DE2110084A1 - New 1,2-methylene-17alpha-acyloxy (or etherified hydroxy) -9beta, lOalpha-steroid compounds of the Pregnan range, pharmaceutical preparations based on these new compounds and processes for the production of these compounds and preparations - Google Patents

Description

PHI.4567 . dJo / ΕΥΗ.

₁ ST AUER

Applicant: HVPHaJ? 5 ^! CLOLL
Act.; p y Λ /

Registration from * ^ ^

Build 1,2-methylene-17 «· -acyloxy (or ve ra ee Hydro3ty) -9 / i, 10d .- «1; * ioid-V # il) iadongen der Piegnmmeihe, phazBaoeutieohe Preparations on Baal of these new compounds and Tezfahxea supports the production of these compounds and preparations.

Aue of the American patent specification Mr. 3,198,792 the Applicant is known that the steroids of the retro series, which are in the In contrast to the steroids of the normal series, have a 9 / S · 10gC configuration, have interesting * endoorinological properties.

Examples of retro steroids are given in the column 11 to 23 d'eeer patent about 800 substances or groups το » Fabrics.

It has now been found that 9, 1θΑ steroids according to the general formula

109838/1898

PHI.4567-

CH ₂ -H ₂₁

wherein X and Y together "in doppeltgebundenea Sauexatoffatoa daxatellen odex X" in Vassexstoffatoa and t iat a Hydxoxy group odax "in · rereatexte Hydroiy group, R," ine _3-keto-4-f dehydxo-

3-K® to-4,6-biadfhydxo- ,

: .- OR «-3 _t 5-biadehydro- or one

5 "OR ⁽ ~ 4 ₍ 6-biadehydxo-Gxuppe iat,

where OR * a vexlthexte or vexeatexte hydroxy group daxatellt, R ^ a WassessioffatOB, a Chloxatom »a Pluoxatoa, a 6,6-Difluox- (rXttppe, a 6,6-Siohlox-Gxuppe odex a methyl group iat, wlhxenä® when Rg iat a Vassexetoffatom, R "is a 6,7-methylene-Gsuppe that divides a R- Vaeeexatoffatom odex a 6,7-methylene-l Gxuppe" t ₉ wlhxend when R "daxatellt a 6,7-methylene group, Rg a hydrogen atom, a Ghloxatoa odex «in Pluoxatoa and R, a 3-K« to-4-dehydio group iat,

R ₁₇ "in" vextthext "Hydxosy-Giuppii with 1 bia 5 carbon atoms or an esterified Hydroxoxy-Gxupp" with 1 bia 8 carbon atoms, R ₂₁ "in WaaaexstoffatoB," in Plooxatom, "ine Hydroxy-Gxuppe or a reacted Hydroxy- Group iat, R ₁ , a «methyl odex an« ethyl group daxatellt,

109838/1698

PHH.4567

have an extremely high endocrinological efficacy.

Di · endoorlnologiaoh · effectiveness and especially the progestatire and anti-orulatoiieoh · Effectiveness of redeeming wishes Group τοπ compounds according to the invention is significantly higher than those of the connections according to columns 11 to 23 of the above mentioned Patent specification. Ea has also shown that progcstative and anti-orulatory effectiveness of the substances according to the invention The "Kai" is higher than that of the normal connections Row ·.

Ea has been found in particular that the dl "compounds according to the general formula

where R, t Regiment red ^R i7 ^"R P1 ^{'X and T VOItrwÄhn} * ^e have meaning, have" surprisingly high in "progeetatire and anti-ovulatoriache effectiveness.

This is especially true of the Fozaeli connections

ς - o

10 9 8 3 8/1698

PHH.4567

where Hal is a chlorine atom or «in fluorine atom and R _{17 has} the aforementioned meaning

Very strongly active compounds, their progestatire and anti-ovulatory effectiveness in oral and parenteral Administration is higher than that of the previously known Connections »include the following

3,20-dione 17-acetate,

1, 2-methylene-6-fluoro-1? -Hydroxy-9 Λ / J, 10 £ -pregna-4,6-diene 3,20-dione 17 acetate,

1,2-methylene-6-fluoro-17 <^ / -hydroxy-9 6 »10 (λ> -pregna-4., 6-dien- 3,20-dione 17-propionate,

1,2-methylene-6-ohlor-17c ^ -hydroxy-9 ^> _v 1O ^ / - pregna-4 _t 6-diene- 3,20-dione 17 propionate.

A heavily lengthened, progestational and anti-ovula Toroidal activity has been found in compounds of the formula

H ₉ C

17th

Shark

where Hal represents a fluorine or a chlorine atom and R ₁ - is an etherified hydroxyl group with 1 to 5 carbon atoms or an esterified hydroxyl group with 4 to β carbon atoms.

109838/1698

Di ·· applies in particular to the connections!

1 _f 2-methylene-6-ehloz-17 <* - tetzabydxopyxanyloxy-9 /?> »1OGH / -pregna-4,6-diene-3 _f 20-dione ₍

1,2-methylene-6'-fluox-17 <A / -tetrahydxopyxanyloxy ^ ß, TOgV-pxegna 4,6-di «n-3» 20-dione,

1 _f 2-Mtthyl * a-6-fleo3i-17c ^ -metboxy-9A »1O (^ - pxegna-4t6-dien-3,20-dione, ·

1 _t 2-Hethy: Un-6-obloi-17 <A / -eethoxjr-9 t 10iA; -px «gna-4 _f 6-dieu-3t20-dion _f

39 20-d ion f 7-oapxoat «

1,2-Kethylene-6-f laox-1 Tfa- hydroxoxy-9 Λ »» "· ⁰ ^ -pi * gna-416-d ien- 3r20-dion 17-oapxomt.

Also read the essential apesifisobic substances sie al · Examples τοπ act as text bindings according to the invention noob exvlhnent

1,2; 6 ₍ 7-Bieaethyl «n-17 </ v '-' bydioxy-9A, 10 <^ ~ pregna-4-en-3» 20-dione 17-aoetat,

1,2; 6,7-biaaethylene-6c (/ - chlox-17 <# -bydxoxy-9 / J " ¹⁰ ^ -P""gna-4- • n-5f20-dione 17 aoetat,

en-3 »20-dione 17-aoetat,

1 _f 2-Kethylene-6,6-diflttor-17 ^ -hydxoxy-9 / i> $ 10 <^ - pxegna-4-en- 3,20-dione 17-acetate,

1 _r 2-M «th] rleii-6-obloz-17 ^ -20 ^ -dihydroxy-9 ^, 10 (Hi-pxegna-4 _f 6-dien- 3 "on 17-aootatt

1,2-methylene-6 »flaox-17 ^, 20 / Q) -dihydroxy-9 ^ , 10X - piegna-4,6 - <! Ien- 3-on 17 aeetatc

109838/1698

PHI.4567.

1,2-Μβ thyl «n-6-fluoro-17 ά), 20 $ -d ibydzoxy-9ft ₍ 10 </ y-pr« gna-4,6-di * n-3-one 17, 20-diac ·did, 1,2-l! I * hyltn-6-ohloi-17 <^, 2Oß -dihydzoxy "9 / i _t 10 $ - pz" gna-4,6-d itn-3-on 17 "20-diac" tat ,

3,20-dione 17 "ae" tat ₍ 1 _f 2-methylene «3-tthoaEy-6-.ohloz-17 ^" - bydroxy-9A * 3 _e 5-di «n-2O-one 17-acetate,

3,5-di «n-2O-one 17 acetate, 6-chloro-3,174 / -dihydzoxy-1,2-eethylene-9 / |) * 10rf / -pz * gna-4,6'-di € n-20-on 3 »17-di * o * tat, S «ehl3x«> 3 / ^ t 17Λ "2θΛ-1 . _: 20-tziao «did

4,6-dies-3f 17 »20-tziaoetat,

4 _? 6-diea-3,20-dione 17-aoetate,

3t20-dione,

1,2-Mithyl «n-6-ntto * -170l / -eethosy-96, 10ii / -psegBa-4,6-dlen-3f 20-dione, 1,2-M · tbyIen-6-flucs-17 <* -piopöxy-9 ^, 10οί; -p »* gna-4, 6-i ie» -3,20-άion, 1,2-M · thylea-6-obloi-17 oC ^ -päopaxy-9/4, 10 «6 -p ** gna -4,6-4ien-3,2O-ion

lfidez «inteztseante Yexbindungen naoh d« z Br find mg sinds 1, a-Mtthylta-ift -fluoz-17oί '-Siya «oxy-9 / i · 10 s6-17-ao« tat ₍

109838/1

PHI.4567

17-acetate,

1 _f 2-methylea-6β-chloro-176 "-hydroxy- ^""10 ^ -pr« gna-4-en-3 _f 20-dione 17-propionate,

1,2-M «thylea-6 / i-fluoz-17 <A / -hydz <« y-9ß, 10öl / -pztgn * »4-« a-3 »2Q-dione 17-propionate,

1,2-methylene-6ß-fluorine-17 <// -tetarahydiopysanyloxy-? ^ f 1O ^ -pztgn- 4- «n-3t20-dione,

1 _t 2-M «-ethylene-6 / i -chlor-neC / -tt-fczahydzopyzanyloxy-9A _t ^ f / -pregu- 4-tn-3 »20-dione,

1 _t 2-methyl «n-6ß -

17-oaproat,

17-oaproat,

1 _t 2-methyl * n-6-ohloz-17 <V-21-dihydzoxy-9Ä, 10o (/ - pzegna-4 _f 6-diene- 3,20-dione 17, 21-diac «tat,

1 _f 2-Mathyl «a-6-flaoz-17c (/ ₁ 21-dihydzoxy-9ß ♦ 10 <^ - px« gna-4,6-di «n- 3,20-dione 17, 21-diac «tat,

1,2-methylene-6,6-diohloz-17c (/ -hydzoxy-9 ß * 10o (/ - pz «gn-4- * n-3f20-dione 17 ac · tat,

1,2-Methyi6n-6-fluoz-17i ^ -hydroxy-18-ethyl-9A, 10 ^ -pzegna- 4,6-di * n-3,20-dione 17 acetate,

1,2-M * thyl * a-6-chloz-17c ^ -hydzoxy-18-B «thyl-9 / i, 10e (/ - pz« gaa- 4,6-diene-3,20-dione 17-ao * tat,

1,2-Mithyl "B-6-chloro-17 (^ - hydzoxy-18-ethyl-9 / l t 10" (/ - pz "gaa-4f6-di" n> 3 (20-dione 17-piopionate,

1 _t 2-M · methylβB-6-fl «oz-17c) / -hydzoxy-18-a * thyl-9 / i>, ΙΟβί '-pz« gaa-4,6-diene-3 _f 20-dione 17 piopionate,

109838/1698.

PHH.4567.

1,2-methylene-6-fluoro-17oi / -tetr * hydropyx »nyloxy-16-ethyl-9 ^ t 10cH / -px «gna-4,6-diene-3» 20-d ion,

1 _t 2-Hethylene-6-chlox-170 </ -tetrahydropyranyloxy-te-inethyl-o./J » 10 <& - pregna-4 _f 6-diene-3,20-dione,

i ^ -Methylene-S-chlox- ^^ - hydroxy-ie-methyl- ^ »lOo ^ -pregna- 4,6-diene-3 »20-dione 17-oaproate,

1 _t 2-.Methylene-6-fluoi- · "!? ^ -Hydxoaty-ie-methyl - ^^, 1Oö (/ - piegna- 4 _t 6-diene-3,20-dione 17-oapioate.

If the subatituent R ,, T or R ₂₁ «in« contains or represents an esterified hydroxy group, this group contains 1 to 20 carbon atoms and is preferably made up of a saturated or unsaturated, aliphatic mono-, silicon or texikaxbons, an alicyclic xarboxylic acid, a mixed aliphatic-alioylol carbonic acid, an aliphatic-aromatic carbonic acid or an aromatic carbonic acid. Examples of vexestextex hydroxyl groups are hydroxoxy groups, the bit formic acid, acetic acid, propionic acid, butyric acid, deoan carbonic acid, cyolohexylpxopionic acid, phenylpropionic acid, phenyl acetic acid, phenyloxyphenylpxopionic acid, pyloxyphenylpxopioneantionic acid, malic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, capoic Citric acid, p-Hexyloxyphenylpxopionsäuxe, Hexahydxobeoic acid, A-Cyolopentylpxopionsäuxe and ^ -cyclohexylpropionic acid are esterified

When R-- is an esterified hydroxoxy group, this is Group derived from a carboxylic acid, as mentioned above, but the acid may contain at most θ carbon atoms.

109838/1698

PHH.4567.

Suitable esterified hydroxyl groups are s.B. Acetoxy, fxopionoxy and capronoxy.

Venn R, an etherified hydroxy group β nth Ht, iet these preferably from an aliphatic, aliphatic, aliphatic or aromatic alcohol derived. Examples of etherified hydroxyl groups are ι methoxy, Aethexy, butoxy, cyolohexyloxy, beniyloxy, tetrahydiofuranylexy, Tetrahydiopyranyloxy.

If R ₁₇ denotes an indexed hydroxy group, this group is derived from an alcohol, as stated below, under the clause that the alcohol may contain axiaal 5 carbon atoms. Suitable etherified hydroxy groups are, for example, methoxy, ethoxy, propoxy and tetrahydropyranyloxy. For the sake of clarity, it should also be pointed out that the 1,2-methylene group in the compounds according to the invention occupies the β position.

The compounds according to the invention are new substances that are known from the production of similar compounds and analogous processes can be produced.

The compounds according to the invention can be produced in that a. one connection of the formula

109338/1698

FHN.45 ^ 7

vobfli Rg, R-, R ₁ ,, R ₂₁ , X and T di · roxexvlbntc have meaning, and R, «ine 3-Kato-4 ~ dehydxo-, or tin ·

3-keto-4,6-biadehydro group · 1st

■ it βinta alkylation · - or Aayliexungaaittel is banded, whereby a tex binding dex forael »

get vlxä * trobsi R ,, R ^, H-, R ₁ , which have the aforementioned meaning,

R _{17 has} the same meaning as Toxex, X ttni 7 gejie | nsaii: a double-bound Sauexstoffatoa daxatellen

odex X a Was β er at off at ois and T is a rcxcatexte Hydroxy-Gxuppe and

R ₂₁ a Wasaexatoffatom, a Fluoratoa odex a rexeatexte Hydroxoxy- Gxuppe darateilt;

b. «In« connection dex Foxaeli

109838/1698

PHI.4567

where Rg, H- and

which have the desired meaning,

R, a 3-keto-4-dehydio- odes one

3-keto-4,6-biadehydro group iat,

X and T together represent a double-bonded oxygen atom odex X a waaistoffatom and T a hydroxy group iat and H _'17 a hydroxoxy group odex a hexagonal hydroxoxy group Bit 1 with 5 carbon atoms odex a rexeetext hydroxy group with 1 to 8 carbon atoms ,

treated with an aoyliexungaaittel vixd, creating a compound the formula »

CE »- QR

is obtained, where R ₅ , Rg, R ₇ and R _{1 have} the aforementioned meaning, R _{17 has} the meaning mentioned above, X and T mean a double-bonded oxygen atom daxatellen odex X a Vaaaexatoffatoa and T a vexeatexte hydroxy group iat and OR an aoyloxy group daxatellt; o. a connection dex Formal

109838/1698

PHH.4567

wotti Rg, R ", R ₁ , and R _{17 have} the YoxcxwXhntc meaning and R, a 3-keto-4 ** dehydzo,

3-keto-4,6-bisdehydro- or a 3-OH-4,6-bisdehydro group iit and

B ₂₁ «in a hydrogen atom, a fluorine atom or a hydroxyl group, Bit an Aoyliexungsaittel is treated, creating a connection

dex forum

where Rg, R-, R ₁ , and R ₁ - have the aforementioned meaning, R, a 3-keto-4-dehydro-,

3-Ket0-4,6-bi «dehydro- odex one

3-OR'-4,6-biadehydro group,

where OR * represents an esterified hydroxoxy group, Rp _{1 is} a hydrogen atom, a Fluozatoa or an esterified hydroxoxy group and

OR represents an aoyloxy group, d. a compound dex formula

109838/1698

ΡΗϊ.4567.

where R ₁ ,, R _1. ,, R ₂₁ , X and T hold the roxezwfthntc meaning »and Rg represents a chloratoa, a fluorine atom or a methyl group, treated with an alkylation« - or aoylating agent, creating a compound of the formula »

is obtained, wherein Rg, R ₁₅ , R ₁₇ , R ₂₁ , X and T are the aforementioned

Have meaning and OR is an etherified or esterified hydroxyl group

e. a tex binding dez Foxaelt ν © ϊ5 »£ SB *

imä "£ i-is

17th

© des e

have _f

is and

109838/16 98

-JkT-

pmr.4567.

Rg a chlorate, a fluorine atom or a methyl group iat _{9 is} subjected to a 6,7-dehydrogenation reaction, woduzoh a compound of the formula

CH ₂ - R ₂₁

—-R

17th

is obtained, where Rg _f I ₁ ,,

To have meaning}

f a Y ^ EbiodUMg dez FozaeXi

, X and T the aforementioned

''. «F; '- ⁵ U- αί , ί. G

^ : T: ι? ^: "u: .4; fs: 2s

109838/1338

PHÄ.4567.

CH

17th

is obtained, wherein Rg, R _1. , R ₁₇ , R ₂₁ , X and T are the aforementioned

Have meaning and OR is an etherified or esterified hydroxyl group,

G. a compound of the formula

CH

^, R ₇ , R ₁ ,, R ₁₇ and R _{21 have} the aforementioned meaning and R, a 5-keto-4-dehydro or a

3-keto-4,6-biadehydro group is included,

a reducing agent is treated with the corresponding 20 Hydrocyan compound is obtained H. a compound of the formula

109838/1698

where R ₇ , R ₁ . and R _{17 have} the aforementioned meaning and

Rg is a hydrogen atom, a fluorine atom or a methyl group,

is treated with AgF in a solvent, whereby the corresponding

21-F connection get wild,

i. a compound of the formula

17th

^R <j7 » ^E 21» ^{X and} * ^{which have T0IeIw} ^ ^n-fc · meaning and

where R ₁

OR is a compounded * or esterified hydroxy group,

is treated with a chlorinated or fluorinated agent, creating a compound of the formula

109838/1

is obtained, where R ₁₃ , R ₁₇ ,

hold and

R ^ represents a chlorine atom or a fluorine atom,

j. a compound of the formula:

, X and Y have the aforementioned meaning

whereby

^and

Except for the combination R ₁

^voreiw * ^ ⁿ * ^e meaning »ait ₁₇ and / or R _{21 is} an esterified hydroxyl group and X and Y together represent a double-bonded oxygen atom and Rg is a hydrogen atom, a chlorine atom or a fluorine atom, is subjected to a methylation reaction, whereby a Connection of the forum

109838/1698

1?

get wixeS, where Rg, L., ^ 17 »

Have meaning

k. a text binding dez form »Is

Y the aforementioned

—-E,

where K ^ 2> ^R i7 » ^K 21 ^{5 X and Y 1} ^ ^{ia V0J! a3if9ijn} ' ^t * have meaning,

Rg a chlorine atom odex a Fiuosatoa is waä QR a vezSthezte Group back »

with a chloxite tongue, if H ^ is a chloro clay, or with a pexchlorylfluoxide, if Hg is a Fluoratoa, is treated,

whereby a compound of the formula »

109 838/16

AL ^ 3PECTHD

^CH 2 - ^B 21

get wild ^ wooei Rg * »R ^» » hateπ and

R'g eiaa 6 ₉ 6-BtGßlos-> odss 6 _e 6 1. a connection of the formula

CH

^{Ui! E} ^ ^{AEIE vorerwahn} * ^s importance

represents

- »17th

whereby

, and

which have the best meaning and

R ~ _t R ₁ ,

Rg a Wasserstoffatcm, "ine methyl-Gruppa or a fluorine atom iat _f s β with Trimethylamine luxe strength and is then treated with a Alkalimetallaoetat, woduroh the corresponding 21-Aoetat compound is obtained, m., A compound of the Formeis

38/1698

CH

H.,

CH ₀ - Ό - C - CH,

ι 2 π 5

C- O

- Ε

17th

where R ₇ , R ₁ , and R _{17 have} the meanings already given and Rg is a hydrogen atom, a Fluoratoa or a methyl group, is hydrolyzed, whereby the corresponding 21-OH compound is obtained, n. a compound of the formula »

17th

Shark

where R--, R-ιγ » ^R pi * * ^and ^ ^the ^ ^eiei * ^e given meaning and Hai have a chlorine atom or a fluoxatoa iat, is catalytically hydrolyzed, creating a compound of the formula

109838 / 1C98

Hal

• r is retained, where E ₁ ,, B ₁₇ ,

Have meaning

o. a connection of the form

, X and T and Hai die Tozezwthnte

CH

whereby

, R

₁₇ ,

, X and T have the previously mentioned meanings and

Z represents a Waeaerptoffatom, a Chlorate or a Bzoaatoa, catalytically hydrated wizd, whereby the en: «eohende 6-methyl-yez bond is obtained, p. a tie of the foraelt

109838/1698

where H ₁ , R ₁ -, H ₂₁ , X and T lift the already mentioned meaning, in the presence of a "solvent" isoezisiezt, whereby a connection of the FoxbcIs

CH,

obtained wizd, where R ₁ ,, ₁₇ to have,

q. a connection of the Fozmel

, R ₂₁ , X and T have the -roxex preferred meaning

_21st

Shark

109830/1698

where R ₁ ,, R _{17 have} the meaning already specified,

X and Y together represent a double-bonded oxygen atom odez X is a Vasaezatoffatom and Y is an esterified hydroxyl group, R _{21 is} a Waasezstoffatom, a Fluoratoa or a vezestezte Hydroxy- Group represents and Hai a Fluor- odez Cblozatom iat,

treated with a dehydrating reagent, whereby a

Compound of formula *

CH

Shark

is obtained, where R ₁ ,, R ₁ -, R ₂₁ , Hal, X and T have the redesignated meaning ·

Wezden the previously very level procedures a bia q being described accordingly. Vo to point out Litezatuzatellen this means that the procedure in question is analogous to the dez literature.

Ad a) Suitable Aoyliezungsoittal aind Kazbonafiuren, Carbon-

β-acid anhydrides, carbonic acid chlorides in the presence of a catalyst such as p-toluenesulfonesBuxe, Trifluozeaaigsäuzaanhydzid or pyridine-HCl or in the presence of an acid binder such as an organic one Base, s.B. Collidine.

You aocytosis reaction will be in the presence of a

109838/1698

Solvents such as a hydrocarbon e.g. benzene or toluene durohead.

The reaction temperature can be between room temperature and the boiling point of the solvent used «fluctuate * If the starting material of the process »a) except for the 17-OH group nooh contains one or more OH groups, these are also esterified «

The acylation reaction can be carried out by the following Procedure to be carried out »

1. A reaction with an alkyl halide or aralkyl halide in the presence of Ag-Of

2, a reaction of bihydropyran or dihydrofuran in one A weakly acidic, weakly alkaline or neutral medium.

The starting materials for process a) are available because a compound of the formula:

where R-jat ^R 21 · ^{X and Y have the aforementioned} meaning, with the exception the combination R ₂₁ »which is an esterified hydroxyl group, and

X and T represent a double bonded oxygen atom, with Birnethylsulfoxoniummethylid is reacted, whereupon in the obtained

1,2-methylene compound, the desired substituent, e.g. 6,7-CH ₂ group, a 6-Cl group, a 6-CH, group or a

66 is introduced.

109838/1698

- 25 - PEN.4567.

The aforementioned introduction of a 1 »2-methyl η group takes place faster and with higher yield if the 17-OH group present in the starting material is protected during the reaction with dimethylsulfoxonium methylide

The 17-OH group is protected by conversion into an ether group, which after completion of the reaction by hydrolysis can be conveniently removed · A suitable 17-ether group has been found to be the 17-tetrahydropyranyloxy group. This group is introduced by treating the 17-OH starting material with dihydropyran in a weakly acidic, alkaline solution or neutral medium introduced · The reaction with dihydropyran It looks particularly good in the presence of p-toxyl alcohol as a catalyst and they too are solvents. The 17-tetrapyranyloxy group can be converted into the 17-OH group by hydrolysis will. For the production of the raw materials, the Embodiments pointed out.

Ad b) The same surfactant as above under Ad A9 is indicated is applicable. If the starting material contains several hydroxyl groups «these are also awarded. Ad o) The esterification takes place with a carbon chloride chloride or anhydride in the presence of a base such as pyridine or collidine. Any hydroxy groups present in the 5- or 21-position become also esterified

Ad 4) The esterification takes place with a carbonic acid chloride or -anbydryd in the presence of a base such as pyridine or colidine. It is etherified by treatment with an alcohol in the presence of a catalytic amount of Sture or OB. Sa starting material for process d) is produced in that the

109838/1698

- 26 - PEN.4567.

speaking compound with a 3-keto oxygen atom is reduced. The reduction in the 5-QH group can be achieved by treatment with XIaBH. in methanol ocles tetrahydrofuran at low temperatures (O * C) or with LiAlH (t.QBu), take place «
β) Leading an & double bond.

The 6,7 double bond can be reversed by the following procedure «
a. by direct 6-dehydrogenation of 3-keto-A -9 / it 1Od / -steroids,

1. with substituted benzoquinones vie C1oranyI

(EJ Agnell © and aD Laubach, J.Am.Chem.Soc 82 (i960) or 2,3-Diahlos _5-f 6-dicyanobenzoquinone (Bowers "J.Am.Chem.Soc _e 8J _-. 5991 (I959) i (HJ lingold üR <5 A, Turnen Cheia. End Ind. 1962 211),

2. with MsBga & äiöxjfä (F · Sonäfeeimer c.ß «i J.Am.Cheai.Soc, 21 5932 (1953)» h _a ßüjjel: EocK; £ 9a von ^ * "- 3-enolSthes-6-haIo8texoiden with a laloges selecteda Beneoquinone such as 2,3-dichloro-59 6 «·

o "by oxidation of 3-enol8therA ⁵ " - ^:) 6-halo8teroiden with tert "or with manganese dioxide in acetic acid ι yield 6" halost®roide (K. Yasudas Chem. Pharn.Bull. 11116? (1965) end H. EIe es.Heslv.Chea.Acta 48 989 (1965). D. BuJ! Cti halogenation of an aes -Group, followed by dehydrohalogenation, where "ine 3-keto-4,6-bia"

dehydxo-6-halo connection will stop

Bit halogenation of a / V '-3-enol ether compound can be carried out with halogen such as bromine or chlorine (L.H. Knox, J. Am. Chem. Soc. 82 1230 (1960) or old H-haloimides like bromomernetimide (same literaturetelie). The halogenation

109838/1698

- 27- PHH.4567.

an A '-3-enol ester compound can also be used with halogen (H.H. Inhofen C.A. 53 456 (1959) or with N-haloimides (C. Djerassi: J. Am. Chem. Soc. 77 J827 (1959).

The dehydrogenation is preferably carried out by reaction with an organic base such as pyridine or collidine.

Ad f) Introduction of a 3-enol ether (or 3-enol ester) -Δ ⁵ ' ⁵ -

Systems

a _e by EnolverStherung a 3-Xeto-A ^ -steroidverbindungen with a Qrthoformataater in the presence of a catalyst e.g. Aetyl-OT ^- Sh of or mat and hydrogen chloride (A, Cerini oe Ber. 71 1766 (1938) or ethyl orthoformate with p-toluenesulfons & ure, (H. Gaxdi css J. Org. Chem. 27 668 (1962) and AD Cross oe »Steroids 6 I98 (1963),

b. Enolver disturbance can e.g. by laopropenyl acetate in the presence an acid catalyst such as p-toluenesulfonic acid or sulfuric acid or by S-acid anhydride in the presence of, for example, p-toluenesulfonic acid.

If the starting compound contains one or more hydrocyanic groups, these will be esterified. Ad g) A 20-keto oxygen atom ISest for example with

LiAlH. or with an alkali metal in the presence of an alcohol 4th

such as absolute ethanol or propanol-2. There a 3-keto oxygen atom is reduced under these conditions, a selective oxidation of the reduction reaction must follow, whereby the 3-OH group is oxidized to a 3-keto-oxygen atom. Suitable oxidizing agents are substituted benzoquinones such as 2,3-dichloro-5,6-dicyanobenzoquinone.

109838/1698

- 28 - PBH.4

Ad h) The reaction takes place in an a-protic solution

medium such as acetone acetonitrile. The reaction is also preferably carried out in the presence of calcium fluoride, for example the CaF ₂ forming the carrier material on which the AgF reagent is suspended. The starting material for process g) is produced by reacting a corresponding 21-CH_ compound with Jp / CaO in methanol at a temperature of about 30 ° C,

Ad i) Introduction of a 6-chlorine or 6-fluorine atom.

a. by chlorination or fluorination of an A ³ * -J-enol steroid with chlorine (LH Knoxj J.Aa.Chem.Soc. 82 1230 (1960), chlorernsteinimide or with ferchloryl fluoride (S. Nakanischi: J.Am.Chem.Soc.

5259 (1959),

b. by chlorination or fluorination of a '-3-enolester steroid with chlorine (H.H. Inhoffeni CA. 53 456 (1959) or chlorobernsteinimide (0. Djerassi * J. Am. Chem. Soc. 77 3827 (1955) or with Perchloryl fluoride (B.M. Bloom: Chem. And Ind. 1959 1317).

Ad j) Introduction of a 6,7-methylene group:

The methylenation reaction takes place with dimethylsulfoxonium methylide in the presence of an a-protic solvent.

Suitable solvents are, for example, ethers such as dioxane or tetrahydrofuran and dimethyl sulfoxide.

The reaction temperature can vary between 0 ^° C. and 80 ^° C. and is preferably 15 to 30 ° C.

The reagent is made by treating trimethylsulfoxonium iodide with a base such as an alkali hydride Presence of a solvent such as dimethyl sulfoxide produced.

109838/1698

Ad k) Suitable chlorinating agents are e.g. Chios and Chlorernsteinsureimide or N-dichlorobenzenesulfonamide. Ad 1) You reactions take place in a solvent like

a ketone e.g. acetone. The reaction temperature is preferably equal to the boiling point of the solvent used «·

Ad m) You hydrolysis is carried out under moderate circumstances

conducted in order to avoid that the substituent R _{17 is} also hydrolyzed. A good hydrolysis is possible with an alkali metal carbonate in the presence of methanol and water.

Ad.n) You catalytically · Hydrogenation is preferably with

the hydrogenation catalyst palladium, e.g. on CaCOz> SrCO ,, BaSO. or carbon is suspended. she The reaction takes place in the presence of a solvent such as an aromatic hydrocarbon e.g. benzene or toluene.

Ad o) You kmtalytische hydrogenation can with the Hydro

generation catalyst palladium are carried out, e.g. on CaCO ,, SrCO ,, BaSO. or carbon is suspended.

Sas starting material of process o), where Z is a Hydrogen atom is obtained by treating a corresponding Steroids without a 6-substituent ait Pjerolflfc and by treating the resulting 3-enamine-3,5-biedehydro-steroida with Metaldehyde in ethanol-benzene and obtained by sehydration of the J-keto-4-dehydro-6-hydroxymethyl compound obtained *

They starting materials of the process "o), wherein Z is a Chios- or Broaatom be duroh reaction, a" 3-alkoxy-5 _r 5-dien-9 ^ J, lO ^ r-eteroid "with Tetrahaloaethan" .B. Triobloraonobromomethane odex with tetrabroranethane and duroh separation of hydrogen chloride or bro «wa« er «toff from des

109838/1698

- 30 - PHH.4567.

obtained J-keto ^ -dehydro-o-trichlor (or tribromo) -methyl-9 / b, 10j) J-steroid made. The latter reaction is preferred with an alkali alkoxide in an alcohol e.g. sodium methoxide carried out in boiling methanol or with an alkaline anion changer of the Dowex-I type.

Ad 'p) The isomerization is carried out with palladium as a catalyst

carried out in a reaction medium which, inter alia, cyclohexea. Sodium acetate and absolute ethanol (solvent) contains. The reaction temperature corresponds to the boiling point of the solvent used.

Ad q) The water extraction can be done e.g. with hydrogen chloride

or hydrogen bromide in a solvent such as dioxane carried out wesdea (K ₉ Brüokneri Chem. Ber. 94 1225 (1961)). The hostilities of method q) are obtainable by the reaction of a 3-keto-A * -steroid with chromyl chloride or by the reaction of a 3-keto-i * -steroid with an organic acid such as monoperphthalic acid according to one of SrÜOknex in Chem. Bar. 94 1225 (1961) described method, wherein the corresponding 6,7-epoxide is formed, whereupon a reaction with hydrogen chloride or hydrogen fluoride takes place. Besides the above-mentioned progestative and anti-ovulatory activity, the compounds according to the invention also have strong deciduom-forming properties. The compounds are also anti-oatrogenic and are also able to maintain pregnancy and induce ovulation.

In terms of their endoorinological effectiveness, » the substances according to the invention for the following purposes

109838 / 16-9 8

- 31 - PHN.4567.

as a contraceptive to maintain pregnancy to combat habitual or threatened abortions, to combat of sterility, aone, hirsutism, dysmenorrhea, menorrhagia, Oligo- and polymenorrhea, primary and secondary amenorrhea ", Hyper- and HypomenorrhS, to combat premenatural tension and for ovulation induction.

A very important and interesting use of the preparations according to the invention is in the field of anti-fertility. The method of treatment for the use of the preparations according to the invention for anti-textile purposes does not differ in principle of the usual methods in this field.

According to the known method, combination preparations according to the invention which also contain an estrogen compound can be used should be administered daily in the form of a tablet. It is also possible, according to the sequence method, to use the combination preparation according to the invention during one part of the menstrual cycle, for example daily for five days and during another To administer an estrogenic substance during part of the cycle. The preparations according to the invention can advantageously be used in use so-called "low progestagen" treatment. After this Method, a progestative substance is administered periodically during the cycle, e.g. daily. As with this method, with who do not use estrogen, it is important to have a highly effective progestogen available to provide the strong effective preparations according to the invention have immediate advantages.

The aforementioned amount of the active substance per unit dosage of the preparation according to the invention can be as follows, depending on the anti-fertility method carried out more precisely:

109838/1698

- 32 - PHN.4567.

a. Usual anti-fertility method:

Dosage; daily administration of one tablet during the cycle. Tablet composition »0.01 to 1 mg 1 _t 2-methylene-6-fluoro-17i7V ^> , hydroxy-9 / i>» 10o (»- piegna-4 | 6-diene-3t20-dione 17-aoetat; 0.01 up to 0.1 mg.ethinyl estradiol, supplemented with carrier material and auxiliary substances up to a tablet weight of 30 to 300 mg.
b. Sequence method:

Dosage! 1. Daily administration of one tablet for five days

dea cycle
2. Daily administration of one tablet for 15 to

16 days of the cycle.
Tablet composition:

The tablet mentioned under 1) has the same composition as stated under a);
The tablet mentioned under 2) contains 0.05 to 0.1 mg mestranol,

supplemented with carrier material and auxiliary materials up to one Tablet weight from 30 to 300 mg. c. "Low progestagen" treatment:

Dosage: daily administration of one tablet during the cycle. Tablet composition: 0.001 to 0.1 mg 1 ^ -Methylene-o-fluoro-1ΊρΧ / -hydroxy-9 ß> , 10o (r-pregna-4,6-diene-3 »20-dione 17-acetate, supplemented with carrier material and excipients up to a tablet weight of 30 to 300 mg.

Instead of oral administration of the preparations, they can also be injected *

For example, an injection preparation according to the invention can be used once to be used per quarter and it contains 0.1 to 1 mg of one active compound according to the invention.

10 9 3 3 8/1698

- 33 - MiN, 4567.

The preparations according to the invention can be ' Mixture of the active substance with solid carrier material or duroh Solution or dispersion in liquid carrier material, if desired with the addition of auxiliaries such as lubricants, binders, decomposing agents, substances with a surface effect and solvents produce·

They are combination preparations according to the invention obtained in that, in addition, an endoorinologically active substance known per se, such as estrogen, is added to the substance to be misused components to be dissolved or dispersed are added

Suitable solid support material ie η for; oral preparations such as tablets and dragees are e.g. disaccharides and polysaccharides such as Saooharose, lactose, glucose, dextrose, cellulose and cellulose derivatives such as carboxylmethyl cellulose, methyl cellulose, ethyl cellulose, hydroxytethyl cellulose, hydroxypropyl cellulose, alginic acids, Salts of alginic acids and hemicelluloses such as gelaotomannan

Suitable liquid carrier materials for the injection preparations are e.g. AraohiaSl, soybean oil, olive oil and mixtures of these and similar vegetable oils, further isopropyl meristate and Ethyl oleate *

The binding agents are ζ..B. usable! Gelatin, pectin, Amylose, agar-agar, tragacanth, polyXthylene glycols, gum arabic and polyvinyl pyrolidone.

Suitable decomposition agents are e.g. Am inopeetine, Starches such as corn starch, potato starch and rice starch, formalin Casein, bentonite, silicon dioxide and ion exchangers

Al «Sliding agents and lubricants can be used, for example« Polyethylene glycols, stearic acid, salts of stearic acid such as Hagneaiua-

109838/1698

- 34 - PHN.4567.

β-tear at and aluminum te ax at.

Usable, superficially effective substances are e.g. Wetting agents such as Hatxiumdiootylsulfosucoinat, ITatiiumlauiyl-Bulfat, PolyoczyKthylenensoxbitan monolaureat, Polyoxyäthylenalkalyl-Ether and aulfatiextei Cetyloleyl alcohol.

Suitable solvents for the preparation of injection preparations are methylene chloride and benzyl alcohol.

Tablets or dragees according to the invention can e.g. are produced by the fact that the active substance in the dex exwon Amount to be mixed with solid carrier material, e.g. with a carrier material from the aforementioned ax, together with auxiliary materials such as Starch, magnesium steaxate and talc. The resulting mixture is homogenized and processed as tablets or dragees "

You can take odex Bragess tablets with you of a sugar sheath, e.g. from the following Beatand parts consists of talc, gelatin, arabic gum, potato starch, sucrose and a coloring agent. Instead of a cup of sugar another shell former can be used, e.g. ethyl cellulose and polyacrylates.

Injection fluids can be obtained, for example, by that the active substance is / are dissolved in methylene chloride Solution taken up in Arachie81 and the solvent on it is evaporated. Traffic lights and bottles are filled with dex so produced solution, sealed and finally duxoh warming 120 * C sterilized for a certain time.

More details dex composition dex preparations according to the invention will emerge from the exemplary embodiments.

109838/1698

- 35 - PEM.4567.

Execution examples ι

!. Manufacture of 1 ^ -Methylene-o-chloro - ^. X-hydroxy ^ / g, 10o (-pregna-4 , 6-d ien-3 »20-d ion 17-acetate ·

In a Stickstoffatmoapltre at a temperature of -2O ^e C is added a solution of 10.1 ml and 67 ml of methylene chloride Chromohlorid an efficient geröhrten, cooled to -20 ^e C solution of 6 g of 1,2-methylene-17ö (hydroxy-9 / 6, 100C -pregna- ^ ö-diene-3,20-dione 17-acetate in 280 ml of methylene chloride was added After a reaction time of 2.5 hours, the reaction mixture is converted into a solution of 43 g of sodium acetate and 75 g of sodium bisulfite in 1 Litex water is poured out and then extracted with methylene chloride and ethyl acetate. The organic extract is washed with water and dried over sodium sulfate, whereupon the solvent is evaporated and the residue is chromatographed on silica gel. The 6-chloro-7-hydroxy compound obtained is dissolved in 23 ml of dry dioxane are dissolved and treated for three hours with 19 ml of dioxane containing 23 mg of HCl / ml. The reaction mixture is diluted with water, extracted with methylene chloride, then neutralized and dried, whereupon the solvent is evaporated ampft and the remainder is chromatographed. Recrystallization gives pure 1,2-methylene-6-chloro-17 ° (-hydroxy-9/4), 10 csi-pregna-4,6-dien-3 »20-d ion 17- ^a ° etat. Melting point 243 to 244 ^C C.

2. Manufacture of 1.2; 6 _t 7-biamethylene-6-chloro-17o <-hydroxy-9y5, 10 ^ -pregna-4-en-3,20-dione 17 acetate.

a) 1,2-methylene-6-chloro-17o (-hydroxy-9 / ^, 10 <\ - pregna -

4,6-diene-3,20-dione.

11.5 g of 1,2-methylene-6-chloro-17O (-hydroxy-9 / o, pregna-4,6-diene-3 »20-dione 17-acetate is a solution of

109838/1698

11 2 sodium storage oxate in 1100 al 0.5H methanol sodium hydroxide solution added. The mixture is stirred for 1 hour for a period of 1 hour with a nitrogenate bosphorus at low temperature, then poured into Waesex and then extracted with ethylene oxide. Dex extract is washed with water and dried over sodium sulfate, whereupon the solvent vapor and bedding and chromatography are uniformly expanded c 6 g! 10oi-piegn «- 4,6-aie-n-3f20-äion, Scheelzpunkt 219 IjIb 219,5 * C Ii) Eise LSeung τοη Diaethyleulfoioniuaaethylid, daditreh hold iat that 5 g Tiifflethylaulfoxonixaajodid has a 100 ml. 1 * 35 S Binethylaulfoxyd reacts with vixd, vixd a solution of 5 β dei untex a). Partial binding in 100 al Diaethylaulfoxyd irritated "The Geaiach is in" inex StickatoffatnoBphSie for one hour "with Ziasextempexatvii and poured out in Eiswaexa. Sas Geaiseh νίτδ ait ethylan chloride estiahiert and the extract is _{washed in sequence ait O 4} IK HaOH solution and water. The extract is then dried and the solvent is evaporated off. The crude 1,2 »6 _f 7-bisfflethylene-6-cl] lor-17 <> C-hydroxy- ₉ 10 ° C-pregn-4-en-3,20 obtained -djon can be used for

the next subsequent heating stage can be used.

The tendon point of the pure Sioff is 230 to 231 _# 5 * C.

c) 5f2 g de. "5 voifiTwälnte" Healriionspxodulctee vird in 50 al Eaaigafiure and G ml EsvienSuiGnifrydria fol (5at. Sach Z-uraiz of 2.5 £ p-Toluf-nsull'onnRui " vir6 dar · Itoaktionsgr one hour left. vg l'ci Linmertfi ^ peTeim f xiU'ii ,, on it ii?

Eiswaaaei trained t and then r.ii Mail-j l ^ neljlrra ·! c- »tra * -f« · -

f ":? H

- 57 - PHN.4567.

The extract is washed in sequence with water, water with a small addition of pyridine, 2N sulfuric acid, water, sodium bicarbonate solution and water.After drying the extract over sodium sulfate, the solvent is evaporated off and the residue is chromatographed on silica gel. Crystallization gives pure 1 _t 2} 6,7-bismethylene-6-chloro-17o <-hydroxy-9 / ,, 10 <X-pregn-4-en-5,20-dione 17-acetate; Melting point 205 tie 205 ⁰ C.

5. Preparation of 1,2j6,7-bismethylene-17 <* -hydroxy-9 / & _$ 10 <* -pregn-4-en-5 »20-dione 17 ~ acetate.

a) 1,2-methylene-17oc-hydroxy-9/3, 10o4-pregna-4,6-diene-5f20-dioa. A reaction mixture of 15 to 5 g of trimethylsulfoxonium

iodide and 5.18 g of sodium hydride (50 % oil suspension) in 150 ml of dimethyl sulfoxide is filtered and a solution of 15.5 g of 17oi -hydroxy-9/5, 10o (-pregna-1,4,6-triene-5 » 20-dione in 500 ml dimethyl sulfoxide is added. The mixture obtained is stirred in a nitrogen atmosphere at room temperature for 5.5 hours and then poured into ice water and extracted with benzene ether. After processing, the above-mentioned substance is obtained practically pure by recrystallization ^e C.

b) A solution of 4 S of the compound given under a)

in 50 ml of diethyl sulfoxide is a solution of dimethyl sulfoxonium methylide added, which the latter is obtained by the fact that 6.2 g triaethylsulfoxonium iodide with 0.95 8 sodium hydride (50 $> oil suspension) is reacted in 28 ml of dimethyl sulfoxide.

The reaction mixture is left for 70 hours at room temperature

and then processed using the usual procedures.

10983 8/1698

- 38 - PHN.1567.

After chromatography on silica gel, pure 1,2; 6 _f 7-bismethylene-17: x -hydroxy-9 4 ,, 10c <"pregn-4-en-3,20-dione" is obtained on the basis of the example 2o specified manner in 1,2; 6,7-bismethylene-17o <. -hydroxy-9/3, 10o <-pregn-4-en-5 _f 20-dione 17-acetate is converted. Melting point 274 to 2J6 * C. 4. Preparation of 1 _f 2-Methyleu-6-fluoi-17 <y-hydroxy-9 / ä, 10o (, - pregn-4-en-3 »20-dione 17-acetate.

a) 1 ^ -Methylene-ncfc-hydroxy -? / ^, 10 <X-pr * gn-4-en-3 »2Q-dione 17-acetate.

3f7 β 1,2-methylene-17 <X -hydroxy-9/3, 10 oi-pregna-4,6-diene-3,20-dione is added to a hydrogenation mixture consisting of 370 mg of palladium from CaCO ₂ . consists in 37 ml of toluene. After the theoretical amount of hydrogen, the reaction mixture is filtered, and the solvent is evaporated off · The remainder is umkxistallisiertt yield 95 f ° pure 1,2-methylene-17 ° <-hydroxy-9 / $, 10c ^ pregn-4-en -3t20-dione 17-acetate. Melting point 205 to 205.5 ^e C

b) A solution of 5 B of the substance mentioned under a) in 120 ml of acetic anhydride is added after adding 5 g of p-toluene s ul fön alt ure kept at room temperature for 24 hours

The reaction mixture is then poured into water and

the precipitate is filtered off · After recrystallization the raw product becomes pure 1 ^ -Hethylene-StHoi-dintfroxy-g / if »

10o ^ -pregna-3,5-dien-20-on 3t17-di ^a oet ** received.

Melting point 118 to 119 "C.

o) Perchloryl fluoride is converted into a solution of 4 »9 β <ä · * under b) specified compound in 250 ml of dioxane and 50 al of water

109838/1698

g * leite * ,, Srnch ei-nei Be »lctloii * a« it τοπ 2 hours Is none ÄuagMignsaiaiial aehi voilimnäeu · Sas Bemkiionagaroiacla vizfl on top «Is · you«! · Lang sezfhzi, vlhzani 5ticket © ff ivzcflgalaifef viii. Lach daa Znamts το "Waasaz viTd dft · BeaktionaaTaaiaob old Jtothylanchloiid« ztzafaiazt and the Eatiakt · vary in consequence old Waesai, Satiioniiicai ^ oiiAtloBung «na ¥ a8S« z waxed. Dax extract wild dana öbei Maiiiunaulfat gatiocknet, äaa wild abjgadaasprt and dax Seatlieatand vlid Xriatalliaiazan «läefazt iaiu * a 1,2-« · * ^

-pz «f» -4-Hia-3 »20-di © n 1? -acat ** ·

τ ε ine »1,2-» itliyl «i 5,20-dione 17-acatati »On 1.2Mtl

4.2% aetbyloittioforxate and 160 sig p-toluansulfosafluza are found in a solution of 4 »8 S 1 # 2-MBtbylen-iS-fliioz-17ai-hydzoxy- 9 / £>» 10 (-pzagii-4-eij-3 _f 2O-aiCB 17-acetate in 90 nl tzocknea Diexan added

Baa mixture wild Zisraezteapezatuz was kept in the dark for 20 hours. After cooling the Gamiachee to 0 * C wezdsn added in the healing sequence »150 ml ice-cold acetone, solution τοπ 1.7 g Matziraaeetat in 17 al Vassaz, 4 * ¹¹ ga> Bzoabeznatainimiä and 1.5 al gum vinegar, the eznaltana mixture is 50 minutes long bsi C * C given, in vassez auegöttes and then with Metlaylanobloxiä eitiabiezt, Ilez Eitiakt wizd in Beibasiclga with ¥ aasei, tinex LSaung tone 5aOH in fcaaaei and v / nasal ge vas even »before the Ext dew-dried and then

1 ü 9: .'- '/ 1 6 9 8

- 40 - HiN.4567

is evaporated medium · Sex Restbeetand is taken up in 20 ml of pyridine and 45 minutes to 90 ^e C heated. After working up and purifying the chromatography, the result is pure 1 _f 2-methylene-6-fluoro-17c> (-hydroxy-9 Ä, 10 o (~ pregna-4,6-diene-3,20-dione 17 ~ acetate. Melting point 249 "to 251 ^e C.

The latter product is also achieved by 1 _f 2-methylene-6öi -fluor-17 «<-hydroxy-9 /6, 10o <-prβgn-4-en-3t20-

17-acetate taken up in dioxane / HCl and then 16 minutes long reacted with 2,3-dichloro-5 »6-dicyanobenzoquinone in dioxane / HCl

r becomes (130 mg HCl / ml dioxane).

The product is also obtained from a solution of 1,2-methylene-6-fluoro-17o ^ -hydroxy-9 / ^ »10o £ -pregn-4-en-3» 20-dione 17-acetate in dry dioxane treated with ethyl orthoformate and p-toluenesulfonic acid and the 3-ethoxy-3 »5-kisdehydro compound obtained is _{reacted with MnO 2} in acetic acid for three hours.

6. Production of 1 ^ -Methylene-ö-methyl-i7 <X -hydroxy-9 ^, 10 ^ - pregna-4,6-diene-3 »20-dione 17-acetate.

ka) 1,2-methylene-17c <-hydroxy-9 / ^ _t 10 o (-pregn-4-en-3,20-aion,

3 »7 g of 1,2-methylene-17 ° <-hydroxy-9 / ^, 10 o <-pregna-4,6-diene-3» 20-dione is added to a hydrogenation mixture consisting of 370 mg of palladium on CaCO, consists in 37 ml of toluene. After the theoretical amount of hydrogen has been absorbed, the reaction mixture is filtered and the solvent is then evaporated. The remainder is recrystallized. Yield 95 2 & pure 1,2-methylene-17iX-hydroxy-9 6 _t 10 ^ -pregn-4-en-3.20 -dion.

1 0 9F33 / 18 98

- 41 - Pffii. 4567.

b) 1,2-methylene-6- (3iohlor-methylen-17o (-hydrox-9/5, 10 tfpregn-4-en-3 »20-dione.

2.3 ml of ethyl orthoformate and 52 mg of p-toluenesulfonic acid are added to a solution of 3.7 8 of the compound mentioned under a) in 52 ml of dry dioxane, whereupon the mixture is kept in the dark for 27 hours. Then 1.5 ml of pyridine and 5.5 ml of trichloroboramethane are added and the whole is exposed to daylight for seven days. The reaction mixture is filtered, the filtrate is diluted with 500 ml of 2N ECl solution, extracted and the extract is washed in sequence with water, sodium bicarbonate solution and water. After drying over silica gel, the solvent is evaporated off. The remainder consists of 1,2-methylene "-6-» trichloromethyl-17 '^ - hydrox-9 / <i »10 oC-pregn-4-en-3,20-d ion.

c) 3 ß 1,2-ethylene-6-trichlo2methyl-17 ° ^ -hydroxy-9yö, 10ol-'p * 6gn ~ 4-eR-3 '20-äioa is added to a chromium (II) chloride solution which This is obtained by reacting 15 g of chromium ( III ) chloride and 12 g of zinc in 105 ml of ethanol and 22.5 ml of hydrochloric acid. The mixture is stirred at room temperature in a nitrogen atmosphere for 45 minutes, then poured into water and then poured out extracted with methylene chloride. The extract is washed with water, sodium bicarbonate solution and water in sequence and then dried. After the solvent has evaporated, the residue is chromatographed and then crystallized. Auebeut «! xeinee 1

9 Ä , 10i> C-p3? Egn-4- «n-3 # 20-diontr

109838/1698

- 42 - RIN.4567.

d) 1,2-methylene-6-o3thy3.-17X "hydroxy" 9 / £, 10 o (-piregRa "

4 »6-d iers-3» 20-d ion.

0.5 g of palladium on carbon is added in a nitrogen atmosphere to a boiling, thoroughly stirred solution of 2.5 g of the previously mentioned compound and 2.5 g of sodium acetate in absolute ethanol. A 1 $ solution of cyclohezene in ethanol is added to the mixture at a dosage of 6 ml / hour. After a reaction time of about 5 hours, the Auagengsmaterial is converted into the 6-Methyl-VcEbiaduRg (ü.V.-Meeeusgen). The reaction gcmiseh vlvä then filtered and diluted with water _f * / 03? E, filtered off on the precipitate and dried ¥ ird _e Itech chromatographic purification irnä dareuffolecRfle lü? letalliEie2rtiriO wisd reince 1,2-methylene-6 · = estljyl ^ 'i 7 Oi ■ = E3yöEO2y-9/6 _t 10 c <= p £ GCHe = 4 ₁ Cd ic n «3,20-dion e» halteη _e g) B & e UHi) OE d) mentioned product virö on dio in Aije- =

filliSöHgstfGlspisI 2o fecEGhEict'Oiia way esterified in 1 _f 2 --- MsthylGn = 6-kgthyl «= 1 T ck -h3fd £ oxy ~ 9 y ^» 10 c ^ «= picgHa-4 _r 6-dicn ~ 3» 20 «Dion

KcsstQlli5se νοϊϊ 1 _s 2-KQtIi5 ^r lcii ° 6-acthyI- »17Oi-hy (3iö3ry-9 / i · f 10 c <^» d ion 1 Y-otprocit, -

£ U »eebGic <j> i..cl 6d & figcgcbetic Piodukt vr in ciasm GoEioeli from Csprcr-ivy uüö
solvedj woseaf the GiSEiEC = Ji iü for 45 minutes at 60 ^e C ciuSriai \: £ red _t Hfeoh Ve »thinntftß rsi ViassQK fe'isd the Gßn ^ G oxtEßhiCEi £ iii KotbylGUQhloifiö Ufid extract wisd in Reilion Successc? _e 5 $ Katuiumbioasbon & i solution usa water gov & £ <chc » _c D & s LöevaieeKitlcl wixö äajfüuf evaporated imü üqz SsBiböeteiicl vii-ö ohsoivriloeüaphiert« H & öh

109838/18 δ S

- 43 - KIN.456 ?.

Crystallization results in pure 1 ^ -methylene-o-methyl-17o4-hydroxy-9 / £ , 10 o <-pregna-4,6-diene-3,20-dione 17 ~ caproate.

8. Production of 1 ^ -Methylene-Hof -hydroxy-9/3, 1Ocx? -Pregna-4 _f 6-diene-3,20-dione 17-caproate.

1 _t 2-methylane »6-fluoi-17o (-hydioxy-9/6, 10q (-pregna-4,6-diene-3,20-dione-17-acetate (see Example 5) wildly on that given in Example 2a It is hydrolyzed in 1,2-methylene-6-fluoro-17 (X-hydroxy-9/6, 10 o (~ pregna-4,6-die n-3 «20-dione. The latter compound is then hydrolyzed with caproic acid esterified by the orphan specified in Example 7, 1 _f 2-methylane-6-fluoro-17e * -hydroxy-9 / ^, 10o (-pi9gna-4 _t 6-diene-3 »20-aion ■ 17-caproate obtained In a similar manner, 1 ^ -methylene-o-fluoro-1Tp ^ -hydroxy-9 Δ, 10 c ^ -pregna-4,6-diene-3 _f 20-dione 17-propionate with melting point 179 to 1B0 ° C manufactured.

9. Preparation of 6-chloro-17o (-hydroxy-9 k , 10 o <-pregna-4,6-diene-3,20-dione 17-acetate.

a) A stirred solution of 4 g of 3 »17» X -dihydroxy-1,2-

methylene-9yS% 10o (-pregna-5 3 _{t-dien-20-one} 3 _f 17-diacetate (see Example 4) in 75 ml of ether are at G ° C a solution of 7.5 E of potassium acetate in 175 nil of acetic acid and 30 ml water and a solution of 1.1 Sq-chloro added in 14 ml of acetic acid. After stirring at 0 ⁰ C wShrend 30 minutes, the mixture is worked up, poured into water and extracted with ether. the ether extract is in sequence with water, 5 Washed sodium bicarbonate solution and water. After drying and evaporative drying, the product is chromatographed over silica gel and then crystallized. This yields pure 6 / i-chloro-17 o <hydroxy-1,2-methylfin-9/5. 10 ^ -pregn-4- en-3 _f 20-dione 17-acetate.

1 0 9 B 3 8/1 6 9 8

- 44 - PM.4567.

Melting point 222.5 to 223 ° C.

b) A solution of 2 g of 6 A ₁ -chloro-17 oC-hydroxy-1 _t 2-methylene-9 / &, 10o (-pregn-4-en-3 # 20-dione 17-acetate in 35 ml dry dioxane 1.9 ml of ethyl orthoformate and 0.075 g of p-toluenesulfonic acid are added and the solution is kept in the dark for 20 hours (-pregna-3,5 ™ dien-20-one 17-acetate is suitable for the next step without further purification.

c) The solution of the 6-chloro-3-a "thoxy- obtained under b)

T ld \ -hydroxy-1,2-methylen-9 / i * 10 ^ -pregna-3,5-en-20-one 17-acetate is added to a stirred suspension of 12 g of manganese dioxide in 100 ml of acetic acid and 12 ml of water . The mixture is filtered after one hour and the filtrate concentrated in vacuo. The residue is dissolved in methylene chloride and the solution is washed in sequence with water, 5 i ° sodium bicarbonate solution and water * After drying and evaporating dry, the residue is chromatographed and pure 6-chloro-17o (-hydroxy-1,2-methylene is obtained -9/5 , 1O ¹ X-pregna-4,6-diene-3,20-dione 17-acetate, melting point 244 to 245 ° C.

10. Manufacture of 6-chloro-3,17o (-dihydroxy-1,2-methylene-9 / ^, 10c <pregna-4,6-dien-20-one 3 »17-diacetate.

a) A stirred solution of 1 g of 6-chloro-17o <-hydroxy-1 _f 2-methylene-9 / S, 10oC-pregna-4 »6-diene-3 # 20-dione 17-» acetate in a mixture of 20 ml of absolute dioxane and 57 ^"1 I absolute ethanol is slowly added dropwise a solution of 675» g of sodium borohydride in 10 ml water at 0 ⁰ C. Naoh half an hour is sexsetzt the excess sodium borohydride with acetic acid and the reaction mixture is poured into water. the

10983Ö / 1C98

- 45 - PHK. «67.

VJasserschicht is extracted with 3 ^ 100 ml of methylene chloride and the organic layer is washed neutral with water. After drying and filtering, the solvent is distilled off under reduced pressure and the rust base is chsoma-feogsaphisrt over SiXieagel. The final result is 6-Ghlos-3, 17 "* -dihydroxy-1, S-mathylen-S? A, 10 o {-pr0gna ° '4 _r 6-di6n-2O-one 17-acetate.

b) 710 mg of the compound thus obtained is in a

Dissolved mixture of 5 nil absolute pyridine and 2 ml acetic anhydride. After 24 hours at room temperature, the reaction mixture is worked up by adding ice and pouring it out in V / as38r and shaking it out with methylene chloride. The organic layer is washed neutral with 5% sodium bicarbonate solution and water. After drying and drying, the residue obtained is chromatographed on silica gel. Yields 6 ~ chloro-5 »17 ^ -dihydroxy-1,2-methylene-9/6» 10 ^ -pregna-4,6-dien-20-one 3,17-dlacetate.

, Production of 3-ethoxy-6-fluoro-17o <f -hydroxy-1,2-methylene-9 / O, 10 iX-pregna-3,5-diene-20-on 17-acetate.

A solution of 8.8 g of 6o <(and6 / 6) fluorine-17 ° ^ -hydroxy-1,2-methylene-9 / ^, 10o ( -pregn-4-en-3,20-dione-17-acetate and ² t5 S p-toluenesulfonic acid in 165 ml of dry dioxane and 95 ml of ethyl orthoformate is stirred in a nitrogen atmosphere for 24 hours at 20 "in the dark. The reaction gas is then poured into 2 liters of petroleum ether (40 to 65 ^° C.) and 5 ml pyridine auageaohüttet and this solution is filtered over silica gel. yield »3-ethoxy-6-fluoro-17o <1 _-hydroxy-f 2-methyl" n-9 / J "10 c <3 ₁ 5-pregna-d ien-20 -on 17-ace did.

10983 8 / 1G98

12. Production of 6,6-difluoro-17 o (-hydroxy-1,2-methylene-9 Δ, 10 o (- pregn-4-en-3 »20-dione 17-acetate ·

A solution of 8.2 g of J-ethoxy-ö-fluoro- ^ o ^ -hydroxy-1,2-methylene-9 / S, 10c * -pregna-3,5 ~ dien-20-one 17-acetate in 160 ml of dry acetate is added to a solution of 4 g of dry potassium acetate in 110 ml of absolute ethanol. At ⁰ ° C., this mixture is treated with perohloryl fluoride passed through for three hours under tubes. Then nitrogen is passed through for one hour, whereupon the solid substance is filtered off and the filtrate is poured into 1500 ml Eiswaaser. The Gemisoh is extracted with methylene chloride and the extract is washed in sequence with water, 5% sodium bicarbonate solution and water. After drying over sodium sulfate, the solvent is evaporated and the residue is chromatographed over silica gel. Yield: pure 6,6-difluoro-17iX-hydroxy-1,2-methylene-9 / J), 10 o4-pregn-4-en-3,20-dione 17-acetate. Melting point 196 to 198 ⁰ C.

13. Manufacture of 6-ChIOr-I? ¹ * -hydroxy-1,2-methylene-9, ^ »10 ° <-

·

pregna-4,6-diene-3 »20-dione 17-piopionate.

0.35 g of 6-chloro-17o (-hydroxy-1,2-methylene -9/6, 1Oc ^ - pregna-4,6-diene-3,20-dione (see example 2a) is in a mixture of I4 ml of propionic acid and 3.5 ml Trifluoressigaäureanhydrid esterified within one hour at 6O ⁰ C. the reaction mixture is processed by pouring into water and extraction with methylene chloride after Wäaohen to neutral, after drying and Trookendampfen the extract results in a residual amount, from which, after Chromatographierung. Upper

109838/1 G98

- 47 - 2ΗΝ, 567.

Silica gel in methylene chloride-acetone mixtures and, after crystallization, pure 6-chloro-17V-hydroxy-1,2-methylene-9.6 »10 <? (- pregna-4» 6-diene-3 »20-dione 17-propionate Melting point 179 to 180 ^° C.

14 »Production of 6-fluoro-17 (X-methoxy-1,2-methylene-9'3» 10 o (-pregna-4,6-d ie n-3 »20-d ion.

A solution of 0.35 g of 6-fluorine-17o ( _b- hydroxy-1 _t 2-methylene-9 / S, 10, X -pregna-4 »6-diene-3,20-d ion in 35 ml of dimethylformamide and 17.5 ml of methyl iodide is stirred at 20 ⁰ C in the presence of 3 »5 g of silver for 70 hours. Then the solid is filtered off and the filtrate is extracted by pouring in Vasaer with methylene chloride · the extract is to neutral after Vaschen and After chromatography on silica gel, the residual beatand yields: 6-fluorine-17 <^ - methoxy-1 _t 2-methylene-9 _/ / 6 »10 oUpregna-4,6-diene-3f20-dione.

By mixing the active substance (s) in a finely divided state with solid carrier material and auxiliary substances tablets and dragees of the following composition are produced.

1098 3 8/1698

O .02 mg O .05 mg 56 .2 mg 30th .0 mg 6th .0 mg 6th .7 mg 1 .0 mg

- 48 - PEN. 4 * 567.

a) tablet:

Active substance according to the invention such as ι 1,2-methylene-6-fluoro (or 6-chloro) -17o \ .- hydroxy- ° y6,

10 ol-pregna-4,6-d ien-3,20-d ion 17-ace tat t

Ethinyl estradiol Lactose

Powdered sugar potato starch talc

Magns s iums te ar at

Total weight 100.0 mg

Tablet diameter 6.3 min. T) tablet:

Active substance according to the invention e.g. «1 ^ -Methylene-ö-fluorocoder chlorine) -17 <* - hydroxy-9/6,

10 -> {-pregna-4,6-diene-3,20-d ion 17-aoetate 0.002 mg

L & ctosa 25.0 mg

Corn starch microcrystalline cellulose Talk

Magres iums te arat

Total weight tablet diameter: 4 πιπί.

mg 6.0 mg 2.5 mg 0.5 mg 40.0 mg.

109833/1 698

Core: fabric according to the invention such as:
1 »2-methylene-6-fluoro (or 6-chloro) -17o (hydroxy-9/6

1Qo (-pregna-.4,6-aien-3,20-dione 17-acetate 0.01 mg

Mestranol 0.08 mg

Lactose 35 * 0 mg

Sucrose 15 x 0 mg

Maizest Starch 50 mg

Talc 3.9 mg

Magnesium stearate 1.0 mg

Total core weight 60.0 mg.

Peel:

Talk Sacoharoee potato starch Gelatin Arabic gum carnauba wax shellac wax dammar resin

Dragee weight: I5O.O mg

18.0 mg 71.2 mg 0.1 mg 0.3 mg 0.3 mg 0.02 mg 0.02 mg O.O3 mg 90.0 mg.

109838/1698

Claims (1)

_ 50 - HM.4567. 211G084 PATENT CLAIM 1. Compounds of the general formula where X and Y together represent a doubly bonded oxygen atom or X is hydrogen and Y is a hydroxy group or a is an esterified hydroxy group, R, a 3-keto-4-dehydro group, a 3-keto-4,6-biadehydro-, a 3-OR ¹ 3,5-bisdehydro- or 3-0R ^l _-4> 6-bisdehydro group where OR · is an etherified or an esterified hydroxy group, Rg is a hydrogen atom, a chlorine atom, a fluorine atom, a 6,6-difluoro group, a 6,6-dichloro group or a methyl group, while when Rg is a hydrogen atom, R _{7 is} a 6,7-methyl group, R _{7 is} a hydrogen atom or a 6,7-methylene group, while when R _{7 is} a 6,7-methylene group, Rg is a hydrogen atom , a chlorate or a fluorine atom and R, is a 3-keto-4-dehydro group, R _{17 is} an etherified hydroxyl group with 1 to 5 carbon atoms or an esterified hydroxyl group with 1 to 8 carbon atoms, R ₂ | is a hydrogen atom, a fluorine atom, a hydroxyl group or an esterified hydroxyl group and R .. represents a methyl or ethyl group. 2. Compounds of general form 109838/1698 PHK.4567. ?1 where R ,, Rg, R ₇ , R- | Have meaning 3 »Connections of the formula ^R ? 1 * ^{X and Y are those} specified in An8 P ^{ruch 1} 17th Shark and where Hai represents a chlorine atom or a fluorine atom, in claim 1 has the meaning given. 4. 1,2-Methylene-6-chloro-17 <7t'-hydroxy-9ii % 3,20-dione 17-acetate. 5. 1,2-methylene-6-fluoro-17oC-hydroxy - «^, 3,20-dione 17-acetate. 6. 1 ^ -Methylene-o-fluoro-i? ^ / -Hydroxy-9 ^, 10o (/ - pregna 3,20-dione 17-propionate. 7. 1 _f 2-methylene-6-chloro-17 (A ^ -hydroxy-9 ^, 10 ^ -pregna-4,6-diene-5,20 dione-17-propionate. 10983 8/1698 4 _f 6-diene-4,6 52 FEN.4567. 8.1 ^ -Methylene-o-chloro- ^ d /, -tetrahydropyranyloxy-9A, 10 <i> -pregna-4,6-d ien-3,20-d ion. 9.1 ^ -Methylene-ö-fluoro- ^ cV-tetrahydropyranyloxy ^ /?), 10 ^ </ - pregna-4,6-diene-3,20-dione. 10. 1,2-Methyien-6-fluoro-17 (A / -niethoxy-9 / ^, 10 (A / -pregna-4,6-diene-3,20-dione. 11. 1 _f 2-methylene-6-chloro-17d / -methoxy-9 $ t 10d (/ - pregna-4,6-dien-3120-d ion. 12. 1,2-methylene-6-chloro-17cM-hydroxy-9 / ⁾ 3 »10 ^ /" - pregna-4,6-dien-3 »20-d ion. 17-caproate. 13. 1,2-methyl9n-6-fluoro-17 ^ / - hydroxy-9 / J, 10j (/ - »pregna-4,6-diene-3,20-dione 14. Process for the preparation of compounds of the general formula: in which formula X and Y together represent an oxygen double bond or X is a hydrogen atom and Y is a hydroxy group or an esterified hydroxy group, R is a 3-keto-4-dehydro-, a 3-keto-4,6 -bisdehydro-, a 3-OR ^l -3 »5-biedehydro or a 3-OR'-4,6-biedehydro group, while when OR 'represents a hard or esterified hydroxyl group, Rg is a hydrogen atom , is a chlorine atom, a fluorine atom, a 6,6-dichloro group or a methyl group, while when Rg is a hydrogen atom, R- is a 6,7-methylene group, R _{7 is} a hydrogen atom or a 6,7-methylene group is, while when R _{7 is} a 6,7-methylene group, 1 0 9 B 3 B / 1 6 9 8 Rg is a hydrogen atom, a fluorine atom or a chlorine atom and Η, a 3-keto-4-dehydro group, R ₁ - represents an etherified hydroxyl group with 1 to 5 carbon atoms or an esterified hydroxyl group with 1 to 8 carbon atoms, R _{21 is} a water atom, a fluorine atom, a hydroxyl group or an esterified hydroxyl group, and R ₁ - represents a methyl or an ethyl group, characterized in that the compounds are known or known per se for the synthesis of similar compounds analogous processes are produced. 15 · method according to claim 14, characterized in that the connections are produced in that a. a «connection dtr form where R ^, R-, R ₁ -, R ₂₁ , X and Y have the meaning given in claim 14 and R, «ine 3-keto-4-dehydro-, or a« 5-keto-4,6-bied "Hydro-Gxupp" is treated with an alkylation or aoylation agent, which is a combination of the formula 109838/1698 PHIJ. Ü5 67. is obtained, where R ,, , R ₇ and R ₁ , have the aforementioned meaning, R ₁ ^ has the meaning given in claim I4, X and Y together represent an oxygen double bond or X is a hydrogen atom and Y is an esterified hydroxyl group and R _{? 1 is} a hydrogen atom, represents a fluorine atom or an esterified hydroxy group; b. a compound of the formula: where Rg, R ₇ , and R .., which have the meaning given in claim 14, R is a 3-keto-4-dehydro or a 3-keto-4,6-bitdehydro group, and X and Y together are one Oxygen double bond or X is a hydrogen atom and Y is a hydroxyl group and R _{'17 is} a hydroxyl group or an etherified hydroxyl group of 1 to 5 carbon atoms or an esterified hydroxyl group with 1 to θ carbon atoms, with a Aoylating agent is treated, whereby 109838/169 8 a compound of the formula: CH ₂ -OR "X is held, where R 1, R, R ₇ and R, .. have the aforementioned meaning, R _{17 has} the meaning given in claim 14," X and Y together represent an oxygen double bond or X a Waosc ^ aSoffatom and Y a esterified hydroxyl group and OH represents an acyloxy group, o. a compound of the formula where R ^, R ₇₁ R .., and R _{17 have} the meaning given in claim 14, R, a 3-keto, a 5-eeto-4 »6-bisdehydro or a 3-0H-4,6- is biadehydro group and R _{31 is} a hydrogen atom, a fluorine atom or a hydroxyl group, is treated with an acylating agent, whereby a compound of the formula 109338/1698 PHI !. 4 ^ 67. is obtained, wherein Rg, R, R _1, and H ₁₇ have the abovementioned meaning, IU a 3-keto-dehydro-4, a 3-KETC-4,6-bisdehydro- or a 3-OR ^l -4 , 6-biadehärdro group, where OH ^{1 is} an esterified hydroxyl group, R _{31 is} a hydrogen atom, a fluorine atom or an esterified hydroxyl group and OR ^{1 is} an acyloxy group, d. a connection of the Fozmels ^R 6 where R ₁ , R ₁ -, Rg ₁ , X and Y have the meaning given in claim 14 and Rg is a chlorine atom, a fluorine atom, a methyl group, is treated with an alkylating or acylating agent, whereby a compound of the formula » 8 ^ 0/1698 PHN.45 ^R 6 is obtained, where Rg, ^R -jx " ^R i7" ^R 21 ' ^{X and Y d} * ^{e have the} aforementioned meaning and OR represents an etherified or an esterified hydroxyl group, e. a connection of the formula CH 17th where R-J2 » ^R - | 7» ^R ? 1 ' ^{X and Y have the} meaning given in the ^ ^ns P ^{rucn 14} , R, a 3-keto-4-dehydro- or a 3-OR'-3> 5 -bisdehydro group, while OR ^{1 is} an etherified or an esterified hydroxy group and R ^ is a chlorine atom, a fluorine atom or a methyl group, is subjected to a 6,7-dehydrogenation reaction, whereby a compound of the formula 109838/1698 FHK, 4567. is obtained, where Rg, L ,, ^ 17 »R? 1 ' ^{X and Y the aforementioned} ^ ^{hn1; e} Have meaning f. a compound of the formula " - fi 17th where Ri z »^ 17» ^ 21 · ^ ^{un <} ^ ^ ^^ * ^ ^m - ^ ^ns P ^zuc ^ 14 have the meaning given, and Rg represents a chlorine atom, a fluorine atom or a methyl group, an enol ether or a Enolvereaterungareaktion is subjected, whereby a compound of the Foraelt 109838/1698 "^ 'ΡΠΝ.4567. is obtained, where Rg, Rj * » ^R -j7» ^R ? 1 * * ^and ^ ^{dit voierwfinn} * · have meaning and OR represents an esterified or an esterified hydroxyl group, g. a compound of the formula: CH ₂ - C-O 17th R ₇ , L., 7 »^? 1 ^^ ^e ^ ^m ^ ^ns P ^ru ° h ^ 4 have given meaning and R represents a 5-keto-4-dehydro or a 3-keto-4,6-bisdehydro group, with a Reducing agent is treated, whereby the corresponding 20-hydroxy compound is obtained, h. a combination of form where R- R ^, and R ^ _ have the meaning given in claim I4 and Rg is a hydrogen atom, a fluorine atom or a methyl group is treated with AgF in a solvent, whereby the corresponding «21-F compound is obtained, 109838/1 698 ΡΗΐϊ.4507. i. a compound of the formula: where R-JZt ^R i7 »^ ?! ' ^{X and Y have the} meaning given in Ans P ^ruch ^ 4 and OR is an etherified or an esterified hydroxyl group, is treated with a chlorinating or fluorinating agent, whereby a compound of the formula » * ^ 17 » ^R P1 ' ^{X unii Y the ν0ΓβΓν} ^ ^ηη * ^β meaning is obtained, where and Rg represents a chlorine atom or a fluorine atom) j. a compound of the formula » 10 9 838/1698 where R.JZ * ^ 17 » ³ 21 * ^ ^{UKd Y d} * ^{e have the meaning given in the} ΑηΒ Ρ ^ϊ00 ^ ^j 4» with the exception of the combination R ₁₇ and / or R ^ ₁ an esterified Hydroay group and X and Y together represent an oxygen double bond and Rg is a Waasstoffatom, a chlorine atom, a fluorine atom, is subjected to a methylenation reaction, whereby a compound of the formula? ^CH 2 - ^H 21 is obtained, where Rg, j Have meaning k. a compound of the formula t ^ 7 » ^R pi ^f t ^R i7 » ^R 21 ' ^{X and Y the} Be given in ^ ⁿ⁸ P ^{ruon 1 4} have meaning, Rg a chlorine atom or a fluorine atom iat and OR represents an etherified hydoxy group, with a chlorinating agent when Rg is a chlorine atom, or with a perohloryl fluoride 109838/1698 PHN.4567. treated wixd when Hg represents a fluorine atom, whereby a Compound of the formula « 1? is obtained, where R ", L", R ₂₁ , X and Y have the aforementioned meaning and Rg * represents a 6,6, -dichloro or a 6,6-difluoro group. A compound of the formula --R ■ 17 where R-, R ₁ , and R .._ have the meaning given in claim 14 and Rg is a water atom, a methyl group or a fluorine atom, treated with triethylaraineasigaSure and then with an alkali metal acetate, whereby the corresponding 21 »acetate Compound is obtained, m, a compound of the formula 109838/1698 ran.4567- CH CH, - O - C - CH_ 'if 2 C-O Λ 17th where R and have the meaning given in claim 14 » and Rg is a hydrogen atom, a fluorine atom or a methyl group, is hydrolyzed to give the corresponding 21-OH compound,
n. a compound of the formula » 17th Shark where R-ITf ^ 17 »^ 21 * * ^unc * ^ ^ * ⁶ *" ^m Anapruah ^ 4 have the meaning given and Hal is a chlorine atom or a fluorine atom, is catalytically hydrogenated, whereby a compound of the formula 10 9 8 3 8/1693 FHN. 456 '.'. CH "- CH 17th Hal is obtained, where E. ,, ^B -j7 »^ 21 * ^ ^and ^ ^and Have meaning o. a compound of the formula » where R ₁ Zt RJ ₇ S Π _? · Ι * X and Y have the meaning given in claim 14 and Z represents a hydrogen atom, a chlorine atom or a bromine atom, is catalytically hydrogenated, whereby the corresponding 6-methyl compound is obtained, p «a compound of the formula: 109838 / 1G98 6 p 17th where R ₁ I * ^H i7 » ^R 21 ' ^{X and Y have the} meaning given in Ans P ^rtl0 ^ ^ 4 is isomexisiext in the presence of a solvent, whereby a compound of the formula» - -R 17th GH, is obtained, where R ,,, ^ 17 » ^R ? 1 ' to have, q. a connection of the Foraelt ^the VOJJJwnte meaning 17th OH Shark 109838/1 - 66 - PHR.4P67. where R-] ι »R _{17 have} the meaning given in claim I4, X and Y together represent an oxygen double bond or X is a hydrogen atom and Y is an esterified hydroxy group, R _{21 is} a hydrogen atom, a fluorine atom or an esterified hydroxy Represents a group and Hai is a fluorine atom or a chlorine atom, is treated with a dehydrating reagent, whereby a compound of the formula * is obtained, where R ₁ ,, Rj ₇ »R? i» **** ■ » ^{x and Y have the} aforementioned meaning. 16 * Method according to claim I4 or 15, characterized in that a Connection of formalt where R ,, R ^, R ₇ , R ₁₇ , R ₂₁ * X and Y have the meaning given in claim I4 is prepared. 109838/1698 - 67 - PHR.4567. 17. The method according to claim I4 or 15, characterized in that a compound of the formula: BaI is prepared, wherein Hal represents a chlorine atom or a fluorine atom and R _{17 has} the meaning given in claim 14. 1Θ, method according to claim I4 or I5, characterized in that 1 _{t of} 2-methylene-6-chloro-17 ^ / - hydro3cy-9.1, 100 ^ -pregna-4,6-diene-3,20-dione 17-acetate is produced will. 19. The method according to claim I4 or 15, characterized in that 1 _f 2-methylene-6-fluoro-17 G ^ -hydroxy-9 / J), 1O (Ä / -pregna-4 _t 6-diene-3.20- dion 17 * acetate is produced, 20. The method according to claim I4 or I5, characterized in that 1,2-methylene-6-fluoro-17 (^ V-hydroxy-9 / i. 19fi (/ -pregna-4,6-diene-3,20-dione 17-propionate is produced. 21. The method according to claim I4 or 15, characterized in that 1,2-methylene-6-chloro-1 TiV-hydroxy-9ft, 10 (Af-pregna-4,6-diene-5,20-dione 17-propionate is produced. 22. The method according to claim I4 or 15 »characterized in that« 1,2-methylene-6-chloro-17 ^ \ / - tetrahydropyranyloxy-9 /?), LOflt / '- pregna-4,6-diene-3,20-dione will be produced. 23. The method according to claims I4 or 15, characterized in that 1,2-Hethylene-6i-fluoro-17a / -tetrahydropyranyloxy- 9 / ί) »10 (K / -pregna-4,6-diene ^< -5 * 20-dione is produced. £ 109 ■ 38/1 G 98 PHH.4567. 24. The method according to claim 14 or 15, characterized in that 1 _t 2-methylene-6-fluoro-17dU-methoxy-9 / l), 10 <) \ / - pregna-4,6-diene-3 _r 20-dione will be produced. 25. The method according to claim I4 or 15, characterized in that 1,2-methylene-6-chloro-17i ^ -methoxy-9 / i), 10 {^ / - pregna-4,6-diene-3,20-dione will be produced. 26. The method according to claim I4 or 15, characterized in that i ^ -Methylene-ö-chloro-Hc ^ -hydroxy - «) / *) * 10o </ - pregna-4 _f 6-diene-3,20-dione 17 -caproat is made. 27. The method according to claim I4 or I5 characterized gekennzeiohne.t that 1,2-methylene-6-fluoro-17 ^ -hydroxy- ⁰ / *), 10 <M -pregna-4,6-diene-3,20- dion 17-cepioate is produced. 28. Pharmaceutical preparation characterized in that it is a Compound the formal 17th where X and Y together represent an oxygen double bond or X is a Vaeseratoffatom and Y is a hydroxyl group or a esterified hydroxy group is, R, a 3 ~ EetQ-4-dehydro-, a 3-Keto-4,6-bisd «hydro-, a 3-OR'-3,5-bisdehydro- or a 3-OR'-4,6-bisdehydro group and OR «is an etherified or a represents esterified hydro group, Rg represents a hydrogen atom Chlorine atom, a fluorine atom, a 6,6-difluoro group, a 6,6-dichloro group or a methyl group, where, when R, is a hydrogen atom 109838 / 1G98 PHN.4567. indicates that R_ is a 6,7-methylene group, R_ is a hydrogen atom or a 6,7-methylene group, while when R _{7 is} a 6,7-methylene group, Rg is a hydrogen atom, a chlorine atom or a Fluorine atom and R ,. is a 3-keto-4-dehydro group, R _{17 is} a variable hydroxy group having 1 to 5 carbon atoms or an esterified hydroxy group having 1 to θ carbon atoms, R _{1 is} a hydrogen atom, a fluorine atom, a hydroxyl group or is a variable hydroxy group and R_. _ represents a methyl or an ethyl group, as an effective component in combination with solid or liquid, inert carrier material. 17th where X and Y together represent an oxygen double bond or X is a hydrogen atom and Y is a hydroxyl group or an esterified hydroxyl group, R is a J-keto-4-dehydro- a 3-keto-4,6-bisdehydro- a 3-OR ^l -5,5-bisdehydro or a 3-0R'-4,6-bisdehydro group, and OR "represents an etherified or esterified hydroxyl group, Rg a hydrogen atom," in chlorine atom, a fluorine atom, a 6,6-dichlorine group, a 6,6-difluoro group or a methyl group 1, wlhrand, 109838/1 698 - ' ^υ - PHN.45Ö7. When Rg is a hydrogen atom, R _{7 is} a 6,7-methylene group, R _{7 is} a hydrogen atom or a 6,7-methylene group, while when R _{7 is} a 6,7-methylene group, Rg is A hydrogen atom, a chlorine atom or a fluorine atom and R 1 represents a 3-keto-4-dehydro group, R _{17 represents} an etherified hydroxyl group having 1 to 5 carbon atoms or an esterified hydroxyl group having 1 to 8 carbon atoms, Rp _{1 represents} A hydrogen atom, a fluorine atom, a hydroxyl group or an esterified hydroxyl group and R ^ - represents a methyl or an asthyl group, contains as an active substance. 30. Preparation or pharmaceutical fitting according to claim 28 or characterized in that it is also known per se Contains estrogen compound. 31. Test device according to claim 28, 29, or 30, characterized in that that there is a compound of the formula CH ₂ - R ₂₁ where R ,, Rg, R ₇ , R ₁₇ * ^R ? 1 * ^{X and} ^ ^^ ^e ^ " ^m * ^ns P ^{ruon 28} have the meaning mentioned as an active substance. 32, PrSparafc according to claim 28, 29 or 30, characterized in that dasa there is one connection of the formula 109 8 38/1698 PHN, 45 ^ 7. where Hal represents a chlorine atom or a fluorine atom and R ^ - has the meaning given in claim 28, all effective Contains substance. 33. Preparation according to claim 28, 29 or 30, characterized in that 1,2-methylene-6-chloro-17i ^{i /} -hydroxy-9 / b, 10 <JJ-pregna-4, 6-diene-3.20 -Contains dione 17-acetate as an active substance. 34. Preparation according to claim 28, 29 or 30, characterized in that it 1,2-ethylene-6-fluoro-176-hydroxy-9 / J, 10i (/ - pregna-4,6-diene-3,20-dione Contains 17-acetate as an active substance. 35. Preparation according to claim 28, 29 or 30, characterized in that it contains 1,2-methylene-6-fluoro-17 ^ -hydroxy-9 /?), · \ Θά) -pregna ^ .ö-dien-3.20 -Contains dione 17-propionate as an active substance. 36. Preparation according to claim 28, 29 or 30, characterized in that it is 1,2-methylene-6-chloro-17fl (/ - hydroxy-9 / b, 10ot / -pregna-4,6-diene-3,20-dione Contains 17-propionate as an active substance. 37. Preparation according to claim 28, 29 or 30, characterized in that it 1,2-ethylene-6-chloro-17 / ^ / - tetrahydropyranyloxy-9 / ^), 10 ^ -pregna-4,6-diene-3,20-dione Contains all active substances. 38. Preparation according to claim 28, 29 or 30, characterized in that it is 1 ^ -Methylene-o-fluoro - ^^ - tetrahydropyranyloxy ^ / l), 10cl / -pregna- 4,6-diene-3,20-dione as contains active substance. 1 0 9 B 3 B / 1 0 9 8 N.V. Philips'Gloeilampenfabrieken vtJdJtd ftf · f ■ Τ f «Τ .. w -jg. - rtn 59. The preparation according to claim 28, 29 or 30, characterized in that “it 1,2-methylene-6-fluoro-17 <fj-methoxy-9ß, 1ü ^ / - pregne-4,6-diene- Contains 3,20-dione as an active substance. 40 »Preparation according to claim 28, 29 or $ 0 daduroh characterized in that it contains 1 _t 2-methylene-6-chloro-17 ^ / -methoxy- ^ · 10 & ~ preg'na-4 ₍ 6-diene- 5,20-dione contains as an active substance » 41. Preparation according to claim 28, 29 or 30 characterized, it does 1,2-methylene-6-chloro-17d / -hydroxy-9 / ^, 1Ow-pregna-4 _t 6-diene-3,20-dione 17 -caproat a.lo contains active substance. 42. Pr Ii par at according to claim 28, 29 or 30, characterized in that it Contains 1,2-methylene-6-fluoro-17 ^ '- hydroxy-9 ^ »10i (/ - pregna-4,6-diene-3,20-dione 17-caproate as an active substance. 43 «Process for the production of a pharmacyutischeη preparation, characterized in that a compound according to one of the claims 1 to 13 mixed with solid carrier material or in liquid Carrier material is dissolved or dispersed, if desired with the addition of estrogen compounds known per se and / or Hilfastoffe. 1098 38 / 1G98