AU9733501A

AU9733501A - Novel cis-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes

Info

Publication number: AU9733501A
Application number: AU97335/01A
Authority: AU
Inventors: Paul Stanley Bury; Lise Brown Christiansen; Poul Jacobsen; Anders Kanstrup; Svend Treppendahl
Original assignee: Novo Nordisk AS
Current assignee: Novo Nordisk AS
Priority date: 1996-10-28
Filing date: 2001-12-19
Publication date: 2002-02-14

Description

-1-

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT 0

ORIGINAL

0 C 0 00000 Name of Applicant/s: Actual Inventor/s: Address for Service: Novo Nordisk A/S Poul Jacobsen and Svend Treppendahl and Paul Stanley Bury and Anders Kanstrup and Lise Brown Christiansen BALDWIN SHELSTON WATERS MARGARET STREET SYDNEY NSW 2000 3710000352 "NOVEL CIS-3,4-CHROMAN DERIVATIVES USEFUL IN THE PREVENTION OR TREATMENT OF ESTROGEN RELATED DISEASES OR SYNDROMES"

CCN:

Invention Title: Details of Original Application No. 47000/97 dated 28 Oct 1997 The following statement is a full description of this invention, including the best method of performing it known to us:- File: 34091AUP00 gp A ufls ralia

S

D o cumr e s received on: 19 D E 2001 J" en

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i 1Catch No: Title Novel cis-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes.

Field of the Invention The present invention relates to new cis-3,4-chroman derivatives and the use of such compounds in the prevention or treatment of estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal, in particular bone loss, osteoporosis, cardiovascular diseases; cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, including flushing and urogenital 10 atrophy, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, post-partum lactation, and the use of such compounds in a contraceptive method or as an aid in ovarian development.

Background of the Invention The osteopenia that accompanies the menopause continues to represent a major public health problem. Left unchecked, the cumulative loss of bone can potentially compromise the skeleton's structural integrity, resulting in painful and debilitating fractures of the wrist, spine and femur. Efforts to reduce the risk and incidence of fractures have focused on the development of therapies that conserve skeletal mass by inhibiting bone resorption.

Among various treatment modalities, estrogen replacement therapy remains the preferred means to prevent the development of post menopausal osteoporosis (Lindsey R, Hart DM, MacClean A 1978, "The role of estrogen/progestogen in the management of the menopause", Cooke ID, ed, Proceedings of University of Sheffield symposium on the role of estrogen and progestogen in the management of the menopause, Lancaster, UK: MTP Press Ltd. pp. 9-25; Marshall DH, Horsmann A, Nordin BEC 1977, "The prevention and management of post-menopausal osteoporosis.", Acta Obstet Gynecol Scand (Suppl) 65:49-56; Recker RR, Saville PD, Heaney RP 1977, "Effect of estrogen and calcium carbonate on bone loss in post-menopausal women", Ann Intern Med. 87:649-655; Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM 1979, "Estrogen replacement therapy", Obstet Gynecol. 53:277-281) and it is now accepted that estrogens significantly decrease fracture incidence and risk (Krieger N, Kelsey JL, Holford TR, O'Connor T 1982, "An epidemiological study of hip fracture in postmenopausal women", Am J Epidemiol.

116:141-148; Hutchinson TA, Polansky SM, Feinstein AR 1979, "Post-menopausal estrogens protect against fractures of hip and distal radius: A case-control study", Lancet 2:705-709; Paginini-Hill A, Ross RK, Gerkins VR, Henderson BE, Arthur M, Mack TM 1981, "Menopausal oestrogen therapy and hip fractures", Ann Intern Med. 95:28-31; Weiss NS, Ure CL, Ballard JH, Williams AR, Daling JR 1980, "Decreased risk of fractures on the hip and lower forearm with post-menopausal use of estrogen", N Eng J Med.

303:1195-1198).

While the beneficial actions of estrogen replacement therapy on the skeleton are clearly significant, there is also considerable evidence for a positive effect of estrogen on the cardiovascular system. Previous studies have attributed these actions to estrogen's 1 5 effects on serum lipids, but recent data has now shown that in addition to the effects on the lipid profile, estrogen can also directly influence vessel wall compliance, reduce *peripheral resistance and prevent atherosclerosis (Lobo RA 1990, "Cardiovascular implication of estrogen replacement therapy", Obstetrics and Gynaecology, 75:18S-24S; Mendelson ME, Karas RH 1994, "Estrogen and the blood vessel wall", Current Opinion in 20 Cardiology, 1994(9):619-626). Based on available epidemiological data, the overall impact of these physiological and pharmacological actions of estrogen is an age independent reduction in cardiovascular mortality and morbidity in women (Kannel WH, Hjortland M, McNamara PM 1976 "Menopause and risk of cardiovascular disease: The Framingham Study", Ann Int Med, 85:447-552). Furthermore, a more recent analysis has concluded that post-menopausal estrogen replacement therapy reduces the risk of cardiovascular disease by approximately 50 percent (Stampfer MJ, Colditz GA 1991, "Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiological evidence", Preventive Medicine, 20:47-63.).

In addition to the positive effects of estrogen on bone and cardiovascular system, there are now data which indicate that the central nervous system can benefit from estrogen replacement therapy. Short term studies in human subjects have shown that increased levels of estrogen are associated with higher memory scores in post menopausal women (Kampen DL, Sherwin BB 1994, "Estrogen use and verbal memory in healthy postmenopausal women", Obstetrics and Gynecology, 83(6):979-983). Furthermore, the administration of exogenous estrogen to surgically post menopausal women specifically enhances short-term memory. Moreover, the effects of estrogen on cognition do not appear confined to short-term effects as epidemiological findings indicate that estrogen treatment significantly decreases the risk of senile dementia-Alzheimer's type in women (Paganini-Hill

A,

Henderson VW, 1994, "Estrogen deficiency and risk of Alzheimer's disease in women", Am J Epidemiol, 140:256-261; Ohkura T, Isse K, Akazawa K, Hamamoto M, Yoshimasa Y, Hagino N, 1995, "Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer Type: 7 case reports", Dementia, 6:99-107). While the mechanism whereby estrogens enhance cognitive function is unknown, it is possible to speculate that the direct effects of estrogen on cerebral blood flow (Goldman H, Skelley 15 Eb, Sandman CA, Kastin AJ, Murphy S, 1976, "Hormones and regional brain blood flow", Pharmacol Biochem Rev. 5(suppl 1):165-169; Ohkura T, Teshima Y, Isse K, Matsuda H, Inoue T, Sakai Y, Iwasaki N, Yaoi Y, 1995, "Estrogen increases cerebral and cerebellar blood flows in postmenopausal women", Menopause: J North Am Menopause Soc.

2(1):13-18) and neuronal cell activities (Singh M, Meyer EM, Simpkins JW, 1995, 'The 20 effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor i messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats", Endocrinology, 136:2320-2324; McMillan PJ, Singer CA, Dorsa DM, 1996,

T

he effects of ovariectomy and estrogen replacement on trkA and choline acetyltransferase mRNA expression in the basal forebrain of the adult female Sprague- Dawley rat", J'Neurosci., 16(5):1860-1865) are potential effectors for these beneficial actions.

The therapeutic applications of naturally occurring estrogens and synthetic compositions demonstrating estrogenic activity alone or in combination are not limited to the chronic conditions described above. Indeed, the more traditional applications of estrogen therapies would include the following: riief of menopausal symptoms flushing and urogenital atrophy); oral contraception; prevention of threatened or habitual abortion, relief of dysmenorrhea; relief of dysfunctional uterine bleeding; an aid in ovarian development; treatment of acne; diminution of excessive growth of body hair in women (hirsutism); treatment of prostatic carcinoma: and suppression of post-partum lactation [Goodman and Gilman, The Pharmacological Basis of Therapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages 1421-1423].

Even though the beneficial effects of estrogen replacement on a wide variety of organ systems and tissues appear indisputable, the dose and duration of estrogen therapy is also associated with an increased risk of endometrial hyperplasia and carcinoma. The use of concomitant cyclic progestins does reduce the risk of endometrial pathology, but this is achieved at the expense of the return of regular uterine bleeding, a result that is objectionable to many patients. In addition to estrogen's stimulatory effect on the endometrium, .there remains considerable controversy regarding reports of an association between longterm estrogen replacement and an increased risk of breast cancer (Bergkvist L, Adami HO, Persson I, Hoover R, Schairer C, 1989, "The risk of breast cancer after estrogen and estrogen-progestin replacement", N Eng J Med, 321:293-297; Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE, 1995, "The use of estrogens and progestins and the risk of breast cancer in postmenopausal women", N Eng J Med, 332(24):1589-1593). Furthermore, there are other side effects of estrogen replacement which, while they may not be life threatening, contraindi- 20 cate estrogen's use and reduce patient compliance.

From the foregoing discussion it would appear that the availability of therapies which could mimic the beneficial actions of estrogen on the bone, cardiovascular system, and central nervous system without the undesirable side effects on uterus and breast, would essentially provide a "safe estrogen" which could dramatically influence the number of patients that would be able to benefit from estrogen replacement therapy. Therefore, in recognition of estrogen's beneficial effects on a number of body systems and disease conditions, there is a continuing need for the development of potent estrogen agonists which can selectively target different body tissues and which display a high bioavailability.

Description of the invention The present invention provides compounds of the formula I in which substituents R 2 and R 3 are arranged in cis-configu ration: wherein: R' is COR 4 CONHR, CONR~ S0 2 NR' S0O 2 NHR, CI- 3 aklo ezl R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR", trihalo-Cl-CC 5 -alkyl, C,-C 8 alkyl, C,-Cs-alkoxy and phenyl; R' is: phenyl substituted with -X-(CH 2 wherein: X is a valency bond, 0 or S, n is an integer in the range of 1 to 12, Y is H, halogen, OH, OR', NHR NR 2, NHCOR', NHSO 2

R

4

CONHR

4 CONR 2 COOHCOO4, 4OR, SOR4, SOH 4 2R~ aC-C 7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of 0, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR', trihalo-Cl-Cs-alkyl, C 1

-C

6 -alkyl and C,-C 6 -alkoxy;

-(CH

2 wherein n and Y are as defined above; or phenyl fused to a C3-C7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C 6 alkyl, C,-C 6 -alkyl and C,-C-alkoxy; and

R

4 is C,-C 6 -alkyl; and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and 10 salts thereof.

The general chemical terms used in the above formula have their usual meanings.

For example the term C,-C-alkyl includes straight-chained as well as branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl and isobutyl.

The term halogen means chloro, bromo, iodo and fluoro.

15 The term C 3 -CT-heterocyclic ring include groups such as pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl.

The compounds of this invention are new estrogen agonists and are useful for prevention and treatment of bone loss, prevention and treatment of.osteoporosis; the prevention and treatment of cardiovascular disease; treatment and prevention of physiological disorders associated with an excess of neuropeptide Y obesity, depression, etc.); and for regulation of glucose metabolism in e.g. non-insulin dependent diabetes melitus; and the prevention and treatment of senile dementia-Alzheimer's type in women. In addition, these estrogen agonists are useful for oral contraception; relief of menopausal symptoms (e.g.

hot flushes, urogenital atrophy, depression, mania, schizophrenia, etc.); incontinence; prevention of threatened or habitual abortion; relief of dysmenorrhea; relief of dysfunctional uterine bleeding; an aid in ovarian development; treatment of acne; diminution of excessive growth of body hair is women (hirsutism); treatment of prostatic carcinoma; and the suppression of post-partum lactation. These agents also lower serum cholesterol and have a beneficial effect on plasma lipid profiles.

While the compounds of this invention are estrogen agonists in bone and cardiovascular tissues, they are also capable of acting as antiestrogens in other estrogen target organs.

For example, these compounds can act as antiestrogens in breast tissue and the colon and therefore would be useful for the prevention and treatment of estrogen-dependent cancers such as breast cancers and colon cancers.

S.

*S S

S

The substituent R'O of formula I is preferably attached position. Accordingly, compounds of the invention having Ib are preferred: to the phenyl ring at the 6- or 7one of the following formulae la or wherein R 2 and R 3 are as defined above.

In a preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula: 8 o COOR 0 wherein R' is as defined above and R is H or C,-Cs alkyl.

In another preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula: wherein R' is as defined above and m is an integer from 0 to In another preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula: o wherein R' is as defined above and m is an integer from 0 to In another preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula: (CH2)' wherein R' and m are as defined above.

0 0 *0 *0 In another preferred embodiment, the present invention is concemed with cis-forms of the compounds of the following formula: wherein R 1 and m are as defined above.

In another preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula:

R

4 wherein m and R' are as defined above and both R 4 independently are as defined above.

In another preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula: wherein R' and R 4 are as defined above.

In another preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula: 01111

R

1 0 0 wherein R" is as defined above.

In another preferred embodiment, the present invention is concerned with cis-forms of the V.0 compounds of the following formula:' 0 N NQ 0

R

1 0 0 wherein R1 is as defined above and R 6 represents one or more of the following substituents: methoxy, hydroxy, trifluormethyl, fluoro and chloro.

In another preferred embodiment the invention is concemed with the following compounds: (+)-cis-3-(4-Fluorophenyl)-7..methoxy-4-(4-(2pyrrolidinoethoxy)phenyl)chromane (+)-cis-3-(4-Fluorophenyl)-7-methoxy-4-(4-(2-piperidinoethoxy)phenyl)chromane (+)-cis-3-(4..Fluoro phenyl)7methoxy-4-(4(3pi peridino pro poxy) phenyl) chrom ane ethoxy- 3 -phenyI.4(4(2piperidinoethoxy)phenyl)chromane 7 -Methoxy.3-pheny..4 4(3piperidinopropo)hn)chrm 7 -Methoxy-3(4methoxypheny).4-(4-(2-pyrrolidinoethoxy)pheny)chrmn 7 Methoxy3(4phenyi-phenyI)4(4(2pyrroidinoethoxy)hny)chrm 7 -Methoxy..3.(4methylphenyl)A -(4-(2-pyrroidinoethox)pheny)chrmn 7 Methoxy3(4-methytphenyl)-4-(4-(2-pipei othox Iey)chrmn 7 Methoxy-(4(2piperidinoethoxy)phy)3( 4 -(trflucoehlpey)crmn (+)-cis 7 Methoxy4(4(2pyrroidinoethoxy)hy)-3( 4 -(trfluooehlpey) chromane (+)-cis-7.Methoxy-3-(3-methylphenyl)..4 (4-(2-prrldinothox)phnlcrm (+)cis3(3.Fluooeyph7-ethy-4-(4-(2-pyA(2idinthx)phnlcr (+)-cis 7 Met oxy..(3mtoxpehyphen4-2-y)4((idinthx)phnlcrm .(+)-cis7Methoxy.3.3mmtoxpeoyphenyf)4(2-ipedothox~hnlcrm (+)-cis-7Methoxy3(3methoxypheny4( 4 3 ierdinpooypenlcrm 7 u.Methoxy-4-(4-(2-pyrrolidinoethox)pheny) 3-(3-(trifluooehlpey chromane (+)-cis-7.Methoxy(4(2piperidithx) phenyl)-3-(3-(trifluoromethyl)pheny)-chromane (+)cis3(2Fluorophenyl)7meth-(4-( 2 -yrldnehxpeylcome (+)-cis-7-Methoxy.3.(2,3,4,5, 6 -pentafluorophenyl).4-(4(2pyrrolidinoethoxy)phenyl)chromane (+)-cis-7-Methoxy-3-(2,3,4,5,6-pentafluorophenyl)-4-(4-(2-piperidinoethoxy)phenyl)chromane ethoxy-3-(4-m ethyl phenyl)..ch roman.4..y)2m ethylbenzoxazole ethoxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane ethoxy-3-(3-hyd roxyph enyl)..4.(4-(2..pyrro lid inoethoxy) phenyl)chrom ane (+)-cis..4-(4-Hexylphenyl)..Tmethoxy.3-phenylchromane (+)-cis-7-Methoxy-3.phenyl4.{4-{2.(pyrrolidin-.1 -yI)ethoxy~phenyl~chromane 3 -(4-Fluorophenyl)-7-methoxy-4-(4-(2-py-olidinoethoxy)phenyl)chromane 3 -(4-Fluorophenyl)-7-methoxy.4(4..(2.piperidinoethoxy)phenyl)chromane 3 -(4-FluorophenyI)-7-methoxy..4-(4-(3-piperidinopropoxy)phenyl)chromane 7 -Methoxy-3-phenyl!A-(4-(2-piperidinoethoxy)phenyl)chromane 5*5*5(-)-cis- 7 -Methoxy-3-phenylA4-(4-(3-piperidinopropoxy)phenyl)chromane 7 -Methoxy-3-(4-methoxypheny).4-(4-(2pyrrolidinoethoxy)phenyl)chromane 7 -Methoxy-3(4-phenyl-phenyl)-4(4(2pyroidinoethoxy)phenyl)chromane (--i--ehx--4mtypey)4(-2proiiotoypey~hoane 7 -Methox.y-3-(4-methylpheny)-4-(4-(2-pproidinoethoxy)phenyl)chroman 7 -Methoxy--(4meh( pey24.(piperidinoethoxy)phnl p4(tiloohyl)py)chromane (-)-cis-7-Methoxy4(4-(2piperridinoethoxy)pheny)-(4-(tr.jfluoromethy)pheny)-chromane 7 -M eth oxy-3-(3-methylphenyl)A4-(4..(2.pyrrolidinoethoxy)phenyt) ch romane 3 3 -Fluorophenyl)-7-methoxy4-(4-(2-pynrolidinoethoxy)phenyr)chromane (-)-cis-7-Methoxy-3-(23,4,5, 6 -penlorophen2-yrrol(2roidinoethoxy)phenyI)mn (cro7maet x--4(-yrliiotoy hnl3-3(rfurmehl h y)crmae (-)-cis-7-Methoxy-3-(2, 3,4,5,6-pentafluorophenyl)-4-(4-(2-piperidino~thoxy)pheny).

chromane 6 -M ethoxy-3-pheny.4-.(4.(2-pyrro lid inoethoxy) phenyI)ch rom ane 15 7 -Methoxy-3-phenyl..4(4{2-(pyrrolidin-1 -yI)ethoxy~phenyl)ch ro mane.

S S The following compounds form part of the present invention: (±-i--4Furpenl--ehx--4(2proiiotoyphenyl)chromane (±)-cis-3-(4Fluorophenyl)7methoxy-4-(4-(3-piperidinopropoxy)phenyI)chrmn 7 -Methoxy-3-phenyl.4..(4..(2..piperdinoethoxy)phenyl)chromane 7 -Methoxy- 3 -phenyl-4-(4-(3-piperidinopropoxy)phenyI)chromane 7 -Methoxy- 3 -(4-methoxyphenyI)-4-(4(2pyrrolidinoethoxy)phenyI)chrom~ne 7 -Methoxy- 3 4 -pheniphenyl)>4-(4-(2-pyrrolidinoethoxy)phenyl)chromane 7 -Methoxy- 3 4 -methylphenyl)A4-(4-(2..pyrroidinoethoxy)phenyl)chromane 7 -Methoxy- 3 -(4-methylphenyI)-4-(4-(2..piperidinoethoxy)phenyI)chromane 7 -M ethoxy-4-(4-(2-piperidinoethoxy) phenyl)3(4-(trifluorom ethyl) phenyl)-ch roma ne 7 -Methoxy-4-(4-(2-pyrroidinoethoxy)pheny)3(4(trifluoro methy)pheny)chromane 9 7 -Methoxy-3-(3methypheny)4(4(2pyrrolidinoethoxy)phenyl)chromane 3 3 -Fuoropheny)7methoxy4(4-(2-pyrrolidinoethoxy) phenyl)chromane 7 -M ethoxy-3-(3-methoxyphenyl)-4-(4.(2..pyrroid inoeth oxy) phenyl)chro mane 7 -Methoxy-3-(3methoxypheny).4(4(2piperidinoethoxy)pheny!)chromane 7 -Methoxy-3(3methoxypheny)4(4-(3piperidinopropoxy)pheny)chromane 7 -M ethoxy-4-(4(2-pyrro lidi noethoxy) phenyl).3-(3(tifl uoromnethy) pheny)- *15 chromane (±)-cis-7-Methoxy..4-(4-(2-piperidinoethoxy) phenyl)-3-(3-(trifluoromethyI)phenyi)-chromane (±)-cis-7-Methoxy-3-(2, 3,4,5, 6 -pentafluorophenyI)-4-(4-(2pyrroidinoethoxy)phenyl)chromane (±)-cis-7-Methoxy-3(234,56pentafluorophenyl).4-(4(2piperidinoethoxy)phenyl)chromane 16 (±--cs7Mtoy3(-etypey)crmn4y)2mty-ezxzl 6 -Methoxy- 3 -phenyl..4-(4(2-pyrrolidinoethoxy)phenyI)chromane ethoxy- 3 3 -hydroxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane 4 4 -Hexylphenyl)-7-methoxy.3-phenyichromane, (±)-(cis-4-(4-(2-Pyrroidinoethoxy) pheny)3(4(trifluorom ethy) pheny)ch rom an- 7 2,2dim ethylipropanoate, (±)-(cis-4-(4-(2-Pyrrolidinoethoxy)phenyl)y3-.(3..(trifluoromethyl)pheny)chroman- 7 2,2dimethyipropanoate hydrochloride, ethylphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chroman-7-y) N, N-diethyl V, carbamate, ethylphenyl)-4-(4(2pyrrolidinoethoxy)pheny)chroman7-yi) N, Ndimethylsulfamic acid ester, cis 7 -Benzyloxy-4-(4-hydroxyphenyl)3phenyl-ch roman, 509 7 -Benzyloxy-4-[4-(4chorobutyoxy).pheny]3phenyl-chroman, *sea*: 15 7 -Benzyloxy..4[4-(2choroethyoxy)pheny]3phenylichroman, 7 -Benzyioxy-4-[4-(6bromohexyloxy)pheny]3phenyl-chroman, **7-Benzyloxy-4-[4-(l 1 -brom odecyloxy)-phe nyl]3phenyljch roman, 3 -(4Fuoropheny)7methoxy4(4(2pyroidinoethox)pheny)chromane, 5 -(cis7Methoxy3(4methypheny)chroman4y)2methyl-benzoxazole (±)-cis-6-Methoxy3pheny...4.(4(2pyrrolidinoethoxy)phenyI)-chromane (±)-cis-4-(4-Hexypheny)7.methoxy3phenylchromane, (+)cis 4 7 -Benzyloxy-3-phenyl-chroman-4-yl)-phenoxy]-acetic acid methyl ester, (,)cis 7 -Benzyloxy-4-[4-(6-morpholinohexyloxy)-plenyl-3-phenyl-chromanl (,)cis 7-Benzyloxy 4 4 6 -dibutylamino-hexyloxy)-phenyl]-3-phenyl-chroman, (-)cis 7-Benzyloxy 4 4 -(dimethylaminodecyloxy)-phenyl]-3-phenyl-chroman, (i,)cis 7-Benzyloxy 4 4 -(morpholinodecyloxy)-phenyl]-3-phenyl-chroman, (,)cis 7-Benzyloxy 4 4 2 -dibutylaminoethyloxy)-phenyl]-3-phenylch roman, (,)cis 7-Benzyloxy 4 4 -(butylaminoethyloxy)-phenyl]-3-phenyl-chroman, (,)cis 7-Benzyloxy 4 -t 4 -(morpholinoethyloxy)-phenyll-3-phenyl-chroman, *0 7-Benzyloxy 4 -f 4 -(N-methyl piperazinoethyloxy)-phenyl]-3-phenyl-chro man, 10 (,)cis 7-Benzyloxy 4 4 -(morpholinobutyloxy)-phenyl]3.phenyl-chroman, including the pure enantiomers thereof.

The compounds of the invention may be prepared by resorting to the chroman chemistry 5 which is well-known in the art, for example in P.K. Arora, P.L. Kole and S. Ray, Indian J.

Chem. 20 B, 41-5, 1981; S. Ray, P.K. Grover and N. Anand, Indian J. Chem. 9, 727-8, 1971; S. S S. Ray, P.K. Grover, V.P. Kamboj, 5.6. Betty, A.B. Kar and N. Anand, J. Med. Chem. 19, S 276-9, 1976; Md. Salman, S. Ray, A.K. Agarwal, S. Durani, B.S. Betty, V.P. Kamboj and N.

Anand, J. Med. Chem. 26, 592-5, 1983; Teo, Sim, Bull. Singapore Natl. Inst. Chem.

22, 69-74, 1994.

However, the invention is furthermore concerned with a general method for the preparation of compounds of formula comprising the steps of: a) reacting a compound of the formula (11) with a compound of the formula (111)

COOH

(III)

wherein R' represents 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SIR 4 trihaio-C,-.CB-alkyl,

C

1

-C

8 -alkyl and

C

1

-C

6 -alkoxy, and R' is as defined above.

in the presence of triethylamine and acetic anh ydride to form a compound of the formula 10

(IV)

cocH 3 0 0 (IV) wherein

R

5 is as defined above, b) reducing a compound of the formula (IV) a compound of formula (V) with a suitable hydride reducing agent to form a.

C

a a 0 (V) wherein R 5 is as defined above, c) hydrogenating a compound of the formula in the presence of a suitable catalyst toform a compound of the formula (VI) with a 3,4-cis configuration

OH

wherein R 5 is as defined above, d) alkylating a compound of the formula (VI) with an appropriate electrophile to form a compound of the formula (VII)

(CH

2

Y

(VII)

wherein n, R 5 and Y are as defined above, e) deprotecting a compound of formula (VII) with a suitable deprotection agent, preferably 5 by pyridine hydrochloride fusion, to form a compound of the formula (VIII)

Y

(VIII)

wherein n, R 5 and Y are as defined above, f) reacting a compound of the formula (VIII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or g) nitrating a compound of the formula (VI) with a suitable nitration agent to form a compound of the formula (IX) 0 (IX) wherein R 5 is as defined above, h) reducing a compound of the formula (IX) with a suitable reducing agent, preferably by catalytic hydrogenation, to form a compound of the formula (X)

OH

NH2

(X)

wherein R 5 is as defined above, i) cyclizing a compound of formula with an appropriate agent to form a compound of the formula (XI) or (XII)

(XII)

C

*CCC..

wherein R 4 and R 5 are as defined above, j) deprotecting a compound of the formula (XI) or (XII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (XIII) or

(XIV)

(XIII)

or

(XIV)

wherein R 4 and R 5 are as defined above, k) reacting a compound of the formula (XIII) or (XIV) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or I) reacting a compound of formula (VI) with trifluoromethane sulphonic acid anhydride to form a compound of the formula (XV) so0 2

CF,

a. a.

a a.

a a wherein R 5 is as defined above, m) cross-coupling a compound of the formula (XV) with the appropriate cross-coupling partner to form a compound of the formula (XVI) I2) n

(XVI)

wherein n, R 5 and Y are as defined above, n) deprotecting a compound of the formula (XVI) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (XVII)

Y

(CH

2 )n

S(XVII)

wherein n, R 5 and Y are as defined above, o) reacting a compound of the formula (XVII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or 5 p) cyclizing a compound of the formula (XVIIl)

R

OH

(XVIII)

wherein R 5 is as defined above, with paraformaldehyde in the presence of dimethylamine to form a compound of the formula (XIX) 1 (XX) 0 0 (XIX) wherein R 5 is as defined above, q) reacting a compound of the formula (XIX) with the appropriate Grignard reagent to form a compound of the formula (XX)

S.

S

S. t5 wherein n, R 5 and Y are as defined above, 5 r) hydrogenating a compound of the formula (XX) in the presence of a suitable catalyst to form a compound of the formula (XXI) with a 3,4-cis configuration

(XXI)

wherein n, R s and Y are as defined above, deprotecting a compound of formula (XXI) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the general formula (XXII)

Y

S(XXII)

wherein n, R 5 and Y are as defined above, t) reacting a compound of the formula (XXII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula u) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XXIII) 0 *r S 9*0* *S S

(XXIII)

wherein R 5 is defined as above, v) deprotecting a compound of the formula (XXIII) with a suitable deprotection agent, such as pyridine hydrochloride fusion or boron tribromide, to form a compound of the formula (XXIV) 0

R

(XXIV)

wherein R 5 is defined as above, w) reacting a compound of the formula (XXIV) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula (XXV) 0 0-' 0 s

RR

(XXV)

wherein R 5 is defined as above, and R 6 is H or methoxy,

(XXVI)

(xxvI) wherein R' is defined as above, and R 6 is H or methoxy, Y) alkylating a compound of the formula (XXVI) with an appropriate electrophile to form a compound of the formula (XXVII) 28 0 ,CH 2

-Y

R

8

R

0

(XXVII)

wherein ni, R' and Y is defined as above, and R 6 is H or methoxy, Z) deprotecting a compound of the formula (XXVII) with a suitable deprotection agent, 10 preferably catalytic hydrogenation for R6 equals H or a strong acid for R' equals methoxy, to form a compound of the formula (XXViII) (CH 2

-Y

(XXVIII)

wherein n, Rs and Y is defined as above, aa) Alkylating a compound of the formula (XXVI) with an appropriate dihalogenated alkane such as 1,2-dibromoethane, 1-bromo-2-chloroethane, 1,4-dibromobutane, 1 6 -dibromohexane, I,8-dibromooctane, 1,1 0-dibromodecane, preferably catalysed by potassium iodide, to form a compound of the formula (XXIX) 0- (CH 2 Hal

R

R R 0

(XXIX)

*wherein n and R 5 is defined as above, R 6 is H or methoxy, and Hal is chioro, bromo, or iodo, 0 R 6 a amie, t fom a ompond o th forula XXX 4 4 whri Ii rm...,adZi HRN 2,o .C7htrcci mn opinal cotiigoye rntoeotoalybigsbtttdwtSo3sb stiuets ideenenlyseecedfrmChe ru cnitigo H H-hlgnnto rh5*5C -akl .C -ly n C -6akxadn 4,adR5i eie as above cc) deprotecting a compound of the formula (XXX) with a suitable deprotection agent, preferably catalytic hydrogenation for R' equals H or a strong acid for R 6 equals methoxy, to form a compound of the formula (XXXI)

R

1

OHO

(XXXI)

*.tl 10 wherein R' is H or methoxy, and Z is NHR 4 NR or a C3-C7 heterocyclic amine optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-C,-C6-alkyl, C,-C6-alkyl and C,-C6-alkoxy, and n, R 4 and R' is defined as above.

0• The starting benzophenones of the formula (11) are easily prepared via Fnriedel-Craft acylation of the appropriate dimethyl ether with p-hydroxybenzoic acid followed by selective monode- S 10wmethylation with hydrobromic acid in acetic acid.

The starting deoxybenzoins of the formula (XVIII) are easily prepared via the Hoesch reaction of the appropriate dimethyl ether and the appropriate substituted phenyl acetic acid derivative followed by selective monodemethylation by hydrobromic acid in acetic acid.

Optical pure compounds of formula 1 can be obtained by introducing in the above method a resolution step. The resolution can be carried out after any step of the process which results in a racemic mixture of enantiomers. Any resolution technique may be used to separate a (-)-enantiomer and/or a (+)-enantiomer from a racemic mixture, including diastereomeric salt formation and chiral HPLC.

The expression "appropriate electrophile" typically means an alkylhalogenide of the formula

Y-(CH

2 )n-Hlg, wherein Y is as defined above and HIg is CI, Br or I.

The cyclization step of the above method can be performed with for example a suitable activated carboxylic acid derivative followed by dehydration.

The expression "appropriate cross-coupling partner" typically means an organometallic reagent together with a transition metal catalyst, for example a Grignard reagent with a Ni(0) catalyst.

The expression "appropriate Grignard reagent" typically means an organometallic compound 10 of the formula wherein M is MgHIg, Hig is Cl, Br or I and Y is as defined above.

S The present invention also relates to pharmaceutical compositions comprising an effective amount of a compound according to the invention and a pharmaceutical carrier or diluent.

Such compositions are preferably in the form of an oral dosage unit or parenteral dosage unit.

15 Furthermore, the invention is concerned with a method of treating or preventing estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogendeficient state in a mammal, comprising administering to a subject in need thereof an effective amount of a compound according to the invention.

The compounds of this invention are new estrogen agonists and are useful for prevention 20 and treatment of bone loss, prevention and treatment of osteoporosis; the prevention and treatment of cardiovascular disease; treatment and prevention of physiological disorders associated with an excess of neuropeptide Y obesity, depression, etc.); and for regulation of glucose metabolism in e.g. non-insulin dependent diabetes melitus; and the prevention and treatment of senile dementia-Alzheimer's type in women. In addition, these estrogen agonists are useful for oral contraception; relief of menopausal symptoms (e.g.

10 In vitro estrogen rceptor binding assay An in vitro receptor binding assay was used to determine the estrogen receptor binding affinity of the compounds of this invention. This assay measures the ability of the compounds of this invention to displace 'H-171-estradiol (17f-E2), from estrogen receptor (ER) obtained from rabbit uterus. Experimentally, the ER rich cytosol from rabbit uterine tissue is diluted with ER poor cytosol isolated from rabbit muscle to achieve approximately 20 25% maximal binding of 0.5 nM "H-171-E2. For each assay, fresh aliquots of cytosol are thawed on the day of analysis and diluted with assay buffer to ca. 3 mg cytosol protein/ml. The assay buffer (PB) is as follows: 10 mM KHPO 4

/KH

2

PO

4 1.5 mM KEDTA, 10 mM monothioglycerol, 10 mM Na2MoO4.2H0, 10 glycerol pH 7.5. Radio-inert 20 171-E2 is obtained from Sigma.

Test solutions are prepared in appropriate solvents (ethanol or DMSO) at a concentration of 8 x 10-3M and serial dilutions prepared with PB or DMSO. Aliquots of 10 pi are incubated in duplicate for each concentration tested in microtitre plates to which have been added 20 pI 3 H-171-E2 (assay concentration equals 0.4 nM) and 50 pi cytosol. For control samples as well as maximal binding sample, 10 pl PB is added in lieu of test compound.

Following an 18 20 hr incubation at 4 0 C the reaction is terminated with 100 pl DCC slurry activated charcoal (Sigma) and 0.005% Dextran T70 (Pharmacia) in PB] added to each sample and incubated with continuous shaking for 15 min at 4 0 C. DCC background counts are assessed using 50 pl of 0.3% BSA in PB in lieu of cytosol.

To separate bound and free 3 H-171-E2, Titertek plates are centrifuged for 10 min (800 x g) at 4°C and aliquots of 100 pl are removed from each sample for scintillation counting using Optiflour scintillation liquid. Standard and control samples are incubated in quadruplicate, while test compounds are incubated in duplicate. The mean counts per minute (cpm) in each sample is calculated, background (DCC) is subtracted, and the percent of maximal 3H-17i1-E2 binding is determined. Individual cpm's are plotted against their respective concentrations of test compound (logarithmic scale), and the IC50 expressed as the compound concentration, required to displace 50% of the maximal binding.

Bone Mineral Density Bone mineral density (BMD) as a measure of bone mineral content (BMC) accounts for greater than 80% of a bone's strength. The loss of BMD with ageing and the accelerated loss following the menopause reduce the strength of the skeleton and render specific sites more susceptible to fracture; i.e. most notably the spine, wrist and hip. True bone density can be measured gravimetrically using Archimede's Principle (an invasive technique). The BMD can also be measured non-invasively using dual energy x-ray absorptiometry (DEXA). In our laboratory, we have utilized a gravimetric method to evaluate changes in BMD due to estrogen deficiency in ovariectomized rodents. Following ovariectomy (the 20 surgical removal of the ovaries), the animals are treated with vehicle, 1713-E2 as a positive control, and/or other estrogen agonists. The objective of these investigations is to evaluate the ability of the compounds of this invention to prevent bone loss in rodent models of human disease.

Female Sprague-Dawley rats (ca. 3 to 5 months old), or female Swiss-Webster mice (ca.

3 to 5 months old) underwent bilateral ovariectomy or sham surgery. Following recovery from anesthesia the animals are randomized to the following groups, minimum of 8 animals per group: sham animals treated with vehicle; ovariectomized animals treated with vehicle; ovariectomized animals treated with 25 pg estradiol/kg; and ovariectomized animals treated with 200 pg/kg of test compound.

All compounds are weighed and dissolved in vehicle solvent in sterile saline and the animals are treated daily via subcutaneous injections for 35 days. At the conclusion of the day protocol, the animals are sacrificed and the femora are excised and cleaned of adherent soft tissue. In rats, the distal 1 cm of the defleshed femora are removed with a diamond wheel cut-off saw and fixed in 70% ethyl alcohol (in mice the distal .5 cm are removed and fixed). Following fixation in 70% ethyl alcohol (EtOH) an automated tissue processor was used to dehydrate the bone specimens in an ascending series of alcohol to 100%. The dehydration program was followed by defatting in chloroform and rehydration in distilled water. All automated tissue processing occurred under vacuum. The hydrated bones were weighed in air and weighed while suspended in water on a Mettler balance 15, equipped with a density measurement kit. The weight of each sample in air is divided by the difference between the air weight and the weight in water to determine total bone density; i.e. organic matrix plus mineral per unit volume of tissue. After the determination of total bone density the samples are ashed overnight in a muffle furnace at 600 The mineral density can then be determined by dividing the ash weight of each sample by the S tissue volume air weight weight suspended in water). The mean bone densities (total and mineral bone densities) are calculated for each group and statistical differences from the vehicle-treated and estrogen-treated controls are determined using computerized statistical programs.

,o Cholesterol lowerinq activity The effects of the compounds of the present invention on the serum levels of total cholesterol were measured either in blood samples taken from the animals in the bone density studies described above or from ovariectomized female rats or mice that had been treated with compound for a period of not less than 28 days. In each type of experiment, blood from treated animals was collected via cardiac puncture and placed in a tube containing 30 pl of 5% EDTA/1 ml of blood. Following centrifugation at 2500 rpm for minutes at 20° C the plasma was removed and stored at -20' C until assayed. Cholesterol was measured using a standard enzymatic determination kit purchased from Sigma Diagnostics (Kit No. 352).

Pharmaceutical oreDaration The compounds of the invention, together with a conventional adjuvant, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral 10 use; in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous administration and infusion). Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active S. compounds or principles, and such unit dosage forms may contain any suitable effective amount of a compound of the invention commensurate with the intended daily dosage range to be employed. Tablets containing ten (10) milligrams of active ingredient or, more broadly, ten (10) to hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

S. The compounds of this invention can thus be used for the formulation of pharmaceutical S. 20 preparation, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Ampoules are convenient unit dosage forms.

Tablets, dragees, or capsules having talc and/or carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch, are particu- 1: 0 larly suitable for oral application. A syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a Pharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 0.1-300 mg/day, preferably l 15 10-100 mg/day, when administered to patients, e.g. humans, as a drug.

*fee A typical tablet which may be prepared by conventional tabletting techniques contains: Active compound 5.0 mg Lactosum 67.0 mg Ph.Eur.

Avicel M 31.4 mg S 20 AmberlitelRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur.

The compounds of the invention may be administered to a subject, a living animal body, including a human, in need of a compound of the invention, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an amount which is effective for the treatment of the disease. Suitable dosage ranges are 1- 200 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.

EXAMPLE 1 A)-(cis-4-(4-(2-Pvrrolidinoethoxy)henvl-3-(4-(trifluoromethyl)DhenvI-chroman-7-vil 2.2 dimethvlpropanoate *o oo 15 A mixture of )-cis-7-hydroxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4-(trifluoromethyl)phenyl)chromane (2.41 g, 4.98 mmol), triethylamine (3.40 ml, 24.4 mmol), 2,2dimethylpropanoyl chloride (3.0 ml, 24.4 mmol) and tetrahydrofuran (150 ml) was stirred at 0• room temperature for 4 days. The mixture was filtered to remove inorganic solids, the filter plug being washed with a little extra tetrahydrofuran. The solvents were then evaporated S. 20 to give a colourless amorphous solid, which was recrystallised from 4:1 ethanol/water ml) to give the product as colourless needles.

Yield 1.80 g of (±)-(cis-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4- (trifluoromethyl)phenyl)-chroman-7-yl) 2 ,2-dimethylpropanoate. M.p 130-134°C.

'H-NMR

(DMSO-d,, 300 MHz) 8: 1.30 9H), 1.62-1.70 4H), 2.40-2.50 4H), 2.70 2H), 3.74 (ddd, 1H), 3.92 2H), 4.28-4.50 3H), 6.50 (dm, 2H), 6.59 (dd, 1H), 6.66 (dm, 2H), 6.71 1H), 6.93 1H), 7.02 (dm, 2H), 7.53 (dm, 2H). LRMS (FAB) 568 484 (M-CsHioN). Elemental analysis; calculated for C33Ha6F 3

NO

4 C, 69.83; H, 6.39; N, 2.47%; found C, 69.70; H, 6.48; N, 2.45%.

EXAMPLE 2 f(Q) 4 ciS-4-(4.(2Prruidinoethox6y-.-1he 2.2-7 dimthyoroanote ydrchoride A mixture Of (±)-cs7hydroxy..4..(44(2pyrroidinoethoxy)phl)- 3 3 -(rfurmty phenyl)-chromane (0.115 g, 0.24 mmol), triethylamine (2.20 ml, 15.8 mmol), 2,2dimethyliropanoyl chloride (2.04 ml, 16.6 mmcl) and tetrahydrofuran (30 ml) was stirred at room temperature for 2 days. The resulting mixture was partitioned between water (100 10 ml) and ethyl acetate (100 ml) and sodium hydrogen carbonate solution (20 ml) added to bas.f. the aqueous layer to pH 9-10. The. aqueous layerwasertdanfuhr 0 exrate with ethyl acetate (3 x 50 ml), then the combined organic lyr eewse with bnine, dried over sodium sulfate, and evaporated t ooresol h rdc a 0 purified by column chromatography on silica gel 60, with 5% methanol in aicnloromethane 15 eluent, giving the product as a colourless gum. This gum was dissolved in ethanol (20 ml) :..00and concentrated hydrochloric acid (1 ml) added with swirling to ensure complete mixing.

0000 The solvents were then evaporated to give the title compound as a colourless solid.

0 Yield 133 mg of roiienoehxy)phenyl)3(3.

.:0.:(trflorm ehy) penyl-chro a -7yJ 2 2 -dimethylpro pan oate hydrochloride.

'H-NMR

(MeOH-d 4 300 MHz)* 5: 1.35 9H), 2.0-2.55 (bin, 4H), 3.10-3.80 (in, 5H), 4.154.35 (in, 0. 0 3H), 4.40 1 4.50 (dd, 1 6.55 (dd, 1 6.60(din, 2H), 6.67 1 6.77 (din, 2H), o 6.85 (in, 1 6.92 1 7.12 (din, 1 7.36 (dd, 1H), 7.46 (dmn, 1H), NH proton not observed. LRMS (FAB) 568 484 (M-C 5

H

10

N).

EXAMPLE 3 Meth lohen l~)A (4 (2 lid.N N-dethv carb at A mixture of potassium carbonate (0.42 g, 3.04 mmol) and (±)-cis-7-hydroxy-3.(4methylphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.45 g, 1.00 mmol) in tetrahydrofuran (10 ml) was treated with N,N-diethyl carbamoyl chloride (0.50 ml, 0.54 mmol) and stirred at room temperature for 20 h. A further quantity of N,N-diethyl carbamoyl chloride (0.50 ml, 0.54 mmol) was added and stirring continued for 24 h. A final quantity of N,Ndiethyl carbamoyl chloride (0.50 ml, 0.54 mmol) was added and stirring maintained for a further 20 h. The resulting mixture was filtered to remove inorganic solids, the filter plug being washed with a little extra tetrahydrofuran, and the filtrate evaporated to give an orange oil. The product was purified by column chromatography on silica gel 60, using a to 10% methanol in dichloromethane gradient eluent. The product was thus isolated, on evaporation and vacuum drying, as an orange coloured foam.

Yield 0.443 g of (±)-(cis-3-(4-methylphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chroman-7yl) N,N-diethyl carbamate. 'H-NMR (CDCI 3 300 MHz) 8: 1.10-1.34 6H), 1.72-1.87 4H), 2.30 3H), 2.55-2.70 4H), 2.85 2H), 3.30-3.50 4H), 3.52 (ddd, 1H), 4.02 2H),4.15-4.27 2H), 4.39 (dd, 1H), 6.45-6.58 4H), 6.58-6.68 (m, 3H), 6.75 1H), 6.90 1H), 6.95 (dm, 2H). LRMS (El) 528 84 (CsHoN, 100%).

**oo EXAMPLE 4 dimethylsulfamic acid este A mixture of potassium carbonate (0.68 g, 5.02 mnmol) and (±)-cis-7-hydroxy-3-(4methylphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.45 g, 1.00 mmol) in tetrahydrofuran (20 ml) was treated with N,N-dimethyl sulfamoyl chloride (1.10 ml, 10.24 mmol) and stirred at 60*C for 20 h. A further quantity of N,N-dimethyl sulfamoyl chloride (1.10 ml, 10.24 mmol) was added and heating continued for 24 h. The resulting mixture was filtered to remove inorganic solids, the filter plug being washed with extra tetrahydrofuran, and the filtrate evaporated to give an orange oil. The product was purified by column chromatography on silica gel 60, using 10% methanol in dichloromethane as the eluent. Thus, the product was isolated, on evaporation and vacuum drying, as an orange coloured foam.

Yield 0.47 g of (±)-(cis-3-(4-Methylphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chroman-7-yl) N,N-dimethylsulfamic acid ester. 'H-NMR (CDCI,, 300 MHz) 5: 1.80-1.90 4H), 2.30 3H), 2.59-2.78 4H), 2.93 2H), 3.00 6H), 3.53 (ddd, 1H), 4.09 (t, 2H). 4.20-4.28 2H), 4.40 (dd, 1H), 6.49 (dm, 2H), 6.55 (dm, 2H), 6.63 (dm, 2H), 6.79 (dd, 1H), 6.90 1H), 6.92-7.00 3H). LRMS (El) 536 84 (C 5 H,oN, 100%).

S* EXAMPLE Step 1: cis Methanesulfonic acid 4 7 -methoxy-3-phenyl-chroman-4-yl)-phenyI ester cis 7-methoxy-4-(4-hydroxy-phenyl)-3-phenyl-hroman (7.5 g, 22.6 mmol) was dissolved in pyridine (35 ml), and methanesulfonylchlorde (3.85 ml, 49.6 mmol) was added dropwise in 5 min. The reaction mixture was refluxed for 30 min, cooled to room temperature, and ethyl acetate (100 ml) was added. The reaction mixture was acidified 20 with 6N Hydrochloric acid (100 ml), and the separated aqueous phase extracted with ethyl acetate (25 ml). The combined organic extracts were washed with 1N hydrochloric acid (50 ml), water (2 x 50 ml), dried with magnesium sulphate and evaporated to give a slightly yellow solid, which was recrystallised from ethanol, and vacuum dried.

Yield 8.6 g (93 of cis Methanesulfonic acid 4 7 -methoxy-3-phenyl-chroman-4-yl)phenyl ester; m.p. 128-130oC.

41 The product was identified by 'H-NMR.

Step 2: cis Methanesulfonic acid 4 7 -hydroxy-3-phenyl-chroman-4-yl)-phenyl ester In dry glassware and under a nitrogen atmosphere, cis Methanesulfonic acid 4-(7methoxy-3-phenyl-chroman-4-yi)-phenyl ester (5.0 g, 12.2 mmol) was dissolved in dry methylene chloride (150 ml), and cooled to 78°C. A solution of 1M boron tribromide in methylene chloride was added dropwise with stirring at such a rate that the temperature did not exceed -70*C. The reaction mixture was stirred at -78*C for 60 min, and for 10 min. after the cooling was removed. A 5% sodium bicarbonate solution (100 ml) was slowly added, and the mixture extracted with ethyl acetate (300 2 x 25 ml). The combined organic extracts were washed with water and brine, dried (magnesium sulphate) and evaporated.

Yield 4.66 g (97 of cis Methanesulfonic acid 4 7 -hydroxy-3-phenyl-chroman-4-yl)- 15 phenyl ester; m.p. 181.6-182.6*C (EtOH).

The product was identified by 'H-NMR.

Step 3: cis Methanesulfonic acid 4 7 -benzyloxy-3-phenyl-chroman-4-yl)-phenyl ester cis Methanesulfonic acid 4 7 -hydroxy-3-phenyl-chroman-4-yl)-phenyl ester (4.9 g, 12.4 mmol), potassium carbonate (8.6 g, 62 mmol) and potassium iodide (0.21 g, 1.24 mmol) was slurried with stirring in acetone (130 ml), and benzyl bromide (1.5 ml, 12.4 mmol) was added dropwise in 10 min. The reaction mixture was stirred overnight and evaporated. Water and ethyl acetate was added, and the aqueous phase extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulphate), and evaporated. The resulting material was' refluxed in ethyl acetate, left to cool overnight, and filtered.

Yield 5.0 g (83 of cis Methanesulfonic acid 4 7 -benzyloxy-3pheny-chroman- 4 yI)-pheny/ ester m.p. 165-165.5*C. (EtOH) The product was identified by 'H-NMR.

Step 4: cis 4 7 -Benzyloxy3phenychroman4yI)-phenb, 0**10 cis Methnesufoni aci 4 7 -benzyloxy3phenylchroman4-yI)phenyI ester (35 g, 71.9 mmol) was added to a solution of potassium hydroxide (350 g) in ethanol (2500 ml) .and refluxed for 90 min. The reaction mixture was cooled, acetic acid (350 ml) was slowly added, and the resulting mixture was stirred overnight. Water (1.5 1) was added dropwise over 60 min, stirring was continued for 120 min, and the precipitated product was filtered. 15 The precipitate was vacuum dried with sicapent (Merck) at 4500 for 4 days.

.Yield 27.9 g (95 of cis 4(-ezlx--hnl-hoa--i-hnl m~.204.5-205.2eC.

The product was identified by 'H-NMR.

EXAMPLE 6 7 ~Benzvloxy.444(4chlorobutyloxv henyl-chh roman 43 (,)cis 7 -Be nzyloxy--(4hyd roxyphen yl)3phenyl-ch roman (0.94 g, 2.3 mmol) was dissolved in toiuene (25 ml), and potassium carbonate (0.68 g, 4.9 mmol), 3M 18B-Crown-6 in toluene (1.6 ml, 4.9 mmol), and finally l-bromo-4-chlorobutane was added. The reaction mixture was refluxed overnight, cooled, evaporated, redissolved in methylene chloride, filtered, and evaporated. The product was crystallised from ether petrol ether.

Yield 1.06 g (88 of 7-Bnyoy4[-4clrbtlx)pey]3pey-hrmn m.p. 94-97.5*C.

The product was identified by 'H-NMR.

The following examples were performed essentially as described above.

EXAMPLE 7 7 -Benzvov44.2.clrehlx h I- nvl3hnlhron From cis 7-Benzyloxy 4 (4-hydroxy-phenyl)-3phenyl-chroman (1 g, 2.45 mmol),and l-Bromo-2-chloroethane (3.3 g, 23 mmol). The product was crystallised from ethyl acetate petrol ether.

Yield 1.01 g (84 of cis 7-ezlx--4(-hootyoy-hnl--hnl chroman, m.p. 66.0-70.60C.

The product was identified by 'H-NMR.

EXAMPLE 8 7 ~BnzyoxyA~r(&bomhexylOXY)-.henyl1-3Dphenyl-chroma From cis 7 -Benzyloxy-4(4hydroxyphenyl)3phenyl-chroman (2 g. 4.9 mmol) and 1 6 -Dibromohexane (3.8 ml g, 24.5 mmol). The product was purified by flash chromatography using petrol ether ethyl acetate toluene methylene chloride 10 0.5 0.5 0.1 as eluent.

Yield 0.99 g (35 of 7 -Benzyloxy-4-4(6bromohexyloxy)phenyl]3phenyl-chroman, m.p. 96.2-96.7*C.

The product was identified by 1

H-NMR.

****EXAMPLE 9 7-Benzyloxy-44-(1 O-bromodecyloxyv.pheny113-Dhenyl-ch roman From cis 7 -Benzyoxy4-(4hydroxyphenyl)-3phenyl-chroman (2 g, 4.9 mmol) and 1,l1O-Dibromodecane (7.4 g, 24.5 mmol). The product was purified by flash chromatography using petrol ether ethyl acetate toluene methylene chloride 10 0.5 0.5 0.1 as eluent.

Yield 2.8 g (91 of 7-BenzyloxyA44(1 O-bromo-decyloxy)phenyl]3phenylchroman,m.p. 149.1-152 0

C.

The product was identified by 'H-NMR.

EXAMPLE (+)cis7.Methx3hnl 42prolidl ')ethoxylohenvlchrman Step 1: 4-( 4 -Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene 4 4 -Acetoxyphenyl)-7-rethoxy-3-phenyl-coumarin (180 g) was dissolved in toluene (2.1 I) at 70 °C and added to a suspension of lithium aluminium hydride (35.4 g) in tetrahydrofuran (2.1 The reaction mixture was kept below 60 OC during the addition. The reaction mixture was cooled down to room temperature. Water (45 ml) was carefully added and then 5 M hydrochloric acid (1.2 The mixture was heated to 60 65 °C and stirred at for 3 hours. The organic phase was separated. The aqueous phase was extracted with toluene (250 mi). The combined organic phase was washed with water (250 ml) and evaporated to an oil. The oil was dissolved in boiling ethanol (600 ml). The solution was cooled and water was slowly added (400 ml) and the mixture was seeded. The crystals were filtered off, washed with water/ethanol; 25/75 (200 ml) and dried.

Yield 126 g of 4-(4-Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene. M.p. 156-157 o C. The product was identified by 'H-NMR and elemental analysis.

5 Step 2: cis- 4 (4-Hydroxyphenyl)-7-methoxy-3-phenylchromane S4-(4-Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene (77.7g) was dissolved in .ethanol (1500 ml) at 50 OC. Palladium on carbon, 10 50 wet (6g) was added to the solution and the mixture was hydrogenated at 55 °C and 1 atmosphere for 8 hours.

20 The catalyst was filtered off, while the suspension was warm, and the filtrate evaporated to an oil which solidified during the evaporation.

Yield 74.3 g (95 m.p. 188-190 The product was identified by 'H-NMR and elemental analysis.

46 Step 3: cis- 7 -Methoxy-3-phenyl 4 4 -[2-(pyrrolidin-1-y/)ethoxy]phenyl}chrorane.

cis-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane (74.3 g) was dissolved in a mixture of toluene (700 ml), water (12 ml) and sodium hydroxide (24.3 g) by heating the mixture to 2 -Chloroethylpyrrolidin hydrochloride (46.2 g) was added in six portions at 75 C with half an hour between each portion. After the last addition the mixture was heated at °C for 4 hours. Water (1000 ml) was added and the mixture stirred until all salt was dissolved. The aqueous phase was separated and extracted with another portion of toluene (300 ml). The combined organic phases was dried over potassium carbonate and 0 evaporated to an oil. The oil was dissolved in refluxing methanol (1000 ml) and the product crystallised by cooling in an ice bath.

Yield 79.6 g (83 m.p. 113-114 C. The product was identified by 'H-NMR and elemental analysis.

15 Step 4: y7-Methoxy- 3-phenyl-4-{4-[2-(yrroidin 1-yl)ethoxy]phenyl)chromane-(+)-O, 0 '-ditocis-7-Methoxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl)chromane (21.5 g) was 2 dissolved in 2 -propanol (300 ml with (+)-O,O'ditoluoyltartaric acid (19.3 The mixture was stirred at ambient temperature overnight. The precipitate was filtered off. The crystals were recrystailised 5 times from 2 -propanol (300 to 150 ml). The enantiomeric purity was determined by Chiral HPLC to be better than 96.7 Chiral HPLC system: Column: ChiraDex 5g, 250 x 4 mm (Merck). Eluent: 70 methanol/buffer (0.25 triethylammonium acetate, pH Flow: 0.5 ml/min. Detector: UV 220 nm.

Yield 2.7 g (13 m.p. 93-96

OC.

The product was identified by 'H-NMR and elemental analysis. The compound crystallised with half a mole of crystal bound 2-propanol.

EXAMPLE 11 7 -Methoxy-3-henvl-444-2-(Dyrrolidin-l -ylethoxv}phenylchromane Step 1: 4-( 4 -Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene 4 4 -Acetoxyphenyl)-7methoxy-3-phenyl-coumarin (180 g) was dissolved in toluene (2.1 I) at 70 *C and added to a suspension of lithium aluminium hydride (35.4 g) in tetrahydrofu- 10 ran (2.1 The reaction mixture was kept below 60 °C during the addition. The reaction mixture was cooled down to room temperature. Water (45 ml) was carefully added and then 5 M hydrochloric acid (1.2 The mixture was heated to 60 65 °C and stirred at for 3 hours. The organic phase was separated. The aqueous phase was extracted with toluene (250 ml). The combined organic phase was washed with water (250 ml) and evaporated to an oil. The oil was dissolved in boiling ethanol (600 ml). The solution was cooled and water was slowly added (400 ml) and the mixture was seeded. The crystals were filtered off, washed with water/ethanol; 25/75 (200 ml) and dried.

°Yield 126 g of 4-(4-Hydroxyphenyl)-7methoxy-3-phenyl3chromene. M.p. 156-157 o C. The product was identified by 'H-NMR and elemental analysis.

Step 2: cis-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane 4-(4-Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene (77.7g) was dissolved in ethanol (1500 ml) at 50 OC. Palladium on carbon, 10 50 wet (6g) was added to the solution and the mixture was hydrogenated at 55 OC and 1 atmosphere for 8 hours.

The catalyst was filtered off, while the suspension was warm, and the filtrate evaporated to an oil which solidified during the evaporation.

Step 3: *cis- 7 -Methoxy-3-phenyl 4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane.

Scis-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane (74.3 g) was dissolved in a mixture 10 of toluene (700 ml), water (12 ml) and sodium hydroxide (24.3 g) by heating the mixture to 75 o C. 2 -Chloroethylpyrrolidin hydrochloride (46.2 g) was added in six portions at 75 °C with half an hour between each portion. After the last addition the mixture was heated at °C for 4 hours. Water (1000 ml) was added and the mixture stirred until all salt was .I dissolved. The aqueous phase was separated and extracted with another portion of 15 toluene (300 ml). The combined organic phases was dried over potassium carbonate and evaporated to an oil. The oil was dissolved in refluxing methanol (1000 ml) and the C* C* product crystallised by cooling in an ice bath.

*C**C

Yield 79.6 g (83 m.p. 113-114 OC. The product was identified by 'H-NMR and elemental analysis.

C C Step 4: 7 -Methoxy-3-phenyl-4-{4-[2-(pyrrolidin- 1-y/)ethoxy]phenyl)chromane-(+)-O,

O'-

ditoluoyltartrate cis-7-Methoxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (21.5 g) was dissolved in 2 -propanol (300 ml with (+)-O,O'ditoluoyltartaric acid (19.3 The mixture was stirred at ambient temperature overnight. The precipitate consisting of methoxy-3-phenyl..4.{4[2-(pyrrolidinl-yl)ethoxy]phenyl)chromane(+)0 ,O'-ditoluoyltartrate was filtered off.

Step cis- 7-Methoxy-3-pheny..4{4j2.(pyrrolidin- l-YI)ethoxyphenylchromane(-+O, 0'ditoluoyltart rate.

The mother liqueur from the crystaillisation of 7 -methoxy3phenyl4[2-(pyrro- *lidin-1yl)ethoxy]phenyl~chromane(+)OOditoluoyltattwaevpaedoanilTh *I 0 10 base was liberated from the (+)-OO0'-ditoluoyltartaric acid by dissolving in toluene (300 *0 00ml), water (200 ml) and sodium hydroxide (50 ml, 4 The organic phase was washed with water (100 ml), dried over potassium carbonate and evaporated to an oil. The oil was *fee* dissolved in 2-propanol (1 1) with (-)-O,O'-ditoluoyltartaric acid (19.8 The mixture was stirred overnight and the precipitate was filtered off. The crystals were recrystallised twice from 2 -propanol (300 ml).

*S~e Yield 6.5 g (31 m.p. 92-96 OC. The enantiomeric purity was determined by Chiral HPLC to be higher than 96.7 Chiral HPLC system: Column: ChiraDex 5p., 250 x 4 mm (Merck). Eluent: 70 methanol/buffer (0.25 triethylammonium acetate, pH Flow: 0.5 mI/mmn. Detector UV 220 nm.

20 The product was identified by 'H-NMR and elemental analysis. The compound crystallised with a content of half a mole of crystal bound 2-propanol.

EXAMPLE 12 U-)-cis-3-(4-=luoroohenyD-7-m dboxy-444-C- ichromane Step 1: 4 4 -Acetoxyphenyl)-3-(4-fluorophenyl)- 7 -methoxy-coumarin A mixture of 2 -hydroxy-4-methoxyphenyl)-(4-hydroxyphenyl)-methanone (7.33 g, 30.0 mmol), acetic anhydride (15 ml), triethylamine (5.5 ml, 39.5 mmol), and 4 -fluorophenyl acetic acid (4.63 g, 30.0 mmol) was stirred at 135"C for 18 h, and the resulting orange coloured solution poured into water (120 ml) and stirred for 3 h. The resulting mixture of aqueous solution plus sticky solid was diluted with ethyl acetate (300 ml) to dissolve the solid, and the organic layer separated. The aqueous phase was further extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with water, and saturated sodium chloride solution, then dried over sodium sulfate and evaporated to give a yellow/orange solid, which was recrystallised from 2:1 ethanol/water (600ml) to give the product as an off-white solid, which was vacuum dried.

Yield 7.98 g of 4(4-acetoxyphenyl)-3-(4fluorophenyl)-7-methoxy-coumarin. M.p 173-176 0 C. 'H-NMR (CDCl,, 300 MHz) 5: 2.32 3H); 3.89 3H); 6.78 (dd, 1H); 6.82- 6.95 3H); 7.03-7.14 6H); 7.15 1H). LRMS (El) 404 362, 334, 319, 43.

Elemental analysis; calculated for C 24

H

17 FO: C, 71.28; H, 4.24%; found C, 71.26; H, 4.25%.

Step 2:

S

3 4 -Fluorophenyl)-4-(4-hydroxyphenyl)- 7 -methoxy-chrom-3-ene 20 Lithium aluminium hydride (0.76 g, 20.03 mmol) was added in small portions to a stirred tetrahydrofuran (150 ml) solution of 4 4 -acetoxyphenyl)-3-(4-fluorophenyl)-7-methoxycoumarin (4.04 g, 9.99 mmol). After complete addition, the mixture was stirred at room temperature for 30 min., then treated dropwise with 6M hydrochloric acid (30 ml). The resulting mixture was heated to 60-65*C for 3 h, cooled and diluted with water (100 ml) and ethyl acetate (50 ml). The aqueous layer was separated and further extracted with ethyl acetate (3 x 100 ml). The combined organic solutions were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to give an orange solid. This was recrystallised from ethanol/water (75ml, 4:1) to give the first crop of solid product as colourless needles. The mother liquors were evaporated to give an orange gum, which was subjected to a second aqueous ethanol recrystallisation to give a second crop of colourless needles. The solids were combined and vacuum dried.

Yield 2.47 g of 3 4 -Fluorophenyl)--4-(4hydroxyphenyl)-7-methoxy-chrom-3-ene M.p. 155-156.5°C. 'H -NMR (CDCI,, 300 MHz) 8: 3.79 3H), 4.80 (bs, 1H), 5.20 2H), 6.40 (dd, 1H), 6.51 1H), 6.70-7.00 9H). LRMS (El) 348 255 (M-PhOH), 253 (M-PhF).

Step 3: 0 (+)-cis-3-(4-Fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chromane Palladium on carbon 0.20 g, 0.19 mmol) was added to a stirred solution of 3-(4fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chrom ene (1.74 g, 4.99 mmol) in ethanol, S(150 ml) and the mixture hydrogenated at room temperature for 20 h. The catalyst was removed by filtration, and the solvent evaporated to give an off-white solid which was 15 purified by recrystallisation from aqueous ethanol. This gave the product as a colourless solid, which was vacuum dried to give colourless platelets which contained 0.75 equivalents of ethanol of crystallisation.

Yield 1.29 g of )-cis-3-(4-fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chromane.

M.p. 164-165*C (aqueous ethanol). 'H-NMR (CDCI,, 300 MHz) 8: 1.25 2.4H, 20 0.75EtOH), 3.55 (ddd, 1H), 3.73 1.6H, 0.75EtOH), 3.81 3H), 4.16-4.25 2H), *4.38 (dd, 1H), 4.90 (bs, 1H), 6.44-6.58 6H), 6:59-6.68 2H), 6.80-6.90 3H).

LRMS (El) 350 227, 211. Elemental analysis: calculated for C2HIFO3-0.75EtOH

C,

73.33; H, 6.13%; found C, 73.32; H, 6.11%.

Step 4: (±)-cis-3-(4-Fluorophenyl)-7-methoxy-4-( 4 2 -pyrrolidinoethoxypheny ccromane A mixture of 3 -(4-fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chromane, (0.53 g, 1.51 mmol) potassium carbonate, (2.10 g, 15.2 mmol) sodium iodide, (0.01 g, 0.07 mmol) 1-( 2 -chloroethyl)pyrrolidine hydrochloride, (0.28 g, 1.65 mmol) and acetone, (35 ml) was stirred at 60°C, under reflux, for 24 h. The resulting mixture was filtered and the solvent evaporated to give a colourless gum, which solidified on cooling. The crude solid was recrystallised from aqueous ethanol to give the product as colourless needles, which were vacuum dried.

Yield 0.57 g of (±cisis-3-(4-fuorophenyl)-7-methoxy-4-(4-(2-piperidinoethoxy)phenyl)chromane. M.p. 93.5-94.5°C (aqueous ethanol). 'H-NMR (CDCI,, 300 MHz) 1.75-1.85 4H), 2.55-2.65 4H), 2.85 2H), 3.55 (ddd, 1H), 3.81 3H), 4.08 (t, 2H), 4.16-4.23 2H), 4.37 (dd, 1H), 6.43-6.53 4H), 6.57-6.66 4H), 6.80-6.88 (m.

3H). LRMS (El) 447 84 (CsHioN).

EXAMPLE 13 -'-5-(cis-7-Methoxy-3-(4-methylpheny-chrom an-4-l)-2-methyl-benzoxazole To a stirred mixture of (±)-cis-4-(3-amino-4-hydroxyphenyl)-7-methoxy-3(4methylphenyl)chromane hydrochloride (0.475 g, 1.19 mmol), triethylamine (0.173 ml, 1.25 mmol) and acetic acid (15 ml) was heated to gentle reflux for 18 giving a deep red coloured 20 mixture. This was cooled to room temperature, poured into water (100 ml) and the product extracted into ethyl acetate (2 x 100 ml). The combined extracts were washed with water (6 x 50 ml), brine, dried over magnesium sulfate and evaporated to give a dark gum. This was purified by column chromatography on silica gel 60, with a 1:1 petrol/ethyl acetate eluent. This gave the product, on vacuum drying, as a stable pale pink coloured foam.

Yield 0.19 g of (±)-5-(cis-7-methoxy-3-(4-methylphenyl)chroman-4-yl)-2-methylbenzoxazole. 'H-NMR (CDCI,, 300 MHz) 5: 2.25 3H), 2.59 3H), 3.61 (ddd, 1H), 3.81 3H), 4.20-4.26 1H), 4.37 1H), 4.45 (dd, 1H), 6.45 (dd, 1H), 6.50-6.56 (m, 4H), 6.81 1H), 6.91 (dm, 2H), 6.96 1H), 7.13 1H). LRMS (El) 385 266, 252, 236, 117.

EXAMPLE 14 (p)-cis-6-Methoxv-3-phenvl-4-2-vrrolidinoethoxv)phenvl).chroma.

Step 1: 4 -Benzyloxyphenyl)-(2, 5 -dimethoxyphenyl)-methanone SButyllithium (2.0M in hexanes, 6.6 ml, 13.2 mmol) was added dropwise under nitrogen, at 78*C to a stirred tetrahydrofuran (20 ml) solution of 4 -benzyloxy-bromobenzene (3.15 g, 11.97 mmol) to give a yellow coloured suspension, which was stirred for 10 minutes. A tetrahydrofuran (10 ml) solution of N,N-dimethyl 2 ,5-dimethoxybenzamide (2.09 g, 9.99 mmol) was then added slowly, and the resulting mixture warmed to room temperature over 20 h. The mixture was diluted with 50ml of 1M hydrochloric acid and the product extracted into dichloromethane (4 x 50 ml). The combined extracts were washed with brine, dried over sodium sulfate and evaporated to a yellow coloured solid. This crude product was purified by column chromatography on silica gel 60, using 4:1 petrol/ethyl acetate as the eluent. This gave the product as a colourless solid, which was recrystallised from hot ethanol (25 ml) to give the product as colourless platelets which were vacuum dried.

Yield 1.61 g of (4-benzyloxyphenyl)-(2,5-dimethoxyphenyl)-methanone. M.p. 111- 113*C (ethanol). 'H-NMR (CDCI,, 300 MHz) 8: 3.70 3H), 3.78 3H), 5.13 2H), 6.85-7.02 5H), 7.30-7.47 5H), 7.82 (dm, 2H). LRMS (El) 348 257, 91.

Step 2: 54 2 -Hydroxy-5-methoxyphenyl)-(4-hydroxyphenyl)-methanone Palladium on carbon catalyst 1.0 g, 0.94 mmol) was added to a stirred ethanol (500 ml) solution of (4-benzyloxyphenyl)-(2,5-dimethoxyphenyl)-methanone (10.86 g, 31.2 mmol) and the suspension hydrogenated for 18 h. The catalyst was removed by filtration, and the solvent evaporated to give an orange coloured gum. This was dissolved in glacial acetic acid (16 ml), hydrogen bromide (33% w/w in acetic acid, 8.20 ml, 46.76 mmol) added, and the resulting mixture heated to 70°C for 18 h. The mixture was diluted with water (25mi) and the product extracted into ethyl acetate (3 x 25 ml). The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to a yellow gum, which was purified by column chromatography on silica gel 60, with 7:3 Spetrol/ethyl acetate as eluent. This gave a yellow gum, which was dissolved in a minimum of ether and precipitated by adding petrol, to give the title product as a yellow powder.

Yield 0.59 g of (2-hydroxy-5-methoxyphenyl)-(4-hydroxyphenyl)-methanone M.p 1 4 4.5-147.5"C (ethyl acetate/petrol). 'H-NMR

(CDCI

3 300 MHz) 5: 3.74 3H), 6.30 (bs, S 15 1H), 6.92 (dm, 2H), 7.01 1H), 7.10 1H), 7.13 (dd, 1H), 7.68 (dm, 2H), 11.50 1H).

LRMS (El) 244 150 (M-PhOH).

Step 3: 4-( 4 -Acetoxyphenyl)-3-phenyl-6-methoxy-coumarin S 20 A mixture of (2-hydroxy-5-methoxypheny)-(4-hydroxyphenyl)-methanone (0.59 g, 2.42 mmol), acetic anhydride (1.15 ml, 12.1 mmol), triethylamine (0.44 ml, 3.16 mmol), and phenyl acetic acid (0.33 g, 2.42 mmol) was stirred at 135 0 C for 18 h. The resulting orange coloured solution was poured into water (20 ml) and stirred for 3 h, and the resulting mixture of aqueous solution plus sticky solid was diluted with ethyl acetate (20 ml) to dissolve the solid, and the organic layer separated. The aqueous phase was further extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with water, then brine, dried over sodium sulfate and evaporated to give a yellow/orange gum.

This gum was dissolved in a minimum of ether and petrol added to precipitate the title compound as an off white powder.

Yield 0.49 g of 4 4 -acetoxyphenyl)-3-phenyl-6-methoxy-coumarin. 'H-NMR (CDCI 3 300 MHz) 8: 2.28 3H), 3.72 3H), 6.70 1H), 7.04-7.25 10H), 7.48 1H).

LRMS (El) 386 344, 327, 316, 43.

Step 4: (±)-cis-6-Methoxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane Lithium aluminium hydride (0.96 g, 2.54 mmol) was added in small portions to a stirred *10 solution of 4 4 -acetoxyphenyl)-3-phenyl-6-methoxy-coumarin (0.49 g, 1.27 mmol) in tetrahydrofuran (75 ml). The resulting mixture was stirred for 30 min., 6M hydrochloric acid (4 ml) added dropwise, and the mixture heated to 65°C for 3 h. The mixture was cooled to room temperature, diluted with 100 ml water, and the product extracted into ethyl acetate (2 x 100 ml). The extracts were washed with brine, dried over sodium sulfate and 15 evaporated to give a yellow gum. This gum was dissolved in ethanol (100 ml), and palladium on carbon 0.045 g, 0.02 mmol) added, then the mixture was hydrogenated for 18 h. The catalyst was removed by filtration and the solvents evaporated to give an orange gum, which was vacuum dried. The gum was dissolved in dry acetone (20 ml) then potassium carbonate (1.87 g, 13.50 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.257 g, 1.51 mmol) and sodium iodide (0.01 g, catalyst) were added and the mixture heated to 60C for 20 h. The inorganic solids were removed by filtration and the solvent removed to give an orange gum, which was purified by column chromatography on silica gel 60 with 9:1 dichloromethane/methanol eluent. This gave the product as a pale orange gum, which was vacuum dried.

Yield 0.34 g of (±)-cis-6-methoxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane. 'H-NMR (CDCI,, 300 MHz) 8: 1.70-1.90 4H), 2.55-2.70 4H), 2.85 (t, 2H), 3.56 (ddd, 1H), 3.69 3H), 4.02 2H), 4.15-4.28 2H), 4.40 (dd, 1H), 6.45-6.55 3H), 6.55-6.72 4H), 6.79 (dd, 1H), 6.90 1H), 7.10-7.20 3H).

56 EXAMPLE (i)-cis-4-(4-Hexylphenvl)-7-methoxv-3-phenvlchromane Step 1: (±)-(cis-4-((7-methoxy-3-phenyl)chroman-4-yl)phenyl trifluoromethanesulfonic acid ester A stirred suspension of (i)-cis-4-(4-hydroxyphenyl)-7-methoxy-3-phenylchromane g, 15 mmol) in a mixture of dichloromethane (50 ml) and triethylamine (2.9 ml, 21 mmol) was treated dropwise at 0°C, under a nitrogen atmosphere, with trifluoromethanesulfonic 10 anhydride (5.0 g, 17 mmol), and the mixture warmed slowly to room temperature. The resulting rather viscous solution was diluted with tetrahydrofuran (100 ml), and stirred for a further 24 hours. The reaction mixture was filtered, the solvents evaporated, and the residue partitioned between dichloromethane (200 ml) and 10% aqueous acetic acid (200 ml). The organic layer was separated, washed with 10% aqueous acetic acid (100 ml), 15 sodium hydrogen carbonate solution (3x100 ml), brine (100 ml), dried over sodium sulfate, and evaporated. The product was purified by column chromatography on silica gel 60, with dichloromethane as the eluent. This gave the product as a clear gum, which was crystallised from diethylether and petrol, to afford the title product as colourless crystals.

Yield 2.88 g of ()-(cis-4-((7-methoxy-3-phenyl)chroman--ypheny 20 trifluoromethanesulfonic acid ester. M.p. 98-99°C. H-NMR (CDCI, 300MHz) 5: 3.65 (m, 1H), 3.81 3H), 4.24-4.40 3H), 6.49 (dd, 1H), 6.53 1H), 6.61-6.69 4H), 6.82 1H), 6.96 2H), 7.11-7.20 3H). LRMS(EI): 464 Step 2: (±)-cis-4-(4-Hexylphenyl)- 7 -methoxy-3-phenylchromane 57 An oven dried 2-necked flask fitted with a reflux condenser and an inlet septum, was charged, under a nitrogen atmosphere, with 9 -borabicylo[3.3.1]nonane) (0.5M in tetrahydrofuran solution, 4.74 ml, 2.37 mmol), which was cooled to 0°C. 1-Hexene (199 mg, 2.37 mmol) was added, and the mixture slowly warmed to room temperature over 7 hours.

Anhydrous dioxane (20 ml), caesium carbonate (1.05 g, 3.23 mmol), tetrakis(triphenylphosphine)palladium (62 mg, 0.05 mmol) and (±)-(cis-4-((7-methoxy- 3 -phenyl)chroman-4-yl)phenyl trifluoromethanesulfonic acid ester (1.0 g, 2.15 mmol) were added, and the mixture heated to gentle reflux for 24 h. The mixture was cooled to room temperature and diluted with hexane (20 ml), then 2M sodium hydroxide (1.6 ml) and hydrogen peroxide (1 ml) were added, and the mixture stirred for 2 hours to destroy the excess borane. The resulting mixture was diluted with ethyl acetate (200 ml) and water o'(200 ml), and the organic layer separated, washed with water (100 ml), brine (100 ml), dried over sodium sulfate, and evaporated. The crude product was purified by column g* e chromatography on silica gel 60, with 2% methanol in dichloromethane as the eluent. This 15 gave the title compound as a clear oil.

Yield 0.758 g of 4 4 -hexylphenyl)-7-methoxy-3-phenylchromane.

'H-NMR

(CDC13., 300 MHz) 0.88 3H), 1.20-1.32 6H), 1.53 2H), 2.50 2H), 3.59 (m, 1H), 3.80 3H), 4.20-4.29 2H), 4.45 1H), 6.42-6.53 4H), 6.61-6.68 2H), 6.82-6.89 3H), 7.08-7.19 3H). LRMS 400 (M EXAMPLE 16 cis 4 7 -Benzvloxv-3-Dhenyl-chroman-4-vl)-ohenoxvl-acetic acid methyl ester cis 4 -(7-Benzyloxy-3-phenyl-chroman-4-yl)-phenol (0.5 g, 1.22 mmol), methyl bromoacetate (0.37 g, 2.44 mmol), 18-crown-6 (0.48 g, 1.83 mmol), and potassium carbonate 0.25 g, 1.83 mmol) was slurried in toluene (25 ml), and stirred at 1000C for min. After cooling the reaction mixture was filtered through a 1.6 x 6 cm silica column, eluted with 10 tetrahydrofuran in toluene and evaporated.

Yield 550 mg (94 Of cis [4(-ezlx--hnlcroa--l-hnxlaei acid methyl ester; m.p. 143.3-144.1 Cc The product was identified by 'H-NMR.

EXAMPLE 17 7-Bcisyloeyi-6bohyexyl(6oy)-henlnoheylxy omnl 3 00mg .5 mo orholine (229 mg, 2.63 mmol, potassium carbonate (145 mg, 1.05 mmol), and potassium iodide (17 mg, 0.11 mmol) was refluxed in toluene (5 ml) for 3 days. The reaction mixture was cooled, filtered, and the precipitate washed with toluene. The combined filtrate and washings were evaporated, triturated with ethanol, and recrystallised from ethanol.

*Yield 229 mg (75 of cis 7Bnyoy4(-6mrhlnhxlx)pey]3 phenyl-chroman, m.p. 85.7-87.5aC.

***The product was identified by 'H-NMR.

The following examples were per-formed essentially as described above.

EXAMPLE 18 cis -ezlx 4 uyami iohylxohv13he vcrman From 7-ezlx--4(-rmhxlx)pey]3pey-hoa (300 mg, 0.53 mmol) and N,N-dibutylamine (339 mg, 2.63 mmol).

59 Yield 184 mg (56 of cis 7 -Benzyloxy-4(4(6dibutylaminohexyloxy)-phenl]-3 phenyl-chroman, m.p. 72-73.5*C.

The product was identified by 1

H-NMR.

EXAMPLE 19 cis 7-enzvloxy 4 -r 4 -(dimethylaminodecvloxy)-phenyll13-henvlchoman From (,)cis 7-Benzyloxy.4-[4-(1 -Bromodecyl)yphenyl]j3phenyl-chromafl 3 00mg, 0.48.

mmol) and dimethylamine.HCI (195mg, 2.4 minD!).

Yield 107 mg (38 of cis 7-Benzyloxy 4-[ 4 -(diinethylaminodecyloxy)phenyl]- 3 phenyl-chroman. Oil IH -NMR (COCl 3 200 MHz) 8: 1.3 (in, 14H); 1.72 (in, 2H); 2.23 (mn, 8H); 3.58 (mn, 1 3.83 2H); 4.22 (in, 2H); 4.93 1 5.03 2H); 6.58 (in, 8H); 6.85 1 7.15 (in, 3H); 7.37 EXAMPLE From cis 7-Hydroxy-4..[4-( O-Bromodecyloxy)phe nylp3-phenyl-chroman 3 00mg, 0.48 inmol) and morpholine (208 ing, 2.4 inmol).

Yield 122 mng (40 of cis 7-Benzyl 4 4 -(morpholinodecyloxy)phenylp3-phenylchroinan. Oil 1 H -NMR (C~DC 3 200 MHz) 8:1.3 (in, 14H); 1.7 (mn, 2H); 2.31 2H); 2.40 (in, 4H); 3.55 (in, I1H); 3.70 (mn, 4H); 3.85 2H); 4.22 (mn, 2H); 4.43 1 5.05 2.H); 6.58 (mn, 8H); 6.85 1 7.15 (in, 3H); 7.38 (mn, EXAMPLE 21 )cis 7-BenzloXV 4 4 4 2 -dibutylamin eh~x~oey1DeVI-chroma cis 7-enzyloxy- 4 4 2 choroethyloxy)pheny]3phenyl-chroa (235 mg, mmoll), 1N,N-dibutylamine (323 mg, 2.5 mmol), potassium carbonate (138 mg, 1 mmol) and potassium iodide (16 mg, 0.1 mmol) in dimethylformamide (5 ml) Was stirred at 6000 for 2 weeks. The reaction mixture was cooled and ether and water was added. The aqueous phase was extracted with ether, and the combined organic phases were washed with *10 water and brine, dried (magnesium sulphate), and evaporated. The product was isolated by silica column choaorpyusing methanol methylenechloride (1 +19) as let Yield 120 mg (43 of cis 7-benzyloxy 4 4 2 -N-dibutylaminoethyoxy)-pheny].

3 .phenyl-chroman, oil, 1 H -NMR (ODCd 3 200 MHz) 8: 0.9 6H); 1.45 (in, 8 2.5 4H); 2.81 2H); 3.55 (in, 1 3.93 2H); 4.2 (mn, 4.4 1 5.1 2H); 6.55 8H); 6.83 1 H)7.23 (mn, 3H); 7.38 (in, EXAMPLE 22 (2~ci 7 Ben yl xv 4 4 butla inoeth loxy)-.Dhenvl13phnvyLch ro na n From (,)cis 7-ezlx--4(-hootylx)pey]3pey-hoa (235 mg, inmol) and butylamine (183 mg, 2.5 minol). The evaporated product was precipitated from ether petrolether to give 160 mg of material, which was chromatographed as described above.

Yield 110 mg (44 of cis 7 -Benzyloxy 4 4 -(butylamin oethyloxy)phenyr-3-phenylchroman. Oil. 'H -NMR (ODC1 3 200 MHz) 5: 0.9 3H);1.43 (in, 4H); 2.70 2H); 3.0 (t, 61 2H); 3.58 (in, 1 4.03 2H): 4.22 (in, 2H); 4.41 1 5.06 2H); 6.6 (in, 8H); 6.83 1 7.14 (in, 3 7.4 (mn, 5 H) EXAMPLE 23 7-Benzyloxy 4 4f 4 -inor holinoethyloxy)o1hen-l3-henyLchronan From cis 7 -Benzyloxy--[4(2choroethyloxy).pheny]3phenyl-chroa (263 mg, 0.56 mmol) and morpholine (243 mg, 2.79 mmol). Reaction time 4 days. The evaporated :product was precipitated from ethanol.

10 Yield 139 mng (48 of cis 7-Benzyloxy 4 4 -(morpholinoethyloxy)phenyll3-phenylchroman, 'H -NMR (CDCI,, 200 MHz) 5: 2.52 4H); 2.75 2H); 3.58 (in, 1H); 3.70 (t, 4H); 4.0 2H); 4.2 (in, 2H); 4.4 1H); 5.05 2H); 6.6 mn (in, 8H); 6.83 1H); 7.13 (in, 3H); 7.38 EXAMPLE 24 From cis 7-Benzyioxv 4 4 -[4(mthlooraoeethloxy)heny3phenylchron(3mg 0.50 inmol) and N-inethylpiperazine (250 mg, 2.5 minol). Reaction time 3 days. The reaction mixture was filtered, and water and ether was added. The aqueous phase was extracted with ether. The combined organic extracts were washed with water, and extracted with 0.01 N hydrochloric acid (x The combined acidic extracts were basified to pH 10 and extracted with ether (x dried, and evaporated. The product was precipitated from ether petrol ether.

62 Yield 122 mg (46 of cis 7-Benzyloxy 4 4 -(N-methylpiperazinoethyloxy)phenyl]- 3 phenyl-chroman, m.p. 103.2-106.8 0

C.

The product was identified by 'H-NMR.

EXAMPLE cis 7-Benzvloxy 4 4r 4 mroilnbt~x~oey1.hnlhoa From (,)cis 7 -Benzyloxy4[4-(4-ch lorobuty Ioxy)phen yl-3-phenyl-ch rmn(300 mg, *.0.60 mmol) and morpholine (240'mg, 3 mmol). Reaction time 4 days. The evaporated *10 product was crystallised from ether petrolether, and further purified by silica column chromatography using methanol methylene chloride (1 +19) as eluent.

*Yield 160 mg (47 of cis 7-Benzyloxy 4 4 -(morpholinobutyloxy)phenyl-3-phenylchroman. Oil. IH -NMR (CDC 3 200 MHz) 5: 1.68 2.38 (in, 6H); 3.55 (in, IH); 3.70 4H); 3.88 2H); 4.2 (in, 2H); 4.40 1 5.03 2H); 6.56 (in, 8H); 6.83 1 7.15 (in, 3H); 7.38 (in,

Claims

1. A compound of the formula I in which substituents RI and R' are arranged in cis- configuration:

9. 9 9 999 9 9. 9. 9 9 99 9. 9 9 9 9999 9999 9* 99 9 999999 .99 9 9 9* 9 99 .9 9 999999 9 9.9. 99 99 9 9999*9 9 wherein: R 1 is COR 4 CONHR 4, CONR', SO 2 NR, S0 2 NHR 4 or benzyl; R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from 10 the group consisting of OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C 6 -alkyl, alkyl, Cl-Cs-alkoxy and phenyl; RI is: phenyl substituted with -X-(CH 2 wherein: X is a valency bond, 0 or S, n is an integer in the range of i to 12, Y is H, halogen, OH, OR', NHR 4 NR 2, NHCOR', NHSO 2 CONHR', CONR 2 COOH, COOR, SO 2 R4, SOR, SONHR' SONR a C 3 7 hercccrigsau rated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of 0, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, yano, S 4 trhl-CI-C 6 -alkyl, C-C 6 -alkyl and C 1 -Cr,-alkoxy; or -(CH 2 wherein n and Y are as defined above; or phenyl fused to a C 3 -C 7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of 0, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen. nitro, cyano, SH, SR", trihalo-C 1 l-- 6 alkyl, C,-C.-alkyl and 0 1 -C 6 -alkoxy; and R" is C,-C,,-alkyl; 10 and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and salts thereof. 2. A compound of the formula I in which substituents RI and R 3 are arranged in cis- configuration: 0 je 6 600 0 00 @0 0 0 S S@ SO @6 S 9 5 0@9b 0 90 do 0 0 060900 0 *0S5 0 *606 50 0 9* 00 0 000090 0 wherein: R 1 is COR 4 CONHR 4 ,CONR 2, SO 2 NR 2 or SO 2 NHR'; R 2 is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 trihalo-C 1 -C 6 -alkyl, alkyl and Cl-Cr,-alkoxy; R' is: phenyl substituted with -X-(CH 2 wherein: X is a valency bond, O or S, n is an integer in the range of 1 to 12, Y is H, OH, OR 4 NHR 4 NR NHCOR 4 NHSOR', CONHR', CONR COOH, COOR 4 SO 2 R 4 SOR 4 SONHR 4 SONR a C 3 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the S. group consisting of O, S and N, optionally being substituted with 1 to 3 substitu- ents independently selected from the group consisting of H, OH, halogen, nitro, 10 cyano, SH, SR 4 trihalo-C,-C 6 -alkyl, C,-C 6 -alkyl and C,-C-alKoxy; or -(CH 2 wherein n and Y are as defined above; or phenyl fused to a C 3 -C 7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C,- alkyl, C,-C 6 -alkyl and C,-C 6 -alkoxy; and R 4 is C,-Ce-alkyl; and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and salts thereof. 3. A compound according to claims 1 or 2 having the formula R3 Ni. (la) 66 R3 R 1 0 R 2 o (Ib) wherein R 2 and R 3 are as defined above. 4. A compound according to anyone of the preceding claims in which R' is COR 4 CONHR', CONR", SONR or SO 2 NHR 4 5. A compound according to anyone of the preceding claims in which R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C-alkyl, C,-Cs-alkyl and C,- C 5 -alkoxy. 6. A compound according to anyone of the preceding claims in which R 2 is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-Ce-alkyl, C,-C 6 -alkyl and C,- C6-alkoxy. *e 7. A compound according to anyone of the preceding claims in which R' is phenyl substituted with -X-(CH 2 wherein: X is a valency bond, O or S, n is an integer in the range of 1 to 12, Y is H, OH, OR 4 NHR 4 NR NHCOR 4 NHSO 2 R 4 CONHR', CONR COOH, COOR 4 SO 2 R4, SOR SONHR 4 SONR a C 3 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of 0, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-Cs-alkyl, C,-C 6 -alkyl and C,-C6-alkoxy. 67 8. A compound according to anyone of the preceding claims in which R 3 is wherein n and Y are as defined above. 9. A compound according to anyone of the preceding claims wherein R' is phenyl fused to a C3-C, heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of 0, S and N, optionally being sub- stituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C 6 -alkyl, C,-C,-alkyl and C,-C 6 -alkoxy. A compound according to claim 1 or 2 having the formula 0 COOR 10 wherein R' is as defined above and R is H or alkyl.

11. A compound according to claim 1 or 2 having the formula o 0 wherein R 1 is as defined above and m is an integer from 0 to 68

12. A compounds according to claim 1 or 2 having the formula 0 o wherein R 1 and m are as defined above.

13. A compound according to claim 1 or 2 having the formula 0 0 wherein R 1 and m are as defined above.

14. A compound according to claim 1 or 2 having the formula *o 69 0 wherein m and R' are as defined above and both R" independently are as defined above.

15. A compound according to claim 1 or 2 having the formula 0 )NR 4 wherein R' and R' are as defined above.

16. A compound according to claim 1 or 2 having the formula wherein R 4 is as defined above. *17. A compound according to claim 1 or 2 having the formula .No R6 0 w h r i I i s d f n d a o e a d R e r s n s o e o o e o h o l w n u s i u ens meh xh dox ,tilomeh l l oo n hoo

18. A o p u d a c rigt*li r2s lce r mt eflo ig -c s 4 -2 P r oii*eh x h n l -4 rf .o o t y )p e y o n 7 y 2 2 diehlroao diets: methoxy, hydroxyhltriflorehyfuranchoo (±)(cis3-(4(2Ptyhnyl--42prolidinoethoxy)pheny(tfl)hoa--i 2,2-ieh carbamnate (±)-(cis3(4Metheylhenyl)A(4.2pyrrolidinoethoxy)phl hmn 7 N, N- dimethylsulfamic acid ester 7 -Benzyloxy-4-(4hydroxyphenyl)3.phenyl-chro man 7 -Benzyloxy-4[4(4ch orobutyloxy)phenyl]3phenyl-chroma 7 Benzyloxy4[4(2choroethyloxy)phenyl-3phenyl-chroa 7 -Benzyloxy~4-4(6bromoheyloxy)phenyl]3phenylhroa 7-Benzyloxy.4-(4-(l l-bromodecyloxy)phenyl].3-phenyl-chr 0 omfl (+)cis 4 7 -Benzyloxy3phenylchroman4yi)-phenoxyl-acetic acid methyl ester (,)cis 7 -Benzyloxy4[4(6morpholinohelxyo)-pheny3pylcroa (,)cis T-Benzyloxy 4-4(-iuyaiohxlx)-hn'y)3pey-hoa )cis 7 -Benzyloxy 4 -I( 4 -(dimethyainodecy Ioxy)phen yl]3phenyl-ch roman 7-Benzyloxy 4 4 -(morph oli nodecyloxy)phenyl]3phenyl-ch roman cis 9.e z l x -4 -i uy a i o th l x )p e y ]3 p e y -h o a (,)cis 7-Benzyloxy 4 4 2 butylaminoethyloxy)phenyl]3phenylcoman (,)cis 7-Benzyloxy 4 4 -(morpholinoethyloxy)phenyl-3-phenyl-chroman (,)cis 7 -Benzyloxy 4 4 -(N-methylpiperazinoethyloxy)phenylI3phenyl-chroman 7-Benzyloxy 4-4(opoiouyoy-hnl--hnlcrmn 9t*9 including the pure enantiomers thereof. 9*

19. A method for the preparation of compounds of formula comprising the steps of: a) reacting a compound of the formula (11 9. 0 00 OH OH with a compound of the formula (111) "COOH (III) wherein R 5 is as defined above, in the presence of tnethylamine and acetic anhydride to form a compound of the formula (IV) *r wherein R 5 is as defined above, b) reducing a compound of the formula (IV) with a suitable hydride reducing agent to form a compound of formula (V) wherein R 5 is as defined above, 0* c) hydrogenating a compound of the formula in the presence of a suitable catalyst to form a compound of the formula (VI) with a 3,4-cis configuration wherein R 5 is as defined above, d) alkylating a compound of the formula (VI) with an appropriate electrophile to form a compound of the formula (VII) (CH2)-Y v O' (VII) wherein n, R 5 and Y are as defined above, e) deprotecting a compound of formula (VII) with a suitable deproctection agent, pref- erably by pyridine hydrochloride fusion, to form a compound of the formula (VIII) (CH 2 -Y (VIII) wherein n, R 5 and Y are as defined above, f) reacting a compound of the formula (VIII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or g) nitrating a compound of the formula (VI) with a suitable nitration agent to form a compound of the formula (IX) wherein R 5 is as defined above, h) reducing a compound of the formula (IX) with a suitable reducing agent, preferably by catalytic hydrogenation, to form a compound of the formula (X) OH ^Y wherein R s is as defined above, i) cyclizing a compound of formula with an appropriate agent to form a compound of the formula (XI) or (XII) 76 0 NR 4 RS 0 0No( I or R 4 .RS 0 0. I wh ri R4 an.'aea d fnda o e mula. (XII) o X (XIII) or (XIV) wherein R 4 and R S are as defined above, k) reacting a compound of the formula (XIII) or (XIV) with the appropriate carboxyiic acid or sulphonic acid derivative to form a compound of the formula or 1) reacting a compound of formula (VI) with trifluoromethane sulphonic acid anhydride to form a compound of the formula (XV) OS0 2 CF, ri asR wherein R 5 is as defined above, m) cross-coupling a compound of the formula (XV) with the appropriate cross-coupling partner to form a compound of the formula (XVI) (XVI) wherein n, R' and Y are as defined above, n) deprotecting a compound of the formula (XVI) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (XVII) (XVII) wherein n, Rs and Y are as defined above, 0) reacting a compound of the formula (XVII) wit h the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or p) cyclizing a compound of the formula (XVIII) (XVIII) wherein R 5 is as defined above, with paraformaldehyde in the presence of dimethylamine to form a compound of the formula (XIX) O RS (XIX) wherein R 5 is as defined above, q) reacting a compound of the formula (XIX) with the appropriate Grignard reagent to form a compound of the formula (XX) wherein n, R 5 and Y are as defined above, r) hydrogenating a compound of the formula (XX) in the presence of a suitable cata- lyst to form a compound of the formula (XXI) with a 3,4-cis configuration (XXI) wherein n, R 5 and Y are as defined above, s) deprotecting a compound of formula (XXI) with a suitable deprotection agent, pref- erably by pyridine hydrochloride fusion, to form a compound of the general formula (XXII) (XXII) wherein n, R 5 and Y are as defined above, t) reacting a compound of the formula (XXII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula 10 u) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XXIII) S S0 IO 3 (XXIII) 81 wherein R 5 is defined as above, v) deprotecting a compound of the formula (XXIII) with a suitable deprotection agent, such as pyridine hydrochloride fusion or boron tribromide, to form a com- pound of the formula (XXIV) 0 0* s .S O O~~ (XXIV) a a a. wherein R 5 is defined as above, w) reacting a compound of the formula (XXIV) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula (XXV) 0 O. o o (XXV) wherein R 5 is defined as above, and R 6 is H or methoxy, x) deprotecting a compound of the formula (XXV) with a suitable deprotection agent, such as sodium or potassium hydroxide in alcohol, to form a compound of for- mula (XXVI) 82 OH R 6 0 O (XXVI) wherein R 5 is defined as above, and R 6 is H or methoxy, y) alkylating a compound of the formula (XXVI) with an appropriate electrophile to form a compound of the formula (XXVII) 0 a a 00 0 a a a a (XXVII) wherein n, R s and Y is defined as above, and R 6 is H or methoxy, z) deprotecting a compound of the formula (XXVII) with a suitable deprotection agent, preferably catalytic hydrogenation for R 6 equals H or a strong acid for R 6 equals methoxy, to form a compound of the formula (XXVIII) 83 O (CH 2)-Y HO R 0 (XXVIII) wherein n, R s and Y is defined as above, aa) Alkylating a compound of the formula (XXVI) with an appropriate dihalogenated alkane such as 1,2-dibromoethane, 1-bromo-2-chloroethane, 1,4-dibromobutane 1, 6 -dibromohexane, 1,8-dibromooctane, 1,10-dibromodecane, preferably cata- 10 lysed by potassium iodide, to form a compound of the formula (XXIX) O (XXIX) wherein n and R is defined as above, R6 is H or methoxy, and Hal is chloro, o^o bromo, or iodo, bb) reacting a compound of the formula (XXIX) with an appropriate nucleophile, pref- erably an amine, to form a compound of the formula (XXX) 84 O (CH 2 R e 0. y (XXX) wherein R 6 is H or methoxy, and Z is NHR 4 NR2, or a C 3 heterocyclic amine optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-Ci-C 6 -alkyl, C,-C 6 -alkyl and C,-C 6 -alkoxy, and n, R 4 and R 5 is 10 defined as above, V, Scc) deprotecting a compound of the formula (XXX) with a suitable deprotection agent, preferably catalytic hydrogenation for R' equals H or a strong acid for R' equals methoxy, to form a compound of the formula (XXXI) O(CH2 -Z I HO o (XXXI) wherein R 6 is H or methoxy, and Z is NHR 4 NR or a C 3 heterocyclic amine optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-C,-C 6 -alkyl, C,-Cs-alkyl and C,-C 6 -alkoxy, and n, R' and R 5 is defined as above. A compound according to any of the claims 1 to 18 for use in the prevention or treatment of estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal.

21. A compound according to any of the claims 1 to 18 for use in the prevention or treatment of bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, including flushing, urogeni- tal atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen- dependent cancers, post-partum lactation or for use as contraception or an aid in ovarian development, preferably in the prevention or treatment of bone loss or osteopo- rosis. SOSlI l

22. A pharmaceutical composition comprising an effective amount of a compound according oOS to claims 1 to 18 or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent. o

23. A pharmaceutical composition according to claim 22 in the form of an oral dosage unit or parenteral dosage unit.

24. The use of a compound according to any of the claims 1 to 18 for the preparation of a medicament for prevention or treatment of estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal.

25. The use of a compound according to any of theclaims 1 to 18 for the preparation of a medicament for use in the prevention or treatment of bone loss, osteoporosis, cardio- vascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms including flushing, urogenital atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen-dependent cancers, post-partum lactation or for use as contraception or an aid in ovarian development, preferably in the prevention or treat- ment of bone loss or osteoporosis. 86

26. A method of treating or preventing estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal, comprising administering to a subject in need thereof an effective amount of a compound according to any of the claims 1 to 18.

27. A method of treating or preventing bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, includ- ing flushing, urogenital atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen-dependent cancers, post-partum lactation, or aiding ovarian development, preferably prevention or treatment of bone loss or osteoporosis, which method com- prises administering to a subject in need thereof an effective amount of a compound according to any of the claims 1 to 18. S28. A contraceptive method comprising administering to a male or female mammal an 15 effective amount of a compound according to any of the claims 1 to 18.

29. A -enantiomer of a compound of the formula I in which substituents R 2 and R' are arranged in cis-configuration: R3 *2 (I) wherein: R 1 is C,-C 3 -alkyl; 87 R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C-alkyl, C,-C6- alkyl, C,-C 6 -alkoxy and phenyl; R 3 is: phenyl substituted with -X-(CH 2 wherein: X is a valency bond, O or S, n is an integer in the range of 1 to 12, Y is H, halogen, OH, OR 4 NHR 4 NR2, NHCOR 4 NHSO 2 R 4 CONHR 4 CONR2, COOH, COOR 4 S0 2 R 4 SOR 4 SONHR 4 SONR4., a heterocyclic ring, saturated 10 or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C-C 6 -alkyl, C,-Ce-alkyl and C,-Ce-alkoxy; or -(CH 2 wherein n and Y are as defined above; or 15 phenyl fused to a C3-C7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, op- tionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C-alkyl, C,-C-alkyl and CI-C 6 -alkoxy; and S 20 R 4 is C,-C 6 -alkyl; and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and salts thereof. A compound according to claim 29 having the formula 88 R 3 Rlo0 o (Ia) or R 3 R 1 0 R 2 (Ib) wherein R 2 and R 3 are as defined in claim 29.

31. A compound according to claims 29-30 in which R' is C,-C 3 -alkyl, preferably methyl. 5 32. A compound according to claims 29-31in which R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C 6 -alkyl, C,-C-alkyl and C,-C,-alkoxy.

33. A compound according to claims 29-32 in which R 3 is phenyl substituted with -X-(CH 2 Y, wherein: X is a valency bond, O or S, n is an integer in the range of 1 to 12, Y is H, OH, OR, NHR 4 NR NHCOR', NHSO 2 R 4 CONHR 4 CONR COOH, COOR 4 S0 2 R 4 SOR 4 SONHR 4 SONR a C 3 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C 6 -alkyl, C,-Cs-alkyl and C,-C 6 -alkoxy.

34. A compound according to claims 29-33 in which R 3 is -(CH 2 wherein n and Y are as defined above. 89 A compound according to claims 29-34 wherein R 3 is phenyl fused to a C3-C, heterocy- clic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro cyano, SH, SR 4 trihalo-C,-C-alkyl, C,-C-alkyl and C,-C,-alkoxy.

36. A compound according to claim 29 having the formula wherein R' is as defined in claim 29 and R is H or alkyl.

37. A compound according to claim 29 having the formula S wherein R' is as defined in claim 29 and m is an integer from 0 to

38. A compounds according to claim 29 having the formula 0 wherein R' is as defined in claim 29 and m is as defined in claim 37.

39. A compound according to claim 29 having the formula 5 wherein R' is as defined in claim claim 29 and m is as defined in claim 37. A compound according to claim 29 having the formula o0 C 2 CH 2 R4 *R4 91 wherein R' is as defined in claim 29 and m is as defined in claim 37 and both R 4 independently are as defined in claim 29.

41. A compound according to claim 29 having the formula a a a a. a a wherein R' and R 4 are as defined in claim 29.

42. A compound according to claim 29 having the formula wherein R 1 and R 4 are as defined in claim 29.

43. A compound according to claim 29 having the formula R'OG 0 wherein RI is as defined in claim 29 and R' represents one or more of the following sub- stituents: methoxy, hydroxy, trifluormethyl, fluoro and chloro.

44. A compound according to claim 29 selected from the following: (+)-cis3(4.Fluorophny)--eyl)7methox(4(2lpe dinehox~hnlcrm (+)-cis-3-(4.Fluorophenyl)-7methoxy-4(4-(-ppidinpooypenlcrmn (+)-cis-7-Methoxy-3.phenylA -(4-(2-piperidinothox)pheny)crmn (+)-cis-7-Methoxy.3-phenyl-4-(4-(3-piperidinorpx) phenyl)chromane (+-i--ehx--4mtoxpey)4(-2proiinoethoxy)phenyl)chromane (+)-cis-7.Methoxy.3-(4-phenyl phenyl)-4-(4-(2-prlidinehx~hnlcrmn .(+)cis7.M ethoxy3..(4mhylpenhlyl)-)A(4(2.ieriidhx)phnlcr ethoxy-4(4(2piperidinoethoxy)phenyl)3(4(4 (tri uoromyl penhl)h roman e.(+)-cis7.Methoxy4((2pyrrolidinoeth )hl) 3 4 -(trfluooehlpey chromane sO(+)-cis7Methox-3(3mhlpehylphen4-2-yrl)4(4(2lehx)phenlcr (+)-cis-3.<3Fluorophenyl)7methoxy4(4-( 2 -yrldnehxpeylcom e (+)-cis-7Methoxy3(3-methoxypheny;)-4-(4-(2-pr[ld inoethoxy)phenyl)chromane (+)cis7Methoxy3(3methoph henyl)-(4(2- 2 .dinehox~hnlcrm (+)-cis7Methoxy3(3methoxyphenyl)( 4 3 ierdnpooypenlcrm 93 (+)-cis7Methoxy.4(4( pyrrdiotdioxyehoy)pheny(tdluor( tylpey) chromane (+)-cis7Methoxy4(4(2piperidinoethoxy)pheny ,3(trflorolthl)pey-crmn 3 -(2-Fuorophenyl)..7.methoxy-4-(4-(2-pyrrolidinoethox)pheny)chrmn (+)-cis-7-Methoxy-3-(2, 3,4,5, 6 -pentafluorophenyl).4-(4-(2-pyrrolidinoethoxy)phenyl)- chromane (+)-cis7Methoxy.3, 456pentafl lorophenyl).A4(4(2ipeiperth)phey) chromane ethoxy- 3 4 methypheny)chroman4yI).2..methyl-benzoxazole (+)-cis-6-Methoxy3pheny;4(4(2pyroidinoethoxy) phenyl)chromane (+)-cis-6-Methoxy.3-(3..hydroxyphenyI)-4-(4-(2-pyrrolidinothox)pheny)crmn (+)-cis-4.(4..Hexylphenyl)7methoxy3phenylchrmn 7 -Methoxy.3-phenyl-4{4.{2-(pyrrolidin-1-yl)ethoxylphenyl~chromane. 15 45. A method for the preparation of compounds of formula comprising the steps of: a) reacting a compound of the formula (11) 200 *O wherein R 5 is as defined above, in the presence of triethylamine and formula (IV) acetic anhydride to form a compound of the (IV) wherein R 5 is as defined above, b) reducing a compound of the formula (IV) with a suitable hydride reducing agent to form a compound of formula (V) OH RS wherein R 5 is as defined above, c) hydrogenating a compound of the formula in the presence of a suitable catalyst to form a compound of the formula (VI) with a 3,4-cis configuration wherein R 5 is as defined above, d) alkylating a compound of the formula (VI) with an appropriate electrophile to form a compound of the formula (VII) (CH2),--Y (VII) wherein n, R 5 and Y are as defined above, e) deprotecting a compound of formula (VII) with a suitable deproctection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (VIII) (CH 2 -Y (VIII) wherein n, R 5 and Y are as defined above, f) reacting a compound of the formula (VIII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or 5 g) nitrating a compound of the formula (VI) with a suitable nitration agent to form a compound of the formula (IX) 9 wherein R 5 is as defined above, h) reducing a compound of the formula (IX) with a suitable reducing agent, preferably by catalytic hydrogenation, to form a compound of the formula (X) wherein R 5 is as defined above, i) cyclizing a compound of formula with an appropriate agent to form a compound of the formula (XI) or (XII) (XI) or (XII) wherein R 4 and R 5 are as defined above, J) deprotecting a compound of the formula (XI) or (XII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (XIII) or (XIV) (XIII) (XIV) *r a. a. wherein R" and R 5 are as defined above, k) reacting a compound of the formula (XIII) or (XIV) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or 5 1) reacting a compound of formula (VI) with trifluoromethane sulphonic acid anhydride to form a compound of the formula (XV) OS0 2 CF 3 RS wherein R 5 is as defined above, m) cross-coupling a compound of the formula (XV) with the appropriate cross-coupling partner to form a compound of the formula (XVI) (XVI) wherein n, R 5 and Y are as defined above, n) deprotecting a compound of the formula (XVI) with -a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (XVII) S S S S. S )n (XVII) wherein n, R 5 and Y are as defined above, o) reacting a compound of the formula (XVII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or P) cyclizing a compound of the formula (XVIII) (XVIII) wherein R 5 is as defined above, with paraformaldehyde in the presence of dimethylamine to form a compound of the formula (XIX) (XIX) wherein R 5 is as defined above, q) reacting a compound of the formula (XIX) with the appropriate Grignard reagent to form a compound of the formula (XX) Y I 0 (XX) 10 wherein n, R 5 and Y are as defined above, r) hydrogenating a compound of the formula (XX) in the presence of a suitable catalyst to form a compound of the formula (XXI) with a 3,4-cis configuration (XXI) wherein n, R 5 and Y are as defined above, s) deprotecting a compound of formula (XXI) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the general formula (XXII) (XXII) wherein n, R 5 and Y are as defined above, t) reacting a compound of the formula (XXII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula u) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XXIII) .S 0 0' S (XXIII) 102 wherein R 5 is defined as above, v) deprotecting a compound of the formula (XXIII) with a suitable deprotection agent, such as pyridine hydrochloride fusion or boron tribromide, to form a compound of the formula (XXIV) a a. a (XXIV) wherein R 5 is defined as above, w) reacting a compound of the formula (XXIV) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula (XXV) o 0 (XXV) wherein R 5 is defined as above, and R 6 is H or methoxy, x) deprotecting a compound of the formula (XXV) with a suitable deprotection agent, 103 such as sodium or potassium hydroxide in alcohol, to formr a compound of formula (XXVI) OH R 5 R (XXVI) 9 9wherein R' is defined as above, and RI is H or methoxy, 99 y) alkylating a compound of the formula (XXVI) with an appropriate electrophile to form a *compound of the formula (XXVII) R 8 R 0 (XX VII) wherein n, R 5 and Y is defined as above, and R' is H or methoxy, 104 Z) deprotecting a compound of the formula (XXVII) with a suitable deprotection agent, preferably catalytic hydrogenation for R' equals H or a strong acid for R 6 equals methoxy, to form a compound of the formula (XXVIII) 0 (CH On-Y R HO (XXVIII1) wherein n, R 5 and Y is defined as above, ag 0 aa) Alkylating a compound of the formula (XXVI) with an appropriate dlihalogenated *alkane such as 1,2-dibromoethane, l-bromo-2-chloroethane, 1, 4 -dibromo butane, 1 6 -dibromohexane, 1 8 -dibromooctane, 1,1 0-dibromodecane, preferably catalysed by potassium iodide, to form a compound of the formula (XXIX) .~(H)-Hal R N. 0 (XXIX) wherein n and R 5 is defined as above, Rr' is H or methoxy, and Hal is chloro, bromo, or iodo, 105 bb) reacting a compound of the formula (XXIX) with an appropriate nucleophile, preferably an amine, to form a compound of the formula (XXX) 0 ,CH 2 S. S eS S S S. S (XXX) wherein R 6 is H or methoxy, and Z is NHR', NR2, or a C 3 heterocyclic amine 10 optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 sub- stituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-C,-Ce-alkyl, C,-C 6 -alkyl and C,-Ce-alkoxy, and n, R 4 and R' is defined as above, cc) deprotecting a compound of the formula (XXX) with.a suitable deprotection agent, preferably catalytic hydrogenation for R 6 equals H or a strong acid for R 8 equals methoxy, to form a compound of the formula (XXXI) 0,(CH)-Z 9 ^p a (XXXI) wherein R 6 is H or methoxy, and Z is NHR 4 NR or a C3-C, heterocyclic amine optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 sub- stituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-C,-C-alkyl, C,-C 6 -alkyl and C,-C 6 -alkoxy, and n, R 4 and R 5 is defined as above.

46. A compound according to any of the claims 29 to 44 for use in the prevention or treatment of estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal.

47. A compound according to any of the claims 29 to 44 for use in the prevention or treatment of bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, including flushing, urogeni- tal atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, 15 dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen- dependent cancers, post-partum lactation or for use as contraception or an aid in ovarian development, preferably in the prevention or treatment of bone loss or osteopo- rosis.

48. A pharmaceutical composition comprising an effective amount of a compound according .0 20 to claims 29 to 44 or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent.

49. A pharmaceutical composition according to claim 48 in the form of an oral dosage unit O*"OO or parenteral dosage unit. The use of a compound according to any of the claims 29 to 44 for the preparation of a medicament for prevention or treatment of estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal.

51. The use of a compound according to any of the claims 29 to 44 for the preparation of a 107 medicament for use in the prevention or treatment of bone loss, osteoporosis, cardio- vascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms including flushing, urogenital atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen-dependent cancers, post-partum lactation or for use as contraception or an aid in ovarian development, preferably in the prevention or treat- ment of bone loss or osteoporosis.

52. A method of treating or preventing estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal, comprising administering to a subject in need thereof an effective amount of a compound according to any of the claims 29 to 44.

53. A method of treating or preventing bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, includ- 15 ing flushing, urogenital atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen-dependent cancers, post-partum lactation, or aiding ovarian development, preferably prevention or treatment of bone loss or osteoporosis, which method com- 20 prises administering to a subject in need thereof an effective amount of a compound O according to any of the claims 29 to 44.

54. A contraceptive method comprising administering to a male or female mammal an effective amount of a compound according to any of the claims 29 to 44. A (-)-enantiomer of a compound of the formula I in which substituents R 2 and R 3 are arranged in cis-configuration: 108 R3 R2 R/O(I) R'O wherein: R' is C.-C 3 -alkyl; R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C 6 -alkyl, C,-C 6 alkyl, C,-C6-alkoxy and phenyl; R' is: phenyl substituted with -X-(CH 2 wherein: 10" X is a valency bond, O or S, n is an integer in the range of 1 to 12, Y is H, halogen, OH, OR 4 NHR 4 NR NHCOR', NHSO 2 R 4 CONHR 4 CONR 2 COOH, COOR 4 SOR 4 SOR 4 SONHR 4 SONR 4 a C-C 7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the 15 group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR4, trihalo-C,-C-alkyl, C 1 -Ce-alkyl and C 1 -Ce-alkoxy; or -(CH 2 )n-Y wherein n and Y are as defined above; or phenyl fused to a C 3 -C 7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, op- tionally being substituted with 1 to 3 substituents independently selected from the group 109 consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-CG-alkyl, C,-C,-alkyl and C,-C 6 -alkoxy; and R 4 is C,-C 6 -alkyl; and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and salts thereof.

56. A compound according to claim 55 having the formula R3 R 2 n o (Ia) R 1 0 (Iaor or R0 R 2 (Ib) wherein R 1 R 2 and R 3 are as defined in claim 10 57. A compound according to claims 55-56 in which R 1 is C,-C 3 -alkyl, preferably methyl.

58. A compound according to claims 55-57 in which R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR', trihalo-Cl-C 6 -alkyl, C,-C 6 -alkyl and C,-C 6 -alkoxy.

59. A compound according to claims 55-58 in which R 3 is phenyl substituted with Y, wherein: X is a valency bond, O or S, n is an integer in the range of 1 to 12, 110 Y is H, OH, OR 4 NHR 4 NR NHCOR 4 NHSOR 4 CONHR', CONR COOH, COOR 4 SOR 4 SOR 4 SONHR', SONR a C,-C 7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C,-alkyl, C,-Cs-alkyl and C,-C-alkoxy. A compound according to claims 55-59 in which R 3 is -(CH 2 wherein n and Y are as defined above.

61. A compound according to claims 55-60 wherein R 3 is phenyl fused to a C 3 heterocy- 0 clic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of 0, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C-alkyl, C,-C 6 -alkyl and C,-C 6 -alkoxy.

62. A compound according to claim 55 having the formula 0 COOR S. 15 0 wherein R' is as defined in claim 55 and R is H or C alkyl. wherein R' is as defined in claim 55 and R is H or C,-C alkyl.

63. A compound according to claim 55 having the formula 111 o R 1 0 0 wherein R' is as defined in claim 55 and m is an integer from 0 to

64. A compounds according to claim 55 having the formula wherein R 1 is as defined in claim 55 and m is as defined in claim 63. A compound according to claim 55 having the formula 0 (CH) YI 0 112 wherein R' is as defined in claim 55 and m is as defined in claim 63.

66. A compound according to claim 55 having fhe formula o (CH) N\ IR 4 R 1 R o wherein R' is as defined in claim 55 and m is as defined in claim 63 and both R 4 5 independently are as defined in claim

67. A compound according to claim 55 having the formula wherein R' and R 4 are as defined in claim

68. A compound according to claim 55 having the formula 113 wherein RI and R4 are as defined in claim

69. A compound according to claim 55 having the formula No *R 0 *0 wh r i R*i s d fn d i l i 5 a d R e re e t n r m r ft e f l o i g s b sttens meh xhdoy *furmtyfur n ho A o p udacodn ocli -4 Fl o o h n l 7 m t o y 4 (4 -y r ldi o t o y p en*c r m n i -4 F u r p e y .e h x -4 i e id n e h x h n l c r m n stituents methx-hy hydroxy, tiorethylnflro ahnd ~chroan )cis3et(4y--Flueorophenyl)..7..methyrolidi(4(3.i)hy)hrmn 5(-)-cis-7-Methoxy-4-(4-(2-pproidinoethoxy) phenyI)-3(4(trfluoromethy)pheny)chromane (--i--ehoy3(-ehypey)4(4-(2-pyrrolidinoethoxy)pheny)chrmn (--i--3Floohn -7mtoy4(4(2pyrrolidinoethoxy)hny)hmn 7 -Methoxy.3-(3-methoxyphenyl)A -(4-(2-piperidinoethoxy)pheny)chrmn (-)-cis7Methoxy3.(3..methoxyphenyl)-4-(4-(3-pipendinoprop x)pheny)chrmn (-)cis-7-Methoxy-4-(4-(2-pyrrolidinoethoxy) phenyl)- 3 3 -(trifluoromethy)pheny)chromane *..(-)-cis-7-Methoxy4-(4(2-piperidinoethoxy)pey)3(-tilomthIhny-crae ph n l)7 m th x -2ph yrl)idi(3etrio romp e hyj )chromane (-)-cis-7-Methoxy-3-(2,3,4,5,-etfurpey)4(-2 pyrrolidinoethoxy)phenyl)chromane *(-)-cis-7-Methoxy-3-(2, 34, 5 6 -pentafluoropheny)4(4(2piperidinoethoxy)pheny)- chrom ane (-)-cis-6-Methoxy3phenyl-4-(4-(2pyrrolid inoethoxy)phenyl)chromane (-)-cis-6-Methoxy-3-(3..hydroxyphenyl) 4-(4-(2-pyrroldinthox)pheny)chrmn ethoxy-3phenyI..4-{4.2(pyrro lid in-1 -yl)ethoxy~phenyllchrom ane.

71. A method for the preparation of compounds of formula comprising the steps of: a) reacting a compound of the formula (11) 0 0 with a compound of the formula (111) r COOR (111) wherein R' is as defined above, in Ithe presence of triethylamine and acetic anhydride to form a compound of e formula (IV) OCOCH 3 0 0 0 (V wherein R' is as defined above, b) reducing a compound of the formula (MV with a suitable hydride reducing agent to form a compound of formula MV 116 OH oR 0 wherein R 5 is as defined above, c) hydrogenating a compound of the formula in the presence of a suitable catalyst to 5 form a compound of the formula (VI) with a 3,4-cis configuration OH wherein R 5 is as defined above, d) alkylating a compound of the formula (VI) with. an appropriate electrophile to form a compound of the formula (VII) (CH 2 (VII) wherein n, R 5 and Y are as defined above, e) deprotecting a compound of formula (VII) with a suitable deproctection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (VIII) (CH2)-Y (VIII) wherein n, R 5 and Y are as defined above, f reacting ;a compound of the formula (VIII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or g) nitrating a compound of the formula (VI) with a suitable nitration agent to form a compound of the formula (IX) 0 0* 0 wherein R 5 is as defined above, h) reducing a compound of the formula (IX) with a suitable reducing agent, preferably by 5 catalytic hydrogenation, to form a compound of the formula (X) OH NH2 0(X) wherein R 5 is as defined above, i) cyclizing a compound of formula with an appropriate agent to form a compound of the formula (XI) or (XII) (XII) wherein R 4 and R s are as defined above, j) deprotecting a compound of the formula (XI) or (XII) with a suitable deprotection agent, 5 preferably by pyridine hydrochloride fusion, to form a compound of the formula (XIII) or (XIV) (XIII) (XIV) wherein R 4 and R 5 are as defined above, k) reacting a compound of the formula (XIII) or (XIV) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or I) reacting a compound of formula (VI) with trifluoromethane sulphonic acid anhydride to form a compound of the formula (XV) 120 OS,0CF, 0^ (XV) wherein R 5 is as defined above, m) cross-coupling a compound of the formula (XV) with the appropriate cross-coupling partner to form a compound of the formula (XVI) (XVI) wherein n, R 5 and Y are as defined above, n) deprotecting a compound of the formula (XVI) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (XVII) 121 Y (CH2) n (o XVII) wherein n, R 5 and Y are as defined above, o) reacting a compound of the formula (XVII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula or 5 p) cyclizing a compound of the formula (XVIII) O *OH H (XVIII) wherein R 5 is as defined above with paraformaldehyde in the presence of dimethylamine to form a compound of the formula (XIX) 0 RS 0 0 (XIX) wherein R 5 is as defined above, 122 q) reacting a compound of the formula (XIX) with the appropriate Grignard reagent to form a compound of the formula (XX) wherein n, R 5 and Y are as defined above, r) hydrogenating a compound of the formula (XX) in the presence of a suitable catalyst to form a compound of the formula (XXI) with a 3,4-cis configuration 6 6 (XXI) wherein n, R 5 and Y are as defined above, s) deprotecting a compound of formula (XXI) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the general formula (XXII) (XXII) wherein n, R' and Y are as defined above, t) reacting a compound of the formula (XXII) with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula 123 u) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XXIII) (XXIII) wherein R 5 is defined as above, v) deprotecting a compound of the formula (XXIl) with a suitable deprotection agent such as pyridine hydrochloride fusion or boron tribromide, to form a compound of the formula (XXIV) (XXIV) wherein R 5 is defined as above, w) reacting a compound of the formula (XXIV) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula (XXV) (XXV) wherein R 5 is defined as above, and R 6 is H or methoxy, x) deprotecting a compound of the formula (XXV) with a suitable deprotection agent, such as sodium or potassium hydroxide in alcohol, to form a compound of formula (XXVI) a. a a. (XXVI) wherein Rs is defined as above, and R 6 is H or methoxy, y) alkylating a compound of the formula (XXVI) with an appropriate electrophile to form a compound of the formula (XXVII) 2) -Y (XXVII) 0* wherein n, R 5 and Y is defined as above, and R 6 is H or methoxy, Z) deprotecting a compound of the formula (XXVII) with a suitable deprotection. agent, preferably catalytic hydrogenation for R' equals H or a strong acid for R" equals 10 methoxy, to form a compound of the formula (XXVIII) (XXVIII) wherein n, R' and Y is defined as above, aa) Alkylating a compound of the formula (XXVI) With an appropriate dihalogenated alkane such as 1 .2-dibromoethane, l-bromo-2-chloroethane, 1 .4-dibromobutane, 1 6 -dibromohexane, 1 8 -dibromooctane, 1, 1 0-dibromodecane, preferably catalysed by potassium iodide, to form a compound of the formula (XXIX) 126 .,(CH 2 -Hal R 8 a NX R 0~ 0 (XXIX) wherein n and R 5 is defined as above, R" is H or methoxy, and Hal is chioro, bromo, or lodo, Sbb) reacting a compound of the formula (XXIX) with an appropriate nucleophile, preferably an amine, to fornm a compound of the formula (XXX) R 100 Sfl0 8 4 *wherein R 6 is H or methoxy, and Z is NHR', NR 2 or a 3C htrcliamn y containing oxygen or nitrogen, optionally. being substituted with 1 to 3 sub- stituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-C 1 -C 6 -alkyl Cl-C 5 -alkyl and C,-C 6 ,-alkoxy, and n, R 4 and R 5 is defined as above, cc) deprotecting a compound of the formula (XXX) with a suitable deprotection agent, preferably catalytic hydrogenation for R 6 equals H or a strong acid for R .equals .methoxy, to form a compound of the formula (XXXI) O ,(CH 2 R HO 0.- (XXXI) :wherein R' is H or methoxy,.and Z is NHR 4 NR or a C 3 heterocyclic amine optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 sub- 10 stituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-Cl-C 6 -alkyl, CI-C 6 -alkyl and C,-C 8 -alkoxy, and n, R 4 and R 5 is defined as above.

72. A compound according to any of the claims 55 to 70 for use in the prevention or treatment of estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal. S"73. A compound according to any of the claims 55 to 70 for use in the prevention or treatment of bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, including flushing, urogeni- tal atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, 20 regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen- dependent cancers, post-partum lactation or for use as contraception or an aid in ovarian development, preferably in the prevention or treatment of bone loss or osteopo- rosis.

74. A pharmaceutical composition comprising an effective amount of a compound according to claims 55 to 70 or a pharmaceutical acceptable salt thereof and a pharmaceutical 128 carrier or diluent. A pharmaceutical composition according to claim 74 in the form of an oral dosage unit or parenteral'dosage unit.

76. The use of a compound according to any of the claims 55 to 70 for the preparation of a medicament for prevention or treatment of estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal.

77. The use of a compound according to any of the claims 55 to 70 for the preparation of a medicament for use in the prevention or treatment of bone loss, osteoporosis, cardio- vascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal 1 0 symptoms including flushing, urogenital atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen-dependent cancers, post-partum lactation or for use as contraception or an aid in ovarian development, preferably in the prevention or treat- ment of bone loss or osteoporosis.

78. A method of treating or preventing estrogen related diseases or syndromes, preferably diseases or syndromes caused by an estrogen-deficient state in a mammal, comprising a administering to a subject in need thereof an effective amount of a compound according to any of the claims 55 to

79. A method of treating or preventing bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, includ- ing flushing, urogenital atrophy, depression, mania and schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen-dependent cancers, post-partum lactation, or aiding ovarian development, preferably prevention or treatment of bone loss or osteoporosis, which method com- prises administering to a subject in need thereof an effective amount of a compound according to any of the claims 55 to 129 A contraceptive method comprising administering to a male or female mammal an effective amount of a compound according to any of the claims 55 to DATED this 19th Day of December, 2001 NOVO NOIRDISK A/s Attorney: JACINTA FLATTERY-O'BRIEN Registered Patent Attorney of The Institute of Patent and Trade Mark Attorneys of* Australia of BALDWIN SHELSTON WATERS 0