NO314229B1

NO314229B1 - Benzothiophene compounds, intermediates, compositions, processes and the use of the same

Info

Publication number: NO314229B1
Application number: NO19960796A
Authority: NO
Inventors: Alan David Palkowitz; Kenneth Jeff Thrasher
Original assignee: Lilly Co Eli
Priority date: 1995-02-28
Filing date: 1996-02-27
Publication date: 2003-02-17
Also published as: NO960796D0; CN1086700C; HU226326B1; HUP9600476A2; CA2170479A1; HU9600476D0; CA2170479C; FI960909A; FI960909A0; BR9600829A; AU4579796A; CZ290200B6; AU699753B2; FI120345B; HUP9600476A3; NO960796L; CN1159448A; TR199600127A2; CZ58896A3

Description

Foreliggende oppfinnelse angår feltet farmasøytisk og organisk kjemi og å fremskaffe nye benzotiofenforbindelser som er nyttige i behandlingen av forskjellige medisinske indikasjoner forbundet med post-menstruelt syndrom og uterin fibroidsykdom, endometriosis og arotal glattmuskelcelleproliferasjon. Foreliggende oppfinnelse angår videre mellomprodukter som er nyttige for fremstilling av farma-søytisk aktive forbindelser ifølge foreliggende oppfinnelse og farmasøytiske sammensetninger, samt anvendelse av benzotiofenforbindelser for fremstilling av legemiddel. The present invention relates to the field of pharmaceutical and organic chemistry and to providing new benzothiophene compounds which are useful in the treatment of various medical indications associated with post-menstrual syndrome and uterine fibroid disease, endometriosis and arotal smooth muscle cell proliferation. The present invention further relates to intermediate products which are useful for the production of pharmaceutically active compounds according to the present invention and pharmaceutical compositions, as well as the use of benzothiophene compounds for the production of medicine.

"Post-menopausalt syndrom" er et uttrykk benyttet for å beskrive forskjellige patologiske tilstander som ofte påvirker kvinner som har kommet inn i eller fullført den fysiologiske metamorfosen kjent som menopause. Selv om forskjellige patologier omfattet ved anvendelse av dette uttrykket, er tre hovedeffekter av post-menopausalt syndrom kilden for de største lange tidsmedisinske bekymringer: osteoporose, kardiovaskulære effekter slik som hyperlipidemi og østrogenavhengig cancer, spesielt bryst- og uterincancer. "Post-menopausal syndrome" is a term used to describe various pathological conditions that often affect women who have entered or completed the physiological metamorphosis known as menopause. Although different pathologies are encompassed by the use of this term, three main effects of post-menopausal syndrome are the source of the greatest long-term medical concerns: osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancer, especially breast and uterine cancer.

Osteoporose beskriver en gruppe sykdommer som kommer fra forskjellige etiologier, men som er kjennetegnet ved en netto tap av benmasse pr. enhetsvolum. Konsekvensen av dette tap av benmasse og resulterende benfraktur er svikten i sjelettet til å gi den adekvate strukturelle støtte for kroppen. En av de vanligste typene osteoporose er den forbundet med menopausen. De fleste kvinner taper fra omkring 20# til omkring 60* av benmassen i det trabekulære området av ben i løpet av 3 til 6 år etter avtak av menstruasjon. Dette hurtige tapet er generelt forbundet med økning i benresorp-sjon og dannelse. Imidlertid er den resorptive syklus mest fremtredende og resultatet er et netto tap av benmasse. Osteoporose er en felles og alvorlig sykdom blant post-menopausale kvinner. Osteoporosis describes a group of diseases that come from different etiologies, but which are characterized by a net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20# to about 60* of the bone mass in the trabecular area of the bone within 3 to 6 years after cessation of menstruation. This rapid loss is generally associated with an increase in bone resorption and formation. However, the resorptive cycle is most prominent and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.

Det er anslått at 25 millioner kvinner i U.S.A alene lider av denne sykdommen. Resultatet av osteoporose er personlig skadelig og står også for store økonomiske tap av dets kroniske natur og behovet for ekstensiv og langtids støtte (hospitalisering og hjemmepleie) fra denne sykdommens følger. Dette er spesielt tilfelle med de eldste pasientene. Dessuten, selv om osteoporose ikke generelt er ansett som en livstruende tilstand, er en 20 til 30* mortalitetsrate relatert til hoftefrakturer hos eldre kvinner. En stor prosentdel av denne mortalitetsraten kan være direkte forbundet med post-menopausal osteoporose. It is estimated that 25 million women in the U.S. alone suffer from this disease. The result of osteoporosis is personally harmful and also accounts for great economic losses due to its chronic nature and the need for extensive and long-term support (hospitalization and home care) from the consequences of this disease. This is especially the case with the oldest patients. Also, although osteoporosis is not generally considered a life-threatening condition, a 20 to 30* mortality rate is related to hip fractures in older women. A large percentage of this mortality rate can be directly linked to post-menopausal osteoporosis.

Det mest utsatte vevet i benet for effektene av post-menopausal osteoporose er det trabekulaere ben. Dette vevet er ofte referert til som svampaktig ben og er spesielt konsentrert nær endene av benet (nær leddene) og i ryggsøylen. Det trabekulaere ben er kjennetegnet ved små osteoide strukturer som er forbundet med hverandre så vel som det mer faste, tette kortlkale vev som utgjør den ytre overflaten og det sentrale skaftet av benet. Dette sammenhengende nettverk av trabekulae gir lateral støtte til den ytre kortlkale struktur og er kritisk for den biomekaniske styrken til den totale strukturen. Ved post-menopausal osteoporose er det primært den nette resorpsjonen og tap av trabekulae som fører til svikt og fraktur av ben. I lys av tap av trabekulae hos post-menopausale kvinner er det ikke overraskende at de vanligste frakturer er de forbundet med ben som er sterkt avhengig av trabekular støtte, f.eks. ryggsøylen, halsen av vektbærende ben slik som femur og forarmen. Faktisk, er hoftefraktur, collies frakturer og vertebrale "crush" frakturer kjennemerker på post-menopausal osteoporose. The most exposed tissue in the bone to the effects of post-menopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy bone and is particularly concentrated near the ends of the bone (near the joints) and in the spine. Trabecular bone is characterized by small osteoid structures that are connected to each other as well as the more firm, dense cortical tissue that makes up the outer surface and central shaft of the bone. This interconnected network of trabeculae provides lateral support to the outer cortical structure and is critical to the biomechanical strength of the overall structure. In post-menopausal osteoporosis, it is primarily the net resorption and loss of trabeculae that leads to failure and fracture of bones. In light of the loss of trabeculae in post-menopausal women, it is not surprising that the most common fractures are those associated with bones that are heavily dependent on trabecular support, e.g. the spine, the neck of weight-bearing bones such as the femur and the forearm. In fact, hip fractures, collie's fractures and vertebral "crush" fractures are hallmarks of post-menopausal osteoporosis.

For tiden er den eneste generelle aksepterte fremgangsmåten for behandling av post-menopausal osteoporose, østrogenerstatningsterapi. Selv om terapien generelt er suksessfull, er pasientaksepten og terapien lav primært på grunn av at østrogenbehandlingen ofte produserer uønskede bieffekter. Gjennom den pre-menopausale tiden, har de fleste kvinner færre tilfeller av kardiovaskulære sykdommer enn jevnaldrende menn. Etter menopausen stiger forekomsten av kardiovaskulære sykdommer hos kvinner sakte og blir lik raten sett hos menn. Dette tap av beskyttelse har vært forbundet med tap av østrogen og, spesielt, tap av østrogenets evne til å regulere nivået av serumlipider. Naturen til østrogenets evne til å regulere serumlipider er ikke godt forstått, men data indikerer at østrogen kan regulere opp lav densitetslipid (LDL) reseptoren 1 leveren for å fjerne overskudd av kolesterol. I tillegg, synes østrogen å ha noen fordelaktige effekter på biosyntesen av kolesterol og andre fordelaktige effekter på kardiovaskulær helse. Currently, the only generally accepted method of treating post-menopausal osteoporosis is estrogen replacement therapy. Although the therapy is generally successful, patient acceptance and the therapy is low primarily because the estrogen treatment often produces unwanted side effects. Throughout the pre-menopausal period, most women have fewer cases of cardiovascular disease than their male peers. After menopause, the incidence of cardiovascular disease in women rises slowly and becomes similar to the rate seen in men. This loss of protection has been associated with loss of estrogen and, in particular, loss of estrogen's ability to regulate the level of serum lipids. The nature of estrogen's ability to regulate serum lipids is not well understood, but data indicate that estrogen can upregulate the low density lipid (LDL) receptor 1 in the liver to remove excess cholesterol. In addition, estrogen appears to have some beneficial effects on the biosynthesis of cholesterol and other beneficial effects on cardiovascular health.

Det har blitt rapportert i litteraturen at post-menopausale kvinner som får østrogenerstatningsterapi har en tilbakegang av serumlipidnivåer til konsentrasjoner lik de i den pre-menopausale tilstanden. Således, vil østrogen synes å være en fornuftig behandling for denne tilstand. Imidlertid, er bieffektene ved østrogenerstatningsterapi ikke akseptable for mange kvinner, noe som begrenser anvendelsen av denne terapien. En ideell terapi for denne tilstanden vil være et middel som vil regulere serumlipldnivået som østrogen, men som ikke hadde bieffektene og risiko forbundet med østrogen-terapi. It has been reported in the literature that post-menopausal women receiving estrogen replacement therapy have a decline in serum lipid levels to concentrations similar to those in the pre-menopausal state. Thus, estrogen would seem to be a reasonable treatment for this condition. However, the side effects of estrogen replacement therapy are not acceptable for many women, which limits the use of this therapy. An ideal therapy for this condition would be an agent that would regulate serum lipid levels like estrogen, but that did not have the side effects and risks associated with estrogen therapy.

En tredje hovedpatologi forbundet med post-menopausalt syndrom er østrogenavhengig brystcancer og til en mindre grad, østrogenavhengige cancere i andre organer, spesielt uterus. Selv om slike neoplasmaer ikke kun er begrenset til en post-menopausal kvinne, er de mer fremtredende i den eldre, post-menopausale pupulasjon. Nåværende terapi av disse cancerne har støttet seg på anvendelsen av antiøstrogenfor-bindelser slik som f.eks. tamoxifen. Selv om blandede agonist-antagonister har fordelaktige effekter for behandling av disse cancerne og de østrogene bieffektene er tolererbare i akutte livstruende situasjoner, er de ikke ideelle. For eksempel, kan disse midlene ha stimulerende effekt på visse cancercellepopulasjoner i uterus på grunn av deres østroge-niske (agonist) egenskaper og de kan derfor være kontrapro-duktiv I noen tilfeller. En bedre terapi for behandlingen av disse cancerne vil være et middel som er en antiøstrogenfor-bindelse som har neglisjerbare eller ingen østrogenagonist-egenskaper i reproduktivt vev. A third major pathology associated with post-menopausal syndrome is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers in other organs, especially the uterus. Although such neoplasms are not limited to a post-menopausal woman, they are more prominent in the older, post-menopausal population. Current therapy of these cancers has relied on the use of antiestrogen compounds such as e.g. tamoxifen. Although mixed agonist-antagonists have beneficial effects for the treatment of these cancers and the estrogenic side effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have a stimulatory effect on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may therefore be counterproductive in some cases. A better therapy for the treatment of these cancers would be an agent that is an antiestrogen compound that has negligible or no estrogen agonist properties in reproductive tissue.

Som respons på det klare behov for nye terapeutiske midler som er I stand til å lette symptomene er blant annet post-menopausalt syndrom, fremskaffer foreliggende oppfinnelse nye benzotlofenforbindelser, farmasøytiske sammensetninger derav og fremgangsmåter for anvendelse av slike forbindelser for behandling av post-menopausalt syndrom og andre østrogen-relaterte patologiske tilstander slik som de nevnt nedenfor. In response to the clear need for new therapeutic agents capable of alleviating the symptoms of, inter alia, post-menopausal syndrome, the present invention provides new benzotlofen compounds, pharmaceutical compositions thereof and methods of using such compounds for the treatment of post-menopausal syndrome and other estrogen-related pathological conditions such as those mentioned below.

UterinfIbrose (uterin fibroid sykdom) er et gammelt og alltid tilstedeværende klinisk problem som går under forskjellige navn, inkludert uterin fibroid sykdom, uterin hypertrof1, fibrosis uteri, og fibrotisk metritis. Essensielt er uterinfibrose en tilstand hvor det er upassende avsetning av fibroidvev på veggen av uterus. Uterine fibroid disease (uterine fibroid disease) is an old and ever-present clinical problem that goes by various names, including uterine fibroid disease, uterine hypertrophy, fibrosis uteri, and fibrotic metritis. Essentially, uterine fibrosis is a condition where there is inappropriate deposition of fibroid tissue on the wall of the uterus.

Denne tilstanden er en årsak til dysmenorrea og Infertilitet hos kvinner. Den ekstakte årsak til denne tilstanden er dårlig forstått, men en tyder på at det er en passende respons i fibroid vev for østrogen. En slik tilstand har blitt produsert i kaniner ved daglig administrasjon av østrogen i 3 måneder. I marsvin har tilstanden blitt produsert ved daglig administrasjon av østrogen i 4 måneder. Videre, forårsaker østrogen i rotter tilsvarende hypertrofi. This condition is a cause of dysmenorrhea and infertility in women. The exact cause of this condition is poorly understood, but one suggests that there is an appropriate response in fibroid tissue to estrogen. Such a condition has been produced in rabbits by daily administration of estrogen for 3 months. In guinea pigs the condition has been produced by daily administration of estrogen for 4 months. Furthermore, estrogen in rats causes corresponding hypertrophy.

Den vanligste behandlingen for uterin fibrose omfatter kirurgiske prosedyrer som både er kostbare og ofte en kilde for komplikasjoner slik som dannelsen av abdominale adhe-sjoner og infeksjoner. I noen pasienter, er initiell kirurgi kun en midlertidig behandling og fibroidene vokser til igjen. I disse tilfellene blir en hysterektoml utført, noe som effektivt avslutter fibroidene, men også det reproduktive livet til pasienten. Ogso gonadotropinfrigivende hormon-antagonister kan bli administrert, selv om deres anvendelse er hemmet av det faktum at de kan føre til osteoporose. Det er således et behov for nye fremgangsmåter for behandling av uterin fibrose og fremgangsmåten ifølge foreliggende oppfinnelse tilfredsstiller det behovet. The most common treatment for uterine fibrosis involves surgical procedures which are both expensive and often a source of complications such as the formation of abdominal adhesions and infections. In some patients, initial surgery is only a temporary treatment and the fibroids grow back. In these cases, a hysterectomy is performed, which effectively ends the fibroids, but also the reproductive life of the patient. Also, gonadotropin-releasing hormone antagonists can be administered, although their use is hampered by the fact that they can lead to osteoporosis. There is thus a need for new methods for treating uterine fibrosis and the method according to the present invention satisfies that need.

Endometriose er en tilstand av alvorlig dysmenorrea som er fulgt av alvorlig smerte, blødning inn i den endometriale masse eller peritoneale kavitet og ofte fører til Infertilitet. Årsaken til symptomene av denne tilstanden synes å være ektopisk endometrialvekst som responderer upassende på normal hormonell kontroll og er ofte lokalisert i gale vev. På grunn av gal lokalisering for endometrialvekst, synes vevet å initiere lokale inflammasjonslignende responser, noe som forårsaker makrofaglnfiltrerlng og kaskade av forbindelser som fører til initiering av smerteresponsen. Den eksakte etiologien i denne sykdommen er Ikke vel forstått og dets behandling med hormonal terapi er forskjellig, dårlig definert og kjennetegnet ved forskjellige uønskede og kanskje farlige bieffekter. Endometriosis is a condition of severe dysmenorrhoea that is followed by severe pain, bleeding into the endometrial mass or peritoneal cavity and often leads to infertility. The cause of the symptoms of this condition appears to be ectopic endometrial growth that responds inappropriately to normal hormonal control and is often located in wrong tissues. Due to mislocalization for endometrial growth, the tissue appears to initiate local inflammatory-like responses, causing macrophage infiltration and a cascade of connections leading to the initiation of the pain response. The exact etiology of this disease is not well understood and its treatment with hormonal therapy is different, poorly defined and characterized by various unwanted and perhaps dangerous side effects.

En av behandlingene for denne sykdommen er anvendelsen av lavdoseøstrogen for å undertrykke endometrialvekst ved negativ feedbackeffekter på sentral gonadotrofinfrigiving og påfølgende ovarlsk produksjon av østrogen; imidlertid, er det noen ganger nødvendig å benytte kontinuerlig østrogen for å kontrollere symptomene. Anvendelsen av østrogen kan ofte føre til uønskede bieffekter og også risiko for endometrialcancer. One of the treatments for this disease is the use of low-dose estrogen to suppress endometrial growth by negative feedback effects on central gonadotrophin release and subsequent ovarian production of estrogen; however, it is sometimes necessary to use continuous estrogen to control symptoms. The use of estrogen can often lead to unwanted side effects and also the risk of endometrial cancer.

En annen behandling omfatter kontinuerlig administrasjon av progestiner som induserer amenorrea og ved undertrykking av ovarisk østrogenproduksjon kan forårsake regressjon av endometrialvekst. Anvendelsen av kronisk progestinterapl er ofte fulgt av ubehagelig CNS bieffekter av progestin og fører ofte til infertilitet på grunn av undertrykkelsen av ovariefunksjonen. Another treatment involves continuous administration of progestins which induce amenorrhea and by suppressing ovarian estrogen production can cause regression of endometrial growth. The use of chronic progestin therapy is often followed by unpleasant CNS side effects of progestin and often leads to infertility due to the suppression of ovarian function.

En tredje behandling omfatter administrasjon av svake androgener som er effektive for kontroll av endometrlosen; imidlertid induserer de alvorlig maskuliniserende effekter. Flere av disse behandlingene for endometriose har også blitt identifisert som årsak for en middel grad av bentap ved fortsatt terapi. Derfor er nye fremgangsmåter for behandling av endometriose ønskelig. A third treatment involves the administration of weak androgens which are effective in controlling endometriosis; however, they induce severely masculinizing effects. Several of these treatments for endometriosis have also been identified as causing a moderate degree of bone loss with continued therapy. Therefore, new methods for treating endometriosis are desirable.

Foreliggende oppfinnelse angår forbindelser med formel I The present invention relates to compounds of formula I

hvor where

R<1> er -H, -OH, -0(<C>1-C4 alkyl), -OCOC7G5, -OCOtC-L-Cfc alkyl), eller -OS02(C2-<C>6 alkyl); R<1> is -H, -OH, -O(<C>1-C4 alkyl), -OCOC7G5, -OCOtC-L-Cf alkyl), or -OSO2(C2-<C>6 alkyl);

R<2> er -H, -OH, -0(C1-C4 alkyl), -0C0C6G5, -OCOfCj-Cfc alkyl), eller -OSOatCg-Cfc alkyl), eller halogen; R<2> is -H, -OH, -O(C1-C4 alkyl), -OC0C6G5, -OCOfCj-Cfc alkyl), or -OSOatCg-Cfc alkyl), or halogen;

R<3> er 1-piperidinyl, 1-pyrrolidlnyl, metyl-l-pyrrolidlnyl, dimetyl-l-pyrrolidino, 4-morfollno, dlmetylamino, dietylamino, diisopropylamino eller 1-heksametylenimino; eller n er 2 eller 3; og R<3> is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dlmethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino; or n is 2 or 3; and

z er -0- eller -S-; z is -0- or -S-;

eller et farmasøytisk akseptabelt salt derav. or a pharmaceutically acceptable salt thereof.

Videre fremskaffet ved foreliggende oppfinnelse er de følgende mellomprodukten som er nyttige for fremstilling av farmasøytisk aktive forbindelser ifølge oppfinnelsen, hvorav hvilke også er farmasøytisk aktive: Also provided by the present invention are the following intermediates which are useful for the production of pharmaceutically active compounds according to the invention, of which are also pharmaceutically active:

hvor where

jj<la> er _n eller -OB<7> hvori R<7> er en hydroksybeskyttende gruppe, jj<la> is _n or -OB<7> wherein R<7> is a hydroxy protecting group,

R<2a> er _Hf halogen, eller -OR<8>, hvori R<8> er en hydroksybeskyttende gruppe; R<2a> is _Hf halogen, or -OR<8>, wherein R<8> is a hydroxy protecting group;

R<3> er 1-piperidlnyl, 1-pyrrolidinyl, metyl-l-pyrrolidinyl, dimetyl-l-pyrrolidinyl, 4-morfollno, dimetylamino, diisopropylamino, eller l-heksametylenlmino; R<3> is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholamino, dimethylamino, diisopropylamino, or 1-hexamethyleneimino;

R<**> er -H eller en hydroksybeskyttende gruppe som kan bli selektivt fjernet; R<**> is -H or a hydroxy protecting group which can be selectively removed;

R<**> er en avspaltbar gruppe; R<**> is a leaving group;

R<11> er ikke-eksisterende eller =0; R<11> is non-existent or =0;

n er 2 eller 3; og n is 2 or 3; and

z er -0- eller -SO; z is -0- or -SO;

Det ble også fremskaffet en fremgangsmåte for fremstilling av forbindelser med formel A method for the preparation of compounds of formula was also provided

hvor where

jjla er _g eller -0R7a, hvor R7a er -E eller en hydroksybeskyttende gruppe; jjla is _g or -OR7a, where R7a is -E or a hydroxy protecting group;

R2a er -H, halogen, eller -0R8a hvor R8a er -H eller en hydroksybeskyttende gruppe; R 2a is -H, halogen, or -OR 8a where R 8a is -H or a hydroxy protecting group;

R<3> er 1-piperidinyl, l-pyrrolidlnyl, metyl-l-pyrrolidinyl, dimetyl-l-pyrrolidinyl, 4-morfolino, dimetylamino, diisopropylamino, eller l-heksametylenimino; R<3> is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diisopropylamino, or 1-hexamethyleneimino;

n er 2 eller 3; og n is 2 or 3; and

z er -0- eller -S-; z is -0- or -S-;

eller et farmasøytisk akseptabel salt derav, omfattende or a pharmaceutically acceptable salt thereof, comprising

a) oksydasjon av svovelatomet av en forbindelse med formel IV a) oxidation of the sulfur atom of a compound of formula IV

hvor where

Rla og Ra er som tidligere definert; og Rla and Ra are as previously defined; and

r<9> er en avspaltbar gruppe; r<9> is a leaving group;

b) reagere produktet fra trinn a) med en forbindelse med formel XIV b) reacting the product from step a) with a compound of formula XIV

med en nukleofil gruppe med formel hvor R<12> er -OH eller -SH; c) reduksjon av produktet fra trinn b), en forbindelse med formel XVI for å gi en forbindelse med formel d) eventuelt fjerne R<*a> og/eller R<2a> hydroksybeskyttende grupper, når tilstede, fra produktet fra trinn c); og e) eventuelt danne et salt av produktet fra trinn c) eller trinn d). with a nucleophilic group of formula where R<12> is -OH or -SH; c) reduction of the product from step b), a compound of formula XVI to give a compound of formula d) optionally removing R<*a> and/or R<2a> hydroxy protecting groups, when present, from the product of step c) ; and e) optionally forming a salt of the product from step c) or step d).

Foreliggende oppfinnelse angår også en fremgangsmåte for fremstilling av en forbindelse med formel I eller et farmasøytisk akseptabelt salt derav ifølge oppfinnelsen, kjennetegnet ved at den omfatter The present invention also relates to a method for producing a compound of formula I or a pharmaceutically acceptable salt thereof according to the invention, characterized in that it comprises

a) a)

(A) reduksjon av en forbindelse med formel XVI (A) reduction of a compound of formula XVI

hvor where

I^a er -H eller -0R7a, hvor R7a er -H eller en hydroksybeskyttende gruppe; I^a is -H or -OR 7a , where R 7a is -H or a hydroxy protecting group;

R2a er -H, halo, eller -0R<8a> hvor R8<a> er -H eller en hydroksybeskyttende gruppe; R2a is -H, halo, or -OR<8a> where R8<a> is -H or a hydroxy protecting group;

R<3> er 1-plperldlnyl, 1-pyrrolldinyl, metyl-l-pyrrolidlnyl, dlmetyl-1-pyrrolidinyl, 4-morfolino, dimetylamino, dletyl-amlno, dllsopropylamino, eller 1-heksametylenlmino; R<3> is 1-plperldlnyl, 1-pyrroldinyl, methyl-1-pyrrolidlnyl, dlmethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, dlethylamino, dlisopropylamino, or 1-hexamethyleneimino;

n er 2 eller 3; og n is 2 or 3; and

Z er -0- eller -S-; Z is -0- or -S-;

eller et farmasøytisk akseptabelt salt derav; or a pharmaceutically acceptable salt thereof;

(B) reagering av en forbindelse med formel Hb (B) reaction of a compound of formula Hb

hvor where

R<7> er en hydroksybeskyttende gruppe; og R<7> is a hydroxy protecting group; and

R<2a> og Z er som definert ovenfor; R<2a> and Z are as defined above;

med en forbindelse med formel V with a compound of formula V

hvor where

Q er en avspaltbar gruppe; og Q is a leaving group; and

R<3> er som definert ovenfor; R<3> is as defined above;

(C) reagere en forbindelse med formel Hb (C) react a compound of formula Hb

hvor where

R<2a>, R<7> og Z er som definert ovenfor, med et alkyleringsmiddel med formelen R<2a>, R<7> and Z are as defined above, with an alkylating agent of the formula

hvor Q og Q' er like eller forskjellige avspaltbare gruppe, produktet av hvilket blir reagert med l-piperidln, 1-pyrrolidin, metyl-l-pyrrolldln, dimetyl-l-pyrrolidin, 4-morfolin, dimetylamin, dietylamin, diisopropylamin, eller 1-heksametylenimin; eller (D) for en forbindelse med formel I, hvor R<1> eller R<2> er -H og den andre R^ eller R<2> substituenten er -OH, i) danne et triflat av hydroksygruppen av en forbindelse med formel where Q and Q' are the same or different leaving groups, the product of which is reacted with l-piperidln, 1-pyrrolidine, methyl-l-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine, or 1 -hexamethyleneimine; or (D) for a compound of formula I, where R<1> or R<2> is -H and the other R^ or R<2> substituent is -OH, i) forming a triflate of the hydroxy group of a compound with formula

hvor where

rI<c> er _oh eller -0-(C1-C4 alkyl); og rI<c> is _oh or -O-(C1-C4 alkyl); and

R<2c> er -OH eller -0-(C1-C4 alkyl); R<2c> is -OH or -O-(C1-C4 alkyl);

forutsatt at når R<lc> er -OH, er R<2c> -0-(C1-C4 alkyl), og når rIc er ^0_(<C>l_C4 alkyl) er R<2c> -OH; provided that when R<lc> is -OH, R<2c> is -O-(C1-C4 alkyl), and when rIc is ^O_(<C>1_C4 alkyl) R<2c> is -OH;

R<3> er 1-piperidin, 1-pyrrolidin, metyl-l-pyrrolidinyl, dimetyl-l-pyrrolidinyl, 4-morfolin, dimetylamino, dietylamino, diisopropylamino, eller 1-heksametylenimino; R<3> is 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholine, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

n er 2 eller 3; og n is 2 or 3; and

Z er -0- eller -S-; Z is -0- or -S-;

eller et farmasøytisk akseptabelt salt derav, og ii) redusere den resulterende triflatgruppen; b) eventuelt fjerne den gjenværende hydroksybeskyttende gruppen eller gruppene; og c) eventuelt danne et salt av produktet fra trinn a) og trinn or a pharmaceutically acceptable salt thereof, and ii) reducing the resulting triflate group; b) optionally removing the remaining hydroxy protecting group or groups; and c) optionally form a salt of the product from step a) and step

b). b).

Foreliggende oppfinnelse angår videre farmasøytiske sammensetninger inneholdende forbindelser med formel I, eventuelt Inneholdende østrogen eller progestin, sammen med en eller flere farmasøytisk akseptable bærere, hjelpestoffer eller fortynnere. The present invention further relates to pharmaceutical compositions containing compounds of formula I, optionally containing estrogen or progestin, together with one or more pharmaceutically acceptable carriers, excipients or diluents.

Som benyttet her, omfatter uttrykket "østrogen" steroidale forbindelser med østrogenisk aktivitet slik som f.eks. 17p-etynylestradiol, estron, konjugert østrogen (Premarin), equine østrogen 17p<->etynylestradiol, og lignende. Som benyttet her, omfatter uttrykket "progestin" forbindelser med progestasjonell aktivitet slik som f.eks. progesteron, noretylnodrel, nongestrel, megastrol acetat, noretindron, og lignende. As used herein, the term "estrogen" includes steroidal compounds with estrogenic activity such as e.g. 17p-ethynylestradiol, estrone, conjugated estrogen (Premarin), equine estrogen 17p<->ethynylestradiol, and the like. As used herein, the term "progestin" includes compounds with progestational activity such as e.g. progesterone, norethylnodrel, nongestrel, megastrol acetate, norethindrone, and the like.

Foreliggende oppfinnelse omfatter også anvendelse av en forbindelse med formel I Ifølge foreliggende oppfinnelse til fremstilling av et legemiddel for letting av symptomene for post-menopausalt syndrom; som osteoporose, en relatert kardlovaskulær sykdom, hyperlipidemi eller hormonavhengig cancer; foruten for hemming av uterin fibroid sykdom, endometriose, aortal glatt muskelcelleproliferasjon eller restenose. The present invention also includes the use of a compound of formula I According to the present invention for the preparation of a drug for alleviating the symptoms of post-menopausal syndrome; such as osteoporosis, a related cardiovascular disease, hyperlipidemia or hormone-dependent cancer; besides for inhibition of uterine fibroid disease, endometriosis, aortic smooth muscle cell proliferation or restenosis.

Forbindelsene ifølge foreliggende oppfinnelse er også nyttige for hemming av uterinfibroidsykdom og endometriosls hos kvinner og aortal glattmuskelcelleproliferasjon, spesielt restenose hos mennesker. The compounds of the present invention are also useful for the inhibition of uterine fibroid disease and endometriosis in women and aortic smooth muscle cell proliferation, particularly restenosis in humans.

Et aspekt ved foreliggende oppfinnelse omfatter forbindelser med formel I One aspect of the present invention comprises compounds of formula I

hvor where

R<1> er -H, -OH, -0(<C>1-C4 alkyl), -OCOC6G5, -OCOtC-t-Cf, alkyl), eller -0S02(C2-<C>6 alkyl); R<1> is -H, -OH, -O(<C>1-C4 alkyl), -OCOC6G5, -OCOtC-t-Cf, alkyl), or -SO2(C2-<C>6 alkyl);

R<2> er -H, -OH, -0(<C>1-C4 alkyl), -0C0C6G5, -OCOtCi-Cf, alkyl), eller -OS02(C2-C(, alkyl), eller halogen; R<2> is -H, -OH, -O(<C>1-C4 alkyl), -OC0C6G5, -OCOtCi-Cf, alkyl), or -OSO2(C2-C(, alkyl), or halogen;

R<3> er 1-plperldlnyl, 1-pyrrolidinyl, metyl-l-pyrrolldinyl, dimetyl-l-pyrrolidlno, 4-morfolIno, dimetylamino, dietylamino, dllsopropylamlno eller 1-heksametylenlmlno; eller n er 2 eller 3; og R<3> is 1-pyrrolidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholamino, dimethylamino, diethylamino, dlisopropylamino or 1-hexamethyleneamino; or n is 2 or 3; and

z er -0- eller -S-; z is -0- or -S-;

Generelle uttrykk benyttet i beskrivelsen av forbindelser beskrevet her har deres vanlige betydning. For eksempel, står "cl~c6 alkyl" for rettkjedede eller forgrenede alifatiske kjeder med 1 til 6 karbonatomer, Inkludert slik som metyl, etyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, heksyl, isoheksyl og lignende. Tilsvarende, står uttrykket "cl~c4 alkoksy" for en C^-C4 alkylgruppe bundet gjennom et oksygenmolekyl og omfatter grupper slik som f.eks. metoksy, etoksy, n-propoksy, isopropoksy, og lignende. General terms used in the description of compounds described herein have their usual meanings. For example, "cl~c6 alkyl" stands for straight or branched aliphatic chains of 1 to 6 carbon atoms, including such as methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl and the like. Correspondingly, the term "cl-c4 alkoxy" stands for a C1-C4 alkyl group bonded through an oxygen molecule and includes groups such as e.g. methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

Startmaterialet for en fremstillingsmåte for forbindelsen med formel I ifølge foreliggende oppfinnelse, forbindelser med formel III, blir fremstilt hovedsakelig som beskrevet av CD. Jones i U.S. patentene nr. 4,418,068 og 4,133,814, som hver er innlemmet her som referanse. Formel III har strukturen The starting material for a preparation method for the compound of formula I according to the present invention, compounds of formula III, is prepared mainly as described by CD. Jones in the U.S. Patent Nos. 4,418,068 and 4,133,814, each of which is incorporated herein by reference. Formula III has the structure

hvor R7 og R2<a> er som definert ovenfor. where R7 and R2<a> are as defined above.

R<7> og R<8> hydroksybeskyttende grupper er grupper som generelt Ikke blir funnet i de endelige terapeutisk aktive forbindelsene med formel I, men som overlagt blir innført under en del av den syntetiske prosessen for en beskyttende gruppe som ellers kan reagere 1 løpet av kjemiske manipulasjoner og blir fjernet ved et senere trinn av syntesen. Da forbindelsene som bærer slike beskyttende grupper er viktige primært som kjemiske mellomprodukter, selv om noen derivater også viser biologisk aktivitet, er deres nøyaktige struktur ikke kritisk. Forskjellige reaksjoner for dannelsen, fjerningen og muligens dannelsen av slike beskyttende grupper er beskrevet i et antall standardarbeider inkludert f.eks. Protective Groups in Organic Chemistry, Plenum Press (London og New York, 1973); Green, T.W., Protective Groups in Organic Synthesis, Wlley (New York, 1981); og The Peptides, bind I, Schrooder og Lubke, Academic Press, (London og New York, 1965 ). R<7> and R<8> hydroxy protecting groups are groups which are generally not found in the final therapeutically active compounds of formula I, but which are deliberately introduced during part of the synthetic process for a protecting group which may otherwise react in the course of by chemical manipulations and is removed at a later stage of the synthesis. Since the compounds bearing such protective groups are important primarily as chemical intermediates, although some derivatives also show biological activity, their exact structure is not critical. Various reactions for the formation, removal and possibly formation of such protecting groups are described in a number of standard works including e.g. Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Green, T.W., Protective Groups in Organic Synthesis, Wllley (New York, 1981); and The Peptides, Volume I, Schroder and Lubke, Academic Press, (London and New York, 1965).

Representative hydroksybeskyttende grupper omfatter f.eks.-Cj-04 alkyl, - C^ C^ alkoksy, -CO-fC^-Cf, alkyl), -S02-(C4-C6 alkyl), og -CO-Ar hvor Ar er benzyl eller eventuelt substituert fenyl. Uttrykket "substituert fenyl" refererer til en fenylgruppe med en eller flere substituenter valgt blant gruppen omfattende Ci~C4 alkyl, C^-C4 alkoksy, hydroksy, nitro, halogen og tri(klor eller fuor)metyl. Uttrykket "halo" refererer til brom, klor, fluor og jod. Representative hydroxy protecting groups include, e.g., -C1-04 alkyl, -C1-C4 alkoxy, -CO-fC2-Cf, alkyl), -SO2-(C4-C6 alkyl), and -CO-Ar where Ar is benzyl or optionally substituted phenyl. The term "substituted phenyl" refers to a phenyl group with one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, nitro, halogen, and tri(chloro or fluoro)methyl. The term "halo" refers to bromine, chlorine, fluorine and iodine.

For forbindelsene med formel III, er foretrukne R<7> og R<8 >(R<2a>) substituenter metyl, isopropyl, benzyl og metoksymetyl. Forbindelser hvor R<7> og R<8> hver er metyl blir fremstilt via prosedyren beskrevet i ovenfor refererte Jones patentet. En annen foretrukket hydroksybeskyttende gruppe er metoksymetyl. Imidlertid, blir en forbindelse med formel IV som vist nedenfor, først fremstilt bærende den foretrukne metyl eller andre hydroksybeskyttende grupper. Disse beskyttende gruppene blir så fjernet, for å danne fenoliske grupper som så blir gjenbeskyttet med metoksymetylbeskyttende grupper. For the compounds of formula III, preferred R<7> and R<8 >(R<2a>) substituents are methyl, isopropyl, benzyl and methoxymethyl. Compounds where R<7> and R<8> are each methyl are prepared via the procedure described in the above referenced Jones patent. Another preferred hydroxy protecting group is methoxymethyl. However, a compound of formula IV as shown below is first prepared bearing the preferred methyl or other hydroxy protecting groups. These protecting groups are then removed to form phenolic groups which are then reprotected with methoxymethyl protecting groups.

Forbindelser med formel II er også foretrukket hvor R<7 >hydroksybeskyttende grupper blir selektivt fjernet for å etterlate R<8>(R<2a>Jhydroksybeskyttende grupper som del av det endelige produktet. Det samme tilfellet hvor R<8> (R<2a>) hydroksybeskyttende grupper blir selektivt fjernet for å etterlate R<7> beskyttende grupper i stedet. For eksempel, er R<7> isopropyl eller benzyl og R<8> (R2a) er metyl. Isopropyl eller benzylgrupper blir selektivt fjernet via standardprosedyrer og R<8> metylbeskyttende gruppe er igjen som en del av det endelige produktet. Compounds of formula II are also preferred where R<7>hydroxy protecting groups are selectively removed to leave R<8>(R<2a>Jhydroxy protecting groups as part of the final product. The same case where R<8> (R<2a >) hydroxy protecting groups are selectively removed to leave R<7> protecting groups instead. For example, R<7> is isopropyl or benzyl and R<8> (R2a) is methyl. Isopropyl or benzyl groups are selectively removed via standard procedures and The R<8> methyl protecting group is left as part of the final product.

De første trinnene i foreliggende fremgangsmåte for fremstilling av visse forbindelser med formel I omfatter selektiv plassering av en avspaltbar gruppe i 3 posisjon i en forbindelse med formel III, kobling av reaksjonsproduktet av det første trinn med et 4-(beskyttet hydroksy)fenol, og fjerning av fenolisk hydroksybeskyttende gruppe. Foreliggende fremgangsmåte er skissert i skjema I nedenfor. I det første trinnet i skjema 1 blir en passende avspaltbar gruppe selektivt plassert i 3-posisjon i startmaterialene med formel II via standardprosedyrer. Passende R^ avspaltbare grupper omfatter sulfonatene slik som metansulfonat, 4-brombenzensulfonat, toluensulfonat, etansulfonat, isopropan-sulfonat, 4-metoksybenzensulfonat, 4-nitrobenzensulfonat, 2-klorbenzensulfonat, triflat og lignende, halogener slik som brom, klor og jod og andre beslektede avspaltbare grupper. For å sikre riktig plassering av den avspaltbare gruppen, er imidlertid de nevnte halogenene foretrukkede og brom er spesielt foretrukket. The first steps in the present process for preparing certain compounds of formula I comprise selectively placing a leaving group in the 3 position of a compound of formula III, coupling the reaction product of the first step with a 4-(protected hydroxy)phenol, and removing of phenolic hydroxy protecting group. The present procedure is outlined in form I below. In the first step of Scheme 1, an appropriate leaving group is selectively placed in the 3-position in the starting materials of formula II via standard procedures. Suitable R^ leaving groups include the sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate, triflate and the like, halogens such as bromine, chlorine and iodine and other related separable groups. However, to ensure correct placement of the leaving group, the aforementioned halogens are preferred and bromine is particularly preferred.

Foreliggende reaksjon blir utført ved anvendelse av standardprosedyrer. For eksempel, når de foretrukne halogene-ringsmidlene blir benyttet, blir en ekvivalent av et slikt halogeneringsmiddel, fortrinnsvis brom, reagert med en ekvivalent av substratet med formel III i nærvær av et passende oppløsningsmiddel slik som f.eks. kloroform eller eddiksyre. Reaksjonen blir kjørt ved en temperatur på omkring 40'C til omkring 80°C. The present reaction is carried out using standard procedures. For example, when the preferred halogenating agents are used, one equivalent of such halogenating agent, preferably bromine, is reacted with one equivalent of the substrate of formula III in the presence of a suitable solvent such as e.g. chloroform or acetic acid. The reaction is run at a temperature of about 40°C to about 80°C.

Reaksjonsproduktet fra prosesstrinnet ovenfor, en forbindelse med formel IV, blir så reagert med et 4-(beskyttet hydroksy)-fenol for å danne forbindelser med formel Ila hvor R<6> er en selektivt avspaltbar hydroksybeskyttende gruppe. Generelt, kan den 4-hydroksybeskyttende delen av fenolet være en hvilken som helst kjent beskyttende gruppe som kan bli selektivt fjernet uten fjerning, i dette tilfellet, R<7> og, når tilstede, R<8> gruppene i en forbindelse med formel Ila. Foretrukne R<6> beskyttende grupper omfatter metoksymetyl, når R<7> og R<8> Ikke er metoksymetyl, og benzyl. Av disse, er benzyl spesielt foretrukket. De 4-(beskyttet-hydroksyJfenolreaktan-tene er kommersielt tilgjengelige eller blir fremstilt via standardprosedyrer. The reaction product from the process step above, a compound of formula IV, is then reacted with a 4-(protected hydroxy)-phenol to form compounds of formula IIa where R<6> is a selectively cleavable hydroxy protecting group. In general, the 4-hydroxy protecting portion of the phenol can be any known protecting group that can be selectively removed without removal, in this case, the R<7> and, when present, the R<8> groups in a compound of formula IIa . Preferred R<6> protecting groups include methoxymethyl, when R<7> and R<8> are not methoxymethyl, and benzyl. Of these, benzyl is particularly preferred. The 4-(protected-hydroxyphenol reactants are commercially available or are prepared via standard procedures).

Koblingsreaksjonen er kjent i teknikken som en Ullman reaksjon og blir kjørt ifølge standard kjemiske prosedyrer The coupling reaction is known in the art as an Ullman reaction and is run according to standard chemical procedures

(se f.eks. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition, 3-16, (J. Maren, ed., John Wiley & Sons, Inc. 1991); Jones, C.D., J. Chem. Soc. Perk. Trans. I, 4:407 (1992)]. (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition, 3-16, (J. Maren, ed., John Wiley & Sons, Inc. 1991); Jones, C.D., J. Chem. Soc. Perc. Trans. I, 4:407 (1992)].

Generelt, blir ekvivalente mengder av to arylsubstrater i nærvær av opptil en ekvimolar mengde av kobber(I)oksyd-katalysator og et passende oppløsningsmiddel, oppvarmet med tilbakeløpskjøling under inertatmosfære. Fortrinnsvis, blir en ekvivalent av forbindelsen med formel IV hvor R^ er brom, reagert med en ekvivalent mengde av 4-benzyloksyfenol i nærvær av en ekvivalent kobber(I)oksyd. In general, equivalent amounts of two aryl substrates in the presence of up to an equimolar amount of copper(I) oxide catalyst and a suitable solvent are heated under reflux under an inert atmosphere. Preferably, one equivalent of the compound of formula IV wherein R 1 is bromine is reacted with an equivalent amount of 4-benzyloxyphenol in the presence of one equivalent of cupric oxide.

Passende oppløsningsmldler for denne reaksjonen er de oppløsningsmidlene eller blandingene av oppløsningsmldler som forblir inert under reaksjon. Typisk er organiske baser, spesielt en hindret base slik som f.eks. 2,4,6-kollIdin, foretrukne oppløsningsmldler. Suitable solvents for this reaction are those solvents or mixtures of solvents which remain inert during reaction. Typically, organic bases, especially a hindered base such as e.g. 2,4,6-collidine, preferred solvents.

Temperaturen benyttet i dette trinnet skal være tilstrekkelig for å gi fullførelse av denne koblingsreaksjonen, og vil påvirke tiden som er nødvendig for dette. Reaksjonsblåndingen blir oppvarmet til tilbakeløpskjøling under inertatmosfære slik som nitrogen, vil tid-til-fullførelse vanligvis være fra omkring 20 til omkring 60 timer. The temperature used in this step must be sufficient to give completion of this coupling reaction, and will affect the time required for this. The reaction mixture is heated to reflux under an inert atmosphere such as nitrogen, time-to-completion will typically be from about 20 to about 60 hours.

Etter kobling, som danner en forbindelse med formel Ila, blir forbindelser med formel Hb fremstilt ved selektiv fjerning av hver av R<**> hydroksybeskyttende gruppe fra en forbindelse med formel Ha via velkjente reduksjonsprosedyrer. Det er påkrevet at den valgte prosedyren ikke vil påvirke R<7> og, når tilstede. R<8> hydroksybeskyttende grupper. After coupling, forming a compound of formula IIa, compounds of formula Hb are prepared by selective removal of each R<**> hydroxy protecting group from a compound of formula Ha via well-known reduction procedures. It is required that the chosen procedure will not affect R<7> and, when present. R<8> hydroxy protecting groups.

Når r<6> er den foretrukkede benzylgruppen og R<7>, og, når tilstede, R<8> hver er metyl, blir foreliggende fremgangsmåte-trinn utført via standard hydrogeneringsprosedyrer. Typisk, blir substratet med formel Ila tilsatt til et passende oppløsningsmiddel eller blanding av oppløsningsmldler, fulgt av tilsetning av en protondonor for å aksellerere reaksjonen og en passende hydrogeneringskatalysator. When r<6> is the preferred benzyl group and R<7> and, when present, R<8> are each methyl, the present process steps are carried out via standard hydrogenation procedures. Typically, the substrate of formula IIa is added to a suitable solvent or mixture of solvents, followed by the addition of a proton donor to accelerate the reaction and a suitable hydrogenation catalyst.

Passende katalysatorer omfatter edelmetaller og oksyder slik som palladium, platina og rodlumoksyd på en støtte slik som karbon eller kalsiumkarbonat. Av disse er palladium på karbon, spesielt 10* palladium på karbon, foretrukket. Suitable catalysts include noble metals and oxides such as palladium, platinum and rhodlum oxide on a support such as carbon or calcium carbonate. Of these, palladium on carbon, especially 10* palladium on carbon, is preferred.

Oppløsningsmldler for denne reaksjonen er de oppløsnlngsmid-lene eller oppløsningsmiddelblandingene som forblir lnerte gjennom reaksjonen. Typisk er etylacetat og alifatiske alkoholer, spesielt etanol, foretrukket. Solvents for this reaction are the solvents or solvent mixtures that remain isolated throughout the reaction. Typically, ethyl acetate and aliphatic alcohols, especially ethanol, are preferred.

For foreliggende reaksjon tjener saltsyre som en passende og foretrukket protondonor. For the present reaction, hydrochloric acid serves as a suitable and preferred proton donor.

Når kjørt under omgivelsestemperatur og trykk i området fra omkring 30 psi til omkring 50 psi, løper foreliggende reaksjon relativt hurtig. Fremdriften av denne reaksjonen kan bli overvåket ved standard kromatografiske teknikker slik som tynnsj iktskromatografi. When run under ambient temperature and pressure in the range of about 30 psi to about 50 psi, the present reaction proceeds relatively rapidly. The progress of this reaction can be monitored by standard chromatographic techniques such as thin layer chromatography.

Forbindelser med formel Ila og Hb er nye og er omfattet innen rammen som er beskrevet her som forbindelse med formel II, og er anvendelige for fremstilling av farmasøytisk aktive forbindelser med formel I. Compounds of formula Ila and Hb are new and are included within the framework described here as compound of formula II, and are applicable for the preparation of pharmaceutically active compounds of formula I.

Etter fremstilling av en forbindelse med formel Hb, blir den reagert med en forbindelse med formel V After preparation of a compound of formula Hb, it is reacted with a compound of formula V

hvor R<3> og n er som definert ovenfor, og Q er brom eller, fortrinnsvis klor, for å danne en forbindelse med formel VI. Forbindelsen med formel VI blir så avbeskyttet for å danne en where R<3> and n are as defined above, and Q is bromine or, preferably, chlorine, to form a compound of formula VI. The compound of formula VI is then deprotected to form a

forbindelse med formel Ia. Disse trinnene ifølge foreliggende fremgangsmåte er vist i skjema II nedenfor. compound of formula Ia. These steps according to the present method are shown in scheme II below.

hvor R<3>, R7, R2<a> og n er som definert ovenfor og R213 er -H,-OH eller halogen. where R<3>, R7, R2<a> and n are as defined above and R213 is -H, -OH or halogen.

I det første trinnet i fremgangsmåten vist 1 skjema II, blir alkyleringen utført via standard prosedyrer. Forbindelsen med formel V er kommersielt tilgjengelige eller kan bli fremstilt ved midler som er velkjente for fagmannen. Fortrinnsvis, blir hydrokloridsaltet av en forbindelse med formel V, spesielt 2-kloretylpiperidin hydroklorid benyttet. In the first step of the process shown in Scheme II, the alkylation is carried out via standard procedures. The compounds of formula V are commercially available or can be prepared by means well known to those skilled in the art. Preferably, the hydrochloride salt of a compound of formula V, especially 2-chloroethylpiperidine hydrochloride, is used.

Generelt, blir minst omkring 1 ekvivalent av substratet med formel Hb reagert med 2 ekvivalenter av en forbindelse med formel V i nærvær av minst 4 ekvivalenter av et alkallmetall-karbonat, fortrinnsvis cesiumkarbonat, og et passende oppløsningsmiddel. In general, at least about 1 equivalent of the substrate of formula Hb is reacted with 2 equivalents of a compound of formula V in the presence of at least 4 equivalents of an alkali metal carbonate, preferably cesium carbonate, and a suitable solvent.

Oppløsningsmldler for denne reaksjonen er de oppløsningsmid-lene eller blanding av oppløsningsmldler som forblir inerte gjennom reaksjonen. N,N-dimetylformamid, spesielt den vannfrie formen derav, er foretrukket. Solvents for this reaction are the solvents or mixture of solvents that remain inert throughout the reaction. N,N-dimethylformamide, especially the anhydrous form thereof, is preferred.

Temperaturen benyttet i dette trinnet skal være tilstrekkelig for å gl fullførelse av denne alkyleringsreaksjonen. Omgivelsestemperatur er tilstrekkelig, og foretrukket. The temperature used in this step must be sufficient to allow completion of this alkylation reaction. Ambient temperature is sufficient, and preferred.

Foreliggende reaksjon blir fortrinnsvis kjørt under en inertatmosfære, spesielt nitrogen. The present reaction is preferably run under an inert atmosphere, especially nitrogen.

Under de foretrukne reaksjonsbetingelsene, vil denne reaksjonen løpe til fullførelse i løpet av 16 til omkring 20 timer. Naturligvis, kan forløpet av reaksjonen bli overvåket ved standard kromatografiske teknikker. Under the preferred reaction conditions, this reaction will run to completion in about 16 to about 20 hours. Naturally, the progress of the reaction can be monitored by standard chromatographic techniques.

Som et alternativ for fremstilling av forbindelser med formel VI, blir en forbindelse med formel Hb reagert med et overskudd av et alkyleringsmiddel med formelen As an alternative for preparing compounds of formula VI, a compound of formula Hb is reacted with an excess of an alkylating agent of the formula

hvor 0 og 0' hver er like eller forskjellige avspaltbare grupper, i en alkalisk oppløsning. Passende avspaltbare grupper er de ovenfor nevnte avspaltbare gruppene benyttet i fremstillingen av forbindelser med formel IV. where 0 and 0' are each the same or different leaving groups, in an alkaline solution. Suitable cleavable groups are the above-mentioned cleavable groups used in the preparation of compounds of formula IV.

En foretrukket alkalisk oppløsning for denne alkyleringsreaksjonen inneholder kallumkarbonat i et inert oppløsningsmid-del, slik som f.eks. metyletylketon (MEK) eller DMF. I denne oppløsningen eksisterer 4-hydroksygruppen I benzoylgruppen av forbindelsen med formel Hb, som et fenoksydion som erstatter en av de avspaltbare gruppene på acyleringsmidlet. A preferred alkaline solution for this alkylation reaction contains calcium carbonate in an inert solvent, such as e.g. methyl ethyl ketone (MEK) or DMF. In this solution, the 4-hydroxy group in the benzoyl group of the compound of formula Hb exists as a phenoxide ion replacing one of the leaving groups on the acylating agent.

Denne reaksjonen er best når den alkaliske oppløsningen Inneholdende reagenser og reaktanter, blir bragt til tilbakeløpskjøllngstemperatur og blir tillatt å løpe til fullførelse. Ved anvendelse av MEK som foretrukket opp-løsningsmiddel, løper reaksjonstiden fra omkring 6 timer til omkring 20 timer. This reaction is best when the alkaline solution containing reagents and reactants is brought to reflux temperature and allowed to run to completion. When using MEK as the preferred solvent, the reaction time runs from about 6 hours to about 20 hours.

Reaksjonsproduktet fra dette trinnet blir så reagert med 1-piperidin, 1-pyrrolidin, metyl-l-pyrrolidin, dimetyl-1-pyrrolldin, 4-morfolin, dimetylamln, dietylamin, diisopropylamin eller 1-heksametylenimin, via standardteknikker for å danne forbindelser med formel VI. The reaction product from this step is then reacted with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine or 1-hexamethyleneimine, via standard techniques to form compounds of formula WE.

Fortrinnsvis, blir hydrokloridsaltet av piperidin reagert med den alkylerte forbindelsen med formel Hb i et inert oppløsningsmiddel slik som vannfri DMF, og oppvarmet til en temperatur I området fra omkring 60"C til omkring 110°C. Når reaksjonsblandingen blir oppvarmet til en foretrukket temperatur på omkring 90<*>C, tar reaksjonen kun omkring 30 minutter til omkring 1 time. Imidlertid, vil forandringer I reaksjonsbetingelsene påvirke tiden denne reaksjonen trenger for å løpe til fullførelse. Naturligvis, kan fremdriften i dette reaksjonstrinnet bli overvåket via standard kromatografiske teknikker. Preferably, the hydrochloride salt of piperidine is reacted with the alkylated compound of formula Hb in an inert solvent such as anhydrous DMF, and heated to a temperature in the range of from about 60°C to about 110°C. When the reaction mixture is heated to a preferred temperature of around 90<*>C, the reaction takes only about 30 minutes to about 1 hour. However, changes in the reaction conditions will affect the time this reaction takes to run to completion. Naturally, the progress of this reaction step can be monitored via standard chromatographic techniques.

Forbindelser med formel VI,' hvor R<7> og når tilstede, R<8>, hver er C1-C4 alkyl, fortrinnsvis metyl, og hvor R<2a> er -H eller halo, er nye og er farmasøytisk aktive for fremgangsmåtene beskrevet her. Følgelig, er slike forbindelser omfattet ved definisjon her av forbindelser med formel I. Compounds of formula VI,' wherein R<7> and when present, R<8>, each is C1-C4 alkyl, preferably methyl, and wherein R<2a> is -H or halo, are novel and are pharmaceutically active for the methods described here. Accordingly, such compounds are encompassed by the definition herein of compounds of formula I.

Visse foretrukne forbindelser med formel I blir fremskaffet ved spaltning av R<7> og, når tilstede, R<8> hydroksybeskyttende grupper i forbindelser med formel VI via velkjente prosedyrer. Forskjellige reaksjoner for dannelsen og fjerning av slike beskyttende grupper er beskrevet i et antall stan-dardverker inkludert f.eks. Protective Groups ln Organic Chemistry, Plenum Press (London og New York, 1973); Green, T.W., Protective Groups in Organic Synthesls, Wiley, (New York, 1981); og The Peptides, bind I, Schrooder og Lubke, Academic Press (London og New York, 1965). Fremgangsmåter for fjerning av foretrukne R<7> og/eller R<8> hydroksybeskyttende grupper, spesielt metyl og metoksymetyl, er essensielt som beskrevet i eksemplene nedenfor. Certain preferred compounds of formula I are prepared by cleavage of R<7> and, when present, R<8> hydroxy protecting groups in compounds of formula VI via well known procedures. Various reactions for the formation and removal of such protective groups are described in a number of standard works including e.g. Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Green, T.W., Protective Groups in Organic Synthesls, Wiley, (New York, 1981); and The Peptides, Volume I, Schroder and Lubke, Academic Press (London and New York, 1965). Procedures for removing preferred R<7> and/or R<8> hydroxy protecting groups, especially methyl and methoxymethyl, are essential as described in the examples below.

Forbindelsene med formel I er nye, er farmasøytisk aktive for fremgangsmåtene beskrevet her og er omfattet av formel I som definert her. The compounds of formula I are new, are pharmaceutically active for the methods described herein and are encompassed by formula I as defined herein.

Forbindelser med formel I, hvor R<1> er -H, blir fremstilt via den syntetiske veien vist nedenfor i skjema III. Ved anvendelse av denne veien, blir avspaltbar gruppe i 3-posisjon (r<9>) plassert på kommersielt tilgjengelig tianaf-talen (formel VII) for å danne en forbindelse med formel VIII, som så blir koblet med en 4-(beskyttet-hydroksy)fenol, for å gl forbindelser med formel IX. Compounds of formula I, wherein R<1> is -H, are prepared via the synthetic route shown below in Scheme III. Using this route, the leaving group in the 3-position (r<9>) is placed on the commercially available thianaphtalene (formula VII) to form a compound of formula VIII, which is then coupled with a 4-(protected- hydroxy)phenol, to gl compounds of formula IX.

hvor R** er en hydroksybeskyttende gruppe som kan bli selektivt fjernet og R^ er en avspaltbar gruppe. where R** is a hydroxy protecting group which can be selectively removed and R^ is a leaving group.

Forbindelsene med formel VII er kommersielt tilgjengelige. Fremstilling av forbindelsene med formel VIII og IX, inkluderer definisjonen av R<6> og R^ substituenter, såvel som foretrukne reaktanter og betingelser, hvis ikke annet her er angitt, er de samme som beskrevet ovenfor og vist i skjema I, over. The compounds of formula VII are commercially available. Preparation of the compounds of formula VIII and IX includes the definition of R<6> and R^ substituents, as well as preferred reactants and conditions, unless otherwise indicated herein, are the same as described above and shown in Scheme I, above.

Forbindelsene med formel IX blir så arylert via Suzuki-kobllng [se, f.eks. Suzuki, A., Pure and Appl. Chem., 6(2):213-222 (1994)]. Ved bruk av en Suzuki-kobling, blir en forbindelse med formel IX selektivt halogenert i 2-posisjonen og blir så koblet via en arylborsyreforbindelse med formel Xla (rute A i skjema IV nedenfor). The compounds of formula IX are then arylated via Suzuki coupling [see, e.g. Suzuki, A., Pure and Appl. Chem., 6(2):213-222 (1994)]. Using a Suzuki coupling, a compound of formula IX is selectively halogenated at the 2-position and is then coupled via an aryl boronic acid compound of formula Xla (Route A in Scheme IV below).

Fortrinnsvis blir Imidlertid en arylborsyre med formel Xb dannet fra en forbindelse med formel IX og så reagert via et haloaren med formel Xlb for å gi nye mellomprodukter med formel lic (rute B i skjema IV nedenfor). Slike nye mellomprodukter er nyttige for fremstilling av farmasøytisk aktive forbindelser Ifølge foreliggende oppfinnelse (formel Ib forbindelser) via alkylering og avbeskyttelse. Preferably, however, an arylboronic acid of formula Xb is formed from a compound of formula IX and then reacted via a haloarene of formula Xlb to give new intermediates of formula lic (route B in Scheme IV below). Such new intermediates are useful for the production of pharmaceutically active compounds according to the present invention (formula Ib compounds) via alkylation and deprotection.

hvor where

R2af jj2bt R<3>0g n er som definert ovenfor; R2af jj2bt R<3>0g n is as defined above;

X er jod, brom eller fluor, 1 den foretrukne rekkefølge; og X<*> er jod, brom eller fluor, 1 den foretrukne rekkefølge eller trlflat. X is iodo, bromo or fluoro, 1 being the preferred order; and X<*> is iodine, bromine or fluorine, 1 the preferred order or trlflat.

Det første trinn i rute A i skjema IV er 2-posisjon jodiner-ing eller brominering av en forbindelse med formel IX ved anvendelse av standard prosedyrer. Generelt, blir en forbindelse med formel IX reagert med et svakt overskudd av n-butyllitium i heksan, I et passende oppløsningsmiddel og under inertatmosfære slik som nitrogen, fulgt av dråpevis tilsetning av et svakt overskudd av det ønskede halogene-rlngsmidlet i et passende oppløsningsmiddel. Fortrinnsvis, er halogeneringsmidlet for dette trinnet jod, men anvendelsen av brom, N-bromsuksinimid er også tillatt. The first step in route A of Scheme IV is the 2-position iodination or bromination of a compound of formula IX using standard procedures. In general, a compound of formula IX is reacted with a slight excess of n-butyllithium in hexane, in a suitable solvent and under an inert atmosphere such as nitrogen, followed by the dropwise addition of a slight excess of the desired halogenating agent in a suitable solvent. Preferably, the halogenating agent for this step is iodine, but the use of bromine, N-bromosuccinimide is also permitted.

Passende oppløsningsmldler omfatter inerte oppløsningsmldler eller blanding av oppløsningsmldler, f.eks. dietyleter, dloksan og tetrahydrofuran (THF). Av disse, er tetrahydrofuran, spesielt vannfri THF, foretrukket. Suitable solvents include inert solvents or mixtures of solvents, e.g. diethyl ether, dloxane and tetrahydrofuran (THF). Of these, tetrahydrofuran, especially anhydrous THF, is preferred.

Den foreliggende selektive 2-posisjon halogeneringsreaksjon blir eventuelt utført ved en temperatur fra omkring -75*C til omkring 85<*>C. The present selective 2-position halogenation reaction is optionally carried out at a temperature from about -75*C to about 85<*>C.

Produktet fra reaksjonen ovenfor, et haloaren med formel Xa, blir så koblet med en arylborsyre med formel Xla via standard Suzuki-koblingsprosedyrer, for å gi forbindelser med formel lic. Forbindelser med formel Xla, hvor R<2a> er -H, halogen, eller -OR<8> (R<8> er en hydroksybeskyttende gruppe som definert ovenfor), blir avledet fra kommersielt tilgjengelige forbindelser via prosedyrer som er velkjent for fagmannen (se f.eks. March J., og Suzuki, A., ovenfor). The product of the above reaction, a haloarene of formula Xa, is then coupled with an aryl boronic acid of formula Xla via standard Suzuki coupling procedures to give compounds of formula lic. Compounds of formula Xla, wherein R<2a> is -H, halogen, or -OR<8> (R<8> is a hydroxy protecting group as defined above), are derived from commercially available compounds via procedures well known to those skilled in the art ( see eg March J., and Suzuki, A., supra).

I foreliggende koblingsreaksjon blir et svakt overskudd av en forbindelse med formel Xla reagert med hver ekvivalent av en forbindelse med formel Xa i nærvær av en palladiumkatalysator og en passende base i et inert oppløsningsmiddel slik som toluen. In the present coupling reaction, a slight excess of a compound of formula Xla is reacted with one equivalent of a compound of formula Xa in the presence of a palladium catalyst and a suitable base in an inert solvent such as toluene.

Selv om forskjellige palladiumkatalysatorer driver Suzukl-koblingsreaksjoner, er den valgte katalysatoren vanligvis reaksjonsspesifIkk. Anvendelsen av tetrakistrifenylfosfinpalladium i foreliggende reaksjon er meget sterkt foretrukket. Although different palladium catalysts drive Suzukl coupling reactions, the catalyst chosen is usually reaction specific. The use of tetrakistriphenylphosphine palladium in the present reaction is very strongly preferred.

Likeledes, kan forskjellige baser bli benyttet i foreliggende koblingsreaksjon. Imidlertid, er det foretrukket anvendelse av kaliummetallkarbonat, spesielt 2N natriumkarbonat. Likewise, different bases can be used in the present coupling reaction. However, it is preferred to use potassium metal carbonate, especially 2N sodium carbonate.

Temperaturen benyttet i dette trinnet skal være tilstrekkelig for å gi fullførelse av koblingsreaksjonen. Typisk, er oppvarming av reaksjonsblandingen til tilbakeløpskjøllng i en periode på omkring 2 til omkring 4 timer tilstrekkelig og foretrukket. The temperature used in this step must be sufficient to give completion of the coupling reaction. Typically, heating the reaction mixture to reflux for a period of about 2 to about 4 hours is sufficient and preferred.

I rute B i skjema IV, blir en 2-posisjon arylborsyre med formel Xb fremstilt ved anvendelse av velkjente prosedyrer. Generelt, blir en forbindelse med formel IX behandlet med et svakt overskudd av n-butyllitlum i heksan, i et passende oppløsningsmiddel og under inert atmosfære slik som nitrogen fulgt av dråpevis tilsetning av et passende trialkylborat. In route B of Scheme IV, a 2-position arylboronic acid of formula Xb is prepared using well known procedures. In general, a compound of formula IX is treated with a slight excess of n-butyllithium in hexane, in a suitable solvent and under an inert atmosphere such as nitrogen followed by dropwise addition of a suitable trialkyl borate.

Passende oppløsningsmldler omfatter et inert oppløsningsmid-del eller en blanding av oppløsningsmldler slik som f.eks. dietyleter, dioksan og tetrahydrofuran (THF). THF, spesielt vannfri THF, er foretrukket. Suitable solvents include an inert solvent or a mixture of solvents such as e.g. diethyl ether, dioxane and tetrahydrofuran (THF). THF, especially anhydrous THF, is preferred.

Det foretrukne trialkylborat anvendt i foreliggende reaksjon er triisopropylborat. The preferred trialkyl borate used in the present reaction is triisopropyl borate.

Produktet fra denne reaksjonen, en forbindelse med formel Xb, blir så reagert med et arylhalld eller aryltriflat med formel Xlb, via standard Suzuki-koblingsprosedyrer, for å gi forbindelser med formel II. De foretrukne reaksjonsbetingelsene for foreliggende reaksjon er de beskrevet for reaksjon av forbindelser med formel Xla til Xa, i skjema IV, som også gir forbindelser med formel lic. The product of this reaction, a compound of formula Xb, is then reacted with an aryl halide or aryl triflate of formula Xlb, via standard Suzuki coupling procedures, to give compounds of formula II. The preferred reaction conditions for the present reaction are those described for the reaction of compounds of formula Xla to Xa, in scheme IV, which also give compounds of formula lic.

Transformasjonen av forbindelsen med formel lic til forbindelser med formel Ia, blir utført som beskrevet ovenfor for omdannelse av forbindelser med formel Ila til forbindelser med formel Ia. The transformation of the compound of formula 11c into compounds of formula Ia is carried out as described above for the conversion of compounds of formula Ila into compounds of formula Ia.

Forbindelser med formel lic og Ild er nye og er nyttige i fremstillingen av farmasøytisk aktive forbindelser ifølge foreliggende oppfinnelse. Compounds of formulas 11c and 11d are new and are useful in the preparation of pharmaceutically active compounds according to the present invention.

Forbindelsene med formel XII og lb er også nye, er nyttige for fremgangsmåtene beskrevet her og er omfattet av formel I som her definert. The compounds of formula XII and lb are also new, are useful for the methods described herein and are encompassed by formula I as herein defined.

Forbindelser med formel I, hvor enten R<*> eller R<2> er -H og den andre R<*> eller R<2> substltuenten er -OH, blir også fremstilt fra forbindelser med formel I hvor både R<*> og R<2> er -OH. Dihydroksyforbindelsene med formel I blir omdannet til en blanding av 6- og 4'-monotriflater og triflatgruppen blir så redusert til hydrogen [se, Saa, J.M., et al., J. Org. Chem., 55:991 (1990)]. Den resulterende blandingen av monohydroksyderivater, enten som fri base eller farmasøytisk akseptablet salt, fortrinnsvis hydroklorldsaltet, kan så bil separert ved standard krystalliseringsteknikker. Compounds of formula I, where either R<*> or R<2> is -H and the other R<*> or R<2> substituent is -OH, are also prepared from compounds of formula I where both R<*> and R<2> is -OH. The dihydroxy compounds of formula I are converted to a mixture of 6- and 4'-monotriflates and the triflate group is then reduced to hydrogen [see, Saa, J.M., et al., J. Org. Chem., 55:991 (1990)]. The resulting mixture of monohydroxy derivatives, either as free base or pharmaceutically acceptable salt, preferably the hydrochloride salt, can then be separated by standard crystallization techniques.

Generelt blir en dihydroksyforbindelse med formel I behandlet med 4 til 6 ekvivalenter av en amidbase, slik som trietylamin, i et ikke-reaktivt oppløsningsmiddel fulgt av tilsetning av en ekvivalent trifluormetansulfonsyreanhydrld. En statisk blanding av mono- og ditriflater blir produsert og separert ved standard kromatografiske teknikker. Et foretrukket oppløsningsmiddel for dette trinnet er vannfri diklormetan. In general, a dihydroxy compound of formula I is treated with 4 to 6 equivalents of an amide base, such as triethylamine, in a non-reactive solvent followed by the addition of one equivalent of trifluoromethanesulfonic anhydride. A static mixture of mono- and ditriflates is produced and separated by standard chromatographic techniques. A preferred solvent for this step is anhydrous dichloromethane.

Når den blir kjørt ved en temperatur i området fra 0'C til omkring 25 "C er foreliggende reaksjon fullført i løpet av 1 til omkring 5 timer. When run at a temperature in the range of 0°C to about 25°C, the present reaction is completed within 1 to about 5 hours.

Den isolerte blandingen av minotriflaterte forbindelser så hydrogenert i et ikke-reaktivt oppløsningsmiddel i nærvær av omkring 3 til omkring 6 ekvivalenter av en aminbase, fortrinnsvis trietylamin, og en hydrogeneringskatalysator slik som palladium-på-karbon, som er foretrukket. Foretrukne oppløsningsmldler av denne reaksjonen omfatter etylacetat og etanol eller, alternativt, en blanding derav. Når dette trinnet fra foreliggende reaksjon blir kjørt under omkring 40 psi hydrogengass ved omgivelsestemperatur, er reaksjonstiden fra omkring 2 til omkring 5 timer. The isolated mixture of minotriflated compounds is then hydrogenated in a non-reactive solvent in the presence of about 3 to about 6 equivalents of an amine base, preferably triethylamine, and a hydrogenation catalyst such as palladium-on-carbon, which is preferred. Preferred solvents for this reaction include ethyl acetate and ethanol or, alternatively, a mixture thereof. When this step of the present reaction is run under about 40 psi of hydrogen gas at ambient temperature, the reaction time is from about 2 to about 5 hours.

Den resulterende blandingen av monohydroksyderivater med formel I har forskjellige oppløsllgheter i etylacetat og 6-hydroksy-4'-hydrogenderivatene kan bli delvis separert fra 6-hydrogen-4'-hydroksyderivatene ved selektiv krystallisering. Videre separering som gir ren monohydroksyforbindelse med formel I, kan bli fremstilt ved omdanning av den anrikede blandingen til hydrokloridsalter fulgt av krystallisering fra etylacetat-etanol. The resulting mixture of monohydroxy derivatives of formula I has different solubilities in ethyl acetate and the 6-hydroxy-4'-hydrogen derivatives can be partially separated from the 6-hydrogen-4'-hydroxy derivatives by selective crystallization. Further separation yielding pure monohydroxy compound of formula I can be prepared by converting the enriched mixture to hydrochloride salts followed by crystallization from ethyl acetate-ethanol.

En mer direkte fremgangsmåte for fremstilling av forbindelsene med formel I i hvilke enten R<1> eller R<2> er -H og den andre R<1> eller R<2> substituenten er -OH, såvel som alternative fremgangsmåter for fremstilling av forbindelsene med formel I, hvor enten R<1> eller R<2> er -H og den andre av R<*> eller R<2 >substituentene er - 0-{ C^- C^ alkyl) benytter en forbindelse med formelen A more direct method for the preparation of the compounds of formula I in which either R<1> or R<2> is -H and the other R<1> or R<2> substituent is -OH, as well as alternative methods for the preparation of the compounds of formula I, where either R<1> or R<2> is -H and the other of the R<*> or R<2 >substituents is - 0-{C^-C^ alkyl) uses a compound of the formula

hvor where

R<3> og n er som definert ovenfor; R<3> and n are as defined above;

Rlc er -OH eller -0-(C1-C4 alkyl); og R 1c is -OH or -O-(C 1 -C 4 alkyl); and

r2<c> er _QH eller -O-fCi-C<4> alkyl); r2<c> is _QH or -O-fCi-C<4> alkyl);

forutsatt at når R<lc> er -OH, er R2c -0-(C1-C4 alkyl), og når Rlc gr -0-(<C>1-C4 alkyl) er R<2c> -OH. provided that when R<lc> is -OH, R2c is -O-(C1-C4 alkyl), and when Rlc gr -O-(<C>1-C4 alkyl) is R<2c> -OH.

I denne fremgangsmåten, blir hydroksygruppen av en slik forbindelse omdannet til et triflatderlvat ved behandling med trifluormetansulfonsyreanhydrld. Triflatgruppen blir så redusert under standard betingelser, fortrinnsvis ved katalytisk hydrogenering. Den hydroksybeskyttende gruppen blir så fjernet ved standard prosedyrer som de beskrevet her, for å gi forbindelser med formel I, hvor enten R<1> eller R<2> er In this method, the hydroxy group of such a compound is converted to a triflate derivative by treatment with trifluoromethanesulfonic anhydride. The triflate group is then reduced under standard conditions, preferably by catalytic hydrogenation. The hydroxy protecting group is then removed by standard procedures such as those described herein to give compounds of formula I, wherein either R<1> or R<2> is

-OH og den andre R^ eller R<2> substituenten er -OH. -OH and the other R^ or R<2> substituent is -OH.

En annen alternativ foretrukket fremgangsmåte for fremstilling av forbindelser Ifølge foreliggende oppfinnelse er vist i skjema V. I foreliggende fremgangsmåte blir svovelatomet av en forbindelse med formel IV (nedenfor) oksydert for å danne et sulfoksyd (formel XIV), som så blir reagert med en nukleofil gruppe for å innføre oksygenet eller svovelatom-linkeren til forbindelser med formel I eller formel II. Sulfoksydgruppen til forbindelser med formel XVI blir så redusert for å gi visse forbindelser Ifølge foreliggende oppfinnelse. Another alternative preferred process for preparing compounds of the present invention is shown in Scheme V. In the present process, the sulfur atom of a compound of formula IV (below) is oxidized to form a sulfoxide (formula XIV), which is then reacted with a nucleophile group to introduce the oxygen or sulfur atom linker to compounds of formula I or formula II. The sulfoxide group of compounds of formula XVI is then reduced to give certain compounds according to the present invention.

hvor hver variabel har sin tidligere definert betydning. where each variable has its previously defined meaning.

I det første trinnet av denne fremgangsmåten, blir en forbindelse med formel IV selektivt oksydert til sulfoksyd. Et antall kjente fremgangsmåter er tilgjengelige for fremgangsmåtetrinnet [se f.eks. 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 Communications, 11 (12), 1025-1030 (1981); Kramer, J.B., et al., 34th National Organic Symposium, Williamsburg, VA, 11.-15. juni 1995]. Imidlertid, gir mange oksydanter kun dårlig omdanning til det ønskede produkt, såvel som signifikant oksydering av sulfonet. Foreliggende, nye prosesser, omdanner imidlertid forbindelser med formel IV til et sulfoksyd med formel XIV med høyt utbytte med liten eller ingen dannelse av sulfoner. Denne prosessen omfatter reaksjon av en forbindelse med formel IV med omkring 1 til omkring 1,5 ekvivalenter hydrogenperoksyd i en blanding av omkring 20* til omkring 50* trifluoreddiksyre i metylenklorid. Reaksjonen blir kjørt ved en temperatur fra omkring 10°C til omkring 50"C, og krever vanligvis fra omkring 1 til omkring 2 timer for fullførelse. In the first step of this process, a compound of formula IV is selectively oxidized to sulfoxide. A number of known methods are available for the method 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 Communications, 11 (12), 1025-1030 (1981); Kramer, J.B., et al., 34th National Organic Symposium, Williamsburg, VA, 11-15. June 1995]. However, many oxidants give only poor conversion to the desired product, as well as significant oxidation of the sulfone. Present novel processes, however, convert compounds of formula IV to a sulfoxide of formula XIV in high yield with little or no formation of sulfones. This process involves reacting a compound of formula IV with about 1 to about 1.5 equivalents of hydrogen peroxide in a mixture of about 20* to about 50* trifluoroacetic acid in methylene chloride. The reaction is run at a temperature of from about 10°C to about 50°C, and generally requires from about 1 to about 2 hours for completion.

Deretter blir den 3-poslsjon avspaltbare gruppen (R^) erstattet ved det ønskede nukleofile derivatet med formel XV. Slike nukleofile derivater blir fremstilt via standard fremgangsmåter. Then the 3-position cleavable group (R^) is replaced by the desired nucleophilic derivative of formula XV. Such nucleophilic derivatives are prepared via standard procedures.

I dette trinnet i fremgangsmåten blir det sure protonet av den nukleofile gruppen fjernet ved behandling av en base, fortrinnsvis et svakt overskudd av natriumhydroksyd eller kalium tertbutoksyd, i et polart aprotisk oppløsningsmiddel, fortrinnsvis DMF eller tetrahydrofuran. Andre baser som kan bli benyttet omfatter kaliumkarbonat og cesiumkarbonat. I tillegg kan andre oppløsningsmldler slik som dioksan eller dlmetylsulfoksyd bli benyttet. Avbeskyttelsen blir vanligvis kjørt ved en temperatur mellom omkring 0°C og omkring 30"C og krever vanligvis omkring 30 minutter for fullførelse. En forbindelse med formel XIV blir så tilsatt til oppløsningen av den nukleofile. Erstatningsreaksjonen blir kjørt ved en temperatur mellom 0<*>C og omkring 50°C og blir vanligvis kjørt i omkring 1 til 2 timer. Produktet blir Isolert ved standard prosedyrer. 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 hydroxide or potassium tert-butoxide, in a polar aprotic solvent, preferably DMF or tetrahydrofuran. Other bases that can be used include potassium carbonate and cesium carbonate. In addition, other solvents such as dioxane or dimethyl sulfoxide can be used. The deprotection is usually run at a temperature between about 0°C and about 30°C and usually requires about 30 minutes to complete. A compound of formula XIV is then added to the solution of the nucleophile. The replacement reaction is run at a temperature between 0<* >C and about 50°C and is usually run for about 1 to 2 hours.The product is isolated by standard procedures.

Når en benzylgruppe blir benyttet som en hydroksybeskyttende gruppe, vil hydrogenolyse av sulfoksydgruppen også vanligvis gi fjerning av den benzylbeskyttende gruppen for å eliminere behovet for selektiv fjerning av en slik gruppe ved et senere trinn av prosessen. When a benzyl group is used as a hydroxy protecting group, hydrogenolysis of the sulfoxide group will also usually provide removal of the benzyl protecting group to eliminate the need for selective removal of such a group at a later stage of the process.

I det neste trinn av foreliggende fremgangsmåte, blir nye sulfoksyder med formelene XVI a, b, c og d (kollektiv formel XVI) redusert til en benzotiofenforbindelse med formel hhv. Hg, Ic, Ile og Id. Før foreliggende reduksjonsprosess, kan forbindelsen med formel Hg og Ile først bli alkylert som beskrevet her. Reduksjon av sulfoksydforbindelsen kan bli utført ved anvendelse av en av flere metoder kjent 1 teknikken inkludert f.eks. hydrldreduksjon (Htiumaluminlum-hydrid), katalytisk hydrogenering, overføringshydrogenolyse og trlmetylsilyljodid (TMS-I). I denne reduksjonen er valget av reagens avhengig av foreneligheten av andre funksjonalite-ter i molekylet. For forbindelsene beskrevet i foreliggende oppfinnelse er lltiumalumlnlumhydrid (LIAIH4) og over-føringshydrogenolyse (palladium black/ammoniumformat) foretrukne reagenser. For LiAlH4 reduksjon, er passende oppløsningsmldler slik som f.eks. dietyleter, dloksan og tetrahydrofuran (THF). Av disse er THF, fortrinnsvis vannfri THF, foretrukket. For overføringshydrogenolyse er alkoholopp-løsningsmldler, spesielt etanol, foretrukket. Reaksjonen blir kjørt ved en temperatur fra omkring 0 til omkring 60°C og krever fra omkring 0,5 til 2 timer for fullførelse. In the next step of the present method, new sulfoxides with the formulas XVI a, b, c and d (collective formula XVI) are reduced to a benzothiophene compound of the formula or Hg, Ic, Ile and Id. Before the present reduction process, the compound of formula Hg and Ile can first be alkylated as described here. Reduction of the sulfoxide compound can be carried out using one of several methods known in the art including e.g. hydride reduction (Htiumaluminum hydride), catalytic hydrogenation, transfer hydrogenolysis and trimethylsilyl iodide (TMS-I). In this reduction, the choice of reagent depends on the compatibility of other functionalities in the molecule. For the compounds described in the present invention, lithium aluminum hydride (LIAIH 4 ) and transfer hydrogenolysis (palladium black/ammonium formate) are preferred reagents. For LiAlH4 reduction, suitable solvents such as e.g. diethyl ether, dloxane and tetrahydrofuran (THF). Of these, THF, preferably anhydrous THF, is preferred. For transfer hydrogenolysis, alcohol solvents, especially ethanol, are preferred. The reaction is run at a temperature of from about 0 to about 60°C and requires from about 0.5 to 2 hours for completion.

Når ønskelig, kan beskyttende grupper eller grupper av produktene i prosessen vist i skjema V, bli fjernet og et salt av produktet fra et hvilket som helst trinn i prosssen. Følgelig gir foreliggende oppfinnelse en fremgangsmåte for fremstilling av en forbindelse med formel When desired, protecting groups or groups of the products of the process shown in Scheme V can be removed and a salt of the product from any step of the process. Consequently, the present invention provides a method for the preparation of a compound of formula

hvor where

g<la> er _g eller -0R<7a> hvor R7a er -H eller en hydroksybeskyttende gruppe; g<la> is _g or -OR<7a> where R7a is -H or a hydroxy protecting group;

R2<a> er _Hj halo eller -0R<8>a hvor R8a er -H eller en hydroksybeskyttende gruppe; R 2<a> is _Hj halo or -OR<8>a where R 8a is -H or a hydroxy protecting group;

R<3> er 1-piperldlnyl, 1-pyrrolldlno, metyl-l-pyrrolidlnyl, dimetyl-l-pyrrolidino, 4-morfolino, dimetylamino, dletyl-amino, diispropylamino eller 1-heksametylenimino; R<3> is 1-piperldlnyl, 1-pyrroldlino, methyl-1-pyrrolidlnyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, dletylamino, diispropylamino or 1-hexamethyleneimino;

n er 2 eller 3; og n is 2 or 3; and

Z er -0- eller -S-; Z is -0- or -S-;

eller et farmasøytisk akseptabelt salt derav, omfattende or a pharmaceutically acceptable salt thereof, comprising

a) oksydering av svovelatomet av en forbindelse med formel IV a) oxidation of the sulfur atom of a compound of formula IV

hvor where

R<*a> og R<2a> er som tidligere definert; og R<*a> and R<2a> are as previously defined; and

r<9> er en avspaltbar gruppe; r<9> is a leaving group;

b) reagering av produktet fra trinn a), en forbindelse med formel XIV b) reacting the product from step a), a compound of formula XIV

med en nuklofil gruppe med formel hvor R1<2> er -OH eller -SH; c) reduksjon av produktet fra trinn b), en forbindelse med formel XVI for å gi en forbindelse med formel d) eventuelt fjerne R^a og/eller R<2a> hydroksybeskyttende grupper når tilstede i produktet fra trinn c); og e) eventuelt danne et salt av produktet fra trinn c) eller trinn d). with a nucleophilic group of formula where R 1<2> is -OH or -SH; c) reducing the product from step b), a compound of formula XVI to give a compound of formula d) optionally removing R^a and/or R<2a> hydroxy protecting groups when present in the product from step c); and e) optionally forming a salt of the product from step c) or step d).

Denne nye fremgangsmåten gir også nye forbindelser med formel XIV og XVI a, b, c og d, hver av hvilke er nyttige mellomprodukter for fremstilling av farmasøytisk aktive forbindelser ifølge foreliggende oppfinnelse. This new method also provides new compounds of formula XIV and XVI a, b, c and d, each of which are useful intermediates for the preparation of pharmaceutically active compounds according to the present invention.

Forbindelsene med formel I hvor Z er S blir også fremstilt ved anvendelse av fremgangsmåten beskrevet nedenfor i skjema VI i hvilken en forbindelse med formel IVa blir metallert. Det resulterende produktet, en forbindelse med formel XVII blir reagert med et 4-(beskyttet hydroksy)fenyldisulfid med formel XVIII, og fenolbeskyttende gruppe fra formel Ile forbindelsen blir fjernet for å gi forbindelser med formel Hf. Man skal notere at ved anvendelse av denne fremgangsmåten, kan ikke R<2> være halo på grunn av kjemiske begrensnin-ger. The compounds of formula I where Z is S are also prepared using the method described below in Scheme VI in which a compound of formula IVa is metallated. The resulting product, a compound of formula XVII is reacted with a 4-(protected hydroxy)phenyl disulfide of formula XVIII, and the phenol protecting group from the compound of formula Ile is removed to give compounds of formula Hf. It should be noted that when using this method, R<2> cannot be halo due to chemical limitations.

hvor where

g<la> er _jj eller -OR<7> og R<7> er en hydroksybeskyttende gruppe; R<2a> er -H eller -OR<8> og R<8> er en hydroksybeskyttende gruppe; R<**> er en hydroksybeskyttende gruppe som kan bli selektivt fjernet; g<la> is _jj or -OR<7> and R<7> is a hydroxy protecting group; R<2a> is -H or -OR<8> and R<8> is a hydroxy protecting group; R<**> is a hydroxy protecting group which can be selectively removed;

r<9> er en avspaltbar gruppe; og r<9> is a leaving group; and

M er et metallion. M is a metal ion.

I de første to trinnene i skjema VI, blir en forbindelse med formel IVa metallert via velkjente prosedyrer. Mest vanlig, og foretrukket, blir en forbindelse med formel IVa behandlet med et svakt overskudd av n-butyllitium i heksan i et passende oppløsningsmiddel, fulgt av dråpevis tilsetning av en oppløsning av en dlsulfidforbindelse med formel XVIII i et passende oppløsningsmiddel. In the first two steps of Scheme VI, a compound of formula IVa is metallated via well-known procedures. Most commonly, and preferably, a compound of formula IVa is treated with a slight excess of n-butyllithium in hexane in a suitable solvent, followed by the dropwise addition of a solution of a dlsulfide compound of formula XVIII in a suitable solvent.

Begge disse reaksjonstrinnene ble kjørt under en Inert atmosfære slik som nitrogen, mens passende oppløsningsmldler for begge trinnene omfatter en eller flere inerte oppløs-ningsmldler slik som dietyleter, dloksan og THF. Av disse er THF foretrukket, spesielt den vannfrie formen derav. I tillegg, blir reaksjonstrinnene kjørt under en temperatur fra omkring -78*C til omkring 85'C. Both of these reaction steps were run under an inert atmosphere such as nitrogen, while suitable solvents for both steps include one or more inert solvents such as diethyl ether, dloxane and THF. Of these, THF is preferred, especially the anhydrous form thereof. In addition, the reaction steps are run under a temperature of from about -78°C to about 85°C.

I det første reaksjonstrinnet i foreliggende reaksjon blir en metallert forbindelse med formel XVII fremskaffet. Den 4-(beskyttede hydroksy)fenylsulfidet (en forbindelse med formel XVIII) som blir reagert med en slik forbindelse med formel XVII for å gi en forbindelse med formel Ile, blir fremstilt ved beskytting av hydroksygruppen av en kommersielt tilgjengelig 4-hydroksyfenylsulfid med en passende beskyttel-sesgruppe via velkjente prosedyrer. En foretrukket R<& >beskyttende gruppe er metoksymetyl, forutsatt at R<7> og R<8>, hvis en eller begge er tilstede, er en hydroksybeskyttende gruppe forskjellig fra metoksymetyl. Det er påkrevet at R^ hydroksybeskyttende gruppe er en gruppe forskjellig fra de dannet ved R<7> og R<8> beskyttende grupper, når tilstede, slik at R<**> gruppen selektivt kan bli fjernet via standard prosedyrer for å gi forbindelsen med formel Hf. In the first reaction step in the present reaction, a metallated compound of formula XVII is obtained. The 4-(protected hydroxy)phenylsulfide (a compound of formula XVIII) which is reacted with such a compound of formula XVII to give a compound of formula Ile is prepared by protecting the hydroxy group of a commercially available 4-hydroxyphenylsulfide with an appropriate protection group via well-known procedures. A preferred R<&> protecting group is methoxymethyl, provided that R<7> and R<8>, if one or both are present, is a hydroxy protecting group other than methoxymethyl. It is required that the R^ hydroxy protecting group be a group different from those formed by R<7> and R<8> protecting groups, when present, so that the R<**> group can be selectively removed via standard procedures to give the compound with formula Hf.

For å gi avbeskyttelse ved fjerning av den R<*>> beskyttende gruppen, blir en forbindelse med formel He reagert i et protisk oppløsningsmiddel eller blanding av oppløsningsmldler i et surt medium inneholdende minst en ekvivalent syre, fortrinnsvis metansulfonsyre, og oppvarming fra omkring 25 til omkring 110<*>C. Typisk, er reaksjonstiden fra omkring 6 til omkring 24 timer, men forløpet av 'reaksjonen kan bli overvåket via standard kromatografiske teknikker. To provide deprotection by removal of the R<*>> protecting group, a compound of formula He is reacted in a protic solvent or mixture of solvents in an acidic medium containing at least one equivalent of acid, preferably methanesulfonic acid, and heating from about 25 to around 110<*>C. Typically, the reaction time is from about 6 to about 24 hours, but the progress of the reaction can be monitored via standard chromatographic techniques.

Passende oppløsningsmldler for foreliggende reaksjon omfatter f.eks. vann og metanol. Suitable solvents for the present reaction include e.g. water and methanol.

Forbindelser med formel Ile og Hf er nye og er nyttige for fremstilling av farmasøytisk aktive forbindelser med formel I og er her omfattet innen rammen av formel II ovenfor. Compounds of formula Ile and Hf are new and are useful for the preparation of pharmaceutically active compounds of formula I and are here encompassed within the framework of formula II above.

Forbindelser med formel Id Compounds of formula Id

hvor where

Rlb er -H eller -OH; R 1b is -H or -OH;

R<2b> er -H eller -OH; og R<2b> is -H or -OH; and

R<3> og n, er som definert ovenfor, blir fremstilt ved anvendelse av de ovenfor beskrevne prosedyrene relatert til prosesstrinnet vist i skjemaene II og IV. Slike forbindelser med formel Id er også nye, er nyttige i fremgangsmåten ifølge foreliggende oppfinnelse og er her omfattet innen den ovenfor angitte beskrivelsen av formel I. R<3> and n, are as defined above, are prepared using the above described procedures related to the process step shown in Schemes II and IV. Such compounds of formula Id are also new, are useful in the method according to the present invention and are here included within the above description of formula I.

Forbindelser med formel I hvor R<1> og R<2> er forskjellige hydroksybeskyttende grupper eller enten R^ eller R<2> er en hydroksybeskyttende gruppe og den andre hydroksy blir selektivt fremstilt ved anvendelse av et modifisert 2-arylbenzotiofenstartmateriale med formel III ovenfor, forutsatt at hydroksybeskyttende grupper betegnet R<7> og R<8> er tilstrekkelig forskjellige slik at en beskyttende gruppe blir fjernet mens den andre forblir. Slike 2-arylbenzotiofener blir fremstilt via prosedyrer som er velkjente i teknikken. Compounds of formula I wherein R<1> and R<2> are different hydroxy protecting groups or either R^ or R<2> is a hydroxy protecting group and the other hydroxy is selectively prepared using a modified 2-arylbenzothiophene starting material of formula III above , provided that the hydroxy protecting groups designated R<7> and R<8> are sufficiently different such that one protecting group is removed while the other remains. Such 2-arylbenzothiophenes are prepared via procedures well known in the art.

Spesielt nyttige for fremstillingen av forbindelsen med formel I hvor R<1> og R<2> er forskjellig beskyttende grupper, er Suzuki-kobling som beskrevet ovenfor i skjema IV. Imidlertid, blir 6-(beskyttet hydroksy)benzotiofen-2-borsyre, reagert med en forbindelse med formel Xlb ovenfor hvor R<2a> er -OR<8> og R<7 >ikke er lik R<8>. Denne reaksjonen tillater fremstilling av forbindelser ifølge foreliggende oppfinnelse hvor R<7> og R<8> er forskjellige hydroksybeskyttende grupper slik at en beskyttende gruppe selektivt kan bli fjernet og den andre forblir som en gruppe I det endelige produktet. Fortrinnsvis, blir den R<7> beskyttende gruppe, spesielt benzyl eller isopropyl, fjernet for å danne en hydroksygruppe mens den R<8> beskyttende gruppen, spesielt metyl, forblir. Particularly useful for the preparation of the compound of formula I where R<1> and R<2> are different protecting groups is Suzuki coupling as described above in Scheme IV. However, 6-(protected hydroxy)benzothiophene-2-boronic acid is reacted with a compound of formula Xlb above wherein R<2a> is -OR<8> and R<7> is not equal to R<8>. This reaction allows the preparation of compounds according to the present invention where R<7> and R<8> are different hydroxy protecting groups so that one protecting group can be selectively removed and the other remains as a group in the final product. Preferably, the R<7> protecting group, especially benzyl or isopropyl, is removed to form a hydroxy group while the R<8> protecting group, especially methyl, remains.

Suzuki-kobling blir også utført ved anvendelse av den ovenfor beskrevne prosedyren, ved å erstatte en forbindelse med formel Xlb med en forbindelse med formel XIX Suzuki coupling is also carried out using the procedure described above, by replacing a compound of formula Xlb with a compound of formula XIX

hvor where

R<8a> er C^- Cf) al kyl sul f onat, fortrinnsvis metansulf onat eller C4-C5 arylsulfonat; og R<8a> is C 1 - C 5 ) alkyl sulfonate, preferably methane sulfonate or C 4 -C 5 aryl sulfonate; and

r<!>° er en avspaltbar gruppe, fortrinnsvis brom eller triflat. r<!>° is a leaving group, preferably bromine or triflate.

I denne fremgangsmåten blir en 6-(beskyttet hydroksy)benzo-tioffen-2-borsyre som beskrevet ovenfor, reagert med en forbindelse med formel XIX for å gi en forbindelse med formel XX, som blir reagert med bortribromid i metylenklorld for å gi en monohydroksyforbindelse som deretter eksempelvis blir omdannet til en benzylgruppe, f.eks. en benzylgruppe, ved standardprosedyrer (formel XXI). 4'-sulfonatesteren blir så selektivt fjernet ved basisk hydrolyse, eller, fortrinnsvis, ved behandling med LiAlB^, i et passende aprotisk oppløs-ningsmiddel slik som f. eks. THF. Denne reaksjonen gir en forbindelse med formel XXII som endelig eksempelvis blir metylert ved 4'-posisjonen ved standardprosedyrer (formel Illa). Naturligvis vil fagmannen se at forskjellige prosesser kan bli benyttet for å gi forbindelser med formel Illa, hvor de hydroksybeskyttende gruppen er andre enn de vist i skjema VII nedenfor, og hvor disse kan bli selektivt fjernet for å gi monohydroksyforbindelser med formel I ifølge foreliggende oppf innelse. In this method, a 6-(protected hydroxy)benzo-thiophene-2-boronic acid as described above is reacted with a compound of formula XIX to give a compound of formula XX, which is reacted with boron tribromide in methylene chloride to give a monohydroxy compound which is then, for example, converted into a benzyl group, e.g. a benzyl group, by standard procedures (formula XXI). The 4'-sulfonate ester is then selectively removed by basic hydrolysis, or, preferably, by treatment with LiAlB 2 , in a suitable aprotic solvent such as e.g. THF. This reaction gives a compound of formula XXII which is finally, for example, methylated at the 4'-position by standard procedures (formula IIIa). Naturally, the person skilled in the art will see that different processes can be used to give compounds of formula IIIa, where the hydroxy protecting groups are other than those shown in scheme VII below, and where these can be selectively removed to give monohydroxy compounds of formula I according to the present invention .

Forbindelser med formel Illa ble så utsatt for forskjellige prosesser beskrevet her for å gl forbindelser med formel I og II ifølge foreliggende oppfinnelse. Compounds of formula IIIa were then subjected to various processes described herein to produce compounds of formula I and II according to the present invention.

Andre foretrukne forbindelser med formel I blir fremstilt ved å erstatte 6- og/eller 4'-posisjon hydroksygrupper, når tilstede, med en gruppe med formel -0-C0-(C^^-C^ alkyl), eller -O-SOg-fCg-Cfc alkyl) via velkjente prosedyrer, se f.eks. U.S. patent nr. 4,358,593. Other preferred compounds of formula I are prepared by replacing 6- and/or 4'-position hydroxy groups, when present, with a group of formula -O-C0-(C^^-C^ alkyl), or -O-SOg -fCg-Cfc alkyl) via well-known procedures, see e.g. U.S. Patent No. 4,358,593.

For eksempel, når en -O-CO-lC^-Cfc alkyl) gruppe er ønsket, blir en mono- eller dihydroksyforbindelse med formel I reagert med et middel slik som acylklorid, bromid, cyanid eller azid, eller med et passende anhydrid eller blandet anhydrid. Reaksjonen blir hensiktsmessig utført I et basisk oppløsningsmiddel slik som pyridin, lutidin, quinolln eller isoquinolin, eller i et tertiært aminoppløsningsmiddel slik som trietylamin, trlbutylamin, metylpiperidin og lignende. Reaksjonen kan også bli utført i et inert oppløsningsmiddel slik som etylacetat, dimetylformamid, dimetylsulfoksyd, dioksan, dimetoksyetan, acetonltril, aceton, metyletylketon og lignende, til hvilket det er tilsatt minst en ekvivalent av en syrefanger (bortsett fra som angitt nedenfor), slik som et tertiært amin. Hvis ønskelig, kan acyleringskatalysatorer slik som 4-dimetylaminopyridin eller 4-pyrrolidinopyrldin bli benyttet. Se f.eks. Haslam, et al., Tetrahedron, 36:2409-2433 For example, when an -O-CO-1C^-Cf 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 anhydride. The reaction is conveniently carried out in a basic solvent such as pyridine, lutidine, quinol or isoquinoline, or in a tertiary amine solvent such as triethylamine, tertbutylamine, methylpiperidine and the like. The reaction may also be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethyl sulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone and the like, to which is added at least one equivalent of an acid scavenger (except as indicated below), such as a tertiary amine. If desired, acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyrridine can be used. See e.g. Haslam, et al., Tetrahedron, 36:2409-2433

(1980). (1980).

Foreliggende reaksjon blir utført ved moderat temperatur i et område fra omkring -25 til omkring 100°C, ofte under Inert atmosfære slik som nitrogengass. Imidlertid, er omgivelsestemperatur vanligvis tilstrekkelig for at reaksjonen skal løpe. The present reaction is carried out at a moderate temperature in a range from about -25 to about 100°C, often under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually sufficient for the reaction to proceed.

Acylering av 6-posisjon og/eller 4'-posisjon hydroksygruppe kan også bli utført med syrekatalyserte reaksjoner av de passende karboksylsyrene i Inerte organiske oppløsningsmld-ler. Syrekatalysatorer slik som svovelsyre, polyfosforsyre, metansulfonsyre og lignende blir benyttet. Acylation of the 6-position and/or 4'-position hydroxy group can also be carried out with acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid and the like are used.

De ovenfor nevnte R<*> og/eller R<2> gruppene i forbindelsen med formel I kan også bli fremskaffet ved å danne en aktiv ester av den passende syren, slik som esteren dannet ved slike kjente reagenser slik som dicykloheksylkarbodiimid, acylimi-dazoler, nitrofenoler, pentaklorfenol, N-hydroksysuksinimid, og 1-hydroksybenzotriazol. Se f.eks. Bull, Chem. Soc. Japan, 38:1979 (1965) og Chem. Ber. 788 og 2024 (1970). The above-mentioned R<*> and/or R<2> groups in the compound of formula I can also be obtained by forming an active ester of the appropriate acid, such as the ester formed by such known reagents as dicyclohexylcarbodiimide, acylimi-dazoles , nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole. See e.g. Bull, Chem. Soc. Japan, 38:1979 (1965) and Chem. Pray. 788 and 2024 (1970).

Hver av de ovenfor nevnte teknikkene som gir -O-CO-fCj-Cf, alkyl)grupper blir reagert ut i oppløsningsmldler som diskutert ovenfor. Disse teknikkene produserer ikke et syreprodukt i løpet av deres reaksjon, noe som naturligvis krever anvendelse av en syrefanger i reaksjonsblandingen. Each of the above mentioned techniques yielding -O-CO-(Cj-Cf, alkyl) groups are reacted in solvents as discussed above. These techniques do not produce an acid product during their reaction, which naturally requires the use of an acid scavenger in the reaction mixture.

Når en forbindelse med formel I er ønsket hvor 6- og/eller 4'-posisjon hydroksygruppen av en forbindelse med formel I blir omdannet til en gruppe med formelen -0-S02-(C2-C^ alkyl), blir mono- eller dihydroksyforbindelsen reagert med f.eks. et sulfonsyreanhydrld eller et derivat av den passende sulfonsyren slik som sulfonylklorid, bromid eller sulfonyl-alumlniumsaltet som lært av King og Monoir, J. Am. Chem. Soc. 97:2566-2567 (1975). Dihydroksyforbindelsen kan også bli reagert med det passende sulfonsyreanhydridet eller de blandede sulfonsyreanhydridene. Slike reaksjoner blir utført under betingelser slik som forklart ovenfor i diskusjonen av reaksjonen med syrehalider og lignende. When a compound of formula I is desired where the 6- and/or 4'-position hydroxy group of a compound of formula I is converted to a group of the formula -O-SO 2 -(C 2 -C 4 alkyl), the mono- or dihydroxy compound becomes reacted with e.g. a sulfonic anhydride or a derivative of the appropriate sulfonic acid such as sulfonyl chloride, bromide, or the sulfonyl aluminum salt as taught by King and Monoir, J. Am. Chem. Soc. 97:2566-2567 (1975). The dihydroxy compound may also be reacted with the appropriate sulfonic anhydride or mixed sulfonic anhydrides. Such reactions are carried out under conditions as explained above in the discussion of the reaction with acid halides and the like.

Selv om fri-baseform av forbindelsene med formel I kan bli benyttet i metoden ifølge foreliggende oppfinnelse, er det foretrukket å fremstille og anvende en farmasøytisk akseptabel saltform. Således danner forbindelsene benyttet i fremgangsmåten ifølge oppfinnelsen primært farmasøytisk akseptable syreaddisjonssalter med et stort antall organiske syrer og uorganiske syrer og omfatter fysiologisk akseptable salter som ofte blir benyttet i farmasøytisk kjemi. Silke salter er også del av oppfinnelsen. Typiske uorganiske syrer benyttet for å danne slike salter er saltsyre, hydrogenbro-mld, hydrogenjodid, salpetersyre, svovelsyre, fosforsyre, hypofosforsyre og lignende. Salter avledet fra organiske syrer slik som alifatiske mono- og dikarboksylsyrer, fenylsubstltuerte alkansyrer, hydroksyalkan- og hydroksy-alkandisyrer, aromatiske syrer, alifatiske og aromatiske sulfonsyrer, kan også bli benyttet. Slike farmasøytisk akseptable salter omfatter således acetat, fenylacetat, trifluoracetat, akrylat, askorbat, benzoat, klorbenzoat, dinitrobenzoat, hydroksybenzoat, metoksybenzoat, metylben-zoat, o-acetoksybenzoat, naftalen-2-benzoat, bromid, isobutyrat, fenylbutyrat, b-hydroksybutyrat, butyn-1,4-dioat, heksyn-1,4-dioat, kaprat, kaprylat, klorid, cinnamat, citrat, format, fumarat, glykollat, heptanoat, hippurat, laktat, malat, maleat, hydroksymaleat, malonat, mandelat, mesylat, nikotinat, isonlkotinat, nitrat, oksalat, ftalat, tereftalat, fosfat, monohydrogenfosfat, dihydrogenfosfat, metafosfat, pyrofosfat, proplolat, propionat, fenylpropionat, salicylat, sebacat, suksinat, suberat, sulfat, bisulfat, pyrosulfat, sulfit, bisulfit, sulfonat, benzensulfonat, p-bromfenylsul-fonat, klorbenzensulfonat, etansulfonat, 2-hydroksyetansul-fonat, metansulfonat, naftalen-l-sulfonat, naftalen-2-sulfonat, p-toluensulfonat, xylensulfonat, tartrat, og lignende. Foretrukne salter er hydroklorid og oksalatsalter. Although the free-base form of the compounds of formula I can be used in the method according to the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form. Thus, the compounds used in the method according to the invention primarily form pharmaceutically acceptable acid addition salts with a large number of organic acids and inorganic acids and include physiologically acceptable salts which are often used in pharmaceutical chemistry. Silk salts are also part of the invention. Typical inorganic acids used to form such salts are hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, sulfuric acid, phosphoric acid, hypophosphoric acid and the like. Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkane and hydroxyalkane acids, aromatic acids, aliphatic and aromatic sulphonic acids, can also be used. Thus, such pharmaceutically acceptable salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonlcotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, proprolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartrate, and the like. Preferred salts are hydrochloride and oxalate salts.

De farmasøytisk akseptable syreaddisjonssaltene ble typisk dannet ved å reagere en forbindelse med formel I med like molar eller overskudds mengde syre. Reaktantene ble generelt blandet i et gjensidig oppløsningsmiddel slik som dietyleter eller etylacetat. Saltene utfelles normalt av oppløsningen i løpet av 1 time til 10 dager og kan bli isolert ved filtrering eller oppløsningsmidlet kan bli strippet av ved kon-vensjonelle midler. The pharmaceutically acceptable acid addition salts were typically formed by reacting a compound of Formula I with an equal molar or excess amount of acid. The reactants were generally mixed in a mutual solvent such as diethyl ether or ethyl acetate. The salts normally precipitate from the solution within 1 hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.

De farmasøytisk akseptable saltene har generelt øket oppløselighetskarakteristikker sammenlignet med forbindelsen fra hvilke de er avledet, og er således ofte mer anvendbare for formulering som væsker eller emulsjoner. The pharmaceutically acceptable salts generally have increased solubility characteristics compared to the compound from which they are derived, and are thus often more useful for formulation as liquids or emulsions.

Representative foretrukne forbindelser med den foreliggende oppfinnelse omfatter de følgende: Gruppe I: [6-metoksy-2-( 4-metoksyfenyl)-3-brom]benzo[b]tiofen-(S-oksyd); Representative preferred compounds of the present invention include the following: Group I: [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide);

[6-isopropoksy-2-(4-metoksyfenyl )-3-brom]benzo[b]tiofen-(S-oksyd); [6-isopropoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide);

[6-metoksy-2-{ 4-isopropoksyfenyl )-3-brom]benzo[b]tiofen-(S-oksyd); [6-Methoxy-2-{4-isopropoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide);

[2-(4-metoksyfenyl)-3-brom]benzo[b]tiofen-(S-oksyd); [2-(4-Methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide);

[6-metoksy-3-[4-[2-(1-piperidlnyl)etoksy]fenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen-(S-oksyd); [6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide);

[3-[4~[2-( 1-piperidinyl )etoksy]fenoksy]-2-(4-metoksyfenyl)]-benzo[b]tiofen-(S-oksyd); [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]-benzo[b]thiophene-(S-oxide);

[6-benzyloksy-2-(4-metoksyfenyl )-3-brom]benzo[b3tiofen-(S-oksyd); [6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b3thiophene-(S-oxide);

[6-isopropoksy-2-(4-metoksyfenyl )-3-brom]benzo[b]tIofen~(S-oksyd); [6-isopropoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (S-oxide);

[6-metoksy-2-( 4-benzyloksyf enyl )-3-brom]benzo[b]tiofen-(S-oksyd); [6-Methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide);

[6-metoksy-2-( 4-isopropoksyfenyl )-3-brom]benzo[b]tiofen-(S-oksyd); [6-Methoxy-2-(4-isopropoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide);

[6-benzyloksy-3-[4 -[2-( 1-piperidinyl )etoksy]fenoksy]-2-(4-metoksyfenyl }]benzo[b]tiofen-(S-oksyd); [6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl}]benzo[b]thiophene-(S-oxide);

[6-isopropoksy-3-[4-[2-( l-plperidlnyl )etoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen-(S-oksyd); [6-Isopropoxy-3-[4-[2-(1-plperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide);

[6-metoksy-3-[4-[2-(1-plperidinyl)etoksy]fenoksy])-2-(4-benzyloksyfenyl)]benzo[b]tiofen-(S-oksyd); [6-methoxy-3-[4-[2-(1-plperidinyl)ethoxy]phenoxy])-2-(4-benzyloxyphenyl)]benzo[b]thiophene-(S-oxide);

[6-metoksy-3-[4-[2-(l-piperidinyl)etoksy]fenoksy]-2-(4-isopropoksyfenyl)]benzo[b]tiofen-(S-oksyd); [6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene-(S-oxide);

[6-metoksy-2-{4-metoksyfenyl)-3-(4-metoksynretylenoksy )-tiofenoksy]benzo[b]tlofen-(S-oksyd); [6-Methoxy-2-{4-methoxyphenyl)-3-(4-methoxyrethyleneoxy)-thiophenoxy]benzo[b]tlophen (S-oxide);

[6-metoksy-2-(4-metoksyfenyl]-3-(4-hydroksy)tiofenoksy]benzo-[b]tlofen. [6-Methoxy-2-(4-methoxyphenyl]-3-(4-hydroxy)thiophenoxy]benzo-[b]tlophene.

Gruppe II: [3-[4-[2-(l-piperldlnylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]-benzo[b]tiofen; Group II: [3-[4-[2-(1-piperidinylethyloxy]phenoxy]-2-(4-hydroxyphenyl)]-benzo[b]thiophene;

3-[4-[2-( 1-piperidlnyl)etoksy]fenoksy]-2-(4-hydroksyfenyl)]-benzo[b]tiofen hydroklorid; 3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]-benzo[b]thiophene hydrochloride;

[3-[4-[2-(l-pyrolidinyl)etoksy]fenoksy]-2-(4-hydroksyfenyl)]-benzo[b]tiofen; [3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]-benzo[b]thiophene;

[3-[4-[2-( 1-heksametylenimino)etoksy]fenoksy]-2-(4-hydroksy-fenyl)]benzo[b]tiofen; [3-[4-[2-( 1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-hydroxy-phenyl)]benzo[b]thiophene;

[3-[4-[2-( l-N.N-dietylamlno Jetoksy] f enoksy]-2-(4-hydroksy-fenyl)]benzo[b]tiofen; [3-[4-[2-(1-N,N-diethylamino-jetoxy]phenoxy]-2-(4-hydroxy-phenyl)]benzo[b]thiophene;

3-[4-[2-[l-piperidinyl )etoksy] f enoksy]-2-(4-metoksyfenyl )]-benzo[b]tiofen hydroklorid; 3-[4-[2-[1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]-benzo[b]thiophene hydrochloride;

[3-[4-[2-( 1-piperidinyl )etoksy] f enoksy]-2-(fenyl )]benzo[b]-tiofen hydroklorid; [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(phenyl)]benzo[b]-thiophene hydrochloride;

[ 3-[4-[2-{1-piperidinyl )etoksy] f enoksy]-2-( 4-f luorf enyl )]-benzo[b]tiofen; [3-[4-[2-{1-piperidinyl)ethoxy]phenoxy]-2-(4-fluorophenyl)]-benzo[b]thiophene;

[6-metoksy-2-(4-metoksyf enyl)-3-(4-benzyloksy)fenoksy]-benzo[b]tiofen; [6-Methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene;

[6-raetoksy-2- ( 4-metoksyfenyl)-3-(4-benzyloksy )fenoksy] - benzo[b]tiofen; [6-ethoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene;

[6-Isopropoksy-2-(4-metoksyfenyl )-3-(4-benzyloksy )fenoksy]-benzo[b]tiofen; [6-Isopropoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene;

[6-metoksy-2-( 4-i sopropoksyfenyl )-3-(4-benzyloksy )fenoksy] - benzo[b]tiofen; [6-Methoxy-2-(4-isopropoxyphenyl)-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene;

[6-metoksy-2-[4-[2-( 1-plperidinyl )etoksy]fenoksy]2-(4-metoksyfenyl)]benzo[b]tiofen; [6-Methoxy-2-[4-[2-(1-plperidinyl)ethoxy]phenoxy]2-(4-methoxyphenyl)]benzo[b]thiophene;

[ 6-metoksy-3-[4-[2-{1-piperidinyl)etoksy]-fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [ 6-Methoxy-3-[4-[2-{1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3 - [4-[2-(1-pyrolodiny1)etoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-heksametylenimino)etoksy]fenoksy]-2-(4-metoksyfenyl )]berizo[b]tiofen hydroklorid; [6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-methoxyphenyl )]berizo[b]thiophene hydrochloride;

[6-metoksy-3-[4-[2-( 1-N ,N-dietylamlno)etoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4 - [2-(morfolino Jetoksy] f enoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(morpholino Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4-[3-(piperIdino Jpropoksy] f enoksy] - 2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[3-(piperIdino Jpropoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4-[3-(l-N,N-dietylamino)propoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[3-(1-N,N-diethylamino)propoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4 - hydroksyfenyl)]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[ 6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen oksalat; [ 6-hydroxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene oxalate;

[6-hydroksy-3-[4-[2-(1-piperidinyl)etoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-pyrrolidinyl Jetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-pyrrolidinyl Jetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3- [4- [2-( 1-heksametylenimino )etoksy] fenoksy] -2-(4-hydroksyfenyl)]benzo[b]tiofen; [6-hydroxy-3- [4- [2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-hy dr oksy-3-[4-[2-(1-N,N-dietylaminoJetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-N,N-diethylaminoJethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(morfolino)etoksy]fenoksy]-2-(4-hydroksy-fenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(morpholino)ethoxy]phenoxy]-2-(4-hydroxy-phenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3- [4 - [3 - (1 -N ,N-dietylamino )propoksy]fenoksy] -2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-Hydroxy-3-[4-[3-(1-N,N-diethylamino)propoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-N,N-diisopropylamino Jetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-N,N-diisopropylamino Jetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[ 6-hydroksy - 3 - [4-[3-(piperidino)propoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [ 6-hydroxy - 3 - [4-[3-(piperidino)propoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3- [4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-benzyl oksy-3-[4 - [2 - (1-piperidinyl Jetoksy] f enoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen; [6-benzyloxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-benzyl ok sy-3- [4- [2-( 1-pyrrol idinyl Jetoksy] fenoksy] -2-(4-metoksyfenyl )]benzo[b]tiofen; [6-benzyl ok sy-3- [4- [2-( 1-pyrroleidinyl Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-benzyl ok sy-3- [4 - [2- (1-heksametyllmlno )etoksy] fenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen; [6-benzyl ok sy-3-[4-[2-(1-hexamethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-benzyloksy-3-[4-[2-(l-N,N-dlmetylamino Jetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-Benzyloxy-3-[4-[2-(1-N,N-dlmethylamino Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-benzyloksy-3-[4-[2-(1-morfol ino Jetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-Benzyloxy-3-[4-[2-(1-morpholino Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-isopropoksyoksy-3-[4-[2-{1-piperidinylJetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-isopropoxyoxy-3-[4-[2-{1-piperidinyljetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-isopropoksy-3-[4-[2-(1-pyrrolidinylJetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-isopropoxy-3-[4-[2-(1-pyrrolidinylJethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-i sopropoksy-3-[4-[2-(1-heksametylimInoJetoksy]fenoksy]-2-(4-metoksyfenylJ]benzo[b]tiofen; [6-isopropoxy-3-[4-[2-(1-hexamethyliminoethoxy]phenoxy]-2-(4-methoxyphenyl)benzo[b]thiophene;

[6-isopropoksy-3-[4-[2-(l-N,N-dimetylamino Jetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-isopropoxy-3-[4-[2-(1-N,N-dimethylamino Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-isopropoksy-3-[4-[2-(1-morfolino Jetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-isopropoxy-3-[4-[2-(1-morpholino Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[ 6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [ 6-hydroxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(1-pyrrolidinylJetoksy]fenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-pyrrolidinylJethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(1-heksametylIminoJetoksy]fenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen; [6-Hydroxy-3-[4-[2-(1-HexamethylIminoJethoxy]phenoxy]-2-(4-Methoxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-{l-N,N-dimetylamlno Jetoksy]fenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen; [6-Hydroxy-3-[4-[2-{1-N,N-dimethylamino]ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3- [4-[2-(l-morfolIno Jetoksy] f enoksy] -2-(4-metoksyfenyl)]benzo[h]tiofen; [6-Hydroxy-3-[4-[2-(1-morpholinojetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[h]thiophene;

[ 6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [ 6-hydroxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-pyrrolidinylJetoksy]fenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-pyrrolidinylJethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-( 1-heksametylimino Jetoksy]fenoksy]-2-(4-metoksyfenylJ]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-( 1-hexamethylimino Jetoxy]phenoxy]-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-N,N-dimetylamlnoJetoksy]fenoksy]-2-{4-metoksyfenylJ]benzo[b]tiofen hydroklorid; [6-Hydroxy-3-[4-[2-(1-N,N-dimethylamlnoJethoxy]phenoxy]-2-{4-methoxyphenylJ]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(l-morfolino Jetoksy] f enoksy] - 2- (4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-morpholino Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metok sy-3- [4-[2 -(1-piperidlnylJetoksy]fenoksy]-2-(4-benzyloksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-piperidinylethyloxy]phenoxy]-2-(4-benzyloxyphenyl)benzo[b]thiophene;

[ 6-metoksy-3-[4-[2-(1-pyrrolIdinylJetoksy]fenoksy]-2-(4-benzyloksyfenyl)]benzo[b]tiofen; [ 6-Methoxy-3-[4-[2-(1-pyrrolidineylethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(l-heksametylenimino Jetoksy]fenoksy]-2-(4-benzyloksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(l-N,N-dimetylamino Jetoksy]fenoksy]-2-(4-benzyloksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-N,N-dimethylamino Jetoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-morfolino Jetoksy]fenoksy]-2-(4-benzyloksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-morpholino Jetoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-{4-isopropoksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-{4-isopropoxyphenyl)]benzo[b]thiophene;

[ 6-metoksy-3-[4-[2-(1-pyrrolidinyl)etoksy]fenoksy]-2-(4-i sopropoksyf enyl)]benzo[b]t i ofen; [ 6-Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]t i ofen;

[6-metoksy-3-[4-[2-(1-heksametylenimino Jetoksy]fenoksy]-2-(4-i sopropoksyf enyl)]benzo[b]ti ofen; [6-Methoxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-N,N-dimetylaminoJetoksy]fenoksy]-2-(4-1sopropoksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-N,N-DimethylaminoJethoxy]phenoxy]-2-(4-1isopropoxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(l-morfol inoJetoksy]f enoksy]-2-( 4-isopropoksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-morpholineethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene;

[6-metok sy-3- [4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen; [6-methoxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[ 6-metoksy-3-[4-[2-{1-pyrrolidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen; [ 6-Methoxy-3-[4-[2-{1-pyrrolidinylJethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-heksametylenimino Jetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(l-NfN-dimetylaminoJetoksy]fenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-NfN-dimethylaminoJethoxy]phenoxy]-2-(4-hydroxyphenylJ)benzo[b]thiophene;

[6-metoksy-3-[4-[2-(l-morfoIino)etoksy]f enoksy]-2-( 4-hydroksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-morphoylino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(l-piperidinyl)etoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[ 6-metoksy-3-[4-[2-{1-pyrrolidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl )]benzo[b]tiofen hydroklorid; [ 6-Methoxy-3-[4-[2-{1-pyrrolidinylJetoxy]phenoxy]-2-(4-hydroxyphenyl )]benzo[b]thiophene hydrochloride;

[ 6-me tok sy-3 - [4 - [2 - ( i-hek same ty len I mino Jetoksy] fenoksy] -2-(4-hydroksyfenyl )]benzo[b]tiofen hydroklorid; [ 6-me toc sy-3 - [4 - [2 - ( i-hexa ty len I mino Jetoxy] phenoxy] -2-(4-hydroxyphenyl )] benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4-[2-(l-N,N-dimetylamino)etoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4 -[2-(1-morfolinoJetoksy]fenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-morpholinoJethoxy]phenoxy]-2-(4-hydroxyphenylJ)benzo[b]thiophene hydrochloride;

[6-benzoyloksy-3 - [4 - [2 - (1-piperidinyl Jetoksy]fenoksy] -2-(4-benzoyloksyfenyl)]benzo[b]tiofen hydroklorid; [6-benzoyloxy-3-[4-[2-(1-piperidinyl Jetoxy]phenoxy]-2-(4-benzoyloxyphenyl)]benzo[b]thiophene hydrochloride;

[6-etylsulfonyloksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-etylsulfonyloksyfenyl)]benzo[b]tiofen hydroklorid; [6-ethylsulfonyloxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-ethylsulfonyloxyphenyl)]benzo[b]thiophene hydrochloride;

[ 6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-etylsulfonyloksyfenyl)]benzo[b]tiofen hydroklorid; [ 6-hydroxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-ethylsulfonyloxyphenyl)]benzo[b]thiophene hydrochloride;

[6-etylsulfonyloksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-ethylsulfonyloxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-trifluormetansulfonyloksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-piperidinylJethoxy]phenoxy]-2-(4-trifluoromethanesulfonyloxyphenyl)benzo[b]thiophene;

3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-benzoyloksy-fenyl)]benzo[b]tiofen hydroklorid; 3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-benzoyloxyphenyl)]benzo[b]thiophene hydrochloride;

3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-pivaloyloksy-fenylJ]benzo[b]tiofen hydroklorid; 3-[4-[2-(1-piperidinylJethoxy]phenoxy]-2-(4-pivaloyloxy-phenyl)benzo[b]thiophene hydrochloride;

3-[4-[2-(4-piperidinylJetoksy]fenoksy]-2-(4-butylsulfonyloks-yfenyl)]benzo[b]tiofen hydroklorid; 3-[4-[2-(4-piperidinyljetoxy]phenoxy]-2-(4-butylsulfonyloxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4 - [2-( 1-piperidinyl Jetoksy] tiofenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-piperidinyl Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-met oksy-3-[4-[2-( 1-py r roi idinyl Jetoksy] tiof enoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-Pyrroidinyl Jetoxy]thiophenoxy]-2-(4-Methoxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-{1-heksametyleniminoJetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-methoxy-3-[4-[2-{1-hexamethyleneiminoethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-met oksy-3-[4-[2-(1-NtN-dImetylamino Jetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-NtN-dimethylamino Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-morfol inoJetoksy]tiofenoksy]-2 - (4-metoksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-morpholineoxy]thiophenoxy]-2-(4-methoxyphenyl)benzo[b]thiophene;

[6-benzyloksy-3-[4-[2-(l-piperidinylJetoksy]tiofenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen; [6-benzyloxy-3-[4-[2-(1-piperidinyljetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-benzyl oksy-3- [4- [2 - (1-pyrrol idinyl Jetoksy] tiof enoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen; [6-benzyloxy-3-[4-[2-(1-pyrroleidinyl Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-benzyloksy-3-[4-[2-(1-heksametylenimino Jetoksy]tiof enoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen; [6-Benzyloxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-benzyloksy-3-[4-[2-(l-N,N-dimetylamino Jetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-Benzyloxy-3-[4-[2-(1-N,N-dimethylamino Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-benzyl oksy-3 - [4 - [2 - (1-morf ol ino Jetoksy] tiof enoksy] -2-(4-metoksyfenylJ]benzo[b]tiofen; [6-benzyloxy-3-[4-[2- (1-morpholinojetoxy]thiophenoxy]-2-(4-methoxyphenyl)benzo[b]thiophene;

[6 - i sopropoksy-3 - [4 - [2 - (1-piperidinyl Jetoksy] tiof enoksy] -2-(4-metoksyfenylJ]benzo[b]tiofen; [6-i isopropoxy-3-[4-[2-(1-piperidinyl Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)benzo[b]thiophene;

[6-isopropoksy-3-[4-[2-(1-pyrrolidinylJetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-isopropoxy-3-[4-[2-(1-pyrrolidinylJethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-i sopropoksy-3 - [ 4 - [2 - (1-heksametylenimino Jetoksy] tiof enoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen; [6-i isopropoxy-3-[4-[2-(1-hexamethyleneiminojetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-isopropoksy-3-[4-[2-(l-N,N-dimetylamino Jetoksy]tiof enoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen; [6-isopropoxy-3-[4-[2-(1-N,N-dimethylamino Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-i sopropoksy-3-[4-[2-(1-morfolinoJetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-isopropoxy-3-[4-[2-(1-morpholinoJethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-{ 1-piperidinyl Jetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-Hydroxy-3-[4-[2-{1-piperidinyl Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-hy dr ok sy-3-[4-[2-(1-pyrrolidinylJetoksy]tiofenoksy]-2-(4-metoksyfenyl}]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-pyrrolidinylJethoxy]thiophenoxy]-2-(4-methoxyphenyl}]benzo[b]thiophene;

[6-hy dr oksy-3-[4-[2-(1-heksametyleniminoJetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-hexamethyleneiminoethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(l-N,N-dimetylamino Jetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-N,N-dimethylamino Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(1-morfolino Jetoksy]tiofenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-morpholino Jetoxy]thiophenoxy]-2-(4-methoxyphenyl )]benzo[b]thiophene;

[6-hydroksy-3-[4- [2-( 1-piperidinyl Jetoksy] tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4- [2-( 1-piperidinyl Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hy dr oksy-3-[4-[2-(1-pyrrolidinylJetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-pyrrolidinylJethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-heksametylenimino Jetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-N,N-dimetylamino Jetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-N,N-dimethylamino Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-morfolinoJetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-morpholinoJethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3 - [4-[2-( 1-pi per Idinyl Jetoksy] tiofenoksy]-2-( 4-benzyloksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-pi per Idinyl Jetoxy]thiophenoxy]-2-(4-benzyloxyphenyl)benzo[b]thiophene;

[6-metoksy-3-[4- [2-( 1-pyrrol idinyl Jetoksy]tiofenoksy]-2-(4-benzyloksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4- [2-( 1-pyrrole idinyl Jetoxy]thiophenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-heksametylenimino Jetoksy]tiofenoksy]-2-(4-benzyloksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]thiophenoxy]-2-(4-benzyloxyphenyl)benzo[b]thiophene;

[6-metoksy-3-[4-[2-{1-N,N-dimetylamino Jetoksy]tiofenoksy]-2-(4-benzyloksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-{1-N,N-dimethylamino Jetoxy]thiophenoxy]-2-(4-benzyloxyphenyl]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-morfolino Jetoksy]tiofenoksy]-2-{4-benzyloksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-morpholino Jetoxy]thiophenoxy]-2-{4-benzyloxyphenyl]benzo[b]thiophene;

[6-met oksy-3-[4 - [2-( 1-piper Idinyl Jet oksy] tiof enoksy]-2-( 4-IsopropoksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-( 1-piper Idinyl J ethoxy] thiopheneoxy]-2-( 4-Isopropoxyphenyl J)benzo[b]thiophene;

[6-metoksy-3-[4-[2-( 1-pyrrol Idinyl Jetoksy]tiofenoksy]-2-(4-i sopropoksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-( 1-pyrrole Idinyl Jetoxy]thiophenoxy]-2-(4-isopropoxyphenyl]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-heksametyleniminoJetoksy]-tiofenoksy]-2-(4-isopropoksyfenyl)]benzo[b]tiofen; [6-methoxy-3-[4-[2-(1-hexamethyleneiminoethoxy]-thiophenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene;

[6-met oksy-3-[4-[2-(l-NtN-dimetylaminoJetoksy]tiofenoksy]-2-(4-isopropoksyfenyl)]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-NtN-dimethylaminoJethoxy]thiophenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene;

[ 6-metoksy-3-[4-[2-{1-morfol ino Jetoksy]tiofenoksy]-2-(4-isopropoksyfenyl)]benzo[b]tiofen; [ 6-Methoxy-3-[4-[2-{1-morpholino]ethoxy]thiophenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene;

[6-metoksy-3 - [4-[2-(1-piperidinyl Jetoksy]tiofenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-piperidinyl Jetoxy]thiophenoxy]-2-(4-hydroxyphenyl]benzo[b]thiophene;

[6-met oksy-3- [4 - [2 - (1-pyrrol Idinyl Jetoksy] tiofenoksy]-2^(4-hydroksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-(1-pyrrole Idinyl Jetoxy]thiophenoxy]-2^(4-hydroxyphenyl)benzo[b]thiophene;

[6-metoksy-3-[4-[2-{1-heksametyleniminoJetoksy]tiofenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen; [6-Methoxy-3-[4-[2-{1-hexamethyleneiminoJethoxy]thiophenoxy]-2-(4-hydroxyphenylJ]benzo[b]thiophene;

[6-metoksy-3-[4-[2-(1-N,N-dimetylaminoJetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]henzo[b]tiofen; [6-methoxy-3-[4-[2-(1-N,N-dimethylaminoJethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]henzo[b]thiophene;

[ 6-metoksy-3-[4-[2-(1-morfolinoJetoksy]tiofenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen; [ 6-Methoxy-3-[4-[2-(1-morpholinoJethoxy]thiophenoxy]-2-(4-hydroxyphenylJ]benzo[b]thiophene;

[6-metoksy-3-[4- [2-( 1-piperidinyl Jetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4- [2-( 1-piperidinyl Jetoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4-[2-(l-pyrrolidinyl Jetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-pyrrolidinyl Jetoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4-[2-(1-heksametylenimino Jetoksy]tiofenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]thiophenoxy]-2-(4-hydroxyphenyl)benzo[b]thiophene hydrochloride;

[6-met oksy-3-[4-[2-(1-N,N-dlmetylamlnoJetoksy]tiofenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-N,N-dlmethylamlnoJethoxy]thiophenoxy]-2-(4-hydroxyphenylJ)benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4-[2-(1-morfolino Jetoksy]tiofenoksy]-2-( 4-hydroksyfenyl}]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4-[2-(1-morpholino Jetoxy]thiophenoxy]-2-(4-hydroxyphenyl}]benzo[b]thiophene hydrochloride;

[6-metoksy-3-[4- [2-( 1-piperidinyl Jetoksy]tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid; [6-Methoxy-3-[4- [2-( 1-piperidinyl Jetoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3- [4- [2 - (1-piperidinyl Jetoksy] tiofenoksy] -2-(4-hydroksyfenylJ]benzo[b]tiofen; [6-hydroxy-3- [4- [2 - (1-piperidinyl Jetoxy]thiophenoxy]-2-(4-hydroxyphenyl)benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(1-pyrrolidinylJetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-pyrrolidinylJetoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-hy dr ok sy -3-[4-[2-(1-heksametyleniminoJetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-hexamethyleneiminoethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(l-N,N-dImetylaminoJetoksy]tiofenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-N,N-dimethylaminoJethoxy]thiophenoxy]-2-(4-hydroxyphenylJ)benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(1-morfolinoJetoksy]tiofenoksy]-2-(4-hydroksyfenyl )]benzo[b]tiofen; [6-hydroxy-3-[4-[2-(1-morpholinoJethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene;

[6-hydroksy-3-[4-[2-(1-piperidinyl Jetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-piperidinyl Jetoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-pyrrolidinylJetoksy]tiofenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-pyrrolidinylJethoxy]thiophenoxy]-2-(4-hydroxyphenylJ)benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-heksametylenimino Jetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-N,N-dimetylaminoJetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-N,N-dimethylaminoJethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

[6-hydroksy-3-[4-[2-(1-morfolinoJetoksy]tiofenoksy]-2-( 4-hydroksyfenyl)]benzo[b]tiofen hydroklorid; [6-hydroxy-3-[4-[2-(1-morpholinoJethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride;

6-hydroksy-3- [4 - [2 - (l-p i per idinyl Jetoksy] fenoksy] -2-fenyl] - benzo[b]tiofen hydroklorid. 6-hydroxy-3- [4 - [2 - (l-p i peridinyl Jetoxy] phenoxy] -2-phenyl] - benzo[b]thiophene hydrochloride.

I de følgende eksemplene er presentert for ytterligere å illustrere fremstilling av forbindelser ifølge oppfinnelsen. Det er ikke ment at oppfinnelsen skal være begrenset i ramme på grunn av noen av de følgende eksemplene. In the following examples are presented to further illustrate the preparation of compounds according to the invention. It is not intended that the invention be limited in scope by reason of any of the following examples.

NMR data for de følgende eksempler ble generert på et GE 300 MHz NMR instrument, og vannfri d-6 DMS ble benyttet som oppløsningsmiddel hvis ikke annet er angitt. NMR data for the following examples were generated on a GE 300 MHz NMR instrument, and anhydrous d-6 DMS was used as solvent unless otherwise noted.

Fremstilling 1 Production 1

Fremstilling av [3-[4-[2-(1-piperidinyl)etoksy]fenoksy]-2-84-hydroksyfenyl)]benzo[b]tiofen [3-(4-benzyloksy)fenoksy]-benzo[b]tiofen Preparation of [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-84-hydroxyphenyl)]benzo[b]thiophene [3-(4-benzyloxy)phenoxy]-benzo[b]thiophene

Til en oppløsning av 3-brom-benzo[b]tiofen (69,62 g, 0,325 mol) i 55 ml vannfri kollidin under N2 ble det tilsatt 4-benzyloksyfenol (97,6 g, 0,488 mol) og kobberoksyd (23,3 g, 0,163 mol). Blandingen ble oppvarmet ved tllbakeløpskjøling i 24 timer. Etter avkjøling, ble reaksjonsblåndingen fortynnet med etylacetat (200 ml) og den rå blandingen ble filtrert gjennom en pute Celite (Aldrich, Milwaukee, Wl) for å fjerne uorganiske salter. Filtratet ble vasket med IN saltsyre (3 x 150 ml). Det organiske laget ble tørket (natriumsulfat) og konsentrert under vakuum for å gi en væske. Tianaften ble fjernet ved destillering (10 mm Hg, 115-120'C). Det gjenværende materialet ble kromatografert (silikondioksyd, heksaner: etylacetat 85:15) for å gi 12,2 g benzo[b]tiofen og 12,95 g (35* basert på gjenvunnet startmateriale) av [3-84-benzyloksy)fenoksy]benzo[b]tiofen som et nær hvitt faststoff, smp. 84-86'C. <!>h NMR (CDC13) d 7,91-7,83 (m, 2H); 7,47-7,34 (m, 7H), 7,04 (q, JAB = 9,0 Hz, 4H), 6,47 (s, 1H), 5,07 (s, 2H). Analyse beregnet for <C>21<H>1602S: C, 75,88; H, 4,85. Funnet: C, 75,75; H, 5,00. To a solution of 3-bromo-benzo[b]thiophene (69.62 g, 0.325 mol) in 55 mL of anhydrous collidine under N2 was added 4-benzyloxyphenol (97.6 g, 0.488 mol) and copper oxide (23.3 g, 0.163 mol). The mixture was heated under reflux for 24 hours. After cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and the crude mixture was filtered through a pad of Celite (Aldrich, Milwaukee, WI) to remove inorganic salts. The filtrate was washed with 1N hydrochloric acid (3 x 150 mL). The organic layer was dried (sodium sulfate) and concentrated under vacuum to give a liquid. Thianaphthene was removed by distillation (10 mm Hg, 115-120°C). The remaining material was chromatographed (silicon dioxide, hexanes:ethyl acetate 85:15) to give 12.2 g of benzo[b]thiophene and 12.95 g (35* based on recovered starting material) of [3-84-benzyloxy)phenoxy] benzo[b]thiophene as an off-white solid, m.p. 84-86'C. <!>h NMR (CDCl 3 ) d 7.91-7.83 (m, 2H); 7.47-7.34 (m, 7H), 7.04 (q, JAB = 9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s, 2H). Analysis calculated for <C>21<H>1602S: C, 75.88; H, 4.85. Found: C, 75.75; H, 5.00.

Fremstilling 2 Production 2

[2-j od-3-(4-benzyloksy)fenoksy]benzo[b]tiofen [2-iod-3-(4-benzyloxy)phenoxy]benzo[b]thiophene

TH en oppløsning av [3-(4-benzyloksy)fenoksy]benzo[b]tiofen (6,00 g, 18,1 mmol) i vannfri tetrahydrofuran (100 ml) under N2 ved -78*C ble det tilsatt n-butyllitium (12,4 ml, 19,9 mmol, 1,6M i heksan) dråpevis via sprøyte. Oppløsningen forandret farve fra farveløst til dyp orange. Etter omrøring i 20 minutter ved -78"C ble blandingen behandlet med lg (5,03 g, 19,9 mmol), tilsatt dråpevis via kanyle som en oppløsning i 50 ml vannfri tetrahydrofuran. Etter fullførelse av tilsetningen ble oppløsningen gul av farge og ble sakte oppvarmet til romtemperatur. Reaksjonen ble stanset ved tilsetning av 0,1N natrlumsulfitoppløsning (200 ml). Lagene ble separert og det vandige laget ekstrahert med etylacetat (2 x 150 ml). Det organiske laget ble slått sammen, tørket (natriumsulfat) og konsentrert under vakuum for å gi en olje som krystalliserte ved henstand. Rekrystallisering fra heksan/etyleter ga 7,10 g (86*) [2-jod-3-(4-benzyloksy)fenoksy]benzo[b]tiofen som et hvitt krystallinsk pulver. Smp. 87-92-C. <X>H NMR (CDC13) d 7,72 (d, J-8.1B.Z, 1H) , 7,47-7,20 (m, 8H), 6,89 (s, 4H), 5,01 (s, 2H). Analyse beregnet for c21<H>15°2sI: c» 55.03; H, 3,30. Funnet: C, 55,29; H, 3,31. TH to a solution of [3-(4-benzyloxy)phenoxy]benzo[b]thiophene (6.00 g, 18.1 mmol) in anhydrous tetrahydrofuran (100 mL) under N 2 at -78°C was added n-butyllithium (12.4 ml, 19.9 mmol, 1.6M in hexane) dropwise via syringe. The solution changed color from colorless to deep orange. After stirring for 20 min at -78°C, the mixture was treated with lg (5.03 g, 19.9 mmol), added dropwise via cannula as a solution in 50 mL of anhydrous tetrahydrofuran. Upon completion of the addition, the solution became yellow in color and was slowly warmed to room temperature. The reaction was quenched by the addition of 0.1N sodium sulfite solution (200 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2 x 150 mL). The organic layer was combined, dried (sodium sulfate) and concentrated under vacuum to give an oil which crystallized on standing.Recrystallization from hexane/ethyl ether gave 7.10 g (86*) of [2-iodo-3-(4-benzyloxy)phenoxy]benzo[b]thiophene as a white crystalline powder. M.p. 87-92-C. <X>H NMR (CDCl 3 ) d 7.72 (d, J-8.1B.Z, 1H) , 7.47-7.20 (m, 8H), 6.89 ( s, 4H), 5.01 (s, 2H). Analysis calcd for c21<H>15°2sI: c» 55.03; H, 3.30. Found: C, 55.29; H, 3.31.

Fremstilling 3 Manufacturing 3

[2 - ( 4-tertbutyloksyf enyl )-3-( 4-benzyl oksy ) fenoksy] - benzo[b]tiofen [2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene

Til en oppløsning av [2-jod-3-(4-benzyloksy)fenoksy]-benzo[b]tiofen (4,50 g, 9,82 mmol) i toluen (20 ml) ble det tilsatt 4-(tertbutoksy)fenyl borsyre (2,28 g, 11,75 mmol) fulgt av tetrakistrifenylfosfinpalladium (0,76 g, 0,66 mmol). Til denne oppløsningen ble det tilsatt 14,5 ml 2N natriumkar-bonatoppløsning. Den resulterende blandingen ble oppvarmet ved tilbakeløpskjøling i 3 timer. Etter avkjøling ble reaksjonen fortynnet med 150 ml etylacetat. Det organiske laget ble vasket med 0,1N natriumhydroksyd (2 x 100 ml) og så tørket (natriumsulfat). Konsentrasjon ga et halvfast stoff som ble oppløst 1 kloroform og ledet gjennom en pute sillsiumdioksyd. Konsentrasjon ga en olje som ble finfordelt fra heksan for å gi 4,00 g (91*) [2-(4-tertbutyloksyfenyl)-3-(4-benzyloksy)fenoksy]benzo[b]tiofen som et hvitt pulver. Smp. 105-108'C. <!>h NMR (CDC13) d 7,77 (d, J»7,7Hz, 1H), 7,68 (d, J=8,6Hz, 2H), 7,43-7,24 (m, 8H), 6,98 (d, J=8,6Hz, 2H), 6,89 (q, JAB=9,3Hz, 4H), 4,99 (s, 2H), 1,36 (s, 9H). FD massespekter: 480. Analyse beregnet for C31<H>2g<0>3S: C, 77,47; H, 5,87. Funnet: C, 77,35; H, 5,99. To a solution of [2-iodo-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene (4.50 g, 9.82 mmol) in toluene (20 mL) was added 4-(tert-butoxy)phenyl boric acid (2.28 g, 11.75 mmol) followed by tetrakistriphenylphosphine palladium (0.76 g, 0.66 mmol). To this solution was added 14.5 ml of 2N sodium carbonate solution. The resulting mixture was heated at reflux for 3 hours. After cooling, the reaction was diluted with 150 ml of ethyl acetate. The organic layer was washed with 0.1N sodium hydroxide (2 x 100 mL) and then dried (sodium sulfate). Concentration gave a semi-solid which was dissolved in 1 chloroform and passed through a pad of silicon dioxide. Concentration gave an oil which was triturated from hexane to give 4.00 g (91*) of [2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene as a white powder. Temp. 105-108°C. <!>h NMR (CDCl 3 ) d 7.77 (d, J»7.7Hz, 1H), 7.68 (d, J=8.6Hz, 2H), 7.43-7.24 (m, 8H ), 6.98 (d, J=8.6Hz, 2H), 6.89 (q, JAB=9.3Hz, 4H), 4.99 (s, 2H), 1.36 (s, 9H). FD mass spectrum: 480. Analysis calculated for C31<H>2g<0>3S: C, 77.47; H, 5.87. Found: C, 77.35; H, 5.99.

Fremstilling 4 Manufacturing 4

Fremstilt pa lignende mate ved anvendelse av 4-metoksyfenyl-borsyre ble [2-(4-metoksyfenyl)-3-(4-benzyloksyJfenoksy]-benzo[b]tiofen Prepared in a similar manner using 4-methoxyphenylboric acid was [2-(4-methoxyphenyl)-3-(4-benzyloxyJphenoxy]-benzo[b]thiophene

Utbytte - 739É. Smp. 115-118'C. ^ NMR {CDCI3) d 7,80-7,90 (m, 3H), 7,33-7,53 (m, 8H), 6,93-7,06 (m, 6H), 5,00 (s, 2H), 3,83 (s, 3H). FD massespekter: 438. Analyse beregnet for C28<H>22°3S: c* 76,69; H, 5,06. Funnet: C, 76,52; H, 5,09. Dividend - 739É. Temp. 115-118'C. ^ NMR {CDCl 3 ) d 7.80-7.90 (m, 3H), 7.33-7.53 (m, 8H), 6.93-7.06 (m, 6H), 5.00 (s , 2H), 3.83 (s, 3H). FD mass spectrum: 438. Analysis calculated for C28<H>22°3S: c* 76.69; H, 5.06. Found: C, 76.52; H, 5.09.

Fremstilling 5 Manufacturing 5

[2- (4-tertbutyloksyfenyl)-3-(4-hydroksy)fenoksy]benzo[b]tiofen [2-(4-tertbutyloxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene

TH en oppløsning av [2-(4-tertbutyloksyfenyl)-3-(4~benzyloksy )fenoksy]benzo[b]tiofen (1,50 g, 3,37 mmol) i 30 ml absolutt etanol inneholdende 1* konsentrert saltsyre, ble det tilsatt 0,50 g 10* palladium på karbon. Blandingen ble hydrogenert ved 40 psi i 1 time, hvoretter reaksjonen ble bedømt å være fullstendig ved tynnsjIktskromatografi. Blandingen ble filtrert gjennom en pute celit og filtratet konsentrert i vakuum. Råproduktet ble oppløst i minimum etylacetat og ledet gjennom en kort silisiumdloksydkolonne for å fjerne celit (etylacetat som elueringsmiddel). Konsentrasjonen ga et hvitt faststoff som ble finfordelt fra heksan/etyleter. Filtrering ga 868 mg (73*) [2-(4-tertbutyl-oksyfenyl )-3-( 4-hydroksy )fenoksy]benzo[b] tiof en , smp. 210-213'C. H NMR (DMS0-d6) d 9,13 (s, 1H), 7,94 (d, J-7,7Hz, 1H), 7,63 (d, J=8,6Hz, 2H), 7,35-7,26 (m, 3H), 7,01 (d, J=8,6Hz, 2H), 6,70 (q, JAB=8, 9Hz, 4H), 1,28 (s, 9H). FD massespekter: 390. Analyse beregnet for C24<H>22<O>3S: C, 73,82; H, 5,68. Funnet: C, 73,98; H, 5,84. TH a solution of [2-(4-tertbutyloxyphenyl)-3-(4~benzyloxy)phenoxy]benzo[b]thiophene (1.50 g, 3.37 mmol) in 30 ml absolute ethanol containing 1* concentrated hydrochloric acid, was 0.50 g of 10* palladium on carbon was added. The mixture was hydrogenated at 40 psi for 1 hour, after which the reaction was judged to be complete by thin layer chromatography. The mixture was filtered through a pad of celite and the filtrate concentrated in vacuo. The crude product was dissolved in a minimum of ethyl acetate and passed through a short silica column to remove celite (ethyl acetate as eluent). Concentration gave a white solid which was triturated from hexane/ethyl ether. Filtration gave 868 mg (73*) [2-(4-tertbutyl-oxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene, m.p. 210-213'C. H NMR (DMS0-d6) d 9.13 (s, 1H), 7.94 (d, J-7.7Hz, 1H), 7.63 (d, J=8.6Hz, 2H), 7.35-7.26 (m, 3H), 7.01 (d, J=8.6Hz, 2H), 6.70 (q, JAB=8, 9Hz, 4H), 1.28 (s, 9H ). FD mass spectrum: 390. Analysis calculated for C24<H>22<O>3S: C, 73.82; H, 5.68. Found: C, 73.98; H, 5.84.

Fremstilling 6 Production 6

Fremstilt på tilsvarende måte ble [2-(4-metoksyfenyl)-3-(4-hydroksy)fenoksy]benzo[b]tiofen Prepared in a similar manner, [2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene

Utbytte = 80*. Smp. 120-125"C. <!>h NMR (CDCI3) d 7,80-7,09 (m, 3H), 7,48 (m, 1H), 7,30-7,48 (m, 2H), 6,90-7,03 (m, 4H), 6,76-6,86 (m, 2H), 3,82 (s, 3H). FD massespekter: 348. Analyse beregnet for C21H1(,03S: C, 72,39; H, 4,63. Funnet: C, 72,68; H, 4,82. Dividend = 80*. Temp. 120-125"C. <!>h NMR (CDCl 3 ) d 7.80-7.09 (m, 3H), 7.48 (m, 1H), 7.30-7.48 (m, 2H), 6.90-7.03 (m, 4H), 6.76-6.86 (m, 2H), 3.82 (s, 3H). FD mass spectrum: 348. Analysis calculated for C21H1(,03S: C, 72.39; H, 4.63. Found: C, 72.68; H, 4.82.

Ulkgem pel 1 Ulkgem pile 1

[3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-{4-hydroksyfenyl)]-benzo[b]tiofen [3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-{4-hydroxyphenyl)]-benzo[b]thiophene

Til en oppløsning av [2-84-tertbutyloksyfenyl )-3-(4-hydr-oksyJfenoksy]benzo[b]tiofen (1,25 g, 3,20 mmolJ i vannfri N,N-dimetylformamid (10 ml J ved omgivelsestemperatur ble det tilsatt cesiumkarbonat (5,70 g, 17,6 mmol). Etter omrøring i 20 minutter ble 2-kloretylpIperidin hydroklorid (1,95 g, 10,56 mmol) tilsatt i små porsjoner. Den resulterende heterogene blandingen ble omrørt kraftig i 24 timer. Innholdet av reaksjonsblandingen ble så fortynnet med vann (200 ml). Den vandige fasen ble ekstrahert med etylacetat (3 x 100 ml). De sammenslåtte organiske lagene ble så vasket med vann (2 x 200 ml). Tørking av det organiske laget (natriumsulfat) og konsentrasjon I vakuum, ga en olje. Kromatografl (5-10* metanol/kloroform) ga 1,47 g (91*) 3-[4-[2-(l-piperidinyl )etoksy] f enoksy]-2-(4-tertbutyloksyf enyl )]benzo-[b]tiofen som ble benyttet direkte i neste trinn uten karakterisering. To a solution of [2-84-tertbutyloxyphenyl)-3-(4-hydroxyJphenoxy]benzo[b]thiophene (1.25 g, 3.20 mmol) in anhydrous N,N-dimethylformamide (10 ml) at ambient temperature was cesium carbonate (5.70 g, 17.6 mmol) was added. After stirring for 20 min, 2-chloroethylpyridine hydrochloride (1.95 g, 10.56 mmol) was added in small portions. The resulting heterogeneous mixture was stirred vigorously for 24 hours. The contents of the reaction mixture were then diluted with water (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were then washed with water (2 x 200 mL). Drying of the organic layer (sodium sulfate) and concentration in vacuo gave an oil Chromatography (5-10* methanol/chloroform) gave 1.47 g (91*) 3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]- 2-(4-tertbutyloxyphenyl)]benzo-[b]thiophene which was used directly in the next step without characterization.

3 - [4-[2-( 1-piperidinyl )etoksy] f enoksy]-2-(4-tertbutyloksy-fenyl)] benzo [b] tiofen (1,37 g, 2,73 mmol) ble oppløst i trifluoreddiksyre (10 ml) ved omgivelsestemperatur. Etter omrøring i 15 minutter ble oppløsnlngsmidlet fjernet under vakuum. Resten ble oppløst i etylacetat (20 ml) og vasket med mettet natriumbikarbonatoppløsnlng (3 x 10 ml). Det organiske laget ble tørket (natriumsulfat) og konsentrert hvorpå en hvit fast utfelling ble dannet i oppløsningen. Produktet ble rekrystallisert fra etylacetat-etyleter for å gl 1,03 g (85*) 3-[4-[2-( 1-piperidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]- 3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-tertbutyloxy-phenyl)]benzo[b]thiophene (1.37 g, 2.73 mmol) was dissolved in trifluoroacetic acid ( 10 ml) at ambient temperature. After stirring for 15 minutes, the solvent was removed under vacuum. The residue was dissolved in ethyl acetate (20 mL) and washed with saturated sodium bicarbonate solution (3 x 10 mL). The organic layer was dried (sodium sulfate) and concentrated whereupon a white solid precipitate formed in the solution. The product was recrystallized from ethyl acetate-ethyl ether to give 1.03 g (85*) of 3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-hydroxyphenyl)]-

benzo[b]tiofen som fargeløse krystaller. Smp. 169-172<*>C. <*>H NMR {DMSO-d6) d 9,81 (s, 1H), 7,93 (d, J-7,7Hz, 1H), 7,54 (d, J=8,5Hz, 2H), 7,36-7,26 (m, 3H), 6,86 (s, 4H), 6,78 (d, J-8,6Hz, 2H), 4,10 (m, 2H), 3,29 (m, 2H), 2,95-2,75 (m, 4H), 1,68-1,40 (m, 6H). Analyse beregnet for C27<H>27N03S*0,55 CF3C02H: C, 66,40; H, 5,46; N, 2,76. Funnet: C, 65,99; H, 5,49; N, 2,61. Eksempel 2 3-[4-[2-( 1-piperidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]-benzo[b]tiofen ble omdannet til dets hydrokloridsalt med 90* utbytte ved behandling med etyleter•saltsyre i etylacetat benzo[b]thiophene as colorless crystals. Temp. 169-172<*>C. <*>H NMR {DMSO-d6) d 9.81 (s, 1H), 7.93 (d, J-7.7Hz, 1H), 7.54 (d, J=8.5Hz, 2H), 7.36-7.26 (m, 3H), 6.86 (s, 4H), 6.78 (d, J-8.6Hz, 2H), 4.10 (m, 2H), 3.29 ( m, 2H), 2.95-2.75 (m, 4H), 1.68-1.40 (m, 6H). Analysis calculated for C27<H>27N03S*0.55 CF3CO2H: C, 66.40; H, 5.46; N, 2.76. Found: C, 65.99; H, 5.49; N, 2.61. Example 2 3-[4-[2-( 1-piperidinylJetoxy]phenoxy]-2-(4-hydroxyphenyl)]-benzo[b]thiophene was converted to its hydrochloride salt in 90* yield by treatment with ethyl ether•hydrochloric acid in ethyl acetate

Data for eksempel 2, smp. 233-240"C. <*>H-NMR (DMS0-d6) d 10,43 (m, 1H), 9,89 (s, 1H), 7,93-7,95 (rn, 1H), 7,60-7,64 (m, 2H), 7,35-7,50 (m, 3H), 6,83-7,03 (m, 6H), 4,27-4,30 (m, 2H), 3,40-3,60 (m, 4H), 2,96-3,10 (m, 2H), 1,70-1,95 (m, 5H), 1,40-1,53 (m, 1H). FD massespekter: 446. Analyse beregnet for <C>27H27N03S-1,0 HC1: C, 67,28; H, 5,86; N, 2,91. Funnet: C, 67,07; H, 5,66; N, 2,96. Data for example 2, m.p. 233-240"C. <*>H-NMR (DMS0-d6) d 10.43 (m, 1H), 9.89 (s, 1H), 7.93-7.95 (rn, 1H), 7 .60-7.64 (m, 2H), 7.35-7.50 (m, 3H), 6.83-7.03 (m, 6H), 4.27-4.30 (m, 2H) , 3.40-3.60 (m, 4H), 2.96-3.10 (m, 2H), 1.70-1.95 (m, 5H), 1.40-1.53 (m, 1H). FD mass spectrum: 446. Analysis calcd for <C>27H27N03S-1.0 HC1: C, 67.28; H, 5.86; N, 2.91. Found: C, 67.07; H, 5 .66; N, 2.96.

Eksempel 3 Example 3

Fremstilt på analog måte ved de følgende eksempler: [3-[4-[2-( 1 - pyrroiidinylJetoksy]fenoksy]-2-(4-hydroksy-fenyl}]benzo[b]tiofen Prepared in an analogous manner by the following examples: [3-[4-[2-( 1 - pyrroiidinylJetoxy]phenoxy]-2-(4-hydroxy-phenyl}]benzo[b]thiophene

Smp. 150-155-C. -^H-NMR (DMSO-d6) d 9,79 (s, 1H), 7,92 (d, J=7,8Hz, 1H), 7,54 (d, J=8,6Hz, 2H), 7,36-7,26 (m, 3HJ, 6,84 (s, 4H), 6,78 (d, J=8,6Hz, 2H), 4,00 (bt, 2H), 2,92 (m, 2H), 2,85 (m, 4H), 1,73 (m, 4Hj. Analyse beregnet for <C>26<H>25N03S"0'33 CF3C02H: C, 68,25; H, 5,44; N, 2,99. Funnet: C, 68,29; H, 5,46; N, 3,19. Temp. 150-155-C. -^H-NMR (DMSO-d6) d 9.79 (s, 1H), 7.92 (d, J=7.8Hz, 1H), 7.54 (d, J=8.6Hz, 2H), 7.36-7.26 (m, 3HJ, 6.84 (s, 4H), 6.78 (d, J=8.6Hz, 2H), 4.00 (bt, 2H), 2.92 (m , 2H), 2.85 (m, 4H), 1.73 (m, 4Hj. Analysis calculated for <C>26<H>25N03S"0'33 CF3CO2H: C, 68.25; H, 5.44; N, 2.99 Found: C, 68.29, H, 5.46, N, 3.19.

Eksempel 4 Example 4

[3-[4-[2-(l-heksametylenimino Jetoksy]fenoksy]-2-(4-hydroksy-fenyl )]benzo[b]tiofen [3-[4-[2-(l-hexamethyleneimino Jetoxy]phenoxy]-2-(4-hydroxy-phenyl )]benzo[b]thiophene

Smp. 189-191'C. <*>E NMR (DMS0-d6) d 7,91 (d, J=7,6Hz, 1H), 7,52 (d, J=8,5Hz, 2H), 7,34-7,25 (m, 3H), 6,81 (s, 4H), 6,75 (d, J-8,6Hz, 2H), 3,89 (bt, 2H), 2,75 (bt, 2H), 2,68 (m, 4H), 1,48 {m, 8H). Analyse beregnet for C28H29N03S"1 •50 H20: c» 69,11; H, 6,79; N, 2,88. Funnet: C, 69,25; H, 6,79; N, 2,58. Temp. 189-191°C. <*>E NMR (DMS0-d6) d 7.91 (d, J=7.6Hz, 1H), 7.52 (d, J=8.5Hz, 2H), 7.34-7.25 (m , 3H), 6.81 (s, 4H), 6.75 (d, J-8.6Hz, 2H), 3.89 (bt, 2H), 2.75 (bt, 2H), 2.68 ( m, 4H), 1.48 (m, 8H). Analysis calculated for C28H29N03S"1 •50 H2O: c» 69.11; H, 6.79; N, 2.88. Found: C, 69.25; H, 6.79; N, 2.58.

Eksempel 5 Example 5

[3 - [4-[2-( l-N,N-dletylamino Jetoksy] f enoksy]-2-(4-hydroksy-fenyl)]benzo[b]tiofen [3-[4-[2-(1-N,N-dletylamino Jetoxy]phenoxy]-2-(4-hydroxy-phenyl)]benzo[b]thiophene

Smp. 70-C. H NMR (DMSO-d6) d 9,91 (bs, 1H), 7,92 (d, J=7,9Hz, 1H), 7,54 (d, J=8,6Hz, 2Hj, 7,35-7,24 (m, 3H), 6,82 (s, 4H), 6,78 (d, J=8,6Hz, 2H), 3,88 (bt, 2H), 2,76 (bt, 2H), 2,51 (m, 4H), 0,91 (m, 6HJ. FD massespekter: 434. Analyse beregnet for <C>26H27N03S'0,50 H20: C,70,56; H, 6,38; N, 3,16. Funnet: C, 70,45; H, 6,26; N, 3,20. Temp. 70-C. H NMR (DMSO-d6) d 9.91 (bs, 1H), 7.92 (d, J=7.9Hz, 1H), 7.54 (d, J=8.6Hz, 2Hj, 7 .35-7.24 (m, 3H), 6.82 (s, 4H), 6.78 (d, J=8.6Hz, 2H), 3.88 (bt, 2H), 2.76 (bt , 2H), 2.51 (m, 4H), 0.91 (m, 6HJ. FD mass spectrum: 434. Analysis calculated for <C>26H27N03S'0.50 H2O: C, 70.56; H, 6.38 ; N, 3.16. Found: C, 70.45; H, 6.26; N, 3.20.

Eksempel 6 Example 6

3-[4-[2-( 1-piperidinyl )etoksy]fenoksy]-2-(4-metoksyfenyl )]-benzo[b]tiofen hydroklorid 3-[4-[2-( 1-piperidinyl )ethoxy]phenoxy]-2-(4-methoxyphenyl )]-benzo[b]thiophene hydrochloride

Smp. 228-230°C. ^ NMR (DMS0-d6) d 7,96 (d, J=7,5Hz, 1HJ, 7,66 (d, J=8,8Hz, 2H), 7,35-7,50 (m, 3HJ, 6,98 (d, J=8,7Hz, 2HJ, 6,86-6,90 (m, 4HJ, 4,28-4,31 (m, 2H), 3,74 (s, 3HJ, 3,37-3,45 (m, 4H), 2,92-2,96 (m, 2H), 2,46-2,48 (m, 5H), 1,74 (m, 1H). FD massespekter: 459. Analyse beregnet for C28H29N03S"1'0 HC1: c» 67,80; H, 6,10; N, 2,82. Funnet: C, 68,06; H, 6,38; N, 2,60. Temp. 228-230°C. ^ NMR (DMS0-d6) d 7.96 (d, J=7.5Hz, 1HJ, 7.66 (d, J=8.8Hz, 2H), 7.35-7.50 (m, 3HJ, 6 .98 (d, J=8.7Hz, 2HJ, 6.86-6.90 (m, 4HJ, 4.28-4.31 (m, 2H), 3.74 (s, 3HJ, 3.37- 3.45 (m, 4H), 2.92-2.96 (m, 2H), 2.46-2.48 (m, 5H), 1.74 (m, 1H). FD mass spectrum: 459. Analysis calcd for C28H29N03S"1'0HC1: c» 67.80; H, 6.10; N, 2.82. Found: C, 68.06; H, 6.38; N, 2.60.

Alternativ syntese av [2-(4-tertbutoksyfenyl)-3-(4-benzyloksy)fenoksy]benzo[b]tiofen Alternative synthesis of [2-(4-tertbutoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene

Fremstilling 7 Manufacturing 7

[3-{4-benzyloksy )fenoksy]benzo[b]tiofen-2-borsyre [3-{4-Benzyloxy)phenoxy]benzo[b]thiophene-2-boronic acid

Til en oppløsning ved -78°C av [3-(4-benzyloksy)fenoksy]-benzo[b]tiofen (5,00 g, 15,1 mmol) i 20 ml vannfri tetrahydrofuran under Ng ble det tilsatt n-butyllitium (9,90 ml, 15,8 mmol), 1,6 M i heksan) dråpevis via sprøyte. Etter omrøring i 15 minutter ble B(01Pr)3 (3,83 ml, 16,6 mmol) tilsatt via sprøyte, og den resulterende blandingen ble oppvarmet til 0°C. Reaksjonen ble stanset ved deling mellom etylacetat og 1,0N saltsyre (hver 100 ml). Lagene ble separert og det organiske laget ble ekstrahert med vann (lx 100 ml). Det organiske laget ble tørket (natrlumsulfat) og konsentrert under vakuum til et fast stoff som ble finfordelt fra etyleter/heksan. Filtrering ga 3,96 g (70*) [3-(4-benzyloksy)fenoksy]benzo[b]tiofen-2-borsyre som et hvitt faststoff. Smp. 115-121'C. ^-H NMR (DMS0-d6) d 8,16 (d, J=8,5Hz, 1H), 7,98 (d, J=9,0Hz, 1H), 7,42-7,23 (m, 7H), 6,90 (q, JAb=9,0Hz, 4H), 5,01 (s, 2H). Analyse beregnet for C21<H>17°4SB: c> 67,04; H, 4,55. Funnet: C, 67,17; H, 4,78. To a solution at -78°C of [3-(4-benzyloxy)phenoxy]-benzo[b]thiophene (5.00 g, 15.1 mmol) in 20 mL of anhydrous tetrahydrofuran under Ng was added n-butyllithium ( 9.90 ml, 15.8 mmol), 1.6 M in hexane) dropwise via syringe. After stirring for 15 min, B(O1Pr)3 (3.83 mL, 16.6 mmol) was added via syringe and the resulting mixture was warmed to 0°C. The reaction was quenched by partitioning between ethyl acetate and 1.0N hydrochloric acid (each 100 ml). The layers were separated and the organic layer was extracted with water (1 x 100 ml). The organic layer was dried (sodium sulfate) and concentrated under vacuum to a solid which was triturated from ethyl ether/hexane. Filtration gave 3.96 g (70*) of [3-(4-benzyloxy)phenoxy]benzo[b]thiophene-2-boronic acid as a white solid. Temp. 115-121'C. ^-H NMR (DMSO-d6) d 8.16 (d, J=8.5Hz, 1H), 7.98 (d, J=9.0Hz, 1H), 7.42-7.23 (m, 7H), 6.90 (q, JAb=9.0Hz, 4H), 5.01 (s, 2H). Analysis calculated for C21<H>17°4SB: c> 67.04; H, 4.55. Found: C, 67.17; H, 4.78.

[3-{4-benzyloksy)fenoksy]benzo[b]tiofen-2-borsyre ble reagert med 4-(tertbutoksy)brombenzen Ifølge betingelsene beskrevet [3-{4-Benzyloxy)phenoxy]benzo[b]thiophene-2-boronic acid was reacted with 4-(tert-butoxy)bromobenzene According to the conditions described

for [2-jod-3-(4-benzyloksy)fenoksy]-benzo[b]tiofen og 4-(tertbutoksy)fenyl borsyre for å gi [2-(4-tertbutyloksy-fenyl )-3-(4-benzyloksy)fenoksy]benzo[b]tiofen med 81* utbytte. for [2-iodo-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene and 4-(tert-butoxy)phenyl boric acid to give [2-(4-tert-butyloxy-phenyl )-3-(4-benzyloxy) phenoxy]benzo[b]thiophene in 81* yield.

Eksempler fremstilt i forbindelse av denne fremgangsmåten er: Eksempel 7 [3-[4-[2-(l-piperidinyl)etoksy] f enoksy] - 2- ( fenyl )] - benzo[b]tiofen hydroklorid Examples prepared in connection with this method are: Example 7 [3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(phenyl)]-benzo[b]thiophene hydrochloride

Smp. 223-226'C. <1>H NMR (DMSO-d6) d 7,99 (d, J=8,2Hz, 1H), 7,71 (d, J-7.3HZ, 1H), 7,44-7,30 (m, 7H), 6,90 (s, 4H), 4,27 (m, 2H), 3,43-3,35 (m, 4H), 2,97-2,88 (m, 2H), 1,73-1,61 (m, 5H), 1,34 (m, 1H). Analyse beregnet for C27H27N02S'1,0 HC1: C, 69,59; H, 6,06; N, 3,00. Funnet: C, 69,88; H, 6,11; N, 3,19. Temp. 223-226°C. <1>H NMR (DMSO-d6) d 7.99 (d, J=8.2Hz, 1H), 7.71 (d, J-7.3HZ, 1H), 7.44-7.30 (m, 7H), 6.90 (s, 4H), 4.27 (m, 2H), 3.43-3.35 (m, 4H), 2.97-2.88 (m, 2H), 1.73 -1.61 (m, 5H), 1.34 (m, 1H). Analysis calcd for C27H27N02S'1.0HCl: C, 69.59; H, 6.06; N, 3.00. Found: C, 69.88; H, 6.11; N, 3.19.

Eksempel 8 Example 8

[3- [4- [2- (1-plperidinyl )etoksy] fenoksy] -2-(4-fluorfenyl)]-benzo[b]tiofen [3- [4- [2-(1-plperidinyl)ethoxy]phenoxy]-2-(4-fluorophenyl)]-benzo[b]thiophene

Smp. 219-226'C. <X>H NMR (DMSO-d6) d 10,20 (bs, 1H), 7,99 (d, J-8,2Hz, 1H), 7,77-7,73 (m, 4H), 7,42-7,25 (m, 5H), 6,90 (s, 4H), 4,27 (m, 2H), 3,44-3,31 (m, 4H), 2,96-2,89 (m, 2H), 1,78-1,61 (m, 5H), 1,34 (m, 1H). FD massespekter: 447. Analyse beregnet for C27<H>26<N>02SF*1,0 HC1: C, 67,00; H, 5,62; N, 2,89. Funnet: C, 67,26; H, 5,67; N, 3,03. Temp. 219-226°C. <X>H NMR (DMSO-d6) d 10.20 (bs, 1H), 7.99 (d, J-8.2Hz, 1H), 7.77-7.73 (m, 4H), 7, 42-7.25 (m, 5H), 6.90 (s, 4H), 4.27 (m, 2H), 3.44-3.31 (m, 4H), 2.96-2.89 ( m, 2H), 1.78-1.61 (m, 5H), 1.34 (m, 1H). FD mass spectrum: 447. Analysis calculated for C27<H>26<N>02SF*1.0 HC1: C, 67.00; H, 5.62; N, 2.89. Found: C, 67.26; H, 5.67; N, 3.03.

Fremstilling 8 Manufacturing 8

Syntese av [6-hydroksy-3-[4-[2-{1-piperidinylJetoksy]-fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen Synthesis of [6-hydroxy-3-[4-[2-{1-piperidinyljetoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-metoksy-2-(4<->metoksyfenyl)-3-brom]benzo[b]tiofen [6-Methoxy-2-(4<->methoxyphenyl)-3-bromo]benzo[b]thiophene

TH en oppløsning av [6-metoksy-2-(4-metoksyfenyl)]-benzo[b]tiofen (27,0 g, 100 mmol) i 1,10 1 kloroform ved 60°C ble det tilsatt brom (15,98 g, 100 mmol) dråpevis som oppløsning i 200 ml kloroform. Etter tilsetningen var fullstendig, ble reaksjonen avkjølt til romtemperatur og oppløsningsmidlet fjernet under vakuum for å gi 34,2 g (100*) [6-metoksy-2-(4-metoksyfenyl)-3-brom]benzo[b]tiofen som et hvitt faststoff. Smp. 83-85'C. <2>H NMR (DMS0-d6) d 7,70-7,62 (m, 4H), 7,17 (dd, J=8,6, 2,0Hz, 1H), 7,09 (d, J=8,4Hz, 2H). FD massespekter: 349, 350. Analyse beregnet for C^^H^QOgSBr: C, 55,03; H, 3,75. Funnet: C, 54,79; H, 3,76. Eksempel 9 [6-metoksy-2-( 4-metoksyfenyl )-3-( 4-benzyloksy )fenoksy] - benzo[b]tiofen TH to a solution of [6-methoxy-2-(4-methoxyphenyl)]-benzo[b]thiophene (27.0 g, 100 mmol) in 1.10 L 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 complete, the reaction was cooled to room temperature and the solvent removed under vacuum to give 34.2 g (100*) of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene as a white solid. Temp. 83-85'C. <2>H NMR (DMS0-d6) d 7.70-7.62 (m, 4H), 7.17 (dd, J=8.6, 2.0Hz, 1H), 7.09 (d, J =8.4Hz, 2H). FD mass spectrum: 349, 350. Analysis calculated for C^^H^QOgSBr: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76. Example 9 [6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene

Til en oppløsning av [6-metoksy-2-(4-metoksyfenyl)-3-broro]benzo[b]tiofen (34,00 g, 97,4 mmol) 1 60 ml kollldin under N2 ble det tilsatt 4-benzyloksyfenol (38,96 g, 194,8 mmol) og kobberoksyd (14,5 g, 97,4 mmol). Den resulterende blandingen ble oppvarmet ved tilbakeløpskjøling 1 48 timer. Etter avkjøling til romtemperatur ble reaksjonsblandingen oppløst i aceton (200 ml) og det uorganiske faststoffet ble fjernet ved filtrering. Filtratet ble konsentrert under vakuum og resten oppløst i metylenklorid (500 ml). Metylen-kloridoppløsningen ble vasket med 3N saltsyre (3 x 300 ml), fulgt av IN natriumhydroksyd (3 x 300 ml). Det organiske laget ble tørket (natriumsulfat) og konsentrert under vakuum. Resten ble tatt opp i 100 ml etylacetat hvorpå det ble dannet et hvitt faststoff som ble oppsamlet ved filtrering [gjenvunnet [6-metoksy-2-(4-metoksyfenyl)]benzo[b]tiofen (4,62 g, 17,11 mmol). Filtratet ble konsentrert under vakuum og så ledet gjennom en kort pute silikagel (metylenklorid som elueringsmiddel) for å fjerne baselinjematerialet. Filtratet ble konsentrert under vakuum og resten krystallisert fra heksan/etylacetat for å gi initielt 7,19 g [6-metoksy-2-(4-metoksyfenyl)-3-(4-benzyloksy)fenoksy]benzo[b]tiofen som et nær hvitt krystallinsk faststoff. Morvæsken ble konsentrert og kromatografert på silikagel (heksan/etylacetat 80:20) for å gi ytterligere 1,81 g produkt. Totalt utbytte av [6-metoksy-2-(4-metoksyfenyl)-3-(4-benzyloksy)fenoksy]-benzo[b]tiofen var 9,00 g (24* basert på gjenvunnet startmateriale). Det basiske ekstraktet ble surgjort til pH 4 med 5N saltsyre, og den resulterende utfellingen oppsamlet ved filtrering og tørket for å gi 13,3 g gjenvunnet 4-benzyloksyfenol. Smp. 100-103'C. ^-H NMR (CDC13): d 7,60 (d, J=8,8Hz, 2H), 7,39-7,24 (m, 7H), 7,90-6,85 (m, 7H), 4,98 (s, 2H), 3,86 (s, 3E), 3,81 (s, 3H). FD massespekter: 468. Analyse beregnet for C29H2404S: C, 74,34; H, 5,16. Funnet: C, 74,64; H, 5,29. 4-Benzyloxyphenol ( 38.96 g, 194.8 mmol) and copper oxide (14.5 g, 97.4 mmol). The resulting mixture was heated at reflux for 148 hours. After cooling to room temperature, the reaction mixture was dissolved in acetone (200 mL) and the inorganic solid was removed by filtration. The filtrate was concentrated under vacuum 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 concentrated under vacuum. The residue was taken up in 100 mL ethyl acetate whereupon a white solid was formed which was collected by filtration [recovered [6-methoxy-2-(4-methoxyphenyl)]benzo[b]thiophene (4.62 g, 17.11 mmol ). The filtrate was concentrated under vacuum and then passed through a short pad of silica gel (methylene chloride as eluent) to remove the baseline material. The filtrate was concentrated under vacuum and the residue crystallized from hexane/ethyl acetate to give initial 7.19 g of [6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene as a near white crystalline solid. The mother liquor was concentrated and chromatographed on silica gel (hexane/ethyl acetate 80:20) to give 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 (24* based on recovered starting material). The basic extract was acidified to pH 4 with 5N hydrochloric acid, and the resulting precipitate collected by filtration and dried to give 13.3 g of recovered 4-benzyloxyphenol. Temp. 100-103'C. 3-H NMR (CDCl 3 ): d 7.60 (d, J=8.8Hz, 2H), 7.39-7.24 (m, 7H), 7.90-6.85 (m, 7H), 4.98 (p, 2H), 3.86 (p, 3E), 3.81 (p, 3H). FD mass spectrum: 468. Analysis calculated for C 29 H 24 O 4 S: C, 74.34; H, 5.16. Found: C, 74.64; H, 5.29.

Fremstilling 9 Production 9

[6-metoksy-2-(4-metoksyfenyl)-3-(4-hydroksyJfenoksy]-benzo[b]tiofen [6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxyJphenoxy]-benzo[b]thiophene

Til en oppløsning av [6-metoksy-2-(4-metoksyfenyl)-3-(4-benzyloksy)fenoksy]benzo[b]tiofen (1,50 g, 3,20 mmol) i 50 ml etylacetat og 10 ml 1* konsentrert saltsyre 1 etanol ble det tilsatt 10* palladlum-på-karbon (300 mg). Blandingen ble hydrogenert ved 40 psi i 20 minutter, etter at reaksjonen ble komplett ved tynnsjiktskromatografi. Blandingen ble sendt gjennom cellt for å fjerne katalysatoren, og filtratet ble konsentrert i vakuum til et hvitt faststoff. Råproduktet ble sendt gjennom en silikagelpute (kloroform som elueringsmiddel). Konsentrasjonen tllvelega 1,10 g (91*) [6-metoksy-2-(4-metoksyfenyl )-3-(4-hydroksy)fenoksy]benzo[b]tiofen som et hvitt faststoff. Smp. 123-126<*>C. <X>H NMR (DMS0-d6) d 9,10 (s, 1H), 7,59 (d, J=8,8Hz, 2H), 7,52 (d, J=2,l Hz, 1H), 7,14 (d, J-(,8Hz, 1H), 6,95 (d, J=8,8Hz, 2H), 6,89 (dd, J=8,8, 2,1Hz, 1H), 6,72 (d, J-9.0HZ, 2H), 6,63 (d, J=9,0Hz, 2H), 3,78 (s, 3H), 3,72 (s, 3H), FD massespekter: 378. Analyse beregnet for C22<H>1804S: C, 69,82; H, 4,79. Funnet; C, 70,06; H, 4,98. 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 ethyl acetate and 10 mL 1 * concentrated hydrochloric acid 1 ethanol, 10* palladium-on-carbon (300 mg) was added. The mixture was hydrogenated at 40 psi for 20 minutes, after the reaction was complete by thin layer chromatography. The mixture was passed through a cell to remove the catalyst and the filtrate was concentrated in vacuo to a white solid. The crude product was passed through a pad of silica gel (chloroform as eluent). The concentration amounted to 1.10 g (91*) [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene as a white solid. Temp. 123-126<*>C. <X>H NMR (DMS0-d6) d 9.10 (s, 1H), 7.59 (d, J=8.8Hz, 2H), 7.52 (d, J=2.1Hz, 1H) , 7.14 (d, J-(,8Hz, 1H), 6.95 (d, J=8.8Hz, 2H), 6.89 (dd, J=8.8, 2.1Hz, 1H), 6.72 (d, J-9.0HZ, 2H), 6.63 (d, J=9.0Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), FD mass spectrum: 378. Analysis calcd for C22<H>1804S: C, 69.82; H, 4.79. Found; C, 70.06; H, 4.98.

Tflraem pRl 1 fl Tflraem pRl 1 fl

[6-metoksy-3- [4- [2-( 1-piperidinyl Jetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen [6-Methoxy-3- [4- [2-( 1-piperidinyl Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

Til en oppløsning av [6-metoksy-2-(4-metoksyfenyl)-3-( 4-hydroksyJfenoksy]benzo[b]tiofen (1,12 g, 2,97 mmol) i 7 ml vannfri N,N-dImetylformamid under N2 ble det tilsatt cesiumkarbonat (3,86 g, 11,88 mmol). Etter omrøring i 10 minutter, ble 2-kloretylpiperidin hydroklorid (1,10 g, 1,48 mmol) tilsatt. Den resulterende blandingen ble omrørt i 18 timer ved omgivelsestemperatur. Reaksjonen ble skilt mellom kloroform/vann (hver 100 ml). Lagene ble separert og det vandige laget ble ekstrahert med kloroform (3 x 50 ml). De organiske lagene ble kombinert og vasket med vann (2 x 100 ml). Tørking av det organiske (natriumsulfat) og konsentrasjon ga en olje som ble kromatografert på silikagel (2* metanol/kloroform). De ønskede fraksjonene ble konsentrert til en olje som ble oppløst i 10 ml etylacetat og behandlet med oksalsyre (311 mg, 3,4 mmol). Etter omrøring 1 10 minutter ble en hvit utfelling dannet og oppsamlet ved filtrering og tørket for å gi 1,17 g (70*) totalt av [6-metok sy- 3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-metoksyfenyl)] benzo [b] tiof en som oksalatsaltet. Smp. 197-200<*>C (dek.). H NMR (DMS0-d6) d 7,60 (d, J=8,7Hz, 2H), 7,55 (d, J-l.lHz, 1H), 7,14 (d, J=8,8Hz, 1H), 7,06 (d, J=8,8Hz, 2H), 6,91 (dd, J-8,8, 1,1Hz, 1H), 6,87 (s, 4H), 4,19 (bred t, 2H), 3,78 (s, 3H), 3,72 (s, 3H), 3,32 (bred t, 2H), 3,12-3,06 (m, 4H), 1,69-1,47 (m, 4H), 1,44-1,38 (m, 2H). FD massespekter: 489. Analyse beregnet for C29H31NO4S' 0,88 H02CC02H: C, 64,95; H, 5,80; N, 2,46. Funnet: C, 64,92; H, 5,77; N, 2,54. To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-( 4-hydroxyJphenoxy]benzo[b]thiophene (1.12 g, 2.97 mmol) in 7 mL of anhydrous N,N-dimethylformamide under N2 was added cesium carbonate (3.86 g, 11.88 mmol). After stirring for 10 min, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) was added. The resulting mixture was stirred for 18 h at ambient temperature. The reaction was partitioned between chloroform/water (each 100 mL). The layers were separated and the aqueous layer was extracted with chloroform (3 x 50 mL). The organic layers were combined and washed with water (2 x 100 mL). Drying of the organic (sodium sulfate) and concentration gave an oil which was chromatographed on silica gel (2* methanol/chloroform). The desired fractions were concentrated to an oil which was dissolved in 10 ml of ethyl acetate and treated with oxalic acid (311 mg, 3.4 After stirring for 1 10 minutes, a white precipitate formed and was collected by filtration and dried to give 1.17 g (70*) in total of [6-methoxy sy- 3-[4-[2-(1-p iperidinylJetoxy]phenoxy]-2-(4-methoxyphenyl)] benzo [b]thiophene as the oxalate salt. Temp. 197-200<*>C (dec.). H NMR (DMS0-d6) d 7.60 (d, J=8.7Hz, 2H), 7.55 (d, J-1.1Hz, 1H), 7.14 (d, J=8.8Hz , 1H), 7.06 (d, J=8.8Hz, 2H), 6.91 (dd, J-8.8, 1.1Hz, 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 spectrum: 489. Analysis calculated for C29H31NO4S' 0.88 H02CC02H: C, 64.95; H, 5.80; N, 2.46. Found: C, 64.92; H, 5.77; N, 2.54.

Eksem pel 11 Example number 11

Behandling med fri base med etyleter■hydrokloridsyre ga [6-metoksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen hydroklorid Treatment of the free base with ethyl ether·hydrochloric acid gave [6-methoxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-(4-methoxyphenyl )]benzo[b]thiophene hydrochloride

Smp. 216-220'C. <*>H NMR (DMS0-d6J d 10,20 (bs, 1EJ, 7,64 (d, J-8,7Hz, 2H), 7,59 (d, J=l,5Hz, 1H), 7,18 (d, J=9,0Hz, 1H), 7,00 (d, J=8,7Hz, 1H), 6,96 (dd, J=9,0, 1,5Hz, 1H), 6,92 (q, JAB=9,0Hz, 4H), 4,31 (m, 2H), 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 massespekter: 489. Analyse beregnet for Cjjgfi^iNC^S' 1,0 HC1: C, 66,21; H, 6,13; N, 2,66. Funnet: C, 66,46; H, 6,16; N; 2,74. Temp. 216-220'C. <*>H NMR (DMSO-d6J d 10.20 (bs, 1EJ, 7.64 (d, J-8.7Hz, 2H), 7.59 (d, J=1.5Hz, 1H), 7, 18 (d, J=9.0Hz, 1H), 7.00 (d, J=8.7Hz, 1H), 6.96 (dd, J=9.0, 1.5Hz, 1H), 6.92 (q, JAB=9.0Hz, 4H), 4.31 (m, 2H), 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 spectrum: 489. Analysis calcd for Cjjgfi^iNC^S' 1.0 HCl: C, 66.21; H, 6.13; N, 2.66. Found: C, 66.46; H, 6.16; N, 2.74.

Fremstilt på analog måte var de følgende eksempler: Produced in an analogous way, the following examples were:

Eksempel 12 [ 6-metoksy-3-[4-[2-(1-pyrrolidinylJetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen Example 12 [6-Methoxy-3-[4-[2-(1-pyrrolidinylJetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

Smp. 95-98'C. ^ NMR (DMSO-d6) d 7,64 (d, J-9,0Hz, 2H), 7,58 (d, J=2,0Hz, 1H), 7,18 (d, J=9,0Hz, 1H), 7,00 (d, J-9.0H.Z, 2H), 6,94 (dd, J-9,0, 2,0Hz, 1H), 6,86 (s, 4H), 3,97 (t, J=6,0Hz, 2H), 3,83 (s, 3H), 3,76 (s, 3H) , 2,73 (t, J=6,0Hz, 2E), 2,51 (m, 4H), 1,66 (m, 4H). FD massespekter: 477. Analyse beregnet for C<ggE>tøgNC^S: C, 70,71; H, 6,15; N, 2,99. Funnet: C, 70,59; H, 6,15; N, 3,01. Temp. 95-98'C. ^ NMR (DMSO-d6) d 7.64 (d, J-9.0Hz, 2H), 7.58 (d, J=2.0Hz, 1H), 7.18 (d, J=9.0Hz, 1H), 7.00 (d, J-9.0H.Z, 2H), 6.94 (dd, J-9.0, 2.0Hz, 1H), 6.86 (s, 4H), 3.97 (t , J=6.0Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H) , 2.73 (t, J=6.0Hz, 2E), 2.51 (m, 4H ), 1.66 (m, 4H). FD mass spectrum: 477. Analysis calculated for C<ggE>tøgNC^S: C, 70.71; H, 6.15; N, 2.99. Found: C, 70.59; H, 6.15; N, 3.01.

Eksempel 13 Example 13

[6-metoksy-3-[4-[2-(1-heksametylenimino Jetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid [6-Methoxy-3-[4-[2-(1-hexamethyleneimino Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 189-192-C. ^ NMR (DMS0-d6) d 10,55 (bs, 1H), 7,64 (d, J=9,0Hz, 2H), 7,58 (d, J-2,0Hz, 1H), 7,19 (d, J-9,0Hz, 1HJ, 7,00 (d, J-9,0Hz, 2H), 6,95 (dd, J-9,0, 2,0Hz, H), 6,86 (s, 4H), 3,94 (t, J=6,0Hz, 2H), 3,83 (s, 3H), 3,76 (s, 3H), 2,80 (t, J=6,0Hz, 2H), 2,66 (m, 4H), 1,53 (m, 8H). Analyse beregnet for C30<H>33<N>04S-1,0 HC1: C, 66,71; H, 6,35; N, 2,59. Funnet: C, 66,43; H, 6,46; N, 2,84. Temp. 189-192-C. ^ NMR (DMS0-d6) d 10.55 (bs, 1H), 7.64 (d, J=9.0Hz, 2H), 7.58 (d, J-2.0Hz, 1H), 7.19 (d, J-9.0Hz, 1HJ, 7.00 (d, J-9.0Hz, 2H), 6.95 (dd, J-9.0, 2.0Hz, H), 6.86 (s , 4H), 3.94 (t, J=6.0Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J=6.0Hz, 2H ), 2.66 (m, 4H), 1.53 (m, 8H). Analysis calcd for C30<H>33<N>04S-1.0 HCl: C, 66.71; H, 6.35; N, 2.59 Found: C, 66.43, H, 6.46, N, 2.84.

Eksempel 14 Example 14

[ 6-metoksy-3- [4-[2-(l-N, N-dietylamino )etoksy] fenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid [6-Methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 208-211<e>C. * E NMR (DMSO-d6) d 10,6 (bs, 1H), 7,63 (d, J=9,0Hz, 2H), 7,60 (d, J=2,0Hz, 1H), 7,20 (J=9,0Hz, 1H), 7,00{d, J-9.0HZ, 2H), 6,97 (dd, J=9,0, 2,0Hz, 1H), 6,91 (q, JAB= 9,0Hz, 4H), 4,29 (m, 2H), 4,08-3,91 (m, 4H), 3,82 (s, 3H), 3,7 (s, 3H), 3,59-3,42 (m, 4H), 3,21-3,10 (m, 2H). Analyse beregnet for C28<H>29N05S-1,0 HC1: C, 63,09; H, 5,73; N, 2,65. Funnet: C, 63,39; H, 5,80; N, 2,40. Temp. 208-211<e>C. * E NMR (DMSO-d6) d 10.6 (bs, 1H), 7.63 (d, J=9.0Hz, 2H), 7.60 (d, J=2.0Hz, 1H), 7, 20 (J=9.0Hz, 1H), 7.00{d, J-9.0HZ, 2H), 6.97 (dd, J=9.0, 2.0Hz, 1H), 6.91 (q, JAB= 9.0Hz, 4H), 4.29 (m, 2H), 4.08-3.91 (m, 4H), 3.82 (s, 3H), 3.7 (s, 3H), 3 .59-3.42 (m, 4H), 3.21-3.10 (m, 2H). Analysis calcd for C28<H>29N05S-1.0 HCl: C, 63.09; H, 5.73; N, 2.65. Found: C, 63.39; H, 5.80; N, 2.40.

Blcaem pel 15 Blcaem pel 15

[6-metoksy-3 - [4 - [2 - (mor f olino )etoksy] fenoksy] -2-( 4-metoksyfenyl)]benzo[b]tiofen hydroklorid [6-Methoxy-3 - [4 - [2 - (mor f olino )ethoxy] phenoxy] -2-( 4-methoxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 208-2ll*C. ^-H-NMR (DMS0-D6) d 10,6 (bs, 1H), 7,63 (d, J=9,0Hz, 2H), 7,60 (d, J=2,0Hz, 1H), 7,20 (J=9,0Hzf 1H), 7,00 Temp. 208-211*C. ^-H-NMR (DMS0-D6) d 10.6 (bs, 1H), 7.63 (d, J=9.0Hz, 2H), 7.60 (d, J=2.0Hz, 1H), 7.20 (J=9.0Hzf 1H), 7.00

(d, J=9,0Hz, 2,H), 6,97 (dd, J=9,0, 2,0Hz, 1H), 6,91 (q, JAB=9,0Hz, 4H), 4,29 (m, 2H), 4,08-3,91 (m, 4H), 3,81 (s, 3H), 3,77 (s, 3H), 3,59-3,42 (m, 4H), 3,21-3,10 (m. 2H). Analyse beregnet for C28<H>29*I05S-1,0 HC1: C, 63,09; H, 5,73; N, 2,65. Funnet; C, 63,39; H, 5,80; N, 2,40. (d, J=9.0Hz, 2.H), 6.97 (dd, J=9.0, 2.0Hz, 1H), 6.91 (q, JAB=9.0Hz, 4H), 4, 29 (m, 2H), 4.08-3.91 (m, 4H), 3.81 (s, 3H), 3.77 (s, 3H), 3.59-3.42 (m, 4H) , 3.21-3.10 (m. 2H). Analysis calcd for C28<H>29*I05S-1.0 HCl: C, 63.09; H, 5.73; N, 2.65. Found; C, 63.39; H, 5.80; N, 2.40.

TCIc gfim pel 1 h TCIc gfim pel 1 h

[6-metoksy-3- [4 - [3-( piperidino Jpropoksy] fenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid [6-Methoxy-3- [4 - [3-(piperidino Jpropoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 195-200<*>C. Ifi-NMR DMS0-d6) d 9,90 (bs, 1H), 7,64 (d, J=9,0Hz, 2H), 7,59 (d, J=2,0Hz, 1H), 7,18 (d, J=9,0Hz, 1H), 7,00 (d, J=9,0Hz, 2H), 6,95 (dd, J=9,0, 2,0Hz, 1H), 6,88 (s, 4H), 3,97 (t, J=6,0Hz, 2H), 3,83 (s, 3H), 3,77 (s, 3H), 3,44 (m, 2H), 3,15 (m, 2H), 2,87 (m, 2H), 2,12 (m, 2H), 1,77 (m, 5H), 1,39 (m, 1H). Analyse beregnet for C30<H>33N04S-1,15 HC1: C, 66,01; H, 6,40; N, 2,73. Funnet: C, 66,01; H, 6,40; N, 2,73. Temp. 195-200<*>C. Ifi-NMR DMS0-d6) d 9.90 (bs, 1H), 7.64 (d, J=9.0Hz, 2H), 7.59 (d, J=2.0Hz, 1H), 7.18 (d, J=9.0Hz, 1H), 7.00 (d, J=9.0Hz, 2H), 6.95 (dd, J=9.0, 2.0Hz, 1H), 6.88 ( s, 4H), 3.97 (t, J=6.0Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.44 (m, 2H), 3.15 (m, 2H), 2.87 (m, 2H), 2.12 (m, 2H), 1.77 (m, 5H), 1.39 (m, 1H). Analysis calcd for C30<H>33N04S-1.15 HCl: C, 66.01; H, 6.40; N, 2.73. Found: C, 66.01; H, 6.40; N, 2.73.

Eksempel 17 Example 17

[6-metoksy-3-[4-[3-(1-N,N-dietylamino Jpropoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid [6-Methoxy-3-[4-[3-(1-N,N-diethylamino Jpropoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 164-166'C. <*>H NMR (DMSO-d6) d 9,77 (bs, 1H), 7,64 (d, J=9,0Hz, 2H), 7,59 (d, J=2,0Hz, 1H), 7,18 (d, J=9,0Hz, 1H), 7,00 (d, J=9,0Hz, 2H), 6,95 (dd, J=9,0, 2,0Hz, 1H), 6,89 (s, 4H), 3,99 (t, J=6,0Hz, 2H), 3,83 (s, 3H), 3,77 (s, 3H), 3,15 (m, 6H), 2,06 (m, 2H), 1,20 (t, J=7,0Hz, 6H). Analyse beregnet for C29<H>33<N>04S-1,0 HC1: C, 65,96; H, 6,49; N, 2,65. Funnet: C, 66,25; H, 6,64; N, 2,84. Temp. 164-166'C. <*>H NMR (DMSO-d6) d 9.77 (bs, 1H), 7.64 (d, J=9.0Hz, 2H), 7.59 (d, J=2.0Hz, 1H), 7.18 (d, J=9.0Hz, 1H), 7.00 (d, J=9.0Hz, 2H), 6.95 (dd, J=9.0, 2.0Hz, 1H), 6 .89 (s, 4H), 3.99 (t, J=6.0Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.15 (m, 6H), 2.06 (m, 2H), 1.20 (t, J=7.0Hz, 6H). Analysis calcd for C 29<H>33<N>O 4 S-1.0 HCl: C, 65.96; H, 6.49; N, 2.65. Found: C, 66.25; H, 6.64; N, 2.84.

Eksempel 18 Example 18

[6-hydroksy-3-[4-[2-(1-piperIdinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen [6-Hydroxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-metoksy-3- [4 - [ 2- (1-piperidinyl Jetoksy] fenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid (10,00 g, 19,05 mmmol) ble oppløt i 500 ml vannfri metylenklorid og avkjølt til 8'C. Til denne oppløsningen ble det tilsatt bortribromid (7,20 ml, 76,20 mmol). Den resulterende blandingen ble omrørt ved 8<*>C i 2,5 timer. Reaksjonen ble stanset ved å helle den i en omrørt oppløsning av mettet natriumbikarbonat (1 1), avkjølt til 0°C. Metylenkloridlaget ble separert og gjenværende faststoff ble oppløst i metylen/etylacetat. Det vandige laget ble ekstrahert med 5* etanol/etylacetat (3 x 500 ml). Alle de organiske ekstraktene (etylacetat og metylenklorid) ble slått sammen og tørket (natriumsulfat). Konsentrasjon under vakuum ga et lysebrunt faststoff som ble kromatografert (sllisiumdioksyd, 1-7* metanol/kloroform) for å gi 7,13 g (81*) [6-hydroksy-3-[4-[2-(l-piperidinyl)etoksy]-fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen som et hvitt faststoff. Smp. 93<*>C. <*>E NMR (DMS0-d6) d 9,73 (bs, 1E), 9,68 (s, 1H), 7,45 (d, J-8,6Hz, 2E), 7,21 (d, J=l,8Hz, 1H), 7,04 (d, J-8,6Ez, 1H), 6,84 (dd, J-8,6, 1,8Hz, 1H (maskert)), 6,81 [6-Methoxy-3- [4-[ 2-(1-piperidinyl Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride (10.00 g, 19.05 mmol) was dissolved in 500 mL of anhydrous methylene chloride and cooled to 8°C. To this solution was added boron tribromide (7.20 mL, 76.20 mmol). The resulting mixture was stirred at 8<*>C for 2.5 hours. The reaction was quenched by pouring it into a stirred solution of saturated sodium bicarbonate (1 L), cooled to 0°C. The methylene chloride layer was separated and the remaining solid was dissolved in methylene/ethyl acetate. The aqueous layer was extracted with 5* ethanol/ethyl acetate (3 x 500 (ml). All the organic extracts (ethyl acetate and methylene chloride) were combined and dried (sodium sulfate). Concentration under vacuum gave a light brown solid which was chromatographed (silica, 1-7* methanol/chloroform) to give 7.13 g ( 81*) [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene as a white solid, mp 93<* >C. <*>E NMR (DMS0-d6) d 9.73 (bs , 1E), 9.68 (s, 1H), 7.45 (d, J-8.6Hz, 2E), 7.21 (d, J=1.8Hz, 1H), 7.04 (d, J -8.6Ez, 1H), 6.84 (dd, J-8.6, 1.8Hz, 1H (masked)), 6.81

(s, 4H), 6,75 (d, J=8,6Hz, 2H), 3,91 (t, J=5,8Hz, 2H), 2,56 (t, J-5,8Hz, 2H), 2,36 (m, 4H), 1,43 (m, 4H), 1,32 (m, 2H). FD massespekter: 462. Analyse beregnet for C27<H>27NO4S: C,70,20;H, 5,90; N, 3,03. Funnet: C, 69,96; H, 5,90; N, 3,14. (s, 4H), 6.75 (d, J=8.6Hz, 2H), 3.91 (t, J=5.8Hz, 2H), 2.56 (t, J-5.8Hz, 2H) , 2.36 (m, 4H), 1.43 (m, 4H), 1.32 (m, 2H). FD mass spectrum: 462. Analysis calculated for C27<H>27NO4S: C, 70.20; H, 5.90; N, 3.03. Found: C, 69.96; H, 5.90; N, 3.14.

Eksempel 19 Example 19

[6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen omdannet til dets oksalatsalt med 805*) ved prosedyren beskrevet ovenfor. Data for [6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofenoksalat [6-Hydroxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene converted to its oxalate salt with 805*) by the procedure described above. Data for [6-hydroxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenoxalate

Smp. 246-249'C (dek.). <*>H NMR (DMS0-d6) d 7,45 (d, J=8,6Ez, 2H), 7,22 (d, J=l,8Hz, 1H), 7,05 (d, J=8,6Hz, 1H), 6,87 (dd, J=8,6, 1,8Hz, 1H (maskert)), 6,84 (s, 4H), 6,75 (d, J=8,6Ez, 2E), 4,08 (bt, 2H), 3,01 (bt, 2H), 2,79 (m, 4E), 1,56 (m, 4E), 1,40 (m, 2E). FD massespekter: 462. Analyse beregnet for <C>27<H>27N04S'0,75 E02CC02E: C, 64,63; H, 5,42; N, 2,64. Funnet: C, 64,61; H, 5,55; N, 2,62. Temp. 246-249'C (dec.). <*>H NMR (DMS0-d6) d 7.45 (d, J=8.6Ez, 2H), 7.22 (d, J=1.8Hz, 1H), 7.05 (d, J=8 ,6Hz, 1H), 6.87 (dd, J=8.6, 1.8Hz, 1H (masked)), 6.84 (s, 4H), 6.75 (d, J=8.6Ez, 2E ), 4.08 (bt, 2H), 3.01 (bt, 2H), 2.79 (m, 4E), 1.56 (m, 4E), 1.40 (m, 2E). FD mass spectrum: 462. Analysis calculated for <C>27<H>27N04S'0.75 E02CC02E: C, 64.63; H, 5.42; N, 2.64. Found: C, 64.61; H, 5.55; N, 2.62.

Eksempel 20 Example 20

[6-hydroksy-3-[4-[2-(l-pIperidinyl)etoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen ble omdannet til dets hydrokloridsalt med 91* utbytte ved behandling av den fri basen i etylacetat med etyleter■saltsyre. Data for [6-hydroksy-3-[4-[2-( 1-piperIdinylJetoksy]fenoksy]-2-(4-hydroksyfenylJ]benzo-[b]tiofen hydroklorid [6-Hydroxy-3-[4-[2-(1-pIperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene was converted to its hydrochloride salt in 91* yield by treatment of the free the base in ethyl acetate with ethyl ether■hydrochloric acid. Data for [6-hydroxy-3-[4-[2-( 1-piperIdinylJethoxy]phenoxy]-2-(4-hydroxyphenylJ)benzo-[b]thiophene hydrochloride

Smp. 158-165'C. ^ NMR (DMS0-d6) d 9,79 (s, 1H), 9,74 (s, 1H), 7,40 (d, J=8,6Hz, 2H), 7,23 (d, J-2,0Ez, 1H), 7,04 (d, J=8,6Hz, 1H), 6,86 (q, JAB=9,3Hz, 4H), 6,76 (dd, J=8,6, 2,0Hz, 1), 6,74 (d, J=8,6Hz, 2H), 4,26 (bt, 2H), 3,37 (m, 4E), 2,91 (m, 2H), 1,72 (m, 5H), 1,25 (m, 1H). FD massespekter: 461. Analyse beregnet for C27<H>27<N>04S<*>1,0 HC1: C, 65,11; H, 5,67; N, 2,81. Funnet: C, 64,84; H, 5,64; N, 2,91. Temp. 158-165'C. ^ NMR (DMSO-d6) d 9.79 (s, 1H), 9.74 (s, 1H), 7.40 (d, J=8.6Hz, 2H), 7.23 (d, J-2 ,0Ez, 1H), 7.04 (d, J=8.6Hz, 1H), 6.86 (q, JAB=9.3Hz, 4H), 6.76 (dd, J=8.6, 2, 0Hz, 1), 6.74 (d, J=8.6Hz, 2H), 4.26 (bt, 2H), 3.37 (m, 4E), 2.91 (m, 2H), 1.72 (m, 5H), 1.25 (m, 1H). FD mass spectrum: 461. Analysis calculated for C27<H>27<N>04S<*>1.0 HC1: C, 65.11; H, 5.67; N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.

Eksempel 21 [6-hydroksy-3-[4-[2-(1-pyrrolidinylJetoksy]fenoksy]-2-( 4-hydroksyfenyl)]benzo[b]tiofen Example 21 [6-hydroxy-3-[4-[2-(1-pyrrolidinylJetoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

Smp. 99-113'C. <*>H NMR (DMS0-d6) d 9,75 (s, 1H), 9,71 (s, 1H), 7,50 (d, J = 9,0Hz, 2H), 7,25 (d, J=2,0Hz, 1H), 7,09 (d, J=9,0Hz, 1HJ, 6,85 (s, 1H), 6,80 (dd, J-9,0, 2,OEz, 1H), 6,79 (d, J=9,0Ez, 2HJ, 3,93 (m, 2H), 2,73 (m, 2H), 2,53 (m, 4H), 0,96 (t, J=7,0Hz, 4H). Analyse beregnet for C26<H>25N04S<*>0»5 H20: C, 68,40; H, 5,74; N, 3,07. Funnet: C, 68,52; H, 6,00; N, 3,34. Temp. 99-113'C. <*>H NMR (DMS0-d6) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0Hz, 2H), 7.25 (d, J=2.0Hz, 1H), 7.09 (d, J=9.0Hz, 1HJ, 6.85 (s, 1H), 6.80 (dd, J-9.0, 2.OEz, 1H) , 6.79 (d, J=9.0Ez, 2HJ, 3.93 (m, 2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 (t, J= 7.0Hz, 4H). Analysis calcd for C26<H>25N04S<*>0»5 H2O: C, 68.40; H, 5.74; N, 3.07. Found: C, 68.52; H , 6.00; N, 3.34.

Eksempel 22 Example 22

[6-hydroksy-3-[4- [2-( 1-heksametylenimino )etoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen [6-hydroxy-3-[4- [2-( 1-hexamethyleneimino )ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

Smp. 125-130'C. % NMR (DMSO-d6) d 9,75 (s, 1H), 9,71 (s, 1H), 7,50 (d, J=9,0Hz, 2H), 7,26 (d, J=2,0Ez, 1H), 7,09 (d, J=9,0Hz, 1H), 6,85 (s, 3H), 6,80 (dd, J-9,0, 2,0Hz, 1H), 6,79 (d, J=9,0Hz), 3,94 (t, J=6,0Hz, 2H), 2,80 (t, J=6,0Hz, 2H), 2,66 (m, 4H), 1,53 (m, 8H). Analyse beregnet for C28<H>29NO4S: C, 70,71; H, 6,15; N, 2,94. Funnet: C, 70,67; H, 6,31; N, 2,93. Temp. 125-130'C. % NMR (DMSO-d6) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J=9.0Hz, 2H), 7.26 (d, J=2 ,0Ez, 1H), 7.09 (d, J=9.0Hz, 1H), 6.85 (s, 3H), 6.80 (dd, J-9.0, 2.0Hz, 1H), 6 .79 (d, J=9.0Hz), 3.94 (t, J=6.0Hz, 2H), 2.80 (t, J=6.0Hz, 2H), 2.66 (m, 4H) , 1.53 (m, 8H). Analysis calculated for C28<H>29NO4S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.67; H, 6.31; N, 2.93.

TCkaem pel 23 TCkaem pel 23

[6-hy drok sy-3-[4-[2-(1-N,N-dletylamino)etoksy]fenoksy]-2-84-hydroksyfenyl)]benzo[b]tiofen [6-hydroxy-3-[4-[2-(1-N,N-dletylamino)ethoxy]phenoxy]-2-84-hydroxyphenyl)]benzo[b]thiophene

Smp. 137-141'C. XE NMR (DMS0-d6) d 9,75 (s, 1H), 9,71 (s, 1H), 7,49 (J=9,0Hz, 1H), 7,25 (d, J=2,0Hz, 1H), 7,09 (d, J=9,0Hz, 1H), 6,85 (s, 4H), 6,80 (dd, J=9,0, 2,0Hz, 1H), 6,79 (d, J=9,0Hz, 2H), 3,95 (t, J=6,0Hz, 2H), 2,74 (t, J=6,0Hz, 2H), 2,51 (m, 4H), 1,66 (m, 6H). Analyse beregnet for C26H27N04S: c- 69,46; H, 6,05; N, 3,12. Funnet: C, 69,76; H, 5,85; N, 3,40. Temp. 137-141'C. XE NMR (DMS0-d6) d 9.75 (s, 1H), 9.71 (s, 1H), 7.49 (J=9.0Hz, 1H), 7.25 (d, J=2.0Hz , 1H), 7.09 (d, J=9.0Hz, 1H), 6.85 (s, 4H), 6.80 (dd, J=9.0, 2.0Hz, 1H), 6.79 (d, J=9.0Hz, 2H), 3.95 (t, J=6.0Hz, 2H), 2.74 (t, J=6.0Hz, 2H), 2.51 (m, 4H) , 1.66 (m, 6H). Analysis calculated for C26H27N04S: c- 69.46; H, 6.05; N, 3.12. Found: C, 69.76; H, 5.85; N, 3.40.

Eksempel 24 Example 24

[6-hydroksy-3-[4-[2-(morfolino )etoksy]fenoksy]-2-(4-hydroksy-fenyl)]benzo[b]tiofen hydroklorid [6-hydroxy-3-[4-[2-(morpholino )ethoxy]phenoxy]-2-(4-hydroxy-phenyl)]benzo[b]thiophene hydrochloride

Smp. 157-162°C. <1>H NMR (DMS0-D6) d 10,60 (bs, 1H), 9,80 (s, 1H), 9,75 (s, 1H), 7,50 (d, J-9,0Hz, 2H), 7,28 (d, J=2,0Hz, 1H), 7,10 (d, J=9,0Hz, 1H), 6,92 (q, JAB~9,0Hz, 4H), 6,81 (dd, J=9,0, 2,0Hz, 1H), 6,80 (d, J=9,0Hz, 2H), 4,30 (m, 2H), 3,95 (m, 2H), 3,75 (m, 2H), 3,51 (m, 4H), 3,18 (m, 2H). Analyse beregnet for C26H25N05S-HC1: C, 62,46; H, 5,24; N, 2,80. Funnet: C, 69,69; H, 5,43; N, 2,92. Temp. 157-162°C. <1>H NMR (DMS0-D6) d 10.60 (bs, 1H), 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d, J-9.0Hz, 2H), 7.28 (d, J=2.0Hz, 1H), 7.10 (d, J=9.0Hz, 1H), 6.92 (q, JAB~9.0Hz, 4H), 6, 81 (dd, J=9.0, 2.0Hz, 1H), 6.80 (d, J=9.0Hz, 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51 (m, 4H), 3.18 (m, 2H). Analysis calcd for C 26 H 25 NO 5 S-HCl: C, 62.46; H, 5.24; N, 2.80. Found: C, 69.69; H, 5.43; N, 2.92.

TClc<g>fimpel 25 TClc<g>fiddle 25

[ 6-hydr oksy-3 - [4-[3-(l-N .N-dietylamino Jpropoksy] fenoksy] -2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid [ 6-hydroxy-3 - [4-[3-(1-N .N-diethylamino Jpropoxy] phenoxy] -2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 185-191° C. ^-H NMR (DMS0-d6) d 9,94 (bs, 1H), 9,81 (s, 1H), 9,75 (s, 1H), 7,50 (d, J=9,0Hz, 2H), 7,27 (dd, J-2,0Hz, 1H), 7,10 (d, J=9,0Hz, 1H), 6,87 (s, 4H), 6,80 (dd, J-9,0, 2,0Hz, 1H), 6,79 (d, J-9,0Hz, 2H), 3,99 (t, J=6,0Hz, 2H), 3,14 (m, 6H), 2,08 (m, 2H), 1,20 (t, J=6,0Hz, 6H). Analyse beregnet for C27<H>29<N>04S-1,30 HC1: C, 63,46; H, 5,98; N; 2,74. Funnet: C, 63,23; H, 6,03; N, 3,14. Temp. 185-191° C. 3-H NMR (DMS0-d6) d 9.94 (bs, 1H), 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d, J =9.0Hz, 2H), 7.27 (dd, J-2.0Hz, 1H), 7.10 (d, J=9.0Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J-9.0, 2.0Hz, 1H), 6.79 (d, J-9.0Hz, 2H), 3.99 (t, J=6.0Hz, 2H), 3.14 ( m, 6H), 2.08 (m, 2H), 1.20 (t, J=6.0Hz, 6H). Analysis calculated for C27<H>29<N>O4S-1.30 HCl: C, 63.46; H, 5.98; N; 2.74. Found: C, 63.23; H, 6.03; N, 3.14.

Eksempel 26 Example 26

[6-hydr ok sy-3-[4-[2-(1-N,N-di i sopropylamino Jetoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid [6-hydroxy-3-[4-[2-(1-N,N-diisopropylamino]ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 128-131<*>C. <*>H NMR (DMS0-d6) d 9,81 (bs, 1H), 9,76 (s, 1H), 9,02 (s, 1H), 7,49 (d, J=9,0Hz, 2H), 7,28 (m, 1H), 7,09 (d, J=9,0Hz, 1H), 6,90 (s, 4H), 6,79 (m, 3H), 4,19 (m, 2H), 3,68 (m, 2H), 3,50 (m, 2H), 1,31 (m, 12H). Analyse beregnet for C28<H>31N04S-1,33 HC1: C, 63,92; H, 6,19; N, 2,66. Funnet: C, 63,81; H, 6,53; N, 2,61. Temp. 128-131<*>C. <*>H NMR (DMS0-d6) d 9.81 (bs, 1H), 9.76 (s, 1H), 9.02 (s, 1H), 7.49 (d, J=9.0Hz, 2H), 7.28 (m, 1H), 7.09 (d, J=9.0Hz, 1H), 6.90 (s, 4H), 6.79 (m, 3H), 4.19 (m , 2H), 3.68 (m, 2H), 3.50 (m, 2H), 1.31 (m, 12H). Analysis calcd for C28<H>31N04S-1.33 HCl: C, 63.92; H, 6.19; N, 2.66. Found: C, 63.81; H, 6.53; N, 2.61.

Eksempel 27 Example 27

[ 6-hydroksy-3 - [4 - [ 3- (piperidino )propoksy] fenoksy] -2-( 4-hydroksyfenyl)]benzo[b]tiofen hydroklorid [ 6-hydroxy-3 - [4 - [ 3-(piperidino )propoxy] phenoxy] -2-( 4-hydroxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 258-262'C. ^ NMR (DMSO-d6) d 9,85 (bs, 1H), 9,81 (s, 1H), 9,75 (s, 1H), 7,50 (d, J=9,0Hz, 2H), 7,27 (d, J=2,0, 1H), 7,10 (d, J=9,0Hz, 1H), 6,87 (s, 4H), 6,80 (dd, J=9,0, 2,0Hz, 1H), 6,79 (d, J=9,0Hz, 2H), 3,97 (t, J=6,0Hz, 2H), 3,44 (m, 2H), 3,15 (m, 2H), 2,88 (m, 2H), 2,11 (m, 2H), 1,73 (m, 5H), 1,39 (m, 1H). Analyse beregnet for C28H2gN04S-0,75 HC1: C, 66,87; H, 5,96; N, 2,78. Funnet: C, 67,04; H, 5,90; N, 2,68. Temp. 258-262°C. ^ NMR (DMSO-d6) d 9.85 (bs, 1H), 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d, J=9.0Hz, 2H), 7.27 (d, J=2.0, 1H), 7.10 (d, J=9.0Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J=9.0 , 2.0Hz, 1H), 6.79 (d, J=9.0Hz, 2H), 3.97 (t, J=6.0Hz, 2H), 3.44 (m, 2H), 3.15 (m, 2H), 2.88 (m, 2H), 2.11 (m, 2H), 1.73 (m, 5H), 1.39 (m, 1H). Analysis calcd for C 28 H 2 g NO 4 S-0.75 HCl: C, 66.87; H, 5.96; N, 2.78. Found: C, 67.04; H, 5.90; N, 2.68.

Alternativt som vist i skjema III ovenfor, ble eksempel 19 fremstilt ved anvendelse av metoksymetyl (MOM) beskyttende grupper 1 stedet for metoksy. Fremgangsmåtene er direkte analoge til de akkurat beskrevet, med unntag av MOM gruppene som ble fjernet i de endelige trinnene ved syrehydrolyse. Alternatively, as shown in Scheme III above, Example 19 was prepared using methoxymethyl (MOM) protecting groups 1 in place of methoxy. The procedures are directly analogous to those just described, with the exception of the MOM groups which were removed in the final steps by acid hydrolysis.

Fremstilling 10 Production 10

[ 6 -metoksy-2-(4-metoksymetyloksyfeny1)-3-(4-benzyloksy )-fenoksy]benzo[b]tiofen [ 6 -Methoxy-2-(4-methoxymethyloxyphenyl)-3-(4-benzyloxy )-phenoxy]benzo[b]thiophene

Smp. 94-96'C. XE NMR (DMS0-d6) d 7,65 (d, J=2,0Hz, 1H), 7,64 (d, J=8,6Hz, 2H), 7,43-7,32 (m, 5H), 7,23 (d, J=8,8Hz, 1H), 7,08 (d, J=8,6Hz, 2H), 7,04 (dd, J=8,8, 2,0Hz, 1H), 6,92 (q, JAB=9,2Hz, 4H), 5,26 (s, 2H), 5,21 (s, 2H) , 5,01 (s, 3H), 3,40 (s, 3H), 3,37 (s, 3H). FD massespekter: 528. Temp. 94-96'C. XE NMR (DMS0-d6) d 7.65 (d, J=2.0Hz, 1H), 7.64 (d, J=8.6Hz, 2H), 7.43-7.32 (m, 5H) , 7.23 (d, J=8.8Hz, 1H), 7.08 (d, J=8.6Hz, 2H), 7.04 (dd, J=8.8, 2.0Hz, 1H), 6.92 (q, JAB=9.2Hz, 4H), 5.26 (s, 2H), 5.21 (s, 2H), 5.01 (s, 3H), 3.40 (s, 3H) , 3.37 (p, 3H). FD mass spectrum: 528.

Fremstilling 11 Production 11

[6-metoksy-2- ( 4-met oksy f eny loksyf enyl)-3-(4-hydroksy )-fenoksy]-benzo[b]tiofen [6-Methoxy-2-(4-Methoxyphenyloxyphenyl)-3-(4-hydroxy)-phenoxy]-benzo[b]thiophene

Smp. 90-91'C. <X>H NMR (DMSO-d6) d 9,15 (s, 1H), 7,65 (d, J=8,lHz, 2H), 7,63 (d, J=2,0Hz, 1H), 7,22 (d, J=8,8Ez, 1H), 7,05 (dd, J=8,8, 2,0Ez, 1E), 6,72 (q, JAB=9,lHz, 4H), 5,26 (s, 2H), 5,21 (s, 2H), 3,40 (s, 3E), 3,37 (s, 3E). FD massespekter: 438. Analyse beregnet for Cg4<H>22°6^: c» 65,74; H, 5,06. Funnet: C, 65,50; E, 4,99. Temp. 90-91'C. <X>H NMR (DMSO-d6) d 9.15 (s, 1H), 7.65 (d, J=8.1Hz, 2H), 7.63 (d, J=2.0Hz, 1H), 7.22 (d, J=8.8Ez, 1H), 7.05 (dd, J=8.8, 2.0Ez, 1E), 6.72 (q, JAB=9.1Hz, 4H), 5 .26 (p, 2H), 5.21 (p, 2H), 3.40 (p, 3E), 3.37 (p, 3E). FD mass spectrum: 438. Analysis calculated for Cg4<H>22°6^: c» 65.74; H, 5.06. Found: C, 65.50; E, 4.99.

Eksempel 28 Example 28

[6-metoksy-2-(4-metoksyfenyl)-3-brom[benzo[b]tiofen-(S-oksyd) [6-Methoxy-2-(4-methoxyphenyl)-3-bromo[benzo[b]thiophene-(S-oxide)

Til en oppløsning av [6-metoksy-2-(4-metoksyfenyl)-3-brom]benzo[b]tiofen (10,0 g, 28,6 mmol) i 50 ml vannfri metylenklorid ble det tilsatt 50 ml trifluoreddiksyre. Etter omrøring i 5 minutter, ble hydrogenperoksyd (4,0 ml, 28,6 mmol, 30* vandig oppløsning), tilsatt. Den resulterende blandingen ble omrørt ved omgivelsestemperatur i 2 timer. Fast natriumbisulf it (1,25 g) ble tilsatt til den mørke oppløsningen fulgt av 15 ml vann. Blandingen ble omrørt kraftig i 15 minutter, så konsentrert under vakuum. Resten ble skilt mellom kloroform, mettet natriumbikarbonatoppløs-nlng (200 ml ea.). Lagene ble separert og det organiske laget ekstrahert med mettet natriumblkarbonatoppløsning. Det organiske laget ble så tørket (natriumsulfat) og konsentrert under vakuum til et faststoff som ble finfordelt fra etyleter/etylacetat. Filtrering ga 8,20 g (80*) [6-metoksy-2-84-metoksyfenyl )-3-brom]benzo[b]tiofen-(S-oksyd) som et gult faststoff som kan bli rekrystallisert fra etylacetat. Smp. 170-173<*>C. <!>h NMR (DMS0-d6) d 7,24 (d, J=2,2Hz, 1H), 7,68 (d, J=8,8Hz, 2H), 7,54 (d, J=8,5Hz, 1H), 7,26 (dd, J-8,5, 2,2Hz, 1H), 7,10 (d, J=8,8Hz, 2H), 3,86 (s, 3H), 3,80 (s, 3H). Analyse beregnet for CifcH^OsSBr: C, 52,62; H, 3,59. Funnet: C, 52,40; H, 3,55. To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (10.0 g, 28.6 mmol) in 50 ml of anhydrous methylene chloride was added 50 ml of trifluoroacetic acid. After stirring for 5 minutes, hydrogen peroxide (4.0 mL, 28.6 mmol, 30% aqueous solution) was added. The resulting mixture was stirred at ambient temperature for 2 hours. Solid sodium bisulphite (1.25 g) was added to the dark solution followed by 15 mL of water. The mixture was stirred vigorously for 15 minutes, then concentrated under vacuum. The residue was separated between chloroform, saturated sodium bicarbonate solution (200 ml each). The layers were separated and the organic layer extracted with saturated sodium bicarbonate solution. The organic layer was then dried (sodium sulfate) and concentrated under vacuum to a solid which was triturated from ethyl ether/ethyl acetate. Filtration gave 8.20 g (80*) [6-methoxy-2-84-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide) as a yellow solid which could be recrystallized from ethyl acetate. Temp. 170-173<*>C. <!>h NMR (DMS0-d6) d 7.24 (d, J=2.2Hz, 1H), 7.68 (d, J=8.8Hz, 2H), 7.54 (d, J=8 ,5Hz, 1H), 7.26 (dd, J-8.5, 2.2Hz, 1H), 7.10 (d, J=8.8Hz, 2H), 3.86 (s, 3H), 3 .80 (p, 3H). Analysis calcd for CifcH^OsSBr: C, 52.62; H, 3.59. Found: C, 52.40; H, 3.55.

Kk stem pel 2Q Kk stem pel 2Q

Fremstilt på analog måte ble [2-(4-metoksyfenyl)-3-brom]-benzo[b]tiofen-(S-oksyd) Prepared in an analogous manner, [2-(4-methoxyphenyl)-3-bromo]-benzo[b]thiophene-(S-oxide)

Smp. 120-125<*>C. lE NMR (DMS0-d6) d 8,06 (d, J=7,6Hz, 1H), 7,78-7,59 (m, 5H), 7,13 (d, J-8,7Hz, 2H), 3,81 (s, 3H). FD massespekter: 335. Analyse beregnet for C^gH^OgSBr: C, 53,75; H, 3,31. Funnet: C, 53,71; H, 3,46. Temp. 120-125<*>C. 1E NMR (DMS0-d6) d 8.06 (d, J=7.6Hz, 1H), 7.78-7.59 (m, 5H), 7.13 (d, J-8.7Hz, 2H) , 3.81 (p, 3H). FD mass spectrum: 335. Analysis calculated for C^gH^OgSBr: C, 53.75; H, 3.31. Found: C, 53.71; H, 3.46.

Fremstillin<g> 12 Manufacture<g> 12

Fremstilling av 4-(2-(1-piperidinylJetoksy)-fenol Preparation of 4-(2-(1-piperidinyljetoxy)-phenol

Til en oppløsning av 4-benzyloksyfenyl (50,50 g, 0,25 mol) i 350 ml vannfri DMF ble det tilsatt 2-kloretylpiperidin (46,30 g, 0,25 mol). Etter omrøring i 10 minutter ble kallumkarbonat (52,Og, 0,375 mol) og ceslumkarbonat (85,0 g, 0,25 mol) tilsatt. Den resulterende heterogene blandingen ble kraftig omrørt ved omgivelsestemperatur i 48 timer. Reaksjonsblandingen ble heilt i vann (500 ml) og ekstrahert med metylenklorid. Det organiske laget ble ekstrahert med IN natriumhydroksyd flere ganger og endelig vasket med saltvann. Det organiske laget ble så tørket (natriumsulfat) og konsentrert under vakuum til en olje. Kromatografi (Si02, 1:1 heksaner/- etylacetat) ga 60,0 g (77*) 4-[2-(1-piperidinylJetoksy]-fenoksybenzyleter som en fargeløse olje. ^-H NMR (DMSO-d^J d 7,40-7,27 (m, 5H), 6,84 (q, JAB=ll,5Hz, 4H), 4,98 (s, 2H), 3,93 (t, J-6,0Hz, 2H), 2,56 (t, J=6,0Hz, 2H), 2,35-2,37 (m, 4H), 1,48-1,32 (m, 6H). FD massespekter: 311. Analyse beregnet for C20H5N02: C, 77,14; H, 8,09; N, 4,50. Funnet: C, 77,34; H, 8,18; N, 4,64. To a solution of 4-benzyloxyphenyl (50.50 g, 0.25 mol) in 350 mL of anhydrous DMF was added 2-chloroethylpiperidine (46.30 g, 0.25 mol). After stirring for 10 minutes, callum carbonate (52.0 g, 0.375 mol) and cesium carbonate (85.0 g, 0.25 mol) were added. The resulting heterogeneous mixture was vigorously stirred at ambient temperature for 48 hours. The reaction mixture was poured into water (500 ml) and extracted with methylene chloride. The organic layer was extracted with 1N sodium hydroxide several times and finally washed with brine. The organic layer was then dried (sodium sulfate) and concentrated under vacuum to an oil. Chromatography (SiO 2 , 1:1 hexanes/-ethyl acetate) gave 60.0 g (77*) of 4-[2-(1-piperidinylJetoxy]-phenoxybenzyl ether as a colorless oil. ^-H NMR (DMSO-d^J d 7 .40-7.27 (m, 5H), 6.84 (q, JAB=ll.5Hz, 4H), 4.98 (s, 2H), 3.93 (t, J-6.0Hz, 2H) , 2.56 (t, J=6.0Hz, 2H), 2.35-2.37 (m, 4H), 1.48-1.32 (m, 6H). FD mass spectrum: 311. Analysis calculated for C20H5N02: C, 77.14; H, 8.09; N, 4.50. Found: C, 77.34; H, 8.18; N, 4.64.

4-[2-[l-piperidinylJetoksy]fenoksybenzyleter (21,40 g, 68,81 mmol) ble oppløst i 200 ml 1:1 EtOH/EtOAc inneholdende 1* konsentrert HC1. Oppløsningen ble overført til en Parr flaske og 5* palladium-på-karbon (3,4 g) ble tilsatt. Blandingen ble hydrogenert ved 40 psi i 2 timer. Blandingen ble ledet gjennom en plugg av Celit for å fjerne katalysatoren. Filtratet ble konsentrert under vakuum for å gl et faststoff som ble oppslemmet i etyleter og filtrert for å gi 12,10 g (83*) 4-(2-(l-plperidinylJetoksy )-fenol. Smp. 148-150'C. <!>h NMR (DMS0-d6) d 8,40 (s, lHj, 6,70 (q, JAB=ll,5Hz, 4H], 3,93 (t, J=6,0Hz, 2H), 2,59 (t, J=6,0Hz, 2H), 2,42-2,38 (m, 4H), 1,52-1,32 (m, 6H). FD massespekter: 221. Analyse beregnet for C13H19N02: C, 70,56; H, 8,09; N, 34,50. Funnet: C, 70,75; H; 8,59; N, 6,54. 4-[2-[1-piperidinyljetoxy]phenoxybenzyl ether (21.40 g, 68.81 mmol) was dissolved in 200 mL of 1:1 EtOH/EtOAc containing 1* concentrated HCl. The solution was transferred to a Parr flask and 5* palladium-on-carbon (3.4 g) was added. The mixture was hydrogenated at 40 psi for 2 hours. The mixture was passed through a plug of Celite to remove the catalyst. The filtrate was concentrated under vacuum to afford a solid which was slurried in ethyl ether and filtered to give 12.10 g (83*) 4-(2-(1-plperidinylJethoxy)-phenol. M.p. 148-150°C. < !>h NMR (DMS0-d6) d 8.40 (s, 1Hj, 6.70 (q, JAB=11.5Hz, 4H]), 3.93 (t, J=6.0Hz, 2H), 2, 59 (t, J=6.0Hz, 2H), 2.42-2.38 (m, 4H), 1.52-1.32 (m, 6H). FD mass spectrum: 221. Analysis calculated for C13H19N02: C , 70.56; H, 8.09; N, 34.50. Found: C, 70.75; H, 8.59; N, 6.54.

Eksempel 30 Example 30

[6-metoksy-3-[4- [ 2-( 1-piper idinyl Jetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen-(S-oksyd) [6-Methoxy-3-[4- [ 2-( 1-piperidinyl Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)

Til en oppløsning av 4-(2-(1-piperidinylJetoksy)-fenol (0,32 g, 1,43 mmol) i 5 ml vannfri DMF ved omgivelsestemperatur ble det tilsatt natriumhydrid (0,57 g, 1,43 mmol, 60* dlspersjon i mineralolje). Etter omrøring i 15 minutter ble [6-metoksy-2-(4-metoksyfenyl)-3-brom]benzo[b]tiofen-(S-oksyd) (0,50 g, 1,37 mmol) tilsatt I små porsjoner. Etter omrøring i 1 time ble reaksjonen gjort fullstendig ved TLC analyse. Oppløs-nlngsmidlet ble fjernet under vakuum og resten ble skillt mellom vann og 10* etanol/etylacetat. Det organiske laget ble vasket flere ganger med vann og så tørket (natriumsulfat). Konsentrasjon under vakuum ga en olje som ble finfordelt fra etylacetat/heksaner for å gi 0,62 g (89*) [6-metoksy-3-[4-[2-(1-piperidinyl )etoksy]fenoksy]-2-(4-metoksyfenyl)]benzo-[b]tiofen-(S-oksyd) som et lys gult faststoff. Smp. 97-100'C. To a solution of 4-(2-(1-piperidinyljetoxy)-phenol (0.32 g, 1.43 mmol) in 5 mL of anhydrous DMF at ambient temperature was added sodium hydride (0.57 g, 1.43 mmol, 60 * dlspersion in mineral oil).After stirring for 15 minutes, [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide) (0.50 g, 1.37 mmol ) was added in small portions. After stirring for 1 hour, the reaction was made complete by TLC analysis. The solvent was removed under vacuum and the residue was partitioned between water and 10* ethanol/ethyl acetate. The organic layer was washed several times with water and then dried (sodium sulfate).Concentration under vacuum gave an oil which was triturated from ethyl acetate/hexanes to give 0.62 g (89*) [6-methoxy-3-[4-[2-(1-piperidinyl )ethoxy]phenoxy ]-2-(4-Methoxyphenyl)]benzo-[b]thiophene-(S-oxide) as a pale yellow solid, mp 97-100°C.

<*>H NMR (DMS0-d6) d 7,68 (d, J-2,lHz, 1H), 7,62 (d, J=8,8Hz, 2H), 7,06-6,92 (m, 6H), 6,85 (d, J=8,8Hz, 2H), 3,94 (t, J=6,0Hz, 2H), 3,81 (s, 3H), 3,72 (s, 3H), 2,56 (t, J-6,0Hz, 2H), 2,39-2,32 (m, 4H), 1,47-1,32 (m, 6H). Analyse beregnet for <C>29<H>31N05S: C, 68,89; H, 6,18; N, 2,77. Funnet: C, 68,95; H, 6,04; N; 2,57. <*>H NMR (DMS0-d6) d 7.68 (d, J-2.1Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.06-6.92 (m , 6H), 6.85 (d, J=8.8Hz, 2H), 3.94 (t, J=6.0Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H ), 2.56 (t, J-6.0Hz, 2H), 2.39-2.32 (m, 4H), 1.47-1.32 (m, 6H). Analysis calculated for <C>29<H>31N05S: C, 68.89; H, 6.18; N, 2.77. Found: C, 68.95; H, 6.04; N; 2.57.

Eksempel 31 Example 31

Fremstilt på analog måte ble [3-[4-[2-(1-piperidinylJetoksy]-fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen-(S-oksyd) Prepared in an analogous manner, [3-[4-[2-(1-piperidinylJetoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)

Olje.. ! e NMR (DMSO-d6) d 8,03 (m, 1H), 7,65 (d, Jo8,7Hz, 2E), 7,53-7,50 (m, 2H), 7,09-6,82 (m, 7H), 7,94 (bt, J<=5,9Hz, 2H), 3,74 (s, 3H), 2,56 (bt, J-5,9Hz, 2H), 2,36-2,33 (m, 4H), 1,45-1,31 (m, 6H). FD massespekter: 475. Analyse beregnet for <C>28<H>29N04S: c« 70»71» H» 6»155 N; 2,94. Funnet: C, 70,44; H, 6,43, N, 3,20. Oil.. ! e NMR (DMSO-d6) d 8.03 (m, 1H), 7.65 (d, Jo8.7Hz, 2E), 7.53-7.50 (m, 2H), 7.09-6.82 (m, 7H), 7.94 (bt, J<=5.9Hz, 2H), 3.74 (s, 3H), 2.56 (bt, J-5.9Hz, 2H), 2.36- 2.33 (m, 4H), 1.45-1.31 (m, 6H). FD mass spectrum: 475. Analysis calculated for <C>28<H>29N04S: c« 70»71» H» 6»155 N; 2.94. Found: C, 70.44; H, 6.43, N, 3.20.

Tgksem pel 32 Tgksem pel 32

[ 6-metoksy-3- [ 4 - [2-( 1-piperIdinyl Jetoksy] fenoksy] -2-( 4-metoksyfenyl)]benzo[b]tiofen hydroklorid [ 6-Methoxy-3- [ 4 - [2-( 1-piperidinyl Jetoxy] phenoxy] -2-( 4-methoxyphenyl)] benzo[b]thiophene hydrochloride

TH en oppløsning av [6-metoksy-3-[4-[2-(1-piperidinyl)-et ok sy] fenoksy] - 2- (4-metoksyfenyl)] benzo [b] tiofen-(S-oksyd) TH a solution of [6-methoxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)

(eksempel 30) (3,00 g, 5,94 mmol) 1 200 ml vannfri THF under nitrogengass ved 0"C ble det tilsatt litiumaluminiumhydrid (0,34 g, 8,91 mmol) i små porsjoner. Etter omrøring 30 minutter ble reaksjonen stanset ved forsiktig tilsetning av 5,0 ml 2,0 N natriumhydroksyd. Blandingen ble omrørt kraftig i 30 minutter og ytterligere 2,ON natriumhydroksyd ble tilsatt for å oppløse salter. Blandingen ble så skillt mellom (Example 30) (3.00 g, 5.94 mmol) 1200 ml of anhydrous THF under nitrogen gas at 0"C was added lithium aluminum hydride (0.34 g, 8.91 mmol) in small portions. After stirring for 30 minutes, the reaction was quenched by the careful addition of 5.0 mL of 2.0 N sodium hydroxide. The mixture was stirred vigorously for 30 minutes and additional 2.0 N sodium hydroxide was added to dissolve salts. The mixture was then partitioned between

vann og 10* natriumhydroksyd. Lagene ble separert og de vandige fasene ekstrahert flere ganger med 10* etanol/- etylacetat. Det organiske laget ble tørket (natriumsulfat) og konsentrert under vakuum til en olje. Råproduktet ble oppløst i 50 ml 1:1 etylacetat/etyleter og behandlet med overskudd av etyleterhydroklorid. Den resulterende utfellingen ble oppsamlet og tørket for å gi 2,98 g (96*) [6-metoksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy-2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid som et hvitt faststoff. water and 10* sodium hydroxide. The layers were separated and the aqueous phases extracted several times with 10% ethanol/ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated under vacuum to an oil. The crude product was dissolved in 50 ml of 1:1 ethyl acetate/ethyl ether and treated with an excess of ethyl ether hydrochloride. The resulting precipitate was collected and dried to give 2.98 g (96*) of [6-methoxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy-2-(4-methoxyphenyl)]benzo[b] thiophene hydrochloride as a white solid.

Eksempel 6 ble også fremstilt fra eksempel 31 ved den samme prosedyren. Example 6 was also prepared from Example 31 by the same procedure.

Fremstilling 13 Production 13

6-metoksybenzo[b]tiofen-2-borsyre 6-Methoxybenzo[b]thiophene-2-boronic acid

Til en oppløsning av 6-metoksybenzo[b]tiofen (18,13 g, 111 mol) i 150 ml vannfri tetrahydrofuran (THF) ved -60*C ble det tilsatt n-butyllitium (76,2 ml, 122 mol, 1,6 M oppløsning 1 heksan), dråpevis via sprøyte. Etter omrøring i 30 minutter ble triisopropylborat (28,2 ml, 122 mol) Introdusert via sprøyte. Den resulterende blandingen fikk gradvis varme seg til 0<*>C og ble så skillt mellom IN saltsyre og etylacetat (hver 300 ml). Lagene ble separert og det organiske laget ble tørket over natriumsulfat. Konsentrasjon under vakuum ga et hvitt faststoff som ble finfordelt fra etyleter/heksan. Filtrering ga 16,4 g (71*) 6-metoksybenzo[b]tiofen-2-borsyre som et hvitt faststoff. Smp. 200°C (dek.). <1>H NMR (DMS0-d6) d 7,83 (s, 1H), 7,78 (d, J=8,6Hz, 1H), 7,51 (d, J=2,0Hz, 1H), 6,97 (dd, J=8,6, 2,0Hz, 1H), 3,82 (s, 3H). FD massespekter: 208. To a solution of 6-methoxybenzo[b]thiophene (18.13 g, 111 mol) in 150 ml of anhydrous tetrahydrofuran (THF) at -60*C was added n-butyllithium (76.2 ml, 122 mol, 1, 6 M solution 1 hexane), 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 partitioned between 1N hydrochloric acid and ethyl acetate (each 300 mL). The layers were separated and the organic layer was dried over sodium sulfate. Concentration under vacuum gave a white solid which was triturated from ethyl ether/hexane. Filtration gave 16.4 g (71*) of 6-methoxybenzo[b]thiophene-2-boronic acid as a white solid. Temp. 200°C (dec.). <1>H NMR (DMS0-d6) d 7.83 (s, 1H), 7.78 (d, J=8.6Hz, 1H), 7.51 (d, J=2.0Hz, 1H), 6.97 (dd, J=8.6, 2.0Hz, 1H), 3.82 (s, 3H). FD mass spectrum: 208.

Fremstilling 14 Production 14

[6-metoksy-2-(4-metansulfonyloksyfenyl)]benzo[b]tiofen [6-Methoxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene

Til en oppløsning av 6-metoksybenzo[b]tiofen-2-borsyre (3,00 g, 14,4 mmol) i 100 ml toluen ble det tilsatt 4-(metansul-fonyloksyJfenylbromid (3,98 g, 15,8 mmol) fulgt av 16 ml 2,0 N natrlumkarbonatoppløsning. Etter omrøring i 10 minutter ble tetrakistrifenylfosfinpalladium (0,60 g, 0,52 mmol) tilsatt og den resulterende blandingen ble oppvarmet ved tilbakeløps-kjøling i 5 timer. Reaksjonsblandingen ble så avkjølt til omgivelsestemperatur hvorpå produktet utfelte fra den organiske fasen. Den vandige fasen ble fjernet og det organiske laget ble konsentrert under vakuum til et faststoff. Finfordeling fra etyleter ga et faststoff som ble filtrert og tørket under vakuum for å gi 3,70 g (77*) [6-metoksy-2-(4-metansulfonyloksyfenyl)]benzo[b]tiofen som et lysebrunt faststoff. Smp. 197-201°C. <l>H NMR (DMS0-d6) d 7,82-7,77 (m, 3H), 7,71 (d, J=8,8Hz, 1H), 7,54 (d, J=2,3Hz, 1H), 7,40 (d, J=8,7Hz, 2H), 6,98 (dd, J=8,7, 1,5Hz, 1H), 3,80 (s, 3H), 3,39 (s, 3H). FD massespekter: 334. Analyse beregnet for <C>16<H>14°4S2: c» 57,46; H, 4,21. Funnet: C, 57,76; H, 4,21. 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-(methanesulfonyloxyJphenyl bromide (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 heated at reflux for 5 hours. The reaction mixture was then cooled to ambient temperature whereupon the product precipitated from the organic phase. The aqueous phase was removed and the organic layer was concentrated under vacuum to a solid. Trituration from ethyl ether gave a solid which was filtered and dried under vacuum to give 3.70 g (77*) [6 -methoxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene as a light brown solid. M.p. 197-201°C. <1>H NMR (DMS0-d6) d 7.82-7.77 (m, 3H), 7.71 (d, J=8.8Hz, 1H), 7.54 (d, J=2.3Hz, 1H), 7.40 (d, J=8.7Hz, 2H), 6, 98 (dd, J=8.7, 1.5Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H). FD mass spectrum: 334. Analysis calculated for <C>16<H>14°4S2: c» 57.46; H, 4.21. Found: C, 57.76; H, 4.21.

Fremstilling 15 Production 15

Fremstilt på analog måte som fremstilling 14 ble [6-metoksy-2-(4-benzyloksyfenyl)]benzo[b]tiofen Prepared in an analogous manner to preparation 14, [6-methoxy-2-(4-benzyloxyphenyl)]benzo[b]thiophene

Utbytte = 73*. Smp. 217-221°C. XE NMR (DMSO-d6) d 7,63-7,60 (m, 3H), 7,59-7,26 (m, 7H), 7,02 (d, J=8,7Hz, 2H), 6,96 (dd, J=8,8, 2,2Hz, 1H), 5,11 (s, 2H), 3,88 (s, 3H). FD massespekter 346. Analyse beregnet for C22His02S: C, 76,27; H, 5,24. Funnet: C, 76,00; H, 5,25. Dividend = 73*. Temp. 217-221°C. XE NMR (DMSO-d6) d 7.63-7.60 (m, 3H), 7.59-7.26 (m, 7H), 7.02 (d, J=8.7Hz, 2H), 6 .96 (dd, J=8.8, 2.2Hz, 1H), 5.11 (s, 2H), 3.88 (s, 3H). FD mass spectrum 346. Analysis calculated for C 22 HisO 2 S: C, 76.27; H, 5.24. Found: C, 76.00; H, 5.25.

Fremstill ing, 16 Produce ing, 16

[6-hydroksy-2-(4-metansulfonyloksyfenyl)]benzo[b]tiofen [6-hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene

Til en oppløsning av [6-metoksy-2-(4-metansulfonyloksy-fenyl)]benzo[b]tiofen (9,50 g, 28,40 mmol) i vannfri metylenklorid (200 ml) ved romtempratur under nitrogengass ble det tilsatt bortribromid (14,20 g, 5,36 ml, 56,8 mmol). Den resulterende blandingen ble omrørt ved omgivelsestemperatur i 3 timer. Reaksjonen ble stanset ved sakte helling av den i overskudd av isvann. Etter kraftig omrøring i 30 minutter ble den hvite utfellingen oppsamlet ved filtrering, vasket flere ganger med vann og sa tørket under vakuum for & gi 8,92 g (9896) [6-hydroksy-2-(4-metansul-fonyloksyfenyl)]benzo[b]tiofen som et hvitt faststoff. Smp. 239-243'C. J-H NMR (DMS0-d6) d 9,70 (s, 1H), 7,76 (d, J=8,7Hz, 2H), 7,72 (s, 1H), 7,62 (d, J=8,7Hz, 1H), 7,38 (d, J=8,7Hz, 2H), 7,24 (d, J=l,7Hz, 1H), 6,86 (dd, J=8,7, 1,7Hz, 1H), 3,38 (s, 3H). FD massespekter: 320. Analyse beregnet for <C>15<H>12°4S2: c» 56,23; H, 3,77. Funnet: C, 56,49; H, 3,68. 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 temperature 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 stopped by slowly pouring it into an excess of ice water. After vigorous stirring for 30 minutes, the white precipitate was collected by filtration, washed several times with water and then dried under vacuum to give 8.92 g (9896) of [6-hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo [b]thiophene as a white solid. Temp. 239-243°C. J-H NMR (DMS0-d6) d 9.70 (s, 1H), 7.76 (d, J=8.7Hz, 2H), 7.72 (s, 1H), 7.62 (d, J=8 ,7Hz, 1H), 7.38 (d, J=8.7Hz, 2H), 7.24 (d, J=1.7Hz, 1H), 6.86 (dd, J=8.7, 1, 7Hz, 1H), 3.38 (s, 3H). FD mass spectrum: 320. Analysis calculated for <C>15<H>12°4S2: c» 56.23; H, 3.77. Found: C, 56.49; H, 3.68.

Fremstilling 17 Production 17

[6-benzyloksy-2-(4-metansulfonyloksyfenyl)]benzo[b]tiofen [6-Benzyloxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene

Til en oppløsning av [6-hydroksy-2-(4-metansulfonyloksy-f enyl)] benzo [b]tiofen (3,20 g, 10,0 mmol) i 75 ml vannfri DMF ble det tilsatt Cs2C03 (5,75 g, 17,7 mmol) fulgt av benzyl-klorid. Den resulterende blandingen ble omrørt kraftig i 24 timer. Oppløsningsmidlet ble fjernet under vakuum og den faste resten ble suspendert i 200 ml vann. Den hvite utfellingen ble oppsamlet ved filtrering og vasket flere ganger med vann. Etter tørking under vakuum, ble råproduktet suspendert i 1:1 heksan:etyleter. Stoffet ble oppsamlet for å gl 3,72 g (9196) [ 6-benzyloksy-2-( 4-metansulfonyloksy-fenyl)]benzo[b]tiofen som et hvitt faststoff. Smp. 198-202<*>C. <!>h NMR (DMS0-d6) d 7,81-7,78 (m, 3H), 7,72 (d, J=8,7Hz, 1H), 7,64 (d, J=2,2Hz, 1H), 7,47-7,30 (m, 7H), 5,15 (s, 2H), 3,39 (s, 3H). FD massespekter: 410. To a solution of [6-hydroxy-2-(4-methanesulfonyloxy-phenyl)] benzo [b]thiophene (3.20 g, 10.0 mmol) in 75 mL anhydrous DMF was added Cs 2 CO 3 (5.75 g , 17.7 mmol) followed by benzyl chloride. The resulting mixture was stirred vigorously for 24 hours. The solvent was removed under vacuum and the solid residue was suspended in 200 ml of water. The white precipitate was collected by filtration and washed several times with water. After drying under vacuum, the crude product was suspended in 1:1 hexane:ethyl ether. The material was collected to give 3.72 g (9196) [6-benzyloxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as a white solid. Temp. 198-202<*>C. <!>h NMR (DMS0-d6) d 7.81-7.78 (m, 3H), 7.72 (d, J=8.7Hz, 1H), 7.64 (d, J=2.2Hz , 1H), 7.47-7.30 (m, 7H), 5.15 (s, 2H), 3.39 (s, 3H). FD mass spectrum: 410.

Fremstilling 18 Production 18

[6-benzyloksy-2-(4-hydroksyfenyl)]benzo[b]tiofen [6-Benzyloxy-2-(4-hydroxyphenyl)]benzo[b]thiophene

TII en oppløsning av [6-benzyloksy-2-(4-metansulfonyloksy-fenyl)]benzo[b]tiofen (12,50 g, 30,50 mmol) i 300 ml vannfri THF under nitrogengass ved omgivelsestemperatur ble det tilsatt litiumaluminiumhydrid (2,32 g, 61,0 mmol) 1 små porsjoner. Blandingen ble så omrørt ved omgivelsestemperatur i 3 timer og så stanset ved forsiktig å slå blandingen i overskudd av kald 1,ON saltsyre. Den vandige fasen ble ekstrahert med etylacetat. De organiske materialene ble vasket flere ganger med vann og så tørket (natriumsulfat) og konsentrert under vakuum til et faststoff. Kromatografi (slllsiumdioksyd, kloroform) ga 8,75 g (87%) [6-benzyloksy-2-(4-hydroksyfenyl )]benzo[b]tiofen som et hvitt faststoff. Smp. 212-216<S>C. <X>H NMR (DMS0-d6) d 9,70 (s, 1H), 7,63 (d, J=8,7Hz, 1H), 7,56 (d, J=2,2Hz, 1H), 7,51-7,30 (m, 8H), 7,00 (dd, J=8,7, 2,2Hz, 1H), 6,80 (d, J=8,6Hz, 2H), 5,13 (s, 2H). FD massespekter: 331. Analyse beregnet for CgjHifcOgS: C, 75,88; H, 4,85. Funnet: D, 75,64; H, 4,85. TII 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 added lithium aluminum hydride (2 .32 g, 61.0 mmol) 1 small portions. The mixture was then stirred at ambient temperature for 3 hours and then quenched by gently slurping the mixture into an excess of cold 1.N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic materials were washed several times with water and then dried (sodium sulfate) and concentrated under vacuum to a solid. Chromatography (sillium dioxide, chloroform) gave 8.75 g (87%) of [6-benzyloxy-2-(4-hydroxyphenyl)]benzo[b]thiophene as a white solid. Temp. 212-216<S>C. <X>H NMR (DMS0-d6) d 9.70 (s, 1H), 7.63 (d, J=8.7Hz, 1H), 7.56 (d, J=2.2Hz, 1H), 7.51-7.30 (m, 8H), 7.00 (dd, J=8.7, 2.2Hz, 1H), 6.80 (d, J=8.6Hz, 2H), 5.13 (p, 2H). FD mass spectrum: 331. Analysis calculated for CgjHifcOgS: C, 75.88; H, 4.85. Found: D, 75.64; H, 4.85.

Eksempel 19 Example 19

[6-benzyloksy-2-(4-metoksyfenyl)]benzo[b]tiofen [6-Benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene

Til en oppløsning av [6-benzyloksy-2-(4-hydroksyfenyl}]-benzo[b]tiofen (8,50 g, 26,40 mmol) i 200 ml vannfri DMF under nitrogengass ved omgivelsestemperatur ble det tilsatt natriumhydrid (1,66 g, 41,5 mmol) 1 små porsjoner. Straks en gassutvikling hadde avtatt, ble jodmetan (3,25 ml, 52,18 mmol) tilsatt dråpevis. Reaksjonsblandlngen ble omrørt i 3 timer ved omgivelsestemperatur. Oppløsningsmiddel ble så fjernet under vakuum og resten ble skillt mellom vann/etylacetat. Lagene ble separert og den organiske fasen ble vasket flere ganger med vann. Det organiske laget ble så tørket (natriumsulfat) og konsentrert under vakuum for å gi 9,00 g (98*) [6-benzyloksy-2-(4-metoksyfenyl)]benzo[b]tiofen som et hvitt faststoff. Smp. 180-185'C. * E NMR (DMS0-d6) d 7,67-7,58 (m, 5H), 7,46-7,29 (m, 5H), 7,02 (dd, J=8,8, 2,2Hz, 1H), 67,98 (d, J=8,7Hz, 2H) , 5,13 (s, 2H), 3,76 (s, 3H). FD massespekter: 346. Analyse beregnet for C22<H>i8°2<S:> c» 76,27; H; 5,24. Funnet: C, 76,54; H; 5,43. To a solution of [6-benzyloxy-2-(4-hydroxyphenyl}]-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) 1 small portions. As soon as gas evolution had subsided, iodomethane (3.25 mL, 52.18 mmol) was added dropwise. The reaction mixture was stirred for 3 h at ambient temperature. Solvent was then removed under vacuum and the residue was partitioned 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 under vacuum to give 9.00 g (98*) of [6-benzyloxy -2-(4-Methoxyphenyl)]benzo[b]thiophene as a white solid, mp 180-185°C.* E NMR (DMS0-d6) d 7.67-7.58 (m, 5H), 7 .46-7.29 (m, 5H), 7.02 (dd, J=8.8, 2.2Hz, 1H), 67.98 (d, J=8.7Hz, 2H) , 5.13 ( s, 2H), 3.76 (s, 3H). FD mass spectrum: 346. Analysis calculated for C22<H>i8°2<S:> c» 76.27; H; 5.24. Found: C, 76 .54; H; 5.43.

Fremstilling 20 Production 20

[6-benzyloksy-2-(4-metoksyfenyl)-3-brom]benzo[b]tiofen [6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene

[6-benzyloksy-2-(4-metoksyfenyl)]benzo[b]tiofen (10,0 g, 28,9 mmol) ble plassert i 200 ml kloroform sammen med 10,0 g fast natrlumbikarbonat ved omgivelsestemperatur. Til denne suspensjonen ble det tilsatt brom (1,50 ml, 29,1 mmol) dråpevis over 30 minutter som en oppløsning av 100 ml kloroform. Etter fullførelse av tilsetningen ble vann (200 ml) tilsatt og lagene ble separert. Den organiske fasen ble tørket (natriumsulfat) og konsentrert under vakuum for å gi et hvitt faststoff. Krystallisering fra metylenklorid/metanol ga 10,50 g (8596) [6-benzyloksy-2-(4-metoksyfenyl)-3-brom]-benzo[b]tiofen som et hvitt faststoff. Smp. 146-150°C. XE NMR (DMS0-d6) d 7,70 (d, J=2,2Hz, 1H), 7,65-7,60 (m, 3H), 7,47-7,30 (m, 5H), 7,19 (dd, J=8,8, 2,2Hz, 1H), 7,06 (d, J=8,7Hz, 2H), 5,17 (s, 2H), 3,78 (s, 3H). FD massespekter: 346. Analyse beregnet for C22<H>i702SBr: C, 62,13; H, 4,03. Funnet: C, 61,87; H, 4,00. [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. To this suspension was added bromine (1.50 mL, 29.1 mmol) dropwise over 30 minutes as a solution in 100 mL of chloroform. After completion of the addition, water (200 mL) was added and the layers were separated. The organic phase was dried (sodium sulfate) and concentrated under vacuum to give a white solid. Crystallization from methylene chloride/methanol gave 10.50 g (8596) of [6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]-benzo[b]thiophene as a white solid. Temp. 146-150°C. XE NMR (DMS0-d6) d 7.70 (d, J=2.2Hz, 1H), 7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7 .19 (dd, J=8.8, 2.2Hz, 1H), 7.06 (d, J=8.7Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H) . FD mass spectrum: 346. Analysis calculated for C22<H>1702SBr: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00.

Fremstilling 21 Production 21

Fremstilt på analog måte ble [6-metoksy-2-(4-benzyloksyfenyl)-3-brom]benzo[b]tiofen Prepared in an analogous manner, [6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo[b]thiophene

Utbytte = 91*. Smp. 125-127°C. * E NMR (DMS0-d6) 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 massespekter: 346. Analyse beregnet for c22<H>17°2SBr: c» 62,13; H, 4,03. Funnet: C, 62,33; H, 3,93. Yield = 91*. Temp. 125-127°C. * E NMR (DMS0-d6) d 7.64-7.61 (m, 4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H), 5, 15 (p, 2H), 3.82 (p, 3H). FD mass spectrum: 346. Analysis calculated for c22<H>17°2SBr: c» 62.13; H, 4.03. Found: C, 62.33; H, 3.93.

Fremstilt på analog måte til eksempel 28 ble eksemplene 33-34. Prepared in an analogous manner to example 28, examples 33-34 were.

Eksempel 33 Example 33

[6-benzyloksy-2-(4-metoksyfenyl)-3-brom]benzo[b] tiofen-(S-oksyd) [6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

Isolert som et gult faststoff ved krystallisering fra etylacetat. Smp. 202-205* C. <1>H NMR (DMS0-d6) d 7,80 (d, J=2,2Hz, 1H), 7,68 (d, J=8,7Hz, 2H), 7,55 (d, J=8,4Hz, 1H), 7,47-7,32 (m, 6H), 7,10 (d, J=8,7Hz, 2H), 5,23 (s, 2H), 3,80 (s, 3H). FD massespekter: 441. Analyse beregnet for c22<H>17°3SBr: C» 59,87; H, 3,88. Funnet: C, 59,59; H, 3,78. Isolated as a yellow solid by crystallization from ethyl acetate. Temp. 202-205* C. <1>H NMR (DMS0-d6) d 7.80 (d, J=2.2Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 7.55 (d, J=8.4Hz, 1H), 7.47-7.32 (m, 6H), 7.10 (d, J=8.7Hz, 2H), 5.23 (s, 2H), 3 .80 (p, 3H). FD mass spectrum: 441. Analysis calculated for c22<H>17°3SBr: C» 59.87; H, 3.88. Found: C, 59.59; H, 3.78.

Eksempel 34 Example 34

[6-metoksy-2-( 4-benzyl oksy f enyl)-3-brom] benzo [b] tiofen-(S-oksyd) [6-Methoxy-2-(4-benzyl oxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

Isolert som et gult faststoff ved kromatografi (SiOg, CHCI3). Smp. 119-123<*>C. ln NMR (DMS0-d6) d 7,73 (d, J=2,2Hz, 1H), 7,68 (d, J=8,8Hz, 2H), 7,55 (d, J=8,5Hz, 1H), 7,46-7,31 (m, 5); 7,26 (dd, J=8,5, 2,2Hz, 1H), 7,18 (d, J=8,8Hz, 2H), 5,16 (s, 2H), 3,86 (s, 3H). FD massespekter: 441. Analyse beregnet for C22<H>i703SBr: C, 59,87; H, 3,88. Funnet: C, 60,13; H, 4,10. Isolated as a yellow solid by chromatography (SiOg, CHCl3). Temp. 119-123<*>C. ln NMR (DMS0-d6) d 7.73 (d, J=2.2Hz, 1H), 7.68 (d, J=8.8Hz, 2H), 7.55 (d, J=8.5Hz, 1H), 7.46-7.31 (m, 5); 7.26 (dd, J=8.5, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H ). FD mass spectrum: 441. Analysis calculated for C 22 <H>i 7 O 3 SBr: C, 59.87; H, 3.88. Found: C, 60.13; H, 4.10.

Fremstilt på en analog måte til eksempel 30 var eksemplene 35-36. Prepared in an analogous manner to Example 30 were Examples 35-36.

Eksempel 35 Example 35

[6-benzyloksy-3-[4 -[2-(1-piperIdinyl Jetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen-(S-oksyd) [6-Benzyloxy-3-[4-[2-(1-piperidinyl Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)

Gul olje. <X>H NMR (DMS0-d6) d 7,76 (d, J=2,2Hz, 1H), 7,62 (d, J=8,8Hz, 2H), 7,44-7,30 (m, 5H), 7,12 (dd, J=8,6, 2,2Hz, 1H), 7,03-6,93 (m, 5H), 6,85 (d, J=8,8Hz, 2H), 5,18 (s, 2H), 3,94 (bt, J=5,8Hz, 2H), 3,73 (s, 3H), 2,56 (bt, J=5,8Hz, 2H), 2,37-2,34 (m, 4H), 1,45-1,32 (m, 6H). FD massespekter: 592. Analyse beregnet for C35<H>35NO5S: C, 72,26; H, 6,06; N, 2,41. Funnet: C, 72,19; H, 5,99; N, 2,11. Yellow oil. <X>H NMR (DMS0-d6) d 7.76 (d, J=2.2Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.44-7.30 (m , 5H), 7.12 (dd, J=8.6, 2.2Hz, 1H), 7.03-6.93 (m, 5H), 6.85 (d, J=8.8Hz, 2H) , 5.18 (s, 2H), 3.94 (bt, J=5.8Hz, 2H), 3.73 (s, 3H), 2.56 (bt, J=5.8Hz, 2H), 2 .37-2.34 (m, 4H), 1.45-1.32 (m, 6H). FD mass spectrum: 592. Analysis calculated for C35<H>35NO5S: C, 72.26; H, 6.06; N, 2.41. Found: C, 72.19; H, 5.99; N, 2.11.

Eksempel 36 Example 36

[6-metoksy-3 -[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-benzyloksyfenyl)]benzo[b]tiofen-(S-oksyd J [6-Methoxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene-(S-oxide J

Gul faststoff. Smp. 89-93" C. <*>H NMR (DMS0-d6) d 7,68 (d, J=2,2Hz, 1H), 7,62 (d, J=8,8Hz, 2H), 7,42-7,28 (m, 5H), 7,08-6,92 (m, 6H), 6,86 (d, J=8,8Hz, 2H), 5,09 (s, 2E), 3,94 (bt, J=5,8Hz, 2H), 3,81 (s, 3H), 2,56 (bt, J=5,8Hz, 2E), 2,37-2,34 (m, 4H), 1,45-1,31 (m, 6H). FD massespekter: 592. Analyse beregnet for C35<H>35N05S-0,25 EtOAc: C, 71,62; E, 6,18; N, 2,32. Funnet: C, 71,32; H, 5,96; N; 2,71. Yellow solid. Temp. 89-93" C. <*>H NMR (DMS0-d6) d 7.68 (d, J=2.2Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.42 -7.28 (m, 5H), 7.08-6.92 (m, 6H), 6.86 (d, J=8.8Hz, 2H), 5.09 (s, 2E), 3.94 (bt, J=5.8Hz, 2H), 3.81 (s, 3H), 2.56 (bt, J=5.8Hz, 2E), 2.37-2.34 (m, 4H), 1 .45-1.31 (m, 6H). FD Mass Spectrum: 592. Analysis Calcd for C35<H>35NO5S-0.25 EtOAc: C, 71.62; E, 6.18; N, 2.32. Found : C, 71.32, H, 5.96, N, 2.71.

Fremstilt på analog måte til eksempel 11 var eksemplene 37-38. Prepared in an analogous manner to example 11 were examples 37-38.

Eksempel 37 Example 37

[6-benzyloksy-3-[4-[2-( 1-piperidinyl Jetoksy]fenoksy]-2-(4-metoksyfeny1)]benzo[b]tiofen [6-Benzyloxy-3-[4-[2-( 1-piperidinyl Jetoxy]phenoxy]-2-(4-methoxypheny1)]benzo[b]thiophene

Isolert med 95* totalt utbytte med utgangspunkt 1 [6-benzyloksy-2-(4-metoksyfenyl)-3-brom]benzo[b]tiofen-(S)-oksyd. Renset ved kromatografi (SiOg, 1-5* metanol/kloroform) for å gi et nær hvitt faststoff. Smp. 105-108'C. <*>H NMR (DMS0-d6) d 7,62 (d, J=2,2Hz, 1H), 7,59 (d, J=8,8Hz, 2H), 7,45-7,30 (m, 5E), 7,15 (dd, J=8,6Ez, 1H), 7,00-6,94 (m, 3H), 6,82 (s, 4H), 5,13 (s, 2H), 3,92 (bt, J=5,8Bz, 2H), 3,72 (s, 3H), 2,55 (bt, J=5,8Ez, 2H), 2,37-2,34 (m, 4H), 1,44-1,31 (m, 4H). FD massespekter: 565. Analyse beregnet for C35H35NO4S: C, 74,31; H, 6,24; N; 2,48. Funnet: C, 74,35; H, 6,07; N, 2,76. Isolated in 95* total yield starting from 1 [6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S)-oxide. Purified by chromatography (SiO2, 1-5* methanol/chloroform) to give an off white solid. Temp. 105-108°C. <*>H NMR (DMS0-d6) d 7.62 (d, J=2.2Hz, 1H), 7.59 (d, J=8.8Hz, 2H), 7.45-7.30 (m , 5E), 7.15 (dd, J=8.6Ez, 1H), 7.00-6.94 (m, 3H), 6.82 (s, 4H), 5.13 (s, 2H), 3.92 (bt, J=5.8Bz, 2H), 3.72 (s, 3H), 2.55 (bt, J=5.8Ez, 2H), 2.37-2.34 (m, 4H ), 1.44-1.31 (m, 4H). FD mass spectrum: 565. Analysis calculated for C35H35NO4S: C, 74.31; H, 6.24; N; 2.48. Found: C, 74.35; H, 6.07; N, 2.76.

Eksempel 38 Example 38

[ 6-metoksy-3- [ 4 - [ 2 - (1-plperidinyl Jetoksy] fenoksy] -2-( 4-benzyloksyfenyl)]benzo[b]tiofen [ 6-Methoxy-3- [ 4 - [ 2 - (1-plperidinyl Jetoxy] phenoxy] -2-( 4-benzyloxyphenyl)] benzo[b]thiophene

Utbytte = 91*. Smp. 106-110°C. <X>H NMR (DMS0-d6) d 7,59 (d, J=8,8Hz, 2H), 7,54 (d, J-2,2Hz, 1H), 7,42-7,28 (m, 5H), 7,13 (d, J=8,8Ez, 1H), 7,03 (d, J=8,8Hz, 2H), 6,82 (s, 4Hj, 5,08 (s, 2H), 3,92 (bt, J = 5,8Ez, 2HJ, 3,78 (s, 3H), 2,55 (bt, J=5,8Hz, 2E), 2,37-2,33 (m, 4H), 1,44-1,31 (m, 4H). FD massespekter: 565. Analyse beregnet for C35<H>3<gN0>4<S:> C, 74,31; H, 6,24; N, 2,48. Funnet: C, 74,26; E, 6,17; N, 2,73. Yield = 91*. Temp. 106-110°C. <X>H NMR (DMS0-d6) d 7.59 (d, J=8.8Hz, 2H), 7.54 (d, J-2.2Hz, 1H), 7.42-7.28 (m , 5H), 7.13 (d, J=8.8Ez, 1H), 7.03 (d, J=8.8Hz, 2H), 6.82 (s, 4Hj, 5.08 (s, 2H) , 3.92 (bt, J = 5.8Ez, 2HJ, 3.78 (s, 3H), 2.55 (bt, J=5.8Hz, 2E), 2.37-2.33 (m, 4H ), 1.44-1.31 (m, 4H). FD mass spectrum: 565. Analysis calculated for C35<H>3<gN0>4<S:> C, 74.31; H, 6.24; N, 2.48 Found: C, 74.26; E, 6.17; N, 2.73.

Eksempel 39 Example 39

[6-hydroksy-3-[4-[2-(1-piperidlnylJetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen [6-Hydroxy-3-[4-[2-(1-piperidlnylJethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

Til en oppløsning av [6-benzyloksy-3-[4-[2-(l-piperidinyl)-etoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen (8,50 g, 15,0 mmol J I 300 ml 5:1 etanol/etylacetat ble det tilsatt palladium black (1,50 g), ammoniumformat (3,50 g, 55,6 mmol) og 30 ml vann. Den resulterende blandingen ble oppvarmet ved tilbakeløpskjøling og overvåket ved TLC. Etter omkring 3 timer ble reaksjonen bedømt fullstendig og oppløsningen ble avkjølt omgivelsestemperatur. Reaksjonen ble filtrert gjennom en pute Celit for å fjerne katalysatoren og filtratet ble konsentrert under vakuum til et faststoff. Konsentratet ble skillt mellom mettet natriumbikarbonatoppløsning og 5* etanol/etylacetat. Lagene ble separert og den organiske fasen ble tørket (natriumsulfat) og konsentrert under vakuum. Råproduktet ble kromatografert (sllisiumdioksyd, 1-5* metanol/kloroform) for å gi 6,50 g (91*) [6-hydroksy-3-[4-[2-(1-piperidinyl )etoksy]fenoksy]-2-(4-metoksyfenyl)]-benzo[b]tiofen som skum som ble omdannet til faststoff ved finfordeling med heksan. Smp. 174-176'C. <1>H NMR (DMS0-d6) d 9,77 (s, 1H), 7,56 (d, J=8,8Hz, 2H), 7,23 (d, J=2,0Hz, 1H), 7,07 (d, J-8,6Hz, 1H), 6,93 (d, J=8,8Hz, 2H), 6,81 (s, 4H), 6,76 (dd, J-8,6, 2,0Hz, 1H), 3,91 (bt, J=5,9Hz, 2H), 3,71 (s, 3H), 2,55 (bt, J=5,9Hz, 2H), 2,38-2,33 (m, 4H), 1,46-1,28 (m, 6H). FD massespekter: 475. Analyse beregnet for C28H29N04S: C, 70,71; H, 6,15; N, 2,94. Funnet: C, 70,46; H, 5,93; N, 2,71. To a solution of [6-benzyloxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene (8.50 g, 15.0 mmol J To 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 at reflux and monitored by TLC . After about 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 the catalyst and the filtrate was concentrated under vacuum to a solid. The concentrate was partitioned between saturated sodium bicarbonate solution and 5* ethanol/ethyl acetate. The layers was separated and the organic phase was dried (sodium sulfate) and concentrated in vacuo The crude product was chromatographed (silica, 1-5* methanol/chloroform) to give 6.50 g (91*) of [6-hydroxy-3-[4 -[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]-benzo[b]thiophene as a foam which was converted to a solid by finfo partitioning with hexane. Temp. 174-176'C. <1>H NMR (DMS0-d6) d 9.77 (s, 1H), 7.56 (d, J=8.8Hz, 2H), 7.23 (d, J=2.0Hz, 1H), 7.07 (d, J-8.6Hz, 1H), 6.93 (d, J=8.8Hz, 2H), 6.81 (s, 4H), 6.76 (dd, J-8.6 , 2.0Hz, 1H), 3.91 (bt, J=5.9Hz, 2H), 3.71 (s, 3H), 2.55 (bt, J=5.9Hz, 2H), 2.38 -2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spectrum: 475. Analysis calculated for C28H29N04S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.46; H, 5.93; N, 2.71.

Eksempel 40 Example 40

Fremstilt på analog måte til eksempel 39 var [6-metoksy-3-[4-[2-( 1-plper idinyl )etoksy] f enoksy] -2-(4-hydroksyf enyl )]-benzo[b]tiofen Prepared analogously to Example 39 was [6-methoxy-3-[4-[2-( 1-plperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]-benzo[b]thiophene

Utbytte = 88*. Smp. 147-150'C. <*>H NMR (DMS0-d6) d 9,72 (s, 1H), 7,51 (d, J-2,0Hz, 1H), 7,48 (d, J=8,6Hz, 2H), 7,11 (d, J=8,8Hz, 1H), 6,88 (dd, J=8,8, 2,2Hz, 1H), 6,81 (s, 4H), 6,76 Dividend = 88*. Temp. 147-150'C. <*>H NMR (DMS0-d6) d 9.72 (s, 1H), 7.51 (d, J-2.0Hz, 1H), 7.48 (d, J=8.6Hz, 2H), 7.11 (d, J=8.8Hz, 1H), 6.88 (dd, J=8.8, 2.2Hz, 1H), 6.81 (s, 4H), 6.76

(d, J=8,6, 2H), 3,91 (bt, J=5,9Hz, 2H), 3,77 (s, 3H), 2,55 (bt, J-5.9HZ, 2H), 2,38-2,33 (m, 4H), 1,46-1,28 (m, 6H). FD massespekter: 475. Analyse beregnet for Cgg<Hgg>NO^S: C, 70,71; H; 6,15; N; 2,94. Funnet: C, 71,00; H, 6,17; N, 2,94. (d, J=8.6, 2H), 3.91 (bt, J=5.9Hz, 2H), 3.77 (s, 3H), 2.55 (bt, J-5.9HZ, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spectrum: 475. Analysis calculated for Cgg<Hgg>NO^S: C, 70.71; H; 6.15; N; 2.94. Found: C, 71.00; H, 6.17; N, 2.94.

Alternativt, kan eksemplene 39 og 40 bli fremstilt ved den samme overføringshydrogenolyseprosedyren direkte med 90* utbytte fra [6-metoksy-3-[4-[2-(l-piperidinyl )etoksy]-fenoksy]-2-{4-benzyloksyfenyl)]benzo[b]tiofen-(S-oksyd) og [6-benzyl ok sy-3- [4 - [2 - (1-piperidinyl )etoksy] fenoksy] -2-( 4-metoksyfenyl)]benzo[b]tiofen-(S-oksyd). Alternatively, Examples 39 and 40 can be prepared by the same transfer hydrogenolysis procedure directly in 90* yield from [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-{4-benzyloxyphenyl) ]benzo[b]thiophene-(S-oxide) and [6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b] thiophene-(S-oxide).

Eksempel 41 Example 41

[ 6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen (eksempel 39) ble omdannet til dets hydrokloridsalt med 85# utbytte ved behandling med etyleter/saltsyre i etylacetat fulgt av krystallisering fra etanol/etylacetat [ 6-Hydroxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene (Example 39) was converted to its hydrochloride salt in 85% yield by treatment with ethyl ether/hydrochloric acid in ethyl acetate followed by crystallization from ethanol/ethyl acetate

Smp. 156-160-C. XE NMR (DMS0-d6) d 10,28 (bs, 1H), 9,85 (s, 1H), 7,56 (d, J=8,8Hz, 2H), 7,25 (d, J=2,0Hz, 1H), 7,06 (d, J=8,7Hz, 1H), 6,93 (d, J=8,8Hz, 2H), 6,87 (q, JAB=9,3Hz, 4H), 4,27 (bt, J=5,9Hz, 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 massespekter: 475. Analyse beregnet for CggHggM^S-1,0 HC1: C, 65,68; H, 5,90; N, 2,73. Funnet: C, 65,98; H, 6,11; N, 2,64. Temp. 156-160-C. XE NMR (DMS0-d6) d 10.28 (bs, 1H), 9.85 (s, 1H), 7.56 (d, J=8.8Hz, 2H), 7.25 (d, J=2 ,0Hz, 1H), 7.06 (d, J=8.7Hz, 1H), 6.93 (d, J=8.8Hz, 2H), 6.87 (q, JAB=9.3Hz, 4H) , 4.27 (bt, J=5.9Hz, 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 spectrum: 475. Analysis calculated for CggHggM^S-1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.98; H, 6.11; N, 2.64.

Eksempel 42 Example 42

Fremstilt på en måte analog med eksempel 41 var [6-hydroksy-3-[4-[2-( 1-piperidinyl Jetoksy]fenoksy]-2-(4-metoksyfenyl )]-benzo[b]tiofen hydroklorid Prepared in a manner analogous to Example 41 was [6-hydroxy-3-[4-[2-( 1-piperidinyl Jetoxy]phenoxy]-2-(4-methoxyphenyl )]-benzo[b]thiophene hydrochloride

Smp. 215-217<*>C. <!>h NMR (DMSO-d6) d 10,28 (bs, 1H), 9,80 (s, 1H), 7,52 (d, J=2,2Hz, 1H), 7,47 (d, J=8,6Hz, 2H), 7,12 (d, J=8,4Hz, 1H), 6,91-6,80 (m, 5H), 6,78 (d, J=8,6Hz, 2H), 4,27 (bt, «105,8Hz, 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 massespekter: 475. Analyse beregnet for C28H29NO4S* 1,0 HC1: C, 65,68; H, 5,90; N, 2,73. Funnet: C, 65,87; H, 5,79; N; 2,99. Temp. 215-217<*>C. <!>h NMR (DMSO-d6) d 10.28 (bs, 1H), 9.80 (s, 1H), 7.52 (d, J=2.2Hz, 1H), 7.47 (d, J=8.6Hz, 2H), 7.12 (d, J=8.4Hz, 1H), 6.91-6.80 (m, 5H), 6.78 (d, J=8.6Hz, 2H ), 4.27 (bt, «105.8Hz, 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 spectrum: 475. Analysis calculated for C28H29NO4S* 1.0 HC1: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.87; H, 5.79; N; 2.99.

Eksempel 43 Example 43

[6-benzyl ok sy-3- [4 -[2 -(1-piperidinyl Jetoksy] f enoksy] -2-(4-benzyloksyfenyl)]benzo[b]tiofen hydroklorid [6-benzyloxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene hydrochloride

TH en oppløsning av eksempel 20 (0,50 g, 1,08 mmol) i 20 ml vannfri tetrahydrofuran ved 0<*>C ble det tilsatt trietylamin TH a solution of example 20 (0.50 g, 1.08 mmol) in 20 ml of anhydrous tetrahydrofuran at 0<*>C was added triethylamine

(1,00 ml). Til denne blandingen ble det tilsatt benzoylklorid (0,28 ml, 2,35 mmol). Etter omrøring ved 0'C i 2 timer, ble reaksjonen stanset ved skilling mellom etylacetat/mettet natriumblkarbonatoppløsning (hver 100 ml). Lagene ble separert og det organiske materialet ble tørket (natriumsulfat) og konsentrert under vakuum til et hvitt faststoff. Råproduktet ble oppløst i 10 ml etylacetat og behandlet med etyleter*saltsyre. En hvit utfelling ble dannet og ble oppsamlet ved filtrering. Tørking ga 390 mg (50*) [6-benzoyloksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-benzoyloksyfenyl)]benzo[b]tiofen hydroklorid som et hvitt faststoff. Smp. 200-204<*>C. <1>H NMR (DMS0-d6) d 9,95 (bs, 1H), 8,18 (m, 1H), 8,16 (m, 2H), 8,12 (dd, J=10,0, 2,0Hz, 2H), 7,87 (dd, J=7,0, 2,0Hz, 2H), 7,78 (m, 2H), 7,64 (m, 2H), 7,42 (d, J=7,0Hz, 2H), 7,34 (dd, J=8,0, 2,0Hz, 1H), 7,00 (s, 4H), 4,32 (m, 2H), 3,45 (m, 4H), 2,99 (m, 2H), 1,75 (m, 5H), 1,39 (m, 1H). Analyse beregnet for C^<H>^<N>OfcS-l.S HC1: C, 67,97; H, 5,08; N, 1,93. Funnet: C, 68,05; H, 5,24; N, 2,01. (1.00 ml). To this mixture was added benzoyl chloride (0.28 mL, 2.35 mmol). After stirring at 0°C for 2 hours, the reaction was quenched by partitioning between ethyl acetate/saturated sodium bicarbonate solution (each 100 mL). The layers were separated and the organic material was dried (sodium sulfate) and concentrated under vacuum to a white solid. The crude product was dissolved in 10 ml of ethyl acetate and treated with ethyl ether*hydrochloric acid. A white precipitate formed and was collected by filtration. Drying gave 390 mg (50*) of [6-benzoyloxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-(4-benzoyloxyphenyl)]benzo[b]thiophene hydrochloride as a white solid, m.p. 200-204<*>C. <1>H NMR (DMS0-d6) d 9.95 (bs, 1H), 8.18 (m, 1H), 8.16 (m, 2H), 8.12 ( dd, J=10.0, 2.0Hz, 2H), 7.87 (dd, J=7.0, 2.0Hz, 2H), 7.78 (m, 2H), 7.64 (m, 2H ), 7.42 (d, J=7.0Hz, 2H), 7.34 (dd, J=8.0, 2.0Hz, 1H), 7.00 (s, 4H), 4.32 (m , 2H), 3.45 (m, 4H), 2.99 (m, 2H), 1.75 (m, 5H), 1.39 (m, 1H). Analysis calculated for C^<H>^< N>OfcS-1.S HCl: C, 67.97, H, 5.08, N, 1.93 Found: C, 68.05, H, 5.24, N, 2.01.

Ved den samme prosedyren ble følgende fremstilt: By the same procedure, the following was produced:

Eksempel 44 [6-etoksysulfonyloksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-etylsulfonyloksyfenyl)]benzo[b]tiofen hydroklorid Example 44 [6-ethoxysulfonyloxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-ethylsulfonyloxyphenyl)]benzo[b]thiophene hydrochloride

Utbytte = 72*. Smp. 110-115<*>C. <!>h NMR (DMS0-d6) d 10,15 (bs, 1H), 8,15 (d, J=2,0Hz, 1H), 7,85 (d, J=7,0Hz, 2H), 7,43 (m, 3H), 7,34 (dd, J=9,0, 2,0Hz, 1H), 6,97 (m, 4H), 4,31 (m, 2H), 3,57 (m, 4H), 3,44 (m, 4H), 2,97 (rn, 2H), 1,76 (m, 5H), 1,40 Dividend = 72*. Temp. 110-115<*>C. <!>h NMR (DMS0-d6) d 10.15 (bs, 1H), 8.15 (d, J=2.0Hz, 1H), 7.85 (d, J=7.0Hz, 2H), 7.43 (m, 3H), 7.34 (dd, J=9.0, 2.0Hz, 1H), 6.97 (m, 4H), 4.31 (m, 2H), 3.57 ( m, 4H), 3.44 (m, 4H), 2.97 (rn, 2H), 1.76 (m, 5H), 1.40

(m, TH). Analyse beregnet for C31<H>35N08S3-1,5 HC1: C, 54,57; H, 5,32; N, 2,05. Funnet: C, 54,36; H, 5,37, N, 2,05. (m, TH). Analysis calculated for C31<H>35N08S3-1.5 HCl: C, 54.57; H, 5.32; N, 2.05. Found: C, 54.36; H, 5.37, N, 2.05.

Ved en tilsvarende prosedyre ved anvendelse av trifluormetansulfonsyreanhydrid ble følgende fremstilt: Eksempel 45 [6-metoksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-(4-trifluormetansulfonyloksyferiyl)]benzo[b]tiofen By a similar procedure using trifluoromethanesulfonic anhydride, the following was prepared: Example 45 [6-methoxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy]-2-(4-trifluoromethanesulfonyloxypheryl)]benzo[b]thiophene

Utbytte = 8196. Olje. ^ NMR (DMS0-d6) d 7,82 (d, J=8,7Hz, 2H), 7,60 (d, J=2,0Hz, 1H), 7,54 (d, J=8,7Hz, 2H), 7,17 (d, J=8,8Hz, 1H), 6,93 (dd, J=8,8, 2,0Hz, 1H), 6,84 (s, 4H), 3,92 (bt, J05,7H 2H), 3,79 (s, 3H), 2,56 (bt, J=5,7Hz, 2H), 2,36-2,30 (m, 4H), 1,44-1,31 (m, 6H). FD massespekter: 607. Analyse beregnet for C29<H>2s<N>06F3S2: C, 57,32; H, 4,64; N, 2,30. Funnet: C, 57,16; H, 4,52; N, 2,01. Yield = 8196. Oil. ^ NMR (DMS0-d6) d 7.82 (d, J=8.7Hz, 2H), 7.60 (d, J=2.0Hz, 1H), 7.54 (d, J=8.7Hz, 2H), 7.17 (d, J=8.8Hz, 1H), 6.93 (dd, J=8.8, 2.0Hz, 1H), 6.84 (s, 4H), 3.92 ( bt, J05.7H 2H), 3.79 (s, 3H), 2.56 (bt, J=5.7Hz, 2H), 2.36-2.30 (m, 4H), 1.44-1 .31 (m, 6H). FD mass spectrum: 607. Analysis calculated for C29<H>2s<N>06F3S2: C, 57.32; H, 4.64; N, 2.30. Found: C, 57.16; H, 4.52; N, 2.01.

Fremstilt fra eksempel 1 ved tilsvarende prosedyrer ble: Prepared from example 1 by corresponding procedures was:

Eksempel 46 3-[4-æ2-{l-piperidlnyl)etoksy]fenoksy]-2-(4-benzoyl-oksyfenyl)]benzo[b]tiofen hydroklorid Example 46 3-[4-α2-{1-piperidinyl)ethoxy]phenoxy]-2-(4-benzoyloxyphenyl)]benzo[b]thiophene hydrochloride

Utbytte = 8596. Smp. 190-198<*>C. <1>H NMR (DMS0-d6) d 10,48 (br s, 1H), 8,00-8,10 (m, 2H), 7,80-8,00 (m, 3H), 7,60-7,53 (m, 4H), 7,40-7,56 (m, 6H), 6,93 (s, 2H), 4,37-4,43 (m, ZH), 3,00-3,05 (m, 2H), 2,53-2,63 (m, 6H), 1,75-1,95 (m, 3H), 1,40-1,50 (m, 1H). FD massespekter: 550. Analyse beregnet for C34H31N04S-1,0 HC1: C, 74,29; H, 5,68; N; 2,55. Funnet: C, 74,52; H, 5,80; N, 2,59. Yield = 8596. Smp. 190-198<*>C. <1>H NMR (DMS0-d6) d 10.48 (br s, 1H), 8.00-8.10 (m, 2H), 7.80-8.00 (m, 3H), 7.60 -7.53 (m, 4H), 7.40-7.56 (m, 6H), 6.93 (s, 2H), 4.37-4.43 (m, ZH), 3.00-3 .05 (m, 2H), 2.53-2.63 (m, 6H), 1.75-1.95 (m, 3H), 1.40-1.50 (m, 1H). FD mass spectrum: 550. Analysis calculated for C34H31N04S-1.0 HC1: C, 74.29; H, 5.68; N; 2.55. Found: C, 74.52; H, 5.80; N, 2.59.

Eksempel 47 Example 47

3-[4-[2-(1-piperidinylJetoksy]fenoksy]-2-84-pivaloyloksy-fenylJ]benzo[b]tiofen hydroklorid 3-[4-[2-(1-piperidinylJethoxy]phenoxy]-2-84-pivaloyloxy-phenylJ]benzo[b]thiophene hydrochloride

Utbytte = 90*. Smp. 193-197'C. AH NMR (DMS0-d6) d 10,10 (br s, 1H), 8,12 (d, J=8,0Hz, 1H), 7,85 (d, J=8,6Hz, 1H), 7,40-7,53 (m, 3H), 7,15 (d, J=6,7Hz, 2H), 7,00 (s, 5H), 4,33-4,40 (m, 2H), 3,45-3,60 (m, 4H), 3,00-3,10 (m, 2H), 1,70-1,90 (m, 6H), 1,40 (s, 9H). FD massespekter: 529. Analyse beregnet for C32H35N04S-1,0 HC1: C, 67,89; H, 6,41; N, 2,47. Funnet: C, 68,94; H, 6,61; N, 1,72. Yield = 90*. Temp. 193-197°C. AH NMR (DMS0-d6) d 10.10 (br s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.85 (d, J=8.6Hz, 1H), 7, 40-7.53 (m, 3H), 7.15 (d, J=6.7Hz, 2H), 7.00 (s, 5H), 4.33-4.40 (m, 2H), 3, 45-3.60 (m, 4H), 3.00-3.10 (m, 2H), 1.70-1.90 (m, 6H), 1.40 (s, 9H). FD mass spectrum: 529. Analysis calculated for C32H35N04S-1.0HCl: C, 67.89; H, 6.41; N, 2.47. Found: C, 68.94; H, 6.61; N, 1.72.

Eksempel 48 Example 48

3-[4-[2-( 1-pi per Idinyl Jetoksy] f enoksy]-2-(4-butylsul f onyl-oksyf enyl )]benzo[b]tiofen hydroklorid 3-[4-[2-( 1-piper Idinyl Jetoxy]phenoxy]-2-(4-butylsulfonyloxyphenyl)]benzo[b]thiophene hydrochloride

Utbytte = 8596 hvitt faststoff. Smp. 98-104<*>C. ^ NMR (DMSO-d6) d 10,20 (br s, 1H), 8,02 (d, J=8,0Hz, 1H), 7,82 (d, J=8,7Hz, 2H), 7,40-7,55 (m, 5H), 7,00 (s, 4H), 4,30-4,40 (m, 2H), 3,46-3,66 (m, 6H), 3,00-3,10 (m, 2H), 1,70-1,95 (m, 6H), 1,40-1,60 (m, 4H), 0,87 (t, J=7,3Hz, 3H). FD massespekter: 565. Analyse beregnet for C31<H>35N05S2-1,0 HC1: C, 61,83; H, 6,03; N, 2,33. Funnet: C, 61,55; H, 6,15; N, 2,25. Yield = 8596 white solid. Temp. 98-104<*>C. ^ NMR (DMSO-d6) d 10.20 (br s, 1H), 8.02 (d, J=8.0Hz, 1H), 7.82 (d, J=8.7Hz, 2H), 7, 40-7.55 (m, 5H), 7.00 (s, 4H), 4.30-4.40 (m, 2H), 3.46-3.66 (m, 6H), 3.00- 3.10 (m, 2H), 1.70-1.95 (m, 6H), 1.40-1.60 (m, 4H), 0.87 (t, J=7.3Hz, 3H). FD mass spectrum: 565. Analysis calculated for C31<H>35N05S2-1.0 HC1: C, 61.83; H, 6.03; N, 2.33. Found: C, 61.55; H, 6.15; N, 2.25.

Fremstilling 21 Production 21

[6-hydroksy-3 -[4 -[2-( 1-piperidinyl Jetoksy]tiofenoksy]-2-(4-hydroksyfenylJ]benzo[b]tiofen [6-Hydroxy-3-[4-[2-( 1-piperidinyl Jetoxy]thiophenoxy]-2-(4-hydroxyphenylJ)benzo[b]thiophene

Fremstilling av 4-(metoksymetyloksy)fenyldisulfid. Preparation of 4-(methoxymethyloxy)phenyldisulfide.

Til en oppløsning av 4-hydroksyfenyldisulfid (650 mg, 2,60 mmol) i 10 ml vannfri N,N-dimetylformamid ved 10'C ble det tilsatt natriumhydrid (230 mg, 5,75 mmol, 60* dispersjon i mineralolje). Etter omrøring i 15 minutter ble klormetyl-metyleter (0,44 ml, 5,75 mmol) tilsatt via sprøyte. Reaksjonsblandingen ble oppvarmet til omgivelsestemperatur og omrørt i 0,5 timer. Blandingen ble skillt mellom saltvann/- etylacetat (hver 20 ml). Lagene ble separert og den vandige fasen ekstrahert med etylacetat (2 x 20 ml). Det organiske laget ble tørket (natriumsulfat) og konsentrert til en gul olje (993 mg, 100*). En analytisk prøve av 4-(metoksymetyl-oksy)-fenyldisulfid ble fremstilt ved kromatografi (silisiumdioksyd, 4* etylacetat/heksaner). ^- H NMR (DMS0-d6) d 7,40 (d, J=6,9Hz, 4H), 7,00 (d, J=6,9Hz, 4H), 5,15 (s, 4H), 3,32 (s, 6H). FD massespekter: 338. Analyse beregnet for Ci^<H>ig<O>^Sg: C, 56,78; H, 5,36. Funnet: C, 57,08; H, 5,44. To a solution of 4-hydroxyphenyl disulfide (650 mg, 2.60 mmol) in 10 ml of anhydrous N,N-dimethylformamide at 10°C was added sodium hydride (230 mg, 5.75 mmol, 60* dispersion in mineral oil). After stirring for 15 minutes, chloromethyl methyl ether (0.44 mL, 5.75 mmol) was added via syringe. The reaction mixture was warmed to ambient temperature and stirred for 0.5 hours. The mixture was partitioned between brine/ethyl acetate (each 20 ml). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 20 mL). The organic layer was dried (sodium sulfate) and concentrated to a yellow oil (993 mg, 100*). An analytical sample of 4-(methoxymethyl-oxy)-phenyl disulfide was prepared by chromatography (silica, 4* ethyl acetate/hexanes). ^- H NMR (DMS0-d6) d 7.40 (d, J=6.9Hz, 4H), 7.00 (d, J=6.9Hz, 4H), 5.15 (s, 4H), 3 ,32 (p, 6H). FD mass spectrum: 338. Analysis calculated for C12<H>12<O>2Sg: C, 56.78; H, 5.36. Found: C, 57.08; H, 5.44.

Eksempel 49 Example 49

[6-metoksy-2-(4-metoksyfenyl)-3-(4-metoksynretylenoksy)-tiof enoksy] benzo.[b].tiof en [6-Methoxy-2-(4-Methoxyphenyl)-3-(4-Methoxynrethyleneoxy)-thiophenoxy] benzo.[b].thiophene

Til en oppløsning av [6-metoksy-2-(4-metoksyfenyl)-3-brom]benzo[b]tiofen (1,82 g, 5,2 mmol) i 10 ml vannfri tetrahydrofuran under Ng ved -60'C ble det tilsatt n-butyllitium (3,15 ml, 5,0 mmol, 1.6M oppløsning i heksan) dråpevis via sprøyte. Den resulterende blandingen ble oppvarmet til -20'C i 10 minutter, så avkjølt til -60*C. 4- To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (1.82 g, 5.2 mmol) in 10 ml of anhydrous tetrahydrofuran under Ng at -60'C n-butyllithium (3.15 ml, 5.0 mmol, 1.6M solution in hexane) was added dropwise via syringe. The resulting mixture was warmed to -20°C for 10 minutes, then cooled to -60°C. 4-

(metoksymetyloksy)-fenyldisulf id (800 mg, 2,36 mmol) i 5 ml vannfri tetrahydrofuran ble tilsatt til blandingen og den resulterende blandingen ble sakte oppvarmet til 0<*>C. Etter omrøring i 20 minutter ble reaksjonsblandingen stanset ved skilling mellom saltvann/etylacetat (hver 50 ml). Lagene ble separert og den vandige fasen ble ekstrahert med etylacetat (2 x 50 ml). De organiske lagene ble kombinert, tørket (natriumsulfat) og konsentrert under vakuum til en olje. Kromatografi (silisiumdioksyd, 5* etylacetat/heksan) ga 287 mg (27*) [6-metoksy-2-(4-metoksyfenyl)-3-(4-metoksymetylen-oksy )tiofenoksy]benzo[b] tiofen som en farveløs olje. ^H NMR (DMS0-d6) d 7,59 (d, J=8,4Hz, 2H), 7,58 (d, J=2,0Hz, 1H), 7,52 (d, J=8,8Hz, 1H), 7,03-6,85 (m, 7H), 5,06 (s, 2H), 3,79 (s, 3H), 3,76 (s, 3H). FD massespekter: 438. Analyse beregnet for C24<H>22<0>4S2: C, 65,73; H, 5,06. Funnet: C, 65,93; H, 5,10. (Methoxymethyloxy)-phenyl disulfide (800 mg, 2.36 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the mixture and the resulting mixture was slowly warmed to 0<*>C. After stirring for 20 minutes, the reaction mixture was quenched by partitioning between brine/ethyl acetate (each 50 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried (sodium sulfate) and concentrated under vacuum to an oil. Chromatography (silica, 5* ethyl acetate/hexane) gave 287 mg (27*) of [6-methoxy-2-(4-methoxyphenyl)-3-(4-methoxymethylene-oxy)thiophenoxy]benzo[b]thiophene as a colorless oil . ^H NMR (DMS0-d6) d 7.59 (d, J=8.4Hz, 2H), 7.58 (d, J=2.0Hz, 1H), 7.52 (d, J=8.8Hz , 1H), 7.03-6.85 (m, 7H), 5.06 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H). FD mass spectrum: 438. Analysis calculated for C24<H>22<0>4S2: C, 65.73; H, 5.06. Found: C, 65.93; H, 5.10.

Eksempel 50 Example 50

[ 6-metoksy-2-(4-metoksyfenyl)-3-(4-hydroksy)tiofenoksy]-benzo[b]tiofen [ 6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)thiophenoxy]-benzo[b]thiophene

Til en Oppløsning av [6-metoksy-2-(4-metoksyfenyl)-3-(4-metoksymetylenoksy)tiofenoksy]benzo[b]tiofen (233 mg, 0,53 mmol) i 10 ml av en 1:1:2 blanding av metanol: vann tetrahydrofuran ble det tilsatt metansulfonsyre (0,2 ml, 2,66 mmol). Blandingen ble oppvarmet ved tilbakeløp i 5 timer. Etter avkjøling til omgivelsestemperatur ble reaksjonsblandlngen fortynnet med vann. Den vandige fasen ble ekstrahert med etylacetat (2x). Det organiske laget ble vasket med mettet natriumbikarbonatoppløsning flere ganger. Det organiske laget ble tørket (natriumsulfat) og konsentrert under vakuum for å gi 206 mg (99*) [6-metoksy-2-(4-metoksyfenyl )-3-(4-hydroksy]tiofenoksy]benzo[b]tiofen som en fargeløs olje. <!>h NMH (DMS0-d6) d 9,43 (s, 1H), 7,63 (d, J-8,4Hz, 2H), 7,61 (d, J-2,0Hz, 1H), 7,59 (d, J=8,8Hz, 1H), 7,08 (d, J=8,4Hz, 2H), 7,02 (dd, J-8,8, 2,0Hz, 1H), 6,90 (d, J=8,6Ez, 2H), 6,63 (d, J=8,6Hz, 2H). FD massespekter: 395. Analyse beregnet for C22Hi8^3^2<:> C, 66,98; H, 4,60. Funnet: C, 67,26; H, 4,78. To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-methoxymethyleneoxy)thiophenoxy]benzo[b]thiophene (233 mg, 0.53 mmol) in 10 mL of a 1:1:2 mixture of methanol:water tetrahydrofuran was added methanesulfonic acid (0.2 mL, 2.66 mmol). The mixture was heated at reflux for 5 hours. After cooling to ambient temperature, the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (2x). The organic layer was washed with saturated sodium bicarbonate solution several times. The organic layer was dried (sodium sulfate) and concentrated under vacuum to give 206 mg (99*) of [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy]thiophenoxy]benzo[b]thiophene as a colorless oil. <!>h NMH (DMS0-d6) d 9.43 (s, 1H), 7.63 (d, J-8.4Hz, 2H), 7.61 (d, J-2.0Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.08 (d, J=8.4Hz, 2H), 7.02 (dd, J-8.8, 2.0Hz, 1H ), 6.90 (d, J=8.6Ez, 2H), 6.63 (d, J=8.6Hz, 2H). FD mass spectrum: 395. Analysis calculated for C22Hi8^3^2<:> C, 66.98; H, 4.60. Found: C, 67.26; H, 4.78.

Eksempel 51 Example 51

[6-metoksy-3- [4-[2-(1-piperidinyl )etoksy]tiofenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen [6-Methoxy-3- [4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

Til en oppløsning av [6-metoksy-2-(4-metoksyfenyl)-3-(4-hydroksy)fenofenoksy]benzo[b]tiofen (242 mg, 0,61 mmol) i 8,0 ml vannfri N,N-dimetylformamid ble det tilsatt cesiumkarbonat (820 mg, 2,5 mmol) fulgt av 2-kloretylpiperidin hydroklorid (194 mg, 1,05 mmol). Den resulterende blandingen ble omrørt i 48 timer ved omgivelsestemperatur og så skillt mellom saltvann/etylacetat. Lagene ble separert og den vandige fasen ble ekstrahert med etylacetat (3x). Det organiske laget ble tørket (natriumsulfat) og konsentrert under vakuum til en olje. Kromatografi (silisiumdioksyd, 0-2* metanol/kloroform) ga 244 mg (92*) [6-metoksy-3-[4-[2-(1-piperIdinyl)etoksy]-tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen som en ravgul olje. To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenophenoxy]benzo[b]thiophene (242 mg, 0.61 mmol) in 8.0 mL of anhydrous N,N- dimethylformamide, cesium carbonate (820 mg, 2.5 mmol) was added followed by 2-chloroethylpiperidine hydrochloride (194 mg, 1.05 mmol). The resulting mixture was stirred for 48 hours at ambient temperature and then partitioned between brine/ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (3x). The organic layer was dried (sodium sulfate) and concentrated under vacuum to an oil. Chromatography (silica, 0-2* methanol/chloroform) gave 244 mg (92*) of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-thiophenoxy]-2-(4-methoxyphenyl) ]benzo[b]thiophene as an amber oil.

Eksempel 52 Example 52

En prøve av [6-metoksy-3-[4-[2-(1-piperidinyl)etoksy]-tiofenoksy]-2-(4-metoksyfenyl)]benzo[b]tiofen ble omdannet til dets bydroklorldsalt ifølge standard prosedyrer med 7296 utbytte A sample of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene was converted to its bydrochlorold salt according to standard procedures with 7296 dividend

Smp. 198-201'C. XE NMR (DMS0-d6) d 7,63 (d, J=8,6Hz, 2H), 7,62 (d, J=2,0Hz, 1H), 7,58 (d, J=8,2Hz, 1H), 7,07 (d, J=8,6Hz, 2H), 7,02 (dd, J=8,2, 2, 0Hz, 1H), 6,92 (q, JAB=9,0Hz, 4H), 4,24 (bt, 2H), 3,82 (s, 3H), 3,80 (s, 3H), 3,49-3,39 (m, 4H), 2,93 (m, 2H), 1,82-1,62 (m, 5H), 1,38 (rn, 1H). Analyse beregnet for C29<H>32<N>03S2■1,0 HC1: C," 64,28; H, 5,95; N, 2,58. Funnet: C, 64,09; H, 6,08; N, 2,78. Temp. 198-201°C. XE NMR (DMS0-d6) d 7.63 (d, J=8.6Hz, 2H), 7.62 (d, J=2.0Hz, 1H), 7.58 (d, J=8.2Hz, 1H), 7.07 (d, J=8.6Hz, 2H), 7.02 (dd, J=8.2, 2, 0Hz, 1H), 6.92 (q, JAB=9.0Hz, 4H ), 4.24 (bt, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.49-3.39 (m, 4H), 2.93 (m, 2H) , 1.82-1.62 (m, 5H), 1.38 (rn, 1H). Analysis calcd for C29<H>32<N>03S2■1.0 HC1: C," 64.28; H, 5.95; N, 2.58. Found: C, 64.09; H, 6.08 ;N, 2.78.

Eksempel 53 Example 53

[6-hydroksy-3-[4-[2-(1-piperidinyl )etoksy] tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

Til en oppløsning av [6-metoksy-3-[4-[2-(1-piperidinyl )-etoksy]t i ofenoksy]-2-(4-metoksyf enyl)]benzo[b]tiofen hydroklorid (160 mg, 0,29 mmol) i 15 ml vannfri metylenklorid ved 0'C under Ng ble det tilsatt bortribromid (0,15 ml). Den resulterende mørke oppløsningen ble omrørt 1 1 time ved 0°c og så umiddelbart heilt i en omrørt oppløsning av etylacetat/mettet natriumbikarbonatoppløsnlng (hver 50 ml). Lagene ble separert og den vandige fasen ble vasket med etylacetat (3 x 30 ml). Det organiske laget ble tørket (natriumsulfat) og konsentrert under vakuum til et hvitt faststoff. Kromatografi (silisiumdioksyd, 0-5* metanol/kloroform) ga 91 mg (60*) [6-hydroksy-3-[4-[2-(l-plperidiny1Jetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen som et hvitt faststoff. Smp. 123-127°C. H NMR (DMS0-d6) d 9,79 (s, 1H), 9,71 (s, 1H), 7,46 (d, J=8,4Hz, 2H), 7,42 (d, J-8,9Hz, 1H), 7,26 (d, J=2,0Hz, 1H), 6,91 (d, J-8,8Hz, 2H), 6,82-6,76 (m, 5H), 3,91 (t, J=8,8Hz, 2H), 2,56 (t, J=5,8Hz, 2H), 2,40 (m, 4H), 1,41-1,28 (m, 6H). FD massespekter: 478. Analyse beregnet for C27H27N03S2: c' 67,90; H, 5,70; N, 2,93. Funnet: C, 68,14; E, 5,84; N, 2,65. To a solution of [6-methoxy-3-[4-[2-(1-piperidinyl)-ethoxy]t in phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride (160 mg, 0, 29 mmol) in 15 ml of anhydrous methylene chloride at 0'C under Ng, boron tribromide (0.15 ml) was added. The resulting dark solution was stirred for 11 hours at 0°C and then immediately poured into a stirred solution of ethyl acetate/saturated sodium bicarbonate solution (each 50 mL). The layers were separated and the aqueous phase was washed with ethyl acetate (3 x 30 mL). The organic layer was dried (sodium sulfate) and concentrated under vacuum to a white solid. Chromatography (silica, 0-5* methanol/chloroform) afforded 91 mg (60*) of [6-hydroxy-3-[4-[2-(1-plperidiny1Jethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[ b]thiophene as a white solid, mp 123-127°C H NMR (DMS0-d6) d 9.79 (s, 1H), 9.71 (s, 1H), 7.46 (d , J=8.4Hz, 2H), 7.42 (d, J-8.9Hz, 1H), 7.26 (d, J=2.0Hz, 1H), 6.91 (d, J-8, 8Hz, 2H), 6.82-6.76 (m, 5H), 3.91 (t, J=8.8Hz, 2H), 2.56 (t, J=5.8Hz, 2H), 2, 40 (m, 4H), 1.41-1.28 (m, 6H). FD mass spectrum: 478. Analysis calcd for C27H27N03S2: c' 67.90; H, 5.70; N, 2.93. Found: C, 68.14; E, 5.84; N, 2.65.

Ekgem pel BA Eggem pel BA

[6-hydroksy-3- [4- [2-(1-piperidlnyl Jetoksy]tiofenoksy] -2-(4-hydroksyfenylJ]benzo[b]tiofen hydroklorid [6-Hydroxy-3- [4- [2-(1-piperidlnyl Jetoxy]thiophenoxy] -2-(4-hydroxyphenylJ)benzo[b]thiophene hydrochloride

Smp. 180-190'C. <!>h NMR (DMS0-d6) d 9,86 (s, lHj, 9,79 (s, 1H), 7,46 (d, J=8,5Hz, 2H), 7,42 (d, J=8,7Hz, 1H), 7,29 (d, J=2,0Hz, 1H), 6,96 (d, J=8,7Hz, 2H), 6,86-6,81 (m, 5H), 4,27 (m, 2H), 3,41-3,37 (m, 4H), 2,96-2,84 (m, 2H), 1,77-1,60 (m, 5H), 1,35-1,28 (m, 1H). FD massespekter: 477. Analyse beregnet for Cg<yHgy>NOsSg'2,2 HC1: C, 58,13; H, 5,28; N, 2,51. Funnet: C, 58,11; H, 5,10; N, 2,61. Temp. 180-190'C. <!>h NMR (DMS0-d6) d 9.86 (s, 1Hj, 9.79 (s, 1H), 7.46 (d, J=8.5Hz, 2H), 7.42 (d, J =8.7Hz, 1H), 7.29 (d, J=2.0Hz, 1H), 6.96 (d, J=8.7Hz, 2H), 6.86-6.81 (m, 5H) , 4.27 (m, 2H), 3.41-3.37 (m, 4H), 2.96-2.84 (m, 2H), 1.77-1.60 (m, 5H), 1 .35-1.28 (m, 1H). FD mass spectrum: 477. Analysis calculated for Cg<yHgy>NOsSg'2.2 HC1: C, 58.13; H, 5.28; N, 2.51. Found : C, 58.11, H, 5.10, N, 2.61.

Fremstilt ved den samme prosedyren ble: Produced by the same procedure were:

Eksempel 55 [6-metoksy-3-[4-[2-(l -py rrol idinyl )etoksy ] tiofenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid Example 55 [6-Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 215-218'C. <*>H NMR (DMSO-d6) d 7,61-7,58 (m, 3H), 7,52 (d, J-8.8HZ, 1H), 7,04-6,95 (m, 5H), 6,86 (d, J=8,8Hz, 2H), 3,22 (bt, 2H), 3,79 (s, 3H), 3,76 (s, 3H), 3,47-3,42 (m, 4H), 3,01 (m, 2H), 1,94-1,80 (m, 4H). FD massespekter: 491. Analyse beregnet for C28H29N03S2* 1,0 HC1: C, 63,67; H, 5,73; N, 2,65. Funnet: C, 63,47; H, 5,78; N, 2,65. Temp. 215-218'C. <*>H NMR (DMSO-d6) d 7.61-7.58 (m, 3H), 7.52 (d, J-8.8HZ, 1H), 7.04-6.95 (m, 5H) , 6.86 (d, J=8.8Hz, 2H), 3.22 (bt, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.47-3.42 (m, 4H), 3.01 (m, 2H), 1.94-1.80 (m, 4H). FD mass spectrum: 491. Analysis calculated for C28H29N03S2* 1.0 HCl: C, 63.67; H, 5.73; N, 2.65. Found: C, 63.47; H, 5.78; N, 2.65.

Eksempel 56 Example 56

[6-hydroksy-3-[4-[2-(1-pyrrolidinylJetoksy]tiofenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid [6-hydroxy-3-[4-[2-(1-pyrrolidinylJetoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride

Smp. 137-140'C (dek.). XE NMR (DMS0-d6) d 9,86 (s, 2H), 9,80 (s, 1H), 7,46 (d, J=8,6Hz, 2H), 7,42 (d, J=8,7Hz, 1H), 7,29 (d, J=2,0Hz, 1H), 6,96 (d, J=8,7Hz, 2H), 6,87-6,81 (m, 5H), 4,21 (bt, 2H), 3,53-3,41 (m, 4H), 3,01 (m, 2H), 1,95-1,82 (m, 4H). FD massespekter: 464. Analyse beregnet for c2bB25m3s2' 1' 0 HC1: c« 62,45; H, 5,24; N, 2,80. Funnet: C, 62,36; H, 5,37; N, 2,61. Temp. 137-140'C (dec.). XE NMR (DMS0-d6) d 9.86 (s, 2H), 9.80 (s, 1H), 7.46 (d, J=8.6Hz, 2H), 7.42 (d, J=8 ,7Hz, 1H), 7.29 (d, J=2.0Hz, 1H), 6.96 (d, J=8.7Hz, 2H), 6.87-6.81 (m, 5H), 4 .21 (bt, 2H), 3.53-3.41 (m, 4H), 3.01 (m, 2H), 1.95-1.82 (m, 4H). FD mass spectrum: 464. Analysis calculated for c2bB25m3s2' 1' 0 HC1: c« 62.45; H, 5.24; N, 2.80. Found: C, 62.36; H, 5.37; N, 2.61.

Eksempel 57 Example 57

Fremstilt fra produktet fra eksempel 45 ved hydrogenolyse av triflatet som beskrevet nedenfor i eksempel 58 ble 6-metoksy-3-[4-[2-(1-piper idinylJetoksy]fenoksy]-2-(fenyl)]benzo[b]tiofen hydroklorid Prepared from the product of Example 45 by hydrogenolysis of the triflate as described below in Example 58 was 6-methoxy-3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-(phenyl)]benzo[b]thiophene hydrochloride

Smp. 187-195'C. XE NMR (DMS0-d6) d 7,66 (d, J=2,8Hz, 2H), 7,58 (d, J=2,0Hz, 1H), 7,39 (t, J=7,5Hz, 2E), 7,28 (m, 1H), 7,17 (d, J=8,8Hz, 1H), 6,91 (dd, J=8,8, 2,0Hz, 1H), 6,89 (s, 4H), 4,23 (bt, J=5,7Hz, 2H), 3,79 (s, 3H), 3,45-3,38 (m, 4H), 2,98 (m, 2H), 1,77-1,61 (m, 5H), 1,31 (m, 1H). FD massespekter: 460. Analyse beregnet for Cgs<H>gg<N>O^S*1,0 HC1: C, 67,80; H, 6,10; N, 2,84. Funnet: C, 67,62; H, 5,89; N, 2,67. Temp. 187-195°C. XE NMR (DMS0-d6) d 7.66 (d, J=2.8Hz, 2H), 7.58 (d, J=2.0Hz, 1H), 7.39 (t, J=7.5Hz, 2E), 7.28 (m, 1H), 7.17 (d, J=8.8Hz, 1H), 6.91 (dd, J=8.8, 2.0Hz, 1H), 6.89 ( s, 4H), 4.23 (bt, J=5.7Hz, 2H), 3.79 (s, 3H), 3.45-3.38 (m, 4H), 2.98 (m, 2H) , 1.77-1.61 (m, 5H), 1.31 (m, 1H). FD mass spectrum: 460. Analysis calculated for Cgs<H>gg<N>O^S*1.0 HC1: C, 67.80; H, 6.10; N, 2.84. Found: C, 67.62; H, 5.89; N, 2.67.

Eksempel 58 Example 58

6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy] a-2-(fenyl)]benzo[b]tiofen hydroklorid 6-hydroxy-3-[4-[2-(1-piperidinyljetoxy]phenoxy] a-2-(phenyl)]benzo[b]thiophene hydrochloride

Til en oppløsning av 6-hydroksy-3-[4-[2-(1-piperidlnyl)-etoksy]fenoksy]-2-(4-hydroksyfenyl)]benzo[b]tiofen hydroklorid (5,00 g, 10,0 mmol) 1 100 ml vannfri metylenklorid ved 0<*>C under N2 hie det tilsatt trietylamin (8,38 ml, 60,0 mmol) fulgt av trifluormetansulfonsyreanhydrid (1,69 ml, 10,0 mmol). Den resulterende blandingen ble gradvis oppvarmet til romtemperatur og omrørt i 1,5 timer. Reaksjonen ble så stanset ved å helle den I 200 ml mettet natriumbikarbonat-oppløsning. Den vandige fasen ble så ekstrahert med etylacetat (3 x 100 ml). Det organiske laget ble tørket (natriumsulfat) og konsentrert i vakuum til en olje. Kromatografi (0-3* metanol/kloroform) ga 2,82 g (39*) 6-trifluormetansulfonat-3-[4-[2-(l-piperidinyl )]benzo[b]tiofen, 1,82 g (31*) av en 1:1 blanding av 6-trifluormetansulfonat-3-[4-[2-(1-piperidinyl)-etoksy]fenoksy]-2-(4-fenyl)]benzo[b]tiofen og 3-[4-[2-(l-plperidinylJetoksy]fenoksy]-2-(4-trifluormetansulfonoat-fenyl)]benzo[b]tiofen og 1,48 g (36*) gjenvunnet startmateriale som fri base. To a solution of 6-hydroxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride (5.00 g, 10.0 mmol) 1,100 ml of anhydrous methylene chloride at 0<*>C under N 2 was added triethylamine (8.38 ml, 60.0 mmol) followed by trifluoromethanesulfonic anhydride (1.69 ml, 10.0 mmol). The resulting mixture was gradually warmed to room temperature and stirred for 1.5 hours. The reaction was then quenched by pouring it into 200 ml of saturated sodium bicarbonate solution. The aqueous phase was then extracted with ethyl acetate (3 x 100 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo to an oil. Chromatography (0-3* methanol/chloroform) gave 2.82 g (39*) of 6-trifluoromethanesulfonate-3-[4-[2-(l-piperidinyl )]benzo[b]thiophene, 1.82 g (31* ) of a 1:1 mixture of 6-trifluoromethanesulfonate-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-phenyl)]benzo[b]thiophene and 3-[4- [2-(1-plperidinylJetoxy]phenoxy]-2-(4-trifluoromethanesulfonate-phenyl)]benzo[b]thiophene and 1.48 g (36*) recovered starting material as free base.

Til en oppløsning av 1:1 blanding av monotriflatderlvater fra den siste reaksjonen (0,50 g, 0,84 mmol) i 60 ml etanoletylacetat (5:1) ble det tilsatt trietylamin (2,0 ml) og 5* palladium-på-karbon (0,50 g). Den resulterende blandingen ble hydrogenert ved 40 psi I 2 timer. Blandingen ble så filtrert gjennom cellt for å fjerne katalysatoren. Filtratet ble konsentrert til en olje. Den resulterende blandingen av monohydroksyderivater ble oppløst i etylacetat fra hvilke 3-[4-[2-(l-pIperidinyl Jetoksy] f enoksy] -2-(4-hydroksyf enyl )]-benzo[b]tiofen ble utfelt. Filtratet besto av en 4:1 blanding av monohydroksyderivater hvor 6-hydroksy-3-[4-[2-(1-piperidinyl Jetoksy]fenoksy]-2-(fenyl)]benzo[b]tiofen var hovedkom-ponenten. Filtratet ble konsentrert under vakuum og det resulterende faststoff oppløst 1 minimalt etylacetat og behandlet med etyleter* saltsyre. Det resulterende faststoffet ble rekrystall Isert fra etanol for å gi 69 mg (18*) av isomert rent 6-hydroksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy] -2-( fenyl J]benzo[b] tiofen hydroklorid. Smp. 217-219'C. To a solution of a 1:1 mixture of monotriflate derlvates from the last reaction (0.50 g, 0.84 mmol) in 60 ml of ethanol ethyl acetate (5:1) was added triethylamine (2.0 ml) and 5* palladium-on -carbon (0.50 g). The resulting mixture was hydrogenated at 40 psi for 2 hours. The mixture was then filtered through cellt to remove the catalyst. The filtrate was concentrated to an oil. The resulting mixture of monohydroxy derivatives was dissolved in ethyl acetate from which 3-[4-[2-(1-pIperidinyl Jetoxy]phenoxy]-2-(4-hydroxyphenyl)]-benzo[b]thiophene was precipitated. The filtrate consisted of a 4:1 mixture of monohydroxy derivatives where 6-hydroxy-3-[4-[2-(1-piperidinyl Jetoxy]phenoxy]-2-(phenyl)]benzo[b]thiophene was the major component. The filtrate was concentrated under vacuum and the resulting solid dissolved in 1 minimal ethyl acetate and treated with ethyl ether* hydrochloric acid The resulting solid was recrystallized from ethanol to give 69 mg (18*) of isomerically pure 6-hydroxy-3-[4-[2-(1- piperidinylJethoxy]phenoxy]-2-(phenyl J]benzo[b]thiophene hydrochloride. M.p. 217-219°C.

% NMR (DMS0-d6) d 9,7 (s, 1H), 7,64 (d, J=7,5Hz, 2H), 7,39-7,26 (m, 4H), 7,10 (d, J-8,6Hz, 1H), 6,89 (s, 4H), 6,78 (dd, J=8,6, 2,0Hz, 1H), 4,22 (bt, 2H), 3,39-3,37 (m, 4H), 2,97-2,90 (m, 2H), 1,74-1,60 (m, 5H), 1,39 (m, 1H). FD massespekter: 446. Analyse beregnet for C27<H>27<N>03S-1,0 HC1; C, 67,28; H, 5,86; N, 2,91. Funnet: C, 67,00; H, 5,59; N, 2,87. Alternativt, ble eksempel 58 fremstilt ved demetylering av produktet fra eksempel 57 som beskrevet i eksempel 18. % NMR (DMS0-d6) d 9.7 (s, 1H), 7.64 (d, J=7.5Hz, 2H), 7.39-7.26 (m, 4H), 7.10 (d , J-8.6Hz, 1H), 6.89 (s, 4H), 6.78 (dd, J=8.6, 2.0Hz, 1H), 4.22 (bt, 2H), 3.39 -3.37 (m, 4H), 2.97-2.90 (m, 2H), 1.74-1.60 (m, 5H), 1.39 (m, 1H). FD mass spectrum: 446. Analysis calculated for C27<H>27<N>03S-1.0 HC1; C, 67.28; H, 5.86; N, 2.91. Found: C, 67.00; H, 5.59; N, 2.87. Alternatively, Example 58 was prepared by demethylation of the product from Example 57 as described in Example 18.

Eksempel 59 Example 59

[6-1 sopropoksy-3- [4- [2-(1-piperidinyl Jetoksy] fenoksy] -2-( 4-metoksyfenyl)]benzo[b]tiofen-(S-oksyd) ble fremstilt som beskrevet for [6-metoksy-3-[4-[2-(1-piperidinyl)etoksy]fenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen-(S-oksyd) (Eksempel 30). [6-1 isopropoxy-3- [4- [2-(1-piperidinyl Jetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide) was prepared as described for [6- methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide) (Example 30).

Gul olje. H NMR (DMS0-d6) d 7,69 (d, J=2,0Hz, 1H), 7,67 (d, J=8,6Hz, 2H), 7,09-6,99 (m, 5H), 6,96-6,87 (m, 3H), 4,76 (septet, J=6,0Hz, IB), 3,99 (bt, J=6,0Hz, 2H), 3,78 (s, 3H), 2,61 (bt, J=6,0Hz, 2H), 2,44-2,37 (m, 4H), 1,53-1,43 (m, 4H), 1,40-1,32 (m, 2H), 1,29 (d, J=6,0Hz, 6H). FD massespekter: 533. Analyse beregnet for C31H35N05S-0,67 H20: C, 68,23; E, 6,71; N, 2,57. Funnet: C, 67,90; H, 6,31; N, 2,53. Yellow oil. H NMR (DMS0-d6) d 7.69 (d, J=2.0Hz, 1H), 7.67 (d, J=8.6Hz, 2H), 7.09-6.99 (m , 5H), 6.96-6.87 (m, 3H), 4.76 (sept, J=6.0Hz, IB), 3.99 (bt, J=6.0Hz, 2H), 3.78 (s, 3H), 2.61 (bt, J=6.0Hz, 2H), 2.44-2.37 (m, 4H), 1.53-1.43 (m, 4H), 1.40 -1.32 (m, 2H), 1.29 (d, J=6.0Hz, 6H). FD mass spectrum: 533. Analysis calculated for C31H35N05S-0.67 H2O: C, 68.23; E, 6.71; N, 2.57. Found: C, 67.90; H, 6.31; N, 2.53.

[6-i s opropoksy-3-[4-[2-(1 -piper i diny 1) etoksy ] fenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen hydroklorid ble fremstilt som beskrevet for [6-metoksy-3-[4-[2-(1-piperidinylJetoksy]fenoksy] -2-(4-metoksyfenyl)]benzo[b]tiofen (eksempel 32). [6-i s opropoxy-3-[4-[2-(1 -piper i diny 1)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride was prepared as described for [6-methoxy -3-[4-[2-(1-piperidinylJetoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene (Example 32).

Smp. 168-170'C. 3-H NMR (DMS0-d6) d 10,37 (s, 1H), 7,58 (d, J-8.6HZ, 2H), 7,52 (d, J=l,3Hz, lHj, 7,12 (d, J=8,8Hz, 1H), 6,95 (d, J-8,6Hz, 2H), 6,92-6,85 (m, 5H), 4,64 (septet, J=6,0Hz, 1H), 4,28 (bt, J=6,0Hz, 2E), 3,72 (s, 3H), 3,44-3,37 (m, 4H), 2,95-2,89 (m, 2H), 1,73-1,60 (m, 5H), 1,36-1,28 (m, 1H), 1,25 (d, J=6,0Hz, 6H). FD massespekter: 517. Analyse beregnet for C31H35N04S-HC1: C, 67,19; H, 6,55; N, 2,53. Funnet: C, 67,15; H, 6,29; N, 2,62. Temp. 168-170'C. 3-H NMR (DMS0-d6) d 10.37 (s, 1H), 7.58 (d, J-8.6Hz, 2H), 7.52 (d, J=1.3Hz, 1Hj, 7.12 (d, J=8.8Hz, 1H), 6.95 (d, J-8.6Hz, 2H), 6.92-6.85 (m, 5H), 4.64 (sept, J=6, 0Hz, 1H), 4.28 (bt, J=6.0Hz, 2E), 3.72 (s, 3H), 3.44-3.37 (m, 4H), 2.95-2.89 ( m, 2H), 1.73-1.60 (m, 5H), 1.36-1.28 (m, 1H), 1.25 (d, J=6.0Hz, 6H). FD mass spectrum: 517 .Analysis calcd for C31H35N04S-HCl: C, 67.19; H, 6.55; N, 2.53. Found: C, 67.15; H, 6.29; N, 2.62.

[6-isopropoksy-3 - [4- [2 - (1-piperidinyl Jetoksy]fenoksy] -2-(4-metoksyfenylJ]benzo[b]tiofen hydroklorid ble omdannet til [6-hydroksy-3-[4-[2-(l-plperidinylJetoksy]fenoksy]-2-(4-metoksyfenyl )]benzo[b]tiofen ved behandling med 2,0 ekvivalenter BCI3 ved 0-10<*>C 1 vannfri diklormetan (metyleteren ble ikke spaltet under disse betingelsene). [6-Isopropoxy-3 - [4- [2 - (1-piperidinyl Jetoxy]phenoxy] -2-(4-methoxyphenylJ)benzo[b]thiophene hydrochloride was converted to [6-hydroxy-3-[4-[2 -(l-plperidinylJetoxy]phenoxy]-2-(4-methoxyphenyl )]benzo[b]thiophene on treatment with 2.0 equivalents of BCI3 at 0-10<*>C 1 anhydrous dichloromethane (the methyl ether was not decomposed under these conditions) .

Testprosedyre Test procedure

Generell fremstillingsprosedyre General manufacturing procedure

I eksemplene illustrerer fremgangsmåtene, ble post-menopausal modell benyttet i hvilken effekten av forskjellig behandling på sirkulerende lipider ble bestemt. 75 dager gamle hunnkjønn Sprague Dawley rotter (vekt 1 området fra 200 til 225 g) ble anskaffet fra Charles Elver Laboratories (Portage, MI). Dyrene ble enten bilateralt ovariektomisert (OVX) eller eksponert for en Sham kirurgisk prosedyre ved Charles Elver Laboratories og så sendt etter en uke. Etter ankomst ble de huset i metallbur i grupper på 3 til 4 pr. bur og hadde ad libltum adgang til for (kalsium-Innhold omkring 0,5*) og vann I en uke. Eomtemperatur ble opprettholdt ved 22,2<*>±1,7°C med minimum relativt fuktighet på 40*. Fotoperioden i rommet var 12 timers lys og 12 timers mørke. In the examples illustrating the methods, a post-menopausal model was used in which the effect of different treatment on circulating lipids was determined. 75-day-old female Sprague Dawley rats (weight 1 range from 200 to 225 g) were obtained from Charles Elver Laboratories (Portage, MI). Animals were either bilaterally ovariectomized (OVX) or exposed to a Sham surgical procedure at Charles Elver Laboratories and then shipped after one week. After arrival, they were housed in metal cages in groups of 3 to 4 each. cage and had ad libltum access to (calcium content about 0.5*) and water for a week. Room temperature was maintained at 22.2<*>±1.7°C with a minimum relative humidity of 40*. The photoperiod in the room was 12 hours of light and 12 hours of darkness.

Doseringsregime, vevsoppsamllng. Etter en ukes akklimatise-ringsperiode (dvs. to uker etter OVX), ble daglig dosering med testforbindelsen Initiert. 17a-etynylestradiol eller testforbindelsen ble gitt oralt hvis ikke annet er angitt, som en suspensjon i 1* karboksymetylcellulose eller oppløst i 20* cyklodekstrin. Dyrene ble dosert daglig i 4 dager. Etter doseringsregime ble dyrene veid og bedøvet med ketamin: Xylazin (2:1, v:v) blanding og en blodprøve ble oppsamlet ved hjertepunkterlng. Dyrene ble så avlivet med asfyksierlng med COg og uterus ble fjernet gjennom et mldtlinjesnitt og en våt uterusvekt ble bestemt. Dosage regimen, tissue collection. After a one-week acclimatization period (ie, two weeks after OVX), daily dosing with the test compound was initiated. 17α-ethynylestradiol or the test compound was given orally unless otherwise indicated, as a suspension in 1* carboxymethyl cellulose or dissolved in 20* cyclodextrin. The animals were dosed daily for 4 days. Following the dosing regimen, the animals were weighed and anesthetized with a ketamine:xylazine (2:1, v:v) mixture and a blood sample was collected by cardiac puncture. The animals were then euthanized by asphyxiation with COg and the uterus was removed through a midline incision and a wet uterine weight was determined.

Kolesterolanalvse. Blodprøver fikk levre seg ved romtemperatur i 2 timer og serum ble oppnådd etter sentrlfugering i 10 minutter ved 3000 omdreininger pr. minutt. Serumkolesterol ble bestemt ved anvendelse av en høyytelse kolesterolanalyse fra Boehringer Mannheim DIagnostics. Kort sagt ble kolesterol oksydert til cholest-4-en-3-one og hydrogenperoksyd. Hydrogenperoksyd ble så reagert med fenol og 4-aminofenazon i nærvær av peroksydase for å gi et p-quinoniminfargestoff som ble avlest spektrofotomestrisk ved 500 nm. Kolesterolkon-sentrasjon ble så beregnet mot en standardkurve. Hele analysen ble automatisert ved anvendelse av en Blomek automatisert arbeidsstasjon. Cholesterol analysis. Blood samples were allowed to settle at room temperature for 2 hours and serum was obtained after centrifugation for 10 minutes at 3000 rpm. minute. Serum cholesterol was determined using a high-throughput cholesterol assay from Boehringer Mannheim DIagnostics. In short, cholesterol was oxidized to cholest-4-en-3-one and hydrogen peroxide. Hydrogen peroxide was then reacted with phenol and 4-aminophenazone in the presence of peroxidase to give a p-quinonimine dye which was read spectrophotometrically at 500 nm. Cholesterol concentration was then calculated against a standard curve. The entire analysis was automated using a Blomek automated workstation.

Uterus eosinofll peroksvdase ( EPO) analyse. Uteri ble holdt ved 4°C inntil den enzymatiske analysen. Uteri ble så homogenisert i 50 volumer 50 mM Tris buffer (pH = 8,0) inneholdende 0,005* Triton X-100. Etter tilsetning av 0,01* hydrogenperoksyd og 10 mM O-fenylendiamin (endelig konsentrasjon) i Tris buffer, ble økningen i absorbans overvåket i 1 minutt ved 450 nm. Nærværet av eosinofiler i uterus er en indikasjon på østrogenaktivitet av en forbindelse. Den maksimale hastighet I et 15 sekunders intervall ble bestemt over den Initielle, lineære delen av reaksjonskurven. Uterine eosinophil peroxidase (EPO) analysis. Uteri were kept at 4°C until the enzymatic analysis. Uteri were then homogenized in 50 volumes of 50 mM Tris buffer (pH = 8.0) containing 0.005* Triton X-100. After addition of 0.01* hydrogen peroxide and 10 mM O-phenylenediamine (final concentration) in Tris buffer, the increase in absorbance was monitored for 1 minute at 450 nm. The presence of eosinophils in the uterus is an indication of estrogenic activity of a compound. The maximum rate in a 15 second interval was determined over the initial, linear portion of the response curve.

Kilde for forbindelse: 17oi-etynylestradlol ble anskaffet fra Sigma Chemical Co., St. Louis, MO. Source of compound: 170i-ethynylestradlol was purchased from Sigma Chemical Co., St. Louis, MO.

Påvirknin<g>en av forbindelser med formel I på serumkolesterol og bestemmelse av agonist/ ikke- agonistaktivitet Data presentert i tabell 1 nedenfor viser komparative resultater blant ovariektomiserte rotter, rotter behandlet med 17a-etynylestradiol (EEg; en oral tilgjengelig form for østrogen), og rotter behandlet med visse forbindelser Ifølge foreliggende oppfinnelse. Selv om EEg forårsaket en reduksjon i serumkolesterol når administrering oralt, ved 0,1 mg/kg/dag, viser den også en stimulerende effekt på uterus slik at EE2 uterinvekt deretter ble større enn uterinvekt til ovariektomiserte testdyr. Denne uterinresponsen overfor et østrogen er vel anerkjent i teknikken. Effect of Compounds of Formula I on Serum Cholesterol and Determination of Agonist/Non-Agonist Activity Data presented in Table 1 below show comparative results among ovariectomized rats, rats treated with 17α-ethynylestradiol (EEg; an orally available form of estrogen), and rats treated with certain compounds According to the present invention. Although EEg caused a reduction in serum cholesterol when administered orally, at 0.1 mg/kg/day, it also shows a stimulating effect on the uterus such that EE2 uterine weight subsequently became greater than the uterine weight of ovariectomized test animals. This uterine response to an estrogen is well recognized in the art.

Ikke bare reduserte forbindelsen ifølge foreliggende oppfinnelse generelt serumkolesterol sammenlignet med ovariektomiserte kontrolldyr, men uterinvekt ble kun minimalt øket til svakt øket med de fleste av de testede forbindelsene ifølge foreliggende forbindelse. Sammenlignet med østrogene forbindelser som er kjent i teknikken, er fordelene med serumkolesterol uten negativ påvirkning av uterinvekt eller sjelden og ønskelig. Not only did the compound of the present invention generally reduce serum cholesterol compared to ovariectomized control animals, but uterine weight was only minimally increased to slightly increased with most of the tested compounds of the present invention. Compared to estrogenic compounds known in the art, the benefits of serum cholesterol without adverse effects on uterine weight are rare and desirable.

Som uttrykt i data nedenfor, ble østrogenlsiteten også undersøkt ved evaluering av negative responser av eoslnofil infiltrering inn i uterus. Forbindelser ifølge foreliggende oppfinnelse forårsaket ikke noen økning i antallet eosinofile observert i det stromale lag hos ovariektomiserte rotter, mens østradiol forårsaker en betydelig, forventet økning i eoslnofil infiltrering. As expressed in the data below, estrogen sensitivity was also examined when evaluating negative responses of eosinophilic infiltration into the uterus. Compounds of the present invention did not cause any increase in the number of eosinophils observed in the stromal layer of ovariectomized rats, while estradiol caused a significant, expected increase in eosinophil infiltration.

Dataene vist i tabell 1 nedenfor reflekterer responsen hos 5 til 6 rotter pr. behandling. I tillegg til de demonstrerte fordelene til forbindelsene ifølge foreliggende oppfinnelse, spesielt sammenlignet med estradiol, demonstrerer dataene ovenfor at forbindelsen med formel I Ikke er østrogenmimetika. Videre, ble det ikke observert noen toksikologiske effekter (overlevelse) med noen behandling. The data shown in Table 1 below reflect the response in 5 to 6 rats per treatment. In addition to the demonstrated advantages of the compounds of the present invention, especially compared to estradiol, the above data demonstrate that the compound of formula I is not an estrogen mimetic. Furthermore, no toxicological effects (survival) were observed with any treatment.

Osteporosetestprosedyre Osteoporosis test procedure

Den følgende generelle prepareringsprosedyren ovenfor, ble rottene behandlet daglig i 35 dager (6 rotter pr. behand-lingsgruppe) og avlivet med et karbondioksyd asfykslering på den 36. dag. Perioden på 35 dager var tilstrekkelig for å tillate maksimal reduksjon i bendensitet målt som beskrevet her. Ved avlivlngstiden ble uteri fjernet, dissekert fri for ekstravev og fluidinneholdene presset ut før bestemmelse av våtvekt for å bekrefte østrogensvikt forbundet med fullstendig ovariektomi. Uterinvekt ble rutinemessig redusert til omkring 7556 som respons på ovariektomi. Uteri ble så plassert i 10S6 nøytral buffret formalin for å tillate påfølgende histologisk analyse. Following the general preparation procedure above, the rats were treated daily for 35 days (6 rats per treatment group) and euthanized by carbon dioxide asphyxiation on the 36th day. The period of 35 days was sufficient to allow the maximum reduction in bone density measured as described here. At the time of sacrifice, the uteri were removed, dissected free of extra tissue and the fluid contents squeezed out before determination of wet weight to confirm estrogen deficiency associated with complete ovariectomy. Uterine weight was routinely reduced to around 7556 in response to ovariectomy. Uteri were then placed in 10S6 neutral buffered formalin to allow subsequent histological analysis.

Høyre femur ble tatt ut og digitaliserte røntgenstråler generert og analysert ved blldeanalyseprogram (NIH avbild-ning) av den distale metafysen. Det proksimale aspekt av tibiae fra disse dyrene ble også scannet ved kvantitativ datatomografi. The right femur was removed and digitized X-rays generated and analyzed by image analysis software (NIH imaging) of the distal metaphysis. The proximal aspect of the tibiae from these animals was also scanned by quantitative computed tomography.

Ifølge prosedyren ovenfor, ble forbindelsene ifølge foreliggende oppfinnelse og etynylestradlol (EEg) i 20* hydroksy-propyl b-cyklodekstrin oralt administrert til testdyrene. Distal femur metafysedata presentert i tabell 2 og 3 nedenfor er resultatene av behandlingen med forbindelser med formel I sammenlignet med Intakte og ovariektomiserte testdyr. Resultatene er rapportert som gjennomsnitt ± standardavvik. Oppsummering, forårsaket ovariektomi på testdyrene en signifikant reduksjon i femurdensitet sammenlignet med intakte, bærerbehandlede kontroller. Oralt administrert etynylestradiol (EEg) forandret dette tapet, men risiko for uterin stimulering med denne behandling er alltid tilstede. Forbindelsene ifølge foreliggende oppfinnelse forhindret også bentap på en generell, doseavhengig måte. Følgelig, er forbindelsen ifølge foreliggende oppfinnelse nyttig for behandling av post-menopausalt syndrom, spesielt osteoporose. According to the above procedure, the compounds of the present invention and ethynylestradlol (EEg) in 20* hydroxy-propyl b-cyclodextrin were orally administered to the test animals. Distal femur metaphyseal data presented in Tables 2 and 3 below are the results of treatment with compounds of formula I compared to intact and ovariectomized test animals. The results are reported as mean ± standard deviation. In summary, ovariectomy in the test animals caused a significant reduction in femur density compared to intact, vehicle-treated controls. Orally administered ethinylestradiol (EEg) reversed this loss, but the risk of uterine stimulation with this treatment is always present. The compounds of the present invention also prevented bone loss in a general, dose-dependent manner. Accordingly, the compound of the present invention is useful for the treatment of post-menopausal syndrome, especially osteoporosis.

MCF- 7 prollferasjonsanalvse MCF-7 proliferation assay

MCF-7 brystadenocarcinomaceller (ATCC HTB 22) ble holdt i MEM (minimal essential medium, fenol rød-frl, Sigma, St. Louis, MO) supplementert med 10* fetalt bovint serum (FBS), (v/v), L-glutamin (2 mM), natriumpyruvat (1 mM), HEPES ((N-[2-hydroksyetyl)piperazin-N<*->[2-etansulfonsyre]10 mM}, ikke-essensielle aminosyrer og bovint insulin (1 jjg/ml) (opprettholdelsesmedium). 10 dager før analysen ble MCF-7 celler byttet til opprettholdelsesmedium tilsatt 10* dekstranbelagt karbonstrippet fetalt bovint serum (DCC-FBS) analysemedium) i stedenfor 10* FBS for å tømme interne lagre av steroider. MCF-7 celler ble fjernet fra opprettholdelsesflaskene ved anvendelse av celledissoslasjonsmedium (Ca++/Mg++ fri HBSS (fenol rød-fritt) supplementert med 10 mM HEPES og 2 mM EDTA). Celler ble vasket to ganger med analysemedium og justert til 80000 celler/ml. MCF-7 breast adenocarcinoma cells (ATCC HTB 22) were maintained in MEM (minimal essential medium, phenol red-frl, Sigma, St. Louis, MO) supplemented with 10* fetal bovine serum (FBS), (v/v), L- glutamine (2 mM), sodium pyruvate (1 mM), HEPES ((N-[2-hydroxyethyl)piperazine-N<*->[2-ethanesulfonic acid]10 mM}, non-essential amino acids and bovine insulin (1 jjg/ml ) (maintenance medium). 10 days before the assay, MCF-7 cells were switched to maintenance medium supplemented with 10* dextran-coated carbon-stripped fetal bovine serum (DCC-FBS) assay medium) instead of 10* FBS to deplete internal stores of steroids. MCF-7 cells were removed from the maintenance flasks using cell dissociation medium (Ca ++ /Mg ++ free HBSS (phenol red-free) supplemented with 10 mM HEPES and 2 mM EDTA). Cells were washed twice with assay medium and adjusted to 80,000 cells/ml.

Omkring 100 ml (8000 celler) ble tilsatt til flatbunnede mlkrokulturbrønner (Costar 3596) og Inkubert ved 37<*>C i en 5* COg fuktet Inkubator i 48 timer for å tillate celleved-hefting og ekvilibrering etter overføring. Serielle fortyn-ninger av et medikament eller DMSO som fortynningskontroll ble fremstilt i analysemedium og 50 ml overført til tripli-kate mikrokulturer fulgt av 50 ml analysemedium til et endelig volum på 200 ml. Etter ytterligere 48 timer ved 37"C i en 5* COg fuktet inkubator, ble mikrokulturer pulsert med tritert tymidin (1 >jCl/brønn) i 4 timer. Kulturer ble terminert ved frysting ved -70<*>C i 24 timer etterfulgt av tining og høsting av mikrokulturer ved anvendelse av Skatron halvautomatiske cellehøster. Prøver ble talt ved væskescin-tillasjonstelling ved anvendelse av en Wallac BetaPlace b teller. Resultatene I tabell 4 nedenfor viser IC5Q av visse forbindelser ifølge foreliggende oppfinnelse. About 100 ml (8000 cells) were added to flat-bottom microculture wells (Costar 3596) and incubated at 37<*>C in a 5* COg humidified Incubator for 48 hours to allow cell attachment and equilibration after transfer. Serial dilutions of a drug or DMSO as a dilution control were prepared in assay medium and 50 ml transferred to triplicate microcultures followed by 50 ml of assay medium to a final volume of 200 ml. After an additional 48 hours at 37"C in a 5* COg humidified incubator, microcultures were pulsed with tritrated thymidine (1 >jCl/well) for 4 hours. Cultures were terminated by freezing at -70<*>C for 24 hours followed by thawing and harvesting of microcultures using Skatron semi-automatic cell harvesters. Samples were counted by liquid scintillation counting using a Wallac BetaPlace b counter. The results in Table 4 below show the IC5Q of certain compounds of the present invention.

DMBA- indusert mammatumorinhiblterlng DMBA-induced mammary tumor inhibition

Østrogenavhengige mammatumorer ble produsert i hunnkjønns Sprague-Dawley rotter som ble anskaffet fra Harlan Industries, Indianapolis, Indiana. Ved omkring 55 dagers alder, mottok rottene en enkel oral foring med 20 mg 7,12-dimetylbenz[a]antracen (DMBA). Omkring 6 uker DMBA administrasjon, ble mammakjertelene palpatert ved ukentlige Intervaller for tilsynekomst av tumorer. Når en eller flere tumorer kom tilsyne, ble den lengste og korteste diameteren av hver tumor målt med en metrisk passer, målene ble registrert og dyrene ble valgt for eksperimentering. Et forsøk ble gjort for uniformt å distribuere de forskjellige størrelsene av tumorer i behandlede og kontrollgrupper, slik at tumorenes gjennomsnittstørrelse ble likt fordelt mellom testgruppene. Kontrollgrupper og testgrupper for hvert eksperiment inneholder 5 til 9 dyr. Estrogen-dependent mammary tumors were produced in female Sprague-Dawley rats obtained from Harlan Industries, Indianapolis, Indiana. At about 55 days of age, the rats received a single oral gavage of 20 mg of 7,12-dimethylbenz[a]anthracene (DMBA). Around 6 weeks of DMBA administration, the mammary glands were palpated at weekly intervals for the appearance of tumors. When one or more tumors appeared, the longest and shortest diameters of each tumor were measured with a metric caliper, the measurements were recorded, and the animals were selected for experimentation. An attempt was made to uniformly distribute the different sizes of tumors in treated and control groups, so that the average size of the tumors was equally distributed between the test groups. Control groups and test groups for each experiment contain 5 to 9 animals.

Forbindelser med formel I ble administrert enten gjennom en intraperitoneal injeksjon i 2* acacia, eller oralt. Compounds of formula I were administered either through an intraperitoneal injection in 2* acacia, or orally.

Oralt administrerte forbindelser ble enten oppløst eller suspendert i 0,2 ml malsolje. Hver behandling, Inkludert acacia og maisolJekontrollbehandlinger, ble administrert en gang daglig til hvert testdyr. Etter den initielle tumor-målingen og utvelgelse av testdyr, ble tumorer målt hver uke ved den ovenfor nevnte fremgangsmåten. Behandlingen og målingen av dyrene fortsatte i 3 til 5 uker ved hvilken tid det endelige arealet av tumorer ble bestemt. For hver forbindelse og kontrollbehandling, ble forandring i gjen-nomsnittlig tumorareal bestemt. Orally administered compounds were either dissolved or suspended in 0.2 ml of malt oil. Each treatment, including acacia and corn oil control treatments, was administered once daily to each test animal. After the initial tumor measurement and selection of test animals, tumors were measured every week by the above-mentioned method. Treatment and measurement of the animals continued for 3 to 5 weeks at which time the final area of tumors was determined. For each compound and control treatment, change in mean tumor area was determined.

Uterin fibrosetestprosedvrer Uterine fibrosis test procedures

Test 1 Test 1

Mellom 3 og 20 kvinner med uterin fibrose ble administrert en forbindelse ifølge foreliggende oppfinnelse. Mengden av en forbindelse administrert er fra 0,1 til 1000 mg/dag, og administrasjonsperioden er 3 måneder. Between 3 and 20 women with uterine fibrosis were administered a compound according to the present invention. The amount of a compound administered is from 0.1 to 1000 mg/day, and the administration period is 3 months.

Kvinnene ble observert under administrasjonsperioden og opp til 3 måneder etter avbruddet av administrasjonen for effektene på uterin fibrose. The women were observed during the administration period and up to 3 months after the interruption of administration for the effects on uterine fibrosis.

Test 2 Test 2

Den samme prosedyren ble benyttet som i test 1, bortsett fra administrasjonsperioden var 6 måneder. The same procedure was used as in test 1, except that the administration period was 6 months.

Test 3 Test 3

Prosedyren ble benyttet som i test 1, bortsett fra at administrasjonsperioden var 1 år. The procedure was used as in test 1, except that the administration period was 1 year.

Test 4 Test 4

A. Induksjon av fibroide tumorer i marsvin. A. Induction of fibroid tumors in guinea pigs.

Forlenget østrogenstimulering ble benyttet for å indusere leiomyomata i seksuelt modne hunnkjønns marsvin. Dyrene ble dosert med estradiol 3 til 5 ganger pr. dag ved injeksjon i 2 til 4 måneder eller Inntil tumorer ble dannet. Behandlinger bestående av forbindelser ifølge oppfinnelsen eller bærere ble administrert daglig i 3-16 uker og så ble dyrene avlivet og uteri høstet og analysert for tumorregressjon. Prolonged estrogen stimulation was used to induce leiomyomata in sexually mature female guinea pigs. The animals were dosed with estradiol 3 to 5 times per day by injection for 2 to 4 months or Until tumors were formed. Treatments consisting of compounds according to the invention or carriers were administered daily for 3-16 weeks and then the animals were killed and uteri harvested and analyzed for tumor regression.

B. Implantering av humant uterin fibroidvev i nakne mus. B. Implantation of human uterine fibroid tissue in nude mice.

Vev fra humane leiomyomas ble implantert I det peritoneale hulrommet og/eller uterine - myometrium i seksuelt modne, kastrerte hunnkjønns nakne mus. Eksogent østrogen ble tilført for å indusere vekst i det eksplanterte vevet. I noen tilfeller, ble de dyrkede tumorcellene dyrket ln vitro før implantering. Behandling omfattende en forbindelse ifølge foreliggende oppfinnelse eller bærere ble tilført ved gastrisk sonde på daglig basis I 3-16 uker og lmplantanter ble fjernet og målt for vekst eller regressjon. Ved av-llvingstiden ble uteri høstet for å måle organets status. Tissues from human leiomyomas were implanted into the peritoneal cavity and/or uterine myometrium of sexually mature, castrated female nude mice. Exogenous estrogen was added to induce growth in the explanted tissue. In some cases, the cultured tumor cells were cultured in vitro before implantation. Treatment comprising a compound of the present invention or carriers was administered by gastric tube on a daily basis for 3-16 weeks and implants were removed and measured for growth or regression. At the weaning time, the uteri were harvested to measure the status of the organ.

Test 5 Test 5

A. Vev fra humane uterin fibroidtumorer ble høstet og opprettholdt ln vitro som primære ikke-transformerte kulturer. Kirurgiske prøver ble trykket gjennom en steril sikt eller sli eller alternativt revet løs fra omgivende vev for å produsere en enkelcellesuspensjon. Celler ble opprettholdt I medium inneholdende 10* serum og antibiotika. Veksthastigheter i nærvær eller fravær av østrogen ble bestemt. Celler ble analysert for deres evne til å produsere kompiementkomponent C3 og deres respons for vekstfaktorer og veksthormon. In vitro kulturer ble målt for deres prolifera-sjonsrespons etter behandling med progestiner, GnRH, en forbindelse ifølge foreliggende oppfinnelse og bærer. Nivåer av steroide hormonreseptorer ble målt ukentlig for å bestemme om viktige cellekarakteristikker ble opprettholdt in vitro. Vev fra 5-25 pasienter ble benyttet. A. Tissues from human uterine fibroid tumors were harvested and maintained in vitro as primary non-transformed cultures. Surgical specimens were pressed through a sterile sieve or slip or alternatively detached from surrounding tissue to produce a single cell suspension. Cells were maintained in medium containing 10* serum and antibiotics. Growth rates in the presence or absence of estrogen were determined. Cells were analyzed for their ability to produce complement component C3 and their response to growth factors and growth hormone. In vitro cultures were measured for their proliferation response after treatment with progestins, GnRH, a compound of the present invention and vehicle. Levels of steroid hormone receptors were measured weekly to determine whether important cell characteristics were maintained in vitro. Tissue from 5-25 patients was used.

Aktivitet i minst en av de ovenfor nevnte testene indikerer at forbindelsen ifølge foreliggende oppfinnelse er poten-sielle for behandling av uterin fibrose. Activity in at least one of the above-mentioned tests indicates that the compound according to the present invention has potential for the treatment of uterine fibrosis.

Endometriosetestprosedvrer Endometriosis test procedures

I testene 1 og 2 ble effekter av 14 dagers og 21 dagers administrasjon av forbindelser ifølge foreliggende oppfinnelse på veksten av eksplanterte endometrialt vev undersøkt. In tests 1 and 2, effects of 14-day and 21-day administration of compounds according to the present invention on the growth of explanted endometrial tissue were examined.

Test 1 Test 1

12 til 30 voksne CD stamme hunnkjønnsrotter ble benyttet som testdyr. De ble delt inn i tre grupper med likt antall. Østrossyklus til alle dyrene ble overvåket. På dagen før østeros, ble kirurgi utført på hvert dyr. Dyrene i hver gruppe fikk det venstre uterinhorn fjernet, seksjonert i små kvadrater og kvadratene ble løst suturert til forskjellige seter naboliggende til den mesenteriske blodstrøm. I tillegg, fikk dyrene i gruppe 2 ovariene fjernet. 12 to 30 adult CD strain female rats were used as test animals. They were divided into three groups of equal numbers. Estrous cycle of all animals was monitored. On the day before estrus, surgery was performed on each animal. The animals in each group had the left uterine horn removed, sectioned into small squares and the squares were loosely sutured to various sites adjacent to the mesenteric blood stream. In addition, the animals in group 2 had their ovaries removed.

Dagen etter kirurgi, mottok dyrene i gruppe 1 og 2 intraperitoneale Injeksjoner av vann i 14 dager mens dyrene 1 gruppe 3 mottok intraperitoneale injeksjoner av 1,0 mg av en forbindelse Ifølge foreliggende oppfinnelse pr. kg kroppsvekt med den samme varighet. Etter 14 dagers behandling ble hvert dyr avlivet og endometrlaleksplantanter, binyrer, gjenværende uterus og ovarier hvor tilstede, ble fjernet og preparert for histologiske undersøkelser. Ovariene og binyrene ble veid; The day after surgery, the animals in groups 1 and 2 received intraperitoneal injections of water for 14 days while the animals in group 1 received intraperitoneal injections of 1.0 mg of a compound according to the present invention per kg body weight with the same duration. After 14 days of treatment, each animal was euthanized and endometrial explants, adrenal glands, remaining uterus and ovaries where present, were removed and prepared for histological examination. The ovaries and adrenal glands were weighed;

Test 2 Test 2

12 til 30 voksne CD stamme hunnkjønnsrotter ble benyttet som testdyr. De ble inndelt i to like grupper. Østrosyklus til alle dyrene ble overvåket. På dagen før østerus ble kirurgi utført på hvert dyr. Dyrene i hver gruppe fikk det venstre uterinhorn fjernet, seksjonert i små kvadrater og kvadratene ble løst suturert til forskjellige steder nærliggende den mesenteriske blodstrøm. 12 to 30 adult CD strain female rats were used as test animals. They were divided into two equal groups. The estrous cycle of all animals was monitored. On the day before oestrus, surgery was performed on each animal. The animals in each group had the left uterine horn removed, sectioned into small squares and the squares were loosely sutured to various locations near the mesenteric blood flow.

Omkring 50 dager etter kirurgi fikk dyrene i gruppe 1 intraperitoneale injeksjoner av vann i 21 dager, mens dyrene i gruppe 2 mottok intraperitoneale injeksjoner av 1,0 mg av en forbindelse ifølge foreliggende oppfinnelse pr. kg kroppsvekt under den samme varighet. Etter 21 dagers behandling ble hvert dyr avlivet og de endometriale eksplantantene og binyrene ble fjernet og veid. Eksplantantene ble målt som en indikasjon på vekst. Østerussykluser ble overvåket. About 50 days after surgery, the animals in group 1 received intraperitoneal injections of water for 21 days, while the animals in group 2 received intraperitoneal injections of 1.0 mg of a compound according to the present invention per kg of body weight during the same duration. After 21 days of treatment, each animal was sacrificed and the endometrial explants and adrenal glands were removed and weighed. The explants were measured as an indication of growth. Estrus cycles were monitored.

Test 3 Test 3

A. Kirurgisk Induksjon av endometriose A. Surgical Induction of endometriosis

Autografer av endometrialt vev ble benyttet for å indusere endometriose hos rotter og/eller kaniner. Hunnkjønnsdyr ved reproduktiv modenhet gjennomgikk bilaterial ooforektoml og østrogen ble tilført eksogent for således å gi spesifikt og konstant nivåhormon. Autologt endometrialt vev ble implantert i peritoneum i 5-150 dyr og østrogen ble tilført for å indusere vekst i det eksplanterte vevet. Behandling bestående av at en forbindelse ifølge foreliggende oppfinnelse bli tilført av sonde på daglig basis i 3 til 16 uker og Implan-tantene ble fjernet og målt for vekst eller regressjon. Ved avlivingstiden ble intakte uterushorn høstet for å måle status av endometrium. Autographs of endometrial tissue were used to induce endometriosis in rats and/or rabbits. Female animals at reproductive maturity underwent bilaterial oophorectomy and estrogen was added exogenously to thus provide specific and constant levels of hormone. Autologous endometrial tissue was implanted into the peritoneum of 5-150 animals and estrogen was added to induce growth in the explanted tissue. Treatment consisting of a compound according to the present invention being administered by probe on a daily basis for 3 to 16 weeks and the implants being removed and measured for growth or regression. At the time of sacrifice, intact uterine horns were harvested to measure the status of the endometrium.

B. Implantering av endometrialt vev I nakne mus. B. Implantation of endometrial tissue In nude mice.

Vev fra humane endometriale lesjoner ble implantert 1 peritoneum på seksuelt modne, kastrerte hunnkjønns nakne mus. Eksogent østrogen ble tilført for å indusere vekst i det eksplanterte vev. I noen tilfeller, ble høstede endometriale celler dyrket in vitro før implantering. Behandling omfattende en forbindelse ifølge foreliggende oppfinnelse tilført ved mavesonde på daglig basis I 3 til 16 uker, og implantan-tené ble fjernet og målt for vekst eller regressjon. Ved avlivingstiden ble uteri høstet for å undersøke status I det Intakte endometrium. Tissue from human endometrial lesions was implanted 1 peritoneum into sexually mature, castrated female nude mice. Exogenous estrogen was added to induce growth in the explanted tissue. In some cases, harvested endometrial cells were cultured in vitro before implantation. Treatment comprising a compound according to the present invention administered by stomach tube on a daily basis for 3 to 16 weeks, and the implant antenna was removed and measured for growth or regression. At the time of killing, the uteri were harvested to examine the status of the intact endometrium.

Test 4 Test 4

A. Vev fra humane endometriale lesjoner ble høstet og opprettholdt in vitro som primære ikke-transformerte kulturer. A. Tissues from human endometrial lesions were harvested and maintained in vitro as primary non-transformed cultures.

Kirurgiske prøver ble presset gjennom en steril skjerm eller sikt eller alternativt revet bort fra omgivende vev for å gi enkeltcellesuspensjoner. Celler ble opprettholdt i medium Inneholdende 10* serum og antiobiotika. Veksthastigheter i nærvær og fravær av østrogen ble bestemt. Celler ble analysert for deres evne til å produsere kompiementkomponent C3 og deres respons for vekstfaktorer og veksthormon. In vltrokulturer ble undersøkt for deres proliferative respons etter behandling med progestiner, GnRH, en forbindelse Ifølge oppfinnelsen og bærer. Nivåer av steroidhormonreseptoren ble analysert ukentlig for å bestemme om implantatcellekarak-teristika ble opprettholdt in vitro. Vev fra 5 til 25 pasienter ble benyttet. Surgical specimens were pressed through a sterile screen or sieve or alternatively scraped away from surrounding tissue to yield single cell suspensions. Cells were maintained in medium containing 10* serum and antibiotics. Growth rates in the presence and absence of estrogen were determined. Cells were analyzed for their ability to produce complement component C3 and their response to growth factors and growth hormone. In vitro cultures were examined for their proliferative response after treatment with progestins, GnRH, a compound according to the invention and vehicle. Steroid hormone receptor levels were analyzed weekly to determine whether implant cell characteristics were maintained in vitro. Tissue from 5 to 25 patients was used.

Aktivitet i en hvilken som helst av analysene ovenfor Indikerer at forbindelsen Ifølge foreliggende oppfinnelsen er nyttige ved behandling av endometriose. Activity in any of the above assays indicates that the compound of the present invention is useful in the treatment of endometriosis.

Foreliggende oppfinnelse fremskaffer også en fremgangsmåte for letting av post-menopausalt syndrom hos kvinner som omfatter den ovenfor nevnte fremgangsmåten ved anvendelse av forbindelser med formel I og ytterligere omfatter administrering til en kvinne en effektiv mengde av østrogen eller progestln. Disse behandlingene er spesielt nyttige for behandling av osteoporose og senking av serumkolesterol da pasienten vil få fordelen av hvert farmasøytisk middel mens forbindelsen ifølge foreliggende oppfinnelse vil hemme uønskede bieffekter av østrogen og progestin. Alternativt til disse kombinasjonsbehandlingene i en hvilken som helst av de post-menopausale testene indikerer at behandlingene i en hvilken som helst av de post-menopausale testene ovenfor, at kombinasjonsbehandlingen er nyttig for letting av symptomene av post-menopausale symtomer hos kvinner. The present invention also provides a method for alleviating post-menopausal syndrome in women comprising the above-mentioned method using compounds of formula I and further comprising administering to a woman an effective amount of estrogen or progestin. These treatments are particularly useful for treating osteoporosis and lowering serum cholesterol as the patient will receive the benefit of each pharmaceutical agent while the compound of the present invention will inhibit unwanted side effects of estrogen and progestin. Alternatively to these combination treatments in any of the post-menopausal tests, the treatments in any of the above post-menopausal tests indicate that the combination treatment is useful for alleviating the symptoms of post-menopausal symptoms in women.

Forskjellige former for østrogen og progestin er kommersielt tilgjengelig. Østrogenbaserte midler omfatter f.eks. etynylestrogen (0,01-0,03 mg/dag), mestranol (0,05-0,15 mg/dag) og konjugert østrogenlske hormoner slik som Premarin (Wyeth-Ayerst; 0,3-2,5 mg/dag). Progestlnbaserte midler omfatter f.eks. medroksyprogestron slik som Provera (Upjohn; 2,5-10 mg/dag), noretylnodrel (1,0-10 mg/dag) og nonetlndron (0,5-2,0 mg/dag). En foretrukket østrogenbasert forbindelse er premarin, og noretylnodrel og noretindron er foretrukne progestinbaserte midler. Various forms of estrogen and progestin are commercially available. Estrogen-based agents include e.g. ethynyl estrogen (0.01-0.03 mg/day), mestranol (0.05-0.15 mg/day) and conjugated estrogenic hormones such as Premarin (Wyeth-Ayerst; 0.3-2.5 mg/day) . Progestln-based agents include e.g. medroxyprogesterone such as Provera (Upjohn; 2.5-10 mg/day), norethylnodrel (1.0-10 mg/day), and nonetlndrone (0.5-2.0 mg/day). A preferred estrogen-based compound is premarin, and norethylnodrel and norethindrone are preferred progestin-based agents.

Fremgangsmåten for administrasjon av hver av de østrogen- og progestinbaserte midlene er i samsvar med det som er kjent 1 teknikken. For majoriteten av fremgangsmåtene ifølge foreliggende oppfinnelse, blir forbindelsen med formel I administrert kontinuerlig fra 1 til 3 ganger daglig. Imidlertid, kan cyklisk terapi være spesielt anvendelig i behandling av endometriose eller kan bli benyttet akutt under smertefulle anfalle av sykdommen. I tilfelle av restenose, kan terapi bli begrenset til korte (1-6 måneder) Intervaller etter medisinske prosedyrer slik som angiopiasti. The method of administration of each of the estrogen- and progestin-based agents is in accordance with what is known in the art. For the majority of the methods according to the present invention, the compound of formula I is administered continuously from 1 to 3 times daily. However, cyclic therapy can be particularly useful in the treatment of endometriosis or can be used acutely during painful attacks of the disease. In the case of restenosis, therapy may be limited to short (1-6 months) intervals after medical procedures such as angioplasty.

Som benyttet her, betyr uttrykket "effektiv mengde" en mengde av en forbindelse Ifølge foreliggende oppfinnelse som er i stand til å lette symptomene til forskjellige patologiske tilstander beskrevet her. Den spesifikke dosen av en forbindelse administrert ifølge foreliggende oppfinnelse vil naturligvis bli bestemt av de bestemte forholdene som gir tilfellet, Inkludert f.eks. den administrerte forbindelsen, administrasjonsvelen, tilstanden til pasienten og den patologiske tilstanden som blir behandlet. En typisk daglig dose vil Inneholdende et ikke-toksisk doseringsnivå fra omkring 5 mg til omkring 600 mg/dag av en forbindelse Ifølge foreliggende oppfinnelse. Foretrukne daglige doser vil generelt være fra omkring 15 mg til omkring 80 mg/dag. As used herein, the term "effective amount" means an amount of a compound of the present invention capable of alleviating the symptoms of various pathological conditions described herein. The specific dose of a compound administered according to the present invention will of course be determined by the particular conditions that present the case, including e.g. the compound administered, the ease of administration, the condition of the patient and the pathological condition being treated. A typical daily dose will contain a non-toxic dosage level of from about 5 mg to about 600 mg/day of a compound according to the present invention. Preferred daily doses will generally be from about 15 mg to about 80 mg/day.

Forbindelsene ifølge oppfinnelsen kan bli administrert på forskjellige måter, inkludert oralt, rektalt, transdermalt, subkutant, intravenøst, Intramuskulært og Intranasalt. Disse forbindelsene blir fortrinnsvis formulert før administrasjon, valget av hvilken vil bil avgjort av behandlende lege. Et annet aspekt ved foreliggende oppfinnelse en således en farmasøytisk sammensetning omfattende en effektiv mengde av en forbindelse med formel I eller et farmasøytisk akseptabelt salt derav, eventuelt inneholdende en effektiv mengde østrogen eller progestin og en farmasøytisk akseptabel bærer, fortynner eller hjelpestoff. The compounds of the invention can be administered in various ways, including orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly and intranasally. These compounds are preferably formulated before administration, the choice of which will be decided by the attending physician. Another aspect of the present invention is thus a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally containing an effective amount of estrogen or progestin and a pharmaceutically acceptable carrier, diluent or excipient.

De totale aktive ingrediensene i slike formuleringer omfatter fra omkring 0,1 til omkring 99,9 vekt-* av formulering. Ved "farmasøytisk akseptable" er det ment at bæreren, fortynneren og hjelpestoffet og saltet må være forenelig med de andre ingrediensene i formuleringen og Ikke er skadelig for mottakeren derav. The total active ingredients in such formulations comprise from about 0.1 to about 99.9% by weight of formulation. By "pharmaceutically acceptable" it is meant that the carrier, diluent and excipient and salt must be compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

Farmasøytiske formuleringer Ifølge foreliggende oppfinnelse kan bli fremstilt ved prosedyrer som er kjent I teknikken ved anvendelse av velkjente og lett tilgjengelige ingredienser. For eksempel, kan forbindelsene med formel I med eller uten østrogen eller progestinforbindelser, bli formulert med vanlige hjelpestoffer, fortynnere eller bærere og formet til tabletter, kapsler, suspensjoner, pulvere og lignende. Eksempler på hjelpestoffer, fortynnere og bærere som er passende for slike formuleringer omfatter de følgende: fyllstoffer og utvidere slik som stivelse, sukkere, mannitol og kiselsyrederlvater; bindemidler slik som karboksymetylcellulose og andre cellulosederivater, alginater, gelatin og polyvinylpyrrolidon; fuktingsmidler slik som glyserol; disintegreringsmidler slik som kalsiumkarbonat og natriumbikarbonat; midler for forsinket oppløsning slik som paraffin; resorpsjonsakselleratorer slik som kvaternære ammoniumforbindelser; overflateaktive midler som cetylalko-hol, glyserol monostearat; adsorptive bærere slik som kaolln og bentonit og smørende midler slik som talk, kalsium og magnesiumstearat, og faste polyetylglykoler. Pharmaceutical formulations according to the present invention can be prepared by procedures known in the art using well-known and easily available ingredients. For example, the compounds of formula I with or without estrogen or progestin compounds may be formulated with common excipients, diluents or carriers and formed into tablets, capsules, suspensions, powders and the like. Examples of excipients, diluents and carriers suitable for such formulations include the following: fillers and extenders such as starches, sugars, mannitol and silicic acid hydrates; binders such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants such as glycerol; disintegrants such as calcium carbonate and sodium bicarbonate; delayed dissolution agents such as paraffin; resorption accelerators such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite and lubricants such as talc, calcium and magnesium stearate, and solid polyethylene glycols.

Forbindelsene kan også bli formulert som eleksirer eller oppløsninger for bekvem oral administrasjon eller som oppløsningsmldler som passer for parenteral administrasjon, f.eks. ved intramuskulær, subkutan eller Intravenøs vei. I tillegg, er forbindelsene vel tilpasset formulering som doseringsformer for vedvarende frigiving og lignende. Formuleringene kan også bli slik sammensatt at de frigir de aktive ingrediensene kun eller fortrinnsvis i spesielle fysiologiske steder, muligens over en tidsperiode. Beleggene, kappene og beskyttende matrikser kan bli fremstilt fra polymere stoffer eller vokser. The compounds may also be formulated as elixirs or solutions for convenient oral administration or as solvents suitable for parenteral administration, e.g. by intramuscular, subcutaneous or intravenous route. In addition, the compounds are well adapted to formulation as dosage forms for sustained release and the like. The formulations can also be composed in such a way that they release the active ingredients only or preferentially in particular physiological locations, possibly over a period of time. The coatings, sheaths and protective matrices can be made from polymeric substances or waxes.

Forbindelsene med formel I, alene eller i kombinasjon med et farmasøytisk middel ifølge foreliggende oppfinnelse, vil generelt bli administrert i en bekvem formulering. De følgende formuleringseksemplene er kun Illustrative og er ikke ment å begrense rammen av foreliggende oppfinnelse. The compounds of formula I, alone or in combination with a pharmaceutical agent according to the present invention, will generally be administered in a convenient formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.

Formuleringer Formulations

I formuleringen som følger, betyr "aktiv Ingrediens" en forbindelse med formel I eller et salt eller solvat derav. In the formulation that follows, "active ingredient" means a compound of formula I or a salt or solvate thereof.

Formulering 1: Gelatinkapsler Formulation 1: Gelatin capsules

Formuleringene ovenfor kan bli forandret I samsvar med de fornuftige variasjonene som er gitt. The above formulations may be changed in accordance with the reasonable variations provided.

En tablettformulering ble fremstilt ved anvendelse av ingrediensene nedenfor: A tablet formulation was prepared using the ingredients below:

Komponentene ble blandet og presset for å danne tabletter. The components were mixed and pressed to form tablets.

Alternativt blir tabletter hver Inneholdende 2,5-1000 mg aktiv Ingrediens fremstilt som følger: Alternatively, tablets each containing 2.5-1000 mg of active ingredient are prepared as follows:

Den aktive ingrediensen, stivelsen og cellulosen ble ledet gjennom en nr. 45 mesh U.S. sikt og blandet grundig. Opp-løsningen av polyvinylpyrrolldon ble blandet med det resulterende pulveret som så ble ledet gjennom en nr. 14 mesh U.S. sikt. Kornene produsert slik ble tørket ved 50-60<*>C og ledet gjennom en nr. 18 mesh U.S. sikt. Natriumkarboksy-metylstivelsen, magnesiumstearatet og talket som på forhånd var ledet gjennom en nr. 60 U.S. sikt ble så tilsatt til kornene som etter blanding ble presset på en tabletterlngs-maskin for å gi tabletter. The active ingredient, starch and cellulose were passed through a No. 45 mesh U.S. sieve and mix thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder which was then passed through a No. 14 mesh U.S. term. The grains thus produced were dried at 50-60<*>C and passed through a No. 18 mesh U.S. term. The sodium carboxymethyl starch, magnesium stearate and talc previously passed through a No. 60 U.S. sieve was then added to the grains which after mixing were pressed on a tableting machine to give tablets.

Suspensjoner hver inneholdende 0,1-1000 mg medikament pr. 5 ml dose blir fremstilt som følger: Suspensions each containing 0.1-1000 mg of drug per The 5 ml dose is prepared as follows:

Formulering 4: Suspensjoner Formulation 4: Suspensions

Medikamentet ble ledet gjennom en nr. 45 mesh U.S. sikt og blandet med natriumkarboksymetylcellulosen og sirupen for å danne en glatt pasta. Benzosyreoppløsningen, smaken og farven ble fortynnet med noe av vannet og tilsatt, under omrøring. Tilstrekkelig vann ble så tilsatt for å produsere det ønskede volum. The drug was passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, taste and color was diluted with some of the water and added, with stirring. Sufficient water was then added to produce the desired volume.

En aerosoloppløsning ble fremstilt inneholdende de følgende Ingredienser: An aerosol solution was prepared containing the following ingredients:

Formulering 5: Aerosol Formulation 5: Aerosol

Den aktive ingrediensen ble blandet med etanol og blandingen tilsatt til en del av propellant 22, avkjølt til 30°C og overført i en påfyllIngsanordning. Den nødvendige mengden ble så tilført en rustfri stålbeholder og fortynnet med det gjenværende drivmidlet. Ventilenheter ble satt på beholderen. The active ingredient was mixed with ethanol and the mixture added to a portion of propellant 22, cooled to 30°C and transferred into a filling device. The required amount was then added to a stainless steel container and diluted with the remaining propellant. Valve assemblies were put on the container.

Stikkpiller ble fremstilt som følger: Suppositories were prepared as follows:

Formulering 6: Stikkpiller Formulation 6: Suppositories

Den aktive Ingrediensen ble ledet gjennom en nr. 60 mesh U.S. sikt og suspendert i de mettede fettsyreglyseridene som på forhånd var smeltet ved anvendelse av minimal nødvendig varme. Blandingen ble så heilt i en stlkkpilleform med en nominell kapasitet på 2 g og avkjølt. The active ingredient was passed through a No. 60 mesh U.S. sifted and suspended in the saturated fatty acid glycerides which had previously been melted using the minimum necessary heat. The mixture was then poured into a pill form with a nominal capacity of 2 g and cooled.

En intravenøs formulering ble fremstilt som følger: An intravenous formulation was prepared as follows:

Formulerin<g> 7: Intravenøs oppløsning Formulerin<g> 7: Intravenous solution

Oppløsningen av ingrediensene ovenfor blir intravenøst administrert til en pasient ved en hastighet på omkring 1 ml pr. minutt. The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 ml per minute.

Formulerin<g> 8: Kombinasjonskapsel I Formulerin<g> 8: Combination capsule I

Formulering 9: Kombinasjonskapsel II Formulation 9: Combination capsule II

Formulering 10: Kombinasjonstablett Formulation 10: Combination tablet

Claims

1. Forbindelse, karakterisert ved formel I hvori R<1> er -H, -OH, -0(C1-C4 alkyl), -0C0C6H5, -OCOfC-t-Cf, alkyl), eller -OSOgfCg-Cf, alkyl); R<2> er -H, -OH, -0(C1-C4 alkyl), -0C0C6H5, -OCOfCj-Cf, alkyl), eller -OSOgtCg-Cf, alkyl), eller halo; r<3> er 1-piperidinyl, 1-pyrrolidinyl, metyl-l-pyrrolidinyl, dimetyl-l-pyrrolidinyl, 4-morfolino, dimetylamino, dietylamino, diisopropylamino, eller 1-heksametylenimino; n er 2 eller 3; og Z er -0- eller -S-; eller et farmasøytisk akseptabelt salt derav.1. Compound characterized by formula I in which R<1> is -H, -OH, -O(C1-C4 alkyl), -OC0C6H5, -OCOfC-t-Cf, alkyl), or -OSOgfCg-Cf, alkyl); R<2> is -H, -OH, -O(C1-C4 alkyl), -OC0C6H5, -OCOfCj-Cf, alkyl), or -OSOgtCg-Cf, alkyl), or halo; r<3> is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and Z is -0- or -S-; or a pharmaceutically acceptable salt thereof.

2. Farmasøytisk formulering, karakterisert ved at den omfatter som en aktiv ingrediens en forbindelse ifølge krav 1 og, eventuelt østrogen eller progestin, sammen med en eller flere farmasøytisk akseptable bærere, hjelpestoffer eller fortynnere.2. Pharmaceutical formulation, characterized in that it comprises as an active ingredient a compound according to claim 1 and, optionally estrogen or progestin, together with one or more pharmaceutically acceptable carriers, excipients or diluents.

3. Forbindelse, karakterisert ved formel XIV hvor g<la> er _g eller -OR<7>, hvor R<7> er en hydroksybeskyttende gruppe; g2a er _u) halo, eller -OR<8>, hvor R<8> er en hydroksybeskyttende gruppe; og r<9> er en avspaltbar gruppe; eller et farmasøytisk akseptabelt salt derav.3. Compound characterized by formula XIV wherein g<la> is _g or -OR<7>, where R<7> is a hydroxy protecting group; g2a is _u) halo, or -OR<8>, where R<8> is a hydroxy protecting group; and r<9> is a leaving group; or a pharmaceutically acceptable salt thereof.

4. Forbindelse, karakterisert ved formelen hvor Rla er _n eller -OR<7>, hvor R<7> er en hydroksybeskyttende gruppe; R<2a> er -H, halo, eller -OR<8>, hvor R<8> er en hydroksybeskyttende gruppe; R^ er -H eller en hydroksybeskyttende gruppe som kan bli selektivt fjernet; R<11> er ikke-eksisterende eller =0; og Z er -0- eller -S-; eller et farmasøytisk akseptabelt salt derav.4. Compound, characterized by the formula where R1a is _n or -OR<7>, where R<7> is a hydroxy protecting group; R<2a> is -H, halo, or -OR<8>, where R<8> is a hydroxy protecting group; R 1 is -H or a hydroxy protecting group which can be selectively removed; R<11> is non-existent or =0; and Z is -0- or -S-; or a pharmaceutically acceptable salt thereof.

5. Forbindelse, karakterisert ved formelen hvori R<la> er -H eller -OR<7> hvor R<7> er en hydroksybeskyttende gruppe; R<2a> er -H, halo eller -OR<8>, hvor R<8> er en hydroksybeskyttende gruppe; og R<3> er 1-piperidinyl, 1-pyrrolidinyl, metyl-1-pyrrolIdinyl, dimetyl-l-pyrrolidinyl, 4-morfolino, dimetylamino, dietylamino, diisopropylamino, eller 1-heksametylenimino"; n er 2 eller 3; og Z er -0- eller -S-; eller et farmasøytisk akseptabelt salt derav.5. Compound, characterized by the formula in which R<1a> is -H or -OR<7> where R<7> is a hydroxy protecting group; R<2a> is -H, halo or -OR<8>, where R<8> is a hydroxy protecting group; and R<3> is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino"; n is 2 or 3; and Z is -0- or -S-; or a pharmaceutically acceptable salt thereof.

6. Forbindelse ifølge krav 1, karakterisert ved at nevnte forbindelse er [6-hydroksy-3-[4-[2-(1-pyrrolldinyl)etoksy]fenoksy]-2-(4-metoksyfeny1)benzo[b]-tiofen, representert ved strukturen eller et farmasøytisk akseptabelt salt derav.6. Compound according to claim 1, characterized in that said compound is [6-hydroxy-3-[4-[2-(1-pyrroldinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)benzo[b]-thiophene, represented by the structure or a pharmaceutically acceptable salt thereof.

7. Forbindelse ifølge krav 6, karakterisert ved at nevnte salt er hydrokloridsaltet.7. Compound according to claim 6, characterized in that said salt is the hydrochloride salt.

8. Fremgangsmåte for fremstilling av en forbindelse med formel I hvor R<*>a er -H eller -0R7<a>, hvor R7<a> er -H eller en hydroksybeskyttende gruppe; R<2a> er -H, halo, eller -0R<8a> hvor R8<a> er -H eller en hydroksybeskyttende gruppe; R<3> ér 1-piperidinyl, 1-pyrrolidinyl, metyl-l-pyrrolidinyl, dimetyl-l-pyrrolidinyl, 4-morfolino, dimetylamino, dietylamino, diisopropylamino, eller 1-heksametylenimino; n er 2 eller 3; og Z er -0- eller -S-; eller et farmasøytisk akseptabelt salt derav; karakterisert ved at den omfatter a) oksydering av svovelatomet med en forbindelse formel IV hvorR*<a> og R<2a> er som ovenfor definert; og r<9> er en avspaltbar gruppe; b) reagering av produktet fra trinn a), en forbindelse med formel XIV med en nukleofil gruppe med formel hvor R<12> er -OH eller -SH; c) reduksjon av produktet fra trinn b), en forbindelse med formel XVI for å gi en forbindelse med formel d) eventuelt fjerne R^<a> og/eller R<2a> hydroksybeskyttende grupper, når tilstede, fra produktet fra trinn c); og e) eventuelt danne et salt av produktet fra trinn c) eller trinn d).8. Process for the preparation of a compound of formula I where R<*>a is -H or -OR7<a>, where R7<a> is -H or a hydroxy protecting group; R<2a> is -H, halo, or -OR<8a> where R8<a> is -H or a hydroxy protecting group; R<3> is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and Z is -0- or -S-; or a pharmaceutically acceptable salt thereof; characterized in that it comprises a) oxidation of the sulfur atom with a compound formula IV where R*<a> and R<2a> are as defined above; and r<9> is a leaving group; b) reacting the product from step a), a compound with formula XIV with a nucleophilic group of formula where R<12> is -OH or -SH; c) reduction of the product from step b), a compound of formula XVI to give a compound of formula d) optionally removing R^<a> and/or R<2a> hydroxy protecting groups, when present, from the product of step c); and e) optionally forming a salt of the product from step c) or step d).

9. Fremgangsmåte for fremstilling av en forbindelse med formel I, eller et farmasøytisk akseptabelt salt derav, som angitt i krav 1, karakterisert ved at den omfatter a) (A) reduksjon av en forbindelse med formel XVI hvor R<1>a er -H eller -0R<7>a, hvor R7<a> er -H eller en hydroksybeskyttende gruppe; R2a er -H, halo, eller -0R<8a> hvor R<8a> er -B eller en hydroksybeskyttende gruppe; R<3> er 1-piperidinyl, 1-pyrrolidinyl, metyl-l-pyrrolidinyl, dlmetyl-l-pyrrolidinyl, 4-morfoHno, dimetylamino, dietyl-amlno, diisopropylamino, eller 1-heksametylenimino; n er 2 eller 3; og9. Process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, as stated in claim 1, characterized in that it comprises a) (A) reduction of a compound of formula XVI where R<1>a is -H or -OR<7>a, where R7<a> is -H or a hydroxy protecting group; R 2a is -H, halo, or -OR<8a> where R<8a> is -B or a hydroxy protecting group; R<3> is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dlmethyl-1-pyrrolidinyl, 4-morphoHino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and

2 er -0- eller -S-; eller et farmasøytisk akseptabelt salt derav; (B) reagering av en forbindelse med formel Hb hvor R<7> er en hydroksybeskyttende gruppe; og R<2a> og Z er som definert ovenfor; med en forbindelse med formel V hvor2 is -0- or -S-; or a pharmaceutically acceptable salt thereof; (B) reaction of a compound of formula Hb where R<7> is a hydroxy protecting group; and R<2a> and Z are as defined above; with a compound of formula V where

0 er en avspaltbar gruppe; og R<3> er som definert ovenfor: (C) reagere en forbindelse med formel Hb hvor R<2a>, R<7> og Z er som definert ovenfor, med et alkyleringsmiddel med formelen hvor Q og 0' er like eller forskjellige avspaltbare gruppe, produktet av hvilket blir reagert med 1-piperidin, 1-pyrrolidin, metyl-l-pyrrolidin, dimetyl~l-pyrrolidin, 4-morfolin, dimetylamin, dietylamln, diisopropylamin, eller 1-heksametylenimln; eller (D) for en forbindelse med formel I, hvor R<1> eller R<2> er -H og den andre R<1> eller R<2> substituenten er -OH, i) danne et triflat av hydroksygruppen av en forbindelse med formel hvor Rlc er -OH eller -0-(C1-C4 alkyl); og R2c er -OH eller -0-(C1-C4 alkyl); forutsatt at når Rlc er -OH, er R2c -0-(Cl-C4 alkyl), og når Rlc er -0-(C1-C4 alkyl) er R2c -OH; R3 er 1-piperidin, l-pyrrolidin, metyl-1-pyrrolidinyl, dimetyl-1-pyrrolidinyl, 4-morfolin, diraetylamino, dietyl-araino, diisopropylamino, eller 1-heksametylenimino; n er 2 eller 3; og Z er -0- eller -S-; eller et farmasøytisk akseptabelt salt derav, og ii) redusere den resulterende triflatgruppen; b) eventuelt fjerne den gjenværende hydroksybeskyttende gruppen eller gruppene; og c) eventuelt danne et salt av produktet fra trinn a) og trinn b).0 is a leaving group; and R<3> is as defined above: (C) reacting a compound of formula Hb where R<2a>, R<7> and Z are as defined above, with an alkylating agent of the formula where Q and O' are the same or different leaving group, the product of which is reacted with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl~1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine, or 1 -hexamethyleneimln; or (D) for a compound of formula I, where R<1> or R<2> is -H and the other R<1> or R<2> substituent is -OH, i) forming a triflate of the hydroxy group of a connection with formula where R 1c is -OH or -O-(C 1 -C 4 alkyl); and R 2c is -OH or -O-(C 1 -C 4 alkyl); provided that when R 1c is -OH, R 2c is -O-(C 1 -C 4 alkyl), and when R 1c is -O-(C 1 -C 4 alkyl) R 2c is -OH; R3 is 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholine, diethylamino, diethylaraino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and Z is -0- or -S-; or a pharmaceutically acceptable salt thereof, and ii) reducing the resulting triflate group; b) optionally removing the remaining hydroxy protecting group or groups; and c) optionally forming a salt of the product from step a) and step b).

10 . Anvendelse av en forbindelse med formel I ifølge et hvilket som helst av kravene 1 til 8 til fremstilling av et legemiddel for letting av symptomene for post-menopausalt syndrom; som osteoporose, en relatert kardiovaskulær sykdom, hyperlipidemi eller hormonavhengig cancer; foruten for hemming av uterin fibroid sykdom, endometriose, aortal glatt muskelcelleproliferasjon eller restenose.10 . Use of a compound of formula I according to any one of claims 1 to 8 for the manufacture of a medicament for alleviating the symptoms of post-menopausal syndrome; such as osteoporosis, a related cardiovascular disease, hyperlipidemia or hormone-dependent cancer; besides for inhibition of uterine fibroid disease, endometriosis, aortic smooth muscle cell proliferation or restenosis.