17α-Ethinyl-18-methyl-19-nortestosterone esters

This invention relates to 17 β-monoesters and 3-enol-17β-diesters of 17α-ethinyl-18-methyl-19-nortestosterone esters. More particularly, this invention is concerned with an improved method for preparing and securing them.

In accordance with the present invention, there are provided 17β-monoesters and 3-enol-17β-diesters of 17α-ethinyl-18-methyl-19-nortestosterone constituting new therapeutic compounds having outstanding properties. These compounds possess progestive activity and are active when administered orally or subcutaneously. They are readily soluble in the conventional pharmaceutical carriers used for steroid hormones as, for example, vegetable oils such as sesame oil, castor oil, cotton seed oil, sunflower oil, olive oil, and the like, as well as in synthetic solvents, for instance glycols, lactic acid esters, benzyl benzoate and the like. Because of their considerable solubility, it is possible to employ solutions of the esters of the invention as injectibles and thereby also to utilize them as hormone depots.

The active compounds of the invention are prepared by reacting 17α-ethinyl-18-methyl-19-nortestosterone with an organic carboxylic acid or reactive derivative thereof in the conventional manner to produce the ester. The 3-enol ester group of the primarily formed 3-enol-17β-diester is thereafter under regeneration of the 3-keto-Δ 4 -group partially saponified.

The new esters demonstrate central inhibiting activity and are accordingly suitable as highly effective ovulation inhibiting agents.

The ovulation inhibiting activity was demonstrated in normal female rats (Sprague-Dawley) where following oral administration the conventional tube inspection tests were carried out and established for 17α-ethinyl-18-methyl-19-nortestosterone-acetate a ED 50 of only 3 mg. In comparison, the free 17α-ethinyl-18-methyl-19-nortestosterone had a ED 50 of 10 mg. (the ED 50 is that dosage which results in inhibition of ovulation in 50% of the experimental animals). Side effects such as weight gain, liver incompatibility or estrogen side reactions were not observed.

The new compounds accordingly are indicated as therapeutic agents for medical conditions where inducing a quiet state in the ovaries is recommended.

As further applications, the compounds can be used for example, in the treatment of dysmenorrhea, endometriosis, cyclic disturbances, and functional sterility.

The compounds of the invention are administered in the conventional dosage forms, such as capsules, granulates, solutions, dragees, and tablets and are compounded together with suitable pharmaceutical carriers. When tablets are prepared they may be made in various sizes (total weight of 50 - 150 mg.) containing from about 0.1 - 0.5 mg. of the drug suitably in combination with another hormone component having estrogenic activity as, for instance, 0.05 mg. ethinyl estradiol. The tablets are generally compounded with binding agents, lubricants and other substances which are commonly used in tablet manufacture such as magnesium stearate, stearic acid, talc, corn starch, lactone or the like. If desired, these tablets may be coated with sugar or shellac preparations in accordance with the common practices in the tablet manufacturing art.

In addition, the higher esters are characterized by an excellent and protracted activity.

The active compounds can be prepared by the conventional methods of steroid chemistry.

The esterification with the desired acid can be conducted in an acid or an alkaline reaction medium. As a result, of the acid esterification, there is directly produced the 17-mono-ester. There must, however, be accepted a higher loss of desired product as simultaneously with the esterification an aromatization of the A-ring takes place. The undesired side reaction can be avoided through the intermediate protection of the 3-keto group, for instance, by ketalization. This procedure implies two steps in the formation of the 17-mono-ester, i.e., ketal formation and ketal splitting.

An alternate reaction is the alkaline esterification effected in the presence of an organic nitrogen base, as for instance pyridine, quinoline, etc., whereby there is produced as the primary product a 3-enol-17β-diacyl ester. The reaction mixture containing the primary product is further worked up, for example, by treatment with neutral ice water or extraction, or through prolonged stirring in alkaline ice water and the resulting 17-mono-acyl-ester isolated.

For use in the esterification, any of the acids suitable in steroid chemistry can be used. Illustrative of suitable acids are aliphatic carboxylic acids having 1 - 11, and most preferably 1 - 8, carbon atoms in the acid group, for example, acetic acid, propionic acid, caproic acid, onanthic acid, undecylic acid. The acids can be saturated or unsaturated, branched or not, polybasic or substituted in the known manner such as trimethylacetic, t.butylacetic, phenylacetic, cyclopentyl-propionic, halogen-acetic, amino-acetic, oxypropionic, benzoic, succinic, adipic acids, etc. The esterification is advantageously carried out at elevated temperatures, preferably at temperatures of from 130° - 200°C. The time required for the reaction is directly dependent on the reaction temperature. Thus the diester is produced after 6 hours with a reaction temperature of 160° C., and in 5 hours with a reaction temperature of 170° C. The said diester, i.e., 3-enol-17β-diacyl ester is thereafter partially saponified in the 3-position.

The following examples are given in order to disclose more clearly the nature of the present invention. It should be understood, however, that the examples are not intended to be a limitation on the scope of the invention.