Ethynerone: Difference between revisions
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In 1966, during its [[clinical development]], ethynerone was found to produce [[mammary gland]] [[tumor]]s in dogs treated with it at very high doses for prolonged periods of time.<ref name="GeilLamar2009">{{cite journal|last1=Geil|first1=R. G.|last2=Lamar|first2=J. K.|title=FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey|journal=Journal of Toxicology and Environmental Health|volume=3|issue=1-2|year=2009|pages=179–193|issn=0098-4108|doi=10.1080/15287397709529557}}</ref><ref name="JacobsHatfield2012">{{cite journal|last1=Jacobs|first1=A. C.|last2=Hatfield|first2=K. P.|title=History of Chronic Toxicity and Animal Carcinogenicity Studies for Pharmaceuticals|journal=Veterinary Pathology|volume=50|issue=2|year=2012|pages=324–333|issn=0300-9858|doi=10.1177/0300985812450727}}</ref><ref name="Lingeman2012">{{cite book|author=C.H. Lingeman|title=Carcinogenic Hormones|url=http://books.google.com/books?id=lOLnCAAAQBAJ&pg=PA149|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-81267-5|pages=149–}}</ref> Subsequent investigation found that [[17α-hydroxyprogesterone]] derivatves included [[anagestone acetate]], [[chlormadinone acetate]], [[medroxyprogesterone acetate]], and [[megestrol acetate]] produced similar mammary gland tumors, and that their ability to do so correlated directly with their progestogenic actions.<ref name="Lingeman2012" /><ref name="JamesPasqualini2013">{{cite book|author1=V. H. T. James|author2=J. R. Pasqualini|title=Hormonal Steroids: Proceedings of the Fifth International Congress on Hormonal Steroids|url=http://books.google.com/books?id=p1AJAwAAQBAJ&pg=PA7|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-5895-2|pages=7–8}}</ref> In contrast, the non-halogenated [[19-nortestosterone]] derivatives [[norgestrel]], [[norethisterone]], [[noretynodrel]], and [[etynodiol diacetate]], which are much less potent as progestogens, did not produce such effects at the dosages tested.<ref name="Lingeman2012" /> Clinical development of ethynerone was discontinued, and many of the 17α-hydroxyprogesterone derivatives were withdrawn for the indication of [[hormonal contraception]].<ref name="Lingeman2012" /><ref name="JamesPasqualini2013" /> Research later on revealed species differences between dogs and humans and established that there is no similar risk in humans.<ref name="RunnebaumRabe2012" /> |
In 1966, during its [[clinical development]], ethynerone was found to produce [[mammary gland]] [[tumor]]s in dogs treated with it at very high doses for prolonged periods of time.<ref name="GeilLamar2009">{{cite journal|last1=Geil|first1=R. G.|last2=Lamar|first2=J. K.|title=FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey|journal=Journal of Toxicology and Environmental Health|volume=3|issue=1-2|year=2009|pages=179–193|issn=0098-4108|doi=10.1080/15287397709529557}}</ref><ref name="JacobsHatfield2012">{{cite journal|last1=Jacobs|first1=A. C.|last2=Hatfield|first2=K. P.|title=History of Chronic Toxicity and Animal Carcinogenicity Studies for Pharmaceuticals|journal=Veterinary Pathology|volume=50|issue=2|year=2012|pages=324–333|issn=0300-9858|doi=10.1177/0300985812450727}}</ref><ref name="Lingeman2012">{{cite book|author=C.H. Lingeman|title=Carcinogenic Hormones|url=http://books.google.com/books?id=lOLnCAAAQBAJ&pg=PA149|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-81267-5|pages=149–}}</ref> Subsequent investigation found that [[17α-hydroxyprogesterone]] derivatves included [[anagestone acetate]], [[chlormadinone acetate]], [[medroxyprogesterone acetate]], and [[megestrol acetate]] produced similar mammary gland tumors, and that their ability to do so correlated directly with their progestogenic actions.<ref name="Lingeman2012" /><ref name="JamesPasqualini2013">{{cite book|author1=V. H. T. James|author2=J. R. Pasqualini|title=Hormonal Steroids: Proceedings of the Fifth International Congress on Hormonal Steroids|url=http://books.google.com/books?id=p1AJAwAAQBAJ&pg=PA7|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-5895-2|pages=7–8}}</ref> In contrast, the non-halogenated [[19-nortestosterone]] derivatives [[norgestrel]], [[norethisterone]], [[noretynodrel]], and [[etynodiol diacetate]], which are much less potent as progestogens, did not produce such effects at the dosages tested.<ref name="Lingeman2012" /> Clinical development of ethynerone was discontinued, and many of the 17α-hydroxyprogesterone derivatives were withdrawn for the indication of [[hormonal contraception]].<ref name="Lingeman2012" /><ref name="JamesPasqualini2013" /> Research later on revealed species differences between dogs and humans and established that there is no similar risk in humans.<ref name="RunnebaumRabe2012" /> |
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==Synthesis== |
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[[File:Ethynerone_synthesis.svg|thumb|center|700px|Ethynerone synthesis:]] |
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Reaction of ketone ('''1''') with the anion obtained by treatment of cis 1,2-dichloroethylene |
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with methyl lithium affords chloroacetylene ('''2'''). This reagent can be generated either by formation of the organometallic agent by abstraction of a proton followed by loss of hydrogen chloride from the adduct or, more likely, by elimination of HCl from the |
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ethylene followed by formation of the lithium reagent from the resulting acetylene. Hydrolysis of the enol ether under mild conditions (acetic acid) affords the unconjugated ketone ('''3'''). Treatment of that compound in [[pyridine]] with [[bromine]] leads to the potent oral progestin ethynerone ('''5'''). This last reaction can be rationalized by assuming that the first step consists of addition of bromine to the double bond at C-5,10 ('''4'''); double [[dehydrohalogenation]] will give the observed product. It is interesting to observe that '''3''' does not enolize to give an aromatic A ring. |
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==References== |
==References== |
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Revision as of 11:40, 28 January 2016
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| Clinical data | |
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| Routes of administration | Oral |
| Identifiers | |
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| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C20H23ClO2 |
| Molar mass | 330.84842 g/mol g·mol−1 |
| 3D model (JSmol) | |
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Ethynerone (INN, USAN) is a steroidal progestin of the 19-nortestosterone group that was developed in the 1960s but was never marketed.[1] Under the developmental code name MK-665, it was studied in combination with mestranol as an oral contraceptive.[2] Development of the drug was discontinued due to concerns surrounding toxicity findings in dogs.[2] It is a chloro-ethynyl derivative of norethisterone.[3]
In 1966, during its clinical development, ethynerone was found to produce mammary gland tumors in dogs treated with it at very high doses for prolonged periods of time.[4][5][6] Subsequent investigation found that 17α-hydroxyprogesterone derivatves included anagestone acetate, chlormadinone acetate, medroxyprogesterone acetate, and megestrol acetate produced similar mammary gland tumors, and that their ability to do so correlated directly with their progestogenic actions.[6][7] In contrast, the non-halogenated 19-nortestosterone derivatives norgestrel, norethisterone, noretynodrel, and etynodiol diacetate, which are much less potent as progestogens, did not produce such effects at the dosages tested.[6] Clinical development of ethynerone was discontinued, and many of the 17α-hydroxyprogesterone derivatives were withdrawn for the indication of hormonal contraception.[6][7] Research later on revealed species differences between dogs and humans and established that there is no similar risk in humans.[2]
Synthesis
Reaction of ketone (1) with the anion obtained by treatment of cis 1,2-dichloroethylene with methyl lithium affords chloroacetylene (2). This reagent can be generated either by formation of the organometallic agent by abstraction of a proton followed by loss of hydrogen chloride from the adduct or, more likely, by elimination of HCl from the ethylene followed by formation of the lithium reagent from the resulting acetylene. Hydrolysis of the enol ether under mild conditions (acetic acid) affords the unconjugated ketone (3). Treatment of that compound in pyridine with bromine leads to the potent oral progestin ethynerone (5). This last reaction can be rationalized by assuming that the first step consists of addition of bromine to the double bond at C-5,10 (4); double dehydrohalogenation will give the observed product. It is interesting to observe that 3 does not enolize to give an aromatic A ring.
References
- ^ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 521–. ISBN 978-1-4757-2085-3.
- ^ a b c Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 134–135. ISBN 978-3-642-73790-9.
- ^ Egon Diczfalusy; World Health Organization. Acta Endocrinologica: Supplementum. Ejnar Munksgaard. p. 261.
- ^ Geil, R. G.; Lamar, J. K. (2009). "FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey". Journal of Toxicology and Environmental Health. 3 (1–2): 179–193. doi:10.1080/15287397709529557. ISSN 0098-4108.
- ^ Jacobs, A. C.; Hatfield, K. P. (2012). "History of Chronic Toxicity and Animal Carcinogenicity Studies for Pharmaceuticals". Veterinary Pathology. 50 (2): 324–333. doi:10.1177/0300985812450727. ISSN 0300-9858.
- ^ a b c d C.H. Lingeman (6 December 2012). Carcinogenic Hormones. Springer Science & Business Media. pp. 149–. ISBN 978-3-642-81267-5.
- ^ a b V. H. T. James; J. R. Pasqualini (22 October 2013). Hormonal Steroids: Proceedings of the Fifth International Congress on Hormonal Steroids. Elsevier Science. pp. 7–8. ISBN 978-1-4831-5895-2.
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