Contraceptive progestins. Various 11-substituents combined with four 17-substituents: 17 alpha-ethynyl, five- and six-membered spiromethylene ethers or six-membered spiromethylene lactones

Norethisterone (NET) is a 19-nortestosterone derivative with progestagenic and some androgenic activity, which was used in the first generation of con traceptives. NET was succeeded by levonorgestrel (LNG) and later on by deso gestrel (DSG) and gestodene (GSD). Although these latter two progestins had increased potency, there was still androgenicity with gestodene and to a l esser extent with desogestrel. New progestins were synthesized in order to further enhance progestagenic and to reduce androgenic activity. Four diffe rent chemical moieties were introduced in position 17 of 19-nortestosterone , viz. 17 alpha -ethynyl, five- and six-membered spiromethylene ethers, and a six-membered-spiromethylene lactone. In combination with these structure s seven different substituents were added at position 11, i.e. methylene, m ethyl, ethyl, ethenyl, ethynyl, 2-propenyl and 1-propynyl. All substituents except for methylene occupied the 11 beta -position. All these 32 compound s were synthesized and analysed in vitro and in vivo against etonogestrel ( ETG, 3-keto-desogestrel), the biologically active metabolite of desogestrel . Their relative binding potency to progesterone (PR), androgen (AR) and es trogen (ER) receptors were determined in cell lysates of human breast tumor MCF-7 cells and to glucocorticoid (GR) receptors in that of human leukemic IM-9 cells. Moreover, their relative agonistic activities were assessed in Chinese hamster ovary cell-based transactivation assays. All in vivo activ ities were determined in McPhail (progestagenic), ovulation inhibition (pro gestagenic and estrogenic), Hershberger (androgenic), hormone screening (gl ucocorticoid and estrogen) and Allen-Doisy (estrogenic) tests after oral an d for the McPhail test also after subcutaneous administration. The progesta genic binding and transactivation potencies of all compounds in the three 1 7-spiro series were higher than those of the corresponding analogues in the 17 alpha -ethynyl series. None of the compounds showed estrogenic or clear androgenic binding and transactivation potential except for a six-membered -spiromethylene lactone with a propynyl group. This compound showed strong androgenic binding. The glucocorticoid binding and transactivation were ver y low for the compounds with the 17 alpha -ethynyl and the five-membered-sp iromethylene ether groups, whereas both six-membered-spiro series showed, d early with methyl and ethynyl substituents, and less pronounced with methyl ene and ethenyl, higher binding and transactivation values. For the 17 alph a -ethynyl series, the McPhail lest showed high potencies with methylene, m ethyl and ethenyl substituents after oral treatment or with propenyl after subcutaneous administration. The introduction of the spiro substituents in position 17 led to high potencies for other 11-substituents as well. Beside s methyl, also ethyl, ethynyl and propynyl were potent substituents. With o vulation inhibition tests, the ethyl, ethenyl and ethynyl substituents were the more potent compounds in all four series. However, compounds with meth yl or ethynyl additions appeared to be glucocorticoidal in the hormone scre ening test irrespective of the 17-substituent, while with the three spiro s eries even methylene and ethenyl groups became active. Androgenicity was on ly observed at dose levels at or above 5 mg/kg, which is 7.5-fold weaker th an ETG. Moreover, estrogenicity appeared negligible with the three spiro se ries, while with the 17 alpha -ethynyl series methyl, ethyl, ethtnyl and et hynyl substituents, a very high estrogenic potential was assessed. Based on the high efficacy and low side-effects, the following compounds sh ow a high selectivity: 17 alpha -ethynyl with ethyl, ethenyl and 2-propenyl substituents, six-membered spiromethylene ether with ethyl and six-membere d-spiromethylene lactone with ethyl, 2-propenyl or 1-propynyl substituents. These compounds have relatively high binding and transactivation values fo r PR, and have high biopotencies in the McPhail and ovulation inhibition te sts, while showing very weak androgenic and glucocorticoid activities. Thes e compounds may be very useful for contraception for either oral and/or sub cutaneous administration. (C) 2000 Elsevier Science Ltd. All rights reserve d.