Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-03-27
2002-10-01
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C552S644000
Reexamination Certificate
active
06458778
ABSTRACT:
BACKGROUND OF THE INVENTION
The use of naturally occurring estrogenic compositions of substantial purity and low toxicity such as PREMARIN (conjugated equine estrogens) has become a preferred medical treatment for alleviating the symptoms of menopausal syndrome, osteoporosis/osteopenia in estrogen deficient women and in other hormone related disorders. The estrogenic components of the naturally occurring estrogenic compositions have been generally identified as sulfate esters of estrone, equilin, equilenin, 17&bgr;-estradiol, dihydroequilenin and 17&bgr;-dihydroequilenin (U.S. Pat. No. 2,834,712). The estrogenic compositions are usually buffered or stabilized with alkali metal salts of organic or inorganic acids at a substantially neutral pH of about 6.5 to 7.5. Urea has also been used as a stabilizer (U.S. Pat. No. 3,608,077). The incorporation of antioxidants to stabilize synthetic conjugated estrogens and the failure of pH control with tris(hydroxymethyl)aminomethane (TRIS) to prevent hydrolysis is discussed in U.S. Pat. No. 4,154,820.
One of the compounds described herein, estra-5(10),7-dien-3&bgr;-ol-17-one 3-sulfate ester sodium salt is a minor component of PREMARIN (conjugated equine estrogens). The preparation of estra-5(10),7-dien-3&bgr;-ol-17-one and estra-5(10),7-dien-3&agr;-ol-17-one have been disclosed by K. Junghans in Chem Ber. 112: 26 (1979); however, no utility is provided for this compound. U.S. Pat. No. 2,930,805 discloses the preparation of 3,17&bgr;-dihydroxy-5(10),7-estradienes, and their use as antiestrogens. U.S. Pat. No. 3,340,278 discloses the preparation of 5(10),7-estradien-3,17-dione, 3,17&bgr;-dihydroxy-5(10),7-estradiene, and 17&bgr;-hydroxy -5(10),7-estradien-3-one, which are useful as intermediates in the preparation of equilin.
DESCRIPTION OF THE INVENTION
In accordance with this invention, there are provided estra-5(10),7-dien-3&bgr;-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester, estra-5(10),7-dien-3&bgr;-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof, estra-5(10),7-dien-3&agr;-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester, and estra-5(10),7-dien-3&agr;-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof. This invention also provides a compound which is a 3-alkali metal salt of estra-5(10),7-dien-3&bgr;-ol-17-one or estra-5(10),7-dien-3&agr;-ol-17-one. These are all collectively referred to as the compounds of this invention. The structures of estra-5(10),7-dien-3&bgr;-ol-17-one and estra-5(10),7-dien-3&agr;-ol-17-one are shown below as compounds 5B and 5A, respectively.
Pharmaceutically acceptable salts of estra-5(10),7-dien-3&bgr;-ol-17-one 3-sulfate ester, estra-5(10),7-dien-3&bgr;-ol-17-one 3-glucuronide, estra-5(10),7-dien-3&agr;-ol-17-one 3-sulfate ester, or estra-5(10),7-dien-3&agr;-ol-17-one 3-glucuronide include, but are not limited to, the alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group. The alkali metal of the 3-alkali metal salts of estra-5(10),7-dien-3&bgr;-ol-17-one or estra-5(10),7-dien-3&agr;-ol-17-one are lithium, sodium, or potassium.
As estra-5(10),7-dien-3&bgr;-ol-17-one 3-sulfate ester sodium salt is a minor component of PREMARIN (conjugated equine estrogens), this invention also provides estra-5(10),7-dien-3&bgr;-ol-17-one 3-sulfate sodium salt in greater than one percent purity.
This invention also provides a compound consisting essentially of estra-5(10),7-dien-3&bgr;-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester or estra-5(10),7-dien-3&bgr;-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof; and a compound consisting essentially of estra-5(10),7-dien-3&agr;-ol-17-one or a pharmaceutically acceptable salt of its 3-sulfate ester or estra-5(10),7-dien-3&agr;-ol-17-one 3-glucuronide or a pharmaceutically acceptable salt thereof.
As used in accordance with this invention, treating covers treatment of an existing condition, ameliorating the condition, or providing palliation of the condition and inhibiting includes inhibiting or preventing the progress or development of the condition.
The compounds of this invention can be prepared from readily available starting materials. For example, the preparation of estra-5(10),7-dien-3&bgr;-ol-17-one (5B), estra-5(10),7-dien-3&agr;-ol-17-one (5A), estra-5(10),7-dien-3&agr;-ol-17-one 3-sulfate ester sodium salt (7), and estra-5(10),7-dien-3&bgr;-ol-17-one 3-sulfate ester triethylammonium salt (15) are shown in Schemes I and II starting from equilin methyl ether (U.S. Pat. No. 3,644,439, which is hereby incorporated by reference) and 17&bgr;-hydroxyestra-5(10),7-dien-3-one (8) (U.S. Pat. No. 2,930,805, which is hereby incorporated by reference). Estra-5(10),7-dien-3&bgr;-ol-17-one 3-glucuronide sodium salt (16) and estra-5(10),7-dien-3&agr;-ol-17-one 3-glucuronide sodium salt (17) can be prepared according to Scheme III.
As shown in Scheme I, the 17-ethylenedioxy derivative of equilin methylether 1 is converted to the triene 2 utilizing a Birch reduction with lithium in liquid ammonia. Mild oxalic acid treatment allows the selective hydrolysis of the enol ether to provide the ketone 3. Sequential reduction of the 3-ketone (lithium aluminum hydride); and deprotection of the 17-ketone (p-tolunesulfonic acid) affords the products 5A and 5B of the invention as a mixture in which the 3&agr;-isomer 5A predominates (4:1 ratio). Separation can be realized directly by preparative high pressure liquid chromatography. Alternatively, inversion of configuration at C-3 to a mixture in which the 3&bgr;-isomer predominates can be achieved by a Mitsunobu reaction. The highly crystalline 3-(3,5-dinitro)benzoates, products of the Mitsunobu inversion, are readily separable by column chromatography. After hydrolysis, 5B was converted to its 3,&bgr;-sulfate 7 with triethylamine:sufur trioxide reagent.
Scheme II outlines the conversion of 17&bgr;-hydroxyestra-5(10),7-dien-3-one (8) to a mixture of 5A and 5B (6.6:1 ratio) by a reduction-oxidation sequence requiring a differential protection-deprotection sequence for the C-3 and C-17 functionalities. Reduction at C-3 utilized lithium tri-tertbutoxyaluminum hydride, a Swern-type oxidation provided the C-17 ketone. Separation of 5A and 5B was achieved by HPLC. The conversion of 5A to the 3&agr;-sulfate 15 with pyridine:sufur trioxide reagent is exemplified. The alkali metal salts of 5A and 5B can be prepared by treatment of the respective alcohol with an alkali metal hydride, such as sodium hydride, in a non-aqueous solvent such as THF or DMF. The alkali metal salts of 5A and 5B are useful as intermediates in the preparation of the sulfate esters (via amine:sulfur trioxide treatment) of 5A and 5B, and are also useful as estrogenic compounds.
Scheme III shows the preparation of estra-5(10),7-dien-3&bgr;-ol-17-one 3-glucuronide sodium salt (16) and estra-5(10),7-dien-3&agr;-ol-17-one 3-glucuronide sodium salt (17) from estra-5(10),7-dien-3&bgr;-ol-17-one (5B) and estra-5(10),7-dien-3&agr;-ol-17-one (5A), respectively. The sodium glucuronides (16) and (17) can be treated with mild acid to provide the respective 3-glucuronides.
The compounds of this invention are estrogenic, as shown in the in vitro and in vivo standard pharmacological test procedures described below in which compounds estra-5(10),7-dien-3&bgr;-ol-17-one (5B) and estra-5(10),7-dien-3&agr;-ol-17-one (5A) were evaluated as representative compounds of this invention.
Estrogen Receptor Binding
An initial evaluation examined the competitive binding properties of 5B and 5A to the human estrogen receptor (hER-&agr;) prepared as a soluble cell extract (cytosol). In this standard pharmacological test procedure, 5B and 5A demonstrated no specific binding activity. However, when estrogen receptor binding was analyzed using a whole cell test procedure, specific bin
Collins Mark A.
Kagan Michael Z.
Kong Fangming
McDonald Leonard A.
Raveendranath Panolil
Badio Barbara P.
Milowsky Arnold S.
Wyeth
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