General Aspects and Inhibition of 17β-HSD1: Steroid hormones are important chemical carriers of information serving for the longterm and global control of cellular functions. They control the growth and the differentiation and function of many organs. On the other hand, they may also have negative effects and favor the pathogenesis and proliferation of diseases in the organism, such as mammary and prostate cancers (Deroo, B J. et al., J. Clin. Invest., 116: 561-570 (2006); Fernandez, S. V. et al., Int. J. Cancer, 118: 1862-1868 (2006)).
The biosynthesis of steroids takes place in the testes or ovaries, where sex hormones are produced. In addition, the production of glucocorticoids and mineral corticoids takes place in the adrenal glands. Moreover, individual synthetic steps also occur outside the glands, namely in the brain or in the peripheral tissue, e.g., adipose tissue (Bulun, S. E. et al., J. Steroid Biochem. Mol. Biol., 79: 19-25 (2001); Gangloff, A. et al., Biochem. J., 356: 269-276 (2001)). In this context, Labrie coined the term “intracrinology” in 1988 (Labrie, C. et al., Endocrinology, 123: 1412-1417 (1988); Labrie, F. et al., Ann. Endocrinol. (Paris), 56: 23-29 (1995); Labrie, F. et al., Horm. Res., 54: 218-229 (2000)). Attention was thus focused on the synthesis of steroids that are formed locally in peripheral tissues and also display their action there without getting into the blood circulation. The intensity of the activity of the hormones is modulated in the target tissue by means of various enzymes.
Thus, it could be shown that the 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes the conversion of estrone (E1) to estradiol (E2), is more abundant in endometriotic tissue and breast cancer cells while there is a deficiency in 17β-HSD type 2, which catalyzes the reverse reaction (Bulun, S. E. et al., J. Steroid Biochem. Mol. Biol., 79: 19-25 (2001); Miyoshi, Y. et al., Int. J. Cancer, 94: 685-689 (2001)).
A major class of steroid hormones is formed by the estrogens, the female sex hormones, whose biosynthesis takes place mainly in the ovaries and reaches its maximum immediately before ovulation. However, estrogens also occur in the adipose tissue, muscles and some tumors. Their main functions include a genital activity, i.e., the development and maintenance of the female sexual characteristics as well as an extragenital lipid-anabolic activity leading to the development of subcutaneous adipose tissue. In addition, they are involved in the pathogenesis and proliferation of estrogen-related diseases, such as endometriosis, endometrial carcinoma, adenomyosis, breast cancer and endometrial hyperplasia (Bulun, S. E. et al., J. Steroid Biochem. Mol. Biol., 79: 19-25 (2001); Miyoshi, Y. et al., Int. J. Cancer, 94: 685-689 (2001); Gunnarsson, C. et al., Cancer Res., 61: 8448-8451 (2001); Kitawaki, J., Journal of Steroid Biochemistry & Molecular Biology, 83: 149-155 (2003); Vihko, P. et al., J. Steroid. Biochem. Mol. Biol., 83: 119-122 (2002); Vihko, P. et al., Mol. Cell. Endocrinol., 215: 83-88 (2004); Saloniemi T. et al., Am. J. Pathol. 176: 1443-1451 (2010)), ovarian cancer, prostate cancer (Elo et al J. Cancer 66: 37 (1996)), acne (Odlind et al., Clin. Endocrinol. 16: 243-249 (1982)), androgen-dependent hair loss and psoriasis (Hughes et al. Endocrinology 138: 3711 (1997)).
The most potent estrogen is E2, which is formed in premenopausal females, mainly in the ovaries. On an endocrine route, it arrives at the target tissues, where it displays its action by means of an interaction with the estrogen receptor (ER) α. After the menopause, the plasma E2 level decreases to 1/10 of the E2 level found in premenopausal females (Santner, S. J. et al., J. Clin. Endocrinol. Metab., 59: 29-33 (1984)). E2 is mainly produced in the peripheral tissue, e.g., breast tissue, endometrium, adipose tissue and skin, from inactive precursors, such as estrone sulfate -EI-S), dehydroepiandrosterone (DHEA) and DHEA-S. These reactions occur with the participation of various steroidogenic enzymes (hydroxysteroid dehydrogenases, aromatase), which are in part more abundantly produced in the peripheral tissue, where these active estrogens display their action. As a consequence of such intracrine mechanism for the formation of E2-, its concentration in the peripheral tissue, especially in estrogen-related diseases, is higher than that in the healthy tissue. Above all, the growth of many breast cancer cell lines is stimulated by a locally increased E2 concentration. Further, the occurrence and progress of diseases such as endometriosis, leiomyosis, adenomyosis, menorrhagia, metrorrhagia and dysmenorrhea is dependent on a significantly increased -E2 level in accordingly diseased tissue.
Endometriosis is an estrogen-related disease affecting about 5 to 10% of all females of childbearing age (Kitawaki, J., Journal of Steroid Biochemistry & Molecular Biology, 83: 149-155 (2003)). From 35 to 50% of the females suffering from abdominal pain and/or sterility show signs of endometriosis (Urdl, W., J. Reproduktionsmed. Endokrinol., 3: 24-30 (2006)). This disease is defined as a histologically detected ectopic endometrial glandular and stromal tissue. In correspondingly severe cases, this chronic disease, which tends to relapse, leads to pain of different intensities and variable character and possibly to sterility. Three macroscopic clinical pictures are distinguished: peritoneal endometriosis, retroperitoneal deep-infiltrating endometriosis including adenomyosis uteri, and cystic ovarial endometriosis. There are various explanatory theories for the pathogenesis of endometriosis, e.g., the metaplasia theory, the transplantation theory and the theory of autotraumatization of the uterus as established by Leyendecker (Leyendecker, G. et al., Hum. Reprod., 17: 2725-2736 (2002)).
According to the metaplasia theory (Meyer, R., Zentralbl. Gynakol., 43: 745-750 (1919); Nap, A. W. et al., Best Pract. Res. Clin. Obstet. Gynaecol., 18: 233-244 (2004)), pluripotent coelomic epithelium is supposed to have the ability to differentiate and form endometriotic foci even in adults under certain conditions. This theory is supported by the observation that endometrioses, in part severe ones, can occur in females with lacking uterus and gynastresy. Even in males who were treated with high estrogen doses due to a prostate carcinoma, an endometriosis could be detected in singular cases.
According to the theory postulated by Sampson (Halme, J. et al., Obstet. Gynecol., 64: 151-154 (1984); Sampson, J., Boston Med. Surg. J., 186: 445-473 (1922); Sampson, J., Am. J. Obstet. Gynecol., 14: 422-469 (1927)), retrograde menstruation results in the discharge of normal endometrial cells or fragments of the eutopic endometrium into the abdominal cavity with potential implantation of such cells in the peritoneal space and further development to form endometriotic foci. Retrograde menstruation could be detected as a physiological event. However, not all females with retrograde menstruation become ill with endometriosis, but various factors, such as cytokines, enzymes, growth factors (e.g., matrix metalloproteinases), play a critical role.
The enhanced autonomous non-cyclical estrogen production and activity as well as the reduced estrogen inactivation are typical peculiarities of endometriotic tissue. This enhanced local estrogen production and activity is caused by a significant overexpression of aromatase, expression of 17β-HSD1 and reduced inactivation of potent E2 due to a lack of 17β-HSD2, as compared to the normal endometrium (Bulun, S. E. et al., J. Steroid Biochem. Mol. Biol., 79: 19-25 (2001); Kitawaki, J., Journal of Steroid Biochemistry & Molecular Biology, 83: 149-155 (2003); Karaer, O. et al., Acta. Obstet. Gynecol. Scand., 83: 699-706 (2004); Zeitoun, K. et al., J. Clin. Endocrinol. Metab., 83: 4474-4480 (1998)).
The polymorphic symptoms caused by endometriosis include any pain symptoms in the minor pelvis, back pain, dyspareunia, dysuria and defecation complaints.
One of the therapeutic measures employed most frequently in endometriosis is the surgical removal of the endometriotic foci (Urdl, W., J. Reproduktionsmed. Endokrinol., 3: 24-30 (2006)). Despite new therapeutic concepts, medicamental treatment remains in need of improvement. The purely symptomatic treatment of dysmenorrhea is effected by means of non-steroidal anti-inflammatory drugs (NSAID), such as acetylsalicylic acid, indomethacine, ibuprofen and diclofenac. Since a COX2 overexpression could be observed both in malignant tumors and in the eutopic endometrium of females with endometriosis, a therapy with the selective COX2 inhibitors, such as celecoxib, suggests itself (Fagotti, A. et al., Hum. Reprod. 19: 393-397 (2004); Hayes, E. C. et al., Obstet. Gynecol. Surv., 57: 768-780 (2002)). Although they have a better gastro-intestinal side effect profile as compared to the NSAID, the risk of cardiovascular diseases, infarction and stroke is increases, especially for patients with a predamaged cardiovascular system (Dogne, J. M. et al., Curr. Pharm. Des., 12: 971-975 (2006)). The causal medicamental theory is based on estrogen deprivation with related variable side effects and a generally contraceptive character. The gestagens with their anti-estrogenic and antiproliferative effect on the endometrium have great therapeutic significance. The most frequently employed substances include medroxyprogesterone acetate, norethisterone, cyproterone acetate. The use of danazole is declining due to its androgenie side effect profile with potential gain of weight, hirsutism and acne. The treatment with GnRH analogues is of key importance in the treatment of endometriosis (Rice, V.; Ann. NY Acad. Sei., 955: 343-359 (2001)); however, the duration of the therapy should not exceed a period of 6 months since a longer term application is associated with irreversible damage and an increased risk of fracture. The side effect profile of the GnRH analogues includes hot flushes, amenorrhea, loss of libido and osteoporosis, the latter mainly within the scope of a long term treatment.
Another therapeutic approach involves the steroidal and non-steroidal aromatase inhibitors. It could be shown that the use of the non-steroidal aromatase inhibitor letrozole leads to a significant reduction of the frequency and severity of dysmenorrheal and dyspareunia and to a reduction of the endometriosis marker CA125 level (Soysal, S. et al., Hum. Reprod., 19: 160-167 (2004)). The side effect profile of aromatase inhibitors ranges from hot flushes, nausea, fatigue to osteoporosis and cardiac diseases. Long term effects cannot be excluded. All the possible therapies mentioned herein are also employed in the combatting of diseases such as leiomyosis, adenomyosis, menorrhagia, metrorrhagia and dysmenorrhea.
Every fourth cancer disease in the female population falls under the category of mammary cancers. This disease is the main cause of death in the western female population at the age of from 35 to 54 years (Nicholls, P. J., Pharm. J., 259: 459-470 (1997)). Many of these tumors exhibit an estrogen-dependent growth and are referred to as so-called HDSC (hormone dependent breast cancer). A distinction is made between ER+ and ER− tumors. The classification criteria are important to the choice of a suitable therapy. About 50% of the breast cancer cases in premenopausal females and 75% of the breast cancer cases in postmenopausal females are ER+ (Coulson, C., Steroid biosynthesis and action, 2nd edition, 95-122 (1994); Lower, E. et al., Breast Cancer Res. Treat., 58: 205-211 (1999)), i.e., the growth of the tumor is promoted by as low as physiological concentrations of estrogens in the diseased tissue.
The therapy of choice at an early stage of breast cancer is surgical measures, if possible, breast-preserving surgery. Only in a minor number of cases, mastectomy is performed. In order to avoid relapses, the surgery is followed by radiotherapy, or else radiotherapy is performed first in order to reduce a larger tumor to an operable size. In an advanced state, or when metastases occur in the lymph nodes, skin or brain, the objective is no longer to heal the disease, but to achieve a palliative control thereof.
The therapy of the mammary carcinoma is dependent on the hormone receptor status of the tumor, on the patient's hormone status and on the status of the tumor (Paepke, S. et al., Onkologie, 26 Suppl., 7: 4-10 (2003)). Various therapeutical approaches are available, but all are based on hormone deprivation (deprivation of growth-promoting endogenous hormones) or hormone interference (supply of exogenous hormones). However, a precondition of such responsiveness is the endocrine sensitivity of the tumors, which exists with HDSC ER+ tumors. The drugs employed in endocrine therapy include GnRH analogues, anti-estrogens and aromatase inhibitors. GnRH analogues, such as gosereline, will bind to specific membrane receptors in the target organ, the pituitary gland, which results in an increased secretion of FSH and LH. These two hormones in turn lead to a reduction of GnRH receptors in a negative feedback loop in the pituitary cells. The resulting desensitization of the pituitary cells towards GnRH leads to an inhibition of FSH and LH secretion, so that the steroid hormone feedback loop is interrupted. The side effects of such therapeutic agents include hot flushes, sweats and osteoporosis.
Another therapeutic option is the use of anti-estrogens, antagonists at the estrogen receptor. Their activity is based on the ability to competitively bind to the ER and thus avoid the specific binding of the endogenous estrogen. Thus, the natural hormone is no longer able to promote tumor growth. Today, therapeutic use involves so-called SERM (selective estrogen receptor modulators), which develop estrogen agonism in tissues such as bones or liver, but have antagonistic andjor minimal agonistic effects in breast tissue or uterus (Holzgrabe, U., Pharm. Unserer Zeit, 33: 357-359 (2004); Pasqualini, J. R., Biochim. Biophys. Acta., 1654: 123-143 (2004); Sexton, M. J. et al., Prim Care Update Ob Gyns, 8: 25-30 (2001)). Thus, these compounds are not only effective in combatting breast cancer, but also increase the bone density and reduce the risk of osteoporosis in postmenopausal females. The use of the SERM tamoxifen is most widely spread. However, after about 12-18 months of treatment, there is development of resistance, an increased risk of endometrial cancers and thrombo-embolic diseases due to the partial agonistic activity at the ER (Goss, P. E. et al., Clin. Cancer Res., 10: 5717-5723 (2004); Nunez, N. P. et al., Clin. Cancer Res., 10: 5375-5380 (2004)).
The enzymatically catalyzed estrogen biosynthesis may also be influenced by selective enzyme inhibitors. The enzyme aromatase, which converts C19 steroids to C18 steroids, was one of the first targets for lowering the E2 level. This enzyme complex, which belongs to the cytochrome P-450 enzymes, catalyzes the aromaticzation of the androgenic A ring to form estrogens. The methyl group at position 10 of the steroid is thereby cleaved off. The first aromatase inhibitor employed for the therapy of breast cancer was aminoglutethimide. However, aminoglutethimide affects several enzymes of the cytochrome P-450 superfamily and thus inhibits a number of other biochemical conversions. For example, among others, the compound interferes with the steroid production of the adrenal glands so heavily that a substitution of both glucocorticoids and mineralocorticoids may be necessary. In the meantime, more potent and more selective aromatase inhibitors, which can be subdivided into steroidal and non-steroidal compounds, are on the market. The steroidal inhibitors include, for example, exemestane, which has a positive effect on the bone density, which is associated with its affinity for the androgen receptor (Goss, P. E. et al., Clin. Cancer Res., 10: 5717-5723 (2004)). However, this type of compounds is an irreversible inhibitor that also has a substantial number of side effects, such as hot flushes, nausea, fatigue. However, there are also non steroidal compounds that are employed therapeutically, for example, letrozole. The advantage of these compounds resides in the lesser side effects, they do not cause uterine hypertrophy, but have no positive effect on the bone density and result in an increase of LDL (Iow density lipoprotein), cholesterol and triglyceride levels (Goss, P. E. et al., Clin. Cancer Res., 10: 5717-5723 (2004); Nunez, N. P. et al., Clin. Cancer Res., 10: 5375-5380 (2004)). Today, aromatase inhibitors are predominantly employed as second-line therapeutic agents. In the meantime, however, the equivalence or even superiority of aromatase inhibitors to SERM, such as tamoxifene, has been proven in clinical studies (Geisler, J. et al., Crit. Rev. Oncol. Hematol., 57: 53-61 (2006); Howell, A. et al., Lancet, 365: 60-62 (2005)). Thus, the use of aromatase inhibitors also as first-line therapeutical agents is substantiated.
However, the estrogen biosynthesis in the peripheral tissue also includes other pathways for the production of E1 and the more potent E2 by avoiding the enzyme aromatase that is locally present in the target tissue, for example, breast tumors. Two pathways for the production of estrogens in breast cancer tissue are postulated (Pasqualini, J. R., Biochim. Biophys. Acta., 1654: 123-143 (2004)), the aromatase pathway (Abul-Hajj, Y J. et al., Steroids, 33: 205-222 (1979); Lipton, A. et al., Cancer, 59: 779-782 (1987)) and the sulfatase pathway (Perei, E. et al., J. Steroid. Biochem., 29: 393-399 (1988)). The aromatase pathway includes the production of estrogens from androgens with participation of the enzyme aromatase. The sulfatase pathway is the pathway for the production of E1/E2 by means of the enzyme steroid sulfatase, an enzyme that catalyzes the conversion of E1 sulfate and DHEA-S to estrone and DHEA. In this way, 10 times as much E1 is formed in the target tissue as compared to the aromatase pathway (Santner, S. J. et al., J. Clin. Endocrinol. Metab., 59: 29-33 (1984)). E1 is then reduced by means of the enzyme 17β-HSD1 to form E2, the most potent estrogen. Steroid sulfatase and 17β-HSD1 are new targets in the battle against estrogen-related diseases, especially for the development of therapeutic agents for mammary carcinomas (Pasqualini, J. R., Biochim. Biophys. Acta., 1654: 123-143 (2004)).
Numerous steroidal sulfatase inhibitors could be found, including the potent irreversible inhibitor EMATE, which exhibited an agonistic activity at the estrogen receptor, however (Ciobanu, L. C. et al., Cancer Res., 63: 6442-6446 (2003); Hanson, S. R. et al., Angew. Chem. Int. Ed. Engl., 43: 5736-5763 (2004)). Some potent non-steroidal sulfatase inhibitors could also be found, such as COUMATE and derivatives as weil as numerous sulfamate derivatives of tetrahydronaphthalene, indanone and tetralone (Hanson, S. R. et al., Angew. Chem. Int. Ed. Engl., 43: 5736-5763 (2004)). Recently, one sulfatase inhibitor has completed a phase I clinical trial in postmenopausal women with breast cancer (Foster, P. A. et al., Anticancer Agents Med Chem. 8(7):732-8 (2008).
The inhibition of 17β-HSD1, a key enzyme in the biosynthesis of E2, the most potent estrogen, could suggest itself as an option in the therapy of estrogen-related diseases in both premenopausal and postmenopausal females (Kitawaki, J., Journal of Steroid Biochemistry & Molecular Biology, 83: 149-155 (2003); Allan, G. M. et al., Mol. Cell Endocrinol., 248: 204-207 (2006); Penning, T. M., Endocr. Rev., 18: 281-305 (1997); Sawicki, M. W. et al., Proc. Natl. Acad. Sci. USA, 96: 840-845 (1999); Vihko, P. et al., Mol. Cell. Endocrinol., 171: 71-76 (2001)). An advantage of this approach is the fact that the intervention is effected in the last step of estrogen biosynthesis, i.e., the conversion of E1 to the highly potent E2 is inhibited. The intervention is effected in the biosynthetic step occurring in the peripheral tissue, so that a reduction of E2 production takes place locally in the diseased tissue. The use of correspondingly selective inhibitors would probably be associated with little side effects since the synthesis of other steroids would remain unaffected. To achieve a selective effect, it would be important that such inhibitors exhibit no or only very little agonistic activity at the ER, especially at the ER α, since agonistic binding is accompanied by an activation and thus proliferation and differentiation of the target cell. In contrast, an antagonistic activity of such compounds at the ER would be tolerated since the inhibitor would prevent the natural substrates from binding at the receptor which in turn will result in a further reduction of the proliferation of the target cells. The use of selective 17β-HSD1 inhibitors for the therapy of numerous estrogen-dependent diseases is discussed, for example, for breast cancer, tumors of the ovaries, prostate carcinoma, endometrial carcinoma, endometriosis, adenomyosis, endometrial hyperplasia, acne, psoriasis, and androgen-dependent hair loss. Highly interesting and completely novel is the proposal to employ selective inhibitors of 17β-HSD1 for prevention when there is a genetic disposition for breast cancer (Miettinen, M. et al., J. Mammary Gland. Biol. Neoplasia, 5: 259-270 (2000)).
Hydroxysteroid dehydrogenases (HSD) can be subdivided into different classes. The 11β-HSD modulate the activity of glucocorticoids, 3β-HSD catalyzes the reaction of Δ5-3β-hydroxysteroids (DHEA or 5-androstene-3β,17β-diol) to form Δ5-3β-ketosteroids (androstenedione or testosterone). 17β-HSDs convert the less active 17-ketosteroids to the corresponding highly active 17-hydroxy compounds (androstenedione to testosterone and E1 to E2) or conversely (Payne, A. H. et al., Endocr. Rev., 25: 947-970 (2004); Peltoketo, H. et al., J. Mol. Endocrinol., 23: 1-11 (1999); Suzuki, T. et al., Endocr. Relat. Cancer, 12: 701-720 (2005)). Thus, the HSD play a critical role in both the activation and the inactivation of steroid hormones. Depending on the cell's need for steroid hormones, they alter the potency of the sex hormones (Penning, T. M., Endocr. Rev., 18: 281-305 (1997)), for example, Ei is converted to the highly potent E2 by means of 17β-HSD1, while E2 is converted to the less potent E1 by means of 17β-HSD2; 17β-HSD2 inactivates E2 while 17β-HSD1 activates E1.
To date, fourteen different mammalian 17β-HSDs have been identified (Haller, F. et al., J. Mol. Biol. doi: 10.1016jj.jmb.2010.04.002 (2010); Zhongyi, S. et al., Endocrinology 148 3827-3836 (2007); Miyoshi, T. et al., Int. J. Cancer 94 (2001) 685-689), and twelve of these enzymes could be cloned (Suzuki, T. et al., Endocr. Relat. Cancer, 12: 701-720 (2005)). They all belong to the so-called short chain dehydrogenasejreductase (SDR) family, with the exception of 17β-HSD5, which is a ketoreductase. The amino acid identity between the different 17β-HSDs is as low as 20-30% (Luu-The, V., J. Steroid Biochem. Mol. Biol., 76: 143-151 (2001)), and they are membrane-bound or soluble enzymes. The X-ray structure of 6 human subtypes is known (Ghosh, D. et al., Structure, 3: 503-513 (1995); Kissinger, C. R. et al., J. Mol. Biol., 342: 943-952 (2004); Zhou, M. et al., Acta Crystallogr. D. Biol. Crystallogr., 58: 1048-1050 (2002). The 17β-HSDs are NAD(H)-dependent and NADP(H)-dependent enzymes. They play a critical role in the hormonal regulation in humans. The enzymes are distinguished by their tissue distribution, catalytic preference (oxidation or reduction), substrate specificity and subcellular localization. The same HSD subtype was found in different tissues. It is likely that all 17β-HSDs are expressed in the different estrogen-dependent tissues, but in different concentrations. In diseased tissue, the ratio between the different subtypes is altered as compared to healthy tissue, some subtypes being overexpressed while others may be absent. This may cause an increase or decrease of the concentration of the corresponding steroid. Thus, the 17β-HSDs play an extremely important role in the regulation of the activity of the sex hormones. Further, they are involved in the development of estrogen-sensitive diseases, such as breast cancer, ovarian, uterine and endometrial carcinomas, as weil as androgenrelated diseases, such as prostate carcinoma, benign prostate hyperplasia, acne, hirsutism etc. It has been shown that some 17β-HSDs are also involved in the development of further diseases, e.g., pseudohermaphrodism (17β-HSD3 (Geissler, W. M. et al., Nat. Genet., 7: 34-39 (1994))), bifunctional enzyme deficiency (17β-HSD4 (van Grunsven, E. G. et al., Proc. Natl. Acad. Sci. USA, 95: 2128-2133 (1998))), polycystic kidney diseases (17β-HSD8 (Maxwell, M. M. et al., J. Biol. Chem., 270: 25213-25219 (1995))) and Alzheimer's (17β-HSD10 (Kissinger, C. R. et al., J. Mol. Biol., 342: 943-952 (2004); He, X. Y. et al., J. Biol. Chem., 274: 15014-15019 (1999); He, X. Y. et al., Mol. Cell Endocrinol., 229: 111-117 (2005); He, X. Y. et al., J. Steroid Biochem. Mol. Biol., 87: 191-198 (2003); Yan, S. D. et al., Nature, 389: 689-695 (1997))). The best characterized member of the 17β-HSDs is the type 1 17β-HSD. The 17β-HSD1 is an enzyme from the SDR family, also referred to as human placenta E2 dehydrogenase (Gangloff, A. et al., Biochem. J., 356 269-276 (2001); Jomvall, H. et al., Biochemistry, 34 6003-6013 (1995)). Its designation as assigned by the enzyme commission is E.C.1.1.1.62.
Engel et al. (Langer, L. J. et al., J. Biol. Chem., 233: 583-588 (1958)) were the first to describe this enzyme in the 1950's. In the 1990's, first crystallization attempts were made, so that a total of 20 crystallographic structures can be recurred to today in the development of inhibitors (Negri, M. et al. PLoS ONE 5(8): e12026. doi: 10.1371/journal.pone.0012026 (2010)). Available are X-ray structures of the enzyme alone, but also of binary and ternary complexes of the enzyme with its substrate and other ligands or substrate/ligand and cofactor.
17β-HSD1 is a soluble cytosolic enzyme. NADPH serves as a cofactor. 17β-HSD1 is encoded by a 3.2 kb gene consisting of 6 exons and 5 introns that is converted to a 2.2 kb transcript (Luu-The, V., J. Steroid Biochem. Mol. Biol., 76: 143-151 (2001); Labrie, F. et al., J. Mol. Endocrinol., 25: 1-16 (2000)). It is constituted by 327 amino acids. The molecular weight of the monomer is 34.9 kDa (Penning, T. M., Endocr. Rev., 18: 281-305 (1997)). 17β-HSD1 is expressed in the placenta, liver, ovaries, endometrium, prostate gland, peripheral tissue, such as adipose tissue and breast cancer cells (Penning, T. M., Endocr. Rev., 18: 281-305 (1997)). It was isolated for the first time from human placenta (Jarabak, J. et al., J. Biol. Chem., 237: 345-357 (1962)). The main function of 17β-HSD1 is the conversion of the less active E1 to the highly potent E2. However, it also catalyzes to a lesser extent the reaction of dehydroepiandrosterone (DHEA) to 5-androstene-3β,17β-diol, an androgen showing estrogenic activity (Labrie, F., Mol. Cell. Endocrinol., 78: CI13-118 (1991); Poirier, D., Curr. Med. Chem., 10: 453-477 (2003); Poulin, R. et al., Cancer Res., 46: 4933-4937 (1986)). In vitro, the enzyme catalyzes the reduction and oxidation between E1 and E2 while it catalyzes only the reduction under physiological conditions. These bisubstrate reactions proceed according to a random catalytic mechanism, i.e., either the steroid or the cofactor is first to bind to the enzyme (Negri, et al. PLoS ONE 5(8): e12026. doi:10.1371/journal.pone.0012026 (2010)). The enzyme consists of a substrate binding site and a channel that opens into the cofactor binding site. The substrate binding site is a hydrophobie tunnel having a high complementarity to the steroid. The 3-hydroxy and 17-hydroxy groups in the steroid form four hydrogen bonds to the amino acid residues His221, Glu282, Ser142 and Tyr155. The hydrophobie van der Waals interactions seem to form the main interactions with the steroid while the hydrogen bonds are responsible for the specificity of the steroid for the enzyme (Labrie, F. et al., Steroids, 62: 148-158 (1997)). Like with all the other enzymes of this family, what is present as a cofactor binding site is the Rossmann fold, which is a region consisting of ex-helices and β-sheets (β-α-β-α-β)2, a generally occurring motif Gly-Xaa-Xaa-Xaa-Gly-Xaa-Gly, and a nonsense region Tyr-Xaa-Xaa-Xaa-Lys within the active site. What is important to the activity is a catalytic tetrade consisting of Tyr155-Lys159-Ser142-Asnl14, which stabilize the steroid and the ribose in the nicotinamide during the hydride transfer (Alho-Richmond, S. et al., Mol. Cell Endocrinol., 248: 208-213 (2006); Labrie, F. et al., Steroids, 62: 148-158 (1997); Nahoum, V. et al., Faseb. J., 17: 1334-1336 (2003)).
The gene encoding 17β-HSD1 is linked with the gene for mammary and ovarian carcinomas that is very susceptible to mutations and can be inherited, the BRCA1 gene, on chromosome 17q11-q21 (Labrie, F. et al., J. Mol. Endocrinol., 25: 1-16 (2000)). As has been demonstrated, the activity of 17β-HSD1 is higher in endometrial tissue and breast cancer cells as compared to healthy tissue, which entails high intracellular E2 levels, which in turn cause proliferation and differentiation of the diseased tissue (Bulun, S. E. et al., J. Steroid Biochem. Mol. Biol., 79: 19-25 (2001); Miyoshi, Y. et al., Int. J. Cancer, 94: 685-689 (2001); Kitawaki, J., Journal of Steroid Biochemistry & Molecular Biology, 83: 149-155 (2003); Pasqualini, J. R., Biochim. Biophys. Acta., 1654: 123-143 (2004); Vihko, P. et al., Mol. Cell. Endocrinol., 171: 71-76 (2001); Miettinen, M. et al., Breast Cancer Res. Treat., 57: 175-182 (1999); Sasano, H. et al., J. Clin. Endocrinol. Metab., 81: 4042-4046 (1996); Yoshimura, N. et al., Breast Cancer Res., 6: R46-55 (2004)). An inhibition of 17β-HSD1 could result in the E2 level being lowered and thus lead to a regression of the estrogen-related diseases. Further, selective inhibitors of 17β-HSD1 could be used for prevention when there is a genetic disposition for breast cancer (Miettinen, M. et al., J. Mammary Gland. Biol. Neoplasia, 5: 259-270 (2000)).
Therefore, this enzyme would suggest itself as a target for the development of novel selective and non-steroidal inhibitors as therapeutic agents in the battle against estrogen-related diseases. Recently, in vivo efficacy of 17β-HSD1 inhibitors has been reported in two animal models. Immunodeficient mice were inoculated either with MCF-7 cells over-expressing human recombinant 17β-HSD1 enzyme (Husen, B. et al., Mol. Cell. Endocrinol., 248, 109-113 (2006); Husen, B. et al., Endocrinology, 147, 5333-5339 (2006)) or with T47D cells naturally expressing 17β-HSD1 (Day, J. M. et al.; Int. J. Cancer, 122, 1931-1940 (2008). In both models, the El induced tumor growth was reduced by 17β-HSD1 inhibitors, validating 17β-HSD1 as a novel target for the treatment of estrogen dependent diseases. Up to date however, no 17β-HSD1 inhibitor has entered clinical trials.
In the literature, only a few compounds have been described as inhibitors of 17βHSD1 (D. Poirier, Anticancer Agents Med. Chem. 9 642-660 (2009); Day, J. M. et al., Minerva Endocrinol., 35(2), 87-108 (2010); D. Poirier, Expert Opin Ther Pat., doi:10.1517/13543776.2010.505604 (2010)). Most inhibitors are steroidal compounds obtained by different variations of the estrogen skeleton (Rouillard, F. et al., Open Enzyme Inhib. J., 1 61-71 (2008); D. Poirier, Anticancer Agents Med. Chem. 9 642-660 (2009); Mazumdar M. et al.; Biochem J., 424(3):357-366 (2009); Möller G et al. Bioorg Med Chem Lett., 19(23): 6740-6744 (2009); Berube M. et al. Molecules 15 1590-1631 (2010)).

Another class of compounds which has been described is the so-called hybrid inhibitors (Berube, M. et al., Can. J. Chem. 87 1180-1199 (2009)), compounds that, due to their molecular structure, not only attack at the substrate binding site, but also undergo interactions with the cofactor binding site. The inhibitors have the following structure:                adenosine moiety or simplified derivatives that can interact with the cofactor binding site;        E2 or E1 moiety, which interacts with the substrate binding site; and        a spacer of varying length as a linking element between the two moieties.

Among these compounds, inhibitors have been synthesized that exhibit a good inhibition of the enzyme and a good selectivity for 17β-HSD2 (compound B (Lawrence, H. R. et al., J. Med. Chem., 48: 2759-2762 (2005)). In addition, the inventors consider that a small estrogenic effect can be achieved by a substitution at the C2 of the steroid skeleton (Cushman, M. et al., J. Med. Chem., 38: 2041-2049 (1995); Leese, M. P. et al., J. Med. Chem., 48: 5243-5256 (2005)); however, this effect has not yet been demonstrated in tests.
However, a drawback of these steroidal compounds may be a low selectivity. With steroids, there is a risk that the compounds will also interfere with other enzymes of the steroid biosynthesis, which would lead to side effects. In addition, due to their steroidal structure, they may have an affinity for steroid receptors and function as agonists or antagonists.
Among the phytoestrogens, which have affinity for the estrogen receptor and act as estrogens or anti-estrogens depending on the physiological conditions, flavones, isoflavones and lignans have been tested for an inhibitory activity (Makela, S. et al., Proc. Soc. Exp. Biol. Med., 217: 310-316 (1998); Makela, S. et aL, Proc. Soc. Exp. Biol. Med., 208: 51-59 (1995); Brooks, J. D. et al., J. Steroid Biochem. Mol. Biol., 94: 461-467 (2005)). Coumestrol was found to be particularly potent, but of course showed estrogenic activity (Nogowski, L., J. Nutr. Biochem., 10: 664-669 (1999)). Gossypol derivatives were also synthesized as inhibitors (US2005/0228038). In this case, however, the cofactor binding site rather than the substrate binding site is chosen as the target site (Brown, W. M. et al., Chem. Biol. Interact., 143-144, 481-491 (2003)), which might entail problems in selectivity with respect to other enzymes utilizing NAD(H) or NADP(H).

In addition to diketones, such as 2,3-butanedione and glyoxal, which were used for studies on the enzyme, suicide inhibitors were also tested. However, these were found not to be therapeutically utilizable since the oxidation rate of the alcohols to the corresponding reactive form, namely the ketones, was too weak (Poirier, D., Curr. Med. Chem., 10: 453-477 (2003)).
In other studies, Jarabak et al. (Jarabak, J. et al., Biochemistry, 8: 2203-2212 (1969)) examined various non-steroidal inhibitors for their inhibitory effect, U-11-100A having been found as the most potent compound in this group. However, as compared to other non steroidal compounds, U-II-100A is a weak inhibitor of 17βHSD1.

Recently, using a pharmacophore model for 17β-HSD1 inhibitors Schuster et al. identified some compounds with 17β-HSD1 inhibitory activity in the micromolar range (Schuster, D. et al., J Med Chem. 51:4188-4199 (2008)). Regarding additional non steroidal 17β-HSD1 inhibitors, 5 templates reveal interesting biological activities: A. Thiophenepyrimidinones (US2005/038053; Messinger, J. et al., Mol. Cell. Endocrinol., 248: 192-198 (2006); W02004jll0459; Lilienkampf, A. et al., J. Med. Chem. 52: 6660-6671 (2009)); B. Biphenyl ethanones (Allan, G. M. et al. Bioorg. Med. Chem. 16: 4438-4456 (2008)); C. Hydroxyphenylnaphtols (WO/08EP/53672; Marchais-Oberwinkler S. et al., J. Med. Chem., 51: 4685-4698 (2008)) Marchais-Oberwinkler, S. et al., J. Med. Chem., 54: 534-547, 2011); D. Heterocyclic substituted biphenylols (Oster, A. et al., Bioorg. Med. Chem., 18: 3494-3505 (2010)); E. Bis(hydroxyphenyl) arenes (W02009/02746; Bey, E. et al., J. Med. Chem., 52: 6724-6743 (2009)).

Most of those classes showed high potency at the protein level (IC50<20 nM; W02004/53424) but a limited inhibitory activity (IC50>200 nM) in cell-based 17β-HSD1 assays (Messinger J. et al, Mol. Cell. Endocrinol., 248: 192-198 (2006) and Bey E. et al, J. Med. Chem., 52: 6724-6743 (2009)), which might be due to poor cell membrane permeability.
Recently described coumarins display only moderate inhibition of 17β-HSD1 (Star{hacek over (c)}ević et al, J. Med. Chem. 54: 248-261 (2011)), whereas bicyclic substituted hydroxyphenylmethanones have been described as potent inhibitors (Oster et al., J. Med. Chem. 53: 8176-8186 (2010)).

Inhibitors with hydroxybenzothiazole core (Spadaro et al. PLoS ONE 7: e29252. doi:10.1371/journal.pone.0029252; J. Med. Chem. 55: 2469-2473 (2012)) are potent but show poor pharmacokinetics. Further, 2-benzoylbenzothiazole derivatives having lipid lowering activity are known from EP-A-735029, and N-(benzothiazol-2-yl)arylcarboxamide and I-(benzothiazol-2-yl)-3-(aryl)urea derivatives and their use for the inhibition of ubiquitination are known from WO2005/037845. Similar N-(benzothiazol-2-yl)arylcarboxamide and 1-(benzothiazol-2-yl)-3-(aryl)urea derivatives including frentizole (1-(6-methoxy-1,3-benzothiazol-2-yl)-3-phenylurea) are also known to interact with amyloid beta (Aβ) peptide and/or (Aβ)-binding alcohol dehydrogenase and are potential anti-Alzheimer agent (Xie, Y. et al., Bioorg. & Med. Chem. Lett. 16: 4657-60 (2006)).
Finally, selective 17β-HSD1 inhibitors with (phenylthiazolyl)(phenyl)methanone (phenylthienyl)(phenyl)methanone and (benzothiazolyl)(phenyl)methanone structure are known from WO2012/025638, and selective 17β-HSD1 inhibitors with (phenyl-1,3-thiazol-4-yl)phenol and (phenylthienyl)phenol structure are known from DE102007040243A1.
17Beta-Hydroxysteroid Dehydrogenase Type 2 Inhibitors: Estrogens and androgens play a crucial role in the development, growth and function of all tissues involved in reproduction and fertility. It is also well known, that E2 and testosterone/dihydrotestosterone (T/DHT) the most active estrogen and androgen, respectively, can be involved in a series of hormone-sensitive diseases. For example estrogens or androgens are often responsible for the development of breast cancer or prostate cancer, respectively, via stimulation of cell proliferation in the corresponding tissues (Travis, R. C. et al., Breast Cancer Res., 5: 239-247 (2003); Wilding, G., Cancer Surv., 14113-14130 (1992)) or insufficient levels of E2 and T/DHT predispose the human skeleton to osteoporosis in both men and women (Pietschmann, P. et al., Gerontology, 55:3-12 (2008)).
Osteoporosis is a systemic skeletal disease characterized by deterioration of bone tissue and low bone mass, resulting in increased fragility of the bone and higher risk of fractures of the hip, spine and wrist. Osteoporotic fractures lead to pain, occasional disability and more important, they increase mortality (Cree, M. et al., J. Am. Geriatr. Soc., 48:283-288 (2000)).
In healthy individuals, bone mass is maintained by a balance between bone resorption and bone formation performed by the osteoclasts (OCs) and osteoblasts (OBs), respectively. This process of bone remodelling facilitates repair of microdamage, provides calcium uptake and therefore brings stability and strength to the bone.
Bone loss is, however, accelerated in post-menopausal women and in elderly men. The mechanisms by which elderly people, both men and women, lose bone are not fully understood and remain under investigation. Decreased quantity of sex hormones is one important factor causing bone loss. In women at menopause, estrogen deficiency (Cree, M. et al., J. Am. Geriatr. Soc., 48:283-288 (2000)) and in older men, estrogen and androgen insufficiency (Fink, H. A. et al., J. Clin. Endocrinol. Metab., 91:3908-3915 (2006); Meier, C. et al., Arch. Intern. Med., 168:47-54 (2008)) result in a disproportionate increase in bone loss as compared with bone formation and often lead to osteoporosis.
Since OBs and OCs express estrogen receptors (Hoyland, J. A. et al., Bone, 20:87-92 (1997)) and respond to estrogen treatments, the most potent estrogen, E2 must have a direct effect on maintenance of bone mineral density. There are also substantial evidence that androgens like testosterone (T) and dihydrotestosterone (DHT) may as well be involved in bone formation, increasing OB activity and therefore protecting the bones against osteoporosis (Vanderschueren, D. et al., Endocr. Rev., 25:389-425 (2004), Vanderschueren, D. et al., Curr. Opin. Endocrinol. Diabetes Obes., 15:250-254 (2008)). T and DHT might act via activation of the androgen receptor (AR) which is present in the OBs (Bland, R., Clin. Sci., 98:217-240 (2000)) or could be the precursor of estrogens (the enzyme aromatase, responsible for the transformation of androgens in estrogens has been identified in the OBs). Controlled increase of E2 and T in bones of osteoporotic patients will simultaneously lower bone resorption (effect of E2) and raise bone formation (effect of T) improving bone loss and osteoporotic fractures. Augmentation of E2 and T levels in bones might be achieved by inhibition of the enzyme 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) which has been identified in OBs (Dong, Y. et al., J. Bone Miner. Res., 13:1539-1546 (1998); Feix, M. et al., Mol. Cell. Endocrinol., 171:163-164 (2001); Janssen, J. Met al., J. Cell. Biochem., 75:528-37 (1999)). A restricted increase in E2 and T in OCs and OBs is important to avoid unwanted side-effects such as induction of breast cancer or prostate cancer. This might be achieved via an intracrine mechanism (Labrie, F., Mol. Cell. Endocrinol. 78:C113-118 (1991)), i.e., the transformation of E2 and T in inactive precursors should be blocked dominantly in the bone cells 17β-HSD2 (Wu, L. et al., J. Biol. Chem., 268:12964-12969 (1993); Lu, M., J. Biol. Chem., 277:22123-22130 (2002)) belongs to the hydroxysteroid dehydrogenase (HSD) superfamily. The HSD enzymes play pivotal roles not only in the activation but also in the inactivation of steroid hormones. Depending on the need of the cell, they modulate the potency of the sex hormones (Penning, T. M. et al., Endocr. Rev., 18:281-305 (1997)). For example, 17β-HSD1 activates E1 into the very potent E2, while 17β-HSD2 oxidizes E2 into E1 thus decreasing the action of the potent E2. It is therefore believed that in physiology 17β-HSD2 protects the cell against excessive level of active estrogen. To date, fourteen different 17β-HSDs have been identified (Lukacik, P. et al., Mol. Cell. Endocrinol. 248:61-71 (2006); Luu-The, V. et al., Best Pract. Res. Clin. Endocrinol. Metab., 22:207-221 (2008)) and twelve different subtypes have been cloned from human tissues. They all belong to the Short-Chain Dehydrogenase/Reductase family (except type 5). The 17β-HSDs show little amino acid identity (20-30%) and are membrane-bound or soluble enzymes. The X-ray structures of six human subtypes (type 1, 4, 8, 10, 11, 14) are known (Moeller, G. et al., Mol. Cell. Endocrinol. 301:7-19 (2009)). All of them are NAD(H)- or NADP(H)-dependent. The 17β-HSDs play therefore a key role in hormonal regulation and function in humans. They differ in tissue distribution, catalytic preference (oxidation or reduction), substrate specificity and subcellular localisation. It is likely that all 17β-HSDs, modulating estrogen and androgen action, are expressed in the different estrogen/androgen-dependent tissues but certainly at different concentrations. In diseased tissues, the ratio between the different subtypes is changed compared to healthy tissues: one enzyme subtype might be overexpressed or completely absent, leading to higher/lower concentrations of the specific steroids. Selective inhibition of one subtype could therefore be a good strategy to influence the level in estrogen and androgen in hormone sensitive diseases. 17β-HSD2 (EC 1.1.1.51) is a transmembrane protein localized in the endoplasmic reticulum (Wu, L. et al., J. Biol. Chem., 268:12964-12969 (1993); Lu, M., J. Biol. Chem., 277:22123-22130 (2002)). Its 3D-structure remains unknown. 17β-HSD2 shows a broad tissue distribution in adult: it is expressed in liver, small intestine, endometrium, urinary tracts and bone osteoblastic (Dong, Y. et al., J. Bone Miner. Res., 13:1539-1546 (1998); Feix, M. et al., Mol. Cell. Endocrinol., 171:163-164 (2001); Eyre, L. J. et al., J. Bone Miner. Res., 13:996-1004 (1998)) and osteoclastic (van der Eerden, B. C. J. et al., J. Endocrinol., 180:457-467 (2004)) cells. It has a predominant oxidative activity on hydroxy groups at the position C17 of the steroids: it converts the highly active 17β-hydroxysteroid estrogen E2 as well as the 17β-hydroxysteroid androgens T and DHT into their inactive keto forms using the cofactor NAD+. The broad tissue distribution together with the oxidative activity of 17β-HSD2 suggests that this enzyme may play an essential role in the inactivation of highly active estrogens and androgens, resulting in diminished sex hormone action in target tissues.
Relatively few inhibitors of 17β-HSD2 have been described. Sam, K. M., J. Med. Chem., 38:4518-4528 (1995); Poirier, D. et al., Mol. Cell. Endocrinol., 171:119-128 (2001); Bydal, P. et al., Eur. J. Med. Chem., 44:632-644 (2009)) reported on the potent steroidal C17-spirolactone 1 (inhibitory activity of 70% at 1 μM and 40% at 100 nM). Cook et al. (Cook, J. H. et al., Tetrahedron Letters, 46:1525-1528 (2005); Gunn, D., Bioorg. Med. Chem. Lett., 15:3053-3057 (2005); Wood, J. et al., Bioorg. Med. Chem. Lett., 16:4965-4968 (2006)) found, using high through-put screening methods, the first new class of potent non-steroidal inhibitors of 17β-HSD2: the 4,5-disubstituted cis-pyrrolidines. The most active compound described is 2 (IC50=10 nM). It has been recently proven in monkeys, using an osteoporosis model for in vivo evaluation of the 17β-HSD2 inhibitor 3, that inhibition of this enzyme helps to maintain a sufficient local level of E2 and T in bones when the level of circulating active sex steroid drops (Bagi, C. M. et al., J. Musculoskelet. Neuronal Interact., 8:267-280 (2008)).

This modulation of steroid levels might be useful for a variety of indications like prevention and treatment of diseases caused by a misbalance of OB/OC activity like osteoporosis, osteopenia and impaired bone fracture healing (Undsay, R. et al., Obst. Gynecol., 76:290-295 (1990); Turner, R. T. et al., Endocr. Rev., 16:275-300 (1994); Meczekalski, B. et al., Gynecol. Endocrinol., 26:652-657 (2010)), postmenopausal symptoms, vaginal atrophy (Klingsberg S. A. et al., Int J Women's Health, 1: 105-111 (2009); Mac Bride, M. B., Mayo Clin. Proc., 85:87-94 (2010); Smith, A. L et al., Discov. Med., 10:500-510 (2010)); colon cancer (Oduwole O. O. et al., J. Steroid. Biochem. Mol. Biol. 87:133-140 (2003)), neuronal diseases (Behl, C. et al., Biochem. Biophys. Res. Commun., 216:473-482 (1995)) like Alzheimer (Pike, C. J., Front Neuroendocrinol., 30:239-258 (2009)) and Parkinson's disease (Bourque, M. et al., Front Neuroendocrinol., 30:142-157 (2009)), depression (Schmidt, P. J. et al., Ann. N.Y. Acad. Sci., 179:70-85 (2009)) anxiety, hypercholesterolemia (Karjalainen, A. et al., Arterioscler. Thromb. Vasc. Biol., 4:1101-1106 (2000)), cardiovascular diseases (Traish, A. M. et al., J. Androl., 30:477-494 (2009); Xing D. et al., Arteriosder. Thromb. Vasc. Biol., 29:289-295 (2009)); hair loss (Mooradian, A. D. et al., Endocr. Rev., 8:1-28 (1987); Georgala S. et al., Dermatology 208:178-9 (2004)), non-insulin-dependent diabetes mellitus (Ferrara A. et al., Diabetes Care 25: 1144-1150 (2001)), rheumatic diseases and inflammatory diseases (Cutolo, M. et al., Ann. N.Y. Sci., 1193:36-42 (2010); Islander U. et al., Mol. Cell. Endocrinol. Doi:10.1016/j.mce. 2010.05.018 (2010)). More recently, non-steroidal 17β-HSD2 inhibitors from different compound classes have been described (Wetzel M. et al., Bioorg. Med. Chem., 19: 807-815 (2011); Wetzel M. et al., J. Med. Chem., 54: 7547-7557 (2011). Wetzel M. et al., Eur. J. Med. Chem., 47:1-17 (2012). Xu K. et al., Eur. J. Med. Chem., 46: 5978-5990 (2011); Xu K. et al., Letters in Drug Design & Discovery, 8: 406-421 (2011); Al-Soud Y. A. et al, Arch. Pharm. (Weinheim), 345: 610-621 (2012); Marchais-Oberwinkler et al. S., J. Med. Chem., 56:167-181 (2013); Perspicace E. et al., Eur. J. Med. Chem., 69:201-215 (2013); Perspicace E. et al., Molecules, 18: 4487-4509 (2013)). Further, selective 17bHSD1 inhibitors with N-benzyl-N-methyl(phenyl)thiophene-carboxamide, N-benzyl-N-methyl-(phenyl)-1,3-thiazole-carboxamide and N-benzyl-N-methyl-biphenyl-3-carboxamide structure are known from WO2012117097.
Related Structures: Thakar K. A. and Padhye A. M., J. Ind. Chem. Soc. LXI: 715-716 (1984) discloses certain mono- and dihalogeno-hydroxyphenyl-furyl-ketones, and mono- and di-halogeno-hydroxyphenyl-thienyl-ketones in the synthesis of furyland thienyl-substituted benzisoxazoles.
Takayama T. et al., Bioorg. & Med. Chem. Lett. 20: 108-111 (2010) and WO2005/123671 disclose (3-amino-4-carboxamido-5-(4′-phenoxy)phenyl-pyrrol-2-yl)-phenyl-ketone derivatives that are inhibitors of lymphocyte-specific kinase and are useful as immunsuppresive agents, e.g. for the treatment of inflammatory diseases and of organ transplant rejection.
EP0801058A1 and U.S. Pat. No. 5,817,691 disclose arylthio-, arylsulfinyl- and arylsulfonylpyrrole compounds having insecticidal activity.
WO2011/079772 discloses the one-pot synthesis of certain 2,5-disubstituted thienes.


The background of the present disclosure and the illustrative embodiments disclosed herein are described in the context of identifying known audio recordings encountered during an outbound telephone call, for example during a call placed from a contact center. However, the present invention has applicability to the identification of any segment of audio or an image (as used herein, the term “image” is intended to encompass both still and moving images), regardless of the type or source of the audio or image, and regardless of in what circumstances the audio or image is encountered. Furthermore, the present invention also has applicability to the identification of any segment of data such as, for example, data obtained from any type of sensor. Therefore, as used herein, the term “dataset” shall encompass a collection of any type of data, whether comprising audio, image, or other type of data.
In a classic contact center scenario, outbound calls are made either automatically (by a class of devices known as “automated dialers” or “autodialers”) or manually. A number of human “agents” are available to join into calls that are determined to reach a live person at the called end. In this way, efficiencies are obtained by not having agents involved in a call until it is determined that there is a live person at the called end with whom the agent may speak. The use of automated equipment to monitor the telephone line during the outbound call is referred to as call progress analysis (CPA). CPA is a class of algorithms that operate on audio and network signaling during call setup. The goal of CPA is to determine the nature of the callee, or the outcome of call setup to an external network (traditional public switched telephone network or Voice over Internet Protocol (VoIP)). Specifically, when a call or session is being established, the caller or initiator must determine whether it was answered by a live speaker, if the line is busy, etc. When the caller is an automated application, such as an automated dialer or message broadcasting system, CPA algorithms are used to perform the classification automatically. CPA is used to interpret so-called call-progress tones, such as ring back and busy, that are delivered by the telephone network to the calling entity. Traditional CPA is performed using low- and high-pass frequency discriminators together with energy measurements over time to qualify in-band signaling tones.
Another method for classifying audio on an outbound call is known as Voice Activity Detection (VAD), which is a class of audio processing algorithms that identify where speech is present in an audio stream. The detected speech may originate from any source, including a live speaker or a prerecorded message. Modern VAD algorithms use spectral analysis to distinguish the utterance of a primary speaker from background noise.
A subclass of CPA algorithms that extract speaking patterns using VAD, and determine whether the patterns originate from a live speaker or a prerecorded message, is known as Answering Machine Detection (AMD). By identifying calls that do not connect to a live speaker, an accurate AMD algorithm can significantly increase throughput of an automated dialer. However, false positives from AMD lead to silent or abandoned calls, causing revenue loss for the contact center, and negative impressions amongst the public. The quality of an AMD algorithm is a function of the accuracy and response time, and some regions of the world (notably the U.S. and U.K.) impose strict legal requirements on both.
AMD is not an exact science, and the optimal approach is an open problem. To achieve acceptable accuracy, speed, and flexibility, AMD algorithms use a combination of heuristics and statistical models such as neural networks to classify an utterance as live or pre-recorded. Although many commercial AMD systems available on the market report high accuracy rates in the marketing literature (e.g., 95% or more), there is no independent auditor for these figures, and the actual accuracy rate is typically much lower in practice (e.g., 80% or less), as reflected by continued widespread complaints. A general ban has been proposed by some consumer advocacy groups, and some contact centers simply cannot use AMD because of its limitations.
A relatively new science of audio identification is known as Acoustic Fingerprinting, in which a system generates a “fingerprint” of a candidate audio stream, and compares it against a database of known fingerprints, analogous to human fingerprinting used in forensics. In this context, a “fingerprint” is a condensed digest of an audio stream that can quickly establish perceptual equality with other audio streams. A database of known fingerprints may associate known fingerprints with meta-data such as “title”, “artist”, etc. The past ten years have seen a rapidly growing scientific and industrial interest in fingerprinting technology for audio and images. Applications include identifying songs and advertisements, media library management, and copyright compliance.
Various acoustic fingerprinting algorithm classes have been proposed, and the most prevalent today are those based on either “landmarks” or “bitmaps”. Landmark-based algorithms extract discrete features from an audio stream called “landmarks”, such as spectral peaks, sudden changes in tone, pitch, loudness, etc. The optimal choice of landmark is an open question guided mostly by heuristics. The acoustic fingerprint is stored as a sequence of data structures that describe each landmark. At runtime, landmarks extracted from a candidate audio stream are compared to a database of fingerprints based on a distance metric.
Bitmap-based algorithms analyze an audio stream as a sequence of frames, and use a filter bank to quantize each frame into a bit vector of size N, where N is typically chosen for convenience as the number of bits in a C-style integer, e.g. N∈{8, 16, 32, or 64}. A popular and well-studied example is known as the “Haitsma-Kalker algorithm”, which computes a binary bitmap using a filter that compares short-term differences in both time and frequency. The Haitsma-Kalker Algorithm has been well-studied in the literature. It's inventors, Jaap Haitsma and Ton Kalker, have published a report of use of the Haitsma-Kalker Algorithm and the comparison of binary acoustic fingerprint bitmaps to identify three (3) second recordings of songs from a database of millions of songs (Haitsma and Kalker, “A Highly Robust Audio Fingerprinting System,” Journal of New Music Research, Vol. 32, No. 2 (2003), pp. 211-221). The complete acoustic fingerprint is stored as a sequence of bit vectors, or a bitmap. As illustrated in FIG. 1A-C, there are shown three images of an audio stream containing a message from a telephone network saying “This number has been disconnected”. FIG. 1A shows the original audio wave signal, with 1.5 seconds of audio sampled at 8000 KHz. FIG. 1B shows a spectrogram of the original audio input signal, with dark regions indicating high energy at a particular frequency. FIG. 1C shows a binary acoustic fingerprint bitmap created using the Haitsma-Kalker algorithm, with height N=16. The height is determined by the number of bits computed at each frame, and the width is determined by the number of frames in the audio stream. At runtime, the bitmap computed from a candidate audio stream is compared to a database of bitmaps based on the number of non-matching bits, also known as the Hamming distance.
The use of bitmap matching and the process of acoustic fingerprinting is a powerful emerging tool in the science of audio recognition; however, it is computationally intense and requires several seconds of sampled audio to make a match in many cases. This delay makes it not well suited for use in call progress analysis. Accordingly, there remains a need for faster and more accurate systems and methods for identifying audio, both in the general case and during an outbound call attempt.


1. Field of the Invention
The present invention relates to a photonic crystal fiber (PCF) preform and a photonic crystal fiber manufactured using the same.
2. Description of the Related Art
A photonic crystal fiber (PCF) is a special kind of optic fiber. A general single-mode optical fiber is made up of a core material which consists of glass and germanium or phosphorus. On the other hand, the photonic crystal fiber is made up of a single, solid and substantially transparent material 1, such as silica glass, and periodically spaced air holes 2 running along the fiber, as shown in FIG. 1. Difference in dielectric constant between the silica glass material 1 and the periodically spaced air holes 2 forms a photonic band gap, which serves to prevent movement of a ray in a specific direction as in an electronic band gap of a semiconductor. In other words, the ray passes through the photonic band gap only when the ray satisfies conditions under which it may pass through.
The photonic crystal fiber has many important technical properties. For example, the photonic crystal fiber may support a single mode over a wide range of wavelengths, and may provide a large mode region. Consequently, the photonic crystal fiber is capable of transmitting high optical power and providing large phase dispersion in a telecommunication wavelength of 1.55 μm. Furthermore, the photonic crystal fiber is increasingly used as a device for controlling nonlinearity or polarization. It is expected based on recent reports on these functions of photonic crystal fiber, that photonic crystal fiber will be widely applied to optical communication and optical-related industries in the near future.
A photonic crystal fiber must originate from a photonic crystal fiber perform, which is drawn into a photonic crystal fiber having an efficiently long length and retaining its
Generally, the photonic crystal fiber preform may have structures schematically shown in FIGS. 2a and 2b.
The photonic crystal fiber preform of FIG. 2a is made up of a circular silica glass rod 10 and a plurality of circular air holes 11 longitudinally formed through the circular silica glass rod 10 in a photonic lattice structure. Index of refraction of the photonic crystal fiber preform with the above-stated construction is distributed as illustrated in FIG. 2b.
The conventional photonic lattice structures, however, limit photonic crystal fiber preform design. Furthermore, the air holes may be deformed when being drawn into desired photonic crystal fibers. The photonic crystal fibers are, as a result, not manufactured according to the originally intended design. Also, the material constituting a core of the photonic crystal fiber is limited as to its properties.


Lithographic projection apparatus (tools) can be used, for example, in the manufacture of integrated circuits (ICs). In such a case, the mask contains a circuit pattern corresponding to an individual layer of the IC, and this pattern can be imaged onto a target portion (e.g. comprising one or more dies) on a substrate (for example, but not limited to a silicon wafer) that has been coated with a layer of radiation-sensitive material (resist). In general, a single wafer will contain a whole array of adjacent target portions that are successively irradiated via the projection system, one at a time. In one type of lithographic projection apparatus, each target portion is irradiated by exposing the entire reticle pattern onto the target portion in one go; such an apparatus is commonly referred to as a wafer stepper. In an alternative apparatus—commonly referred to as a step-and-scan apparatus—each target portion is irradiated by progressively scanning the mask pattern under the projection beam in a given reference direction (the “scanning” direction) while synchronously scanning the substrate table parallel or anti-parallel to this direction; since, in general, the projection system will have a magnification factor M (generally <1), the speed V at which the substrate table is scanned will be a factor M times that at which the mask table is scanned. More information with regard to lithographic apparatus as here described can be gleaned, for example, from U.S. Pat. No. 6,046,792, incorporated herein by reference.
In a manufacturing process using a lithographic projection apparatus, a mask pattern is imaged onto a substrate that is at least partially covered by a layer of radiation-sensitive material (resist). Prior to this imaging step, the substrate may undergo various procedures, such as priming, resist coating and a soft bake. After exposure, the substrate may be subjected to other procedures, such as a post-exposure bake (PEB), development, a hard bake and measurement/inspection of the imaged features. This array of procedures is used as a basis to pattern an individual layer of a device, e.g. an IC. Such a patterned layer may then undergo various processes such as etching, ion-implantation (doping), metallization, oxidation, chemo-mechanical polishing, etc., all intended to finish off an individual layer. If several layers are required, then the whole procedure, or a variant thereof, will have to be repeated for each new layer. Eventually, an array of devices will be present on the substrate (wafer). These devices are then separated from one another by a technique such as dicing or sawing. Thereafter, the individual devices can be mounted on a carrier, connected to pins, etc. Further information regarding such processes can be obtained, for example, from the book “Microchip Fabrication: A Practical Guide to Semiconductor Processing”, Third Edition, by Peter van Zant, McGraw Hill Publishing Co., 1997, ISBN 0-07-067250-4, incorporated herein by reference.
The lithographic tool may be of a type having two or more substrate tables (and/or two or more mask tables). In such “multiple stage” devices the additional tables may be used in parallel, or preparatory steps may be carried out on one or more tables while one or more other tables are being used for exposures. Twin stage lithographic tools are described, for example, in U.S. Pat. No. 5,969,441 and WO 98/40791, incorporated herein by reference.
The photolithography masks referred to above comprise geometric patterns corresponding to the circuit components to be integrated onto a silicon wafer. The patterns used to create such masks are generated utilizing CAD (computer-aided design) programs, this process often being referred to as EDA (electronic design automation). Most CAD programs follow a set of predetermined design rules in order to create functional masks. These rules are set by processing and design limitations. For example, design rules define the space tolerance between circuit devices (such as gates, capacitors, etc.) or interconnect lines, so as to ensure that the circuit devices or lines do not interact with one another in an undesirable way.
Of course, one of the goals in integrated circuit fabrication is to faithfully reproduce the original circuit design on the wafer (via the mask). Another goal is to use as much of the semiconductor wafer real estate as possible. As the size of an integrated circuit is reduced and its density increases, however, the CD (critical dimension) of its corresponding mask pattern approaches the resolution limit of the optical exposure tool. The resolution for an exposure tool is defined as the minimum feature that the exposure tool can repeatedly expose on the wafer. The resolution value of present exposure equipment often constrains the CD for many advanced IC circuit designs.
Furthermore, the constant improvements in microprocessor speed, memory packing density and low power consumption for micro-electronic components are directly related to the ability of lithography techniques to transfer and form patterns onto the various layers of a semiconductor device. The current state of the art requires patterning of CD's well below the available light source wavelengths. For instance the current production wavelength of 248 nm is being pushed towards patterning of CD's smaller than 100 nm. This industry trend will continue and possibly accelerate in the next 5-10 years, as described in the International Technology Roadmap for Semiconductors (ITRS 2000).
This continued demand for improved performance has resulted in the development of various techniques aimed at improving resolution. Such techniques are typically referred to as Resolution Enhancement Techniques (RET's) and comprise a very wide range of applications. Examples include: light source modifications (e.g. Off-Axis Illumination), use of special masks, which exploit light interference phenomena (e.g. Attenuated Phase Shift Masks, Alternating Phase Shift Masks, Chromeless Masks, etc.), and mask layout modifications (e.g. Optical Proximity Corrections).
Of the foregoing techniques, dipole illumination is one of the most attractive RET candidates due to its high image contrast for dense pitches and superior resolution capabilities. As is known, dipole illumination is an extreme case of OAI and is capable of providing enhanced imaging contrast with improved process latitude for very low K1 imaging.
However, one of the limitations associated with dipole illumination is that a single illumination only enhances resolution for features that are orthogonal to the illumination pole axis. As a result, in order to take full advantage of dipole illumination during wafer printing, the mask pattern must be decomposed into horizontal and vertical orientations. Once the mask pattern is converted in this manner, a Y-pole exposure is utilized to image the horizontally oriented features, and a X-pole exposure is utilized to image the vertically oriented features. One important aspect of dipole illumination is that when imaging the horizontally oriented features, the vertically oriented features must be protected (i.e., shielded) so the vertically oriented features are not degraded. The opposite is true when vertically oriented features are imaged (i.e., the horizontally oriented features must be protected).
FIG. 1 illustrates the basic concepts of double dipole imaging. As stated, typically there are at least two exposures when utilizing dipole illumination. In the first exposure, the X dipole aperture 10 provides a maximum aerial image intensity (i.e., maximum modulation) for the vertical portion of the lines 12 to be printed. The resulting image profile is illustrated by line 24 in FIG. 1. In the second exposure, which utilizes the Y-dipole aperture 16, there is no image modulation for lines 12. It is noted, however, that during the second exposure using the Y-dipole aperture, the vertical portions of the lines 12 need to be shielded so that the vertical features formed during the first exposure are not degraded during the second exposure. FIG. 1 illustrates shielding the lines 12 with shields 15, each of which is 20 nm wide in the horizontal direction. As a result, when exposing the horizontal lines using the Y dipole aperture, there is substantially no imaging (i.e., modulation) of the vertical features 12. The aerial image is a DC modulation as shown by line 17 in FIG. 1, which corresponds to the 20 nm shielding. The final aerial image intensity, which is represented by line 14 in FIG. 1, corresponds to the sum of the first exposure using the X dipole aperture and the second exposure using the Y dipole aperture.
It is further noted that, assuming the exposure energy is constant, increasing the width of the shielding from a 20 nm shield 15 to a 40 nm shield 20 for the vertical lines 12 causes the minimal intensity level of the resulting image to shift to a lower level. This is represented by line 22 in FIG. 1, which represents the aerial image associated with the vertical portions of the features. As shown, the aerial image 22 is just a DC modulation. However, it is lower than the DC modulation 17 associated with the 20 nm shield. As a result, the composite image 19 formed utilizing the 40 nm shielding provides better imaging results than the composite image 14 formed utilizing the 20 nm shielding.
As a result of the need to separate the horizontally and vertically oriented features, one of the challenges for the lithographer, when utilizing dipole illumination, is determining how to convert the original IC design data into its horizontal or vertical pattern components and generate two masks for the dual exposure process that can take full advantage of the dipole imaging performance. One factor that reduces performance and which should be considered when generating the mask patterns is background light due to lens flare or scattering. As is known, lens flare results in unwanted background light (i.e., noise) that degrades the image contrast at the image plane. Thus, it is desirable to reduce “flare” as much as possible. This is especially true when utilizing dipole illumination techniques due to the multiple exposures associated therewith.
The “aerial image with flare” is equal to the “aerial image without flare” convolved with a point-spread function (PSF) plus the scattering. The foregoing can be expressed as:Iflare(x,y)=InoflarePSFflare+Inoflare(I−TIS)  (1)
where TIS is the total integrated scattering (TIS) for lens having a surface roughness with a Gaussian-like distribution. Under such conditions, TIS can be expressed as:TIS=[(4πσ cos θ)/λ]2  (2)
where λ is the wavelength of the exposure tool, σ is the rms roughness of the lens, and θ is the scattering angle. As a result of current lens making capabilities, which result in lens exhibiting extremely low surface roughness, the foregoing equation can be approximated as:TIS˜1/λ2  (3)
Equation (3) makes clear that as the wavelength of the exposure tool is reduced, the amount of scattered light increases significantly. For example, the total integrated scattering (TIS) of light for an exposure tool having a wavelength of 193 nm is approximately 1.65 times greater that the TIS associated with an exposure tool having a wavelength of 248 nm.
It is noted that the first term is equation (1) is the “diffuse halo” which causes the focused image to spread out. The second term in equation (1) is the contribution due to scattering. The overall effect is an unwanted DC background light that reduces the aerial image contrast. Furthermore, besides the negative impact on image contrast, flare is also unevenly distributed across the scanning slit and is not uniform with the exposure field, which can cause intrafield CD variations. Therefore, protecting features and reducing background stray light becomes increasingly critical. The issue of how to reduce or negate the effects of background stray light becomes even more important as the wavelengths of the exposure tools are reduced.
Currently, one known technique for reducing the negative effects of flare comprises the step of adding solid chrome shielding on the large areas of the mask pattern (i.e., background portions) that do not contain any geometry (i.e., features). As shown in FIGS. 2a and 2b, when utilizing dipole illumination, the solid chrome shielding, referred to as background light shielding (BLS), is applied to the background areas in both the horizontal mask and the vertical mask. The solid chrome shield functions to protect the background area during both exposures. FIG. 2a illustrates an example of the use of this shielding technique in conjunction with the printing of horizontally oriented features 29 utilizing the Y dipole 16. As shown in FIG. 2a, each of the vertical features 27 are provided with shielding 210 (i.e., main feature shielding) in the manner discussed above in conjunction with FIG. 1. In addition, the solid chrome shield 220 is provided in the background area where there are no features to be imaged on the wafer. In a similar manner, FIG. 2b illustrates the vertical mask, in which the horizontal oriented features are shielded, while the vertical features are printed. As shown, the vertical mask also includes a solid chrome shield 220 disposed in the background area. It is further noted that both the horizontal mask and the vertical mask contain assist features 103 (e.g., scatter bars).
However, as a result of such background shielding 220, when utilizing a positive resist, the intensity in the background areas becomes too low to completely clear the resist. FIGS. 3a and 3b illustrate a simulated resist pattern corresponding to the portion of the masks of FIGS. 2a and 2b defined by area 30, which includes the solid chrome shielding 220. The simulation was performed assuming NA (numerical aperture)=0.75, ArF double exposure x-pole, y-pole, σouter/σinner=0.89/0.65. As is shown by FIGS. 3a and 3b, portions of the resist 221 in the background areas remain after illumination using the vertical and horizontal masks. As a result, a third exposure utilizing a trim mask is necessary in order to completely remove the resist from the background shielded areas. Thus, such a solution for reducing the effects of flare is undesirable as it results in an increase in the number of exposures and masks required for imaging the wafer. Referring to FIG. 3a, the areas indicated by reference numeral 51 correspond to the areas where resist remains after the double exposures, and these areas are contrasted against areas of either the vertical or horizontal mask that had chrome disposed thereon (i.e., either feature or shielding).
Furthermore, the foregoing solid chrome shielding technique can also negatively interfere with assist features, such as scatter bars, and cause the assist features to print underneath the shielding of either the horizontal or vertical mask, as also illustrated in FIGS. 3a and 3b. For example, referring to FIG. 3b, as shown in the resist simulation, the assist features 103, which are intended to be sub-resolution, are printed as a result of the BLS 220. This problem imposes an additional constraint on the placement of assist features, which can prevent the assist features from being placed in the optimal position, thereby causing a reduction in printing performance.
Accordingly, there exists a need for a method for negating the effects of flare in the exposure process which does not result in an increase in the number of exposures and masks required for imaging the wafer, and which does not impact the use and/or placement of assist features in the mask.


The embodiments described herein relate to a coil receiving MR signals from a subject, and an MRI (magnetic resonance imaging) system including the coil.
A reception coil for receiving MR signals from a subject is employed in MRI apparatus.
The reception coil known from, for example Japanese Patent Application No. Hei 08-252234, has a problem in which application of low frequency noise to the reception coil results in artifacts such as ghosts appearing in an MR image.


The invention relates to a height adjustment device of a vehicle seat, which comprises a control valve means serving for controlling the degree of filling of at least one compressed air actuator holding the seat body at a desired height and thereby providing a vertical elastic supporting action, such control valve means being so provided with at least one actuating member for cooperation with at least one control cam slide that in accordance with use dependent alteration of the weight to be borne by the at least one compressed air actuator a relative switching over movement causing the switching over of the control valve means takes place between a component bearing the control cam slide and another component bearing the associated actuating member.
The invention furthermore relates to a vehicle seat fitted with such a height adjustment device, comprising a seat body, which is arranged on a seat bracket fitted with a height adjustment device, such seat bracket having at least one compressed air actuator, with the aid of which the seat body may be set at different heights and is able to be vertically resiliently supported at the respectively set height, the seat bracket having at least two support elements changing the distance between them during vertical movement of the seat body, one support element of the seat bracket being kinematically coupled with at least one control cam slide, which so cooperates with at least one actuating member kinematically coupled with the other support element and associated with a control valve means serving for control of the degree of filling of the at least one compressed air actuator that in the case of an alteration in the use dependent weight carried by the at least one compressed air actuator a relative switch over between the at least one control cam slide and the components bearing the actuating member associated with the control cam slide and the actuating member associated with it.
Such a height adjustment device with an associated vehicle seat is disclosed in the German patent publication DP 4335199. The seat bracket of the vehicle seat in this case comprises two support elements, coupled together to form a scissor-like structure, which alter their angular position when the height of the seat body changes, for example owing to a varying weight load. The change in angle is detected by two control valves, whose actuating members control cam slide down two curved control cam slides while performing an arcuate switching over movement and, if they are deflected sufficiently, cause compressed air to be supplied to the compressed air actuator or let off therefrom. Accordingly it is possible to ensure that the seat height is automatically set to the right height independently of weight.
Owing to their quite complex structure the known height adjustment devices appear to be in need of improvement. This also applies for alternative designs of height adjustment devices and the vehicle seats fitted with them, which are described in the German patent publications DE 19705010 A1, DE 3517503 C2 and DE 3517505 C2.


This invention relates to a synchronization signal processing system for use in a mobile communication network which comprises a plurality of mobile service switching centers and a plurality of base transceiver stations and is operable in a time division fashion.
The mobile communication network has an overall service area which is divided into cells or radio zones assigned with the base transceiver stations, respectively, and in which a plurality of mobile stations are present, namely, either moving or staying standstill, at a time. Each mobile station may be either a portable telephone device carried by a user or a subscriber's terminal installed in an automobile or in a like mobile vehicle and is movable from a first zone of the cells to a second zone of the cells.
It is possible to understand that each mobile service switching center is connected to a plurality of fixed subscriber substations either directly or through at least one exchange office. Some of the mobile service switching centers are connected to the base transceiver stations. More particularly, each of such mobile service switching centers is connected to a certain number of base transceiver stations.
The mobile service switching centers are connected to one another by wired communication lines. The mobile service switching centers and the base transceiver stations may be connected through wired communication lines. Among the overall service area, some of the cells are often referred to collectively as a radio communication area when assigned to the base transceiver stations which are served by one of the mobile service switching centers.
Each base transceiver station is for transmitting and receiving radio message signals to and from at least one of the mobile stations that is currently present in the cell assigned with the base transceiver station under consideration. For use in time division multiple access (TDMA), the radio message signals are carried by a radio carrier signal of a radio frequency in a plurality of time slots. A predetermined number of such time slots are successively arranged in a frame in the manner known in the art.
When a particular station of the mobile stations moves between the first and the second zones assigned with first and second stations of the base transceiver stations, the first and the second stations use different radio frequencies and different time slots in transmitting and receiving the radio message signals to and from the particular station. The first and the second stations may be connected either to one or to two of the base transceiver stations. In either event, the particular station is inevitably subjected to a handover processing between the first and the second stations. It is therefore desirable to preliminarily synchronize the frames and the time slots in the base transceiver stations in order to reduce a time necessary for such a handover processing as a handover processing time.
In the manner which will later be described, a conventional synchronization signal processing system comprises an individual synchronization signal generating circuit in each mobile service switching center. When connected to such a mobile service switching center, the base transceiver station can generate synchronized frames and synchronized time slots for the mobile stations which are currently present in the radio communication area served by the base transceiver station under consideration.
A little more in detail, the synchronization signal generating circuit comprises first and second time division switches, each comprising controllable connection paths and producing a switch trouble signal when a trouble occurs therein. A controller device is cross connected to the first and the second time division switches and is supplied with the switch trouble signal to control the connection paths of one of the first and the second time division switches that is not producing the switch trouble signal and serves as an active switch with the other of the first and the second time division switches used as a standby switch. A synchronization signal generator is connected to the active switch to supply a synchronization signal to the connection paths of the active switch. Output trunk circuits are connected to the connection paths of the first and the second time division switches to supply the synchronization signal to at least one of the output trunk circuit from the connection paths controlled by the controller device to the base transceiver stations served by mobile service switching center in question.
It is liable that the synchronization signal generator is involved into a trouble. First and second synchronization signal generators are therefore cross connected to the first and the second time division switches. Alternatively, it is possible to understand that the first and the second synchronization signal generators are connected to the active switch. In either event, each synchronization signal generator produces a generator trouble signal when a trouble occurs therein. Supplied with the generator trouble signal, the controller device controls the connection paths of the active switch to supply the output trunk circuits with the synchronization signal generated by one of the first and the second synchronization signal generators that is not producing the generator trouble signal.
As a consequence, the conventional synchronization signal processing system can deal with troubles that may occur in the time division switches and/or in the synchronization signal generators. It is, however, impossible to keep the phase of the synchronization signal when the first and the second synchronization signal generators are switched from one to the other.


It is described in German Published Patent Application No. 35 36 820 and ISO 14819 that traffic messages in the form of digitally encoded messages plus radio programs may be broadcast over radio frequencies to describe traffic-relevant situations, in particular traffic disturbances in the highway system. These TMC (Traffic Message Channel) traffic messages include location information about the location of a traffic disturbance in an encoded form.
ISO 14819 also describes so-called multisequence messages in which traffic information is transmitted in several groups of the RDS signal, but the several groups which include traffic information must always be transmitted in direct succession.
German Published Patent Application No. 199 05 893 describes an expansion of traditional traffic messages according to the TMC standard. It is provided there that a supplementary location description, which is announced in a header preceding the actual message, is to be added to the standardized messages, which regularly contain a location code and thus a reference to a location of a traffic-relevant event. Thus, a location description is no longer limited merely to highway junctions, highway intersections and interchanges and the like and/or the sections in between that are encoded in the TMC location database but instead it allows a further description of the event location.
A more accurate localization of an event location is also the subject of German Published Patent Application No. 100 15 935. It is proposed there that in addition to a section of road affected by a traffic disturbance, which may be defined by an adjacent location encoded in the TMC location database, a portion of a section or comparable linear parameters may also be transmitted, permitting a more accurate localization of the event location on the encoded section of road.
The traffic situations to be transmitted via a traffic message may be simple or complex; for example, “10 km backed-up traffic” is a simple description of the situation and “10 km backed-up traffic, construction site, lane closure, average speed=20 km/h” is a complex description of the situation. Such complex situation descriptions may be described by so-called “multisequence messages,” i.e., multiple indexed successive individual messages in TMC (Traffic Message Channel, as specified in ISO 14819).
One disadvantage here is that all the individual events of a complex situation description must always be based on the same location, i.e., the same section of road, so that the message may be displayed on the terminal as a complex situation description. Furthermore, all the events of a situation must be sent at the same point in time. Although updating is possible, all messages, including all the events they contain, must always be updated. It is impossible to append additional events to a message already sent. Expanded complex example: “Between Laatzen junction and Hildesheim junction 10 km backed-up traffic, construction site, lane closure, average speed=20 km/h.” The individual events of “backed-up traffic,” “construction site,” “lane closure,” and “average speed=20 km/h” must be based on the same location, namely in this case the same section of road between junctions. If the events overlap or if they are based on different neighboring locations, multiple separate messages must be transmitted. It is very complex to combine the messages at the terminal end to allow a compact presentation.
It is also a disadvantage that it is impossible to correlate messages originating from different sources. In the future it may be expected that situation descriptions of differing content will be supplied by different sources. For example, traffic disturbances such as congestion or accidents are compiled by the police via the state reporting offices, while long-term status information such as construction sites or gridlock is supplied by third-party providers—possibly even as a paid service. Example: real situation: “10 km congestion and 5 km construction site.” It is assumed that the construction site will remain in existence for a longer period of time and the message will be transmitted regularly by provider X, e.g., a radio station. Congestion occurs spontaneously and is reported by a state reporting office for a relatively short period of time. With the digitally encoded TMC traffic messages currently being transmitted by radio, there is no possibility of connecting two individual messages to form one complex message.