AU624096B2 - Derivatives of 19-norprogesterone, their preparation and their use - Google Patents

Description

NO7 PcT OPI DATE 23/05/89 APPLN. ID 26295 88 DEMANDE INTERNATIONA'L _P~ME PCW/in88/0&'; S (PCT (51) Classification internationale des bre~ts'1) urro publication internationale: WO 89/ 03839 C07J 9/00, 17/00, A61 K 31/575 Al (43) Date de publication internationale: 5 mai 1989 (05.05.89) (21) Nurniro de la demnande internationale: PCT/FR88/00527 (74) Mandataire: BURTIN, Jean-Frangois; Cabinet Gefib, 6, place Boulnois, F-75017 Paris (FR).

(22) Date dedep~t international: 27 octobre 1988 (27.10.88) (81) Etats disign~s: AT (brevet europ~en), AU, BE (brevet (31) Num~ro de la demande prioritaire: 87/14806 europ~en), BJ (brevet OAPI), CF (brevet OAPI), CG (brevet OAPI), CH i(brevet europ~en), CM (brevet (32) Date de priorit6: 27 octobre 1987 (27.10.87) OAPI), DE (brevet europ~en), DK, FI, FR (brevet europ6-en), GA (brevet OAPI), GB (brevet europ~en), (33) Pays de priorit6: FR IT (brevet europ~en), JP, KR, LU (brevet europ~en), ML (brevet QAPI), MR (brevet OAr!), NL (brevet europ~en), NO, SE (brevet europ~en), SN (brevet (71) De6posant (pour tous les Etats disign~s sauf US): LABO- OAPI), SU, TI) (brevet QAPI), TG (brevet OAPI), RATOIRE THERAMEX S.A. [MC/MC]; 2, boule- us.

yard Charles-III, Monaco (MC).

(72) Inventeurs; et Puble Inventeurs/Deposants (US seulement) PIASCO, Alain Avec rapport de recherche internationale.

[FR/FR]; "La Cimiane", 19, avenue Fr~d~ric-Mistral, F-06100 Nice NASRAQUT, Mohamed, Nejib [TN/FR]; 103, avenue H.-Dunant, Bdt. 10, F-06100 Nice (FR).

(54) Title: DERIVATIVES OF 19-NORPROGESTERONE, THEIR PREPARATION AND THEIR USE (54) Titre: DERIVES DE LA 19-NOR PROGESTERONE, LEUR PREPARATION ET LEUR UTILISATION

OR

(57) Abstract The invention relates to the field of chemistry and more particularly to the field of therapeutic chemistry. Its specific subject matter concerns compounds of general formula in which R is a hydrogen atom, a lower alkyl, rnethoxymethyl, or t.trahydropyranyl radical, or an acyl residue of a carboxylic, aliphatic or aromatic carbonic organic acid containing I to 10 carbon atoms, and a process for preparing them. The compounds of general formula are used as the active principie in pharmaceutical compositions with a progesterone-type action.

(57) Abregi L'invention se rapporte au domaine de la chimie et plus particuli~rement au domaine de la chimie th~rapeutique.

Elie a sp~cifiquement pour objet les composes de formule g~n~rale dans laquelle R est un hydrog~ne, un radical alcoyle inf~rieur, m~thoxym~thyle, t~trahydropye'anyle, ou un reste acyle d'un acide organique carboxylique ou carbonique aliphatique ou aromatique ayant de I i 10 atoines de carbone ainsi qu'un proc6d& pour les; preparer. Les composes de formule g~n~rale servent de principe actif pour des compositions pharmaceutiques i action progest~ronique.

T

fv -1- NDVWE DERIVATIVES OF 19-MR PROESTERNE P1DESS FOR PRODUCIM THE AND THE PHARMAC)TICAL COMPOSITIONS INMMRPORATIM THEKI This invention relaties to novel derivatives of 19-nor progesterone having the side-chain beared by the carbon 17, including three carbon atoms.

More precisely it has as subject matter derivatives of 19-nor progesterone having on the steroid in position 6 a methyl group, on the carbon in 17 position a free, etherified or esterified hydroxyl group and the hydrocarbon side-chain in 170- is a propanone-3 chain.

Specifically it has a .ubject matter the novel derivatives of 19-nor progesterone having the general formula I

OR

Wherein R is a hydrogen, radical, a tetrahydropyranyl carboxylic or carbonic acid, carbon atoms.

a lower alkyl radical, a methoxymethyl radical or the acyl residue of an organic aliphatic or aromatic, having from I to In particular this invention relaties to the following compounds which are presently the preferred ones 17c-hydroxy 6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-dien 17-acetoxy 6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-dien 17-butyryloxy 6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-dien 2 17o-tetrahydropyranyloxy 6,21-dimethyl 1,20-dioxo 19-nor pregna 4,6-dien 17-caproyloxy 6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-dien 17-heptanoyloxy 6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-dien.

They were already disclosed derivatives of 19-nor progesterone having a methyl substituent in position 6 such as Nomegestrol which is a strong progestative agent endowed with pure progesteronic properties.

They where already known derivatives of 19-nor progesterone the side chain of which in position 17 included 3 carbon atoms and namely S3,20-dioxo 17a, 21-dimethyl 19-nor pregna 4,9-dien disclosed in french patent 2.077.877. This kind of compounds shows only mild progestomimetic properties in comparison with their lower homologs.

It has now be found that the compound of general formula I show very intersting progestomimetic properties, mainly through oral way and that their strong binding to the receptors of progesterone implies a strong progestative activity.

The efficiency of these new compounds may be attributed to the steroidal ring structure bearing two bulky substituents, a methyl in position 6 and a methyl in position 21 which without altering the Sability to bind on the receptcr sites, impedes or refrain the metabolization of the compound in the body through the reducing or hydrogenating enzymes.

In formula I the substituent R may be a lower alkyl radical such as for example a methyl, an ethyl, or an isopropyl. It may also be an acyl residue from an alkyl, or an aryl carboxylic acid such as for example the acetyl residue, the propionyl residue, rte butyryl residue, the peutanoyl residue, the hexanoyl residue, the benzoyl radical or the naphtoyl radical. It mal further be derivated from an unsaturated acid such as croconxc, senecioic, or 2-methyl pentenoic acids, or cycloalkyl carbonic acid such as cyclohexyl, or cyclopentyl carbonic acid.

-7 I-3 This invention also relates to a process for producing the compounds of formula I which essentially consists in submiting a 17-keto 18-methyl gonadien selected from the group consisting of the 3-alkoxy estra 1,3,5-TriLens of general formula II a wherein R 1is a lower alkyl radical having from 1 to 6 carbon atoms and the 3-alkoxy estra 3,5-diens of general formula I 0

R

1 0 wherein to the thereof R is defined as previously given action of a (triaryl propyi)phosphonium halide or the ylide having the general formulas for the phosphonium halide r0 IArfor the corresponding ylide Ar P CH CH 2

CH

3 Ar '-7 I 3a wherein Ar is an unsubstituted or substituted phenyl radical and Hal is a halogen other than fluorine for example propyl triphenyl phosphoniumn bromide.

J04 4and -iial is-a-haleaen ther ta ~fi to produce a propylidenic derivative selected of from the group consisting S.

S

the estra 1,3,5-dien derivatives of general formula IIIa (ilia)

RO

(in the form of a E or Z isomer) wherein Riis defined as previously given and the estra 3,5-dien derivatives of general formulaIIb (IlIb), RO1 (in the form of a E or Z isomer) wherein R 1 is defined as previously given.

subinits the compounds of general formula "'Ia to a hydrogenation according to the Birch's method to produce a 3-oxo, estra 4-en which is I a converted into a compound of general formula IIIb by reacting it with an alkylating agent in acidic medium reacting the said compound of general formula IIIb with a formylating agent of the Vilsmeier-Hack type, to produce the corresponding 6-formylated derivative having the general formula IV CH -CH2-CH 3

(IV)

R

1 0

CHO

(in the form of a E ou Z isomer) wherein R 1 is defined as previously given one reduces the 6-formylated derivative by means of a mixed alkali metal hydride then one deshydrates the so-formed 6-hydroxy methylated derivative, in acidic medium to produce a 3-oxo 6-methylenic derivative of formula V CH -CH,-CH 3 H S, L (V) (in the form of a E or Z isomer) one isomerizes the latter by reacting it with an isomerizing catalyst, to form a 3-oxo 6-methyl estra 4,6-dienic derivative of formula VI lll~-LI i 6 CH -<M-IM

(VI))

(in the form of a E or Z isomer) a one submits the latter to a bis-hydroxylatior using a bis-hydroxylating readent made of Osmium Tetroxyde and the hydroperoxyde of a N-oxyde in an inert medium to form the corresponding 17a-hydroxy derivative having the formula SCO -CH2-CH 3

OH

which may be alkylated by means of an alkyl halide in basic medium, or tetrahydropyranylated using dihydropyran in an acidic medium, or acylated using a functional derivative of a carboxylic, or carbonic acid in the presence of an acidic reaqe cAwL B r lw.

The reaction of the compound of formula II a OR IIb with triarylpropyl phosphium halide or the ylide thereof, mainly leads to the Z isomer in position 17. Howewer the E isomer which is produced only in a limited proportion may be isolated using physical methods and the further steps of this synthesis may well be performed without narked difference either with the Z isomer or with the E isomer.

'4" C NI 1 -7- The process according to this invention may also be following features which are presently preferred defined by the 1. The reaction of the 17-oxo gonane of formula II a or IIb with a triaryl propyl phosphonium halide is performed in a basic medium in a polar solvent.

2. The basic reagent is sodium hydride, lithium isopropylamide, potassium terbutylate or sodium amide.

3. The polar solvent is dimethyl sulfoxyde, or hexamethyl phosphorotriamide.

4. The reduction of the compound of formula IIIa according to the Birch's method is carried out by reduction in liquid ammonia, followed by a treatment with a strong acid such as hydrochloric acid.

5. The Vilsmeier-Hack's reagent is produced by reaction between phosphorus oxychloride wiJ a tertiary amine-such as dimethylaniline or a disubstituted amide such as dimethyl formamide.

S6. The reduction of the 6-formylated compound is performed using an alkali metal aluminohydride or an alkali metal borohydride in a non-reactive solvent such as a cyclic ether or an alkanol.

7. The deshydratation of the 6-hydroxy methylated dec..vative into a 6-methylenic derivative is carried out by treating it with a strong acid such as hydrochloric acid, perchloric acid or sulphuric acid.

8. The isomerizing reagent is a metal of the family of platinum absorbed on an inert carrier, such as palladium on coal, platinum on coal, or palladium on calcium carbonate.

9. The bis-hydroxylating reaction is performed using Osmium Tetroxyde and a hydroperoxyde of a N-oxyde of tertiary or secundary amine such as the N-oxyde of Trimethylamine, the N-oxyde of Triethylamine or the N-oxyde of Morpholine.

Ee a: S *1 i I -8- The a-ylation of the 17ct-hydroxy derivative is carried out by means of a chloride or an anhydride of an acid in the presence of a strong mineral acid such as hydrochloric acid, or sulphuric acid or a Lewis acid such as Boron trifluoride.

11. Alkylation of the 17m-hydroxy derivative is performed by means of methoxy methanol or dihydropyran in the presence of p.toluene sulphonic acid in an inert solvent.

This invention also includes the pharmaceutical compositions containing as active ingredient at least one compound of general formula I in admixture or conjunction with an inert non-toxic pharmaceuticalyacceptable carrier or vehicle.

I These pharmaceutical compositions are intended for administration through the parenteral, oral, rectal, prmnucous, percutaneous or pernasal ways of administration.

For the administration by parenteral way the compounds of general S...formula I are given in the form of injectible solutions or suspensions packed in ampuls, in multi-dosis flasks or auto-injectible syringes.

For the administration by oral way, the compounds of general formula I are given in the form of coated or uncoated tablets, dragees, soft gelatine capsules, capsules, pills, powiders or granulates.

For the administration by rectal way, the compounds of general formula I are in the form of rectal suppositories or capsules.

For the administration through the permucous way, the compounds of general forimula I are formulated as an oily solution as a cream, as a gel or in the form of capsule. It is possible to administrate the compounds of general formula I either through the vaginal mucosa either through the nasal mucosa in the form of a spray or a gel.

For the percutaneous way of administration the compounds of general formula I are formulated as a solution or as a cream in a penetrating A solvent such as benzylic alcohol, dimethylsulfoxyde or Azone r These pharmaceutical compositions find a therapeutic use for treating 9 the gynecological disorders bound to a luteal insufficiency such as a menstrual dysfunction, dysmenorrhea, premenstrual syndrom and menopausial disturbances.

The usual dosology ranges from 0.05 to 2. mg per unit and the daily dosology ranges from 0.1 to 50 mg in continuous or intermittent administration.

This invention still extends to the intermediate compounds obtained during the synthesis as a mean, to say the 6-formyl 3-alkoxy 17(20)-propyliden 19-nor estra 3,5-diens (in i ::the form of a E or Z isomer) having the general formula IV the 6-methylen 3-oxo 17(20)-propyliden 19-nor estra 4-en (in the form of a E or Z isomer) having the formula V the 6-methyl 3-oxo 17(20)-propyliden estra 4,6-dien (in the form of an E or Z isomer) having the formula VI The following examples are merely intended to illustrate the invention.

EXAMPLE I 6,21-dimethyl 17a-hydroxy 3,20-dioxo 19-nor pregna 4,6-dien Step A 3-alkoxy 21-methyl 19-nor prena 3,5,17(20)Trien Using the process disclosed by A.M Krubiner and co-workers in J. Org. Chem. 33 (1968) 1713 starting from 3-methoxy 17-keto estra 1,3,5(10)trien they are successively obtained 3-methoxy 21-methyl estra 1,3,5(10) 17(20)tetraen (V) (MP 760 [a]D 590) then 3-keto 21-methyl 19-nor pregna 4,17(20)dien (VI) obtained after reduction according to the method of Birch-Nelson in the form of a fluid straw-yellowish oil This compound is converted-under the action of triethyl orthoformate in the presence of traces of p.toluene sulphonic acid in an ethanolic medium-into 3-ethoxy 21-methyl 19-nor pregna 3,5,17(20) trien (III).

~Nr Q.

N j d i 10 In the same manner 3-keto 21-methyl 19-nor pregna 4,17(20)dien (VI) is converted into 3-methoxy 21-methyl 19-nor pregna 3,5,17(20)trien (VII) using trimethyl orthoformate in or methanolic medium in the presence of traces of p.toluene sulphonic acid.

The yield amounts to 79 MP 118 0

C

Step B 3-ethoxy 6-formyl 21-methyl 19-nor pregna 1,5,17(20)Trien Isomer Z (VIII) To 30 g of 3-Ethoxy 21-methyl 19-nor pregna 3,5,17(20)Trien, isomer Z (III) and 300 ml dimethyl formamide it is added a Vilsmeier-Hack's reagent made of 15,5 ml phosphorous oxychloride and 124 ml dimethyl formamide at The reaction mixture is kept under stirring for 75 mn 140 ml of an aqueous saturated solution of sodium acetate are added thereto. It appears a cristalline yellow precipitate. After mn standing, the mixture is filtered and washed with water.

After filtration and washing, 20,2 g of 3-ethoxy 6-formyl 21-methyl 19-nor pregna 1,5,17(20)Trien (isomer Z) (VIII) are recovered as yellow cristalls.

The yield amounts to 62 The MF Df the pure compound is 99 0 C. Rotatory power 21,50 (C 1% dioxan) Step C 6-methylen 3-oxo 21-methyl 19-nor pregna 4,17(20)dien (isomer Z) (IX) 14,3 g Ethoxy 6-formyl 21-methyl 19-nor pregna 1,5,17(20)Trien (isomer Z) (VIII) and 140 ml methanol are kept under stirring for 80 mn with 960 mg Sodium Borohydride at O*C. 15 ml of a 2N solution of hydrochloric acid are then showly added. The mixture is stirred until cristalls are obtained. 8,7 g of 6-methylen 3-oxo 21-methyl 19-nor pregna 4,17(20)dien (isomer Z) (IX) are recovered.

The yield amounts to 71 The melting point is 110-114°C. The rotation power [a]D is 2180 (C 1% dioxan).

U.V SPECTRUM: X max 261 nm e 10.600 ;i 1 t I' I I* 11 StepD 6,21-dimethyl 3-oxo 19-nor pregna 4,6,17(20)trien z) (X) g 6-methylen 3-oxo 21-methyl 19-nor pregna 4,17(20)dien (isomer Z) 35 g sodium acetate and 1,4 g palladized coal at 5% in 350 ml ethanol, are refluxed for 90 mn. The reaction medium is filtered, extracted with chloroform and the organic phase is washed with water. The organic phases are chromatographied on silica. In the eluates 3,1 g 6,21-dimethyl 3-oxo 19-nor pregna 4,6,17(20)-Trien (isomer Z) are recovered in the form of slightly yellowish oil. The yield is S88 The rotatory power is [a]D -31 (C 1 dioxan) U.V SPECTRUM X max 288 nm e 22.000 4 Step E 6,21-dimethyl 17o-hydroxy 3,20-dioxo 19-nor pregna 4,6-dien 2.9 g 6,21-dimethyl 3-oxo 19-nor pregna 4,6,17(20)Trien in 29 ml tertbutanol. 0,58 ml of a 2,5% Osmium tetroxyde solution in tertbutanol and 4,06 g of the complex triethylamine N-oxyde hydroperoxyde are stirred for 24 hours at room temperature.

3 g Celite are further added thereto, then 2 g sodium sulfite in solution in water. They are kept under stirring for further 2 hours.

The whole mixture is extracted by toluene then the organic phase is percolated on a bed of silica for chromatography. The i eluates are evaporated off and the dry residue is taken in methanol in the hot. After crystallisation 1,66 g 6,21-dimethyl 17c-hydroxy 3,20-dioxo 19-nor pregna 4,6-dien are recovered. The yield is 52 MP 204°C i-? 4 ro uj 12- EXMPLE II 17at-acetoxy 6, 21-dimethyl 3, 20-dioxo 19-nor pregna 4, 6-dien 1 g 6,21-dimethyl l7a--hydroxy 3,20-dioxo 19-nor pregna 4,6-dien, 10 ml chloroform, 0,8 ml acetic anhydride and 0.15 g p.toluene suiphonic acid are heated to reflux for 50 inn. 2 ml methanol and 0.1 ml concentrated hydrochloric acid are added and, heated to reflux for a further one hour. The reaction mixtuice 'is extracted with chloroform. The chioroformic solution is washed with water, then the solution is evaporated off under reduced pressure.

The residue is taken off in methanol for crystallisation. 780 mng of 17ct-acetoxy 6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-dien are recovered as crystalls. The yield is 69 e

V

V

V

V.

V

9*

V

V

V

I.

V.

I

V

V

V

V.

V

U.V SPECTRUM :X max 288 rm s= 23.400 M.P 203 0

C

Rotatory power cc]D -340 (C 1% dioxan) RICA SPECTRUM :in 0,68 Hz 1,05 Hz 1,86 Hz 2,08 Hz 5,95 Hz 6,05 Hz CDC1 3 3H in C 18 3H (t) 7 Hz

C

2 2 3H methyl in C 6 3H CH 3

CO

1H H in C 7 1H H in C 6 According to the same process, l7cc--propionyloxy 19-nor pregna 4,6-dien has using propionyl chloride.

6.21-dime thyl been obtained using the same method by means of caproyl 6,21-dimethyl l7cet-caproyloxy 19-nor pregna 4,6obtained.

Using the same method by means of trimethyl acetyl 6, 21-dimethyl 17cc-trimethyl acetyloxy 19-nor pregna is obtained.

chloride -dien is chloride 4,6-dien iv -13- -Using the same method by means of benzoyl chloride, 6,21-dimethyl 17w-benzoyloxyq 19-nor pregna 4,6-dien is obtained.

-Using the same method by means of mono chioracetyl chloride, H ~6,21-dimethyl l7ct-chloracetyloxy 19-nor pregna 4,6-dien is obtained.

4EXAMPLE III Pharmacological study The binding to the receptors of progesterone as measured on the uterine receptors versus labelled progesterone, shows for the compounds according to this invention, a specific affinity 2,5 times that of f~ ':progesterone.

*0 EXAMPLE IV *Tablets of 2,5 mg l7cet-acetoxy 6,21-dimethy1 3,20-dioxo 19-nor preqnia 04,6-dien Active Ingredient 2,5 g 110 g Mais starch 7,5 g Corn 8,1 g Carboxymethyl starch 4,5 g (sodium salt) VMagnesium stearate 12,4 g for 1000 tablets finished at an a-verage weight of 155 g U T R4.

b'V TO.

Claims (2)

1. 20- A compound according to claim 10 i.e l7ct-hydroxy 3,20-dioxo 6,21-dimethyl 19-nor pregna 4,6-dien. 30 A compound according to claim 10 i.e 17m-acetoxy 3,20-dioxo 6,21-dimethyl 19-nor pregna 4,6-dien. A compound according to claim 10 i.e 17cc-tetrahydropyranyloxy 6,21-dimethylA19-nor pregna 4,6-dien. A process for producing the compounds of general formula I CO CH2 -13 OR H 15 wherein R is defined as previously-given characterized in that a 17-keto 18-methyl gonadien (II) selected from the group consisting of the 3-alkoxy estra 1,3,5 triens of general formula II R o I I I a) R 1 0 wherein R is a lower alkyl radical having from 1 to 6 carbon 1 atoms and the 3-alkoxy estra 3,5-diens of the general formula IIb :0 (IIb) *0 'I *RO wherein R 1 has the above-given definitions is reacted with a triaryl propylphosphonium halide having the general formula Ar A P CH I- CH C Hale I 7 16 or the corresponding ylide of the general formula Ar H+ Ar P C H CH2 CH3 Ar wherein Ar is a phenyl. or substituted phenyl radical and Hal is a halogen atom other than flucrine to produce a propylidenic derivative selected from the consistLig of: group the derivatives of estra 1,3,S-trien of the general formula IIIa (IIla) RlO (in the form of a E or Z isomer) wherein 9. 1 is defined as previously-given and the derivatives of estra 3,5-dien of general formulaIIb Cii CH 2 CH (Ilub) 17 (in the form of a E or Z isomer) wherein R 1 has the previously-given definition the compounds of general formula III are hydrogenated according to the Birch's method to produce a 3-oxo estra 4-en which is converted into a compound of general formula IIIb using an alkylating agent in acidic medium, the compound of general formula III b is reacted with a formylating agent of the Vilsmeier-Hack's type to produce the corresponding 6-formylated derivative of general formula IV CH CH2 CH S* S* (IV) F SF. .CHO (in the form of aE or Z isomer) wherein R 1 has the above-given definition the 6-formylated derivative is reduced by means of an alkali metal Smixed hydride then the thus-formed 6-hydroxymethylated derivative is treated in acidic medium to form a 3-keto 6-mthylenic 1 derivative of formula V H CH CH 2 CH 3 C 2 T'vr :A ~~LLI '~Nr .4 (in the form of a E or Z isomer) the latter is isomerized by means of an isomerizing catalyst to form the 3-oxo 6-methyl estra 4,6-dienic derivative of fbrmula VI C H2 CH3 H (VI) Cl 3 (in the form of a E or Z isomer) the latter is bis hydroxylated using a bis hydroxylating reagent made of Osmium tetroxyde and a hydroperoxyde in an inert medium, to form the corresponding l7ct-hydroxy 20-ketonic derivative of formula 4 *9 9 9 9~ 9* 9* 9 S 9@ S 0 9**S S. S S .9 9 9* 9 9* 99 S 9. .9 9* 9. 4. 9 9 9* .4 9 99*9*9 4 CO CH~ 2 H which may be alkylated by means of an alkyl halide in a basic medium, tetrahydropyranylated by means of dihydorpyran in acidic medium or acylated by means of a furctional derivative of a carboxylic or carbonic acid in the presence of an acidic medium. A proces5 according to claim 50 in which the triaryl propylphosphonium halide is propyl triphenyl phosphonium bromide. C -li-FI-- *n;li 1 9 7 A process according to claim 5° in which the bis hydroxylating reagent is made of Osmium tetroxyde and triethylamine N-oxide hydroperoxide. 8 The pharmaceutical compositions containing as active ingredient at least one compound of general formula I according to claim 10 in admixture or conjunction with an inert non-toxic pharmaceutically acceptable carrier or vehicle. 9 A pharmaceutical composition according to claim 80 wherein the amount of active ingredient ranges from 0.50 to 25 mg per unit dosage. 1 0- A pharmaceutical composition according to one of the claims 8 and 90 wherein the carrier or vehicle is one of those suitable for parenteral, oral, rectal, permucous or percutaneous ways of administration. 1 Compounds according to any of the claims 1 to 40, the 6-formyl 3 alkoxy 17(20)propyliden estra 3,5-diens in the form of a E or Z isomer, having the general formula IV H CH 2 C1 (IV) CHO
2. 120- Compounds according to any of the claims 1 to the 6-methylen 3-oxo 17(20)propyliden estra 4-en of formula V sCH L2 Ci3 (V) 0 2 1 30- Compounds according to any of the claims 1 to 40, 6-methyl 3-oxo 17(20)- propyliden estra 4,6-dien of formula V1. CI0 2 ~J 3 DATED this 11Ith day of March, 1992 LABO1RATOIRE THEBAMEX SA. *5 S. WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BUR WOOD ROAD HAWTHORN VICTORIA 3122 AUSTRAUA AU2629588.WPC(DOC.010) IAS:EK 27 s 1 ABSTRACT This invention relates to the field the field of medicinal Chemistry. It has specifically as subject formula I H 0 of chemistry and moi' matter the compounds precisely to of general S SOS. S. S S 55 S. S *5 55 S S. S S 5 S 55.5 S. S 55 S. S S. S .5 55 S *555 S. 0S 5e S S S 55 5 5* S. S S *55*55 S C"2 C3 OR MI wherein R is a hydrogen, a lower alkyl radical a methoxymethyl, a tetrahydropyranyl or the acyl residue of an organic carboxylic .7 1 r INTERNATIONAL SEARCH REPORT International Application No PCT/FR 88/00527 I. CLASSIFICATION OF SUBJECT MATTER (If several classification symbols apoly, Indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC 4 Int.C1.: C 07 J 9/00; C 07 J 17/00; A 61 K 31/575 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols 4 Int.C1.: C 07 J 9/00 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched I Ill. DOCUMENTS CONSIDERED TO BE RELEVANT' Category Citation of Document, with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 13 A GB, A, 924981 (CHAS PFIZER) 1 May 1963, 1,8-10 see pages A FR, A, 2271833 GASTAUD) 19 December 1975, 1,8-10 see the whole document A FR, A, 2077877 (ROUSSEL UCLAF) 5 November 1971 1,8-10 Spocial categories of cited documents: lo later document published after the international filing date document defining the general state of the art which is not or priority date and not in conflict wito the application but considered to be of particular relevance citod to understand the principle or theory underlying the invention earer document but published on or after the international document of particular relevance; the claimed invention iling date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance;' the claimed Invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 26 January 1989 (26.01.89) 15 February 1989 (15.02.89) International Searching Authority Signature of Authorized Officer European Patent Office Form PCT/ISA/210 (second sheet) (January 1985) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. FR 8800527 SA 25276 This annex lists the patent family members relating to thc patent documents cited in the above-mentioned interjiationnl sczrch report. The members are as contained in the European Patent Office EDP file on 08/02/89 The European Patent office is in no way liable for these particulars which are merely given for the purpose of information. Patent document I Publication Patent family Publication cited in search report -7date member(s) date GB-A- 924981 FR-A- 2271833 19-12-75 !JE-A- GB-A- JP-A- U S-A- 2522533 1515284 50160258 4544555 04-12-75 21-06-78 25-12-75 01-10-85 FR-A- 2077877 05-11-71 NL-A- DE-A, 8, C US-A- GB-A- US-A- BE-A- US-A- GB-A- BE-A- CH-A- FR-A- DE-A- NL-C- NL-B- AU NL-B- 7102150 2107835 3679714 1291205 3761591 763099 2866125 790427 535542 335427 1122284 1107835 110569 188741 206825 184990 24-08-71 02-09-71 25-07-72 04-10-72 25-09-73 17-08-71 C m. C A. i.i For more details about this annex see Official Journal of the European Patent Office, No. 12/82 RAPPORT DE RECHERCHE INTERNATIONALE Demands Internationais N* PCT /FR 8 8 /00 527 1. CLASSIMENT 03 L'INVENTION (si plualours symbol..s do classification aont appllcables, lea Indliquer tous) I Solon to classification Internationale des brevet@ (CIS) oa 4b Ia tole selon as classif'ication nationals at Ia CIS CIB 4 C 07 J 9/00; C 07 J 17/00; A 61. K 31/575 11. DOMAINES SUR LESQUELS LA RECHERCHE A PORTE Documentation minimal. consult#* I Documentation consutt~ sutre quo Is documentation minimal* done Is meaurs o4 do ltsl documents font Pentio des docmains sur leequels I& recherchie a poflA 9 Ill. DOCUMENTS CONSIDERI1S COMME PERTINENTS Is Cat~gorle *Identification do* documents citte, 1 1 avec Indication, ai n~cessairt, N* do* rondlcations des passages portlnents 12 vla6a Is A GB, A, 924981 (CHAS PFIZER) 1 mai 1963, 1,8-10 voir pages A FR, A, 2271833 GASTAUD)- 1,8-10 19 d6cembre 1975, voir le document en entier A FR, A, 2077877 (ROUSSEL UCLAF) 1,8-10 novembre 1971. *Cat69oris spicialsa do documents citits: It" eTx document ultdriour publi6 postdriourementh Iodated* ddp6t A*document ditfinissant I'dtat g~ndral do Is techinique, non international ou Ah Is date do prioriti at naportenant pas consid~~~~~~~~r6 com'Atcuirmn eriet6tat de Is technique pertinent. mais citil pour comprondre conad~rAcomm pancul~remnt prtinnto Principe ou Is thdoris constituant Is base do Vinvention aE a document anitreur, mala publid 4A In date do ddp6t Interna. X a document particulibrement Pertinent: linvention revendi- tional ou apr~s catts date quie no pout Mrs considirde comme nouvells ou comma oL a document pouvant setar tan doute aur tans revendicatlon do impilquant unse ctiviA Inventive prioritt ota cit6 Pour dilterminer I& date do publication d'une Ys document partieui~rement pertinent: Ilinvention reven- outro citation ou pour une raisonpciale (tell@qu'nlquils) dliquile no pout Atrs considilrA. comme impliquant une sOn document se r~f~rant A une divulgatlon orile, A tan usage, A activitil inventive loreque I* document sot asocit 4k un Cu tano exposition Cu tous autrae maoena piuaiouresautre. documents do m~ins nature, calle combi. aP a document pubiA avant as date do d~p~t international. male naienn A6tant didente pour une porsonne du matter. poatdrieuroetnt A Is date do prioritA revendiqu~s, a Aa document qul felt part!@ do Is m~ins famlille do brevets Iv. CERTIFICATION Date A laquelie to recherche International@ a it eftctivement Date deoxp~dition du privent rapport do rechierche international* achevie 26 janvier 1989 Administration charg~ o a I recherche international. onction I autoreAl OFFICE EUROPEEN DES BREVETS Formtjlalre PCTIISAIMIO (dousibimo feuill) (Janvolow)gu 11 1 ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMANDE INTERNATIONALE NO. FR 8800527 SA 25276 La presente annexe indique les membres de la famille de brevets relatifs aux documents brevets citi.s dans le rapport de recherche international visi ci-dessus. Lesdits members sont contenus au fichier informatique de l'Officec urop~en des brevets a la date du 08/02/39 Les renscignenlents fournis sont donn6s tirre rndicatif et n'cngagent pas la responsabilit6 de l'Olice europcen des brevets. Document brevet citi Date de Meribre(s) de la Date de au rapport de recherche publication familie de brevet(s) publication GB-A- 924981 Aucun FR-A- 2271833 19-12-75 DE-A- 2522533 04-12-75 GB-A- 1515284 21-06-78 JP-A- 50160258 25-12-75 US-A- 4544555 01-10-85 FR-A- 2077877 05-11-71 NL-A- 7102150 24-08-71 DE-A,B,C 2107835 02-09-71 US-A- 3679714 25-07-72 GB-A- 1291205 04-10-72 US-A- 3761591 25-09-73 BE-A- 763099 17-08-71 US-A- 2866125 GB-A- 790427 BE-A- 535542 CH-A- 335427 -FR-A- 1122284 DE-A- 1107835 NL-C- 110569 NL-B- 188741 AU-B- 206825 NL-B- 184990 0 Pour tout renseignement concernant cette annexe :voir Journal officiel di l'Olffce .reetNo128 brevets, No.12/82