AU744403B2 - Novel trans-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes - Google Patents
Novel trans-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes Download PDFInfo
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- AU744403B2 AU744403B2 AU47718/97A AU4771897A AU744403B2 AU 744403 B2 AU744403 B2 AU 744403B2 AU 47718/97 A AU47718/97 A AU 47718/97A AU 4771897 A AU4771897 A AU 4771897A AU 744403 B2 AU744403 B2 AU 744403B2
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- Australia
- Prior art keywords
- phenyl
- trans
- hydroxy
- chromane
- phenylchromane
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- 239000000262 estrogen Substances 0.000 title claims description 70
- 229940011871 estrogen Drugs 0.000 title claims description 69
- 238000011282 treatment Methods 0.000 title claims description 34
- 230000002265 prevention Effects 0.000 title claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 22
- 201000010099 disease Diseases 0.000 title claims description 19
- 208000011580 syndromic disease Diseases 0.000 title claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 154
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 84
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 76
- -1 methoxy, hydroxy Chemical group 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 206010065687 Bone loss Diseases 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 208000001132 Osteoporosis Diseases 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 206010000242 Abortion threatened Diseases 0.000 claims description 9
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 9
- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 claims description 9
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 9
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 9
- 208000008899 Habitual abortion Diseases 0.000 claims description 9
- 206010020112 Hirsutism Diseases 0.000 claims description 9
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- 206010000496 acne Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 230000006408 female gonad development Effects 0.000 claims description 9
- 230000006651 lactation Effects 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 206010021639 Incontinence Diseases 0.000 claims description 7
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- 230000002950 deficient Effects 0.000 claims description 6
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
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- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 claims description 5
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- QRXWEZWALGJSQO-AHKZPQOWSA-N (3r,4r)-3-phenyl-4-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC([C@H]2[C@@H](COC3=CC=C(C=C32)O)C=2C=CC=CC=2)=CC=C1OCCN1CCCC1 QRXWEZWALGJSQO-AHKZPQOWSA-N 0.000 claims description 4
- FEWTWAWFVZLIEF-XTEPFMGCSA-N (3r,4r)-3-phenyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC([C@H]2[C@@H](COC3=CC=C(C=C32)O)C=2C=CC=CC=2)=CC=C1OCCCN1CCCC1 FEWTWAWFVZLIEF-XTEPFMGCSA-N 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
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- ODECIUXODNSCIA-AHKZPQOWSA-N (3r,4r)-3-(4-fluorophenyl)-4-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=C(F)C=C1 ODECIUXODNSCIA-AHKZPQOWSA-N 0.000 claims description 3
- NNJOKTCOFIDQHG-LMSSTIIKSA-N (3r,4r)-3-phenyl-4-[4-(4-pyrrolidin-1-ylbutoxy)phenyl]-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC([C@H]2[C@@H](COC3=CC=C(C=C32)O)C=2C=CC=CC=2)=CC=C1OCCCCN1CCCC1 NNJOKTCOFIDQHG-LMSSTIIKSA-N 0.000 claims description 3
- YNPQNTHVZOELEV-MFMCTBQISA-N (3r,4r)-3-phenyl-4-[4-(5-pyrrolidin-1-ylpentoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCCCCN3CCCC3)=CC=2)=CC=CC=C1 YNPQNTHVZOELEV-MFMCTBQISA-N 0.000 claims description 3
- RFKYLSUUYGYRRM-IGYGKHONSA-N (3r,4r)-3-phenyl-4-[4-(6-pyrrolidin-1-ylhexoxy)phenyl]-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC([C@H]2[C@@H](COC3=CC=C(C=C32)O)C=2C=CC=CC=2)=CC=C1OCCCCCCN1CCCC1 RFKYLSUUYGYRRM-IGYGKHONSA-N 0.000 claims description 3
- XSUBMTWBMHIMSR-XDFJSJKPSA-N (3r,4r)-3-phenyl-4-[4-(7-pyrrolidin-1-ylheptoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCCCCCCN3CCCC3)=CC=2)=CC=CC=C1 XSUBMTWBMHIMSR-XDFJSJKPSA-N 0.000 claims description 3
- WNXOCOSJUXYVPJ-CQTOTRCISA-N (3r,4r)-3-phenyl-4-[4-(8-pyrrolidin-1-yloctoxy)phenyl]-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC([C@H]2[C@@H](COC3=CC=C(C=C32)O)C=2C=CC=CC=2)=CC=C1OCCCCCCCCN1CCCC1 WNXOCOSJUXYVPJ-CQTOTRCISA-N 0.000 claims description 3
- DOPQUFLXONLVEE-AHKZPQOWSA-N (3r,4r)-4-[4-[4-(dimethylamino)butoxy]phenyl]-3-phenyl-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC(OCCCCN(C)C)=CC=C1[C@@H]1C2=CC(O)=CC=C2OC[C@H]1C1=CC=CC=C1 DOPQUFLXONLVEE-AHKZPQOWSA-N 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- GMRIKHKIIWJYBG-WIOPSUGQSA-N ethyl 2-[4-[(3r,4r)-7-hydroxy-3-phenyl-3,4-dihydro-2h-chromen-4-yl]phenoxy]acetate Chemical compound C1=CC(OCC(=O)OCC)=CC=C1[C@@H]1C2=CC=C(O)C=C2OC[C@H]1C1=CC=CC=C1 GMRIKHKIIWJYBG-WIOPSUGQSA-N 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 3
- MOUNBIRCKLXMJL-XTEPFMGCSA-N (3r,4r)-3-phenyl-4-[4-(2-piperidin-1-ylethoxy)phenyl]-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC([C@H]2[C@@H](COC3=CC=C(C=C32)O)C=2C=CC=CC=2)=CC=C1OCCN1CCCCC1 MOUNBIRCKLXMJL-XTEPFMGCSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 230000000052 comparative effect Effects 0.000 claims 7
- WYWQJIZGMRBSFY-AHKZPQOWSA-N (3r,4r)-3-(4-hydroxyphenyl)-4-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1=CC(O)=CC=C1[C@H]1[C@H](C=2C=CC(OCCN3CCCC3)=CC=2)C2=CC=C(O)C=C2OC1 WYWQJIZGMRBSFY-AHKZPQOWSA-N 0.000 claims 2
- XRYHBRYPVSOINX-PUDHBBIYSA-N (3r,4r)-3-phenyl-4-[4-(11-pyrrolidin-1-ylundecoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCCCCCCCCCCN3CCCC3)=CC=2)=CC=CC=C1 XRYHBRYPVSOINX-PUDHBBIYSA-N 0.000 claims 2
- MSZCMMBXIGHNFQ-YBZKQSBQSA-N (3r,4r)-3-phenyl-4-[4-(12-pyrrolidin-1-yldodecoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCCCCCCCCCCCN3CCCC3)=CC=2)=CC=CC=C1 MSZCMMBXIGHNFQ-YBZKQSBQSA-N 0.000 claims 2
- LMHXWDHVXMWULI-XTEPFMGCSA-N (3r,4r)-3-phenyl-4-[4-(2-piperidin-1-ylethoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCN3CCCCC3)=CC=2)=CC=CC=C1 LMHXWDHVXMWULI-XTEPFMGCSA-N 0.000 claims 2
- SFKMEMGGAWLNHS-LMSSTIIKSA-N (3r,4r)-3-phenyl-4-[4-(3-piperidin-1-ylpropoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCCN3CCCCC3)=CC=2)=CC=CC=C1 SFKMEMGGAWLNHS-LMSSTIIKSA-N 0.000 claims 2
- MDJSUOVVRLOVCS-LMSSTIIKSA-N (3r,4r)-3-phenyl-4-[4-(4-pyrrolidin-1-ylbutoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCCCN3CCCC3)=CC=2)=CC=CC=C1 MDJSUOVVRLOVCS-LMSSTIIKSA-N 0.000 claims 2
- NDDKTRSBZBKDLS-MFMCTBQISA-N (3r,4r)-3-phenyl-4-[4-(5-pyrrolidin-1-ylpentoxy)phenyl]-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC([C@H]2[C@@H](COC3=CC=C(C=C32)O)C=2C=CC=CC=2)=CC=C1OCCCCCN1CCCC1 NDDKTRSBZBKDLS-MFMCTBQISA-N 0.000 claims 2
- USRISCCNOFMKPS-CQTOTRCISA-N (3r,4r)-3-phenyl-4-[4-(8-pyrrolidin-1-yloctoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCCCCCCCN3CCCC3)=CC=2)=CC=CC=C1 USRISCCNOFMKPS-CQTOTRCISA-N 0.000 claims 2
- POOKMKUEQPGERL-UZNNEEJFSA-N (3r,4r)-3-phenyl-4-[4-(9-pyrrolidin-1-ylnonoxy)phenyl]-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=CC(OCCCCCCCCCN3CCCC3)=CC=2)=CC=CC=C1 POOKMKUEQPGERL-UZNNEEJFSA-N 0.000 claims 2
- LVOWUOOVASCCHV-WMZHIEFXSA-N (3r,4r)-4-(3,4-dihydro-2h-1,4-benzoxazin-6-yl)-3-phenyl-3,4-dihydro-2h-chromen-6-ol Chemical compound C1([C@@H]2COC3=CC=C(C=C3[C@H]2C=2C=C3NCCOC3=CC=2)O)=CC=CC=C1 LVOWUOOVASCCHV-WMZHIEFXSA-N 0.000 claims 2
- FHDXPSLWTRTWIK-WMZHIEFXSA-N (3r,4r)-4-(3,4-dihydro-2h-1,4-benzoxazin-6-yl)-3-phenyl-3,4-dihydro-2h-chromen-7-ol Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2)O)C=2C=C3NCCOC3=CC=2)=CC=CC=C1 FHDXPSLWTRTWIK-WMZHIEFXSA-N 0.000 claims 2
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- WGOCGUDRZINCHZ-GBXCKJPGSA-N (3r,4r)-4-(4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)-3-phenyl-3,4-dihydro-2h-chromen-6-ol Chemical compound C1([C@H]2[C@@H](C3=CC(O)=CC=C3OC2)C2=CC=C3OCCN(C3=C2)C)=CC=CC=C1 WGOCGUDRZINCHZ-GBXCKJPGSA-N 0.000 claims 2
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- JNSNCCMDOCERET-AHKZPQOWSA-N (3r,4r)-4-[4-[2-(diethylamino)ethoxy]phenyl]-3-phenyl-3,4-dihydro-2h-chromen-7-ol Chemical compound C1=CC(OCCN(CC)CC)=CC=C1[C@@H]1C2=CC=C(O)C=C2OC[C@H]1C1=CC=CC=C1 JNSNCCMDOCERET-AHKZPQOWSA-N 0.000 claims 2
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- SHBRMVVMAMKPPS-AZGAKELHSA-N (3r,4r)-4-[4-[2-[ethyl(methyl)amino]ethoxy]phenyl]-3-phenyl-3,4-dihydro-2h-chromen-6-ol Chemical compound C1=CC(OCCN(C)CC)=CC=C1[C@@H]1C2=CC(O)=CC=C2OC[C@H]1C1=CC=CC=C1 SHBRMVVMAMKPPS-AZGAKELHSA-N 0.000 claims 2
- XFJQTKHQWTZHHZ-AZGAKELHSA-N (3r,4r)-4-[4-[2-[ethyl(methyl)amino]ethoxy]phenyl]-3-phenyl-3,4-dihydro-2h-chromen-7-ol Chemical compound C1=CC(OCCN(C)CC)=CC=C1[C@@H]1C2=CC=C(O)C=C2OC[C@H]1C1=CC=CC=C1 XFJQTKHQWTZHHZ-AZGAKELHSA-N 0.000 claims 2
- CPOLGXKCMAZWRH-BHBYDHKZSA-N benzyl 2-[4-[(3r,4r)-6-hydroxy-3-phenyl-3,4-dihydro-2h-chromen-4-yl]phenoxy]acetate Chemical compound C1=CC([C@H]2[C@@H](COC3=CC=C(C=C32)O)C=2C=CC=CC=2)=CC=C1OCC(=O)OCC1=CC=CC=C1 CPOLGXKCMAZWRH-BHBYDHKZSA-N 0.000 claims 2
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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Description
Title Novel trans-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 trans-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 Any discussion of the prior art throughout the specification should in no way be S. 15 considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
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 20 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 14 inhibiting bone resorption. Among various treatment modalities, estrogen replacement latherapy 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 *o *go *o *oo WO 98/18774 PCT/DK97/00481 2 carbonate on bone loss in post-menopausal women", Ann Intern Med. 87:649-655; Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM 1979, "Estrogen replacement therapy", Obstet Gynecol. 53:277-281) and it is now accepted that estrogens significantly decrease fracture incidence and risk (Krieger N, Kelsey JL, Holford TR, O'Connor T 1982, "An epidemiological study of hip fracture in postmenopausal women", Am J Epidemiol.
116:141-148; Hutchinson TA, Polansky SM, Feinstein AR 1979, "Post-menopausal estrogens protect against fractures of hip and distal radius: A case-control study", Lancet 2:705-709; Paginini-Hill A, Ross RK, Gerkins VR, Henderson BE, Arthur M, Mack TM 1981, "Menopausal oestrogen therapy and hip fractures", Ann Intern Med. 95:28-31; Weiss NS, Ure CL, Ballard JH, Williams AR, Daling JR 1980, "Decreased risk of fractures on the hip and lower forearm with post-menopausal use of estrogen", N Eng J Med.
303:1195-1198).
While the beneficial actions of estrogen replacement therapy on the skeleton are clearly significant, there is also considerable evidence for a positive effect of estrogen on the cardiovascular system. Previous studies have attributed these actions to estrogen's 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.).
WO 98/18774 PCT/DK97/00481 3 In addition to the positive effects of estrogen on bone and cardiovascular system, there are now data which indicate that the central nervous system can benefit from estrogen replacement therapy. Short term studies in human subjects have shown that increased levels of estrogen are associated with higher memory scores in post menopausal women (Kampen DL, Sherwin BB 1994, "Estrogen use and verbal memory in healthy postmenopausal women", Obstetrics and Gynecology, 83(6):979-983). Furthermore, the administration of exogenous estrogen to surgically post menopausal women specifically enhances short-term memory. Moreover, the effects of estrogen on cognition do not appear confined to short-term effects as epidemiological findings indicate that estrogen treatment significantly decreases the risk of senile dementia-Alzheimer's type in women (Paganini-Hill
A,
Henderson VW, 1994, "Estrogen deficiency and risk of Alzheimer's disease in women", Am J Epidemiol, 140:256-261; Ohkura T, Isse K, Akazawa K, Hamamoto M, Yoshimasa Y, Hagino N, 1995, "Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer Type: 7 case reports", Dementia, 6:99-107). While the mechanism whereby estrogens enhance cognitive function is unknown, it is possible to speculate that the direct effects of estrogen on cerebral blood flow (Goldman H, Skelley 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 -4conditions 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 of dysmenorrhea; relief of dysfunctional uterine bleeding; an aid in ovarian development; treatment of acne; diminution of excessive growth of body hair in women (hirsutism); treatment of prostatic carcinoma: and suppression of post-partum lactation [Goodman and Gilman, The Pharmacological Basis of Therapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages 1421-1423].
Even though the beneficial effects of estrogen replacement on a wide variety of organ systems and tissues appear indisputable, the dose and duration of estrogen therapy is also associated with an increased risk of endometrial hyperplasia and carcinoma. The use of concomitant cyclic progestins does reduce the risk of endometrial pathology, but this is achieved at the expense of the return of regular uterine bleeding, a result that is objectionable to many patients. In addition to estrogen's stimulatory effect on the ••15 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, 20 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, contraindicate estrogen's use and reduce patient compliance.
-4a WO 96/21444 discloses the use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of gynaelogical disorders, including endometriosis, dysfunctional bleedings, endometrial cancer, polycystic ovarian syndrome, anovulatoric bleeding and for thinning of the endometrium.
WO 94/20098 discloses the use of 3,4-diarylchromans and their pharmaceutically acceptable salts for the manufacture of pharmaceutical compositions for the treatment of bone loss due to osteoporosis.
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,
S
S
S
there is a continuing need for the development of potent estrogen agonists which can selectively target different body tissues.
Description of the Invention According to a first aspect, the present invention provides a compound of the formula in which substituents R 2 and R 3 are arranged in trans-configuration:
R
3
R
2 wherein: R' is H, COR 4
CONHR
4 CONR SO 2 NR 4 or SO 2 NH 4 a..
a a a..
a a
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-Ci-C 6 -alkyl, Ci-C 6 -alkyl, Ci-C 6 -alkoxy and phenyl;
R
3 is: phenyl substituted with -X-(CH 2 wherein: X is a valency bond, O or S, n is an integer in the range of 1 to 12, Y is H, halogen, OH, OR 4
NHR
4
NR
4
NHCOR
4
NHSO
2
R
4
CONHR
4 CONR 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 -6from 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-Cl-C 6 -alkyl, Ci-C 6 -alkyl and Ci-C 6 -alkoxy;
-(CH
2 )n-Y wherein n and Y are as defined above; or phenyl fused to a C 3
-C
7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, 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
-C
6 -alkyl, Ci-C 6 -alkyl and Ci-C 6 -alkoxy; and
R
4 is CI-C 6 -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.
According to a second aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent.
According to a third aspect, the present invention provides the use of a compound according to any one of the claims 1 to 19 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.
syndromes caused by an estrogen-deficient state in a mammal.
-7- According to a fourth aspect, the present invention provides the use of a compound according to any one of the claims 1 to 19 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 schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen-dependent cancers, post-partum lactation or for use as contraception or an aid in ovarian development, preferably in the prevention or treatment of bone loss or osteoporosis.
Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, not limited to".
For example the term Ci-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, 20 pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl.
7a- 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 ofneuropeptide 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 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 in women (hirsutism); treatment of prostatic carcinoma; and the suppression ofpost-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 a preferred embodiment, the present invention provides a compound of the formula I in which substituents R 2 and R 3 are arranged in trans-configuration: SR3 •o
R'O'
7b wherein: R' is H, COR 4
CONHR
4 CONR SO 2 NR or SO 2
NHR
4
R
2 is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 trihalo-C 1
-C
6 -alkyl, Ci-C 6 -alkyl and Ci-C 6 -alkoxy;
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 4
NHR
4 NR NHCOR 4 NHS0 2
R
4
CONHR
4 CONR COOH, :oOO 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 trihalo-C 1
-C
6 -alkyl, Ci-C 6 -alkyl and Ci-C 6 -alkoxy;
-(CH
2 )n-Y wherein n and Y are as defined above; or
S
S* phenyl fused to a C 3
-C
7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, o 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, Ci-C 6 -alkyl and Ci-C 6 -alkoxy; and 7c
R
4 is CI-C 6 -alkyl; and optical and geometrical isomers, pharmaceutically acceptable esters, ethers and salts thereof The substituent R 1 0 of 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 Ia or lb are preferred:
R
R 1 0 R'00 or 0 (lb *0 WO 98/18774 PCT/DK97/00481 8 wherein R 1
R
2 and R 3 are as defined above.
In a preferred embodiment, the present invention is concerned with trans-forms of the compounds of the following formula: 0 COOR wherein R is H or C,-C 6 alkyl.
In another preferred embodiment, the present invention is concerned with trans-forms of the compounds of the following formula: 0 (CH 2 )m
HO
0 wherein m is an integer from 0 to In another preferred embodiment, the present invention is concerned with trans-forms of the compounds of the following formula: WO 98/18774 PCT/DK97/00481
(CH
2 )m
N
C)
wherein m is as defined above.
In another preferred embodiment, the present invention is concerned with trans-forms of the compounds of the following formula: O (CH 2 m
N
HO wherein m is as defined above.
In another preferred embodiment, the present invention is concerned with trans-forms of the compounds of the following formula: WO 98/18774 PCT/DK97/00481 0 (CH 2 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 trans-forms of the compounds of the following formula:
NR
4
HO
0 wherein R 4 is as defined above.
In another preferred embodiment, the present invention is concerned with trans-forms of the compounds of the following formula: WO 98/18774 WO 9818774PCT/DK97/00481 wherein R 4 is as defined above.
In another preferred embodiment, the present invention is concerned with trans-forms of the compounds of the following formula: wherein R' represents one or more of the following substituents: methoxy, hydroxy, trifluormethyl, fluoro and chloro.
The most preferred compounds are the following: (+)-trans-4-(4-(Carboxymethoxy)phenyl)q..hydroxy-3-phenylchrom ane, (-)-trans- 4 4 -(Carboxymethoxy)phenyl)7hydroxy-3phenylchromane, (+)-trans- 7 -Hyd roxy-4(4.(methoxycarbo nylmethoxy)phenyl).3-phenylch ro mane, (-)-trans- 7 -Hydroxy-4-(4-(methoxycarbonylmethoxy)phenyl).3-phenylchromane, WO 98/18774 WO 9818774PCT/DK97/00481 12 (+)-trans- 4 4 -(Ethoxycarbonylmethoxy)phenyl).q..hydroxy-3-phenyichromane, (-)-trans- 4 -(4-(Ethoxycarbonylmethoxy)phenyl)-7-hydroxy3phenylchromane, (+)-trans- 4 4 -(Benzyloxycarbonymethoxy)pheny).q-hydroxy-3phenylchromane, (-)-trans- 4 4 -(Benzyloxycarbonylmethoxy)pheny)-7-hydroxy..3.phenylchromane, (+)-trans- 7 -Hydroxy-3-phenyl..4.(4-(2..pyrrolidinoethoxy)pheny!)chromane, (-)-trans- 7 -Hydroxy-3-phenyI-4-(4-(2-pyrrolidinoethoxy)phenyI)chromane, (+)-trans- 7 -Hydroxy-3-phenyi-4-(4-(3pyrrolidinopropoxy)phenyI)chromane, (-)-trans- 7 -H yd roxy-3-phenyl-4-(4-(3-pyrrolidn opro poxy)phenyI) ch roma ne, (+)-trans- 7 -Hydroxy3phenyl-4(4(4pyrrolidinobutoxy)pheny)chromane, (-)-trans- 7 -Hydroxy-3-phenyI-4-(4(4pyrrolidinobutoxy)phenyI)chromane, (+)-trans- 7 -Hydroxy3-phenyI4-(4-(5pyrrolidinopentoxy)phenyl)chromane, (-)-trans- 7 -Hydroxy-3-phenyl-4-(4(5pyrrolidinopentoxy)phenyl)chromane, (+)-trans- 7 -Hydroxy3phenyl-4(4(6pyrroidinohexyoxy)phenyl)chromane, (-)-trans- 7 -Hydroxy-3-phenyI4.(4-(6-pyrrolidinohexyloxy)phenyl)chromane, (+)-trans- 7 -Hydroxy-3-phenyl.4.(4.(7-pyrrolidinoheptyloxy)phenyI)chromane, (-)-trans- 7 -Hydroxy-3-phenyl-4-(4-(7pyrrolidinoheptyloxy)phenyl)chromane, (+)-trans- 7 -Hydroxy-3-pheny.4.(4.(8-pyrrolidinooctyloxy)phenyI)chromane, (-)-trans- 7 -Hydroxy-3.phenyl-4(4(8pyrroidinooctyoxy)phenyl)chrom ane, (+)-trans- 7 -Hydroxy-3-phenyl-4(4-(9pyrroidinononyloxy)phenyl)chromane, (-)-trans- 7 -Hydroxy-3-phenyI..4(4(9-pyrrolidinononyloxy)pheny,)chromane, (+)-trans-7-Hydroxy.3-.phenyl.4-(4.(1 O-pyrrolidinodecyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3-phenyl-4-(4-(l O-pyrrolidinodecyloxy)phenyl)chromane, )-trans-7-Hydroxy-3-phenyl-4-(4.(1I -pyrrolidinoundecyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3-phenyt4-.(4-(1 1 -pyrrolidinoundecyloxy)phenyl)chromane, (+)-trans- 7 -Hydroxy-3-pheny-4(4(12-pyrrolidinododecyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3-.phenyl-4-.(4-(1 2 -pyrrolidinododecyloxy)phenyl)chromane, (+)-trans- 7 -Hydroxy..3-phenylA..(4..(2.piperidinoethoxy)phenyI)chromane, (-)-trans- 7 -Hydroxy-3-pheny4(4(2piperidinoethoxy)phenyl)chromane, (+)-trans-7-Hydroxy.3-phenylA...(4.(3.pi peridinopropoxy)phenyl)chromane, (-)-trans- 7 -Hydroxy-3-phenyI.4(4(3piperidinopropoxy)phenyl)chromane, (+)-trans-7-Hydroxy-3phenyl4.(4.(4-pi peridinobutoxy)phenyl)chromane, (-)-trans- 7 -Hydroxy3phenyl.4-(4-(4piperidinobutoxy)phenyl)chromane, WO 98/18774 WO 9818774PCT/DK97/00481 13 (+)-trans- 7 -Hyd roxy-4(4- (2-perhyd ro azepi noeth oxy) phenyl)3p henylch romane, (-)-trans-7-Hydroxy-4-(4-(2-perhydroazepinoethoxy) phenyl)-3-phenylchromane, -trans- 7 Hyd roxy-4-(4-(3..perhydroaze pin opro poxy) phenyl)-3-phenylch rom ane, (-)-trans- 7 -Hydroxy-4-(4-(3-perhydroazepinopropoxy)phenyl)3phenylchromane, (+)-trans- 7 -HydroxyA4-(4-(4-perhydroazepinobutoxy)pheny).3-phenylchromane, (-)-trans- 7 -Hydroxy-4-(4-(4-perhydroazepinobutoxy)phenyl).3-phenylchromane, (+)-trans- 4 4 2 -Dimethylaminoethoxy)phenyl)7hydroxy-3-phenylchromane, (-)-trans- 4 2 -Dimethylaminoethoxy)phenyl)..7-hydroxy.3-phenylchromane, (+)-trans- 4 4 2 -Diethylaminoethoxy)phenyl)7hydroxy-3phenyjchromane, (-)-trans- 4 4 2 -Diethylaminoethoxy)phenyl)-7-hydroxy-3phenylchromane, (+)-trans-4-( 4 2 -(N-EthylIN.methylamino)ethoxy)pheny)7hydroxy3phenylchromane, (-)-trans- 4 4 2 -(N-Ethy-Nmethyamno)ethoxy)pheny)7hydroxy3phenylchromane, (+)-trans- 4 4 3 -Dimethylaminopropoxy)phenyl).7-hydroxy..3-phenylchromane, (-)-trans- 4 -(4-(3-Dimethyiaminopropoxy)phenyl)-7-.hydroxy.3-phenylchromane, (+)-trans- 4 4 4 Dimethylaminobutoxy)phenyl)7hydroxy3phenylchromane, (-)-trans- 4 -(4-(4-Dimethylaminobutoxy)phenyl).7-hydroxy.3.phenylchromane, (+)-trans-4-(2,3-Dihydro- 1, 4 -benzoxazin-6-yI)-7-hydroxy-3-phenylchromane, 3-Dihydro- 1, 4 -benzoxazin-6-yI)-7-hydroxy-3-phenylchromane, (+)-trans-7-Hydroxy-4-.(4-methyl.2, 3-dihyd ro-1 ,4-benzoxazin-6-yI)-3-phenylch rom ane, (-)-trans-7-Hydroxy-4-(4-methyl.2,3-dihydro- 1 ,4-benzoxazin-6-yI)-3-phenylchrom ane, (+)-trans-4-(4-Ethy.2 3-dihydro-1 4 -benzoxazin-6-yI)-7-hydroxy-3-phenylchromane, (-)-trans-4-(4-Ethyl..2,3-dihydro-1 4 -benzoxazin-6-yI)-7-hydroxy-3-phenylchromane, (+)-trans- 7 -Hydroxy-3.(4..hydroxyphenyl)4(4-(2pyrrolidnoethoxy)phenyl)chromane, (-)-trans- 7 -Hydroxy-3-(4-hydroxypheny)4(4(2pyrrolidinoethoxy)phenyl)chromane, (+)-trans- 7 -Hydroxy-3-.(4trifluoromethylphenyl)4(4(2pyrrolidinoethoxy)phenyl)chromane, (-)-trans- 7 -Hydroxy-3-(4-trifuoromethypheny4...-(4-(2pyrrolidinoethoxy)phenyl)chromane, (+)-trans-7-Hydroxy-3(4fluoropheny)4b(4.(2pyrroid inoethoxy)phenyl)ch romane, (--rn--yrx--4furpey)4(-2proiiotoypey~hoae (+)-trans- 3 4 -Chlorophenyl)7-hydroxy.4.(4..(2.pyrrolidinoethoxy)phenyl)chromane, (-)-trans- 3 -(4-Chloropheny)7hydroxy.4-(4(2pyrroidinoethoxy)phenyl)chromane, (+)-trans- 3 3 ,4-Dimethoxyphenyly..7-hydroxy4-(4-(2-pyrroidinoethoxy)phenl)chromane, (-)-trans- 3 -(3,4-Dimethoxyphenyl)7.hydroxy-4(4-(2-pyrroidinoethoxy)phenyl)chromane, WO 98/18774 WO 9818774PCTIDK97/00481 14 (+)-trans-7-Hydroxy-3-(pentafluorophenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (-)-trans- 7 -Hydroxy-3-(pentafluorophenyl)-4-(4-(2-pyrroiidinoethoxy)phenyl)chromane, (+)-trans-4-(4-(Carboxymethoxy)phenyl)-6-hydroxy-3-phenylchromane, (-)-trans-4-(4-(Carboxymethoxy)phenyl)-6-hydroxy-3-phenylchromane, (+)-trans-6-Hydroxy-4-(4-(methoxycarbonylmethoxy)phenyl)-3.phenylchromane, (-)-trans-6-Hydroxy-4-(4-(methoxycarbonyl methoxy) phenyl)-3-phenylchromane, (+)-trans-4-(4-(Ethoxycarbonylmethoxy)phenyl).6-.hydroxy.3.phenylchromane, (-)-trans- 4 -(4-(Ethoxycarbonylmethoxy)phenyI)-6-hydroxy-3-phenylchromane, (+)-trans-4-(4-(Benzyloxycarbonylmethoxy)phenyl)..6hydroxy3phenylchromane, (-)-trans-4-(4-(Benzyloxycarbonytmethoxy)phenyl)-6-hydroxy3phenylchromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-(3-pyrrolidinopropoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(3-pyrrolidinopropoxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenylkb(4-(4-pyrrolidinobutoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(4-pyrrolidinobutoxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-(5-pyrrolidmnopentoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(5-pyrrolildnopentoxy)phenyt)chromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-(6-pyrrol idinohexyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl..4-(4-(6-pyrrolidinohexyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyk4(4-(7-pyrrolidinoheptyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyi-.4-(4-(7-pyrrolidinoheptyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl.4-(4-(8.pyrrol idinooctyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(8-pyrrolidinooctyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-.(9..pyrrolidinononyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(9-pyrrolidmnononyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4.(1 0-pyrrolidinodecyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(1 0-pyrrolidinodecyloxy)phenyl)chromane, (-')-trans-6-Hydroxy-3-phenyl-4-(4-(1 1-pyrrolidinoundecyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-( 1 -pyrrolidinoundecyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl-4.(4.(1 2-pyrrolidinododecyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-( 12-pyrrolidinododecyloxy)phenyl)chromane, WO 98/18774 WO 9818774PCTIDK97/00481 (+)-trans-6-Hydroxy-3-phenyl4(4-(2-piperidinoethoxy)phenyl)chromane, (-)-trans- 6 Hydroxy-3-phenyl-4-(4-(2-piperidinoethoxy)pheny;)chromane, (+)-trans- 6 -Hyd roxy-3-phenyl4-(4-(3-piperidino pro poxy) phenyl) ch rom ane, (-)-trans- 6 -Hyd roxy-3-phenyl-4-(4- (3-piperidi no pro poxy)phenyl)ch roma ne, (+)-trans-6-Hydroxy-3-phenyl-4-(4.(4-piperidinobutoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(4-piperidinobutoxy)phenyl)chromane, (+)-trans- 6 -Hydroxy-4-(4-(2-perhydroazepinoethoxy)phenyjl.3-phenylchromane, (-)-trans- 6 -Hydroxy-4-(4-(2-perhydroazepinoethoxy)phenyl)-3-phenylchromane, (+)-trans- 6 -Hydroxy-4-(4(3..perhydroazepinopropoxy)phenyl)-3phenylchromane, (-)-trans- 6 -Hydroxy-4-(4-(3-perhydroazepinopropoxy)phenyl)3phenylchromane, (+)-trans- 6 -Hydroxy-4-.(4(4perhydroazepinobutoxy)phenyl)3phenylchromane, (-)-trans- 6 -Hydroxy-4-(4-(4-perhydroazepinobutoxy)phenyj)..3-phenylchromane, 4 trans--(4-(2-Dimethylaminoethoxy)phenyl).6-.hydroxy3-phenylchromane, (-)-trans- 4 -(4-(2-Dimethylaminoethoxy)phenyly6hydroxy-3-phenylchromane, (+)-transA4-(4-(2-Diethylaminoethoxy)phenyl).6..hydroxy-3-phenylchromane, (-)-trans-4-(4-(2-Diethy lam inoethoxy) phenyy.6-.hyd roxy-3..phenylch romane, (+)-trans- 4 4 -(2-(N.EthyI..Nmethylamino)ethoxy)pheny)6hydroxy3phenylchromane, (-)-trans- 4 4 2 -(N-Ethyl-N-methyamino)ethoxy)phenyl)-6-hydroxy-3phenyichromane, (+)-trans- 4 -(4-(3-Dimethylaminopropoxy)phenyl)-6hydroxy-3-phenylchromane, (-)-trans- 4 4 -(3-Dimethylaminopropoxy)phenyl6hydroxy-3phenylchromane, (+)-trans-4-(4-(4..Dimethylaminobutoxy) phenyl)-6-hydroxy-3-phenylchromane, (-)-trans- 4 -(4-(4-Dimethylaminobutoxy)phenyl)-6hydroxy-3-phenylchromane, (+)-trans-4-(2,3-Dihydro-1, 4 -benzoxazin-6-yi)-6-hydroxy-3-phenyichromane, 3-Dihydro-1 4 -benzoxazin-6-yI)-6-hydroxy-3-phenylchromane, (+)-trans-6-Hydroxy-4-(4-methyl-2, 3-dihydro-1 ,4-benzoxazin-6-yI)-3-phenylchromane, (-)-trans-6-Hydroxy-4-(4-methyl.2,3-dihydro-1 ,4-benzoxazin-6-yI)-3-phenyichromane, (+)-transA4-(4-Ethylk2, 3-dihydro- 1,4-benzoxazin-6-yI)-6-hydroxy-3-phenytchromane, (-)-trans-4-(4-Ethyl-2 1 3-dihydro- 1, 4 -benzoxazin-6-yI)-6-hydroxy-3-phenylchromane, (+)-trans- 6 -Hydroxy-.3-(4-hydroxyphenyl)A..(4-.(2-pyrrolidinoethoxy)phenyl)chromane, (-)-trans- 6 -Hydroxy-3-(4-hydroxypheny)4(4-(2pyrroidinoethoxy)pheny)chromane, (+)-trans- 6 -Hydroxy-3-(4-trifluoromethylphenyl)-4(4(2pyrroidinoethoxy)phenyI)chromane, (-)-trans-6-Hydroxy-3-(4-trifluoromethylphenyl)-4(4-(2-pyrrol idinoethoxy)phenyl)chromane, WO 98/18774 WO 9818774PCT/DK97/00481 16 (+)-trans- 6 -Hydroxy-3-(4 4 fluorophenyl)..4.(4(2pyrrolidinoethoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-(4-fluorophenyl)-4-(4-(2-pyrrolidi noethoxy)phenyl)chromane, (+)-trans- 3 4 -Chlorophenyl)..
6 .hydroxy4(4-(2pyrrolidinoethoxy)phenyl)chromane, (-)-trans-3-(4-Chlorophenyl)-6-hydroxy-4-(4-(2-pyrrolid inoethoxy)phenyl)chromane, (+)-trans- 3 3 4 -Dimethoxyphenyl)..6.hydroxy4.(4-(2pyrrolidinoethoxy)phenyl)chromane, (-)-trans- 3 3 4 -Dimethoxyphenyl)-6-hydroxy4-.(4-(2pyrrolidinoethoxy)phenyl)chromane, (+)-trans- 6 -Hydroxy- 3 (pentafluorophenyl).4(4-(2-.pyrrolidinoethoxy)phenyl)chromane, (-)-trans- 6 -Hydroxy- 3 -(pentafluorophenyl)-4(4(2.pyrrolidinoethoxy)phenyI)chromane, and any mixture thereof, including racemic mixtures.
The following compounds also form part of the disclosure of the present invention: (±)-trans- 7 -Hydroxy-3-phenyl-4(4-(2-pyrrolidinoethoxy)phenyl)chromane, (±)-trans- 7 -Hydroxy-3-(4-fluorophenyl)-4-.(4-(2-.pyrrolidinoethoxy)phenyl)chromane, (±)-trans- 7 -Hydroxy-3-(4-fluorophenyl)A...(4.(2-.piperidinoethoxy)phenyl)chromane, 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, Sim, Bull. Singapore Natl. Inst. Chem.
22, 69-74, 1994.
However, the invention is furthermore concerned with a general method for the preparation of compounds of formula comprising the steps of: a) reacting a compound of the formula (11) WO 98/18774 PCT/DK97/00481 with a compound of the formula (III)
(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,-C 6 -alkyl, C,-C 6 -alkyl and
C,-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)
OCOCH
3
R
(IV)
WO 98/18774 PCT/DK97/00481 18 wherein R 5 is as defined above, b) reducing a compound of the formula (IV) with a suitable hydride reducing agent to form a compound of formula (V)
OH
wherein R 5 is as defined above, c) hydrogenating a compound of the formula in the presence of a suitable catalyst to form a compound of the formula (VI) with a 3,4-cis configuration wherein R 5 is as defined above, d) alkylating a compound of the formula (VI) with an appropriate electrophile to form a compound of the formula (VII) WO 98/18774 PCT/DK97/00481 (CH2) n--Y
(VII)
wherein n, R 5 and Y are as defined above, e) epimerizing a compound of the formula (VII) with a suitable base to form a compound of the formula (VIII) with a 3,4-trans configuration
S(CH
2 n-Y o 0 wherein n, R 5 and Y are as defined above, f) deprotecting a compound of formula (VIII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula wherein R' is hydrogen; or g) nitrating a compound of the formula (VI) with a suitable nitration agent to form a compound of the formula (IX) WO 98/18774 PCT/DK97/00481 wherein R 5 is as defined above, h) reducing a compound of the formula (IX) with a suitable reducing agent, preferably by catalytic hydrogenation, to form a compound of the formula (X) wherein R 5 is as defined above, i) cyclizing a compound of formula with an appropriate agent to form a compound of the formula (XI) or (XII) WO 98/18774 WO 9818774PCT/DK97/00481 21 R 4
NR
4 0 (X I) 0 N .I o r 0XI wherein R' and R' are as defined above, j) epimerizing a compound of the formula (Xl) or (XII) with a suitable base to form a compound of the formula (XIII) or (XIV) with a 3,4-trans configuration
(XIII)
or WO 98/18774 PCT/DK97/00481 22
R
4 O N 0 (XIV) wherein R 4 and R 5 are as defined above, k) deprotecting a compound of the formula (XIII) or (XIV) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (I) wherein R 1 is hydrogen; or I) reacting a compound of formula (VI) form a compound of the formula (XV) with trifluoromethane sulphonic acid anhydride to (Xv) wherein R 5 is as defined above, m) cross-coupling a compound of the formula (XV) with the appropriate cross-coupling partner to form a compound of the formula (XVI) WO 98/18774 PCT/DK97/00481
(XVI)
wherein n, R 5 and Y are as defined above, n) epimerizing a compound of the formula (XVI) with a suitable base to form a compound of the formula (XVII) with a 3,4-trans configuration
(XVII)
wherein n and R 5 are as defined above, o) deprotecting a compound of the formula (XVII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the formula (I) wherein R 1 is hydrogen; or p) cyclizing a compound of the formula (XVIII) WO 98/18774 PCT/DK97/00481
(XVIII)
wherein R 5 is as defined above, with paraformaldehyde in the presence of dimethylamine to form a compound of the formula (XIX)
(XIX)
wherein R 5 is as defined above, q) reacting a compound of the formula (XIX) with the appropriate Grignard reagent to form a compound of the formula (XX)
Y
(CH2)n (XX) 0 (xx) wherein n, R 5 and Y are as defined above, r) hydrogenating a compound of the formula (XX) in the presence of a suitable catalyst to form a compound of the formula (XXI) with a 3,4-cis configuration WO 98/18774 PCT/DK97/00481
Y
(CH2) n
(XXI)
wherein n, R 5 and Y are as defined above, s) epimerizing a compound of the formula (XXI) with a suitable base to form a compound of the formula (XXII) with a 3,4-trans configuration,
Y
I
(CH2) n I I 0
(XXII)
wherein n, R 5 and Y are as defined above, t) deprotecting a compound of formula (XXII) with a suitable deprotection agent, preferably by pyridine hydrochloride fusion, to form a compound of the general formula wherein R' is hydrogen; or u) reacting a compound of the formula wherein R 1 is hydrogen with the appropriate carboxylic acid or sulphonic acid derivative to form a compound of the formula wherein R 1 is COR 4
CONHR
4 CONR SO 2 NR or SO 2
NHR
4 wherein R 4 is as defined above.
v) reacting a compound of the formula (VI) with methanesulfonylchloride to form a compound of the formula (XXIII) WO 98/18774 PCT/DK97/00481 26
O
0
.S
o
R
0 0
(XXIII)
wherein R 5 is defined as above, w) deprotecting a compound of the formula (XXIII) with a suitable deprotection agent, such as pyridine hydrochloride fusion or boron tribromide, to form a compound of the formula (XXIV) o 'o 0
R
HO
(XXIV)
wherein R 5 is defined as above, x) reacting a compound of the formula (XXIV) with a suitable protection agent, such as benzyl bromide or 4-methoxybenzyl bromide, to form a compound of formula (XXV) WO 98/18774 PCT/DK97/00481 27 0 0 R
(XXV)
wherein R 5 is defined as above, and R 6 is H or methoxy, y) deprotecting a compound of the formula (XXV) with a suitable deprotection agent, such as sodium or potassium hydroxide in alcohol, to form a compound of formula
(XXVI)
OH
R
6
R
(XXVI)
wherein R 5 is defined as above, and R 6 is H or methoxy, z) alkylating a compound of the formula (XXVI) with an appropriate electrophile to form a compound of the formula (XXVII) WO 98/18774 PCT/DK97/00481 28 O/(CH2),-Y
R
6
(XXVII)
wherein n, R' and Y is defined as above, and R 6 is H or methoxy, aa) deprotecting a compound of the formula (XXVII) with a suitable deprotection agent, preferably catalytic hydrogenation for R 6 equals H or a strong acid for R 6 equals methoxy, to form a compound of the formula (XXVIII)
(XXVIII)
wherein n, R s and Y is defined as above, bb) Alkylating a compound of the formula (XXVI) with an appropriate dihalogenated alkane such as 1,2-dibromoethane, 1-bromo-2-chloroethane, 1,4-dibromobutane, WO 98/18774 PCT/DK97/00481 29 1,6-dibromohexane, 1,8-dibromooctane, 1,10-dibromodecane, preferably catalysed by potassium iodide, to form a compound of the formula (XXIX)
O/(CH
2 Hal
R
6
R
O
o
(XXIX)
wherein n and R 5 is defined as above, R' is H or methoxy, and Hal is chloro, bromo, or iodo, cc) reacting a compound of the formula (XXIX) with an appropriate nucleophile, preferably an amine, to form a compound of the formula (XXX)
(XXX)
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, WO 98/18774 PCT/DK97/00481 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, dd) deprotecting a compound of the formula (XXX) with a suitable deprotection agent, preferably catalytic hydrogenation for R 6 equals H or a strong acid for R 6 equals methoxy, to form a compound of the formula (XXXI)
(XXXI)
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 1
-C
6 -alkyl, Ci-Cr-alkyl and C,-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 monodemethylation with hydrobromic acid in acetic acid.
The starting deoxybenzoins of the formula (XVIII) are easily prepared via the Hoesch reaction of the appropriate dimethyl ether and the appropriate substituted phenyl acetic acid derivative followed by selective monodemethylation by hydrobromic acid in acetic acid.
WO 98/18774 PCT/DK97/00481 31 Optical pure compounds of formula can be obtained by introducing in the above method a resolution step. The resolution can be carried out after any step of the process which results in a racemic mixture of enantiomers. Any resolution technique may be used to separate a (-)-enantiomer and/or a (+)-enantiomer from a racemic mixture, including diastereomeric salt formation and chiral HPLC.
The expression "appropriate electrophile" typically means an alkylhalogenide of the formula
Y-(CH
2 )n-Hlg, wherein Y is as defined above and HIg is CI, Br or I.
The cyclization step of the above method can be performed with for example a suitable activated carboxylic acid derivative followed by dehydration.
The expression "appropriate cross-coupling partner" typically means an organometallic reagent together with a transition metal catalyst, for example a Grignard reagent with a Ni(0) catalyst.
The expression "appropriate Grignard reagent" typically means an organometallic compound of the formula M-(CH 2 wherein M is MgHIg, HIg is CI, Br or I and Y is as defined above.
The epimerization of 3,4-cis chromans to 3,4-trans chromans by means of a base has previously been described by A.K. Scrivastava, J. Lal, R.C. Gupta and P.K. Grover in Indian J. Chem. 333, 773-4, 1994.
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 estrogendeficient state in a mammal, comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
WO 98/18774 PCT/DK97/00481 32 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.
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-17(f-estradiol (1711-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-171-E2. For each assay, fresh aliquots of cytosol are thawed on the day of analysis and diluted with assay buffer to ca. 3 mg cytosol protein/ml. The assay buffer (PB) is as follows: 10 mM K 2
HPO
4
/KH
2
PO
4 1.5 mM K 2
EDTA,
mM monothioglycerol, 10 mM Na 2 MoO 4 .2H 2 0, 10 glycerol pH 7.5. Radio-inert WO 98/18774 PCT/DK97/00481 33 17B-E2 is obtained from Sigma.
Test solutions are prepared in appropriate solvents (ethanol or DMSO) at a concentration of 8 x 10-3M and serial dilutions prepared with PB or DMSO. Aliquots of 10 pi are incubated in duplicate for each concentration tested in microtitre plates to which have been added 20 pl 3 H-171-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 4 0 C. DCC background counts are assessed using 50 pl of 0.3% BSA in PB in lieu of cytosol.
To separate bound and free 3 H-17(-E2, Titertek plates are centrifuged for 10 min (800 x g) at 4 0 C and aliquots of 100 pi 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 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 WO 98/18774 PCT/DK97/00481 34 BMD due to estrogen deficiency in ovariectomized rodents. Following ovariectomy (the surgical removal of the ovaries), the animals are treated with vehicle, 1713-E2 as a positive control, and/or other estrogen agonists. The objective of these investigations is to evaluate the ability of the compounds of this invention to prevent bone loss in rodent models of human disease.
Female Sprague-Dawley rats (ca. 3 to 5 months old), or female Swiss-Webster mice (ca.
3 to 5 months old) underwent bilateral ovariectomy or sham surgery. Following recovery from anesthesia the animals are randomized to the following groups, minimum of 8 animals per group: sham animals treated with vehicle; ovariectomized animals treated with vehicle; ovariectomized animals treated with 25 pg estradiol/kg; and ovariectomized animals treated with 200 pg/kg of test compound.
All compounds are weighed and dissolved in vehicle solvent in sterile saline and the animals are treated daily via subcutaneous injections for 35 days. At the conclusion of the day protocol, the animals are sacrificed and the femora are excised and cleaned of adherent soft tissue. In rats, the distal 1 cm of the defleshed femora are removed with a diamond wheel cut-off saw and fixed in 70% ethyl alcohol (in mice the distal .5 cm are removed and fixed). Following fixation in 70% ethyl alcohol (EtOH) an automated tissue processor was used to dehydrate the bone specimens in an ascending series of alcohol to 100%. The dehydration program was followed by defatting in chloroform and rehydration in distilled water. All automated tissue processing occurred under vacuum. The hydrated bones were weighed in air and weighed while suspended in water on a Mettler balance 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 WO 98/18774 PCT/DK97/00481 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 p1 of 5% EDTA/1 ml of blood. Following centrifugation at 2500 rpm for minutes at 200 C the plasma was removed and stored at -200 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 WO 98/18774 PCT/DK97/00481 36 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 monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Ampoules are convenient unit dosage forms.
Tablets, dragees, or capsules having talc and/or carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch, are 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.
WO 98/18774 PCT/DK97/00481 37 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.
AvicelTM 31.4 mg Amberlite
TM
IRP 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.
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 the appended claims.
WO 98/18774 PCT/DK97/00481 38 EXAMPLE 1 (+)-trans- 7 -Hydroxv-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenvlchromane Step 1: 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 I) at 70 °C and added to a suspension of lithiumaluminium 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 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 WO 98/18774 PCT/DK97/00481 39 4-(4-Hydroxyphenyl)-7-methoxy-3-phenyl-3-chromene (77.7g) was dissolved in ethanol (1500 ml) at 50 OC. Palladium on carbon, 10 50 wet (6g) was added to the solution and the mixture was hydrogenated at 55 oC and 1 atmosphere for 8 hours.
The catalyst was filtered off, while the suspension was warm, and the filtrate evaporated to an oil which solidified during the evaporation.
Yield 74.3 g (95 m.p. 188-190 OC. The product was identified by 1 H-NMR and elemental analysis.
Step 3: (±)-cis-7-Methoxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane cis-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane (74.3 g) was dissolved in a mixture of toluene (700 ml), water (12 ml) and sodium hydroxide (24.3 g) by heating the mixture to 2-Chloroethylpyrrolidin hydrochloride (46.2 g) was added in six portions at 75 °C with half an hour between each portion. After the last addition the mixture was heated at 75 oC for 4 hours. Water (1000 ml) was added and the mixture stirred until all salt was dissolved. The aqueous phase was separated and extracted with another portion of toluene (300 ml). The combined organic phases was dried over potassium carbonate and 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 of (±)-cis-7-methoxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane. M.p. 113-114*C. The product was identified by 'H-NMR and elemental analysis.
Step 4: WO 98/18774 PCT/DK97/00481 (±)-trans-7-Methoxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane cis-7-Methoxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (5.2 g) was dissolved in a solution of dimethyl sulfoxide (12.5 ml) and potassium hydroxide (0.55 g) at 70 oC for 5 hours. The reaction mixture was cooled down to room temperature. Water ml) was added. The mixture was stirred for a quarter of an hour and the sticky precipitate was filtered off and washed several times with water before further reaction.
Yield 2.3 g, of (±)-trans-7-methoxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane. The product was identified by 'H-NMR.
Step (±)-trans-7-Hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane trans-7-Methoxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (2 g) was dissolved in melted pyridinium chloride, prepared from a mixture of pyridine (10 ml) and conc.
hydrochloric acid where the water has been removed by distillation at 140 oC. The mixture was heated for 75 min. Cooled down to room temperature. Water was added (15 ml) and pH adjusted to 12 with sodium hydroxide (32.5 The mixture was extracted with toluene ml). The organic phase was separated, dried over potassium carbonate and evaporated.
The resulting oil was purified by column chromatography on two successive silica gel columns, the first using 1:1 ethyl acetate/methanol as the eluent, the second using 1:1 dichloromethane/methanol eluent.
Yield 0.14 g of (±)-trans-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane. The product was identified by 'H-NMR and elemental analysis.
WO 98/18774 PCT/DK97/00481 41 EXAMPLE 2 (±)-trans- 7 -Hydroxy- 3 4 -fluorophenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane Step 1: 4-(4-Acetoxyphenyl)-3-(4-fluorophenyl)-7-methoxy-coumarin A mixture of 2 -hydroxy-4-methoxyphenyl)-(4-hydroxyphenyl)-methanone (7.33 g, 30.0 mmol), acetic anhydride (15 ml), triethylamine (5.5 ml, 39.5 mmol), and 4-fluorophenyl acetic acid (4.63 g, 30.0 mmol) was stirred at 135°C for 18 h, and the resulting orange coloured solution poured into water (120 ml) and stirred for 3 h. The resulting mixture of aqueous solution plus sticky solid was diluted with ethyl acetate (300 ml) to dissolve the solid, and the organic layer separated. The aqueous phase was further extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with water, and saturated sodium chloride solution, then dried over sodium sulfate and evaporated to give a yellow/orange solid, which was recrystallised from 2:1 ethanol:water (600ml) to give the product as an off-white solid, which was vacuum dried.
Yield 7.98 g of 4 4 -acetoxyphenyl)-3-(4-fluorophenyl)-7-methoxy-coumarin. M.p 173-1760C. 1 H-NMR (CDCI, 300 MHz) 6: 2.32 3H); 3.89 3H); 6.78 (dd, 1H); 6.82- 6.95 3H); 7.03-7.14 6H); 7.15 1H). LRMS (El) 404 362, 334, 319, 43.
Elemental analysis; calculated for C 2 4
H,
7 FOs: C, 71.28; H, 4.24%; found C, 71.26; H, 4.25%.
Step 2: 3-(4-Fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chrom-3-ene Lithium aluminium hydride (0.76 g, 20.03 mmol) was added in small portions to a stirred WO 98/18774 PCT/DK97/00481 42 tetrahydrofuran (150 ml) solution of 4 4 -acetoxyphenyl)-3-(4-fluorophenyl)-7-methoxycoumarin (4.04 g, 9.99 mmol). After complete addition, the mixture was stirred at room temperature for 30 min., then treated dropwise with 6M hydrochloric acid (30 ml). The resulting mixture was heated to 60-65"C for 3 h, cooled and diluted with water (100 ml) and ethyl acetate (50 ml). The aqueous layer was separated and further extracted with ethyl acetate (3 x 100 ml). The combined organic solutions were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to give an orange solid. This was recrystallised from ethanol/water 75 ml) to give the first crop of solid product as colourless needles. The mother liquors were evaporated to give an orange gum, which was subjected to a second aqueous ethanol recrystallisation to give a second crop of colourless needles. The solids were combined and vacuum dried.
Yield 2.47 g of 3 4 -Fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chrom-3-ene.
M.p. 155-156.5°C. 'H-NMR (CDCI 3 300 MHz) 5: 3.79 3H), 4.80 (bs, 1H), 5.20 2H), 6.40 (dd, 1H), 6.51 1H), 6.70-7.00 9H). LRMS (El) 348 255 (M-PhOH), 253 (M-PhF).
Step 3: 3 4 -Fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chromane Palladium on carbon 0.20 g, 0.19 mmol) was added to a stirred solution of 3-(4fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chrom-3-ene (1.74 g, 4.99 mmol) in ethanol, (150 ml) and the mixture hydrogenated at room temperature for 20 h. The catalyst was removed by filtration, and the solvent evaporated to give an off-white solid which was purified by recrystallisation from aqueous ethanol. This gave the product as a colourless solid, which was vacuum dried to give colourless platelets which contained 0.75 equivalents of ethanol of crystallization.
Yield 1.29 g of 3 4 -fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chromane.
M.p. 164-165*C (aqueous ethanol). 'H-NMR (CDCI 3 300 MHz) d: 1.25 2.4H, WO 98/18774 WO 9818774PCT/DK97/00481 43 0.75EtOH), 3.55 (ddd, 1H), 3.73 1.6H, 0.75EtOH), 3.81 3H), 4.16-4.25 (i,2H), 4.38 (dd, 1H), 4.90 (bs, 1H), 6.44-6.58 (in, 6H), 6.59-6.68 (in, 2H), 6.80-6.90 (i,3H).
LRMS (El) 350 227, 211. Elemental analysis: calculated for C 22
H
1 F0 3 *0.75EtOH C, 73.33; H, 6.13%; found C, 73.32; H, 6.11 Step 4: (±)-cis-3-(4-Fluorophenyl) 7 -methoxy- 4 -(4-(2-pyrrolidnoethoxy)phenyl)chromane A mixture of (±-i--4furpey)4(-ydoyhnl--ehx-hoae (0.53 g, 1.51 inmol) potassium carbonate, (2.10 g, 15.2 minol) sodium iodide, (0.01 g, 0.07 minol) 1-(2-chloroethyl)pyrrolidine hydrochloride, (0.28 g, 1.65 minol) and acetone, (35 ml) was stirred at 6000, under reflux, for 24 h. The resulting mixture was filtered and the solvent evaporated to give a colourless gum, which solidified on cooling. The crude solid was recrystallised from aqueous ethanol to give the product as colourless needles, which were vacuum dried.
Yield 0.57 g of (±)-cis-3-(4-fluorophenyl)-7.methoxy-4(4-(2.
piperidinoethoxy)phenyl)-chroinane. M.p. 93. 5-94.5"C (aqueous ethanol). 1 H-NMR (CDC1 3 300 MHz) 8: 1.75-1.85 (in, 4H), 2.55-2.65 (in, 4H), 2.85 2H), 3.55 (ddd, 1IH), 3.81 (s, 3H), 4.08 2H), 4.16-4.23 (in, 2H), 4.37 (dd, 1H), 6.43-6.53 (mn, 4H), 6.57-6.66 (in, 4H), 6.80-6.88 (mn. 3H). LRMS (El) 447 84 (CS9HI 0
N).
Step (±)-trans- 3 4 Fuoropheny)7methoxy4(4-(2pyrroidinoethoxy)pheny,)-chromane A mixture of 3 4 fluorophenyl)7methoxy-4(4.(2pyrrolidinoethoxy)phenyl).
chromane (1.0 g, 2.23 mmol) and powdered potassium hydroxide (0.25 g, 4.46 inmol) in dry DM50S (5 ml) was heated to 8000 for 3 h. The mixture was diluted with water (100 ml) WO 98/18774 PCT/DK97/00481 44 and the products extracted into ethyl acetate (3 x 100 ml). The combined extracts were washed with water, brine, dried over magnesium sulfate, and evaporated to give the crude multi-component product mixture as an orange gum. The title compound was partially purified by means of column chromatography on silica gel with 5% methanol in dichloromethane as eluent. On evaporation the title compound was isolated as a mixture of the title compound with some of the unreacted cis-isomeric starting material. The title compound was fully purified by means of preparative HPLC: column: YMC 120A,15pm, 250x10 mm; eluent: 60% methanol in 50mM aqueous ammonium acetate; flow: 10 ml/min; UV detection at 220 nm. Evaporation of the appropriate fractions gave the title compound as a colourless wax.
Yield 0.11 g of (±)-trans-3-(4-fluorophenyl)-7-methoxy-4-(4-(2pyrrolidinoethoxy)phenyl)-chromane. 'H-NMR (CDCI3, 300 MHz) 6: 1.73-1.88 4H), 2.60-2.72 4H), 2.90 2H), 3.20 (ddd, 1H), 3.75 3H), 4.04 2H), 4.05-4.25 (m, 2H), 4.30 (dd, 1H), 6.40 (dd, 1H), 6.45 1H), 6.67 1H), 6.74 (dm, 2H), 6.80-6.95 (m, 4H), 6.95-7.04 2H). LRMS (El) 447 84 (CsHioN, 100%). Analytical HPLC, Rt 5.62 min. (LiChrosorb RP-18 (7pm), 250x4 mm column); 90% methanol/10% (pH7, aqueous 0.25% triethylamine/phosphoric acid) buffer eluent, 220 nm UV detection; 0.9 ml/min flow rate.
Step 6: (±)-trans- 7 -Hydroxy-3-(4-fluorophenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane A mixture of anhydrous pyridine hydrochloride (0.289 g, 2.50 mmol) and (±)-trans-3-(4fluorophenyl)-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane (0.11 g, 0.25 mmol) was heated to 135°C for 18 h. The resulting dark brown solid was dissolved in a mixture of methanol (10 ml), water (50 ml) and sodium hydrogen carbonate solution (5 ml), and the product extracted into 9:1 dichloromethane /methanol (3 x 50 ml). The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to an orange gum.
The product was purified by column chromatography on silica gel 60, with 5% methanol in WO 98/18774 WO 9818774PCT/DK97/00481 dichioromethane eluent, giving the purified product as a colourless wax.
Yield 40 mg of (±)-trans-7-hydroxy-3-(4-fluorophenyl)4(4-(2 pyrrolidinoethoxy)phenyl)-chromane. 'H-NMR (MeOH-d 4 200 MHz) 8: 1.85-2.10 (in, 4H), 3.00-3.18 (in, 4H), 3.18-3.38 (in, 3H), 4.05-4.25 (in, 5H), 6.22 (dd, 1H), 6.30 1H), 6.46 1 6.80 (din, 2H), 6.84-6.98 (in, 4H), 7.04-7.16 (in, 2H). LRMS (El) 433 84
(C
5
H
10 N, 100%).
EXAMPLE 3 (t)-tra ns- 7 -Hydroxy-3-(4-fl uoro ph en vl)-4.(4-(2pipe rid in oethoxy) phenyl)-ch romane The title compound was prepared in an exactly analogous fashion to that described for Example 2, with substitution of 1-(2-chloroethyl)piperidine hydrochloride for the 1-(2chloroethyl)pyrrolidine hydrochloride electrophile in step 4.
The intermediate, (±)-trans- 3 4 -fluorophenyl)-7-methoxy.4(4-(2piperidinoethoxy)phenyl)chroinane (70 mg, 0.152 mmol) was de-inethylated by heating with pyridine hydrochloride (0.176 g, 1.52 inmol) for 18 h; giving the title compound as a colourless foam after purification.
Yield. 25 mng of (:)tas7hdoy3(-loohnl)4(-2pprdnehx)pey) chroinane. 'H-NMR (MeOH-d 4 200 MHz) 8: 1.40-1.55 (in, 2H), 1.55-1.70 (mn, 4H), 2.50- 2.62 (in, 4H), 2.78 2H), 3.15-3.30 (in, 1H), 4.05 2H), 4.10-4.25 (mn, 3H), 6.23 (dd, 1H), 6.28 1H), 6.49 1H), 6.75 (din, 2H), 6.85-6.98 (mn, 4H), 7.05-7.16 (in, 2H), phenol OH not observed. LRMS (El) 447 98 (C 6
H
12 N, 100%).
Claims (31)
- 2. A compound of the formula I in which substituents R 2 and R 3 are arranged in trans- configuration: R 3 R2 (I) I-O R 1 0 wherein: R' is H, COR 4 CONHR 4 CONR SO 2 NR or SO 2 NHR 4 WO 98/18774 PCT/DK9700481 48 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-C 6 -alkyl, C 1 -C 6 alkyl and C,-C6-alkoxy; 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 4 NHR 4 NR NHCOR 4 NHSO 2 R 4 CONHR 4 CONR COOH, COOR 4 S0 2 R 4 SOR 4 SONHR 4 SONR 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 trihalo-C 1 -C 6 -alkyl, C,-C6-alkyl and C,-C 6 -alkoxy; -(CH 2 )n-Y wherein n and Y are as defined above; or phenyl fused to a C3-C7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-C,-C 6 alkyl, C,-C 6 -alkyl and C,-C 6 -alkoxy; and R 4 is C 1 -C 6 -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 -49- R 2 RO O RR R0 or RIO@ R 2 0 (Ib) wherein R R 2 and R 3 are as defined in claim 1 or claim 2.
- 4. A compound according to any one of the preceding claims in which R' is H, COR 4 CONHR 4 CONR SO 2 NR or S02NHR 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-Cl-C 6 -alkyl, C 1 -C 6 -alkyl and C 1 i C 6 -alkoxy. 10 6. 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-Cl-C 6 -alkyl, CI-C6-alkyl and C 1 C 6 -alkoxy.
- 7. A compound according to any one of the preceding claims in which R 3 is phenyl 15 substituted with -X-(CH 2 wherein:
- 9. 9 n is an integer in the range of 1 to 12, Y is H, OH, OR 4 NHR 4 NR NHCOR 4 NHSO 2 R 4 CONHR 4 CONR COOH, COOR 4 SO 2 R 4 SOR 4 SONHR 4 SONR a C 3 -C7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting ofO, 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-Ci-C 6 -alkyl, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy. 8. A compound according to any one of the preceding claims wherein R 3 is -(CH 2 )n-Y wherein n and Y are as defined in claim 1 or claim 2. 9. A compound according to any one of the preceding claims wherein R 3 is phenyl fused to a C 3 -C 7 heterocyclic ring, saturated or unsaturated, containing one or two heteroatoms independently selected from the group consisting of O, S and N, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 trihalo-Ci-C 6 -alkyl, Ci-C 6 -alkyl and Ci-C 6 alkoxy. 15 10. A compound according to claim 1 or 2 having the formula 0 COOR wherein R is H or C-Calkyl.
- 11. A compound according to claim 1 or 2 having the formula -51 wherein m is an integer from 0 to
- 12. A compound according to claim 1 or 2 having the formula mis asdefined in claiml11.
- 13. A compound according to claim 1 or 2 having the formnula wherein m is as defined in claim 11.
- 14. A compound according to claim 1 or 2 having the formula -52- wherein m is as defined in claim 11 and both R 4 independently are as defined in claim 1 or claim 2. A compound according to claim 1 or 2 having the formula a wherein R 4 is as defined in claim 1 or claim 2.
- 16. A compound according to claim 1 or 2 having the formula wherein R 4 is as defined in claim 1 or claim 2. 53
- 17. A compound according to claim 1 or 2 having the formula NQ *5 S S S *5 S S S S wherein R6 represents one or more of the following substituents: methoxy, hydroxy, trifluormethyl, fluoro and chioro.
- 18. A compound according to claim I or 2 selected from the following: (+)-trans-7-Hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (±)-trans-7-Hydroxy-3-(4-fluorophenyl)-4-(4-(2-pyrrolidinoethoxy)pheny)chromane, (+)-trans-7-Hydroxy-3-(4-fluorophenyl)-4-(4-(2-piperidinoethoxy)phenyl)-chromane, including the pure enantiomers thereof. 10 19. A compound according to claim I or 2 selected from the following: (+)-trans-4-(4-(Carboxymethoxy)phenyl)-7-hydroxy-3-phenylchromane, (-)-trans-4-(4-(Carboxyrnethoxy)phenyl)-7-hydroxy-3-phenylchromane, (+)-trans-7-Hydroxy-4-(4-(methoxycarbonyh-nethoxy)phenyl)-3-phenylchromane, (-)-trans-7-Hydroxy-4-(4-(methoxycarbonylmethoxy)phenyl)-3-phenylchromane, 15 (+)-trans-4-(4-(Ethoxycarbonylmethoxy)phenyl)-7-hydroxy-3-phenylchromane, (-)-trans-4-(4-(Ethoxycarbonylmethoxy)phenyl)-7-hydroxy-3-phenylchromane, (+)-trans-4-(4-(Benzyloxycarbonylmethoxy)phenyl)-7-hydroxy-3-.phenylchromane, (-)-trans-4-(4-(Benzyloxycarbonylmethoxy)phenyl)-7-hydroxy-3-phenylchromane, (+)-trans-7-Hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (+)-trans-7-Hydroxy-3-phenyl-4-(4-(3-pyrrolidinopropoxy)phenyl)chromane, -54- (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(3-pyrrolidinopropoxy)phenyl)chromane, (±)-trans-7-Hydroxy-3 -phenyl-4-(4-(4-pyrrolidinobutoxy)phenyl)chromane, (-)-trans-7-Hydroxy-3-phenyl-4-(4-(4-pyrrolidinobutoxy)phenyl)chromane, (+)-trans-7-Hydroxy-3 -phenyl-4-(4-(5-pyrrolidinopentoxy)phenyl)chromane, (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(5-pyrrolidinopentoxy)phenyl)chromane, (+)-trans-7-Hydroxy-3 -phenyl-4-(4-(6-pyrrolidinohexyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(6-pyrrolidinohexyloxy)phenyl)chromaie, (+)-trans-7-Hydroxy-3-phenyl-4-(4-(7-pyrrolidinoheptyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(7-pyrrolidinoheptyloxy)phenyl)chromane, (+)-trans-7-Hydroxy-3-phenyl-4-(4-(8-pyrrolidinooctyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(8-pyrrolidinooctyloxy)phenyl)chromane, (+)-trans-7-Hydroxy-3 -phenyl-4-(4-(9-pyrrolidinononyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3-phenyl-4-(4-(9-pyrrolidinononyloxy)phenyl)chromane, (+)-trans-7-Hydroxy-3 -phenyl-4-(4-( 1 -pyrrolidinodecyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3-phenyl-4-(4-( 1 -pyrrolidinodecyloxy)phenyl)chromane, (+)-trans-7-Hydroxy-3 -phenyl-4-(4-(1 1 -pyrrolidinoundecyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3 -phenyl-4-(4-( 11 -pyrrolidinoundecyloxy)phenyl)chromane, (+)-trans-7-Hydroxy-3-phenyl-4-(4-(1 2-pyrrolidinododecyloxy)phenyl)chromane, (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(1 2-pyrrolidinododecyloxy)phenyl)chromane, (+)-trans-7-Hydroxy-3-phenyl-4-(4-(2-piperidinoethoxy)phenyl)chromane, (--rn--Hdoy3phnl* .2-ieiioehx~hny~hoae (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(2-piperidinoethoxy)phenyl)chromane, (--rn--ydoy3pey*. *3ppriiorpx~hey~hoae (+)-trans-7-Hydroxy-3-phenyl-4-(4-(3-piperidinopropoxy)phenyl)chromane, (-)-trans-7-Hydroxy-3 -phenyl-4-(4-(3-piperidinopropoxy)phenyl)chromane, (+)-trans-7-Hydroxy-3-phenyl-4-(4-(4-zpirdnotoxy)phenyl)3pychromane, 25(-)-trans-7-Hydroxy-3 -phenyl-4-(4-(4-pirnotoxy)phenyl)pychromane, (+)-trans-7-Hydroxy-4-(4-(2-perhydroazepinoethoxy)phenyl)-3-phenylchromane, *rn--yrx-4(-3pryraepnpooypey)--hnlhoae (-)-trans-7-Hydroxy-4-(4-(-perhydroazepinotoxy)phenyl)-3-phenylchromane, ()-trans-7-Hydroxy-4-(4-(4-perhydroazepinoprooxy)phenyl)-3-phenylchromane, (-)-trans-7-Hydx--(4-(4-pmierhozeboxy)phenyl)rx-3-phenylchromane, ~T (-)-trans-4-(4-(2-Dimethylaminoethoxy)phenyl)-7-hydroxy-3-phenylchromane, 55 (+)-trans-4-(4-(2-Diethylaminoethoxy)phenyl)-7-hydroxy-3-phenylchromane, (-)-trans-4-(4-(2-Diethylaminoethoxy)phenyl)-7-hydroxy-3-phenylchromane, (+)-trans-4-(4-(2-(N-Ethyl-N-methylamino)ethoxy)phenyl)-7-hydroxy-3-phenylchromane, (-)-trans-4-(4-(2-(N-Ethyl-N-methylamino)ethoxy)phenyl)-7-hydroxy-3 -phenylchromane, -Dimethylamninopropoxy)phenyl)-7-hydroxy-3-phenylchromane, -Dimethylaminopropoxy)phenyl)-7-hydroxy-3 -phenylchromane, (+)-trans-4-(4-(4-Dimethylaminobutoxy)phenyl)-7-hydroxy-3 -phenylchromane, (-)-trans-4-(4-(4-Dimethylaminobutoxy)phenyl)-7-hylroxy-3-phenylchromane, (+)-trans-4-(2,3-Dihydro- 1,4-benzoxazin-6-yl)-7-hydroxy-3-phenylchromane, (-)-trans-4-(2,3-Dihydro- 1,4-benzoxazin-6-yl)-7-hydroxy-3-phenylchromane, (+)-trans-7-Hydroxy-4-(4-methyl-2,3-dihydro- 1,4-benzoxazin-6-yl)-3-phenylcbromane, (-)-trans-7-Hydroxy-4-(4-methyl-2,3-dihydro- 1,4-benzoxazin-6-yl)-3 -phenylchromane, (+)-trans-4-(4-Ethyl-2,3-dihydro- 1,4-benzoxazin-6-yl)-7-hydroxy-3-phenylchromane, (-)-trans-4-(4-Ethyl-2,3-dihydro- 1,4-benzoxazin-6-yl)-7-hydroxy-3-phenylchromane, (+)-trans-7-Hydroxy-3 -(4-hydroxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (-)-trans-7-Hydroxy-3-(4-hydroxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (+)-trans-7-Hydroxy-3 -(4-trifluoromethylphenyl)-4-(4-(2- pyrrolidinoethoxy)phenyl)chromane, (-)-trans-7-Hydroxy-3-(4-trifluoromethylphenyl)-4-(4-(2- pyrrolidinoethoxy)phenyl)chromane, (*-rn--yroy3(-looh. )4(-2pyrldnehx*pey~hoae (+)-trans-7-Hydroxy-3 -(4-fluorophenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, 4Choohnl--ydoy4(-2pyrldnehx~pey~hoae (-)-trans-7-yry3-(4-fluorophenyl)rx-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (+)-trans-3 -(34-hltorophenyl)-7-hydroxy-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (-)-trans-3-(34-hlorophenyl)-7-hydroxy-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, ,4-menty phenyl)yrx-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (-)-trans-Hrx-3-( -ientyphenyl)yox-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, ~(+)-trans-7(-ydroxy(etaflorphenyl)--(4do-(-prolnehxhnlchromane, (+)-trans-Hrx-4-(4-(ehoyarboxymnethoxy)phenyl)-hyry -3-phenylchromane, (--rn--yrxy4(-mtoyaboymtoy*ey)--hnlhoae 0(-)-trans-4-(4-(Ctoyarbo lmethoxy)phenyl)-6-hydroxy-3-phenylchromane, -56- (-)-trans-4-(4-(Ethoxycarbonylmethoxy)phenyl)-6-hydroxy-3-phenylchromane, (+)-trans-4-(4-(Benzyloxycarbonylmethoxy)phenyl)-6-hydroxy-3-phenylchromane, (-)-trans-4-(4-(Benzyloxycarbonylmethoxy)phenyl)-6-hydroxy-3 -phenylchromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3 -phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (+)-trans-6-Hydroxy-3 -phenyl-4-(4-(3 -pyrrolidinopropoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3 -phenyl-4-(4-(3 -pyrrolidinopropoxy)phenyl)chromane, (+)-trans-6-Hydroxy-3 -phenyl-4-(4-(4-pyrrolidinobutoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(4-pyrrolidinobutoxy)phenyl)chromane, (+)-trans-6-Hydroxy-3 -phenyl-4-(4-(5-pyrrolidinopentoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(5-pyrrolidinopentoxy)phenyl)chromane, (+)-trans-6-Hydroxy-3 -phenyl-4-(4-(6-pyrrolidinohexyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(6-pyrrolidinohexyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3 -phenyl-4-(4-(7-pyrrolidinoheptyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(7-pyrolidinoheptyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-(8-pyrrolidinooctyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3 -phenyl-4-(4-(8-pyrrolidinooctyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-(9-pyrrolidinononyloxy)phenyl)cromane, (-)-trans-6-Hydroxy-3 -phenyl-4-(4-(9-pyrrolidinononyloxy)phenyl)chromane, (+)-trans-6-Hydroxy-3 -phenyl-4-(4-( 1 -pyrrolidinodecyloxy)phenyl)chromane, 0: (-)-trans-6-Hydroxy-3-phenyl-4-(4-(I 1 -pyrrolidinodecyloxy)phenyl)chromane, (*-rns6Hdrx- -pey*-4( proiioneyoypey~hoae ()-trans-6-IHydroxy-3 -phenyl-4-(4-( 11 -pyrrolidinoundecyloxy)phenyl)chromane, (-)-trans-6-Hydroxy-3 -phenyl-4-(4-( 11-pyrrolidinoundecyloxy)phenyl)chromane, ()-trans-6-Ilydroxy-3-phenyl-4-(4-( 12-pyrrolidinododecyloxy)phenyl)chromane, 25(-)-trans-6-Hydroxy-3 -phenyl-4-(4-( 12-pyproidinodeyoxy)phenyl)chromane, (+)-trans-6-Hydroxy-3-phenyl-4-(4-(2-piperidinoethoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3 -phenyl-4-(4-(2-piperidinothoxy)phenyl)chromane, (--rn--yrx--hey -4(-ieiiopooypeyShoae 30(+)-trans-6-Hydroxy-3-phenyl-4-(4-(3-piperidinopropoxy)phenyl)chromane, (-)-trans-6-Hydroxy-3-phenyl-4-(4-(4-piperidinopropoxy)phenyl)chromane, 3S R, (+)-trans-6-Hydroxy-4-(4-(2-perhydroazepinoethoxy)phenyl)-3-phenylchromane, S(-)-trans-6-Hydroxy-4-(4-(2-perhydroazepinoethoxy)phenyl)-3-phenylcbromane, 57 (+)-trans-6-Hydroxy-4-(4-(3 -perhydroazepinopropoxy)phenyl)-3 -phenylchromane, (-)-trans-6-Hydroxy-4-(4-(3 -perhydroazepinopropoxy)phenyl)-3-phenylchromane, (+)-trans-6-Hydroxy-4-(4-(4-perhydroazepinobutoxy)phenyl)-3-phenylchromane, (-)-trans-6-Hydroxy-4-(4-(4-perhydroazepinobutoxy)phenyl)-3-phenylchromane, (+)-trans-4-(4-(2-Dimethylaminoethoxy)phenyl)-6-hydroxy-3-phenylchromane, (-)-trans-4-(4-(2-Dimethylaminoethoxy)phenyl)-6-hydroxy-3-phenylchromane, (+)-trans-4-(4-(2-Diethylaminoethoxy)phenyl)-6-hydroxy-3-phenylchromane, (-)-trans-4-(4-(2-Diethylamninoethoxy)phenyl)-6-hydroxy-3-phenylchromane, (+)-trans-4-(4-(2-(N-Ethyl-N-methylamino)ethoxy)phenyl)-6-hydroxy-3-phenylchromane, (-)-trans-4-(4-(2-(N-Ethyl-N-methylamino)ethoxy)phenyl)-6-hydroxy-3-phenylchromane, (+)-trans-4-(4-(3-Dimethylaminopropoxy)phenyl)-6-hydroxy-3-phenylciromane, -Dimethylaminopropoxy)phenyl)-6-hydroxy-3 -phenylchromane, (+)-trans-4-(4-(4-Dimethylaminobutoxy)phenyl)-6-hydroxy-3-phenylchromane, (-)-trans-4-(4-(4-Dimethylaminobutoxy)phenyl)-6-hydroxy-3-phenylchromane, (+)-trans-4-(2,3-Dihydro- 1,4-benzoxazin-6-yl)-6-hydroxy-3-phenylchromane, (-)-trans-4-(2,3-Dihydro- 1,4-benzoxazin-6-yl)-6-hydroxy-3 -phenylchromane, (+)-trans-6-Hydroxy-4-(4-methyl-2,3 -dihydro- 1 ,4-benzoxazin-6-yl)-3-phenylchromane, (-)-trans-6-Hydroxy-4-(4-methyl-2,3 -dihydro- 1,4-benzoxazin-6-yl)-3-phenylchromane, (+)-trans-4-(4-Ethyl-2,3-dihydro- 1 ,4-benzoxazin-6-yl)-6-hydroxy-3-phenylchromane, (-)-trans-4-(4-Ethyl-2,3-dihydro- 1,4-benzoxazin-6-yl)-6-hydroxy-3-phenylchromane, (*-rn--ydoy3(-ydoyhnlC,(-2proidnehx *ey~hoae ()-trans-6-Hydroxy-3 -(4-hydroxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (-yrxpey)4(-2pyrrolidinoethoxy)phenyl)chromane, 25()-trans-6-Hydroxy-3-(4-trifluoromethylphenyl)-4-(4-(2- a 6 pyrrolidinoethoxy)phenyl)chromane, 25(-)-trans-6-Hydroxy-3 -(4-trfluoromyphenyl)-4-(4-(2-oinetxyhelcrma, (--rn--yrx--4furpey)4(-2pyrrolidinoethoxy)phenyl)chromane, (*-rn--4Clrpey) Syrx--4(-yrldiotoypey~hoae 30()-trans-6-Hydroxy-3 -(4-fluorophenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, *(-)-trans-6-Hydro-3 -(4-fophenyl)-yx-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, (--rn--34Dmtoyhnla-yrx-4(-2proiiotoypey~hoae (+)-trans-Hrx-3-(4-Chlflorophenyl)x-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, -58- (-)-trans-6-Hydroxy-3-(pentafluorophenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane, or any mixture thereof, including racemic mixtures. A compound according to any one of claims 1 to 19 when used in the prevention or treatment of an estrogen related disease or syndrome.
- 21. A compound according to claim 20 wherein the estrogen related disease or syndrome is an estrogen-deficient state in a mammal.
- 22. A compound according to any one of claims 1 to 19 when used 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 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.
- 23. A compound according to claim 22 when used in the prevention or treatment of bone loss or osteoporosis.
- 24. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent.
- 25. A pharmaceutical composition according to claim 24 in the form of an oral dosage S 20 unit or parenteral dosage unit.
- 26. Use of a compound according to any one of claims 1 to 19 for the preparation of a medicament for prevention or treatment of an estrogen related disease or syndrome. -59-
- 27. Use accordingly to claim 26 wherein the estrogen-related disease or syndrome is a disease or syndrome caused by an estrogen-deficient state in a mammal.
- 28. Use of a compound according to any one of claims 1 to 19 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 schizophrenia, incontinence, obesity, depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen-dependent cancers, post-partum lactation or for use as contraception or an aid in ovarian development.
- 29. Use of a compound according to any one of claims 1 to 19 for the preparation of a medicament for the prevention or treatment of bone loss or osteoporosis. A method of preventing or treating an estrogen-related disease or syndrome comprising administering an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 24 or claim
- 31. A method according to claim 30 wherein the estrogen-related disease or syndrome V0000 :0 is an estrogen-deficient state in a mammal.
- 32. A method of preventing or treating bone loss, osteoporosis, cardiovascular diseases, cognitive disorders, senile dementia-Alzheimer's type, menopausal symptoms, including go•• flushing, urogenital atrophy, depression, mania and schizophrenia, incontinence, obesity, o. depression, regulation of glucose metabolism, dysmenorrhea, threatened or habitual abortion, dysfunctional uterine bleeding, acne, hirsutism, prostatic carcinoma, estrogen- i- ~dependent cancers, post-partum lactation comprising administering an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 24 or claim
- 33. A method of contraception comprising administering an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 24 or claim
- 34. A method of aiding ovarian development comprising administering an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 24 or claim A method of preventing or treating bone loss or osteoporosis comprising administering an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 24 or claim
- 36. A compound of the formula I as defined in claim 1 or claim 2, substantially as herein described with reference to any one of the examples but excluding comparative examples.
- 37. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or claim 2, substantially as herein described with reference to any one of the examples but excluding comparative examples. •leo
- 38. Use of a compound according to formula I as defined in claim 1 or claim 2 for the •eeo• preparation of a medicament, substantially as herein described with reference to any one 20 of the examples but excluding comparative examples. °*ee -61
- 39. A method of preventing or treating an estrogen-related disease or syndrome, substantially as herein described with reference to any one of the examples but excluding comparative examples. A method of preventing or treating 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, substantially as herein described with reference to any one of the examples but excluding comparative examples.
- 41. A method of contraception, substantially as herein described with reference to any one of the examples but excluding comparative examples.
- 42. A method of aiding ovarian development, substantially as herein described with reference to any one of the examples but excluding comparative examples. DATED this 2 0 th Day of December 2001 NOVO NORDISK A/S 20 Attorney: JACINTA FLATTERY-O'BRIEN Registered Patent Attorney of The Institute of Patent and Trade Mark Attorneys of Australia of BALDWIN SHELSTON WATERS o***o
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK120196 | 1996-10-28 | ||
| DK1201/96 | 1996-10-28 | ||
| PCT/DK1997/000481 WO1998018774A1 (en) | 1996-10-28 | 1997-10-28 | Novel trans-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU4771897A AU4771897A (en) | 1998-05-22 |
| AU744403B2 true AU744403B2 (en) | 2002-02-21 |
Family
ID=8102120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU47718/97A Ceased AU744403B2 (en) | 1996-10-28 | 1997-10-28 | Novel trans-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0937059A1 (en) |
| JP (1) | JP2001502706A (en) |
| AU (1) | AU744403B2 (en) |
| CA (1) | CA2269936A1 (en) |
| IL (1) | IL129623A0 (en) |
| NO (1) | NO992009L (en) |
| WO (1) | WO1998018774A1 (en) |
| ZA (1) | ZA979643B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6153768A (en) * | 1996-12-13 | 2000-11-28 | C & C Research Laboratories | Benzopyran derivatives |
| DK1140889T3 (en) * | 1998-12-30 | 2003-12-22 | Signal Pharm Inc | Compounds and Methods for Modulation of Estrogen Receptors |
| PT1355906E (en) * | 2001-01-24 | 2005-05-31 | Chiesi Farma Spa | 2H-1-BENZOPYRANE DERIVATIVES PROCESSES FOR THEIR PREPARATION AND THEIR PHARMACEUTICAL COMPOSITIONS |
| JP4976649B2 (en) * | 2004-09-21 | 2012-07-18 | マーシャル エドワーズ，インク． | Compound |
| US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
| CA2581316C (en) | 2004-09-21 | 2013-09-10 | Novogen Research Pty Ltd | Substituted chroman derivatives, medicaments and use in therapy |
| EP2635273B1 (en) | 2010-11-01 | 2020-01-08 | MEI Pharma, Inc. | Isoflavonoid compositions and methods for the treatment of cancer |
| CN116139125A (en) | 2015-02-02 | 2023-05-23 | 梅制药公司 | combination therapy |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3340276A (en) * | 1964-04-01 | 1967-09-05 | Ciba Geigy Corp | 3, 4-diphenyl-chromans |
| DE1543749A1 (en) * | 1966-02-16 | 1969-12-11 | Merck Ag E | Process for the preparation of 3,4-cis-4-aryl-isoflavans |
| US5280040A (en) * | 1993-03-11 | 1994-01-18 | Zymogenetics, Inc. | Methods for reducing bone loss using centchroman derivatives |
| HUP9702244A3 (en) * | 1995-01-13 | 1999-12-28 | Novo Nordisk As | Use of 3,4-diphenyl chromans for manufacture of a pharmaceutical composition for treatment or prophylaxis of gynaecological disorders |
-
1997
- 1997-10-28 AU AU47718/97A patent/AU744403B2/en not_active Ceased
- 1997-10-28 EP EP97910262A patent/EP0937059A1/en not_active Ceased
- 1997-10-28 IL IL12962397A patent/IL129623A0/en unknown
- 1997-10-28 CA CA002269936A patent/CA2269936A1/en not_active Abandoned
- 1997-10-28 ZA ZA9709643A patent/ZA979643B/en unknown
- 1997-10-28 JP JP10519940A patent/JP2001502706A/en active Pending
- 1997-10-28 WO PCT/DK1997/000481 patent/WO1998018774A1/en not_active Ceased
-
1999
- 1999-04-27 NO NO992009A patent/NO992009L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998018774A1 (en) | 1998-05-07 |
| IL129623A0 (en) | 2000-02-29 |
| JP2001502706A (en) | 2001-02-27 |
| CA2269936A1 (en) | 1998-05-07 |
| NO992009L (en) | 1999-06-25 |
| AU4771897A (en) | 1998-05-22 |
| ZA979643B (en) | 1998-04-28 |
| NO992009D0 (en) | 1999-04-27 |
| EP0937059A1 (en) | 1999-08-25 |
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