NOVEL CIS-3,4-CHROMAN DERIVATIVES USEFUL IN THE PREVENTION OR TREATMENT OF ESTROGEN RELATED DISEASES OR SYNDROMES

Abstract: The present invention relates to therapeutically active compounds of formula (I), a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in the prevention or treatment of estrogen related diseases or syndromes.

Description: Title Novel c/s-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 c/s-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 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. 303:1 195-1 198). 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 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 postmeno- pausal 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 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 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 (i.e. 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 objection- able to many patients. In addition to estrogen's stimulatory effect on the endometrium, there remains considerable controversy regarding reports of an association between long- term 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 postmeno- pausal 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- 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 compounds of the formula I in which substituents R 2 and R 3 are arranged in cis-configuration: wherein: 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 r C 6 -alkyl, C r C 6 - alkyl, C r C 6 -alkoxy and phenyl; R 3 is phenyl substituted with -X-(CH 2 ) π -Y, wherein: X is a valency bond, O or S, n is an integer in the range of 4 to 12, preferably 6 to 12, Y is H, halogen, OH, OR 4 , NHR 4 , NR 4 , NHCOR 4 , NHS0 2 R 4 , CONHR 4 , CONR 4 2 , COOH, COOR 4 , S0 2 R 4 , SOR 4 , SONHR 4 , 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 , thhalo-C r C 6 -alkyl, C C 6 -alkyl and C r C 6 -alkoxy; R 4 is C r C β -alkyl; and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and salts thereof. The general chemical terms used in the above formula have their usual meanings. For example the term C r C 6 -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 -C 7 -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 (e.g. 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 following formulae la or lb are preferred: wherein R 1 , R 2 and R are as defined above. In a preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula: wherein m is an integer from 2 to 10, preferably 4 to 10. In another preferred embodiment, the present invention is concerned with cis-forms of the compounds of the following formula: 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: 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: wherein m is as defined above and both R 4 independently are as defined above. The most preferred compounds are the following: (-)-c/s-7-Hydroxy-3-phenyl-4-(4- (5-pyrrolidinopentoxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (6-pyrrolidinohexyloxy)phenyl)chromane, (-)-c/ ' s-7-Hydroxy-3-phenyl-4-(4- (7-pyrrolidinoheptyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (8-pyrrolidinooctyloxy)phenyl)chromane, (-)-c s-7-Hydroxy-3-phenyl-4-(4 (9-pyrrolidinononyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (10-pyrrolidinodecyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (11 -pyrrolidinoundecyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (12-pyrrolidinododecyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4- (5-pyrrolidinopentoxy)phenyl)chromane, (-)-c s-6-Hydroxy-3-phenyl-4-(4 (6-pyrrolidinohexyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4 (7-pyrrolidinoheptyloxy)phenyl)chromane, (-)-c/ ' s-6-Hydroxy-3-phenyl-4-(4- (8-pyrrolidinooctyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4- (9-pyrrolidinononyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4 (10-pyrrolidinodecyloxy)phenyl)chromane, (-)-c/ ' s-6-Hydroxy-3-phenyl-4-(4- (11 -pyrrolidinoundecyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4 (12-pyrrolidinododecyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4' -(5-pyrrolidinopentoxy)phenyl)chromane, (+)-c/ ' s-7-Hydroxy-3-phenyl-4-(4 -(6-pyrrolidinohexyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4 -(7-pyrrolidinoheptyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4 (8-pyrrolidinooctyloxy)phenyl)chromane, (+)-c s-7-Hydroxy-3-phenyl-4-(4-(9-pyrrolidinononyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4-(10-pyrrolidinodecyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4-(11-pyrrolidinoundecyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4-(12-pyrrolidinododecyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(5-pyrrolidinopentoxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(6-pyrrolidinohexyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(7-pyrrolidinoheptyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(8-pyrrolidinooctyloxy)phenyl)chromane, (+)-c/ ' s-6-Hydroxy-3-phenyl-4-(4-(9-pyrrolidinononyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(10-pyrrolidinodecyloxy)phenyl)chromane, (+)-c s-6-Hydroxy-3-phenyl-4-(4-(11-pyrrolidinoundecyloxy)phenyl)chromane, (+)-c s-6-Hydroxy-3-phenyl-4-(4-(12-pyrrolidinododecyloxy)phenyl)chromane, and any mixture thereof including racemic mixtures. The following compounds form part of the disclosure of the present invention: (±)-cis-4-(4-Hexylphenyl)-7-hydroxy-3-phenylchromane, (+,-) cis 7-hydroxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3-phenyl-chroman, (+,-) cis 4-[4-(6-Dibutylaminohexyloxy)-phenyl]-7-hydroxy-3-phenyl-chroman, (+,-) cis 7-Hydroxy 4-[4-(morpholinobutyloxy)-phenyl]-3-phenyl-chroman, (+,-) cis 7-Hydroxy 4-[4-(morpholinodecyloxy)-phenyl]-3-phenyl-chroman including the pure enantiomers thereof. 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. Agarwal, S. Durani, B.S. Betty, V.P. Kamboj and N. Anand, J. Med. Chem. 26, 592-5, 1983; Teo, C, Sim, K., 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 (I) comprising the steps of: a) reacting a compound of the formula (II) with a compound of the formula (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 r C 6 -alkyl, C r C 6 -alkyl and C r C 6 -alkoxy, and R 4 is as defined above, in the presence of triethylamine and acetic anhydride to form a compound of the formula (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) wherein R 5 is as defined above, c) hydrogenating a compound of the formula (V) 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) wherein R 5 , Y and n are as defined above, e) deprotecting a compound of formula (VII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (I); or f) reacting a compound of formula (VI) with trifluoromethane sulphonic acid anhydride to form a compound of the formula (XI) wherein R 5 is as defined above, g) cross-coupling a compound of the formula (XI) with the appropriate cross-coupling partner to form a compound of the formula (XII) wherein R 5 , Y and n are as defined above, h) deprotecting a compound of the formula (XII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (I), i) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XIII) (XIII) wherein R 5 is defined as above, j) deprotecting a compound of the formula (XIII) with a suitable deprotection agent, such as pyridine hydrochloride fusion or boron tribromide, to form a compound of the formula (XIV) (XIV) wherein R 5 is defined as above, k) reacting a compound of the formula (XIV) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula (XV) wherein R 5 is defined as above, and R 6 is H or methoxy, I) deprotecting a compound of the formula (XV) with a suitable deprotection agent, such as sodium or potassium hydroxide in alcohol, to form a compound of formula (XVI) (XVI) wherein R 5 is defined as above, and R 6 is H or methoxy, m) alkylating a compound of the formula (XVI) with an appropriate electrophile to form a compound of the formula (XVII) (XVll) wherein n, R 5 and Y is defined as above, and R 6 is H or methoxy, n) deprotecting a compound of the formula (XVII) with a suitable deprotection agent, preferably catalytic hydrogenation for R 6 equals H or a strong acid for R s equals methoxy, to form a compound of the formula (XVIII) (XVIII) wherein n, R 5 and Y is defined as above, o) Alkylating a compound of the formula (XVI) with an appropriate dihalogenated alkane such as 1 ,4-dibromobutane, 1 ,6-dibromohexane, 1 ,8-dibromooctane, 1 ,10- dibromodecane, preferably catalysed by potassium iodide, to form a compound of the formula (XIX) (XIX) wherein n and R 5 is defined as above, R 6 is H or methoxy, and Hal is chloro, bromo, or iodo, reacting a compound of the formula (XIX) with an appropriate nucleophile, preferably an amine, to form a compound of the formula (XX) (XX) wherein R 6 is H or methoxy, and Z is NHR 4 , NR 4 , or a C 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-CrCe-alkyl, C^Ce-alkyl and C r C 6 -alkoxy, and n, R 4 , and R 5 is defined as above, q) deprotecting a compound of the formula (XX) 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 (XXI) (XXI) wherein R 6 is H or methoxy, and Z is NHR 4 , NR 4 , or a C 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 r C 6 -alkyl, C r C 6 -alkyl and C r C 6 -alkoxy, and n, R 4 and R 5 is defined as above. 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 monode- methylation with hydrobromic acid in acetic acid. Optical pure compounds of formula (I) 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 Hlg is Cl, Br or I. 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 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. Furthermore, the invention is concerned with 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 the invention. 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 (e.g. 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 dysfunc- tional 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. 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 compounds of this invention to displace 3 H-17β-estradiol (17β-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 3 H-17β-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 K 2 HP0 4 /KH 2 P0 4 , 1.5 mM K 2 EDTA, 10 mM monothioglycerol, 10 mM Na 2 Mo0 4 .2H 2 0, 10 % glycerol (v/v); pH 7.5. Radio-inert 17β-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 μl are incubated in duplicate for each concentration tested in microtitre plates to which have been added 20 μl 3 H-17β-E2 (assay concentration equals 0.4 nM) and 50 μl cytosol. For control samples as well as maximal binding sample, 10 μl PB is added in lieu of test compound. Following an 18 - 20 hr incubation at 4°C the reaction is terminated with 100 μl DCC slurry [0.5% 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°C. DCC background counts are assessed using 50 μl of 0.3% BSA in PB in lieu of cytosol. To separate bound and free 3 H-17β-E2, Titertek plates are centrifuged for 10 min (800 x g) at 4°C and aliquots of 100 μl are removed from each sample for scintillation counting using Optiflour scintillation liquid. Standard and control samples are incubated in quadru- plicate, 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-17β-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 surgical removal of the ovaries), the animals are treated with vehicle, 17β-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 μg estradiol/kg; and ovariectomized animals treated with 200 μg/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 35 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 °C. The mineral density can then be determined by dividing the ash weight of each sample by the tissue volume (i.e. 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 μl of 5% EDTA/1 ml of blood. Following centrifugation at 2500 rpm for 10 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 preparations 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 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. The compounds of this invention can thus be used for the formulation of pharmaceutical 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 monoglyce des 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 particularly 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 10-100 mg/day, when administered to patients, e.g. humans, as a drug. A typical tablet which may be prepared by conventional tabletting techniques contains: Active compound 5.0 mg Lactosum 67.0 mg Ph.Eur. Avicel™ 31.4 mg Amberlite™IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur. The compounds of the invention may be administered to a subject, e.g., 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 hydrobro- mide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, e.g., 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 (±)-cis-4-(4-Hexylphenyπ-7-hvdroxy-3-phenylchromane Step 1 : (±)-(cis-4-((7-methoxy-3-phenyl)chroman-4-yl)phenyl trifluoromethanesulfonic acid ester A stirred suspension of (±)-cis-4-(4-hydroxyphenyl)-7-methoxy-3-phenylchromane (5.0 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 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), 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 (41%) of (±)-(cis-4-((7-methoxy-3-phenyl)chroman-4-yl)phenyl trifluoromethanesulfonic acid ester. M.p. 98-99°C. 1 H-NMR (CDCI 3 , 300MHz) δ: 3.65 (m, 1 H), 3.81 (s, 3H), 4.24-4.40 (m, 3H), 6.49 (dd, 1 H), 6.53 (d, 1 H), 6.61-6.69 (m, 4H), 6.82 (d, 1 H), 6.96 (d, 2H), 7.11-7.20 (m, 3H). LRMS(EI): 464 (M + ). Step 2: (±)-cis-4-(4-Hexylphenyl)-7-methoxy-3-phenyichromane 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 tetrahy- drofuran 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 (0) (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 30% 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 (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 chromatography on silica gel 60, with 2% methanol in dichloromethane as the eluent. This gave the title compound as a clear oil. Yield 0.758 g (88%) of (±)-cis-4-(4-hexylphenyl)-7-methoxy-3-phenylchromane. 1 H-NMR (CDCI 3ι , 300 MHz) δ: 0.88 (t, 3H), 1.20-1.32 (m, 6H), 1.53 (m, 2H), 2.50 (t, 2H), 3.59 (m, 1 H), 3.80 (s, 3H), 4.20-4.29 (m, 2H), 4.45 (t, 1 H), 6.42-6.53 (m, 4H), 6.61-6.68 (m, 2H), 6.82-6.89 (m, 3H), 7.08-7.19 (m, 3H). LRMS (El): 400 (M + ). Step 3: (±)-cis-4-(4-Hexylphenyl)-7-hydroxy-3-phenylchromane A mixture of (±)-cis-4-(4-hexylphenyl)-7-methoxy-3-phenylchromane (0.46 g, 1.15 mmol) and anhydrous pyridine hydrochloride (6.60 g, 57.4 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 (100 ml), hot ethanol (10 ml) and di- chloromethane (100 ml). The organic layer was separated and the aqueous layer further extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate and evaporated to a dark coloured oil, which was purified by column chromatography on silica gel 60, with 2% methanol in dichloromethane as eluent; giving the title compound as a red oil. Yield 158 mg (35%) of (±)-cis-4-(4-Hexylphenyl)-7-hydroxy-3-phenylchromane. 1 H-NMR (CDCI 3 , 300MHz) δ: 0.87 (t, 3H), 1.20-1.32 (m, 6H), 1.51 (m, 2H), 2.49 (t, 2H), 3.57 (m,1 H), 4.18-4.25 (m, 2H), 4.43(t, 1 H), 4.78 (s, 1 H), 6.36 (dd, 1 H), 6.46 (d, 1 H), 6.49 (d, 2H), 6.62 (dd, 2H), 6.79-6.88 (m, 3H), 7.08-7.20 (m, 3H). Elemental analysis: calculated for C 27 H 30 O 2 : C, 83.91 ; H, 7.82%; Found: C, 83.45; H, 7.78%. LRMS (El): 386 (M + ). EXAMPLE 2 (+.-) cis 7-hydroxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3-phenyl-chroman Step l : (+, -) cis 7-Benzyloxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3-phenyl-chroman 7-Benzyloxy-4-[4-(6-bromohexyloxy)-phenyl]-3-phenyl-chroman (300 mg, 0.53 mmol), morpholine (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 7-Benzyloxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3- phenyl-chroman, m.p. 85.7-87.5°C. The product was identified by 1 H-NMR. Step 2: (+, -) cis 7- ydroxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3-phenyl-chroman (+,-) cis 7-Benzyloxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3-phenyl-chroman (150 mg, 0.26 mmol) was dissolved in a solution of 1 % Hydrochloride in ethanol (5 ml). The solution was added to a 10 % palladium on carbon catalyst, and hydrogenated (1 atm.) overnight. The reaction mixture was filtered and evaporated to give an oil which solidified. Yield 1 17 mg (86 %) of (+,-) cis 7-hydroxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3-phenyl- chroman.HCI m.p. 97-99°C. The product was identified by 1 H-NMR. The following example was performed essentially as described above. EXAMPLE 3 (+.-) cis 4-[4-(6-Dibutylaminohexyloxy)-phenyl]-7-hydroxy-3-phenyl-chroman Step 1 : (+,-) cis 7-benzyloxy 4-[4-(6-dibutylamino-hexyloxy)-phenyl]-3-phenyl-chroman From 7-Benzyloxy-4-[4-(6-bromohexyloxy)-phenyl]-3-phenyl-chroman (300 mg, 0.53 mmol) and N,N-dibutylamine (339 mg, 2.63 mmol). Yield 184 mg (56 %) of (+,-) cis 7-Benzyloxy-4-[4-(6-dibutylaminohexyloxy)-phenyl]-3- phenyl-chroman, m.p. 72-73.5°C. The product was identified by 1 H-NMR. Step 2: (+, -) cis 4-[4-(6-Dibutylaminohexyloxy)-phenyl]-7-hydroxy-3-phenyl-chroman From (+,-) cis 7-Benzyloxy-4-[4-(6-dibutylaminohexyloxy)-phenyl]-3-phenyl-chroman (150 mg, 0.24 mmol). Yield 135 mg (98 %) of (+,-) cis 4-[4-(6-Dibutylaminohexyloxy)-phenyl]-7-hydroxy-3- phenyl-chroman, m.p. 85-87°C. The product was identified by 1 H-NMR. EXAMPLE 4 (+.-) cis 7-Hydroxy 4-[4-(morpholinodecyloxy)-phenyl]-3-phenyl-chroman Step 1 : (+,-) cis 7-Benzyloxy 4-[4-(morpholinodecyioxy)-phenyl]-3-phenyl-chroman From (+,-) cis 7-Hydroxy 4-[4-(10-Bromodecyloxy)-phenyl]-3-phenyl-chroman (300mg, 0.48 mmol) and morpholine (208 mg, 2.4 mmol). Yield 122 mg (40 %) of (+,-) cis 7-Benzyl 4-[4-(morpholinodecyloxy)-phenyl]-3-phenyl- chroman. Oil 1 H -NMR (CDCI 3 , 200 MHz) δ:1.3 (m, 14H); 1.7 (m, 2H); 2.31 (t, 2H); 2.40 (m, 4H); 3.55 (m, 1 H); 3.70 (m, 4H); 3.85 (t, 2H); 4.22 (m, 2H); 4.43 (t, 1 H); 5.05 (s, 2H); 6.58 (m, 8H); 6.85 (d, 1 H); 7.15 (m, 3H); 7.38 (m, 5H). Step 2: (+,-) cis 7-Hydroxy 4-[4-(morpholinodecyloxy)-phenyl]-3-phenyl-chroman From (+,-) cis 7-Benzyl 4-[4-(morpholinodecyloxy)-phenyl]-3-phenyl-chroman.HCl (122 mg, 0.19 mmol). The evaporated product was evaporated from acetone (x 3) to give a solid. Yield 64 mg (61 %) of (+,-) cis 7-Hydroxy-4[4-(morpholinodecyloxy)-phenyl]-3- phenylchroman.HCI. 1 H -NMR (CDCI 3 , 200 MHz) δ: 1.35 (m, 14H); 1.7 (m, 2H); 2.85 (m, 4H); 3.1 ( , 2H); 3.55 (m, 1 H); 3.82 (m, 4H); 3.85 (t, 2H); 4.22 (m, 2H); 4.43 (t, 1 H); 5.05 (s, 2H); 6.3 (m, 2H); 6.65 (m, 7H); 7.1 (m, 3H). EXAMPLE 6 (+,-) cis 7-Hydroxy 4-[4-(morpholinobutyloxy)-phenyl]-3-phenyl-chroman Step 1 : (+,-) cis 7-Benzyloxy 4-[4-(morpholinobutyloxy)-phenyl]-3-phenyl-chroman (+,-) cis 7-Benzyloxy-4-[4-(4-chlorobutyloxy)-phenyI]-3-phenyl-chroman (300 mg, 0.60 mmol), morpholine (240 mg, 3 mmol), potassium carbonate 165 mg, 1.2 mmol), and potassium iodide (19 mg, 0.12 mmol) in dimethylformamide (5 ml) was stirred at 60°C for 4 days. The reaction mixture was cooled and ether and water was added. The aquous phase was extracted with ether, and the combined organic phases were washed water and brine, dried (magnesium sulphate), and evaporated. The evaporated 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-phenyl- chroman Oil. 1 H -NMR (CDCI 3 , 200 MHz) δ: 1.68 (m,4H); 2.38 (m, 6H); 3.55 (m, 1 H); 3.70 (t, 4H); 3.88 (t, 2H); 4.2 (m, 2H); 4.40 (t, 1 H); 5.03 (s, 2H); 6.56 (m, 8H); 6.83 (d, 1 H); 7.15 (m, 3H); 7.38 (m, 5H). Step 2: (+, -) cis 7-Hydroxy-4-[4-(morpholinobutyloxy)-phenyl]-3-phenyl-chroman (+,-) cis 7-Benzyloxy-4-[4-(morpholinobutyloxy)-phenyl]-3-phenyl-chroman (160 mg, 0.29 mmol) was dissolved in a solution of 1 % hydrochloride in ethanol (5 ml). The solution was added to a 10 % palladium on carbon catalyst, and hydrogenated (1 atm.) overnight. The reaction mixture was filtered and evaporated, The evaporated product crystallised. Yield 130 mg (92 %) of (+,-) cis 7-Hydroxy-4-[4-(morpholinobutyloxy)-phenyl]-3-phenyl- chroman. HCI m.p. 79.8 - 81.8°C The product was identified by 1 H-NMR.

Claims: Claims 1. A compound of the formula I in which substituents R 2 and R 3 are arranged in cis- configuration: wherein: 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 r C 6 -alkyl, C r C 6 - alkyl, C r C 6 -alkoxy and phenyl; R 3 is phenyl substituted with -X-(CH 2 ) n -Y, wherein: X is a valency bond, O or S, n is an integer in the range of 4 to 12, preferably 6 to 12, Y is H, halogen, OH, OR 4 , NHR 4 , NR 4 , NHCOR 4 , NHS0 2 R 4 , CONHR 4 , CONR 4 , COOH, COOR 4 , S0 2 R 4 , SOR 4 , SONHR 4 , SONR 4 , 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 6 -alkyl, C,-C 6 -alkyl and C r C 6 -alkoxy; and R 4 is C r C 6 -alkyl; and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and salts thereof. 2. A compound of the formula I in which substituents R 2 and R 3 are arranged in cis- configuration: wherein: 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 r C 6 -alkyl, C r C 6 - alkyl and C r C 6 -alkoxy; R 3 is phenyl substituted with -X-(CH 2 ) n -Y, wherein: X is a valency bond, O or S, n is an integer in the range of 4 to 12, preferably 6 to 12, Y is H, OH, OR 4 , NHR 4 , NR 4 , NHCOR 4 , NHS0 2 R 4 , CONHR 4 , CONR 4 , COOH, COOR 4 , S0 2 R 4 , SOR 4 , SONHR 4 , SONR 4 , 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-β-alkyl, C r C 6 -alkyl and C r C 6 -alkoxy; and R 4 is d-Cβ-alkyl; and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and salts thereof. 3. A compound according to claim 1 or 2 having the formula wherein R 1 , R 2 and R 3 are as defined above. A compound according to claim 1 or 2 having the formula wherein m is an integer from 2 to10, preferably 4 to 10. 5. A compounds according to claim 1 or 2 having the formula wherein m is as defined above. 6. A compound according to claim 1 or 2 having the formula wherein m is as defined above. A compound according to claim 1 or 2 having the formula wherein m is as defined above and both R 4 independently are as defined above. 8. A compound according to claim 1 or 2 selected from the following: (-)-c/ ' s-7-Hydroxy-3-phenyl-4-(4 (5-pyrrolidinopentoxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (6-pyrrolidinohexyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4- (7-pyrrolidinoheptyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (8-pyrrolidinooctyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (9-pyrrolidinononyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (10-pyrrolidinodecyloxy)phenyl)chromane, (-)-c/s-7-Hydroxy-3-phenyl-4-(4 (11 -pyrrolidinoundecyloxy)phenyl)chromane, (-)-c/ ' s-7-Hydroxy-3-phenyl-4-(4 (12-pyrrolidinododecyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4- (5-pyrrolidinopentoxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4-ι (6-pyrrolidinohexyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4 (7-pyrrolidinoheptyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4 (8-pyrrolidinooctyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4 (9-pyrrolidinononyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4- (10-pyrrolidinodecyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4- (11 -pyrrolidinoundecyloxy)phenyl)chromane, (-)-c/s-6-Hydroxy-3-phenyl-4-(4- (12-pyrrolidinododecyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4- -(5-pyrrolidinopentoxy)phenyl)chromane, (+)-c/ ' s-7-Hydroxy-3-phenyl-4-(4- -(6-pyrrolidinohexyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4- -(7-pyrrolidinoheptyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4- -(8-pyrrolidinooctyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4- (9-pyrrolidinononyloxy)phenyl)chromane, (+)-c/ ' s-7-Hydroxy-3-phenyl-4-(4- (10-pyrrolidinodecyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4' (11 -pyrrolidinoundecyloxy)phenyl)chromane, (+)-c/s-7-Hydroxy-3-phenyl-4-(4- (12-pyrrolidinododecyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4' (5-pyrrolidinopentoxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4 (6-pyrrolidinohexyloxy)phenyl)chromane, (+)-c/ ' s-6-Hydroxy-3-phenyl-4-(4 (7-pyrrolidinoheptyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4 (8-pyrrolidinooctyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(9-pyrrolidinononyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(10-pyrrolidinodecyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(11-pyrrolidinoundecyloxy)phenyl)chromane, (+)-c/s-6-Hydroxy-3-phenyl-4-(4-(12-pyrrolidinododecyloxy)phenyl)chromane, or any mixture thereof including racemic mixtures. 9. A compound according to claim 1 or 2 selected from the following: (±)-cis-4-(4-Hexylphenyl)-7-hydroxy-3-phenylchromane, (+,-) cis 7-hydroxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3-phenyl-chroman, (+,-) cis 4-[4-(6-Dibutylaminohexyloxy)-phenyl]-7-hydroxy-3-phenyl-chroman, (+,-) cis 7-Hydroxy 4-[4-(morpholinobutyloxy)-phenyl]-3-phenyl-chroman, (+,-) cis 7-Hydroxy 4-[4-(morpholinodecyloxy)-phenyl]-3-phenyl-chroman, including the pure enantiomers thereof. 10. A method for the preparation of compounds of formula (I) comprising the steps of: a) reacting a compound of the formula (II) with a compound of the formula (III) ( III ) 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 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 (V) 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) 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 (I); or f) reacting a compound of formula (VI) with trifluoromethane sulphonic acid anhydride to form a compound of the formula (XI) wherein R 5 is as defined above, g) cross-coupling a compound of the formula (XI) with the appropriate cross- coupling partner to form a compound of the formula (XII) wherein R 5 , Y and n are as defined above, h) deprotecting a compound of the formula (XII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (I), i) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XIII) (XIII) wherein R 5 is defined as above, j) deprotecting a compound of the formula (XIII) with a suitable deprotection agent, such as pyridine hydrochloride fusion or boron tribromide, to form a compound of the formula (XIV) (XIV) wherein R 5 is defined as above, k) reacting a compound of the formula (XIV) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula (XV) wherein R 5 is defined as above, and R 8 is H or methoxy, I) deprotecting a compound of the formula (XV) with a suitable deprotection agent, such as sodium or potassium hydroxide in alcohol, to form a compound of formula (XVI) (XVI) wherein R 5 is defined as above, and R 6 is H or methoxy, m) alkylating a compound of the formula (XVI) with an appropriate electrophile to form a compound of the formula (XVll) (XVll) wherein n, R 5 and Y is defined as above, and R 6 is H or methoxy, n) deprotecting a compound of the formula (XVll) 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 (XVIII) (XVIII) wherein n, R 5 and Y is defined as above, o) Alkylating a compound of the formula (XVI) with an appropriate dihalogenated alkane such as 1 ,4-dibromobutane, 1 ,6-dibromohexane, 1 ,8-dibromooctane, 1 ,10-dibromodecane, preferably catalysed by potassium iodide, to form a compound of the formula (XIX) (XIX) wherein n and R 5 is defined as above, R 6 is H or methoxy, and Hal is chloro, bromo, or iodo, p) reacting a compound of the formula (XIX) with an appropriate nucleophile, preferably an amine, to form a compound of the formula (XX) (XX) wherein R 6 is H or methoxy, and Z is NHR 4 , NR 4 , or a C 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-CrCs-alkyl, C r C 6 -alkyl and C 1 -C 6 -alkoxy, and n, R 4 , and R 5 is defined as above, q) deprotecting a compound of the formula (XX) 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 (XXI) (XXI) wherein R 6 is H or methoxy, and Z is NHR 4 , NR 4 , or a C 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 r C 6 -alkyl, C r C 6 -alkyl and C r C 6 -alkoxy, and n, R 4 and R 5 is defined as above. 11. A compound according to any of the claims 1 to 9 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. 12. A compound according to any of the claims 1 to 9 for use in the prevention or treatment of bone loss, osteoporosis, cardiovascular 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 abor- tion, 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 osteoporosis. 13. A pharmaceutical composition comprising an effective amount of a compound according to claims 1 to 9 or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent. 14. A pharmaceutical composition according to claim 13 in the form of an oral dosage unit or parenteral dosage unit. 15. The use of a compound according to any of the claims 1 to 9 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. 16. The use of a compound according to any of the claims 1 to 9 for the preparation of a medicament for use in the prevention or treatment of bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms including flushing, urogenital atrophy, depression, mania and schizophre- nia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenor- rhea, 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 osteoporosis. 17. 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 9. 18. A method of treating or preventing bone loss, osteoporosis, cardiovascular 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 aiding ovarian de- velopment, preferably prevention or treatment of bone loss or osteoporosis, which method comprises administering to a subject in need thereof an effective amount of a compound according to any of the claims 1 to 9. 19. A contraceptive method comprising administering to a male or female mammal an effective amount of a compound according to any of the claims 1 to 9.

Inventors: BURY PAUL STANLEY, CHRISTIANSEN LISE BROWN, JACOBSEN POUL, KANSTRUP ANDERS, TREPPENDAHL SVEND, BURY, PAUL, STANLEY, CHRISTIANSEN, LISE, BROWN, JACOBSEN, POUL, KANSTRUP, ANDERS, TREPPENDAHL, SVEND
Applicants: NOVONORDISK AS, NOVO NORDISK A/S
Application year: 1997
Main classification: C07D311
IPC codes: A61K31, A61P5, A61P19, A61P25, C07D311