U.S. patent application number 11/498109 was filed with the patent office on 2006-11-30 for 16-hydroxyestratrienes as selectively active estrogens.
Invention is credited to Ulf Boemer, Karl-Heinrich Fritzemeier, Christa Hegele-Hartung, Rudolf Knauthe, Dirk Kosemund, Hermann Kuenzer, Monika Lessl, Gerd Mueller.
Application Number | 20060270845 11/498109 |
Document ID | / |
Family ID | 36974459 |
Filed Date | 2006-11-30 |
United States Patent
Application |
20060270845 |
Kind Code |
A1 |
Kuenzer; Hermann ; et
al. |
November 30, 2006 |
16-Hydroxyestratrienes as selectively active estrogens
Abstract
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 16.alpha.- and
16.beta.-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.
Inventors: |
Kuenzer; Hermann; (Berlin,
DE) ; Knauthe; Rudolf; (Berlin, DE) ; Lessl;
Monika; (Berlin, DE) ; Fritzemeier;
Karl-Heinrich; (Berlin, DE) ; Hegele-Hartung;
Christa; (Muelheim a.d. Ruhr, DE) ; Boemer; Ulf;
(Berlin, DE) ; Mueller; Gerd; (Jena, DE) ;
Kosemund; Dirk; (Erfurt, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
36974459 |
Appl. No.: |
11/498109 |
Filed: |
August 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09497891 |
Feb 4, 2000 |
7109360 |
|
|
11498109 |
Aug 3, 2006 |
|
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60131268 |
Apr 27, 1999 |
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Current U.S.
Class: |
540/106 ;
552/515; 552/626 |
Current CPC
Class: |
C07J 1/00 20130101; C07J
9/00 20130101; A61K 31/565 20130101; C07J 41/00 20130101 |
Class at
Publication: |
540/106 ;
552/515; 552/626 |
International
Class: |
C07J 41/00 20060101
C07J041/00; C07J 1/00 20060101 C07J001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 9, 1999 |
DE |
199 06 159.9 |
Claims
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: ##STR4## in which radicals R.sup.1 to
R.sup.17, independently of one another, have the following
meanings: R.sup.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.sup.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.sup.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.sup.7 means a halogen atom in
.alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated, optionally partially or completely
fluorinated alkyl group with 1 to 10 carbon atoms in .alpha.- or
.beta.-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.sup.8
means a hydrogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with 1
to 10 carbon atoms in .alpha.- or .beta.-position or a cyano group
in .alpha.- or .beta.-position; R.sup.9 means a hydrogen atom in
.alpha.- or .beta.-position, a methyl, ethyl, trifluoromethyl or
pentafluoroethyl group in .alpha.- or .beta.-position; R.sup.11
means a nitrooxy group in .alpha.- or .beta.-position, a hydroxyl
or mercapto group in .alpha.- or .beta.-position, a halogen atom in
.alpha.- or .beta.-position, a chloromethyl group in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with 1 to 10 carbon atoms in .alpha.- or .beta.-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.sup.13
means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in
.beta.-position; and either R.sup.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
.alpha.- or .beta.-position or a hydrogen atom in .alpha.- or
.beta.-position, and R.sup.15 means a halogen atom in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with 1 to 10 carbon atoms in .alpha.- or .beta.-position that
can be interrupted by one or more oxygen atoms, sulfur atoms,
sulfoxide or sulfone groups or imino groups=NR.sup.15'
(R.sup.15'=hydrogen atom, methyl, ethyl, propyl, i-propyl) or a
hydrogen atom, or R.sup.14 and R.sup.15 together mean a
14.alpha.,15.alpha.-methylene or 14.beta.,15.beta.-methylene group
that is optionally substituted with one or two halogen atoms;
R.sup.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 .alpha.- or .beta.-position, a
trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a
hydrogen atom in .alpha.- or .beta.-position; and R.sup.17 means a
halogen atom in .alpha.- or .beta.-position, a straight-chain or
branched-chain, saturated or unsaturated, optionally partially or
completely fluorinated alkyl group with 1 to 10 carbon atoms in
.alpha.- or .beta.-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.sub.1-C.sub.14 mono- or
polycarboxylic acid or an aromatic carboxylic acid or with an
.alpha.- or .beta.-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 .alpha.- or .beta.-position; and wherein the following compounds
are excluded: estra-1,3,5(10)-triene-3,16.alpha.-diol,
estra-1,3,5(10)-triene-3,16.beta.-diol,
estra-1,3,5(10),7-tetraene-3,16.alpha.-diol,
estra-1,3,5(10),7-tetraene-3,16.beta.-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.sup.1 to R.sup.17, independently of one another, have
the following meanings R.sup.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.sup.2 means a fluorine atom, a
hydroxyl group, a methoxy or ethoxy group or a hydrogen atom;
R.sup.4 means a fluorine atom, a methyl, ethyl, trifluoromethyl,
methoxy or ethoxy group or a hydrogen atom; R.sup.7 means a
fluorine atom in .alpha.- or .beta.-position, a methyl, ethyl,
propyl or i-propyl group in .alpha.- or .beta.-position, an
optionally substituted aryl radical, a trifluoromethyl group in
.alpha.- or .beta.-position or a hydrogen atom; R.sup.8 means a
hydrogen atom in .alpha.- or .beta.-position, a methyl or ethyl
group in .alpha.- or .beta.-position; R.sup.9 means a hydrogen atom
in .alpha.- or .beta.-position, a methyl, ethyl, trifluoromethyl or
pentafluoroethyl group in .alpha.- or .beta.-position; R.sup.11
means a nitrooxy group in .alpha.- or .beta.-position, a hydroxyl
group in .alpha.- or .beta.-position, a fluorine atom in .alpha.-
or .beta.-position, a choromethyl group in .alpha.- or
.beta.-position, a methyl group in .alpha.- or .beta.-position, a
methoxy group in .alpha.- or .beta.-position, a phenyl- or
3-methylthien-2-yl radical in .alpha.- or .beta.-position or a
hydrogen atom; R.sup.13 means a methyl or ethyl group in
.beta.-position; and either R.sup.14 means a hydrogen atom in
.alpha.- or .beta.-position or a methyl group in .alpha.- or
.beta.-position, and R.sup.15 means a fluorine atom in .alpha.- or
.beta.-position, a methyl group in .alpha.- or .beta.-position, or
a hydrogen atom, or R.sup.14 and R.sup.15 together mean a
14.alpha.,15.alpha.-methylene group or a
14.beta.,15.beta.-methylene group; R.sup.16 means a methyl, ethyl,
ethinyl, propinyl or trifluoromethyl group; R.sup.17 means a
fluorine atom in .alpha.- or .beta.-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.sup.7 means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with 1
to 10 carbon atoms in .alpha.- or .beta.-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.sup.1, R.sup.2, R.sup.4, R.sup.8, R.sup.9, R.sup.11,
R.sup.14, R.sup.15, R.sup.16 and R.sup.17 in each case mean a
hydrogen atom.
79. The method of claim 53, wherein, in the compound of formula I:
R.sup.11 means a nitrooxy group in .alpha.- or .beta.-position, a
hydroxyl or mercapto group in .alpha.- or .beta.-position, a
halogen atom in .alpha.- or .beta.-position, a chloromethyl group
in .alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated, optionally partially or completely
fluorinated alkyl group with 1 to 10 carbon atoms in .alpha.- or
.beta.-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.sup.1,
R.sup.2, R.sup.4, R.sup.7, R.sup.8, R.sup.9, R.sup.14, R.sup.15,
R.sup.16 and R.sup.17 in each case mean a hydrogen atom.
80. The method of claim 53, wherein, in the compound of formula I:
R.sup.15 means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with 1
to 10 carbon atoms in .alpha.- or .beta.-position that can be
interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or
sulfone groups or imino groups=NR.sup.15' (R.sup.15'=hydrogen atom,
methyl, ethyl, propyl, i-propyl), and R.sup.1, R.sup.2, R.sup.4,
R.sup.7, R.sup.8, R.sup.9, R.sup.11, R.sup.14, R.sup.16 and
R.sup.17 in each case mean a hydrogen atom.
81. The method of claim 53, wherein, in the compound of formula I:
R.sup.7 means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with 1
to 10 carbon atoms in .alpha.- or .beta.-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.sup.11 means a nitrooxy group in .alpha.- or
.beta.-position, a hydroxyl or mercapto group in .alpha.- or
.beta.-position, a halogen atom in .alpha.- or .beta.-position, a
chloromethyl group in .alpha.- or .beta.-position, a straight-chain
or branched-chain, saturated or unsaturated, optionally partially
or completely fluorinated alkyl group with 1 to 10 carbon atoms in
.alpha.- or .beta.-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.sup.1, R.sup.2, R.sup.4, R.sup.8, R.sup.9, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 in each case mean a hydrogen
atom.
82. The method of claim 53, wherein, in the compound of formula I;
R.sup.7 means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with 1
to 10 carbon atoms in .alpha.- or .beta.-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.sup.15 means a halogen atom in .alpha.- or
.beta.-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 .alpha.- or .beta.-position that
can be interrupted by one or more oxygen atoms, sulfur atoms,
sulfoxide or sulfone groups or imino groups=NR.sup.15'
(R.sup.15'=hydrogen atom, methyl, ethyl, propyl, i-propyl), and
R.sup.1, R.sup.2, R.sup.4, R.sup.8, R.sup.9, R.sup.11, R.sup.14,
R.sup.16 and R.sup.17 in each case mean a hydrogen atom.
83. The method of claim 53, wherein, in the compound of formula I:
R.sup.11 means a nitrooxy group in Ca- or .beta.-position, a
hydroxy or mercapto group in .alpha.- or .beta.-position, a halogen
atom in .alpha.- or .beta.-position, a chloromethyl group in
.alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated, optionally partially or completely
fluorinated alkyl group with 1 to 10 carbon atoms in .alpha.- or
.beta.-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.sup.15
means a halogen atom in .alpha.- or .beta.-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 .alpha.- or .beta.-position that can be
interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or
sulfone groups or imino groups=NR.sup.15' (R.sup.15'=hydrogen atom,
methyl, ethyl, propyl, i-propyl), and R.sup.1, R.sup.2, R.sup.4,
R.sup.7, R.sup.8, R.sup.9, R.sup.14, R.sup.16, and R.sup.17 in each
case mean a hydrogen atom.
84. The method of claim 53, wherein, in the compound of formula I:
R.sup.7 means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with 1
to 10 carbon atoms in .alpha.- or .beta.-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.sup.11 means a nitrooxy group in .alpha.- or
.beta.-position, a hydroxyl or mercapto group in .alpha.- or
.beta.-position, a halogen atom in .alpha.- or .beta.-position, a
chloromethyl group in .alpha.- or .beta.-position, a straight-chain
or branched-chain, saturated or unsaturated, optionally partially
or completely fluorinated alkyl group with 1 to 10 carbon atoms in
.alpha.- or .beta.-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.sup.15 means a halogen atom in .alpha.- or
.beta.-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 .alpha.- or
.beta.-position that can be interrupted by one or more oxygen
atoms, sulfur atoms, sulfoxide or sulfone groups or imino
groups=NR.sup.15' (R.sup.15'=hydrogen atom, methyl, ethyl, propyl,
i-propyl), and R.sup.1, R.sup.2, R.sup.4, R.sup.8, R.sup.9,
R.sup.14, R.sup.16 and R.sup.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 .alpha.-
or .beta.-amino acid.
85. The method of claim 53, wherein the compound of formula I is
selected from:
14.alpha.,15.alpha.-Methylen-estra-1,3,5(10)-triene-3,16.alpha.-di-
ol,
14.beta.,15.beta.-Methylen-estra-1,3,5(10)-triene-3,16.alpha.-diol,
14.beta.,15.beta.-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16.alpha.-diol-
, Estra-1,3,5(10),8(9)-tetraene-3,16.alpha.-diol,
Estra-1,3,5(10),8(14)-tetraene-3,16.alpha.-diol,
Estra-1,3,5(10),6,8-pentaene-3,16.alpha.-diol,
7.alpha.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
11.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
11.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
8a-Estra-1,3,5(10)-triene-3,16.alpha.-diol
Estra-1,3,5(10)-triene-2,3,16.alpha.-triol
17.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
18a-Homo-estra-1,3,5(10)-triene-3,16.alpha.-diol,
18a-Homo-estra-1,3,5(10),8(9)-tetraene-3,16.alpha.-diol,
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10)triene-3,16.alpha.-d-
iol,
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10),8(9)-tetraene--
3,16.alpha.-diol,
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10),6,8-pentaene-3,16.a-
lpha.-diol.
14.alpha.,15.alpha.-Methylen-estra-1,3,5(10)-triene-3,16.beta.-diol
14.beta.,15.beta.-Methylen-estra-1,3,5(10)-triene-3,16.beta.-diol
14.beta.,15.beta.-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16.beta.-diol,
Estra-1,3,5(10),8(9)-tetraene-3,16.beta.-diol,
Estra-1,3,5(10),8(14)-tetraene-3,16.beta.-diol,
Estra-1,3,5(10),6,8-pentaene-3,16.beta.-diol,
7.alpha.-Fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
11.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.beta.-diol
11.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
8.alpha.-Estra-1,3,5(10)-triene-3,16.beta.-diol
Estra-1,3,5(10)-triene-2,3,16.alpha.-triol
17.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
18a-Homo-estra-1,3,5(10)-triene-3,16.beta.-diol,
18a-Homoestra-1,3,5(10),8(9)-tetraene-3,16.beta.-diol,
18a-Homo-14.alpha.,15.alpha.a-methylen-estra-1,3,5(10)-triene-3,16.beta.--
diol,
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10),8(9)-tetraene-
-3,16.beta.-diol,
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10),6,8-pentaene-3,16.b-
eta.-diol, 7.alpha.-Ethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-i-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-i-Propenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Thiomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Cyanomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.beta.-Ethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
70.beta.-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
70.beta.-i-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
.sup.7.beta.-i-Propenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.beta.-Phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol,
70.beta.-Thiomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.beta.-Cyanomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Ethyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-i-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-i-Propenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Thiomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Cyanomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
70.beta.-Ethyl-estra-1,3,5(10)-triene-3,16,.beta.-diol,
7.beta.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
70.beta.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.beta.-i-Propenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
70.beta.-Phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.beta.-Thiomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.beta.-Cyanomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Ethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Allyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-i-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-i-Propenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Thiomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Ethyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.alpha.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.alpha.-Allyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.alpha.-i-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.alpha.-i-Propenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.alpha.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.alpha.-Thiomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Methyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-Ethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-Allyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-i-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-i-Propenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-Thiomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-Methyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Ethyl-estra-1,3,5(10)triene-3,16.beta.-di
15.beta.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Allyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-i-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-i-Propenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Methoxy-estra-1,3,5(10)triene-3,16.beta.-diol,
15.beta.-Thiomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Trifluoromethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alph-
a.-diol,
7.alpha.-Pentafluoroethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-
-3,16.alpha.-diol,
7.alpha.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-i-Propyl-11-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-di-
ol,
7.alpha.-Phenyl-11.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-di-
ol,
7.alpha.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-d-
iol,
7.alpha.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alph-
a.-diol,
7.alpha.-Cyanomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16-
.alpha.-diol,
7.beta.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.beta.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.beta.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.beta.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-di-
ol,
7.beta.-Phenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-dio-
l,
7.beta.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-dio-
l,
7.beta.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.--
diol,
7.beta.-Cyanomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alp-
ha.-diol,
7.alpha.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta-
.-diol,
7.alpha.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-
-diol,
7.alpha.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta-
.-diol,
7.alpha.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.b-
eta.-diol,
7.alpha.-Phenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-dio-
l,
7.alpha.-Cyanomethyl-11.beta.-fluoroestra-1,3,5(10)-triene-3,16.beta.--
diol,
7.beta.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-dio-
l,
7.beta.-Propyl-11.beta.-fluoro-estra-1,3,5(10)triene-3,16.beta.-diol,
7.beta.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.beta.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol-
,
7.beta.-Phenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.beta.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)triene-3,16.beta.-diol,
7.beta.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol-
,
7.beta.-Cyanomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-d-
iol,
15.alpha.-Methyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.--
diol,
15.alpha.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.--
diol,
15.alpha.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-
-diol,
15.alpha.-Allyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-
-diol,
15.alpha.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alp-
ha.-diol,
15.alpha.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,1-
6.alpha.-diol,
15.alpha.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol-
,
15.alpha.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-
-diol,
15.alpha.-Methyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-
-diol,
15.alpha.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.--
diol,
15.alpha.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.--
diol,
15.alpha.-Allyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-d-
iol,
15.alpha.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha-
.-diol,
15.alpha.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.-
alpha.-diol,
15.alpha.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol-
,
15.alpha.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.--
diol,
15.beta.-Methyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.--
diol,
15.beta.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-d-
iol,
15.beta.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-d-
iol,
15.beta.-Allyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-di-
ol,
15.beta.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)triene-3,16.alpha.-d-
iol,
15.beta.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alph-
a.-diol,
15.beta.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)triene-3,16.alph-
a.-diol,
15.beta.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.-
alpha.-diol,
15.beta.-Methyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Ethyl-11-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Propyl-11.beta.-fluoro-estra-1,3,5(10)triene-3,16.beta.-diol,
15.beta.-Allyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-di-
ol,
15.beta.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-di-
ol,
15.beta.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)triene-3,16.beta.--
diol,
14.alpha.,15.alpha.-Methylene-7.alpha.-phenyl-estra-1,3,5(10)-trien-
e-3,16.alpha.-diol,
14.beta.,15.beta.-Methylene-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.a-
lpha.-diol,
14.beta.,15.beta.-Methylene-7.alpha.-phenyl-estra-1,3,5(10),8(9)-tetraene-
-3,16.alpha.-diol,
7.alpha.-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16.alpha.-diol,
7.alpha.-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16.alpha.-diol,
7.alpha.-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16.alpha.-diol,
11.beta.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
11.beta.-Fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Phenyl-8.alpha.-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Phenyl-estra-1,3,5(10)-triene-2,3,16.alpha.-triol,
17.beta.-Fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
18a-Homo-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
18a-Homo-7.alpha.-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16.alpha.-diol,
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10)-tr-
iene-3,16.alpha.-diol,
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10),8(-
9)-tetraene-3,16.alpha.-diol,
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10),6,-
8-pentaene-3,16.alpha.-diol,
14.alpha.,15.alpha.-Methylene-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16-
.beta.-diol,
14.beta.,15.beta.-Methylene-7.alpha.-phenyl-estra-1,3,5(10)triene-3,16.be-
ta.-diol,
14.beta.,15.beta.-Methylene-7.alpha.-phenyl-estra-1,3,5(10),8(9-
)-tetraene-3,16.beta.-diol,
7.alpha.-Phenyl-estra-1,3,5(10),8(9)-tetraene-3,16.beta.-diol,
7.alpha.-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16.beta.-diol,
7.alpha.-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16.beta.-diol,
11.beta.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
11.beta.-Fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Phenyl-8.alpha.-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Phenyl-estra-1,3,5(10)-triene-2,3,16.alpha.-triol,
17.beta.-Fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
18a-Homo-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
18a-Homo-7.alpha.-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16.beta.-diol,
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10)-tr-
iene-3,16.beta.-diol,
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10),8(-
9)-tetraene-3,16.beta.-diol,
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10),6,-
8-pentaene-3,16.beta.-diol,
15.alpha.-Methyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Ethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.alpha.-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol-
,
15.alpha.-Allyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol-
,
15.alpha.-i-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-d-
iol,
15.alpha.-i-Propenyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alp-
ha.-diol,
15.alpha.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.a-
lpha.-diol,
15.alpha.-Thiomethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-d-
iol,
15.alpha.-Methyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-d-
iol,
15.alpha.-Ethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-di-
ol,
15.alpha.-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-di-
ol,
15.alpha.-Allyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-dio-
l,
15.alpha.-i-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-d-
iol,
15.alpha.-i-Propenyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.bet-
a.-diol,
15.alpha.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.be-
ta.-diol,
15.alpha.-Thiomethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.beta.-diol,
15.beta.-Methyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-Ethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
15.beta.-Allyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
15.beta.-i-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol-
,
15.beta.-i-Propenyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.--
diol,
15.beta.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-
-diol,
15.beta.-Thiomethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.al-
pha.-diol,
15.beta.-Methyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Ethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-Allyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-i-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
15.beta.-i-Propenyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-di-
ol,
15.beta.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-di-
ol,
15.beta.-Thiomethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-
-diol,
15.alpha.-Methyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-t-
riene-3,16.alpha.-diol,
15.alpha.-Ethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.alpha.-diol,
15.alpha.-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.alpha.-diol,
15.alpha.-Allyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.alpha.-diol,
15.alpha.-i-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)triene--
3,16.alpha.-diol,
15.alpha.-i-Propenyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)trien-
e-3,16.alpha.-diol,
15.alpha.-Methoxy-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene--
3,16.alpha.-diol,
15.alpha.-Thiomethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trie-
ne-3,16.alpha.-diol,
15.alpha.-Methyl-11-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.be-
ta.-diol,
15.alpha.-Ethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-
-triene-3,16.beta.-diol,
15.alpha.-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.beta.-diol,
15.alpha.-Allyl-11.beta.-fluoro7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.beta.,-diol,
15.alpha.-i-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-
-3,16.beta.-diol,
15.alpha.-i-Propenyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trie-
ne-3,16.beta.-diol,
15.alpha.-Methoxy-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene--
3,16.beta.-diol,
15.alpha.-Thiomethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trie-
ne-3,16.beta.-diol,
15.beta.-Methyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.alpha.-diol,
15.beta.-Ethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.alpha.-diol,
15.beta.-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.alpha.-diol,
15.beta.-Allyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.alpha.-diol,
15.beta.-i-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene--
3,16.alpha.-diol,
15.beta.-i-Propenyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trien-
e-3,16.alpha.-diol,
15.beta.-Methoxy-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.alpha.-diol,
15.beta.-Thiomethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trien-
e-3,16.alpha.-diol,
15.beta.-Methyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)triene-3,1-
6.beta.-diol,
15.beta.-Ethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.beta.-diol,
15.beta.-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.beta.-diol,
15.beta.-Allyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.beta.-diol,
15.beta.-i-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene--
3,16.beta.-diol,
15.beta.-i-Propenyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trien-
e-3,16.beta.-diol,
15.beta.-Methoxy-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.beta.-diol,
15.beta.-Thiomethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)triene-
-3,16.beta.-diol,
11.beta.-[2-(3-Methylthien)-yl)estra-1,3,5(10)-triene-3,16.alpha.-diol,
11.beta.-[2-(3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,16.beta.-diol.
11.beta.-methylestra-1,3,5(10)-triene-3,16.alpha.-diol,
11.beta.-methylestra-1,3,5(10)-triene-3,16.beta.-diol,
11.beta.-methyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol,
11.beta.-methyl-18a-homoestra-1,3,5(10)-triene-3,16.beta.-diol,
11.beta.-ethylestra-1,3,5(10)-triene-3,16.alpha.-diol,
11.beta.-ethylestra-1,3,5(10)-triene-3,16.beta.-diol,
11.beta.-ethyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol,
11.beta.-ethyl-18a-homoestra-1,3,5(10)-triene-3,16.beta.-diol,
9.alpha.-methylestra-1,3,5(10)-triene-3,16.alpha.-diol, or
9.alpha.-methyl-18a-homoestra-1,3,5(10)triene-3,16.alpha.-diol.
86. The method of claim 53, wherein the compound of formula I is
selected from:
7.alpha.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol,
7.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
7.alpha.-Methyl-estra-1,3,5(10-triene-3,16.alpha.-diol, or
18.alpha.-Homo-estra-1,3,5(10)-triene-3,16.alpha.-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:
##STR5## in which radicals R.sup.1 to R.sup.17, independently of
one another, have the following meanings: R.sup.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.sup.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.sup.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.sup.7 means a
halogen atom in .alpha.- or .beta.-position, a straight-chain or
branched-chain, saturated or unsaturated, optionally partially or
completely fluorinated alkyl group with 1 to 10 carbon atoms in
.alpha.- or .beta.-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.sup.8 means a hydrogen atom in .alpha.- or .beta.-position,
a straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with 1
to 10 carbon atoms in .alpha.- or .beta.-position or a cyano group
in .alpha.- or .beta.-position; R.sup.9 means a hydrogen atom in
.alpha.- or .beta.-position, a methyl, ethyl, trifluoromethyl or
pentafluoroethyl group in .alpha.or .beta.-position; R.sup.11 means
a nitrooxy group in .alpha.- or .beta.-position, a hydroxyl or
mercapto group in .alpha.- or .beta.-position, a halogen atom in
.alpha.- or .beta.-position, a chloromethyl group in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with 1 to 10 carbon atoms in .alpha.- or .beta.-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.sup.13
means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in
.beta.-position; and either R.sup.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
.alpha.- or .beta.-position or a hydrogen atom in .alpha.- or
.beta.-position, and R.sup.15 means a halogen atom in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with 1 to 10 carbon atoms in .alpha.- or .beta.-position that
can be interrupted by one or more oxygen atoms, sulfur atoms,
sulfoxide or sulfone groups or imino groups=NR.sup.15'
(R.sup.15'=hydrogen atom, methyl, ethyl, propyl, i-propyl) or a
hydrogen atom, or R.sup.14 and R.sup.15 together mean a
14.alpha.,15.alpha.-methylene or 14.beta.,15.beta.-methylene group
that is optionally substituted with one or two halogen atoms;
R.sup.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 .alpha.- or .beta.-position, a
trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a
hydrogen atom in .alpha.- or .beta.-position; R.sup.17 means a
halogen atom in .alpha.- or .beta.-position, a straight-chain or
branched-chain, saturated or unsaturated, optionally partially or
completely fluorinated alkyl group with 1 to 10 carbon atoms in
.alpha.- or .beta.-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.sub.1-C.sub.14 mono- or
polycarboxylic acid or an aromatic carboxylic acid or with an
.alpha.- or .beta.-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 .alpha.- or
.beta.-position; and wherein the following compounds are excluded:
estra-1,3,5(10),7-tetraene-3,16.alpha.-diol, and
estra-1,3,5(10),7-tetraene-3,16.beta.-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.
Description
FIELD OF THE INVENTION
[0001] This invention relates to 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.
[0002] The chemical compounds are novel, steroidal,
tissue-selective estrogens.
BACKGROUND OF THE INVENTION
[0003] Established estrogen therapies for treatment of
hormone-deficiency-induced symptoms and the protective action of
estrogens on bones, brains, vessels and other organ systems.
[0004] The efficiency of estrogens in the treatment of
hormone-deficiency-induced symptoms such as hot flashes, atrophy of
estrogen target organs and incontinence, as well as the successful
use of estrogen therapies for prevention of bone mass loss in peri-
and postmenopausal women, is well documented and generally accepted
(Grady et al. 1992, Ann Intern Med 117: 1016-1037). It is also well
documented that estrogen replacement therapy in postmenopausal
women or in women with ovarian dysfunction that is caused in some
other way reduces the risk of cardiovascular diseases compared to
non-estrogen-treated women (Grady et al., loc. cit.).
[0005] In addition, more recent studies confirm a protective action
of estrogens against neurodegenerative diseases, such as, e.g.,
Alzheimer's disease (Henderson 1997, Neurology 48 (Suppl 7):
S27-S35; Birge 1997, Neurology 48 (Suppl 7): S36-S41), a protective
action with respect to brain functions, such as memory and learning
capacity (McEwen et al. 1997, Neurology 48 (Suppl 7): S8-S15;
Sherwin 1997, Neurology 48 (Suppl 7): S21-S26), as well as against
hormone-deficiency-induced mood swings (Halbreich 1997, Neurology
48 (Suppl 7): S16-S20).
[0006] In addition, estrogen replacement therapy has proven
effective relative to the reduction of the incidence of colorectal
carcinoma (Calle, E. F. et al., 1995, J Natl Cancer Inst 87:
517-523).
[0007] In conventional estrogen or hormone replacement therapy
(=HRT), natural estrogens, such as estradiol, and conjugated
estrogens that consist of equine urine are used either by
themselves or in combination with a gestagen. Instead of the
natural estrogens, derivatives that are obtained by esterification,
such as, e.g., 17.beta.-estradiol-valerate, can also be used.
[0008] Because of the stimulating action of the estrogens that are
used on the endometrium, which results in an increase of the risk
of endometrial carcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166:
1986-1992), estrogen/gestagen combination preparations are
preferably used in hormone replacement therapy. The gestagenic
component in the estrogen/gestagen combination avoids hypertrophy
of the endometrium, but the occurrence of undesirable intracyclic
menstrual bleeding is also linked to the gestagen-containing
combination.
[0009] Selective estrogens represent a more recent alternative to
the estrogen/gestagen combination preparations. Up until now,
selective estrogens have been defined as those compounds that have
an estrogen-like effect on the brain, bones and vascular system,
owing to their antiuterotrophic (i.e., antiestrogenic) partial
action, but they do not have a proliferative effect on the
endometrium.
[0010] A class of substances that partially meet the desired
profile of a selective estrogen are the so-called "Selective
Estrogen Receptor Modulators" (SERM) (R. F. Kauffman, H. U. Bryant
1995, DNAP 8 (9): 531-539). In this case, there are partial
agonists of estrogen receptor subtype "ER.alpha.." This substance
type is ineffective, however, with respect to the therapy of acute
postmenopausal symptoms, such as, e.g., hot flashes. As an example
of a SERM, the raloxifene that was recently introduced for the
indication of osteoporosis can be mentioned.
Estrogen Receptor Beta (ER.beta.)
[0011] Estrogen receptor .beta. (ER.beta.) was recently discovered
as a second subtype of the estrogen receptor (Kuiper et al. (1996),
Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996)
Febs Letters 392: 49-53; Tremblay et al. (1997), Molecular
Endocrinology 11: 353-365). The expression pattern of ER.beta.
differs from that of the ER.alpha. (Kuiper et al. (1996),
Endocrinology 138: 863-870). ER.beta. thus predominates over
ER.alpha. in the rat prostate, while ER.alpha. predominates over
ER.beta. in the rat uterus. Areas in which in each case only one of
the two ER-subtypes is expressed were identified in the brain
(Shugrue et al. (1996), Steroids 61: 678-681; Li et al. (1997),
Neuroendocrinology 66:63-67). ER.beta. is expressed in, i.a., areas
that are considered to be important for cognitive processes and
"mood" (Shugrue et al. 1997, J Comparative Neurology 388:
507-525).
[0012] Other organ systems with comparatively higher
ER.beta.-expression comprise the bones (Onoe, Y. et al., 1997,
Endocrinology 138: 4509-4512), the vascular system (Register, T.
C., Adams, M. R. 1998, J. Steroid Molec Biol 64: 187-191), the
urogenital tract (Kuiper, G. J. M. et al. 1997, Endocrinology 138:
863-870), the gastrointestinal tract (Campbell-Thopson 1997, BBRC
240: 478-483), as well as the testis (Mosselmann, S. et al. 1996
Febs Lett 392 49-53) including the spermatides (Shugrue et al.
1998, Steroids 63: 498-504). The tissue distribution suggests that
estrogens regulate organ functions via ER.beta.. The fact that
ER.beta. is functional in this respect also follows by studies in
ER.alpha.-(ERKO) or ER.beta.-(.beta.ERKO)-knockout mice:
ovariectomy produces bone mass loss in ERKO-mice, which can be
cancelled out by estrogen substitution (Kimbro et al. 1998,
Abstract OR7-4, Endocrine Society Meeting New Orleans). Estradiol
in the blood vessels of female ERKO mice also inhibits vascular
media and smooth muscle cell proliferation (Iafrati, M. D. et al.
1997, Nature Medicine 3: 545-548). These protective actions of
estradiol are carried out in the ERKO mouse presumably via
ER.beta..
[0013] Observations of .beta.ERKO mice provide an indication on a
function of ER.beta. in the prostate and bladder: in the case of
older male mice, symptoms of prostate and bladder hyperplasia occur
(Krege, J. H. et al. 1998, Proc Natl Acad Sci 95: 15677-15682). In
addition, female ERKO mice (Lubahn, D. B. et al. 1993, Proc Natl
Acad Sci 90: 11162-11166) and male ERKO mice (Hess, R. A. et al.
1997, Nature 390: 509-512) as well as female .beta.ERKO mice
(Krege, J. H., 1998) have fertility disorders. Consequently, the
important function of estrogens with respect to maintaining testis
and ovary functions as well as fertility is confirmed.
[0014] Westerlind et al., 1998, describe a differential action of
16.alpha.-hydroxyestrone on the bones, on the one hand, and
reproductive organs of female rats, on the other (Westerlind et al.
1998, J Bone and Mineral Res 13: 1023-1031).
[0015] Some studies showed that 16.alpha.-hydroxyestrone binds
three times better to the human estrogen receptor .beta. (ER.beta.)
than to the human estrogen receptor .alpha. (ER.alpha.). The RBA
value of the substance on the rat prostate estrogen receptor is
five times better than the RBA value of the substance on the rat
uterus estrogen receptor. According to some findings, the
dissociation of the substance that is described by Westerlind can
be attributed to their preference for ER.beta. rather than
ER.alpha..
[0016] It was possible to achieve a selective estrogen action on
specific target organs by subtype-specific ligands based on the
different tissue or organ distribution of the two subtypes of the
ERs. Substances with a preference for ER.beta. compared to
ER.alpha. in the in vitro receptor binding test were described by
Kuiper et al. (Kuiper et al. (1996), Endocrinology 138: 863-870). A
selective action of subtype-specific ligands of the estrogen
receptor on estrogen-sensitive parameters in vivo was not
previously shown.
[0017] The object of this invention is therefore to prepare
compounds that have in vitro a dissociation with respect to the
binding to estrogen receptor preparations from rat prostates and
rat uteri and that have in vivo a dissociation with respect to
bones rather than the uterus action. The compounds are to 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 many times higher potency with respect to protection
against hormone-deficiency-induced bone mass loss in comparison to
uterus-stimulating action.
[0018] In the broader sense, a structure-action relationship, which
allows for access to compounds that-have the above-formulated
pharmacological profile of better estrogenic action on bones than
on the uterus, is to be made available by this invention.
[0019] According to the invention, the object above is achieved by
the provision of 16.alpha.- and
16.beta.-hydroxy-estra-1,3,5(10)-trienes of general formula I
##STR1## in which radicals R.sup.1 to R.sup.17, independently of
one another, have the following meanings: [0020] R.sup.1 means a
halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl
group, a methoxy group, an ethoxy group or a hydrogen atom; [0021]
R.sup.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; [0022] R.sup.4 means a halogen
atom, a straight-chain or branched-chain, saturated or unsaturated
alkyl group with up to 10 carbon atoms, a trifluoromethyl or
pentafluoroethyl group, a straight-chain or branched-chain,
saturated or unsaturated alkoxy group with up to 6 carbon atoms or
a hydrogen atom; [0023] R.sup.7 means a halogen atom in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with up to 10 carbon atoms in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated alkoxy
group with up to 6 carbon atoms, an optionally substituted aryl or
heteroaryl radical or a hydrogen atom; [0024] R.sup.8 means a
hydrogen atom in .alpha.- or .beta.-position, a straight-chain or
branched-chain, saturated or unsaturated, optionally partially or
completely fluorinated alkyl group with up to 10 carbon atoms in
.alpha.- or .beta.-position, or a cyano group in .alpha.- or
.beta.-position; [0025] R.sup.9 means a hydrogen atom in .alpha.-
or .beta.-position, a methyl, ethyl, trifluoromethyl or
pentafluoroethyl group in .alpha.- or .beta.-position; [0026]
R.sup.11 means a nitrooxy group in .alpha.- or .beta.-position, a
as hydroxyl or mercapto group in .alpha.- or .beta.-position, a
halogen atom in .alpha.- or .beta.-position, a chloromethyl group
in .alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated, optionally partially or completely
fluorinated alkyl group with up to 10 carbon atoms in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an
optionally substituted aryl or heteroaryl radical or a hydrogen
atom; [0027] R.sup.13 means a methyl, ethyl, trifluoromethyl or
pentafluoroethyl group in .beta.-position; and either [0028]
R.sup.14 means a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with up to 10 carbon atoms in .alpha.- or .beta.-position or
a hydrogen atom in .alpha.- or .beta.-position and [0029] R.sup.15
means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position that can be
interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or
sulfone groups or imino groups=NR.sup.15' (R.sup.15'=hydrogen atom,
methyl, ethyl, propyl, i-propyl) or a hydrogen atom or [0030]
R.sup.14 and R.sup.15 together mean a 14.alpha.,15.alpha.-methylene
or 14.beta.,15.beta.-methylene group that is optionally substituted
with one or two halogen atoms; [0031] R.sup.16 means a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position, a
trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a
hydrogen atom in .alpha.- or .beta.-position; [0032] R.sup.17 means
a halogen atom in .alpha.- or .beta.-position, a straight-chain or
branched-chain, saturated or unsaturated, optionally partially or
completely fluorinated alkyl group with up to 10 carbon atoms in
.alpha.- or .beta.-position, a hydrogen atom or a hydroxyl group
and the dotted lines - - - in rings B, C and D optionally mean one
or more double bonds, and the wavy lines mean the arrangement of
the respective substituent in .alpha.- or .beta.-position, for
treatment of estrogen-deficiency-induced diseases and
conditions.
[0033] According to a variant of the invention, preferably
compounds of general formula I are used,
in which radicals R.sup.1 to R.sup.17, independently of one
another, have the following meanings
[0034] R.sup.1 means a fluorine atom, a hydroxyl group, a methyl
group, a trifluoromethyl group, a methoxy group, an ethoxy group or
a hydrogen atom; [0035] R.sup.2 means a fluorine atom, a hydroxyl
group, a methoxy or ethoxy group or a hydrogen atom; [0036] R.sup.4
means a fluorine atom, a methyl, ethyl, trifluoromethyl, methoxy or
ethoxy group or a hydrogen atom; [0037] R.sup.7 means a fluorine
atom in .alpha.- or .beta.-position, a methyl, ethyl, propyl or
i-propyl group in .alpha.- or .beta.-position, a trifluoromethyl
group in .alpha.- or .beta.-position or a hydrogen atom; [0038]
R.sup.8 means a hydrogen atom in .alpha.- or .beta.-position, a
methyl or ethyl group in .alpha.- or .beta.-position; [0039]
R.sup.9 means a hydrogen atom in .alpha.- or .beta.-position, a
methyl, ethyl, trifluoromethyl or pentafluoroethyl group in
.alpha.- or .beta.-position; [0040] R.sup.11 means a nitrooxy group
in .alpha.- or .beta.-position, a hydroxyl group in .alpha.- or
.beta.-position, a fluorine atom in .alpha.- or .beta.-position, a
choromethyl group in .alpha.- or .beta.-position, a methyl group in
.alpha.- or .beta.-position, a methoxy group in .alpha.- or
.beta.-position, a phenyl- or 3-methylthien-2-yl radical in
.alpha.- or .beta.-position or a hydrogen atom; [0041] R.sup.13
means a methyl or ethyl group in .beta.-position; and either [0042]
R.sup.14 means a hydrogen atom in .alpha.- or .beta.-position or a
methyl group in .alpha.- or .beta.-position and [0043] R.sup.15
means a fluorine atom in .alpha.- or .beta.-position, a methyl
group in .alpha.- or .beta.-position, or a hydrogen atom, or [0044]
R.sup.14 and R.sup.15 together mean a 14.alpha.,15.alpha.-methylene
group or a 14.beta.,15.beta.-methylene group; [0045] R.sup.16 means
a methyl, ethyl, ethinyl, propinyl or trifluoromethyl group; [0046]
R.sup.17 means a fluorine atom in .alpha.- or .beta.-position, a
methyl group, a hydrogen atom or a hydroxyl group, and the dotted
lines - - - in rings B, C and D optionally mean an additional
double bond between carbon atoms 9 and 11.
[0047] In addition to the above use of the compounds of general
formula I, the invention also relates to the compounds of general
formula I' themselves. These are the compounds of general formula I
excluding the compounds estra-1,3,5(10)-triene-3,16.alpha.-diol,
estra-1,3,5(10)-triene-3,16.beta.-diol, estra-1,3,5(10),
7-tetraene-3,16.alpha.-diol as well as estra-1,3,5(10),
7-tetraene-3,16.beta.-diol. These last-mentioned compounds are
already known; a selective estrogenic action and its use in the
context of this invention has not yet been described, however.
[0048] 16.alpha.-Hydroxy-17-methylene estrogens were described as
compounds that have an anti-inflammatory action and that are
suitable for the therapy of immunological diseases, especially
auto-immune diseases (WO 97/08188).
[0049] A differentiated action of 16.alpha.-hydroxyestrone was
already described by Westerlind et al., see above, but not a
different action between the brain functions and the vascular
system, on the one hand, and on the uterus, on the other.
[0050] 3,16.alpha.-Dihydroxy-estratriene was already described by
Stack and Gorski as "estrogen that has a short-term effect" (Stack,
Gorski 1985).
[0051] Nothing is known to date on a use of this last-mentioned
compound as a selective estrogen.
[0052] In the compounds of general formulas I and I' as well as in
partial structures II and II' that are described below, a fluorine,
chlorine, bromine or iodine atom can always stand for a halogen
atom; a fluorine atom is preferred in each case.
[0053] The alkoxy groups in the compounds of general formulas I and
I' as well as in partial structures II and II' that are described
below can contain 1 to 6 carbon atoms in each case, whereby
methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are
preferred.
[0054] As representatives of the alkylthio groups, for example,
methylthio, ethylthio and trifluoromethylthio groups can be
mentioned.
[0055] Within the context of this invention, an aryl radical is a
phenyl, 1- or 2-naphthyl radical; the phenyl radical is
preferred.
[0056] Unless expressly indicated, aryl always also includes a
heteroaryl radical. Examples of a heteroaryl radical are the 2-, 3-
or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or
3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4-
or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.
[0057] As substituents for an aryl or heteroaryl radical, for
example, a methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-,
trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-,
halogen-(fluorine, chlorine, bromine, iodine), hydroxy-, amino-,
mono(C.sub.1-8 alkyl) or di(C.sub.1-8 alkyl)amino, whereby both
alkyl groups are identical or different, di(aralkyl)amino, whereby
both aralkyl groups are identical or different, can be
mentioned.
[0058] As representatives of straight-chain or-branched-chain alkyl
groups with 1-10 carbon atoms, for example, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl,
neopentyl, heptyl, hexyl, decyl can be mentioned; methyl, ethyl,
propyl and isopropyl are preferred.
[0059] The alkyl groups can be partially or completely fluorinated
or substituted by 1-5 halogen atoms, hydroxy groups or
C.sub.1-C.sub.4 alkoxy groups.
[0060] As perfluorinated alkyl groups, for example,
trifluoromethyl, pentafluoroethyl and nonafluorobutyl can be
mentioned. Representatives of partially fluorinated alkyl groups
are, for example, 2,2,2-trifluoroethyl,
5,5,5,4,4-pentafluoropentyl, 9,9,9,8,8,7,7,6,6-nonafluorohexyl,
etc.
[0061] Monochloromethylene, monofluoromethylene or
difluoromethylene can stand for the halogen-substituted
14,15-methylene group.
[0062] Other variants of the invention provide one or more
conjugated double bonds in rings B, C and D of the estratriene
skeleton:
[0063] A double bond between C atoms 6 and 7 or between C atoms 7
and 8 or between C atoms 8 and 9 or between C atoms 9 and 11 or
between C atoms 8 and 14 or between C atoms 14 and 15 or double
bonds between C atoms 6 and 7 and C atoms 8 and 9 or between C
atoms 8 and 9 and C atoms 14 and 15 or between C atoms 6 and 7, C
atoms 8 and 9 and C atoms 11 and 12 or between C atoms 6 and 7, C
atoms 8 and 9 and C atoms 14 and 15 or between C atoms 6 and 7, C
atoms 8 and 9, C atoms 11 and 12 and C atoms 14 and 15.
[0064] One or both hydroxyl groups at C atoms 3 and 16 can be
esterified with an aliphatic, straight-chain or branched-chain,
saturated or unsaturated C.sub.1-C.sub.14 mono- or polycarboxylic
acid or an aromatic carboxylic acid or with an .alpha.- or
.beta.-amino acid.
[0065] Suitable as such carboxylic acids for esterification are,
for example:
[0066] Monocarboxylic acids: formic acid, acetic acid, propionic
acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid,
pivalic acid, lauric acid, myristic acid, acrylic acid, propiolic
acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic
acid, elaidic acid.
[0067] Dicarboxylic acids: oxalic acid, malonic acid, succinic
acid, glutaric acid, adipic acid, pimelic acid, suberic acid,
azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic
acid, citraconic acid, and mesaconic acid.
[0068] Aromatic carboxylic acids: benzoic acid, phthalic acid,
isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and
p-toluic acid, hydratropic acid, atropic acid, cinnamic acid,
nicotinic acid, and isonicotinic acid.
[0069] As amino acids, the representatives of these classes of
substances that are known sufficiently to one skilled in the art
are suitable, for example, alanine, .beta.-alanine, arginine,
cysteine, cystine, glycine, histidine, leucine, isoleucine,
phenylalanine, proline, etc.
[0070] The 16-oxy group in the compounds according to the invention
and the structural parts that are described below can be both in
.alpha.-position and in .beta.-position.
[0071] A variant of the invention provides that in compounds of
general formulas I and I' as well as in the structural parts of
formula II' [0072] R.sup.7 means a halogen atom in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with up to 10 carbon atoms in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated alkoxy
group with up to 6 carbon atoms and/or an optionally substituted
aryl or heteroaryl radical and
[0073] R.sup.1, R.sup.2, R.sup.4, R.sup.8, R.sup.9, R.sup.11,
R.sup.14 , R.sup.15, R.sup.16 and R.sup.17 in each case mean a
hydrogen atom.
[0074] According to another embodiment of the invention, in the
compounds of general formulas I and I', and in the structural parts
of formula II' [0075] R.sup.11 means a nitrooxy group in .alpha.-
or .beta.-position, a hydroxyl or mercapto group in .alpha.- or
.beta.-position, a halogen atom in .alpha.- or .beta.-position, a
chloromethyl group in .alpha.- or .beta.-position, a straight-chain
or branched-chain, saturated or unsaturated, optionally partially
or completely fluorinated alkyl group with up to 10 carbon atoms in
.alpha.- or .beta.-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 [0076] R.sup.1, R.sup.2, R.sup.4, R.sup.7, R.sup.8,
R.sup.9, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 in each case
mean a hydrogen atom.
[0077] Another configuration of the compounds of general formulas I
and I' as well as the structural parts of formula II' provides that
[0078] R.sup.15 means a halogen atom in .alpha.- or .beta.-position
or a straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position that can be
interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or
sulfone groups or imino groups=NR.sup.15' (R.sup.15'=hydrogen atom,
methyl, ethyl, propyl, i-propyl), and
[0079] R.sup.1, R.sup.2, R.sup.4, R.sup.7, R.sup.8, R.sup.9,
R.sup.11, R.sup.14, R.sup.16 and R.sup.17 in each case mean a
hydrogen atom.
[0080] In another variant of the compounds of general formulas I
and I' according to the invention as well as the structural parts
of formula II', [0081] R.sup.7 means a halogen atom in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with up to 10 carbon atoms in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated alkoxy
group with up to 6 carbon atoms or an optionally substituted aryl
or heteroaryl radical, and [0082] R.sup.11 means a nitrooxy group
in .alpha.- or .beta.-position, a hydroxyl- or mercapto group in
.alpha.- or .beta.-position, a halogen atom in .alpha.- or
.beta.-position, a chloromethyl group in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with up to 10 carbon atoms in .alpha.- or .beta.-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 [0083] R.sup.1,
R.sup.2, R.sup.4, R.sup.8, R.sup.9, R.sup.14, R.sup.15, R.sup.16
and R.sup.17 in each case mean a hydrogen atom.
[0084] In another variant of the compounds of general formulas I
and I' according to the invention as well as the structural parts
of formula II', [0085] R.sup.7 stands for a halogen atom in
.alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated, optionally partially or completely
fluorinated alkyl group with up to 10 carbon atoms in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated alkoxy group with up to 6 carbon atoms or an optionally
substituted aryl or heteroaryl radical, and [0086] R.sup.15 stands
for a halogen atom in .alpha.- or .beta.-position or a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position that can be
interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or
sulfone groups or imino groups=NR.sup.15' (R.sup.15'=hydrogen atom,
methyl, ethyl, propyl, i-propyl), and
[0087] R.sup.1, R.sup.2, R.sup.4, R.sup.8, R.sup.9, R.sup.11,
R.sup.14, R.sup.16 and R.sup.17 in each case stand for a hydrogen
atom.
[0088] According to another embodiment of the compounds of general
formulas I and I' according to the invention and the structural
parts of formula II', [0089] R.sup.11 stands for a nitrooxy group
in .alpha.- or .beta.-position, a hydroxyl or mercapto group in
.alpha.- or .beta.-position, a halogen atom in .alpha.- or
.beta.-position, a chloromethyl group in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with up to 10 carbon atoms in .alpha.- or .beta.-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 [0090] R.sup.15 stands
for a halogen atom in .alpha.- or .beta.-position or a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position that can be
interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or
sulfone groups or imino groups=NR.sup.15' (R.sup.15'=hydrogen atom,
methyl, ethyl, propyl, i-propyl), and
[0091] R.sup.1, R.sup.2, R.sup.4, R.sup.7, R.sup.8, R.sup.9,
R.sup.11, R.sup.16, and R.sup.17 in each case stand for a hydrogen
atom.
[0092] There are also embodiments of the compounds of general
formulas I and I' according to the invention as well as the
structural parts of formula II', in which [0093] R.sup.7 means a
halogen atom in .alpha.- or .beta.-position, a straight-chain or
branched-chain, saturated or unsaturated, optionally partially or
completely fluorinated alkyl group with up to 10 carbon atoms in
.alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated alkoxy group with up to 6 carbon atoms or
an optionally substituted aryl or heteroaryl radical, [0094]
R.sup.11 means a nitrooxy group in .alpha.- or .beta.-position, a
hydroxyl or mercapto group in .alpha.- or .beta.-position, a
halogen atom in .alpha.- or .beta.-position, a chloromethyl group
in .alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated, optionally partially or completely
fluorinated alkyl group with up to 10 carbon atoms in .alpha.- or
.beta.-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, [0095]
R.sup.15 means a halogen atom in .alpha.- or .beta.-position, or a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position that can be
interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or
sulfone groups or imino groups=NR.sup.15' (R.sup.15'=hydrogen atom,
methyl, ethyl, propyl, i-propyl), and
[0096] R.sup.1, R.sup.2, R.sup.4, R.sup.8, R.sup.9, R.sup.14,
R.sup.16 and R.sup.17 in each case mean a hydrogen atom.
[0097] In the variants of the compounds of general formula I
according to the invention that are indicated above as well as the
partial structures of general formula II', [0098] R.sup.7
preferably stands for a fluorine atom in .alpha.- or
.beta.-position, a methyl, ethyl, propyl or i-propyl group in
.alpha.- or .beta.-position, a trifluoromethyl group in .alpha.- or
.beta.-position or a hydrogen atom; [0099] R.sup.11 preferably
stands for a nitrooxy group in .alpha.- or .beta.-position, a
hydroxyl group in .alpha.- or .beta.-position, a fluorine atom in
.alpha.- or .beta.-position, a chloromethyl group in .alpha.- or
.beta.-position, a methyl group in .alpha.- or .beta.-position, a
methoxy group in .alpha.- or .beta.-position, a phenyl or
3-methylthien-2-yl radical in .alpha.- or .beta.-position or a
hydrogen atom and [0100] R.sup.15 preferably stands for a fluorine
atom in .alpha.- or .beta.-position, a methyl group in .alpha.- or
.beta.-position or a hydrogen atom.
[0101] Preferred according to this invention are the compounds
below: [0102]
14.alpha.,15.alpha.-Methylen-estra-1,3,5(10)-triene-3,16.alpha.-d-
iol [0103]
14.beta.,15.beta.-Methylen-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0104]
14.beta.,15.beta.-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16.alp-
ha.-diol, [0105] Estra-1,3,5(10),8(9)-tetraene-3,16.alpha.-diol,
[0106] Estra-1,3,5(10),8(14)-tetraene-3,16.alpha.-diol, [0107]
Estra-1,3,5(10),6,8-pentaene-3,16.alpha.-diol, [0108]
7.alpha.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol, [0109]
11.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol, [0110]
7.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0111]
11.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol, [0112]
8.alpha.-Estra-1,3,5(10)-triene-3,16.alpha.-diol [0113]
Estra-1,3,5(10)-triene-2,3,16.alpha.-triol [0114]
17.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol, [0115]
18a-Homo-estra-1,3,5(10)-triene-3,16.alpha.-diol, [0116]
18a-Homo-estra-1,3,5(10),8(9)-tetraene-3,16.alpha.-diol, [0117]
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10)-triene-3,16.alpha.--
diol, [0118]
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10),8(9)-tetraene-3,16.-
alpha.-diol, [0119]
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10),6,8-pentaene-3,16.a-
lpha.-diol. [0120]
14.alpha.,15.alpha.-Methylen-estra-1,3,5(10)-triene-3,16.beta.-diol
[0121]
14.beta.,15.beta.-Methylen-estra-1,3,5(10)-triene-3,16.beta.-diol
[0122]
14.beta.,15.beta.-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16.be-
ta.-diol, [0123] Estra-1,3,5(10),8(9)-tetraene-3,16.beta.-diol,
[0124] Estra-1,3,5(10),8(14)-tetraene-3,16.beta.-diol, [0125]
Estra-1,3,5(10),6,8-pentaene-3,16.beta.-diol, [0126]
7.alpha.-Fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol, [0127]
11.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol, [0128]
7.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0129]
11.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol, [0130]
8.alpha.-Estra-1,3,5(10)-triene-3,16.beta.-diol [0131]
Estra-1,3,5(10)-triene-2,3,16.alpha.-triol [0132]
17.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol, [0133]
18a-Homo-estra-1,3,5(10)-triene-3,16.beta.-diol, [0134]
18a-Homo-estra-1,3,5(10),8(9)-tetraene-3,16.beta.-diol, [0135]
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10)-triene-3,16.beta.-d-
iol, [0136]
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10),8(9)-tetraene-3,16.-
beta.-diol, [0137]
18a-Homo-14.alpha.,15.alpha.-methylen-estra-1,3,5(10),6,8-pentaene-3,16.b-
eta.-diol, [0138]
7.alpha.-Ethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0139]
7.alpha.-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0140]
7.alpha.-i-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0141]
7.alpha.-i-Propenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0142]
7.alpha.-Phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0143]
7.alpha.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol [0144]
7.alpha.-Thiomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0145]
7.alpha.-Cyanomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0146]
7.beta.-Ethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0147]
7.beta.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0148]
7.beta.-i-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0149]
7.beta.-i-Propenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0150]
7.beta.-Phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0151]
7.beta.-Methoxy-estra-1,3,5 (10) -triene-3,16.alpha.-diol [0152]
7.beta.-Thiomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0153]
7.beta.-Cyanomethyl -estra-1,3,5(10)-triene-3,16.alpha.-diol [0154]
7.alpha.-Ethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0155]
7.alpha.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0156]
7.alpha.-i-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0157]
7.alpha.-i-Propenyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0158]
7.alpha.-Phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0159]
7.alpha.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol [0160]
7.alpha.-Thiomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0161]
7.alpha.-Cyanomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0162]
7.beta.-Ethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0163]
7.beta.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0164]
7.beta.-i-Propyl-estra-1,3,51(10)-triene-3,16.beta.-diol [0165]
7.beta.-i-Propenyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0166]
7.beta.-Phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0167]
7.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol [0168]
7.beta.-Thiomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0169]
7.beta.-Cyanomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0170]
15.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0171]
15.alpha.-Ethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0172]
15.alpha.-Propyl-estra-1,3,5(10) -triene-3,16.alpha.-diol [0173]
15.alpha.-Allyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0174]
15.alpha.-i-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0175]
15.alpha.-i-Propenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0176]
15.alpha.-Methoxy-estra-1,3,5 (10)-triene-3,16.alpha.-diol [0177]
15.alpha.-Thiomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0178]
15.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0179]
15.alpha.-Ethyl-estra-1,3,5(10) -triene-3,16.beta.-diol [0180]
15.alpha.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0181]
15.alpha.-Allyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0182]
15.alpha.-i-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0183]
15.alpha.-i-Propenyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0184]
15.alpha.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol [0185]
15.alpha.-Thiomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0186]
15.beta.-Methyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0187]
15.beta.-Ethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0188]
15.beta.-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0189]
15.beta.-Allyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0190]
15.beta.-i-Propyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0191]
15.beta.-i-Propenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0192]
15.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol [0193]
15.beta.-Thiomethyl-estra-1,3,5(10)-triene-3,16.alpha.-diol [0194]
15.beta.-Methyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0195]
15.beta.-Ethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0196]
15.beta.-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0197]
15.beta.-Allyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0198]
15.beta.-i-Propyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0199]
15.beta.-i-Propenyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0200]
15.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol [0201]
15.beta.-Thiomethyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0202]
7.alpha.-Trifluoromethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alph-
a.-diol [0203]
7.alpha.-Pentafluoroethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alp-
ha.-diol [0204]
7.alpha.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0205]
7.alpha.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha-
.-diol [0206]
7.alpha.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0207]
7.alpha.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.-
alpha.-diol [0208]
7.alpha.-Phenyl-11.beta.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0209]
7.alpha.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alph-
a.-diol [0210]
7.alpha.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-di-
ol [0211]
7.alpha.-Cyanomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-d-
iol [0212]
7.beta.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0213]
7.beta.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-
-diol [0214]
7.beta.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0215]
7.beta.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.al-
pha.-diol [0216]
7.beta.-Phenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0217]
7.beta.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha-
.-diol [0218]
7.beta.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-dio-
l [0219]
7.beta.-Cyanomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16-
.alpha.-diol [0220]
7.alpha.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0221]
7.alpha.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-
-diol [0222]
7.alpha.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0223]
7.alpha.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.b-
eta.-diol [0224]
7.alpha.-Phenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0225]
7.alpha.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta-
.-diol [0226]
7.alpha.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-dio-
l [0227]
7.alpha.-Cyanomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,1-
6.beta.-diol [0228]
7.beta.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0229]
7.beta.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.--
diol [0230]
7.beta.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0231]
7.beta.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.be-
ta.-diol [0232]
7.beta.-Phenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0233]
7.beta.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-
-diol [0234]
7.beta.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0235]
7.beta.-Cyanomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.-
beta.-diol [0236]
15.alpha.-Methyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0237]
15.alpha.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha-
.-diol [0238]
15.alpha.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0239]
15.alpha.-Allyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha-
.-diol [0240]
15.alpha.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-dio-
l [0241]
15.alpha.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,1-
6.alpha.-diol [0242]
15.alpha.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0243]
15.alpha.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16-
.alpha.-diol [0244]
15.alpha.-Methyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0245]
15.alpha.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-
-diol [0246]
15.alpha.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0247]
15.alpha.-Allyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-
-diol [0248]
15.alpha.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0249]
15.alpha.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16-
.beta.-diol [0250]
15.alpha.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0251]
15.alpha.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.-
beta.-diol [0252]
15.beta.-Methyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0253]
15.beta.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-
-diol [0254]
15.beta.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0255]
15.beta.-Allyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-
-diol [0256]
15.beta.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0257]
15.beta.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.-
alpha.-diol [0258]
15.beta.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0259]
15.beta.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.a-
lpha.-diol [0260]
15.beta.-Methyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0261]
15.beta.-Ethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.--
diol [0262]
15.beta.-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0263]
15.beta.-Allyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.--
diol [0264]
15.beta.-i-Propyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0265] 15.beta.-i-Propenyl-11.beta.-fluoro-estra-1,3,5(10
)-triene-3,16.beta.-diol [0266]
15.beta.-Methoxy-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.beta.-diol
[0267]
15.beta.-Thiomethyl-11.beta.-fluoro-estra-1,3,5(10)-triene-3,16.b-
eta.-diol [0268]
14.alpha.,15.alpha.-Methylene-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16-
.alpha.-diol [0269]
14.beta.,15.beta.-Methylene-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.a-
lpha.-diol [0270]
14.beta.,15.beta.-Methylene-7.alpha.-phenyl-estra-1,3,5(10),8(9)-tetraene-
-3,16.alpha.-diol, [0271]
7.alpha.-Phenyl-estra-1,3,5(10),8(9)-tetraene-3,16.alpha.-diol,
[0272]
7.alpha.-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16.alpha.-diol,
[0273]
7.alpha.-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16.alpha.-diol,
[0274]
11.beta.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
[0275]
11.beta.-Fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alph-
a.-diol, [0276]
7.alpha.-Phenyl-8.alpha.-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0277] 7.alpha.-Phenyl-estra-1,3,5(10)-triene-2,3,16.alpha.-triol
[0278]
17.beta.-Fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
[0279]
18a-Homo-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol,
[0280]
18a-Homo-7.alpha.-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16.alph-
a.-diol, [0281]
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10)-tr-
iene-3,16.alpha.-diol, [0282]
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10),8(-
9)-tetraene-3,16.alpha.-diol, [0283]
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10),6,-
8-pentaene-3,16.alpha.-diol, [0284]
14.alpha.,15.alpha.-Methylene-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16-
.beta.-diol [0285]
14.beta.,15.beta.-Methylene-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.b-
eta.-diol [0286]
14.beta.,15.beta.-Methylene-7.alpha.-phenyl-estra-1,3,5(10),8(9)-tetraene-
-3,16.beta.-diol, [0287]
7.alpha.-Phenyl-estra-1,3,5(10),8(9)-tetraene-3,16.beta.-diol,
[0288]
7.alpha.-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16.beta.-diol,
[0289]
7.alpha.-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16.beta.-diol,
[0290]
11.beta.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
[0291]
11.beta.-Fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-
-diol, [0292]
7.alpha.-Phenyl-8.alpha.-estra-1,3,5(10)-triene-3,16.beta.-diol
[0293] 7.alpha.-Phenyl-estra-1,3,5(10)-triene-2,3,16.alpha.-triol
[0294]
17.beta.-Fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
[0295]
18a-Homo-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol,
[0296]
18a-Homo-7.alpha.-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16.beta.-
-diol, [0297]
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10)-tr-
iene-3,16.beta.-diol, [0298]
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10),8(-
9)-tetraene-3,16.beta.-diol, [0299]
18a-Homo-14.alpha.,15.alpha.-methylene-7.alpha.-phenyl-estra-1,3,5(10),6,-
8-pentaene-3,16.beta.-diol, [0300]
15.alpha.-Methyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16
.alpha.-diol [0301]
15.alpha.-Ethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0302]
15.alpha.-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alph-
a.-diol [0303]
15.alpha.-Allyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0304]
15.alpha.-i-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.al-
pha.-diol [0305]
15.alpha.-i-Propenyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-d-
iol [0306]
15.alpha.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0307]
15.alpha.-Thiomethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16-
.alpha.-diol [0308]
15.alpha.-Methyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol
[0309]
15.alpha.-Ethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-
-diol [0310]
15.alpha.-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol
[0311]
15.alpha.-Allyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-
-diol [0312]
15.alpha.-i-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol
[0313]
15.alpha.-i-Propenyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16-
.beta.-diol [0314]
15.alpha.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol
[0315]
15.alpha.-Thiomethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.-
beta.-diol [0316]
15.beta.-Methyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0317]
15.beta.-Ethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-
-diol [0318]
15.beta.-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0319]
15.beta.-Allyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-
-diol [0320]
15.beta.-i-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0321]
15.beta.-i-Propenyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.-
alpha.-diol [0322]
15.beta.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0323]
15.beta.-Thiomethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.a-
lpha.-diol [0324]
15.beta.-Methyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol
[0325]
15.beta.-Ethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.--
diol [0326]
15.beta.-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol
[0327]
15.beta.-Allyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.--
diol [0328]
15.beta.-i-Propyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol
[0329]
15.beta.-i-Propenyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.b-
eta.-diol [0330]
15.beta.-Methoxy-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol
[0331]
15.beta.-Thiomethyl-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,16.b-
eta.-diol [0332]
15.alpha.-Methyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.alpha.-diol [0333]
15.alpha.-Ethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.alpha.-diol [0334]
15.alpha.-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.alpha.-diol [0335]
15.alpha.-Allyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.alpha.-diol [0336]
15.alpha.-i-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-
-3,16.alpha.-diol [0337]
15.alpha.-i-Propenyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trie-
ne-3,16.alpha.-diol [0338]
15.alpha.-Methoxy-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene--
3,16.alpha.-diol [0339]
15.alpha.-Thiomethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trie-
ne-3,16.alpha.-diol [0340]
15.alpha.-Methyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.beta.-diol [0341]
15.alpha.-Ethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.beta.-diol [0342]
15.alpha.-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.beta.-diol [0343]
15.alpha.-Allyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.beta.-diol [0344]
15.alpha.-i-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-
-3,16.beta.-diol [0345]
15.alpha.-i-Propenyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trie-
ne-3,16.beta.-diol [0346]
15.alpha.-Methoxy-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene--
3,16.beta.-diol [0347]
15.alpha.-Thiomethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trie-
ne-3,16.beta.-diol [0348]
15.beta.-Methyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.alpha.-diol [0349]
15.beta.-Ethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.alpha.-diol [0350]
15.beta.-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.alpha.-diol [0351]
15.beta.-Allyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.alpha.-diol [0352]
15.beta.-i-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene--
3,16.alpha.-diol [0353]
15.beta.-i-Propenyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trien-
e-3,16.alpha.-diol [0354]
15.beta.-Methoxy-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3-
,16.alpha.-diol [0355]
15.beta.-Thiomethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trien-
e-3,16.alpha.-diol [0356]
15.beta.-Methyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.beta.-diol [0357]
15.beta.-Ethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.beta.-diol [0358]
15.beta.-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,-
16.beta.-diol [0359]
15.beta.-Allyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene-3,1-
6.beta.-diol [0360]
15.beta.-i-Propyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-triene--
3,16.beta.-diol [0361]
15.beta.-i-Propenyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trien-
e-3,16.beta.-diol [0362]
15-Methoxy-11.beta.-fluoro-7.alpha.-phenyl-estra-13,5(10)-triene-3,16.bet-
a.-diol [0363]
15.beta.-Thiomethyl-11.beta.-fluoro-7.alpha.-phenyl-estra-1,3,5(10)-trien-
e-3,16.beta.-diol [0364]
11.beta.-[2-(3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0365]
11.beta.-[2-(3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,16.beta.-
-diol and of the latter in turn especially the compounds [0366]
7.alpha.-Fluoro-estra-1,3,5(10)-triene-3,16.alpha.-diol, [0367]
7.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.beta.-diol [0368]
7.alpha.-Methyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
18.alpha.-Homo-estra-1,3,5(10)-triene-3,16.alpha.-diol.
[0369] Another aspect of this invention relates to the use of the
structural part of formula II ##STR2## as a component of the total
structure of compounds that have a dissociation in favor of their
estrogenic action on bone rather than the uterus.
[0370] The possible substituents in carbon atoms 7, 8, 9, 11, 13,
14, 15 and 17 can be respectively in .alpha.- or .beta.-position.
The dotted lines - - - in rings B, C and D stand for one or more
possible double bonds between the corresponding carbon atoms.
[0371] This invention preferably relates to those structural parts
of general formula II' ##STR3## in which radicals R.sup.1' to
R.sup.17', independently of one another, have the following
meanings [0372] R.sup.1' means a halogen atom, a hydroxyl group, a
methyl group, a trifluoromethyl group, a methoxy group, an ethoxy
group or a hydrogen atom; [0373] R.sup.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; [0374] R.sup.4' means a halogen atom, a straight-chain or
branched-chain, saturated or unsaturated alkyl group with up to 10
carbon atoms, a trifluoromethyl or pentafluoroethyl group, a
straight-chain or branched-chain, saturated or unsaturated alkoxy
group with up to 6 carbon atoms or a hydrogen atom; [0375] R.sup.7'
means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position, a straight-chain
or branched-chain, saturated or unsaturated alkoxy group with up to
6 carbon atoms, an optionally substituted aryl or heteroaryl
radical or a hydrogen atom; [0376] R.sup.8' means a hydrogen atom
in .alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated, optionally partially or completely
fluorinated alkyl group with up to 10 carbon atoms in .alpha.- or
.beta.-position or a cyano group in .alpha.- or .beta.-position;
[0377] R.sup.9' means a hydrogen atom in .alpha.- or
.beta.-position, a methyl, ethyl, trifluoromethyl or
pentafluoroethyl group in .alpha.- or .beta.-position; [0378]
R.sup.11' means a nitrooxy group in .alpha.- or .beta.-position, a
hydroxyl or mercapto group in .alpha.- or .beta.-position, a
halogen atom in .alpha.- or .beta.-position, a chloromethyl group
in .alpha.- or .beta.-position, a straight-chain or branched-chain,
saturated or unsaturated, optionally partially or completely
fluorinated alkyl group with up to 10 carbon atoms in .alpha.- or
.beta.-position, a straight-chain or branched-chain, saturated or
unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an
optionally substituted aryl or heteroaryl radical or a hydrogen
atom; [0379] R.sup.13' means a methyl, ethyl, trifluoromethyl or
pentafluoroethyl group in .beta.-position; and either [0380]
R.sup.14' means a straight-chain or branched-chain, saturated or
unsaturated, optionally partially or completely fluorinated alkyl
group with up to 10 carbon atoms in .alpha.- or .beta.-position or
a hydrogen atom in .alpha.- or .beta.-position and [0381] R.sup.15'
means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position that can be
interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or
sulfone groups or imino groups=NR.sup.15' (R.sup.15'=hydrogen atom,
methyl, ethyl, propyl, i-propyl) or a hydrogen atom or [0382]
R.sup.14' and R.sup.15' together mean a
14.alpha.,15.alpha.-methylene group or a
14.beta.,15.beta.-methylene group that is optionally substituted
with one or two halogen atoms; [0383] R.sup.16' means a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position, a
trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a
hydrogen atom in .alpha.- or .beta.-position; [0384] R.sup.17'
means a halogen atom in .alpha.- or .beta.-position, a
straight-chain or branched-chain, saturated or unsaturated,
optionally partially or completely fluorinated alkyl group with up
to 10 carbon atoms in .alpha.- or .beta.-position, a hydrogen atom
or a hydroxyl group,
[0385] and the dotted lines - - - in rings B, C and D optionally
mean one or more double bonds, and the wavy lines mean the
arrangement of the respective substituent in .alpha.- or
.beta.-position.
[0386] In this patent application, novel structures for selective
estrogens are described, which have in vitro dissociation with
respect to binding to estrogen receptor preparations of rat
prostates and rat uteri and which have in vivo dissociation with
respect to bone action rather than uterus action: the substances
act in a bone-protective manner over a wide dose range without
stimulating the uterus. In the same dose range, their liver action
is small. In addition, the substances exert estrogen-like action on
the vascular system and brain functions.
[0387] The invention also relates to pharmaceutical preparations
that contain at least one compound of general formula I (or
physiologically compatible addition salts with organic and
inorganic acids of them) and the use of these compounds for the
production of pharmaceutical agents, especially for the indications
below.
[0388] The compounds can be used for the following indications both
after oral and parenteral administration.
[0389] The novel selective estrogens that are described in this
patent can be used as individual components in pharmaceutical
preparations or in combination especially with antiestrogens or
gestagens. Especially preferred is the combination of selective
estrogens with ER.alpha.-selective antiestrogens, or with
antiestrogens that are peripherally-selectively active, i.e., that
do not pass through the blood-brain barriers.
[0390] The substances and the pharmaceutical agents that contain
them are especially suitable for the treatment of peri- and
postmenopausal symptoms, especially hot flashes, sleep
disturbances, irritability, mood swings, incontinence, vaginal
atrophy, and hormone-deficiency-induced emotional diseases. The
substances for hormone substitution and therapy of
hormone-deficiency-induced symptoms in the case of surgical,
medicinal or ovarian dysfunction that is caused in some other way
are also suitable. Prevention of bone mass loss in postmenopausal
women, in women who have undergone hysterectomies or in women who
were treated with LHRH agonists or LHRH antagonists is also part of
this.
[0391] The compounds are also suitable for alleviating symptoms of
male menopause and female menopause, i.e., for male and female
hormone replacement therapy (HRT), specifically both for prevention
and for treatment, in addition for treatment of symptoms that are
accompanied by a dysmenorrhea as well as for treatment of acne.
[0392] In addition, the substances can be used for prophylaxis
against hormone-deficiency-induced bone mass loss and osteoporosis,
for prevention of cardiovascular diseases, especially vascular
diseases such as arteriosclerosis, for prevention of the
proliferation of arterial smooth muscle cells, for treatment of
primary pulmonary high blood pressure and for prevention of
hormone-deficiency-induced neurodegenerative diseases, such as
Alzheimer's disease, as well as hormone-deficiency-induced
impairment of memory and learning capacity.
[0393] In addition, the substances can be used for treatment of
inflammatory diseases and diseases of the immune system, especially
auto-immune diseases, such as, e.g., rheumatoid arthritis.
[0394] In addition, the compounds can be used for the treatment of
male fertility disorders and prostatic diseases.
[0395] The compounds can also be used in combination with the
natural vitamin D3 or with calcitriol analogues for bone formation
or as supporting therapies to therapies that cause bone mass loss
(for example, therapy with glucocorticoids, chemotherapy).
[0396] Finally, the compounds of general formula I can be used in
connection with progesterone receptor antagonists, specifically
especially for use in hormone replacement therapy and for treatment
of gynecological disorders.
[0397] A therapeutic product that contains an estrogen and a pure
antiestrogen for simultaneous, sequential or separate use for the
selective estrogen therapy of perimenopausal or postmenopausal
conditions is already described in EP-A 0 346 014.
[0398] The amount of a compound of general formula I that is to be
administered varies within a wide range and can cover any effective
amount. On the basis of the condition that is to be treated and the
type of administration, the amount of the compound that is
administered can be 0.01 .mu.g/kg-10 mg/kg of body weight,
preferably 0.04 .mu.g/kg-1 mg/kg of body weight, per day.
[0399] In humans, this corresponds to a dose of 0.8 .mu.g to 800
mg, preferably 3.2 .mu.g to 80 mg, daily.
[0400] According to the invention, a dosage unit contains 1.6 .mu.g
to 200 mg of one or more compounds of general formula I.
[0401] The compounds according to the invention and the acid
addition salts are suitable for the production of pharmaceutical
compositions and preparations. The pharmaceutical compositions or
pharmaceutical agents contain as active ingredient one or more of
the compounds according to the invention or their acid addition
salts, optionally mixed with other pharmacologically or
pharmaceutically active substances. The production of the
pharmaceutical agents is carried out in a known way, whereby the
known and commonly used pharmaceutical adjuvants as well as other
commonly used vehicles and diluents can be used.
[0402] As such vehicles and adjuvants, for example, those are
suitable that are recommended or indicated in the following
bibliographic references as adjuvants for pharmaceutics, cosmetics
and related fields: Ullmans Encyklopadie der technischen Chemie
[Ullman's Encyclopedia of Technical Chemistry], Volume 4 (1953),
pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52
(1963), page 918 ff., issued by Czetsch-Lindenwald, Hilfsstoffe fur
Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and
Related Fields]; Pharm. Ind., Issue 2, 1961, p. 72 and ff.: Dr. H.
P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und
angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics,
Cosmetics and Related Fields], Cantor K G, Aulendorf in Wurttemberg
1971.
[0403] The compounds can be administered orally or parenterally,
for example intraperitoneally, intramuscularly, subcutaneously or
percutaneously. The compounds can also be implanted in the
tissue.
[0404] For oral administration, capsules, pills, tablets, coated
tablets, etc., are suitable. In addition to the active ingredient,
the dosage units can contain a pharmaceutically compatible vehicle,
such as, for example, starch, sugar, sorbitol, gelatin, lubricant,
silicic acid, talc, etc.
[0405] For parenteral administration, the active ingredients can be
dissolved or suspended in a physiologically compatible diluent. As
diluents, very often oils with or without the addition of a
solubilizer, a surfactant, a suspending agent or an emulsifying
agent are used. Examples of oils that are used are olive oil,
peanut oil, cottonseed oil, soybean oil, castor oil and sesame
oil.
[0406] The compounds can also be used in the form of a depot
injection or an implant preparation, which can be formulated so
that a delayed release of active ingredient is made possible.
[0407] As inert materials, implants can contain, for example,
biodegradable polymers, or synthetic silicones such as, for
example, silicone rubber. In addition, for percutaneous
administration, the active ingredients can be added to, for
example, a patch.
[0408] For the production of intravaginal systems (e.g., vaginal
rings) or intrauterine systems (e.g., pessaries, coils, IUDs,
Mirena.RTM.) that are loaded with active compounds of general
formula I for local administration, various polymers are suitable,
such as, for example, silicone polymers, ethylene vinyl acetate,
polyethylene or polypropylene.
[0409] To achieve better bio-availability of the active ingredient,
the compounds can also be formulated as cyclodextrin clathrates.
For this purpose, the compounds are reacted with .alpha.-, .beta.-,
or .gamma.-cyclodextrin or derivatives of the latter
(PCT/EP95/02656).
[0410] According to the invention, the compounds of general formula
I can also be encapsulated with liposomes.
Methodology
Estrogen Receptor Binding Studies
[0411] The binding affinity of the new selective estrogens was
tested in competitive experiments with use of 3H-estradiol as a
ligand to estrogen receptor preparations of rat prostates and rat
uteri. The preparation of prostate cytosol and the estrogen
receptor test with prostate cytosol was carried out as described by
Testas et al. (1981) (Testas, J. et al., 1981, Endocrinology 109:
1287-1289).
[0412] The preparation of rat uterus cytosol, as well as the
receptor test with the ER-containing cytosol were basically
performed as described by Stack and Gorski, 1985 (Stack, Gorski
1985, Endocrinology 117, 2024-2032) with some modification as
described in Fuhrmann et al. (1995) (Fuhrmann, U. et al. 1995,
Contraception 51: 45-52).
[0413] The substances that are described in this patent have higher
binding affinity to the estrogen receptor of rat prostates than to
estrogen receptors of rat uteri. In this case, it is assumed that
ER.beta. predominates in the rat prostates over ER.alpha., and
ER.alpha. predominates in rat uteri over ER.beta.. Table 1 shows
that the ratio of the binding to prostate and uterus receptors
qualitatively coincides with the quotient of relative binding
affinity (RBA) to human ER.beta. and ER.alpha. of rats (according
to Kuiper et al. (1996), Endocrinology 138: 863-870) (Table 1).
[0414] Some studies with human estrogen receptors .alpha. and
.beta., which were produced by means of the Baculovirus/SF-9
expression is system, confirm the agreement of the `RBA
prostate-ER/RBA uterus-ER` ratio with the `RBA ER.beta./RBA
ER.alpha.` quotient (Table 2).
[0415] In addition, the predictability of the `prostate-ER versus
the uterus-ER test system` was confirmed with respect to
tissue-selective action by in vivo studies. Substances with a
preference for prostate-ER are dissociated in vivo with respect to
bone and uterus action in favor of action on bones.
Bone Studies
[0416] Three-month-old female rats are ovariectomized and treated
once daily with the test compound immediately after the operation
for 28 days. The administration is carried out subcutaneously in
arachis oil/ethanol. The animals are sacrificed on the day after
the last administration, and tibia as well as uteri are removed.
The uteri are weighed, fixed and worked up for histological
studies. The determination of bone density is carried out ex vivo
on prepared long bones by means of pQCT (quantitative computer
tomography). The measurements are made at a distance of 4-6 mm from
the ball of the joint of the proximal tibia.
[0417] The ovariectomy reduces the density of the trabecular bone
in the measured area by about 400 mg of Ca.sup.2+/cm.sup.3 to about
300 mg of Ca.sup.2+/cm.sup.3. By treatment with a compound of
general formula I according to this invention, the degradation of
the bone density is prevented or inhibited. The bone density in the
proximal tibia was measured.
[0418] Table 3 shows the results for the compound
estra-1,3,5(10)-triene-3,16.alpha.-diol that is to be used
according to the invention. In accordance with the higher binding
affinity to ER.beta. than to ER.alpha., [ER.beta. (RBA)/ER.alpha.
(RBA)=6] shows a higher binding affinity to the estrogen receptor
of rat prostates [ER(RBA)=50] than to the estrogen receptor of rat
uteri [ER(RBA)=9]. Estra-1,3,5(10)-triene-3,16.alpha.-diol reflects
this in vivo in the greatly different amounts, which produce a 50%
bone protection [3 .mu.g/animal] or a 50% uterus stimulation [30
.mu.g/animal], relative to the bone mass loss, which can be
measured in ovariectomized, untreated female rats 28 days after the
ovariectomy unlike in intact animals that are subjected to sham
operations.
[0419] The vascular action of the estrogens according to the
invention is determined in the model of the ApoE-knockout mouse, as
described by R. Elhage et al., 1997, (Elhage, R. et al. 1997,
Arteriosclerosis, Thrombosis and Vascular Biology 17:
2679-2684).
[0420] To detect the action of estrogens in the brain function, the
oxytocin receptor mRNA expression is used as a surrogate parameter
(Hrabovszky, E. et al. 1998, Endocrinology 1339: 2600-2604).
Ovariectomized rats are treated for 7 days with the test substance
or vehicle (administration: subcutaneous or oral, six times daily).
On day 7 after the first administration, the animals are
decapitated, the uterus weight is determined, and the oxytocin
receptor mRNA level is studied by means of in situ hybridization in
suitable brain sections. The ED.sub.50 values are determined with
respect to stimulation of uterus growth and induction of the
oxytocin receptor mRNA.
Production of the Compounds According to the Invention
[0421] For the production of the compounds according to the
invention, i.e., modified/substituted derivatives of
estra-1,3,5(10)-triene-3,16.xi.-diols, mainly two generally
applicable synthesis strategies are used.
[0422] On the one hand, especially 3,16-protected derivatives of
estra-1,3,5(10)-triene-3,16.xi.-diols can be used, however,
optionally also the free diols can be used for modifications to
individual positions of the skeleton. The synthesis of 11-nitrate
esters represents a typical example. The known diacetate of
estra-1,3,5(10)-triene-3,16.beta.-diol (J. Biol. Chem. 1955, 213,
343), which first is oxidized in C(9) and C(11)-positions according
to a method by Sykes et al. (Tetrahedron Letters 1971, 3393), forms
the starting point. The reductive removal of the benzylic
C(9)-hydroxyl group already yields the 11-nitrate ester of
estra-1,3,5(10)-triene-3,11.beta.,16.beta.-triol that is protected
as a diacetate. After saponification, the epimeric 11-nitrate ester
of estra-1,3,5(10)-triene-3,16.alpha.-diol then results from an
inversion of the C(16)-hydroxyl group. The synthesis diagram that
is outlined above can also run in reverse, if the diacetate of the
estra-1,3,5(10)-triene-3,16.alpha.-diol is selected as a starting
point. In this way, the 11-nitrate ester in the 16.alpha.-hydroxy
series is produced first. Other compounds that result from
intermediate products, such as, e.g., 11-nitrate esters of
estra-1,3,5(10)-triene-3,9,11.beta.-16.xi.-tetraole are also
obtained after cleavage of protective groups at C(3), C(16).
[0423] On the other hand, corresponding modified estrone analogs,
which can be obtained in large numbers in known methods
(characteristic but not limiting synthesis processes, which are
useful for provision of representative substation patterns in the
estrone skeleton, also in combination in several substituents, are
found in, for example, C(1) J. Chem. Soc. (C) 1968, 2915; C(7)
Steroids 54, 1989, 71; C(8.alpha.) Tetrahedron Letters 1991, 743;
C(8.beta.) Tetrahedron Letters 1964, 1763; Tetrahedron 1969, 25,
4011; J. Org. Chem. 1970, 35, 468; C(11) J. Steroid Biochem. 31,
1988, 549; C(9) J. Chem. Soc. Perk. 1 1973, 2095; C(15) J. Chem.
Soc. Perk. 1 1996, 1269), offer flexible access to the compounds
according to the invention by transposition of the oxygen
functionality (Z. Chem. 1970, 221) of C(17) to C(16). Such novel
derivatives of estrone are also suitable for this purpose,
however.
[0424] For the case of C(3)-methyl ether of
8.alpha.-estra-1,3,5(10)-trien-17-one (Bull. Soc. Chim. Fr. 1967,
561), an in-depth typical description is given. After the ketone is
converted into a sulfonylhydrazone, in the simplest case by
reaction with phenylsulfonyl hydrazide, the formation of the
C(16)-C(17) olefin is carried out in a decomposition reaction (Z.
Chem. 1970, 10, 221-2; Liebigs Ann. Chem. 1981, 1973-81), on which
hypobromide is stored in a regio/stereocontrolled way. Reductive
dehalogenation and removal of the protective group at C(3) produce
the 16.beta.-alcohol, which can be converted into the
16.alpha.-epimer according to known methods.
[0425] Another variant for the introduction of the hydroxyl group
to C atom 16 exists in the hydroboration of the 16(17)-double bond
with sterically exacting boranes. It is known of this reaction that
it results in 16-oxygenated products (Indian J. Chem. 1971, 9,
287-8). Consequently, the reaction of
3-methoxyestra-1,3,5(10),16-tetraene and
3-methoxy-18a-homoestra-1,3,5(10),16-tetraene with
9-borabicyclo[3.3.1]nonane produces 16.alpha.-hydroxyestratrienes
after oxidation with alkaline hydrogen peroxide. To a lesser
extent, the epimeric 16.beta.-hydroxy steroids are formed in this
reaction. After the cleavage of the 3-methoxy group,
estra-1,3,5(10)-3,16.alpha.-diols are obtained. By inversion of the
configuration at C atom 16, e.g., by Mitsunobu reaction (Synthesis
1980, 1), the 16.beta.-hydroxyestratrienes are in turn
obtained.
[0426] The broad applicability of the synthesis method that is
outlined above is demonstrated in additional examples, thus, for
example, for 3-methoxy-7.alpha.-methylestra-1,3,5(10)-trien-17-one
(Helv. Chim. Acta 1967, 281) or
1,3-dimethoxy-1,3,5(10)-trien-17-one (J. Org. Chem. 1967, 32,
4078).
[0427] The production of the central C(16)-C(17) olefinic
intermediate stages is not limited to the arylsulfonylhydrazone
method. If substituents on the steroid skeleton are not compatible
with the basic reaction conditions of olefination, other processes,
especially the conversion of the C(17) ketones into vinyl iodide
(Tetrahedron 1988, 147) or enol triflates (Tetrahedron Letters
1984, 4821) and their subsequent reduction are suitable as
alternatives.
[0428] If a synthesis pathway that runs through C(16)-keto
derivatives, which then are converted into C(16)-alcohols or, by
inversion, into C(16)a-alcohols, is selected, the possibilities for
C(17). -.fwdarw. C(16)-ketotransposition are also selected. For a
concrete example, refer to J. Chem. Soc. Perk. 1, 1976, 1350.
[0429] The introduction of fluorine atoms on carbon atoms 15 and 17
of the 16-hydroxyestratrienes according to the invention is
possible by hydroboration of 15-fluoroestra-1,3,5(10),16-tetraenes
or 17-fluoroestra-1,3,5(10),16-tetraenes with a sterically exacting
borane and oxidation with alkaline hydrogen peroxide. The synthesis
of 15-fluoroestra-1,3,5(10),16-tetraenes can be carried out from,
for example, 15-hydroxyestra-1,3,5(10)-trien-17-ones. First, the
secondary hydroxyl group must be substituted on carbon atom 15 by a
fluorine atom. In this respect, for example, the
15.alpha.-hydroxyestrone that is accessible according to U.S. Pat.
No. 3,375,174 is converted with known processes into
15.beta.-fluoroestrone, by having reacted with diethylamino sulfur
trifluoride or the corresponding 15.alpha.-mesylate being reacted
with tetra-n-butylammonium fluoride (J. Chem. Res. (M) 1979,
4728-55). The thus accessible
15.beta.-fluoroestra-1,3,5(10)-trien-17-ones are converted into
tosyl hydrazones. The Bamford-Stevens reaction of the
15-fluorinated tosyl hydrazones produces the
15-fluoroestra-1,3,5(10),16-tetraenes that are required for the
introduction of the 16-hydroxyl group. The
17-fluoroestra-1,3,5(10),16-tetraenes that are necessary for the
synthesis of 17-fluorinated 16-hydroxyestratrienes are accessible
according to established processes. Corresponding ketones can be
converted into geminal difluorides by reaction with sulfur
tetrafluoride (J. Org. Chem. 1971, 36, 818-20) or
dialkylaminosulfur trifluorides, such as diethylaminosulfur
trifluoride (U.S. Pat. No. 3,976,691). Hydrogen fluoride can be
eliminated from these geminal difluorides by heating with aluminum
oxide in an inert solvent according to U.S. Pat. No. 3,413,321,
whereby fluoro-olefins are obtained. In addition, such
fluoro-olefins can be obtained directly from ketones, if the
ketones are reacted with diethylaminosulfur trifluoride in polar
solvents with the addition of strong acids, e.g., fuming sulfuric
acid (U.S. Pat. No. 4,212,815). The
17-fluoroestra-1,3,5(10),16-tetraen-3-ol that is described in U.S.
Pat. No. 3,413,321 can be converted into a
17.beta.-fluoroestra-1,3,5(10)-trien-3,16.alpha.-ol after the
reaction with a sterically exacting borane and subsequent oxidation
with alkaline hydrogen peroxide.
[0430] As a further modification, the introduction of double bonds
may be useful. In addition to their pharmacological importance as
selective estrogens in the context of this invention, these
unsaturated derivatives represent valuable intermediate products
for the synthesis of novel 16-hydroxyestra-1,3,5(10)-trienes.
Below, the procedure for introducing a 9(11)-double bond is
explained: A-ring-aromatic steroids are converted into the
9.alpha.-hydroxy steroids by dimethyl dioxiram; their dehydration
results in estra-1,3,5(10),9(11)-tetraenes (Tetrahedron 1994, 50,
10709-20). By action of in-situ-produced dimethyl dioxiram on
18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diyldiacetate, the
corresponding 9.alpha.-hydroxy compound can be produced. The
dehydration of this tertiary alcohol results in
18a-homoestra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diyldiacetate.
After saponification,
18a-homoestra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diol is
obtained.
[0431] The compounds of general formula I according to the
invention are produced as described in the examples. Additional
compounds of general formula I can be obtained by an analogous
procedure using reagents that are homologous to the reagents that
are described in the examples.
[0432] Etherification and/or esterification of free hydroxy groups
is carried out according to methods that are common to one skilled
in the art.
[0433] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0434] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
[0435] The entire disclosure of all applications, patents and
publications, cited above, and of corresponding German application
No. 199 06 159.9 filed Feb. 9, 1999, is hereby incorporated by
reference.
EXAMPLE 1
8.alpha.-Estra-1,3,5(10)-triene-3,16.beta.-diol
3-Methoxy-8.alpha.-estra-1,3,5(10)-trien-17-one-17-phenylsulfonylhydrazone
[0436] A suspension of 5.68 g (20 mmol) of
3-methoxy-8.alpha.-estra-1,3,5(10)-trien-17-one and 4.30 g (25
mmol) of benzenesulfonic acid hydrazide in 70 ml of ethanol is
mixed with 3 drops of concentrated hydrochloric acid and then
allowed to react at a bath temperature of 80-90.degree. C. for
three hours while being stirred vigorously. After the reaction
solution is cooled, the precipitated product is suctioned off,
rewashed with a little cold ethanol, and the hydrazone is dried in
a vacuum. 8.10 g (92%) of product, which melts at 183-185.degree.
C., is obtained.
3-Methoxy-8.alpha.-estra-1,3,5(10),16-tetraene
[0437] A suspension of 8.10 g (18.5 mmol) of the above-described
hydrazone in 140 ml of dry ether is cooled in an ice bath in a
moisture-free environment (argon atmosphere) to 0.degree. C. and
mixed drop by drop with 36 ml of methyllithium (57 mmol) in ether.
After the addition is completed, the cold bath is removed and
stirred for another 3 hours at room temperature. For working-up,
the reaction mixture is cooled to 0.degree. C. and carefully mixed
with saturated aqueous ammonium chloride solution (30 ml) while
being stirred vigorously. This mixture is mixed with ethyl acetate,
the organic phase is washed with water/brine and dried on sodium
sulfate. The crude product is chromatographed on silica gel
(hexane/ethyl acetate, 95:5). 3.60 g (72%) of product is
obtained.
17.alpha.-Bromo-3-methoxy-8.alpha.-estra-1,3,5(10)-trien-16.beta.-ol
[0438] 3.40 g (12.67 mmol) of the olefin in 75 ml of dimethyl
sulfoxide is brought into solution, then mixed with 5 ml of water,
and 2.80 g of N-bromosuccinimide (15.75 mmol) in one portion is
added while being stirred vigorously. For working-up after 4.5
hours of reaction at room temperature, the reaction solution is
poured onto water, extracted with ethyl acetate (300 ml), the
organic phase is washed first with water, then with brine and dried
on sodium sulfate. The crude product is chromatographed on silica
gel (toluene/acetone, 9:1), yield 3.50 g (75%) as an oil.
3-Methoxy-8.alpha.-estra-1,3,5(10)-trien-16.beta.-ol
[0439] A solution of 3.50 g (9.60 mmol) of
17.alpha.-bromo-3-methoxy-8.alpha.-estra-1,3,5(10)-trien-16.beta.-ol,
3.50 g (12.03 mmol) of tributyl tin hydride and 50 mg of
azobisisobutyronitrile in 30 ml of dry tetrahydrofuran is refluxed
for 2 hours while being stirred in an argon atmosphere. For
working-up, it is allowed to cool, concentrated by evaporation in a
vacuum in a Rotavapor, and the residue is taken up in ethyl acetate
(300 ml). After the organic phase is washed with aqueous
hydrochloric acid, water and brine, it is dried on sodium sulfate.
The residue is chromatographed on silica gel (dichloromethane/ethyl
acetate, 9:1), yield 2.70 g (98%).
8.alpha.-Estra-1,3,5(10)-triene-3,16.beta.-diol (1)
[0440] A solution of 1.10 g (3.80 mmol) of methyl ether in 35 ml of
diisobutyl aluminum/toluene (1.2 molar solution) is refluxed for 4
hours under an argon atmosphere in a moisture-free environment.
Then, the reaction mixture is cooled in an ice bath and carefully
mixed with ethyl acetate/water while being stirred. The precipitate
that is produced is separated by filtration, thoroughly rewashed
with ethyl acetate, and the organic phase is concentrated in a
vacuum. The crude product is recrystallized from acetone/hexane,
yield 679 mg (65%), melting point 181-182.degree. C., rotation
[.alpha.].sub.D+13.6.degree. (c 0.52, CH.sub.3OH)
EXAMPLE 2
8.alpha.-Estra-1,3,5(10)-triene-3,16.alpha.-diol
3-Methoxy-8.alpha.-estra-1,3,5(10)-trien-16.alpha.-ol
[0441] 1.22 ml (7.85 mmol) of azodicarboxylic acid diethyl ester,
dissolved in 2 ml of toluene, is slowly added in drops to a mixture
of 1.50 g (5.24 mmol) of
3-methoxy-8.alpha.-estra-1,3,5(10)-trien-16.beta.-ol, 2.06 g (7.85
mmol) of triphenylphosphine and 0.3 ml of formic acid in 10 ml of
toluene while being stirred. Then, it is allowed to react for two
hours at room temperature. For working-up, it is taken up in ethyl
acetate (300 ml), the organic phase is washed with water/brine and
dried on sodium sulfate. The crude product is chromatographed on
silica gel (hexane/acetone, gradient of up to 4:1). 1.40 g of
16.alpha.-formate is obtained, which is dissolved in 50 ml of 3%
methanolic potassium hydroxide solution for saponification. After
one hour at room temperature, it is mixed with aqueous hydrochloric
acid, taken up in ethyl acetate (300 ml), the organic phase is
washed with water/brine and dried on sodium sulfate. The crude
product is chromatographed on silica gel (dichloromethane/ethyl
acetate, gradient of up to 7:3), yield 940 mg (63%).
8.alpha.-Estra-1,3,5(10)-triene-3,16.alpha.-diol
[0442] A solution of 740 mg (2.58 mmol) of methyl ether in 25 ml of
diisobutyl aluminum/toluene (1.2 molar solution) is refluxed for 4
hours in a moisture-free environment in an argon atmosphere
(130.degree. bath temperature). Then, the reaction mixture is
cooled in an ice bath and carefully mixed with ethyl acetate/water.
The precipitate is separated by filtration, thoroughly rewashed
with ethyl acetate, and the organic phase is concentrated in a
vacuum. The crude product is recrystallized from acetone/hexane,
yield 323 mg (46%), melting point 239-240.degree. C., rotation
[.alpha.].sub.D+19.8.degree. (c 0.52, CH.sub.3OH)
EXAMPLE 3
7.alpha.-Methylestra-1,3,5(10)-triene-3,16.beta.-diol
3-Methoxy-7.alpha.-methylestra-1,3,5(10)-trien-17-one-17-phenylsulfonylhyd-
razone
[0443] 4.70 g (66%) of the corresponding phenylsulfonylhydrazone,
which crystallizes out during cooling of the reaction mixture, is
produced from 4.70 g (15.75 mmol) of
3-methoxy-7.alpha.-methylestra-1,3,5(10)-trien-17-one, melting
point 167-170.degree. C.
3-Methoxy-7.alpha.-methylestra-1,3,5(10),16-tetraene
[0444] 2.35 g (85%) of olefin, which crystallized from ethanol as
white scales after chromatography on silica gel (hexane/ethyl
acetate, 9:1), resulted from the olefination of 4.40 g (9.72 mmol)
of phenylsulfonylhydrazone, melting point 114-116.degree. C.
17.alpha.-Bromo-3-methoxy-7.alpha.-methylestra-1,3,5(10)-trien-16.beta.-ol
[0445] The bromohydrin formation with 2.00 g (7.08 mmol) of olefin
produced 2.14 g (80%) of adduct, melting point 145-146.degree. C.
(ether/pentane), while being decomposed.
3-Methoxy-7.alpha.-methylestra-1,3,5(10)-trien-16.beta.-ol
[0446] 1.40 g (91%) of product, amorphous, was obtained from 1.94 g
(5.12 mmol) of bromide by reductive dehalogenation.
7.alpha.-Methylestra-1,3,5(10)-triene-3,16.beta.-diol (3)
[0447] The cleavage of 1.40 g (4.66 mmol) of methyl ether provided
1.25 g (92%) of the diol, whose melting point was 209-210.degree.
C. (acetone/hexane), [.alpha.].sub.D+73.8.degree. (c 0.50,
CH.sub.3OH).
EXAMPLE 4
7.alpha.-Methylestra-1,3,5(10)-triene-3,16.alpha.-diol (4)
[0448] It was possible to obtain 0.434 g (59%) of the
16.alpha.-derivative from 0.74 g (2.58 mmol) of 3,16.beta.-diol by
epimerization/saponification at C(16), melting point
217-219.degree. C. (acetone/hexane), [.alpha.].sub.D+84.4.degree.
(c 0.52, CH.sub.3OH)
EXAMPLE 5
1-Methoxyestra-1,3,5(10)-triene-3,16.beta.-diol
1,3-Dimethoxyestra-1,3,5(10)-trien-17-one-17-phenylsulfonylhydrazone
[0449] According to the general recipe for hydrazone formation,
3.14 g (10 mmol) of 1,3-dimethoxyestra-1,3,5(10)-trien-17-one
yielded 4.0 g (85%) of the 17-benzenesulfonic acid hydrazone, which
recrystallized from the ethanolic reaction solution, melting point
200-202.degree. C.
1,3-Dimethoxyestra-1,3,5(10),16-tetraene
[0450] The olefination of 4.0 g (8.54 mmol) of hydrazone resulted
in 1.96 g (76%) of tetraene, which was recrystallized from ethanol
after chromatography, melting point 109-111.degree. C.
1,3-Dimethoxyestra-1,3,5(10) -trien-16.beta.-ol
[0451] 0.872 g (55%) of the 16.beta.-alcohol was obtained from 1.50
g (5.03 mmol) of the olefin by bromohydrin formation and
dehalogenation.
1,3-Dimethoxyestra-1,3,5(10)-trien-16.alpha.-ol
[0452] The inversion of 0.50 g (1.58 mmol) of 16.beta.-alcohol
yielded 0.46 g (92% ) of the 16.alpha.-epimer.
1-Methoxyestra-1,3,5(10)-triene-3,16.beta.-diol (5)
[0453] 0.25 g (0.79 mmol) of 1,3-dimethoxy derivative was
monodemethylated to 0.18 g (75%) of methoxydiol. Melting point
after trituration in toluene 90-93.degree. C.
EXAMPLE 6
1-Methoxyestra-1,3,5(10)-triene-3,16.alpha.-diol (6)
[0454] The demethylation of 0.35 g (1.11 mmol) of dimethoxy
derivative in the 16.alpha.-series produced 0.218 g (65%) of
monomethylether, melting point 240-242.degree. C.
(acetone/chloroform).
EXAMPLE 7
3,11.beta.,16.beta.-Trihydroxyestra-1,3,5(10)-triene-11-nitrate
ester
3,16.beta.-Diacetyloxyestra-1,3,5(10)-triene
[0455] 8.00 g (29.4 mmol) of estra-1,3,5(10)-triene-3,16.beta.-diol
is introduced at room temperature into 50 ml of pyridine, it is
mixed with 10 ml of acetic acid anhydride while being stirred and
then allowed to react overnight. For working-up, the reaction
mixture is put into ice water (3 l), whereby the reaction product
is deposited as precipitate. The precipitate is collected on a
frit, washed thoroughly with distilled water, dried, and finally
taken up in dichloromethane (500 ml). The organic phase is washed
with dilute bicarbonate solution and water and dried on sodium
sulfate. The organic residue is recrystallized from acetone/hexane,
yield 8.40 g (80%).
3,16.beta.-Diacetyloxy-9,11.beta.-dihydroxyestra-1,3,5(10)-triene-11-nitra-
te ester
[0456] A suspension of 7.85 g (22.0 mmol) of
3,16.beta.-diacetyloxyestra-1,3,5(10)-triene in 200 ml of aqueous
acetic acid (90%) is mixed for ten minutes in portions with 60.31 g
(110 mmol) of cerium ammonium nitrate while being stirred. The
steroidal educt goes into solution during the course of the
reaction. After five hours, the reaction solution is poured onto
ice water (6 l), and the yellow-red-colored precipitate is
suctioned off, which is then dried in air. The crude product is
then taken up in ethyl acetate (600 ml), the organic phase is
washed with water/brine and dried on sodium sulfate. The
red-brown-colored crude product is chromatographed on silica gel
(dichloromethane/ethyl acetate, 9:1), yield 5.10 g (53%), melting
point 173-175.degree. C. (acetone/hexane).
3,16.beta.-Diacetyloxyestra-1,3,5(10)-trien-11.beta.-ol-11-nitrate
ester
[0457] 5.0 ml of boron trifluoride-etherate is added in drops to a
solution of 2.42 g (5.58 mmol) of
3,16.beta.-diacetyloxyestra-1,3,5(10)-triene-9,11.beta.-diol-11-nitrate
ester and 2.90 ml (18.31 mmol) of triethylsilane in 60 ml of dry
dichloromethane that is cooled to -15.degree. C. while being
stirred. It is allowed to react first for one hour at -15.degree.
C., then for another hour at 0.degree. C. before the reaction
mixture is stirred into bicarbonate-containing ice water. The
product mixture is extracted with dichloromethane, the organic
phase is washed with water and dried on sodium sulfate. The crude
product is chromatographed on silica gel (hexane/ethyl acetate,
gradient of up to 7:3). Yield 1.58 g (68%), melting point
188-190.degree. C. (acetone/hexane)
3,11.beta.,16.beta.-Trihydroxyestra-1,3,5(10)-triene-11-nitrate
ester (7)
[0458] 1.31 g (3.14 mmol) of the above-described diacetate is taken
up in 60 ml of dichloromethane, mixed with 20 ml of methanolic
potassium hydroxide solution (3%) and stirred for four hours in a
protective gas atmosphere (argon). For working-up, it is mixed with
500 .mu.l of acetic acid, diluted with dichloromethane, the organic
phase is washed with water and dried on sodium sulfate. The crude
product is recrystallized from dichloromethane, yield 874 mg (83%),
melting point 170-171.degree. C., while being decomposed.
[.alpha.].sub.D+68.9.degree. (c 0.52, CH.sub.3OH).
EXAMPLE 8
3,11.beta.,16.alpha.-Trihydroxyestra-1,3,5(10)-triene-11-nitrate
ester (8)
[0459] 2.26 g (8.62 mmol) of triphenylphosphine and 325 .mu.l of
formic acid are added to a solution of 820 mg (2.46 mmol) of
3,16.beta.-diol in 25 ml of dry tetrahydrofuran. Then, 1.34 ml
(8.62 mmol) of azodicarboxylic acid diethyl ester is slowly added
in drops at room temperature to this solution while being stirred.
After addition has been completed, it is stirred for another 30
minutes at room temperature before the reaction solution is poured
onto water and extracted with ethyl acetate. The organic phase is
washed with water/brine and dried on sodium sulfate. The crude
product is taken up in 20 ml of dichloromethane, mixed with 10 ml
of methanolic potassium hydroxide solution (3%) and stirred for 2.5
hours at room temperature in an environment devoid of atmospheric
oxygen. For working-up, it is acidified with dilute hydrochloric
acid, extracted with dichloromethane (200 ml), washed with water
and dried on sodium sulfate. The crude product is chromatographed
on silica gel (dichloromethane/acetone, gradient of up to 4:1),
yield 704 mg (85%) as a foam. [.alpha.].sub.D+71.4.degree. (c 0.50,
CH.sub.3OH)
EXAMPLE 9
18a-Homoestra-1,3,5(10)-triene-3,16.alpha.-diol
3-Methoxy-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol
[0460] 7.41 g of 3-methoxy-18a-homoestra-1,3,5(10),16-tetraene is
dissolved in 50 ml of anhydrous tetrahydrofuran under protective
gas and mixed with 6.4 g of 9-borabicyclo[3.3.1]nonane. It is
stirred at room temperature until reaction has been completed.
Then, it is mixed with 75 ml of water. After gas generation has
been completed, 45 ml of 3 M sodium hydroxide solution is added. 45
ml of hydrogen peroxide solution (30%) is then slowly added in
drops to the reaction mixture while being cooled. It is stirred for
1 hour at room temperature and extracted with ethyl acetate. The
chromatography of the crude product on silica gel (eluant:
cyclohexane/ethyl acetate 3+1) yields 6.03 g of
18.alpha.-homoestra-1,3,5(10)-triene-3,16.alpha.-diol. After
recrystallization from methanol, colorless crystals are obtained;
flash point 109 . . . 111.degree. C.; [.alpha.].sub.D=+71.degree.
(chloroform, c=1.02).
18a-Homoestra-1,3,5(10)-triene-3,16.alpha.-diol (9)
[0461] 2 g of 3-methoxy-18a-homoestra-1,3,5(10)-trien-16.alpha.-ol
is suspended under protective gas in 40 ml of toluene. 26 ml of a
solution of diisobutyl aluminum hydride (30% by vol.) in toluene is
added in drops to this suspension and refluxed until the reaction
has been completed (about 10 hours). 10.6 ml of ethanol and,
carefully while being cooled, 32 ml of semiconcentrated
hydrochloric acid are added to the cooled batch. After extraction
with ethyl acetate, 1.85 g of crude
18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol is obtained.
Recrystallization from ethyl acetate yields 1.34 g of colorless
crystals; flash point 194 . . . 198.degree. C.;
[.alpha.].sub.D=+69.degree. (dioxane, c=0.99).
EXAMPLE 10
18a-Homoestra-1,3,5(10)-triene-3,16.beta.-diol (10)
[0462] 0.5 g of 18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol is
dissolved in 25 ml of toluene with the addition of 3.66 g of
triphenylphosphine and 3.42 g of 4-nitrobenzoic acid. 6.4 ml of
diethylazodicarboxylate solution (40% in toluene) is slowly added
in drops to the above. After 48 hours of reaction at room
temperature, it is diluted with ethyl acetate, and the organic
phase is washed with sodium bicarbonate solution, water and sodium
chloride solution. It is dried on magnesium sulfate and
concentrated by evaporation.
[0463] The product that is obtained is dissolved in 30 ml of
methanol and mixed with 4.82 g of potassium carbonate. It is
stirred at room temperature until saponification has been
completed. For working-up, the main amount of methanol is distilled
off, and the residue is taken up in ethyl acetate. It is washed
with sodium chloride solution and dried on magnesium sulfate. After
concentration by evaporation, 0.45 g of crude
18a-homoestra-1,3,5(10)-triene-3,16.beta.-diol is obtained. The
recrystallization from ethyl acetate yields 0.26 g of colorless
crystals; flash point 210 . . . 213.degree. C.;
[.alpha.].sub.D=+67.degree. (dioxane, c=1.01).
EXAMPLE 11
18a-Homoestra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diol
18a-Homoestra-1,3,5(10)-triene-3,16.alpha.-diyldiacetate
[0464] 1 g of 18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol is
mixed with 4 ml of pyridine and 4 ml of acetic anhydride and 10 mg
of 4-dimethylaminopyridine and allowed to stand overnight. For
working-up, it is mixed with ice and extracted with ethyl acetate.
The combined extracts are washed with copper sulfate solution (10%)
and saturated sodium chloride solution and dried on magnesium
sulfate. 1.32 g of
18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diyldiacetate is
isolated methylene chloride, 18 ml of water, 15 ml of acetone, 5.4
g of sodium bicarbonate and 12 mg of tetra-n-butylammonium hydrogen
sulfate. After temperature equalization to 10.degree. C., 11.1 g of
potassium monopersulfate (Caroat.sup.(R)) is successively added.
The reaction mixture was stirred for 4.5 hours at 10.degree. C.
Then, it was filtered with a frit to separate the salts, and the
organic phase of the filtrate was separated. The aqueous phase is
subsequently re-extracted with methylene chloride, and the combined
extracts are dried on magnesium sulfate. After the solvent is
evaporated, 1.73 g of crude
9.alpha.-hydroxy-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diyldiacetate
is obtained. The latter is dissolved in 12 ml of methylene
chloride. The solution is temperature-equalized to -10.degree. C.
and mixed with 0.16 ml of sulfuric acid (70%). After the reaction
has been completed, it is mixed with saturated sodium bicarbonate,
and the organic phase is separated. After the solvent is dried and
evaporated, 1.33 g of a brown oil is obtained. The purification on
silica gel (eluant: cyclohexane/ethyl acetate 3+1) yields 0.63 g of
18a-homoestra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diyldiacetate as
a colorless foam.
18a-Homoestra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diol (11)
[0465] 0.63 g of
18a-homoestra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diyldiacetate is
dissolved in 50 ml of methanol and mixed with 4.72 g of potassium
carbonate. It is stirred at room temperature until saponification
has been completed. For working-up, the main amount of methanol is
distilled off, and the residue is taken up in ethyl acetate. It is
washed with sodium chloride solution and dried on magnesium
sulfate. After concentration by evaporation, 0.49 g of
18a-homoestra-1,3,5(10),9(11)tetraene-3,16.alpha.-diol is obtained
as a yellowish crystallizate.
EXAMPLE 12
Estra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diol
Estra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diyldiacetate
[0466] Analogously to Example 11, 12.69 g (35.8 mmol; 64% of
theory) of estra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diyldiacetate
is obtained starting from 19.9 g (55.82 mmol) of
estra-1,3,5(10)-triene-3,16.alpha.-diyldiacetate.
Estra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diol
[0467] Analogously to Example 11, 12.5 g (35.26 mmol) of
estra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diyldiacetate is
saponified. 9.53 g (35.26 mmol; 99% of theory) of
estra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diol is obtained as
almost colorless crystallizate. Recrystallization from ethyl
acetate yields colorless crystals; flash point 237 . . .
244.degree. C.; [.alpha.].sub.D=###.degree. (., c=###).
EXAMPLE 13
13.alpha.-Estra-1,3,5(10)-triene-3,16.alpha.-diol
3-Methoxy-17-tosylhydrazono-13.alpha.-estra-1,3,5(10)-triene
[0468] 2.5 g (8.79 mmol) of
3-methoxy-13.alpha.-estra-1,3,5(10)-trien-17-one and 1.96 g (10.55
mmol) of tosylhydrazide are refluxed in 15 ml of a mixture that
consists of ethanol and glacial acetic acid (4+1, v/v) for 6 hours.
The cooled reaction solution is mixed with saturated sodium
bicarbonate solution and extracted with ethyl acetate. The organic
phase is washed with saturated sodium bicarbonate solution and with
saturated sodium chloride solution and dried on magnesium sulfate.
The dark brown oil that is obtained is chromatographed on silica
gel (eluant: cyclohexane/ethyl acetate 4+1). 2.49 g of a colorless,
amorphous solid is obtained; [.alpha.].sub.D=-58.degree. (dioxane,
c=0.99).
3-Methoxy-13.alpha.-estra-1,3,5(10),16-tetraene
[0469] 2.43 g (5.37 mmol) of
3-methoxy-17-tosylhydrazono-13.alpha.-estra-1,3,5(10)-triene is
suspended in 20 ml of anhydrous methyl-tert-butylether. 1.61 ml of
a 10 M n-butyllithium solution in hexane is slowly added in drops
to this suspension. It is stirred for 1 hour at room temperature.
While being cooled, 50 ml of saturated ammonium chloride solution
is added in drops. After the organic phase is separated, it is
extracted with ethyl acetate. The combined organic phases are
washed with water and saturated sodium chloride solution and dried
(MgSO.sub.4). The crude product (2.1 g of brown oil) is
chromatographed on silica gel, whereby 0.81 g of
3-methoxy-13.alpha.-estra-1,3,5(10),16-tetraene is obtained as a
colorless oil; [.alpha.].sub.D=-6.degree. (chloroform; c=0.94).
3-Methoxy-13.alpha.-estra-1,3,5(10)-trien-16.alpha.-ol
[0470] 0.81 g (3 mmol) of
3-methoxy-13.alpha.-estra-1,3,5(10),16-tetraene is dissolved under
a cover gas in 10 ml of anhydrous tetrahydrofuran and mixed with
0.73 g of 9-bora-bicyclo[3.3.1]nonane. It is stirred at room
temperature until the reaction is completed. Then, it is mixed with
15 ml of water. After gas generation is completed, 7.8 ml of 3 M
sodium hydroxide solution is added. 7.8 ml of hydrogen peroxide
solution (30%) is then slowly added in drops to the reaction
mixture while being cooled. It is stirred for 1 hour at room
temperature and extracted with ethyl acetate. The chromatography of
the crude product on silica gel (eluant: cyclohexane/ethyl acetate
4+1) yields 604 mg of
3-methoxy-13.alpha.-estra-1,3,5(10)-trien-16.alpha.-ol in the form
of a colorless oil.
13.alpha.-Estra-1,3,5(10)-triene-3,16.alpha.-diol
[0471] 0.55 g of
3-methoxy-13.alpha.-estra-1,3,5(10)-trien-16.alpha.-ol is dissolved
hot under a cover gas in 10 ml of toluene. A mixture of 2.3 ml of
diisobutylaluminum hydride and 5.4 ml of toluene is added in drops
to this solution and refluxed until the reaction is completed
(about 4 hours). 2.1 ml of ethanol is added to the cooled batch,
and 6 ml of semi-concentrated hydrochloric acid is carefully added
while being cooled. After extraction with ethyl acetate, the
organic phase is washed neutral and dried on magnesium sulfate. 362
mg of 13.alpha.-estra-1,3,5(10)-triene-3,16.alpha.-diol is
obtained. The recrystallization from methanol yields colorless
crystals; flash point 224 . . . 231.degree. C.;
[.alpha.].sub.D=+61.degree. (pyridine, c=1.13).
EXAMPLE 14
9.beta.-Estra-1,3,5(10)-triene-3,16.alpha.-diol
3-Methoxy-17-tosylhydrazono-9.beta.-estra-1,3,5(10)-triene
[0472] Produced analogously to Example 13. Colorless foam.
3-Methoxy-9.beta.-estra-1,3,5(10),16-tetraene
[0473] Produced analogously to Example 13. Colorless oil.
3-Methoxy-9.beta.-estra-1,3,5(10)-trien-16.alpha.-ol
[0474] Produced analogously to Example 13. Colorless oil.
9.beta.-Estra-1,3,5(10)-triene-3,16.alpha.-diol
[0475] Produced analogously to Example 13. Colorless crystals;
flash point 140 . . . 145.degree. C.; [.alpha.].sub.D=###.degree.
(c=).
EXAMPLE 15
3,16.alpha.-Bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-11-one
3,16.alpha.-Bis(benzyloxy)-18a-homoestra-1,3,5(10),9(11)-tetraene
[0476] 4 g of sodium hydride (80% in paraffin oil, 25.52 mmol) is
added under a cover gas to 32 ml of anhydrous
N,N-dimethylformamide. A solution of 7.67 (26.97 mmol) of
18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol in 40 ml of
tetrahydrofuran is added in drops to this mixture. After gas
generation is completed, 13.84 g (80.91 mmol) of benzyl bromide is
added. After the reaction is completed, the reaction solution is
slowly added in drops to water (about 1l). After extraction with
ethyl acetate, 14 g of brown oil is obtained. Chromatography on
silica gel yields 10.2 g (21.9 mmol; 81.3% of theory) of
3,16.alpha.-bis(benzyloxy)-18a-homoestra-1,3,5(10),9(11)-tetraene
as a colorless oil; [.alpha.].sub.D=+110.degree. (chloroform,
c=1.01).
3,16.alpha.-Bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-11.alpha.-ol
[0477] 10 g (21.5 mmol) of
3,16.alpha.-bis(benzyloxy)-18a-homoestra-1,3,5(10),9(11)-tetraene
is dissolved under a cover gas in 60 ml of anhydrous
tetrahydrofuran, and 12.9 g (107.61 mmol) of catechol borane and
0.99 g (43.1 mmol) of lithium borohydride are added. After the
reaction is completed, it is carefully hydrolyzed with 100 ml of
water. 95 ml of 3N sodium hydroxide solution is then added, and 95
ml of hydrogen peroxide (30%) is added in drops while being cooled.
It is stirred for 1 hour at room temperature and subsequently
extracted with ethyl acetate. The chromatography of the crude
product on silica gel (eluant: cyclohexane/ethyl acetate 4+1)
yields 8.73 g (18.08 mmol; 84% of theory) of
3,16.alpha.-bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-11.alpha.-ol
as a colorless foam; [.alpha.].sub.D=###.degree. (., c=###).
3,16.alpha.-Bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-11-one
[0478] 0.89 g (1.84 mmol) of
3,16.alpha.-bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-11.alpha.-ol
is dissolved in 20 ml of methylene chloride and mixed with 0.98 g
(4.6 mmol) of pyridium chlorochromate. It is stirred for 4 hours.
The reaction mixture is then diluted with tetrachloromethane and
filtered on silica gel. The filtrate is concentrated by evaporation
and chromatographed on silica gel (eluant: cyclohexane/ethyl
acetate 4+1). 0.63 g (1.31 mmol; 71% of theory) of
3,16.alpha.-bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-11-one is
obtained as a colorless solid; [.alpha.].sub.D=###.degree. (.,
c=###).
EXAMPLE 16
3,16.alpha.-Bis(benzyloxy)estra-1,3,5(10)-trien-11-one
3,16.alpha.-Bis(benzyloxy)estra-1,3,5(10),9(11)-tetraene
[0479] Analogously to Example 15, 12.83 g (28.47 mmol; 88% of
theory) of 3,16.alpha.-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraene
is obtained as a colorless oil from 8.7 g (32.17 mmol) of
estra-1,3,5(10),9(11)-tetraene-3,16.alpha.-diol;
[.alpha.].sub.D=+96.degree. (chloroform, c=1).
3,16.alpha.-Bis(benzyloxy)estra-1,3,5(10)-trien-11.alpha.-ol
[0480] Analogously to Example 15, 9.43 g (20.2 mmol; 71% of theory)
of 3,16.alpha.-bis(benzyloxy)-estra-1,3,5(10)-trien-11.alpha.-ol is
obtained as a colorless solid from 12.74 g (28.27 mmol) of
3,16.alpha.-bis(benzyloxy)-estra-1,3,5(10),9(11)-tetraene;
[.alpha.].sub.D=###.degree. (., c=###).
3,16.alpha.-Bis(benzyloxy)estra-1,3,5(10)-trien-11-one
[0481] Analogously to Example 15, 1.91 g (4.09 mmol; 64% of theory)
of 3,16.alpha.-bis(benzyloxy)estra-1,3,5(10)-trien-11-one is
obtained from 3 g (6.4 mmol) of
3,16.alpha.-bis(benzyloxy)estra-1,3,5(10)-trien-11.alpha.-ol;
[.alpha.].sub.D=###.degree. (., c=###).
EXAMPLE 17
9.alpha.-Methyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol
3,16.alpha.-Bis(benzyloxy)-9.alpha.-methyl-18a-homoestra-1,3,5(10)-trien-1-
1-one
[0482] Under a cover gas, 0.8 g (7.13 mmol) of
potassium-tert-butylate is dissolved in 6.26 ml of tert-butanol;
0.8 g (1.66 mmol) of
3,16.alpha.-bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-11-one is
dissolved in 15.57 ml of methyl iodide and added in drops to the
first solution. After 15 minutes, 50 ml of saturated sodium
chloride solution is added. The extraction with ethyl acetate
yields a yellow foam, which is chromatographed on silica gel
(eluant: cyclohexane/ethyl acetate 7+1). 0.6 g (1.21 mmol; 73% of
theory) of
3,16.alpha.-bis(benzyloxy)-9.alpha.-methyl-18a-homoestra-1,3,5(10)-trien--
11-one is obtained as a colorless foam;
[.alpha.].sub.D=+216.degree. (chloroform, c=1.03).
3,16.alpha.-Bis(benzyloxy)-9.alpha.-methyl-18a-homoestra-1,3,5(10)-triene
[0483] 0.76 g (1.54 mmol) of
3,16.alpha.-bis(benzyloxy)-9.alpha.-methyl-18a-homoestra-1,3,5(10)-trien--
11-one is introduced into a flask with 5 ml of triethylene glycol.
A solution of 2.16 g (38.15 mmol) of potassium hydroxide in 15 ml
of triethylene glycol and 1.54 g (30.8 mmol) of hydrazine hydrate
are added to this mixture. This mixture is heated for 4 hours to
210.degree. C. Then, it is mixed with saturated sodium chloride
solution and extracted with ethyl acetate. The organic phases are
washed with dilute hydrochloric acid, water and sodium chloride
solution. The crude product is chromatographed on silica gel
(eluant: cyclohexane/ethyl acetate 14+1). In this case, 0.66 g
(1.37 mmol; 89% of theory) of
3,16.alpha.-bis(benzyloxy)-9.alpha.-methyl-18a-homoestra-1,3,5(10)-triene
accumulates as a colorless oil; [.alpha.].sub.D=+47.degree.
(chloroform, c=0.93).
9.alpha.-Methyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol
[0484] 0.65 g (1.37 mmol) of
3,16.alpha.-bis(benzyloxy)-9.alpha.-methyl-18a-homoestra-1,3,5(10)-triene
is dissolved in 20 ml of tetrahydrofuran, mixed with 0.65 g of
palladium-carbon (10% Pd) and hydrogenated. The catalyst is
filtered off, and the filtrate is concentrated by evaporation,
whereby 0.4 g (1.33 mmol; 97% of theory) of
9.alpha.-methyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol
remains. Recrystallization from methanol yields colorless crystals;
flash point 210 . . . 215.degree. C.; [.alpha.].sub.D=###.degree.
(., c=###).
EXAMPLE 18
9.alpha.-Methylestra-1,3,5(10)-triene-3,16.alpha.-diol
3,16.alpha.-Bis(benzyloxy)-9.alpha.-methylestra-1,3,5(10)-trien-11-one
[0485] Analogously to Example 17, 0.379 g (0.78 mmol; 73% of
theory) of
3,16.alpha.-bis(benzyloxy)-9.alpha.-methylestra-1,3,5(10)-trien-11-one
is obtained as a colorless foam from 0.497 g (1.06 mmol) of
3,16.alpha.-bis(benzyloxy)estra-1,3,5(10)-trien-11-one;
[.alpha.].sub.D=+231.degree. (chloroform, c=1.03).
3,16.alpha.-Bis(benzyloxy)-9.alpha.-methylestra-1,3,5(10)-triene
[0486] Analogously to Example 17, 0.458 g (0.98 mmol; 66% of
theory) of
3,16.alpha.-bis-(benzyloxy)-9.alpha.-methylestra-1,3,5(10)-triene
is obtained as a colorless oil from 0.715 g (1.48 mmol) of
3,16.alpha.-bis(benzyloxy)-9.alpha.-methylestra-1,3,5(10)-trien-11-one;
[.alpha.].sub.D=+61.degree. (chloroform, c=1.16).
9.alpha.-Methylestra-1,3,5(10)-triene-3,16.alpha.-diol
[0487] Analogously to Example 17, 0.292 g (1 mmol; 99% of theory)
of 9.alpha.-methylestra-1,3,5(10)-triene-3,16.alpha.-diol is
obtained from 0.476 g (1.01 mmol) of
3,16.alpha.-bis(benzyloxy)-9.alpha.-methylestra-1,3,5(10)-triene.
The recrystallization yields colorless crystals; flash point 182 .
. . 186.degree. C.; [.alpha.].sub.D=###.degree. (., c=###).
EXAMPLE 19
11.beta.-Methyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol
3,16.alpha.-Bis(benzyloxy)-11.alpha.-methyl-18a-homoestra-1,3,5(10)-trien--
11.beta.-ol
[0488] 0.6 g (1.25 mmol) of
3,16.alpha.-bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-11-one is
dissolved under a cover gas in 20 ml of anhydrous tetrahydrofuran.
This solution is cooled to -15.degree. C. and mixed with 4.17 ml of
3M methylmagnesium bromide solution. After the reaction is
completed, saturated ammonium chloride solution is added and
extracted with ethyl acetate. The crude product is chromatographed
on silica gel (eluant: cyclohexane/ethyl acetate 6+1), whereby 0.59
g (1.18 mmol; 95% of theory) of
3,16.alpha.-bis(benzyloxy)-11.alpha.-methyl-18a-homoestra-1,3,5(10)-tr-
ien-11.beta.-ol accumulates as a colorless oil;
[.alpha.].sub.D=-1.degree. (chloroform, c=0.99).
3,16.alpha.-Bis(benzyloxy)-11.beta.-methyl-18a-homoestra-1,3,5(10)-triene
[0489] 0.5 g (1 mmol) of
3,16.alpha.-bis(benzyloxy)-11.alpha.-methyl-18a-homoestra-1,3,5(10)-trien-
-11.beta.-ol is dissolved under a cover gas in methylene chloride
and mixed with 1.75 g (2.4 ml; 15.3 mmol) of triethylsilane. It is
cooled to -10.degree. C. and mixed with 5.69 g (5 ml, 40 mmol) of
boron trifluoride ethyl etherate. After the reaction is completed,
it is mixed with saturated sodium bicarbonate solution and
extracted. The crude product is purified on silica gel (eluant:
cyclohexane/ethyl acetate 9+1). 0.327 g (0.68 mmol; 68% of theory)
of
3,16.alpha.-bis(benzyloxy)-11.beta.-methyl-18a-homoestra-1,3,5(10)-triene
is isolated as a colorless oil; [.alpha.].sub.D=+119.degree.
(chloroform, c=0.99).
11.beta.-Methyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol
[0490] 0.45 g (0.93 mmol) of
3,16.alpha.-bis(benzyloxy)-11.beta.-methyl-18a-homoestra-1,3,5(10)-triene
is dissolved in 20 ml of tetrahydrofuran, mixed with 0.45 g of
palladium-carbon (10% Pd) and hydrogenated. The catalyst is
filtered off, and the filtrate is concentrated by evaporation,
whereby 0.264 g (0.87 mmol; 94% of theory) of
11.beta.-methyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol
remains. Recrystallization from ethyl acetate yields colorless
crystals; flash point 244 . . . 251.degree. C.;
[.alpha.].sub.D=###.degree. (., c=###).
EXAMPLE 20
11.beta.-Methyl-18a-homoestra-1,3,5(10)-triene-3,16.beta.-diol
[0491] 0.1 g (0.33 mmol) of
11.beta.-methyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol is
dissolved in toluene with the addition of 0.35 g (1.33 mmol) of
triphenylphosphine and 0.22 g (1.33 mmol) of 4-nitrobenzoic acid.
0.6 ml (1.33 mmol) of diethylazodicarboxylate solution (40% in
toluene) is slowly added in drops to it. It is heated to 50.degree.
C. until the reaction is completed. Then, it is diluted with ethyl
acetate, and the organic phase is washed with sodium bicarbonate
solution, water and sodium chloride solution. It is dried on
magnesium sulfate and concentrated by evaporation.
[0492] The product that is obtained is dissolved in 20 ml of
methanol and mixed with 0.81 g (5.85 mmol) of potassium carbonate.
It is stirred at room temperature until the saponification is
completed. For working-up, the main amount of the methanol is
distilled off, and the residue is taken up in ethyl acetate. It is
washed with sodium chloride solution and dried on magnesium
sulfate. The crude product is chromatographed on silica gel
(eluant: cyclohexane/ethyl acetate 2+1), whereby 0.79 g (0.26 mmol;
78% of theory) of
11.beta.-methyl-18a-homoestra-1,3,5(10)-triene-3,16.beta.-diol is
obtained. The recrystallization from ethyl acetate yields colorless
crystals; flash point 175 . . . 188.degree. C.;
[.alpha.].sub.D???.degree. (???, c=###).
EXAMPLE 21
11.beta.-Methylestra-1,3,5(10)-triene-3,16.alpha.-diol
3,16.alpha.-Bis(benzyloxy)-11.alpha.-methylestra-1,3,5(10)-trien-11.beta.--
ol
[0493] Produced analogously to Example 19. Colorless oil;
[.alpha.].sub.D=+2.degree. (chloroform, c=0.92).
3,16.alpha.-Bis(benzyloxy)-11.beta.-methylestra-1,3,5(10)-triene
[0494] Produced analogously to Example 19. Colorless oil;
[.alpha.].sub.D=+112.degree. (chloroform, c=1).
11.beta.-Methylestra-1,3,5(10)-triene-3,16.alpha.-diol
[0495] Produced analogously to Example 19. Colorless crystals from
methyl-tert-butyl ether; flash point 243 . . . 250.degree. C.;
[.alpha.].sub.D+172.degree. (dioxane, c=0.96).
EXAMPLE 22
11.beta.-Methylestra-1,3,5(10)-triene-3,16.beta.-diol
[0496] Produced analogously to Example 20. Colorless crystals from
cyclohexane/ethyl acetate; flash point 194 . . . 199.degree. C.;
[.alpha.].sub.D=###.degree. (., c=###).
EXAMPLE 23
11.beta.-Ethyl-18a-homoestra-1,3,5(10o)-triene-3,16.alpha.-diol
3,16.alpha.-Bis(benzyloxy)-11.alpha.-ethyl-18a-homoestra-1,3,5(10)-trien-1-
1.beta.-ol
[0497] Produced analogously to Example 19. Colorless oil.
3,16.alpha.-Bis(benzyloxy)-11.beta.-ethyl-18a-homoestra-1,3,5(10)-triene
[0498] Produced analogously to Example 19. Colorless oil.
11.beta.-Ethyl-18a-homoestra-1,3,5(10)-triene-3,16.alpha.-diol
[0499] Produced analogously to Example 19. Colorless crystals 242 .
. . 255.degree. C.
EXAMPLE 24
11.beta.-Ethyl-18a-homoestra-1,3,5(10)-triene-3,16.beta.-diol
[0500] Produced analogously to Example 20. Colorless crystals 152 .
. . 156.degree. C.
EXAMPLE 25
11.beta.-Ethylestra-1,3,5(10)-triene-3,16.alpha.-diol
3,16.alpha.-Bis(benzyloxy)-11.alpha.-ethylestra-1,3,5(10)-trien-11.beta.-o-
l
[0501] Produced analogously to Example 19. Colorless oil;
[.alpha.].sub.D=-3.degree.. (chloroform, c=1).
3,16.alpha.-Bis(benzyloxy)-11.alpha.-ethylestra-1,3,5(10)-triene
[0502] Produced analogously to Example 19. Colorless oil;
[.alpha.].sub.D=+97.degree. (chloroform, c=1).
11.beta.-Ethylestra-1,3,5(10)-triene-3,16.alpha.-diol
[0503] Produced analogously to Example 19. Colorless crystals from
ethyl acetate; flash point 245 . . . 250.degree. C.;
[.alpha.].sub.D=###.degree. (., c=###).
Example 26
11.beta.-Ethylestra-1,3,5(10)-triene-3,16.beta.-diol
[0504] Produced analogously to Example 20. Amorphous solid.
EXAMPLE 27
11.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol
11.beta.-Methoxy-17-tosylhydrazono-estra-1,3,5(10)-trien-3-ol
[0505] In a mixture of 6 ml of ethanol and 4 ml of glacial acetic
acid, 1 g (3.3 mmol) of
3-hydroxy-11.beta.-methoxy-estra-1,3,5(10)-trien-17-one and 0.7 g
(.3.8 mmol) of toluene-4-sulfonic acid hydrazide are refluxed.
After a reaction time of about 5 hours at boiling heat, the
reaction mixture is cooled, and the product is isolated in about
100 ml of water by addition in drops. By boiling the crude product
in n-hexane, the water that is contained is azeotropically
removed.
[0506] 1.14 g of product (73% of theory) is obtained.
11.beta.-Methoxy-estra-1,3,5(10),16-tetraen-3-ol
[0507] 469 mg (1 mmol) of
11.beta.-methoxy-17-tosylhydrazono-estra-1,3,5(10)-trien-3-ol is
introduced into 15 ml of tetrahydrofuran. The solution is mixed at
room temperature with 1 ml (10 mmol) of n-butyllithium solution (10
M, n-hexane) under inert gas and while being stirred vigorously.
The reaction solution is refluxed. After about 10 minutes of
reaction time and cooling, the working-up is carried out by the
addition in drops of 20 ml of saturated ammonium chloride solution
and 30 ml of ethyl acetate. The organic phase is washed with
water/common salt solution and dried on sodium sulfate. The crude
product is purified by chromatography on silica gel
(cyclohexane/ethyl acetate, 1:1). Yield 170 mg (60% of theory).
[0508]
11.beta.-Methoxy-3-triethylsilyloxy-estra-1,3,5(10),16-tetraene
[0509] 284 mg (1 mmol) of
11.beta.-methoxy-estra-1,3,5(10),16-tetraen-3-ol is reacted in 10
ml of tert-butylmethyl ether and 1 ml of pyridine with 0.6 ml of
triethylbromosilane. After 1 hour, 30 ml of water is added to the
reaction suspension. The organic phase is separated, washed, dried
and concentrated by evaporation in a vacuum. The oily product that
is thus obtained is used immediately in the next stage
(hydroboration). Yield: 380 mg (95% of theory)
-11.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol (27)
[0510] 380 mg (0.95 mmol) of
11.beta.-methoxy-3-triethylsilyloxy-estra-1,3,5(10),16-tetraene is
dissolved in 20 ml of tetrahydrofuran under inert gas. After 464 mg
(3.8 mmol) of 9-borabicyclo[3.3.1]nonane is added, the reaction
solution is stirred at room temperature until the reaction is
completed. Then, 5 ml of water is added in drops, and after gas
generation is completed, 2 ml of 5N sodium hydroxide solution and 2
ml of 30% hydrogen peroxide solution are added in drops. It is
stirred for 1 hour at room temperature, and the product that is
produced is extracted with ethyl acetate. The crude product that is
obtained is purified by chromatography on silica gel
(n-hexane/chloroform/methanol 45/45/10) and crystallized from ethyl
acetate/n-hexane. Colorless crystals are obtained: 230 mg (80% of
theory).
[0511] Melting point 212-222.degree. C.;
[.alpha.].sup.20.sub.D=+101.degree. (dioxane, c=0.53)
EXAMPLE 28
11.beta.-Methoxy-estra-1,3,5(10)-triene-3,16.beta.-diol (28)
[0512] 229 mg (0.76 mmol) of
11.beta.-methoxy-estra-1,3,5(10)-triene-3,16.alpha.-diol is
dissolved in 30 ml of toluene together with 1.8 g (6.8 mmol) of
triphenylphosphine and 1.14 g (6.8.mmol) of 4-nitrobenzoic acid.
2.7 ml (6.8 mmol) of azodicarboxylic acid diethyl ester (40% in
toluene) is added drop by drop to this solution. After a 24-hour
reaction at room temperature, the reaction solution was mixed with
ethyl acetate. The organic phase that is thus obtained is extracted
with sodium bicarbonate solution, water and sodium chloride
solution. The organic phase is concentrated by evaporation, and
then the product is taken up in methanol. After 2.5 g of potassium
carbonate is added, the suspension is refluxed until saponification
is completed. For working-up, the methanol is distilled off, and
the crude product is taken up in ethyl acetate, washed with water
and sodium chloride solution, and the solution is concentrated by
evaporation. After recrystallization from chloroform/cyclohexane,
almost colorless crystals are obtained:
[0513] 195 mg (85% of theory); melting point 195-200.degree. C.;
[.alpha.].sup.20.sub.D=+86.degree. (dioxane, c=1.18)
EXAMPLE 29
11.beta.-Phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol
[0514]
11.beta.-Phenyl-17-tosylhydrazono-estra-1,3,5(10)-trien-3-ol
[0515] 590 mg (1.71 mmol) is reacted with toluene-4-sulfonic acid
hydrazide as described in Example 28. By cooling the reaction
solution, in this case a proportion of the product precipitates.
The solid product is suctioned off, washed with ethanol and dried.
450 mg of yellowish crystallizate (51% of theory) is obtained. The
product that is still contained in the mother liquor can be
isolated by extraction and corresponding chromatographic working-up
(303 mg, 38% of theory).
11.beta.-Phenyl-estra-1,3,5(10),16-tetraen-3-ol
[0516] 515 mg (1 mmol) of
11.beta.-phenyl-17-tosylhydrazono-estra-1,3,5(10)-trien-3-ol is
reacted with 1 ml (10 mmol) of n-butyllithium solution as in
Example 28. 450 mg of crude product is obtained, which is reacted
to triethylsilylether in the next stage.
11.beta.-Phenyl-3-triethylsilyl-estra-1,3,5(10),16-tetraene
[0517] Corresponding to Example 28, 450 mg of
11.beta.-phenyl-estra-1,3,5(10),16-tetraen-3-ol (crude product) is
reacted to triethylsilylether. The product that is obtained is
purified by chromatography on silica gel (cyclohexane/ethyl
acetate, 6/1), and the solution is concentrated by evaporation in a
vacuum. An oily substance is obtained. Yield 320 mg (72% of theory
relative to 515 mg of
11.beta.-phenyl-17-tosylhydrazono-estra-1,3,5(10)-trien-3-ol).
11.beta.-Phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol (29)
[0518] The hydroboration is carried out according to Example 27.
320 mg (0.72 mmol) of
11.beta.-phenyl-3-triethylsilyl-estra-1,3,5(10),16-tetraene yielded
183 mg (73% of theory) after working-up and purification by
chromatography on silica gel (toluene/ethyl acetate, 70/30) and
crystallization from methanol.
[0519] Melting point 254-261 [.alpha.].sup.2.sub.D=-103.degree.
(dioxane, c=0.09)
EXAMPLE 30
11.beta.-Phenyl-estra-1,3,5(10)-triene-3,16.beta.-diol (30)
[0520] The inversion of the 16-hydroxy group was performed
according to Example 28. 36 mg (0.1 mmol) of
11.beta.-phenyl-estra-1,3,5(10)-triene-3,16.alpha.-diol yielded 25
mg (69% of theory) of colorless crystals after chromatography on
silica gel (toluene/ethyl acetate, 70/30) and crystallization from
toluene.
[0521] Melting point 241-247.degree.
[.alpha.].sup.20.sub.D=-930.degree. (dioxane, c=0.31)
EXAMPLE 31
16.alpha.-Ethinyl-18a-homo-estra-1,3,5(10)-triene-3,16.beta.-diol
(31)
[0522] At a temperature of about 0.degree. C., 30 ml of
tetrahydrofuran is saturated with ethine. Then, 3.4 ml (8.4 mmol)
of n-butyllithium solution (2.5 M, toluene) is added to the
solution while being cooled and stirred, The temperature should be
about 0.degree. C. A solution of 141 mg (0.5 mmol) of
3-hydroxy-18a-homo-estra-1,3,5(10)-trien-16-one in 10 ml of
tetrahydrofuran is added to the suspension of lithium acetylide
that is thus obtained. After 30 minutes of reaction time at about
0.degree. C., the reaction solution is mixed with dilute
hydrochloric acid. After the tetrahydrofuran is distilled off, the
organic residue is taken up in toluene, the phases are separated,
the organic phase is washed with water, and the crude product is
isolated by concentration by evaporation of the solution under
vacuum. A purification of the product is achieved by chromatography
on silica gel (toluene/acetone, 7/1) and crystallization from
toluene. 131 mg (85% of theory) of crystalline substance is
obtained.
[0523] Melting point 197-202.degree. C.
[.alpha.].sup.20.sub.D=+100.degree. (dioxane, c=1.06)
EXAMPLE 32
16.beta.-Ethinyl-18a-homo-estra-1,3,5(10)-triene-3,16.alpha.-diol
(32)
[0524] The production of
16.beta.-ethinyl-18a-homo-estra-1,3,5(10)-triene-3,16.alpha.-diol
is performed analogously to Example 31. The increase of the
reaction temperature to room temperature produced a larger
proportion of 16.beta.-ethinyl product. By chromatography on silica
gel (cyclohexane/ethyl acetate, 3/1), it was possible to isolate
the product.
[0525] Yield: 20% of theory, 213-219.degree. C.,
[.alpha.].sup.20.sub.D=+48.degree. (dioxane, c=1.04)
EXAMPLE 33
11.beta.-Fluoro-7.alpha.-methylestra-1,3,5(10)-triene-3,16.beta.-diol
11.beta.-Fluoro-7.alpha.-methylestra-1,3,5(10)-triene-3,16.alpha.-diol
11.beta.-Fluoro-7.alpha.-methylestr-4-ene-3,17-dione
[0526] A suspension of 15.2 g (79.8 mmol) of copper iodide in 70 ml
of dry tetrahydrofuran is cooled to 0.degree. C., mixed with 28.7 g
(330 mmol) of lithium bromide and 27.8 ml of DMPU, stirred first
for 30 minutes at this temperature and then cooled to -30.degree.
C. While being stirred, 52 ml of methylmagnesium bromide in diethyl
ether (3 molar solution) is then added in drops, stirred for
another 30 minutes, and the gray-colored suspension is mixed with a
solution that consists of 10.0 g (34.7 mmol) of
11.beta.-fluoroestra-4,6-diene-3,17-dione, 24.3 ml of DMPU and 23
ml of trimethylsilyl chloride in 60 ml of dichloromethane. After
the addition is completed, it is allowed to stir for another 1.5
hours between -30--10.degree. C., the cold bath is removed, and 35
ml of ethyl acetate is carefully added at room temperature while
being stirred vigorously. For working-up, the reaction solution is
diluted with ethyl acetate, washed with saturated aqueous ammonium
chloride solution that is free of copper, and the organic phase is
dried on sodium sulfate. The crude product is chromatographed on
silica gel (hexane-ethyl acetate, gradient of up to 1:1), yield 3.1
g (30%).
11.beta.-Fluoro-3-hydroxy-7.alpha.-methylestra-1,3,5 (10)
-trien-17-one
[0527] 8.3 g (27.2 mmol) of
11.beta.-fluoro-7.alpha.-methylestr-4-ene-3,17-dione in 260 ml of
acetonitrile is mixed with 7.0 g (31.3 mmol) of copper(II) bromide,
and the reaction mixture is stirred for 7 hours at room
temperature. For working-up, the reaction solution is diluted with
ethyl acetate, the organic phase is washed with aqueous ammonium
chloride solution, sodium bicarbonate solution, and finally with
water and dried on sodium sulfate. The crude product is
chromatographed on silica gel (toluene-ethyl acetate, gradient of
up to 7:3), yield 3.3 g (40%), [.alpha.].sub.D+166.8.degree. (c 0.5
methanol).
Acetyloxy-11.beta.-fluoro-7.alpha.-methylestra-1,3,5(10)-trien-17-one
[0528] 3.0 g (9.9 mmol) of
11.beta.-fluoro-3-hydroxy-7.alpha.-methylestra-1,3,5(10)-trien-17-one
in 12 ml of pyridine and 6 ml of acetic acid anhydride are
dissolved and allowed to react overnight at room temperature. For
working-up, the reaction mixture is stirred into ice water, the
precipitate is suctioned off, which then is taken up in ethyl
acetate. The organic phase is first washed with dilute hydrochloric
acid, then with water and dried on sodium sulfate. 3.4 g of product
is obtained, which is sufficiently pure for further processing.
3-Acetyloxy-11.beta.-fluoro-7.alpha.-methylestra-1,3,5(10),16-tetraene
[0529] 3.8 g (18.4 mmol) of 2,6-di-tert-butyl-4-methylpyridine is
added to a solution of 2.7 g (7.9 mmol) of
3-acetyloxy-11.beta.-fluoro-7.alpha.-methyletra-1,3,5(10)-trien-17-one
in 40 ml of dry dichloromethane, cooled under a cover gas
atmosphere (argon) to 0.degree. C., and 2.64 ml (16 mmol) of
trifluoromethanesulfonic acid anhydride is added in drops while
being stirred. The cold bath is removed, and stirred for 1.5 more
hours at room temperature. For working-up, it is diluted with ethyl
acetate, the organic phase is washed with water and dried on sodium
sulfate. The crude product (6.0 g) is then taken up in 15 ml of
dimethylformamide, mixed at room temperature with 5.72 ml of
tributylamine, 0.11 g (0.15 mmol) of
bis(acetato)-bis(triphenylphosphine) palladium, 0.61 ml (16 mmol)
of formic acid and stirred for 30 minutes at a bath temperature of
60.degree. C. (argon atmosphere). For working-up, it is poured into
ice water, extracted with ethyl acetate, the organic phase is
washed first with dilute hydrochloric acid, then with water
and-dried on sodium sulfate. The crude product is chromatographed
on silica gel (heptane-acetone, gradient of up to 9:1), yield 1.71
g (66%).
11.beta.-Fluoro-7.alpha.-methylestra-1,3,5(10)-triene-3,160-diol
[0530] A solution of 1.67 g (5.22 mmol) of
3-acetyloxy-11.beta.-fluoro-7.alpha.-methylestra-1,3,5(10),16-tetraene
in 30 ml of DMSO and 2.4 ml of water is replaced in portions with
1.36 g of N-bromosuccinimide while being stirred at 0.degree. C.,
the cold bath is removed after the addition of NBS is completed,
and it is stirred for 45 more minutes at room temperature. For
working-up, the reaction mixture is poured into ice water,
extracted with ethyl acetate, the organic phase is washed with
water and dried on sodium sulfate. The crude bromohydrin (2.3 g) is
then taken up in 25 ml of dry tetrahydrofuran, mixed with 5 ml
(18.6 mmol) of tributyl tin hydride, a first spatula tip full of
AIBN (a total of 200 mg dispersed over the reaction time), and
stirred for 10 hours at a bath temperature of 80.degree. C. under
an argon atmosphere. For working-up, it is diluted with ethyl
acetate, the organic phase is washed with dilute hydrochloric acid
and water and dried on sodium sulfate. For saponification, the
crude product is dissolved in 50 ml of methanol and 5 ml of
dichloromethane, and it is mixed with 2.0 g of potassium carbonate.
The reaction mixture is stirred for 1.5 hours under argon and
poured into ice water for working-up. It is made hydrochloric with
dilute acid, and it is extracted with ethyl acetate. The organic
phase is washed with water and dried on sodium sulfate. The crude
product is chromatographed on silica gel
(chloroform-tert-butylmethylether, gradient of up to 95:5), yield
1.16 g (75%), melting point 239-240.degree. C. while decomposing,
[.alpha.].sub.D+96.80 (c 0.51 methanol).
11.beta.-Fluoro-7.alpha.-methylestra-1,3,5(10)-triene-3,16.alpha.-diol
[0531] A solution of 0.60 g (2.0 mmol) of
11.beta.-fluoro-7.alpha.-methylestra-1,3,5(10)-triene-3,16.beta.-diol
in 20 ml of dry tetrahydrofuran is mixed with 1.82 g (6.9 mmol) of
triphenylphosphine and 0.26 ml of formic acid. Under an argon
atmosphere, 1.10 ml of DEAD is then added in drops to this solution
while being stirred at room temperature. After a reaction time of
30 minutes, it is mixed with water, extracted with ethyl acetate,
the organic phase is washed with water and dried on sodium sulfate.
The crude product is chromatographically purified on silica gel
(dichloromethane-ethyl acetate, gradient of up to 95:5). The
formates that are thus obtained are dissolved in 15 ml of
dichloromethane, mixed with. 7.5 ml of 3% methanolic potassium
hydroxide solution, and left for 2 hours at room temperature under
argon. For working-up, it is mixed with aqueous acetic acid,
extracted with ethyl acetate, the organic phase is washed with
water and dried on sodium sulfate. The crude product is purified by
crystallization from acetone/hexane. Yield: 0.45 g (75%), melting
point 221-222.degree. C. while decomposing,
[.alpha.].sub.D+104.2.degree. (c 0.52 methanol).
[0532] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0533] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions. TABLE-US-00001 TABLE 1 Rat Rat
prost. hER.alpha. hER.beta. ER.beta./ uterus prost. ER/uterus
Estrogen Structure RBA* RBA* ER.alpha. ER(RBA) ER(RBA) ER Estradiol
100 100 1 100 100 1 Estrone 60 37 0.6 3 2 0.8 17.alpha.- 58 11 0.2
2.4 1.3 0.5 Estradiol Estriol 14 21 1.5 4 20 5 5-Androstenediol 6
17 3 0.1 5 50 Genisteine 5 36 7 0.1 10 100 Coumestrol 94 185 2 1.3
24 18 *Cited from: Kuiper et al. (1996), Endocrinology 138:
863-870
[0534] TABLE-US-00002 TABLE 2 Rat Rat prost. hER.alpha. hER.beta.
ER.beta./ uterus prost. ER/uterus Estrogen Structure RBA* RBA*
ER.alpha. ER(RBA) ER(RBA) ER Estradiol 100 100 1 100 100 1
Ethinylestradiol 111 46 0.4 345 35 0.1 Cyclotriol 36 10 0.3 50 17
0.3 Estrone 7 5 0.7 3 2 0.8 Estriol 7 14 2 4 20 5 5-Androstenediol
1.7 10 6 0.1 5 50 Genisteine 0.4 23 57 0.1 10 100 Coumestrol 23 100
4.5 1.3 24 18 Raloxifene 63 9 0.14 91 1.5 0.02 Anordiol 15 0.2 0.01
6.6 <0.01 <0.01
[0535] TABLE-US-00003 TABLE 3 In vitro Receptor In vivo binding 50%
50% ER.beta. Rat Rat bone uterus (RBA)/ prost. uterus protection
stimulation Compound Structure ER.alpha.(RBA) ER(RBA) ER(RBA)
[.mu.g/animal] 16.alpha.-Estradiol 6 50 9 3 30
* * * * *