the current invention concerns the discovery hat a select group of 2 - phenyl - 3 - aroylbenzothiophenes ( benzothiophenes ), those of formula i , are useful for inhibiting environmental estrogen effects . in particular , the methods of the invention encompass inhibiting the reproductive effects of environmental estrogens . the methods of use provided by this invention are practiced by administering to a human or other animal in need thereof a dose of a compound of formula i or a pharmaceutically acceptable salt or solvate thereof , that is effective to inhibit the effects of environmental estrogens . the term &# 34 ; inhibit &# 34 ; includes its generally accepted meaning which includes prohibiting , preventing , restraining , and slowing , stopping or reversing . as such , the present method includes both medical therapeutic and / or prophylactic administration , as appropriate . raloxifene , a compound of this invention wherein it is the hydrochloride salt of a compound of formula 1 , r 1 and r 3 are hydrogen and r 2 is 1 - piperidinyl , is a nuclear regulatory molecule . raloxifene has been shown to bind to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was that of an anti - estrogen in that it blocked the ability of estrogen to activate uterine tissue and estrogen dependent breast cancers . indeed , raloxifene does block the action of estrogen in some cells ; however in other cell types , raloxifene activates the same genes as estrogen does and displays the same pharmacology , e . g ., osteoporosis , hyperlipidemia . as a result , raloxifene has been referred to as an anti - estrogen with mixed agonist - antagonist properties . the unique profile which raloxifene displays and differs from that of estrogen is now thought to be due to the unique activation and / or suppression of various gene functions by the raloxifene - estrogen receptor complex as opposed to the activation and / or suppression of genes by the estrogen - estrogen receptor complex . therefore , although raloxifene and estrogen utilize and compete for the same receptor , the pharmacological outcome from gene regulation of the two is not easily predicted and is unique to each . generally , the compound is formulated with common excipients , diluents or carriers , and compressed into tablets , or formulated as elixirs or solutions for convenient oral administration , or administered by the intramuscular or intravenous routes . the compounds can be administered transdermally , and may be formulated as sustained release dosage forms and the like . the compounds used in the methods of the current invention can be made according to established procedures , such as those detailed in u . s . pat . nos . 4 , 133 , 814 , 4 , 418 , 068 , and 4 , 380 , 635 all of which are incorporated by reference herein . in general , the process starts with a benzo [ b ] thiophene having a 6 - hydroxyl group and a 2 -( 4 - hydroxyphenyl ) group . the starting compound is protected , acylated , and deprotected to form the formula i compounds . examples of the preparation of such compounds are provided in the u . s . patents discussed above . optionally substituted phenyl includes phenyl and phenyl substituted once or twice with c 1 - c 6 alkyl , c 1 - c 4 alkoxy , hydroxy , nitro , chloro , fluoro , or tri ( chloro or fluoro ) methyl . the compounds used in the methods 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 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 . salts derived from organic acids , such as aliphatic mono and dicarboxylic acids , phenyl substituted alkanoic acids , hydroxyalkanoic and hydroxyalkandioic acids , aromatic acids , aliphatic and aromatic sulfonic acids , may also be used . such pharmaceutically acceptable salts thus include acetate , phenylacetate , trifluoroacetate , acrylate , ascorbate , benzoate , chlorobenzoate , dinitrobenzoate , hydroxybenzoate , methoxybenzoate , methylbenzoate , o - acetoxybenzoate , naphthalene - 2 - benzoate , bromide , isobutyrate , phenylbutyrate , β - hydroxybutyrate , butyne - 1 , 4 - dioate , hexyne - 1 , 4 - dioate , caprate , caprylate , chloride , cinnamate , citrate , formate , fumarate , glycollate , heptanoate , hippurate , lactate , malate , maleate , hydroxymaleate , malonate , mandelate , mesylate , nicotinate , isonicotinate , nitrate , oxalate , phthalate , teraphthalate , phosphate , monohydrogenphosphate , dihydrogenphosphate , metaphosphate , pyrophosphate , propiolate , propionate , phenylpropionate , salicylate , sebacate , succinate , suberate , sulfate , bisulfate , pyrosulfate , sulfite , bisulfite , sulfonate , benzene - sulfonate , p - bromophenylsulfonate , chlorobenzenesulfonate , ethanesulfonate , 2 - hydroxyethanesuifonate , 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 typically formed by reacting a compound of 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 . the salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means . bases commonly used for formation of salts include ammonium hydroxide and alkali 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 addition salts include ammonium hydroxide , potassium carbonate , methylamine , diethylamine ethylene diamine and cyclohexylamine . the pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived , and thus are often more amenable to formulation as liquids or emulsions . pharmaceutical formulations can be prepared by procedures known in the art . for example , the compounds 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 carboxymethyl cellulose and other cellulose derivatives , alginates , gelatin , and polyvinyl pyrrolidone ; moisturizing agents such as glycerol ; disintegrating agents such as calcium carbonate and sodium bicarbonate ; agents for retarding 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 bentonire ; and lubricants such as talc , calcium and magnesium stearate , and solid polyethyl glycols . the compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration , for instance by intramuscular , subcutaneous or intravenous routes . additionally , the compounds are well suited to formulation as sustained release dosage forms and the like . the formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract , possibly over a period of time . the coatings , envelopes , and protective matrices may be made , for example , from polymeric substances or waxes . the particular dosage of a compound of formula i required to inhibit the effects of environmental estrogens according to this invention will depend upon the severity of the condition , the route of administration , and related factors that will be decided by the attending physician . generally , accepted and effective daily doses will be from about 0 . 1 to about 1000 mg / day , and more typically from about 50 to about 200 mg / day . such dosages will be administered to a subject in need thereof from once to about three times each day , or more often as needed to effectively treat the syndrome or at least one of its symptoms . it is usually preferred to administer a compound of formula i in the form of an acid addition salt , as is customary in the administration of pharmaceuticals bearing a basic group , such as the piperidino ring . it is also advantageous to administer such a compound by the oral route . for such purposes the following oral dosage forms are available . in the formulations which follow , &# 34 ; active ingredient &# 34 ; means a compound of formula i . ______________________________________ingredient quantity ( mg / capsule ) ______________________________________active ingredient 0 . 1 - 1000starch , nf 0 - 650starch flowable powder 0 - 650silicone fluid 350 centistokes 0 - 15______________________________________ the ingredients are blended , passed through a no . 45 mesh u . s . sieve , and filled into hard gelatin capsules . examples of specific capsule formulations of raloxifene that have been made include those shown below : ______________________________________ingredient quantity ( mg / capsule ) ______________________________________raloxifene 1starch , nf 112starch flowable powder 225 . 3silicone fluid 350 centistokes 1 . 7______________________________________ ______________________________________ingredient quantity ( mg / capsule ) ______________________________________raloxifene 5starch , nf 108starch flowable powder 225 . 3silicone fluid 350 centistokes 1 . 7______________________________________ ______________________________________ingredient quantity ( mg / capsule ) ______________________________________raloxifene 10starch , nf 103starch flowable powder 225 . 3silicone fluid 350 centistokes 1 . 7______________________________________ ______________________________________ingredient quantity ( mg / capsule ) ______________________________________raloxifene 50starch , nf 150starch flowable powder 397silicone fluid 350 centistokes 3 . 0______________________________________ the specific formulations above may be changed in compliance with the reasonable variations provided . ______________________________________ingredient quantity ( mg / tablet ) ______________________________________active ingredient 0 . 1 - 1000cellulose , microcrystalline 0 - 650silicon dioxide , fumed 0 - 650stearate acid 0 - 15______________________________________ alternatively , tablets each containing 0 . 1 - 1000 mg of active ingredient are made up as follows : ______________________________________ingredient quantity ( mg / tablet ) ______________________________________active ingredient 0 . 1 - 1000starch 45cellulose , microcrystalline 35polyvinylpyrrolidone 4 ( as 10 % solution in water ) sodium carboxymethyl cellulose 4 . 5magnesium stearate 0 . 5talc 1______________________________________ the active ingredient , starch , and cellulose are passed through a no . 45 mesh u . s . sieve and mixed thoroughly . the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a no . 14 mesh u . s . sieve . the granules so produced are dried at 50 °- 60 ° c . and passed through a no . 18 mesh u . s . sieve . the sodium carboxymethyl starch , magnesium stearate , and talc , previously passed through a no . 60 u . s . sieve , are then added to the granules which , after mixing , are compressed on a tablet machine to yield tablets . suspensions each containing 0 . 1 - 1000 mg of medicament per 5 ml dose are made as follows : ______________________________________ingredient quantity ( mg / 5 ml ) ______________________________________active ingredient 0 . 1 - 1000 mgsodium carboxymethyl cellulose 50 mgsyrup 1 . 25 mgbenzoic acid solution 0 . 10 mlflavor q . v . color q . v . purified water to 5 ml______________________________________ the medicament is passed through a no . 45 mesh u . s . sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste . the benzoic acid solution , flavor , and color are diluted with some of the water and added , with stirring . sufficient water is then added to produce the required volume . in the examples illustrating the methods , a post - menopausal model was used in which effects of different treatments upon circulating lipids were determined . seventy - five day old female sprague dawley rats ( weight range of 200 to 225 g ) were obtained from charles river laboratories ( portage , mich .). the animals were bilaterally ovariectomized ( ovx ) charles river laboratories , and shipped after one week . upon arrival , they were housed in metal hanging cages in groups of 3 or 4 per cage and had ad libitum access to food ( calcium content approximately 0 . 5 %) and water for one week . room temperature was maintained at 22 . 2 ± 1 . 7 ° c . with a minimum relative humidity of 40 %° the photoperiod in the room was 12 hours light and 12 hours dark . after a one week acclimation period ( therefore , two weeks post - ovx ) daily dosing with test compound ( raloxifene ) was initiated . zearanol and the test compound were given orally in a 20 % cyclodextrin vehicle . animals were dosed daily for 4 days . following the dosing regimen , animals were weighed and anesthetized with a ketamine : xylazine ( 2 : 1 , v : v ) mixture and a blood sample was collected by cardiac puncture . the animals were then sacrificed by asphyxiation with co 2 , the uterus was removed through a midline incision , and a wet uterine weight was determined . blood samples were allowed to clot at room temperature for 2 hours , and serum was obtained following centrifugation for 10 minutes at 3000 rpm . serum cholesterol was determined using a boehringer mannhelm diagnostics high performance cholesterol assay . briefly the cholesterol was oxidized to cholest - 4 - en - 3 - one and hydrogen peroxide . the hydrogen peroxide was then reacted with phenol and 4 - aminophenazone in the presence of peroxidase to produce a p - quinone imine dye , which was read spectrophotemetrically at 500 nm . cholesterol concentration was then calculated against a standard curve . the entire assay was automated using a biomek automated workstation . uteri were kept at 4 ° c . until time of enzymatic analysis . the uteri were then homogenized in 50 volumes of 50 mm tris buffer ( ph -- 8 . 0 ) containing 0 . 005 % triton x - 100 . upon addition of 0 . 01 % hydrogen peroxide and 10 mm o - phenylenediamine ( final concentrations ) in tris buffer , increase in absorbance was monitored for one minute at 450 nm . the presence of eosonophils in the uterus is an indication of estrogenic activity of a compound . the maximal velocity of a 15 second interval was determined over the initial , linear portion of the reaction curve . as demonstrated in table 1 , the example environmental estrogen , zearanol , produced a three - fold increase in uterine wet weight and led to a significant increase in uterine eosinophilia ( epo vmax for ovx controls was 4 mod / min ) and a reduction in serum cholesterol . each of these activities are qualitatively similar to those produced by estrogenic drugs ( i . e . 17α ethynyl - estradiol ) in this assay system . the test compound when given in combination with zearanol , bllunted the uterine stimulatory and cholesterol reducing activity of the environmental estrogen . at dose levels of 10 mg / kg , both test compounds led to significant attenuation of zearanol induced uterine weight stimulation , uterine epo elevation and serum cholesterol reduction . table i______________________________________ uterine serum wt . cholesterol (% ↑ vs uterine (% ↓ vs . ovx epo ovx control ) ( vmax ) control ) ______________________________________zearanol ( 10 mg / kg ) 200 . 5 403 . 8 82 . 8zearanol 10 mg / kg + test 189 . 2 429 . 6 77 . 7cmpd . ( 0 . 1 mg / kg ) zearanol 10 mg / kg + test 202 . 2 360 . 3 66 . 2cmpd . ( 1 mg / kg ) zearanol 10 mg / kg + test 91 . 2 177 . 9 52 . 4cmpd . ( 10 mg / kg ) 17 α - ethynylestradiol 109 . 2 177 . 9 86 . 4 ( 0 . 1 mg / kg ) ______________________________________ between 5 and 40 individuals with known exposure to an environmental estrogen who present symptomatology ( i . e . cancer , gynocomostia , decreased sperm count ) are used . the individuals are treated with a compound of formula i for between four and twelve months , during which time the effects of the environmental estrogen are measured for regression . utility of the compounds of the invention is illustrated by the impact they have on the effects of environmental estrogens when used in one of the studies above . between 5 and 40 individuals with known exposure to an environmental estrogen who present symptomatology ( i . e . cancer , gynocomostia , decreased sperm count ) are used . the individuals are treated with a compound of formula i for between four and twelve months , during which time the effects of the environmental estrogen are measured for regression . utility of the compounds of the invention is illustrated by the impact they have on the effects of environmental estrogens when used in one of the studies above .
a method of inhibiting effects of environmental estrogens comprising administering to a human or other animal in need thereof an effective amount of a compound having the formula ## str1 ## wherein r 1 and r 3 are independently hydrogen , - ch 3 , ## str2 ## wherein ar is optionally substituted phenyl ; r 2 is selected from the group consisting of pyrrolidine , hexamethyleneamino , and piperidino ; or a pharmaceutically acceptable salt of solvate thereof .