BE623844A - - Google Patents

Description

       

   <Desc / Clms Page number 1>
 



  Strold ketones.



   The present invention relates to steroidal 19-nortestosterone-related clones, processes for their preparation and pharmaceutical compositions containing them.



   The steroid compounds of the present invention are represented by structure (1)
 EMI1.1
 where nI is a saturated alkyl group containing at least 2 carbon atoms, R2 is an alkyl group in trans configuration with respect to 5. R @, the substituents attached to the ter- carbon atoms

 <Desc / Clms Page number 2>

 
 EMI2.1
 tiaries of the C ring are in the trans11 'configuration and the A ring comprises an ethylenic bond terminating in the 5 pool. These CJ: npos6s are therefore' -ketones comprising an ethylenic bond in the 4,55 position (unsaturated ap cptones ) or in position 5.10 (unsaturated γ ketones).



  The term "allyl group" as used herein refers to both substituted alkyl groups.
 EMI2.2
 as unsubstituted alkyl groups. Thus, an alkyl group can be a substituted straight or branched chain group or
 EMI2.3
 no. Preferably R1 and Ru are unsubstituted alkyl groups, and contained no more than 6 carbon atoms. Ru 'can
 EMI2.4
 be, for example, an ethyl, n-propyl, isopropyl,
 EMI2.5
 a-butyl or isobutyl. R2 can be a saturated alkyl group or, for example, U1, thyl, ethyl, vinyl, ethynyl, α- 'propyl, 3sc-propyl, allyl, 1-propynyl, α-butyl and 1- or 2-m <thullyl.



  Of particular interest are those in which R 1 is an ethyl, vinyl, vinyl group (ie 1a-holno compounds).
 EMI2.6
 ethynyl or n-propyl.



  Compounds of the present invention which are of particular interest are as follows:
 EMI2.7
 18-hoo..i7a-tiy x..9-narteststrona 17'-s- "thyl-1 !! - hoNo-17p-hydroxy-osstr- $ (10)" in "3-'ona, la. ?, - st: y.13 - '. ao-.3,9-nortestasterane 18-hoso-17a-vinyl-'l9-nortestosterone la: L'-et: ymy3-, 8-hana-1' .- hydrox; wocstr-5 {1Ci) rn-3-onb la .7a-etynyl-18-bona..3.9-nortestost rone la 18-ho.no-i9-nor-x7a-p: upyltpstotrone la 18,19-bisnor -17a-n'-thyl-13-} i-propyltsstostf? Rone 18t19-b, snor-1? A-thy7.-l: - propyltestnstrone 18,19-bisnar-17a-ct: aynyl-1.3- -pzopyltastostroria 18i19-bisnor-13-r-botyl..l7ayéthy: y.'testostrone.
 EMI2.8
 



  One of the methods of preparing a steroid ketone
 EMI2.9
 1vant the invention comprises the hydrolysis of a corresponding coapose!

 <Desc / Clms Page number 3>

 structure dant (II),
 EMI3.1
 where the group X contains an organic radical linked to ring A by
 EMI3.2
 a hydrogen atom the ring A and / or the ring B are unsaturated and the group X and the unsaturation form a system of atoms such that acid hydrolysis gives a 4,5-ethyl- 3-cetane: fuck.
 EMI3.3
 



  The X group in position 3 of the etérolde molecule, coq- holds an organic radical 1.1 in ring A by a hetero-ntomt which is in practice an oxygen, sulfur or nitrogen atom. 1 The organic radical can be 1. the carbon atom in position 3 through two hetero atoms. Preferably, the organic radical of X is an all-hydrocarbon radical. X can therefore be an alkoxy group, (for example methoxy, ethoxy, raethoetoxy or dihydroxypropyloxy), an alkylthio group (for example, an
 EMI3.4
 6t'ylthio or benzylthio group), an acyloxy group (eg, an acetoxy group), a dialKylaaino group (eg, an N-pyrrolidyl group), an alkylenedioxy group) (eg, ple, an etlenedloxy group) ), an al.Vlèneditiio or alkylene-thiooxy group.



   The unsaturation of ring A or of B, associated with the group X so as to form a system of atoms such as hy-
 EMI3.5
 Acid drolysis gives a 3-ketone., 5-etzy.srique, may consist of a single ethylenic bond ending in position 5 (so that it may be in position 4,5; 5,6 or 5,10) . The unsaturation can also be in the form of two ethylenic bonds, one of which ends in position 3 (so that it can be in 2,3 or 3,4) and the other in position 5; these bonds can be conjugated or '

 <Desc / Clms Page number 4>

 
 EMI4.1
 or not.

   Compounds that have only one bond
 EMI4.2
 ethylenic are those in which two hetero "ato, nes are bonded to the carbon atom in position 3, for example 3-etals, 3-ser aptols, and 3-hénithioketals, all of which are de-
 EMI4.3
 riveted with a ketone in position 3. Compounds which have two ethylenic bonds are those which have only one
 EMI4.4
 hetero-atom attached to the carbon atom in position 3, for example enolic ethers, enolated thioethers and the ainotertla1resqul disclosures are derivatives of the enol form 4o la
 EMI4.5
 ketone in position 3.
 EMI4.6
 



  Arrangements characteristic of unsaturation and of the X group are found in 3-al & oxy-3.5 and -3.5 (3.0) - dienes (enolic ethers of 4e5-6tlylene 3-eetones), 3-alkoxy- 2,5 (10) -dienes (5,10-6-ethylenic 3-oetones enohers), 3-acyl.oxy-3, r5-dines (dnole esters of 4,5-ethylenic, -ketones), 3r3 -al :: yhnedio.f5- and -5 (10) - enes (alkylene ketals obtained from 4,5-ethylene ketones), 3,3-alkylenedloxy¯5 (10) -enes (a1ky1ne ketals 5,10-ethylenic, -ketones) and 3-tertio-al'yiamino-3,5 (6) -dienes (tertiary enanins of 4,5-ethylenic 3-ketones).
 EMI4.7
 Particularly interesting hydrolysis processes use
 EMI4.8
 known starting products of 3-a1:

  {ox-2,5 (10) -dienes (e.g. 3-nr'thoxy compounds), 3 * '3-al.'Vlenedioer-9- and-5 (iQ) -enes (e.g. compounds 3 , 3-ethylsnedioxy) and 3-alkoaty-3,5 (6) - or -3,5 (10) -dienes (eg 3-etho compounds).
 EMI4.9
 The starting products suitable for hydrolysis are described in the applicant's patent of the same date entitled
 EMI4.10
 "Steroid compounds". The hydrolysis can be carried out by putting
 EMI4.11
 the starting material in contact with an acid and water to
 EMI4.12
 an appropriate temperature.

   In the event that the starting product
 EMI4.13
 contains an ethylenic bond in position 5,10, the ketories
 EMI4.14
 Unsaturated py of the present invention can be obtained under mild hydrolysis conditions, for example using a

 <Desc / Clms Page number 5>

 hydroalcoholic solution of oxalic acid at 30 C or cures; under more vigorous acidic conditions, for example using a-
 EMI5.1
 6N aqueous hydrochloric acid at 800, the isonization to unsaturated ketones is facilitated and the product obtained is the conjugated ketone. In the event that the starting material does not contain
 EMI5.2
 ethylenic bond in position 5> 1Q, hydrolysis occurs with formation of the ketone conjugated unsaturation.

   In some cases, for example when X is an acw .oxy group, the hydrolysis reaction can be carried out using a base, for example sodium hydroxide in aqueous methanol. In. in many cases hydrolysis in the presence of water is not necessary, and a hydroxyl medium, for example an alcohol or a carboxylic acid is sufficient,
The steroid ketones of the present invention which
 EMI5.3
 have an ethylenic bond in position., 5 may be obtained by isoarization of the corresponding compounds having an ethylenic bond in position 5,10.

   This iâomerization can be carried out under basic conditions, for example with the aid of potassium hydroxide, or sodium hydroxide in aqueous-alcoholic medium at room temperature, or with the aid of a sodium alkoxide in an alcohol at 60. The acidic conditions i
 EMI5.4
 vigorous, for example heating in ethanol in the presence of concentrated hydrochloric acid can also be used.
 EMI5.5
 This isoraization process reveals a hydrogen atom in the 10p position in the MIL configuration with respect to the 11Y atone. drogen in position 9.



   The steroid ketones of the present invention particularly those which have an ethylenically bonded posi-
 EMI5.6
 tion 4e5. can also be obtained by selectively reducing other steroid ketones in which the R2 group exhibits a higher degree of unsaturation. Thus, a compound comprising an ethynyl group or an allyl group in position 17
 EMI5.7
 can be catalytically hydrogenated to a corresponding compound wherein R2 is vinyl, ethyl or n-propyl.

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  The hydrogenation of these compounds can be carried out by dissolving the compound in a suitable solvent and stirring the solution in a hydrogen atmosphere and in the presence of a palladium or Raney nickel catalyst, until the amount is absorbed. of hydrogen ensuring the selective transformation of the R2 group.



   According to another method of the present invention, a steroid ketone of the invention can be obtained by oxidizing a
 EMI6.1
 corresponding 3téiolde diol of structure (III)
 EMI6.2
 containing an ethylenic bond ending in position 5.



  Such oxidation can be carried out using a reagent
 EMI6.3
 from Oppenauer, <: 0; 1 ..; 13 aluminum isopropoxide, or chromic diacid.



   The starting materials suitable for such an oxidation
 EMI6.4
 tion obtainable by an alkylation of the skin in position 17 corresponding using appropriate organometallic coupos. Thus, a l-ho: ua-i9..zoxaodzo; t5 () en-o.-lane can be treated with an orga.no)! J3gnslen halide or with an orga..ol1 thiql1e compound (for example lithium acetylide or ethyl thium), and the resulting 17-alkyl compound can then be oxidized using dPal isopropylate = înlut2 to doru1er a ii-alkyl-18-homo * -19 noztestostNrone * The homologated norandrostnolone can be obtained itself from the corresponding 19-nornrcmt4 en-3,17-dione 17-ethylene ketal by acylation in pyridine with acetic anhydride or aetyl chloride followed by reduction with sodium borohydride and acid hydrolysis.

   Alternatively, homo-norandrost4nolone can be obtained from the corresponding 19-homo-nortestosterone by

 <Desc / Clms Page number 7>

 (a) acylation with acetyl chloride and acetyl anhydride
 EMI7.1
 tick in pyridine to give the enol diacetate, followed by (b) reduction with sodium borohydride to give 5 4) -l-3..1 17-acetate, (C) protecting the hydroxy group in position 3 by transformation into pyranyl ether by reaction with dihydropyran in the presence of hydrochloric acid as a catalyst, (d) basic hydrolysis of the acetate group in 17, (e) oxidation of the hydroxy group in 17 by chronic acid to obtain the ketone in 17, and finally (f) regeneration of the hydroxy group in position 3 by acid hydrolysis.

   The 18-homo-
 EMI7.2
 19-nora-ndrost-4-bn-3 # 17-dione 17-4thyl% ene cited and 18-homo-19-nortcstosterones are described in patent no.608,370.



  In structures (I) to (III) above, the co.npos4o 13P and 13a are not distinct; indeed in the product of a total synthesis' without splitting, the tories 13ss and 13a se-
 EMI7.3
 are present in an equiraolecular mixture or in reduced form. Preferably, the starting material is an enantiomorph 131 of resolution.

   The invention particularly relates to enantiomorphs which carry the 13ss-alicyl group, associated
 EMI7.4
 or not to the 1.3c-aI'.y3.és enantionorphs and therefore the 13p-ethyl resolving compounds and the compounds 130 in mixtures with a racemic mixtures. the compounds of the present invention are interesting
 EMI7.5
 As pharmaceuticals having anabolic properties, prdg e stationary or other useful properties steroidesj hormones in addition, they are active orally. It has been found that these compounds have in general properties superior to those of the corresponding compounds bearing a 13- = thyl group or which differ from them.

   The difference between the properties of the compounds of the invention and those of the corresponding 13-alphaethyl compounds is further not only quantitative but also qualitative.

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  In particular, it has been observed that the approval by a
 EMI8.1
 additional carbon at position 18 (to give a group; 1.3-ethyl) generally makes it possible to retain or enhance the valuable properties of the corresponding 13-methyl compounds. The compounds of the invention which carry an n-propyl or n-butyl group in position 13 generally have a lower activity, but they are still interesting because their physiological activities are distributed differently than those of the compounds 13-.
 EMI8.2
 corresponding thY19S.

   The approval of the angular group of 17-'alyl-19-nortestosterones, which is the basis of the invention in its general aspects is therefore important because it increases the possibilities of exerting a single particular hormonal action without causing the unwanted side effects
 EMI8.3
 due to the corresponding ethylated steroid 13 used under the same conditions. This is particularly so for anabolic properties and the separation of anabolic and anabolic activities, because anabolic activity is closely related to the chemical structure.
 EMI8.4
 



  Anabolic and androgynous actlvlt
The anabolic (myotrophic) activity of some of the compounds of the invention was studied using the test of
 EMI8.5
 Hershberger and & 1 * ,, Froc. SQ.Ç .. Biol. 1.4eçl., 1953, II, 195i according to which weaned rats weighing 45-50 g are castrated and treated daily for 7 days. On the eighth day, the rats are killed and the levator ani muscle is removed and weighed, the increase in weight being taken as a measure of anabolic activity. We establish by the least squares a curve d-. dose responses from a series of tests, and the dose of
 EMI8.6
 se required to double the weight of the core is measured gra-! phically.

   In this way, the relative activity can be determined with respect to a standard anabolic product, testosterone propiorate, this relative activity being defined as (100 doses of testosterone propionate required to double

 <Desc / Clms Page number 9>

 the weight): (dose of the component $ 6 tested giving the same result.) At the same time as the determination of the anabolic activity by
 EMI9.1
 Herôergé's test, the androgenic activity of the products is determined by the growth of the prostate gland. 'We establish
 EMI9.2
 a horn-born dose response curve preceded and cuticle the activities relative to testosterone propionate.

   From the anabolic and androgenic activities thus obtained, the ratio of anabolic activities to androgenic activities is calculated.



   Anabolic activity is thus determined, Inactivity
 EMI9.3
 androgenic, and, the anabolic activity / androgenic activity ratios of the various products, including for (+) -17a-ethyl- 19-nortestosteibhe (which is an anabolic product of com: aerce) which gives the following values:

   
 EMI9.4
 
<tb> Activity <SEP> Activity <SEP> Report
<tb>
<tb> Anabolic <SEP> Androsnia
<tb>
 
 EMI9.5
 (+) - 19-Hortestosterone 60 4 15 â.9-crtestostrones 17 * -substituted (+) - 17a - <! Thyl 85 12 7 Çi) -lS Homo-17āTalthyl 110 89 1 (i) -17a-Ethyl -18-hoao 340 17 20 (t) -13-Hono-17a-s-propyl 13 z7 19 (* r3.? A- "t'yl.? .. or-.3, -prapyl 270 34 8 (t ) -17a-Ethyl-18-nor-13-n-propyl 54 11
 EMI9.6
 The anabolic and androgenic activities of the active dextrog / res (+) enantionorphs are obviously proportionately higher than that of the race compounds. 19-Nortestosterone is inactive by oral route, unlike the other compounds in the list: for example, () -i'Ta- = thyl-18-io: o-19-naxtestostror, and has activity by route oral equal to 1/10 of its activity par'entf: rale.

   The anabolic activity and reachable selectivity of (-) - 17o-ethyl-18-homo-19-nortestostomy activities are evident. On the other hand, the compound (= -Ig-zawo-1? A- = 4t. *, Iylated has remarkable androgenic activity.

 <Desc / Clms Page number 10>

 



  In practice, in determining the anabo-
 EMI10.1
 1lque! and androgens, it is often found that the dose response curves do not parallel the curves for the standard product, testosterone propionate, and the above method of.
 EMI10.2
 identification of activities does not take this fact into account. To take this factor into account, the dose response curves are analysts as follows.

   It is considered (a) that all doses of the compound above the point on the response-dose curve for
 EMI10.3
 the levator ani muscle cuts it. te curve, where are abolic doses and (b) all doses above the point where the prostate dose response curve intersects the control curve are androgenic. For a particular product, when the point of intersection of the curve for the muscle, role- '
 EMI10.4
 anal value corresponds to a dose lower than the point of intersection of the curve for the prostate, the compound is more anabolic thanandrogenic and the levator ani muscle poir1s at the point of intersection with the curve for prostate expresses growth mt: .n:

  'wt. for non-artclrocrnest doses,
The following table gives the points of intersection (VP and LA), the weight of the levator muscle of abuse (W) at the point
 EMI10.5
 of intersection and myotrophic power, which is defined COW1e the possible increase in (%) of levator ani muscle for non-androgenic doses of composts.
 EMI10.6
 
<tb>



  VP <SEP> LA <SEP> W <SEP>%
<tb>
<tb> Testosterone <SEP> <SEP> <SEP> <SEP> 3.5 <SEP> 15.5 <SEP> 33
<tb>
 
 EMI10.7
 19-Nortestostrone 83 33 48 45o5 .9 - ^: ortestostror.es 17a-substitutes (+) - 17a-Ethyl 17 8.6 42.2 28 (+) -18-Hoco-17e-mdthyl 2.3 2 , 1 34 3 () 17a-thyl-18-ixo: o 20 7,7 48 46 (i) -18-Homo-17a- ± -rropyl 290 250 36 9 (±) -17o-Methyl-18-nor- 13-a- propyl 12 7.5 40 21 () -1? N-Etràyl-i8 = nor-13-n¯- 25 39 33
 EMI10.8
 
<tb> propyl
<tb>
 
 EMI10.9
 The remarkable properties of (t) -! 7a-dthyl-le-

 <Desc / Clms Page number 11>

 
 EMI11.1
 rorao-.9-rsortestastaronë are again evident.

   Further tests related to the effect of this 18-hono compound on growth; seminal vesicles of rats hold against that it possesses
 EMI11.2
 ron 15% of the activity a.t: .drogon of testosterone propior.ate, measured from the r: 1 ::: e Kanière. ctivitntjl.-pes.tron.e ActiJ; f ... arJ; i-o.e.s.tr9F; è.rU
The antestrogenic activity of a compound can be measured by the vaginal daub assay in mice, following
 EMI11.3
 Edgren, jPrp.c,.,, ± .o.ci..iJ'jcpJ.¯i.B.ipil> .1l Hed. ,,. J.96p,, 1 ,,, 252, whereby the test product is mixed with a total dose of 2 µg of estrone and the mixture is administered in four equal daily injections.

   Potency is measured in terms of the activity of progesterone. The results of this test using various compounds are given in the following table. :
 EMI11.4
 
<tb> Progesterone <SEP> 100
<tb>
 
 EMI11.5
 19-Nortestosterone 200 19-Nortestosterone 17a-substituted (+) - 17c-Methyl 1800 (* -1? A-Ethy 1 2100 (*) 1? A-Hthyny1 910 () -.7 $ -Horco-7.? E -mthyl 5000 () -. Hoo-1? cx-âtüyl 3160 # () .., a = Ethynyy18.Iamo 5370
 EMI11.6
 In addition, =) - 17a-cthyl.-1S-hoo -. ^ R-hydror-aestr-5 (lOÎ-en-3-one- is 5 times more active than (+) - 17e-ethyl-17p Estrogen antagonist as a man. Measurements of progestational activity by the Olauberg method described by Elton and Edzren, ,, oerizolo, .958,6, .6., gave the following results. :

   

 <Desc / Clms Page number 12>

 
 EMI12.1
 
<tb> Progesterone <SEP> 100
<tb>
 
 EMI12.2
 19-lifortestottérorles 17āsubs titubes (+ j-1? A-Ethyl 750 (+ ,, -17 a-Ethynyl 10 (t) -17a-Etlril-18-homo 500
 EMI12.3
 
<tb> (i) <SEP> -17a-Ethynyl-18 <SEP> -horao <SEP> 100
<tb>
 
 EMI12.4
 (t) -17et-Ethynyl-18 -! 'ior-13P-n-propyl 250 () -13' - Eutyi-1.7a-Cth; Iziyz 25
 EMI12.5
 In addition, the compounds {= j-1? A-ethynyl-I8-haro and (i) -17a-cthynyl-18-nor-13P * n-propyls have been found to maintain the state.
 EMI12.6
 gestation in rats after ovarectonia while the
 EMI12.7
 compound (+) - 17o - <? thynyl does not give this result.



  (+) - 17α-ôthynyl-17p-hydxo3ty-estr-5 (10) -èn-3-one is an important progestogen of CO ', J "". Crce but it has the in-
 EMI12.8
 suitable to manifest 7% of the estrogenic activity of estrone
 EMI12.9
 It has been found that the progestational agent of interest, α-17 ac-thynyl. l8-haao-l'7-hy? ram-uEStr-5 {i0j-êr .-- onP exhibits only 0.3% of the metrotropic estrogenic activity of estrone, but has greater progestational activity than (+) (19e-thy-nyl-17r-hydroxy-oeetr-5 (10) -ên, -3-one.



  Ocliolest4rolérrial activity
 EMI12.10
 Daily injection for 9 days to male rats
 EMI12.11
 adults at doses of 100, 300 and 100opg of (d-1? yy '= tryl-3.-homo.
 EMI12.12
 19-nortestosterone, and the blood test on the tenth day gives
 EMI12.13
 blood cholesterol levels of 44 to 39b and 42 mg percent that '
 EMI12.14
 correspond to reductions in the content of blood chloesterol
 EMI12.15
 guin of 87, 78 and 8310, respectively, compared to witnesses.



  Studies on (t) -17a-ethyl-18-homo-19-n6riesto-
 EMI12.16
 sterone have been shown to exhibit remarkable toxicity
 EMI12.17
 low when administered to animals.
 EMI12.18
 it offers advantages over the important anabolic product
 EMI12.19
 both commercially available (+) - 17a-ethyl¯19-nortesterone: this latter has an LD 50 of 1.0 mg / kg, while the compound 18-hom 'has been administered to mice in amounts up to 5 g / k, by 1 chalk route or by ir.trayêxitar.ûle route without mortality. The Treaty-

 <Desc / Clms Page number 13>

 ment of the female rats by the compound 18-homo over a period of 8 menstrual cycles does not have an adverse effect on the reproductive possibilities (fertility and fecundity) of the female rats.
 EMI13.1
 



  It has thus been shown that () -1.7a.dt hyl-lt3-hamo-19-nortes-, tosterone is a remarkable anabolic agent having a very high anabolic action, a high antiestrogenic activity, a low androgone activity, a pronounced progestational activity and blood lipid lowering properties, as well as very low toxicity.
 EMI13.2
 that it has no appreciable estrogenic activity.



  The steroid ketones of the invention also have
 EMI13.3
 Of interest are chemical intermediates for the preparation of other steroids, for example, the corresponding 4.9 (10) -d.ene-3-ones.



   The invention is illustrated by the following examples
 EMI13.4
 where the temperatures are in OC, the digital infrared absorption (IR) values refer to the positions of the
 EMI13.5
 maxima in ent-1 and the numerical values of ultraviolet absorption (UV), refer to the positions of the maxima in an *,, the values in brackets denoting the extinction coefficient
 EMI13.6
 molar at these wavelengths, EyiPLjBJ ,.



  . 3-methyl ether of (*) - lr, .. dihydro-1? 'Sz-thyl-.f- homo-estradiol (5g) is stirred in methanol (430 CM3) containing water. (87 em3) and dihydric oxalic acid (6e6 g) until the solid has completely dissolved. Extraction with ether gives a crystalline product (4., 559). melting point 7.6.-13. which after repeated crystallizations from ethyl acetate, gives (t) -17a-dt> iyl-l8-homo-17p-hydroxy-oestr-5 (10) -en-3-one, Melting point 1.2 -143.5 C; IR: k50,1.710; (Found Cp79.6; H110el. Calculated for C21 H3202 C, 799; Fi, 10.26). EXEKPLE (+ -) - 1,4-di'.Iiydro-17a-dthyr-71- 18-homo-oestradiol 3-methyl ether (0.6 g) in methanol (30 om3) is added to a solution of oxalic acid dihydrate (0.46 g) in

 <Desc / Clms Page number 14>

 
 EMI14.1
 water (6 cm3).

   After leaving at room temperature for 45 minutes, ether (60 eM3) is added and the ethereal solution is washed, dried and evaporated. the residual autumn is dissolved in benzene (5 cm3) and chromatographed on activated fuller's earth (50 g); elution with petroleum ether containing benzene in increasing proportion gives a secondary product
 EMI14.2
 crystalline, then the desired () -Z? a-ethynyl.-18-homo -.?- hyc3roy-estr-5 (10) -èn-3-one which is recrirtallized from a mixture of petroleum ether and ethyl acetate to give the pure compound (0.15 g), mp 169-173 C; IR: 3351, 3241, 1706.



    EXAMPLE
 EMI14.3
 F: XF '..! PhP; Ether 3-mtbyi ,, ue of () -. 7c-al.y1-1, .- dihydro-18 .. homo-estradiol (1.5 g) is suspended in methanol (50 cm3). and water (5 cm3). Add oxalic acid (1 g)
 EMI14.4
 then dioxane (20 ent3) e and the mixture is stirred until complete dissolution, then a further 20 minutes. Water is added gradually and the product which precipitates is filtered,
 EMI14.5
 washed with water and dried. By recrystallication in a mixture of ac-
 EMI14.6
 ethyl tate and, -hexsnei gives the () 17c-zlZy, -18 riomo-17..hydrcxy-oestx-5 (1i r-3-one (1 g); UV: no selective absorption at beyond 220 IR 9 e400e 1640, 1610.



  EX¯FPL. 4 ..



  (') -I, 4-dihydro-18-homo-I7a-propynyloestradiol 3-methyl ether (g) is suspended in 11118 in methanol (200 cm3) and water (20 em3). adds oxalic acid (4 g) then dioxane (100 cm3) and the mixture is stirred until complete dissolution and then for 20 minutes. Water is added and the product which precipitates is filtered off, washed with water and dried. By recrystallization from a mixture of ethyl acetate and
 EMI14.7
 from a-hexane we get (. 18-homo-l't -hydrory..l7a-propynyloestr-5 (10) -èn-3-one melting point 156-159OC; UV: then selective absorption above 220; IR: 2200, 1710.



    EXAMPLE 5.
 EMI14.8
 



  (I) -1, 4-dihydro-18-hoao-17a- (2-mEthallylj-estradiol 3-methyl ether) (1.5 gj is suspended in

 <Desc / Clms Page number 15>

 methanol (50 cm3 and water (5 cn3) 'Oxalic acid (1 g) then dioxin (20 cm3) is added, and the mixture is stirred until complete dissolution then for another 30 minutes. Water is added and the product is extracted with ether, the ethereal solution is washed, dried and evaporated and the residue is recrystallized from a mixture of ethyl acetate and n- hexane to give
 EMI15.1
 (} .f-.hoo-i7-hydraxy-1, '7cx- {2-.thally.joestr - {10} Wn-3-one; UY: p33 of selective absorption above 220; IR: 345â , 1710164, 970.



    EXAMPLE 6.-
 EMI15.2
 (I) -1,4-ditvdro-17a-raethyl-18-) nor-13-n-propyloestradiol 3-methyl ether (Oe3 g; in methanol (30 ca3) is added to a solution of oxalic acid dihydrate (0.46 g) in,
 EMI15.3
 water (6 om3). After stirring at room temperature pen.-; After 20 minutes, dissolution is not complete, isopropanol (30 cn \ 3) is added and stirring is continued for 80 ai-; nutes; the product is then taken up in lel # lther and recrystallized, - is in a mixture of ether and hexane to give {} 1'7a mdthyl-3.7-hydresxy-I8 tar-13-n propYZoestr-5 (1 ) ¯n¯, ¯one (0 $ 29) th melting point 158-163 C; UV: no selective absorption above 220 IR: 1695 (carbonyl proup).
 EMI15.4
 



  (-) -1, 4-Diiiydro-17a-ethynyl-18-nor-13-n-propyloestradiol 3-ethyl ether (0.24 g) in methanol (40 cs! 3) is added to a solution of oxalic acid dihydrate (0.58 g) in water (7.6 em3) and the mixture is stirred for 90 minutes at room temperature in a nitrogen atmosphere. Water is added, the product is treated with ether and the residue obtained is
 EMI15.5
 purified by chromatography on fuller's earth and finally reeristallized in cyclohexane and then in ethyl acetate to give () (.7a.-thynyl-17-hydoxy-18.-nor 13-r-propyloestr-. {.C} .. é: -3- one (0.037 s), Melting point 201-2050 TR: 344.325.17x0: {t: cv C, 80> 5; H, 8.6. Calculated for C., 3fl: C, 80eg; H 9.3%).



  'LEi 3.



  () -Lt4-dihydrol8-nor-13p- "propyl-17 -propynyloestradlol 3-methyl ether (2e5 g) is stirred giving 2 hours.

 <Desc / Clms Page number 16>

 
 EMI16.1
 in methanol (80 ca3) containing water (10 ce3), oxalic acid di hydrate (1.75 g) and tetrahydrofuran (60 cm3, The mixture is poured into brine and the product is extracted with ether. The lava and dry extracts are evaporated to give a residue which is recrystallized from a mixture of acetate.
 EMI16.2
 ethyl and 11-hexane to give (') -1? hydrocy-18-nar-L3 -.- propyl-17 ,, -propynYloestr-5 (10) -n-3-one mp 147-150 ° C (Found: C, 80.8; Hp 9.4. Calculated for Cz3H3OZt CP81el; H, 9.5%). pXEPLE 9 ..



  (T) -13e-11-butyl-1,4-dihydro-.? A-fthynyî-18-naroestradial 3-methyl ether (2 g) is stirred in a deactivated atmosphere for 2 hours in 4a methanol ( 50 cm3) containing oxalic acid dihydrate (0.9 g) and water (12 cm3). The mixture is poured into water and extracted with ether.

   The washed and dried extracts are evaporated to give a residue which is purified by chromatography on activated earthenware and then recrystallized from a mixture of ethyl acetate and n-hexane.
 EMI16.3
 to give (') -13-n-butyl-1? a-et: ynyl-17p-hydroxy-estr-5 (1Q) -en-3-one (0.75 g), melting point 160-164 *VS; IR: 3480, 3250, 1720.
 EMI16.4
 ffXEHPLS 10.- A solution of 3-methyl ether of (*) - 1 ,, - dihydro-lg- homo-1? ac-mtly.-aestrdiol (0.5 g) in methanol (55 cm3) is heated. boiling in a nitrogen atmosphere and adding 3N hydrochloric acid (0.6 cm3). The solution is cooled to room temperature and maintained in a nitrogen atmosphere for 3 hours; water is then added and the mixture is extracted with ether.

   The washed and dry extracts are evaporated and the residue is recrystallized from a mixture of ether and hexane, then in
 EMI16.5
 benzene, to give (i) -18-homo-17a-Bethyl-19-nortestosterone as its solvate with benzine, which is freed from benzene by drying at 100 "for 7 hours,

 <Desc / Clms Page number 17>

 
 EMI17.1
 obtains the free compound (0.2 g), melting point 128-129 Cj te: 240 (16.200) IR: 3390, 1663.



    EXAMPLE. 11.
 EMI17.2
 



  (Ji, 4-dihydro.-17a-tv; tL-, 8-homo-oestrad1 3-methyl ether (0.29 g) is added to 15 cm3 of a solution prepared by mixing Concentrated hydrochloric acid (2,4 C3), water (cia3) and sethanol (36 cn3). The mixture is stirred for 10 minutes, during which the solid dissolves. After - 2 hours, the solution is poured into water (50 cm3) and the
 EMI17.3
 The mixture is extracted with ether. Extracts 1a \: 5, dry and evaporated, give a crystalline residue (0.255 g) which is recrystallized from a mixture of ethyl acetate and petroleum ether to give.
 EMI17.4
 ner la (*) - 7c-tly; .- Z8-r.omo-1, -nortestosterone (0.196 g), melting point 139-141 ° C UV: 240 (15,000); IR: 35001665.



  EXAMPLE 12 - (-) - 1.4¯ d.hydra -. 'C-cthJny3.-18-homo..oestradio 3-rPthr. Ether is added to a solution. z7 g) in the mt '.: a.:o1 (36 cm3), water (1.6 cm3) and concentrated hydrochloric acid (2.4 cm3), After leaving at room temperature for 2 hours, ether is added and the washed and dried ether phase is evaporated to give a gum which is dissolved in benzene (5 cm3) and the solution is adsorbed on earth
 EMI17.5
 fuller (50 g). Elution with petroleum ether containing increasing proportions of benzene gives a product
 EMI17.6
 secondary crystalline;

   further elution with benzene running a small proportion of ether gives crystalline product i which is recrystallized from ethyl acetate to give
 EMI17.7
 () -17α-ethynyl-18-homo-19-nortestosterone (0.11 g), mp 203-206 C; IR: 3370, 3300, 1660.



  EXE'IPLE 13.



  A solution of (°) -1,4-dihydro-18-ho: α-3fia-n-propyyoestradio -methyl ether. (0.53 g) in a Qmixture of ndthano2 (22.5 cs! 3) of 12N hydrochloric acid (1, cn3) and water (1.5 cc: 3)

 <Desc / Clms Page number 18>

 
 EMI18.1
 is kept in a nitrogen atmosphere for 2.5 hours at ordinary temperature; ice water is then added (75 ct'3) $ and the precipitate is filtered and dissolved in the ;; t1 {> r (50 con3), the ethereal phase is washed, dried and vFor4e r-ojr give a solid residue which is recrystallized several times from ethyl acetate to give (i) -1-ho o-1-ior w? rz =: rn; st.at. eats (0.23 g, melting point 132-, 3 f 50 UV: 40 (1; .900) IR: 3.f 5, 1660, 1618; (found C, 79, S?, 10.2 calculated for C 22 II 34 0 - 2 C, 79e5; H, 10.4%).



  EXAMPLE 4 ,.



  From 1> 3-raethyl ether of {"-.?-:i. I - ,, i ° dityhro-28 ho: no-oesl: r, t ,: (2 g) is suspended from", the 1 :. mixture of siethanol (72 c3), c'ilorhydric acid c, lces :: (4> il) and water (3.2 --131 in enoto atmosphere. Du 11.j) '; :: \: 1 "(30 era3) is added and the 'f t'.Z.w'1,, T, e is aciti, u: ay',! É 1: t) s'.i: '' 1 complete, then for a further 20 :: 1i.l :: utez "water is rc5 ::: cnp-tite and the mixture is extracted with ether. The phase (t'1J;: rf ('is washed with a saturated solution of sodium bicarbonate? :: w then with water and dried. Evaporation of the solvent gives the (-) - 17a- allyl- 18-ho30-19-nortestost- <rone? UV: 240 (15.600): in:: 3.C3, 1660,
 EMI18.2
 1610.
 EMI18.3
 



  YE "! L? TE 15-- Ether 3t: ly: .3LlP of {j -β, ..:;: 0.;>" .L7-? Ii propynyloestradiol (I, 5 g) is put in suspended in methanol (36 ta3) and stirred with acid c: ilorxf3r .: e co {'e11.trj (2.4. c: n3); water (1.6 tsp !: 13) and dioxin (10 cc), ascv '' dissolving conpiute, then for another 20 minutes. The product is precipitated by adding water, filtered, washed and left (.. La rccr.sta'3i.sation; in a mixture of acetate of - 'thj'le and nh " ": I.: 1'J gives (-) - 18- j ho! No-19-nor-17a- propynyltestosterory, melting point 124.- Il50C; UV: 240 (15,600); IR: 3300, 2190, 1660,

 <Desc / Clms Page number 19>

   EXAMPLE 16.
 EMI19.1
 



  (J-1,4-dihydr -13-honō17a- (2-: nt: ally.joestrûdio.) 3-methyl ether (1.5 g) is suspended in a mixture of! J1.5t''1a. '' 101 (36 c "i3), concentrated hydrochloric acid (w, dC .: 3 water (46em3) and dioxane (10 cn3). After dissolution of the product, water is added and the product which precipitates is filtered and ag: .t again with '1i: thanol (36 eli3), designed hydrochloric acid (2.4 C! n3) and water (1.6 cubic centimeters making 20: ni- nides. Water is then gradually added and the precipitate is filtered, washed with water, dried and recrystallized from a mixture of ethyl acetate and from n-he: cane, then in aoéto: ltrl1e to give the () -1-hozrp-.17a- (2 - ^: t.la1? ylj-19-nortAstost, o: le, (2 g) ; UV: 240 (16,800); IR: 3450, 1670, 1610, S80.



  EXAMPLE 17.
 EMI19.2
 



  (I -;., 4-d;: ydro-'1.'Ta-eth ;; 1 .-. 8-nor-13-s-propyloestrndiol (1.0 g ) is stirred with 44 cc? 3 of an aqueous solution (1tarl of hydrochloric acid similar to that of Example 2, and stirred for 2 hours; the mixture is then worms. water and the product is extracted with ether;
 EMI19.3
 purification by time line on silica gel (elution with ether) and recrystallization from a:! t61a. "'1.ge è) 4t'iyl acetate and hexane give the (* j-13,19 - :, snor-l7az-t'i; l-13¯ n-propyltestostrone (0.35 g), melting point 134-135, 5 C UV: 240 (18.100) j IR: 1660.



    EXEMPTS 18.
 EMI19.4
 



  A mixture of () -1,4-dihydro-17a- ethyl-1S-nor-13-n-propyloes.tradiol 3-methyl ether (0.8 g), ttrahydrofuran (20 cat3), n-'thanol (50 c :::. 3), 12N hydrochloric acid (3.3c-3) and water (2.2 cm3) is stirred at room temperature for 2.5 hours then poured into a solution of sodium, the mixture is extracted with ether and the extracts are washed, dried and evaporated.

   The crystalline residue (0.8 g) is dissolved
 EMI19.5
 in a mixture (25 cni3) of volu-nes {[; aux of #berx? .3nc and of: 1! Y,: re. and chroma graphed on silica gel; l ', read and ":: 1 by a ::: l:.: nze de

 <Desc / Clms Page number 20>

 equal volumes of benzene and chloroform gives a crystalline product which is recrystallized from a mixture of benzene and petroleum ether to give a solvate with benzine
 EMI20.1
 melting point 33-9o C; recrystallization of this product from a mixture of hexane and ethyl acetate gives the solvent-free product, {f) -i3a 1.9-bisnor-i7aaeth51-: L3 - progyltestostrone (0.2 g); anointed with fusion 9-1.40 C; UV: 240 (15,700); IR: 3415, 1660, 1619.
 EMI20.2
 x "s:." 'LE 7 3-rt ethe y11'1u.e of () -1, .- dihydro-1? a-bthyryl ..



  1S-nor13 - propyrloestradiol (0.31 g) is stirred with a solution of concentrated hydrochloric acid (0.81 cz; 3), water (0.54 cm3) and nethanol (12.15 cm3) until 'when dissolved, solid. After addition of water and extraction with ether, purification by chromatography on neutral alumina and recrystallization from cylo-
 EMI20.3
 hexane gives () -13,19-b.sior-7a-etzynyl.-13-n-prop; testost.rone (0.1 g), melting point 14g-150.5 C; UV: 240 (15,700); IR: 3345, 3265, 1655, 1623: (found: C, 81.0; H, 9.3; calculated for C H 0: C, 80.9; H, 9.3%).



   22 30 2 EXAMPLE 20.-
 EMI20.4
 () -1) -17a-bis-n-proPY1-lj4dihydro-18-naroestradiol 3-methyl ether (1.07à is stirred in a nitrogen atmosphere for 2 hours at room temperature in methanol.
 EMI20.5
 (50 cc) containing water (2.5 em3) and hydrochloric acid 31R (3, S eu3). Water is then added and the product is extracted with ether.

   The evaporation of the washed and dried extracts gives a residue which is purified by chromatography on alumina, then by repeated recrystallization from ethyl acetate and finally
 EMI20.6
 by sublimation at 145 C under 0.003 min to give (-) - 18,19 bisnor-13P-173-bis-n-propyltestosterone (0.34 g), melting point 147-149 C; UV: 241 (16,600); IR: 3440, 1660, 1610.

 <Desc / Clms Page number 21>

 
 EMI21.1
 ; Xj'YL: 21. - Du (:) - 17a-allyl-1,4-uihydro-19-nor-13p-n-propyloestradiol (Oy77 g) cit stirred for 2.5 hours in a nitrogen atmosphere in isopropyl alcohol (25 cm 3) containing chlorhyuri- acid
 EMI21.2
 
 EMI21.3
 that 11H - (2.4 cm) and water (1.6 in ''). The: 1i ': lEnee is filtered, poured into brine and the product is extracted with ethc-r.

   Lpz extracts ï.fvÉ s and s (; ch6s are evaporated to produce a rtsiMu which
 EMI21.4
 is purified by chromatography on active fuller's earth then
 EMI21.5
 by reconstitution in ethyl acetate to give (i) -17a-allyl-16,19-bisnor-13p-D-prPyltestosterone, mp 1.35-137 C; UV: 2tβ (17,500); 11 ': 3390, 16t.O, 162C; (Find: C, 80lk; H, 9, i3 Calculate for Cz3tï30z: C, E0, t, 5; fi ,, 1C, 0;). ' i;:! :: i'L :; 22.- 3-methyl ether of () -1, 4-dihydro-.l-mr-13-n-propyl-17a-propynyloestradiol (, 5 g). Is prepared in a nitrogen atmosphere with uu ffi0thanol (135 in * ') containing hydrochloric lyac4t.e 111: (9 cm3) and water (oe ^ x3}. After 2 hours, this isopropyl alcohol (35 cm) is added and continues the agitation for.
 EMI21.6
 
 EMI21.7
 another .30 minutes. The is poured into sairure and the product is extracted with 8ther.

   The lava and dry extracts are evaporated to form a vitreous residue which is taken up by benzene and c3ro: ^ atohraphiÉ on activated fuller's earth. Benzene containing 5. '"u' f: ther elutes a product which, on recrystallization of ethyl and n-hexane, gives the () * 119 -bisnor-13-n-propyl-17o-propynyltestostronej. melting point 10; -li: 14 C :. UV: 240 (1G.'lU (); (Trouva: C, ë0.95; H, 9 ,. .

   Calculated for C23H3202: Ce 81.1; u, 9p5, -). ill3. - Following the procedure of Example 20, 7.'ther 3-methyl- du) -1,4-dlhydro-l'la- (2-m (thallYl) .lb-nor-l3-n-propyloestra . diol is hydrolyzed with calorhyjric acid and the product is
 EMI21.8
 

 <Desc / Clms Page number 22>

 
 EMI22.1
 purified by chromatography on fuller's earth l, and! vle and recri3- lise in ethyl acetate to form the (+) - le, J v-bianor- .7a - (- methallyl) -13-: x-PropyltestosteronE, point <.: 1: fusion 11+ 3., 5-1043.5 C; Utr: <.4l (lt> .700); lut 3lu0, 10ùO, 1t; 0; (Found C, 80.8; H, 9.9. Calculated for C24u) f.PZt C, 80, J-'5; : 1, 10 ,,).



  EXAMPLE 24.- 3axEtxzyl ether, ue of (+} - 1,4-ditz ,, ro-17a - (1-mcthnl-., Ly2> -IS-nor-13t> -n-propyloestradiol (1 , g) is aa t, 'en: itMOiJph & re of nitrogen with inethanol (90 in) containing 1 M hydrochloric acid (9 cm) and water (6 cm' '). The ir.? ^ The brine is poured in and the product is extracted with {'¯her. The washed and s (sides are evaporated to give li <<1 :) -1 ::', 1 '; I-bi ::; - nl) r- l'7a- (1-zxahully.) - 13-t: -propyltestostran; U ;:; '40 (1.500);! Ih: 910.



  EXH.1PLK 25.- A solution of 3-rxthyliue uu (+) - i3-i -l? Utyl- I, -c.üiydro-1.'la-éthy.-1-ndreestrad :! at. (10 Ü d;,!. 'A:.,' ¯1 year of tetrf.hyarofurl1ne (15 cia), ae r ... 'tixr.ol (4 c: n4j, \ 1 "aci ,. hydrochloride li; N (- ,, 0 cm ") and water (Z, en ') is zz.y.:n..onzn'e for 2 hours at room temperature and then poured c: ^ x.:; De In. Brine (350 in).

   The ether extraction results in a: 0: - :: ': <: z0 g) which is taken up by a: ether laxye of p (trolc fit ne 0er.s; -ne (; 5 CM3) and chromatogrophied on gel of; illcc..1.1 '{L ..:': on benzene containing a small proportion C1 '(ther lJr.ne a crystalline side product (0.1 g); another elutlon with a mixture of ether, benzene and chloroform (in the proportions: 4; 1 by volume) gives a crystalline product which is r (.crlstt111i :::.: 'in hexane then in hexane containing a little c: ';: c' c: 4e d'r'1.:. yl to give () -lt, ly-bisnor-Iz-butyl in .. 't: 3 << ltcstostran (0.2.3 g) , mp 78-80 C;

   UV: <40 (1;. 'Lv..î; lhl: 470, 16 & 8, 1619. fXI'PL.). 2u ue stu r 3-r, zcthyl du () -1,:;, - r .¯ti; t 1 1, -dihyr.iro-.

 <Desc / Clms Page number 23>

 
 EMI23.1
 1 "a-ethynyl 1ts-noroestradiol (2 g), is hydrolyzed using
 EMI23.2
 process of 1. ' example 24 and the product is purified by chromatography
 EMI23.3
 phy on fuller's earth activated then recrystallized in a mixture
 EMI23.4
 
 EMI23.5
 n-hexane ether to give} -13-n-butyl-Ia-Ethyyl-18.1Y-bisnortestosteroid (0.71 g), mp 159-103 C; .



  U y: 240. (1.5.9u); iR: 1070; (found: 0. dU, 8; H, 9.3. Calculate for '332J2' C, b1, 1; li, 9.5).
 EMI23.6
 EXAMPLE 27.
 EMI23.7
 A mixture (0.05 g) of () .. 1? A-ethyl-3,3-ethylziediox3r.



  18-homo-estr-y-en-17p-ol and de () -1? A-cethyl-3, 3-éthyJ.nediôsy-1 $ - hoM) -oestr-5 (lO) -cn-17-ol is hydrolyzed in mothanol by hydrochloric acid according to the procedure of Example 11 ;, and 1-s product is isolated in the other and recrystallized to give .a (+) 17a-ethyl-18- hoino-19 -nortestcse, rone (0.04 g), melting point 138-19 ° C, not lowered after niëlfjige with the product of Example 11;

   UV: 240 (16JC0) J EXMPLr .. 23. - Un m, '1 & nge (0.15 g) of (+) - 3,3-ethylenettioxy-17cL-ethynyl- ls-homo-1? 3-: ydrox- y-estr-5-enE and (+) - 3,3-ethylenedioxy-17a- ethynyl-18-homo-17-hydroxy-estr-5'10) -èrie is hydrolyzed in methanol by elilcrhydric acid : ue following the procedure * of the example!
 EMI23.8
 11, and the product is isolated from ether and recrystallized to give '
 EMI23.9
 la (+) - 17u-ethynyl-18-homo-19-nortE! stosterone (0.09 g), melting point 206 C, not lowered after mixing with the product in Example 12, UVS 240 (16.900 ) ..; EXAMPLE 29. (} -3-ethoxy-17n-ethynyl-1S-homo-1? (3-hydraxy.-vestra-3,5-diene (0.1 g) is stirred with -ethanol (10 c: n3; containing
 EMI23.10
 
 EMI23.11
 concentrated hydrochloric acid (1 em. 3) and the mixture tst abandoned
 EMI23.12
 at room temperature for 1 hour.

   Water is then added and the precipitate is filtered off and recrystallized from a mixture.
 EMI23.13
 ethyl acetate and n-hexane to give (., t) -17a-ethynyl-18-homo-19-nortestosterone, melting point 1w-1; C, not lowered after mixing with the substance prepared in Example 11.

 <Desc / Clms Page number 24>

 



  EXAMPLE, 30 .-
 EMI24.1
 T} -17a..nthyl-18-horr.o-.1'p-hydroxy..oester-5 (lt} -n-3-one (12.2 g) is stirred with a mixture of methanol ( 442 cm3),
 EMI24.2
 of water (22 cc) and <1'80i (concentrated hydrochloric acid (30 cc) and the mixture is left for 2 hours at room temperature.



  The product is precipitated by adding water and the reaction mixture is extracted with ether. Washed and dried extracts are
 EMI24.3
 evaporated and the residue is recrystallized from acetonitrile to give (*) - 1α-ethyl-18-Yromo-19-nortestosterone (7.9 g;, melting point U4-U5 CII UV; 240 (15. 6PO); 13s 3420, 1670, 1610; (Found C, 79.85; H, 10.05; Calculated for C21-13.03: C, 79.7; H, 10.2) EXAMPLE 31 ..-.



  (} -1Va-ethynyl-18-hoaro-17-hyiroxy-estr-5 (10) .- bn.



  3-one (0.1 g) is stirred with a mixture of methanol (36 cm3), water (1.6 cm) and concentrated hydrochloric acid (2.4 cm3) for 1 hour. Water is added, the product is isolated from ether and recrystallized from a mixture of ether and n-hexane for
 EMI24.4
 give (} -l'cx-ethyny3.-13-horo-19-nrtestosterone, melting point 203-206 * C; IR: 3280, 2860, 1650, 1060.



  EXAMPLE 32.- {-} - 17a-ethynyl-18-homo-19-nortestosterone (0.5 g) in pyridine (20 cm3) containing a 2% catalyst of palladium on calcium carbonate (0 , 15 g) is stirred with hydrogen at atmospheric pressure until absorption of one molecular equivalent of hydrogen. Isolation in ether gives a product which is recrystallized from a mixture of ether and n-hexane and dried for 4 hours at 65 C under 0.005 mm, to give the
 EMI24.5
 (+) - 18-homo-19-nor-17a-vinyltestosterone (melting point 108-1110C) ;, UV: 240 (15,200); IR: 920; (Found: C, 80.4; H, 9.7. Calculated for
 EMI24.6
 2 'gQ, 2; H, 9.6).

 <Desc / Clms Page number 25>

 



  EXAMPLE 33.-
 EMI25.1
 La) -1 ', a-t, hynyl-7.8..homo-19-nortestost rone (1 g) in benzene (15 cm3) and ethanol (5 cm) is added to a pre-reduced suspension at 2% palladium on calcium carbonate (0.3 g) in benzene (10 cm3) and the mixture is stirred in a hydrogen atmosphere until absorption of 163 cm3 (2.1 moles) of hydrogen. The catalyst is filtered off, the solvent is removed and the product (0.55 g) in methanol (10 cm3) is stirred with a solution of sodium metabisulfite (1.7 g) in water (8 cm3) for 5 minutes.

   Water is added and the product is isolated from ether and recrystallized from acetone to give (+) - 17a-ethyl-13-homo-19-nortestosterone (0.4 g), melting point 144 VS; UV; 241 (17,250); IR: 3440, 1670, 1620.
 EMI25.2
 



  XEtdPLi 34. - (+) - 17a-ethynyl-18,19-bisnor-13p - ,, q-propyltestosterone (0.5 g) is hydrogenated according to the process of Example 3.2, and the product is isolated and recrystallized from the led way to
 EMI25.3
 give (j;) - 18,19-bisnor-13-n-propyl-17a-vinyltestostrone (0.425 g), mp 94-97 C, UV: 240 (15,600); IR: 920; (Found: C, 81.1; rm 9.9. Calculated for C20H320 2: C, 80.4; H, 9.8%).



  EXAMPLE 3 - Du () -3,? P-dihyd.roxy-7a-ethyl-1.-homo-estr-5-ene (0.1 C), mp 178-182C; IR: 3330, 1640e 830, is dissolved in acetone (30 cm3) and treated with small fragments of solid carbon dioxide. An 8N solution of chronic acid is added dropwise until the coloration of the acetone solution remains orange (3 drops); Isopropanol (1 cm3) is then added. The mixture is stirred for 5 minutes with a 10% aqueous solution of sodium hydroxide (50 car), then added with benzene (30 car) and the mixture. organic phase is separated, washed, dried and evaporated.

   The residue is triturated with ether and the remaining crystalline product is recrystallized from porous ether.

 <Desc / Clms Page number 26>

 
 EMI26.1
 give (t) -17a-ethyl-18-homo-19-nortestosterone, melting point 138-14.2 C, not lowered after mixing with the substance prepared in Example 11.



   The pharmaceutical compositions according to the present invention comprise a compound according to the invention associated with a pharmaceutically acceptable carrier. Such a composition is prepared by a process in which a compound of the invention is admixed or otherwise associated with a pharmaceutically acceptable carrier.



   The pharmaceutically acceptable carrier can be solid or liquid. The solid compositions are powders, tablets, dispersible granules, capsules, cachets and suppositories. The solid carrier may consist of one or more substances which may also act as flavorings, solubilizers, lubricants, suspending agents, binding agents or tablet disintegrating agents; it can also be a material for capsules. In the case of powders, the carrier is a finely divided solid in admixture with the finely divided compound equally. In tablets, the compound is mixed with amounts appropriate to the carrier having the necessary binding properties and the mixture is compressed into shape and dimensions desired.

   The powders and tablets preferably contain between 5 or 10% and 99% of active ingredient.



  Suitable solid carriers are, for example, magnesium carbonate, magnesium stearate, sheet metal, lucre, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose. , a low melting point wax, and cocoa butter. By "composition" is meant. also capsules containing the compound with or without other carrier, the capsule material itself being an associated carrier. Likewise, the compositions can also take the form of cachets. Tablets, powders, cachets and

 <Desc / Clms Page number 27>

 capsules can be used for oral administration.



   Liquid preparations are, for example, solutions, suspensions and emulsions. The compounds are insoluble in water, but can be dissolved in aqueous solutions of propylene glycol for parenteral use. They can also be in the form of solutions in aqueous solutions of polyethylene glycol with a molecular weight of 400.



  Aqueous suspensions for oral use can be prepared by dispersing the finely divided compound in water with sodium carboxymethylcellulose as a suspending agent. Oily suspensions can be prepared by dispersing the finely divided compound in peanut oil.



   Preferably, the pharmaceutical composition is in unit dose form. Herein, the composition is subdivided into unit doses which contain appropriate amounts of the compound: the unit dose may be a packaged composition, the package containing a number of separate unit doses, for example. powders in sachets or ampoules or vials. The unit dose can be the capsule, cachet or tablet or it can be formed by the appropriate number of either of these packaged forms.

   The amount of the coin-posed in a unit dose of the composition can vary from 1 mg to 100 mg (generally 2.5 to 25 mg) depending on the particular application and the activity of the active ingredient.



   The invention is further illustrated by the following examples of pharmaceutical compositions.



    EXAMPLE 36.-
A pharmaceutical tablet suitable as an anabolic agent for oral use comprises:

 <Desc / Clms Page number 28>

 
 EMI28.1
 
<tb> mg
<tb>
 
 EMI28.2
 () -17athyl-l .horo-1.-no r te s ta s t rone 5 Carboxymethylcellulose (viscosity 400 cps) 15
 EMI28.3
 
<tb> Lactose <SEP> in <SEP> powder <SEP> 25
<tb>
<tb> Starch <SEP> of <SEP> but <SEP> re-dried <SEP> 25
<tb>
<tb>
<tb>
<tb> Magnesium <SEP> <SEP> stearate <SEP> in <SEP> powder
<tb>
<tb>
<tb> Silicate <SEP> of <SEP> calcium <SEP> in <SEP> powder <SEP> q.s.
<tb>
<tb>
<tb>



  200
<tb>
 Compresses are prepared by dissolving the steroid in benzene,
 EMI28.4
 mixing the solution with the excess proportion of starch, knowing the mixture in a stream of air, adding the other constituents in the correct proportions, mixing and compressing the composition into pellets, and finally regranulating and pressing the composition formed so that each tablet contains 5 mg of steroid.



   Alternatively, the tablets are prepared by dissolving the steroid in benzine, mixing the solution with the lactose powder and drying the mixture in a stream of air.
 EMI28.5
 then adding the caroo7.y. ,, iethylellulose., calcium silicate and half of the starch. The obtained powder is mixed with a starch paste prepared with the rest of the starch, the mixture is granulated in the wet state, the granules are dried, the stearate is added and the composition is pressed into tablets. each containing 5 mg of steroid.



  EXAMPLE 37. -
A capsule suitable as an anabolic agent for oral use contains, in gelatin for capsules, the following constituents;

 <Desc / Clms Page number 29>

 
 EMI29.1
 f. ' 3 (t) -11a-ethyl-1S-homo-19-nostestosterone 5 Finely divided silica 5 Magnesium stearate powder as a lubricant 5 Corn starch powder 113 Lactose powder q. z. \ 245
The composition is prepared by mixing the powdered components in the correct proportions and filling them into hard gelatin capsules, so that each capsule contains 5 mg of active component.



    EXAMPLE 38. -
 EMI29.2
 A suspension of anabolic agent for oral use contains per 5 cm3 the following constituents
 EMI29.3
 
<tb> mg
<tb>
 
 EMI29.4
 () -1? A-Ethyl-18..haruo-13-nortestasterane 5.0 Aluminum-magnesium silica (C-1paisell'r-L'nt agent) 37.5 Low viscosity carboxymethylcellulose 37.5 Monolurate of polyoxyethylene sorbitan 50.0
 EMI29.5
 
<tb> Glycerin <SEP> 250.0
<tb>
<tb> Sucrose <SEP> 2000.0
<tb>
 
 EMI29.6
 Ciethyl E-Hydrar.yber.zoate 5.0 j-Propyl hydroxybenzoate 1.0
 EMI29.7
 
<tb> Perfume <SEP> and <SEP> distilled <SEP> water <SEP> q.s.
<tb>
 



   The finely divided steroid is stirred with a vehicle prepared in the other components in the proportions
 EMI29.8
 the water is injected, and the final volume is adjusted so that each cm3 contains 1 11 '(; of the steroid.



   A suspension of anabolic agent for parenteral use contains, per cm3, the following constituents:

 <Desc / Clms Page number 30>

 
 EMI30.1
 
<tb> g
<tb>
 
 EMI30.2
 ) -Z7a-thyl-l-hama-19-noctesterone 0.0005
 EMI30.3
 
<tb> Benzyl alcohol <SEP> <SEP> 0.01
<tb>
<tb> <SEP> sodium <SEP> chloride <SEP> 0.09
<tb>
 
 EMI30.4
 Sodium carboxymethylcellulose zus Polyoxyethylnf sorbitan monooleate 0.004
 EMI30.5
 
<tb> Water <SEP> for <SEP> injection <SEP> q.s.
<tb>
 



  Benzyl alcohol, sodium chloride and carboxy-
 EMI30.6
 sodium methyl cellulose and polyoxyethylene sorbitan monooleate are mixed with the water for injection and the mixture is sterilized in the autoclave. The sterile sterile in a finely divided ream is then mixed with the vehicle in a proportion such that each cm3 contains 0.5 mg.



    EXAMPLE 40.-
Drops of anabolic agent for pediatric use contain, per drop (0.05 cm3) the following constituents:
 EMI30.7
 
<tb> mg
<tb>
 
 EMI30.8
 L) -1? A-ethyl-18-horao-19-: ortestosterone 0.500
 EMI30.9
 
<tb> Magnesium-aluminum <SEP> <SEP> silicate <SEP> (agent
<tb>
<tb> thickener) <SEP> 0.375
<tb>
 
 EMI30.10
 Polyoxyethylene sorbitan monolaurate 0.500
 EMI30.11
 
<tb> Phosphate <SEP> disoaic <SEP> heptahydrate <SEP> 0.375
<tb>
<tb> <SEP> citric acid <SEP> monohytlra. <SEP> t6 <SEP> 0.060
<tb>
<tb> Glycerin <SEP> 1.250
<tb>
 
 EMI30.12
 , methyl p-Hydroxybenzcate 005 Propyl B-Hyaroxybenzoste 0.005 Butyl p-Hydroxybenzoate 0.020
 EMI30.13
 
<tb> Distilled <SEP> water <SEP> 0.015
<tb>
<tb> Saccharin <SEP> sodium <SEP> 0.013
<tb>
<tb> Sorbitol <SEP> and <SEP> perfume <SEP> q.s.
<tb>
 



  We prepare a vehicle by mixing all the constituents
 EMI30.14
 except the steroid; the steroid under finely divided forrae is then added and the volume is adjusted with sorbitol so

 <Desc / Clms Page number 31>

 so that 0.05 cm contains 0.5 mg of steroid.



    FXLKPLh 41.-
One tablet of long-lasting anabolic agent contains the following constituents:
 EMI31.1
 
<tb> mg
<tb>
 
 EMI31.2
 () -.i7a-ethyl-18-hotno-19-nortestosterone 5 folY11l'e cs.rboy-v1ny11cue acid, insoluble in water; acrylic aciüe copolymarized with U, 75-2, of polyallyl sucrose (Carbopol 934 in patent m: lric /; '1n 2.9U9.462) 150
 EMI31.3
 
<tb> Stearate <SEP> ce <SEP> magnesium <SEP> in <SEP> powder <SEP> 2
<tb>
<tb> Lactose <SEP> the *
<tb>
<tb> 200
<tb>
 
The steroid is mixed with the lactose and the carboxy-vinyl polymer and compressed into pellets: the composition is then granulated, the stearate is added and the mixture is compressed into tablets containing 5 mg of steroid.
 EMI31.4
 



  LX i-1 L E 2. - A tablet suitable as a prcgestationnel agent is prepared coptr'.e in Example 36, but using () -7c-eth: nyl-; 18-homo-19-nortestostërone (5 mg) as active ingredient instead of the corresponding 17a-ethyl compound.



    EXAMPLE 43.-
A capsule suitable as a progestational agent is prepared known in Example 37, but ae la (¯) -17 [alpha] - is used.
 EMI31.5
 ethynyl-18-homo-19-nortestosterone (5 mag) as the active constituent instead of the corresponding 17a-ethyl compound.



  PEOPLE 4. ¯ A suspension suitable as a pro-estational agent for oral use is prepared as in Example 38, but (; s -) - 17x-ethynyl-lb-ho: no-19-nortestostcrorie (5 mg) is used as an active component instead of the corresponding 17a-ethyl compound.

 <Desc / Clms Page number 32>

 



    EXAMPLE 45.-
 EMI32.1
 Anabolic agent compositions are prepared as in Examples 36 to 38, but using (t) -1f3-hoJI10- l-1Ior-170-n-propyl t \ :: stosterone (10 mg) instead of the corresponding 17α-ethylated compound.



  EXAMPLE 46. -
Progestational agent compositions are prepared
 EMI32.2
 as in Examples 36 to 38, but In (.; t) -ltl, 19- blsbor-17a-ethynyl-13-āpropyltestostcrone (5 ng) is used instead of the compound 17a-dthyl6-18-homo corresponding.



  CLAIMS.



  ¯.r¯-ww ... w ....- .. r .., ...,. R ... "...-- ¯ 1. Steroid ketone of structure:
 EMI32.3
 where R1 is a saturated alkyl group containing at least 2 carbon atoms, R2 is an alkyl group in the trans configuration with respect to R1, the substituents linked to the tertiary carbon atoms of the
 EMI32.4
 ring C are in the trans -anti -trans configuration and ring A has an ethylenic bond ending in position 5.


    

Claims (1)

2. Ketone according to claim 1, characterized in that R1 and R are unsubstituted alkyl groups. 3. Ketone according to claim 2, characterized in that R1 and R2 each contain no more than 6 carbon atoms. 4. Ketone according to claim 2 or 3, characterized EMI32.5 in that it has a 13p -alkylated group, in the presence or in <Desc / Clms Page number 33> the absence of its 13a-alkyl enantiomorph. 5. Ketone according to claim 4, characterized in that is an ethyl group. o. Ketone according to claim 4, characterized in that is an n-propyl or n-butyl group. 7. Ketone according to either of claims 4, EMI33.1 5 and fr, curzictf'ris4e in that n2 is an ethyl or 4.7'th> nyl group. 8. Ketone according to any one of the claims EMI33.2 5 and 6, characterized in that nu is an aothyl, vinyl, n-propyl, allyl or 1-propynyl group. 9. Ketone according to either of the claims EMI33.3 4 to 8, characterized in that it comprises an e, hy.s aique bond in position 5 (lU). 10. Ketone according to any one of the claims EMI33.4 4 to 8, .characterized in that it comprises an f-thylénicue bond in position .i 5. He. 17a-Lthyl-18-ho: o-27-hyüroxy-estr-5 (1.) -i.n .-: - one. 12. 17a-Bthyny1-1d-hoLIO-17 .; - hydroxy-estr-5 (10) -en-3-one. 13. 18-Hojpo-17a-Mthyl-1-nortestostrone. \ z. J.'la.-iahyl-1-ho: r.o-19-nortstostrone. 15. lo-Homo-17a-vinyl-19-nortestosterone. the . 27u-Lthynyl-18-ha: no-1? -NartestostNrone. / 17. 2-noo-ll nor-2'7a -.- propyltes heap trane. 18. 1G, 1-xüsnor-7.7s-rï: thyl-.3-n-prapyltestost: rc.rne. 1 ': 1. 18,19-Biinor-17a-dthyl-13-i} -propyltestosterone. 20. 1,19-sisnor-1'la-Etn; ny.-1.3 - propyltea wosterone. 21. 18.1.H - .. snor-1 -, - butyl-1.la-: thynYl.testostrone. 22. A process for preparing a steroid ketone followed by EMI33.5 According to either of the preceding claims, carncttGr1Sl in that a corresponding compound of structure is hydrolyzed: <Desc / Clms Page number 34> EMI34.1 where group X contains an organic radical bonded to ring A through a hetero atom, ring A and / or ring si are unsaturated, and group X and unsaturation form a system of atoms such that EMI34.2 acid hydrolysis gives a 3-ketone 4,5-t> thyr: 'n3 ue. 23. The method of claim 22, characterized in that the hydrolyzed compound is a 3-alkQ: ry- ;, 5 (1U) 13 f: ne. 24. The method of claim 23, characterized in that the hydrolysis is carried out under mild conditions and the EMI34.3 product is a 5 (10) -en # 3-one 25. The method of claim 23, characterized in that the hydrolysis is carried out under energetically acidic conditions. EMI34.4 ques and the product is a 4-th ... 3-th. 26. The method of claim 22, characterized in that the hydrolyzed compound is a 3,3-d.kylziediaxy.-5- or 5 (10) -ene. 27, The method of claim 22, ca3rctrl, sf in that the hydrolyzed compound is a 3-nlkaxy-3, 5 (6) - or -.3, 5 (J.U diene ,. EMI34.5 28. A process for preparing a steroid ketone according to claim 10, characterized in that a steroid ketone according to claim 9 is isom'ized. 29. The following method of preparing a steroid ketone EMI34.6 either of the claims 1 in which a corresponding ketone is selectively reduced, the R2 group of which has a higher degree of unsaturation. 30. Process for the preparation of a steroid ketone following; <Desc / Clms Page number 35> EMI35.1 either of these claims i l 21,: rc: N = ri; in that we ûiyuu a corresponding u101, of 5truC '' ';. 1.:,rt' EMI35.2 EMI35.3 : c:; riFc, u an iy, t-nicue bond ending in position 5. 3 Ph & nunc9ut.iue composition comprising ur.e ketone sttruîae following i''me or the other (le.4 rfvim1clH; 1on:.> J to 1, in association with a pha vehicle: rHmoeut1quenlcnt acceptable.