CA2286207A1 - Prevention of breast cancer with selective estrogen receptor modulators - Google Patents

Abstract

The present invention provides a method of preventing breast carcinoma or cancer in a patient comprising administering a therapeutically effective amount of a compound having the structure (I) in which R1 and R2 are independently hydroxy or alkoxy of one to four carbon atoms; and R3 and R4 are independently methyl or ethyl, or R3 and R4, taken together with the nitrogen atom to which they are attached, form a pyrrolidino, methyl-pyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring.

Description

Prevention of Breast Cancer with Selective Estrogen Receptor Modulators Technical Field The present application relates to medical methods of treatment. More particularly, the present invention concerns the use of a class of substituted benzo[b]thiophene compounds for the prophylaxis or prevention of breast carcinoma in a patient in need of such treatment.
Background of the Invention Breast carcinoma or breast cancer is the most common form of cancer and the second most common cause of death in women in the United States. In the years 1994 and 1995, an estimated 182,000 new cases of breast cancer in women occurred with mortality estimated at 46,000.
Currently, it is estimated that, statistically, most women have a one in ten chance of developing this disease in their lifetime. Breast carcinoma is a major cause of mortality in women, as well as a cause of disability, psychological trauma, and economic loss. A large percentage of women contracting this disease eventually die from its effects either directly or indirectly from complications, e.g., metastasis, loss of general health, or collateral effects from therapeutic interventions, such as surgery, radiation, or chemotherapy.
The epidemiology of this disease, although the subject of intense investigation, is still poorly understood. There appears to be a substantial genetic component which . predisposes some patients to contract the disease. Yet it is not clear whether this genetic component is causative or permissive to the disease or only predictive of the disease process. It has been known for a long time that breast carcinoma tends to occur more frequently in some families, IF

WO 98/45286 PCTlUS98/06989 although such analysis is not accurately predictive of disease occurrence in other family members.
A great deal of clinical and pharmacological 40 investigation has been carried out attempting to elucidate the relationship between the hormone estrogen, and the cause, maintenance, and treatment of breast carcinoma.
Although a great deal is known about the relationship of estrogen in the maintenance and treatment of the disease, 45 there is a great deal of controversy associated with the effect of estrogen on the epidemiology of this disease, i.e., whether estrogen is a causative agent (carcinogen) or an obligatory co-factor (permissive) in the initiation of the disease.
50 The estrogens, which include 17b-estradiol, estrone, and their active metabolites, are major sex-related hormones in women, but additionally, appear to be important homeostatic hormones in both men and women throughout their adult life. Normally, everyone has some level of estrogen.
55 Cancer of the male breast is a rare disease, accounting for less than to of all cancers in males. The American Cancer Society reported that in 1994 an estimated 1,000 men in the United States were diagnosed as having breast cancer, with mortality estimated at 300.
60 Ductal carcinoma in situ (DCIS) of the breast is an early form of breast cancer in which malignant epithelial cells proliferate in the ductile system without microscopic evidence of invasion through the basement membrane into the surrounding breast tissue. The median age of patients with 65 DCIS at the time of diagnosis is about 52 years of age. The increasingly widespread use of mammography has led to the earlier detection of DCIS since most cases are detected in otherwise asymptomatic women undergoing screening mammography .
Hormone Replacement Therapy (HRT), recommended for postmenopausal and peri-menopausal women to alleviate cardiovascular disease, osteoporosis, and other menopausal sequelae, has generated a great deal of debate as to the potential of this therapy to increase the risk of 75 contracting breast carcinoma. Currently, the conclusions from HRT studies, most of which were postspective studies, appear to indicate a small increase in risk.
In contrast to the problematic role of estrogen in the initiation of this disease, a great deal (although 80 incomplete) of understanding has been achieved relating estrogen with established breast carcinoma. Estrogen is a growth factor required by most breast carcinoma cells in the early stages of this disease. Also it has been established, but yet not fully understood why, that during the course of 85 this disease the cancer cells lose their sensitivity to the effects of estrogen. Eventually, a majority of carcinoma cells become no longer dependent on estrogen for growth and are no longer responsive to any hormonally based therapy, which included "anti-estrogens", GNRH agonists, progestins, 90 and androgens.
A great deal of benefit has been achieved with the use of hormonally based therapeutic interventions. The most widely used therapy is the use of tamoxifen. The five-year survival rate for women with breast carcinoma has been 95 dramatically improved with this therapy; however, the longer-term survival (ten-year+) rate has not improved to the same extent. This lack of improvement in the long-term rate has been attributed to the gradual evolution of the carcinoma cells from estrogen dependence to independence.
100 Thus, even with the best combinations of treatment modalities, (surgery, radiation, and/or chemotherapy), the long-term prognosis for patients is poor, especially if metastatic disease is present. Clearly, there is a great need for improved therapies and, perhaps, more importantly, 105 a need for the prevention of the disease in the first instance (de novo).
For the last decade it has been argued that "anti-estrogen" therapy, especially the use of tamoxifen, should be examined for its potential to prevent de novo breast 110 carcinoma. However, partially because of the lack of _ q _ evidence of a benefit, and known and potential toxicity of tamoxifen, no prospective prevention trials have been conducted in healthy women.
Clearly, a great need exists for a breast cancer 115 prevention therapy useful for the entire population, including individuals at high or no particular risk, and including both men and women.
Brief Summary of the Invention 120 In accordance with the present invention, there is provided a method for the prophylaxis or prevention of breast carcinoma in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound having the structure O~N,R4 I
O
R~ \ S ( \

I
or a pharmaceutically acceptable salt or pro-drug thereof.
130 The invention further relates to a method for preventing breast cancer by administrating to human for a sufficient term an effective dose of a compound of formula I
or pharmaceutically acceptable salt or pro-drug thereof, where the human has not been diagnosed with, but is 135 determined to be at risk for, developing breast cancer.

In the structure shown above, R1 and R2 are independently selected from the group consisting of hydroxy and alkoxy of one to four carbon atoms.
R3 and R4 are independently selected from methyl or 140 ethyl, or R3 and R4, taken together with the nitrogen atom to which they are attached, form a pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring.
The compounds of the present invention are selective 145 estrogen receptor modulators (SERM's), that is, compounds which produce estrogen agonism in one or more desired target tissues while producing estrogen antagonism and/or minimal (i.e. clinically insignificant) agonism in reproductive tissue such as the breast or uterus.

Detailed Description The current invention concerns the discovery that compounds of formula I above are useful for preventing breast cancer. The methods provided by this invention are 155 practiced by administering to a patient in need thereof a dose of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, that is effective to prevent breast cancer.
Throughout this specification and the appended claims, 160 general terms bear their usual meanings.
The terms "prevention of", "prophylaxis" and "prevent"
includes reducing the likelihood of a patient incurring or developing breast cancer.
The term "de novo", as used in the current invention, 165 means the lack of transformation or metamorphosis of normal breast cells to cancerous or malignant cells in the first instance. Such a transformation may occur in stages in the same or daughter cells via an evolutionary process or may occur in a single, pivotal event. This de novo process is 170 in contrast to the metastasis, colonization, or spreading of already transformed or malignant cells from the primary tumor site to new locations. This invention also relates to the administration of a compound of formula I to a patient who is at risk of developing de novo breast cancer.
175 A person who is at no particular risk of developing breast cancer is one who may develop de novo breast cancer, has no evidence or suspicion of the potential of the disease above normal risk, and who has never had a diagnosis of having the disease. The greatest risk factor contributing 180 to the development of breast carcinoma is a personal history of suffering from the disease, or an earlier occurrence of the disease, even if it is in remission with no evidence of its presence. Another risk factor is family history of the disease.
185 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-butyl, tert-butyl and the like.
190 "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 and the like. In the present invention, methoxy is the 195 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 compound of the present invention. In particular, such pro-200 drug compounds include those in which either or both of the substituent groups R1 and R2 of the structure shown above are hydroxy groups which have been protected by a pharmaceutically acceptable hydroxy protecting group which is metabolically cleaved in the body to yield a 205 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., -New York, 1991. Simple ether and ester groups are preferred 210 as pro-drug hydroxy protecting groups.
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 215 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 220 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 9,133,814. The starting materials have the formula l:

R$O \ S

wherein R5 and R6 are independently -H or a hydroxy 230 protecting group.
The R5 and R6 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 235 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, 240 and reformation of such protecting groups are described in a number of standard works including, for example, Protective _ g _ Groups in Organic 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, 245 Schrooder and Lubke, Academic Press, (London and New York, 1965).
Representative hydroxy protecting groups include, for example, -C1-C4 alkyl, -C1-Cq alkoxy, -CO-(Cl-C6 alkyl), -S02-(Cq-C6 alkyl), and -CO-Ar in which Ar is benzyl or 250 optionally substituted phenyl. The term "substituted phenyl" refers to a phenyl group having one or more substituents selected from the group consisting of C1-Cq alkyl, C1-Cg alkoxy, hydroxy, nitro, halo, and tri(chloro or fluoro) methyl. The term "halo" refers to bromo, chloro, 255 fluoro, and iodo.
For compounds of formula 1, preferred R5 and R6 substituents are methyl, isopropyl, benzyl, and methoxymethyl. Compounds in which R5 and R6 each are methyl are prepared via the procedure described in the above-260 referenced Jones patent.
Compounds of formula _1 are also prepared in which the RS hydroxy protecting group is selectively removed, leaving R6 as a hydroxy protecting group as part of the final product. The same is true in the case in which the R6 265 hydroxy protecting group is selectively removed, leaving the R5 hydroxy protecting group in place. For example, R5 can be isopropyl or benzyl and R6 methyl. The isopropyl or benzyl moiety is selectively removed via standard procedures, and the R6 methyl protecting group is left as 270 part of the final product.
As shown in Reaction Scheme I, the first steps of the present process for preparing certain compounds of the present invention include selectively placing a leaving group, R~ at the 3 position of a compound of formula _1, to 275 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 R8 _ g _ hydroxy protecting group to form a compound of formula 5.
In the sequence of steps shown in Reaction Scheme I, the 280 hydroxy protecting groups R5, R6 and R8 are chosen in such a manner that, in the final step, the hydroxy protecting group R8 can be selectively removed in the presence of hydroxy protecting groups R5 and R6.
285 Reaction Scheme I
R~
I I ,. I I
R50 S I R50 S ' 1 ~ OR 6 I

ORB
I
I
OH
OH ORB
i I I
I I O ~ O
Rs0 ~ S ~ R50 ~ I S i I
~ OR6 4 ~ OR6 In the first step of Reaction Scheme I, an appropriate 290 leaving group is selectively placed at the 3-position of the formula 1 starting material via standard procedures.
Appropriate R~ leaving groups include the sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzene-295 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 300 especially preferred.
The present reaction is carried out using standard procedures. For example, when the preferred halogenating agents are used, an equivalent of such a halogenating agent, preferably bromine, is reacted with an equivalent of the 305 formula 1 substrate, in a suitable solvent such as, for example, chloroform or acetic acid. The reaction is typically run at a temperature from about 40°C to about 80°C.
The reaction product from the above process step, a 310 compound of formula 2, is then reacted with a 4-(protected-hydroxy)phenol, 3, to form compounds of formula _4 in which Re 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 315 removed without removing, in this instance, the RS and, when present, R6 moieties of a formula 3 compound. Preferred R8 protecting groups include methoxymethyl, when R5 and/or R6 are not methoxymethyl, and benzyl. Of these, benzyl is especially preferred. The 4-(protected-hydroxy)phenol 320 reactants are commercially available or can be prepared via standard procedures.
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 325 procedures [see, e.g., "Advanced Organic Chemistry;
Reactions, Mechanisms, and Structure," Fourth Edition, 3-16, (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 330 substrates, in the presence of up to an equimolar amount of a copper(I) oxide catalyst and an appropriate solvent, are heated to reflux under an inert atmosphere. Preferably, an equivalent of a formula 2 compound in which R~ is bromo is reacted with an equivalent amount of,4-benzyloxyphenol in 335 the presence of an equivalent of cuprous oxide.

WO 98!45286 PCT/US98/06989 Appropriate solvents for this reaction are those solvents or mixture of solvents which remain inert ' throughout the reaction. Typically, organic bases, particularly a hindered base such as, for example, 2,4,6-340 collidine, are preferred solvents.
The temperature employed in this step is generally sufficient to effect completion of this coupling reaction, and will influence the amount of time required therefore.
When the reaction mixture is heated to reflux under an inert 345 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 of formula 3, to form a formula 4 compound, formula _5 compounds are prepared by selectively removing the R8 350 hydroxy protecting group of a formula _4 compound via well known reduction procedures. It is imperative that the selected procedure will not affect the R5 and, when present, R6 hydroxy protecting groups.
When R8 is the preferred benzyl moiety, and R5 and, 355 when present, R6 each are methyl, the present process step is carried out via standard hydrogenolysis procedures.
Typically, the formula 4 substrate is added to a suitable solvent or mixture of solvents, followed by the addition of a proton donor to accelerate the reaction and an appropriate 360 hydrogenation catalyst.
Appropriate catalysts include noble metals and oxides such as palladium, platinum, and rhodium oxide on a support such as carbon or calcium carbonate. Of these, pailadium-on-carbon, particularly 10~ palladium-on-carbon, is 365 preferred. Solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the reaction. Typically, ethylacetate and C1-CQ aliphatic alcohols, particularly ethanol, is preferred. For the present reaction, hydrochloric acid serves as an adequate 370 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 kilopascals), the present reaction runs quite rapidly.
Progress of this reaction may be monitored by standard 375 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 380 R4R5N-(CH2)2-Q

wherein R4 and R5 are as defined above, and Q is a bromo or, preferably, chloro, to form a compound of formula 7. The 385 formula 7 compound is then deprotected to form a compound of formula I.

Reaction Scheme II
OH R~ R4, N~\O
N
~ ~ Ra I
p I
O
R50 ~' gI \ 5 ~ I I
R O S
OR6 I ~ OR6 R4.N~\O
I
O
I
Rs0 .' S ~ \

z Ta, R' - R° - H
I b , RS - H
Ic, R6 - H
390 In the first step of the process shown in Reaction 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 395 salt of a formula 6 compound is used. In a particularly 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 _6 400 compound in the presence of at least about 4 equivalents of 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 405 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 alkyiation reaction. Typically, ambient temperature is sufficient and preferred. The present reaction preferably 410 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.
415 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:
420 Q-(CH2)n-Q' in which Q and Q' are the same or different leaving groups.
Appropriate leaving groups are those mentioned above.

425 Reaction Scheme III
Ohi QUO
' Q
I ~ ~Q, I ~
O
/ I I ~~' ~I I O
RIO S I ~ R~O~S
ORs ~ s OR

R R3 r R4~Nw/'O R4~N1/'O
I' i O
i ~ O
I I
w S I RIO ~ I S I
_ORs ~ s OR
I a , R5 - R6 - H
Ib, R5 - H
Ic, R6 - H
A preferred alkali solution for this alkylation 430 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 compound is converted to a phenoxide ion which displaces one of the leaving groups of the alkylating agent.
435 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 to about 20 hours.

440 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, dimethylamine, diethylamine, diisopropylamine, or 1-445 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 typically carried out with the alkylated compound of formula 450 9 in an inert solvent, such as anhydrous DMF, and heated to a temperature in the range from about 60°C to about 110°C.
When the mixture is heated to a preferred temperature of about 90°C, the reaction only takes about 30 minutes to about 1 hour. However, changes in the reaction conditions 455 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 by cleaving the R5 and, when present, R6 hydroxy protecting 460 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 Chemistry, Plenum Press (London and New York, 1973); Greene, 465 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~ and/or R8 hydroxy protecting groups, particularly methyl and methoxymethyl, are essentially as 470 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 sulfur atom of a formula 2 compound is oxidized to form a 475 sulfoxide, 11, which is then reacted with a nucleophilic group to introduce the oxygen atom linker of formula I

compounds. The sulfoxide moiety of formula 12 compounds is then reduced to provide certain compounds of the present invention.

Reaction Scheme IV
r R~ i R~
I -> ~ ~ I
R50 S I ~ R50 S
ORs O ~ORs 1~

I ~ O~ N~ Ra HO
Ra Rs t Ra~N~O R4~N~0 I
i .r-- i i O i O
I ~ I
R50 S ~~ R50 ~' S
I s O ~~ s OR OR

I a , R5 - R6 - H
Ib, R5 _ H
Ic, R6 - H
485 In the first step of this process, a compound of 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);
490 1287-1290 (1981); Drabowicz, J., et al., Synthetic' Communications, 11 (12); 1025-1030 (1981); Kramer, J.B., et al., 34th National Orcfanic Sym osium, Williamsburg, VA., June 11-15, 1995]. However, many oxidants provide only poor conversion to the desired product as well as significant 495 over-oxidation to the sulfone. The preferred process, 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 500 peroxide in a mixture of about 20o to about 500 trifluoroacetic acid in methylene chloride. The reaction is run at a temperature from about 20° C to about 50° C, and usually required from about 1 to about 2 hours to run to completion.
505 Next, the 3-position leaving group, R~, is displaced by 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, 510 preferably a slight excess of sodium hydride or potassium 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 515 employed. The deprotonation is usually run at a temperature between about 0° C and about 30° 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 0° C
520 and about 50° C, and is usually run in about 1 to about 2 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.
525 When desired, the hydroxy protecting group or groups of 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.

Pro-drug ester compounds of formula I are prepared by 530 replacing the 6- and/or 4'-position hydroxy moieties, when present, with a moiety of the formula -OCO(C1-C6 alkyl), or -OS02(C2-C6 alkyl) via well known procedures. See, e.g., U.S. Pat. No. 4,358,593.
For example, when an -OCO(C1-C6 alkyl) group is 535 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 anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or 540 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 solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, 545 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 desired, acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g., Haslam, _et 550 al., Tetrahedron, 36:2409-2433 (1980).
These reactions are carried out at moderate temperatures, in the range from about -25° C to about 100°
C, frequently under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually adequate for 555 the reaction to run.
Acylation of a 6-position and/or 4'-position hydroxy group also may be performed by acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents.
Acid catalysts such as sulfuric acid, polyphosphoric acid, 560 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, such as the esters formed by such known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, 565 pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Ja an, 38:1979 (1965), and Chem. Ber., 788 and 2024 (1970).
Each of the above techniques which provide -OCO(C2-C6 alkyl) moieties are carried out in solvents as discussed 570 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 6-575 and/or 4'-position hydroxy group of a formula I compound is converted to a group of the formula -OS02(CZ-C6 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 580 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 585 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 590 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 595 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 600 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 salts formed by typical inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, 605 phosphoric, hypophosphoric, and the like as well as salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. 'Such 610 pharmaceutically acceptable organic acid addition salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, 615 isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, 620 isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfate, 625 sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluene-sulfonate, xylenesulfonate, tartarate, and the like. Preferred salts 630 are the hydrochloride and oxalate salts.
The pharmaceutically acceptable acid addition salts are 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 635 or ethyl acetate. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.

The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.

Pharmaceutical Formulations The compounds of this invention are administered by a variety of routes including oral, rectal, transdermal, subucutaneus, intravenous, intramuscular, and intranasal.
650 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 655 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 660 comprises from O.lo to 99.90 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.
665 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 670 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 O.lo to 99.9°s by weight of the formulation.
675 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.
The formulations may be specially formulated for oral 680 administration, in solid or liquid form, for parenteral 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, 685 rectally, intravaginally, parenterally, topically (by means 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, 690 intraperitoneal, instrasternal, subcutaneous, or intraarticular injection or infusion.
Pharmaceutical compositions of this invention for parenteral administration comprise sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, 695 as well as sterile powders which are reconstituted 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 700 as glycerol, propylene glycol, polyethylene glycol), and 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 705 maintenance of proper particle size in the case of 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 710 microorganisms is ensured by the inclusion of antibacterial 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, and the like. Prolonged absorption of injectable 715 formulations may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it, is desirable to slow the absorption of the drug 720 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 by dissolving or suspending the drug in an oil vehicle. In the case of the subcutaneous or intramuscular injection of a 725 suspension containing a form of the drug with low water solubility, the rate of absorption of the drug depends upon its rate of dissolution.
Injectable "depot" formulations of the compounds of this invention are made by forming microencapsulated 730 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 (anhydrides) these materials which are described in the art.
Depending upon the ratio of drug to polymer and the 735 characteristics of the particular polymer employed, the rate of drug release can be controlled.
Injectable formulations are sterilized, for example, by filtration through bacterial-retaining filters, or by presterilization of the components of the mixture prior to 740 their admixture, either at the time of manufacture or just prior to administration (as in the example of a dual chamber syringe package).
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such 745 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 or extenders such as starches, lactose, glucose, mannitol, and silicic acid, (b) binding agents such as carboxymethyl-750 cellulose, alginates, gelatin, poly(vinylpyrrolidine), 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, 755 (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 polyethylene glycols), 760 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 765 such as lactose as well as high molecular weight polyethylene 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 770 in the pharmaceutical formulating art. The coatings may contain opacifying agents or agents which release the active ingredients) in a particular part of the digestive tract, as for example, acid soluble coatings for release of the active ingredients) in the stomach, or base soluble 775 coatings for release of the active ingredients) in the intestinal tract.
The active ingredients) may also be microencapsulated in a sustained-release coating, with the microcapsules being made part of a pill of capsule formulation.
780 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 785 pharmaceutically acceptable solvents, solubilizing agents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, ground nut, corn, germ, 790 olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols), fatty acid esters of sorbitol, and mixtures thereof.
Besides inert diluents, the liquid oral formulations may also include adjuvants such as wetting agents, 795 emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Liquid suspension, in addition to the active ingredients) may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol 800 and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite clay, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or intravaginal administration are prepared by mixing one or more compounds of the present 805 invention with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or any suppository wax 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 810 are dissolved in the melted wax, formed into the desired shape, and allowed to harden into the finished suppository formulation.
Compounds of the present invention may also be administered in the form of liposomes. As is know in the 815 art, liposomes are generally derived from phospholipids or other lipid substances. Lipososome formulations are formed by mono- or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, pharmaceutically acceptable, and metabolizable lipid capable 820 of forming liposomes can be used. The present compositions in liposome form can contain, in addition to one or more active compounds of the present invention, stabilizers, excipients, preservatives, and the like. The preferred lipids are phospholipids and the phosphatidyl cholines 825 (lecithins), both natural and synthetic.
Methods for forming liposomes are know in the art as described, for example, in Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq.

Method of the Present Invention Induction of mammary tumors in rats by administration of the carcinogen N-nitroso-N-methylurea is a well-accepted animal model for the study of breast cancer and has been 835 found suitable for analyzing the effect of chemopreventive agents.
In two separate studies, 55-day old female Sprague-Dawley rats were given an intravenous (Study 1) or intraperitoneal (Study 2) dose of 50 mg of N-nitroso-N-840 methylurea per kilogram of body weight one week prior to feeding ad libitum a diet into which varying amounts of a) 6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinylethoxy)-phenoxy]benzo[b]thiophene hydrochloride, b) (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine base 845 (tamoxifen base), or c) control were blended. The control comprised the vehicle employed in combination with the active compounds.
In Study l, the dietary doses of 60 mg/kg of diet and 20 mg/kg of diet translated into roughly comparable doses of 850 3 and 1 mg/kg of body weight for the test animals.
In Study 2, the dietary doses of 20, 6, 2, and 0.6 mg/kg of diet translated roughly into comparable doses of 1, 0.3, 0.1 and 0.03 mg/kg of body weight for the test animals.
Rats were observed for evidence of toxicity and were 855 weighed and palpated for tumor formation once a week. The animals were sacrificed after thirteen weeks (Study 1) or eighteen weeks (Study 2) and tumors were confirmed and weighed at autopsy. The results of these studies are shown in Table 1 (Study 1) and Table 2 (Study 2) below.

Table 1 Prevention of Mammary Cancer in Female Sprague-Dawley Rats by Administration of 6-Hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinylethoxy)-865 phenoxy]benzo[b]thiophene Hydrochloride (Example 15) Treatment Tumor-Free Avg. No. of Avg. Tumor Rats Tumors Per Burden Per Rat Rat 9m) Control 3/24 (12%) 3.0 11.0 Cmpd. of Ex. 15 11/12 (92%) 0.08 0.05 60 mg/kg of diet Compd. of Ex. 11/12 (92%) 0.08 0.03 20 mg/kg of diet Table 2 Prevention of Mammary Cancer in 870 Female Sprague-Dawley Rats by Administration of 6-hydroxy-2-(4-Methoxyphenyl)-3-[4-(2-piperidinylethoxy)-phenoxy]benzo[b]thiophene Hydrochloride (Example 15) or Tamoxifen Base Treatment Tumor-Free Avg. No. of Avg. Tumor Rats Tumors Per Burden Per Rat Rat gm?

Control 6/23 (26%) 1.8 9.0 Cmpd. of Ex. 15 11/12 (92%) 0.08 0.43 20 mg/kg of diet Compd. of Ex. 7/12 (58%) 0.50 1.50 6 mg/kg of diet Cmpd. of Ex. 15 8/12 (67%) 0.50 3.40 2 mg/kg of diet Cmpd. of Ex. 15 6/I2 (50%) 0.75 I.60 0.6 mg/kg of diet Tamoxifen 7/11 (64%.) 0 0 base . .

2 mg/kg of diet Tamoxifen 7/12 (5B%) 09 2 base . .

0.6 mg/kg of diet Examination of the data in Table 1 shows that administration of the compound of Example 15 of the present invention resulted in a significant decrease in tumor incidence (87%), average numbers of tumors per rat (97%) and 880 average tumor burden per rat (99%) compared to control.
Examination of the data appearing in Table 2 shows that administration of doses as low as 0.6 mg/kg of diet of the compound of Example 15 of the present invention were sufficient to significantly reduce the incidence of tumor 885 formation, number of tumors per rat, and average tumor burden per rat when compared with control. The observed effects were dose dependent and comparable to those observed with tamoxifen.
The observation of an effect at all doses tested 890 prevented a definitive comparison between the two compounds since a plateau-like effect was observed at the lower doses for both compounds. However, the data from Tables 1 and 2 indicate that the compound of Example 15 is at least as effective, or more effective than tamoxifen as an agent for 895 the inhibition or prevention of breast cancer.
Thus, administration of an effective amount of a compound of the present invention, in particular 6-hydroxy-2-(4-methoxyphenyl)-3-[9-(2-piperidinoethoxy)phenoxy]-benzo[b)thiophene, is a useful method for the prophylaxis, 900 prevention or inhibition of breast tumor formation.
As used herein, the term "effective amount" means an amount of compound of the present invention which is capable of inhibiting or preventing breast tumor formation. The specific dose of a compound administered according to this 905 invention is determined by the particular circumstances surrounding each situation including, for example, the potency of the compound administered, the route of administration, the prior medical history of the patient, and the pathological condition being treated. A typical 910 daily dose will contain a nontoxic dosage level of from about 5 mg to 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 915 standard practice in the medical arts of dose titrating the patient; that is, initially administering a low dose of the compound, and gradually increasing the does until the desired therapeutic effect is observed.
920 The following examples are presented to further 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.
925 NMR data for the following Examples were generated on a GE 300 MHz NMR instrument, and anhydrous hexadeutero-dimethylsulfoxide was used as the solvent unless otherwise indicated.
930 Example 1 Preparation of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene oxalate salt ~ (COOH) 2 NCO
i O
I
H3C0 ~ S
I

Step a: Preparation of [6-methoxy-2-(4-methoxy-phenyl)-3-bromo]benzo[b]thiophene Br I

To a solution of [6-methoxy-2-(4-methoxyphenyl)]benzo-[b]thiophene (27.0 g, 100 mmol)in 1.10 L of chloroform at 60° C was added bromine (15.98 g, 100 mmol) dropwise as a solution in 200 mL of chloroform. After the addition was 945 complete, the reaction was cooled to room temperature, and the solvent removed in vacuo to provide 34.2 g (1000) of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene as a white solid. mp 83-85° C. 1H NMR (DMSO-d6) d 7.70-7.62 (m, 4H) , 7. 17 (dd, J = 8. 6, 2.0 Hz, 1H) , 7.09 (d, J = 8. 4 Hz, 950 2H). FD mass spec: 349, 350. Anal. Calcd. for C16H1302SBr:
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 O
I/
/ O
I

I

To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-bromo] benzo[b]thiophene (34.00 g, 97.4 mmol) in 60 mL of 960 collidine under N2 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 acetone (200 mL), and the inorganic solids were removed by 965 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 acid (3 X 300 mL), followed by 1N sodium hydroxide (3 x 300 mL). The organic layer was dried (sodium sulfate), and 970 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-methoxyphenyl)]benzo-[b]thiophene (4.62 g, 17.11 mmol]. The filtrate was concentrated in vacuo, and then passed through 975 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 acetate to provide initially 7.19 g of [6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]-thiophene as 980 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 g of product. Total yield of [6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene was 9.00 g (240 985 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 give 13.3 g of recovered 4-benzyloxyphenol. mp 100-103° C.
1H NMR (CDC13): d 7.60 (d, J = 8.8 Hz, 2H), 7.39-7.24 (m, 990 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 C2gH2qOq5: C, 74.34; H, 5.16. Found: C, 74.64; H, 5.29.

Step c): Preparation of [6-methoxy-2-(4-methoxyphenyl)-3-995 (4-hydroxy)phenoxy]benzo[b]thiophene OH
~J
O

To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-1000 benzyloxy)phenoxy]benzo[b]thiophene (1.50 g, 3.20 mmol) in 50 mL of ethyl acetate and 10 mL of to concentrated hydrochloric acid in ethanol was added loo palladium-on-carbon (300 mg). The mixture was hydrogenated at 40 psi for 20 minutes, after which time the reaction was judged 1005 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 was passed through a pad of silica gel (chloroform as eluant). Concentration provided 1.10 g (910) of [6-methoxy-1010 2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]-thiophene as a white solid. mp 123-126° C. 1H NMR (DMSO-d6) d 9.10 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 2.1 Hz, 1H), 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 1015 (d, J = 9.0 Hz, 2H) , 3.78 (s, 3H) , 3.72 (s, 3H) . FD mass spec: 378. Anal. Calcd. for C22H1e09S: C, 69.82; H, 4.79.
Found: C, 70.06; H, 4.98.
Step d): Preparation of [6-methoxy-3-[4-[2-(1-piperidinyl)-1020 ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]-thiophene oxalate salt To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene (1.12 g, 2.97 mmol) in 7 mL of anhydrous N,N-dimethylformamide under N2 was added WO 98/45286 PCT/US98l06989 1025 cesium carbonate (3.86 g, 11.88 mmol). After stirring for minutes, 2-chioroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) was added. The resultant mixture was stirred for 18 hours at ambient temperature. The reaction was the distributed between chloroform/water (100 mL each). The 1030 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 chromatographed on silica gel (2o methanol/chloroform). The 1035 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 dried to provide 1.17 g (70%) overall of [6-methoxy-3-[4-[2-1040 (1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]
thiophene as the oxalate salt. mp 197-200° C (dec). 1H NMR
(DMSO-d6~ 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), 6.91 (dd, J = 8.8, 1.1 Hz, 1H), 6.87 (s, 4H), 4.19 (broad t, 1045 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 C29H31NOqS~0.88 H02CC02H: C, 64.95; H, 5.80; N, 2.46. Found: C, 64.92; H, 5.77; N, 2.54.

_ _ _ _ __.___~_ __ Example 2 Preparation of[6-methoxy-3-[4-[2-(1-piperidinyl)ethox phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride 1055 salt ~ HCI
~N~
O
I
i O
I

Treatment of the oxalate salt from Example 1 with aqueous base to produce the free base, followed by reaction 1060 with diethyl ether saturated with HC1 yielded the title salt, mp 216-220° C. 1H NMR (DMSO-d6~ 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) , 1065 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 C2gH31NOqS~1.0 HC1: C, 66.21; H, 6.13; N, 2.66. Found:
C, 66., 46; H, 6.16; N, 2.74.

1070 Example 3 Preparation of [6-Methoxy-3-[4-[2-(1-pyrolodinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thio hene ~N~
O
i O
I

The title compound was prepared in the same manner as the compound of Example l, mp 95-98° C. 1H NMR (DMSO-d6) c1 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.18 (d, 1080 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 C28H2gNOqS: C, 70.71; H, 6.15; N, 2.99. Found: C, 70.59; H, 1085 6.15; N, 3.01.

Example 4 Preparation of [6-Methoxy-3-[4-[2-(1-hexamethyleneimino)-1090 ethoxy]phenoxy]-2-(4-methoxyphenyl)lbenzo[b]thiophene hydrochloride ~HCI
N'.~ O
i O
I

1095 The title compound was prepared in the same manner as the compound of Example l, mp 189-192° C. 1H NMR (DMSO-d6) 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 =
1100 6.0 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Anal. Calcd. for C3oH33NOqS~1.0 HC1: C, 66.71; H, 6.35; N, 2.59. Found: C, 66.43; H, 6.46; N, 2.84.

1105 Example 5 Preparation of [6-Methoxy-3-[4-[2-(1-N,N-diethylamino)-ethoxy]phenoxy)-2-(4-methoxyphenyl))benzo[b)thiophene hydrochloride 1 .HCi ~N~O
i O
H3C0 S ~

The title compound was prepared in the same manner as the compound of Example 1, mp 196-198° C. 1H NMR (DMSO-d6) 1115 d 10.48 (bs, 1H), 7.69 (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. 0~
(m, 4H), 2.00 (m, 3H), 1.88 (m, 3H). Anal. Calcd. for 1120 C28H31N04S~1.5 HC1: C, 63.18; H, 6.15; N, 2.63. Found: C, 63.46; H, 5.79; N, 2.85.
__._ _ . _ . ___.___--.____T _.,.

Example 6 1125 Preparation of {6-Methoxy-3-[4-[2-(morpholino)ethoxy]-phenoxyJ-2-(4-methoxyphenyl)Jbenzo[bJthiophene hydrochloride 0'1 ~HCi I

~i I

1130 The title compound was prepared in the same manner as the compound of Example 1, mp 208-211° C. 1H NMR (DMSO-d6) 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, JpB = 9. 0 Hz, 4H) , 1135 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 C28HZgN05S~1.0 HC1: C, 63.09; H, 5.73; N, 2.65. Found: C, 63.39; H, 5.80; N, 2.40.

1140 Example 7 Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene O
O
HO S
1145 ~ OH
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo(b]thiophene hydrochloride (10.00 g, 19.05 mmol) was dissolved in 500 mL of anhydrous methylene 1150 chloride and cooled to 8° C. To this solution was added boron tribromide (7.20 mL, 76.20 mmol). The resultant mixture was stirred at 8° C for 2.5 hours. The reaction was quenched by pouring into a stirring solution of saturated sodium bicarbonate (1 L), cooled to 0° C. The methylene 1155 chloride layer was separated, and the remaining solids were dissolved in methanol/ethyl acetate. The aqueous layer was then extracted with 5o methanol/ethyl acetate (3 x 500 mL).
All of the organic extracts (ethyl acetate and methylene chloride) were combined and dried (sodium sulfate).
1160 Concentration in vacuo provided a tan solid that was chromatographed (silicon dioxide, 1-7% methanol/chloroform) to provide 7.13 g (81 0) of [6-hydroxy-3-[4-[2-(1-piperidinyl) ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]-thiophene as a white solid. mp 93° C. 1H NMR (DMSO-d6) a 1165 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), 2.36 (m. 4H), 1.43 (m, 4H), 1.32 (m, 2H). FD mass spec:

1170 462. Anal. Calcd. for C2~H2~NOqS: C, 70.20; H, 5.90; N, 3.03. Found: C, 69.96; H, 5.90; N, 3.14.
Example 8 1175 Preparation of [6-Hydroxy-3-[4-[2-(1- iperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thio hene oxalate salt ~N ~~(C\OOH) 2 O
I
I
O
I
HO S
OH
1180 The title compound was prepared in 80% yield from the free base, mp 246-249° C (dec) . 1H NMR (DMSO-d6) ct ?.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, 4H) , 6.75 (d, J = 8 . 6 Hz, 2H) , 4. 08 (bt, 2H) , 3. 01 (bt, 2H} , 1185 2.79 (m, 4H), 1.56 (m, 4H), 1.40 (m, 2H). FD mass spec 462.
Anal. Calcd. for C2~H2~NOqS~0.75 H02CCOzH: C, 64.63; H, 5.42;
N, 2.64. Found: C, 64.61; H, 5.55; N, 2.62.

Example 9 Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride ~ HCI
O
I
O
I
HO S
OH

The title compound was prepared in 91o yield by treatment of the corresponding free base with HCl saturated diethyl ether, mp 158-165° C. 1H NMR (DMSO-d6) d 9.79 (s, 1H) , 9.74 (s, 1H) , 7 .40 (d, J = 8 . 6 Hz, 2H) , 7.23 (d, J =
1200 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 (m, 4H) , 2.91 (m, 2H) , 1 .72 (m, 5 H), 1.25 (m, 1H). FD mass spec 461. Anal. Calcd. for C27H27NOqS~1.0 HCl: C, 65.11; H, 5.67; N, 2.81. Found: C, 1205 64.84: H, 5.64; N, 2.91.

Example 10 Preparation of [6-Hydroxy-3-[4-[2-(1-pyrolidinyl)ethoxy]-1210 phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene ~N..~
O
'J
O
W
HO S
OH
The title compound was prepared from the product of 1215 Example 3 in a manner similar to that employed in Example 7 above; mp 99-113° C. 1H NMR (DMSO-d6) r1 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 1220 (m, 2H) , 2. 53 (m, 4H) , 0. 96 (t, J = 7. 0 Hz, 4H) . Anal.
Calcd. for C26H25NOqS~0.5 H20: C, 68.40; H, 5.74; N, 3.07.
Found: C, 68.52; H, 6.00; N, 3.34.

Example 11 Preparation of [6-Hydroxy-3-[4-[2-(1-hexamethyleneimino)-ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene N~ O
~J
O
W
Ho s ~
OH

The title compound was prepared from the product of Example 4 in a manner similar to that employed in Example 7 above; mp 125-130° C. 1H NMR (DMSO-d6) 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) , 1235 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.
Calcd. for CZ8H2gNOqS: C, 70.71; H, 6.15; N, 2.94. Found:
C, 70.67; H, 6.31; N, 2.93.

_._-_. T ___-.__. _.

WO 98/45286 PCT/US98/Ob989 Example 12 Preparation of [6-Hydroxy-3-[4-[2-(1-N,N-diethylamino ) ethoxy] phenoxy] -2- ( 4-1245 hydroxyphenyl)]benzo[b]thin hene w.N~O
I
I
O
I
HO S
OH
The title compound was prepared from the product of 1250 Example 5 in a manner similar to that employed in Example 7 above; mp 137-14I° C. 1H NMR (DMSO-d6) 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, 1255 2H) , 2. 74 ( t, J = 6. 0 Hz, 2H) , 2 .51 (m, 9H) , 1 . 66 (m, 6H) .
Anal. Calcd. for C26H2-7NOqS: C, 69.46; H, 6.05; N, 3.12.
Found: C, 69.76; H, 5.85; N, 3.40.

Example 13 Preparation of [6-Hydroxy-3-[4-[2-(morpholino)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride o'~ ~HCi ~'N'~'o ~J

W
Ho s OH

The title compound was prepared from the product of Example 6 in a manner similar to that employed in Example 7 above; mp 157-162° C. 1H NMR (DMSO-d6) a 10.60 (bs, 1H), 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.28 1270 (d, J = 2. 0 Hz, 1H) , 7.10 (d, J = 9.0 Hz, 1H) , 6.92 (q, JRB
- 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 (m, 4H), 3.18 (m, 2H). Anal. Calcd. for C26H25N05S~HC1: C, 62.46; H, 5.24; N, 2.80. Found: C, 69.69; H, 5.43; N, 2.92.

Example 14 Preparation of [6-Hydroxy-3-[4-[2-(1-pi eridinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene ~N~~
__ O
i O
HO S

Step a): Preparation of 6-Methoxybenzo[b]thiophene-2-boronic acid i OH
To a solution of 6-methoxybenzo[b]thiophene (18.13 g, 0.111 mol) in I50 mL of anhydrous tetrahydrofuran (THF) at -1290 60° 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 0° C and then distributed between 1N
1295 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 (710) of 6-methoxybenzo[b]
1300 thiophene-2-boronic acid as a white solid. mp 200° C (dec).
1H NMR (DMSO-d6) d 7.83 (s, 1H) , 7.78 (d, J = 8. 6 Hz, 1H) , 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.
1305 Step b): Preparation of [6-Methoxy-2-(4-methanesulfonyl-oxyphenyl)]benzo[b] thiophene i 1310 To a solution of 6-methoxybenzo[b]thiophene-2-boronic 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. lifter stirring for 10 minutes, tetrakistriphenylphosphinepalladium 1315 (0.60 g, 0.52 mmol) was added, and the resulting mixture was 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 1320 solid. Trituration from ethyl ether yielded a solid that was filtered and dried in vacuo to provide 3.70 g (77%) of [6-methoxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as a tan solid. mp 197-201° C. ~H NMR (DMSO-d6) d 7.82-7.77 (m, 3H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1325 1H) , 7 . 40 (d, J = 8 . 7 Hz, 2H) , 6. 98 (dd, J = 8. 7, 1 . 5 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H). FD mass spec 334. Anal.
Calcd. for C16H14~4S2: C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21.
1330 Step c): Preparation of [6-Hydroxy-2-(4-methanesulfonyl-oxyphenyl)]benzo[b] thiophene __._____- T

HO S

1335 To a solution of [6-methoxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene (9.50 g, 28.40 mmol) in anhydrous 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 1340 hours. The reaction was quenched by slowly pouring into excess ice water. After vigorously stirring for 30 minutes, the white precipitate was collected by filtration, washed several times with water, and then dried in vacuo to provide 8.92 g (980) of [6-hydroxy-2-(4-methanesulfonyloxyphenyl)]
1345 benzo[b]thiophene as a white solid. mp 239-243° C. 1H NMR
(DMSO-d6) a 9.70 (s, 1H) , 7.76 (d, J = 8.7 Hz, 2H) , 7.72 (s, 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 C15H1204S2:
1350 C, 56.23; H, 3.77. Found: C, 56.49; H, 3.68.
Step d): Preparation of [6-Benzyloxy-2-(4-methanesulfonyl-oxyphenyl)]benzo[b]thiophene i s ~.

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 Cs2C03 (5.75 g, 17.7 mmol) followed 1360 by benzylchloride (1.72 mL, 11.0 mmol). The resulting mixture was stirred vigorously for 24 hours. The solvent was removed in vacuo, and the solid residue was suspended in 200 mL of water. The white precipitate was collected by filtration and washed several times with water. Upon drying 1365 in vacuo, the crude product was suspended in 1:1 hexanes:ethyl ether. The solid was collected to provide 3.72 g (910) of [6-benzyloxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as a white solid. mp 198-202° C.
1H NMR (pMSO-d6) a 7.81-7.78 (m, 3H), 7.72 (d, J = 8.7 Hz, 1370 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.
Step e): Preparation of [6-Benzyloxy-2-(4-hydroxyphenyl)]-1375 benzo[b]thiophene O S
OH
i To a solution of [6-benzyloxy-2-(4-methanesulfonyloxy-1380 phenyl)]benzo[b]thiophene (12.50 g, 30.50 mmol) in 300 mL of anhydrous THF under nitrogen gas at ambient temperature was 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 1385 pouring the mixture into an excess of cold 1.0 N
hydrochloric acid. The aqueous phase was extracted with 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, 1390 chloroform) provided 8.75 g (870) of [6-benzyloxy-2-(4-hydroxyphenyl)]benzo[b] thiophene as a white solid. mp 212-216° C. 1H NMR (DMSO-d6) 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 1395 (s, 2H). FD mass spec 331. Anal. Calcd. for C21H1602S: C, 75.88; H, 4.85. Found: C, 75.64; H, 4.85.
Step f): Preparation of [6-Benzyloxy-2-(4-methoxyphenyl)]-- benzo[b]thiophene i E I
s I

i To a solution of [6-benzyloxy-2-(4-hydroxyphenyl)]
benzo[b]thiophene (8.50 g, 26.40 mmol) in 200 mL of 1405 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 hours at ambient temperature. The solvent was then removed 1410 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 provide 9.00 g (980) of [6-benzyloxy-2-(4-methoxyphenyl)]
1415 benzo[b]thiophene as a white solid. mp 180-185° C. 1H NMR
(DMSO-d6) 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 C22H1802S : 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 I

i [6-Benzyloxy-2-(4-methoxyphenyl)]benzo[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 temperature. Ta this suspension was added bromine (1.50 mL, 1430 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 to a white solid. Crystallization from methylene chloride/
1435 methanol provided 10.50 g (850) of [6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo-[b]thiophene as a white solid.
mp 146-150° C. 1H NMR (DMSO-d6) 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 Hz, 1H) , 7. 06 (d, J = 8.7 Hz, 2H) , 5.17 (s, 2H) , 3.78 (s, 1440 3H). FD mass spec 346. Anal. Calcd. for C22H1~02SBr: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00.
Step h): Preparation of [6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide) Br I
S

i The title compound was prepared by oxidation of the product from step g) with 1.5 equivalents of hydrogen 1450 peroxide in a mixture of trifluoroacetic acid in methylene chloride. The product was isolated as a yellow solid by crystallization from ethyl acetate. mp 202-205° C. 1H NMR
(DMSO-d6) d 7. 80 (d, J = 2.2 Hz, 1H) , 7. 68 (d, J = 8.7 Hz, 2H), 7.55(d, J = 8.4 Hz, 1H) 7.47-7.32 (m, 6H), 7.10 (d, J =
1455 8.7 Hz, 2H) , 5.23 (s, 2H) , 3.80 (s, 3H) . FD mass spec 441.
Anal. Calcd. for C22H1~03SBr: C, 59.87; H, 3.88. Found: C, 59.59; H, 3.78.
__.-_ _... T. .. __..-._. ~ ......__.~__.-,.,.--_ ___._._....... .. _. .. _...
._.._._....--._.__---.____ .T__._.._.....

Step i): Preparation of [6-Benzyloxy-3-[4-[2-(1-1460 piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]-benzo [b] thiophene- (S-oxide) CND
O
lw r O
I
w O ~~.

r 1465 Reaction of the product of step i) above with 4-(2-piperidinoethoxy)phenol in base yielded the title compound as a yellow oil. 1H NMR (DMSO-d6) 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 1470 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 (m, 6H). FD mass spec 592. Anal. Calcd. for C35H35N05S: C, 72.26; H, 6.06; N, 2.41. Found: C, 72.19; H, 5.99; N, 2.11.

WO 98/45286 PCT/iJS98/06989 Step j): Preparation of [6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]-benzo[b]thiophene ~N~
O
I
i O
I
J \ s i Reduction of the product of step i) above yielded the title compound, isolated in 950 overall yield. Purification by chromatography (Si02, 1-5o methanol/chloroform) provided 1485 an off-white solid, mp 105-108°C. 1H NMR (DMSO-dg) 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, 1490 4H). FD mass spec 565. Anal. Calcd. for C35Hg5NOqS: C, 74.31; H, 6.24; N, 2.48. Found: C, 74.35; H, 6.07; N, 2.76.
_.._ ~_~_.__ _.__. _ __ __T __.

Step k): Preparation of [6-Hydroxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]-1495 thiophene ~N~.
O
i O
I
Ho ~ s I
~OCH3 To a solution of [6-benzyloxy-3-{4-[2-(1-piperidinyl) 1500 ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene (8.50 g, 15.0 mmol) in 300 mL of 5:1 ethanol/ethyl acetate was 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 1505 3 hours, the reaction was judged complete and the solution was cooled to ambient temperature. The reaction was 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 1510 bicarbonate solution and 5s ethanol/ethyl acetate. The layers were separated, and the organic phase was dried (sodium sulfate) and concentrated in vacuo. The crude product was chromatographed (silicon dioxide, 1-50 methanol/chloroform) to provide 6.50 g (910) of [6-hydroxy-1515 3-[4-[2-(1-piperidinyl) ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo{b]thiophene as foam that converted to solid upon trituration with hexanes. mp 174-176° C. 1H NMR
(DMSO-d6) 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 1520 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, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spec 475. Anal. Calcd. for C2gH2gNOqS: C, 70.71; H, 6.15; N, 2.99. Found: C, 70.46; H, 5.93; N, 2.71.

Example 15 Preparation of [6-Hydroxy-2-(4-methoxyphenyl)3-[4-(2-piperidin-1-ylethoxy)phenoxy]benzo[b]thiophene 1530 hydrochloride salt ~ HCI
~N~.
O
i O
I
HO S

The product of Example 14 was converted to the corres-1535 ponding hydrochloride salt in 85o yield by treatment with a mixture of HCl saturated diethyl ether in ethyl acetate followed by crystallization from ethanol/ethyl acetate; mp 156-160° C. 1H NMR (DMSO-dg) 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, 1540 J = 8 . 7 Hz, 1H) , 6. 93 (d, J = 8 . 8 Hz, 2H) , 6. 87 (q, J,~ _ 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 C2gH2gNOqS~1.0 HC1: C, 65.68; H, 5.90; N, 2.73. Found: ~C, 1545 65.98; H, 6.11; N, 2.64.
_ _____ _ T _ _.__ __ _ _ ._.___ _._ __. ___ __-T _ - 57 _ Example 16 1550 Preparation of [6-methoxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thio hene O
I
O
I

OH
1555 Step a): Preparation of [6-methoxy-2-(4-benzyloxyphenyl)]-benzo[b]thiophene i I
H3C0 S I ~
O
I
1560 Following the general procedures of steps a) through g) of Example 14, the title compound was obtained in 73o yield, mp 217-221°C. 1H NMR (DMSO-d6) c1 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.
1565 Anal. Calcd. for C22H1g02S: C, 76.27; H, 5.24. Found: C, 76.00; H, 5.25.

Step b): [6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo-[b]thiophene Br I I

O
I
The title compound was obtained in 91o yield, mp 125-127°C. 1H NMR (DMSO-dg) d 7.64-7.61 (m, 4H), 7.46-7.31 (m, 1575 5H), 7.15-7.09 (m, 3H), 5.15 (s, 2H), 3.82 (s, 3H). FD mass spec 346. Anal. Calcd. for C2zH1~02SBr: C, 62.13; H, 4.03.
Found: C, 62.33; H, 3.93.
Step c): [6-Methoxy-2-(9-benzyloxyphenyl)-3-bromo]benzo[b]-1580 thiophene-(S-oxide) Br I I

O ~ O
The title compound was isolated as a yellow solid by 1585 chromatography (Si02, CHC13). mp 119-123° C. 1H NMR (DMSO-d6) d 7.73 (d, J = 2.2 Hz, 1H) , 7 . 68 (d, J = 8. 8 Hz, 2H) , 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 1590 C22H1~03SBr: C, 59.87; H, 3.88. Found: C, 60.13; H, 4.10.
___-~__. __T _ _..__________..~. __._.__~,._ .T__ ._.

Step d): [6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]
2-(4-benzyloxyphenyl)]benzo[b]thiophene-(S-oxide) ~N~
O
i O
H3C0 ~ S
O O
i The title compound was obtained as a yellow solid, mp 89-93° C. 1H NMR (DMSO-d6) 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), 1600 6.86 (d, J = 8.8 Hz, 2H) , 5.09 (s, 2H) , 3.94 (bt, J = 5.8 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 C35H35N05S~0.25 EtOAc: C, 71.52; H, 6.18; N, 2.32.
Found: C, 71.32; H, 5.96; N, 2.71.

Step e): [6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]
2-(4-benzyloxyphenyl)]benzo[b]thiophene ~N~.
O
i O
I
H3C0 ~ S
I
O

The title compound was obtained in 91% yield, mp 106-110°C. 1H NMR (DMSO-d6) a 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) , 1615 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 C35H35N04S: C, 74.31; H, 6.24; N, 2.48. Found: C, 74.26; H, 6.17; N, 2.73.
1620 Step f): Preparation of [6-methoxy-3-[4-[2-(1-piperidinyl) ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene OH
CND.
O

1625 The title compound was obtained in 88$ yield, mp 147-150° C. 1H NMR (DMSO-d6) 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 =
8 . 6, 2H) , 3 . 91 (bt, J = 5. 9 Hz, 2H) , 3. 77 (s, 3H) , 2.55 (bt, 1630 J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD
mass spec 475. Anal. Calcd. for C28H2gNOqS: C, 70.71; H, 6.15; N, 2.94. Found: C, 71.00; H, 6.17; N, 2.94.
Example 17 Preparation of [6-methoxy-3-[4-[2-(1- i eridinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride ~O
I

I I

OH

The title compound was prepared in a manner analogous to that employed in Example 15 to yield the title compound, mp 215-217° C. ~H NMR (DMSO-d6) d 10.28 (bs, 1H), 9.80 (s, 1H) , 7.52 (d, J = 2.2 Hz, 1H) , 7. 47 (d, J = 8 . 6 Hz, 2H) , 1645 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 C2gH2gNOqS~1.0 HC1: C, 65.68; H, 5.90; N, 2.73. Found: C, 1650 65.87; H, 5.79; N, 2.99.
~ HCI
N

Formulation Examples In the formulations which follow, "active ingredient"
1655 means a compound of formula I, or a salt or solvate thereof.
Formulation Example 1 Gelatin Capsules Ingredient Quantity (mg/capsule) Active ingredient 0.1 - 1000 Starch, NF 0 - 650 Starch flowable powder 0 - 650 Silicone fluid 350 centistokes 0 - 15 Formulation Example 2 Tablets Ingredient Quantity (mg/tablet) Active ingredient 2.5 - 1000 Cellulose, microcrystalline 200 - 650 Silicon dioxide, fumed 10 - 650 Stearate acid 5 - 15 1665 Formulation Example 3 Tablets Ingredient Quantity (mg/tablet) Active ingredient 25 - 1000 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone 4 (as loo solution in water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1 _- _.. __- .. .....__ T.._ _ ..-__ _ ._..___. ___.. _ __ .T __ _.

The active ingredient, starch, and cellulose are passed 1670 through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S.
sieve. The granules so produced are dried at 50°-60° C and passed through a No. 18 mesh U.S. sieve. The sodium 1675 carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S.~sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
1680 Formulation Example 4 Suspensions Ingredient Quantity (mg/5 ml) Active ingredient 0.1 - 1000 mg Sodium carboxymethyl cellulose 50 mg S yrup 1.25 mg Benzoic acid solution 0.10 mL
Flavor q.v, Color q .v.
Purified water to 5 mL
The medicament is passed through a No.45 mesh U.S.
1685 sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

1690 Formulation Example 5 Aerosol Ingredient Quantity (o by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00 The active ingredient is mixed with ethanol and the 1695 mixture added to a portion of the propellant 22, cooled to 30° C, and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container.

Formulation Example 6 Suppositories Ingredient Quantity (mg/suppository) Active ingredient 2S0 Saturated fatty acid 2,000 glycerides 1705 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 heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

Formulation Example 7 Injectable Formulations Ingredient Quantity Active ingredient 50 mg Isotonic saline 1,000 mL

1715 The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute.

Claims (16)

WE CLAIM:

1. A method for the prevention of breast carcinoma in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound having the structure or a pharmaceutically acceptable salt or pro-drug thereof wherein R1 and R2 are independently selected from hydroxy and alkoxy of one to four carbon atoms; and R3 and R4 are independently selected from methyl or ethyl, or R3 and R4, taken together with the nitrogen atom to which they are attached, form a pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring.

2. The method of Claim 1 wherein the patient has not been diagnosed with, but is determined to be at risk for, breast cancer.

3. The method of Claim 1 wherein R1 and R2 are both hydroxy.

4. The method of Claim 1 wherein R1 is hydroxy and R2 is alkoxy of one to four carbon atoms.

5. The method of Claim 4 wherein R2 is methoxy.

6. The method of Claim 2 wherein R1 and R2 are both hydroxy.

7. The method of Claim 2 wherein R1 is hydroxy and R2 is alkoxy of one to four carbon atoms.

8. The method of Claim 7 wherein R2 is methoxy.

9. The method of Claim 1 wherein R3 and R4 combine with the nitrogen atom to which they are attached to form a piperidino ring.

10. The method of Claim 2 wherein R3 and R4 combine with the nitrogen atom to which they are attached to form a piperidino ring.

11. The method of Claim 1 comprising the administration of a therapeutically effective amount of a compound having the structure or a pharmaceutically acceptable salt or pro-drug thereof, wherein R2 is hydroxy or methoxy.

12. The method of Claim 2 comprising the administration of a therapeutically effective amount of a compound having the structure or a pharmaceutically acceptable salt or pro-drug thereof, wherein R2 is hydroxy or methoxy.

13. The method of Claim 11 wherein said compound is 6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)-phenoxy]benzo[b]thiophene or a pharmaceutically acceptable salt thereof.

14. The method of Claim 11 wherein said compound is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)-phenoxy]benzo[b]thiophene or a pharmaceutically acceptable salt thereof.

15. The method of Claim 12 wherein said compound is 6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)-phenoxy]benzo[b]thiophene or a pharmaceutically acceptable salt thereof.

16. The method of Claim 12 wherein said compound is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)-phenoxy]benzo[b]thiophene or a pharmaceutically acceptable salt thereof.