Crystalline (-)-3r,4r-trans-7-methoxy-2,2-dimethyl-3 - phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chroman, gidrofumarat, method thereof, pharmaceutical composition, a method of reducing or preventing the rarefaction of the bone

 

(57) Abstract:

The invention relates to a new crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chromane hydrofolate, method thereof, pharmaceutical compositions on the basis and method of reducing or preventing the rarefaction of bone, including the introduction to the patient an effective amount of the specified new connection. The invention can be used in medicine as a therapeutic agent. 4 C. and 5 C.p. f-crystals, 1 table.

The scope 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, hydrofolate, referred to here as the fumarate levormeloxifene, its preparation and use as therapeutic agent.

Background of the invention

U.S. patent N 5280040 and N 5464862 describe the class of 3,4-diarylamino and their salts, are suitable for the reduction of osteoporosis). U.S. patent N 5453442 describes ways to reduce cholesterol in the serum and inhibition of cell proliferation of smooth muscles in the body and inhibiting the disease, uterine fibroids and e is irishwoman described in U.S. patent N 3822287 and work Suprabhat Ray et al. in J. Med. Chem. 19, 276 (1976), the content of which is contained in the description as a reference. Separation of (+/- ) 3,4-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl)chromane on its optical antipodes is described in U.S. patent N 4447622 included in the description by reference. Example 1 discloses the receipt of the (-) enantiomer, represented by formula I.

< / BR>
(In this description, the compound of formula I is called levormeloxifene).

In example 2 of U.S. patent N 4447622 of levormeloxifene receive in the form of a free base and cleaners containing hydrochloride salt.

However, the free base has a very low solubility in water, and hydrochloride on I salt is pharmaceutically some undesirable properties. Cleaners containing hydrochloride salt is hygroscopic, it 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-hygroscopic, with good bioavailability, easy to use and reproducible crystalline form.

Summary of the invention

In one aspect the present invention provides crystalline (-)-3R, 4R-TRANS-7 what about the aspect of the present invention features a pharmaceutical composition, containing crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl}chroman, gidrofumarat optionally in combination with a pharmaceutically acceptable carrier or diluent.

In still another aspect of the present invention proposes a method of obtaining crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4- [2-(pyrrolidin-1-yl)ethoxy]phenyl)chroman, hydrofolate, which involves the dissolution of fumaric acid and (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-chroman in a common solvent and crystallization of the salts from the solution.

In still another aspect of the present invention proposes a method of using compounds of the present invention to prevent or reduce the rarefaction of bone.

Detailed description of the invention

It was found that crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl)chroman, gidrofumarat has the above desirable properties. Unlike hydrochloridee salt, which is very hygroscopic, gidrofumarat salt nephroscopy. Moreover, gidrofumarat salt has a good characterislics form.

Accordingly, the present invention provides crystalline fumarate levormeloxifene as a new material, in particular in pharmaceutically acceptable form.

The present invention also provides a method of obtaining a crystalline (-)-3R, 4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-(4-[2-(pyrrolidin-1-yl)ethoxy] phenyl}chromane, hydrofolate, which includes the stage of dissolving fumaric 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 crystallization of the salts from the solution.

Examples of common solvents include, but are not limited to, organic solvents, in particular lower aliphatic alcohols, such as ethanol, 2-propanol, 2-butanol, 1-hexanol, and solvents, such isobutylmethylxanthine and tetrahydrofuran. The preferred solvent is ethanol. The mixture components are conveniently get at temperatures from 40 to 60oWith before cooling to 5oWith and collecting 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)chroman, g is of Polymetal (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chroman, hidrovo-Marat can be used in human medicine and in veterinary medicine for the regulation of bone metabolism. The present invention thus provides, in accordance with another aspect of the method of preventing or reducing the rarefaction of the bone in a mammal in need of such treatment or prevention, comprising introducing a therapeutically effective amount of the compounds of the present invention. Fumarate levormeloxifene can be used, for example, in the treatment of patients suffering from bone loss as a result of osteoporosis (including postmenopausal osteoporosis and glucocorticoid - related osteoporosis), Paget's disease, hyperparathyroidism, malignant hypercalcemia and other conditions characterized by excessive levels of bone resorption and/or decreased rates of bone formation, or for patients who are susceptible to bone loss. Moreover, the connection has an effect on the cardiovascular system, where it reduces the content of serum cholesterol, inhibits the accumulation of lipids in the artery walls, acts as a vasodilator and inhibits the coagulation process, so it can be used for prophylactically, for example, for the treatment of patients women suffering from endometriosis, dysfunctional bleeding, uterus cancer, polycystic ovarian syndrome, bleeding in the anovulation and breast cancer, and patients men with gynecomastia, prostatic hypertrophy and carcinoma of the prostate. It can also be used to stimulate endometrial thinning before surgery intrauterine cavity. Moreover, it can be used, for example, for the treatment of menopausal symptoms and atrophy of the mucous membranes and skin. The connection can be used, for example, in the treatment of patients suffering from obesity or 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} chroman, gidrofumarat can be combined in a composition with a pharmaceutically acceptable carrier or excipient to obtain medicines for parenteral, oral, nasal, rectal, subcutaneous or intradermal or transdermal injection in accordance with the conventional methods. The composition can optionally include one or more diluents, fillers, Mach, as liquids, powders, emulsions, suppositories, liposomes, transdermal pads, means controlled selection, skin implants, pills and so on. Specialist in this field can get the connection properly and in accordance with accepted practice, such as described in Remington''s Pharmaceutical Sciences, Gennaro, ed. , Mack Publishing Co., Easton, PA, 1990.

Compositions of the present invention is usually adapted for oral administration or in the form of compositions for dissolving parenteral. The oral intake is preferable.

For oral administration of crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chroman, gidrofumarat receive in a form suitable for oral administration such as tablet or capsule. Usually the connection is combined with a carrier and pressed into a pill. Suitable in this respect carriers include starch, sugar, secondary acidic calcium 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, and so forth.

Pharmaceutical cosily - this is the amount that provides a clinically significant effect. Such amounts will depend, in particular, on the specific condition that should be treated, age, weight and General health of the patient and other factors evident to the experts in this field.

The pharmaceutical compositions can be administered in a standard dose once or more per day or per week. Alternatively, they may be provided in the form of compositions for the controlled selection suitable for dermal implantation. Implants prepared in such a way as to ensure the release of active compounds within the required time period, which can last up to several years. Compositions for the controlled selection are described, for example, in the work of Sanders et al., J. Pharm. Sci., 73 (1964), 1294-1297,1984; the U.S. patent N 4489056; and N 4210644, which are included in the description by reference.

The composition is usually represented as a composition of a standard dose, containing 0.1-1000 mg of the compounds of the present invention for oral dosing. A typical dosage of, for example, for the osteoporotic effect will vary in the range of 0.1-500 mg, preferably 0.1 to 280 mg per day, either in one go or with whom her.

Preferred standard forms include solid forms, tablets or capsules, in liquid form solutions, suspensions, emulsions, elixirs, or filled their capsules or in the form of sterile solutions for injection, or overlays, vagatore, vaginal rings, or implants with long-lasting effects.

The composition of the present invention can be prepared by generally accepted methods of medical pharmacology.

Conventional excipients are pharmaceutically acceptable organic or inorganic substance carrier suitable for parenteral or oral administration and which do not react in an undesirable way with the active connection.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyalkane castor oil, syrup, peanut oil, olive oil, gelatine, lactose, gypsum, sucrose, agar, pectin, acacia, amylose, magnesium stearate, talc, silicic acid, stearic acid, monoglycerides and diglycerides of fatty acids, esters of pentaerythritol, fatty acids, hydroxymethylcellulose, polyvinylpyrrolidone and calcium phosphate.

The pharmaceutical preparations of the lubricant, preservatives, disintegrant, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring additives, and the like, which do not interact in an unwanted manner with the active connection.

For parenteral application, particularly suitable are solutions or suspensions for injection, preferably, aqueous solutions with dissolved in polyhydroxyalkane castor oil active connection.

For oral administration are particularly suitable are tablets, coated tablets or capsules containing talc and/or hydrocarbon carrier or binder, or the like, the carrier preferably is lactose or calcium phosphate and/or corn starch and/or potato starch. When can be used sweetened filler, can be used syrup, elixir and the like.

A typical tablet which can be manufactured by a conventional method of manufacturing tablets contains

The active compound, 10 mg

Lactosum and 67.8 mg Ph.Eur.

Avicel- to 31.4 mg

Talc 1.0 mg

Magnesii stearas - 0.25 mg Ph.Eur.

The present invention is additionally illustrated by the following Pref above description and the following examples, may, both separately and in any combination, be material for realizing the present invention in its various forms.

Fumarate levormeloxifene was synthesized, purified and crystallized as described in the following example.

Example 1

(-)-3R, 4R-TRANS-7-methoxy - 2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chroman, gidrofumarat (fumarate levormeloxifene)

To a stirred solution of (+/-)-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chromane (1.00 kg, 2,19 mol) in methanol (10 l) with temperature 50oWith the add (+)-ditawarkan acid (464 g, 1.20 mol). The suspension is stirred at 50oWith up until the solution is homogeneous.

To the solution was added formic acid (73 g of 1.59 mol), and the temperature allowed to drop to 30-40oC. if, at this temperature, the crystallization does not occur, the solution strawley crystals, and temperature give further reduced to 20oC. the Suspension is stirred for two hours at 20oC and then cooled to 5-10oWith over two hours, the crystals are collected by filtration. Exit 742,

Recrystallization from deleverage methanol (2 the dryer. Exit 556, the melting point of 136-138oC (decomp.)

(-)-3R, 4R-TRANS-7-methoxy - 2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chroman, (+)-getawaylocated (500 g) is suspended in a mixture of toluene (2.5 l), water (2 l) and sodium carbonate (157 g) at ambient temperature. The mixture is stirred to dissolve the salts. The aqueous phase is separated. Toluene phase washed with water (2 l) and evaporated to an oil. The oil is dissolved in ethanol (1 l) at 40-60oC, and the solution added to a solution of fumaric acid (69 g, 0.59 mol) in ethanol (2 l). Fumaric salt is easily crystallized, and the mixture is stirred for hours at 40-60oC, and then cooled to 5oC. the Target compound is collected by filtration and dried at 50oWith obtaining 321 g (57%).

The melting point of 225o(DSC)

1H-NMR (DMSO-d6, TMS): (M. D.): 2,90(4H,m) of 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), or 3.28(1H,d), 7,31(2H,ush.C.), then 7.20(2H,m), 7,11(1H,m) and 1.15(3H,s) of 1.27(3H,s), 3,68(3H,s), 6,53(2H,s), 10.0 g(2N,C).

Mass spectroscopy: 457,2632(M+measured), 457,2617(M+calculated).

Elemental analysis: (C30H35NO3WITH4H4O4)

calculated: C:71,18%, N:6,85%, N:2,44%,

found: C is zero).

Hygroscopicity cleaners containing hydrochloride and fumaric salts levormeloxifene presented in table 1.

1. Crystalline (-)-3R, 4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chroman, gidrofumarat.

2. Connection on p. 1, useful for obtaining a pharmaceutical composition for reducing or preventing the rarefaction of bone.

3. The method of obtaining crystalline (-)-3R, 4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chromane, hydrofolate under item 1, comprising dissolving fumaric 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 crystallization of the salts from the solution.

4. Pharmaceutical composition comprising crystalline (-)-3R, 4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chroman, gidrofumarat under item 1, optionally together with a pharmaceutically acceptable carrier or diluent.

5. The pharmaceutical composition under item 4 in the form of a unit dose containing approximately 0.1 to 280 mg per day.

6. Pharmaceutical composition for reducing or preventing the rarefaction of the bone of the patient containing term or diluent.

7. The pharmaceutical composition according to p. 6, where the bone loss caused by osteoporosis.

8. A method of reducing or preventing the rarefaction of bone, comprising the administration to a patient in need of such treatment or prevention, an effective amount of the compounds under item 1.

9. The method according to p. 8, where the bone loss caused by osteoporosis.

 

Same patents:

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where a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, - inhibitors of 5-lipoxygenase, are useful for the treatment or relief of inflammatory diseases, Allergy and cardiovascular diseases

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< / BR>
where R (1) denotes hydrogen, alkyl with 1-4 C-atoms, alkoxy with 1-4 C-atoms, fluorine, chlorine, bromine, iodine, CF3, NH2, NH-alkyl with 1-4 C-atoms, N(alkyl)2with 1-4 C-atoms in the same or different alkyl residues, or S-alkyl with 1-4 C-atoms;

R (2a) denotes hydrogen or alkyl with 1 or 2 C-atoms;

R (2b) and R (2d), which are identical or different, denote hydrogen, alkyl with 1 or 2 C-atoms not substituted phenyl, substituted phenyl, unsubstituted benzyl or substituted phenyl residue, benzyl, and as the substituents in the phenyl residues are up to three identical or different substituents selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

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Q represents (CH2)n;

where n = 1 or 2;

Z denotes serousily, selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

or

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< / BR>
where B denotes albaniles or alkylene with 3, 4, 5 or 6 C-atoms, which is unsubstituted or substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 C-atoms;

or

A denotes the residue of a bicyclic system of the formula:

< / BR>
< / BR>
< / BR>
< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

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R0represents hydrogen or A;

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-CH2NHAc, -CH2NHSO2CH3,

or

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