MXPA06005278A - NOVEL 17beta HYDROXYSTEROID DEHYDROGENASE TYPE I INHIBITORS - Google Patents

Abstract

The present invention relates to novel 3, 15 substituted estrone derivatives which represent inhibitory compounds of the 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD1), to their salts, 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 3, 15 substituted estrone derivatives, particularly their use in the treatment or prevention of steroid hor-mone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of 17beta-hydroxysteroid dehydrogenase type I enzymes and/or requiring the lowering of the endogenous 17beta-estradiol concentration. In addition, the present invention relates to the general use of selective 17beta-hydroxysteroid dehydrogenase type 1 inhibitors which possess in addition no or only pure antagonistic binding affinities to the estrogen receptor for the treatment and prevention of benign gynaecological disorders, in particular endometriosis.

Description

NEW INHIBITORS OF DEHYDROGENASE TYPE I / 3-HYDROXYSTEROID FIELD OF THE INVENTION The present invention relates to new 3, 15-substituted estrone derivatives which represent compounds inhibitors of the enzyme dehydrogenase 17 ^ -hydroxysteroid type I (173-HSD1), to its salts, to pharmaceutical preparations containing these compounds and processes for the preparation of these compounds. In addition, the invention relates to the therapeutic use of said new 3, 15-substituted estrone derivatives, particularly to their use in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone-dependent diseases or disorders that require inhibition of the enzyme 17/3-HSD1 and / or requiring the decrease in the concentration of endogenous 17/3-estradiol. Furthermore, the present invention relates to the general use of selective 173-HSD1 inhibitors which also possess no or only pure binding affinities to the estrogen receptor for the treatment and prevention of benign gynecological disorders, in particular endometriosis.

BACKGROUND The publications and other materials used in the present specification to illustrate the background of the invention and, in particular, the cases to provide additional details with respect to the practice, are incorporated by reference. Mammalian 17/3-hydroxysteroid dehydrogenases (17/3-HSD) are NAD (H) or NADP (H) -dependent enzymes that catalyze - among other reactions - the final stages in the biosynthesis of male and female sex hormones. These enzymes convert the inactive 17-keto-steroids into their active 17 /? -hydroxy forms or catalyze the oxidation of the 17/3-hydroxy forms in the 17-keto-steroids. Since both estrogens and androgens have the highest affinity for their receptors in the 17/3-hydroxy form, the 17/3-HSD enzymes play an essential role in the selective tissue regulation of the activity of sex steroid hormones. So far, 10 human members of the family of 17/3-HSD enzymes (types 1-5, 7, 8, 10-12) have been described. Members of the human 17/3-HSD family share less than 30% analogy in their primary structure. The 17/3-HSD are expressed in different models, although in some cases they overlap. The different types of 17/5-HSD also differ in their substrate and cofactor specificities. In cells intact in a culture, the 17/3-HSD catalyze the reaction in a unidirectional way: types 1, 3, 5 and 7 use NADP (H) as a cofactor and catalyze the reductive reaction (activation), while types 2, 4, 8 and 10 catalyze the oxidant reaction (inactivation) using NAD (H) as a cofactor [see, for example, Labrie et al. (2000) Trends Endocrinol Metab., 11: 421-7 and Adamski and Ja ob (2001) Mol Cell Endocrinol, 171: 1-4]. Due to its essential function in selective tissue regulation of sex steroid hormone activity, 17/3-HSD may be involved in the appearance and development of estrogen-sensitive pathologies (eg, breast, ovarian and endometrial cancers). ) and androgen sensitive pathologies (for example, prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc.). In addition, it has been shown that many types of 17/3-HSD are involved in the pathogenesis of particular human disorders. For example, it is known that 17/3-HSD type 3 is involved in the development of pseudohermaphroditism, 17/3-HSD8 plays a role in polycystic kidney disease and 17/3-HSD4 is related to the appearance of bifunctional enzyme deficiency. Therefore, the treatment of steroid-sensitive sex diseases has been suggested by the administration of specific inhibitors of the 17/3-HSDs enzymes, optionally in combination with potent and specific antiestrogens and antiandrogens [Labrie F et al. (1997) Steroids, 62: 148-58]. Due to the fact that each type of 17/3-HSD has a selective substrate affinity, a directional activity (reductive or oxidant) in intact cells and a particular tissue distribution, the selectivity of the drug action could be achieved by directing to target a particular 17/3-HSD isozyme. By modulating the individual 17/3-HSDs individually, it is possible to influence or even regulate the local and paracrine concentration of estrogens and androgens in different target tissues. The best characterized member of the 17/3-HSD family is 17/3-HSD1 [EC 1.1.1.62]. This enzyme could be crystallized in different states of functionality (for example, with and without ligand and / or cofactor). The enzyme 17/3-HSID1 catalyzes in vitro the reduction and oxidation between estrone (El) and estradiol (E2). However, under physiological conditions in vivo the enzyme only catalyzes the reductive reaction from estrone (El) to estradiol (E2). It was found that 17/3-HSD1 was expressed in a variety of hormone-dependent tissues, for example placental tissue, mammary glands or tissues of the uterus and endometrium, respectively. Estradiol itself is, significantly compared to estrone, significantly less active, a very potent hormone, which regulates the expression of a variety of genes by binding to the estrogen receptor. nuclear and plays an essential role in the proliferation and differentiation of the target cell. Physiological as well as pathological cell proliferations may be dependent on estradiol. Especially, many breast cancer cells are stimulated by a locally high concentration of estradiol. In addition, the appearance or course of benign pathologies such as endometriosis, uterine leiiornas (fibroids or myomas), adenomyosis, menorrhagia, metrorrhagia and dysmenorrhea are dependent on the existence of significantly elevated estradiol levels. Endometriosis is a well-known gynecological disorder that affects 10 to 15% of women of reproductive age. It is a benign disease defined as the presence of viable endometrial gland cells and stroma outside the uterine cavity. Most often it is found in the pelvic area. In women who develop endometriosis, the endometrial cells that enter the peritoneal cavity through retrograde menstruation (the most likely mechanism) have the ability to adhere 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 to the endometrium in the uterus. Infiltrating lesions and blood from these lesions that are unable to leave the body cause inflammation of the surrounding tissue. The most common symptoms of Endometriosis are dysmenorrhea, dyspareunia and abdominal (chronic) pain. The appearance of these symptoms is not related to the extent of the injuries. Some women with severe endometriosis are asymptomatic, while women with mild endometriosis may have severe pain. So far, no reliable non-invasive assays are available to diagnose endometriosis. Laparoscopy should be performed to diagnose the disease. Endometriosis is classified according to the 4 stages exposed by the American Fertility Society (AFS). Stage I corresponds to minimal disease, while stage IV is serious, depending on the location and extent of endometriosis. Endometriosis is found in up to 50% of women with infertility. However, no causal relationship between mild endometriosis and infertility has been demonstrated at present. Moderate to severe endometriosis can cause tubal deterioration and adhesions that lead to infertility. The objectives of the treatment of endometriosis are pain relief, resolution of 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. The uterine leiomorphins (fibroids or myomas), benign clonal tumors, arise from the smooth muscle cells of the human uterus. They are clinically evident even in a % of women and are the only and most common indication of hysterectomy. They cause significant morbidity, including prolonged and heavy menstrual bleeding, pressure and pain in the pelvis, urinary problems and, in rare cases, reproductive dysfunction. The pathophysiology of myomas is not well understood. Myomas are found submucosally (behind the endometrium), intramural (in the myometrium) and subserosal (projecting out of the serosal compartment of the uterus), but mainly are mixed forms of these 3 different types. The presence of estrogen receptors in leiomyoma cells has been studied by Tamaya et al.

[Tamaya et al. (1985) Obstet Gynecol Scand Act. 64 (4): 307-9].

They have shown that the ratios of estrogen receptor levels compared with progesterone and androgen receptors were higher in leiomyomas than in the corresponding normal myometrium. Surgery has long been the main treatment for fibroids. In addition, medical therapies have been proposed to treat fibroids that include the administration of a variety of steroids such as the androgen steroids danazol or gestrinone, GnRH agonists and progestogenes, whereby administration is often associated with a variety of serious side effects All that has been discussed above in relation to the treatment of uterine leiomyomas and the Endometriosis is equally applicable to other benign gynecological disorders, particularly adenomyosis, functional menorrhagia and metrorrhagia. These benign gynecological disorders are all sensitive to estrogen and are treated in a manner comparable to that described herein above in connection with uterine leiomyomas and endometriosis. The available pharmaceutical treatments, however, suffer from the same main drawbacks, ie they have to be interrupted once the side effects become more serious than the symptoms to be treated, and the symptoms reappear after the interruption of therapy. Since the aforementioned malignant and benign pathologies are all dependent on 17/3-estradiol, a reduction in the concentration of endogenous 17/3-estradiiobl in the respective tissue will result in a difficult or reduced proliferation of 17 / 3- cells estradiol in said tissues. Therefore, it can be concluded that the selective inhibitors of the enzyme 17/3-HSD1 are well suited to be used to hinder the endogenous productions of estrogens, in particular 17/3-estradiol in fibroids, and endometriotic, adenomytic and endometrial The application of a compound that acts as a selective inhibitor on the 17/3-HSD1 that preferentially catalyzes the reductive reaction will result in a decreased intracellular estradiol concentration, since the reducing conversion of estrone to active estradiol is reduced or has been suppressed. Therefore, reversible or even irreversible inhibitors of 17/3-HSD1 may play a significant role in the prophylaxis and / or treatment of disorders or diseases dependent on steroid hormones, in particular 173-estradiol. In addition, reversible or even irreversible inhibitors of 17/3-HSD1 must have no or only pure binding activities antagonists to the estradiol receptor, in particular with respect to the estrogen receptor subtype a, since the agonist binding of the estrogen receptor would lead to activation and, therefore - by regulating a variety of genes - to the proliferation and differentiation of the target cell. In contrast, estrogen receptor antagonists, so-called anti-estrogens, bind competitively to the specific receptor protein, and thus prevent access of endogenous estrogens to their respective specific binding site. It is currently described in the literature that various malignancies such as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia can be treated by administering a 17 / 3- inhibitor. HSD1 selective. In addition, a selective 17/3-HSD1 inhibitor may be useful for the prevention of dependent cancers of hormones mentioned above, especially breast cancer. The international patent application ES 2004/080271 describes the use of a particular 17/3-HSD1 inhibitor, the so-called compound A, for the prevention or treatment of disorders caused by the activity of the enzyme 17/3-HSD1, in particular breast cancer. In addition, the international patent application WO 03/017973 describes the use of a selective estrogen enzyme modulator (SEEM) in the manufacture of a vehicle for the delivery of drugs to be used in a method for treating or preventing a benign gynecological disorder in a mammalian female, said benign gynecological disorder being selected from the group consisting of uterine leiomyomas, endometriosis, adenomyosis, functional menorrhagia and metrorrhagia, in which the method comprises the intravaginal administration of the SEEM to the female suffering from the benign gynecological disorder in a therapeutically effective dosage to prevent or reduce the symptoms of said benign gynecological disorder, and said SEEMs are selected from the group consisting of aromatase inhibitors, cyclooxygenase 2 (COX-2) inhibitors, 17 / 3-HSD1 and its combinations. Several reversible or irreversible inhibitors of the 17/3-HSD1 enzyme of steroid and even non-steroid origin are already known in the literature. The characteristics of these inhibitory molecules, which mainly have a structure of substrate or nucleus of cofactor type, have been described in the literature [reviewed in: Poirier D. (2003) Curr Med Chem. 10: 453-77]. For example, Tremblay and Poirier describe an estradiol derivative, 16- [carbamoyl- (bromo-methyl) -alkyl] -estradiol, and tested it for its inhibition of estradiol formation catalyzed by the enzyme 17 / 3- HSD1 [Tremblay & Poirier (1998) J. Steroid Biochem. Molec. Biol., 66: 179-191]. Poirier and co-workers describe a 6/3-thiaheptan-butyl-methyl-amide derivative of estradiol as a potent and selective inhibitor of the 17HSD1 enzyme [Poirier et al. (1998) J. Steroid Biochem. Molec. Biol., 64: 83-90]. In addition, Poirier et al. Describe new 17/3-estradiol derivatives with N-butyl and N-methyl-alkylamido side chains of three different lengths (n = 8, 10 or 12) at position 15, which could be potential inhibitors. of the enzyme 17/3-HSD [Poirier et al. (1991) Tetrahedron, 47 (37): 7751-7766]. The biological activity of these compounds was only tested with respect to the binding affinity to estrogen receptors, estrogenic and anti-estrogenic activity [Poirier et al. (1996) Bioorg Med Chem Lett 6 (21): 2537-2542]. In addition, Pelletier and Poirier describe new 17/3-estradiol derivatives with different bromoalkyl side chains, which may be potential inhibitors of the 17/3-HSD enzyme [Pelletier & Poirier (1996) Bioorg Med Chem, 4 (10): 1617-1628]. Sam and his collaborators describe various estradiol derivatives with a halogenated alkyl side chain in a 16th position; or 17Q; of the steroid D ring that possesses inhibitory properties of 17/3-HSD1 [Sam et al. (1998) Drug Design and Discovery, 15: 157-180]. In addition, the discovery that some anti-estrogens, such as tamoxifen, have weak inhibitory properties of 17/3-HSD suggested that it may be possible to develop a potent 17/3-HSD1 inhibitor that is also anti-estrogenic [reviewed in: Poirier D. (2003) Curr Med Chem. 10: 453-77]. Several of the aforementioned and already known compounds also exhibit anti-estrogenic properties (for example, the 6/3-thiaheptan-butyl-methyl-amide estradiol derivative described by Poirier and co-workers [Poirier et al. (1998) J) Steroid Biochem, Molec, Biol., 64: 83-90]). None of the aforementioned compounds has been clinically used until now. In addition, the international patent application WO 2004/085457 describes a variety of estrone derivatives with different substituents at the C3, C6, C16 and / or C17 position as potent inhibitors of 17/3-HSD1. In addition, the synthesis of different carboxylic esters of estradiol substituted on rings B-, C- and D- was described by Labaree et al. [Labaree et al. (2003) J. Med. Chem. 46: 1886-1904]. However, these esters were only analyzed with respect to their potential capacity estrogenic The related international patent application WO 2004/085345 discloses estradiol compounds substituted at 15a carrying a side chain - (CH2) m-CO-0-R, wherein R is H, a Ci to C5 alkyl group, optionally substituted with at least one halogen group, such as CH2CH2F, or another group (for example, a group CH2CHF2, CH2CF3 or CF3); and m is 0-5. These esters of 15ce-estradiol are described as locally active estrogens without any significant systemic action. Accordingly, there is a need to develop compounds that are suitable for the treatment and / or prevention of steroid hormone dependent diseases or disorders such as breast cancer, endometriosis and uterine leiomyomas selectively inhibiting the enzyme 17/3-HSD1, while desirably not it reaches to substantially inhibit other members of the 17/3-HSD family of proteins or other catalysts of the degradation or activation of sex steroids. In particular, it is an object of the present invention to develop selective inhibitors of the enzyme 17/3-HSD1, whereby in addition the compounds do not have any of the antagonistic affinities of binding or only the pure ones with respect to the estrogen receptor (of the subtypes o ¿and ß). In addition to this, there is still a need to provide a new type of therapy regimen for benign gynecological disorders dependent on estrogen, particularly for pre- and peri-menopausal females, with which therapy should not cause serious side effects.

SUMMARY OF THE INVENTION Therefore, it is an object of the present invention to develop new inhibitors of the 17/3-HSD1 enzyme having useful pharmacological properties and which are suitable for the treatment of estrogen-dependent diseases and disorders. It has now been found that the new 3, 15-substituted-estrone derivatives carrying a side chain of the amide, ester, carbonyl, hydrazone, alcohol, ether, urea, carbamate, "retro" -amide, sulfonyl-urea, sulfamide, sulfamate, "retro" -sulfonamide, "retro" -carbamate, "retro" -ester or sulphonylcarbamate at position 15 would be useful for therapy, especially in the treatment or prevention of diseases or disorders dependent on steroid hormones that require inhibition of enzymes 17/3-HSD. In particular, the compounds of the formula (I) represent potent inhibitors of the enzyme 17/3-HSD1 and possess useful pharmacological properties for the treatment and / or prophylaxis of steroid-dependent diseases or malignancies such as breast cancer, carcinoma of prostate, 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, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia or urinary dysfunction, or lower urinary tract syndrome. Additional estrogen-dependent diseases that can be treated and / or prevented with an effective amount of a compound of the invention are multiple sclerosis, rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts. Furthermore, it was an object of the present invention to provide a new therapy regimen for the treatment of benign gynecological diseases or disorders dependent on estradiol such as endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia or urinary dysfunction by the administration of an effective amount of a selective inhibitor of the enzyme 17/3-HSD1. Preferably, the selective inhibitor of the enzyme 17/3-HSD1 possesses none or only the pure affinities of antagonistic binding with respect to the estrogen receptor. In particular, the new type of therapy regimen for benign estrogen-dependent disorders is suitable for pre- and peri-menopausal females. Accordingly, the present invention relates to a compound having the structural formula I (I) in which (i) X represents: (a) a bond, (b) -NR3-, or (c) -O-; A represents: (a) -CO-, or (b) with the condition of X represents -NR3, A represents -S02-; Y represents: (a) -NR4 (b) -O-, with the proviso that X represents a bond or -NR3-, (c) a bond, (d) -NH-S02-, with the proviso that X represent -NR3 and A represents -CO-, (e) -NH-S02-NR4, with the proviso that X represents -O-, or (f) -NH-NR4-, with the proviso that X represents a link, or (ii) -X-A-Y- together represents -0-; and wherein R1 and R3 are independently selected from: (a) -H, (b) -alkyl (C? -C6), which is optionally substituted with halogen, nitrile, -OR6, -SRS or -COOR5; the number of said substituents being up to three for the halogens and up to two for any combination of said halogen, nitrile, -OR6, -SR5 or -COOR6 moieties, (c) -phenyl, which is optionally substituted with halogen, nitrile, -OR6 '-SR6' -R6 or -COOR6, the number of said substituents being up to perhalo for halogen and up to two for any combination of said halogen, nitrile, -OR6, -SR5, -R6 or -COOR6, ( d) -alkyl (C? -C4) -phenyl, wherein the alkyl part is optionally substituted with up to three halogens; and the phenyl part is optionally substituted with halogen, nitrile, -OR6, -SR6 '-R6 or -COOR6' and the number of substituents of said phenyl part is up to perhalo for halogen and up to two for any combination of said halogen, nitrile, -OR6, -SR6, -R6 or -COOR6 moieties; R2 and R4 are independently selected from: (a) -H, where if X represents a bond, A represents -CO- and Y represents -0- or a bond, then R2 is different from -H; (b) optionally substituted alkyl, optionally substituted (c) acyl, with the proviso that Y represents -NH-NR4-, (d) optionally substituted aryl, (e) optionally substituted heteroaryl, and (f) optionally substituted cycloheteroalkyl, or , with the proviso that Y represents -NR4-, -NH-NR4- or -NH-S02-NR4-, R2 and R4 together with the nitrogen atom to which R2 and R4 are attached, form a heterocyclic ring of 4, 5, 6, 7 or 8 members, which is optionally saturated, partially unsaturated or aromatic, optionally containing up to three additional heteroatoms selected from N, O or S, the number of additional N atoms being 0, 1, 2 or 3 and the number of atoms of 0 and S being each of 0, 1 or 2; and the ring is optionally part of a multiple system of fused rings, wherein the ring or ring system is optionally substituted; R6 represents H, -alkyl (C? -C4) or halogenated alkyl (d-d); and n represents 0, 1, 2, 3, 4, 5 or 6, where if X represents -NR3 or -O-, then n is different from 0, and all stereoisomers, pharmacologically salts acceptable and prodrugs thereof. Accordingly, the present invention relates to a compound of the general formula I, wherein -XAY-represents together (a) -CO-NR4-, (b) -CO-O-, (c) -CO-, ( d) -CO-NH-NR4, (e) -NR3-CO-NR4-, (f) -NR3-CO-0-, (g) -NR3-CO-, (h) -NR3-CO-NH- S02-, (i) -NR3-S02-NR4-, (j) -NR3-S02-0-, (k) -NR3-S02- (1) -O-CO-NR4-, (m) -O- CO-, (n) -0-CO-NH-S02-NR4-, or (o) -0-. In a further embodiment, the present invention relates to a compound of the general formula I, which is a 15th enantiomer; optically pure having the formula (II) or a physiologically acceptable salt thereof. In a further embodiment, the present invention relates to the enantiomer 15cf having the formula (II), wherein n represents 1, 2, 3 or 4, if X represents -NR3- or -O-, or wherein represents 0, 1, 2 or 3 if X represents a link. In another embodiment, the present invention relates to a compound of the general formula I, which is an optically pure 15/3 enantiomer having the formula (III) or a physiologically acceptable salt thereof. In a further embodiment, the present invention relates to the 15/3 enantiomer having the formula (III), wherein n represents 2, 3, 4 or 5 if X represents a bond, or where n represents 3, 4 , 5 or 6 if X represents -NR3- or -0-.

A preferred embodiment of the present invention relates to compounds of the general formula I, wherein R1 and R3, if R3 is present, are independently selected from H, (C? -C4) alkyl, preferably methyl and phenyl-alkyl ( C? -C), preferably benzyl. A further preferred embodiment of the present invention relates to compounds of the general formula I, wherein R1 and R3, if R3 is present, are independently selected from H and methyl. A further preferred embodiment of the present invention relates to compounds of the general formula I, wherein if X represents -NR3- or -O- and Y represents -NR2R4-, then R4 is -H. A further preferred embodiment of the present invention relates to compounds of the general formula I, in which R2 and R4 are independently selected from: (a) -H, wherein if X represents a bond, A represents -CO- and Y represents -0- or a bond, then R2 is different from -H, (b) -alkyl (d-d2) optionally substituted with up to five substituents independently selected from the group consisting of halogen, hydroxyl, thiol, nitrile, alkoxy, aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamido, acyl, carboxyl, acylamino, aryl, aryl that is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C? -C3) alkoxy / (C? -C6) alkyl, (C? - alkyl) C6) halogenated, halogenated (d-C6) alkoxy, carboxyl (C? -C6) alkyl, thiol, nitrile, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, alkylthio (Ci-d), arylthio, arylalkylthio, amino, amido , acyl, acylamino and heteroaryl; or aryl which is optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic system of 5, 6, 7 or 8 members, optionally containing up to three heteroatoms, such as N, O or S, the number of atoms of N being 0-3 and the number of atoms of O and S each being 0-2; heteroaryl, heteroaryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C? -C6) alkoxy (C? -C6) alkyl, halogenated (C? -C6) alkyl, alkoxy (d) -C6) halogenated, carboxyl (C? -C6) alkyl, thiol, nitrile, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, alkylthio (d-C6), arylthio, arylalkylthio, amino, amido, acyl, acylamino, aryl-alkyl (C? -C4) and aryl; wherein each aryl group is optionally substituted with up to three independently selected substituents between the group consisting of hydroxyl, halogen, alkoxy (d-C6), alkyl (C? -C6), halogenated (C? -C6) alkyl and halogenated (Ci-Cg) alkoxy; and cycloheteroalkyl, cycloheteroalkyl group which is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C? -C8) alkyl, aryl, aryl-alkyl (-d), hydroxyl, (C? -C5) alkoxy , carboxyl-alkyl (d-C6), thiol, nitrile, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, alkylthio (dC6), arylthio, arylalkylthio, amino, amido, acyl and acylamino, wherein each aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkyl (d-C4), alkoxy (dd), halogenated alkyl (dd) and halogenated (C? -C4) alkoxy; (c) acyl- (C = 0) -R ', wherein R' represents hydrogen, (C? -C4) alkyl, aryl or aryl (C? -C4) alkyl or heteroarylalkyl (C? -C4); aryl that is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkoxy (d-d) alkyl (C? -C) or halogenated (C? -C4) alkyl; (d) aryl aryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, alkoxy (Ci-d), alkyl (dd), halogenated (C? -C6) alkyl, halogenated (Ci-Cg) alkoxy, carboxyl-alkyl (d-d) ), thiol, nitrile, nitro, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, alkyl (dd) -sulfonyl, arylsulfonyl, alkylthio (C? -C6), arylthio, arylalkylthio, amino, amido, acyl, acylamino and heteroaryl; or aryl that is optionally substituted with two groups that are bonded to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic system with 5, 6, 7 or 8 membered rings, which optionally contains up to three heteroatoms such as N, O or S, the number of atoms of N being 0-3 and the number of atoms of O and S each being 0-2; (e) heteroaryl, heteroaryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, alkoxy (d-C6), alkyl (d-C6) alkyl (dd) halogenated, alkoxy (C? C6) halogenated, carboxyl-alkyl (d-C6), thiol, nitrile, sulfamoyl, sulfonamido, arylsulfoxy, carboxyl, aryloxy, arylalkyloxy, alkylsulfonyl (Ci-d) 'arylsulfonyl, alkylthio (Ci-Cg), arylthio, arylalkylthio, amino , amido, acyl, acylamino, aryl-alkyl (C? -C4) and aryl, wherein each aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkoxy (C? -C6), alkyl (d-d), halogenated (C? -C6) alkyl and halogenated (C-C6) alkoxy; or (f) cycloheteroalkyl, cycloheteroalkyl which is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (d-C4) alkyl, aryl, aryl-alkyl (C? -C4), hydroxyl, alkoxy (d-) C6), carboxyl-alkyl (d-Ce) / thiol, nitrile, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, alkylthio (C? -C3), arylthio, arylalkylthio, amino, amido, acyl and acylamino, in which each group aryl is optionally further substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkyl (d_d) alkoxy (Ca-C4), halogenated (C? -C4) alkyl and halogenated (Cx-C4) alkoxy; or wherein, with the proviso that Y represents -NR4, -NH- NR4- or -NH-S02-NR4-, R2 and R4 form, together with the nitrogen atom to which R2 and R4 are attached, a heterocyclic ring of 4, 5, 6, 7 or 8 members, which is optionally saturated or partially unsaturated, optionally containing up to three additional heteroatoms selected from N, 0 or S, being the number of additional N atoms of 0-3 and the number of O and S atoms each being 0-2; and ring which is optionally part of a multiple system of fused rings, wherein the ring or ring system is optionally substituted (i) with up to three substituents independently selected from the group consisting of (C? -C8) alkyl, halogen, hydroxyl, carboxyl, thiol, nitrile, (C? -C6) alkoxy, carboxyl-alkyl (Ca-C6), aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamido, aryl, aryl-alkyl (Ci) -d) / heteroaryl and cycloheteroalkyl, wherein the (C? -C8) alkyl group is optionally substituted with up to three substituents independently selected from hydroxyl, halogen, alkoxy (dd) / alkoxy (C? -C4) or alkoxy (C) ? -C) halogenated, in which the alkyl chain of the alkoxy moiety (d-C4) is optionally substituted with hydroxyl; wherein the aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkyl (d-C4), alkoxy (C? -C4), halogenated (C? -C4) alkyl, alkoxy ( dd) halogenated and carboxyl-alkyl (C? -C6), or wherein the aryl moiety is optionally substituted with two groups that are bonded to adjacent carbon atoms and are combined in form of a saturated or partially unsaturated cyclic system with rings of 5, 6, 7 or 8 members, optionally containing up to three heteroatoms such as N, 0 or S, the number of N atoms being 0-3 and the number being of 0 and S atoms each of 0-2; wherein the heteroaryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C 1 -C 4) alkyl, (C 3 -C 4) alkoxy, halogenated (d ~d) alkyl, alkoxy ( C1-C4) halogenated and carboxyl-alkyl (dd); wherein the cycloheteroalkyl group is optionally substituted with up to three substituents independently selected from the group consisting of oxo, alkyl (d ~ C8), aryl, aryl-alkyl (dC), hydroxyl, (C? -C6) alkoxy, carboxyl- (C? -C6) alkyl and carboxyl, wherein each aryl group is optionally further substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkyl (d-C4), alkoxy (d-C4), alkyl (d-C4) halogenated and halogenated (C1-C4) alkoxy; or (ii) with two groups that are attached to the same carbon atom and are combined in the form of a saturated or partially unsaturated cyclic system with 4, 5, 6, 7 or 8 member rings, optionally containing up to three heteroatomssuch as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2, wherein the cyclic ring system is optionally substituted with up to two substituents independently selected from oxo, alkyl (C? -C6), aryl and aryl-alkyl (dd) and wherein n represents (a) 1, 2, 3, 4, 5 or 6, with the proviso that X represents -NR3 - u -O-, or (b) 0, 1, 2, 3, 4 or 5, with the proviso that X represents a link. In a preferred embodiment of the present invention, in the compounds of the general formula I, the residues R2 and R4 can independently represent -H, wherein if X represents a bond, A represents -CO- and Y represents -O- or a link, then R2 is different from -H. In a further embodiment of the present invention, the term "optionally substituted alkyl", wherein R 2 and / or R 4 can be independently selected, refers to (i) -alkyl (C 1 -C 8), optionally substituted with sus- constituents independently selected from the group consisting of (a) hydroxyl, (b) nitrile, (c) -O-R7 '; (d) -O-phenyl, > (e) -O-alkyl (C? -C4) -phenyl, (f) alkylamino, (g) alkylamido, preferably carbamoyl, (h) -S-R7Y and (i) - (C = 0) -OR8 '; the number of substituents in said alkyl part being up to five for hydroxyl and one, two or three, more preferably up to two for any combination of said other substituents, and wherein R7 'represents (C? -C4) alkyl, preferably alkyl ( C? -C2), optionally substituted on the alkyl chain with one or two hydroxyl groups; and R8 'represents hydrogen, (C? -C4) alkyl, preferably methyl or (C? -C4) alkyl-phenyl, preferably benzyl; (ii) -alkyl (d-C4), substituted with one or two substituents independently selected from the group consisting of (a) aryl, wherein the aryl is preferably selected from phenyl, naphthyl, indanyl, indenyl and 1, 2 , 3,4-tetrahydro-naphthalene-1-yl, more preferably the aryl is phenyl or naphthyl, and aryl which is optionally substituted with halogen, hydroxyl, (C? -C6) alkoxy, (d-C6) alkyl? Alkyl ( C? -C4) halogenated, halogenated, sulfamoyl or alkylamido alkoxy (C? -C4); the number of substituents in said aryl portion being up to five, more preferably up to three for halogen and up to three, more preferably up to two for any combination of said other substituents; or aryl which may be optionally substituted with two groups that are bonded to adjacent carbon atoms and are combined in the form of a ring saturated system of 5 or 6 members, optionally containing up to three heteroatoms, such as N or O, being the number of N atoms of 0-3 and the number of O atoms each being 0-2; (b) heteroaryl, wherein the heteroaryl is preferably selected from pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzofuran. and benzo [b] thiophene, more preferably the heteroaryl is thienyl, furyl, imidazolyl, pyridinyl, indolyl or benzoimidazolyl, and heteroaryl which is optionally substituted with up to two, preferably with a substituent independently selected from the group consisting of alkoxy (C? -C4), preferably methoxy, or (C? -C4) alkyl, preferably methyl; and (c) cycloheteroalkyl, wherein the cyclohete-roalkyl group is preferably selected from the group it consists of pyrrolidinyl, tetrahydrofuranyl, dihydro-lH-pyrrolyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,3-dihydro-benzoimidazolyl, azepanyl, diazepanyl, oxazepanyl and thiazepanyl, preferably the cycloheteroalkyl group is piperidinyl or morpholinyl; and cycloheteroalkyl which may be optionally substituted with up to three substituents independently selected from the group consisting of oxo, hydroxyl, alkyl (C? -C4), phenyl, -alkyl (C? -C4) -phenyl, preferably benzyl, -C ( = 0) -O-alkyl (C? -C4) and alkylamino, preferably the cycloheteroalkyl moiety is unsubstituted; (iii) -cycloalkyl (C3-C8), optionally substituted with hydroxyl; (iv) -alkyl (C? -C4) -cycloalkyl (C3-C8), optionally substituted with hydroxyl; (v) a bicyclic ring system 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, Bicyclo [3.3.2] decanil; or (vi) a system of condensed rings of up to 10 carbon atoms, preferably adamantyl. In a further embodiment of the present invention, the expression "optionally substituted acyl", wherein R2 and / or R4 can be independently selected with the proviso that Y represents -NH-NR4-, refers to acyl- (C = 0) -R !, wherein R 'represents hydrogen, (C? -C4) alkyl, aryl or aryl-alkyl (Ca-C4) or heteroaryl-alkyl (C? -C4); aryl or arylalkyl (C? -d) which is optionally substituted on the aryl moiety, preferably phenyl, with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C) alkoxy, alkyl (d-C4) ) or halogenated (C? -C4) alkyl. In a further embodiment of the present invention, the term "optionally substituted aryl", wherein R 2 and / or R 4 can be independently selected, refers to aryl, which is preferably selected from phenyl, naphthyl, indanyl, indenyl and 1, 2, 3, 4-tetrahydro-naphthalen-1-yl. According to one aspect of the invention, the aryl group is optionally substituted with up to five, more preferably up to three substituents independently selected from the group consisting of (i) hydroxyl, (ii) halogen, preferably fluorine or chlorine, (iii) alkoxy ( C? -C6), preferably (d-C2) alkoxy / (iv) (C? -C6) alkyl, preferably (C-C4) alkyl, (v) halogenated (d-C6) alkyl, preferably alkyl (C? C4) halogenated, more preferably trifluoromethyl, (vi) halogenated (C? -C6) alkoxy, preferably halogenated (C? -C4) alkoxy, more preferably trifluoromethoxy, - (vii) -alkyl (C? -C4) - (C = 0) -OR8 ', (viii) ) nitrile, (ix) nitro, (x) sulfamoyl, (xi) - (C = 0) -R8 ', (xii) - (C = 0) -OR8', (xiii) -NH- (C = 0) -R8 ', (xiv) -S-R8', (xv) -S02-R8 ', (xvi) alkylamino, (xvii) alkylamido, preferably carbamoyl, (xviii) phenyl, and (xix) an additional heteroaryl group, optionally substituted with alkyl (C? -C4), preferably 6-methyl-benzothiazolyl; wherein R8 represents hydrogen, (C-C4) alkyl, preferably methyl or (C? -C) -phenyl alkyl, preferably benzyl; or aryl which may be optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic system with 5, 6, 7 or 8 membered rings, which optionally contains up to three heteroatoms such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2. In a further embodiment, the aryl moiety, wherein R 2 and / or R 4 can be independently selected, is optionally substituted with halogen, (C 1 -C 6) alkoxy, alkyl (C-C4) halogenated, preferably halogenated methyl, nitro, nitrile, -CO-alkyl (C? -C4), -CO-0-alkyl (C-C4), -NH-CO-alkyl (C? -C4) , alkyl (C? -C4) -sulfonyl, phenyl or heteroaryl, and the number of substituents in said aryl portion being up to perhalo for halogen and up to two for any combination of said alkyl (C? -C3) or alkyl (C? -C4) halogenated. In a further embodiment of the present invention, the term "optionally substituted heteroaryl", wherein R 2 and / or R 4 can be independently selected, refers to heteroaryl, which is preferably selected from pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzofuran and benzo [b] thiophene; more preferably, heteroaryl is furyl, thiazolyl, pyrazolyl, pyridinyl, quinolinyl or benzo [b] thiophene. Heteroaryl is optionally substituted with up to three, preferably up to two substituents independently selected from the group consisting of (i) halogen, (ii) alkyl (C? -C4), (iii) hydroxyl, (iv) halogenated (C? -C4) alkyl, (v) -alkoxy (C? C), (vi) -alkyl (dd) - (C = 0) -OR8 '-, (vii) -O-Ar1, (viii) -302-Ar1 (ix) phenyl, (x) -alkyl (C? -C4) -phenyl, (xi) nitrile, (xii) alkylamino, and (xiii) alkylamido, preferably carbamoyl; wherein R8 'represents hydrogen, (d-C4) alkyl, preferably methyl or (C? -C4) alkyl-phenyl, preferably benzyl; and Ar1 'represents phenyl optionally substituted with up to three halogens. In addition, the heteroaryl moiety, wherein R2 and / or R4 can be independently selected, is optionally substituted with up to three, preferably up to two, substituents independently selected from the group consisting of halogen, (C? -C4) alkyl, preferably methyl, halogenated (C? -C) alkyl, preferably halogenated methyl, alkyl (C? -C4) - (C = 0) -O-alkyl (C? -C), -S02-phenyl, -0-phenyl and phenyl . In a further embodiment of the present invention, the term "optionally substituted cycloheteroalkyl", wherein R 2 and / or R 4 can be independently selected, refers to cycloheteroalkyl, which is preferably selected from pyrrolidinyl, tetrahydrofuranyl, dihydro-1H-pyrrolyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,3-dhydro-benzoimidazolyl, azepanyl, diazepanyl, oxazepanyl and thiazepanyl; more preferably, cycloheteroalkyl is pyrrolidinyl, morpholinyl, tetrahydrofuranyl, piperidinyl or azepanyl, and cycloheteroalkyl which is optionally substituted with up to three, preferably one or two substituents independently selected from the group consisting of (i) oxo, (ii) alkyl (C? -C), (iii) phenyl, (iv) -alkyl (d-C4) -phenyl, (v) hydroxyl, (vi) alkoxy (d-C4), and (vii) -alkyl (d-C4) - ( C = 0) -OR8 '; wherein R8 'represents hydrogen, (d-C4) alkyl, preferably methyl or (C? -C4) -phenyl alkyl, preferably benzyl. In addition, the cycloheteroalkyl group, wherein R2 and / or R4 can be independently selected, is optionally substituted with one or two substituents independently selected from the group consisting of oxo, (C? -C4) alkyl, preferably methyl and alkyl (C? -C4) -phenyl, preferably benzyl. In a further embodiment, the invention relates to a compound of the general formula I, wherein, with the proviso that Y represents -NR4-, -NH-NR4- or -NH-S02-NR4-, R2 and R4 they can form, together with the nitrogen atom to which R2 and R4 are attached a 4, 5, 6, 7 or 8 member heterocyclic ring, which may be saturated or partially unsaturated, which may contain up to three additional heteroatoms selected from N, 0 or S, the number of additional N atoms being 0-3 and the number of atoms of 0 and S each being 0-2, and the ring being part of a system of multiple condensed rings. According to one embodiment, said ring or ring system is selected from the group consisting of Even more preferably, said ring or ring system is selected from the group consisting of Said ring or ring system may be optionally substituted with up to three substituents independently selected from the group consisting of (i) hydroxyl, (ii) (C? -C4) alkyl optionally substituted with up to two hydroxyl groups and / or (C? -C4) alkoxy, in which the alkyl chain of the (C? -C4) alkoxy moiety can optionally be substituted with up to two, preferably a hydroxyl; (iii) (C3-C8) cycloalkyl; (iv) - (C = 0) -O-alkyl (C? -C4); (v) phenyl optionally substituted with halogen, (C? -C4) alkyl, preferably methyl, (C? -C4) alkoxy or halogenated (C? -C) alkyl, preferably halogenated methyl, the number of said substituents being the remainder phenyl of up to three for halogen, and one or two for any combination of said other substituents; (vi) phenyl-alkyl (d-C4), preferably benzyl, optionally substituted on the phenyl group with up to three halogens, or optionally substituted on the phenyl group with two groups that are bonded to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic ring system with 5 or 6 members, optionally containing up to two O atoms; (vii) alkylamido, preferably carbamoyl; (viii) heteroaryl, wherein the heteroaryl is preferably selected from the group consisting of pyridinyl, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, benzoimidazolyl or benzo [b] thiophene, more preferably heteroaryl is pyridinyl; Y (ix) cycloheteroalkyl, in which the cycloheteroalkyl is preferably selected from the group consisting of pyrrolidinyl, 1,3-dihydro-benzoimidazolyl, morpholinyl, tetrahydrofuranyl, piperidinyl and azepanyl; more preferably, the cycloheteroalkyl group is pyrrolidinyl or 1,3-dihydro-benzoimidazolyl, cycloheteroalkyl group which is optionally substituted with oxo. Alternatively, said ring or ring system may be optionally substituted with two groups which are attached to the same carbon atom and are combined in the form of a saturated or partially unsaturated cyclic system with 4, 5, 6, 7 or 8 member rings , which optionally contains up to three heteroatoms, such as N, 0 or S, the number of N atoms being 0-3 and the number of atoms 0 and S each being 0-2, wherein the cyclic system of rings may optionally be further substituted with up to two substituents independently selected from oxo and phenyl. In a further preferred embodiment, the invention relates to a compound of the general formula I, wherein R4 represents (a) -H, with the proviso that X represents -? R3- or that X represents a bond Y represents -? R4-, (b) an alkyl group selected from (i) -alkyl (C? -C6), optionally substituted with substituents independently selected from the group consisting of hydroxyl, nitrile, alkylamino, -O-alkyl (C? -C4), the number of substituents of said alkyl part being up to five for hydroxyl and up to three, more preferably up to two for any combination of said other substituents; (ii) -alkyl (C? -C), preferably -alkyl (C? -C2), substituted with up to two, preferably a substituent independently selected from aryl and heteroaryl, wherein the aryl is preferably phenyl or naphthyl and wherein the heteroaryl is preferably pyridinyl; (iii) (C3-C8) cycloalkyl, preferably (C3-C6) cycloalkyl; (iv) (C3-C8) cycloalkyl-(C? -C4) alkyl, preferably (C3-C6) -alkyl (C? -C2) cycloalkyl; or (c) cycloheteroalkyl, wherein the cycloheteroalkyl is preferably piperidinyl, cycloheteroalkyl group which is optionally substituted with one or two, preferably a (C? -C4) alkyl, preferably a methyl group. In one embodiment, the invention relates to a compound of the following formula VI wherein R1 represents H, (C? -C4) alkyl, preferably methyl or phenyl-alkyl (C? -C4), preferably benzyl; and n represents 0, 1, 2, 3, 4, or 5. In this embodiment, R2 preferably represents (i) -alkyl (C? -C4), (ii) -cycloalkyl (C3-C5), (iii) -alkyl (C? -C4) -aryl, in which the aryl is phenyl or naphthyl, phenyl which is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen and (d-C4) alkoxy, or phenyl which is optionally substituted with two groups that are bonded to adjacent carbon atoms and are combined in the form of a cyclic system saturated with 5 or 6 membered rings, containing 1 or 2 O atoms; or (iv) heteroaryl or (C-C4) alkyl-heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl, pyridinyl, indolyl or benzoimidazolyl; heteroaryl which is optionally substituted with one or two substituents independently selected from the group consisting of alkyl (C? -C) and alkyl (C? -C) - (C = 0) -0-alkyl (C? -C4); and preferably R4 is independently selected from H or -alkyl (C? -d) / 'R2 and R4 can form together with the nitrogen atom to which R2 and R4 are attached a ring or ring system, which is selected from the group consisting of group consisting of morpholino and thiomorpholino. In a further embodiment, the invention relates to a compound of the following formula XL wherein R3 is defined as above; preferably R3 represents H; Y represents -NH-, a bond u -0-; R1 represents H, alkyl (C? -C), preferably methyl, or phenyl-alkyl (C? -C), preferably benzyl; 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 R3 is defined as above; preferably R3 represents H; R1 represents H, alkyl (d ~ d) / preferably methyl, or phenyl-alkyl (C? -C4), preferably benzyl; and n represents 1, 2, 3 or 4, preferably 3 or 4. In this embodiment, R2 preferably represents (i) -alkyl (C? -C4), (ii) -cycloalkyl (C3-C8), (iii) -alkyl (C? -C4) -cycloalkyl (C3-C8), (iv) aryl, wherein the aryl is phenyl or naphthyl, phenyl which is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, -CO-0-alkyl (C? -C4) and alkoxy (C? -C4); or phenyl which is optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a cyclic system saturated with 5 or 6 membered rings, containing 1 or 2 O atoms, or (v) -alkyl (dd) -phenyl. A further embodiment of the invention relates to a compound of the following formula XXIII, (XXIII) in which R, 3 is as defined above; preferably R3 represents H; R 1 represents H, (d-C 4) alkyl, preferably methyl, or phenyl-C 1 -C 4 alkyl, preferably benzyl; and n represents 1, 2, 3 or 4. In this embodiment, R2 preferably represents (i) -alkyl (C? -C4), (ii) -cycloalkyl (C3-C8), (iii) -alkyl (C? -C4) ) -cycloalkyl (C3-C8), (iv) -alkyl (C? -C4), substituted with one or two substituents independently selected from the group consisting of -O-alkyl (d-C4) and -O-alkyl (C? -C4) -phenyl, ( v) phenyl, phenyl which is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen and (C? -C4) alkoxy; (vi) -alkyl (C? -C4) -phenyl; or (vii adamantyl.) An additional embodiment of the invention relates to a compound of the following formula XXIV, wherein R3 is as defined above; preferably R3 represents H or -alkyl (C? -C4); Ra represents H, alkyl (C? -C), preferably methyl, or phenyl-alkyl (C? -C4), preferably benzyl; n represents 1, 2, 3 or 4.

In this embodiment, R2 preferably represents (i) aryl, wherein the aryl is selected from phenyl and naphthyl, aryl which is optionally substituted by one or two substituents independently selected from the group consisting of halogen, nitro, alkoxy (C? C4) and alkyl (dd); or (ii) heteroaryl, wherein the heteroaryl is furyl, thienyl, or thiazolyl or indolyl, heteroaryl which is optionally substituted with one or two substituents independently selected from the group consisting of -S02-phenyl and alkyl (C? -C4) . A further embodiment of the invention relates to a compound of the following formula XXVI, wherein R 1 represents H, (C 1 -C 4) alkyl, preferably methyl, or phenyl-C 1 -C 4 alkyl, preferably benzyl; n represents 3, 4, 5 or 6. In this mode, R2 preferably represents phenyl or naphthyl, phenyl which is optionally substituted by one or two substituents independently selected from the group consisting of hydroxyl, halogen, nitro, -C0-0-alkyl (C? -C4) and (C? -C4) alkoxy and alkyl (C? -C4) halogenated; or phenyl which is optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a cyclic system saturated with 5 or 6 membered rings, containing 1 or 2 atoms of 0. A further embodiment of the invention refers to a compound of the following formula XXVIII, (XXVIII) R 1 represents H, (C 1 -C 4) alkyl, preferably methyl, or phenyl-C 1 -C 4 alkyl, preferably benzyl; n represents 3, 4, 5 or 6. In this embodiment, R2 preferably represents (i) -alkyl (C? -C4), (ii) -cycloalkyl (C3-C8), (iii) -alkyl (C? - C4) -phenyl, (iv) phenyl, or (v) heteroaryl or -alkyl (C? -C4) -heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl, pyridinyl, indolyl or benzoimidazolyl; and preferably R4 is independently selected from H, -alkyl (C? -C4) and -alkyl (C? -d) -phenyl; or R2 and R4 can form, together with the nitrogen atom to which R2 and R4 are attached, a ring, which is selected from the group consisting of morpholino, thiomorpholino and piperazyl, and which is optionally substituted by alkyl (C? - C4). A further embodiment of the invention relates to a compound of the following formula XXXI, wherein R1 represents H, (C? -C4) alkyl, preferably methyl, or phenyl-alkyl (C? -C), preferably benzyl; n represents 1, 2, 3, 4, 5 or 6, preferably 3 or 4. Preferred embodiments of the invention relate to the following compounds: No. 1. 3-Hydroxy-15 / 3- (4-morpholine-4) -yl-4-oxo-butyl) - estra-1, 3,5 (10) -trien-17-one No. 2. 3-Methoxy-15 / 3- (4-morpholin-4-yl-4-oxo-butyl) • estra-1, 3, 5 (10) -trien-17-one No. 3B. N-Benzyl-4- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -butyramide No. 3A. N-Benzyl-4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -butyramide No. 31. 4- (3-Methoxy-17-oxo) -estra-l, 3,5 (10) -trien-15/3-yl) -N- [2- (7-methyl-lH-indol-3-yl) -ethyl] -butyramide No. 36. 4- (3-Hydroxy-17-oxo-estra-l, 3,5 (10) -trien-15 (3-yl) -N- [2- (7-methyl-lH-indol-3-yl) -ethyl] -butyramide No. 37. N- (2,4-Difluoro-benzyl) -4- (3-hydroxy-17-oxo-estra-1, 3, 5 (10) -trien-15/3-yl) -butyramide No. 38. N-Benzyl-4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -N-methyl-butyramide No. 39. N- Benzyl-4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15?! -yl) -butyramide No. 40. 3 -Hydroxy-150! - (4-morpholine- 4-yl-4-oxo-butyl) -estra-1, 3, 5 (10) -trien-17-one No. 105. (5-Methyl-thiazol-2-yl) -amide 3-methoxy- 17-oxo-estra-1, 3,5 (10) -trien-15o; -carboxylic No. 310. N-Cyclohexyl-3- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien-15/3-yl) -propionamide No. 311. N-Cyclooctyl-3- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien-15/3-yl) - propionamide No. 313. N-Cyclohexyl-3- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien-15/3-yl) -N-methyl-propionamide No. 324. N- [2- (4-Hydroxy-phenyl) -ethyl] -3- (3-methoxy-17-oxo-estra-1, 3,5 (10) -trien-15/3-yl) -propionamide No. 329. 3- (3-Methoxy-17-oxo-estra-l, 3,5 (10) -trien-15/3-yl) -N- (5-methyl-thiazol-2-yl) -propionamide No. 331. 5- (3-Methoxy-17-oxo-estra-1,3,5 (10) -trien-15/3-yl) -pentanoic acid cyclohexylamide No. 332. 5- (3-methoxy-17-cyclooctylamide -oxo-estra-1, 3, 5 (10) -trien-15/3-yl) -pentanoic No. 333. (Furan-2-ylmethyl) -amide of 5- (3-methoxy-17-oxo- estra-l, 3, 5 (10) -trien-15/3-yl) -pentanoic No. 335. (Benzo [1,3] dioxol-5-ylmethyl) -amide of 5- (3-methoxy-17) -oxo-estra-l, 3,5 (10) -trien-15/3-yl) -pentanoic No. 338. (Pyridin-3-ylmethyl) -amide of 5- (3-methoxy-17-oxo- estra-l, 3,5 (10) -trien-15/3-yl) -pentanoic No. 339. (Pyridin-4-ylmethyl) -amide of 5- (3-methoxy-17-oxo-estra-l) , 3, 5 (10) -trien-15/3-yl) -pentanoic No. 340. Bencil 5- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien-15P-yl) -pentanoic acid amide No. 341. 2- (3-methoxy) -methoxy-benzylamide -17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -pentanoic No. 342. 3-Fluoro-benzylamide of 5- (3-methoxy-17-oxo-estradiol) 1, 3,5 (10) -trien-15/3-yl) -pentanoic No. 343. 4-Chloro-benzylamide of 5- (3-methoxy-17- oxo-estra-1, 3, 5 (10) -trien-15/3-yl) -pentanoic No. 344. Benzyl-methyl-amide of 5- (3-methoxy-17-oxo-estra-1, 3) , 5 (10) -trien-15/3-yl) -pentanoic No. 345. Butylamide of 5- (3-methoxy-17-oxo-estra-1, 3, 5 (10) -trien-15/3 acid -yl) -pentanoic No. 346. 5- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-153- (2-thiophen-2-yl-ethyl) -amide. il) -pentanoic No. 347. [5- (3-methoxy-17-oxo-estra-l, 3, 5 (5- (3-methoxy-l, l-indol-3-yl) -ethyl] -amide. 10) -trien-15/3-yl) -pentanoic No. 348. 6- (3-Methoxy-17-oxo-estra-1, 3,5 (10) -trien-153-yl) -hexanoic acid cyclohexylamide No. 350. (6- (3-methoxy-17-oxo-estra-l, 3,5 (10) -trien-15/3-yl) -hexanoic acid furan-2-ylmethyl) -amide. (Benzo [1, 3] dioxol-5-ylmethyl) -amide of acid 6- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -hexanoic No. 354. 3-Methoxy-15 / 3- (6-morpholin-4) -yl-6-oxo-hexyl) -estra-1, 3, 5 (10) -trien-17-one No. 355. 3-Methoxy-15 / 3- (6-oxo-6-thiomorpholin-4-yl) -hexyl) -estra-1, 3, 5 (10) -trien-17-one No. 356. (Pyridin-3-ylmethyl) -amide of 6- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -hexanoic No. 357. (Pyridin-4-ylmethyl) -amide of 6- (3-methoxy-17-oxo-estra-l, 3,5 (10) -trien-15/3-yl) -hexanoic No. 359. 6- (3-methoxy-17-oxo-) acid benzylamide estra-1, 3, 5 (10) -trien-15/3-yl) -hexanoic No. 360. 2-methoxy-benzylamide of 6- (3-methoxy-17-oxo-estra-l, 3,5 (10) -trien-153-yl) -hexanoic No. 361. 3-Fluoro-benzylamide of 6- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3 -yl) -hexanoic No. 363. [2- (4-Hydroxy-phenyl) -ethyl] -amide of 6- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien- 15/3-yl) -hexanoic No. 364. Benzyl-methyl-amide of 6- (3-methoxy-17-oxo-estra-1, 3,5 (10) -trien-15/3-yl) - hexanoic No. 365. 6- (3-Methoxy-17-oxo-estra-1,3, 5 (10) -trien-15/3-yl) -hexanoic acid butylamide No. 366. (2-Tiofen-2) -6-ethyl) -amide of 6- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -hexanoic acid no. 443. 1- [3- (3-Methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -propyl] -3- (3-methoxy-phenyl) -urea No. 446. 1- [ 3- (3-Methoxy-17-oxo-estra-l, 3,5 (10) -trien-15/3-yl) -propyl] -3- (4-methoxy-phenyl) -urea No. 449. l -Isopropyl-3- [3- (3-methoxy-17-oxo-estra-1, 3, 5 (10) -trien-15 (3-yl) -propyl] -urea No. 450. l-Cyclohexyl-3- [3- (3-methoxy-17-oxo-estra-1,3,5 (10) trien-15/3-yl) -propyl] -urea No. 452. l -Benzyl-3- [3- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien-15/3-yl) -propyl] -urea No. 464. 1- (3, 4-Dimethoxy-phenyl) -3- [3- (3-methoxy-17-oxo-estra-1, 3, 5 (10) -trien-15/3-yl) -propyl] -urea No. 465. l-Benzo [l, 3] dioxol-5-yl-3- [3- (3-methoxy-17-oxo-estra-1,3, 5 (10) trien-15/3-yl) -propyl] -urea No. 477. l-Benzyl-3- [4- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien-15j-yl) -butyl] -urea No 488. 1- (3,4-Dimethoxy-phenyl) -3- [4- (3-methoxy-17-oxo-estra-1, 3,5 (10) -trien-15/3-yl) -butyl ] -urea No. 490. Ethyl ester of 4- acid. { 3- [4- (3-hydroxy-17-oxo-estra-1, 3, 5 (10) -trien-15cf-yl) -butyl] -ureido} -benzoic No. 491. l-Cyclohexylmethyl-3- [4- (3-hydroxy-17-oxo-estra-1, 3, 5 (10) -trien-lda-yl) -butyl] -urea No. 661. (3-Hydroxy-17-oxo-estra-l, 3,5 (10) -trien-15o; -ylmethyl) -amide of naphthalene-2-sulfonic acid No. 662. (3-Hydroxy-17-oxo-enter) thiofen-2-sulfonic acid-l, 3,5 (10) -trien-15o! -ylmethyl) -amide No. 664. N- (3-Hydroxy-17-oxo-estra-l, 3.5 (10 ) -trien- 15o; -ylmethyl) -benzenesulfonamide No. 665. 4-Fluoro-N- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-15o! -ylmethyl) -benzenesulfonamide No. 668. N- (3-Hydroxy-17-oxo-estra-l, 3,5 (10) -trien-15?! - ilmethyl) -4-methoxy-benzenesulfonamide No. 677. N- (3-Hydroxy) -17-oxo-estra-l, 3,5 (10) -trien-15a-ylmethyl) -3-methyl-benzenesulfonamide No. 681. (3-Hydroxy-l7-oxo-estra-l, 3.5 (10 ) N-682-naphthalene-2-sulfonic acid-methylamide-1,5-methyl-amide-3-hydroxy-17-oxo-estra-l, 3,5 (10) -trien-15o; thiophene-2-sulfonic acid-methyl-amide-no. 684. N- (3-Hydroxy-17-oxo-estra-l, 3,5 (10) -trien-15o; -ylmethyl) -N-methyl -benzenesulfonamide No. 685. 4-Fluoro-N- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-15o! -ylmethyl) -N-methyl-benzenesulfonamide No. 688. N - (3-Hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15cf-ylmethyl) -4-methoxy-N-methyl-benzenesulfonamide No. 693. 3-Chloro-N- (3- hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15o; -ylmethyl) -N-methyl-benzenesulfonamide No. 694. N- (3-Hydroxy-17-oxo-estra-l, 3 , 5 (10) -trien-l5o; -ylmethyl) -3, N-dimethyl-benzenesulfonamide No. 696. (3-Hydroxy-17-oxo-enter-1, 3,5 (10) -trien-15Q! 4-benzenesulfonyl-thiophene-2-sulfonic acid-4-methyl-amide No. 748. 3- (3-Methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15 / 3- ester) il) -propyl benzo [1,3] dioxol-5-yl-carbamic acid No. 823. 3-Hydroxy-15 / 3- (3-hydroxypropyl) -estra-1,3,5 (10) -trien- 17-one or one of its physiologically acceptable salts. The pharmaceutically acceptable salts of the compounds of the invention, as well as the commonly used prodrugs and the active metabolites of these compounds are also within the scope of the invention. Additionally, the invention relates to a compound of the invention for use as a medicament. The invention also relates to pharmaceutical compositions comprising one or more of the compounds of the invention, or their salts or prodrugs, as an active agent and at least one pharmaceutically acceptable carrier. Furthermore, the invention relates to the use of an effective amount of a compound of the invention for the treatment or prevention of a disease or disorder dependent on steroid hormones in a mammal, particularly a human being. Preferably, the steroid hormone-dependent disease or disorder is an oestradiol-dependent disease or disorder. In addition, 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 disease or disorder dependent on steroid hormones in a mammal, in particular a human being. Preferably, the steroid hormone-dependent disease or disorder is an oestradiol-dependent disease or disorder. In a further embodiment of the invention, the disease or disorder dependent on steroid hormones requires the inhibition of a 17/3-HSD enzyme, preferably the human 17/3-HSD1 enzyme. In addition, the invention also relates to a method for treating a mammal, such as a human being, that it has a status related to 17/3-HSD1 activity, which comprises 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. The administration of compounds of this invention is contemplated in combination with other pharmaceutical products used in the treatment of the mentioned states. The conditions to be treated include, but are not limited to, a malignant disease or disorder dependent on estradiol such as breast cancer, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia. According to a further aspect of the invention, the oestradiol-dependent disease is breast cancer and the mammal is a post-menopausal human female. In addition, the states to be treated include, but are not limited to, benign oestradiol-dependent diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, and urinary dysfunction. In a further embodiment, the invention relates to the use of an effective amount of a compound of the invention for the treatment or prevention of one of the aforementioned benign gynecological diseases or disorders in a mammal, in which the mammal is a human , preferably a female and most preferably a female pre- or peri-menopausal. According to one aspect of the present invention, the steroid hormone-dependent disease or disorder is selected from the group consisting of prostate carcinoma, prostadynia, benign prostatic hyperplasia, urinary dysfunction, and lower urinary tract syndrome. According to one aspect of the invention, the steroid hormone-dependent disease or disorder to be treated requires a decrease in the concentration of endogenous 17/3-estradiol in a generalized and / or tissue-specific manner. Therefore, additional estrogen-dependent diseases that can be treated with an effective amount of a compound of the invention are rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts. The described compounds are also useful as diagnostic agents (for example in diagnostic kits or for use in clinical laboratories.), For assessing the presence or absence of 17/3-HSD1 activity. to the use of a selective inhibitor of the enzyme 17/3-HSD1 for the treatment and / or prophylaxis of a benign disease or disorder dependent on estradiol in a mammal, in particular a human being, preferably a female and most preferably a pre- or peri-menopausal female. In a preferred embodiment of the present invention, the selective inhibitor of the enzyme 17/3-HSD1 used for the treatment and / or prophylaxis of a benign disease or disorder dependent on estradiol possesses no or only pure affinities of antagonistic binding with respect to the receptor. of estrogen. The invention also relates to a method for treating a mammal such as a human being, having a benign, estradiol-dependent state, comprising administering to the mammal an amount of a selective inhibitor of the enzyme 17/3-HSD1, wherein said inhibitor preferably also possesses no or only pure affinities of antagonist binding to the estrogen receptor, and amount that is effective to treat the condition. The administration of a selective inhibitor of the enzyme 17/3-HSD1 is contemplated which additionally possesses no or only the pure affinities of antagonistic binding with respect to the estrogen receptor of this invention in combination with other pharmaceutical products used in the treatment of the mentioned states . The benign dependent states of estradiol that have to be treated with a selective inhibitor of the enzyme 17/3-HSD1 includes, but is not limited to, endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, and dysfunction urinary The invention also relates to the use of a selective inhibitor of the enzyme 17/3-HSD1 for the preparation of a pharmaceutical composition for the treatment and / or prevention of a benign disease or disorder dependent on estradiol in a mammal. The benign oestradiol-dependent disease or disorder is preferably endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia or urinary dysfunction. In addition, the enzyme 17/3-HSD1 preferably has none or only the pure affinities of antagonist binding to the estrogen receptor. In a preferred embodiment, the invention relates to the use of an effective amount of a selective inhibitor of the enzyme 17/3-HSD1 for the preparation of a pharmaceutical composition for the treatment and / or prevention of a benign disease or disorder dependent on estradiol. in a mammal, in which the mammal is a human being, preferably a female and most preferably a pre- or peri-menopausal female. Furthermore, the present invention relates to the use of a selective inhibitor of the 17/3-HSD1 enzyme that shows nothing or only the pure affinities of estrogen receptor antagonistic binding for the prevention of breast cancer in a post-menopausal female, and to the use of said inhibitors selective for the elaboration of a medically for the prevention of breast cancer in a post-menopausal female.

DESCRIPTION OF THE INVENTION Definitions: The following terms and expressions are used to describe various constituents of the chemical composition useful in this invention. The terms are defined as follows: As used herein, the terms "comprising" and "including" are used herein in their broad, non-limiting sense. The word "compound" should be understood herein to encompass any and all isomers (e.g., enantiomers, stereoisomers, diastereomers, rotomers or tautomers) or any mixture of isomers, prodrugs and any pharmaceutically acceptable salt of said compound . When the plural form is used for compounds, salts and the like, it should be interpreted as meaning also a single compound, salt or the like. The term "substituted" means that the specified group or moiety carries one or more substituents. When any group can carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and not They need to be the same. The expression "unsubstituted" means that the specified group does not carry any substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. Any of the asymmetric carbon atoms may be present in the (R), (S) or (R, S) configuration, preferably in the (R) or (S) configuration, whichever is more active. The substituents on a double bond or on a ring may be present in the cis (= Z-) or trans (= E-) form. The compounds of formula I contain at least one chiral carbon atom, namely the carbon atom carrying the side chain at position 15 of the steroid structure. Thus, the compounds can be present in two optically active stereoisomeric forms or as a racemate. The present invention includes both the racemic mixtures and the compounds of the formula I isomerically pure. The position of the substituents at the C15 position is characterized by o; or ß. A C15ce derivative according to the present invention is represented by a compound of the following formula (II) (III) while a C15 / 3 derivative according to the present invention is represented by a compound of the following formula (III) The compounds of the present invention may contain additional asymmetric centers in the molecule, depending on the nature of the various substituents. In certain cases, the asymmetry may also be present due to the restricted rotation around the central link joining the two aromatic rings of the specified compounds. It is expected that all isomers (including enantiomers and diastereomers), by the nature of the asymmetric centers or by the restricted rotation as described above, in the form of separate, pure or partially purified isomers or their racemic mixtures, are included within the scope of the present invention. The term "halogen" refers to fluorine atoms (F, fluoro-), bromine (Br, bromo-), chlorine (Cl, chloro-) and iodine (I, iodo-).

The terms "dihalogen", "trihalogen" and "perhalogen" refer to two, three and four substituents, respectively, individually selected each from the group consisting of fluorine, bromine, chlorine and iodine atoms. The term "hydroxyl" refers to the -OH group. The term "oxo" refers to the group = 0. The term "carbamoyl" refers to the group -C0-NH2. The term "uncle" refers to the group = S. The term "thiol" refers to the group -SH. The term "sulfanyl" refers to the group -S-. The term "sulfoxy" or "sulfonyl" refers to the group -S (0) 2-. The term "sulfamoyl" refers to the group -S02-NH2. The term "nitro" refers to the group -N02. The term "nitrile" or "cyano" refers to the group -CN For the purposes of the present invention, the carbon content of various hydrocarbon-containing moieties is indicated by a suffix indicating the minimum and maximum number of carbon atoms in the remainder, for example the suffix d-Cj defines the number of atoms of carbon present from the whole number "i" to the whole number "j" inclusive. Thus, C?-C 4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and their isomeric forms.

The term "alkyl" represents a hydrocarbon radical which may be linear, cyclic or branched, with a single or multiple branching, in which the alkyl group comprises 1 to 12 carbon atoms. In one embodiment, the term "alkyl" represents a linear or branched alkyl chain (with single or multiple branching) of 1 to 8 carbon atoms, exemplified by the term alkyl (d-C8), more preferably from 1 to 6 carbon atoms. carbon exemplified by the term alkyl (C? -C6). The term alkyl (C? -C8) is further exemplified by groups such 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. The alkyl or (C? -C8) alkyl group may be partially unsaturated, forming groups such as, for example, vinyl, propenyl (allyl), butenyl, pentenyl, pentynyl, hexenyl, octadienyl and the like. The term "alkyl" further comprises cycloalkyl groups, preferably (C3-C8) cycloalkyl which refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl and its isomeric forms such as methylcyclopropyl, 2- or 3-methylcyclobutyl, 2- or 3-methylcyclopentyl and the like. The cycloalkyl group can also be partially unsaturated to form groups such as, for example, cyclohexenyl, cyclopentenyl, cyclooctadienyl and Similar. In addition, the term "alkyl" comprises a cycloalkyl group comprising 4 to 12 carbon atoms, preferably "- (C 1 -C 4) alkyl- (C 3 -C 8) cycloalkyl" which refers to an alkyl group of 1 to 4 carbon atoms as described above substituted with a (C3-C8) cycloalkyl group as described above, forming groups such as, for example, cyclopropylmethyl, cyclohexylmethyl, cyclopentylmethyl or cyclohexylethylethyl. The term "alkyl" further comprises 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] octi-lo, bicyclo [3.2.2] nonanil, bicyclo [3.3. l] nonanyl, bike-clo [3.3.2] decanyl; and the like, preferably bike-clo [2.2.1] heptyl, and fused ring systems of up to 10 carbon atoms such as adamantyl and the like. The alkyl group may be optionally substituted with up to five, more preferably up to three substituents independently selected from the group consisting of halogen, hydroxyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloheteroalkyl, thiol, nitro, nitrile, alkoxy, aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamido, acyl, carboxyl and acylamino, as described herein.

These groups can be attached to any carbon atom of the alkyl moiety. The substituted alkyl is preferably substituted with halogen, nitrile, hydroxyl, C 1 -C 4 alkoxy (in which the alkyl chain may be optionally substituted with up to three hydroxyl groups), phenoxy, benzyloxy, C 1 -C 4 alkylthio, alkylamino, a group carboxyl - (C =) -OR ', and alkylamido (preferably carbamoyl), the number of substituents in said alkyl portion being up to five for hydroxyl and up to three, more preferably up to two for any combination of said other substituents; as well as with optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cyclo-heteroalkyl, as defined herein. The cycloalkyl is preferably substituted with hydroxyl. The alkyl group substituted with up to three independently selected aryl groups preferably refers to "aryl-alkyl (C? -C4) or diaryl-alkyl (d-C4), wherein the aryl is phenyl, naphthyl, indanyl, indenyl or , 2,3,4-tetrahydro-naphthalene-1-yl, preferably aryl is phenyl or naphthyl, forming groups such as, for example, benzyl, diphenylmethyl, phenethyl, phenylpropyl, diphenylpropyl, phenylbutyl, naphthalenylmethyl or naphthalethylethyl. additionally substituted as defined above, for example, the alkyl chain can carry an additional hydroxyl group, in addition, the alkyl chain can be partially unsaturated, such as a vinyl group. The aryl moiety may be optionally substituted as defined herein; preferably, the aryl moiety is substituted with substituents selected from the group consisting of halogen, hydroxyl, (C? -C3) alkoxy, (C? -C3) alkyl, halogenated (Ca-d) alkyl, (C? -C4) alkoxy ) halogenated, alkylamido, preferably carbamoyl and sulphamoyl; the number of said substituents being up to five for halogen and up to three for any combination of said other substituents. In addition, said aryl may be optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a saturated cyclic ring system with 5 or 6 members, optionally containing up to three heteroatoms such as N or Or, the number of N atoms being 0-3 and the number of O atoms being 0-2, such as, for example, substituted with a [1,3] -dioxol group. The alkyl group substituted with up to three independently selected heteroaryl groups preferably refers to "heteroaryl (C? -C4) alkyl", wherein the heteroaryl is pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl , pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzofuran, benzo [b] thiophene, preferably heteroaryl is furyl, indolyl, benzoimidazolyl, pyridinyl, thienyl or imidazolyl, forming groups such as, for example, benzoimidazolylmethyl, pyridinylmethyl, thienylmethyl, furylmethyl, indolylethyl, thienylethyl, pyridinylethyl or imidazolylpropyl. The heteroaryl moiety may be optionally substituted as defined herein; preferably, the heteroaryl moiety is substituted with substituents selected from the group consisting of (C? -C4) alkoxy, preferably methoxy, alkyl (C? -d), preferably methyl, or halogenated (C? -C4) alkyl, the number of said substituents of up to two for any combination of said substituents. The alkyl group substituted with up to three independently selected cycloheteroalkyl groups preferably refers to "cycloheteroalkyl-alkyl (d-C4), wherein the cycloheteroalkyl is pyrrolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and thiazepanyl, preferably cycloheteroalkyl is piperidinyl, pyrrolidinyl or morpholinyl, forming groups such as, for example, morpholinylethyl, morpholinylpropyl, piperidinylethyl or pyrrolidinylethyl The term "alkoxy" refers to a group -OR, wherein R can be alkyl (at wherein the alkyl chain may be optionally further substituted as defined herein, preferably with up to three hydroxyl groups or up to five halogen residues), carbonyl, or acyl as defined herein. Preferably, the term "alkoxy" refers to -O-alkyl (C? -C6) (or (C? -C6) alkoxy), with the alkyl group (C? -C6) as defined above and optionally substituted with up to three hydroxyl groups. The term "aryloxy" refers to an -OAr group, wherein Ar represents aryl as defined herein, which is optionally substituted on the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, alkyl (C ? -C4), alkoxy (C? -C), alkyl (C? -C4) halogenated or halogenated (C? -C4) alkoxy; the number of said substituents being up to five for halogen and up to three for any combination of said other substituents.

Preferably, aryloxy refers to phenoxy, optionally substituted as defined above. The term "arylalkyloxy" refers to a group -0-alkyl (C-C4) -Ar, where Ar represents aryl, which is optionally substituted on the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, alkyl (C? -C), alkoxy (C? -C4), halogenated (C? -C4) alkyl or halogenated (C? -C4) alkoxy; the number of said substituents being up to five for halogen and up to three for any combination of said other substituents. Preferably, arylalkyloxy refers to benzyloxy, optionally substituted as defined above.

The term "acyl" refers to a group - (C = 0) -R, wherein R can be hydrogen, alkyl (optionally substituted on the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (C? -C4) alkoxy, aryl or aryl (C? -C4) alkyl (both optionally substituted on the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, alkyl (d-C4) (C? -C4) alkoxy, halogenated (d-C4) alkyl or halogenated (C? -d) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents), heteroaryl or heteroaryl (C? -C4) alkyl (both optionally substituted on the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein. Preferably, the term "acyl" refers to a group - (C = 0) -R ', wherein R' represents hydrogen, (C? -C4) alkyl, phenyl or phenyl-alkyl (C? -C4), preferably benzyl or heteroaryl-alkyl (C? -C), preferably indolyl-methyl; wherein the phenyl moiety can be optionally substituted with independently selected substituents, especially hydroxyl, halogen, (C? -C4) alkoxy, (C? -C4) alkyl or halogenated (C-C4) alkyl, the number of said Substituents up to five for halogen and up to three for anycombination of said other substituents. The term "carbonyl" represents a preferred selection of the term "acyl" and refers to the group -CHO. The term "alkylate" represents a preferred selection of the term "acyl" and refers to a group - (C = 0) -alkyl, preferably - (C = 0) -alkyl (C? -C4). The term "carboxyl" refers to a group - (C = 0) -OR, wherein R can be hydrogen, alkyl (optionally substituted on the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (C? -C4) alkoxy, aryl or aryl-alkyl (C -C ^) (both optionally substituted on the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, alkyl (d-C4) alkoxy (dd) / halogenated alkyl (dC) or halogenated (C? -C4) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents), heteroaryl or heteroaryl-C (-C 4) alkyl (both optionally substituted on the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein. Preferably, the term "carboxyl" refers to a group - (C = 0) -OR ', wherein R' represents hydrogen, alkyl (C? -C), phenyl or phenyl-alkyl (C? -C4), preferably benzyl; in which the phenyl moiety may be optionally substituted with substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C4) alkoxy, (C? -C4) alkyl, halogenated (C? - C4) alkyl and alkoxy (d-? C4), the number of said substituents being up to five for halogen and up to three for any combination of said other substituents. The terms "carboxyl-alkyl (C? -C3)" and "carboxyl-alkyl (C-C4)" refer to -alkyl (C? -C3) - (C = 0) -OR and alkyl (C? C4) - (C = 0) -OR, respectively, which refer to an alkyl group of 6 and 4 carbon atoms, respectively, as described above, substituted with a group -C (C = 0) -0R as It was described earlier. Preferably, the carboxyl group refers to - (C = 0) -OR ', wherein R' represents hydrogen, alkyl (C? -C), phenyl or alkyl (C? -C) -phenyl, preferably benzyl. Preferred examples of these carboxyl-alkyl groups (C? -C6) include methyl ester of acetic acid, ethyl ester of acetic acid, benzyl ester of propionic acid, ethyl ester of propionic acid, methyl ester of butyric acid and methyl ester of acid 3 -methyl-butyric. The term "amino" refers to the group -NRR ', wherein R and R' can independently be hydrogen, alkyl (optionally substituted on the alkyl chain with up to five independently selected substituents such as is defined herein, in particular hydroxyl, halogen or (C? -C4) alkoxy, aryl or aryl-alkyl (Ca-C4) (both optionally substituted in the aryl group with up to five independently selected substituents as defined in present, in particular hydroxyl, halogen, alkyl (dd) / (C? -C4) alkoxy, halogenated (C? -C4) alkyl or halogenated (C? -C) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents), heteroaryl or heteroaryl (C? -C4) alkyl (arabos optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined in the present. The term "alkylamino" represents a preferred selection of the term "amino" and refers to the group -NRR ', wherein R and R' may independently be hydrogen or alkyl (dd) • The term "alkylthio" or "alkylsulfonyl" refers to a group -SR, wherein R represents alkyl, optionally substituted on the alkyl chain with up to five substituents as defined herein, preferably hydroxyl, alkoxy (C -C4) or halogen; preferably, R represents alkyl (C? -C6), in particular (C? -C4) alkyl, as defined above. The term "arylthio" or "arylsulfañilo" refers to a -S-Ar group, in which Ar represents aryl, which is optionally substituted on the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, alkyl (d-C4), alkoxy (C-) C), halogenated (C? -C4) alkyl or halogenated (C? -C4) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents. Preferably, arylthio refers to phenylsulfanyl, optionally substituted as defined above. The term "arylalkylthio" or "arylalkylsulfañilo" refers to a group -S-alkyl (C? -C4) -Ar, in which Ar represents aryl, which is optionally substituted in the aryl group with independently selected substituents as defined in present, in particular hydroxyl, halogen, alkyl (Ci-C4), alkoxy (d-C4) halogenated (C? -C4) alkyl or halogenated (C? -C4) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents. Preferably, arylalkylthio refers to benzylsulfañil, optionally substituted as defined above. The term "alkylsulfonyl" refers to a -S02-R group, wherein R represents alkyl, optionally substituted on the alkyl chain with up to five substituents as defined herein, preferably hydroxyl, (C? -C) alkoxy or halogen; preferably, R represents alkyl (C? -C6), in particular (C? -C4) alkyl, as defined above. The term "arylsulfonyl" refers to a group -S02-Ar, where Ar represents aryl, which is optionally substituted on the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, alkyl (C? -C4), (C-C4) alkoxy, halogenated (C? -C4) alkyl or halogenated alkoxy (dd), the number of said substituents being up to five for halogens and up to three for any combination of said other substituents Preferably, arylsulfonyl refers to benzenesulfonyl, optionally substituted as defined above. The term "arylalkylsulfonyl" refers to a group -S02-alkyl (C? -C4) -Ar, where Ar represents aryl, which is optionally substituted on the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (d-C4) alkyl, (C? -C) alkoxy, halogenated (C? -C4) alkyl or halogenated (C? -C4) alkoxy, the number of said substituents being up to five for halogen and of up to three for any combination of said other substituents. Preferably, arylalkylsulfonyl refers to benzylsulfonyl, optionally substituted as defined above.

The term "amido" refers to the group - (C = 0) -NRR ', wherein R and R' may independently be hydrogen, alkyl (optionally substituted on the alkyl chain with up to five independently selected substituents as defined in present, in particular hydroxyl, halogen or (C 1 -C 4) alkoxy, aryl or aryl-alkyl (d ~ d) (both optionally substituted on the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, alkyl (C? -C), alkoxy (d-C4), halogenated (C? -C4) alkyl or halogenated (C? -C4) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents), heteroaryl or heteroaryl (C? -C4) alkyl (both optionally substituted on the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein. rent "mido" represents a preferred selection of the term "amido" and refers to the group - (C = 0) -NRR ', wherein R and R' can be independently selected from hydrogen or (C? -C4) alkyl. The term "acylamino" refers to the group -NR-CO-R ', wherein R and R' may independently be hydrogen, alkyl (optionally substituted on the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (C? -C4) alkoxy, aryl or aryl (C? -C4) alkyl (both optionally substituted on the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, alkyl (C? - C4), alkoxy (d-C4), halogenated (C? -C) alkyl or halogenated (C? -C4) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents ), heteroaryl or heteroaryl (C? -C4) alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein. Preferably, acylamino refers to -NH-CO-alkyl (C? -C4). The term "carbonylamino" represents a preferred selection of the term "acylamino" and refers to the group -NR-CO-CH2-R ', wherein R and R' can be independently selected from hydrogen or alkyl (C? -C4) . The term "sulfonamide" refers to the group -S02-NRR ', wherein R and R' can be independently selected from hydrogen or (C? -C4) alkyl. Halogenated alkyl, halogenated alkoxy and halogenated alkylthio are substitutes in which the alkyl radicals (preferably alkyl (C? -C6), more preferably alkyl (d-C4) and most preferably methyl) are partially or completely substituted with halogens, generally with chlorine and / or fluorine. Preferred examples of these substituents are trifluoromethyl, trifluoromethoxy, trifluoromethylthio, dichloromethyl, pentafluoroethyl, dichloropropyl, fluoromethyl and difluoromethyl. The term "cycloheteroalkyl" refers to a four to eight member heterocyclic ring containing at least one heteroatom such as N, O or S, the number of N atoms being 0-3 and the number of O atoms being S each of 0-1, system that can be saturated, partially unsaturated or hydroaromatic, and ring that can be part of a multi-ring system in which some rings can be aromatic. Examples of these cycloheteroalkyls include pyrrolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-lH-pyrrolyl, 3,6-dihydro-2H-pyridinyl , 1,3-dihydro-benzoimidazolyl and the like. Preferred examples of these cycloheteroalkyl groups are pyrrolidinyl, morpholinyl, tetrahydrofuryl, piperidinyl or azepanyl. The cycloheteroalkyl group can be optionally substituted with up to three substituents, independently selected from the group consisting of oxo, alkyl, aryl or arylalkyl (C? -C4), hydroxyl, (C6-C6) alkoxy, halogenated (C? -C6) alkyl , halogenated (C? -C6) alkoxy, carboxyl (C? -C3) alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy, alkylthio (d-C6) arylthio or arylalkylthio, amino, amido, acyl and acylamino, as defined herein, wherein the aryl groups are optionally substituted with independently selected substituents as defined herein, in particular hydroxyl, halogen, (C? -C4) alkyl, (C? -C) alkoxy, halogenated (C? -C4) alkyl or halogenated (C? -C) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents. The substituents of the cycloheteroalkyl groups can be attached to any carbon atom of the cycloheteroalkyl moiety. The substituted cycloheteroalkyl is preferably substituted with oxo, (C 1 -C 4) alkyl, preferably methyl, phenyl and / or phenyl-alkyl (C 1 -C), in particular benzyl. The terms "aryl" or "Ar" refer 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 fused rings in which at least one ring is aromatic. Preferably, aryl is phenyl, naphthyl, indanyl, indenyl or 1, 2, 3, 4-tetrahydro-naphthalen-1-yl. The term "heteroaryl" refers to an aromatic carbocyclic group having a single ring of 4 to 8 members or multiple fused rings comprising 6 to 14, more preferably 6 to 10 atoms in the ring and containing at least one heteroatom such as N, O or S, with at least one ring, the number of N atoms being 0-3 and the number of O atoms being S each from 0-1; a group in which at least one heterocyclic ring is aromatic. Examples of these groups include pyrrolyl, thienyl, firyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoimidazolyl, 1,3-dihydrobenzoimidazolyl, benzofuran. , benzo [b] thiophene and the like. Preferably, heteroaryl is quinolinyl, furyl, benzoimidazolyl, pyridinyl, thienyl, indolyl, benzo [b] thiophene, pyridinyl, imidazolyl, pyrazolyl or thiazolyl. The aryl group and the heteroaryl group may be optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, (C? -C6) alkoxy, (C? -C6) alkyl, halogenated (C-C6) alkyl, alkoxy (C? -C6) halogenated, carboxyl-alkyl (Ci-C6), oxo, thiol, nitro, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy, alkylthio (d-C3), arylthio or arylalkylthio, alkylsulfonyl, arylsulfonyl, amino, amido, acyl and acylamino, as defined herein, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents; wherein the aryloxy, arylalkyloxy, arylthio or arylalkylthio group can be optionally substituted on the aryl moiety with independently selected substituents as defined herein, in particular hydroxyl, halogen, alkyl (C? -C), alkoxy (d-C4) ), halogenated (C? -C) alkyl or halogenated (C? -C) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents. The heteroaryl group may also be optionally substituted with an aryl group, which may be optionally substituted on the aryl moiety with substituents, especially, hydroxyl, halogen, (C? -C6) alkoxy, (d-C6) alkyl / alkyl (C? -C6) halogenated or halogenated (C? -C3) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents. The aryl group may also be optionally substituted with a heteroaryl group or a second aryl group. Substituted aryl is preferably substituted with substituents selected from the group consisting of (C? -C4) alkyl, halogen, halogenated (C? -C4) alkyl, preferably halogenated methyl, (C? -C6) alkoxy, (C? C6) halogenated, hydroxyl, alkylaryl, carboxyl, nitro, nitrile, acylamino, alkyl (C? -C) -sulfonyl, arylsulfonyl and sulphamoyl, the number of said substituents being up to five for halogen and up to three, preferably up to two for any combination of said other substituents. Preferably, substituted aryl is substituted phenyl. The aryl can be further substituted with two groups that are bonded to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic system of 5, 6, 7 or 8 membered rings, optionally containing up to three heteroatoms such as N, O or S, the number of atoms of N being 0-3 and the number of atoms of O and S each being 0-2. Preferably, the two groups which are bonded to adjacent carbon atoms are combined in the form of a cyclic saturated system of 5 or 6 membered rings, optionally containing up to 3 heteroatoms, such as N or O, the number of N atoms being of 0-3 and the number of atoms of 0 each being 0-2. This cyclic ring system may also be optionally substituted with an oxo group. Preferred examples of these substituted aryl groups are benzo [1,3] dioxole and 1,3-dihydro-benzomidazole-2-on. The substituted heteroaryl is preferably substituted with up to three, preferably up to two substituents selected from the group consisting of halogen, (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, preferably methyl, halogenated (C 1 -C 4) alkyl , preferably halogenated methyl, halogenated (C? -C4) alkoxy, phenoxy (optionally substituted with up to three, preferably a halogen), benzyloxy, benzenesulfonyl, phenyl or carboxyl-alkyl (C-C4) with a carboxyl group - (C = 0) -OR 'in which R' represents hydrogen, alkyl (C? -C), preferably methyl or alkyl (dd) phenyl, preferably benzyl. It is noted that when two side chains are in a single N, they can be combined, including the N to which they are attached, in the form of a heterocyclic ring of 4, 5, 6, 7 or 8 atoms, which can be saturated, partially unsaturated or aromatic, and which optionally can contain up to three additional heteroatoms selected from N, 0 or S, the number of N atoms being 0-3 and the number of atoms of 0 and S each being 0- 2; and ring that can be part of a system of multiple condensed rings, in which some rings can be aromatic. Preferred examples of these heterocyclic ring systems, including the N to which the respective side chains are attached, are: The aforementioned heterocyclic ring system can be optionally substituted with up to 3 substituents, which can be attached to any carbon or nitrogen atom of the heterocyclic ring system. Preferred examples of substituted heterocyclic ring systems are: The up to three optional substituents independently selected for the heterocyclic ring system can be chosen from optionally substituted alkyl, halogen, hydroxyl, oxo, thiol, nitro, nitrile, (C? -C6) alkoxy, aryl, heteroaryl, optionally substituted cycloheteroalkyl, aryloxy , arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamide, acyl, carboxyl and acylamino, as defined herein, wherein all aryl or heteroaryl moieties may be optionally substituted with up to five, preferably up to three independently selected substituents as defined herein. Preferably, the system Heterocyclic rings are optionally substituted with substituents independently selected from the group of hydroxyl, oxo, carboxyl, carboxyl-alkyl (C? -C6), amido; optionally substituted cycloheteroalkyl; aryl or aryl (C? -C4) alkyl (optionally substituted aryl in the aryl group with substituents independently selected from hydroxyl, halogen, (C? -C4) alkyl, (C? -C4) alkoxy, alkyl (C? -C ) halogenated or halogenated (C? -C) alkoxy, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents, or wherein the aryl moiety may be optionally substituted with two groups which they are bonded to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic system of 5, 6, 7 or 8 member rings, optionally containing up to three heteroatoms such as N, O or S, the number being N atoms of 0-3 and the number of atoms of O and S each being 0-2), heteroaryl and (C? -C8) alkyl (optionally substituted with up to five substituents independently selected from hydroxyl, halogen, alkoxy ( C-C4) or alkoxy (C? -C4) h allogenated, wherein the alkyl chain of the alkoxy moiety (d-C) may also be optionally substituted with up to three hydroxyls), the number of said substituents being up to three, more preferably up to two, for any combination of said substituents. Even more preferably, the system of heterocyclic rings is optionally substituted with substituents independently selected from the group of hydroxyl, oxo, alkylamido, preferably carbamoyl; alkyl (C? -C4); cycloalkyl (C3-C8); a carboxyl group - (C = 0) -OR ', wherein R' represents hydrogen or alkyl (C? -C); alkyl (C? -C4) optionally substituted with up to two hydroxyls and / or (C? -C4) alkoxy groups (in which the alkyl chain of the alkoxy moiety (C? -C4) may also be optionally substituted with up to two, preferably a hydroxyl group); phenyl optionally substituted with halogen, (C? -C4) alkyl, preferably methyl, (C? -C4) alkoxy or alkyl (C? -C4) halogenated, preferably halogenated methyl, the number of said substituents on the phenyl moiety being up to five for halogen and up to three for any combination of said other substituents; phenyl-(C? -C4) alkyl, preferably benzyl, optionally substituted on the phenyl group with substituents independently selected from halogen, (C? -C4) alkyl, (C? -C4) alkoxy or halogenated (C? -C) alkyl , preferably halogen, the number of said substituents being up to five for halogen and up to three for any combination of said other substituents, or is optionally substituted on the phenyl group with two groups that are bonded to adjacent carbon atoms and are combined in form of a saturated or partially unsaturated cyclic ring system with 5 or 6 members, which optionally contains up to two O atoms; heteroaryl, preferably pyridinyl, heteroaryl-C (-C 4) alkyl or cycloheteroalkyl, preferably pyrrolidinyl or 1,3-dihydro-benzoimidazolyl, cycloheteroalkyl group which is optionally substituted with oxo. In addition, the aforementioned heterocyclic ring system can be substituted with two groups which are attached to the same carbon atom and are combined in the form of a saturated or partially unsaturated cyclic system of 4, 5, 6, 7 or 8 rings. members, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms being 0-2. This cyclic ring system may also be optionally substituted with up to three substituents independently selected from oxo, (C? -C6) alkyl, aryl, preferably phenyl and aryl (C? -C4) alkyl, preferably benzyl. Preferred examples of these substituted heterocyclic ring systems are 1, 4-dioxa-8-azaspiro [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] -decano and 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one. The term "prodrug" as used herein, represents derivatives of the compounds of the invention which are drug precursors which, following a administration to the patient, they release the drug in vivo through a chemical or physiological procedure. In particular, the prodrugs are derivatives of the compounds of the invention in which the functional groups carry additional substituents which can be cleaved under physiological conditions in vivo and thus release the active principle of the compound (for example, a prodrug after being taken to a Physiological pH or through an enzymatic action is converted into the desired drug form). The term "pharmaceutically acceptable salts" refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject to which the compounds of the invention are being administered. Pharmaceutically acceptable salts of compounds of formula I include acid addition salts or conventional and stoichiometric base addition salts, formed from organic or inorganic acids or inorganic bases which are suitable and non-toxic. Salts by the addition of acids, for example, from compounds of the formula I with a basic nitrogen atom, are preferably formed with organic or inorganic acids. Suitable inorganic acids are, for example, acids derived from halogens such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphoric or sulphonic acids, for example acetic acid, acid propionic acid, glycolic acid, lactic acid, hydroxybutyric acid, malic acid, malic acid, malonic acid, salicylic acid, fumaric acid, succinic acid, adipic acid, tartaric acid, citric acid, glutaric acid, 2- or 3-glycerophosphoric acid and others mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in a conventional manner. The compounds containing acidic substituents can also form salts with inorganic or organic bases. Examples of suitable bases for the formation of salts include, but not limited thereto, inorganic bases such as alkali or alkaline earth metal hydroxides (eg, sodium, potassium, lithium, calcium or magnesium), and those derived from ammonium hydroxides (eg, quaternary ammonium hydroxide such as tetramethylammonium hydroxide). Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine, benzylamines, piperidines and pyrrolidines and the like. Certain compounds will be acidic in nature, for example compounds having a carboxyl or phenolic hydroxyl group. Salts of phenols can be prepared by heating acidic compounds with any of the aforementioned bases according to procedures well known to the experts in the art. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts . The term "effective amount", as used herein, means an amount of a compound or composition that is sufficient 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 to be used 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 the concurrent therapy, the particular active ingredient (s) being employees, the particular pharmaceutically acceptable excipients or vehicles that are being used, and similar factors within the knowledge and experience of the attending physician.

Forms of administration The method of the invention is primarily intended for the treatment of a mammal, preferably humans and other primates, of steroid hormone-dependent diseases or disorders, in particular oestradiol-dependent diseases or disorders, in which the disease or steroid hormone-dependent disorder preferably requires the inhibition of a 17/3-HSD enzyme, preferably the enzyme 17/3-HSD1. The compounds may be administered orally, dermally, parenterally, by injection, by pulmonary or nasal delivery, or sublingually, rectally or vaginally in formulations of dosage units. The term "administered by injection" includes intravenous, intraarticular, intramuscular injections (eg, injection from reservoir in which the active compounds are slowly released into the blood from the reservoir and are transported from there to the target organs), intraperitoneal, intradermal, subcutaneous and intrathecal, as well as the use of infusion techniques. Dermal administration may include a topical application or a transdermal administration. One or more compounds may be present in association with one or more non-toxic and pharmaceutically acceptable auxiliary substances such as excipients, adjuvants (e.g., buffers), carriers, inert solid diluents, suspending agents, preservatives, fillers, stabilizers, antioxidants. , food additives, bioavailability enhancers, coating materials, granulating and disintegrating agents, agents binders, etc. and, if desired, other active ingredients. The pharmaceutical composition can be formulated, for example, in the form of formulations of immediate release, sustained release, pulse release, release in two or more stages, from a reservoir or other type of release. The preparation of the pharmaceutical compositions according to the invention can be carried out according to methods known in the art and will be explained in more detail later. Commonly known and pharmaceutically acceptable auxiliary products, as well as other suitable diluents, flavors, sweetening agents, coloring agents, etc., may be used, depending on the intended mode of administration, as well as on the particular characteristics of the active compound to be used. such as solubility, bioavailability, etc. Suitable auxiliary products and additional ingredients may be as recommended in the pharmaceutical, cosmetic and related fields and which are preferably cited in the European Pharmacopoeia, approved by the FDS or listed in the "GRAS" list (FDA list of food additives). are "generally recognized as safe" (GRAS)). One method of application of the compounds of the general formula (I) or of pharmaceutical compositions comprising one or more of said compounds is the oral application, for example by means of tablets, pills, dragees, gel capsules hard and soft, granules, nodules, aqueous solutions, lipids, oily or others, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, compounds suitable for the purposes of the present invention, as defined above, can be mixed with commonly known and used adjuvants and excipients such as, for example, gum arabic, talc, starch , sugars (such as, for example, mannose, methylcellulose or lactose), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, agents for flavor (eg, ethereal oils), solubility enhancers (eg, benzyl benzoate or benzyl alcohol) or bioavailability enhancers (eg, Gelucire). In the pharmaceutical composition, the active ingredients may also be dispersed in a microparticle composition, for example nanoparticles. For parenteral administration, the active agents can be dissolved or suspended in a physiologically acceptable diluent such as, for example, water, a buffering agent, oils with or without solubilizers, surfactants, dispersants or emulsifiers. As oils, for example and without limitation, can be used olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil. More generally speaking, for parenteral administration, the active agent may be in the form of an aqueous, lipid, oily or other solution or suspension, or even be administered in the form of liposomes or nanosuspensions. The transdermal application can be performed by suitable patches, as is generally known in the art, specifically designed for the transdermal delivery of active agents, optionally in the presence of specific permeability enhancers. In addition, emulsions, ointments, pastes, creams or gels can also be used for a transdermal supply. Another suitable mode of administration is through intravaginal devices (e.g., vaginal rings) or intrauterine systems (IUS) that contain reservoirs for the controlled release of active agents for extended periods of time. For rectal or vaginal administration of the drug, the compounds can 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, therefore, will melt in the rectum or vagina to release the drug.

Another mode of application is by implantation of a reservoir implant comprising an inert carrier material, such as biologically degradable polymers or synthetic silicones such as, for example, silicone rubber. These implants are designed to release the active agent in a controlled manner for a prolonged period of time (for example, 3 to 5 years). It will be appreciated by those skilled in the art that the particular administration method will depend on a variety of factors, all of which are routinely considered when administering therapeutic products. However, it will also be understood that the actual dosages of the agents of this invention for any given patient will depend on 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, in addition, the age of the patient, the patient's body weight, the patient's general health status, the patient's sex, the patient's diet, the rate of excretion, the combinations of drugs and the severity of the state undergoing therapy. It will further be appreciated by one skilled in the art that the optimum course of treatment, ie the mode of treatment and the daily number of doses of a compound of the formula I or a pharmaceutically acceptable salt thereof provided for a defined number of days, can be determined by those skilled in the art using conventional treatment assays. Optimal dosages for a given set of conditions can be determined by those skilled in the art using conventional assays for determining the dosage taking into account the experimental data for a given compound. For oral administration, an example of a daily dose generally employed will be from about 0.01 μg / kg to about 100 mg / kg of total body weight, whereby the courses of treatment can be repeated at appropriate time intervals. The administration of prodrugs can 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 μg / kg to about 100 mg / kg of total body weight. A daily rectal dosing regimen will generally be from about 0.01 μg / kg to about 200 mg / kg of total body weight. A daily vaginal dosing regimen will generally be from about 0.01 μg / kg to about 100 mg / kg of total body weight. The daily topical dosage regimen will generally be from about 0.1 μg / kg to about 100 mg / kg administered between one and four times a day. Concentration Transdermal will usually be required to maintain a daily dose of 0.01 μg / kg to 100 mg / kg of total body weight.

Abbreviations and acronyms As used in the present specification, the following terms have the meanings indicated. ACN acetonitrile Bn benzyl BOC tert-butoxycarbonyl conc. concentrate EtOAc ethyl acetate d day (s) DCM dichloromethane CH2C12 DHP 3,4-dihydro- [2H] -piran Dibal diisobutyl aluminum hydride DMF N, N-dimethylformamide DMSO dimethylsulfoxide DIPEA N, N-diisopropylethylamine Estrone E2 estradiol EDCl 'HCl hydrochloride of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide ER estrogen receptor h HMPA hexamethylphosphoramide HOBT 1-hydroxybenzotriazole hydrate HSD dehydrogenase hydroxysteroid NAD (P) [H] nicotinamide-adenine-dinucleotide (phosphate) [NAD (P) reduced] NMR Nuclear magnetic resonance MeOH methanol min. minute (s) PG protection group pTosOH para-toluene sulfonic acid T.A. room temperature TBME tert-butyl methyl ether THF tetrahydrofuran THP tetrahydropyran TLC thin layer chromatography TMSCl trimethylsilyl chloride General preparation methods The compounds of the present invention can be prepared using known chemical reactions and procedures. However, the following general methods of preparation are presented to assist the reader in the synthesis of 17/3-HSD1 inhibitors, with specific details provided later in the experimental section to illustrate working examples. All the variable groups of these methods are as described in the generic description if they are not specifically defined later. It should be recognized that the compounds of the invention with each optional functional group claimed may not be prepared by each of the methods mentioned below. Within the scope of each method, optional substituents may appear on reagents or intermediates that may act as protective or non-participating groups in some other way. Using methods well known to those skilled in the art, these groups are introduced and / or separated during the course of the synthesis schemes provided by the compounds of the present invention. Flow diagrams Certain compounds of the formula I, in which X represents a bond, A represents CO, Y represents NH or NR4 and n represents an integer from 0 to 5, can be prepared by a reaction as shown in the Diagram of flow the The free acid (IV) can be converted to the reactive acyl halide (V), in particular the acid chloride, by reaction with S0C12, C0C12, PC15 or PBr3 or the like. The amide derivatives (VI) can be prepared by a base catalyzed addition-elimination reaction, in which the halogen residue is substituted with the appropriate amine R2NH2 or R2NHR4 in the presence of a base, for example DIPEA. Alternatively, in a particularly suitable manner for derivatives with n > 2, the amide derivatives can be prepared directly from the free acids by nucleophilic substitution with the appropriate amine. Alternatively, the amide derivatives can be prepared directly from the free acids by nucleophilic substitution with the appropriate amine as shown in Flow diagram Ib; Certain compounds of formula I, in which X represents a bond, A represents CO, Y represents 0 and n represents an integer from 0 to 5 can be prepared by a reaction as shown in Flow Diagram II: The ester derivatives (VII) can be prepared from the free acid (IV) by esterification with the appropriate alcohol R2-OH. Certain compounds of the formula I, wherein X represents a bond, A represents CO, Y represents a bond and n represents an integer from 0 to 5 can be prepared by a reaction as shown in Flow Chart III: (XXXI) (XXXIII) Alcohol (XXXI) can be converted into corresponding aldehyde (XXXIII) through a Dess-Martin oxidation. Subsequently, the aldehyde can be converted by a nucleophilic addition-elimination reaction with a Grignard reagent or other organometallic reagent, substituted with the appropriate residue R2 in the corresponding secondary alcohol (XXI), which can then be oxidized again to the desired ketone. (VIII). Certain compounds of the formula I, in which X represents a bond, A represents CO, Y represents NH-NR4 or NH-NH and n represents an integer from 0 to 5, can be prepared by a reaction as shown in the Diagram of flow IVa: The free acid (IV) can be converted to the reactive acyl halide (V), in particular the acid chloride, by reaction with S0C12, C0C12, PC15 or PBr3 or the like. The hydrazide derivatives (XLI) can be prepared by a base catalyzed addition-elimination reaction, in which the halogen residue is substituted with the appropriate hydrazine H2N-NHR2 or H2N-NR2R4 in the presence of a base, for example DIPEA. Alternatively, in a particularly suitable manner for derivatives with n > 2, the hydrazide derivatives can be prepared directly from the free acids by nucleophilic substitution with the appropriate hydrazine using, for example, polymer-bound carbodiimide, HOBT and DCM, as shown in Flow Diagram IVb: Certain compounds of the formula I, in which X represents NH, A represents CO, Y represents NH and n represents an integer from 1 to 6, can be prepared by a reaction as shown in the Flow Chart Va: The urea derivatives of the general formula (XVII) can be prepared by reacting the amine building block (XV) with an appropriately substituted isocyanate (R2-N = C = 0). After the addition, the ketal function is converted to the keto function. Alternatively, the amine can be reacted first with carbodiimidazole or triphosgene to form a reactive carbamoyl compound, which can be further reacted with a suitable amine R2R4-NH. A further variant of the synthesis can use the unprotected amine (XXIX) as the starting material for the reaction with an appropriately substituted isocyanate (R2-N = C = 0) as shown in the Flow Digra Vb: Certain compounds of the formula I, in which X represents NR3, A represents S02, Y represents NH and n represents an integer from 1 to 6, can be prepared by a reaction as shown in Flow Chart VI: In a first step, the amine building block (XV) can be converted into a protected sulfamide compound, for example, protected with Boc, by a reaction with the appropriately protected chlorosulfonyl isocyanate. In a second step, the protected sulfamide compound is allowed to react with the appropriate bromine reagent (R2-Br) to provide the substituted and still protected sulfamide derivative of the formula (XVIII). After deprotection, the protected sulfamide derivative is obtained in Desired N of the formula (XIX). Certain compounds of the formula I, in which X represents NR3, A represents CO, Y represents O and n represents an integer from 1 to 6, can be prepared by a reaction as shown in Flow Diagram VII: The carbamate derivatives of the general formula (XX) can be prepared by reacting the amine building block (XV) with an appropriate chloroformic acid ester (R2-0-C0-Cl). After the addition-elimination reaction, in a second stage the ketal function is converted to the keto function. Certain compounds of the formula I, in which X represents NR3, A represents S02, Y represents O and n represents an integer from 1 to 6, can be prepared by a reaction as shown in Flow Diagram VIII: (XXII) The sulfamate derivatives of the general formula (XXII) can be prepared by the reaction of the block of construction of amines (XV) with an appropriate chlorosulfonic acid ester (R2-0-S02-Cl). After the addition-elimination reaction, in a second stage the ketal function is converted to the keto function. Certain compounds of the formula I, in which X represents NR3, A represents CO, Y represents a bond and n represents an integer from 1 to 6, can be prepared by a reaction as shown in Flowchart IXa: (XXIII) The "retro" -amide derivatives of the general formula (XXIII) can be prepared by reaction of the amine building block (XV) with an appropriate acid halide, for example an acid chloride (R2-CO-Cl). After the addition-elimination reaction, in a second stage the ketal function is converted to the keto function. Alternatively, the reaction with an appropriate acid halide, for example an acid chloride (R2-C0-C1), can be carried out using the amino-hydrochloride salt of estrone (XXIX) as starting material, as shown in the following Flowchart IXb: (XXIII) Certain compounds of the formula I, in which X represents NR3, A represents S02, Y represents a bond and n represents an integer from 1 to 6, can be prepared by a reaction as shown in the Flowchart For: The sulfonamide derivatives of the general formula (XXIV) can be prepared by reacting the amine building block (XV) with an appropriate sulphonic acid halide, for example a sulfonic acid chloride (R2-S02-Cl). After the addition-elimination reaction, in a second stage the ketal function is converted to the keto function. Alternatively, the reaction with an appropriate sulphonic acid halide, for example sulfonic acid chloride (R2-S02-C1), can be carried out using the amino-hydrochloride salt of estrone (XXIX) as the starting material, is shown in the following Xb flowchart: Certain compounds of formula I, in which X represents NR3, A represents CO, Y represents NH-S02 and n represents an integer from 1 to 6, can be prepared by the reaction shown in Flow Chart XI: The sulfonyl urea derivatives of the general formula (XXV) can be prepared by reaction of the amine building block (XV) with an appropriately substituted sulfonyl isocyanate (R2-S02-N = C = 0). After the addition, the ketal function is converted to the keto function. Certain compounds of the formula I, in which X represents O, A represents CO, Y represents NR4 and n represents an integer from 1 to 6, can be prepared by a reaction as shown in Flow Diagram XII: The "retro" -carbamate derivatives of the general formula (XXVI) can be prepared by the reaction of the estrone-alcohol building block (XXXI) with an appropriately substituted isocyanate (R2-N = C = 0) and a subsequent purification . Certain compounds of the formula I, in which X represents O, A represents CO, Y represents a bond and n represents an integer from 1 to 6, can be prepared by a reaction as shown in the Flowchart XIII: The "retro" -ester derivatives of the general formula (XXVII) can be prepared by esterification of the estrone-alcohol building block (XXXI) with the acid carboxylic acid R-COOH and a subsequent purification. Certain compounds of the formula I, in which X represents 0, A represents CO, Y represents NH-S02-NR4 and n represents an integer from 1 to 6, can be prepared by a reaction as shown in Flow Chart XIV : The sulfonyl carbamate derivatives of the general formula (XXVIII) can be prepared by a two-step synthesis: in a first step, the estrone-alcohol building block (XXXI) is converted to the chlorosulfonyl carbamate intermediate by a reaction with chlorosulfonyl isocyanate. Subsequently, the intermediate is allowed to react with the appropriate primary or secondary amide HNR2R4 in order to provide the desired sulfonyl carbamate derivative. Certain compounds of the formula I, wherein X-A-Y represents O and R2 is different from H, can be prepared by a reaction as shown in Flow Diagram XV: (X) (XXX) The ether derivatives of the general formula (XXX) can be prepared by the reaction of an appropriate Grignard reagent BrMg- (CH2) n-0-R2 (for n = 3-6) with the derivative of estrone 15, 16-unsaturated of the formula X. Alternatively, ether derivatives can be prepared by derivatization of the corresponding alcohol of the general formula (XXXI). The synthesis of certain compounds of the formula I, in which X-A-Y represents 0, R2 represents H and n represents an integer from 1 to 6, according to the general formula (XXXI), is described in the section "intermediates".

Numbering of formulas and intermediates of compounds The general structural formulas are typically designated with a number in Roman format, followed by ce or ß indicating the stereochemistry at the C15 atom of the estrone nucleus if necessary. If the number of methylene groups bound at position C15 (ie, the value of "n") is specified, the Roman numeral is followed by a hyphen and a number indicating the amount of methylene groups. Finally, a letter a, b or c is joined after the number "n", indicating the nature of the substituent R 1 at the 0 atom at the C 3 position of the estrone nucleus (a = hydrogen, b = methyl and c = benzyl). For example, compound IV is the general acid building block: (IV) Therefore, a compound IV / 3-3a would represent an IV derivative with β-stereochemistry at C15, three methylene groups and a hydroxy group at the C3 position, ie: If particular structures of synthesized examples fall within a general formula, then the designation of the general formula is followed by the particular number of this example, that is, Example n ° 652 of the formula (XXXVIIIa-a) -652 .

(XXXIIIa-1a) -652 This Example 652 is a particular compound of the general formula XXXIIIa; -la, wherein R2 is a 4-fluoro-phenyl residue.

Intermediate I. The estrona 15, 16 - unsaturated of the formula X The enone intermediate of the formula X in which R1 = benzyl as the protecting group can be prepared according to a process described by Labaree and set out in the following scheme 1 [Labaree et al. (2003) J. Med. Chem. 46: 1886-1904].

SCHEME 1 The starting compound - the ketal - of the formula (IXa), for example, can be prepared according to Nambara [Nambara et al. (1976) Steroids 27: 111-122]. The methyl derivative of the formula (IXb, R1 = CH3) is prepared using Mel and acetone, while the benzyl derivative of the formula (IXc, Rl = benzyl) is prepared using benzyl bromide, DIPEA and acetone. Intermediates of enones with other substituents on R1, in particular optionally substituted (C? -C4) alkyl, can be prepared accordingly using the optionally substituted alkyl bromide (C? -C4) or optionally substituted (C? -C4) alkyl iodide. . Finally, the ketal derivative is hydrolyzed to provide the appropriate enone derivative X (Xb for R1 = CH3 and Xc for R1 = benzyl). Alternatively, the enone intermediate of formula X can be prepared according to a procedure described by Poirier et al. [Poirier et al. (1991) Tetrahedron, 47 (37): 7751-7766].

II. The ketal derivative of estrone-15o; -yl-carbaldehyde of the formula XIII-0 The protected aldehyde intermediate of the formula XIII-0, wherein R1 = CH3 (XlIIb) or R1 = benzyl (XIIIc) can be prepared according to a process set out in the following scheme 2 SCHEME 2 (XII) (Xlll-O) The 15, 16-unsaturated estrone of the formula (X) was converted into the corresponding cyanoestrone (XI) by a Michael addition of cyanide in the D ring. The nitrile was introduced into the beta configuration as demonstrated by 2D-NMR. The epimerization of this spherical center was carried out at a later stage. First, the ketone functionality was protected in the form of the acetal (XII), followed by the conversion of the nitrile to the corresponding aldehyde (XIII-0) by the addition of Dibal-H to the nitrile and the subsequent hydrolysis of the imine product. In this step, the epimerization took place for approximately 90% (2D-NMR). The consecutive washing of the mixture with aqueous bicarbonate gave the ce isomer with a d.e. = 98%.

Detailed Synthesis Cyanostrone Xlb: 3-Methoxy-17-oxo-estra-l, 3, 5 (10) -triene-15/3-carbonyltrile Cyanoestrone XIc: 3-Benzyloxy-17-oxo-estra-l, 3, 5 ( 10) -triene-15/3-carbonitrile KCN (17.0 g, 261 mmol) (NaCN can also be used) to DMF (200 mL) was added at room temperature. H20 (100-200 mL, minimum amount) was added until an almost clear solution was obtained. Esterone Xb or unsaturated Xc (25 mmol) was dissolved in DMF (400 mL) and added dropwise to the KCN solution as slowly as possible for 8-10 h and a clear solution was maintained. After the addition was complete, the reaction mixture was stirred for a night. Water (1-2 L) was slowly added to the stirring reaction mixture. The product was isolated by filtration and titered twice with H20. The white solid was dissolved in DCM, the residual water was separated and the organic layer was dried with Na2SO4. Evaporation to dryness afforded cyanothrones Xlb in the form of a white foam with variable yields of 54% -90% (0.21 mole scale). Cyano-estrone XIc needed further purification by column chromatography (DCM / TBME, gradient 0-20%): 51% yield in the form of a white foam when carried out on a scale of 20 mmol.

Cetal Xllb: Cetal of 3-methoxy-17-oxo-estra-l, 3, 5 (10) -triene-15/3-carbonitrile Cetal XIII: Cetal of 3-benzyloxy-17-oxo-estra-l, 3, 5 (10) -triene-15/3-carbonitrile A suspension of cyano-estrone Xlb or XIc (89.2 mmol), ethylene glycol (11.7 mL, 178 mmol) and p-TSA (0.5 g, cat.) In diglyme (500 mL) was stirred overnight. In most cases, a clear solution was obtained. The reaction mixture was concentrated in vacuo in a bath with water at 70 ° C until precipitation began. After cooling to room temperature, the product was collected by filtration. The mother liquors were evaporated to dryness and the residue was recrystallized from diglyme. Performance of Xllb: 28.6 g (100%) in shape of white flakes. On a scale of 0.4 mmol, compound XIIc was also obtained with a yield of 100%.

Aldehyde XIII-Qb: Cetal of 3-methoxy-17-oxo-estra-l, 3, 5 (10) -triene-15af-carbaldehyde Aldehyde XIII-Oc: Cetal of 3-benzyloxy-17-oxo-estra-l, 3, 5 (10) -triene-15ce-carbaldehyde A solution of ketal Xllb or XIIc (3.7 mmol) in dry THF (50 mL) was added dropwise to Dibal-H (20 mL, 25% in toluene, 30 mmol ) in THF at -80 ° C. After the addition was complete, the reaction was stirred for 20 min and slowly warmed to T.A. during one night. The reaction was quenched at -10-0 ° C by the dropwise addition of 30% AcOH in H20 (100-300 mL) until there was no gaseous release and a clear solution was obtained. EtOAc (200 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with NaHCO3 (aqueous) until there was no gas evolution and dried with Na2SO4. Column chromatography (DCM to separate the impurities, TBME / DCM (1: 1) to collect the product) gave XIIIc (1.0 g) with a yield of 62% and XlIIb with a yield of 85% (0.14 mol, CH2C12 fast ).

III. Compounds of formula IV (acid building block): estrone-15-yl-C0-C5-carboxylic acid Acid building block IV- 0: (n = 0) IV-Ob: (n = 0 and Rl = CH3): 3-methoxy-l7-oxo-estra-1,3,5 (10) -trienic acid l-5-yl-carboxylic acid IV-Oc: (n = 0 and Rl = Bn): 3-benzyloxy-17-oxo-estra-1,3,5 (10) -trien-l5-a-yl-carboxylic acid The individual steps in the synthesis of the acid building block of formula IV-0b are set out in the following scheme 3 SCHEME 3 (IV-0) (XIII-0) The ketal derivative of 17-oxo-estra-l, 3, 5 (10) -trien-15ce-il-carbaldehyde of the formula XIII-0 is oxidized in the corresponding carboxylic acid and is converted to the unprotected 15e-substituted estrone derivative of the formula IV-0.

Detailed Synthesis IV-Ob: (n = 0 and Rl = CH3): 3 -methoxy acid-17-oxo-estra-1, 3,5 (10) -trien-fifteenth; -yl-carboxylic acid was added dropwise drop KMn04 (7.5 g, 47.6 mmol) dissolved in H20 (80 mL) to a solution of aldehyde XIII-Ob (10.0 g, 28 mmol) in acetone (400 mL) at such a rate that 45 ° C < T < 55 ° C. After the addition was complete, the mixture was stirred at 50 ° C for 1 h, cooled to T. A. and treated (dropwise) with NaHS03 (aqueous) until the purple color disappeared. The reaction mixture was filtered through Celite and H0 (400 mL) and AcOH (20 mL) were added consecutively. The obtained emulsion was evaporated until a sticky oil was obtained at the bottom of the flask. The supernatant was separated by decantation. After drying the oil in vacuo, a yellowish foam (10.0 g, 100%) was obtained. The foam was dissolved in CH2C12 (100-200 mL) and stirred with HCl (100 mL, 30% in H20) over a weekend. The aqueous layer was extracted with CH2C12 (2 x 200 mL). The combined organic layers were extracted with 4 N NaOH (3 x 200 mL). The aqueous layer was acidified to pH ~ 1 and extracted with CH2C12. The organic layer was dried with Na 2 SO 4 and concentrated to -20 mL and transferred to a silica column (CH 2 C 12). An elution with CH2Cl2 / AcOH 99: 1 yielded compound IV-Ob (4.6 g, 50%, 90% purity). The final purification was a recrystallization from CH2C12 / heptane (3x) by evaporation of CH2C12 at ambient pressure and Reflux temperature until crystallization occurs.

Acid building block IV-1: (n = 1): IV-Ib (n = 1 and Rl = CH3): 3-methoxy-17-oxo-estra-1,3,5 (10) -trienic acid 15c-il-acetic IV-lc: (n = 1 and Rl = Bn): 3-benzyloxy-17-oxo-estra-1,3,5 (10) -trien-15c-yl-acetic acid The IV-1 acid building block could be synthesized through two different routes. The individual steps of the first synthesis route of the acid building block IV-1 are set out in the following scheme 4. The same type of procedure can be applied for n = 2 and for the other side chains in the position of R1.

SCHEME 4 The ketal derivative of the 17-oxo-estra-l, 3, 5 (10) -trien-15ce-yl-carbaldehyde of formula XIII-0 is converted into the methyl enol ether of the formula XXXIV via a Wittig reaction with MeOCHLiP (Ph) 3. Hydrolysis with aqueous HCl supplied the unprotected acetaldehyde derivative XXXIII-1. The acetaldehyde derivative is then further oxidized to the corresponding carboxylic acid IV-1.

Detailed Synthesis XXXIVb: 3 -methoxy-15ce- (2-methoxy-vinyl) -estra-1, 3, 5 (10) -trien-17-one was added dropwise dropwise n-BuLi (16.8 mL, 2.5 M in hexanes , 42 mmol) to a suspension of chloride of (methoxymethyl) triphenyl-phosphonium (14.4 g, 42 mmol) in THF (120 mL) at -78 ° C. After slowly heating the reaction to T. A. the orange suspension became a clear, deep red solution. After 3 h, the reaction mixture was cooled to -78 ° C and a solution of the aldehyde XIII-Ob was added. (10.0 g, 28 mmol) in THF (100 mL). The reaction mixture was allowed to warm to T.A. overnight and evaporated to dryness. The residue was suspended in NaOH (1 N, 200 mL). Extraction with CH2C12 followed by flash column chromatography (CH2Cl2 / heptane, 1: 1) to remove the main impurities (OP (Ph) 3) gave a crude mixture of XXXIVb as a white foam (8.9 g).

XXXIII-Ib: 3-methoxy-17-oxo-estra-l, 3,5 (10) -trien-15c-yl-acetaldehyde HCl (aqueous) (6 N, 200 mL) was added to a mixture containing XXXIVb ( 8.9 g) dissolved in CH2C12 (200 mL) and this reaction mixture was stirred overnight. The organic layer was dried (Na2SO4) and evaporated to dryness followed by column chromatography (CH2Cl2 / heptane, 1: 1 gradually increasing the polarity to CH2C12 / TBME, 8: 3). The aldehyde XXXIII-lb was isolated as the main product (2.89 g, 30%).

IV-Ib: (n = 1 and Rl CH3): 3-methoxy-17-oxo-estra-1, 3, 5 (10) -trien-5-acetyl-acetic acid An oxidation of XXXIII-lb (2.3 g, 6.7 mmoles), analogous to the procedure for IV-0b (see what above), provided compound IV-Ib (2.1 g, 91%, almost 95% pure). The product was further purified by column chromatography (CH2Cl2 / AcOH, (95: 5)) and by consecutive crystallization from CH2Cl2 / heptane (3x).

Alternative synthesis route for the IV-1 acid building block: (n = 1): IV-Ib: (n 1 and Rl = CH3): 3-methoxy-17-oxo-estra-acid 1.3, 5 (10) -trien-15a-yl-acetic Alternatively, compound IV-Ib can be prepared directly from the enone derivative of formula X according to the following synthesis scheme 5: SCHEME 5 (IV-1b) A Michael addition of the dimethyl malonate anion to the enone derivative supplied the diester XXXVIb, which became the acid building block of the Formula IV-b by alkaline ester hydrolysis and decarboxylation in refluxing acetic acid.

Detailed Synthesis XXXVIb: Estrone-Carbaldehyde Dimethyl Ester The dimethyl malonate anion was prepared by dropwise addition of a solution of dimethyl malonate (18.7 g, 142 mmol) in THF (200 mL) to a suspension of NaH ( 7.42 g, 170 mmol) in THF (200 mL) at 0 ° C. The reaction mixture was kept at 0 ° C for 1 h. The reaction mixture was converted to a gray solid mass which disappeared after a reaction by the dropwise addition of enone Xb (10 g, 35.5 mmol in 240 mL of THF) and stirred to T. A. over a weekend. The reaction is quenched by the dropwise addition of H20. Subsequently, H20 (400 mL) was added and most of the THF was removed by evaporation in vacuo. The product was isolated by filtration and triturated with heptane. The solid was dissolved in EtOAc (200-300 mL) and dried with Na 2 SO 4. Evaporation to dryness gave XXXVIb (11.0 g, 84%) as a colorless oil which solidified upon standing.

IV-Ib: (n = 1 and Rl = CH3): 3-methoxy-17-oxo-estra-1, 3,5 (10) -trien-15a-yl-acetic acid Hydrolysis of diester XXXVIb (11.0 g, 29.8 mmoles) by dissolving in THF and adding concentrated aqueous NaOH (50 mL) and stirring overnight. The organic solvent was removed by evaporation in vacuo and the residue was acidified with HCl (30%) until pH ~ 1. The product was extracted with CH2C12 (2 x 200 mL). The combined organic layers were dried with Na 2 SO 4 and evaporated to dryness. The residue was a mixture of compounds (partially decarboxylated). Dissolution of the residue in AcOH (200 mL) and reflux overnight provided complete decarboxylation. Evaporation to dryness and column chromatography (CH2Cl2 / AcOH, (95: 5)) gave a white solid material IV-Ib (4.92 g, 52%). The product was further purified by column chromatography (CH2Cl2 / AcOH, (95: 5)) and by consecutive crystallization from CH2C1 / heptane (3x).

Acid building blocks IV / 3-2, IV / 3-3, IV / 3-4, IV / 3-5, IVP-3b (n = 3 and Rl = CH3): 4- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien-15 (3-yl) -butyric acid The individual stages in the synthesis of the block of The construction of acids of the formula IV / 3-3b are shown in the following scheme 6. The same type of procedure can be applied for n = 4, 5 or 6 and for other alkyl chains within the position of R1 using the BrMg- (C5-C7-THP) alkoxy suitable as Grignard reagent In addition, this reaction scheme also supplies the estrone-alcohol building block in the form of the intermediate of formula XXXI / 3-4b.

SCHEME 6 4-Bromo-butanol-THP was prepared by adding a solution of HBr to THF under reflux. The resulting bromide was dissolved in CH2C12, p-TosOH and DHP were added at 0 ° C to provide the protected alcohol. This was filtered over Si02 and further purified by column chromatography, yielding a 9.3% yield over 2 steps. The protected alcohol was dissolved in THF and added to activated magnesium, and the resulting Grignard reagent was added to Cul2 in HMPA. The 15, 16-unsaturated estrone derivative of formula Xb, dissolved in THF and TMSCl, was added at -40 ± 5 ° C. Subsequently, after hydrolysis of the silyl ether, the resulting compound XXX-4b-THIP was deprotected with p-TosOH / MeOH to provide the alcohol derivative XXXI-4b which was converted, without purification, to the free acid IV-3b by an oxidation of Jones. The oil was purified by column chromatography, yielding the free acid of formula IV-3b in 30% yield in three steps.

Detailed synthesis: 4-bromo-butanol A solution of HBr (48% HBr in water, 1280 mL, 11.22 moles) was added dropwise to dry THF at reflux (810 mL, 9.99 moles) over a period of 2.25 hours. Upon completion of the addition, an A-NMR analysis of a sample showed that the reaction had been completed. The reaction mixture was cooled to T. A., transferred to a 10 1 reaction flask and, while stirring mechanically, it was neutralized carefully with a solution of NaHCO3. The layers were separated and the organic layer was washed with brine, dried over Na 2 SO 4 and the solvent was removed on a rotary evaporator. The resulting yellow oil was used in the next step without further purification. 2- (4-Bromo-butoxy) -tetrahydro-pyran The crude product of 4-bromobutanol was dissolved in DCM (500 mL) and dried over Na 2 SO 4 and pTosOH (500 mg) was added. Dihydropyran (1181 mL) was added dropwise at 0 ° C and during the addition the temperature was kept below 8 ° C. The reaction was allowed to reach T to A. overnight, washed with saturated NaHCO 3 solution (2 x 300 mL) and brine (9.3 1). The aqueous layers were washed with TBME (300 mL) and the combined organic layers were dried over anhydrous K2C03. The mixture was separated by filtration and the solvent was removed in a rotary evaporator. This produced 593 g (yield = 25% over 2 stages). The 4-bromo-butanol-THP obtained was filtered twice over Si02 (DCM with 1% MeOH). Finally, the compound was purified by column chromatography (20 1 SiO 2, DCM with 1% MeOH). This produced 220.6 g of 2- (4-bromo-butoxy) -tetrahydro-pyran (yield = 9.3% over 2 steps) as a pure light yellow oil by TLC. 3-Methoxy-15 / 3- [4- (tetrahydro-pyran-2-yloxy) -butyl] -estra-1,3,5 (10) -trien-17-one (XXX-4b-THP) Magnesium was stirred (29.6 g, 2.0 moles) overnight with glass broken under N2 in a flame-dried 3-neck flask. Magnesium was further activated by the addition of some iodine and adding a few drops of pure 2- (4-bromo-butoxy) -tetrahydro-pyran. After the Grignard reaction had begun, 2- (4-bromo-butoxy) -tetrahydropyran (121 g, 510 mmol) in 500 mL of dry THF was added dropwise, maintaining a gentle reflux. After the addition of the reaction mixture was completed, it was stirred for 0.5 hours. The solution was transferred to a flame-dried 3-neck flask containing copper (I) iodide (9 g, 47 mmol) and HMPA (100 mL). The resulting reaction mixture was cooled to -40 + 5 ° C, after which a mixture of 15, 16-unsaturated estrone of formula Xb (24 g, 85 mmol) and TMSC1 (21 mL) was added dropwise. , 196 mmoles) dissolved in dry THF (500 mL). After completing the addition, the mixture was allowed to reach the T.A. over 3 days. 10% NH 4 Cl (in ice water, 11) was added to the reaction mixture. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and the solvent was removed on a rotary evaporator. This produced 103.6 g of a yellow oil, which contained HMPA. The oil is The mixture was then stirred with K2C03 (12.1 g, 87 mmol) in methanol (2.75 1) under N2 to hydrolyze the silyl ether. The hydrolysis was followed by TLC (EtOAc / heptane: 1/9), which after 40 minutes showed that the reaction was complete. 0.75 1 was added and most of the methanol was removed on the rotary evaporator. 500 mL of EtOAc were added, the layers were separated and the aqueous layer was extracted with EtOAc (2 x 500 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed on a rotary evaporator. This produced 82.5 g of a yellow oil containing the product, XXX-4b-THP, HMPA and silyl residues. / 3- (4-hydroxybutyl) -3-methoxy-estra-1, 3,5 (10) -trien-17-one (XXXI / 3-4b) The crude compound XXX-4b-THP (82.5 g of a yellow oil) was dissolved in MeOH (2.5 1) and p-TosOH (6 g, 32 mmol) was added. The reaction was followed by TLC (toluene / acetone: 3/1) and ESRKI. After 1 hour, the reaction was complete. Most of the MeOH was removed on the rotary evaporator and after this 1 l of water was added. The resulting mixture was extracted with DCM (3 x 400 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed on a rotary evaporator. This yielded 46.8 g, which were purified by column chromatography (400 g of Si02-toluene / acetone: 3/1) to yield 31.9 g of XXXI / 3-4b as a yellow oil impure 4- (3-Methoxy-17-oxo-estra-l, 3,5 (10) -trien-15/3-yl) -butyric acid (IV / 3-3b) To a cooled solution of alcohol XXXI / 3- 4b (31.9 g, 89 mmol) at 0 ° C in acetone (11) was added dropwise 140 mL of Jones reagent (prepared from 700 mL of water, 300 mL of H2SO4 and 100 g of Cr03). Each drop leaves an orange color, which disappeared shortly after it formed. The color finally changes to green. After completing the addition, the reaction was followed by TLC (EtOAc / heptane: 1/1) and completed after 10 minutes. The reaction was stirred for a further 30 minutes and then quenched with 500 mL of a cold saturated solution of NaS203 and 500 mL of water. The resulting mixture was extracted with EtOAc (3 x 400 mL). The organic layers were combined, dried over Na 2 SO and the solvent was removed on a rotary evaporator. The resulting oil was purified by column chromatography (Si02; toluene / acetone: 3/1) This yielded 9.2 g (30% over 3 steps) of the compound of the formula (IV / 3-3b) in the form of a yellow solid with a purity of 93%.

IV / 3-2b (n = 2 and Rl = CH3): 3- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien-15/3-yl) -propanoic acid For n = 2, the corresponding carboxylic acid IV / 3-2b can be prepared by oxidation of the alcohol derivative of the formula XXXI / 3-3b according to the preparation of the carboxylic acid IV / 3-3b (see section for the preparation of the alcohol derivatives listed below for the synthesis of XXXI | ß-3b). LC-MS (ES-): ta 5.25 min, m / z (intensive re.) 355 [(MH) k 100%] [a] D20 = +79.6 (c = 0.304, MeOH) A? -RMN (400 MHz , CDCl3) d (ppm) 1.05 (s, 3H), 1.42-1.58 (m, 4H), 1.63-1.81 (m, 3H), 1.90-2.05 (m, 2H), 2.09-2.14 (m, 1H), 2.28-2.51 (m, 7H), 2.85-3.01 (m, 2H), 3.78 (s, 3H), 6.65 (d, ÍH), 6.71 (dd, ÍH), 7.19 (d, ÍH). 13 C-NMR (100.6 MHz, CDC13) d (ppm) 17.8, 25.5, 26.0, 26. 7, 29.5, 33.6, 33.9, 34.0, 36.0, 42.0, 44.6, 47.1, 52.7, 55.3, 111.5, 114.0, 126.0, 132.2, 137.7, 157.8, 178.5, 220.4.

Acid building block IV / 3-3c: 4- (3-benzyloxy-l7-oxo-estra-l, 3,5 (10) -trien-15/3-yl) -butyric acid The individual steps are carried out in the synthesis of the acid building block of formula IV / 3-3c according to the procedure set forth in scheme 7. In addition, this reaction scheme also supplies the building block of estrone-alcohol in intermediate form of formula XXXI / 3-4C. The same type of procedure can be applied for n = 4, 5 or 6 and for other alkylaryl substituents at the position of R1 using the appropriate BrMg-C5-C7 alkoxy-THP as the Grignard reagent.

SCHEME 7 4-Bromo-butanol-THP-ether was prepared by adding a solution of HBr to THF under reflux. The resulting bromide was dissolved in CH2C12. P-TosOH and DHP were added at 0 ° C to provide the protected alcohol. This was filtered over S102 and further purified by column chromatography, yielding a 9.3% yield over 2 steps. The protected alcohol was dissolved in THF and added to the activated magnesium, and the resulting Grignard reagent was added to Cul2 in HMPA. The unsaturated estrone derivative 15, 16 of formula Xc is dissolved in dry THF and TMSC1, added at -40 ± 5 ° C. Subsequently, the resulting compound XXX-4c-THP was deprotected with p-TosOH / MeOH to provide XXXI / 3-4c by 47% over 2 steps, which was converted, without purification, into free acid IV-3c by an oxidation of Jones with a yield of 96%.

Detailed synthesis: 4-Bromo-butanol and 2- (4-bromo-butoxy) -tetrahydro-pyran: see above 3-Benzyloxy-15 / 3- [4- (tetrahydro-pyran-2-yloxy) butyl] estra - 1,3,5 (10) -trien-17-one (XXX-4C-THP) Magnesium (10 g, 425 mmol) was stirred overnight with broken glass under N 2 in a 3-neck flask flame-dried . Magnesium was activated additionally by adding some iodine and adding a few drops of 2- (4- bromo-butoxy) - pure tetrahydro-pyran. After starting the Grignard reaction, 2- (4-bromo-butoxy) -tetrahydropyran (25.2 g, 106 mmol) in 200 mL dry THF was added dropwise, maintaining a gentle reflux. After completing the addition of the reaction mixture, it was stirred for 0.5 hours. The solution was transferred to a flame-dried 3-neck flask containing copper (I) iodide (1.8 g, 9.5 mmol) and HMPA (20 mL). The resulting reaction mixture was cooled to -40 ± 5 ° C, after which a mixture of the 15, 16-unsaturated estrone derivative of the formula Xc (6 g, 18 mmol) and TMSC1 (4.5) was added dropwise. mL, 35 mmol) dissolved in dry THF (100 mL). After the addition was complete, the mixture was allowed to reach T.A. over 3 days. 10% NH4C1 (in water and ice, 200 mL) was added to the reaction mixture. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over Na 2 SO 4 and the solvent was removed on a rotary evaporator. This produced 22.7 g of yellow oil containing HMPA. The oil was then stirred with K2C03 (3 g, 22 mmol) in MeOH (650 mL) under N2 to hydrolyze the silyl ether. The hydrolysis was followed by TLC (EtOAc / heptane: 1/9), which after 60 minutes showed that the reaction was complete. 200 mL of water was added and most of the methanol was removed on the rotary evaporator. 150 mL of EtOAc were added, the layers separated and the aqueous layer was extracted with EtOAc (2 x 150 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed on a rotary evaporator. This produced 15.1 g of a yellow oil containing the product, HMPA and silyl residues. 3 - . 3-Benzyloxy-15 / 3- (4-hydroxy-butyl) -estra-1, 3, 5 (10) -trien-17-one (XXXIff-4c) The crude compound (XXX-4C-THP) (15.1 g of a yellow oil) was dissolved in MeOH (500 mL) and p-TosOH (1.2 g, 6.3 mmol) was added. The reaction was followed by TLC (toluene / acetone: 3/1) and A-NMR. After 1.5 hours the reaction was completed. Most of the MeOH was removed on the rotary evaporator and after this 200 mL of water was added. The resulting mixture was extracted with DCM (3 x 100 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed on a rotary evaporator. This produced 8.2 g, which were purified by column chromatography (400 g of SiO2, toluene / acetone: 3/1) to yield 3.6 g (8.3 mmol, 47% over 2 steps) of XXXI / 3-4c in shape of a yellow oil. 4- (3-Benzyloxy-17-oxo-estra-1,3,5 (10) -trien-15/3-yl) -butyric acid (IV / 3-3c) To a cooled solution of alcohol XXXI / 3- 4c (3.6 g, 8. 3 mmol) at 0 ° C in acetone (100 mL) were added dropwise 13.3 mL Jones Reagent (prepared from 700 mL of water, 300 mL of H2SO4 and 100 g of Cr03). Each drop leaves an orange color, which disappeared shortly after it formed. The color finally changes to green. After the addition was complete, the reaction was followed by TLC (EtOAc / heptane: 1/1) and completed after 10 minutes. The reaction was then quenched with 100 ml of a cold saturated solution of NaS203, during which the temperature was raised from 6 to 18 ° C, and 300 ml of water and 200 ml of EtOAc. The resulting mixture was stirred overnight and then the layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 ml). The organic layers were combined, dried over Na2SO4 and the solvent was removed on a rotary evaporator. This produced 3.6 g of IV / 3-3c (8.0 mmoles, y = 97%) as a yellow solid.

Acid construction block with stereochemistry at C15: IVa-3a (n = 3 and Rl = H): 4- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-15c acid .-il) butyric The individual steps in the synthesis of the acid building block of the formula IVa-3a are carried out according to the procedure set forth in Scheme 8. In addition, this reaction scheme also supplies the estrone-alcohol building block still protected with ketal in the form of the intermediate of the formula XLIVa-lc. The debenzylation and deprotection provides the estrone-alcohol XXXIa-la.

SCHEME 8 Reduction of the aldehyde XIII-Oc with NaBH 4 (EtOH, 2 h, T. A.) provided the alcohol XLIVa-lc, which was further treated with iodine, triphenylphosphine and imidazole to provide the XLV iodide. Subsequently, ethyl acrylate was coupled to iodine XLV and gave compound XLVI after purification by column chromatography. The reduction of compound XLVI was carried out under H 2 atmosphere to provide compound XLVII, which was transformed into the protected carboxylic acid building block XLVIIIa-3a by saponification. The carboxylic acid IVa-3a was obtained by deprotection.

Detailed synthesis Derived from 17-ketal of 3-benzyloxy-15-hydroxymethi-estra-1,3,5 (10) -trien-17-one (XLIVa-lc) Aldehyde XIII-0c (1.23 g, 2.84 mmol) was dissolved in EtOH (13 ml) and cooled to 0 ° C. NaBH4 (32.8 mg, 0.89 mmol) was added and the temperature was allowed to reach T. A. After 2 h at T. A. acetic acid (0.313 ml) and H2O (33 ml) were carefully added. The reaction mixture was stirred at T.A. for 30 minutes and then extracted with CH2C12 (2 x 25 ml). The organic layer was separated, dried over NaSO4 and concentrated to yield 1.2 g of a colorless oil. Purification was carried out by column chromatography (eluent: heptane / ethyl acetate 3: 1, Rf = 0.3) to provide 1.09 g (88%) of alcohol XLIVa-lc as a white solid.

Derivative of 3-benzyloxy-15-iodomethyl-estral ketal, 3,5 (10) -trien-17-one (XLV) Imidazole (749 mg, 11.0 = 1), PPh3 (1.44 g, 5.5 mmol) were stirred. I2 (1.33 g, 5.2 mmol) in CH2C12 (20 mL) for 30 min. The mixture was cooled to 0 ° C. A solution of alcohol XLIVa-lc (1.09 g, 2.50 mmol) in CH2C12 (10 mL) was added dropwise over a period of 10 min. The reaction flask was covered with an aluminum foil and the mixture was stirred for 90 min at T. A. The solids were separated by filtration over celite and the filtrate was washed with 10% aqueous Na2S204. The organic layer was separated, dried over NaSO 4 and concentrated to yield an oil which was purified by column chromatography (eluent: heptane / ethyl acetate 1: 1, Rf = 0.8) to provide 0.944 g (69%) of iodide XLV in the form of a white foam.

Derivative of 4- (3-benzyloxy-17-oxo-estra-1,3,5 (10) -trien-15-yl) -butyric acid ethyl ester ketal (XLVI) NiCl2-6H20 (409 mg, 1.72 mmole) in pyridine (7.3 mL). Subsequently, activated zinc (566 mg, 8.66 mmol) and ethyl acrylate (868 μL, 8.0 mmol) were added. and the mixture was stirred at 56 ° C for 20 min. A catalytic amount of iodine was added and the heating was stopped. When the temperature reached 40 ° C, a solution of XLV (944 mg, 1.73 mmol) in pyridine (5.2 mL) was added dropwise and stirring was continued for 90 min at RT. The solids were removed by filtration and the filtrate was filtered. concentrated. EtOAc (25 mL) was added and the organic layer was washed with brine (3 x 10 mL). The organic layer was separated, dried over Na2SO4 and concentrated to yield 1.18 g of an oil which was purified by column chromatography (eluent: heptane / ethyl acetate 5: 1, Rf = 0.4) to give 0.449 g (50% ) of ethyl ester XLVI in the form of a colorless oil.

Derivative of 4- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-15-yl) butyric acid ethyl ester ketal (XLVII) XLVI ethyl ester was dissolved (0.449 g, 0.86 mmol) in THF (15 mL). A small spoonful of Pd / C in THF was added (2 mL) and the reaction mixture was stirred for three days at T.

A. with pressure of 1 bar of H2. The solids were separated by filtration over Celite and washed with THF (10 mL). Concentration of the organic layer gave 0.385 mg of compound XLVII in the form of a yellow foam. Purification was carried out by column chromatography (eluent: heptane / ethyl acetate 5: 1, Rf = 0.2) to provide 0.313 g (84%) of compound XLVII as a white solid.

Derivative of 4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15-yl) -butyric acid ketal (XLVIIIa-3a) to a heated solution (60 ° C) of phenol XLVII (0.313 g, 0.73 mmol) in MeOH (12 mL) was added 2N aqueous KOH (3.52 mL). The mixture was stirred for 30 min at 60 ° C. The mixture was cooled by adding ice to the mixture. The pH was carefully adjusted to 3 to 4 using 5 N aqueous HCl. The XLVIIIa-3a carboxylic acid was extracted with TBME (50 mL), the organic layer was dried over Na2SO and concentrated to produce 0. 266 g (91%) of carboxylic acid XLVIIIa-3a as a white solid. No purification was necessary. 4- (3-Hydroxy-17-oxo-estra-1, 3,5 (10) -trien-15-yl) butyric acid (IVa-3a) If necessary, the unprotected carboxylic acid can be obtained by treating the cetal derivative XLVIIIa-3a with an inorganic acid and subsequent purification.

IV. Compounds of the formula XXXI (alcohol derivatives): -hydroxy-alkyl (Cx-C6) -estrone Alcohol XXXIa-la: 15a-hydroxymethyl-3-hydroxy-estra-l, 3, 5 (10) -trien-17-one Alcohol XXXIa-lb: 15a-hydroxymethyl- 3-methoxy-estral, 3, 5 (10) -trien-17-one Alcohol XXXIa-lc: 3-benzyloxy-15a-hydroxymethyl-estral, 3, 5 (10) trien-17-one The synthesis of alcohols derivatives XXXIa-la (RAH), xxxice-lb (R1 = CH3) and XXXIa-lc (R1 = benzyl) is shown in the following scheme 9: SCHEME 9 (Xlll-0) (XXXIa-1) (XXXIa-1c) (XXXIa-1a) Reduction of aldehydes XlII-Ob or XIII-Oc using NaBH4, followed by hydrolysis with ketal provided the corresponding alcohols XXXIa-lb and XXXIa-lc. Alcohol XXXIa-lc was debenzylated to provide XXXIa-la using Pd / C and a hydrogen atmosphere at 5 bar.

Detailed Synthesis Alcohol XXXIa-lb: 15a-hydroxymethyl-3-methoxy-estral, 3,5 (10) -trien-17-one Alcohol XXXIa-lc: 3-benzyloxy-15a-hydroxymethyl-estra-l, 3, 5 ( 10) -trien-17-one NaBH4 (500 mg, 13.2 mmol) in aliquots of 100 mg per 10 min was added to a solution of aldehyde XlII-Ob or XIII-Oc (2.3 mmol) in THF (20 mL) and the reaction was continued overnight. The reaction was quenched after the addition of MeOH (20 mL). The reaction mixture was evaporated to dryness (high vacuum). The residue was dissolved in CH2C12 (50 mL) and stirred with HCl (15%, 50 mL) for 72 h. CH2C12 (50 mL) was added and the organic layer was dried with Na2SO4 and evaporated to dryness. A yield of 95-98% was obtained for both products (HPLC-MS: 90% pure). A sample of XXXI-lb was obtained (230 mg) with a purity of more than 95% by crystallization in CH2Cl2 / MeOH after standing in air. Compound XXXIa-lc was used in the next step without further purification.

Alcohol XXXIa-la: 15a-hydroxymethyl-3-hydroxy-estra-1,3,5 (10) -trien-17-one A suspension of estrone XXXIa-lc (0.81 g, 90% pure), Pd / C (50 -100 mg, cat) in MeOH (100 mL) was stirred under an atmosphere of H2 at 5 bar for 30 min. Pd / C was separated by filtration through Celite. Evaporation to dryness (0.52 g, 90% pure) and recrystallization of the residue from MeOH gave XXXIa-la as an off-white solid (308 mg).

Alcohol building blocks XXXI-3 (n = 3): 15 / 3- (3-hydroxypropyl) -3-methoxyestra-l, 3, 5 (10) -trien-17-one (XXXI-3b): Detailed synthesis: To a solution of 2- (3-bromopropyloxy) -tetrahydro-2H-pyran (4.45 g, 19.95 mmol) in dry THF (50 mL) at -78 ° C under a nitrogen atmosphere was added t-BuLi ( 1.5 M solution in pentane, 25 mL, 37.5 mmol). After 30 minutes of stirring, CuCN (0.89 g, 9.94 mmol) was added. The mixture was stirred for an additional 30 min while the reaction mixture was allowed to reach -40 ° C. After cooling to -78 ° C it added dropwise a solution of the 15, 16-unsaturated estrone derivative of the formula Xb (1.50 g, 5.24 mmol) and TMSC1 (1.3 mL, 10 mmol) in 50 mL of THF over a period of 15 min. The mixture was allowed to reach 0 ° C (over a period of 4 h). Then a saturated solution of NH 4 Cl was added, the layers were separated and the aqueous phase was extracted with ethyl acetate. The crude product was dissolved in methanol (250 mL) and K2CO3 (0.80 g, 5.97 mmol) was added. After 2 h of stirring at RT, water (50 mL) was added and most of the methanol was evaporated. The mixture was diluted with EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The crude product was dissolved in methanol (250 L) and p-TosOH (0.80 g, 4.21 mmol) was added. The reaction mixture was stirred for 90 min. Most of the methanol was removed on the rotary evaporator. Water was added and the aqueous phase was extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and the solvent was removed. The crude product was purified by column chromatography (Si02, cyclohexane / ethyl acetate 1: 1) to yield compound XXXI-3b (0.81 g, 45%) as a colorless oil. LC-MS (ES +): rt 5.75 min, m / z (replete.) 343 [(M + H) +, 40%], 360 [(M + NH4 +, 100%] Ai NMR (400 MHz, CDC13) d (ppm) 1.03 (s, 3H), 1.44-1.76 (m, 9H), 1.88-1.92 (m, ÍH), 2.03-2.07 (m, ÍH), 2.27-2.48 (m, 5H), 2.91-2.95 (m, 2H), 3.65-3.69 (m, 2H), 3.78 (s, 3H), 6.65 (d, ÍH), 6.71 (dd, ÍH), 7.19 (d, ÍH) ). 13 C NMR (100.6 MHz, CDC13) d (ppm) 17.8, 25.5, 26.8, 27.2, 29.5, 32.8, 34.0, 34.2, 36.1, 42.7, 44.6, 47.1, 52.9, 55.2, 62.6, 76.7, 77.0, 77.4, 111.5, 113.9, 126.0, 132.4, 137.7, 157.7, 221.0. [a] D20 = +79.6 (c = 0.314, MeOH) Alcohol building blocks XXXI-3c and XXXI-3a (n = 3, R1 = benzyl, n = 3, R1 = H) 3-Benzyloxy-15 / 3- (3-hydroxypropyl) -estra-1, 3, 5 (10) -trien-17-one (XXXI -3c) 3-Hydroxy-15 / 3- (3-hydroxypropyl) -estra-1, 3,5 (10) -trien-17-one (XIII-3a) The synthesis of the building blocks of alcohols of the formula XXXI-3c and XIII-3a is shown in the following scheme 10.

SCHEME 10 Detailed Synthesis 3-Benzyloxy-15 / 3- (prop-2-enyl) -estra-1, 3, 5 (10) -trien-17-one (XXXV-3C) Cul (18.76) was introduced into a 3-neck flask. g; 98.5 moles) and lithium chloride (4.17 g, 98.4 moles) and was brought to vacuum and purged with N2 (2x). THF (dry, 150 mL) was added and the mixture was stirred at T. A. for 20 minutes. The resulting clear green solution was cooled to -78 ° C. Allyl magnesium bromide (1.0 M solution in diethyl ether, 100 mL, 100 mmol) was added dropwise at -78 ° C. After completing the addition, trimethylsilyl chloride (9.1 mL, 71.2 moles) was added, immediately followed by the dropwise addition of a solution of 15, 16-unsaturated estrone Xc (10.08 g, 28.1 mmol) in THF (dry, 120 mL). After the addition was complete, the suspension was stirred for 1 hour at -78 ° C. The mixture heated to T. A. and stirred for 3 days. Saturated NH 4 Cl (500 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with HCl (1 M, 2 x 300 L) and aqueous ammonia (25%, 3 x 300 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated. The resulting brown oil was crystallized from EtOAc to yield XXXV-3c (5.81 g, 51%). 3 - . 3 - . 3-Benzyloxy-15 / 5- (prop-2-enyl) -estra-1, 3, 5 (10) -trien-17-dioxolane (ketal XXXV-3c) Triethyl orthoformate (25 mL, 150 mmol) was added and ethylene glycol (11 mL, 197 mmol) at XXXV-3c (10 g; . 0 mmol). P-TosOH (0.40 g, 2.10 mmol) was added to the suspension which was heated at 35 ° C overnight. Next, the reaction mixture was poured into ice (100 mL) and pyridine (3 mL) was added. This mixture was stirred for 5 h.

The mixture was diluted with ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were washed with water (2 x 100 mL), dried over Na 2 SO 4 and evaporated. The crude product was purified by column chromatography (heptane / EtOAc 9: 1) to yield ketal XXXV-3C (9.94 g, 90%). 3-Benzyloxy-15 / 3- (3-hydroxypropyl) -estra-1, 3, 5 (10) -trien-17-dioxolane XXXII-3c The ketal compound XXXV-3c (9.94 g; 22. 36 mmol) in THF (500 mL). Borane dimethylsulfide (2 M in diethyl ether, 72 mL, 144 mmol) was added and the solution was heated to reflux for 2 hours. The solution was then cooled in a bath with ice and NaOH was added dropwise (3 M, 99 mL). H202 (35%, 50 mL) was then added and the resulting biphasic system was stirred overnight at 40 ° C.

The excess peroxide was destroyed by the addition of dimethyl sulfide. After one treatment, XXXII-3c (8.22 g) containing "40% of a secondary product was obtained. The crude product was used in the next step without further purification. 3-Benzyloxy-15 / 3- (3-hydroxypropyl) -estra-1, 3, 5 (10) -trien-17-one XXX-3c The crude compound XXXII-3c (8.82 g) was dissolved in acetone (88). mL) and water (22 mL) and p-TosOH were added (0.36 g, 1.89 mmol). The solution was stirred for 3 days at T.

A. After workup, the crude product was purified by column chromatography (heptane / EtOAc 1: 1, Rf 0.3) to yield compound XXX-3c (2.90 g, 31% over 2 steps). 3-Hydroxy-15 / 3- (3-hydroxypropyl) -estra-1, 3, 5 (10) -trien-17-one XXX-3a Compound XXX-3c (2.90 g, 6.93 mmol) was dissolved in MeOH (250 mL) and Pd / C was added as a suspension in MeOH. The mixture was stirred overnight at T. A. under an atmosphere of H2. The reaction mixture was filtered over Celite. The filtrate was evaporated and the product was dissolved in EtOAc (50 mL) and crystallized as needles, which were filtered off and washed with pentane to yield compound XXX-3a (1.63 g, 72%). (LC-MS (ES-): rt 5.75 min, m / z (intens reí.) 327 [(M-H) +, 100%]).

Alcohol building blocks XXXI -4b, XXXI-5b, XXXI-6b (n = 4, 5, 6] 15 / 3- (4-Hydroxy-alkyl d-Cs) -3-methoxy-estra-l, 3, 5 (10) -trien-17-one: The general synthesis of the alcohol building block of the formula XXXI-4/5 / 6b is shown in the following scheme 11.

SCHEME 11 General procedure Magnesium (3-10 eq) is added in a dry three-necked flask under N2 atmosphere and activated by iodine. The bromine compound (2-6.5 eq) dissolved in dry THF is added dropwise to magnesium. The reaction mixture is allowed to react for 1-2 h at T. A. or reflux. The solution is transferred to a dry three-necked flask containing Cul (0.06-0.7 eq) and DMPU or HMPA (2-7 eq) in dry THF cooled to -40 ° C. The resulting mixture is stirred for 30 min at -40 ° C, after which a mixture of 15, 16-unsaturated estrone derivative of formula X (1 eq) and TMSCl (2-2.5 eq) is added dropwise. dissolved in THF. After the addition is complete, the mixture is allowed to reach T. A. Then NH 4 Cl solution is added, the layers are separated and the aqueous phase is extracted with ethyl acetate (3x). The combined organic phases are dried over Na2SO4 and the solvent is separated. The raw product is dissolve in methanol and add KC03 (1 eq) to hydrolyze the silyl ether. After the hydrolysis is complete, water is added and most of the methanol is evaporated. The mixture is diluted with EtOAc, the layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The resulting product of the general formula XXX is then further treated to provide the alcohol of the general formula XXXI.

Detailed synthesis XXXI-4b (n = 4 and Rl = CH3): 15 / 3- (4-hydroxybutyl) -3-methoxy-estra-1,3,5 (10) -trien-17-one The detailed synthesis of this The compound has already been discussed in the section for the synthesis of the acid building block of formula IV-3b above.

XXXI-5b (n = 5 and Rl = CH3): 15 / 3- (5-hydroxypentyl) -3-methoxy-estra-1, 3,5 (10) -trien-17-one According to the general procedure set forth in SCHEME 11, the copper reagent was prepared from magnesium (3.80 g, 156 mmol), 2- (5-bromopentyloxy) -THP (23.6 g, 94.00 mmol), Cul (0.54 g, 2.83 mmol) and DMPU (12 mL, 10 mmol) in THF. A mixture of the estrone derivative of the formula Xb (13.68 g, 48.5 mmol) and TMSCl (13 mL, 100 mmol) in THF was added dropwise. The reaction mixture was allowed to reached the T.A. and stirred for two days. After treatment and hydrolysis of the silyl ether, the crude product was dissolved in methanol (50 mL) and p-TosOH (11.4 g, 60 mmol) was added. The reaction mixture was allowed to stir overnight. Most of the methanol was removed on the rotary evaporator. Water was added and the aqueous phase was extracted with DCM (3x) The combined organic layers were dried over Na2SO and the solvent was removed. The crude product was purified by column chromatography (Si02 # cyclohexane / ethyl acetate gradient from 10: 1 to 2: 1) to yield XXXI-5b (14.21 g, 79%).

LC-MS (ES +): rt 6.31 min, m / z (intensive re.) 388 (M + NH4 +, 100%] [a] D20 = +85.7 (c = 0.105, CH2C12) XXXI-6b (n = 6 and Rl = CH3): 15 / 3- (6-hydroxyhexy) -3-methoxy-estra-1, 3, 5 (10) -trien-17-one According to the general procedure set forth in SCHEME 11, the copper reagent was prepared from magnesium (2.19 g, 91.00 mmol), 2- (6-bromohexyloxy) -THP (20.67 g, 78.00 mmol), Cul (1.98 g, 10.40 mmol) and DMPU (9.4 mL, 7.8 mmol) in THF. A mixture of the estrone derivative of the formula Xb (7.33 g, 26.0 mmol) and TMSC1 (5.56 g, 52.00 mmol) in THF was added dropwise. The reaction mixture was allowed to reach T.A. and stirred for two days.

After treatment and hydrolysis of the silyl ether, the crude product was dissolved in methanol (200 mL) and p-TosOH (0.95 g, 5.00 mmol) was added. The reaction mixture was stirred for 1 h. Most of the methanol was removed on the rotary evaporator. Water was added and the aqueous phase was extracted with DCM (3 x). The combined organic layers were dried over Na2SO4 and the solvent was removed. The crude product was purified by column chromatography (Si02, cyclohexane / ethyl acetate gradient from 10: 1 to 2: 1) to yield XXXI-6b (7.50 g, 75%).

LC-MS (ES-): rt 6.63 min, m / z (intensive re.) 443 [(+ OAc) ", 100%] Alcohol building block XXXI-4C (n = 4, R1 benzyl) and XXXI-4a (n = 4, R1 = H) 3-Benzyloxy-15 / 3- (4-hydroxybutyl) -estra-1, 3, 5 (10) trien-17-one (XXXI-4c) 3-Hydroxy-15 / 3- (4-hydroxybutyl) -estra-1,3,5 (10) -trien-17-one (XXXI-4a) The detailed synthesis of this compound has already been exposed in the section for the synthesis of the acid building block of formula IV-3c above. The 3-hydroxy derivative can be obtained by hydrolysis of compound XXXI-4c.

Construction blocks of alcohols XXXI-5C and XXXI-5a (n = 5, R1 = benzyl, n = 3, R1 = H): 3-Benzyloxy-15 / 3- (5-hydroxypentyl) -estra-1,3, 5 (10) trien-17-one (XXXI-5c) 3-Hydroxy-15 / 3- (5-hydroxypentyl) -estra-1, 3,5 (10) -trien-17-one (XXXI-5a) The synthesis of the building block of alcohols of the formula XXXI-5c and XXXI-5a is shown in the following scheme 12.

SCHEME 12 XXXV-5c-ketal XXXII-dc (XXXI-5C) (XXXI-5a) Detailed Synthesis 3-Benzyloxy-15 / 3- (pent-4-enyl) -estra-1, 3, 5 (10) -trien-17-one (XXXV-5c) Magnesium filings (4.43 g, 0.182 moles) were activated ) by adding a crystal of I and a drop of pure bromide. A solution of 5-bromo-1-pentene (19.5 mL, 0.164 mol) in THF (dry, 160 mL) was added dropwise, while maintaining reflux. After the addition was complete, the mixture was stirred at T. A. for 1 hour. Cul (30.47 g, 0.159 mol) and lithium chloride (6.78 g, 0.159 mol) were introduced into a 3-neck flask and a vacuum was applied and purged with N2 (2x). THF (dry, 240 mL) was added and the mixture was stirred to T. A. during 20 minutes. The resulting clear green solution was cooled to -78 ° C. The Grignard reagent was added dropwise between -78 ° C and -70 ° C. After the addition was complete, trimethylsilyl chloride (20.4 mL, 0.159 mol) was added to the brown reaction mixture at -78 ° C, immediately followed by the dropwise addition of a solution of 15, 16-unsaturated estrone Xc (22.94). g; 0.064 mol) in THF (dry, 280 mL). After the addition was complete, the suspension was stirred for 1 hour at -78 ° C. The mixture was heated to T. A. and stirred for 3 days. Saturated NH 4 Cl (500 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with HCl (1 M, 2 x 300 mL) and aqueous ammonia (25%, 3 x 300 mL). The aqueous layer was dried over Na2SO4 and the solvent was evaporated. The resulting brown oil was crystallized from EtOAc to yield XXXV-5C (18 g, 66%). 3-Benzyloxy-15 / 3- (pent-4-enyl) -estra-1, 3, 5 (10) -trien-17-dioxolane (ketal XXXV-5c) Triethyl orthoformate (42 mL; 252 mmole) and ethylene glycol (19 mL, 340 mmol) to compound XXXV-5C (18 g, 42.0 mmol). P-TosOH (0.67 g, 3.52 mmol) was added to the suspension which was heated at 35 ° C overnight. Next, the reaction mixture was poured into ice (100 mL) and pyridine (3 mL) was added. This mixture was stirred for 5 h. The mixture was diluted with ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were washed with water (2 x 100 mL), dried over Na 2 SO 4 and evaporated. The crude product was purified by column chromatography (heptane / EtOAc 9: 1) to yield ketal XXXV-5c (18.85 g, 95%). 3 - . 3-Benzyloxy-15 / 3- (5-hydroxypentyl) -estra-1, 3,5 (10) -trien-17-dioxolane (XXXII-5c) Compound XXXV-5c (18.85 g, 39.88 mmol) was dissolved in THF (850 mL). Borane-dimethyl sulfide (2 M in diethyl ether, 128 mL, 256 mmol) was added and the solution was heated to reflux for 2 hours. The solution was then cooled in an ice bath and NaOH (3 M, 176 mL) was added dropwise. H202 (35%, 89 mL) was then added and the resulting biphasic system was stirred overnight at 40 ° C. The excess peroxide was destroyed by the addition of dimethyl sulfide (380 mL). The solvent was evaporated and water (500 mL) and ethyl acetate (500 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (500 mL). The organic layer was dried over Na 2 SO 4 and the solvent was evaporated to yield XXXII-5c (15.36 g). The crude product was used in the next step without further purification. 3-Benzyloxy-15 / 3- (5-hydroxypentyl) -estra-1, 3, 5 (10) -trien-17-one (XXXI-5c) The crude compound XXXII-5c (15.36 g) was dissolved in acetone (135 mL) and water (35 mL) and p-TosOH (0.62 g, 3.26 mmol) were added. The solution was stirred for 3 d at T. A. Saturated NaHCO 3 solution (50 mL) was added and the solvent was evaporated. Additional saturated NaHCO3 solution (20 mL) was added and the mixture was extracted with CH2C12 (2 x 100 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated. The crude product was purified by column chromatography (heptane / EtOAc 1: 1, Rf 0.3) to produce XXXI-5C (8.65 g, 49% over 2 steps).3-Hydroxy-15 / 3- (5-hydroxypentyl) -estra-1, 3,5 (10) -trien-17-one (XXXI-5a) Compound XXXI-5C (8.65 g, 19.37 mmol) was dissolved in MeOH (95 mL) and Pd / C (2.3 g) was added in the form of a suspension in some MeOH. Ammonium formate (9.77 g, 154.9 mmol) was added and the solution was stirred at T.A. After 1 hour and 45 minutes, an NMR spectrum (in CD3OD) showed complete conversion. The reaction mixture was filtered over Celite and washed with MeOH (30 mL). The filtrate was evaporated, leaving a sticky material that was stirred in water (100 mL) at T. A. The compound was converted to a solid and the water was separated by decantation after 5 hours. EtOH (100 mL) was added and evaporated to remove water. The oil evaporated twice in EtOAc (100 mL), yielding 6 g of a white foam, which contained 10% of the secondary alcohol as an impurity. The secondary product was separated by transformation into the acetic acid ester (with pyridine and acetic anhydride) and separation by column chromatography (heptane / EtOAc from 2: 1 to 1: 2). The ester was cleaved by heating with potassium carbonate in MeOH. After treatment, the product XXXI-5a (2.21 g, 32%) was obtained in the form of a colorless foam. LC-MS (ES-): rt 5.23 min, m / z (intens reí.) 355 [(M-H) +, 100%] Alcohol building blocks XXXI-6c and XXXI-6a (n = 6, R1 = benzyl, n = 3, R1 = H): 3-Benzyloxy-15 / 3- (6-hydroxyhexyl) -estra-1,3, 5 (10) -trien-17-one (XXXI -6c) 3-Hydroxy-153- (6-hydroxyhexyl) -estra-1, 3,5 (10) -trien-17-one (XXXI-6a) 3 - . 3-Benzyloxy-15 / 3- (6-hydroxyhexyl) -estra-1, 3,5 (10) trien-17-one (XXXI-6c) According to the general procedure shown in the SCHEME 11, the copper reagent was prepared from magnesium (6.56 g, 2.70 mmol), 2- (6-bromohexyloxy) tetrahydro-2H-pyran (47.2 g, 180 mmol), Cul (3.18 g, 17 mmol) and HMPA (33 mL, 190 mmoles) in THF. A mixture of the 15, 16-unsaturated estrone derivative Xc (10.1 g, 28.00 mmol) and TMSC1 (8 mL, 63 mmol) in THF was added dropwise. The reaction mixture was allowed to reach T.A. and stirred overnight. After treatment and hydrolysis of the silyl ether, the crude product was dissolved in methanol (890 L) and p-TosOH (3.30 g, 17.35 mmol) was added. The reaction mixture was stirred overnight. Most of the methanol was removed on the rotary evaporator. Water was added and the aqueous phase was extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and the solvent was removed. The crude product was purified by column chromatography (Si02, heptane / ethyl acetate 2: 1) to yield XXXI-6C (7.99 g, 62%). 3-Hydroxy-15 / 3- (6-hydroxyhexyl) -3-estra-l, 3, 5 (10) -trien-17-one (XXXI-6a) Compound XXXI-6c (7.99 g; 17. 35 mmole) in MeOH. Pd / C (in water, 2.3 g) was added, followed by ammonium formate (8.58 g, 136 mmol). The mixture was stirred at T. A. for 1.5 hours, after which the mixture was filtered over Celite. The filtrate was evaporated and dissolved in EtOAc (200 mL) and water (150 mL). The layers separated, the layer organic was dried over Na2SO4 and the solvent was evaporated. Purification by column chromatography (Si02, heptane / EtOAc 1: 1) afforded the title compound (2.69 g, 42%). LC-MS (ES-): rt 5.49 min, m / z (intensive re.) 369 [(M-H) +, 100%] V. Compounds of formula XV (protected amine building block) (n = 1-6); R3 preferably H XV-1: (n = 1): XV-lb: ketal derivative of 15a-aminomethyl-3-methoxyestra-1,3,5 (10) -trien-17-one XV-lc: ketal derivative of the 15a-aminomethyl-3-benzyloxy-estra-1, 3, 5 (10) -trien-17-one The individual steps in the synthesis of the amine building block of the formula XV-1 are set out in the following scheme 13.

SCHEME 13 (XV-1) (XXIX-1) The dissolution of the aldehydes XlII-Ob (R '= CH3) or XIII-0c (R1 = benzio) in benzylamine and the reduction of the residual imine in THF provided the benzylamine XIV-Ib (R1 = CH3) and XV-la (R1 = benzyl), which were debenzylated to XV-Ib (R1 = CH3 and XV-la (R1 = H), using Pd / C and H2 at 5 bar, and dissolved in dilute HCl to give the respective ammonium chlorides XXIX-lb (R1 = CH3) and XXIX-la ( R1 = benzyl).

Standard purification methods failed due to what appears to be an instability of these ammonium salts. For these amines it is known that these must be treated in the form of HCl salts, since the free amine is not stable (eno-amines), but even the salts appear to be at least sensitive to heat. The crude reaction mixture had a purity of -90% (HPLC-MS).

Detailed synthesis XlV-lb: Cetal 15a- (benzylamino-methyl) -3-methoxy-estra-1,3,5 (10) -trien-17-one XIV-lc: Cetal 15a- (benzylamino-methyl) - 3-benzyloxy-estra-1,3,5 (10) -trien-17-one The aldehyde XlIIb or XIIIc (0.93 mmol) was dissolved in benzylamine (0.4 mL, 3.9 mmol) and MeOH (10 mL) after heating and the The mixture was stirred for 30 min and evaporated to dryness. The residue was dissolved in dry THF and 50 mg aliquots of NaBH4 were added every hour until 300 mg (4.0 mmol) was added. The mixture was stirred overnight: only one baseline spot was observed by TLC (TBME). The mixture was evaporated to dryness and the residue was stirred with aqueous NaHCO3 (200 mL) until no gaseous evolution was observed. The suspension was extracted with CH2C12 (2 x 200 mL) and after drying the organic layer with Na2SO4 and evaporating to dryness, XlVb and XIVc compounds were obtained in the form of colorless oils: yield 92-100%.

XV-Ib: Derivative of ketal of 15a-aminomethyl-3-methoxy-estra-1,3,5 (10) -trien-17-one XV-la: Derivative of ketal of 15a-aminomethyl-3-hydroxy-stratum 1,3,5 (10) -trien-17-one A suspension of benzylamine XlVb or XIVc (22 mmol) and Pd / C (10%, 1.0 g, cat.) In MeOH (500 mL) was stirred under an atmosphere of H2 at 5 bars during 48 h. Filtration through Celite and evaporation to dryness gave the crude amines XV-la and XV-lb. Amine XV-la was purified by column chromatography (CHCl2 / MeOH (7 N, NH3); 925: 75) to give XV-la as a colorless oil (5.0 g, 63% for the three steps starting from aldehyde XIIlc ). The XV-lb amine was broken down in many products after being at rest for one night. Therefore, in a second attempt it was used instantaneously without purification in the next step.

XXIX-Ib: 15a-aminomethyl-3-methoxy-estra-1, 3, 5 (10) -trien-17-one / HCl XXIX-la: 15a-aminomethyl-3-benzyloxy-estra-l, 3, 5 (10) -trien-17-one / HCl A solution of amine XV-lb (1.1 mmol) in MeOH (10 mL) was added to HCl (5 mL, 30% in H20). The reaction mixture was stirred overnight and concentrated until crystallization began. Filtration gave the product XXIX-lb (130 mg, 33%). A pure sample (more than 95%) of XXIX-la was obtained by dissolving XV-la in 1 N HCl (20 mL) and isolating XXIX-a through preparative HPLC (20 passes of injections of 1 mL of the reaction mixture). Evaporation of the eluent in vacuo at 40-45 ° C introduced the degradation product for 3-4%. Compound XIV-1 is an example of a secondary amine which can be used as a building block for further synthesis of the compounds according to the invention, in which the residue R3 is other than hydrogen. Other secondary amines according to formula XIV-1 which can be used as building blocks, can be synthesized by the addition of the appropriate primary amines in the first stage of the above-described synthesis scheme SCHEME 13. A further example of a secondary amine which can be used as a building block is 15a- (methylaminomethyl) -3-methoxy-estra-1, 3,5 (10) -trien-17-one: XXXVIII-la: Ceta of 15a- (methylamino-methyl) -3-hydroxyestra-1,3, 5 (10) -trien-17-one XXXVIII-lb: Cetal of 15a- (methylamino-methyl) -3-methoxy- estra-1,3,5 (10) -trien-17-one XXXVIII-lc: Cetal of 15a- (methylamino-methyl) -3-benzyloxy-estra-1,3,5 (10) -trien-17-one (XXXVIII-1) The individual steps in the synthesis of the secondary amine building block of formula XXXVIII-1 are set forth in the following scheme 14.

SCHEME 14 (Xlll-Oc) (XXXIX-1a) (XXXVIII-1a) The conversion of the aldehydes XlIIb and XIIIc to the methylimine using Ti (i-OPr) and the consecutive reduction of imine gave the methylamines XXXVIII-lc. The debenzylation of XXXVIII-lc gave XXXVIII-la. Dissolution of XXXVIII-la in dilute HCl and crystallization from MeOH / H20 yielded XXXIX-la.

The individual steps in the synthesis of the secondary amine building block of the formulas XXXVIII-Ib and XXXVIII-Ic are set forth in the following scheme 15.

SCHEME 15 The conversion of aldehydes XlII-b (R1 = CH3) and XIII-c (R1 = benzyl) to the methylimine using Ti (i-0Pr) 4 and the consecutive reduction of imine gave the respective methylamine XXXVIII-lc and XXXVIII-Ib. The solution of XXXVIII-lc or XXXVIII-Ib in dilute HCl and crystallization from MeOH / H20 yielded XXXIX-lb (R1 = CH3) and XXXIX-1C (R1 = benzyl).

Detailed synthesis XXXVIII-lb: Cetal of 15a- (methylamino-methyl) -3-methoxy-estra-1,3, 5 (10) -trien-17-one XXXVIII-lc: Cetal of 15a- (methylamine-methyl) - 3-benzyloxy estradiol 1,3,5 (10) -trien-17-one NH 2 Me (9.26 mL, 2.0 M in MeOH, 18. 52 mmole) to a suspension of aldehyde XlIIb or XIIIc (1.85 mmole) in Ti (i-oPr) 4 (0.84 mL, 2.78 mmole). The suspension became a clear solution after stirring for 2.5 h. This reaction had to be followed by TLC (TBME / CH2C12, 1: 1). When the reaction was complete, MeBH4 (500 mg, 13.2 mmol) was added and the reaction was continued overnight. NaHCO3 (aqueous) (200 mL) was added and the mixture was evaporated to dryness. The residue was extracted with CHC13 (100 mL) using ultrasound. This extraction was repeated until a yield of at least 75% was obtained.

XXXVIII-la: Cetal 15a- (methylamino-methyl) -3-hydroxy-estra-1,3,5 (10) -trien-17-one The debenzylation of XXXVIII-lc with Pd / C (10%, 1.0 g , cat) in MeOH (500 mL) in an atmosphere of H2 at 5 bar for 48 h provided the crude amine XXXVIII-a XXXVIII-la: 15a- (methylamino-methyl) -3-hydroxy-estra-l, 3, 5 (10) -trien-17-one XXXVIII-Ib: 15a- (methylamino-methyl) -3-methoxy-estradiol 1, 3, 5 (10) -trien-17-one A solution of the amine XXXVIII-lb or XXXVIII-la (1.1 mmol) in MeOH (10 mL) was added to HCl (5 L, 30% in EJO). The reaction mixture was stirred overnight and evaporated to dryness. In the case of XXXIX-la, fractional recrystallization of the residue (-90% pure) in MeOH gave a sample of pure material (110 mg). In the case of XXXIX-lb, one sample (100 mg) was isolated by column chromatography (CH3Cl / NEt3 / MeOH, 17: 2: 1).

XVa-3 amine building block: (n = 3): XVa-3a: Cetal derivative of 15a-aminopropyl-3-hydroxy-estra-1, 3, 5 (10) -trien-17-one XVa- 3b: Derivative of ketal of 15a-aminopropyl-3-methoxyestra-1,3,5 (10) -trien-17-one The individual steps in the synthesis of the amine building block of the formula XVa-3 are set out in the following scheme 16.

SCHEME 16 The protected aldehyde derivative of the formula (XIIIa-0) is converted into the corresponding aminopropenyl by a Wittig reaction (see also SCHEME 4).

The aminopropenyl (XXXVII-3) is subsequently reduced to the 15-aminopropyl derivative of the formula XVa-3. The protective ketal group is converted to the 17-oxo group by acid hydrolysis. The same type of procedure can be applied using Wittig reagents different from the general formula Hal (F) 3P- (CH2) n = 3-5-R * in order to obtain building blocks of amines with longer side chains (ie, n = 4, 5 or 6), in which R * represents, for example, -N = P (F) 3, -N3 or -NH-CO-O-CH3. Amine building block XVa-4: (n = 4): XVa-4a: Derivative of 15a-aminobutyl-3-hydroxyestra-1,3,5 (10) -trien-17-one ketal derivative XVa-4b: Derivative of ketal of 15a-aminobutyl-3-methoxyestra-1,3,5 (10) -trien-17-one In addition, the amine building block XVa-4b was synthesized correspondingly to SCHEME 16 using HalF3P-CH2-CH2-CH2-N3 as a Wittig reagent. (LC-MS (ES +): rt 4.57 min, m / z (intensive re.) 386 [(M + H) +, 100%]) XV / 3-4: (n = 4): XV / 3-lb: Derivative of ketal of the 15/3-aminobutyl-3-methoxy-estra-1, 3, 5 (10) -trien- 17 -one XV / 3-lc: Derivative of ketal of the 15/3-aminobutyl-3-benzyloxy -estra-1, 3, 5 (10) -trien-17-one (XV-4) The individual steps in the synthesis of the amine building block of the formula XV / 3-4 with β configuration at the C15 atom of the steroid nucleus are shown in the following scheme 17.

SCHEME 17 In a first step, the 17 -oxo function of the butanol derivative of the formula XXXI / 3-4 (for the synthesis of XXXI / 3-4 see above) is converted to the ketal group (composed of the formula XXXI / 3-4). Next, the alcohol function is selectively reduced to the aldehyde to provide the compound of the formula XIII / 3-3. The aldehyde derivative protected from formula XIII / 3-3 is converted to a secondary amine by the addition of benzylamine and subsequent reduction (reductive amination). An additional reduction of the secondary amine supplies the desired, still protected amine building block of formula XV / 3-4. The protective ketal group can be converted to the 17 -oxo group by acid hydrolysis. The same type of procedure can be applied for n = 5 or 6 and for other substituents in the position of R1. In addition, compound XIV / 3-4 is an example of a secondary amine which can be used as a building block for further synthesis of the compounds according to the invention, in which the residue R3 is other than hydrogen. Other secondary amines which can be used as building blocks can be synthesized by the addition of the appropriate primary amines in the first step of synthesis scheme 17 indicated above. Amine construction block (n 6); RJ preferably = H of the general formula XXIX Alternatively, the synthesis of the blocks of The construction of amines of the general formula XXIX can also be carried out starting from an activated alcohol function and a subsequent substitution reaction, and does not need any protection from the estrone-17 keto function according to the following general scheme 18.

SCHEME 18 EXAMPLE XXIX / 3-4b: 15/3-Aminobutyl-3-methoxy-estral, 3,5 (10) -trien-17-one (XXIXß-4) HkHCI Detailed synthesis XLl1 / 3-4b: 4- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15-yl) -butyl methanesulfonic acid ester (XLII with n = 4 and R1 = CH and ß-configuration in C15) 4 g (11.22 mmol) of alcohol were cooled to 0 ° C (XXXI / 3-4b) dissolved in 50 mL of THF under dry conditions before adding 1 eq of TEA and 1 eq of methanesulfonic acid chloride dropwise. After stirring for 3 hours at 0 ° C, another 0.25 eq of TEA and methanesulfonic acid chloride were added; this procedure was repeated after 2 hours to bring the reaction to completion. For the treatment, the reaction mixture was poured into ice / water the next morning. The water was extracted twice with EE, which was then combined and washed with 1 molar solution of NaHCO3. After evaporation, 5.19 g of an oil containing compound XLII / 3-4b (LC MS: MH + 435, rt 6.50 min, still containing some solvent residues) was obtained, which was used without any further purification.

XLIII / 3-4b: 15- (4-Azido-butyl) -3-methoxy-13-methyl-estra-1,3,5 (10) -trien-17-one (XLIII with n = 4 and R1 = CH3 and ß-configuration at C15) 5.19 g of XLII / 3-4b obtained in the previous step (approximately 11 mmol) and 0.91 g of NaN3 in 150 mL of ethanol were dissolved and kept under reflux for 10 h. The next morning, most of the ethanol had been distilled off under reduced pressure. Subsequently, the residue was divided into parts between water and EE. The aqueous layer was extracted twice with EE. The organic layers were combined, dried with Na 2 SO 4 and evaporated to yield 4.4 g of XLIII / 3-4b oil (LC-MS: MH + = 382, rt 7.32 min, still containing some solvent residues) which was used without purification additional .

XXIX / 3-4b: 15/3-Aminobutyl-3-methoxy-estra-1, 3, 5 (10) -trien-17-one 3.3 g of anid (XLIII / 3-4b) was dissolved in 300 mL of ethanol. 20 mL of 18% aqueous HCl and 50 mg of Pd at 5% / C. The suspension was placed in a stirring device which was subjected to a pressure with 3 bar of hydrogen for 6 hours. After filtration, the filtrate was evaporated and the remaining solid was dried for 4 hours at 60 ° C in a vacuum drying oven, yielding 3.2 g of the amine hydrochloride salt XXIX / 3-4b (LC-MS: MH + : 356; rt: 4.84 min) Experimental part Examples of preparations of compounds of the invention are provided in the following detailed synthesis procedures. In the tables of compounds that follow, the synthesis of each compound is again referred to these examples of preparative stages.

In synthesis of single compounds, as well as in combination synthesis, all reactions were magnetically agitated or agitated with an orbital shaker, unless otherwise indicated. The liquids and sensitive solutions were transferred through a syringe or cannula, and introduced into reaction vessels through rubber compartments, in these cases the reaction was carried out under a positive pressure of dry argon or dry nitrogen. Commercial grade reagents and solvents were used without further purification. Unless otherwise stated, the term "concentration under reduced pressure" refers to the use of a Buchi or Heidolph rotary evaporator ("Rotavapor") or vacuum centrifuges ("GeneVac") at approximately 15 mm Hg. All temperatures are expressed uncorrected in degrees Celsius (° C). Unless otherwise indicated, all parts and percentages are in volume. Thin layer chromatography (TLC) was performed on silica gel on a Merck® pre-coated glass support or plates of 250 μm 60A F-254 aluminum foil. The visualization of the plates was carried out by one or more of the following techniques: (a) ultraviolet illumination (254 nm or 266 nm), (b) exposure to iodine vapor, (c) spraying the plate with reagent solution Schlittler followed by heating, (d) spraying the plate with anisaldehyde solution followed by heating, and / or (e) spraying the plate with Rauxz reagent solution followed by heating. Column chromatography (flash chromatography) was performed using ICN silica gel, SiliTech 60A 230-630 mesh. The melting points (mp) were determined using a Reichert Thermovar melting point apparatus or a Mettler DSC822 automated melting point apparatus and are uncorrected. Infrared spectra of the Fourier transform were obtained using a Perkin Elmer spectrophotometer. The proton nuclear magnetic resonance (NMR) spectra (A) were measured on a Bruker ARX (400 MHz) or Bruker ADVANCE (500 MHz) spectrometer with Me4Si (d 0.00) or residual protonated solvent (CHC13 d 7.26; CHD20D d 3.30; DMSO-D3 d 2.50) as pattern. The NMR spectra with carbon (13C) were measured with a Bruker ARX spectrometer (100 MHz) with Me4Si (d 0.00) or solvent (CDC13 d 77.05, CD3OD d 49.0, DMSO-d6 d 39.45) as standard. The HPLC electrospray mass spectra (HPLC ES-MS) were obtained using the following method and installation: the samples were separated by inverted phase high pressure liquid chromatography (RP-HPLC) coupled to a quadrupol MS. HPLC was performed at a flow rate of 1000 μl / min using XterraMS C18 columns (d.i. 4.6 mm, length 50 mm, particle size 2.5 μm) or Phenomenex Luna C18 (2) 30 * columns of 4.6 mm. For most samples, a gradient from 0% of eluent B to 95% of B was made in 10 min, in which the eluent A consisted of water, 10 mM ammonium acetate at pH 5 + 5% acetonitrile and the eluent B consisted of acetonitrile. Two different settings were used: 1. Waters Alliance 2795 coupled to a Waters ZQ MS, a Waters 2996 diode array detector (DAD) and an evaporative light scattering detector (ELSD, EL-ELS1000, PolymerLabs). Ionization: electrospray in positive and negative mode ES +/-. 0 2. LC200 (PE) pump coupled to an API100 MS device (Applied Biosystems Sciex), a Waters 2487 variable wavelength detector set at 225 nm and an ELSD (Sedex 75), ES +. In the two adjustment versions, the spectra were scanned with an exploration interval of m / z 100 to 800 or 100 to 900. Gas chromatography - mass spectral analyzes (GC-MS) were performed with an Agilent gas chromatograph. 6890 equipped with a DB-5MS column (0.25 di, length 30 m) and an Agilent 5973 MSD quadrupol detector (ionization with electronic impact TT at 70 eV; temperature of the source 230 ° C). The elemental analyzes were carried out by means of a VarioEL elemental analyzer (Elementar Analysensysteme) for the determination of C, H and N. Acetanilide was used for conditioning and calibration.

The NMR, LRMS, elemental analysis and HRMS spectra of the compounds were congruent with the assigned structures.

EXAMPLES In order to illustrate in more detail the nature of the invention and the manner of putting it into practice, the following examples are presented, but should not be construed as limiting.

EXAMPLES 1, 2, 3A, 3B and 4B No. 1. 3-Hydroxy-15 / 3- (4-morpholin-4-yl-4-oxo-butyl) -estra-1, 3, 5 (10) -trien -17-one (VI / 3-3a) -1 No. 2. 3-Methoxy-15 / 3- (4-morpholin-4-yl-4-oxo-butyl) -estra-1, 3, 5 (10 ) -trien-17-one (VI / 3-3b) -2 No. 3A. N-Benzyl-4- (3-hydroxy-17-oxo-estra-1,3,5 (10) trien-15β-yl) -butyramide (VI / 3-3a) -3A No. 3B. N-Benzyl-4- (3-methoxy-17-oxo-estra-1,3,5 (10) trien-15β-yl) -butyramide (VI / 3-3b) -3B No. 4B. 4- (3-Methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -N-methyl-butyramide (VI / 3-3b) -4B The individual steps in the synthesis of examples 1, 2, 3., 3.B and 4.B are shown in the following scheme 19.

SCHEME 19 Starting from the free acid building block of formula IV / 3-3b, the corresponding acid chloride was prepared using oxalyl chloride. The acid chloride was reacted with an amine of general structure R2R4NH representing morpholine, for the synthesis of compounds No. 1 and 2, benzylamine for compounds No. 3A and 3B, and methylamine for compound No. 4B, supplying after the first synthesis step the amides of the formula generates (VI / 3-3b): compound No. 2 (with -NR2R4 = morpholine), 3B (with -NR2R4 = -NH-benzyl) and 4B (with -NR2R4 = -NH-CH3). Compound 3B was purified by column chromatography followed by trituration with Et20 and isolation in 8% yield. Compound 4B was purified by trituration with Et20 and some MeOH and isolated in 48% yield. Compound 2 was purified by column chromatography and was obtained with a yield of 33%. The demethylation of the 3-hydroxy function was satisfactory for compound No. 2 and No. 3B with BBr3, giving rise to the amide of the general formula (VI / 3-3a) representing compounds No. 1 and No. 3A with a yield of 21 and 48% respectively. Compound No. 1 was obtained, after column chromatography, in the form of a mixture of isomers a and β. The purification of compound No. 3A was carried out by column chromatography.

Detailed synthesis EXAMPLE No. 2: 3-Methoxy-15 / 3- (4-morpholin-4-yl-4-oxo-butyl) -estra-1,3,3,5 (10) trien-17-one of the formula (VI / 3-3b) ) -2 The acid building block IV / 3-3b (1.1 g, 2.7 mmol) was dissolved in DCM (20 ml) and 1 drop of DMF was added. The reaction mixture was cooled to 0 ° C and oxalyl chloride (0.25 ml, 2.7 mmol) was added dropwise. After stirring the mixture for 1 hour at 0 ° C, the solvent was separated in the rotary evaporator. The acid chloride was dissolved in DCM (20 ml) and morpholine (0.31 ml, 3.51 mmol) was added dropwise. The reaction mixture was stirred overnight. Water (20 ml) and DCM (30 ml) were added. After separating the layers, the aqueous layer was extracted with DCM (2 x 25 ml). The combined organic layers were washed with water (20 ml) and brine (60 ml). The organic layer was dried over Na 2 SO 4 and the solvent was removed on a rotary evaporator. This yielded 1.3 g of a yellow oil, which was dissolved in TBME and Et20 / EtOH, and some brown solid precipitated. The liquid phase was separated by decantation and the solvent was removed on a rotary evaporator. This produced 865 mg of a yellow / white solid. An HPLC analysis showed that the compound was approximately 80% pure. The solid was purified by column chromatography (50 g of Si02 / EtOAc / heptane: 1/2). This produced 670 mg with a purity of 86% according to HPLC. A second purification by column chromatography (25 g of Si02, EtOAc / heptane: 2/1) finally gave 414 mg (0.94 mmol, 33%) of the desired compound No. 2 as a white solid with a purity of 96%. according to HPLC [MS m / z 439, 1] EXAMPLE No. 1: 3-Hydroxy-15 / 3- (4-morpholin-4-yl-4-oxo-butyl) -estra-1,3,5 (10) trien-17-one of the formula (VI / 3-3a) -1 The methoxy compound of (Vl / á-JD) -2 (898 mg, 2.0 mmol) was dissolved in DCM (20 mL) and cooled to 0 ° C. A solution of BBr3 (12.3 ml, 1M in CH2C12) was added dropwise while the temperature was maintained at 0 ° C. The color changed from colorless to yellow / orange, to orange / red and even pink. The reaction was followed by TLC (SiO2 / EtOAc) and after 1 3/4 hour the reaction was complete. 40 ml of water were measured followed by 30 ml of saturated NaHCO 3 solution and an additional 200 ml of water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na 2 SO and the solvent was removed on a rotary evaporator. This produced 915 mg of a yellow oily solid. The product was purified by column chromatography (50 g of SiO2, toluene / acetone: 3/1) to give 183 mg (0.43 mmol, 21%) of the desired compound No. 1 as a yellow solid, with a purity of 95% [MS m / z 425.2].

EXAMPLE No. 3B N-Benzyl-4- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) butyramide of the formula (VI / 3-3b) - 3B The acid building block IV / 3-3b (1.2 g, 3.3 mmol) was dissolved in DCM (20 ml) and 1 drop of DMF was added. The reaction mixture was cooled to 0 ° C and oxalyl chloride (0.28 ml, 3.3 mmol) was added dropwise. The mixture was stirred for 1 hour at 0 ° C and the solvent was removed on a rotary evaporator. The acid chloride was dissolved in 20 ml of DCM and benzylamine (0.48 ml, 4.34 mmol) was added dropwise. The yellow / orange solution turned cloudy yellow / white. Stirring was continued for 0.5 hours at room temperature and then 20 ml of water and 25 ml of DCM were added. The aqueous layer was extracted with DCM (2 x ml) and the combined organic layers were washed with water (20 ml) and brine (20 ml). The organic layer was dried over Na 2 SO and the solvent was removed on a rotary evaporator. This produced 1.3 g of a yellow oil (56% pure according to an HPLC analysis), which was then purified by column chromatography (53 g of Si02 / TBME / heptane: 2/1). This purification produced 668 mg of a white solid (44%, 87% pure according to HPLC analysis). 400 mg was used for the demethylation to prepare (VI / 3-3a) -3A; 268 mg were triturated with Et20 to yield 124 mg of a white solid (0.27 mmol, 8%) with a purity of 94% by HPLC [MS m / z 459.1].

EXAMPLE No. 3A N-Benzyl-4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-ISff-yl) -butyramide of the formula (VI / 3-3a) -3A To a solution of the methoxy compound (VI / 3-3a) -3B (400 mg, 0.87 mmol) in DCM (100 ml) at 0 ° C was added dropwise 5.2 ml of a 1 M solution of BBr3 in DCM at a rate such that the temperature was kept at 0 ° C. The color changed from colorless to orange. After the addition was complete, the reaction was checked by TLC (EtOAc / heptane: 2/1). The reaction was completed after 1.5 h. Then water (40 ml), saturated NaHCO 3 solution and more water (150 ml) were added. The layers were separated and the aqueous layer was extracted with DCM (2 x 100 ml). The organic layers were combined, dried over Na2SO4 and the solvent was removed on a rotary evaporator.

This produced 310 mg of red / purple product, which was purified by column chromatography (15 g of Si02, toluene / acetone: 3/1) to give 173 mg of a yellow foam with a purity of 82%. The product was again purified by column chromatography (11 g of SiO2, toluene / acetone: 3/1). This purification afforded 160 mg of a yellow solid (0.36 mmol, 41%) with a purity of 93% according to HPLC [MS m / z 445.1].

EXAMPLE No. 4B 4- (3-Methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15/3-yl) -N-methyl-butyramide of the formula (VI / 3-3b) -4B The building block of acids IV / 3-3b (846 mg, 2. 3 mmol) was dissolved in DCM (20 ml) and 1 drop of DMF was added. The reaction mixture was cooled to 0 ° C and oxalyl chloride (0.20 ml, 2.3 mmol) was added dropwise. After stirring for 1 hour at 0 ° C, the solvent was removed on a rotary evaporator. The acid chloride was dissolved in DCM (20 ml) and 5.7 ml of a 2 M solution of methylamine in THF were added dropwise. The reaction mixture was stirred for 0.5 hours. Water (20 ml) and DCM (25 ml) were added. After separating the layers, the aqueous layer was extracted with DCM (2 x 25 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml). The organic layer was dried over Na 2 SO and the solvent was removed on a rotary evaporator. This produced 593 mg of a solid, which was stirred in Et20 and some MeOH. The white solid was isolated, filtered and dried. This produced 424 mg (1.1 mmol, 48%) with a purity of 95% according to HPLC [MS m / z 383.2].

EXAMPLES 4A and 4C No. 4A. 4- (3-Hydroxy-17-oxo-estra-l, 3,5 (10-trien-15/3-yl) -N-methyl-butyramide (VI / 3-3a) No. 4C. -Benzyloxy-17-oxo-estra-l, 3,5 (10) -trien-15 ^ -yl) -N-methyl-butyramide (VI / 3-3a) The individual steps in the synthesis of Examples No. 4A (Compound (VI / 3-3a) -4A) and No. 4C (Compound (VI / 3-3c) -4C) are set forth in the following scheme 20 (according to general flow diagram Ib).

SCHEME 20 Starting from the free acid building block of formula IV / 3-3C, the corresponding acid chloride was prepared using oxalyl chloride and this was converted to the amide (VI / 3-3c) -4C (yield = 26%). Finally, this amide was debenzylated to produce the compound (VI / 3-3a) -4A (yield = 13%) in the form of a white solid with a purity of 83% (mixture of isomers a and β).

Detailed synthesis No. 4C: 4- (3-Benzyloxy-17-oxo-estra-l, 3,5 (10) -trien-ISff-il) -N-methyl-butyramide The acid building block IV / 3-3c (1.9 g, 4.4 mmol) was dissolved in DCM (40 ml) and 1 drop of DMF was added. The reaction mixture was cooled to 0 ° C and oxalyl chloride (0.38 ml, 4.4 mmol) was added dropwise. After stirring for 1 hour at 0 ° C, the solvent was removed on a rotary evaporator. The acid chloride was dissolved in DCM (20 ml) and 13.1 ml of a 2 M solution of methylamine in THF was added dropwise. The reaction mixture was stirred overnight. To the light yellow mixture was added water (40 ml) and DCM (50 ml). After separating the layers, the aqueous layer was extracted with DCM (2 x 40 ml). The combined organic layers were washed with water (40 ml) and brine (40 ml). The organic layer was dried over Na 2 SO 4 and the solvent was removed on a rotary evaporator. This yielded 1.4 g of a solid, which was purified by column chromatography (42 g of Si0, toluene / acetone: 3/1). This produced 509 mg (11.2 mmol, 26%) of the compound (VI / 3-3c) -4C as a yellow / white solid with a purity of 91% according to HPLC.

No. 4A. 4- (3-hydroxy-17-oxo-estra-l, 3,5 (10) -trien-15/3-yl) -N-methyl-butyramide (VI / 3-3a) -4A The compound (VI / 3-3c) -3C (509 mg, 11.2 mmol) was dissolved in MeOH (75 mL) and N2 was bubbled through it for a few minutes. Pd / C (500 mg) was added and an H2 balloon was placed over the flask. The mixture was stirred overnight. The mixture was then filtered over Celite and the MeOH was separated on a rotary evaporator until crystallization began. The white precipitate was filtered off and dried. This purification afforded 54 mg (0.146 mmol) of the compound (VI / 3-3a) -4A (13%) as a mixture of isomers a and β, with a purity of 83% according to HPLC [MS m / z 369.1].

EXAMPLES 5 to 35 A variety of compounds of the formula I were prepared (examples 5 to 35), wherein X represents a bond, A represents CO, Y represents NR4 n is 3, R1 represents CH3 and C15 is substituted at the position ß, by means of a parallel chemistry using a reaction as shown in the following scheme 21 (according to the general flow diagram Ib): SCHEME 21 A mixture of 0.13 mmol of the acid building block of the formula (IV-3b), 0.19 mmol of the respective amine (R2-NH2 or R2-NH-R4), 0.19 mmol of hydroxybenzotriazole, 0.19 mmol of N-methylmorpholine and 0.19 mmol of EDCI were dissolved in DCM and stirred for 24 h at RT. The DCM was evaporated and replaced with EtOAc. The organic layer was washed twice with water. If necessary, the material was purified by flash chromatography. The material was subsequently analyzed by LC-MS. The following group of compounds was prepared by this method (Table 1): Table 1: Compounds of the formula VI / 3-3b, wherein R4 is H and R2 is varied, and with the general name N- "R2" -4- (3-methoxy-17-oxo-estra-1, 3, 5 (10) -trien-15-yl) -butyramide: EXAMPLES 36 TO 38 In addition, the following compounds No. 36-38 of the general formula (VI / 3-3a) were prepared by debenzylation of the acid building block (IV / 3-3c) by the method described for the synthesis of Example No. 4A, but using THF as solvent and subsequent reaction of the acid building block obtained (IV / 3-3a) with the corresponding amine according to the method described in SCHEME 21.

No. 36: 4- (3-Hydroxy-17-oxo-estra-l, 3,5 (10) -trien-15/3-yl) -N- [2- (7-methyl-lH-indole-3 -yl) -ethyl] -butyramide (VI / 3-3a) -36 13 C-NMR: (solvent dDMSO): 16.6, 17.15, 25.33, 26.09, 28.84, 29.63, 33.47, 33.54, 35.15, 35.6, 39.24, 39.45, 41.97, 43.85, 46.28, 51.76, 112.22, 112.58, 114.83, 115.71, 118.28 , 120.27, 121.26, 122.09, 125.58, 126.8, 130.15, 135.64, 136.99, 154.94, 171.76, 219.82 ppm.

No. 37: N- (2,4-Difluoro-benzyl) -4- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-15/3-yl) -butyramide (VI / 3-3a) -37 LC-MS: MH + 482; rt 5.50 min; fragments: M-17: 464; ML7: 464; M-287: 194; M-324: 157; M-354: 127 No. 38: N-Benzyl-4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-153-yl) -N-methyl-butyramide (VI / 3-3a) - 38 P.f. : 160-162 ° C LC-MS: MH + 560, rt 5.77 min 13 C-NMR: 221.23, 173.42 / 172.95 (amide rotamer), 154.13, 137.92, 137.28 / 136.53 (amide rotamer), 131.88, 128.99, 128.62, 128.02, 127.72 / 127.43 (amide rotamer), 126.20, 126.00, 115.34, 112.80, 53.48 / 50.97 (amide rotamer), 52.84, 47.15, 44.51, 42.76 / 42.72 (amide rotamer), 35.99, 34.89 / 34.38 (rotamer of amide), 34.33 / 34.27 (amide rotamer), 33.89, 33.36 / 332.83 (amide rotamer), 30, 85, 29.29, 26, 70, 25, 53, 25.41 / 25.17 (amide rotamer), 17.72 / 17.68 (amide rotamer).

EXAMPLE 39: N-Benzyl-4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15a-yl) -butyramide (VIa-3a) -39 Compound (VIa-3a) -39 was prepared in a two-step synthesis starting from the acid building block protected with ketal XLVIIIa-3a as set forth in the following scheme 22. In the first step, the acid building block XLVIIIa-3a is reacted with benzylamine using EDCl, HOBt as coupling agent and subsequent purification. Deprotection of the ketone provided the desired compound (VIa-3a).

SCHEME 22 Detailed synthesis Cetal of N-Benzyl-4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15a-yl) -butyramide (XLIXa-3a) To a solution of carboxylic acid XLVIIIa-3a (0.266 g, 0.664 mmol) in THF (12.4 ml) were added benzylamine (85 mg, 796 mmol), N-methylmorpholine (218 μl, 1.98 mmol), HOBt (107 mg, 793 mmol) and EDCI (152 mg, 796 mmol). The reaction mixture was stirred for 32 h at T. A., concentrated and taken up in CH2C12 (50 ml) and washed with 1 N aqueous HCl. The organic layer was dried over Na2SO4 and concentrated to produce 0. 353 g of crude benzylamide XLIVa-3a. Purification was carried out by column chromatography (eluent: heptane / ethyl acetate 1: 1, Rf = 0.4) to provide 0.220 g (67%) of benzylamide XLIXa-3a as an almost white oil.

N-Benzyl-4- (3-hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15a-yl) -butyramide (VIa-3a) -39 To a solution of benzylamide XLIXa-3a ( 0.220 g, 0. 44 mmol) in THF (11 mL) was added 4N aqueous HCl (2.8 mL). After 1 h at T. A. CH2C12 (25 ml) and H2O (25 ml) were added. The organic layer was dried over Na2SO4 and concentrated to yield 0.178 g of a white foam. Purification was carried out by column chromatography (eluent ethyl acetate, Rf = 0.8) to give 0.170 g of a white solid. The solid was further purified by stirring in Et20 (50 ml) for 30 min. The solid was separated by filtration, washed with Et20 (20 ml) and dried to provide 120 mg (60%) of pure (Vía-3a) -39 as a white solid (purity greater than 95% based on LC-MS). 13 C-NMR: (solvent CDC13). 219.6; 172.5; 153.7 138.2; 137.6; 131.8; 128.8 (* 2); 127.9 (* 2); 127.7; 127.0; 115.0 113.1; 54.8; 50.4; 44.2; 43.8; 43.1; 39.7; 36.8; 36.3; 36.1 31.6; 29.8; 27.8; 26.5; 24.4; 15.7 ppm EXAMPLE 40 3 -Hydroxy-15a- (4-morpholin-4-yl-4-oxo-butyl) -estra-1, 3, 5 (10) trien-17-one (VIa-3a) -40 In addition, the following compound No. 40 of the general formula (VIa-3a) representing the stereoisomer a of the compound No. 1 was prepared according to the method set forth in SCHEME 22 starting from the acid building block of the formula ( XLVIIIa-3a) and the appropriate amine (morpholine) and subsequent cleavage of ketal according to the procedures described for the synthesis of compounds No. 39. 13C-NMR: (CDC13 solvent): 219.7; 171.7; 154.2 137.5; 131.3; 126.82; 115.1; 113.14; 66 9; 66.8; 54.7; 50.4 46.1; 44.1; 43.1; 42.1; 39.6; 36.3; 36.1; 33.2; 31.6; 29.8 twenty-one . fifteen; 26.5; 23.8; 15.7 ppm EXAMPLES 41 to 309-amides A variety of compounds of the formula I was prepared (Examples 41 to 309) in which X represents a bond, A represents CO, Y represents NR4 'R1 represents CH3, n is 0 (Scheme 23) or 1 (Scheme 24) and C15 is substituted at position a by a parallel chemistry using a reaction as shown in the following reaction schemes 23 and 24 (according to the general flow diagram la): SCHEME 23 SCHEME 24 Preparation of V-Ob and V-lb acid chlorides: 1,714 g of compound IV-Ob were dissolved (5,219 mmoles) in 85 ml of toluene, 55.2 ml of a 0.189 M solution of SOCl2 (10,438 mmoles of S0C12) was added, which was prepared by dissolving 5,613 g of S0C12 in toluene until 25 ml of solution was obtained, and stirred for 17 hours. After the reaction had not yet been completed, 55.2 ml of a 0.189 M solution of S0C12 (10,438 mmoles of S0C12) were again added and stirred for an additional 24 h at RT. The LC-MS analysis showed a 96% conversion of the adduct in the V-Ob acid chloride (detection with pyrrolidine). 1,670 g of compound IV-Ib (4.877 mmol) were dissolved in 85 ml of toluene, 51.6 ml of a 0.189 M solution of SOCl2 (9.754 mmoles of SOCl2) were added, which was prepared by dissolving 5.613 g of S0C12 in toluene until obtained 25 ml of solution, and stirred for 17 h at RT. Analysis by LC-MS showed a conversion of 99% of the precursor in the V-lb acid chloride (detection with pyrrolidine). Both solutions were evaporated at 40 ° C using the rotary evaporator. The oily residues were dissolved in THF at a concentration of 0.25 M.

Preparation of amides VI-0b and VI-Ib: DIPEA was dissolved in THF to produce a 0.25M solution. Stock solutions (B) of different amines R2NH2 and R2NHR4 were prepared in THF at a concentration of 0.25 M. Reactions were carried out performed in a 24-well format. In each well was mixed 100 μl of the respective V-Ob acid chloride or V-lb with 100 μl of an amine solution (B) and with 100 μl of the DIPEA solution. The reaction mixtures in the 24-well plates were allowed to react for 17 h at 30 ° C with shaking for an additional 48 h at 15 ° C with shaking. The solutions were evaporated at 40 ° C for 180 min with a final pressure of 5 mbar using the GeneVac device. To each oily residue was added 1000 μl of a 5% solution of NaHCO 3. The solution was extracted twice with 1.5 ml of EtOAc, and the extracts obtained were washed twice with 500 μl of water. The solutions washed with EtOAc were transferred to collection vials and then evaporated in the GeneVac device under the same conditions as above. The products obtained were analyzed by ESI-MS. The following groups of compounds were prepared by this method (Tables 2 to 4 for n = 0 and Tabas 5 to 7 for n = 1): Table 2: Compounds of the formula VI-0b in which R 4 is H and R 2 is varied, with the general name "R 2" - 3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15-sarboxilico Table 3: Compounds of formula VI-Ob, in which R2 and R4, together with the nitrogen atom to which they are attached, form a ring or variable ring system, and with the general name 15- ["(-NR2R4 ) "-carbonyl] -3-methoxy-estra-1,3,5 (10) -trien-17-one: Table 4: Compounds of the formula VI -Ob, wherein R 2 and R 4 are individually varied, with the general name "R 2" - "R 4" - 3-methoxy-17-oxo-estra-1, 3-aramid acid , 5 (10) trien-15-carboxylic: Table 5: Compounds of the formula VI-Ib in which R4 is H and R2 is varied, with the general name 2- (3-methoxy-17-oxo-estra-1,3,5 (10) -trien- 15-yl) -N- (R2) -acetamide: Table 6: Compounds of the formula VI-Ib, wherein R2 and R4, together with the nitrogen atom to which they are attached, form a variable ring or ring system, with the general name 15- [2- ("- NR2R4") -2-oxo-ethyl] -3-methoxy-estra-l, 3, 5 (10) -trien-17-one: Table 7: Compounds of the formula VI-Ib, in which R2 and R4 are individually varied, with the general name 2- (3-methoxy-17-oxo-estra-l, 3.5 (10) -trien- 15-yl) -N- "R2" -N- "R4" -acetamide: EXAMPLES 310 to 368-amides Additional compounds of the formula I were prepared (Examples 310 to 368) in which X represents a bond, A represents CO, Y represents NR4, R1 represents CH3 and C15 is substituted in the β position with side chains of different length (n = 2, n = 4 and n = 5 ) using a parallel chemistry using a reaction as shown in SCHEME 21 with the following building blocks (IV-2b, IV-4b and IB-5b) as starting material.

The following groups of compounds were prepared by this method (Tables 8, 9 and 10). Table 8: Compounds of formula VI-2b: Table 9: Compounds of the formula VI-4b: (VI-4b) Table 10: Compounds of the formula VI-5b: EXAMPLE 329A: 3- (3-Hydroxy-17-oxo-estra-l, 3, 5 (10) -trien-15-yl) -N- (5-methyl-thiazol-2-yl) -propionamide Example 329A of formula (VI-2a) -329A was synthesized according to the method set forth in SCHEME 20 using the acid building block IV / 3-2c as the starting material and the appropriate amine, and a subsequent debenzylation according to described procedures for the synthesis of compounds No. 4C and 4A. 13 C-NMR (ppm) 219.76, 170.78, 156.18, 155.05, 137.17, 134.61, 130.19, 125.90, 125.75, 114.96, 112.67, 51.73, 46.38, 44.09, 41.47, 35.62, 34.73, 33.75, 33.40, 28.98, 26.13, 25.92, 25.15, 17.34, 11.05 EXAMPLE 363A: 6- (3-hydroxy-7-oxo-estra-1,3,5 (10) -trien-15-yl) -hexanoic acid [2- (4-hydroxy-phenyl) -ethyl] -amide.

Example 363A of formula (VI-5a) -363A was synthesized according to the method set forth in SCHEME 20 using the acid construction block IV / 3-5C as starting material and the appropriate amine, and a subsequent debenzylation according to the procedures described for the synthesis of compounds No. 4C and 4A. 13 C-NMR (ppm) 214.67, 166.64, 147.42, 146.66, 129.27, 122.90, 121.75, 121.20 (* 2), 117.39, 106.73, 106.63 (* 2), 104.28, 44.58, 38.96, 36.38, 34.28, 32.65, 28.05, 27.55, 26.21, 26.17, 25.65, 22.56, 21.03, 20.89, 20.67, 18.51, 17.49, 17.24, 8.74 EXAMPLE 369: 6- (3-Methoxy-17-oxo-estra-1,3,5 (10) -trien-15-yl) -hexanoic acid isopropyl ester A compound of the formula I, wherein X represents a bond, A represents CO, Y represents O, n is 5 and C15 is substituted at the β-position (VII-5b-369) was prepared by a reaction as shown in the following scheme 25 (according to the general flow diagram II) : SCHEME 25 6- (3-Methoxy-17-oxo-estra-l, 3,5 (10) -trien-5-yl) -hexanoic acid isopropyl ester (VII-5b) -369 A mixture of 0.13 mmol of the free acid of formula (IV-5b), 0.26 mmol of isopropanol, 0.26 mmol of hydroxybenzotriazole, 0.26 mmol of N-methylmorpholine and 0.26 mmol of EDC1-HC1 were dissolved in DCM and stirred for 4 h at RT. After filtering the organic layer was washed twice with a 1 M solution of KHS04. The material was purified by flash chromatography after evaporation (cyclohexane / EE 5: 1 → 4: 1) yielding 29 mg of a white foam (VII-5b) -369 (LC-MS: MH + 441; rt 7.81 min) . 13 C-NMR: (Solvent CDC13): 17.74, 21.89, 21.89, 25.58, 26.81, 29.53, 31.00. 33.95, 34.39, 34.61, 36.08, 42.88, 44.55, 47.17, 52.95, 55.25, 67.44, 111.47, 113.96, 125.99, 132.47, 137.77, 157.73, 173.24, 221.22 EXAMPLE 370: 3-Methoxy-15- (3-oxo-pentyl) -estra-1, 3,5 (10) -trien-17-one A compound of the formula I, wherein X represents a bond, A represents CO, Y represents a link, n is 2 and C15 is substituted at the position β (VIII-2b-370) was prepared by a reaction as shown in the following scheme 26 (according to general flow diagram III): SCHEME 26 Detailed synthesis 3- (3-Methoxy-17-oxo-estra-l, 3,5 (10) -trien-15-yl) -propionaldehyde (XXXIII-2b): 505 mg of the alcohol (XXXI-3b) was dissolved ( 1.47 mmole) in 50 ml of DCM and cooled to 0 ° C. Then 4.5 ml (2.2 mmol) of Dess Martin reagent was added at 0 ° C and the reaction mixture was stirred for an additional hour. The organic layer was subsequently washed with saturated NaHCO3, twice with iM solution of Na2S203, dried over Na2SO4 and evaporated. After purifying the material by flash chromatography (cyclohexane / EE 3: 1 solvent) 420 mg of solid material XXXIII-2b was obtained. - (3-Hydroxy-pentyl) -3-methoxy-estra-l, 3,5 (10) -trien-17-one (XXI-2b) -370 The aldehyde of formula XXXIII-2b was dissolved in 20 ml of dry THF and cooled to 0 ° C. At this temperature, ethylmagnesium bromide and tetramethyldiaminoethane, both separately dissolved, were added slowly. After a further 2 hours of stirring the reaction mixture was left overnight at room temperature. Subsequently, 5 ml of saturated NHC1 solution was added and the mixture was extracted several times with 50 ml of EE. After drying the combined organic layers over Na 2 SO and evaporating the solvent, 160 mq of solid material (XXI-2b) -370 were obtained which were used in the next step without further purification (LCMS: MH +: 371; rt 6.35 min). 3 - . 3-Methoxy-15- (3-oxo-pentyl) -estra-1, 3, 5 (10) -trien-17-one (VIII-2b) -370 The alcohol previously obtained (XXI-2b) -370 was dissolved in 10 ml of acetone and cooled to 0 ° C. At that temperature Jones reagent was added, until the reaction mixture remained green. The reaction was stirred for 1 hour at T. A. before excess Jones reagents were destroyed by adding 2 ml of isopropanol. The reaction mixture was subsequently diluted with 200 ml of EE and 100 ml of saturated NaCl solution. After separation, the organic layer was washed with saturated NaCl solution twice before drying over Na 2 SO 4 and evaporating under reduced pressure. to dryness The material obtained was purified by flash chromatography (cyclohexane / EA 3: 1), yielding 33 mg of solid material (VIII-2b) -370. 13 C-NMR (solvent CDC13): 220.4; 210.8; 157.6 137.7; 132.2; 125.9; 113.8; 111.4; 55.2; 52.7; 47.0; 44.6 42.0; 41.54; 36.1; 36.0; 33.9; 33.8; 29.5; 26.7; 25.4; 24.7 17.8; 7.8 ppm EXAMPLES 371 to 418 - Hydrazides A variety of compounds of the formula were prepared I, where X represents a bond, A represents CO, Y represents NE-NR4 or NH-NH and C15 is substituted at the position with side chains of different length (n = 2, 3, 4 5) by a parallel chemistry using a reaction as shown in the following scheme 27 (according to general flow diagram IVb): SCHEME 27 Acids of the general formula IV (0.057 mmol per reaction) were used as stock solutions in DCM and were added to a mixture of the respective hydrazine H2N-NR2R4 (0.8 eq), polymer-bound carbodiimide (3 eq), HOBT (1.7 eq) and 5 ml of DCM. After stirring for 24 hours at T A. approximately 40 mg of trisaminomethyl bound to polymer was added to cleave the excess acid. After a reaction time of a further 24 hours, the suspension was filtered and the filtrate was evaporated under reduced pressure. The products obtained from the general formula XLl were analyzed by LC-MS.

Four groups of compounds were prepared according to formula XLI-2b, XLI-3b, XLI-4b and XLI-5b by this method as set forth in the following Tables 11, 12, 13 and 14.

Table 11: Compounds of formula XLl-2b: Table 12: Compounds of the formula XLI-3b: (XLI-3b) Table 13: Compounds of formula XLl -4b: Table 1: Compounds of the formula (XLl -5b) EXAMPLES 419 to 440 - Urea Derivatives: A variety of compounds of the formula I was prepared, wherein X represents NH or NCH3, A represents CO, Y represents NH and n represents 1 and C15 is substituted at the a position, by a parallel chemistry using a reaction as shown in the following scheme 28A and 28B, respectively (according to the general flow diagram Va): SCHEME 28A SCHEME 28B Detailed synthesis Stage 1: 0.11 mmol isocyanate was dissolved (R2N = C = 0) in 2 ml of ACN. To this solution was added 2 ml of amines building block of the formula XV-la or XVIII-la (0.09 mmol) dissolved in ACN. The reaction mixture was stirred T. A. for 24 h. In order to remove the unreacted isocyanate or amine, isocyanate and trisamine attached to polymer were added. Again the reaction mixture was stirred for 24 h at T. A. The solid material was separated by filtration. The solvent was evaporated in a vacuum centrifuge. Without further purification, this material was used in the next step. Step 2: The material obtained in Step 1 was dissolved in 2 ml of acetone. 2 mg of pTsOH was added. The reaction mixture was kept in a microwave oven in a sealed tube at 150 ° C for 3 minutes. Subsequently, the solvent was separated in a vacuum centrifuge. The material obtained was separated between EtOAc and NaHCO3 solution. The organic layer was collected and evaporated again. The material was subsequently analyzed by LC-MS. Two groups of compounds were prepared according to formula XVII-lb by this method as set forth in the following Tables 15 and 16.

Table 15: Compounds of the formula XVII-Ib, in which R = H Table 16: Compounds of the formula XVII-lb, in which R = -CH3 EXAMPLES 441 to 489 - Urea derivatives: Additional compounds of the formula I were prepared, in which X represents NH, A represents CO, Y represents NH and n represents 3 or 4 and C15 is substituted in the β position, by means of a parallel chemistry using a reaction as shown in the following schemes 29A and 29B (according to the general flow diagram Vb) -.

SCHEME 29A SCHEME 29B Detailed synthesis 0.11 mmol of isocyanate (R2-N = C = 0) was dissolved in 2 ml of ACN. To this solution, 2 ml of the block of construction of amines of the formula XXIX-3b or XXIX-4b (0.09 mmol) dissolved in ACN and approximately 40 mg of polymer-bound diisopropylethylamine. The reaction mixture was stirred at T. A. for 24 h. In order to remove the unreacted isocyanate or amine, polymer-bound isocyanate and trisamine were added, again the reaction mixture was stirred for 24 h at T. A. The solid material was separated by filtration. The solvent was evaporated in a vacuum centrifuge. The material obtained was analyzed by LC-MS. Two groups of compounds according to formula XVII-3b and XVII-4b were prepared by this method, as set forth in the following Tables 17 and 18.

Table 17: Compounds of formula XVII-3b XVII-3b Table 18: Compounds of formula XVII -4b EXAMPLES 490 to 492 - Urea Derivatives: Three additional compounds of the formula I were prepared, wherein X represents NH, A represents CO, Y represents NH, n represents 4 and C15 is substituted at the a position, by individual synthesis using a reaction as shown in scheme 28C and described above for scheme 28A (according to the general flow diagram Va). The individual compounds of formula XVIIa-4a are set forth in Table 19.

SCHEME 28C Table 19: Compounds of the formula XVIIa-4A EXAMPLES 493 to 537-sulfonamides A variety of compounds of the formula I can be prepared, wherein X represents 111, A represents S02, Y represents NH and n represents 2 and C15 is substituted at the a position, by means of a parallel chemistry using a reaction as shown in the following scheme 30 (according to the general flow diagram VI): SCHEME 30 Detailed synthesis Step 1: Tert-butyl alcohol (6.5 ml = 5.13 g = 69.3 mmol) in 30 ml of DCM is added dropwise to a cold solution of 6.0 ml (9.76 g = 68.9 mmol) of chlorosulfonyl isocyanate in 40 ml of DCM. After 30 min, the mixture is diluted with DCM to 100 ml to obtain a 0.854 molar stock solution. (18.29 g / 100 ml, density 1318 g / ml, LC-MS found the mass M + H 216). 2 ml of this solution are added to the amine building block of the formula XV-lb (0.5 mmol) and triethylamine (1 mmol) dissolved in DCM at 0 ° C. The mixture is stirred overnight at T. A. The reaction mixture is treated by liquid / liquid extraction with DCM / water. The crude product is purified on silica gel with dichloromethane as eluent.

Step 2: 0.1 mmol of the Boc-protected sulfamide obtained in Step 1 are dissolved in acetone. 0.3 mmol of K2C03 and 0.1 mmol of bromo-alkane (or corresponding bromine reagent) are added. The reaction is maintained at 60 ° C for 24 h. After filtration and concentration, the crude mixture is purified by column chromatography on silica gel. Step 3: The material obtained in Step 2 is dissolved in 2 ml of acetone. 2 mg of p-TosOH are added. The reaction mixture is kept in a microwave oven in a sealed tube at 150 ° C for 3 minutes. Subsequently, the solvent is separated in a vacuum centrifuge. The material obtained is separated between EtOAc and NaHCO 3 solution. The organic layer is collected and evaporated again. The material is subsequently analyzed by LC-MS. A group of compounds according to formula XIX-2b can be prepared by this method; The compounds listed in Table 12 represent the reaction products of a compound of the formula XV-2b with a bromine reagent (R2-Br).

Table 20: Compounds of formula XIX-2b, which are prepared by reaction with variable compounds R2-Br: No. Reactant R-Br 493 (2-BROMOETHYL) BENZENE J 494 1- (2-BROMOETHYL) AFTALENE No. Reactant R2-Br 495 1-BR0M0-3, 3-DIFENYLPROPAN 496 1-BROMO-3 -METILBUTANE 497 1-BROMOMETIL-2- ((PHENYL-SULFONYL) METHYL) BENZENE 498 2- (BROMOMETIL) NAFTALENE 499 2- (DIFLUOROMETOXY) BENCILO 500 BROMIDE 2- (N- (2-BROMOETHYL) ANYLINO) -ETHANOL 501 2,5-BIS BROMIDE (TRIFLUOROMETHYL) BENCILO 502 2-BROMOETITE ACETATE 503 N- (1-NAFTHL) CARBAMATE OF 2-BROMOETILO 504 N- (2,3-DICHLOROPHENYL) CARBAMATE OF 2-BROMOETILO 505 2-BROMOMETIL-1, 4-BENZODIOXANO 506 2 -BROMOMETIL-5-FLUOROCOUMARANO 507 BROMIDE OF 2-PHENYLBENCIL 508 3 - (2-BROMOETHYL) INDOL 509 METHYL ESTER OF ACID 3- (BROMOMETIL) BENZOIC 510 BROMIDE OF 3, 4 -DICLOROBENCILO [ 511 3, 5-BIS (TRIFLUOROMETHYL) BENCILO 512 BROMIDE 3-BENZOYLBENCIL BROMIDE 513 3-BROMO-1, 2-PROPANODIOL 514 3 -BROMOMETHYL-2 - (4-CHLOROBENZOYL) BENZOFURANE 515 ETHYL ESTER OF 3-BROMOPROPIONIC ACID 516 BROMIDE OF 3-PHENOXYPROPYL [ No. Reactant R -Br 517 4- (2-BROMOETHYL) -ACETOPHENONE 518 4- (4-BROMOMETILPHENYL) -1, 2, 3-TIADIAZOL 519 METHYL ESTER OF ACID 4- (BROMOMETHYL) BENZOIC PHENACILL ESTER OF ACID 4- 520 (BROMOMETIL) PHENYLACETHIC 521 BROMIDE OF 4- (TERC-BUTIL) BENCILO 517 4- (2-BROMOETHYL) -ACETOPHENONE 518 4- (4-BROMOMETILFENIL) -1, 2, 3 -TIADIAZOL 519 METHYL ESTER OF ACID 4- (BROMOMETIL ) BENZOIC PHENACILAL ESTER OF ACID 4- 520 (BROMOMETIL) PHENYLACETHIC 521 BROMIDE OF 4- (TERC-BUTIL) BENCILO 522 ETHYL ESTER OF 4-BROMOBUTIRIC ACID 523 4-BROMOMETIL-7-METOXICOUMARIN 524 4-BROMOMETILBENCILO 525 4-METILSULFONILBENCILO BROMIDE 526 4-PHENOXYBUTYL BROMIDE 5 - 5- (BROMOMETIL) BENZOFURAZAN 528 6-AMINO-9- (2-BROMOETHYL) -9H-PURINE 529 ALPHA- BROMO-M-TOLUNITRILO 530 ALPHA-BROMO-O-TOLUNITRILE 531 ALPHA-BROMO-P-TOLUMITRILO EXAMPLES 538 and 539 - Carbamates Two compounds of formula I were prepared, wherein X represents NH, A represents CO, Y represents O, n represents 1 and C15 is substituted at position a using a reaction as shown in the following scheme 31 (according to the general flow diagram VII): SCHEME 31 Detailed Synthesis Step 1: 0.132 mmol of chloroformic acid ester (R2-0-CO-Cl) was dissolved in 2 ml of DCM. To this solution were added 2 ml of the amine building block of the formula XV-la (0.112 mmol) dissolved in DCM. The reaction mixture was stirred at T. A. for 24 h. To isolate the unreacted chloroformic acid ester, isocyanate bound to amine polymer and trisamine was added. Again the reaction mixture was stirred for 24 h at T. A. The solid material was separated by filtration. The solvent was evaporated in a vacuum centrifuge. Without further purification, this material was used in the next step. Step 2: The material obtained in Step 1 was dissolved in 2 ml of acetone. 2 mg of p-toluenesulfonic acid were added. The reaction mixture was kept in a microwave oven in a sealed tube at 150 ° C for 3 minutes. Subsequently, the solvent was separated in a vacuum centrifuge. The material obtained was separated between EtOAc and NaHCO3 solution. The organic layer was collected and evaporated again. The material was subsequently analyzed by LC-MS. Two compounds were prepared according to the general formula XX-a by this method as set forth in Table 21.

Table 21: Compounds of the formula XX-la: EXAMPLES 540 to 543 - Sulphamates A variety of compounds of the formula I can be prepared, wherein X represents NH, A represents SO2, Y represents O and n represents for example 1, and C15 is substituted at the a position, by a chemical parallel using a reaction as shown in the following scheme 32 (according to the general flow diagram VIII): SCHEME 32 Detailed Synthesis Step 1: To a solution of 0.132 mmol of chlorosulfonic acid ester (R2-0-S02-Cl) in 2 ml of DCM is added 0.112 mmol of the amine building block XV-lb, dissolved in 2 ml of DCM , and an excess of polymer-bound morpholine subsequently at -40 ° C. After one hour, the reaction mixture is heated to 20 ° C and left overnight. To isolate the unreacted chlorosulfonic acid ester and amine-bonded polymer, isocyanate and trisamine are added. Again the reaction mixture is stirred for 24 h at T. A. The solid material is separated by filtration. The solvent is evaporated in a rotary centrifuge. Without purification additional, this material is used in the next stage. Step 2: The material obtained in Step 1 is dissolved in 2 ml of acetone. 2 mg of p-TosOH are added. The reaction mixture is kept in a microwave oven in a sealed tube at 150 ° C for 3 minutes. Subsequently, the solvent is separated in a vacuum centrifuge. The material obtained is separated between EtOAc and NaHCO 3 solution. The organic layer is collected and evaporated again. The material is subsequently analyzed by LC-MS. A group of compounds according to the formula XXII-Ib can be prepared by this method; the compounds represent reaction products of a compound of the formula XV-lb with a chlorosulfonic acid ester (R2-0-S02-Cl). Table 14 shows the number of reaction products together with the corresponding chlorosulfonic acid ester (R2-0-S02-Cl).

Table 14: Compounds of formula XXII-lb, prepared by reaction with (R2-0-S0; - Cl).

No. Reactant R2-0-S02-Cl 537 Chlorosulphonic acid ethyl ester 538 Chlorosulphonic acid butyl ester 539 Chlorosulphonic acid benzyl ester | 1 54 ° Chlorosulfonic acid phenyl ester EXAMPLES 544 to 570 - "retro" -amides A variety of compounds of the formula I was prepared, wherein X represents -NH, A represents CO, Y represents a bond, n represents. 1, R1 represents CH3 and R2 can be varied, and C15 is substituted at position a, by a parallel chemistry using a reaction as shown in the following scheme 33 (according to the general flow diagram IXa). The group of compounds prepared by this method is shown in Table 23.

SCHEME 33 Detailed Synthesis Step 1: 0.132 mmol of the appropriate acid chloride R2-CO-Cl was dissolved in 2 ml of DCM. To this solution were added 2 ml of the amine building block of the formula XV-lb (0.112 mmol) dissolved in DCM and 160 mg of polymer-bound morpholine. The reaction mixture was stirred at T. A. for 48 h. To remove unreacted acid chloride, isocyanate bound to amine polymer was added and trisamine. Again the reaction mixture was stirred for 24 h at T. A. The solid material was separated by filtration. The solvent was evaporated in a vacuum centrifuge. Without further purification, this material was used in the next step. Step 2: The material obtained in Step 1 was dissolved in 2 ml of acetone. 2 mg of p-toluene sulfonic acid was added. The reaction mixture was kept in a microwave oven in a sealed tube at 150 ° C for 3 minutes. Subsequently, the solvent was separated in a vacuum centrifuge. The material obtained was separated between EtOAc and NaHCO3 solution. The organic layer was collected and evaporated again. The material was subsequently analyzed by LC-MS.

Table 23: Compounds of the formula XXIII-Ib, wherein R2 is varied: EXAMPLES 571 to 593 - "retro" -amides: A variety of compounds of the formula I was prepared, wherein X represents -NH, A represents CO, Y represents a bond, n represents 4, R1 represents H, R2 represents make vary and C15 is substituted at position a, by a parallel chemistry using a reaction as shown in the following scheme 34 and described above for scheme 33 (according to the general flow diagram IXa). The compounds are listed in Table 24.

SCHEME 34 Table 24: Compounds of the formula XXIIIa-4a, wherein R2 is varied: EXAMPLES 594 to 651 - "retro" -amides A variety of compounds of the formula I was prepared, wherein X represents -NH, A represents CO, Y represents a bond, n represents 3 or 4, R1 represents H or CH3, R2 is varied and C15 is substituted at the a or β position by a parallel chemistry using a reaction as shown in the following schemes 35A, 35B and 35C (according to the general flow diagram IXb).

SCHEME 35A SCHEME 35B SCHEME 35C Detailed synthesis 0.132 mmol of the appropriate acid chloride R2-CO-Cl was dissolved in 2 ml of DCM. To this solution was added 2 ml of the amine building block of the formula XXIXa-3a, XXIX / 3-3b, or XXIX / 3-4b (0.112 mmol) dissolved in DCM and 160 mg of polymer-bound morpholine. The reaction mixture was stirred at T. A. for 48 h. To separate the unreacted acid chloride or the amine-bonded polymer, isocyanate and trisamine were added. Again the reaction mixture was stirred for 24 h at T. A. The solid material was separated by filtration. The solvent was evaporated in a vacuum centrifuge. The material was subsequently analyzed by LC-MS.

Three groups of compounds were prepared according to the general formulas XXIIIa-3a, XXIII / 3-3b and XXIII / 3-4b by this method as set forth in the following Tables 25, 26 and 27, respectively.

Table 25: Compounds of the formula XXIIIa-3a, wherein R2 is varied Table 26: Compounds of the formula XXIII / 3-3b, wherein R2 is varied: XXIIIß-3b Table 27: Compounds of the formula XXIII / 3-4b, wherein R2 is varied: XXIIIß-4b EXAMPLES 652 to 660 - "retro" -amides Alternatively, particular compounds of the formula I in which X represents -NH, A represents CO, Y represents a bond and R2 is varied individually, using a reaction as shown in Example 1, were individually prepared. the following scheme 36 (according to the general flow diagram IXb), but using the appropriate free acid R2-C00H instead of the acid chloride R2-CO-C1.

SCHEME 36 (XXIII) Detailed synthesis: 0.132 mmol of the appropriate acid (R2-COOH) was dissolved in 2 ml of DCM. To this solution, 2 ml of stock solution of amine building blocks in DCM of the general formula XXIX (each vial 0.112 mmol), approximately 120 mg of polymer-bound morpholine, 120 mg of polymer-bound carbodiimide and 125 mg of polymer bound HOBT. The reaction mixture was stirred at T. A. for 2 days. To remove the unreacted acid and the amine, approximately 40 mg of isocyanate and trisamine attached to the polymer were added. After stirring the reaction mixture for another 24 hours, the solid material was separated by filtration. After removal of the solvent under reduced pressure, the samples were analyzed by LC-MS.

EXAMPLE 652: 4-Fluoro-N- (3-hydroxy-17-oxo-estral, 3,5 (10) -trien-15-ylmethyl) -benzamide Example 652 of formula (XXXIIIa-la) -652 was synthesized according to SCHEME 36 using XXIXa-la as starting material (MH + 422, Rt 5.34 min).

EXAMPLE 653 3,4-Dichloro-N- [3- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-15-yl) -propyl] -benzamide Example 653 of formula (XXXIIIa-3a) -653 was synthesized according to SCHEME 36 using XXIXa-3a as starting material (MH + 500, Rt 4.17 min).

EXAMPLE 654: 3,4-Dichloro-N- [4- (3-hydroxy-17-oxo-estral, 3,5 (10) -trien-15-yl) -butyl] -benzamide Example 654 of formula (XXXIIIa-4a) -654 was synthesized according to SCHEME 36 using XXIXa-4a as starting material (MH + 514; Rt 6.31 min).

EXAMPLE 655: 2- (4-Fluoro-phenyl) -N- [4- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-15-yl) -butyl] -acetamide Example 655 of formula (XXXIIIa-4a) -655 was synthesized according to ES-BEME 36 using XXIXa-4a as starting material (MH + 478, Rt 5.72 min).

EXAMPLE 656 4-Fluoro-N- [4- (3-hydroxy-17-oxo-estral, 3,5 (10) -trien-15-yl) -butyl] -benzamide Example 656 of formula (XXXIIIa-4a) -656 was synthesized according to SCHEME 36 using XXIXa-4a as starting material (MH + 464; Rt 5.70 min).

EXAMPLE 657 2, 4-Difluoro-N- [4- (3-hydroxy-17-oxo-estra-1,3,5 (10) -trien-15-yl) -butyl] -benzamide Example 657 of formula (XXXIIIa-4a) -657 was synthesized according to SCHEME 36 using XXIXa-4a as the starting (MH + 482; Rt 5.86 min).

EXAMPLE 658: N- [5- (3-Methoxy-17-oxo-estra-l, 3,5 (10) trien-15-yl) pentyl] -benzamide Example 658 of formula (XXXI11jß-5b) -658 was synthesized according to SCHEME 36 using XXIX / 3-5b as starting material (MH + 474, Rt 6.80 min).

EXAMPLE 659: N- [5- (3-Methoxy-17-oxo-estra-l, 3, 5 (10) trien-1501) -pentyl] -acetamide Example 659 of formula (XXXIII ^ -5b) -659 was synthesized according to SCHEME 36 using XXIX / 3-5b as starting material (MH + 412, Rt 6.90 min).

EXAMPLE 660: 4-Fluoro-N- [5- (3-Methoxy-l7-oxo-estral, 3,5 (10) trien-15-yl) -pentyl] -benzamide Example 660 of formula (XXXIII / 3-5b) -660 was synthesized according to SCHEME 36 using XXIX / 3-5b as starting material (MH + 492; Rt 6.68 min).

EXAMPLES 661 to 697 - "retro" -sulfonamides A variety of compounds of the formula I was prepared, wherein X represents NH or NCH3, A represents S0, Y represents a bond, n represents 1 and C15 is substituted at the , by means of a parallel chemistry using a reaction as shown in the following scheme 37 (according to the general flow diagram Xa). Two groups of compounds according to formula XXIV-la and XXIV-la * were prepared by this method and are reported in Tables 28 and 29 below.

SCHEME 37 Detailed synthesis: Step 1: 0.062 mmol of the respective sulphonic acid chloride R2-S02-C1 was dissolved in 2 ml of DCM. To this solution were added 2 ml of the amine building block of the formula XV-la or XXVIII-la (0.056 mmol) dissolved in DCM and 100 mg of polymer-bound morpholine. The reaction mixture was stirred at T. A. for 24 h. To remove the unreacted sulphonic acid chloride, polymer-bound trisamine was added. Again the reaction mixture was stirred for 24 h at T. A. The solid material was separated by filtration. The solvent was evaporated in a vacuum centrifuge. Without further purification, this material was used in the next step. Step 2: The material obtained in Step 1 was dissolved in 2 ml of acetone / methanol / water (1: 10: 0.1). HE they added 2 mg of p-TosOH. The reaction mixture was kept in a microwave oven in a sealed tube at 150 ° C for 3 minutes. Subsequently, the solvent was separated in a vacuum centrifuge. The material obtained was separated between EtOAc and NaHCO3 solution. The organic layer was collected and evaporated again. The material was subsequently analyzed by LC-MS. Two groups of compounds were prepared according to formula XXIV-la and XXIV-la * by this method (Tables 28 and 29).

Table 28: Compounds of formula XXIV-la: Table 29: Compounds of formula XXIV-la *: EXAMPLES 698 to 737"retro" -sulfonamides Additional compounds of the formula I were prepared, wherein X represents NH, A represents S02, Y represents a bond, n represents 3 or 4 and C15 is substituted at the position β, by a parallel chemistry using a reaction as shown in the following schemes 38A and 38B (according to the general flow diagram Xb): SCHEME 38A SCHEME 38B Detailed Synthesis 0.062 mmol of the respective sulphonic acid chloride R2-S02-C1 was dissolved in 2 ml of DCM. To this solution were added 2 ml of the amine building block of the formula XXIX / 3-3b or XXIX3-4b (0.056 mmol) dissolved in DCM and 100 mg of polymer-bound morpholine. The reaction mixture was stirred at T. A. for 24 h. To remove the unreacted sulphonic acid chloride, polymer-bound trisamine was added.

Again the reaction mixture was stirred for 24 h at T. A. The solid material was separated by filtration. After removal of the solvent under reduced pressure, the samples were analyzed by LC-MS. Two groups of compounds were prepared according to formula XXIV / 3-3b and XXIV / 3-4b by this method (Tables 30 and 31).

Table 30: Compounds of formula XXIV / 3-3b: Table 31: Compounds of the formula XXIV / 3-4b: EXAMPLES 738 and 739 - "retro" - sulfonamides Two additional compounds of the formula I, in which X represents NH or NCH3, A represents S02, Y represents a bond, n represents 3 6 5 and C15 is substituted in the β position, they were individually synthesized according to the reaction shown in schemes 38A and 38B (according to the flow chart General Xb), using the respective amine building blocks as the starting material.

EXAMPLE 738: N- [3- (3-Methoxy-17-oxo-estra-l, 3,5 (10) -trien-15-yl) -propyl] -4-methyl-benzenesulfonamide Example 738 of the formula (XXIV / 3-3b) -738 was synthesized according to SCHEME 38A using XXIX / 3-3b as starting material (MH + 496, Rt 6.85 min).

EXAMPLE 739: N- [3- (3-Methoxy-17-oxo-estra-l, 3,5 (10) -trien-15-yl) pentyl] -4-methyl-benzenesulfonamide Example 739 of the formula (XXIV (3-5b) -739 was synthesized according to SCHEME 38B using XXIX / 3-5b as starting material (MH + 524, Rt 6.91 min).

EXAMPLES 740 to 743 - sulfonylurea derivatives A variety of compounds of formula I, wherein X represents NH, A represents CO, Y represents NH-S02- and n represents, for example, 2 and C15 is substituted at position a, they can be prepared by a parallel chemistry using a reaction as shown in the following scheme 39 (according to the general flow diagram XI): SCHEME 39 Detailed Synthesis Step 1: Dissolve 0.224 mmol of the appropriate sulfonyl isocyanate in 2 ml of THF. To this solution is added 2 ml of the amine building block of the formula XV-b (0.112 mmol) dissolved in THF. The reaction mixture was stirred 60 ° C for 5 h. To separate the unreacted sulfonyl isocyanate, polymer-bound trisamine was added. The mixture of The reaction is stirred for an additional 24 h at T. A. The solid material is separated by filtration. The solvent is evaporated in a vacuum centrifuge. This material is used without further purification in the next step. Step 2: The material obtained in Step 1 is dissolved in 2 ml of acetone. 2 mg of p-TosOH are added. The reaction mixture is kept in a microwave oven in a sealed tube at 150 ° C for 3 minutes. Subsequently, the solvent is separated in a vacuum centrifuge. The material obtained is separated between EtOAc and NaHCO 3 solution. The organic layer is collected and evaporated again. The material is subsequently analyzed by LC-MS. A group of compound according to formula XXV-2b can be prepared by this method; the compounds represent reaction products of a compound of the formula XV-2b with a sulfonyl isocyanate (R-S02-N = C = 0). Table 17 shows the number of the reaction products together with the corresponding sulfonyl isocyanate (R2-S02-N = C = 0).

Table 32: Compounds of the formula XXV-2b, which can be prepared by reaction with variable sulfonyl isocyanate compounds (R2-S02-N = C = 0): EXAMPLES 744 to 773 - "retro" -carbamate A variety of compounds of formula I was prepared, wherein X represents O, A represents CO, Y represents NH, R1 represents CH3, n is 3, 4, 5 or 6 and C15 is substituted in the β position, by a parallel chemistry using a reaction as shown in the following scheme 40 (according to the general flow diagram XII): SCHEME 40 (XXXIβ-5b) (XXXIβ-6b) (XXVIß-6b) Detailed Synthesis 0.06 mmol of estrone-alcohol XXXI was dissolved in 5 ml of acetonitrile. To this solution 0.072 mmol was added of the respective isocyanate. The entire reaction mixture was stirred for 24 h at T. A. The excess isocyanate was subsequently cleaved by adding polymer-bound trisaminoethylamine (approximately 20 mg) and stirring for an additional 4 h. The suspension was filtered. The solid residue was washed twice with 0.5 ml of acetonitrile. The filtrate was evaporated under reduced pressure in a vacuum centrifuge. A control with LC-MS showed that further purification was necessary, therefore, isocyanate bound to polymer was added to cleave the remaining estrone-alcohol in the same manner as mentioned above. In the event that further purification was necessary, rapid chromatography or preparative HPLC was used. The following groups of compounds were prepared by this method (Table 33 for n = 3, Table 34 for n 4, Table 35 for n = 5 and Table 36 for n = 3): Table 33: Compounds of formula XXVI / 3-3b: Table 34: Compounds of the formula XXVI¡8-4b: (XXVIß-4b) Table 35: Compounds of formula XXVI / 3-5b: (XXVIß-5b) Table 36: Compounds of formula XXVI / 3-6b: EXAMPLES 774 and 775 - "retro" -ester Two compounds of formula I were prepared individually, wherein X represents 0, A represents CO, Y represents a bond, R1 represents CH3, n is 4 or 5 and C15 is substituted at position β, by a reaction as shown in the following scheme 41 (according to general flow diagram XIII): SCHEME 41 Detailed Synthesis No 774: 4- (3-methoxy-17-oxo-estra-l, 3, 5 (10) trien-15-yl) -butyl ester of 2, 2-dimethyl-propionic acid 124.6 mg (0.35 mg) mmol) of estrone-alcohol XXXI / 3-4b, 71.4 mg (0.4 mmol) of pivalic acid, 0.7 mmol of 4-dimethylaminopyridine (DMAP) and 0.7 mmol of EDCI in 50 ml of dry dichloromethane and stirred for 20 h at T. A. A control by TLC showed complete conversion. For treatment, the mixture was extracted twice with 20 ml of 1 M solution of KHS04 and 20 ml of 1 M solution of NaHCO3. After evaporation, the residue was further purified by flash chromatography on silica gel 60 with cyclohexane / ethyl acetate (ratio 99/1 to 90/10). 184 mg of oil was obtained which crystallized overnight in ether; the crystals were filtered and dried to yield 87 mg of pure material (XXVIIjS-4b) -774. P.f. : 75-84 ° C LC-MS: MH + 441, Rt 7.85 min No. 775: Ester 5- (3-methoxy-17-oxo-estra-l, 3, 5 (10) trien-15-yl) -pentyl of 2, 2-dimethyl-propionic acid The compound (XXVI / 3- 5b) -775 was prepared accordingly, using estrone-alcohol XXXI / 3-5b as starting material. LC-MS: MH + 455, Rt 8.07 min EXAMPLES 776 to 819 - sulfonyl carbamate A variety of compounds of the formula were prepared I, in which X represents O, A represents CO, Y represents NH-X02-NR4, R1 represents CH3, n is 3, 4, 5 or 6 and C15 is substituted in the β-position, by means of a parallel chemistry using a reaction as shown in the following scheme 42 (according to the general flow diagram XIV): SCHEME 42 (XXVIIIß-5b) (XXVIIIß-6b) Detailed synthesis Estrone-alcohol XXXI (0.055 mmol) dissolved in 1 ml of DCM was added dropwise to a cold solution of 1.1 eq of chlorosulfonyl isocyanate (CSI) in 0.5 ml of DCM. The mixture was left for 30 min at T A. Then 1.2 eq of DIPEA and 1.1 eq of amine were added and the solution was stirred overnight. If desired, TLC (silica gel 60; eluent: 80 toluene / 20 ethanol / 1 ammonia) can be used to control the reaction. The treatment of the reaction mixture was made by extraction with 1M citric acid. After evaporation a solid material was obtained, which was subjected to further purification by flash chromatography. This procedure was used for the synthesis of unique compounds, as well as for the production of libraries. The following groups of compounds were prepared by this method (table 37 for n = 5 (synthesis of single compound), table 38 for n = 3, table 39 for n = 4, table 40 for n = 5 and table 41 for n = 6, all for the production of libraries): Table 37: Compounds of formula XXVIII / 3-5b, which were prepared individually: (XXVIIIß-5b) Apart from the products, the by-products could be isolated by rapid chromatography which showed the following structures, most likely obtained due to water contamination of the reaction mixtures.

EXAMPLE 785: Carbamic acid 5- (3-methoxy-17-oxo-estra-l, 3, 5 (10) -trien-15-yl) pentyl ester (XXVI / 3-5b) -785 (XXVIß-5b) -785 LC-MS rt .: 4.53 min, MH + 414 EXAMPLE 786 5- (3-methoxy-17-o? O-estra-l, 3, 5 (10) -trien-15-yl) pentyl sulphamic acid ester (786) No.786 LC-MS Rt: 4.37 min, MH + 450 Table 38: Compounds of the formula XXVIII / 3-3b, which were prepared by library synthesis: Table 39: Compounds of formula XXVIII / 3-4b, which were prepared by library synthesis: (XXVIIIß-4b) Table 40: Compounds of formula XXVIII / 3-5b, which were prepared by library synthesis: (XXVIIIß-5b) Table 41: Compounds of the formula XXVIII / 3-6b, which were prepared by library synthesis: EXAMPLES 820 to 834 - alcohols The synthesis of the following estrone-alcohol derivatives of the general formula XXXI, which also showed inhibitory properties of 17/3-HSD1, is described in the section "Intermediates, Chapter IV". EXAMPLE 820: 15a-Hydroxymethyl-3-hydroxy-estra-1,3,5 (10) -trien-17-one (XXXIa-la) EXAMPLE 821: 15a-Hydroxymethyl-3-methoxy-estra-1,3,5 (10) -trien-17-one (XXXIa-lb) EXAMPLE 822: 3-Benzyloxy-15a-hydroxymethyl estra-1,3,5 (10) -trien-17-one (XXXIa-lc) EXAMPLE 823: 3- Hydroxy-15 / 3- (3-Hydroxypropyl) -estra-1,3,5 (10) -trien-17-one (XXXI / 3-3a) EXAMPLE 824: 15 / 3- (3-Hydroxypropyl) -3- methoxyestra-1,3,5 (10) -trien-17-one (XXXI / 3-3b) EXAMPLE 825: 3-Benzyloxy-15 / 3- (3-hydroxypropyl) -estra-1,3,5 (10) -trien-17-one (XXXI / 3-3c) EXAMPLE 826: 3-Hydroxy-15 / 3- (4-hydroxybutyl) -estra-1,3,5 (10) -trien-17-one (XXXI / 3 -4a) EXAMPLE 827: 15 / 3- (4-Hydroxybutyl) -3-methoxy-estra-1,3,5 (10) -trien-17-one (XXXI / 3-4b) EXAMPLE 828: 3-Benzyloxy- 15 / 3- (4-hydroxybutyl) -estra-1,3,5 (10) -trien-17-one (XXXI / 3-4c) EXAMPLE 829: 3-Hydroxy-15 / 3- (5-hydroxypentyl) - estra-1,3,5 (10) -trien-17-one (XXXI / 3-5a) EXAMPLE 830: 15 / 3- (5-Hydroxypentyl) -3-methoxy-estra-1,3,5 (10) -trien-17-one (XXXI | S-5b) EXAMPLE 831: 3-Benzyloxy-15/3 - (5-hydroxypentyl) -estra-1,3,5 (10) -trien-17-one (XXXI ^ -5c) EXAMPLE 832: 3-Hydroxy-15 / 3- (6-hydroxyhexyl) -3-estradiol 1,3,5 (10) -trien-17-one (XXXI / 3-6a) EXAMPLE 833: 15 / 3- (6-Hydroxyhexyl) -3-methoxy-estra-1,3,5 (10) -trien -17-ona (XXXIj6 ~ 6b) EXAMPLE 834; 3-Benzyloxy-15 / 3- (6-hydroxyhexyl) -estra-1,3,5 (10) -trien-17-one (XXXI / 3-6c) EXAMPLES 835 and 836 - Ether Derivatives Two compounds of the formula I are prepared individually in which XAY represents 0, R1 represents CH3, n is 3 or 4 and C15 is substituted in the β-position, according to the general flow diagram XV EXAMPLE 835: 3-Methoxy-153- (3-methoxypropyl) -estra-1, 3, 5 (10) -trien-17-one (XXX / 3-3b) -835 The compound (XXX / 3-3b) - 835 was prepared as outlined in the following scheme 43 SCHEME 43 (Xb) (XXXß-3b) -835 Detailed synthesis According to the general procedure described for SCHEME 11, the copper reagent was prepared from magnesium (0.252 g, 10.50 mmol), l-bromo-3-methoxypropane (0.813 g, 5.31 mmol), Cul (0.200 mg, 1.05 mmol) and DMPU (0.53 ml, 4.40 mmol) in THF. A mixture of estrone Xb 15.16-unsaturated (0.500 mg, 1.77 mmol) and TMSC1 (0.56 ml, 4.38 mmol) in THF was added dropwise. The reaction mixture was allowed to reach T. A. and allowed to stir overnight.

After a treatment and hydrolysis, the compound was obtained (XXX / 3-3b) -835 (0.605 g, 96%) (purity by HPLC> 99%). LC-MS (ES +): Rt 6.8 min, m / z (Intens reí.) 374 [(M + NH4 +, 100%] EXAMPLE 836: 3-Methoxy-15 / 3- (4-phenoxybutyl) -estra-1, 3, 5 (10) trien-17-one (XXX / 3-4b) -836 The compound (XXX / 3-4b) -836 was prepared as outlined in the following scheme 44.

SCHEME 44 Detailed synthesis According to the general procedure described for SCHEME 11, the copper reagent was prepared from magnesium (0.212 g, 8.72 mmol), 3-phenoxybutyl bromide (0.917 g, 4.00 mmol), Cul (0.133 mg, 0.70 mmol) and DMPU (0.45 mL, 3.73 mmol) in THF. A mixture of 15.16-unsaturated estrone Xb (0.282 mg, 1.00 mmol) and TMSCl (0.32 mL, 2.5 mmol) in THF was added dropwise. The reaction mixture was allowed to reach T.A. and stirred overnight. After treatment and hydrolysis of the silyl ether, the crude product was purified by column chromatography (Si02, cyclohexane / ethyl acetate 10: 1) to yield (XXX / 3-4b) -836 (0.240 g, 55% ). LC-MS (ES +): Rt 7.77 min, m > (Intens reí.) 450 [(M + NH4) +, 100%] MATERIALS AND METHODS 1. Inhibition PE BIOLOGICAL ASSAYS enzyme dehydrogenase 17/3-hydroxysteroid Purification type 1 17/3-HSD1: Recombinant baculoviruses were generated by the "Bac to Bac Expression System" (Invitrogen) "Recombinant system bácnido was transfected into Sf9 insect cells using a "Cellfectin Reagent" reagent (Invitrogen). After 60 h the cells were harvested; The microsomal fraction was isolated as described by Puraren et al. 199 The aliquots were stored frozen until the determination of the enzymatic activity.

Assay - Inhibition dehydrogenase 17/3-hydroxysteroid type 1 recombinant human: recombinant protein (0.1 ug / ml was incubated in KH2P04 20 mM, pH 7.4, with 3 H-estrone 30 nM and 1 mM NADPH for 30 min at RT, in the presence of potential inhibitors at concentrations of 1 uM or 0.1 uM. mothers inhibitor solutions were prepared in DMSO. the final concentration of DMSO was adjusted to 1% in all samples. the enzymatic reaction was stopped by adding tricloroacé acid ico 10 % (final concentration) The samples were centrifuged in a microtiter plate at 4,000 rpm for 10 min.The supernatants were applied to inverted-phase HPLC on a Waters Symmetry C18 column, equipped with a Waters Sentry Guard column. performed isocratic HPLC experiments to T. A. at a flow rate of 1 ml / min acetonitrile: water 48:52 as solvent for the experiments. The radioactivity was monitored in the eluate using a Packard Flow Scintillation Analyzer. The total radioactivity for estrone and estradiol was determined in each sample and the percent conversion of estrone to estradiol was calculated according to the following formula: % conversion = 100 x. { (cpm estradiol in sample with inhibitor) / [(cpm estrone in sample with inhibitor) + (cpm estradiol in sample with inhibitor)]} . { (cpm estradiol in sample without inhibitor) / [(cpm estrone in sample without inhibitor) + (cpm estradiol in sample without inhibitor)] Percent inhibition was calculated as follows:% inhibition = 100 -% conversion The inhibition values "were determined for compound examples, and the results are summarized in Table 42.

Table 42: Inhibition of enzyme 17/3-HSD type I 2 . Estrogen receptor binding assay The binding affinity of the compounds of the invention to the estrogen receptor a and the estrogen β receptor can be determined according to the in vitro ER binding assays described by Koffmann et al. [Koffmann et al. (1991) J. Steroid. Biochem. Mol. Biol. 3_8: 135]. Alternatively, an estrogen receptor binding assay can be performed according to the international patent application PCT / US / 17799 (published as WO 00/07996). 3. Estrogen receptor transactivation assays Compounds of the invention that show an affinity of binding to the estrogen receptor can be further tested with respect to their individual potential estrogen or anti-estrogen (agonist binding or antagonistic binding to the ERa or ER / 3). The determination of the estrogen receptor agonist activity can be carried out according to an in vitro assay system using a MMTV-ERE-LUC reporter system which is described, for example, in the U.S. patent application Ser. No. 10/289079 (published as US 2003/0170292): To test the estrogen receptor agonist activity, Hela cells were grown in 24-well microtiter plates and then transiently co-transfected with two plasmids using lipofectamine. The first plasmid comprises 7DNA encoding human estrogen repertoire (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 elements upstream regulators comprising four copies of the vitellogenin estrogen response element (ERE) cloned in the mouse mammary tumor virus promoter (MMTV) (the full name of the reporting system is "MMTV") -ERE-LUC "). The cells are exposed to the compounds of the invention in RPMI 1640 medium supplemented with 10% fetal calf serum treated with 10% charcoal, 2 mM L-glutamine, 0.1 mM non-essential amino acids and 1 mM sodium pyruvate during 42-48 hours at 37 ° C in a 5% carbon dioxide incubator. Concurrently, cells exposed to estradiol (1 mM) serve as positive controls. Replicated wells exposed to the solvent in which the compounds of the invention are dissolved (ie, ethanol or methanol) were used as negative controls. After the incubation period of 42-48 h, the cells were rinsed with phosphate-buffered saline (PBS), lysis buffer (Promega Corp.) and the used cells were collected for luciferase activity measurement with a luminometer. The estrogenic activity of the compounds of the invention is expressed as the times that the luciferase activity increased compared to that observed in the cells of the negative controls. Alternatively, the determination of estrogen receptor transactivation activity (estrogenicity assay or agonist assay) and for the inhibitory potency of transactivation activity (antiestrogenicity assay or antagonist assay) can be performed according to the international PCT patent application. US / 17799 (published as WO 00/07996).

REFERENCED BIBLIOGRAPHY • Adamski J & Jakob FJ (2001) "A guide to 17/3-hydroxysteroid dehydrogenases" Molecular and Cellular Endocrinology, 171: 1-4 • Koffmann B et al. (1991) J. Steroid. Biochem. Mol. Biol. 38: 135 • Labaree DC et al. (2003) "Synthesis and Evaluation of B-, C- and D-ring substituted estradiol carboxylic acid esters as locally active estrogens" J. Med. Chem. 46: 1886-1904 • Labrie F et al. (2000) "Role of 17 beta-hydroxysteroid dehydrogenases in sex steroid formation in peripheral intracrine tissues" Trends Endocrinol Metab. , 11: 421-7 • Labrie F et al. (1997) "The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology." Steroids, 62: 148-58 • Nambara T et al. (1976) "Synthesis of Estetrol Monoglucuronides" Steroids 27: 111-122 • Pelletier JD & Poirier D (1996) "Synthesis and evaluation of estradiol derivatives with 16a- (bromoalkylamide), 16a- (bromoalkyl) or 16a- (bromoalkynyl) side chain as inhibitors of 17/3 ~ hydroxysteroid dehydrogenase type 1 without estrogenic activity" Bioorg Med Chem , 4 (10): 1617-1628. • Poirier D (2003) "Inhibitors of 17 beta-hydroxysteroid dehydrogenases" Curr Med Chem. 10: 453-77 • Poirier D et al. (1998) "A 6 / 3- (Thiaheptanamide) Derivative of Estradiol as inhibitor of 17/3-Hydroxysteroid Dehydrogenase Type 1", J. Steroid Biochem. Molec. Biol., 64: 83-90 • Poirier D et al. (1996) "D-Ring alkylamine derivatives of estradiol: effect on ER-binding affinity and antiestrogenic activity" Bioorg Med Chem Lett 6 (21): 2537-2542. • Poirier D et al. (1991) "Synthesis of 17/3-estradiol derivatives with N-Butyl, N-methyl alkylamide side chain at position 15." Tetrahedron, 47 (37): 7751-7766 • Sam KM et al. (1998) "C16 and C17 Derivatives of Estradiol as Inhibitors of 17/3-Hydroxysteroid Dehydrogenase Type 1: Chemical Synthesis and Structure-Activity Relationships", Drug Design and Discovery, 15: 157-180 • Tamaya et al. (1985) "Comparison of cellular levéis of steroid receptors in uterine leiomyoma and myometrium." Obstet Gynecol Scand., 64: 307-9 • Tremblay MR & Poirier D (1998) "Overview of a Rational Approach to Design Type I 17 β-Hydroxysteroid Dehydrogenase Inhibitors Without Estrogenic Activity: Chemical Synthesis and Biological Evaluation", J. Steroid Biochem. Molec. Biol., 66: 179-191 • WO 03/017973 - A METHOD FOR TREATING BENIGN GYNECOLOGICAL DISORDERS AND A DRUG SUPPLY VEHICLE FOR USE IN THIS METHOD • Document WO 2004/080271 - METHOD FOR FORECASTING THE PROGRESS OF CANCER MAMAS AND USEFUL COMPOUNDS FOR YOUR PREVENTION OR TREATMENT • WO 2004/085345 - ESTERS OF CARBOXYLIC ACIDS OF ESTRADIOL 15a-SUBSTITUTED AS LOCALLY ACTIVE ESTROGENS • Document WO 2004/085457 - Compound

Claims (50)

1. CLAIMS 1. Compound in accordance with general formula I, characterized in that (i) X represents: (a) a bond, (b) -NR3-, or (c) -0-; A represents: (a) -CO-, or (b) with the proviso that X represents -NR3, A represents -S02-; Y represents: (a) -NR4 (b) -O-, with the proviso that X represents a bond or -NR3-, (c) a bond, (d) -NH-S02-, with the proviso that X Represent -NR3 and A represents -CO-, (e) -NH-S02-NR4, with the proviso that X represents -O-, or (f) -NH-NR4-, with the proviso that X represents a bond , or (ii) -XAY-jointly represents -0-; and wherein R1 and R3 are independently selected from: (a) -H, (b) -alkyl (C? -Ce), which is optionally substituted with halogen, nitrile, -0RS, -SRb -COOR6; the number of said substituents being up to three for halogens and up to two for any combination of said halogen, nitrile, -OR, -SR ° COORk (c) residues -phenyl, which is optionally substituted with halogen, nitrile, -OR6 '-SR6' -R6 or -COOR6, the number of said substituents being up to perhalo for halogen and up to two for any combination of said halogen, nitrile, -OR6, -SR6, -R6 or -COOR6, (d) -alkyl (C? -C4) -phenyl moieties, wherein the alkyl part is optionally substituted with up to three halogens; and the phenyl part is optionally substituted with halogen, nitrile, -OR6, -SR6 '-R6 or -COOR6' and the number of substituents of said phenyl part is up to perhalo for halogen and up to two for any combination of said halogen, nitrile, -OR6, -SR6, -R6 or -COOR6 moieties; R2 and R4 are independently selected from: (a) -H, wherein if X represents a bond, A represents -CO- and Y represents -0- or a bond, then R2 is different from -H; (b) optionally substituted alkyl, optionally substituted (c) acyl, with the proviso that Y represents -NH-NR4-, (d) optionally substituted aryl, (e) optionally substituted heteroaryl, and (f) optionally substituted cycloheteroalkyl, or , with the proviso that Y represents -NR4-, -NH-NR4- or -NH-S02-NR4-, R2 and R4 together with the nitrogen atom to which R2 and R4 are attached, form a heterocyclic ring of 4, 5, 6, 7 or 8 members, which is optionally saturated, partially unsaturated or aromatic, optionally containing up to three additional heteroatoms selected from N, O or S, the number of additional N atoms being 0. 1, 2 or 3 and the number of atoms of O and S being each of 0. 1 or 2; and the ring is optionally part of a multiple system of fused rings, in which the ring or ring system is optionally substituted; R6 represents H, -alkyl (C? -C) or halogenated (C? -C) alkyl; and n represents 0, 1, 2, 3, 4, 5 or 6, wherein if X represents -NR3 or -O-, then n is different from 0, and all stereoisomers, pharmacologically acceptable salts and prodrugs thereof. Compound according to claim 1, characterized in that R2 and R4 are independently selected from: (a) -H, wherein if X represents a bond, A represents -CO- and Y represents -O- or a bond, then R2 is different from -H, (b) -alkyl (C? -C12), optionally substituted with up to five substituents independently selected from the group consisting of halogen, hydroxyl, thiol, nitrile, alkoxy, aryloxy, arylalkyloxy, amino, amido , alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamido, acyl, carboxyl, acylamino, aryl, aryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C? -C6) alkoxy, alkyl (C? -C6), halogenated (C? -C6) alkyl, halogenated (C? -C6) alkoxy, carboxyl (C? -C6) alkyl, thiol, nitrile, sulfamoyl, ulfonamido, carboxyls, aryloxy, rylalkyloxy, alkylthio (Cx-Cß), arylthio, arylalkylthio, mino, amido, acyl, acylamino and heteroaryl; or aryl which is optionally substituted with two groups which are nested to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic system of 5, 6, 7 or 8 members, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2; heteroaryl, heteroaryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, (C? -C3) alkoxy, (C? -C6) alkyl, halogenated (C? -C3) alkyl, alkoxy ( C-C6) halogenated, carboxyl-alkyl (C? -C6), thiol, nitrile, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, alkylthio (Ci-Crs), arylthio, arylalkylthio, amino, amido, acyl, acylamino , aryl-alkyl (C? -C) and aryl; wherein each aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C6) alkoxy, (C? -Ce) alkyl, halogenated (C? -C6) alkyl and alkoxy (C? -C6) halogenated; and cycloheteroalkyl, cycloheteroalkyl group which is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C? -C8) alkyl, aryl, aryl-alkyl (C? -C), hydroxyl, alkoxy (C? C6), carboxyl-C (-C6) alkyl, thiol, nitrile, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, alkylthio (C6C6), arylthio, arylalkylthio, amino, amido, acyl and acylamino, in which each Aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C) alkyl, (C? -C4) alkoxy, halogenated (C? -C) alkyl and halogenated (C? -C) alkoxy; (c) acyl- (C = 0) R ', wherein R' represents hydrogen, (C? -C4) alkyl, aryl or arylalkyl (C? -C) or heteroarylalkyl (Cx-C ^); aryl that is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C4) alkoxy, (C? -C4) alkyl or halogenated (C? -C4) alkyl; (d) aryl, aryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C? -C6) alkoxy, (C? -C6) alkyl, halogenated (C? -C6) alkyl , halogenated (C? -C3) alkoxy, carboxyl (C? -C6) alkyl, thiol, nitrile, nitro, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, (C? -C6) alkyl-sulfonyl, arylsulfonyl, alkylthio ( C? -C6), arylthio, arylalkylthio, amino, amido, acyl, acylamino and heteroaryl; or aryl that is optionally substituted with two groups that are bonded to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic system with 5, 6, 7 or 8 member rings, optionally containing up to three heteroatoms such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2; (e) heteroaryl, heteroaryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C? -C6) alkoxy, alkyl (C? -C6), halogenated (C-C6) alkyl, halogenated (C? -C6) alkoxy, carboxyl (C? -C6) alkyl, thiol, nitrile, sulfamoyl, sulfonamido, arylsulfoxy, carboxyl, aryloxy, arylalkyloxy , alkyl (C? -C6) -sulfonyl, arylsulfonyl, alkylthio (C? -C6), arylthio, arylalkylthio, amino, amido, acyl, acylamino, arylalkyl (C? -C) and aryl, wherein each aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C3) alkoxy, (C? -C6) alkyl, halogenated (C? -C6) alkyl and halogenated (C? -C6) alkoxy; or (f) cycloheteroalkyl, cycloheteroalkyl which is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C? -C) alkyl, aryl, aryl (C? -C) alkyl, hydroxyl, alkoxy (C) C6), carboxylalkyl (C6C6), thiol, nitrile, sulfamoyl, sulfonamido, carboxyl, aryloxy, arylalkyloxy, alkylthio (C6Ce), arylthio, arylalkylthio, amino, amido, acyl and acylamino, in that each aryl group is optionally further substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C4) alkyl, (C? -C) alkoxy, halogenated (C? -C) alkyl and alkoxy (C? -C) halogenated; or wherein, with the proviso that Y represents -NR4, -NH- NR4- or -NH-S02-NR4-, R2 and R4 form, together with the nitrogen atom to which R2 and R4 are attached, a heterocyclic ring of 4, 5, 6, 7 or 8 members, which is optionally saturated or partially unsaturated, optionally containing up to three additional heteroatoms selected from N, 0 or S, the number of additional N atoms being 0-3 and the number of atoms of 0 and S each being 0-2; and ring which is optionally part of a multiple system of fused rings, wherein the ring or ring system is optionally substituted (i) with up to three substituents independently selected from the group consisting of (C? -C8) alkyl, halogen, hydroxyl, carboxyl, thiol, nitrile, (C? -C6) alkoxy, carboxyl-alkyl (C? -C6), aryloxy, arylalkyloxy, amino, amido, alkylthio, arylthio, arylalkylthio, sulfamoyl, sulfonamido, aryl, aryl-alkyl (C? -C4), heteroaryl and cycloheteroalkyl, in which the alkyl group (C? C8) is optionally substituted with up to three substituents independently selected from hydroxyl, halogen, (C? -C4) alkoxy, or (C? -C4) alkoxy or alkoxy (C-C4) halogenated, in which the alkyl chain of the alkoxy moiety (C? -C) is optionally substituted with hydroxyl; wherein the aryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C4) alkyl, alkoxy (C? -C4), halogenated (C? -C4) alkyl, halogenated (C? -C4) alkoxy and carboxyl (C? -C3) alkyl, or wherein the aryl moiety is optionally substituted with two groups that are attached to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic system with rings of 5, 6, 7 or 8 members, optionally containing up to three heteroatoms such as N, 0 or S, the number of N atoms being 0-3 and the number of carbon atoms being O and S each from 0-2; wherein the heteroaryl group is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C) alkyl, (C? -C) alkoxy, halogenated (C? -C4) alkyl, alkoxy (C? -C) halogenated and carboxyl-alkyl (C? -C6); wherein the cycloheteroalkyl group is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C? -C8) alkyl, aryl, aryl (C? -C) alkyl, hydroxyl, (C? -C6) alkoxy ), carboxyl (C? -C6) alkyl and carboxyl, in which each aryl group is optionally further substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C4) alkyl, alkoxy (C? -C4), halogenated (C-C4) alkyl and halogenated (C? -C) alkoxy; or (ii) with two groups that are linked to the same carbon atom and are combined in the form of a saturated or partially unsaturated cyclic system with 4, 5, 6, 7 or 8 member rings, optionally containing up to three heteroatoms such as N, 0 or S, the number of atoms of N being 0-3 and the number of atoms of 0 and S each being 0-2, in which the cyclic ring system is optionally substituted with up to two substituents independently selected from oxo, (C-C6) alkyl, aryl, and aryl-alkyl (C? -C); and where n represents (a) 1, 2, 3, 4, 5 or 6, with the proviso that X represents -NR3- or -O-, or (b) 0. 1, 2, 3, 4 or 5 , with the proviso that X represents a link. 3. Compound according to claim 2, characterized in that R2 and R4 are independently selected from: (a) -H, wherein if X represents a bond, A represents -CO- and Y represents -0- or a bond, then R2 is different from -H, b) -alkyl (C? -C12), optionally substituted with up to five substituents independently selected from the group consisting of halogen, hydroxyl, nitrile, -0- R7; -0-Ar1, -O-alkyl (C? -C4) -Ar1, alkylamino, alkylamido, -S-R7, -S-Ar1, -S-alkyl (Cx-C) -Ar1, '- (C = 0 ) - OR8, aryl, heteroaryl and cycloheteroalkyl, in which the aryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C? -C6) alkoxy, (C? -C6) alkyl, alkyl (C? -C3) halogenated, halogenated (C -C6) alkoxy, -alkyl (C-C6) - (C = 0) -OR8, nitrile, sulfamoyl, - (C = 0) -0R8, -0-Ar1, -0-alkyl (C? -C4) -Ar1, alkylthio (C? -C3), -S-Ar1, -S-alkyl (C? -C4) -Ar1, alkylamino and alkylamido; or wherein the aryl is optionally substituted with two groups that are bonded to adjacent carbon atoms and are combined in the form of a cyclic system saturated with rings of 5 or 6 members, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2; wherein the heteroaryl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C-C6) alkoxy, alkyl (Ca-C6), halogenated (C? -C) alkyl, alkoxy (C? -C6) halogenated, -alkyl (C? -C6) - (C = 0) -OR8, nitrile, sulfamoyl, - (C = 0) -OR8, -O-Ar1, -CO-alkyl (C? -C4) -Ar1, alkylthio (C? -C6), -S-Ar1, -S-alkyl (C? -C4) -Ar1, alkylamino, alkylamido, alkyl (C? -C4) -Ar1 and Ar1; and wherein the cycloheteroalkyl group is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C? -C8) alkyl, Ar1, -alkyl (C? -C4) -Ar1, hydroxyl, alkoxy (C? -C6), -alkyl (C-C6) - (C = 0) -OR8, nitrile, - (C = 0) -OR8, -O-Ar1, -0- alkyl (C? -C4) -Ar1, alkylthio (C? -C6), -S-Ar1, -S-alkyl (C? -C4) -Ar1, alkylamino and alkylamido; (c) aryl, aryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxyl, (C? -C6) alkoxy, alkyl (C? -Ce), halogenated (C? -Ce) alkyl , halogenated alkoxy (Cx-Ce), -alkyl (C? -C6) - (C = 0) -0R8, nitro, nitrile, sulfamoyl, - (C = 0) -OR8, - (C = 0) -R8, -O-Ar1, -0-alkyl (C? -C4) -Ar1, alkylthio (C? -C6), -S-Ar1, -S-alkyl (C? -C4) -Ar1, alkyl (C? -C4) ) -sulfonyl, -SOa-Ar1, alkylamino, alkylamido, -NH-CO-R8, Ar1 and heteroaryl; or aril which is optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a ring saturated system with 5 or 6 members, optionally containing up to three heteroatoms, such as N or O, the number being N atoms of 0-3 and the number of O atoms each being 0-2; (d) heteroaryl, heteroaryl which is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, (C? -C6) alkoxy, (C? -C6) alkyl, halogenated (C? -C3) alkyl , halogenated (C? -C6) alkoxy, -alkyl (C? -C6) - (C = 0) -OR8, nitrile, sulfamoyl, - (C = 0) -OR8, -O-Ar1, -O-alkyl (C? -C4) -Ar1, alkylthio ( C? -C6), -S-Ar1, -S-alkyl (C1-C4) -Ar1, alkyl (C? -C) -sulfonyl, -S02-Ar1, alkylamino, alkylamido, -alkyl (C? -C4) -Ar1 and Ar1; or (e) cycloheteroalkyl, cycloheteroalkyl group which is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C? -C8) alkyl, Ar1, -alkyl (C? -C) -Ar1, hydroxyl, alkoxy (C? -C6), -alkyl (C? -C6) - (C = 0) -OR8, nitrile, - (C = 0) -OR8, -O-Ar1, -0- alkyl (C? -C4) -Ar1, alkylthio (C? -C6), -S-Ar1, -S-alkyl (C? -C4) -Ar1, alkylamino and alkylamido; wherein R7 represents (C? -C6) alkyl, optionally substituted with up to three hydroxy groups on the alkyl chain or halogenated (C? -C6) alkyl, R8 represents hydrogen, (C? -C4) alkyl, phenyl or alkyl (C) ? -C) -phenyl, in which the phenyl moiety is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkoxy (C-C), alkyl (C? -C4), halogenated (C? -C) alkyl and alkoxy (C? -C4) halogenated; and Ar1 represents phenyl or naphthyl, which are optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C4) alkyl, (C? -C4) alkoxy, alkyl (Cx-Ci) halogenated or halogenated (C? -C4) alkoxy; or wherein, with the proviso that Y represents -NR4-NH- NR4- or -NH-S02-NR4-, the ring or ring system formed by R2 and R4, together with the nitrogen atom to which R2 and R4 are united, it is selected from the group consisting of in which the ring or ring system is optionally substituted (i) with up to three substituents independently selected from the group consisting of alkyl (C? -C8), oxo, hydroxyl, (C? -C6) alkoxy, -alkyl (C? -C6) - (C = 0) - OR8 ', nitrile, - (C = 0) -OR8, -O-Ar2, -O- alkyl (CC) -Ar2, alkylthio (C? -Cs) alkylamino, alkylamido, aryl, arylalkyl (C? -C), heteroaryl and cycloheteroalkyl, in which the aryl and arylalkyl group (C? -C4) are optionally substituted in the aryl moiety with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkyl (C? -C4), alkoxy (C? -C4), halogenated (C? -C4) alkyl, alkoxy (C? - C) halogenated and carboxyl-alkyl (C? -C6), or in which the aryl moiety is optionally substituted with two groups that are bonded to adjacent carbon atoms and are combined in the form of a saturated or partially unsaturated cyclic ring system with 5, 6, 7 or 8 members, optionally containing up to three heteroatoms such as N, 0 or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2; and wherein the (C? -C8) alkyl group is optionally substituted with up to three substituents independently selected from hydroxyl, halogen, halogenated (C? -C4) alkoxy or (C? -C4) alkoxy, whereby the alkyl chain of the Alkoxy radical (C? -C4) is optionally substituted with up to three hydroxyl, in which the heteroaryl is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C4) alkyl, (C-C6) alkoxy, halogenated (C? -C4) alkyl and halogenated (C? -C6) alkoxy; and wherein the cycloheteroalkyl is optionally substituted with up to three substituents independently selected from the group consisting of oxo, (C? -C8) alkyl, hydroxyl, (C-C6) alkoxy, - (C = 0) -OR9 and -alkyl (C? -C6) - (C = 0) -OR9; or (ii) with two groups that are bonded to the same carbon atom and are combined in the form of a saturated or partially unsaturated cyclic system of 5, 6, 7 or 8 members, optionally containing up to three heteroatoms such as N, O or S, the number of atoms of N being 0-3 and the number of atoms being 0 and S each 0-2; wherein the cyclic ring system is optionally substituted with up to three independent substituents selected from oxo, (C? -C6) alkyl, aryl and aryl (C? -C4) alkyl, wherein Ar2 represents phenyl or naphthyl, which are optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, (C? -C) alkyl, (C? -C4) alkoxy, halogenated (C? -C4) alkyl or halogenated (C? -C) alkoxy , R9 represents hydrogen, (C? -C) alkyl, phenyl or (C? -C4) alkyl-phenyl, wherein the phenyl is optionally substituted with up to three substituents independently selected from the group consisting of hydroxyl, halogen, alkoxy ( C? -C4), alkyl (C? -C), halogenated (C? -C4) alkyl and halogenated (C? -C) alkoxy. 4. Compound according to claim 3, characterized in that, R2 and R4 can be independently selected from: (a) -H, wherein if X represents a bond, A represents -CO- and Y represents -O- or a bond, then R2 is different from -H, (b) an alkyl group selected from (i) -alkyl (C? -C8), optionally substituted with substituents independently selected from the group consisting of hydroxyl, nitrile, -O-R7 '; -0-phenyl, -O-alkyl (C? -C) -phenyl, alkylamino, -S-R7 'and - (C = 0) -OR8', the number of substituents in said alkyl part being up to five for hydroxyl and one, two or three for any combination of said other substituents; (ii) -alkyl (C? -C), optionally substituted with one or two substituents independently selected from the group consisting of aryl, heteroaryl and cycloheteroalkyl, aryl which is optionally substituted with halogen, hydroxyl, (C? -C6) alkoxy , alkyl (C? -C6), halogenated (C? -C) alkyl, halogenated (C? -C4) alkoxy, sulfamoyl or alkylamido, the number of substituents in said aryl part being up to three for halogens and one or two for any combination of said other substituents; or aryl which may be optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a ring saturated system of 5 or 6 members, optionally containing up to three heteroatoms, such as N or 0, the number of N atoms being 0-3 and the number of O atoms each being 0-2; heteroaryl which is optionally substituted with one or two substituents independently selected from the group consisting of (C? -C) alkoxy or (C? -C) alkyl; (iií) -cycloalkyl (C3-C8), optionally substituted with hydroxyl; (iv) -alkyl (C? -C4) -cycloalkyl (C3-C8), optionally substituted with hydroxyl; (v) a bicyclic ring system of 6 to 10 carbon atoms, selected from the group consisting of 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.l] nonanyl, bicyclo [3.3.2] decanyl; and (vi) adamantyl; (c) aryl, aryl which is optionally substituted with halogen, (C? -C6) alkoxy, halogenated (C? -C4) alkyl, halogenated (C? -C6) alkoxy, nitro, nitrile, -CO-alkyl (C-) C4), -C0-0-alkyl (C? -C4), -NH-CO-alkyl (C? -C4), alkyl (C? -C4) -sulfonyl, phenyl or heteroaryl, the number of substituents of said aryl part of up to three for halogen and one or two for any combination of said other residues; or aryl which is optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a ring saturated system with 5 or 6 members, optionally containing up to three heteroatoms, such as N or 0, the number of N atoms of 0-3 and the number of atoms of 0 being 0-2; (d) heteroaryl, heteroaryl which is optionally substituted with up to two substituents independently selected from the group consisting of halogen, (C? -C4) alkyl, halogenated (C? -Ci) alkyl, -alkyl (C? -C4) - (C = 0) -OR8 ', -O-Ar1' and phenyl; or (e) cycloheteroalkyl, cycloheteroalkyl group which is optionally substituted with one or two substituents independently selected from the group consisting of oxo, (C? -C4) alkyl and (C? -C) -phenyl alkyl; wherein R7 'represents (C? -C4) alkyl, optionally substituted on the alkyl chain with one or two hydroxyl groups, R8' represents hydrogen, (C? -C4) alkyl or (C? -C2) alkyl-phenyl; and Ar1 'represents phenyl optionally substituted with up to three halogen atoms; or in that, with the proviso that Y represents -NR4-, -NH- NR4- or -NH-S02-NR4-, the ring or ring system formed by R2 and R4, together with the nitrogen atom to which R2 and R4 are joined, it is selected from the group consisting of in which the ring or ring system is optionally substituted (i) with up to three substituents independently selected from the group consisting of (a) hydroxyl, (b) oxo, (c) alkyl (? -0 ^) optionally substituted with up to two hydroxyl and / or alkoxy groups (C) ? -C), in which the alkyl chain of the alkoxy moiety (C? -C4) can be further substituted with one or two hydroxyl groups; (d) (C3-C8) cycloalkyl; (e) - (C = 0) -O-alkyl (C? -C); (f) phenyl optionally substituted with halogen, (C? -C4) alkyl, (C? -C4) alkoxy or halogenated (C? -C4) alkyl, the number of said substituents being on the phenyl moiety of up to three for halogen, and one or two for any combination of said other substituents; (g) phenyl-(C? -C4) alkyl, optionally substituted on the phenyl group with up to three halogens, or optionally substituted on the phenyl group with two groups which are bonded to adjacent carbon atoms and are combined in the form of a system saturated or partially unsaturated cyclic ring with 5 or 6 members, optionally containing up to two O atoms; (h) alkylamido; (i) heteroaryl, wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, benzoimidazolyl or benzo [bltiofen; and (j) cycloheteroalkyl, wherein the cycloheteroalkyl is selected from the group consisting of pyrrolidinyl, 1,3-dihydro-benzoimidazolyl, morpholinyl, tetrahydrofuranyl, piperidinyl or azepanyl; cycloheteroalkyl group which is optionally substituted with oxo; or (ii) with two groups that are bonded to the same carbon atom and are combined in the form of a cyclic system saturated or partially saturated with 5, 6 or 7 membered rings, optionally containing up to three heteroatoms such as N or O, the number of N atoms being 0-3 and the number of O atoms being 0-2, wherein the cyclic ring system can be further substituted with up to two substituents independently selected from oxo and phenyl. 5. Compound of the general formula I according to any of the preceding claims, characterized in that it is an optically pure enantiomer having the formula (ID or a physiologically acceptable salt thereof. 6. Compound of the general formula I according to any of the preceding claims 1 to 5, characterized in that it is an optically pure enantiomer having the formula (III) or a physiologically acceptable salt thereof. Compound according to any one of claims 1 to 6, characterized in that R1 represents H, (C? -C) alkyl or phenyl-alkyl (C-C). Compound according to claim 7, characterized in that R1 represents H, methyl or benzyl. 9. Compound according to any of claims 1 to 8, characterized in that R3, if present, represents H, alkyl (C? -Ci) or phenyl-alkyl (C? -C4). 10. Compound according to claim 9, characterized in that, R3 represents H, methyl or benzyl. 11. Compound according to any of claims 1 to 10, characterized in that R4, if present, represents (a) -H, (b) an alkyl group selected from (i) (C? -C6) alkyl, optionally substituted with substituents independently selected from the group consisting of hydroxyl, nitrile, alkylamino, (C? -C4) alkoxy, the number of substituents of said alkyl part being up to five for hydroxyl and up to two for any combination of said other substituents; (ii) aryl-alkyl (C? -C4) or heteroaryl-alkyl (C? -C4), wherein the aryl is phenyl or naphthyl and the heteroaryl is pyridinyl; (iii) (C3-C6) cycloalkyl; (iv) (C3-C3) cycloalkyl-alkyl (C? -C2); (c) piperidinyl, which is optionally substituted with an alkyl group (C-C4). Compound according to claim 11, characterized in that if X represents -NR3- or -O- and Y represents -NR2R4-, then R4 is -H. 13. Compound according to claim 1, characterized in that X represents a bond, A represents -C0-; Y represents (a) -NR4-, (b) -0-, (c) a bond, O (d) -NH-NR4-; and n represents 0, 1, 2, 3, 4 or 5. 14. Compound in accordance with the claim 13, in which Y represents -NR4- and n represents 0, 1, 2, 3, 4 or 5. 15. Compound deconfromity with claim 14, characterized in that R2 represents (i) -alkyl (C? -C4), ( ii) -cycloalkyl (C3-C8), (iii) -alkyl (C? -C4) -aryl, wherein the aryl is phenyl or naphthyl, phenyl which is optionally substituted with one or two substituents independently selected from the group consisting of in hydroxyl, halogen and alkoxy (Cx-C4); or phenyl which is optionally substituted with two groups that are attached to carbon atoms adjacent and are combined in the form of a cyclic system saturated with rings of 5 or 6 members, containing 1 or 2 O atoms; or (iv) heteroaryl or -alkyl (C? -C4) -heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl, pyridinyl, indolyl or benzoimidazolyl; heteroaryl which is optionally substituted with one or two substituents independently selected from the group consisting of alkyl (C? -C4) and -alkyl (C? -C4) - (C = 0) -O-alkyl (C? -C4); and R4 is independently selected from H or -alkyl (C? -C4); or R2 and R4 form, together with the nitrogen atom to which R2 and R4 are attached, a ring or ring system, which is selected from the group consisting of morpholino, thiomorpholino and piperazyl. 16. Compound according to claim 1, characterized in that X represents -NH-; A represents -C0-; Y represents (a) -NH-; (b) -0-, or (c) a bond, and n represents 1, 2, 3, 4, 5 or 6. 17. Compound according to claim 16, characterized in that X represents -NH-, Y represents -NH - or a bond, and n represents 1, 2, 3 or 4. 18. Compound according to claim 17, characterized in that Y represents -NH-. 19. Compound according to claim 17, characterized in that R2 represents (i) -alkyl (C? -C4), (ii) -cycloalkyl (C3-C8), (iii) -alkyl (C? -C4) -aryl , in which the aryl is phenyl or naphthyl, phenyl which is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, -CO-Oalquii (C? -C4), and (C? -C) alkoxy, or phenyl which is optionally substituted by two groups which are bonded to adjacent carbon atoms and are combined in the form of a cyclic system saturated with 5 or 6 membered rings, containing 1 or 2 0 atoms; or (v) -alkyl (C? -C4) -phenyl. 20. Compound according to claim 17, characterized in that Y represents a bond. 21. Compound according to claim 20, characterized in that R2 represents (i) -alkyl (C? -C), (ii) -cycloalkyl (C3-C8), (iii) -alkyl (C? -C4) -cycloalkyl (C3-C8), (iv) -alkyl (C? -C4), substituted with one or two substituents independently selected from the group consisting of -O-alkyl (C? -C4) and -0-alkyl (C? ~ C) -phenyl, (v) phenyl, phenyl which is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen and (C? -C4) alkoxy; (vi) -alkyl (C? -C) -phenyl; or (vii) adamantilo. 22. Compound according to claim 1, characterized in that X represents -NR3-; A represents -S02-; Y represents (a) -NH-, (b) -0-, or (c) a bond; and n represents 1, 2, 3 or 4. 23. Compound in accordance with the claim 22, characterized in that Y represents a bond and R3 represents H or -alkyl (C? -C4). 24. Compound in accordance with the claim 23, characterized in that R2 represents (i) aryl, wherein the aryl is selected from phenyl and naphthyl, aryl which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, nitro, (C? -C4) alkoxy ) and -alkyl (C? -C4); or (ii) heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl or indolyl, heteroaryl which is optionally substituted with one or two substituents independently selected from the group consisting of -S02-phenyl and (C? -C) alkyl. 25. Compound according to claim 1, characterized in that X represents -O-; A represents -C0-; Y represents: (a) -NH-, (b) a bond, or (c) -NH-S02-NR4-; and n represents 1, 2, 3, 4, 5 or 6. 26. Compound in accordance with the claim 25, characterized in that Y represents -NH- and n represents 3, 4, 5 or 6. 27. Compound in accordance with the claim 26, characterized in that R2 represents phenyl or naphthyl, phenyl which is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, halogen, nitro, -CO-O- (C? -C4) alkyl and alkoxy (C? -C4) and halogenated (C? -C) alkyl; or phenyl which is optionally substituted with two groups which are bonded to adjacent carbon atoms and are combined in the form of a cyclic system saturated with 5 or 6 membered rings, containing 1 or 2 atoms of 0. 28. Compound in accordance with Claim 25, characterized in that Y represents -NH-S02-NR4-. 29. Compound according to claim 28, characterized in that R2 represents (i) -alkyl (C? -C4), (ii) -cycloalkyl (C3-C8), (iii) -alkyl (C? -C) -phenyl , (iv) phenyl, or (v) heteroaryl or -alkyl (C? -C4) -heteroaryl, wherein the heteroaryl is furyl, thienyl, thiazolyl, pyridinyl, indolyl or benzoimidazolyl; and R4 is independently selected from H, -alkyl (C? -C4) and -alkyl (C? -C) -phenyl, or R2 and R4 can form, together with the nitrogen atom to which R2 and R4 are attached, a ring, which is selected from the group consisting of morpholino, thiomorpholino and piperazyl, and which is optionally substituted with alkyl (Cx-C4). Compound according to claim 1, characterized in that -XAY- represents -O-, and in which R2 represents -H and n represents 1, 2, 3, 4, 5 or 6. 31. Compound in accordance with the claim 1, selected from the group characterized in that it consists of the compounds of examples 1, 2, 3B, 3A, 31, 36, 37, 38, 39, 40. 105, 310. 311, 313, 324, 329, 331, 332 , 333, 335, 338, 339, 340. 341, 342, 343, 344, 345, 346, 347, 348, 350. 353, 354, 355, 356, 357, 359, 360. 361, 363, 364, 365, 366, 443, 446, 449, 450. 452, 464, 465, 477, 488, 490. 491, 661, 662, 664, 665, 668, 677, 681, 682, 684, 685, 688, 693, 694, 696, 748, and 823 or a pharmaceutically acceptable salt thereof. 32. Compound according to any of claims 1 to 31, characterized in that it is used as a medicine. 33. Pharmaceutical composition, characterized in that it comprises as active agent a compound of the formula (I) according to any of claims 1 to 31, and at least one pharmaceutically acceptable carrier. 34. Use of an effective amount of a compound of the formula (I) according to any of the preceding claims 1 to 31, characterized by the treatment or prevention of a disease or disorder dependent on steroid hormones in a mammal. 35. Use of a compound of the formula (I) according to any of the preceding claims 1 to 31, characterized by the preparation of a medicament for the treatment or prevention of a disease or disorder dependent on steroid hormones in a mammal. 36. Use of a compound of the formula (I) according to claim 34 or 35, characterized in that the disease or disorder dependent on steroid hormones is an oestradiol-dependent disease or disorder. 37. Use of a compound of the formula (I) according to claim 36, characterized in that the oestradiol-dependent disease or disorder is malignant and is selected from the group consisting of breast cancer, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia. 38. Use of a compound of the formula (I) according to claim 37, characterized in that the oestradiol-dependent disease is breast cancer and the mammal is a human post-menopausal female. 39. Use of a compound of the formula (I) according to claim 36, characterized in that the oestradiol-dependent disease or disorder is benign and is selected from the group consisting of endometriosis, uterine fibroids, uterine leiomyoma, ademoniosis, dysmenorrhea , menorrhagia, metrorrhagia and urinary dysfunction. 40. Use of a compound of the formula (I) according to claim 37 or 39, characterized in that the mammal is a pre- or peri-menopausal human female. 41. Use of a compound of the formula (I) according to claim 34 or 35, characterized in that the steroid hormone-dependent disease or disorder is selected from the group consisting of prostate carcinoma, prostadynia, benign prostatic hyperplasia, urinary dysfunction and lower urinary tract syndrome. 42. Use of a compound of the formula (I) according to claim 34 or 35, characterized in that the treatment or prevention of the disease or disorder dependent on steroid hormones requires the decrease of the concentration of endogenous 17/3-estradiol of a generalized and / or tissue-specific manner. 43. Use of a compound of the formula (I) according to claim 42, characterized in that the disease or disorder dependent on steroid hormones is rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts. 44. Use of an effective amount of a selective inhibitor of the type 17/3-hydroxysteroid type 1 dehydrogenase enzyme characterized by the treatment or prevention of a benign disease or disorder dependent on estradiol in a mammal. 45. Use of a selective inhibitor of the enzyme 17/3-hydroxysteroid dehydrogenase type 1, characterized by the preparation of a medicament for the treatment or prevention of a benign disease or disorder dependent on estradiol in a mammal. 46. Use of a selective inhibitor of the enzyme 17/3-hydroxysteroid dehydrogenase type 1 according to claim 44 or 45, characterized in that the Selective inhibitor shows no or only pure affinities of estrogen receptor antagonist binding. 47. Use of a selective inhibitor of the enzyme 17/3-hydroxysteroid type 1 dehydrogenase according to any of claims 44 to 46, characterized in that the benign oestradiol-dependent disease or disorder is selected from the group consisting of endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia or urinary dysfunction. 48. Use of a selective inhibitor of the enzyme 17/3-hydroxysteroid type 1 dehydrogenase according to claim 47, characterized in that the mammal is a human female, preferably a pre- or peri-menopausal female. 49. Use of an effective amount of a selective inhibitor of the 17/3-hydroxysteroid type 1 dehydrogenase enzyme characterized by showing no or only pure affinities of estrogen receptor antagonist binding, for the prevention of breast cancer in a female post-menopausal 50. Use of a selective inhibitor of the enzyme 17/3-hydroxysteroid dehydrogenase type 1 characterized in that it shows no or only the pure affinities of antagonist binding for the estrogen receptor, for the elaboration of a medication for the prevention of breast cancer in a post-menopausal female.