Long-acting Contraceptive Agents Research Articles

Long-acting contraceptive agents: testosterone esters of unsaturated acids

The synthesis of 13 new esters of testosterone is described, with the esterifying acids bearing acetylenic, olefinic, or polyunsaturated functions in the chain, for evaluation as long-acting androgens.

Potential long-acting contraceptive agents: Esters of testosterone with alkoxy- and halogeno-substituted carboxylic acids

The chemical synthesis and physical data of several new esters of testosterone (17β -hydroxyandrost-4-en-3-one), which contain either a halogeno or an alkoxy substituent in the acid chain, are reported.

Potential long-acting contraceptive agents: Esters and ethersof testosterone with α-and/or β-chain branching

The synthesis of ten esters and two ethers of testosterone (17 β-hydroxyandrost-4-en-3-one) is described. All these possess some form of α-and/or β—substitution in the ester/ether sidechain. The work was undertaken in order to evaluate the long-acting antifertility effect of such compounds in males.

Long-acting contraceptive agents: Norethisterone esters of polyunsaturated acids

Some new derivatives of norethisterone (17α-ethynyl-17β-hydroxyestr-4-en-3-one) are described in which the 17β-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: Norethisterone esters of monoalkenyl and monoalkynyl acids

The synthesis of nine new esters of norethisterone (17α-ethynyl-17β-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: Bile acid esters of norethisterone

The synthesis of the esters of norethisterone (17α-ethynyl-l7β-hydroxyestr-4-en-3-one) with three bile acids and of the cholesteryl carbonate of norethisterone are described.

Long-acting contraceptive agents: Carbonates and carbamates of norethisterone

The preparation of three carbonates and two carbamates of norethi-sterone (17α-ethynyl-17β-hydroxyestr-4-en-3-one) are described. Due to instability of the carbonates and the very low solubility of the carbamates these compounds could not be submitted to biological testing.

Long-acting contraceptive agents: Analysis and purification of steroid esters

More than 200 samples of esters of norethisterone (17α-ethynyl-17β-hydroxyestr-4-en-3-one) and levonorgestrel (13β-ethyl-17α-ethynyl-17β-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: Norethisterone esters of arylcarboxylic acids

The synthesis of esters of norethisterone (17α-ethynyl-17β-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: Structure activity relationships in a series of norethisterone and levonorgestrel esters

A large number of esters of norethisterone (17α-ethynyl-17β-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one) were synthesized and tested for biological activity. The test employed in these studies was the duration of estrus suppression in cycling mature rats. In the norethisterone series several esters exhibited duration of activity comparable to that of norethisterone enarthate. In the levonorgestrel series the butanoic, cyclobutylcarboxylic and cyclopropylcarboxylic esters were longer acting than medroxyprogesterone acetate (17α-acetoxy-6α-methylpregn-4-ene-3, 20-dione) when prepared as aqueous microcrystalline suspensions.

Long-acting contraceptive agents: Design of the who chemical synthesis programme

The great demand for improved long-acting injectable steroid contraceptives, particularly in developing countries, and the relative lack of interest from the pharmaceutical industry to develop such products stimulated WHO to launch a synthetic and screening programme to find improved, safe and acceptable injectable preparations. More than 210 esters of norethisterone (17α-ethynyl-17β-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one) have been prepared in university-based research laboratories situated mainly in developing countries, and then screened by NICHHD in animal models. The following three compounds, levonorgestrel butanoate, cyclopropylcarboxylate and cyclobutylcarboxylate, proved to be particularly long-acting when administered as microcrystalline suspensions. The overall strategy of this research and development programme is described.

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 (17α-ethynyl-17β-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: Levonorgestrel esters of unsaturated acids

Esters of levonorgestrel (13β-ethyl-17β-ethynyl-17β-hydroxygon-4-en-3-one) with a variety of unsaturated carboxylic acids have been synthesized for evaluation as potential long-acting, injectable contraceptive agents.

Long-acting contraceptive agents: The influence of pharmaceutical formulation upon biological activity of esters of norethisterone

17β-esters of norethisterone (17α-ethynyl-17β-hydroxyestr-4-en-3-one) have been formulated as aqueous microcrystalline suspensions and oily solutionsfor administration to rats to assess the length of progestogenic activity. Results show that, for some of the esters, the rate-controlling step in prolonging activity is the rate of drug release from the injected formulation. For these esters, when formulated as suspensions, it is proposed that crystal size and form will have a critical effect upon duration of estrus suppression. The influence of crystal form has been demonstrated with the 4-(butoxy)phenylacetate ester for which two different crystal forms have been identified. The lower melting point, more soluble crystal form shows marked prolongation of action, whereas the other form is ineffective.

Long-acting contraceptive agents: Aliphatic and alicyclic carboxylic esters of levonorgestrel

Esters of levonorgestrel (13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en -3-one) with a variety of aliphatic and alicyclic carboxylic acids have been prepared and characterised. In tests for the suppression of estrus in rats, esters with short-chain aliphatic acids and with cyclobutane-carboxylic acid were considerably more active than the standard, norethisterone enanthate (17α-ethynyl-17β-hydroxyestr-4-en-3-one). Such esters show great promise for development as long-acting progestogens.

Long-acting contraceptive agents: Cyclopropyl and cyclobutyl esters of norethisterone

Several esters of norethisterone (17α-ethynyl-17β-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: Esters of norethisterone with α- and/or β-chain branching

The synthesis of eighteen esters of norethisterone (17α-ethynyl-17β-hydroxyestr-4-en-3-one) is described. These all possess some form of α- and/or β-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: Furylalkylcarboxylic acid esters of norethisterone

5-Methyl- and 5-ethyl-furylalkylcarboxylic esters of norethisterone (17α-ethynyl-17β-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.

Long-acting contraceptive agents: The influence of physicochemical properties of some esters of norethisterone upon the plasma levels of free norethisterone

Four 17β-esters of norethisterone (17α-ethynyl-17β-hydroxyestr-4-en -3-one), formulated both as oily solutions and aqueous suspensions, were administered intramuscularly to rabbits and free plasma levels measured for periods up to 9 weeks. For all formulations of the compounds, the disappearance of norethisterone following peak plasma levels obeyed first-order kinetics. Since different slope values were obtained for different formulations of the same compound, the values reflected the release rates of the esters from the formulations. Fusion data, partition coefficients and solubilities of the compounds in 2,2,4-trimethyl-pentane and water were obtained and these properties were related to the biological activity of the formulations. For oily solutions, the differences in plasma levels were ascribed to the different partition coefficients of the esters between the oil and tissue fluids. For suspensions, the different activity in relation to an oily solution of an ester was related to the strength of intermolecular forces in the crystal lattice and to the relative thermodynamic activity in the two formulations. The results demonstrate that microcrystalline suspensions do not always have a longer duration of activity than oily solutions of the same compound after intramuscular injection.