18- methyl-19-nortestosterone

Methyl 3a,6a-dihydroxycholanate, 240 1-Methylestrone 3-methyl ether, 10, 27 4b/3-Methyl-7-ethylenedioxy-1,2,3,4, 4a ,4b/3,5,6,7,8,10,1 Oaa-dodecahydro-phenanthrene-1 /3,4/3-diol, 236 14C-Methyl iodide, 211 ds-Methyl iodide, 210, 214 Methyl lithocholate tosylate, 329 1-Methyl-19-nortestosterone, 27 6a-Methylprednisolone, 410 6a-Methylprednisolone BMD, 410 16/3-Methylprednisone, 87 18-Methylpregn-4-ene-3/3,17a,20f-triol, 243 20-Methylpregn-5-en-3/3-ol, 415 17a-Methylpregnenolone acetate, 48 17a-Methyltestosterone, 438 16/3-Methyl- 11a,17a,21 -trihydroxy- 5 /3-pregnane-3,20-dione 21-acetate, 299, 300 20-Methyl-3/3-trityloxypregn-5-ene, 415 3/3-Methoxycholestane, 136 1-Methoxycyclohexene, 18 3-Methoxyestra-3,5(10)-diene, 18, 27... 

Sundaram, K., Kumar, N. and Bardin, C.W. (1993) 7 a-methyl-nortestosterone (MENT) the optimal androgen for male contraception. Annals of Medicine, 25, 199-205. 

Although methylation of 3-keto-A -steroids generally leads to 4,4-dimethyl derivatives,Atwater has reported a practicable4-monoaikylation procedure. Thus 4-methyl- (44%), 4-vinyl- (46%), 4- -butyltestosterone (62%) and 4-methyl-19-nortestosterone (50%) are obtained when the alkyl halide is added dropwise with stirring to a refluxing basic solution of testosterone or 19-nortestosterone over a period of 2.5 hours. A" -3-Keto steroids are not methylated under these conditions. 

The Roussel group has described recently a novel method for the synthesis of 2,2-dimethyl-A" -3-keto steroids. Thus addition of potassium t-butoxide to a solution of 19-nortestosterone (25) in tetrahydrofuran containing methyl iodide and hexamethylphosphorous triamide at —70° affords the 2,2-dimethyl compound (26) in good yield.Methylation of A" -3-ketone by the classical conditions, namely addition of methyl iodide to a solution of the steroid and potassium /-butoxide, leads to the 4,4-dimethyl product. 

The presence of a 7a-methyl group has been found to potentiate anabolic activity. Acetylation of 19-nortestosterone affords the corresponding 17-acetate... 

Testosterone (5.45) is the prototypic androgen sex hormone. Testosterone is synthesized by the testes, and must be reduced to dihydrotestosterone (5.46, DHT) before it will bind to the receptor. Among highly active synthetic testosterone analogs, 7a-methyl-19-nortestosterone (5.47) and oxandrolone (5.48) have about 100 times greater activity than testosterone as androgens. 17a-Methyltestosterone (5.49) is orally active. 

Ethynylestradiol 3-methyl ether, 4, 20 17-Ethynyl-19-nortestosterone, 8, 44, 52 16/3-(Ethylthio)estradiol 3-methyl ether, 5 Experimental conditions for Birch reduction, 25... 

N-methylmorpholine oxide-hydrogen peroxide, 184, 221, 223 4-Methyl-19-nortestosterone, 89 16/3-Methyl-l 6a, 17a-oxidopregn-4-ene-... 

Similar results are obtained when 19-nortestosterone and related androgens 346> as well as various nucleosides347 are esterified with adamantane carboxylic acids. Whereas 107 exhibits a long duration of myotropic activity coupled with significantly reduced androgenicity, the 3-methyl and 3,5-di-... 

SCHEME 4. Conversion of the 3-methyl ether of estrone to 19-nortestosterone. 

Another route to (+)-19-nortestosterone (73) started firom 2-methyl-l,3 cyclopentanedione (74). The asymmetric aldol condensation of the Michael adduct using L-phenylalanine produced the opticaUy active enone (75). The PdCh-catalyzed oxidation yielded crystalline trione (76) in 77% ee, which was recrystallized as an optically pure form. Reduction of the double bond and aldol condensation afforded the desired cd tratu-fused ketone (77). The construction of the A-ring was carried out by alkylation with... 

An 8-d old agar slant of Helminthosporium kusanoi Nisik. obtained from CBS (see Table 1) and maintained on oatmeal/ agar, is used to inoculate two 2-L conical flasks each containing 500 mL of nutrient medium. Incubation of the flasks is carried out for 2 d on a rotary shaker (250 rpm, 2.5 cm stroke). The culture obtained is used to inoculate 15 L of nutrient medium in a stainless steel fermentor equipped with stirrer and air inlet (200 rpm. 10 L air/min. 28 °C). 24 h after inoculation, 7.5 g (0.027 mol) of 19-nortestosterone (3) are added as a suspension in 100 mL of sterile water. 48 h laler, conversion of the substrate is complete (monitored by TLC CHC13 acetone 3 1). The mycelial mass is removed by filtration and the filtrate (pH 6.80) is extracted with four 4-L portions of 4-methyl-2-pentanone. After concentration to 100 mL under reduced pressure, the solution is treated with 0.5 g of charcoal. Concentration to 20 mL, cooling and filtration gives crude 4 yield 4.05 g (54%). Recrystallization is from 1.2-dichloroethane/aq ethanol yield 2.30 g (30.6%) mp 213 JC. 

Nortestosterone. 1 -Methyl-A -3-desoxo-5a-dihydro 17-acetate (N-64), la-methyl 5a-dihydro (N-48), la-methyl 5a-dihydro 17-acetate (N-61), la-hydroxy 5a-dihydro 17-acetate (N-62), la,2a-methylene 5a-dihydro 17-acetate (N-63), and la-methyl-A -5a-dihydro 17-acetate (N-65) substitutions all markedly decrease the androgenic activity while the anabolic activity is decreased in a smaller degree. The anabolic-androgenic ratio becomes favorable. 

A -Nortestosterone (N-95), 17a-methyl-A -nortestosterone (N-96) subcutaneously, and 17a-ethyl-A -nortestosterone (N-97) all exhibit greatly decreased androgenic activities while the anabolic activities are increased. I7a-Methyl-A -nortestosterone (N-96) orally shows increased androgenic and anabolic activities. The anabolic-androgenic ratio is very favorable in all cases. 

Total synthetic studies at Roussel-UCLAF produced a large number of compounds having this type of extended unsaturation. A ,A"-Nortes-tosterone 17-acetate (N-103), A, A -nortestosterone 17/3-methoxymethyl ether (N-104), A ,A -nortestosterone 17/3-decanoate (N-105), A A -nortestosterone 17-carbobenzoxy-ate (N-106), A ,A"-17a-methyl-... 

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