KR20110060653A - Cyclicsulfonamide derivatives having an acetamide group, preparation thereof and pharmaceutical composition containing same - Google Patents

Abstract

PURPOSE: A cyclic sulfonamide derivative with an acetamide group is provided to suppress activation of 11beta-hydroxysteroid dehydrogenase type1(11beta-HSD1) and to treat various diseases. CONSTITUTION: A cyclic sulfonamide derivative with an acetamide group is denoted by chemical formula 1. A pharmaceutical composition for preventing or treating 11beta-HSD1-mediated diseases contains cyclic sulfonamide derivative of chemical formula 1 or pharmaceutically acceptable salt as an active ingredient and pharmaceutically acceptable carrier. The 11beta-HSD2-mediated diseases are insulin-dependent diabetes, insulin non-dependent diabetes, arthritis, obesity, hypertension, hyperlipidemia, or depression.

Description

CYCLICSULFONAMIDE DERIVATIVES HAVING AN ACETAMIDE GROUP, PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING SAME}

The present invention is 11-beta-hydroxy steroid dehydrogenase type of claim 1 (11 β -hydroxysteroid dehydrogenase type1, 11 β -HSD1) cyclic having acetamide capable of inhibiting the activity of the sulfonamide derivatives, methods for their manufacture and this It relates to a pharmaceutical composition containing as an active ingredient.

With the recent changes in the environment, the number of patients with obesity, hyperglycemia, hypertension, hyperlipidemia and metabolic syndrome overlapping with these multiple risk factors due to changes in diet and lifestyle is increasing worldwide. This leads to obesity, especially visceral obesity, type 2 diabetes, hyperlipidemia, hypertension, atherosclerosis, cardiovascular heart disease and ultimately chronic kidney failure (C. T. Montague et al. (2000), Diabetes, 49, 883-888).

Glucocorticoids and 11β-HSD1 are known to be important factors in the differentiation of fat stromal cells into mature adipocytes. 11β-HSD1 mRNA levels are increased in visceral stromal cells of obese patients compared to subcutaneous tissues. Also, in transgenic mice, overexpression of 11β-HSD1 in adipose tissue is associated with adipose tissue, visceral obesity, insulin-dependent diabetes (1). Type diabetes mellitus), insulin independent diabetes mellitus (type 2 diabetes), hyperlipidemia and bulimia (H. Masuzaki et al. (2001), Science, 294, 2166-2170). Thus, 11β-HSD1 is primarily involved in the development of visceral obesity and metabolic syndrome.

Cortisol, a glucocorticoid hormone, binds to the glucocorticoid receptor with a very strong affinity. This combination activates transcription of various genes, resulting in decreased insulin secretion, hepatic gluconeogenesis and increased adipocyte differentiation due to problems with insulin signaling. It causes a variety of metabolic diseases, including.

Hydroxysteroid dehydrogenase (HSDs) exist in a number of classes, which regulate the occupancy and activation of steroid hormones by converting steroid hormones to their inactive metabolites (Nobel et al., Eur. J.). Biochem. 2001, 268: 4113-4125). That is, 11β-HSD1 is an enzyme for converting cortisone to cortisol, and 11β-HSD2 is an enzyme for converting cortisol to cortisone.

Isoform 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is widely expressed in liver, adipose tissue, brain, lung and other glucocorticoid tissues, while isoform 2 (11β- Expression of HSD2) is limited to tissues that express mineralocorticoid receptors such as kidney, intestine and placenta. At this time, inhibition of 11β-HSD2 is associated with serious side effects such as hypertension.

Inhibition of 11β-HSD1 reduces the differentiation of fat stromal cells and increases their proliferation. In addition, glucocorticoid deficiency (adrenal resection) enhances the ability of insulin and leptin to promote anorexia and weight loss, and this effect is reversed by glucocorticoid administration (PM Stewart et al. (2002), Trends Endocrin. Metabol, 13, 94-96).

Excessive cortisol is associated with a number of disorders, including diabetes, obesity, dyslipidemia, insulin resistance and hypertension. Administration of an 11β-HSD1 inhibitor reduces the levels of cortisol and other 11β-hydroxysteroids in the target tissue, thereby reducing excess cortisol and other 11β-hydroxysteroid effects. Thus, 11β-HSD1 is a potential therapeutic target associated with many disorders that can be alleviated by decreased glucocorticoid action. Thus, inhibition of 11β-HSD1 can be used to prevent, treat or control diseases mediated by abnormally high levels of cortisol and other 11β-hydroxysteroids, such as diabetes, obesity, hypertension or dyslipidemia. . Inhibiting 11β-HSD1 activity in the brain, such as lowering cortisol levels, may also be useful for treating or reducing anxiety, depression, cognitive impairment or age-related cognitive dysfunction (Seckl, et al., Endocrinology, 2001, 142: 1371-1376).

Cortisol is an important and well-known anti-inflammatory hormone, which also acts as an antagonist to insulin action in the liver to reduce insulin sensitivity, resulting in elevated levels of glucose in the liver and increased gluconeogenesis. Patients with already impaired glucose tolerance are more likely to develop type 2 diabetes if abnormally high levels of cortisol are present (Long et al., J. Exp. Med. 1936, 63: 465-490; Houssay, Endocrinology 1942, 30: 884-892). In addition, 11β-HSD1 has been shown to play an important role in the regulation of glucose production in the liver and in the regulation of local glucocorticoid effects (Jamieson et al., J. Endocrinol. 2000, 165: 685-692). In Walker, et al., J. Clin. Endocrinol. Metab. 1995, 80: 3155-3159, administration of the non-specific 11β-HSD1 inhibitor carbenoxolone improves human liver insulin sensitivity. This has been reported.

In addition, the hypothesized mechanism of action of 11β-HSD1 in the treatment of diabetes was supported by various experiments conducted in mice and rats. These findings indicate that the activity and mRNA levels of two important enzymes in hepatic glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), resulted in the administration of 11β-HSD1 inhibitors. Decreased at hr. In addition, blood glucose levels and hepatic glucose production have been shown to be reduced in 11β-HSD1 knockout mice. Additional data collected using these mice knockout models confirm that basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids, so that inhibition of 11β-HSD1 will not cause hypoglycemia (Kotelevtsev et al. Proc. Natl. Acad. Sci. USA 1997, 94: 14924-14929).

Thus, administering a therapeutically effective amount of 11β-HSD1 inhibitor is effective for treating, controlling and alleviating the symptoms of diabetes, particularly non-insulin dependent diabetes mellitus (NIDDM, type 2 diabetes), and regularly administers a therapeutically effective amount of 11β-HSD1 inhibitor. Administration delays or prevents the onset of diabetes, particularly in humans.

The effect of elevated levels of cortisol is also observed in patients with Cushing's Syndrome, which is a metabolic disease characterized by high levels of cortisol in the bloodstream. NIDDM often develops in patients with Cushing's syndrome.

Excess levels of cortisol are associated with obesity, probably due to increased liver gluconeogenesis. Abdominal obesity is closely related to other factors of metabolic syndrome, such as glucose tolerance, diabetes, hyperinsulinemia, hypertriglyceridemia, and hypertension, elevated VLDL and decreased HDL (Montague et al., Diabetes, 2000 , 49: 883-888). 11β-HSD1 has also been reported to reduce the rate of differentiation into adipocytes in pre-adipocytes (stromal cells). This is expected to lead to diminished (possibly reduced) expansion of the omental fat depot, which can reduce central obesity (Bujalska et al., Lancet 1997, 349: 1210-1213).

Thus, administering an effective amount of 11β-HSD1 inhibitor is useful for the treatment or control of obesity. Long-term treatment with 11β-HSD1 inhibitors is also useful for delaying or preventing the onset of obesity, especially when the patient uses an 11β-HSD1 inhibitor in combination with a controlled diet and exercise.

By reducing insulin resistance and maintaining serum glucose at normal concentrations, the compounds of the present invention also treat and prevent abnormalities involving type 2 diabetes and insulin resistance, including metabolic syndrome, obesity, reactive hypoglycemia and diabetic dyslipidemia Has utility in

Inhibition of 11β-HSD1 in mature adipocytes is expected to reduce the secretion of plasminogen activator inhibitor 1 (PAI-1), which is described by Halleux et al., J; Clin.endocrinol. Metab. 1999, 84: 4097-4105), is an independent cardiovascular risk factor. In addition, there appears to be a correlation between glucocorticoid activity and certain cardiovascular risk factors. This suggests that reduced glucocorticoid effect would be beneficial for the treatment or prevention of certain cardiovascular diseases (Walker et al., Hypertension 1998, 31: 891-895; and Fraser et al., Hypertension 1999, 33: 1364 1368).

Since hypertension and dyslipidemia lead to the development of atherosclerosis and the inhibition of 11β-HSD1 activity and the decrease in the amount of cortisol are beneficial for the treatment or control of hypertension, administering a therapeutically effective amount of the 11β-HSD1 inhibitor of the present invention It may also be particularly beneficial for the treatment, control or delay of the development of atherosclerosis, or the prevention of atherosclerosis.

11β-HSD1 is also involved in appetite control processes and is thought to play an additional role in weight-related disorders. Adrenalectomy is known to reduce the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This suggests that glucocorticoids play a role in promoting food intake and that inhibition of 11β-HSD1 in the brain can increase satiety and thus reduce food intake (Woods et al., Science 1998, 280: 1378-1383).

Another possible therapeutic effect related to the regulation of 11β-HSD1 is the effect associated with various pancreatic aliments. Inhibition of 11β-HSD1 in rat pancreatic β-cells has been reported to increase glucose stimulated insulin secretion (Davani et al., J. Biol. Chem. 2000, 275: 34841-34844). This is due to the fact that glucocorticoids reduce pancreatic insulin release in vivo (Billaudel et al., Horm. Metab. Res. 1979, 11: 555-560). Thus, inhibition of 11β-HSD1 is thought to have other beneficial effects in the treatment of diabetes in addition to fat reduction and the expected effects on the liver.

Excessive levels of cortisol in the brain may cause neuronal loss or dysfunction through potentiation of neurotoxins. Administration of an effective amount of 11β-HSD1 inhibitor reduces, alleviates, regulates or prevents cognitive and neuronal dysfunctions associated with aging. Cognitive impairment is associated with aging and excessive levels of cortisol in the brain (see J. R. Seckl and B. R. Walker, Endocrinology, 2001, 142: 1371 1376, and references cited therein). 11β-HSD1 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) . Stress and / or glucocorticoids are known to affect cognitive function (de Quervain et al., Nature 1998, 394: 787-790), and unknown results are in rats treated with non-specific 11β-HSD1 inhibitors. Shows a significant improvement in memory. These reports, in addition to the known effects of glucocorticoids in the brain, suggest that inhibition of 11β-HSD1 in the brain can have a positive therapeutic effect on anxiety, depression and related abnormalities (Tronche et al., Nature Genetics 1999, 23: 99-103). 11β-HSD1 can inactivate 11-dihydrocorticosterone to corticosterone and potentiate kinase neurotoxicity in hippocampal cells, resulting in age-related learning impairment. Therefore, selective inhibitors of 11β-HSD1 are thought to inhibit hippocampal function decline with age (Yau et al., Proc Natl. Acad. Sci. USA 2001, 98: 4716-4721). Thus, inhibition of 11β-HSD1 in the human brain is believed to reduce the deleterious glucocorticoid-mediated effects on neuronal function, such as cognitive impairment, depression, and increased appetite.

11β-HSD1 is also thought to play an immunomodulatory role based on the general recognition that glucocorticoids suppress the immune system. It is known that there is a dynamic interaction between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis (Rook, Baillier's Clin. Endocrinol. Metab. 2000, 13: 576-581), and glucocorticoids can be used between cell-mediated and humoral responses. Help balance Increased glucocorticoid activity, which can be induced by stress, is associated with humoral responses, and thus inhibiting 11β-HSD1 can shift the response towards cell-based responses. In certain disease states such as tuberculosis, leprosy and psoriasis, and even under conditions of excessive stress, high glucocorticoid activity shifts the immune response to a humoral response, in which a cell-based response may in fact be more favorable to the patient. Inhibition of 11β-HSD1 activity and concomitant decreases in glucocorticoid levels, on the other hand, shifts the immune response towards cellular response (D. Mason, Immunology Today, 1991, 12: 57-60, and GAVt. Rook, Baillier's Clin. Endocrinol Metab., 1999, 13: 576-581). The alternative utility of 11β-HSD1 inhibition then enhances the transient immune response associated with immunization and ensures that a cellular response is obtained.

The level of HSD of glucocorticoid target receptors is associated with susceptibility to glaucoma (J. Stokes et al., Invest. Ophthalmol. 2000, 41: 1629-1638). In addition, an association between inhibition of 11β-HSD1 and lower intraocular pressure has recently been reported (Walker et al., Poster P3-698 at the Endocrine society meeting June 12-15, 1999, Sandiego). Administration of the nonspecific 11β-HSD1 inhibitor carbenoxolone has been shown to reduce intraocular pressure by 20% in normal patients. In the eye, 11β-HSD1 is expressed entirely in corneal epithelium, corneal non-pigmented epithelium (site of aqueous production), ciliary muscle, and basal cells of the sphincter and dilator muscle of the iris. In contrast, distant isoenzyme 11beta-hydroxysteroid dehydrogenase type 2 (“11β-HSD2”) is highly expressed in non-pigmentary epithelium and corneal endothelium. No HSD was found in trabecularmeshwork, which is a drainage site. Thus, 11β-HSD1 has been shown to play a waterproofing role, and inhibiting 11β-HSD1 activity is useful for reducing intraocular pressure in the treatment of glaucoma.

Glucocorticoids play an essential role in skeletal development and function but, when excessively present, are disadvantageous to such development and function. Glucocorticoid-induced bone loss results, in part, from inhibition of osteoblast proliferation and collagen synthesis (CH Kim et al., J. Endocrinol. 1999, 162: 371 379). et al., J. Endocrinol. 1999, 162: 371 379). It has been reported that the deleterious effects of glucocorticoids on bone nodule formation can be reduced by the administration of carbenoxolone, which is a non-specific 11β-HSD1 inhibitor (CG Bellows et al., Bone 1998, 23 119-125). An additional report suggests that 11β-HSD1 may increase active glucocorticoid levels in osteoclasts and thus increase bone uptake (M. S. Cooper et al., Bone 2000, 27: 375-381). This data suggests that inhibition of 11β-HSD1 may have a beneficial effect on osteoporosis through one or more mechanisms that can act in parallel.

11β-HSD1 inhibitors are disclosed, for example, in JP2007197369, WO2005 / 108361, WO2007 / 068330, WO2004 / 010629, WO2003 / 065983, WO2004 / 089896, WO2004 / 089380, WO2004 / 065351, WO2004 / 033427 and WO2004 / 041264. Although JP2007197369 discloses a cyclic sulfonamide derivative, the cyclic sulfonamide derivative having an acetamide group according to the present invention and its inhibitory activity against 11β-HSD1 are not disclosed in any of the documents.

Accordingly, it is an object of the present invention to provide a novel cyclicsulfonamide derivative capable of effectively inhibiting the activity of 11 β- HSD1 and a method for preparing the same.

Another object of the present invention is to provide a pharmaceutical composition for treating or preventing a disease mediated by 11 β- HSD1, which contains the cyclic sulfonamide derivative as an active ingredient.

In order to achieve the above object, the present invention provides a cyclic sulfonamide derivative having a acetamide group or a pharmaceutically acceptable salt thereof represented by the following general formula (1):

Where

, 나프틸, 피리딜,

, 1-아다만틸, 2-아다만틸 또는 사이클로헥실이고;R ₁ is

, Naphthyl, pyridyl,

, 1-adamantyl, 2-adamantyl or cyclohexyl;

R ₂ is hydrogen or C _1-6 alkyl;

, C_{1 -6} 알킬, C_{3 -6} 사이클로알킬 또는 아다만틸이고, 이때 R^c는 1개 내지 5개의 치환기로서, 각각 독립적으로 수소, C_{1 -6} 알킬, C_{3 -6} 사이클로알킬, C_{1 -6} 알콕시, OCF₃, 할로겐, NO₂, CN 또는 CF₃이고; R ₃ is

, C _{1 -6} alkyl, C _{3 -6} cycloalkyl, or adamantyl, wherein R ^c is a 1 to 5 substituents, each independently selected from hydrogen, C _{1 -6} alkyl, C _{3 -6} cycloalkyl, C _1-6 alkoxy, OCF _3, halogen, NO _2, CN or CF ₃ and;

R ₄ is hydrogen or methyl;

R ^a is 1 to 5 substituents, each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, OCF ₃ , halogen, NO ₂ , CN, CF _3, COOR ^b , N-morpholinyl, SCH ₃ or NR ^d R ^e, wherein R ^d and Each R ^e is independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl;

R ^b is hydrogen or C _1-6 alkyl.

Since the cyclic sulfonamide derivatives having a 2-acetamide group represented by the formula (1) according to the present invention and pharmaceutically acceptable salts thereof exhibit high inhibitory activity against 11 β- HSD1, the pharmaceutical composition comprising them as an active ingredient Is useful for the treatment or prevention of diseases mediated by 11 β- HSD1, eg, insulin dependent diabetes mellitus, insulin independent diabetes mellitus, arthritis, obesity, hyperlipidemia, hypertension, glaucoma, cognitive disorders, immune disorders, depression and osteoporosis Can be used.

Cyclicsulfonamide derivatives of the present invention include prodrugs, solvates, stereoisomers and mixtures of all proportions thereof.

이고; R^a는 1개 내지 5개의 치환기로서, 각각 독립적으로 수소, C_{1 -6} 알킬, C_1-6 알콕시, OCF₃, 할로겐, CN 또는 CF₃이다. 이 때, 더욱 바람직하게는, R₃는

이고; R^c는 1개 내지 5개의 치환기로서, 각각 독립적으로 수소, C_{1 -6} 알킬, C_{1 -6} 알콕시 또는 할로겐이다.In the cyclic sulfonamide derivative of Formula 1, preferably, R ₁

ego; R ^a is a 1 to a 5 substituents, each independently selected from hydrogen, C _{1 -6} alkyl, C _1-6 alkoxy, OCF _3, halogen, CN or CF _3. At this time, More preferably, R ₃ is

ego; R ^c is a 1 to 5 substituents, each independently selected from hydrogen, C _{1 -6} alkyl, C _{1 -6} alkoxy or halogen.

And most preferably, in view of excellent inhibitory activity against 11β-HSD1, the cyclicsulfonamide derivative of Formula 1 may be one of the following compounds:

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acetamide, 1,1 -Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-adamantyl) -acetamide, 1,1-dioxide,

2- (3-acetyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-methyl-N-phenylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (1-adamantyl) -acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-hydroxy-1-adamantyl) -acetamide, 1 , 1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (pyridin-2-ylmethyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-benzylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (pyridin-4-yl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-methoxyphenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluorophenyl) acetamide, 1,1-dioxide,

N- (benzo [d] [1,3] dioxol-5-yl) -2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) Acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-morpholinophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-chloro-4-fluorophenyl) acetamide, 1,1 -Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethyl) phenyl) acetamide, 1,1 -Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (pyridin-3-yl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (biphenyl-2-yl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-cyclohexylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (1H-pyrazol-3-yl) acetamide, 1,1- Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (isoxazol-3-yl) acetamide, 1,1-dioxide ,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (naphthalen-2-yl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (isoquinolin-1-yl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluoro-3-nitrophenyl) acetamide, 1,1 -Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,5-difluorophenyl) acetamide, 1,1- Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,4-difluorophenyl) acetamide, 1,1- Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,5-bis (trifluoromethyl) phenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethoxy) phenyl) acetamide, 1, 1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluoro-3- (trifluoromethyl) phenyl) acet Amides, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (methylthio) phenyl) acetamide, 1,1-dioxide ,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -1-morpholinoethanone, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -1-thiomorpholinoethanone, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -1- (4-methylpiperazin-1-yl) ethanone, 1,1 -Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-ethylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N, N-diethylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-fluorophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N'-phenylacetohydrazide, 1,1-dioxide,

2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

N- (2-fluorophenyl) -2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1 , 1-dioxide,

N- (2-chlorophenyl) -2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1, 1-dioxide,

2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide,

2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-methyl-N-phenylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-methoxybenzyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (1-phenylethyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-o-tolylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-m-tolylacetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (furan-2-ylmethyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoro methyl) benzyl) acetamide, 1,1 -Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluorobenzyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,6-difluorobenzyl) acetamide, 1,1- Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (1- (4-fluorophenyl) ethyl) acetamide, 1, 1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-ethylbenzyl) acetamide, 1,1-dioxide,

2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide,

N- (2-chlorophenyl) -2- (3- (4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1, 1-dioxide,

2- (3- (4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide,

2- (3- (4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

2- (3- (4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide,

2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acetamide, 1,1 -Dioxide,

2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-fluorophenyl) acetamide, 1,1-dioxide,

2- (4-hydroxy-3- (3-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

N- (2-chlorophenyl) -2- (4-hydroxy-3- (3-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1, 1-dioxide,

2- (4-hydroxy-3- (3-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide,

N- (4-fluorophenyl) -2- (4-hydroxy-3- (3-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1 , 1-dioxide,

2- (3- (2-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

2- (3- (2-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acet Amides, 1,1-dioxide,

2- (3- (2-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluorophenyl) acetamide, 1, 1-dioxide,

2- (3- (2-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1 -Dioxide,

2- (3- (3-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenyl acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,3-dihydro-1H-inden-4-yl) acet Amides, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,5-dimethylphenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluoro-2-methylphenyl) acetamide, 1,1- Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,5-dimethylphenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-chloro-2-methylphenyl) acetamide, 1,1-dioxide ,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,6-diethylphenyl) acetamide, 1,1-dioxide ,

N- (2-chlorophenyl) -2- (3- (3-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1, 1-dioxide,

2- (3- (3-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluorophenyl) acetamide, 1 , 1-dioxide,

2- (3- (3-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-cyanophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-ethylphenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-ethylphenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-tert-butylphenyl) acetamide, 1,1-dioxide ,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-isopropylphenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-bromo-2-fluorophenyl) acetamide, 1, 1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,4-dichlorophenyl) acetamide, 1,1-dioxide ,

2- {3- (1-adamantyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl} -N-phenylacetamide, 1,1-dioxide,

2- {3- (1-adamantyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl} -N- (3-trifluoromethylphenyl) acetamide, 1,1-dioxide,

2- {3- (1-adamantyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl} -N- (2-chlorophenyl) acetamide, 1, 1-dioxide,

2- {3- (1-adamantyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl} -N- (4-fluorophenyl) acetamide, 1 , 1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,5-difluorophenyl) acetamide, 1,1- Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-fluorophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-fluoro-4-methylphenyl) acetamide, 1,1- Dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-chlorophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-chlorophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-bromophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-cyanophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-cyanophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-nitrophenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-methoxyphenyl) acetamide, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-methoxyphenyl) acetamide, 1,1-dioxide,

2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide,

2- (4-hydroxy-3- (4-methylbenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

2- (4-hydroxy-3- (4-methylbenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acet Amides, 1,1-dioxide,

N- (2-chlorophenyl) -2- (4-hydroxy-3- (4-methylbenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1,1 -Dioxide,

2- (3- (3-chloro-4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (pyridin-2-yl) Acetamide, 1,1-dioxide,

Ethyl 3- (2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamido) benzoate, 1,1-dioxide,

Ethyl 4- (2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamido) benzoate, 1,1-dioxide,

3- (2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamido) benzoic acid, 1,1-dioxide,

2- (3- (3-chloro-4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1 -Dioxide,

2- (3- (3-chloro-4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acet Amides, 1,1-dioxide,

2- (3- (3-chloro-4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoro Methyl) phenyl) acetamide, 1,1-dioxide,

4- (2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamido) benzoic acid, 1,1-dioxide,

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-p-tolylacetamide, 1,1-dioxide,

2- (3- (3-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide,

2- (3- (3-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1 -Dioxide,

2- (3- (3-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acet Amide, 1,1-dioxide.

The compound of formula 1 according to the present invention is prepared according to the synthetic route represented by Scheme 1 or 2 (Scheme 1: when R ₄ is hydrogen, Scheme 2: when R ₄ is C _1-6 alkyl).

According to a first embodiment according to Scheme 1 (wherein R ₄ is hydrogen), the present invention comprises the steps of (1) hydrolyzing a compound of formula 6 to produce a compound of formula 7; And (2) condensation of a compound of Formula 7 with a compound of Formula 8 (R ₁ R ₂ NH) to provide a process for preparing a cyclicsulfonamide derivative of Formula 1a:

Wherein R ₁ , R ₂ and R ₃ are as defined above.

Looking at the method for producing a cyclic sulfonamide derivative of Formula 1a according to the first embodiment in detail for each step as follows.

In hydrolysis of the compound of formula (6) in step (1), bases such as caustic soda (NaOH), KOH, LiOH and the like can be used. At this time, tetrahydrofuran (THF), methanol, water or a mixture thereof may be used as the reaction solvent, and it is preferable to proceed for 1 to 20 hours at a reaction temperature of 0 to 100 ° C. The completion of the reaction can be confirmed by thin layer chromatography, and when the reaction is completed, the reaction solvent is removed by concentration under reduced pressure, and the residue is treated with dilute acid to recover the resulting solid by filtration or extracted with ethyl acetate. To yield the compound of 7.

The condensation reaction of step (2) then comprises, for example, 1,1′-carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1 It can proceed in the presence of one or more condensing agents selected from the group consisting of, 3-dicyclohexylcarbodiimide (DCC), in addition to the presence of various condensing agents known to those skilled in the art. The amount of the condensing agent used is preferably about 1 to 2 equivalents based on 1 equivalent of the compound of formula 7. The amount of the compound of Formula 8 is preferably about 1 to 2 equivalents based on 1 equivalent of Compound 7 of Formula 7. It is also preferred to condense the cyclicsulfonamide 2-acetic acid of formula 7 and the commercially available amino compound of formula 8 in the presence of an amine base. In addition, as a solvent for the condensation reaction, although not particularly limited, aliphatic hydrocarbon solvents such as dichloromethane and chloroform can be preferably used, and the condensation reaction proceeds for 2 to 24 hours at a reaction temperature of 20 to 70 ° C. This is preferred.

The end point of the reaction described above is determined by the point at which all of the compound of Formula 7 is consumed, which can be confirmed by thin layer chromatography.

On the other hand, unlike the manufacturing method according to the first embodiment described above, according to the second embodiment according to the following Scheme 2 (when R ₄ is C _1-6 alkyl), the present invention is also (i) Alkylating a compound of Formula 6 with an alkyl halide to prepare a compound of Formula 9; (ii) hydrolyzing the compound of Formula 9 to prepare a compound of Formula 10; And (iii) condensing the compound of formula 10 with a compound of formula 8 (R ₁ R ₂ NH): a cyclicsulfonamide derivative of formula (Ib):

Wherein R ₁ , R ₂ and R ₃ are as defined above,

R ₄ ′ is C _1-6 alkyl and X is halogen.

According to this second embodiment, the compound of formula 6 is alkylated using an alkyl halide to produce the compound of formula 9, and then finally the compound of formula 1b may be finally prepared through hydrolysis and condensation reactions. Since the specific configuration of each reaction is based on the conventional method or described above in the preparation method according to the first embodiment, further description thereof will be omitted.

Compounds of the formula (6) used as starting materials in Schemes 1 and 2 (cyclic sulfonamide 2-ethyl acetate) are, as shown in Scheme 3 below, in an organic solvent (eg dimethylformamide (DMF)) A compound of formula 2 (saccharin sodium salt) and a compound of formula 3 (1-bromoacetophenone) are reacted to produce a compound of formula 4, which is reacted with sodium ethoxide to form a compound of formula 5 (cyclic Sulfonamide) can be produced and reacted with ethyl 2-bromoacetate. The preparation of such compounds of formula (6) is according to well known methods (Harold Zinnes, Roger A. Comes, Francis R. Zuleski, Albert N. Caro, and John Shavel Jr., J. Org. Chem ., 1965 , 30 , 2241-2246; and JG Lombardino, EH Wiseman, and WM McLamore, J. Med. Chem. 1971 , 14 , 1171.

Wherein R ₃ is as defined above.

In addition, the present invention provides a method for treating or preventing a disease mediated by 11 β- HSD1, including a cyclic sulfonamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier as an active ingredient. It provides a pharmaceutical composition for.

As described above, since the cyclic sulfonamide derivatives having the 2-acetamide group represented by the formula (1) and the pharmaceutically acceptable salts thereof exhibit high inhibitory activity against 11 β- HSD1, pharmaceuticals containing them as active ingredients The composition is useful for the treatment or prevention of diseases mediated by 11 β- HSD1, such as insulin dependent diabetes mellitus, insulin independent diabetes mellitus, arthritis, obesity, hyperlipidemia, hypertension, glaucoma, cognitive disorders, immune disorders, depression and osteoporosis. Can be used.

The pharmaceutical compositions may be formulated in various oral or parenteral dosage forms. For example, it may be in any dosage form for oral administration, such as tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs. Such oral dosage forms may contain, in addition to the active ingredient, a diluent such as, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, silica, talc, or the like according to the conventional composition of each formulation. And pharmaceutically acceptable carriers such as lubricants such as stearic acid and its magnesium or calcium salts and / or polyethylene glycols.

In addition, when the oral dosage form is a tablet, it may include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and Depending on the disintegrant, such as starch, agar, alginic acid or its sodium salt, boiling mixtures and / or absorbents, colorants, flavoring or sweetening agents and the like may be included.

In addition, the pharmaceutical composition may be formulated in a parenteral dosage form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. At this time, in order to formulate the formulation for parenteral administration, the pharmaceutical composition is an active ingredient, that is, a cyclic sulfonamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water with a stabilizer or a buffer solution Or in suspension, and such solutions or suspensions may be prepared in unit dosage forms of ampoules or vials.

In addition, the pharmaceutical composition may be sterile, or may further include adjuvants such as preservatives, stabilizers, hydrating or emulsifiers, salts and / or buffers for controlling osmotic pressure, and may further include other therapeutically useful substances. It may be formulated according to conventional methods of mixing, granulating or coating.

In addition, the active ingredient, that is, the cyclic sulfonamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg / kg (body weight) per day, preferably for mammals including humans. An effective amount of 0.5 to 100 mg / kg body weight may be included in the pharmaceutical composition, and the pharmaceutical composition may be divided once or twice a day and administered by oral or parenteral route.

On the other hand, the present invention also provides a method for inhibiting 11 β- HSD1 comprising administering to a subject mammal a therapeutically effective amount of a cyclicsulfonamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides a cyclic sulfonamide derivative or pharmaceutically acceptable salt administered a therapeutically effective amount thereof to the target mammalian method for treating diseases mediated by the 11 β -HSD1, comprising the formula (I).

At this time, the disease mediated by 11 β- HSD1 may be, for example, insulin dependent diabetes mellitus, insulin independent diabetes mellitus, arthritis, obesity, hyperlipidemia, hypertension, glaucoma, cognitive disorders, immune disorders, depression or osteoporosis And other diseases known to be related to the activity of other 11 β- HSD1.

In addition, the specific administration method and therapeutically effective amount of the cyclic sulfonamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof may include the type of mammal, the type of disease, the type of cyclic sulfonamide derivative of Formula 1, and In consideration of the inhibitory activity of 11 β- HSD1 and the like can be obviously determined by those skilled in the art, it is not particularly limited.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments. However, this is presented as an example of the present invention by any means is not limited by the scope of the present invention, the scope of the present invention is defined only in accordance with the claims below.

Preparation Example 1

Preparation of 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide

[Stage 1]

Saccharin sodium salt (10 g, 0.049 mol) was dissolved in DMF (100 ml), and 2-bromoacetophenone (11.75 g, 0.059 mol) was added. After stirring the reaction mixture at 100 ° C. for 5 hours, when the reaction was completed, the reaction mixture was poured into iced water, and the resulting solid was filtered and dried to obtain 2- (2-oxo-2-phenylethyl) -1,2-benziso. Thiazol-3 (2H) -one, 1,1-dioxide (13 g, yield = 88%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.12 (d, J = 6.6 Hz, 1H), 8.01 (m, 5H), 7.65 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H), 5.15 (s, 2H).

[Step 2]

Sodium (Na, 2.3 g, 33.18 mmol) was added to ethanol (100 ml), heated to 40 ° C. to dissolve, and then 2- (2-oxo-2-phenylethyl) -1,2-benzisothiazole-3 (2H ) -One, 1,1-dioxide (5.0 g, 16.59 mmol) was added in one portion, kept at 50-55 ° C. and stirred for 3 hours. The reaction mixture was cooled to room temperature, the resulting solid was filtered and dried and washed with 50% ethanol solution. The recovered solid was dried in vacuo at 60 ° C. to obtain 3-benzoyl-4-hydroxy-1,2-benzothiazine-1,1-dioxide (3.9 g, yield = 80%).

¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.25 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 6.9 Hz, 2H), 7.94 (m, 1H), 7.82 (m, 2H) , 7.58 (m, 3 H), 5.82 (brs, 1 H).

[Step 3]

3-benzoyl-4-hydroxy-1,2-benzothiazine-1,1-dioxide (1 g, 3.319 mmol) was dissolved in ethanol (25 ml), 1N NaOH (5 ml) and ethyl bromoacetate (665 mg, 3.98). mmol) was added dropwise sequentially and stirred at room temperature for 12 hours. When the reaction was completed, the resulting solid was filtered, washed with distilled water and dried in vacuo to ethyl 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) Acetate, 1,1-dioxide (587 mg, yield = 45%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 8.13-8.08 (m, 1H), 7.88-7.81 (m, 5H), 7.60-7.48 (m, 3H), 3.92 (s, 2H), 3.67 (q, J = 7.1 Hz, 2H), 0.78 (t, J = 7.1 Hz, 3H).

[Step 4]

Ethyl 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetate, 1,1-dioxide (100 mg, 0.258 mmol) in tetrahydrofuran (5 ml ) And methanol (5ml), LiOH.H ₂ O (60mg, 1.425mmol) / H ₂ O (5ml) was added to the solution and stirred for 5 hours at room temperature. When the reaction was completed, the reaction mixture was concentrated, iced water was added, treated with 2N HCl (pH = 1), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to 2- (3-benzoyl-4-hydroxy- 2H-benzo [e] [1,2] thiazin-2-yl) acetic acid and 1,1-dioxide (85 mg, yield = 92%) were obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 12.67 (s, 1H), 8.18-8.15 (m, 1H), 8.00-7.98 (m, 2H), 7.93-7.90 (m, 3H), 7.72 ˜7.58 (m, 3 H), 3.80 (s, 2 H).

[Step 5]

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (40 mg, 0.112 mmol), aniline (13 mg, 0.135 mmol ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 32 mg, 0.168 mmol) and 4-dimethylaminopyridine (DMAP, 14 mg) were added to CH ₂ Cl ₂ (5 ml). . The reaction mixture was stirred at room temperature for 5 hours, treated with 2N HCl solution, and the separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography (EA: Hex = 1: 2) to give 2- (3- Benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide and 1,1-dioxide (25 mg, yield = 51%) were obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 9.85 (brs, 1H), 9.13-7.85 (m, 6H), 7.85 (m, 3H), 7.18-7.16 (m, 4H), 6.96-6.72 (m, 1 H), 3.95 (s, 2 H).

Production Example 2

Preparation of 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1-dioxide

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (40 mg, 0.112 mmol), 2-chloroaniline (17 mg , 0.135 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 32 mg, 0.168 mmol) and 4-dimethylaminopyridine (DMAP, 17 mg) were dissolved in CH ₂ Cl ₂ (5 ml). ) The reaction mixture was stirred at room temperature for 5 hours, treated with 2N-HCl solution, and the separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography (EA: Hex = 1: 2) to give 2- (3 -Benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1-dioxide (29 mg, yield = 55% )

¹ H NMR (500 MHz, DMSO-d ₆ ): δ = 9.54 (s, 1H), 8.15-8.14 (m, 1H), 8.04 (m, 2H), 7.90-7.88 (m, 3H), 7.71-7.74 (m, 3H), 7.40-7.38 (m, 1H), 7.31 (m, 1H), 7.20-7.13 (m, 1H), 7.12-7.09 (m, 1H), 4.08 (s, 2H).

Production Example 3

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-trifluoromethyl-phenyl) -acetamide, 1,1 Preparation of Dioxide

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (50 mg, 0.139 mmol), 3- (trifluoro Methyl) aniline (27 mg, 0.167 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 40 mg, 0.209 mmol) and 4-dimethylaminopyridine (DMAP, 17 mg) ₂ Cl ₂ (5 ml) was added. The reaction mixture was stirred at room temperature for 5 hours, treated with 2N HCl solution, and the separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography (EA: Hex = 1: 2) to give 2- (3- Benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1-dioxide (21 mg, yield = 30% )

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 15.07 (s, 1H), 10.17 (s, 1H), 8.19-7.18 (m, 13H), 4.00 (s, 2H).

Preparation Example 4

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-adamantyl) -acetamide, of 1,1-dioxide Produce

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (50 mg, 0.13 mmol), 2-adamantamine Hydrochloride (32 mg, 0.167 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 40 mg, 0.209 mmol) and 4-dimethylaminopyridine (DMAP, 17 mg) were converted to CH ₂ Cl ₂ (5 ml) was added. The reaction mixture was stirred at room temperature for 5 hours, treated with 2N HCl solution, and the separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography (EA: Hex = 1: 2) to give 2- (3- Benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-adamantyl) -acetamide, 1,1-dioxide (38 mg, yield = 55 %) Was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 8.05-7.42 (m, 9H), 7.19 (brd, 1H), 3.76 (s, 2H), 3.48-3.41 (m, 1H), 1.68-1.34 (m, 14 H).

Preparation Example 5

Preparation of 2- (3-acetyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (phenyl) -acetamide, 1,1-dioxide

[Stage 1]

Saccharin (10 g, 54.59 mmol) was dissolved in DMF (70 ml), NaH (60% wt, 1.965 g, 81.88 mmol) was added thereto, and the mixture was stirred at 50 ° C. for 30 minutes. 1-chloropropan-2-one (6.06 g, 65.50 mmol) was added dropwise thereto and stirred at 50 ° C. for 4 hours. After the reaction was completed, poured into iced water, and the resulting solid was filtered and dried in vacuo to give 2- (2-oxopropyl) -1,2-benzisothiazol-3 (2H) -one, 1,1-dioxide (3.98 g). , Yield = 30%).

¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.11-8.08 (m, 1H), 7.97-7.84 (m, 3H), 4.48 (s, 2H), 2.29 (s, 3H).

[Step 2]

Sodium (2.8 g, 116.48 mmol) was added to ethanol (250 ml) and heated to reflux for 30 minutes followed by 2- (2-oxopropyl) -1,2-benzisothiazol-3 (2H) -one, 1,1 Dioxide (3.98 g, 16.64 mmol) was added. Then, the mixture was heated to reflux for 4 hours to change the color to yellow or reddish brown. Then, the reaction was terminated. After adding 1N HCl solution to pH = 2 ~ 3, poured into ice water, and the resulting solid was filtered and It dried and obtained 1- (4-hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-yl) ethanone (2.23g, yield = 56%).

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 9.87 (s, 1H), 8.02-8.00 (m, 1H), 7.81 (m, 3H), 2.29 (s, 3H).

[Step 3]

1- (4-hydroxy-1,1-dioxido-2H-1,2-benzothiazin-3-yl) ethanone (800 mg, 3.344 mmol) was dissolved in ethanol (20 ml). 1N NaOH (4ml) was then added dropwise, ethyl bromoacetate (670 mg, 4.013 mmol) was added dropwise and stirred at room temperature for 12 hours. After the reaction was completed, the solid produced during the reaction was filtered, washed well with distilled water and dried in vacuo to give 2- (3-acetyl-4-hydroxy-2H-benzo [e] [1,2] thiazine-2- I) acetate, 1,1-dioxide (230 mg, yield = 21%, white solid) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 8.10-8.06 (m, 1H), 7.90-7.83 (m, 3H), 4.31 (s, 2H), 3.88 (q, J = 7.1 Hz, 2H ), 2.43 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H).

[Step 4]

2- (3-acetyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetate, 1,1-dioxide (230 mg, 0.707 mmol) in tetrahydrofuran (5 ml) Dissolved in methanol (5 ml) and dissolved in LiOH.H ₂ O (60 mg, 1.425 mmol) / H ₂ O (5 ml) and stirred at room temperature for 5 hours. Upon completion of the reaction, the reaction mixture was concentrated, iced water was added, treated with 2N HCl (pH = 1), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to 2- (3-acetyl-4-hydroxy-2H -Benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (210 mg, yield = 99%, white solid) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 8.06 (m, 1H), 7.85 (m, 3H), 4.19 (s, 2H), 2.43 (s, 3H).

[Step 4]

2- (3-acetyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (50 mg, 0.168 mmol), aniline (19 mg, 0.201 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (64 mg, 0.336 mmol) and 4-dimethylaminopyridine (DMAP, 41 mg) were added to CH ₂ Cl ₂ (5 ml). The reaction mixture was stirred at room temperature for 5 hours, treated with 2N HCl solution, and then the separated organic layer was dried over anhydrous magnesium sulfate, concentrated and separated by column chromatography to give 2- (3-acetyl-4-hydroxy-2H- Benzo [e] [1,2] thiazin-2-yl) -N- (phenyl) -acetamide, 1,1-dioxide (30 mg, yield = 47%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 8.04-7.99 (m, 1H), 7.81-7.62 (m, 3H), 7.48-7.40 (m, 2H), 7.29-7.21 (m, 2H) , 7.03-6.97 (m, 1H), 4.13-3.89 (m, 2H), 2.48-2.47 (m, 3H).

Preparation Example 6

Preparation of 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-methyl-N-phenylacetamide, 1,1-dioxide

2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (60 mg, 0.167 mmol), N-methylaniline (22 mg , 0.2 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 48 mg, 0.251 mmol) and 4-dimethyl aminopyridine (DMAP, 21 mg) were dissolved in CH ₂ Cl ₂ (5 ml). ) The reaction mixture was stirred at room temperature for 5 hours, treated with 2N HCl solution, and the separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography (EA: Hex = 1: 3) to give 2- (3- Benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-methyl-N-phenylacetamide, 1,1-dioxide (28 mg, yield = 37%) Got it.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.28-8.25 (m, 1H), 7.90-7.85 (m, 3H), 7.80-7.75 (m, 2H), 7.47-7.74 (m, 3H), 7.26 ~ 7.22 (m, 3H), 6.85-6.82 (m, 3H), 2.94 (s, 3H).

Preparation Example 7

Preparation of 2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide

[Stage 1]

Ethyl 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetate, 1,1-dioxide (100 mg, 0.258 mmol) in acetone (10 ml) It was dissolved, K ₂ CO ₃ (72 mg, 0.516 mmol) and methyl iodide (220 mg, 1.55 mmol) were added and stirred under reflux for 24 hours. After the reaction was completed, brine was added to the reaction mixture, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (EtOAc: Hex = 1: 3) to ethyl 2- (3- Benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) acetate, 1,1-dioxide (60 mg, yield = 58%, white solid) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 7.92-7.69 (m, 7H), 7.60-7.55 (m, 2H), 4.26 (s, 2H), 3.83 (q, J = 7.1 Hz, 2H ), 3.43 (s, 3H), 0.83 (t, J = 7.1 Hz, 3H).

[Step 2]

Ethyl 2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) acetate, 1,1-dioxide (60 mg, 0.149 mmol) was added to tetrahydrofuran ( 3 ml) and methanol (3 ml) were dissolved, and a solution dissolved in LiOH.H ₂ O (31 mg, 0.745 mmol) / H ₂ O (3 ml) was added and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated, iced water was added, treated with 2N HCl (pH = 1), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to give 2- (3-benzoyl-4-methoxy- 2H-benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (50 mg, yield = 90%, yellow solid) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 12.9 (s, 1H), 7.96-7.70 (m, 7H), 7.62-7.57 (m, 2H), 3.44 (s, 3H).

[Step 3]

2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) acetic acid, 1,1-dioxide (70 mg, 0.19 mmol), aniline (22 mg, 0.266 mmol ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 54 mg, 0.282 mmol) and 4-dimethylaminopyridine (DMAP, 33 mg) were added to CH ₂ Cl ₂ (5 ml). The reaction mixture was stirred at room temperature for 5 hours, treated with 2N HCl solution, and the separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography (EA: Hex = 1: 2) to give 2- (3- Benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide (11 mg, yield = 13%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 9.98 (s, 1H), 7.97-7.62 (m, 7H), 7.71-7.72 (m, 1H), 7.58-7.53 (m, 2H), 7.32 7.19 (m, 4H), 7.02-6.97 (m, 1H), 4.32 (s, 2H), 3.45 (s, 3H).

Structural and NMR spectral data of a representative example of a cyclic sulfonamide derivative having a 2-acetamide group represented by Chemical Formula 1 including a part of the cyclic sulfonamide derivatives obtained in Preparation Examples 1 to 7 are shown in Table 1 below. The cyclicsulfonamide derivatives disclosed in Table 1 below were prepared in a similar manner to the methods described in Preparation Examples 1-7 described above.

The molecular structures of the cyclic sulfonamide derivatives shown in Preparation Examples 1 to 7 and Table 1 were confirmed by nuclear magnetic resonance spectra and mass spectroscopy.

Test Example: Pharmacological Activity Test

Inhibitory activity of 11 β- HSD1 was tested for the compound of Preparation Example 1 and its pharmaceutically acceptable acid addition salt as follows.

(1) enzyme source

Lipofectamine plus extranuclear genes (plasmids) incorporating cDNA encoding the full length of human and mouse 11β-HSD1 into mammalian cell expression vector pcDNA (Promega). The reagent (Invitrogen) was used to introduce CHO cells for 5 hours and then stabilized for 48 hours. These cells were treated with 0.8 μg / ml puromycin (purigcin, Sigma) once every three days for 11 weeks to overexpress 11β-HSD1 in humans and mice to obtain a stabilized cell line. The overexpressed cells were proliferated, frozen, and thawed and stabilized every time the enzyme inhibition experiment was performed.

(2) Determination of enzyme inhibition constant

The ability of test compounds to inhibit human 11β-HSD1 enzyme activity in vitro was assessed by scintillation proximity assay (SPA).

Human and mouse 11β-HSD1 overexpressed cells were passaged in 96-well plates with 2.5 × 10 ⁴ cells and stabilized for 24 hours. 160 nM of cortisone (cortisone, Sigma) and the media diluted drug by concentration were put 100 ul per well and incubated in a 37 ℃ cell culture for 3 hours. 10 ul of the culture solution was placed in a 384 well plate, and the amount of cortisol produced was measured according to the following conditions using a cortisol kit (Cisbio international). The control group contained only 160 nM cortisone and 0.1% dimethyl sulfoxide (DMSO). The background value was only 160 nM of cortisone and 0.1% DMSO in the same way as the control group without cells. The method of calculating the% inhibition is as follows (negative ratio of (ii) is derived from the negative control group, and the negative control group replaces 10 ul of diluent, cortisol instead of drug, 5 ul of reconstitution buffer, and 5 ul of anti-cortisol cryptate):

(i) ratio = fluorescence measured at 665 nm / fluorescence measured at 620 nm X 10 ⁴

(ii) Delta F value = (ratio of drug-negative ratio) / negative ratio X 100

(iii) normalized value = delta f value of drug-delta f value of control

(iv)% inhibition = standardized value of drug / background value x 100

For calculating the 11 β -HSD1 IC ₅₀ value as the inhibitory effect of the test compounds as in the method (a 11β-HSD1 activity concentration at the time when 50% inhibition) are shown in Table 2.

As can be seen in Table 2 above, the compounds of the present invention and their pharmaceutically acceptable salts exhibit excellent 11 β- HSD1 inhibitory activity, thereby effectively treating or preventing a disease mediated by 11 β -HSD1. It has been confirmed that it can be used.

Claims (6)

A cyclic sulfonamide derivative having a acetamide group represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

Where R ₁ is

, Naphthyl, pyridyl,

, 1-adamantyl, 2-adamantyl or cyclohexyl; R ₂ is hydrogen or C _1-6 alkyl; R ₃ is

, C _{1 -6} alkyl, C _{3 -6} cycloalkyl, or adamantyl, wherein R ^c is a 1 to 5 substituents, each independently selected from hydrogen, C _{1 -6} alkyl, C _{3 -6} cycloalkyl, C _1-6 alkoxy, OCF _3, halogen, NO _2, CN or CF ₃ and; R ₄ is hydrogen or methyl; R ^a is a 1 to 5 substituents, each independently selected from hydrogen, C _{1 -6} alkyl, C _{3 -6} cycloalkyl, C _{1 -6} alkoxy, OCF _3, halogen, NO _2, CN, CF _3, COOR ^b , N-morpholinyl, SCH ₃ or NR ^d R ^e, wherein R ^d and R ^e are each independently hydrogen, C _{1 -6} alkyl, C _{3 -6} cycloalkyl; R ^b is hydrogen or C _1-6 alkyl. The method of claim 1, R ₁ is

ego; R ^a is a 1 to 5 substituents, each independently selected from hydrogen, C _{1 -6} alkyl, C _{1 -6} alkoxy, OCF _3, halogen, characterized in that the CN or CF _3, cyclic sulfonamide derivative or its Pharmaceutically acceptable salts. The method of claim 2, R ₃

ego; R ^c is a 1 to 5 substituents, each independently selected from hydrogen, C _{1 -6} alkyl, C _{1 -6,} characterized in that halogen or alkoxy, a cyclic sulfonamide derivative or a pharmaceutically acceptable salt thereof. The method of claim 1, A cyclic sulfonamide derivative or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds: 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acetamide, 1,1 -Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-adamantyl) -acetamide, 1,1-dioxide, 2- (3-acetyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-methyl-N-phenylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (1-adamantyl) -acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-hydroxy-1-adamantyl) -acetamide, 1 , 1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (pyridin-2-ylmethyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-benzylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (pyridin-4-yl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-methoxyphenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluorophenyl) acetamide, 1,1-dioxide, N- (benzo [d] [1,3] dioxol-5-yl) -2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) Acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-morpholinophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-chloro-4-fluorophenyl) acetamide, 1,1 -Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethyl) phenyl) acetamide, 1,1 -Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (pyridin-3-yl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (biphenyl-2-yl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-cyclohexylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (1H-pyrazol-3-yl) acetamide, 1,1- Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (isoxazol-3-yl) acetamide, 1,1-dioxide , 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (naphthalen-2-yl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (isoquinolin-1-yl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluoro-3-nitrophenyl) acetamide, 1,1 -Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,5-difluorophenyl) acetamide, 1,1- Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,4-difluorophenyl) acetamide, 1,1- Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,5-bis (trifluoromethyl) phenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethoxy) phenyl) acetamide, 1,1 -Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluoro-3- (trifluoromethyl) phenyl) acet Amides, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (methylthio) phenyl) acetamide, 1,1-dioxide , 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -1-morpholinoethanone, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -1-thiomorpholinoethanone, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -1- (4-methylpiperazin-1-yl) ethanone, 1,1 -Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-ethylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N, N-diethylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-fluorophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N'-phenylacetohydrazide, 1,1-dioxide, 2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, N- (2-fluorophenyl) -2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1 , 1-dioxide, N- (2-chlorophenyl) -2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1, 1-dioxide, 2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide, 2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-methyl-N-phenylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-methoxybenzyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (1-phenylethyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-o-tolylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-m-tolylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (furan-2-ylmethyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethyl) benzyl) acetamide, 1,1 -Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluorobenzyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,6-difluorobenzyl) acetamide, 1,1- Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (1- (4-fluorophenyl) ethyl) acetamide, 1, 1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-ethylbenzyl) acetamide, 1,1-dioxide, 2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide, N- (2-chlorophenyl) -2- (3- (4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1, 1-dioxide, 2- (3- (4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide, 2- (3- (4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, 2- (3- (4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide, 2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acetamide, 1,1 -Dioxide, 2- (3-benzoyl-4-methoxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-fluorophenyl) acetamide, 1,1-dioxide, 2- (4-hydroxy-3- (3-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, N- (2-chlorophenyl) -2- (4-hydroxy-3- (3-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1, 1-dioxide, 2- (4-hydroxy-3- (3-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide, N- (4-fluorophenyl) -2- (4-hydroxy-3- (3-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1 , 1-dioxide, 2- (3- (2-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, 2- (3- (2-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acet Amides, 1,1-dioxide, 2- (3- (2-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluorophenyl) acetamide, 1, 1-dioxide, 2- (3- (2-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1 -Dioxide, 2- (3- (3-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,3-dihydro-1H-inden-4-yl) acet Amides, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,5-dimethylphenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluoro-2-methylphenyl) acetamide, 1,1- Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,5-dimethylphenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-chloro-2-methylphenyl) acetamide, 1,1-dioxide , 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2,6-diethylphenyl) acetamide, 1,1-dioxide , N- (2-chlorophenyl) -2- (3- (3-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1, 1-dioxide, 2- (3- (3-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-fluorophenyl) acetamide, 1 , 1-dioxide, 2- (3- (3-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-cyanophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-ethylphenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-ethylphenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-tert-butylphenyl) acetamide, 1,1-dioxide , 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-isopropylphenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-bromo-2-fluorophenyl) acetamide, 1, 1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,4-dichlorophenyl) acetamide, 1,1-dioxide , 2- {3- (1-adamantyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl} -N-phenylacetamide, 1,1-dioxide, 2- {3- (1-adamantyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl} -N- (3-trifluoromethylphenyl) acetamide, 1,1-dioxide, 2- {3- (1-adamantyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl} -N- (2-chlorophenyl) acetamide, 1, 1-dioxide, 2- {3- (1-adamantyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl} -N- (4-fluorophenyl) acetamide, 1 , 1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3,5-difluorophenyl) acetamide, 1,1- Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-fluorophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-fluoro-4-methylphenyl) acetamide, 1,1- Dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-chlorophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-chlorophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-bromophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-cyanophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (4-cyanophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-nitrophenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3-methoxyphenyl) acetamide, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-methoxyphenyl) acetamide, 1,1-dioxide, 2- (4-hydroxy-3- (4-methoxybenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) Acetamide, 1,1-dioxide, 2- (4-hydroxy-3- (4-methylbenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, 2- (4-hydroxy-3- (4-methylbenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acet Amides, 1,1-dioxide, N- (2-chlorophenyl) -2- (4-hydroxy-3- (4-methylbenzoyl) -2H-benzo [e] [1,2] thiazin-2-yl) acetamide, 1,1 -Dioxide, 2- (3- (3-chloro-4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (pyridin-2-yl) Acetamide, 1,1-dioxide, Ethyl 3- (2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamido) benzoate, 1,1-dioxide, Ethyl 4- (2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamido) benzoate, 1,1-dioxide, 3- (2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamido) benzoic acid, 1,1-dioxide, 2- (3- (3-chloro-4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1 -Dioxide, 2- (3- (3-chloro-4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acet Amides, 1,1-dioxide, 2- (3- (3-chloro-4-fluorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoro Methyl) phenyl) acetamide, 1,1-dioxide, 4- (2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) acetamido) benzoic acid, 1,1-dioxide, 2- (3-benzoyl-4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-p-tolylacetamide, 1,1-dioxide, 2- (3- (3-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N-phenylacetamide, 1,1-dioxide, 2- (3- (3-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (2-chlorophenyl) acetamide, 1,1 -Dioxide, and 2- (3- (3-chlorobenzoyl) -4-hydroxy-2H-benzo [e] [1,2] thiazin-2-yl) -N- (3- (trifluoromethyl) phenyl) acet Amide, 1,1-dioxide. Claim 1 of formula (I) as an active ingredient a cyclic sulfonamide derivative or a pharmaceutical for the treatment or prevention of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, including a possible, diseases mediated by 11 β -HSD1 Composition. The method of claim 5, The 11 β- HSD1 mediated disease is insulin-dependent diabetes, insulin-independent diabetes, arthritis, obesity, hyperlipidemia, hypertension, glaucoma, cognitive disorders, immune disorders, depression or osteoporosis.