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Definitions

• the present invention relates to novel, substituted estratrien derivatives which represent inhibitory compounds of the 17 ⁇ -hydroxysteroid dehydrogenase type 1 (17 ⁇ -HSD1 ), type 2 (17 ⁇ -HSD2) or type 3 (17 ⁇ -HSD3) enzyme, as well as to the salts of these compounds, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds. Furthermore, the invention concerns the therapeutic use of said novel substituted estratrien derivatives, particularly their use in the treatment or prevention of steroid hormone dependent diseases or disorders requiring the inhibition of the 17 ⁇ -HSD1 , 17 ⁇ -HSD2 or 17 ⁇ -HSD3 enzymes and/or requiring the lowering of the endogenous 17 ⁇ -estradiol and/or androgen concentration.
• 17 ⁇ -HSDs Mammalian 17 ⁇ -hydroxysteroid dehydrogenases
• NAD(H) or NADP(H) dependent enzymes which convert inactive 17-keto-steroids into their active 17 ⁇ -hydroxy- forms or catalyse the oxidation of the 17 ⁇ -hydroxy-forms into the 17-keto-steroids.
• 17 ⁇ -HSD enzymes play an essential role in the tissue-selective regulation of the activity of sex steroid hormones.
• 17 ⁇ -HSDs have been described (types 1-5, 7, 8, 10-12), whereby each type of 17 ⁇ -HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution. Due to their essential role in the tissue-selective regulation of the activity of sex steroid hormones, 17 ⁇ -HSDs can be involved in the occurrence and development of estrogen- sensitive pathologies (f. ex. breast, ovarian, and endometrium cancers etc.) and andro- gen-sensitive pathologies (f. ex. prostate cancer, benign prostatic hyperplasia, acne, hir- sutism, etc).
• estrogen- sensitive pathologies f. ex. breast, ovarian, and endometrium cancers etc.
• andro- gen-sensitive pathologies f. ex. prostate cancer, benign prostatic hyperplasia, acne, hir- sutism, etc.
• 17 ⁇ -HSD has been shown to be involved in the pathogenesis of particular human disorders such as pseudohermaphroditism (17 ⁇ -HSD3), polycystic kidney disease (17 ⁇ -HSD8) and bifunctional enzyme deficiency (17 ⁇ -HSD4) [reviewed by: Mindnich et al (2004)]. Therefore treatment of sex steroid-sensitive diseases by administration of specific inhibitors of the 17 ⁇ -HSDs enzymes have been suggested, optionally in combination with potent and specific anti-estrogens and anti-androgens [Labrie et al. (1997)].
• the best characterized member of the 17 ⁇ -HSD family is the 17 ⁇ -HSD1 [EC 1.1.1.62].
• the 17 ⁇ -HSD1 enzyme catalyzes in vitro the reduction and the oxidation between estrone (E1 ) and estradiol (E2). However, under physiological in vivo conditions the enzyme only catalyses the reductive reaction from the estrone (E1 ) to the estradiol (E2).
• the 17 ⁇ - HSD1 was found to be expressed in a variety of hormone-dependent tissues, e.g. placenta, mammary gland tissue or uterus and endometrium tissue, respectively.
• Estradiol itself is, especially in comparison to the significantly less active estrone, a very potent hormone, which regulates the expression of a variety of genes by binding to the nuclear estrogen receptor and plays an essential role in the proliferation and differentiation of the target cell.
• Physiological as well as pathological cell proliferations can be estradiol dependent.
• breast cancer cells are stimulated by a locally raised es- tradiol concentration.
• benign pathologies such as endometriosis, uterine leiomyomas (fibroids or myomas), adenomyosis, menorrhagia, metrorrhagia and dysmenorrhoea is dependent from the existence of significantly high estradiol levels.
• Endometriosis is a well-known gynaecological disorder that affects 10 to 15% of women in the reproductive age. Endometriosis is an estrogen-dependent disease, which does not occur before puberty and is rare after the menopause. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area. In women developing endometriosis, the endo- metrial cells entering the peritoneal cavity by retrograde menstruation (the most likely mechanism) have the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow.
• the implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus.
• Estrogen synthesis within endo- metriotic foci is increased due to aberrantly high local levels of aromatase and 17 ⁇ -HSD1 , accompanied by reduced expression of the estradiol inactivating enzyme 17 ⁇ HSD2 [Zei- toun et al. (1998)].
• These higher local estrogen concentrations induce in turn the production of prostaglandin E2, which then stimulates further aromatase activity. Consequently, this vicious circle leads to additional estrogen production.
• the infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tissue.
• endometriosis The most common symptoms of endometriosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain.
• Laparoscopy has to be performed to diagnose the disease.
• Endometriosis is classified according to the 4 stages set up by the American Fertility Society (AFS). Stage I corresponds to minimal disease while stage IV is severe, de- pending on the location and the extent of the endometriosis.
• Endometriosis is found in up to 50% of the women with infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility.
• the aims of treatment of endometriosis are pain relief, resolution of the endometriotic tissue and restoration of fertility (if desired).
• the two common treatments are surgery or anti-inflammatory and/or hormonal therapy or a combination thereof.
• Uterine leiomyomas fibroids or myomas
• myomas benign clonal tumours
• They are clinically apparent in up to 25% of women and are the single, most common indication for hysterectomy. They cause significant morbidity, in- eluding prolonged and heavy menstrual bleeding, pelvic pressure and pain, urinary problems, and, in rare cases, reproductive dysfunction.
• Myomas are found submucosally (beneath the endometrium), intramurally (within the myometrium) and subserosally (projecting out of the serosal compartment of the uterus), but mostly are mixed forms of these 3 different types.
• Dysfunctional uterine bleeding disorders are forms of pathological bleeding that are not attributable to organic changes in the uterus (such as, e.g., endometrial carcinoma, myomas, polyps, etc.), systemic coagulation disorders, or a pathological pregnancy (e.g., ectopic pregnancy, impending abortion).
• the average blood loss during normal menstruation is about 30 ml, whereby the period lasts for an average of 5 days. If the blood loss exceeds 80 ml, it is classified as pathological.
• Metrorrhagias are defined as bleeding that may or may not be accompanied by pain and that cannot be linked to menstruation or cycle.
• Menorrhagia is menstruation that may or may not be accompanied by pain, normally every 27-28 days, which, when it lasts over 7 days, is associated in most cases with an increased blood loss.
• Menorrhagia is a syndrome of unknown origin and one of the most common problems in gynecology. 60% of women refereed with menorrhagia have a hysterectomy within five years.
• Hypermenorrhea is defined as menstruation that may or may not be accompanied by pain, normally every 27-28 days for 4-5 days with an elevated blood loss.
• dysfunctional uterine bleeding mainly metrorrhagias and menor- rhagias
• follicle- stimulating disorders, anovulation, and yellow-body and follicle persistence occur in clusters.
• the incidence of dysfunctional uterine bleeding is high and represents one of the most frequent reasons for gynecological consultation for women of reproductive age.
• a compound acting as selective inhibitor on the 17 ⁇ -HSD1 which preferentially catalyses the reductive reaction will result in a lowered intracellular estradiol- concentration, since the reductive conversion of the estrone into the active estradiol is reduced or suppressed. Therefore, reversible or even irreversible inhibitors of the 17 ⁇ -HSD1 may play a significant role in the prophylaxis and/or treatment of steroid-hormone, in par- ticular 17 ⁇ -estradiol, dependent disorders or diseases.
• the reversible or even irreversible inhibitors of the 17 ⁇ -HSD1 should have no or only pure antagonistic binding activities to the estradiol receptor, in particular to the estrogen receptor ⁇ subtype, since agonistic binding of the estrogen receptor would lead to activation and subsequently to the proliferation and differentiation of the target cell.
• antagonists of the es- trogen receptor so called anti-estrogens, bind competitively to the specific receptor protein thus preventing access of endogenous estrogens to their specific binding site.
• a selective 17 ⁇ -HSD1 inhibitor may be useful for the prevention of the aforementioned hormone-dependent cancers, especially breast cancer (e.g. WO2004/080271 ).
• international patent application WO2003/017973 describes the use of a selective estrogen enzyme modulator (SEEM) in the manufacture of a drug delivery vehicle for intravaginal administration to treat or prevent a benign gynaecological disorder such as endometriosis in a mammalian female.
• SEEM selective estrogen enzyme modulator
• HSD1 inhibitors For example, Tremblay and Poirier describe an estradiol derivative, 16- [carbamoyl-(bromo-methyl)-alkyl]-estradiol, and tested the same in respect of its inhibition of the estradiol formation catalysed by the enzyme 17 ⁇ -HSD1 [Tremblay & Poirier (1998)]. Poirier and colleagues describe a 6 ⁇ -thiaheptan-butyl-methyl-amide derivative of estradiol as a potent and selective inhibitor of the 17 ⁇ -HSD1 enzyme [Poirier et al. (1998)].
• the international application WO2005/047303 discloses novel 3, 15 substituted 17 ⁇ - estradiol derivatives with different kind of side chains at position 15, which are potent and selective 17 ⁇ -HSD1 inhibitors. Furthermore novel 3, 15 substituted 17 ⁇ -estradiol derivatives with additional modifications of the steroidal core at positions C2, C3 and/or C17 have been described within international application WO2006/125800 as potent 17 ⁇ -HSD1 inhibitory compounds.
• 17 ⁇ -HSD3 A further well characterized member of the 17 ⁇ -HSD family is the 17 ⁇ -HSD type 3 enzyme (17 ⁇ -HSD3).
• the 17 ⁇ -HSD3 has a distinct feature compared to other 17 ⁇ -HSDs: it is found to be expressed almost exclusively the testis, whereas the other isoenzymes are expressed more widely in several tissues.
• 17 ⁇ -HSD3 has a crucial role in androgen biosynthesis. It converts 4-androstene-3,17-one (A) to testosterone (T).
• A 4-androstene-3,17-one
• T testosterone
• the biological signifi- cance of the 17 ⁇ -HSD3 is of undeniable physiological importance.
• prostate cancer the primary cancer cells mostly retain their responsiveness to androgens in their regulation of proliferation, differentiation, and programmed cell death for some period.
• androgen deprivation is the only effective systemic hormonal therapy available for prostate cancer.
• the development of selective inhibitors against 17 ⁇ -HSD3 is a new therapeutic approach for the treatment of androgen dependent disease [Labrie et al. (2000)].
• Oefelein et al. reported that the depot GnRH analogue fails, in nearly 20% of cases, to achieve castrate levels of T in men [Oefelein MG & Cornum R (2000)].
• ⁇ -HSD3 Besides prostate cancer, many other androgen-sensitive diseases, i.e. diseases whose onset or progress is aided by androgenic activity, may be treated by selectively inhibiting 17 ⁇ -HSD3 activity. These diseases include but are not limited to pros- tadynia, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome. Furthermore, considering the fact that 17 ⁇ -HSD3 is found mainly in the testis, the develop- ment of potent inhibitors could be of interest for blocking spermatogenesis and as an anti- fertility agent for males.
• Acne is a polyetiological disease caused by the interplay of numerous factors, such as in- heritance, sebum, hormones, and bacteria.
• the most important causative factor in acne is sebum production; in almost all acne patients sebaceous glands are larger and more sebum is produced than in persons with healthy skin.
• the development of the sebaceous gland and the extent of sebum production is controlled hormonally by androgens; therefore, androgens play a crucial role in the pathogenesis of acne.
• DHEA dehydroepiandrosterone
• DHEAS sulfate conjugate
• Androgenetic male alopecia is very common in the white races, accounting for about 95% of all types of alopecia.
• Male-pattern baldness is caused by an increased number of hair follicles in the scalp entering the telogen phase and by the telogen phase lasting longer. It is a genetically determined hair loss affected through androgens. Elevated serum DHEA but normal testosterone levels have been reported in balding men compared with non- balding controls, implying that target tissue androgen production is important in androgenetic alopecia.
• Hirsutism is the pathological thickening and strengthening of the hair which is character- ized by a masculine pattern of hair growth in children and women. Hirsutism is androgen induced, either by increased formation of androgens or by increased sensitivity of the hair follicle to androgens.
• WO2004/110459, WO2005/032527 and WO2005/084295 disclose compounds which have a 17 ⁇ -HSD3 inhibitory activity, for the treatment of hormone sensitive diseases.
• 17 ⁇ -HSD type 2 Microsomal 17 ⁇ -hydroxysteroid dehydrogenase of human endometrium and placenta (designated 17 ⁇ -HSD type 2 or 17 ⁇ -HSD2) was cloned by expression cloning, and found to be equally active using androgens and estrogens as substrates for oxidation [Anders- son (1995)].
• the recombinant 17 ⁇ -HSD2 converts the highly active 17 ⁇ -hydroxysteroids such as estradiol (E2), testosterone (T), and dehydrotestosterone (DHT) to their inactive keto forms.
• E2 estradiol
• T testosterone
• DHT dehydrotestosterone
• the 17 ⁇ -HSD2 can, to a lesser extent, also convert 20 ⁇ - hydroxyprogesterone (20 ⁇ P) to progesterone (P).
• This modulation of steroid levels may be employed for a wide variety of indications, including the following: for the prevention and treatment of osteoporosis, for the treatment of ovarian cancer, breast cancer or endometrial cancer, for the treatment of prostate cancer and/or for the treatment of androgen-dependent hair-loss.
• 17 ⁇ -HSD2 Several reversible or irreversible inhibitors of the 17 ⁇ -HSD2 enzymes of steroidal and even non-steroidal origin are already known from the literature. The characteristics of these inhibitory molecules have been reported in the literature [reviewed in: Poirier D. (2003)].
• the international patent application WO02/26706 discloses 17 ⁇ -HSD2 inhibitors of non-steroidal origin.
• 17 ⁇ -HSD1 , 17 ⁇ -HSD2 or 17 ⁇ -HSD3 inhibitors may be useful for the prevention and treatment of further estrogen- or androgen-dependent diseases or disorders and/or diseases or disorders requiring the lowering of the endogeneous estrogen or androgen concentration in a generalized or tissue-specific manner, such as inflammatory and autoimmune diseases, e.g.
• 17 ⁇ -HSD inhibitors might be also useful for the enhancement of cognitive function, especially in the treatment of senile dementia, including Alzheimer's disease,.
• Further estrogen-dependent diseases which may be treated and/or prevented with an effective amount of a compound of the invention are squamous cell carcinoma and colon cancer.
• estrogen or androgen derivatives have been disclosed in the literature as being inhibitors or activators of further enzymes of sex steroid conversion:
• US patent No. 6,541 ,463 discloses androsterone and estratriene derivatives carrying mainly modifications in the C17 position, which were developed as inhibitors of the 17 ⁇ -HSD5 enzyme and optionally additionally of the 17 ⁇ -HSD3 enzyme.
• Some of the examples disclosed (EM-1404, EM-1403, EM-1401 , EM-1388) carry a carboxy, a carboxy- methyl or an amide group in the C3 position of the steroidal core.
• these compounds have been developed as selective inhibitors of the 17 ⁇ -HSD5 enzyme and do not show significant inhibitory potential of the 17 ⁇ -HSD1 , 17 ⁇ -HSD2 or 17 ⁇ -HSD3 enzyme.
• Estratrien derivatives with a modification of the D-ring as dual inhibitors of the 17 ⁇ -HSD1 and of the steroid sulphatase enzyme have been described in international patent application WO02/32409.
• Estrone and estradiol derivatives carrying a boronic acid substitution in C3 position were recently disclosed by Ahmed et al. as inhibitors of the steroid sulphatase enzyme [Ahmed et al. (2006)].
• the selective inhibitors of the 17 ⁇ -HSD1 enzyme should have no inhibitory potential on the 17 ⁇ -HSD2 enzyme.
• an in- creased metabolic stability of the compounds would be desirable, in order to prevent conversion of the compounds to metabolites with less inhibitory potential on the 17 ⁇ -HSD1 enzyme.
• HSD1 , 17 ⁇ -HSD3 or 17 ⁇ -HSD2 enzyme which have valuable pharmacological properties and which are suited for the treatment of sex steroid hormone dependent diseases and disorders.
• estratriene derivatives as described herein would be valuable in therapy, especially in the treatment or prevention of steroid hormone dependent diseases or disorders requiring the lowering of the endogeneous estradiol concentration, in animals, in particular mammals, and humans.
• compounds of formula (I) represent potent inhibitors of the 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or 17 ⁇ -HSD3 enzyme, whereas selective inhibitors of the 17 ⁇ -HSD1 should have no inhibitory potential on the 17 ⁇ -HSD2 enzyme.
• the compounds of the invention possess valuable pharmacological properties for the treatment and/or prophylaxis of malignant steroid dependent diseases or disorders such as breast cancer, prostate cancer, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia, but also for the treatment and/or prophylaxis of benign steroid dependent diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhoea, menorrhagia, metrorrhagia, urinary dysfunction, prostadynia, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome and/or lower urinary tract syndrome.
• malignant steroid dependent diseases or disorders such as breast cancer, prostate cancer, ovarian cancer, uterine cancer
• estrogen- dependent diseases which may be treated and/or prevented with an effective amount of a compound of the invention are osteoporosis, multiple sclerosis, rheumatoid arthritis, sys- temic lupus erythematosus, myastenia gravis, thyroiditis, vasculitis, ulcerative colitis, Crohn's disease, graft versus host and host versus graft disease (organ rejection following transplantation), type I and Il diabetes, asthma, squamous cell carcinoma, colon cancer, cognitive dysfunctions, senile dementia, Alzheimer's disease, psoriasis, contact dermatitis, eczema, tissue wounds, skin wrinkles and/or cataracts.
• compounds of formula (I) may be useful for blocking spermatogenesis and as an anti-fertility agent for males.
• the present invention relates to a compound of the general formula I,
• R 3 represents -H or -(d-C 4 )alkyl
• R 1 is selected from the group consisting of: (a) -B(OR 9 XOR 10 ) (b) -CO-OR 6
• R 5 represents -H or -(d-C 4 )alkyl
• R 6 , R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of: (a) -H
• R 7 and R 8 form together with the nitrogen atom, to which they are attached, a heterocyclic 4, 5, 6, 7 or 8 membered ring, which is optionally saturated, partly unsaturated or aromatic; which optionally contains 1 , 2 or 3 additional heteroatoms selected from the group consisting of N, O or S, the number of additional N atoms being 0, 1 , 2 or 3 and the num- ber of O and S atoms each being 0, 1 or 2; and which ring is optional part of a multiple condensed ring system, wherein the ring or the ring-system is optionally substituted;
• R 5 and R 6 may also form together with the nitrogen atom, to which R 5 is attached, and the carbonyl group, to which R 6 is attached, a 4, 5, 6, 7 or 8 membered lactam ring,
• R 5 and R 6 may also form together with the nitrogen atom, to which R 5 is attached, and the sulfoxyd group, to which R 6 is attached, a 4, 5, 6, 7 or 8 membered sultam ring, or
• R 9 and R 10 form together with the boronic acid group, to which they are attached, a 5 or 6 membered ring, which is optionally substituted with 1 , 2, 3 or 4 -(Ci-C 4 )alkyl groups;
• n 1 , 2, 3, 4, 5 or 6, or, if -X-A-Y- represents -CO-NR 4 -, -CO-O-, -CO- or - CO-NH-NR 4 -, then n may also represent 0;
• R 11 represents H, -(Ci-Ci 4 )alkyl, (Ci-Ci 4 )alkoxy, or (Ci-Ci 4 )alkoxy-(Ci-Ci 4 )alkyl;
• R 2 and R 4 are independently selected from:
• R 2 and R 4 form together with the nitrogen atom, to which R 2 and R 4 are attached, a heterocyclic 4, 5, 6, 7 or 8 memberred ring, which is optionally saturated, partly unsaturated or aromatic; which optionally contains 1 , 2 or 3 additional heteroatoms selected from N, O and S, the number of additional N atoms being 0, 1 , 2 or 3 and the number of O and S at- oms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring- system, wherein the ring or the ring-system is optionally substituted;
• the present invention relates to a compound of the general formula I, which is an optically pure 15 ⁇ enantiomer having the formula (II)
• the present invention relates to the 15 ⁇ enantiomer having formula (II), wherein n represents 1 , 2, 3 or 4.
• the present invention relates to a compound of the general formula I, which is an optically pure 15 ⁇ enantiomer having the formula (III)
• the present invention relates to the 15 ⁇ enantiomer having formula (III), wherein n represents 2, 3, 4, or 5.
• One embodiment of the present invention relates to compounds of formula I, Ia, Ib, Il or III, wherein wherein -X-A-Y- together represent a group selected from
• -X-A-Y- together represent a group selected from -CO-NR 4 - and a group
• R 2 and R 4 are independently selected from:
• each aryl group is optionally substituted with 1 , 2 or 3 substituents independently selected from the group consisting of hydroxyl, halogen, (d-C 6 )alkoxy, -(Cr C 6 )alkyl, halogenated -(Ci-C 6 )alkyl and halogenated -(Ci-C 6 )alkoxy;
• R 2 and R 4 form together with the nitrogen atom, to which R 2 and R 4 are attached, a heterocyclic 4, 5, 6, 7 or 8 membered ring, which is optionally saturated or partly unsaturated; which optionally contains 1 , 2 or 3 additional heteroatoms selected from N, O and S, the number of additional N atoms being O, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system, which ring or ring-system is optionally substituted with 1 , 2 or 3 substituents independently selected from the group consisting of oxo, -(Ci-C 6 )alkyl, halogen, -OR 14 , -COOR 14 , -(Ci-C 6 )alkyl-COOR 14 , -SR 14 , -CN, -NR 15 R 16 , -CONR 15 R 16 , -SO 2 NR 15 R 16 , aryl
• each aryl or heteroaryl moiety is optionally substituted with 1 , 2 or 3 sub- stituents independently selected from the group consisting of hydroxyl, halogen, -
• R 14 , R 15 , R 16 , R 17 and R 18 are independently selected from the group consisting of -H, -(Ci-C 4 )alkyl, halogenated -(Ci-C 4 )alkyl, aryl and aryl-(Ci-C 4 )alkyl, or wherein R 15 and R 16 form together with the nitrogen atom, to which they are attached, a heterocyclic 5, 6 or 7 membered ring, optionally containing 1 or 2 additional heteroatoms selected from N, O and S, the number of N atoms being 0, 1 or 2 and the number of O and S atoms each being 0 or 1.
• this ring or ringsystem is selected from the group consisting of
• the residues R 2 and R 4 in the compounds of the general formula I may independently represent -H, wherein, if -X-A-Y- to- gether represents -CO-O- or -CO-, then R 2 is different from -H.
• the invention relates compounds of of formula I, Ia, Ib, Il or III, wherein R 6 , R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of: (a) -H (b) -(Ci-Ci 2 )alkyl, which is optionally substituted by halogen, -CN, -OR 14 , -SR 14 , - NR 15 R 16 , -CONR 15 R 16 , -SO 2 NR 15 R 16 , -CO-R 17 , -COOR 14 , -NH-CO-R 17 , or -O- SO 2 -R 18 ; the number of said substituents being up to five for halogen, and 1 or 2 for any combination of substituents; (c) aryl and aryl-(Ci-Ci 2 )alkyl, in which the aryl moiety of the aryl or aryl-(Ci-Ci 2 )alkyl
• heteroaryl and heteroaryl-(Ci-Ci 2 )alkyl in which the heteroaryl moiety is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR 19 , -(Ci-C 6 )alkyl, halogenated -(Ci-C 6 )alkyl, -
• R 7 and R 8 form together with the nitrogen atom, to which they are attached, a hetero- cyclic 4, 5, 6, 7 or 8 membered ring, which is optionally saturated, partly unsaturated or aromatic; which optionally contains 1 , 2 or 3 additional heteroatoms selected from the group consisting of N, O or S, the number of additional N atoms being O, 1 , 2 or 3 and the number of O and S atoms each being O, 1 or 2; and which ring is optional part of a multiple condensed ring system, and which ring or ring-system is optionally substituted by 1 , 2 or 3 substituents independently selected from the group consisting of oxo, -(Ci-C 6 )alkyl, halogen, -OR 19 , -COOR 19 , -(Ci-C 6 )alkyl-COOR 19 , -SR 19 , -CN, -NR 20 R 21 , -CONR 20 R 21 , -SO 2 NR 20 R 21
• R 19 , R 20 , R 21 , R 22 and R 23 are independently selected from the group consisting of -H, -(Ci-C 4 )alkyl, halogenated -(C r C 4 )alkyl, aryl and aryl-(C r C 4 )alkyl, or wherein R 20 and R 21 form together with the nitrogen atom, to which they are attached, a heterocyclic 5, 6 or 7 membered ring, optionally containing 1 or 2 additional heteroatoms selected from N, O and S, the number of N atoms being 0, 1 or 2 and the number of O and S atoms each being 0 or 1 ,
• R 5 and R 6 may also form together with the nitrogen atom, to which R 5 is attached, and the carbonyl group, to which R 6 is attached, a heterocyclic 4, 5, 6, 7 or 8 membered lactam ring,
• R 5 and R 6 may also form together with the nitrogen atom, to which R 5 is attached, and the sulfoxyd group, to which R 6 is attached, a heterocyclic 4, 5, 6, 7 or 8 membered sultam ring, or
• R 9 and R 10 form together with the boron atom, to which they are attached, a heterocyclic 5 or 6 membered ring, which is optionally substituted with 1 , 2, 3 or 4 -(Ci-C 4 )alkyl groups.
• a further preferred embodiment of the present invention relates to compounds of formula I, Ia, Ib, Il or III, wherein R 1 is selected from the group consisting of: (a) -B(OH) 2 . (b) -CO-OH
• one embodiment is directed to compounds of formula I, Ia, Ib, Il or III, wherein R 1 is -CO-NR 7 R 8 , and R 7 and R 8 are independently selected from the group consisting of -H and -(d-C 6 )alkyl.
• another embodiment is directed to compounds of formula I, Ia, Ib, Il or III, wherein R 1 is -NR 5 -CO-R 6 , and R 5 and R 6 form together with the nitrogen atom, to which R 5 is attached, and the carbonyl group, to which R 6 is attached, a heterocyclic 5 or 6 membered lactam ring.
• R 7 and R 8 are preferably independently selected from the group consisting of:
• heteroaryl and heteroaryl-(Ci-C 4 )alkyl which heteroaryl moiety is optionally substi- tuted with 1 or 2 oxo groups;
• R 7 and R 8 form together with the nitrogen atom, to which they are attached, a hetero- cyclic 5, 6 or 7 membered ring, which is optionally saturated, partly unsaturated or aromatic, which optionally contains 1 or 2 additional heteroatoms selected from the group consisting of N, O or S, the number of additional N atoms being 0, 1 or 2 and the number of O and S atoms each being 0 or 1 ; and which ring is optional part of a multiple condensed ring system, and which ring or ring-system is optionally substituted by 1 or 2 substituents independently selected from the group consisting of oxo, -(CrC 4 )alkyl, -OR 19 , aryl and aryl-(Ci- C 2 )-alkyl, in which each aryl moiety is optionally substituted with 1 , 2 or 3 substituents inde- pendently selected from the group consisting of hydroxyl, halogen, -(d-C 4 )alkyl,
• R 19 , R 20 and R 21 are independently selected from the group consisting of -H, - (Ci-C 4 )alkyl and halogenated -(Ci-C 4 )alkyl, or wherein R 20 and R 21 form together with the nitrogen atom, to which they are attached, a heterocyclic 5 or 6 membered ring, optionally containing 1 additional heteroatom selected from N, O and S.
• R 2 and R 4 are independently selected from: (a) -H, wherein, if -X-A-Y- together represents -CO-O- or -CO-, then R 2 is different from -H,
• heteroaryl and heteroaryl-(Ci-C 4 )alkyl in which the heteroaryl moiety is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, -OR 14 , -(C r C 6 )alkyl and halogenated -(C r C 6 )alkyl;
• R 2 and R 4 form together with the nitrogen atom, to which R 2 and R 4 are attached, a heterocyclic 5, 6 or 7 membered ring, which is optionally saturated or partly unsaturated; which optionally contains 1 or 2 additional heteroatoms selected from N, O and S, the number of additional N atoms being 0, 1 or 2 and the number of O and S atoms each being 0 or 1 ; and which ring is optionally part of a multiple condensed ring-system, which ring or ring-system is optionally substituted with 1 or 2 substituents independently selected from the group consisting of oxo, -(CrC 6 )alkyl, halogen and -OR 14 ,
• R 14 is selected from the group consisting of -H, -(d-C 4 )alkyl and halogenated -
• This ring or ringsystem may be selected from the group consisting of
• Another embodiment of the present invention relates to compounds of of formula I, Ia, Ib,
• R 11 represents H, -(C r C 4 )alkyl, (C r C 4 )alkoxy, or (Ci-C 4 )alkoxy-(C r C 4 )alkyl.
• R 11 represents H, ethyl, propyl, methoxyethyl, methoxy, ethoxy or methoxyethoxy.
• R 11 represents H.
• n 2, 3 or 4, preferably n represents 2 or 3.
• compounds of of formula I, Ia, Ib, Il or III are disclosed, wherein n represents 3.
• n represents 3.
• the compound is an optically pure enantiomer having the formula (ll-b)
• Another embodiment of the invention relates to compounds of formula I, Ia, Ib, Il or III, wherein -X-A-Y- together represent -CO-NHR 4 -.
• Another embodiment of the invention relates to compounds of formula I, Ia, Ib, Il or III, wherein -X-A-Y- together represent a group
• a further embodiment relates to compounds of formula I, Ia, Ib, Il or III, wherein R and
• R 3 13 each individually represent F.
• the invention relates to a compound of the following formula XLII wherein
• Y represents -NR 4 -, -O-, a bond or -N H-N R 4 -, i.e. compounds of formula I, wherein -X-A-Y- together represent a group selected from (a) -CO-NR 4 -,
• the invention relates to a compound of the following formula Vl
• n 0, 1 , 2, 3, 4, or 5, preferably n represents 2, 3 or 4.
• R 2 more preferably represents (i) -(Ci-C 4 )alkyl, which is optionally substituted with one or two (Ci-C 4 )alkoxy groups;
• heteroaryl or -(CrC 4 )alkyl-heteroaryl wherein the heteroaryl is thiazolyl, pyridinyl, indolyl, or indazolyl; which heteroaryl is optionally substituted with one or two -(Ci-C 4 )alkyl groups; and R 4 is independently selected from -H, -(Ci-C 4 )-alkyl or -(Ci-C 4 )-alkyl-phenyl, wherein the phenyl group is optionally substituted with one or two (d- C 4 )alkoxy groups; or R 2 and R 4 form together with the nitrogen atom, to which R 2 and R 4 are attached, a ring, which is selected from the group consisting of morpholine, piperidine, and piperazine, wherein the ring is optionally substituted with a -(CrC 4 )alkyl group.
• R 2 represents a -(Ci-C 4 )alkylphenyl, preferably a benzyl group, or a thiazolyl group, optionally substituted with -(Ci-C 4 )-alkyl, preferably methyl, and R 4 represents -H; or R 2 and R 4 form together with the nitrogen atom, to which R 2 and R 4 are attached, a morpholine group, and n represents 2 or 3.
• Y represents -NH-, a bond, or -O-; i.e compounds of formula I, wherein -X-A-Y- together represent -NH-CO-NH-, -NH-CO-O-, or -NH-CO-; the preferred meanings of R 1 , R 2 , R 4 , R 11 , R 12 and R 13 are as indicated herewithin; and n represents 1 , 2, 3, 4, 5 or 6, preferably 1 , 2, 3 or 4.
• a further embodiment of the invention relates to a compound of the following formula XVII, wherein the preferred meanings of R 1 , R 2 , R 11 , R 12 and R 13 are as indicated herewithin; and n preferably represents 1 , 2, 3, or 4, even more preferably 3 or 4.
• R 2 preferably represents (i) -(CrC 4 )alkyl, (ii) -(C 3 -C 8 )cycloalkyl, (iii) -(Ci-C 4 )alkyl-(C 3 -C 8 )cycloalkyl, (iv) aryl, wherein the aryl is phenyl or naphthyl, which phenyl is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, -CO- O(Ci-C 4 )alkyl and (C r C 4 )alkoxy; or which phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6- membered ring system, containing 1 or 2 O atoms, or
• a further embodiment of the invention relates to a compound of the following formula XXIII,
• R 2 preferably represents (i) -(d-C 4 )alkyl
• the present invention relates to compounds of formula (I), wherein -X-A-Y- together represent a group selected from -NH-SO 2 -NH-, -NH-SO 2 - O-, and -NH-SO 2 -, and n represents 1 , 2, 3, or 4.
• a further embodiment of the invention relates to a compound of the following formula XXIV,
• R 1 , R 2 , R 11 , R 12 and R 13 are as indicated herewithin; and n preferably represents 1 , 2, 3, or 4.
• R 2 preferably represents
• aryl wherein the aryl is selected among phenyl and naphthyl, which aryl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, nitro, (CrC 4 )alkoxy, and -(Cr C 4 )alkyl; or
• heteroaryl wherein the heteroaryl is furyl, thienyl, or thiazolyl, or indolyl, which heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of -SO 2 -phenyl and (Ci-C 4 )alkyl.
• the present invention relates to compounds of formula (I), wherein -X-A-Y- together represent a group selected from -O-CO-NH-, -O-CO-, and -O-CO-N H-S(VN R 4 -, and n represents 1 , 2, 3, 4, 5 or 6.
• a further embodiment of the invention relates to a compound of the following formula XXVI,
• R 1 , R 2 , R 11 , R 12 and R 13 are as indicated herewithin; and n preferably represents 3, 4, 5 or 6.
• R 2 preferably represents phenyl or naphthyl, which phenyl is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, nitro, -CO-O(CrC 4 )alkyl and (Cr C 4 )alkoxy and halogenated (Ci-C 4 )alkyl; or which phenyl is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6-membered ring system, containing 1 or 2 O atoms.
• a further embodiment of the invention relates to a compound of the following formula XXVIII,
• R 1 , R 2 , R 4 , R 11 , R 12 and R 13 are as indicated herewithin; and n preferably represents 3, 4, 5 or 6.
• R 2 preferably represents (i) -(CrC 4 )alkyl, (ii) -(C 3 -C 8 )cycloalkyl, (iii) -(Ci-C 4 )alkyl-phenyl, (iv) phenyl, or
• heteroaryl or -(Ci-C 4 )alkyl-heteroaryl wherein the heteroaryl is furyl, thienyl, thiazolyl, pyridinyl, indolyl, or benzoimidazolyl; and preferably R 4 is independently selected from H, -(Ci-C 4 )-alkyl and -(Ci-C 4 )alkyl- phenyl; or R 2 and R 4 may form together with the nitrogen atom, to which R 2 and R 4 are attached, a ring, which is selected from the group consisting of morpholine, thiomorpholine and piperazyl, and which is optionally substituted with (Ci-C 4 )-alkyl.
• a further embodiment of the invention relates to a compound of the following formula XXXI,
• R 1 , R 10 , R 11 , R 12 and R 13 are as indicated herewithin; and n represents 1 , 2, 3, 4, 5 or 6, preferably 3 or 4.
• a further embodiment of the invention relates to a compound of formula I, Ia, Ib, Il or III, wherein
• R 1 represents -CO-OH or -CO-NR 7 R 8 , wherein R 7 and R 8 are independently selected from -H and -(C r C 4 )alkyl;
• -X-A-Y- together represent -CO-NR 4 -;
• R 11 represents -H;
• R 2 and R 4 have the meanings as indicated herewithin.
• a further embodiment of the invention relates to a compound of formula I, Ia, Ib, Il or III, wherein R 1 represents -B(OH) 2 , -X-A-Y- together represent -CO-NR 4 -; R 11 represents -H;
• R 2 and R 4 have the meanings as indicated herewithin.
• a further embodiment of the invention relates to a compound of formula I, Ia, Ib, Il or III, wherein R 1 represents -NR 5 -CO-R 6 , wherein R 5 and R 6 form together with the nitrogen atom, to which R 5 is attached, and the carbonyl group, to which R 6 is attached, a heterocyclic 5 membered lactam ring;
• -X-A-Y- together represent -CO-NR 4 -;
• R 2 and R 4 have the meanings as indicated herewithin.
• a further embodiment of the invention relates to a compound of formula I, Ia, Ib, Il or III, wherein
• R 1 represents -NR 7 R 8 ,
• -X-A-Y- together represent -CO-NR 4 -;
• R 11 represents -H
• R 2 and R 4 have the meanings as indicated herewithin, and
• R 7 and R 8 have the meanings as indicated herewithin.
• R 7 and R 8 are preferably independently selected from: (a) -H
• phenyl and phenyl-(Ci-C 2 )alkyl in which the phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, -OR 19 , -(Ci-C 4 )alkyl, halogenated -(d-C 4 )alkyl, -CN and -SO 2 NR 20 R 21 ; or in which the phenyl moiety is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5 or 6 membered ring system, optionally containing 1 or 2 heteroa- toms selected from the group consisting of O and S, the number of O and S atoms each being 0, 1 or 2, and which ring system is optionally substituted with 1 or 2 oxo groups;
• heteroaryl and heteroaryl-(Ci-C 2 )alkyl in which the heteroaryl moiety is selected from the group consisting of indolyl, quinolinyl, benzothienyl and pyridinyl, which heteroaryl moiety is optionally substituted with 1 or 2 oxo groups;
• cycloheteroalkyl and cycloheteroalkyl-(CrC 4 )alkyl in which the cycloheteroalkyl moiety is selected from the group consisting of pyrrolidinyl and oxazolidinyl, and in which the cycloheteroalkyl moiety is optionally substituted with an oxo group;
• R 7 and R 8 form together with the nitrogen atom, to which they are attached, a hetero- cyclic 5 or 6 membered saturated ring, which is saturated or partly unsaturated, which optionally contains 1 additional heteroatom selected from the group consisting of N and O; and which ring is optional part of a multiple condensed ring system, and which ring or ring-system is optionally substituted by a substituent selected from the group consisting of oxo, phenyl and phenyl-(Ci-C 2 )-alkyl, in which each phenyl moiety is optionally substituted with a substituent selected from the group consisting of halogen and -(Ci-C 4 )alkoxy;
• R 19 , R 20 and R 21 are independently selected from the group consisting of -H, - (Ci-C 4 )alkyl and halogenated -(Ci-C 4 )alkyl, or wherein R 20 and R 21 form together with the nitrogen atom, to which they are attached, a heterocyclic 6 membered ring, optionally containing 1 additional heteroatom selected from N and O.
• R 2 and R 4 are preferably independently selected from: (a) -H,
• phenyl and phenyl-(Ci-C 2 )alkyl in which the phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen and -OR 14 , or in which the phenyl moiety is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, the number of N, O and S atoms each being 0, 1 or 2;
• heteroaryl and heteroaryl-(Ci-C 2 )alkyl in which the heteroaryl moiety is selected from the group consisting of imidazolyl, pyridinyl, indolyl and thiazolyl, and in which the heteroaryl moiety is optionally substituted with -(d-C 4 )alkyl;
• R 2 and R 4 form together with the nitrogen atom, to which R 2 and R 4 are attached, a heterocyclic 5, 6 or 7 membered saturated ring, which optionally contains 1 additional heteroatom selected from N and O; which ring is optionally substituted with -(Cr C 4 )alkyl;
• R 14 is selected from the group consisting of -H, -(Ci-C 4 )alkyl and halogenated - (Ci-C 4 )alkyl.
• a further embodiment of the invention relates to a compound of formula I, Ia, Ib, Il or III, wherein R 1 represents -B(OH) 2 ,
• R 2 is preferably selected from the group consisting of (a) -(Ci-C 6 )alkyl,
• phenyl and phenyl-(Ci-C 2 )alkyl in which the phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, -(Ci-C 4 )alkyl, halogenated -(C r C 4 )alkyl, -OR 14 , and -COOR 14 , wherein R 14 is selected from the group consisting of -H, -(d-C 4 )alkyl and halogenated - (CrC 4 )alkyl.
• the invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.
• the invention relates to a compound of the invention for use as a medicament.
• the invention relates to the use of an effective amount of a compound of the invention for the treatment or prevention of a steroid hormone dependent disease or disorder in an animal, preferably a mammal, or human.
• the steroid hormone dependent disease or disorder is an estradiol dependent disease or disorder.
• the steroid dependent disease or disorder is an androgen-dependent disease or disorder.
• the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal, in particular a human.
• the steroid hormone dependent disease or disorder is an estradiol dependent disease or disorder.
• the steroid dependent disease or disorder is an androgen-dependent disease or disorder.
• the steroid hormone dependent disease or dis- order requires the inhibition of a 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or 17 ⁇ -HSD3 enzyme, preferably the human 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or 17 ⁇ -HSD3 enzyme.
• the steroid hormone dependent disease or disorder requires the inhibition of the human 17 ⁇ - HSD1 enzyme.
• the invention also relates to a method of treating a mammal such as a human having a condition related to 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or 17 ⁇ -HSD3 activity or which condition can be treated by inhibition of one, two or all of said enzymes, comprising administering to the mammal an amount of a compound of this invention, or a salt or a prodrug thereof, which amount is effective to treat the condition.
• a mammal such as a human having a condition related to 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or 17 ⁇ -HSD3 activity or which condition can be treated by inhibition of one, two or all of said enzymes
• administering comprising administering to the mammal an amount of a compound of this invention, or a salt or a prodrug thereof, which amount is effective to treat the condition.
• Administration of com- pounds of this invention in combination with other pharmaceuticals used in treatment of the listed conditions is contemplated.
• the conditions to be treated include but are not limited to malign estradiol dependent disease or disorder such as breast cancer, ovarian cancer, uterine cancer, endometrial can- cer, and endometrial hyperplasia.
• the malign disease or disorder is characterized by a detectable level of 17 ⁇ -HSD1 within a cancer tissue sample.
• a detectable level of 17 ⁇ -HSD1 means that a certain level of 17 ⁇ -HSD1 mRNA or of 17 ⁇ -HSD1 protein can be detected by conventional molecular biology methods such as hybridization, PCR reactions, Northern or Western Blotting etc.
• An alternative detection method for 17 ⁇ -HSD1 ex- pression is the measurement of the corresponding enzyme activity.
• the estradiol dependent disease is breast cancer and the mammal is a human post-menopausal female.
• the conditions to be treated include but are not limited to benign estradiol dependent diseases or disorders such as endometriosis, uterine fibroids, uterine leio- myoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia and urinary dysfunction.
• the invention relates to use of an effective amount of a compound of the invention for the treatment or prevention of one of the aforementioned benign gynaecological diseases or disorders in a mammal whereby the mammal is a hu- man, preferably a female and most preferably a pre- or peri-menopausal female.
• the steroid hormone dependent disease or disorder is an androgen-dependent disease or disorder.
• said an- drogen-dependent disease or disorder is selected from the group consisting of prostate cancer, prostadynia, benign prostatic hyperplasia, urinary dysfunction, lower urinary tract syndrome, prostatitis, acne, seborrhea, androgenetic alopecia, hirsutism, precocious puberty, adrenal hyperplasia and polycystic ovarian syndrome.
• the compounds of the invention can be useful in the manufacture of a phar- maceutical composition for blocking spermatogenesis and/or for use as an anti-fertility agent for males.
• the steroid hormone dependent disease or disorder to be treated is an estrogen- or androgen dependent disease or disorder requir- ing the lowering of the endogeneous estrogen or androgen concentration in a generalized or tissue-specific manner.
• steroid-dependent diseases which may be treated with an effective amount of a compound of the invention are selected from the group consisting of squamous cell carcinoma, colon cancer, osteoporosis, rheumatoid arthritis, multiple sclerosis, myastenia gravis, thyroiditis, vasculitis, ulcerative colitis, Crohn's disease, type I and Il diabetes, psoriasis, contact dermatitis, skin wrinkles, eczema, tissue wounds, systemic lupus erythematosus, graft versus host disease, organ rejection following transplantation, cataracts and asthma.
• a compound of the present invention may be used for the enhancement of cognitive function, i.e. in the treatment or prevention of cognitive dysfunctions, such as senile dementia, including Alzheimer's disease.
• the disclosed compounds are also useful as diagnostic agents (e.g. in diagnostic kits or for use in clinical laboratories) for screening for the presence or absence of 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or 17 ⁇ -HSD3 enzyme activity.
• Isotopically-labeled compound of formula (I) or pharmaceutically acceptable salts thereof including compounds of formula (I) isotopi- cally-labeled to be detectable by PET or SPECT, are also included within the scope of the invention, and same applies to compounds of formula (I) labeled with [ 13 C]-, [ 3 H]-, [ 125 I]- or other radioactive atoms, suitable for enzyme activity or metabolism studies.
• the compounds of the invention possess inhibiting activity on the 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or 17 ⁇ -HSD3 enzyme.
• the inhibiting activities of the compounds of the invention are readily demonstrated, for example, using one or more of the assays described herein or known in the art.
• An advantage of the present invention is that the compounds of the pre- sent invention can act as selective 17 ⁇ -HSD1 , 17 ⁇ -HSD2 or 17 ⁇ -HSD3 inhibitorsPrefera- bly, the compounds of the invention possess inhibiting activity on one of the 17 ⁇ -HSD1 , 17 ⁇ -HSD2 or 17 ⁇ -HSD3 enzyme, but does not inhibit the respective other enzymes.
• An advantage of the com- pounds of the present invention is that they may be potent in vivo and suited for the therapeutic use in mammals, especially humans.
• Some of the compounds of the present invention may additonally be non-estrogenic compounds.
• non-estrogenic means exhibiting no or substantially no estrogenic activity on the estrogen receptor.
• Another advantage is that some of the compounds may not be capable of being metabolised to compounds which display or induce hormonal activity.
• Some of the compounds of the present invention are also advantageous in that they may be orally active.
• compound shall here be understood to cover any and all isomers (e. g., enantiomers, stereoisomers, diastereomers, rotomers, tautomers) or any mixture of isomers, prodrugs, and any pharmaceutically acceptable salt of said compound, unless the formula depicting the compound explicitly shows a particular stereochemistry.
• 17 ⁇ -hydroxysteroid dehydrogenase type I or “17 ⁇ -HSD1” for short is used for the enzyme EC 1.1.1.62 and reduces estrone (E1 ) to the biologically active estrogen, estradiol (E2).
• inhibitor and “inhibition” include the meaning of to reduce and/or eliminate and/or mask and/or prevent a certain enzyme action.
• 17 ⁇ -HSD1 inhibitor as used herein with respect to the compound of the present invention means a compound that can inhibit 17 ⁇ -HSD1 activity, such as to reduce and/or eliminate and/or mask and/or prevent the action of 17 ⁇ -HSD1.
• the 17 ⁇ - HSD1 inhibitor may act as an reversible or irreversible inhibitor of 17 ⁇ -HSD1.
• the ability of compounds to inhibit 17 ⁇ -HSD1 activity can be assessed using cell lines recombinantly expressing the human 17 ⁇ -HSD1 enzyme or using the recombinantly produced and purified 17 ⁇ -HSD1 enzyme. Details on a suitable Assay Protocol are presented in the Examples section. It is to be noted that the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit 17 ⁇ - HSD1 activity; in particular a 17 ⁇ -HSD1 inhibitor may have antagonistic activity towards the nuclear estrogen receptor.
• 17 ⁇ -HSD2 inhibitor as used herein with respect to the compound of the present invention means a compound that can inhibit 17 ⁇ -HSD2 activity, such as to reduce and/or eliminate and/or mask and/or prevent the action of 17 ⁇ -HSD2.
• the 17 ⁇ - HSD2 inhibitor may act as an reversible or irreversible inhibitor of 17 ⁇ -HSD2.
• the ability of compounds to inhibit 17 ⁇ -HSD2 activity can be assessed using cell lines recombinantly expressing the human 17 ⁇ -HSD2 enzyme or using the recombinantly produced and purified 17 ⁇ -HSD2 enzyme. Details on a suitable Assay Protocol are known to the skilled artisan. It is to be noted that the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit 17 ⁇ -HSD2 activity.
• 17 ⁇ -HSD3 inhibitor as used herein with respect to the compound of the present invention means a compound that can inhibit 17 ⁇ -HSD3 activity, such as to reduce and/or eliminate and/or mask and/or prevent the action of 17 ⁇ -HSD3.
• the 17 ⁇ - HSD3 inhibitor may act as an reversible or irreversible inhibitor of 17 ⁇ -HSD3.
• the ability of compounds to inhibit 17 ⁇ -HSD3 activity can be assessed using cell lines recombinantly expressing the human 17 ⁇ -HSD3 enzyme or using the recombinantly produced and purified 17 ⁇ -HSD3 enzyme. Details on a suitable Assay Protocol are presented in the Examples section. It is to be noted that the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit 17 ⁇ - HSD3 activity; in particular a 17 ⁇ -HSD3 inhibitor may have antagonistic activity towards the nuclear androgen receptor.
• selective and “selectivity” as used herein with respect to the compounds of the present invention means a compound that can inhibit 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or
• a compound of the present invention has at least about a 10Ofold selectivity to the desired target, preferably at least about a 150fold selectivity to the desired target, preferably at least about a 200fold selectivity to the desired target, preferably at least about a 250fold selectivity to the desired target, preferably at least about a 300fold selectivity to the desired target, preferably at least about a 350fold selectivity to the desired target.
• leaving group shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
• Any asymmetric carbon atoms may be present in the (R)-, (S)- or (Reconfiguration preferably in the (R)- or (S)-configuration, whichever is most active, unless the stereochemistry is explicitly depicted in the corresponding compound formula.
• the compounds of formula (I) have a defined stereochemistry within the steroidal core structure according to the natural configuration for estrogenic steroids such as estrone:
• stereochemistry within the steroidal core structure is always shown in the corresponding compound formula and should not vary within the scope of the present invention, whereas the stereochemistry at the carbon atoms in the steroidal core carrying additional side chains and the stereochemistry of any asymmetric carbon atom within the side chains themselves is not fixed. Therefore, the term “compounds of formula (I)” or “compounds of formula (II)” etc also comprises the stereoisomers of the depicted compounds, unless a particular stereochemistry is explicitly shown within the formula. The stereochemistry shown in the respective formula prevails over the general term "stereoisomers".
• the compounds of the formula I contain at least one additional chiral carbon atom, namely the carbon atom carrying the side chain in the 15-position of the steroide structure.
• the compounds can thus be present at least in two optically active stereoisomeric forms or as a racemate.
• the present invention includes both the racemic mixtures and the isomerically pure compounds of the formula I. The position of the substituents within the
• a C15 ⁇ derivative according to the present invention is represented by a compound of the following formula (II)
• the compounds of the present invention may contain further asymmetric centers on the molecule, depending upon the nature of the various substituents. In certain instances, asymmetry may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds. It is intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the ambit of the instant invention, unless a particular stereochemistry is explicitly depicted in the formula representing a respective compound.
• halogen refers to fluorine (F, Fluoro-), bromine (Br, Bromo-), chlorine (Cl, ChIo- ro), and iodine (I, lodo-) atoms. Preferred in the context of the present invention are F, Cl and Br.
• dihalogen trihalogen
• perhalogen refer to two, three and four substituents, respectively, each individually selected from the group consisting of fluorine, bromine, chlorine, and iodine atoms.
• hetero as in 'heteroalkyl, heteroaromatic' etc, means containing one or more N, O or S atoms.
• hydroxyl refers to the group -OH
• thiol refers to the group -SH
• sulfoxy or "sulfonyl” refers to the group -SO 2 -
• sulfamoyl refers to the group -SO 2 -NH 2
• nitro refers to the group -NO 2
• nitrile or "cyano” refers to the group -CN
• the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C-C j defines the number of carbon atoms present from the integer "i" to the integer "j" inclusive.
• Ci-C 4 -alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
• alkyl stands for a hydrocarbon radical which may be linear, cyclic or branched, with single or multiple branching. If not otherwise indicated, the the alkyl group comprises 1 to 14 carbon atoms, exemplified by the term (Ci-Ci 4 )alkyl, preferably 1 - 12 carbon at- oms, exemplified by the term (Ci-Ci 2 )alkyl.
• alkyl stands for a linear or branched (with single or multiple branching) alkyl chain of 1 to 8 carbon atoms, exemplified by the term (d-C 8 )alkyl, more preferably of 1 to 6 carbon atoms exemplified by the term (Ci-C6)alkyl, and even more preferred of 1 to 4 carbon atoms exemplified by the term (d-C 4 )alkyl.
• (d-C 8 )alkyl is further exemplified by such groups as methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl; tert-butyl; n-pentyl; isopentyl; neopentyl; tert-pentyl; 2- or 3-methylpentyl; n-hexyl; isohexyl, heptyl, octyl and the like.
• Any alkyl group, in particular the (Ci-C 8 )alkyl group, may be partially unsaturated, forming such alkenyl or alkynyl groups as, for example, vinyl, propenyl (allyl), butenyl, pentenyl, pentynyl, 1-butynyl, 2-butynyl,hexenyl, octadienyl, and the like.
• alkyl further comprises cycloalkyl groups; in particular, the the (Ci-C 8 )alkyl group comprises cyclo(C 3 - C 8 )alkyl groups which refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and isomeric forms thereof such as methylcyclopropyl; 2- or 3-methylcyclobutyl; 2-, or 3-methylcyclopentyl, and the like.
• the cycloalkyl group may also be partly unsaturated, forming such groups as, for example, cyclohexenyl, cyclopentenyl, cyclooctadienyl, and the like.
• alkyl pin particular the terms "(Ci-Ci 2 )alkyl” and "(d- Ci 4 )alkyl”
• alkyl comprise cycloalkyl-alkyl groups comprising 4 to 12 carbon atoms, preferably "- (Ci-d)alkyl-cyclo(C 3 -C 8 )alkyl” which refers to an alkyl group of 1 to 4 carbon atoms as described above substituted with a cyclo(C 3 -C 8 )alkyl group as described above, forming such groups as for example cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl or cyclohexenylethyl.
• (d-d2)alkyl and “(d-d 4 )alkyl” further comprise bicyclic ring systems of 6 to 10 carbon atoms, preferably Bicyclo[2.1.1]hexyl, Bicyclo[2.2.1]heptyl, Bicyclo[3.2.1]octyl, Bicyclo[2.2.2]octyl, Bicyclo[3.2.2]nonanyl, Bicyclo[3.3.1]nonanyl, Bicy- clo[3.3.2]decanyl; and the like, preferably Bicyclo[2.2.1]heptyl, and fused ring systems of up to 10 carbon atoms such as adamantyl, noradamantyl and the like.
• the alkyl group may optionally be substituted by 1 , 2, 3, 4 or 5, more preferably 1 , 2 or 3 substituents independently selected from the group consisting of halogen, hydroxyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cyclohet- eroalkyl, thiol, nitro, nitrile, alkoxy, aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, acyl, carboxyl, and acylamino, as defined herein. These groups may be attached to any carbon atom of the alkyl moiety.
• alkoxy refers to a group -O-alkyl, wherein the alkyl chain may be optionally further substituted as defined herein.
• alkoxy refers to -O-(Ci-Ce)alkyl (or (Ci-C 6 )alkoxy), with the (Ci-C 6 )alkyl group as defined above and optionally substituted with 1 , 2 or 3 hydroxyl groups.
• aryloxy refers to a group -O-Ar, where Ar represents aryl as defined herein, which is optionally substituted in the aryl group with one or more independently selected substituents as defined herein, in particular hydroxyl, halogen, (d-C 4 )alkyl, (d-C 4 )alkoxy, halogenated (Ci-C 4 )alkyl, or halogenated (Ci-C 4 )alkoxy; the number of said substituents being 1 , 2, 3 4 or 5 for halogen, and 1 , 2 or 3 for any combination of said other substituents.
• aryloxy refers to phenoxy, optionally substituted as defined above.
• arylalkyloxy refers to a group -O-alkyl-Ar, preferably -O-(CrC 4 )alkyl-Ar, wherein Ar represents aryl, which is optionally substituted in the aryl group with one or more independently selected substituents as defined herein, in particular hydroxyl, halogen, (Ci-C 4 )-alkyl, (Ci-C 4 )-alkoxy, halogenated (Ci-C 4 )alkyl, or halogenated (Ci-C 4 )alkoxy; the number of said substituents being 1 , 2, 3 4 or 5 for halogen, and 1 , 2 or 3 for any combination of said other substituents.
• arylalkyloxy refers to benzyloxy, optionally substituted as defined above.
• amino refers to a nitrogen atom that may be either terminal or a linker between two other groups, wherein the group may be a primary, secondary or tertiary (two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogen atom, respectively) amine.
• amino refers to the group - NRR', where R and R' are residues as particularly defined herein, and may independently be hydrogen, optionally substituted alkyl, optionally substituted aryl or aryl-alkyl, or optionally substituted heteroaryl or heteroaryl-alkyl, each as defined herein.
• acylamino refers to the group -NR-CO-R', where R and R' are residues as particularly defined herein, and may independently be hydrogen, option- ally substituted alkyl, optionally substituted aryl or aryl-alkyl, preferably aryl-(Ci-C 4 )alkyl, or optionally substituted heteroaryl or heteroaryl-alkyl, preferably heteroaryl-(Ci-C 4 )alkyl, each as defined herein.
• acylamino refers to -NH-CO-(Ci-C 4 )-alkyl.
• sulfonamide refers to the group -SO 2 -NRR', wherein R and R' are residues as particularly defined herein, and may independently be selected from hydrogen or (d- C 4 )alkyl.
• Halogenated alkyl, halogenated alkoxy and halogenated alkylthio are substituents in which the alkyl moieties (preferably (Ci-C 6 )alkyl, more preferred (Ci-C 4 )alkyl, and most preferred methyl) are substituted either partially or in full with halogens, generally with chlorine and/or fluorine.
• Preferred examples of such substituents are trifluoromethyl, trifluoromethoxy, trifluoromethylthio, dichloromethyl, pentafluoroethyl, dichloropropyl, fluoromethyl and difluoromethyl.
• cycloheteroalkyl refers to a 4, 5, 6, 7 or 8 membered heterocyclic ring containing at least one heteroatom, such as N, O or S, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2, which system may be saturated, partly unsaturated or hydroaromatic, and which ring can be part of a multiple condensed ring-system in which some rings may be aromatic.
• Preferred examples of such cycloheteroalkyl groups are pyrrolidinyl, morpholinyl, tetrahydrofuryl, piperidinyl or azepanyl.
• cycloheteroalkyl-alkyl refers to an alkyl group substituted with up to three independently selected cycloheteroalkyl groups; preferably the term “cycloheteroalkyl-alkyl” refers to "cycloheteroalkyl-(Ci-Ci 4 )alkyl", “cycloheteroalkyl-(Ci-Ci 2 )alkyl", “cycloheteroal- kyl-(Ci-C 8 )alkyl” or “cycloheteroalkyl-(Ci-C 4 )alkyl", wherein the cycloheteroalkyl moiety is as defined herein, preferably cycloheteroalkyl is piperidinyl, pyrrolidinyl, or morpholinyl, forming such groups as for example morpholinylethyl, morpholinylpropyl, piperidinylethyl or pyrrolidinylethyl.
• the cycloheteroalkyl group may optionally be substituted by 1 , 2 or 3 substituents, independently selected from the group consisting of oxo, alkyl, optionally substituted aryl or aryl-(Ci-C 4 )-alkyl, hydroxyl, (Ci-C 6 )alkoxy, halogenated (Ci-C 6 )alkyl, halogenated (d- C 6 )alkoxy, carboxyl-(CrC 6 )alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy, (Ci-C 6 )alkylthio, arylthio or arylalkylthio, amino, amido, acyl, and acylamino, as defined herein.
• the substituents of the cycloheteroalkyl groups may be attached to any carbon atom of the
• aryl refers to an aromatic carbocyclic group comprising 6 to 14, more preferably 6 to 10 carbon atoms and having at least one aromatic ring or multiple con- densed rings in which at least one ring is aromatic.
• aryl is phenyl, naphthyl, in- danyl, indenyl, fluorenyl or 1 ,2,3,4-tetrahydro-naphthalen-1-yl or biphenyl.
• arylalkyl refers to an alkyl group substituted with up to three independently se- lected aryl groups; preferably the term “arylalkyl” refers to "aryl-(Ci-Ci 4 )alkyl” and “diaryl- (Ci-Ci 4 )alkyl", “aryl-(Ci-Ci 2 )alkyl” and “diaryl-(Ci-Ci 2 )alkyl", “aryl-(Ci-C 8 )alkyl” and “diaryl- (Ci-C 8 )alkyl", "aryl-(Ci-C 4 )alkyl” and “diaryl-(Ci-C 4 )alkyl", respectively, wherein the aryl is as defined herein, preferably aryl is phenyl or naphthyl, forming such groups as for example benzyl, diphenylmethyl, phenethyl, phenylpropyl
• the alkyl chain may be further substituted as defined above; for example the alkyl chain may carry an additional hydroxyl group. Furthermore, the alkyl chain may be partially unsaturated, such as a vinyl group. The aryl moiety may optionally be substituted as defined herein.
• heteroaryl refers to an aromatic carbocyclic group of having a single 4, 5, 6, 7 or 8 membered ring or multiple condensed rings comprising 6 to 14, more preferably 6 to 10, ring atoms and containing at least one heteroatom selected from N, O and S, within at least one ring, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2; in which group at least one heterocyclic ring is aromatic.
• Examples of such groups include pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazo[2,1-b][1 ,3]thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridaz- inyl, 1 ,3,5-triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, purinyl, quinolinyl, isoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, benzothiazolyl, benzimidazolyl, 1 ,3-dihydro-benzoimidazolyl, benzofuryl, benzo[b]thienyl and the
• het- eroaryl is quinolinyl, furyl, benzoimidazolyl, pyridinyl, thienyl, indolyl, benzo[b]thiophene, pyridinyl, imidazolyl, pyrazolyl or thiazolyl.
• heteroaryl-alkyl refers to an alkyl group substituted with up to three independently selected heteroaryl groups; preferably the term “heteroaryl-alkyl” refers to "het- eroaryl-(Ci-Ci 4 )alkyl", “heteroaryl-(Ci-Ci 2 )alkyl", “heteroaryl-(Ci-C 8 )alkyl” and “heteroaryl- (Ci-C 4 )alkyl", wherein the heteroaryl is as defined herein, preferably heteroaryl is furyl, indolyl, benzoimidazolyl, pyridinyl, thienyl or imidazolyl, forming such groups as for example benzoimidazolylmethyl, pyridinylmethyl, thienylmethyl, furylmethyl, indolylethyl, thienylethyl, pyridinylethyl, or imidazo
• the heteroaryl moiety may optionally be substituted as defined herein.
• the aryl and the heteroaryl group may optionally be substituted by one or more substitu- ents independently selected from the group consisting of halogen, hydroxyl, (Cr C 6 )alkoxy, (CrC 6 )alkyl, halogenated (CrC 6 )alkyl, halogenated (CrC 6 )alkoxy, carboxyl- (Ci-C6)alkyl, oxo, thiol, nitro, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalky- loxy, (Ci-C 6 )alkylthio, arylthio or arylalkylthio, alkylsulfonyl, arylsulfonyl, amino, amido, acyl, and acylamino, as defined herein, the number of said substitu
• the heteroaryl group may further be optionally substituted with an aryl group, which may be optionally substituted in the aryl moiety with independently selected substituents as defined herein.
• the aryl group may further be optionally substituted with a heteroaryl group or a second aryl group.
• the aryl may be further substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7 or 8 mem- bered ring system, optionally containing 1 , 2 or 3 heteroatoms selected from the group consisting of N, O and S, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2.
• the two groups which are attached to adjacent carbon atoms are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing 1 , 2 or 3 heteroatoms selected from the group consisting of N and O, the number of N atoms being 0, 1 , 2 or 3 and the number of O atoms being 0, 1 or 2.
• This cyclic ring system may optionally be further substituted by one or two oxo group.
• Preferred examples of such a substituted aryl groups are benzo[1 ,3]dioxol and 1 ,3-dihydro- benzoimidazol-2-one.
• heterocyclic ring systems including the N, to which the respective side chains are attached, comprise:
• heterocyclic ring or ring system is optionally substituted by 1 , 2 or 3 substituents, which can be attached to any carbon or nitrogen atom of the heterocyclic ring system.
• substituted heterocyclic ring systems are:
• the optional 1 , 2 or 3 independently selected substituents for the heterocyclic ring system may be chosen among optionally substituted alkyl, halogen, hydroxyl, oxo, thiol, nitro, ni- trile, (Ci-C 6 )-alkoxy, aryl, heteroaryl, optionally substituted cycloheteroalkyl, aryloxy, ary- lalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, acyl, car- boxyl, and acylamino, as defined herein, whereby all aryl or heteroaryl moieties may be optionally substituted with 1 , 2, 3, 4 or 5, preferably 1 , 2 or 3 independently selected sub- stituents as defined herein.
• the aforementioned heterocyclic ring system may be substituted by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4, 5, 6, 7, or 8 membered ring system, optionally containing 1 , 2 or 3 heteroatoms, selected from the group consisting of N, O and S, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2.
• This cyclic ring system may optionally be further substituted by up to three substitutents independently selected from oxo, (Ci-C 6 )-alkyl, aryl, preferably phenyl, and aryl-(CrC 4 )-alkyl, preferably benzyl.
• Preferred examples of such substituted heterocyclic ring systems are 1 ,4- dioxa-8-aza-spiro[4.5]decane, 1 ,3,8-triaza-spiro[4.5]decane, 1 ,3,8-triaza-spiro[4.5]decan- 4-one, 1-Phenyl-1 ,3,8-triaza-spiro[4.5]decane, and 1-Phenyl-1 ,3,8-triaza-spiro[4.5]decan- 4-one.
• prodrug represents derivatives of the compounds of the invention that are drug precursors which, following administration to a patient by any known route, release the drug in vivo via a chemical or physiological process.
• pro-drug include metabolic precursors.
• Pro-drugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (Medicinal Chemistry: Principles and Practice, 1994, Ettmayer et al. [2004], Stella P [2004]).
• pro-drugs are derivatives of the com- pounds of the invention in which functional groups carry additional substituents which may be cleaved under physiological conditions in vivo and thereby releasing the active principle of the compound (e. g., a pro-drug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form).
• Pro-drugs of the compounds mentioned above are also within the scope of the present invention.
• Pro-drugs that are metabolised to compounds having formula (I) belong to the invention.
• the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
• this relates to com- pounds with primary or secondary amino or hydroxy groups.
• Such compounds can be re-acted with organic acids to yield compounds having formula (I) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an O- (acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
• pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well-known in the art.
• the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting compounds of the invention with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.
• metabolites refers to active compounds derived from catabolism of a compound of formula I upon introduction into a biological milieu, such as a human.
• metabolism includes primary metabolites as well as secondary metabolites of a compound of formula I.
• solvates pertains to the association of suitable organic solvent molecules with molecules or ions of a compound of formula I.
• solvates refers both to stable solvates, containing a defined number of solvent molecules pro molecule of a compound of formula I, and inclusion complexes, which are less stable and contain a variable number of solvent molecules pro molecule of a compound of formula I.
• composition as used herein is intended to encompass a product comprising the specified ingredients in the predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• (therapeutically) effective amount refers to an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e. g., provide a positive clinical response).
• the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. Thus, it is not useful to specify an exact effective amount in advance.
• treatment refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1 ) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it, (2) inhibiting the disease or condition, i.e., arresting its development, (3) relieving the disease or condition, i.e., causing regression of the condition, or (4) relieving the conditions caused by the disease, i.e., stopping the symptoms of the disease.
• medical therapy as used herein is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
• subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
• the compounds of the invention are primarily intended for treatment in a mammal, preferably in humans and other primates, of steroid hormone dependent diseases or disorders, in particular estradiol dependent diseases or disorders, wherein the steroid hormone dependent disease or disorder preferably requires the inhibition of a 17 ⁇ -HSD enzyme, preferably the 17 ⁇ -HSD1 , 17 ⁇ -HSD2 or 17 ⁇ -HSD3 enzyme.
• the compounds may be administered orally, dermally, parenterally, by injection, by pulmonal or nasal delivery, or sublingually, rectally or vaginally in dosage unit formulations.
• administered by injection includes intravenous, intraarticular, intramuscular (e.g. by depot injection where the active compounds are released slowly into the blood from the depot and carried from there to the target organs), intraperitoneal, intradermal, subcutaneous, and intrathecal injections, as well as use of infusion techniques.
• Dermal administration may include topical application or transdermal administration.
• One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable auxiliaries such as excipients, adjuvants (e.g.
• buffers such as, but not limited to, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styl, sulfate, styl, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene,
• the pharmaceutical composition may be formulated for example as immediate release, sustained release, pulsatile release, two or more step release, depot or other kind of release formulations.
• auxiliaries as well as further suitable diluents, flavorings, sweetening agents, coloring agents etc. may be used, depending on the intended mode of administration as well as particular characteristics of the active compound to be used, such as solubility, bioavailability etc.
• Suitable auxiliaries and further ingredients may be such as recommended for pharmacy, cosmetics and related fields and which preferably are listed in the European Pharmacopoeia, FDA approved or cited in the "GRAS" list (FDA List of food additives that are 'generally recognized as safe' (GRAS)).
• One mode of application of the compounds of general formula (I) or of pharmaceutical compositions comprising one or more of said compounds is oral application, e. g., by tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixiers, solid emulsions, solid dispersions or dispersible powders.
• the compounds suitable for the purposes of the present invention as defined above can be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars, gelatine, surface-active agents, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents, solubility enhancers or bioavailability enhancers.
• the active ingredients may also be dispersed in a microparticle, e. g. a nanoparticulate, composition.
• the active agents can be dissolved or suspended in a pharmaceutically acceptable diluent, such as, e. g., water, buffer, oils, with or without solubilizers, surface-active agents, dispersants or emulsifiers. More generally spoken, for parenteral administration the active agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.
• a pharmaceutically acceptable diluent such as, e. g., water, buffer, oils, with or without solubilizers, surface-active agents, dispersants or emulsifiers.
• Transdermal application can be accomplished by suitable patches, as generally known in the art, specifically designed for the transdermal delivery of active agents, optionally in the presence of specific permeability enhancers. Furthermore, also emulsions, ointments, pastes, creams or gels may be used for transdermal delivery.
• intravaginal devices e. g. vaginal rings
• IUS intrauterine systems
• the compounds may also be administered in the form of suppositories.
• These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
• a depot implant comprising an inert carrier material, such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber.
• an inert carrier material such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber.
• Such implants are designed to release the active agent in a controlled manner over an extended period of time (e.g. 3 to 5 years).
• the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the actual dosages of the agents of this invention for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the particular composition formulated, the mode of administration, time of administration, route of administration and the particular site, host, and disease being treated, and furthermore the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
• the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days
• Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound.
• an exemplary daily dose generally employed will be from about 0.01 ⁇ g/kg to about 100 mg/kg of total body weight, whereby courses of treatment may be repeated at appropriate time intervals.
• Administration of pro-drugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active compounds.
• the daily dosage for parenteral administration will generally be from about 0.01 ⁇ g/kg to about 100 mg/kg of total body weight.
• a daily rectal dosage regimen will generally be from about 0.01 ⁇ g/kg to about 200 mg/kg of total body weight.
• a daily vaginal dosage regimen will generally be from about 0.01 ⁇ g/kg to about 100 mg/kg of total body weight.
• the daily topical dosage regimen will generally be from about 0.1 ⁇ g to about 100 mg administered between one to four times daily.
• the transdermal concentration will generally be that required to maintain a daily dose of from 0.01 ⁇ g/kg to 100 mg/kg of total body weight.
• the general structure formulas are typically designated with a number in roman format, followed by ⁇ or ⁇ indicating the stereochemistry at the C15 atom of the estrone core if necessary. If the number of methylen groups attached at the C15 position is specified (i.e. the value of "n"), the roman number plus ⁇ or ⁇ is followed by a hyphen and a number in- dicating the amount of methylen groups. This "number" is set in parantheses.
• the prefix C2 in front of the parantheses indicates that the compound may be substituted in C2 by a residue R 11 .
• a prefix F, F in front of the number indicates that the -CO- function in C17 may be replaced by -CF 2 -.
• a modification of the C3 hydroxy function is designated in the compound formula following the parantheses.
• compound IV is the general acid building block:
• a compound IV ⁇ -3 would represent a derivative of IV with ⁇ stereochemistry at C15 and three methylen groups, i.e.:
• a compound C2-(IV ⁇ -3) would represent a derivative of IV with ⁇ stereochemistry at C15, three methylen groups and a substituent in C2, i.e.:
• a compound F,F-C2-(IV ⁇ -3) would represent a derivative of IV with ⁇ stereo- chemistry at C15, three methylen groups, a substituent in C2 and a difluoro group in C17 position, i.e.:
• a compound F,F-C2-(IV ⁇ -3)-B(OH) 2 would represent a derivative of IV with ⁇ stereochemistry at C15, three methylen groups, a substituent in C2, a difluoro group in C17 position and a boronic acid group in C3 position, i.e.:
• the compounds of the present invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are pre- sented to aid the reader in synthesizing the 17 ⁇ -HSD1 , 17 ⁇ -HSD2 and/or 17 ⁇ - HSD3inhibitors, with specific details provided below in the experimental section to illustrate working examples.
• the compounds of the present invention are characterized by replacement of the C3 hydroxy function of the steroidal core with a boronic acid, carboxylic acid, carbo- amide, amino, amide or sulphonamide moiety.
• R 1 , R 2 , R 11 , R 12 , R 13 , X, A and Y have the meanings as defined herein, and PG is a common protecting group.
• Steps A The introduction of the R 11 substituent in C2 position - if present in the final compound - has to take place first, starting from the 17 ⁇ -estradiol using methods well known in the art (Steps A).
• the C17-OH function is oxidized to the corresponding keto function.
• a suitable protecting group may be introduced at this point in order to protect the oxygen in C3 position.
• the estrone derivative of formula (V) is converted into the central intermediate, the 15, 16-unsatu rated estrone of formula X (Steps B), which is fur- ther derivated in the C15 position by introduction of the basic side chain ("so called building blocks").
• Steps C These building blocks are reacted with the appropriate compounds carrying the R 2 /R 4 substitutents to lead to the desired C15 substituted compound (Steps C). I fde- sired, the obtained educt may be further modified within the C17 position by replacement of the oxygen with a difluoro group (Steps D). Finally, the protection group in C1 position is substituted with an alternative R 1 side chain to deliver the compounds of the invention (Steps E).
• R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , X, A and Y have the meanings as defined herein, and PG is a common protecting group, and wherein any reactive group, especially in the C15 side chain, might be optionally protected by a conventional protecting or otherwise non- participating group if necessary, also if not explicitly indicated within this scheme.
• Steps A In parallel, the C17-OH function is oxidized to the corresponding keto function.
• a suitable protecting group may be introduced at this point in order to protect the oxygen in C3 position.
• the estrone derivative of formula (V) is converted into the central intermediate, the 15, 16-unsatu rated estrone of formula X (Steps B), which is further derivated in the C15 position by introduction of the basic acid, alcohol, amid or al- kenyl side chain delivering the so called building blocks (Steps C(I)).
• the difluoro group might be introduced into C17 position of the steroidal core (Step D).
• the boronic acid or carboxylic acid or amino group in C3 position might be introduced (Step E).
• Steps C(II) The so-obtained building blocks are reacted with the appropriate compounds carrying the R 2 /R 4 substitutents to lead to the desired C15 substituted compound (Steps C(II)). Finally, the protection group in C1 position is substituted with an alternative R 1 side chain to deliver the compounds of the invention (Steps E) or any still necessary modifications at the C3 position are carried out.
• Step A Introduction of a R 11 side chain in C2 position of 17 ⁇ -Estradiol or Estrone
• R has the meanings as defined herein, and PG is a common protecting group.
• estrone core The introduction of various side chains in the estrone core is known from the literature, e.g. Rao et al (2002) describe the synthesis of 2-methoxyestradiol, and the synthesis of 2- ethoxy-estradiol was disclosed by Verdier-Pinard et al (2000).
• 2-Ethyl-estrone may be prepared from estrone by Friedel-Crafts acetylation of estrone-3-O-methyl ether and catalytic hydrogenation, followed by demethylation, which produced the desired product.
• the newly introduced hydroxy group may be further alkylated, followed by reduction of the ketone, resulting in an alkoxy-alkyl substituted estradiol derivative.
• An alternative strategy to introduce an alkoxy-alkyl group is exemplified for the methoxy-ethyl group: After MOM-protection of the 17 ⁇ -estradiol, the MOM-protected estradiol is iodi- nated [Mohanakrishnan & Cushman (1999)]. Then, the MOM-group is replaced with a TBDMS group. Negishi coupling with allylbromide gives the 2-allyl substituted estrone derivative, which can be oxidised and methylated (including some protective group manipulations).
• estrone or estradiol derivatives have been displayed previously [see e.g. Mohanakrishnan & Cushman (1999); Day et al. (2003); Cushman et al (1995), and Lunn & Farkas (1968)]
• the synthesis of further estrone derivatives with various substituents in 2-position was disclosed by Cushman et al (2002).
• the 3-hydroxy function of the steroidal core is typically protected with a methyl or benzyl group (exemplified by PG).
• PG methyl or benzyl group
• the methyl derivative can be prepared using MeJ and acetone, whereas the corresponding Benzyl-derivative may be prepared using Benzylbromid, DIPEA and acetone.
• Step B Synthesis of the 15, 16-unsaturated Estrone of formula X (Intermediate I)
• the "Step B" reaction was fully disclosed in international patent applications WO2005/047303 for estrone and WO2006/125800 for C2 substituted estrone derivatives.
• the ketal of the formula (IX) can be prepared according to Nambara [Nambara et al. (1976)] as depicted within the following SCHEME 1. If not yet protected, the introduction of PG groups in C3 position can be achieved according to a procedure described by Labaree (2003).
• the enone intermediate of formula X can be prepared from the correspond- ing estrone derivative according to a procedure described by Poirier et al. (1991 ).
• Step C Introduction of the side chain in C15 position
• Step C the introduction of the side chain in C15 position - is carried out in two major steps:
• a first step C(I) the 15, 16-unsaturated Estrone of formula X is converted into a so-called building block carrying an alkyl side chain in C15 position with a terminal amino, carboxy, or alcohol function.
• the synthesis of some exemplary building blocks is depicted in the Experimental Section "Intermediates", and was fully disclosed for nearly all kinds of building blocks in international patent application WO2005/047303 for estrone and WO2006/125800 for C2 substituted estrone derivatives. How to obtain es- trone intermediates with azide or alkine side chain in C15 position was disclosed within unpublished International patent application PCT/EP2007/059785.
• the second step C(II) of the "Step C” modification - the conversion of the building blocks into the desired derivatives carrying the complete side chain in C15 position - is exempli- fied below by using one of the following synthetic schemes as shown in Flow Diagrams I to XV. Again, the synthesis of some exemplary intermediates or even final compounds of formula (I) carrying particular side chains is depicted in the Experimental Section "Inter- mediates” or under “Examples”. The synthesis of a variety of different C15 side chains was fully disclosed in international patent application WO2005/047303 for estrone and WO2006/125800 for C2 substituted and/or C17 modified estrone derivatives.
• Certain formula I compounds in which X-A-Y represents -CO-NH- or -CO-NR 4 - and n represents an integer from 0 to 5, may be prepared by a reaction as shown in Flow Diagram Ia.
• W represents R 1 or -O-PG
• R 1 , R 2 , R 4 , R 11 , R 12 and R 13 have the meanings as defined herein
• PG is a common protecting group.
• the free acid (IV) may be converted to the reactive acyl halide, in particular the acid chloride, by reaction with SOCb, COCI 2 , PCI 5 or PBr 3 Or the like.
• the amide derivatives C2-(VI) may be prepared by a base catalyzed addition-elimination reaction, where the halogen residue is substituted with the appropriate amine R 2 NH 2 or R 2 NHR 4 in the presence of a base, for example DIPEA.
• the amide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appropriate amine.
• the amide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appropriate amine as shown in Flow Diagram Ib:
• ester derivatives C2-(VII) may be prepared from the free acid (IV) by esterification with the appropriate alcohol R 2 -OH.
• W represents R 1 or -O-PG
• R 1 , R 2 , R 11 , R 12 and R 13 have the meanings as defined herein
• PG is a common protecting group.
• the alcohol (XXXI) may be converted to the corresponding aldehyde (XXXIII) via Dess-Martin Oxidation. Subsequently the aldehyde may be converted by a nucleophilic addition-elimiation reaction with a Grig- nard or other organometallic reagent, substituted with the appropriate R2 residue to the corresponding secondary alcohol (XXI), which thereafter can be oxidized again to the desired ketone C2-(VIII).
• Certain formula I compounds in which -X-A-Y- represents -CO-NH-NR 4 - or -CO-NH- NH-, and n represents an integer from 0 to 5, may be prepared by a reaction as shown in Flow Diagram IVa.
• W represents R 1 or -O-PG
• R 1 , R 2 , R4,R 11 , R 12 and R 13 have the meanings as defined herein
• PG is a common protecting group.
• the free acid (IV) may be converted to the reactive acyl halide, in particular the acid chloride, by reaction with SOCI 2 , COCI 2 , PCI 5 or PBr 3 Or the like.
• the hydrazide derivatives C2-(XLI) is then prepared by a base catalysed addition-elimination reaction, where the halogen residue is substituted with the appropriate hydrazine H 2 N-NHR 2 or H 2 N-NR 2 R 4 in the presence of a base, for example DIPEA.
• a base for example DIPEA.
• the hydrazide derivatives may be prepared directly from the free acids by nucleophilic substitution with the ap- intestinalte hydrazine using e.g. polymer bound carbodiimid, HOBT and DCM, as shown in Flow Diagram IVb:
• W represents R 1 or -O-PG
• R 1 , R 2 , R 4 , R 11 , R 12 and R 13 have the meanings as defined herein, and PG is a common protecting group.
• Certain formula I compounds in which -X-A-Y- represents -NH-CO-NH-, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram Va: wherein W represents R 1 or -O-PG, and R 1 , R 2 and R 11 have the meanings as defined herein, and PG is a common protecting group.
• the amine may be first reacted with car- bodiimidazol or triphosghen to form a reactive carbamoyl compound, which than can react further with a suitable amine R 2 R 4 -NH.
• W represents R 1 or -O-PG
• R 1 , R 2 , R 3 , R 4 , R 11 , R 12 and R 13 have the meanings as defined herein, and PG is a common protecting group.
• Certain formula I compounds in which -X-A-Y- represents -NH-SO 2 -NH-, and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram Vl wherein W represents R 1 or -O-PG, and R 1 , R 2 and R 11 have the meanings as defined herein, and PG is a common protecting group.
• the amine building block (XV) may be converted into a protected, for example Boc-protected, sulfamide compound by a reaction with the appropriately protected chlorosulfonyl isocyanate.
• the protected sulfamide compound is allowed to react with the appropriate Bromo-reagent (R 2 -Br) to provide the still protected, substituted sulfamide derivative of the formula (XVIII). After deprotection, the desired N-substituted sulfamide derivative of formula C2-(XIX) is obtained.
• W represents R 1 or -O-PG
• R 1 , R 2 and R 11 have the meanings as defined herein
• PG is a common protecting group.
• the sulfamate derivatives of the general formula C2-(XXII) may be prepared by the reaction of the amine building block (XV) with an appropriate chlorosulfonic acid ester (R 2 -O-SO 2 -CI). After the addition-elimination reaction, in a second step the ketal function is converted into the keto function.
• the "retro"-amide derivatives of the gen- eral formula C2-(XXIII) may be prepared by the reaction of the amine building block (XV) with an appropriate acid halide, e.g. an acid chloride (R 2 -CO-CI). After the addition- elimination reaction, in a second step the ketal function is converted into the keto function. Alternatively, the reaction with an appropriate acid halide, e.g.
• an acid chloride (R 2 -CO- Cl)
• R 2 -CO- Cl an acid chloride
• XXIX the amino-hydrochloride salt of the estrone
• IXb Flow Diagram IXb: wherein W represents R 1 or -O-PG, and R 1 , R 2 , R 11 , R 12 and R 13 have the meanings as defined herein, and PG is a common protecting group.
• the sulfonamide derivatives of the general formula C2-(XXIV) may be prepared by the reaction of the amine building block (XV) with an appropriate sulfonic acid halide, e.g. a sulfonic acid chloride (R2-SO 2 -CI). After the addition-elimination reaction, in a second step the ketal function is converted into the keto function.
• the reaction with an appropriate sulfonic acid halide, e.g. sulfonic acid chloride (R 2 -SO 2 -CI) can be performed using the amino-hydrochloride salt of the es- trone (XXIX) as starting material as shown in the following Flow Diagram Xb:
• W represents R 1 or -O-PG
• R 1 , R 2 , R 11 , R 12 and R 13 have the meanings as defined herein
• PG is a common protecting group.
• Certain formula I compounds in which -X-A-Y- represents -O-CO- and n represents an integer from 1 to 6, may be prepared by a reaction as shown in Flow Diagram XIII: wherein W represents R 1 or -O-PG, and R 1 , R 2 , R 11 , R 12 and R 13 have the meanings as defined herein, and PG is a common protecting group.
• the "retro"-ester derivatives of the general formula C2-(XXVII) may be prepared by the esterification of the estrone alcohol building block (XXXI) with the appropriate carboxylic acid R 2 -COOH and subsequent purification.
• the sulfonylcarbamate derivatives of the general formula C2-(XXVIII) may be prepared by a two-step synthesis: In a first step, the estrone alcohol building block (XXXI) is converted to the chlorosulfonylcar- bamate intermediate by reaction with chlorosulfonyl isocyanate. Subsequently, the intermediate is allowed to react with the appropriate primary or secondary amine HNR 2 R 4 in in order to give the desired sulfonylcarbamate derivative.
• ether derivatives may be prepared by derivatisation of the corresponding alcohol of the general formula (XXXI).
• R 311 has the meaning as defined herein, and PG is a common protecting group.
• W represents R 1 or -O-PG
• R 1 , R 2 , R 11 , R 12 and R 13 have the meanings as defined herein
• PG is a common protecting group.
• the synthesis of the C15 substituted azide derivate might be achieved by conventional synthesis methods as already de- picted within international patent application WO2005/047303, in patent application WO2006/125800, in unpublished International patent application PCT/EP2007/059785 and as described herein in the "intermediates" section.
• the coupling of the azide with a terminal alkinyl delivering the desired triazole derivatives may be carried out by using a method for the formation of 1 ,4 disubstituted triazoles well known to one skilled in the art of organic synthesis (see e.g. WO2006/063585 and WO2003/101972 and references cited therein).
• R 11 , R 12 and R 13 have the meanings as defined herein, and PG is a common pro- tecting group.
• the synthesis of the C15 substituted alkine derivate might be achieved by conventional synthesis methods by coupling the respective 15,16-unsaturated estron with the corresponding alkine compound in a Grignard reaction (e.g. as depicted within international patent application WO2005/047303, in patent application WO2006/125800, and unpublished International patent application PCT/EP2007/059785). Then the triazoles are prepared from the alkine substituted estron derivate and the corresponding R2 halides via in situ generated azides (as depicted in unpublished International patent application PCT/EP2007/059785). The one pot synthesis for specific aryl triazoles is described in detail in Andersen et al. (2005).
• the aim of this step is the difluorination of the C17 carbonyl function to obtain one of the following intermediate compounds according to reaction SCHEMES 2 or 3: SCHEME 2
• the difluorination of the C17 atom of the estrone core is a reaction well known in the art and was already disclosed in US patents US 3,413,321 and US 3,347,878. Furthermore, the difluorination of the C17 atom of the estrone core may be achieved using the DAST (N,N-diethylaminosulfur trifluoride) reagent [Liu et al (1992)].
• DAST N,N-diethylaminosulfur trifluoride
• the compounds of the present invention are characterized by replacement of the C3 hydroxy function of the steroidal core by a boronic acid, carboxylic acid, carboamide, amino, amide or sulphonamide moiety, i.e. the compounds of formula (I) carry a R 1 residue represented by
• This substitution step E is carried out with the building blocks as starting material and/or after introduction of the finally desired C15 side chain (step C(II)) as depicted in the following SCHEME 4:
• step E(a) Introduction of a boronic acid or boronic ester group in C3 position
• the step E(a) reaction to obtain a steroid derivative in which the 3-OH of estrone is replaced by B(OH) 2 can be achieved according to the protocol disclosed by Ahmed et al (2006) and as displayed in the following SCHEME 5:
• a steroid de- rivative was converted into the corresponding C3 triflate [obtainable e.g. as described in Li et al (1995) or as described herewithin in the section Intermediates "Step E"].
• the estrone triflate was reacted with pinacolborane in the presence of a palladium catalyst to give the corresponding boronate ester.
• Subsequent reaction of the ester with NalO4 in ammonium acetate/water for several days gave the desired boronic acid compound.
• the borone cross-coupling can be achieved by coupling with either bis(pinacolato)diborone or bis(neopentylgluconato)diboron at 100 0 C for 14h, or with pinacolborane in the presence of 10% DMSO.
• Saponification of the boronic acid can also be achieved with LiOH or in 3N HCI under addition of phenylboronic acid (coated on polymer).
• the pinacolyl boronate ester is converted into the corresponding po- tassium trifluoroborate salt through treatment with excess potassium hydrogen fluoride, and subsequently treatment of the potassium trifluoroborate salt i with trimethylsilyl chlo- ride in water/acetonitrile mixture afforded the free boronic acid [Yuen & Hutton (2005)].
• the exact conditions may vary depending on the actual substitution of the steroid core.
• the C3 triflate of the estrone derivative is directly reacted with a borane ester delivering the desired compounds, whereas the second alternative uses the pathway described in SCHEME 5 and subsequent esterification of the free boronic acid.
• step E(b) Introduction of a carboxylic acid group in C3 position
• the step E(b) reaction to obtain a steroid derivative in which the 3-OH of estrone is replaced by -CO-O-R 6 , wherein R 6 has the meaning as defined herewithin, can be achieved according to the protocol disclosed by Lesma et al (2006) and variations thereof as displayed in the following SCHEME 6B:
• a steroid derivative was converted into the corresponding C3 triflate (step A) [obtainable e.g. as described in Li et al (1995) or as described herewithin in the section Intermediates "Step E"].
• alkoxycarbonylation of the substituted steroid tri- flates is carried out using palladium (0) as metal catalyst (in situ generated from Pd(II) and a suitable phosphine ligand) and Mo(CO) 6 as a commercially available, stable and solid carbon monoxide source in a microwave system.
• palladium (0) as metal catalyst (in situ generated from Pd(II) and a suitable phosphine ligand) and Mo(CO) 6 as a commercially available, stable and solid carbon monoxide source in a microwave system.
• the reaction is carried out in water, the corresponding carboxylic acids are directly available (step B(I)).
• step B(II) when adding the corresponding R 6 -OH alcohol in a suitable solvent, the corresponding carboxylic acid ester is obtained (step B(II)).
• the carboxylic acid is converted into the desired amide via a well known nucleophilic substitution reaction with the corresponding primary or secondary amine R 7 R 8 -NH as nucleophilic substituent carried out in a suitable aprotic solvent, in the presence of a suitable coupling reagent (e.g. HOBT) and/or a compound with a carbodiim- ide functionality (e.g. PS-Carbodiimide or EDCI) and an appropriate unreactive base if desired, added to activate the carboxylic acid.
• a suitable coupling reagent e.g. HOBT
• a compound with a carbodiim- ide functionality e.g. PS-Carbodiimide or EDCI
• First a steroid derivative is converted into the corresponding C3 triflate (step A) [obtainable e.g. as described in Li et al (1995) or as described here- within in the section Intermediates "Step E"].
• a suitable carbon monoxide source e.g. carrying out the reaction under CO atmosphere or, more convenient Mo(CO)6 as described above for SCHEME 6B
• step E(d) reaction to obtain a steroid derivative in which the 3-OH of estrone was replaced by -NR 7 R 8 , wherein R 7 and R 8 have the meanings as defined herewithin, can be achieved according to the protocol disclosed by Schoen et al (2005) and variations thereof as displayed in the following SCHEME 6D:
• First a steroid derivative is converted into the corresponding C3 triflate (step A) [obtainable e.g. as described in Li et al (1995) or as described herewithin in the section Intermediates "Step E"].
• the reaction is carried out in a micro- wave system using DMF as solvent.
• the secondary or tertiary amine can be subsequently hydrogenated to deliver the corresponding primary amine (step C).
• the amine is converted into the desired carbo amide via a well known nucleophilic substitution reaction with the corresponding carboxylic acid R 6 -COOH or carboxylic acid halide R 6 -CO-Hal carried out in a suitable aprotic, inert solvent.
• a carboxylic acid R 6 -COOH is used, the reaction has to be carried out in the presence of a suitable coupling reagent (e.g. HOBT) and/or a compound with a carbodiimide functionality (e.g. PS-Carbodiimide or EDCI) and an appropriate unreactive base if desired, to activate the carboxylic acid.
• a carboxylic acid halide R 6 -CO-Hal the reaction has to be carried out in the presence of an unreactive base, e.g. H ⁇ nig base.
• step E(f) Introduction of a sulphonamide amino group in C3 position
• the step E(f) reaction to obtain a steroid derivative in which the 3-OH of estrone is replaced with -NR 5 -SO 2 -R 6 , wherein R 5 and R 6 have the meanings as defined herewithin, can be achieved starting from the corresponding primary or secondary amine obtained according to SCHEME 6D as displayed in the following SCHEME 6F,
• the amine is converted into the desired sulphonamide via a well known nucleophilic substitution reaction with the corresponding sulfonic acid halide R 6 -S ⁇ 2 -Hal carried out in a suitable aprotic, inert solvent and in the presence of an unreactive base, e.g. H ⁇ nig base.
• concentration under reduced pressure refers to use of a Buchi or Heidolph rotary evaporator (“Rotavapor”) or vaccum centrifuges ("GeneVac” or "Christ alpha RVC”) at approximately 15 mm of Hg. All temperatures are reported uncor- rected in degrees Celsius ( 0 C). Unless otherwise indicated, all parts and percentages are by volume.
• Thin-layer chromatography was performed on Merck® pre-coated glass-backed sil- ica gel or aluminium sheets 6OA F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination (254 nm or 266 nm), (b) exposure to iodine vapor, (c) spraying of the plate with Schlittler's reagent solution followed by heating, (d) spraying of the plate with anisaldehyde solution followed by heating, and/or (e) spraying of the plate with Rauxz reagent solution followed by heating. Column chromatography (flash chromatography) was performed using 230-630 mesh ICN, SiliTech 6OA silica gel.
• Proton ( 1 H) nuclear magnetic resonance (NMR) spectra were measured with a Bruker ARX (400 MHz) or Bruker ADVANCE (500 MHz) spectrometer with either Me 4 Si ( ⁇ 0.00) or residual protonated solvent (CHCI 3 ⁇ 7.26; CHD 2 OD ⁇ 3.30; DMSOd 5 ⁇ 2.50) as standard.
• Carbon ( 13 C) NMR spectra were measured with a Bruker ARX (100 MHz) or Bruker ADVANCE (126 MHz) spectrometer with either Me 4 Si ( ⁇ 0.00) or solvent (CDCI 3 ⁇ 77.05; CD 3 OD ⁇ 49.0; DMSO-d 6 ⁇ 39.45) as standard.
• HPLC electrospray mass spectra were obtained using the following method and equipment: Samples were separated by reversed phase high pressure liquid chromatography (RP-HPLC) coupled to a quadrupol MS. HPLC was performed at a flow of 1000 ⁇ l/min using XterraMS C18 columns (i.d. 4.6 mm, length 50 mm, particle size 2.5 ⁇ m) or Phenomenex Luna C18(2) 30 * 4.6mm columns.
• 3-Benzyloxy-estra-1 ,3,5(10)-trien-2,17-diol can be prepared starting from estradiol by introduction of the hydroxy side chain in C2 position as described by Rao et al. (2002) in which a Fries rearrangement and a Baeyer Villiger reaction is used. Its detailed synthesis is displayed in international patent application WO2006/125800.
• 3-Benzyloxy-2-propyl-estra-1 ,3,5(10)-triene-17one was prepared starting from estradiol by introduction of the propionate side chain in C2 position as described by Rao et al. (2002) using a Fries rearrangement. Then the keto function is reduced to obtain the propyl side chain by reaction with Pd/C and H 2 [Gonzalez et al (1982)]. The subsequent oxidation of the C17 hydroxyl function was achieved by TPAP oxidation using the procedures of Ley et al. (1994). Then the benzyloxy group is reduced to the hydroxyl function.
• the detailed synthesis protocol is displayed in international patent application WO2006/125800.
• the optionally 2-substituted 15,16-unsaturated estrone of formula (X) is converted into the corresponding cyano-estrone (Xl) by a cyanide Michael addition at the D-ring.
• the nitrile was introduced in the beta configuration as was proven by 2D-NMR. Epimerization of this stereocenter had been accomplished in a following step. First the ketone functionality was protected as the acetal (XII), followed by conversion of the nitrile to the corresponding aldehyde (XIII-O) by the addition of DIBAH to the nitrile and the consecutive hydrolysis of the imine product. At this stage the epimerization took place for about 90% (2D-NMR). Consecutive washing of the mixture with aqueous bicarbonate gave the ⁇ -isomer with a d.e ⁇ 98%.
• the acid building block IV-1 may be synthesized via two different routes.
• the individual steps of the first synthesis route of acid building block IV-1 are depicted in the following SCHEME 9.
• the ketal derivative of the 17-oxo-estra-1 ,3,5(10)-trien-15 ⁇ -yl-carbaldehyde of formula XIII-O is converted into the methyl enol ether of the formula XXXIV via a Wittig reaction with MeOCH 2 LiP(Ph) 3 .
• Hydrolysis with HCI( aq ) delivered the unprotected acetaldehyde de- rivative XXXIII-1.
• the acetaldehyde derivative is then further oxidized to the corresponding carboxylic acid IV-1.
• a Michael addition of the dimethylmalonate-anion to the enone derivative delivered the diester XXXVIb, which was converted into the acid building block of formula IV-b by alkaline ester hydrolysis and decarboxylation in refluxing acetic acid.
• the 15, 16-unsaturated Estrone derivative of formula X is subjected to a 1 ,4 addition using a freshly prepared Gringard Reagent delivering the corresponding alkoxy-THP derivative XXX-4,5,6,7-TI-IP.
• This is further hydroxylated p-TosOH/MeOH to give the alcohol derivative XXXI-4,5,6,7b, which is converted, without purification, into the free acid IV-3b by a Jones oxidation.
• Acid building block IV ⁇ -2 (n 2): optionally 2-substituted 3-(3-Hvdroxy-17-oxo-estra- 1 ,3,5(10)-trien-15 ⁇ -yl)-propanoic acid
• the optionally 2-substituted carboxylic acid IV ⁇ -2 can be prepared by oxidation of the alcohol derivative of formula XXXI ⁇ -3 (synthesis see below) according to the preparation of the carboxylic acid IV ⁇ -3.
• the 15, 16-unsaturated estrone derivative of formula X may be converted selectively in a single step into the corresponding alkenyl (XIII) via a copper mediated addition using a freshly prepared Gringard Reagent.
• the alkenyl is hydroxylated (XXXII).
• the resulting compound was subjected to a Jones' oxidation to provide the corresponding acid. Deprotection of the ketone (by removal of the ketal or oxidation) delivered the desired compound IV ⁇ .
• reaction scheme 14 also delivers the still ketal- protected estrone-alcohol building block in form of the intermediate of formula XLIVoI c. Debenzylation and deprotection delivers the estrone-alcohol XXXI ⁇ -i a.
• the allyl group was introduced into the optionally C2 substituted, 15, 16-unsaturated Estrone derivative of formula Xc by reaction with allylmagnesium chloride or bromide, followed by an oxy-cope rearrangement catalysed by KH and 18-Crown-6. Subsequently, the resulting compound XXX-2c was reacted with acrylic acid methyl ester using a Grubb Il catalyst, known as olefin metathesis. The free acid (IVa-3a) is obtained by hydrogena- tion, deprotection, and, in the last step, hydrolysation of the methyl ester with LiOH.
• alcohol building blocks XXXIb- 3,4,5,6 can be already seen in synthesis SCHEME 13 above delivering the corresponding C17 protected alcohol of formula XXXII and subsequent deprotection of the C17 function (by removal of the ketal or oxidation).
• alcohol building blocks XXXIb-4,5,6 can be synthesized as depicted in general SCHEME 1 1 above.
• C17 difluorinated building blocks of formula IV can be achieved according to the following protocols given for exemplary compounds IV ⁇ -2 and IV ⁇ -3: 3-(17, 17-Difluoro-3-hvdroxy-estra-1 , 3,5(10)-trien-15 ⁇ -yl)-propanoic acid (F,F-IV ⁇ -2a)
• the acid building block of formula F,F-IV ⁇ -3a was synthesized starting from intermediate compound Xc and using the reaction steps as depicted in SCHEME 15:
• the allyl group was introduced into the 15, 16-unsaturated estrone derivative of formula Xc by reaction with allylmagnesium chloride, followed by an oxy-cope rearrangement catalysed by KH and 18-Crown-6.
• the resulting compound XXX-2c was reacted with acrylic acid methyl ester using a Grubb Il catalyst (olefin metathesis).
• estronyiP-butanoic acid ((IV ⁇ -3)-B(OH) ? )
• reaction mixture was stirred at ambient temperature for 18 h and then quenched with water (50 ml_).
• the water layer was extracted with DCM (3x 50 ml.) and the combined organic layers washed with 1 N aq. HCI (50 ml_), brine (50 ml.) and dried with Na 2 SO 4 .
• the organic layer was concentrated in vacuo yielding compound 1-16 (3.02 g, 5.75 mmol, 97 %) as a clear oil that was not purified prior to further use.
• Vll ⁇ -2b (1 1.26 g, 25.2 mmol, can be obtained according to SCHEME 16), Pd/C (1.6 g), methanol (300 ml.) and EtOAc (120 ml.) was stirred at 1 bar H 2 for 20 h.
• the protected aldehyde derivative of formula (Xlll ⁇ -0) is converted into the corresponding aminopropenyl by a Wittig reaction (see also SCHEME 9).
• the aminopropenyl (XXXVII-3) is subsequently reduced to the 15-aminopropyl derivative of formula XV ⁇ -3.
• the protecting ketal group is converted into the 17-oxo group via acid hydrolysis.
• the 17 oxo function of the butanol derivative of the formula XXXI ⁇ (for synthesis of XXXI ⁇ ) is converted into the ketal group (compound of formula XXXI I ⁇ ).
• the alcohol function is selectively reduced to the aldehyde giving compound of the formula Xlll ⁇ .
• the protected aldehyde derivative of the formula Xlll ⁇ is converted into a secondary amine by addition of Benzylamine and subsequent reduction (reductive amination). Further reduction of the secondary amine delivers the desired, still protected amine building block of the formula XV ⁇ .
• the protecting ketal group can be converted into the 17-oxo group via acid hydrolysis.
• the synthesis of the amine and azide building blocks of general formula XXIX and XLIII, respectively, can also be performed starting with an activated alcohol function and a subsequence substitution reaction, and does not need any protection of the estrone-C17 keto function according to the following general SCHEME 20
• Example 1 was prepared according to the procedure displayed in SCHEME 6B and 6C(I) and starting from 3-Hydroxy-15 ⁇ -(4-morpholin-4-yl-4-oxo-butyl)-estra-1 ,3,5(10)-trien-17- one, the detailed synthesis of which is displayed within international patent application WO2005/047303 (Example 40 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 14 or 15 and of flow diagram Ia or Ib.
• reaction mixture is filtered over Celite and reduced to obtain 3 g crude 15 ⁇ -(4-morpholin-4-yl-4-oxobutyl)-17- oxoestra-1 (10),2,4-triene-3-carboxylic acid butyl ester (a compound also falling under the scope of the present invention), which is directly used in the next reaction.
• Example 2 was prepared according to the procedure displayed in SCHEME 6B and starting from 3-Hydroxy-15 ⁇ -(4-morpholin-4-yl-4-oxo-butyl)-estra-1 ,3,5(10)-trien-17-one, the detailed synthesis of which is displayed within international patent application WO2005/047303 (Example 40 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 14 or 15 and of flow diagram Ia or Ib. The detailed synthesis of EXAMPLE 2 is already described during the synthesis of EXAMPLE 1.
• Example 3 was was prepared according to the procedure displayed in SCHEME 6B and 6C(I) and as described for Example 1 herewithin starting from 3-(3-Hydroxy-17-oxo-estra- 1 ,3,5(10)-trien-15 ⁇ -yl)-N-(5-methyl-thiazol-2-yl)-propionamide, the detailed synthesis of which is displayed within international patent application WO2005/047303 (Example 329A therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 13 and of flow diagram Ia or Ib herewithin.
• Example 4 was prepared according to the procedure displayed in SCHEME 6B and as described for Example 2 herewithin starting from 3-(3-Hydroxy-17-oxo-estra-1 ,3,5(10)- trien-15 ⁇ -yl)-N-(5-methyl-thiazol-2-yl)-propionamide, the detailed synthesis of which is displayed within international patent application WO2005/047303 (Example 329A therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 13 and of flow diagram Ia or Ib herewithin. The detailed synthesis of EXAMPLE 4 is already described during the synthesis of EXAMPLE 3.
• Example 5 was prepared from 15beta- ⁇ 3-[(5-methyl-1 ,3-thiazol-2-yl)amino]-3-oxopropyl ⁇ - 17-oxoestra-1 (10),2,4-triene-3-carboxylic acid (Example 4) according to the procedure displayed in SCHEME 6C-I.
• Example 6 was prepared according to the procedure displayed in SCHEME 6B and 6C(I) and starting from 4-(17,17-Difluoro-3-hydroxy-estra-1 , 3,5(10)-trien-15 ⁇ -yl)-1-morpholin-4- yl-butan-1-one, the detailed synthesis of which is displayed within international patent application WO2006/125800 (Example 91 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 14 or 15, as described for Intermediate F,F-IV ⁇ -3a and of flow diagram Ia or Ib herewithin.
• 4-(17,17-Difluoro-3-triflate-estra-1 ,3,5(10Hrien-15 ⁇ -yl)-1 -morpholin-4-yl-butan-1 -one is prepared from 4-(17,17-Difluoro-3-hydroxy-estra-1 , 3,5(10)-trien-15 ⁇ -yl)-1 -morpholin-4- yl-butan-1-one according to the procedure described in Example 1 , first step.
• Example 7 was prepared according to the procedure displayed in SCHEME 6B and start- ing from 4-(17,17-Difluoro-3-hydroxy-estra-1 , 3,5(10)-trien-15 ⁇ -yl)-1 -morpholin-4-yl-butan-
• WO2006/125800 (Example 91 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 14 or 15, as described for Intermediate F,F-IV ⁇ -3a and of flow diagram Ia or Ib herewithin.
• the detailed synthesis of EXAMPLE 7 is already described during the synthesis of EXAMPLE 6.
• Example 8 was prepared according to the procedure displayed in SCHEME 6B and 6C(I) and starting from 3-(17,17-Difluoro-3-hydroxy-estra-1 ,3,5(10)-trien-15 ⁇ -yl)-N-(5-methyl- thiazol-2-yl)-propionamide, the detailed synthesis of which is displayed within international patent application WO2006/125800 (Example 93 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 13, SCHEME 16 and of flow diagram Ia or Ib herewithin.
• the compound was prepared from 3-(17,17-Difluoro-3-triflate-estra-1 , 3,5(10)-trien-15 ⁇ -yl)- N-(5-methyl-thiazol-2-yl)-propionamide using the procedure as described in Example 6 (step 2)
• Example 9 was prepared according to the procedure displayed in SCHEME 6B and start- ing from 3-(17,17-Difluoro-3-hydroxy-estra-1 , 3,5(10)-trien-15 ⁇ -yl)-N-(5-methyl-thiazol-2- yl)-propionamide, the detailed synthesis of which is displayed within international patent application WO2006/125800 (Example 93 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 13, SCHEME 16 and of flow diagram Ia or Ib herewithin. The detailed synthesis of EXAMPLE 9 is already described during the synthe- sis of EXAMPLE 8.
• Example 10 was prepared according to the procedure displayed in SCHEME 5 and starting from 3-Hydroxy-15 ⁇ -(4-morpholin-4-yl-4-oxo-butyl)-estra-1 ,3,5(10)-trien-17-one, the detailed synthesis of which is displayed within international patent application WO2005/047303 (Example 40 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 14 or 15 and of flow diagram Ia or Ib.
• TLC control (cyclohex- ane/ethylactate/methanol 15:15:0.1 ) show complete conversion.
• the reaction mixture was quenched by adding 50 ml waster. Additional 70 ml DCM were used to enlarge the organic layer. After separation the organic layer was washed with 2N HCI-solution, water and 1 molare NaCI solution. After drying the organic layer over Na 2 SC> 4 the organic layer was evaporated to dryness.
• Example 11 was prepared according to the procedure displayed in SCHEME 5 and as described for Example 10 herewithin starting from 3-(3-Hydroxy-17-oxo-estra-1 ,3,5(10)-trien- 15 ⁇ -yl)-N-(5-methyl-thiazol-2-yl)-propionamide, the detailed synthesis of which is dis- played within international patent application WO2005/047303 (Example 329A therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 13 and of flow diagram Ia or Ib herewithin.
• Example 47 was prepared according to the procedure displayed in SCHEME 5 and as described for Example 10 herewithin starting from 4-(17,17-Difluoro-3-hydroxy-estra- 1 ,3,5(10)-trien-15 ⁇ -yl)-1-morpholin-4-yl-butan-1-one, the detailed synthesis of which is displayed within international patent application WO2006/125800 (Example 91 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 14 or 15, as described for Intermediate F,F-IV ⁇ -3a and of flow diagram Ia or Ib herewithin
• Example 58 was prepared according to the procedure displayed in SCHEME 5 and as described for Example 10 herewithin starting from 3-(17,17-Difluoro-3-hydroxy-estra- 1 ,3,5(10)-trien-15 ⁇ -yl)-N-(5-methyl-thiazol-2-yl)-propionamide, the detailed synthesis of which is displayed within international patent application WO2006/125800 (Example 93 therein) and can be generally achieved following reactions of SCHEME 1 , SCHEME 13, SCHEME 16 and of flow diagram Ia or Ib herewithin.
• estrogen receptor binding and functional assay • in vivo assays, e.g. UWT assay, tumor model, and
• 17 ⁇ -HSD1 or 17 ⁇ -HSD2 purification Recombinant 17 ⁇ -HSD1 and 17 ⁇ -HSD2 baculovi- ruses were generated by the "Bac to Bac Expression System” (Invitrogen). Recombinant 17 ⁇ -HSD1 or 17 ⁇ -HSD2 bacmids were transfected to Sf9 insect cells using "Cellfectin Reagent" (Invitrogen). 6Oh later cells were harvested; the fractions including 17 ⁇ -HSD1 or 17 ⁇ -HSD2 were isolated as described by Puranen et al. (1994). Aliquots were stored frozen until determination of enzymatic activity.
• Recombinant 17 ⁇ -HSD1 assay Recombinant protein homogenate (0.1 ⁇ g/ml) was incubated in 20 mM KH 2 PO 4 pH 7.4 reaction buffer, including protease inhibitors (Complete Protease Inhibitor Cocktail tablet, Roche Diagnostics, 1697498), with 30 nM estrone (Sigma, E9750) as substrate, 800 000 cpm/ml 3 H-estrone (PerkinElmer, NET319001 MC) as a tracer substrate, and 1 mM NADPH (Sigma, N1630) as a co-factor for 30 min at RT, in the presence of potential inhibitors at concentrations of 1 ⁇ M or 0.1 ⁇ M.
• protease inhibitors Complete Protease Inhibitor Cocktail tablet, Roche Diagnostics, 1697498
• 30 nM estrone Sigma, E9750
• 800 000 cpm/ml 3 H-estrone PerkinElmer, NET319001 MC
• Inhibitor stock solutions were prepared in DMSO. The enzyme reaction was stopped by addition of trichloroacetic acid (1 % final concentration). Samples were centrifuged in a microtiter plate at 4000 rpm for 10 min. Supernatants were applied to reverse phase HPLC on a Waters Symmetry C18 column, equipped with a Waters Sentry Guard column, lsocratic HPLC runs were performed at RT at a flow rate of 1 ml/min of acetonitrile:water 48:52 as running solvent. Radioactivity was monitored in the eluate by a Packard Flow Scintillation Analyzer. Total radioactivity for estrone and estradiol were determined in each sample and percent inhibition of estradiol conversion by the respective inhibitor was calculated
• Recombinant 17 ⁇ -HSD2 assay Recombinant 17 ⁇ -HSD2 assay was performed as described for 17 ⁇ -HSD1 but with following modifications: 6 ⁇ g/ml of recombinant protein homogenate, 50 nM Estradiol (Sigma, E8875) as a substrate, 800 000 cpm/ml 3 H-estradiol (PerkinElmer, NET317) as a tracer substrate and 1 mM ⁇ -NAD (Sigma N7004) as a co- factor were used. Total radioactivity for estrone and estradiol were determined in each sample and percent inhibition of estrone conversion by the respective inhibitor was calculated.
• % conversion 100 * ⁇ (cpm 'end product' in sample with inhibitor) /
• the compounds were screened in respect of 17 ⁇ -HSD3 enzyme activity in vitro on estab- lished MCF-7 cell lines, each stably expressing the 17 ⁇ -HSD3 enzyme.
• the interconver- sion of substrate by 17 ⁇ -HSD3 and the 17 ⁇ -HSD3 inhibiting activity of chemical compounds in these cell lines were detected by HPLC system.
• Varying amounts of the test compounds were incubated in the growth medium of the 17 ⁇ - HSD3 expressing cells together tritium labeled androstenedione (2 nM). The medium samples were removed after exact incubation time and the reaction is stopped by trichloroacetic acid (TCA). The samples were analyzed by HPLC-coupled flow scintillation analysis.
• TCA trichloroacetic acid
• the binding affinity of the compounds of the invention to the estrogen receptor ⁇ and to the estrogen receptor ⁇ may be determined according to the in vitro ER binding assays described by Koffman et al (1991 ). Alternatively, an estrogen receptor binding assay may be performed according to international patent application WO00/07996.
• Compounds of the invention showing binding affinity towards the estrogen receptor may be further tested with regard to their individual estrogenic or anti-estrogenic potential (agonistic binding or antagonistic binding to the ERa or ER ⁇ ).
• the determination of the estrogen receptor agonist activity may be performed according to an in vitro assay system using the MMTV-ERE-LUC reporter system which is for example described within published US patent application US2003/0170292:
• HeIa cells are grown in 24-well microtiter plates and then transiently co-transfected with two plasmids using lipofectamine.
• the first plasmid comprises DNA encoding human estrogen receptor (either ER-alpha or ER-beta), and the second plasmid comprises an estrogen-driven reporter system comprising: a luciferase reporter gene (LUC) whose transcription is under the control of upstream regulatory elements comprising 4 copies of the vitellogenin estrogen response element (ERE) cloned into the mouse mammary tumor virus (MMTV) promoter (the full name for the re- porter system being "MMTV-ERE-LUC").
• LEC luciferase reporter gene
• Cells are exposed to the compounds of the invention in RPMI 1640 medium, supplemented with 10% charcoal-treated fetal calf serum, 2 mM L-glutamine, 0.1 mM non-essential amino acids and 1 mM sodium pyruvate for 42- 48 h at 37°C in a 5% carbon dioxide incubator. Concurrently, cells exposed to estradiol (1 nM) serve as positive controls. Replicate wells exposed to the solvent in which the com- pounds of the invention are dissolved (i.e. ethanol or methanol) are used as negative con- trols.
• estrogenic activity of the compounds of the invention is expressed as fold-increase in luciferase activity as compared to that observed in negative control cells.
• the determination of the estrogen receptor transactivation activity (estro- genicity assay or agonist assay) and of the inhibitory potency of transactivation activity (anti-estrogenicity assay or antagonist assay) may be performed according to international patent application WO 00/07996.
• the compounds of the invention show good inhibitory potential of the 17 ⁇ -HSD1 , 17 ⁇ - HSD2 and/or of the 17 ⁇ -HSD3 enzyme.
• the compounds of the invention are therefore regarded as being suited for the treatment of several estrogen and androgen dependent diseases and disorders, respectively.
• a reduction of the endogenous 17 ⁇ -estradiol concentration in the respective tissue e.g.
• the selective inhibitors of the 17 ⁇ -HSD1 enzyme as described herein are well suited to impair also endogenous productions of estrogens, in particular of 17 ⁇ - estradiol, in myomas, endometriotic, adenomyotic and endometrial tissue.
• Hard gelatin capsules are prepared using the following ingredients:
• COMPOUND No. 1 0.5 Starch, dried 105.5
• the above ingredients are mixed and filled into hard gelatin capsules in 120 mg quantities.
• a tablet is prepared using the ingredients below:
• Suppositories each containing 1 mg of active ingredient, may be made as follows:
• An intravenous formulation may be prepared as follows:
• the compound is dissolved in the glycerol and then the solution is slowly diluted with iso- tonic saline.

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