Norgestrel

Medical uses

Norgestrel is used in combination with ethinylestradiol or quinestrol in combined birth control pills, alone in progestogen-only birth control pills, and in combination with estradiol or conjugated estrogens in menopausal hormone therapy.

Side effects

Pharmacology

Pharmacodynamics

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

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

Pharmacokinetics

The pharmacokinetics of norgestrel have been reviewed.

Chemistry

Norgestrel, also known as rac-13-ethyl-17α-ethynyl-19-nortestosterone or as rac-13-ethyl-17α-ethynylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. It is a racemic mixture of stereoisomers dextronorgestrel (the C13α isomer; l-norgestrel, L-norgestrel, or (+)-norgestrel) and levonorgestrel (the C13β isomer; d-norgestrel, D-norgestrel, or (–)-norgestrel), the former of which is inactive (making norgestrel exactly half as potent as levonorgestrel). Norgestrel is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the gonane (18-methylestrane) subgroup of the 19-nortestosterone family of progestins.

Synthesis

Chemical syntheses of norgestrel have been published.

The chemical synthesis was first proposed by Smith & Hughes: Commercial: 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: Improved ethynylation procedure: German: Dane's method:

History

Norgestrel was first introduced, as a birth control pill in combination with ethinylestradiol, under the brand name Eugynon in Germany in 1966. It was subsequently marketed as a combined birth control pill with ethinylestradiol in the United States under the brand name Ovral in 1968, and was marketed in many other countries as well.

The contraceptive efficacy of norgestrel was established in the U.S. with the original approval for prescription use in 1973.

In July 2023, the FDA approved norgestrel for over-the-counter sale. The FDA granted the approval to Laboratoire HRA Pharma which was acquired by Perrigo Company plc.

Society and culture

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. It is also known as dl-norgestrel, DL-norgestrel, or (±)-norgestrel.

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.

References

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