Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-10-13
2002-03-12
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S182000, C540S107000, C540S113000, C552S523000
Reexamination Certificate
active
06355630
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention provides estra-1,3,5(10)-triene-7&agr;-thioethers which are useful as estrogenic and antiestrogenic agents.
The last decade or so, has witnessed the introduction of a new class of antiestrogenic substances devoid of any estrogenic activity. The prototypical compounds are 7&agr; substituted steroids reported by ICI in the 1980's. (Wakeling and Bowler, J. Steroid Biochem. 30: 141-147 (1988); U.S. Pat. No. 4,659,516). Since then, there have been additional reports of steroidal compounds purported to have a purely antiestrogenic activity (See WO 93/10741 and some references contained therein). The potential advantage of these compounds is that they lack the residual agonistic properties of some mixed agonists such as tamoxifen (sold as Novadex® brand tamoxifen citrate by Zeneca Pharmaceuticals, Wilmington, Del.). The residual agonistic activity of tamoxifen can be significant in some tissues such as the uterus and the bone. While the activity in the bone may be appreciated, the estrogenic activity in the uterus may be associated with the increase in uterine cancer risk observed in longer term tamoxifen users. The pure antiestrogens reported by ICI show no trophic or proliferative activity on the uterus and would presumably not increase the risk of estrogen associated uterine cancer. Additionally, the tendency for women who are being treated chronically with tamoxifen to develop tamoxifen resistant tumors has been well documented. It is hoped that the application of antiestrogens which are devoid of any agonistic activity will be able to positively impact on tamoxifen resistant tumors by providing a more complete estrogen withdrawal from the estrogen dependent tumor types. (Wakeling, et al. J.Mol.Endocr. 2: 225-234 (1989)).
Substituents in the 7-position of estratrienes must have the a stereochemistry in order to show a good affinity for the estrogen receptor as well as good antiestrogenic efficacy (Wakeling, et al, vide supra). The prior art to date (relating to antiestrogens) on estratrienes substituted at the 7 position has been limited to side chains connected to the backbone of the steroid by carbon-carbon bonds. A 7-thiopropionate linked has been described in the literature for the purpose of conjugating to serum bovine albumins. The compound was synthesized by the radical addition of &bgr;-mercaptopropionate to 1,3,5(10),6-estratetraenes (Cook, et al Life Sci. (1974), 14 (6), 1075-1087). A series of 1,3,5(10) estratrienes wherein a broad number of claims is attached to functionality at the 7 position including thioalkyl, thioalkenyl and thioalkynyl ethers has been described with chain length up to 6 carbons.(Damato, et al, U.S. Pat. No. 5,504,074).
DESCRIPTION OF THE INVENTION
This invention provides of Formula I having the structure
wherein:
R is
R
1
and R
2
are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups which are taken together to form a 5-7 membered saturated heterocycle;
X is hydroxy, alkoxy of 1-6 carbon atoms, or —OC(O)R
3
;
W is
hydroxy, alkyl of 1-6 carbon atoms, halogen, —CF
3
,
alkoxy of 1-6 carbon atoms, —CHO, cyano, alkylcarbonyl of 2-7 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, trifluoromethoxy, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, —CN, —SO
3
H, or —CO
2
H.
R
3
is alkyl of 1-6 carbon atoms;
R
4
is hydrogen, alkyl of 1-6 carbon atoms, alkoyl of 2-7 carbon atoms, or benzoyl;
Q is hydrogen, —OR
5
, or —NR
6
R
7
;
R
5
is hydrogen or alkyl of 1-6 carbon atoms;
R
6
and R
7
are each, independently, alkyl of 1-6 carbon atoms, or are alkyl groups which are taken together to form a 5-7 membered saturated heterocycle;
n=4-12; and
p=2-6;
or a pharmaceutically acceptable salt thereof which are useful as estrogenic or antiestrogenic agents.
Alkyl, and the alkyl chain of alkoxy include both straight chain as well as branched moieties. Alkoyl of 2-7 carbon atoms is defined as an alkyl carbonyl moiety in which the alkyl chain is from 1-6 carbon atoms; for example, an acetyl group. When R
4
is benzoyl the phenyl group maybe optionally mono-, di-, or tri- substituted with substituents selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2-12 carbon atoms, hydroxy, halogen, cyano, —CO
2
H, nitro, alkylcarbonyl of 2-7 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, and thiol. Halogen means bromine, chlorine, fluorine, and iodine.
The pharmaceutically acceptable salts include those derived from organic and inorganic acids such as, but not limited to: acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. Carboxylate salts, preferably alkali metal salts, for example, sodium, lithium, or potassium may also be prepared as salts of carboxylic acids when a compound of this invention contains a carboxylate moiety.
Preferred compounds are those in which
Z is
those in which:
Z is
and Y is
and those in which:
Z is
Y is
and R
4
is hydrogen or alkoyl of 2-7 carbon atoms.
Compounds of this invention in which R is
are antiestrogenic, and the compounds of this invention in which R is
are estrogenic.
The compounds of this invention can be synthesized from 7&agr;-bromo-3,17&bgr;-dihydroxy-estra-1,3,5(10)-trien-6-one diacetate I [CAS Registry No.97829-67-9] by the route shown in Scheme 1. Reaction of I with the appropriate thiol and sodium hydride in DMF results in substitution of the bromide which occurs with retention of the &agr; stereochemistry at the 7-position to yield II. The acetyl group at the 3-position often comes off (at least partially) during this step. If the acetyl group is only partially removed during this step, one may desire to complete the removal by stirring the compound in methanol with potassium carbonate. The ketone II may be subsequently reduced to a 6&agr;-hydroxy-7&agr;-thioether III, and this reduction occurs diastereoselectively (Wintersteiner, et al, J. Org. Chem., 29, 1325 (1964); Smith, et al, J. Org. Chem., 37, 4000 (1972)). The deoxygenation is subsequently accomplished with trifluoroacetic acid and triethylsilane to give IV. The 17-&bgr; acetate may be hydrolyzed, if desired, to yield V.
The syntheses of the cinnamamides shown in Scheme 2 are based on the same intermediate I as used for compounds of the type in Scheme 1. Displacement of the 7&agr;-bromo substituent occurs with retention of configuration providing the desired 7&agr;-(4′-bromophenyl) thioether VI. This reaction results in the cleavage of the labile 3-acetate. Reduction of the carbonyl group gives the 6&agr;-hydroxy derivative VII. If the 6&bgr;-hydroxy compound is desired, one can activate the 6&agr;-hydroxy group of VII as a mesylate and displace it with hydroxide or a suitably protected alkoxide. Alternatively, VII may be subjected to the Mitsunobu reaction (triphenylphosphine, diethylazodicarboxylate, and acetic acid) followed by hydrolysis of the intermediate 6&bgr;-acetate.
The 6&agr;-hydroxy compound is subsequently deoxygenated with triethylsilane and trifluoroacetic acid to afford compound VIII. The bromine is replaced by the dialkyl acrylamide (or acrylate esters) using a Heck coupling reaction to give compounds of the type IX. If desired, the 17&bgr;-acetate and the acrylate ester can be hydrolyzed using NaOH/MeOH to give a 3,17&bgr;-dihydroxy estratriene X.
The dialkylaminoethoxy derivatives can be synthesized according to Scheme 3. The bromoketone XI [CAS Registry No; 6218-36-6] is reacted with 4-hydroxythiophenol to render XII. The ketone is reduced to give XIII and subsequently deoxygenated with TFA/Et
3
SiH to give XIV. The free phenol is alkylated with the appropriate dialkylaminoet
Jirkovsky Ivo
Miller Chris P.
Tran Bach Dinh
American Home Products Corporation
Coleman Brenda
Milowsky Arnold S.
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