Estrógenos: terapia anticonceptiva / Estrogens: anticonceptive therapy

Para estudiar el fenómeno competitivo molecular del Etinil-Estradiol (EE-2) contenido en los anticonceptivos orales, en contra del estradiol (E-2) endógeno intra/extra-celular, muestras de plasma y endometrio fueron simultáneamente obtenidas en diferentes días del pseudociclo menstrual de mujeres bajo tratamiento con EE-2 + Norgestrel (30 ug + 500 ug) y EE2 + Noretindrona (50 ug + 1.0 mg). Los compuestos que contienen 30 ug de estrógeno sintético administrados crónicamente independientemente del contenido progestacional mostraron la no supresión del fenómeno cíclo hacia el 17 ß estradiol ovárico; ese fenómeno no se observó en el tejido endometrial. Un mecanismo local interceptivo debiera ser reconsiderado como un mecanismo farmacológico en el futuro de la regulación de la fertilidad

Steroid hormones and the Luftwaffe. A venture into fundamental strategic research and some of its consequences: the Birch reduction becomes a birth reduction.

I recount my involvement in the development of biologically active, totally synthetic steroid hormones since 1941. The reasons for my approach to the first total synthesis of a potent androgen are given. I touch on the even more important general synthetic outcomes from ideas generated by the search for useful amounts of a cortically active hormone, such as novel angular methylations, partial hydrogenations of aromatic systems (Birch reductions), and novel usages in synthesis based on the unique structures so generated. The Birch process was critical for synthesis of the first oral contraceptives. A need to explain the structures of Birch reduction products and the experimental requirements resulted in further elucidations of the mechanism of reduction processes, notably for aromatic compounds. The first theoretical and practical distinction between structures of products as determined by a reaction rate or an equilibrium position was first exploited experimentally in the deconjugation of cholest-4-en-3-one in the final step of the first facile total synthesis of cholesterol. A knowledge gained of the biosynthesis of steroids and its specific enzymes helped to initiate my general polyketide theory of biosynthesis and also my idea of outdoing enzyme achievements with organometallic complexes ("inorganic enzyme chemistry"). I assert the high historic importance of steroids in promoting the advance of general organic chemistry within many fields.

PIP: Arthur J. Birch, chemistry professor at Australian National University, reviewed his role in developing the biologically active, totally synthetic steroid hormones beginning in 1941 after graduating from Oxford University in the UK. His supervisor asked him to serve at the Dyson Perrins Laboratory at Oxford, affiliated with ICI which was affiliated with the UK Government, to produce cortically active hormones for RAF pilots, since it was rumored that German Luftwaffe pilots used them. His research and ideas led him to develop new angular methylations, partial hydrogenations of aromatic systems (Birch reductions), and new synthesis practices based on the unique structures so generated. The Birch reductions were a key element to synthesis of the first oral contraceptives. Specifically, Gregory Pincus orally administered the synthetic 19-nor ethinyl derivatives obtained from Birch reduction and found them to be active progestagens, leading to the development of oral contraceptives. His research into revealing the structures of chemicals produced by Birch reductions and the experimental requirements brought about more clarity of the mechanism of reduction processes, especially for aromatic compounds. His first attempt to differentiate between structures of products as determined by a reaction rate or an equilibrium position was deconjugation of cholest-4-en-3-one in the last step of the first elementary total synthesis of cholesterol. The knowledge acquired from biosynthesis of steroids and of specific enzymes contributed to his general polyketide theory of biosynthesis and to his theory of outdoing enzyme achievements with organometallic complexes, which he called inorganic enzyme chemistry. Professor Birch's research has maintained the very historic significance of steroids in furthering the progress of general organic chemistry within many fields.

11 beta-nitrate estrane analogues: potent estrogens.

Various estrane derivatives 1 reacted with cerium ammonium nitrate (CAN) selectively and efficiently to provide 9 alpha,11 beta-defunctionalized derivatives 2, which were subsequently deoxygenated at C-9 with triethylsilane/boron trifluoride etherate to the desired target 11 beta-nitratoestranes 3a, 3b, and 5. When examined for estrogenic and postcoital antifertility activity, 11 beta-nitrates 2c, 2d, and 3b most notably displayed more potent oral activity than did ethynylestradiol.

[Synthesis of gestodene]. / Synthesen von Gestoden.

The synthesis of the new progestogen, 17 alpha-ethinyl-17 beta-hydroxy-18-methyl-4,15-estradien-3-one (gestodene, 6), starting from 18-methyl-4-estren-3,17-dione (1) can be accomplished by several methods. The oral progestational activity of gestodene is greater than that of levonorgestrel. Gestodene, in combination with ethinylestradiol, is contained in a recently developed oral contraceptive.

Long-acting contraceptive agents: design of the WHO Chemical Synthesis Programme.

The great demand for improved long-acting injectable steroid contraceptives, particularly in developing countries, and the relative lack of interest from the pharmaceutical industry to develop such products stimulated WHO to launch a synthetic and screening programme to find improved, safe and acceptable injectable preparations. More than 210 esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) have been prepared in university-based research laboratories situated mainly in developing countries, and then screened by NICHHD in animal models. The following three compounds, levonorgestrel butanoate, cyclopropylcarboxylate and cyclobutylcarboxylate, proved to be particularly long-acting when administered as microcrystalline suspensions. The overall strategy of this research and development programme is described.

Long-acting contraceptive agents: levonorgestrel esters of unsaturated acids.

Esters of levonorgestrel (13 beta-ethyl-17 beta-ethynyl-17 beta-hydroxygon-4-en-3-one) with a variety of unsaturated carboxylic acids have been synthesized for evaluation as potential long-acting, injectable contraceptive agents.

PIP: This paper describes the synthesis of esters of levonorgestrel (13 beta-ethyl-17 beta-ethynyl-17 beta-hydroxygon-4-en-3-one) with a variety of unsaturated carboxylic acids for evaluation as potential longacting injectable contraceptive agents. 1-Cyclohexenylacetic acid was prepared by the hydrolysis of 1-cyclohexenylacetonitrile. The synthesis of E-penta-2,4-dienoic acid was achieved by the condensation of acrolein with malonic acid. Reformatsky reaction between crotonaldehyde and ethyl 2-bromopropionate followed by dehydration of the condensation product was used for the synthesis of E,E-2-methylhexa-2,4-dienoic acid. In the preparation of 5-methyl-2-furylacetic acid, 5-methylfurfural was subjected to condensation reaction with rhodanine followed by hydrolysis. The levonorgestrel esters were synthesized by reaction of the appropriate acid chloride with the thallim salt of levonorgestrel, which was obtained by use of thallous ethoxide. The esters prepared were levonorgestrel 1-cyclohexenylacetate; levonorgestrel 1-cyclopentenylacetate; levonorgestrel E-penta-2,4-dienoate; levonorgestrel E,E-2methylhexa-2,4-dienoate; levonorgestrel 5-methyl-2-furylethaoate; levonorgestrel 3-(5'-methyl-2'-furyl)propanoate; levonorgestrel 3-(5'-ethyl-2'-furyl)propanoate; leveonorgestrel 4-(5'-methyl-2'-furyl)butanoate; levonorgestrel E-non-2-en-4-ynoate; 1-cyclohexenylacetic acid; 1-cyclopentenylacetic acid; E-penta-2,4-dienoic acid; E,E-2-methylhexa-2,4-dienoic acid; 5-methyl-2-furylacetic acid; and E-non-2-en-4-ynoic acid.

Long-acting contraceptive agents: aliphatic and alicyclic carboxylic esters of levonorgestrel.

Esters of levonorgestrel (13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) with a variety of aliphatic and alicyclic carboxylic acids have been prepared and characterised. In tests for the suppression of estrus in rats, esters with short-chain aliphatic acids and with cyclobutane-carboxylic acid were considerably more active than the standard, norethisterone enanthate (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one). Such esters show great promise for development as long-acting progestogens.

Long-acting contraceptive agents: analysis and purification of steroid esters.

More than 200 samples of esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3 -one) have been analysed by a combination of techniques, including high performance liquid chromatography (HPLC). Compounds having a purity below the required limit (99.5%) were purified, mainly by preparative HPLC, prior to formulation and biological evaluation as long-acting progestogens.

Chemical synthesis and bioassay of anordrin and dinordrin I and II.

The chemical synthesis of 2 alpha, 17 alpha-diethynyl-A-nor-5 alpha-androstane-2 beta, 17 beta-diol dipropionate (Anordrin) and the corresponding diacetate is reported. Similarly, the preparation of the 2 alpha, 17 alpha-diethynyl-A-nor-5 alpha-estrane-2 beta, 17 beta-diol, its diacetate and dipropionate (Dinordrin I), along with the corresponding 2 beta-epimer (Dinordrin II) from 17 beta-hydroxy-A-nor-5 alpha=estran-2-one is described. In rat uterotrophic activity bioassay, the slope of ethynylestradiol differed significantly from the slopes of the other three compounds, thus vitiating potency estimates with this reference compound. Dinordrin I was 20 times more potent than Anordrin and considerably more potent then Dinordrin II. The single-dose oral antifertility effect in rats generally paralleled uterotrophic activity. Immediate postovulatory contraceptive effectiveness was assessed in adult cycling female baboons given two doses daily for 4 days. Both Anordrin and Dinordrin I showed antifertility activity worthy of further study. Moreover, a definite luteolytic effect, with depression of both plasma estrogen and progesterone levels, was observed with these two steroids.

Antifertility agents. 12. Structure-activity relationship of 3,4-diphenylchromenes and -chromans.

Synthesis and antiimplantation activity of variously substituted 2,2-dialkyl-3,4-diphenylchromenes and 3,4-cis- and trans-chromans derived from them are described. Pregnancy-inhibiting activity in rats was exhibited by a number of these compounds, which was particularly marked in the case of 3,4-trans-3-phenyl-4-p-(beta-pyrrolidinoethoxy)-phenyl-7-methoxychroman (32), the corresponding 2,2-dimethyl analog 34, and 3-phenyl-4-p-(beta-pyrrolidinoethoxy)phenyl-7-methoxychromene (26). The structure-activity relationship of these compounds is discussed.

Studies in antifertility agents. 11. Secosteroids. 5. Synthesis of 9,11-secoestradiol.

9,11-Secoestradiol (9) and 11-hydroxy-9,11-secoestradiol (12) have been synthesized starting from 17-acetoxyestradiol 3-methyl ether (1) and found to possess significant antifertility activity in rats. 3-Methoxy-9,11-seco-9-oxo-17beta-acetoxyestra-1,3,5(10)-trien-11-oic acid (2), prepared by CrO3 oxidation of 1, on hydrogenolysis gave methyl 17beta-hydroxy-3-methoxy-9,11-secoestra-1,3,5(10)-triene-11-carboxylate (3). The 17-O-THP derivative of 3 was treated with LiAlH4 to give 17beta-(O-tetrahydropyranyl)-3-methoxy-11-hydroxy-9,11-secoestra-1,3,5(10)-triene (5). The 11-O-mesylate of 5 on LiAlH4 reduction followed by mild acid treatment and demethylation under alkaline conditions gave 9. LiAlH4 reduction of 3 gave 9,11-seco-11-hydroxyestradiol 3-methyl ether (11) which on demethylation gave 9,11-seco-11-hydroxyestradiol (12).