EP1404701A1

EP1404701A1 - Method for preparing oestrogen derivatives

Info

Publication number: EP1404701A1
Application number: EP02747527A
Authority: EP
Inventors: Françoise BENEDETTI; Alain Mazurie; François Nique; Denis Prat; Christian Wehrey
Original assignee: Aventis Pharma SA
Current assignee: Aventis Pharma SA
Priority date: 2001-06-13
Filing date: 2002-06-12
Publication date: 2004-04-07
Also published as: WO2002100880A1; US20040171595A1; FR2826004A1; US7381718B2; JP2004534796A; FR2826004B1

Abstract

The invention concerns a method for preparing compounds of formula (I) wherein: R1, R2, R3 and n are such as defined in the description, the use of said compounds as intermediates for preparing oestrogen derivatives and the intermediate compounds prepared when such a method is implemented.

Description

Process for the preparation of estrogen derivatives

The subject of the present invention is a process for the preparation of estrogenic steroids as well as the intermediates of this process.

Osteoporosis is a bone disease that affects 50 million people worldwide, most notably women. Its development is linked to age and most often begins after menopause. This disease is characterized by a reduction in bone density, leads to deformations, vertebral compression and ultimately spontaneous fractures. Osteoporosis therefore represents a serious public health issue. The main treatment consists in taking estradiol regularly which reduces bone loss, which however can be accompanied by certain side effects (bleeding, hot flushes, risk of breast cancer, etc.). A new series of molecules called SERM (Selective Estrogen Receptor Modulator) allows the treatment of osteoporosis while avoiding some of the side effects. (W098 / 45316, W099 / 67274, W098 / 28324, W099 / 25725, EP605193).

The object of the present application is the development of a new process for the preparation of a key intermediate (compound of formula I), and the use of this intermediate in the synthesis of certain estrogen derivatives having a dissociated activity.

The subject of the invention is a process for the preparation of compounds of formula (I):

in which :

- either Ri and R ₂ , identical or different, represent a benzyl group or a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing from 1 to 8 carbon atoms,

either Ri and R ₂ form together with the nitrogen atom which carries them a heterocycle of 5 to 6 links, saturated or unsaturated, aromatic or non-aromatic possibly containing from 1 to 3 additional heteroatoms and optionally attached to another cycle,

R ₃ represents a hydrogen atom or a protecting group for the hydroxy function, n is an integer from 2 to 8, characterized in that a compound of formula (II) is treated

K representing a protected ketone function in particular in the form of a ketal, thioketal or mixed ketal, with a silylating agent in the presence of a base, in order to obtain the silylated enol of formula (III):

in which Ra, Rb and Rc, which are identical or different, represent an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical, which is reacted with

an organocuprate derivative derived from organometallics of formulas R ₅ MgHal or RsLi, Hal being a halogen atom and generated in a catalytic or stoichiometric manner, in which R ₅ represents the group R1 "

N— (CH ₂ ) R2 ^' _n _ ₀ ^ Q

n, Ri and R ₂ being as defined above, the binding being carried out at the phenyl level, in order to obtain a compound of formula (III ¹ ) which is isolated or not isolated:

- then a deprotection agent in order to obtain a compound of formula (IV)

which is treated with a flavoring agent to obtain the expected compound of formula (I) which, where appropriate, is subsequently deprotected to obtain a compound of formula (I) with R ₃ representing a hydrogen atom. As an example of a linear or branched alkyl radical containing from 1 to 8 carbon atoms, mention may be made of methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl radicals and the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl , isohexyl, 3-methyl-pentyl,, sec-butyl, tert-butyl, tert-pentyl. The preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. As an example of a cyclic alkyl radical, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl or cyclononyl radicals which may be substituted for example by an alkyl group containing

1 to 4 carbon atoms. Preferably, the substituted cycloalkyl groups are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

As an example of an alkenyl radical, mention may be made of vinyl, 1-propenyl, allyl, butenyl or 3-methyl-2-butenyl radicals. As an example of alkynyl radicals, mention may be made of ethynyl, 1-propynyl or propargyl radicals. Of course, these alkenyl or alkynyl radicals contain at least

2 carbon atoms and are linked to the nitrogen atom via a -CH ₂ - group.

As an example of a protective group which R ₃ may represent, there may be mentioned in particular a group (C _I -C _Ê ) - alkyl, (Ci-Ce) -alkyl-CO- such as CH ₃ CO or benzoyl, benzyl, phenyl- ( Ci-C _δ ) -alkyl such as benzyl, as well as all the protective groups known to those skilled in the art, for example those described in Greene, Wuts, Protective Group iή Organic Synthesis, wiley, 1991. Preferably R3, as protective group, is an acyl group.

As an example of a protective group for the keto in position 3 of the steroid which may represent = K, there may be mentioned in particular

- cyclic ketal such as -O- (CH ₂₎ _m -0-, -0- (CH ₂₎ _m -S-, -S- (CH ₂₎ _m -S-, -0-CH ₂ -C ( c ₁ _ ₄ -alkyl) ₂ -CH ₂ -0-,

- acyclic ketals such as (CH ₃ 0) ₂ / (EtO) ₂

- as well as all the protective groups of

• keto group known to those skilled in the art, for example those described in Greene, Wuts, Protective Group in Organic Synthesis, Wiley, 1991.

Preferably, = K is a cyclic ketal and, in particular a 3, 3-ethylenedioxy group.

Hal represents a halogen and preferably chlorine or bromine.

Ra, Rb and Rc preferably represent a methyl group. As silylation agent, mention may be made of all agents capable of silylating enols or enolates known to a person skilled in the art and, where appropriate, cited in the monograph.

Van Look, G.; Simchen, G.; Heberle, J., Silylating Agents; Fluka Chimica, Fluka Chemie AG; Buchs, Switzerland, 1995. These can be the following silylating agents:

Me ₃ Si-N = C (Me) -0-SiMe ₃ N, O-bis (trimethylsylil) acetamide Me ₃ Si-NH-C0 ₂ -SiMe ₃ N, O-bis (trimethylsylil) carbamate

(Me ₃ Si) ₂ N-CHO N, N '-bis (trimethylsilyl) for amide

(Me ₃ SiO) ₂ S0 ₂ bis (trimethylsilyl) sulfate

F ₃ CC (OSiMe ₃ ) = N-SiMe ₃ N, 0, bis (trimethylsilyl) trifluoroacetamide

(Me ₃ SiNH) ₂ CO N, N 'bis (trimethylsilyl) urea EtS-SiMe ₃ Ethylthiotrimethylsilane Me ₃ Si-CH ₂ -C0 ₂ And Ethyltrimethylsilylacetate) Me ₃ Si-CH ₂ -C0 ₂ Me Methyltrimethylsilylacetate Me ₃ Si-SiMe ₃ Hexamethyldisilane CH ₃ -C (0SiMe ₃ ) = CH ₂ Isopropenylox trimethylsilane

(CH ₃ ) ₂ C = C (OMe) (OSiMe ₃ ) 1 methoxy 2-methyl-1-trimethylsilyl-oxypropene

CH ₃ CO-N (Me) -SiMe ₃ N-methyl N trimethylsilylacetamide CF ₃ CO-N (Me) -SiMe ₃ N-methyl N tri ethylsilyltrifluoroacetamide

C ₃ F7-CO-N (Me) -SiMe ₃ N-methyl N trimethylsilylhepta- fluorobutyramide

Me ₃ SiBr Trimethylbromosilane

Me ₃ Si- I Trimé hyliodosilane

PhS0 ₃ -SiMe ₃ Trimethylsilylbenzenesulfonate

MeS0 ₃ SiMe ₃ Trimethylsilylmethanesulfonate

Me ₃ Si-CN Trimethylsilyl cyanide

Triméthylsilyiimidazole

C ₄ F ₉ S0 ₃ SiMe ₃ Trimethylsilyl-nonaflate

CF ₃ S0 ₃ SiMe ₃ Trimethylsilyl-triflate

CF ₃ -C0 ₂ -SiMe ₃ Trimethylsilyl-trifluoroacetate

CCl ₃ -C0 ₂ -SiMe ₃ Trimethylsilyl-trichloroacetate tBuSiMe ₂ Cl t-Butyldimethylchlorosilane tBuSiPh ₂ Cl t-Butyldiphenylchlorosilane

PhSiMe ₂ Cl dimethylphenylchlorosilane

Ph ₂ SiMeCl diphenylmethylchlorosilane iPrSiMeCl Isopropyldimethylchlorosilane

Me ₃ Si-NHSiMe ₃ Hexamethyldisilazane nBu ₃ SiCl Tributylchlorosilane - And ₃ SiCl Triethylchlorosilane

- (iPr) ₃ SiCl Triisopropylchlorosilane

- Ph ₃ SiCl Triphenylchlorosilane

- (nPr) ₃ SiCl Tripropylchlorosilane this silylation reaction is generally carried out in the presence of a strong base such as Li-HMDS ((Me ₃ Si) ₂ N- Li), LDA ((iPr) ₂ N-Li ), a tertiary amine such as TEA (triethylamine), Na-naphthalene, pyridine and its derivatives such as DMAP (Dimethylaminopyridine), urea, DBU, imidazole, potassium hydride, sodium hydride, n-BuLi, tBuOK or even t-AmONa, DBN and others.

The silylation reaction is generally carried out in two stages: 1) enolization of the compounds of formula (II) in the presence of a strong base such as LDA in order to obtain the corresponding enolate of formula (II ¹ ):

2) addition of the silylating agent such as chlorotrimethylsilane.

However, all of these silylating agents do not necessarily require prior enolate of the compounds of formula (II).

The solvents used are known to a person skilled in the art for this type of reaction (JK Rasmussen, Synthesis 91 (1977),

E. Colvin Silicon in Organic synthesis Butterworth (1981);

WP Weber "silicon reagent for Organic synthesis", Springer

Verlag (1983) P. Brownbridge, Synthesis 1 (1983)). Obviously, avoid protic or insoluble solvents. Preferably the silylation reaction will be carried out with the

ClSiMe ₃ in the presence of LDA or Li-HMDS in a mixture of

THF and solvents of the pentane, hexanes, cyclohexane, heptane, toluene type. The arylation reaction by coupling the organometallic of formula R ₅ MgHal, R ₅ Li or (Rs) ₂ CuLi with the silylated derivative of formula (II) is carried out according to the conventional conditions known to those skilled in the art. This arylation will preferably be carried out with an organometallic derivative RsMgBr in THF alone or as a mixture (eg hexane, toluene, dichloromethane) in the presence of cuprous chloride (CuCl) or other copper salts (I) or (II) (such as: CuOAc, CuBr, Cu (OAc) ₂ , CuCl ₂ ) to form the cuprate intermediate. The preparation of organomagnesium derivatives from

The corresponding halogen is carried out in an aprotic medium in an oxygenated solvent such as ether or THF.

It forms after treatment an intermediate alcohol of formula (III ') which in general is not isolated and whose two protecting groups of the keto functions in 17 and 3 are cleaved by conventional methods, generally by hydrolysis in acid medium and more particularly by the action of hydrochloric acid.

The norsteroid aromatization reaction is a conventional reaction which is carried out in particular according to the methods described in EP 298,020. This aromatization can be carried out by catalysis with palladium or preferably in the presence of acetyl bromide and acetic anhydride. The deprotection of the acetyl group in 3 formed is generally carried out in the presence of sodium hydroxide in methanol.

A more particular subject of the invention is a process as defined above, characterized in that the silylated derivative is a trimethylsilyl derivative which makes it possible to obtain a silylated enol of formula (II) in which Ra, Rb and Rc each represent methyl.

The invention particularly relates to a process as defined above, characterized in that the silylated derivative is ClSiMe ₃ .

The invention particularly relates to a process as defined above, characterized in that the silylation reaction is carried out in the presence of LDA or Li-HMDS.

The subject of the invention is more particularly a process as defined above, characterized in that an organometallic derivative of formula R ₅ -MgBr is used. A very particular subject of the invention is a process as defined above, characterized in that an organometallic derivative of formula R ₅ -MgBr is used in which:

- either i and R _2, identical or different, represent a linear or branched alkyl radical containing from 1 to 4 carbon atoms

- either Ri and R ₂ form together with the nitrogen atom to which they are linked a group

- n is an integer between 2 and 5, in order to obtain a compound of formula (III ') then (IV) corresponding.

A more particular subject of the invention is a process as defined above, characterized in that the deprotective agent used on the compound of formula (III ¹ ) to obtain the compound of formula (IV) is an agent allowing acid hydrolysis and in particular hydrochloric acid. The invention more particularly relates to a process as defined above, characterized in that the flavoring agent is acetyl bromide in the presence of acetic anhydride.

The invention particularly relates to a process as defined above, characterized in that a compound of formula (II) is treated with ClSiMe ₃ in the presence of a base in order to obtain the silylated enol of formula ( Illa):

which is reacted with an organocuprate derivative derived from an organometallic of formula R ₅ -MgHal in which n is an integer equal to 2 to 5 and

- either Ri and R _{2, which are} identical or different, represent a linear or branched alkyl radical containing from 1 to 4 carbon atoms

in order to obtain a compound of formula (III 'a) isolated or not isolated

which is subjected to acid hydrolysis, in order to obtain the corresponding compound of formula (IV).

The subject of the invention is also a process as defined above, characterized in that the compound of formula (I) is used as an intermediate product for the preparation of a derivative having an estrogenic activity of formula (la):

by the action of an organometallic alkylating agent of type R ₄ M, R ₄ being an alkyl radical containing from 1 to 4 carbon atoms unsubstituted or substituted by one or more halogen atoms and M representing Mg-Hal or Li .

The invention particularly relates to a process as defined above characterized in that Ri and R represent an alkyl radical containing 1 to 4 carbon atoms or form together with the nitrogen atom which carry them a saturated heterocycle chosen from

n is an integer equal to 2 to 5 and R ₃ is a hydrogen atom and R ₄ is a methyl.

The invention particularly relates to a process as defined above characterized in that the alkylating agent is MeMgBr in the presence of cerium chloride. The subject of the invention is also a process as defined above, characterized in that the compound of formula (I) is used as an intermediate product for the preparation of a derivative having an estrogenic activity of formula (Ib):

by action of a ketone reducing agent. The invention more particularly relates to a process as defined above characterized in that Ri and R ₂ represent an alkyl radical containing 1 to 4 carbon atoms or form together with the nitrogen atom which wear a saturated heterocycle chosen from

n is an integer equal to 2 to 5 and R ₃ is a hydrogen atom The invention particularly relates to a process as defined above, characterized in that the reducing agent is NaBH ₄ .

The compounds of formulas (I) and (Ib), as defined above, in which n is an integer equal to 5, R ₃ is a hydrogen atom and NRιR ₂ represents a pyrrolidine or a piperidine are new and therefore make l subject of this request. They are active vis-à-vis the estrogen receptor, exhibit dissociated activity and exhibit interesting cardiovascular activity. _^

A subject of the invention is therefore also the compounds of formulas (I) and (Ib), as defined above as medicaments, in particular for the prevention or treatment of osteoporosis, as well as the pharmaceutical compositions containing at least a medicament as defined above and a pharmaceutically acceptable vehicle.

The subject of the invention is also a process as defined above, characterized in that the compound of formula (I) is used as an intermediate product for the preparation of a derivative having an estrogenic activity of formula (Ie):

by action a) of a halogenation reagent then b) of an agent for reducing the ketone function in position 17 or a) an agent for reducing the ketone function in position 17 then b) a halogenation reagent.

The invention more particularly relates to a process as defined above characterized in that Ri and R represent an alkyl radical containing 1 to 4 carbon atoms or form together with the nitrogen atom which carry them a saturated heterocycle chosen from

n is an integer equal to 2 to 5 and R ₃ is a hydrogen atom and X is a chlorine atom.

The invention particularly relates to a process as defined above, characterized in that the halogenating agent, making it possible to introduce the halogen in position 4 of the steroid is N-chlorosuccinimide or N-bromosuccinimide, chlorine or bromine in an acid medium and the reducing agent is sodium borohydride. In general, the halogenation reaction takes place before the reduction.

The invention also relates to a process for the preparation of the compounds of formula (III) from the compounds of formula (II) according to the method as defined above. The invention also relates to a process for preparing the compounds of formula (IV) from the compounds of formula (III) according to the method as defined above.

The invention also relates to a process for the preparation of the compounds of formula (I) from the compounds of formula (IV) according to the method as defined above.

The compounds of formula (II) are known and their preparation is described in EP97572 (pages 23, 34), in FR95149 or also in J. Chem. Soc. Perkin Trans (1990) 11 3045-3048.

Certain compounds of formula (IV) are described specifically in FR2640977 (NRιR ₂ = morpholine, piperidine and n = 2). The compounds of formula (I) are generally known and described in the following patents EP-B-0097572, FR-B-2640977 and EP-B-305942.

The subject of the invention is also, as intermediate compounds, the compounds of formulas (III), (III ') and (IV) it being understood that the compounds of formula (IV) in which

-NRιR ₂ represents a pyrrolidine and n is an integer equal to 2 -NRιR ₂ represents a morpholine group and n is an integer equal to 2 are excluded.

The compounds of formula R ₅ -M are prepared according to conventional methods in organic chemistry from the corresponding halogen derivative Rs-Hal. In general, the reagents

Grignards are prepared in situ before the arylation reaction and transformed into cuprate in situ, catalytically in the presence of CuCl.

The halogen derivatives of formula R ₅ -Hal are known or generally prepared by the action of a chloroamine of formula RιR ₂ N- (CH ₂ ) _n -Cl with parabromophenol in basic medium.

Experimental part Preparation 1 Aryl bromide of formula R ₅ -Hal: (4- (2- (1-piperidinyl) ethoxy) 1-bromobenzene).

To a stirred solution of 4-bromophenol (MW: 173.0; 10 g; 0.578 mole), 1-piperidino-2-chloroethyl hydrochloride (MW: 184.1; 117 g; 1.1 eq.), And TEBAC (chloride of triethylbenzylammonium; 10 g) in dichloromethane (600 ml) at 20 ° C, was added a 30% aqueous solution of sodium hydroxide (MW: 40.0; 170 g; 2.2 eq.). The mixture is stirred vigorously at 30-35 ° C for 18 h. The mixture is then diluted in water, and the organic phase is decanted, washed with water, dried over sodium sulfate and concentrated to dry vacuum (162 g yellow oil; yield: 98.5%; purity (CG) : 98%): Cι ₃ Hι ₈ BrNO; PM: 284.2; IR (CHCI ₃ , cm ^-1 ): 1591, 1579, 1489 cm ^"1

^X H NMR (CDCl _3, ppm): 1.44 (m, 2H); 1.59 (m, 4H); 2.48 (m, 4H); 2.75 (t, J = 6Hz, 2H); 4.06 (t, J = 6Hz, 2H); 6.78 and 7.35 (AA'BB ', 4H) SM (ES + m / z): 284 (M ⁺ ) 111.85 Preparation 2

Aryl bromide of formula R ₅ -Hal: (4- (5- (l- pirrolidinyl) penthoxy) 1-bromobenzene) hydrochloride and its base. The mixture consisting of 1,5-dibromopentane (6.92 g; 30 mmol), methylethycetone (9.2 ml) and potassium carbonate (2.07 g; 15 mmol) is brought to reflux, then added in 1 hour at reflux 4-bromophenol (2.62 g; 15 mmol). It is maintained at reflux for 4 hours then added potassium carbonate (3.1 g; 22.5 mmol) and in 15 goes the pyrrolodine (3.13 ml; 37.5 mmol). The mixture is again refluxed for 20 minutes, cooled to room temperature, filtered and the solvent evaporated under reduced pressure. A yellow oil is obtained which is diluted with ethyl acetate (21 ml), water (27.5 ml) and brine (2.5 ml). Decanted, extracted with ethyl acetate and acidified with 3N hydrochloric acid (7.5 ml). The mixture is stirred at 0-5 ° C. and the crystallization is observed. The crystals are washed, dried under vacuum at ambient temperature and 3.13 g of expected product is obtained in the form of the hydrochloric acid salt (mp = 130 ° C. then 138 ° C.).

^X NMR H (CDCl _3, pp): 1.56 (m, 2H); 1.82 (m, 2H); 1.98 (m, 2H); 2.14 (si, 4H); 2.80 (si, 2H); 3.05 (m, 2H); 3.76 (si, 2H); 3.93 (t, 2H); 6.76 and 7.36 (AA'BB ', 4H); 12.24 (si, 1H). MS (El; m / z): 311 (M ⁺ ), 310, 140, 84, 38, 36.

The base is obtained by dissolving 22 g of the hydrochloride in 88 ml of dichloromethane and then adding 110 ml of 10% potassium carbonate in water, after stirring at room temperature, decanting, extract with dichloromethane, drying the phases organic, filter and evaporate under reduced pressure until an oil is obtained which is taken up in 88 ml of heptane. After filtration, rinsing and concentration to dryness, 19.5 g of product are obtained expected (oil). Yield: 54%.

1 H NMR (CDCl ₃ , ppm): 1.42-1.64 (m, 4H); 1.72-1.85 (m, 6H); 2.41-2.53 (m, 6H); 3.91 (t, 2H); 6.76 and 7.35 (AA'BB ', 4H). MS (El; m / z): 311 (M ⁺ ), 172, 155, 140, 84. Preparation 3

4- (5- (1-pirrolidinyl) penthoxy) 1-bromobenzene magnesium

To a suspension under nitrogen of magnesium turns (686 mg, 28.2 mmol) in THF (2 ml), is added in 40 minutes, after priming, a solution of aminoaryl bromide (P2) (8 g, 25, 6 mmol) in THF (12 ml) while maintaining the temperature around 60 ° C. Then stirred for one hour at 60 ° C and then cooled to room temperature. There is thus obtained a suspension of aminoarylmagnesium at about 1 M in THF which is then used for the preparation of the product of Example 2 (stage b). Preparation 4 Dehydration of Cerium trichloride heptahydrate.

Cerium trichloride heptahydrate is heated under vacuum with stirring from 20 to 140 ° C at 10-20 Torr in 4 h, then at 140 ° C at 10-20 Torr for 11 h; allowed to cool under an argon atmosphere.

Example 1: 17-alpha-methyl-ll-beta- (4- (2- (1-piperidinyl) ethoxy) phenyl) -estra-1,3,5 (10) -triene-3,17-beta-diol Stage a: 3, 3-ethylenedioxy-10-alpha-epoxy-estr-9 (11) -ene-17-one. (compound of formula (II))

3, 3-ethylenedioxy-estra-5 (10), 9 (11) -diene-17-one (50 g; M: 314.4; 0.159 mole), 1 hexachloroacetone (98%; 2.5 ml; 0.1 eq.), Pyridine (0.25 ml), 50% hydrogen peroxide (approx. 18 M; 15 ml; 1.7 eq) and dichloromethane (250 ml) are vigorously mixed for 18 h at 20- 25 ° C. After reduction in the presence of aqueous metabisulfite, washing (water) and extractions (dichloromethane), the organic phase is concentrated to a total volume of approximately 200 ml. Then the dichloromethane is replaced by ethyl acetate by a continuous distillation at constant volume, until the internal temperature reaches 77 ° C. The mixture is cooled to 30 ° C. and spontaneous crystallization of the epoxide is observed. The suspension is cooled to 0 ° C and stirred for 1 h, then the product is filtered and dried under vacuum for 18 h at 40 ° C (22.5 g white solid; yield: 42.8%; HPLC purity: 93%): C ₂ oH ₂₆ 0 ₄ ; MW: 330.4; . IR (CHC1 ₃ , cm ^"1 ): 1733, 1636 ¹ H NMR (CDC1 ₃ , ppm): 0.88 (s, 3H); 3.94 (m, 4H); 6.05 (m, 1H).

Step b: d ^# silylated enol ether 3: 3.3 ethylenedioxy-5,10-alpha-epoxy-17-trimethylsilyloxy-estra-9 (11), 16 (17) -diene. N-Butyllithium (1.6 M solution in a mixture of hexanes; 400 ml; 1.06 eq.) Was added in 20-30 min to a stirred solution of diisopropylamine (M: 101.2; d: 0.714; 100 ml; 1.17 eq.) in anhydrous THF (600 ml), at -10 ° C. A solution of epoxide prepared in stage A (200 g; 0.605 mole) in THF (1.3 L) was added for 30-40 min at -10 ° C, and the mixture was stirred for 15 min at - 10 ° C. Triethylchlorosilane (M: 108.6; d: 0.856; 100 ml; 1.3 eq.) Was added for 20-30 min at -10 ° C, and the mixture was stirred for 3 h at 13 ° C, then concentrated under empty to a final volume of approximately 400 ml. The solvents were then replaced by toluene at constant volume at 30 ° C maximum. The salts were then removed by filtration and then washed with toluene. The filtrate was concentrated to dryness under vacuum, which gave the expected product 3 in the form of a white solid (252 g): C ₂₃ H ₃₄ 0 ₄ Si; PM: 402.6; IR (CHC1 ₃ , cm ^"1 ): 1621, 1254, 849

^X H NMR (CDC1 _3, ppm): 0.19 (s, 9H); 0.80 (s, 3H); 3.85-4.00 (m, 4H); 4.47 (dd, J = 1.5 and 1 Hz, 1H); 6.03 (m, 1H) MS (m / z): 402 (M ⁺ ), 387 (M ⁺ -CH ₃ ), 99 Stage c: 11-beta- (4- (2- (1-piperidinyl) ethoxy ) phenyl) - estra-4,9-diene-3,17-dione.

To a suspension of magnesium (turnings; MW = 24.3; 28 g; 1.9 eq.) In THF (60 ml) at 20-22 ° C with stirring, 20 ml of a solution of aryl bromide Pi ( 296 g; PM = 284.2; 1.72 eq.) In THF (1 L). The mixture is stirred at around 60 ° C. until the Grignard reagent is formed (exothermic; gray color). The rest of the solution is then carefully added for approximately 90 minutes at around 60 ° C., and the suspension is stirred for 60 minutes at the same temperature, then allow to cool. Cuprous chloride (MW = 99.0; 6 g; 0.10 eq.) Is added at 20 ° C and the suspension is cooled to -5 ° C. The silylated enol ether as prepared above (0.60 moles) is diluted with THF (600 ml) and this solution is added for 1 h at around -5 ° C. to the mixture of Grignard reagents and cuprate formed in situ . The mixture is stirred for 1 h at 0 ° C., then poured into a two-phase mixture of ammonium chloride (600 g) in water (4 L). Extraction is carried out with dichloromethane. The organic phase is then washed with water and concentrated in vacuo. Dichloromethane (1.2 L) and water (600 ml) are added. The mixture is cooled to 0-5 ° C and 36% hydrochloric acid (300 ml; 5.8 eq.) Is added over 30 min. The biphasic system is vigorously agitated for 2 h at around 12 ° C. The organic phase is decanted and washed with water. The amino side products are eliminated in the acidic aqueous phase while the hydrochloric acid salt of enone 4 remains in dichloromethane. The organic phase is neutralized with aqueous sodium hydrogencarbonate, washed with water and then concentrated until a final volume of approximately 600 ml is obtained. Dichloromethane is replaced by diisopropyl ether at 40-45 ° C at constant volume. The expected enone crystallizes, and is filtered at 20-22 ° C and then dried under vacuum at 35-40 ° C. (236 g white solid; yield: 82.3%; (from epoxy 2): C ₃ ιH ₃₉ 0 ₃ ; PM: 473.7;

IR (CHC1 _3, cm ^"1): 1735, 1658, 1609, 1581, 1509 NMR ^X H (CDCl _3, ppm): 0.56 (s, CH _3); 2.50 (m, 4H); 2, 75 (t, J = 7Hz, 2H); 4.06 (t, J = 7Hz, 2H); 4.37 (if, J = 7Hz, 1H); 5.79 (if, 1H); 6.82 and 7.07 (AA'BB ', 4H)

Stage d: 11-beta- (4- (2- (1-piperidinyl) ethoxy) phenyl) - estra-1,3,5 (10) -trien-3-ol-17-one.

A solution of enone prepared in the previous stage (50 g; 0.105 moles) in dichloromethane (200 ml) is added acetic anhydride (MW = 102.1; d = 1.09; 30 ml; 3.1 eq.) And acetyl bromide (MW = 123.0; d = 1.66; 30 ml; 3.9 eq.), at 20-25 ° C (exothermic addition). The brown solution is stirred for 5 h at 20-25 ° C then poured carefully in a suspension of sodium hydrogencarbonate (120 g) in water (500 ml) (evolution of carbon dioxide). The mixture is vigorously stirred overnight at 20-25 ° C., then the organic phase is washed with water and then concentrated to a final volume of 150 ml. Dichloromethane is replaced by methanol at constant volume by distillation under progressive vacuum at approximately 40 ° C. The saponification of estrone acetate is carried out by adding a solution of potassium hydroxide (MW = 56.0; 8.85 g; 1.5 eq.) In methanol (100 ml) at 0-5 ° C. The mixture is mixed for 1.5 h at 0-5 ° C, then poured into water (250 ml) and dichloromethane (250 ml). The organic phase is washed with water. Water and 36% hydrochloric acid (22.5 ml; 2.5 eq.) Are added. The organic phase is dried over sodium sulfate, filtered and concentrated until a final volume of 250 ml is obtained. The residual methanol is replaced by dichloromethane at constant volume by azeotropic distillation. Arylestrone hydrochloride spontaneously crystallizes and is filtered at 0 ° C, but not dried. Dichloromethane (400 ml) and a solution of potassium carbonate (MW = 138.2; 13.6 g; 0.94 eq.) In water (200 ml) are added to the solid at 20-22 ° C. The mixture is stirred until dissolution, then the organic phase is decanted, washed with water and concentrated until a final volume of 250 ml is obtained. Acetone (500 ml), then silica gel (Merck Si 60; 50 g) are added at 20-22 ° C. The suspension is stirred for 1 h at 20-22 ° C, and the silica is removed by filtration and washed with a 2/1 mixture of acetone and dichloromethane. The filtrate is concentrated to 400 ml, and the solvent is replaced by isopropyl ether at constant volume (final T: 68 ° C). Arylestrone 5 crystallizes during distillation and is filtered at 20-22 ° C, then dried under vacuum at 40-50 ° C. (36.9 g white solid; yield: 74.4% on the dry substance; HPLC purity: 99.9%): C ₃ ιH ₃₉ N0 ₃ ; MW: 473.7; IR (CHC1 ₃ , cm ^"1 ): 3598, 1732, 1610, 1580, 1512

1H NMR (CDCI ₃ , ppm): 0.49 (s, 3H); 3.90-4.05 (m, 3H); 6.38 (dd, J = 8.5 and 2.5 Hz, 1H); 6.44 (bs, 1H); 6.80 (d, J = 8.5 Hz, 1H); 6.44 and 6.95 (AA'BB ', 4H)

MS (m / z): (FAB ⁺ ; m / z): 474 (MH ⁺ ), 112, 98

Stage e: 17-alpha-methyl-11-beta- (4- (2- (1-piperidinyl) ethoxy) phenyl) -estra-1,3,5 (10) -triene-3, 17-beta-diol) . A suspension of 39 g of cerium trichloride

(dehydrated as described above (preparation 4); water: 1.1%; MW = 246.5; 3.0 eq.) in THF (500 ml) is stirred at reflux (67 ° C) for 2 hours, then cooled to 20-22 ° C. Nethylmagnesium chloride (3M solution in THF; 70 ml; 4.0 eq.) Is added over 15-20 min at 20-22 ° C. The gray suspension is stirred for 1 h at 20-22 ° C. A solution of arylestrone 5 (25 g; 52.8 mmol) in THF (100 ml) is added for 15-20 min at 20-22 ° C, and the mixture is stirred 1.5 h at 20-22 ° vs. Acetone (PM = 58.1; d = 0.79; .16 ml; 4.1 eq) is added 15-20 min at 20-22 ° C. The mixture is stirred for 15 min at 20-22 ° C, then poured into a mixture of saturated aqueous ammonium chloride (250 ml), water (250 ml) and ethyl acetate (500 ml) under agitation. The organic phase is washed with aqueous ammonium chloride, dried over sodium sulfate and concentrated under reduced pressure. The white solid is dissolved in methanol (75 ml) at 45-50 ° C, and the solution is acidified to pH 5.5 by addition of 36% aqueous hydrochloric acid, at 33-37 ° C. Methyl arylestradiol hydrochloride crystallizes after cooling. The suspension is stirred for 30 min at 20-22 ° C, then ethyl acetate (500 ml) is added; the hydrochloride is filtered at 0-2 ° C and dried under vacuum at 40 ° C (27.2 g white solid; yield: 98% (85.4% on dry substances); HPLC purity: 99.9%; solvation: 13% ): C ₃₂ H ₄₄ C1N0 ₃ ; PM: 526.2. Methylarylestradiol hydrochloride (20 g) is dissolved in methanol (100 ml) at 50-52 ° C, then water (200 ml) is added at the same temperature. The pH is adjusted to 5.6-6.0 by addition of an aqueous solution (3.3%) of potassium carbonate. The solution is concentrated to a final volume of 200 ml, then the methanol is replaced by water at constant volume (final T = 97 ° C). Under these conditions, the anhydrous hydrochloride crystallizes upon cooling to 80 ° C, and is stirred for 30 min at 80-82 ° C. He is very important to get the anhydrous form this way; otherwise, imperfect forms of methylarylestradiol can be obtained after neutralization. The hydrochloride is neutralized by addition in 30 min at 80-82 ° C of an aqueous solution of potassium carbonate at 3.3% (about 120 ml). The suspension is stirred for 4 h at 80-82 ° C in order to complete the transformation of the anhydrous hydrochloride into methylarylestradiol hydrate. The white solid is filtered at 20-22 ° C, washed with water and dried under vacuum at 35-40 ° C. Weight: 16.9 g; total yield: 86.1% compared to dry substances; HPLC purity: 99.8%, solvation: 3.6% water; C ₃ H ₄₃ 0 ₃ ; PM: 489.7;

IR (CHC1 ₃ , cm-1): 3602, 1610, 1580, 1512 1 H NMR (CDCI ₃ , ppm): 0.51 (s, 3H); 1.29 (s, 3H); 3.98 (m, 3H); 6.41 (m, 2H); 6.78 (d, J = 8Hz, 1H); 6.41 and 6.94 (AA'BB ', 4H)

MS (FAB +; m / z): 490 (MH ⁺ ), 112, 98 Example 2: Stage a: Arylation 11-beta- (4- (2- (1-pirrolidinyl) pentoxy) phenyl) -estra-4, 9 - diene-3, 17-dione

The silylated derivative obtained, example 1 stage b, (13 mmol) is mixed in THF (13 ml) with cuprous chloride (130 mg), cooled to -5 ° C. and 16 ml of magnesium (P3) are added in 10 minutes. Is maintained for 1 hour at 0 ° C and then added to the reaction medium the mixture consisting of ice (43 g), water (43 ml), NH ₄ C1 (26 g) and dichloromethane (43 ml). The mixture is stirred for 5 min, washed, extracted with dichloromethane, dried, filtered and evaporated under reduced pressure (compound of formula (III ')).

The dry extract is diluted in dichloromethane (26 ml), water (13 ml) is added, cooled to about 2 ° C, 37% 12N hydrochloric acid (6.3 ml) is added and stirred one hour at around 2 ° C. After washing with water, extraction is carried out with dichloromethane, the organic phases are poured into a saturated aqueous solution of NaHCO ₃ (21 ml), stirred, reextracted with dichloromethane, dried, filtered and evaporated under reduced pressure until obtaining 8.84 g of raw product in the form of an oil which is crystallized with isopropyl ether. Filtered and 4.93 g of expected product is obtained. Yield: 75.6%; C ₃₃ H ₄₃ Nθ ₃ ; MW: 501.7; Mp = 166 ° C; MS (ES +; m / z): 502 (MH ⁺ ) Stage b: Flavoring

3-acetoxy-ll-beta- (4- (2- (1-pirrolidinyl) pentoxy) phenyl) - estra-1,3,5 (10) -trien-17-one (not isolated) ll-beta- (4 - (2- (1-pirrolidinyl) pentoxy) phenyl) -estra- 1,3,5 (10) -trien-3-ol-17-one (isolated) To a solution of enone prepared in the previous stage (1 g , 2 mmol) in dichloromethane (4 ml), acetic anhydride (0.57 ml, 6 mmol) and acetyl bromide (0.57 ml, 7.5 mmol) are added at room temperature and stirred 3.5 h at room temperature. The reaction medium is then poured into a NaHCO ₃ solution (2.18 g,

26 mmol) in water (10 ml), wash with IN sodium hydroxide solution (5 ml) and water, reextract with dichloromethane, dry, filter and concentrate under reduced pressure.

Diluted in methanol (9 ml) then added, at approximately 0 ° C, potassium hydroxide in pellets (168 mg; 3 mmol) and stirred 45 minutes at approximately 0 ° C and with nitrogen bubbling. Dichloromethane and water are then added, the mixture is stirred for 5 min, washed with water, re-extracted with dichloromethane, dried, filtered and evaporated under reduced pressure. 800 mg of expected product are obtained. Yield: 80%; C ₃₃ H ₄₃ NO ₃ ; PM: 501.7;

IR (CHC1 ₃ , cm ^"1 ): 3598, 1732, 1610, 1580, 1512 ¹ H NMR (CDCI ₃ , ppm): 0.47 (s, 3H); 1.79 (m, 4H); 2.55 (m, 4H); 3.90 (t, 2H); 3.98 (tl, 1H); 6.35 (dd, 1H); 6.57 (d, 1H); 6.79 (d, 1H) ; 6.59 and 6.95 (AA'BB ', 4H) Stage c: reduction

11-beta- (4- (2- (1-pirrolidinyl) -pentoxy) phenyl) -estra- 1,3,5 (10) -trien-3, 17-beta-diol

600 mg of the ketone prepared in the preceding stage (1.2 mmol) are dissolved in 6 ml of methanol, cooled to 0 ° C. and introduced in fractions of 95% NaBH ₄ (62 mg, 1.5 eq.). After 2 hours, acetone (0.5 ml) is added, the mixture is stirred for 5 min and then dichloromethane (6 ml) and water are added. (6 ml). Decanted, washed with water, reextracted with dichloromethane, brings together the organic phases, dried over NaS0 ₄ , filtered and evaporated under reduced pressure to obtain 590 mg of expected alcohol. Yield: 98%; C ₃₃ H ₄₅ NO ₃ ; PM: 503.7

IR (CHC1 ₃ , cm ^"1 ): 3604, 1610, 1580, 1512

1 H NMR (CDCl ₃ , ppm): 0.34 (s, 3H); 1.84 (m, 4H); 2.65 (m, 4H); 3.68 (m, 1H); 3.81 (t, 2H); 3.91 (bt, 1H); 6.36 (dd, 1H); 6.57 (d, 1H); 6.77 (d, 1H); 6.57 and 6.77 (AA'BB ', 4H) MS (El, m / z): 503 (M ⁺ ), 362, 260, 140, 84. Example 3: llβ- hydrochloride (4- (2 - (diethylamino) ethoxy) phenyl) - estra-1,3,5 (10) -trien-3-ol-17-one. To a solution of 11-beta- (4- (2- (diethylamino) ethoxy) phenyl) -estra-4, 9-diene-3, 17-dione obtained in a similar manner to that of Example 1 stage c but with 4- (2-diethylamino) ethoxy) 1-bromobenzene (MW: 461.6; 35 g; 0.076 mole) in dichloromethane (140 ml) is added acetic anhydride (7.8 ml; 1.1 eq) and bromide acetyl (14 ml; 2.5 eq.), at 20-25 ° C (exothermic addition). The brown solution is stirred for 5 h at 20-25 ° C and then poured carefully into a solution of sodium hydrogencarbonate (84 g) in water (350 ml) ^• (evolution of carbon dioxide). The mixture is stirred vigorously for approximately 18 h 20-25 ° C., then the organic phase is decanted, washed with water until the end of bromides and concentrated to 105 ml. The dichloromethane is exchanged with methanol at constant volume by vacuum distillation at around 40 ° C. The estrone acetate is saponified by addition of a potassium solution (6.37 g; 1.5 eq.) In methanol (70 ml) at 0-5 ° C. The medium is stirred 1.5 h at 0-5 ° C, then poured into water (175 ml) and dichloromethane (175 ml). The organic phase is washed with water at the end of bromides. Water, methanol (if decantation problem) and 36% hydrochloric acid (15.7 ml; 2.4 eq.) Are added. The organic phase is stirred, decanted and dried over sodium sulfate, and concentrated to 175 ml. The solvents are removed by distillation at constant volume, by regular addition of 2- butanone (final T: 78 ° C). Arylestrone hydrochloride crystallizes; it is filtered at 20-22 ° C, and dried under vacuum at 40-60 ° C. (34.0 g beige solid; yield: 89.9% HPLC purity: 98.7%; solvation: 12%): C ₃₀ H ₄₀ ClNO ₃ ; PM: 498.1; IR (CHC1 _3, cm ^"1): v 3601, 2456, 1733, 1610, 1584, 1511; NMR ^X H (CDCl _3, ppm): δ 0.42 (s, 3H), 1.31 (m, 6H ), 3.16 (m, 4H), 3.31 (m, 2H), 3.96 (tl, 1H), 4.17 (m, 2H), 6.51 (m, 1H), 6.68 (m, 1H), 6.73 (m, 1H), 6.51 and 6.95 (AA'BB ', 4H), 11.36 (si; 1H); SM (El; m / z): 461 (M ⁺ ), 446, 362, 86, 38 and 36 (HCl). 4-chloro-11β- (4- (2- (diethylamino) ethoxy) phenyl) phenyl) -estra-1,3,5 (10) hydrochloride -trien-3-ol-17-one.

To a solution of arylestrone hydrochloride prepared in the previous stage (50 g; 0.100 mole) in dichloromethane (250 ml) and ethanol (250 ml) is added at about 10 ° C 36% hydrochloric acid (4 ml; 0.47 eq) then, in fractions, N-chloro succinimide (12.6 g; 1.0 eq on dry) (exothermic addition). The solution is stirred for 1 to 3 h at 8-12 ° C. (parasitic formation of 2-chloro and 2,4-dichloro derivatives is observed by HPLC). It is treated by pouring carefully into a solution of sodium thiosulfate (25 g) and 30% sodium hydroxide (14 ml; 1.5 eq) in water (500 ml). Extraction is carried out with dichloromethane (250 ml). The organic phase is decanted, and water and 36% hydrochloric acid (12.5 ml; 1.6 eq) are added thereto. The aqueous phases are decanted and extracted with a dichloromethane-methanol mixture. The organic phases are combined and dried over sodium sulfate and concentrated to 250 ml. The methanol is removed with dichloromethane at constant volume by azeotropic distillation (final T: 39.8 ° C). Chloroarylestrone hydrochloride crystallizes; it is filtered at 20-22 ° C, and dried under vacuum at 40 ° C. (41.0 g white solid; yield: 77%; HPLC purity: 98.8%; solvation: 3%): C ₃ oH3 ₉ Cl ₂ N0 ₃ ; PM: 532.6; IR (CHCI ₃ , cm ^"1 ): v 1727, 1610, 1582, 1568, 1511, 1493;

^X H NMR (CDCl _3, ppm): δ 0.45 (s, 3H), 1.41 (t, 6H); 3.21 (m, 4H), 3.37 (m, 2H), 3.99 (tl, 1H), 4.38 (m, 2H), 5.87 (OH), 6.68 (d, 1H ), 6.78 (d, 1H), 6.60 and 6.94 (AA'BB ', 4H), 12.30 (if, 1H);

MS (ES ⁺ ; m / z): 498, 496 (MH ⁺ ).

Claims

1) A process for the preparation of compounds of formula (I)

in which

- either R ¹ and R ² , which are identical or different, represent a benzyl group or a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing from 1 to 8 carbon atoms

either RI and R2 form together with the nitrogen atom which carries them a 5 to 6-membered heterocycle, saturated or unsaturated, aromatic or non-aromatic optionally containing from 1 to 3 additional heteroatoms and optionally attached to another cycle,

R ³ represents a hydrogen atom or a protecting group for the hydroxy function, n is an integer from 2 to 8, characterized in that a compound of formula (II) is treated

K representing a protected ketone function in particular in the form of a ketal, thioketal or mixed ketal, with a silylating agent in the presence of a base, in order to obtain the silylated enol of formula (III) in which

Ra, Rb and Rc, identical or different, represent an alkyl radical containing from 1 to 4 carbon atoms, or a phenyl radical which is reacted with

- an organocuprate derivative derived from organometallic

RsMgHal or R ₅ Li Hal being a halogen atom and generated in a catalytic or stoichiometric manner, in which R ₅ represents the group

then a deprotection agent in order to obtain a compound of formula (IV) which is treated with a flavoring agent to obtain the expected compound of formula (I) which, where appropriate, is subsequently deprotected to obtain a compound of formula (I) with R ₃ representing a hydrogen atom.

2) A process as defined in claim 1 characterized in that the silylated derivative is a trimethylsilyl derivative which makes it possible to obtain a silylated enol of formula (II) in which Ra, Rb and Rc are identical and represent methyl.

3) A method according to claim 1 or 2 characterized in that the silylated derivative is ClSiMe ₃ . 4) A method according to any one of claims 1 to 3 characterized in that the silylation reaction is carried out in the presence of LDA or LiHMDS.

5) A process as defined in claim 1 characterized in that an organometallic derivative of formula R ₅ - MgBr is used, R ₅ being as defined in claim 1.

6) A process as defined in claim 1 characterized in that an organometallic derivative of formula RsMgBr is used, R ₅ being as defined in claim 1 and in which - either Ri and R ₂ identical or different represent a radical linear or branched alkyl containing 1 to 4 carbon atoms

7) Method according to claim 1 characterized in that the deprotection agent used on the compound of formula

(III ') to obtain the compound of formula (IV) is an agent allowing an acid hydrolysis and in particular hydrochloric acid.

8) Method as defined in claim 1 characterized in that the flavoring agent is acetyl bromide in the presence of acetic anhydride.

9) Process as defined in claim 1 characterized in that a compound of formula (II) is treated with ClSiMe ₃ in the presence of a base in order to obtain the silylated enol of formula (Illa):

- either Ri and R form together with the nitrogen atom to which they are linked a group

in order to obtain a compound of formula (III 'a) isolated or not isolated

10) Method according to claim 1 characterized in that the compound of formula (I) is used as an intermediate product for the preparation of a derivative having an estrogenic activity of formula (la):

by the action of an organometallic alkylating agent of type R ⁴ M, R ⁴ being an alkyl radical containing from 1 to 4 carbon atoms unsubstituted or substituted by one or more halogen atoms and M representing Mg-Hal or Li .

11) Process according to claim 10 characterized in that Ri and R ₂ represent an alkyl radical containing from 1 to 4 carbon atoms or form together with the nitrogen atom which carry them a saturated heterocycle chosen from

n is an integer equal to 2 to 5 and R3 is a hydrogen atom and R4 is methyl

12) Process according to claim 10 or 11 characterized in that the alkylating agent is MeMgBr in the presence of CeCl ₃ .

13) Method according to claim 1 characterized in that the compound of formula (I) is used as an intermediate product for the preparation of a derivative having an estrogenic activity of formula (Ib):

by action of a ketone reducing agent. 14) Process according to claim 12 characterized in that Ri and R ₂ represent an alkyl radical containing from 1 to 4 carbon atoms or form together with the nitrogen atom which carry them a saturated heterocycle chosen from

n is an integer equal to 2 to 5 and R ₃ is a hydrogen atom. 15) Method according to claim 12 characterized in that the reducing agent is NaBH.

16) Method according to claim 1 characterized in that the compound of formula (I) is used as an intermediate product for the preparation of a derivative having an estrogenic activity of formula (le):

by action a) of a halogenation reagent then b) of an agent for reduction of the ketone function or a) of an agent for reduction of the ketone function in position 17 then b) of a reagent d 'halogenation.

17) Process according to claim 16 characterized in that Ri and R ₂ represent an alkyl radical containing from 1 to 4 carbon atoms or form together with the nitrogen atom which carry them a saturated heterocycle chosen from

n is an integer equal to 2 to 5 and R ₃ is a hydrogen atom and X is a chlorine atom. 18) Method according to claim 16 or 1 characterized in that the halogenating agent is N-chlorosuccinimide or N-bromosuccinimide and the reducing agent is NaBH ₄ .

19) Process for the preparation of the compounds of formula (III) from the compounds of formula (II) according to the method as defined in claim 1.

20) Process for the preparation of the compounds of formula (IV) from the compounds of formula (III) according to the method as defined in claim 1.

21) As intermediate compounds, the compounds of formulas (III), (III ') and (IV) as defined in claim 1, it being understood that the compounds of formula (IV) in which

NRιR ₂ represents a pyrrolidine and n is an integer equal to 2 - NRιR ₂ represents a morpholine group and n is an integer equal to 2 are excluded.

22) The compounds of formulas (I) and (Ib), as defined in claim 1, in which n is an integer equal to 5, R ₃ is a hydrogen atom and NRιR represents a pyrrolidine or a piperidine.

23) As medicament the compounds as defined in claim 22. 24) Pharmaceutical compositions containing at least one medicament as defined in claim 23 and a pharmaceutically acceptable vehicle.