Novel Estrogen Receptor Ligands And MethodsⅠ

专利摘要:
The present invention relates to compounds and their derivatives, their synthesis, and their use as estrogen receptor modulators. Compounds of the present invention are ligands for estrogen receptors and include bone loss, bone resorption, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, hot flashes, increased LDL cholesterol levels, cardiovascular disease, cognitive impairment, Useful for treating and / or preventing a variety of diseases related to estrogen function, such as cerebral artery degeneration disorders, retinopathy, gynecomastia, angioblast proliferation, obesity, incontinence, autoimmune, lung cancer, colon cancer, breast cancer, uterine cancer, and prostate cancer Do.
公开号:KR20030076600A
申请号:KR10-2003-7008991
申请日:2001-12-24
公开日:2003-09-26
发明作者:콘라드 코에히레르；헨센세시리아；닐선마리타；미케엘 질네르；예 리유；안드레이 사닌；윌켄잉로버트알；로날드 더블유. 레트크리피
申请人:카로 바이오 아베；머크 앤드 캄파니 인코포레이티드；
IPC主号:

专利说明:

Novel Estrogen Receptor Ligands And Methods I
[2] Estrogen receptors (ER) are ligands that are activated by mammalian transcription factors involved in the up and down regulation of genes. Natural hormones for estrogen receptors are β-17-estradiol (E2) and related metabolic products. Binding of estradiol to the estrogen receptor causes dimerization of the receptor, which in turn binds to the estrogen response elements (ERE's) on the DNA. The ER / DNA complex recruits transcription factors from ERE that transcrib the underlying DNA into mRNA, which eventually translates into protein. Alternatively, the interaction of ER with DNA may be indirect through the mediation of other transcription factors, mostly fos and jun. Since the expression of a large number of genes is regulated by the estrogen receptors and the estrogen receptors are expressed in many cell types, the regulation of the estrogen receptors through the binding of natural hormones or synthetic ER ligands may be the physiology and pathology of the organism Physiological effects are very important in this respect.
[3] Estrogen is important for female reproductive development. In addition, estrogen has been shown to play an important role in maintaining bone density, regulating lipid levels in the blood, and having neuroprotective effects. In conclusion, the production of reduced estrogen in postmenopausal women is associated with diseases such as osteoporosis, atherosclerosis, and cognitive impairment. Conversely, proliferative disease types such as breast and uterine cancer and endometriosis are promoted by estrogen and thus antiestrogens (ie, estrogen antagonists) are useful in preventing these types of disorders.
[4] Meanwhile, women suffering from breast cancer and men with prostate cancer may also see the effects of anti-estrogenic compounds. Prostate cancer is often endocrine-sensitive, and androgen suppression inhibits tumor growth, while androgen stimulation causes tumor growth. Estrogen administration lowers gonadotropin levels, ie, androgen levels, and therefore, estrogen administration is useful for the treatment and control of prostate cancer.
[5] It is known that the use of natural and synthetic estrogens in hormone replacement therapy significantly reduces the risk of osteoporosis. There is also evidence that hormone replacement therapy has cardiovascular and neuroprotective effects. But hormone replacement therapy is also associated with an increased risk of breast and uterine cancer. Some types of synthetic ER ligands show an agonist / antagonist profile of mixed activity as an effector in some tissues and as an antagonist in some tissues. Such ligands are called selective estrogen receptor modulators (SERMS). For example, tamoxifen and raloxifene exhibit antagonist properties in the breast (thus lowering the risk of breast cancer), while they are known as effectors in bone (and thus prevent osteoporosis). However, just as SERMS is not as effective as estradiol in preventing bone loss, tamoxifen and raloxyphene are not ideal for hormone replacement therapy. In addition, the use of tamoxifen is still associated with increased cervical cancer, and both tamoxifen and raloxyphene exacerbate hot flashes.
[6] In history, only one estrogen receptor has been known to exist. Recently, however, a second subtype (ER-β) has been discovered. "Traditional" ER-α and more recently found ER-β are widely distributed in other tissues, while nevertheless they exhibit markedly different cell types and tissue distributions. Thus, synthetic ligands selective for ER-α or ER-β reduce the risk of undesired side effects while preserving the useful effects of estrogen.
[7] What is required in this field is compounds with positive reactions, such as estrogen replacement therapy, which do not have negative side effects. There is also a need for compounds such as estrogen that produce selective effects on other tissues of the human body.
[8] Compounds of the present invention are ligands for estrogen receptors, which are responsible for various symptoms associated with estrogen function, such as bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, hot flashes, LDL cholesterol Increased levels, cardiovascular disease, cognitive impairment, cerebral artery degeneration disorders, restinosis, gynecomastia, autoimmune, vascular myocyte proliferation, obesity, incontinence, and lung, colon, breast, uterine and prostate cancers It is useful for prevention or treatment.
[1] The present invention relates to estrogen receptor ligands, more particularly new compounds selective to the estrogen receptor α or β isoforms, methods of preparing such compounds, and the compounds to estrogen hormone replacement therapy or estrogen receptors. To control osteoporosis, elevated triglyceride levels in the blood, atherosclerosis, endometriosis, cognitive impairment, incontinence, autoimmunity, and lung, colon, breast, uterine and prostate cancers and methods of using these compounds. It is about.
[9] According to the present invention there is provided a compound which is an estrogen receptor ligand and has the general formula I, II, or III:
[10]
[11] Wherein a bond between C1 and C2 carbon atoms (in the compound of Formula I) or a bond between C2 and C3 (in the compound of Formula II) or a bond between C1 and C10 (in the compound of Formula III) is Or a double bond;
[12] R ₁ (in compounds of formula I or III) is a R ^A group, not a phenyl group;
[13] R ^A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl or arylalkyl;
[14] R ₁ α and R ₁ β (in the compound of Formula II) are the same or different and each is a R ^A group;
[15] R ₂ (in the compound of formula I or II) is a hydroxyl or R ^A group or is hydroxyalkyl or aminoalkyl of 1 to 2 carbon atoms;
[16] R ₃ α and R ₃ β (in the compound of Formula I) may both be monooxygen or sulfur atoms; Or R ₃ α and R ₃ β can both be short nitrogen atoms which in turn bind to a group selected from R ^A or OR ^A ; Or R ₃ α and R ₃ β can both be short carbon atoms (that is, exo methylene carbon atoms) that bind to two R ^A groups, which in turn can be the same or different; Or R ₃ α and R ₃ β may be the same or different and each is an R ^A R ^A, the same or different are considered to be one with the attachment and the intervening atoms to form a ring of 3-8 members OR ^A, SR ^A Or N (R ^A ) ₂ group;
[17] R ₂ α and R ₂ β (in the compound of Formula III) may both be monooxygen or sulfur atoms; Or R ₂ α and R ₂ β can both be short nitrogen atoms which in turn bind to a group selected from R ^A or OR ^A ; Or R ₂ α and R ₂ β can both be single-carbon atoms that bind to two R ^A groups, which in turn can be the same or different; Or R ₂ α and R ₂ β can be the same or different and each is hydroxyalkyl, aminoalkyl, considered to be one with the same or different R ^A and optionally attached and intervened to form a ring of 3-8 members. , R ^A , OR ^A , SR ^A , or N (R ^A ) ₂ group;
[18] R ₃ (in the compound of formula II or III) is a group of R ^A ;
[19] R ₄ is a R ^A group;
[20] R _4a is a hydrogen atom or a methyl or ethyl group in the compound of Formula I or II, or a methyl or ethyl group in the compound of Formula III;
[21] R ₇ is a hydrogen atom or a straight or branched alkyl or cycloalkyl group or acyl group of 1 to 4 carbon atoms;
[22] R _10a is a R ^A group;
[23] Provided that all of R ₁ , R ₂ , R ₃ and R ₄ are not hydrogen in the compound of formula I or II, and R ₄ is not hydrogen in the compound of formula III; Also pharmaceutically acceptable salts or stereoisomers thereof.
[24] The present invention relates to compounds having the above general formulas I, II or III useful as estrogen receptor modulators.
[25] One embodiment of the invention relates to compounds according to general formula I, II or III, wherein substituents R _4a and R _10a have trans relative stereochemistry.
[26] Another embodiment of the invention relates to compounds according to general formula I or III, wherein R ₁ is R ^B and R ^B is hydrogen, n-propyl, 2-propenyl, 2-propynyl, n-butyl, 2 -Butenyl, 3-butenyl, 2-butynyl, 3-butynyl, n-pentyl, 3-methylbutyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methylpentyl , 3-ethylpentyl, cyclopropylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclopentylpropyl, benzyl, and phenethyl.
[27] Another embodiment of the present invention relates to a compound according to Formula II, wherein R ₁ α is R ^B (wherein R ^B is defined as above) and R ₁ β is a hydrogen atom or a methyl group.
[28] Another embodiment of the invention relates to a compound according to general formula I, II or III, wherein R ₁₀ α is R ^B.
[29] Another embodiment of the invention relates to a compound according to general formula I or II, wherein R ₂ is a hydrogen atom or a methyl, ethyl or hydroxymethyl group.
[30] Another embodiment of the present invention relates to a compound according to general formula III, wherein R ₂ α and R ₂ β may be the same or different, and each R ^A group (R ^A is defined as above) is the same or different and optional Hydroxyalkyl, R ^A , OR ^A , or SR ^A together with the atoms attached and involved to form a ring of 3-8 members.
[31] Another embodiment of the present invention relates to a compound according to general formula I, wherein R ₃ α and R ₃ β may be the same or different, and each R ^A group (R ^A is defined as above) is the same or different and is optional Is selected from R ^A , OR ^A , or SR ^A together with the atoms attached and involved to form a ring of 3-8 members.
[32] Another embodiment of the invention relates to a compound according to general formula I, II or III, wherein R ₄ is a hydrogen atom or a methyl or ethyl group.
[33] Another embodiment of the invention relates to a compound according to general formula I, II or III, wherein R ₇ is a hydrogen atom or an acyl group of 1 to 4 carbon atoms.
[34] Another embodiment of the invention relates to compounds according to general formula I or III, wherein R ₁ is selected from hydrogen, methyl or ethyl groups and R _10a is R ^B.
[35] Another embodiment of the invention relates to compounds according to general formula I or III, wherein R ₁ is R ^B and R _10a is selected from hydrogen, methyl, or ethyl.
[36] Another embodiment of the present invention relates to a compound according to general formula III, wherein R ₂ α and R ₂ β may be the same or different, and each R ^A group (R ^A is defined as above) is the same or different and optional Hydroxyalkyl, R ^A , OR ^A , or SR ^A together with the atoms attached and involved to form a ring of 3-8 members.
[37] Another embodiment of the invention relates to a compound according to formula II, wherein R ₁ α is R ^B and R _10a is selected from hydrogen, methyl, or ethyl.
[38] Another embodiment of the invention relates to a compound according to formula II, wherein R ₁ α is selected from hydrogen, methyl, or ethyl and R _10a is R ^B.
[39] The compounds according to the invention are not limited thereto but are as follows:
[40] (rac)-(4aS, 10aS) -7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (El);
[41] (rac)-(4aS, 10aS) -3,3- ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E2);
[42] (rac)-(4aR, lOaS) -7-hydroxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one (E3a);
[43] (rac)-(4aS, 10aS) -7-hydroxy-1Oa-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (E3b);
[44] (rac)-(4aS, 10aS) -10-butyl-7-hydroxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (E4);
[45] (rac)-(1S, 4aS, 10aS) -1-butyl-7-hydroxy-1,4,4a, 9,10,10-hexahydro- 2H -phenanthrene-3-one (E5a);
[46] (rac)-(1R, 4aS, 10aS) -1-butyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E5b);
[47] (rac)-(1S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro-phenan Tren (E6a);
[48] (rac)-(1R, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10Oa-octahydro-phenan Tren (E6b);
[49] (rac)-(lS, 4aS, 1OaS) -1-butyl-7-hydroxy-1Oa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one (E7 );
[50] (rac)-(1S, 4aS, 10aS)-1- butyl-3,3-ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a- Octahydro-phenanthrene (E8);
[51] (rac)-(1S, 4aS, 10aS) -1-butyl-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E9);
[52] (rac)-(4aS, 10aR) -10a-ethyl-7-hydroxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-1 member (ElOa);
[53] (rac)-(4aR, lOaR) -lOa-ethyl-7-hydroxy-3-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-l-one (ElOb);
[54] (rac)-(1R, 2S, 4aS, 10aS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one (Ella);
[55] (rac)-(1R, 2R, 4aS, 10aS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (Ellb);
[56] (rac)-(1s, 4R, 4aR, 10aS) -1- butyl-7-hydroxy-4-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (Ellc);
[57] (rac)-(1R, 2R, 4aS, lOaS) -l-butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10, 10a-octahydro-phenanthrene (E12a);
[58] (rac)-(1R, 2S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10, 10a-octahydro-phenanthrene (E12b);
[59] (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene 3-membered (E13);
[60] (rac)-(lS, 4aS, 1OaS) -3,3 -ethanediyldimercapto-7-hydroxy-1- (3-methyl-butyl) -1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E14);
[61] (rac)-(1S, 4aS, 10aS) -7-hydroxy-lOa-methyl-l-phenethyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one ( E15);
[62] (rac)-(1S, 2S, 4aS, 10aS) -7-hydroxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10Oa-hexahydro- 2H- phenanthrene-3-one (E16a);
[63] (rac)-(1S, 2R, 4aS, 10aS) -7-hydroxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one (E16b);
[64] (rac)-(4bS, 8S, 8aS) -6,6-dimethoxy-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octa Hydro-phenanthrene-2-ol (E17a);
[65] (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene 3-membered (El7b);
[66] (rac)-(1S, 4aS, 1OaS) -3,3- ethanediyldioxy-7-hydroxy-1- (3-methyl-butyl) -1Oa-methyl-1,2,3,4,4a, 9,10, lOa-octahydro-phenanthrene (E18);
[67] (rac)-(4bS, 8R, 8aS) -8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2- ol (E19a);
[68] (rac)-(46S, 6R, 8S, 8aS) -6-ethylsulfonyl-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10- Octahydro-phenanthrene-2-ol (E19b);
[69] (rac)-(1S, 4aS, 1OaS) -3,3- (propane-1,3- diyldimercapto ) -7-hydroxy-1- (3-methyl-butyl) -1Oa-methyl-1,2 , 3,4,4a, 9,10,10a-octahydro-phenanthrene (E20); (rac)-(4aS, 10aS) -7 -hydroxy-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one (E21);
[70] (rac)-(4aS, 10aS) -3,3 -ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10Oa-octahydro-phenanthrene ( E22);
[71] (rac)-(4aS, 10aS) -10a- ethyl-7-hydroxy-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one (E23);
[72] (rac)-(4aS, lOaS) -3,3 -ethanediyldimercapto-10a-ethyl-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene ( E24);
[73] (rac)-(1S, 4aS, 10aS) -1- (3-methyl-butyl) -10a-ethyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene 3-membered (E26);
[74] (1S, 4aS, lOaS) -7 -hydroxy-1Oa-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E27);
[75] (lR, 4aRS, lOaR) -7-benzyloxy-1Oa-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10O-hexahydro- 2H- phenanthrene-3-one (E28);
[76] (rac)-(1S, 4aS, 10aS) -1- (3-methyl-butyl) -3,3-ethanediyldimercapto-7-hydroxy-1,4,4a, 9,10,10Oa-octahydro Phenanthrene (E29);
[77] (rac)-(4aR, 10aR) -7 -hydroxy-4a, lOa-dimethyl-3,4,4a, 9,10, lOa-hexahydro- 1H- phenanthrene-2-one (E30);
[78] (rac)-(lS, 4aS, lOaS) -7-hydroxy-1Oa-methyl-4-phenyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E31 );
[79] (rac)-(4R, 4aS, 1OaS) -3,3 -ethanediyldimercapto-7-hydroxy-10a-methyl-4-phenyl-1,4,4a, 9,10,1Oa-octahydro-phenan Tren (E32);
[80] (rac)-(1S, 4aS, 10aS) -3,3- (ethane-1,2- diyldimercapto ) -7-hydroxy-1- (2-phenylethyl) -10a-methyl-1,2, 3,4,4a, 9,10,10a-octahydro-phenanthrene (E33); (rac)-(1S, 4aS, 10aS) -3,3- ethanediyldioxy-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10Oa-octahydro-phenan Tren (E34a);
[81] (rac)-(lS, 4aS, lOaR) -3,3 -ethanediyldioxy-7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenan Tren (E34b);
[82] (rac)-(3S, 4aS, 10aS) -7 -hydroxy-3-pentyl-1Oa-methyl-1,2,3,4,4a, 9,1,10a-octahydro-phenanthrene (E35a);
[83] (rac)-(3R, 4aS, lOaS) -7-hydroxy-3-pentyl-1Oa-methyl-1,2,3,4,4a, 9,1,10a-octahydro-phenanthrene (E35b);
[84] (rac)-(1S, 2R, 4aS, 10aS) -2,10a-dimethyl-3,3- (ethane-1,2-diyldimercapto) -7-hydroxy-1- (3-methyl-butyl- 1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E36); (rac)-(1S, 4aS, 10aS) -7 -hydroxy-1- (3'-methyl- Butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E37);
[85] (rac)-(4aS, 10aS) -3,3- (propane-1,3-diyldimercapto) -7-hydroxy-1,2,3,4,4a, 9,10,10Oa-octahydro- Phenanthrene (E38);
[86] (rac)-(1S, 4S, 4aS, 10aS) -7-hydroxy-1-butyl-4,10a-dimethyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3 -Circle (E39);
[87] (rac)-(4S, 4aS, 10aS) -3,3 -ethanediyldimercapto-7-hydroxy-4,10a-dimethyl-1,2,3,4,4a, 9,10,1Oa-octahydro Phenanthrene (E40);
[88] (rac)-(4S, 4aS, 10aS) -7 -hydroxy-4-benzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E41a );
[89] (rac)-(4aS, 10aS) -7 -hydroxy-4,4-dibenzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one ( E41b);
[90] (rac)-(4aS, 10aS) -7 -hydroxy-1Oa-methyl-3,3-methylene-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (E42);
[91] (rac)-(4aS, 10aS) -3,3-ethanediyl-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (E43);
[92] (rac)-(3R, 4aS, 1OaS) -1 ', 2', 3 ', 4'-tetrachloro-7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10, 10a-octahydrospiro [henanthrene-3,6'-cyclohexane] -1 ', 3'-diene (E44);
[93] (rac)-(3S, 4aS, 1OaS) -3,7-dihydroxy-10a-methyl-3- [1- (phenylthio) cyclopropyl] -1,2,3,4,4a, 9,10 , l0-octahydrophenanthrene (E45);
[94] (rac)-(3S, 4aS, 1OaS) -7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,2'-cyclo Butane] -1'-one (E46a);
[95] (rac)-(3R, 4aS, 10aS) -7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,2'-cyclo Butane] -1'-one (E46b);
[96] (rac)-(3S, 4aS, lOaS) -l ', l'-ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro Spiro [henanthrene-3,2'-cyclobutane] (E47); (rac)-(4aS, 1OaS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,1'-cyclobutane] (E48);
[97] (rac)-(4aS, 10OaS) -3- (1-cyclopenten-1-yl) -7-hydroxy-10a-methyl-1,4,4a, 9,10,10a-hexahydrophenanthrene (E49 );
[98] (rac)-(3S, 4aS, 10aS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dode Carhydrospiro [henanthrene-3,2'-furan] (E50a);
[99] (rac)-(3R, 4aS, 10aS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dode Carhydrospiro [henanthrene-3,2'-furan] (E50b);
[100] (rac)-(3S, 4aS, 10aS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 3 ', 4', 5 ', 6'-dode Carhydrospyro [henanthrene-3,2'- 2H -pyran] (E51a);
[101] (rac)-(3R, 4aS, 10aS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 3 ', 4', 5 ', 6'-dode Carhydrospyro [henanthrene-3,2'- 2H -pyran] (E51b);
[102] (rac)-(1S, 3R, 4aS, 10aS) -hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a, 2 ', 3 ', 4', 5'-dodecahydrospiro [henanthrene-3,2'-furan] (E52);
[103] (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10Oa-octahydrospiro [ Phenanthrene-3,1'-cyclobutane] (E53);
[104] (rac)-(1S, 4aS, 10aS) -7-hydroxy-3- (3-hydroxypropyl) -10a-methyl-1- (3-methylbutyl) -1,4,4a, 9,10, 10a-hexahydrophenanthrene (E54a);
[105] (rac)-(1S, 3S, 4aS, lOaS) -7 -hydroxy-1Oa-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a, 2 ' , 3 ', 4', 5'-dodecahydrospiro [henanthrene-3,2'-furan] (E54b);
[106] (rac)-(4aR, lOaR) -lOa-butyl-7-hydroxy-4a-methyl-3,4,4a, 9,10, lOa-hexahydro- lH -phenanthrene-2-one (E55);
[107] (rac) -7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one (E56);
[108] (rac) -4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E57);
[109] (rac) -7-hydroxy-1,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E58);
[110] (rac) -4a, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E59); (rac) -4b, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E60a, E60b, E60c, E60d);
[111] (rac)-(3S, 4aR) -7-hydroxy-3,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E61);
[112] (rac)-(4S, 4aR) -7 -hydroxy-4a-methyl-4-propyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E62);
[113] (rac)-(4R, 4aR) -7-hydroxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one (E63a);
[114] (rac)-(4S, 4aR) -7-hydroxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one (E63b);
[115] (rac) -l-ethyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E64);
[116] (rac) -8-ethyl-4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E65); (rac)-(4aR, 10aR, 1S) -1-ethyl-7-hydroxy-4a-methyl-1,4,4a, 9,10,10a-hexahydro- 3H -phenanthrene-2-one (E66 );
[117] (rac) -1-butyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E67);
[118] (rac) -8-butyl-4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E68); (rac)-(8R, 4bR, 8aR) -8-butyl-4b-methyl-4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2-ol (E69a);
[119] (rac)-(8S, 4bR, 8aR) -8-butyl-4b-methyl-4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2-ol (E69b);
[120] (rac) -4a-butyl-7-hydroxy-l-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E70);
[121] (rac) -4a-butyl-7-hydroxy-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E71);
[122] (rac)-(4aR, 10aR) -4a- butyl-7-hydroxy-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one (E72a);
[123] (rac)-(4aR, 10aS) -4a-butyl-7-hydroxy-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one (E72b);
[124] (rac)-(4aR, lOaS) -7 -hydroxy-4a-methyl-3,4,4a, 9,10, lOa-hexahydro- 1H -phenanthrene-2-one (E73);
[125] (rac)-(4aR, 10aS) -2,2-ethanediyldimercapto-7-hydroxy-4a-methyl-1,2,3,4,4a, 9,10,10Oa-octahydrophenanthrene (E74 );
[126] (rac)-(4aR, 10aS) -7 -hydroxy-4a-methyl-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one oxime (E75);
[127] And pharmaceutically acceptable salts and stereoisomers thereof.
[128] Another embodiment of the invention is a method of inducing an estrogen receptor modulating effect in a mammal in need thereof, comprising administering to the mammal an effective amount for the treatment of a compound or pharmaceutical composition described above.
[129] One class of this example is how the estrogen receptor regulatory effect is an acting effect.
[130] The first subclass of this example is the method in which the estrogen receptor is the ERα receptor.
[131] The second subclass of this example is the method where the estrone receptor is the ERβ receptor.
[132] The third subclass of this example is the method in which the estrogen receptor regulatory effect is a mixed acting effect of ERα and ERβ.
[133] The second class of this example is a method in which the estrogen receptor regulatory effect is an antagonistic effect.
[134] The first subclass of this example is the method in which the estrogen receptor is the ERα receptor.
[135] The second subclass of this example is the method where the estrone receptor is the ERβ receptor.
[136] The third subclass of this example is the method where the estrogen receptor regulatory effect is a mixed antagonistic effect of ERα and ERβ.
[137] Another embodiment of the present invention relates to a method for preventing or treating hot flashes in a mammal in need thereof by administering to the mammal an effective amount for treating the compound or pharmaceutical composition described above.
[138] The practice of the present invention relates to pharmaceutical compositions and pharmaceutically acceptable carriers comprising such compounds. Furthermore, the practice of the present invention is a pharmaceutical composition made by combining any two or more of the compounds described above with a pharmaceutically acceptable carrier. An illustration of the invention is the process of making a pharmaceutical composition comprising / combining any one of the compounds with a pharmaceutically acceptable carrier.
[139] As a specific embodiment of the invention, to fill a zero size gelatin capsule, (rac)-(1R, 2R, 4aS, lOaS) -l-butyl-3,3-ethanediyldimercapto-7-hydroxy 140 mg of 2-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene are formulated to provide a total of 580 mg to 590 mg with sufficiently finely divided lactose.
[140] As a specific embodiment of the present invention, 200 mg of (rac) -4b, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol with sufficiently finely divided lactose Formulated to provide a total of 580 mg to 590 mg.
[141] The practice of the present invention is also the use of a compound as described above in the preparation of a medicament for treating and / or preventing osteoporosis in a mammal in need thereof. Another embodiment of the present invention is bone loss, bone resorption, bone fracture, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, hot flashes, increased LDL cholesterol levels, cardiovascular disease, impaired cognitive function, cerebral artery degeneration disorders, restino Drugs for treating and / or preventing disorders associated with cirrhosis, gynecomastia, angioblast proliferation, obesity, incontinence, autoimmunity, lung cancer, colon cancer, breast cancer, uterine cancer, prostate cancer, and / or estrogen function It is a use of the compound described above in the preparation of.
[142] The invention also relates to a combination of one or more agents useful in the prevention or treatment of osteoporosis with any compound or pharmaceutical composition described above. For example, the compounds of the present invention can be administered effectively in combination with pharmaceutically effective amounts of other drugs such as organic bis phosphonides or cathepsin K inhibitors. Non-limiting examples of the organic bis phosphonide include adendronate, clathronate, ethedronate, ibandronate, incadronate, minodronate, neridronate, rezedronate, pyridro Nates, pamidronates, tiludronates, zoledronicates, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. Preferred organic bis phosphonides include alendronate and pharmaceutically acceptable salts and mixtures thereof. Most preferred is alendronate monosodium trihydrate.
[143] The exact dose of bisponate will vary depending on the dosing schedule, oral efficacy of the particular bis phosphonide selected, age, gender and condition of the mammal or human, the nature and severity of the disorder to be treated, and other related medical and physical factors. Thus, the exact pharmaceutically effective amount cannot be predetermined and can be determined immediately by the clinician or caregiver. Appropriate amounts can be determined by routine experiments from animal models or human clinical studies. In general, a suitable amount of bis phosphonate is selected to obtain a bone resorption inhibitory effect, that is to say that a bone resorption amount of bis phosphonate is administered. For humans, the effective oral dose of bis phosphonate is typically from about 1.5 to about 6000 μg / kg of weight, preferably from about 10 to 2000 μg / kg of weight.
[144] For oral compositions comprising human alendronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, unit dosages are typically based on allandronic acid active weight, i.e., the corresponding acid, The compound comprises about 8.75 mg to about 140 mg.
[145] The compounds of the present invention can be used in combination with other agents useful for treating estrogen-mediated health conditions. The individual components of such a combination may be administered at different times during treatment, and may be administered simultaneously or in combination at a time. Accordingly, the present invention will be understood to encompass all prescription regimens for concurrent or altered treatment, and the term “administration” will be interpreted accordingly. The scope of the combination of the compounds of the invention with other agents useful for treating the condition of estrogen-mediated includes the combination of pharmaceutical compositions useful for treating disorders related to estrogen function.
[146] The compounds of the present invention can be administered orally in the form of tablets, capsules (each of which is a sustained release or secretory formulation after a period of time), pills, powders, particulates, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they are also administered by methods well known to those skilled in the pharmaceutical arts, such as intravenous (pill or infusion), intraperitoneal, topical (eg eye drops), subcutaneous, intramuscular, or transdermal (eg patch) forms. Can be.
[147] Prescription dosages using the compounds of the present invention may vary depending on various factors such as type, species, age, weight, sex, and the patient's medical condition, the severity of the condition to be treated, the route of administration, the function of the patient's kidneys or liver, and The compound or salt thereof is considered in consideration. Ordinary physicians, veterinarians or clinicians can easily determine and prescribe the pharmacologically effective amount of the drug required to prevent, counter or prevent the development of the condition.
[148] The oral dosage of the present invention used for the indicated effect is between about 0.01 mg (mg / kg / day) to about 100 mg (mg / kg / day) per kg of weight per day, preferably per kg of weight per day From about 0.01 mg (mg / kg / day) to about 10 mg (mg / kg / day), more preferably from 0.1 to about 5.0 mg / kg / day. For oral administration, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 mg active factors for symptomatic dose adjustments to patients to be treated. It is preferably provided in the form of a containing tablet. A drug typically contains from about 0.01 mg to about 500 mg of active factor, and preferably from about 1 mg to about 100 mg of active factor. Intravenously, the most preferred dose is 0.1 to 10 mg / kg / min during continuous infusion. Advantageously, the compounds of the present invention can be taken once a day or divided into two, three or four times a day to administer a daily dose. In addition, the compounds of the present invention may preferably be administered topically via topical using suitable nasal carriers, or may be administered by the transdermal route using transdermal skin patch forms well known to those skilled in the art. In order to be administered in the form of a transdermal delivery system, dosage administration will naturally last longer than intermittent through dosage regimens.
[149] In the method according to the invention, the compounds described in detail herein can be in the form of an active factor and are selected from pharmaceutically suitable diluents, excipients or carriers selected for dosage forms such as oral tablets, capsules, elixirs, syrups, etc. Commonly referred to herein as "carrier" substances) and administered by typical pharmaceutical techniques.
[150] For example, for oral administration in the form of a tablet or capsule, the active drug ingredient may be an oral, nontoxic, pharmaceutically acceptable, lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, diphosphate Compound with inert carriers such as calcium, calcium sulfate, mannitol, sorbitol, and the like; For oral administration in liquid form, the active drug ingredient may be combined with an inert carrier such as oral, nontoxic, pharmaceutically acceptable, ethanol, glycerol, water, and the like. In addition, if necessary, suitable binders, lubricants, dispersants and coloring agents may also be added to the mixture. Suitable binders include natural and synthetic rubbers such as starch, gelatin, glucose or beta-lactose, corn sweeteners, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycols, waxes, and the like. . Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Dispersants include, without limitation, starch, methylcellulose, agar, bentonite, xant rubber, and the like.
[151] The compounds of the present invention can be administered via liposome delivery systems such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed, for example, from 1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine (cephalin), or phosphatidylcholine (lecithin).
[152] The following is a definition of terms used throughout the specification unless otherwise defined in a specific example.
[153] The term "estrogen receptor ligand" as used herein is intended to include a moiety that binds to the estrogen receptor. The ligand serves as an effector, antagonist, partial effector or partial antagonist. Ligands exhibit ERα and ERβ activity selective or mixed with ERα or ERβ.
[154] The term "aliphatic hydrocarbon" as used herein is an acyclic straight chain or mill containing an alkyl, alkenyl or alkynyl group.
[155] The term "aromatic hydrocarbon" as used herein is defined as a group comprising an aryl group.
[156] Unless otherwise specified, the terms "lower alkyl", "alkyl" or "alk" as used herein alone or as part of another group refer to 1 to 12 carbon atoms (if alkyl) in the normal chain, Preferably methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-methylpentyl, octyl, 2,2,4-trimethylpentyl And both straight chain and ground hydrocarbons, including 1 to 6 carbons, such as nonyl, decyl, undecyl, dodecyl.
[157] As used herein, alone or as part of another group, the term “cycloalkyl” refers to a saturated monocyclic ring system of 3 to 7 members, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl .
[158] As used herein alone or as part of another group, the term “cycloalkylalkyl” includes from 3 to 7 carbon atoms attached to a straight or branched alkyl radical comprising 1 to 6 carbons through the effective carbon. Cycloalkyl, including but not limited to cyclopropylmethyl (-CH ₂ C ₃ H ₅ ), cyclobutylethyl (CH ₂ CH ₂ C ₄ H ₇ ), and cyclopentylpropyl (-CH ₂ CH ₂ CH ₂ C ₅ H ₉ ).
[159] As used herein alone or as part of another group, the term “aryl” refers to a monocyclic or bicyclic aromatic group containing 6 to 10 carbons in the ring portion, including but not limited to phenyl, 1-naphthyl, And 2-naphthyl and includes hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, amino, trifluoromethyl, trilomethoxy, alkynyl, hydroxy, nitro, via an effective carbon atom And optionally substituted with 1, 2, or 3 groups selected from cyano, or carboxy.
[160] As used herein, alone or as part of another group, the term “arylalkyl” refers to an aryl group containing 6 to 10 carbons attached to a straight or pulverized alkyl radical containing 1 to 6 carbons via an effective carbon atom; , But not limited to, benzyl (-CH ₂ Ph), phenethyl (-CH ₂ CH ₂ Ph), phenpropyl (-CH ₂ CH ₂ CH ₂ Ph), and 1-naphthylmethylene (-CH ₂ C ₁₀ H ₇ ).
[161] Unless otherwise specified, the term "lower alkenyl" or "alkenyl" used herein alone or as part of another group includes from 2 to 12 carbons, preferably from 2 to 6 carbons in the normal chain. As straight chain or ground radicals, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3- One to six double bonds in the normal chain, such as heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, and the like.
[162] Unless otherwise specified, the term "lower alkynyl" or "alkynyl" used herein alone or as part of another group includes from 2 to 12 carbons, preferably from 2 to 6 carbons in the normal chain. As straight chain or ground radical, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptinyl, 3-heptinyl One triple bond in the normal chain, such as 4-heptinyl, 3-octynyl, 3-noninyl, 4-decynyl, 3-undecynyl, 4-dodecynyl, and the like.
[163] The terms "halogen" or "halo" used here alone or as part of another group refer to CF ₃ as well as chlorine, bromine, fluorine, and iodine.
[164] As used herein alone or as part of another group, the term “acyl” refers to a carbonyl group (C═O) which in turn is bonded to a straight or branched alkyl group of 1 to 4 carbon atoms, including but not limited to acetyl [-(C═O) CH ₃ ], propionyl [-(C═O) CH ₂ CH ₃ ], and butyryl [— (C═O) CH ₂ CH ₂ CH ₃ ].
[165] As used herein, alone or as part of another group, the term “hydroxyalkyl” refers to a straight chain alkyl radical containing 1 to 2 carbons attached to a hydroxyl group via an effective carbon atom, but is not limited thereto. , Hydroxymethyl (-CH ₂ 0H), 1-hydroxyethyl [-CH ₂ (OH) CH ₃ ], and 2-hydroxyethyl (-CH ₂ CH ₂ 0H).
[166] As used herein, alone or as part of another group, the term “aminoalkyl” refers to a straight chain alkyl radical containing 1 to 2 carbons attached to a first, second, or third amino group via an effective carbon atom, Without limitation, aminomethyl (-CH ₂ NR ₂ ), 1-aminoethyl [-CH ₂ (NR ₂ ) CH ₃ ], and 2-aminoethyl (-CH ₂ , wherein R is a hydrogen atom or a methyl or ethyl group CH ₂ NR ₂ ).
[167] The compound of formula I, II or III may be in the form of salts, in particular pharmaceutically acceptable salts. If the compounds of formula I, II or III have, for example, at least one base center, they can form salts with the addition of an acid. They are, for example, strong inorganic acids such as mineral acids, strong organic carboxylic acids such as alkanescarboxylic acids of 1 to 4 carbon atoms, unsubstituted or substituted with sulfuric acid, phosphoric acid or hydrohalic acid, for example by halogen. Together with acetic acid, oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid with saturated or unsaturated dicarboxylic acid, ascorbic, glycolic, lactic, malic with hydroxycarboxylic acid , Tartaric or citric acid, an amino acid (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or for example aryl unsubstituted or substituted by halogen, or (C _1- Together with organic sulfonic acids such as C ₄ ) -alkyl-sulfonic acid, they form methane or p-toluenesulfonic acid. Salts in which the corresponding acid is added may be formed to have additional base centers, if desired. Compounds of formula I, II or III having at least one acid group (eg COOH) may also form salts with bases. Suitable salts with bases are, for example, metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or morpholines, thiomorpholines, piperidine, pyrrolidines, for example Mono-, di- or tri-lower alkylamines such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethyl-propylamine, or for example mono, di, or tri- Salts with ammonia or organic amines such as mono, di, or trihydroxy lower alkylamines such as ethanolamine. Corresponding internal salts may be further formed. Salts which are unsuitable for pharmaceutically use but which can be used, for example, to separate or purify the compounds of formula I, II or III or their pharmaceutically acceptable salts are also included.
[168] Preferred salts of the compounds of formulas I, II or III containing base groups include monohydrochloride, hydrosulfate, methanesulfonate, phosphate or nitrate.
[169] Preferred salts of the compounds of formula I, II or III containing acid groups include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
[170] The compounds of the present invention comprise at least one chiral center and thus exist as optical isomers. The present invention therefore includes optically inert racemic ( rac ) mixtures (one-to-one mixing of enantiomers), optically pure individual enantiomers, as well as optically enriched scalemic mixtures. Compounds of the present invention may also exist as diastereomers, including one or more chiral centers. Thus, when the compounds of the present invention have one or more stereocenters, not only diastereomeric mixtures but also individual diastereomers are included. The compounds of the present invention may also contain acyclic alkenes or oximes and therefore may exist as E (entgegen) or Z (zusammen) isomers. The present invention therefore encompasses each of the E or Z isomers as well as mixtures of the E and Z isomers when the compound contains acyclic alkene or oxime functional groups. Also included within the scope of the present invention are polymorphs, hydrates, and solvates of the compounds according to the invention.
[171] Prodrugs of the compounds according to the invention are also included within the scope of the invention. In general, such prodrugs may be functional derivatives of the compounds of the present invention that can be converted to the required compounds immediately in vivo. Thus, in the methods of treatment of the present invention, the term “administration” encompasses treatment of various conditions described in the specifically disclosed compounds or in compounds not specifically disclosed, but after administration to the patient is converted to the particular compound in vivo. Traditional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "prodrug design" (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated by reference in its entirety. Metabolites of compounds include the active species produced when the compounds of the invention are introduced into a biological environment.
[172] The invention also relates to a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier.
[173] The invention also relates to a method of making the pharmaceutical composition according to the invention.
[174] The present invention also provides a variety of symptoms associated with estrogen function by administering the compounds and pharmaceutical compositions according to the invention to mammals in need thereof, such as bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, Fibroids, autoimmune disease, lungs, colon, breast, uterus, or prostate cancer, hot flashes, cardiovascular disease, cognitive impairment, cerebral artery degeneration, restinosis, gynecomastia, angiomyocyte proliferation, obesity and A method for preventing or treating urinary incontinence.
[175] The invention also relates to a method for reducing bone loss, lowering LDL cholesterol levels and inducing vasodilatory effects by administering the compounds and pharmaceutical compositions according to the invention to mammals in need thereof.
[176] The novel compounds of the present invention can be prepared according to the following schemes and examples using the appropriate materials and can be further embodied by the specific examples below. However, only the compounds shown in the examples should not be construed as forming the kind regarded as the present invention. Those skilled in the art will appreciate that various modifications of conditions and changes in the following preparations can be used to prepare these compounds. Compounds I and II of the present invention are prepared according to the general method as shown in Schemes 1-4 and also as described. Compound III of the present invention is prepared according to the general method as shown in Scheme 5-6 and as described. All temperatures refer to degrees Celsius unless otherwise specified. The following describes the abbreviations to be used below reagents, expressions or equipment: 20-25 ° C. (room temperature, rt), molar equivalents (eq.), Dimethyl formamide (DMF), dichloromethane (DCM), ethyl acetate (EtOAc), tetrahydrofuran (THF), lithium isopropylamide (LDA), methyl t -butyl ether (MTBE), rotary glass paper coated with a mixture of gypsum and silica gel used for chromatographic purification (chromatto Tron, Chromatronron), Preparative Liquid Chromatography (PHPLC), Gas Chromatography Mass Spectroscopy (GC-MS), Electrospray Mass Spectroscopy (ES-MS) to be.
[177] The general route for the structure of the tetrahydro-phenanthrone nucleus of formulas I and II is shown in Scheme 1. This method is described in Dyker, et al., J. Org. Chem. Based on chemistry described by 1998, 63, 6043-6047. In step 1, aryl iodide 1 is paired with homoallyl alcohol 2a or 2b under the influence of a palladium catalyst to produce 3a or 3b, respectively. Compounds 3a or 3b are then cyclized under acid or base conditions in step 2 to form tetrahydro-phenanthrone derivatives 4 or 5, respectively.
[178] Representative protocols for Step 1 (Method A) and Step 2 (Method B or Method C) of Scheme 1 are as follows:
[179] [Method A]
[180] Aryl iodide 1 (Scheme 1, 1.0 eq.), Homoallyl alcohol "J" (2, "K" eq. In Scheme 1), ethyl diisopropylamine ("L" eq.), And DMF (aryl iodide) To a mixture of LiCl (1.0 eq.) In "M" mL / mmol) of water, Pd (OAc) ₂ (0.05 eq.) Is added. This mixture is then stirred in a sealed tube for "N" time before adding DCM at 80 ° C. under a nitrogen atmosphere.
[181] This DCM solution is then filtered through a short plug of silica gel and eluted with EtOAc before vacuum to produce the raw material in vacuo (10 mmHg / 60 ° C.).
[182] [Method B]
[183] The raw material in Method A is taken up in DCM ("N" mL) and treated with concentrated HCl (aq., "O" mL) for "Q" time at concentrated "P" ° C. The mixture is then washed first with saturated aqueous sodium hydrogen carbonate and then with water. Back extraction of the mixed aqueous layer is performed with EtOAc. The mixed organic layer is then dried over anhydrous sodium sulfate and concentrated in vacuo to produce a raw material.
[184] [Method C]
[185] The raw material from Method A is dissolved in EtOAc (“N” mL) and this volume 1/3 of saturated HCl / EtOAc is added and stirred at r.t. for “Q” time. The raw material is obtained by concentrating this solution in vacuo.
[186] Homoallyl alcohols 2a and 2b used as starting materials in Scheme 1 can be prepared by known methods such as allylation of aldehydes when not commercially available (Wada, et al., Tetrahedron Lett. 1997, 38, 8045-8048 and references cited therein). A general method of using Mg / BiC1 ₃ as a reagent for this purpose is outlined in Scheme 2. When allyl bromide 6a or 6b reacts with formaldehyde under these conditions, first homoallyl alcohol 2a is produced. Second homoallyl alcohol 2b is obtained by reaction with aldehyde 7 by a similar method. Representative protocols for the reactions shown in Scheme 2 are as follows:
[187] [Method D]
[188] While stirring at room temperature, allyl bromide 6a or 6b (Scheme 2, 1.0 eq.) Was converted to bismuth trichloride (1.1 eq.) And magnesium scrap (2.4 eq.) In THF-H ₂ 0 (4: 1) added to the mixture. After 20 minutes of further stirring, aldehyde formaldehyde 7 (Scheme 2, “J” eq.) Is added to the portion. The resulting mixture is then stirred for "K" time before cooling to 1.OM HCl. The organic material is extracted with diethyl ether and the mixed organic extracts are washed with water and saturated aqueous NaCl, then dried over anhydrous sodium sulfate and concentrated in vacuo to produce a raw material.
[189] Scheme 1: General route to tetrahydrophenanthrene-3-one (4) and tetrahydro-phenanthrene-1-one (5) derivatives.
[190]
[191] Scheme 2: Synthesis of homoallyl alcohol by allylation of aldehyde.
[192]
[193] Substituted benzylideneacetone 1 used as starting material in Scheme 1 may be prepared from the corresponding aromatic aldehyde 8 by traditional methods of aldol condensation with ketone 9 as shown in Scheme 3. If ketone 9 is not symmetrical (ie, R ^II and R ^III are different), the reaction site can be controlled by varying the reaction conditions according to known methods (Irie, et al., Bull. Chem. Soc. Jpn. 1980,53, 1366-1371 and Iranpoor, et al., Tetrahedron 1998, 55, 9475-9480 and references cited therein). If R ¹ of 8 is hydrogen, then the non-hydrogen protecting group can be introduced in 1 phase after aldol condensation.
[194] Scheme 3: Synthesis of substituted benzylideneacetone derivatives.
[195]
[196] 4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one-4 (Scheme 1), as shown in Scheme 4, uses a well-known method for the reaction of an enone and a carbonyl functional group. It can be further modified by. For example, in the step of Scheme 41, the non-hydrogen R ^Ⅵ in the 10-substituent is R ^Ⅵ - can be introduced by treatment of 4 with yugidong (organocopper) reagents which have a substituent (Lipshuts BH "Organometallics in Synthesis" See "Synthetic Procedures Involving Organocopper Reagents" , Schlosser M. (ed.), John Wiley & Sons 1994). A representative protocol (method E) for the introduction of a non-hydrogen ^RVI -substituent (step 1 of Scheme 4) is as follows:
[197] [Method E]
[198] Organometallic reagent "N" (with stirring) in a cooled mixture (dry ice / acetone bath) of copper (I) -reagent "J"("K" eq.) In (addition) "L" mL of solvent "M""O" eq.) Is added. The mixture is then left at 0 ° C. for 15 minutes before cooling again (dry ice / acetone bath). Add Enone 4 (Scheme 4, 1.0 eq.) Solution drop by drop. Before cooling to NH ₄ Cl, stirring is continued at “P” ° C. for “Q” time. The organic material is then dissolved in EtOAc. This solution is dried over anhydrous sodium sulfate and filtered through a short plug of silica gel before concentrating in vacuo to produce a raw material.
[199] Another example is the introduction of hydrogen as ^RVI -substituent at (10) by hydrogen addition of 4 in step 1 of Scheme 4. A representative protocol (method F) for hydrocracking is as follows:
[200] [Method F]
[201] Empty the flask containing the mixture of the substrate to be hydrogenated / hydrocracked (1.0 eq.) And the catalyst "L" ("M" mg) in solvent "J" ("K" mL) and "N" at room temperature and atmospheric pressure. Fill with hydrogen three times before stirring for hours. Workup is done by filtration of the mixture through a short plug of Celite®, after which the filtrate is concentrated in vacuo to obtain the raw material.
[202] In step 2 of Scheme 4, the carbonyl group of ketone 10 can be altered using typical carbonyl chemistry to produce derivative 11 with R ^VII -and R ^VII -substituents introduced. For example, thioketals can be prepared from 10 by treatment with thiols or dithiols in acidic conditions. A representative protocol (method G) for preparing ^thioketals (11, R ^Ⅶ , R ^Ⅷ = S-alkyl) from 10 is as follows:
[203] [Method G]
[204] Thiol or dithiol "K"("L" eq.) Is added to a cooled (dry ice / acetone bath) solution of ketone 10 (Scheme 4, 1.0eq.) In dry DCM ("J" mL), and Then BF ₃ 0Et ₂ (1.5 eq.) Is added with stirring. The mixture is then slowly brought to room temperature and stirred for "M" time at that temperature before cooling to saturated aqueous sodium carbonate. The organic material is dissolved in EtOAc. This solution is dried over anhydrous sodium sulfate and filtered through a short plug of silica gel before concentrating in vacuo to produce a raw material.
[205] Another embodiment is to provide a ketal of general formula 11 (R ^{Ⅶ, Ⅷ} R = O- alkyl) from 10. Representative protocols (method H) are as follows:
[206] [Method H]
[207] Cell mixture of ketone 10 (Scheme 4, 1.0 eq.), Alcohol or diol "J" ("K" mL), Amberlyst15® ("L" mg), and DCM ("M" mL) Stir at "N" ° C for "O" hours before filtering through the Lite®. The Celite®-bed is then washed with DCM, the mixed filtrate is washed with water, dried over anhydrous sodium sulfate and filtered through a short plug of silica gel. The raw material is obtained by concentrating this filtrate in vacuo.
[208] The R ^II -and R ^III -substituents of 10 (Scheme 4) can be separated from hydrogen to non-hydrogen by alkylation of the corresponding enolates of 10. Thus, non-hydrogen R ^II -substituents can be introduced by alkylation of 10 (Enoleate B) while non-hydrogen R ^III -substituents can be introduced by alkylation of 10 (Enoleate A). Enoleate 10 (Enoleate A) can be prepared from (4) (R ^III = H), for example, by adding 1,4- to the enone moiety of a negative nucleophilic atom. Another common method for the production of enolates involves treating the corresponding ketone with a strong base such as LDA. The R ^Ⅶ -and R ^Ⅷ -substituents of 11 are attached via a sulfur atom (ie, R ^Ⅶ , R ^Ⅷ = S-alkyl) as in ^thioketal, and one or both of R ^Ⅶ and R ^는 are Raney Can be converted to hydrogen by treatment of desulfurization chemicals such as) -Ni. Two representative protocols (Method I and Method J) for the desulfurization of Scheme 11 (Scheme 4) are as follows:
[209] [Method I]
[210] To a stirred solution of thioketal 11 (Scheme 4, R ^케 , R ^Ⅷ = S-alkyl, 1.0 eq.) In anhydrous ethanol (“J” mL) is added Raney-Ni (“K” mg). The weight of Raney-Ni is measured by the weight of the wet material obtained on a flat snowplow after collecting from the precipitated suspension in anhydrous ethanol. The mixture is then stirred at high speed for "M" time at "L" ° C before filtration through Celite® and washed continuously with anhydrous ethanol and EtOAc. The raw material is obtained by concentrating the mixed filtrate and washing in vacuo.
[211] [Method J]
[212] Al-Ni-alloy (Aldrich no. 22, 165-1, "J" in thioketal 11 (Scheme 4, R ^Ⅶ , R ^Ⅷ = S-alkyl, 1.0 eq.) And anhydrous EtOH ("K" mL)) To the stirred mixture of mg) slowly add 3.0 M NaOH (aq., "L" drops) at room temperature. Another portion of anhydrous EtOH (“M” mL) is added after stirring for “N” hours before filtering through Celite®. The filtrate is then partitioned between ammonium acetate and MTBE. The organic layer is dried over anhydrous sodium sulfate and filtered through a short plug of silica gel before concentrating in vacuo to obtain the raw material.
[213] Scheme 4: Introduction of more substituents and 4a, 9,10,10a-tetrahydro- 4H-Synthetic formula of phenanthrene-3-one.
[214]
[215] Removing protecting group (i.e., R ^I with hydrogen in the non-hydrogen-substituent changes in) is R ^I - can be done by a number of different known processes depending on the nature of the substituents. For example, protecting groups can be removed by hydrocracking if R ^I = CH ₂ Ph (refer to method F for a representative protocol) and protecting groups can be removed by treatment with BBr ₃ if R ^I = CH ₃ . (See Method K for a representative protocol).
[216] [Method K]
[217] Cooling of the aryl methylether substrate (1.0 eq.) In dry DCM ("J" mL) (dry ice / acetone bath) and addition of BBr ₃ (1.OM sol in DCM, "K" eq.) To the stirred solution do. The mixture is then brought to “L” ° C. and stored at this temperature for “M” hours before being cooled with saturated aqueous sodium carbonate. The organic layer is dissolved in EtOAc. This solution is dried over anhydrous sodium sulfate before passing through a short plug of silica gel and concentrated in vacuo to provide the raw material.
[218] The general route for the structure of the tetrahydro-phenanthrone nucleophilic atom of formula III is shown in Scheme 5. This method is described in CR Hebd Seances Acad Sci, 1957, 245 , described by Fetizon and Delobelle; 850-852 and Howell and Taylor, J. Chem. Soc, 1958, 1248-1253. In step 1, tetratron 12 is formed by oxidation of Enone 11 by mCPBA. Robinson-type annulations of Enone 13 and Tetraron 12 produce phenanthrone 14. Representative protocols of Step 1 (Method L) and Step 2 (Method M) of Scheme 5 are as follows:
[219] [Method L]
[220] To the cooled (˜5 ° C.) olefin solution in 1.0 eq. Of DCM was added mCPBA (50 weight% dispersed in water, 1.2 eq.) With stirring at a rate that the temperature never exceeded 10 ° C. The mixture was then stirred for 12 hours before filtering through Celite® at 5-10 ° C. and the filtrate was washed with saturated aqueous sodium carbonate, water, and saturated aqueous NaCl. To the solution thus obtained was added PPTS (0.05 eq.) Before heating at reflux for 2.5 h. Then it was concentrated in vacuo to get the raw material.
[221] [Method M]
[222] To a stirred solution of tetraron (1.0 eq.) In toluene or benzene, an enone coupling partner (1.2 eq.) Was first added followed by a pTsOH catalyst (0.05 eq.). The mixture was heated at 85 ° C. for 20 hours and then filtered through a short plug of silica gel. The plug was eluted with sufficient MTBE to ensure that all the desired product was delivered and the eluate was concentrated in vacuo to obtain the raw material.
[223] Scheme 5: General route of tetrahydrophenanthrene-2-one derivatives 4
[224]
[225] Removing protecting group (i.e., R ^I in the ratio of hydrogen to the hydrogen-conversion of the substituent) is R ^I - it can be done in a number of ways of the other known, depending on the nature of the substituents. For example, when R ^I = CH ₃ , protecting group removal can be done by treatment of BBr ₃ (see method 0 for a representative protocol).
[226] [Method O]
[227] To the stirred solution of arylmethylether (1.0 eq.) In dry DCM (dry ice / acetone bath) and BBr ₃ (1.0 M sol in DCM) were added. The mixture was then allowed to reach -20 ° C and held at that temperature for a predetermined time before cooling with saturated aqueous sodium carbonate. At this time the organic material was dissolved in EtOAc. This solution was dried (sodium sulphate anhydrous) and concentrated in vacuo to yield the raw material before passing through a short plug of silica gel.
[228] 3,4,4a, 9,10,10a- hexahydro - lH - phenanthrene-2-circle 14 (Scheme 5) in a known method for the reaction of carbonyl group paddy feature as illustrated in Scheme 6 It can be further formulated by use. For instance, non-hydrogen R ^Ⅳ in 20-substituent is R 14 and ^Ⅳ -. Treatment of yugidong reagent having a substituent (Lipshuts BH "Organomettalics in Synthesis" in "Synthetic Procedures Involving Organocopper Reagents", Schlosser M. (ed), John Wiley & Sons 1994), or treatment of 4 with an organotitaniumate complex (Flemming, S. et. Al., Tet. Lett 1994, 35 (33), 6075-6078 and Kabbara, S. et. al., Liebigs Ann. 1995, 401-406). The protocol for the introduction of non-hydrogen R ^IV -substituents (see Step 1 of Scheme 6, Methods P and Q) is as follows:
[229] [Method P]
[230] Alkyl lithium solution was added to the cooling (dry ice / acetone bath) suspension of CuCN in diethyl ether while stirring. The mixture was then allowed to reach 0 ° C. before cooling again (dry ice / acetone bath). Next Enon 1.0 eq. The solution was added dropwise. Stirring was continued at that temperature for a designated time before cooling to saturated aqueous NH ₄ Cl. The organic material was then dissolved in EtOAc. This solution was dried (sodium sulfate anhydride) and filtered through short silica gel before concentration in vacuo to yield the raw material.
[231] [Q]
[232] An alkyl magnesium chloride (alkyl magnesium chloride) solution was added with stirring to a cooled (-30 ° C.) suspension of titanium (IV) isopropoxide in anhydrous THF. The mixture was then allowed to reach 0 ° C. before cooling again (dry ice / acetone bath). Then nickel (II) acetylacetonate (0.05 eq.) And a solution of enone (1.0 eq.) In dry THF were added dropwise. Stirring was continued for 30 min at -15 [deg.] C. and the next mixture was stirred at r.t overnight. The mixture was diluted with diethyl ether and cooled with water. After stirring for 1 hour, the precipitate was filtered off and the remainder was concentrated in vacuo to yield raw material.
[233] In step 2 of Scheme 6, the carbonyl functional group of 14 can be reduced using conventional carbonyl chemistry. Representative protocols for the reduction of carbonyl groups (method R) are as follows:
[234] [Method R]
[235] Sodium borohydride (5.0 eq.) Is added to the cooled (-40 ° C.) solution of enone (1.0 eq.) In acetonitrile with stirring, followed by trifluoro acetic acid (volume of acetonitrile 1/4) was added. The remaining mixture was then allowed to reach room temperature for nearly 1 hour and then stirred at room temperature for 2 hours before cooling with saturated aqueous sodium carbonate. The organic material was dissolved in EtOAc, dried (sodium sulfate) and filtered through short silica gel before concentration in vacuo to yield the raw material.
[236] Another example is the introduction of hydrogen, such as the ^RIV -substituent, in (10) by hydrogenation of 4 or 6 (steps 3 and 4 of Scheme 6). A representative protocol (method S) for hydrogenation is as follows:
[237] [Method S]
[238] The flask containing the solution of the substrate (1.0 eq.) And the palladium catalyst was emptied and the mixture filled with hydrogen three times before stirring at room temperature, atmospheric pressure for the specified time. Work up was done by filtration of the mixture through a short plug of Celite®, and the filtrate was concentrated in vacuo to get the raw material.
[239] In steps 5 and 6 of Scheme 6, the carbonyl group of ketone 7 can be changed using traditional carbonyl chemistry to produce derivatives 19 and 20. For example, thioketal 19 can be prepared from 17 by treatment with dithiol under acidic conditions, and N-oxime 20 (R ^Ⅶ = N) can be prepared from 17 by hydroxyamine treatment and thioketan 10 (R ^Ⅶ = S) can be prepared from 17 by treatment with Lawesson's reagent. Representative protocols (methods T and U) for the preparation of thioketal ((19), R ^V , ^RVI = S-alkyl) and N-oxime from 17 are as follows:
[240] [Method T]
[241] To a cooled (dry ice / acetone bath) solution of ketone 17 (Scheme 6, 1.0 eq.) In dry DCM was added dithiol (2.0 eq.) Followed by addition of BF ₃ · OEt ₂ (1.5 eq.) With stirring. It was. The mixture was then allowed to slowly reach room temperature and stirred for a designated time before cooling to saturated aqueous sodium carbonate at that temperature. At this time, the organic layer was dissolved in EtOAc. This solution was dried over anhydrous sodium sulfate before being concentrated in vacuo through short silica gel to obtain a raw material.
[242] [Method U]
[243] A mixture of ketone, NH ₂ 0H.HCl (10 eq.) And sodium acetate (10 eq.) Was stirred in methanol under N ₂ atmosphere at room temperature for 3 days. Water was added and then the organic material dissolved in EtOAc. This solution was dried over anhydrous sodium sulfate before being concentrated in vacuo through short silica gel to obtain a raw material.
[244] Method V
[245] 5-Bromo-l-pentene in anhydrous THF is added to magnesium in anhydrous THF at the rate at which the mixture is gently refluxed (I ₂ crystals are added to start the reaction). After addition, the reaction mixture was heated at 70 ° C. for 30 minutes and then allowed to cool to room temperature.
[246] To a stirred solution of Grignard reagent (4.0 eq.) Described above is added ketone 20 (l eq.) Of Scheme 4 at room temperature and the reaction mixture is stirred for 20 minutes before cooling to saturated aqueous NH ₄ Cl. The organic layer was then dissolved in EtOAc. The solution is dried over anhydrous sodium sulfate and filtered through short silica gel to obtain the raw material.
[247] Scheme 6: Formula at position 10 of tetrahydrophenanthrene-2-one 14.
[248]
[249] The following examples are specific examples of the present invention, but do not limit the present invention. Examples 1-54 relate to compounds of Formulas I and II, and Examples 55-75 relate to compounds of Formula III.
[250] Example 1 Synthesis of (rac)-(4aS, 10aS) -7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (El).
[251]
[252] Step 1: 2-iod-4-methoxy-benzaldehyde. POCl ₃ (1.1 eq.) was added dropwise to a stirred mixture of m -iodine-anisole (47.2 g, 202 mmol) and DMF (20 mL). The mixture was then heated at 100 ° C. for 12 hours and then stirred again at 100 ° C. for 12 hours before further addition of DMF (12 mL) and POC1 ₃ (0.5 eq.). The dark mixture was poured into 500 mL of 2.0 M NaOH before extraction with diethyl ether and DCM. The mixed extract is dried over anhydrous sodium sulfate and filtered through short silica gel to obtain the raw material. The mixed extract was dried over anhydrous sodium sulfate before being concentrated in vacuo to get the raw material as a dark syrup, and twice with EtOAc / n-heptane (8: 2, v: v) as eluent using silica gel flash chromatography. Purified. The solution obtained after chromatography was slowly concentrated to give 2-iod-4-methoxy-benzalade as a white needle. Another portion of 2-iod-4-methoxy-benzalade was obtained from the mother liquor. ¹ H NMR (270 MHz, CDCl ₃ ) δ 9.90 (s, 1H), 7.85 (d, 1H), 7.40 (d, 1H), 6.95 (ddd, 1H), 3.85 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 195.05, 165.5, 131.75, 128.75, 125.60, 114.95, 102.30, 55.70.
[253] Step 2: 4- (2-iodo-4-methoxy-phenyl) -but-3-ene-2-one. Aqueous NaOH (16.0 M, 1.2 eq.) Was refluxed in a stirred mixture of 2-iod-4-methoxy-benzalade (558 mg, 2.13 mmol) in a water-acetone mixture (6.0 mL, 3: 2). At 10 min before heating. The yellow precipitate obtained by cooling to room temperature was collected, washed with water and dried over P ₂ O ₅ to give 4- (2-iodo-4-methoxy-phenyl) -but-3-ene-2-one. . ¹ H NMR (270 MHz, CDC1 ₃ ) δ 7.70 (d, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 6.90 (DD, 1H), 6.45 (d, 1H), 3.80 (s, 3H), 2.40 (s, 3H).
[254] Step 3: (rac)-(4aR, 10aS) -7 -methoxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4aS, 10aS) -7- Methoxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one. Aryl iodine 4- (2-iod-4-methoxy-phenyl) -but-3-ene-2-one (362 mg) was prepared using Method A ("J" = but-3-en-1-ol , "K" = 2.5, "L" = 8. 0, "M" = 4, "N" = 3.5). The obtained product was treated according to Method B ("N" = 3 0, "O" = 0.3, "P" = 25, "Q" = 20). The obtained raw material was EtOAc: n-heptane (2.5: 97.5, 5 : 95, 1: 9, stepwise gradient) was purified by silica gel flash chromatography using eluent, and then fractionated by PHPLC. The first eluted fraction is (rac)-(4aR, 10aS) -7 -methoxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (yellow solid), the second is (rac )-(4aS, 10aS) -7-methoxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (white solid).
[255] (rac)-(4aR, 10aS) -7 -methoxy-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one: ES / MS m / z: 229.3 (pos., M + H ); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.95-7.05 (m, 2H), 6.75 (dd, 1H), 6.65 (d, 1H), 6.05 (dd, 1H), 3.80 (s, 3H), 3.35- 3.45 (m, 1H), 2.85-2.95 (m, 2H), 2.55-2.75 (m, 3H), 1.70-2.00 (m, 2H).
[256] (rac)-(4aS, 10aS) -7-methoxy-4a, 9,10,1Oa-tetrahydro- 4H -phenanthrene-3-one: ES / MS m / z: 229.3 (pos., M + H ); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.10 (d, 1H), 6.95 (dd, 1H), 6.75 (dd, 1H), 6.70 (d, 1H), 6.10 (dd, 1H), 3.75 (s, 3H), 3.20 (dd, 1H), 2.90-3.10 (m, 3H), 2.25-2.50 (m, 2H), 2.10-2.20 (m, 1H), 1.65-1.80 (m, 1H).
[257] Step 4: (rac)-(4aS, 10aS) -7-methoxy-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one.
[258] Substrate (rac)-(4aS, 10aS) -7-methoxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (30 mg) Method F ("J" = Methanol, " K "= 5.0," L "= 5% Pd / C," M "= 10," N "= 24) and treated according to (rac)-(4aS, 1OaS) -7-methoxy-1,4, 4a, 9, 10, 10O-hexahydro- 2H -phenanthrene-3-one was obtained. ES / MS m / z: 231. 1 (pos., M + H).
[259] Step 5: (rac)-(4aS, 10aS) -7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one.
[260] Substrate (rac)-(4aS, 10aS) -7 -methoxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (28 mg) Method K (“J” = 1.0, "K" = 3.0, "L" = -20, "M" = 4.0). The raw material was purified on chromatography using EtOAc: n-heptane (3: 7, v: v) as eluent to give (rac)-(4aS, 10aS) -7-hydroxy-1,4,4a, 9,10. , 10a-hexahydro- 2H -phenanthrene-3-one (white solid) was obtained. ES / MS m / z: 217.0 (pos., M + H), 215.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.00 (d, 1H), 6.65 (dd, 1H), 6.60 (s, 1H), 4.70 (s, 1H), 3.05-3.15 (m, 1H), 2.75- 3.00 (m, 2H), 2.60-2.70 (m, 1H), 2.35-2.55 (m, 2H), 2.25 (t, 1H), 2.05-2.15 (m, 1H), 1.95-2. 05 (m, 1 H), 1.40-1.80 (m, 3 H).
[261] Example 2 (rac)-(4aS, 10aS) -3,3- ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene ( Synthesis of E2).
[262]
[263] Ketone (rac)-(4aS, 1OaS) -7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (9.3 mg) was prepared using Method G ("J"). = 2.5, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 12). The raw material was purified on chromatography using EtOAc: n-heptane (2: 8, v: v) as eluent to give (rac)-(4aS, 10aS) -3,3- ethanediyldimercapto-7-hydroxy-. 1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (white solid) was obtained. ES / MS m / z: 292.9 (pos., M + H), 290.8 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.10 (d, 1H), 6.60 (dd, 1H), 6.55 (d, 1H), 4.50 (s, 1H), 3.25-3.40 (m, 4H), 2.70- 2.90 (m, 3H), 2.45-2.55 (m, 1H), 2.20 (dq, 1H), 2.00 (dt, 1H), 1.75-1.90 (m, 3H), 1.40-1.60 (m, 2H), 1.20- 1.35 (m, 1 H).
[264] Example 3: (rac)-(4aR, lOaS) -7-hydroxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one (E3a); And (rac)-(4aS, 10aS) -7 -hydroxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (E3b).
[265]
[266] Step 1: (rac)-(4aR, lOaS) -7-methoxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4aS, lOaS ) -7-methoxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one.
[267] Aryl iodine 4- (2-iodo-4-methoxy-phenyl) -but-3-ene-2-one (325 mg) Method A ("J" = 2-methyl-but-3-ene 1-ol, "K" = 2.5, "L" = 8.0, "M" = 10, "N" = 3.0). The product obtained was then treated according to Method B ("N" = 25, "O" = 0.5, "P" = 40, "Q" = 4). The obtained raw material was purified on chromatography using EtOAc: n-heptane (2: 8, 9: 1, slow step gradient) as eluent. The first eluted fraction contains (rac)-(4aS, 10aS) -7-methoxy-1Oa-methyl-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one (solid), The second is (rac)-(4aR, 10aS) -7 -methoxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4aS, lOaS ) -7-methoxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one, third is (rac)-(4aR, 10aS) -7- meth It contained oxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one.
[268] (rac)-(4aS, 10aS) -7-methoxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one: ES / MS m / z: 243.4 (pos. , M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.00 (d, 1H), 6.90 (d, 1H), 6.75 (dd, 1H), 6.70 (d, 1H), 5.95 (d, 1H), 3.80 (s, 3H), 3.20 (dd, 1H), 3.05 (dd, 1H), 2.90-3.00 (m, 2H), 2.40-2.55 (m, 1H), 1.80-1.90 (m, 2H), 0.95 (s, 3H) .
[269] Step 2: (rac)-(4aR, lOaS) -7 -hydroxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4aS, 10aS ) -7-hydroxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one.
[270] As a substrate, (rac)-(4aR, 10aS) -7-methoxy-1Oa-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4aS, 10aS) ) -7-methoxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one (43 mg, 3: 2) was prepared using Method K ("J" = 3.0, "K" = 4.0, "L" =-20, "M" = 12).
[271] The raw material thus obtained was purified on chromatography using EtOAc: n-heptane (3: 7) as eluent and then fractionated on PHPLC. The first eluted fraction contains (rac)-(4aR, 10aS) -7-hydroxy-10a-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one, the second being (rac)-(4aR, 10aS) -7 -hydroxy-1Oa-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4aS, 10aS) -7 A mixture of -hydroxylOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one.
[272] (rac)-(4aR, 10aS) -7 -hydroxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one: ES / MS m / z: 229.3 (pos. , M + H), 227.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.95 (d, 1H), 6.70 (d, 1H), 6.65 (dd, 1H), 6.60 (d, 1H), 5.95 (d, 1H), 5.00-5.30 ( br.s, 1H), 3.00 (dd, 1H), 2.80-2.85 (m, 2H), 2.65 (dd, 1H), 2.50 (dd, 1H), 1.80-1.95 (m, 1H), 1.60-1.70 ( m, 1 H), 1.15 (s, 3 H); ¹³ C NMR (CDCl ₃ ) δ (rac)-(4aS, 10aS) -7-hydroxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one: ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.95 (d, 1H), 6.90 (d, 1H), 6.60-6.70 (m, 2H), 6.00 (d, 1H), 3.20 (dd, 1H), 3.05 (dd, 1H ), 2.90-3.00 (m, 2H), 2.45 (dd, 1H), 1.80-1.90 (m, 2H), 0.95 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 199.70, 161.05, 154.00, 136.95, 129.25, 127.35, 125.80, 115.55, 113.10, 42.50, 37.50,35.45,34.55, 25.90, 17.00.
[273] Example 4 Synthesis of (rac)-(4aS, 10aS) -10a-butyl-7-hydroxy-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one (E4).
[274]
[275] Step 1: (rac) -2-butyl-but-3-ene-1-l-ol. Raw material using allyl bromide l-bromo-2-heptene (9.5 g) and aldehyde formaldehyde (37% solution in water) according to Method D ("J" = 3.0, "K" = 18) as starting material Got. This was purified by distillation (79-81 ° C / 65 mmHg) to give a colorless oil (rac) -2-butyl-but-3-ene-1-ol. ¹ H NMR (270 MHz, CDCl ₃ ) δ 5.40-5.80 (m, 1H), 4.90-5.20 (m, 2H), 3.85-4.05 (m, 1H-OH), 3.55 (dd, 1H), 3.40 (dd , 1H), 1.90-2.25 (m, 1H), 1.05-1.45 (m, 6H), 0.80 (t, 3H).
[276] Step 2: (rac)-(4as, 10aS) -10a-butyl-7-methoxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one. Aryl iodine 4- (2-iodo-4-methoxy-phenyl) -but-3-ene-2-one (107 mg) was prepared using Method A ("J" = (rac) -2-butyl-butyrate ). 3-en-1-1-ol, "K" = 2.5, "L" = 8.0, "M" = 28, "N" = 72). The resulting product was then treated according to Method B ("N" = 5.0, "O" = 0.5, "P" = 40, "Q" = 2). The obtained raw material (rac)-(4aS, 10aS) -10a- butyl-7-methoxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one was used directly in step 3.
[277] Step 3: (rac)-(4aS, 10aS) -10a- butyl-7-hydroxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one. Substrate (rac)-(4aS, 10aS) -10a-butyl-7-methoxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (10 mg) Method K ("J" = 1.0, "K" = 4.0, "L" = -20, and "M" = 12). The raw material was (rac)-(4aS, 10aS) -10a-butyl-7-hydroxy-4a, 9,10, l0a-tetrahydro- using EtOAc: n-heptane (2: 8) as eluent on chromatography. 4H -phenanthrene-3-one was obtained. ES / MS m / z: 271.3 (pos., M + H), 268.9 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.00 (dd, 2H), 6.70 (dd, 1H), 6.6 (s, 1H), 6.05 (d, 1H), 3.25 (dd, 1H), 3.05 (dd, 1H), 2.85-2.90 (m, 2H), 2.55 (dd, 1H), 2.10-2.15 (m, 1H), 1.70-1.80 (m, 1H), 1. 15-1.50 (m, 6H), 0.85 ( t, 3H).
[278] Example 5: (rac)-(1S, 4aS, 10aS) -1-butyl-7-hydroxy-1,4,4a, 9,10,10ahexahydro- 2H -phenanthrene-3-one (E5a) ; And (rac)-(1R, 4aS, 10aS) -1-butyl-7-hydroxy1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E5b).
[279]
[280] Step 1: (rac)-(1S, 4aS, 10aS) -1- butyl-7-methoxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one and (rac )-(1R, 4aS, 10aS) -1- butyl-7-methoxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one. Enon (rac)-(4aS, 10aS) -7-methoxy-4a, 9,10,10a-tetrahydro- 4H in Example 1 dissolved in diethyl ether / THF (3.0 mL, 2: 1) Phenanthrene-3-one (39 mg) was prepared using Method E ("J" = CuCN, "K" = 2.2, "L" = 2.0, "M" = diethyl ether, "N" = n-butyl lithium [hexane 1.6M solution in water], "O" = 4.2, "P" = -78, "Q" = 0.5). (rac)-(1S, 4aS, 10aS) -1-butyl-7-methoxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one and (rac)-( lR, 4aS, lOaS) -1-Butyl-7-methoxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one is a raw material consisting of the following steps (step 2 ) Was used.
[281] Step 2: (rac)-(1S, 4aS, 10aS) -1- butyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one and (rac )-(lR, 4aS, lOaS) -1-butyl-7-hydroxy-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one. As a substrate, (rac)-(1S, 4aS, 10aS) -1- butyl-7-methoxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3- in Step 1 A mixture of raw and (rac)-(1S, 4aS, 10aS) -1-butyl-7methoxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (47 mg ) Was treated according to method K ("J" = 1.0, "K" = 3.0, "L" = -20, "M" = 4.0). The obtained raw material was purified on chromatography using (rac)-(1S, 4aS, 10aS) -1- butyl-7-hydroxy-1,4 using EtOAc: n-heptane (3: 7, v: v) as eluent. , 4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one and (rac)-(1R, 4aS, lOaS) -1 -butyl-7-hydroxy-1,4,4a, 9, A mixture of 10,10a-hexahydro- 2H -phenanthrene-3-one was obtained as a glass. ES / MS m / z (mixture): 273.1 (pos., M + H), 271.0 (neg., MH); ¹ H NMR (distinguishable from signal of mixture, 270 MHz, CDCl ₃ ) δ 7.05 (d, H-C5, minority isomer), 7.00 (d, H-C5, minority isomer), 4.57 (s, -OH, minority isomer ), 4.55 (s, -OH, major isomer).
[282] Example 6: (rac)-(1S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10a- Octahydro-phenanthrene; (E6a) and (rac)-(1r, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, Synthesis of 9,10,10a-octahydro-phenanthrene (E6b).
[283]
[284] Ketone (rac)-(lS, 4aS, 1OaS) -1-butyl-7-hydroxy-1,4,4a, 9,10,1Oa-hexahydro-2H-phenanthrene-3-one and (rac)- (1R, 4aS, 1OaS) -1-butyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro-2H-phenanthrene-3-one (2: 1 or 1: 2, 10.5 mg) was treated according to Method G ("J" = 2.5, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 12). The obtained raw material was subjected to (rac)-(1S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7- hydr on EtOAc using EtOAc: n-heptane (2: 8) as eluent. Roxy-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene and (rac)-(1R, 4aS, 1OaS) -1-butyl-3,3-ethanediyldimercapto-7 A mixture of -hydroxy-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene was obtained as a colorless glass. ES / MS m / z (mixture): 349.3 (pos., M + H), 347.2 (neg., MH); ¹ H NMR (distinguishable from signal of mixture, 270 MHz, CDCl ₃ ) δ 7.110 (d, H-C5, minor isomer), 7.120 (d, H-C5, major isomer), 4.505 (s, -OH, minor isomer ), 4.495 (s, -OH, major isomers), 0.875 (t, CH, minor isomers), 0.905 (t, CH ₃ , major isomers).
[285] Example 7: (rac)-(1S, 4aS, 10aS) -1-butyl-7-hydroxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3 Synthesis of Circle (E7).
[286]
[287] Step 1: (rac)-(1S, 4aS, 10aS) -1-butyl-7-methoxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3- won. Enon (rac)-(4aS, lOaS) -7-methoxylOa-methyl-4a, 9,10,10a-tetrahydro-4H-phenanthrene in Example 3 dissolved in diethyl ether (1.5 mL) 3-one (39 mg) Method E ("J" = CuCN, "K" = 2.0, "L" = 2.5, "M" = diethyl ether, "N" = n-butyl lithium [1.6 in hexane M solution], "O" = 4.0, "P" = -78, "Q" = 0.5) and used in the next step as raw material (rac)-(1S, 4aS, 10aS) -1-butyl-7 -Methoxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one was obtained.
[288] Step 2: (rac)-(1S, 4aS, 10aS) -1-butyl-7-methoxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3- won. (Rac)-(1S, 4aS, 10aS) -1-butyl-7-methoxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene as a substrate at all stages 3-one (49 mg) was treated according to Method K ("J" = 2.0, "K" = 3.5, "L" = -20, "M" = 5.0). The obtained raw material was prepared using (rac)-(1S, 4aS, 10aS) -1-butyl-7- using EtOAc: n-heptane (2: 8, 4: 6, v: v; stepwise gradient) as an eluent on a chromatography. Hydroxy-lOa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one was obtained. ES / MS m / z: 287.2 (pos., M + H), 285.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.90 (d, 1H), 6.60-6.65 (m, 2H), 5.00 (br. S, 1H0, 3.00 (dd, 1H), 2.70-2.95 (m, 4H) , 2.45 (dt, 1H), 2.30 (t, 1H), 1.90-2.05 (m, 1H), 1.70-1.80 (m, 1H), 1.55-1.65 (m, 1H), 1.40-1.50 (m, 2H) , 1.10-1.35 (m, 4H), 1.05 (s, 3H), 0.90 (t, 3H); ¹³ C NMR (CDCl ₃ ) δ 14.00, 17.95, 22.70, 26.70, 27.95, 30.15, 32.55, 35.05, 38.60, 41.75, 41.85, 46.35, 112.85, 115.05, 126.25, 130.45, 137.25, 154.05, 212.40.
[289] Example 8 (rac)-(1S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-l0a-methyl-1,2,3,4,4a, 9, Synthesis of 10,10a-octahydro-phenanthrene (E8).
[290]
[291] Ketone (rac)-(1S, 4aS, 10aS) -1-butyl-7-hydroxy-1Oa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one ( 11 mg) was treated according to Method G ("J" = 2.0, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 12). The raw material was (rac)-(1S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7 using EtOAc: n-heptane (2: 8, v: v) as eluent on chromatography. -Hydroxy-10a-methyl-1,2,3,4,4a, 9,10, lOa-octahydro-phenanthrene was obtained. ES / MS m / z: 363.4 (pos., M + H), 361.3 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.05 (d, 1H), 6.50-6.65 (m, 2H), 4.65 (s, 1H), 3. 25-3.35 (m, 4H), 1.80-2.95 (m , 9H), 1.10-1.65 (m, 7H), 0.85 (t, 3H), 0.80 (s, 3H).
[292] Example 9: (rac)-(lS, 4aS, lOaS) -1-butyl-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene Synthesis of (E9).
[293]
[294] Thioketal (rac)-(1S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10 , 10a-octahydro-phenanthrene (6.2 mg) was treated according to Method J ("J" = 100, "K" = 3.0, "L" = 5, "M" = 10, "N" = 96) (rac)-(1S, 4aS, lOaS) -1 -butyl-7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene was obtained. MS m / z: 273.4 (pos., M + H), 271.3 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.05 (d, 1H), 6.60 (d, 1H), 6.55 (d, 1H), 3.0-4.0 (br. S, 1H), 2.65-2.95 (m, 2H ), 2.60 (dd, 1H), 2.10 (dd, 1H), 1.70-1.95 (m, 2H), 1.10-1.70 (m, 12H), 0. 90 (t, 3H), 0.85 (s, 3H).
[295] Example 10 (rac)-(1S, 4aS, 10aR) -10a- ethyl-7-hydroxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-1-one (E10a ); And (rac)-(1S, 4aR, 10aR) -10a- ethyl-7-hydroxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-one-ElOb .
[296]
[297] Step 1: (rac)-(2R, 3R)-(rac)-(2S, 3R) -3-ethyl-pent-4-en-2-ol. Allyl bromide l-bromo-2-pentene (2.49 g) and aldehyde acetaldehyde were used according to Method D ("J" = 3.0, "K" = 18) as starting material. The raw material was purified by silica gel flash chromatography using (rac)-(2R, 3R)-(rac)-(2S, 3R) -3-ethyl-pent- with EtOAc: n-heptane (3: 7) as eluent. 4-en-2-ol was obtained as an oil. ¹ H NMR (270 MHz, DMSO-d6) δ 5.45-5.65 (m, 1H), 4.95-5.20 (m, 2H), 3.50-3.75 (m, 1H), 1.30-2.00 (m, 3H), 1.10 ( d, 3H), 0.85 (t, 3H).
[298] Step 2: (rac)-(4aS, 10aR) -lOa-ethyl-7-methoxy-3-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-1-one and (rac)- (4aR, 10aR) -10a- ethyl-7-methoxy-3-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-1-one. Aryl iodine 4- (2-iod-4-methoxy-phenyl) -but-3-ene-2-one (51 mg) was prepared using Method A ("J" = (rac)-(2R, 3R) -(rac)-(2S, 3R) -3-ethyl-pent-4-ene-2-ol, "K" = 2.5, "L" = 8.0, "M" = 44, "N" = 48) Treated accordingly. The resulting residue was dissolved in DCM (9.OmL) and the solution was stirred for 12 h at reflux with 2.0M aqueous KOH (1.0 mL) before washing with water. Back extraction of the aqueous layer was carried out with EtOAc, and the mixed organic layer was dried over anhydrous sodium sulfate, and these were concentrated in vacuo to give (rac)-(4aS, 10aR) -10a- ethyl-7-methoxy-3 used in the next step. -Methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-1-one and (rac)-(4aR, l0aR) -10a- ethyl-7-methoxy-3-methyl-4a, 9, A mixture of 10,10a-tetrahydro- 4H -phenanthrene-1-one was obtained.
[299] (rac)-(4aS, 10aR) -lOa-ethyl-7-methoxy-3-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-1-one: ES / MS m / z: 271.3 (pos., M + H); ¹ HNMR (270 MHz, CDCl ₃ ) δ 7.1 (d, 1H), 6.55-6.75 (m, 2H), 5.75-5.90 (m, 1H), 3.75 (s, 3H), 3.1-3.3 (m, 1H) , 2.7-2.9 (m, 3H), 2.3-2.5 (m, 2H), 1.8-2.1 (m, 3H), 1.0-1.7 (m, 3H), 0.6-0.9 (m, 3H). (rac)-(4aR, 10aR) -1Oa-ethyl-7-methoxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-1-one: ES / MS m / z: 271.3 (pos., M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.20 (d, 1H), 6.55-6.75 (m, 2H), 5.75-5.90 (m, 1H), 3.75 (s, 3H), 3.1-3.3 (m, 1H ), 2.7-2.9 (m, 3H), 2.3-2.5 (m, 2H), 1.8-2.1 (m, 3H), 1.0-1.7 (m, 3H), 0.6-0.9 (m, 3H).
[300] Step 3: (rac)-(4aS, 10aR) -10a-ethyl-7-hydroxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-1-one and (rac)- (4aR, 10aR) -10a-ethyl-7-hydroxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-l-one. As the substrate, (rac)-(4aS, 10aR) -10a-ethyl-7-methoxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-1-one and (rac)- A mixture of (4aR, 10aR) -lOa-ethyl-7-methoxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-1-one (26 mg) was prepared using Method K ("J "= 2.5," K "= 4.0," L "= -20," M "= 12).
[301] The raw material thus obtained was purified using (rac)-(4aS, lOaR) -10a-ethyl-7-hydroxy-3-methyl-4a, 9,10 using EtOAc-n-heptane (3: 7) as eluent on chromatography. , lOa-tetrahydro- 4H -phenanthrene-1-one and (rac)-(4aR, lOaR) -10a-ethyl-7-hydroxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H A mixture of phenanthrene-1-one was obtained. (rac)-(4aS, 10aR) -10a- ethyl-7-hydroxy-3-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-l-source: ES / MS m / z: 257.2 (pos, M + H), 255.1 (neg, MH); ¹ HNMR (500 MHz, CDCl ₃ ) δ 7.00 (d, 1H), 6.70 (d, 1H), 6.60 (s, lH), 5.90 (s, 1H), 4.95 (s, 1H, OH), 3.15-3.25 (m, lH), 2.70-2.85 (m, 3H), 2.40-2.45 (m, 2H), 1.95 (s, 3H), 1.50-1.60 (m, 1H), 1.35-1-45 (m, 2H) , 0.80 (s, 3 H). (rac)-(4aR, 10aR) -10a-ethyl-7-hydroxy-3-methyl-4a, 9,10, lOa-tetrahydro- 4H- phenanthrene-1-one: ES / MS m / z: 257.2 (pos., M + H), 255.1 (neg., MH); ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.10 (d, 1H), 6.70 (d, 1H), 6.60 (s, 1H), 5.85 (s, 1H), 5.00 (s, H-OH), 3.15- 3.25 (m, 1H), 2.70-2.85 (m, 3H), 2. 40-2.45 (m, 2H), 2.0 (s, 3H), 1.50-1.60 (m, 1H), 1.35-1-45 (m , 2H), 0.75 (s, 3H).
[302] Example 11 (rac)-(1R, 2S, 4aS, 10aS) -1-Butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene 3-membered (E11a); (rac)-(1R, 2R, 4aS, 10aS) -1- butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E11b); And (rac)-(1S, 4R, 4aR, 10aS) -1-butyl-7-hydroxy-4-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3- Synthesis of Ellc.
[303]
[304] Step 1: (rac)-(1R, 2S, 4aS, 10aR) -1-Butyl-7-methoxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene- 3-membered and (rac)-(1R, 2R, 4aS, 10aS) -1- butyl-7-methoxy-2-methyl-1,4,4a, 9,10, l0a-hexahydro- 2H -phenanthrene 3-membered and (rac)-(1S, 4R, 4aR, 10aS) -1-butyl-7-methoxy-4-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenan Tren-3-one. Enone (rac)-(4aS, 10aS) -7-methoxy-4a, 9,10,1Oa-tetrahydro-4H from Example 1 dissolved in diethyl ether / THF (3.0 mL, 2: 1) -Phenanthrene-3-one (31 mg) Method E ("J" = CuCN, "K" = 2.2, "L" = 2.0, "M" = diethyl ether, "N" = n-butyl lithium [ 1.6M solution in hexane], "O" = 4.2, "P" = -78, "Q" = 0.5).
[305] Methyl iodide (65 eq.) Was added to the reaction mixture and stirring was continued for 40 hours at room temperature before cooling. The raw material was (rac)-(lR, 2S, 4aS, lOaS) -1-butyl , which was used in the next step (step 2) using EtOAc: n-heptane (1: 9, v: v) as eluent on chromatography. -7-methoxy-2-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H- phenanthrene-3-one, (rac)-(1R, 2R, 4aS, 10aS) -1- Butyl-7-methoxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one and (rac)-(1S, 4R, 4aR, 10aS) -1 -Butyl-7-methoxy-4-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one was obtained.
[306] Step 2: (rac)-(1R, 2S, 4aS, 10aS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene- 3-membered and (rac)-(1R, 2R, 4aS, lOaS) -1- butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene 3-membered and (rac)-(1S, 4R, 4aR, 10aS) -1- butyl-7-hydroxy-4-methyl-1,4,4a, 9,10, l0a-hexahydro- 2H -phenan Tren-3-one. As a substrate, (rac)-(1R, 2S, 4aS, 10aS) -1- butyl-7-methoxy-2-methyl-1,4,4a, 9,10,10a- from the previous step (step 1) Hexahydro- 2H -phenanthrene-3-one, (rac)-(1R, 2R, 4aS, 10aS) -1- butyl-7-methoxy-2-methyl-1,4,4a, 9,10,10Oa -Hexahydro - 2H -phenanthrene-3-one and (rac)-(1S, 4R, 4aR, 10aS) -1-butyl-7-methoxy-4-methyl-1,4,4a, 9,10, A mixture of 10a-hexahydro- 2H- phenanthrene-3-one (22.5 mg) was prepared according to Method K ("J" = 2.0, "K" = 3.0, "L" = -20, "M" = 20) Treated. The raw material thus obtained was purified on chromatotron with EtOAc: n-heptane (3: 7) as eluent. This raw material was further fractionated using PHPLC. (rac)-(1S, 4R, 4aR, 10aS) -1-butyl-7-hydroxy-4-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one (3.5 mg) was obtained from the first eluted fraction, (rac)-(1R, 2S, 4aS, 10aS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10, 10a-hexahydro- 2H -phenanthrene-3-one and (rac)-(lR, 2R, 4aS, 10OS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10 In a second, a mixture of 1Oa-hexahydro- 2H -phenanthrene-3-one is added to (rac)-(1R, 2R, 4aS, lOaS) -1-butyl-7-hydroxy-2-methyl-1, A 4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one was obtained third. (rac)-(1S, 4aS, 10aS) -1- butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one: ES / MS m / z: 287.2 (pos., M + H), 285.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.00 (d, 1H), 6.65 (dd, 1H), 6.60 (d, 1H), 4.65 (br. S, 1H), 2.80-3.05 (m, 4H), 2.70 (t, 1H), 2.20 (t, 1H), 1.95-2.10 (m, 2H), 1.65-1.90 (m, 2H), 1.00-1.40 (m, 6H), 1.05 (d, 3H, CH _3- C2), 0.85 (t, 3 H). (rac)-(1R, 2S, 4aS, l0aS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one : ¹ H NMR (270 MHz, CDCl ₃ , selected signal) δ 1.25 (d, 3H, CH ₃ -C 2). (rac)-(1S, 4R, 4aR, 10aS) -1-butyl-7-hydroxy-4-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one : ES / MS m / z: 287.2 (pos., M + H), 285.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ , selected signal) δ 0.95 (d, 3H, CH ₃ -C 4).
[307] Example 12: (rac)-(1R, 2R, 4aS, 10aS) -1- butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E12a); And (rac)-(1R, 2S, 4aS, 10aS) -1- butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10 Synthesis of, 10a-octahydro-phenanthrene (E12b).
[308]
[309] Ketone (rac)-(1S, 4aS, 10aS) -1- butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one and (rac)-(1R, 2R, 4aS, 10aS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one Mixture (6.0 mg, 1: 1) was treated according to Method G ("J" = 2.5, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 12). Raw materials were fractionated using PHPLC. From the first eluted fraction (rac)-(1R, 2S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4 , 4a, 9,10,10a-octahydro-phenanthrene was obtained and (rac)-(1R, 2R, 4aS, 10aS) -1-butyl- 3,3ethanediyldimercapto -7-hydroxy-2-methyl -1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene was obtained in the second. (rac) -1 (R, 2S, 4aS, 10aS)-1- butyl-3,3-ethanediyldimercapto-7- hydroxy2 -methyl-1,2,3,4,4a, 9,10, 10a-octahydro-phenanthrene: ES / MS m / z: 361.3 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.10 (d, 1H), 6.60 (dd, 1H), 6.55 (d, 1H), 3.5-4.5 (br. S, 1H), 3.35-3.45 (m, 2H ), 3.15-3.25 (m, 2H), 2.70-2.90 (m, 3H), 2.45-2.55 (m, 2H), 1.90-2.05 (m, 1H), 1.70-1.90 (m, 2H), 1.50-1.70 (m, 4H), 1.10-1.50 (m, 4H), 1.30 (d, 3H), 0.90 (t, 3H). (rac)-(1R, 2R, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10, 10a-octahydro-phenanthrene: ES / MS m / z: 361.3 (neg., MH); ¹ HNMR (270 MHz, CDCl ₃ ) δ 7.15 (d, 1H), 6.60 (dd, 1H), 6.50 (d, 1H), 3.5-4.0 (br. S, 1H), 3.10-3.40 (m, 4H) , 2.70-2.90 (m, 3H), 2.15-2.25 (m, 1H), 1.80 (t, 1H), 1.50-1.75 (m, SH), 1.05-1.40 (m, 6H), 1. 25 (d, 3H), 0.85 (t, 3H).
[310] Example 13 (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1 (3-methyl-butyl-1,4,4a, 9,10,10a-hexahydro- 2H- Synthesis of Phenanthrene-3-one (E13).
[311]
[312] Step 1: 2-iodo-4- (4-methoxy-benzyloxy) -benzaldehyde in DCM (500 mL). 4-hydroxy-2-iodo-benzaldehyde (26.45 g, 106.6 mmol), p-methoxybenzyl chloride (1.3 eq.), Ethyl diisopropylamine (1.4 eq.), And sodium iodide (0.1 eq.) was refluxed for 69 hours. The reaction mixture was then dried over magnesium sulfate anhydride with 1.OM HCl (aq., 3 × 100 mL), water (200 mL), saturated sodium carbonate (100 mL), and saturated NH ₄ Cl (100 mL) and vacuum. Washed before concentration in the stomach. The raw material thus obtained was purified by silica gel flash chromatography using EtOAc: n-heptane (1: 9, 2: 8, 3: 7, stepwise gradient) as eluent to obtain pure 2-iodo-4- (4 -Methoxy-benzyloxy) -benzalaldehyde was obtained as a yellow solid in the first eluate with unconsumed 4-hydroxy-2-iodo-benzaldehyde, and pure 2-iodo-4- (4-meth Toxy-benzyloxy) -benzaldehyde was obtained in the second. ¹ H NMR (270 MHz, CDCl ₃ ) δ 9.90 (s, 1H), 7.85 (d, 1H), 7.50 (d, 1H), 7.35 (d, 2H), 7.00 (dd, 1H), 6.90 (d, 2H), 5.05 (s, 2H), 3.80 (s, 3H).
[313] Step 2: 4- [2-iodo-4- (4-methoxy-benzyloxy) -phenyl] -but-3-ene-2-one. To a suspension of 2-iodo-4- (4-methoxy-benzyloxy) -benzaldehyde (14.7 g, 39.9 mmol) in a stirred water: acetone mixture (150 mL, 1: 2) was dissolved in aqueous NaOH (16.0 M, 1.2 eq.) Was added before heating at reflux for 10 minutes. Another portion of water (100 mL) was added and after cooling to room temperature a yellow precipitate formed, washed with water, dried over P ₂ 0 ₅ , and then 4- [2-iodo-4- (4-methoxy- Benzyloxy) -phenyl] -but-3-ene-2-one. ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.70 (d, 1H), 7.50-7.55 (m, 2H), 7.30 (d, 2H), 6.95 (dd, 1H), 6.90 (d, 2H), 6.45 ( d, 1H), 5.00 (s, 2H), 3.80 (s, 3H), 2.40 (s, 3H).
[314] Step 3: (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4aS , lOaS) -7 -hydroxy-1Oa-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one. Aryl iodine 4- [2-iodo-4- (4-methoxy-benzyloxy) -phenyl] -but-3-ene-2-one (2.02 g) Method A (“J” = 2- Methyl-but-3-ene-1-ol, "K" = 1.5, "L" = 4.0, "M" = 2, "N" = 1.5). The obtained raw material was then treated according to Method C ("N" = 100, "Q" = 12). The obtained raw material was fractionated by PHPLC. The first eluted fraction was (rac)-(4aR, lOaS) -7-hydroxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H- phenanthrene-3-one and (rac)- (4aS, 10aS) -7-hydroxy-1Oa-methyl-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one, and the second also contains a mixture, The ratio is different.
[315] Step 4: (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -Phenanthrene-3-one. Approximately a third of the total amount of 1-bromo-3-methylbutane was added to the rapidly stirred magnesium turning (6.25 eq.) Surrounded by dry THF (1.0 mL). The remaining 1-bromo-3-methylbutane (total 2.08 eq.) Was then added in small portions, and the reaction started with small iodine crystals and then heated at 60 ° C. for 301 minutes. Another portion of dry THF (3.0 mL) was added before cooling (dry ice / acetone bath). To this cooled mixture was added a suspension of CuI (0.5 eq.) In THF (1.0 mL) before reaching 0 ° C. for 10 minutes and cooled again (dry ice / acetone bath). Next, enone (rac)-(4aR, 10aS) -7 -hydroxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one in THF (2.0 mL) and (rac A drop of a mixture solution (220 mg, 1.0 eq.) Of (a)-(4aS, lOaS) -7-hydroxy-lOa-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one Added freshly. Stirring was carried out at −78 ° C. for 2 hours before cooling and work up as in Method E. The raw material was (rac)-(1S, 4aS, lOaS) -7- hydrous using EtOAc: n-heptane (2: 8, 3: 7, 4: 6, v: v; stepwise gradient) as eluent on chromattron. Roxy-Oa-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one was obtained. ES / MS m / z: 299.2 (neg., MH); ¹ H NMR (270 MHz, CD ₃ 0D) δ 6.90 (d, 1H), 6.5-6.6 (m, 2H), 3.00 (dd, 1H), 2.75-2.90 (m, 4H), 2.40 (t, 2H) , 1.90-2.05 (m, 1H), 1.65-1.80 (m, 2H), 1.40-1.60 (m, 2H), 1.25-1.40 (m, 1H), 0.95-1.20 (m, 2H), 1.05 (s, 3H), 0.90 (t, 6H).
[316] Example 14: (rac)-(1S, 4aS, 10aS) -3,3-ethanediyldimercapto-7-hydroxy-1- (3-methyl-butyl) -10a-methyl-1,2,3, Synthesis of 4,4a, 9,10,10a-octahydrophenanthrene (E14).
[317]
[318] Ketone (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10Oa-hexahydro- 2H -phenan Tren-3-one (48.5 mg) was treated according to Method G ("J" = 3.0, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 12). The raw material was (rac)-(1S, 4aS, 10aS) -3,3- ethanediyldimercapto-7-hydroxy- using EtOAc: n-heptane (2: 8, v: v) as eluent on chromatography. 1- (3-Methyl-butyl) -lOa-methyl-l, 2,3,4,4a, 9,10, lOa-octahydro-phenanthrene was obtained as glass. ES / MS m / z: 377.2 (pos., M + H), 375.1 (neg., MH); ¹ H NMR (270 MHz, CD ₃ 0D) δ 7.00 (d, 1H), 6.55 (dd, 1H), 6.50 (d, 1H), 3.20-3.40 (m, 4H), 2.55-2.90 (m, 4H) , 2.50 (dd, 1H), 2.25 (d, 1H), 1.00-1.95 (m, 9H), 0.90 (dd, 6H), 0.85 (s, 3H).
[319] Example 15 (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1-phenethyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene- Synthesis of 3-membered (El5).
[320]
[321] To rapidly cooled magnesium turning (24 eq.) Surrounded by dry THF (1.0 mL), approximately 1/3 of the total amount of 2-bromoethylbenzene was added. Then the remainder of 2-bromoethylbenzene (2.08 eq. In total 2.0 mL THF) was added in small portions and the reaction started with small crystals of iodine and then heated at 60 ° C. for 30 minutes. Another portion of dry THF (3.0 mL) was added before cooling (dry ice / acetone bath). To this cooled mixture was added a suspension of CuI (0.5 eq.) In THF (0.5 mL) for 10 minutes before reaching 0 ° C. and cooled again (dry ice / acetone bath). Enon (rac)-(4aR, 1OaS) -7-hydroxylOa-methyl-4a, 9,10,1Oa-tetrahydro- 4H -phenanthrene-3 in THF (2.0 mL) from Example 3 then A solution of a mixture of -one and (rac)-(4aS, 10aS) -7-hydroxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (78 mg, 1 0 eq.) Was added dropwise. Stirring was continued for 2 hours at −78 ° C. before cooling and the work up as in Method E. The raw material was purified by silica gel flash chromatography using EtOAc: n-heptane (1: 9, 15:85, 2: 8, v: v; stepwise gradient) as eluent and (rac)-( by PHPLC. 1S, 4aS, lOaS) -7-hydroxylOa-methyl-1-phenethyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one not consumed (rac )-(4aS, lOaS) -7 -hydroxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one. ES / MS m / z: 335.2 (pos., M + H), 333.4 (neg., MH); ¹ H NMR (270 MHz, CD ₃ CN) δ 7.10-7.30 (m, 5H), 6.90 (d, 1H), 6.45-6.75 (m, 3H), 2.95 (dd, 1H), 2.60-2.95 (m, 5H), 2.25-2.50 (m, 3H), 1.65-2.00 (m, 3H), 1.15-1.45 (m, 2H), 0.95 (s, 3H).
[322] Example 16: (rac)-(1S, 2s, 4aS, 10aS) -7-hydroxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4-4a, 9,10,10a -Hexahydro- 2H -phenanthrene-3-one (E16a); And (rac)-(1S, 2R, 4aS, 10aS) -7-hydroxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro Synthesis of 2H -phenanthrene-3-one (E16b).
[323]
[324] Step 1: 4-benzyloxy-2-iodo-benzaldehyde in DCM (500 mL). 4-hydroxy-2-iodo-benzaldehyde (28.73 g, 248 mmol), benzyl bromide (1.3 eq.), Ethyl diisopropylamine (1.4 eq.), And iodide sodium (0.1 eq.) The mixture of was refluxed for 12 h. The remaining mixture was dried over anhydrous magnesium sulfate and concentrated in vacuo prior to 1.OM HC1 (aq., 3x100 mL), water (200 mL), saturated sodium carbonate (100 mL), and saturated NH ₄ Cl (100 mL). )). The raw material thus obtained was purified by silica gel flash chromatography using EtOAc: n-heptane (0: 100, 1: 9, 2: 8, stepwise gradient) as the eluent, to obtain 4-benzyloxy-2-iodo. -Benzaldehyde was obtained as a yellow powder.
[325] Step 2: 4- (4-benzyloxy-2-iodo-phenyl) -but-3-ene-2-one. Water: reflux water soluble NaOH (16.OM, 1.2 eq.) In a stirred suspension of 4-benzyloxy-2-iodo-benzaldehyde (17.73 g, 52.4 mmol) in acetone mixture (150 mL, 1: 2) It was added before heating for 10 minutes at. Another portion of water (100 mL) was added and after cooling to room temperature a yellow precipitate formed, washed with water and dried over P ₂ 0 ₅ to 4- (4-benzyloxy-2-iodo-phenyl) -butyrate. 3-en-2-one was obtained as a yellow powder.
[326] Step 3: (rac)-(4aS, lOaR) -7-benzyloxy-lOa-methyl-4a, 9,10,10a-tetrahydro-4H-phenanthrene-3-one and (rac)-(4aS, lOaS ) -7-benzyloxy-1Oa-methyl-4a, 9,10,10a-tetrahydro-4H-phenanthrene-3-one. Aryl iodine 4- (4-benzyloxy-2-iodo-phenyl) -but-3-ene-2-one (6.175 g) was prepared as Method A ("J" = 2-methyl-but-3-ene -1-ol, "K" = 1.3, "L" = 4.0, "M" = 0.5, "N" = 1.5). The obtained raw material was processed according to Method C ("N" = 150, "Q" = 2). The obtained raw material was purified by silica gel flash chromatography using EtOAc: n-heptane (5:95, 1: 9, 2: 8, stepwise gradient) as the eluent, and (rac)-(4aS, 10aS) -7. Benzyloxy-lOa-methyl-4a, 9,10, lOa-tetrahydro-4H-phenanthrene-3-one (yellow powder) was obtained as the first eluting material. The second eluting material is (rac)-(4aS, lOaS) -7-benzyloxylOa-methyl-4a, 9,10, lOa-tetrahydro-4H-phenanthrene-3-one and (rac)-(4aS , 10aR) -7-benzyloxy-10a-methyl-4a, 9,10, lOa-tetrahydro 4H-phenanthrene-3-one.
[327] Step 4: (rac)-(1S, 2S, 4aS, 10aS) -7-benzyloxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a- Hexahydro- 2H -phenanthrene-3-one and (rac)-(1S, 4aS, 10aS) -7-benzyloxy-2,1Oa-dimethyl-1- (3-methyl-butyl) -1,4,4a , 9,10,10a-hexahydro- 2H -phenanthrene-3-one. Enone (rac)-(4aS, 1OaS) -7-benzyloxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H- phenanthrene-3-one (70 mg ) dissolved in THF (2.0 mL) Method E ("J" = Lithium 2-thienylcyanocuprate [Aldrich, no. 32,417-5, 0.25M solution in THF], "K" = 2.0, "L" = 1.0, "M" = THF, "N" = 3-methyl-1-butyl magnesium bromide [0.5M solution in THF], "O" = 2.0, "P" = 0, "Q" = 0.5) with the following exceptions; Methyl iodide (dissolved in 16 eq. 2.0 mL DMPU) was added to the reaction mixture and stirring was continued for 96 hours at room temperature before cooling. The raw material was purified on PHPLC to be used in the next step (step 5) (rac)-(lS, 2S, 4aS, lOaS) -7-benzyloxy-2, lOa-dimethyl-l- (3-methyl-butyl)- 1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one and (rac)-(1S, 2R, 4aS, 10aS) -7-benzyloxy-2,10a-dimethyl-1 -(3-Methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one (white powder) was obtained.
[328] Step 5: (rac)-(1S, 2R, 4aS, 10aS) -7 -hydroxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a- Hexahydro- 2H -phenanthrene-3-one and (rac)-(1S, 2R, 4aS, 10aS) -7-hydroxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4 , 4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one. As a substrate, (rac)-(1S, 2S, 4aS, 10aS) -7-benzyloxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4 from the previous step (step 4), 4a, 9,10,1Oa-hexahydro- 2H -phenanthrene-3-one and (rac)-(lS, 2R, 4aS, lOaS) -7-benzyloxy-2,1Oa-dimethyl-1- (3- Methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (29 mg) was prepared using Method F ("J" = THF: HOAc [95: 5], " K "= 3.0," L "= 5% Pd / C," M "= 10," N "= 72). The raw material was purified by PHPLC to give (rac)-(1S, 2S, 4aS, 1OaS) -7 -hydroxy-2,1Oa-dimethyl-1- (3-methyl-butyl) -1,4,4a, 9,10 , 10a-hexahydro- 2H -phenanthrene-3-one and (rac)-(1S, 2R, 4aS, lOaS) -7 -hydroxy-2,1Oa-dimethyl-1- (3-methyl-butyl)- A mixture of 1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one was obtained as a colorless glass. ES / MS m / z (mixture): 315.4 (pos., M + H), 313.3 (neg., MH); ¹ H NMR (270 MHz, CD ₃ CN, selected signal of the mixture) δ 6.95 (d, H-C5, major isomer), 6.90 (d, H-C5, minor isomer), 6.10 (d, CH ₃ -C2, Major isomers), 0.95 (d, CH ₃ -C 2, minor isomers).
[329] Example 17 (rac)-(4bS, 8S, 8aS) -6,6-dimethoxy-8a-methyl-3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10- Octahydro-phenanthrene-2-ol (El7a) and (rac)-(lS, 4aS, lOaS) -7 -hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, Synthesis of 9,10,10a-hexahydro- 2H -phenanthrene-3-one (El7b).
[330]
[331] Step 1: (rac)-(1S, 4aS, 10aS) -7-benzyloxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -Phenanthrene-3-one. Enone (rac)-(4aS, 10aS) -7-benzyloxy-10a-methyl-4a, 9,10, lOa-tetrahydro- 4H- phenanthrene-3 from Example 16 dissolved in THF (4.0 mL) Source (303 mg) Method E ("J" = lithium 2-thienylcyanocuprate (Aldrich, no. 32,417-5, 0.25M solution in THF), "K" = 2.0, "N" = 3-methyl-1- Butyl magnesium bromide (0.5M solution in THF), "O" = 2.0, "P" = 0, "Q" = 0.25). The raw material was purified on chromatography using EtOAc: n-heptane (1: 9, 2: 8, v: v, stepwise gradient) as eluent (rac)-(lS, 4aS, 10aS) -7-benzyloxy- lOa-Methyl-1- (3-methyl-butyl) -1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one was obtained as a white powder.
[332] Step 2: (rac)-(1S, 4aS, lOaS) -7-hydroxy-1Oa-methyl-l- (3-methyl-butyl) -1,4,4a, 9,10, lOa-hexahydro- 2H -Phenanthrene- 3-one and (rac)-(4bS, 8S, 8aS) -6,6-dimethoxy-8a-methyl-8- (3-methylbutyl) -4b, 5,6,7,8, 8a, 9,10-octahydro-phenanthrene-2-ol. As substrate, (rac)-(1S, 4aS, l0aS) -7-benzyloxy-l0a-methyl-l- (3-methyl-butyl) -l, 4,4a, 9,10,10a-hexahydro- 2H -Phenanthrene-3-one method F ("J" = Methanol: EtOAc [7: 3], "K" = 15, "L" = 5% Pd / C, "M" = 40, "N" = Treatment according to 16). The raw material was fractionated on EtOAc using EtOAc: n-heptane (1: 9, 2: 8, 3: 7, v: v, step gradient) as eluent to give (rac)-(4bS, 8S, 8aS) -. First fraction of 6,6-dimethoxy-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2-ol Obtained as a colorless glass in (rac)-(1S, 4aS, 10aS) -7 -hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a- Hexahydro- 2H -phenanthrene-3-one (for alternative synthetic methods, the spectral data is the same as in the previous example) was obtained as a colorless glass in the second fraction. (rac)-(4bS, 8S, 8aS) -6,6-dimethoxy-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octa Hydro-phenanthrene-2-ol: ES / MS m / z: 345.1 (neg., MH); ¹ H NMR (270 MHz, CD ₃ 0D) δ 7.05 (d, 1H), 6.55 (dd, 1H), 6.50 (d, 1H), 3.25 (s, 3H), 3.15 (s, 3H), 2.60-2.90 (m, 3H), 2.50 (dt, 1H), 2.10 (dt, 1H), 1.85 (dt, 1H), 1.75 (dd, 1H), 1.25-1.60 (m, 7H), 1.05-1.15 (m, 1H ), 0.90 (dd, 6H), 0.85 (s, 3H); ¹³ C NMR (CD ₃ 0D) δ 154.60, 137.25, 129.90, 126.00, 114.75, 112.65, 101.35, 46.45, 46.35, 44.60, 38.45, 35.50, 35.10, 33.80, 31.70, 29.65, 28.35,26.65, 24.85, 22.30, 21.50 , 17.55.
[333] Example 18: (rac)-(1S, 4aS, 10aS) -3,3- ethanediyldioxy-7-hydroxy-1- (3-methyl-butyl) -10a-methyl-1,2,3, Synthesis of 4,4a, 9,10,10a-octahydro-phenanthrene (E18).
[334]
[335] Ketone (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenan Tren-3-one (10.4 mg) Method H ("J" = 1,2-dihydroxyethane, "K" = 0.5, "L" = 50, "M" = 1.0, "N" = 22, "O" = 5). The raw material was purified on chromatography using EtOAc: n-heptane (2: 8, 3: 7, v: v, stepwise gradient) as eluent to (rac)-(1S, 4aS, 10aS) -3,3- ethane. Diyldioxy-7-hydroxy-1- (3-methyl-butyl) -1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene was obtained as a colorless glass. . ES / MS m / z: 345.4 (pos., M + H), 343.3 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.05 (d, 1H), 6.55-6.65 (m, 2H), 4.60 (s, 1H), 3.90-4.10 (m, 4H), 2.65-2.95 (m, 3H ), 2.25 (dt, 1H), 1.75-2.00 (m, 3H), 1.20-1.65 (m, 7H), 1.00-1.15 (m, 1H), 0.90 (dd, 6H), 0.85 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 153.15, 137.85, 131.90, 126.85, 115.15, 112.80, 110.20, 64.80, 63.80, 44.70, 38.35, 36.85, 35.25, 35.00, 33.60, 31.80, 28.40, 27.05, 24.95, 23.35, 22.35, 22.35 18.25.
[336] Example 19: (rac)-(4bS, 8R, 8aS) -8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octahydrophenanthrene -2-ol (E19a); And (rac)-(4bS, 6R, 8S, 8aS) -6-ethylsulfonyl-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10 -Synthesis of octahydro-phenanthrene-2-ol (E19b).
[337]
[338] Substrate (rac)-(1S, 4aS, 1OaS) -3,3 -ethanediyldimercapto-7-hydroxy-1- (3-methyl-butyl) -1Oa-methyl-1,2,3,4,4a , 9,10,10a-octahydro-phenanthrene (14.7 mg) was treated according to Method I ("J" = 1.0, "K" = 240, "L" = 22, "M" = 16). The raw material was first purified on PHPLC, then fractionated using EtOAc: n-heptane (2: 8, 3: 7, v: v, stepwise gradient) as eluent on chromatotron (rac)-(4bS, 8R , 8aS) -8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2-ol was colorless in the first fraction Obtained as glass and (rac)-(4bS, 6R, 8S, 8aS) -6-ethylsulfonyl-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9 , 10-octahydro-phenanthrene-2-ol (1.3 mg) was obtained in the second fraction. (rac)-(4bS, 8R, 8aS) -8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octahydrophenanthrene-2-ol : ES / MS m / z: 287.2 (pos., M + H), 285.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.10 (d, 1H), 6.60 (dd, 1H), 6.50 (d, 1H), 4.40 (s, 1H), 2.65-2.95 (m, 2H), 2.60 ( dd, 1H), 2.05-2.20 (m, 1H), 1.70-2.00 (m, 2H), 1.00-1.70 (m, 11H), 0.875 (dd, 6H), 0.85 (s, 3H); ¹³ C NMR CDCl ₃ ) δ 152.95, 138.00, 133.00, 126.75, 115.10, 112.60, 44.45, 38.90, 38.40, 35.45, 34.15, 28.45, 27.00, 25.20, 24.0 (two peaks), 23.15, 22.45, 21.10, 18.45.
[339] (rac)-(4bS, 6R, 8S, 8aS) -6-ethylsulfonyl-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10- Octahydro-phenanthrene-2-ol: ES / MS m / z: 347.2 (pos., M + H), 345.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.05 (d, 1H), 6.60 (dd, 1H), 6.55 (d, 1H), 4.40 (s, 1H), 3.25-3.35 (m, 1H), 3.05 ( dd, 1H), 2.65-2.95 (m, 2H), 2.60 (q, 2H), 2.30 (br. d, 1H), 2.20 (dt, 1H), 1.00-2.00 (m, lOH), 1.25 (t, 3H), 0.90 (dd, 6H), 0.85 (s, 3H).
[340] Example 20: (rac)-(1S, 4aS, 10aS) -3,3- (propane-1,3- diyldimercapto ) -7-hydroxy-1- (3-methyl-butyl) -10a-methyl Synthesis of -1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E20).
[341]
[342] Ketone (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenan Tren-3-one (11 mg) was treated according to Method G ("J" = 3.0, "K" = 1,3-propanedithiol, "L" = 2.0, "M" = 16). The raw material was purified on chromatography using EtOAc: n-heptane (2: 8, v: v) as eluent to give (rac)-(1S, 4aS, lOaS) -3,3- (propane-1,3-diyl). Dimercapto) -7-hydroxy-1- (3-methyl-butyl) -lOa-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (colorless glass) was obtained. . ES / MS m / z: 391.3 (pos., M + H), 389. 2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.10 (d, 1H), 6.65 (dd, 1H), 6.55 (d, 1H), 4.50 (s, 1H), 2.65-3.20 (m, 8H), 1.70- 2.35 (m, 7H), 1.30-1.60 (m, 5H), 1.05-1.15 (m, 1H), 0.90 (dd, 6H), 0.85 (s, 3H).
[343] Example 21 of (rac)-(4aS, 10as) -7 -hydroxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E21) synthesis.
[344]
[345] Substrate (rac)-(4aS, 10aS) -7-hydroxy-10a-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one (16 mg) Method F (“J” = Methanol, "K" = 1.5, "L" = 5% Pd / C, "M" = 5, "N" = 16) and treated according to (rac)-(4aS, lOaS) -7 -hydroxy- lOa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one was obtained. ES / MS m / z: 229.0 (neg., MH); ¹ H NMR (270 MHz, CD ₃ 0D) δ 6.90 (d, 1H), 6.45-6.60 (m, 2H), 2.60-3.00 (m, 5H), 2.25-2.40 (m, 2H), 1.50-1.90 ( m, 4H), 0.90 (s, 3H).
[346] Example 22 (rac)-(4aS, 10aS) -3,3-ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro Synthesis of Phenanthrene (E22).
[347]
[348] Ketone (rac)-(4aS, 1OaS) -7-hydroxy-1Oa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (12 mg) ("J" = 3.0, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 16). The raw material was purified on chromatography by using EtOAc: n-heptane (1: 9, 2: 8, v: v, stepwise gradient) as eluent to (rac)-(4aS, 10aS) -3,3- ethanediyl. Dimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene was obtained as a white powder. ES / MS m / z: 307.3 (pos., M + H), 305.2 (neg., MH); ¹ H NMR (270 MHz, CD ₃ 0D) δ 6.90 (d, 1H), 6.45-6.55 (m, 2H), 3.20-3.40 (m, 4H), 2.55-2.90 (m, 4H), 2.15-2.30 ( m, 1H), 2.00 (dq, 1H), 1.90 (t, 1H), 1.50-1.60 (m, 4H), 0.70 (s, 3H).
[349] Example 23 of (rac)-(4aS, 10aS) -10a-ethyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E23) synthesis.
[350]
[351] Step 1: (rac) -2-ethyl-but-3-ene-1-ol. According to Method D ("J" = 3.0, "K" = 18), using allyl bromide l-bromo-2-pentene (10.0 g) and aldehyde formaldehyde (37% solution in water) as starting materials Got. This was purified by distillation (68-70 ° C / 80 mmHg) to give (rac) -2-ethyl-but-3-ene-1-l-ol as a colorless oil. ¹ H NMR (270 MHz, CDCl ₃ ) δ 5.45-5.70 (m, 1H), 5.05-5.20 (m, 2H), 3.55 (dd, 1H), 3.40 (dd, 1H), 2. 00-2.20 (m , 1H), 1.15-1.60 (m, 2H), 0.90 (t, 3H).
[352] Step 2: (rac)-(4aR, 10aS) -7 -benzyloxy-lOa-ethyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4aS, 10aS) ) -7-benzyloxy-10a-ethyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one. Aryl iodine 4- (4-benzyloxy-2-iodo-phenyl) -but-3-ene-2-one (1.0 g) Method A ("J" = (rac) -2-ethyl-but 3-en-1-ol, "K" = 2.0, "L" = 4.0, "M" = 8.0, and "N" = 4.0). The resulting product was then treated according to Method C ("N" = 70, "Q" = 16). The obtained raw material was purified by silica gel flash chromatography using EtOAc: n-heptane (2: 8). The first eluted fractions were further fractionated using PHPLC. First elutes (rac)-(4aR, 10aS) -7 -benzyloxy-10a-ethyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one (yellowish white solid) Obtained in fractions. (rac)-(4aS, 10aS) -7-benzyloxy-1Oa-ethyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (yellowish solid) in the second elution fraction Got it. (rac)-(4aR, 10aS) -7-benzyloxy-10a-ethyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one: ES / MS m / z: 333.1 (pos. , M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.30-7.45 (m, 5H), 7.00 (d, 1H), 6.80 (d, 1H), 6.75 (d, 1H), 6.70 (d, 1H), 6.00 ( d, 1H), 5.05 (s, 2H), 3.15 (dd, 1H), 2.75-2.85 (m, 2H), 2.45-2. 60 (m, 2H), 1.85-1.95 (m, 1H), 1.65-1.75 (m, 1H), 1.50 (q, 2H), 0.90 (s, 3H). (rac)-(4aS, 10aS) -7-benzyloxy-10a-ethyl-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one: ES / MS m / z: 333.1 (pos. , M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.30-7.50 (m, 5H), 7.00 (d, 2H), 6.82 (d, 1H), 6.78 (d, 1H), 6.05 (d, 1H), 5.05 ( s, 2H), 3.30 (dd, 1H), 3.05 (dd, 1H), 2.85-2.95 (m, 2H), 2.60 (dd, 1H), 2.10-2.20 (m, 1H), 1.65-1. 75 (m, 1 H), 1.35-1. 50 (m, 2H), 0.90 (s, 3H).
[353] Step 3: (rac)-(4aS, 10aS) -10a-ethyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one. As a substrate, (rac)-(4aS, 10aS) -7-benzyloxy-l0a-ethyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (34 mg) was prepared using Method F (" J "= MeOH / EtOAc [4: 3]," K "= 4.0," L "= 5% Pd / C," M "= 11, N = 24). The raw material was purified on chromatography and using EtOAc: n-heptane (1: 9) as eluent. The main fraction contained (rac)-(4aS, 10aS) -10a- ethyl-7-hydroxy-1,4,4a, 9,10, lOa-hexahydro-2H-phenanthrene-3-one. ES / MS m / z: 241.3 (neg., MH), ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.95 (d, 1H), 6.70-6.75 (m, 2H), 5.15 (bs, 1H) 2.90- 3.00 (m, 2H), 2.70-2.80 (m, 2H), 2.35-2.45 (m, 3H), 2.05-2.15 (m, 1H), 1.95-2.00 (m, 1H), 1.40-1.55 (m, 3H ), 1.20-1.30 (m, 1 H), 0.95 (t, 3 H).
[354] Example 24 (rac)-(4aS, 10aS) -3,3-ethanediyldimercapto-10a-ethyl-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro Synthesis of Phenanthrene (E24).
[355]
[356] Ketone (rac)-(4aS, 10aS) -10a-ethyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (8.9 mg) ("J" = 0.8, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 4). The raw material was purified on chromatography and using EtOAc: n-heptane (2: 8, v: v) as eluent. The first eluted fraction was further fractionated using PHPLC to give (rac)-(4aS, lOaS) -3,3-ethanediyldimercapto-lOa-ethyl-7-hydroxy-1,2,3,4, 4a, 9,10,10a-octahydro-phenanthrene (white powder). ES / MS m / z: 320.9 (pos., M + H), 319.3 (neg., MH); ¹ HNMR (270 MHz, CDCl ₃ ) δ 7.10 (d, 1H), 6.55-6.60 (m, 2H), 4.50 (bs, 1H), 3.25-3.40 (m, 4H), 2.70-2.90 (m, 3H) , 2.55-2.65 (m, 1 H), 1.95-2.20 (m, 3 H), 1.75-1. 90 (m, 2H), 1.25-1.50 (m, 3H), 0.95-1.10 (m, 1H), 0.75 (t, 3H). ¹³ C NMR δ 153.29, 138.26, 130.68, 125.83, 115.34, 112.53, 69.22, 46.08, 40.64, 38.99, 38.17, 38.01, 34.66, 34.08, 32.81, 26.1, 17.54, 7.37.
[357] Example 25 (rac)-(1R, 2R, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4,4a, A pharmaceutical formulation comprising 9,10, lOa-octahydro-phenanthrene.
[358] 140 mg of (rac)-(1R, 2R, 4aS, l0aS) -1- butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3, in Example 12, 4,4a, 9,10,10a-octahydro-phenanthrene was formulated with sufficiently finely divided lactose to provide a total amount of 580-590 mg to fill a size 0, hard gelatin capsule.
[359] Example 26 (rac)-(1S, 4aS, 10aS) -1- (3-methyl-butyl) -l0a-ethyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E26).
[360]
[361] Step 1: Enone (rac)-(4aS, lOaS) -7-benzyloxy-lOa-ethyl-4a, 9,10, lOa-tetrahydro-4H-phenanthrene-3-one dissolved in 2.0 mL of THF 54.5 mg; 0.15 mmol), Method E ("J" = lithium-2-thienylcyanocuprate [Aldrich, no. 32, 417-5, 0.25M solution in THF], "K" = 2, "M" = THF, Treatment according to "L" = 2.0, "N" = 3-methyl-1 -butyl magnesium bromide [0.5 M solution in THF], "0" = 2eq., "P" = 0, "Q" = 1) It was. The raw material was purified on chromatography and purified using EtOAc: n-heptane (2: 8) as eluent to give 35 mg of (rac)-(lS, 4aS, lOaS) -7-benzyloxy-1- (3-methyl-butyl ) -1,4,4a, 9,10,10a-hexahydro-2H-phenanthrene-3-one was obtained as a yellowish oil. ES-MS m / z: 405.4 (pos., M + H), 403.0 (neg., MH; ¹ HNMR (CDCl ₃ ) δ 7.30-7.45 (m, 5H), 6.95 (d, 1H), 6.75 (d , 1H), 5.05 (s, 2H), 3.15 (dd, 1H), 2.90 (dd, 1H), 2.70-2.80 (m, 2H), 2.60 (dd, 1H), 2.30-2.45 (m, 2H), 1.40-2.00 (m, 5H), 1.20-1.40 (m, 6H), 0.85 (m, 9H).
[362] Step 2: The reaction was carried out at 32.5 mg (0.080 mmol) of (rac)-(1S, 4aS, 10aS) -7-benzyloxy-1- (3-methyl-butyl) -1,4,4a, 9,10,10a Method F on "hexahydro-2H-phenanthrene-3-one (" J "= THF," K "= 4.0," L "= 10% Pd / C," M "= 33," N "= 20) It was performed according to. The raw material was purified by chromatography using EtOAc: n-heptane (2: 8) as eluent and (rac)-(1S, 4aS, 10aS) -1- (3-methyl-butyl) -10a-ethyl7- Hydroxy-1,4,4a, 9,10,10a-hexahydro-2H-phenanthrene-3-one (18.6 mg) was obtained as a white solid. ES-MS m / z: 315.1 (pos., M + H), 313.3 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.90 (d, 1H), 6.65 (d, 1H), 6.60 (s, 1H), 3.15 (dd, 1H), 2.90 (ddd, 1H), 2.70-2.80 (m , 2H), 2.60 (dd, 1H), 2.35-2.45 (m, 2H), 1.40-2.00 (m, 5H), 1.20-1.40 (m, 5H), 1.00-1. 10 (m, 1 H), 0.85 (m, 9 H).
[363] Example 27 (1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene Synthesis of 3-membered (E27).
[364]
[365] Step 1: (1S, 4aS, 10aS) -7-benzyloxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- from Example 13 The racemic mixture of 2H -phenanthrene-3-one was purified by chiral HPLC to give (1R, 4aR, 10aR) -7-benzyloxy-10a-methyl- 1, two pure enantiomers (17 and 21 mg). -(3-Methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one, (lS, 4aS, lOaS) -7-benzyloxylOa-methyl- 1- (3-Methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one was obtained, respectively.
[366] Step 2: The reaction was carried out at 17 mg (1R, 4aR, l0aR) -7-benzyloxylOa-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro-2H- It was carried out on phenanthrene-3-one for 20 hours using THF (4.0 mL) as solvent and 10% Pd / C (33.0 mg) as catalyst according to Method F. The raw material was purified by PHPLC to give (1R, 4aR, 1OaR) -methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one. (1.5 mg) was obtained as a white solid. ES-MS m / z: 301.3 (pos., M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.90 (d, 1H), 6.60-6.65 (m, 2H), 4.50 (s, 1H), 3.05 (dd, 1H), 2.70-3.05 (m, 4H), 2.25 -2.45 (m, 2H), 1.90-2.05 (m, 1H), 1.40-1.75 (m, 4H), 1.25-1.40 (m, 1H), 0.95-1.20 (m, 2H), 1.05 (s, 3H) , 0.85 (t, 6 H).
[367] Example 28: (1R, 4aRS, lOaR) -7-benzyloxylOa-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro-2H-phenanthrene Synthesis of 3-membered (E28).
[368]
[369] The reaction was carried out at 21 mg (1S, 4aS, 10aS) -7-hydroxylOa-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro-2H-phenan 20 h on Tren-3-one was carried out using THF (4.0 mL) as solvent and 10% Pd / C (33.0 mg) as catalyst according to Method F. The raw material was purified by PHPLC to give (1S, 4aS, 10aS) -7-benzyloxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H. -Phenanthrene-3-one (3.9 mg) was obtained as a white solid. ES-MS m / z: 301. 3 (pos., M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.90 (d, 1H), 6.60-6.65 (m, 2H), 4. 65 (s, 1H), 3.05 (dd, 1H), 2.70-3.00 (m, 4H) , 2. 25-2.45 (m, 2H), 1.90-2.00 (m, 1H), 1.40-1.75 (m, 4H), 1.25-1. 40 (m, 1H), 0.95-1.20 (m, 2H), 1.05 (s, 3H), 0.85 (t, 6H).
[370] Example 29: (rac)-(1S, 4aS, 10aS) -1- (3-methyl-butyl) -3,3-ethanediyldimercapto-7-hydroxy-1,4,4a, 9,10, Synthesis of 10a-octahydrophenanthrene (E29).
[371]
[372] The reaction was carried out at 15 mg (0.048 mmol) of (rac)-(1S, 4aS, 10aS) -1- (3-methylbutyl) -7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 1 eq on 2H -phenanthrene-3-one, according to Method G ("J" = 1.0, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 4) Was performed using BF ₃ .OEt ₂ . The raw material was purified on EtOAc using EtOAc: n-heptane (2: 8) as eluent and then (rac)-(lS, 4aS, lOaS) -1- (3-methyl-butyl) -3, by PHPLC . 3-ethanediyldimercapto-7-hydroxy-1,4,4a, 9,10,10a-octahydrophenanthrene (7.7 mg) was obtained as a white powder. ES-MS m / z: 391. 3 (pos., M + H), 389. 2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.05 (d, 1H), 6.60 (dd, 1H), 6.55 (s, 1H), 4.50 (bs, OH), 3.35 (m, 4H), 3.00 (dd, 1H ), 2.55-2.80 (m, 4H), 2.35-2.45 (dd, 1H), 2.15-2.25 (m, 1H9, 2.00-2.10 (m, 1H), 1.40-1.80 (m, 8H), 1.05-1.30 ( m, 1H), 0.90 (d, 6H), 0.75 (t, 3H).
[373] Example 30: (rac) - (4aR , 10aR) -7- hydroxy -4a, 10a- dimethyl -3,4,4a, 9,10,10a- hexahydro - lH - phenanthrene-2-circle (E30 ) Synthesis.
[374]
[375] Step 1: 7-methoxy-4-methyl-1,2-dihydro-naphthalene: 31.8 g (180 mmol, 1.0 eq.) Of 6-methoxy-1-tetranal solution in dry THF (100 mL) Was added dropwise to the methyl lithium (1.6 M in diethyl ether, 2.3 eq.) Solution with stirring for about one hour. Stirring was continued for another 2 hours before slowly adding 200 mL of 5.0 M aqueous HCl. The layers were separated by vigorous stirring for 3 hours. The aqueous layer was extracted with diethyl ether (4 x 100 mL) and the mixed organic layer was dried over anhydrous sodium sulfate. The concentration of the extract in vacuo gave a brown oil which was purified by silica gel flash chromatography with EtOAc: n-heptane. 7-methoxy-4-methyl-1,2-dihydro-naphthalene was obtained as a colorless glass using (0:10, 1: 9, stepwise gradient) as eluent. ¹ H NMR (CDCl ₃ ) δ 7.22 (d, 1H), 6.80-6.85 (m, 2H), 5.75-5.80 (m, 1H), 3.85 (s, 3H), 2.75-2.85 (m, 2H), 2.25 -2.35 (m, 2H), 2.15 (s, 3H).
[376] Step 2: (rac) -6-methoxy-1-methyl-3,4-dihydro- 1H -naphthalene-2-one: the reaction was carried out on 24.8 g (142 mmol) of 11 dissolved in 600 mL of DCM, and performed according to the method L (rac) -6- methoxy -l- methyl-3,4-dihydro-naphthalene-2 by the source of silica gel to the raw material as an oil exhibits the nureonbit flash chromatography, - lH EtOAc: n-heptane (1: 9, 2: 8, step gradient) was obtained after purification using eluent. ¹ HNMR (CDCl ₃ ) δ 7.10 (d, 1H), 6.80 (d, 1H), 6.75 (s, 1H), 3.80 (s, 3H), 3.45 (m, 1H), 3.00-3.10 (m, 2H) , 2.45-2.65 (m, 2 H), 1.45 (t, 3 H); ¹³ C NMR (CDCl ₃ ) δ 213.18, 158.77, 138.31, 139.22, 127.36, 113.35, 112.34, 55.15, 46.48, 36.93, 27.95, 14.04.
[377] Step 3: (rac) -7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one: (rac) -6 dissolved in toluene (10 mL) Methoxy-l-methyl-3,4-dihydro- 1H -naphthalene-2-one (2.10 g, 11.0 mmol) and but-3-ene-2-one were coupled according to Method M and the raw material was silica gel. Purification by flash chromatography using EtOAc: n-heptane (3: 7) as eluent and (rac) -7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro-3H-phenanthrene A 2-membered was obtained as a yellowish solid. ES-MS m / z: 243.4 (pos., M + H); ¹ H NMR (CDCl ₃ ) δ 7.10 (d, 1H), 6.70 (dd, 1H), 6.50 (d, 1H), 5.80 (s, 1H), 3.70 (s, 3H), 1.80-2. 85 (m, 8 H), 1.40 (s, 3 H); ¹³ C NMR (CDCl ₃ ) δ 199. 26, 170.35, 157.96, 136.22, 127.38, 124.26, 113.40, 112.99, 54.93, 38.38, 36.80, 34.51, 30.98, 30.80, 27.37.
[378] Step 4: 7-methoxy-4a, lOa-dimethyl-3,4,4a, 9,10, lOa-hexahydro- lH- phenanthrene-2-one: reaction was 200 mg dissolved in THF (10 mL) On ( rac) -7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one of (0.83 mmol) was carried out under the following conditions according to Method Q: Titanium (IV) isopropoxide (1.3 eq., Suspension in 3 mL THF), methylmagnesium chloride (3M solution in THF, 1.3 eq.), Nickel (II) acetylacetonate (0.05 eq.), Reaction time and Temperature (1 hour at -15 ° C to 0 ° C, chill at room temperature). The raw material was purified using PHPLC to obtain 7-methoxy-4a, 10a-dimethyl-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one as a yellowish oil. . ES-MS m / z: 259.0 (pos., M + H); ¹ H NMR (CDCl ₃ ) δ 7.30 (d, 1H), 6.80 (dd, 1H), 6.60 (d, 1H), 3.75 (s, 3H), 2.85 (t, 3H), 1.80-2.50 (m, 7H ), 1.25 (s, 3 H), 1.00 (t, 3 H); ¹³ C NMR (CDCl ₃ ) δ 157.85, 136.33, 135.25, 127.04, 113.89, 113.01, 54.97, 50.17, 40.00, 39.29, 38.40, 35.67, 31.38, 25.87, 25.41, 23.06.
[379] Step 5: (rac) - (4aR , 1OaR) -7- hydroxy -4a, 1Oa- dimethyl -3,4,4a, 9,10,1Oa- hexahydro - lH - phenanthrene-2 source: The reaction is 3.5 eq. On 55 mg of 7-methoxy-4a, 10a-dimethyl-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one dissolved in 1.0 mL DCM. It was carried out according to Method 0 for 4 hours using BBr ₃ . The raw material was purified by PHPLC to give (rac)-(4aR, lOaR) -7-hydroxy-4a, lOa-dimethyl-3,4,4a, 9,10, lOa-hexahydro- lH -phenanthrene-2- The circle was obtained as a yellowish oil. ES-MS m / z: 245.2 (pos., M + H), 243.4 (neg., MH); ¹ H NMR (CDCl ₃ ) δ 7.20 (d, 1H), 6.70 (dd, 1H), 6.55 (d, 1H), 5.30 (bs, 1H), 2.80 (t, 3H), 1.80-2.40 (m, 7H ), 1.25 (s, 3 H), 1.00 (t, 3 H).
[380] Example 31 (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-4-phenyl1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3- Synthesis of Circle (E31).
[381]
[382] Step 1: (Z) -5- (4-benzyloxy-2-iodo-phenyl) -4-phenyl-pent-4-ene-2-one. The reaction was carried out on 2.0 g (5.9 mmol) of 4-benzyloxy-2-iodo-benzaldehyde, Method L ("J" = 10, "K" = 1.02, "L" = 0.1, "M" = 20) It was performed according to. The raw material was purified by flash chromatography using EtOAc: n-heptane (2: 8) as the eluent and (Z) -5- (4-benzyloxy-2-iodo-phenyl) -4-phenyl-pent- 4-en-2-one was obtained as a yellowish oil. ES-MS m / z: 455.2 (pos., M + H), 452.9 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.65 (s, 1H), 7.50 (d, 1H), 7.20-7.40 (m, 7H), 7.05-7.10 (m, 2H), 7.15-7.20 (m, 1H ), 6.60 (d, 2H), 5.00 (s, 2H), 2.45 (s, 3H).
[383] Step 2: (4aS, lOaS) -7-benzyloxyl-lOa-methyl-4-phenyl-4a, 9,10,10-tetrahydro- 4H -phenanthrene-3-one. The reaction was carried out on 630 mg (1.39 mmol) of (Z) -5- (4-benzyloxy-2-iodo-phenyl) -4-phenyl-pent-4-en-2-one, Method A (“J”). = 2-methyl-but-3-ene-1-ol, "K" = 1.5, "L" = 4.0, "M" = 2.9, "N" = 4). Next, the obtained raw material was treated according to Method C to obtain raw material (4aS, 10aS) -7-benzyloxy-l0a-methyl-4-phenyl-4a, 9,10,10-tetrahydro- 4H -phenanthrene-3-one ( 90 mg).
[384] Step 3: (4R, 4aS, 10aS) -7-benzyloxy-10a-methyl-4-phenyl-4a, 9,10,10-tetrahydro- 4H -phenanthrene-3-one. (4aS, 10aS) -7 -benzyloxy10a-methyl-4-phenyl-4a, 9,10,10-tetrahydro-4H-phenanthrene-3-one by flash chromatography with EtOAc: n-heptane (5: 1) was purified using eluent to obtain two isomers in a ratio of 2.5: 1. Separation by PHPLC afforded (4R, 4aS, 1OaS) -7-benzyloxy-10a-methyl-4-phenyl-4a, 9,10,10-tetrahydro-4H-phenanthrene-3-one. ES-MS m / z: 395.2 (pos., M + H), 393.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.10-7.20 (m, lOH), 7.00 (d, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 6.50 (dd, 1H), 6.05 (d , 1H), 5.00 (s, 2H), 3.95 (d, 1H), 3.90 (d, 1H); 3.00 (m, 1 H), 2.95 (m, 1 H); 2.05 (m, 1 H), 1.95 (m, 1 H), 0. 90 (s, 3H).
[385] Step 4: (4R, 4aS, 10aS) -7-hydroxy-10a-methyl-4-phenyl-1,4,4a, 9,10,10-hexahydro- 2H -phenanthrene3-one. The reaction was carried out on 13 mg of (4R, 4aS, lOaS) -7-benzyloxy-10a-methyl-4-phenyl-4a, 9,10,10-tetrahydro- 4H- phenanthrene-3-one, Method F ( "J" = ethanol, "K" = 5, "L" = 10% Pd / C, "M" = 2, "N" = 24). The raw material was purified by PHPLC to give 9.0 mg of (4R, 4aS, lOaS) -7-hydroxy-10a-methyl-4-phenyl-1,4,4a, 9,10,10-hexahydro-2H-phenanthrene -3-membered. ES-MS m / z: 307.3 (pos., M + H), 305.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.20-7.40 (m, 5H), 6.70 (d, 1H), 6.60 (d, 1H), 6.35 (dd, 1H), 4.80 (s, b 1H), 3.80 (d, 1 H), 3.50 (d, 1 H); 2. 80 (m, 2 H), 2.60 (m, 2 H); 2.00 (m, 2H), 1.80 (m, 1H), 1.65 (m, 1H), 0.85 (s, 3H).
[386] Example 32: (rac)-(4R, 4aS, 10aS) -3,3 -ethanediyldimercapto-7-hydroxy-10a-methyl-4-phenyl-1,4,4a, 9,10,10a- Synthesis of Octahydro-Phenanthrene (E32).
[387]
[388] The reaction was carried out at 7.0 mg (0.023 mmol) of (4R, 4aS, 10aS) -7-hydroxy-1Oa-methyl-4-phenyl-1,4,4a, 9,10,10-hexahydro- 2H -phenanthrene- On a 3-membered, 6 eq. Of BF ₃ · OEt ₂ , according to Method G ("J" = 1.0, "K" = 1,2-ethanedithiol, "L" = 9, "M" = 2) It was performed using. The raw material was purified by preparative TLC using EtOAc: n-heptane (1: 7) as eluent and (rac)-(4R, 4aS, lOaS) -3,3- ethanediyldimercapto-7-. Hydroxy-lOa-methyl-4-phenyl-1,4,4a, 9,10,10a-octahydro-phenanthrene (5.3 mg) was obtained as a white solid. ES-MS m / z: 383. 2 (pos., M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.55 (d, 1H), 7.35 (d, 1H), 7.30 (m, 1H), 7.20 (m, 1H), 7.10 (m, 1H), 6.60 (d, 1H), 6.45 (d, 1H), 6.25 (dd, 1H), 4.40 (bs, 1H), 3.50 (d, 1H), 3.20 (d, 1H); 3.00 (m, 1H), 2.85 (m, 2H), 2.65 (m, 1H), 2.50 (m, 1H), 2.35 (m, 2H), 1.85 (m, 4H), 1.45 (m, 1H), 0.55 (s, 3 H).
[389] Example 33: (rac)-(1S, 4aS, 10aS) -3,3- (ethane-1,2-diyldimercapto) -7hydroxy-1- (2-phenylethyl) -10a-methyl-1 Synthesis of 2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E33).
[390]
[391] Step 1: (rac)-(1S, 4aS, 10aS) -3,3 -ethane-1,2- diyldimercapto ) -7-hydroxy-1-phenylethyl-10a-methyl-1,2,3, 4,4a, 9,10,10a-octahydro-phenanthrene. The reaction was carried out at 8 mg (24 mmol) of (rac)-(1S, 4aS, 10aS) -7-hydroxy-1-phenylethyl-10a-methyl-1,4,4a, 9,10,10Oa-hexahydro-2H. On phenanthrene-3-one, it was carried out according to Method G ("J" = 2.0, "K" = 1,3-ethanediol, "L" = 2.0, "M" = 6). The raw material was purified on chromatography by using EtOAc: n-heptane (2: 8, v: v) as eluent and (rac)-(1S, 4aS, 10aS) -3,3- (ethane-1,2-diyl). Dimercapto) -7-hydroxy-1-phenylethyl-lOa-methyl-10a-methyl-l, 2,3,4,4a, 9,10, lOa-octahydro-phenanthrene was obtained as a colorless glass. ES / MS m / z: 409.3 (neg., MH): ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.10-7.30 (m, 5H), 7.05-7.10 (d, 1H), 6.50-6.65 (m, 3H ), 4.50 (s, OH); 3.30-3.45 (m, 4H), 2.40-3.00 (m, 7H), 1.80-2.10 (m, 3H), 1.10-1.65 (m, 3H), 0.90 (s, 3H). ¹³ C NMR (270 MHz, CDCl ₃ ) δ S 153.3, 143.0, 137.9, 131.1, 128.5, 128.4, 127.0, 126.0, 115.3, 112.8, 68.9, 45.3, 43.4, 40.4, 38.8, 37.5, 37.4, 35.0, 34.7, 33.8 , 30.0, 26.8, 18.5.
[392] Example 34 (rac)-(1S, 4aS, 10aS) -3,3- ethanediyldioxy-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a- Octahydro-phenanthrene (E34a) and (rac)-(1S, 4aS, 10aR) -3,3- ethanediyldioxy-7-hydroxy-10a-methyl-1,2,3,4,4a, 9 Synthesis of, 10,10a-octahydro-phenanthrene (E34b).
[393]
[394] (rac)-(4aS, lOaS) -3,3- ethanediyldioxy-7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10, lOa-octahydro-phenanthrene. The reaction was carried out at 320 mg (1.39 mmol) of (rac)-(4aS, 10aS) -7-hydroxy-1Oa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one. And ( 1: 1 ) of (rac)-(1S, 4aS, 1OaR) -7-hydroxy-1Oa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one ) On the mixture was carried out according to Method H ("J" = 1,2-dihydroxyethane, "K" = 10, "L" = 500, "N" = 20, "O" = 16). The raw material was purified by MPLC using CH ₂ Cl ₂ : MTBE (100: 0, 90:10, v: v) as eluent and mixed with 10% E34b and 10% ElOla (rac)-(4aS , lOaR) colorless mixed with -3,3-ethanediyldioxy-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (ElOlb) Free of (rac)-(4aS, 10aS) -3,3 -ethanediyldioxy-7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydro- Phenanthrene (E34a) was obtained. ES / MS m / z: 275.2 (pos., M + H), 273.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ , Isomer A) δ 7.00 (d, 1H), 6.65-6.70 (m, 2H), 4.80 (bs, OH), 3.90-4.10 (m, 4H), 2.75-2.90 (m , 2H), 2.70-2.75 (m, 1H), .20-2.30 (m, 1H), 1.80-1.90 (m, 1H), 1.65-1.70 (m, 1H), 1.50-1.65 (m, 5H), 0.75 (s, 3 H) .; ¹ H NMR (270 MHz, CDCl ₃ , Signal of Isomer A and Other Isomers B) δ 6.90 (d, 1H), 6.55 (m, 2H), 3.90-4.00 (m, 4H), 5.10 (bs, OH), 0.80 (s, 3 H).
[395] Example 35 (rac)-(3S, 4aS, 10aS) -7 -hydroxy-3-pentyl-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E35a) and (rac)-(3R, 4aS, lOaS) -7 -hydroxy-3-pentyl-10a-methyl-1,2,3,4,4a, 9,1,10a-octahydro-phenanthrene Synthesis of (E35b).
[396]
[397] Step l: (rac)-(4aS, 10aS) -7-benzyloxy-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one and (rac)- (4aR, lOaS) -7-benzyloxy-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one. The reaction was carried out in 707 mg (2.22 mmol) of (rac)-(4aS, lOaS) -7-benzyloxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3 in Example 3. On a (6: 4) mixture of -one and (rac)-(4aR, 10aS) -7-benzyloxy-10a-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one, Method F (“L” = 5% Pd / C, “M” = 70, THF / HOAC (95: 5, v: v), rt 8 days). The raw mixture was purified by MPLC using EtoAC: n-heptane (0: 100, 10:90, v: v) as eluent and (rac)-(4aS, 10aS) -7-benzyloxy-10a-methyl- 1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one and (rac)-(4aR, l0aS) -7-benzyloxylOa-methyl-1,4,4a, 9 , 10,10a-hexahydro- 2H -phenanthrene-3-one was obtained as a yellowish solid. ES / MS m / z: 321.1 (pos., M + H).
[398] Step 2: (rac)-(3S, 4aS, 10aS) -7 -benzyloxy-3-hydroxy-3- (1-pentyl) -l0a-methyl-1,2,3,4,4a, 9,10 , 10a-octahydro-phenanthrene and (rac)-(3S, 4aR, lOaS) -7 -benzyloxy-3-hydroxy-3- (1-pentyl-5-ene) -lOa-methyl-1,2 , 3,4,4a, 9,10,10a-octahydro-phenanthrene. The reaction was carried out at 40 mg (0.125 mmol) of (rac)-(4aS, 10aS) -7-benzyloxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 4H- phenanthrene-3- Circle and (rac)-(4aR, lOaS) -7-benzyloxylOa-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one (85:15 mixture) Phase, according to Method V, to obtain the raw material used in the next step without purification.
[399] Step 3: (rac)-(3S, 4aS, lOaS) -7-hydroxy-3- (l-pentyl) -lOa-methyl-1,2,3,4,4a, 9,10,10a-octahydro -Phenanthrene. The raw material in step 2 was treated with phosphoric acid (85%) at 40 ° C. for 1 hour, then extracted with EtOAc / H ₂ O and dried over anhydrous sodium sulfate. The resulting yellowish-brown oil was treated according to Method F, ("L" = 10% Pd / C, "J" = MeOH / THF, "M" = 15). The raw material was purified on chromatography using EtOAc / n-heptane (1: 9, v: v) as eluent and then PHPLC to give (rac)-(3S, 4aS, lOaS) -7 -hydroxy-3- ( l-pentyl) -l0a-methyl-l, 2,3,4,4a, 9,10, lOa-octahydro-phenanthrene
[400] (E35a) and (rac)-(3R, 4aS, 10aS) -7-hydroxy-3- (1-pentyl) -Oa-methyl-1,2,3,4,4a, 9,10,10a-octa A mixture of hydro-phenanthrene (E35b) was obtained. ES / MS m / z: 287.2 (pos., M + H), 285.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ , Selected signal) δ 7.10 (d, 1H), 6.50-6.60 (m, 3H), 2.60-2.90 (m, 3H), 2.00-2.40 (m, 4H), 0.90 (s , 3H), 0.70 (s, 3H).
[401] Example 36: (rac)-(1S, 2R, 4aS, 10aS) -2,10a-dimethyl-3,3- (ethane-1,2 - diyldimercapto) -7-hydroxy-1- (3- Synthesis of Methyl-butyl-1,2,3,4,4a, 9,10, lOa-octahydro-phenanthrene (E36).
[402]
[403] (rac)-(1S, 2R, 4aS, 10aS) -2,10a-dimethyl-3,3- (ethane-1,2 - diyldimercapto) -7-hydroxy-1- (3-methyl-butyl- 1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene The reaction is 9 mg (30 μmol) of (rac)-(1S, 2R, 4aS, 10aS) -2,1Oa-dimethyl On -7-hydroxy-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one, Method G ("J" = 1.0, "K" = 1,2-ethanediol, "L" = 2.0, "M" = 6) The raw material was EtOAc: n-heptane (1: 9, 2: 8, 3: 7 on chromatography). , v: v) as eluent, (rac)-(lS, 2R, 4aS, lOaS) -3,3- (ethane-1,2 -diyldimercapto ) -7-hydroxy-1-phenylethyl- 10a-methyl-1,2,3,4,4a, 9,10,10Oa-octahydro-phenanthrene was obtained as a colorless glass ES / MS (mixture) m / z: 391.3 (pos., M + H ), 389.2 (neg., MH): ¹ H NMR (270 MHz, CDCl ₃ , selected signal of mixture) δ 7.10 (d, 1H), 6.50-6.70 (m, 1H), 3.30-3.50 (m, 4H isomer A ) 3.10-3.30 (m, 4H isomer B), 0.85-0.90 (m, 9H) ^l3 C NMR (270 MHz, CDCl ₃ , mixed Water) δ 153.2, 137.8, 131.2, 127.0, 115.2, 112.8, 73.9, 52.9, 45.9, 43.4, 40.6, 39.1, 38.2, 36.4, 33.3, 31.9, 29.1, 28.8, 26.7, 22.8, 22.6, 22.4, 18.8, 15.9 , 14.2.
[404] Example 37: (rac)-(1S, 4aS, 10aS) -7 -hydroxy-1- (3'-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenan Synthesis of Tren-3-one (E37).
[405]
[406] Step 1: (rac)-(4aS, 10aS) -7-benzyloxy-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one. Aryl iodine 4- (2-iodo-4-benzyloxy-phenyl) -but-3-ene-2-one (6.12 g) Method A ("J" = but-3-ene-1-ol , "K" = 1.3, "L" = 4.0, "M" = 2, and "N" = 2.0). The obtained raw material was next processed according to Method C ("N" = 150, "Q" = 14). The obtained raw material was purified by silica gel flash chromatography using EtOAc: n-heptane (5:95, 1: 8 step gradient) as the eluent, and then fractionated with PHPLC to give (rac)-(4aS, 10aS)- 7-benzyloxy-4a, 9,10, lOa-tetrahydro-4H-phenanthrene-3-one (white solid) was obtained. ES / MS m / z: 305.2 (pos., M + H); ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.30-7. 50 (m, 5H), 7.10 (d, 1H), 6.90 (dd, 1H), 6.80 (dd, 1H), 6.75 (d, 1H), 6.10 (d, 1H), 5.05 (s, 2H), 3.20 (dd, 1H), 2.90-3.10 (m, 3H), 2.45 (t, 1H), 2.35 (dd, 1H), 2.10-2.20 (m, 1H), 1.65-1.75 (m, 1H).
[407] Step 2: (rac)-(1S, 4aS, 10aS) -7-benzyloxy-1- (3'-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene -3-won. Method E using rac- (4aS, lOaS) -7-benzyloxy-4a, 9,10, lOa-tetrahydro-4H-phenanthrene-3-one (50 mg) dissolved in THF (5.0 mL) ("J" = lithium 2-thienylcyanocuprate (Aldrich, no. 32, 417-5, 0.25M solution in THF), K "= 2.0," N "= 3-methyl-1-butyl magnesium bromide (0.5 in THF M solution), “0” = 2.0, “P” = 0, “Q” = 2) The raw material was purified by silica gel flash chromatography using EtOAc: n-heptane (1: 8) eluent. Purified and fractionated with PHPLC to give 23 mg of (rac)-(lS, 4aS, lOaS) -7-benzyloxy-l- (3'-methyl-butyl) as a white powder used in the next step (step 3). -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one was obtained ES / MS m / z: 377.2 (pos., M + H).
[408] Step 3: (rac)-(1S, 4aS, 10aS) -7-hydroxy-1- (3'-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene -3-won. Substrate (rac)-(1S, 4aS, 10aS) -7-benzyloxy-1- (3'-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3 Source (14 mg) Method F ("J" = THF: HOAc [95: 5], "K" = 4.0, "L" = 10% Pd / C, "M" = 4, "N" = 2 Treatment). The raw material was purified by PHPLC to give (rac)-(1S, 4aS, 10aS) -7 -hydroxy-1- (3'-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (white solid) was obtained. ES / MS m / z: 285.1 (neg., MH); ¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.00 (d, IH), 6.60 (dd, 1H), 6.55 (d, 1H), 2.75-2.95 (m, 4H), 2.55 (dd, 1H), 2.40 (dt, 1H), 2.20 (t, 1H), 1.95-2.05 (m, 1H), 1.65-1.85 (m, 2H), 1.40-1.55 (m, 2H), 1.20-1.35 (m, 2 H), 1.05-1. 15 (m, 1 H), 0. 85 (t, 6 H).
[409] Example 38 (rac)-(4aS, 10aS) -3,3- (propane-1,3-diyldimercapto) -7-hydroxy-1,2,3,4,4a, 9,10,10a Synthesis of Octahydro-Phenanthrene (E38).
[410]
[411] Ketone (rac)-(4aS, 10aS) -7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (18 mg) Method G (“J” = 4, "K" = 1,3-propanedithiol, "L" = 2.0, "M" = 12). The raw material was purified by column chromatography on silica gel using EtOAc: n-heptane (2: 8, v: v) as eluent, and (rac)-(4aS, 10aS) -3,3 -propanediyl. Dimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene was obtained. ES / MS m / z: 307.3 (pos., M + H), 305.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.05 (d, 1H), 6.55 (dd, 1H), 6.45 (d, 1H), 2.90-3.00 (m, 2H), 2.60-2.85 (m, 6H), 2.40 (m, 1H), 1.95 (m, 2H), 1.55-1.85 (m, 4H), 1.35-1.50 (m, 3H), 1.20-1.30 (m, 1H).
[412] Example 39 (rac)-(1S, 4S, 4aS, 10aS) -7-hydroxy-1-butyl-4,10a-dimethyl 1,4,4a, 9,10,10a-hexahydro- 2H -phenan Tren-3-one (E39).
[413]
[414] Step 1: (rac)-(4R, 4aS, 10aS) -7-benzyloxy-4,10a-dimethyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one and (rac)- (4S, 4aS, lOaS) -7-benzyloxy-4, lOa-dimethyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one. Enon (rac)-(4aS, 10aS) -7-benzyloxy-1Oa-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3- dissolved in THF (3.0 mL) of Example 15 Circle (101 mg) was obtained using Method E ("J" = diisopropylamine, "K" = 10, "L" = 2.0, "M" = THF, "N" = n-butyl lithium [1.6M solution in hexane ], "0" = 10, "P" = -78, and "Q" = 1) were handled with the following exception. Methyl iodide (10 eq.) Was added to the reaction mixture and stirring was continued for another 20 hours at room temperature before cooling. The raw material was purified on chromatography using EtOAc: n-heptane (1: 8, v: v) as eluent, 71 mg of (rac)-(4R, 4aS, 10aS) -7-benzyloxy-4, 10a-dimethyl-4a, 9,10,1Oa-tetrahydro- 4H -phenanthrene-3-one and (rac)-(4S, 4aS, 10aS) -7-benzyloxy-4,1Oa-dimethyl-4a, 9 , 10,10O-tetrahydro- 4H -phenanthrene-3-one was obtained.
[415] Step 2: (rac)-(1S, 4S, 4aS, 10aS) -7-benzyloxy-1-butyl-4,10a-dimethyl-1,4,4a, 9,10,10Oa-hexahydro- 2H -phenan Tren-3-one. Enone (rac)-(4R, 4aS, lOaS) -7-benzyloxy-4,1Oa-dimethyl-4a, 9,10,1Oa-tetrahydro- 4H -phenanthrene-3- dissolved in THF (2.0 mL) Circle and (rac)-(4S, 4aS, lOaS) -7-benzyloxy-4, lOa-dimethyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one (25 mg) E ("J" = CuCN, "K" = 2, "L" = 2.0, "M" = THF, "N" = n-butyl lithium [1.6M solution in hexane], "O" = 4.0, "P "= -78," Q "= 2) was handled with the following exception; CuCN and n-butyl lithium were mixed at 0 ° C. and stirred at room temperature for 1 hour. The raw material was purified on PHPLC to give 18 mg of (rac)-(1S, 4S, 4aS, 10aS) -7-benzyloxy-1-butyl-4,10a-dimethyl-1,4, used in the next step (step 3). 4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one (white powder) was obtained. ES / MS m / z: 379.0 (pos., M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7. 30-7.50 (, 5H), 7.00 (d, lH), 6.75-6.85 (m, 2H), 5.05 (s, 2H), 2.60-2.75 (m, 5H), 2.45 (dd, 1H), 2.00-2.15 (m, 1H), 1.65-1.75 (m, 2H), 1.0-1.5 (m, 9H), 0.90 (t, 3H), 0.75 (s, 3H) .
[416] Step 3: (rac)-(1S, 4S, 4aS, 10aS) -7-hydroxy-1-butyl-4,10a-dimethyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenan Tren-3-one. As a substrate, (rac)-(1S, 4S, 4aS, 10aS) -7-benzyloxy-1-butyl-4,10a-dimethyl-1,4,4a, 9,10,10a from the previous step (step 2) -Hexahydro - 2H- phenanthrene-3-one (12 mg) Method F ("J" = THF: HOAc [95: 5], "K" = 3.0, "L" = 5% Pd / C, " M "= 5," N "= 24). The raw material was purified by PHPLC to give (rac)-(1S, 4S, 4aS, 10aS) -7-hydroxy-1-butyl-4,10a-dimethyl-1,4,4a, 9,10, l0a-hexahydro- 2H -phenanthrene-3-one was obtained. ES / MS m / z (mixture): 301.3 (pos., M + H), 299.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.95 (d, lH), 6.65-6.75 (m, 2H), 4.77 (s, 1H), 2.60-2.75 (m, 5H), 2.45 (dd, 1H), 2.00-2.15 (m, 1H), 1.65-1.75 (m, 2H), 1.0-1.5 (m, 9H), 0.90 (t, 3H), 0.70 (s, 3H).
[417] Example 40: (rac)-(4s, 4aS, 10aS) -3,3 -ethanediyldimercapto-7-hydroxy-4,10a-dimethyl-1,2,3,4,4a, 9,10, Synthesis of 10a-octahydro-phenanthrene (E40).
[418]
[419] Step 1: (rac)-(4S, 4aS, 10aS) -7-hydroxy-4,10a-dimethyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one. As a substrate, (rac)-(4R, 4aS, lOaS) -7-benzyloxy-4,1Oa-dimethyl-4a, 9,10,10a-tetrahydro- 4H- phenanthrene-3-one in Example 39 And a mixture of (rac)-(4S, 4aS, 1OaS) -7-benzyloxy-4,10a-dimethyl-4a, 9,10, lOa-tetrahydro- 4H- phenanthrene-3-one (20 mg) Method F ("J" = THF: HOAc [95: 5], "K" =
[420] 4.0, "L" = 10% Pd / C, "M" = 7, "N" = 12). The raw material was purified by PHPLC to give (rac)-(4S, 4aS, 10aS) -7-hydroxy-4,10a-dimethyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3 -Got a circle. ES / MS m / z (mixture): 245.2 (pos., M + H), 243.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.95 (d, lH), 6.65-6.75 (m, 2H), 5.05 (s, 1H), 2.65-2.08 (m, 3H), 2.40-2.55 (m, 3H ), 1.55-1.90 (m, 4H), 1.30 (t, 3H), 0.60 (s, 3H).
[421] Step 2: (rac)-(4s, 4aS, 10aS) -3,3- ethanediyldimercapto-7-hydroxy-4,10a-dimethyl-1,2,3,4,4a, 9,10,10a Octahydro-phenanthrene. Ketone (rac)-(4s, 4aS, 10aS) -7-hydroxy-4, lOa-dimethyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one (9.4 mg ) Was treated according to Method G ("J" = 5.0, "K" = 1,2-ethanedithiol, "L" = 2.0, "M" = 12). The raw material was purified by PHPLC to give (rac)-(4s, 4aS, 10aS) -3,3- ethanediyldimercapto-7-hydroxy-4,10a-dimethyl-1,2,3,4,4a, 9, 10,10a-octahydro-phenanthrene was obtained as glass. ES / MS m / z: 321.1 (pos., M + H), 319.0 (neg., MH); ¹ H NMR (270 MHz, CD ₃ 0D) δ 7.00 (d, 1H), 6.60-6.70 (m, 2H), 4.60 (s, 1H), 3.20-3.35 (m, 4H), 2.70 (dt, 1H) , 2.35-2.55 (m, 2H), 2.10-2.25 (m, 3H), 1.45-1.85 (m, 4H), 1.35 (d, 3H), 0.35 (s, 3H).
[422] Example 41 (rac)-(4S, 4aS, 10aS) -7-hydroxyl-4-benzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene- 3-membered (E41a) and (rac)-(4aS, 10aS) -7-hydroxy-4,4-dibenzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- Phenanthrene-3-one (E41b).
[423]
[424] Step 1: (rac)-(4s, 4aS, 10aS) -7-benzyloxy-4-benzyl-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3- Circle and (rac)-(4aS, 10aS) -7-benzyloxy-4,4-dibenzyl-1Oa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3- won. Enon (rac)-(4aS, 1OaS) -7-benzyloxy-10a-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (50 mg ) dissolved in THF (3.0 mL) ) Method E ("J" = diisopropylamine, "K" = 10, "L" = 2.0, "M" = THF, "N" = n-butyl lithium [1.6M solution in hexane], "O "= 10," P "= -78," Q "= 0.1) was handled with the following exception. Benzyl bromide (1 eq.) Was added to the reaction mixture and stirring was continued for another 14 hours at room temperature before cooling. The crude was purified by PHPLC to give 12 mg of (rac)-(4S, 4aS, 10aS) -7-benzyloxy-4-benzyl-l0a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-circle. ES / MS m / z: 409.3 (pos., M + H); And 23 mg of (rac)-(4aS, 10aS) -7-benzyloxy-4,4-dibenzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene- 3-circle. ES / MS m / z: 499.6 (pos., M + H); was obtained.
[425] Step 2: (rac)-(4S, 4aS, 10aS) -7-hydroxy-4-benzyl-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3- won. As a substrate, (rac)-(4S, 4aS, lOaS) -7-benzyloxy-4-benzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3- Circle (8 mg) Method F ("J" = THF: HOAc [95: 5], "K" = 3.0, "L" = 10% Pd / C, "M" = 4, "N" = 12) Treated according to. The raw material was purified by chromatography on a silica gel column using EtOAc: n-heptane (1: 8, 2: 8, v: v, stepwise gradient) as the eluent, and (rac)-(4s, 4aS, 10aS ) -7-hydroxy-4-benzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one was obtained. ES / MS m / z (mixture): 321.1 (pos., M + H), 319.0 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.15-7.25 (m, 5H), 7.00 (d, lH), 6.60-6. 70 (m, 2H), 2.95-3.30 (m, 3H), 2.70 (d, 2H), 2.45-2.55 (m, 1H), 2.25-2.35 (m, 1H), 1.60-1.85 (m, 3H), 1.30-1.50 (m, 2H), 0.60 (s, 3H).
[426] Step 3: (rac)-(4aS, 10aS) -7 -hydroxy-4,4-dibenzyl-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3 -won. As a substrate, (rac)-(4aS, 10aS) -7-benzyloxy-4,4-dibenzyl-1Oa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3 -Source (17 mg) Method F ("J" = THF: HOAc [95: 5], "K" = 3.0, "L" = 10% Pd / C, "M" = 5, "N" = 24 Treatment). The raw material was purified by chromatography on a silica gel column using EtOAc: n-heptane (1: 8, 2: 8, v: v, step gradient) as the eluent, and 13 mg of (rac)-(4aS, 10aS) -7-hydroxy-4,4-dibenzyl-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one was obtained. ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.85 (8, 1H), 7.15-7.30 (u, 5H), 7.00-7.05 (m, 3H), 6.80-6.90 (m, 3H), 6.65 (d, lH ), 3.45 (dd, 2H), 2.95-3.10 (m, 4H), 2.75-2.90 (m, 2H), 2.45-2.60 (m, 2H), 2.20-2.35 (m, 2H), 1.60-1.70 (m , 1H), 1.00 (s, 3H).
[427] Example 42: (rac)-(4aS, 10aS) -7 -hydroxy-10a-methyl-3,3-methylene-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene ( Synthesis of E42).
[428]
[429] (rac)-(4aS, lOaS) -7-hydroxy-lOa-methyl-3,3-methylene-l, 2,3,4,4a, 9,10, lOa-octahydro-phenanthrene. n- BuLi (2.0 mL of 1.6 M solution in hexanes, 3.15 mmol) was added to a suspension of methyltriphenylphosphonium bromide (1.13 g, 3.15 mmol) in THF (80 mL) well stirred at −78 ° C. The cooling bath was removed and the resulting mixture was allowed to rise to room temperature. The resulting yellow solution was cooled to 0 ° C. and (rac)-(4aS, lOaS) -7-hydroxy-1Oa-methyl-1,4,4a, 9,10,10Oa-hexahydro- in THF (5 mL). A solution of 2H- phenanthrene-3-one (145 mg, 0.63 mmol) was added. The resulting mixture was stirred at room temperature for 3 days and then cooled with saturated aqueous NH ₄ Cl (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (3 x 15 mL). The organic mixed solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated. The raw material was purified by silica gel flash chromatography using Et ₂ 0: iso-hexane (1: 4) as eluent and (rac)-(4aS, l0aS) -7-hydroxylOa-methyl-3,3- Methylene-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (132 mg) was obtained as a white oil. ES-MS m / z: 229.3 (pos., M + H), 227.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.05 (d, 1H), 6.60 (dd, 1H), 6.55 (d, 1H), 4.75 (d, 1H), 4.70 (d, 1H), 4.50 (bs, 1H), 3.00-2.70 (m, 3H), 2.50-1.95 (m, 4H); 1.70-1.45 (m, 3H), 1.40-1.15 (m, 1H), 0.80 (s, 3H).
[430] Example 43: (rac)-(4aS, 10aS) -3,3 -ethanediyl-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10, lOa-octahydrophenanthrene Synthesis of (E43).
[431]
[432] (rac)-(4aS, 10aS) -3,3-ethanediyl-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene. Me ₃ Al (0.24 mL of a 2.0 M solution in hexane) was added to (rac)-(4aS, 10aS) -7-hydroxy-10a-methyl-3,3-methylene in iso-hexane (10 mL) well stirred at room temperature. -1,2,3,4,4a, 9,10, lOa-octahydrophenanthrene (50 mg, 0.219 mmol) and CH ₂ I ₂ (63 mg, 0.263 mmol) were added to the solution. The resulting mixture was stirred at rt for 3 h and then cooled with 1 M aqueous HCl (20 mL). The raw material was extracted with Et ₂ 0 (3 × 15 mL), and the mixed extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The raw material was purified by PHPLC to give (rac)-(4aS, 1OaS) -3,3-ethanediyl-7-hydroxylOa-methyl-1,2,3,4,4a, 9,10, lOa-octahydro Phenanthrene (20 mg) was obtained as a white oil. ES-MS m / z: 259.9 (pos., M + NH ₄ ⁺ ), 241.0 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6. 92 (d, 1H), 6.65-6.50 (m, 2H), 4.60 (bs, 1H), 2. 95-2.70 (m, 2H), 2.65 (dd , 1H); 2.10 (dddd, 1H), 1.80 (ddd, 1H), 1.70-1.35 (m, 4H), 1.25 (ddd, 1H), 0.75 (s, 3H), 0.75-0.60 (m, 1H), 0.45- 0.29 (m, 2H), 0.29-0. 15 (m, 2 H).
[433] Example 44 (rac)-(3R, 4aS, 10aS) -1 ', 2', 3 ', 4'-tetrachloro-7-hydroxy-10a-methyl-1,2,3,4,4a, Synthesis of 9,10,10a-octahydrospiro [henanthrene-3,6'-cyclohexane] -1 ', 3'-diene (E44).
[434]
[435] (rac)-(3R, 4aS, 1OaS) -1 ', 2', 3 ', 4'-tetrachloro-7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10, lOa-octahydrospiro [henanthrene-3,6'-cyclohexane] -1 ', 3'-diene. (Rac)-(4aS, 10aS) -7 -hydroxy-10a-methyl-3,3-methylene-1,2,3,4,4a, 9,10,10a- in ditloethane (20 mL) Octahydrophenanthrene (75 mg, 0.33 mmol) and tetrachlorothiophene-1,1-dioxide (167 mg, 0.66 mmol) solutions were refluxed at 100 ° C. for two days. An additional amount of tetrachlorothiophene-1,1-dioxide (419 mg, 1.65 mmol) was added and the reaction mixture was further refluxed for 2 days. The solvent was evaporated and the residue was purified by silica gel flash chromatography using Et ₂ 0: iso-hexane (1: 3) as eluent to afford 90 mg of raw material (˜70% purity). Subsequent PHPLC separation yielded 54 mg of higher purity (~ 80%) raw material. For further purification the hydroxy group was converted to the t-butyldimethylsilyloxy moiety according to the following procedure. Crude (rac)-(3R, 4aS, lOaS) -1 ', 2', 3 ', 4'-tetrachloro-7-hydroxy-lOa-methyl-l, 2, in CH ₂ Cl ₂ (10 mL) 3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,6'-cyclohexane] -1 ', 3'-diene (54 mg, ˜0.13 mmol), t -butyldimethylsilylchloride (TBDMS) (196 mg, 1.30 mmol) and Et ₃ N (132 mg, 1.30 mmol) solution were stirred overnight at 40 ° C., then the solvent was evaporated and the residue was removed by Et ₂ O: iso-hexane by a short silica gel column. (1: 1) was purified using the eluent. The raw TBDMS-protected compound was purified using PHPLC to give 31 mg of pure product. 9 mg of this compound was removed using tetrabutylammonium fluoride (TBAF) (52 mg, 0.20 mmol) in THF (10 mL). The mixture was stirred at rt for 1 h, then the solvent was evaporated and water (5 mL) was added to the residue to extract the product with CH ₂ Cl ₂ (4 × 5 mL). Evaporate the solvent to give pure (rac)-(3R, 4aS, 10aS) -1 ', 2', 3 ', 4'-tetrachloro-7-hydroxy-10a-methyl-1,2,3,4,4a , 9,10,10a-octahydrospiro [henanthrene-3,6'-cyclohexane] -1 ', 3'-diene (7 mg) was obtained as a white oil. ES-MS m / z: 417.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.00 (d, 1H), 6.64-6.55 (m, 2H), 4.62 (bs, 1H), 2.98-2.73 (m, 3H), 2.90 (s, 2H), 2.52 (dd, 1 H); 2.20-2.03 (m, 2H), 1.84 (dd, 1H), 1.70-1.35 (m, 5H), 0.73 (s, 3H).
[436] Example 45: (rac)-(3s, 4aS, 10aS) -3,7-dihydroxy-10a-methyl-3- [1- (phenylthio) cyclopropyl] -1,2,3,4,4a , 9,10,10a-octahydrophenanthrene (E45).
[437]
[438] (rac)-(3rS, 4aS, lOaS) -3,7-dihydroxy-10a-methyl-3- [l- (phenylthio) cyclopropyl] -1,2,3,4,4a, 9,10 , 10a-octahydrophenanthrene. n- BuLi (2.36 mL of 1.6 M solution in hexanes, 3.78 mmol) was added to a solution of cyclopropylphenylsulfide (379 mg, 2.52 mmol) in THF (15 mL) with cooling to 0 ° C. The reaction mixture was allowed to warm up to room temperature and then stirred at room temperature for 2 hours. The reaction solution was cooled to 0 ° C. and ketone (rac)-(4aS, 10aS) -7 -hydroxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H in THF (5 mL). A solution of phenanthrene-3-one (145 mg, 0.63 mmol) was added. The resulting mixture was stirred overnight at room temperature and then cooled with water (5 mL) and saturated aqueous NH ₄ Cl (1 mL).
[439] The organic layer was separated and the aqueous layer was further extracted with EtOAc (3 × 10 mL). The mixed organic solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated. The raw material was purified by PHPLC to give (rac)-(3s, 4aS, 10aS) -3,7 -dihydroxy-10a-methyl-3- [1- (phenylthio) cyclopropyl] -1,2,3, 4,4a, 9,10,10a-octahydrophenanthrene (100 mg) was obtained as a pale yellow oil. ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.50-7.43 (m, 2H), 7.31-7.22 (m, 2H), 7.14 (tt, 1H), 6.90 (d, 1H), 6.59-6.52 (m, 2H ), 4.70 (bs, 1H), 2.90-2.67 (m, 3H), 2.20 (ddd, 1H), 1.88-1.74 (m, 1H); 1.68-1.48 (m, 5H), 1.42-1.24 (m, 3H), 1.10-0.95 (m, 2H), 0.64 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 153.17, 137.96, 137.49, 131.53, 128.62 (2C), 128.41 (2C), 125.60 (2C), 115.24, 112.43, 74.44, 39.57, 37.62, 36.17, 35.71, 33.97, 32.08, 29.55 , 26.21, 14.59, 13.58, 13.32.
[440] Example 46: (rac)-(3S, 4aS, 10aS) -7 -hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3, 2'-cyclobutane] -1'-one (E46a) and (rac)-(3R, 4aS, 10aS) -7 -hydroxy-10a-methyl-1,2,3,4,4a, 9,10, Synthesis of 10a-octahydrospiro- [henanthrene-3,2'-cyclobutanl-1'-one (E46b).
[441]
[442] (rac)-(3s, 4aS, 10aS) -7 -hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro- [henanthrene-3,2'- Cyclobutane] -1' -one and (rac)-(3R, 4aS, 10aS) -7-hydroxylOa-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [ Phenanthrene-3,2'-cyclobutane] -1'-one. (Rac)-(3S, 4aS, 10aS) -3,7 -dihydroxy-10a-methyl-3- [1- (phenylthio) cyclopropyl] -1,2,3,4 in toluene (20 mL) A mixture of, 4a, 9,10,10a-octahydrophenanthrene (80 mg, 0.21 mmol) and 4-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol) was stirred at 100 ° C. overnight. The resulting mixture was cooled with saturated aqueous NaHCO ₃ (10 mL), the organic layer was separated and the solvent was evaporated. The residue was purified by PHPLC to give two diastereomers, (rac)-(3S, 4aS, 10aS) -7 -hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octa Hydrospiro [henanthrene-3,2'-cyclobutane] -1'-one (32 mg) and (rac)-(3R, 4aS, l0aS) -7-hydroxy-l0a-methyl-1,2,3 , 4,4a, 9,10,10a-octahydrospiro [henanthrene-3,2'-cyclobutane] -1'-one (10 mg) was obtained as a white oil. (rac)-(3S, 4aS, lOaS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,2'cyclobutane ] -1'-source: ES-MS m / z: 288.2 (pos., M + NH ₄ ⁺ ), 268.8 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.95 (d, 1H), 6.65-6.50 (m, 2H), 5.26 (bs, 1H), 3.07 (t, 2H), 2.92-2.68 (m, 2H), 2.44 (d, 1H), 2.25 (ddd, 1H), 2.00-1.80 (m, 3H), 1.66-1.45 (m, 5H), 1.34 (ddd, 1H), 0.68 (s, 3H). (rac)-(3R, 4aS, 10aS) -7 -hydroxy-10a-methyl-1,2,3,4,4a, 9,10, lOa-octahydrospiro [henanthrene-3,2'-cyclo Butane] -1′-one: ES-MS m / z: 288.2 (pos., M + NH ₄ ⁺ ), 270.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.97 (d, 1H), 6.64-6.46 (m, 2H), 4.84 (bs, 1H), 3.00 (t, 2H), 2.90-2.68 (m, 2H), 2.43 (dd, 1H), 1.97-1.35 (m, lOH), 0.68 (s, 3H).
[443] Example 47: (rac)-(3S, 4aS, 10aS) -1 ', 1'-ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10, Synthesis of 10a-octahydrospiro [henanthrene-3,2'-cyclobutane] (E47).
[444]
[445] (rac)-(3S, 4aS, 10aS) -1 ', 1'-ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro Spiro [henanthrene-3,2'-cyclobutane]. The reaction was carried out with 28.0 mg (0.10 mmol) of (rac)-(3S, 4aS, 10aS) -7 -hydroxy-10a-methyl-1,2,3,4,4a, 9,10, lOa-octahydrospiro [ On phenanthrene-3,2'-cyclobutane] -1'-method, Method G ("J" = 10, "K" = 1,2-ethanedithiol, "L" = 2, "M" = 18 ), Using 3 eq. Of BF ₃ .OEt ₂ complex. The raw material was purified by silica gel flash chromatography using Et ₂ 0: iso-hexane (1: 1) as eluent, and (rac)-(3S, 4aS, 10aS) -1 ', 1'-ethanediyldimercapto -7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,2'-cyclobutane] (31 mg) was obtained as a white oil. . ES-MS m / z: 347.2 (pos., M + H), 391.0 (neg., M + HCOOH-H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7. 12 (d, lH), 6.62 (dd, 1H), 6. 55 (d, 1H), 4.60 (bs, 1H), 3.30-3.10 (m, 4H ), 2.90-2.70 (m, 2H), 2.60-2.46 (m, 2H), 2.45-2.34 (m, 2H), 1.98-1.76 (m, 4H), 1.62-1.24 (m, 5H), 0.69 (s , 3H).
[446] Example 48 (rac)-(4aS, 10aS) -7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,1 ' -Cyclobutane] (E48).
[447]
[448] (rac)-(4aS, lOaS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,1'-cyclobutane] . The reaction was carried out at 24.0 mg (0.070 mmol) of (rac)-(3S, 4aS, 10aS) -1 ', l'-ethanediyldimercapto-7-hydroxy-l0a-methyl-1,2,3,4,4a On, 9,10, lOa-octahydrospiro [henanthrene-3,2'-cyclobutane] Method J ("J" = 100, "K" = 15, "L" = 20, "M" = 0 , (Rac)-(4aS, 10aS) -7 -hydroxy-10a-methyl-1,2,3,4,4a, 9,10, lOa-octa, carried out at 80 ° C. according to “N” = 24). Hydrospiro [henanthrene-3,1'-cyclobutane] (18 mg) was obtained as a white oil. ES-MS m / z: 257.2 (pos., M + H), 255.1 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.08 (d, 1H), 6.61 (dd, 1H), 6.55 (d, 1H), 4.40 (bs, 1H), 2.94-2.67 (m, 2H), 2.33 ( dd, 1H), 2.20 (ddd, 1H), 1.98-1.18 (m, 13H), 0.67 (s, 3H).
[449] Example 49: (rac)-(4aS, 10aS) -3- (1-cyclopenten-1-yl) -7-hydroxy-10a-methyl-1,4,4a, 9,10,10a-hexahydro Synthesis of Phenanthrene (E49).
[450]
[451] Step 1: (rac)-(4aS, 10aS) -3,7 -dihydroxy-10a-methyl-3- [1- (phenylsulfonyl) cyclopentyl] -1,2,3,4,4a, 9 , 10,10a-octahydrophenanthrene (mixture of diastereomers). n- BuLi (1.60 mL of 1.6 M solution in hexanes, 2.40 mmol) was added to a solution of cyclopentylphenylsulfoxide (466 mg, 2.40 mmol) in THF (15 mL) with cooling to −70 ° C. The reaction mixture was allowed to warm to room temperature and then cooled to 0 ° C. (Rac)-(4aS, 10aS) -7 -hydroxy-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one in THF (5 mL) (110 mg, 0.478 mmol) was added and the resulting mixture was stirred at rt overnight. The resulting mixture was cooled with saturated aqueous NH ₄ Cl (10 mL) with water (10 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (3 x 15 mL). The mixed organic solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated. Product, (rac)-(4aS, 10aS) -3,7-dihydroxy-10a-methyl-3- [1- (phenylsulfinyl) cyclopentyl] -1,2,3,4,4a, 9 A mixture of diastereomers of, 10,10a-octahydrophenanthrene was used in the next step without purification or separation.
[452] Step 2. (rac)-(4aS, l0aS)-3- (1-cyclopenten-l-yl) -7-hydroxy-lOa-methyl-l, 4,4a, 9,10, lOa-hexahydrophenanthrene. TiCl ₄ (1.43 mmol, 271 mg) was converted to Zn powder (2.87 mmol, 188 mg) and TH- (4aS, 10aS) -3,7-dihydroxyl0a-methyl-3- in THF (25 mL). Well-stirred [1- (phenylsulfinyl) cyclopentyl] -1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (a mixture of diastereomers of the previous step, about 0.48 mmol) To the mixture was added cooling to 0 ° C. The resulting mixture was stirred at room temperature for 2 hours and then cooled with saturated aqueous NaHCO ₃ (10 mL). The organic layer was separated and the aqueous layer was further extracted with Et ₂ 0 (3 × 15 mL). The mixed organic solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated. The residue was purified by PHPLC to give (rac)-(4aS, 10aS) -3- (1-cyclopenten-1-yl) -7-hydroxy-10a-methyl-1,4,4a, 9,10,10a- Hexahydrophenanthrene (20 mg) was obtained as a pale yellow oil. ES-MS m / z: 281.2 (pos., M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.19 (d, 1H), 6.66 (dd, 1H), 6.57 (d, 1H), 5.79 (s, 1H), 5.68 (dd, 1H), 4.55 (bs, 1H), 3.33-2.81 (m, 2H), 2.86-2.60 (m, 2H), 2.55-2.38 (m, 4H), 2.14-1.84 (m, 5H), 1.72-1.50 (2H), 0.75 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 153. 15, 144.35, 137.87, 132.85, 131.85, 127.26, 123.92, 123.05, 115.08, 112.93, 41.65, 40.78, 37.11, 33.06, 32.22, 30.97, 28.43, 26.31, 23.08, 16.19.
[453] Example 50: (rac)-(3s, 4aS, 10aS) -7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-3,2'-furan] (E50a) and (rac)-(3R, 4aS, 10aS) -7-hydroxy-10a-methyl-1,2,3,4 Synthesis of 4a, 9,10,10a, 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-32'-furan] (E50b).
[454]
[455] Step 1: (rac)-(4aS, 10aS) -3,7-dihydroxy-1Oa-methyl-3- [3- (phenylmethoxy) propyl] -1,2,3,4,4a, 9, 10,1Oa-octahydrophenanthrene (mixture of diastereomers). A mixture of Mg flour (114 mg, 4.70 mmol) and benzyl 3-bromopropyl ether (538 mg, 2.35 mmol) in THF (20 mL) was stirred at 60 ° C. for 2 hours. (Rac)-(4aS, l0aS) -7-hydroxy-l0a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one in THF (5 mL) (108) mg, 0.47 mmol) was added to the resulting mixture at room temperature. The resulting mixture was stirred overnight at room temperature and then cooled with saturated aqueous NH ₄ Cl (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was further extracted with Et0Ac (3 × 15 mL). The mixed organic solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated. Product (rac)-(4aS, lOaS) -3,7-dihydroxy-1Oa-methyl-3- [3- (phenylmethoxy) propyl] -1,2,3,4,4a, 9,10 A mixture of diastereomers of, 10a-octahydrophenanthrene was used without purification or separation in the next step.
[456] Step 2: (rac)-(4aS, lOaS) -3,7 -dihydroxy-3- (3-hydroxypropyl) -lOa-methyl-l, 2,3,4,4a, 9,10,10a Octahydrophenanthrene (mixture of diastereomers). (Rac)-(4aS, 10aS) -3,7-dihydroxy-10a-methyl-3- [3- (phenylmethoxy) propyl] -1,2,3,4,4a, 9 from the previous step A mixture of diastereomers of, 10,10a-octahydrophenanthrene (about 0.47 mmol) was prepared using Method F ("J" = THF, "K" = 20, "L" = 10% Pd / C (wet, 50 of water) %), "M" = 140, "N" = 72) (rac)-(4aS, 10aS) -3,7-dihydride, a mixture of diastereomers used in the next step without purification or separation Oxy-3- (3-hydroxypropyl) -10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene was obtained.
[457] Step 3: (rac)-(3s, 4aS, 10aS) -3,7 -dihydroxy-3- [3-[(4-methylphenyl) sulfonyloxy] propyl] -1Oa-methyl-1,2,3 , 4,4a, 9,10,10a-octahydrophenanthrene and (rac)-(3R, 4aS, lOaS) -3,7 -dihydroxy-3- [3-[(4-methylphenyl) sulfonyloxy ] Propyl] -lOa-methyl-1,2,3,4,4a, 9,10, lOa-octahydrophenanthrene. (Rac)-(4aS, 1OaS) -3,7 -dihydroxy-3- (3-hydroxypropyl) -lOa-methyl-1,2,3 at all stages in CH ₂ C1 ₂ (25 mL) Diastereomer of 4,4a, 9,10, lOa-octahydrophenanthrene (about 0.47 mmol), 4-methylphenylsulfonyl chloride (448 mg, 2.35 mmol), 4-dimethylaminopyridine (57 mg, 0.47 mmol ) And pyridine (372 mg, 4.70 mmol) were stirred at 40 ° C. overnight. The resulting mixture was diluted with CHCl ₃ (50 mL) and subsequently washed with saturated aqueous NaHCO ₃ (2 × 15 mL), 1 M aqueous HCl (2 × 15 mL), water (10 mL) and then again saturated aqueous NaHCO ₃ ( 15 mL). The resulting solution was dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated. The residue was separated using PHPLC and purified (rac)-(3S, 4aS, lOaS) -3,7 -dihydroxy-3- [3-[(4-methylphenyl) sulfonyloxy] propyl] -lOa-methyl -1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (53 mg) and (rac)-(3R, 4aS, 10aS) -3,7 -dihydroxy-3- [3 -[(4-methylphenyl) sulfonyloxy] propyl] -Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (65 mg) was obtained as a white oil. (rac)-(3S, 4aS, 10aS) -3,7 -dihydroxy-3- [3-[(4-methylphenyl) sulfonyloxy] propyl] -10a-methyl-1,2,3,4, 4a, 9,10,10a-octahydrophenanthrene: ES-MS m / z: 444.4 (pos., M + H), 485.2 (neg., M + HCOOH-H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.70 (d, 2H), 7.29 (d, 2H), 7.04 (d, 1H), 6.75 (d, 1H), 6.65 (dd, 1H), 3.87 (t, 2H), 2.90-2.66 (m, 2H), 2.43 (s, 3H), 2.38 (dd, 1H), 2.07 (ddd, 1H), 2.02-1.88 (m, 2H), 1.88-1.42 (m, 7H) , 1.35-1.17 (m, 2H), 0.70 (s, 3H). (rac)-(3R, 4aS, 10aS) -3,7 -dihydroxy-3- [3- (4-methylphenyl) sulfonyloxy] propyl] -Oa-methyl-1,2,3,4,4a , 9,10,10a-octahydrophenanthrene: ES-MS m / z: 444.4 (pos., M + H),
[458] 485.2 (neg., M + HCOOH-H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7. 67 (d, 2H), 7.27 (d, 2H), 7.02 (d, 1H), 6.71 (d, 1H), 6.62 (dd, 1H), 3.81 ( t, 2H), 2.86-2.64 (m, 3H), 2.42 (s, 3H), 2.11 (dd, 1H), 2.00-1.86 (m, 2H), 1.78-1.46 (m, 9H), 1.44-1.29 ( m, 2H), 0.64 (s, 3H).
[459] Step 4: (rac)-(3S, 4aS, 10aS) -7 -hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5 '-Dodecahydrospiro [henanthrene-3,2'-furan]. Tert-butoxide potassium (t-BuOK) (67 mg, 0.595 mmol) was added (rac)-(3s, 4aS, 10aS) -3,7 -dihydroxy-3- [3- () in THF (20 mL). 4-methylphenyl-sulfonyloxy) propyl] -1Oa-methyl-1,2,3,4,4a, 9,10, lOa-octahydrophenanthrene (53 mg, 0.119 mmol) was added to the solution. The reaction mixture was stirred for 30 min at room temperature and then cooled with saturated aqueous NH ₄ Cl (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was further extracted with Et ₂ 0 (3 × 15 mL). The mixed organic solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated. The product was purified by silica gel flash chromatography using Et ₂ 0: iso-hexane (1: 1) as eluent and (rac)-(3S, 4aS, lOaS) -7-hydroxy-1Oa-methyl-1, 2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-3,2'-furan] (26 mg) was obtained as a white solid. . ES-MS m / z: 273.2 (pos., M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.00 (d, 1H), 6.68-6.50 (m, 2H), 5.76 (bs, 1H), 3.92 (t, 2H), 2.94-2.68 (m, 2H), 2. 37 (dd, 1H), 2.23 (ddd, 1H), 2.06-1.42 (m, 9H), 1. 35-1. 17 (m, 2 H), 0.72 (s, 3 H); ¹³ C NMR (CDCl ₃ ) δ 153.65, 137.61, 131.03, 125.66, 115.31, 112.58, 84.63, 66.47, 43.06, 38.53, 37.88, 36.15, 34.89, 32.80, 32.36, 26.34, 26.00, 15.14.
[460] Step 5: (rac)-(3R, 4aS, l0aS) -7 -hydroxy-l0a-methyl-1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5 '-Dodecahydrospiro [henanthrene-3,2'-furan].
[461] (rac)-(3R, 4aS, 10aS) -3,7 -dihydroxy-3- [3-[(4-methylphenyl) sulfonyloxy] propyl] -Oa-methyl-1,2,3,4, 4a, 9,10, lOa-octahydrophenanthrene (65 mg, 0.146 mmol) was treated as described in step 4 to (rac)-(3R, 4aS, lOaS) -7-hydroxy-1Oa-methyl-1 , 2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-3,2'-furan] (37 mg) as a white solid Got it. ES-MS m / z: 273.4 (pos., M + H), 271.4 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.98 (d, 1H), 6.65-6.47 (m, 2H), 5.71 (s, 1H), 3.87 (td, 2H), 2.90-2.64 (m, 2H), 2.19 (dd, 1 H), 2.06-1.24 (m, 11 H), 0.68 (s, 3 H); ¹³ C NMR (CDCl ₃ ) δ 153.27, 137.94, 131.75, 125.57, 115.27, 112.37, 84.41, 66.73, 40.52, 38.81, 37.81, 36.71, 35.22, 32.00, 31.94, 26.25, 25.27, 14.89.
[462] Example 51 (rac)-(3S, 4aS, 10aS) -7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a, 3 ', 4', 5 ', 6'-dodecahydrospiro [henanthrene-3,2'-2H-pyran] (E5la) and (rac)-(3R, 4aS, 10aS) -7-hydroxy-10a-methyl-1,2,3 Synthesis of 4,4a, 9,10,10a, 3 ', 4', 5 ', 6'-dodecahydrospiro [henanthrene-3,2'-2H-pyran] (E51b).
[463]
[464] Step 1: (rac)-(3S, 4aS, lOaS) -3,7 -dihydroxy-3- (4-hydroxybutyl) lOa-methyl-1,2,3,4,4a, 9,10 , 1Oa-octahydrophenanthrene and (rac)-(3R, 4aS, 1OaS) -3,7 -dihydroxy-3- (4-hydroxybutyl) -1Oa-methyl-1,2,3,4, 4a, 9,10,1Oa-octahydrophenanthrene. Benzyl 4-bromobutyl ether (571 mg, 2.35 mmol) was added to a suspension of Rieke® Mg (114 mg, 4.70 mmol) in well stirred THF (20 mL) at room temperature and the resulting mixture was stirred at 50 ° C. for 2 hours. Stirred. (Rac)-(4aS, 10aS) -7-hydroxy-10a-methyl-1,4,4a, 9,10, l0a-hexahydro- 2H -phenanthrene-3-one in THF (5 mL) (108) mg, 0.47 mmol) was added to the mixture at room temperature and the resulting mixture was stirred at room temperature for 3 days. The mixture was cooled with saturated aqueous NH ₄ Cl (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was further extracted with Et0Ac (3 × 15 mL). The mixed organic solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated. The residue was purified by silica gel flash chromatography using Et ₂ 0: MeOH (97: 3) as eluent and (rac)-(3S, 4aS, 1OaS) -3,7 -dihydroxy-3- (4- Hydroxybutyl) -10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (49 mg) and (rac)-(3R, 4aS, 1OaS) -3,7- Dihydroxy-3- (4-hydroxybutyl) -1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (76 mg) was obtained as a white solid.
[465] Step 2: (rac)-(3S, 4aS, 1OaS) -3,7-dihydroxy-1Oa-methyl-3- [4-[(4-methylphenyl) -sulfonyloxy] butyl] -1,2, 3,4,4a, 9,10,10a-octahydrophenanthrene. (rac)-(3S, 4aS, 10aS) -3,7 -dihydroxy-3- (4-hydroxybutyl) -10a-methyl-1,2,3,4,4a, 9,10,10a- Octahydrophenanthrene (49 mg, 0.161 mmol) was treated in the procedure described in Example 50, step 3 to be used in the next step without purification or separation (rac)-(3S, 4aS, 10aS) -3,7 -di Hydroxy-3- [4-[(4-methylphenyl) sulfonyloxy] l-butyl] -1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene was obtained.
[466] Step 3: (rac)-(3S, 4aS, lOaS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 3 ', 4', 5 ', 6 '-Dodecahydrospiro [henanthrene-3,2'-2H-pyran]. Raw material (rac)-(3S, 4aS, lOaS) -3,7-dihydroxylOa-methyl-3- [4-[(4-methylphenyl) sulfonyloxy] butyl] -1,2 at the previous step , 3,4,4a, 9,10,10a-octahydrophenanthrene (about 0.16 mmol) was treated according to the procedure described in Example 50, step 4 to (rac)-(3S, 4aS, 10aS) -7-. Hydroxy-10a-methyl-1,2,3,4,4a ,, 10,10a, 3 ', 4', 5 ', 6'-dodecahydrospiro [henanthrene-3,2'-2H-pyran (31 mg) was obtained as a white oil. ES-MS m / z: 287.2 (pos., M + H), 285.0 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.04 (d, 1H), 6.67-6.55 (m, 2H), 5.71 (s, 1H), 3.90-3.71 (m, 2H), 2.95-2.69 (m, 2H ), 2.50-2.37 (m, 2H), 1.98 (dd, 1H), 1.82-1.20 (m, 12H), 0.72 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 153.59, 137.76, 131.20, 125.57, 115.32, 112.57, 74.62, 61.25, 41.02, 37.89, 37.06, 34.88, 33.02, 31.70, 30.17, 26.33, 26.25, 19.02, 15.31.
[467] Step 4: (rac)-(3R, 4aS, lOaS) -3,7 -dihydroxy-1Oa-methyl-3- [4-[(4-methylphenyl) sulfonyloxy] butyl] -1,2,3 , 4,4a, 9,10,10Oa-octahydrophenanthrene. (rac)-(3R, 4aS, 10aS) -3,7 -dihydroxy-3- (4-hydroxybutyl) -1Oa-methyl-1,2,3,4,4a, 9,10,10a- Octahydrophenanthrene (76 mg, 0.25 mmol) was treated according to Example 50, step 3 to be used without purification in the next step (rac)-(3R, 4aS, lOaS) -3,7 -dihydroxy-3 -[4-[(4-methylphenyl) sulfonyloxy] -1-butyl] -1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene was obtained.
[468] Step 5: (rac)-(3R, 4aS, 10aS) -7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a, 3 ', 4', 5 ', 6 '-Dodecahydrospiro [henanthrene-3,2'-2H-pyran]. Preliminary raw material (rac)-(3R, 4aS, lOaS) -3,7-lOa-methyl-3- [4-[(4-methylphenyl) sulfonyloxy] butyl] -1,2,3,4,4a , 9,10, lOa-octahydrophenanthrene (about 0.25 mmol) was treated according to the procedure described in Example 50, step 4 to (rac)-(3R, 4aS, 10aS) -7-hydroxy-10a-methyl -1,2,3,4,4a, 9,10,10a, 3 ', 4', 5 ', 6'-dodecahydrospiro [henanthrene-3,2'-2H-pyran] (56 mg) Was obtained as a white oil. ES-MS m / z: 287.2 (pos., M + H), 285.2 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.02 (d, 1H), 6.63-6.52 (m, 2H), 5.78 (s, 1H), 3.66 (dd, 2H), 2.91-2.64 (m, 3H), 2.50 (ddd, 1H), 1.93 (ddd, 1H), 1.78-1.34 (m, 10H), 1.26 (ddd, 1H), 1.14 (dd, 1H), 0.67 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 153.24, 138.07, 131.85, 125.52, 115.29, 112.39, 72.58, 60.56, 38.61, 37.89,37.59, 35.08, 32.63, 32.52, 29.65, 26.30, 26.14, 19.00, 15.08.
[469] Example 52: (rac)-(1S, 3R, 4aS, 10aS) -7 -hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10, Synthesis of 10a, 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-3,2'-furan] (E52).
[470]
[471] Step 1: (rac)-(1S, 3R, 4aS, 10aS) -3,7-dihydroxy-10a-methyl-1- (3-methylbutyl) -3- [3- (phenylmethoxy) propyl] -1,2,3,4,4a, 9,10,10a-octahydrophenanthrene. (rac)-(1s, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10, lOa-octahydrophenanthrene The 3-membered (83 mg, 0.277 mmol) was treated according to the procedure described in Example 50, step 1 except that the reaction mixture was stirred at 50 ° C. overnight. The raw material was purified by silica gel flash chromatography using Et ₂ 0: iso-hexane (1: 1) as eluent and the only diastereomer, (rac)-(1S, 3R, 4aS, 10aS) -3,7- Dihydroxy-10a-methyl-1- (3-methylbutyl) -3- [3- (phenylmethoxy) propyl] -1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (119 mg) was obtained as a white oil.
[472] Step 2: (rac)-(lS, 3R, 4aS, 10aS) -3,7 -dihydroxy-3- (3-hydroxypropyl) -lOa-methyl-l- (3-methylbutyl) -1, 2,3,4,4a, 9,10, lOa-octahydrophenanthrene.
[473] (rac)-(1S, 3R, 4aS, 10aS) -3,7 -dihydroxy-10a-methyl-1- (3-methylbutyl) -3 [3- (phenylmethoxy) propyl] -1,2 , 3,4,4a, 9,10,10a-octahydrophenanthrene (119 mg, 0.264 mmol) was prepared using Method F ("J" = THF, "K" = 20, "L" = 10% Pd / C ( wet, 50% of water), treated according to "M" = 140, "N" = 72), and (rac)-(1S, 3R, 4aS, 10aS) -3,7 -dihydroxy3- (3- Hydroxypropyl) -10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (95 mg) was obtained as a white solid. ¹ H NMR (270 MHz, CD ₃ COCD ₃ ) δ 7.93 (s, 1H), 7.06 (d, 1H), 6.58 (dd, 1H), 6.54 (d, 1H), 3.87 (t, 1H), 3.60 ( d, 1H), 3.57 (d, 1H), 3.21 (s, 1H), 3.03 (dd, 1H), 2.83 (ddd, 1H), 2.71 (ddd, 1H), 2.20 (ddd, 1H), 2.00-1.25 (m, 15H), 1.17-1.05 (m, 1H), 0.89 (d, 3H), 0.86 (d, 3H), 0.80 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 155.47, 138.16, 131.85, 127.27, 115.76, 113.58, 79.10, 72.45, 63.34, 45.35, 43.30, 39.27, 38.16, 35.94, 34.92, 34.86, 34.23, 29.09, 27.50, 27.46, 23.46, 23.51 22.69, 18.44.
[474] Step 3. (rac)-(1S, 3R, 4aS, 10aS) -3,7 -dihydroxy-10-methyl-1- (3-methylbutyl) -3- [3-[(4-methylphenyl) sulfonyloxy] Propyl] -1,2,3,4,4a, 9,10,10Oa-octahydrophenanthrene. (rac)-(1S, 3R, 4aS, 10aS) -3,7 -dihydroxy-3- (3-hydroxypropyl) -10a-methyl-1- (3- = methylbutyl) -1,2, 3,4,4a, 9,10,10a-octahydrophenanthrene (47 mg, 0.13 mmol) was treated according to the procedure described in Example 50, step 3 to be used without purification in the next step (rac)-(1S , 3R, 4aS, 10aS) -3,7 -dihydroxylOa-methyl-1- (3-methylbutyl) -3- [3-[(4-methylphenyl) sulfonyloxy] propyl] -1,2 , 3,4,4a, 9,10,10a-octahydrophenanthrene was obtained.
[475] Step 4: (rac)-(1S, 3R, 4aS, 10aS) -7 -hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a , 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-3,2'-furan]. (Rac)-(1S, 3R, 4aS, 10aS) -3,7 -dihydroxy-10a-methyl-1- (3-methylbutyl) -3- [3-[(4-methylphenyl) from the previous step Sulfonyloxy] propyl] -1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (about 0.13 mmol) was treated according to the procedure described in Example 13, step 4 to (rac)- (1S, 3R, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-3,2'-furan] (34 mg) was obtained as a white oil. ES-MS m / z: 343. 4 (pos., M + H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.07 (d, 1H), 6.57 (dd, 1H), 6.52 (d, 1H), 5.00 (s, 1H), 3.95-3.76 (m, 2H), 2.94 ( dd, 1H), 2.92-2.63 (m, 2H), 2.19 (ddd, 1H), 2.00-1.82 (m, 3H), 1.82-1.63 (m, 5H), 1.58-1.21 (m, 6H), 1.26- 1.10 (m, 1 H), 0.88 (d, 3 H), 0.86 (d, 3H), 0.81 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 152.91, 137.97, 132.44, 126.85, 115.04, 112.63, 82.81, 67.13, 44.78, 40.00, 38.60, 36.76, 35.54, 34.89, 33.86, 32.80, 28.38, 26.96, 25.69, 25.18, 23.30, 22.34, 18.15.
[476] Example 53: (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl (3-methylbutyl) -1,2,3,4,4a, 9,10,10a-octahydrospiro [Phenanthrene-3, 1'-cyclobutane] (E53).
[477]
[478] Step 1: (rac)-(1S, 3R, 4aS, 10aS) -3,7 -dihydroxy-1Oa-methyl-1- (3-methylbutyl) -3- [1- (phenylthio) cyclopropyl] -1,2,3,4,4a, 9,10,10a-octahydrophenanthrene. (rac)-(lS, 4aS, lOaS) -7-hydroxy-1Oa-methyl-l- (3-methylbutyl) -1,2,3,4,4a, 9,10, lOa-octahydrophenanthrene The 3-membered (34 mg, 0.112 mmol) was described according to the method described in Example 45 to describe the only diastereomer, (rac)-(1S, 3R, 4aS, 10aS) -3,7-dihydroxy-10a -Methyl-1- (3-methylbutyl) -3- [1- (phenylthio) cyclopropyl] -1,2,3,4,4a, 9,10,1Oa-octahydrophenanthrene (27 mg) Obtained as a white oil. ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.50-7.42 (m, 2H), 7.31-7.22 (m, 2H), 7.15 (tt, 1H), 7.01 (d, 1H), 6.58 (dd, 1H), 6.53 (d, 1H), 4.90 (s, 1H), 3.56 (d, 1H), 2.99 (dd, 1H), 2.83 (ddd, 1H), 2.70 (ddd, 1H), 2.12 (ddd, 1H), 2.00 -1.00 (m, 15H), 0.88 (d, 3H), 0.84 (d, 3H), 0.77 (s, 3H).
[479] Step 2: (rac)-(1S, 4aS, 10aS) -7 -hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a-octa Hydrospirophenanthrene-3,2'-cyclobutane] -1'-one (mixture of diastereomers). (rac)-(1S, 3R, 4aS, 10aS) -3,7-dihydroxy-10a-methyl-1- (3-methylbutyl) -3- [1- (phenylthio) cyclopropyl] -1, 2,3,4,4a, 9,10,10a-octahydrophenanthrene was treated according to the method described in Example 45 to be used without purification in the next step (rac)-(1S, 4aS, 10aS) -7- Hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,2'-cyclobutane] -1 ' A mixture of the original diastereomers was obtained.
[480] Step 3. (rac)-(1S, 4aS, 10aS) -1 ', 1'-ethanediyldimercapto-7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a , 9,10,10a-octahydrospiro [henanthrene-3,2'-cyclobutane] (mixture of diastereomers). (Rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a- from the previous step Octahydrospiro [henanthrene-3,2'-cyclobutane] -1'-one (about 0.05 mmol) was prepared using Method G ("J" = 10, "K" = 1,2-ethanedithiol, "L" = 2, "M" = 18), using 3 eq. BF ₃ .OEt ₂ complex. The raw material was purified by silica gel flash chromatography using Et ₂ 0: iso-hexane (1: 1) as eluent, and a mixture of diastereomers (rac)-(1S, 4aS, 1OaS) -1 ′, 1 '-Ethanediyldimercapto-7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10, lOa-octahydrospiro [henanthrene-3, 2'-cyclobutane] (17 mg) was obtained as a white oil.
[481] Step 4: (rac)-(1S, 4aS, lOaS) -7 -hydroxy-l0a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10, lOa-octa Hydrospiro [henanthrene-3,1'-cyclobutane]. (rac)-(1S, 4aS, l0aS) -1 ', 1'-ethanediyldimercapto-7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a , 9,10,10a-octahydrospiro [henanthrene-3,2'-cyclobutane] (17 mg, 0.041 mmol) was prepared using Method J ("J" = 100, "K" = 15, "L" = 20 , "M" = 0, "N" = 24) and the raw material was purified by PHPLC to give (rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1 -(3-methylbutyl) -1,2,3,4,4a, 9,10,10a-octahydrospiro [henanthrene-3,1'-cyclobutane] (5.4 mg) was obtained as a white oil. ES-MS m / z: 327.4 (pos., M + H), 325.3 (neg., MH); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.20 (d, 1H), 6.63 (dd, 1H), 6.55 (d, 1H), 4.48 (bs, 1H), 2.86 (ddd, 1H), 2.71 (ddd, 1H), 2.64 (dd, 1H), 2.43 (ddd, 1H), 2.10-1.16 (m, 17H), 0.89 (d, 3H), 0.87 (d, 3H), 0.80 (s, 3H).
[482] Example54 : (rac)-(1S, 4aS, 10aS) -7-hydroxy-3- (3-hydroxypropyl) -10a-methyl-1- (3-methylbutyl) -1,4,4a, 9,10,10a-hexahydrophenanthrene (E54a) and (rac)-(1S, 3S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2, Synthesis of 3,4,4a, 9.10,10a, 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-3,2'-furan] (E54b).
[483]
[484] (rac)-(1S, 4aS, 1OaS) -7-hydroxy-3- (3-hydroxypropyl) -lOa-methyl-l- (3-methylbutyl) -l, 4,4a, 9,10, 1Oa-hexahydrophenanthrene and (rac)-(1S, 3S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9 , 10,10a, 2 ', 3', 4 ', 5'-dodecahydrospiro [henanthrene-3,2'-furan]. (Rac)-(1S, 3R, 4aS, 10aS) -3,7-dihydroxy-3- (3-hydroxypropyl) -10a-methyl-1- (3-methylbutyl) in toluene (20 mL) -1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (47 mg, 0.13 mmol) and 4-toluenesulfonic acid monohydrate (2.5 mg, 0.013 mmol) were stirred at 100 ° C. overnight. The resulting mixture was cooled with saturated aqueous NaHCO ₃ (10 mL), the organic layer was separated and the solvent was evaporated. The residue was purified by silica gel flash chromatography using Et ₂ 0: iso-hexane (1: 1) as eluent and purified (rac)-(1S, 4aS, 10aS) -7 -hydroxy-3- (3). -Hydroxypropyl) -10a-methyl-1- (3-methylbutyl) -1,4,4a, 9,10,10a-hexahydrophenanthrene (18 mg) and (rac)-(1S, 3S, 4aS, 10aS) -7-hydroxy-10a-methyl-l- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dode Carhydrosspiro [henanthrene-3,2'-furan] (5.3 mg) was obtained as a white oil. (rac)-(1S, 4aS, 10aS) -7-hydroxy-3- (3-hydroxypropyl) -10a-methyl-1- (3-methylbutyl) -1,4,4a, 9,10, lOa-hexahydrophenanthrene: ES-MS m / z: 343.4 (pos., M + H), 387.4 (neg., M + HCOOH-H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.11 (d, 1H), 6.64 (dd, 1H), 6.55 (d, 1H), 5.56 (d, 1H), 5.10 (bs, 1H), 3.68 (t, 2H), 2.94-2.61 (m, 3H), 2.54 (dd, 1H), 2.13 (t, 2H), 1.88-1.04 (m, 11H), 0.88 (d, 3H), 0.85 (d, 3H), 0.77 (s, 3 H). (rac)-(1S, 3S, 4aS, 10aS) -7-hydroxy-10a-methyl-l- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a, 2 ' , 3 ', 4', 5'-dodecahydrospiro [henanthrene-3,2'-furan]: ES-MS m / z: 343.4 (pos., M + H), 387.4 (neg., M + HCOOH-H); ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.09 (d, 1H), 6.60 (dd, 1H), 6.56 (d, 1H), 4.75 (s, 1H), 3.94-3.74 (m, 2H), 2.94- 2.66 (m, 2H), 2.60 (dd, 1H), 2.19-1.60 (m, 8H), 1.60-1.06 (m, 8H), 0.89 (d, 3H), 0.87 (d, 3H), 0.85 (s, 3H); ¹³ C NMR (CDCl ₃ ) δ 153.27, 137.95, 131.78, 126.83, 115.23, 112.83, 82.62, 65.55, 44.87, 38.46, 37.70, 36.69, 36.49, 35.21, 34.53, 33.87, 28.48, 27.06, 26.63, 25.52, 23.24 22.33, 18.49.
[485] Example 55 (rac)-(4aR, lOaR) -l0a-butyl-7-hydroxy-4a-methyl-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one (E55).
[486]
[487] Step 1: (rac)-(4aR, lOaR) -l0a-butyl-7-methoxy-4a-methyl-3,4,4a, 9,10, l0a-hexahydro- 1H -phenanthrene-2-one: The reaction was carried out in 200 mg (0.83 mmol) of (rac) -7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2- dissolved in diethyl ether (3 mL). The following conditions were used except that CuI was used for CuCN according to Method P on the circle; CuI (1.2 eq., Suspension in 10 mL diethyl ether), alkyl lithium (n-BuLi [1.6M solution in hexane], 2.2 eq.), Reaction time and temperature (30 min at −78 ° C., chilled at −40 At ℃). Raw material was fractionated on EtOAc using EtOAc: n-heptane (3: 7, v: v) as eluent. The first collected fractions on chromatography were purified using PHPLC and further purified by (rac)-(4aR, 10aR) -l0a-butyl-7-methoxy-4a-methyl-3,4,4a, 9,10, lOa- hexahydro - lH - phenanthrene-2 to obtain a circle as an oil exhibits the nureonbit. ES-MS m / z: 301.3 (pos., M + H); ¹ H NMR (CDCl ₃ ) δ 7.25 (d, 1H), 6.75 (dd, 1H), 6.60 (d, 1H), 3.75 (s, 3H), 2.70-2.75 (m, 2H), 2.10-2.30 (m , 5H), 1.90-2.05 (m, 1H), 1.65-1.70 (m, 2H), 1.40 (s, 3H), 1.20-1.40 (m, 6H), 0.90 (t, 3H).
[488] Step 2: (rac)-(4aR, lOaR) -10a-butyl-7-hydroxy-4a-methyl-3,4,4a, 9,10,10a-hexahydro-1H-phenanthrene-2-one ( E55): The reaction was carried out in 11.9 mg of (rac)-(4aR, lOaR) -1Oa-butyl-7-methoxy-4a-methyl-3,4,4a, 9,10,10a-hexa dissolved in 1.0 mL DCM. It was carried out according to Method 0 for 16 hours using 3. eq. BBr ₃ on hydro-1H-phenanthrene-2-one. The raw material was purified on chromatography using EtOAc: n-heptane (3: 7, v: v) as eluent to afford E55 as a yellowish oil. ES-MS m / z: 287.2 (pos., M + H), 285.1 (neg., MH); ¹ H NMR (DMSO) δ 7.20 (d, 1H), 6.60 (dd, 1H), 6.45 (s, 1H), 3.60 (s, 3H), 2.60 (t, 2H), 1.50-2.20 (m, 10H) , 1.20-1.40 (m, 4H), 0.95 (t, 3H).
[489] Example 56 Synthesis of (rac) -7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one (E56).
[490]
[491] The reaction was carried out at 2.5 eq. Of BBr ₃ on 50 mg of (rac) -7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one dissolved in 3.0 mL DCM. Was carried out according to Method 0 for 4 h. The raw material was purified on chromatography using EtOAc: n-heptane (4: 6, v: v) as eluent to afford E56 as a yellowish solid. GC-MS m / z: 228.5 (M), 213.4 (M-CH ₃ ) ¹ HNMR (CD ₃ 0D) δ 7.15 (d, 1H), 6.65 (dd, 1H), 6.50 (d, 1H), 5.85 ( s, 1H), 2.35-2.90 (m, 7H), 1.95-2.00 (m, 1H), 1.55 (s, 3H); ¹³ C NMR (CD ₃ 0D) δ 201.15, 173.43, 155.44, 135.99, 134.93, 127.17, 123.15, 114.23, 114.07, 38.41, 36.69, 33.99, 30.64, 30.53, 26.32.
[492] Example 57: Synthesis of (rac) -4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E57).
[493]
[494] The reaction was carried out in Method R on (rac) -7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one dissolved in 5.0 mg of acetonitrile (2.0 mL). Followed. The raw material was purified on chromatography using EtOAc: n-heptane (3: 7) as eluent to afford E57. ES-MS m / z: 213.0 (neg., MH); ¹ H NMR (CD ₃ 0D) δ 7.10 (d, 1H), 6. 55 (dd, 1H), 6.40 (d, 1H), 5.40 (s, 1H), 1.45-2.80 (m, lOH), 1.40 ( s, 3H).
[495] Example 58: (rac) -7-hydroxy-1,4a-dimethyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one (E58).
[496]
[497] Step l: (rac) -7-methoxy-1,4a-dimethyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one: 200 mg (1.05) dissolved in toluene (2.0 mL) 6-methoxy-1-methyl-3,4-dihydro- 1H -naphthalene-2-one and pent- 1 -ene-3-one of mmol) were coupled according to Method M for further purification in the next step. (Rac) -7-methoxy-1,4a-dimethyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one was obtained without use. ES-MS m / z: 257.2 (pos., M + H).
[498] Step 2: (rac) -7-hydroxy-1,4a-dimethyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one (E58): The reaction was a raw material dissolved in 2.0 mL DCM. (rac) Method 0 for 16 hours using 3.5 eq. of BBr ₃ on -7-methoxy-1,4a-dimethyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one It was performed according to. A quarter of the raw material was purified by PHPLC to give E58 as a yellow solid. ES-MS m / z: 243.4 (pos., M + H), 241.3 (MH); ¹ H NMR (CD ₃ 0D) δ 7.20 (d, 1H), 6.65 (dd, 1H), 6.50 (d, 1H), 2.40-2.90 (m, 7H), 1. 80-1.95 (m, 1H), 1.89 (s, 3 H), 1.45 (s, 3 H); ¹³ C NMR (CD ₃ 0D) δ 200.05, 165.26, 155.30, 136.88, 135.90, 127.92, 126.64, 114.04, 113.91, 38.86, 35.84, 33.46, 29.30, 26.74, 25.64, 9.10.
[499] Example 59: Synthesis of (rac) -4a, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E59).
[500]
[501] The reaction was carried out in a quarter portion of raw (rac) -7-hydroxy-1,4a-dimethyl-4,4a, 9,10-tetrahydro-3H dissolved in a mixture of acetonitrile and DCM (2.0 + 2.0 mL). -Phenanthrene-2-one (up to 0.262 mmol) was carried out according to Method R (0.20 mL of trichloroacetic acid was used). The raw material was purified on chromatography using EtOAc: n-heptane (15:85) as eluent and PHPLC to afford E59. ES-MS m / z: 229.3 (pos., M + H); ¹ H NMR (CDCl ₃ ) δ 7.10 (d, 1H), 6.70 (bs, 1H), 6.65 (dd, 1H), 6.50 (d, 1H), 2.65-2.70 (m, 2H), 1.50-2.15 (m , 8H), 1.70 (s, 3H), 1.35 (s, 3H).
[502] Example 60: Synthesis of (rac) -4b, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E60a, E60b, E60c, E60d).
[503]
[504] The reaction is carried out on 4.0 mg of (rac) -4b, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol except that the reaction takes place under pressure (5.0 bar) Methanol (3.0 mL) was used as a method S for 12 hours using 5% Pd / C (5.0 mg) as a catalyst. A raw material consisting of a mixture of four possible diastereomers E60a + E60b + E60c + E60d was obtained. GC-MS m / z: 215.2 (M-CH ₃ ) 230.2 (M).
[505] Example 61 Synthesis of (rac)-(3S, 4aR) -7-hydroxy-3,4a-dimethyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one (E61).
[506]
[507] Step 1: (rac)-(3S, 4aR) -7-methoxy-3,4a-dimethyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one: in toluene (2.0 mL) Dissolved 200 mg (1.05 mmol) of (rac) -6-methoxy-1-methyl-3,4-dihydro- 1H -naphthalene-2-one and 3-methyl-but-3-ene-2-one (Rac)- (3S, 4aR) -7-methoxy-3,4a-dimethyl-4,4a, 9,10-tetrahydro- which is used according to Method M without further purification in the next step. 3H-phenanthrene-2-one was obtained. GC-MS m / z: 256.1 (M), 241.1 (M-CH ₃ ).
[508] Step 2: (rac) -(3S, 4aR) -7-hydroxy-3,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (28) Using 3.3 eq.BBr ₃ on (rac)-(3S, 4aR) -7 -methoxy-3,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one According to Method 0 it was carried out for 16 hours. The raw material was purified by PHPLC to obtain E61. GC-MS m / z: 242.1 (M), 227.1 (M-CH 3); ¹ H NMR (CDCl ₃ ) δ 7. 15 (d, 1H), 6.75 (dd, 1H), 6.55 (d, 1H), 5.86 (s, 1H), 5.15 (bs, 1H), 2.40-3.00 (m , 6H), 2.30 (dd, 1H), 1.55 (s, 3H), 1.15 (d, 3H).
[509] Example 62: (rac)-(4S, 4aR) -7-hydroxy-4a-methyl-4-propyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E62) synthesis.
[510]
[511] Step 1: (rac)-(4S, 4aR) -7-methoxy-4a-methyl-4-propyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one: toluene (2.0 mL how the source and the naphthalene-2-hept-3-en-2-one-6-methoxy-1-methyl-3,4-dihydro - - lH) (rac) of 200 mg (1.05 mmol) dissolved in Raw material (rac)-(4S, 4aR) -7 -methoxy-4a-methyl-4-propyl-4,4a, 9,10-tetrahydro- which is used according to M coupling without further purification in the next step 3H -phenanthrene-2-one was obtained. ES-MS m / z: 285.1 (pos., M + H).
[512] Step 2: (rac)-(4S, 4aR) -7-hydroxy-4a-methyl-4-propyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E62): reaction 3.3 eq. BBr on silver raw material (rac)-(4S, 4aR) -7-methoxy-4a-methyl-4-propyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one ₃ was used for 16 hours according to Method 0. The raw material was purified by PHPLC to obtain E62. GC-MS m / z: 270.0 (M); ¹ H NMR (CDCl ₃ ) δ 7.15 (d, 1H), 6.75 (dd, 1H), 6.60 (d, 1H), 6.35 (bs, 1H), 5.90 (s, 1H), 2.80-2. 85 (m, 1H), 2.75-2.80 (m, 1H), 2.60 (dd, 1H), 2.55 (m, 2H), 2.30 (dd, 1H), 2.00-2.10 (m, 1H), 1.60-1.70 ( m, 1H), 1.45 (s, 3H), 1.30-1.45 (m, 2H), 0.95-1.1 (m, 1H), 0.85 (t, 3H); ¹³ C
[513] NMR (CDCl ₃ ) δ 139.55, 133.0, 130.72, 123.68, 115.26, 113.0, 43.96, 43.59, 39.73, 33.13, 32.11, 22.0, 19.89, 13.86.
[514] Example 63 (rac)-(4R, 4aR) -7-hydroxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E63a) and (rac Synthesis of )-(4S, 4aR) -7 -hydroxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E63b).
[515]
[516] Step 1: (rac)-(4R, 4aR) -7-methoxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one and (rac)-(4S , 4aR) -7-methoxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one: 200 mg (1.05 mmol) dissolved in toluene (2.0 mL) (rac) -6-methoxy-1-methyl-3,4-dihydro- 1H- naphthalene-2-one and pent-3-ene-2-one were coupled according to Method M to obtain the raw material (rac)- (4R, 4aR) -7-methoxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one and (rac)-(4S, 4aR) -7-meth A mixture of oxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one was obtained. GC-MS m / z: 256.0 (M).
[517] Step 2: (rac)-(4R, 4aR) -7-hydroxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E63a) and (rac) -(4S, 4aR) -7-hydroxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E63b): The reaction is a raw material (rac)-(4R , 4aR) -7-methoxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one and (rac)-(4S, 4aR) -7-methoxy- A mixture of 4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one was added at 3.3 eq. Was carried out according to Method 0 for 16 h using BBr ₃ . The raw material was purified by PHPLC to obtain a mixture of E63a and E63b. ¹ H NMR (CD ₃ 0D) δ 7.15 (d, 1H), 6.65 (dd, 1H), 6.55 (d, 1H), 5.80 (s, 1H), 2.00-2.80 (m, 7H), 1.45 (s, 3H), 1.10 (d, 3H).
[518] Example 64: Synthesis of (rac) -1-ethyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one (E64).
[519]
[520] Step 1: (rac) -1-ethyl-7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one.
[521] 569 mg (2.99 mmol) of (rac) -6-methoxy-1-methyl-3,4-dihydro- 1H -naphthalene-2-one and hex- 1 -ene-3 dissolved in toluene (5.0 mL) (Rac) -l-ethyl-7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene- which is used without purification in the next step by coupling the source according to Method M 2-membered. ES-MS m / z: 271.3 (pos., M + H).
[522] Step 2: (rac) -l-ethyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one. The reaction was carried out in crude (rac) -1-ethyl-7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (up to 2.99 mmol) dissolved in 6.0 mL DCM. Phase, using 3.0 eq. Of BBr ₃ for 5 hours according to Method 0. The crude was purified on chromatography using EtOAc: n-heptane (3: 7, 6: 5, 5: 5, v: v, step gradient) as eluent to afford E64. ES-MS m / z: 257.2 (pos., M + H), 255.4 (neg., MH); ¹ H NMR (CD ₃ 0D) δ 7.1-7.2 (m, 1H), 6.10 (dd, 1H), 6.55 (d, 1H), 2.25-3.00 (m, 10H), 1.55 (s, 3H), 1.25 ( t, 3H).
[523] Example 65 Synthesis of (rac) -8-ethyl-4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E65).
[524]
[525] The reaction was carried out in 33 mg (0.13 mmol) of (rac) -1-ethyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene dissolved in acetonitrile (5.0 mL). Performed according to Method R on 2-membered. The raw material was purified by PHPLC to obtain E65. ES-MS m / z: 243.4 (pos., M + H), 241.3 (neg., MH); ¹ H NMR (CDCl ₃ , 500 MHz) δ 7.15 (d, 1H), 6.65 (dd, 1H), 6.50 (d, 1H), 2.65-2.85 (m, 3H), 2.15-2.25 (m, 1H), 2.10 -2.15 (m, 1H), 1.95-2.10 (m, 4H), 1.70-1.80 (m, 2H), 1.50-1.55 (m, 1H), 1.35 (s, 3H), 0.95 (t, 3H).
[526] Example 66: (rac)-(4aR, 10aR, 1S) -1-ethyl-7-hydroxy-4a-methyl-1,4,4a, 9,10,10a-hexahydro- 3H -phenanthrene-2 -Circle (E66).
[527]
[528] The reaction was carried out over 55 mg of (rac) -1-ethyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one in methanol according to Method S (3.0 mL). ) Was performed for 16 hours using 5% Pd / C (31 mg) as a catalyst as a solvent. The raw material was purified by PHPLC to obtain E66. ES-MS m / z: 259.3 (pos., M + H), 257.2 (neg., MH); ¹ H NMR (CD ₃ 0D, 500 MHz) δ 7.15 (d, 1H), 6.70 (dd, 1H), 6.45 (d, 1H), 2.80-2.85 (m, 2H), 2.60-2.70 (m, 1H), 2.50-2.60 (ddd, 1H), 2.35-2.44 (m, 2H), 1.90-1.95 (m, 1H), 1.80-1.90 (m, 1H), 1.65-1.80 (m, 3H), 1.55-1.65 (m , 1H), 1.30 (s, 3H), 0.85 (t, 3H).
[529] Example 67 Synthesis of (rac) -1- Butyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E67).
[530]
[531] Step 1: (rac) -Butyl-7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one: 220 mg dissolved in toluene (2.0 mL) ( Rac) -6-methoxy-1-methyl-3,4-dihydro- 1H -naphthalene-2-one and oct- 1 -ene-3-one of (1.16 mmol) were coupled according to Method M and The raw material was purified by silica gel flash chromatography using EtOAc: n-heptane (3: 7) as the eluent, and (rac) -1-butyl-7-methoxy-4a-methyl-4,4a, 9, 10-Tetrahydro- 3H -phenanthrene-2-one was obtained as a yellowish oil. ES-MS m / z: 299.2 (pos., M + H); ¹ H NMR (CDCl ₃ ) δ 7.15-7.20 (m, 1H), 6.70-6.85 (m, 1H), 6.55-6.65 (m, 1H), 3.75 (s, 3H), 2.00-3.00 (m, lOH) , 1.45-1.50 (m, 1H), 1.25-1.30 (m, 6H), 0.90 (t, 3H).
[532] Step 2: (rac) -Butyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (40). The reaction was carried out with 3.5 eq of 220 mg of (rac) -1-butyl-7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one dissolved in 5.0 mL DCM. Was performed for 4 hours according to Method 0 using BBr ₃ . The raw material was purified on chromatography and using EtOAc: n-heptane (3: 7, v: v) as eluent to afford E67 as a yellowish oil. ES-MS m / z: 285.1 (pos., M + H), 283.0 (neg., MH); ¹ H NMR (CDCl ₃ ) δ 7.15 (d, 1H), 6.75 (dd, 1H), 6.60 (d, 1H), 2.20-3.00 (m, 10H), 1.31 (s, 1H), 1.25-1.30 (m , 6H), 0.90 (t, 3H). ¹³ C NMR (CDCl ₃ ) δ 199.22, 164.04, 154.11, 136.79, 136.64, 133.43, 127.16, 114.60, 114.40, 39.35, 36.51, 34.51, 31.97, 30.86, 27.67, 26.84, 25.02, 22.96, 14.13.
[533] Example 68: Synthesis of (rac) -8-butyl-4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E68).
[534]
[535] The reaction was carried out with 40 mg (6.14 mmol) of (rac) -1-butyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro-3H-phenanthrene dissolved in acetonitrile (10 mL). Performed according to Method P on 2-membered. Raw material E68 (yellowish oil) was used without further purification. ES-MS m / z: 271.0 (pos., M + H), 269. 2 (neg., MH); ¹ H NMR (CDCl ₃ ) δ7.15 (d, 1H), 6.65 (dd, 1H), 6.50 (d, 1H), 4.50 (bs, 1H), 2.65-2.75 (m, 3H), 1.95-2.25 ( m, 6H), 1.70-1.75 (m, 2H), 1.50-1.55 (m, 1H), 1.25-1.35 (m, 7H), 0.90 (t, 3H).
[536] Example 69: (rac)-(8R, 4bR, 8aR) -8-butyl-4b-methyl-4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2-ol ( E69a), and (rac)-(8S, 4bR, 8aR) -8-butyl-4b-methyl-4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2-ol ( Synthesis of E69b).
[537]
[538] The reaction was carried out with 25 mg of (rac) -8-butyl-4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol under reaction pressure (6.0 bar) and methanol (2.0). mL)) was carried out for 12 hours according to Method S, except that 5% Pd / C (12 mg) was used as the solvent. Raw material was fractionated by PHPLC to give E69a as the first eluting material and E69b for the second time. E69a: ES-MS m / z: 273.1 (pos., M + H) 271.0 (neg., MH); ¹ H NMR (CDCl ₃ ) δ 7.10 (d, 1H), 6.60 (dd, 1H), 6.55 (d, 1H), 2.70-2.75 (m, 1H), 2.55-2.65 (m, 1H), 2.30 (d , 1H), 2.00-2.05 (m, 1H), 1.80-1.85 (m, 1H), 1.65-1.70 (m, 1H), 1.45-1.50 (m, 2H), 1.05-1.35 (m, lOH), 1.10 (s, 3H), 0.95-1.00 (m, 1H), 0.90 (t, 3H). E69b: ES-MS m / z: 273.1 (pos., M + H), 271.0 (neg., MH); ¹ H NMR (CDCl ₃ ) δ 7.10 (d, 1H), 6.60 (dd, 1H), 6.50 (d, 1H), 2.80 (dd, 2H), 2.25 (d, 1H), 1.90-2.00 (m, 1H ), 1.65-1.75 (m, 2H), 1.60-1.75 (m, 1H), 1.60-1.65 (m, 2H), 1.50-1.60 (m, 1H), 1.45-1.50 (m, 1H), 1.25-1.45 (m, 8H), 1.10 (s, 3H), 0.90 (t, 3H).
[539] Example 70: Synthesis of (rac) -4a-butyl-7-hydroxy-1-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E70).
[540]
[541] Step 1: 4-Butyl-7-methoxy-1,2-dihydro-naphthalene: approx. 5.29 g (30 mmol, 1.0 eq.) Of 6-methoxy-1-tetral source in dry THF (25 mL) Dropwise was added to the mixture of butyl lithium (1.6M solution in hexanes, 2.1 eq.) And THF (40 mL) with stirring for 30 minutes. Stirring was continued for another 30 minutes before slowly adding 2.0 M aqueous HCl (150 mL). The layers separated after vigorous stirring for 2 hours. The aqueous layer was extracted with diethyl ether (3 x 50 mL) and the mixed organic layer was dried over anhydrous sodium sulfate. The raw material obtained by concentrating the extract in vacuo was purified by silica gel flash chromatography using EtOAc: n-heptane (0:10, 1: 9, stepwise gradient) as the eluent, and 4-butyl-7-meth. Toxy-1,2-dihydro-naphthalene was obtained as a yellowish oil. _{^{l H NMR (CDCl 3) δ}} 7.15 (d, 1H), 6.70-6.75 (m, 2H), 5.80 (t, 1H), 3.80 (s, 3H), 2.70 (t, 2H), 2.30-2.45 (m , 2H), 2.10-2.25 (m, 2H), 1.20-1.55 (m, 4H), 0.90 (t, 3H).
[542] Step 2: (rac) -1-butyl-6-methoxy-3,4-dihydro- 1H -naphthalene-2-one: The reaction was carried out in 1.28 g (5.92 mmol) of 4-butyl-7 dissolved in 50 mL DCM. Performed according to Method L on -methoxy-1,2-dihydro-naphthalene and the raw material was purified by silica gel flash chromatography, EtOAc: n-heptane (5:95, 2: 8, stepwise gradient) as eluent Purification was carried out to obtain (rac) -1-butyl-6-methoxy-3,4-dihydro- 1H -naphthalene-2-one as a yellowish oil. GC-MS m / z: 232.1 ¹ H NMR (CDCl ₃ ) δ 7.05 (d, 1H), 6.75-6.80 (m, 2H), 3.80 (s, 3H), 3.30-3.40 (m, 1H), 2.95- 3.15 (m, 2H), 2.45-2.60 (m, 2H), 1.75-1.85 (m, 2H), 1.20-1.30 (m, 4H), 0.85 (t, 3H).
[543] Step 3: (rac) -4a-Butyl-7-methoxy-l-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one: 100 mg (dissolved in benzene (1.0 mL) 0.43 mmol) of (rac) -1-butyl-6-methoxy-3,4-dihydro- 1H -naphthalene-2-one and pent-1-ene-3-one according to Method M, The raw material was purified by silica gel flash chromatography using EtOAc: n-heptane (1:99, 1: 9, stepwise gradient) as the eluent (rac) -4a-butyl-7-methoxy-1-methyl- 4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one was obtained. ES-MS m / z: 299.0 (pos., M + H); ¹ H NMR (CDCl ₃ ) δ 7.15 (d, 1H), 6.75 (dd, 1H), 6.65 (d, 1H), 3.80 (s, 3H), 1.70-3.00 (m, 10H), 1.80 (s, 3H ), 1.00-1.30 (m, 4H), 0.80 (t, 3H).
[544] Step 4: (rac) -4a-butyl-7-hydroxy-1-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E70). The reaction is 3.0 eq on 13 mg of (rac) -4a-butyl-7-methoxy-1-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one dissolved in 2.0 mL DCM. Was performed for 4 hours according to Method 0 using BBr ₃ . The raw material was purified on chromatographic column with EtOAc: n-heptane (3: 7, v: v) as eluent to afford E70. ¹ H NMR (CD ₃ 0D) δ 7.10 (d, 1H), 6.55-6.60 (m, 2H), 2.30-2.80 (m, lOH), 1.75 (s, 3), 1.00-1.30 (m, 4H), 0.80 (t, 3 H).
[545] Example 71: Synthesis of (rac) -4a-butyl-7-hydroxy-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E71).
[546]
[547] Step 1: (rac) -4a-butyl-7-methoxy-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one: 100 mg (0.43 mmol) dissolved in benzene (1.0 mL) (Rac) -1-butyl-6-methoxy-3,4-dihydro- 1H -naphthalene-2-one of (Bu-3-en-2-one) according to Method M and the raw material was silica Purification by gel flash chromatography using EtOAc: n-heptane (1:99, 2: 8, stepwise gradient) as eluent, (rac) -4a-butyl-7-methoxy-4,4a, 9, A 10-tetrahydro-3H-phenanthrene-2-one was obtained. ¹ H NMR (CDCl ₃ ) δ 7.15 (d, 1H), 6.80 (dd, 1H), 6.60 (d, 1H), 5.90 (s, 1H), 3.80 (s, 3H), 1.80-3.00 (m, lOH ), 1.10-1.30 (m, 4H), 0.80 (t, 3H); ¹³ C NMR (CDCl ₃ ) δ 199.72, 170.86, 158.00, 137.39, 134.16, 127.43, 124.93, 113.18, 113.02, 55.02, 41.84, 40.40, 36.06, 34.35, 32.46, 30.49, 27.72, 23.04, 13.53.
[548] Step 2: (rac) -4a-butyl-7-hydroxy-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E71). The reaction was carried out on 3.0 mg of (rac) -4a-butyl-7-methoxy-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one dissolved in 2.0 mL DCM, 3.0 eq. Of BBr. ₃ was used for 4 hours according to Method 0. The raw material was purified on chromatography and using EtOAc: n-heptane (3: 7, v: v) as eluent to afford E71 as a yellowish solid. ES-MS m / z: 271.0 (pos., M + H), 269.0 (neg., MH); ¹ H NMR (CD ₃ 0D) δ 7.20 (d, 1H), 6.65 (dd, 1H), 6.55 (d, 1H), 5.90 (s, 1H), 1.80-3.00 (m, 10H), 1.10-1.30 ( m, 4H), 0.80 (t, 3H).
[549] Example 72: (rac)-(4aR, 10aR) -4a- butyl-7-hydroxy-3,4,4a, 9,10, lOa-hexahydro- 1H -phenanthrene-2-one (E72a); And (rac)-(4aR, 10aS) -4a- butyl-7-hydroxy-3,4.4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one (E72b).
[550]
[551] The reaction was carried out on 10 mg of (rac) -4a-butyl-7-hydroxy-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one with methanol (5.0 mL) as solvent according to Method R. , 5% Pd / C (10 mg) as catalyst was carried out for 2 hours. The raw material was fractionated by PHPLC to give E72a as the first eluted material and E72b to the second. E72a: ES-MS m / z: 273.4 (pos., M + H), 271.3 (neg., MH); ¹ H NMR (CD ₃ 0D) δ 7.15 (d, 1H), 6.60 (dd, 1H), 6.50 (d, 1H), 1.60-2.80 (m, 13H), 1.20-1.25 (m, 2H), 0.85 ( t, 3H); E72b: ES-MS m / z: 273.4 (pos., M + H), 271.3 (neg., MH); ¹ H NMR (CD ₃ 0D) δ 7.10 (d, 1H), 6.55 (dd, 1H), 6.50 (d, 1H), 1.50-2.80 (m, 13H), 1.20-1.25 (m, 2H), 0.85 ( t, 3H).
[552] Example 73: (rac)- (4aR, 10aS) -7-hydroxy-4a-methyl-3,4,4a, 9,10,10a-hexahydro- 1H- phenanthrene-2-one (E73).
[553]
[554] Step 1: (rac) -7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one: reaction was 570 mg (2.35 mmol) dissolved in 10.0 mL DCM On (rac) -7-methoxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one, using 3.5 eq. BBr ₃ for 20 hours according to method 0 Was performed. The raw material was purified on chromatography using EtOAc: n-heptane (3: 7) as eluent and (rac) -7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene. 2-membered (190 mg) was obtained as a yellow solid. ES-MS m / z: 229.3 (pos., M + H), 227.2 (neg., MH); ¹ H NMR (CDCl ₃ ) δ 7.15 (d, 1H), 6.70 (dd, 1H), 6.55 (d, 1H), 5.85 (s, 1H), 4.80 (s, OH), 1.80-2.85 (m, 8H ), 1.50 (s, 3 H).
[555] Step 2: (rac)-(4aR, 10aS) -7-hydroxy-4a-methyl-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one (E73): reaction 133.0 mg (0.58 mmol) of (rac) -7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one in THF (6.0 mL) according to Method S Was carried out for 2 hours using a solvent, 10% Pd / C (133.0 mg) as a catalyst. The raw material was purified by PHPLC to give E73 (81 mg) as a white solid. ES-MS m / z: 231.1 (pos., M + H), 229.3 (neg., MH); ¹ H NMR (CDCl ₃ ) δ 7.20 (d, 1H), 6.65 (dd, 1H), 6.55 (d, 1H), 5.00 (s, OH), 2.75-2.85 (m, 2H), 2.35-2.50 (m , 2H), 2. 20-2.30 (m, 3H), 2.00-2.20 (m, 2H), 1.75-1.90 (m, 1H), 1.55-1.60 (m, lH), 1.30 (s, 3H).
[556] Example 74: (rac)-(4aR, 10aS) -2,2-ethanediyldimercapto-7-hydroxy-4a-methyl-1, 2, 3,4,4a, 9,10,10a-octahydro Synthesis of Phenanthrene (E74).
[557]
[558] The reaction was carried out in 15 mg (0.065 mmol) of (rac)-(4aR, lOaS) -7 -hydroxy-4a-methyl-3,4,4a, 9,10,10a-hexa dissolved in 1.0 mL dichloromethane. On hydro- 1H -phenanthrene-2-one, according to Method T, 2eq. Of 1,2-ethanedithiol, 1eq. Of BF ₃ .OEt ₂ and the reaction time were carried out at 5 hours. The crude was purified on chromatography using EtOAc: n-heptane (3: 7) as eluent to afford E74 (15 mg) as a white solid. ES-MS m / z: 307.3 (pos., M + H), 305.2 (neg., MH); ¹ H NMR (CDCl ₃ ) δ 7.15 (d, 1H), 6.60 (dd, 1H), 6.50 (d, 1H), 4.45 (s, OH), 3.25 (s, 4H), 2.60-2.80 (m, 2H ), 2.10-2.35 (m, 3H), 1.90 (m, 4H), 1.70-1.80 (m, 2H), 1.50 (s, 3H).
[559] Example75 (rac)-(4aR, 10aS) -7 -hydroxy-4a-methyl-3,4,4a, 9,10, l0a-hexahydro- 1H -phenanthrene-2-one oxime (E75) Synthesis.
[560]
[561] The reaction is 1.5 mL of 16 mg (0.065 mmol) dissolved in methanol (rac) - (4aR, 10aS ) - 7- hydroxy -4a- methyl -3,4,4a, 9,10,1Oa- hexahydro - lH According to Method U on phenanthrene-2-one, it was carried out using lOeq. NH ₂ OH.HCl and 10eq. Sodium acetate. The raw material was purified by chromatography using EtOAc: n-heptane (2: 8) as eluent to afford two isomers E75 as a white solid in a ratio of 2: 1 (11 mg). ES-MS m / z: 246.1 (pos., M + H); ¹ H NMR (CDCl ₃ ) δ 7.15 (d, 1H), 6.65 (dd, 1H), 6.55 (d, 1H), 2.60-2.80 (m, 2H), 1.80-2.40 (m, 7H), 1.55-1.75 (m, 2 H), 1.30 (s, 3 H).
[562] Example 76: Pharmaceutical formulation containing (rac) -4b, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol.
[563] 200 mg of (rac) -4a, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol in Example 59 was formulated with sufficiently finely divided lactose A total of 580-590 mg size 0, hard gelatin capsules were to be filled.
[564] [Description of ScintiStrip ER Binding Assay]
[565] [Introduction]
[566] Scintistrip assays differ from traditional hormonal binding assays in that they do not require removal of the free tracer before measurement of the receptor binding tracer. The scintillation reagent is in the polystyrene forming the incubation vial and thus radioactive molecules in the portion proximate to the surface will induce flashing of the plastic. ^{For 3} [H] -labeled ligands, the distance between the free tracer and the island and the polystyrene surface is plastic even though the ³ [H] -labeled ligand bound to the surface anchored receptor is close enough to induce flashing It is too far to induce the flash of, so the competition between the reagent (tested compound) and the fixed center of the tracer ( ³ [H] -estradiol) that reacts with the non-radioactive estrone receptor can be measured.
[567] [Materials and methods]
[568] ³ [H] -β-estradiol (NET 317), hereinafter referred to as ³ [H] -E2, was purchased from New England Nuclear, Boston, MA. Scintistrip wells (1450-419) and Scintistrip counters (Microbeta 1450-Plus and 1450-Trilux) were all obtained from Walluck, Turku and Finland. Human estrogen receptor (hER) alpha and beta were extracted from the nuclei of SF9-cells infected with recombinant baculovirus transplant vectors containing cloned hFR genes. Recombinant baculovirus was generated using the BAC-TO-BAC expression system (Life Technologies) according to the supplier's instructions. hER coding sequences were cloned into baculovirus transplant vectors using standard techniques. Recombinant baculovirus expressing hER was amplified and used to infect SF9 cells. Infected cells were grown for 48 hours after infection. Nuclear portion obtained as described was the nucleus are extracted with high salt buffer _{(17mM K 2 HPO 4, 3mM} K 2 HPO 4, 1mM MgCl 2, 0.5mM EDTA, 6mM MTG, 400mM KCl, 8.7% glycerol). The concentration of hER in the extract was determined by [ ³ H] -E2 binding to specific G25- Assay ³ and for hER-alpha, 400 pmols of specific binding [ ³ H] -E2 / mL nuclear extract was obtained from hER-beta. It was determined to contain 1000 pmols of specific binding [ ³ H] -E ² / mL nuclear extract. The total concentration of protein in the nuclear extract (determined by Bradford reagent according to the Bio-Rad manufacturer's instructions) was ˜2 mg / mL. The equilibrium binding constant (Kd) for [ ³ H] -E2 for hER is 0.05 nM for G25-analytical hER-alpha for high dilution extracts (hER to 0.1 nM) and 0.07 nM for hER-beta. It was decided. The extract was stored at -80 ° C divided.
[569] Sinti strip analysis 1: Briefly, the nuclear extract was coating buffer _{(17mM K 2 HPO 4, 3mM} K 2 HPO 4, 6mM MTG, 40mM KCl) was diluted in (hER- alpha 50 times, 110 times hER- beta). Diluted extracts were added to the scin strip wells (200 μL / well) and incubated 18-20 hours at room temperature (22-25 ° C.) in the surrounding environment. The final estimated concentration of fixed hER in all experiments was ˜nM. All cultures were performed in 17 mM K ₂ HPO ₄ , 3 mM K ₂ HPO ₄ , 6 mM MTG, 140 mM KCl (Buffer A). The wells were coated twice with 250 μL buffer before the addition of the culture solution and washed twice. All steps were performed at room temperature (22-25 ° C.) of the surrounding environment.
[570] Determination of Equilibrium Binding Constant for Fixed hER: Dilutions of [ ³ H] -E2 in Buffer ± TritonX100 were added to the wells (200 μL / well) and incubated for 3 hours and measured in microbeta. After measuring a portion of the buffer, it was taken out and calculated by normal liquid scintillation counting to determine the glass portion of [ ³ H] -E 2. For correction of non-specific binding parallels, the cultivation was performed in the presence of more than 200-fold of unlabeled 17-β-E2. The equilibrium distribution constant (K _d ) was calculated as the free concentration of [ ³ H] -E2 by the data given in the Hill equation at half the highest bond; b is the specific bond of [ ³ H] -E2, b _max is the highest bond number, L is the free concentration of [ ³ H] -E2, n is the Hill coefficient (Hill equation is equal to Michaelis-Menten equation when n = 1 B = (b _max x L ⁿ ) / (L _n + K _d ⁿ ). The equilibrium binding constant was 0.15-0.2 nM for all hER types.
[571] General competitive binding: Samples containing ³ nM [ ³ H] -E2 and a range of dilutions of the compounds to be tested were added to the wells (200 μL / well) with immobilized hER and incubated 18-20 hours at room temperature in the surrounding environment. . The compound to be tested was diluted in 100% DMSO to a concentration 50 times higher than the desired final concentration and the final concentration of DMSO was therefore 2% in all samples. For compounds capable of substituting [ ³ H] -E2 from the receptor, the IC ₅₀ -value (concentration required to inhibit 50% of the binding of [ ³ H] -E2) is determined by a nonlinear four parametric logic model. Determined; I is the added concentration of binding inhibitor, IC ₅₀ is the concentration of inhibitor at half of the highest binding and S is the slope factor b = ((b _max -b _min ) / (1+ (I / IC ₅₀ ) s)) + b _min . To determine the concentration of [ ³ H] -E2 in the usual scintillation counting solution in Wallac Rackbeta 1214, scintillation cocktail Supermix ™ (Wallac) was performed.
[572] The microbeta-tool produces a cpm (counts per minute) value / minute of the mean and a calibrated cpm value by calibrating each variable between the meters. The counting efficiency between meters differs by less than 5 percent.
[573] Haggblad, J., Carlsson, B., Kivela, P., Siitari, H., (1995) Biotechniques 18,146-151
[574] 2) Barkhem, T., Carlsson, B., Simons, J., Moller, B., Berkenstam, A., Gustafsson J. A. G., Nilsson, S. (1991) J Steroid Biochem. Molec. Biol. 38,667-75
[575] 3) Salomonsson, M., Carlsson, B., Haggblad, J., (1994) J Steroid Biochem. Molec. Biol. 50,313-318
[576] 4) Schultz, J. R., Ruppel, P. I., Johnson, M. A., (1988) in Biopharmaceutical Statistics for Drug Development (Peace, K. E., Ed.) Pp. 21-82, Dekker, New York
[577] The compounds of Examples 1-48 have IC ₅₀ 3 to represent a bond with the characteristics I receptor by type α- est between 10,000nM, IC ₅₀ 3 to indicate the binding characteristics to the entire receptor β- type as est between 10,000nM.

权利要求:
Claims (31)
[1" claim-type="Currently amended] Compounds having Formula I, II, or III:

Wherein a bond between C1 and C2 carbon atoms (in the compound of Formula I) or a bond between C2 and C3 (in the compound of Formula II) or a bond between C1 and C10 (in the compound of Formula III) is Or a double bond;
R ₁ (in compounds of formula I or III) is a R ^A group, not a phenyl group;
R ^A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl or arylalkyl;
R ₁ α and R ₁ β (in the compound of Formula II) are the same or different and each is a R ^A group;
R ₂ (in the compound of formula I or II) is a hydroxyl or R ^A group or is hydroxyalkyl or aminoalkyl of 1 to 2 carbon atoms;
R ₃ α and R ₃ β (in the compound of Formula I) may both be monooxygen or sulfur atoms; Or R ₃ α and R ₃ β can both be short nitrogen atoms which in turn bind to a group selected from R ^A or OR ^A ; Or R ₃ α and R ₃ β can both be short carbon atoms (that is, exo methylene carbon atoms) that bind to two R ^A groups, which in turn can be the same or different; Or R ₃ α and R ₃ β may be the same or different and each is an R ^A R ^A, the same or different are considered to be one with the attachment and the intervening atoms to form a ring of 3-8 members OR ^A, SR ^A Or N (R ^A ) ₂ group;
R ₂ α and R ₂ β (in the compound of Formula III) may both be monooxygen or sulfur atoms; Or R ₂ α and R ₂ β can both be short nitrogen atoms which in turn bind to a group selected from R ^A or OR ^A ; Or R ₂ α and R ₂ β can both be single-carbon atoms that bind to two R ^A groups, which in turn can be the same or different; Or R ₂ α and R ₂ β can be the same or different and each is hydroxyalkyl, aminoalkyl, considered to be one with the same or different R ^A and optionally attached and intervened to form a ring of 3-8 members. , R ^A , OR ^A , SR ^A , or N (R ^A ) ₂ group;
R ₃ (in the compound of formula II or III) is a group of R ^A ;
R ₄ is a R ^A group;
R _4a is a hydrogen atom or a methyl or ethyl group in the compound of Formula I or II, or a methyl or ethyl group in the compound of Formula III;
R ₇ is a hydrogen atom or a straight or branched alkyl or cycloalkyl group or acyl group of 1 to 4 carbon atoms;
R _10a is a R ^A group;
Provided that all of R ₁ , R ₂ , R ₃ and R ₄ are not hydrogen in the compound of formula I or II, and R ₄ is not hydrogen in the compound of formula III; And also pharmaceutically acceptable salts or stereoisomers thereof.
[2" claim-type="Currently amended] The method of claim 1,
The substituents R _4a and R _10a have a trans relative stereochemistry.
[3" claim-type="Currently amended] The method of claim 2,
R ₁ is R ^B and R ^B is hydrogen, n-propyl, 2-propenyl, 2-propynyl, n-butyl, 2-butenyl, 3-butenyl, 2-butynyl, 3-butynyl, n-pentyl, 3-methylbutyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methylpentyl, 3-ethylpentyl, cyclopropylethyl, cyclopentylethyl, cyclohexylethyl, cyclo A compound according to formula I or III, which is selected from the group consisting of heptylethyl, cyclopropylpropyl, cyclopentylpropyl, benzyl, and phenethyl.
[4" claim-type="Currently amended] The method of claim 2,
R ₁ α is R ^B (wherein R ^B is defined as in claim 3) and R ₁ β is a hydrogen atom or a methyl group according to Formula II.
[5" claim-type="Currently amended] The method according to any one of claims 2 to 4,
Wherein R ₁₀ α is R ^B.
[6" claim-type="Currently amended] The method according to any one of claims 2 to 5,
R ₂ is a hydrogen atom or a compound according to Formula I or II, characterized in that methyl, ethyl, or hydroxymethyl group.
[7" claim-type="Currently amended] The method according to any one of claims 2 to 5,
The R ₂ α and R ₂ β may be the same or different, and each of the R ^A group (R ^A is defined as above) is the same or different, and optionally with atoms attached and intervened to form a ring of 3-8 members. ^A compound according to formula (III), characterized in that it is selected from hydroxyalkyl, R ^A , OR ^A , or SR ^{A together} .
[8" claim-type="Currently amended] The method according to any one of claims 2 to 6,
The R ₃ α and R ₃ β may be the same or different, and each of the R ^A group (R ^A is defined as above) is the same or different, and optionally with atoms attached and intervened to form a ring of 3-8 members. ^A compound according to formula I or II, characterized in that it is selected from R ^A , OR ^A , or SR ^A considered together.
[9" claim-type="Currently amended] The method according to any one of claims 2 to 8,
R ₄ is a hydrogen atom or a compound characterized in that the methyl or ethyl group.
[10" claim-type="Currently amended] The method according to any one of claims 2 to 9,
R ₇ is a hydrogen atom or an acyl group of 1 to 4 carbon atoms.
[11" claim-type="Currently amended] The method according to any one of claims 2 to 10,
R ₁ is selected from hydrogen, methyl or ethyl group and R _10a is R ^B.
[12" claim-type="Currently amended] The method according to any one of claims 2 to 10,
R ₁ is R ^B and R _10a is selected from hydrogen, methyl, or ethyl.
[13" claim-type="Currently amended] The method according to any one of claims 2, 9, 10, 11 or 12,
The R ₂ α and R ₂ β may be the same or different, and each of the R ^A group (R ^A is defined as above) is the same or different, and optionally with atoms attached and intervened to form a ring of 3-8 members. ^A compound according to formula (III), characterized in that it is selected from hydroxyalkyl, R ^A , OR ^A , or SR ^{A together} .
[14" claim-type="Currently amended] The method according to any one of claims 2 to 10,
R ₁ α is R ^B and R _10a is selected from hydrogen, methyl, or ethyl.
[15" claim-type="Currently amended] The method according to any one of claims 2 to 10,
R ₁ α is selected from hydrogen, methyl, or ethyl and R _10a is R ^B.
[16" claim-type="Currently amended] The method of claim 1,
The compound is,
(rac)-(4aS, 10aS) -7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (El);
(rac)-(4aS, 10aS) -3,3- ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E2);
(rac)-(4aR, lOaS) -7-hydroxy-lOa-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-3-one (E3a);
(rac)-(4aS, 10aS) -7-hydroxy-1Oa-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (E3b);
(rac)-(4aS, 10aS) -10-butyl-7-hydroxy-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-3-one (E4);
(rac)-(1S, 4aS, 10aS) -1-butyl-7-hydroxy-1,4,4a, 9,10,10-hexahydro- 2H -phenanthrene-3-one (E5a);
(rac)-(1R, 4aS, 10aS) -1-butyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E5b);
(rac)-(1S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro-phenan Tren (E6a);
(rac)-(1R, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-1,2,3,4,4a, 9,10,10Oa-octahydro-phenan Tren (E6b);
(rac)-(lS, 4aS, 1OaS) -1-butyl-7-hydroxy-1Oa-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one (E7 );
(rac)-(1S, 4aS, 10aS)-1- butyl-3,3-ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a- Octahydro-phenanthrene (E8);
(rac)-(1S, 4aS, 10aS) -1-butyl-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E9);
(rac)-(4aS, 10aR) -10a-ethyl-7-hydroxy-3-methyl-4a, 9,10,10a-tetrahydro- 4H -phenanthrene-1 member (ElOa);
(rac)-(4aR, lOaR) -lOa-ethyl-7-hydroxy-3-methyl-4a, 9,10, lOa-tetrahydro- 4H -phenanthrene-l-one (ElOb);
(rac)-(1R, 2S, 4aS, 10aS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one (Ella);
(rac)-(1R, 2R, 4aS, 10aS) -1-butyl-7-hydroxy-2-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (Ellb);
(rac)-(1s, 4R, 4aR, 10aS) -1- butyl-7-hydroxy-4-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (Ellc);
(rac)-(1R, 2R, 4aS, lOaS) -l-butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10, 10a-octahydro-phenanthrene (E12a);
(rac)-(1R, 2S, 4aS, 10aS) -1-butyl-3,3-ethanediyldimercapto-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10, 10a-octahydro-phenanthrene (E12b);
(rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene 3-membered (E13);
(rac)-(lS, 4aS, 1OaS) -3,3 -ethanediyldimercapto-7-hydroxy-1- (3-methyl-butyl) -1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E14);
(rac)-(1S, 4aS, 10aS) -7-hydroxy-lOa-methyl-l-phenethyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one ( E15);
(rac)-(1S, 2S, 4aS, 10aS) -7-hydroxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10Oa-hexahydro- 2H- phenanthrene-3-one (E16a);
(rac)-(1S, 2R, 4aS, 10aS) -7-hydroxy-2,10a-dimethyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one (E16b);
(rac)-(4bS, 8S, 8aS) -6,6-dimethoxy-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octa Hydro-phenanthrene-2-ol (E17a);
(rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene 3-membered (El7b);
(rac)-(1S, 4aS, 1OaS) -3,3- ethanediyldioxy-7-hydroxy-1- (3-methyl-butyl) -1Oa-methyl-1,2,3,4,4a, 9,10, lOa-octahydro-phenanthrene (E18);
(rac)-(4bS, 8R, 8aS) -8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2- ol (E19a);
(rac)-(46S, 6R, 8S, 8aS) -6-ethylsulfonyl-8a-methyl-8- (3-methyl-butyl) -4b, 5,6,7,8,8a, 9,10- Octahydro-phenanthrene-2-ol (E19b);
(rac)-(1S, 4aS, 1OaS) -3,3- (propane-1,3- diyldimercapto ) -7-hydroxy-1- (3-methyl-butyl) -1Oa-methyl-1,2 , 3,4,4a, 9,10,10a-octahydro-phenanthrene (E20); (rac)-(4aS, 10aS) -7 -hydroxy-10a-methyl-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one (E21);
(rac)-(4aS, 10aS) -3,3 -ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10Oa-octahydro-phenanthrene ( E22);
(rac)-(4aS, 10aS) -10a- ethyl-7-hydroxy-1,4,4a, 9,10, lOa-hexahydro- 2H -phenanthrene-3-one (E23);
(rac)-(4aS, lOaS) -3,3 -ethanediyldimercapto-10a-ethyl-7-hydroxy-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene ( E24);
(rac)-(1S, 4aS, 10aS) -1- (3-methyl-butyl) -10a-ethyl-7-hydroxy-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene 3-membered (E26);
(1S, 4aS, lOaS) -7 -hydroxy-1Oa-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E27);
(lR, 4aRS, lOaR) -7-benzyloxy-1Oa-methyl-1- (3-methyl-butyl) -1,4,4a, 9,10,10O-hexahydro- 2H- phenanthrene-3-one (E28);
(rac)-(1S, 4aS, 10aS) -1- (3-methyl-butyl) -3,3-ethanediyldimercapto-7-hydroxy-1,4,4a, 9,10,10Oa-octahydro Phenanthrene (E29);
(rac)-(4aR, 10aR) -7 -hydroxy-4a, lOa-dimethyl-3,4,4a, 9,10, lOa-hexahydro- 1H- phenanthrene-2-one (E30);
(rac)-(lS, 4aS, lOaS) -7-hydroxy-1Oa-methyl-4-phenyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E31 );
(rac)-(4R, 4aS, 1OaS) -3,3 -ethanediyldimercapto-7-hydroxy-10a-methyl-4-phenyl-1,4,4a, 9,10,1Oa-octahydro-phenan Tren (E32);
(rac)-(1S, 4aS, 10aS) -3,3- (ethane-1,2- diyldimercapto ) -7-hydroxy-1- (2-phenylethyl) -10a-methyl-1,2, 3,4,4a, 9,10,10a-octahydro-phenanthrene (E33); (rac)-(1S, 4aS, 10aS) -3,3- ethanediyldioxy-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10Oa-octahydro-phenan Tren (E34a);
(rac)-(lS, 4aS, lOaR) -3,3 -ethanediyldioxy-7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydro-phenan Tren (E34b);
(rac)-(3S, 4aS, 10aS) -7 -hydroxy-3-pentyl-1Oa-methyl-1,2,3,4,4a, 9,1,10a-octahydro-phenanthrene (E35a);
(rac)-(3R, 4aS, lOaS) -7-hydroxy-3-pentyl-1Oa-methyl-1,2,3,4,4a, 9,1,10a-octahydro-phenanthrene (E35b);
(rac)-(1S, 2R, 4aS, 10aS) -2,10a-dimethyl-3,3- (ethane-1,2-diyldimercapto) -7-hydroxy-1- (3-methyl-butyl- 1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene (E36); (rac)-(1S, 4aS, 10aS) -7 -hydroxy-1- (3'-methyl- Butyl) -1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E37);
(rac)-(4aS, 10aS) -3,3- (propane-1,3-diyldimercapto) -7-hydroxy-1,2,3,4,4a, 9,10,10Oa-octahydro- Phenanthrene (E38);
(rac)-(1S, 4S, 4aS, 10aS) -7-hydroxy-1-butyl-4,10a-dimethyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3 -Circle (E39);
(rac)-(4S, 4aS, 10aS) -3,3 -ethanediyldimercapto-7-hydroxy-4,10a-dimethyl-1,2,3,4,4a, 9,10,1Oa-octahydro Phenanthrene (E40);
(rac)-(4S, 4aS, 10aS) -7 -hydroxy-4-benzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H -phenanthrene-3-one (E41a );
(rac)-(4aS, 10aS) -7 -hydroxy-4,4-dibenzyl-10a-methyl-1,4,4a, 9,10,10a-hexahydro- 2H- phenanthrene-3-one ( E41b);
(rac)-(4aS, 10aS) -7 -hydroxy-1Oa-methyl-3,3-methylene-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (E42);
(rac)-(4aS, 10aS) -3,3-ethanediyl-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (E43);
(rac)-(3R, 4aS, 1OaS) -1 ', 2', 3 ', 4'-tetrachloro-7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10, 10a-octahydrospiro [phenanthrene-3,6'-cyclohexane] -1 ', 3'-diene (E44);
(rac)-(3S, 4aS, 1OaS) -3,7-dihydroxy-10a-methyl-3- [1- (phenylthio) cyclopropyl] -1,2,3,4,4a, 9,10 , l0-octahydrophenanthrene (E45);
(rac)-(3S, 4aS, 1OaS) -7-hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [phenanthrene-3,2'-cyclo Butane] -1'-one (E46a);
(rac)-(3R, 4aS, 10aS) -7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [phenanthrene-3,2'-cyclo Butane] -1'-one (E46b);
(rac)-(3S, 4aS, lOaS) -l ', l'-ethanediyldimercapto-7-hydroxy-10a-methyl-1,2,3,4,4a, 9,10,10a-octahydro Spiro [phenanthrene-3,2'-cyclobutane] (E47); (rac)-(4aS, 1OaS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a-octahydrospiro [phenanthrene-3,1'-cyclobutane] (E48);
(rac)-(4aS, 10OaS) -3- (1-cyclopenten-1-yl) -7-hydroxy-10a-methyl-1,4,4a, 9,10,10a-hexahydrophenanthrene (E49 );
(rac)-(3S, 4aS, 10aS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dode Carhydrospiro [phenanthrene-3,2'-furan] (E50a);
(rac)-(3R, 4aS, 10aS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 2 ', 3', 4 ', 5'-dode Carhydrospiro [phenanthrene-3,2'-furan] (E50b);
(rac)-(3S, 4aS, 10aS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 3 ', 4', 5 ', 6'-dode Carhydrospyro [phenanthrene-3,2'- 2H -pyran] (E51a);
(rac)-(3R, 4aS, 10aS) -7 -hydroxy-1Oa-methyl-1,2,3,4,4a, 9,10,10a, 3 ', 4', 5 ', 6'-dode Carhydrospyro [phenanthrene-3,2'- 2H -pyran] (E51b);
(rac)-(1S, 3R, 4aS, 10aS) -hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a, 2 ', 3 ', 4', 5'-dodecahydrospiro [phenanthrene-3,2'-furan] (E52);
(rac)-(1S, 4aS, 10aS) -7-hydroxy-10a-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10Oa-octahydrospiro [ Phenanthrene-3,1'-cyclobutane] (E53);
(rac)-(1S, 4aS, 10aS) -7-hydroxy-3- (3-hydroxypropyl) -10a-methyl-1- (3-methylbutyl) -1,4,4a, 9,10, 10a-hexahydrophenanthrene (E54a);
(rac)-(1S, 3S, 4aS, lOaS) -7 -hydroxy-1Oa-methyl-1- (3-methylbutyl) -1,2,3,4,4a, 9,10,10a, 2 ' , 3 ', 4', 5'-dodecahydrospiro [phenanthrene-3,2'-furan] (E54b);
(rac)-(4aR, lOaR) -lOa-butyl-7-hydroxy-4a-methyl-3,4,4a, 9,10, lOa-hexahydro- lH -phenanthrene-2-one (E55);
(rac) -7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro-3H-phenanthrene-2-one (E56);
(rac) -4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E57);
(rac) -7-hydroxy-1,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E58);
(rac) -4a, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E59); (rac) -4b, 8-dimethyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E60a, E60b, E60c, E60d);
(rac)-(3S, 4aR) -7-hydroxy-3,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E61);
(rac)-(4S, 4aR) -7 -hydroxy-4a-methyl-4-propyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E62);
(rac)-(4R, 4aR) -7-hydroxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one (E63a);
(rac)-(4S, 4aR) -7-hydroxy-4,4a-dimethyl-4,4a, 9,10-tetrahydro- 3H- phenanthrene-2-one (E63b);
(rac) -l-ethyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E64);
(rac) -8-ethyl-4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E65); (rac)-(4aR, 10aR, 1S) -1-ethyl-7-hydroxy-4a-methyl-1,4,4a, 9,10,10a-hexahydro- 3H -phenanthrene-2-one (E66 );
(rac) -1-butyl-7-hydroxy-4a-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E67);
(rac) -8-butyl-4b-methyl-4b, 5,6,7,9,10-hexahydro-phenanthrene-2-ol (E68); (rac)-(8R, 4bR, 8aR) -8-butyl-4b-methyl-4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2-ol (E69a);
(rac)-(8S, 4bR, 8aR) -8-butyl-4b-methyl-4b, 5,6,7,8,8a, 9,10-octahydro-phenanthrene-2-ol (E69b);
(rac) -4a-butyl-7-hydroxy-l-methyl-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E70);
(rac) -4a-butyl-7-hydroxy-4,4a, 9,10-tetrahydro- 3H -phenanthrene-2-one (E71);
(rac)-(4aR, 10aR) -4a- butyl-7-hydroxy-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one (E72a);
(rac)-(4aR, 10aS) -4a-butyl-7-hydroxy-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one (E72b);
(rac)-(4aR, lOaS) -7 -hydroxy-4a-methyl-3,4,4a, 9,10, lOa-hexahydro- 1H -phenanthrene-2-one (E73);
(rac)-(4aR, 10aS) -2,2-ethanediyldimercapto-7-hydroxy-4a-methyl-1,2,3,4,4a, 9,10,10Oa-octahydrophenanthrene (E74 );
(rac)-(4aR, 10aS) -7 -hydroxy-4a-methyl-3,4,4a, 9,10,10a-hexahydro- 1H -phenanthrene-2-one oxime (E75);
And pharmaceutically acceptable salts and stereoisomers thereof.
[17" claim-type="Currently amended] The method according to any one of claims 1 to 16,
The compound is characterized in that for medical treatment.
[18" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.
[19" claim-type="Currently amended] A method of making a pharmaceutical composition comprising combining a compound according to any one of claims 1 to 16 with a pharmaceutically acceptable carrier.
[20" claim-type="Currently amended] A method of inducing an estrogen receptor modulating effect in a mammal in need thereof comprising administering to the mammal an effective amount for treating the compound according to any one of claims 1 to 16.
[21" claim-type="Currently amended] The method of claim 20,
And said estrogen receptor modulating effect is an estrogen receptor acting effect.
[22" claim-type="Currently amended] The method of claim 21,
Wherein said estrogen receptor acting effect is an ERα receptor acting effect.
[23" claim-type="Currently amended] The method of claim 21,
Wherein said estrogen receptor acting effect is an ERβ receptor acting effect.
[24" claim-type="Currently amended] The method of claim 21,
Wherein said estrogen receptor acting effect is a mixed acting effect of ERα and ERβ receptors.
[25" claim-type="Currently amended] The method of claim 20,
Wherein said estrogen receptor modulating effect is an estrogen receptor antagonistic effect.
[26" claim-type="Currently amended] The method of claim 25,
The estrogen receptor antagonist effect is characterized in that the ERα receptor antagonistic effect.
[27" claim-type="Currently amended] The method of claim 25,
The estrogen receptor antagonist effect is characterized in that the ERβ receptor antagonistic effect.
[28" claim-type="Currently amended] The method of claim 25,
Wherein said estrogen receptor antagonistic effect is a mixed antagonistic effect of ERα and ERβ receptors.
[29" claim-type="Currently amended] A method for preventing or treating a disease regulated by an estrogen receptor in a mammal in need thereof by administering to said mammal an effective amount for treating the compound according to any one of claims 1 to 16.
[30" claim-type="Currently amended] A method for the treatment of a compound according to any one of claims 1 to 16 in a mammal in need thereof by administering an effective amount for bone loss, bone resorption, bone fracture, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, Hot flashes, increased LDL cholesterol levels, cardiovascular disease, cognitive impairment, cerebral artery degeneration, restinosis, gynecomastia, vascular myocyte proliferation, obesity, incontinence, autoimmune, lung cancer, colon cancer, breast cancer, uterine cancer, prostate cancer Methods for treating and / or preventing a disease.
[31" claim-type="Currently amended] Bone loss, bone resorption, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, hot flashes, increased LDL cholesterol levels, cardiovascular disease, cognitive impairment, cerebral artery degeneration, restinosis, gynecomastia Use of a compound according to any one of claims 1 to 16 in the manufacture of a medicament for treating and / or preventing proliferation, obesity, incontinence, autoimmunity, lung cancer, colon cancer, breast cancer, uterine cancer, prostate cancer .

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-01-04|Priority to GB0100163.5

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2001-01-04|Priority to GB0100164A

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2001-01-04|Priority to GB0100163A

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2001-01-04|Priority to GB0100164.3

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2001-03-15|Priority to GB0106434A

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2001-03-15|Priority to GB0106434.4

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2001-12-24|Application filed by 카로 바이오 아베, 머크 앤드 캄파니 인코포레이티드

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2001-12-24|Priority to PCT/EP2001/015230

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2003-09-26|Publication of KR20030076600A

优先权:

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申请号 | 申请日 | 专利标题

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GB0100163.5|2001-01-04|

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GB0100164A|GB0100164D0|2001-01-04|2001-01-04|Novel estrogen receptor ligands and methods II|

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GB0100163A|GB0100163D0|2001-01-04|2001-01-04|Novel estrogen receptor ligands and methods|

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GB0100164.3|2001-01-04|

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GB0106434.4|2001-03-15|

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GB0106434A|GB0106434D0|2001-03-15|2001-03-15|Novel estrogwen receptor ligands and methods II|

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PCT/EP2001/015230|WO2002053522A2|2001-01-04|2001-12-24|Novel estrogen receptor ligands and methods i|