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Method of making and using 7alpha,11beta-dimethyl-17beta-hydroxyestr-4-en-3-one 17-undecanoate

Method of making and using 7alpha,11beta-dimethyl-17beta-hydroxyestr-4-en-3-one 17-undecanoate description/claims

This application is a continuation of co-pending U.S. patent application Ser. No. 11/040,964, filed Jan. 21, 2005, which is a continuation of U.S. patent application Ser. No. 10/260,854, filed Sep. 30, 2002, which is a continuation of International Application No. PCT/US01/10293, filed Mar. 30, 2001, claiming the benefit of U.S. Provisional Patent Application No. 60/193,530, filed Mar. 30, 2000 and 60/194,440, filed Apr. 4, 2000. The disclosures of the '964 application, the '854 application, the '293 application, the '530 application and the '440 application are incorporated herein by reference.

The present invention generally relates to methods of making and using esters of androgenic steroids.

Androgen is a term used to identify the human male sex hormones. These hormones, which are chemically classified as steroids, are produced in the body by the testis, the cortex of the adrenal gland and, to a much lesser extent, by the ovaries. Testosterone is perhaps the most widely recognized androgen, and is responsible for the development of male characteristics in a human, including secondary sexual characteristics, libido and the ability to produce sperm.

When a person is unable to synthesize testosterone, therapy directed at replacing the missing hormone is commonly undertaken. In practice, however, this therapy can be problematic. For example, testosterone exhibits only weak activity when administered orally. While parenteral administration is possible, it is impractical because testosterone remains active in the body for only a short time. Research has therefore focused on identifying so-called synthetic androgens that are acceptable substitutes for natural testosterone.

A number of oral and injectable synthetic androgens have been developed over the years, including esters of various androgens. While these esters are hydrolyzed in the body into their corresponding biologically-active alcohols, they are nonetheless administered because they slow the rapid degradation of the synthetic androgen by the body. This maximizes the amount of the biologically active alcohol that reaches the bloodstream.

Unfortunately, the activity of these androgen esters is unpredictable. Different androgens sharing the same ester group exhibit varying and unpredictable levels of activity, as do androgens having the same basic chemical structure, but different ester groups.

One of the esters that has emerged as a viable injectable synthetic androgen is testosterone enanthate. This enanthate is presently used extensively via intramuscular (IM) injection for hormone replacement therapy in hypogonadal men, and as the androgenic component of several experimental male contraceptives. One drawback of this active is that it is not exceptionally long-acting—it must be administered IM every two weeks to maintain testosterone levels within a normal (therapeutic) range in hypogonadal men.

More specifically, testosterone enanthate is presently administered IM for the treatment of hypogonadism at a dose of 200 mg every two or three weeks. If this enanthate is used for male contraception, it may be administered parenterally at from about 200-400 mg every week, and if used as the androgenic component with estrogen or progestins for contraception, it may be administered at about 200 mg every two weeks. Testosterone bucyclate is another synthetic androgen disclosed in, e.g., U.S. Pat. No. 4,948,790. If administered parenterally for the treatment of hypogonadism, this bucyclate would require a dose of about 1200 mg (given as 3 injections of 1 ml each due to its solubility) to retain activity for about 2-3 months.

The development of androgens that exhibit activity after oral administration has been less successful. At present, the most widely used effective oral formulation includes methyltestosterone as the active ingredient, administered at 10-50 mg methyltestosterone/day. However, this active cannot be administered on a long-term basis, as is required in androgen replacement therapy, because of its associated liver toxicity. It is well known that androgens alkylated at the C17 position, such as methyltestosterone, exhibit such toxicity. While removal of the C17 alkyl group may appear at first glance to be an obvious solution to this problem, alkylation at this position is believed to be necessary to prevent degradation of the active by the liver after oral administration.

Illustrative of the development efforts relating to synthetic androgens is U.S. Pat. No. 5,952,319. While this patent identifies a number of potentially-active synthetic androgens, including 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one 17β-trans-4-n-butylcyclohexane carboxylate (referred to herein as 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate), it provides no data regarding the biological activity of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate. There is similarly no data available concerning the biological activity of another synthetic androgen, 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate.

A need therefore exists for a means of overcoming the foregoing and other problems associated with androgen replacement and other therapies that require the administration of androgens.

The present invention meets the aforesaid and other needs by providing, in one aspect, a method for providing hormonal therapy to a patient comprising the oral administration of about 1 mg/day to about 25 mg/day of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate, 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate, or a mixture thereof, to a patient in need thereof.

This aspect of the invention is predicated in significant part on the unexpected discoveries that 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate (also referred to herein as “the bucyclate”) and 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate (also referred to herein as “the undecanoate”) do not degrade after oral administration even though each lacks an alkyl group at the C17 position, and exhibit activity far in excess of the current oral standard, methyltestosterone. These surprising discoveries permit hormonal therapies requiring the administration of an androgen to be conducted utilizing oral dosages of the bucyclate and/or the undecanoate that are significantly lower than those required when administering oral methyltestosterone to effect the same therapy. A further expected benefit of using the bucyclate and undecanoate is that liver toxicity, if any, should be minimal because these compounds are not alkylated at the C17 position.

In another aspect, the present invention comprises a method for providing hormonal treatment comprising the parenteral administration of from about 1 mg up to about 100 mg of the bucyclate and/or the undecanoate at intervals of at least about two weeks, and preferably up to about 600 mg at much longer intervals, e.g., a single administration of 600 mg providing effective therapy for up to about three months.

This aspect of the invention is predicated in part on the surprising relatively high potency, and unexpected long-term activity, of the bucyclate and undecanoate when administered parenterally, which potency is higher and activity longer-lasting than esters of other potent androgenic steroids, even bucyclic esters thereof. This activity was unexpected in view of the preparation and evaluation of several bucyclic esters of potent androgenic steroids other than 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate, the former group of esters yielding disappointing results.

Another aspect of the present invention includes separate processes for preparing the bucyclate and undecanoate, which provide these actives in relatively high yield, and advantageously in a solid form, preferably crystalline, at room temperature. As both can be produced in solid form, the preparation of aqueous microcrystalline suspensions for parenteral administration is possible. Moreover, because these actives are solid at room temperature, one is able to control the average particle size and particle size distribution of the solids, thereby positively affecting the duration of activity after parenteral administration of the respective suspensions.

Related aspects of the present invention include certain intermediates, in amorphous or, preferably, crystalline form, as well as one or more steps used in the aforementioned preferred process for preparing the bucyclate and the undecanoate.

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