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WO2012025638A1 - Inhibiteurs sélectifs de la 17-bêta-hydroxystéroïde déshydrogénase de type 1 - Google Patents

Inhibiteurs sélectifs de la 17-bêta-hydroxystéroïde déshydrogénase de type 1 Download PDF

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Publication number
WO2012025638A1
WO2012025638A1 PCT/EP2011/064842 EP2011064842W WO2012025638A1 WO 2012025638 A1 WO2012025638 A1 WO 2012025638A1 EP 2011064842 W EP2011064842 W EP 2011064842W WO 2012025638 A1 WO2012025638 A1 WO 2012025638A1
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Prior art keywords
hydroxy
methanone
hydroxyphenyl
benzothiazol
thienyl
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Inventor
Rolf Hartmann
Martin Frotscher
Sandrine Marchais-Oberwinkler
Alexander Oster
Alessandro Spadaro
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Universitaet des Saarlandes
ElexoPharm GmbH
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Universitaet des Saarlandes
ElexoPharm GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to selective, non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 (17p-HSDl) inhibitors their production and use, especially for the treatment and/or prophylaxis of hormone-related diseases.
  • 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)).
  • 17p-hydroxysteroid dehydrogenase type 1 which catalyzes the conversion of estrone (El) to estradiol (E2)
  • 17p-HSD type 2 which catalyzes the reverse reaction
  • estrogens 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.
  • 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.
  • 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.
  • E2 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) a. 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)).
  • ER estrogen receptor
  • E2 is mainly produced in the peripheral tissue, e.g., breast tissue, endometrium, adipose tissue and skin, from inactive precursors, such as estrone sulfate -El-S), dehydroepiandrosterone (DHEA) and DHEA-S.
  • inactive precursors such as estrone sulfate -El-S
  • DHEA dehydroepiandrosterone
  • DHEA-S DHEA-S
  • steroidogenic enzymes hydroxysteroid dehydrogenases, aromatase
  • 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 afflicting 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. Resorbsmed. 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.
  • peritoneal endometriosis retroperitoneal deep-infiltrating endometriosis including adenomyosis uteri, and cystic ovarial endometriosis.
  • 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)).
  • 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.
  • 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 metallo- proteinases), 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 17p-HSDl and reduced inactivation of potent E2 due to a lack of 17p-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, 0. 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.
  • NSAID non-steroidal anti-inflammatory drugs
  • 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 dysmenorrhea 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.
  • ER+ Coulson, C, Steroid biosynthesis and action, 2nd edition, 95-122 (1994); Lower, E. et al., Breast Cancer Res. Treat., 58 : 205-211 (1999)
  • 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).
  • a precondition of such responsiveness is the endocrine sensitivity of the tumors, which exists with HDBC ER+ tumors.
  • the drugs employed in endocrine therapy include GnRH analogues, anti-estrogens and aromatase inhibitors.
  • GnRH analogues such as gosereline
  • gosereline will bind to specific membrane receptors in the target organ, the pituitary gland, which results in an increased secretion of FSH and LH.
  • 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.
  • SERM selective estrogen receptor modulators
  • 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 aromatic- zation 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 aminogluthetimide. However, aminogluthetimide affects several enzymes of the cytochrome P-450 superfamily and thus inhibits a number of other biochemical conversions.
  • the compound interferes with the steroid production of the adrenal glands so heavily that a substitution of both glucocorticoids and mineral corticoids may be necessary.
  • 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)).
  • this type of compounds is an irreversible inhibitor that also has a substantial number of side effects, such as hot flushes, nausea, fatigue.
  • the estrogen biosynthesis in the peripheral tissue also includes other pathways for the production of El 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 (Perel, E.
  • 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 El sulfate and DHEA-S to estrone and DHEA. In this way, 10 times as much El 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)).
  • E2 the most potent estrogen.
  • Steroid sulfatase and 17p-HSDl 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)).
  • 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 well as numerous sulfamate derivatives of tetrahydronaphthalene, indanone and tetralone (Hanson, S.R.
  • Hydroxysteroid dehydrogenases can be subdivided into different classes.
  • the l ip-HSD modulate the activity of glucocorticoids
  • 3p-HSD catalyzes the reaction of A5-3p-hydroxysteroids (DHEA or 5-androstene-3p,17p-diol) to form ⁇ 5-3 ⁇ - ketosteroids (androstenedione or testosterone).
  • 17p-HSDs convert the less active 17-ketosteroids to the corresponding highly active 17-hydroxy compounds (androstenedione to testosterone and El to E2) or conversely (Payne, A.H . et al., Endocr. Rev., 25 : 947-970 (2004); Peltoketo, H.
  • El is converted to the highly potent E2 by means of 17p-HSDl, while E2 is converted to the less potent El by means of 17p-HSD2; 17p-HSD2 inactivates E2 while 17p-HSDl activates El .
  • the 17p-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 17p-HSDs are expressed in the different estrogen-dependent tissues, but in different concentrations.
  • 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.
  • the 17p-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 well as androgen-related diseases, such as prostate carcinoma, benign prostate hyperplasia, acne, hirsutism etc.
  • 17p-HSDs are also involved in the development of further diseases, e.g., pseudohermaphrodism (17p-HSD3 (Geissler, W.M . et al ., Nat. Genet., 7 : 34-39 (1994))), bifunctional enzyme deficiency (17p-HSD4 (van Grunsven, E.G. et al ., Proc. Natl . Acad. Sci . USA, 95 : 2128-2133 (1998))), polycystic kidney diseases (17p-HSD8 (Maxwell, M . M. et al ., J. Biol.
  • the best characterized member of the 17p-HSDs is the type 1 17p-HSD.
  • the 17p- 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); Jornvall, H . et al ., Biochemistry, 34 6003-6013 (1995)). Its designation as assigned by the enzyme commission is E.C. I .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 ON E 5(8) : el2026. doi : 10.1371/journal. pone.0012026 (2010)). Available are X-ray stuctures 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.
  • 17p-HSDl is a soluble cytosolic enzyme. NADPH serves as a cofactor. 17p-HSDl 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)).
  • 17p-HSDl 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 17p-HSDl is the conversion of the less active El to the highly potent E2.
  • DHEA dehydroepiandrosterone
  • 5-androstene-3p,17p-diol an andro- gen showing estrogenic activity
  • DHEA dehydroepiandrosterone
  • 5-androstene-3p,17p-diol an andro- gen showing estrogenic activity
  • the enzyme catalyzes the reduction and oxidation between El and E2 while it catalyzes only the reduction under physiological conditions.
  • 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) : el2026. 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 hydrophobic 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, Serl42 and Tyrl55.
  • the gene encoding 17 ⁇ - ⁇ 5 ⁇ 1 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 17ql l-q21 (Labrie, F. et al ., J. Mol . Endocrinol ., 25 : 1-16
  • 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 El moiety which interacts with the substrate binding site; and a spacer of varying length as a linking element between the two moieties.
  • inhibitors have been synthesized that exhibit a good inhibition of the enzyme and a good selectivity for 17p-HSD2 (compound B (Lawrence, H. R. et al., J. Med. Chem ., 48 : 2759-2762 (2005)).
  • compound B Lawrence, H. R. et al., J. Med. Chem ., 48 : 2759-2762 (2005).
  • 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.
  • 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.
  • 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).
  • 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)).
  • Biphenyl ethanones (Allan, G.M. et al. Bioorg. Med. Chem. 16 4438-4456 (2008)); 3. Hydroxyphenylnaphtols (WO/08EP/53672; Marchais-Oberwinkler S. et al., J. Med. Chem., 51, 4685-4698 (2008)) Marchais-Oberwinkler, S. et al. J. Med. Chem., submitted (2010)); 4. Heterocyclic substituted biphenylols (Oster, A. et al., Bioorg. Med. Chem., 18(10), 3494-3505 (2010)); 5. Bis(hydroxyphenyl) arenes (WO2009/02746; Bey, E. et al., J. Med. Chem., 52, 6724-6743 (2009)).
  • 2-benzoylbenzothiazole derivatives having lipid lowering activity are known from EP-A-735029,and /V-(benzothiazol-2-yl)arylcarboxamide and l-(benzothiazol- 2-yl)-3-(aryl)urea derivatives and their use for the inhibition of ubiquitination are known from WO2005/037845.
  • a 17beta-hydroxysteroid dehydrogenase type 1 (hereinafter shortly)
  • Rl represents H, OH, alkoxy or acyloxy
  • R2, R3, R5 and R6 independently represent -H, -R, haloalkyl, halogen, -N0 2 , -OR', -SR', -COR', -NR'R', -CN, -COOR', -N HS0 2 R, -S0 2 NR'R', -SON R'R', -NHSOR, -NHCOR', -CONR'R', -OC(0)R', -CH 2 NR'R',-CH 2 OR', -S0 2 R or -SOR (wherein R is an alkyl group, a homoaromatic group that may be condensed with a 5- or 6- membered, aliphatic or aromatic heterocyclic ring, a benzyl group, or an aliphatic or aromatic heterocyclic group that may be condensed with a benzene ring, each of said groups may be substituted with up to 5 substituents independently selected from
  • X represents:
  • Y if present, represents an 0 or S atom
  • R7 and R8 independently represent -H or lower alkyl
  • the aryl ring is a 5-membered heteroaromatic ring which carries up to 3 heteroatoms independently selected from N, S and 0 and may be condensed with a benzene ring, said benzene ring may then carry said substituents R4 and/or R5;
  • R4 represents -H, -OH, an alkyl or an alkoxy group (each of which may carry phenyl and halogen substituents, wherein said phenyl substituent may carry up to 3 substituents independently selected from -OH, alkyl, haloalkyl, alkoxy, halogen, amino, -CN and -N0 2 ), a 6-membered aromatic group (which may carry 1 to 3 substituents independently selected from -R, haloalkyl, halogen, -N0 2 , -OR', -SR', - COR', -NR'R', -CN, -COOR', -NHS0
  • the third substituent may be located on the 6-membered aromatic group or on the ring condensed thereto), or a 5- or 6-membered aliphatic or aromatic heterocyclic group (which carries up to 3 heteroatoms independently selected from N, S and 0 and may carry 1 to 3 substituents independently selected from -R, haloalkyl, halogen, -N0 2 , -OR', -SR', - COR', -NR'HR', -CN, -COOR', -NHS0 2 R, -S0 2 NR'R', -SONR'R', -NHSOR, -NHCOR', -CONR'R', -OC(0)R', -CH 2 NR'R', -CH 2 OR', -S0 2 R and -SOR (wherein R and R' is as defined above) or two of said substituents, together with the adjacent carbon atoms of the
  • the above defined 17p-HSDl inhibitor includes inhibitors of the formula (I) wherein R3 is -H and X represents
  • the inhibitor has the formula (la)
  • Rl, R2, R4, R5, R6 and X have the same meaning as in (1) above, or R4 and R5, together with the adjacent carbon atoms of the 6-membered aromatic group, may form a 5- or 6-membered, aliphatic or aromatic, homocyclic or heterocyclic ring condensed to said 6-membered aromatic group, wherein the heterocyclic ring carries up to 3 heteroatoms independently selected from N, S and 0, and wherein the substituent R6 may be located on the 6-membered aromatic group or on the ring condensed thereto, the aryl ring is a 5-membered heteroaromatic ring, which carries up to 3 heteroatoms independently selected from N, S and 0, and
  • W is C or N
  • the inhibitor has the formula (Ila)
  • the inhibitor has the formula (Ilia)
  • the inhibitor has the formula (IVa)
  • the inhibitor has the formula (lb) or (Ic),
  • Rl, R2, R3, R4, R5 and X have the same meaning as in (1) above, and the aryl ring is a 5-membered heteroaromatic ring, which carries up to 3 heteroatoms independently selected from N, S and 0, preferably the inhibitor has the formulas
  • Rl represents -H, OH, alkoxy or acyloxy
  • R2, R3, R5 and R6 independently represent-H, -R, haloalkyl, halogen, -N0 2 , -OR', -SR', -COR', -NR'R', -CN, -COOR', -NHS0 2 R, -S0 2 NR'R', -SON R'R', -NHSOR, -NHCOR', -CONR'R', -OC(0)R', -CH 2 NR'R',-CH 2 OR', -S0 2 R or -SOR (wherein R is an alkyl group, a homoaromatic group that may be condensed with a 5- or 6- membered, aliphatic or aromatic heterocyclic ring, a benzyl group, or an aliphatic or aromatic heterocyclic group that may be condensed with a benzene ring, each of said groups may be substituted with up to 5 substituents independently selected from halogen
  • Y if present, represents a 0 or S atom
  • R7 and R8 independently represent -H or lower alkyl
  • the aryl ring is a 5-membered heteroaromatic ring which carries up to 3 heteroatoms independently selected from N, S and 0;
  • R4 represents -H, -OH, an alkyl or an alkoxy group (each of which may carry phenyl and halogen substituents, wherein said phenyl substituents may carry up to 3 substituents independently selected from -OH, alkyl, haloalkyl, alkoxy, halogen, amino, -CN and -N0 2 ), a 6-membered aromatic group (which may carry 1 to 3 substituents independently selected from -R, haloalkyl, halogen, -N0 2 , -OR', -SR', - COR', -NR'R', -CN, -COOR', -NHS0 2 R, -S0 2 NR'R', -SONR'R', -NHSOR, -NHCOR', -CONR'R', -OC(0)R', -CH 2 NR'R', -CH 2 OR', -S0 2 R and -
  • the third substituent may be located on the 6-membered aromatic group or on the ring condensed thereto), or a 5- or 6-membered aliphatic or aromatic heterocyclic group (which carries up to 3 heteroatoms independently selected from N, S and 0 and may carry 1 to 3 substituents independently selected from -R, haloalkyl, halogen, -N0 2 , -OR', -SR', - COR', -N R'HR', -CN, -COOR', -NHS0 2 R, -S0 2 NR'R', -SONR'R', -NHSOR, -NHCOR', -CONR'R', -OC(0)R', -CH 2 NR'R', -CH 2 OR', -S0 2 R and -SOR (wherein R and R' is as defined above) or two of said substituents, together with the adjacent carbon atoms of
  • the above defined compound with 17p-HSDl inhibitor activity includes inhibitors of the formula (I) wherein R3 is -H and X represents
  • a pharmaceutical composition or medicament comprising at least one compound of aspect (5) above, or a pharmaceutically acceptable salt thereof or a prodrug thereof, and optionally a suitable carrier or excipient.
  • a method for the treatment and/or prophylaxis of hormone-related diseases in a patient which comprises administering the patient a suitable amount of the inhibitor of aspects (1) to (4) above or a compound of aspect (5) above, or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  • AlkyI and "alkoxy" residues within the meaning of the invention may be straight- chain, branched-chain or cyclic, and saturated or (partially) unsaturated. Preferable alkyl residues and alkoxy residues are saturated or have one or more double and/or triple bonds. Of straight-chain or branched-chain alkyl residues, preferred are those having from 1 to 10 carbon atoms, more preferably those having from 1 to 6 carbon atoms, even more preferably those having from 1 to 3 carbon atoms. Of the cyclic alkyl residues, more preferred are mono- or bicyclic alkyl residues having from 3 to 15 carbon atoms, especially monocyclic alkyl residues having from 3 to 8 carbon atoms.
  • “Lower alkyl” and “lower alkoxy” residues within the meaning of the invention are straight-chain, branched-chain or cyclic saturated lower alkyl residues and lower alkoxy residues or those having a double or triple bond. Of the straight-chain ones, those having from 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, are particularly preferred.
  • Aryls and “homocyclic aromatic groups” within the meaning of the present invention include, if not specified otherwise, mono-, bi- and tricyclic aryl residues having from 3 to 18 ring atoms, which may optionally be anellated with one or more saturated rings. Particularly preferred are anthracenyl, dihydronaphthyl, fluorenyl, hydrindanyl, indanyl, indenyl, naphthyl, naphthenyl, phenanthrenyl, phenyl and tetralinyl .
  • heteroaryl residues and “heterocyclic groups” are mono- or bicyclic heteroaryl residues having from 3 to 12 ring atoms and preferably having from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be anellated with one or more saturated rings.
  • the preferred monocyclic and bicyclic heteroaryls include benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, quinolyl, quinoxalinyl, cinnolinyl, dihydroindolyl, dihydroisoindolyl, dihydropyranyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isoindolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, phthalazinyl, piperazinyl, piperidyl, pteridinyl, purin
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Halo-, halogenated or “optionally halogenated” residues within the meaning of the present invention include any residues in which one to all H atoms have been replaced by the above mentioned halogen atoms or combinations of such halogen atoms.
  • Prodrugs within the meaning of thepresent invention refers to compounds of the invention in which certain functional groups are protected to increase its bioavailability or stability, to avoid degradation or to increase its transport to the site of action and the like. It specifically refers to compounds of the invention bearing phenolic hydroxyl group(s) (i.e., compounds of the invention wherein one or more of R1-R6 or one or more of its substituents is a phenolic hydroxyl or bears an aromatic substituent that is a phenol), in which the phenolic hydroxy group(s) are coupled with carboxylic acid derivatives, carbamic acid derivatives or carbonic acid derivatives to form more metabolic stable esters, carbamates and carbonates, respectively. Examples of the carbonic acid derivatives suitable to protect the phenolic hydroxyl group functions from metabolism include the following :
  • “Pharmaceutically acceptable salts” and “salts” within the meaning of the present invention include salts of the compounds with organic acids (such as lactic acid, acetic acid, amino acids, oxalic acid etc.), inorganic acids (such as HCI, HBr, phosphoric acid etc.), and, if the compounds have acid substituents, also with organic or inorganic bases including amino acids. Preferred are salts with HCI.
  • “Pharmacologically suitable carriers” within the meaning of the present invention are selected by the skilled person, depending on the desired dosage form .
  • the aryl ring if present, is a thiadiazole, triazole, oxadiazole, oxathiadiazole, isothiadiazole, isooxadiazole, thiazole, oxazole, imidazole, pyrazole, isoxazole, isothiazole, furane, pyrrole or thiophene;
  • Rl is -H, -OH or lower alkoxy
  • R2 and R5 independently represent -H, -R, haloalkyl, halogen, -N0 2 , -OR', -N R'R', - CN, -NHS0 2 R, -S0 2 NR'R', -NHCOR' or -CONR'R', (wherein R is alkyl, aryl, benzyl, an aliphatic or aromatic heterocyclic group, each of which may be substituted with up to 3 substituents independently selected from halogen, lower alkyl, lower haloalkyl, -OH, -N0 2 , lower alkoxy, -NH 2 , phenyl, -CN, -N HCOR", -CON HR", -NHS0 2 R” and S0 2 NHR” (wherein R" is -H, lower alkyl, lower haloalkyl or phenyl); and R' is R or -H);
  • R3, if present, is -H
  • R6, if present, is selected from -H, -OH, lower alkyl, lower alkoxy, and halogen;
  • R4 represents -H, -OH, an alkyl or an alkoxy group (each of which may carry phenyl and halogen substituents, wherein said phenyl substituent may carry up to 3 substituents independently selected from -OH, alkyl, haloalkyl, alkoxy, halogen, amino, -CN and -N0 2 ), a 6-membered aromatic group (which may carry 1 to 3 substituents independently selected from -R, haloalkyl, halogen, -N0 2 , -OR', -NR'R', -CN, -NHS0 2 R, -S0 2 NR'R',-NHCOR', -CONR'R' (wherein R and R' is as defined above) or two of said substituents, together with the adjacent carbon atoms of the 6-membere
  • Rl is -OH
  • R2 is selected from -H, -OH, alkoxy, alkyl, haloalkyl, halogen and -N0 2 ;
  • R4 represents -H, -OH, an alkyl or an alkoxy group (each of which may carry phenyl and halogen substituents, wherein said phenyl substituent may carry up to 3 substituents independently selected from -OH, alkyl, haloalkyl, alkoxy, halogen, amino, -CN and -N0 2 ), a 6-membered aromatic group (which may carry 1 to 2 substituents independently selected from -R, haloalkyl, halogen, -OR', -N HS0 2 R and -NHCOR', (wherein R and R' is as defined above) or two of said substituents, together with the adjacent carbon atoms of the 6-membered aromatic group, may form a 5- membered, aliphatic or aromatic, homocyclic or heterocyclic ring condensed to said 6-membered aromatic group, wherein the heterocyclic ring carries up to 3 heteroatoms independently selected from N, S and 0);
  • R5 is selected from -H, -OH and alkoxy
  • R6, if present, is selected from -H, -OH and halogen.
  • Rl is a hydroxy group in meta position relative to the -X- or -CO- junction.
  • Particular preferred embodiments of the inhibitor for use in the treatment and/or prophylaxis of hormone-related diseases of aspects (1) to (3) above are the following compounds (1) to (53) :
  • aryl with the benzene moiety condensed thereto is a benzimidazole, benzo- thiazole, benzoxazole, benzisoxazole, benzothiophene, indole, isoindole, indazole, benzofurane, benzotriazole or benzisothiazole;
  • Rl is -H, -OH or lower alkoxy
  • R4 represents -H, -OH, an alkyl or an alkoxy group (each of which may carry phenyl and halogen substituents, wherein said phenyl substituent may carry up to 3 substituents independently selected from -OH, alkyl, haloalkyl, alkoxy, halogen, amino, -CN and -N0 2 ), a 6-membered aromatic group (which may carry 1 to 3 substituents independently selected from -R, haloalkyl, halogen, -N0 2 , -OR', -NR'R', -CN, -NHS0 2 R, -S0 2 NR'R',-NHCOR', -CONR'R' (wherein R and R' is as defined above) or two of said substituents, together with the adjacent carbon atoms of the 6-membered aromatic group, may form a 5- or 6-membered, aliphatic or aromatic, homocyclic or heterocyclic ring
  • 5- or 6-membered aliphatic or aromatic heterocyclic group (which carries up to 3 heteroatoms independently selected from N, S and 0 and may carry 1 to 3 substituents independently selected from -R, haloalkyl, halogen, -N0 2 , -OR', -NR'R', -CN,-NHS0 2 R, -S0 2 NR'R', -NHCOR', -CON R'R', (wherein R and R' is as defined above) or two of said substituents, together with the adjacent carbon atoms of the 5- or 6-membered aliphatic or aromatic heterocyclic group, may form a 5- or 6- membered, aliphatic or aromatic ring condensed to said 5- or 6-membered aliphatic or aromatic heterocyclic group, wherein the third substituent may be present on the 5- or 6-membered aliphatic or aromatic heterocyclic group or on the ring condensed thereto); and/or
  • R5, if present, represents -H, -OH, halogen, alkyl, haloalkyl, benzyloxy or alkoxy.
  • Rl is -OH
  • R2 is selected from -H, -OH, alkoxy, alkyl, haloalkyl and halogen
  • R4 and R5, if present, are independently selected from -H, -OH, halogen, alkoxy, benzyloxy and haloalkyl.
  • Rl is a hydroxy group in meta position relative to the -X-, -CO- or -CONH- junction and/or R4 is a -OH or lower alkoxy.
  • Particular preferred embodiments of the inhibitor for use in the treatment and/or prophylaxis of hormone-related diseases of aspect (4) above are the following compounds (101) to (128) : l,3-Benzothiazol-2-yl(3-hydroxyphenyl)methanone (101), (6-methoxy-l,3-benzothiazol-2-yl)(3-methoxyphenyl)methanone (102), (6- hydroxy-l,3-benzothiazol-2-yl)(3-hydroxyphenyl)methanone (103), (6-hydroxy- l,3-benzothiazol-2-yl)(4-hydroxyphenyl)methanone (104), (6-hydroxy-l,3-benzo- thiazol-2-yl)(4-methoxyphenyl)methanone (105), l,3-benzothiazol-2-yl(4-fluoro-3- hydroxyphenyl)methanone (106), (4-fluoro-3-hydroxyphenyl)(
  • Preferred embodiments of the compound of aspect (5) above includes the preferred compounds of formula (I) is as defined for aspects (2) and (3) above.
  • the inhibitor for use in the treatment and/or prophylaxis of hormone-related diseases of aspects (1) to (4) above, the pharmaceutical composition or medicament of aspect (7) above, the medicament of aspect (8) above and the method for the treatment and/or prophylaxis of hormone-related diseases of aspect (9) above is particularly suitable for the propylaxis and/or treatment of estrogen-related diseases, notably diseases in which a modulation of the estradiol level is required, such as the treatment and/or prophylaxis of endometriosis, endometrial carcinoma, endometrial hyperplasia, adenomyosis, breast cancer, and ovarian carcinoma.
  • the variables W and Z represent "functional groups capable of being condensed to form X", wherein the meaning of W and Z strongly depend of the type of X to be formed.
  • W and Z can be donor molecules (including amines and derivatives thereof, metalorganic compounds such as Grignard reagents, etc) and acceptor molecules (such as carbonyl compounds, activated carbonyl compounds, alkyl halogenides, etc).
  • W and Z can be donor molecules (including amines and derivatives thereof, metalorganic compounds such as Grignard reagents, etc) and acceptor molecules (such as carbonyl compounds, activated carbonyl compounds, alkyl halogenides, etc).
  • Particular classes of compounds that can to be used as compounds of formula (V) are
  • the condensation reaction is performed according to the following reaction scheme 1 :
  • Z H, CHO or NH 2 ;
  • Method A AICI 3 , anhydrous CH 2 CI 2 , 0 °C, 0.5 h and then rt, 1 h
  • Method H anhydrous THF, 80 °C, 3 h
  • Method I 2-iodoxybenzoic acid, anhydrous THF, 0 °C, 10 min and 60 °C, 18 h
  • Method O 1) nBuLi, anhydrous THF, -70 to -20 °C, 1 h, 2) anhydrous THF, -15 °C, 90 min; 3) Method I: 2-iodoxybenzoic acid, anhydrous THF, 0 °C, 10 min and 60 °C, 18 h
  • Method P pyridine, rt to 100 ° C, 4h.
  • Method N 1) NaN0 2 , H 3 P0 4 (85%), -10 °C, 20 min, 2) H 3 P0 2 , H 3 P0 4 (85%), -10 °C to rt, overnight;
  • Method A AICI 3 , anhydrous CH 2 CI 2 , 0 °C, 0.5 h and then rt, 1 h;
  • Method H anhydrous THF, 80 °C, 3 h, 2) Method I: 2- iodoxybenzoic acid, anhydrous THF, 0 °C, 10 min and 60 °C, 18 h;
  • Method B Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/water (1 : 1), reflux, 2 h;
  • Method C Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/EtOH/water (1 : 1 : 1), microwave conditions (150
  • Method A AICI 3 , anhydrous CH 2 CI 2 , 0 °C, 0.5 h and then rt, 1 h, for compounds la-3a. 4b, 6a-10a: (b) Method Bl : Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/water (1 : 1), reflux, 2 h, for compounds 14a-16a.
  • Method C Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/EtOH/water (1 : 1 : 1), microwave conditions (150 W, 15 bar, 150 °C, 15 min), for compounds 4a, 5a, l la-13a, 18a :
  • Method D BBr 3 , CH 2 CI 2 , -78 °C, 20 h, for compounds 1-16.
  • Method H anhydrous THF, 80 °C, 3 h, for compounds 21c- 24c
  • Method I 2-iodoxybenzoic acid, anhydrous THF, 0 °C, 10 min and 60 °C, 18 h, for compounds 21 ⁇ 23 ⁇ 4 and 24a
  • Method Bl Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/water (1 : 1), reflux 2 h, for compounds 21a-23a
  • Method D BBr 3 , CH 2 CI 2 , -78 °C, 20 h, for compounds 21 and 23
  • Method E pyridinium hydrochloride, 220 °C, 18 h, for compounds 22 24-
  • Method B2 Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/water (1 : 1), reflux, 4 h, for compound 24b.
  • Method A AICI 3 , anhydrous CH 2 CI 2 , 0 °C, 0.5 h followed by rt, 1 h for compound 4b;
  • Method D BBr 3 , CH 2 CI 2 , -78 °C, 18 h for compounds 17a, 26 a nd 44-46:
  • Method C Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/EtOH/water (1 : 1 : 1), microwave conditions (150 W, 15 bar, 150 °C, 15 min) for compound 26a;
  • Method B2 Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/water (1 : 1) reflux, 4 h for compounds 44a -46a and 53;
  • Method Bl Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/water (1 : 1) reflux, 2 h
  • Method A AICI 3 , anhydrous CH 2 CI 2 , 0 °C, 0.5 h and then rt, lh.
  • Method Bl Cs 2 C0 3 , Pd(PPh 3 ) 4 , DME/water (1 : 1), reflux, 2h.
  • Method D BBr 3 , CH 2 CI 2 , -78°C to rt, overnight, d) Method Q: Pyridine, ArS0 2 CI, rt, overnight.
  • Method N 1) NaN0 2 , H 3 P0 4 (85%), -10 °C, 20 min, 2) H3PO2, H 3 P0 4 (85%), -10 °C to rt, overnight;
  • Method O 1) nBuLi, anhydrous THF, -70 °C to -20 °C, 1 h, 2) anhydrous THF, -15 °C, 90 min;
  • Method I 2-iodoxybenzoic acid, anhydrous THF, 0 °C to 60 °C, overnight;
  • Method F BF 3 S(CH 3 ) 2 , anhydrous CH 2 CI 2 , rt, overnight for compounds 101-104;
  • Method E pyridinium hydrochloride, 220 °C, 4 h for compound 105.
  • Method M benzylbromide, potassium carbonate, reflux, overnight
  • Method L tert-butyldimethylsilyl chloride, imidazole, DMF, 0 °C for lh followed by rt for 6h
  • Method O 1) nBuLi, anhydrous THF, -70 °C to -20 °C, 1 h, 2) anhydrous THF, -15 °C, 90 min
  • Method I 2-iodoxybenzoic acid, anhydrous THF, 0 °C to 60 °C, overnight
  • Method G TBAF, anhydrous THF, rt, 2h for compounds 108b.
  • Method D BBr 3 , CH 2 CI 2 , -78 °C, 18 h for compound 112;
  • benzene boronic acid copper (II) acetate, molecular sieves (4 A), anhydrous CH 2 CI 2 , triethylamine, rt, 18 h for compound 108a :
  • Method F BBr 3 , CH 2 CI 2 , -78 °C, 18 h for compound 108.
  • Method P pyridine, rt to 100 0 C, 4h;
  • Method F BF 3 S(CH 3 ) 2 , anhydrous CH 2 CI 2 , rt, 18h for compounds 113-115;
  • Method D BBr 3 , CH 2 CI 2 , -78 °C, 18 h for compound 116-128.
  • Signals are described as s, d, t, dd, ddd, m, dt, td and q for singlet, doublet, triplet, doublet of doublets, doublet of doublets of doublets, multiplet, doublet of triplets, triplet of doublets and quadruplet, respectively. All coupling constants (J) are given in hertz (Hz).
  • Tested compounds have > 95 % chemical purity as measured by HPLC.
  • Several final compounds were purified via an Agilent Technologies Series 1200-preparative HPLC using a linear gradient run (solvents: acetonitrile, water) starting from 20% acetonitrile up to 100% in 36 min.
  • Method A general procedure for Friedel-Crafts acylation : A mixture of mono- substituted thiophene derivative (1 eq), arylcarbonyl chloride (1 eq) and alumi- niumtrichloride (1 eq) in anhydrous dichloromethane was stirred at 0 °C for 0.5 h. The reaction mixture was warmed to room temperature (rt) and stirred for 1 h. 1M HCI was used to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness. The product was purified by CC.
  • Method B general procedures for Suzuki coupling : A mixture of arylbromide (1 eq), boronic acid derivative (1.2 eq), caesium carbonate (4 eq) and tetrakis(tri- phenylphosphine) palladium (0.01 eq) in an oxygen free DME/water (1 : 1) solution was refluxed under nitrogen atmosphere for 2h (method Bl) or for 4 h (method B2). The reaction mixture was cooled to room temperature. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness. The product was purified by CC followed by preparative TLC or preparative HPLC, respectively.
  • Method E general procedure for ether cleavage: A mixture of methoxybenzene derivative (1 eq) and pyridinium hydrochloride (37 eq per methoxy function) was heated to 220 °C for 18 h. After cooling to rt, water, 1 M HCI and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The product was purified by CC followed by preparative TLC or preparative HPLC, respectively.
  • Method F general procedure for ether cleavage : To a solution of methoxybenzene derivative (1 eq) in dry dichloromethane at rt, boron trifluoride methyl sulfide complex in dichloromethane (1 M, 75 eq per methoxy function) was added dropwise. The reaction mixture was stirred for 18 h at rt under nitrogen atmosphere. Water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness. The product was purified by CC, preparative TLC, preparative HPLC or recrystallisation, respectively.
  • Method G general procedure for ether cleavage : To a solution of tert butyl dimethyl silane ether derivative (1 eq) in THF at 0 °C tetra-n-butylammonium fluoride (TBAF) in THF (1 M, 1.3 eq per ether function) was added dropwise. The reaction mixture was stirred for 2 h at rt under nitrogen atmosphere. Water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness. The product was purified by CC, preparative TLC, preparative HPLC or recrystallisation, respectively.
  • TBAF tetra-n-butylammonium fluoride
  • Method I general procedure for oxidation : A mixture of aliphatic alcohol-derivative (1 eq) and 2-iodoxybenzoic acid (2 eq) in anhydrous THF was stirred at 0 °C. After 10 min, the reaction mixture was stirred and heated to 60 °C for 18 h. After cooling to rt, saturated sodium thiosulfate solution was added to quench the reaction and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successiveively with 1 M NaOH and brine, dried over magnesium sulfate, filtered and concentrated to dryness. The product was purified by CC.
  • Method N general procedure for diazotation : A solution of 6-methoxy-benzothiazol- 2-ylamine (1 eq) in 40 ml of aqueous H 3 P0 4 (85 %) was warmed up to 60 °C to form a homogeneous solution . The reaction mixture was then cooled to -8 °C and a concentrated aqueous solution of NaN0 2 (6 eq) was added slowly and carefully under vigorous stirring in order to not rise a temperature of -4 °C. The resultant thick yellow syrup was added to 15 ml of prechilled (0 °C) H 3 P0 2 (50 %) dropwise with stirring and then allowed to warm to rt overnight.
  • the solution was diluted with cold water, neutralized with sodium carbonate and extracted (3x) with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness. The product was purified by CC or recrystallisation.
  • Method P general procedure for nucleophilic substitution : To a solution of 6-meth- oxy-benzothiazol-2ylamine (1 eq) in anhydrous pyridine arylcarbonyl chloride, aryl- isocyanate or arylisothiocyanate (1 eq) was added. The reaction mixture was stirred for 4 h at 100 °C. A solution of water was added to quench the reaction at rt and the aqueous layer was extracted (3x) with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness. The product was purified by CC or recrystallisation.
  • the title compound was prepared by reaction of 2-(4-methoxyphenyl)thiophene (6b) (150 mg, 0.79 mmol), 3-methoxy-4-methylbenzoyl chloride (146 mg, 0.79 mmol) and aluminum chloride (105 mg, 0.79 mmol) according to method A.
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- methoxyphenyl)methanone (4b) (200 mg, 0.67 mmol), 3,4-dimethoxybenzene boronic acid (146 mg, 0.80 mmol), caesium carbonate (873 mg, 2.68 mmol) and tetrakis(triphenylphosphine) palladium (8 mg, 7 ⁇ ) according to method C.
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 4-hydroxy-3- methoxybenzene boronic acid pinacol ester (160 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • r4-f4-Methoxy-3-methylphenv0-2-thienyl1f3-methoxyphenv0methanone (21a).
  • the title compound was prepared by reaction of (4-bromo-2-thienyl)(3- methoxyphenyl)methanone (21b) (200 mg, 0.67 mmol), 4-methoxy-3- methylbenzeneboronic acid (133 mg, 0.80 mmol), caesium carbonate (873 mg, 2.68 mmol) and tetrakis(triphenylphosphine) palladium (8 mg, 7 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (IZa) (150 mg, 0.53 mmol), 3-methoxybenzene boronic acid (97 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 4-methoxybenzene boronic acid (97 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 6-methoxypyridine-3- boronic acid (98 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3,4-dimethoxybenzene boronic acid (117 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 2,3,4-trimethoxybenzene boronic acid (136 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 2-ethoxybenzene boronic acid (106 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3-ethoxybenzene boronic acid (106 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 4-ethoxybenzene boronic acid (106 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a ' ) (150 mg, 0.53 mmol), 3-(benzyloxy)benzene boronic acid (146 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3-[(2-methoxy- benzyl)oxy]benzene boronic acid (165 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (!Za) (150 mg, 0.53 mmol), 3-[(3-methoxy- benzyl)oxy]benzene boronic acid (165 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3-[(4- methoxybenzyl)oxy]benzene boronic acid (165 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (IZa) (150 mg, 0.53 mmol), 3-[(3,5- dimethoxybenzyl)oxy]benzene boronic acid (184 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3-[(2-chloro- benzyl)oxy]benzene boronic acid (168 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3-[(3-chloro- benzyl)oxy]benzene boronic acid (168 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3-[(4-chloro- benzyl)oxy]benzene boronic acid (168 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3-methoxy- phenyl)methanone (4b) (300 mg, 1.01 mmol), 3-[(methylsulfonyl)amino]boronic acid (178 mg, 1.21 mmol), caesium carbonate (1.32 g, 4.04 mmol) and tetrakis(triphenylphosphine) palladium (12 mg, 10 ⁇ ) according to method B2.
  • the title compound was prepared by reaction of /V- ⁇ 3-[5-(3-methoxybenzoyl)-2- thienyl]phenyl ⁇ methanesulfonamide (45a) (200 mg, 0.52 mmol) and boron tribromide (1.56 mmol) according to method D. The crude mixture was washed with MeOH.
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3-methoxyphen- yl)methanone (4b) (200 mg, 0.67 mmol), 3- ⁇ [(methylsulfonyl)amino]methyl ⁇ boro- nic acid (183 mg, 0.80 mmol), caesium carbonate (1.32 g, 4.04 mmol) and tetra- kis(triphenylphosphine) palladium (12 mg, 10 ⁇ ) according to method B2.
  • the title compound was prepared by reaction of /V- ⁇ 3-[5-(3-methoxyphenyl)-2- thienyl]benzyl ⁇ methanesulfonamide (46a) (253 mg, 0.63 mmol) and boron tribromide (1.89 mmol) according to method D. The crude mixture was washed with MeOH . The resulted suspension was filtered and the precipitated product was evaporated to dryness.
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3- ⁇ [(4- methylphenyl)sulfonyl]amino ⁇ benzene boronic acid (239 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl . The crude mixture was washed with MeOH . The resulted suspension was filtered and the precipitated product was evaporated to dryness.
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 2-naphthaleneboronic acid (110 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 2,3-dihydro-l-benzofuran- 5-boronic acid (105 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), l,3-benzodioxole-5- boronic acid (106 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl.
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), indol-5-boronic acid (103 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(tri- phenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl.
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), indol-6-boronic acid (103 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(tri- phenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 2H-indazole-5-boronic acid (104 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(tri- phenylphosphine) palladium (6 mg, 5 ⁇ ) according to method B2 refluxing the mixture for 14 h instead of 4 h.
  • the title compound was prepared by reaction of (5-bromo-2-thienyl)(3- hydroxyphenyl)methanone (17a) (150 mg, 0.53 mmol), 3-aminobenzeneboronic acid (86 mg, 0.64 mmol), caesium carbonate (691 mg, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (6 mg, 5 ⁇ ) according to method Bl .
  • the crude reaction product was subjected to ether cleavage according to method D.
  • the purified product was the subjected to a sulfonamide coupling according to method Q.
  • 102a (6-Methoxy-l,3-benzothiazol-2-yl)(3-methoxyphenyl)methanol (102a).
  • the title compound was prepared by reaction of 6-methoxy-l,3-benzothiazole (102b) (0.5 g, 3.03 mmol), nBuLi (1.6 ml, 3.94 mmol) and 3-methoxy-benzaldehyde (0.19 ml, 3.03 mmol) according to method O.
  • 106a l,3-Benzothiazol-2-yl(4-fluoro-3-methoxyphenyl)methanone
  • 106b The title compound was prepared by reaction of l,3-benzothiazol-2-yl(4-fluoro-3- methoxyphenyl)methanol (106b) (0.25 g, 0.86 mmol) and 2-iodoxybenzoic acid (0.48 g, 1.72 mmol) was according to method I.
  • l,3-Benzothiazol-2-yl(4-fluoro-3-hvdroxyphenv0methanone (106).
  • the title compound was prepared by reaction of l,3-benzothiazol-2-yl(4-fluoro-3- methoxyphenyl)methanone (106a) (0.25 g, 0.87 mmol) and pyridinium hydrochloride (3.72 g, 32.2 mmol) according to method E.
  • phenyllmethanone (108c) .
  • the title compound was prepared by reaction of (6- methoxy-l,3-benzothiazol-2-yl)[3-methoxy-4-(tert-butyl-di methyl-si lanyloxy)phen- yijmethanol (108d) (0.34 g, 0.78 mmol) and 2-iodoxybenzoic acid (0.44 g, 1.56 mmol) according to method I.
  • Triethylamine (0.22 ml, 1.58 mmol) was added dropwise and the reaction mixture was stirred for 18 h at room temperature under nitrogen atmosphere. After completion, water was added to quench the reaction and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness.
  • 6-Hvdroxy-benzothiazole ⁇ 109 ⁇ The compound was synthesised following the procedure of Hiroyuki O. et al., Chem . & Pharm . Bull. 26(5), 1443-1452 (1978).
  • 6-Benzyloxy-benzothiazole (109e).
  • the title compound was prepared by reaction of 6-hydroxy-benzothiazole (109 ⁇ (0.82 g, 5.42 mmol), benzyl bromide (0.71 ml, 5.97 mmol) and potassium carbonate (3.25 g, 38.0 mmol) according to method M .
  • the title compound was prepared by reaction of 4-methoxy-/V-(6-methoxy-l,3- benzothiazol-2-yl)benzamide (113a) (0.5 g, 1.59 mmol) and boron trifluoride methyl sulfide complex in dichloromethane (1 M, 25.1 ml, 239.00 mmol) according to method F.
  • the product was purified by preparative HPLC; yield : 13 % (0.06 g).
  • 2,6-difluoro-3-hvdroxy-A/-(6-hvdroxy-l,3-benzothiazol-2-yl)benzamide (124).
  • the title compound was prepared by reaction of 2,6-difluoro-3-methoxy-/V-(6-methoxy- l,3-benzothiazol-2-yl)benzamide (124a) (0.18 g, 0.51 mmol) and boron tribromide (3.1 mmol) according to method D.
  • Inhibition of 17p-HSDl Inhibitory activities were evaluated by an established method with minor modifications [Kruchten P. et al ., Mol. Cell . Endocrinol. 301, 154-157 (2009)] . Briefly, the enzyme preparation was incubated with NADH [500 ⁇ ] in the presence of potential inhibitors at 37 °C in a phosphate buffer (50 mM) supplemented with 20 % of glycerol and EDTA (1 mM). Inhibitor stock solutions were prepared in DMSO. The final concentration of DMSO was adjusted to 1 % in all samples.
  • the enzymatic reaction was started by addition of a mixture of unlabelled- and [2, 4, 6, 7- 3 H]-El (final concentration : 500 nM, 0.15 ⁇ ). After 10 min, the incubation was stopped with HgCI 2 and the mixture was extracted with diethylether. After evaporation, the steroids were dissolved in acetonitrile. El and E2 were separated using acetonitrile/water (45 : 55) as mobile phase in a C18 reverse phase chromatography column (Nucleodur C18 Gravity, 3 ⁇ , Macherey-Nagel, Duren) connected to a HPLC-system (Agilent 1100 Series, Agilent Technologies, Waldbronn). Detection and quantification of the steroids were performed using a radioflow detector (Berthold Technologies, Bad Wildbad). The conversion rate was calculated after analysis of the resulting chromatograms according to the following
  • T47D cells A stock culture of T47D cells was grown in RPMI 1640 medium supplemented with 10 % FCS, L-glutamine (2 mM), penicillin (100 IU/ml), streptomycin (100 g/ml), insulin-zinc-salt (10 pg/ml) and sodium pyruvate (1 mM) at 37 °C under 5 % C0 2 humidified atmosphere.
  • the cells were seeded into a 24-well plate at lxlO 6 cells/well in DMEM medium with FCS, L- glutamine and the antibiotics added in the same concentrations as mentioned above.
  • Table 2 Inhibition of 17p-HSDl in cellular assay.

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Abstract

L'invention concerne des inhibiteurs (17β-HSD1) sélectifs de la 17-bêta-hydroxystéroïde déshydrogénase de type 1, leur production et leur utilisation, en particulier pour traiter et/ou prévenir les maladies associées aux hormones.
PCT/EP2011/064842 2010-08-27 2011-08-29 Inhibiteurs sélectifs de la 17-bêta-hydroxystéroïde déshydrogénase de type 1 Ceased WO2012025638A1 (fr)

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WO2015101670A3 (fr) * 2014-01-03 2015-12-03 Elexopharm Gmbh Inhibiteurs des 17bêta-hydroxystéroïde déshydrogénases de type 1 et 2
WO2017201313A1 (fr) 2016-05-18 2017-11-23 Shengkan Jin Nouveaux découplants mitochondriaux pour le traitement de maladies métaboliques et du cancer
JP2018500388A (ja) * 2014-11-18 2018-01-11 ラットガーズ、ザ ステート ユニバーシティ オブ ニュージャージー 代謝疾患及び癌の治療のための、新規ミトコンドリアアンカップラー
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JP2022505439A (ja) * 2018-10-17 2022-01-14 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィック がんを治療及び／又は予防するためのウレア誘導体
US11427558B1 (en) 2019-07-11 2022-08-30 ESCAPE Bio, Inc. Indazoles and azaindazoles as LRRK2 inhibitors
WO2024022546A1 (fr) * 2022-07-25 2024-02-01 Univerzita Hradec Kralove Dérivés de 2-arylbenzothiazole, leur procédé de préparation et leur utilisation

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