MXPA98009293A - Hydrogen smoke of (-) - 3r, 4r-trans-7-metoxy-2,2-dimethyl-3-fenil-4. { 4- [2- (pirrolidin-1-il) etoxy] fenil} crystal crystal - Google Patents

Abstract

The present invention relates to: hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} novel crystalline chroman, useful for reducing or preventing bone loss, as well as pharmaceutical compositions containing the same. A process for preparing hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4 is described. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} chroma

Description

Hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) -ethoxy] phenyl} crystalline chroman FIELD OF THE INVENTION The present invention relates to hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrol idinl-il) ethoxy] phenyl} crystalline chroman, referred to herein as levormeloxifen fumarate, to its preparation and to its use as a therapeutic agent.

BACKGROUND OF THE INVENTION U.S. Patent No. 5,280,040 and U.S. Patent No. 5,646,862 describe a class of 3,4-diarylchromans and their salts useful in reducing bone loss. U.S. Patent 5,453,442 discloses methods for lowering serum cholesterol and inhibiting the proliferation of smooth muscle cells in humans, and for inhibiting uterine fibroid disease and endo etriosis in women, by administering the compounds of formula I shown therein.

REF: 28492 The preparation of 3, -transdiarilcrsmanos is described in US Pat. No. 3,822,287 and by Suprabhat et al. In Med. Chem. 19,276 (1976), the content of which is incorporated herein by reference. The resolution of (+/-) - 3, 4-trans-7-methoxy-2, 2-dimethyl-3-pheny1-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} chroman in its optical antipodes is described in US Pat. No. 4,447,622 incorporated herein by reference. Example 1 describes the preparation of fewer enantiomers, shown by formula I: (I) (in this specification the compound of formula I is referred to as levormeloxifen).

In Example 2 of US Patent No. 4,447,622 the levorioxifene is obtained as the free base and as 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, is very poorly soluble in water and 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.

BRIEF DESCRIPTION OF THE INVENTION Within one aspect, the present invention provides, hydrogen fumarate of (-) - 3R, 4R-trans-7-meto-2, 2-dimethyl-3-pheny1-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} crystalline chroman. Within another aspect of the invention, there is provided a pharmaceutical composition, hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} crystalline chroman, 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 hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} crystalline chroman, the process comprises dissolving fumaric acid and hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-. { 4- [2- (pyrro1idin-1-yl) ethoxy] phenyl} crystalline chroman in a common solvent, and crystallize the salt resulting from the solution. Within another aspect of the invention, there is provided a method for using the compound according to the invention to prevent or reduce bone loss.

DETAILED DESCRIPTION OF THE INVENTION It has now been discovered that the hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} Crystalline chroman has the desired properties described above. In contrast to the hydrochloride salt, which is very hygroscopic, the hydrogen fumarate salt is non-hygroscopic. Additionally, the hydrogen fumarate salt has good stability characteristics, good bioavailability, good handling properties and a reproducible crystalline form. In consequence, the present invention provide crystalline levormeloxifen fumarate as a novel material, in particular in pharmaceutically acceptable form. The present invention also provides a process for the preparation of hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} crystalline chroman, the process comprises dissolving fumaric acid and hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} crystalline chroman in a common solvent, and crystallize the salt resulting from the solution. Examples of the common solvents include but are not limited to inorganic solvents, in particular lower aliphatic alcohols such as ethanol, 2-propanol, 2-butanol, 1-hexanol and solvents such as isobutylmethretone and tetrahydrofuran. A preferred solvent is ethanol. The mixing of the components is conveniently carried out at temperatures from 40 to 60 ° C before cooling to 5 ° C and collecting the crystals by filtration.

The present invention also provides a pharmaceutical composition comprising (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-hydrogen fumarate. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} crystalline chroman, optionally together with a pharmaceutically acceptable carrier or diluent. The hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2, 2-dimethy1-3-phenyl- -. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} Crystalline chroman can be used in human and veterinary medicine for the regulation of bone metabolism. The present invention thus provides according to another aspect a method for preventing or reducing bone loss in a mammal in need of such treatment or prevention, which comprises administering a therapeutically effective amount of the compound according to the invention. Levormeloxifen fumarate can 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 characterized conditions by excessive rates of bone resorption and / or decreased rates of bone formation, or in patients susceptible to bone loss. Additionally, the compound has effects on the cardiovascular system where serum cholesterol decreases, inhibits the accumulation of lipids, in the arterial wall, acts as a vasodilator and interferes with the coagulation process, so it can be used for prevention and treatment of, for example, atherosclerosis, hyperlipidemia and hypercoagulability. It can also be used, for example, in the treatment of female patients suffering from endometriosis, dysfunctional bleeding, endo-etrial cancer, polycystic ovarian syndrome, anavelatory bleeding and breast cancer, and male patients with gynecomastia, prostatic hypertrophy and carcinoma of the prostate. . It can also be used to induce endometrial thinning before intrauterine surgery. Additionally, it can be used, for example, to treat menopausal symptoms, and atrophy of mucous membranes and skin. The compound can be used as, for example, in the treatment of patients suffering from obesity and Alzheimer's disease. For use within the present invention, the hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2, 2-dimethyl-3-pheny1-4-. { - [2- (pyrrolidin-1-yl) ethoxy] phenyl} Crystalline chroman can 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. The formulations may additionally 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 systems, dermal implants. , tablets, etc. One skilled in the art can formulate the compound in an appropriate manner, and in accordance with accepted practices, such as those described in Reminton 's Pharmaceuticals Sciences, Gennaro ed., Mack Publishing Co., Easton, PA, 1990. Compositions of this invention are usually adapted for oral administration, or as formulations for their dissolution for parenteral administration. Oral administration is preferred. For oral administration, the hydrogen fumarate of (-) -3R, 4R-trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} Crystalline chroman is prepared in a form suitable for oral administration, such as tablets or capsules. Typically, the compound is combined with a carrier and molded into a tablet. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions may additionally include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, coloring additives, etc. The pharmaceutical compositions are administered one or more times per day or per week. An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect. Such amounts will depend in part on the particular condition to be treated, the age, weight, and general health of the patient, and other factors evident to those skilled in the art. The pharmaceutical compositions can be administered in unit dosage form one or more times per day or per week. In the alternative, they can be provided as controlled release formulations suitable for their dermal implant. The implants are formulated to provide the release of the active compound during the desired period of time, which may be up to several years. Formulations for controlled release are described, for example, Sanders et al., J Pharm Sci 73 (1964), 1294-1297; 1984; U.S. Patent No. 4,489,056; and U.S. Patent No. 4,210,644, which are incorporated herein by reference. The composition is usually presented as a unit dose composition containing 0.1-1000 mg of a compound according to the invention for oral dosing. Typical dosages for for example an osteoporotic effect would vary between 0.1-500 mg preferably between 0.1-280 mg per day either in one dose or divided into 2 or 3 doses when administered orally, or 2 or 3 times per week or once. per week, or once per 14 days. Preferred unit dosage forms include in solid form, tablets or capsules, in liquid form, solutions, suspensions, emulsions, elixirs or capsules filled therewith, or in the form of sterile injectable solutions, or patches, vagiums, vaginal rings or implants. of prolonged duration. The composition of this invention can be formulated by conventional galenic pharmacy methods. Conventional excipients are those pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application, which do not react in a harmful manner with the active compound. Examples of such carriers are water, saline solutions, alcohols, polyethylene glycols, psyllhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, agar, pectin, acacia, amylose, stearate magnesium, talc, cylindric acid, stearic acid, monoglycerides and diglycerides of fatty acid, fatty acid esters of pentaerythritol, hydroxymethylcellulose and polyvinylpyrrolidone and calcium phosphates. The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as binders, lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers and / or coloring substances and the like. , that do not react in a harmful way with the active compound. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

For oral administration, particularly suitable are tablets, dragees or capsules, having talc and / or a carbohydrate carrier or binder or the like, the carrier preferably being lactose or calcium phosphate and / or corn starch and / or starch dad. A syrup, elixir or the like can be used when a sweetened vehicle can be employed. A typical tablet, which can be prepared by conventional tableting techniques, contains: Active compound 10 mg Lactose 67.8 mg Ph.Eur. © Avicel 4 mg Talcum 1.0 mg Magnesium stearate 0.25 mg Ph.Eur.

The present invention is further illustrated by the following examples, which however are not to be construed as limiting the scope of protection. The aspects described in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention in the various forms thereof.

The levormeloxifen fumarate was synthesized, purified and crystallized as described in the following example.

EXAMPLE 1 hydrogen fumarate of (-) -3R, R-trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrol idin-1-yl) ethoxy] phenyl} crystalline chroman (levormeloxifen fumarate).

To a solution stirred and heated to 50 ° C of - (+/-) -trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} Chroman (1.00 kg, 2.19 mol) in methanol (10 1) was added (+) - tartaric acid 464 g, 1.20 mol). The suspension was stirred at 50 ° C until the solution was homogeneous.

Formic acid (73 g, 1.59 mol) was added to the solution, and the temperature was allowed to drop to 30-40 ° C. If the crystallization did not start at this point, the solution was seeded, and the temperature was further lowered to 20 ° C. The suspension was stirred for two hours at 20 ° C, and then cooled to 5-10 ° C for two hours, and the crystals were collected by filtration. Yield 742 g. Recrystallization from refluxing methanol (26 1) gave 5-10 ° C and filtration of pure crystals of the salt of (+) - ditoluoyltartrate of Levormeloxifen. Yield 556 g. P.f. 136-138 ° C (decomposition). The (-) - 3R, R-trans-7-methoxy-2, 2-dimethy-l-3-phenyl-4 was suspended. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} chroman, (+) - ditoluoyltartrate (500 g) in a mixture of toluene (2.5 1), water (2 1) and sodium carbonate (157 g) at room temperature. The mixture was stirred until the salts dissolved. The aqueous phase was separated. The toluene phase was washed with water (2 1) and evaporated to give an oil. The oil was dissolved in ethanol (11) at 40-60 ° C, and the solution was added to a solution of fumaric acid (69 g, 0.59 mol) in ethanol (2 1). The fumarate salt crystallized easily, and the mixture was stirred for one hour at 40-60 ° C, and then cooled to 5 ° C. The title compound was collected by filtration and dried at 50 ° C to give 321 g (57%). P.f. 225 ° C. (DSC). RMN-1 !. (DMSO-de, TMS): d (ppm): 2.90 (4H, m), 1.75 (4H, m), 3.10 (2H, t), 4.06 (2H, t), 6.69 (2H, d), 7.01 ( 2H, d), 4.50 (1H, d), 6.44 (1H, m), 6.33 (1H, m), 6.38 (1H, m), 3.28 (1H, d), 7.31 (2H, broad), 7.20 ( 2H, m), 7.11 (1H, m), 1.15 (3H, s), 1.27 (3H, s), 3.68 (3H, s), 6.53 (2H, s), 10.0 (2H, s).

MS: 457.2632 (M + measured), 457.2617 (M + calculated).

Elemental Analysis: (C30H35NO3, C4H4O4), Calculated: C: 71.18%, H: 6.85%, N: 2.44%, Found: C: 71.23%, N: 7.15%, N: 2.31% Optical rotation: [a] D = -153.8 ° (c = 0.5 p / v% in ethanol).

Hygroscopicity of Levormeloxifen hydrochloride and fumarate salts It is noted that in relation to this date, the best method known by the applicant to carry out the present invention, is the conventional one for the manufacture of the objects to which it refers. Having described the invention as above, the content of the following is claimed as property:

Claims (10)

1. Hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} crystalline chroman.

2. A process for the preparation of hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pi rolidin-1-yl) ethoxy] f nil} crystalline chroman according to claim 1, the process is characterized in that it comprises dissolving fumaric acid and (-) - 3R, 4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-. { 4- [2- (? Irrolidin-1-yl) ethoxy] phenyl} chroman in a common solvent, and crystallize the salt resulting from the solution.

3. A pharmaceutical composition characterized in that it comprises hydrogen fumarate of (-) - 3R, 4R-trans-7-methoxy-2, 2-dimethyl-3-phenyl-4-. { 4- [2- (pyrslidin-1-yl) ethoxy] phenyl} Crystalline chroman according to claim 1, optionally together with a pharmaceutically acceptable carrier or diluent.

4. The pharmaceutical composition according to claim 3, characterized in that it is in the form of a dosage unit containing about 0.1-280 mg per day.

5. A pharmaceutical composition for use in reducing or preventing bone loss in a patient, characterized in that it comprises a therapeutically effective amount of a crystalline salt according to claim 1, together with a pharmaceutically acceptable carrier or diluent.

6. A pharmaceutical composition according to claim 5, characterized in that the bone loss is due to osteoporosis.

7. The use of a compound according to claim 1, characterized in that it is like a medicine.

8. The use of a compound according to claim 1, characterized in that it is for the preparation of a pharmaceutical composition for reducing or preventing bone loss. A method for reducing or preventing bone loss, characterized in that it comprises administering to a patient in need of such treatment or prevention an effective amount of the compound according to claim 1. 10. A method according to claim 9, characterized in that Bone loss is due to osteoporosis.