(Androst-5-en-17beta -yl)alkyl sulfoxides and sulfones and their use for control of fertility

#The invention relates to (androst-5-en-17β-yl)alkyl sulfoxides and sulfones, to pharmaceutical compositions containing the same, as well as to the use: of these (androst-5-en-17β-yl)alkyl sulfoxides and sulfones for the preparation of a medicament for the control of fertility.

#Sexual reproduction involves a cyclic alternation of diploid and haploid states: diploid cells divide by the process of meiosis to form haploid cells, and the haploid cells fuse in pairs at fertilization to form new diploid cells. The process of meiosis is characterized by two meiotic divisions, unique to both male and female germ cells. During the process two cell divisions, following one round of DNA replication, give rise to four haploid cells from one single diploid cell. Chromosomal crossover events, during which paternal and maternal genetic material is exchanged, occur during the prophase of the first meiotic division. At the end of the first meiotic division one member of each chromosome pair, composed of two sister chromatids is distributed to each daughter cell. The second meiotic division segregates each sister chromatide into a separate haploid cell. Male and female germ cells are subject to similar meiotic divisions but differ in the regulation of these processes. In the male meiosis is a continuous process in germ cells derived from a population of immature germ cells, the stem cell spermatogonia. After sexual maturation of the male, spermatogonia from this stem cell population embark on meiosis. The first and second meiotic division proceed without interruption and eventually give rise to four mature spermatozoa.

#In the female, primary oocytes start the first meiotic division already during the embryonic stage but they remain arrested in the prophase (dictyate stage) until the female becomes sexually mature. Meiosis resumes at the time of ovulation (egg maturation) after which the first meiotic division is completed and the second meiotic division is initiated. In most vertebrates the second meiotic division is arrested at the metaphase and only completed after fertilization. At the end of the first and of the second meiotic division the cytoplasm divides asymmetrically to produce two secondary oocytes, each with a haploid number of single chromosomes, but greatly differing in size: one is a small polar body, which eventually degenerates, and the other is a large cell containing all the developmental potential. Finally one mature ovum is produced.

#The invention is further illustrated by the following examples.

#i)—Pyridinium p-toluenesulfonate (0.31 g) was added to a solution of (3β,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylpregn-5-en-3-ol (WO9852965; 7.28 g) in dichloromethane (50 ml) and ethyl vinyl ether (20 ml). After stirring of the reaction mixture for 6 h at room temperature it was poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into dichloromethane; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregn-5-ene (8.19 g), which was used in the following step without further purification.

#ii)—A solution of the product obtained in the previous step (8.19 g) in a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 35 ml) was stirred at room temperature for 5 h. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (3β,20S)-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregn-5-en-21-ol (5.17 g).