Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/16—Masculine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/06—Anabolic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/26—Androgens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
  • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
  • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
  • C07J1/0074—Esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J21/005—Ketals
  • C07J21/006—Ketals at position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
  • C07J71/0005—Oxygen-containing hetero ring
  • C07J71/001—Oxiranes

Definitions

• 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.
• 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.
• 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.
• Testosterone bucyclate is another synthetic androgen disclosed in, e.g., U.S. Patent 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.
• 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 7 ,l l ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate, the former group of esters yielding disappointing results.
• Further aspects of the present invention include various formulations of these two actives, including tablets, caplets, extended release tablets, soft gelcaps containing the bucyclate and/or undecanoate in an oily carrier, transdermal patches, pre-filled syringes, vials and the like, in which the amount of the bucyclate and/or undecanoate included therein may be determined in view of their unexpected relatively high potency and long-term activity.
• the hormonal therapy of the present invention includes, but is not limited to, hormone replacement therapy in males and females, male contraception, and the treatment of certain cancers, such as breast cancer in females.
• Fig. 2A illustrates the chemical structure of methyltestosterone.
• Fig. 4 is a graph comparing the androgenic potency of 7 ⁇ , 11 ⁇ - dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate and that of other compounds after oral administration.
• Fig. 6 is a graph comparing the androgenic potency of 7 ⁇ , 11 ⁇ - dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate and that of other compounds after oral and subcutaneous injection.
• Fig. 7 is a graph comparing the androgenic potency of 7 ⁇ ,l 1 ⁇ - dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate and that of other compounds after subcutaneous injection.
• Fig. 8 is a graph comparing the duration of activity of 7 ⁇ , 11 ⁇ - dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate and that of other compounds after subcutaneous injection.
• Fig. 9 is a graph comparing the duration of activity of 7 ⁇ , 11 ⁇ - dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate and that of other compounds after subcutaneous injection.
• Fig. 10 is a graph comparing testosterone serum levels (pg ml) after subcutaneous injection of 7 ⁇ ,l l ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate and other compounds.
• Fig. 14 is a graph comparing the androgenic potency of 7 ⁇ , 11 ⁇ - dimethyl-17 ⁇ -hydroxyestr-4-en-3-one 17-undecanoate and methyltestosterone after oral administration.
• Fig. 15 is a graph comparing the duration of activity of 7 , 11 ⁇ - dimethyl-17 ⁇ -hydroxyestr-4-en-3-one 17-undecanoate and that of testosterone enanthate (CDB-112F) after subcutaneous injection.
• the present invention provides a variety of methods for providing hormonal therapy to a patient in need thereof. Each method requires the administration of particular actives, 7 ⁇ ,l l ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3- one bucyclate, and 7 ⁇ ,l l ⁇ -dimethyl-17 ⁇ -hydroxyestr-4-en-3-one 17- undecanoate, either in combination or, preferably, alone.
• the chemical structure of the bucyclate and undecanoate actives, with numerals identifying the various carbon atom positions, are set forth in Figs. 1 and 12, respectively.
• the present invention rests upon the discovery that both 7 ⁇ , 11 ⁇ -dimethyl- 17 ⁇ -hydroxy-4-estren-3-one bucyclate and 7 ⁇ , 11 ⁇ - dimethyl-17 ⁇ -hydroxyestr-4-en-3-one 17-undecanoate exhibit surprising and unexpected properties in vivo. These properties permit these actives to be administered either orally or parenterally, in relatively lower amounts, at longer time intervals, and with less side effects, as compared to existing alternative synthetic androgens, e.g., methyltestosterone, testosterone enanthate.
• the chemical structures of these two well-known compounds are set forth in Figs. 2A and 2B, respectively.
• the actives may be administered to promote and maintain muscle growth and maintenance. These properties can be particularly important in persons afflicted with muscle wasting diseases such as AIDS, but are more generally applicable to the elderly who typically have relatively low muscle mass.
• the actives may be used for the treatment of cancer, e.g., the pilliative treatment of breast cancer in women.
• cancer e.g., the pilliative treatment of breast cancer in women.
• the effective oral dosage of 7 ,l l ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate for any hormone replacement therapy which requires an androgen, e.g., the treatment of hypogonadism will be about one-fourth the oral dosage of methyltestosterone required to provide the same effect.
• 7 ⁇ ,l l ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate may be orally administered in therapeutically effective amounts.
• the oral dosage regimens described herein, set forth on the basis of milligrams/day, includes any dosage regiment is able to provide that dosage level to a patient per day.
• an extended release formulation of the bucyclate or undecanoate would not need to be administered each day, yet would provide the required daily dosage.
• administration of the therapeutic dosage on a daily basis the preferred method of treatment.
• the effective oral dosage of bucyclate for the treatment of cancer e.g., breast cancer in women can vary, but will range from at least about 10 mg/day, advantageously at least about 25 mg/day, and preferably at least about 50 mg/day.
• an effective oral dose may range from about 1 mg/day to about 25 mg/day, advantageously from about 2 mg/day to about 20 mg/day, and up to about 15 mg/day.
• Administration of the undecanoate to effect this therapy may, as before, be undertaken within the foregoing bucyclate therapeutic dosage ranges, but is preferably undertaken at relatively greater levels relative to that of the bucyclate.
• the undecanoate may be administered in an amount ranging from about 1 mg/day to about 50 mg/day, advantageously from about 2 mg/day to about 40 mg/day, and up to about 30 mg/day.
• an injectable bucyclate and/or undecanoate formulation is preferably administered.
• This preference is based upon the unexpected discovery that these actives are surprisingly potent and long-acting when dispersed (preferably as a suspension) in an aqueous formulation.
• the bucylate and undecanoate may be administered in an aqueous formulation at lower doses compared to both testosterone enanthate (in an oily carrier) and testosterone bucyclate, and at relatively long intervals.
• the bucyclate and undecanoate may be administered at intervals equal to, or in excess of, about two weeks. More specifically, they may be administered at intervals of about one month, preferably about two months, and most preferably once about every three months. This provides a significant advantage to a patient relative to existing regimens which require therapeutic injections on a more frequent basis.
• the dosage of either the bucyclate or undecanoate administered parenterally in an aqueous formulation at any intervals will be significantly less than the amount of testosterone enanthate used to achieve substantially similar therapeutic results.
• the bucyclate and undecanoate may be administered in amounts ranging from about 1 mg up to about 100 mg about every two weeks, and advantageously from about 25 to about 75 mg during that period; up to about 200 mg about every month, and advantageously from about 50 mg to about 150 mg during that time period; up to about 400 mg about every 2 months, and advantageously from about 100 to about 300 mg during that time period; and up to about 600 mg about every 3 months, and advantageously from about 150 mgto about 450 mg during that time period.
• dosages of the bucyclate or undecanoate effective for male contraception via parenteral administration may range from about 25 mg/week up to about 200 mg/week, advantageously up to about 150 mg/week, and preferably from about 50 mg/week to about 100 mg/week.
• the bucyclate or undecanoate may be administered alone in the treatment of cancer, it is preferably administered in coordination with one or more anti-cancer agents, e.g., therapeutically-effective amounts of chemotherapeutic agents, such as, cisplatin, carboplatin, doxorubicin, paclitaxel, taxotere, methotrexate, fluorouracil, camptothecin, cyclophosphamide and mixtures thereof, as well as therapeutically-effective amounts of anti-angiogenesis agents, either alone or in combination.
• chemotherapeutic agents such as, cisplatin, carboplatin, doxorubicin, paclitaxel, taxotere, methotrexate, fluorouracil, camptothecin, cyclophosphamide and mixtures thereof, as well as therapeutically-effective amounts of anti-angiogenesis agents, either alone or in combination.
• suitable anti-tumor and anti- angiogenesis agents and associated dosage regimens are
• the bucyclate and undecanoate stand in marked contrast to testosterone enanthate.
• the latter exists as a liquid at room temperature, adversely affecting its activity over long periods of time. Further, the enanthate is precluded from commercialization as a lyophilizate or powder for reconstitution, or as a tablet, caplet or other solid dosage form.
• Fig. 11 the preferred synthesis of 7 ⁇ , 11 ⁇ -dimethyl-
• Step (a) may also yield an undesirable by-product, Compound 3
• step (f) one may ketalize the 1 l ⁇ - and 1 l ⁇ -methyl isomers of Compound 7 to provide Compound 8
• a preferred synthesis route for the preparation of the undecanoate is set forth. This synthesis comprises steps (a)-(g) used in the bucyclate synthesis as set forth above. Thereafter, however, Compound 10 is esterified to provide Compound II (the undecanoate).
• any type of carrier that maintains the benefits of the invention as described herein may be used.
• the bucyclate and/or undecanoate is suspended in an aqueous carrier suitable for injection.
• the water component of the aqueous carrier should constitute at least half thereof, on a weight percent basis, preferably at least about 80 wt.%, and more preferably at least about 90 wt.% of the aqueous carrier.
• Illustrative of a preferred parenteral formulation is one that, includes up to 300 mg of the active suspended in about 1 ml of an aqueous carrier.
• CDB-4386 which may be referred to as "close” to 7 ⁇ ,l l ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate from a chemical structure perspective, nevertheless exhibits relatively low activity as compared to 7 ⁇ ,l l ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate.
• both the potency and long-term activity of the higher dosage of testosterone bucyclate (1.0 mg) was significantly less than that provided by the lower dosage of 7 ⁇ ,l l ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate (0.6 mg) in an aqueous suspension.
• EXAMPLE 3 [0074] This example illustrates the relative androgenic activity of testosterone and its derivatives.
• Immature (about 21 -day-old) Sprague-Dawley rats were orchidectomized under anesthesia, and randomly assignee to groups often animals for each dose level of the active undergoing testing. Each active was dissolved in 10% ethanol/sesame oil and administered by gavage (oral) or subcutaneous injection each day for seven days beginning on the date of the orchidectomy. The animals were sacrificed 24 hours after the last dose, and the ventral prostate and seminal vesicles were excised, cleaned of fat and connective tissue, blotted on moist filter paper and weighed to the nearest 0.1 mg. Regression analysis was performed by conventional methods using a PROPHET data management system.
• the oral activity of 7 ⁇ ,l 1 ⁇ -dimethyl- 17 ⁇ -hydroxy-4-estren-3-one bucyclate may be due to its resistance to degradation in the gastrointestinal tract and or rapid metabolism by the liver. It is also possible that the lipophilic nature of 7 ⁇ ,l 1 ⁇ -dimethyl- 17 ⁇ - hydroxy-4-estren-3-one bucyclate permits absorption of the active into the thoracic lymph, thereby avoiding direct entrance into the portal system and metabolism by the liver.
• the lack of activity experienced by 7 ⁇ , 11 ⁇ -dimethyl- 17 ⁇ - hydroxy-4-estren-3-one bucyclate under subcutaneous administration may reflect the slow release, and possibly metabolism, of the active from the injection site over the relatively brief 7-day administration period. This same property, however, conveys long-acting activity on 7 ⁇ ,l 1 ⁇ -dimethyl- 17 ⁇ -hydroxy-4-estren-3-one bucyclate after parenteral administration in an aqueous vehicle.
• the androgenic potency and relative binding affinity to the androgen receptor of several free alcohols after subcutaneous administration of their corresponding esters was also determined. The results are presented in the following Table.
• Immature (about 21 -day-old) Sprague-Dawley rats were orchidectomized under anesthesia, and randomly assignee to groups of 40 or more. Animals received a single subcutaneous injection of 0.6 mg of each ester in 0.2 ml of an aqueous suspending carrier and or oily carrier (10% ethanol/90% sesame oil or ethyl oleate) on the date of the orchidectomy. In cases where the ester was not solid at room temperature, 10% ethanol/sesame oil or ethyl oleate was used as the carrier.
• the carrier used to provide the aqueous suspension was formulated as follows: lg benzyl alcohol, 0.5 g sodium carboxylethyl cellulose 50, 0.376 g disodium hydrogen phosphate dihydrate, 1.495 g sodium dihydrogen phosphate dihydrate, with water for injection (WFI) being added to bring volume of the carrier up to 100 ml.
• WFI water for injection
• Ventral prostate weight was used as the endpoint because it is the sensitive organ to androgenic stimulation. Regression analysis was performed by conventional methods using the PROPHET data management system previously identified.
• FIG. 9 is a graph of the ventral prostate weights at various time intervals up to 20 weeks after administration of several different bucyclate esters: 7 ⁇ ,ll ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate (CDB-4386A), 7 ⁇ - Methyl- 14-dehydro- 19-nortestosterone- 17 ⁇ -bucyclate (CDB-4327A), 7 ⁇ - Methyl- 19-nortestosterone- 17 ⁇ -bucyclate (CDB-4288), 7 ⁇ -Methyl- 16-dehydro- D-homo-19-nortestosterone-17 ⁇ -bucyclate (CDB-4318) and 7 ⁇ -Methyl-5 ⁇ - dihydro-19-nortestosterone- 17 ⁇ -bucyclate (CDB-4289).
• CDB-4386A 7 ⁇ ,ll ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate
• CDB-4327A 7 ⁇ - Methyl-
• Serum samples taken from the animals at autopsy showed the presence of the free alcohol (7 ⁇ ,ll ⁇ -dimethyl-19-nortestosterone) which decreased with time over the 10 week observation period.
• the results are provided in Fig. 10. 7 ⁇ ,l 1 ⁇ -dimethyl-17 ⁇ -hydroxy-4-estren-3-one bucyclate, suspended in the aqueous carrier, provided the highest levels of the free alcohol, and maintained these relatively high levels over the 10-week observation period.
• Lithium wire (253 mg, 36.45 mmol), cut into small pieces, was added to redistilled (from sodium) ammonia (300 mL) and the mixture was stirred at ammonia reflux (-35°C) for V2 hr. The mixture was chilled to -78°C and a solution of the dienone (Compound 7b, 3.65 g 12.15 mmol) in THF (300 mL) and t-butanol (1.16 mL, 12.15 mmol) was added dropwise. Upon completion of the addition, the reaction was stirred for 15 min before any excess lithium was destroyed with the addition of isoprene (ca.
• Fig. 13 This data indicates that the subcutaneous androgenic activity of the undecanoate (CDB-4521A) is about half that of testosterone (0.52 times, at a 95% confidence interval, 0.29-0.93) when administered in the oily carrier. This data was surprising when compared to the results obtained when the undecanoate was administered in an aqueous carrier.
• the animals were sacrificed 24 hours after the last dose, and the ventral prostate and seminal vesicles were excised, cleaned of fat and connective tissue, blotted on moist filter paper and weighed to the nearest 0.1 mg. See, e.g., Hershberger, L. et al, Myotrophic Activity of 19-nortestosterone And Other Steroids Determined By Modified Levator And Muscle Method, Proc. Soc. Exptl. Biol. Med. 83 175-180 (1953). Regression analysis was performed by conventional methods using a PROPHET data management system.
• the enanthate ester was formulated using the 10% ethanol/sesame oil or ethyloleate carrier as a first standard, with the 10% ethanol/sesame oil carrier used as a second standard.
• AUC area under the curve

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