| Therapeutically active thiophenepyrimidinone compounds and their use -> Monitor Keywords |
|
|
  Therapeutically active thiophenepyrimidinone compounds and their useUSPTO Application #: 20080103131Title: Therapeutically active thiophenepyrimidinone compounds and their use Abstract: Thiopheneprymidinone 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 17β-hydroxysteroid dehydrogenase (17β-HSD) such as 17β-HSD type 1, type 2 or type 3 enzyme. (end of abstract) Agent: Crowell & Moring LLP Intellectual Property Group - Washington, DC, US Inventors: Kristiina Waehaelae, Annamaria Lilienkampf, Sari Alho, Kaisa Huhtinen, Nina Johansson, Pasi Koskimies, Kimmo Vihko USPTO Applicaton #: 20080103131 - Class: 514214020 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of One Nitrogen And Six Carbons, Polycyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos, Ring Nitrogen Of The Seven-membered Hetero Ring Is Shared By An Additional Cyclo Of The Polycyclo Ring System, Plural Ring Nitrogens In The Polycyclo Ring System The Patent Description & Claims data below is from USPTO Patent Application 20080103131. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a division of co-pending application Ser. No. 10/861,922, filed Jun. 7, 2004, which in turn claimed priority from U.S. provisional patent application No. 60/477,017, filed Jun. 10, 2003. FIELD OF THE INVENTION [0002] The present invention relates to novel thiophenepyrimidinone derivatives which represent inhibitory compounds of the 17.beta.-hydroxysteroid dehydrogenase enzymes, preferably of the 17.beta.-hydroxysteroid dehydrogenase type 1 (17.beta.-HSD1), type 2 (17.beta.-HSD2) or type 3 (17.beta.-HSD3) enzyme, to their salts, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds. Furthermore, the invention concerns the therapeutic use of said thiophenepyrimidinone derivatives, particularly their use in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of 17.beta.-hydroxysteroid dehydrogenase enzymes, in particular 17.beta.-HSD type I enzymes, and/or requiring the modulation of the endogenous 17.beta.-estradiol and/or testosterone concentration. BACKGROUND OF THE INVENTION [0003] The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference. [0004] Mammalian 17.beta.-hydroxysteroid dehydrogenases (17.beta.-HSDs) are NAD(H) or NADP(H) dependent enzymes which catalyze--besides other reactions--the final steps in male and female sex hormone biosynthesis. These enzymes convert inactive 17-keto-steroids into their active 17.beta.-hydroxy-forms or catalyze the oxidation of the 17.beta.-hydroxy-forms into the 17-keto-steroids. Because both estrogens and androgens have the highest affinity for their receptors in the 17.beta.-hydroxy form, 17.beta.-HSD enzymes play an essential role in the tissue-selective regulation of the activity of sex steroid hormones. [0005] At present, 10 human members of the 17.beta.-HSD enzyme family have been described (types 1-5, 7, 8, 10, 11 and 12). The human 17.beta.-HSD family members share less than 30% similarity in their primary structure. The 17.beta.-HSDs are expressed in distinct, though in some cases, overlapping patterns. The different types of 17.beta.-HSDs also differ in their substrate and cofactor specificities. In intact cells in culture, the 17.beta.-HSDs catalyze the reaction in a unidirectional way: types 1, 3, 5 and 7 use NADP(H) as a cofactor and catalyze the reductive reaction (activation), while types 2, 4, 8 and 10 catalyze the oxidative reaction (inactivation) using NAD(H) as a cofactor. [see e.g. Labrie et al. (2000) Trends Endocrinol Metab., 11:421-7]. [0006] Due to their essential role in the tissue-selective regulation of the activity of sex steroid hormones 17.beta.-HSDs can be involved in the occurrence and development of estrogen-sensitive pathologies (f. ex. breast, ovarian, uterine and endometrium cancers etc.) and androgen-sensitive pathologies (f. ex. prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Furthermore, many types of 17.beta.-HSD have been shown to be involved in the pathogenesis of particular human disorders. For example, 17.beta.-HSD3 is known to be involved in the development of pseudohermaphroditism, the 17.beta.-HSD8 plays a role in polycystic kidney disease and the 17.beta.-HSD4 is related to the occurrence of bifunctional enzyme deficiency. Therefore treatment of sex steroid-sensitive diseases by administration of specific inhibitors of the 17.beta.-HSDs enzymes have been suggested, optionally in combination with potent and specific antiestrogens and antiandrogens [Labrie F et al. (1997) Steroids, 62:148-58]. [0007] Due to the fact that each type of 17.beta.-HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution, the selectivity of drug action could be achieved by targeting a particular 17.beta.-HSD isozyme. By individual modulation of the particular 17.beta.-HSDs it is possible to influence or even control the local and paracrine concentration of estrogens and androgens in different target tissues. [0008] The best characterized member of the 17.beta.-HSD family is the type 1 17.beta.-HSD [EC 1.1.1.62]. This enzyme could be crystallized in different states of functionality (e.g. with and without ligand and/or co-factor). The 17.beta.-HSD1 catalyzes in vitro the reduction as well as the oxidation between estrone (E1) and estradiol (E2). However, under physiological in vivo conditions the enzyme only catalyzes the reductive reaction from the estrone (E1) to the estradiol (E2). The 17.beta.-HSD1 was found to be expressed in a variety of hormone-dependent tissues, e.g. placenta, mammary gland tissue or uterus and endometrium tissue, respectively. Estradiol itself is, especially in comparison to the significantly less active estrone, a very potent hormone, which regulates the expression of a variety of genes by binding to the nuclear estrogen receptor and plays an essential role in the proliferation and differentiation of the target cell. Physiological as well as pathological cell proliferations can be estradiol dependent. Especially many breast cancer cells are stimulated by a locally raised estradiol concentration. Furthermore, the occurrence or course of benign pathologies such as endometriosis, uterine leiomyomas (fibroids or myomas), adenomyosis, menorrhagia, metrorrhagia and dysmenorrhea is dependent from the existence of significantly high estradiol levels. [0009] Endometriosis is a well-known gynecological disorder that affects 10 to 15% of women in the reproductive age. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area. In women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde menstruation (the most likely mechanism) have the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow. The implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus. The infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tissue. The most common symptoms of endometriosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions. Some women with severe endometriosis are asymptomatic, while women with mild endometriosis may have severe pain. Endometriosis is found in up to 50% of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility. The aims of treatment of endometriosis are pain relief, resolution of the endo-metriotic tissue and restoration of fertility (if desired). The two common treatments are surgery or anti-inflammatory and/or hormonal therapy or a combination thereof. [0010] Uterine leiomyomas (fibroids or myomas), benign clonal tumours, arise from smooth muscle cells of the human uterus. They are clinically apparent in up to 25% of women and are the single, most common indication for hysterectomy. They cause significant morbidity, including prolonged and heavy menstrual bleeding, pelvic pressure and pain, urinary problems, and, in rare cases, reproductive dysfunction. The pathophysiology of myomas is not well understood. Myomas are found submucosally (beneath the endometrium), intramurally (within the myometrium) and subserosally (projecting out of the serosal compartment of the uterus), but mostly are mixed forms of these 3 different types. 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]. They have shown that the ratios of estrogen receptor compared to progesterone and androgen receptor levels were higher in leiomyomas than in the corresponding normal myometrium. Surgery has long been the main treatment for myomas. Furthermore, medical therapies that have been proposed to treat myomas include administration of a variety of steroids such as the androgenic steroids danazol or gestrinone, GnRH agonists and progestogens, whereby the administration is often associated a variety of serious side-effects. [0011] Everything that has been said above in relation to the treatment of uterine leiomyomas and endometriosis equally applies to other benign gynecological disorders, notably adenomyosis, functional menorrhagia and metrorrhagia. These benign gynecological disorders are all estrogen sensitive and are treated in a comparable way as described herein before in relation to uterine leiomyomas and endometriosis. The available pharmaceutical treatments, however, suffer from the same major drawbacks, i.e. they have to be discontinued once the side-effects become more serious than the symptoms to be treated and symptoms reappear after discontinuation of the therapy. [0012] Since the aforementioned malign and benign pathologies are all 17.beta.-estradiol dependent, a reduction of the endogenous 17.beta.-estradiol concentration in the respective tissue will result in an impaired or reduced proliferation of 17.beta.-estradiol cells in said tissues. Therefore, it may be concluded that selective inhibitors of the 17.beta.-HSD1 enzyme are well suited for their use to impair endogenous productions of estrogens, in particular of 17.beta.-estradiol, in myomas, endometriotic, adenomyotic and endometrial tissue. The application of a compound acting as selective inhibitor on the 17.beta.-HSD1 which preferentially catalyzes the reductive reaction will result in a lowered intracellular estradiol-concentration since the reductive conversion of the estrone into the active estradiol is reduced or suppressed. Therefore, reversible or even irreversible inhibitors of the 17.beta.-HSD1 may play a significant role in the prophylaxis and/or treatment of steroid-hormone, in particular 17.beta.-estradiol, dependent disorders or diseases. Furthermore, the reversible or even irreversible inhibitors of the 17-HSD1 should have no or only pure antagonistic binding activities to the estradiol receptor, in particular to the estrogen receptor .alpha. subtype, since agonistic binding of the estrogen receptor would lead to activation and therefore--by regulation of a variety of genes--to the proliferation and differentiation of the target cell. In contrast, antagonists of the estrogen receptor, so called anti-estrogens, bind competitively to the specific receptor protein thus preventing access of endogenous estrogens to their specific binding site. At present it is described in the literature that several malignant disease as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia may be treated by the administration of a selective 17.beta.-HSD1 inhibitor. Furthermore, a selective 17.beta.-HSD1 inhibitor may be useful for the prevention of the aforementioned hormone-dependent cancers, especially breast cancer. [0013] Several reversible or irreversible inhibitors of the 17.beta.-HSD1 enzyme of steroidal and even non-steroidal origin are already known from the literature. The characteristics of these inhibitory molecules, which mainly have a substrate or cofactor-like core structure, have been reported in the literature [reviewed in: Poirier D. (2003) Curr Med. Chem. 10:453-77]. [0014] A further well characterized member of the 17.beta.-HSD family is the 17.beta.-HSD type 3 enzyme (17.beta.-HSD3). The 17.beta.-HSD3 has a distinct feature compared to other 17HSDs: it is found to be expressed almost exclusively the testis, whereas the other isoenzymes are expressed more widely in several tissues. 17.beta.-HSD3 has a crucial role in androgen biosynthesis. It converts 4-androstene-3,17-one (A) to testosterone (T). The biological significance of the 17.beta.-HSD3 is of undeniable physiological importance. Mutations in the gene for 17.beta.-HSD3 have found to lead to decreased T formation in the fetal testis and consequently to a human intersex disorder termed male pseudohermaphroditism [Geissler W M et al. (1994) Nat. Genet., 7:34-9]. [0015] With regard to the indication prostate cancer, the primary cancer cells mostly retain their responsiveness to androgens in their regulation of proliferation, differentiation, and programmed cell death for some period. At present, androgen deprivation is the only effective systemic hormonal therapy available for prostate cancer. The development of selective inhibitors against 17.beta.-HSD3 is a new therapeutic approach for the treatment of androgen dependent disease [Labrie et al. (2000) Trends Endocrinol Metab., 11:421-7]. Furthermore, Oefelein et al. reported that the depot GnRH analogue fails, in nearly 20% of cases, to achieve castrate levels of T in men [Oefelein MG & Cornum R (2000) J Urol.; 164:726-9]. In order to improve the response rate to endocrine therapy for men with prostate cancer it may be important to selectively inhibit testicular 17.beta.-HSD3 activity. Besides prostate cancer, many other androgen-sensitive diseases, i.e. diseases whose onset or progress is aided by androgenic activity, may be treated by selectively inhibiting 17.beta.-HSD3 activity. These diseases include but are not limited to benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome. Furthermore, considering the fact that 17.beta.-HSD3 is found mainly in the testis, the development of potent inhibitors could be of interest for blocking spermatogenesis and as an anti-fertility agent for males. [0016] Several reversible or irreversible inhibitors of the 17.beta.-HSD3 enzymes of steroidal and even non-steroidal origin are already known from the literature. The characteristics of these inhibitory molecules have been reported in the literature [reviewed in: Poirier D. (2003) Curr Med Chem. 10:453-77]. For example, U.S. Pat. No. 6,541,463 discloses androsterone derived inhibitors for 17.beta.-HSD3. These derivatives have been synthesized by parallel solid- and liquid-phase chemistry and some of these compounds showed 2 to 18-fold higher inhibition activity than that of the natural substrate of the enzyme, A-dione, used itself as a inhibitor. Furthermore, the international patent application WO 01/42181 discloses benzyl-tetralins, the chemical structure of which is related to that of the phytoestrogen biochanin, as 17.beta.-HSD3 inhibitors. Furthermore, international patent applications WO 98/32724, WO 98/30556 and WO 99/12540 disclose tetralone, benzopyrane and benzofuranone derivatives, which have a 17.beta.-HSD inhibitory activity, for the treatment of hormone sensitive diseases. [0017] Microsomal 17.beta.-hydroxysteroid dehydrogenase of human endometrium and placenta (designated 17.beta.-HSD type 2 or 17.beta.-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]. The recombinant 17.beta.-HSD2 converts the highly active 17.beta.-hydroxysteroids such as estradiol (E2), testosterone (T), and dehy-drotestosterone (DHT) to their inactive keto forms. In addition, the 17.beta.-HSD2 can, to a lesser extent, also convert 20.beta.-hydroxyprogesterone (20.beta.P) to progesterone (P). The broad tissue distribution together with the predominant oxidative activity of 17.beta.-HSD2 suggest that the enzyme may play an essential role in the inactivation of highly active 17.beta.-hydroxysteroids, resulting in diminished sex hormone action in target tissues. Dong and colleagues showed significant 17.beta.-HSD2 activity in cultured human osteoblasts and osteoblast-like osteosarcoma cells MG63 and TE85, but not in SaOS-2 [Dong Y et al. (1998) J. Bone Min. Res., 13:1539-1546]. The potential for interconversion of E1 to E2, T to A, and DHT to A by bone cells could therefore represent important mechanism for the local regulation of intracellular ligand supply for the estrogen and androgen receptors in the osteoblasts and other steroid sensitive cells. This modulation of steroid levels may be employed for a wide variety of indications, including the following: for the prevention and treatment of osteoporosis, for the treatment of ovarian cancer, 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 androgen-dependent hair-loss. [0018] Several reversible or irreversible inhibitors of the 17.beta.-HSD2 enzymes of steroidal and even non-steroidal origin are already known from the literature. The characteristics of these inhibitory molecules have been reported in the literature [reviewed in: Poirier D. (2003) Curr Med Chem. 10:453-77]. In addition, the international patent application WO 02/26706 discloses 17.beta.-HSD2 inhibitors of non-steroidal origin. Some thienopyrimidinones derivatives that are described as being useful in therapy have already been disclosed in the literature: The German patent application DE 2411273 (Schering AG) discloses compounds having anti-inflammatory activity. Manhas et al de-scribe the synthesis and antiinflammatory activity of some substituted thienopyrimidinones [Manhas M S et al. (1972) J Med Chem. 15(1):106-7]. Kapustina et al. describe the synthesis and antibacterial and chemotherapeutic or antitubecular activity of some substituted thienopyrimidones [Kapustina M V et al. (1992) Khimiko-Farmatsevticheskii Zhurnal 26(1):56-7; and Kapustina M V et al (1991) Khimiko-Farmatsevticheskii Zhurnal 25(7): 38-9]. [0019] Furthermore, several other Thienopyrimidinones derivatives have been described but were not related to any medical use so far. For example, the compounds 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-carboxaldehyde (CAS reg. no. 333774-42-8) and 1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(chloro)-[1]benzothieno-[2',3':4,5]- pyrimido[1,2-a]azepine-3-carboxaldehyde (CAS reg. no 299962-60-0) are commercially available. Further substituted thienopyrimidones have already been disclosed, e.g.: [0020] 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 (CA reg. no. 333774-26-8); [0021] 2,3,8,9,10,11-hexahydro-[1]benzothieno[2',3':4,5]pyrimido[1,2-a]azepine-4- ,13(1H,7H)-dione (CA reg. no. 141581-80-8); [0022] 2,3,8,9-Tetrahydro[1]benzothieno[2,3-d]pyrrolo[1,2-a]pyrimidine-6,10(1H,7- H)-dione (CA reg. no. 141581-81-9), [0023] 8,9,10,11-tetrahydro-4-hydroxy-[1]benzothieno[2',3':4,5]pyrimido[1,2-a]az- epin-13(7H)-one (CA reg. no. 333780-19-1); [0024] 3-Butyl-2,7-dimethyl-4-b,5,6,7,8,8a-hexahydro-3H-benzo[4,5]thieno[2,3-d]p- yrimidin-4-one (CA reg. no. 39625-80-4); [0025] 1,2,3,4,5,8,9,10,11,12-Decahydro-14H-cyclohepta[4',5']thieno[2',3':4,5]py- rimido-[1,2a]azepin-14-one-4-oxime (CA reg. no. 299962-59-7); [0026] 1,2,3,4,5,8,9,10,11,12-Decahydro-14H-cyclohepta[4',5']thieno[2',3':4,5]py- rimido-[1,2-a]azepin-14-one-3-oxime (CA reg. no. 296798-31-7); [0027] 1,2,3,4,7,9,10,12-Octahydro-12-oxo-8H-[1]benzothieno[2,3-d]pyrido[1,2-a]p- yrimidine-7-carboxylic acid ethyl ester (CA reg no. 329059-69-0); [0028] 1,2,3,4-Tetrahydro-12H-[1]benzothieno[2,3-d]pyrido[1,2-a]pyrimidin-12-one (CA Reg. No. 60943-07-9), and [0029] 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 (CA Reg. No. 677320-14-8) [0030] However, according to the inventors' knowledge none of the already known compounds described above has been described as useful in the treatment and/or prevention of a steroid hormone dependent disease or disorder, particularly a steroid hormone dependent disease or disorder requiring the inhibition of the 17.beta.-hydroxysteroid dehydrogenase (17HSD) type 1, type 2 or type 3 enzyme. [0031] There is a need for the development of compounds that are selectively inhibiting the 17.beta.-HSD1, 17.beta.-HSD3 and/or 17.beta.-HSD2 enzyme, while desirably failing to inhibit substantially other members of the 17.beta.-HSD protein family, or other catalysts of sex steroid degradation or activation. In particular, it is an aim of the present invention to develop selective inhibitors of the 17.beta.-HSD1 enzyme, whereby in addition the compounds have no or only pure antagonistic binding affinities to the estrogen receptor (both subtypes .alpha. and .beta.). Continue reading... Full patent description for Therapeutically active thiophenepyrimidinone compounds and their use Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Therapeutically active thiophenepyrimidinone compounds and their use patent application. Patent Applications in related categories: 20080103130 - Benzazepin-2(1h)-one derivatives - and pharmaceutically acceptable salts thereof are agonists at the beta-2 adrenoceptor. They are useful as feed additives for livestock animals. Compounds of formula (I) ... ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Therapeutically active thiophenepyrimidinone compounds and their use or other areas of interest. ### Previous Patent Application: Benzazepin-2(1h)-one derivatives Next Patent Application: Fused heterocyclic compounds Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Therapeutically active thiophenepyrimidinone compounds and their use patent info. IP-related news and info Results in 0.2922 seconds Other interesting Feshpatents.com categories: Novartis , Pfizer , Philips , Polaroid , Procter & Gamble , |
||
