MXPA00012805A - Testosterone derivative - Google Patents

Abstract

The invention is the novel androgen (7&agr;,17&bgr;)-7-methyl-17-[(1-oxoundecyl)oxy]estr-4-en-3-one (MENT undecanoate). This compound distinguishes favourably from other testosterone derivatives in that it has a good solubility in oily media. It particularly exhibits a good dissolved potency relative to testosterone. The compound is particularly suitable for administration by means of injection.

Description

TESTOSTERONE DERIVATIVE The invention belongs to the field of androgenic hormones; more specifically, to the testosterone derivatives. The testosterone derivatives are known. Testosterone itself, the natural male hormone, has many known drawbacks, as far as methods for its administration are concerned. It has activity of short duration, is insoluble in the usual pharmaceutically acceptable media and is not very potent. The most potent dihydrotestosterone (the 5-alpha-reduced form of testosterone) is considered a health risk, mainly for the prostate. A somewhat better soluble derivative is testosterone undecanoate, which is known as the active substance of the Andrill® product. The most potent androgens are 7alpha-methyl-19-nortestosterone (MENT) and related compounds, such as those described in FR 4,521 M and in US 5,342,834. However, MENT suffers from poor solubility and a short time of action. New androgenic hormones are needed, which, among other things, satisfy the demands related to new areas of interest, such as male contraception and male HFIT (hormone replacement therapy). Thus, for example, male contraception may comprise a regimen of administration of hormones in which a progestagen serves to obtain a contraceptive effect and an androgen serves to supplement the resulting decreased level of testosterone. Olra option is to carry out male contraception with an androgen hormone alone. The regular ingestion of androgens, necessary for this, requires androgens that are improved in terms of potency and duration of action, and for which a practical route of administration is available. Since a low frequency of administration is desired, there is demand for androgens that have physicochemical properties that make them susceptible to solution, particularly a solution by which androgen can be administered by injection, preferably once a week or less frequently, or orally by half of a capsule that is taken, for example, daily. This means that a desired basic property for a novel androgen is that it has an improved solubility in one or more pharmaceutically acceptable liquids. An androgen that has a favorable ratio of potency and solubility is even more convenient, since a weak androgen will require that it be dissolved in order to reach the same activity as a more powerful androgen. This means that an androgen having a relative, improved "dissolved potency", hereinafter referred to as PDR, where the RDP is an androgen in a given medium, is the product of its androgen potency in relation to that of testosterone, the hormone natural male, and its solubility in the medium, in relation to that of testosterone. It is an object of the invention to provide an androgenic hormone that satisfies the above demand. For this purpose the invention consists of the compounds (7alpha, 17beta) -7-methyl-17 - [(1-oxoundecyl) oxy] estr-4-en-3-one, which has the following structural formula: The compound of the invention is also known as 7alpha-methyl-19-nortestosterone undecanoate, abbreviated as MENT undecanoate. The compound of the invention has significantly better solubility than would be expected based on the known testosterone derivatives. Additionally, the compound of the invention has a surprisingly higher RDP than that of the known compounds. The compound of the invention can be prepared by esterifying the 17-OH group of MENT with undecanoic acid or its derivatives. This esterification can be carried out using methods well known in the art or readily available from the chemical literature, for example, using methods and catalysts described in Advanced Organic Chemistry, J. March, 4a. edition, pages 1281-1282, 1992. MENT can be prepared as described in FR 4, 521 M and US 5,342,834. The invention also relates to MENT undecanoate as a medicine. The compound of the invention being powerful androgen, it can be used, inter alia, in male contraception or in female hormone replacement therapy. Thus, the invention also relates to a method for the treatment of androgen insufficiency, by administering to a human, male or female, an effective amount of MENT undecanoate. The invention is also in the use of MENT undecanoate for the preparation of a medicine for treating androgen insufficiency. In the context of this invention, the term "androgen insufficiency" should be understood as referring to all kinds of diseases, disorders and symptoms in which a man or a woman suffer from too low a testosterone level, such as in a hypogonadal man. In particular, the androgen insufficiency to be treated by the compound of the invention is the reduction of the level of testosterone in which a male falls as a result of age (the compound of the invention is then used as a male hormone replacement therapy) or when he is subject to male contraception. In the context of male contraception, the compound of the invention serves especially to neutralize the effect of male hormonal contraceptive regimens in which the sterilant, such as a progestogen or LHRH (luteinizing hormone-releasing hormone) is administered regularly, for example daily, or it is used as the only male contraceptive substance. The invention also relates to pharmaceutical formulations comprising MENT undecanoate and a pharmaceutically acceptable carrier. Thus, the carrier can have the solid form or the liquid form, and the formulation can be an oral dose unit, such as a tablet, or preferably, an oral solution, for example, in a capsule. The methods and compositions for forming these dosage units form those SD dose units? well known to those skilled in the art. For example, conventional techniques for forming tablets and pills, containing active ingredients, are described in the common reference, Gennaro and co-authors, Remington's Pharmaceutical Sciences, (18th edition, Mack Publishing Company, 1990; see in particular part 8: Pharmaceutical Preparations and Their Manufacture). The compound can also be administered by means of an implant, a patch or any other device suitable for the sustained release of an androgen composition. The preferred oral dosage unit is that of a capsule containing the compound of the invention, taken in a liquid medium, as described further below. In order to obtain the benefit of most of the androgen activity of the compound, administration of the compound dissolved in an oil is preferred; that is, orally, as stated above, or mainly by injection (intramuscular). MENT undecanoate has a solubility in oily media which makes it particularly suitable for a liquid pharmaceutical formulation comprising MENT undecanoate dissolved in a pharmaceutically acceptable oil. Suitable oils are, for example, arachid oil, oleic acid, castor oil, sesame oil and the like. The arachid oil is preferred. For injection, the preferred injection device is a needleless injection system, for example, as described in US 5,599,302. For this purpose, the compound can also be suspended in an aqueous medium; but the above solutions in oil are preferred. Methods and compositions for making liquids suitable for parenteral administration are known in the art; see, for example, Remington's, pages 1545 et seq. For oral administration, any capsule made from a pharmaceutically acceptable wall material can be used. Methods and compositions for making capsules suitable for oral administration are known in the art; see, for example, Remington's, pages 1658 et seq. A preferred material is a soft gel, such as that used for Andriol® capsules. The invention also relates to a method for treating androgenic insufficiency by administering to a male, by means of injection or by means of an oral dose unit, an effective amount of MENT undecanoate dissolved in a pharmaceutically acceptable oil. The invention also consists in the use of MENT undecanoate to prepare a medicine for treating androgen insufficiency, by injecting a human male with an effective amount of MENT undecanoate dissolved in a pharmaceutically acceptable oil, or orally administering said oily solution. The dose and administration regimen of MENT undecanoate or a pharmaceutical composition thereof, to be administered, will obviously depend on the therapeutic effect to be achieved and will vary with the route of administration and with the age and condition of the subject individual to whom the medication is to be administered and / or the particular contraceptive or HRT regimen in which it is used. Typical doses are 100 mg or more for three months, by intramuscular administration, and 50-250 mg, more preferably, 80 mg per day, when administered orally. The invention will be further explained in what follows, with reference to the following examples.

EXAMPLE 1 (7alpha, 17beta) -7-methyl-17-f (1-oxoundecyl) oxy-estr-4-en-3-one A total of 2.23 grams of undecanoyl chloride, commercially available, was added to a stirred solution of 1.58 g of (7alpha, 17beta) -17-hydroxy-7-methyltr-4-en-3-one at 0 -5 ° C. The reaction mixture was allowed to reach room temperature and stirred overnight. Then ice was added and then stirred for another two hours and the reaction mixture was poured into ice water, which contained 4 ml of concentrated sulfuric acid, after which it was extracted with ethyl acetate. The organic layers were washed with water, with 1N sodium hydroxide solution and with brine; dried over sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica. Elution with heptane-ethyl acetate (4: 1) and evaporation gave a fatty solid which was collected. Yield: 1.42 g [a] D20 = 36 ° (c = 1; dioxane); MS (ESI); 456 (17beta) -17-r (1-oxoundecyl) oxy1androst-4-en-3-one. The "testosterone undecanoate" is available commercially.

EXAMPLE 2 About 20-30 mg of compound was converted to powder and then dissolved in the minimum amount of solvent that was necessary to dissolve all visible particles. The solution was obtained by heating in a 50 ° C water bath and shaking on a Vortex® shaker for 15 minutes. Solubility was calculated by determining the amount of compound (in mg) dissolved per mg of solvent.

COMPARATIVE EXAMPLE The solubility and androgen potency of the compound of the invention and three reference compounds were used to determine RDP. The results are given in the following tables. With respect to clinically desirable anabolic and antigonadotropic effects (androgenic effects) MENT is ten times more potent than testosterone in rats (Kumar N et al., Endocrinology 130: 3677-3683 (1992) and J. Steroid Biochem. Molec. Biol. , 52: 105-112 (1995)) and in monkeys (Cummings D and coauthors, J. Clin Endocrine Metab, 83, 4212-4219 (1998)). The PDR is determined as follows' compound x compound solubility relative to that of testosterone testosterone solubility TABLE 1 It can be seen from the table that the solubility of MENT undecanoate in arachis oil is much better than that of any other androgen. The solubility of MENT undecanoate in oleic acid is also better than expected, in view of that of known androgens TABLE 2

Claims (6)

1. - The compound (7a, 17ß) -7-methyl-17 - [(1 -oxoundecyl) oxy] estr-4-en-3-one (MENT undecanoate). 2.- MENT undecanoate, as medicine. 3.- The use of MENT undecanoate for the preparation of a medicine to treat androgen insufficiency. 4. A pharmaceutical formulation, characterized in that it comprises MENT undecanoate and a pharmaceutically acceptable carrier. 5. A pharmaceutical formulation according to claim 4, further characterized in that the carrier is a liquid in which the MENT undecanoate is dissolved. 6. A contraceptive device for men, comprising means for the administration of a progestin and means for the administration of an androgen; characterized in that the latter means is a pharmaceutical formulation according to claim 5.