A simple and convenient synthetic route to Ulipristal acetate.

We set out to describe a new and efficient route for preparing Ulipristal acetate with a good yield. The selected epoxidization conditions gave out 80% of 5α,10α-epoxide 2a in the two diastereoisomers which greatly improved the yield of 11ß-substituted isomer 4a. And phenyl-sulfinyl compound 6 was synthesized from ketone 5 directly treated with phenylsulfenyl chloride in the presence of triethylamine. These synthetic procedures is only 8 steps, less than currently reported in the literature, but more suitable for industrial process.

Design and synthesis of 3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception.

We designed a series of 25 3-(azol-1-yl)phenylpropanes which yielded 10 compounds (3, 4, 7, 8, 13, 14, 19, 21, 23, 26) that irreversibly immobilized 100% human sperm at 1% (w/v) concentration in 60s; 12 compounds (8, 9, 15, 16, 19-21, 23-25, 27, 28) that showed potent microbicidal activity at 12.5-50 µg/mL against Trichomonas vaginalis; and 17 compounds (3-11, 13, 15, 19, 21, 23, 26, 28, 30) that exhibited potent anticandida activity with minimum inhibitory concentration (MIC) of 12.5-50 µg/mL. Almost all the compounds exhibited high level of safety towards normal vaginal flora (Lactobacillus) and human cervical (HeLa) cells in comparison to the marketed spermicide nonoxynol-9 (N-9). All the biological activities were evaluated in vitro. Two compounds (4, 8) with good safety profile exhibited multiple (spermicidal, antitrichomonas and anticandida) activities, warranting further lead optimization for furnishing a prophylactic vaginal contraceptive.

Preclinical studies of alkylureas as anti-HIV-1 contraceptive.

The HIV-1 epidemic continues to spread at a rate of over 15, 000 new cases daily. HIV-1 transmission through heterosexual contact became the dominant risk for women globally. About half of the over 40 million HIV-1 infected individuals worldwide are now women. The lack of empowerment of women is the fundamental cause for the rampant spread of HIV-1 in women. Topical microbicides applied intravaginally offer an option for female-initiated HIV-1 prevention. There is an urgent need to develop microbicides with and without contraceptive qualities to also address socio-cultural settings where the woman's status is linked to fertility. A safe and efficacious anti-HIV-1 vaginal formulation is not yet available though a large number of candidates are in preclinical or clinical studies. Presently marketed topical microbicides are by and large toxic and damage the vaginal mucosa with frequent use. The microbicidal system of alkylureas evaluated here lends itself to contraceptive and non-contraceptive anti- HIV-1 formulations. Alkylureas are agents that irreversibly disrupt free and intracellular HIV-1, have a wide margin of safety and are spermicidal above their virucidal concentration without any mucosal toxicity. Butylurea, the lead compound is also effective against other sexually transmitted diseases (STDs) while sparing the normal vaginal flora. Alkylureas with longer alkyl chains still have to be explored and may have a greater selective microbicidality.

Synthesis and structure-activity relationship of novel 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones as progesterone receptor modulators leading to the potent and selective nonsteroidal progesterone receptor agonist tanaproget.

Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.

Synthesis and biological evaluation of some novel 4H-benzopyran-4-one derivatives as nonsteroidal antiestrogens.

The preparation and characterization of some novel 2- and 3-substituted-7-methoxy-4H-1-benzopyran-4-one are presented. The synthesized compounds were evaluated for their uterotrophic, antiuterotrophic and antiimplantation activities in mature female albino rats. 3-Benzyl-7-methoxy-4H-1-benzopyran-4-one (14) showed the highest uterotrophic activity (87%) based on dry uterine weight gain. The antifertility activity, as assessed by the post-coital antiimplantation activity test, was of weak potency for most compounds (14-29%). Among the products, the 2-(4'-methoxyphenyl)-7-methoxy-4H-1-benzopyran-4-one (19) exhibited the highest antiestrogenic activity of 65%. It also elicited 31% of the uterotrophic activity of estradiol.

Synthesis and progestational activity of 16-methylene-17 alpha-hydroxy-19-norpregn-4-ene-3,20-dione and its derivatives.

16-Methylene-17 alpha-hydroxy-19-norpregn-4-ene-3,20-dione 1 and its 17 alpha-acylated derivatives were synthesized. The length of the 17 alpha-side-chain ranges from C2-C6. As anticipated, compound 1 did not show any progestational activity or receptor binding activity; whereas, the acylated compounds, especially the butyrate, showed remarkable ability to bind to progesterone receptors. These compounds also showed progestational activity in an in vitro T47D cell culture assay in which progestins increase alkaline phosphatase activity and in an in vivo ovulation inhibition assay. All of the compounds synthesized were without estrogenic activities. The results showed that acylation of 16-methylene-17 alpha-hydroxy-19-norprogesterone can increase progestational activity. The progestational activities of these compounds varied with the 17 alpha-side chain.

Synthesis of novel 6-aza-B- and 11-aza-C-homoestranes as antifertility agents.

Reaction of 3,9 alpha, 17 beta-trihydroxyestra-1,3,5(10)-trien-11-one 17-acetate 3-methyl ether (3) with N3H-BF3 etherate leads mainly to lactam (4) along with the N-azido compound (5) as a minor product. Under similar conditions, 3,17 beta-dihydroxyestra-1,3,5(10)-trien-6-one 17-acetate 3-methyl ether gives lactam (12) and the tetrazole derivative (9). Similar reaction of the diacetate (8) gives only the tetrazole derivative (11). Compounds 4, 6, and 10 prevent implantation in rats at 5-, 10-, and 5-mg/kg doses, respectively. Compounds 4, 6, 9, and 10 show significant estrogenic activity at the respective contraceptive doses.

PIP: Scientists at the Central Drug Research Institute in Lucknow, India, synthesized and evaluated new 6-aza-B-and 11-aza-C-homoestranes to determine the effect of structural changes around C-11 and C-6 in estradiol on its estrogenic and antifertility activities. They used sperm-positive female albino rats (180-220 g) to test the compounds anti-implantation activity and ovariectomized immature rats (25-30 g) to test their estrogenic activity. Adding N3H-BF3 etherate to 3, 9-alpha,17-beta-trihydroxyestra-1,3,5(10)-trien-11-one 17-acetate 3-methyl ether created 11-aza-3,17beta-dihydroxy-C-homoestra-1,3,5(10),8(9)-tetraen-12-one 17-acetate 3-methyl ether and the N-azido compound as a minor product. Adding N3H-BF3 etherate to 3, 17beta-dehyroxyestra-1,3,5(10)-trien-6-one 17-acetate 3-methyl ether created 6-aza-3,17beta-dihydroxy-B-homoestra-1,3,4(10)-trien-7-one 17-acetate 3-methyl ether and the tetrazolo derivative. When N3H-BF3 etherate was added to diacetate, just the tetrazole derivative emerged. 1-aza-3,17beta-dihydroxy-C-homoestra-1,3,5(10),8(9)-tetraen-12-one 17-acetate 3-methyl ether (5 mg-kg dose), 11-aza-3,17beta-dihydroxy-C-homoestra-1,3,5(10),8(9)-tetraen-12-one 3-methyl ether (10 mg/kg dose), and 6-aza-3,17beta-dihydroxy-B-homoestra-1,3,4(10)-trieno[6,7-d]tetrazole 3-methyl ether (5 mg/kg dose) all delivered subcutaneously, prevented implantation in all rats. These compounds and 6-aza-3,17beta-dihydroxy-B-homoestra-1,3,5(10)-trieno[6,7-d] tetrazole 17-acetate 3-methyl ether (10mg/kg dose) showed significant estrogenic activity.

Regioselective reactions of 1,2-dehydroprogesterone: syntheses of pregnane derivatives as possible contragestational agents.

A few pregnane derivatives were synthesized from 1,2-dehydroprogesterone (1). Ring A of 1,2-dehydroprogesterone was aromatized without affecting C-20, and the resulting acetoxy compound (2) after hydrolysis yielded 1-hydroxy-4-methyl-19-norpregna-1,3,5(10)-trien-20-one (3). Reactions of the phenol (3) with alkyl halides yielded the ethers 6a-6b and 7. Opening of the oxirane ring in 7 with secondary amines furnished the aminoalcohols 8a-8b. Friedelcraft's reaction of 3 with maleic anhydride and chloracetyl chloride led to the formation of 9 and 10, respectively. Base-catalyzed ring closure of 10 yielded 1-acetyl-12a-methyl-8-oxo-5[H]-1,2,3,3a,3b,4,8,9,10b,11,12, 12a-dodecahydrocyclopenta (7,8)-phenanthro (3,4-b) furan (11), which reacted with aromatic aldehydes regioselectively to furnish 12a-12b. Reaction of 1 with triethylorthoformate in the presence of boron trifluoride etherate involved the participation of C-21, and the carbonyl at C-3 remained unaffected. The product 13 was identified as 21-[2-hydroxyvinyl]-21-norpregna-1,4-diene-3,20-dione. Reductive amination with sodium cyanoborohydride in the presence of ammonium acetate did not attack ring A and smoothly furnished the amine 14 which, on reaction with succinic anhydride, gave 20-succinamylpregna-1,4-dien-3-one (15).

[Synthesis of ST-1435 derivatives as contraceptive for lactating women].

Four new ST-1435 derivatives 4-7 were synthesized. Both 4 and 5 are mixture of Z- and E-isomers. 4 was separated into Z- and E-isomers by spinning TLC. Their binding ability to progesterone receptor was examined and found to be less than ST-1435.

Development and use of a radioimmunoassay for D-(-)-norgestrel 17 beta-cyclopentanecarboxylate.

The synthesis of the 6 alpha-carboxymethylmercapto BSA and homologous histamine conjugate of D-(-)-norgestrel 17 beta-cyclopentanecarboxylate is reported. Using the BSA conjugate as an immunogen for the development of antibody in the rabbit and the 125I-histamine conjugate as the radioligand, a radioimmunoassay (RIA) for the ester was developed. Serum profiles of the free alcohol and ester were determined following IV or IM injection in macaques. Peak values for the ester (about 12 ng/mL) were observed 2 min following an IV bolus of 0.5 mg in one rhesus monkey. Blood levels dropped rapidly within the first 30 min and were barely detectable at 24 h. Serum levels of the free alcohol rose to a peak at 30 min and then declined slowly to very low values by 24 h. Following IM injection of 20 mg in cynomolgus monkeys, peak levels of the ester were observed within a few days while the free alcohol reached a maximum about day 30. Serum concentrations of D-(-)-norgestrel had fallen to about 0.4 ng/mL 160 days post-injection when levels of the ester fell below 0.2 ng/mL.

Studies in spiro heterocycles. Part 4(1): Investigation of the reactions of fluorinated 3-aroylmethylene-indol-2-ones with hydrazine and phenylhydrazine and synthesis of spiro [indole-3,3'-pyrazol]-2-ones.

Reactions of various 3-aroylmethylene-indol-2-ones with hydrazine and phenylhydrazine under exactly similar conditions have been carried out. The reaction with phenylhydrazine has not been investigated earlier. It was found that although the reaction with hydrazine hydrate afforded a spiro derivative viz., spiro[3H-indole-3,3'-(3H)pyrazol]-2(1H)-one, that with phenylhydrazine yielded simply a hydrazone derivative. Representative spiro compounds have been screened for antifertility activity but none was found active at a dose of 10 mg/kg in adult female rats.

Studies in antifertility agents--Part XLI : Secosteroids--X : Syntheses of various stereoisomers of (+/-) 2,6 beta -diethyl-7 alpha -ethynyl-3-(p-hydroxyphenyl)-trans-bicyclo[4.3.0]nonan-7 beta-ol.

The syntheses of (+/-) 2 alpha,6 beta -diethyl-7 alpha -ethynyl-3 alpha-(p-hydroxyphenyl)-trans- bicyclo[4.3.0]nonan-7 beta-ol (8), (+/-)2 beta,6 beta-diethyl-7 alpha-ethynyl-3 beta-(p-methoxy-phenyl)-trans-bicyclo[4.3.0]nonan-7 beta-ol 12 and (+/-) 2 alpha,6 beta-diethyl-7 alpha-ethynyl-3 beta-(p-hydroxyphenyl)- trans-bicyclo[4.3.0]nonan-7 beta-ol (18) and their derivatives, which are essentially B-seco-steroids having cis-anti-trans, cis-syn-trans and trans-anti-trans geometries have been carried out. A study of their antiimplantation activities (AI) and receptor binding affinities (RBA) show that trans-anti-trans compounds are biologically most potent, followed by the corresponding cis-anti-trans and cis-syn-trans compounds. The most potent compound 18 is active at 1 mg/kg in rats. Introduction of 7 alpha-ethynyl group increases their AI activity; however, no significant effect on their RBA is observed.