DE2023450C3 - 1,2 a-Methylen-spiroxenone, process for their production and medicinal products containing them - Google Patents

Description

The subject matter of the invention is defined in the claims.

Halogen is preferably to be understood as meaning chlorine or fluorine.

The compounds of the invention are specific androgenic agonists useful as therapeutic agents for the treatment of hy |> crandrogenic disorders are useful. They are particularly useful for treatment of acne caused by hypocrine drugs. You can use it orally, subcutaneously, or topically administered in suitable formulations. For example, a hydrophilic ointment that can be used for topical application is suitable and 5% by weight 1,2 \ - Nfethylene - 6,7.x - dichloromethylene - 20 - spirox-4-C11-3-OI1 contains in a dipropylene glycol and polyethylene glycol carrier, are prepared by the warm components are mixed and cooled. Ointments with 0.5 to 20% by weight Steroid compound.

A cream type preparation as a carrier for the active ingredient can also be prepared. A polyethylene glycol (molar weight = 200 to 3 (X)), the 6% 1,2 »-methylene-7, x-acety lthio-20-spirox-4-en-3-one contains, is mixed together with benzyl alcohol, benzyl benzate and sodium stearate. You get one translucent viscous cream. Creams of this nature can contain 3 to 20% by weight of the desired steroid getting produced.

The active compounds of the present invention can also be used in pharmaceutical compositions, like solid pieces of ointment that have been shaped into the desired shape, or lotions mixed in will. The latter can be base suspensions of the UI-in-water or water-in-oil type using non-toxic and commonly used waxes and esters.

The preparation of the compounds of the invention is illustrated by Reaction Schemes 1-4. The individual schemes explain the process variants given below as claim 2:

Kcaklionsschcnu

Va na Ii I c + Ba Aa away C. Ac Dx t- Port

Reaction scheme

(A)

CH,

cn,

CU.,

R.

(111: 0

CH ₂

CII,

ch \;

S C-CH,

(Ma)

The starting matorial according to formula scheme 1 is 20-Spirox-4.6-dicn-3-one. Connection (Λ). This connection can be prepared by the process described in US Pat. No. 3,254,074. How out This connection can be clearly seen by the oimclschcma I can be used in at least two process variants, one lühii for connection la and the others to connections 11 a and purple.

The variant leading to connection la concerns first the halomethylene subsidiary at the 6: 7-

Double bond of the connection Λ and then the approach a 1: 2 double bond in ring Λ of the resulting sleroid. The I: 2 double binching can then be substituted by a methylene group to form the compound la.

In the preparation of the compound la (1.2% -Me-Ihylen - 6.7 \ - dihalomelliylcn - 20- spirox - 4 - en - 3 - one) compound Λ (20-spirox-4,6-dien-3-one) in an organic solvent with an irhalosubstituted alkali metal acetate of the formula

X X-C -COOM

I γ

wherein M can be sodium, potassium or the like, Y is chlorine and X is the same as in formula I has implemented. The molar ratio 2> of compound A to Halogcnacctal is about From 1 to 30, preferably a 10-fold excess of halogenated carbon is used. The reaction temperature is 150 to 250 C. preferably 180 to 225 C. The implementation takes place in 1 to 5 hours, in general mean within about 2 to 3 hours.

The organic solvent can be any solvent which is present in the presence of the two Main participant is unresponsive. It is preferably freshly distilled or at least r> free of dissolved oxygen impurities. Suitable solvents include diethylene glycol dimethyl ether and triethyl glycol dimethyl ether.

The specially used trihaloalkali metal acetal depends on the identity of the substituents <to X in the 6.7 - »- halomethylene group. If you use z. B. the preferred trihalosodium acetate. so will C'hlordifiuornatriumacetat used when 6.7 \ -Difiuormethylene it is asked for. If 6.7 \ -dichloromethylcn is desired, trichlorosodium acetate is suitable. If 6.7> -Chloriluormethylene is the desired product, then dichlorofluorosodium acetal can be used.

The connection created by the implementation of (A) obtained with the halogenated sodium acelate is compound (B). 6.7 \ -dihalomethyl-20-spi- ! ox-4-en-3-one. This compound is purified according to conventional methods and can then be treated with an equivalent, molar amount up to about a 1 molar excess of 2,3-dichloro-5,6-dicyanobenzoquinone in an inert organic solvent such as benzene, xylene or toluene are reacted. After a short time To mix, the mixture is refluxed for 1 to 8 hours. After finished This is implemented in the reduction of the quinone t> o Hydroquinone secondary products formed were removed from the solution by filtration. The product. Compound C (6.7 \ - dihalomethylene - 20 - spirox-1.4-dicn-3-one), can be purified by chromatography on silica gel and treated with a suitable organic solvent5 solvents such as ether and benzene are eluted.

After purification, compound C "is added to a dimethyl sulfoxide solution of freshly prepared C'orcy-Rcagcns, namely dimethylsulfoxonium-melhy-Md or [CH ₂ = SO (C ¹ H ₁ I ₂ ] -Das Corcy Rcagcns is in an approximately 5-fold molar excess is used, although the molar ratio of compound C to Corcy reagent can be 1: 1 5. The mixture is reacted for 3 to 24 hours at ambient temperature and then deactivated by the addition of water. The product, 1,2 \ -Methylcn-6, 7 \ -dihalomethylcn-20-spirox-4-en-3-one (compound Ia) precipitates and can be purified by customary working techniques.

For the preparation of the compounds of formula la A second method can be used, see Form 2 below. Fs was found that this Another method is particularly useful when the 1.2 \ - methylene - 6.7 \ - dichloromethylcn - 20 - spirox-4-en-3-one compound it is asked for. Starting from compound A, the keto group becomes in the 3-position using sodium borohydride. Lithium tri-t-butoxy aluminum hydride or lithium aluminum hydride reduced to a hydroxyl group (compound F). This hydroxy group then becomes acylicrt. to protect them from further implementation. In an acylation process, acetic anhydride becomes used in pyridine to prepare the 3-acetoxy derivative (compound G). This latter connection is then reacted with Phcnyltrichloromethyl-mercury, resulting in the addition of the 6,7A-Dichlormklhylengruppe Do (compound H). The acyl group is then removed by hydrolysis (Compound J). Suitable Hydrolyzers are potassium carbonate or sodium hydroxide in methanol. The 3-hydroxysleroid is then oxidized to give the 3-keto substituent. The connection established in this way is 6 ^ -dichloromethylene-20-spirox-4-en-3-one (compound B). This compound can then be combined with dichlorodicyanobenzoquinone with formation of 6.7% dichloromethylene-20-spirox-1,4-dien-3-one treated: the latter can be reacted with Dimethylsulfoxoniummclhylid be to 1,2 \ -methylene-6,7 \ -dichlormethy-ten-20-spirox-4-en-3-one to manufacture. It is clear that the o ^ -Chlorftuor- and Difiuormethylcndcrivale under Use of the appropriate phenyltrihalomelhyl mercury compound can also be produced.

Reaklkmsschem-i 2

AcO-

CH,

AcO-I.

HO

IO

cn.,

(H)

CX,

CH,

CX,

/ N

CH ,,

CX,

Il

To make the connections Ha and lila according to reaction scheme I wild the compound Λ first implemented to 1,4,6-triene (compound D). Subsequently, to produce the compound H the I'-bond methylenierl. Depending on the choice of reagents, this latter compound can then be converted into the 6-position can be halogenated to form the compound IHa or with the Aeetyllhio group in the 7-position are substituted to produce the compound II a.

In the preparation of the compound II a, the starting material, compound A, with an equivalent, molar amount to about a 1 molar excess an!,. VDichlor-S.o-dicyaiioherizoehifion in one inert organic solvent implemented. After mixing briefly, the mixture will be 1 to H hours slowly refluxed. After the reaction has ended, the 2, M) chloro-5,6-diyanohydroehinone by-product is removed by filtration and the desired 1,4,6-triene by chromatography of the material remaining in the kiltral isolated.

After purification, the 1,4,6-triene (compound I)) is ^{substituted on the I 1} bond to form the 1,2 \ -methylene steroid. A solution of the freshly prepared Dimethylsulfoxoniunimelhylids [VH ₁ - SO (CH,),] in dimethyl sulfoxide is added to compound D. The Corey reagent is used in about 1 to 2-fold excess, although the molar ratio of compound I) to reagent 1: 1 5 can be. The mixture is reacted at room temperature for 3 to 24 hours and then quenched by the addition of water. The product, compound I, falls out and is cleaned according to standard work principles.

Compound K, 1,2 \ -methylene-20-spirox-4,6-dien-3-one can then be used with a 1 to 10 molar excess a peracid such as m-chlorobenzoic acid, perphthalic acid, perbenzoic acid or the like in one organic solvents (chloroform or methylene chloride are suitable). the Conversion stalls in 8 to 24 hours at room temperature. The solution is then made by adding diluted by further solvent and washed with aqueous, basic and saline solutions. To Concentration gives an oily intermediate which is the 6,7-lipoxy compound. This connection are added to a strong Ilalogenminenilic acid in a chlorinated solvent (HF or HCI in Chloroform) at room temperature for 8 to 24 hours. This is obtained after treatment with water I-x-chloromethyl-o-chloro- or -fluoro-2 () - spiro \ - ■> 4,6-diene-3-one intermediate. This material is redistilled in a suitable solvent, such as Collidine, dissolved and refluxed for 2 to 6 hours. After acidification, the solution is with extracted with a suitable solvent. From the

The extract is obtained after recrystallization i> - halo, 2 \ - methylene-20-spirox -4,6-diene -3-one. Connection purple.

Compound E can also be used to produce compound Ha. The steroid will

Γ) with a large excess of thioacetic acid (1 to 2 () molar excess) (CH., C = OSH) treated and reacted at 20 to 100 "C for 1 to 12 hours. After neutralizing the reaction mixture with an inorganic base (sodium bicarbonate is

jo) the steroid is made with an organic Solvent, such as ether, extracted. After the ether extract is dried, the steroid is through liincngcn and obtained by chromatography Purified silica gel. Compound Ha, I, 2 \ -Melhylen-

- >> 20-spirox-4-en-7-acetylthio-3-one is recrystallized from heptane.

The starting material for the process shown in reaction scheme 3 is 17 \ - (3-hydroxypropyl) -17 / i'-hydroxyandrost-4-en-3-one (Compound K). These

κι compound is with an alkyl orthoformate and an alcohol, such as methanol or ethanol, in Presence of a mineral acid reacted to form the 3-alkoxy-3,5-diene group. Methyl orthoformate and ethyiorthoformate are preferred

π reagents, although also other C,. ,, - alkyl groups may be suitable. This process leads to the creation of connection L. The latter then becomes treated with chloranil at reflux in an inert solvent, which serves to remove the compound

dehydrate in and remove the alkyl group, thereby Connection M is established. The latter is then made using the desired Trihalonalriumaeetats as described in reaction scheme 1 in the 6.7 \ position with a dihalomethylene group

r> provided. The resulting connection is conn in the H N.

Reaction scheme 3

OH

ΠΙ, ΓΗ, ΟΙ.ΟΜ

(K)

CH ₁ CH ₁ CH ₁ OH

(L)

(R ² = non-alkyl)

OH

CH, CH, CH, OH

CH ₂ CH ₂ C! 1, OH

(M)

OH

CH, CH, CH, OH

CF ₂

R ₃ O — CH, _/ CH ₂ CH ₂
V Λ cn.

(Ia)

CH, CH, CH, () H

The compound N can then with Dichlordicyanobcnzoquinone treated to create a double bond at the 1,2-position (compound P). the latter can be made with Corey's reagent of 1,2 \ -Melhylensteroid (compound Q) are implemented. t> o

Compound Q is converted to compound I a by treating the former with an alkyl or aryl sulfonyl chloride implemented in pyridine solution. Suitable reagents are toluenesulfonyl chloride or methanesulfonyl chloride. The alkyl or aryl sulfonyl chloride is added to the solution of the compound Q in pyridine solution and the solution is stirred for several hours after purging the vessel with nitrogen.

CF ₂

the temperature being kept at around 0 ° C. When the reaction has ended, water and ice are added and the precipitate formed is permeated Extraction with a suitable solvent such as ethyl acetate removed. The extract comes with immediately cold, aqueous, dilute mineral acid, such as sulfuric acid, then with water and with dilute aqueous Washed sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. That Solvent is removed by distillation under reduced pressure. The residue is! ^ - methylene - 6.7 \ - difluoroethylene - 20 - spirox -4 - cn - 3 - one, compound I a.

Ze a υ CC

Compound Q can also be converted into compound 1b by terminating with a ring oxidizing agents, e.g. B. chromic acid in acetone, and the desired 1,2 \ -methylene-6,7 \ -difluoromethylene-20-spirox-4-en-3,21-dione, Compound Ib.

The compounds of the formulas II and III can be prepared using the formula shown in formula scheme no Process are produced. The starting compound is 17 \ - (3-hydroxypropyl) -17 / j "-hydroxyandrosla-4,6-dien-3-one (Compound M of formula scheme No. 3). The double bond at C-I becomes formed by reaction with dichlorodicyanobenzoquinone to produce the compound (S) and the latter is reacted with Dimethylsulfoxoniummelhyiid to form the 1,2-methylensleroid compound (T) to manufacture.

The latter compound can then, similar to the compound E in Reaction Scheme I, sequentially with a peracid, a halogen mineral acid in a chlorinated solvent and redeslilled Collidine can be treated. The compound (V), 1,2-methylene-6-halo-17-hydroxy-17x- (3-hydroxypropyl) -androsta-4,6-dien-3-one is obtained.

Then either a ring closure with a sulfonyl chloride in pyridine or an oxidation is carried out with subsequent ring closure, the end compound HIa), 1,2-methylene-6-halo-20-spiroxa-4,6-dien-3-one is obtained accordingly or IHb 1,2 \ -Meihyien-6-halo-2ii-spirox-4,6-dicn-3,2! -ilion.

Compound T can also be used to make compounds Ha and Hb. she will substituted first with the acctylthio group at the 7-position to produce compound (U), then follows either ring closure with a sulfonyl chloride in pyridine, as above, or oxidation with subsequent Ring closure to the end compound II a, 1,2 \ -Melhylen-7-acetylthio-20-spirox-4-en-3-one or Hb, 1,2 \ -methylene-7-acetyllhio-20-spirox-4-ene 3,21-dione to manufacture accordingly.

The 3-i-olc and acyl ester of the compounds I and III can easily be made by having a of the compounds Ia, Ib, Illb or IIIa with a Reducing agents such as sodium borohydride, lithium tri-t-buloxyaluminum hydride or lithium aluminum hydride converts. This process corresponds to the reduction of compound A to compound F ", conversion scheme 2. The 3-OI compound prepared in this way can then be aylated, for example with acetic anhydride in pyridine.

The examples illustrate the invention.

Example I.
6.71) Illuminium-20-spirox-4-cn-3-one

1μ 20-Spirox-4.6-dien-3-one is dissolved in 5 cm ¹ I of triälhyleneglykoldimethylether (distilled over LiAIIl ₁ ). 6 g of chlorodilluor sodium acetate (dried) in 50 cm ^{1 of} dry triethylene glycol dimelhyl ether are added dropwise over a period of 2 hours, the reaction being carried out at 195 to 200 ° C. with constant stirring. The reaction mixture is poured onto ice and extracted with ether. The ether extracts are washed with water and dried. The crude reaction product winl over a 100: 1 silica gel colony first with benzene, then with increasing percentages • in Aiher in Benzo! eluted. The product, fi, 7 \ -Di !! iu>:

mclhylen-10-spirox- ^ en-. Von, is recrystallized from heptane and has a melting point of 130 to 132 C.

In the same way, using Diehlorfiuornodium Acelal and Trichloromalrium Acelate the 6,7 \ -Chlorlluormethylen-20-spirox-4-en-3-one and the 6,7 \ -dichloromethylene-20-spirox-4-en-3-one produced.

ίο B e i s ρ i e I 2

6,7 \ -dilluormethylene-20-spiroxa-1,4-diene-3-> n

A solution of 628 mg of 6,7 \ -difluoromelhylen-20-spirox-4-en-3-one (prepared in Example 1) in 7 ml

ii Benzene is mixed with 497 mg of 2,3-dichloro-5,6-dicyanobenzoehinone treated with stirring at room temperature. The reaction mixture is refluxed and refluxed for 4 hours under nitrogen. The solution is filtered to obtain the

> o major part of the 2,3-dichloro-5,6-dicyanohydroehinone by-product to remove.

The product is purified by passing it through a column filled with KK): I silica gel. It is increasing with benzene first and then with

> ^r > percentages of ether eluted in benzene. The eluent fractions from 5% ether to 100% ether are combined. These fractions are purified again by being sent through a column filled with 100: 1 neutral aluminum oxide.

so Schiiciilieh is eluted with ΐίΐ'Ίι ether in iknzoi.

The purified product, 6,7 \ -dilluormethylene-2 () - spirox-l, 4-dien-3-one, is recrystallized from heptane and has a melting point of 149 to 153 C.

When using 6.7 \ -Chlorlluormelhylen-

j ^r > 20-spirox-4-en-3-one and fi, 7 \ -dichloromelhylen-2 () - spirox-4-en-3-one, prepared as in Examples 1 or 12, the treatment with 2 leads , 3-dichloro-5.6-dicyanobenzoehinone in an analogous process to the products: 6,7 \ -chlorofluoromethylene-20-spiiox-

■ III 1,4-dien-3-one or 6,7 \ -dichloromethylene-20-spiroxl, 4-dien-3-one.

Example 3
1.2 \ -Melhylen-6.7 \ -dilluormethvlene-

2 () - spirox-4-en-3-one

A solution of Corey reagent is prepared by adding 2.20 mg of 1 1 iniethylsulfoxoniuin iodide to a suspension of sodium hydride (40 mg of a 55% dispersion in mineral oil) in 2 ml of diethylsulfoxide. The addition is carried out at room temperature under flowing nitrogen made. After one hour, the mixture becomes clear. dissolve 100 mg 6.7 \ -l) illuornielhylen-20 Spirox-l.4-dien-3-one. prepared as in example 2, in 2 ml Dimcthylsulfoxyd. Man there is / u the Corcy reagent and let it react overnight.

Reaction mixing is deactivated (extinguished) by adding about 20 ml of water. The product stops working immediately. FIs are distilled off and washed well with water. The product is purified by passing it through a column filled with 100: 1 silica gel. First, elute with benzene. then with 5 "ci ether in benzene. 77.5 mg 1,2 \ -melhylene-ft, 7 \ -dilluormylhylcn-20-spirox-4-en-1-one. Is is recrystallized, first with Ixaii. then mil ether and petroleum ether. The melting point amounts to 155 to j ς "r ■

When using 6,7-chloromethylene-20-spirox-1,4-dien-3-one and 6,7 \ -dichloromethylene-20-spirox-1,4-dien-3-one, produced as in example 2, the treatment with Corey-Rcagcns results in one analogous process / u the products: I, 2 \ -Methylcn- ϊ 6,7 \ -chlorofluoromethylene-20-spirox-4-en-3-one or 1,2 \ -Melhylen-6,7 \ -dichloromethylene-20-spirox-4-en-3-one.

Example 4 in

20-Spi roxa-1,4,6-t rien-3-on

Kino solution of 5 g of 20-Spirox-4,6-dien-3-one in 40 ml of benzene is mixed with 3.85 g of 2,3-dichloro-5,6-dieyanobenzoehinone while stirring at room temperature acts. The mixture is brought to reflux and refluxed under nitrogen for 2.5 hours and then kept at room temperature overnight. The solution is then nitrated to the greatest part of the hydroquinone / u. When hanging the _> o Hydrats leaves a deep amber-colored oil.

This material is about 250 g of basic aluminum oxide sent. The desired trienone is eluted with 10% diethyl ether in benzene, through the first fractions of pure ether give 2 ~> 3.25 g. After recrystallization from hexane with With the aid of methylene chloride, 2.66 g of 20-spiroxa-1,46-trien-3-one with a melting point are obtained from 161 to 162 C.

Example 5
1,2 \ -methylene-20-spiroxa-4,6-dicn-3-one

A solution of Corey's reagent is prepared by adding 3.30 g of trimethylsulfoxonium iodide to a suspension of sodium hydride (from 5 ^l ), 8 mg of a 55% suspension in mineral oil, washed with pentane) in 20 ml of anhydrous dimethylsulfoxide at room temperature under protection against slipperiness. gives. After stirring for about 5 minutes, a clear solution is obtained. The steroid, 20-spiroxal, 4,6-trien-3-one (1.50 g), prepared according to the method of Example 4, is added as an alcohol substance and goes into solution very slowly. After 1.5 hours at room temperature, the mixture is deactivated (quenched) by adding 25 ml of water and stirred overnight at room temperature. It is diluted with water and nitrated and results in a light yellow residual substance. After drying in air and crystallization from methanol and then from hexane -.ti, 1,2-methyl-2-methyl-2 () -spirox-4,6-dien-3-one with a melting point of 143 to 144 ° C. is obtained

Example 6
1,2. \ - Mclhylcn-ft-clilor-2 () - spiro \ a-4,6-dien-3-on ''

Line 1 solution of 300 mg 1,2 \ -methylene-20-spiroxa-4,6-dien-3-one, prepared as in Example 5, and 660 mg of m-chloroprene / acid in 12 ml of chloroform liil.il stand overnight at room temperature. The wi solution is then diluted with methylene chloride and washed with aqueous sodium bicarbonate, water, potassium iodide, water, sodium bisulfate and then narrowed to a light yellow ΠΙ.

The Ul is dissolved in 5 ml of chloroform and poured into an ir> saturated solution of anhydrous hydrogen chloride in 5 ml of chloroform at room temperature. The mixture is sealed in a tube and left to stand at room temperature overnight. she is then treated with water and worked up, whereby about 330 mg of crude, crystalline 1 \ -Chlormethyl-o-chloro-IO-spiroxa - ^ - dienO-one receives

This material is in about 8 ml of collidine (redistillierl) dissolved and refluxed for 3 hours. Ls is on an excess of a 2.5N HCl solution poured and extracted with ether. It is worked up and concentrated and about 250 mg of crude, crystalline material is obtained Product. It is then recrystallized from methanol and 165 mg 1,2 \ -methylene-6-chloro-20-spiroxa-4,6-dien-3-one are obtained with a melting point of 170 to 172 C.

The same procedure is followed as above, except that anhydrous hydrogen fluoride is used is reacted with the TJI, and is then treated with collidine, then 1,2 \ -Melhylen-2O-spiroxa-4,6-dien-6-fluoro-3-one is obtained.

Example 7
1,2 \ -methylene-7-acelylthio-20-spirox-4-en-3-one

400 mg of the steroid 1,2 \ -Methylene-20-spiroxa-4,6-dicn-3-one prepared as in Example 5 are with 8 ml of thioacetic acid treated. The mixture is heated in a water bath to about 80 ° C. for one hour. The reaction mixture is then treated with aqueous sodium bicarbonate solution. The raw sleroid product is made with Ether extracted and dried over sodium sulfate. The solvent is removed, leaving a yellowish color Precipitation remains.

This precipitate is purified by passing it through a column containing 25 g of silica gel is filled and one elutes with ether.

The eluate fractions are recrystallized from heptane after Linengen and give pure 1,2 \ -Melhylen-7-acetyllhio-2 () - spirox-4-en-3-one with a melting point of 201 to 209 C.

Example 8
3 · I hydroxy-20-spiroxa-4,6-diene

2.0 g of 2 () - spiroxa-4,6-dien-3-one are dissolved in 25 cm ^{1 of} methanol and cooled to -15 ° C. in a melhanol ice bath while stirring. 1.0 g of sodium borohydride is added in small portions and the mixture is stirred for 2 hours, the temperature being kept below 0.degree. After 2 hours, 4 cm of Lis acetic acid are added and the reaction mixture is diluted with 100 cm ^{1 of} water. The mixture is concentrated under reduced pressure on a water bath, then diluted with water and allowed to crystallize. It is then filtered, washed with water and sucked dry. After recrystallization from methanol and thin-film chromatographic purification, 3-hydroxy-20-spiroxa-4,6-diene is obtained.

Example ^l )
3-acetoxy-2 () - spiroxa-4,6-diene

1.523 g of 3-hydroxy-20-spiroxa-4,6-diene, prepared according to the method of Example 8, are dissolved in 1.3% of pyridine by heating on a steam bath. Add 4 cm ^{1 of} aqueous anhydride and heat the solution on the steam bath for 10 minutes. The reaction mixture is poured onto 100 cm of ice and white crystals separate out.

The crystals are filtered off, carefully washed with water and sucked dry. After cleaning crystallization from methanol gives the product: 3-aceloxy-20-spiroxa-4,6-diene.

Example 10
3-acetoxy-6,7 ^ -dichloromethylene-20-spirox-4-en

Using the 3-Acctoxy-20-spiro ^v -4,6-diene, prepared by the method of Example 9 and dissolved 200 mg of the steroid and 210 mg Phcnyltrichlormethyl mercury in 5 cm ^J benzene and heated with stirring under nitrogen for 67 At reflux for hours.

The reaction mixture is then cooled and filtered. The Nicderschlag is phenylmercuric chloride. The fillrate is evaporated to dryness and a yellow oil is obtained. According to the thin-layer chromalographic Purification gives a clear UI. which crystallizes from methanol Vv ird. The crystalline Product is called 3-acetoxy-6,7 \ -dichloromctliylcn-20-spirox-4-en identified with a melting point of 152 to 155 C.

Example 11
3-Hydroxy-6,7 \ -dichloromethylcn-20-spirox-4-en

The 3-acetoxy-6,7 \ -dichloromethylcn-20-spirox-4-cn, prepared by the method of Example 10, is used and 25 mg of the steroid is dissolved in 2, ScKV ¹ methanol and added to a solution of 0.11 cm 'of water containing 21.5 mg of potassium carbonate. This mixture is refluxed for one hour. It is then cooled and diluted with water. The excess methanol is evaporated off under reduced pressure. The crude product is separated off by filtration and sucked dry. Thin-layer chromatographic purification leads to 3-hydroxy-6,7> -dichloromethylcn-20-spirox-4-ene with a melting point = 118 to 120 C.

Example 12
6,7 \ -DichIormeth}! En 20-spirox-4-cn-3-one

The S-hydroxy-ojA-dichloromethylene ^ O-spirox-'i-cn is prepared according to the procedure of Example 11. 500 mg of the steroid are dissolved in 75 cm ^{3 of} chloroform. 5.0 g of manganese dioxide are added and the mixture is stirred for one hour at room temperature. It is filtered and then washed several times with chloroform. After evaporation to a clear oil and recrystallization, 6,7> -dichloromethylene-20-spirox-4-cn-3-one with a melting point of 151 to 153 ° C. is obtained.

This product is identical to that made according to the procedure of Example 1 was and can then be treated to 6,7-v-dichloromethylcn-20-spiroxa-1,4-dicn-3-one by following the procedure of Example 2. The latter compound can be used in that described in Example 3 Process used to produce 1,2 \ -methylcn-6,7 \ -dichlorethylene-20-spirox-4-cn-3-one.

Example 13

1 7 \ - (3-hydroxypropyl) -l 7 // - hydroxyandrosla-

4,6-dicn-3-one

To I g l7 \ - (3-Hydroxypmpyl) -17 / (- hydroxyandiOsl-4-CI1-3-OI1 (A) add one in 10 ml of dry ethanol 1.5 ml of ethyl orthoformate and 1 g of toluenesulfonic acid. The mixture is briefly at room temperature stirred and then diluted with water, whereby the crude 3-Älhoxy-3,5-diene is obtained. This results in

^r > the treatment with N-bromosuccinimide in 30 ml ^r % igcm aqueous dioxane, which contains 3 ml glacial acetic acid, the 6-bromine compound, which when heated for several hours to 90 with 0.5 g lithium bromide and 0.4 g lithium carbonate in 10 ml dimethylformamide under

κι nitrogen the diene, 17> - (3-hydroxypropyl) -17 / <- hydroxyandrosta-4,6-dien-3-one results.

Example 14

17 \ - (3-hydroxypropyl) -1 7 / i-hydroxyandrosal, 4,6-trien-3-one

1 g of the 4,6-dinene prepared in Example 13 is dissolved in 10 ml of benzene with 0.9 g of 2,3-dichloro-5,6-dicyanobenzoquinone briefly under reflux under nitrogen

2 (i crhitzl. The hydroquinone by-product is removed and the triene product further by chromatography on silica gel by elution with methanol / Chloroform mixtures purified and as 17 / * - (3-hydroxypropyl) -17 /; - hydroxyan lrosta-l, 4,6-lricn-3-one

2> identified.

Example 15

1,2 \ -Methylcn-l 7 \ - (3-hydroxypropy!) - 17 _/ ; -hydroxyandrosla-4,6-dicn-3-one

Add 2 g of 17 \ - (3-hydroxypropyl) -17 // - hydroxyandrosta-1, 4,6-tricn-3-one, prepared in Example 14, to fresh Corcy-Rcagens, dimethylsulfoxonium methylide. and allows the reaction to proceed as in Example 5. The reaction mixture is processed as in Example 5. Recrystallization from methanol gives 1,2 \ - methylene -17λ - (3-hydroxypropyl) -17 _/ '-hydroxyandrosta-4,6-dien-3-one.

4 (i B e i s ρ i e I 16

1,2 \ -Methylcn-6,7> -cpoxy-17 \ - (3-hydroxypropyl) -17 / (- hydroxyandrost-4-cn-3-one

A solution of 1.5 g of that prepared in Example 15; th material in 50 ml of chloroform is overnight at room temperature with 3.3 g of m-Chlorpcrbenzoic acid agitated The solution is washed with bicarbonate, sodium iodide, and then sodium bisulfite with water. It is then dried and concentrated in vacuo to a thick oil, which essentially 1,2 \ -Methylcn-6,7 -> - cpoxy-17 \ - (3-hydroxypropyl) -! 7 // - hydroxyandrosl-4-cn-3-one is.

Example 17

^J> 1.2A-Methylcn-6-chloro-17 \ - (3-hydroxypropyl) -17 ^ -hydroxyandrosta-4,6-dien-3-one

The crude epoxy prepared in Example 16 (1.55 g) is redissolved in 25 ml of chloroform and with a

Wi solution of anhydrous hydrogen chloride in 25 ml Treated chloroform at 0. The mixture is allowed to warm to room temperature overnight, it will washed with cold bicarbonate and then with water. When narrowing down, you get the raw, critical

b ^r ) stalline I \ -chloromethyl-6-chloro derivative. If this is boiled under reflux in 40 ml of collidine for 4 hours and then quenched with excess 3N HCl solution, mim is obtained with the extraction

Ether the crude 1,2-methylcn-6-chloro-17A- (3-hydroxypropyl) -17 / ί - hydroxyandrosta - 4,6 - diene - 3 - one, which is purified by recrystallization from methanol.

Example 18
l ^ -Methylene-o-chlorine ^ O-spiroxa ^ o-diene-. of (IIIa)

A solution of 500 mg of the material from Example 17 in 10 ml of pyridine is 1.1 equivalent p-Toluenesulfonyl chloride overnight at room temperature treated. The mixture is diluted with ether, with bicarbonate and then with water washed. The solution is then dried and concentrated to dryness, giving the crude spiro compound receives. Recrystallization from methanol gives the crude l ^ -Methylene-o-chloro ^ O-sproxa-4,6-dien-3-one, Mp. = 170 to 172 ° C.

Example 19

l, 2a-methylene-6-chloro-20-spiroxa-4,6-diene-3,21-dione (HIb)

A solution of 500 mg of the material from Example 17 in 30 ml of acetone is mixed with 0.50 ml of 8η chromic acid solution treated at 10 °. The mixture is stirred for 10 minutes and then with chloroform diluted and washed with water. Drying the organic layer and concentrating in vacuo gives the raw spirolactone. Recrystallization from ethyl acetate gives pure 1,2 * -methylene-6-chloro-20-spiroxa-4,6-diene-3,21-dione.

Example 20

1,2 "-Methylene-7-acetylthio-17 \ - (3-hydroxypropyI) -17 / i-hydroxyandrost-4-en-3-one

400 mg of the steroid prepared in Example 15, 1,2 * - methylene-17, \ - (3-hydroxypropyl) -17fi-hydroxyandrosta-4,6-dien-3-one, are treated with 8 ml of thioacetic acid, whereupon heated in a water bath at about 70 ⁰ C for 1 hour. The mixture is then _{treated with aqueous NaHCO 3} solution until neutral. The crude product is extracted with ether and dried over sodium sulfate. The solvent is removed and the residue is purified by chromatography. Subsequent recrystallization from methanol gives pure 1,2 * -methylene-7-acetylthio-17 »- (3-hydroxypropyl) -17 / <- hydroxyandrost-4-en-3-one.

Example 21

l ^ -Methylene ^ -acetylthio ^ O-spirox-4-en-3,21-dione (Hb)

A solution of 500 mg of the steroid from Example 20 in 30 ml of acetone is dissolved in 0.50 ml of 8 η chromic acid solution treated at 10 °. The mixture is stirred for 10 minutes and then diluted with chloroform and washed with water. After the solution has been dried, it is concentrated and the residue is recrystallized from ethyl acetate, pure 1,2 * -methylene-7-acetylthio-20-spirox-4-en-3,21-dione receives.

Example 22

1,2 -> - methylene-7-acetylthio-20-spirox-4-en-3-one (Ha)

A solution of 500 mg of the steroid from example! 20 in pyridine is mixed with 1.1 equivalents of p-toluene treated sulfonyl chloride overnight at room temperature. The mixture is diluted with ether, mil Bicarbonate and then washed with water. After ίο isolation and recrystallization, mar the pure I, 2 "-methylene-7-acetylthio-20-spirox-4-en-3-one, melting point = 207 to 210 C.

Be i sρ i el 23

6,7 "-Difluoromethylene-17a- (3-hydroxypropyl) -17 / i-hydroxyandrost-4-en-3-one

One gram of the 4,6-diene product of Example 1: is dissolved in 5 ml of triglyme and heated to 200 unc dropwise over the course of an hour at about £ 200 ° treated with a solution of 5 g of sodium chlorodifluoroacetate in 50 ml of the same solvent The mixture is cooled, quenched in ice and extracted with ethyl acetate. After the dryer and concentration gives the crude 6,7 * -difluoromethylene derivative. Recrystallization from acetone: hexane leads to the purified compound: 6,7-v-difluoromethylene - 17 »- (3 - hydroxypropyl) -17 / J - hydroxyandrost-4-en-3-one.

Example 24

6,7, -k-Difluoromethylene-17 \ - (3-hydroxypropyl) -17 / i-hydroxyandrost-1 , 4-dien-3-one

j) 1 g of the difluoromethylene derivative prepared in Example 23 is in 15 ml of benzene with 0.95 g of 2,3-dichloro-5,6-dicyanobenzoquinone at reflux under nitrogen! Heated for two hours. The hydroquinone by-product is filtered off and the diene product by elution chromatography on silica gel with methanol / chloroform mixtures further purified and as 6,7 »-difluoromethylene - ^ - (3-hydroxypropyI) -17 // - hydroxyandrost-1,4-dien-3-one identified.

Example 25

1,2n-methylene-6,7 \ -difluoromethylene-17A- (3-hydroxypropyl) -17 / i-hydroxyandrost-4-en-3-one

2 g of the dienone prepared in Example 24 are treated with the Corey reagent as in Example 3. When the crude product is recrystallized from methanol, 1,2 * -methylene-6,7A-difluoromethylene is obtained - 17 »- (3 - hydroxypropyl) - 17 / i - hydroxyandrost-4-en-3-one.

Example 26

1,22-methylene-6,7 * -difluoromethylene-20-spirox-4-en-3-one (la)

A solution of 750 mg of the dimethylene steroid prepared in Example 25 in 15 ml of pyridine becomes treated with 1.05 equivalents of p-toluenesulfonyl chloride overnight at room temperature. Dilute the mixture with benzene, washing with bicarbonate and then with water leads to the crude spiro compound. Recrystallization from hexane and then from ether / petroleum ether gives pure Ia, 1,2 \ -methylene-6,7 \ -difluoromethylene-20-spirox-4-en-3-one, Mp = 155 to 158 ° C.

at

spat

27

Example 28

1,2 \ -Methylene-6,7A-difluoromethylcn-20-spiroxa-4-en-3-ol-2l-one

2.0 g of 1,2 \ - methylene - 6,7. \ - difluoromethylene-20-spiroxa-4-en-3,21-dione, as it was prepared in Example 27, are dissolved in 25 cm 'of methanol and in cooled in an ice bath with stirring. 1.0 g of sodium borohydride is added in small portions and the mixture is stirred for 2 hours, the temperature being kept below 0 ^° C. After 2 hours

1,2 \ -methylene-6,7 \ -difluoromethylene-20-spiroxa-4-en 3,21-dione (Ib)

A solution of 750 mg of the dimethylene derivative of Example 25 in 100 ml of acetone is 0.60 mg 8 η chromic acid solution treated at 10 "with stirring. After 10 minutes the mixture is diluted with chloroform and washed. Drying and concentration in vacuo gives the crude spirolactone. Recrystallization from ether / petroleum ether leads to the pure 1,2ii-methylene-20-spiroxa-4-en-3,2l-dione.

^{4 cm 3 of} glacial acetic acid are added and the reaction mixture is diluted with 100 cm 3 of water. The mixture is concentrated, diluted with water and crystallized. After filtration and recrystallization, 1,2 \ -methylene-6,7i-difluoromethyl-20-spiroxa-4-cn-3-ol-21-one is obtained.

Example 29

D e ι s ρ ι e ι zv

l ^ -MethyleneO-aceloxy-ojA-difluoromethylene
20-spiroxa-4-en-21-one

One uses 1,2 »-methylene-6,7» -difluoromethylene ^ O-spiroxa ^ en-S-oWl-one of Example 28 and dissolves the parent steroid in pyridine. As in Example 9, add acetic anhydride and heat the solution on a steam bath. The end product, 1,2 »- methylene - 3 - aceloxy - 6.7.» - difluoromethylene-20-spiroxa-4-en-2l-one obtained after crystallization and cleaning.

Similarly as described in Examples 28 and 29, the compounds: 1,2-methylene-6-chloro-20-spiroxa-4,6-dien-3-ol-21-one; 1,2-t-methylene-3-acetoxy-6-chloro-20-spiroxa-4,6-diene-21-one; 1 , 2 \ - methylene - 6 - fluoro - 20 - spiroxa - 4,6 - diene - 3 - ol-21 - one and 1,2 * - methylene - 3 - acetoxy - 6 - fluoro-20-spiroxa-4, 6-dien-2l-one can be produced.

Claims (3)

Patent claims: 1. 1,2 / »- McthyIen-2 () - spirox-4-ene oxygenated in the 3-position the general formula CH ₃ CH, in which the ring B has the following meaning C - halogen halogen Ri is a hydrogen atom or a methyl group, R _{4 is} a methylene (-CH ₂ ) or keto group 4 ^r > (C = (»and
R _{5 is} an oxygen atom, a hydroxyl group or a lower alkanoyloxy group having 1 to 6 carbon atoms. 2. Process / ur preparation of the compounds according to claim I, characterized in that man A) for the preparation of 1,2 <x-methylene-6,7 * -dihalogenmelhylcr.-20-spirox-4-en-3-one a) a 20-spirox-4,6-dien-3-one with a halogen substituent Reacts alkali metal acetate, the ÖJm-Dihalogenmelhylcn ^ O-spirox-4-en-3-one obtained treated with dichlordieyanobenzochi-IiοIi and the 6,7 »-dihalogenethylene-20-spiroxa-1,4-dien-3-one formed treated with dimethylsulfoxonium methylide or b) from a 2 () - spiroxa-4,6-dien-3-one in two stages a 3-alkanoyloxy-2 () - spiroxa-4,6-diene produces, reacts this product with Phcnyltrihalogcnmet hy! mercury, the 3-alkanoyloxy-6,7 »-dihalogen- Yi melhylen-2 () - spirox-4-cn hydrolyzes and oxidizes and the 6,7 \ -dihalomethylene-20-spirox-4-cn-3-one formed according to Λ) a) with dichlorodicyanobenzoquinone and then with dimethylsulfoxonium methylide treated or c) a l ^ x-Mcthylen-oJx -dihalogcnmethylen-17 » - (3 - hydroxypropyI) - 17 / i - hydroxy - androsl -4-cn-3-one with an alkyl or aryl sulfonyl chloride converts it into pyridine solution, B) for the preparation of 1,2 \ -Mclhylcn-6-halogcn-20-spiroxa-4,6-dien-3-ones or 1,2 "-Methylene-7-acclylthio-2 () - spirox-4-en-3-ones a) a 20-spiroxa-4,6-dicn-3-one with dichlorodicyanobcnzoquinone implements, the formed 20-Spiroxa-1,46-trien-3-one with Dimelhylsulfoxoniuinmelhylid converts and the 1,2.x - methylene - 20 - spiroxa-4,6-dien-3-one formed ») Either one after the other with a peracid and a halominal acid and then treated in a suitable solvent or /> ') treated with thioacetic acid or b) a 1,2 »-methylene-17» - (3-hydroxypropyl) -17 // - hydroxyandrost-4,6-dien-3-one . \) either substituted with the acctyl thio group in the 7-piece !! img and
the 1,22-methylene-7-acetylthio-17 »- (3 - hydroxypropyl) - 17 // - hydroxyandrost-4-e-3-one formed is cyclized with a sulfonyl chloride in pyridine or /> ') one after the other with a peracid, a halogenated mineral acid in a chlorinated one Solvent and then treated with collidine and the 1,2 formed. »- methylene-6-halogen-17 /» ' - hydroxy - 17. » - (3-hydroxypropyl) -androsta-4,6-dicn-3-one subject to ring closure with a sulfonyl chloride in pyridine, C) for the production of 1,2x-melhylene-6,7. \ - dihalogennicthylcn-20-spiroxa-4-cn-3,21 -dioncn a 1,22-methyl-6,7 <x -dihalogcnmethylcn-l7rt- (3-hydroxypropyl) -17 // - hydroxyandro.sl-4-cn-3-one treated with a ring-shaped oxidizing agent and I)) for the production of 1,2 * -Melhylen-6-halogen-2 () - spiroxa-4,6-dicn-3,2l-dione or
1,2 * - methylene - 7 - acctylthio - 20 - spirox - 4 - ene-3,21-dione a 1,2 "-methylene-l7 \ - (3-hydroxypropyl) -! 7 // - hydroxyandrosta - 4,6 - diene - 3 - one n) either reacted in succession with a peracid and a halocralsic acid and then treated in a solvent and the l, 2 »-Methylcn-l7» - (3-hydroxypropyl) - 17 /; - hydroxy - 6 - halogenandrosta-4,6-dicn-3-one treated with a ring-closing oxidizing agent or l'i) substituted with det acetyithio group in the 7-position and subjected to an oxidation with subsequent ring closure and the compounds obtained, optionally with a reducing agent, to the corresponding ones 3-i-ols reduced and this optionally acylicrl. 3. Medicinal preparations with anti-androgenic effects, characterized by a housing on a connection according to claim I.