AU620341B2

AU620341B2 - New steroids containing a spiro ring 3,4 or 6 links in position 17, the process and intermediates for their preparation, their use as medicaments and the pharmaceutical compositions containing them

Info

Publication number: AU620341B2
Application number: AU22246/88A
Authority: AU
Inventors: Martine Moguilewsky; Lucien Nedelec; Andre Clauss Ner; Daniel Philibert
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1987-09-11
Filing date: 1988-09-16
Publication date: 1992-02-20
Anticipated expiration: 2008-09-16
Also published as: EP0306846A3; IL87721A0; AU2201888A; AU2224688A; ZA886716B; EP0306846A2; DK500388D0; KR890004700A; DK500388A; JPH01100118A

Description

I

1 118 6 150 dot lsa t 1 s 0 oit .3bd d es Inv aldeS Dect L '7507PARI Par ls, France ti. ~uyT.p~~vx Par proCulratioii HUbert FRITEL Chef du Ilk *e

AUSTRALIA

PATENTS AC.T 1952 6-20 3 4F01 Fs COlJPLET SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Appli.cation Number: Lodged: :CompLete Specification Lodged: Accepted: Lapsed: Published: Priority: ',.Rel ated Art: o, 00 P TO BE CCJAP LTED BY APPLICANT Name of Applicant: :.*'.Address of Applicant: :Actual Inventors: Address for Seice:

ROUSSEL-UCLAF

35 Boulevard des Invalides, 75007, Paris, France LUCIEN NEDELEC, ANDRE CLAUS1SNER, MARTINE MOGUILWSKY DANIEL PHILIBERT and CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Ricbitond 3121, VQ-toria, Australia.

complet.- Specification for the invention entitled: NEW STEROIDS CONTAINING A SPIRO RING 3,4 OR 6 LINKS IN POSITION 17, THE PROCESS AND INTERMEDIATES FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS AND THE PHARMACQEUTICAL COMPOSITIONS CONTAINING THEM The following statemnt As a full description of this invention, including the best me~thod of perforn~ig 't known to us:la New steroids containing a spiro ring with 3, 4 or 6 links in position 17, the orocess and intermediates for their prenaration, their use as medicaments and the pharmaceutical compositions containing them.

The present invention concerns new steroids containing a spiro ring with 3, 4 or 6 links in position 17, the process and intermediates for their preparation, their use as medicaments and the pharmaceutical compositions containing them.

5 A subject of the invention is products of general formula i 0

R

*9 radical, optionally substituted, R2 in alpha or beta position, represents a hydrocarbon radical containing from 1 to 18 carbon atoms, S 15 thq wavy line of the spiro ether indicates that the oxygen atom can be in alpha or beta position, X represents a (CH2)n radical in which n a inrepresents a integer 1, 2 or 4, or X represents a -CH=CH-CH2rn-CH represents a hydrocarbon radical containing from 1 to 18 carbon atoms, radical, rings A and B having one of the following structures: a) either A and B represents the group: tI 20 in which R' and RP", identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, b) or A and B represent the group: -2- A :j3 Reo in which Re represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, optionally substituted, or an acyl radical:, c) -or A, B and C represent the group:

R

C

d) or A n ersettegop r ita e5) or A and B represent the group: prfral each rersn ydoe tm When R4 represents an optionally substituted carbocyclic aryl or aralkyl radical, it is preferably a phenyl or benzyl radical. These aromatic radicals can be substituted in ortho, meta or pr L position by one or more alkyl radicals containing preferably from 1 to 8 carbon atoms; by one or more alkoxy radicals having preferably f rom 1 to 8 carbon atoms such ad methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, alkenyloxy such as vinyloxy or allyloxy, all these radicals being optionally substituted; by one or more halogen atoms, such as fluorine, chlorine, bromine, iodine, and preferably chlorine or fl.uorine; by one or more radicals chosen from 3 hydroxyl, trifluoromethyl radicals, acyl radicals, having from 1 to 6 carbon atoms such as acetyl, propionyl, optionally esterifie carboxy such as methoxycarbonyl, ezhoxycarbonyl, prcpoxycarbonyl, alkyithio having from I to 8 carbon atoms sucn as methylthio or ethylthio optionally oxidized 3 in tih form of sulphoxide or of sulphone; by one or more amino radicals or amino radicals, mono- or disubstituted by alkyl radicals cortaining from I to 8 carbon atoms, themselves optionally substituted, such as methylamino, dimethylamino and bis (chloroethyl) amino radicals, the amino or mono- or disubstituted amino radicals optionally being oxidized into N-oxide, the amino radicals incorporated in a heterocycle o optionally containing a hetercatom chosen from the group formed by oxygen, nitrogen and sulphur, such as morpholino or piperidinyl radicals; of course the aryl or aralkyl radicals can be substituted by a combination of these various radicals such as for example 2-methylm thinethoxy, 3-fluoro, 4-dimethylamino; R 1 can also represent a heterocyclic aryl radical optionally substituted by the various radicals considered above. The following radicals can be cited: thienyl, furyl, isothienyl, isofuryl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl or piperidinyl and the heterocycles known to an expert.

F t .As a substituent on the aryl nucleus, there can also be considered an amino-substituted alkyl radical such as one of the following radicals: dimethylamino methyl, dimethylamino ethyl, methyl (dimethyl aminoethyl) amino; amino-substituted alkyloxy such as dimethylamino ethyloxy, There can also be cited the radicals containing a silicon atom such as a trimethylsilyl phenyl radical.

The previously cited radicals containing a nitrogen atom or a sulphur atom can be oxidized.

Generally, the products in which the substituent R 1 contains a heteroatom, preferably nitrogen or sulphur, are preferred.

Among the various radicals R 1 there can be cited the folleing, d 6

JI

I T 1-: jl j E b B

Z

4 -0-3 3 8-

F

C

'-KIIV'

-0-SCH3 KScH 3 i ft ~~10 a. a a a a a, a 6 99 a 15 -955 -O SE b 0

;N

M--

a: *a a arr p 94 25 a. a a a a ,h-;3I -ci~3 -Q -"3 Q~x

J

29} fcNit- 0 3 No1 /CH3-y

N

-if> ii

~I

1 ii i L.1/ 1 cy 3: 3 o i 'h A c

A

-1 1

SI

The radical Rn preferably represents a saturated linear or branched alkyl radical, containing from 1 to 4 carbon atoms, for example, a methyj,, ethyl, prcpyl or butyl radical.

It is preferred for Rn to represent a methyl or ethyl radical.

It is more particularly preferred for R, to represent a methyl radical.

The radical R 2 can be in alpha or beta position. The products are preferred in which R, is in beta position. In 'he latter case, the oxygen atom of the spiro ether function is in 17-beta position.

10 When R 1 contains a carboxy function, the latter can be salified.

w* Among the possible salts, there can be cited, for example, the salts of S the following: sodium, potassium, lithium, calcium, magnesium or S. ammonium. There can be cited, among the organic bases, methylamine,

S.

propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethyl- •e ethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexyl amine, niorpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

When Ri contains a function which can be salified by an acid and *a in particular an amino function, addition salts are obtained with acids.

20 The invention of course extends to the addition salts with acids *n of the salifiable compounds of formula such as, for example, the salts formed with one of the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, t propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulphonic such as methane or ethane sulphonic, arylsulphonic such as benzene or paratoluene sulphonic, and arylcarboxylic.

Among the products of formula the product corresponding to formula are preferrda:

R,

~(II)

0 in which R I represents a carbocyclic or hetrocyclic aryl or aralky Il radical, opticnally substituted, R in beta position represents a hydrocarbon radical containing from 1 to 18 carbon atoms, the oxygen atom of the spiro ether is in position 17-beta, X represents a -(CH2)n radical in which n represents an integer Z or 4 or X represents a -CH=CH-CH-CH.- radical, as well as their salts. Among the products of formula the products are also preferred in which R, represents either an aryl radical or an aralkyl radical carrying an amine function: R3

-N

4

R

4 in which R 3 and R 4 each represents a primary, secondary or tertiary h4yd: alkyl radical containing from 1 to 8 carbon atoms or R 3 and R 4 form, together with the nitrogen atom to which they are linked, a heterocycle optionally containing another heteroatom chosen from the group formed by oxygen, nitrogen, sulphur and silicon, or an aryl radical carrying a methylthio or ethylthio function, as well as their salts.

Among the latter products cited, in particular the products of 4" formula are preferred in which R 1 is a phenyl radical, the 9 9 substitUent carried by this phenyl radical is in Para position, as well S as their salts, as well as the products of formula in which R 1 4 in epresents onea primary, secondary or tertiaryof the following radicas as well as their salts.

179 II -L i:i i L 11 ii Amonq the values of Rthe following radicals are preferred: The products of formula which are preferred are particularly those described in the examples. Among the products described, the following are preferretd: tttt (17R) llbeta-[4-(dimethylamino)phenyl] spiro (estra-4,9-dien-17,21oxetan)-3-one.

-(17R) llbeta-(4-(methylthio)phenyljspiro (estra-4,9-dien-i7,2'oxetan)-3-one.

Also a subject of the invention is a process for the preparation of products of fQrmula as defined above, characterizedi in that: a) to preparo the, products of formula (IA): R R 2 0 C 1,

R

(IA)

in which RIand R, keep the same significance as above, R' and R" each C: 5 represents a hydrogen atom or an alkyl radical, or one represents a hydrogen atom and the other represents an alkyl radical, a product of formula (11):R 1. X K 0ff in which K 1,epresents a blocked ketone group, is submitted to the action of a dehydratiorn reagent which is also capable of freeing the ketone function, i,.f order to obtain the products of formula (IA) in -8 which R' and R" represent a hydrogen atom, and, if desired, the products of formula (IA) in which Rj contains a sulphur or nitrogen atom are submitted to an oxidation in order to obtain the products in which Ri contains a sulphur atom 2xidized into sulphoxide or into sulphone or a nitrogen atom oxidized into N-oxide, and if desired, the products of formula (1A) are submitted to the action of a strong base, then to the action of an alkyl halogenide in order to obtain a product of formula (IA) in which R' and/or R" represent an alkyl radical having from 1 to 4 carbon atoms: 10 b) to prepare the products of formula (IB): qo 9 i S* (IB) 0* 0 r* Y 6 in which RI, R 2 and Re keep the same significance as abovte a product Sof formula R 0 (I A) 0 a in which R i and R 2 have the significance already Indicated, is S" submitted to the action of an aromatization agent, then if necessary or desired, to the action of a saponification agent and finally i£ desired the product of formula (Ig) in which Re is a hydrogen atom is submitted to an alkylation reagent; c) to prepare the products of formula (Ic): R 0 o A pn/in which R, and R, keep the same significance 4,s above, a product of iormula t.I'A) is submitted to the action of an acylation agent and then of a saponification agent; d) to prepare the products of formula (ID): R

R

in wnich R 1 and R, keep the same significance as above, a product of -formula is submitted to the action of an epoxidation agent; e) to prepare the products of formula (1r); 0 in 15ic RadR eptesm1infiac saoe yrxlm 20 in wich a anfed m epthed sfae in outniica e a bove, p ross, mne is coaeso tof raton product of formua eyrto egn wit af necesarn ur or deirditha prduts of formunlbnzn polymer) suIort and oeve obaned care saiiea cdsc shyrclrcai aacidIn a spreferr methd fc a carngolu te sabove prcss the 2 coverin th o ml (1 prdut of canoermulaent by adehyratio rchagen wimthyt polystyrene potyee or"dmeh( withh# asyrn/dviy/bnzn poye otasoium aci sulpae a watmermthYe I oie mxu The oxidation agent which is made to react on the, productz of 10 i formula lIA) or the epoxidation agent whicn is made to react in order to obtain the products of formula (ID) is preferably a peracid such as merachloroperbenzoic acid, peracetic acid or perphthalic acid.

Hydrogen peroxide can also be used, n its own or in the presence of hexachloro- or hexafluoro-acetone.

Of course, according to the number of functions which can be subjected to an oxidation, one or more equiialents of oxidizing agent can be used.

Thus, for example, if it is desired to oxidize the sulphur atom contained by RI, into sulphone, at least two equivalents of oxidizing agent must of course be used.

The strong base used on the products of formula (IA) can be an amide of alkali metal, such as sodium or lithium amide optionally prepared in situ; the alkyl halogenide used is preferably an iodide such as methyl iodide; the aromatization agent used to prepare the products of formula (IB) is preferably an acyl halogenide such as acetyl bromide or an acid anhydride aurh as acetic anhydride, or a mixture of the two; the optional acylation of the products of formula (IB) and the acylation leading to the products of formula (I

C

are brought about according to the usual methods; an acyl halogenide is preferably used; the optional alkylation of the products of formula (IB) is carried Sa' out according to the usual methods. For example, an alkyl halogenide is used; the saponification agent used to obtain the products of formula (Ig) or (I1) is preferably an alkaline base such as sodium or potassium hydroxide and the reaction is brought about in a lower alcohol such as methanol or ethanol; formation of oximes from the products of formula is carried out using hydroxylamine in the form of a salt, preferably the hydrochloride in an alcohol at the temperature of reflux The salification is carried out in standard conditions. The operation can be done, for example, in the presence of ethanolic sodium hydroxide. A sodium salt can also be used such as sodium or potassium carbonate or sodium or potassium acid carbonate, 2

_T

t 11 Also. the salification by an acid is carried out in the usual conditions. The operation is done preferably with hydrochloric acid, for example Lri an ether solution.

Also a subject of the invention is a process for the preparation of products of general formula as defined above in which X represents a -(CH'n) 4 Or -CH=CH-C1 2 CH2- group characterized in that a product of formula (III): *9 9 9 99 vi 0 9 09*9 09 99 9 @0 *0 4 99 9 99 90 9 90 9*

S

99090* 090* 9 19 @9 9 9 00*1*0 9 9 *0*9*0 0 9 C )420 H 2 C H

(III)

in which R, and keep the same significance as above and the dotted line indicates the possible presence of a double bond between the carbons which ca:~ry it, is treated by the action of a cyclization reagent, in order' to obtain a product of formula 0* 9 9* *9 0* 0 9 II 9 90 l2~.

ii

(IIIA)

corresponding, to a product of formula (IA) in which RO and each represents a hydrogen atom and x represents the groups 2 4 and -C11=Cl-CHz -C112-, which products of formula Are converted into products of formula (IA) in which one of the radicals R! or, RII or the two radicals R' and R" represent ci alkyl radical having from I to 4 carbon atoms, and into products formulae (IC)' (1b) and (IEs) according to the pro~cess described above.

In a preferred method of carrYlng out the jprocess described above, Ithe cyclization reagent which Is preferably made to react on the products of formula (III) is tosyl chloride in. the presence of pyridineos there can Also be used methylsuiphonyl chltwide.

in vwhich R' and identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, b) or A and B represent the group: /2 604 41. 0 0 !k0 *00 S12~ The products of formula kl) as well as heir pharmaceutically acceptable salts are carticular!V interesting; proauccs :ram a pharrnacological point of view.

The study of the products cn hormone-receotors has enabled the progestomimetic or anti4progestomirnetc. andrcgen or antiandrogen activities to be brought to light.

The products of formula possess in particular a remarkable antiprogestomimetic activity.

The products of formula also possess an antigiucocorticoid activity, as is shown by the results of the tests set out hereafter.

However, some products show an antiprogestamimetic activity which is greater than their antiglucorticoid property.

The products of formula as well as their pharmaceutically acceptable salts which possess antiprogestomimetic properties can be 15 used as contraceptives: they can be used against hormone irregularities.

Some products of formula (:jas well as their pharmacIeutically acceptable sralts can also of fer progestomimetic propert.Leg ead can also be employed in the treatment of amenorrhea, dysmenorrhea and luteal "0 The products of formul~a as Oell as their pharmaceutically acceptable salts can therefore be used as medicaments rnainl~l for combating side-effects of glucocorticoids; they also enable the combating of disorders due to a hyper-secretlon of glucocorticoids and in particular the combating of ageing in general and more particularly 'IS of hypertension, atherosclerosis, osteoporosis, diabetes, obesity as oell as immuno-depression and insomnia.

The products of formula as well as their pharmaceutically accoptable salts which offer antiaridrogen properties can be used in the treatment of hypertrophies and of cancer of the prostate, of hyperancirogeny, of anaemia, of hirsutism and of acne.

The products of' formula as well as their pharmaceutically acceptable salts also possess antiprolifen~tive properties which make them of use in the trqatment of 4',-rmone44deperxdejht cancers, in particular mammary carcinomas and their metastasese- These properties also~ make them of Use in the treatment f benign tumours.

$OMe of the products of formula (1)11 as well as their pharmat* too 0

(A

H

:1 Al

A

13 ceutically acceptable salts possess estrogen and/or anti-estrogen properties. The anti-estrogen properties make them of use in the treatment of estrogeno-.ependent cancers.

The estrcger properties which can also be offered by the said products of formula as, well as their pharmaceutically acceptable salts also make them of use in tho treatment of disorders connected with a hypofolliculinemia, for example amenorrhea, dysmenorrhea, repeated miscarriages, premenstrual disorders as well as in the treatment of the menopause.

A subject of the invention is therefore, as medicaments, the products of formula pharmaceutically acceptable, that is to say non-toxic, at the doses used, as well as their pharmaceutically S. acceptable salts.

0, 4 "A subject of the invention is in particular, as medicaments, the 004, 15 preferred products mentioned above and quite particularly the products of Which the names follow: (17R) llbeta-(4-(dimethylamino)phenyl] spiro (estra-4,9-dien-17,2'oxetan)-3-one.

(17R) llbeta-(4-(methylthio)phenylJ spiro (estra-4,9-dien-17,2'- ZO oxetan)-3-one.

'6 The useful posology varies as a function of the affection treated e t4 and the administration route; it can vary for example from 10 mg to I g per day in an adult by oral route.

t ;The new products of formula and their salts, as defined above, can be used to prepare pharmaceutical compositions containing, as active principle, at least one of the said products.

The products of formula and their salts are used by digestive, parenteral or local route. They can be prescribed in the form of simple or sugar-coated tablets, gelules, granules, suppositories and injectable preparations, ointments, creams, gels, Which are prepared according to standard methods.

The active principle or principles can be incorporated with excipients usually employed in these pharmaceutical compsitions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fauty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, Ii

A

14dispersing or emulsiiying agents, and preservatives.

A subject of the invehcicn Ls therefore pharmaceutical compositions containing as active principle at least one product of formula or at least one of their pharmaceuticallIy acceptable salts.

subject of the invention is also, as new industrial products andI4 in particular as new industrial products for the preparation of products of formula the products of formula (II') 101 in which R 1 R2 and K.have the significance indicated above and X I i represents -(CH2)nl- in which n1i 2 or 4, or XI represents 5 H-H-C2 The products of formula (III) can be prepared by cyclization of .E the corresponding products of formula (IV):

(IV)

*h prdut offrua(V antesle eprprdsatn 4H$ in which R' and identical or different, represent a hydrogen atom or an alkyl radical having from I to 4 carbon atoms, b) or A and B represent the group:

MINIMUM*

I

N

15 by the action on these products of darivatives of formulae: H-C=C-(CHn) 2 0H or CH 3

CO

2 Alk in the presence of a strong base, (,%=a1lky) C 1 4 followed if necessary by a separa,"Aon of the isomer mixtures obtained by t:he usual methods such as chrometoqraphy.

The products obtainea in which ring D has the ','qllowing structure: 1 run AJ1.

*0 0* 0 *000 0 *0 0 00

SS

0 00 *0 0* 0 O S 0 00 0.

0 0 0* 0 00 0* 0 0 00 00*0 0* 0O 0 are then submitted to a partial or total hydrogenation for the primary products in order to obtain the products of formula (IV) in which1- X' represents respectively a radical -CH=CH-C"2-CHZ- or -(CH2)ni in is which ni represents the numeral 4.

The products of formula are submitted to a reducing reagent in order to obtain the products of formula (IV) in which X' represents (CH,2) 2 The products of formula (II) in which X represents can be prepared by the action of a trimethyl suiphonium halogenide on the products of formula in the presence of a strong base.

Some methods of preparation for products of this type are found in European Patent EP 04192,598.

The products of formula (III') can also be prepared in the following manner: on a product of formula(V) 00 0 0 #0*0 00*0*0 0 0

(VT)

there is made to react, either a 'product of formula; H-C=C-(CHn)ZOH in order to obtain a having the same ring D as the product above and' then the product is submitted to a partial or total hydrogenation reac'tion: allyloxy, all these radicals being optionally substituted; by one or more halogen atoms,. such as fluorine, chlorine, bromine, iodine, and preferably chlorine or fluorine; by one or more radicals chosen from,/

KT

15 2r a product of formula: CH 3 COjAlk in order to obtain a~ product having the same ring D as the product above and then This product is submitted to a reducing agent, in order to cbtair. a orcouct cf formula

(VII):

(VII)

k *~f

S.

C S 0 5555 5* 0 0 0e e5 S q J 0g eq 0

S

*5 *5 0 0 eq 5* *0 9 5.

Sq.

C

*6 S *0 S C Ce,.

S

in which X' and R2 have the previous significance, and formula (VII) are submitted to a cyclization agent, in a product of formula (VIIT): the products of order to obtain (Vill) in which R and X' have the previous significance, which is submitted to an epoxidatiin reagent, In order to obtain a product of formula (IX)

(IX)

on which product a reagent is made to react which Is chosen from the following; (Rj) 2 CuLi, RiMgI'al in the presence of cuprous or cupric salts or (R 1 2 CuCNLij, in order to obtain the expected products of formula In a preferred method of carrying out the process above, the agent which cyclizes the products of formula (IV) Into products of formula (111) is toluene suiphonyl chloride or methane sulphonyl chloride in pyridine.

4 Iii

I!

17 1 The action of the product of formula: H-C=C-(CH 2 2 OH on the product of formula is carried out preferably in the presence of potassium tert-butylate or of butyl or methyl lithium in a solvent such as tetrahydrofuran, The action of the product of formula: CH 3 COAlk in which Alk is preferably tert-butyl is carried out preferably in the presence of lithium diisopropylamide in a solvent such as tetrahydrofuran.

The total hydrogenation of the product is carried out for example by a mixture of methanol and palladium on charcoal or by chlorotristriphenyl phosphino rhodium in b(nzene or a benzene/ethanol mixture and passage of hydrogen. The pa;rtial hydrogenation can be carried out by hydrogen in the presence of palladium on barium sulphate poisoned by an amine such as quinoline or triethylamine, in a solvent such as ethyl acetate.

S* 15 The reduction of the products can be carried out preferably with lithium aluminium hydride, for example in tetrahydrofuran.

The formation of the epoxide in position 17,20 is carried out preferably by the action of trimethylsulphonium iodide in the presence Sof potassium tert-hutylate in a solvent or a mixture of solvents such as tetrahydrofuran and dimethyl sulphoxide.

So* The products of formula (III) can be prepared by the action, on the previously cited products of formula of a dehydration reagent also capable of freeing the ketone function which is chosen from the t2( reagents cited above and in particular dilute acetic acid or hydrot i chloric acid in methanol.

This reaction can in addition be carried out starting with the products above without isolation of the product the partial or total hydrogenation reaction of the products being followed by the deprotection re .tion of the ketone function.

The epoxidation reaction used to convert the products of formula (VIII) into products of formula (IX) is hydrogen peroxide in hexafluoroacetone. The undesired beta isomer is separated by chromatoqraphy.

The reagent which is preferably made to react on the product of formula (IX) is the product R 1 MgBr in the presence of cuprous chloride.

Some examples of carrying out such preparations will be found 1 I~ I i :t r

I

~Ci *a:1

/INC

-G

18 hereafter in the experimental part.

In aadition to the iollowing examples which illustrate the invention without however limiting it, the iollowng products constitute products which can be cotained within the framework of the present invention.

The products of formula I I

A)

4 b, I i 4* U Vy r* r4

C

F 4 ja

U

4 .4r 4, 4 in which R 1 R2 and X have the following value aud the oxygen atom of the spiro ether is in position 17-beta.

crt ~r

I

i i i i i iM 41' j r :i i i

I

i r in which R, represents a carbocyclic or het !rccyclic aryl or W 09 II go If -C H

H

I I CHCH-CHI-CW, I I~ -H 2 It~~

CH~

0C 2 2 IC I go~ I CH 2 2 L I CH=CH-CH,-CH7 I I (CH 2 IZ

CH

2 2 I I C CH 2 4 soC

H

I (CH 2 )4 H 2 4~ I (CH 2 2 CI CH2 (CH2) 2 I CHCHCHZCH2 A

I

ii

I

4 t 0 *o 4 4 as well astheir salts' C I f1 CC=~-H (CH,)i I CHC

-CH,

:a i i i I CHi

I,

44 CI 4 .v 4~r q444 94 4 4 4 4 .4 44

I,

.4

S.I

*i 4,I

I

II

i# I

-I

(I

(CH)L

C H, 4F

(CH)

4 SC HZ 2 2 CH=CH-CH-CH2W -cx-,

(CH)

2

(CH)

4

-CH-

(CH

2 )2

CCHCH,-CH,

(CH 2 2 Is

(I

it

CH=CH-CH,)-CH)

-CH2

(CH

2 2 I CH=CH-CH 2 -CHi I, -CH 2

S(CH

2 2 I CH=CH-CI-b-CHZ :H=cH CHL

(CH)

C cH 2l 2 tH:6HeHZ2 4

AI-

in which K rlepresents, a blocked ketone group, is submitted to the action of a dehydration reagent which is also capable of freein g the ketone function, ixi order to, obtain the Products of formula (IA) i.n I x I CHC C H 3

C

(CH

2 0 fI rI-

(CH,)

Lr, J I -CH 2 I I I CH=CH-CH ,-CH, E -CH 2 I. CH=CI-CH 2 -CH71

(CHZ)

2 I I CH-IcH-CH,;-CH-; I -CHZ 4 I I I CH=CH-CH 2 -CH2 sc. ~i 3

-CH

2 I I CCHZ) 4I III CHCH-CH-CH--' I I-CH2 I

(CH

2 )2 I (CH2) 4 I CH-CH-CH2-CHI2 4

~L.

LI

(CH,)

I(CH

2 4 S CHH-CH,-CH., (CH-2)2 I CH=CH-CHi-CH,

-CH

2 I (CH2)2 co

CCH,,,,

4 .9 '.94 9 6 9 @9

S

4.

9 6* 9* 9 9* @9

I

4 9, 6 *9 699~4 9944 4 9' 93 4 6 9' 4

I'

II

I'

It II

'I

it CH 2

(CH

2 2 C4 2 4

CH=CH-CH

2 -rcH2

-CH

2

CH"CH-CH

2 -CH2 -CH2

(CH

2 2

(CH

2 4 CH: CR-CH 2 -CHz

(CH

2 2

(CH

2 4

(CH

2 7 CK-CCH-CH2-CH7 I r-l- 0 dimethylketal, dioxy ethylene, Z,2-dimethyl propari-l,3 dioxy, a corresponding thioketal, aii oxime or a methyloxime.

The oxidation agent w.hich is made to react on the products of 2 22 I C H I (CH 2 4 rv V.2.I I CH=CH-CHZ-CHN 2 I I (CH 2

(CH

2 2

CHCH-CH-

2 -CH2 I I (CH 2 4 if Hf CC 4 C 0 0# o CH 2 )4-CH I I CH=CH-CHZCHZ operation can be done, for example, in the presence of ethanolic sodium hydroxide. A sodium salt can also be used such as sodium or potassium carbonate or sodium or potassium acid carbonate.

)t ii: iL I;vl

B

11

F

1/ 2 4 *r 9 S*4 CC4 9 9 44i 4 99 44 $9 4 i4 4) 44 4 *4 8 4, 8: 4O 4 8*9* 44 I 41'l Examkjq_1: (17R) 1lbeta (di Lami n dien-t72' -axetan)-3-one Stage A: (1,1-dlmetflyl ethyl 1 2--3tanedl bis oxyl 17betahydroxy 19-nor 17alpha-pregna-5( 10), 9(1i)-dien-21-oate.

A solution o4 568 cm3 of lithium diisopropylamide titrating 0.51M in 1.4 litres of tetrahydroiuran is cooled to -73 C; over 20 minutes at -73 C/-720C, 37.3 cm o4 tert-nutyl acetate is introduced and agitation is carried out for one hour at -73 3C. The temperature is allowed to rise to -60 0 C, 17.38 g of cyclic 3,3-(1,2-ethanediyl) acetal of estra- 5(10),9(11)-dien-3,l7-dione in 260 cm3 of tetrahydrofuran is introduced over 30 minutes and then agitation is carried out for one hour minutes at -60 C.

The temperature i the medium is taken to 0aC and over 15 minutes 520 cm 3 o4 ammonium chloride in saturated aqueous solution is added.

15 After agitating for one hour at ambient temperature and decanting, the aqueous phase is extracted With methylene chloride, The organic phases are washed with sodium chloride in a saturated aqueous solution, dried and brought to dryness, The residue is chromazographed on silica, eluting with a cyclohexane-ethlacetatc -triethylamon mix4ture 95-5-0.001.

20 20.3 g of expected product is isolated, NMP spctrum (CDCl 3 1 drooCSD 5 4) 3.97 ppm; H ethylene dioxy In 3 5.6 ppm: Hil 0.9 ppm: Hi 8 25 455 ppm: ON ppmI: H cf tBu Preparition, of lithium di isopropyiamide 6-cording to House and cr.lTX. J.

Org. Chez. 434, 704 (1978).

Starting with 68 cm 3 of diisoproipryiamine the ex4perted product was obtained in solution: titer 0.51$.

Stage 1: Cyclic (ilZ-ethanediYl) acetal of 17,21-dihydroxy 13-nor 17alphapregna-(1O) ,9(11)-dien-3-one.

20.3 5 of product obtained above is dIssol'/ed in 400 cm 3of tetrahydrofuran tinder inert atmosphere and 14.3e 9 ef lithium aluminium hydride LS added 611er 5 mnUtes at +18 C/*2C. a The Whole is heated to for one hour, After cooling to *IS 0 /+20 0C 600 cm of methylene i

IE

IL

T

L;__i1 In a preferred method of carryfl-g out the process described above, the cyclization reagent which is preferably made to react on the products of formula (III) is tosyl chloride in the presence of pyridine; there can also be used methylsuiphonyl. chloiride.

-24chloride is added, the mixture is taken tu 0 C/+5 C and 130 cm' of saturated aqueous solution of sodium bicarbonate 1.s slowly addeO. The precipitate obtained is filtered and washed by trituration with methylene chloride. The filtrate is decanted and the aqueous phase is Sextracted with metbylene chloride. The organic phases are washed with sodium chloride in a saturated aqueous solution, dr~ed and brought to dryness. The residue is triturated with ether, separated, dried under reduced pressure and 12.47 g of expected product is obtained.

NMR Spectrum (CDC1 3 1 drop C 5

D

5

N)

3.96 ppm: H of ett *'-qne dioxy 9q 9 5.59 ppnm: H'±i *too 0-S8 ppm: H18 0 o, 3.97 ppm: H 21 #4 0 3.33 ppm: H of OH Stage C: (17R) cyclic (1,2-ethanediylt) acetal of spiro(estra- 5 (10) 9 (11) -dien-17, 21-oxatan) -3-one.

12.147 g Of product obtained above is dissolved in 250 cm of 9 9, pyridine. Little by little 24.94 g of tosyl chloride is added and 9' agitation is carried out for two hours at ambient temperature, ice and 99 20 water are added and extract,: n is carried out With ethyl acetatp, The 9000, organic phases are washed With a saturated aqueous Isol,ution of sodium chloride, dried and brought to dryness by entraipment wi.th toltuene, The 19.80 g of tosylate obtained is put tn suspension in 890 cm of04 potassium hydroxide with 5% ethanol and a ated at ref 1uX for minutes. The ethanol is distilled off under Veduced pressure, wator and ice are Added 4a agitatiOn is carried out ,or 10 minutes. The precipitate is separated, Washed with Water until neutral, dissolved in methylene chloride, the Water is decanted and the remainder is dried and brought 14o dryness4 The residue is dhromatographed on silica (eluent:. cyclOheXane-ethyl acetate-.triethylamlne 90-10-0.001 and 8,97g 0 of expected product is isolated, m.p, 136 C:, ft1 Snegtr~im (CDC13) ~3.95 ppm: H of ethylene dioxy 5.64 Opm1 H 11 3S 0.76 ppm: Rja 4.30 to 4,50 ppm: 0t 2 j1 also make them of use in the treatment fbenign tumours.

Some of the products of. formula (I)Jas well as their pharma- St~q2(n (1R cylc(,-taei- cta f5lh,1apae 4 S~miture is7R cclitc-0C -7 h cndjyf a5e0a hdoe Saphaoid ispaep IS,minutde t-33 a '-xetand-n aitsto sarrieda fo 3heur at.97 V+ 0 o prouc c ,t.ne preioule is disoled ine 180 cm3 o~zf a sturaed chlrieonc of eiuchbironacte andsddedun thioe a3 I auredi cole to5 C/ 0 0 27ti her io 0%hde peroxide ist.Afe trgaic ove are minute a t h 3 ater and ait uatiod carred forof hrsoatum chlori.dTe drid midbrut is pore ovse 300 cm of chrsatra ed, ouin ofic soiun bcrboae, and odiuy actaiouipatriethy1-amine 80-20-0.0Q1 and 1.82 g of product epoxy and 5.36 g of product Salpha,10alpha-epoxy are isolated.

IR Spectrum (CkHCJ 3 alpha epoxy: 973 cm-I P82 -1 jj 20 beta epoxy: 981 cm 830 cm NNR SoectrUm (CDC11) alpha epoxy: 0.76 HI 8 3.92 ppm ketal 6.09 prr" I 4.30 to 4.46 ppm ft 21 beta epoxy: 0.75 ppm HIS :5.92 ppm al 4.30 j 4.46 ppm Hn, Stage E; (17R) Cccic (1,2-.ethanedi~t) acetal of Salpha-hydroXy Ilbeta- 4 (ietya n)pe~)7sp a et -n 7 'oea)- oe 0.861 g of Salpha-10.alpha epoXide obtained above is caistiolved in 18 cm of tetrahydrofuran, under inert atmosphere a-rd 24 mg of cUproUs o o 3 chloride is addod, After cooling to 0 c/+S C 8.3 cm of 4-dimethyldmit~ephenyl magnesium brozi±4t in solution 87M) in tetrahydrofuran is aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, }7 I 7 Z6 4 444.

4r: .4, 44 9. .i i 44 S*4 q44 4 t tr introduced over thirty minutes and agitation is carried out for one hour at this temperature. The reactive mixture is poured at 0 o 3 C/+20 C over 40 cm of ammonium chloride Ln a saturated aqueous solution. After agitation for 10 minutes and decanting, the aqueous phase is extracted with ethyl acetate. The organic phases are washed with a saturated solution of sodium chloride, dried and brought to dryness. The residue is chromatographed on silica (eluent: cyclohexane-ethyl acetate-triethylamine 70-30-0.001. 1 g of expected product is isolated. m.p. 178 C.

NMR Spectrum (CDC1 3 4.00 ppm: H ethylene dioxy 2.91 ppm: H dimethylamino 4.28 to 4.45 ppm: H 11 i and H21 0.40 ppm: H 18 15 4.31 ppm: QH Stage F: (17R) llbeta-(4-(dimethylamino)phenyl]spiro(estra-4,9-dien- 17,2'-oxetan)-3-one.

0.944 g of product prepared above is dissolved in 6.6 cm 3 of acetic acid, heated to 41 C/430C and agitated for 2 hours 15 minutes.

0 O 0 20 After cooling to 0 C/+5 C, ammonia is added to give a pH greater than 8, and extraction is carried out With methylene chloride. The extracts ar washed with a saturated solution of sodium chloride and brought to dryness. The residue is chromatographed on silica (elUent: cyclohexane-ethyl acetate 80-20) and 0.468 g of expected product is isolated.

After recrystallization from isopropanol the product melts at 108 C.

IR Spectrum (CHC1 3 -1 Conjugated ketone: 1654 cm -i C=C 1612 cm -1 Aromatic t 1561 cm UV soectrum (EtH) Max. 260 nm E 17,400 Max. 302 nm t, 20,500 EtOH HCl 0.1N Max. 300 nT e 18,900 Infi. 218 240 nm.

i k 1

B

1 i t i F T fii jl'f f r i'

I

-27- NMR .oectrum (CDC1) 2.92 ppm: H dimethylamino 5.76 ppm: H 4 0.43 ppm: H 1 8 S 4.40 ppm: H 1 1 and H1, 6.37]) aromatics 7.07 Example 2: (17R) Ilbeta-(4-(methylthio)phenyl Illpiro-(estra-4,9-dien- 17,2'-oxetan)-3-one.

Stage A: (1,7R) cyclic (1,2-ethanediy) acetal of 5alpha-hydroxy l1beta- (4-(methylthio)phenyllspirojestr--en-17,2'-oxetan)-3-one.

3 55.3 cm of 4-(methylthio) phenyl magnesium in tetrahydrofuran OV 000 0 (titer 0.81M) and 0.148 g of cuprous chloride are cooled to 0 Of *s for 15 minutes under inert atmosphere. 5.36 g of (17R) cyclic (1,2- 15 ethane diyl) acetal of 5alpha,loalpha-epoxy spiro(estra-5(10),9(11)dien-17,2'-oxetan)-3-one in 53 cm3 of tetrahydrofuran is introduced over 25 minutes at +3.5 C/+50C and the whole is agitated at 0 C/+5 C q ifor one hour and a half. The operation is thon carried out as in stage E of example 1 so obtaining 0.24 g of the expected product.

NMR Spectrum (CDCl 3 2.46 ppm H 3

C-S

3.9 to 4. 1 ppm H ethylene dioxy 0.38 ppm HIS 4.30 to 4.45 ppm: H 11

H

21 and OH *t 25 7.16 ppm aromatics StageB: (17R) llbeta..(4-(methylthio)phenyljspiro-(estra-,4.9-dien- 17,2'-oxetan)-3-one.

2 9 of the product obtained as above is dissolved in 40 cm3 of ethanol, 2 g of Amberlite IRC 84 resin (Rohm Haas) and the whole is heated at reflux for 7 hours under inert, atmosphere. At ambient temperature, the mixture of resin and products is separated, rinsed with ethanol and with methylene chloride; the filtrate is brought to dryness in order to obtain 1.194 g of expected product. m.p, 154%.

After two recrystallizations from 99.8% ethanol, 4 p, .i t. is obtained melting at 160 C.

IR Spectrum (CHCl.)) product haigthe saering D as the 'product above and'.then the product is submitted to a partial or total hydrogenation reaction: C=O 1653 cm -40n 6 0.44 160\ HIS a.1ro m aroatic 5.77 ppm: Ex.46l pp: (S -CH-,4(ietyaiophnl-f,15,1 0.44hdr ppm:eta4,-in-7Z (2H 1 8 a)--n tetrdieahyo siro) penyr 17-dien-7 (hd) pyr) 1-3-oyn)est--n3o 3 205 g of potassium tert-butylate is dissolved in 20 cm of anhydrous 0 tetrahydrofuran and after cooling to -5 C, 1.9 g of cyclic (1,2-ethane Ik 4, 4diyl) acetal of 5aipha-hydroxy llbeta-(4-(dimethylapilno)phenylI estr-9en-3-one is introduced over 5 minutes. After agitation for 10 minutes a zolution of 2.4 cm 3of 3-butynol in 20 cm 3of tetrahydrofuran is introduced. over 15 minutes and the whole is poured into 200 cm 3of a 25 saturateq( solution of monosodium phosphate. Then the aqueous phase is extracted vith methYlene chloride, dried and brought to dryness. The residue is purified on silica, eluting with a cyclohexane-ethyl acetate mixture then with ethyl acetate, with 1% of ammonia. 1.775 g of expected product is recovered.

NMhR Spectrum (CDCI 3 I drop C 5

DSN)

2.90 ppm: R of dimethylamino 3.97 ppm: H ethylene dioxY ppm: H 18 3.73 ppm: CH 2 -0H 6.62 and 7.04 ppm: aromatics Stage B: I be ta- 4- (dime thylamino) phely .'I-l7beta-hydroxy l7alpha-(4- ~35 is toluene sulphonyl chloride or methane sulphonyl chloride in pyridine.

-29 hydroxy butyl) estra-4,9-dien-3-one.

3 871 mg of the product obtained above is hydrogenated in 40 cm of methanol in the presence of 0.4 g of palladium/charcoal. After filtration, and elimination of the solvents, the residue is taken up in 0 o 10 cm of 10% acetic acid and agitated for one hour at 45 C. After neutralizing with a saturated aqueous solution of sodium bicarbonate extraction is carried out with methylene chloride. The organic phase is dried and brought to dryness under reduced pressure. The residue is chromatographed on silica, eluting with ethyl acetate, and 640 mg of expected product is obtained.

Spectrum (CHC1 3 C=0 1654 cm -1 S1612 cm 1 1561 cm 15 L1518 cm S 0 -1 OH 3615 cm NMR Spectrum (CDC1 3 2.9 ppm: 20 4,33 ppm: Hii 0.57 ppm: H 18 S5.73 ppm: H 4 3.67 ppm: CH 2

OH

S6.65 and 7.02 ppm: aromatics 25 'sage C: (17S) llbeta-(4-(dimethylamino)phenyll ,6'-tetrahydro spiro(estra-4,9-dien-17,2'(2H) pyran)-3-one.

A solution containing 788 mg of product obtained in the previous 3 o stage and 15 cm of anhydrous pyridine is cooled to 0 C, 1.5 g of tosyl chloride is added and the whole is agitated for one hour at ambient temperature. 30 cm of ice is added and then the mixture is neutralized with 14.5 cr 3 of concentrated hydrochloric acid. The aqueous phase is extracted with methylene chloride, dried and brought to dryness. The residue is purified by passage through silica, eluting with methylene chloride-acetone (95-5) and 0.2 g of expected product is recovered.

NMR spectrum (CDCi 3 ii formula (IX) is the product RjMgBr in the presence of cuprous chloride.

Some examples of carrying out such preparations will be found

A

30 4 t 46 t( t ~4 64 4 94

I~

$6 4 I I $4

I.

p 99 *~4 9 *4 U I, I 2.90 ppm: H of dimethylamino 4.33 p pm: H I 0.53 ppm: Hl8 21.46 and 3.74 ppm: -CH-nO 55.74 ppm: H 4 7.02 and 6.64 ppm: aromatics Example 4: (17S) llbeta-r4-(dimethylamino)phenylI spiro(estra-4,9-dien- 17,2' -oxiran) -3--one The operation is done as in stage B of example Z~ starting with 2.42 o- 2 cyclic (1,2-ethane diyl) acetal of llbeta-.f4-(dimethylamino)phenyll 5alpha-hydroxy spi ro (estr-9--n- 1 7 Z' -oxi ran) -3 -one with Amberlite IRC 84 resin.

Aftercoolig, 'te rein isfilteed, insedwith 0 cm3of-tal 3 and brought to dryness. The residue is triturated in 30I cm of 15 isopropyl ether, agitating at 40 0C. After chilling, separating, rinsing .dith isopropyl ether and drying under reduced pressure, 0.844 cl a! expected product is obtained. A further 0.273 g of product is recovered from the mother liquors. tnp =228'C.

After purification by chromatog raphy on silica, eluent: cyclo- 20 hexane-ethyl acetate (70-30), 0.750 g of product is isolated from the first lot.

m.p. =234 0

C.

[alpha]D +270 0C 3.5 0C (t 0.5% CHCI 3 NMR Sectrum (CDCl 3 2 5 2.92 ppm: H of dimethylamino 5.8 ppm: H 4 4.33 ppm: H 11 0.6 ppm: H 18 2.63 and 2.98 ppm: H of oxirane 6.67 and 7.01 ppm: aromazics Example 5: 17) 1btt4mehthoPnl]spiro-.festra-4,9-dien- 17, 2'-oxiran )-3-one Stage A: Cyclic, 3,3-(1,Z-ethanediyl) acetal of Salpha-hydroxy libeta- (4-(methylthio)phenyll estr-9-en-3,17-diene.

3 0.672 g of cupric chloride, 0.212 g of lithium chloride, 165 cm of anhydrous tetrahydrofuran and 16.5 g of cyclic 3,3-(Ij2-ethanediyl) Ictlo apa1aparpx sr,7(1e-.1-in r oldt -6 Cad10Qm fa075 ouinof-'ehlt )pey magnsiu brmideis ntrduce drp b dro ovr oe hor ad 1 mnt. Tewoe saiaedudrier tophr.t-0- o n acth ater drfe 5pand concentrated stodryn1esn-7drredared pooedsuto Thagnesiubie is pinoduceddron bydop oerne houaraned a wthexanoe.s Agterdyn under inuert atmospre at 60 C foron 0 n hour 100 of a csauraed proution obtandump chord 2020 dde wthy acitato (1or 1 0 1 nte lmn) adrcytalzt 0 from ethyl acetate, the product is obtained melting at 209 C.

S.S 15 Stage B; (17S) cyclic (1,2-ethanediyl) acetal of llbeta-44-(methylthio)- 12,7 cm 3of a 0,9M~ solution of potassium tert-butylate, 22 cm 3Of 3.

tetrahydrofuran and 127 cm of anhydrous dimethylsulphoxide are cooled 0 S OS to 5 C. 2.20 g of trimethyl sulphonium iodide is added over a few 1- 0 minutes with agitation for 30 minutes at 5 0 C. Then 2.45 g of the product obtained above is poured into 30 cm 3of anhydrous tetrahydrofuran at 5 C over 7 minutes# and the whole is agitated for one hour at 0 3 0 C/+5 C. The reactive mixture is poured over 300 cm of water and 6 041 extracted with ethyl acetate. The extracts are washed with a saturated aqueous solution of sodium chloride, dried and brought to dryness. The 3 residue it taken up by 15 cm of ethyl ether, chilled, separated.

triturated with a minimal amount of cold ethyl ether and dried underreduced pressure., 2.1 g of expected product is obtained. m.p. 130 0

C

(inst.) IP. Spectrum (CHud 3 OH :3508 cm Aromatics: 1592 cm 1555 cm 1493 cm stage..C: (17S) 11beta-(4-(methylthio)phenyll spirok'dstra-4,9-dien- 17,2'-oxiran)-3-onei I '4ig CH 2 )4

CH=CH-CH

2

-CHZ

Gc~ I

I

3 I. g o~f the product prepared above is dissolved in 100 cm of ethanol under inert atmosphere. 4.2 g oi Amberlite IRC 34 resin (RHOM- H-AAS) is added and the whole is taken to reilux ior 15 hours minutes. After cooling, the mixture is feedand washed with ethanol and 'he filtrata ts evaporated. Having been 'Kept czold for one hour the product is separated and triturated with a minimal amount of cold ethanol and dried under reduced pressure; 0.49 g of expected product is isolated. m.p. 121-122 0

C.

After recrystallization from an ethanol -methylene chlori ,de mixture a product is obtained melting at', 122 C, then 167 C.

UV Spectrum MIW 406.6 Max. 2459 nm =15,700 Max. 300 nm F.v18,700 NMR Spectrum (CDC1 3 15 2.43 ppm: 9LH 3

S

5.76 ppm: H 4 4.32 ppm: H 11 0.55 ppm: HIS 2.61 and 2.94 ppm: H of oxirane 20 7.02 and 7.13 ppm: aromatics ~r I Itt 94 4 (4 4' *1 4 9 44 *9 .4 9 9* 9* S 9* o 9.4 o 9 .4 S a U, It 1 1 411 Pharmiacological study of the products of the invention of the invention study of the activity of the products of the invention on hormonereceptors: 25 Progestogen receptor oi the uterus of a doe-rabbit: Impuberal doe-rabbits of about I kg receive a cutaneous application of 25 j of estradiol. 5 days after this treatment, the animals are killed, the uteri are removed, weighed and homogenised at 00 C in a Potter teflon-dish in a buffered solution TS (Tris 10 mm, sacoharose 0.25M1, HC1 pH 7,4) (1 g of tissue per 50 ml of TS) The homogenate is then Ultra-centrifuged (105,000 g x 90 minutes), at 0 0C.

Aliquots of the supernatant thus obtained are incubated at 0 0C for a time t, with a constant conicdntration of tritiated product R (17,21-dimethyl 14--nor 4..,'-pregnadlien-3,20-dione) in the presence of increasing concentr~t onO- 2500 X 10 M) either of cold R, or of cold progesteron, ro product under test, cold. The concen- SI(CH 2 SCH 2 4

SCH=CH-CH

2

-CH

2 *11 I tr I 33tration of bonded tritiated R is then measured in each incubate by the tecnnique of adsorption on dextran carbon.

Glucocorticoid receptor of the thymus of a rat: Sprague-Dawley EPOS male rats weighing 150 to 200 g are suprarenralectomized. 4 to 8 days after this removal, the animals are killed and the thymus aro removed and homogenised at 0 C in a buffer Tris saccharose 0.25. dithiothreitol 2mM, HC1 pH 7.4, with a Potter polytetrailuoroethylene-ish (1 g of tissue per 10 ml of TS). The o homogenate is then ultra-centrifuged (105,000 g x 90 minutes) at 0 c.

Aliquots of the supernatant thus obtained are incubated at 0 C for a 'i time t, with a constant concentration of tritiated dexamethasone in -9 the presence of increasing concentrations (0 2500 x 10 M) either of S cold dexamethasone, or of cold product under test. The concentration of bonded tritiated dexamethasone is then measured in each incubate by the technique of adsorption on dextran carbon.

Calculation of the relative bond affinity: The calculation of the relative bond affinity (RBA) is the same for all the receptors.

The following 2 curves are drawn: the percentage of bonded tritiated 20 hormone B as a function of the logarithm of the concentration of the cold reference hormone and 3 as a function of the logarithm of the

T

Si, concentration of the cold product under test.

The straight line of the equation I50 (B max B min)/2 T T is determined.

B max percentage of bonded tritiated hormone for an incubation of

T

this hormone tritiated at a concentration B min percentage of bonded tritiated hormone for an incubation of

T

this tritiated hormone at a concentration in the presence of a -9 large excess of cold hormone (2500 x 10 M).

The intersections of the straight line 1 5 0 and the curves enables the concentrations of cold reference hormone (CH) and of cold product under i "it 1 r r 1- I CH=CH-CH 2

-CH

2

V

*1 f

I

34 test (CX) which inhibit by receptor to be evaluated.

The relative bond affinity ,'he equation: CO0% the bond of the tritjated hormone on the (RBA) of the product tested is determined by

(CH)

RBA =100 (C1%) The results obtained are the following: p.

ft ft.,.

ft ft.., ft. ft ft S 'ft S& S 4 ft ft ft ftp ft5 ft ft.

ft ftp ft pft ft ft ft ft.

ft 4.

6P ft ft ift ft...

ft* ft. S pp *4 ft 4090

I

ft Incubation Time at 0 0C Products of examples---- Progestogen Glucocorticoid z H 4!-H 2 H 4 H 1 93 415 126 4- 223 67 56 22 3 24 157 23 24 Conclusion: The products studied,~ particularly the product of example 1, show a marked affinity for glucocorticoid and progestogen receptors.

From the results obtained it can be concluded that the products can offer agonistic or antagonistic activities for glucoc~orticoids and progestogens.

I1. Antiglucocort.Icoid activity: The technique used derives from thie method described by Dausse and Coll. in Molecular Pharmacology 13, 948 955 (1977) ("tthe relationship between glucocorticoid structure and eff ects upon Thymocytes t for thymocytes of mice.

~1 (C H 2

CH=CH-CH

2 -CH7

Y

IA

I

I,.

99 9 9444 94 9 *9 @4 9I~ 9 4.

94 94 9 99 94 9 94 *9 9 @4 94 9* 4 4,4 94*4 t *4 9* t~ I tI 35 Thymoc~ytes of suprarenalectomized rats are incubated at 37 aC for 3 hours, in a nutritive medium containing 5.10- M of dexamethasone in the prqisence or not of a product under test at various concentrations.

Tr~itiated uridin is added and incubation is continued for one hour.

The incubates are cooled, treated with a 5% 5o?.ution of trichioroacetic acid, filtered an Whatrnan GF/A paper and washed three times with a solution of trichiloroacetic acid. The radioactivity retained by the filter is determined.

Glucocorticoids and in particular dexamethasone cause a decrease 10 in the incorporation of tritiated uridin. The products of examples 1 to 4 oppose this effect.

is Product of 5.10- am de-:-amethasone and, inhibition of the example the product under test at a effect of de~amethaconcentration of sone 20 1 10-8 10-I7 M 122 1 -8 -7 10 M27 Mi 76 310K 8 M7 N0 2 106 93 it has been n~oted in additton that used on their tested do not cause any glucocortidoid- type eifflctown the products It 36 Conclusion: The products studied show a very marked anti-glucocorticaid activity while being deprived of glucocorticoid activity.

Ill. Abortive activity in a female rat Day D, of the gestation is determined by the presence of spermnatozoids in the vaginal smear, on day 0 0 of the g~estation, the product is administered in suspension in carboxymethyl cellulo!3e containing 0.5% Twqeen.

The animals are Killed 72 hours after the treatment and the uterus is examined in order to determtne the state of gestation.

A complete abortion in all the animals of the grou4p is noted with the product of example I administered at a dose of 3 mg/kg, 9 too* 9a o of t C 9 4

Claims

5.64 PPM: H 11 0.76 ppm: H 18 4.30 to 4.50 ppm: H 21 K 37 The claims defining the invention are as ifoiiowst 1) The products of general formula a' 10 9 a ~t .4,4 .9 4 I 9 at *6 S .4
9. 15 .9 in which R, represents a carbocyclic or heterocyclic aryl or aralkyl radical, optionally substituted, R 2 in alpha or beta position, represents a hydrocarbon radical containing from 1 to 18 carbon atoms, the wavy line of the spliro ether indicates that the oxygen atom can be In alpha or beta position, X represents a (CH2b)n- radical ir, which n represents an irteger 1, 2 or 4, or X, represents a -CI-J=CH-CHZ-CH 2 Z- radical, rings A and B having one pf the fol~lowing structures: a) either A and B represents the group-. 9 99 *9 9 49 9 9* a a 99 .44' 19 II~ I RA 13 0 in which 91 and identical or different, represent a hydrogen atom or an alkyl radical having from I to 4 carbon atoms, b) or A and B represent the group: Al 0--BC in which Re represents 4 hy~drogen atom, an alkyl radical, anl alkyl. radical having from 1 to 6 carbon atoms, optionally substituted, or an acyl radical; c) or A, B and C roqri.erit group., chloride is added. After cooling to OOC/+5U'C, 8.3 cm" of 4-dimethyl- aminopheny. magnesium broi~ida_ in solution (0.87M) in tetrahydrofuran is V N I 1 A 38 A and B represent the group: 1 e) -or k and B represent the group; It V I V 'Vet 4~ V Vt II V I V Vt Vt V I V II I II 4 94 4S *9 9 6 49 Well as their salts. The products of form~ula as defined h- clain 1, corresponding the formula 4 44 1 0 4 4. (11) in which R, reprskents a carbocyclic or, heterocyclic aryl or aralkyl radical, optionally substituted, R2 in beta posi~tion represents a hydr-ocarbon radical containing from I to 18 carbon atoms, the oxygen atom of the spiro ether is in position 17beta, X repr'esents a -C21 adical in which n represents Pn Integer 2 or 4 or X represents a SO -CHC-CH2,-CH 2 radical as well as their salts. 3) The products of formula as defineo in any one of claim~s 1 or Zj in which R, represents either an, aryl radicall or an aral~yl radlical car~rying an amine functiont. f 4% L IlL 'I t '4 'I 39 in which 7 and R4each represents a primary, secondary or tertiary alkyl radical containing from I to 8 carbor, atoms or R 3 and R4~ form, together with the nitrogen atom to which they are linked, a heterocycle optionally containing another heteroatom chosen from the group formed by oxygen, nitrogen, sulphur and silicon, or an aryl radial carrying a methylthio or ethylthio function, a well as their salts. 4) The products of formula as defined in any one of claims 1 to 3, in which R 1 is a phenyl radical, the substituent carried by this phenyl radical is in pare. position, as well as their salts. 5) The products of formaula as defined in any one of claims 1 to 4 in which R, represents one of the following radicals: *0 0 9 0099 009* p *0 ~0 90 9 4.0 o *0 9* 0 00 9* .40 0 0 0 9* CH 3 H 3 H 0 nd l CHO defined in claim 5, in wh-ich R1j 99 9 9 99 09 9 0 9 00 90*9 99 09 0 04 09 9 9090 0 0 20 ~c Cz -O \CH 3 as well as their salts, 6) VThe products of formula as Z5 represents a radical: 7 C 3 or a radical: \-C3as well as their salts. 7) The products of formula as defined in~ any one of claims 1 to 6, of which the names follow: (17R) 1be ta 4- (dime thy air'o) phenlyl Ispiro (estra-4,9-dien-17,2'- oxetan) -3-one, melting at 160 0 c. IR Spectrum (CHCl1I) 'I I 40 (17R) Ilbeta-(4-kmethyIthic)phenyl] spiro(estra-4,9-dien-17,2'- oxetan)-3-one. 8) Process for the preparation of products of general formula as defined in claim 1 characterized in that: a) in order to prepare the products of formula (IA): I, (IA) **04 0 4 *9 w I I t to t 1 in which R 1 and R 2 keep the same significance as in claim 1, a' and R" each represents a hydrogen atom or an alkyl radical, or one tlpresents a hydrogen atom and the other represents an alkyl radical, a product of 15 formula (II): (II) o01 in which K represents a blocked ketone group, is submitted to the action of a dehydration reagent which is also capable of freeing the ketone function, in order to obtain the products of formula (I A in 25 which R' and R" represent a hydrogen atom, and, if desired, the products of formula (IA) in which R 1 contains a sulphur or nitrogen atom are submitted to an oxidation in order to obtain the products in which RI contains a sulphur atom oxidized into sulphoxide or into sulphone or a nitrogen atom oxidized into N-oxide, and that if desired, the products of formula (IA) are submitted to the action of a strng base, then to the action of an alkyl halogenide in ord(er to obtain a product of formula (IA) in which R' and/or R" represent an alkyl radical having from 1 to 4 carbon atoms; b) to prepare the products of formula (IB): I I 4 6.62 and 7.04 ppm: aromatics Stage B: llbeta-[4-(dimethylamino)pheny'.]-17beta-hYdroxy 17alpha-(4- 41 (IB) in which R 1 R 2 and Re keep the same significance as in claim 1, a product of formula o~ a a 04 0 a. *0 a a 4 04 4* a *4 44 (I'A) in which RI and R Z have the significance already indicated, obtained as described above, is submitted to the action of an aromatization agent, then if necessary or desired, to the action of a saponification agent and finally if desired the product of formula (I B in which Re is a hyurogen atom is submitted to an alkylation reagent; c) to prepare the products of formula (IC): (Ic) in which RI and R 2 keep the same significance as in claim 1, a product of formula is submitted to the action of an acylation agent and then of a saponification agent; d) to prepare the products of formula (I6): (ID) 'A i'4VS 'S product is recovered. NMR Spectrum (CDC1 3 A -42 -Z Ln which Rand keep the same significance as in claim 1, a product of iormula 'I1A) is submitted to the action of an opoxidation agent; e) to prepare the products of formula E: r 4~ ~f I~ 4* .4 U. *4 9* U 0* *4 U *0SU~*~9 9 S 9 S L ~f (E) in which R, 1 and R, keep the same significance as in claim 1, hydroxcylamine is made to react on a product of formula f) if necessary or desired, the products of formula (IC), (ID) and (IE) obtained are salified. 9) Process for the preparation of products of general formula as def ined in claim 1 in which X represents a group: -(CH)4-or -CH=CH-CH 2 -C1 2 Characterized in that a product of formula (III) IV (III) 2S in which R1 and R2, keep the same signif icance as in claim 1 and the dotted lire indicates the possible presence of a double bond between the carbons which carry it, is submitted to he action of a cyclization reagent, in order to obtain a product of formula I10A) I IIIA) corresponding to a product of for~tula, (IA) in Which R' and WO each 0.672 g of cupric chloride, 0.212 g of lithium chloride, 165 cm 3 of anhydrous tetrahydrofuran and 16.5 g of cyclic 3 ,2-ethanediyl) I:: o I:. \I :-I -43- represents a hydrogen atom and X represents the groups -(CH) 4 and -CH=CH-CH 2 -CH 2 which products of formula are oonverted into corresponding products of formula (IA) in which one of the radicals R' or R" or both radicals R' and R" represent an alkyl radical having from 1 to 4 carbon atoms, and into products of formulae (ID) and 1 E) according to the process described in claim 8. As medicaments, the products of general formula as defined in claim 1, as well as their pharmaceutically acceptable salts.
11. As medicaments, the products of general formula as defined in any one of claims 2 to 6, as well as their pharmaceutically acceptable salts.
12. As medicaments, the products of general formula as defined in claim 7, as well as their pharmaceutically acceptable salts.
13. Pharmaceutical compositions containing as active principle at least one of the medicaments according to any one of claims 10 to 12 together with a pharmaceutically acceptable carrier, diluent or adjuvant.
14. As new industrial products, the products of formula cfl 4. e e 4.,i i. 0 Ci~r (If) t fi c in which R 1 R 2 are as defined in claim 1 and K has the significance indicated in claim 8 and X' represents -(CH 2 )n 1 in which ntl 2 or 4 or X' represents: -CH=CH=CCH,CH. The products of general formula as defined in claim 1, substantially as herein described with reference to any one of the Examples but excluding any Comparative Examples. UW T 'Ai '1' Stage C: (17S) llbeta-(4-(methylthio)phenyl] spiro;(estra-4,9-dien- 17,2'-oxiran)-3-one. -44-
16. Process for preparing the products of general formula as defined in claim 1 which process is substantially as herein described with reference to any one of the Examples but excluding any Comparative Examples.
17. Pharmaceutical compositions as defined in claim 13, substantially as herein described with reference to any one of the Examples but excluding any Comparative Examples.
18. A method of treating hormone irregularities in a patient/mammal requiring said treatment which method comprises administering to said patient/mammri an effective amount of a compound as defined in claim 1 or a pharmaceutical composition as defined in claim 13.
19. A method of treating amenorrhoea, dysrnenorrhoea and luteal insufficiencies in a patient/mammal requiring said treatment which method comprises administering to said patient/mammal an effective amount of a compound as defined in claim 1 or a pharmaceutical composition as defined in claim 13.
20. A method of combating ,;de-effects of glucocorticoids in a patient/mammal requiring said treatment which method comprises administering to said patient/mammal an effective amount of a compound as defined in claim 1 or a pharmaceutical composition as defined in claim 13.
21. A method of combating of disorders due to a hyper-secretion of glucocorticoids in a patient/mammal requiring said treatment which method comprises administering to said patient/mammal an effective amount of a compound as defined in claim 1 or a pharmaceutical composition as defined in claim 13.
22. A method of treating hypertension, atherosclerosis, ostereoporosis, diabetes, obesity, immuno-depression and insomnia in a patient/mammal requiring said treatment which method comprises administering to said patient/mammal an effective amount of a compound as defined in claim 1 or a pharmaceutical composition as defined in claim 13. 14 19 ,4I 'I li,z1-almetnyl ±a-'nor 4,9-pregnaclen-J,20-dione) in the presence of increasing concentrationsi (0 2500 X 10 either of cold R, or of cold progesteron, or product under test, cold. The concen-
23. A method of treating hypertrophies, cancer of the prostate, hyperandrogency, anaemia, hirsutism and acne in a patient/mammal requiring said treatment which method comprises administering to said patient/mammal an effective amount of a compound as defined in claim 1 or a pharmaceutical composition as defined in claim 13.
24. A method of treating hormone-dependent cancers in a patient/mammal requiring said treatment which method comprises administering to said patient/mammal an effective amount of a compound as defined in claim 1 or a pharmaceutical composition as defined in claim 13.
25. A method of treating disorders connected with hypofolliculinemia in a patient/mammal requiring said treatment which metihod comprises administering to said patient/mammal an effective amount of a compound as defined in claim 1 S or a pharmaceutical composition as defined in claim 13. DATED this 27th day of November 1991, 4 ROUSSEL-UCLAF By their Patent Attorneys: S. CALLINAN LAWRIE 4 4 U i AiiE S