AU9733601A

AU9733601A - Novel (+)-enantiomers of cis-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes

Info

Publication number: AU9733601A
Application number: AU97336/01A
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

ORIGINAL

000..

0 0 0 Name of Applicants: Actual Inventors: 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 (+)-ENANTIOMERS OF 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. 47719/97 dated 28 October 1997 The following statement is a full description of this invention, including the best method of performing it known to us:- File: 34090AUP00 Title Novel (+)-enantiomers of 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 (+)-enantiomers of 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 o atrophy, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, post-partum lactation, and the use of such com- O O pounds 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 15 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.

S* 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/progestogeri 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 Intem 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 10 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 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 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 3 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 S* 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 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, "The 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: relief of menopausal symptoms flushing and urogenital atrophy); oral contraception; prevention of threatened or habitual abortion, relief 4 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 10 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.

Description of the. invention The present invention provides (+)..enantiomers of compounds of the formula I in which substituents R 2 and R' are arranged in cis-configuration: 0)(I

HO

wheein R 2 is p e y pi n ly s b ttt d wt o 5 s b tt e t n e e d nl ee t dfo 5*04 (a whereintttd:ih X(C2,-Y heen X isavaec bn,0 rS ratpeny optinaually, substienith 1n tor 5w susttuents independently selected o susiunsidpnetyslce rmthe group consisting of H OH, halogen,niocaoSHSR tha-CC 8 aklCC- 0 alkyl c y- 6 akoxyHS and p h l -lyC -,-lkladC -,-lo wherein n and Y are as defined above; or phenyl fused to 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,alkyl, C,-C 6 -alkyl and C 1

-C

6 -alkoxy; and

R

4 is C,-C 6 -akyl; and pharmaceutically acceptable esters, ethers and salts thereof.

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

0 For example the term C,-C6-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.

The term C 3 -C7-heterocyclic ring include groups such as pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrol, 2H-pyrrol, 15 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.

The hydroxy substituent on the phenyl ring in formula I is preferably attached to the phenyl ring at the 6- or 7-position. Accordingly, compounds of the invention having one of the 10 following formulae la or Ib are preferred: (Ia) wherein

R

2 and R 3 are as defined above.

In a preferred embodiment, the present invention is concemed with (+)-cis-forms of the compounds of the following formula: 0 COOR wherein R is H or C,-C 6 alkyl.

0 0.0.

0 o..

o: 0. 0 0. In another preferred embodiment, the present invention is concerned with (+)-cis-forms of the compounds of the following formula:

HO

0 wherein 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: 9 o 0 wherein m is as defined above.

::In another preferred embodiment, the present invention is concerned with (+)-cis-forms of the compounds of the following formula: (c2

N

S. 5 0 wherein m is as defined above.

In another preferred embodiment, the present invention is concerned with (+)-cis-forms of the compounds of the following formula: R4

N

wherein m is 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

4 is as defined above.

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.

In another preferred embodiment, the present invention is concerned with (+)-cis-forms of the compounds of the following formula: wherein R" represents one or more of the following substituents: methoxy, hyd .roxy, trifluormethyl, fluoro and chioro.

The most preferred compounds are the following: (+)-cis-4-(4.(Carboxymethoxy)phenyl)..7.hydroxy-3..phenylchromane, 7 -Hydroxy-4-(4.(methoxycarbonylmethox) phenyl)-3-phenylchromane, (+-i--4(toyabnlehx~hnl--yrx--hnlhoae (+-i--4(ezlxcroymtoy~hnl--yrx--hnlhoae (+)-cis 7 -Hydroxy3.pheny lA(4(2-pyrrolidinoeth)hl)chroa 7 -Hydroxy3phenyI-4-(4-(3-pyrroldinpO~YPey~hoa 7 Hyd roxy3phenyI-4-(4-(4-pyrroldinbuto )hnlcr ae 7 -Hydroxy.3u.phenyl..4-(4u(5pyoidinopentoxy)phefly,)chroae 7 Hydroxy3pheny(4(6pyoldhxxi hny~hoae (+)-cis-7uHydroxy.3pheny(4(7pyrridhtylxI hnl~hoae (+)-cis 7 Hydroxyu3phenyIA-(4(48pyr.ldinotyxI hnl~hoae (+)-cis-7-Hydroxy-3uph enylI4(4.(g pyrr lid innnlxI hn lcrmae (+)-cis-7Hydroxy3phenyI4-(4-( lO-pyrro lid inodecyloxy) 'phenYI)chromane, (+)-cis.7uHydroxy3phenyI4(4-(1 1-pyrro lid in oundecyloxy)ph enyl) chrom ane, (+)-cis-7-Hydroxy3phenyl4(4-(l 2 -pyrrolidinododecyjoxy)phenyl)chromane.

7 -Hydroxy-3-phenyl-4-(4-(2-pp idinothox)peychoa, ***(+)-cis.7-Hydroxy-3-phenyl-4-(4-(3-pprdnpooypey~hoae .(+)-cis..7.Hydroxy-3-phenyl-4-(4-(4-piperdinbuoypeychma, (*-i-7Hdo (2pryrozpnotoyphenyl)3pychromane (+)-cis.7Hydroxy-4- 4(ehpraepinodropx~hny)3peyhhoa (+)-cis7Hydroxy4.(4(hydopinhydrozepenyrl) 3 henlhoa ***(+)-cis-4-(u-(yDroxtya(4(etxrhe)7hyd roy3peblhoa (+)-cis.4(4.(2Dilmiethy~penetl) 7 hrx-phncroa Ethy-Nminetha iox )eh o) h en--yrx h nlho a e 20 ino--4-3-imtethiapo oxy)phenyl)dox--hydroylpheomncr (+)cis-4(4-(3Dim ethyl am in oo) heny)7hdo-3pn y1)7omn .(+)-cis-4(4..(Dihdom,-ethylain-6but)-hydoy--hnycroae -H dr x -4 m t y 2,dihydro-1,4 b n o a i -l -h n l h o a (+)-cisu.7..-Ehydrox..4.(4.mhyro-2 -dihydoa- -enzoxazin6y3phenychromane (+)-cis-7~-EthroyI3dihydroxyhnl 14(-yrldiotoypey~hoae .HYdoy3-4fuoohny4 4bnoxainpyoiinhoxy~phenychromane *.(+)-cs3-7..Hldroxheyl)(4hydroxyhI)( 4 2 yrldtohxypeycrma, (+)-cis-3-3,4Droxethox(4.triloromhypheI.

4 4 2 rolnhI. xypeylcroa (+)cis..7.Hydroxyu.3u(entfluoropheny )-4-(4-(2-prrdinotho)peychoae (+)-cis-43(4Diaromethoxyphe)6h doy3penlhoa (+)-cisu6Hydroxy4-(4(methoxycarbonylmethoxy)pheny)..3-phenlhoa (+)-cis.4(4.(Ethoxycaonymth)phenl--yrx--hnlh (+)-cis4(4-(Benzyloxycarbonymetho,)phenyl).6royd 3 hnhI ae (+)-cis 6 Hydroxy3pheny pyrrioetoxidinthnI)chroa 6 -Hydroxy.3-pheny..4-(4-(3-pyrrolidiW Iox~hey)choa (+)-cis 6 Hydroxy3phenyi-4-(4-(4-pyrrolid inobutox Iey)chroa 6 Hydroxpey4-(4hen-yrro(4(5nprono)hny)cho 6 -Hydroxy..3.phenylI4-(4-(6-pyrrolidinol)pheny)choa 6 -Hydroxy..3.pheny..4-(4-(7-pyrrolidinohepylxyphny)chroa 6 -Hydroxy-3-pheny!.4-(4-(8-pyrrolidinootylox Iey)choae (+)-cis-6-Hydroxy.3..pheny..4 (4-(9-pyrrolidinon lx~ hen,)hoae (+)-cis.-6.Hydroxy3.phenyIA(4-( lO-pyrrolidinodecyloxy)phenyl)chromane, (+)-cis-6..Hydroxy.3-pheny..4(4.(l 1l-pyrroidinoundecyoxy)phenyI)chromane, ~(+)-cis-6-Hydroxy-3-phenyl.4..(4.( l 2 -pyrrolidinododecyloxy)phenyl)chromane, .(+)cis 6 Hydroxy3pheny !.A4(2-piedinoeith)pheychoa *(+)-cis-6..Hydroxy-3pheny4(4(3piperidinopropoxy)phenyl)chroa 6 .Hydroxy.3hephenyA(44piperidibt)pheychoa (+)cis6Hydroxy..-4-(- (2pdoaepydoeth)phenl--hnlho **.(+)cis6.HydroxYA(4(4(3-ehdophyropoei)phnl--hnlhoa (+)cis 6 Hydr x-(4(4-perhydroaz bt)phenl--hnlhoa (+)-cis..4-(4.(2-.Dimethylaminoethoxy) phenyI)-6-hydroxy3phenylchromane, (+)-cis4(4-(2..Diethylamnoethoxy)phy) 6 hydrx-phnlroa (+).cis4(4.(2(NEthyNlmhino)thx)phnl--yrx--hnlhoa (+)cis4(4.(3Dimethyaminopropox)hny)- 6 hyrx3-hnlroa (+)-cis4(4(4.Dimethya minobutoxy)hy) 6 h yrx--hnlhoa 3-Dihydro-1 t 4 -benzoxazin-6-yl)...hydroxy.3phenyichromane, (+)-cis-6-.HydroxyA..(4..methyl-2,3-dihydro-1 4 -benzoxazin-6-yi)-3-.phenylchromane, (+)-cis-.4.(4EthylI2,3-dihydro-1 4 -benzoxazin-6y)6hydroxy-3phenychromane, (+).cis.6.Hydroxy3(4hydroxyphy)4( 4 2 -proiiotoy hnlc ae (+)-cis6Hydroxy3(4trfluoromethypheny)-(4(2.pyrroidinoethc)phny)chroa (+)-cis6.Hydroxy3(4fluoropheny)4( 4 2 -proiiotoypey~hoa (+)-cis3.(4..Choropheny)6hydro4( 4 2 -proiiotoypey~hoa 4 -Dimethoxypheny)6hydroy-4( 4 2 -prrldinehx hey~h ane, (+)-cis6Hydroxy3(pentafluorophl)- 4 2 -proiiotoypey~hoae (+)-cis7.Hy drox3phenyI(4{4(pyroidi- -yl)ethoxylphenyl)chromane, (+)-cis7-Hydroy.4(4(2pyrroid th)phenl--4(rfurmty~hnl-ho 14 (+)-cis-7-Hydroxy-3-(4-methylphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (+)-cis-7-Hydroxy-3-(3-hydoxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane.

The compounds of the invention may be prepared by resorting to the chroman chemistry 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. Ray, P.K. Grover, V.P. Kamboj, S.B. Betty, A.B. Kar and N. Anand, J. Med. Chem. 19, 276-9, 1976; Md. Salman, S. Ray, A.K. Agarwa!, 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 (ll) with a compound of the formula (111)

'COOH

(III)

wherein R 5 represents 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-Cs-alkyl,

CI-C

6 -alkyl and C,-Cs-alkoxy, and R 4 is as defined above, in the presence of triethylamine and acetic anhydride to form a compound of the formula

(IV)

OCOCH

3 0 0 (Iv) 0 0@0 oet S see* 6000

G

S* 55 0 0 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, c) hydrogenating, a compound of the formula in the presence of a suitable catalyst to form a racemic mixture of and enantiomers of a compound of the formula

(VI)

with a 3,4-cis configuration v (VI) 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) 0* o (CH2)n-

(VII)

wherein n, R 5 and Y are as defined above, e) resolving the racemic mixture of and.(-)-enantiomers of a compound of formula

(VII),

f) deprotecting a (+)-enantiomer of a compound of formula (VII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, 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 (VIII)

(VIII)

9 *9 9 wherein

R

5 is as defined above, h) reducing a compound of the formula (VIII) with a suitable reducing agent, preferably by 5 catalytic hydrogenation, to form a compound of the formula

(IX)

OH

(IX)

wherein Rs is as defined above, i) cyclizing a compound of formula (IX) with an appropriate agent to form a compound of the formula or (XI) wherein R 4 and R 5 are as defined above, j) resolving the racemic mixture of and'(-)-enantiomers of a compound of formula (X) 5 or (XI), k) deprotecting a (+)-enantiomer of a compound of the formula or (XI) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula or 1) reacting a compound of formula (VI) with trifluoromethane sulphonic acid anhydride to 10 form a compound of the formula (XII) OS02CF 3 Rs

(XII)

wherein R 5 is as defined above, m) cross-coupling a compound of the formula (XII) with the appropriate cross-coupling 19 partner to form a compound of the formula

(XIII)

2 )n

(XIII)

wherein n, R 5 and Y are as defined above, n) resolving the racemic mixture of and (-)-enantiomers of a compound of formula

(XIII),

o) deprotecting a (+)-enantiomer of a compound of the formula (XIII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula or P) cyclizing a compound of the formula (XIV) 0 R II

R

(XIV)

wherein

R

5 is as defined above, with paraformaldehyde in the presence of dimethylamine to form a compound of the formula

(XV)

wherein

R

5 is as defined above, q) reacting a compound of the formula (XV) with the appropriate Grignard reagent to form a compound of the formula (XVI) a t

(XVI)

wherein n, R 5 and Y are as defined above, r) hydrogenating a compound of the formula (XVI) in the presence of a suitable catalyst to form a racemic mixture of and (-)-enantiomers of a compound of the formula (XVII) with a 3,4-cis configuration

(XVII)

wherein n, R 5 and Y are as defined above, s) resolving the racemic mixture of and (-)-enantiomers of a compound of formula (XVll), t) deprotecting a (+)-enantiomer of a compound of formula (XVII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the general formula u) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XVIII)

O.S

I O

S

(XVIII)

wherein

R

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

HO

(XIX)

wherein

R

5 is defined as above, w) reacting a compound of the formula (XIX) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula

(XX)

O

S

O I O

(XX)

*r wherein R 5 is defined as above, and R 6 is H or methoxy, x) deprotecting a compound of the formula (XX) with a suitable deprotection agent, such as sodium or potassium hydroxide in alcohol, to form a compound of formula (XXI)

(XXI)

wherein R 5 is defined as above, and R' is H or methoxy, y) alkylating a compound of the formula (XXI) with an appropriate electrophile to form a compound of the formula

(XXII)

O (CH2)'-Y

R

0

(XXII)

wherein n, R 5 and Y is defined as above, and R 6 is H or methoxy, z) deprotecting a compound of the formula (XXII) with a suitable deprotection agent, 10 preferably catalytic hydrogenation for R 6 equals H or a strong acid for R 6 equals methoxy, to form a compound of the formula (XXIII) (C H2) Y

R

HO0

(XXIII)

ee wherein n, R 5 and Y is defined as above, aa) Alkylating a compound of the formula (XXI) with an appropriate dihalogenated alkane such as 1, 2 -dibromoethane, l-bromo-2-chloroethane, 1,4-dibromobutane, 1,6dibromohexane, 1,8-dibromooctane, 1,10-dibromodecane, preferably catalysed by potassium iodide, to form a compound of the formula

(XXIV)

0 ,(PH 2 )W-Hal

JOR

0

(XXIV)

wherein n and RI is defined as above, R' is H or methoxy, and Hal is chioro, bromo, or iodo, bbY reacting a compound of the formula (XXIV) with an appropriate nucleophile, preferably *.10 an amine, to form a compound of the formula (XXV) R

R

6

R

0N

(XXV)

*wherein R 6 is H or methoxy, and Z is NHR 4 NR 4 or a 0 3

-C

7 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 1

-C

6 .alkyl,

C

1

-C

6 -alkyl and C 1 -C6-alkoxy, and n, R 4 and R' is defined as above, cc) deprotecting a compound of the formula (XXV) 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 (XXVI) 0

(CH

2

I

R

HO

(XXVI)

10 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- .:'stituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, trihalo-C,-C6-alkyl, C,-C6-alkyl and C,-C 6 -alkoxy, and n, R 4 and R s is defined as above.

.i The resolution of racemates carried out in steps j) and n) of the above process, may alternatively be carried out after any step of the process which results in a racemic mixture.

S* Any resolution technique may be used to separate the (+)-enantiomer from the racemic mixture, including diastereomeric salt formation and chiral HPLC.

The starting benzophenones of the formula (II) are easily prepared via Friedel-Craft acylation of the appropriate dimethyl ether with p-hydroxybenzoic acid followed by selective monodemethylation with hydrobromic acid in acetic acid.

The starting deoxybenzoins of the formula (XIV) are easily prepared via the Hoesch reaction of the appropriate dimethyl ether and the appropriate substituted phenyl acetic acid 26 derivative followed by selective monodemethylation by hydrobromic acid in acetic acid.

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 Cl, 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 M-(CH 2 wherein M is MgHIg, HIg is CI, 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 S unit.

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.

In vitro estrogen receptor 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 S compounds of this invention to displace 3 H-177-estradiol (171-E2), from estrogen receptor (ER) obtained from rabbit uterus. Experimentally, the ER rich cytosol from rabbit uterine S 15 tissue is diluted with ER poor cytosol isolated from rabbit muscle to achieve approximately 20 -25% maximal binding of 0.5 nM 3 H-17B-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/mi. The assay buffer (PB) is as follows: 10 mM K 2 HP0 4

/KH

2

PO

4 1.5 mM K 2

EDTA,

10 mM monothioglycerol, 10 mM Na 2 MoO4.2H0, 10 glycerol pH 7.5. Radio-inert 20 1711-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 pl are incubated in duplicate for each concentration tested in microtitre plates to which have been added 20 pl 3 H-17B-E2 (assay concentration equals 0.4 nM) and 50 pl 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 40C. 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-171-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 15 more susceptible to fracture; i.e. most notably the spine, wrist and hip. True bone density c an be measured gravimetrically using Archimede's Principle (an invasive technique). The S. 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, 17-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 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 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.

•Cholesterol lowering 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 Dreparations 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 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 compounds or principles, and such unit dosage forms may contain any suitable effective amount of a 15 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.

2 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.

31 The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or olouring substances and the like, which do not deleteriously react with the active compounds n For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aueous 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 particularly suitable for oral application. A syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.

10-100 mg/day, when administered to* patiens, e.g. humans, as a drug.

Smg in a pharmaceut whic mally aeptable cprepareder per unit dosage.nal tableng echnqus cntin 25 10-100 mg/day, when administered to patients, e.g humans, as a drug Active compound 5.0 mg Lactosum 67.0 mg Ph.Eur.

SAvicel 31.4 mg Amberlitet"lRP 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.

.:.ee 0 a The invention is explained more in detail in the below examples, which illustrates the invention. It is not to be considered as limiting the scope of the invention being defined by 15 the appended claims.

EXAMPLE 1 +)-cis-7-Hvdroxy-3-Dhenv-4-4- rroi n- -yletho xvhenvllchromane 00 Step 1: 20 4 4 -Hydroxyphenyl)- 7 -methoxy-3-phenyl-3-chromene 4-(4-Acetoxyphenyl)-7-methoxy-3-phenyl-coumarin (180 g) was dissolved in toluene (2.1 1) 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 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)-7-methoxy-3-phenyl-3-chromene. M.p. 156-157 OC. The product was identified by 'H-NMR and elemental analysis.

Step 2: cis- 4 -(4-Hydroxyphenyl)- 7 -methoxy-3-phenylchromane *O 4-(4-Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene 7 7.7g) 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.

15 Yield 74.3 g (95 m.p. 188-190 OC. The product was identified by 1 H-NMR and elemental analysis.

0 Step 3: cis- 7 -Methoxy-3-phenyl 4 2 -(pyrrolidin-1-y/ethxyphenychromane.

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 OC 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 c ombined organic phases was dried over potassium carbonate and 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 (83 113-114 OC The product was identified by 'H-NMR and elemental analysis.

Step 4: 7-Methoxy.3pheny4f4[2-pyrr lid.n l-Yl) ethoxypheny)chromane-(+).O, 0 '-dito- Iuoyltartrate.

cis- 7 Methoxy3phenyl4{4[2(pyoli1yl)eth]hnllchrm (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 was filtered off The crystals were recrystallised 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: *15 ChiraDex 5lg, 250 x 4 mm (Merck). Eluent: 70 methanol/buffer (0.25 triethylammonium acetate, pH Flow: 0.5 mI/mmn. Detector UV 220 nm.

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

The product was identified by 'H-NMR and elemental analysis. The compound crystallised 0 0 0 0with half a mole of crystal bound 2 -propanol.

Step The base was liberated from (+-i--ehx--hny -4[-proii--yl)ethoxylphenyl)chromane O'-ditoluoyltartrate (2.5 g) by dissolving in a mixture of toluene ml) and water (30 ml) made alkaline (pH 9-10) with sodium hydroxide (2 ml, 32.5 The aqueous phase was extracted with another portion of toluene (20 ml). The combined organic phase was dried over potassium carbonate and evaporated. The oil was dissolved in pyridine (20 ml). Concentrated hydrochloric acid (24 ml) was added and the water removed from the mixture by distillation until the bottom temperature in the reaction vessel reached 150 The heating was maintained for 5 hours. The mixture was cooled down to room temperature, water (30 ml) and toluene (30 ml) was added and the mixture made alkaline (pH 10) with sodium hydroxide (32.5 The organic phase was separated and the aqueous phase was extracted with another portion of toluene (30 ml). The combined organic phases was dried over potassium carbonate and evaporated. The oil was dissolved in ethanol (100 ml) made pH 2 with conc. hydrochloric acid. The solution was neutralised with sodium hydroxide to pH 7. The precipitate was filtered off and washed with ethanol and washed thoroughly with water.

Yield 0.4 g (31 m.p. 219-221 [a]D 20 =+3310 (c=0.989 in ethanol/3M HCI, 80/20).

S* The enantiomeric purity of the product was verified by Chiral HPLC to be better than 98 15 Chiral HPLC system: Column: ChiraDex 5p, 250 x 4 mm (Merck); Eluent: 70 methanol/buffer (0.25 triethylammonium acetate, pH Flow: 0.5 ml/min. Detector: UV 220 nm. The product was identified by 'H-NMR and elemental analysis.

*o g EXAMPLE 2 20 (+)-cis-7-Hydroxy-4-(4-(2-pyrrodinoetho hn Step 1: 4-( 4 -Acetoxypheny)-7-methoxy-3-(4(trifuoromethyl)phenyl)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- (trifluoromethyl)phenyl 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, saturated sodium chloride solution, dried over sodium sulfate and evaporated to give a yellow/orange solid, which was recrystallised from 6:1 ethanol/water (350 ml) to give the product as a colourless solid, which was vacuum dried.

Yield 9.56 g of 4-( 4 -acetoxyphenyl)-7-methoxy-3-(4-(trifluoromethyl)phenyl)coumarin. M.p. 198-201 0 C (aqueous ethanol). 'H-NMR (CDCI,, 300 MHz) 8: 2.31 3H), 10 3.90 3H), 6.79 (dd, 1H), 6.93 1H), 7.05-7.15 4H), 7.17 1H), 7.21-7.27 (m, 2H), 7.42-7.49 2H). LRMS (El) 454 412, 384, 369, 43. Elemental analysis: calculated for C2sH 1 7 3 ,FO; C, 66.08; H, 3.77%; found C, 66.04; H, 3.77%.

Step 2: 15 4-( 4 -Hydroxypheny7-methoxy-3-(4(trifluoromethyl)phenychrom-ene Lithium aluminium hydride (0.76 g, 20.03 mmol) was added in small portions to a stirred tetrahydrofuran (200 ml) solution of 4 4 -acetoxyphenyl)-7-methoxy-3-( 4 (trifluoromethyl)phenyl)-coumarin (4.54 g, 9.99 mmol). After complete addition, the mixture was stirred at room temperature for 30 min., then treated dropwise with 6M hydrochloric 20 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 (65 ml,10:3) 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 3.59 g (91 of 4 4 -hydroxyphenyl)7methoxy3(4(trifluoromethl)phey)crm 3-ene. M.P. 169-1 71 1 H -NMR (ODCd 3 300 MHz) 5: 3.80 3H), 4.85 (bs, 1 5.05 (s, 2H), 6.42 (dd, 1IH), 6.52 1IH), 6.72-6.82 (in, 3H), 6.96 (din, 2H), 7.07 (din, 2H), 7.40 (din, 2H). LRMS (El) 398 305 (M-PhOH), 253 PhCF 3 Elemental analysis: calculated for C,3H 17

F

3 0 3 C, 69.34; H, 4.30%; found C, 69.00; H, 4.27%.

Step 3: *..(±)-cis-4-(4-Hydroxyphenyl). toy3-4(rfuroehlpenlcrmn 10 Palladium on carbon 0.40 g, 0.4 mmol) was added to a stirred solution of 4-(4hydoxyhenl)--mehox-3-4-(riluoomehylpheyl~hro-3-ne(2.99 g, 7.51 mmol) *in ethanol, (100 ml) and the mixture hydrogenated at room temperaturefo24hTe catalyst was removed by filtration, and the solvent evaporated to give an off-white solid which was purified by recrystallisation from 50 ml ethanol. This gave the first crop of 15I product-as colourless needles. The mother liquors were evaporated and the recrystallisa tion repeated from aqueous ethanol, to give a second crop of colourless needles. The solids were combined and vacuum dried.

Yield 2.52 g of 4 -(4-hydroxyphenyl).7methoxy3.( 4 *(trifluorom ethyl) phenyl)ch romane. M.p. 21 1-213*C. 'H-NMR (CDCd 3 300 MHz) 8: 3.63 (ddd, 1 3.81 3H), 4.20-4.28 (in, 2H), 4.44 (dd, 1 4.60 (bs, 1 6.43-6.58 (in, 6H), 6.79 (dirn, 2H), 6.84 I1H), 7.41 (din, 2H). LRMS (El) 400 227, 211. Elemental analysis: calculated for C23HigF 3 o 3 C, 68.99; H, 4.78%; found C, 69.06; H, 4.78%.

Step 4: (±)-cis-7-methoxy-4-(4-(2-pyrrolidinoethoxy)pheny/)-3-( 4 -(trifluoromethyl)phenyl)chromane A mixture of ()-cis-4-(4-hydroxyphenyl)-7-methoxy-3-(4-(trifluoromethyl)phenyl)chromane (0.801 g, 2.00 mmol), potassium carbonate (2.76 g, 19.97 mmol), sodium iodide (0.01 g, 0.07 mmol), 1-( 2 -chloroethyl)pyrrolidine hydrochloride, (0.38 g, 2.23 mmol) and acetone, (100 ml) was stirred at 60C, 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 20 ml ethanol to give the product as colourless needles, which contained 0.5 equivalents of ethanol of crystallisation after vacuum drying.

Yield 0.926 g of (±)-cis-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-( 4 S. (trifluoromethyl)phenyl)chromane. M.p. 119-120C. 'H-NMR (CDC3, 300 MHz) 8: 1.75- 1.85 4H), 2.55-2.65 4H), 2.85 2H), 3.62 (ddd, 1H), 3.81 3H), 4.01 2H), 4.19-4.28 2H), 4.44 (dd, 1H), 6.44-6.54 4H), 6.64 (dm, 2H), 6.78 (dm, 2H), 6.84 (d, 1H), 7.40 (dm, 2H). LRMS (El) 497 84 (CsH,oN).

Step (+)-cis-7-Hydroxy-4-(4-(2-pyrrolidinoethoxy)pheny/)-3-(4-(trfluoromethy/)-pheny/)chromane S- A mixture of (+)-cis-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4-(trifluoromethyl)- 20 phenyl)chromane (0.30 g, 0.60 mmol) and anhydrous pyridine hydrochloride (3.50 g, 30.3 mmol) was heated to 150-155"C as a melt for 18 hours. The mixture was cooled to room temperature, and the resulting orange coloured wax dissolved in a mixture of water ml), hot ethanol (20 ml) and dichloromethane (100 ml). The aqueous layer was basified to pH 14 by adding 10M sodium hydroxide, then 1M hydrochloric acid was added until pH 8- 9. The organic layer was collected and the aqueous layer further extracted with dichloromethane (2 x 75 ml). The combined organics were washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to a dark coloured gum, which was purified by column chromatography on silica gel, with 6% methanol in dichloromethane as eluent, giving the product as a colourless solid.

Yield 0.20 g of (±)-cis7hydroxy4(4(2pyrrolidinoethoxy)hl)3-4 (trifluoromethyl)phenyl)chromane. M.p. 100*C (dec). 1 H-NMR (ODC1 3 300 MHz) 5: 1.80- 1.95 (in, 4H), 2.65-2.82 (in, 4H), 2.82-2.94 (in, 1H), 3.0-3.12 (in, 1H), 3.62 (ddd, 1H), 3.77-4.08 (in, 2H), 4.16 (dd, 1H), 4.21 1H), 4.38 (dd, 1H), 6.36 (dd, 1H), 6.41 1H), 6.41-6.45 (in, 4H), 6.72-6.79 (in, 3H), 7.37-7.44 (in, 2H), phenol OH not observed.

LRMS

(El) 483 84 (CAH 1 N, 100%). Analytical chiral HPLC: (Chiradex 5jpim, 250 x 4 mm column; 70% methanol, 30% buffer (O.

2 5%w/w triethylaminoniuin acetate, pH 5.20); mI/min flow rate; 220 nm UV detection) enantiomer signals at Rt 22.7 and 38.6 min.

Step 6: 7 -hydroxy4(4(2.pyrolidinoethoxy)pheny) 3 4 (tri~ooefl hnl)crmn The title compound was separated from the raceinic mixture, (±)-cis-7-hydroxy-4-(4.(2- .yrldnehx~hnl--4(tilooehlpey~hoa by means of preparative chiral HPLC on a Chiradex 5gm, 250 x 25 mm column. The title compound was the more rapidly eluted enantioiner.

*Yield 25.9 ing of (+-i--yrx--4(-yrldnehx~hnl--4 (trifluoroinethyl)phenyl)chromane. Analytical chiral HPLC: (Chiradex 5gm, 250x4 mm column; 70% methanol, 30% (O.25%wlw triethylainioniuin acetate, pH 5.20) eluent; *mI/mmn flow;. 220 nin UV detection). Rt 22.7 mm ee. 'H-NMR

(CDC

3 300 MHz) 8: 1.80-1.95 (in, 4H), 2.65-2.82 (in, 4H), 2.82-2.94 (in, 1H), 3.0-3.12 (in, 1H), 3.62 (ddd, 1H), 4.01 2H), 4.16 (dd, 1H), 4.21 1H), 4.38 (dd, 1H), 6.36 (dd, 1H), 6.41 1H), 6.41-6.45 (in, 4H), 6.72-6.79 (in, 3H), 7.37-7.44 (in, 2H), phenol OH not observed. [ctI 0 +246.2* (c 1.0% in methanol).

EXAMPLE 3 7 Hydroxy.3 4-m hI etvlhenA fA fl~ t The title compound was prepared in a manner exactly analogous to that described for Example 2, with substitution of 4-methylphenyl acetic acid for the 4 -(trifluoromethyl)phenyl acetic acid used in Step% 1.

Thus (±)-cis 7 methoxy3(4m ethpeyle)A4(4(2pyolidthx)phnl-omn was de-methylated by heating with pyridine hydrochloride to give the racemic mixture, ci--yrx--4mtypey)4(-(-yrldnehx)pey~hoae The title compound was then separated from this racemic mixture by means of preparative chiral HPLC {Chiradex 5g.m, 250 x 25 mm column; flow' 20 mI/mmn; 50% methanol, 50% buffer (02%aueu triethylammonium acetate, pH 3.5) eluent, 220 nm UIV detection). Thetil compound was the more rapidly eluted enantiomer, Rt =10-18 min.

Yield 14.7 mg of )-i--yrx--4mehlpey)4(-2prodnotoyphenyl)chromane. Analytical chiral HPLC: {Chiradex 5g~m, 250 x 4 mm column; methanol, 60% (0.1%w/w triethylammonium acetate, pH 4.20) eluent; 0.8 mI/mmn flow; 220 nm UV detection). Rt 13.8 min, >99% ee. 'H-NMR (MeOH-d 4 300 MHz) 5: 1.78-1.93 4H), 2.2 3H), 2.67-2.84 (in, 4H), 2.94 2H), 3.47 (ddd, 1H), 4.03 2H), 4.13 OV (dd, 1 4.19 1 4.37 (dd, I1H), 6.30 (dd, 1 6.34 1 6.51 (din, 2H), 6.58 (din, 2H), 6.62 (din, 2H), 6.67 1IH), 6.93 (dmn, 2H), phenol OH not observed. [ajO~o +303.40 (c 0.62% in methanol).

EXAMPLE 4 (+)-cis7Hyrx33yrxpey.( 4 2

V

The title compound was. prepared in a manner exactly analo gous to that described for Example 2, with substitution of 3 -methoxyphenyl acetic acid for the 4 -(trifluoromethy)phenyl acetic acid used in Step 1.

Thus (±)..cis..7.methoxy3(3..methoxyphenyl)-4-(4-(2-py[oidinoehoypey-crmn was de-methylated by heating with pyridine hydrochloride to give the racemic mixture, cis- 7 hydroxy33hydroxeylhenyl)(4Cpy pyrriolth)heychoa The title compound was then separated from this racemnic mixture by means of preparative chiral HPLC {Chiradex 5jam, 250 x 25 mm column; flow 20 mI/mmn; 40% methanol, 60% buffer aqueous triethylammoniumn acetate, pH 3.5) eluent, 220 nm UV detection). The title compound was the more rapidly eluted enantiomer, Rt 22-34 min.

*Yield 20.9 mg of 7 hydroxy33hydroxyphenyl)..-4-(4pyr j.dioehoy) phenyl)chromane. Analytical chiral HPLC: {Chiradex 5j.im, 250 x 4 mm column; .*methanol, 60% (0.1%w/w triethylammonium acetate, pH 4.20) eluent; flow 0.8 mi/min; 220 nm UV detection). Rt 11.4 min, 95.2% ee. 'H-NMR (MeOH-d 4 300 MHz) 5: 1.80- 15 1.95 (in, 4H), 2.72-2.90 4H), 3.00 2H), 3.44 (ddd, 1H), 4.05 Ct, 2H), 4.15 (dd, 1H), 4.21 1 4.34 (dd, 1IH), 6.14 (in, I 6.23 (din, 1 6.31 (dd, I1-I), 6.34 1 6.50- 6-59 (in, 3H), 6.60-6.71 (in, 3H), 6.93 (dd, 1H), phenol OH signals not observed. [a]_020..

+278.00 (c =0.87% in methanol).

Claims

1. A (+)-enantiomer of a compound of the formula I in which substituents R 2 and R 3 are arranged in cis-configuration: S wherein: R' is phenyl optionally substituted with 1 to 5 substituents indep endently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C, -C 6 -alkyl, C 1 -0 6 alkyl, C,-C, 6 -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 4 NHR 4 NR 2 NHCOR',NHSO 2 R 4 CONHR 4 CONR2, COOH, COOR, S0 2 R 4 SOR, SONHR',SONR 2 a C,-C 7 heterocyclic ring, satu- 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, onitro, cyano, SH, SR 4 trihalo-Cl-C 6 -alkyl, Cl-C 6 -alkyl and Cl-C 6 -alkoxy; or 43 -(CHz)n-Y wherein n and Y are as defined above; or phenyl fused to a C3-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 4 trihalo-C,-C6- alkyl, C,-C 6 -alkyl and C,-C 6 -alkoxy; and R' is Cl-C 6 -alkyl; and pharmaceutically acceptable esters, ethers and salts thereof.

2. A (+)-enantiomer of a compound of the formula I in which substituents R 2 and R 3 are 10 arranged in cis-configuration: S wherein: R 2 is phenyl optionally substituted with 1 to.3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C 1 -Ce-alkyl, C,-C6- alkyl and C,-Cs-alkoxy; R 3 is: phenyl substituted with -X-(CH 2 wherein: X is a valency bond, O or S, 44 n is an integer in the range of 1 to 12, Y is H, OH, OR, NHR 4 NR NHCOR, NHSO 2 R, CONHR 4 CONR COOH, COOR 4 SO 2 R 4 SOR, SONHR 4 SONR 2 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 substitu- ents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihaio-C,-Ce-aikyi, C,-C 6 -alkyl and C,-C 6 -alkoxy; or -(CH 2 wherein n and Y are as defined above; or phenyl fused to a C3-C, heterocyclic ring, saturated or unsaturated, containing 10 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 1 alkyl, C 1 -C 6 -alkyl and C,-C 6 -alkoxy; and R 4 is C,-C 6 -alkyl; 15 and pharmaceutically acceptable esters, ethers and salts thereof.

3. A compound according to claim 1 or 2 having the formula (a) or R 3 HO R2 (Ib) wherein R 2 and R 3 are as defined above.

4. A compound according to any one 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 6 -alkyl, C 1 -Ce-alkyl and Cj- C 6 -alkoxy.

5. A compound according to any one 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-alkyi and C- Cs-alkoxy.

6. A compound according to any one of the preceding claims in which 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, OH, OR', NHR NR NHCOR 4 NHSO 2 CONHR', CONR COOH, COOR', S0 2 R 4 SOR, SONHR, SONR 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.

7. A compound according to any one of the preceding claims wherein R' is 20 wherein n and Y are as defined above.

8. A compound according to any one of the preceding claims wherein R' is phenyl fused to 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 sub- stituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihaloCl--C 6 -alkyl, C,-C 6 -alkyl and C,-C 6 -alkoxy.

9. A compound according to claim 1 or 2 having the formula 46 H 0 wherein R is H or Cl-C 6 alkyl. A compound according to claim 1 or 2 having the formula 0 0 0: 0.0 1 A c m o n s ac o d n o c a m 1 or2 h v n h o m l o *0(C wherein m is as defined above. 47

12. A compound according to claim 1 or 2 having the formula O (CH 2 )m 0 HO wherein m is as defined above.

13. A compound according to claim 1 or 2 having the formula HO S** g• wherein m is as defined above and both R 4 independently are as defined above.

14. A compound according to claim 1 or 2 having the formula ooeei* 48 wherein R 4 is as defined above. A compound according to claim 1 or 2 having the formula wherein R 4 is as defined above. 5 16. A compound according to claim 1 or 2 having the formula wherein R 6 represents one or more of the following substituents: methoxy, hydroxy, trifluormethyl, fluoro and chloro.

17. A compound according to claim 1 or 2 selected from the following: (+)-cis-4-(4-(Carboxymethoxy)phenyl)-7hydroxy-3-phenylchromane (+)-cis-7-Hydroxy-4-(4-(methoxycarbonylmethoxy)phenyl)-3-phenylchromane, (+)-cis-4-(4-(Ethoxycarbonylmethoxy)phenyl)-7-hydroxy-3-phenylchromane, (+)-cis-4-(4-(Benzyloxycarbonylmethoxy) phenyl)-7-hydroxy3phenylchromane, 7 -Hydroxy-.3-phenylIA.(4..(2-pyrrouidinoethoxy) phenyl)chromane, 7 -Hydroxy..3-phenylA.-(4u.(3-pyrhoidinopropoxy) pheny!)chromane, (+)-cis 7 Hydroxy3pheny.4-(44pyldnobutiob)phy)chro 7 -Hydroxy.3pheny..4-(4-(5-pyrrolidinopentox)pheny)chroa (+)-cis 7 Hydroxy3pheny..4-( 6pyroldiohexlohxy)hny)chr 7 -Hydroxy.-3.phenyl.4.(4.(7.py1oidinoheptyoxy)phenyl)chromae 7 Hydroxy3 pheny..4-(-yroidnpyoxi )hy)chroa 7 -Hydroxy.3 phenylA(4(4(yrr roid inonoxy)hny)chr 7 Hydroxy..3-phenylIA (4 (1 0-pyrrolidinodl)pheny)chroa *(+)-ci's-7.Hydroxyu3.phenyIA(4-( ll-pyrrolidinoundecyloxy)phenyl)chromane, (+)-cis-7-Hydroxy..3.phenylA..(4.( 12 -pyrrolidinododecyloxy)phenyl)chromane, (+)-cis-7-Hydroxy..3.phenylI4-(4-(2-piperidinoethox Iey)chroae 7 -Hydroxy..3.phenylIA (4-(3-pipeidinopropx)pheny)chroa 15 7 -Hydroxy3pheny;4(4-(4-pipeidinobutoy) phenyl)chrom are, (+)-cis 7 Hydroxy4.(4.perhydroazepinoeth ~heny) 3 henlhoa (+)-cis-7.Hydrox.4(3 (3pdoaepinorozpx)pheny)-3-hncroa ***(+)-cis7Hydroxy.4-((44perh droazeibuto)pheny)3-hnlro (.+)cis4.(4..(2mehDaiethy~aminy)hdr7h 3 henlhoa (+)-cis.4.(4.(2Diethylaminoethoxy)ph)7hydrx3-hnlroa (+).cis4.(4.(2NEtlN-metthylaiohmiox h)hey)- 7 hyrx-phnlroae ***(+)-cis-4(4.(3.Dimethytaminopopopeny)ph,)dry 3 -hnlro *(+)cis4.(4(4.Dime hyaiamanboxyey)phehddoy 3 henlhoa (+)-cis-4-(2,3-Dihydro-1 4 -benzoxazin-6-yl)-7-hydroxy-.3phenylchromane, 25 7 -HydroxyA4(4-methyl12,3-dihydro- li 4 -benzoxazin-6-yl)3phenylchromane, (+)-cis4-(4-Ethyl-2,3-dihydro-1,4bnoai--i 7hyrx--hnlhoae **(+)-cis..7.Hydroxy3(4hydroxypheny)A4( 4 2 -prlidinehx.hny~hoae (+)-cis.7-Hydroxy..3-(4-trifluoromethylpheny)-4-(4-(2pyroinetxyhnycrma, (+)-cis7.Hydroxy3(4fuo hen-(-(yrro(4(2uoethoypeychma (+)-cis3.(4.Choropheny)7hydroxy-4(4-(2-prrldinehoypelchma, (+)-cis3-(34..Dimethoxyphenyl).7hydro-4-(4 (2..pyrriothoh)hel)chroa (+)-cis.7.Hydroxy3(pentafluorophenl)( 4 2 roiioehx.hny~hoa (+)-cis4.(4-(Carboxymethoxy)phenyl) 6hdroy 3 henlhoae (+)-cis6-.Hydroxy-(4(methoxycarbonylmethoxy)phenyl) 3 phlchrmn, (+)-cis-4(4.(Ethoxycarbonymethoxy)phe) 6 hydrx-phniroae (+)-cis.4.(4.(Benzyloxycarbonylmethoxy)phe)6hydrx-phnlroae (+)-cis-6Hydroxy3phenyi4(4-(2-pyrrolidinoethoxy)phenhl)chrane, 6 .Hydrox-peyl..phen-yA((3ploidinopooype)hroa (+)-cis 6 Hydroxy.3- pheny..4-(44-.yrr o idin)phy)chro (+)cis 6 (+)cis6Hydroxpeyl..phen-yrroliinohpyoxydhen)h oa (+)cis 6 .Hydrox-peyl3..phenyroidinoptyloxyh)pheychoa (+)-cis 6 Hydroxyhenl.phen8-yrroli4(8pyuidit)pheychoa, (+)-cis-6..Hydroxy3phenyliA (4-(9-pyrrolidinnoylx)heny)choa (+)-cis-6..Hydroxy..3.phenyI-.4-(4 (1 O-pyrroiidinodecyloxy)phenyl)chromane, (+)-cis-6-.Hydroxy.3.phenylA(4-( ll-pyrrolidinoundecyloxy)phenyl)chromane, (+)-cis-6Hydroxy3phenyIA4(-( 1 2-pyrrolid inododecyloxy)phenyl)chromane, 6 -Hydroxy3.phenylA.(4.(2-.piperidinoethoxy)phenyI)chroa 156 6 -Hydroxy..3-phenyl-4-(4-(3-pp idinpopx)pheychoa (+)-cis 6 Hy drox3-heyl.3pheny-iA(4(4..but)phenyl)chromane, -cis6Hydroxy-(4(perhydroazepi th)phenl-hnhoae (+)cis-Hydro yA.4..(3.yrozprhyroazep)hn)-phnlrma (+)-cis 6 Hydroxy((4 .perhydroaze noutoxyey) 3 hnhI ae 20 (+)cis.4(4(2Dimethylamnothox)phenl--yrx--hnlhoa (+)cis4(4(2Diethyamot)phl) 6 hydrx-phncroae

666.(+)-cis4(4(3Dimethyamipopo hny)-6hyrx-phnlroa *6(+)-cis4.(4.(4Dimethymiuoy)hy)- 6 hyrx-phnlroa (+)-cis-4-(2,3Dihydro-1, 4 -benzoxazin6yl)-6hydroxy-3phenylchromane, (+)cis6-Hdroy-4(4-ethl-23-dhydo-, 4 -benzoxazin-6-yl)-3-phenylchromane, (+)-cis4-(4.Ethy23dihydro-1 4 -benzoxazin-.6.y)6hydroxy3phenylchromane, (+)-cis-6Hydroxy3(4hydroxyphey)4( 4 2 -proiiotoypey~hoa (+)-cis-6Hydroxy-3.(trifluoromethypheny)4(4(2..pyrroidinoetho,)phey)chroa 6 Hydroxy3(4fluorophenl)4(4( 2 -proiiotoypey~hoae (+)-cis-3.(4.Choropheny)6hydroy 4 4 2 -proiiotoypey~hoa (+)cis-3(34Dimethoxypy)hydryI6hd(4(2-yrld~otoypey~ho (+)-cis.6.Hydroxy3(pentafluorophy)A4( 4 -(2proinetxyhnlcrma (+)-cis7Hydroxy3pheny4{{2(roidin -y)ethoxylphenyllchromane, 51 (+)-cis 7 Hydroxy4(4(2pyrroidinoethoxy)phey) 3 4 -(tdflurmtyphni-roa (+)cis 7 Hydroxy3(4methyphenyl).(4(2pyldnoeiioh)hey)chroa (+)-cis 7 Hydroxy3.(3yrydryh enyI)A(4(2pypyro idin thx)peychoa. 18. A method for the preparation of compounds of formula comprising the steps of: a) reacting a compound of the formula (11) 0 0 JI I OH OH 00 q 0 0* 0* 0 0 0 00 00 0 0 0 0@ OSS* 0 0000 @0 00 0 with a compound of the formula (111) (111) @0 0 00 0e @00 .00 0 0(0 00 to 0 000000 S wherein R 5 is as defined above, in the presence of triethylamine and acetic anhydride to form a compound of the .formula (IV) wherein R s is as defined above, 0 0 0 b) reducing a compound of the formula (IV) with a suitable hydride reducing agent to form a compound of formula (V) OH o (V) 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 0- o (VI) 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) S. S(CH 2 (VII) wherein n, R 5 and Y are as defined above, e) resolving the racemic mixture of and (-)-enantiomers of a compound of formula (VII), f) deprotecting a (+)-enantiomer of a compound of formula (VII) with a suitable de- protection agent, preferably by pyridine hydrochloride fusion, 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 (VIII) (VIII) wherein R 5 is as defined above, h) reducing a compound of the formula (VIII) with a suitable reducing agent, prefera- bly by catalytic hydrogenation, to form a compound of the formula (IX) OH "2 0 (IX) wherein R 5 is as defined above, i) cyclizing a compound of formula (IX) with an appropriate agent to form a com- pound of the formula or (XI) oo x or R4 O NS "0 (XI) wherein R 4 and R are as defined above, oo. Y j) resolving the racemic mixture of and (-)-enantiomers of a compound of formula S(X) or (XI), k) deprotecting a (+)-enantiomer of a compound of the formula or (XI) with a suit- able deprotection agent, preferably by pyridine hydrochloride fusion, 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 (XII) (XII) wherein R 5 is as defined above, m) cross-coupling a compound of the formula (XI) with the appropriate cross-coupling partner to form a compound of the formula (XII) S.. S (CH 2 n (XIII) *SSS. wherein n, R 5 and Y are as defined above, n) resolving the racemic mixture of and (-)-enantiomers of a compound of formula (XIII), o) deprotecting a (+)-enantiomer of a compound of the formula (XII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a com- pound of the formula or p) cyclizing a compound of the formula (XIV) (XIV) wherein R S is as defined above, with paraformaidehyde in the presence of dimethylamine to form a compound of the formula (XV) (XV) wherein R 5 is as defined above, q) reacting a compound of the formula (XV) with the appropriate Grignard reagent to form a compound of the formula (XVI) (XVI) wherein n, R 5 and Y are as defined above, r) hydrogenating a compound of the formula (XVI) in the presence of a suitable cata- lyst to form a racemic mixture of and (-)-enantiomers of a compound of the formula (XVII) with a 3,4-cis configuration (XVII) wherein n, R 5 and Y are as defined above, s) resolving the racemic mixture of and (-)-enantiomers of a compound of formula (XVII), t) deprotecting a (+)-enantiomer of a compound of formula (XVII) with a suitable de- protection agent, preferably by pyridine hydrochloride fusion, to form a compound of the general formula u) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XVIII) *oci o (XVIII) wherein R 5 is defined as above, v) deprotecting a compound of the formula (XVIII) with a suitable deprotection agent, such as pyridine hydrochloride fusion or boron tribromide, to form a compound of the formula (XIX) 0S 0' HO 0 (XIX) wherein R 5 is defined as above, w) reacting a compound of the formula (XIX) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula (XX) S O* 0 0 s O 0 R 0* (XX) 15 wherein R 5 is defined as above, and R 6 is H or methoxy, x) deprotecting a compound of the formula (XX) with a suitable deprotection agent, such as sodium or potassium hydroxide in alcohol, to form a compound of formula (XXI) R 6 OH RR O (x) (XXI) wherein R 5 is defined as above, and R 6 is H or methoxy, y) alkylating a compound of the formula (XXI) with an appropriate electrophile to form a compound of the formula (XXII) a a. a. (XXII) wherein n, R 5 and Y is defined as above, and R 6 is H or methoxy, z) deprotecting a compound of the formula (XXII) with a suitable deprotection agent, preferably catalytic hydrogenation for Re equals H or a strong acid for R 6 equals methoxy, to form a compound of the formula (XXIII) 61 0(XXIII) wherein n, R 5 and Y is defined as above, aa) Alkylating a compound of the formula (XXI) with an appropriate dihalogenated alkane :':such as 1,2-dibromoethane, l-bromo-2-chloroethane, l, 4 -dibromobutane, 1,6- dibromohexane l, 8 -dibromooctane, 1,10-dibromodecane, preferably catalysed by potassium iodide, to form a compound of the formula (XXIV 0 ,(CH 2 Hal RIR 0 0 (XXIV) wherein n and R' is defined as above, R' is H or methoxy, and Hal is chloro, bromo, or iodo, bb) reacting a compound of the formula (XXIV) with an appropriate nucleophile, preferably an amine, to form a compound of the formula (XXV), 62 0 ,CH 2 0N 0 (XXV) wherein R' is H or methoxy, and Z is NHR NR2 or a 03-07 heterocyclic amine 9optionally containing oxygen or nitrogen, optionally being substituted with 1 to 3 sub- 9stituents independently selected from the group consisting of H, OH, halogen, nitro, 10 cyano, trihalo-C,-C, 6 -alkyl, Cl-Cr,-alkyl and C 1 -C6-alkoxy, and n, and R 5 is defined as above, cc) deprotecting a compound of the formula (XXV) with a suitable deprotection agent, preferably catalytic hydrogenation for R' equals H or a strong acid for R' equals *,15 methoxy, to form a compound of the formula (XXVI) R N N H 0- 0 (XXVI) wherein R 6 is H or methoxy, and Z is NHR, NR', or a C307etocccamn 63 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,-C 6 -alkyl and C,-Cs-alkoxy, and n, R 4 and R 5 is defined as above. 19. A compound according to any of the claims 1 to 17 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. A compound according to any of the claims 1 to 17 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, S" 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. 21. A pharmaceutical composition comprising an effective amount of a compound according to claims 1 to 17 or a pharmaceutical acceptable salt thereof and a pharmaceutical carrer or diluent. 22. A pharmaceutical composition according to claim 21 in the form of an oral dosage unit or parenteral dosage unit. 23. The use of a compound according to any of the claims 1 to 17 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. 24. The use of a compound according to any of the claims 1 to 17 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, 64 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. 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 17. 26. A method of treating or preventing bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, includ- S: 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 preventic,a or treatment of bone loss or osteoporosis, which method com- Sprises administering to a subject in need thereof an effective amount of a compound according to any of the claims 1 to 17. 27. A contraceptive method comprising administering to a male or female mammal an 20 effective amount of a compound according to any of the claims 1 to 17. DATED this 19th Day of December, 2001 o *NOVO NORDISK A/S Attorney: JACINTA FLATrERY-O'BRIEN Registered Patent Attorney of The Institute of Patent and Trade Mark Attorneys of Australia of BALDWIN SHELSTON WATERS