MXPA05012871A - Thiophenepyrimidinones as 17-beta-hydroxysteroid dehydrogenase inhibitors - Google Patents

Abstract

This invention relates to compounds useful in therapy, especially for use in the treatment and/or prevention of a steroid hormone dependent disorder, preferably a steroid hormone dependent disease or disorder requiring the inhibition of a 170&bgr;-hydroxysteroid dehydrogenase (1 7&bgr;-HSD) such as 17&bgr;-HSD type 1, type 2 or type 3 enzyme.

Description

THIOPHENOPIRIMIDINONES AS INHIBITORS 17-BETA-HYDROXYSTEROIDE- DEHYDROGENASES FIELD OF THE INVENTION The present invention relates to new thiophene-pyrimidinone derivatives which represent inhibitory compounds of the 17β-hydroxysteroid-dehydrogenase enzymes, preferably of the 17β-hydroxysteroid dehydrogenases type 1 (17β-HSDl), type 2 (17β- HSD2) or type 3 (17β-HSD3), their salts, pharmaceutical preparations containing these compounds and process for their preparation. In addition, the invention relates to the therapeutic use of thiophene-pyrimidinone derivatives, particularly their use in the treatment or prevention of diseases or conditions dependent on steroid hormones, such as steroid hormone-dependent conditions or diseases requiring the inhibition of steroids. -hydroxysteroid dehydrogenases, in particular the 17β-HSD type 1 enzymes, and / or which require the modulation of the concentration of endogenous 17β-estradiol and / or testosterone.

BACKGROUND OF THE INVENTION The publications and other materials used herein to illustrate the background of the invention, and in particular the cases that provide additional details with respect to its practice are incorporated by reference. The 17ß-hydroxysteroid dehydrogenases of mammals (17ß-HSDs) are NAD (H) or NADP (H) -dependent enzymes that, in addition to other reactions, catalyze the final stages in the biosynthesis of the male and female sex hormone. These enzymes convert inactive 17-keto-steroids into their 17β-hydroxy active forms or catalyze the oxidation of the 17β-hydroxy forms to the 17-keto-steroids. Since both estrogens and androgens have the highest affinity for their receptors in the 17β-hydroxy form, the 17β-HSD enzymes play an essential role in the selective tissue regulation of sex steroid hormone activity. Currently, 10 human members of the family of 17β-HSD enzymes have been described (types 1-5, 7, 8, 10, 11 and 12). Members of the human 17β-HSD family share less than 30% similarity in their primary structure. The 17ß-HSDs are expressed in different patterns although in some cases overlapping. The different types of 17β-HSDs also differ in their substrate and cofactor specificities. In intact cells in culture the 17ß-HSDs catalyze the reaction in unidirectional form: 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. to the. (2000) Trends Endrocrinol Metab., 11: 421-7].

Due to its essential role in selective tissue regulation of sex steroid hormone activity, 17ß-HSDs may be involved in the production and development of estrogen-sensitive pathologies (eg, mammary, ovarian, uterine and endrometrial cancers, etc.) and pathologies sensitive to androgens (for example, prostate cancer, benign prostatic hyperplasia, acne, hirsutis or, etc.). In addition, it has been shown that many types of 17ß-HSD are involved in the pathogenesis of certain human conditions. For example, it is known that 17β-HSD3 is involved in the development of pseudohermaphroditism, 17β-HSD8 plays a role in polycystic kidney disease and 17β-HSD4 is related to the appearance of "bifunctional enzyme deficiency. the treatment of sex steroid sensitive diseases has been suggested by administration of specific inhibitors of the 17ß-HSDs enzymes, optionally in combination with powerful and specific antiestrogens and antiandrogens [Labrie F. et al. (1997) Steroids, .62: 148 -58] Due to the fact that each type of 17ß-HSD has a selective affinity to substrates, a directional activity (reductive or oxidant) in intact cells, and a particular tissue distribution, the selectivity of the action of the drug could be achieved by targeting a determined 17β-HSD isoenzyme. By means of the individual modulation of the determined 17β-HSD it is possible to influence or even control the local and paracrine concentration of estrogens and androgens in different target tissues. The best characterized member of the 17β-HSD family is 17β-HSD type 1 [EC 1.1.1.62]. This enzyme could be crystallized in different states of functionality (for example with and without ligand and / or co-factor). The 17ß-HSDl catalyzes in vitro the reduction as well as the oxidation between estrone (El) and estradiol (E2). However, under physiological conditions in vivo the enzyme only catalyzes the reducing reaction of estrone (El) to estradiol (E2). It was found that 17β-HSDl was expressed in a variety of hormone-dependent tissues, for example, in the placenta, mammary gland tissue or uterus and endometrial tissue, respectively. Estradiol by itself and especially compared to significantly less active estrone, is a very potent hormone that regulates the expression of a variety of genes by combining with the nuclear estrogen receptor and plays an essential role in the proliferation and differentiation of the cell Diana. Physiological as well as pathological cell proliferations may be dependent on estradiol. Especially many breast cancer cells are stimulated by a locally increased estradiol concentration. In addition, the appearance or course of benign pathologies, such as endometriosis, uterine leiomyomas (fibroids or myomas), adeno iosis, menorrhagia, metrorrhagia and dysmenorrhea depends on the existence of significantly elevated levels of estradiol. Endometriosis is a well-known gynecological condition that affects 10 to 15% of women of reproductive age. It is a benign disease defined as the presence of viable endometrial and stromal gland cells outside the uterine cavity. It is found most often in the pelvic area. In women who develop endometriosis, the endometrial cells that enter the peritoneal cavity by retrograde menstruation (which is the most likely mechanism) have the ability to adhere to the peritoneal wall and invade it and are then able to implant and proliferate. The implants respond to steroid hormones of the menstrual cycle similar to the endometrium in the uterus. Infiltration injuries and blood from these lesions that are unable to leave the body, produce 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 lesions. Some women with severe endometriosis are asymptomatic, while women with mild endrometriosis can have acute pain. Endometriosis is found in up to 50% of infertile women. However, at present no causal relationship between mild endometriosis and infertility has been proven. Moderate to severe endometriosis can produce tubal injury and adhesions that lead to infertility. The purpose of the treatment of endometriosis is pain relief, endometriosis resolution and restoration of fertility (if desired). The two most common treatments are surgery or anti-inflammatory and / or hormonal therapy or a combination thereof. Uterine leiomorphins (fibroids or myomas), benign clonal tumors, are produced from smooth muscle cells of the human uterus and appear clinically in up to 25% of women and are the most common individual cause for hysterectomy. They produce significant morbidity, including prolonged and intense menstrual bleeding, pelvic pain and pressure, urinary problems and, in isolated cases, reproductive dysfunction. The pathophysiology of myomas is not well understood. Fibroids are found submucosally (below the endometrium), intramurally (inside the myometrium) and subserosally (projecting out of the serosal compartment of the uterus), but most are mixed forms of those 3 different types. The presence of estrogen receptors in leiomyoma cells has been studied by Tamaya et al, [Tamaya et al, (1985) Acta Obstet Gynecol Scand., 64: 307-9]. It has been shown that the estrogen receptor ratios compared to the levels of 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, various medical therapies have been proposed to treat fibroids, including the administration of a variety of spheroids, such as the endogenous steroids danazol or gestrinone, GnRH agonists and progestogens, whose administration is frequently associated with a variety of severe side effects. All that has been said above regarding the treatment of uterine leiomyomas and • endometriosis also applies to other benign gynecological conditions, particularly adenomyosis, functional menorrhagia, and metrorrhagia. These benign gynecological disorders are all sensitive to estrogen and are treated in a comparable manner as described above in relation to uterine leiomyomas and endometriosis. The available pharmaceutical treatments, however, suffer from the same severe inconveniences, that is, they must be interrupted once the side effects become more serious than the symptoms to be treated and the symptoms reappear after the therapy is interrupted. Since the aforementioned benign and malignant pathologies are all dependent on 17β-estradiol, a reduction of the endogenous 17β-estradiol concentration in the respective tissues will result in a delayed or reduced proliferation of 17β-estradiol cells in said tissues . Therefore, it can be concluded that the selective inhibitors of the 17β-HSDl enzyme are very suitable for use to affect the endogenous production of estrogens, in particular of 17β-estradiol in fibroids, endometrio, adenomiótico and endometrial tissue. Application of a compound that acts as a selective inhibitor of 17β-HSDl that preferably catalyzes the reductive reaction will result in a lower intracellular estradiol concentration because the reducing conversion of estrone to the active estradiol is reduced or suppressed. Therefore, reversible or even irreversible inhibitors of 17β-HSDl may play a significant role in the prophylaxis and / or treatment of spheroid hormone-dependent conditions or diseases, particularly 17β-estradiol. In addition, reversible or even irreversible inhibitors of 17β-HSDl should not have estradiol receptor binding activity or only purely antagonistic activity, in particular to the estrogen receptor subtype a, because the estrogen receptor agonist binding would produce the activation and therefore, by regulation of a variety of genes, the proliferation and differentiation of the target cell. In contrast, estrogen receptor antagonists, so-called antiestrogens, combine competitively with the specific receptor protein, thus preventing access of endogenous estrogens to their specific binding site. It is now described in the literature that various severe malignancies, such as breast cancer, prostatic carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia can be treated by administration of a selective inhibitor of 17β-HSDl. In addition, a selective 17β-HSDl inhibitor may be useful for the prevention of the above-mentioned hormone-dependent cancers, especially breast cancer. Various reversible or irreversible inhibitors of the 17β-HSDl enzyme of spheroidal or even non-spheroidal origin are known in the literature. The characteristics of these inhibitory molecules, which may have a core structure similar to cofactor or substrate, have been published in the literature [summarized in Poirier D. (2003) Curr Med. Chem. 10: 453-77]. Another well-characterized member of the 17β-HSD family is the 17β-HSD type 3 enzyme (17β-HSD3). 17ß-HSD3 has a distinctive feature compared to other 17ß-HSDs: It is found expressed almost exclusively in the testes, while other isoenzyms are expressed more widely in various tissues. 17ß-HSD3 has a fundamental role in the biosynthesis of androgens and converts 4-androstene-3, 17-one (A) to testosterone (T). The biological significance of 17ß-HSD3 is of undeniable physiological importance. Mutations in the gene for 17β-HSD3 have led to a decreased formation of T in the fetal testes and thus to a human intersexual disorder called pseudoher male aphrodisit. [Geissier WM et al, (1994) Nat. Genet, 7: 34-9]. With respect to the indication of prostate cancer, primary cancer cells retain most of their response to androgens in their regulation of cell proliferation, differentiation and programmed cell death for some period. Currently, androgen deprivation is the only effective systemic hormone therapy available for prostate cancer. The development of selective inhibitors against 17ß-HSD3 is a novel therapeutic attempt for the treatment of androgen-dependent diseases [Labrie et al, (2000) Trends Endocrinol Metab., 11: 421-7], In addition, Oefelein et al, reported that the GnRH deposit analog fails in almost 20% of cases, in achieving levels of T castrated in men [Oefelein MG & amp; amp;; Cornum R (2000) J. Urol., 164: 726-9]. To improve the response regimen to endocrine therapy for men with prostate cancer, it may be important to selectively inhibit the testicular activity of 17β-HSD3. In addition to prosthetic cancer, many other androgen-sensitive diseases, ie, diseases whose 'initiation or progression is aided by androgenic activity, can be treated by selective inhibition of 17β-HSD3 activity. These diseases include, but are not limited to, benign hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome. In addition, considering the fact that 17ß-HSD3 is found mainly in the testes, the development of potent inhibitors may be of interest in blocking spermatogenesis and as an antifertility agent for men. Several reversible or irreversible inhibitors of 17β-HSD3 enzymes of spheroidal or even non-spheroidal origin are already known in the literature. The characteristics of these inhibitory molecules have been reported in the literature [summarized in: Poirier D. (2003) Curr Med. Chem. 10: 453-77].

For example, US Pat. No. 6,541,463 describes inhibitors for 17ß-HSD3 derived from androsterone. These derivatives have been synthesized by parallel chemistry of solid and liquid phase and some of these compounds showed an inhibitory activity 2 to 18 times higher than that of the natural substrate of the enzyme, A-dione, which in turn is useful in itself as inhibitor. In addition, the international patent application WO 01/42181 describes benzyl-tetralins, whose chemical structure is related to that of the phytoestrogen biocanin, as inhibitors of 17β-HSD3. In addition, international patent applications WO 98/32724, WO 98/30556 and WO 99/12540 describe tetralone, benzopyran and benzofuranone derivatives, which have an inhibitory activity of 17β-HSD for the treatment of hormone-sensitive diseases. The microsomal 17β-hydroxysteroid dehydrogenase from human endometrium and placenta (called 17β-HSD type 2 or 17β-HSD2) was cloned by expression cloning and found to be equally active using androgens and estrogens as substrates for oxidation [Andersson S. (1995) J. Steroid Biochem. Molec. Biol., 55: 533-534]. Recombinant 17β-HSD2 converts the highly active 17β-hydroxysteroids such as estradiol (E2), testosterone (T), and dehydrotestosterone (DHT) in its inactive ketonic forms. In addition, 17β-HSD2 can be used to a lesser extent to convert 20β-hydroxyprogesterone (20βP) to progesterone (P). The broad tissue distribution together with the predominantly oxidative activity of 17β-HSD2 suggests that the enzyme may play a special role in the activation of highly active 17β-hydroxysteroids resulting in decreased sexual hormonal action in the target tissues. Dong and colleagues showed significant 17β-HSD2 activity in cultured human osteoblasts and osteosarcoma cells similar to MG63 and TE85 osteoblasts, but not in SaOS-2 [Dong Y et al, (1998) J. Bone Min. Res., 13: 1539 -1546]. The potential for the interconversion of El to E2, T to A and DHT to A by bone cells may therefore represent an important mechanism for local regulation of the intracellular delivery of ligands to the estrogen and androgen receptors in osteoblasts and other cells sensitive to steroids. This modulation of steroid levels can be used for a wide variety of indications, including the following: for the prevention and treatment of osteoporosis, for the treatment of ovarian cancer, for the treatment of breast cancer, for the treatment of endometrial cancer , for the treatment of endometriosis, for the treatment of prostate cancer and / or for the treatment of loss of androgen-dependent hair. Several reversible or irreversible t-inhibitors of the 17β-HSD2 enzymes of spheroidal and even non-spheroidal origin are known in the literature. The characteristics of the inhibitory molecules have been summarized in the literature [Poirier D. (2003) Curr Med Chem. 10: 453-77]. In addition, international patent application WO 02/26706 describes inhibitors of 17β-HSD2 of non-spheroid origin. Some thienopyrimidone derivatives that have been reported as useful in therapy have been described in the literature. German patent application DE 2411273 (Schering AG) describes compounds with anti-inflammatory activity. Manhas et .al describes the synthesis and antiinflammatory activity of some substituted thienopyrimidinones [Manhas MS et al. (1072) J. Med. Chem. 15 (1) ': 106-107]. Kapustina et al. describes the synthesis and antibacterial and chemotherapeutic or antitubercular activity of some substituted thienopyrimidinones ([Kapustina MV et al. (1992) Khimiko-Farmatsevticheskii Zhurnal 26 (l): 56-7; and Kapustina MV et al. (1991) Khimiko-Farmatsevticheskii Zhurnal 25 (7): 38-9.] Other thienopyrimidinone derivatives have also been described but were not related to any medical use., 2,7,8,9,10,11,13-octahydro-13-oxo-4- (phenylthio) - [1] -benzothieno [2 ', 3': 4,5] pyrimido [1,2-a ] azepine-3-carboxyaldehyde (CAS Registration No. 333774-42-8) and 1,2,7,8,9,11,11,13-octahydro-13-oxo-4- (chloro) -] 1] -benzothieno- [2f, 3 ': 4, 5] -pyrimido [1,2- a] azepine-3-carboxyaldehyde (CAS Registration No. 299962-60-0) are commercially available. Other substituted thienopyrimidones have also been described, for example, 1, 2, 7, 8, 9, 10, 11, 13-octahydro-4-hydroxy [1] -benzothieno- [2 ', 3': 4, 5] -pyrimido [1, 2-a] azepin-13 (7H) -one (Register CAN 333774-26-8); 2,3,8,9,10, ll-hexahydro [l] benzothieno [2 ', 3': 4,5] dirimido [1,2-a] azepin-4, 13 (1H, 7H) -dione (CA Registration No. 141581-80-8); 2,3,8, 9-tetrahydro [1] benzothiens [2,3-d] pyrrolo [1,2-a] pyrimidin-6, 10 (1H, 7H) -dione (CA Registration No. 141581-81- 9), 8, 9, 10, 11-tetrahydro-4-hydroxy- [1] -benzothieno- [2 ', 3': 4, 5] -pyrimido [1,2-a] azepin-13- (7H) -ona (CA Registration No. 333789-19-1); 3-Butyl-2, 7-dimethyl-4b, 5,6,7,8, 8a-hexahydro-3H-benzo- [4,5] -thieno [2,3d] pyrimidin-4-one (CA Registration No. 39625-80-4;) 1, 2, 3, 4, 5, 8, 9, 10, 11, 12-decahydro-14H-cyclohepta- [4 ', 5'] -thieno [2 ', 3': 4 , 5] pyrimido- [1,2-a] azepin-14-one-4-oxime (Ca. Registration No. 299962-59-7); 1,2,3,4,5,8,9, 10,11,12-decahydro-14H-cyclohepta- [4 ', 5'] -thieno- [2 '3':, 5] pyrimido- [1, 2-a] azepin-14-one-3-oxime (CA Registration No. 296798-31-7); 1, 2,3,4,7,9,10,12-octahydro-12-oxo-8H- [l] benzothieno [2,3-d] pyrido [1,2-a] pyrimidine-7-carboxylic acid ethyl ester (CA Registration No. 239059-69-0); 1, 2, 3, 4-tetrahydro-12H- [l] benzothieno [2,3-d] pyrido [1,2-a] pyrimidin-12-one (CA Registration No. 60943-07-9), and 3-methyl-2, 3, 4, 7, 8, 9, 10, 11-octahydro- [1] -benzothieno- [2 ', 3': 4, 5] -pyrimido- [1,2-a] azepin -13 (lH) -one (CA Registration No. 677320-14-8). However, to the best of the knowledge and understanding of the inventors, none of the compounds described above has been described as being useful in the treatment and / or prevention of a disease or condition dependent on steroid hormones, particularly a disease or condition dependent on steroid hormones. which requires the inhibition of the enzyme 17β-hydroxysteroid dehydrogenase (17HSD) type 1, type 2 and type 3. There is a need for the development of compounds that selectively inhibit the enzyme 17β-HSDl, 17β-HSD3 and / or 17β-HSD2 while which desirably do not substantially inhibit other members of the 17β-HSD family of proteins or other catalysts of sex steroid degradation or activation. In particular the purpose of the present invention is to develop selective inhibitors of the 17β-HSD1 enzyme, and that in addition the compounds lack affinity for antagonistic binding to the estrogen receptor or only have a purely antagonistic binding affinity (both subtypes a and β ).

THE INVENTION Therefore, the purpose of the present invention is to develop new inhibitors of the enzyme 17β-HSD1 and 17β-HSD2, which have valuable pharmacological properties and which are suitable for the treatment of conditions "and estrogen-dependent diseases. Another purpose of the present invention is to develop new inhibitors of the 17β-HSD3 enzyme which have valuable pharmacological properties and which are suitable for the treatment of androgen-dependent diseases and conditions.It has now been found that the thiophene-pyrimidinone derivatives of The present invention would be effective in therapy and especially in the treatment or prevention of diseases or conditions dependent on steroid hormones, such as diseases or conditions dependent on steroid hormones that require the inhibition of 17β-hydroxysteroid dehydrogenase (HSD) enzymes. In particular, the compounds of the formula (I) represent they have potent inhibitors of the 17β-HSDl, 17β-HSD3 and / or 17β-HSD2 enzyme and possess valuable pharmacological properties for the treatment and / or prophylaxis of steroid-dependent diseases or malignancies, such as breast cancer, prostatic carcinoma, cancer ovarian cancer, uterine cancer, endometrial cancer or endometrial hyperplasia, but also for the treatment and / or prophylaxis of benign diseases or conditions dependent on steroids, such as endometriosis, uterine fibroids, uterine leiomyomas, adenomyosis, dysmenorrhea, menorrhagia, prostadynia, prosthetic hyperplasia benign, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome or urinary dysfunction. Other estrogen-dependent diseases that can be treated or prevented with an effective amount of the compound of the invention are multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue lesions, skin wrinkles and cataracts. In addition, the compounds of the formula (I) may be useful for the prevention and treatment of osteoporosis and for blocking spermatogenesis and as a male antifertility agent.

Therefore the present invention relates to the use of a compound of the structural formula (I) wherein Ri and R represent the same or different alkyl, or one is alkyl and another is H, or Ri and R2 form together with the carbon atoms which are attached, a cyclic system of 5-, 6-, 7- or 8 members, which is saturated or containing one or more double bonds between the ring atoms, said ring optionally containing up to two heteroatoms in addition to the nitrogen atom to which Ri is attached, where 0-2 is the number of N and 0 atoms -1 the number of O or S atoms respectively, and wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl or arylalkyl, wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido; R3 and R form together with the carbon atoms to which a 5-, 6-, 7- or 8-membered hydrocarbon cyclic system is attached, which is saturated or which contains one or more double bonds between the carbon atoms, and in wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, said aryl group being optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxy, acyl, carboxyl, thiocarboxyl, and amido; except 1, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (phenylthio) - [1] -benzothieno [2 ', 3': 4,5] pyrimido [1, 2 , -a] azepine-3-carboxyaldehyde; for the preparation of a medicament for the treatment and / or prevention of a disease or condition dependent on steroid hormones, preferably for a disease or condition dependent on steroid hormones that requires the inhibition of a 17β-hydroxysteroid dehydrogenase enzyme (17β-HSD) , most preferably requiring the inhibition of the 17β-HSD enzyme of type 1, 17β-HSD type 2 or 17β-HSD type 3. According to another aspect the present invention relates to a compound of the formula (II) (ID where Ri and R2 represent the same or different Ci-Cd alkyl one is C-Cs alkyl and the other is H, or Ri and R2 form together with the carbon atoms to which a cyclic ring system is attached. 5-, 6-, 7- or 8 members, which is saturated or which contains one or more double bonds between the ring atoms, said ring optionally containing up to two nitrogen atoms in addition to the nitrogen atom to which Ri is attached, the ring being optionally substituted with up to two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, whose aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo , halogen, amino, oxime, acyl, carboxyl, thiocarboxyl and amido, the hydrocarbon chain -C (R5) -C (R6) C (CH) n- of the cyclic system adjacent to the thiophene ring is saturated or contains one or more double bonds between carbon atoms; n is an integer from 1 to 4, and R5 and R6 are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or aryl, whose aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxy, acyl, carboxyl, thiocarboxyl, already gone; with the proviso that in the case where n represents the numbers 1, 2 or 3, and R1 and R2 are independently selected from hydrogen or C? _4 alkyl, or that together they form an unsubstituted alkylene group of three to five groups methylene or an imino-alkylene group of two to four methylene groups in the alkylene group, optionally substituted on the N atom, then at least (i) R5 or R6 must be other than hydrogen, C _ C4-alkyl or alkylcarboxyl, or ( ii) the hydrocarbon chain -C (R5) C (R6) - (CH) n of the cyclic system adjacent to the thiophene ring must be unsaturated or aromatic; in the case where n represents 2 and R1-R2 form an unsubstituted alkylene group of 3 to 5 methylene groups and R5 represents a hydroxyl or oxo group, then R6 must be other than bromine, dibromo or phenylthio, or in the case of where n represents 2 and R1-R2 form an unsubstituted pentamethylene group, and R6 represents carbonyl, then R5 must be other than phenylthio; for use in therapy. A third aspect of the present invention relates to a new compound of the formula (II) wherein Ri and R2 represent alkyl radicals of C__C8 equal to or different from each other or one of them is alkyl of C? _Cs and the other is H, or Ri and R2 form together with the carbon atoms to which a cyclic system is attached of 5-, 6-, 7- or 8 members, which is saturated or which contains one or more double bonds between the ring atoms, the ring optionally containing up to two N atoms in addition to the nitrogen atom to which Rx is attached, the ring is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl or arylalkyl, which aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and ainido; the hydrocarbon chain -C (R5) -C (R6) - (CH) n- of the cyclic system adjacent to the thiophene ring is saturated or contains one or more double bonds between the carbon atoms; n is an integer from 1 to 4, and R5 and R6 are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or alkylaryl, which aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxy, acyl, carboxyl, thiocarboxyl and amido, with the proviso that in the case where n represents 1, 2 or 3, and R1 and R2 are independently selected from hydrogen or C alquilo_C alkyl or form together an unsubstituted alkylene group of 3 to 5 methylene groups or an iminoalkylene group of 2 to 4 • methylene groups in the alkylene group, optionally substituted on the N atom, then (i) at least R5 or R6 must be other than hydrogen, C? _4 alkyl, alkylcarboxyl or = N-OH, or (ii) the hydrocarbon chain -C (R5) -C (R6) - (CH) n- of the cyclic system adjacent to the The thiophene ring must be unsaturated or aromatic; in case n represents 2 and R1-R2 form an unsubstituted alkylene group of 3 or 5 methylene groups, and R5 represents a hydroxyl or oxo group, then R6 must be different from hydrogen, bromine, dibromo or phenylthio; in the case where n represents 2 and R1-R2 form an unsubstituted pentamethylene group, and R6 represents carbonyl, then R5 must be other than phenylthio or chloro; in the case where n represents 2, the hydrocarbon chain -C (R5) -C (R6) - (CH) n- of the cyclic system adjacent to the thiophene ring is saturated and R1-R2 together with the carbon atoms at the which are bonded form an unsubstituted pyridine ring, then at least one of R5 or R6 must be other than hydrogen; or in the case where -C (R5) -C (R6) - (CH) n- represents an unsubstituted tetramethylene group, then R1-R2 must be other than a tetramethylene group substituted with a carboxyethyl ester group. According to a fourth aspect, the invention relates to a pharmaceutical composition comprising as active agent a compound of formula (II) as defined herein, for which a use in therapy has not been previously published, and less a pharmaceutically acceptable vehicle. According to a fifth aspect, the invention relates to the use of a compound of the formula (I), preferably of the formula (II) as defined herein, for the treatment or prevention of a disease or condition dependent on a spheroid hormone. Preferably the steroid hormone-dependent disease or condition is a disease or condition that requires the inhibition of a 17β-hydroxysteroid dehydrogenase enzyme, preferably 17β-HSD type 1, 17β-HSD type 2, or 17β-HSD type 3.

According to a sixth aspect, the invention relates to a method of preparing the new compounds of the formula (I), in which a) a compound of the formula or an analog thereof modified in the ring or substituted in the ring, is oxidized, preferably by the action of PCC and celite, to give an oxo-substituted compound of the formula 3 or its analog, b) the oxo-substituted compound of step a) is optionally further subjected to the reaction of Vilsmeier, preferably by P0C13-DMF, to give a carbonyl-substituted compound of the formula 4 or its analog, c) the chloro substituent on the carbonyl substituted compound obtained in step b) is optionally replaced by an alkylthio or arylthio group by subjecting it to the action of a suitable thiol in the presence of a base to give a compound substituted with arylthio or alkylthio of the Formula 5 or its analog, d) the compound substituted with arylthio or alkylthio obtained in step c) is then optionally i) reduced to a compound of formula 6, ii) or reacted with NH 2 OH to give a compound of the formula 7, e) the compound obtained in step b) is optionally i) reduced to replace the carbonyl group with hydroxyalkyl, or ii) subjected to the action of a suitable thiol in the presence of a base and acetone to replace the chloro substituent with a thiol group and to replace the carbonyl group with oxo-substituted alkenyl, of) the compound obtained in step a) is optionally subjected to the action of acetal DMF to introduce a dimethylaminomethylene substituent into the ring adjacent to the oxo substituent.

DETAILED DESCRIPTION OF THE INVENTION Definitions The following terms are used to describe the various constituents of the chemical compositions useful for the present invention. These terms are defined as follows: In the present the term "comprising" e "including" is used in a non-limiting open sense. The word "compound" is understood to cover any and all isomers, (e.g., enantiomers, stereoisomers, diastereomers, rotomers and tautomers), racemates or any mixture of isomers, prodrugs, and any pharmaceutically acceptable salt of the compound. When the plural form is used for compounds, salts and the like, this also refers to the individual compound, salt or the like. The term "substituted" means that the specified group or moiety of the compound carries one or more substituents. When a group can have multiple substituents and a variety of possible substituents are provided, the substituents are independently chosen and do not have to be the same. The term "unsubstituted" means that the specified group does not carry any substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. Any asymmetric carbon atoms can exist in a configuration (R) -, (S) - or (R, S) -, preferably in the (R) or (S) configuration, whichever is more active. Substituents in a double bond or in a ring can exist in the cis- (= Z ~) or trans (= E-) form. The compounds of the present invention may contain asymmetric centers in the molecule, according to the nature of the various substituents. In some cases there may also be asymmetry due to restricted rotation around the central bond that binds the two aromatic rings of the specified compounds. It is the intention that all isomers (including the enantiomers and diastereomers), either by the nature of the asymmetric centers or by restricted rotation as described above, in the form of separate, pure or partially purified isomers or racemic mixtures thereof , are included in the scope of the present invention. The term "halogen" refers to fluorine (F, fluoro-), (Br, bromine), chlorine (Cl, chlorine), and iodine (I, iodine). In the context of the present invention, Br, Cl, and F are preferred. The terms "dihalogen", "trihalogen" and "perhalogen" refers to two, three and four substituents, respectively, each individually selected 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 "uncle" refers to the group = S. The term "thiol" refers to the group -SH. The term "sulfonyl" refers to the group -S (0)? 2- For the purposes of the present invention, the carbon concentration of the various residues containing hydrocarbon fractions is indicated by a prefix that designates the minimum and maximum amount of carbon atoms in the remainder, ie the prefix Ci-C-, defines the amount of carbon atoms present from the whole number "i" to the whole number "j" inclusive. Thus C 1 -C 4 alkyl refers to alkyl radicals of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and their isomeric forms. The term "alkyl" refers to a hydrocarbon radical which may be linear, cyclic or branched, with single or multiple branching, and wherein the "alkyl" group comprises 1 to 12 carbon atoms. In one embodiment, the term "alkyl" refers to a straight or branched alkyl chain (with single or multiple branching) of 1 to 8 carbon atoms exemplified by the term (C 1 -C 3) -alkyl, preferably, from 1 to 4 carbon atoms exemplified by the term alkyl of (C? -C4). The term alkyl of (C? -Cs) is further exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, tertiary pentyl, 2- or 3-methylpentyl, n-hexyl, isohexyl and the like. The alkyl group can be partially unsaturated to form groups, such as, for example, methylenyl, ethenyl, ethylene, propenyl (allyl), methyl-propenyl, butenyl, pentenyl, pentynyl, hexenyl, octadienyl, and the like. The term "alkyl" also comprises cycloalkyl, preferably (C-C8) alkyl groups which refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and isomeric forms thereof, such as methylcyclopropyl, 2- or 3-methylcyclobutyl , 2-, or 3-methylcyclopentyl, and the like. The cycloalkyl group may also be partially unsaturated to form groups such as, for example, cyclohexenyl, cyclopentenyl, cyclooctadienyl, and the like. In addition the term "alkyl" comprises a cycloalkyl-alkyl group of 4 to 12 carbon atoms, preferably "(C3-C8) alkyl (C__C4) alkyl", which refers to an alkyl group of 1 to 4 carbon atoms. carbon as described above substituted with a (C3-C8) alkyl group as described above, forming groups such as, for example, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, or cyclohexylethylethyl. The term "substituted alkyl" refers to alkyl as described above substituted with up to five, more preferably up to three, and most preferably with one or two substituents independently selected from the group consisting of halogen, hydroxyl, thiol, nitro, nitrile , alkoxy, aryloxy, acyloxy, amino, imino, oxime, amido, acylamino, alkylthio, arylthio, acyl, carboxyl, sulfamoyl, sulfonamide, and alkylsulfonyl, as defined herein. These groups can be attached to any carbon atom of the alkyl moiety. A substituted alkyl group is preferably substituted with hydroxyl, halogen, C?-C4-alkoxy, C?-C8-alkyl-thio, arylthio, preferably phenylthio, an -alkyl-acyl group -CO-R ", a carbonyl group ~ (C = 0) -0R ", an alkylamino group -NR" 2, an alkylimino group = NR ", or an alkyloxime group = N-0-R", wherein R "represents hydrogen or C? -C alkyl. Preferably substituted alkyl refers to substituted C 1 -C 4 alkyl, preferably methyl, substituted methylene and C 2 -C 4 -substituted alkenyl. The term "alkoxy" refers to a group -OR, where R can be alkyl, arylalkyl, substituted arylalkyl, as defined herein, wherein the alkyl chain may be optionally further substituted as defined herein. Preferably the term "alkoxy" refers to O-alkyl of (C? _C4) (or (C? _ C4) alkoxy), with the alkyl group of (C1-C4) defined as indicated above, or to -0- ( C? _ C4) alkyl-phenyl, preferably benzoxy or phenethyloxy, optionally substituted on the aryl group with up to five independently selected substituents and in particular hydroxyl, halogen, (C? _C4) alkyl or (C? _C) alkoxy, with up to five being the number of substituents for halogen, and up to three for any combination of said other substituents. The term "aryloxy" refers to the group -OAr, wherein Ar can be aryl or substituted aryl, as defined herein. Preferably Ar represents aryl as defined herein, optionally substituted on the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, (C__C4) alkyl or (C__C), the amount of 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 in the above indicated manner. The term "acyloxy" refers to the group -0-CO-R, wherein R may be alkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, as defined above, and wherein the alkyl chain may optionally be further replaced. The term "alkylacyloxy" represents a preferred selection of the term "acyloxy" refers to a group -0-C0-C-C12 alkyl, preferably -O-CO-C-C8 alkyl and more preferably -O-CO -alkyl of C__C4. The term "arylacyloxy" represents a preferred selection of the term "acyloxy" and refers to the group -O-CO-Ar wherein Ar represents aryl, as defined herein, preferably phenyl, optionally substituted in the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy, with up to five being the number of substituents for halogen and up to three for any combination of the other substituents. The term "acyl" refers to a group - (C = 0) -R, wherein R can be hydrogen, alkyl, aryl or aryl-alkyl of (C__C4) (both optionally substituted on the aryl group, with independently selected substituents as defined herein). Preferably the term "acyl" refers to a group - (C = 0) -R ', wherein R' represents hydrogen, (C 1 -C 4) alkyl, phenyl, or phenyl-(C 1 -C 4) alkyl, preferably benzyl 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 of (C? _C). The term "arylacil" represents a preferred selection of the term "acyl" and refers to the group -CO-Ar, wherein Ar represents aryl as defined herein, preferably phenyl, optionally substituted on the aryl group as defined in ' the present. The term "carboxyl" refers to a group - (C = 0) -OR, wherein R can be hydrogen, alkyl, substituted alkyl, aryl or aryl-alkyl (C? _C4) (both optionally substituted on the aryl group with independently selected substituents as defined herein), as defined herein. Preferably the term "carboxyl" refers to a group - (C = 0) -OR ', wherein R' represents hydrogen, (C 1 -C 4) alkyl phenyl, or (C 1 -C 4) -phenyl alkyl, preferably benzyl, wherein the phenyl moiety can be optionally substituted with substituents independently selected from the group comprising hydroxyl, halogen, (C__C4) alkoxy, alkyl (C? _C4), with up to five being the number of substituents for halogen and up to three for any combination of said substitutesites. The term "alkylcarboxyl" represents a preferred selection of the term "carboxyl" and refers to a group ~ (C = 0) -OR, where R is hydrogen or C ?C 4 alkyl. The term "thiocarboxyl" refers to a group - (C = 0) -SR wherein R can be hydrogen, alkyl, substituted alkyl, aryl or aryl (C? -C) alkyl (both optionally substituted in the aryl group with substituents independently selected as defined herein), as defined herein. Preferably the term "thiocarboxyl" refers to a group - (C = 0) -SR ', wherein R' represents hydrogen, (C 1 -C 4) alkyl, phenyl, or (C 1 -C 4) -phenyl alkyl, preferably benzyl, wherein the phenyl moiety can be optionally substituted with substituents independently selected from the group comprising hydroxyl, halogen, (C? _ C4) alkoxy, (C? _ C4) alkyl, with up to five being the number of substituents for halogen and up to three for any combination of said substituents. The term "alkylthio" ("alkylsulfanyl") and "alkylsulfonyl" refers to a group -SR and S (O) n =? - 2-R, respectively, wherein R can be alkyl, substituted alkyl, arylalkyl or substituted arylalkyl, as defined herein. Preferably, the term "alkylthio" ("alkylsulfanyl") refers to a group -SR 'and the term "alkylsulfonyl" refers to a group -S (0) n =? - 2- R', respectively, wherein R 'represents alkyl of (C? _C4), or (C? _4) -phenyl alkyl, preferably benzyl, optionally substituted on the alkyl chain with up to three substituents as defined herein, preferably hydroxyl, (C1-C4) alkoxy ) or halogen.

The term "arylthio" (arylsulfa ilo ") and" arylsulfonyl "refers to a group -S-Ar and -S (0) n =? - 2-Ar, respectively, where Ar represents aryl or substituted aryl, as defined in the present Preferably Ar represents aryl, optionally substituted on the aryl group, with independently selected substituents as defined herein, particularly hydroxyl, halogen, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy, being up to five the amount of halogen substituents and up to three for any combination of the other substituents.Preferably arylthio refers to phenylsulfamyl, optionally substituted as defined above.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, as defined herein, particularly hydroxyl, halogen, or (C1-C4) alkoxy), or aryl-alkyl of (C? _C4) (both optionally substituted on the aryl group with up to five independently selected substituents as defined herein, particularly hydroxyl, halogen, (C? _4) alkyl or (C1-) alkoxy C4), with up to five being the amount of substituents for halogen and up to three for any combination of said other substituents, as defined herein.

The term "alkylamino" represents a preferred selection of the term "amino" and refers to the term -NRR ', wherein R and R' may independently be hydrogen or (C? -C) alkyl. The term "imino" refers to the group = NR, where R can be hydrogen, alkyl (optionally substituted on the alkyl chain with up to five independently selected substituents, as defined herein, particularly hydroxyl, halogen, or (Ci-C4) alkoxy, aryl or aryl-alkyl of (C1 -C4) (both optionally substituted in the aryl group with up to five independently selected substituents as defined herein, particularly hydroxyl, halogen, (C__C4) alkyl or (C1-C4) alkoxy, with up to five being the number of substituents for halogen and up to three for any combination of said other substituents, as defined herein The term "alkyl imino" represents a preferred selection of the term "imino" and refers to the group = NR, where R can be hydrogen or alkyl of (C? _ C4) The term "oxime" refers to the group = N-OR, where R can be hydrogen, alkyl (optionally substituted on the alkyl chain with up to five independent substituents) selected as defined herein, particularly hydroxyl, halogen, or '(C 1 -C 4) alkoxy, aryl or aryl (C 1 -C 4) alkyl (both optionally substituted on the aryl group with up to five substituents independently selected as defined herein, particularly hydroxyl, halogen, (C_-C4) alkyl or (C1-C4) alkoxy, with up to five being the number of substituents for halogen and up to three for any combination of said other substituents, as defined herein. The term "alkyl oxime" represents a preferred selection of the term "oxime" and refers to the group = N-0-R, where R can be hydrogen or alkyl of (C? _C_). 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, particularly hydroxyl, halogen or (C 1 -C 4) alkoxy, aryl or aryl (C 1 -C 4) alkyl (both optionally substituted on the aryl group with independently selected substituents as defined herein, particularly hydroxyl, halogen, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy, with up to five being the amount of substituents for halogen and up to three for any combination of the other substituents) as defined herein. The term "alkylamido" 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 and (C__C) alkyl. The term "aryl" refers to an aromatic carbocyclic group of 6 to 14, preferably 6 to 10, carbon atoms and having at least one aromatic ring or multiple fused rings wherein at least one ring is aromatic. Preferably aryl is phenyl, naphthyl, indanyl, indenyl, fluorenyl, 1, 2, 3, 4-tetrahydronaphthalene-1-yl or biphenyl. The aryl group can be optionally substituted with substituents independently selected from the group comprising halogen, hydroxyl, (C? -C6) alkoxy, (C? -Cg) alkyl, oxo, thiol, carboxyl, aryloxy or arylalkyloxy (both optionally substituted on the aryl moiety with independently selected substituents as defined herein), (C? -C6) alkylthio, arylthio or arylalkylthio (both optionally substituted on the aryl moiety with independently selected substituents as defined herein), amino, amido, acyl , and acylamino, as defined herein, with up to five being the amount of substituents for halogen and up to three for any combination of said other substituents. Substituted aryl is preferably substituted with substituents selected from the group comprising (Ci-Cg) alkoxy, preferably methoxy, hydroxyl, (C 1 -C 4) alkyl, halogen, with up to five being the number of substituents for halogen and up to four and preferably up to three for any combination of said other substituents. Preferably substituted aryl is substituted phenyl. The term "arylalkyl" refers to an alkyl group substituted with up to three independently selected aryl groups; preferably the term "arylalkyl" refers to "aryl-alkyl of (C? _C4) or diaryl-alkyl of (C? _C4) where aryl is the aryl group defined above." Alkylaryl is preferably benzyl (-CH2- phenyl) or phenethyl (-CH2-CH2-phenyl) The term "substituted arylalkyl" refers to an arylalkyl group as defined above wherein the aryl group is substituted in the manner defined above. ", as used herein, represents derivatives of the compounds of the invention which are precursors of the drugs which after release to a patient release the drug in vivo through a chemical or physiological process. In particular, the drugs are derivatives of the compounds of the invention, the functional groups of which carry additional substituents which can be split up under physiological conditions in vivo, thus releasing the active principle of the compound (e.g. I am a pro-drug when it is taken to physiological pH or that through an enzymatic action is converted to 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 compound of the invention is administered. The pharmaceutically acceptable salts of the compounds of the formula (I) include conventional and stoichiometric acid addition salts or conventional and stoichiometric base addition salts formed from non-toxic organic or inorganic acids or bases. Acid addition salts, for example, of compounds of the formula (I) with a basic nitrogen atom are preferably formed with organic or inorganic acids: Suitable inorganic acids are, for example, halogenated acids, such as, for example, hydrochloric acid, sulfuric or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic or sulphonic acids, for example, acetic, propionic, glycolic, lactic, hydroxybutyric, malic, maleic, malonic, salicylic, fumaric, succinic, adipic, tartaric, citric, glutaric, 2 - or 3-glycerophosphonic and other mineral and carboxylic acids known to experts in these techniques. The salts are prepared by contacting the basic form 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 organic or inorganic bases. Examples of suitable bases for salt formation include, but are not limited to, inorganic bases, such as alkali metal or alkaline earth metal hydroxides, (eg, sodium, potassium, lithium, calcium, or magnesium), and those derived from hydroxides. of ammonium (for example, a quaternary ammonium hydroxide, such as tetramethylammonium hydroxide). Also taken into account are salts formed with pharmaceutically acceptable amines, such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine, benzylamines, piperidines, pyrrolidines and the like. Some compounds will be acidic in nature, for example, compounds having a carboxyl group or a phenolic hydroxyl group. The salts of the phenols can be prepared by heating the acidic compounds with any of the above-mentioned bases following conventional procedures well known to those skilled 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 phrase "effective amount" used herein means an amount of a compound or composition sufficient to significantly and positively modify the conditions and / or symptoms 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 to be treated, the severity of the condition, the duration of the treatment, the nature of the concurrent therapy, and the particular active ingredient used, excipients / pharmaceutically acceptable vehicles used and similar factors included in the knowledge and expertise of the attending physician.

Preferred Modalities According to a preferred embodiment of the present invention, the compound used for the manufacture of a medicament for the treatment and / or prevention of a spheroidal hormone-dependent disease or condition, preferably a disease or condition dependent on steroid hormones that it requires the inhibition of an enzyme 17β-hydroxysteroid dehydrogenase, and most preferably requires inhibition of the enzymes 17β-HSD type 1, 17β-HSD type 2, or 17β-HSD type 3, is defined as follows: the compound has the formula (II) wherein Ri and R2 represent the same or different alkyl of C? _CB, or one is C? _C8 alkyl and the other is H, or Ri and R2 form together with the carbon atoms to which they are attached a cyclic 5-, 6-, 7- or 8 members, which is saturated or which contains one or more double bonds between the ring atoms, the ring optionally containing up to two nitrogen atoms in addition to the nitrogen atom to which R_ is attached, and wherein the ring is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl or arylalkyl, the group being optionally substituted aryl, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido; the hydrocarbon chain -C (R5) -C (R6) - (CH) n- of the cyclic system adjacent to the thiophene ring is saturated or contains one or more double bonds between carbon atoms, n is an integer from 1 to 4 , and R5 and R6 are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or arylkyl, the group being optionally substituted aryl, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen , amino, oxime, acyl, carboxyl, thiocarboxyl, and amido; provided that such a compound is not 1,2,7,8,9,11,13-octahydro-13-oxo-4- (phenylthio) - [i] -benzothieno- [2 ', 3': 4,5] -pyrimido: 1, 2-a] azepine-3-carboxyaldehyde. In a preferred embodiment, the compound of the formula (II) is characterized in that the cyclic system of 5, 6, 7 or 8 members formed by Ri and R2 is optionally substituted with up to two substituents independently selected from the group consisting of oxo, - CO-R, -CO-OR, -OR, C? -C4 alkyl, optionally substituted with -OR, -SR or N (R) 2; R5 and R6 are individually selected from the group consisting of hydrogen, oxo, halogen, -OR ', -SR', -SO-R ', -CO-R, -CO-OR, or-C1-C4 alkyl, alkenyl of C? _C4, or = alkylene of C? _C4, optionally substituted on the alkyl chain with -0-R, -SR, -N (R) 2, -CO-R, or = N-0-R, wherein R represents hydrogen or C 1 -C 4 alkyl; and R 'represents hydrogen, C?-C8 alkyl, which may be linear, cyclic or branched, aryl-C?-C4 alkyl, preferably benzyl or aryl, preferably phenyl. Especially preferred compounds are those in which Ri and R2 together with the carbon atoms to which they are attached form a cyclic system of 5-, 6-, 7- or 8-membered, optionally substituted, which is saturated or which contains one or more double bonds between the ring atoms, the ring optionally containing up to two nitrogen atoms in addition to the nitrogen atom to which Ri is attached. Particularly preferred compounds of the formula (II) are those in which R5 is selected from the group consisting of hydrogen, oxo, halogen, -OH, -0-C? _C4-alkyl, -S-alkyl of C__C, -S- C3-C3-cycloalkyl, -S-phenyl, -S0-phenyl. Other preferred compounds of the formula (II) are those in which R6 is selected from the group consisting of hydrogen, carbonyl, alkylcarboxyl, preferably -COOH, -alkyl of C? _C4, -alkenyl of C__C, or = alkylene of C_-. C4 / optionally substituted on the alkyl chain with -OR, -N (R) 2, -CO-R, or = N-0-R, wherein R represents hydrogen or alkyl of. C__C4. In a preferred embodiment, the invention relates to compounds selected from the group consisting of the following illustrative compounds: 2,3,8,9,10, 11-hexahydro [1] benzothieno [2 ', 3':, 5] pyrimido [1, 2-a] azepin-4, 13 (1H, 7H) -dione; 1,2,6,7,8,9, 10-heptahydrocyclopenta [4 ', 5'] thieno- [2 ', 3': 4, 5] -pyrimido] -!, 2-a] ~ azepin-3, 12-dione; • 1,2, 3, 4, 8, 9, 10, 11, 12-nonahydrocyclohepta [4 ', 5'] thieno- [2 ', 3': 4, 5] pyrimido- [1,2-a] azepin- 5 (5aH), 14-dion-a; -l, 2,7,8,9,10, 11, 12-octahydro [l] benzothieno [2 ', 3': 4,5] pyrimido- [1,2-a] azocin-4, 14 (3H) -diona; • 1, 2, 3, 4, 7, 8, 9, 10-octahydro-12H- [1] benzothieno [2,3-d] pyrido- [1,2-a] pyrimidin-12-one; 5,6-dihydro-2,3-dimethyl [1] benzothieno [2,3-d] pyrimidin-4,8 (3H, 7H) -dione; 5,6-dihydro-3-methyl [1] benzothieno [2,3-d] pyrimidin-4,8 (3H, 7H) -dione; 5,6-dihydro-3-ethyl-2-methyl [1] benzothieno [2,3-d] pyrimidin-4,8 (3H, 7H) -dione; 4-chloro-l, 2, 3, 7, 8, 9, 10, 11, 12-octahydro [1] benzothieno- [2 ', 3': 4, 5] pyrimido [1,2-a] azocin-14 -one-4-carboxyaldehyde; 1,2,3,4,5,8,9,10,11, 12-decahydro-14H-cyclohepta [4 ', 5'] thieno- [2 ', 3': 4,5] pyrimido [1,2 -a] azepin-14-one; 8-chloro-5,6-dihydro-3-methyl [l] benzothieno [2,3-d] pyrimidin-4 (3H) -one-7-carboxyaldehyde; 1,2,7,8,9, 10,11,13-octahydro-13-oxo-4- (ethylthio) [1] enzotiene- [2 ', 3':, 5] pyrimido- [1,2-a ] azepine-3-carboxyaldehyde; 1, 2,7,8,9,10,11,13-octahydro-13-oxo-4- (propylthio) [1] -benzothieno- [2 ', 3': 4, 5] -pyrimido- [1, 2-a] azepine-3-carboxyaldehyde; l, 2,7,8,9,10,11,13-octahydro-13-oxo-4- (butylthio) [1] benzo-thieno [2 ', 3': 4,5] pyrimido- [1,2 -a] azepine-3-carboxyaldehyde; 1, 2,7,8,9,10,11,13-octahydro-13-oxo-4- (isopropylthio) [1] benzo-thieno [2 ', 3': 4,5] pyrimido [1, 2 a] azepine-3-carboxyaldehyde; 1,2,7,8,9,10,11,13-octahydro-13-oxo-4- (t-butylthio) [1] benzo-thieno [2 ', 3': 4,5] pyrimido [1, 2-a] azepine-3-carboxyaldehyde; 1,2,7,8,9,10,11,13-octahydro-13-oxo-4- (cyclopentylthio) - [1] benzo-thieno [2 ', 3'; 4,5] pyrimido- [1, 2-a] azepine-3-carboxyaldehyde; 1, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (cyclohexylthio) [l] benzo-thieno [2 ', 3': 4, 5] -pyrimido- [1, 2-a] azepine-3-carboxyaldehyde; 1,2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (phenylthio) [1] benzothieno- [2 ', 3': 4,5] -pyrimido [1,2- a] azepine-3-hydroxymethyl; 1,2,7,8,9,10,11,13-octahydro-13-oxo-4- (cyclohexylthio) [1] benzo-thieno- [2 ', 3': 4,5] -pyrimido [1, 2-a] azepine-3-hydroxymethyl; Octahydro-13-oxo-4- (phenylthio) [1] benzothieno [2 ', 3': 4,5] pyrimido- [1,2-a] azepin-3-oxime-methyl; 4-chloro-l, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo] 1] benzothieno- [2 ', 3': 4,5] pyrimido [1,2-a] azepin -3-hydroxymethyl; 3-N, N-dimethylamino-methylene-2,3,8,9,10, 11-hexahydro [1] benzo-thieno [2 ', 3': 4,5] pyrimido [1,2-a] azepin- '4.13 (1H, 7H) -dione; 1, 2,7,8,9,10,11,13-octahydro-13-oxo-4- (propylthio) [1] benzo-thieno [2 ', 3':, 5] pyrimido- [1,2- a] azepin-3- (3-oxo) butene-1, yl, 2,7,8,9,10,11,13-octahydro-13-oxo-4- (butylthio) [l] benzothien- [2 '] , 3'; 4, 5] pyrimido- [1,2-a] azepin-3- (3-oxo) butene-1, 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 considered to fall within the scope of the present invention. The invention also relates to pharmaceutical compositions comprising one or more of the compounds of the invention for which a therapeutic use or their salts or prodrugs as active agents and at least one pharmaceutically acceptable carrier have not been previously published. Furthermore, the invention relates to the use of an effective amount of a novel compound as defined herein for the treatment or prevention of a spheroidal hormone-dependent disease or condition in a mammal, and particularly a human. Preferably, the disease or condition dependent on the hormone esteriode is a disease or condition dependent on estradiol or testosterone. In a preferred embodiment, the invention relates to the use of an effective amount of a novel compound as defined herein for the treatment or prevention of a spheroidal hormone-dependent disease or condition in a mammal., wherein the spheroidal hormone-dependent disease or disorder requires the inhibition of a 17β-hydroxysteroid dehydrogenase (HSD) enzyme, preferably the human type 17β-hydroxysteroid dehydrogenase (HSD) type 1, type 2 or type 3 enzyme. Further preferred embodiment of the invention, the disease or disorder dependent on the spheroidal hormone to be treated or prevented requires the decrease of the concentration of endogenous 17β-estradiol or testosterone in a generalized and / or specific tissue form. The invention also relates to a method for treating a mammal such as a human being having a condition related to the activity of a 17β-hydroxysteroid dehydrogenase (HSD) type 1, type 2 or type 3, and which comprises administering to the mammal means an amount of a compound of the present invention, or a salt or prodrug thereof, said amount being effective to treat that condition. The administration of compounds of the present invention in combination with other drugs used in the treatment of the indicated states is contemplated. The states to be treated and / or prevented in the context of the present invention include, but are not limited to, breast cancer, prostatic carcinoma, ovarian cancer, uterine cancer, endometrial canker, endometrial hyperplasia, endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea. , menorrhagia, metrorrhagia, prostadynia, benign prosthetic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome and urinary dysfunction. Another condition that can be treated and / or prevented in the context of the present invention includes osteoporosis. Other estrogen-dependent diseases that can be treated or prevented with an effective amount of a compound according to the invention are multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue lesions, skin wrinkles and cataracts. In a preferred embodiment, the invention relates to the use of an effective amount of the compound of the invention for the treatment or prevention of one of the above-mentioned diseases or disorders in a mammal wherein said mammal is a human being, preferably a human female and most preferably a pre or peri-menopausal female human being in the case of gynecological disorders. In addition, the compounds of the formula (I) may be useful for blocking spermatogenesis and as an anti-fertility agent for male beings. The indicated compounds are also useful as diagnostic agents (for example in diagnostic kits or for use in clinical laboratories) to determine the presence or absence of 17β-hydroxysteroid dehydrogenase (HSD) activity of type 1, type 2 and / or type. 3. It will be appreciated that the methods of the present invention can be incorporated in the form of a variety of modalities, of which only a few are indicated. It will be obvious to experts in these techniques that there are other embodiments that are within the spirit of the present invention. Therefore these modalities are non-restrictive.

Forms of administration The method of the invention is primarily intended for the treatment in a mammal, preferably a human being and other primates, of diseases or disorders dependent on the spheroid hormone, particularly diseases or disorders dependent on estradiol, wherein the disease or disorder Spheroidal hormone-dependent requires the inhibition of the 17β-hydroxysteroid dehydrogenase (HSD) enzyme, preferably the type 1 enzyme of the 17β-hydroxysteroid dehydrogenase (HSD) [EC 1.1.1.62]. The compounds can be administered orally, dermally, parenterally, by injection, by pulmonary or nasal administration, sublingually, rectally or vaginally in unit dose formulations. The term "administration by injection" includes intravenous, intra-articular, intra-muscular injection (eg injection by depot where the active compounds are slowly released into the blood stream from the reservoir to be driven to the target organs), intraperitoneally, intradermal, subcutaneous and intrathecal, as well as infusion techniques. Dermal administration may include topical or transdermal application. One or more compounds may exist in association with one or more pharmaceutically acceptable non-toxic auxiliaries such as excipients, adjuvants (e.g. buffers), carriers, inert solid diluents, suspending agents, preservatives, fillers, stabilizers, antioxidants, additives "for food, bioavailability enhancers, coating materials, granulation and disintegration agents, binding agents, etc., and if desired other active agents The pharmaceutical composition can be formulated, for example, as immediate release, continuous release, pulsed release, release in two or more stages, deposit or other types of release formulations of the active ingredient The preparation of the pharmaceutical compositions according to the present invention can be carried out by methods known in the art and will be detailed below. known and commonly accepted ables, as well as other diluents, flavors, sweeteners, suitable colorants, etc., depending on the desired mode of administration as well as on the particular characteristics of the active compound to be used such as solubility, bioavailability, etc. Suitable auxiliaries and other ingredients may be such as are recommended in the pharmaceutical, cosmetic and related fields and are preferably indicated in the European Pharmacopoeia, which are approved by the FDA or which are listed in the "GRAS" list (List of additives FDA food products - generally recognized as safe '(GRAS)). One way of applying the compounds of the general formula (I) or of the pharmaceutical compositions including one or more of said compounds is the oral application, for example by tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, 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 adjuvants and excipients commonly known and used such as for example gum arabic, talc, starch, sugars, (as for example mannose, methylcellulose, lactose), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavorings (for example, ethereal oils), solubility enhancers (for example benzyl benzoate or benzyl alcohol) or bioavailability enhancers (for example Gelucire (MR)). In the pharmaceutical composition, the active ingredient may also be dispersed in a microparticle composition, for example nanoparticles. For parenteral administration, the active agent can be dissolved or suspended in an f-isiologically acceptable diluent, such as for example water, buffers, oils with or without solubilizers, surfactants, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil can be used. In general for parenteral administration the active agent can be in the form of an aqueous, lipid, oil or other solution or suspension, or it can be administered in the form of liposomes or nanosuspensions. The transdermal application can be carried out by suitable plasters, as are known in these techniques, and specifically designed for the transdermal administration of the active agent, optionally in the presence of specific permeability enhancers. Emulsions, ointments, pastes, creams or gels can also be used for transdermal administration. Another suitable mode of administration is through intravaginal devices (e.g., vaginal rings) or intrauterine systems (IUDs) that contain reservoirs for the controlled release of active agents over an extended period. 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, solid at suitable temperatures but liquid at rectal or vaginal temperature, and which will therefore melt in the rectum or vagina to release the drug. Another mode of application is by implantation of a reservoir comprising an inert carrier such as a biologically degradable polymer or synthetic silicones such as for example silicone rubber. These implants are designed to release the active agent in a controlled manner over a prolonged period (for example 3 to 5 years). The experts in these techniques will appreciate that the particular method of administration will depend on a variety of factors that are routinely considered when administering therapeutics.

The doses effectively required of the agents of the present invention for any given patient will depend on a variety of factors, including in a non-limiting manner the activity of the specific compound used, the particular condition under treatment related to HSD type 1, type 2 or type 3 , the particular composition formulated, the mode of administration, time and duration of the administration, route of administration and the particular site being treated, and also the patient's age, the patient's weight, the general health of the patient, the patient's sex, their diet, excretion regimen, drug combinations, and severity of the condition undergoing therapy. It will also be appreciated by those skilled in the art that the optimum course of treatment, ie the mode of treatment and the daily dose amount of a compound of the formula I or a pharmaceutically acceptable salt thereof given during a given number of days can be determined. by experts in these techniques through conventional treatment trials. The optimum doses for a set of data conditions can be determined by those skilled in these techniques using the dosage determination assays in view of the experimental data for a given compound. For oral administration, an illustrative daily dose generally used will be from about 0.01 μg / kg to about 100 mg / kg of total body weight, and wherein the courses of treatment may be repeated at appropriate time intervals. The administration of prodrugs can be dosed at weight levels that are chemically equivalent to the weight levels for fully active compounds. The daily dose for parenteral administration will generally be from about 0.01 μg / kg to about 100 mg / kg of total body weight, a daily regimen of rectal dose will generally require 0.01 μg / kg to about 200 mg / kg of total weight , a daily regimen of vaginal dosing will generally be from about 0.01 μg / kg to about 100 mg / kg of total weight. The daily topical dosing regimen will generally be from about 0.01"μg / kg to about 100 mg / kg administered between one and four times per day.The transdermal concentration will generally be what is needed to maintain a daily dose of μg / kg up to 100 mg / kg of total weight.

Abbreviations and Acronyms As used herein, the following terms have the indicated meanings: 20ßP 20β-hydroxyprogesterone A 4-androsten-3, 17-one Ac acetyl AcOH acetic acid HSD hydroxysteroid-dehydrogenase DHT dehydrotestosterone DMF N, N -dimetillformamide Estrone E2 estradiol ER estrogen receptor EtOAc ethyl acetate GnRH GRAS gonadotropin releasing hormone generally recognized as safe MS mass spectrometry NAD (P) [H] nicotinamide-adenine-dinucleotide (phosphate) [NAD (P) reduced] NMR nuclear magnetic resonance P progesterone PCC pyridinium chlorochromate T testosterone TBAB tetrabutylammonium bromide THF tetrahydrofuran TOF 'Time of flight' EXPERIMENTAL SECTION General preparation procedures. The compounds of the present invention can be prepared using known chemical procedures and reactions. However, the following general methods of preparation are presented to assist the reader in synthesizing 17β-hyoxysteroid dehydrogenase inhibitors with specific details provided below in the experimental section to illustrate operative examples. All the variable groups in these procedures are as described in the generic description if they are not specifically defined below. It is recognized that the compounds of the invention with each optional functional group claimed may not be prepared by each of the methods set forth below. Within the scope of each procedure, optional substituents may appear on reagents or intermediates which may act as protective groups or other non-participating groups. Using methods well known to experts in these techniques, these groups are introduced and / or eliminated during the course of the synthesis schemes that give rise to the compounds of the present invention. The compounds of the present invention can be prepared as shown in Schemes 2 to 6 described in the Experimental Section. It is evident that other compounds substituted or modified in the rings and defined by the formula (I) of the claims can be prepared ogously, for example, using ogs substituted or modified in the rings of the initial reactants (2) in the Scheme 1. The invention will be illustrated by the following non-limiting Experimental Section. In order to illustrate more clearly the nature of the invention and the way to put it into practice, the following examples are presented, which should not be considered as limiting.

EXAMPLE 1 Scheme 1. Synthesis of compounds, classes 2-5 Table 1. Individual compounds of the classes of compounds 2-4 prepared General procedure for the synthesis of 2a-i: 2a 2,3,4,7,8,9, 10,11-octahydro [1] benzothieno [2 ', 3': 4,5] pyrimido- [1, 2 a] azepine-13 (1H) -one: A 0.22 mol of 2-amino-4,5,6,7-tetrahydrobenzo b) thiophene-3-carboxylic acid ethyl ester Ib and 0.33 mol of e-caprolactam in 1500 ml of dry dichloroethane were added dropwise 0.27 mol of POC13. The mixture was heated under reflux until no starting material could be detected by TLC, after which 4/5 of the solvent was evaporated. 200 ml of water were added and the solution was made alkaline with 20% KOH. The solution was extracted with CH2C12, washed with saline and water and dried with Na2SO4. After filtration the solvent was evaporated and recrystallization from ethanol gave compound 2a as white crystals in 90% yield. 2HNMR d 1.85 (10H, m), 2.75 (2H, m), 3.00 (4H, m), 4.35 (2H, m) 2b, 2,3, β, 7,8,9,10-Octahydro-12H-cyclopenta- [4 ', 5'] -thieno- [2 ', 3': 4,5] pyrimido [1, 2- a] -azepin-12-one 2b was synthesized in l described but using ethyl 2-amino-cyclopenta (b) -thiophene-3-carboxylate. XHNMR d 1.83 (8H, m), 2.45 (2H, qn), 3.00 (4H,), 4.37 (2H, m) 2c 1, 2, 3, 4, 5, 8, 9, 10, 11, 12-Decahydro-14H-cyclohepta- [4 ', 5'] -thieno- [2 ', 3': 4,5] pyrimido- [1,2-a] azepin-14-one 2c was synthesized in the above described manner but using 2-aminocyclo-hepta (b) thiophene-3-carboxylic acid ethyl ester. 1H NMR d 1.77 (12H, m), 2.82 (2H, m), 3.01 (2H, m), 3.35 (2H, m), 4.36 (2H, m) 2d 2, 3, 4, 7, 8, 9, 10, 11, 12-decahydro- [1] -benzothieno- [2 ', 3': 4,5] -pyrimido- [1,2-a] azocin- 14 (1) -one O 10. A. 2d was synthesized in the described arrioba form but using "2-azacyclooctanone XH NMR d 1.40 (2H, m), 1.56 (2H, m), 1.89 (8H, m), 2.76 (2H, 15 m), 2.99 (4H , m), 4.27 (2H,) 2e 1,2,3,4,7,8,9, 10 ~ Octahydro-12i? - [1] enzotiene [2,3-d] -pyrido-. [1, 2-a] -pyrimidin-12-one O 0 'C 2e was synthesized in the manner described above but using? -valerolactam 2H NMR d 1.91 (8H, m), 2.75 (2H, m), 2.97 (4H , m), 4.02 (2H, t) 2f 2.3, 6,7,8,9-Hexahydro [l] benzothieno [2,3-d] pyrrolo [l, 2-a] pyrimidin-10. { 1H) -one 2f was synthesized in the manner described above but using 2-pyrrolidinone. E NMR d 1.86 (4H, m), 2.28 (2H, qn), 2.76 (2H, m), 3.00 (2H, m), 3.14 (2H, t), 4.16 (2H, t) 2g 5,6,7, 8-Tetrahydro-2,3-dimethyl [1] benzothieno [2,3-d] pyrimidin-4 (3H) -one 2g was synthesized in the manner described above but using JY-methylacetamide. XH NMR d 1.86 (4H, m), 2.58 (3H, s), 2.76 (2H, m), 3.00 (2H, m), 3.56 (3H, m) 2h 5,6,7,8-Tetrahydro-3-methyl [1] benzothieno [2,3-d] pyrimidin-4 (3H) -one 2h was synthesized in the manner described above but using acetamide. XH NMR d 1.87 (4H, m), 2.78 (2H, m), 3.03 (2H, m), 3.56 (3H, s), 7.91 (1H, s) 2 i 5, 6, 7, 8-Tetrahydro-2 -ethyl-3-methyl [1] benzothieno [2,3-d] pyrimidin-4 (3H) -one 2i was synthesized in the manner described above but using N-methylpropanamide. XH NMR d 1.36 (3H, t), 1.85 (4H, m), 2.78 (4H, m), 3.01 (2H, m), 3.57 (3H, s) General procedure for the synthesis of 3a-i: 37 mmol of PCC, 20 g of Celite and 7.3 mmol of compound 2a were mixed to give a fine powder and 150 ml of dry benzene were added. The reaction mixture was heated under reflux overnight. The cooled solution was filtered through a plug of Celite and the solvent was evaporated. Recrystallization from methanol gave a white powder with a yield of 50%. 3a 2,3, 8, 9,10, 11-Hexahydro [1] -benzothieno [2 ', 3': 4, 5] dirimido [1,2-a] azepin-4, 13 (1H, 7H) -dione ? NMR d 1.58 (6H, m), 2.23 (2H, qn), 2.67 (2H, t), 3.07 (2H, m), 3.28 (2H, t), 4.36 (2H, m) 3b 1.2.6, 7,8,9,10-heptahydrocyclopenta [4 ', 5'] thieno [2 ', 3': 4, 5] pyrimido [1,2-a] -azepin-3, 12-dione XH NMR d 1.88 (4H, m), 2.92 (2H, m), 3.09 (2H, m), 3.33 (2H, m), 4.39 (2H, m) 3c 1,2,3,4,8, 9,10,11,12-nonahydro-cyclohepta [4 ', 5'] thieno [2 ', 3': 4,5] pyrimido- [1,2-a] azepine-5 (5afí.), 14 -dione aH NMR d 1.90 (12H, m), 2.83 (2H, m), 3.05 (2H, m), 3.57 (2H, m), 4.36 (2H, m) 3d 1,2,7, 8,9,10, 11, 12-octahydro [1] benzothieno [2 ', 3': 4,5] pyrimido- [1,2-a] azocin-4, 14 (3H) -diona XH NMR d 1.45 (2H, m), 1.61 (2H, m), 1.97 (4H, m), 2.24 (2H, qn), 2.67 (2H, m), 3.02 (2H, m), 3.29 (2H, t ), 4.31 (2H, m) 3e 1,2,3,4, 7, 8, 9, 10-Octahydro-12iT- [1] benzothieno [2,3-d] pyrido [1,2-a] pyrimidin-12-one ^? NMR d 1.99 (4H, m), 2.23 (2H, qt), 2.66 (2H, t), 3.01 (2H, t), 3.28 (2H, t), 4.03 (2H, t) 3f 2,3, 8,9-Tetrahydro [1] benzothieno [2,3-d] pyrrolo [1,2-a] pyrimidin-6, 10 (1H, 1H) -dione XH NMR d 2.29 (4H, m), 2.67 (2H, t), 3.24 (4H, m), 4.19 (2H, t) 3g 5,6-Dihydro-2,3-dimethyl [1] benzothieno [2,3-d] pyrimidine-4,8. { 3H, 7H) -dione XE NMR d 2.24 (2H, qn), 2.63 (3H, s), 2.66 (2H, m), 3.28 (2H, t), 3.59 (3H, s) 3h 5,6-Dihydro-3-methyl [1] benzothieno [2,3-d] pyrimidin-4,8 (3H, 1H) -dione XH NMR d 2.25 (2H, qn), 2.6 3.31 (2H, t) , 3.60 (3H, s), 8.08 (1H, s) 3i 5,6-Dihydro-3-ethyl-2-methyl [1] benzothieno [2,3-d] pyrimidine-4,8 (3H, 7H) -dione XH NMR d 1.39 (3H, t), 2.23 (2H, qn), 2.67 (2H, m), 2.81 (2H, q), 3.29 (2H, t), 3.59 (3H, s) General procedure for the synthesis of 4a-4e: 135 mmol of POCl3 were added dropwise to 170 mmol of DMF and 3 ml of CH2C12 at 0 ° C. After 30 minutes, 17 mmol of compound 3a were added dropwise in 15 ml of CH2C12. The reaction mixture was allowed to reach room temperature and stirred for 48 hours. The reaction was quenched with saturated NaOAc, extracted with CH2C1 / washed with saline and water and dried with Na2SO4. After filtration the solvent was evaporated and the product was purified by flash chromatography using CH2Cl2-EtOAc 9: 1 as eluent . Recrystallization from ethanol gave 4a as yellow crystals in 75% yield. 4a 4-Chloro-l, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo [1] benzothieno [2 ', 3': 4, 5] pyrimido [1,2-a] azepin -3-carboxyaldehyde XH NMR d 1.86 (2H, m), 2.81 (2H, dt), 3.07 (2H, m), 3.28 (2H, dt), 4.37 (2H, m), 10.21 (1H, s) 4b 4-Chloro-l, 2,3,7, 8,9, 10, 11, 12-octahydro [1] benzothieno [2 ', 3': 4, 5] pyrimido- [1,2-a] -azocin -14-ona-4-carboxyaldehyde: Purification by flash chromatography gave compound 4b as the main product and compound 11 as a secondary product: XE NMR d 1.44 (2H, m), 1.60. (2H, m), 1.93 (4H, m), 2.76 (2H, m), 3.02 (2H, m), 3.28 (2H, m), 4.31 (2H, m), 10.21 (1H, s) 11, 4-Chloro-l, 2,7,9,10,11,14,14-octahydro-14-oxo-8H- [1] benzothieno [2 ', 3': 4,5] pyrimido- [1, 2-a] -azocin-3, 7-dicarbaldehyde 2H NMR d (CDC13) 1.31 (2H, m), 1.82 (5H,), 2.43 (1H, m), 2.81 (2H, t) 3.29 (2H, m), 3.? 5 (2H, m), 4.93 (1H, m), 9.92 (1H, s), 10.21 (1H, s.4C 8 -Chloro-4-oxo-l, 2, 3, 4, 8, 9-hexahydro [1] benzothieno [2, 3-d] pyrrolo [1, 2-a] pyrimidine-7-carbaldehyde ^ • H NMR d 2.33 (2H, m), 2.81 (2H, m), 3.25 (4H, m), 4.20 (2H, m), 10.20 (1H, s) 4d 1,2,3,4,5,8,9,10,11, 12-Decahydro-14H-cyclohepta [4 ', 5'] thieno [2 ', 3': 4, 5] -pyrimido [1, 2-a] azepin-14-one XH NMR d 2.82 (2H, m), 3.31 (2H, m), 3.60 (3H, s), 8.04 (1H, s), 10.22 (1H, s) xH NMR d 2.82 (2H, m), 3.31 (2H , m), 3.60 (3H, s), 8.04 (1H, s), 10.22 (1H, s) 4e 8-Chloro-5,6-dihydro-3-methyl [1] -benzothieno [2,3-d] pyrimidin-4 (3H) -one-7-carboxal XH NMR d 2.81 (2H, m), 3.31 (2H, m), 3.59 (3H, s), 8.03 (1H, s), 10.22 (1H, s) Table 2. Individual compounds prepared from class 5 General procedure for the synthesis of 5a-5h: 0.62 mmol of compound 4a in 20 ml of THF followed by 0.93 ml of 1M NaOH were added dropwise to 1.06 mmol of thiophenol in 2 ml of THF a - 18 ° C. The reaction mixture was allowed to reach room temperature and stirred until no more starting material was detected by TLC. The reaction mixture was poured into a large excess of water and stirred for one hour. The product was filtered and recrystallization gave 5a as yellow crystals with a yield of 85%. 5a I, 2,7,8,9,10,11,13-Octahydro-13-oxo-4- (phenylthio) [1] benzothieno [2 ', 3': 4, 5] -pyrimido- [1, 2 -a] azepine-3-carboxyaldehyde XH NMR d 1.77 (6H, m), 2.82 (2H, m), 2.95 (2H, m), 3.25 (2H, m), 4.29 (2H, m), 7.23 (5H, m), 10.47 (1H, s) 5b 1,2,7,8,9,10,11,18-Octahydro-13-oxo-4- (ethylthio) [1] benzothieno [2 ', 3': 4, 5] -pyrimido- [1,2 -a] azepine-3-carboxyaldehyde 5b was synthesized in the manner described but using ethanethiol. XH NMR d 1.26 (3H, t), 1.85 (6H, m), 2.76 (2H,), 2.91 (2H, q), 3.07 (2H, m), 3.22 (2H, m), 4.37 (2H, m) , 10.48 (1H, s). M / z 360 5c 1,2,7, 8,9,10,11,13-Octahydro-13-oxo-4- (propylthio) [1] benzothieno [2 ', 3': 4, 5] -pyrimido- [1, 2 -a] azepine-3-carboxaldehyde 5c was synthesized in the manner described but using propanothiol. XH NMR d 0.99 (3H, t), 1.63 (2H, m), 1.86 (6H, m), 2.76 (2H, m), 2.87 (2H, t), 3.06 (2H, m), 3.22 (2H, m ), 4.37 (2H,), 10.49 (1H, s). M / z 374 5d 1.2, 7, 8, 9, 10, 11, 13-Octahydro-13-oxo-4- (butylthio) [1] -benzothieno [2 ', 3': 4, 5] -pyrimido- [1, 2-a] azepine-3-carboxaldehyde 5d was synthesized in the manner described but using butanothiol. XH NMR d 0.89 (3H, t), 1.46 (4H, m), 1.86 (6H, m), 2.76 (2H, m), 2.89 (2H, t), 3.06 (2H,), 3.22 (2H,), 4.37 (2H, m), 10.48 (1H, s). M / z 388 5e 1.2, 7, 8.9, 10, 11, 13-Octahydro-13-oxo-4- (isopropylthio) [1] -benzothieno [2 ', 3': 4, 5] -pyrimido- [1, 2-a] azepine-3-carboxaldehyde 5e was synthesized in the manner described but using 2-propanothiol. XH NMR d 1.31 (6H, d), 1.85 (6H, m), 2.77 (2H, m), 3.06 (2H, m), 3.23 (2H, m) 3.41 (1H, septet), 4.37 (2H,), 10.47 (1H, m). M / z 374 5f L, 2 / 7,8,9,10, 11, 13-Octahydro-13-oxo-4- (t-butylthio) [1] -benzothieno [2 ', 3': 4,5] -pyrimido- [1, 2-a] azepin-3-carboxaldehyde XH NMR d 1.37 (9H, s), 1.86 (6H, m), 2.80 (2H, t), 3.06 (2H,), 4.37 (2H, m), 10.42 (1H, s) 5g 1.2, 7, 8, 9, 10, 11, 13-Octahydro-13-oxo-4- (cyclopentylthio) [1] benzothieno [2 ', 3': 4, 5] -pyrimido- [1, 2 -a] azepine-3-carboxaldehyde XH NMR d 1.60-1.85 (14H, m), 2.76 (2H, t), 3.22 (2H, t), 3.61 (1H, m), 4.37 (2H, m), 10.46 (1H, s) 5h 1.2.7, 8.9, 10.11, 13-Octahydro-13-oxo-4- (cyclohexylthio) [1] benzothieno [2 ', 3': 4, 5] -pyrimido- [1, 2 -a] azepine-3-carboxaldehyde ? L NMR d XH NMR d 1.25-1.99 (16H, m), 2.77, 2H, m), 3.06-3.27 (5H, m), 4.36 (2H, m), 10.47 (1H, s) 5i 1, 2,7,9,10,11,14,14-octahydro-14-oxo-4- (propylthio) -8JÍ- [1] benzothieno [2 ', 3': 4,5] pyrimido- [1 , 2-a] -azocin-3-carbaldehyde Compound 5i was synthesized in the manner described but using 4b as starting material. XH NMR (CDC13) d 0.99 (3H, t), 1.44 (2H, m), 1.62 (4H, m), 1.93 (4H, m), 2.76 (2H, m), 2.87 (2H, m), 3.02 ( 2H, m), 3.22 (2H, m), 4.30 (2H, broad s), 10.49 (1H, s) EXAMPLE 2 Scheme 2. Synthesis of compounds 6 and 7.

Table 3 General procedure for the synthesis of 6a-6b and 8: 0.66 mmol of NaBH was added to 0.52 mmol of compound 5a in 300 ml of ethanol. After stirring for 20 minutes, 65 ml of water were added followed by acidification with HCl. The ethanol was evaporated and the product was filtered giving compound 6a as a light yellow powder in 98% yield. 6a 1,2, 7, 8, 9, 10, 11, 13-Octahydro-13-oxo-4- (phenylthio) [1] benzothieno [2 ', 3': 4, 5] -pyrimido- [1,2 -a] azepin-3-hydroxymethyl LH NMR d 1.80 (6H, m), 2.79 (2H, m), 2.99 (2H, m), 3.29 (2H, m), 4.33 (2H, m), 4.61 (2H, s), 7.17 (5H, m ). M / z 410 6b 1,2,7, 8,9,10,11,13-Octahydro-13-oxo-4- (cyclohexylthio) [1] -benzothieno- [2 ', 3': 4,5] pyrimido [1, 2 -a] azepine-3-hydroxymethyl XH NMR d 1.22-1.92 (16H, m), 2.66 (2H, m), 2.9-3.1 (3H, m), 3.21 (2H, m), 4.36 (2H, m) 4.59 (2H, s) 6c 1, 2,8,9,10,11-Hexahydro-3- (hydroxymethyl) -4- (propylthio) - [1] -benzothieno [2 ', 3': 4, 5] -pyrimido- [1,2 -a] azepin-13 (7ff) -one Compound 6c was synthesized in the manner described for 6a-b using compound 5c as the starting material. XH NMR (D6-acetone) d 0.96 (3H, t), 1.60 (2H, m), 1.84 (6H, m), 2.68 (4H, m), 3.10 (4H, m), 4.38 (2H, m), 4.57 (2H, broad s) MS. { m / z) 37'6 Synthesis of 7: 0.50 mmol of NaOAc were added to 0.50 mmol of NH 2 OH-HCl in 3 ml of absolute ethanol followed by the addition of 0.26 mmol of compound 5a in 7 ml of THF. The reaction mixture was allowed to reach room temperature and stirred overnight. The reaction was quenched with water, extracted with CH2C12, washed with saline and water and dried with Na2SO4. After filtration the solvent was evaporated giving compound 7 in 95% yield. Recrystallization from ethanol gave a light yellow powder. 7 Octahydro-13 -oxo-4- (phenylthio) [1] -benzothieno [2 ', 3': 4, 5] -pyrimido- [1,2-a] azepin-3-oxime-methyl XH NMR d 1.81 (6H, m), 2.96 (4H, m), 3.30 (2H, m), 4.34 (2H, m), 7.18 (5H, m), 7.61 (1H, broad s), 8.76 (1H, s). M / z 423 EXAMPLE 3 Scheme 3. Synthesis of compound 8 8 4-Chloro-1,2,7,8,9,10,11,13-octahydro-13-oxo [1] -benzothieno [2 ', 3':, 5] -pyrimido [1, 2-a] azepin-3-hydroxymethyl XH NMR d 1.84 (6H, m), 2.71 (2H, m), 3.05 (2H, m), 3.25 (2H,), 4.36 (2H, m) , 4.45 (2H, s). M / z 366 EXAMPLE 4 Scheme 4. Synthesis of compound 9 Synthesis of 9: 5 ml of dry DMF, 1.56 mmol of acetal DMF and 0.36 mmol of compound 3b were heated under reflux for 2 hours under a tube of CaCl 2, after which the DMF was separated by distillation and the crude product was dried in vacuo. Flash column purification using acetone as eluent gave compound 9 in 55% yield. XH NMR (CDC13) d 1.86 (6H, m), 3.08 (2H, m), 3.17 (6H, s), 4.08 (2H, s), 4.40 (2H, m), 7.41 (1H, s).

EXAMPLE 5 Scheme 5. Synthesis of compound 10 (10a R7 = -CH2CH2CH3, 10bR7 = -CH2CH2CH2CH3H) General procedure for the synthesis of 10a-10b: 0.58 mmol of KOH and 0.59 mmol of EtSH in 5 ml of EtOH were stirred for 30 minutes, followed by the addition of compound 4a in 40 ml of acetone. After 30 minutes, 250 ml of water were added and the mixture was stirred until the product was precipitated. Filtration 10a was obtained as a yellow powder, with a yield of 86%. 10a 1,2,7,8,9,10,11,18-Octahydro-13-oxo-4- (propylthio) [1] benzothieno [2 ', 3': 4,5] -pyrimido- [1,2 -a] azepin- 3- (3-oxo) but-1-ene XH NMR (CDC13) d 1.00 (3H, t), 1.60 (2H, m), 1.85 (6H, m), 2.39 (3H, s), 2.75 (4H, m), 3.05 (2H, m), 3.27 (2H, m), 4.37 (2H, m), 6.35 (1H, d), 8.28 (1H, d) 10b I, 2,7,8,9,10,11,13-Octahydro-13-oxo-4- (butylthio) [1] -benzothieno [2 ', 3': 4,5] -pyrimido- [1, 2-a] azepin-3- (3 -oxo) but-1-ene XH NMR (CDCl 3) d 0.88 (3H, t), 1.46 (4H, m), 1.85 (6H, m), 2.38 (3H, s ), 2.76 (4H, m), 3.05 (2H, m), 3.27 (2H, m), 4.37 (2H, m), 6.35 (1H, d), 8.27 (1H, d) OTHER EXAMPLES 12 7,8,9,10,11,13-Hexahydro-13-oxo-4- (phenylthio) - [1] -benzothieno [2 ', 3': 4,5] pyrimido [1,2-a] ] azepin-3-carbaldehyde 100 mg (245 mmol) of compound 5a and 67 mg (295 mmol) of DDQ were heated at reflux overnight in 15 ml of dry benzene. The reaction mixture was cooled to room temperature and filtered through a short column of silica gel. The solvent was evaporated. The product 12 was recrystallized from EtOH / petroleum ether. XH NMR (CDCl 3) d 1.86 (6H, m), 3.12 (2H, m), 4.47 (2H, m), 7.16 (5H, m), 8.16 (1H, d), 8.72 (1H, d), 10.78 ( 1H, s) 13 1,2,3,4,7,8, 9, 10, 11, 12-Decahydro-4-hydroxy-14ii- [1] -benzothieno [2 ', 3': 4,5] pyrimido [1,2 -a] azocin-14-one To 200 mg (0.66 mmol) of the 3d compound in 5 ml of THF and 15 ml of EtOH were added 33 mg (0.86 mmol) of NaBH 4 and the reaction mixture was stirred for 15 minutes. The reaction was quenched with water and extracted with CH2C12. The organic layer was washed with saline and dried over Na2SO4. After filtration the solvent was evaporated and the product was purified by flash chromatography using CH2C12 / EtOAc 1: 1 as eluent. XH NMR (CDC13) d 1.42 (2H, m), 1.59 (2H, m), 1.95 (7H, m), 2.14 (2H, m), 3.05 (4H,), 4.29 (2H, m), 4.87 (1H , m) 14 9-Methyl-2,3,4,7,8,9,10, 11-octahydro- [1] -benzothieno [2 ', 3': 4,5] pyrimido [1,2-a] azepin-13 (1H) -one The compound was synthesized by the method described for 2a-i using 4-methyl caprolactam as the starting material. XH NMR d 0.98 (3 H, d), 1.26 (2 H, m), 1.84 (5 H, m), 2.04 (2 H, m), 2.74 (2 H, m), 3.01 (4 H, m), 3.51 (1 H, m ), 5.17 (1H, m) MS (m / z) 288 15 Ethyl ester 1, 2, 3, 4, 7, 9, 10, 12-Octahydro-12-oxo-8H- [1] -benzothieno [ 2, 3-d] pyrido [1,2-a] pyrimidine-7-carboxylic acid.

The compound was synthesized by the method described for 2a-i using 3-ethoxy-carbonyl-2-piperidone as the starting material. XH NMR d 1.24 (3H, t), 1.99 (7H, m), 2.27 (1H, m), 2.74 (2H, m), 2.99 (2H, m), 4.01 (3H, m), 4.20 (2H, q ) MS (m / z) 332 16 Ethyl ester of acid 1, 2, 3,, 7, 8, 9, 10, 11, 13-Decahydro-13-oxo- [1] -benzothieno [2 ', 3': 4, 5] -pyrimido [1 , 2-a] azepine-9-carboxylic acid The compound was synthesized by the method described for 2a-i using ethyl 7-oxo-4-azepane carboxylate as the starting material. XH NMR d 1.23 (3H, t), 1.88 (6H, m), 2.15 (2H, m), 2.72 (3H, m), 3.03 (4H, m), 3.91 (1H, m), 4.13 (2H, q ), 4.84 (1H, m) 17 2.3, 8.9.10, 11-Hexahydro-9-methyl- [1] -benzothieno [2 ', 3': 4,5] pyrimido [1,2-a ] azepine-4, 13 (1H, 1H) -dione To 4.0 g (13.9 mmol) of compound 14, 11.3 g (41.6 mmol) of potassium peroxo-disulfate and CuSO4 • 5H20 were added. 250 ml of acetonitrile / water 1: 1. The mixture was heated to reflux for 30 minutes. The reaction was quenched with water and extracted with CH2C12. The organic layer was washed with 10% sodium thiosulfide and saline and dried over Na 2 SO 4. After filtration the solvent was evaporated and the product was purified by flash chromatography using CH2C12 / EtOAc 9: 1 as eluent. XH NMR (CDC13) d 1.00 (3H, d), 1.28 (2H, m), 1.90 (1H, m), 2.08 (2H, m), 2.23 (2H, m), 2.66 (2H, m), 3.06 ( 2H, m), 3.28 (2H, m), 3.55 (1H, m), 5.16 (1H, m) MS (m / z) 302 18 Ethyl ester of 4, 12-Dioxo-l, 2, 3, 4, 7, 9, 10, 12-octahydro-8H- [1] -benzothieno [2, 3-d] pyrido [1, 2-a] ] pyrimidine-7-carboxylic acid.

Compound 18 was synthesized by the method described for compound 17 using compound 15 as starting material. XH NMR (CDC13) d 1.26 (3H, t), 1.80 (1H, m), 2.18 (4H, m), 2.62 (3H, m), 3.24 (3H, m), 3.81 (1H, m), 4.28 ( 3H, m) 19 Ethyl ester of acid 4, 13-dioxo-l, 2, 3, 4, 7, 8, 9, 10, 11, 13-decahydro- [1] -benzothieno [2 ', 3': 4, 5] - pirimido [1, 2-a] zepin-9-carboxyl Compound 19 was synthesized by the method described for compound 17 using compound 16 as starting material. X H NMR (CDCl 3) d 1.28 (3 H, t), 1.97 (2 H, m), 2.21 (4 H, m), 2.66 (2 H, m), 2.79 (1 H, m), 3.03 (1 H, m), 3.24 ( 3H, m), 4.01 (1H, m), 4.18 (2H, q), 4.84 (1H, m) 4-Chloro-9-methyl-l, 2,7,8,9,10,11,13-octahydro-13-oxo- [1] -benzothieno [2 ', 3': 4,5] pyrimido [1 , 2-a] azepin-3 -carbaldehyde 2.91 mmol of POCl3 were added dropwise to 3.02 mmol of DMF in 2 ml of CHC13 at 0 ° C. After 30 minutes, 0.36 mmol of compound 17 was slowly added dropwise in 6 ml of CHC13. The reaction mixture was allowed to reach room temperature and stirred overnight, after which the reaction mixture was heated at 50 ° C for 12 hours. The reaction mixture was cooled to room temperature, the reaction was quenched with saturated NaOAc, extracted with CH2C12, washed with saline and water and dried over Na2SO4. After filtration the solvent was evaporated and the product was purified by flash chromatography using CH2Cl2-EtOAc 9: 1 as eluent. XH NMR (CDCl 3) d 1.00 (3H, d), 1.29 (2H, m), 1.90 (1H, m), 2.09 (2H, m), 2.80 (2H, m), 3.06 (2H, m), 3.27 ( 2H, m), 3.55 (1H, m), 5.15 (1H, m), 10.20 (1H, s) 21 Ethyl ester of 4-chloro-3-formyl-l, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo- [1] -benzothieno [2 ', 3': 4, 5 ] -pyrimido [1,2-a] azepine-9-carboxylic acid Compound 21 was synthesized by the method described for 4a using compound 19 as the starting material, with the exception that the reaction mixture was stirred for 8 days.

XH NMR (CDCl 3) d 1.28 (3H, t) 1.98 (2H, m), 2.22 (2H, m), 2.79 (3H, m), 3.03 (1H, m), 3.24 (3H, m), 4.01 (1H , m), 4.18 (2H, q), 4.85 (1H, m), 10.20 (1H, s) Ethyl ester 3-formyl-l, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (propylthio) - [1] -benzothieno [2 ', 3': 4,5] -pyrimido [1,2-a] azepine-9-carboxylic acid Compound 22 was synthesized by the method described for 5c using compound 21 as starting material. X H NMR (CDCl 3) d 0.99 (3 H, t), 1.27 (3 H, t), 1.62 (2 H, m), 1.97 (2 H, m), 2.22 (2 H, m), 2.77 (3 H, m), 2.86 ( 2H, t), 3.02 (1H, m), 3.21 (3H, m), 4.00 (1H, m), 4.17 (2H, q), 4.86 (1H, m), 10.49 (1H, s) 23 Methyl ester of 3-formyl-1, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (propylthio) - [1] -benzothieno [2 ', 3': 4] , 5] -pyrimido [1,2-a] azepine-9-carboxylic acid or xpCcM 80.37 mmol of compound 22 were dissolved in 10 ml of MeOH and 0.98 mmol of KOH in 5 ml of MeOH was added. The reaction mixture was stirred for two hours at room temperature. The reaction mixture was poured into water, acidified with HCl and extracted with CH2C12. The organic layer was washed with saline and dried over Na2SO4. After filtration the solvent was evaporated. Purification by flash chromatography using CH2Cl2-Et0Ac 9: 1 as eluent gave compound 23 as the main product and compound 24 as a by-product. XH NMR (CDC13) d 0.99 (3H, t), 1.63 (2H, m), 1.98 (2H, m), 2.23 (2H, m), 2.77 (3H, m), 2.86 (2H, t), 3.02 ( 1H, m), 3.21 (3H, m), 3.73 (3H, s), 4.01 (1H, m), 4.84 (1H, m), 10.49 (1H, s) 24 Methyl ester of 3-formyl-4-methoxy-1,2,7,8,9,10,11-octahydro-13-oxo- [1] -benzothieno [2 ', 3': 4,5 ] -pyrimido [1,2-a] azepine-9-carboxylic acid XH NMR (CDCl 3) 1.98 (2H, m), 2.20 (2H, m), 2.72 (2H, m), 2.80 (1H, m), 3.02 (1H, m), 3.21 (3H, m), 3.73 (3H , s), 4.04 (3H, s), 4.04 (1H, m., .4.84 (1H, m), 10.19 (1H, s) 1 / 2,3, 4-Tetrahydro-12H- [1] benzothieno [2,3-d] pyrido [1,2-a] pyrimidin-12-one 2-Bromopyridine and ethyl 2-amino-4,5,6,7-tetrahydrobenzo (b) thiophene-3-carboxylate Ib were heated at 165 ° C for 3 and a half hours under argon. After cooling the solids crystallized from EtOH. The crystallized product was purified by flash chromatography using CH2Cl2-EtOAc 9: 1 as eluent. XH NMR (CDC13) d 1.92 (4H, m), 2.81 (2H, m), 3.14 (2H, m), 7.00 (1H, m), 7.57 (2H, m), 9.04 (1H, m) MS [m / z) 256 26 2,3-Dihydro-12H- [1] -benzothieno [2,3-d] pyrido [1,2-a] pyrimidine-4,12 (1H) -dione Compound 26 was synthesized by the method described for compound 17 using compound 25 as starting material. XH NMR (CDCl 3) d 2.30 (2H, m) 2.71 (2H, -m), 3.40 (2H, t), 7.12 (1H, m), 7.62 (1H, m), 7.76 (1H, m), 9.05 ( 1H, m) 27 3-Methyl-2, 3,4, 7, 8,9,10, 11-octahydro- [1] -benzothieno [2 ', 3': 4,5] pyrimido- [1,2-a] azepin- 13 (1H) -one Compound 27 was synthesized by the method described for 2a-i using 2-amino-4,5,6,7-tetrahydro-6-methyl-benzo [b] -thiophene-3-carboxylic acid ethyl ester as starting material . XH NMR (CDC13) d 1.09 (3H, d), 1.44 (1H, m), 1.89 (8H, m), 2.37 (1H, m), 2.85 (2H, m), 3.02 (2H, m), 3.21 ( 1H, m), 4.35 (2H, m) MS (m / z) 288 28 2,3,8,9, 10, 11-Hexahydro-3-methyl- [1] -benzothieno [2 ', 3': 4,5] pyrimido [1,2-a] azepin-4, 13 (1H , 1H) -dione Compound 28 was synthesized by the method described for compound 17 using compound 27 as starting material. XH NMR (CDCl 3) d 1.28 (3H, d), 1.85 (6H, m), 1.98 (1H, m), 2.29 (1H, m), 2.67 (1H, m), 3.06 (2H, m), 3.13 (1H, m), 3.50 (1H,), 4.36 (2H, m) 29 3-t-Butyl-2,3,4, 7,8,9, 10, 11-octahydro- [lf] -benzothieno [2 ', 3': 4,5] pyrimido- [1,2-a] azepin-13. { 1H) -one Compound 29 was synthesized by the method described for 2a-i using 2-amino-4,5,6,7-tetrahydro-6-t-butylbenzo [b] -thiophene-3-carboxylic acid ethyl ester as a starting material. XH NMR (CDC13) d 0.95 (9H, s), 1.35 (1H, m), 1.55 (1H, m), 1.79 (6H, m), 2.06 (1H, m), 2.51 (1H, m), 2.76 ( 2H, m), 3.01 (2H, broad s), 3.32 (1H, m), 4.35 (2H, m) L, 2,7,8,9,10,11,13-Octahydro-13-oxo-4- (phenylsulfinyl) - [1] -benzothieno [2 ', 3': 4, 5] -pyrimido- [1 , 2-a] azepine-3-carbaldehyde or? -S 100 mg (0.25 mmol) of compound 5a and 89 mg (0.52 mmol) of m-chloroperbenzoic acid in 25 ml of dry CH2C12 were stirred for 3 days at room temperature. The reaction was quenched with water and extracted with CH2C12. The organic layer was washed with 10% sodium thiosulfate and saline and dried over Na2SO4. After filtration the solvent was evaporated and the product was purified by flash chromatography using CH2Cl2 / EtOAc 8: 2.

XH NMR (CDCl 3) d 1.80 (6H, m), 2.71 (2H, m), 3.03 (2H, m), 3.06 (1H, m), 3.57 (1H, m), 4.31 (2H, m), 7.47 ( 3H, m), 7.69 (2H, m), 10.65 (1H, s) 31 Acid 4-chloro-l, 2,7, 8, 9, 10, 11, 13-octahydro-13-oxo- [1] -benzothieno [2 ', 3': 4,5] pyrimido [1,2- a] azepine-3-carboxylic acid 335 mg (1.00 mmol) of compound 4a and 1.06 ml (10.01 mmol) of 2-methyl-2-butene were dissolved in 50 ml of THF. A freshly prepared solution of 339 mg (3.00 mmol) of 80% NaCl02 and 414 mg (3.00 mmol) of NaH2P04-H20 in 55 ml of 5: 1 t-BuOH / H20 was added. The reaction mixture was stirred at room temperature for 6 hours. The reaction was quenched with water and extracted with CH2C12. The organic phase was extracted with saturated NaHS04. The aqueous phase was acidified with HCl and extracted with CH2C12. The organic layer was washed with saline and dried over Na2SO4. After filtration, the solvent was evaporated and the product was recrystallized from ethanol. XH NMR (Dg-DMSO) 1.71 (6H, m), 2.79 (2H, m), 3.06 (2H, m), 3.14 (2H, m), 4.31 (2H, m), 13.07 (1H, broad) 32 4-Hydroxy-3-methyl-2,3,4,7,8,9,10,19-octahydro- [1] -benzothieno [2 ', 3': 4,5] pyrimido- [1,2- a] azepine-13 (1H) -one Compound 32 was synthesized as a mixture of diastereomers by the method described for compound 13 using compound 28 as the starting material. XH NMR (CDC13) d 1.14 (2H, d) 1.16 (2H, d), 1.58-2.04 (20H, m), 2.82 (1H, m), 2.95 (1H, m), 3.04 (4H, m), 3.13 (1H, m), 3.25 (1H, m), 3.75 (2H, m), 4.35 (4H, m), 4.42 (1H, m), 4.67 (1H, m) 33 3-formyl-l, 2,7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (propylthio) - [1] -benzothieno acid [2 ', 3': 4, 5] pyrimido [1,2-a] azepine-9-carboxylic acid 130 mg of compound 22 in 2 ml of THF and 0.7 ml of 10% KOH H2? / MeOH (2: 1) were stirred overnight at room temperature. The reaction mixture was poured into water and washed with ether. The aqueous phase was acidified with HCl and extracted with EtOAc. The organic phase was washed with saline and dried over Na2SO4. After filtration the solvent was evaporated and the product was recrystallized from ethanol. XH NMR (Dg-DMSO) d 0.93 (2H, t), 1.55 (2H, m), 1.71 (2H, m), 2.14 (2H, m), 2.65 (2H, t), 2.67 (2H, m), 2.91 (2H, m), 3.10 (2H, m), 3.12 (2H, m), 3.97 (1H, m), 4.74 (1H, m), 10.36 (1H, s), 12.37 (1H, broad s) MS. { m / z) '418 34 9-Methyl-l, 2, 7,8, 9,10, 11, 13-octahydro-13-oxo-4- (propylthio) - [1] benzothieno [2 ', 3': 4,5] -pyrimido [1,2-a] azepin-3-carbaldehyde Compound 34 was synthesized by the method described for compound 5c using compound 21 as starting material. XH NMR (CDC13) d 0.99 (3H, t), 1.00 (3H, d), 1.28 (2H, m), 1.63 (2H, m), 1.89 (1H, m), 2.08 (2H, m), 2.75 ( 2H, m), 2.86 (2H, t), 3.06 (2H, m), 3.21 (2H, m), 3.55 (1H, m), 5.16 (1H, m), 10.49 (1H, s) 9- CHhydroxymethyl) -2, 3, 4, 7, 8, 9, 10, 11-octahydro- [1] -benzothieno [2 ', 3': 4,5] pyrimido [1,2- a] azepin- 13 (1H) -one 0.72 mmol of compound 16 in 6 ml of dry THF were added dropwise to 1.95 mmol of LiAlH4 in 2 ml of THF under argon at 0 ° C. The reaction mixture was stirred for 20 minutes. The reaction was quenched with water and 10% NaOH was added and extracted with ether. The organic layer was washed with saline and dried over Na2SO4. After filtration the solvent was evaporated and the product was purified by flash chromatography using EtOAc as eluent. XH NMR (CDC13) d 1.31 (2H, m), 1.80 (6H, m), 2.18 (2H, m), 2.75 (2H, m), 3.01 (3H, m), 3.11 (1H, m), 3.51 ( 3H, m), 5.25 (1H, m) It is evident that the compounds defined by the formula (1) of the claims and which are substituted or modified in the ring in another way can be prepared analogously, ie by using analogs modified or substituted in the ring of the initial compounds ( 2) of Scheme 2. Other compounds of the general formula (IV) falling within the scope of the general formula (I) can be prepared by parallel chemistry using a reaction as indicated under the following Scheme 6: Scheme 6: General procedure for the synthesis of pyrimidinone with amino esters of thiophene with lactams.

Sequentially 0.25 M lactam, 0.25 M amino ester and 0.25 M POCl3 are sequentially arranged in a reaction vessel at room temperature. Of all the reagents, an equivalent is used as a solution or suspension in chlorobenzene. After stirring for 80 hours at 100 ° C the mixture is cooled to room temperature, washed with 5% NaOAc and extracted with EtOAc. The organic layers are combined and concentrated to give the desired compound. The material obtained from formula IV was then analyzed by LC-MS. The LC-MS system consisted of 2 Perkin micropumps Elmer 200 series. The pumps are connected to each other by means of a 50 μl T-mixer. The mixer is connected to the Gilson 215 autosampler. The LC method consists of the following stages: Stage Total time Flow (ul / min) A (%) B (%) 0 0 2300 95 5 1 1.8 2300 0 100 2 2.5 2300 0 100 3 2.7 2300 95 5 4 3.0 2300 95 5 Solution A = 100% Water with 0.025% HCOOH and 10 mmol NH4HCOO pH = + / - 3 Solution B = 100% MeOH with 0.025% HCOOH.

The autosampler has a 2 μl injection loop. The autosampler is connected to a Varian Polaris C18A 30 * 4.6 mm column with 3 μm particles. The column is thermostated in a Per in Elmer 200 series oven at 40 ° C. The column is connected to an Applied Biosystems ABI 785 UV detector with a 2.7 μl flow cell. The wavelength is set at 254 nm. The UV detector is connected to a Sciex API 105EX mass spectrometer that has the following parameters: Sweep range: 150-900 urn, Polarity: positive, scan mode: profile, resolution Ql: Unit, step size: 0, 10 ballot box, time per sweep: 0.500 s, NEB: 10, CUR: 10, IS: 5200, TEM: 325, DF: 30, FP: 225, EP: 10. The light scattering detector is a Sedere Sedes 55 running at 50 ° C and 3 bars of pressure of N2. The complete system is controlled by a Dell optiplex GX400 computer running under Windows NT. The following table 4 lists the compounds No. 41 to 53 of the general formula IV, which were prepared according to he Scheme 6, starting from the lactams and the amino acid esters mentioned in the 2nd and 3rd row. In addition, the Molecular Weight and the Retention Time of the synthesized compounds determined by the LC-MS analysis are shown.

Table 4: Compounds No. 41 to 53 of the general formula IV: MATERIALS AND METHODS OF BIOLOGICAL TEST 1. Inhibition of the enzyme 17-hydroxysteroid dehydrogenase type 1, type 2 and type 3 The compounds were tested for the enzymatic activity of 17-HSD in vitro on established MCF-7 cell lines, each stably expressing one of the respective isoenzymes 17-HSD. The interconversion of substrate by each isoenzyme and the inhibitory activity 17-HSD of the chemical compounds in these cell lines were detected by the HPLC system. Variable amounts of the test compounds were incubated in the culture medium of 17-HSD expression cells together with tritium-labeled substrate (2nM estrone for 17-HSD type 1; 2 nM estradiol for 17-HSD type 2; 2 nM androstendiona for 17-HSD type 3). The samples of the medium were removed after an exact incubation time and the reaction was stopped by trichloroacetic acid (TCA). The samples were analyzed by flow-through scintillation analysis coupled with HPLC. For each type of enzyme, the HSD inhibitory activity of an individual test compound was calculated by comparing the conversion of a control sample without any test compound (called "Negative Control") to the (reduced) conversion of the test sample. containing the particular compound to be tested (referred to as "Test Sample").

Conversion in Negative Control - Conversion in Test Sample % inhibition = 100 x Conversion in Negative Control The results obtained are summarized in Table 3 below. Two concentrations of each compound were used. The compound number refers to the numbers indicated in the Experimental Section.

Table 3:% inhibition of enzymes 17 -HSD type 1, type 2 and type 3 by the compounds of the invention x): two tests were done n.d. : undetermined 2. Estrogen Receptor Binding Assay The binding affinity of the compounds of the invention to the estrogen receptor a and the estrogen receptor can be determined according to the in vitro ER binding assays described by Koff et al. [Koff B et al. (1991) J. Steroid. Biochem. Mol. Biol .. 3_8: 135]. Alternatively, a receptor-to-estrogen binding assay can be carried out according to the international patent application PCT / US / 17799 (published as WO 00/07996). 3. Estrogen Receptor Transactivation Assay The compounds of the invention that show binding affinity to the estrogen receptor can be further tested for their individual estrogenic or anti-estrogenic potential (agonist or antagonist linkage to ERa or ER). The determination of the estrogen receptor agonist activity is carried out according to an in vitro assay system using the MMTV-ERE-LUC reporter system which is described, for example, in US Patent Application No. 10/289079 (published as US 2003/0170292); To test the estrogen receptor agonist activity, Hela cells are cultured in 24-well microtiter plates and then co-transfected transiently with two plasmids using lipofectamine. The first plasmid comprises DNA encoding the huestrogen receptor (either ER-alpha or ER-beta), and the second plasmid comprises an estrogen-driven reporter system comprising a luciferase reporter gene (LUC) whose transcription is low the control of upstream regulatory elements comprising 4 copies of the vitellogenin estrogen response element (ERE) cloned into the mouse mammary tumor virus (MMTV) promoter (the full name being for the reporting system "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 charcoal, 2 mM L-glutamine, 0.1 mM non-essential amino acids and 1 mM pyruvate sodium for 42 to 48 hours at 37 ° C in an incubator with 5% carbon dioxide. Concurrently, cells exposed to estradiol (1 nM) serve as positive controls. Replicated wells exposed to the solvent in which the compounds of the invention are dissolved (ie, ethanol or methanol) are used as negative controls. After the incubation period of 42 to 48 hours, the cells are washed with phosphate buffered saline (PBS), lysis buffer (Promega Corp) is added, and the cells used for measuring the activity of the cells are collected. Luciferase with a luminometer. The estrogenic activity of the compounds of the invention is expressed as a multiple of the increase in luciferase activity in comparison with that observed in negative control cells. As an alternative, the determination of estrogen receptor transactivation activity (estrogenicity assay or agonist assay) and the inhibitory potency of transactivation activity (anti-estrogenicity assay or antagonist assay) can be carried out according to International patent application PCT / US / 17799 (published as WO 00/07996). It will be appreciated that the methods of the present invention may be incorporated in a variety of embodiments, of which only a few have been described herein. It is obvious to experts in these techniques that there are other modalities that do not depart from the spirit of the invention. Therefore, the modalities described are illustrative and should not be considered as restrictive.

REFERENCED BIBLIOGRAPHY • Labrie 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 Tamaya et al. (1985) "Comparison of cellular levéis of steroid receptors in uterine leiomyoma and myometrium." Acta Obstet Gynecol Scand. , 64: 307-9 Poirier D. (2003) "Inhibitors of 17 beta-hydroxysteroid dehydrogenases" Curr Med Chem. 10: 453-77 Geissler WM et al. (1994) "Male pseudohermaphroditism caused by mutations of testicular 17beta-hydroxysteroid dehydrogenase 3." Nat Genet., 7: 34-9. Oefelein MG '& Cornum R (2000) "Failure to achieve the levéis of testosterone during luteinizing hormone releasing hormone agonist therapy: the case for monitoring serum testosterone and a treatment decision algorithm." J Urol .; 164: 726-9. US 6,541,463 WO 01/42181 WO 98/32724 WO 98/30556 WO 99/12540 Andersson S. (1995) "Molecular genetics of androgenic 17 - Hydroxysteroid Dehydrogenases. J. Steroid Biochem. Molec.

Biol., 55: 533-534]. Dong Y et al. (1998) "17 -hydroxysteroid dehydrogenases in human bone cells" J. Bone Min. Res., 13: 1539-1546 WO 02/26706 • DE2411273 • Manhas MS, Sharma SD, Amin SG. (1972) "Heterocyclic compounds 4. Synthesis and antiinflammatory activity of some substituted thienopyrimidinones." J Med Chem. 15 (1): 106-7. • Kapustina MV; Kharizomenova IA; Shvedov VI; Radkevich TP; Shipilova LD (1992) "Synthesis and biological activity of 4, 8-dioxo-3, 4,5,6,7, 8-hexahydrobenzothieno [2,3- d] pyrimidine derivatives" Khimiko-Farmatsevticheskii Zhurnal 26 (l): 56 -7 • Kapustine MV; Amelkin OYu; Kharizomenova IA; Shvedov VI; Filitis LN (1991) "Synthesis and tuberculostatic activity of benzothieno [2, 3-d] pyrimidines" Khimiko-Farmatsevticheskii Zhurnal 25 (7): 38-9 • Koffman B, Modarress-KJ, Beckerman T, Bashirelahi N. (1991) "Evidence for involvement of tyrosine in estradiol binding by rat uterus estrogen receptor." J Steroid Biochem Mol Biol. 38 (2): 135-9. • WO 00/07996 • US 2003/0170292

Claims (16)

1. CLAIMS 1. Use of a compound of the formula (I) wherein R_ and R2 represent the same or different alkyl, or one is alkyl and another is H, or R_ and R2 form together with the carbon atoms to which they are attached, a cyclic ring system of 5-, 6-, 7- or 8 members, which is saturated or which contains one or more double bonds between ring atoms, the ring optionally containing up to two heteroatoms in addition to the nitrogen atom to which Rx is attached, where 0-2 is the number of atoms in the ring. N and 0-1 being the number of O or S atoms each, and wherein the ring is optionally substituted with up to three substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl or arylalkyl, wherein the group aryl is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido; R3 and R4 together with the carbon atoms to which they are attached form a 5-, 6-, 7- or 8-membered cyclic hydrocarbon ring system, which is saturated or contains one or more double bonds between the carbon atoms and wherein the ring is optionally substituted with up to three substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, said group being optionally substituted aryl, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido; provided that the compound is not 1,2,7,8,9,10,11,13-octahydro-13-oxo-4- (phenylthio) - [1] -benzothieno [2 ', 3': 4 , 5] dirimido [1, 2, -a] azepin-3-carboxyaldehyde; for the preparation of a medicament for the treatment and / or prevention of a disease or condition dependent on steroid hormones, preferably of a disease or condition dependent on steroid hormones that requires the inhibition of an enzyme 17 -hydroxysteroid dehydrogenase (17 -HSD) , and most preferably requiring the inhibition of the enzyme 17 -HSD of type 1, 17 -HSD type 2 or 17 -HSD type 3.
2. 2. Use of a compound according to claim 1, wherein the compound has the formula II) wherein R_ and R2 represent the same or different alkyl of ci-cs, or one is alkyl of ci-cs AND the other is H, or R_ and R2 form together with the carbon atoms to which a ring system is attached cyclic 5-, 6-, 7- or 8-membered, which is saturated or which contains one or more double bonds between the ring atoms, the ring optionally containing up to two nitrogen atoms in addition to the nitrogen atom to which it is attached R_ , wherein the ring is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, wherein the aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl and amido; the hydrocarbon chain -C (R5) -C (R6) C (CH) n- of the cyclic system adjacent to the thiophene ring is saturated or contains one or more double bonds between the carbon atoms; n is an integer from 1 to 4, and R5 and R6 are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or aryl, wherein the aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amine, oxime, acyl, carboxyl, thiocarboxyl, and amido.
3. 3. Compound of the formula (II) (ID characterized in that R_ and R 2 represent the same or different alkyl of ci-cs, or one is C alquilo-cβ alkyl and the other is H, or Ri and R 2 together with the carbon atoms to which they are attached are cyclic ring system of 5-, 6-, 7- or 8 members, which is saturated or which contains one or more double bonds between the ring atoms, the ring optionally containing up to two nitrogen atoms in addition to the nitrogen atom to which Rx is attached, wherein the ring is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, wherein the aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl , carboxyl, thiocarboxyl and amido; the hydrocarbon chain -C (R5) -C (R6) C (CH) n- of the cyclic system adjacent to the thiophene ring is saturated or contains one or more double bonds between the carbon atoms; n is an integer from 1 to 4, and R5 and R6 are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or aryl, whose aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio , arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido; with the proviso that in the case where n represents the numbers 1, 2 or 3, and Rl and R2 are independently selected from hydrogen, or C? -C4 alkyl, or that together they form an unsubstituted alkylene group of three to five methylene groups or an imino-alkylene group of two to four methylene groups in the alkylene group, optionally substituted on the N atom, then at least (iii) R5 or R6 must be other than hydrogen, alkyl of c? -c4 or alkylcarboxyl, or (iv) the hydrocarbon chain -C (R5) C (R6) - (CH) n- of the cyclic system adjacent to the thiophene ring must be unsaturated or aromatic; in the case where n represents 2 and R1-R2 form an unsubstituted alkylene group of 3 to 5 methylene groups, and R5 represents a hydroxyl or oxo group, then R6 must be other than bromine, dibromo or phenylthio; or in the case where n represents 2 and R1-R2 form an unsubstituted pentamethylene group, and R6 represents carbonyl, then R5 must be other than phenylthio, for use in therapy.
4. 4. New compound of the formula (II) characterized in that Ri and R2 represent the same or different alkyl of ci-cs, or one is alkyl of ci-cs and the other is H, oiy R2 together with the carbon atoms to which a 5-, 6-, 7- or 8-membered cyclic system is attached, which is saturated or which contains one or more double bonds between the ring atoms, containing the ring optionally up to two nitrogen atoms in addition to the nitrogen atom to which R_ is attached, the ring being optionally substituted with up to two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, wherein the aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl and amido; the hydrocarbon chain -C (R5) -C (R6) C (CH) n- of the cyclic system adjacent to the thiophene ring is saturated or contains one or more double bonds between the carbon atoms; n is an integer from 1 to 4, and R5 and R6 are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or annihil, wherein the aryl radical is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido; with the proviso that in the case where n represents the numbers 1, 2 or 3, and Rl and R2 are independently selected from hydrogen, or C?-C 4 alkyl, which together form an unsubstituted alkylene group of three to five methylene groups or an imino-alkylene group of two to four methylene groups on. the alkylene group, optionally substituted at the N atom, then (iii) at least R5 or R6 must be other than hydrogen, c?-c4 alkyl, alkylcarboxyl or = N-OH, or (iv) the hydrocarbon chain -C (R5) -C (R6) - (CH) _.- of the cyclic system adjacent to the thiophene ring must be unsaturated or aromatic; in the case where n represents 2, R1-R2 form an unsubstituted alkylene group of 3 or 5 methylene groups, and R5 represents a hydroxyl or oxo group, then R6 must be other than hydrogen, bromine, dibromo or phenylthio; in the case where n represents 2, R1-R2 form an unsubstituted pentamethylene group, and R6 represents carbonyl, then R5 must be other than phenylthio or chloro; in the case where n represents 2, the hydrocarbon chain -C (R5) -C (R6) - (CH) n ~ of the cyclic system adjacent to the thiophene ring is saturated and R1-R2 together with the carbon atoms at the which are bound form an unsubstituted pyridine ring, then at least one of R5 or R6 must be other than hydrogen; in the case where -C (R5) -C (R6) - (CH) n- represents an unsubstituted tetramethylene group, R1-R2 should be other than a tetramethylene group substituted with a carboxyethyl ester group.
5. 5. A new compound of formula (II) according to claim 4, characterized in that the cyclic ring system of 5-, 6-, 7- or 8-members which R_ and R2 together form is optionally substituted with up to two substituents independently selected from the group consisting of oxo, -CO-R, -CO-OR, -OR, -alkyl of C? -C4, optionally substituted by -OR, -SR c -N (R); R5 and R6 are individually selected from the group consisting of hydrogen, halogen, oxo, -O-R ', -S-R', -SO-R ', -CO-R, -CO-OR or alkyl of _? - c4, alkenyl of c? -c4 or = alkylene of c? -c4, optionally substituted on the alkyl chain with -OR, -SR, -N (R) 2, -CO-R or = N-0-R, in where R represents hydrogen or alkyl of _? - c4; and er? where R 'represents hydrogen, alkyl of c? -c8, which may be linear, cyclic or branched, aryl-alkyl of c? -c4, preferably benzyl; or aryl, preferably phenyl.
6. 6. A new compound of the formula (II) according to claim 4 or 5, characterized in that R_ and R2 form, together with the carbon atoms to which a cyclic ring system of, 6-, 7- or 8 members, optionally substituted, which is saturated or which contains one or more double bonds between the ring atoms, the ring optionally containing up to two nitrogen atoms in addition to the nitrogen atom to which R_ is attached.
7. 7. A new compound of the formula (II) according to any of the preceding claims 4 to 6, characterized in that R5 is selected from the group consisting of hydrogen, oxo, halogen, -OH, -0-alkyl of _? -c4 , -S-alkyl of c? -c4, -S-C3-C8-cycloalkyl, -S-phenyl, -SO-phenyl.
8. 8. A new compound of formula (II) according to any of the preceding claims 4 to 7, characterized in that R6 is selected from the group consisting of hydrogen, carbonyl, alkylcarbonyl, preferably COOH, -alkyl of -C4, -alkenyl of C1.C4 or = alkylene of c? -c4, optionally substituted on the alkyl chain with -OR, -N (R) 2, -CO-R or = N-0-R, where R represents hydrogen or -alkyl of C? -c4 • .
9. 9. A new compound of the formula (II) according to claim 4, selected from: 2,3,8,9,10,11-hexahydro [1] benzothieno [2 ', 3': 4,5] pyrimido [1, 2-a] azepin-4, 13 (1H, 7H) -dione; 1, 2, 6, 7, 8, 9, 10-heptahydrocyclopenta [4 ', 5'] thieno- [2 ', 3': 4,5] -pyrimido] -1,2-a] -azepin-3, 12 -diona; 1,2,3,4, 8,9,10, 11,12-nonahydrocyclohepta [4 ', 5'] thieno- [2 ', 3': 4,5] pyrimido- [1,2-a] azepin- 5 (5aH), 14-dione; 1,2, 7, 8, 9, 10, 11, 12-octahydro [1] benzothieno [2 ', 3': 4, 5] pyrimido- [1,2-a] azocin-4, 14 (3H) - diona; 1,2,3,4,7,8,9,10-octahydro-12H- [1] benzothieno [2,3-d] pyrido- [1,2-a] pyrimidin-12-one; 5,6-dihydro-2,3-dimethyl [1] benzothieno [2,3-d] pyrimidin-4,8 (3H, 7H) -dione; 5,6-dihydro-3-methyl [1] benzothieno [2,3-d] pyrimidin-4,8 (3H, 7H) -dione; 5,6-dihydro-3-ethyl-2-methyl [1] benzothieno [2,3-d] pyrimidin-4,8 (3H, 7H) -dione; 4-chloro-l, 2, 3, 7,8, 9, 10, 11, 12-octahydro [1] 'benzothieno- [2', 3 ': 4, 5] pyrimido [1,2-a] azocin- 14-ona-4-carboxyaldehyde; 1, 2, 3, 4, 5, 8, 9, 10, 11, 12-decahydro-14H-cyclohept [4 ', 5'] thieno- [2 ', 3': 4, 5] pyrimido [1, 2 -a] azepin-14-one; 8-chloro-5,6-dihydro-3-methyl [1] benzothieno [2,3-d] pyrimidin-4 (3H) -one-7-carboxyaldehyde; 1,2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (ethylthio) [1] benzothieno- [2 ', 3': 4,5] pyrimido- [1,2- a] azepine-3-carboxyaldehyde; 1,2,7,8,9,10,11,13-octahydro-13-oxo-4- (propylthio) [1] -benzothieno- [2 ', 3': 4,5] -pyrimido- [1, 2-a] azepine-3-carboxyaldehyde; 1, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (butylthio) [1] benzo-thieno [2 ', 3': 4, 5] pyrimido- [1, 2 -a] azepine-3-carboxyaldehyde; 1, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (isopropylthio) [1] benzo-thieno [2 ', 3': 4,5] pyrimido [1, 2- a] zepin-3-carboxyaldehyde; 1,2, 7, 8, 9, 10, 11, 13-octahydro-13 -oxo-4- (t-butylthio) [1] benzo-thieno [2 ', 3': 4,5] pyrimido [1, 2-a] azepine-3-carboxyaldehyde; 1,2,7,8,9,10,11,13-octahydro-13-oxo-4- (cyclopentylthio) - [1] benzo-thieno [2 ', 3'; 4,5] pyrimido- [1,2-a] azepine-3-carboxyaldehyde; 1,2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (cyclohexylthio) [1] benzo-thieno [2 ', 3': 4, 5] -pyrimido- [1, 2-a] azepine-3-carboxaldehyde; 1, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (phenylthio) [1] benzothieno- [2 ', 3' -.4,5] -pyrimido [1,2 -a] azepin-3-hydroxymethyl; 1,2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (cyclohexylthio) [1] benzo-thieno- [2 ', 3': 4,5] -pyrimido [1, 2-a] azepin-3-hydroxymethyl; Octahydro-13-oxo-4- (phenylthio) [1] benzothieno [2 ', 3': 4, 5] pyrimido- [1,2-a] azepin-3-oxime-methyl; 4-chloro-l, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo] 1] benzothieno- [2 ', 3': 4,5] pyrimido [1,2-a] azepin -3-hydroxymethyl; 3-N, N-dimethylamino-methylene-2, 3,8,9,10, 11-hexahydro [1] benzo-thieno [2 ', 3': 4,5] pyrimido [1,2-a] azepin- 4.13 (1H, 7H) -dione; 1, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (propylthio) [1] benzo-thieno [2 ', 3': 4, 5] pyrimido- [1,2 -a] zepin-3- (3-oxo) butene-1, and 1, 2, 7, 8, 9, 10, 11, 13-octahydro-13-oxo-4- (butylthio) [1] benzothieno- [ 2 ', 3'; 4,5] pyrimido- [1,2-a] azepin-3- (3-oxo) butene-1, or one of its physiologically acceptable salts.
10. 10. Compound of the formula (I) according to any of the preceding claims 4 to 9, for use • 5 in therapy.
11. 11. Use of a compound of the formula (I) according to any one of the preceding claims 3 to 9, for the treatment or prevention of a condition or disease dependent on a 10 spheroid hormone.
12. 12. Use according to claim 11, wherein the spheroidal hormone-dependent condition or disease is a condition or disease that requires the inhibition of a 17β-hydroxysteroid dehydrogenase enzyme, Preferably of the enzymes 17β-HSD type 1, 17β-HSD type 2, or 17β-HSD type 3.
13. 13. Use of a compound of the formula (I) according to the invention as defined by any of claims 2 to 9. precedents, for the preparation of a A medicament for the treatment and / or prevention of a spheroidal hormone-dependent disease or condition, preferably for a spheroidal hormone-dependent disease or condition that requires the inhibition of a 17β-hydroxysteroid dehydrogenase enzyme, most preferably of 25 the enzymes 17β-HSD type 1, 17β-HSD type 2, or 17β-HSD type 3.
14. 14. Use according to claims 12 or 13, wherein the disease or condition dependent on the spheroid hormone is selected from the group consisting of breast cancer, prostatic carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia, endometriosis, fibroids uterine, uterine leiomyomas, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome, urinary dysfunction, osteoporosis, multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue lesions, skin wrinkles and cataracts.
15. 15. Pharmaceutical composition characterized in that it comprises as an active agent at least one of the compounds of the formula (I) according to any one of claims 2 to 9, and at least one pharmaceutically acceptable carrier.
16. 16. Method of preparing a compound of the formula (I) according to claim 1, characterized in that: g) a compound of the formula or an analog thereof modified in the ring or substituted in the ring, is oxidized, preferably by the action of PCC and celite, to give an oxo-substituted compound of the formula 3 or its analog, h) the oxo-substituted compound of step a) is optionally further subjected to the reaction of Vilsmeier, preferably by P0C13-DMF, to give a carbonyl-substituted compound of the formula 4 or its analog, i) the chloro substituent on the carbonyl substituted compound obtained in step b) is optionally replaced by an alkylthio or arylthio group by subjecting it to the action of a suitable thiol in the presence of a base to give a compound substituted with arylthio or alkylthio of the Formula 5 or its analog, j) the compound substituted with arylthio or alkylthio obtained in step c) is then optionally i) reduced to a compound of formula 6, ii) or reacted with NH 2 OH to give a compound of the formula 7, ok) the compound obtained in step b) is optionally i) reduced to replace the carbonyl group with hydroxyalkyl, or ii) subjected to the action of a suitable thiol in the presence of a base and acetone to replace the chloro substituent with a thiol group and to replace the carbonyl group with oxo-substituted alkenyl, or 1) the compound obtained in step a) is optionally subjected to the action of acetal DMF to introduce a dimethylaminomethylene substituent into the ring adjacent to the oxo substituent.