Note: Descriptions are shown in the official language in which they were submitted.
WO 98/09619101520253035CA 02264943 1999-03-05PCT/US97/15475NVL DSFigld of the InventionThe present invention relates to therapeutic agents that are tissue selectiveestrogen agonist/antagonist compounds that have been found to be useful in thetreatment and prevention of cardiovascular disease in postmenopausal women.Background of the InventionThe decrease in estrogen that occurs at the menopause is an importantetiological factor in the increased incidence of cardiovascular disease inpostmenopausal women. Estrogen therapy after the menopause has been shown tohave beneï¬cial effects on a number of independent risk factors for cardiovasculardisease including serum levels of LDL-cholesterol and lipoprotein (a) (lp(a)) andplasma levels of fibrinogen. For references please see Levenson J et al. (1995),Arterioscler Thromb Vasc Biol, 15, 1263-1268. Kroon et al (1994), Thomb Hemost,71, 420-423. Ettinger B (1990) Obstet Gynecol Clinics of North America, 17, 741-757. Mendoza S et al (1994) J Lab Clin Med 123, 837-841. These effects mayexplain in part the epidemiological observations that estrogen therapy causes areduction in the incidence of cardiovascular disease. However unopposed estrogengiven alone increases the risk of endometrial cancer and may also be associated withan increased risk of breast cancer. For these reasons and because of troublesomeside effects (principally breast tenderness and vaginal bleeding) few womencontinue HRT for long enough to benefit from the cardioprotective effects. An idealtherapy would retain the desirable cardiovascular effects of estrogen without havingthe unwanted effects on reproductive tissues. Consequently, efforts have been madeto identify compounds that have tissueâselective estrogen agonist or antagonistproperties. Such tissue selective effects could produce the beneficial effects ofestrogen on risk factors for cardiovascular disease without the unwanted effects inbreast and uterine tissue.Summg 9f the InventionThis invention provides a method for the prevention and treatment ofcardiovascular disease in postmenopausal women without having an overtuterotrophic effect, or promoting an increased risk of breast cancer or causing anincreased incidence of vaginal bleeding and breast tenderness. The methodcomprises administering to a human in need thereof an effective amount of acompound of formula I-1-CA 02264943 1999-03-05WO 98/09619 PCTIUS97/15475(1)wherein X represents 3- or 4- iodo or bromo and the R1 and R2 symbols, which may5 be the same or different. represent C 1-3 alkyl, especially methyl or ethyl, groups orR1 represents a hydrogen atom and R2 a C 1_3 alkyl group or R1 and R2 togetherwith the nitrogen atom to which they are attached represent a saturated heterocyclicgroup, typically having 5 or 6 ring atoms, especially a pyrrolidino, piperidino, 4-methylpiperidino or morpholino group, and their pharmaceutically acceptable acid10 addition salts.Detailed Description of the InventionThe present invention is a therapeutic method for preventing and treatingcardiovascular disease in postmenopausal women with a group of compounds that15 have been previously prepared and evaluated as effective in the treatment of estrogenreceptor-positive breast cancer. These compounds are described in formula I aboveand in U.S. patent 4,839,155.The preferred compound for the described method of treatment isOK0 O "O OI(E)- l-{2-[4-[ l-(4-lodophenyl)-2-phenyl-1-butenyl]phenoxy]pyrrolidine20Such compounds are known to bind to the estrogen receptor and to cause25 either estrogen agonist or antagonist effects depending on the tissue being studied.A beneficial effect on cardiovascular disease would be produced by estrogen agonist-3-10152025WO 98109619CA 02264943 1999-03-05PCTIUS97/15475effects on the liver ( to alter the lipid proï¬le and levels of fibinogen). Howeverestrogen agonist effects on the arterial wall may also contribute to a reduction in therisk of cardiovascular disease.The term "cardiovascular disease" refers to atherosclerotic cardiovasculardiseases such as myocardial infarction, stroke. angina. intermittent claudicationtransient blindness. transient ischernic attacks (TIA) and peripheral vascular disease.The method of this invention is useful in producing a plasma lipid profile that isassociated with a reduced risk of atherosclerosis and a reduction of raised LDLcholesterol levels Additionally this method is useful in producing a reduction ofother independent cardiovascular risk factors such as plasma fibrinogen levels andserum levels of lp(a).The ability to reduce the risk of cardiovascular disease is assessed by studiesof the effect of idoxifene a number of different risk factors for cardiovascular diseasein postmenopausal women. These include different parameters of the lipid profileand levels of coagulation and fibrinolysis markers.Three different doses of idoxifene (2.5. 5 and 10mg/day) were comparedwith placebo in a study of three months duration in postmenopausal women.Changes in the levels of different lipid parameters, fibiinogen and othercoagulation/ï¬brinolysis parameters were measured before and after treatment. Theresults of this study are described below. All changes are described as percentagechange from the baseline value. Statistically significant differences from placeboare designated by the following notation: *=p<0.01, **=p<0.001.Placebo 2.5 5.0 10.0Total chol 0.5 (1.1) -0.9 (1.1) -4.2 (1.2)* -9.8 (l.l)**LDL-chol 1.3 (1.5) -1.3 (2.0) -4.7 (1.7)* -15.2 (1.6)**HDL-chol 2.4 (1.4) 2.7 (1.5) -1.4 (1.5) 0.8 (1.7)HDL/LDL ratio 2.2 (1.6) 7.1 (2.6) 5.2 (2.1) 21.7 (3.1)**lipoprotein (a) 5.0 (3.0) -2.0 (6.0) 1.0 (4.0) -6.0 (4.0)triglycerides 1.3 (3.8) 1.8 (3.9) -3.2 (3.6) 3.8 (3.8)Fibrinogen 5.8 (3.0) -1.7 (2.4) -8.3 (3.l)* -16.9 (2.4)**Dâdimer 0.0 (3.1) 4.7 (4.3) -2.1 (2.7) -7.1 (2.7)Factor VII 5.4 (2.4) -10.1(2.4)** -9.6 (2.1)** -11.1 (l.6)**-3-W0 98/09619l0I520253035CA 02264943 1999-03-05PCT/US97/15475In the same study the incidence of vaginal bleeding and breast tendernesswas reduced compared to placebo and there were no cases of histologically deï¬nedendometrial hyperplasia in idoxifene treated patients as compared to one case in theplacebo cohort.These results show that in humans idoxifene is able to produce the desiredbeneï¬cial effects of estrogen on cardiovascular risk factors without the undesirableeffects on reproductive tissues.The compounds of the instant invention and their pharmaceuticallyacceptable salts which are active when given orally can be formulated as liquids. forexample syrups. suspensions or emulsions. tablets, capsules and lozenges.A liquid formulation will generally consist of a suspension or solution of thecompound or pharmaceutically acceptable salt in a suitable liquid carrier(s) forexample, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol,oils, or water with a suspending agent. preservative, ï¬avoring or coloring agent.A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solid formulations. Examplesof such carriers include magnesium stearate. starch, lactose, sucrose and cellulose.A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example. pellets containing the active ingredient canbe prepared using standard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using any suitablepharmaceutical carrier(s). for example aqueous gums. celluloses, silicates or oils andthe dispersion or suspension then filled into a soft gelatin capsule.The compounds of the instant invention and their pharmaceuticallyacceptable salts which are active when administered parenterally (i.e. by injection ofinfusion) can be formulated as solutions or suspensions.A composition for parenteral administration will generally consist of asolution or suspension of the active ingredient in a sterile aqueous carrier orparenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone.lecithin. arachis oil or sesame oil. Alternatively, the solution can be lyophilised andthen reconstituted with a suitable solvent just prior to administration.A typical suppository composition comprises a compound of the instantinvention or a pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent such as polymeric-4-WO 98/09619 â1015202530CA 02264943 1999-03-05PCT/US97/ 15475glycols. gelatins or coca butter or other low melting vegetable or synthetic waxes orfats.A typical transderrnal formulation comprises a conventional aqueous or non-aqueous vehicle. for example. a cream. ointment lotion or paste or in the form of amedicated plaster. patch or membrane.For topical administration, the pharmaceutical compositions adapted includesolutions, suspensions, ointments. and solid inserts. Typical pharmaceuticallyacceptable carriers are, for example, water. mixtures of water and waterâmisciblesolvents such as lower alkanols or vegetable oils. and water solubleophthalmologically acceptable nonâtoxic polymers, for example, cellulosederivatives such as methyl cellulose. The pharmaceutical preparation may alsocontain non-toxic auxiliary substances such as emulsifying, preserving, wetting andbodying agents. as for example, polyethylene glycols; antibacterial components suchas quaternary ammonium compounds; buffering ingredients such as alkali metalchloride; antioxidants such as sodium rnetabisulfite; and other conventionalingredients such as sorbitan monolaurate.Preferably the composition is in unit dose form. Doses of the compounds ofthe instant invention in a pharmaceutical dosage unit will be an efï¬cacious, non-toxic quantity selected from the range of .01 - 200 mg/kg of active compound,preferably .1 - 100 mg/kg. The selected dose is administered to a human patient inneed of treatment or prevention of cardiovascular disease is or in the lowering ofplasma cholesterol from 1-6 times daily, orally, rectally, topically, by injection. orcontinuously by infusion. Oral dosage units for human administration preferablycontain from 10 to 500 mg of active compound. Lower dosages are used generallyfor parenteral administration. Oral administration is used when safe, effective. andconvenient for the patient.No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the present invention.Example lAn oral dosage form for administering orally active Formula (1) compoundsis produced by screening, mixing and filling into hard gelatin capsules theingredients in proportions, for example, as shown below.CA 02264943 1999-03-05WO 98/09619 PCT/US97/ 15475Ingredients Amounts(E)-1-[2-[4-[l-(4-lodophenyl)-2-phenyl-1-butenyl]phenoxyjpyrrolidine 100 mgmagnesium stearate 10 mg5 lactose 100 mgExample 2The sucrose calcium sulfate dihydrate and orally active Formula (1)compounds are mixed and granulated with a 10% gelating solution. The wetl0 granules are screened, dried. mixed with the starch, talc and stearic acid, screenedl5and compressed into a tablet.Ingredients Amounts(E)- l-[2-[4-[1-(4-lodophenyl)-2-phenyl- l-butenyl]phenoxy]pyrrolidine 75 mgcalcium sulfate dihydrate , 100 mgsucrose 15 mgstarch 8 mgtalc 4 mg20 steanc acid 2 mgExa e 3(E)-l-[2-[4-[1-(4-lodophenyl)-2-phenyl-l-butenyl]phenoxy]pyrrolidine, 50mg, is dispersedin 25 ml of normal saline to prepare an injectable preparation.
