosphere 8.40 g of dimethyl sulfide-CuBr complex

dissolved in 40 ml of THF.

  The mixture is stirred for 15 min at 0 ° C. and then added

  dropwise a solution of 5 g of 6-methyl-5,10c-epoxy-170-

  hydroxy-17α- (1-propynyl) -3,3-ethylenedioxy-9 (11) -estrene in 25 ml

THF.

  The reaction mixture is stirred for 2 h at 0 ° C. and is then allowed to return to room temperature and the reaction is stopped with 200 ml of ice-cold solution of ammonium chloride.

20%.

  The solution is extracted with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride and then dried and the solvent is distilled under reduced pressure to obtain a crude product. This is chromatographed on silica gel and eluted with cyclohexane: ethyl acetate: triethylamine 50: 50: 0.2 to give 3.4 g of 60-methyl-5a,

  -dihydroxy-17m- (1-propynyl) -110- (3-N, N-dimethylaminopropyl) -3,3

  ethylenedioxy-9 (10) -estrène; NMR (CDCl3) 6: 0.45 (3H, s); 1.05

  (3H, d); 1.90 (3H, s); 2.25 (6H, s); 4.00 (4H, m); 4.15 (1H, m).

Example 8

  A 1M solution of p-trifluoromethylphenylmagnesium bromide in ml of THF is cooled to -25 ° C. under an inert atmosphere of dry argon and then 0.22 g of CuCl is added. The mixture is stirred for 10 minutes, then a solution is added dropwise.

  2.5 g of 61-methyl-5,10c-epoxy-170-hydroxy-17α- (1-propynyl) -3,3-

  9-ethylenedioxy-9 (11) -estrene in 20 ml of anhydrous THF while still

  holding the temperature at -25 C. The solution is stirred for 90 min, then the reaction is stopped with 100 ml of 5% aqueous NH4Cl and ice. The mixture is extracted with ethyl ether and the organic phase is washed with saturated saline solution and dried. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel using a mixture of methylene chloride: methanol 90:10 as eluent for

  obtain 1.8 g of 6α-methyl-5α, 17α-dihydroxy-17α- (1-propynyl) -11f-

  (4-trifluoromethylphenyl) -3,3-ethylenedioxy-9 (10) -estrène; NMR (CDCl3) b: 0.45 (3H, s); 1.04 (3H, d); 1.96 (3H, s); 4.00

  (4H, m); 4.15 (1H, m); 6.71 (2H, d); 7.10 (2H, d).

Example 9

  To a solution of 4.2 g of dimethylsulfide complex

  CuBr in 15 ml of anhydrous THF is added dropwise under

  Dry nitrogen atmosphere 40 ml of bromide solution of 4- (N, N-)

  1M dimethylamino-ethoxy) -phenylmagnesium in THF while

  now the reaction temperature at 0 C by a refrigerated bath

  external rant. After stirring for 30 minutes, add drop to

  drop a solution of 2.5 g of 60-methyl-5,10α-epoxy-17f-

  hydroxy-17α- (1-propynyl) -3,3-ethylenedioxy-9 (11) -estrene in ml of anhydrous THF. The reaction mixture is stirred for 1 h at 0 ° C. and then the reaction is stopped with 100 ml of ice-cold 5% ammonium chloride solution. The solution is extracted with ethyl ether and the organic layer is washed with brine and dried. The ether is then removed to give a crude product which is purified on silica gel with n-hexane ethyl acetate: triethylamine 60: 40: 0.1 as eluent.

  to give 1.75 g of 63-methyl-5e, 17β-dihydroxy-17α- (1-propynyl) -

  - (4-N, N-dimethylaminoethoxy-phenyl) -3,3-ethylenedioxy-9 (10) -

  pure estrene; NMR (CDCL3) 6: 0.46 (3H, s); 1.05 (3H, d); 1.95 (3H, s);

  2.38 (6H, s); 4.00 (4H, m); 6.75 (2H, d); 7.10 (2H, d).

Example 10

  To a solution of 11.3 g of 61-methyl-5α, 171-dihydroxy-17α

  (1-propynyl) -11f- (4-diméthlaminophényl) -3,3-ethylenedioxy-9 (10) -

  Estrene in 400 ml of methanol, 14 ml of hydrochloric acid are added.

  concentrated solution and the solution is stirred at 25 ° C. for 30 minutes. The decetalization is completed in this time and the reaction mixture is diluted with 1000 ml of ethyl ether and

  neutralized with 350 ml of 1N aqueous sodium hydroxide solution.

  Separate the organic phase and extract the layer

aqueous by ethyl ether.

  The organic extracts are combined, washed with an aqueous NaCl solution, dried and the ether removed. The residue is purified on a column of silica gel with n-hexane: ethyl acetate 50:50 as eluent to give 9.2 g of 6-methyl-170-hydroxy-17α- (1-propynyl) -110. - (4-Dimethylaminophenyl) -4 (5), 9 (10) -estradien-3-one pure; [?] D = + 149.5 (c = 1, CHCl3); UV spectrum (EtOH) ν max: 262, E = 17764; max = 306, E = 19403; NMR (CDCl 3) δ: 0.55 (3H, s); 1.28 (3H, d); 1.87 (3H, s); 2.88

  (6H, s); 4.36 (1H, m); 5.80 (1H, s); 6.68 (2H, d); 7.04 (2H, d).

Example 11

  Using the procedure described in Example 10, from the appropriate intermediates prepared according to the examples

  6, 7, 8 and 9, the following compounds are obtained :.

  6 '- (methyl-173-hydroxy-17? (1-propynyl) -11f- (4-dimethylamino

  phenyl) -4 (5) 9 (10) -estradiène-3-one;

  methyl-170-hydroxy-17α- (1-propynyl) -11- (3-N, N-dimethylamino)

  propyl) -4 (5) 9 (10) -estradiène-3-one;

  methyl-17? -hydroxy-17m- (1-propynyl) -111- (4-trifluoromethyl

  phenyl) -4 (5) 9 (10) -estradiène-3-one;

  60-methyl-170-hydroxy-17o- (1-propynyl) -11l- (4-N, N-dimethylamino

  ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one;

  7a-methyl-17-hydroxy-17 "- (1-propynyl) -110- (4-dimethylaminophenyl) -

4 (5), 9 (10) -estradiène-3-one;

  7a-methyl-17? -Hydroxy-17? (1-propynyl) -111- (3-N, N-dimethylamino

  propyl) -4 (5) 9 (10) -estradiène-3-one;

  7a-methyl-170-hydroxy-17? (1-propynyl) -111- (4-trifluoromethyl

  phenyl) -4 (5) 9 (10) -estradiène-3-one;

  7a-methyl-17? -Hydroxy-17? (1-propynyl) -110- (4-N, N-dimethylamino

  ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one;

  61-methyl-171-hydroxy-17α- (1-propynyl) -11- (4-methoxyphenyl) -

4 (5), 9 (10) -estradiène-3-one;

  61-ethyl-17-hydroxy-17? (1-propynyl) -113- (4-dimethylaminophenyl)? -

4 (5), 9 (10) -estradiène-3-one;

  -ethyl-179-hydroxy-17m- (1-propynyl) -110- (3-N, N-dimethylamino

  propyl) -4 (5) 9 (10) -estradiène-3-one;

  -ethyl-170-hydroxy-17? (1-propynyl) -111- (4-trifluoromethyl

  phenyl) -4 (5) 9 (10) -estradiène-3-one;

  -ethyl-170-hydroxy-17ct- (1-propynyl) -11- (4-N, N-dimethylamino

  ethoxyphenyl) -4 (5) 9 (lo) -estradiène-3-one;

  7α-ethyl-170-hydroxy-17α- (1-propynyl) -1,1- (4-dimethylaminothiazine)

  phenyl) -4 (5) 9 (10) -estradiène-3-one;

  7a-ethyl-170-hydroxy-17aT- (1-propynyl) -113- (3-N, N-dimethylamino

  propyl) -4 (5) 9 (10) -estradiène-3-one; 7α-ethyl-17α-hydroxy-17α- (1-propynyl) -11- (4-trifluoromethylphenyl) -4 (5), 9 (10) -estradien-3-one;

  7a-ethyl-170-hydroxy-17? (1-propynyl) -11t- (4-N, N-dimethylamino

  ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one; 7α-ethyl-170-hydroxy-17α- (1-propynyl) -111- (4-methoxyphenyl) -4 (5), 9 (10) -estradien-3-one; 6-methyl-17α-hydroxy-17α-ethynyl-11D- (4-dimethylaminophenyl) -4 (5), 9 (10) -stradien-3-one;

  6f-methyl-17? -Hydroxy-17cx-ethynyl-11- (3-N, N-dimethylamino

  propyl) -4 (5) 9 (10) -estradiène-3-one; 60-methyl-17D-hydroxy-17α-ethynyl-11 (4-trifluoromethylphenyl) -4 (5), 9 (10) -estradien-3-one;

  6-methyl-170-hydroxy-17a-ethynyl-110- (4-N, N-diméthyLaminoéthoxy-

  phenyl) -4 (5) 9 (10) -estradiène-3-one; 7α-methyl-17-hydroxy-17α-ethynyl-11 (4-dimethylaminophenyl) -4 (5), 9 (10) -estradien-3-one;

  7 "-methyl-17i-hydroxy-17a-ethynyl-11P- (3-N, N-dimethylamino

  propyt) -4 (5) 9 (10) -estradiène-3-one; 7α-methyl-170-hydroxy-17α-ethynyl-10- (4-trifluoromethylphenyl) -4 (5), 9 (10) -estradien-3-one;

  7'-methyl-17I-hydroxy-17c-ethynyl-110- (4-N, N-diméthylaminoéthoxy-

  phenyl) -4 (5) 9 (10) -estradiène-3-one;

  6-méthyL1-170-hydroxy-17a-ethynyl-110- (4-methoxyphenyl) -4 (5) 9 (10) -

  estradiene-3-one; -ethyl-17β-hydroxy-17α-ethynyl-11D- (4-dimethylaminophenyl) -4 (5), 9 (10) -estradien-3-one; ethyl-175-hydroxy-17aethynyl-11- (3-N, N-dimethylaminopropyl) -4 (5), 9 (10) -estradien-3-one; ethyl-173-hydroxy-17α-ethynyl-11- (4-trifluoromethylphenyl) -4 (5), 9 (10) estradien-3-one;

  60-ethyl-170-hydroxy-17a-ethynyl-110- (4-N, N-diméthylaminoéthoxy-

  phenyl) -4 (5) 9 (10) -estradiène-3-one; 7α-ethyl-173-hydroxy-17α-ethynyl-110β (4-dimethylaminophenyl) -4 (5), 9 (10) -estradien-3-one;

  7a-ethyl-170-hydroxy-17t-ethynyl-110- (3-N, N-dimethylamino

  propyl) -4 (5) 9 (10) -estradiène-3-one; 7α-ethyl-17α-hydroxy-17α-ethynyl-11α (4-trifluoromethylphenyl) -4 (5), 9 (10) -estradien-3-one; 7α-ethyl-170-hydroxy-17α-ethynyl-11- (4-N, N-dimethylaminoethoxy-phenyl) -4 (5), 9 (10) -stradien-3-one;

  7a-ethyl-171-hydroxy-17a-ethynyl-115- (4-methoxyphenyl) -4 (5) 9 (10) -

estradiene-3-one.

Example 12

  To a solution of 1.12 g of 6α-methyl-17β-hydroxy- (1-

  propynyl) -11- (4-dimethylaminophenyl) -4 (5), 9 (10) -estradien-3-one in 4 ml of dimethylsulfoxide, 7 ml of the ylide prepared from 2 is added dropwise, 3 g of triphenylphosphonium iodide

  and 0.52 g of potassium tert-butoxide in 10 ml of dimethyl

  sulfoxide. The solution is stirred under an inert atmosphere for 4 hours at room temperature, and then the reaction is stopped by

  ammonium chloride solution and extracted with ethyl ether.

  The solvent is removed and the crude product is purified on silica gel with 85:15 n-hexane: ethyl acetate as

  eluent to obtain 0.68 g of 6α-methyl-3-methylene-17e-hydroxy-17α.

  (1-propynyl) -110- (4-dimethylaminophenyl) -4 (5) 9 (10) -estradiène.pur. The 3-methylene derivatives of the compounds indicated in Example 11 are prepared in the same manner, in particular:

  -methyl-3-methylene-17a-hydroxy-17c- (1-propynyl) -110- (4-dimethyl-

  aminophenyl) -4 (5) 9 (10) -estradiène; and

  7α-methyl-3-methyl-17β-hydroxy-17α- (1-propynyl) -11- (4-dimethyl)

  aminophenyl) -4 (5) 9 (10) -estradiène.

Example 13

  A solution of 2.35 g of 65-methyl-17β-

  hydroxy-17? (1-propynyl) -111- (4-dimethylaminophenyl) -4 (5) 9 (10) -

  estradiene-3-one in 25 ml of methanol with 1 ml of ethane-1,2-di-

thiol and 0.7 g of boron trifluoride.

  The mixture is stirred for 1 h at room temperature

  and then evaporated to obtain 3-thioketal.

  To a suspension of 2.4 g of 60-methyl-3,3-ethylene-

  crude dithio-4 (5), 9 (10) -estradiene in 20 ml of anhydrous ethyl ether and 50 ml of liquid ammonia is added 0.5 g of sodium metal; ethanol is then added until it disappears

  of the blue color and the ammonia is evaporated.

  The residue is treated with 50 ml of a 5% aqueous ammonium chloride solution and then extracted with ethyl ether. Purification on a column of silica gel with hexane: ethyl acetate 80:20 as eluent gives 1.35 g.

  60-methyl-170-hydroxy-. 7t- (1-propynyl) -111- (4-dimethylamino

  phenyl) -4 (5) - (10) -estradiene pure.

  Following a similar procedure, the 3-deoxo derivatives of estradien-3-ones listed in Example 11 are prepared in

  especially 7α-methyl-17α-hydroxy-17α- (1-propynyl) -110- (4-dimethyl)

  aminophenyl) -4 (5) 9 (10) -estradiène.

Example 14

  Tablets each weighing 0.120 g and containing 50 mg of the active substance composition (per 10,000 tablets) are manufactured as follows.

  63-methyl-17-hydroxy-17 -? (1-propynyl) -110- (4-

  dimethylaminophenyl) -4 (5), 9 (10) -estradien-3-one 500 g Lactose 500 g Corn starch 180 g Talcum powder 15 g Magnesium stearate 5 g

  6α-methyl-17α-hydroxy-17α- (1-propynyl) -11- is mixed.

  (4-dimethylaminophenyl) -4 (5), 9 (10) -estradien-3-one, lactose and half of corn starch; we then force

  the mixture through a sieve with a mesh size of 0.5 mm.

  10 g of the corn starch are suspended in 90 ml of water

  warm and the resulting paste is used to granulate the powder.

  The granulate is dried, grinded on a sieve with a mesh size of 1.4 mm, then the remaining amount of starch, talc, is added.

  magnesium stearate is carefully mixed and

form into tablets.

  It should be understood that the invention is not limited to the preferred embodiments described above by way of illustration and that those skilled in the art may make various modifications and changes thereof without departing from the scope of the invention. and the spirit

of the invention.

Claims (11)

  1. 116-substituted steroids, characterized in that they correspond to the general formula I): R5 R6 "R7 R4 (I) R1 3 3   Wherein R 1 and R 2 are both hydrogen or R 1 and R 2 taken together represent an oxo residue or = CH 2; R3 is a substituent at the 6 or 7 position selected from C1-C6 alkyl, C2-C5 alkenyl and C2-C5 alkynyl radicals; R4 is a group of the formula - (CH2) n-A-Z, wherein n is 0 or an integer of 1 to 3; A is a bond or represents a C4-C7 cycloalkyl ring, a phenyl ring or a saturated or unsaturated heteromonocyclic ring containing one or more heteroatoms selected from O, Set N; and R8 Z represents: (a) hydrogen; (b) a group of the formula -N wherein R8 and R9 are each independently hydrogen, C1-C6 alkyl or phenyl, or R8 and R9 taken together with the nitrogen atom to which they are attached; linked, form a saturated hetero-cyclic ring containing one or more heteroatoms selected from O, S and N; (c) an R10 group of the formula -Si R11 wherein R10, R11 and R12 R12 are the same or different and each represents a C1-C6 alkyl or phenyl group; (d) a group of the formula -O- (CH2) p-R13 wherein p is 0 or an integer / R8 of 1 to 5 and R13 is a hydrogen atom or a group -N1 R   wherein R8 and R9 are defined as above; or (e) a halogen atom or a halo-C1-C6 alkyl group; R 5 is C 1 -C 6 alkyl, R 6 is hydroxy and R 7 is hydrogen, C 1 -C 6 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl, or R 6 and R 7 taken together represent the group = CH2, and their salts.   2. Compounds of formula (I) according to claim 1, characterized in that: R1 and R2 taken together form an oxo residue; R3 is a C1-C6 alkyl group; R4 is a - (CH2) nAZ group wherein n is - R8 an integer of 1 to 3, A is a bond and Z is a group -NR, wherein R8 and R9 are each independently hydrogen or an alkyl group C1C6; R5 is a C1-C2 alkyl group; R6 is a hydroxy group and R7 is a C1-C6 alkyl, alkenyl group   C2-C5 or C2-C5 alkynyl, and salts thereof.   3. Compounds according to claim 1, characterized in that they are chosen from the following:   63-methyl-170-hydroxy-17? (1-propynyl) -110- (3-N, N-dimethylamino   propyl) -4 (5) 9 (10) -estradiène-3-one;   7a-methyl-17? -Hydroxy-17? (1-propynyl) -11l- (3-N, N-dimethylamino   propyl) -4 (5) 9 (10) -estradiène-3-one;   61-ethyl-17 $ -hydroxy-17? (1-propynyl) -110- (3-N, N-dimethylamino   propyl) -4 (5) 9 (10) -estradiène-3-one;   7m-ethyl-17f-hydroxy-17c- (1-propynyl) -11- (3-N, N-dimethylamino   propyl) -4 (5) 9 (10) -estradiène-3-one; and their salts.   4. Compounds of formula (I) according to claim 1, characterized in that: R1 and R2 taken together form an oxo residue or = CH2; R3 is a C1-C6 alkyl group; R4 is - (CH2) nAZ wherein R n is 0, A is phenyl and Z is (i) -N R8-9 wherein R8 and R9 are each hydrogen or a group C1-C6 alkyl or (ii) -O- (CH2) p-R13 wherein p is 1 or 2 and R13 is hydrogen or -N R8 in which - R9s wherein R8 and R9 are defined as above or (iii) a halogen atom or a C1-C6 haloalkyl group; R5 is a C1-C2 alkyl group; R6 is a hydroxy group and R7 is an alkyl group   C1-C6, C2-C5 alkenyl or C2-C5 alkynyl, and their salts.   5. Compounds of formula (I) according to claim 1, characterized in that they are chosen from the following:   -methyl-175-hydroxy-17? (1-propynyl) -115- (4-dimethylaminophenyl) - 4 (5), 9 (10) -estradiène-3-one;   -methyl-170-hydroxy-17ct- (1-propynyl) -11B- (4-trifluoromethyl   phenyl) -4 (5) 9 (10) -estradiène-3-one;   60-methyl-17? -Hydroxy-17? (1-propynyl) -110- (4-N, N-dimethylamino   ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one;   7a-methyl-175-hydroxy-17ct- (1-propynyl) -11- (4-dimethylaminophenyl) - 4 (5), 9 (10) -estradiène-3-one;   7a-methyl-170-hydroxy-17? (1-propynyl) -11f- (4-trifluoromethylphenyl) - 4 (5), 9 (10) -estradiène-3-one;   7a-methyl-170-hydroxy-17o- (1-propynyl) -110- (4-N, N-dimethylamino   ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one;   6f-methyl-175-hydroxy-17? (1-propynyl) -113- (4-methoxyphenyl) - 4 (5), 9 (10) -estradiène-3-one;   60-ethyl-17t-hydroxy-17c- (1-propynyl) -11t- (4-dimethylaminophenyl) - 4 (5), 9 (10) -estradiène-3-one;   -ethyl-170-hydroxy-17m- (1-propynyl) -11B- (4-trifluoromethylphenyl) - 4 (5), 9 (10) -estradiène-3-one;   -ethyl-17B-hydroxy-17m- (1-propynyl) -115- (4-N, N-dimethylamino   ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one;   ? 7? -Ethyl-17-hydroxy-17c- (1-propynyl) -11i- (4-dimethylaminophenyl) - 4 (5), 9 (10) -estradiène-3-one;   7a-ethyl-17.beta.-hydroxy-17m- (1-propynyl) -11- (4-trifluoromethylphenyl) - 4 (5), 9 (10) -estradiène-3-one;   7α-ethyl-17α-hydroxy-17α- (1-propynyl) -11- (4-N, N-dimethylamino);   ethoxyphenyl) -4 (5) 9 (10) -estradiène-3-one; 7α-ethyl-17α-hydroxy-17α- (1-propynyl) -1- (4-methoxyphenyl) -4 (5), 9 (10) -estradien-3-one;   6f-methyl-3-methylene-173-hydroxy-17o- (1-propynyl) -110- (4-dimethyl-   aminophenyl) -4 (5) 9 (10) -estradiène-3-one;   7α-methyl-3-methylene-17-hydroxy-17α- (1-propynyl) -110- (4-dimethyl)   aminophenyl) -4 (5) 9 (10) -estradiène-3-one; and their salts.   6. Process for the manufacture of a compound of formula (I) according to claim I or a salt thereof, characterized in that it consists in dehydrating a compound of formula (II) R5R6AR   R4R R'i R '| In which R3, R4, R5, R6 and R7 are as defined in claim 1, R'1 and R'2 are both hydrogen or taken together,   form a protected oxo residue or the group = CH2.   The process according to claim 6, further characterized in that a compound of formula (I) is converted into a other compound of formula (I).   The process according to claim 6 or 7, further characterized in that a compound of formula (I) is converted into one of its salts.   9. Method according to any one of claims 6   at 8, further characterized in that a free compound is obtained from one of its salts.   10. Method according to any one of claims 6   at 9, further characterized in that a mixture of isomers is separated   of formula (I) in the isolated isomers.   11. New drug, useful especially in medicine   human or veterinary agent as antiprogesterone and antiglucose   corticosteroid and in the treatment of hormone-dependent tumors, characterized in that it contains as active ingredient a compound   of formula (I) according to claim 1 or an acceptable salt thereof.   tables in human or veterinary pharmacy, in combination with a suitable vehicle or diluent.