DD209635A5 - PROCESS FOR THE PREPARATION OF 11BETA CHLORO STEROIDS - Google Patents

Abstract

(for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) 1. 11 beta-chlorosteroids of general formula I see diagramm : EP0092173,P6,F1 wherein R is hydrogen or an acyl group of an organic carboxylic acid of up to 15 carbon atoms. (for the Contracting : AT) Process for the preparation of 11 beta-chlorosteroids of general formula I see diagramm : EP0092173,P7,F1 wherein R is hydrogen or an acyl group of an organic carboxylic acid of up 15 carbon atoms characterized in that a 11 beta-chloro-17-oxosteroid of the general formula II see diagramm : EP0092173,P7,F2 wherein, Y is a free oxo group of a hydrolyzable protected oxo group and see diagramm : EP0092173,P7,F3 is a double bond in the 4,5-, 5,6- or 5,10-positions or two double bonds in the 3- and 5-positions, is converted, in a known manner, with an organometallic chloroethynyl compound to a compound of general formula I in which R is hydrogen, a primary introduced 3-oxo protecting group is hydrolyzed and depending on the finally desired meaning of R, the 17-hydroxy group is optionally esterified, before or after removal of the protecting group.

Description

AP C 07 J / 249 873/1 62 014 11

Process for the preparation of 11β-chloro-8-teroids Field of application of the invention

The invention relates to a process for the preparation of 11ß-chloro-steroids with valuable pharmacological properties, in particular gestagenic effect. They are used as medicaments, for example for the treatment of gynecological disorders or as contraceptive.

The invention further relates to pharmaceutical preparations containing the compounds according to the invention.

Characteristic of the known technical solutions

It is already known that H-chloro steroids have valuable biological properties. In UL-OS 7,209

4, for example, 11β-chloro-17c-ethynyl-18-methyl-estrene which show a strong gestagenic action,

Object of the invention

The aim of the invention is the provision of new compounds with more gestagener effect.

Explanation of the essence of the invention

The invention has for its object to find new compounds with stronger gestagener effect and process for the preparation.

According to the invention 11ß-chloro-steroids of the general formula I.

C 07 J / 249 873/1 62 014 ·

IL

Cl

r- c = c - ci

(I)

produced, in which

E represents a hydrogen atom or an acyl group.

Preferred compounds according to the invention are, for example:

Hβ-chloro-17c-chloroethyi7l-17β-n7drox7-18-metyl-4-oestrene-3-one,

17-acetoxy-11.beta.-chloro-17c? C-ciilorethinyl-i8-met] iyl-4-estrene-3-one,

17β-butyryloxy-11β-chloro-17c-chloroethynyl-18-methyl-4-oestrene-3-one,

11β-Chloro-17oC-chloro-ethynyl-i7β-hepto-anoyloxy-18-methyl-4-estrene-3-one.

Ss has been found that the not yet described corresponding 17 & -Chlorethiny! Compounds of general formula I are about 3 ^m sl gestagen more potent than those of the ML-08 7 209299 17 known (X-ethynyl compounds.

AP C 07 J / 249 873/1 62 014 11

Q /

The gestagenic effect was determined in the usual Clauberg'Iest after oral administration to infantile female rabbits.

The minimum amount needed to achieve a positive effect is expressed by the McPhail value 1.5 *

The following table summarizes the results of the test:

table

connection Dose (mg) McPhail A 11β-Chi or-17IX-Chior ethinyl 0.1 3.3 i7fi-hydroxy-i8-methyl-4- 0.03 3.0 estrene-3-one 0.01 1.9 '0, Όθ3 1 »2 B • 11β-chloro-17 O -ethynyl-17β- 0.03 2.5 hydroxy-18-methyl-4-östren- 0.01 1.4 3-one 0,003 1.1

J 1

From the table shows that the threshold dose (McPhail 1.5) for the gestagenic effect in the inventions to the invention compound A is about 0.003 mg and in the known compound B is about 0.01 mg.

Furthermore, A has only a very slight androgenic side effect, as shown by the high competition factor K _p = 15 in the androgen receptor test. In contrast, the steroid B, for which the competition factor is K "= 6.3 in the same test, is still weakly androgenically active.

-. Because of the gestagenic action, the compounds of the general formula I can be used, for example, in anticonceptive preparations, where they are used as progestogen component in combination with an estrogen-active hormone component, such as, for example, ethinyl oestradiol, or as the sole active component. However, the compounds can also be used in preparations for the treatment of gynecological disorders.

The novel compounds can be processed into the customary forms of medicaments with the additives, excipients and flavoring agents customary in galenic pharmacy by methods known per se. For oral administration, tablets, dragees, capsules, pills, suspensions or solutions are particularly suitable. For parenteral administration in particular oily solutions, such as sesame oil or castor oil solutions in question, which may optionally additionally contain a diluent, such as benzyl benzoate or benzyl alcohol. The concentration of the active ingredient depends on the application form. For example, tablets for oral administration preferably contain 0.01-0.5 mg of active ingredient and solutions for parenteral administration preferably 1-100 mg of active ingredient per 1 ml of solution.

The dosage of the medicaments according to the invention may vary with the form and the purpose of the administration: for example, the daily contraceptive dose for oral administration is 0.01-0.5 ng of the new gestagen, optionally in combination with 0.01-0 , 05 mg ethinyl estradiol.

The acyl groups R according to formula I are derived from acids which are commonly used in steroid chemistry for esterification. Preferred acids are organic carboxylic acids having "up to 15 carbon atoms, in particular lower and middle aliphatic carboxylic acids having up to 7 carbon atoms." The acids can also be unsaturated, branched, polybasic or in a customary manner, for example by hydroxy, acyloxy, alkoxy, Also suitable are cycloaliphatic, aromatic, mixed aromatic-aliphatic and heterocyclic acids which may also be substituted in the usual way.

Examples which may be mentioned are the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, onanic acid, caprylic acid, pelargonic acid, capric acid, undecynic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, β Cyclopentylproionic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, mono-, di- and tri-chloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, 0-tridecanoylglycolic acid, succinic acid, adipic acid, benzoic acid, nicotinic acid, isonicotinic acid, furan-2 carboxylic acid.

AP C 07 J / 249 873/1 62 014 11

The inventive method is carried out according to known methods with an organometallic Chlorethinylverbindung by reacting the 17-oxo-steroid in a suitable solvent with the organometallic Chlorethinylverbindung. The chloroethynyl compound is formed in situ from 1,2-dichloroethylene and an ethereal alkyl alkali metal solution, such as methyl or butyllithium solution. Suitable solvents are tetrahydrofuran and diethyl ether.

The 3 * keto group is expediently protected from chloroethynylation. The oxo-protecting group Y of formula II forms with the double bond (s) which "is present in ring A or B" or "are such an arrangement of atoms that the compound is converted to a 4,5-unsaturated ketone by acid hydrolysis In a preferred embodiment, the keto group is protected by ketal formation The ketal radicals are derived from the alcohols and thioalcohols customarily used for the protection of free oxo groups, for example: ethylene glycol, 2,2-dimethylpropanaiol- (1,3) and ethanedithiol (1,2), but the 3-keto group can also be partially protected by Enoläther-, Snolester- or Snaminbildung.

The cleavage of the 3-keto protective group, which can take place before or even after the possible esterification, is carried out according to the methods known to the person skilled in the art. For cleavage, mineral acids, such as perchloric acid, sulfuric acid or hydrochloric acid, or organic acids, such as oxalic acid 'come into consideration. The cleavage is preferably carried out in alcoholic solution or in other polar solvents, such as acetone, at temperatures between about 20 and 100 ^° C.

In the case of the thioketal protective group, the cleavage takes place in

AP C 07 J / 249 873/1 62 014 11

«J / π Q 7 Q ii ^

alcoholic solution, preferably in water-moist methanol, with Methyljc-did with addition of sodium or potassium acetate or carbonate at temperatures between room temperature and boiling point of the solvent

The optionally subsequent esterification of the 17-hydroxy group is carried out by methods which are commonly used in steroid chemistry for the esterification of tertiary hydroxyl groups. As a suitable esterification method, for example, the reaction of the steroids with acid anhydrides or acid chlorides in the presence of basic catalysts such as sodium bicarbonate, Ealiumhydrogenkarbonat, potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine, lutidine, collidine, triethylamine or 4-dimethylaminopyridine mentioned. According to a preferred embodiment. Form the esterification is carried out in the presence of pyridine and 4-dimethylaminopyridine.

The starting compounds of the general formula II used according to the invention can be prepared from 11β-chloro-18-methyl-4-oestrene-3,17-dione (NL-OS 7,209,299), for example by ketalization, as follows:

11.beta.-chloro-3,3- ^(2>, 2'-dimethyl-trimethylenedioxy) -18-methyl-5-estrene-17-one

500 mg of 11β-chloro-18-methyl-4-estrene-3,17-dione are dissolved at room temperature in 5 ml of methylene chloride and 0.5 ml of triethyl o-formate with 1 g of 2,2-dimethyl-1,3-propanediol and 5 mg of p-toluenesulfonic acid added. After 6 hours, it is diluted with methylene chloride, washed neutral and dried. The crude product is chromatographed on silica gel. With acetone / hexane, 300 mg of 11β-chloro-3,3- (2 ', 2'-dimethyl-tri-

AP C 07 J / 249 873/1 62 014 11

methyl ene-dioxy) -18-methyl-5-estrene-17-one of melting point. 161.2 ⁰ C eluted.

Ausführungsbeispi.el

The invention will be explained below with reference to some examples.

9 8 / J 1 - 9 -

example 1

a) 1Tβ-Chloro-17a-chloroethynyl-3,3- (2 ', 2'-dimethyl-trimethylenedioxy) -18-methyl-5-oestrene-17β-ol

21 ml of a 5% strength ethereal methyllithium solution are added dropwise to 2.8 l of dichloroethylene in 20 ml of absolute ether under ice / water cooling and introduction of argon. After 30 minutes, 1.2 g of 11β-chloro-3,3- (2 ', 2'-dimethyl-trimethylenedioxy) -18-methyl-5-oestrene-17-one are added. in 5 ml of absolute tetrahydrofuran. The mixture is stirred at room temperature, treated after 20 minutes with saturated ammonium chloride solution, diluted with ether, washed with water and dried. After recrystallization from acetone / hexane, 1.1 g of 1 1ß-chloro-17 <x-chloroethinyl-3 »3- (2 ¹ , 2'-dimethyl-trimethylenedioxy) -18-methyl-5-estrene-17ß-ol of melting point 1 Qh, 2 ° C.

b) 1-chloro-1-chloro-ethinyl-β-hydroxy-1-methyl- 3-one-one

1.0 g of 11β-chloro-17α-chloroethynyl-3,3- (2 ', 2'-dimethyltrimethylene-dioxy) -18-methyl-5-oestrene-17β-ol are added under argon at room temperature in 20 ml of acetone with 0 , 5 ml of half-concentrated hydrochloric acid. After 1 hour, neutralized with NaHCO 3 solution, concentrated in vacuo, the residue is dissolved in ethyl acetate, washed with water and dried. The crude product yields after recrystallization from acetone / hexane 433 mg of 11β-chloro-17a-chloroethynyl-17ßhydroxy-i8-methyl-4-estrene-3-one of melting point 239.2 ° C.

Example 2

17-acetoxy-11.beta.-chloro-17a-chloroethynyl-18-methyl-4-estrene-3-one

mg of 1β-chloro-α-chloroethynyl-ββ-hydroxy-iso-methyl-α-estrene-3-one in 4 ml of pyridine are added at room temperature with the addition of 50 mg of 4-dimethylaminopyridine with 2 ml of acetic anhydride

24.3 α / ö ι -10 -

touched. The mixture is added after 2 hours in acetic acid-containing ice / water. The precipitated product is filtered off with suction, dissolved in methylene chloride and washed with water. After chromatography of the crude product on silica gel with hexane / acetone, 190 mg of 17ß-acetoxy-11ßchlor-1Tot-chloroethynyl-i8-methyl-4-estrene-3-one as a foam.

Example 3

17-butyryloxy-11.beta.-chloro-17a-chloroethynyl-18-methyl-4-estrene-3-one

110 mg of 1-chloro-α-chloroethynyl-β-hydroxy-is-methyl-4-estrene-3-one. in 1 ml of pyridine are stirred with the addition of 100 mg of 4-dimethylaminopyridine with 0.5 nil butyric anhydride at room temperature. After 5 hours, the mixture is poured into ice / water and the product extracted with methylene chloride. After chromatographing the crude product on silica gel with hexane / acetone to obtain 73 mg of 17β-butyryloxy-11β-chloro-17a-chloroethynyl-18-methyl-4-estrene-3-one as an oily product.

example k

11.beta.-chloro-17a-chloroethynyl-17.beta.-heptanoyloxy-18-methyl-4-estrene-3-one

300 mg of 1-β-chloro-α-chloroethynyl-β-hydroxy-is-methyl-3-oestrene-3-one in 3 ml of pyridine are added at room temperature with 1.5 ml of onanthic anhydride and 100 mg of ^ -dimethylaminopyridine. After Ik hours, the solution is poured into ice / water and extracted with methylene chloride. After chromatographing the crude product on silica gel, 160 mg of 1 1 β-chloro-17ctchloroethynyl-17β-heptanoyloxy-18-methyl-4-oestrene-3-one are obtained as an oil.

Claims (1)

~ = L 4 3 0
Srfindungsanspruch - / 14 1, Process for the preparation of Hβ-chloro steroids of general formula I. OE Cl c = σ - ei (D, wherein R is a hydrogen atom or an acyl group , characterized in that an I1ß-chlor ^ 17-O2co-steroid of the general formula II Cl (II) AP G 07 J / 24-9 873/1 62 014 11 wherein Y represents a free oxo group or an acid-hydrolyzable oxo protecting group, and means a double bond in the 4-, 5-, 5-6- or 5.10-position or two double bonds starting from the 3-position and the 5-position, according to methods known per se with an organometallic chloroethynyl compound to give a compound of the general formula I in which R is a hydrogen atom, hydrolyzes a primary 3-oprotective group, and, depending on the ultimately desired meaning of R, optionally the Hydroxy group esterified before or after the deprotection. 2 »Procedure according to point. 1, characterized in that 1? 1ß-chloro-17cC-chloroethynyl-17ß-hydroxy-i8-methyl-4? Esten-3-one is prepared. 3 »process according to item 1, characterized in that i7β-acetoxy-11β-chloro-17 <s-chloro-ethynyl-18-methyl-4-estrene-3-one is prepared · Process according to item 1, characterized in that i7β-butyryloxy-11β-chloro-17α-ciilorethinyl-18-methyl-4-estrene-3-one is prepared. AP G 07 J / 24-9 873/1 62 014 11 5. The method according to item 1, characterized in that 11ß "-Chlor-17ot-chlcrethinyl-17ß-heptanoylo2cy-i8-methyl-4 - estrene-3-one is prepared.