The Synthesis of Some 7α- and 7β-Methyl Steroid Hormones<sup>1</sup>

Campbell, J. Allan; Babcock, John C.

doi:10.1021/ja01524a063

Cited by 75 publications

(15 citation statements)

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“…Recently, we have documented that norethisterone (NET), a nonphenolic, nonaromatizable synthetic progestin, activates rat male sexual behavior through its intrinsic androgenic potency coupled with the estrogen-like potency of its 3,5a-and 3at,5ax-tetrahydro metabolites; these findings provide evidence that NET does not require enzyme-mediated aromatization for stimulating male copulatory activity [18]. The present study was aimed at investigating the activity of the potent synthetic androgen 7o-methyl-19-nortestosterone (MENT) [19,20] in restoring male sexual behavior in long-term castrated adult rats. Such a study was of interest since this synthetic steroid does not undergo 5Sa-reduction in vitro or in vivo [21,22].…”

Section: Introductionmentioning

confidence: 99%

Induction of Male Sexual Behavior in the Rat by 7α-Methyl-19-Nortestosterone, an Androgen that does not Undergo 5α-Reduction1

Moralí

Lemus

Munguía

et al. 1993

Biology of Reproduction

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The synthetic steroid 7 alpha-methyl-19-nortestosterone (MENT) binds with high affinity to the androgen receptor and exerts biological effects at some peripheral target tissues with a potency greater than that of naturally occurring androgens. In vivo, MENT does not undergo enzymatic 5 alpha-reduction and as a consequence, its biologic action on prostate and other organs of the male reproductive tract is not amplified as is that of testosterone (T). Thus, in castrated rats, a dose of MENT that will maintain normal muscle mass and gonadotropin levels will not maintain normal prostate and seminal vesicle weights. To investigate the ability of MENT to restore male sexual behavior in castrated rats, varying doses of MENT acetate were administered for 4 wk by use of s.c. mini-osmotic pumps. Animals treated with T acetate (200 micrograms/day) and nontreated intact animals served as positive controls, while a group of animals receiving vehicle alone were the negative controls. Steroid acetates are rapidly converted to T and MENT in blood. Appropriate steroid delivery was assessed by measurement of serum androgen concentrations. Male behavioral parameters were recorded twice per week. At the end of treatment, the weights of sex accessory organs were also recorded. The administration of MENT acetate at daily doses of 100 micrograms and 10 micrograms induced full copulatory behavior in a manner similar to that observed with doses of 200 micrograms T acetate.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Introductionmentioning

confidence: 99%

Induction of Male Sexual Behavior in the Rat by 7α-Methyl-19-Nortestosterone, an Androgen that does not Undergo 5α-Reduction1

Moralí

Lemus

Munguía

et al. 1993

Biology of Reproduction

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“…product of 7a,17a-dimethyltestosterone (Myagen) [1,2], In animal screening studies the 7[3 isomer showed slight androgenic and anabolic activity and no other endocrine or anti-endocrine effect [3]. Animal antitumor screens showed no efficacy against the R-35 mammary adenocarcinoma in the Sprague-Dawley rat, 11095 squamous cell prostatic carcinoma or R-3149 acute myelocytic leukemia in the Fischer 344 rat, WR-6 acute lymphocytic leukemia or WL/12 myelocytic leukemia in the Wistar-Furth rat, sarcoma 180 in the Swiss mouse, or against leukemia L-1210 or Lewis lung tumor in the BDF!…”

mentioning

confidence: 99%

Calusterone (7β,17α-DimethyItestosterone) as Primary and Secondary Therapy of Advanced Breast Cancer

Gs¹,

Halden²,

Horn³

et al. 1973

Oncology

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The antitumor efficacy of calusterone, 200 mg/day by mouth, against objectively progressing advanced breast cancer was evaluated by the Cooperative Breast Cancer Group criteria in 117 women. In 41, calusterone was the first treatment for advanced breast cancer, in 49 it was given as secondary steroidal therapy, and in 27 it followed cytotoxic chemotherapy. Part of the study included comparison by the double-blind technique of calusterone in 23 women with Δ¹-testololactone, 1,000 mg/day by mouth, in 25 similar patients randomly distributed for site of most significant metastasis and for age with respect to the menopause. Calusterone produced objective regressions lasting an average of 9.8 months in 51% of patients in whom it was primary or secondary hormonal therapy, but in only 19% of patients with previous cytotoxic chemotherapy. In the last group, regressions lasted only 6 months. Calusterone was equally effective in women with or without visceral metastasis, in all age groups, and in castration failures. In the double-blind study, calusterone produced regressions in 52% and Δ¹-testololactone in 32% of patients. In the crossover, patients who had not responded to calusterone also failed to respond to Δ¹-testololactone, while 33% of Δ¹-testololactone failures or responders obtained regression on calusterone therapy. Calusterone is a weak androgen, and, like other 17α-alkylated steroids, produces nausea in 28 % of patients and BSP retention almost uniformly. There was no cholestatic jaundice or hepatocellular damage. Nausea was usually transient, but of sufficient severity in five patients to necessitate termination of therapy. Unlike other androgens, calusterone causes no rise in hematocrit, but a striking increase in the platelet count and a slight rise in the white blood cell count. By the rigorous criteria of the Cooperative Breast Cancer Group, calusterone is the most effective antitumor steroid thus far identified in a statistically adequate sample.

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“…Die Beobachtung, dass bei der Behandlung rnit Kaliumcyanid in Alkohol bei Zimmertemperatur nur die 7b-Methylverbindung rnit aquatorialer Lage der Methylgruppe reagiert , wahrend das 7u-Isomere praktisch unverandert bleibt, vereinfachte die Auftrennung des Isomerengemisches wesentlich. Das bekannte Verfahren [5], das in der Trennung der epimeren 7-Methylverbindungen durch selektive Dehydrierung des 7LLIsomeren rnit Chloranil besteht, war in unserem Falle nicht anwendbar, da unter den Reaktionsbedingungen die Ketalgruppe in 17-Stellung gespalten wurde. Die Dehydrierung von XIV zu XI1 wurde zunachst rnit Dichlor-dicyan-benzochinon versucht , wobei jedoch nur Ausbeuten um 50% erreicht wurden.…”

Section: %unclassified

Synthese von 7α‐Methylöstron. Über Steroide, 210. Mitteilung

Wieland

Anner

1967

Helvetica Chimica Acta

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Volumen 50, Fasciculus 1 (1967) -No. 34 259 34. Synthese von 7a-Methylostron Uber Steroide, 210. Mitteilungl) von P. Wieland und G. Anner (3. XII. 66) Herrn Prof. Dr. A. WETTSTEIN zum 60. Geburtstag gewidmet.In der vorangehenden Mitteilung [l] beschrieben wir die Herstellung einer Anzahl hochaktiver Verbindungen, die sich vom 7a-Methylostron (XI) ableiten. Die dort beschriebene Herstellung des Ausgangsstoffes erwies sich jedoch als wenig ergiebig, so dass wir einen neuen, in besserer Ausbeute verlaufenden Zugangsweg suchten, woruber im folgenden kurz berichtet werden soll.Als Ausgangsverbindung wahlten wir zunachst das in 60-proz. Ausbeute aus 0-Propionyltestosteron (I) zugangliche 0-Propionyl-6-dehydro-testosteron (11) [2] 2). Dieses lieferte bei der Umsetzung mit Methylmagnesiumbromid neben 5% der 7/3-Methylverbindung [4] 43% 7a-Methyltestosteron (111) [5]. Letzteres wurde zunachst in 17-Stellung zu VI [6] und dann in 1,2-Stellung zum 3,17-Dioxo-7a-methyl-Ll1;4androstadien (IX) dehydriert. Das daraus hergestellte 17-Ketal X I I lieferte bei der Aromatisierung nach dem Verfahren von DRYDEN et al. [7] mit Lithium und Diphenyl in Tetrahydrofuran und anschliessender Ketalspaltung 7a-Methylostron (XI) in 68-proz. Ausbeute. Die Gesamtausbeute ausgehend von 0-Propionyltestosteron (I) betrug ca. 8,3y0. Die hier angegebenen und auch alle folgenden Ausbeuten stellen Gewichtsprozente dar.Ein attraktives Ausgangsmaterial schien uns das aus 0-Propionyltestosteron (I) in 87-proz. Ausbeute erhaltliche O-Propionyl-l,6-bisdehydro-testosteron (IV) [8].In dieser Verbindung sind bereits die fur die Einfuhrung der 7a-Methylgruppe notwendige 6,7-Doppelbindung wie auch die fur die Aromatisierung erforderliche 1,Z-Doppelbindung vorhanden. Da jedoch d1;4;6-3-0xo-Steroide Methylmagnesiumhalogenide bevorzugt in 1,2-Stellung anlagern [9], musste vor der Einfuhrung der 7u-Methylgruppe ein Schutz der 1,2-Doppelbindung angestrebt werden. Es ist bereits bekannt, dass 41;4;s-3-Oxo-Steroide mit Thioessigsaure zu l a , 7a-Bisacetylthio-A4-3-0x0-Steroiden reagieren [lo] [ll] 3). Diese setzen sich jedoch in alkalischem Medium zu A~~4-3-0~0-7a-mercapto-Steroiden um, so dass an Stelle der 1,2die 6,7-Doppelbindung geschutzt ist . Bei Verwendung eines nur geringen Uberschusses an Thioessigsaure gelang uns jedoch die selektive Anlagerung in 1,2-Stellung beim O-Propionyl-1,6-bisdehydro-testosteron (IV), wobei 94% Thioacetat V erhalten wurde. Die Uberfuhrung in das Diketon I X durch Umsetzung rnit Methylmagnesiumbromid, nachfolgende Verseifung und Oxydation gelang jedoch nur in ca. 7-proz. Ausbeute. Dieser Weg zum Dienon XII, der Vorstufe zum 7a-Methylostron (XI), war somit dem vorher ~ 1) 209. Mitteilung: [l]. 2) Die Dehydrierung wurde nach [31 durchgefuhrt. 3) Eine Ausnahme bildet das d1;*;6-Androstatrien-3,17-dion, wo das 1-Monoaddukt direkt kristallin aus der Reaktionslosung ausfallt [ll].

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The Synthesis of Some 7α- and 7β-Methyl Steroid Hormones¹

Cited by 75 publications

References 0 publications

Induction of Male Sexual Behavior in the Rat by 7α-Methyl-19-Nortestosterone, an Androgen that does not Undergo 5α-Reduction1

Induction of Male Sexual Behavior in the Rat by 7α-Methyl-19-Nortestosterone, an Androgen that does not Undergo 5α-Reduction1

Calusterone (7β,17α-DimethyItestosterone) as Primary and Secondary Therapy of Advanced Breast Cancer

Synthese von 7α‐Methylöstron. Über Steroide, 210. Mitteilung

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The Synthesis of Some 7α- and 7β-Methyl Steroid Hormones1

Cited by 75 publications

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Induction of Male Sexual Behavior in the Rat by 7α-Methyl-19-Nortestosterone, an Androgen that does not Undergo 5α-Reduction1

Induction of Male Sexual Behavior in the Rat by 7α-Methyl-19-Nortestosterone, an Androgen that does not Undergo 5α-Reduction1

Calusterone (7β,17α-DimethyItestosterone) as Primary and Secondary Therapy of Advanced Breast Cancer

Synthese von 7α‐Methylöstron. Über Steroide, 210. Mitteilung

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The Synthesis of Some 7α- and 7β-Methyl Steroid Hormones¹