US 2004O152713A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0152713 A1 Petrie (43) Pub. Date: Aug. 5, 2004

(54) METHODS FORTREATING JOINT PAIN OR (52) U.S. Cl...... 514/266.2, 514/310; 514/314; IMPROVING SLEEP USING AN ESTROGEN 514/256 AGONISTIANTAGONIST (57) ABSTRACT (75) Inventor: Charles D. Petrie, Cranston, RI (US) The present invention provides methods, pharmaceutical Correspondence Address: compositions and kits for treating joint pain and/or improv PFIZER INC. ing sleep using a SERM of formula (I): PATENT DEPARTMENT, MS8260-1611 EASTERN POINT ROAD

GROTON, CT 06340 (US) (I) (73) Assignee: Pfizer Inc. (21) Appl. No.: 10/761,672 (22) Filed: Jan. 21, 2004 Related U.S. Application Data (60) Provisional application No. 60/441,830, filed on Jan. 22, 2003. Publication Classification wherein the variables A, B, D, E, e, G, Y and Z are as (51) Int. Cl.' ...... A61K 31/517; A61K 31/4709 defined in the Specification. US 2004/0152713 A1 Aug. 5, 2004

METHODS FOR TREATING JOINT PAIN OR ceSS is associated with changes to an individual's circadian IMPROVING SLEEP USING AN ESTROGEN and diurnal rhythms. With increasing age the total amount of AGONISTIANTAGONIST Sleep tends to shorten and the amount of deep sleep can decrease or disappear. Sleep may become more fragmented FIELD OF THE INVENTION and interrupted for the elderly and these changes with timing 0001. This invention relates to methods for treating joint and Structure of Sleep are often associated with Significant pain and/or improving sleep using an estrogen agonist/ morbidity. Similarly, non-elderly individuals may also antagonist also known as Selective estrogen receptor modu exhibit disturbances in the normal Sleep process. These lators (hereinafter referred to as SERMs). The invention also disturbances in the normal Sleep process have been corre relates to pharmaceutical compositions useful for improving lated with more frequent napping, decreased daytime alert Sleep. neSS and declining intellectual function and cognitive ability. 0006 For individuals suffering from a sleep disorder the BACKGROUND OF THE INVENTION normal Sleep cycle is also disrupted. The Sleep disorder 0002 Almost all persons by age forty have some patho generally affects the afflicted individual’s ability to fall logical change in weight bearing joints. Men and women are and/or stay asleep, and involve Sleeping too little, Sleeping equally affected, but onset is earlier in men. Joint cartilage, too much or resulting in abnormal behavior associated with also called hyaline cartilage, is made up of 95% water and Sleep. There are numerous types of Sleep disorders with the extracellular matrix and 5% chondrocytes. The extracellular International Classification of Sleep Disorders having over matrix comprises proteoglycans and Type II collagen. Joint Seventy Sleep disorders listed. Sleep disorders, Such as pain can result from various progressive diseases as well as various types of dySSomnias and parasomnias, can lead to a various acute conditions related to the joints. Typical Symp lowered quality of life and reduced personal health for those tomatic treatment of joint pain includes the management of afflicted with them. Sleep disorders can also endanger public pain by administration of medicaments and changes in Safety by contributing to traffic and industrial accidents. In lifestyle Such as diet and exercise. certain instances the sleep disorder can be life threatening. 0.003 Examples of compounds that have been used to 0007 Examples of current drugs used to improve sleep treat joint pain include nonsteroidal anti-inflammatory drugs include those that act as hypnotic Sedatives and that may also (NSAIDs), Such as aspirin, acetominophen, ibuprofen, act as anxiolytics. BenZodiazepines, which act as anxiolytics naproxen, ketoprofen, nabumetone, etodolac, Salsalate, and are also useful for inducing Sleep, enhance the effect of Sulindac, diclofenac, tolmetin, flurbiprofen, piroXicam, the inhibitory neurotransmitter gamma-aminobutyric acid fenoprofen, indomethacin, meclofenamate, Oxaprozin, (GABA). Benzodiazepines, Such as diazepam (Valium(E)) diflunisal and ketorolac, and Selective cyclooxygenase-2 and temazepam (RestorilE), are used as sleeping pills. (COX-2) inhibitors such as 4-5-(4-methylphenyl)-3-(trif Triazolam and estazolam are also used to induce Sleep. luoromethyl)-1H-pyrazol-1-ylbenzenesulfonamide (cele Zolpidem, including its tartrate Salt, is used to induce Sleep coxib), 4-4-(methylsulfonyl)phenyl)-3-phenyl-2(5H)-fura and acts by a mechanism similar to the benzodiazepines. none (rofecoxib), Valdecoxib and etoricoxib. NSAIDs can Over the counter remedies used to induce Sleep include have unwanted side effects Such as ulcers, therefore NSAIDs preparations containing antihistamines, Such as diphenhy are Sometimes administered with other compounds that dramine. Sedative antidepressants Such as amitryptyline and ameliorate the side effects of the NSAIDs. Typical com traZodone have also been used as Sleep inducing agents. pounds that are used in combination with NSAIDs include Dopaminergic agents Such as levodopa/carbidopa, bro proton pump inhibitorS Such as omeprazole; antacids Such as mocriptine meSylate and pergolide, and opiods Such as Sucralfate; and H2 blockerS Such as ranitidine, cimetidine, codeine, propoxyphene, oxycodone, pentazocrine, hydroc famotidine, and nizatidine. In addition, products derived odone and methadone have also been used as Sleep inducing from natural Substances have been used to treat various agents. The known therapeutic regimens Suffer from numer types of joint pain. Examples of natural Substances include ous problems, including residual effects in daytime function, hyaluronic acid, glucosamine, chondroitin Sulfate and cap impairment of memory, potential for addiction or rebound Saicin. Intraarticular corticosteriods have also been used to insomnia which may be associated with increased dream treat joint pain. intensity and the occurrence of nightmares and the like. There is a continuing need for new methods of improving 0004) The use of SERMs, such as those of formula I, for Sleep in patients in need thereof. the treatment of osteoarthritis has been disclosed in U.S. patent application Publication No. 2001-0041718A1. The 0008. It has been found that the SERMs of Formula (I), use of SERMs, such as those of formula I, for the treatment described hereinafter, are useful in the treatment of joint pain of rheumatoid arthritis has been disclosed in U.S. patent and/or in improving Sleep. The present invention provides application Publication No. 2002-0049198A1. There is a methods of treating or preventing joint pain and/or improv continuing need for new methods of treating joint pain in ing sleep using a SERM of Formula (I). patients Suffering from or at risk of Suffering from joint pain. SUMMARY OF THE INVENTION 0005 Sleep is a complex process with many parts of the nervous System being involved in controlling it and influ 0009. The present invention provides methods of treating encing its different Stages. The Stages or levels of Sleep joint pain and/or improving sleep, the methods comprising include drowsiness, light sleep, deep sleep and dream Sleep. administering to a patient in need thereof, a therapeutically Individuals vary widely in their requirements for Sleep, effective amount of a SERM. A first embodiment of the which is influenced by a variety of factors including the present invention is the method of treating joint pain and/or individual's current emotional State. The natural aging pro improving Sleep, the method comprising administering to a US 2004/0152713 A1 Aug. 5, 2004

patient in need thereof, a therapeutically effective amount of 0027) G is a SERM of formula (I): 0028) (a)-NR'R';

(I) (b)b y CH2)m- \ -N 72 V

0029 wherein n is 0, 1 or 2; m is 1, 2 or 3; Z is -NH-, -O-, -S-, or -CH2-, optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three sub Stituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R"; or 0030) (c) a bicyclic amine containing five to 0010) wherein: twelve carbon atoms, either bridged or fused and 0.011) A is selected from CH and NR; optionally substituted with 1-3 substituents inde 0012 B, D and E are independently selected from pendently selected from R"; or CH and N: 0031 Z' and G in combination may be 0013 Y is 0014 (a) phenyl, optionally substituted with 1-3 R2 Substituents independently selected from R"; 0015 (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R"; 0016 (c) C-C cycloalkyl, optionally substituted with 1-2 substituents independently selected from R; 0032) W is 0017 (d) C-C cycloalkenyl, optionally substi 0033) (a) -CH-; tuted with 1-2 substituents independently selected 0034 (b) -CH=CH-; from R"; 0035) (c) -O-; 0018 (e) a five membered heterocycle containing up to two heteroatoms Selected from the group 0036) (d) -NR-; consisting of -O-, -NR- and -SO), , 0037 (e) -S(O) ; optionally substituted with 1-3 substituents inde pendently selected from R"; 0019 (f) a six membered heterocycle containing (f) O| up to two heteroatoms Selected from the group consisting of -O-, -NR- and -SO), optionally substituted with 1-3 substituents inde pendently selected from R"; or 0038 (g) –CR(OH)–: 0020 (g) a bicyclic ring system consisting of a 0039) (h)-CONR-; five or six membered heterocyclic ring fused to a phenyl ring, Said heterocyclic ring containing up 0040 (i) –NRCO-; to two. heteroatoms Selected from the group con sisting of -O-, -NR- and -SO), , optionally substituted with 1-3 substituents inde () . pendently selected from R"; 0021 Z is 0022) (a)-(CH), W(CH.) : 0041 or 0023) (b) –O(CH.), CRR-. 0042) (k) -C=C-;

0024) (c)-O(CH), W(CH), ; 0043 R is hydrogen or C-C1. 6 alkyl; 0025) (d) –OCHRCHR-; or 00441 R and Rare independentlp y 0026 (e) –SCHRCHR-; 0045 (a) hydrogen; or US 2004/0152713 A1 Aug. 5, 2004

0046) (b) C-C alkyl; 0083) q is 0, 1, 2 or 3; 0047 R is 0084 or an optical or geometric isomer thereof; or a 0048 (a) hydrogen; pharmaceutically acceptable Salt, N-oxide, ester, quaternary ammonium Salt or prodrug thereof. 0049) (b) halogen; 0085. A second embodiment of the present invention is 0050 (c) C-C alkyl; the method of treating joint pain and/or improving sleep, the 0051) (d) C-C alkoxy; method comprising administering to a patient in need thereof, a therapeutically effective amount of a SERM of 0052 (e) C-C acyloxy; formula (IA) 0053 (f) C-C alkylthio; 0054 (g) C-C alkylsulfinyl; (IA) OCH2CHG 0055 (h) C-C alkylsulfonyl; 0056 (i) hydroxy (C-C)alkyl; 0057) () aryl (C-C)alkyl; 0058 (k) -COH; 0059) (I)-CN: 0060 (m) –CONHOR; 0061 (n) -SONHR; 0062 (o) -NH; 0063 (p) C-C alkylamino; 0.086 wherein G is 0064 (q) C-C dialkylamino; 0065 (r) –NHSOR; 0066 (s) -NO; 0067 (t) -aryl; or 0068 (u) –OH: 0069 R and R are independently C-C alkyl or 0087) R' is H, OH, F, or Cl; and B and E are indepen together form a C-C carbocyclic ring; dently selected from CH and N or an optical or geometric 0070 R7 and Rare independently isomer thereof, or a pharmaceutically acceptable Salt, N-OX 0071 (a) phenyl; ide, ester, quaternary ammonium Salt, or a prodrug thereof. 0088 A third embodiment of the present invention is the 0072 (b) a C-C carbocyclic ring, saturated or method of treating joint pain and/or improving Sleep, the unsaturated; method comprising administering to a patient in need 0073 (c) a C-Co heterocyclic ring containing up thereof, a therapeutically effective amount of (-)-cis-6- to two heteroatoms, selected from -O-, -N- phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tet and -S-; rahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable Salt, N-oxide, ester, 0074) (d) H; quaternary ammonium Salt, or a prodrug thereof. 0075 (e) C-Calkyl; or 0089. A fourth embodiment of the present invention is the 0076 (f) form a 3 to 8 membered nitrogen con method of treating joint pain and/or improving Sleep, the taining ring with R or R'; method comprising administering to a patient in need thereof, a therapeutically effective amount of the D-tartrate 0.077 R7 and R in either linear or ring form may Salt of (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)- optionally be substituted with up to three substitu phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol. ents independently selected from C-C alkyl, halo gen, alkoxy, hydroxy and carboxy, 0090 Another embodiment of the present invention is the method of treating joint pain, the method comprising admin 00781 a ring9. formed bwy R7 and Rimavy be optionallp y istering to a patient in need thereof a therapeutically effec fused to a phenyl ring, tive amount of a first compound and a therapeutically e is 0, 1 or 2; effective amount of a Second compound. The first compound 0079 is a SERM as described in any of the first through fourth 0080 m is 1, 2 or 3; embodiments above. The Second compound is Selected from the group consisting of acetominophen, aspirin, ibuprofen, 0081 n is 0, 1 or 2; naproxen, ketoprofen, nabumetone, etodolac, Salsalate, 0082 p is 0, 1, 2 or 3; Sulindac, diclofenac, tolmetin, flurbiprofen, piroXicam, US 2004/0152713 A1 Aug. 5, 2004 fenoprofen, indomethacin, meclofenamate, Oxaprozin, mecloqualone, melatonin, mephobarbital, meprobamate, diflunisal, ketorolac, celecoxib, rofecoxib, Valdecoxib, etori methadone, methaqualone, midaflur, midazolam, nefaz coxib, hyaluronic acid, glucosamine, chondroitin and cap odone, nisobamate, nitrazepam, nortriptyline, oxazepam, Saicin. The joint pain referred to in the present methods is Oxycodone, paraldehyde, paroxetine, pentazocrine, pento not joint pain resulting from Osteoarthritis or rheumatoid barbital, pergolide, perlapine, perphenazine, phenelZine, arthritis. A preferred first compound in the combination phenobarbital, prazepam, promethazine, propofol, pro method of treating joint pain is (-)-cis-6-phenyl-5-4-(2- poxyphene, protryptyline, quazepam, reclazepam, roleta pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naph mide, Secobarbital, Sertraline, Suproclone, temazepam, thior thalene-2-ol, D-tartrate Salt. Preferred Second compounds in idazine, tracazolate, tranylcypromaine, traZodone, the combination method of treating joint pain include cele triazolam, trepipam, tricetamide, triclofoS, trifluoperazine, coxib, rofecoxib, Valdecoxib and etoricoxib. trimetozine, trimipramine, uldazepam, Venlafaxine, Zale 0.091 Another embodiment of the present invention is the plon, Zolazepam, and Zolpidem, or pharmaceutically accept method of improving Sleep, the method comprising admin able salts thereof. A preferred form of (-)-cis-6-phenyl-5- istering a therapeutically effective amount of a first com 4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro pound and a therapeutically effective amount of a Second naphthalene-2-ol for use in the pharmaceutical composition compound. The first compound is a SERM as described in is its D-tartrate Salt. A preferred Second compound for use in any of the first through fourth embodiments above. The the pharmaceutical composition of this invention is Sertra Second compound is Selected from the group consisting of line, or its hydrochloride Salt. adinazolam, allobarbital, alonimid, alprazolam, amitryp 0093. The present invention also provides kits for use by tiline, amobarbital, amoxapine, bentazepam, benzoctamine, a consumer to treat joint pain and/or to improve Sleep, the bromocriptine, brotizolam, bupropion, buSpirone, butabar kits comprising: bital, butalbital, capuride, carbocloral, chloral betaine, chlo ral hydrate, chlordiazepoxide, clomipramine, cloperidone, 0094 (a) a pharmaceutical composition comprising cloraZepate, clore thate, clozapine, codeine, cyprazepam, a SERM as described in any of the first through desipramine, dexclamol, diazepam, dichloralphenaZone, fourth embodiments, above, and a pharmaceutically divalproex, diphenhydramine, doxepin, estazolam, ethchlo acceptable carrier, vehicle or diluent, and rVynol, etomidate, fenobam, flunitrazepam, flurazepam, flu Voxamine, fluoxetine, foSazepam, glutethimide, halazepam, 0.095 (b) instructions describing a method of using hydrocodone, hydroxy Zine, imipramine, lithium, lorazepam, the pharmaceutical composition to treat joint pain lormetazepam, maprotaline, mecloqualone, melatonin, and/or to improve Sleep. mephobarbital, meprobamate, methadone, methaqualone, 0096. In a preferred embodiment of the kits, the SERM is midaflur, midazolam, nefazodone, nisobamate, nitrazepam, (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5, nortriptyline, oxazepam, Oxycodone, paraldehyde, paroxet 6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric ine, pentazocrine, pentobarbital, pergolide, perlapine, per phenazine, pheneizine, phenobarbital, prazepam, promet isomer thereof, or a pharmaceutically acceptable Salt, N-OX hazine, propofol, propoxyphene, protryptyline, quazepam, ide, ester, quaternary ammonium Salt or a prodrug thereof. reclazepam, roletamide, Secobarbital, Sertraline, Suproclone, 0097. In another preferred embodiment of the kits, (-)- temazepam, thioridazine, tracazolate, tranylcypromaine, tra cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7, Zodone, triazolam, trepipam, tricetamide, triclofoS, trifluop 8-tetrahydro-naphthalene-2-ol is a D-tartrate Salt. erazine, trimetozine, trimipramine, uldazepam, Venlafaxine, Zaleplon, Zolazepam, Zolpidem and pharmaceutically DETAILED DESCRIPTION OF THE acceptable Salts thereof. A preferred first compound in the INVENTION combination method of improving sleep is (-)-cis-6-phenyl 0098. The terms “treat”, “treatment” and “treating” 5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro include preventative (e.g., prophylactic) and palliative treat naphthalene-2-ol, D-tartrate Salt. A preferred Second com ment or the act of providing preventative or palliative pound in the combination method of improving Sleep is treatment. In the present invention, these terms include the Sertraline and its hydrochloride Salt. amelioration of joint pain, which means the methods of the 0092 Another embodiment of the present invention is a present invention are effective in reducing the intensity of pharmaceutical composition comprising (-)-cis-6-phenyl-5- the joint pain. The term "pain' is used in the general Sense 4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro and is meant to encompass pain levels from the merely naphthalene-2-ol or a pharmaceutically acceptable Salt uncomfortable to the virtually unbearable. The term “joint thereof, and a Second compound Selected from the group pain' is used to identify pain in the joint areas of the afflicted consisting of adinazolam, allobarbital, alonimid, alpra patient, Such as, but not limited to, pain in the finger, toe, Zolam, amitryptiline, amobarbital, amoxapine, bentazepam, wrist, elbow, Shoulder, hip, knee or ankle joints. The term benzoctamine, bromocriptine, brotizolam, bupropion, bus “improving Sleep’ as used herein means enhancing or pirone, butabarbital, but albital, capuride, carbocloral, chlo improving Sleep quality, in particular by increasing Sleep ral betaine, chloral hydrate, chlordiazepoxide, clomi efficiency and augmenting sleep maintenance, as well as by pramine, cloperidone, cloraZepate, clore thate, clozapine, preventing and treating Sleep disorders and Sleep distur codeine, cyprazepam, desipramine, dexclamol, diazepam, bances in a patient. The term “improving Sleep” includes the dichloralphenaZone, divalproex, diphenhydramine, doxepin, following: an increase in the value which is calculated from estazolam, ethchlorVynol, etomidate, fenobam, fluni the time that a subject sleeps divided by the time that a trazepam, flurazepam, fluvoxamine, fluoxetine, foSazepam, Subject is attempting to Sleep; a decrease in Sleep latency, glutethimide, halazepam, hydrocodone, hydroxy Zine, imi i.e., the time it takes to fall asleep; a decrease in difficulties pramine, lithium, lorazepam, lormetazepam, maprotaline, in falling asleep; a decrease in the number of awakenings US 2004/0152713 A1 Aug. 5, 2004

during sleep; a decrease in nocturnal arousals, a decrease in the time spent awake following the initial onset of Sleep; an -continued (IA) increase in the total amount of sleep; and increase in the OCH2CH2G amount and percentage of rapid eye movement (REM) Sleep; an increase in the duration and occurrence of REM Sleep; a reduction in the fragmentation of REM sleep; an increase in the amount and percentage of Stage 2 Sleep; an enhancement of EEG-delta activity during sleep; a decrease in the number of awakenings, a decrease in nocturnal arousals, especially early morning awakenings, an increase in daytime alertness, an increased Satisfaction with the intensity of Sleep; and increased sleep maintenance. Sec ondary outcomes that may be provided by the present invention include enhanced cognitive function and increased memory retention. 0.103 the optical and geometric isomers thereof; and the nontoxic pharmacologically acceptable acid addition Salts, 0099. The term “patient’ means animals, particularly N-oxides, esters, quaternary ammonium Salts and prodrugs mammals. Preferred patients are humans. thereof, wherein the variables A, B, D, E, Y, Z, G and e are 0100. An “estrogen agonist/antagonist' is a compound as defined hereinabove for the compound of formula (I) and that affects Some of the Same receptors that estrogen does, the variables G, R", B and E are as defined hereinabove for but not all, and in Some instances, it antagonizes or blockS the compound of formula (IA). estrogen. Estrogen agonists/antagonistS may also be referred 0104 Especially preferred compounds used in the meth to as antiestrogens although they have Some estrogenic ods, compositions and kits of the invention are: cis-6-(4- activity at Some estrogen receptors. Estrogen agonists/an fluoro-phenyl)-5-4-(2-piperidin-1-yl-ethoxy)-phenyl-5,6, tagonists are therefore not what are commonly referred to as 7,8-tetrahydro-naphthalene-2-ol; (-)-cis-6-phenyl-5-4-(2- "pure antiestrogens'. Antiestrogens that can also act as pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro agonists are referred to as Type I antiestrogens. Type I naphthalene-2-ol; cis-6-phenyl-5-4-(2-pyrrolidin-1-yl antiestrogens activate the estrogen receptor to bind tightly in ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol; cis-1- the nucleus for a prolonged time but with impaired receptor 6'-pyrrolidinoethoxy-3-pyridyl-2-phenyl-6-hydroxy-1,2, 3,4-tetrahydronaphthalene, 1-(4-pyrrolidinoethoxyphenyl)- replenishment (Clark, et al., Steroids 1973:22:707, Capony 2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4- et al., Mol Cell Endocrinol, 1975;3:233). tetrahydroisoquioline; cis-6-(4-hydroxyphenyl)-5-4-(2- 0101 The SERMs used in the methods, compositions and piperidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro kits of the invention may be administered Systemically or naphthalene-2-ol; and 1-(4'-pyrrolidinoethoxyphenyl)-2- locally. For systemic use, the SERMs herein are formulated phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline and for parenteral (e.g., intravenous, Subcutaneous, intramuscu pharmaceutically acceptable Salts thereof. An especially lar, intraperitoneal, intranasal or transdermal) or enteral preferred salt of (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl (e.g., oral or rectal) delivery according to conventional ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol used methods. Intravenous administration can be by a Series of in the methods, compositions and kits of the present inven injections or by continuous infusion over an extended tion is (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)- period. Administration by injection or other routes of dis phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate. cretely spaced administration can be performed at intervals 0105. Other SERMs that can be used in the methods, ranging from weekly to once to three or more times daily. compositions and kits of the present invention are disclosed 0102) The compounds of formula (I) and formula (IA) in U.S. Pat. No. 5,047,431, including droloxifene. used in the methods, compositions and kits of the present 0106 Additional SERMs that can be used in the methods, invention are described in U.S. Pat. No. 5,552,412. Those compositions and kits of the present invention are tamox compounds are described by the formulae designated herein ifen. (ethanamine, 2--4-(1,2-diphenyl-1-butenyl)phenoxy as formula (I) and (IA) given below: N,N-dimethyl, (Z)-2-, 2-hydroxy-1,2,3-propanetricarboxy late(1:1)) and other compounds as disclosed in U.S. Pat. No. 4,536,516, 4-hydroxytamoxifen (i.e., tamoxifen wherein the (I) 2-phenyl moiety has a hydroxy group at the 4 position) and other compounds as disclosed in U.S. Pat. No. 4,623,660; raloxifene: (methanone, 6-hydroxy-2-(4-hydroxyphenyl )benzobthien-3-yl 4-2-(1 -piperidinyl)ethoxyphenyl-, hydrochloride) and other compounds as disclosed in U.S. Pat. Nos. 4,418,068; 5,393,763; 5.457,117; 5,478,847 and 5,641,790; toremifene: (ethanamine, 2-4-(4-chloro-1,2- diphenyl-1-butenyl)phenoxy-N,N-dimethyl-, (Z)-, 2-hy droxy-1,2,3-propanetricarboxylate (1:1) and other com pounds as disclosed in U.S. Pat. Nos. 4,696,949 and 4,996, 225; centchroman: 1-2-4-(-methoxy-2.2, dimethyl-3- phenyl-chroman-4-yl)-phenoxy-ethyl-pyrrolidine and US 2004/0152713 A1 Aug. 5, 2004

other compounds as disclosed in U.S. Pat. No. 3,822,287; of (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phe idoxifene: pyrrolidine, 1-I-4-1-(4-iodophenyl)-2-phenyl nyl-5,6,7,8-tetrahydro-naphthalene-2-ol is the D-(-)-tar 1-butenylphenoxyethyl and other compounds as disclosed trate salt. On the other hand, if the compound used in the in U.S. Pat. No. 4,839,155; arzoxifene, 6-hydroxy-3-(4-2- methods, compositions and kits of this invention is desired (piperidin-1-yl)ethoxy)-phenoxy)-2-(4-methoxyphenyl in the free base form, it is isolated from a basic final wash )benzobthiophene hydrochloride, and other compounds as Step, according to the usual practice. Likewise, pharmaceu disclosed in U.S. Pat. No. 5,723,474, 6-(4-hydroxy-phenyl)- tically-acceptable cationic Salts are conveniently formed, as 5-4-(2-piperidin-1-yl-ethoxy)-benzyl-naphthalen-2-ol and is usual in organic chemistry, by reacting the compound used other compounds as disclosed in U.S. Pat. No. 5,484,795; in the methods, compositions and kits of this invention with and {4-2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl a Suitable base. The Salts are quickly formed in high yields I6-hydroxy-2-(4-hydroxy-phenyl)-benzobthiophen-3-yl)- at moderate temperatures, and often are prepared by merely methanone and other compounds as disclosed in published isolating the compound from a Suitable basic wash as the international patent application WO95/10513. Other pre final Step of the Synthesis. The Salt-forming base is dissolved ferred compounds include GW 5638 and GW 7604. The in an appropriate organic Solvent, or aqueous organic Sol synthesis of these compounds is described in Willson et al., vent, Such as an alkanol, ketone or ester. It will also be J. Med. Chem., 1994:37: 1550-1552. recognized that it is possible to administer an amorphous 0107 Further SERMs that can be used in the methods, form of a SERM. compositions and kits of the present invention include 0110. One of ordinary skill in the art will recognize that EM-652 and EM-800. The synthesis of EM-652 and certain SERMs used in the methods, compositions and kits EM-800 and the activity of various enantiomers is described of this invention will contain one or more atoms which may in Gauthier et al., J. Med. Chem., 1997:40:2117-2122. be in a particular Stereochemical, tautomeric, or geometric Further SERMs that can be used in the methods of the configuration, giving rise to Stereoisomers, tautomers and present invention include baZedoxifene (TSE 424) and other configurational isomers. All Such tautomers and isomers and compounds disclosed in U.S. Pat. No. 5,998,402, U.S. Pat. mixtures thereof are included in this invention. Hydrates and No. 5,985,910, U.S. Pat. No. 5,780,497, U.S. Pat. No. Solvates of the SERMs used in the methods, compositions 5,880,137, U.S. Pat. No. 5,998,402, U.S. Pat. No. 6,127,404, and kits of this invention are also included. U.S. Pat. No. 6,225,308, U.S. Pat. No. 6,232,307, U.S. Pat. 0111. The methods, compositions and kits of this inven No. 6,291,451, U.S. Pat. No. 6,326,367 and U.S. patent tion also include the use of isotopically-labeled SERMs, application Publication 2001021719. which are structurally identical to those disclosed above, but 0108. The expression “pharmaceutically acceptable for the fact that one or more atoms are replaced by an atom Salts' includes both pharmaceutically acceptable acid addi having an atomic mass or mass number different from the tion Salts and pharmaceutically acceptable cationic Salts. atomic mass or mass number usually found in nature. The expression “pharmaceutically-acceptable cationic Salts' Examples of isotopes that can be incorporated into com is intended to define but is not limited to Such salts as the pounds used in the invention include isotopes of hydrogen, alkali metal Salts, (e.g. Sodium and potassium), alkaline carbon, nitrogen, oxygen, phosphorous, Sulfur, fluorine and earth metal Salts (e.g., calcium and magnesium), aluminum chlorine, such as H, H, °C, “C, N, O, 7O, P, PP, Salts, ammonium Salts, and Salts with organic amines Such as S, F and Cl, respectively. Compounds used in the benzathine (N,N'-dibenzylethylenediamine), choline, methods, compositions and kits of the present invention, diethanolamine, ethylenediamine, meglumine (N-methyl prodrugs thereof, and pharmaceutically acceptable Salts of glucamine), benethamine (N-benzylphenethylamine), Said compounds and of Said prodrugs which contain the diethylamine, piperazine, tromethamine (2-amino-2-hy aforementioned isotopes and/or other isotopes of other droxymethyl-1,3-propanediol) and procaine. The expression atoms are within the Scope of this invention. Certain isoto “pharmaceutically-acceptable acid addition Salts' is pically labeled compounds used in the methods, composi intended to define but is not limited to Such salts as the tions and kits of the present invention, for example those hydrochloride, hydrobromide, Sulfate, hydrogen Sulfate, into which radioactive isotopes such as H and 'C are phosphate, hydrogen phosphate, dihydrogenphosphate, incorporated, are useful in drug and/or Substrate tissue acetate, Succinate, tartrate, citrate, methaneSulfonate (mesy distribution assays. Tritiated, i.e., H, and carbon-14, i.e., late) and p-toluenesulfonate (tosylate) salts. 'C, isotopes are particularly preferred for their ease of 0109 The SERMs used in the methods, compositions and preparation and detectability. Further, Substitution with kits of this invention can be administered in the form of heavier isotopes such as deuterium, i.e., H., may afford pharmaceutically acceptable Salts. The acid-addition Salts certain therapeutic advantages resulting from greater meta are conveniently formed, as is usual in organic chemistry, by bolic stability, for example increased in vivo half-life or reacting the compound used in the methods, compositions reduced dosage requirements and, hence, may be preferred and kits of this invention with a Suitable acid. The salts are in Some circumstances. Isotopically labeled compounds quickly formed in high yields at moderate temperatures, and used in the methods, compositions and kits of this invention often are prepared by merely isolating the compound from and prodrugs thereof can generally be prepared by carrying a Suitable acidic wash as the final Step of the Synthesis. The out known or referenced procedures and by Substituting a Salt-forming acid is dissolved in an appropriate organic readily available isotopically labeled reagent for a non Solvent, or aqueous organic Solvent, Such as an alkanol, isotopically labeled reagent. ketone or ester. A preferred technique for preparing hydro 0112 Those of ordinary skill in the art will recognize that chlorides is to dissolve the free base in a Suitable solvent and physiologically active compounds which have accessible dry the Solution thoroughly, as over molecular Sieves, before hydroxy groups can be administered in the form of phar bubbling hydrogen chloride gas through it. A preferred Salt maceutically acceptable esters. The compounds used in the US 2004/0152713 A1 Aug. 5, 2004

methods, compositions and kits of this invention can be kits of this invention the general range of effective admin effectively administered as an ester, formed on the hydroxy istration rates of the second compound is from about 0.001 groups, just as one skilled in pharmaceutical chemistry mg/day to about 2000 mg/day. However, in any given case, would expect. It is possible, as has long been known in the amount of the Second compound administered will pharmaceutical chemistry, to adjust the rate or duration of depend on Such factors as the potency of the Specific Second action of the compound by appropriate choices of ester compound, the Solubility of the compound, the formulation groupS. used and the route of administration. 0113 Certain ester groups are preferred when a com 0118 Methods of formulation are well known in the art pound used in the methods, compositions and kits of this and are disclosed, for example, in Remington's Pharmaceu invention contains an ester. The SERMs, including the tical Sciences, Mack Publishing Company, Easton, Pa., 19th compounds of formula (I) and (IA), may contain ester Edition (1995). Pharmaceutical compositions for use within groups at various positions as defined herein above, where the present invention can be in the form of Sterile, non these ester groups are represented as -COOR, in which R' pyrogenic liquid Solutions or Suspensions, coated capsules, is C-C alkyl, C-C chloroalkyl, C-C fluoroalkyl, C-C, Suppositories, lyophilized powders, transdermal patches or cycloalkyl, phenyl, or phenyl mono- or disubstituted with other forms known in the art.

C-C1. alkyl, C-C alkoxy, hydroxy, nitro, chloro, fluoro or 0119) Capsules are prepared by mixing the compound tri(chloro or fluoro)methyl. with a Suitable diluent and filling the proper amount of the 0114 AS used herein, the term “therapeutically effective mixture in capsules. The usual diluents include inert pow amount’ means an amount of compound that is capable of dered Substances Such as Starch of many different kinds, treating and/or preventing joint pain or of improving Sleep. powdered cellulose, especially crystalline and microcrystal The Specific dose of a compound administered according to line cellulose, SugarS Such as fructose, mannitol and Sucrose, this invention will, of course, be determined by the particu grain flours and Similar edible powders. lar circumstances Surrounding the case including, for 0120 Tablets are prepared by direct compression, by wet example, the compound administered, the route of admin granulation, or by dry granulation. Their formulations usu istration, the State of being of the patient, the Severity of the ally incorporate diluents, binders, lubricants and disintegra joint pain being treated or the level of Sleep improvement tors as well as the compound. Typical diluents include, for Sought. It is intended that a therapeutically effective amount example, various types of Starch, lactose, mannitol, kaolin, of a Second compound is used when a Second compound is calcium phosphate or Sulfate, inorganic Salts. Such as Sodium used in the methods, compositions and kits of this invention. chloride and powdered Sugar. Powdered cellulose deriva 0115 The magnitude of the prophylactic or therapeutic tives are also useful. Typical tablet binders are Substances dose of a compound used in the methods, compositions and Such as Starch, gelatin and SugarS Such as lactose, fructose, kits of this invention to be administered to a patient in the glucose and the like. Natural and Synthetic gums are also acute or chronic management of joint pain and/or Sleep convenient, including acacia, alginates, methylcellulose, improvement is rather widely variable and subject to the polyvinylpyrrolidine and the like. Polyethylene glycol, eth judgement of the attending physician. It should be noted that ylcellulose and waxes can also serve as binders. it may be necessary to adjust the dose of a compound when 0121. A lubricant may be necessary in a tablet formula it is administered in the form of a Salt, Such as a laureate, the tion to prevent the tablet and punches from Sticking in the Salt forming moiety of which has an appreciable molecular die. The lubricant is chosen from Such slippery Solids as talc, weight. magnesium and calcium Stearate, Stearic acid and hydroge 0116. The following dosage amounts and other dosage nated vegetable oils. amounts Set forth elsewhere in this description and in the 0.122 Tablet disintegrators are substances that facilitate appendant claims are for an average human Subject having the disintegration of a tablet to release a compound when the a weight of about 65 kg to about 70 kg. The skilled tablet becomes wet. They include Starches, clays, celluloses, practitioner will readily be able to determine the dosage algins and gums, more particularly, corn and potato Starches, amount required for a Subject whose weight falls outside the methylcellulose, agar, bentonite, wood cellulose, powdered 65 kg to 70 kg range, based upon the medical history of the natural Sponge, cation-exchange resins, alginic acid, guar Subject. All doses Set forth herein, and in the appendant gum, citrus pulp and carboxymethylcellulose, for example, claims, are daily doses of the free base form of the SERMs. may be used as well as Sodium lauryl Sulfate. Calculation of the dosage amount for other forms of the free 0123 Tablets are often coated with Sugar as a flavorant base form Such as Salts or hydrates is easily accomplished by and Sealant, or with film- forming protecting agents to performing a simple ratio relative to the molecular weights modify the dissolution properties of the tablet. The com of the Species involved. pounds may also be formulated as chewable tablets, by using 0117 The general range of effective administration rates large amounts of pleasant-tasting Substances Such as man of a SERM is from about 0.001 mg/day to about 200 mg/day. nitol in the formulation, as is now well-established in the A preferred rate range is from about 0.010 mg/day to about art. 100 mg/day. It is often practical to administer the daily dose 0.124. When it is desired to administer a compound as a of compound in portions, at various hours of the day. Suppository, the typical bases may be used. Cocoa butter is However, in any given case, the amount of compound a traditional Suppository base, which may be modified by administered will depend on Such factors as the potency of addition of waxes to raise its melting point slightly. Water the specific SERM, the solubility of the compound, the miscible Suppository bases comprising, particularly, poly formulation used and the route of administration. When a ethylene glycols of various molecular weights are in wide Second compound is used in the methods, compositions and Sc. US 2004/0152713 A1 Aug. 5, 2004

0.125 The topical formulation can be in the form of a replacement of a hydrogen atom in the amine group with a cream, jelly, ointment, gel, lotion, paste or for application by group such as R-carbonyl, R*O-carbonyl, NR'R''-carbo a patch. The topical preparation can be administered to the nyl where R' and R'' are each independently (C-Clio)alkyl, skin at or in the vicinity of the joint pain. (C-C)cycloalkyl, benzyl, or R^-carbonyl is a natural 0.126 The effect of the compounds may be delayed or C-aminoacyl or natural C-aminoacyl-natural C-aminoacyl, prolonged by proper formulation. For example, a slowly —C(OH)C(O)OY wherein Y is H., (C-C)alkyl or ben Soluble pellet of the compound may be prepared and incor zyl), -C(OY)Y^' wherein Y^' is (C-C) alkyland Y^ porated in a tablet or capsule. The technique may be is (C-C)alkyl, carboxy(C-C)alkyl, amino(C-C)alkyl or improved by making pellets of Several different dissolution mono-N- or di-N,N-(C-C)alkylaminoalkyl, -CO) rates and filling capsules with a mixture of the pellets. Y wherein Y^i is H or methyl and Y^i is mono-N- or Tablets or capsules may be coated with a film which resists di-N,N-(C-C)alkylamino, morpholino, piperidin-1-yl or dissolution for a predictable, period of time. Topical, for pyrrolidin-1-yl. mulations may be designed to yield delayed and/or pro 0131 Advantageously, the present invention also pro longed percutaneous absorption of a compound. Even the vides kits for use by a consumer to treat joint pain and/or parenteral preparations may be made long-acting, by dis improve sleep. The kits comprise a) a pharmaceutical com Solving or Suspending the compound in oily or emulsified position comprising a SERM and a pharmaceutically accept vehicles which allow it to disperse only slowly in the serum. able carrier, vehicle or diluent; and b) instructions describing a method of using the pharmaceutical compositions to treat 0127. The term “prodrug” means a compound that is joint pain and/or improve Sleep. The instructions may also transformed in Vivo to yield a compound used in the indicate that the kit is to treat joint pain and/or improve Sleep methods, compositions and kits of the present invention. The while Substantially reducing the concomitant liability of transformation may occur by various mechanisms, Such as through hydrolysis in blood. A discussion of the use of adverse effects associated with estrogen administration. prodrugs is provided by T. Higuchi and W. Stella, “Pro 0.132. A “kit' as used in the instant application includes drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. a container for containing the pharmaceutical compositions Symposium Series, and in Bioreversible Carriers in Drug and may also include divided containerS Such as a divided Design, ed. Edward B. Roche, American Pharmaceutical bottle or a divided foil packet. The container can be in any Association and Pergamon Press, 1987. conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for 0128. For example, if a compound used in the methods, example a paper or cardboard box, a glass or plastic bottle compositions and kits of the present invention contains a or jar, a re-sealable bag (for example, to hold a “refill” of carboxylic acid functional group, a prodrug can comprise an tablets for placement into a different container), or a blister ester formed by the replacement of the hydrogen atom of the pack with individual doses for pressing out of the pack acid group with a group Such as (C-C)alkyl, (C- according to a therapeutic Schedule. The container employed C.)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from can depend on the exact dosage form involved, for example 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having a conventional cardboard box would not generally be used from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl hav to hold a liquid Suspension. It is feasible that more than one ing from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl container can be used together in a single package to market having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycar a single dosage form. For example, tablets may be contained bonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxy carbonyl)aminomethyl having from 3 to 9 carbon atoms, in a bottle, which is in turn contained within a box. 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 car 0.133 An example of Such a kit is a so-called blister pack. bon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyro Blister packs are well known in the packaging industry and lacton-4-yl, di-N, N-(C-C)alkylamino(C-C)alkyl (Such are being widely used for the packaging of pharmaceutical as N,N-dimethylaminoethyl), carbamoyl-(C-C)alkyl, unit dosage forms (tablets, capsules, and the like). Blister N,N-di(C-C)alkylcarbamoyl-(C-C)alkyl and piperi packs generally consist of a sheet of relatively Stiff material dino-, pyrrolidino- or morpholino(C-C)alkyl. covered with a foil of a preferably transparent plastic mate rial. During the packaging process, recesses are formed in 0129. Similarly, if a compound used in the methods, the plastic foil. The recesses have the size and shape of compositions and kits of the present invention comprises an individual tablets or capsules to be packed or may have the alcohol functional group, a prodrug can be formed by the Size and shape to accommodate multiple tablets and/or replacement of the hydrogen atom of the alcohol group with capsules to be packed. Next, the tablets or capsules are a group Such as (C-C)alkanoyloxymethyl, 1-((C- placed in the recesses accordingly and the sheet of relatively C.)alkanoyloxy)ethyl, 1-methyl-i-((C- Stiff material is Sealed against the plastic foil at the face of C.)alkanoyloxy)ethyl, (C-C)alkoxycarbonyloxymethyl, the foil which is opposite from the direction in which the N-(C-C)alkoxycarbonylaminomethyl, Succinoyl, (C- recesses were formed. As a result, the tablets or capsules are C.)alkanoyl, C.-amino(C-C)alkanoyl, arylacyl and C-ami individually Sealed or collectively Sealed, as desired, in the noacyl, or CL-aminoacyl-C-aminoacyl, where each C-ami recesses between the plastic foil and the sheet. Preferably the noacyl group is independently Selected from the naturally Strength of the sheet is Such that the tablets or capsules can occurring L-amino acids, P(O)(OH), -P(O)(O(C- be removed from the blister pack by manually applying C.)alkyl) or glycosyl (the radical resulting from the preSSure on the recesses whereby an opening is formed in the removal of a hydroxyl group of the hemiacetal form of a sheet at the place of the receSS. The tablet or capsule can then carbohydrate). be removed via Said opening. 0.130) If a compound of the present invention comprises 0.134. It may be desirable to provide a written memory an amine functional group, a prodrug can be formed by the aid, where the written memory aid is of the type containing US 2004/0152713 A1 Aug. 5, 2004 information and/or instructions for the physician, pharmacist phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol is the D-tar or patient, e.g., in the form of numbers next to the tablets or trate. The coadministration can be in the same dosage form capsules whereby the numbers correspond with the days of or different dosage forms and at the Same time or at different the regimen which the tablets or capsules So Specified should times. All possible modes and Schedules of administration be ingested or a card which contains the same type of are contemplated. In addition, products derived from natural information. Another example of Such a memory aid is a Substances have been used to treat joint pain. Examples calendar printed on the card e.g., as follows “First Week, include hyaluronic acid, glucosamine, chondroitin Sulfate Monday, Tuesday,” . . . etc . . . . “Second Week, Monday, and capsaicin. Corticosteriods have also been used to treat Tuesday, ... '' etc. Other variations of memory aids will be readily apparent. A "daily dose” can be a Single tablet or joint pain. The Second compound from the compounds that capsule or Several tablets or capsules to be taken on a given are used to treat and/or prevent joint pain can be adminis day. tered at a dosage that is therapeutically effective for the treatment of joint pain. All of the above compounds and 0135 Another specific embodiment of a kit is a dispenser others that can be used to treat joint pain can be used in designed to dispense the daily doses one at a time. Prefer combination with the SERMs used in the methods, compo ably, the dispenser is equipped with a memory-aid, So as to Sitions and kits of the present invention. further facilitate compliance with the regimen. An example of Such a memory-aid is a mechanical counter that indicates 0.138 Compounds that are used to improve sleep and the number of daily doses that has been dispensed. Another which can also be used in combination with the SERMs in example of Such a memory-aid is a battery-powered micro the methods, compositions and kits of the present invention chip memory coupled with a liquid crystal readout, or include adinazolam, allobarbital, alonimid, alprazolam, audible reminder Signal which, for example, reads out the amitryptiline, amobarbital, amoxapine, bentazepam, ben date that the last daily dose has been taken and/or reminds Zoctamine, bromocriptine, brotizolam, bupropion, bus one when the next dose is to be taken. pirone, butabarbital, but albital, capuride, carbocloral, chlo 0.136 The kits of the present invention may also include, ral betaine, chloral hydrate, chlordiazepoxide, in addition to a SERM, one or more additional pharmaceu clomipramine, cloperidone, cloraZepate, clorethate, clozap tically active compounds. Preferably, the additional com ine, codeine, cyprazepam, desipramine, dexclamol, diaz pound is another SERM or another compound useful to treat epam, dichloralphenaZone, divalproex, diphenhydramine, joint pain or to improve Sleep. The additional compounds doxepin, estazolam, ethchlorVynol, etomidate, fenobam, may be administered in the same dosage form as the SERM flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fos or in different dosage forms. Likewise, the additional com azepam, glutethimide, halazepam, hydrocodone, hydrox pounds can be administered at the same time as the SERM yZine, imipramine, lithium, lorazepam, lormetazepam, or at different times. maprotaline, mecloqualone, melatonin, mephobarbital, 0.137 Compounds that are used to treat and/or prevent meprobamate, methadone, methaqualone, midaflur, mida joint pain and which can be used in combination with the Zolam, nefazodone, nisobamate, nitrazepam, nortriptyline, SERMs in the methods, compositions and kits of the present Oxazepam, Oxycodone, paraldehyde, paroxetine, pentaZO invention include nonsteroidal anti-inflammatory drugs crine, pentobarbital, pergolide, perlapine, perphenazine, (NSAIDs), Such as aspirin, acetominophen, ibuprofen, pheneizine, phenobarbital, prazepam, promethazine, propo naproxen, ketoprofen, nabumetone, etodolac, Salsalate, fol, propoxyphene, protryptyline, quaZepam, reclazepam, Sulindac, diclofenac, tolmetin, flurbiprofen, piroXicam, roletamide, Secobarbital, Sertraline, Suproclone, temazepam, fenoprofen, indomethacin, meclofenamate, Oxaprozin, thioridazine, tracazolate, tranylcypromaine, traZOdone, tria diflunisal and ketorolac, and Selective cyclooxygenase-2 Zolam, trepipam, tricetamide, triclofoS, trifluoperazine, tri (COX-2) inhibitors such as rofecoxib (Vioxx(R), celecoxib metozine, trimipramine, uldazepam, Venlafaxine, Zaleplon, (Celebrex(R), Valdecoxib (Bextra(R) and etoricoxib. NSAIDs Zolazepam, Zolpidem and pharmaceutically acceptable Salts can have unwanted Side effects Such as ulcers, therefore thereof. The Second compound from the compounds that are NSAIDs are sometimes administered with other compounds used to improve Sleep can be administered at a dosage that that ameliorate the Side effects. Typical compounds that are is therapeutically effective for the improvement of sleep. All used in combination with NSAIDs include proton pump of the above compounds and others that can be used to inhibitorS Such as omeprazole; antacids Such as Sucralfate; improve sleep can be used in combination with the SERMs and H2 blockerS Such as ranitidine, cimetidine, famotidine used in the methods, compositions and kits of the present and nizatidine. Thus, the combination aspect of the present invention. invention comprises a SERM, an NSAID and a compound 0139. It is noted that the SERMs can be administered in that reduces a side effect of an NSAID. In addition, the the same dosage form (e.g., a tablet) or in different dosage combination aspect of the present invention also includes the forms. The compounds can be administered at the same time coadministration of a SERM and a COX-2 inhibitor. For or at different times. All Such variations are intended to be example, (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)- encompassed by the combination aspect of the present phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or invention. geometric isomer thereof; a pharmaceutically acceptable Salt, N-oxide, ester, quaternary ammonium Salt, or a prodrug 0140. The effects of a SERM on joint pain can be thereof can be administered with 4-5-(4-methylphenyl)-3- determined by administering a compound to a patient hav (trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide ing, or at risk of having, joint pain for a time and observing (celecoxib), 4-4-(methylsulfonyl)phenyl)-3-phenyl-2(5H)- the results. Likewise, the effects of a SERM on improving furanone (rofecoxib), Valdecoxib or etoricoxib. A preferred Sleep can be determined by administering a compound to a Salt of (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)- patient in need of Sleep improvement for a time and observ US 2004/0152713 A1 Aug. 5, 2004

ing the results. All documents cited herein, including patents would warrant open label estrogen therapy were excluded and patent applications, are hereby incorporated by refer from the study. Women with a history of medical disease that CCC. might be associated with the development of metabolic bone disease including: bone marrow disease; hereditary disor EXAMPLE 1. ders of calcium or mineral metabolism; Paget's Disease; 0141 The Effects of Oral Administration of (-)-cis-6- untreated or inadequately treated endocrine disorders phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tet including untreated thyrotoxicosis, hyper- or hypoparathy rahydro-naphthalene-2-ol, D-tartrate Salt (Iasofoxifene) on roidism, adrenal disorders, and insulin-dependent diabetes Joint Pain: A Randomized, Double Blind, Placebo Con mellitus, rheumatoid arthritis or other connective tissue trolled Study disorders, gastrointestinal diseases including chronic liver 0142. Subjects: A double blind, randomized, placebo disease, partial or total resection of the Stomach or bowel, or controlled trial of approximately three hundred and Seventy malabsorption Syndrome were also excluded from the Study. five women between the ages of 50 and 74 years of age inclusive, and 1-20 years postmenopausal was carried out. 0144) Women with a history of other significant medical The subjects selected for the study were ambulatory females disorders currently requiring chronic medical therapy that between the ages of 50 and 74 years of age (inclusive) who may interfere with the conduct of the study (disorders such gave written informed consent for participation in the Study. as any degree of renal insufficiency, poorly controlled hyper The Subjects last menstrual period or episode of vaginal tension or that requiring more than 2 agents for control, bleeding was at least one year, but not more than 20 years unstable angina, or Subjects with history of myocardial prior to the initial Screening Visit and their estradiol level infarction within the previous 6 months) were excluded from was <110 pmol/L (30 pg/ml) and follicle-stimulating hor the study. Women with a history of malignancy within the mone (FSH)>30 IU/L. Minor deviations from these post previous five years with the exception of basal cell carci menopausal criteria, in Subjects who are clearly postmeno noma, curatively treated by Surgery and/or localized gyne pausal, could be accepted on a case-by-case basis. The cological cancer treated by total hysterectomy were Subjects Selected for the Study had a body mass indeX leSS excluded from the study. than 32 with the body mass index being defined as the 0145 Women who had undergone therapy with an inves weight in kilograms divided by the height in meters Squared. tigational drug during the last 30 days preceding admission In all cases, however, the Subjects weight was less than or to the Study or administration of estrogen or estrogenic equal to 94kg and height less than 72 inches (183 cm). The compounds (including hormonal estrogen agonistantago Subject's Screening/Baseline mean L1-L4 lumbar bone min nists Such as tamoxifen, raloxifene, idoxifene, levormelox eral density (BMD) of the spine must be less than +2.0 ifene, toremifene, phytoestrogens, or DHEA and. Similar Standard deviations and greater than -2.5 standard devia agents) within the 3 months prior to Screening visit, calci tions of age-and sex-matched bone mineral density (Z-Score) tonin or related products within the 3 months prior to as determined by standards of the manufacturer of the Dual Screening, or Sodium fluoride (at doses >2 mg/day) or any of X-ray Absorptiometer (DXA) used in the determination of the bisphosphonates (e.g. didronel oralendronate) within the that BMD. The subjects' CBC with differential and platelet 12 months prior to Screening Visit were also excluded from count, urinalysis; and Multichem 23 or equivalent (calcium, the Study. inorganic phosphorus, Sodium, potassium, chloride, lactic acid dehydroenase (LDH), Serum glutamic oxaloacetic tran 0146) Subjects taking any of the following medications Saminase (SGOT (AST)), Serum glutamic pyruvic transami within the previous 12 months: anabolic Steroids, chronic nase (SGPT (ALT)), total bilirubin, alkaline phosphatase, glucocorticoid or related Steroids, glutethimide, heparin, total protein, globulin, albumin, blood urea nitrogen (BUN), coumadin, anticonvulsants of any kind, doses of Vitamin D creatinine, uric acid, glucose) were within +/-10% of the above 800 units daily, doses of calcium above 1500 mg limits of the upper and lower range of normal. Serum thyroid daily, Sodium fluoride (above 2 mg/day), inhaled Steriods for stimulating hormone (TSH) will be between 0.4 and 6.0 asthma or chronic obstructive pulmonary disease (COPD) mIU/ml, inclusive (Subjects on a fixed dose of thyroid were excluded from the study. Women who smoke more hormone for six months or more, with TSH values within the than 10 cigarettes per day or consume more than 2 units per Specified range, are eligible for inclusion). The Subjects day of alcohol were excluded from the study. A unit of resting 12-lead electrocardiogram were within clinically alcohol is defined as 2 ounces of hard liquor, 4 ounces of normal limits and the Subjects gynecological examination wine, or 12 ounces of beer. Women with a personal history including Papanicolaou (Pap) Smear were normal. Minor of recurrent Superficial phlebitis, deep venous thrombosis, abnormalities in cervical cytology, e.g. minor atypia or pulmonary embolus, retinal vein thrombosis, or greater than inflammation, were not grounds for exclusion. The Subjects 6 months use of anticoagulants at any time in their past or endometrial thickneSS were typically <5 mm as determined Women with a strong family history of recurrent deep vein by transvaginal ultrasound (TVU) and subjects outside of thrombosis (DVT) or pulmonary embolism were also this criteria were asked to undergo additional baseline evalu excluded from the study. ation following initial randomization. The Subjects had a 0147 Women with scoliosis or other clinical spinal mammogram within the 3 months prior to Screening exami deformity Severe enough to invalidate lumbar bone densi nation that showed neither cancer nor Suspicion of cancer tometry in the L1-L4 region were excluded from the Study. warranting biopsy or, if a mammogram had not been Other Such conditions include Spinal fusion Surgery, previ obtained within the previous 3 months, subjects had one ouS traumatic fracture of the Spine, or aortic calcifications obtained as part of the Screening procedure. Severe enough to invalidate bone mineral density assessment 0143 Women with a current history of severe or dis in the lumbar region. Evaluation for Such exclusions may be abling postmenopausal Symptoms (i.e. hot flushes) that based on clinical history, Spine DXA evaluation, or plain US 2004/0152713 A1 Aug. 5, 2004 11 radiographs of the Spine. Women with a history of nontrau matic fractures of the vertebrae, or recurrent fractures of TABLE 1. other bones Such as the wrist, foot, rib or pelvis, that Joint Pain Changes Resulting Reduction in Suggests the presence of underlying metabolic bone disease From Treatment Joint Pain other than normal postmenopausal bone loSS or a fracture of Treatment Group (Mean Change from Baseline) Compared to Placebo either hip were excluded from the study. Subjects deter mined by transvaginal ultrasound (TVU) to have significant Lasofoxifene -8.16 P = O.OO12 0.25 mg ovarian pathology (simple cysts >2 cm or complex cysts of Lasofoxifene 4.52 P = 0.99O2 any size) or uterine pathology (endometrial thickness >5 mm 1.0 mg and/or hyperplasia/cancer). Placebo 5.26 O 0148 Patients were randomly allocated to one of four treatment regimen groups (Groups A, B, C, D) using a computer generated pseudo-random code generated using EXAMPLE 2 the method of random permutated blocks. These patients 0157 The Effects of Oral Administration of (-)-cis-6- received (in a double blind fashion): phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tet 0149 Group A (n=75) placebo rahydro-naphthalene-2-ol, D-tartrate Salt (lasofoxifene) on Sleep: A Randomized, Double Blind, Placebo Controlled O150 Groupp B (n=75) 0.25 mg/dayg/day of (-)-cis-6- Study phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6, 7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt 0158 Subjects: A double blind, randomized, placebo controlled trial of approximately three hundred and Seventy 0151 Group C (n=75) 1.0 mg/day of (-)-cis-6- five women between the ages of 50 and 74 years of age phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6, inclusive, and 1-20 years postmenopausal was carried out. 7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt The subjects selected for the study were ambulatory females between the ages of 50 and 74 years of age (inclusive) who 0152 Group D (n=150) 60.0 mg/day of raloxifene gave written informed consent for participation in the Study. The Subjects last menstrual period or episode of vaginal 0153. Each patient also received two tablets daily, each bleeding was at least one year, but not more than 20 years tablet containing calcium 500 mg and vitamin D 125 IU. prior to the initial screening visit and their estradiol level 0154) The placebo, 0.25 mg/day and 1.0 mg/day of was <110 pmol/L (30 pg/ml) and FSH>30 IU/L. Minor (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5, deviations from these postmenopausal criteria, in Subjects 6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt (lasofox who are clearly postmenopausal, could be accepted on a ifene) and raloxifene tablets were dispensed in blister pack case-by-case basis. The Subjects Selected for the Study had a cards. The patients were instructed to take the medication in body mass index less than 32 with the body mass index the morning or if the patient had difficulty in complying with being defined as the weight in kilograms divided by the morning dosing then to take the medication at bedtime or height in meterS Squared. In all cases, however, the Subject's with the evening meal. Neither the investigator or patient weight was less than or equal to 94 kg and height less than was aware of the constituents of the tablets provided in the 72 inches (183 cm). The subject's Screening/Baseline mean blister packs. L1-L4 lumbar bone mineral density (BMD) of the spine must be less than +2.0 Standard deviations and greater than O155 Assessment Method: Patients were asked to record -2.5 Standard deviations of age-and Sex-matched bone min their pain Score using a Standardized linear Visual analog eral density (Z-Score) as determined by Standards of the scale (VAS; 100 mm scale, 0 mm=no pain, 100 mm=worst manufacturer of the Dual X-ray Absorptiometer (DXA) used pain). The patients were asked to provide the pain Score at in the determination of that BMD. The subjects' CBC with 3 months, 6 months, 12 months, 18 months and 24 months differential and platelet count; urinalysis; and Multichem 23 of the study. or equivalent (calcium, inorganic phosphorus, Sodium, 0156 Result: The results of the 3 months assessment for potassium, chloride, LDH, SGOT (AST), SGPT (ALT), total joint pain in the 0.25 lasofoXifene, 1.0 mg lasofoXifene and bilirubin, alkaline phosphatase, total protein, globulin, albu placebo treatment groups are provided in Table 1 below. min, BUN, creatinine, uric acid, glucose) were within +/- Adjusted Analysis of Variance (ANCOVA) technique was 10% of the limits of the upper and lower range of normal. used to examine the effects of the various treatments on Serum thyroid stimulating hormone (TSH) will be between Self-reported joint pain at the 3 months assessment. At the 3 0.4 and 6.0 mIU/ml, inclusive (Subjects on a fixed dose of months assessment the lasofoXifene 1.0 mg treatment group thyroid hormone for six months or more, with TSH values reported a mean change from baseline of 4.52 for joint pain within the Specified range, are eligible for inclusion). The whereas the placebo treatment group reported a mean Subjects resting 12-lead electrocardiogram were within change from baseline of 5.26 for joint pain. At the 3 months clinically normal limits and the Subjects gynecological assessment the lasofoXifene 0.25 mg treatment group examination including Papanicolaou (Pap) Smear were nor reported a mean change from baseline of -8.16 for joint pain mal. Minor abnormalities in cervical cytology, e.g. minor whereas the placebo treatment group reported a mean atypia or inflammation, were not grounds for exclusion. The change from baseline of 5.26 for joint pain. These mean Subjects endometrial thickness were typically <5 mm as change Scores from baseline revealed a Statistically signifi determined by transvaginal ultrasound (TVU) and subjects cant (p<0.001) reduction in self-reported joint pain in the outside of this criteria were asked to undergo additional lasofoXifene 0.25 mg treatment group compared to the baseline evaluation following initial randomization. The placebo treatment group at the 3 months assessment. Subjects had a mammogram within the 3 months prior to US 2004/0152713 A1 Aug. 5, 2004

Screening examination that showed neither cancer nor SuS Other Such conditions include Spinal fusion Surgery, previ picion of cancer warranting biopsy or, if a mammogram had ouS traumatic fracture of the Spine, or aortic calcifications not been obtained within the previous 3 months, subjects had Severe enough to invalidate bone mineral density assessment one obtained as part of the Screening procedure. in the lumbar region. Evaluation for Such exclusions may be 0159 Women with a current history of severe or dis based on clinical history, Spine DXA evaluation, or plain abling postmenopausal Symptoms (i.e. hot flushes) that radiographs of the Spine. Women with a history of nontrau would warrant open label estrogen therapy were excluded matic fractures of the vertebrae, or recurrent fractures of from the study. Women with a history of medical disease that other bones Such as the wrist, foot, rib or pelvis, that might be associated with the development of metabolic bone Suggests the presence of underlying metabolic bone disease disease including: bone marrow disease; hereditary disor other than normal postmenopausal bone loSS or a fracture of ders of calcium or mineral metabolism; Paget's Disease; either hip were excluded from the study. Subjects deter untreated or inadequately treated endocrine disorders mined by transvaginal ultrasound (TVU) to have significant including untreated thyrotoxicosis, hyper- or hypoparathy ovarian pathology (simple cysts >2 cm or complex cysts of roidism, adrenal disorders, and insulin-dependent diabetes any size) or uterine pathology (endometrial thickness 25 mellitus, rheumatoid arthritis or other connective tissue mm and/or hyperplasia/cancer). disorders, gastrointestinal diseases including chronic liver disease, partial or total resection of the Stomach or bowel, or 0.164 Patients were randomly allocated to one of four malabsorption Syndrome were also excluded from the Study. treatment regimen groups (Groups A, B, C, D, E) using a computer generated pseudo-random code generated using 0160 Women with a history of other significant medical disorders currently requiring chronic medical therapy that the method of random permutated blocks. These patients may interfere with the conduct of the study (disorders such received (in a double blind fashion): as any degree of renal insufficiency, poorly controlled hyper 0.165 Group A (n=50) placebo tension or that requiring more than 2 agents for control, unstable angina, or Subjects with history of myocardial 0166 Groupp B (n=50) 0.40 mg/dayg/day of (-)-cis-6- infarction within the previous 6 months) were excluded from phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6, the study. Women with a history of malignancy within the 7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt previous five years with the exception of basal cell carci noma, curatively treated by Surgery and/or localized gyne 0167 Groupp C (n=50) 1.25 mg/dayg/day of (-)-cis-6- cological cancer treated by total hysterectomy were phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6, excluded from the study. 7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt 0.161 Women who had undergone therapy with an inves 0168 Group D (n=50) 5.0 mg/day of (-)-cis-6- tigational drug during the last 30 days preceding admission phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6, to the Study or administration of estrogen or estrogenic compounds (including hormonal estrogen agonist/antago 7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt nists Such as tamoxifen, raloxifene, idoxifene, levormelox 0169 Group E (n=50) 0.625 mg/2.5 mg of conju ifene, toremifene, phytoestrogens, or DHEA and Similar gated estrogens/medroxyprogesterone (Prem ProE)) agents) within the 3 months prior to Screening visit, calci tonin or related products within the 3 months prior to 0170 Each patient also received two tablets daily, each Screening, or Sodium fluoride (at doses >2 mg/day) or any of tablet containing calcium 500 mg and vitamin D 125 IU. the bisphosphonates (e.g. didronel oralendronate) within the 0171 The placebo, 0.4 mg/day, 1.25 mg/day and 5.0 12 months prior to Screening visit were also excluded from mg/day of (-)-cis-6-phenyl-5-4-(2-pyrrolidin- 1-yl the Study. ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol, D-tar 0162 Subjects taking any of the following medications trate Salt (lasofoxifene) and 0.625 mg/2.5 mg of conjugated within the previous 12 months: anabolic Steroids, chronic estrogens/medroxyprogesterone (PremPro(R)) tablets were glucocorticoid or related Steroids, glutethimide, heparin, dispensed in blister pack cards. The patients were instructed coumadin, anticonvulsants of any kind, doses of Vitamin D to take the medication in the morning or if the patient had above 800 units daily, doses of calcium above 1500 mg difficulty in complying with morning dosing then to take the daily, Sodium fluoride (above 2 mg/day), inhaled Steriods for medication at bedtime or with the evening meal. Neither the asthma or COPD were excluded from the study. Women who investigator or patient was aware of the constituents of the Smoke more than 10 cigarettes per day or consume more tablets provided in the blister packs. than 2 units per day of alcohol were excluded from the Study. A unit of alcohol is defined as 2 ounces of hard liquor, 4 The effects of Iasofoxifene on Sleep ounces of wine, or 12 ounces of beer. Women with a personal history of recurrent Superficial phlebitis, deep 0172 Assessment Method: Patient self-report recorded venous thrombosis, pulmonary embolus, retinal vein throm on Sleep Problems Subscale of Standardized questionnaire, bosis, or greater than 6 months use of anticoagulants at any Women's Health Questionnaire (WHO; Hunter, M. 1992. time in their past or women with a strong family history of Psychology and Health, 7: 45-54). recurrent deep vein thrombosis (DVT) or pulmonary embo 0173 Result: in adjusted between group t-tests, the dif lism were also excluded from the study. ference in the mean change Scores from baseline revealed a 0163 Women with scoliosis or other clinical spinal Statistically significant improvement in Sleep (ie, less Sleep deformity Severe enough to invalidate lumbar bone densi disturbance) in the lasofoxifene 0.4mg treatment group VS. tometry in the L1-L4 region were excluded from the Study. placebo at 3 months assessment. US 2004/0152713 A1 Aug. 5, 2004 13

Z' is TABLE 2 (a)-(CH), W(CH), ; Mean Change Difference Treatment Grp from Baseline from Placebo (b) —O(CH),CRR-. Lasofoxifene 0.4 mg -0.09 P = 0.05 Placebo O.O3 O (c) -O(CH), W(CH-)-; (d) –OCHRCHR ; or (e) –SCHRCHR-; What is claimed is: 1. A method of treating joint pain or improving sleep in a G is patient, the method comprising administering to Said patient (a)-NR'R'; in need thereof a therapeutically effective amount of a SERM of formula (I): (b) y H. v. -N 72 (I) V

wherein n is 0, 1 or 2; m is 1, 2 or 3; Z is -NH-, -O-, -S-, or -CH-, optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently Substituted on carbon with one to three Substituents and, optionally, inde pendently on nitrogen with a chemically Suitable substituent selected from R'; or (c) a bicyclic amine containing five to twelve carbon wherein: atoms, either bridged or fused and optionally Sub stituted with 1-3 substituents independently selected A is selected from CH and NR; from R'; or B, D and E are independently selected from CH and N; Z" and G in combination may be Y is (a) phenyl, optionally substituted with 1-3 substituents independently selected from R"; (b) naphthyl, optionally substituted with 1-3 substitu ents independently selected from R"; (c) C-C cycloalkyl, optionally Substituted with 1-2 substituents independently selected from R"; (d) C-C cycloalkenyl, optionally Substituted with 1-2 W is substituents independently selected from R"; (a) -CH-; (e) a five membered heterocycle containing up to two heteroatoms Selected from the group consisting of (b) -CH=CH-; O-, -NR-and-S(O), , optionally substi (c) -O-; tuted with 1-3 substituents independently selected from R'; (d) -NR; (f) a six membered heterocycle containing up to two (e) -S(O) ; heteroatoms Selected from the group consisting of O-, -NR’- and -S(O), optionally substi tuted with 1-3 substituents independently selected (f) from R'; or (g) a bicyclic ring System consisting of a five or six membered heterocyclic ring fused to a phenyl ring, Said heterocyclic ring containing up to two heteroa (g) -CR (OH)-; toms Selected from the group consisting of -O-, -NR-and-S(O), , optionally substituted with (h) -CONR-; 1-3 substituents independently selected from R"; (i) —NR’CO-; US 2004/0152713 A1 Aug. 5, 2004 14

R" and R in either linear or ring form may optionally be Substituted with up to three substituents independently Selected from C-C alkyl, halogen, alkoxy, hydroxy () . and carboxy, a ring formed by R and R may be optionally fused to a phenyl ring, (k) -C=C-; e is 0, 1 or 2; R is hydrogen or C-C alkyl, m is 1, 2 or 3; R and Rare independently n is 0, 1 or 2; (a) hydrogen; or p is 0, 1, 2 or 3; (b) C-C alkyl, q is 0, 1, 2 or 3; R" is or an optical or geometric isomer thereof, or a pharma (a) hydrogen; ceutically acceptable Salt, N-oxide, ester, quaternary ammonium Salt or prodrug thereof, and provided that (b) halogen; Said joint pain is not joint pain resulting from Osteoar (c) C-C alkyl, thritis or rheumatoid arthritis. 2. The method of claim 1 wherein the SERM is a (d) C-C alkoxy; compound of formula (IA) (e) C-C acyloxy; (f) C-C alkylthio; (IA) OCH2CHG (g) C-C alkylsulfinyl, (h) C-C alkylsulfonyl; (i) hydroxy (C-C)alkyl; aryl (C-C)alkyl, (k) -COH: (l) -CN; (m) –CONHOR; (n) -SONHR; (o) -NH; wherein G is (p) C-C alkylamino; (q) C-C dialkylamino; (r) -NHSOR; (s) -NO; (t) -aryl; or (u) -OH; R" is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric RandR are independently C-C alkyl or together form isomer thereof, or a pharmaceutically acceptable Salt, a C-Clio carbocyclic ring; N-oxide, ester, quaternary ammonium Salt, or a prodrug R7 and R are independently thereof. 3. The method of claim 1 wherein the SERM is (-)-cis (a) phenyl, 6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8- (b) a C-C carbocyclic ring, Saturated or unsaturated; tetrahydro-naphthalene-2-ol or an optical or geometric iso mer thereof; a pharmaceutically acceptable Salt, N-oxide, (c) a C-Co heterocyclic ring containing up to two ester, quaternary ammonium Salt, or a prodrug thereof. heteroatoms, selected from -O-, -N- and 4. The method of claim 3 wherein the SERM is (-)-cis -S-; 6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8- (d) H; tetrahydro-naphthalene-2-ol, D-tartrate Salt. 5. The method of any one of claims 1-4 wherein the (e) C-C alkyl, or method is the method of treating joint pain. (f) form a 3 to 8 membered nitrogen containing ring 6. The method of any one of claims 1-4 wherein the with R or R. method is the method of improving sleep. US 2004/0152713 A1 Aug. 5, 2004

7. A method of treating joint pain in a patient, the method G is comprising administering to Said patient in need thereof a therapeutically effective amount of a first compound, Said (a)-NR'R'; first compound being a SERM of formula (I): (b)b yCH2)m as V -N Z. (I) VeH-/

wherein n is 0, 1 or 2; m is 1, 2 or 3; Z is -NH-, -O-, -S-, or -CH-, optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently Substituted on carbon with one to three Substituents and, optionally, inde pendently on nitrogen with a chemically Suitable substituent selected from R'; or (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally Sub wherein: stituted with 1-3 substituents independently selected A is selected from CH and NR; from R'; or B, D and E are independently selected from CH and N; Z" and G in combination may be Y is (a) phenyl, optionally substituted with 1-3 substituents independently selected from R"; (b) naphthyl, optionally substituted with 1-3 substitu ents independently selected from R"; (c) C-C cycloalkyl, optionally Substituted with 1-2 substituents independently selected from R"; W is (a) -CH-; (d) C-C cycloalkenyl, optionally Substituted with 1-2 substituents independently selected from R"; (b) -CH=CH-; (e) a five membered heterocycle containing up to two (c) -O-; heteroatoms Selected from the group consisting of (d) -NR-; O-, -NR-and-S(O), , optionally substi tuted with 1-3 substituents independently selected (e) -S(O) ; from R"; (f) a six membered heterocycle containing up to two (f) heteroatoms Selected from the group consisting of O-, -NR’- and -S(O), optionally substi - C-: tuted with 1-3 substituents independently selected from R'; or (g) -CR (OH)-; (g) a bicyclic ring System consisting of a five or six (h) -CONR-; membered heterocyclic ring fused to a phenyl ring, Said heterocyclic ring containing up to two heteroa (i) —NR’CO-; toms Selected from the group consisting of -O-, -NR-and-S(O), , optionally substituted with 1-3 substituents independently selected from R"; () Z is (a)-(CH), W(CH-) ; (k) -C=C-; (b) —O(CH), CRR-; R is hydrogen or C-C alkyl, (c) -O(CH), W(CH-)-; R° and Rare independently (d) –OCHRCHR ; or (a) hydrogen; or (e) –SCHRCHR ; (b) C-C alkyl, US 2004/0152713 A1 Aug. 5, 2004

R" is or an optical or geometric isomer thereof, or a pharma ceutically acceptable Salt, N-oxide, ester, quaternary (a) hydrogen; ammonium Salt or prodrug thereof, and (b) halogen; a therapeutically effective amount of a Second compound, (c) C-C alkyl, Said Second compound Selected from the group con (d) C-C alkoxy; Sisting of acetominophen, aspirin, ibuprofen, naproxen, ketoprofen, nabumetone, etodolac, Salsalate, Sulindac, (e) C-C acyloxy; diclofenac, tolmetin, flurbiprofen, piroXicam, fenopro fen, indomethacin, meclofenamate, Oxaprozin, (f) C-C alkylthio; diflunisal, ketorolac, celecoxib, rofecoxib, Valdecoxib, (g) C-C alkylsulfinyl, etoricoxib, hyaluronic acid, glucosamine, chondroitin and capsaicin; provided that Said joint pain is not joint (h) C-C alkylsulfonyl; pain resulting from Osteoarthritis or rheumatoid arthri (i) hydroxy (C-C)alkyl, tis. 8. The method of claim 7 wherein the first compound is (j) aryl (C-C)alkyl, (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5, (k) -COH: 6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt. 9. The method of claim 8 wherein the second compound (l) -CN; is celecoxib, rofecoxib, Valdecoxib or etoricoxib. (m) –CONHOR; 10. A method of improving Sleep in a patient, the method comprising administering to Said patient in need thereof a (n) -SONHR; therapeutically effective amount of a first compound, Said (o) -NH; first compound being a SERM of formula (I): (p) C-C alkylamino; (q) C-C dialkylamino; (I) (r) -NHSOR; (s) -NO; (t) -aryl; or (u) -OH; RandR are independently C-Cs alkyl or together form a C-Clio carbocyclic ring; R" and Rare independently (a) phenyl, (b) a C-Cocarbocyclic ring, Saturated or unsaturated; wherein: (c) a C-C heterocyclic ring containing up to two A is selected from CH and NR; heteroatoms, selected from -O-, -N- and -S-; B, D and E are independently selected from CH and N; (d) H; Y is (e) C-C alkyl, or (a) phenyl, optionally substituted with 1-3 substituents independently selected from R"; (f) form a 3 to 8 membered nitrogen containing ring with R or R; (b) naphthyl, optionally substituted with 1-3 substitu R" and R in either linear or ring form may optionally be ents independently selected from R"; Substituted with up to three substituents independently (c) C-C cycloalkyl, optionally Substituted with 1-2 Selected-from C-C alkyl, halogen, alkoxy, hydroxy substituents independently selected from R"; and carboxy, a ring formed by R and R may be optionally fused to a (d) C-C cycloalkenyl, optionally Substituted with 1-2 phenyl ring; substituents independently selected from R"; (e) a five membered heterocycle containing up to two e is 0, 1 or 2; heteroatoms Selected from the group consisting of m is 1, 2 or 3; O-, -NR-and-S(O), , optionally substi tuted with 1-3 substituents independently selected n is 0, 1 or 2; from R'; p is 0, 1, 2 or 3; (f) a six membered heterocycle containing up to two q is 0, 1, 2 or 3; heteroatoms Selected from the group consisting of US 2004/0152713 A1 Aug. 5, 2004 17

O-, -NR’- and -S(O), optionally substi tuted with 1-3 substituents independently selected from R'; or (f) O (g) a bicyclic ring System consisting of a five or six membered heterocyclic ring fused to a phenyl ring, Said heterocyclic ring containing up to two heteroa- (g) -CR (OH)-; toms Selected from the group consisting of -O-, -NR-and-S(O), , optionally substituted with (h) -CONR-; 1-3 substituents independently selected from R"; (i) —NR’CO-; Z' is (a)-(CH), W(CH.) : () (s) (b) -O(CH), CRR-; ; or (c) -O(CH), W(CH-)-; (d) –OCHRCHR ; or (k) -C=C-: R is hydrogen or C-C alkyl, (e) –SCHRCHR ; R° and Rare independently G is (a) hydrogen; or (a) NR'R;78. (b) C-C alkyl, R" is (b) ". N Z2 (a) hydrogen; V (b) halogen; oil-/ (c) C-C alkyl, (d) C-C alkoxy; wherein n is 0, 1 or 2; m is 1, 2 or 3. Z is -NH-, (e) C-C acyloxy; -O-, -S-, or -CH-, optionally fused on adjacent carbon atoms with one or two phenyl rings (f) C-C alkylthio; and, optionally independently Substituted on carbon (g) C-C alkylsulfinyl, with one to three Substituents and, optionally, inde pendently on nitrogen with a chemically Suitable (h) C-C alkylsulfonyl; substituent selected from R'; or (i) hydroxy (C-C)alkyl, (c) a bicyclic amine containing five to twelve carbon (j) aryl (C-C)alkyl, atoms, either bridged or fused and optionally Sub- (k) -COH: stituted with 1-3 substituents independently selected from R'; or (l) -CN; Z" and G in combination may be (m) –CONHOR; (n) -SONHR; (o) -NH; A (p) C-C alkylamino; N -oil-O ) (q) C-C dialkylamino; n (r) -NHSOR; (s) -NO; W is (t) -aryl; or (a) -CH-; (u) -OH; R and Rare independently C-Cs alkyl or together form (b) -CH=CH-; a C-Co carbocyclic ring; (c) -O-; R" and Rare independently (d) -NR-; (a) phenyl, (e) -S(O), ; (b) a C-Cocarbocyclic ring, Saturated or unsaturated; US 2004/0152713 A1 Aug. 5, 2004 18

(c) a C-Co heterocyclic ring containing up to two tamide, Secobarbital, Sertraline, Suproclone, heteroatoms, selected from -O-, -N- and temazepam, thioridazine, tracazolate, tranylcypro -S-; maine, traZOdone, triazolam, trepipam, tricetamide, tri clofoS, trifluoperazine, trimetozine, trimipramine, (d) H; uldazepam, Venlafaxine, Zaleplon, Zolazepam, Zolpi (e) C-C alkyl, or dem, and pharmaceutically acceptable Salts thereof. 11. The method of claim 10 wherein the first compound is (f) form a 3 to 8 membered nitrogen containing ring (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5, with R or R; 6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt. R" and R in either linear or ring form may optionally be 12. The method of claim 11 wherein the second com Substituted with up to three substituents independently pound is Sertraline. Selected from C-C alkyl, halogen, alkoxy, hydroxy 13. A pharmaceutical composition comprising: (-)-cis-6- and carboxy, phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tet a ring formed by R and R may be optionally fused to a rahydro-naphthalene-2-ol or a pharmaceutically acceptable phenyl ring; Salt thereof, and a Second compound Selected from the group consisting of adinazolam, allobarbital, alonimid, alpra e is 0, 1 or 2; Zolam, amitryptiline, amobarbital, amoxapine, bentazepam, m is 1, 2 or 3; benzoctamine, bromocriptine, brotizolam, bupropion, bus pirone, butabarbital, but albital, capuride, carbocloral, chlo n is 0, 1 or 2; ral betaine, chloral hydrate, chlordiazepoxide, clomi pramine, cloperidone, cloraZepate, clore thate, clozapine, p is 0, 2 or 3; codeine, cyprazepam, desipramine, deXciamol, diazepam, q is 0, 1, 2 or 3; dichloralphenaZone, divalproex, diphenhydramine, doxepin, or an optical or geometric isomer thereof, or a pharma estazolam, ethchlorVynol, etomidate, fenobam, fluni ceutically acceptable Salt, N-oxide, ester, quaternary trazepam, flurazepam, fluvoxamine, fluoxetine, foSazepam, ammonium Salt or prodrug thereof, and a therapeuti glutethimide, halazepam, hydrocodone, hydroxy Zine, imi cally effective amount of a Second compound, Said pramine, lithium, lorazepam, lormetazepam, maprotaline, Second compound being Selected from the group con mecloqualone, melatonin, mephobarbital, meprobamate, Sisting of adinazolam, allobarbital, alonimid, alpra methadone, methaqualone, midaflur, midazolam, nefaz Zolam, amitryptiline, amobarbital, amoxapine, ben odone, nisobamate, nitrazepam, nortriptyline, oxazepam, tazepam, benzoctamine, bromocriptine, brotizolam, Oxycodone, paraldehyde, paroxetine, pentazocrine, pento bupropion, buSpirone, butabarbital, butalbital, capu barbital, pergolide, perlapine, perphenazine, pheneizine, ride, carbocloral, chloral betaine, chloral hydrate, chlo phenobarbital, prazepam, promethazine, propofol, pro rdiazepoxide, clomipramine, cloperidone, cloraZepate, poxyphene, protryptyline, quazepam, reclazepam, roleta clorethate, clozapine, codeine, cyprazepam, mide, Secobarbital, Sertraline, Suproclone, temazepam, thior desipramine, dexclamol, diazepam, dichloral idazine, tracazolate, tranylcypromaine, traZodone, phenaZone, divalproex, diphenhydramine, doxepin, triazolam, trepipam, tricetamide, triclofoS, trifluoperazine, estaZolam, ethchlorVynol, etomidate, fenobam, fluni trimetozine, trimipramine, uldazepam, Venlafaxine, Zale trazepam, flurazepam, fluvoxamine, fluoxetine, fos plon, Zolazepam, and Zolpidem, or pharmaceutically accept azepam, glutethimide, halazepam, hydrocodone, able salts thereof. hydroxy Zine, imipramine, lithium, lorazepam, 14. The pharmaceutical composition of claim 13 wherein lormetazepam, maprotaline, mecloqualone, melatonin, the (-)-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phe mephobarbital, meprobamate, methadone, methaqua nyl-5,6,7,8-tetrahydro-naphthalene-2-ol is in the form of lone, midaflur, midazolam, nefazodone, nisobamate, the D-tartrate salt. nitrazepam, nortriptyline, Oxazepam, Oxycodone, 15. The pharmaceutical composition of claim 14 wherein paraldehyde, paroxetine, pentazocrine, pentobarbital, the Second compound is Sertraline, or a pharmaceutically pergolide, perlapine, perphenazine, phenelZine, phe acceptable Salt thereof. nobarbital, prazepam, promethazine, propofol, pro poxyphene, protryptyline, quazepam, reclazepam, role k k k k k