MXPA99001760A - Amorphous benzothiophenes, methods of preparation, and methods of use - Google Patents

Abstract

The instant invention provides an amorphous form of a compound of formula (I). Methods of preparing the material, as well as methods of using same, are also provided.

Description

BENZOTIOFENOS AMORPOS, METHODS OF PREPARATION AND METHODS OF USE Osteoporosis describes a group of diseases that arise from various etiologies, but that are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and fracture of the resulting bone is the failure of the skeleton to provide adequate support to the body. One of the most common types of osteoporosis is associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menstruation. This rapid loss is generally associated with an increase in bone resorption and formation. However, the resorption cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among postmenopausal women.

There is an estimated 25 million women in the United States alone who are afflicted with this disease. The results of osteoporosis are personally harmful, and also account for a large economic loss due to its chronicity and the need for extensive and long-term support (hospitalization and nursing at home) for the after-effects of the disease. This is especially true in the 5 oldest patients. Additionally, although osteoporosis in general is not thought of as a life-threatening condition, a mortality rate of 20% to 30% is related to hip fractures in older women. A large percentage of this 0 mortality rate can be directly associated with ^^ postmenopausal osteoporosis.

The most vulnerable tissue in the bone for the effects of postmenopausal osteoporosis is trabecular bone. This tissue is often referred to as cancellous or cancellous bone and is particularly concentrated ^^ near the extremities of the bone (near the joints) and in the vertebrae of the spine.

The trabecular tissue is characterized by small osteoid structures that interconnect with each other, as well as the more solid and dense cortical tissue that forms the outer surface and the central axis of the bone. This interconnected network of trabécles gives lateral support to the external lateral structure and is critical for the biomechanical resistance of the overall structure. In postmenopausal osteoporosis it is mainly the resorption and net loss of the trabeculae which leads to bone failure and fracture. In view of the loss of the trabéculos of the postmenopausal woman, it is not surprising that the most common fractures are those associated with bones that are highly dependent on the trabecular support, for example, the vertebrae, the neck of the bones that have weight such as the femur and the forearm. In 0 reality, hip fracture, colles fractures, ^^ and fractures of vertebrae are marks of postmenopausal osteoporosis.

In general, the most accepted method for the treatment of postmenopausal osteoporosis is estrogen replacement therapy. Although the ^^ therapy in general is successful, patient compliance with therapy is low, mainly due to the fact that the treatment of estrogen frequently produces undesirable side effects. An additional method of treatment would be the administration of a bisphosphonated compound, such as, for example, Fosamax® (Merck &Co., Inc.).

During postmenopausal time, most women have a lower incidence of cardiovascular disease than men of the same age. After menopause, however, the rate of cardiovascular disease in women increases slightly to equal the rate observed in men. This loss of protection has been linked to the loss of estrogen, in particular, to the loss of estrogen's ability to regulate lipid levels in serum. The nature of the capacity of estrogen to regulate serum lipids is not ^^ understand well, but the evidence so far indicates that estrogen can regulate low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen seems to have some effect on the biosynthesis of cholesterol, and other beneficial effects on health ^^ cardiovascular.

It has been reported in the literature that serum lipid levels in postmenopausal women who have estrogen replacement therapy return to concentrations found in the premenopausal state. Thus, estrogen would seem to be a reasonable treatment for this condition. However, the side effects of estrogen replacement therapy are not acceptable for many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent that regulates serum lipid levels in a manner analogous to estrogen, but which is free of the side effects and risks associated with estrogen therapy.

A number of structurally unrelated compounds are able to interact with the estrogen receptor and produce unique profiles in vivo. Compounds with in vivo profiles typical of a "pure" antagonist (e.g., ICI 164,384) or of a relatively "pure" agonist (e.g., 17b-estradiol) represent the opposite ends of a spectrum in this classification. Between these two extremes fall the SERM ("selective estrogen receptor modulator"), characterized by clinical and / or preclinical selectivity as full or partial agonists in certain desired tissues (eg, bone), and minimal antagonists or agonists in tissues reproductive Within this pharmacological class, SERMs could also be differentiated based on activity profiles in reproductive tissues. Raloxifene, a second-generation SERM, exhibits potentially useful selectivity in uterine tissue with apparent advantages over triphenylethylene-based estrogen receptor ligands. As such, raloxifene seems to be very suitable at least for the treatment of post-enopausal complications, which include osteoporosis and cardiovascular disease. It is anticipated that, with further advances are made in the pharmacology and molecular biology of active agents 0 of the 'estrogen receptor, subclassifications ^^ additional ESRM could be developed in the future along with an increased understanding of the therapeutic usefulness of these new classes of estrogenic compounds.

The raloxifene breakthrough, in particular, has been ^ - ^ somewhat difficult because of its physical characteristics, such as bioavailability and processing. For example, raloxifene is generally insoluble, which could affect bioavailability. Evidently, any improvement in the physical characteristics of raloxifene and in closely related compounds would potentially offer more beneficial therapy and improved processing capabilities.

Thus, it would be a significant contribution to the art to provide amorphous forms of raloxifene and related compounds that have increased solubility, preparation methods, pharmaceutical formulations, and methods of use.

The present invention provides a compound of formula I OR where R1 and R3 are independently hydrogen, -CH3, -CO (Cj-C alkyl, or COAr, where Ar is optionally substituted phenyl; R- is selected from the group consisting of pyrrolidinyl, hexamethyleneimino, and piperidinyl; or a pharmaceutically acceptable salt or solvate thereof in an amorphous form.

Figure 1 illustrates the mean levels of raloxifene in plasma of dogs treated with crystalline or amorphous forms of a compound of formula I.

The present invention further provides pharmaceutical formulations containing a compound of formula I.

In addition, processes for the preparation of amorphous forms of compounds of formula I are provided by the present invention.

The present invention also provides methods of use for the compounds of formula I, including the inhibition of bone loss and bone resorption.

The general terms used in the description of compounds described herein have their usual meanings. For example, the term "Ci-Cg alkyl" represents a linear or branched alkyl chain having from 1 to 6 carbon atoms. Typical C: -C6 alkyl groups include methyl, ethyl, n-propyl, and n-butyl. The term "Ci-C * alkoxy" represents groups such as methoxy, ethoxy, n-propoxy, and n-butoxy.

Optionally substituted phenyl includes phenyl and phenyl substituted by alkoxy alkyl hydroxy, nitro, chloro, fluoro, or tri (chloro or fluoro) methyl, and the like.

The term "inhibits" generally includes its accepted term which includes prohibiting, avoiding, restricting and / or delaying, stopping, or reversing the progression, severity, or improvement of a resulting symptom or effect.

Preferred embodiments of the present invention are compounds of formula I which include ^ - compounds wherein R1 and R3 are hydrogen, and R2 is pyrrolidinyl, piperidinyl, or a hexamethyleneimino group. Compounds representative of this preferred group include: 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-Dirrolidinyletoxy) benzoyl] benzo [b] -thiophene, 6-hydroxy-2- (4-h idrox if en il) - 3 - [4 - (2-p iperidi ni l-ethoxy) benzoyl] benzo [b] thiophene, and 6-hydroxy-2- (4-hydroxy-phenyl) -3- [4- (2-hexamethyleneiminoethoxy) benzoyl] benzo [ b] -thiophene.

More preferably, the product of the present invention are the compounds of Formula I wherein R2 is a pyriridinyl group. A representative compound of this most preferred group includes: 6-hydroxy-2- (4-hydroxyphenyl-3- [4- (2-piperidinylethoxy) benzoyl] benzo [b] thiophene.

The compounds of the present invention could be made according to established procedures, such as those detailed in U.S. Pat. Us. 4,133,814, 4,418,068, and 4,380,635, and the Application for European Patent 95306050.6, Publication No. 0699672, Kjell, et al., Filed on August 30, 1995, published on March 6, 1996, all of which are incorporated herein by reference. In addition, the information set forth in published European Patent Application No. 0670162 Al, published on September 6, 1995, is incorporated herein by reference. A crystalline form of raloxifene hydrochloride could be prepared by the methods set forth in the Examples section, infra.

The term "amorphous" includes a physical state that could be verified by X-ray diffraction and other means. include but are not limited to observation with a polarized light microscope and differential scanning calorimetry.

In general, the process starts with a benzo [b] thiophene having a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group. The initial compound is protected, acylated and deprotected to form the compounds of formula I. Further examples of the preparation of such compounds are also provided in the references discussed above.

The compound of formula I according to the present invention is conveniently prepared by means of a process which constitutes a further feature of the present invention, and which comprises recovering a compound of formula I from a solution thereof under conditions by means of which you get an amorphous product.

The amorphous material of the present invention was prepared by dissolving a crystalline form of a compound of formula I in a suitable solvent or mixture of solvents, such as, for example, methanol and water, followed by recovery of the material by any suitable means . Techniques that could be employed to recover the amorphous compounds of formula I from the solution include those wherein the solvent is removed from the solution, preferably rapidly, and the product is deposited, and those where it is precipitated from a solution. Methods involving the use of these procedures that have been found to be satisfactory include spray drying, rotary drying, solvent precipitation, rotary evaporation, and freeze drying. Particularly preferred for the practice of the present invention is the spray drying method.

Solvents that could be employed in the practice of the present invention will be chosen according to technique and conditions to be employed, and include water, methanol, ethanol, and the like, including mixtures thereof, if desired.

The concentration of a compound of formula I in the solvent is advantageously as high as possible, commensurate with an amorphous form of a compound of formula I to be obtained, with preferable concentrations that are in the range of about 5 mg / ml at approximately 40 mg / ml. The highest concentrations obtained will typically depend on the solvent system employed in the preparation, and / or the presence or absence of povidone (PVP) or hydroxypropyl-b-cyclodextrin (HPBCD). The solvents could, if desired, be heated as an aid to solubility and removal of the solvent.

In general, the compounds of formula I have sufficient thermal stability to withstand spray drying and the like, and therefore, spray drying is the preferred method of recovery. The spray drying systems could be operated in a known manner to obtain an amorphous product essentially free of crystalline material as well as free of particulate contaminants. Closed loop spray drying systems in which the drying medium is recycled are particularly safe and economical to use in obtaining the product of the present invention.

The drying gas used in the process could be air, but those preferred for use with flammable solvents are inert gases such as, for example, nitrogen, argon and carbon dioxide. The preferred one would be nitrogen. The inlet temperature of the gas to the spray dryer is chosen according to the solvent used, but would be, for example, in the range of about 75 ° C to about 150 ° C.

The presence of the amorphous form of a compound of formula I was determined by observing the material under a polarized light microscope, and determining whether the material was birefringent. If birefringence was not observed, the material material was considered to be amorphous.

A compound of formula I according to the present invention is preferably essentially free of the crystalline form of the material. Long term studies have indicated that the amorphous form of the present invention is very stable. However, once recovered as amorphous material, conversion to the crystalline form could be prevented by the addition of any number of stabilizing materials known in the art, such as, for example, povidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose ( HPC), polyethylene glycol (PEG), hydroxypropyl-b-cyclodextrin (HPB), cyclodextrin, and the like.

The solubility of the amorphous form was shown to be about 250 times greater than the crystalline form. The advantages of increased solubility include but are not limited to ease in the processing of the amorphous material, which includes equipment cleaning problems; ease in the formulation and release of the material, and the like.

A compound of formula I in an amorphous form could also be combined with a number of other materials before or after spray drying, or processed differently to provide amorphous material, which in turn could also be formulated for processing.

Compounds of formula I that are amorphous have been shown to have several advantages, including but not limited to a high degree of bioavailability, as well as being in a form of effective methods of administration.

The term "solvate" represents an aggregate comprising one or more molecules of the solute, such as a compound of formula I, with one or more solvent molecules. Although the free base form of the compounds of formula I can be used in the methods of In the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form. The term "Pharmaceutically acceptable salt" refers to salts by addition of acid or base that are known to be non-toxic and are commonly used in pharmaceutical literature. The pharmaceutically acceptable salts ^^ have generally improved solubility characteristics compared to the compounds from which they are derived, and thus are often more suitable for formulation as liquids or emulsions. The compounds 5 used in the methods of this invention mainly form acid addition salts Pharmaceutically acceptable with a wide variety of organic and inorganic acids, and include the physiologically acceptable salts that are often used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Also, salts derived from organic acids, such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroalkanedioic acids, aromatic acids, aromatic and aliphatic sulfonic acids, could be used. Such pharmaceutically acceptable salts include thus acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphtha 1 en-2 -be nz or to, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyn-1,4-dioate, ^ hexin-1, 4-diqato, caproate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroximelate, malonate, mandelate, mesylate, 5 nicotinate, isonicot inato, nitrate , oxalate, phthalate, terephthalate, phosphate, mo noh irogenfos fa to, Dihydrogenase phosphates, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, 0 pyrosulfate, sulfite, busulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenes, ethophonate, ethanesulfonate, 2 - hydroxyethane sulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.

The pharmaceutically acceptable acid addition salts are those typically formed by reacting a compound of formula I with an equimolar or excess acid amount. The reagents are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt normally precipitates in the solution in about one hour to 10 days and can be isolated by filtration, the solvent can be removed by conventional means. The present invention further provides pharmaceutically acceptable formulations for administering to a mammal, including humans, in need of treatment, comprising an effective amount of a compound of formula I and a pharmaceutically acceptable diluent or carrier.

As used herein, the term "effective amount" means an amount of compound of the present invention that is capable of inhibiting, alleviating, improving, treating, or avoiding additional symptoms in mammals, including humans, that suffer from estrogen stripping, by example, menopause or ovariectomy, or inappropriate stimulation of estrogen such as uterine fibrosis or endometriosis, or suffering from proliferation of smooth muscle cells of the aorta or restenosis. In the case of estrogen-dependent cancers, the term "effective amount" means the amount of compound of the present invention that is capable of alleviating, improving, inhibiting cancer growth, treating, or preventing cancer and / or its symptoms in mammals, including humans.

By "pharmaceutically acceptable formulation" it is meant that the carrier, diluent, excipients and salt must be compatible with the active ingredient (a compound of formula I) of the formulation, and not be deleterious to the recipient thereof. The pharmaceutical formulations can be prepared by methods known in the art. For example, the compounds of this invention can be formulated with common excipients, diluents or vehicles, and formed into tablets, capsules, and the like. Examples of excipients, diluents and vehicles that are suitable for such formulations include the following: fillers and dilators such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; wetting agents such as glycerol; disintegrating agents such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents 5 for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorption vehicles such as kaolin and bentonite; Y lubricants such as talc, calcium stearate and f ^ magnesium and solid polyethylene glycols. The final dosage forms could be: pills, tablets, powders, dragees, pills, capsules, or sterile packaged powders, and the like, depending on the type of excipient used.

^^ In addition, the compounds of this invention are well suited for formulation as prolonged release dosage forms. The formulations may also be constituted so that they release the active ingredient alone or preferentially in a particular part of the intestinal tract, possibly over a period of time. Such formulations would involve coatings, coatings, or protective matrices that could be made from polymeric substances or waxes.

The particular dosage of a compound of formula I requires treating, inhibiting, or avoiding the symptoms and / or disease of a mammal including humans, which suffer from the above diseases according to this invention will depend on the particular disease, symptoms, and severity. The dosage, routes of administration, and frequency of dosing is best decided through medical care. In general, the accepted and effective doses will be from 15 mg to 1000 mg, and more typically from 15 mg to 80 mg; Such dosages will be administered to a patient who needs treatment one to three times each day or as often as needed for efficiency, and for periods of at least two months, more typically for at least six months, or chronically.

As a further embodiment of the invention, the compounds of formula I could be administered together with an effective amount of an additional therapeutic agent, including but not limited to estrogen, progestin, benzothiophene compounds which include rafene, naphthyl compounds having anticancer activity. iestrogen, bisphosphonate compounds such as alendronate and tiludronate, parathyroid hormone (PTH), which includes truncated and / or recombinant PTH forms such as, for example, PTH (1-34), calcitonin, bone morphogenic proteins (BMP), or combinations thereof. The different forms of these additional therapeutic agents available as well as the various utilities associated therewith and the applicable dosage regimens are well known to those skilled in the art.

Various forms of estrogen and progestin are commercially available. As used herein, the term "estrogen" includes compounds that have estrogen activity and agents based on estrogen. Estrogen compounds useful in the practice of the present invention include, for example, estradiol estrone, estriol, equilin, equilenin, estradiol cypionate, estradiol valerate, ethinyl estradiol, potassium phosphate 1-tetradio 1, estropipate, diethyl sterol, dienestrol. , chlorotrianisene, and mixtures thereof. Agents based on estrogen, include, for example, 17-a-ethinyl estradiol (0.01-0.03 mg / day), mestranol (0.05-0.15 mg / day), and conjugated estrogenic hormones such as Premarin® (Wyeth-Ayerst; 0.2 -2.5 mg / day). As used herein, the term "progestin" includes compounds having progestational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, progestin-based agents, and the like. Progestin-based agents include, for example, medroxyprogesterone such as Provera8 (Upjohn, 2.5-10 mg / day), norethylnodrel (1.0-10.0 mg / day), and norethindrone (0.5-2.0 mg / day). A preferred compound based on estrogen is Premarin8, and norethylnodrel and norethindrone are the preferred agents based on progestin. The method of administration of each agent based on estrogen and progestin is consistent with that known in the art.

The following formulations are given for purposes of illustration and are not intended to be limited in any way. The total of active ingredients in such formulations comprises from 0.1% to 99.9% by weight of the formulation. The term "active ingredient" means a compound of formula I.

Formulation 1: Gelatin capsules Ingredient Quantity (mg / capsule) Active Ingredient 0.1-1000 NF 0-500 starch 0-500 Fluidizable Starch Fluidized Silicone 350 0-15 cent istokes The ingredients are mixed, passed through a No. 45 U.S. mesh screen, and filled into hard gelatin capsules.

Formulation 2: Tablets Ingredient Quantity (mg / tablet) Active Ingredient 2.5-1000 Starch 10-50 Cellulose, 10-20 microcrystalline Polyvinylpyrrolidone 5 (as 10% solution in water) Carboxymethylcellulose 5 Sodium Magnesium stearate 1 Talc 1-5 The active ingredient, starch, and cellulose are passed through a No. 45 U.S. mesh screen. and they mix completely. The polyvinylpyrrolidone solution is mixed with the resulting powders which are then passed through a No. 14 U.S. mesh screen. The granules thus produced are dried at 50-60 ° C and passed through a No. 18 U.S. mesh screen. Sodium carboxymethylcellulose, magnesium stearate, and talcum are passed through a No. 60 U.S. mesh screen, added to the previous granules and mixed thoroughly. The resulting material is compressed in a machine that makes tablets to produce the tablets.

Formulation 3: Suppositories Weight Ingredient Active Ingredient 150 mg Fatty acid glycerides 3000 mg saturated The active ingredient is passed through a mesh screen No. 60 U.S. and is suspended in the fatty acid glycerides that had previously been heated to their melting point. The mixture is poured into a suppository mold and allowed to cool.

The following examples and preparations are provided to better elucidate the practice of the present invention and should not be construed in any way as limiting the scope thereof. Those skilled in the art will recognize that various modifications could be made without deviating from the spirit and scope of the invention. All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains.

The NMR results for the following Examples were generated on a 300 MHz GE NMR instrument, and anhydrous d-6 DMSO was used as the solvent unless otherwise indicated.

All experiments were run under positive pressure of dry nitrogen. All solvents and reagents were used as obtained. The percentages were calculated in general on a mass basis (w / w); except for HPLC solvents that were calculated on a volume basis (v / v). The proton nuclear magnetic resonance spectrum (H NMR) was obtained on a Bruker AC-300 FTNMR spectrometer at 300.135 MHZ. The melting points were determined by a differential scanning calorimeter (DSC) in a TA Instrument DCS 2920 using a closed cell and a heating rate of 2 ° C / minute. The reactions were monitored in general for the term using high performance liquid chromatography (HPLC). The X-ray power diffraction spectrum was obtained in the Siemens D5000 X-ray Power Diffraktometer, using copper radiation and a Si (Li) detector. Some reactions were monitored using a Zorbax Rx-C8 column (25 cm x 4.6 mm ID, 5 m particle) eluting with a mixture of 60 mM phosphate (KH2P04) and 10 mM octansulfonate (pH 2.0) / acetonitrile (60:40) .

The acylation, dealkylation, or acylation / dealkylation reactions were also monitored for the term with HPLC. A sample of the reaction mixture was tested using a Zorbax Rx-C8 column, (25 cm x 4.6 mm ID, 5 m particle) eluting with a gradient as shown below: GRADIENT OF THE SOLVENT SYSTEM Time (min.) A (%) B (%) 0 60 40 5 60 40 10 45 55 20 38 62 25 45 55 32 45 55 37 60 40 42 60 40 A: HC104 0.05 M (pH = 2.0) B: acetonitrile The reaction mixture was analyzed by diluting a sample of 0.1 to 0.2 mL to 50 mL with a 60:40 mixture of A / B. Similarly, the mother liquor of the recrystallizations was sampled in a similar manner.

The amount (percentages) of 6-hydroxy-2- (4-hydroxy-phenyl) -3- [4 - (2-piperidinylethoxy) benzoyl] benzo [b] thiophene hydrochloride in the crystalline material (potency) was determined by the next method. A sample of the crystalline solid (5 mg) was weighed into a 100-mL volumetric flask, and dissolved in a 70/30 (v / v) mixture of 75 mM potassium phosphate buffer (pH 2.0) and acetonitrile. An aliquot of this solution (10 mL) was tested by high performance liquid chromatography, using a Zorbax Rx-C8 column (25 cm x 4.6 mm ID, 5 m particle) and UV detection (280 nm). The gradient of the following solvent system was used: Gradient of the Solvent System (Power) time (min) A (%) B (%) 0 70 30 12 70 30 14 25 75 16 70 30 25 70 30 A: 75 mM KHrP04 buffer (pH 2.0) B: acetonitrile The percentage of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinylethoxy) enzoyl] benzo [b] thiophene hydrochloride in the sample is calculated using the peak area, the slope (m) , and the intercept (b) of the calibration curve with the following equation peak area - b sample volume. { L) % power = x m weight of the sample (mg) The amount (percent) of solvent, such as methanol, ethanol, or 1,2-dichloroethane present in the crystalline material is determined by gas chromatography. A sample of the crystalline solid (50 mg) was weighed into a 10-mL volumetric flask, and dissolved in a solution of 2-butanol (0.025 mg / mL) in dimethylsulfoxide. A sample of this solution was analyzed in a gas chromatograph using a DB Wax column (30 m x 0.53 mm ID, 1 m particle), with a column flow of 10 mL / min and detection by flame ionization. The temperature of the column was heated from 35 ° C to 230 ° C for a period of 12 minutes. The amount of solvent was determined by comparison to the internal standard (2-butanol), using the following formula: C E G% solvent = - x - x - x I D F H where : C = solvent ratio in the sample D = average ratio of the standard for the specific solvent E = average weight of the standard F = weight of the sample (mg) G = volume of the sample (10ml) H = volume of the standard (10,000 mL) ) I = purity of the standard (%) Preparation 1 0 6-Methoxy-2- (4-methoxyphenyl) benzo [b] thiophene A solution of 3-methoxybenthiol (100 grams) and potassium hydroxide (39.1 grams) in water (300 mL) was added to denatured ethanol (750 mL), and the resulting mixture was cooled to about 0 ° C. The cold mixture was treated with 4'-methoxyphenacyl bromide (164 grams) in several small portions. Upon completion of the addition, the mixture was cooled for an additional ten minutes, then allowed to warm to room temperature. After three hours, the mixture was concentrated 0 i n va cuo, and the residue was treated with water (200 mL). The resulting mixture was treated with ethyl acetate, and the phases were separated, the organic phase was washed with water (2x), sodium bicarbonate solution (2x), and sodium chloride solution (2x). The organic phase was then dried with magnesium sulfate, filtered, and evaporated to dryness in vacuo to give 202 grams of a- (3-methoxyphenylthio) -4-methoxyacetophenone. This crude product was crystallized from methanol and washed with hexane to give 158 grams. Melting point 53 ° C.

Polyphosphoric acid (930 grams) was heated to 85 ° C and treated with the previous intermediate (124 # grams) in small portions for 30 minutes. In the complete addition, the resulting mixture was stirred at 90 ° C. After an additional 45 minutes, the reaction mixture was allowed to cool to room temperature. The mixture was treated with crushed ice while the mixture was cooled in an ice bath. The resulting mixture ^^ was treated with water (100 mL) producing a bright pink precipitate. The precipitate was isolated by filtration, washed with water and methanol, and dried in vacuo at 40 ° C to give 119 grams of 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene. This crude product was suspended in hot methanol, filtered, and washed with cold methanol. The resulting solid material was recrystallized from ethyl acetate (4 liters), filtered, washed with hexane, and dried to 68 grams of the title compound.

Melting point 187-190.5 ° C.

Preparation 2 5 Ethyl 4- (2-piperidinylethoxy) benzoate A mixture of ethyl 4-hydroxybenzoate (8.31 g), l- (2-chloroethyl) piperidine monohydrochloride (10.13 g), potassium carbonate (16.59 g), and methyl ethyl ketone (60 ls mL) was heated to 80 °. C. After one hour, the mixture was cooled to about 55 ° C and treated with additional 1- (2-chloroethyl) piperidine monohydrochloride (0.92 g). The resulting mixture was heated to 80 ° C. The reaction was monitored by thin layer chromatography (TLC), using plates of silica gel and ethyl acetate / acetonitrile / triethylamine (10: 6: 1, v / v). Additional portions of l- (2-chloroethyl) piperidine hydrochloride were added until the initial 4-hydroxybenzoate ester was consumed. At the end of the reaction, the reaction mixture was treated with water (60 mL) and allowed to cool to room temperature. The aqueous layer was discarded and the organic layer was concentrated at 40 ° C and 40 mm Hg. The resulting oil was used in the next step without further purification.

Preparation 3 4- (2-piperidinyletoxy) benzoic acid hydrochloride A solution of the compound prepared as described in Preparation 2 (about 13.87 g) in methanol (30 mL) was treated with 5 N sodium hydroxide (15 mL), and heated to 40 ° C. After 4 i = hours, water (40 mL) was added. The resulting mixture was cooled to 5-10 ° C, and concentrated hydrochloric acid (18 mL) was slowly added. The title compound was crystallized during acidification. This crystalline product was collected by filtration, and dried at 40-50 ° C to yield 83% yield of the title compound. Melting point 270-271 ° C.

Preparation 4 6-Methoxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinylethoxy) benzoyl] -benzo [b] thiophene hydrochloride A mixture of the compound prepared as described in Preparation 1 (8.46 grams) and the acid chloride prepared as described in Preparation 3 (10.0 grams) in methylene chloride (350 mL) was cooled to about 20-25 ° C. . The cold mixture was treated with boron trichloride (2.6 mL), and the resulting mixture was mechanically stirred. The reaction was monitored with HPLC using the test described above. After 85 minutes, the HPLC yield in itself based on a standard of 6-methoxy-2- (4-methoxy phenyl) -3- [4- (2-piperidinylethoxy) benzoyl] benzo [b] thiophene was 88 %.

Preparation 5 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinylethoxy) benzoyl] -benzo [b] thiophene hydrochloride Solvate 1,2-dichloroethane (Crystal Form I) A solution of 6-methoxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinylethoxy) benzoyl] benzo [b] thiophene hydrochloride (2.0 g) in 1,2-dichloroethane (20 mL) was treated with boron trichloride at 35CC for approximately 18 hours. A mixture of ethanol and methanol (10 mL, 95: 5, 3A) was treated. with the above reaction mixture, putting the alcoholic mixture in reflux. Upon completion of the addition, the resulting crystalline suspension was stirred at 25 ° C. After one hour, the crystalline product was filtered, washed with cold ethanol (10 L), and dried at 40 ° C in vacuo to give 1.78 g of the title compound. The powder X-ray diffraction pattern is identical to that reported in Table 1.

Power: 80.2% 1,2-Dichloroethane: 7.5% (gas chromatography) Table 1. X-ray Diffraction Pattern for Form I of the Crystal.

Spacing d-line I / Io (Angstroms) (xlOO) 16. 1265 3.80 . 3744 8.63 8.3746 5.29 7.9883 36.71 7.2701 .5.06 6.5567 70.77 6.2531 6.79 5.5616 24.05 5.3879 100.00 5.0471 89.64 4.7391 85.96 4.6777 39.36 4.6332 62.60 4.5191 77.56 4.2867 36.82 4.2365 41.66 4.1816 49.60 4.0900 11.21 3.9496 11.85 3.7869 36.25 3.7577 56.16 3.6509 40.62 3.5751 15.65 3.5181 21.52 3.4964 18.53 3.4361 33.60 3.3610 6.21 3.3115 4.95 3.2564 7.36 3.2002 3.80 3.1199 15.77 3.0347 14.84 2. 8744 9.67 2. 8174 10.82 2. 7363 11.51 The amount of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinylethoxy) benzoyl] benzo [b] thiophene hydrochloride present in the crystalline material is about 87.1%, as determined using a high resolution liquid chromatography (HPLC) test described above. The amount of 1,2-dichloromethane present in the crystalline material is about 0.55 molar equivalents, as determined by nuclear magnetic resonance spectroscopy of the proton.

Preparation 6 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinylethoxy) benzoyl] -benzo [b] thiophene hydrochloride 1,2-dichloroethane solvate (Crystal Form I) A mixture of the compound prepared as described in Preparation 2 (15 g) and dimethylformamide (0.2 mL) in 1,2-dichloroethane (250 mL) was cooled to 0 ° C. Phosgene (8.25 L) was condensed in a cold, chamfered (-10 ° C) addition funnel, and added to the cold mixture for a period of two minutes. The resulting mixture was heated to about 47 ° C. After approximately two and a half hours, the reaction was tested with HPLC for completion. Additional phosgene could be added to bring the reaction to term. The excess phosgene was removed by vacuum distillation at 30-32 ° C and 105-110 mm Hg.

After about three to four hours, the reaction solution was treated with the compound prepared as described in Preparation 1 (13.52 g). The resulting solution was cooled to 0 ° C. Boron trichloride (12.8 mL) was condensed in a graduated cylinder, and added to the cold reaction mixture. After eight hours at 0 ° C, the reaction solution was treated with additional boron trichloride (12.8 mL). The solution • The resultant was heated to 30 ° C. After 15 hours, the reaction was monitored for HPLC termination.

A mixture of ethanol and methanol (125 mL, 95: 5, 3A) was heated to reflux, and treated with the reaction solution above for a period of 60 minutes. At the end of the addition, the acylation / demethylation reaction flask was rinsed with additional ethanol (30 L). The resulting suspension was allowed to cool to room temperature with stirring. After one hour at room temperature, the crystalline product was filtered, washed with ethanol (75 L), and dried at 40 ° C in va cuo to give 25.9 g of the compound of F ^ * title. The powder X-ray diffraction pattern is reported in Table 1. Melting point 261 ° C.

Power: 87.1% 1, 2-dichloroethane: 0.55 molar equivalents (1E NMR) Preparation 7 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinyletoxy) benzoyl] -benzo [b] thiophene hydrochloride Chlorobenzene solvate (Crystal Form 3) A solution of the compound prepared as described in Preparation 1 (2.92 grams) and the acid chloride prepared as described in Preparation 4 (3.45 grams) in chlorobenzene (52 mL) was cooled to about 0 ° C. The cold solution was treated with boron trichloride (2.8 mL). The resulting mixture was mechanically stirred at 0 ° C. approximately. After three hours, additional boron trichloride (2.8 mL) was added, and the reaction mixture was allowed to warm to room temperature. After approximately after 16-20 hours, the reaction mixture was cooled to 0 ° C. The cold reaction was stopped by the slow addition of ethanol (26 mL) for 30 minutes. During the addition of alcohol, a crystalline solid formed. Upon completion of the alcohol addition, the resulting mixture was stirred at room temperature for one hour. The crystalline solid was separated by filtration, washed with cold ethanol (25 mL), and dried at -40 ° C to give 5.94 grams of the title compound as a yellow solid. The powder X-ray diffraction pattern is identical to that reported in Table 2. Melting point 247 ° C: Power: 78.6% Chlorobenzene: 12.3% (HPLC) Table 2. X-ray diffraction pattern of Form III of the Crystal. d-line spacing I / lo (Angstroms) (xioo; 14. 3511 7.24 . 3335 6.17 8. 8305 4.29 7. 9475 38.16 6. 5904 64.25 6.2848 6.52 5.6048 28.06 5.4107 100.00 5.1544 11.26 5.0493 53.26 5.0224 46.11 4.8330 76.94 4.7694 34.23 4.6461 50.22 .5754 38.61 4.4953 72.65 4.3531 49.15 4.2940 41.64 4.2425 35.75 4.1856 21.63 4.1331 9.47 4.0793 12.69 3.9960 18.50 3.9037 9.03 3.7854 40.39 3.7521 54.16 3.6787 28.60 3.6509 17.96 3.5444 31.72 3.4679 41.55 3.3899 7.69 3.3101 5.72 3. 2561 7.42 3. 1784 15.19 3. 0445 11.17 3. 0146 8.94 2. 9160 11.89 2. 8217 18.23 2. 7500 12.06 2. 6436 9.65 2. 6156 6.97 The amount hydrochloride of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinylethoxy) benzoyl] benzo [b] thiophene present in the crystalline material is about 78.6%. The amount of chlorobenzene present in the crystalline material is approximately 12.3%, as determined by HPLC.

Preparation 8 6-Hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinylethoxy) -benzoyl] benzo [b] thiophene hydrochloride A solution of sodium hydroxide (0.313 g) in methanol (10 mL) was diluted with additional methanol (40 mL) and water (10 mL). This solution was treated with the compound prepared as described in Example 5 (4.0 g). The resulting solution was extracted with hexane (2 x 50 mL) 10 to remove the chlorobenzene. The methanolic phase was treated with 2 N hydrochloric acid (4 L), producing a crystalline suspension. After one hour, the crystalline product was filtered, washed with methanol (5). # ^ mL), and dried at 60 cm cu m to give 2.23 g of the title compound. The powder X-ray diffraction pattern was identical to that reported in Table 3.

Table 3. X-ray diffraction pattern for non-solvated crystal form.

Spacing d-line I / Io (Angstroms) (xlOO) 13. 3864 71.31 9. 3598 33.16 8. 4625 2.08 7. 31 7.57 6. 9907 5.80 6. 6346 51.04 6. 1717 29.57 . 9975 5.67 . 9135 9.87 . 6467 38.47 5.4773 10.54 5.2994 4.74 4.8680 4.03 4.7910 5.9í 4.6614 57.50 4.5052 5.75 4.3701 9.03 4.2516 69.99 4.2059 57.64 4.1740 65.07 4.0819 12.44 3.9673 22.53 3.9311 100.00 3.8775 9.07 3.7096 33.38 3.6561 21.65 3.5576 3.36 3.5037 7.97 3.4522 18.02 3.413! 4.65 3.2731 10.23 3.1857 8.90 3.1333 6.24 3.0831 9.43 3.0025 12.13 2.9437 4.96 2.8642 7.70 2. 7904 11.95 2. 7246 3.05 2. 6652 3.32 2. 5882 7.30 The amount of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinylethoxy) benzoyl] benzo [b] thiophene hydrochloride present in the crystalline material is at least 95%.

This unsolvated crystalline form is particularly preferred for use in the manufacture of pharmaceutical compositions.

Example 1 Preparation of Amorfa forms The amorphous material of the present invention was prepared by dissolving 5 g of crystalline raloxifene hydrochloride in 300 ml of methanol and 22.5 ml of water. The amorphous material was recovered by spray drying the solution using a Buchi Model 5 190 Mini spray dryer under the following conditions: inlet equilibrium temperature: 84 ° C; output equilibrium temperature 60 ° C; Atomization rate approximately: 2.5 ml / min .; established value of the vacuum cleaner: 20; Air flow indicator: 500-600; atomization pressure: 35 psi. The process was completed in 2 hours and 10 minutes.

The material recovered after spray drying was observed in a polarized light microscope to determine if the product was birefringent. No birefringence was observed, and the material was considered to be amorphous.

Table 4 provides comparative results of water solubility between crystalline and amorphous material: Table 4 Form Solubility Temp. , ° C (ms / ml) crystalline 0.08 room temperature Amorphous 42.2 room temperature amorphous 120 37 ° C * * in sonicator The amorphous material was also made as a complex with povidone, with ratios of raloxifene HCL to PVP as follows: 9: 1, 3: 1, and 1: 1 (w / w). Complexes were also prepared with hydroxypropyl-b-cyclodextrin (HPBCD) ', with a ratio of raloxifene HCL to HPBCD of 1: 1 to 1: 4 (p / p). These were added to increase the solubility and avoid any potential crystallization of the material, for example, it could or could not occur when a supersaturated solution was prepared from the amorphous form. Some batches were recovered as crystalline material, or the material was converted to a crystalline form in about a week or 10 days after the preparation. The lots were recovered as amorphous material that did not crystallize in about 10 days it was observed that they remained amorphous.

Example 2 Bioavailability Study The degree and rate of absorption of the crystalline and amorphous forms of raloxifene HCL were determined. The two forms of the compound were formulated in PEG vehicle as follows: Component% by weight polyethylene glycol 1450 70 lactose dried by 1.5 atomization 1.5 colloidal silicon dioxide polysorbate 80 2.0 Rloxifene HCL 25 Six dogs were dosed as follows: three dogs received the amorphous form, while three dogs received the crystalline form, both at a dose of 4mg / kg. The plasma levels of the two compound forms were then determined over a period of 10 hours. The results of this study are provided in Figure 1. This study indicated greater bioavailability with the amorphous form.

The following discussions illustrate methods of use for compounds of formula I in experimental models or in clinical studies. These examples are for illustration purposes and does not mean that they are limiting in any way.

A. Osteoporosis: Experimental models of postmenopausal osteoporosis are known in the art. Relevant to this invention is the ovariectomized rat model that is provided in U.S. 5,393,763. The compounds of formula I would be active in this model and would demonstrate an effective treatment or prevention of bone loss due to the stripping of estrogen.

An additional demonstration of the method to treat or prevent osteoporosis due to the stripping of estrogen would be as follows: One hundred patients would be chosen, who are healthy postmenopausal women, age 45-60 and who would normally be considered candidates for estrogen replacement therapy. This includes women with an intact uterus, who have had a last menstrual period for more than six months, but less than six years. Patients excluded for the study would be those who have taken, estrogens, progestins, or corticosteroids six months before the study or who have also taken bi-phosphonates.

Fifty women (test group) would receive 15-80 mg of a compound of formula I, eg, Formulation 1 (above), per day. The other fifty women (control group) would receive a uniform placebo per day. Both groups would receive calcium carbonate tablets (648 mg) per day. The study is a double-variable design. Neither the researchers nor the patients would know to which group each patient was assigned.

A baseline of each patient's examination includes the quantitative measurement of urinary calcium, creatine, hydroxyproline, and pyridoline cross-links. Blood samples are measured for osteocalcin serum levels, and bone-specific alkaline phosphates. Baseline measurements would also include a uterine examination and determination of bone mineral density by means of photon absorptiometry.

This study would continue for six months, and each patient would be examined for changes in the above parameters. During the course of treatment, patients in the treatment group would show a decreased change in the biochemical markers of bone resorption compared to the control group. Also, the treatment group would show little or no decrease in bone mineral density compared to the control group. Both groups would have similar uterine histology, indicating that the compounds of formula I have little or no urotropic effect.

B. Hyperlipidemia: Experimental models of postmenopausal hyperlipidemia are known in the art. Pertinent to this invention is the ovariectomized rat model detailed in U.S. 5,464,845. Estrogenicity could also be evaluated by evaluating the eosinophilic infiltration response in the uterus. A demonstration of the method to treat hyperlipidemia due to the stripping of estrogen would be as follows: one hundred patients would be chosen, who are healthy postmenopausal women, age 45-60, and who would normally be considered candidates for estrogen replacement therapy. This would include women with an intact uterus, who have not had a menstrual period for more than six months, but less than six years. Patients excluded for the study would be those who have taken estrogens, progestins, or corticosteroids.

Fifty women (test group) would receive 15-80 mg of a compound of formula I, for example, using Formulation 1 (above), per day. The other fifty women (control group) would receive a uniform placebo per day. The study is a double-variable design. Neither the researchers nor the patients would know to which group each patient was assigned.

A baseline examination of each patient would include serum deination of cholesl levels and t-glycerides. At the end of the study period (six months), each patient would have had their serum lipid profile taken. The analysis of the results would confirm a decrease in serum lipids, for example, cholesl and / or tri-glycerides, in the test group against the control.

From the aforementioned, it will be noted that this invention is well adapted to achieve all the purposes set forth hereinbefore together with the advantages inherent in the invention. It will be understood that certain characstics and subcombinations are useful and could be used without reference to other characstics and subcombinations. This is contemplated by and within the scope of the claims. Because many possible embodiments of the invention could be made without departing from the scope thereof, it is understood that any matset forth herein will be construed as illustrative and not in a sense of limitation.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (20)

1 . A compound of formula I (I) characterized because: R: and R: "are independently hydrogen, -CH3, -CO (C: -C6 alkyl), or COAr, wherein Ar is optionally substituted phenyl; Rr is selected from the group consisting of pyrrolidinyl, hexamethyleneimino, and piperidinyl; or a pharmaceutically acceptable salt or solvate thereof, in an amorphous form.

2. A compound according to Claim 1, characterized in that R1 and R3 are each hydrogen, R2 is piperidinyl, and the hydrochloride salt thereof

3. A compound according to Claim 1, characterized in that it is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4-piperidinylethoxy) benzoyl] benzo [b] thiophene.

4. A process for preparing an amorphous form of a compound of formula I (I) where R: and R3 are independently hydrogen, -CH3, -CO (C ^ alkyl, or COAr, where Ar is optionally substituted phenyl; R2 is selected. of the group consisting of pyrrolidinyl, hexamethyleneimino, and piperidinyl; or a pharmaceutically acceptable salt or solvate thereof; characterized because: comprising the preparation of a solution of a crystalline form of a compound of formula I in a suitable solvent, and then spray drying the solution to recover an amorphous form of a compound of formula I.

5. The process of Claim 4, characterized in that the suitable solvent is a mixture of methanol and water.

6. The process of Claim 4 or Claim 5, characterized in that the spray drying is carried out in the presence of an inert gas.

7. A pharmaceutical formulation, characterized in that it comprises a compound according to any of Claims 1-3 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

8. A compound according to any of Claims 1-3, characterized in that it is used to inhibit bone loss or bone resorption in a patient.

9. The compound according to Claim 8, characterized in that the bone loss or bone resorption is presented as a result of menopause or ovariectomy.

10. A compound according to any of Claims 1-3, characterized in that it is used to inhibit serum cholesterol levels in a patient.

11. A compound according to any of the Claims 1-3, characterized in that it is used to alleviate the symptoms of post-menopausal syndrome in a patient.

12. A compound according to Claim 11, characterized in that the symptom of the pathological condition of the post-menopausal syndrome is osteoporosis.

13. A compound according to Claim 11, characterized in that the symptom of the pathological condition of the post-menopausal syndrome is a cardiovascular disease.

14. A compound according to claim 13, characterized in that the cardiovascular disease is hyperlipidemia.

15. A compound according to Claim 11, characterized in that the symptom of the pathological condition of the post-menopausal syndrome is estrogen-dependent cancer.

16. A compound according to claim 15, characterized in that the estrogen-dependent cancer is breast or uterine cancer.

17. A compound according to any of Claims 1-3, characterized in that it is used to alleviate the symptoms of fibroid uterus disease in a patient.

18. A compound according to any of Claims 1-3, characterized in that it is used to alleviate the symptoms of endometriosis in a patient.

19. A compound according to any of Claims 1-3, characterized in that it is used to alleviate the symptoms of smooth muscle cell proliferation in a patient.

20. A compound according to any of Claims 1-3, characterized in that it is used to alleviate the symptoms of restenosis in a patient.