FR2465748A1 - A-NOR-, A-NOR-18-HOMO-STEROIDS AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS NEW CHEMICAL COMPOUNDS AND METHODS FOR THEIR PREPARATION. THESE ARE COMPOUNDS OF THE FORMULA: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS EITHER A HYDROGEN ATOM, OR AN ALCOYL OR ARYL GROUP, OR A FREE OR PROTECTED HYDROXYL GROUP; R REPRESENTS A HYDROGEN, AN ALKANE, ALCENE OR ALCYNE CHAIN OF CONFIGURATION A AND B; R REPRESENTS A HYDROGEN OR A METHYL GROUP; R REFERS TO A METHYL, ETHYL OR PROPYL CHAIN; R REPRESENTS A HYDROGEN, AN ALKANE, ALCENE OR ALCYNE CHAIN; R REPRESENTS A HYDROGEN, AN ETHER OR AN ESTER; N CORRESPONDS TO 0, 1, 2 OR 3 METHYLENE GROUPS. THESE COMPOUNDS ARE USEFUL IN PARTICULAR FOR THE CONTROL OF FERTILITY.

Description

The present invention relates to novel A-nor-steroids of

  estran, androstane and gonane, as well as series

  18-homo and D-homo corresponding, their derivatives and methods of pre-

paration of such compounds.

  More particularly this invention relates to A-nor-5a-oestra-

  hydrocarbon-substituted hydrocarbons, group androstanes and

  The compounds of this invention may be represented by the chemical structural formula: alkyl and / or alcohols, ethers, esters and halogens at the 2-position and hydroxylated at position 17. R4.

  wherein R 1 represents either a hydrogen atom or a group

  alkyl (methyl, ethyl, propyl, cyclopropyl, butyl) or aryl, or a hydroxyl group, or the corresponding ethers or esters (acetate, propionate, trichloroacetate, oenanthate, undecanoate and esters

  related); R2 represents either hydrogen or alkali groups;

  alkenes, alkenes and substituted or unsubstituted lower alkynes, so many

  that e; the symbol R3 represents a hydrogen atom or a group

  methylation; R4 refers to an aliphatic chain such as methyl, ethyl, propyl; R5 represents either a hydrogen, alkane groups, alkenes and substituted or unsubstituted lower alkynes; R6 represents

  a hydrogen atom, an ether or an ester (acetate, propionate, trichlo-

  roacetate, oenanthate, undecanoate and related esters); n corresponds to 0, 1, 2 and 3. The compounds according to the invention can also carry additional substituents on the ring, such as alkyl groups, by

  methyl or ethyl, and / or halogen atoms such as ato-

  fluorines at positions I and / or 4 and / or 6 and / or 7.

  The new compounds of this invention have properties

  important physiological In particular, they are useful for

  the estrogen cycle in mammals and

  anti-nesting tee. In some cases they are antiandrogens

  sand for the control of fertility, as well as for the treatment of some affections, such as certain dermatoses. The compounds according to the invention can be administered in combination with vehicles or

  pharmacologically acceptable excipients.

  The starting compounds, which allow the preparation of the products l

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  according to the invention are commercially available compounds. In particular, 1,5-hydrindane-diones are prepared by conventional methods (see CJV Scanio, Synthesis, 12, 651 (1970), J. Org Chem., 38, 3239 (1973); Comm., 275 (1977), R. Boeckman, J. Org Chem, 42, 3630 (1977), F. Wiechert, Angew Chem Int, Ed Engl.,

16, 506 (1977)).

  A, 19-dinor-5a-estran-dione-2,17

  10) by treating the sulfone of 7α-methyl-6H-7,7a-dihydro-

  1,5-optically active indane-1,5-dione (I, R4 = Me) (see G. Sauer, U. Eder, G. Haffer, G. Neef and R. Wiechert, Angew Chem Int.Eng. , 417

  (1975)) with 6,6-cycloethylenecetal-3-oxooctanoate (2) (see Z.G.

  Jos and D. R. Parrish, J. Org. Chem., 38, 3239, 3244 (1973)) in toluene

  in the presence of sodium hydride which gives the substituted bicyclic derivative

  killed (3). Cyclization to e-keto acid (4) followed by decarboxylation

  tricyclic compound (5) is carried out in an alkaline medium according to

  known methods (see P. Muller and B. Siegfried, Tetrahedron Letters, 3565 (1973), B. S. Huang, E. J. Parish and D. H. Miles, J. Org Chem., 39, 2647 (1974)). Hydrogenation of the ethylenic bond of the product (5)

  is carried out in ethyl alcohol, in the presence of a trace of

  ethylamine and palladium on charcoal as a catalyst. The grouping

  dioxolane of the substituted diketone (6) is released in an acid medium,

  trione-tricyclic (7), easily cyclized in basic medium into a mixture of enones (8) and (9). Reduction of the double bond by lithium treatment in liquid ammonia provides the known dione (10) (Crabbe, P., Fillion, Y. Letourneux, E., Diczfalusy, A., Aedo, J.).

  W. Goldzieher, A.A. Shaikh and V.D. Castracane, Steroids, 33, 85 (1979)).

  This preparation process, applicable to the series of estrane (R4 = Me) as well as 13-ethyl-gonane (R4 = Et), androstane, D-homo-androstane, D-homo- estran and D-homo-13-ethyl-gonane,

  is supplemented by an alkylation reaction as shown in the Scheme

  ma A below, wherein R3 and R4 are as defined above.

  Scheme A 94 O, rIt G a ..- 0vf C 'L sI 0 o ±

+ I -;

  o O Co, v / -O% '0 <Cda30 l O m -6''1 = \ C 1- - M. 0o H: the 2.3 Il c) 4- o A 9,4 0 M or O 0, 7

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  The following process can be used for the production of a 2,17-

  A-nor-5a-estran diether substituted at the 2- and 17-positions, wherein the ether groups are the same and the other substituents at C-2 and

  C-17 are the same or different. A-nor-5a-estran is reacted

  2,17-dione (compound 10) with an organometallic reagent, such as, for example,

  a Grignard reagent or an alkyl lithium, to form the 2,17-

  corresponding dihydroxy-A-nor-5a-oestran substituted at C-2.

  Specifically, the addition of acetylene at position 2 (either at the

  of Grignard reagent is alkynyl lithium in dimethylsulphonate.

  anhydrous oxide) to the compound (10) provides the acetylenic derivative (12). The sinuous lines (,) indicate that the substituent may have the

  The dotted links indicate that the configuration

  guration is a, as for the strong lines, they mean that the configuration of the substituent is S.

  Similarly, the addition of acetylene in position 2 to the compound

  (13) provides the corresponding acetylenic derivative in the form of a

  lange of isomers 2a and 28 separated by acetylated product chromatography

  (14) and (15) in pure form, as shown in Scheme B below. Diagram B

O 40 0

H O

<4 I-I- = C

Oh

ô-, - C -CHF

/ 3> 0 St C_ C H ciC I-

-t 3 0

H ___

- O {

H c c c

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  It is possible to reduce beforehand the carbonyl at position 17, for example

  at the level of the product (4) (Scheme A). Subsequent oxidation of the hydroxyl group at position 17, followed by treatment with a reagent of

  Grignard, which may be the same as above or different, or by a

  a mixture of lithium acetylide and ethylenediamine in solution in the di-

  methylsulfoxide and tetrahydrofuran, give the 2,17-dihydroxy-A-nor-

  c-steroids disubstituted in positions 2 and 17. This compound is then treated with a reagent such as methyl lithium or butyl lithium;

  presence of a basic substituted alkyl halide, such as, for example,

  a diethylaminoethyl iodide, or silver oxide or a halide

  basic substituted alkyl, to form the desired symmetrical diether

  Substituted in 2 and in 17. If the substituent at C-2 or C-17

  holds a hydrogen atom or a moderately mobile atom, for example of the type found in an alkynyl group, and that an alkyl or aryl lithium is used as a base, it is preferred that the amount of the base used be between about 1 and 1.2 equivalents. The reaction stages described above are shown in Scheme C, in which R1, R2,

  R3, R4, R5 and R6 as well as n have the same meanings as above.

  above. ## STR2 ## Substituted 2-hydroxy-α-nor-5α-estran-17-one can be converted to

  C-2 to a 2,17-diether of A-nor-5a-estrane-2,17-disubstituted, in the

  wherein the two ether groups and the substituent groups are the same or different, by a process which comprises reacting the product with dihydropyran to obtain the 2-tetrahydropyranyl ether, which

  it is then treated to obtain the corresponding compound substituted in

  17. The ether group is introduced at C-17 and the tetrahydropyranyl group is hydrolyzed at the 2-position by treatment with a weak acid to obtain a C-17 ether of 2-hydroxy-N-nor-estran substituted at the 2-position ( and / or 17). We can etherify this last compound in a way

  similar to obtain the corresponding diether. The stages of the reaction

  which have just been described are shown in Figure D in

  R1, R2, R3, R4, R5, R6 and n have the same meanings as above.

  above. Scheme D R4 O Ht H R, or: 'oH

H 23

  A 2,17-diether of A-nor-5a-estran in which the ether groups are the same or different can be prepared from the compound (11),

  by a process which consists in treating this compound with an ethereal agent

  in order to obtain the corresponding C-17 ether, to react the C-2 carbonyl of the latter product with a reducing agent such as lithium aluminum hydride or zinc or sodium borohydride, or of potassium, thus obtaining the corresponding 2-hydroxy-17-ether. We

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  etherifies the latter produced by an etherifying agent which can be

  the same or different from that used for the 17-hydroxyl group.

  A substituent at position 17 can also be introduced by reaction.

  of the corresponding 17-keto-steroid with a Grignard reagent such as bromide or ethyl magnesium iodide, and organomagnesium reagents.

similar.

  A 2 or 17-tetrahydropyranyloxy group is hydrolyzed by treatment with a solution of a mineral acid in a lower alcohol, extraction of the reaction mixture with a water-immiscible solvent such as

  ether, drying and evaporation to dryness.

  The carbonyl group at the 2 or 17 position of a sterol can be reduced

  to a hydroxyl group using a nonacidic reducing agent like

  zinc or sodium or potassium borohydride or lithium hydride

  thium and aluminum. For reduction with zinc borohydride or

  sodium or potassium, the reducing agent is added to a solution of keto

  steroid in a lower alkanol (methanol or ethanol) which may contain

  an organic base in solution, preferably pyridine. We shake

  mixture for a period of about 0.5 to 4 hours and neutralize

  then with an aqueous solution of a very mild acid, for example

  aqueous ammonium chloride, or other mild acid that can not

  lyse the tetrahydropyranyl ether group. To carry out the reduction with lithium aluminum hydride, the reducing agent is poured into a

  solution of the keto steroid in an ethereal solvent such as diethyl ether

  tetrahydrofuran or a mixture of both. Stir the mixture

  for about 0.5 to 3 hours and neutralized as above.

  After reduction, the 17-hydroxy steroid is recovered by diluting the neutralized reaction mixture with water, extracting with a suitable solvent such as ether or ethyl acetate, washing the extract with water. , in

  drying and distilling off the solvent under reduced pressure.

  The esters in position 2 and / or position 17 of the steroids described below

  above are prepared by conventional methods, that is to say either by reaction of the alcohol in the presence of the appropriate acid chloride (acetic acid,

  propionic, oenetic, undecanoic and their analogues), either by reaction

  alcohol with the anhydride of the acid in the presence of pyridine or

  an amine. In general, the reaction is one night at room temperature

  - for a secondary alcohol and requires brief heating,

  moderate amounts, for a tertiary alcohol.

  The compounds which fall within the scope of the invention are in particular: 2α-ethynyl-17e-hydroxy-A-nor-5a-estran; 2α-ethynyl-17α-hydroxy-α-nor5a-estrane;

8- 2465748

  2α, 7α-diethynyl-20,17-dihydroxy-N-nor-5α-estran; 2a, 7adiethynyl 2B, 17β-dihydroxy-N-nor-5α-androstane; 2α, 17α-diethynyl 2B, 17α-dihydroxy-N-nor-5α-13β-ethyl-gonane;

  Acetates and diacetates, trichloroacetates, propionates and dipro-

  pionates, oenanthates and dioenanthates, corresponding undecanoates and diundecanoates; The identical derivatives of the D-homo-estran series; The identical derivatives of the 13e-ethyl-D-homo-gonane series; The identical derivatives of the D-homo-androstane series and

  the corresponding ethers and esters.

  The novel compounds of the invention may be administered orally or parenterally and for this purpose a wide variety of assays may be used for which the compounds may be combined with an inert solid diluent or may be dissolved, dispersed or

  in suspension in a suitable liquid vehicle. When they are combined

  with an inert solid diluent, the compounds may be

  administered in unit dose form and in particular in the form of a tablet, a dose of powder or a capsule. When combined with a liquid diluent, the compositions may exist under

  form of solutions, emulsions or suspensions.

  The following examples serve to illustrate the invention, both in

  products that the processes implemented, without any

limit its scope.

Example 1

  Refluxed for 18 hours. a solution containing 22.8 g. hexa-

  2,5-nedione, 12.4 g. ethylene glycol and 0.5 g. p-toluenesulfonium

  than in toluene. After cooling, it is washed with sodium bicarbonate

  diol, dried over potassium carbonate, evaporated the solvent and distilled

mono-ketal under vacuum.

Example 2

  4.32 g. of sodium hydride (50% oily solution), washed with penta

  no, is suspended in 30 ml. anhydrous ether. We add to the reflux of

  ther 5.4 g. of dimethyl carbonate, then a solution of 4.74 g. mono-ketal obtained above, in 20 ml. anhydrous ether. After 4 hours. the reaction is complete. 5 ml is added. of ethanol, poured into 100 ml. of water containing 7 ml. of acetic acid. It is neutralized with sodium bicarbonate,

  extract, wash and dry. After removal of the solvent, the

keto ester (2) under vacuum.

Example 3

  640 mg is reacted. sulfone (1) and 550 mg. keto ester (2)

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  in solution in 20 ml of anhydrous toluene, in the presence of 240 mg. hy-

  sodium drure. After 2 h, the solvent is removed in vacuo.

  The crude product is dissolved in 20 ml. of methanol added to

  500 mg. of sodium hydroxide in 5 ml. of water. After 10 pm The methanol is evaporated under partial vacuum and an aqueous solution of acetic acid is added.

  tick and extracted with methylene chloride. The extracts are washed, separated

  filtered and then the solvents are removed. 30 ml are then added.

  toluene and bring to reflux. The solvent is then evaporated and the

  The decarboxylated salt (5) is purified by chromatography on silica gel.

Example 4

  To a solution containing 506 mg. of enone (5) in 50 ml. of ethyl alcohol and 0.5 ml. triethylamine is added 50 mg. palladium on

  5% coal. The mixture is stirred under a hydrogen atmosphere. After ab-

  sorption of a molecule of hydrogen, the catalyst is filtered off, the

  solvent and purifies the saturated product (6) by chromatography.

Example 5

  500 mg is dissolved. of ketal (6) in 30 ml. of acetone and add 2 ml.

  of a solution I N of hydrochloric acid. After 30 min. at ambient temperature

  The mixture is neutralized with dilute sodium bicarbonate solution, methylene chloride is added, extracted, washed and dried. After

  Evaporation of the solvent gives tricyclic triolone (7).

Example 6

  A mixture of 276 mg was refluxed. of trione (7) in

  ml. of methanol containing 1.7 g. of potassium hydroxide. After evapo-

  solvent, water is added, acidified with acetic acid, neutralized

  tralise with sodium bicarbonate, and extracted with methylene chloride. The extracts are dried, filtered and the solvents evaporated under vacuum. We obtain a mixture of enones (8) and (9) which is not separated, but directly

submitted to the reduction stage.

Example 7

  50 mg is added. Enone mixture in 2 ml. anhydrous ether,

  a solution of 100 mg. of lithium in 20 ml. of liquid ammonia. We let

  react for 30 minutes, then add I g. of ammonium chloride. After

  evaporation of the ammonia, the residue is dissolved in methylene chloride

  lene. The extracts are oxidized with 500 mg. pyridinium chlorochromate.

  Wash with potassium carbonate, dry and evaporate the solvents. After

  Chromatography gives the crystalline A-nor-5a-oestran-2,17-dione (10)

  same as an authentic sample.

Example 8.

  It is bubbled for 30 minutes. a stream of dry acetylene in a

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  solution, maintained between 0 and 5, containing 250 mg. of the diketone

  above, dissolved in 5 ml. anhydrous DMSO, at which 272 mg. of com

  Lithium acetylide plexes in ethylene diamine were added. The mixture is left to stand overnight at room temperature and is then poured into water and, after chromatography, gives 2α, 17n-diethynyl 28,17e-dihydroxy-

  A-nor-5a-estran expected, easily separated from the 2B isomer.

  The diacetates, dipropionates, divalaters, dibutyrates, dibenzoates, dioenthates, diund.-croates and other corresponding diesters are prepared by dissolving the diols (about 700 mg.) In about 3 to 5 ml. anhydrous pyridine and adding 7 ml. anhydride

  acid. It is heated in an oil bath (110-115) overnight. We add

  then methanol to destroy the excess of anhydride, then ice

  this. The diester is extracted, washed, dried, filtered and removed solvents

  under vacuum. The pure diesters are obtained by chromatography.

  The diesters can also be prepared by treatment of the diols with

  acid chlorides in an inert solvent under mild conditions.

  Diethers can be prepared by reaction with dihydropyran, by

  example, in the presence of a trace of an acid such as p-toluenesulphonic acid

Picnic.

  Monoethers can also be prepared by successive etherification.

ve, as mentioned above. -

  The 18-homo homologues are prepared using the product (1), in

  which R4 = E (G. Sauer, U. Eder, G. Haffer, G. Neef and R. Wiechert, An-

  gew. Chem. Int. Edit., 14, 417 (1975)), and by applying the methods described in

written above.

Claims (2)

  Steroid compounds characterized in that they correspond to the following formula: ## STR1 ## in which R represents either a hydroxyl group or a ester group; R2 represents a lower substituted or unsubstituted alkyne group, of both configuration a and 8, in particular an ethynyl group; R4 represents an aliphatic chain especially methyl, ethyl, propyl R5 represents a substituted lower alkyne group or   no, both configuration a than B, especially a group-   ethynyl; R6 represents a hydrogen atom, an ether or an ester (acetate, propionate, trichloroacetate, valerate, oenanthate, undecanoate) and n corresponds to 1,   the symbol R1 defined above can have the configuration a or 8.   2. Process for the preparation of A-nor-homosterol   and A-nor-18-homosteroids according to claim 1, characterized in that it comprises the following step: a) the reaction of a bicyclic diceto-sulfone whose rings are trans-optically active of formula: R4 O - of J-> -H CH2S020   with 6,6-cyclo-6-methylenoctethalo-x-octanoate to obtain a tricetonic derivative   (b) hydrolysis, cyclization and decarboxyline   the product obtained according to step a) to obtain a enone c) the catalytic hydrogenation of said enone to obtain a dione of the acid hydrolysis to obtain a trione e) the cyclization of the product of step d) S to obtain a mixture of isomeric enones   (f) the submission of the aforesaid mixture to a treatment   Lithium solution in liquid ammonia to reduce the double bond and oxidation to obtain the corresponding saturated 2,7-dione with trans stereochemistry A: B g) ethynylation of the product according to f) to obtain a mixture of isomers 2 a and 2 e and   h) the separation of the isomers by chromatograph.