Norgestrel

Pharmacodynamics

Norgestrel is a progestogen, or an agonist of the progesterone receptor.^[6] The biological activity of norgestrel lies in the levo enantiomer, levonorgestrel, whereas the dextro isomer is inactive.^[6] As such, norgestrel is identical in its hormonal activity to levonorgestrel except that it is half as potent by weight.^[6] Levonorgestrel, and by extension norgestrel, have some androgenic activity, but no estrogenic, antimineralocorticoid, or glucocorticoid activity.^[6]

The ovulation-inhibiting dose of norgestrel appears to be greater than 75 μg/day, as ovulation occurred in 50 to 75% of cycles with this dosage of norgestrel in studies.^[17] The ovulation-inhibiting dosage of levonorgestrel, which is twice as potent as norgestrel, is approximately 50 to 60 μg/day.^[6][18][17] One review lists the ovulation-inhibiting dose of norgestrel as 100 μg/day.^[19] The endometrial transformation dose of norgestrel is listed as 12 mg per cycle and the menstrual delay test dose of norgestrel is listed as 0.5 to 2 mg/day.^[19][20]

Pharmacokinetics

The pharmacokinetics of norgestrel have been reviewed.^[21]

Synthesis

Chemical syntheses of norgestrel have been published.^[21]

The chemical synthesis was first proposed by Smith & Hughes:^{[25][26][27][28][29]} Commercial:^[30] NB: Although the synthesis has involved the formation of no fewer than 6 chiral centers, only two of the possible 64 possible isomers are formed.

The halogenation of 3-(3-methoxyphenyl)propan-1-ol [7252-82-6] (1) with phosphorus tribromide gave 1-(3-bromopropyl)-3-methoxybenzene [6943-97-1] (2). Treatment with ethynylsodium led to 5-m-methoxyphenylpent-1-yne [1424-70-0] (3). (Ex 1) Mannich reaction with formalin and diethylamine led to 1-Diethylamino-6-m-methoxyphenylhex-2-yne, PC21485597 (4). (Ex 8) An oxymercuration reaction with mercury(II) sulfate in aqueous sulfuric acid gives a mixture of 1-(diethylamino)-6-(3-methoxyphenyl)hexan-3-one [3706-69-2] (5) and 6-m-methoxyphenylhex-1-en-3-one, PC10798238 (6). (Ex 17) Treatment with 2-Ethyl-1,3-cyclopentanedione [823-36-9] (7) in the presence of pyridine base causes a Michael reaction to occur to give 2-Ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione, PC21485569 (8). (Ex 43) The cyclodehydration step was achieved by refluxing with a catalytic amount of TsOH in a DS-trap to give [848-07-7] (9). (Ex 68) Catalytic hydrogenation over Raney nickel gives (10). (Ex 83) Reduction with sodium borohydride leads to PC12598343 (11). (Ex 108) Birch reduction with lithium metal in and liquid ammonia in 1-methoxypropan-2-ol gives (12). (Ex 116) Oppenauer oxidation of the alcohol gives the ketone (13). (Ex 121) Reaction with ethynyllithium led to (14). (Ex 170) Hydrolysis in mineral acid completed the synthesis of norgestrel (15).

Alternative route:^[31] Improved ethynylation procedure:^[32] German:^[33] Dane's method:^[34]

Generic names

Norgestrel is the generic name of the drug and its international nonproprietary name, United States Adopted Name, United States Pharmacopeia, British Approved Name, Dénomination Commune Française, Denominazione Comune Italiana, and Japanese Accepted Name.^[3][4][5][7] It is also known as dl-norgestrel, DL-norgestrel, or (±)-norgestrel.^[3][4][5][7]

Brand names

Norgestrel is marketed under a variety of brand names including Cyclacur, Cryselle, Cyclo-Progynova, Duoluton, Elinest, Eugynon, Microgynon, Lo/Ovral, Low-Ogestrel, Logynon, Microlut, Minicon, Nordette, Neogest, Opill, Ogestrel, Ovral, Ovran, Ovranette, Ovrette, Planovar, Prempak, Progyluton, and Trinordiol among others.^{[3][4][7][35]}