Controlled delivery system for norethindrone based on biodegradable poly-alpha,beta-(hydroxyalkyl)-DL-aspartamide.

The article describes the preparation of poly-(hydroxyalkyl)-DL-aspartamide (PHAA) by a (ring) opening reaction by hydroxyalkylamino; norethindrone (NET), as a model drug, was coupled to the polymers via hydroxyalkylamino spacers. PHAA and NETPHAA conjugates were characterized by FTIR, DSC, x-ray,(13)C NMR, and scanning electron microscopy and their structure were confirmed. The biocompatibility of PHAA was tested. The study showed that PHAA was a hydrophilic, nontoxic in vivo, nonantigenic material and had good biocompatibility as a drug carrier. The effect on drug release from the polymer of length of side chain, initial drug loading, and particle size of the polymer drug were investigated in tris-HCl buffer solution (pH 7.4, t = 37 degrees C). In vivo release in rabbits also was performed for 120 days. The experiment indicated that the concentration of NET in rabbits can be 1-2 microg/ml serum after 1 month; 10% of NET had been released from the polymer.

Steroid research at Syntex: "the pill" and cortisone.

The period from late 1949 through 1951 was an extraordinarily productive one in steroid chemistry and especially so at Syntex S.A. in Mexico City. Two of the most important Syntex contributions--the synthesis of 19-nor-17 alpha-ethynyltestosterone (norethindrone) and of cortisone from diosgenin--are described from a historical perspective.

PIP: The pharmaceutical industry contributed more to the published record of steroid research during the 1950s than any industry has ever contributed before to any chemical subdiscipline. Syntex, a research-oriented company in Mexico city, contributed much of the publication of industrial research of steroids. Dr. Djerassi arrived at Syntex in 1949 as associate director of chemical research. He conducted partial aromatization studies leading him to the 1st synthesis of an oral contraceptive (OC) on October 15, 1951. This steroid was 19-nor-17 alpha-ethynyltestosterone, later called norethistrone or norethindrone. Syntex submitted the product to a commercial laboratory in Madison, Wisconsin, for biological evaluation. It was indeed the most active, orally effective progestational hormone at the time. Syntex applied for a patent in November 1951. In November 1954, clinical results of norethindrone used to treat various menstrual disorders and fertility problems was presented. G.D. Searle & Co. filed for a patent for the synthesis of the double bond isomer 13 of norethindrone called norethynodrel in August 1953. Acid or human gastric juice converts norethynodrel into norethindrone. Had it not been for Searle using norethindrone in its antimotion sickness drug, Dramamine, Syntex would have filed suit against Searle. Syntex sponsored contraceptive trials with norethindrone. Various incidents prevented Syntex from obtaining US Food and Drug Administration approval to use norethindrone for contraceptive indications before Searle obtained approval to use norethynodrel. By 1964, 3 companies including Syntex were marketing 2 mg doses of Syntex's norethindrone, the most widely used active ingredient in OCs. Dr. Djerassi also played a key role in the synthesis of cortisone from diosgenin, a chemical derived from Mexican yams. This synthesis was a more economical industrial route to cortisone than previous routes.

[Simple synthesis of a complete set of unconjugated norethisterone metabolites and their deutero-analogs]. / Prostoi sintez polnogo nabora nekon"iugirovannykh metabolitov norétisteronea i ikh deiteroanalogov.

The short-step synthesis of all norethisterone (NET) hydrogenated metabolites and their deuteroanalogues has been accomplished. Reduction of NET by NaBH4 in the presence of N,N,N',N'-tetramethylethylenediamine provided 19-norpregn-20-yn-3,17-diols as a mixture of 3- and 5-epimers. The individual isomers were isolated by flash chromatography and oxidyzed by PyHCrO3Cl into 5 alpha- and 5 beta-dihydro-NET. These products were converted, on isotopic exchange with D2O--MeOD in alcaline conditions followed by reduction with NaBD4, into four stereoisomeric 2,2,3,4,4-pentadeuterated 19-norpregn-20-yn-3,17-diols; two isomeric 2,2,3,4,4,16,16,17-octadeuterated estrane-3,17-diols were also isolated as side products. All compounds obtained will be used as internal standards for chromato-mass-fragmentographic analysis.

Synthesis of 5,17-dihydroxy-5 alpha, 17 alpha,-19-norpregn-20-yn-3-one, a major photodegradation product of norethindrone.

A convenient synthesis of 5,17-dihydroxy-5 alpha,17 alpha-19-norpregn-20-yn-3-one in multigram quantities from norethindrone is reported. Confirmation of the structural assignment of this major photodegradation product of norethindrone is thus made.

Norethisterone and levonorgestrel esters: a novel synthetic method.

Aliphatic, alicyclic and arylcarboxylic esters of norethisterone and levonorgestrel were prepared in a one-step synthesis and in near-quantitative yield using trifluoroacetic anhydride.

7 alpha-Methylnorethindrone enanthate 10 beta-hydroperoxide: isolation and characterization.

10 beta-Hydroperoxy-7 alpha-methylnorethindrone 17-heptanoate (II), a product of allylic autoxidation of 7 alpha-methylnorethindrone enanthate (I), has been isolated and characterized. The synthesis of the hydroperoxide (II) from the 3-ethylene ketal of 7 alpha-methylnorethynodrel (III) was achieved. Esterification of alcohol (III), subsequent deketalization, and photochemical oxygenation resulted in the hydroperoxide (II). Reduction of the hydroperoxide (II) to the 10 beta-alcohol (VI) and acetylation of (II) to the 10 beta-acetoxyperoxide (VII) are described. A single subcutaneous injection of the compounds (II), (VI), and (VII) to rats failed to produce long term inhibition of fertility in contrast to the parent compound (I) which is at least five times more effective than norethindrone enanthate as measured by suppression of vaginal cornification and estrous cycles.

Long-acting contraceptive agents: analysis and purification of steroid esters.

More than 200 samples of esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3 -one) have been analysed by a combination of techniques, including high performance liquid chromatography (HPLC). Compounds having a purity below the required limit (99.5%) were purified, mainly by preparative HPLC, prior to formulation and biological evaluation as long-acting progestogens.

Long-acting contraceptive agents: esters of norethisterone with alpha- and/or beta-chain branching.

The synthesis of eighteen esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) is described. These all possess some form of alpha- and/or beta-substitution in the ester side-chain. The work was undertaken in order to evaluate any long-acting fertility control effect intrinsic in such compounds. A pentamethyl disiloxy ether was also included in the group of substances prepared for testing because of its similar substitution pattern.

Long-acting contraceptive agents: norethisterone esters of monoalkenyl and monoalkynyl acids.

The synthesis of nine new esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) is described, with the esterifying acids bearing an acetylenic or olefinic function in a chain of eight or nine carbon atoms, for evaluation as long-acting contraceptive agents.

Long-acting contraceptive agents: esters of norethisterone with alkoxy- and halogeno-substituted carboxylic acids.

The chemical synthesis and physical data of several new esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) are reported, which contain either a chloro- or an alkoxy-group as a substituent in the acid side-chain.

Long-acting contraceptive agents: norethisterone esters of polyunsaturated acids.

Some new derivatives of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) are described in which the 17 beta-hydroxyl group of the steroid is esterified with polyunsaturated aliphatic acids. The potential of these compounds as long-acting contraceptive agents has been evaluated.

Long-acting contraceptive agents: cyclopropyl and cyclobutyl esters of norethisterone.

Several esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) with carboxylic acids containing a cyclopropyl or cyclobutyl ring have been synthesized and the stereochemistries of the side-chains determined.

Long-acting contraceptive agents: norethisterone esters of arylcarboxylic acids.

The synthesis of esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxy-estr-4-en-3-one) with acids containing a benzene ring is described, two methods of esterification being compared in terms of yield and convenience. The activities of these esters as long-acting contraceptive agents have been evaluated.

Long-acting contraceptive agents: furylalkylcarboxylic acid esters of norethisterone.

5-Methyl- and 5-ethyl-furylalkylcarboxylic esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) were prepared in high yield in the presence of thallous ethoxide. The activities of these compounds as long-acting contraceptive agents have been evaluated.