AU6966198A - Treatment or prophylaxis of prostatic cancer and benign prostatic hyperplasia with selective estrogen receptor modulators - Google Patents

Description

WO98/45288 PCT/US98/07274 - 1 Treatment or Prophylaxis of Prostatic Cancer and Benign Prostatic Hyperplasia with Selective Estrogen Receptor Modulators 5 Technical Field The present application relates to the use of a class of biologically active compounds for antagonizing the proliferation of benign and malignant prostatic cells. More particularly, the present invention concerns the use of a 10 class of substituted benzo[b]thiophene compounds for the treatment or prophylaxis of prostatic cancer and benign prostatic hyperplasia. Background of the Invention 15 Mortality due to prostatic cancer when the strategem of watchful waiting is adopted is generally low (9%-15%) in men who have localized tumors. However, these rates pertain to patients with localized disease; they do not necessarily apply to younger men at higher risk. Younger men with stage 20 Tla tumors have a longer projected period of risk than older men with the same stage of the disease and are therefore candidates for a potentially curative treatment. In studies of watchful waiting, the high rates of disease progression (34%-80%) indicate that few clinically evident prostate 25 cancers are dormant. Radiation therapy has been widely used for Stage T1 or T2 clinically localized disease, and has been preferentially used in older, less healthy patients and those with higher grade, more clinically advanced tumors. 30 However, this treatment neither cures nor eradicates all cancer cells in men with occult metasteses. Administration of estrogens to decrease circulating androgens is an effective hormonal ablative therapy for disseminated prostatic cancer (J. Waxman, J. R. Soc. Med., 35 78: 129-135 (1985)). Estrogen antitumor responses are mediated primarily through decreases in circulating WO98/45288 PCT/US98/07274 - 2 testosterone which result from inhibition of luteinizing hormone secretion. Administration of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4 (2-pyrrolidinoethoxy)benzoyl]benzo[b]thiophene, 1, or 5 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl]benzo[b]thiophene, (2), both selective estrogen receptor modulating (SERM) compounds, to PAIII tumor-bearing male Lobund-Wistar rats has been shown to produce significant inhibition of tumor metastasis from the primary 0 tumor in the tails to the gluteal and iliac lymph nodes and to the lungs. (See B. L. Neubauer, et al., Prostate, 27: 220-229 (1995) r-(CH 2)n NJ, 110 HO S OH 1 n=2 2 n=3 5 "Selective estrogen receptor modulators" are defined as compounds producing estrogen agonism in one or more desired target tissues, together with estrogen antagonism and/or minimal (i.e. clinically insignificant) agonism in 0 reproductuve tissues. Raloxifene possesses, in addition to its antiestrogenic activity, the ability to act as a physiological antagonist of androgen action in intact male animals. The PAIII adenocarcinoma in Lobund-Wistar rats is a 5 model that is useful in evaluating agents to treat metastatic prostate cancer. When PAIII cells are injected subcutaneously into the tails of male Lobund-Wistar rats, a reproducible, time-dependent sequential spread of the tumor WO98/45288 PCT/US98/07274 - 3 through the gluteal and iliac lymph nodes to the lungs is observed. The morphology of the PAIII tumor resembles anaplastic lesions in humans, supporting the utility of the tumor as a 5 model in evaluating cytotoxic and antimetastatic agents for human use. Benign prostatic hyperplasia (BPH) is the most common benign neoplasm in men. It has been estimated that approximately 50% of American men over the age of 50 years LO suffer from BPH. BPH is the enlargement of the prostate gland caused by benign overgrowth of the stromal tissue of the prostate and leads to symptoms which include increased urinary urgency and frequency which, if left untreated, can lead to L5 associated complications which include bladder and kidney damage. The typical treatment for BPH is transurethral prostatectomy, a procedure which is both expensive and time consuming. The mortality for transurethral resection of the 20 prostate has been reduced to 0.2% over the past thirty years, but the procedure itself has not changed significantly in that time, and postoperative morbidity has remained unchanged at about 18%. An estimated 29% of men with benign prostatic 25 hyperplasia will require surgical treatment. This translates into more than 400,000 surgical procedures per year. It has been estimated that, if current rates prevail, a 40-year old man in the United States lives to age 80 will have a 29% chance of a prostatectomy. 30 The high cost of this procedure, both in time and money, has generated considerable interest in seeking less expensive and morbid means for treating BPH. Brief Summary of the Invention 35 In accordance with the present invention, there is provided a method for the treatment or prophylaxis of prostatic cancer or benign prostatic hyperplasia (BPH) in a WO98/45288 PCT/US98/07274 - 4 patient in need of such treatment comprising administering a therapeutically effective amount of a selective estrogen receptor modulating compound of the structure R3 I O o. N- R 4 0 5 R2f or a pharmaceutically acceptable salt or pro-drug thereof. In the structure shown above, R I and R 2 are 10 independently selected from the group consisting of hydroxy and alkoxy of one to four carbon atoms.

R

3 and R 4 are independently selected from methyl or ethyl, or R 3 and R 4 , taken together with the nitrogen atom to which they are attached, form a pyrrolidino, 15 methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring. Brief Description of the Drawing In the drawing: 20 FIGURE 1 is a plot of E 2 Rb binding activity in the LNCaP human prostatic adenocarcinoma cell line. Detailed Description Throughout this specification and the appended claims, 25 general terms bear their usual meanings.

WO98/45288 PCT/US98/07274 - 5 The term "alkyl" denotes a monovalent radical derived by removal of one hydrogen atom from methane, ethane, or a straight or branched hydrocarbon and includes such groups as methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso 5 butyl, tert-butyl and the like. "Alkoxy" means an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom and includes such groups as methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy 10 and the like. In the present invention, methoxy is the preferred alkoxy group. The term "pro-drug," as used herein means a compound of the present invention bearing a group which is metabolically cleaved in a human to produce a therapeutically active 15 compound of the present invention. In particular, such pro drug compounds include those in which either or both of the substituent groups R and R 2 of the structure shown above are hydroxy groups which have been protected by a pharmaceutically acceptable hydroxy protecting group which 20 is metabolically cleaved in the body to yield a corresponding monohydroxy or dihydroxy compound of the present invention. Hydroxy protecting groups are described in Chapter 2 of T. W. Greene, et al., "Protective Groups in Organic Synthesis," Second Edition, John Wiley & Sons, Inc., 25 New York, 1991. Simple ether and ester groups are preferred as pro-drug hydroxy protecting groups.

WO98/45288 PCT/US98/07274 - 6 Preferred compounds of the present invention include 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidino ethoxy)phenoxy]benzo[b]thiophene or a pharmaceutically acceptable salt or pro-drug thereof; and 5 6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidino ethoxy)phenoxy]benzo[b]thiophene or a pharmaceutically acceptable salt or pro-drug thereof. Preparation of Compounds of the Invention 0 The starting material for one route for preparing compounds of the present invention is prepared essentially as described by C. D. Jones in U.S. Patents. No's. 4,418,068, and 4,133,814. The starting materials have the formula 1: .5 _5 R50 S

OR

6 1 wherein R 5 and R 6 are independently -H or a hydroxy 0 protecting group. The R s 5 and R 6 hydroxy protecting groups are moieties which are intentionally introduced during a portion of the synthetic process to protect a group which otherwise might react in the course of chemical manipulations, and is then 5 removed at a later stage of the synthesis. Since compounds bearing such protecting groups are of importance primarily as chemical intermediates (although some derivatives also exhibit biological activity), their precise structure is not critical. Numerous reactions for the formation, removal, 0 and reformation of such protecting groups are described in a number of standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Greene, T.W., Protective Groups in Organic WO 98/45288 PCT/US98/07274 - 7 Synthesis, Wiley (New York, 1981); and The Peptides, Vol. I, Schrooder and Lubke, Academic Press, (London and New York, 1965). Representative hydroxy protecting groups include, for 5 example, -C1-C 4 alkyl, -C 1

-C

4 alkoxy, -CO-(C 1

-C

6 alkyl), SO 2

-(C

4

-C

6 alkyl), and -CO-Ar in which Ar is benzyl or optionally substituted phenyl. The term "substituted phenyl" refers to a phenyl group having one or more substituents selected from the group consisting of C 1

-C

4 .0 alkyl, C 1

-C

4 alkoxy, hydroxy, nitro, halo, and tri(chloro or fluoro) methyl. The term "halo" refers to bromo, chloro, fluoro, and iodo. For compounds of formula 1, preferred R 5 and R 6 substituents are methyl, isopropyl, benzyl, and 5 methoxymethyl. Compounds in which R 5 and R 6 each are methyl are prepared via the procedure described in the above referenced Jones patent. Compounds of formula 1 are also prepared in which the

R

5 hydroxy protecting group is selectively removed, leaving 0 R 6 as a hydroxy protecting group as part of the final product. The same is true in the case in which the R 6 hydroxy protecting group is selectively removed, leaving the

R

5 hydroxy protecting group in place. For example, R 5 can be isopropyl or benzyl and R 6 methyl. The isopropyl or .5 benzyl moiety is selectively removed via standard procedures, and the R 6 methyl protecting group is left as part of the final product. As shown in Reaction Scheme I, the first steps of the present process for preparing certain compounds of the '0 present invention include selectively placing a leaving group, R 7 at the 3 position of a compound of formula 1, to form a compound of formula 2, coupling the product of that reaction with a 4 -(protected-hydroxy)phenol, 3, to form a compound of formula 4, and selectively removing the R 8 .5 hydroxy protecting group to form a compound of formula 5. In the sequence of steps shown in Reaction Scheme I, the hydroxy protecting groups R 5 , R 6 and R 8 are chosen in such a WO98/45288 PCT/US98/07274 manner that, in the final step, the hydroxy protecting group

R

8 can be selectively removed in the presence of hydroxy protecting groups R 5 and R 6 . 5 Reaction Scheme I OW R7 1I 1_ II

R

5 0 S

R

5 0 -S 1 OR 6 2 OR 6

OR

8 I OH OH

OR

8 - 0 - 0 I I

R

5 0 'S

R

5 0 S 5 OR 6 4 OR 6 In the first step of Reaction Scheme I, an appropriate LO leaving group is selectively placed at the 3-position of the formula 1 starting material via standard procedures. Appropriate R 7 leaving groups include the sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4 -methoxybenzene L5 sulfonate, 4-nitrobenzenesulfonate, 2 chlorobenzenesulfonate, triflate, and the like, halogens such as bromo, chloro, and iodo, and other related leaving groups. However, to insure proper placement of the leaving group, the named halogens are preferred, and bromo is 20 especially preferred. The present reaction is carried out using standard procedures. For example, when the preferred halogenating WO98/45288 PCT/US98/07274 - 9 agents are used, an equivalent of such a halogenating agent, preferably bromine, is reacted with an equivalent of the formula 1 substrate, in a suitable solvent such as, for example, chloroform or acetic acid. The reaction is 5 typically run at a temperature from about 40 0 C to about 80 0 C. The reaction product from the above process step, a compound of formula 2, is then reacted with a 4-(protected hydroxy)phenol, 3, to form compounds of formula 4 in which 10 R 8 is a selectively removable hydroxy protecting group. Generally, the 4-hydroxy protecting moiety of the phenol may be any known protecting group which can be selectively removed without removing, in this instance, the R 5 and, when present, R 6 moieties of a formula 3 compound. Preferred R 8 15 protecting groups include methoxymethyl, when R 5 and/or R 6 are not methoxymethyl, and benzyl. Of these, benzyl is especially preferred. The 4-(protected-hydroxy)phenol reactants are commercially available or can be prepared via standard procedures. 20 The coupling reaction between compounds of formula 2 and those of formula 3 is known in the art as an Ullman reaction and is generally run according to standard procedures [see, e.g., "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," Fourth Edition, 3-16, 25 (J. March, ed., John Wiley & Sons, Inc. 1992); Jones, C.D., J. Chem. Soc. Perk. Trans. I, 4:407 (1992)]. In general, equivalent amounts of the two aryl substrates, in the presence of up to an equimolar amount of a copper(I) oxide catalyst and an appropriate solvent, are 30 heated to reflux under an inert atmosphere. Preferably, an equivalent of a formula 2 compound in which R 7 is bromo is reacted with an equivalent amount of 4 -benzyloxyphenol in the presence of an equivalent of cuprous oxide. Appropriate solvents for this reaction are those 35 solvents or mixture of solvents which remain inert throughout the reaction. Typically, organic bases, WO98/45288 PCT/US98/07274 - 10 particularly a hindered base such as, for example, 2,4,6 collidine, are preferred solvents. The temperature employed in this step is generally sufficient to effect completion of this coupling reaction, 5 and will influence the amount of time required therefore. When the reaction mixture is heated to reflux under an inert atmosphere such as nitrogen, the time-to-completion is usually from about 20 to about 60 hours. Following coupling of a compound of formula 2 with one LO of formula 3, to form a formula 4 compound, formula 5 compounds are prepared by selectively removing the R 8 hydroxy protecting group of a formula 4 compound via well known reduction procedures. It is imperative that the selected procedure will not affect the R 5 and, when present, L5 R 6 hydroxy protecting groups. When R 8 is the preferred benzyl moiety, and R 5 and, when present, R 6 each are methyl, the present process step is carried out via standard hydrogenolysis procedures. Typically, the formula 4 substrate is added to a suitable 20 solvent or mixture of solvents, followed by the addition of a proton donor to accelerate the reaction and an appropriate hydrogenation catalyst. Appropriate catalysts include noble metals and oxides such as palladium, platinum, and rhodium oxide on a support 25 such as carbon or calcium carbonate. Of these, palladium on-carbon, particularly 10% palladium-on-carbon, is preferred. Solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the reaction. Typically, ethylacetate and C 1

-C

4 aliphatic 30 alcohols, particularly ethanol, is preferred. For the present reaction, hydrochloric acid serves as an adequate and preferred proton donor. When run at ambient temperature and a pressure ranging form about 30 psi (206.8 kilopascals) to about 50 psi 344.7 35 kilopascals), the present reaction runs quite rapidly. Progress of this reaction may be monitored by standard WO98/45288 PCT/US98/07274 - 11 chromatographic techniques such as thin layer chromatography. As shown in Reaction Scheme II, upon preparation of a formula 5 compound, it is reacted with a compound of formula 5

R

4

R

5

N-(CH

2 )2-Q 6 wherein R 4 and R 5 are as defined above, and Q is a bromo or, 0 preferably, chloro, to form a compound of formula 7. The formula 7 compound is then deprotected to form a compound of formula I.

WO98/45288 PCTIUS98/07274 - 12 Reaction Scheme II R3 II OH R3 R4O R50 N R4 Q - 0 I II 0O RSO~ S N I I R 50 R R s O S z OR 6

R

3 I R45 N O I IR I 55 RSO~OR6 Ia, R 5 = R 6 = H Ib, R 5 = H Ic, R 6 = H In the first step of the process shown in Reaction 5 Scheme II, the reaction is carried out via standard procedures. Compounds of formula 6 are commercially available or are prepared by means well known to one of ordinary skill in the art. Preferably, the hydrochloride salt of a formula 6 compound is used. In a particularly 0 preferred case of the compounds of the present invention, 2 chloroethylpiperidine hydrochloride, is used. Generally, at least about 1 equivalent of a formula 5 substrate is reacted with 2 equivalents of a formula 6 compound in the presence of at least about 4 equivalents of WO98/45288 PCT/US98/07274 - 13 an alkali metal carbonate, preferably cesium carbonate, and an appropriate solvent. Suitable solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the 5 reaction. N,N-dimethylformamide, especially the anhydrous form thereof, is preferred. The temperature employed in this step should be sufficient to effect completion of this alkylation reaction. Typically, ambient temperature is sufficient and preferred. The present reaction preferably LO is run under an inert atmosphere, particularly nitrogen. Under the preferred reaction conditions, this reaction will run to completion in about 16 to about 20 hours. The progress of the reaction can be monitored via standard chromatographic techniques. L5 In an alternative process for preparing compounds of the present invention, shown in Reaction Scheme III below, a formula 5 compound is reacted in an alkali solution with an excess of an alkylating agent of formula 8: 20 Q-(CH2)n-Q' 8 in which Q and Q' are the same or different leaving groups. Appropriate leaving groups are those mentioned above.

WO 98/45288 PCT/US98/07274 - 14 Reaction Scheme III OH Q- O S 0 R50 IsI

OR

6 -I RSOR O Ro R O C6 OR

R

3

R

4 NH

R

3

R

3 R 4'0R 4 ' N,,-.,O R4O R4N O 0 0

R

5 0 0R . OR 6 R OR 6 I a, R 5 = R 6 H Ib, R 5 = H 6 Ic, R = H 5 A preferred alkali solution for this alkylation reaction contains potassium carbonate in an inert solvent such as, for example, methyethyl ketone (MEK) or DMF. In this solution, the unprotected hydroxy group of the formula 5 compound is converted to a phenoxide ion which displaces 10 one of the leaving groups of the alkylating agent. This reaction proceeds best when the alkali solution containing the reactants and reagents is brought to reflux and allowed to run to completion. When using MEK as the preferred solvent, reaction times range from about 6 hours 15 to about 20 hours.

WO98/45288 PCT/US98/07274 - 15 The reaction product from this step, a compound of formula 9 is then reacted with a compound of formula 10 selected from 1-piperidine, 1-pyrrolidine, methyl-1 pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, 5 dimethylamine, diethylamine, diisopropylamine, or 1 hexamethyleneimine, via standard techniques, to form compounds of formula 7. Preferably, the hydrochloride salt of a compound of formula 10 is employed, with piperidine hydrochloride being particularly preferred. The reaction is 10 typically carried out with the alkylated compound of formula 9 in an inert solvent, such as anhydrous DMF, and heated to a temperature in the range from about 60 0 C to about 110 0 C. When the mixture is heated to a preferred temperature of about 90 0 C, the reaction only takes about 30 minutes to 15 about 1 hour. However, changes in the reaction conditions will influence the amount of time this reaction needs to be run for completion. The progress of this reaction step can be monitored via standard chromatographic techniques. Certain preferred compounds of formula I are obtained 20 by cleaving the R 5 and, when present, R 6 hydroxy protecting groups of formula I compounds via well known procedures. Numerous reactions for the formation and removal of such protecting groups are described in a number of standard works including, for example, Protective Groups in Organic 25 Chemistry, Plenum Press (London and New York, 1973); Greene, T.W., Protective Groups in Organic Synthesis, Wiley, (New York, 1981); and The Peptides, Vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965). Methods for removing preferred R 7 and/or R 8 hydroxy protecting groups, 30 particularly methyl and methoxymethyl, are essentially as described in the Examples, infra. An alternative, and preferred, method for the preparation of compounds of the present invention is shown in Reaction Scheme IV. In the process shown there, the 35 sulfur atom of a formula 2 compound is oxidized to form a sulfoxide, 11, which is then reacted with a nucleophilic group to introduce the oxygen atom linker of formula I WO 98/45288 PCT/US98/07274 - 16 compounds. The sulfoxide moiety of formula 12 compounds is then reduced to provide certain compounds of the present invention. 5 Reaction Scheme IV 1111 :1111

R

5 0 R 5 0 R" % OR6 R O OR6 12 Ho' O N.R4 R 3

R

3 I I R4 No R4 No 0 -R 0 OR6 R

OR

6 oo Kao 14 Ia, R 5 = R 6 = H Ib, R 5 = H Ic, R 6 H In the first step of this process, a compound of 0 formula 2 is selectively oxidized to the sulfoxide, 12. A number of known methods are available for the process step [see, e.g., Madesclaire, M., Tetrahedron, 42 (20); 5459-5495 (1986); Trost, B.M., et al., Tetrahedron Letters, 22 (14); 1287-1290 (1981); Drabowicz, J., et al., Synthetic 5 Communications, 11 (12); 1025-1030 (1981); Kramer, J.B., et WO98/45288 PCTIUS98/07274 - 17 al., 34th National Organic Symposium, Williamsburg, VA., June 11-15, 1995]. However, many oxidants provide only poor conversion to the desired product as well as significant over-oxidation to the sulfone. The preferred process, 5 however, converts a formula 2 compound to a sulfoxide of formula 12 in high yield with little or no formation of sulfones. This process involves the reaction of a formula 2 compound with about 1 to about 1.5 equivalents of hydrogen peroxide in a mixture of about 20% to about 50% LO trifluoroacetic acid in methylene chloride. The reaction is run at a temperature from about 100 C to about 500 C, and usually required from about 1 to about 2 hours to run to completion. Next, the 3-position leaving group, R 7 , is displaced by L5 the desired nucleophilic derivative of formula 13. Such nucleophilic derivatives are prepared via standard methods. In this step of the process, the acidic proton of the nucleophilic group is removed by treatment with a base, preferably a slight excess of sodium hydride or potassium W0 tertbutoxide, in a polar aprotic solvent, preferably DMF or tetrahydrofuran. Other bases that can be employed include potassium carbonate and cesium carbonate. Additionally, other solvents such as dioxane or dimethylsulfoxide can be employed. The deprotonation is usually run at a temperature 25 between about 00 C and about 300 C, and usually requires about 30 minutes for completion. A compound of formula XIV is then added to the solution of the nucleophile. The displacement reaction is run at a temperature between 00 C and about 500 C, and is usually run in about 1 to about 2 30 hours. The product is isolated by standard procedures. In the next step of the present process, the sulfoxide of formula 14 is reduced to a benzothiophene compound of formula I. When desired, the hydroxy protecting group or groups of 35 the products of the process shown in Reaction Scheme IV can be removed, and a salt of the product of any step of the process.

WO98/45288 PCT/US98/07274 - 18 Pro-drug ester compounds of formula I are prepared by replacing the 6- and/or 4'-position hydroxy moieties, when present, with a moiety of the formula -OCO(Cl-C 6 alkyl), or

-OSO

2

(C

2

-C

6 alkyl) via well known procedures. See, e.g., 5 U.S. Pat. No. 4,358,593. For example, when an -OCO(Cl-C 6 alkyl) group is desired, a mono- or dihydroxy compound of formula I is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed LO anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine, and the like. The reaction also may be carried out in an inert L5 solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, and the like, to which at least one equivalent of an acid scavenger (except as noted below), such as a tertiary amine, has been added. If 20 desired, acylation catalysts such as 4 -dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g., Haslam, et al., Tetrahedron, 36:2409-2433 (1980). These reactions are carried out at moderate temperatures, in the range from about -250 C to about 1000 25 C, frequently under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually adequate for the reaction to run. Acylation of a 6-position and/or 4'-position hydroxy group also may be performed by acid-catalyzed reactions of 30 the appropriate carboxylic acids in inert organic solvents. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid, and the like are used. The aforementioned ester pro-drug compounds also may be provided by forming an active ester of the appropriate acid, 35 such as the esters formed by such known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1- WO98/45288 PCT/US98/07274 - 19 hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan, 38:1979 (1965), and Chem. Ber., 788 and 2024 (1970). Each of the above techniques which provide -OCO(C 1

-C

6 alkyl) moieties are carried out in solvents as discussed 5 above. Those techniques which do not produce an acid product in the course of the reaction, of course, do not call for the use of an acid scavenger in the reaction mixture. When a formula I compound is desired in which the 6 LO and/or 4'-position hydroxy group of a formula I compound is converted to a group of the formula -OS0 2

(C

2

-C

6 alkyl), the mono- or dihydroxy compound is reacted with, for example, a sulfonic anhydride or a derivative of the appropriate sulfonic acid such as a sulfonyl chloride, bromide, or L5 sulfonyl ammonium salt, as taught by King and Monoir, J. Am. Chem. Soc., 97:2566-2567 (1975). The dihydroxy compound also can be reacted with the appropriate sulfonic anhydride or mixed sulfonic anhydrides. Such reactions are carried out under conditions such as were explained above in the 20 discussion of reaction with acid halides and the like. Preparation of Pharmaceutically Acceptable Salts of Compounds of the Present Invention Although the free-base form of formula I compounds can 25 be used in the medical methods of treatment of the present invention, it is preferred to prepare and use a pharma ceutically acceptable salt form. The compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of 30 organic and inorganic acids. Such salts are also contemplated as falling within the scope of the present invention. The term "pharmaceutically acceptable salts" as used throughout this specification and the appended claims 35 denotes salts of the types disclosed in the article by Berge, et al., J. Pharmaceutical Sciences, 66(1): 1-19 (1977). Suitable pharmaceutically acceptable salts include WO98/45288 PCT/US98/07274 - 20 salts formed by typical inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like as well as salts derived from organic acids, such as aliphatic mono and 5 dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable organic acid addition salts include acetate, phenylacetate, trifluoroacetate, acrylate, 10 ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyne-l,4 dioate, hexyne-l,4-dioate, caprate, caprylate, chloride, 15 cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, 20 metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2 25 hydroxyethanesulfonate, methanesulfonate, naphthalene-1 sulfonate, naphthalene-2-sulfonate, p-toluene-sulfonate, xylenesulfonate, tartarate, and the like. Preferred salts are the hydrochloride and oxalate salts. The pharmaceutically acceptable acid addition salts are 30 typically formed by reacting a compound of formula I with an equimolar or slight molar excess of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt normally precipitates out of solution within about one hour to 10 days and can be 35 isolated by filtration or the solvent can be stripped off by conventional means.

WO98/45288 PCT/US98/07274 - 21 The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions. 5 Pharmaceutical Formulations The compounds of this invention are administered by a variety of routes including oral, rectal, transdermal, subucutaneus, intravenous, intramuscular, and intranasal. LO These compounds preferably are formulated prior to administration, the selection of which will be decided by the attending physician. Thus, another aspect of the present invention is a pharmaceutical composition comprising an effective amount of a compound of Formula I, or a .5 pharmaceutically acceptable salt thereof, optionally containing an effective amount of estrogen or progestin, and a pharmaceutically acceptable carrier, diluent, or excipient. The total active ingredients in such formulations .0 comprises from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" it is meant the carrier, diluent, excipients and salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof. .5 Pharmaceutical formulations of the present invention are prepared by procedures known in the art using well known and readily available ingredients. For example, the compounds of Formula I, either alone, or in combination with an estrogen or progestin compound, are formulated with 0 common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, solutions, injectables, aerosols, powders, and the like. The total active ingredients in such formulations comprises from 0.1% to 99.9% by weight of the formulation. 5 By "pharmaceutically acceptable" it is meant the carrier, diluent, excipients and salt must be compatible with the WO98/45288 PCTIUS98/07274 - 22 other ingredients of the formulation, and not deleterious to the recipient thereof. The formulations may be specially formulated for oral administration, in solid or liquid form, for parenteral 5 injection, topical or aerosol administration, or for rectal or vaginal administration by means of a suppository. The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, intravaginally, parenterally, topically (by means LO of powders, ointments, creams, or drops), bucally or sublingually, or as an oral or nasal spray. The term "parenteral administration" refers herein to modes of administration which include intravenous, intramuscular, intraperitoneal, instrasternal, subcutaneous, or L5 intraarticular injection or infusion. Pharmaceutical compositions of this invention for parenteral administration comprise sterile aqueous or non aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders which are reconstituted 20 immediately prior to use into sterile solutions or suspensions. Examples of suitable sterile aqueous and non aqueous carriers, diluents, solvents or vehicles include water, physiological saline solution, ethanol, polyols (such as glycerol, propylene glycol, poly(ethylene glycol), and 25 the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by the maintenance of proper particle size in the case of 30 dispersions and suspensions, and by the use of surfactants. Parenteral compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms is ensured by the inclusion of antibacterial 35 and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, WO98/45288 PCTIUS98/07274 - 23 and the like. Prolonged absorption of injectable formulations may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. 5 In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug following subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous material of low water solubility or LO by dissolving or suspending the drug in an oil vehicle. In the case of the subcutaneous or intramuscular injection of a suspension containing a form of the drug with low water solubility, the rate of absorption of the drug depends upon its rate of dissolution. L5 Injectable "depot" formulations of the compounds of this invention are made by forming microencapsulated matrices of the drug in biodegradable polymers such as poly(lactic acid), poly(glycolic acid), copolymers of lactic and glycolic acid, poly (orthoesters), and poly 0 (anhydrides) these materials which are described in the art. Depending upon the ratio of drug to polymer and the characteristics of the particular polymer employed, the rate of drug release can be controlled. Injectable formulations are sterilized, for example, by 25 filtration through bacterial-retaining filters, or by presterilization of the components of the mixture prior to their admixture, either at the time of manufacture or just prior to administration (as in the example of a dual chamber syringe package). 30 Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active component is mixed with at least one inert, pharmaceutically acceptable carrier such as sodium citrate, or dicalcium phosphate, and/or (a) fillers 35 or extenders such as starches, lactose, glucose, mannitol, and silicic acid, (b) binding agents such as carboxymethyl cellulose, alginates, gelatin, poly(vinylpyrrolidine), WO98/45288 PCT/US98/07274 - 24 sucrose and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, silicates and sodium carbonate, (e) solution retarding agents such as paraffin, 5 (f) absorption accelerating agents such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerin monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid poly(ethylene glycols), 10 sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also comprise the fill in soft or hard gelatin capsules using excipients 15 such as lactose as well as high molecular weight poly(ethylene glycols) and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can also be prepared with coatings or shells such as enteric coatings or other coatings well known 20 in the pharmaceutical formulating art. The coatings may contain opacifying agents or agents which release the active ingredient(s) in a particular part of the digestive tract, as for example, acid soluble coatings for release of the active ingredient(s) in the stomach, or base soluble 25 coatings for release of the active ingredient(s) in the intestinal tract. The active ingredient(s) may also be microencapsulated in a sustained-release coating, with the microcapsules being made part of a pill of capsule formulation. 30 Liquid dosage forms for oral administration of the compounds of this invention include solution, emulsions, suspensions, syrups and elixirs. In addition to the active components, liquid formulations may include inert diluents commonly used in the art such as water or other 35 pharmaceutically acceptable solvents, solubilizing agents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, WO98/45288 PCT/US98/07274 - 25 propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, ground nut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, poly(ethylene glycols), fatty 5 acid esters of sorbitol, and mixtures thereof. Besides inert diluents, the liquid oral formulations may also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. LO Liquid suspension, in addition to the active ingredient(s) may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite clay, agar-agar, and tragacanth, L5 and mixtures thereof. Compositions for rectal or intravaginal administration are prepared by mixing one or more compounds of the present invention with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or any suppository wax 0 which is a solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active component(s). The compounds are dissolved in the melted wax, formed into the desired shape, and allowed to harden into the finished suppository 25 formulation. Compounds of the present invention may also be administered in the form of liposomes. As is know in the art, liposomes are generally derived from phospholipids or other lipid substances. Lipososome formulations are formed 30 by mono- or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, pharmaceutically acceptable, and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to one or more 35 active compounds of the present invention, stabilizers, excipients, preservatives, and the like. The preferred WO98/45288 PCTIUS98/07274 - 26 lipids are phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods for forming liposomes are know in the art as described, for example, in Prescott, Ed., Methods in Cell 5 Biology, Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq. Method of the Present Invention BPH - The fibromuscular stroma of male accessory sex LO organs from several species is sensitive to the stimulatory effects of androgens and estrogens. This tissue is believed to play an important role in both the initial development and subsequent progression of benign prostatic hyperplasia (BPH). Target organ estrogenic responses can be inhibited L5 by certain non-steroidal antagonists such as tamoxifen or clomiphene, but the utility of these compounds in males may be limited by their feminizing effects related to their inherent estrogen agonist properties. Pharmacological antagonism of estrogen action may be 20 useful in the treatment of BPH. Tamoxifen administered to human BPH patients was relatively ineffective in altering the relative distribution of prostatic glandular and stromal tissue, but these results may flow from the partial agonistic activity of the compound with the attendant 25 stimulation of prostatic fibromuscular stroma. Prostate carcinoma - Recently G. G. Kuiper, et al. Proc. NAt'l. Acad. Sci. USA, 93: 5925-5930 (1996) have reported the cloning from rat prostateic and ovarian tissue the gene sequence for a novel estrophilic protein. This new 30 estrophile, which has been designated ERb, shares a >95% DNA binding domain homology and about 55% ligand binding domain homology with uterine estrogen receptor (ER). ERb may be the principal receptor mediating estrogen action in the prostate. Interestingly, ERb mRNA expression has also been 35 demonstrated in the LNCaP human prostatic cancer cell line in our laboratories. This observation that human prostatic cancer cells express ERb indicates that a selective estrogen WO98/45288 PCT/US98/07274 - 27 receptor modulating compound of the present invention is useful in the treatment and prevention of prostatic cancer. Selective estrogen receptor modulating compounds of the present invention have a relatively pure antagonistic 5 profile with high affinity for estrogen receptors, but lack the detrimental cardiovascular and feminizing liabilities of estrogen agonists. Administration of an effective amount of a compound of the present invention is effective in the management or treatment of both benign and malignant LO hormone-sensitive urogenital neoplasms. In the experiments described below, the abilities of compounds of the present invention to bind at estrogen receptors in several human prostatic cancer cell lines were evaluated. L5 Lysates of the LNCaP, DU-45 and PC-3 human prostatic cancer cell lines were prepared in a TEG medium comprising 50 nM Tris*-HCl pH 7.4, 1.5 mM ethylenediamine tetraacetic acid (EDTA) 0.4 M KCl, 10% glycerol, 0.5 mM 2-ME, and 10 mM sodium molybdate further containing the protease inhibitors .0 pepstatin (1 mg/mL), leupeptin (2 mg/mL), aprotinin (5 mg/mL) and phenylmethylsulfonyl fluoride (PMSF, 0.1 mM) (TEGP). The cell lysates were centrifuged and the pellets resuspended in cold TEGP (1 mL TEGP/100 mg of pellet) and .5 sonicated for 30 seconds (duty cycle 70%, output 1.8) on a Branson Model 450 Sonifier. Lysates were pelleted by centrifugation at 10,000 x G for 15 minutes at 4 C after which the supernates were withdrawn and either used immediately or stored at -70 0 C. 30 Competitive Binding Assay The binding buffer was TEG in which the 0.4 M KCl was replaced by 50 mM NaCl and to which 1 mg/mL of ovalbumin had been further added (TEGO). Selected compounds of the present invention were diluted to 20 nM in TEGO from which 35 3-fold serial dilutions were prepared. Assays were performed in round-bottom polyprolylene microplates in triplicate microwells. Each well received 35 mL of WO98/45288 PCT/US98/07274 - 28 tritiated 17b-estradiol (0.5 iM, specific activity 60.1 Ci/mmol, DuPont-New England Nuclear, Boston, MA) and 35 mL of cold competitot test compound (0.1 nM - 5 mM) or TEGO, and following incubation for 5 minutes at 4 0 C with shaking, 5 70 mL of MCF-7 cell line lysate. Plates were incubated for 24 hours at 4 0 C after which time 70 mL of dextran-coated charcoal (DCC) was added to each well followed by vigorous shaking for 8 minutes at 4oC. The plates were then centrifuged at 1500 x G for 10 minutes LO at 4 0 C. Supernate was harvested from each well into a flexible polystyrene microplate for scintillation counting in a Wallac Micobeta Model 1450 counter. Radioactivity was expressed as disintegrations per minute (DPM) after correcting for counting efficiency (35-40%) and background. L5 Additional controls were total counts and total counts + DCC to defined the lower limit of DCC extractabke counts. The results of these competitive binding assays are expressed as mean percent bound (% Bound) +/- standard deviation using the formula: 20 DPMtest compound- DPMtotal count + DCC % Bound = x 100 DPMno test compound DPMtotal count + DCC In Figure 1 there is shown a plot of E 2 Rb binding activity in the LNCaP human prostatic adenocarcinoma cell 25 line. In this study, high affinity (i.e. dissociation constant (Kp = 6.5 nM), saturable (Bmax = 160 fmol/mg cellular protein or about 37,000 receptors per cell) binding of tritiated E 2 wass demonstrated in cultures of LNCaP cells. 30 As used herein, the term "effective amount" means an amount of compound of the present invention which is capable of alleviating the symptoms of the conditions herein described. The specific dose of a compound administered according to this invention is determined by the particular 35 circumstances surrounding the case including, for example, WO 98/45288 PCT/US98/07274 - 29 the potency of the compound administered, the route of administration, the state of being of the patient, and the pathological condition being treated. A typical daily dose will contain a nontoxic dosage level of from about 5 mg to 5 about 600 mg/day of a compound of the present invention. Preferred daily doses generally will be from about 15 mg to about 80 mg/day. The exact dose is determined, in accordance with the standard practice in the medical arts of dose titrating" the LO patient; that is, initially administering a low dose of the compound, and gradually increasing the does until the desired therapeutic effect is observed. The following examples are presented to further L5 illustrate the preparation of compounds of the present invention. The Examples are not to be read as limiting the scope of the invention as it is defined by the appended claims. NMR data for the following Examples were generated on a 0 GE 300 MHz NMR instrument, and anhydrous hexadeutero dimethylsulfoxide was used as the solvent unless otherwise indicated. Example 1 ,5 Preparation of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy] phenoxy]-2-(4-methoxyphenyl)]benzo[blthiophene oxalate salt * (COOH) 2 CH0 0 00H 3 WO 98/45288 PCT/US98/07274 - 30 Step a: Preparation of [6-methoxy-2-(4-methoxy-phenyl)-3 bromo]benzo[b]thiophene !P Br

H

3 CO S

OCH

3 5 To a solution of [6-methoxy-2-(4-methoxyphenyl)]benzo [b]thiophene (27.0 g, 100 mmol)in 1.10 L of chloroform at 600 C was added bromine (15.98 g, 100 mmol) dropwise as a solution in 200 mL of chloroform. After the addition was LO.0 complete, the reaction was cooled to room temperature, and the solvent removed in vacuo to provide 34.2 g (100%) of [6 methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene as a white solid. mp 83-850 C. 1H NMR (DMSO-d 6 ) d 7.70-7.62 (m, 4H), 7.17 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, L5 2H). FD mass spec: 349, 350. Anal. Calcd. for C16H130 2 SBr: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76. Step b): Preparation of [6-methoxy-2-(4-methoxyphenyl)-3 (4-benzyloxy)phenoxy] benzo [b] thiophene 20 0 H3CO S

OCH

3 To a solution of [6-methoxy-2-(4-methoxyphenyl)-3 bromo] benzo[b]thiophene (34.00 g, 97.4 mmol) in 60 mL of 25 collidine under N 2 was added 4-benzyloxyphenol (38.96 g, 194.8 mmol) and cuprous oxide (14.5 g, 97.4 mmol). The resultant mixture was heated to reflux for 48 hours. Upon cooling to room temperature, the mixture was dissolved in WO98/45288 PCT/US98/07274 - 31 acetone (200 mL), and the inorganic solids were removed by filtration. The filtrate was concentrated in vacuo, and the residue dissolved in methylene chloride (500 mL). The methylene chloride solution was washed with 3N hydrochloric 5 acid (3 X 300 mL), followed by 1N sodium hydroxide (3 x 300 mL). The organic layer was dried (sodium sulfate), and concentrated in vacuo. The residue was taken up in 100 mL of ethyl acetate whereupon a white solid formed that was collected by filtration [recovered [6-methoxy-2-(4 .0 methoxyphenyl)]benzo-[b]thiophene (4.62 g, 17.11 mmol]. The filtrate was concentrated in vacuo, and then passed through a short pad of silica gel (methylene chloride as eluant) to remove baseline material. The filtrate was concentrated in vacuo, and the residue crystallized from hexanes/ethyl .5 acetate to provide initially 7.19 g of [6-methoxy-2-(4 methoxyphenyl)-3-( 4 -benzyloxy)phenoxy]benzo[b]-thiophene as an off-white crystalline solid. The mother liquor was concentrated and chromatographed on silica gel (hexanes/ethyl acetate 80:20) to provide an additional 1.81 .0 g of product. Total yield of [6-methoxy-2-(4-methoxyphenyl) 3-( 4 -benzyloxy)phenoxy]-benzo[b]thiophene was 9.00 g (24% based on recovered starting material). The basic extract was acidified to pH = 4 with 5N hydrochloric acid, and the resultant precipitate collected by filtration and dried to 5 give 13.3 g of recovered 4-benzyloxyphenol. mp 100-1030 C. 1 H NMR (CDCl 3 ): d 7.60 (d, J = 8.8 Hz, 2H), 7.39-7.24 (m, 7H), 6.90-6.85 (m, 7H), 4.98 (s, 2H), 3.86 (s, 3H) 3.81 (s, 3H). FD mass spec: 468. Anal. Calcd. for C 29

H

2 4 0 4 S: C, 74.34; H, 5.16. Found: C, 74.64; H, 5.29. 10 WO 98/45288 PCT/US98/07274 - 32 Step c): Preparation of [6-methoxy-2-(4-methoxyphenyl)-3 (4-hydroxy)phenoxy] benzo[b] thiophene OH 0 I

H

3 CO S

OCH

3 5 To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4 benzyloxy)phenoxy]benzo[b]thiophene (1.50 g, 3.20 mmol) in 50 mL of ethyl acetate and 10 mL of 1% concentrated hydrochloric acid in ethanol was added 10% palladium-on LO carbon (300 mg). The mixture was hydrogenated at 40 psi for 20 minutes, after which time the reaction was judged complete by thin layer chromatography. The mixture was passed through Celite to remove catalyst, and the filtrate concentrated in vacuo to a white solid. The crude product L5 was passed through a pad of silica gel (chloroform as eluant). Concentration provided 1.10 g (91%) of [6-methoxy 2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]-thiophene as a white solid. mp 123-1260 C. 1 H NMR (DMSO-d 6 ) d 9.10 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 2.1 Hz, 1H), 20 7.14 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8.8, 2.1 Hz, 1H), 6.72 (d, J = 9.0 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H). FD mass spec: 378. Anal. Calcd. for C 22

H

18 0 4 S: C, 69.82; H, 4.79. Found: C, 70.06; H, 4.98. 25 Step d) : Preparation of [ 6 -methoxy-3-[4-[2-(1-piperidinyl) ethoxy]lphenoxy] -2-(4-methoxyphenyl) ]benzo[b] thiophene oxalate salt To a solution of [ 6 -methoxy-2-(4-methoxyphenyl)-3-(4 30 hydroxy)phenoxy]benzo[b]thiophene (1.12 g, 2.97 mmol) in 7 mL of anhydrous N,N-dimethylformamide under N 2 was added WO 98/45288 PCT/US98/07274 - 33 cesium carbonate (3.86 g, 11.88 mmol). After stirring for 10 minutes, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) was added. The resultant mixture was stirred for 18 hours at ambient temperature. The reaction was the 5 distributed between chloroform/water (100 mL each). The layers were separated and the aqueous extracted with chloroform (3 x 50 mL). The organic was combined and washed with water (2 x 100 mL). Drying of the organic (sodium sulfate) and concentration provided an oil that was 10 chromatographed on silica gel (2% methanol/chloroform). The desired fractions were concentrated to an oil that was dissolved in 10 mL of ethyl acetate and treated with oxalic acid (311 mg, 3.4 mmol). After stirring for 10 minutes, a white precipitate formed and was collected by filtration and 15 dried to provide 1.17 g (70%) overall of [6-methoxy-3-[4-[2 (1-piperidinyl)ethoxy] -phenoxy] -2-(4-methoxyphenyl) ]benzo [b] thiophene as the oxalate salt. mp 197-2000 C (dec). 1 H NMR (DMSO-d 6 ) d 7.60 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 1.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 20 6.91 (dd, J = 8.8, 1.1 Hz, 1H), 6.87 (s, 4H), 4.19 (broad t, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (broad t, 2H), 3.12 3.06 (m, 4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H). FD mass spec: 489 . Anal. Calcd. for C 2 9

H

3 1

NO

4 S*0.88 HO 2

CCO

2 H: C, 64.95; H, 5.80; N, 2.46. Found: C, 64.92; H, 5.77; N, 2.54. 25 WO 98/45288 PCT/US98/07274 - 34 Example 2 Preparation of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy] phenoxyl]-2-(4-methoxyphenyl)]benzo[b] thiophene hydrochloride 5 salt * HCI N O0 0 00H H3CO S OCH 3 Treatment of the oxalate salt from Example 1 with aqueous base to produce the free base, followed by reaction 10 with diethyl ether saturated with HCI yielded the title salt, mp 216-2200 C. 1 H NMR (DMSO-d 6 ) d 10.20 (bs, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 1.5 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.96 (dd, J = 9.0, 1.5 Hz, 1H), 6.92 (q, JAB = 9.0 Hz, 4H), 4.31 (m, 2H), 15 3.83 (s, 3H), 3.77 (s, 3H), 3.43 (m, 4H), 2.97 (m, 2H), 1.77 (m, 5H), 1.37 (m, 1H). FD mass spec: 489 . Anal. Calcd. for C 29

H

31

NO

4 S*'1.0 HCl: C, 66.21; H, 6.13; N, 2.66. Found: C, 66.,46; H, 6.16; N, 2.74.

WO 98/45288 PCT/US98/07274 - 35 Example 3 Preparation of [6-Methoxy-3-[4-[2-(1-pyrolodinyl)ethoxy] phenoxy] -2-(4-methoxyphenyl) ]lbenzo [b] thiophene 5 NO0 0 H3CO S OCH

OCH

3 The title compound was prepared in the same manner as the compound of Example 1, mp 95-980 C. 1H NMR (DMSO-d 6 ) d L0 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.94 (dd, J = 9.0, 2.0 Hz, 1H), 6.86 (s, 4H), 3.97 (t, J = 6.0 Hz, 2H), 3.83 ( s, 3H), 3.76 (s, 3H), 2.73 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 4H). FD mass spec: 477. Anal. Calcd. for L5 C 2 8

H

2 9

NO

4 S: C, 70.71; H, 6.15; N, 2.99. Found: C, 70.59; H, 6.15; N, 3.01.

WO 98/45288 PCT/US98/07274 - 36 Example 4 Preparation of [6-Methoxy-3-[4-[2-(1-hexamethyleneimino) ethoxy]phenoxy]-2-(4-methoxyphenyl) ]benzo[b] thiophene 5 hydrochloride O *HCI N O 0 0

H

3 CO SCH

OCH

3 The title compound was prepared in the same manner as 10 the compound of Example 1, mp 189-1920 C. 1 H NMR (DMSO-d 6 ) d 10.55 (bs, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, H), 6.86 (s, 4H), 3.94 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J = 6.0 15 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Anal. Calcd. for

C

3 0

H

3 3

NO

4 S*1.0 HCl: C, 66.71; H, 6.35; N, 2.59. Found: C, 66.43; H, 6.46; N, 2.84.

WO 98/45288 PCT/US98/07274 - 37 Example 5 Preparation of [6-Methoxy-3-[4-[2-(l-N,N-diethylamino) ethoxylphenoxy]-2-(4-methoxyphenyl) ]benzo[b]thiophene 5 hydrochloride *HCI

N

O

H

3 C S 33

OCH

3 The title compound was prepared in the same manner as LO the compound of Example 1, mp 196-1980 C. 1 H NMR (DMSO-d 6 ) d 10.48 (bs, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, 1H), 6.87 (q, JAB= 9.0 Hz, 4H), 4.25 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.54 (m, 2H), 3.09 L5 (m, 4H), 2.00 (m, 3H), 1.88 (m, 3H). Anal. Calcd. for

C

2 8

H

3 1 N0 4 S*1.5 HCl: C, 63.18; H, 6.15; N, 2.63. Found: C, 63.46; H, 5.79; N, 2.85.

WO 98/45288 PCT/US98/07274 - 38 Example 6 Preparation of [6-Methoxy-3-[4-[2-(morpholino)ethoxy] phenoxy] -2-(4-methoxyphenyl) ]benzo[b] thiophene hydrochloride 5 O *HCI I- N I HaCO S

OCH

3 The title compound was prepared in the same manner as the compound of Example 1, mp 208-2110 C. 1 H NMR (DMSO-d 6 ) LO d 10.6 (bs, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.20 (J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, 1H), 6.91 (q, JAB = 9.0 Hz, 4H), 4.29 (m, 2H), 4.08-3.91 (m, 4H), 3.82 (s, 3H), 3.77 (s, 3H), 3.59-3.42 (m, 4H), 3.21-3.10 (m, 2H). Anal. Calcd. for L5 C2 8

H

2 9

NO

5 S*1.0 HCl: C, 63.09; H, 5.73; N, 2.65. Found: C, 63.39; H, 5.80; N, 2.40.

WO 98/45288 PCT/US98/07274 - 39 Example 7 Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy] phenoxy] -2-(4-hydroxyphenyl) ]benzo[b] thiophene 5 0 NOyl I HO S OH [6-methoxy-3-[4-[2- (1-piperidinyl)ethoxy]phenoxy] -2-(4 methoxyphenyl)]benzo[b]thiophene hydrochloride (10.00 g, LO 19.05 mmol) was dissolved in 500 mL of anhydrous methylene chloride and cooled to 80 C. To this solution was added boron tribromide (7.20 mL, 76.20 mmol). The resultant mixture was stirred at 8 0 C for 2.5 hours. The reaction was quenched by pouring into a stirring solution of saturated L5 sodium bicarbonate (1 L), cooled to 00 C. The methylene chloride layer was separated, and the remaining solids were dissolved in methanol/ethyl acetate. The aqueous layer was then extracted with 5% methanol/ethyl acetate (3 x 500 mL). All of the organic extracts (ethyl acetate and methylene .0 chloride) were combined and dried (sodium sulfate). Concentration in vacuo provided a tan solid that was chromatographed (silicon dioxide, 1-7% methanol/chloroform) to provide 7.13 g (81 %) of [6-hydroxy-3-[4-[2-(1 piperidinyl) ethoxy]phenoxy]-2-(4-hydroxyphenyl) ]benzo[b] .5 thiophene as a white solid. mp 930 C. 1 H NMR (DMSO-d 6 ) d 9.73 (bs, 1H), 9.68 (bs, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 1.8 Hz, 1H), 7.04 (d, J= 8.6 Hz, 1H), 6.84 (dd, J = 8.6, 1.8 Hz, 1H (masked)), 6.81 (s, 4H), 6.75 (d, J = 8.6 Hz, 2H), 3.92 (t, J = 5.8 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 0 2.36 (m. 4H), 1.43 (m, 4H), 1.32 (m, 2H). FD mass spec: WO 98/45288 PCT/US98/07274 - 40 462. Anal. Calcd. for C 2 7

H

2 7 N0 4 S: C, 70.20; H, 5.90; N, 3.03. Found: C, 69.96; H, 5.90; N, 3.14. Example 8 5 Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy] phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene oxalate salt N (COOH) 2 0 NO I HO S OH 10 The title compound was prepared in 80% yield from the free base, mp 246-2490 C (dec). 1 H NMR (DMSO-d 6 ) d 7.45 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.87 (dd, J = 8.6, 1.8 Hz, 1H (masked)), 6.84 (s, 15 4H), 6.75 (d, J = 8.6 Hz, 2H), 4.08 (bt, 2H), 3.01 (bt, 2H), 2.79 (m, 4H), 1.56 (m, 4H), 1.40 (m, 2H). FD mass spec 462. Anal. Calcd. for C 2 7

H

2 7 N0 4 S*0.75 HO 2

CCO

2 H: C, 64.63; H, 5.42; N, 2.64. Found: C, 64.61; H, 5.55; N, 2.62.

WO 98/45288 PCT/US98/07274 - 41 Example 9 Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy] phenoxy] -2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride 5 * HCI 0 I HO S OH The title compound was prepared in 91% yield by treatment of the corresponding free base with HC1 saturated 10 diethyl ether, mp 158-1650 C. 1 H NMR (DMSO-d 6 ) d 9.79 (s, 1H), 9.74 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.86 (q, JAB= 9.3 Hz, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1), 6.74 (d, J = 8.6 Hz, 2H), 4.26 (bt, 2H), 3.37 (mn, 4H), 2.91 (m, 2H), 1.72 (m, 5 15 H), 1.25 (m, 1H). FD mass spec 461. Anal. Calcd. for C2 7

H

27

NO

4 S*1.0 HCl: C, 65.11; H, 5.67; N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.

WO 98/45288 PCT/US98/07274 - 42 Example 10 Preparation of [6-Hydroxy-3-[4-[2-(1-pyrolidinyl)ethoxy] phenoxy]-2-(4-hydroxyphenyl) ]benzo[b] thiophene 5 ONO 0 I HO S OH The title compound was prepared from the product of Example 3 in a manner similar to that employed in Example 7 0 above; mp 99-1130 C. 1 H NNR (DMSO-d 6 ) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.93 (m, 2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 (t, J = 7.0 Hz, 4H). Anal. 5 Calcd. for C 26

H

25 N0 4 S*0.5 H 2 0: C, 68.40; H, 5.74; N, 3.07. Found: C, 68.52; H, 6.00; N, 3.34.

WO 98/45288 PCT/US98/07274 - 43 Example 11 Preparation of [6-Hydroxy-3-[4-[2-(1-hexamethyleneimino) ethoxy]phenoxy]-2-(4-hydroxyphenyl) ]benzo[b]thiophene 5 0 HO N I OH The title compound was prepared from the product of Example 4 in a manner similar to that employed in Example 7 .0 above; mp 125-1300 C. 1 H NMR (DMSO-d 6 ) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.85 (s, 3H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz), 3.94 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Anal. L5 Calcd. for C 2 8

H

2 9

NO

4 S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.67; H, 6.31; N, 2.93.

WO 98/45288 PCT/US98/07274 - 44 Example 12 Preparation of [6-Hydroxy-3-[4-[2-(1-N,N diethylamino)ethoxy] phenoxy] -2-(4 5 hydroxyphenyl) ]lbenzo[b]thiophene NO N0 I HC) S 0 OH The title compound was prepared from the product of LO Example 5 in a manner similar to that employed in Example 7 above; mp 137-1410 C. 1H NMR (DMSO-d 6 ) d 9.75 (s, 1H), 9.71 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.25 (d, j = 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.85 (s, 4H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.95 (t, J = 6.0 Hz, 15 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H). Anal. Calcd. for C 2 6

H

2 7

NO

4 S: C, 69.46; H, 6.05; N, 3.12. Found: C, 69.76; H, 5.85; N, 3.40.

WO 98/45288 PCT/US98/07274 - 45 Example 13 Preparation of [6-Hydroxy-3-[4-[2-(morpholino)ethoxy] phenoxy] -2-(4-hydroxyphenyl) ]benzo[b] thiophene hydrochloride 5 N 0 HO S OH The title compound was prepared from the product of Example 6 in a manner similar to that employed in Example 7 0 above; mp 157-1620 C. 1H NNR (DMSO-d 6 ) d 10.60 (bs, 1H), 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.92 (q, JAB = 9.0 Hz, 4H), 6.81 (dd, J = 9.0, 2.0 Hz, 1H), 6.80 (d, J = 9.0 Hz, 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51 5 (m, 4H), 3.18 (m, 2H). Anal. Calcd. for C26H 25

NO

5 S.HCl: C, 62.46; H, 5.24; N, 2.80. Found: C, 69.69; H, 5.43; N, 2.92.

WO 98/45288 PCT/US98/07274 - 46 Example 14 Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl)-ethoxy] phenoxy] -2-(4-methoxyphenyl) ]benzo[b] thiophene 5 wNO HO S I SI

OCH

3 Step a): Preparation of 6-Methoxybenzo[b]thiophene-2 boronic acid 0

H

3 CO

B'

O H OH To a solution of 6-methoxybenzo[b]thiophene (18.13 g, 0.111 mol) in 150 mL of anhydrous tetrahydrofuran (THF) at .5 600 C was added n-butyllithium (76.2 mL, .122 mol, 1.6 M solution in hexanes), dropwise via syringe. After stirring for 30 minutes, triisopropyl borate (28.2 mL, .122 mol) was introduced via syringe. The resulting mixture was allowed to gradually warm to 00 C and then distributed between 1N 0 hydrochloric acid and ethyl acetate (300 mL each). The layers were separated, and the organic layer was dried over sodium sulfate. Concentration in vacuo produced a white solid that was triturated from ethyl ether hexanes. Filtration provided 16.4 g (71%) of 6-methoxybenzo[b] 5 thiophene-2-boronic acid as a white solid. mp 2000 C (dec). 1 H NMR (DMSO-d 6 ) d 7.83 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), WO 98/45288 PCT/US98/07274 - 47 7.51 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.6, 2.0 Hz, 1H), 3.82 (s, 3H). FD mass spec: 208. Step b): Preparation of [6-Methoxy-2-(4-methanesulfonyl 5 oxyphenyl)]benzo[b] thiophene

H

3 CO S U OSO2CH3 To a solution of 6-methoxybenzo[b]thiophene-2-boronic 0 acid (3.00 g, 14.4 mmol) in 100 mL of toluene was added 4 (methanesulfonyloxy)phenylbromide (3.98 g, 15.8 mmol) followed by 16 mL of 2.0 N sodium carbonate solution. After stirring for 10 minutes, tetrakistriphenylphosphinepalladium (0.60 g, 0.52 mmol) was added, and the resulting mixture was .5 heated to reflux for 5 hours. The reaction mixture was then allowed to cool to ambient temperature whereupon the product precipitated from the organic phase. The aqueous phase was removed and the organic layer was concentrated in vacuo to a solid. Trituration from ethyl ether yielded a solid that 0 was filtered and dried in vacuo to provide 3.70 g (77%) of [6-methoxy-2-(4-methanesulfonyloxy-phenyl) ]lbenzo[b] thiophene as a tan solid. mp 197-2010 C. 1H NMR (DMSO-d 6 ) d 7.82 7.77 (m, 3H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 6.98 (dd, J = 8.7, 1.5 Hz, 5 1H), 3.80 (s, 3H), 3.39 (s, 3H). FD mass spec 334. Anal. Calcd. for C 1 6

HI

4 0 4

S

2 : C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21. Step c): Preparation of [ 6 -Hydroxy-2-(4-methanesulfonyl 0 oxyphenyl)]benzo[b] thiophene WO 98/45288 PCT/US98/07274 - 48 HO S K SI OS0 2

CH

3 To a solution of [6-methoxy-2-(4-methanesulfonyloxy phenyl)]benzo[b]thiophene (9.50 g, 28.40 mmol) in anhydrous 5 methylene chloride (200 mL) at room under nitrogen gas was added boron tribromide (14.20 g, 5.36 mL, 56.8 mmol). The resulting mixture was stirred at ambient temperature for 3 hours. The reaction was quenched by slowly pouring into excess ice water. After vigorously stirring for 30 minutes, LO the white precipitate was collected by filtration, washed several times with water, and then dried in vacuo to provide 8.92 g (98%) of [6-hydroxy-2-(4-methanesulfonyloxyphenyl)] benzo[b]thiophene as a white solid. mp 239-2430 C. 1 H NMR (DMSO-d 6 ) d 9.70 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.72 (s, L5 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1H), 6.86 (dd, J = 8.7, 1.7 Hz, 1H), 3.38 (s, 3H). FD mass spec 320. Anal. Calcd. for C 1 5

H

12 0 4

S

2 : C, 56.23; H, 3.77. Found: C, 56.49; H, 3.68. 20 Step d): Preparation of [ 6 -Benzyloxy-2-(4-methanesulfonyl oxyphenyl) ]benzo[b] thiophene O00 2 CH3 25 To a solution of [ 6 -hydroxy-2-(4-methanesulfonyloxy phenyl)] benzo[b]thiophene (3.20 g, 10.0 mmol) in 75 mL of anhydrous DMF was added Cs2CO3 (5.75 g, 17.7 mmol) followed by benzylchloride (1.72 mL, 11.0 mmol). The resulting mixture was stirred vigorously for 24 hours. The solvent 30 was removed in vacuo, and the solid residue was suspended in WO 98/45288 PCT/US98/07274 - 49 200 mL of water. The white precipitate was collected by filtration and washed several times with water. Upon drying in vacuo, the crude product was suspended in 1:1 hexanes:ethyl ether. The solid was collected to provide 5 3.72 g (91%) of [6-benzyloxy-2-(4-methanesulfonyloxy phenyl)]benzo[b]thiophene as a white solid. mp 198-2020 C. 1 H NMR (DMSO-d 6 ) d 7.81-7.78 (m, 3H), 7.72 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.47-7.30 (m, 7H), 5.15 (s, 2H), 3.39 (s, 3H). FD mass spec 410. L0 Step e): Preparation of [6-Benzyloxy-2-(4-hydroxyphenyl)] benzo[b]thiophene I I 0 S L5 OH To a solution of [6-benzyloxy-2-(4-methanesulfonyloxy phenyl)]benzo[b]thiophene (12.50 g, 30.50 mmol) in 300 mL of anhydrous THF under nitrogen gas at ambient temperature was 20 added lithium aluminum hydride (2.32 g, 61.0 mmol) in small portions. The mixture was then stirred at ambient temperature for 3 hours and then quenched by carefully pouring the mixture into an excess of cold 1.0 N hydrochloric acid. The aqueous phase was extracted with 25 ethyl acetate. The organic was then washed several times with water and then dried (sodium sulfate) and concentrated in vacuo to a solid. Chromatography (silicon dioxide, chloroform) provided 8.75 g (87%) of [6-benzyloxy-2-(4 hydroxyphenyl)]benzo[b] thiophene as a white solid. mp 212 30 2160 C. 1 H NMR (DMSO-d 6 ) d 9.70 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.51-7.30 (m, 8H), 7.00 (dd, J = 8.7, 2.2 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 5.13 WO 98/45288 PCT/US98/07274 - 50 (s, 2H). FD mass spec 331. Anal. Calcd. for C2 1

H

16 0 2 S: C, 75.88; H, 4.85. Found: C, 75.64; H, 4.85. Step f): Preparation of [6-Benzyloxy-2-(4-methoxyphenyl)] 5 benzo[b]thiophene 0 OI

OCH

3 To a solution of [6-benzyloxy-2-(4-hydroxyphenyl)] .0 benzo[b]thiophene (8.50 g, 26.40 mmol) in 200 mL of anhydrous DMF under nitrogen gas at ambient temperature was added sodium hydride (1.66 g, 41.5 mmol) in small portions. Once gas evolution had ceased, iodomethane (3.25 mL, 52.18 mmol) was added dropwise. The reaction was stirred for 3 .5 hours at ambient temperature. The solvent was then removed in vacuo, and the residue distributed between water/ethyl acetate. The layers were separated, and the organic phase was washed several times with water. The organic layer was then dried (sodium sulfate) and concentrated in vacuo to 0 provide 9.00 g (98%) of [6-benzyloxy-2-(4-methoxyphenyl)] benzo[b]thiophene as a white solid. mp 180-1850 C. 1 H NMR (DMSO-d 6 ) d 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J = 8.8, 2.2 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 5.13 (s, 2H), 3.76 (s, 3H). FD mass spec 346. Anal. Calcd. for ?5 C 2 2

H

1 8 0 2 S: C, 76.27; H, 5.24. Found: C, 76.54; H, 5.43. Step g): Preparation of [6-Benzyloxy-2-(4-methoxyphenyl)-3 bromo] benzo[b] thiophene Br 0 OCH 30 WO 98/45288 PCT/US98/07274 - 51 [6-Benzyloxy-2-(4-methoxyphenyl) ]lbenzo[b] thiophene (10.0 g, 28.9 mmol) was placed in 200 mL of chloroform along with 10.0 g of solid sodium bicarbonate at ambient 5 temperature. To this suspension was added bromine (1.50 mL, 29.1 mmol) dropwise over 30 minutes as a solution in 100 mL of chloroform. Upon completion of the addition, water (200 mL) was added and the layers were separated. The organic phase was dried (sodium sulfate) and concentrated in vacuo 0 to a white solid. Crystallization from methylene chloride/ methanol provided 10.50 g (85%) of [6-benzyloxy-2-(4 methoxyphenyl)-3-bromo]benzo-[b]thiophene as a white solid. mp 146-1500 C. 1 H NMR (DMSO-d 6 ) d 7.70 (d, J = 2.2 Hz, 1H), 7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J = 8.8, 2.2 5 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H). FD mass spec 346. Anal. Calcd. for C22H 1 70 2 SBr: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00. Step h): Preparation of [6-Benzyloxy-2-(4-methoxyphenyl)-3 .0 bromo]benzo[b]thiophene-(S-oxide) O 7Br 00S 0 OCH3 The title compound was prepared by oxidation of the 5 product from step g) with 1.5 equivalents of hydrogen peroxide in a mixture of trifluoroacetic acid in methylene chloride. The product was isolated as a yellow solid by crystallization from ethyl acetate. mp 202-2050 C. 1H NMR (DMSO-d 6 ) d 7.80 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.7 Hz, 0 2H), 7.55(d, J = 8.4 Hz, 1H) 7.47-7.32 (m, 6H), 7.10 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H), 3.80 (s, 3H). FD mass spec 441. Anal. Calcd. for C22H170 3 SBr: C, 59.87; H, 3.88. Found: C, 59.59; H, 3.78.

WO 98/45288 PCT/US98/07274 - 52 Step i): Preparation of [6-Benzyloxy-3-[4-[2-(l piperidinyl)ethoxy]lphenoxy] -2-(4-methoxyphenyl) ] benzo[b] thiophene-(S-oxide) 5 NO 0 0 O

OCH

3 Reaction of the product of step i) above with 4-(2 piperidinoethoxy)phenol in base yielded the title compound L0 as a yellow oil. 1 H NMR (DMSO-d 6 ) d 7.76 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.44-7.30 (m, 5H), 7.12 (dd, J = 8.6, 2.2 Hz, 1H), 7.03-6.93 (m, 5H), 6.85 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 3.94 (bt, J = 5.8 Hz, 2H), 3.73 (s, 3H), 2.56 (bt, J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.32 L5 (m, 6H). FD mass spec 592. Anal. Calcd. for C3 5

H

35

NO

5 S: C, 72.26; H, 6.06; N, 2.41. Found: C, 72.19; H, 5.99; N, 2.11.

WO 98/45288 PCT/US98/07274 - 53 Step j).: Preparation of [6-Benzyloxy-3-[4-[2-(l piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl) ] benzo[b]thiophene 0 so

NOH

3 Reduction of the product of step i) above yielded the title compound, isolated in 95% overall yield. Purification by chromatography (SiO 2 , 1-5% methanol/chloroform) provided 10 an off-white solid, mp 105-108 0 C. 1 H NMR (DMSO-d 6 ) d 7.62 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.45-7.30 (m, 5H), 7.15 (dd, J = 8.6 Hz, 1H), 7.00-6.94 (m, 3H), 6.82 (s, 4H), 5.13 (s, 2H), 3.92 (bt, J = 5.8 Hz, 2H), 3.72 (s, 3H), 2.55 (bt, J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.44-1.31 (m, 15 4H). FD mass spec 565. Anal. Calcd. for C3 5

H

3 5

NO

4 S: C, 74.31; H, 6.24; N, 2.48. Found: C, 74.35; H, 6.07; N, 2.76.

WO 98/45288 PCT/US98/07274 - 54 Step k): Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl) ethoxy]phenoxy] -2-(4-methoxyphenyl) ]benzo[b] thiophene 0 Ij I HO So 5 OCH 3 To a solution of [6-benzyloxy-3-[4-[2-(l-piperidinyl) ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene (8.50 g, 15.0 mmol) in 300 mL of 5:1 ethanol/ethyl acetate was LO added palladium black (1.50 g), ammonium formate (3.50 g, 55.6 mmol), and 30 mL of water. The resulting mixture was heated to reflux and monitored by TLC. After approximately 3 hours, the reaction was judged complete and the solution was cooled to ambient temperature. The reaction was L5 filtered through a pad of Celite to remove catalyst, and the filtrate was concentrated in vacuo to a solid. The concentrate was distributed between saturated sodium bicarbonate solution and 5% ethanol/ethyl acetate. The layers were separated, and the organic phase was dried 20 (sodium sulfate) and concentrated in vacuo. The crude product was chromatographed (silicon dioxide, 1-5% methanol/chloroform) to provide 6.50 g (91%) of [6-hydroxy 3-[4-[2-(1-piperidinyl) ethoxy]phenoxy]-2-(4 methoxyphenyl)]benzo[b]thiophene as foam that converted to 25 solid upon trituration with hexanes. mp 174-1760 C. 1H NMR (DMSO-d 6 ) d 9.77 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.81 (s, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H), 3.91 (bt, J = 5.9 Hz, 2H), 3.71 (s, 3H), 2.55 (bt, J = 5.9 Hz, WO 98/45288 PCT/US98/07274 - 55 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spec 475. Anal. Calcd. for C 2 8

H

2 9 N0 4 S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.46; H, 5.93; N, 2.71. 5 Example 15 Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy] phenoxy] -2-(4-methoxyphenyl) ]benzo[b] thiophene hydrochloride salt .0 N" HCI 0 ,, 0 I. I HO So

OCH

3 The product of Example 14 was converted to the corres ponding hydrochloride salt in 85% yield by treatment with a .5 mixture of HCl saturated diethyl ether in ethyl acetate followed by crystallization from ethanol/ethyl acetate; mp 156-1600 C. 1 H NMR (DMSO-d 6 ) d 10.28 (bs, 1H), 9.85 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.87 (q, JAB = 0 9.3 Hz, 4H), 4.27 (bt, J = 5.9 Hz, 2H), 3.71 (s, 3H), 3.44 3.31 (m, 4H), 2.98-2.88 (m, 2H), 1.74-1.60 (m, 5H), 1.36 1.29 (m, 1H) FD mass spec 475. Anal. Calcd. for

C

2 8

H

2 9

NO

4 S*1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.98; H, 6.11; N, 2.64. 5 WO 98/45288 PCT/US98/07274 - 56 Example 16 Preparation of [6-methoxy-3-[4-[2-(1-piperidinyl) ethoxy]phenoxy]-2-(4-hydroxyphenyl) ]lbenzo[b]thiophene 5 0NO I I I

H

3 CO S OH Step a): Preparation of [6-methoxy-2-(4-benzyloxyphenyl)] benzo [b] thiophene 10

H

3 CC) S O Following the general procedures of steps a) through g) of Example 14, the title compound was obtained in 73% yield, 15 mp 217-221 0 C. 1 H NMR (DMSO-d 6 ) d 7.63-7.60 (m, 3H), 7.59 7.26 (m, 7H), 7.02 (d, J = 8.7 Hz, 2H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 5.11 (s, 2H), 3.88 (s, 3H). FD mass spec 346. Anal. Calcd. for C 2 2

H

1 8 0 2 S: C, 76.27; H, 5.24. Found: C, 76.00; H, 5.25. 20 WO 98/45288 PCT/US98/07274 - 57 Step b): [6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo [b] thiophene Br

H

3 CO S 0 5 The title compound was obtained in 91% yield, mp 125 127 0 C. 1 H NMR (DMSO-d 6 ) d 7.64-7.61 (m, 4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H), 5.15 (s, 2H), 3.82 (s, 3H). FD mass spec 346. Anal. Calcd. for C 2 2

H

1 70 2 SBr: C, 62.13; H, 4.03. 0 Found: C, 62.33; H, 3.93. Step c): [6-Methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo[b] thiophene-(S-oxide) Br r

H

3 CO S 5 0 The title compound was isolated as a yellow solid by chromatography (SiO 2 , CHC1 3 ). mp 119-1230 C. 1 H NMR (DMSO d 6 ) d 7.73 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 0 7.55 (d, J = 8.5 Hz, 1H) 7.46-7.31 (m, 5), 7.26 (dd, J = 8.5, 2.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H). FD mass spec 441. Anal. Calcd. for C2 2

H

1 70 3 SBr: C, 59.87; H, 3.88. Found: C, 60.13; H, 4.10.

WO 98/45288 PCT/US98/07274 - 58 Step d) [6-Methoxy-3-[4-[2-(l-piperidinyl)ethoxy]phenoxy] 2-(4-benzyloxyphenyl) ]lbenzo[b] thiophene-(S-oxide) ON 0

H

3 CO o1 1 5 The title compound was obtained as a yellow solid, mp 89-930 C. 1 H NMR (DMSO-d 6 ) d 7.68 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.42-7.28 (m, 5H), 7.08-6.92 (m, 6H), 6.86 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 3.94 (bt, J = 5.8 L0 Hz, 2H), 3.81 (s, 3H), 2.56 (bt, J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H). FD mass spec 592. Anal. Calcd. for C 3 5

H

35 NO5S'*0.25 EtOAc: C, 71.62; H, 6.18; N, 2.32. Found: C, 71.32; H, 5.96; N, 2.71.

WO 98/45288 PCT/US98/07274 - 59 Step e) [6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy] 2-(4-benzyloxyphenyl)]benzo[b]thiophene 0N

H

3 00 H3CO SO 0 5 The title compound was obtained in 91% yield, mp 106 110 0 C. 1 H NNR (DMSO-d 6 ) d 7.59 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.42-7.28 (m, 5H), 7.13 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), LO 3.92 (bt, J = 5.8 Hz, 2H), 3.78 (s, 3H), 2.55 (bt, J = 5.8 Hz, 2H), 2.37-2.33 (m, 4H), 1.44-1.31 (m, 4H). FD mass spec 565. Anal. Calcd. for C3 5

H

3 5

NO

4 S: C, 74.31; H, 6.24; N, 2.48. Found: C, 74.26; H, 6.17; N, 2.73. 15 Step f): Preparation of [6-methoxy- 3 -[4-[2-(l-piperidinyl) ethoxy]phenoxy] -2-(4-hydroxyphenyl) ]benzo[b] thiophene I 0

H

3 CO S

-OH

WO 98/45288 PCT/US98/07274 - 60 The title compound was obtained in 88% yield, mp 147 1500 C. 1 H NMR (DMSO-d 6 ) d 9.72 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.2 Hz, 1H), 6.81 (s, 4H), 6.76 (d, J = 5 8.6, 2H), 3.91 (bt, J = 5.9 Hz, 2H), 3.77 (s, 3H), 2.55 (bt, J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spec 475. Anal. Calcd. for C 28

H

29

NO

4 S: C, 70.71; H, 6.15; N, 2.94. Found: C, 71.00; H, 6.17; N, 2.94. .0 Example 17 Preparation of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy] phenoxy] -2-(4-hydroxyphenyl) ]benzo[b] thiophene hydrochloride ON * HCI CNO 0 I

H

3 CO S L5 OH The title compound was prepared in a manner analogous to that employed in Example 15 to yield the title compound, mp 215-2170 C. 1 H NMR (DMSO-d 6 ) d 10.28 (bs, 1H), 9.80 (s, 20 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 6.91-6.80 (m, 5H), 6.78 (d, J = 8.6 Hz, 2H), 4.27 (bt, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.43 3.34 (m, 4H), 2.97-2.91 (m, 2H), 1.78-1.61 (m, 5H), 1.36 1.29 (m, 1H). FD mass spec 475. Anal. Calcd. for .5 C 2 8

H

2 9

NO

4 S*1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.87; H, 5.79; N, 2.99.

WO98/45288 PCTIUS98/07274 - 61 Formulation Examples In the formulations which follow, "active ingredient" means a compound of formula I, or a salt or solvate thereof. 5 Formulation Example 1 Gelatin Capsules Ingredient Quantity (mg/capsule) Active ingredient 0.i - 1000 Starch, NF 0 - 650 Starch flowable powder 0 - 650 Silicone fluid 350 centistokes 0 - 15 Formulation Example 2 LO Tablets Ingredient Quantity (mg/tablet) Active ingredient 2.5 - 1000 Cellulose, microcrystalline 200 - 650 Silicon dioxide, fumed 10 - 650 Stearate acid 5 - 15 Formulation Example 3 Tablets L5 Ingredient Quantity (mg/tablet) Active ingredient 25 - 1000 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone 4 (as 10% solution in water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1 WO98/45288 PCT/US98/07274 - 62 The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. 5 sieve. The granules so produced are dried at 500-600 C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on 10 a tablet machine to yield tablets. Formulation Example 4 Suspensions Ingredient Quantity (mg/5 ml) Active ingredient 0.1 - 1000 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified water to 5 mL 15 The medicament is passed through a No.45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and 20 added, with stirring. Sufficient water is then added to produce the required volume. Formulation Example 5 Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00 WO98/45288 PCT/US98/07274 - 63 The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 300 C, and transferred to a filling device. The required amount is then fed to a stainless steel container and 5 diluted with the remaining propellant. The valve units are then fitted to the container. Formulation Example 6 Suppositories 10 Ingredient Quantity (mg/suppository) Active ingredient 250 Saturated fatty acid 2,000 glycerides The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary 15 heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. Formulation Example 7 Injectable Formulations 20 Ingredient Quantity Active ingredient 50 mg Isotonic saline 1,000 mL The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute.

Claims (18)

1. A method for the treatment or prophylaxis of benign prostatic hyperplasia or prostatic cancer in a patient 5 in need of such treatment comprising administering a therapeutically effective amount of a compound having the structure R3 I OpN'R 4 0 R ' S R

2 R 2 10 or a pharmaceutically acceptable salt or pro drug thereof, wherein R 1 and R 2 are independently selected from the group 15 consisting of hydroxy and alkoxy of one to four carbon atoms; and R 3 and R 4 are independently selected from methyl or ethyl, or R 3 and R 4 , taken together with the 20 nitrogen atom to which they are attached, form a pyrrolidino, methylpyrrolidino, dimethyl pyrrolidino, piperidino, morpholino, or hexa methyleneimino ring. 25 WO98/45288 PCT/US98/07274 - 65 2. The method of Claim 1 wherein said method comprises the treatment or prophylaxis of prostatic cancer in a patient in need of such treatment. 5

3. The method of Claim 1 wherein said method comprises the treatment or prophylaxis of benign prostatic hyperplasia in a patient in need of such treatment.

4. The method of Claim 1 wherein R 1 and R 2 are both .0 hydroxy.

5. The method of Claim 2 wherein R 1 and R 2 are both hydroxy. 5

6. The method of Claim 3 wherein R 1 and R 2 are both hydroxy.

7. The method of Claim 1 wherein R 1 is hydroxy and R 2 is alkoxy of one to four carbon atoms. 0

8. The method of Claim 2 wherein R 1 is hydroxy and R 2 is alkoxy of one to four carbon atoms.

9. The method of Claim 3 wherein R 1 is hydroxy and R 2 5 is alkoxy of one to four carbon atoms.

10. The method of Claim 1 wherein R 3 and R 4 combine with the nitrogen atom to which they are attached to form a piperidino ring. 0

11. The method of Claim 2 wherein R 3 and R 4 combine with the nitrogen atom to which they are attached to form a piperidino ring. 5

12. The method of Claim 3 wherein R 3 and R 4 combine with the nitrogen atom to which they are attached to form a piperidino ring. WO98/45288 PCTIUS98/07274 - 66

13. A method for the treatment or prophylaxis of prostatic cancer in a patient in need of such treatment comprising administering a therapeutically effective amount 5 of a compound having the structure R3 N I O R 4 O II R 2 or a pharmaceutically acceptable salt or pro-drug L0 thereof, wherein R 2 is hydroxy or methoxy.

14. The method of Claim 13 wherein said compound is L5 6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy) phenoxy]benzo[b]thiophene or a pharmaceutically acceptable salt thereof.

15. The method of Claim 13 wherein said compound is ?0 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-( 2 -piperidinoethoxy) phenoxy]benzo[b]thiophene or a pharmaceutically acceptable salt thereof.

16. A method of treating benign prostatic hyperplasia 25 in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound having the structure WO 98/45288 PCT/US98/07274 - 67 R3 I Op N - R 4 I O HO S R2 or a pharmaceutically acceptable salt or pro-drug 5 thereof, wherein R 2 is hydroxy or methoxy.

17. The method of Claim 16 wherein said compound is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy) phenoxy]benzo[b]thiophene or a pharmaceutically acceptable LO salt thereof.

18. The method of Claim 16 wherein said compound is 6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy) phenoxy]benzo[b]thiophene or a pharmaceutically acceptable L5 salt thereof.