Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-10
2003-11-25
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S525000
Reexamination Certificate
active
06653479
ABSTRACT:
BACKGROUND OF THE INVENTION
6-Hydroxy-3-(4-[2-(piperidin-1-yl)ethoxyl]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride (arzoxifene) was first described generically in U.S. Pat. No. 5,510,357 and was specifically disclosed in U.S. Pat. No. 5,723,474 ('474) and European Patent Application 0729956. Arzoxifene is a nonsteroidal mixed estrogen antagonist/agonist, useful for, inter alia, lowering serum cholesterol and for inhibiting hyperlipidemia, osteoporosis, estrogen dependent cancers including breast and uterine cancer, endometriosis, CNS disorders including Alzheimer's disease, aortal smooth muscle cell proliferation, and restenosis.
Specifically, arzoxifene is useful for, and is being clinically evaluated for the treatment of receptor positive metastatic breast cancer; the adjuvent treatment of receptor positive patients following appropriate systemic or local therapy; the reduction of recurrence of invasive and noninvasive breast cancer; and the reduction of the incidence of invasive breast cancer and ductal carcinoma in situ (DCIS). Arzoxifene is also useful in combination with radiotherapy, aromatase inhibitors, LHRH analogues, and acetyl choline esterase (AChE) inhibitors.
X-ray powder diffraction (XRD), thermogravimetric (TGA), proton nuclear magnetic resonance (
1
H NMR) and Karl Fischer (KF) analyses of bulk arzoxifene isolated by the procedures taught in '474 later indicated that said material was hydrated, poorly crystalline, and contained variable amounts of an organic volatile (ethyl acetate) in its lattice.
Poorly crystalline materials are typically less desirable than highly crystalline materials for formulation processing. In addition, it is generally not desirable to formulate pharmaceuticals containing substantial amounts of organic solvent (e.g., ethyl acetate) due to potential solvent toxicity to the recipient thereof and changes in potency of the pharmaceutical as a function of the solvent.
Although the arzoxifene prepared by the procedures taught in '474 could be used as a pharmaceutical, it would be highly desired and advantageous to find a more crystalline form of arzoxifene that did not contain an organic solvent within its crystal lattice which could be reproducibly and efficiently prepared on a commercial scale.
SUMMARY OF THE INVENTION
The present invention is related to a novel non-stoichiometric hydrated crystalline form of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride (F-I) having an X-ray diffraction pattern which comprises the following peaks: 7.9±0.2, 10.7±0.2, 14.9±0.2, 15.9±0.2, 18.3±0.2, and 20.6±0.2° in 2&thgr;; when obtained from a copper radiation source.
Moreover the present invention relates to a pharmaceutical formulation comprising F-I; one or more pharmaceutical carriers, diluents, or excipients; and optionally estrogen, optionally progestin, optionally an aromatase inhibitor, optionally an LHRH analogue and optionally an acetyl choline esterase (AChE) inhibitor.
In addition, the present invention is related to methods for using F-I to inhibit pathological conditions such as: uterine fibrosis, endometriosis, aortal smooth muscle cell proliferation, restenosis, breast cancer, uterine cancer, prostatic cancer, benign prostatic hyperplasia, bone loss, osteoporosis, cardiovascular disease, hyperlipidemia, CNS disorders, and Alzheimer's disease and for using F-I for the manufacture of a medicament for inhibiting same.
The present invention is further related to methods for using F-I to up-regulate choline acetyltransferase (ChAT) and for using F-I for the manufacture of a medicament for up-regulating same.
REFERENCES:
patent: 5510357 (1996-04-01), Palkowitz
patent: 5723474 (1998-03-01), Palkowitz
patent: 5856339 (1999-01-01), Palkowitz et al.
patent: 5856340 (1999-01-01), Palkowitz
patent: 5919800 (1999-07-01), Palkowitz
patent: 5977093 (1999-11-01), Palkowitz
patent: 5998441 (1999-12-01), Palkowitz
patent: 6077852 (2000-06-01), Bales et al.
patent: WO 9845286 (1998-10-01), None
patent: WO 9845288 (1998-10-01), None
patent: WO 2001085147 (2001-11-01), None
Drugs Future, 24 (6) :599-604, 1999.
Bush Julie Kay
Conrad Preston Charles
Flom Merlyn Gerard
Luke Wayne Douglas
Chang Ceila
Covington Raymond
Eli Lilly and Company
Voy Gilbert T.
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