WO2011092127A1 - 14,17-bridged estratriene derivatives comprising heterocyclic bioisosteres for the phenolic a-ring - Google Patents

Abstract

The present invention is directed to novel 14, 17-bridged pyrazolo-estrien and triazolo- estrien- derivatives, pharmaceutical compositions containing them and their use in the treatment or prevention of disorders and diseases mediated by an estrogen receptor such as hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, hormone sensitive cancers and hyperplasia (in tissues including breast, endometrium, and cervix in women and prostate in men), endometriosis, uterine fibroids, osteoarthritis; and as contraceptive agents either alone or in combination with a progestogen or progestogen antagonist. The compounds of the invention are selective estrogen receptor agonists..

Description

14,17-BRIDGED ESTRATRIENE DERIVATIVES COMPRISING HETEROCYCLIC BIOISOSTERES FOR THE PHENOLIC A-RING

The present invention is directed to novel 14, 17-bridged pyrazolo-estrien and triazolo- estrien-derivatives, pharmaceutical compositions containing them and their use as contraceptive agents either alone or in combination with a progestogen or progestogen antagonist or their use in the treatment or prevention of disorders and diseases mediated by an estrogen receptor such as hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, hormone sensitive cancers and hyperplasia (in tissues including breast, endometrium, and cervix in women and prostate in men), endometriosis, uterine fibroids, osteoarthritis. The compounds of the invention are selective estrogen receptor agonists.

Estrogens are a group of female hormones essential for the reproductive process and for the development of the uterus, breasts, and other physical changes associated with puberty. Estrogens have an effect on various tissues throughout a woman's body, not only those involved in the reproductive process, such as the uterus, breasts, and external genitalia, but also tissues in the central nervous system, bones, the liver, skin, and the urinary tract. The ovaries produce most of the estrogens in women's body. Endogenous estrogens, such as 17beta-estradiol and estrone, play a central role in the development of and maintenance of the female sex organs, mammary glands, and other sexual characteristics. In addition to their role as female sex hormone, estrogens are involved in the growth and function of a number of other tissues, such as the cardiovascular system, the central nervous system, and the skeleton, both in females and males. The significance of the estrogens in the development of the female reproductive system led to the development of a variety of compounds that interact with the estrogen receptors, such as contraceptives and agents for treatment of breast cancers.

Combined oral contraceptive pills (COCPs) were developed to prevent ovulation by suppressing the release of gonadotropins. Combined hormonal contraceptives, including COCPs, inhibit follicular development and prevent ovulation as their primary mechanism of action (Trussell, James (2007). "Contraceptive Efficacy", in Hatcher, Robert A., et al: Contraceptive Technology, 19th rev. ed., New York: Ardent Media.; Speroff, Leon; Darney, Philip D. (2005). "Oral Contraception", A Clinical Guide for Contraception, 4th ed., Philadelphia: Lippincott Williams & Wilkins, pp. 21 -138; Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins" in Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.): Goodman & Gilman's, The Pharmacological Basis of Therapeutics, 1 1 th ed., New York: McGraw-Hill, pp. 1541 -1571 ; Glasier, Anna (2006). "Contraception", in DeGroot, Leslie J.; Jameson, J. Larry (eds.): Endocrinology, 5th edition, Philadelphia: Elsevier Saunders, pp. 2993-3003; Rivera R, Yacobson I, Grimes D (1999). "The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices". Am J Obstet Gynecol 181 (5 Pt 1 ): 1263-9). Progestagen negative feedback decreases the pulse frequency of gonadotropin- releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and greatly decreases the release of luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestagen negative feedback and the lack of estrogen positive feedback on LH release prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation (Trussell, James (2007). "Contraceptive Efficacy", in Hatcher, Robert A., et al: Contraceptive Technology, 19th rev. ed., New York: Ardent Media.; Speroff, Leon; Darney, Philip D. (2005). "Oral Contraception", A Clinical Guide for Contraception, 4th ed., Philadelphia: Lippincott Williams & Wilkins, pp. 21 -138; Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins", in Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.): Goodman & Gilman's, The Pharmacological Basis of Therapeutics, 1 1th ed., New York: McGraw-Hill, pp. 1541 -1571 ).

Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the release of FSH, which inhibits follicular development and helps prevent ovulation (Trussell, James (2007). "Contraceptive Efficacy", in Hatcher, Robert A., et al: Contraceptive Technology, 19th rev. ed. , New York: Ardent Media. ; Speroff, Leon; Darney, Philip D. (2005). "Oral Contraception", A Clinical Guide for Contraception, 4th ed., Philadelphia: Lippincott Williams & Wilkins, pp. 21 -138; Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins", in Brunton, Laurence L. ; Lazo, John S. ; Parker, Keith L. (eds.): Goodman & Gilman's The Pharmacological Basis of Therapeutics, 1 1 th ed., New York: McGraw-Hill, pp. 1541 -1571 ). Although the oral contraceptives are highly effective, their use is associated with unpleasant side effects (such as nausea, depression, weight gain, and headache) and an increased long-time risk of severe disease (such as thromboembolism, stroke, myocardial infarction , hepatic adenoma, gall bladder disease, and hypertension). Bleeding irregularities (such as breakthrough bleeding, spotting, and amenorrhea) are also frequent. A progestin, when administered alone, causes an increased incidence of changes in menstrual patterns, especially a marked increase in the amou nt and duration of menstrual bleeding. The estrogen receptor beta (ER beta) was discovered as a second subtype of the estrogen receptor (Kui per et al . (1 996), Proc. Natl . Acad . Sci . 93 : 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53; Tremblay et al. (1997), Molecular Endocrinology 1 1 : 353-365). Intensive efforts are being made to investigate the distribution and role of ER alpha and ER beta in several tissues.

The estrogen receptor alpha (ER alpha) is expressed in neurons projecting to GnRH positive neurons in the hypothalamus and is required for mediating the positive estradiol feedback leading to the preovulatory LH surge. On the other hand, estrogen receptor alpha in the pituitary and in the hypothalamus is involved in mediating the negative feedback of estradiol which leads to suppression of LH/FSH secretion. Estrogen receptor alpha activation is important for the induction of progesterone receptor expression in some reproductive organs such as the uterus and the hypothalamus. In other words, estrogen receptor activation is a prerequisite for progestin action. Estrogen receptor alpha mediates estrogenic responses in the uterus (stimulation of epithelial cell proliferation), in the mammary gland (stimulation of epithelial cell proliferation), the bone (prevention of osteoblast apoptosis) and the brain (prevention of hot flushes).

The primary role of the estrogenic component in combined oral contraception is the maintenance of a regular bleeding pattern during the pill-free days. The contraceptive function, i.e. ovulation inhibition is primarily mediated by the progestagenic component. However, ovulation inhibition leads to suppression of endogenous estradiol levels which would cause hot flushes and bone loss in young women . Addition of estrogens in combined oral contraception prevents these symptoms. Moreover, the estrogenic com ponent is requ ired to ind uce the progesterone receptor and to enable the contraceptive action of the progestagenic component. In other words, without estrogen addition , much higher doses of progestins would be required to induce ovulation inhibition.

Intensive efforts have focused on the selective estrogen receptor modulators for treatment and prevention of postmenopausal conditions, such as osteoporosis, coronary artery disease, depression and Alzheimer disease.

Menopause is defined as the permanent cessation of menses due to loss of ovarian follicular function and the almost termination of estrogen production . The midlife transition of menopause is characterized by a decrease in estrogen that provokes both short-term and long-term symptoms with the vasomotor, urogenital, cardiovascular, and skeletal and central nervous systems, such as hot flushes, u rogen ital atrophy, increased risk of cardiovascular disease, osteoporosis, cognitive and psychological impairment, including an increased risk of cognitive disorders and Alzheimer's disease (AD). All these menopausal symptoms can be treated successfully with estrogen. Since estradiol stimulates uterine epithelial cell proliferation and thus increases the risk for endometrial carcinoma, the addition of progestins is required in postmenopausal women that still have a uterus. Progestins inhibit the estradiol activated uterine epithelial cell proliferation.

Seventy-five percent of all women experience some occu rrence of vasomotor symptoms associated with the onset of menopause such as body sweating and hot flushes. These complaints may begin several years before menopause and in some women may continue for more than 10 years either relatively constant or as instant attacks without a definable, provoking cause.

Urogenital symptoms associated with the onset of menopause involving the vagina include a sensation of dryness, burning, itching, pain during intercourse, superficial bleeding and discharge, along with atrophy and stenosis. Symptoms involving the urinary tract include a burning sensation during urination, frequent urgency, recurrent urinary tract infections, and urinary incontinence. These symptoms have been reported to occur in up to 50% of all women near the time of menopause and are more frequent a few years after menopause. If left untreated, the problems can become permanent. Heart attack and stroke are major causes of morbidity and mortality among senior women. Female morbidity from these diseases increases rapidly after menopause. Women who undergo prematu re menopause are at greater coronary risk than menstruating women of similar age. The presence of serum estrogen has a positive effect on serum lipids. The hormone promotes vasodilatation of blood vessels, and enhances the formation of new blood vessels. Thus the decrease in serum estrogen levels in postmenopausal women results in adverse cardiovascular effect. Additionally, it is theorized that differences in the ability of blood to coagulate may account for the observed difference in the occurrence of heart disease before and after menopause. The skeleton is under a continuous process of bone degeneration and regeneration in a carefully regulated interaction among the bone cells. These cells are directly affected by estrogen. Estrogen deficiency results in a loss of bone structure and a decrease of bone strength. Rapid loss of bone mass during the year immediately following menopause leads to postmenopausal osteoporosis and increased risk of fracture.

Estrogen deficiency is also one of the causes for the degenerative changes in the central nervous system and may lead to Alzheimer's disease and decline of cognition. Recent evidence suggests an association between estrogen, menopause and cognition. More particularly, it has been reported that estrogen replacement therapy and the use of estrogen in women may prevent the development of Alzheimer disease and improve cognitive function.

Hormone replacement therapy (HRT) - more specifically estrogen replacement therapy (ERT) - is commonly prescribed to address the medical problems associated with menopause, and also to help h inder osteoporosis and primary card iovascu lar complications (such as coronary artery disease) in both a preventive and therapeutical manner. As such, HRT is considered as a medical therapy for prolonging the average life span of postmenopausal women and providing a better quality of life.

ERT effectively relieves the climacteric symptoms and urogenital symptoms and has shown sign ificant benefits in the prevention and treatment of heart d isease i n postmenopausal women. Clinical reports have shown that ERT lowered heart attack rates and mortality rates in populations that received ERT versus similar populations not on ERT. ERT initiated soon after menopause may also help maintain bone mass for several years. Controlled investigations have shown that treatment with ERT has a positive effect even in older women up to age of 75 years.

However, as mentioned above, there are numerous undesirable effects associated with ERT that reduce patient compliance. Venous thromboembolism, gallbladder disease, resumption of menses, mastodynia and a possible increased risk of developing uterine and/or breast cancer are the risks associated with ERT. Up to 30% of women who were prescribed ERT did not fill the prescription, and the discontinuation rate is between 38% and 70%, with safety concerns and adverse effects (bloating and break-through bleeding) the most important reasons for discontinuation. WO 2004/0053 1 4 d es c ri b e s novel estrieno[3.2-b]/[3,4-c]pyrrole derivatives, pharmaceutical compositions containing them and their use in the treatment or prevention of disorders and diseases mediated by an estrogen receptor such as hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, hormone sensitive Cancers and hyperplasia (in tissues including breast, endometrium , and cervix in women and prostate in men), endometriosis, uterine fibroids, osteoarthritis; and as contraceptive agents either alone or in combination with a progestogen or progestogen antagonist.

WO 2007/089291 discloses non-steroidal pyrazole derivatives which are useful for treating or preventing a variety of conditions related to estrogen functioning, especially for eliciting an estrogen receptor modulating effect in a mammal in need thereof. The described compounds are also relatively weak Estrogen Receptor agonists.

For combined contraception Ethinylestradiol is the current market standard. However, the administration of Ethinylestradiol is associated with an increased risk for venous thrombembolism and a high inter- and intraindividual variability of the bioavailability. Unpublished EP 08161 108.9 describes novel pyrazolo-estrien and triazolo-estrien derivatives, which are selective estrogen receptor modulators. The claimed compounds show an oral bioavailability comparable to Ethinylestradiol and also have considerably reduced hepatic estrogenicity compared to the current market standard Ethinylestradiol.

It is an object of the present invention to provide further compounds which are estrogen receptor agonists and also have an oral bioavailability at least comparable to Ethinylestradiol. The object is achieved according to the present invention by the provision of compounds of the general formula (I)

(I) is selected from the group consisting of nitrogen, CH, CCI and CF are independently from each other selected from the grou p of hydrogen, fluorine, chlorine, hydroxyl and methyl or R^6a and R^6b stand together for an oxygen atom,

R^11a and R^11b are independently from each other selected from the group of hydrogen, fluorine, chlorine, hydroxyl, methyl and methoxy or stand together for an oxygen atom,

is selected from the group of hydrogen, fluorine, chlorine, hydroxyl and methyl, or stands together with R¹⁶ for an additional bond is selected from the group of hydrogen, fluorine, chlorine, hydroxyl and methyl, or stands together with R¹⁵ for an additional bond or a pharmaceutically acceptable salt thereof.

All unsubstituted positions have hydrogens in alpha or beta direction

The com pou nds accord i ng to the present i nvention show a com parable oral bioavailability as Ethinylestradiol.

Preferably, the compounds according to the present invention exhibit agonistic activity on the Estrogen Receptor (ER) in the uterus, in the bone and brain as well as in the breast like ethinyl estradiol and estradiol. Therefore, they are suitable for oral contraception.

Therefore, use of the compounds of the present invention for contraception alone or in combination with an additional active ingredient is an embodiment of this invention. The ER agonistic activity in the uterus allows a sufficient bleeding control which is desirable for a contraception method. The ER agonistic activity in the bone and brain is preferred in order to prevent young women who are taking combined oral contraception from bone loss and hot flushes. Additionally, the compounds of the invention are suitable for the treatment and prevention of decreasing systemic estrogen levels. Preferably the compounds according to the invention are suitable for ERT, especially for the treatment and prevention of vasomotor, urogenital and cognitive disorders

Illustrative of the invention is a pharmaceutical composition which comprises at least one compound described in formula (I) and optionally at least one pharmaceutically suitable excipient and/or carrier. A further embodiment of the present invention is a pharmaceutical composition comprising compounds of the general formula I and, optionally at least one additional active ingredient. According to the present invention the additional active ingredient is a SERM (selective estrogen receptor modulator) or a SERD (selective estrogen receptor destabilizer) or a progestogen.

An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediated by one or more estrogen receptors in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the: compounds or pharmaceutical compositions described above.

Illustrating the invention is a method of contraception comprising administering to a subject in need thereof co-therapy with an effective amount of any of the compounds described herein with a progestogen. Progestogens which are useful for such co- therapy are progesterone, trimegestone, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, chlormadinone acetate, nestorone, levonorgestrel , norgestimate, desogestrel, ethonogestrel (3-Ketodesogestrel), nomegestrol acetate (NOMAC), norethisterone acetate (NETA), drospirenone, gestodene, dienogest, norethindrone acetate, danazole, norgestrel, and tanaproget. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) hot flashes, (b) vaginal dryness, (c) osteopenia, (d) osteoporosis, (e) hyperlipidemia, (f) loss of cognitive function, (g) a degenerative brain disorder, (h) a cardiovascular disease, (i) a cerebrovascular disease (j) breast cancer, (k) endometrial cancer, (I) cervical cancer, (m) prostate cancer, (n) benign prostatic hyperplasia, (o) endometriosis, (p) uterine fibroids, (q) osteoarthritis and for (r) contraception in a subject in need thereof. For these indications the compounds according to the invention can likewise be used in combination with any given Selective Estrogen Receptor Destabilizer (SERD) or Selective Estrogen Receptor Modulator (SERM) or with a progestogen.

Suitable for combination with the compounds according to the invention in this connection are for example the following: fulvestrant and compounds claimed in WO98/007740, WO03/045971 and WO01/00652 (SERDs) as well as Tamoxifen, Raloxifen, Bazedoxifen, Arzoxifen, Lasofoxifen, Clomiphene, Ormeloxifene,

Levormeloxifene, Toremifene, Ospemifene, TAS-108 ((7alpha)-21 -[4-[(Diethylamino)~ eihyi]-2-methoxyphenoxyj~7~methyi~19-norpregna-1 ,3.5(10}-triene-3-o!-2-hydroxy-1 ,2,3- propanetricarboxyiate, CHF-4227 (3~(4~Me hoxyphenylV4-[4-[2~(1 ~pipendinyr)- ethoxy3benzyi]-2H-1 -benzopyran-7-o! hydrochloride), LY-2066948 (6-(4-Methane- sulfonylhenyl)-5-[4-(2-piperidin-1 -yl-ethoxy)phenoxy]-naphthalen-2-ol) and the compounds claimed in WO01/68634 and WO 03/033461 (SERMs) as well as progesterone, trimegestone, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, chlormadinone acetate, nestorone, levonorgestrel, norgestimate, desogestrel, ethonogestrel (3-Ketodesogestrel), nomegestrol acetate (NOMAC), norethisterone acetate (NETA), drospirenone, gestodene, dienogest, norethindrone acetate, danazole, norgestrel, and tanaproget (progestogens).

The present invention is preferably directed to compounds of formula (I)

wherein X, R^11a, R^11b R¹⁵, R¹⁶are as herein defined. As mentioned above, the compounds of the present invention are agonists of the estrogen receptor alpha and hence useful for the treatment and prevention of disorders associated with estrogen depletion, including, but not limited to hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cogn itive function , degenerative brain diseases, cardiovascular diseases and cerebrovascular diseases; for the treatment of hormone sensitive cancers and hyperplasia (in tissues including breast, endometrium, and cervix in women and prostate in men); for the treatment and prevention of endometriosis, uterine fibroids, and osteoarthritis. The compounds of the present invention are especially suitable as contraceptive agents either alone or in combination with a progestogen. Examples for useful progestogens are mentioned above.

For the combined oral contraception any of the compounds described herein have to be combined with a progestogen like progesterone, trimegestone, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, chlormadinone acetate, nestorone, levonorgestrel , norgestimate, desogestrel, ethonogestrel (3-Ketodesogestrel), nomegestrol acetate (NOMAC), norethisterone acetate (NETA), drospirenone, gestodene, dienogest, norethindrone acetate, danazole, norgestrel, and tanaproget.

As used herein, the term "disease or disorder modulated or mediated by an estrogen receptor" shall mean any disease or disorder which is mediated by the estrogen receptor alpha, any disease or disorder which is mediated by the estrogen receptor beta or any disease or disorder which is mediated by both the estrogen receptors alpha and beta. For example, hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, a degenerative brain disorder, cardiovascular disease, cerebrovascular disease, breast cancer, endometrial cancer, cervical cancer, prostate cancer, benign prostatic hyperplasia (BPH), endometriosis, uterine fibroids, osteoarthritis and contraception.

As used herein, the term "degenerative brain disease" shall include cognitive disorder, dementia (regardless of underlying cause) and Alzheimer's disease. As used herein, the term "cardiovascular disease" shall include elevated blood lipid levels, coronary arteriosclerosis and coronary heart disease.

As used herein, the term "cerebrovascular disease" shall include abnormal regional cerebral blood flow and ischemic brain damage. The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other cli nician , wh ich includes alleviation of the symptoms of the disease or disorder being treated. Wherein the present invention is directed to co-therapy comprising administration of one or more compound(s) of formula (I) and a progestogen, "therapeutically effective amount" shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response. For example, the therapeutically effective amount of co-therapy comprising administration of a compound of formula (I) and progestogen or SERM or SERD would be the amount of the compound of formula (I) and the amount of the progestogen, SERM or SERD that when taken together or sequentially have a combined effect that is therapeutically effective. Further, it will be recognized by one skilled in the art that in the case of co-therapy with a therapeutically effective amount, as in the example above, the amount of the compound of formula I and/or the amount of the progestogen or SERM or SERD individually may or may not be therapeutically effective.

As used herein, the term "co-therapy" shall mean treatment of a subject in need thereof by administering one or more compounds of formula (I) with a progestogen or SERM or SERD, wherein the compound(s) of formula (I) and the progestogen, SERM or SERD are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation. Where the compound(s) of formula (I ) and the progestogen, SERM or SERD are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different. The compound(s) of formula (I ) and the progestogen, SERM or SE RD may be administered via the same or different routes of administration. Examples of suitable methods of ad ministration include, but are not limited to, oral , intravenous (iv.), intramuscular (im.), subcutaneous (sc.), transdermal, intravaginal, intrauterine, application as a nasal spray, application as a wafer (buccal, lingual), and rectal. Compounds may also be administered directly to the nervous system including, but not limited to, intracerebral, intraventricular, intracerebroventricular, intrathecal, and intracisternal, intraspinal and/ or pert-spinal routes of administration by delivery via intracranial or intravertebral needles and/ or catheters with or without pump devices. The compound(s) of formula (I) and the progestogen or SERM or SERD may be administered according to simultaneous or alternating regimens , at th e same or different times during the course of the therapy, concurrently in divided or single forms. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be usefu l in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the com pounds of the invention carry an acidic moiety, su itable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylinitrate, methylsulfate, mucate, napsylate, nitrate, N-methyl- glucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

The present invention is preferably directed to compounds of formula (II) with a hydrogen atom at position 8 beta in combination with a hydrogen atom at 9 alpha and with an alpha-orientated 14,17-CH₂-CH2 bridge::

The definitions of X, R^6a, R^6b, R^11a, R^11b, R¹⁵ and R¹⁶ are as given above for compounds of formula (I).

In an embodiment of the present invention X stands for nitrogen, CH or CF.

In an embodiment of the present invention R⁶ is selected from hydrogen, fluorine and hydroxy.

In a further embodiment of the present invention R¹¹ is selected from hydrogen, fluorine and hydroxy.

In an embodiment of the present invention R¹⁵ is selected from hydrogen, fluorine and hydroxy.

In an embodiment of the present invention R¹⁶ is selected from hydrogen, fluorine and hydroxy.

The compounds mentioned below, and the uses thereof, are preferred according to the invention:

3'H-Triazolo[4',5':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol hydrochloride

2^,H-5'Chlor-pyrazolo[3',4^,:3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

2'H-5'Fluor-pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

2'H-Pyrazolo[3',4':3,4]14,17-ethano-6alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol

2'H-Pyrazolo[3',4':3,4]14,17-ethano-6beta-fluoro-estra-1 ,3,5(10)-trien-17-ol

2^,H-Pyrazolo[3',4':3,4]14,17-ethano-1 1 alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol 2^,H-Pyrazolo[3',4':3,4]14,17-ethano-1 1 beta-fluoro-estra-1 ,3,5(10)-trien-17-ol

2'H-Pyrazolo[3',4':3,4]14alpha,17alpha-ethano-16alpha-hydroxy-estra-1 ,3,5(10)-trien- 17-01 2^,H-Pyrazolo[3'_!4^,:3,4]14alpha, 17alpha-ethano-16beta-fluoro-estra-1 ,3,5(10)-trien-17-ol 3'H-Triazolo[4',5':3,4]14,17-ethano-6alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol

3'H-Triazolo[4',5':3,4]14,17-ethano-6beta-fluoro-estra-1 ,3,5(10)-trien-17-ol

3'H-Triazolo[4',5':3,4]14,17-ethano-1 1 alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol

3'H-Triazolo[4',5':3,4]14,17-ethano-1 1 beta-fluoro-estra-1 ,3,5(10)-trien-17-ol

3'H-Triazolo[4',5':3,4]14alpha, 17alpha-ethano-16alpha-hydroxy-estra-1 ,3,5(10)-trien-17- ol

3'H-Triazolo[4',5':3,4]14alpha, 17alpha-ethano-16beta-fluoro-estra-1 ,3,5(10)-trien-17-ol 3'H-Triazolo[4',5':3,4]14,17-ethenoestra-1 ,3,5(10)-trien-17-ol

2^,H-Pyrazolo[3',4':3,4]14,17-ethenoestra-1 ,3,5(10)-trien-17-ol

The compounds may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention.

In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography.

The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+ )-d i-p-tol uoy l-L-ta rta ric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/ or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 . The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The utility of the compounds of the instant invention to treat disorders mediated by an estrogen receptor may be determined according to the procedures described below: Biological Characterization of the Compounds According to the Invention

Estrogen Receptor Binding Studies

Binding to estrogen receptor a

This assay monitors the binding of tool compounds to the estrogen receptor a (ERa) using competition experiments with radioactively labelled Estradiol. The ERa protein used in the binding assay was purified from cytosolic fractions of Hi5 cells transfected with recombinant baculoviruses encoding either the human ERa. Aliquots of cytosolic fractions were stored at -80°C and had protein concentrations of 5 - 7 mg/ml (as determined by the BCA method).

The binding assay was performed in Greiner microtiter plates with conical wells. 5 μΙ of the test compound (various concentrations dissolved in 10% DMSO) were mixed with 15 μΙ of 16.66 nM ³H-estradiol ([2,4,6,7-³H(N)-estradiol, 70 - 1 15 Ci/mmol, NEN) in assay buffer (10 mM TRIS/HCI pH 7.4, 1 .5 mM EDTA, 10% glycerol).

30 μΙ of cytosol were added leading to a final volume of 50 μΙ per well. Final protein concentration was 50 - 200 μg per well , final cold estradiol or tool compou nd concentration ranged from 0.3 nM to 1 μΜ. All samples were tested in duplicate. Unspecific binding was determined in the presence of 10 μΜ cold estradiol; total binding was measured in the absence of cold estradiol or test compound. Incubation of ERa with the different concentrations of estradiol or tool compound in the presence of radioactively labelled Estradiol was performed for 1 h at room temperature. Afterwards, 45 μΙ of the incubation mixture were transferred to microtiter filtration plates preloaded with 50 μΙ per well cold charcoal suspension (2% charcoal, 0.2% dextran T70 in 10 mM TRIS/HCI pH 7.4, 1 .5 mM EDTA, 15% glycerol) (EVENT plates, 0.2 μπι pores, low protein binding filters by Eppendorf) to bind non-receptor bound radioactivity. The mixtures were filtered into Picoplates using a vacuum pump to separate protein-bound from unbound radioactive estradiol. The protein-bound radioactivity was measured by addition of 200 μΙ Microszint-40 (Canberra Packard) to each well using a TopCount scintillation counter. Dose-response curves were generated and the IC₅₀ values for estradiol and the test compounds were calculated . I n addition , KF values were determined by dividing the IC₅₀ of the test compound by the IC₅₀ of the reference (i.e. estradiol). By definition, the KF of estradiol is 1 .

Transactivation assay in stably transfected MCF-7 cells (MVLN assay)

To analyse activation of the ERa by diverse tool compounds in a second cellular system, we used MCF-7 cells endogenously expressing ERa and stably transfected with the estrogen-responsive vitellogenin-tk-luciferase reporter plasmid. Cells were starved for at least 3 days in phenolred-free DMEM containing 5% charcoal-stripped serum, 4 mM glutamine, 100 U/ml penicillin and 100 μg ml streptomycin. 6000 cells were seeded in 25 μΙ medium per well on a 384 well plate and stimulated for 24 hours with vehicle, estradiol or test compounds (concentration range as 10^"6 - 10^"13 M). Luciferase activity was measured after addition of 25 μΙ steady-Glo in a TopCount. Dose response curves were generated and EC₅₀ values were calculated using Sigma plot.

Stimulation of uterine growth in vivo

One classical ERa-mediated in vivo action is the stimulation of uterine growth in castrated animals. To assess the in vivo potency of test compounds at ERa, adult female Wistar rats were ovariectomized . 14 days after ovariectomy, animals were treated daily subcutaneously for 8 days with either vehicle (benzylbenzoate/ ricinusoil 1 :4 v/v) or different doses of the test compounds. Animals were sacrificed on day 8 of treatment and the relative uterine weights were determined. Dose response curves were generated in Sigma plot to determine the in vivo activity of the test compounds at ERa in comparison to estradiol as standard. It has to be noticed, that any compound that shows in vivo activity at ERa by stimulating uterine growth, is also able to prevent bone loss and osteoporosis in ovariectomized animals and postmenopausal women, since this process is also ERa-mediated in vivo (Korach et al. (1996); Rec. Prog. Horm. Res. 51 :159-186)

Stability in Hepatocytes

The metabolic stability of test compounds with respect to phase 1 and phase 2 metabolisms was investigated by incubation of the compounds with hepatocytes. These investigations were performed for characterisation of compounds in case of phase 2 metabolism is to be expected. The different test compounds were incubated for a sufficient period of time with a suspension of human cryopreserved hepatocytes of comparable metabolic activity (no. of hepatocytes in homogenous suspension). After analytical workup the concentrations of the test compounds after different incubation periods were related to the initial concentration of the respective test compound (zero hour's time point). The resulting area under the concentration-time-curve of the test compound investigated in the assay is used to derive the respective Fmax value. This data gives the maximal theoretical bioavailability of the test compound investigated.

Activity in the central nervous system

Only estrogenic compounds that are able to cross the blood brain barrier and that are estrogen receptor alpha agonists can successfully treat hot flushes. To judge whether an estrogenic compound is able to cross the blood brain barrier, another readout paradigm relying on estrogen receptor alpha activation in the central nervous system can be used. It is well established that estradiol acting via estrogen reveptor alpha influences feeding behaviour and body weight regulation in females (Geary et al . (2001 ); Endocrinology 142(1 1 ):4751 -4757). Both, ovariectomized rodents as well as postmenopausal women present with increased body weight that is due to increased food uptake. Estradiol application in ovariectomized animals reduces body weight and visceral fat. To analyse, whether an estrogenic compound has estrogen receptor alpha activity in the brain, rats are ovariectomized and 14 days after ovariectomy, the animals are treated with either vehicle (benzyl benzoate/ ricinusoil 1 :4 v/v) or different doses of the test compounds for 8 days. The body weights of the animals are determined on day 1 and on day 8 of treatment. While castrated, vehicle-treated animals gain body weight during the observation period, animals treated with estrogenic compounds that are able to activate estrogen receptor alpha in the central nervous system loose body weight. Estrogen receptor alpha ligands that induce body weight loss in castrated animals are also able to treat hot flushes, since such compounds reach the central nervous system.

Prevention of bone loss

The skeleton is under a continuous process of bone degeneration and regeneration in a carefully regulated interaction among the bone cells. These cells are directly affected by estrogen. Estrogen deficiency results in a loss of bone structure and a decrease of bone strength. Rapid loss of bone mass during the year immediately following menopause leads to postmenopausal osteoporosis and increased risk of fracture. Using estrogen receptor alpha deficient mice it was possible to demonstrate that ERalpha and not ERbeta is required for the prevention of osteoporosis and bone mass loss (Korach et al. (1996), Rec. Prog. Horm. Res. 51 : 159-186). Therefore, prevention of bone loss is only successful, if the used estrogenic ligands are able to activate estrogen receptor alpha.

Results

Compounds of the present invention were tested according to the procedures described above for binding to ERa, for transactivation at ERa, for activity in the MVLN assay, for induction of alkaline phosphatase in Ishikawa cells, and for in vivo activity with regard to stimulation of uterine growth.

As can be seen in Table 1 exemplary for, but not limited to compound from example 7 the compounds of the present invention are potent ERalpha agonists in vitro regarding binding and transactivation and in vivo regarding uterine growth induction exhibiting a significant higher oral bioavailability than estradiol based on human hepatocyte stability.

Table 1

As can be seen from table 2 the compounds of the invention are potent ERalph agonists in vitro regarding transactivation. Table 2

As can be seen from table 3, exemplary for, but not limited to exam ple 7, the compounds of the present invention are suitable for the prevention of body weight gain in castrated animals and therefore demonstrate activity on ERa in the central nervous system that is also required for the successful treatment of hot flushes.

Table 3

Dosages

The present invention therefore provides a method of treating disorders mediated by an estrogen receptor in a subject in need thereof which comprises administering any of the compounds as defined herein in a quantity effective to treat said disorder. The com pou n d m ay be ad m i n istered to a pati ent by a ny conventi on a l route of administration, including, but not limited to, intravenous, oral, subcutaneous, intra- muscular, intradermal, transdermal, intravaginal, intrauterine, and parenteral (i.e. rectal, as nasal spray, or as buccal or lingual wafer). The quantity of the compound which is effective for contraception or treating a disorder mediated by an estrogen receptor is between 0.1 μg per kg and 1 mg per kg of subject body weight per day depending on route of administration, indication and potency of the respective compound. The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, transdermal, intravaginal, intrauterine, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.005 mg to about 100 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran , sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating a disorder mediated by an estrogen receptor described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0,005 and 1000 mg, preferably about 5 to 500 m g, most preferably 0.015 to 0.050 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lu bricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or fou r ti mes dai ly. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and colouring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatine, natural sugars such as glucose or beta lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sod iu m stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavoured suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidepheno I , o r polyethyleneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid , polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-lin ked or am ph i path ic block copolymers of hydrogels.

The compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever contraception or treatment of a disorder mediated by an estrogen receptor is required. The daily dosage of the products may be varied over a wide range from 5 μg to 100 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.005, 0.025, 0.1 , 0.5, 1 .0, 5.0, 10.0, 15.0, 25.0, 50.0, 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the woman in need of contraception or patient to be treated. Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, and the strength of the preparation and the advancement of the d isease condition . I n addition , factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

The following examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter. The compounds of the present invention can be prepared according to the following general schemes, using appropriate materials, and are further exemplified by the subsequent specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.

The final compounds of the present invention are synthesized as outlined in Schemes 1 to 4.

GENERAL PROCESSES AND EXPERIMENTAL DETAILS

The new compounds of formula (I) are prepared according to the process outlined in scheme 1 . The synthesis starts generally with 3-Hydroxy-estratrien starting materials of type 1 (for synthesis of the starting materials see: Bull, James „; Thomson, RusseH f. Journal of the Chemical Society, Chemical Communications, 1986 , (6), p. 451 - 453 ; Bull, James R,; Thomson, RusseH L, Journal of the Chemical Society, Perkin Transactions 1 : Organic and Bio-Organic Chemistry (1972-1999), 1990 , (2), p. 241 - 252), Formylation with formaldehyde under basic conditions yields the 4-formyl- steroids of formula 2 (see J. Org. C em. 2007, 72, 8824-8830 and references therein). Depending on the type of reaction these intermediates are obtained in mixture of varying ratios with their corresponding 2-formyl-isomers. The compounds can be separated by chromatographic methods on this step. Alternatively a protection group in position 2 can be employed (e.g. tert-Butyl) to govern the formylation in position 4. In this case after deprotection the 4-formyl-isomer is obtained exclusively. Another option is to further follow the synthesis path with a mixture of 2-formyl and 4-formyl-isomers and separate later on any of the following steps.

The salicylaldehydes of formula 2 can be converted to sulfonicester derivatives 3 of the phenols by reacting with alkyl- or arylsulfonic acid derivatives such as methanesulfonic acid chloride or nonafluorbutanesulfonic acid fluoride under basic conditions. Reaction of these compounds with benzaldehyde-protected hydrazine under palladium catalysis gives hydrazine derivatives 4. The last step combines the deprotection of the hydrazine under acidic conditions and the subsequent cyclization to the desired pyrazoles 5.

Scheme 1

The triazoles can be prepared as outlined in scheme 2. A 4-nitro-estratrien derivative of type 6 can be obtained by nitration of a 3-hydroxy-estratriene of typee 1 (Horwitz et al., J. Med. Chem. 29, 692 (1986). Depending on the type of reaction these intermediates are obtained in mixture with their corresponding 2-nitro-isomers. The compounds can be separated by chromatographic methods on this step. Compounds of type 6 can be transformed to 3-amino derivatives 7 by making a 2-methyl-propionicamide-ethers and subsequent treatment of the intermediate in a polar solvent, (see: J. Chem. Soc. 1990, 767-71 ; Org. Lett. 7, (2005), 3629-31 ). Cleavage of the propionic acid anilide gives the free aniline 7. The amino-nitro derivative 7 can be reduced to the corresponding diamino-derivative 8 by well known reduction methods.

Scheme 2

The triazoles of type 9 can be made by nitrosation for example with potassium nitrite and sulphuric acid (Chemische Berichte; 9; 222 (1876)).

Substituents in position 6, 1 1 , 15 or 16 can be introduced by microbiological oxidative biotransformation of the corresponding su bstrates with different strains. These transformations allow the introduction of a hydroxyl group in the respective positions of the steroid. These hydroxylated derivatives can then be further reacted by standard functional group transformations to the corresponding fluorides or chlorides. The general procedure is illustrated for the 6-hydroxylated derivative 10 in scheme 3. Following this route as described above the corresponding isomers with substituents in positions 1 1 , 15 or 16 of the steroid are obtained in analogous manner..

Scheme 3 Reaction of pyrazoles of type 5 with n-Chloro-succinimide gives the corresponding chloro-pyrazoles 12, which can be further modified to the fluoro-pyrazoles 13 by halogen exchange reactions with fluorides, for example cesium fluoride (see scheme 4).

Scheme 4

Example 1

1 ) 3'H-Triazolo[4',5':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

a) 4-Nitro-14, 17-ethanoestra-1 ,3,5(10)-trien-17-ol

14,17-Ethanoestra-1 ,3,5(10)-2,17-diol were dissolved in 300 ml acetic acid at 60°C. After cooling to 0°C a mixture of 2.26 ml nitric acid (65%) and 90 mg sodium nitrite in 90 ml of water were added dropwise. After stirring overnight at room temperature the reaction mixture was filtered and 500 ml water were added to the filtrate. The thus formed precipitate was isolated by filtration and the filtrate diluted with 1000 ml water. The newly formed precipitate again was isolated by filtration. Both precipitates were combined and subjected to column chromatography on silica gel with a mixture of n-hexane and ethyl acetate to yield 3.3 g 4-Nitro-14,17-ethanoestra-1 ,3,5(10)-trien-17-ol.

MS (ES-): m/z = 342 (M-1 );

¹H-NMR (400 MHz, DMSO-d6): δ = 10.45 (s, 1 H); 7.27 (d, 1 H); 6.81 (d, 1 H); 4.46 (s, 2H); 2.53 (m, 2H); 2.25 (m, 1 H); 0.99-1 .85 (m, 15H); 0.75 (s, 3H) b) 2-[[17-Hydroxy-4-nitro-14,17-ethanoestra-1 ,3,5(10)-trien-3-yl]oxy]-2- methylpropanamide

4-Nitro-14,17-ethanoestra-1 ,3,5(10)-trien-17-ol,

9.25 g Cs₂C0₃ and 1 .56 g 2-Bromo-2-methyl-propionamide were mixed in 650 ml acetonitrile and stirred at 40°C over night. After cooling to room temperature the reaction mixture was diluted with 640 ml dichloromethane and filtered. The filtrate was evaporated to dryness and subjected to column chromatography on silica gel with a mixture of n-hexane and ethyl acetate to yield 3.26 g 2-[[17-Hydroxy-4-nitro- 14,17-ethanoestra-1,3,5(10)-trien-3-yl]oxy]-2-methylpropanamide.

MS (ES+): m/z = 429 (M+1);

¹H-NMR (400 MHz, DMSO-d6): δ = 7.51 (s, 1H); 7.41 (d, 1H); 7.36 (s, 1H); 6.85 (d, 1H); 4.48 (s, 1H); 2.49-2.67 (m, 3H); 2.28 (m, 1H); 1.51-1.86 (m, 5H); 1.34 (s, 3H): 1.33 (s, 3H); 1.02-1.46 (m, 9H); 0.76 (s, 3H) c) 2-Hydroxy-2-methyl-/V-[17-hydroxy-4-nitro-14,17-ethanoestra-1 ,3,5(10)- trien-3-yl]propanamide

3.25 g 2-[[17-Hydroxy-4-nitro-14,17-ethanoestra-1 ,3,5(10)-trien-3-yl]oxy]-2- methylpropanamide and 0.91 g powdered sodium hydroxyde were mixed in 90 ml DMF and stirred at 50°C for 1.5 hours. The reaction mixture then was poured into 500 ml of water to precipitate the product. After filtration and drying 3.2 g 2-Hydroxy- 2-methyl-/V-[17-hydroxy-4-nitro-14,17-ethanoestra-1 ,3,5(10)-trien-3-yl]propanamide were isolated.

MS (ES+): m/z = 429 (M+1);

¹H-NMR (400 MHz, DMSO-d6): δ = 9.51 (s, 1H); 7.57 (d, 1H); 7.53 (d, 1H); 5.85 (s, 1H); 4.49 (s, 1H); 2.74 (m, 1H); 2.59 (m, 2H); 2.32 (m, 1H); 1.51-1.88 (m, 5H); 1.27 (s, 3H): 1.25 (s, 3H); 1.00-1.50 (m, 9H); 0.76 (s, 3H)

d) 3-Amino-4-nitro-14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

3.2 g 2-Hydroxy-2-methyl-/V-[17-hydroxy-4-nitro-14,17-ethanoestra-1 ,3,5(10)-trien- 3-yl]propanamide were refluxed in a mixture of 20 ml concentrated hydrochloric acid and 20 ml dioxane for 2 hours. Under ice cooling the reaction mixture was then made basic by adding 50 ml of a 5 m sodium hydroxyde solution. After stirring for 30 minutes the precipitated product was isolated by filtration. After drying 2.67 g 3- Amino-4-nitro-14,17-ethanoestra-1 ,3,5(10)-trien-17-ol were obtained.

MS (ES+): m/z = 343 (M+1 );

¹H-NMR (400 MHz, DMSO-d6): δ = 7.20 (d, 1 H); 6.70 (d, 1 H); 5.67 (s, 2H); 4.45 (s, 1 H); 2.39-2.56 (m, 2H); 2.21 (m, 1 H); 0.99-1 .85 (m, 15H); 0.75 (s, 3H) e) 3,4-Diamino-14, 17-ethanoestra-1 ,3,5(10)-trien-17-ol

3-Amino-4-nitro-14,17-ethanoestra-1 ,3,5(10)-trien-17-ol in 130 ml methanol a solution of 25 g iron(ll)-sulphate heptahydrate in 76 ml water was added followed by 22.4 ml of a concentrated (33%) aqueous ammonia solution.

After stirring at 95°C for 4.5 hours the reaction mixture was cooled to room temperature and fi ltered . After wash i n g th e fi lter cake with a m ixtu re of dichloromethane and dioxane the filtrate was evaporated to dryness to yield 2 g of crude 3,4-Diamino-14,17-ethanoestra-1 ,3,5(10)-trien-17-ol, which was subjected to the next step without further purification.

To a mixture of 2 g 3,4-Diamino-14,17-ethanoestra-1 ,3,5(10)-trien-17-ol in 88 ml acetic acid a solution of 0.49 g sodium nitrite in 1 1 ml water was added. After stirring at ambient temperature for 65 hours the reaction mixture was poured into water and strongly acidified with 4 N hydrochloric acid, to precipitate the product. After filtration the filterake was suspended in 15 ml dioxane and 200 ml of a pH6 phosphate buffer. After stirring of the suspension for 90 minutes the product was isolated by filtration to yield, after drying, 1 .9 g 3'H-Triazolo[4',5':3,4]14,17-ethanoestra- 1 , 3,5(10)-trien-17-ol. MS (EI+): m/z = 323 (M+);

¹H-NMR (400 MHz, DMSO-d6, 353Kelvin): δ = 15.51 (s); 7.61 (d, 1 H); 7.37 (d, 1 H); 4.48 (s, 1 H); 2.85-3.21 (m, 2H); 2.72 (m, 1 H); 2.38 (s, 1 H); 1 .04-1 .94 (m, 14H); 0.77 (s, 3H) Example 2

2) 2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol -ethano-4-formyl-estra-1 ,3,5(10)-trien-3,17-diol 17-formiate

The reaction was done in analogy to that described in J. Org.Chem 2007, 72, 8824: 30 .2 g 1 4 , 1 7-ethano-estra-1 ,3,5(10)-trien-3,17-d i o l wa s d i s s o l v e d i n 755 m l tetrahydrofuran. 77.1 g magnesiumchloride, 30.4 g formaldehyde and 1 12.8 ml triethylamine were added. The reaction mixtrue was heated for 8 hours at reflux. After cooling down 500 ml of 1 N hydrochloric acid were added and the mixture was extracted with 500 ml ethylacetate. The organic phase was washed with water and brine, subsequently dried over magnesium sulphate and concentrated in vacuo. The raw product was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate to yield 1 1.7 g of the product as mixture of the 2-formyl and 4-formyl- derivatives (appr. ratio: 2F : 4F = 6.1 ). MS (EI+): m/z = 354 (M+);

1 H-NMR (400 MHz, CDCI₃, 353Kelvin): δ = 1 1 .98 (s, 1 H; 4F); 10.77 (s, 1 H; 2F); 10.36 (s, 1 H, 4F); 9.80 (s, 1 H, 2F); 8.06 (s, 1 H); 7.51 (d, 1 H, 4F); 7.44 (s, 1 H, 2F); 6.80 (d, 1 H, 6.68, s, 1 H, 2F) 1 .25-2.90 (m, 18H); 0.95 (s, 3H) b ) 1 4 , 1 7-ethano-4-formyl-17-formyloxy-estra-1 ,3,5(10)-trien-3-o I 3- nonafluorbutanesulfonate

49 g of the the isomeric mixture of phenols described in example 2a was dissoved in 1470 ml tetrahydrofuran. The solution was cooled to 0°C and 29 ml triethylamine, 31.7 ml nonafluorbutanesulfonicacid fluoride and 26.9 ml diazabicycloundecane were added. The resulting mixture was stirred for 20 hours at room temperature. To the mixture 250 ml of saturated sodiumbicarbonate solution and 250 of water were added. The mixture was extracted three times with 500 ml ethylacetate. The organic phase was washed with water and brine, subsequently dried over magnesium sulphate and concentrated in vacuo. The raw product was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate to yield 15.57 g of the product as mixture of the 2-formyl and 4-formyl-derivatives (appr. ratio: 2F : 4F = 6.1 ).

MS (EI+): m/z = 636 (M+);

1 H-NMR (400 MHz, CDCI₃, 353Kelvin): δ = 10.50 (s, 1 H; 4F); 10.20 (s, 1 H; 2F); 8.06 (s, 1 H); 7.90 (s, 1 H, 2F); 7.61 (d, 1 H, 4F); 7.21 (d, 1 H, 4F); 7.07 (s, 1 H, 2F) 1 .30-2.95 (m, 18H); 0.95 (s, 3H) c) 1 4, 1 7-ethano-4-formyl-17-formyloxy-estra-1 ,3,5(10)-trien-3-ol - 3-(diphenyl- methano)-hydrazine

34.1 g cesium carbonate, 2.2 g xanthphos, 0.84 palladium(ll)acetate were suspended in 345 ml 1 ,4-dioxane. The mixture was stirred for 10 minutes at room temperature. Then 0.52 ml triethylamine were added and the resulting mixture is stirred for further 10 minutes. Then a solution, that was prepared from 47.6 g of the the isomeric mixture of nonaflates described in example 2b and 17.6 g benzophenone-hydrazone in 345 ml 1 ,4-dioxane was added to the reaction mixture. The resulting mixture was heated for 6 hours at 100°C. The mixture was allowed to cool to room temperature and then 500 ml of saturated sodiumbicarbonate solution were added. The mixture was extracted twice with 500 ml ethylacetate. The organic phase was washed with water and brine, subsequently dried over magnesium sulphate and concentrated in vacuo. The raw product was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate to yield 9.82 g of the product as mixture of the 4-formyl and 2-formyl- derivatives (appr. ratio: 2F : 4F = 3 : 1 )

MS (EI+): m/z = 532 (M+);

1 H-NMR (400 MHz, CDCI₃, 353Kelvin): δ = 1 1 .83 (s, 1 H; 4F); 1 1 .12 (s, 1 H; 2F); 10.12 (s, 1 H, 4F); 9.61 (s, 1 H, 2F); 8.07 (s, 1 H); 7.82 (d, 1 H, 4F); 7.51 (d, 1 H, 4F); 7.30 - 7.70 (m, 10 H); 1 .30-3.10 (m, 18H); 0.98 (s, 3H) 'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

In 98.2 ml of 4N hydrochloric acid in 1 ,4-dioxane and 1 .2 ml water 9.82 g of thejsomeric mixture of hydrazones were dissolved. The reaction mixture was heated to 60°C for three hours. The resulting suspension was cooled to 0°C and filtered. The precipitate was washed twice with 5 ml of diethylether and dried in vacuo. The resulting off-white solid (3.26 g) was an mixture of the 3,4-pyrazole and the isomeric 2,3-pyrazole as hydrochlorides in a appr. ratio of 1 :3. This was subjected to HPLC prurification to obtain pure isomers.

e) Purification of 2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

The mixture of isomeric pyrazoles is purified over a Chiralpak IC 5μΜ 250x30mm column. The eluent is hexane / ethanol 60:40 + 0.1 % diethylamine. The flow is 40 ml/min. 3.26 g of the mixture described under 2d are dissolved in 50 ml methanol. The mixture is chromatographed in 25 injections of 2 ml each. The two isomers are obtained: 705 mg of 2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol (peakl , retention time: 5.1 - 5.5 min) and 1965 mg 2'H-Pyrazolo[3',4':3,2]14,17- ethanoestra-1 ,3,5(10)-trien-17-ol (peak 2, retention time: 6.2 - 7.8 min).

2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol:

MS (EI+): m/z = 322 (M+);

1 H-NMR (400 MHz, CDCI₃, 353Kelvin): δ = 12.80 (s, 1 H); 7.96 (s, 1 H); 7.25-7.35 (2 x d, 2H); 1 .05-3.10 (m, 18H); 0.75 (s, 3H) Example 3

2'H-5-Chloro-pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

To a solution of 100 mg of 2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol in 4.6 ml 1 ,4-dioxane 2.6 ml of 3N sodium hydroxide solution were added at room temperature. Then 180 mg of N-chloro-succinimide were added. The resulting mixture was stirred at room temperatu re for 20 hou rs. The mixture was extracted with ethylacetate. The organic phase was washed with water and brine, subsequently dried over magnesium sulphate and concentrated in vacuo. The raw product was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate to yield 18 mg of the product 2'H-5-Chloro-pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)- trien-17-ol and 19 mg of the starting material.

MS (CI+): m/z = 357/359 (M+H)⁺;

1 H-NMR (400 MHz, CDCI₃, 353Kelvin): δ = 7.42 (d, 1 H); 7.20 (d, 1 H); 3.60 (m, 1 H); 3.15 (m, 1 H); 2.75 (m, 1 H); 2.40 (m, 1 H); 1 .20-2.05 (m, 14H); 0.90 (s, 3H)

Example 4 a) 3'H-Triazolo[4',5':3,4]14,17-ethano-6alpha-hydroxy- estra-1 ,3,5(10)-trien-17-ol

For the hydroxylation in position 6 200 mg of the starting material 3Ή- Triazolo[4',5':3,4]14,17-ethano-estra-1 ,3,5(10)-trien-17-ol was incubated with the strain Rhizoctonia solani at 27°C at a substrate concentration of 100 mg/L in aquous culture medium with 0.5 % dimethylformanide as solubilizer. After 72 hours the culture broth was extracted twice with 1 L methyl-isobutyl-ketone. The organic phase was washed with water and brine, subsequently dried over sodium sulphate and concentrated in vacuo. The raw product was purified by column chromatography on silica gel with a mixture of dichloromethane and acetone to yield 96 mg of the product 3Ή- Triazolo[4',5':3,4]14,17-ethano-6alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol.

MS (ESI): m/z = 340 (M+H)⁺;

1 H-NMR (400 MHz, DMSO-d6, 353Kelvin): δ = 15.18 (s, 1 H); 7.78 (d, 1 H); 7.31 (d, 1 H); 5.28 (m, 1 H); 4.99 (s, 1 H); 1 .09-2.70 (m, 16H); 0.75 (s, 3H)

Example 5

a) 3'H-Triazolo[4',5':3,4]14alpha,17alpha-ethano-16alpha-hydroxy-estra-1 ,3,5(10)- trien-17-ol

For the hydroxylation in position 16 200 mg of the starting material 3Ή- Triazolo[4',5':3,4]14,17-ethano-estra-1 ,3,5(10)-trien-17-ol was incubated with the strain Rhizoctonia solani at 27°C at a substrate concentration of 100 mg/L in aquous culture medium with 0.5 % dimethylformanide as solubilizer. After 72 hours the culture broth was extracted twice with 1 L methyl-isobutyl-ketone. The organic phase was washed with water and brine, subsequently dried over sodium sulphate and concentrated in vacuo. The raw product was purified by column chromatography on silica gel with a mixture of dichloromethane and acetone and an addional HPLC column with water/acetontril to yield 1 1 mg of the product 3'H-Triazolo[4',5':3,4]14alpha,17alpha- ethano-16alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol. MS (CI): m/z = 340 (M+H)⁺;

1 H-NMR (400 MHz, DMSO-d6, 353Kelvin): δ = 15.50 (s, 1 H); 7.65 (d, 1 H); 7.40 (d, 1 H); 4.52 (m, 1 H); 4.42 (s, 1 H); 4.00 (s, 1 H); 1 .09-2.70 (m, 16H); 0.80 (s, 3H)

Example 6

3'H-Triazolo[4',5':3,4]14,17-ethano-6beta-fluoro-estra-1 ,3,5(10)-trien-17-ol a) 3'H-Triazolo[4',5':3,4]14,17-ethano-6alpha-p(toluensulfonyloxy)-estra-1 ,3,5(10)- trien-17-ol

100 mg of 3'H-Triazolo[4',5':3,4]14,17-ethano-6alpha-hydroxy-estra-1 ,3,5(10)-trien-17- ol were suspended in 1 .5 ml dichloromethane. 68 mg p-toluenesulfonylchloride, 0.24 ml pyridine and 1 mg 4-(N,N-dimethylamino)-pyridine are added at room temperature. After the reaction mixture was stirred for 20 hours at room temperature 10 ml of water were added. The mixture was extracted twice with 25 ml ethylacetate. The organic phase was washed with water and brine, subsequently dried over sodium sulphate and concentrated in vacuo. The raw product was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate to yield 60 mg of the product 3Ή- triazolo[4',5':3,4]14,17-ethano-6alpha-p(toluensulfonyloxy)-estra-1 ,3,5(10)-trien-17-ol.

MS (CI): m/z = 494 (M+H)⁺;

1 H-NMR (400 MHz, DMSO-d6, 353Kelvin): δ = 7.95 (d, 2H); 7.90 (d, 1 H); 7.70 (d, 1 H); 7.41 (d, 2H); 5.32 (m, 1 H); 2.31 (s, 3H); 1 .05-2.80 (m, 16H); 0.70 (s, 3H) b) 3'H-Triazolo[4',5':3,4]14,17-ethano-6beta-fluoro-estra-1 ,3,5(10)-trien-17-ol

60 mg 3'H-triazolo[4',5':3,4]14,17-ethano-6alpha-p(toluensulfonyloxy)-estra-1 ,3,5(10)- trien-17-ol were dissolved in 1 .5 ml 1 -methyl-2-pyrolidone. 185 mg of cesium fluoride were added at room temperature. The reaction mixture was stirred for 6 hours at room temperature and subsequently 10 ml of water are added. The resulting mixture was extracted twice with 25 ml ethylacetate. The organic phase was washed with water and brine, subsequently dried over sodium sulphate and concentrated in vacuo. The raw product was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate to yield 12 mg of the product 3'H-Triazolo[4',5':3,4]14,17-ethano- 6beta-fluoro-estra-1 ,3,5(10)-trien-17-ol. MS (EI+): m/z = 341 (M+);

1 H-NMR (400 MHz, DMSO-d6, 353Kelvin): δ = 7.78 (d, 1 H); 7.33 (d, 1 H); 5.01 (m, 1 H); 1 .08-2.80 (m, 16H); 0.77 (s, 3H)

Example 7

2) 2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol hydrogen chloride

I n 4 ml of 4 N hydroch loric acid in 1 ,4-dioxane and 0.2 ml water 100 mg of the isomerically pure 4-formylhydrazone of example 2c (purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate) were dissolved. The reaction mixture was heated to 60°C for 3 hours. The resulting suspension was cooled to 0°C and filtered. The precipitate was washed twice with 0.6 ml of diethylether and dried in vacuo to yield 37 mg of the product 2'H-pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)- trien-17-ol hydrogen chloride

MS (CI+): m/z = 323 (M+, of parent compound);

1 H-NMR (400 MHz, DMSO-d6, 353Kelvin): δ = 7.96 (s, 1 H); 7.25-7.35 (2 x d, 2H); 1 .05- 3.10 (m, 18H); 0.75 (s, 3H)

Claims

1 . A compound of formula (I)

(I)

wherein

X is selected from the group consisting of nitrogen, CH, CCI and CF

R^6a and R^6b are independently from each other selected from the group of hydrogen, fluorine, chlorine, hydroxyl and methyl or R^6a and R^6b stand together for an oxygen atom,

R"^a and R^11b are independently from each other selected from the group of hydrogen, fluorine, chlorine, hydroxyl, methyl and methoxy or R^11a and R^11b stand together for an oxygen atom,

R¹⁵ is selected from the group of hydrogen, fluorine, chlorine, hydroxyl and methyl, or stands together with R¹⁶ for an additional bond

R 16

is selected from the group of hydrogen, fluorine, chlorine, hydroxyl and methyl, or stands together with R¹⁵ for an additional bond

or a pharmaceutically acceptable salt thereof.

2. A compound according to Claim 1 with a hydrogen atom at position 8 beta in combination with a hydrogen atom at 9 alpha and with an alpha-orientated 14,17-CH₂-CH2 bridge as demonstrated in formula (II):

3. A compound according to Claim 1 wherein X stands for nitrogen, CH or CF.

4. A compound according to Claim 1 , wherein R⁶ is selected from hydrogen, fluorine and hydroxy.

5. A compound according to Claim 1 , wherein R¹¹ is selected from hydrogen, fluorine and hydroxy

6. A compound according to Claim 1 wherein R¹⁵ is selected from hydrogen, fluorine and hydroxy.

7. A compound according to Claim 1 wherein R¹⁶ is selected from hydrogen, fluorine and hydroxy.

8. Compounds according to claim 1 to 12, namely

3'H-Triazolo[4',5':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

2'H-Pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol hydrochloride 2^,H-5'Chlor-pyrazolo[3',4^,:3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

2'H-5'Fluor-pyrazolo[3',4':3,4]14,17-ethanoestra-1 ,3,5(10)-trien-17-ol

2'H-Pyrazolo[3',4':3,4]14,17-ethano-6alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol 2'H-Pyrazolo[3',4':3,4]14,17-ethano-6beta-fluoro-estra-1 ,3,5(10)-trien-17-ol 2^,H-Pyrazolo[3',4':3,4]14,17-ethano-1 1 alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol 2^,H-Pyrazolo[3',4':3,4]14,17-ethano-1 1 beta-fluoro-estra-1 ,3,5(10)-trien-17-ol 2'H-Pyrazolo[3^, _!4^,:3_!4]14alpha,17alpha-ethano-16alpha-hydroxy-estra-1 ,3,5(10)- trien-17-ol

2'H-Pyrazolo[3',4':3,4]14alpha,17alpha-ethano-16beta-fluoro-estra-1 ,3,5(10)- trien-17-ol

3'H-Triazolo[4',5':3,4]14,17-ethano-6alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol

3'H-Triazolo[4',5':3,4]14,17-ethano-6beta-fluoro-estra-1 ,3,5(10)-trien-17-ol 3'H-Triazolo[4',5':3,4]14,17-ethano-1 1 alpha-hydroxy-estra-1 ,3,5(10)-trien-17-ol 3'H-Triazolo[4',5':3,4]14,17-ethano-1 1 beta-fluoro-estra-1 ,3,5(10)-trien-17-ol 3'H-Triazolo[4',5':3,4]14alpha,17alpha-ethano-16alpha-hydroxy-estra-1 ,3,5(10)- trien-17-ol

3'H-Triazolo[4',5':3,4]14alpha,17alpha-ethano-16beta-fluoro-estra-1 ,3,5(10)- trien-17-ol

3'H-Triazolo[4',5':3,4]14,17-ethenoestra-1 ,3,5(10)-trien-17-ol

2^,H-Pyrazolo[3',4':3,4]14,17-ethenoestra-1 ,3,5(10)-trien-17-ol

9. Pharmaceutical composition comprising at least one compound of the general formula I according to any of Claims 1 to 8 and, optionally at least one additional active ingredient together with pharmaceutically suitable excipients and/or carriers.

10. Pharmaceutical composition according to claim 9, wherein the additional active ingredient is a SERM (selective estrogen receptor modulator) or a SERD (selective estrogen receptor destabilizer).or a progestogen.

1 1 . Pharmaceutical compositions according to claim 10, wherein the progestogen is drospirenon, dienogest, gestodene, levonorgestrel or cyproterone acetate.

12. A process for making a pharmaceutical composition comprising mixing a compound of Claim 1 and optionally at least one additional active ingredient with a pharmaceutically acceptable carrier.

13. Use of compounds according to claim 1 to 8 for manufacturing a medicament.

14. Compounds according to claim 1 to 8 for the manufacture of a medicament.

15. Use of compounds according to claim 1 to 8 for manufacturing a medicament for the treatment of a disorder mediated by an estrogen receptor.

16. Use according to Claim 15, wherein the disorder mediated by an estrogen receptor is selected from the group consisting of hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, cancer of the breast tissue, hyperplasia of the breast tissue, cancer of the endometrium, hyperplasia of the endometrium, cancer of the cervix, hyperplasia of the cervix, cancer of the prostate, benign prostatic hyperplasia, endometriosis, uterine fibroids and osteoarthritis.

17. Use according to Claim 16, wherein the disorder mediated by an estrogen receptor is selected from the group consisting of osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis.

18. Use of compounds according to claim 1 to 8 for contraception.

19. , Use of compounds according to claim 18 alone or in combination with an

effective amount of a compound as in Claim 1 to 8 and a progestogen.

20. Use of compounds according to claim 19, wherein the progestogen is Drospireneone, Dienogest, Gestodene, Levonorgestrel or Cyproteronacetat.