MX2008007554A - 2-adamantylurea derivatives as selective 11î²-hsd1 inhibitors - Google Patents

Abstract

The present invention relates to 2-adamantylurea derivatives of formula (I) as selective inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and the use of such compounds for the treatment and prevention of metabolic syndrome, diabetes, insulin resistance, obesity, lipid disorders, glaucoma, osteoporosis, cognitive disorders, anxiety, depression, immune disorders, hypertension and other diseases and conditions.

Description

DERIVATIVES OF 2-ADAMANTI UREA AS SELECTIVE INHIBITORS OF 11BETA-HSD1 FIELD OF THE INVENTION The present invention relates to 2-adamantylurea derivatives as selective inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSDl) and to the use of such compounds for the treatment and prevention of metabolic syndrome, diabetes, insulin resistance, obesity, lipid disorders, glaucoma, osteoporosis, cognitive disorders, anxiety, depression, immune disorders, hypertension and other diseases and conditions. BACKGROUND OF THE INVENTION Hydroxysteroid dehydrogenases (HSD) regulate the occupation and activation of steroid hormone receptors by converting steroid hormones into their inactive metabolites. For a recent review, see Nobel et al., Eur. J. Biochem. 2001, 268: 4113-4125. There are numerous kinds of HSD. The 11-beta-hydroxy-steroids dehydrogenases (llß-HSD) catalyze the interconversion of active glucocorticoids (such as cortisol and corticosterone), and their inert forms (such as cortisone and 11-dehydrocorticosterone). The isoform 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSDl) is widely expressed in the liver, adipose tissue, brain, REF. : 192751 lung and other glucocorticoid tissue, while the expression of isoform 2 (11β-HSD2) is limited to tissues that express the mineralocorticoid receptor, such as kidney, intestine and placenta. Then, the inhibition of llß-HSD2 is associated with serious side effects, such as hypertension. Excess cortisol is associated with numerous disorders, including diabetes, obesity, dyslipidemia, insulin resistance and hypertension. The administration of llß-HSDl inhibitors reduces the level of cortisol and other llß-hydroxysteroids in target tissues, thus decreasing the effects of excessive amounts of cortisol and other llß-hydroxysteroids. Thus, llß-HSDl is a potential target for therapy associated with several disorders that can be alleviated by reducing the action of glucocorticoids. Accordingly, the inhibition of llß-HSDl can be used to prevent, treat or control diseases mediated by abnormal elevated levels of cortisol and other llß-hydroxysteroids, such as diabetes, obesity, hypertension or dyslipidemia. Inhibition of llß-HSDl activity in the brain to reduce cortisol levels may also be useful in treating or reducing anxiety, depression, cognitive impairment or age-related cognitive dysfunction (Seckl, et al., Endocrinology, 2001, 142: 1371-1376). Cortisol is an important anti-inflammatory hormone and very recognized that also acts as an antagonist to the action of insulin in the liver, so that sensitivity to insulin is reduced, resulting in increased gluconeogenesis and high levels of glucose in the liver. Patients who already have impaired glucose tolerance are more likely to develop type 2 diabetes in the presence of abnormal high levels of cortisol (Long et al., J. Exp. Med. 1936, 63: 465-490; Houssay, Endocrinology 1942, 30: 884-892). In addition, it was found that llß-HSDl plays an important role in regulating the effect of local glucocorticoids and the production of glucose in the liver (Jamieson et al., J. Endocrinol, 2000, 165: 685-692). In Walquer, et al., J. Clin. Endocrinol Metab. 1995, 80: 3155-3159, administration of the nonspecific IIß-HSDl inhibitor carbenoxolone was reported to result in increased sensitivity to hepatic insulin in humans. On the other hand, the hypothetical mechanism of action of llß-HSD1 in the treatment of diabetes has supported several experiments conducted in mice and rats. These studies demonstrated that mRNA levels and the activities of two key enzymes of hepatic glucose production, phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (GdPase) were reduced after administration of llß-HSDl inhibitors. In addition, it was shown that blood glucose levels and Hepatic glucose production were reduced in llß-HSDl knockout mice. Additional data gathered by this murine knockout model also confirm that the inhibition of llß-HSDl does not cause hypoglycemia, since the basal levels of PEPCK and GdPase are regulated independently of the glucocorticoids (Kotelevtsev et al., Proc. Nati. Acad. Sci. USA 1997, 94: 14924-14929). Accordingly, administration of a therapeutically effective amount of a llß-HSDl inhibitor is effective in the treatment, control and alleviation of diabetes symptoms, especially non-insulin dependent diabetes (NIDDM, type 2 diabetes mellitus) and regular administration A therapeutically effective amount of a llß-HSDl inhibitor delays or prevents the onset of diabetes, particularly in humans. The effect of elevated cortisol levels is also seen in patients with Cushing's syndrome, a metabolic disease characterized by elevated levels of cortisol in the bloodstream. Patients with Cushing's syndrome often develop NIDDM. Excess cortisol levels have been associated with obesity, perhaps due to an increase in hepatic gluconeogenesis. Abdominal obesity is closely associated with glucose intolerance, diabetes, hyperinsulinemia, hypertriglyceridemia and other metabolic syndrome factors, such as high blood pressure, high VLDL and reduced HDL (Montague et al., Diabetes, 2000, 49: 883-888). It has also been reported that the inhibition of llß-HSDl in preadipocytes (stromal cells) results in a decrease in the rate of differentiation in adipocytes. It is anticipated that this results in less expansion (possibly reduction) of the omental fat deposit, which may lead to a reduction of central obesity (Bujalska et al., Lancet 1997, 349: 1210-1213). Accordingly, administration of an effective amount of a llß-HSDl inhibitor is useful in the treatment or control of obesity. Long-term treatment with a llß-HSDl inhibitor is also useful in delaying or preventing the onset of obesity, especially if the patient uses a llß-HSDl inhibitor in combination with diet and exercise control. By reducing insulin resistance and maintaining serum glucose at normal concentrations, the compounds of the present invention are also useful in the treatment and prevention of conditions that accompany type 2 diabetes and insulin resistance, including metabolic syndrome, obesity , reactive hypoglycaemia and diabetic dyslipidemia. It is anticipated that the inhibition of llß-HSDl in mature adipocytes will attenuate the secretion of plasminogen activator inhibitor 1 (PAI-1), which is a risk factor independent cardiovascular, as reported in Halleux et al., J. Clin. Endocrinol Metab. 1999, 84: 4097-4105. In addition, the existence of a correlation between glucocorticoid activity and certain cardiovascular risk factors has been demonstrated. This suggests that reducing the effects of glucocorticoids would be beneficial in the treatment or prevention of certain cardiovascular diseases (Alquer et al., Hypertension 1998, 31: 891-895; and Fraser et al., Hypertension 1999, 33: 1364 1368 ). Since hypertension and dyslipidemia contribute to the development of atherosclerosis, and that the inhibition of llß-HSDl activity and the reduction of the amount of cortisol are beneficial in the treatment or control of hypertension, the administration of a therapeutically effective amount Effectiveness of a llß-HSDl inhibitor of the present invention may also be especially beneficial in the treatment, control or delay of onset or prevention of atherosclerosis. IIß-HSDl has also been implicated in the appetite control process and, consequently, is thought to play an additional role in weight-related disorders. It is known that adrenalectomy attenuates the effect of fasting in the increase of food intake and hypothalamic expression of neuropeptide Y. This suggests that glucocorticoids play an important role in the promotion of food intake and that the inhibition of llß-HSDl on the brain can increase satiety, which results in a decrease in food intake (Woods et al., Science 1998, 280: 1378-1383). Another possible therapeutic effect associated with the modulation of llß-HSDl refers to its relationship with various pancreatic pathologies. It has been reported that the inhibition of llβ-HSDl in murine pancreatic beta cells increases insulin secretion stimulated by glucose (Davani et al., J. Biol. Chem. 2000, 275: 34841-34844). This is the conclusion of the previous discovery that glucocorticoids were previously responsible for the reduced pancreatic release of insulin in vivo (Billaudel et al., Horm Metab. Res. 1979, 11: 555-560). Accordingly, it is suggested that the inhibition of llß-HSDl would result in other beneficial effects in the treatment of diabetes, in addition to the expected effects on the liver and fat reduction. Excessive levels of cortisol on the brain can also result in loss or neuronal dysfunction by potentiation of neurotoxins. The administration of an effective amount of a llß-HSDl inhibitor results in the reduction, alleviation, control or prevention of cognitive impairment associated with age and neuronal dysfunction. Cognitive impairment has been associated with aging, and excessive levels of cortisol in the brain (see J. R. Seckl and B. R. Walquer, Endocrinology, 2001, 142: 1371-1376, and the references cited therein). 11β-HSDl also regulates glucocorticoid activity in the brain and thus contributes to neurotoxicity (Rajan et al., Neuroscience 1996, 16: 65-70, Seckl et al., Necroendocrinol., 2000, 18: 49-99). It is known that stress and / or glucocorticoids influence cognitive function (de Quervain et al., Nature 1998, 394: 787-790), and unpublished results indicate significant improvement of memory in rats treated with a non-specific inhibitor. of llß-HSDl. These reports, in addition to the known effects of glucocorticoids on the brain, suggest that the inhibition of llß-HSDl in the brain may have a positive therapeutic effect against anxiety, depression and related conditions (Tronche et al., Nature Genetics 1999 , 23: 99-103). llß-HSDl reactivates 11-dehydrocorticosterone to corticosterone in hippocampal cells and can potentiate the neurotoxicity of kinases, which results in impaired learning related to aging. Accordingly, it is believed that selective inhibitors of llß-HSD1 protect against the decline of hippocampal function with aging (Yau et al., Proc Nati, Acad Sci USA 2001, 98: 4716-4721). Consequently, it has been hypothesized that the inhibition of llß-HSDl in the Human brain could protect against the deleterious effects mediated by glucocorticoids on neuronal function, such as cognitive decline, depression, and increased appetite. On the other hand, llß-HSDl is thought to play an important role in immunomodulation based on the general perception that glucocorticoids suppress the immune system. It is known that there is a dynamic interaction between the immune system and the HPA axis (hypothalamic-pituitary-adrenal) (Rook, Baillier's Clin, Endocrinol, Metab, 2000, 13: 576-581), and glucocorticoids contribute to the balance between responses measured by cells and humoral responses. The increase in glucocorticoid activity, which can be induced by stress, is associated with a humoral response and as such, the inhibition of llß-HSDl can result in a variation of the response to a cellular reaction. In certain disease states, such as tuberculosis, leprosy and psoriasis, and even in conditions of excessive stress, the high activity of glucocorticoids varies the immune response to humoral, when in fact a cellular response would be more beneficial for the patient. The inhibition of llß-HSDl activity and the corresponding reduction of glucocorticoid levels on the other hand varies the immune response towards a cellular response (D. Mason, Immunology Today, 1991, 12: 57-60, and G. A. Vt. Rook, Baillier's Clin. Endocrinol Metab., 1999, 13: 576-581). Accordingly, an alternative utility of the inhibition of llß-HSDl would be to increase a temporary immune response associated with immunization to ensure that a cellular response is obtained. Recent reports suggest that the levels of the glucocorticoid target and HSD receptors are connected to the susceptibility to glaucoma (J. Stokes et al., Invest, Ophthalmol, 2000, 41: 1629-1638). In addition, a connection was recently reported between the inhibition of llß-HSDl and a reduction in infraocular pressure (Walquer et al., Poster P3-698 at the Congress of the Endocrine Society on June 12-15, 1999, San Diego) . It was demonstrated that administration of the non-specific inhibitor of llß-HSDl carbenoxolone results in the reduction of infraocular pressure by 20% in normal patients. In the eye, llß-HSDl is expressed exclusively in the basal cells of the cornea epithelium, the non-pigmented epithelium of the cornea (the site of aqueous production), the ciliary muscle, and the sphincter muscles and iris dilators . In contrast, the distant isoenzyme 11-hydroxysteroid dehydrogenase type 2 ("llß-HSD2") has high expression in the non-pigmented ciliary epithelium and the endothelium of the cornea. No HSD has been found in the trabecular meshwork, which is the site of sewer system. Accordingly, it is suggested that llß-HSDl has an important role in aqueous production and the inhibition of llß-HSDl activity is useful in reducing infraocular pressure in the treatment of glaucoma. Glucocorticoids also play an essential role in the development and function of the skeleton but are detrimental to such development and function when they are in excess. Glucocorticoid-induced bone loss is partially derived from the suppression of osteoblast proliferation and collagen synthesis, as reported in C. H. Kim et al., J. Endocrinol. 1999, 162: 371-379. It has been reported that the detrimental effects of glucocorticoids on the formation of bone nodules can be diminished by the administration of carbenoxolone, which is a non-specific inhibitor of llß-HSDl (CG Bellows et al., Bone 1998, 23: 119- 125). Other reports suggest that llß-HSDl may be responsible for providing increased levels of active glucocorticoids in osteoclasts, and consequently in increased bone resorption (M. S. Cooper et al., Bone 2000, 27: 375-381). These data suggest that the inhibition of llß-HSDl may have beneficial effects against osteoporosis through one or more mechanisms that could act in parallel. Inhibitors of llß-HSDl are known, for example, from WO0410629, WO03065983, WO04089896, WO04089380, WO04065351, WO04033427 or WO04041264. However, the 2-adamantylurea derivatives are not described as active inhibitors of llß-HSDl. The adamantylurea derivatives are described, for example, in US4349552 or WO03078400. The description of these publications, however, does not cover derivatives of 2-adamantylurea of the present invention or the use of the compounds described as llß-HSDl inhibitors. Accordingly, since the continuing need for advantageous therapeutic agents is maintained, a preferred object of the present invention is to provide new pharmaceutically active compounds for the treatment of diseases such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders. , depression, hypertension and others. The citation of any reference in this application does not represent an admission that the reference is prior art of the present application. SUMMARY OF THE INVENTION Surprisingly, it was found that the compounds of the present invention are highly active llß-HSDl inhibitors. Accordingly, one embodiment of the present invention are compounds of the formula I wherein is H, OH, F, Br or ORB, is O or S, Rz is H, methyl, ethyl or isopropyl, or R2, Y and the N to which they are attached form a saturated Cs-C8 ring, optionally substituted with R3, R4 and / or R5; is a direct bond or alkyl C? ~ C4 or alkyl C? ~ C4-oxy, W is C4-Cβ cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted with R3, R4 and / or R5; RJ R ^ R- are, independently of each other, H, Hal, OH, alkyl, C 1 -C 4 alkyl-oxy, benzyloxy, phenoxy, phenyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfañyl, dimethylamino, S (O) n (CH2) mCH3, C 1 -C 4 -alkyloxycarbonyl alkyl, C 1 -C 4 alkylcarbonyl or R 6 R 7 N- C 1 -C 8 alkyl-oxy, is 0-2, R6, R7 are, independently of each other, C? -C4 alkyl or form, together with the N atom, a heterocyclic ring saturated with 4-8 C atoms, R8 is alkyl, C (0) R9, C ( 0) NH2 or C (0) NR9R10, R9 is H, C? -C8 alkyl or C? -C8 cycloalkyl, R10 is alkyl or the group NR9R10 in C (0) NR9R10 is heterocyclyl, and its salts, derivatives, prodrugs, Physiologically acceptable solvates and stereoisomers, including their mixtures in all proportions. A preferred embodiment of the present invention are compounds according to formula I, wherein R1 is H, Z is O, R2 is H or methyl, and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Another preferred embodiment of the present invention are compounds according to formula I, wherein R1 is OH or F, Z is O, R2 is H or methyl, and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Another preferred embodiment of the present invention are compounds according to formula I, wherein R1 is OR8 and its physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers, including mixtures thereof in all proportions. Another preferred embodiment of the present invention are compounds according to formula I, wherein W is C4-C8 cycloalkyl or aryl, optionally substituted with R3, R4 and / or R5; and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Another preferred embodiment of the present invention are compounds according to formula I, wherein W is cyclopentyl, phenyl, naphthyl or indanyl, and their physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers, including their mixtures in all proportions. Another particularly preferred embodiment of the present invention are compounds according to formula I, wherein W is phenyl, and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions.

Another preferred embodiment of the present invention are compounds according to formula I, wherein And it is a direct bond, and its salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Another preferred embodiment of the present invention are compounds according to formula I, wherein W is heterocyclyl or heteroaryl, optionally substituted with R3, R4 and / or R5; and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Another preferred embodiment of the present invention are compounds according to formula I, wherein W is piperidinyl, pyrrolidinyl, furanyl, imidazolyl, pyridinyl, thiophenyl, triazolyl, benzodioxinyl or isoxazolyl, and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Another preferred embodiment of the present invention are compounds according to formula I, wherein And it is a direct bond, and its salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Another particularly preferred embodiment of the present invention are compounds according to formula I, selected from the group consisting of a) l-Adamantan-2-yl-3- (4-methoxy-2-methyl-phenyl) -urea b) l-Adamantan-2-yl-3- (3-trifluoromethyl-phenyl) -urea c) l-Adamantan-2-yl-3- (3-chloro-phenyl) -urea d) l-Adamantan-2-yl-3- (2-trifluoromethyl-phenyl) -urea e) l-Adamantan- 2-yl-3- (2,3-dichloro-phenyl) -urea f) l-Adamantan-2-yl-3- (3,5-bis-trifluoromethyl-phenyl) -urea g) Ethyl ester of 2-acid (3-adamantan-2-yl-ureido) -benzoic h) l-Adamantan-2-yl-3- (3, 5-dimethoxy-phenyl) -urea i) l-Adamantan-2-yl-3- (4 -chloro-2-trifluoromethyl-phenyl) -urea j) l-Adamantan-2-yl-3- (2,4,5-trimethyl-1-phenyl) -urea k) l-Adamantan-2-yl-3- (4 -butoxy-phenyl) -urea 1) 4- (3-adamantan-2-yl-ureido) -benzoic acid butyl ester m) 1-Adamantan-2-i1-3-phenethyl-urea n) Dimethyl acid ester - (3-adamantan-2-yl-ureido) -isophthalic o) l-Adamantan-2-yl-3- (2-methylsulfanyl-phenyl) -urea p) l-Adamantan-2-yl-3-biphenyl-4-yl-urea q) l-Adamantan-2-yl-3- (2-thiophen-2-yl-ethyl) -urea r) l-Adamantan- 2-yl-3- (-bromo-phenyl) -urea s) l-Adamantan-2-yl-3- (3-chloro-4-methyl-phenyl) -urea t) l-Adamantan-2-yl-3 - (3, -dimethyl-phenyl) -urea u) l-Adamantan-2-yl-3- (3-ethyl-phenyl) -urea v) l-Adamantan-2-yl-3- (4-chloro-3) -trifluoromethyl-phenyl) -urea w) l-Adamantan-2-yl-3- (4-iodo-phenyl) -urea x) l-Adamantan-2-yl-3-naphthalen-2-yl-urea y) l -Adamantan-2-yl-3- (3-fluoro-4-methyl-phenyl) -urea z) l-Adamantan-2-yl-3- (5-fluoro-2-methyl-phenyl) -urea aa) l -Adamantan-2-yl-3- (2,6-dichloro-pyridin-4-yl) -urea bb) l-Adamantan-2-yl-3- (3,4-difluoro-phenyl) -urea) -Adamantan-2-yl-3- (4-benzyloxy-phenyl) -urea dd) l-Adamantan-2-yl-3- (2-phenoxy-phenyl) -urea ee) l-Adamantan-2-yl-3 - (4-bromo-2-fluoro-phenyl) -urea ff) l-Adamantan-2-yl-3- (2,3, -trifluoro-phenyl) -urea gg) l-Adamantan-2-yl-3- (4-dimethylamino-phenyl) -urea hh) l-Adamantan-2-yl-3- (3-trifluoromethylsulfanyl-phenyl) -urea ii) l-Adamantan-2-yl-3- (3-methyl-benzyl) -urea jj) l-Adamantan-2- il-3- (2-fluoro-3-trifluoromethyl-phenyl) -urea kk) l-Adamantan-2-yl-3- (2, -dibromo-phenyl) -urea 11) l-Adamantan-2-yl-3- (3,5-dichloro-2-hydroxy-4-methyl-phenyl) -urea) methyl ester of 2- (3-adamantan-2-yl-ureido) acid -benzoic nn) l-Adamantan-2-yl-3-cyclopentyl-urea oo) l-Adamantan-2-yl-3- (2-methoxy-phenyl) -urea pp) l-Adamantan-2-yl-3- (3-methylsulfanyl-phenyl) -urea qq) l-Adamantan-2-yl-3- (5-chloro-2-methoxy-phenyl) -urea rr) 1- (4-Acetyl-phenyl) -3-adamantan- 2-yl-urea ss) l-Adamantan-2-yl-3-furan-2-ylmethyl-urea tt) l-Adamantan-2-yl-3- (4-methoxy-benzyl) -urea uu) l-Adamantan -2-yl-3- (4-chloro-phenyl) -urea vv) l-Adamantan-2-yl-3- (4-methoxy-phenyl) -urea ww) l-Adamantan-2-yl-3- ( 2-fluoro-5-methyl-phenyl) -urea xx) l-Adamantan-2-yl-3- (2,4-difluoro-phenyl) -urea yy) 1- (3-Acetyl-phenyl) -3-adamantan -2-il-urea zz) l-Adamantan-2-yl-3- (2-ethoxy-phenyl) -urea aaa) Methyl ester of 4- (3-adamantan-2-yl-ureido) -benzoic acid bbb) l-Adamantan-2- il-3- (2,4-dimethoxy-phenyl) -urea ecc) l-Adamantan-2-yl-3- (2, 5-dimethoxy-phenyl) -urea ddd) l-Adamantan-2-yl-3- (3, 4-dimethoxy-phenyl) -urea eee) l-Adamantan-2-yl-3- (3-chloro-4-methoxy-phenyl) -urea fff) 3- (3-adamantan-2) methyl ester -yl-ureido) -2-methyl-benzoic ggg) l-Adamantan-2-yl-3- [2- (2, 3-dimethoxy-phenyl) -ethyl] -urea hhh) l-Adamantan-2-yl- 3- [2- (3, 5-dimethoxy-phenyl) -ethyl] -urea iii) l-Adamantan-2-yl-3- (5-chloro-2,4-dimethoxy-phenyl) -urea jjj) l- Adamantan-2-yl-3- ((R) -l-phenyl-ethyl) -urea kkk) l-Adamantan-2-yl-3- (2-difluoromethoxy-phenyl) -urea 111) l-Adamantan-2- il-3- (4-difluoromethoxy-phenyl) -urea mmm) l-Adamantan-2-y1-3- (6-fluoro-H- benzo [1,3] dioxin-8-yl) -urea nnn) 1- Adamantan-2-i1-3-thiophen-3-yl-urea ooo) l-Adamantan-2-yl-3- (4-fluoro-phenyl) -urea PPP) l-Adamantan-2-yl-3- (3-methoxy-phenyl) -urea qqq) l-Adamantan-2-yl-3- (4-fluoro-3-methyl-phenyl) -urea (rrr) l-Adamantan-2-yl-3- (4-methylsulfanyl) phenyl) -urea sss) l-Adamantan-2-yl-3- (4-ethoxy-phenyl) -urea ttt) 3- (3-adamantan-2-yl-ureido) -benzoic acid methyl ester uuu) -Adamantan-2-yl-3- (3-methyl-5-phenyl-isoxazol-4-yl) -urea vvv) l-Adamantan-2-yl-3- (1-phenyl-ethyl) -urea www) l -Adamantan-2-yl-3- [1- (4-methoxy-phenyl) -ethyl] -urea xxx) 1- (5-hydroxy-adamantan-2-yl) -3- (4-methoxy-2-methyl) phenyl) -urea yyy) l-Adamantan-2-yl-3- (2-hydroxy-l-phenyl-ethyl) -urea zzz) l-Adamantan-2-yl-3-indan-l-yl-urea aaaa ) Adamantan-2-pyrrolidin-1-carboxylic acid ilamide bbbb) Adamantan-2-ylide of piperidin-1-carboxylic acid cccc) Adamantan-2-ylamide of 3-methyl-piperidine-1-carboxylic acid dddd) l-Adamantan -2-il-3- (1H- [l, 2,4] triazol-3-yl) -urea eeee) 3-Adamantan-2-yl-l-methyl-l- (2-pyridin-2-yl-ethyl) -urea ffff) 4- [2- (3-adamantan-2-yl-l-methyl -ureido) - ethoxy] -benzoic gggg) 4- [2- (3-Adamantan-2-yl-1-methyl-ureido) -ethoxy] -benzoic acid methyl ester hhhh) 3- (3-adamantan-2 acid -yl-ureido) -2-methylbenzoic acid iiii) 2- (3-adamantan-2-yl-ureido) -benzoic acid jjjj) 4- (3-adamantan-2-yl-ureido) -benzoic acid kkkk) -Adamantan-2-yl-3- (4-hydroxy-2-methyl-phenyl) -urea lili) l-Adamantan-2-yl-3- (2-methyl-4- (2-piperidin-1-yl- etoxil) phenyl) -urea mmmm) 4- (((S) -3-methyl-piperidin-l-carbonyl) -amino] -adamantan-1-yl acetic acid ester nnnn) 4- ((S) - ester 3-methyl-piperidin-1-carbonyl) -amino] -adamantan-1-yl of cyclohexanecarboxylic acid oooo) 4- [((S) -3-methyl-piperidin-1-carbonyl) -amino] -adamantan-1 ester - 2,2-dimethylpropionic acid and its physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers, including mixtures in all proportions. The nomenclature used herein to define compounds, especially the compounds according to the invention, is generally based on the rules of the IUPAC organization for chemical compounds and especially organic compounds. "Alkyl", as well as other groups having the prefix "alc / alq", such as alkoxy and alkanoyl, means carbon chains which may be linear or branched and their combinations, unless the carbon chain is otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. Where the number of carbon atoms specified, for example, of C3-C2O permits, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C? -C6 is intended. Especially preferred is C alquilo ~C alkyl. A C 1 -C 4 alkyl radical is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. C4-C8-cycloalkyl is a subgroup of alkyl and is understood as a monocyclic hydrocarbon saturated with 4 to 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. A cycloalkyl group is in general monocyclic, unless otherwise stated. The cycloalkyl groups are saturated, unless otherwise defined. A C-C8 cycloalkyl radical is, for example, a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. The term "C 1 -C 4 alkyl-oxy" means alkoxy groups of a straight or branched configuration with the indicated number of carbon atoms. The C 1 -C 4 -oxi alkyl is, for example, a methoxy, ethoxy, propoxy, isopropoxy and the like. The term "C 1 -C 4 -alkyloxycarbonyl" refers to straight or branched chain esters of a carboxylic acid derivative of the present invention with 1-4 C atoms, ie, methyloxycarbonyl (MeOCO-), ethyloxycarbonyl or butyloxycarbonyl . The term "C 1 -C 4 alkylcarbonyl" refers to straight or branched chain alkyl with 1-4 C atoms and a carboxylic acid group. "Aryl" means a system of mono- or polycyclic aromatic rings containing carbon ring atoms. Preferred aryls are monocyclic or bicyclic aromatic ring systems of 6-10 members. Examples of "aryl" groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, indanyl, and substituted derivatives thereof. The most preferred aryl is phenyl.

"Heterocycle" and "heterocyclyl" refer to saturated or unsaturated nonaromatic ring systems or systems containing at least one heteroatom selected from 0, S, and N, which also include the oxidized forms of sulfur, namely, SO. and S02. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3 -Ditian, oxatian, thiomorpholine, and the like. "Heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from 0, S and N. Heteroaryls thus include heteroaryls fused to other types of rings such as aryls, cycloalkyls and heterocycles that are not aromatic. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl. , pyridazinyl, indazolyl, isoxazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxinyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, thiophenyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and the like. For the heterocyclyl and heteroaryl groups, rings and ring systems containing from 3 to 15 atoms, forming 1-3 rings, are included. The term "Hal" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. Fluorine has the highest preference when the halogens are substituted in an alkyl or alkoxy group (for example CF3 and CF30). The term "alkylsulfonyl" refers to straight or branched chain alkylsulfones of the specified number of carbon atoms (eg, C alqu-6-sulfonyl alkyl), or any number within this range [i.e., methylsulfonyl (MeSO-) , ethylsulphonyl, isopropylsulfonyl, etc.]. The term "composition", as in pharmaceutical composition, encompasses a product comprising the active ingredient (s) and the inert ingredients that constitute the carrier, as well as any product that results, directly or indirectly, from the combination, complexization or aggregation of two or more of the ingredients, or of the dissociation of one or more of the ingredients, or of other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention comprise any composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier. The terms "administration of" and "administering" a compound should be understood as providing a compound of the invention or a prodrug of a compound of the invention for the individual need. As used herein, the term "effective amount" means the amount of a drug or pharmaceutical agent that will produce the biological or medical response of a tissue, system, animal or human that is being investigated, eg, by a researcher or doctor. On the other hand, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject that did not receive such an amount, results in a better treatment, cure, prevention or reduction of a disease, disorder or side effect or a decrease in the rate of progression of a disease or disorder. The term also includes within its scope effective amounts to improve normal physiological function. The compounds of structural formula I may contain one or several asymmetric centers and, thus, may be presented as racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. The present invention comprises all forms isomers of the compounds of structural formula I. Some of the compounds described herein contain olefinic double bonds, and unless otherwise specified, include both E and Z geometric isomers. Some of the compounds described herein may exist as tautomers such as keto-enol tautomers. The individual tautomers, as well as their mixtures, are comprised within the compounds of the structural formula I. The compounds of the structural formula I can be separated into the individual diastereomers, for example, by crystallization by fractionation from an appropriate solvent, methanol; or ethyl acetate or a mixture thereof, or by means of chiral chromatography using an optically active stationary phase. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates that are derived, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Alternatively, any stereoisomer of a compound of general structural formula I can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. In a different aspect of the invention, a pharmaceutical composition refers to I comprising a compound of according to structural formula I, or one of its pharmaceutically acceptable salts or solvates, in combination with a pharmaceutically acceptable carrier. By "solvate" is meant a hydrate, an alcoholate or other crystallization solvate. Another embodiment of the present invention is a method for the preparation of the compounds of the present invention, characterized in that a) an adamantylamine is reacted according to formula II, wherein R1 is as defined above, with a isocyanate according to formula III, wherein Y, R3, R4 and R5 are as before, or II III b) an adamantyl isocyanate is reacted according to formula IV, wherein R 1 is as defined above, with an amine according to formula V, wherein Y, R 2, R 3, R 4 and R 5 are as defined previously, or IV V c) an adamantylamine is reacted according to formula II, wherein R1 is as defined above, with a carbonyldiimidazole to give the corresponding acylimidazole according to formula VI and the acylimidazole is reacted with an amine according to the formula V, where Y, R2, R3, R4 and R5 are as previously defined, or VI V di is reacted an adamantylurea derivative according to formula VII, wherein Y, R1, R2, R3, R4 and R5 are as defined above, to give the corresponding phenol and the phenol is alkylated with a dialkylaminoethyl, wherein R6 and R7 are as defined above, or Vile e) a residue R1, R2, R3, R4, R5, R6 and / or R7, as defined above, is converted into another residue R1, R2, R3, R4, R5, R6 and / or R7 eg When introducing an alkyl group, of) a compound of the formula I is isolated and / or treated with an acid or a base, to obtain its salt. All crude products were subjected to standard chromatography using solvent mixtures containing methanol, ethanol, isopropanol, n-hexane, cyclohexane or petroleum ether, respectively. For a more detailed description of the production processes, also see the examples and the following general description of the conditions of preference. A physiologically acceptable salt of a compound according to formula I can also be obtained by isolating and / or treating the compound of the formula I obtained by means of the reaction described with an acid or a base. The compounds of the formula I and also the starting materials for their preparation are additionally obtained by methods known per se, as described in the literature (for example, in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart, Organic Reactions, John Wiley &Sons, Inc., New York), to be precise, under reaction conditions that are known and appropriate for such reactions. The variants known per se can also be used here, but are not mentioned here in greater detail. The starting materials for the claimed process can also be formed, if desired, in situ by not isolating them from the reaction mixture, but by immediately converting them into the compounds of the formula I. On the other hand, it is possible to carry out the reaction in stages. Preferably, the reaction of the compounds is carried out in the presence of an appropriate solvent which is preferably inert in the respective reaction conditions. Examples of suitable solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or mono-ethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO); nitrogen compounds, such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of said solvents or mixtures with water. In general, polar solvents are preferred. Examples of suitable polar solvents are chlorinated hydrocarbons, alcohols, glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. Amides are more preferred, especially dimethylformamide (DMF). As stated above, the reaction temperature is between about -100 ° C and 300 ° C, depending on the reaction stage and the conditions used. The reaction times are generally in the range of a few minutes to several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Appropriate reaction times are easily determined by methods known in the art, for example, control of the reaction. Based on the Reaction temperatures given above, the appropriate reaction times are, in general, in the range between 10 min and 48 h. A base of formula I can be converted into the associated salt by addition of acids using an acid, for example, by reaction of equivalent amounts of base and acid in a preferably inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acid, such as hydrochloric acid or hydrobromic acid, phosphoric acids such as, for example, orthophosphoric acid, sulfamic acid, also organic acids , in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example, formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, acid pivalic, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methano- or ethanesulfonic acid, Ethanesulfonic acid, 2-hydroxyethyl acid ansulfonic, acid benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalene monohydric acid and -disulfonic or lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of the formula I. On the other hand, the compounds of the formula I can be converted into the corresponding metal salts, in particular salts of alkali metal or alkaline earth metal salts, or in the corresponding ammonium salts, using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). Suitable salts are also substituted ammonium salts, for example, dimethyl-, diethyl- and diisopropylammonium salts, monoethanol-, diethanol- and diisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts, dibenzylethylenediammonium salts, also, for example, salts with arginine or lysine. If desired, the free bases of the formula I can be released from their salts by treatment with strong bases, such as sodium hydroxide, potassium hydroxide, carbonate of sodium or potassium carbonate, as long as no other acid groups are present in the molecule. In cases where the compounds of the formula I have free acid groups, the formation of salts can also be carried out by treatment with bases. Suitable bases are alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines. Each reaction step described herein may optionally be followed by one or more processing methods and / or isolation procedures. These suitable methods are known in the art, for example, from standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart). Examples of such procedures include, but are not limited to, evaporation of a solvent, distillation, crystallization, fractionation crystallization, extraction procedures, washing procedures, digestion procedures, filtration procedures, chromatography, HPLC chromatography, and drying procedures. in particular vacuum and / or high temperature drying processes. The compounds described herein are selective inhibitors of the llß-HSDl enzyme. Thus, the present invention relates to the use of the compounds of the present invention to inhibit the activity of the reductase of llß-hydroxysteroid dehydrogenase 1, which is responsible for the conversion of cortisone to cortisol. The llß-HSDl inhibitors of structural formula I have, in general, an IC5o inhibition constant of less than about 500 nM, and preferably less than about 100 nM. In general, the ratio IC5o 11β-HSD2 to 11β-HSDl of a compound is at least about two or more, and preferably about ten or more. Even more preferred are compounds with an IC50 ratio of 11β-HSD2 to 11β-HSDl of about 20 or more. For example, the compounds of the present invention ideally demonstrate an inhibition constant of IC50 against llß-HSD2 greater than about 1000 nM, and preferably greater than 5000 nM. The present invention includes the use of a llß-HSDl inhibitor for the treatment, control, improvement, prevention, delay of onset or reduction of the risk of development of the diseases and conditions described herein, such as those mediated by amounts Surplus or uncontrolled cortisol and / or other corticosteroids in a mammalian patient, in particular a human being, by administering an effective amount of a compound of structural formula I or a pharmaceutically acceptable salt or solvate thereof. Inhibition of the llß-HSD1 enzyme limits the conversion of cortisone, which is normally inert, in cortisol, which can cause c contribute to the symptoms of these diseases and conditions if it is present in excessive amounts. Accordingly, a preferred embodiment of the present invention is the use of a compound of the present invention as a llß-HSDl inhibitor. Another preferred embodiment of the present invention is the use of a compound of the present invention for the preparation of a medicament. Another preferred embodiment of the present invention is the use of a compound of the present invention for the preparation of a medicament for the treatment and / or prevention of diseases caused, mediated and / or propagated by high levels of cortisol. Another preferred embodiment of the present invention is the use of a compound of the present invention for the preparation of a medicament for the treatment and / or prevention of one or several diseases or conditions selected from the group consisting of metabolic syndrome, diabetes , especially non-insulin dependent diabetes mellitus, prediabetes, insulin resistance, low glucose tolerance, hyperglycemia, obesity and weight-related disorders, lipid disorders such as dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or high levels from LDL, glaucoma, osteoporosis, glucocorticoid-mediated effects on neuronal function, such as cognitive impairment, anxiety or depression, neurodegenerative disease, immune disorders such as tuberculosis, leprosy or psoriasis, hypertension, atherosclerosis and its sequelae, vascular restenosis, cardiovascular diseases, pancreatitis, retinopathy, neuropathy and nephropathy. In another aspect of the invention, there is disclosed a method of treating a condition selected from the group consisting of: hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low MEL levels, high levels of LDL, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, metabolic syndrome, hypertension and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient a compound according to structural formula I in an amount that is effective to treat said condition. In another aspect of the invention, there is disclosed a method for delaying the onset of a condition, selected from the group consisting of hyperglycemia, low tolerance to glucose, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low levels of EMIL, high levels of LDL, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, metabolic syndrome, hypertension and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient a compound according to structural formula I in an amount which is effective to delay the onset of said condition. Another preferred embodiment of the present invention is a pharmaceutical composition, characterized in that it contains a therapeutically effective amount of one or more compounds according to the invention. Another embodiment of the present invention is a pharmaceutical composition, characterized in that it also contains one or more additional compounds, selected from the group consisting of excipients, auxiliaries, adjuvants, diluents, physiologically acceptable carriers and pharmaceutically active agents other than the compounds according to the invention. with the invention A further preferred embodiment of the present invention is a set consisting of separate packages of a) a therapeutically effective amount of one or more compounds according to the invention and b) a therapeutically effective amount of one or more other pharmaceutically active agents other than the compounds according to the invention . The compounds of structural formula I can be used in combination with one or more other drugs in the treatment, prevention, suppression or improvement of diseases or conditions for which the compounds of structural formula I or the others are useful. drugs. Typically, the combination of the drugs is safer or more effective than the drug alone, or the combination is safer or more effective than what is expected based on the additive properties of the individual drugs. These other drugs can be administered by a route and in a quantity commonly used at the same time or sequentially with a compound of structural formula I. When a compound of the structural formula I is used at the same time with one or more of the other drugs, a combination of product containing such other drugs and the compound of the structural formula I is preferred. However, the combination therapy also includes therapies wherein the compound of structural formula I and one or more other drugs are administered in different schedules superimposed. It is contemplated that, when used in combination with other active ingredients, the compound of the present invention or the other active ingredient or both may be effectively used in low doses, rather than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those which contain one or more of the other active ingredients, in addition to a compound of structural formula I. Examples of the other active ingredients that can be administered in combination with a composed of structural formula I, and either separately or in the same pharmaceutical composition, include, but are not limited to: dipeptidylpeptidase IV inhibitors (DP-IV); Insulin sensitizing agents include PPAR agonists? such as glitazones (for example troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) and other PPAR ligands, including dual PPARa /? agonists, such as KRP-297, and PPAROI agonists such as gemfibrozil, clofibrate, fenofibrate and bezafibrate, and biguanides, such as metformin and phenformin; insulin or insulinomimetics; sulfonylureas and other insulin secretagogues such as tolbutamide, glipizide, meglitinide and related materials; α-glucosidase inhibitors, such as acarbose; glucagon receptor antagonists such as those described in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810; GLP-1, GLP-1 analogs and GLP-1 receptor agonists such as those described in WO00 / 42026 and WO00 / 59887; GIP, GIP mimetics such as those described in WO00 / 58360, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP 3 receptor agonists such as those described in WO 01/23420; cholesterol-lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, rosuvastatin, and other statins), bile acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives) dextran cross-linked), nicotinic alcohol, nicotinic acid or one of its salts, cholesterol absorption inhibitors, such as ezetimibe and beta-sitosterol, inhibitors of acyl CoA: cholesterol acyltransferase, such as, for example, avasimibe, and antioxidants, such as probucol; PPARd agonists, such as those described in W097 / 28149; anti-obesity compounds such as fenfluramine, dextenfluramine, phentermine, sibutramine, orlistat, neuroleptide antagonists Y1 or Y5, inverse agonists and antagonists of the CB1 receptor, adrenergic receptor agonists, melanocortin receptor agonists, in particular melanocortin-4 receptor agonists , ghrelin antagonists, and melanin concentrating hormone (MCH) receptor antagonists; inhibitors of bile acid transport; agents intended for the use of inflammatory conditions other than glucocorticoids, such as aspirin, nonsteroidal anti-inflammatory drugs, azulfidine and selective inhibitors of cyclooxygenase-2; inhibitors of the protein tyrosine phosphatase IB (PTP-1B); antihypertensives including those acting on the angiotensin or renin systems, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibitors, such as captopril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril , zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telnisartan and valsartan; and cholesteryl ester transfer protein (CETP) inhibitors. The above combinations include a compound of structural formula I, or a pharmaceutically acceptable salt or solvate thereof, with one or more other active compounds. Non-limiting examples include combinations of compounds of structural formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors, and compounds anti-obesity In another aspect of the invention, a method is described to reduce the risk of developing a condition selected from the group consisting of hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, metabolic syndrome, hypertension and other conditions and disorders where insulin resistance is a component in a mammalian patient in need of such treatment, which comprises administering to the patient a compound according to structural formula I in an amount that is effective to reduce the risk of developing said condition. In another aspect of the invention, a method of treating a condition selected from the group consisting of hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low levels is described. of HDL, high levels of LDL, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, metabolic syndrome, hypertension and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient an effective amount of a compound as defined in structural formula I and a compound selected from the group consists of: dipeptidylpeptidase-IV inhibitors (DP-IV); insulin-sensitive agents selected from the group consisting of PPARα agonists, PPARα agonists, dual PPARα / β agonists, and biguanides; insulin and insulinomimetics; sulfonylureas and other insulin secretagogues; a-glucosidase inhibitors; glucagon receptor antagonists; GLP-1, GLP-1 analogs and GLP-1 receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP 3 receptor agonists; agents that reduce cholesterol selected from the group consisting of HMG-CoA reductase inhibitors, sequestrants, nicotinic alcohol, nicotinic alcohol and its salts, inhibitors of cholesterol absorption, inhibitors of acyl CoA: cholesterol acyltransferase, and antioxidants; PPARd agonists; anti-obesity compounds; inhibitors of ileal bile acid transporters; anti-inflammatory agents, excluding glucocorticoids; inhibitors of the protein tyrosine phosphatase IB (PTP-1B); and antihypertensive, including those acting on the angiotensin or renin systems, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibitors, such as captopril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril , candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan and valsartan; wherein said compounds are administered to the patient in an amount that is effective to treat said condition. Inhibitors of dipeptidylpeptidase-IV which can be combined with the compounds of structural formula I include those described in WO 03/004498, WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/00025; WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181. Specific inhibitor compounds of DP-IV include thiazolidide of isoleucine; NVP-DPP728; P32 / 98; and LAF 237. The anti-obesity compounds which may be combined with the compounds of structural formula I include fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuroleptide antagonists Y1 or Y5, CB1 cannabinoid receptor antagonists or inverse agonists, melanocortin receptor, in particular, melanocortin-4 receptor agonists, ghrelin antagonists, and hormone receptor antagonists Melanin concentrator (MCH). About a review of antiobesity compounds that can be combined with the compounds of structural formula I, see S. Chaki et al., "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity", Expert Opin. Ther. Patents, 11: 1677-1692 (2001) and D. Spanswick and K. Lee, "Emerging antiobesity drugs", Expert Opin. Emerging Drugs, 8: 217-237 (2003). Neuropeptide Y5 antagonists that can be combined with the compounds of structural formula I include those described in U.S. Pat. No. 6,335,345 and WO 01/14376; and the specific compounds identified as GW59884A; GW569180A; LY366377; and COP-71683A. CB 1 cannabinoid receptor antagonists that can be combined with the compounds of formula I include those described in PCT publication WO 03/007887; U.S. Patent No. 5,624,941, as rimonabant; PCT publication WO 02/076949, such as SLV-319; U.S. Patent No. 6,028,084; PCT publication WO 98/41519; PCT publication WO 00/10968; PCT publication WO 99/02499; U.S. Patent No. 5,532,237; and U.S. Patent No. 5,292,736. Melanocortin receptor agonists that can be combined with the compounds of formula I include those described in WO 03/009847; WO 02/068388; WO 99/64002; WO 00/74679; WO 01/70708 and WO 01/70337, as well as those described in J. D. Speake et al., "Recent advances in the development of melanocortin-4 receptor agonists", Expert Opin. Ther. Patents, 12: 1631-1638 (2002). In another aspect of the invention, there is described a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high levels of LDL, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of said treatment. treatment, which comprises administering to the patient a therapeutically effective amount of a compound as defined in structural formula I and an inhibitor of HMG-CoA reductase. More particularly, in another aspect of the invention, there is described a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high levels of LDL, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient. which needs such treatment, wherein the HMG-CoA reductase inhibitor is a statin. Even more particularly, in another aspect of the invention, there is disclosed a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low levels of HAL, high levels of LDL, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a a mammalian patient in need of such treatment, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravastatma, cepvastatin, fluvastatin, atorvastatin, itavastatin and rosuvastatin. In another aspect of the invention, a method is described for reducing the risk of developing a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low levels of HDL, high levels of LDL, hyperlipidemia, hypertriglycemia and dyslipidemia, and the sequelae of such conditions, comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound as defined in structural formula I and an HMG-CoA reductase inhibitor. In another aspect of the invention, a method is described for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment, comprising administering to said patient an effective amount of a compound as defined in structural formula I and an inhibitor of HMG-CoA reductase. More particularly, a method is described for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment, wherein the HMG-CoA reductase inhibitor is a statin. More particularly, a method is described for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin and rosuvastatin. More particularly, a method is described for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment, wherein the statin is simvastatin. In another aspect of the invention, a method is described for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment, wherein the HMG-CoA reductase inhibitor is a statin and also comprises the administration of a inhibitor of cholesterol absorption. More particularly, in another aspect of the invention, a method is described for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment, wherein the HMG-CoA reductase inhibitor is a statin and the inhibitor of The absorption of cholesterol is ezetimibe. In another aspect of the invention, a A pharmaceutical composition comprising a compound according to structural formula I, a compound selected from the group consisting of: DP-IV inhibitors; insulin sensitizing agents I selected from the group consisting of PPARa agonists; PPAR agonists ?, dual PPARa agonists /? and biguanides; insulin and insulinomimetics; sulfonylureas and other insulin secretagogues; a-glucosidase inhibitors; glucagon receptor antagonists; GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP 3 receptor agonists; agents that reduce cholesterol selected from the group consisting of HMG-CoA reductase inhibitors, sequestrants, (nicotinic alcohol, nicotinic alcohol or one of its salts, cholesterol absorption inhibitors, acyl CoA: cholesterol acyltransferase inhibitors, and antioxidants; PPARD agonists; anti-obesity compounds; inhibitors of ileal bile acid transporters; anti-inflammatory agents other than glucocorticoids; inhibitors of protein tyrosine phosphatase IB (PTP-1B); and antihypertensive drugs, including those acting on angiotensin or renin systems, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibitors, such as captopril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan and valsartan; inhibitors of cholesteryl ester transfer protein (CETP); and a pharmaceutically acceptable carrier. Another embodiment of the present invention is a process for the preparation of said pharmaceutical compositions, characterized in that one or several compounds according to the invention and one or more compounds selected from the group consisting of excipients, auxiliaries, adjuvants, diluents, carriers solids, liquids or semi-liquids and pharmaceutically active agents other than the compounds according to the invention, are converted into an appropriate dosage form. The pharmaceutical compositions of the present invention can be administered by any means that achieves the intended purpose. For example, administration can be oral, parenteral, topical, enteral, intravenous, intramuscular, by inhalation, nasally, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal or buccal. Alternatively or concurrently, administration can be carried out orally. The dose administered will depend on the age, health and weight of the recipient, the type of concurrent treatment, if some, frequency of treatment and the nature of the desired effect. Parenteral administration is preferred. Oral administration is especially preferred. Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semisolids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, adhesive bands, eye drops, solutions, syrups. , aerosols, suspensions, emulsions, which can be produced according to methods known in the art, for example, as described as follows: Tablets: mixture of active ingredient or active and auxiliary ingredients, understanding said mixture in tablets ( direct compression), optionally granulation of part of the mixture before compression. Capsules: mixture of active ingredient or active and auxiliary ingredients to obtain a flowable powder, optionally powder granulation, powder filling / granulation in open capsules, closed capsules. Semisolids (ointments, gels, creams): dissolution / dispersion of active ingredient or active ingredients in an aqueous or fatty carrier; subsequent mixing of the aqueous / fat phase with the complementary fatty / aqueous phase, homogenization (only creams). Suppositories (rectal and vaginal): dissolution / dispersion of active ingredient or active ingredients in heat-liquefied carrier material (rectal: carrier material, usually a wax, vaginal: carrier usually a heated solution of gelling agent), molding said mixture in molds of suppositories, sealing and removal of the suppositories from the molds. Aerosols: dispersion / dissolution of active ingredient or active ingredients in a propellant, packaging of said mixture in an atomizer. In general, non-chemical routes for the production of pharmaceutical compositions and / or pharmaceutical preparations comprise the steps of processing in appropriate mechanical means known in the art which transfer one or more compounds according to the invention in a suitable dosage form for administration to a patient who needs such treatment. Usually, the transfer of one or more compounds according to the invention in such a dosage form comprises the addition of one or more compounds selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds according to the invention. invention. Appropriate processing steps include, but without limitation, combining, grinding, mixing, granulating, dissolving, dispersing, homogenizing, molding and / or compressing the respective active and non-active ingredients. The mechanical means for carrying out said processing steps are known in the art, for example, from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this regard, the active ingredients are preferably at least one compound according to this invention and one or more additional compounds other than the compounds according to the invention, which show valuable pharmaceutical properties, preferably those pharmaceutical active agents other than the compounds according to the invention, which are described herein. Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use, suppositories suitable for parenteral use, solutions, preferably solutions with oil or aqueous base. , also suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilisates can be used, for example, for the preparation of injectable preparations. The stated preparations can be sterilized and / or comprise assistants, such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts to modify the pressure osmotic, buffer substances, dyes, flavors and / or a plurality of other active ingredients, for example one or several vitamins. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the new compounds, for example water, vegetable oils, benzylic alcohols, alkylene glycols, polyethylene glycols, triacetate glycerol, gelatin, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or hydrogen calcium phosphate, magnesium stearate, talc, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and / or petrolatum. If desired, disintegrating agents such as the aforementioned starches and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, may be added. Auxiliaries include, without limitation, flow regulating agents and lubricants, for example, silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with appropriate coatings that, if desired, are resistant to gastric juices. For this purpose, solutions of concentrated saccharides which optionally may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquered solutions and suitable solvents or mixtures of organic solvents may be used. In order to produce coatings resistant to gastric juices or to provide a dosage form to achieve the advantage of a prolonged action, the tablet, the dragee or the pill may comprise an internal dosage component and an external dosage component, having the latter the shape of a cover with respect to the first. The two components can be separated by means of an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact to the duodenum or be delayed in its release. A variety of materials can be used for such enteric coatings or coatings, such materials being used as a quantity of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of appropriate cellulose preparations such as acetyl phthalate. cellulose, cellulose acetate or hydroxypropylmethyl cellulose phthalate. Tinctures or pigments may be added to the coatings of tablets or dragees, for example, for identification or purpose of characterizing combinations of active compound doses. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral or topical administration and which do not react with the new compounds, for example water, vegetable oils, benzylic alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories for enteral administration, solutions, preferably oily or aqueous solutions, suspensions, emulsions or implants, for parenteral administration, and ointments, creams or powders are used. use for topical application. The new compounds can also be lyophilized and the obtained lyophilizates can be used, for example, for the production of injectable preparations. The stated preparations can be sterilized and / or contain excipients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, colos, flavors and / or flavors. If desired, they may also contain one or more other active compounds, for example one or more vitamins.

Other pharmaceutical preparations that can be used orally include pressure setting capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The pressure adjustment capsules may contain the active compounds in the form of gles, which may be mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compounds dissolve or dissolve, preferably in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added.

Liquid forms in which the new compositions of the present invention can be incorporated for oral administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dext sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. The appropriate formulations for administration via parenteral include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds can be administered as appropriate injectable oil suspensions. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran, optionally the suspension may also contain stabilizers. To be administered as a spray by inhalation, it is possible to use sprays in which the active ingredient is dissolved or suspended in a propellant gas or propellant gas mixture (for example C02 or chlorofluorocarbons). The active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents, for example ethanol, may be present. Solutions for inhalation can be administered with the help of conventional inhalers. Possible pharmaceutical preparations that can be used rectally include, for example, suppositories, which they consist of a combination of one or several active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffinized hydrocarbons. In addition, it is also possible to use rectal gelatin capsules, which consist of a combination of the active compounds with a base. Possible base materials include, eg, liquid triglycerides, polyethylene glycols or paraffinized hydrocarbons. For use in medicine, the compounds of the present invention will take the form of pharmaceutically acceptable salts. However, other salts will be useful in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Appropriate pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which can be formed, for example, by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. On the other hand, when the compounds of the invention carry an acidic moiety, their appropriate pharmaceutically acceptable salts may include alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, for example calcium or magnesium salts; and salts formed with appropriate organic bases, for example quaternary ammonium salts. The present invention includes within its scope prodrugs of the compounds of the present invention above. In gel, such prodrugs will be functional derivatives of the compounds of the present invention, which can be easily converted in vivo into the required compound of the present invention. Conventional procedures for the selection and preparation of appropriate pharmacological derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. Pharmaceutical preparations can be used as medicines in human and veterinary medicine. As used herein, the term "effective amount" means the amount of a drug or a pharmaceutical active ingredient that elicits the biological or medical response in a tissue, system, animal or human being sought or intended, for example, by a researcher or a doctor. On the other hand, the term "therapeutically effective amount" means any amount which, in comparison with a corresponding subject that did not receive said amount, results in a better treatment, cure, prevention or improvement of a disease, disorder or side effect, or a decrease in the rate of progress of a disease or disorder. The Expression also includes within its scope effective amounts to improve normal physiological function. Said therapeutic effective amount of one or more of the compounds according to the invention is known to the person skilled in the art or can be easily determined by means of standard methods known in the art. The substances according to the invention are generally administered analogously to commercial preparations. Usually, appropriate doses that are therapeutically effective are in the range of 0.0005 mg to 1000 mg, preferably 0.005 mg to 500 mg and especially 0.5 to 100 mg per unit dose. The daily dose is preferably between about 0.001 and 10 mg / kg of body weight. The skilled artisan will readily appreciate that dose levels may vary depending on the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred doses for a given compound are readily determinable by those skilled in the art through multiple means. A preferred means is to measure the physiological potency of a given compound. The host or patient can be of any mammalian species, eg, primate sp., In particular human; rodents, including mice, rats and hamsters; rabbits equines, bovines, canines, felines; etc. Animal models are of interest for experimental investigations, providing a model for the treatment of human disease. The specific dose for each individual patient depends, however, on multiple factors, for example, on the efficacy of the specific compounds used, age, body weight, general state of health, sex, type of diet, time and route of administration, the rate of excretion, the type of administration and the dosage form to be administered, the pharmaceutical combination and the severity of the particular disorder to which the therapy refers. The effective therapeutic dose specific to the individual patient can be easily determined by routine experimentation, for example, through the doctor or physician, who indicates or assists the therapeutic treatment. In the case of several disorders, the susceptibility of a particular cell to treatment with the subject compounds can be determined by in vitro tests. Typically, a cell culture is combined with an object compound in various concentrations for a sufficient period to allow the active agents to show a relevant reaction, usually between about one hour and one week. For the m vitro tests, cultured cells from a biopsy sample can be used.

Even without further details, it is assumed that a person skilled in the art will be able to use the above description in its broadest scope. The preferred embodiments should therefore be considered merely as a descriptive disclosure, which is not limitative at all. Before and after, all temperatures are indicated in ° C. In the following examples, "conventional processing" means that, if necessary, the solvent is removed, water is added if necessary, the pH is adjusted, if necessary, between 2 and 10, depending on the constitution of the final product, The mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is washed with saturated NaHCO3 solution, if desired, with water and saturated NaCl solution, dried over sodium sulfate, filtered and evaporated. , and the product is purified by chromatography on silica gel, by preparative HPLC and / or by crystallization. The purified compounds are lyophilized, if desired. Mass spectrometry (MS): ESI (electrospray ionization) (M + H) + List of abbreviations and acronyms: AcOH acetic acid, anhydrous anh, atm atmosphere (s), BOC tert-butoxycarbonyl CDI 1, 1'-carbonyldiimidazole, conc concentrate, day (s), decomposition decomposition, DMAC NN-dimethylacetamide, DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, DMF NN-dimethylformamide, DMSO dimethylsulfoxide, DPPA diphenylphosphorylazide, EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, EtOAc ethyl, EtOH ethanol (100%), Et20 diethyl ether, Et3N triethylamine, h hour (s), MeOH methanol, pet ether. Petroleum ether (boiling range 30-60 ° C), temp. temperature, THF tetrahydrofuran, TFA trifluoroAcOH, Tf trifluoromethanesulfonyl. Example 1: Preparation methods The compounds of the present invention can be prepared by means of the general methods A, B, C and D indicated below. In all methods of preparation, all starting materials are known or can be easily prepared from known starting materials. General method A: When coupling an adamantylamine, wherein R is defined as above, with an isocyanate, wherein Y, R3, R4 and R5 are defined as above, under standard conditions (for example by using ethanol or dimethylformamide as a solvent and in the presence of a tertiary base when hydrochloride is used of adamantylamine; For example : General method B: By reacting an adamantyl isocyanate, wherein R 1 is defined as above and which can be prepared from adamantylamine according to Angew. Chem. Itn; Ed. Engl. 1995, 34, 2497-2500, with an amine, wherein Y, R2, R3, R4 and R5 are defined as before, under standard conditions. General method C: When coupling an adamantylamine, where R1 is defined as before, with carbonyldiimidazole in an inert solvent such as DCM to give the corresponding acylimidazole and in doing reacting the latter with an amine, wherein Y, R, R, R4 and R5 are defined as before, under standard conditions (eg DCM as a solvent and in the presence of a tertiary base when amine hydrochloride is used). For example: General method D: Vile By reacting an anisole group by means of a agent such as pyridinium hydrochloride or boron tribromide to give the corresponding phenol and by alkylating this phenol with a dialkylaminoethyl chloride, wherein R6 and R7 are defined as above, in the presence of a base such as potassium carbonate in a polar solvent such as dimethylformamide. Example 2: General Method A-l-Adamantan-2-yl-3- (4-methoxy-2-methyl-f-enyl) -urea A mixture of 2.5 g (13.3 mmol) of 2-adamantylamine hydrochloride 1.84 ml (13.3 mmol) of triethylamine in 50 ml of ethanol was heated to reflux. Then 1.94 ml (13.3 mmol) of 4-methoxy-2-methylphenylisocyanate was added and the mixture was stirred at reflux for 2 h. After cooling to room temperature, the precipitate was filtered, washed with ethanol and dried under vacuum to give 4.2 g (61%) of a white solid. p. F. 186 ° C HPLC-MS (M + H +) 315.2 HXRMN (DMSO d6) 1.5-1.9 (m, 14H), 2.15 (s, 3H), 3.39-3.47 (m , 1H), 3.67 (s, 3H), 6.59-6.71 (m, 3H), 7.51 (s, 1H), 7.6 (d, 1H) The following compounds were prepared from a similar to the way described in Example 1 Example 3: Compounds 2-1, 2-2, 2-3, 2-4 and 2-5 1- (cis-5-hydroxy-adamantan-2-yl) -3- (4-methoxy-2-methyl- phenyl) -urea and 1- (trans-5-hydroxy-adamantan-2-yl) -3- (4-methoxy-2-methyl-phenyl) -urea A mixture of l-hydroxy-4-aminoadamantane 669 mg (4 mmol), prepared as described by LN Lavrova & Coll. Khim. Farm. Z; 24 (1), 29-31, 1990, in 20 ml of ethanol was heated to reflux. Then 0.594 ml (4 mmol) of 4-methoxy-2-methylphenylisocyanate was added and the mixture was stirred at reflux for 2 h, then overnight at room temperature. The precipitate was filtered, washed with diethyl ether and dried under vacuum to give 0.566 g as a white solid. The washing solution of diethyl ether was concentrated until dryness to obtain 0.800 g as a beige solid. The purification of each solid was carried out by flash chromatography on silica gel (eluents: 3-5% MeOH in CH2C12) to give the title compounds. Ex. 2-1: 1- (cis-5-hydroxy-adamantan-2-yl) -3- (4-methoxy-2-methyl-phenyl) -urea p. F. 231-232 ° C M + H = 331 XH-NMR (200 MHz, DMSOd6) d.1.4-2.05, (m, 13H), 2.17 (s, 3H), 3.64 (d, 1H), 3.70 (s, 3H), 4.48 (s, 1H), 6.6-6.8 (m, 3H), 7.55 (s, 1H), 7.65 (d, 1H) E. 2-2: 1- (trans-5-hydroxy-adamantan-2-yl) -3- (4-methoxy-2-methyl-phenyl) -urea p. F. 244-245 ° C M + H = 331 XH-NMR (200 MHz, DMSOd6) d 1.35-2.1 (m, 13H), 2.19 (s, 3H), 3.72 (s, 4H) , 4.45 (s, 1H), 6.55-6.80 (m, 3H), 7.55 (s, 1H), 7.62 (d, 1H) Ex. 2-3: 4- (((S) -3-methyl-piperidin-1-carbonyl) -amino] -adamantan-1-yl ester of acetic acid A mixture of (5-hydroxy-adamantan-2-yl) - acid amide (S) -3-methyl-piperidine-l-carboxylic acid 0.15 g (0.51 mmol), 0.109 ml of acetyl chloride, 3 ml of pyridine in 1.5 ml of methylene chloride was stirred at room temperature for the night. A saturated solution of NaHCO 3 was added, the organic phase was extracted with methylene chloride, washed with 1N HCl solution and dried over sodium sulfate. Flash chromatography on silica gel (eluent CH2Cl2 / MeOH: 95/05) yielded 75 mg of the title compound. M + H = 335.2 X H NMR (300 MHz, DMSO-D 6) d 0.69 (d, 3 H), 0.85-2.25 (m, 22 H), 2.53 (td, 1 H), 3 , 47 (yes, 1H), 3.6-3.9 (, 2H), 5.75 (d, 1H) The following compounds were prepared in a manner similar to that described in Example 2-3 Ex. 2-4: Ester 4- [((S) -3-methyl-piperidin-l-carbonyl) -amino] -adamantan-1-yl of cyclohexanecarboxylic acid XH NMR (300 MHz, DMSO-D6) d 0.85 ( d, 3H), 0.91-2.37 (m, 30H), 2.53 (td, 1H), 3.55 (yes, 1H), 3.8-3.97 (m, 2H), 5.75 (d, 1H) Ex. 2-5: 4- [((S) -3-methyl-piperidin-1-carbonyl) -amino] -adamantan-1-yl ester of 2, 2-dimethyl-propionic acid XH NMR (300 MHz, DMSO-D6 ) d 0.84 (d, 3H), 0.88-2.39 (m, 28H), 2.56 (td, 1H), 3.55 (yes, 1H), 3.8-3.97 (m, 2H), 5.75 (d, 1H) Example 4: General Method B-l-Adamantan-2-yl-3- ((R) -2-hydroxy-l-phenyl-ethyl) -urea A solution of 2-adamantylamine hydrochloride 0.4 g (2.1 mmol) ), triethylamine 0.324 ml (2.3 mmol), 4-dimethylaminopyridine 0.286 g (2.3 mmol) in 4 ml of DMF was cooled to -15 ° C. Then a solution of (Boc) 20 was added 511.5 mg (2.3 mmol) in DMF, the reaction mixture was stirred at -15 ° C for 45 minutes and allowed to stand at room temperature. Amine 0.321 g (2.3 mmol) was added and the mixture was heated to 55 ° C overnight. After cooling, water (15 ml) was added, the precipitate was filtered, washed with water, diethyl ether and dried under vacuum to give 350 mg (52%) as a white solid. M + H = 315 The following compounds were prepared in a manner similar to that described in Example 3 Example 5: General Method C 3-Adamantan-2-? Ll-met? II- (2-pr? D? N-2-l-ethyl) -urea hydrochloride a) Adamantan-2? -lactate acid 4H-im-dazole-l-carboxyl? Co A solution of 2-adamant hydrochloride? Lamma 3 g (15.98 mmol), carbonildumidazole 2.59 g (15.98 mmol), triethylamine 2.215 ml (15.98 mmol) in CH2C12 100 ml was stirred overnight at room temperature. Water was added, the organic phase was separated, dried and concentrated to dryness to give the title crude product 3.69 g (94%) as a white solid. XH-NMR (200 MHz, CDC13) d.1.6-2.1 (m, 14H), 4.05 (d, 1H), 6.0 (s, 1H), 7.01 (s, 1H) , 7.28 (s, 1H), 8.04 (s, 1H) b) 3-Adamantan-2-yl-l-methyl-l- (2-pyridin-2-yl-ethyl) -urea hydrochloride solution of adamantan-2-ylamide of 4-imidazole-1-carboxylic acid 1 g (4.08 mmol) and 2- (N-methylamino-ethyl) pyridine 0.567 ml (4.08 mmol) in methylene chloride 10 ml stirred at room temperature for 2 days. Water was added, the organic phase was extracted, dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluent DCM / MeOH: 95/05) to give 1.13 g of the title compound as a free base. M + H = 314 XH-NMR (200 MHz, CDC13) d 1.45-1.9 (m, 14H), 2.8 (s, 3H), 2.97 (t, 2H), 3.61 ( t, 2H), 3.77 (d, 1H), 5.3 (d, 1H), 7.05-7.15 (m, 2H), 7.528 (t, 1H), 8.42 (d, 1H) ) By triturating the above base 255 mg (0.81 mmol) with a solution of 2 M HCl in diethyl ether, 22.3 mg of the title hydrochloride salt were obtained.

XH-NMR (200 MHz, DMSOd6) d 1.35-2 (m, 14H), 2.52 (s, 2H), 2.93 (s, 3H), 3.26 (m, 2H), 5, 5 (yes, 1H), 7.95 (di, 2H), 8.5 (t, 1H), 8.78 (d, 1H) Example 6: General method C 4- [2- (3-adamantan- 2-yl-l-methyl-ureido) -ethoxy] -benzoic acid a) 4- [2- (3-adamantan-2-yl-l-methyl-ureido) -ethoxy] -benzoic acid methyl ester A solution of adamantan -2-4-imidazole-1-carboxylic acid ilamide 0.5 g (2.04 mmol) and 4- (2-methylamino-ethoxy) -benzoic acid methyl ester 426.8 mg (2.04 mmol) in Methylene chloride 10 ml was stirred at room temperature for 2 days. Water was added, the organic phase was extracted, dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluent DCM / MeOH: 100/0 to 95/05) giving 596 mg as a white solid, e.g. F. 126 ° C M + H = 387 XH-NMR (200 MHz, CDC13) d 1.5-1.9 (m, 14H), 2.93 (s, 3H), 3.62 (t, 2H), 3 , 79 (s, 3H), 3.86 (d, 1H), 4.1 (t, 2H), 5 (d, 1H), 6.84 (d, 2H), 7.89 (d, 2H) b) 4- [2- (3-Adamantan-2-yl-l-methyl-ureido) -ethoxy] -benzoic acid A solution of 4- [2- (3-adamantan-2-yl-1) methyl ester -methyl-ureido) -ethoxy] -benzoic acid 562 mg (1.45 mmol), 1 N NaOH 3 ml in THF 5 ml was stirred at RT overnight. Then 1 N NaOH 4 ml was added and the reaction mixture was stirred overnight. Water was added and the mixture was acidified to pH = 2. The precipitate was filtered and dried under vacuum to give the title compound 305 mg (51%) as a white solid, e.g. F. 207 ° C M + H = 373 XH-NMR (200 MHz, CDC13) d 1.2-2.1 (m, 14H), 2.96 (s, 3H), 3.72 (t, 2H), 3 , 8 (d, 1H), 4.14 (yes, 2H), 5 (yes, 1H), 6.88 (d, 2H), 7.99 (d, 2H) Example 7: Compounds 6-1 and 6 -2- 3- (3-Adamantan-2-yl-ureido) -2-methyl-benzoic acid A solution of 3- (3-adamantan-2-yl-ureido) -2-methyl-benzoic acid methyl ester 70 mg (0.204 mmol), 0.408 mL 1 N NaOH in 2 mL methanol was stirred overnight at 55 ° C. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The aqueous phase was acidified to pH 1 and the precipitate was filtered and dried under vacuum to give 53 mg (79%) as a white solid. M + H = 329 The following compounds were prepared in a manner similar to that described in Example 5 Example 8: General Method D l-Adamantan-2-yl-3- (4-hydroxy-2-methyl-phenyl) -urea To a suspension of l-adamantan-2-yl-3- (4-methoxy-2-) methyl-phenyl) -urea 1.56 g (4.88 mmol) in DCM 20 ml was added at -78 ° C under argon a solution of 1 M boron tribromide in DCM 14.67 ml (14.67 mmol). The reaction mixture was stirred at -78 ° C for 1 h, then allowed to come to room temperature. 60 ml water was added, the precipitate was filtered, washed with water and dried under vacuum to give 1.36 g (92%) a white solid. p. F. 212-214 ° C M + H = 301 XH-NMR (200 MHz, DMSOd6) d 1.5-1.95 (m, 14H), 2.08 (s, 3H), 3.71 (s, 1H), 6.4-6.55 (m, 3H), 7.37 (m, 2H) Example 9: General method D-Adamantan-2-yl-3- ( 2-methyl-4- (2-piperidin-1-yl-ethoxyl) phenyl) -urea A suspension of the compound of Example 8 (700 mg, 2.33 mmol), potassium carbonate (966 mg 6.9 mmol), hydrochloride 2-Chloroethylpiperidine (643 mg, 3.49 mmol) in acetonitrile 20 ml was heated to reflux overnight. The reaction mixture was filtered, washed with acetonitrile. To the organic solution was added water and the precipitate was filtered and dried to obtain the title compound 120 mg as a white solid, e.g. F. 196 ° C M + H = 412 XH-NMR (200 MHz, DMSOd6) d 1.5-2.15 (m, 20H), 2.36 (s, 3H), 2.62 (yes, 4H), 2 , 81 (t, 2H), 3.95 (d, 1H), 4.19 (t, 2H), 6.85 (t, 2H), 6.93 (s, 1H), 7.75 (s, 1H), 7.79 (d, 1H) Example 10: Selectivity for human llbeta-HSDl We found that compounds with this structure are potent and selective inhibitors of human 11-beta-HSD-l. Example 11: Tests - measurement of inhibition constants The human llbeta-hydroxysteroid dehydrogenase type 1 (llbeta-HSDl) and type 2 (llbeta-HSD2) enzymes were expressed in E. coli. Mouse and rat liver microsomal fractions of TEBU were obtained. The enzymatic assay of llbeta-HSDl was carried out in 96-well microtiter plates in a total volume of 100 μl with 30 mM HEPES buffer, pH 7.4 with 1 mM EDTA, mixture of cortisone / NADPH substrate (200 nM / 200 μM), G-6-P (1 mM) and inhibitors in serial dilutions. Reactions were initiated by the addition of 10 μl of llbeta-HSDl (3 μg) of E. coli, either as microsomal fractions of rat or mouse liver (2.5 μg). After mixing, the plates were shaken for 150 minutes at 37 ° C. The reactions were terminated with 10 μl of glyceratinic acid Id stop solution. The determinations of cortisol levels in preparations of 11 beta-HSDl were monitored by means of HTRF (cortisol HTRF assay from Cis bio international). The activity is expressed in% control or concentration to inhibit 50% of the enzymatic activity (IC50). This test was applied similarly to llbeta-HSD2, where cortisol, NAD and carbenoxolone were used as substrate, cofactor and arrest agent, respectively.

Example 12: BOTTLES-AMPOLLA FOR INJECTABLE A solution of 100 g of an active compound of the present invention and 5 g of disodium hydrogen phosphate in 3 1 of 'double-distilled water is adjusted to a pH of 6.5 using hydrochloric acid 2 N, it is filtered in sterile form, Transfer to ampule bottles for injection, lyophilize under sterile conditions and aseptically sealed. Each vial-ampoule for injection contains 5 mg of active compound. EXAMPLE 13: SUPPOSITORIES A mixture of 20 g of an active compound of the present invention is fused with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active compound. EXAMPLE 14: SOLUTION A solution of 1 g of active compound of the present invention, 9.38 g of NaH2P04 • 2 H20, 28.48 g of Na2HP04 • 12 H20 and 0.1 g of benzalkonium chloride in 940 ml is prepared. of double-distilled water. The solution is adjusted to a pH of 6.8, completed to 1 1 and sterilized by irradiation. This solution can be used in the form of ophthalmic drops. EXAMPLE 15: SUCTION 500 mg of an active compound of the present invention are mixed with 99.5 g of Vaseline under aseptic conditions. EXAMPLE 16: COMPRESSES A mixture of 1 kg of an active compound of the present invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed. conventional way to form tablets, such that each tablet contains 10 mg of active compound.

EXAMPLE 17: COATED TABLETS Analogously to the previous example, the tablets are pressed, which are then coated conventionally with a covering of sucrose, potato starch, talcum, tragacanth gum and dye. EXAMPLE 18: CAPSULES 2 kg of an active compound of the present invention are placed in a conventional manner in hard gelatin capsules, so that each capsule contains 20 mg of active ingredient. It is noted that in relation to this date, the best method known to the applicant to carry out the practice of said invention is that which is clear from the present description of the invention.

Claims (21)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compound of the formula I characterized in that R1 is H, OH, F, Br or ORB, Z is O or S, Rz is H, methyl, ethyl or isopropyl, or R2, Y and the N to which they are attached form a saturated C5-? ring, optionally substituted with R3, R4 and / or R5; is a direct bond or C1-C4 alkyl or C1-C4 alkyl-OXI, W is C4-C8 cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted with R3, R4 and / or R5; RJ Rq R- are, independently of each other, H, Hal, OH, alkyl, C 1 -C 4 -oxi, benzyloxy, phenoxy, phenyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfanyl, dimethylamino, S (O) n (CH2) mCH3, C 1 -C 4 alkyl-oxycarbonyl, C 1 -C 4 alkylcarbonyl or R 6 RNalkyl C 4 -C oxy, n is 0-2, m is 1-3, R6, R7 are, independently of each other, C1-C4 alkyl or form, together with the N atom, a heterocyclic ring saturated with 4-8 C atoms, R8 is alkyl, C (0) R9 , C (0) NH2 or C (0) NR9R10, R9 is H, C? -C8 alkyl or C? -C8 cycloalkyl,
2. R10 is alkyl or the group NR9R10 in C (0) NR9R10 is heterocyclyl, and physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all proportions. Compound according to claim 1, characterized in that R1 is H, Z is 0, R2 is H or methyl, and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions.
3. 3. Compound according to claim 1, characterized in that R1 is OH or F, Z is O, R2 is H or methyl, and their physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers, including their mixtures in all proportions.
4. 4. Compound according to claim 1, characterized in that R1 is OR8 and its physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers, including mixtures thereof in all proportions. Compound according to any of claims 1 to 4, characterized in that W is C4-C8 cycloalkyl or aryl, optionally substituted with R3, R4 and / or R5; and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Compound according to any one of claims 1 to 5, characterized in that it is cyclopentyl, phenyl, naphthyl or indanyl, and its salts, derivatives, prodrugs, solvates and stereoisomers physiologically acceptable, including their mixtures in all proportions. Compound according to any of claims 1 to 6, characterized in that W is phenyl, and its salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. Compound according to any one of claims 1 to 7, characterized in that Y is a direct bond, and its salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. 9. Compound according to any of claims 1 to 4, characterized in that it is heterocyclyl or heteroaryl, optionally substituted with R3, R4 and / or R5; and their salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. 10. Compound according to any of claims 1, 2, 3, 4 and 9, characterized in that it is piperidinyl, pyrrolidinyl, furanyl, imidazolyl, pyridinyl, thiophenyl, triazolyl, benzodioxinyl or isoxazolyl, and its salts, derivatives, prodrugs, solvates and physiologically acceptable stereoisomers, including their mixtures in all proportions. 11. Compound according to any of claims 1, 2, 3, 4 and 10, characterized in that Y is a direct link, and its physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers, including mixtures thereof in all proportions. 12. Compound selected from the group characterized in that it consists of a) l-Adamantan-2-yl-3- (4-methoxy-2-methyl-phenyl) -urea b) l-Adamantan-2-yl-3- (3- trifluoromethyl-phenyl) -urea c) l-Adamantan-2-yl-3- (3-chloro-phenyl) -urea d) l-Adamantan-2-yl-3- (2-trifluoromethyl-phenyl) -urea e) l-Adamantan-2-yl-3- (2,3-dichloro-phenyl) -urea f) l-Adamantan-2-yl-3- (3,5-bis-trifluoromethyl-phenyl) -urea g) Ethyl ester of 2- (3-adamantan-2-yl-ureido) -benzoic acid h) l-Adamantan-2-yl-3- (3,5-dimethoxy-phenyl) -urea i) l-Adamantan-2-yl- 3- (4-Chloro-2-trifluoromethyl-phenyl) -urea j) l-Adamantan-2-yl-3- (2,4,5-trimethy1-phenyl) -urea k) l-Adamantan-2-yl- 3- (4-butoxy-phenyl) -urea 1) 4- (3-adamantan-2-yl-ureido) -benzoic acid butyl ester m) l-Adamantan-2-yl-3-phenethyl-urea n) 5- (3-Adamantan-2-yl-ureido) -isophthalic acid dimethyl ester o) l-Adamantan-2-yl-3- (2-methylsulfanyl-phenyl) -urea p) l-Adamantan-2 il-3-biphenyl-4-yl urea q) l-Adamantan-2-yl-3- (2-thiophen-2-yl-ethyl) -urea r) l-Adamantan-2-yl-3- (4 -bromo-phenyl) -urea s) l-Adamantan-2-yl-3- (3-chloro-4-methyl-phenyl) -urea t) l-Adamantan-2-yl-3- (3,4-dimethyl) phenyl) -urea u) l-Adamantan-2-yl-3- (3-ethyl-phenyl) -urea v) l-Adamantan-2-yl-3- (4-chloro-3-trifluoromethyl-phenyl) - urea w) l-Adamantan-2-yl-3- (4-iodo-phenyl) -urea x) 1-Adamantan-2-yl-3-naphthalen-2-yl-urea y) l-Adamantan-2-yl -3- (3-fluoro-4-methyl-phenyl) -urea z) l-Adamantan-2-yl-3- (5-fluoro-2-methyl-phenyl) -urea aa) l-Adamantan-2-yl -3- (2,6-dichloro-pyridin-4-yl) -urea bb) l-Adamantan-2-yl-3- (3,4-difluoro-phenyl) -urea ce) l-Adamantan-2-yl -3- (4-benzyloxy-phenyl) -urea dd) l-Adamantan-2-yl-3- (2-phenoxy-phenyl) -urea ee) l-Adamantan-2-yl-3- (4-bromo- 2-fluoro-phenyl) -urea ff) l-Adamantan-2-yl-3- (2, 3, 4-trifluoro-phenyl) '- urea gg) l-Adam antan-2-yl-3- (4-dimethylamino-phenyl) -urea hh) l-Adamantan-2-yl-3- (3-trifluoromethylsulfanyl-phenyl) -urea ii) l-Adamantan-2-yl-3- (3-methyl-benzyl) -urea j) l-Adamantan-2-yl-3- (2-fluoro-3-trifluoromethyl-phenyl) -urea kk) l-Adamantan-2-yl-3- (2,4-dibromo-phenyl) -urea 11) l-Adamantan-2-yl-3- (3,5-dichloro-2-hydroxy-4-methyl-phenyl) -urea) methyl ester of 2- (3-adamantan-2-yl-ureido) benzoic acid nn ) l-Adamantan-2-yl-3-cyclopentyl-urea oo) l-Adamantan-2-yl-3- (2-methoxy-phenyl) -urea pp) l-Adamantan-2-yl-3- (3- methylsulfanyl-phenyl) -urea qq) l-Adamantan-2-yl-3- (5-chloro-2-methoxy-phenyl) -urea rr) 1- (4-Acetyl-phenyl) -3-adamantan-2-yl -urea ss) l-Adamantan-2-yl-3-furan-2-ylmethyl-urea tt) l-Adamantan-2-yl-3- (4-methoxy-benzyl) -urea uu) l-Adamantan-2- il-3- (4-chloro-phenyl) -urea vv) l-Adamantan-2-yl-3- (4-methoxy-phenyl) -urea ww) l-Adamantan-2-yl-3- (2-fluoro) -5-methyl-phenyl) -urea xx) l-Adamantan-2-yl-3- (2,4-difluoro-phenyl) -urea yy) 1- (3-Acetyl-phenyl) -3-adamantan-2- il-urea zz) l-Adamantan-2-yl-3- (2-ethoxy-phenyl) -urea aaa) 4- (3-adamantan-2-yl-ureido) benzoic acid methyl ester bbb) l-Adamantan- 2-yl-3- (2,4-dimethoxy-fe nil) -urea ecc) l-Adamantan-2-yl-3- (2, 5-dimethoxy-phenyl) -urea ddd) l-Adamantan-2-yl-3- (3,4-dimethoxy-phenyl) -urea eee) l-Adamantan-2-yl-3- (3-chloro-4-methoxy-phenyl) -urea fff) 3- (3-Adamantan-2-yl-ureido) -2-methyl-benzoic acid methyl ester ggg) l-Adamantan-2-yl-3- [2- (2, 3-dimethoxy-phenyl) -ethyl] -urea hhh) l-Adamantan-2-yl-3- [2- (3,5-dimethoxy phenyl) -ethyl] -urea iii) l-Adamantan-2-yl-3- (5-chloro-2,4-dimethoxy-phenyl) -urea j j j) l-Adamantan-2-yl-3- ((R) -1-phenyl-ethyl) -urea kkk) l-Adamantan-2-yl-3- (2-difluoromethoxy-phenyl) -urea 111) l-Adamantan-2-yl-3- (4-difluoromethoxy-phenyl) -urea mmm) l-Adamantan-2-yl-3- (6-fluoro-4H-benzo [1,3] dioxin-8- il) -urea nnn) l-Adamantan-2-yl-3-thiophen-3-yl-urea ooo) l-Adamantan-2-yl-3- (4-fluoro-phenyl) -urea PPP) l-Adamantan- 2-yl-3- (3-methoxy-phenyl) -urea qqq) l-Adamantan-2-yl-3- (4-fluoro-3-methyl-phenyl) -urea rrr) l-Adamantan-2-yl- 3- (4-methylsulfanyl-phenyl) -urea sss) l-Adamantan-2-yl-3- (4-ethoxy-phenyl) -urea ttt) 3- (3-adamantan-2-yl-ureido) methyl ester ) - benzoic uuu) l-Adamantan-2-yl-3- (3-methyl-5-phenyl-isoxazol-4-yl) -urea vvv) l-Adamantan-2-yl-3- (1-phenyl-ethyl) ) -urea www, l-Adamantan-2-yl-3- [1- (4-methoxy-phenyl) -ethyl] -urea xxx) 1- (5-hydroxy-adamantan-2-yl) -3- (4-methoxy-2-methyl-phenyl) -urea yyy) l-Adamantan-2-yl-3- (2-hydroxy-l-) phenyl-ethyl) -urea zzz) l-Adamantan-2-yl-3-indan-l-yl-urea aaaa) Adamantan-2-ylamide of pyrrolidin-1-carboxylic acid bbbb) Adamantan-2-ylamide of piperidinic acid 1-carboxylic acid cccc) Adamantan-2-ylamide of 3-methyl-piperidine-l-carboxylic acid dddd) l-Adamantan-2-yl-3- (1H- [1,2, 4] triazol-3-yl) - urea eeee) 3-Adamantan-2-yl-l-methyl-l- (2-pyridin-2-yl-ethyl) -urea ffff) 4- [2- (3-adamantan-2-yl-l-methyl -ureido) -ethoxy] - benzoic gggg) 4- [2- (3-adamantan-2-yl-l-methyl-ureido) -ethoxy] -benzoic acid methyl ester hhhh) 3- (3-adamantan-2) -yl-ureido) -2-methyl-benzoic iiii) 2- (3-Adamantan-2-yl-ureido) -benzoic acid jjjj) 4- (3-adamantan-2-yl-ureido) -benzoic acid kkkk) -Adamantan-2-yl-3- (4-hydroxy-2-methyl-phenyl) -urea 1111) l-Adamantan-2-yl-3- (2-methyl-4- (2-piperidin-1-yl- etoxil) phenyl) -urea look) Ester 4- [((S) -3-methyl-piperidin -l-carbonyl) -amino] - adamantan-1-yl of acetic acid nnnn) Ester 4- [((S) -3-methyl-piperidin-l-carbonyl) -amino] - cyclohexanecarboxylic acid adamantane-1-yl ester) 4- [((S) -3-methyl-piperidin-1-carbonyl) -amino] -damantan-1-yl ester of 2,2-dimethyl-propionic acid and its salts physiologically acceptable derivatives, prodrugs, solvates and stereoisomers, including mixtures thereof in all proportions. 13. Method for the preparation of a compound according to any of claims 1 to 12, characterized in that a) an adamantylamine is reacted according to formula II, wherein R1 is as defined in claim 1, with a isocyanate according to formula III, wherein Y, R3, R4 and R5 are as defined in claim 1, or b) an adamantyl isolate is reacted according to formula IV, wherein R1 is as defined in claim 1, with an amine according to formula V, wherein Y, R2, R3, R4 and R5 are as define in claim 1, or IV V c) an adamantylamine is reacted according to formula II, wherein R1 is as defined in claim 1, with a carbonyldiimidazole to give the corresponding acylimidazole according to formula VI and the acylimidazole is reacted with an amine according to formula V, wherein Y, R2, R3, R4 and R5 are as defined in claim 1, or VI V d) an adamantylurea derivative is reacted according to formula VII, wherein Y, R1, R2, R3, R4 and R5 are as defined in claim 1, with to give the corresponding phenol and the phenol is alkylated with a chloride dialkylaminoethyl, wherein R6 and R7 are as defined in claim 1, or Vile e) a residue R1, R2, R3, R4, R5, R6 and / or R7 is converted, as defined in claim 1, into another residue R1, R2, R3, R4, R5, R6 and / or R7 upon introduction , for example, an alkyl group, of) a compound of the formula I is isolated and / or treated with an acid or a base to obtain one of its salts. 14. Use of a compound according to any of claims 1 to 12 as a llß-HSDl inhibitor. 1
5. 5. Use of a compound according to any of claims 1 to 12 for the preparation of a medicament. 1
6. 6. Use of a compound according to any of claims 1 to 12 for the preparation of a medicament for the treatment and / or prevention of diseases caused, mediated and / or spread by high levels of cortisol. 1
7. 7. Use of a compound according to any of claims 1 to 12 for the preparation of a medicament for the treatment and / or prevention of one or several diseases or conditions selected from the group consisting of metabolic syndrome, diabetes, especially non-insulin-dependent diabetes mellitus, prediabetes, insulin resistance, low glucose tolerance, hyperglycemia, obesity and weight-related disorders, lipid disorders such as dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or high levels of LDL, glaucoma, osteoporosis, glucocorticoid-mediated effects on neuronal function, such as cognitive impairment, anxiety or depression, neurodegenerative disease, immune disorders such as tuberculosis, leprosy or psoriasis, hypertension, atherosclerosis and its sequelae, vascular restenosis, cardiovascular diseases, pancreatitis, retinopathy, neuropathy and nephropathy a. 1
8. 8. Pharmaceutical composition, characterized in that it contains a therapeutically effective amount of one or more compounds according to any of claims 1 to 12. 1
9. 9. Pharmaceutical composition according to claim 18, characterized in that it contains one or several additional compounds selected from the group consisting of excipients, auxiliaries, adjuvants, diluents, physiologically acceptable carriers and pharmaceutically active agents other than the compounds of conformity with any of claims 1 to 12. 20. Set characterized in that it consists of separate packages of a) a therapeutically effective amount of one or more compounds according to any of claims 1 to 12 and b) a therapeutically effective amount of one or several other pharmaceutically active agents other than the compounds according to any of claims 1 to 12. 21. Process for the preparation of a pharmaceutical composition, characterized in that one or more compounds according to any of claims 1 to 12 and one or more compounds selected from the group consisting of excipients, auxiliaries, adjuvants, diluents, solid, liquid or semi-liquid carriers and pharmaceutically active agents other than the compounds according to any one of claims 1 to 12, they are converted into an appropriate dosage form.