16-Hydroxyestratrienes as selectively active estrogens
The invention describes new compounds as pharmaceutical active ingredients, which have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo a preferential action on bone rather than the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. The new compounds are 16α- and 16β-hydroxy-estra-1,3,5(10)-estratrienes, which carry additional substituents on the steroid skeleton and can have one or more additional double bonds in the B-, C- and/or D-rings.
1 .- 52 . (canceled)
53 . A method for the treatment of an estrogen-deficiency-induced disease in a female or male patient which comprises administering an effective amount of 3,16-dihydroxyestra-1,3,5(10)-triene compound of formula I:
in which radicals R 1 to R 17 , independently of one another, have the following meanings:
R 1 means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;
R 2 means a halogen atom, a hydroxyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atoms;
R 4 means a halogen atom, a straight-chain or branched-chain, saturated or unsaturated alkyl group with 1 to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms or a hydrogen atom;
R 7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
R 8 means a hydrogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position or a cyano group in α- or β-position;
R 9 means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in α- or β-position;
R 11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with 1 to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
R 13 means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in β-position;
and either
R 14 means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position or a hydrogen atom in α- or β-position,
and
R 15 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups=NR 15′ (R 15′ =hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom,
or
R 14 and R 15 together mean a 14α,15α-methylene or 14β,15β-methylene group that is optionally substituted with one or two halogen atoms;
R 16 means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a hydrogen atom in α- or β-position; and
R 17 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a hydrogen atom or a hydroxyl group;
wherein one or both hydroxyl groups at C atoms 3 and 16 are optionally esterified with an aliphatic, straight-chain or branched-chain, saturated or unsaturated C 1 -C 14 mono- or polycarboxylic acid or an aromatic carboxylic acid or with an α- or β-amino acid;
wherein the bonds in rings B, C and D optionally mean a single bond or optionally a double bond, and the wavy lines mean the arrangement of the respective substituent in α- or β-position; and
wherein the following compounds are excluded: estra-1,3,5(10)-triene-3,16α-diol, estra-1,3,5(10)-triene-3,16β-diol, estra-1,3,5(10),7-tetraene-3,16α-diol, estra-1,3,5(10),7-tetraene-3,16β-diol and estriol.
54 . The method of claim 53 , wherein the disease is a peri- or post-menopausal symptom.
55 . The method of claim 53 , wherein the disease is a peri- or post-male-menopausal symptom.
56 . The method of claim 53 , wherein the disease is hot flashes, a sleep disturbance, irritability, mood swings, incontinence, vaginal atrophy, or a hormone-deficiency-induced emotional disease.
57 . The method of claim 53 , wherein the disease is a disease in the urogenital tract.
58 . The method of claim 53 , wherein the disease is a gastrointestinal disease.
59 . The method of claim 53 , wherein the disease is an ulcer or hemorrhagic diatheses in the gastrointestinal tract.
60 . The method of claim 53 , wherein the disease is a neoplasias.
61 . The method of claim 53 , wherein the disease is a male infertility and the administration is in-vitro.
62 . The method of claim 53 , wherein the disease is male infertility and the treatment is in-vivo.
63 . The method of claim 53 , wherein the disease is female infertility and the treatment is in-vitro.
64 . The method of claim 53 , wherein the disease is female infertility and the treatment is in-vivo.
65 . The method of claim 53 , wherein the treatment is a hormone replacement therapy (HRT).
66 . The method of claim 53 , wherein the disease is a hormone-deficiency-induced symptom due to surgery or medical treatment or from ovarian dysfunction.
67 . The method of claim 53 , wherein the disease is hormone-deficiency-induced bone mass loss.
68 . The method of claim 53 , wherein the disease is osteoporosis.
69 . The method of claim 53 , wherein the disease is a cardiovascular disease.
70 . The method of claim 53 , wherein the disease is a vascular disease.
71 . The method of claim 53 , wherein the disease is arteriosclerosis.
72 . The method of claim 53 , wherein the disease is neointimal hyperplasias.
73 . The method of claim 53 , wherein the disease is a hormone-deficiency-induced neurodegenerative disease.
74 . The method of claim 53 , wherein the disease is Alzheimer's disease or hormone-deficiency-induced impairment of memory and learning capacity.
75 . The method of claim 53 , wherein the disease is an inflammatory disease or disease of the immune system.
76 . The method of claim 53 , wherein the disease is benign prostate hyperplasia (BPH).
77 . The method of claim 53 , wherein, in the compound of formula I, radicals R 1 to R 17 , independently of one another, have the following meanings
R 1 means a fluorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;
R 2 means a fluorine atom, a hydroxyl group, a methoxy or ethoxy group or a hydrogen atom;
R 4 means a fluorine atom, a methyl, ethyl, trifluoromethyl, methoxy or ethoxy group or a hydrogen atom;
R 7 means a fluorine atom in α- or β-position, a methyl, ethyl, propyl or i-propyl group in α- or β-position, an optionally substituted aryl radical, a trifluoromethyl group in α- or β-position or a hydrogen atom;
R 8 means a hydrogen atom in α- or β-position, a methyl or ethyl group in α- or β-position;
R 9 means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in α- or β-position;
R 11 means a nitrooxy group in α- or β-position, a hydroxyl group in α- or β-position, a fluorine atom in α- or β-position, a choromethyl group in α- or β-position, a methyl group in α- or β-position, a methoxy group in α- or β-position, a phenyl- or 3-methylthien-2-yl radical in α- or β-position or a hydrogen atom;
R 13 means a methyl or ethyl group in β-position;
and either
R 14 means a hydrogen atom in α- or β-position or a methyl group in α- or β-position,
and
R 15 means a fluorine atom in α- or β-position, a methyl group in α- or β-position, or a hydrogen atom,
or
R 14 and R 15 together mean a 14α,15α-methylene group or a 14β,15β-methylene group;
R 16 means a methyl, ethyl, ethinyl, propinyl or trifluoromethyl group;
R 17 means a fluorine atom in α- or β-position, a methyl group, a hydrogen atom or a hydroxyl group,
and the bonds in rings B, C and D are single bonds and the bond between carbon atoms 9 and 11 means either a single or a double bond.
78 . The method of claim 53 , wherein, in the compound of formula I:
R 7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical
and
R 1 , R 2 , R 4 , R 8 , R 9 , R 11 , R 14 , R 15 , R 16 and R 17 in each case mean a hydrogen atom.
79 . The method of claim 53 , wherein, in the compound of formula I:
R 11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl radical, and
R 1 , R 2 , R 4 , R 7 , R 8 , R 9 , R 14 , R 15 , R 16 and R 17 in each case mean a hydrogen atom.
80 . The method of claim 53 , wherein, in the compound of formula I:
R 15 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups=NR 15′ (R 15′ =hydrogen atom, methyl, ethyl, propyl, i-propyl), and
R 1 , R 2 , R 4 , R 7 , R 8 , R 9 , R 11 , R 14 , R 16 and R 17 in each case mean a hydrogen atom.
81 . The method of claim 53 , wherein, in the compound of formula I:
R 7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,
R 11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with 1 to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and
R 1 , R 2 , R 4 , R 8 , R 9 , R 14 , R 15 , R 16 and R 17 in each case mean a hydrogen atom.
82 . The method of claim 53 , wherein, in the compound of formula I;
R 7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,
R 15 means a halogen atom in α- or β-position or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups=NR 15′ (R 15′ =hydrogen atom, methyl, ethyl, propyl, i-propyl), and
R 1 , R 2 , R 4 , R 8 , R 9 , R 11 , R 14 , R 16 and R 17 in each case mean a hydrogen atom.
83 . The method of claim 53 , wherein, in the compound of formula I:
R 11 means a nitrooxy group in Ca- or β-position, a hydroxy or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with 1 to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,
R 15 means a halogen atom in α- or β-position or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups=NR 15′ (R 15′ =hydrogen atom, methyl, ethyl, propyl, i-propyl), and
R 1 , R 2 , R 4 , R 7 , R 8 , R 9 , R 14 , R 16 , and R 17 in each case mean a hydrogen atom.
84 . The method of claim 53 , wherein, in the compound of formula I:
R 7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,
R 11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with 1 to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,
R 15 means a halogen atom in α- or β-position, or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups=NR 15′ (R 15′ =hydrogen atom, methyl, ethyl, propyl, i-propyl), and
R 1 , R 2 , R 4 , R 8 , R 9 , R 14 , R 16 and R 17 in each case mean a hydrogen atom.
84 . The method of claim 53 , wherein, in the compound of formula I, one or both hydroxyl groups is (are) esterified at C atoms 3 and 16 with an aliphatic or aromatic carboxylic acid or with an α- or β-amino acid.
85 . The method of claim 53 , wherein the compound of formula I is selected from:
14α,15α-Methylen-estra-1,3,5(10)-triene-3,16α-diol,
14β,15β-Methylen-estra-1,3,5(10)-triene-3,16α-diol,
14β,15β-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,
Estra-1,3,5(10),8(9)-tetraene-3,16α-diol,
Estra-1,3,5(10),8(14)-tetraene-3,16α-diol,
Estra-1,3,5(10),6,8-pentaene-3,16α-diol,
7α-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,
11β-Methoxy-estra-1,3,5(10)-triene-3,16α-diol,
7α-Methyl-estra-1,3,5(10)-triene-3,16α-diol
11β-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,
8a-Estra-1,3,5(10)-triene-3,16α-diol
Estra-1,3,5(10)-triene-2,3,16α-triol
17β-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,
18a-Homo-estra-1,3,5(10)-triene-3,16α-diol,
18a-Homo-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,
18a-Homo-14α,15α-methylen-estra-1,3,5(10)triene-3,16α-diol,
18a-Homo-14α,15α-methylen-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,
18a-Homo-14α,15α-methylen-estra-1,3,5(10),6,8-pentaene-3,16α-diol.
14α,15α-Methylen-estra-1,3,5(10)-triene-3,16β-diol
14β,15β-Methylen-estra-1,3,5(10)-triene-3,16β-diol
14β,15β-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,
Estra-1,3,5(10),8(9)-tetraene-3,16β-diol,
Estra-1,3,5(10),8(14)-tetraene-3,16β-diol,
Estra-1,3,5(10),6,8-pentaene-3,16β-diol,
7α-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,
11β-Methoxy-estra-1,3,5(10)-triene-3,16β-diol,
7α-Methyl-estra-1,3,5(10)-triene-3,16β-diol
11β-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,
8α-Estra-1,3,5(10)-triene-3,16β-diol
Estra-1,3,5(10)-triene-2,3,16α-triol
17β-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,
18a-Homo-estra-1,3,5(10)-triene-3,16β-diol,
18a-Homoestra-1,3,5(10),8(9)-tetraene-3,16β-diol,
18a-Homo-14α,15αa-methylen-estra-1,3,5(10)-triene-3,16β-diol,
18a-Homo-14α,15α-methylen-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,
18a-Homo-14α,15α-methylen-estra-1,3,5(10),6,8-pentaene-3,16β-diol,
7α-Ethyl-estra-1,3,5(10)-triene-3,16α-diol,
7α-Propyl-estra-1,3,5(10)-triene-3,16α-diol,
7α-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol,
7α-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol,
7α-Phenyl-estra-1,3,5(10)-triene-3,16α-diol,
7α-Methoxy-estra-1,3,5(10)-triene-3,16α-diol,
7α-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol,
7α-Cyanomethyl-estra-1,3,5(10)-triene-3,16α-diol,
7β-Ethyl-estra-1,3,5(10)-triene-3,16α-diol,
70β-Propyl-estra-1,3,5(10)-triene-3,16α-diol,
70β-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol,
7 β-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol,
7β-Phenyl-estra-1,3,5(10)-triene-3,16α-diol,
7β-Methoxy-estra-1,3,5(10)-triene-3,16α-diol,
70β-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol,
7β-Cyanomethyl-estra-1,3,5(10)-triene-3,16α-diol,
7α-Ethyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-Propyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-Phenyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-Methoxy-estra-1,3,5(10)-triene-3,16β-diol,
7α-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-Cyanomethyl-estra-1,3,5(10)-triene-3,16β-diol,
70β-Ethyl-estra-1,3,5(10)-triene-3,16,β-diol,
7β-Propyl-estra-1,3,5(10)-triene-3,16β-diol,
70β-Propyl-estra-1,3,5(10)-triene-3,16β-diol,
7β-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol,
70β-Phenyl-estra-1,3,5(10)-triene-3,16β-diol,
7β-Methoxy-estra-1,3,5(10)-triene-3,16β-diol,
7β-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol,
7β-Cyanomethyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Methyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Ethyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Propyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Allyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Methoxy-estra-1,3,5(10)-triene-3,16α-diol,
15α-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Methyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Ethyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Propyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Allyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Methoxy-estra-1,3,5(10)-triene-3,16β-diol,
15α-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Methyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Ethyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Propyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Allyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Methoxy-estra-1,3,5(10)-triene-3,16α-diol,
15β-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Methyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Ethyl-estra-1,3,5(10)triene-3,16β-di
15β-Propyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Allyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Methoxy-estra-1,3,5(10)triene-3,16β-diol,
15β-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-Trifluoromethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-Pentafluoroethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-i-Propyl-11-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-Phenyl-11β-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7 α-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7β-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7β-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7α-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7α-Cyanomethyl-11β-fluoroestra-1,3,5(10)-triene-3,16β-diol,
7β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7β-Propyl-11β-fluoro-estra-1,3,5(10)triene-3,16β-diol,
7β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7β-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7β-Methoxy-11β-fluoro-estra-1,3,5(10)triene-3,16β-diol,
7β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
7β-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15α-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15α-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15β-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15β-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15β-i-Propyl-11β-fluoro-estra-1,3,5(10)triene-3,16α-diol,
15β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15β-Methoxy-11β-fluoro-estra-1,3,5(10)triene-3,16α-diol,
15β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol,
15β-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15β-Ethyl-11-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15β-Propyl-11β-fluoro-estra-1,3,5(10)triene-3,16β-diol,
15β-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol,
15β-Thiomethyl-11β-fluoro-estra-1,3,5(10)triene-3,16β-diol,
14α,15α-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
14β,15β-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
14β,15β-Methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,
7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,
7α-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16α-diol,
7α-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16α-diol,
11β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
11β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
7α-Phenyl-8α-estra-1,3,5(10)-triene-3,16α-diol,
7α-Phenyl-estra-1,3,5(10)-triene-2,3,16α-triol,
17β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
18a-Homo-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
18a-Homo-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,
18a-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
18a-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,
18a-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),6,8-pentaene-3,16α-diol,
14α,15α-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
14β,15β-Methylene-7α-phenyl-estra-1,3,5(10)triene-3,16β-diol,
14β,15β-Methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,
7α-Phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,
7α-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16β-diol,
7α-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16β-diol,
11β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
11β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-Phenyl-8α-estra-1,3,5(10)-triene-3,16β-diol,
7α-Phenyl-estra-1,3,5(10)-triene-2,3,16α-triol,
17β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
18a-Homo-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
18a-Homo-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,
18a-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
18a-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,
18a-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),6,8-pentaene-3,16β-diol,
15α-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol
15β-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)triene-3,16α-diol,
15α-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)triene-3,16α-diol,
15α-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15α-Methyl-11-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Allyl-11β-fluoro7α-phenyl-estra-1,3,5(10)-triene-3,16β,-diol,
15α-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15α-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,
15β-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)triene-3,16β-diol,
15β-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,
15β-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)triene-3,16β-diol,
11β-[2-(3-Methylthien)-yl)estra-1,3,5(10)-triene-3,16α-diol,
11β-[2-(3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,16β-diol.
11β-methylestra-1,3,5(10)-triene-3,16α-diol,
11β-methylestra-1,3,5(10)-triene-3,16β-diol,
11β-methyl-18a-homoestra-1,3,5(10)-triene-3,16α-diol,
11β-methyl-18a-homoestra-1,3,5(10)-triene-3,16β-diol,
11β-ethylestra-1,3,5(10)-triene-3,16α-diol,
11β-ethylestra-1,3,5(10)-triene-3,16β-diol,
11β-ethyl-18a-homoestra-1,3,5(10)-triene-3,16α-diol,
11β-ethyl-18a-homoestra-1,3,5(10)-triene-3,16β-diol,
9α-methylestra-1,3,5(10)-triene-3,16α-diol, or
9α-methyl-18a-homoestra-1,3,5(10)triene-3,16α-diol.
86 . The method of claim 53 , wherein the compound of formula I is selected from:
7α-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,
7α-Methyl-estra-1,3,5(10)-triene-3,16β-diol,
7α-Methyl-estra-1,3,5(10-triene-3,16α-diol, or
18α-Homo-estra-1,3,5(10)-triene-3,16α-diol.
87 . The method of claim 53 , wherein the compound f formula I has a dissociation in favor of its estrogenic action on bone rather than on the uterus.
88 . A 3,16-dihydroxyestra-1,3,5(10)-triene compound of formula I:
in which radicals R 1 to R 17 , independently of one another, have the following meanings:
R 1 means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;
R 2 means a halogen atom, a hydroxyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;
R 4 means a halogen atom, a straight-chain or branched-chain, saturated or unsaturated alkyl group with 1 to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms or a hydrogen atom;
R 7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
R 8 means a hydrogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position or a cyano group in α- or β-position;
R 9 means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in αor β-position;
R 11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with 1 to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;
R 13 means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in β-position;
and either
R 14 means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position or a hydrogen atom in α- or β-position,
and
R 15 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups=NR 15′ (R 15′ =hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom, or
R 14 and R 15 together mean a 14α,15α-methylene or 14β,15β-methylene group that is optionally substituted with one or two halogen atoms;
R 16 means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a hydrogen atom in α- or β-position;
R 17 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with 1 to 10 carbon atoms in α- or β-position, a hydrogen atom or a hydroxyl group;
wherein one or both hydroxyl groups at C atoms 3 and 16 are optionally esterified with an aliphatic, straight-chain or branched-chain, saturated or unsaturated C 1 -C 14 mono- or polycarboxylic acid or an aromatic carboxylic acid or with an α- or β-amino acid;
wherein the bonds in rings B, C and D mean a single bond or optionally a double bond, provided that at least one of the bonds is a double bond, and the wavy lines mean the arrangement of the respective substituent in α- or β-position; and
wherein the following compounds are excluded: estra-1,3,5(10),7-tetraene-3,16α-diol, and estra-1,3,5(10),7-tetraene-3,16β-diol.
89 . A compound according to claim 88 , wherein there is a double bond between C atoms 6 and 7.
90 . A compound according to claim 88 , wherein there is a double bond between C atoms 7 and 8.
91 . A compound according to claim 88 , wherein there is a double bond between C atoms 8 and 9.
92 . A compound according to claim 88 , wherein there is a double bond between C atoms 9 and 11.
93 . A compound according to claim 88 , wherein there is a double bond between C atoms 8 and 14.
94 . A compound according to claim 88 , wherein there is a double bond between C atoms 11 and 12.
95 . A compound according to claim 88 , wherein there is a double bond between C atoms 14 and 15.
96 . A compound according to claim 88 , wherein there are double bonds between C atoms 6 and 7 and C atoms 8 and 9.
98 . A compound according to claim 88 , wherein there are double bonds between C atoms 8 and 9 and C atoms 14 and 15.
99 . A compound according to claim 88 , wherein there are double bonds between C atoms 6 and 7, C atoms 8 and 9 and C atoms 11 and 12.
100 . A compound according to claim 88 , wherein there are double bonds between C atoms 6 and 7, C atoms 8 and 9 and C atoms 14 and 15.
101 . A compound according to claim 88 , wherein there are double bonds between C atoms 6 and 7, C atoms 8 and 9, C atoms 11 and 12 and C atoms 14 and 15.