DE2048231C3 - Progestin or fertility control agent - Google Patents

Description

The present invention relates to a gestagenic agent or agent which is used to regulate fertility and is suitable for enteral or parenteral administration and contains 3,20-dioxo-6a-methylf 7'i-acetoxy-19-nor-A ⁴ -pregnene.

The new pharmaceutical preparations have a high progestative and anti-ovulatory effectiveness and are thus primarily for use as progestins and for regulating fertility suitable.

This can be proven in animal experiments, where the said active ingredient z. B. given subcutaneously on rabbits A progestative is given at 0.0001 to 0.001 mg / kg / day or orally at 0.001 to 0.03 mg / kg / day Effect. The anti-ovulatory effectiveness can e.g. B. by inhibiting spontaneous ovulation the rat are proven that with subcutaneous administration at doses of 0.003 to 0.03 mg, kg / day and occurs when administered orally at doses of 0.01 to 0.3 mg kg / day.

• \ uch in comparison with the known and next \ related 3-hydroxy-6α-methyl-l7fi-acetoxy-19-nor-A'-pregnen (B) and 3,20-Dioxo-6 </ - methyi-I7u-acetoxy-A'-pregnen (C, "Medroxyprogesterone", French patent specification BSM 249 / M) shows the above Active ingredient (A) disclosed in U.S. Patent 34 88 346 without any data as a starting material mentioned is an excellent effectiveness. So scored in the well-known Claubcrg test, on castrated female rats sensitized with oestron

(A) with 0.002 mg / kg / the C3) with 0.01 mg / kg; the
(C) with 0.015 mg kg / die

(for 5 days, given orally) a full gestagenic activity.

The new preparations contain the active ingredient together with a pharmaceutical carrier material, which is suitable for enteral or parenteral administration. f: s can be liquid or solid, in particular substances that do not react with the new compound, such as water, gelatin, Milk sugar, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, polyalkylene glycols or other known excipients. The new preparations can, for. B. as tablets, coated tablets, Capsules or in liquid form as solutions or primarily suspensions. Possibly are they sterilized and / or contain auxiliaries such as preservatives or stabilizers, salts for Change in osmolic pressure or buffer.

The new preparations contain z. B. for oral use, expediently in the form of tablets, coated tablets or capsules, preferably 1 to 100 mg of the 231

active substance per dosage unit, expediently 5 to 50 mg. The dosage of the new preparations is aimed according to the needs of the individual patient.

The preparations are obtained using drug formulation methods known per se.

The active ingredient is z. B. obtained if a 3-enol ether of 3,20-dioxo-6-formy! -17α-acetoxy-19. nor-A ⁴ -pregnadiens reduced and the 3,20-dioxo-6a-methyl-17a-acetoxy-19-nor-A ⁴ -pregnene isolated from the mixture obtained, optionally after isomerization using a strong acid such as hydrochloric acid. The reduction of the 6-formyl compound is preferably carried out with palladium carbon in cyclohexene, a mixture of the 6a and 6 / J-methyl isomers being obtained. A first portion of the desired 6α-methyl compound can be isolated from this by chromatography. The isomerization is effected in particular with a strong acid. These reactions are carried out in a manner known per se.

The following examples are intended to explain some of the application forms of the preparations:

example 1
oily solution for injection

Composition:

S ^ O-Dioxo-ofz-methyl-nu-acetoxy-

19-nor-A ⁴ -pregnen 100 mg

Benzyl benzoate 350 mg

Benzyl alcohol 90 mg

Sesame oil up to 1.0 ml.

The active substance is dissolved in a mixture of benzyl benzoate and benzyl alcohol at 40 ° C. and added to the clear solution while stirring so much sesame oil heated to 40 C that per ml of solution 100.0 mg des Active ingredient are included. The solution is sterile-filtered in the usual manner and under aseptic conditions filled in ampoules.

Example 2
Oily solution for injection

Composition:

3,20-Dioxo-6 «-methyl-17u-acetoxy-

19-nor-A ⁴ -pregnen 30.0 mg

Benzyl alcohol 90.0 mg

Sesame oil up to 1.0 ml.

The active substance is dissolved in benzyl alcohol at 40 ^° C. Sesame oil heated to 40 ° C. is added to the clear solution with stirring so that 30.0 mg of active ingredient is contained per ml of solution. The solution is sterile-filtered in the usual way and filled into ampoules under aseptic conditions.

Example 3
Suspension for injection
Composition:

S ^ O-Dioxo-ori-methyl-nß-acetoxy-

^ -nor-A ^ -pregnen 10.0 mg

Sodium carboxymethyl cellulose

mean viscosity 5.0 mg

Sodium chloride 7.5 mg

Primary sodium phosphate 1.5 mg

Secondary sodium phosphate 1.5 mg

3 w 4

Polyvinylpyrrolidone 0.5 mg progesterone eluted. The one from methylene chloride / ether

Sodium ethyl mercurithiosalicilate 0.02 mg recrystallized compound melts at 163 to 165 C.

distilled water up to 1.0 ml. In the mother liquors and the higher chromatographic

gram fractions is the epimeric 6 / J-methyl-

The sterile microcrystals of the active ingredient are enriched in 5 derivative. The mixture is for the purpose of isolating aseptic conditions in the previous mergerization in 6-position dissolved in chloroform and put and suspended sterilized vehicle. The solution, with cooling, homogenized with hydrogen chloride The suspension is saturated under aseptic conditions. After 1 hour, nitrogen is passed through for 15 minutes The yellowish reaction solution was blown through into previously heat-sterilized 1 ml ampoules, then bottled and sealed so that per ml of suspension io with water, sodium hydrogen carbonate solution and 10.0 mg of active ingredient are included. then washed with water, dried and im

Evaporated water jet vacuum. By chromato-

. - _d graph on silica gel (compare above) and then

Example 4 ßende crystallization further amounts are pure

Hormone tablet 15 oa-Methvl-net-acetoxy - ^ - norprogesteron from Smp.

., _ ,, 163 to 165C won.

Composition per tablet: _{The a} , _{$ Off} | _angsstoff used formyl connec-

3,20-Dioxo-6a-methyl-l7 / i-acetoxy- dung is z. B. manufactured as follows:

19-nor-A ⁴ -pregnen 5.0 mg 13.0 g ITn-acetoxy-lii-norprogesterone are used in

Milk sugar 80.0 mg * 160 ml of benzene dissolved. Then about 25 ml are distilled

Ärosil 7.0 mg solvent off, adds 6.5 ml freshly distilled

Wheat starch 46.0 mg of methyl o-formate, 0.65 ml of methanol and

Talc 6.3 mg 130 mg p-toluenesulfonic acid and boils under

Magnesium stearate 0.7 mg, stirring for 2.5 h on the reflux condenser. Within 30 minutes

145.0 mg. 25 then another part (10 ml) of the solvent distilled off, the mixture cooled, after adding

The active ingredient is diluted with a portion of the milk sugar 1.3 ml of pyridine with ether, successively premixed with homogeneous. This premix is washed with saturated sodium hydrogen carbonate solution and the rest of the milk sugar, Arosil and some of the water, dried and mixed in a water jet strength, moistened with water and evaporated to the usual 30 vacuum. The crystallization of the back way granulated and dried. Standes from methanol (in the presence of small amounts The remaining starch, Pyndin, is added to the dry granulate), the talc, which melts at 202 to 212 C, and magnesium stearate are added and the 3-methoxy-17a-acetoxy-20-o \ oA _3i5 -19-norpregnahomogene Mixture to tablets of 145.0 mg CIedien.

weight pressed. 35 10.0 g of this compound in 25 ml of methylene-The active ingredient can be z. Q. chloride dissolved in the following way and obtained at 6 C to that of 5.8 g of dimethyl: formamide and 3 ml of phosphorus oxychloride in 20 ml of 2.0 g of palladium carbon (10%) are rubbed with 4 ml of ice-methylene chloride Vilsmeier vinegar prepared at 0 C. , filtered off after about 5 min, added dropwise with reagent. The red solution is stirred for 2 h with methanol until it reacts neutral, and then washed at 40 ° C. and allowed to warm to 18 ° C. within 1 h, then transferred to the reaction vessel with about 10 ml of methanol . Then add 10.0 g of 3-methoxy-6-formyl suspension of 22 g of anhydrous sodium acetate in l7fi-acetoxy-20-oxo- _A3i5 -19-norpregnadiene and 20 ml of 70 ml of 90 ° _o igem methanol and added for 30 min with freshly distilled cyclohexene and stirred for 18 h at room temperature. It is then diluted with simultaneous refluxing. The reaction water and methylene chloride is washed, the organic mixture is cooled to room temperature, the layers are filtered off twice in succession with water, once with the catalyst, with 7.4 g of magnesium silicate in a 4 "strength potassium carbonate solution and once with cat Boiled under reflux for min, cooled again, water, the washing water is extracted with methylene, diluted with ether, filtered and refluxed in a water jet chloride, dried and evaporated in a water jet vacuum.

(9.1 g) is dissolved in 100 ml of toluene and the resulting crude 3-methoxy-6-formyl-17a-

Amount by weight of silica gel chromatographed. With toacetox> -20-oxo-A ₃ , ₅ -19-norpregnadiene (UV spectrum:

luoI-ethyl acetate (90:10) mixture is used in the λ mu \, f ^ 220 /! 00OO and 3? .O / 145OO) without cleaning

the 6a-methyl-17a-acetoxy-19-normalization was subjected to reduction in the first fractions.

Claims (1)

'JO 20th Claim: Gestagenic agent or agent used to "regulate fertility and suitable for enteral or parenteral administration, characterized by a content of 3,20-dioxo-6" -methyl-17a-acetoxy-19-rior-A ⁴ -pre _t nen.