Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-06-08
2002-04-16
Solola, T. A. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S525000
Reexamination Certificate
active
06372776
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate herein referred to as levormeloxifene maleate, its preparation and use as therapeutic agent.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,280,040 and U.S. Pat. No. 5,464,862 discloses a class of 3,4-diarylchromans and their salts useful for reducing bone loss. U.S. Pat. No. 5,453,442 describes methods of lowering serum cholesterol and inhibiting smooth muscle cell proliferation in humans and inhibiting uterine fibroid disease and endometriosis in women by administering compounds of formula I as shown therein.
The preparation of 3,4-trans diarylchromanes is described in U.S. Pat. No. 3,822,287 and by Suprabhat Ray et al. in J. Med. Chem. 19, 276 (1976), the contents of which are incorporated herein by reference. The resolvation of (+/−)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in its optical antipodes is described in U.S. Pat. No. 4,447,622 incorporated herein by reference. Example 1 describes the preparation of the minus enantiomer, shown by formula I:
(In this specification the compound of formula I is referred to as levormeloxifene.)
In example 2 of U.S. Pat. No. 4,447,622 levormeloxifene is obtained as the free base and the hydrochloride salt.
However, the free base has a very poor solubility in water and the hydrochloride salt has some pharmaceutically undesirable properties. The hydrochloride salt is hygroscopic, it is quite heavy soluble in water and it forms a solid gel in aqueous suspension.
For commercial use it is important to have a physiologically acceptable salt with good stability, non-hygroscopicity, good bioavailability, good handling properties, and a reproducible crystalline form.
SUMMARY OF THE INVENTION
Within one aspect, the present invention provides crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate.
Within another aspect of the invention there is provided a pharmaceutical composition comprising crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate optionally in combination with a pharmaceutically acceptable carrier or diluent.
Within another aspect of the invention there is provided a process for the preparation of crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate, which process comprises dissolving maleic acid and (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in a common solvent, and crystallizing the resulting salt from the solution.
Within another aspect of the present invention there is provided a method of using the compound according to the invention to prevent or reduce bone loss.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate has the above described desired properties. In contrast to the hydrochloride salt, which is very hygroscopic, the hydrogen maleate salt is non-hygroscopic. Furthermore the hydrogen maleate salt has good stability characteristics, good bioavailability, good handling properties, and a reproducible crystalline form
Accordingly, the present invention provides crystalline levormeloxifene maleate as a novel material, in particular in pharmaceutically acceptable form.
The present invention also provides a process for the preparation of crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate, which process comprises dissolving maleic acid and (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in a common solvent, and crystallizing the resulting salt from the solution.
Examples of the common solvents include but are not limited to organic solvents in particular lower aliphatic alcohol's such as ethanol, 2-propanol, 2-butanol, 1-hexanol and solvents like toluene, isobutylmethylketone and tetrahydrofuran. The mixture of the components are conveniently performed at temperatures from 40 to 60° C. before cooling down to 5° C. and collection of the crystals by filtration.
The present invention also provides a pharmaceutical composition comprising crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate optionally together with a pharmaceutically acceptable carrier or diluent.
Crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate may be used in human and veterinary medicine for the regulation of bone metabolism. The present invention provides thus according to another aspect a method of preventing or reducing bone loss in a mammal in need of such treatment or prevention comprising administering a therapeutically effective amount of the compound according to the invention. Levormeloxifene maleate may be used, for example, in the treatment of patients suffering from bone loss due to osteoporosis (including post-menopausal osteoporosis and glucocorticoid-related osteoporosis), Paget's disease, hyperparathyroidism, hypercalcemia of malignancy and other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation or in patients susceptible to bone loss. Furthermore, the compound has effects on the cardiovascular system where it lowers serum cholesterol, inhibits lipid accumulation in the arterial wall, acts as a vasodilator and interferes with the coagulation process, wherefore it may be used for the prevention and treatment of, for example, atherosclerosis, hyperlipidemia and hypercoagulability. It may also be used, for example, in the treatment of female patients suffering from endometriosis, dysfunctional bleeding, endometrial cancer, polycystic ovarian syndrome, anovulatory bleeding and breast cancer and male patients with gynecomastia, prostate hypertrophy and prostate carcinoma. It may also be used to induce endometrial thinning prior to intrauterine surgery. Furthermore, it may be used, for example, to treat menopausal symptoms, and atrophy of mucous membranes and skin. The compound may be used, for example, in the treatment of patients suffering from obesity and Alzheimer's disease.
For use within the present invention, crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, hydrogen maleate may be formulated with a pharmaceutically acceptable carrier or excipient to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transdermal administration according to conventional methods. Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc. One skilled in this art may formulate the compound in an appropriate manner, and in accordance with accepted practices, such as those disclosed in
Remington's Pharmaceutical Sciences,
Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990.
The compositions of this invention are usually adapted for oral administration, or as formulations for dissolution for parenteral administration. Oral administration is preferred.
For oral administration crystalline (−)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)eth
Jensen Klaus Snej
McGraw Scott Eugene
Treppendahl Svend
Agris, Esq. Cheryl H.
Green, Esq. Reza
Novo Nordisk A S
Solola T. A.
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