MXPA98006763A - Benzotiophenes and formulations that contain them - Google Patents

Abstract

The invention provides the new benzothiophene compounds

Description

BENZOTIOPHENES, AND FORMULATIONS THAT CONTAIN THEM FIELD OF THE INVENTION This invention is refers to the fields of pharmaceutical and organic chemistry, and provides benzothio pheno compounds, which are useful for the treatment of various medical indications associated with post-menopausal syndrome and the treatment of breast cancer and its prevention. The invention also relates to pharmaceutical compositions.

BACKGROUND OF THE INVENTION Osteoporosis describes a group of diseases that arise from various etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and the resulting fracture of the bones is the failure of the skeleton to provide adequate structural support for the body. One of the most common types of osteoporosis is that associated with REF. 28011 menopause. Most women lose from approximately 20% to approximately 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after cessation of menses. This rapid loss is generally associated with an increase in bone resorption and formation. However, the restoring cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women. There are approximately 25 million women in the United States alone who are affected by this disease. The results of osteoporosis are personally harmful and also represent a large economic loss due to their chronicity and the need for long-term and extensive support (hospitalization and nursing home care) due to the sequelae of the disease. This is especially true in older patients. In addition, although it is generally thought that osteoporosis is not a life-threatening condition, a mortality rate of 20% to 30% is related to hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post-menopausal osteoporosis. The most vulnerable tissue in the bone for the effects of post-menopausal osteoporosis is trabecular bone. This tissue is often referred to as cancellous or cancerous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which are interconnected with each other, as well as the more solid and dense cortical tissue which constitutes the outer surface and the central axis of the bone. This interconnected network of trabeculae gives lateral support to the outer cortical structure and is critical to the biomechanical strength of the entire structure. In post-menopausal osteoporosis, it is mainly the resorption and net loss of trabeculae that leads to failure and bone fracture. In light of the loss of trabeculae in post-menopausal women, it is not surprising that most common fractures are those associated with bones that are highly dependent on trabecular support, for example, the vertebrae, the neck of the bones that hold weight such as the femur and the forearm. Of course, hip fracture, neck fractures, and vertebral crush fractures are hallmarks of post-menopausal osteoporosis. At this time, the only two methods generally accepted for the treatment of post-menopausal osteoporosis are estrogen replacement therapy and administration of bis-phosphonate. Although therapy is generally successful, the patient's compliance with estrogen therapy is low mainly because estrogen treatment often produces undesirable side effects. Bisphosphonate therapy is successful in the treatment of osteoporosis with few serious side effects; however, it has no effect on the other symptoms related to menopause. Throughout the pre-menopausal period, 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 slowly to equal the rate observed in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen's ability to regulate serum lipid levels. The nature of estrogen's ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can up-regulate low-density lipid (LDL) receptors in the liver to eliminate excess cholesterol. In addition, estrogen seems to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health. It has been reported in the literature that post-menopausal women who have estrogen replacement therapy have a return of serum lipid levels to concentrations similar to those of the pre-menopausal state. In this way, it would seem that estrogen is 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 could regulate the level of serum lipid as estrogen does, but which would be devoid of the side effects and risks associated with estrogen therapy.

Estrogen-dependent cancers, especially breast carcinoma, are a major medical problem in women, particularly between the ages of thirty-five to sixty-five. It is estimated that most women have an opportunity in ten to develop breast cancer in their life. Breast carcinoma is a leading cause of mortality in women, as well as a cause of disability, psychological trauma and economic loss. A large percentage of women who contract this disease eventually die from its effects, either directly or indirectly from complications, for example, metastasis, loss of general health, or side effects of therapeutic interventions, such as surgery, radiation, or chemotherapy. A great benefit has been achieved with the use of hormone-based therapeutic interventions. The most widely used therapy is the use of tamoxifen. The five-year survival rate for women with breast carcinoma has been dramatically improved with this therapy; however, the longer-term survival rate (over ten years) has not improved in the same degree. Thus, even with the best conditions of the treatment modalities, for example, surgery, radiation, and / or chemotherapy, the long-term prognosis for patients is poor, especially if ethastatic disease is present. Clearly, there is a great need for improved therapies, and perhaps more importantly, a need for disease prevention in the first instance. In response to the clear need for new pharmaceutical agents that are capable of alleviating the symptoms of, among others, post-menopausal syndrome and the treatment of estrogen-dependent cancers, the present invention provides benzothiophene compounds, pharmaceutical compositions of the and methods of using such compounds for the inhibition of bone loss / osteoporosis, in decreasing serum cholesterol levels, and for inhibiting estrogen-dependent cancers. It is well known in organic chemistry that the oxidation of a nitrogen in a compound leads to a reduction in its alkalinity and an increase in its polarity, for example, these compounds become more neutral and generally more soluble in water. In vi, it is common for many drugs that contain amines to be oxidized to their N-oxides, as part of their metabolism and excretion, since it is a common mechanism for living organisms to eliminate a basic or alkaline compound. Frequently the oxidation of nitrogen leads to compounds that are pharmacologically less active or inactive compared to their parent bases; however, this is unpredictable and should be examined on a case-by-case basis (see: Goodman and Gilman's "The Pharmacological Basis of Therapeutics," 6th Ed., Macmillan Publishing Co., NYC, Chapter 1, 1980). For example, the N-oxidation of the anticancer compounds ie the Vinca alkaloids or Vi nca per Vi n ca, lead to biological inactivity (see: Barnett, CJ, et al., J. Med. Ch em. 1), p.88-96, 1978).

DESCRIPTION OF THE INVENTION This invention provides the compounds of the formula I (I) where R1 is hydrogen, hydroxyl, alkoxy of 1 to 4 O II carbon atoms, -O-CO (alkyl of 1 to 6 carbon atoms), -OC- (alkyl of 1 to 6 carbon atoms), O O -OC-O-Ar, -OC-Ar, wherein Ar is optionally substituted phenyl, or -OS02 (straight chain alkyl of 4 to 6 carbon atoms); Rz is R1, Cl or F; R3 and R4 are independently alkyl of 1 to 4 carbon atoms or combine to form a polymethylene of 4 to 6 carbon atoms or, together with the nitrogen to which they are attached form morpholine, and 0 II X is -CH2- , -CHOH2-, -0-, or -C-; or a pharmaceutically acceptable salt or solvate thereof. The present invention further relates to pharmaceutical compositions containing a compound of formula I, alone or in combination with other active ingredients.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the discovery that a select group of the N-oxides of 2-aryl-3-aroyl- (3-arylmethyl, or 3-phenoxy) benzo [b] thiophen-amine, for example, the compounds of Formula I are useful for the treatment or prevention of osteoporosis, hyperlipidemia, and estrogen-dependent cancers, especially breast cancer. In the above formula, the term "alkyl of 1 to 6 carbon atoms" represents a linear or branched alkyl chain having from 1 to 6 carbon atoms. Typical alkyl groups of 1 to 6 carbon atoms include methyl, ethyl, n-propyl and n-butyl. The term "alkoxy of 1 to 4 carbon atoms" represents groups such as methoxy, ethoxy, n-propoxy and n-butoxy. The optionally substituted phenyl includes phenyl and phenyl substituted once or twice with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, nitro, chloro, fluoro, or tri (chloro or fluoro) ethyl. When R3 and R4 form a polymethylene of 4 to 6 carbon atoms, it includes tetramethylene, pentamethylene and hexamethylene. With the nitrogen to which they are then bound, R3 and R4 form, for example, pyrrolidino, piperidino, and hexamethyleneimino. The term "solvate" represents an aggregate comprising one or more molecules of the solute, such as a compound of the formula I, with a solvent molecule. The term inhibit is defined to include its generally accepted meaning, which includes prohibition, prevention, restriction, alleviation, improvement, decrease, arrest or reversal of progression, or severity, or such action on a resulting symptom. As such, the present invention includes medical therapeutic and / or prophylactic administration, as appropriate.

Preferred compounds of the present invention include: [2- (4-hydroxy f eni 1) -6-h id rox ibenzofbjt ien-3-yl] [4- [2- (1-piperidinyl) e toxijf in il] metronose, N-oxide hydrochloride of [2- (-hydroxyf nyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (l-piperidini 1) ethoxy] phenyl ] methanone, [2- (4-hydroxy-f-enyl) -β-hydroxy-benzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] -fenyl-methane N-oxide, [6-hydroxy] 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxymethyl)] benzo [b] thiophene-N-oxide [6-hydroxy-3- [4- [2- ( 1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene-N-oxide, The compounds of the present invention (formula I) are prepared by selective oxidation of the basic nitrogen of the compounds of the Formula II, next.

II The compounds of the formula II can be prepared according to established procedures. The compounds of formula II, wherein X is -CO-, can be prepared by the procedures detailed in U.S. Patent Nos. 4,133,814, 4,418,068, and 4,380,635, all of which are incorporated by reference herein. In general, the process begins with a benzo [b] thiophene having a 6-hydroxyl group and a 2- (-hydroxyphenyl) group. The initial compound is protected, acylated, and deprotected to form the compounds of formula II. Examples of the preparation of such compounds are provided in the North American Patents discussed above. The compounds of the formula II which are carboxylic esters or sulfonates can be prepared by the methods described in US Patents Nos. 5,393,763, 5,482,949 and ,482,949, each of which is incorporated by reference herein. They may be necessary -modifications to the above methods to accommodate the reactive functional groups of the particular substituents. Such modifications would be apparent and easily evaluated by those with experience in the technique of organic chemistry. The compounds of formula II, wherein X is -CH2- or -CHOH-, can be prepared by the methods described in US Patent No. 5,484,798, which is incorporated by reference herein. In summary, the reduction of carbonyl to carbinol, and subsequently to methylene, can be achieved by steps or from carbonyl to methylene in a single pass. The carbonyl compounds of the formula II can be reduced to the carbinol with LiAlH 4, NaBH 4, or the like in suitable solvents such as chlorocarbons, tetrahydrofuran, ether, etc. at temperatures from 0 to 30 ° C. Carbinol can be reduced to methylene with alkylsilanes and trifluoroacetic acid, for example, triethylsilane, in appropriate solvents such as, methylene chloride, or tetrahydrofuran at ambient temperatures. Alternatively, the carbonyl compound can be reduced directly to the methylene by the use of LiAlH 4 in a high boiling point solvent such as propyl benzene at reflux temperatures. The compounds of formula II, wherein X is -O-, - can be prepared by the methods described in US Patent No. 5,488,058, which is incorporated by reference herein. In summary, a 2-ar-yl-benzo [b] thiophene is brominated at position 3. This bromide is displaced by a phenoxide containing the basic side chain, under the Ullman reaction conditions. Oxidation of the nitrogen on the 3-aroyl, 3-phenoxy, or 3-arylmethyl side chain of the compounds of the formula II is carried out by the use of dilute aqueous solutions of H202 with a co-solvent such as methanol or ethanol or halogenated hydrocarbons. The reaction conditions for this reaction can be in the range of room temperature to 100 ° C and for a duration of 1 to 72 hours. It should be noted that care must be taken in selecting the oxidizing agent and that many commonly used agents, for example, Cr03, K nO and the like, capable of oxidizing nitrogen, can not be used, since these will also oxidize to the sulfur of the benzo [b] thiophene. Thus, a mild agent such as hydrogen peroxide (H202) is preferred. Examples of the preparation of the compounds of the formula I using this procedure are listed below.

The following are examples of the preparation of the compounds of the formula I. These are presented for purposes of illustration and are not to be considered as limiting the scope of this invention.

Example 1 N-oxide of [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy-phenyl-methanone Two grams (4.23 mraol) of [2- (4-hydroxy phenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl-1) ethoxy-phenyl] -methanone were dissolved in 150 ml of refluxed ethanol and 15 ml of 30% aqueous hydrogen peroxide were added. The reaction mixture was heated to reflux for eighteen hours, then checked for completion by thin layer chromatography. An additional 15 ml of 30% hydrogen peroxide was added and the reaction was allowed to continue for an additional period of eighteen hours at reflux temperature. The reaction was allowed to cool and the volatile solvents were removed by evaporation in vacuo. The crude material was redissolved in chloroform and partitioned with water. The chloroform layer was dried by filtration through anhydrous sodium sulfate and evaporated to dryness. This produces 1590 mg of the title compound as a pale yellow amorphous powder. RMP (MAGNETIC RESONANCE OF PROTONS): (CDC13-DMS0-d6) 7.70 6 (d, J = 6Hz, 2H), 7.43 (d, J = 4Hz, ÍH), 7. 27 (d, J = 1Hz, 1H), 7.15 (d, J = 5Hz, 2H), 6.87 (dd, J: = 4Hz, J2 = 1Hz, ÍH), 6.77 (d, J = 5Hz, 2H), 6.65 (d, J = 6Hz, 2H), 4.54 (t, J = 2Hz, 2H), 3.71 ( t, J = 2Hz, 2H), 3.38 (m, 4H), 2.16 (m, 2H), 1.72 (, 3H), 1.48 (m, ÍH) MS: m / e = 490 (M +) FD pKa: 6.28 Weight Apparent Molecular (pa) = 487 (66% DMF) Rf: 0.05 silica gel CHCl3-MeOH (19: 1) (v / v) EA: Cale: C, 66.3; H, 5.73; N, 2.76 Found: C, 66. 46; H, 5.62; N, 2.76 C28H27NO_, S-H20 Example 2 N-oxide of [2 - (4-methoxy f nyl) -6-m toxibenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy-phenyl-methanone 1190 mg (2.38 mmol) of [2- (4-methoxyphenyl) -6-methoxybenzo [bjthien-3-yl] [4- [2- (l-piper idinyl) ethoxyjphenyl] ethanone were dissolved in 100 ml of methanol and added 30 ml of 30% hydrogen peroxide. The reaction mixture became turbid, but cleared after several hours. The reaction was allowed to proceed for 72 hours at room temperature. The reaction mixture was evaporated to dryness and extracted into 100 ml of ethyl acetate. The ethyl acetate solution was washed with dilute aqueous Nalco and dried by filtration through anhydrous sodium sulfate. Hexane was added and the solution allowed to crystallize at -20 ° C. A solid color burned was filtered and dried, yielding 720 mg of the title compound. RMP: consistent with proposed structure MS: m / e = 501 (M-16) FD pKa: 6.39 pma = 517 (66% DMF) Rf: 0.07 silica gel CHCl3-MeOH (19: 1) (v / v) Example 3 N-oxide of [2- (4-hydroxy phenyl) -6-hydroxybenzo [bjthien-3-yl] [4- [2- (N, N-di ethyl) ethoxy-phenyl-methanone 2000 mg (4.33 mmol) of [2- (4-hydroxyf nyl) -6-hydroxybenzo [bjthien-3-yl] [4- [2- (N, Nd i et i 1) ethoxy phenyljmetanone was dissolved in 60 ml of methanol and 10 ml of 30% hydrogen peroxide were added. The reaction was allowed to proceed for eighteen hours at room temperature. The reaction mixture was evaporated to dryness and redissolved in 100 ml of ethyl acetate. The ethyl acetate solution was washed with water and dried with sodium sulfate and evaporated to dryness. This resulted in obtaining 1150 mg of the title compound as an amorphous color-burned powder. RMP: consistent with proposed structure MS: m / e = 478 (M +) and 462 (M-16) FD pKa: ß.15 pma = 498 (66% DMF) Rf: 0.14 silica gel CHCl3-MeOH (19: 1 ) (v / v) Example 4 N-oxide of [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-ylj [4- [2- (1-morpholine)) ethoxy-phenyl-methanone 1100 mg (2.23 mmol) of [2- (4-hydroxy phenyl) -6-hydrobenzo [bjthien-3-yl] [4- [2- (1-morpholino) ethoxyjphenyl] methanone was dissolved in 50 ml of methanol and 30 ml of 10% hydrogen peroxide. The reaction was allowed to proceed for eighteen hours at room temperature. The reaction was verified by thin layer chromatography and 10 ml of 30% hydrogen peroxide was added. The reaction was continued for an additional period of eighteen hours. The reaction mixture was evaporated to dryness and redissolved in 100 ml of ethyl acetate. The ethyl acetate solution was washed with dilute aqueous sodium chloride, and dried with sodium sulfate and evaporated to dryness. This produced 460 mg of the title compound as an amorphous colored burned powder. RMP: consistent with the proposed structure MS: m / e = 492 (M +) and 475 (M-16) FD Rf: 0.04 silica gel CHCl_ = MeOH (19: 1) (v / v) Example 5 N- [2- (4-n-Butyl-sulphon-onyl-phenyl) -β-n-butylsulfonyl-benzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy-enyl-methyl-a] 1250 mg (1.27 mmol) of [2- (4-n-butylsulfonoylphenyl) -6-n-butylsulfonoylbenzo [bjthien-3-yl] [4- [2- (1-piperidinyl) ethoxyjphenyl] methanone was dissolved in 125 ml of methanol and 25 ml of ethanol and 30 ml of hydrogen peroxide were added. The reaction was allowed to proceed for eighteen hours at room temperature. The reaction mixture was evaporated to dryness and redissolved in 100 ml of ethyl acetate. The ethyl acetate solution was washed with water and dried with sodium sulfate and evaporated to dryness. This resulted in 390 mg of the title compound as an amorphous color burned powder. RMP: consistent with the proposed structure MS: m / e = 730 (M +) and 714 (M-16) FD Rf: 0.16 silica gel CHCl3-MeOH (19: 1) (v / v) Example 6 N-oxide of [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxyphfeni IJmetaño1 A solution of 10 ml of 10% hydrogen peroxide and 100 ml of methanol was prepared. To this solution was added 476 mg (1 mmol) of [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy-phenyl-methanol. The reaction was allowed to proceed for twenty hours at room temperature. The reaction mixture was evaporated to dryness and triturated several times with toluene. The product was dried under vacuum. This yielded 210 mg of the title compound as an amorphous colored burned powder. RMP: consistent with the proposed structure MS: m / e = 492 (M +) and 476 (M-16) FD pKa = 6.41 EA: Cale. For C28H29N05S-2H20: C, 63.7; H, 5.87; N, 2.65 Found: C, 63.13; H, 5.81; N, 2.43.

Example 7 N-oxide of [2- (4-hydroxy phenyl) -6-hydroxybenzo [bJthien-3-yl] [4- [2- (1-piperidinyl) ethoxyphyphenyl] methane A solution of 20 ml of 10% hydrogen peroxide and 100 ml of methanol was prepared, to which was added 1500 mg (3.27 mmol) of [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl [ 4- [2- (1-piperidinyl) ethoxy-phenylj-methane. The reaction mixture was stirred at room temperature for twenty hours. The reaction mixture was evaporated to dryness in vacuo and triturated several times with toluene. The reaction product was dried under vacuum at room temperature for several days. This produced 1090 mg of the title compound as an amorphous color-burned powder. RMP: (CDC13) 7.42 d (d, J = 4Hz, 4H), 7.40 (d, J = 4Hz, ÍH), 7.38 (d, J = 1Hz, ÍH), 7.18 (d, J = 4Hz, 2H), 7.00 (d, J = 4Hz, 2H), 6.98 (m, ÍH), 6.92 (d, J = 4Hz, 2H), 4.69 (t, J = 2Hz, 2H), 4.27 (s, 2H), 3.78 (t , J = 2Hz, 2H), 2.35-2.60 (m, 4H), 2.38 (m, 2H), 1.83 (m 2H), 1.60 (m, ÍH) MS: m / e = 459 (m-lß FD pKa: 6.49 pma = 461 EA: Cale.For C28H29N04S: C, 70.71; H, 6.15; N, 2.95 Found: C, 70.12; H, 6.11; N, 3.09.

Example 9 [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy-phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophen-N-oxide To a solution of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy-phenoxy] -2- (4-methoxyphenyl) -benzo [b] thiophene (50 mg, 0.10 mmol) in 3 ml of methanol / chloroform 1: 1 hydrogen peroxide (0.5 ml of a 30% solution) was added. The resulting mixture was heated gently on a steam bath until thin layer chromatography analysis showed that the reaction was complete (1 to 2 hours). The solvent was then removed in vacuo to give a yellow solid that was triturated from ethanol / diethyl ether. Filtration gave 46 g (92%) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy-phenoxy] -2- (4-methoxyphenyl) -benzo [b-thiophen-N-oxide] as a solid yellow . Mp 120-125 ° C. XR-NMR (DMSO-d6) d 10.30 (broad s, HH), 7.53 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 2.0 Hz, HH), 7.00 (d, J = 8.7 Hz, ÍH) ), 6.93 (d, J = 8.8 Hz, 2H), 6.79 (s, 4H), 6.72 (dd, J = 8.7, 2.0 Hz, 1H), 4.38 (m, 2H), 3.71 (s, 3H), 3.50 -3.03 (m, 6H), 2.02 (m 2H), 1.51-1.13 (m, 3H), 1.05 (, 1H). Mass spectrum FD: 492, 475, 390, 364. Analysis Calculated for C28H29NO5S * 0.45H20: C, 67.30; H, 6.03; N, 2.80. Found: C, 67.31; H, 5.96; N, 2.57.

Example 10 [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxyJphene]] -2- (4-hydroxyphenyl)] benzo [bjhiophene-N-oxide] Prepared in a similar manner described in Example 10, the title compound was obtained. Mp 125-130 ° C. XH NMR (DMSO-d6) d 7.39 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 2.1 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 6.77 (s, 4H) , 6.73 (dd, J = 8.7 Hz, 2.1 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 4.37 (, 2H), 3.52 (m, 2H), 3.38-3.03 (m, 4H), 2.04 (m, 2H), 1.53-1.49 (m, 3H), 1.31 (m, ÍH). Mass spectrum FD: 477, 460. Analysis Calculated for C27H27NO5S »0.5H20: C, 66.65; H, 5.80; N, 2.88. Found: C, 66.66; H, 5.98; N, 2.89.

The following examples illustrate the methods for the use of the compounds of the formula I in experimental models or in clinical studies.

Test Procedure General Preparation Procedure In the examples that illustrate the methods, a post-menopausal model was used in which the effects of the different treatments on the circulating lipids were determined. Seventy-five-day-old female Sprague Dawley rats (weight range 200 to 225 g) were obtained from Charles River Laboratories (Portage, MI). The animals are either bilaterally ovariectomized (OVX) or exposed to a Sham surgical procedure at Charles River Laboratories, and then boarded after a week. After arrival, they were placed in metal hanging cages in groups of 3 or 4 per cage and had access to food (calcium content approximately 0.5%) and water for a week. The ambient temperature was maintained at 22.2 ° ± 1.7 ° C with a minimum relative humidity of 40%. The photoperiod in the room is 12 hours of light and 12 hours of darkness.

Fabric Collection of the Dosing Regimen. After a week of acclimation period (therefore, two weeks post-OVX) the daily dosing with the test compound was started. 17a-ethynyl tradiol or the compound of test orally, unless otherwise stated, as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. The animals were dosed daily for 4 days. After the regime of After dosing, the animals were weighed and anesthetized with ketamine: xylazine mixture (2: 1, v: v) and a blood sample was collected by cardiac puncture. The animals were then sacrificed by asphyxia with C02, the uteri removed through an incision in the intermediate line, and the wet weight of the uterus was determined.

Cholesterol analysis. The blood samples were allowed to clot at room temperature for 2 hours, and serum was obtained after centrifugation by Q-? > * > 10 minutes at 3000 rpm. Serum cholesterol was determined using the high precision cholesterol assay from Boehringer Mannheim Diagnostics. In summary, cholesterol is oxidized to cholest-4-en-3-one and hydrogen peroxide. The hydrogen peroxide is then reacted with phenol and 4-aminophenazone in the presence of peroxidase to produce a p-quinone-imine dye, which is read spectrophotometrically at 500 nm. The cholesterol concentration is then calculated against a standard curve. The complete test is automated using a Biomek Automated orkstation device.

Uterine Eosinophilic Peroxidase (EPO) assay. The uteri are kept at 4 ° C. until the time of the enzymatic analysis: i, co. The uteri are then homogenized in 50 volumes of buffer Tris 50 M (pH 8.0) containing 0.005% Triton X-100. After the addition of 0.01% hydrogen peroxide and 10 mM O-phenylenediamine (final concentrations) in Tris buffer, the increase in absorbance is checked periodically for one minute at 450 nm. The presence of eosinophils in the uterus is an indication of the estrogenic activity of a compound. The maximum speed of a 15 second interval is determined on the initial linear portion of the reaction curve.

Source of Compound: 17a-ethynyl-estradiol was obtained from Sigma Chemical Co. , Saint Louis, MO.

Hyperlipidemia: The data presented in Table 1 show the comparative results between ovariectomized rats, rats treated with 17-a-ethynyl-estradiol (EE2), and rats treated with certain compounds of this invention. Although EE2 caused a decrease in serum cholesterol when orally administered at 0.1 mg / kg / day, it also exerted a simulating effect on the uterus, so that the uterine weight of the rats treated with EE2 was substantially greater than the uterine weight. of ovariectomized animals. This uterine response to an estrogen is well recognized in the art. The compounds of the present invention reduced serum cholesterol compared to ovariectomized animals. As expressed in the following data, trogenicity was also assessed by evaluating the response of eosinophil infiltration to the uterus. The compounds of this invention did not cause a large increase in the number of eosinophils observed in the stromal layer of the uteri of ovariectomized rats. EE2 caused a substantial and expected increase in the infiltration of eosinophils. The data presented in Table 1 reflects the response of five or six rats per treatment group. 0 Table 1 Compound No. Dose Uterine Weight Uterine Eosinophils Cholesterol mg / kga% I cb (Vmax) c Serum% Desc.d EE2 0.1 207.5 * 205.8 * 87.3 * 1 0.1 31.2 * 4.4 44.9 * 1.0 29.6 * 4.6 68.7 * 10.0 8.3 2.5 70.3 * 2 1.0 49.2 * 11.2 65.7 * 3 1.0 77.5 * 21.7 * 64.2 * 1.0 62.5 * 4.1 56.2 * 1.0 44.4 * 4.7 74.9 * 17-a-ethynyl-estradiol b Percent increase in uterine weight versus ovariectomized controls c V exima of eosinophil peroxidase d Decrease in serum cholesterol versus ovariectomized controls * p < 0.05 Qsteoporosis Test Procedure Following the Preparation Procedure General, above, the rats were treated daily for 35 days (6 rats per treatment group) and sacrificed by asphyxiation by carbon dioxide on day 36. The time period of 35 days is sufficient to allow the maximum reduction in the bone density, measured as described herein. At the time of sacrifice, the uteri were removed, dissected to release them from the foreign tissue, and the fluid contents were issued before the determination of wet weight in order to confirm the estrogenic deficiency associated with complete ovariectomy. The uterine weight is routinely reduced by approximately 75%, in response to ovariectomy. The uteri were then placed in 10% neutral buffered formalin, to allow subsequent histochemical analysis. The right femurs were removed and digitalized X-rays were generated, and analyzed by an image analysis program (NIH image) in the distal metaphysis. The proximal aspect of the tibias of these animals is also explored by quantitative computed tomography. In accordance with the above procedures, the compounds of the present invention and the ethinylestradiol (EE2) in 20% hydroxypropyl-β-cyclodextrin are orally administered to the animal's body. In summary, the ovariectomy of the test animals causes a significant reduction in femoral density, compared to intact vehicle-treated controls. Ethinyl-is tradiol (EE2) orally administered prevented this loss, but the risk of uterine stimulation with this treatment is always present. The compounds of the present invention prevent bone loss in a general dose-dependent manner.

MCF-7 Proliferation Assay MCF-7 breast adenocarcinoma cells (ATCC HTB 22) are maintained in MEM (minimum essential medium, free of phenol red, Sigma, Saint Louis, MO) supplemented with 10% fetal bovine serum (FBS) (v / v), L-glutamine (2 mM), sodium pyruvate (1 mM), HEPES. { (N- [2-hydroxyethyl] -piperazine-N '- [2-etansulonic acid, 10 mM], non-essential amino acids and bovine insulin (1 μg / ml) (maintenance medium) Ten days before the test, the MCF cells -7 are changed to the maintenance medium supplemented with the test medium of bovine fetal serum purified with 10% dextran-coated mineral charcoal (DCC-FBS)) in place of 10% FBS to decrease internal steroid stores. The MCF-7 cells are removed from the maintenance flasks using the cell dissociation medium (HBSS free of Ca ++ / Mg ++ (free of phenol red) supplemented with 10 mM HEPES and 2 mM EDTA). The cells are washed twice with assay medium and adjusted to 80,000 cells / ml. Approximately 100 μl (8,000 cells) are added to the flat bottom microculture wells (Costar 3596) and incubated at 37 ° C in a humidified incubator with 5% C02 for 48 hours, to allow adherence of the cells and the balance after the transfer. Serial dilutions of the drugs or DMSO as a diluent control are prepared in assay medium and 50 μl is transferred to the microcultures in triplicate, followed by 50 μl of assay medium for a final volume of 200 μl. After an additional 48 hours at 37 ° C in a humidified incubator with 5% C02, the microcultures are pulsed with tritiated thymidine (1 μCi / well) for 4 hours. The cultures are terminated by freezing at -70 ° C for 24 hours, followed by freezing and harvesting of the microcultures using a Skatron Semiautomatic Cell Harvester. Samples are counted by liquid scintillation using a ß Wallac BetaPlace counter. For example, in this assay, the compound of Example 1 has an IC50 of about 1 μM.

Inhibition of mammary tumor induced by DMBA Estrogen-dependent mammary tumors are produced in female Sprague-Dawley rats which are purchased from Harlan Industries, Indianapolis, Indiana. At approximately 55 days of age, the rats receive a simple oral 20 mg diet of 7,12-dimethylbenz [a] anthracene (DMBA). Approximately 6 weeks after the administration of DMBA, the mammary glands are palpated at weekly intervals for the appearance of tumors. Whenever one or more tumors appear, the longest and shortest diameters of each tumor are measured with a metric gauge, measurements are recorded, and that animal is selected for experimentation. An attempt is made to uniformly distribute the various sizes of tumors in the treated and control groups, such that tumors of average size are equivalently distributed among test groups. The control groups and the test groups for each experiment contain 5 to 9 animals. The compounds of the formula I are administered either through intraperitoneal injections in 2% acacia, or orally. The orally administered compounds are either dissolved or suspended in 0.2 ml of corn oil. Each treatment, including control treatments with acacia and corn oil, is administered once a day to each test animal. After the measurement of the initial tumor and the selection of the test animals, the tumors are measured every week by the aforementioned method. The treatment and measurements of the animals continue for 3 to 5 weeks, at which time the final areas of the tumors are determined. For each compound and control group, the change in the mean tumor area is determined. The activity in at least one of the above assays illustrates the usefulness of the compounds of the formula I. The compounds of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases, and include the physiologically acceptable salts which are frequently used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric acids, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. It is also possible to use salts derived from organic acids, such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, sulphonic, aliphatic and aromatic acids. Such pharmaceutically acceptable salts include in this manner the salts of acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β -hydroxybutyrate, butyn-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate , mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, onoacid phosphate, diacid phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate , benzenesulfonate, p-bromophenylsulfonate, c-lorobenzenesulfonate, etansul-fonate, 2-h-idroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulphonate, p-toluenesulfon ato, xylene sulfonate, tartrate, and the like. A preferred salt is the hydrochloride salt.

The pharmaceutically acceptable acid addition salts are typically formed by the reaction of a compound of the formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene, methanol, ethanol, or acetone. The salt is usually precipitated from the solution within about one hour to 10 days, and can be isolated by filtration, or the solvent can be removed by conventional means. The bases commonly used for the formation of salts include ammonium hydroxide and alkali metal and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. Bases especially useful in the preparation of the addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine and cyclohexylamine. The pharmaceutically acceptable salts generally have improved solubility characteristics compared to the compound from which they are derived, and are thus often more suitable for formulation as liquids or emulsions. It is usually preferred to administer a compound of the formula I in the form of a salt by the addition of acid, as is customary in the administration of pharmaceutical products having an alkaline or basic group, such as the piperidino ring. It is also advantageous to administer such compound by the oral route. As used herein, the term "effective amount" means an amount of a compound of the formula I, or optionally, an amount of a compound of the formula I combined with an amount of a compound of the formula II, which is capable of alleviating the symptoms of the various pathological conditions described herein. The specific dose of a compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration, the general condition of the patient, and the pathological condition that it is about. A typical daily dose will contain a non-toxic dose level of from about 0.1 mg to about 1000 mg / day of a compound of the present invention, and more particularly will be from about 20 mg to about 200 mg / day. The compounds of this invention can be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal routes. These compounds are preferably formulated before administration, the selection of which will be decided by the attending physician. The total active ingredients in such formulations comprise from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" is meant the carrier, diluent, excipients and salt which must be compatible with the other ingredients of the formulation, and not harmful to the container thereof. An active ingredient in the formulations, below, means a compound of formula I. The pharmaceutical formulations of the present invention can be prepared by methods known in the art, using well-known and readily available ingredients. For example, compounds of formula I with or without another active agent, such as a compound of formula II, can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like . Examples of excipients, diluents and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for delaying dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylglycols. The compounds can also be formulated as elixirs or solutions for convenient oral administration, or as solutions suitable for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes.

In addition, the compounds are well suited for formulation as sustained release dosage forms and the like. The formulations may be constituted so as to release the active ingredient uniquely or preferably at a particular physiological site, possibly over a period of time. Coatings, wraps, and protective matrices can be made, for example, from polymeric substances or waxes. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.

Formulations Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg / capsule) Active ingredient 0.1-1000 Starch, NF 0-650 Fluid starch powder 0-650 Fluid silicone 350 centistokes 0-15 The above formulation can be changed in compliance with the reasonable variations provided. A tablet formulation is prepared using the following ingredients: Formulation 2: Tablets Ingredient Quantity (mg / tablet) Active ingredient 2.5-1000 Microcrystalline cellulose 200-650 Silicon dioxide, smoked 10-650 Stearic acid 5-15 The components are mixed and compressed to form tablets. Alternatively, the tablets each containing 2.5-1000 mg of active ingredient are constituted as follows: Formulation 3: Tablets Ingredient Quantity (mg / tablet) Active ingredient 25-1000 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water, Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredient, starch, and cellulose are passed through a No. 45 mesh American sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resultant powders which are then passed through a No. 14 North American mesh screen. The granules thus produced are dried at 50-60 ° C and passed through a wire mesh screen. North American mesh No. 18. Sodium carboxymethylcellulose, magnesium stearate, and talc previously passed through a No. 60 mesh American sieve are then added to the granules which, after mixing, are compressed in a machine tablet former to produce tablets. Suspensions each containing 0.1 to 1000 mg of medication per 5 ml of dose are made as follows: Formulation 4: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.1-1000 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Flavoring (as long as it is sufficient) css. Color css Purified water up to 5 ml 10 The medicament is passed through a No. 45 mesh American sieve and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The acid solution benzoic, the flavoring, and the color are diluted with some water and added, with agitation. It is added B! LX !! ^ 3? * B 'laego enough water to produce the required volume.

An aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 70.00 The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C, and transferred to a filling device. The required amount is then fed to a stainless steel vessel and diluted with the remaining propellant. The valve units are then adjusted to the container.

Suppositories are prepared as s igue Formulation 6: Suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 Saturated fatty acid glycerides 2000 The active ingredient is passed through a No. 60 mesh American sieve and suspended in the melted saturated fatty acid glycerides, using the minimum necessary heat. The mixture is then emptied into a suppository mold of nominal 2 g capacity, and allowed to cool.

An intravenous formulation is prepared as follows: Formulation 7: intravenous solution Ingredient Quantity Active ingredient 50 mg Isotonic saline 1,000 ml txr "n ^ r * -» The solution of the above ingredients is administered intravenously to a patient at a rate of approximately 1 ml per minute.

Formulation 8: Capsule in combination I Ingredient Quantity (mg / capsule) Active ingredient 50 Premarin 1 Avicel pH 101 50 Starch 1500 117.50 Silicone oil 2 Tween 80 0.50 Cab-O-Sil 0.25 Formulation 9: Capsule in combination II Ingredient Quantity (mg / capsule) Active ingredient 50 Noreti lnodrel 5 Avicel pH 101 82. 50 Starch 1500 90 Silica oil 2 Tween 80 0. 50 Formulation 10: Tablet in combination Ingredient Quantity (mg / capsule) Active ingredient 50 Premarin 1 Corn starch NF 50 Povidone, K29-32 Avicel pH 101 41.50 Avicel pH 102 136.50 Crospovidone XL10 2.50 Magnesium stearate 0.50 Cab-O-Sil 0.50 Formulation 8; Gelatin capsules Gelatin capsules are prepared using the following: Ingredient Amount (mg / capsule) Compound of Formula I 0.1-1000 Compound of Formula II 0.1-1000 Starch NF 0-650 Flowable Powder of Starch 0-650 Fluid Silicone of 350 centistokes 0-15 The above formulation can be changed in compliance with the reasonable variations provided. A tablet formulation is prepared using the following ingredients: Formulation 9: Tablets Ingredient Quantity (mg / tablet) Compound of Formula II 2.5-1000 Compound of Formula I 0.25-100 Microcrystalline Cellulose 200-650 Smoked Silicon Dioxide 10-650 Stearic Acid 5-15 The components are mixed and compressed to form tablets. Alternatively, the tablets each containing 25 to 1000 mg of active ingredient, are made as follows: Formulation 10: Tablets Ingredient Quantity (mg / tablet) Compound of Formula II 24.75-990 Compound of Formula I 0.25-10 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch, and cellulose are passed through a No. 45 mesh American sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a No. 14 mesh American sieve. The granules thus produced are dried at 50 ° -60 ° C and passed through a US No. 18 mesh screen. Sodium carboxymethylcellulose, magnesium stearate, and talc, previously passed through a No. 60 mesh US sieve, are then added to the granules which, after mixing, they compress in a tablet-making machine, to produce the tablets.

Formulation 11: Tablets Ingredient Quantity (mg / tablet) Compound of Formula II 25-1000 Compound of Formula I 0.025-1.0 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch, and cellulose are passed through a No. 45 mesh American sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a No. 14 North American mesh screen. The granules thus produced are dried at 50 ° -60 ° C and passed through a North American mesh screen No. 18. Sodium carboxymethylcellulose, starch, magnesium stearate, and talc, previously passed through a No. 60 mesh US sieve, are then added to the granules which, after the mixed, they are compressed into a tablet forming machine to produce tablets.

Formulation 12: Tablets Ingredient Quantity (mg / tablet) Compound of Formula II 60 Compound of Formula I 0.06-0.18 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) 1 Sodium carboxymethylcellulose '4.5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch, and cellulose are passed through a No. 45 mesh American sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a No. 14 North American mesh screen. The granules thus produced are dried at 50 ° -60 ° C and passed through a North American mesh screen No. 18. Sodium carboxymethylcellulose, starch, magnesium stearate, and talc, previously passed through a No. 60 mesh US sieve, are then added to the granules which, after the mixed, they are compressed into a tablet forming machine to produce tablets.

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, property is claimed as contained in the following:

Claims (15)

1. A compound of the formula I (I) where R is hydrogen, hydroxyl, alkoxy of 1 O carbon atoms, -O-CO (alkyl of 1 to 6 carbon O-atoms -OC- (alkyl of 1 to 6 carbon atoms! O O -OC-O-Ar, -OC-Ar, wherein Ar is optionally substituted phenyl, or -OS02 (straight chain alkyl of 4 to 6 carbon atoms); R2 is R1, Cl or F; R3 and R4 are indeently alkyl of 1 to 4 carbon atoms or combine to form a polymethylene of 4 to 6 carbon atoms or, together with the nitrogen to which they are attached, form morpholine, and II X is -CH2-, -CH0H2-, -0-, or -C-; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, characterized in that the compound is [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxyjfeni 1-methanone-N -oxide.

3. A compound according to claim 2, characterized in that the compound is the hydrochloride salt thereof.

4. A compound according to claim 1, characterized in that the compound is [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (4-methoxyphenyl)] benzo [b] thiophen-N- oxide.

5. A compound according to claim 1, characterized in that the compound is [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy-phenoxy] -2- (< -methoxy phenyl) J-benzo [b] thiophene- N-oxide.

6. A compound according to claim 4, characterized in that the compound is the hydrochloride salt thereof.

7. A method for inhibiting osteoporosis, characterized in that it comprises administering to the patient in need thereof, an effective amount of a compound according to claim 1.

8. A method for lowering serum cholesterol levels, characterized in that the method comprises administering to a patient in need thereof an effective amount of a compound according to claim 1.

9. A method for inhibiting estrogen-deent cancer, characterized in that it comprises administering to a patient in need thereof an effective amount of a compound according to claim 1.

10. A formulation, characterized in that it comprises a compound of formula I according to claim 1 and, optionally, pharmaceutically acceptable carriers, diluents, or excipients therefor.

11. A pharmaceutical formulation comprising a compound of formula I according to claim 1, and further comprising the hydrochloride of [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl [4- [2- (1-piperidinyl) ethoxy-phenyl-ketone and, optionally, pharmaceutically acceptable carriers, diluents, or excipients therefor.

12. A formulation according to claim 11, characterized in that the compound of the formula I comprises less than 10% by weight of the total active ingredients.

13. A formulation according to claim 12, characterized in that the compound of the formula I comprises less than 1% by weight of the total active ingredients.

14. A formulation according to claim 13, characterized in that the compound of the formula I comprises less than 0.3% by weight of the total active ingredients.

15. A formulation according to claim 11, characterized in that the compound of the formula I is [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-yl] [4- [2- (l-piperidinyl) ethoxy-phenyl) ] methanon-N-oxide.