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.

Established estrogen therapies for treatment of hormone-deficiency-induced symptoms and the protective action of estrogens on bones, brains, vessels and other organ systems.
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.).
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).
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).
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., 17β-estradiol-valerate, can also be used.
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.
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.
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 "ERα." 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 (ERβ)
Estrogen receptor β (ERβ) 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 ERβ differs from that of the ERα (Kuiper et al. (1996), Endocrinology 138: 863–870). ERβ thus predominates over ERα in the rat prostate, while ERα predominates over ERβ 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). ERβ 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).
Other organ systems with comparatively higher ERβ-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 ERβ. The fact that ERβ is functional in this respect also follows by studies in ERα-(ERKO) or ERβ-(βERKO)-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 ERβ.
Observations of βERKO mice provide an indication on a function of ERβ 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 βERKO 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.
Westerlind et al., 1998, describe a differential action of 16α-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).
Some studies showed that 16α-hydroxyestrone binds three times better to the human estrogen receptor β (ERβ) than to the human estrogen receptor a (ERα). 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 ERβ rather than ERα.
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 ERβ compared to ERα 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.
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.
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.
According to the invention, the object above is achieved by the provision of 16α- and 16β-hydroxy-estra-1,3,5(10)-trienes of general formula I
in which radicals R1 to R17, independently of one another, have the following meanings:                R1 means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;        R2 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;        R4 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;        R7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-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;        R8 means a hydrogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, or a cyano group in α- or position;        R9 means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in α- or β-position;        R11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;        R13 means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in β-position;        and either        R14 means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position or a hydrogen atom in α- or β-position and        R15 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15′ (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom or        R14 and R15 together mean a 14α,15α-methylene or 14β,15β-methylene group that is optionally substituted with one or two halogen atoms;        R16 means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a hydrogen atom in α- or β-position;        R17 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-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 α- or β-position,for treatment of estrogen-deficiency-induced diseases and conditions.
According to a variant of the invention, preferably compounds of general formula I are used,
in which radicals R1 to R17, independently of one another, have the following meanings
                R1 means a fluorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;        R2 means a fluorine atom, a hydroxyl group, a methoxy or ethoxy group or a hydrogen atom;        R4 means a fluorine atom, a methyl, ethyl, trifluoromethyl, methoxy or ethoxy group or a hydrogen atom;        R7 means a fluorine atom in α- or β-position, a methyl, ethyl, propyl or i-propyl group in α- or β-position, a trifluoromethyl group in α- or β-position or a hydrogen atom;        R8 means a hydrogen atom in α- or β-position, a methyl or ethyl group in α- or β-position;        R9 means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in α- or β-position;        R11 means a nitrooxy group in α- or β-position, a hydroxyl group in α- or β-position, a fluorine atom in α- or β-position, a choromethyl group in α- or β-position, a methyl group in α- or β-position, a methoxy group in α- or β-position, a phenyl- or 3-methylthien-2-yl radical in α- or β-position or a hydrogen atom;        R13 means a methyl or ethyl group in β-position; and either        R14 means a hydrogen atom in α- or β-position or a methyl group in α- or β-position and        R15 means a fluorine atom in α- or β-position, a methyl group in α- or β-position, or a hydrogen atom, or        R14 and R15 together mean a 14α,15α-methylene group or a 14β,15β-methylene group;        R16 means a methyl, ethyl, ethinyl, propinyl or trifluoromethyl group;        R17 means a fluorine atom in α- or β-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.
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-3,16α-diol, estra-1,3,5(10)-triene-3,16β-diol, estra-1,3,5(10),7-tetraene-3,16α-diol as well as estra-1,3,5(10),7-tetraene-3,16β-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.
16α-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).
A differentiated action of 16α-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.
3,16α-Dihydroxy-estratriene was already described by Stack and Gorski as "estrogen that has a short-term effect" (Stack, Gorski 1985).
Nothing is known to date on a use of this last-mentioned compound as a selective estrogen.
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.
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.
As representatives of the alkylthio groups, for example, methylthio, ethylthio and trifluoromethylthio groups can be mentioned.
Within the context of this invention, an aryl radical is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred.
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.
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(C1-8 alkyl) or di(C1-8 alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, can be mentioned.
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.
The alkyl groups can be partially or completely fluorinated or substituted by 1–5 halogen atoms, hydroxy groups or C1–C4 alkoxy groups.
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.
Monochloromethylene, monofluoromethylene or difluoromethylene can stand for the halogen-substituted 14,15-methylene group.
Other variants of the invention provide one or more conjugated double bonds in rings B, C and D of the estratriene skeleton:
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.
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 C1–C14 mono- or polycarboxylic acid or an aromatic carboxylic acid or with an α- or β-amino acid.
Suitable as such carboxylic acids for esterification are, for example:
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.
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.
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.
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, β-alanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline, etc.
The 16-oxy group in the compounds according to the invention and the structural parts that are described below can be both in α-position and in β-position.
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′                R7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-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
R1, R2, R4, R8, R9, R11, R14, R15, R16 and R17 in each case mean a hydrogen atom.
According to another embodiment of the invention, in the compounds of general formulas I and I′, and in the structural parts of formula II′                R11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and        R1, R2, R4, R7, R8, R9, R14, R15, R16 and R17 in each case mean a hydrogen atom.
Another configuration of the compounds of general formulas I and I′ as well as the structural parts of formula II′ provides that                R15 means a halogen atom in α- or β-position or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15′ (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl), and        R1, R2, R4, R7, R8, R9, R11, R14, R16 and R17 in each case mean a hydrogen atom.
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′,                R7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-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        R11 means a nitrooxy group in α- or β-position, a hydroxyl- or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and        R1, R2, R4, R8, R9, R14, R15, R16 and R17 in each case mean a hydrogen atom.
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′,                R7 stands for a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-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        R15 stands for a halogen atom in α- or β-position or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15′ (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl), and        R1R2, R4, R8, R9, R11, R14, R16 and R17 in each case stand for a hydrogen atom.
According to another embodiment of the compounds of general formulas I and I′ according to the invention and the structural parts of formula II′,                R11 stands for a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and        R15 stands for a halogen atom in α- or β-position or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15 (R15=hydrogen atom, methyl, ethyl, propyl, i-propyl), and        R1, R2, R4, R7, R8, R9, R14, R16, and R17 in each case stand for a hydrogen atom.
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                R7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-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,        R11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,        R15 means a halogen atom in α- or β-position, or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15′ (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl), and        R1, R2, R4, R8, R9, R14, R16, and R17 in each case mean a hydrogen atom.
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′,                R7 preferably stands for a fluorine atom in α- or β-position, a methyl, ethyl, propyl or i-propyl group in α- or β-position, a trifluoromethyl group in α- or β-position or a hydrogen atom;        R11 preferably stands for a nitrooxy group in α- or position, a hydroxyl group in α- or β-position, a fluorine atom in α- or β-position, a chloromethyl group in α- or β-position, a methyl group in α- or β-position, a methoxy group in α- or β-position, a phenyl or 3-methylthien-2-yl radical in α- or position or a hydrogen atom and        R15 preferably stands for a fluorine atom in α- or position, a methyl group in α- or β-position or a hydrogen atom.
Preferred according to this invention are the compounds below:    14α,15α-Methylen-estra-1,3,5(10)-triene-3,16α-diol    14β,15β-Methylen-estra-1,3,5(10)-triene-3,16α-diol    14β,15β-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    Estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    Estra-1,3,5(10),8(14)-tetraene-3,16α-diol,    Estra-1,3,5(10),6,8-pentaene-3,16α-diol,    7α-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,    11-Methoxy-estra-1,3,5(10)-triene-3,16α-diol,    7α-Methyl-estra-1,3,5(10)-triene-3,16α-diol    11′-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,    8α-Estra-1,3,5(10)-triene-3,16α-diol    Estra-1,3,5(10)-triene-2,3,16α-triol    17β-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10),6,8-pentaene-3,16α-diol.    14α,15α-Methylen-estra-1,3,5(10)-triene-3,16β-diol    14β,15β-Methylen-estra-1,3,5(10)-triene-3,16β-diol    14β,15β-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    Estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    Estra-1,3,5(10),8(14)-tetraene-3,16β-diol,    Estra-1,3,5(10),6,8-pentaene-3,16β-diol,    7α-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,    11β-Methoxy-estra-1,3,5(10)-triene-3,16β-diol,    7α-Methyl-estra-1,3,5(10)-triene-3,16β-diol    11β-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,    8α-Estra-1,3,5(10)-triene-3,16β-diol    Estra-1,3,5(10)-triene-2,3,16α-triol    17β-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10),6,8-pentaene-3,16β-diol,    7α-Ethyl-estra-1,3,5(10)-triene-3,16α-diol    7α-Propyl-estra-1,3,5(10)-triene-3,16α-diol    7α-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol    7α-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol    7α-Phenyl-estra-1,3,5(10)-triene-3,16α-diol    7α-Methoxy-estra-1,3,5(10)-triene-3,16α-diol    7α-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol    7β-Cyanomethyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Ethyl-estra-1,3,5(10)-triene-3,16≢-diol    7β-Propyl-estra-1,3,5(10)-triene-3,16α-diol    7β-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol    7β-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol    7β-Phenyl-estra-1,3,5(10)-triene-3,16α-diol    7β-Methoxy-estra-1,3,5 (10)-triene-3,16α-diol    7β-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol    7β-Cyanomethyl-estra-1,3,5(10)-triene-3,16α-diol    7α-Ethyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Propyl-estra-1,3,5(10)-triene-3,16β-diol    7α-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol    7α-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Phenyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Methoxy-estra-1,3,5(10)-triene-3,16β-diol    7α-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Cyanomethyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Ethyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Propyl-estra-1,3,5(10)-triene-3,16β-diol    7β-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol    7β-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Phenyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Methoxy-estra-1,3,5(10)-triene-3,16β-diol    7β-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Cyanomethyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Ethyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Propyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Allyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methoxy-estra-1,3,5(10)-triene-3,16α-diol    15α-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Ethyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Propyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Allyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methoxy-estra-1,3,5(10)-triene-3,16β-diol    15α-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Ethyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Propyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Allyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methoxy-estra-1,3,5(10)-triene-3,16α-diol    15β-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Ethyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Propyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Allyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methoxy-estra-1,3,5(10)-triene-3,16β-diol    15β-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Trifluoromethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Pentafluoroethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Phenyl-11α-Fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    14α,15α-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    14β,15β-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    14β,15β-Methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    7α-Phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    7α-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16α-diol,    7α-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16α-diol,    11β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    11β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    7α-Phenyl-8α-estra-1,3,5(10)-triene-3,16α-diol    7α-Phenyl-estra-1,3,5(10)-triene-2,3,16α-triol    17β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),6,8-pentaene-3,16α-diol,    14α,15α-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    14β,15β-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    14β,15β-Methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    7α-Phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    7α-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16β-diol,    7α-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16β-diol,    11β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    11β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,    7α-Phenyl-8α-estra-1,3,5(10)-triene-3,16β-diol    7α-Phenyl-estra-1,3,5(10)-triene-2,3,16α-triol    17β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16%-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),6,8-pentaene-3,16β-diol,    15α-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16-diol    15α-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Allyl-7 μL-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15′-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    11β-[2-(3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,16α-diol    11β-[2-(3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,16β-dioland of the latter in turn especially the compounds    7α-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,    7α-Methyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Methyl-estra-1,3,5(10)-triene-3,16α-diol    18α-Homo-estra-1,3,5(10)-triene-3,16α-diol.
Another aspect of this invention relates to the use of the structural part of formula II
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.
The possible substituents in carbon atoms 7, 8, 9, 11, 13, 14, 15 and 17 can be respectively in α- or β-position. The dotted lines ----- in rings B, C and D stand for one or more possible double bonds between the corresponding carbon atoms.
This invention preferably relates to those structural parts of general formula II′
in which radicals R1′ to R17′, independently of one another, have the following meanings                R1′ means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;        R2′ 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;        R4′ 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;        R7′ means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-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;        R8′ means a hydrogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position or a cyano group in α- or β-position;        R9′ means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in α- or β-position;        R11′ means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;        R13′ means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in β-position;        and either        R14′ means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position or a hydrogen atom in α- or position and        R15′ means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15 (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom or        R14′ and R15′ together mean a 14α,15α-methylene group or a 14β,15β-methylene group that is optionally substituted with one or two halogen atoms;        R16′ means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a hydrogen atom in α- or β-position;        R17′ means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-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 α- or β-position.
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.
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.
The compounds can be used for the following indications both after oral and parenteral administration.
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 ERα-selective antiestrogens, or with antiestrogens that are peripherally-selectively active, i.e., that do not pass through the blood-brain barriers.
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.
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.
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.
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.
In addition, the compounds can be used for the treatment of male fertility disorders and prostatic diseases.
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).
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.
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.
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 μg/kg–10 mg/kg of body weight, preferably 0.04 μg/kg–1 mg/kg of body weight, per day.
In humans, this corresponds to a dose of 0.8 μg to 800 mg, preferably 3.2 μg to 80 mg, daily.
According to the invention, a dosage unit contains 1.6 μg to 200 mg of one or more compounds of general formula I.
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.
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 Encyklopädie 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 für 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 für Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor KG, Aulendorf in Wurttemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue.
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.
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.
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.
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.
For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, coils, IUDs, Mirena®) 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.
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 α-, β-, or γ-cyclodextrin or derivatives of the latter (PCT/EP95/02656).
According to the invention, the compounds of general formula I can also be encapsulated with liposomes.
Methodology
Estrogen Receptor Binding Studies
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).
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).
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 ERβ predominates in the rat prostates over ERα, and ERα predominates in rat uteri over ERβ. 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 ERβ and ERα of rats (according to Kuiper et al. (1996), Endocrinology 138: 863–870) (Table 1).
Some studies with human estrogen receptors α and β, which were produced by means of the Baculovirus/SF-9 expression system, confirm the agreement of the 'RBA prostate-ER/RBA uterus-ER' ratio with the 'RBA ERβ/RBA ERα' quotient (Table 2).
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
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.
The ovariectomy reduces the density of the trabecular bone in the measured area by about 400 mg of Ca2+/cm3 to about 300 mg of Ca2+/cm3. 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.
Table 3 shows the results for the compound estra-1,3,5(10)-triene-3,16α-diol that is to be used according to the invention. In accordance with the higher binding affinity to ERβ than to ERα, [ERα (RBA)/ERα (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-3,16α-diol reflects this in vivo in the greatly different amounts, which produce a 50% bone protection [3 μg/animal] or a 50% uterus stimulation [30 μg/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.
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).
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 ED50 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
For the production of the compounds according to the invention, i.e., modified/substituted derivatives of estra-1,3,5(10)-triene-3,16ξ-diols, mainly two generally applicable synthesis strategies are used.
On the one hand, especially 3,16-protected derivatives of estra-1,3,5(10)-triene-3,16ξ-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-3,16β-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-3,11β,16β-triol that is protected as a diacetate. After saponification, the epimeric 11-nitrate ester of estra-1,3,5(10)-triene-3,16α-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-3,16α-diol is selected as a starting point. In this way, the 11-nitrate ester in the 16α-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-3,9,11β-16ξ-tetraole are also obtained after cleavage of protective groups at C(3), C(16).
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(8α) Tetrahedron Letters 1991, 743; C(8β) 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.
For the case of C(3)-methyl ether of 8α-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 16β-alcohol, which can be converted into the 16α-epimer according to known methods.
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-18α-homoestra-1,3,5(10),16-tetraene with 9-borabicyclo[3.3.1]nonane produces 16α-hydroxyestratrienes after oxidation with alkaline hydrogen peroxide. To a lesser extent, the epimeric 16β-hydroxy steroids are formed in this reaction. After the cleavage of the 3-methoxy group, estra-1,3,5(10)-3,16α-diols are obtained. By inversion of the configuration at C atom 16, e.g., by Mitsunobu reaction (Synthesis 1980, 1), the 16β-hydroxyestratrienes are in turn obtained.
The broad applicability of the synthesis method that is outlined above is demonstrated in additional examples, thus, for example, for 3-methoxy-7α-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).
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.
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)–→C(16)-ketotransposition are also selected. For a concrete example, refer to J. Chem. Soc. Perk. 1, 1976, 1350.
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 15α-hydroxyestrone that is accessible according to U.S. Pat. No. 3,375,174 is converted with known processes into 15β-fluoroestrone, by being reacted with diethylamino sulfur trifluoride or the corresponding 15α-mesylate being reacted with tetra-n-butylammonium fluoride (J. Chem. Res. (M) 1979, 4728–55). The thus accessible 15β-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 17β-fluoroestra-1,3,5(10)-trien-3,16α-ol after the reaction with a sterically exacting borane and subsequent oxidation with alkaline hydrogen peroxide.
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 9α-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 18α-homoestra-1,3,5(10)-triene-3,16α-diyldiacetate, the corresponding 9α-hydroxy compound can be produced. The dehydration of this tertiary alcohol results in 18α-homoestra-1,3,5(10),9(11)-tetraene-3,16α-diyldiacetate. After saponification, 18α-homoestra-1,3,5(10),9(11)-tetraene-3,16α-diol is obtained.
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.
Etherification and/or esterification of free hydroxy groups is carried out according to methods that are common to one skilled in the art.
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.
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.
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.

16-hydroxyestratrienes as selectively active estrogens

Abstract: The new compounds are 16α- and 16β-hydroxy-estra-1,3,5(10)-estratrienes, which carry additional substituents on the steroid skeleton and can have one or more additional double bonds in the B-, C- and/or D-rings.


Phototherapeutic instruments are disclosed for providing substantially uniform energy distribution to a major portion of an area exposed during phototherapy. These instruments include an element for directing radiation toward the walls of a lumen and a device for centering the radiation directing element within the lumen. The instruments also allow the flow of blood, therapeutic fluid, or air past the exposure site. The instruments are particularly useful as part of a fiber optic-based medical laser system for photodynamic therapy within the bronchia of the lung, blood vessels or other liquid-filled lumens.

The technical field of this invention is phototherapy and, in particular, instruments employing optical fibers or other flexible light waveguides to deliver radiation to a targeted biological site.
Fiber optic phototherapy is an increasingly popular modality for the diagnosis and/or treatment of a wide variety of diseases. For example, some have proposed the use of fiber-delivered radiation to treat artherosclerotic disease. U.S. Pat. No. 4,878,492 (Sinofsky et al. '492), herein incorporated by reference, discloses the used of infrared radiation to heat blood vessel walls during balloon angioplasty in order to fuse the endothelial lining of the blood vessel and seal the surface. Another application of fiber-delivered radiation is disclosed in U.S. Pat. No. 5,053,033 (Clarke '033), herein incorporated by reference. Clarke '033 teaches that restenosis following angioplasty can be inhibited by application of UV radiation to the angioplasty site to kill smooth muscle cells which would otherwise proliferate in response to angioplasty-induced injuries to blood vessel walls.
Moreover, fiber optic delivery systems have been incorporated in endoscopic or catheter-based instruments to deliver photoactivating radiation to light sensitive drugs within a body lumen or cavity. U.S. Pat. No. 4,336,809 (Clark '809), herein incorporated by reference, and U.S. Reissue Pat. No. RE 34,544 (Spears '544), herein incorporated by reference, disclose that hematoporphyrin dyes and the like selectively accumulate in atheromatous plaque or tumorous tissue. These patents further teach that when cancerous tissue has taken up the dye, such tissue can be preferentially destroyed by radiation, typically by high intensity red light.
When a patient is catheterized with a light-emitting catheter that is inserted into the diseased artery or other body lumen, the placement is often likely to be offset from the longitudinal axis of the lumen. Such a configuration will result in a nonuniform exposure of the walls of the lumen by the light-emitting portion of the catheter. Nonuniform radiation exposure of the walls can result in damage to the lumen and/or nonuniform activation of the absorbed hematoporphyrin-like dyes.
In one embodiment of the Spears '544 patent, a light-emitting balloon catheter is employed to address the "centering problem." The catheter includes an inflatable balloon secured to the distal end of the catheter tube for inflation with gas from a remote source, and optical fibers which are disposed within the catheter, such that upon inflation of the balloon, light can be transmitted through the interior of the balloon to irradiate the target region of the lumen.
Although such a balloon catheter can act to center the light-emitting portion of the catheter, the balloon also acts to obstruct the flow of blood, therapeutic fluids, or air. Phototherapeutic treatments can take more than fifteen minutes. Thus, the duration of these procedures can preclude using a balloon catheter as a device for centering the light-emitting portion of the optical fiber since blocking a bloodstream or airway for an extended period of time is often impractical.
Accordingly, there exists a need for better apparatus for fiber-optic phototherapy. In particular, devices that can provide substantially uniform radiation exposure of a patient's lumen by centering a light-emitting catheter without occluding the lumen would meet a particularly important need in the field of minimally-invasive phototherapeutic surgery. Moreover, a device that can help stabilize the phototherapeutic instrument in operation (such as within an airway or blood vessel) would also be particularly useful. Uniform radiation exposure of the walls of the lumen while allowing flow of fluids past the light delivery device will make fiber optic phototherapy more practical and predictable.

Non-occluding phototherapy probe stabilizers


Mechanically alloyed hydrogen storage materials having a major atomic percentage of magnesium and a minor atomic percentage of at least two elements selected from the group consisting of nickel, molybdenum, iron and titanium. Preferably the mechanical alloy comprises a multi-phase material, including at least one amorphous phase. Also, the at least two elements are preferably either nickel (from about 5 to 15 at. %) and molybdenum (from about 0.5 to 5 at. %) or iron (from about 5 to 15 at. %) and titanium (from about 5 to 15 at. %). The hydrogen storage materials are created by mechanical alloying in a milling apparatus under an inert atmosphere, such as argon, or a mixed atmosphere, such as argon and hydrogen. The speed and length of the milling are varied.

Growing energy needs have prompted specialists to take cognizance of the fact that the traditional energy resources, such as coal, petroleum or natural gas, are not inexhaustible, or at least that they are becoming costlier all the time, and that it is advisable to consider replacing them gradually with other energy sources, such as nuclear energy, solar energy, or geothermal energy. Hydrogen, too, is coming into use as an energy source.
Hydrogen may be used, for example, as fuel for internal-combustion engines in place of hydrocarbons. In this case it has the advantage of eliminating atmospheric pollution through the formation of oxides of carbon or of sulfur upon combustion of the hydrocarbons. Hydrogen may also be used to fuel hydrogen-air fuel cells for production of the electricity needed for electric motors.
One of the problems posed by the use of hydrogen is its storage and transportation. A number of solutions have been proposed:
Hydrogen may be stored under high pressure in steel cylinders, but this approach has the drawback of requiring hazardous and heavy containers which are difficult to handle (in addition to having a low storage capacity of about 1% by weight). Hydrogen may also be stored in cryogenic containers, but this entails the disadvantages associated with the use of cryogenic liquids; such as, for example, the high cost of the containers, which also require careful handling. There are also "boil off" losses of about 2-5% per day.
Another method of storing hydrogen is to store it in the form of a hydride, which then is decomposed at the proper time to furnish hydrogen. The hydrides of iron-titanium, lanthanum-nickel, vanadium, and magnesium have been used in this manner, as described in French Pat. No. 1,529,371.
The MgH.sub.2 --Mg system is the most appropriate of all known metal-hydride and metal systems that can be used as reversible hydrogen-storage systems because it has the highest percentage by weight (7.65% by weight) of theoretical capacity for hydrogen storage and hence the highest theoretical energy density (2332 Wh/kg; Reilly & Sandrock, Spektrum der Wissenschaft, April 1980, 53) per unit of storage material.
Although this property and the relatively low price of magnesium make the MgH.sub.2 --Mg seem the optimum hydrogen storage system for transportation, for hydrogen-powered vehicles that is, its unsatisfactory kinetics have prevented it from being used up to the present time. It is known for instance that pure magnesium can be hydrided only under drastic conditions, and then only very slowly and incompletely. The dehydriding rate of the resulting hydride is also unacceptable for a hydrogen storage material (Genossar & Rudman, Z. f. Phys. Chem., Neue Folge 116, 215 [1979], and the literature cited therein).
Moreover, the hydrogen storage capacity of a magnesium reserve diminishes during the decomposition-reconstitution cycles. This phenomenon may be explained by a progressive poisoning of the surface, which during the reconstitution renders the magnesium atoms located in the interior of the reserve inaccessible to the hydrogen.
To expel the hydrogen in conventional magnesium or magnesium/nickel reserve systems, temperatures of more than 250.degree. C. are required, with a large supply of energy at the same time. The high temperature level and the high energy requirement for expelling the hydrogen have the effect that, for example, a motor vehicle with an internal combustion engine, cannot exclusively be operated from these stores. This occurs because the energy contained in the exhaust gas, in the most favorable case (full load), is sufficient for meeting 50% of the hydrogen requirement of the internal combustion engine from a magnesium or magnesium/nickel store. Thus, the remaining hydrogen demand must be taken from a hydride store. For example, this store can be titanium/iron hydride (a typical low-temperature hydride store) which can be operated at temperatures down to below 0C. These low-temperature hydride stores have the disadvantage of only having a low hydrogen storage capacity.
Storage materials have been developed in the past, which have a relatively high storage capacity but from which hydrogen is nevertheless expelled at temperatures of up to about 250.degree. C. U.S. Pat. No. 4,160,014 describes a hydrogen storage material of the formula Ti.sub.[1-x] Zr.sub.[x] Mn.sub.[2-y-z] Cr.sub.[y] V.sub.[z], wherein x=0.05 to 0.4, y=0 to 1 and z=0 to 0.4. Up to about 2% by weight of hydrogen can be stored in such an alloy. In addition to this relatively low storage capacity, these alloys also have the disadvantage that the price of the alloy is very high when metallic vanadium is used.
Moreover, U.S. Pat. No. 4,111,689 has disclosed a storage alloy which comprises 31 to 46% by weight of titanium, 5 to 33% by weight of vanadium and 36 to 53% by weight of iron and/or manganese. Although alloys of this type have a greater storage capacity for hydrogen than the alloy according to U.S. Pat. No. 4,160,014, hereby incorporated by reference, they have the disadvantage that temperatures of at least 250.degree. C. are necessary in order to completely expel the hydrogen. At temperatures of up to about 100.degree. C., about 80% of the hydrogen content can be discharged in the best case. However, a high discharge capacity, particularly at low temperatures, is frequently necessary in industry because the heat required for liberating the hydrogen from the hydride stores is often available only at a low temperature level.
In contrast to other metals or metal alloys, especially such metal alloys which contain titanium or lanthanum, magnesium is preferred for the storage of hydrogen not only because of its lower material costs, but above all, because of its lower specific weight as a storage material. However, the hydriding EQU Mg+H.sub.2 .fwdarw.MgH.sub.2
is, in general, more difficult to achieve with magnesium, inasmuch as the surface of the magnesium will rapidly oxidize in air so as to form stable MgO and/or Mg(OH).sub.2 surface layers. These layers inhibit the dissociation of hydrogen molecules, as well as the absorption of produced hydrogen atoms and their diffusion from the surface of the granulate particles into the magnesium storage mass.
Intensive efforts have been devoted in recent years to improve the hydriding ability of magnesium by doping or alloying it with such individual foreign metals as aluminum (Douglass, Metall. Trans. 6a, 2179 [1975]) indium (Mintz, Gavra, & Hadari, J. Inorg. Nucl. Chem. 40, 765 [1978]), or iron (Welter & Rudman, Scripta Metallurgica 16, 285 [1982]), with various foreign metals (German Offenlegungsschriften 2 846 672 and 2 846 673), or with intermetallic compounds like Mg.sub.2 Ni or Mg.sub.2 Cu (Wiswall, Top Appl. Phys. 29, 201 [1978] and Genossar & Rudman, op. cit.) and LaNi5 (Tanguy et al., Mater. Res. Bull. 11, 1441 [1976]).
Although these attempts did improve the kinetics somewhat, certain essential disadvantages have not yet been eliminated from the resulting systems. The preliminary hydriding of magnesium doped with a foreign metal or intermetallic compound still demands drastic reaction conditions, and the system kinetics will be satisfactory and the reversible hydrogen content high only after many cycles of hydriding and dehydriding. Considerable percentages of foreign metal or of expensive intermetallic compound are also necessary to improve kinetic properties. Furthermore, the storage capacity of such systems are generally far below what would theoretically be expected for MgH.sub.2.
It is known that the storage quality of magnesium and magnesium alloys can also be enhanced by the addition of materials which may help to break up stable oxides of magnesium. For example, such an alloy is Mg.sub.2 Ni, in which the Ni appears to form unstable oxides. In this alloy, thermodynamic examinations indicated that the surface reaction Mg.sub.2 Ni+O.sub.2 .fwdarw.2MgO+Ni extended over nickel metal inclusions which catalyze the hydrogen dissociation-absorption reaction. Reference may be had to A. Seiler et al., Journal of Less-Common Metals 73, 1980, pages 193 et seq.
One possibility for the catalysis of the hydrogen dissociation-absorption reaction on the surface of magnesium lies also in the formation of a two-phase alloy, wherein the one phase is a hydride former, and the other phase is a catalyst. Thus, it is known to employ galvanically-nickeled magnesium as a hydrogen storage, referring to F. G. Eisenberg et al. Journal of Less-Common Metals 74, 1980, pages 323 et seq. However, there were encountered problems during the adhesion and the distribution of the nickel over the magnesium surface.
In order to obtain an extremely dense and good adherent catalyst phase under the formation alone of equilibrium phases, it is also known that for the storage of hydrogen there can be employed an eutectic mixture of magnesium as a hydride-forming phase in conjunction with magnesium copper (Mg.sub.2 Cu), referring to J. Genossar et al., Zeitschrift fur Physikalische Chemie Neue Folge 116, 1979, pages 215 et seq. The storage capacity per volume of work material which is achieved through this magnesium-containing granulate does not, however, meet any high demands because of the quantity of magnesium copper which is required for the eutectic mixture.
The scientists of this era looked at various materials and postulated that a particular crystalline structure is required for hydrogen storage, see, for example, "Hydrogen Storage in Metal Hydride", Scientific American, Vol. 242, No. 2, pp. 118-129, February, 1980. It was found that it is possible to overcome many of the disadvantages of the prior art materials by utilizing a different class of materials, disordered hydrogen storage materials. For example, U.S. Pat. No. 4,265,720 to Guenter Winstel for "Storage Materials for Hydrogen" describes a hydrogen storage body of amorphous or finely crystalline silicon. The silicon is preferably a thin film in combination with a suitable catalyst and on a substrate.
Laid-open Japanese Patent Application No. 55-167401, "Hydrogen Storage Material," in the name of Matsumato et al, discloses bi or tri-element hydrogen storage materials of at least 50 volume percent amorphous structure. The first element is chosen from the group Ca, Mg, Ti, Zr, Hf, V, Nb, Ta, Y and lanthanides, and the second from the group Al, Cr, Fe, Co, Ni, Cu, Mn and Si. A third element from the group B, C, P and Ge can optionally be present. According to the teaching of No. 55-167401, the amorphous structure is needed to overcome the problem of the unfavorably high desorption temperature characteristic of most crystalline systems. A high desorption temperature (above, for example, 150.degree. C.) severely limits the uses to which the system may be put.
According to Matsumoto et al, the material of at least 50% amorphous structure will be able to desorb at least some hydrogen at relatively low temperatures because the bonding energies of the individual atoms are not uniform, as is the case with crystalline material, but are distributed over a wide range.
Matsumoto et al claims a material of at least 50% amorphous structure. While Matsumoto et al does not provide any further teaching about the meaning of the term "amorphous," the scientifically accepted definition of the term encompasses a maximum short range order of about 20 Angstroms or less.
The use by Matsumato et al of amorphous structure materials to achieve better desorption kinetics due to the non-flat hysteresis curve is an inadequate and partial solution. The other problems found in crystalline hydrogen storage materials, particularly low useful hydrogen storage capacity at moderate temperature, remain.
However, even better hydrogen storage results, i.e., long cycle life, good physical strength, low absorption/desorption temperatures and pressures, reversibility, and resistance to chemical poisoning, may be realized if full advantage is taken of modification of disordered metastable hydrogen storage materials. Modification of disordered structurally metastable hydrogen storage materials is described in U.S. Pat. No. 4,431,561 to Stanford R. Ovshinsky et al. for "Hydrogen Storage Materials and Method of Making the Same". As described therein, disordered hydrogen storage materials, characterized by a chemically modified, thermodynamically metastable structure, can be tailor-made to possess all the hydrogen storage characteristics desirable for a wide range of commercial applications. The modified hydrogen storage material can be made to have greater hydrogen storage capacity than do the single phase crystalline host materials. The bonding strengths between the hydrogen and the storage sites in these modified materials can be tailored to provide a spectrum of bonding possibilities thereby to obtain desired absorption and desorption characteristics. Disordered hydrogen storage materials having a chemically modified, thermodynamically metastable structure also have a greatly increased density of catalytically active sites for improved hydrogen storage kinetics and increased resistance to poisoning.
The synergistic combination of selected modifiers incorporated in a selected host matrix provides a degree and quality of structural and chemical modification that stabilizes chemical, physical, and electronic structures and conformations amenable to hydrogen storage.
The framework for the modified hydrogen storage materials is a lightweight host matrix. The host matrix is structurally modified with selected modifier elements to provide a disordered material with local chemical environments which result in the required hydrogen storage properties.
Another advantage of the host matrix described by Ovshinsky, et al. is that it can be modified in a substantially continuous range of varying percentages of modifier elements. This ability allows the host matrix to be manipulated by modifiers to tailor-make or engineer hydrogen storage materials with characteristics suitable for particular applications. This is in contrast to multi-component single phase host crystalline materials which generally have a very limited range of stoichiometry available. A continuous range of control of chemical and structural modification of the thermodynamics and kinetics of such crystalline materials therefore is not possible.
A still further advantage of these disordered hydrogen storage materials is that they are much more resistant to poisoning. As stated before, these materials have a much greater density of catalytically active sites. Thus, a certain number of such sites can be sacrificed to the effects of poisonous species, while the large number of non-poisoned active sites still remain to continue to provide the desired hydrogen storage kinetics.
Another advantage of these disordered materials is that they can be designed to be mechanically more flexible than single phase crystalline materials. The disordered materials are thus capable of more distortion during expansion and contraction allowing for greater mechanical stability during the absorption and desorption cycles.
One drawback to these disordered materials is that, in the past, some of the Mg based alloys have been difficult to produce. Particularly those materials that did not form solutions in the melt. Also, the most promising materials (i.e. magnesium based materials) were extremely difficult to make in bulk form. That is, while thin-film sputtering techniques could make small quantities of these disordered alloys, there was no bulk preparation technique.
Then in the mid 1980's, two groups developed mechanical alloying techniques to produce bulk disordered magnesium alloy hydrogen storage materials. Mechanical alloying was found to facilitate the alloying of elements with vastly different vapor pressures and melting points (such as Mg with Fe or Ti etc.), especially when no stable intermetallic phases exist. Conventional techniques like induction melting have been found to be inadequate for such purposes.
The first of the two groups was a team of French scientists which investigated mechanical alloying of materials of the Mg-Ni system and their hydrogen storage properties. See Senegas, et al., "Phase Characterization and Hydrogen Diffusion Study in the Mg--Ni--H System", Journal of the Less-Common Metals, Vol. 129, 1987, pp. 317-326 (binary mechanical alloys of Mg and Ni incorporating 0, 10, 25 and 55 wt. % Ni); and also, Song, et al. "Hydriding and Dehydriding Characteristics of Mechanically Alloyed Mixtures Mg-xwt. % Ni (x=5, 10, 25 and 55)", Journal of the Less-Common Metals, Vol. 131, 1987, pp. 71-79 (binary mechanical alloys of Mg and Ni incorporating 5, 10, 25 and 55 wt. % Ni).
The second of the two groups was a team of Russian scientists which investigated the hydrogen storage properties of binary mechanical alloys of magnesium and other metals. See Ivanov, et al., "Mechanical Alloys of Magnesium--New Materials For Hydrogen Energy", Doklady Physical Chemistry (English Translation) vol. 286:1-3, 1986, pp. 55-57, (binary mechanical alloys of Mg with Ni, Ce, Nb, Ti, Fe, Co, Si and C); also, lvanov, et al. "Magnesium Mechanical Alloys for Hydrogen Storage", Journal of the Less-Common Metals, vol. 131, 1987, pp.25-29 (binary mechanical alloys of Mg with Ni, Fe, Co, Nb and Ti); and Stepanov, et al., "Hydriding Properties of Mechanical Alloys of Mg--Ni", Journal of the Less-Common Metals, vol. 131, 1987, pp.89-97 (binary mechanical alloys of the Mg--Ni system). See also the collaborative work between the French and Russian groups, Konstanchuk, et al., "The Hydriding Properties of a Mechanical Alloy With Composition Mg-25% Fe", Journal of the Less-Common Metals, vol. 131, 1987, pp.181-189 (binary mechanical alloy of Mg and 25 wt. % Fe).
Later, in the late 1980's and early 1990's, a Bulgarian group of scientists (sometimes in collaboration with the Russian group of scientists) investigated the hydrogen storage properties of mechanical alloys of magnesium and metal oxides. See Khrussanova, et al., "Hydriding Kinetics of Mixtures Containing Some 3d-Transition Metal Oxides and Magnesium", Zeitschrift fur Physikalische Chemie Neue Folge, Munchen, vol. 164, 1989, pp.1261-1266 (comparing binary mixtures and mechanical alloys of Mg with TiO.sub.2, V.sub.2 O.sub.5, and Cr.sub.2 O.sub.3); and Peshev, et al., "Surface Composition of Mg--TiO.sub.2 Mixtures for Hydrogen Storage, Prepared by Different Methods", Materials Research Bulletin, vol. 24, 1989, pp.207-212 (comparing conventional mixtures and mechanical alloys of Mg and TiO.sub.2). See also, Khrussanova, et al., "On the Hydriding of a Mechanically Alloyed Mg(90%)-V.sub.2 O.sub.5 (10%) Mixture", International Journal of Hydrogen Energy, vol. 15, No. 11, 1990, pp.799-805 (investigating the hydrogen storage properties of a binary mechanical alloy of Mg and V.sub.2 O.sub.5); and Khrussanova, et al., "Hydriding of Mechanically Alloyed Mixtures of Magnesium With MnO.sub.2, Fe.sub.2 O.sub.3, and NiO", Materials Research Bulletin, vol. 26, 1991, pp. 561-567 (investigating the hydrogen storage properties of a binary mechanical alloys of Mg with and MnO.sub.2, Fe.sub.2 O.sub.3, and NiO). Finally, see also, Khrussanova, et al., "The Effect of the d-Electron Concentration on the Absorption Capacity of Some Systems for Hydrogen Storage", Materials Research Bulletin, vol. 26, 1991, pp. 1291-1298 (investigating d-electron concentration effects on the hydrogen storage properties of materials, including mechanical alloys of Mg and 3-d metal oxides); and Mitov, et al., "A Mossbauer Study of a Hydrided Mechanically Alloyed Mixture of Magnesium and Iron(III) Oxide", Materials Research Bulletin, vol. 27, 1992, pp. 905-910 (Investigating the hydrogen storage properties of a binary mechanical alloy of Mg and Fe.sub.2 O.sub.3).
Most recently, a group of Chinese scientists have investigated the hydrogen storage properties of some mechanical alloys of Mg with other metals. See, Yang, et al., "The Thermal Stability of Amorphous Hydride Mg.sub.50 Ni.sub.50 H.sub.54 and Mg.sub.30 Ni.sub.70 H.sub.45 ", Zeitschrift fur Physikalische Chemie, Munchen, vol. 183, 1994, pp. 141-147 (Investigating the hydrogen storage properties of the mechanical alloys Mg.sub.50 Ni.sub.50 and Mg.sub.30 Ni.sub.70); and Lei, et al., "Electrochemical Behavior of Some Mechanically Alloyed Mg--Ni-based Amorphous Hydrogen Storage Alloys", Zeitschrift fur Physikalische Chemie, Munchen, vol. 183, 1994, pp. 379-384 (investigating the electrochemical [i.e. Ni--MH battery] properties of some mechanical alloys of Mg--Ni with Co, Si, Al, and Co--Si).
The present inventors have continued the investigation of mechanical alloys of Mg with other metals for use as hydrogen storage materials and have achieved outstanding results with the magnesium mechanical alloys disclosed herein.

Magnesium mechanical alloys for thermal hydrogen storage


The present invention relates to a Braille reading display terminal device in which a non-intelligence-type Braille reading input/output unit is connected to a host computer through an expansion bus, an expansion bus interface is interposed between the input/output sections of the Braille reading input/output unit and the expansion bus, and unit input/output elements of the input/output sections sections are accessed or controlled through the expansion bus based on software in the host computer.

1. Field of the Invention
The present invention relates to a Braille reading display terminal device which has an improved interface between the unit and its host computer.
2. Description of the Related Art
A conventional Braille reading display device is connected to a personal computer serving as a host computer and has an intelligence function of inputting Braille information, reading the information from a tactile pins display, and outputting the information as a voice in combination with a voice synthesizer.
The conventional Braille reading display device comprises a microprocessor having a ROM for storing Braille codes and a RAM for temporarily storing processing information to input/output Braille information, and a DIP SW (dual inline package switch) for selecting various Braille notations (e.g., six-dot pattern and eight-dot pattern) from the ROM.
Like generally-used peripheral terminal units of personal computers, the conventional Braille reading display device is connected to various personal computers through RS-232C or CENTRONICS, both of which are standard interfaces, with the result that information is transferred in series o in parallel between the device and the personal computers through the interface. Information processing peculiar to the Braille reading display device is executed by the microprocessor included therein.
However, the conventional braille reading display device has the following drawbacks.
(1) Since a widespread Braille notation method has not yet been established, information stored in a ROM has to be rewritten and the ROM has to be exchanged with another in accordance with various Braille notation methods. Since an exchange of ROMs is difficult for users, it is usually performed by makers. In most cases, however, it is difficult even for makers because the ROMs are widely used.
(2) It is troublesome to select one of interfaces RS-232C and CENTRONICS and set a transfer speed, various parameters, etc. using the DIP SW, in order to select a necessary one from various Braille notations stored in a ROM.
(3) Since a program of grammar (e.g., Six-Dot Japanese Braille Notation) proper to Braille notations has to be stored in a ROM, the capacity of the ROM is increased.
(4) Since there are different, methods for representing, Chinese characters by Braille notations, the Braille reading display device cannot be applied to all the methods.
(5) Since various peripheral units are required in addition to a CPU, a ROM, and a RAM, the cost of hardware is increased.
As described above, the conventional Braille display device has the drawback of increased total costs including running costs, debug costs, and the like, which puts much strain on both makers and users.