KR101407697B1 - Composition for Preventing or Treating Brain Diseases or Ischemic Heart Diseases Comprising Sulfamide Derivatives Having Adamantyl Group as Active Ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cerebral diseases and ischemic heart diseases, which comprises a sulfamide derivative having an adamantyl group as an active ingredient.
Oh sulfamic polyimide compound having an adamantyl derivative of this invention effectively suppressed by the 11 β -HSD1 activity, as well as ischemic heart disease, neurodegenerative diseases, such as cerebrovascular diseases and mental disease caused by ischemic or reperfusion 11 β -HSD1 And can be usefully used for the prevention or treatment of various brain diseases that are mediated by < RTI ID = 0.0 >

Description

TECHNICAL FIELD [0001] The present invention relates to a composition for preventing or treating brain diseases or ischemic heart diseases, which comprises a sulfamide derivative having an adamantyl group as an active ingredient,

The present invention relates to a composition for preventing or treating brain diseases or ischemic heart diseases, which comprises a sulfamide derivative having an adamantyl group as an active ingredient.

If blood supply to the brain and heart is blocked due to thrombosis or rupture of atherosclerotic plaque, the balance between oxygen demand and supply is broken, resulting in myocardial infarction and ischemic stroke. If reperfusion does not occur early in the injury, the brain and heart will progressively undergo intracellular pathological changes, ultimately leading to irreversible cell death and tissue necrosis, resulting in damage to the brain and myocardial tissue. Although reperfusion may limit irreversible damage, it has been reported that even after reperfusion, pathological processes such as oxidative stress and inflammatory response due to reactive oxygen species are induced, and brain and heart are likely to be damaged (Eltzschig and Eckle , Nat Med, 2011, 17, 1391-401). Therefore, there is a desperate need for a therapeutic agent for delaying the damage caused by ischemia and minimizing the damage after reperfusion.

Glucocorticoid is a steroid hormone that regulates various metabolic and homeostatic processes and is a major factor in the response to stress. It binds with high affinity to glucocorticoid receptors and regulates the expression of various genes. The action of glucocorticoids can be controlled not only by hormone levels and receptor expression in target tissues, but also at the tissue level by the modulation of 11β-11β-hydroxysteroid dehydrogenase (11β-11β-HSD), two known subtypes Sandeep TC & Walker BR, Trends Endocrinol & Metab, 2001, 12, 446-53). 11β-HSD2, which is restrictedly expressed in tissues that express mineralocorticoid receptors as minerals such as the kidneys, colon and placenta, is an enzyme that converts the active glucocorticoid cortisol into an inactive form of cortisone, 11β-HSD1 is an enzyme that converts cortisone to cortisol in liver, fat and brain tissue and plays an important role in the activation of glucocorticoid receptors. Excessive increases in intracellular cortisol may result in increased hepatic glucose production, adipocyte differentiation and increased insulin resistance. Thus, the 11 [beta] -HSDl inhibitor may be used as a therapeutic agent for metabolic syndrome such as type 2 diabetes, obesity and hyperlipidemia, which are non-insulin dependent diabetes caused by glucocorticoids (Masuzaki et al, Science, 2001, 294, Walker et al, J Clin Endocrinol Metab, 1995, 80, 3155-9). In the brain, 11β-HSD1 is involved in neurotoxicity by regulating glucocorticoid activity. High-glucose glucocorticoids in neurons decrease neurotoxicity by decreasing glucose uptake, inducing excitotoxicity, and increasing reactive oxygen species J Cereb Blood Flow Metab, 2009, 29, 130-6). In addition, high levels of glucocorticoids lead to depression. Inhibiting 11beta-HSD1 activity may be useful in relieving anxiety and depression (Seckl et al, Endocrinology, 2001, 142). It is also known that 11β-HSD1 activated in memory centers in senescence is involved in memory depression and it has been reported that such memory and learning deterioration are mitigated by treatment with an effective amount of 11β-HSD1 inhibitor (Sooy et al, J Neurosci, 2010, 30, 13867-72). There is also a correlation between glucocorticoid activity and specific cardiovascular risk factors. It has been reported that administration of glucocorticoids increases the risk even in the presence of cardiovascular disease. Thus, a reduction in glucocorticoid effects is expected to be useful for the treatment or prevention of certain cardiovascular diseases (Walker et al, Hypertension, 1998, 31, 891-5; Small et al, Proc Natl Acad Sci USA, 2005, 102, 12165- 70). 11β-HSD1 has also been shown to be responsible for glaucoma by affecting intraocular pressure. Inhibition of 11β-HSD1 has been shown to alleviate glaucoma-associated increases in IOP (Rauz et al, QJM, 2003, 96, 481-90 ), Suggesting the role of ll [beta] -HSDl inhibitors in the treatment of glaucoma. However, studies with carbenoxolone, a nonspecific inhibitor that inhibits both 11 [beta] -HSDl and 11 [beta] -HSD2, have been shown to increase blood pressure (Kotelevtsev et al, Clin Invest, 1999, 103, 683- 9), and side effects that lead to cerebrovascular deformation (Osmond and Dorrance, Endocrinology, 2009, 150, 713-9). Therefore, it is important to develop selective inhibitors of ll [beta] -HSDl, and selective inhibition of this ll [beta] -HSDl may be useful for the treatment of various diseases mediated by insulin-independent type 2 diabetes, obesity, stroke, heart disease and excessive glucocorticoid action And a safe and effective approach to treat the symptoms.

As described above, there is a strong demand for the establishment of an effective and safe therapeutic method for the treatment of acute ischemia such as myocardial infarction and cerebral infarction. The present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a therapeutic agent for myocardial infarction and stroke, which is effective as a mechanism different from conventional therapeutic agents and can be taken for a long time.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have found that by inhibiting 11? -Hydroxysteroid dehydrogenase type 1 (11? -HSD1) which regulates glucocorticoid activity in the brain and contributes to neurotoxicity, it is possible to provide an effective treatment for various brain diseases and ischemic heart diseases induced by 11? And tried to develop a composition. As a result, it was confirmed that a sulfamide derivative having an adamantyl group represented by the structure of the following formula (1) effectively inhibited 11? -HSD1 activity in brain tissues and markedly decreased myocardial infarction due to ischemia Thereby completing the present invention

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating brain diseases or ischemic heart diseases.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided a medicament for preventing or treating brain diseases or ischemic heart diseases comprising a sulfamide derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient ≪ / RTI >

Formula 1

는 단일결합 또는 이중결합을 나타내며; R₄ 내지 R₆는 인접한 고리탄소와 이중결합을 형성하는 경우는 각각 독립적으로 산소 또는 CH₂이고, 단일결합을 형성하는 경우는 각각 독립적으로 수소 또는 C₁-C₃ 알킬이며; n은 0-2의 정수이다.In the above formulas, R ₁ to R ₃ are each independently hydrogen, halogen, nitro or C ₁ -C ₃ Alkyl;

Represents a single bond or a double bond; R ₄ to R ₆ are independently oxygen or CH ₂ when they form a double bond with the adjacent ring carbon, and when they form a single bond, they are each independently hydrogen or C ₁ -C ₃ Alkyl; n is an integer of 0-2.

The present inventors have developed an effective therapeutic composition for various brain diseases caused by 11? -HSD1 by inhibiting 11? -Hydroxysteroid dehydrogenase type 1 (11? -HSD1) which regulates glucocorticoid activity in the brain and contributes to neurotoxicity I tried my best. As a result, it was confirmed that a sulfamide derivative having an adamantyl group represented by the structure of the above formula (1) effectively inhibited 11? -HSD1 activity in brain tissue and markedly decreased myocardial infarction due to ischemia Thereby completing the present invention.

According to the present invention, the compound of formula (I) of the present invention is useful for inactivating 11-dihydrocorticosterone to corticosterone in hippocampal cells, increasing kinase neurotoxicity to decrease hippocampal function reduction, RTI ID = 0.0 > llbeta-HSDl. ≪ / RTI > Accordingly, the compounds of the present invention can be usefully used for treating or preventing neurodegenerative diseases, cerebrovascular diseases, mental diseases and ischemic heart diseases.

As used herein, the term " alkyl " means a straight or branched saturated hydrocarbon group, including, for example, methyl, ethyl, propyl, isobutyl, pentyl or hexyl. C ₁ -C ₃ Alkyl means an alkyl group having an alkyl unit having 1 to 3 carbon atoms, and when C ₁ -C ₃ alkyl is substituted, the number of carbon atoms of the substituent is not included. In formula (1), C ₁ -C ₃ Alkyl is preferably C ₁ Alkyl (methyl).

As used herein, the term " halogen " refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

As used herein, the term " brain disease " refers to a pathologic condition in which the function of brain tissue is reversibly or irreversibly degraded or lost by damage of cerebral blood vessels or brain nerves. Preferably, the brain disease to be prevented or treated with the composition of the present invention is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases due to ischemia or reperfusion, and mental illnesses.

More preferably, said neurodegenerative diseases are selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis.

More preferably, the disease caused by ischemia or reperfusion is ischemic stroke.

More preferably, the mental disorder is selected from depression, schizophrenia and post-traumatic stress disorder.

As used herein, the term " ischemic heart disease " refers to a disease caused by the narrowing or occlusion of the coronary arteries supplying blood to the heart, resulting in reduced blood flow to the heart muscle. Preferably, the ischemic heart disease that is prevented or treated with the composition of the present invention is selected from the group consisting of angina pectoris, myocardial infarction and heart failure.

According to a preferred embodiment of the present invention, R ₁ to R ₃ in formula (1) of the present invention are each independently hydrogen, chloro, bromo, nitro, methyl or trifluoromethyl; R ₄ to R ₆ each independently represent hydrogen or methyl when they form a single bond with the adjacent ring carbon; n is 1.

According to a more preferred embodiment of the present invention, R ₄ or R ₅ of formula (I) of the present invention forms a double bond with the adjacent ring carbon, and R ₆ forms a single bond with the adjacent ring carbon.

Even more preferably, the sulfamide derivative of the present invention is selected from the group consisting of the compounds represented by the following formulas (2) to (11)

 (2)

            (4)

           (6)

          (8)

         (10)

The present invention includes sulfamide derivative compounds having an adamantyl group represented by the general formula (1) as well as pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts of the derivatives of formula I of the present invention include acid addition salts formed by pharmaceutically acceptable free acids.

Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

Preferably, the pharmaceutically acceptable salts to be added in the present invention are hydrochloride, sulfate, acetate, trifluoroacetate, phosphate, fumarate, maleate, citrate, methanesulfonate or lactate.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, , Or may be prepared by drying, or after the solvent and excess acid are distilled off under reduced pressure, followed by drying or crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In addition, the present invention encompasses not only the arylsulfonamide derivative having an adamantyl group represented by the above formula (1) and pharmaceutically acceptable salts thereof, but also solvates, hydrates and stereoisomers thereof which can be prepared therefrom .

According to a most preferred embodiment of the present invention, the sulfamide derivative of the present invention is selected from the group consisting of the compounds represented by the above formulas (6), (9) and (11).

According to the present invention, the three compounds listed above exhibit very high% inhibition of 11? -HSD1 inhibitory activity in the brain, And thus can be usefully used as a highly effective therapeutic composition of various brain diseases associated with ll [beta] -HSDl.

When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration or the like.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg / kg.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

According to a preferred embodiment of the present invention, the composition of the present invention inhibits the activity of 11? -Hydroxysteroid dehydrogenase type 1 (11? -HSD1).

According to the present invention, the compounds of the present invention effectively inhibit the activity of 11? -HSD1, an enzyme that converts cortisone to cortisol. As used herein, the term " inhibiting " means reducing the in vivo expression level or biological activity of a subject substance to a significant level.

The features and advantages of the present invention are summarized as follows:

(a) The present invention provides a pharmaceutical composition for preventing or treating brain diseases and ischemic heart diseases, which comprises a sulfamide derivative having an adamantyl group as an active ingredient.

(b) The sulfamidic derivative compound having an adamantyl group of the present invention efficiently inhibits the activity of 11 ? -HSD1, thereby providing not only ischemic heart disease but also neurodegenerative diseases, cerebrovascular diseases caused by ischemia or reperfusion, can be usefully used for the prevention or treatment of various brain diseases mediated by ? -HSD1.

FIG. 1 is a graph showing the results of measurement of neurological behavior indicators measured on the first day after cerebral ischemia-reperfusion in a group administered with the compound of the present invention (compound of formula (VI)) and a control group not administered.
FIG. 2 is a graph showing that the ischemic stroke infarct size of the group administered with the compound of the present invention is significantly lower than that of the control group. It was confirmed that the compound of the present invention significantly reduced the infarct structure through the photographs of the dyed brain tissue sections of each group (FIG. 2A) and the results of cerebral infarction volume measurement (FIG. 2B).

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Manufacturing example

(2- (1,1-dioxido-6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin-2-yl) acetamido) adamantane- 1-carboxamide (E) (Formula 2)

Synthesis of 2- (2,4,6-trichlorophenyl) -1,2,6-thiadiazine, 1.1-dioxide Synthesis

^{1 H NMR (300 MHz, DMSO} -d6): δ 7.40 (s, 2H), 6.80 ~ 6.75 (brm, NH), 3.77 ~ 3.45 (m, 4H), 1.82 ~ 1.74 (m, 2H) LC / MS MH + 316

Ethyl 2- (6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin-2-yl) acetate, 1.1-

^{1 H NMR (300 MHz, CDCl} 3): δ 7.39 (s, 2H), 4.23 (q, J = 7.1Hz, 2H), 4.15 (s, 2H), 3.95 ~ 3.91 (m, 2H), 3.84 ~ 3.80 (m, 2H), 2.20-1.95 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). LC / MS MH < + > 402

2- (6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin-2-yl) acetic acid, 1.1-

^{1 H NMR (300 MHz, DMSO} -d6): δ 12.80 (br, OH), 7.79 (s, 2H), 4.04 (s, 2H), 3.77 ~ 3.72 (m, 4H), 1.92 ~ 1.87 (m, 2H ). LC / MS MH < + > 374

^{1 H NMR (300 MHz, CDCl} 3): δ 7.41 (s, 2H), 6.94 (brd, J = 7.0Hz, NH), 5.56 (br, NH2), 5.22 (br, NH2), 4.18 ~ 4.14 (m (M, 2H), 4.00 (s, 2H), 3.87-3.82 (m, 2H), 3.71-3.41 (m, 2H), 2.14-1.61 (m, 15H). LC / MS MH < + > 550

(2- (4-methyl-1,1-dioxido-6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin- Adamantane-1-carboxamide (Formula 3)

Methyl 2- (4-methyl-1,1-dioxido-6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin-

(3.0 g, 8.3 mmol), 2-methylpropane-1,3-diol (1.18 ml, 8.3 mmol), and methyl 2 - ((N- (2,4,6- trichlorophenyl) sulfamoyl) amino) After dissolving PPh ₃ (5.4 g, 20.7 mmol), DIAD (4 ml, 20.7 mmol) was slowly added dropwise while adjusting the external temperature to 0 ° C, followed by stirring at room temperature for 3 hours. After the reaction was completed, water was added, and the mixture was extracted with EtOAc, dried (Na ₂ SO ₄ ), filtered, concentrated under reduced pressure and purified by column chromatography (MeOH / DCM 1%) to obtain the title compound g, y = 65%).

¹ H NMR (300 MHz, CDCl ₃ )? 7.41 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 4.44 J = 7.1 Hz, 3H), 0.94 (t, J), 3.75-3.13 (m, = 7.1 Hz, 3H)

2- (4-methyl-1,1-dioxido-6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin-2-yl) acetic acid

A solution of methyl 2- (4-methyl-1,1-dioxido-6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin- mmol) was dissolved in THF (12 ml) and MeOH (12 ml). LiOH (1.1 g, 27.0 mmol) was dissolved in H ₂ O and then slowly added dropwise to the mixture. The mixture was stirred at room temperature for 3 hours. When the reaction was completed, the reaction mixture was concentrated, and water was added thereto, followed by adjusting the pH to 3 with 2N HCl. Extraction with EtOAc, drying (Na ₂ SO ₄ ), filtration, and cone concentration yielded the title compound (solid, 2.0 g, y = 83%).

¹ H NMR (300 MHz, CDCl ₃ )? 7.42 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 4.53 1H, m, 4H), 3.40-3.38 (m, IH), 3.20-3.15 (m, IH), 2.57-2.11

4- (2- (4- methyl -1,1- Dioxido -6- (2,4,6- Trichlorophenyl ) -1,2,6- Tiadia Jin -2- yl ) Acetamido ) Adamantan -1-carboxamide

(900 mg, 3.9 mmol) was dissolved in DMSO (40 ml) and i- prOH (50 ml), and then DIPEA (2.5 g, 19.5 mmol) (2,4,6-trichlorophenyl) -1,2,6-thiadiazin-2-yl) acetic acid (1.8 g, 4.7 mmol) , EDC (894 mg, 4.7 mmol) and HOBT (632 mg, 4.7 mmol) were added, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was extracted with EtOAc, dried (Na ₂ SO ₄ ), filtered, concentrated under reduced pressure and purified by column chromatography (MeOH / DCM 5%) to obtain the title compound (solid, 980 mg, y = 64%) E-form

^{1 H NMR (300 MHz, DMSO} -d 6) δ 7.41 (d, J = 2.4Hz, 1H), 7.39 (d, J = 2.4Hz, 1H), 5.58 (s, 1H), 5.35 (s, 1H) , 4.35 (d, J = 17 Hz, 1H), 4.08-4.00 (m, 2H), 3.91-3.85 2.70 - 2.54 (m, 1 H), 2.17 - 1.54 (m, 13 H); LC / MS (M + H): 563.10

4- (2- (6- (2,6- Dichloro -4-( Trifluoromethyl ) Phenyl ) -1,1- Dioxido -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan-l- Carboxamide  (Formula 4)

(4) was obtained in the same manner as in the preparation of the compound of formula (2).

^{1 H NMR (300 MHz, CDCl} 3): δ 7.66 (s, 2H), 6.95 (d, J = 7.8Hz, 1H), 5.57 (s, 1H), 5.29 (s, 1H), 4.07-4.04 (m , 3H), 3.88 (t, J = 5.7 Hz, 4H), 2.21 - 1.56 (m, 15H)

4- (2- (4-methylene-1,1- Dioxido -6- (2,4,6- Trichlorophenyl ) -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan -1-car Le Copy My (Formula 5)

Ethyl 2- (4-methylene-1,1- Dioxido -6- (2,4,6- Trichlorophenyl ) -1,2,6- Tiadia Jin Yl) acetate

Amino) acetate (300 mg, 0.83 mmol), 2-methylenepropane-1,3-diol (73 mg, 0.83 mmol) and Triphenylphosphine (544 mg, 2.08 mmol) was dissolved in anhydrous THF (30 mL), and air in the reactor was removed while introducing nitrogen gas, followed by cooling to -20 ° C. DIAD (420 mg, 2.08 mmol) was slowly added dropwise to the mixture, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography with dichloromethane: hexane: ethyl acetate (5: 4: 1) to obtain 305 mg (89%) of the desired compound as a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.40 (s, 2H), 5.25 (s, 1H), 5.16 (s, 1H), 4.36 (s, 2H), 4.27-4.20 (m, 4H), 4.08 (s, 2H), 1.33-1.28 (t, 3H, J = 7.1, 7.1 Hz).

2- (4-methylene-1,1- Dioxido -6- (2,4,6- Trichlorophenyl ) -1,2,6- Tiadia Jin -2 days) Acetic Acid

Ethyl 2- (4-methylene-1,1-dioxido-6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin- 0.74 mmol) was dissolved in THF (10 mL) and MeOH (10 mL), and then LiOH monohydrate (155 mg, 3.69 mmol) dissolved in water (3 mL) was slowly added dropwise and the mixture was stirred at room temperature for 5 hours . Ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture, which was adjusted to pH 3 with 1N HCl, and the organic layer was extracted. Concentrated under reduced pressure after dried over MgSO ₄ to yield the ethyl acetate (1 mL) and hexanes (10mL) dropped desired compound 253 mg (89%) as determined using a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.42 (s, 2H), 5.26 (s, 1H), 5.16 (s, 1H), 4.41 (s, 2H), 4.33 (s, 2H), 4.09 (s , 2H).

4- (2- (4-methylene-1,1- Dioxido -6- (2,4,6- Trichlorophenyl ) -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan -One- Carboxamide  (E form )

(127 mg, 0.55 mmol) was dissolved in DMSO (700 mg), and then DIPEA (357 mg, 2.75 mmol), i-PrOH (10 mL), 2- (253 mg, 0.66 mmol), EDCI (211 mg, 1.10 < RTI ID = 0.0 > mmol) and HOBt (169 mg, 1.10 mmol) were added in this order, and the mixture was stirred at room temperature for 12 hours. After concentrating under reduced pressure at 50 ° C and adding saturated NH ₄ Cl solution (20 mL), the solution was allowed to stand for 1 hour, crystallized, washed three times with water (20 mL) and then filtered. The solid was washed with dichloromethane: methanol 3) to obtain 122 mg (39%) of the desired compound as a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.42 (s, 2H), 6.93 (d, 1H J = 8.0 Hz), 5.58 (s, 1H), 5.29 (m, 2H), 5.21 (s, 1H) 2H), 4.26 (s, 2H), 4.06 (m, 1H), 3.97 (s, 2H), 2.17-1.58 (m, 13H).

4- (2- (6- (2,6- Dichloro -4-( Trifluoromethyl ) Phenyl )-4- methyl -1,1- Dioxido -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan -One- Carboxamide  (Formula 6)

Ethyl 2 - (( Chlorosulfonyl ) Amino) acetate

After dissolving the glycine ethyl ester hydrochloride (5.00 g, 35.8 mmol) in CH ₃ CN (200 mL) was added sulfuryl chloride (29.00 g, 214.8 mmol), and concentrated under reduced pressure and the mixture was refluxed for 12 hours. After concentration, diethyl ether (100 mL) was added and the mixture was concentrated under reduced pressure (2 X). The mixture was dried under vacuum (used in the next reaction without further purification).

Ethyl 2 - (( N - (2,6- Dichloro -4-( Trifluoromethyl ) Phenyl ) Sulfamoyl ) Amino) acetate

Ethyl 2 - ((chlorosulfonyl) amino) acetate (3.60 g, 17.9 mmol) was dissolved in CH ₂ Cl ₂ (100 mL) and cooled to -20 ° C. After dissolving 2,6-dichloro-4- (trifluoromethyl) aniline (2.50 g, 10.7 mmol) and pyridine (2.53 g, 32.1 mmol) in CH ₂ Cl ₂ (70 mL) ≪ / RTI > sulfonyl) amino) acetate was slowly added dropwise to the mixture. After the dropwise addition, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water (100 mL) was added to the reaction solution to extract an organic layer. Dried over MgSO ₄ , concentrated under reduced pressure and columned with hexane: ethyl acetate (7: 3) to give 2.11 g (16%) of the desired compound as a yellow solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.41 (s, 1H), 6.58 (s, 1H, N H), 5.22 (brs, 1H, N H), 4.31-4.24 (q, J = 7.14, 7.17 , 7.11Hz, 2H), 4.08-4.06 ( d, J = 7.14Hz, 2H, -OC H 2 CH 3), 1.34-1.29 (t, 3H, J = 7.11, 7.17Hz, -OCH 2 C H 3) .

Ethyl 2- (6- (2,6- Dichloro -4-( Trifluoromethyl ) Phenyl )-4- methyl -1,1- Dioxido -1,2,6- Tiadia Jin -2- yl )acetate

Amino) acetate (300 mg, 0.76 mmol), 2-methylpropane-1,3-diol (75 mg, mg, 0.76 mmol) and triphenylphosphine (498 mg, 1.90 mmol) were dissolved in anhydrous THF (30 mL), and air in the reactor was removed while introducing nitrogen gas, followed by cooling to -20 ° C. DIAD (384 mg, 1.90 mmol) was slowly added dropwise to the mixture, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and the residue was subjected to column chromatography with dichloromethane: hexane: ethyl acetate (5: 4: 1) to obtain 225 mg (66%) of the desired compound as a pale yellow solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.65 (s, 1H), 7.63 (s, 1H), 4.44-4.38 (m, 1H), 4.30-4.17 (m, 2H), 4.11-4.03 (m, 1H), 3.98-3.87 (m, 2H ), 3.53-3.44 (m, 1H), 3.24-3.17 (m, 1H), 2.59 (m, 1H), 1.31 (t, 3H, J = 7.1Hz), 0.94 (d, 3H, J = 6.7 Hz).

2- (6- (2,6- Dichloro -4-( Trifluoromethyl ) Phenyl )-4- methyl -1,1- Dioxido -1,2,6- Tiadia Jin -2 days) Acetic  Acid

Ethyl 2- (6- (2,6-dichloro-4- (trifluoromethyl) phenyl) -4-methyl-1,1-dioxido-1,2,6-thiadiazin- Acetate (220 mg, 0.45 mmol) was dissolved in THF (10 mL) and MeOH (10 mL), LiOH monohydrate (94 mg, 0.45 mmol) dissolved in water (3 mL) was slowly added dropwise, Lt; / RTI > Ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture, and the mixture was adjusted to pH 3 with 1N HCl. The organic layer was extracted. Concentrated under reduced pressure after dried over MgSO ₄ to yield the ethyl acetate (1 mL) and hexanes (10mL) dropped desired compound 163 mg (86%) as determined using a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.67 (s, 1H), 7.64 (s, 1H), 4.53-4.47 (m, 1H), 4.12-3.91 (m, 3H), 3.46-3.42 (m, 1H), 3.26-3.19 (m, 1H), 2.59 (m, 1H), 0.96 (d, 3H, J = 6.7 Hz).

4- (2 - ((S) -6- (2,6- Dichloro -4-( Trifluoromethyl ) Phenyl )-4- methyl -1,1- Dioxido -1,2,6- Tiadia Jin Yl) acetamido) Adamantan -One- Carboxamide  (E form )

(74 mg, 0.32 mmol) was dissolved in DMSO (800 mg) and then DIPEA (208 mg, 1.60 mmol), i-PrOH (25 mL), 2- (6- Thiadiazin-2-yl) acetic acid (160 mg, 0.38 mmol) was reacted with 4- (trifluoromethyl) EDCI (123 mg, 0.64 mmol) and HOBt monohydrate (124 mg, 0.64 mmol) were added in this order, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure at 50 ° C, saturated NH ₄ Cl solution (20 mL) was added, and the mixture was allowed to stand for 1 hour to crystallize, followed by filtration and washed three times with water (20 mL). The filtered solid was columned with dichloromethane: methanol (97: 3) to give 113 mg (49%) of the desired compound as a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.69 (s, 1H), 7.65 (s, 1H), 6.95 (d, 1H, J = 6.8 Hz), 5.58 (s, 1H), 5.29 (s, 1H ), 4.40-4.34 (m, IH), 4.12-3.90 (m, 3H), 3.78-3.72 (m, IH), 3.33-3.21 (m, 2H), 2.62-2.59 (m, 13H), 0.97 (d, 3H, J = 6.0 Hz). LC / MS MH < + > 597

4- (2- (1,1- Dioxido -5-oxo-6- (2,4,6- Trichlorophenyl ) -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan -One- Carboxamide  (Formula 7)

Adamantyl amine hydrochloride (150 mg, 0.65 mmol) was dissolved in DMSO (800 mg) and then DIPEA (422 mg, 3.25 mmol), i-PrOH (25 mL), 2- (250 mg, 0.65 mmol), EDCI (249 mg, 0.65 mmol), acetic acid mg, 1.30 mmol) and HOBt monohydrate (251 mg, 1.30 mmol) were successively added thereto, and the mixture was stirred at room temperature for 12 hours. After concentrating under reduced pressure at 50 ° C and adding saturated NH ₄ Cl solution (25 mL) and allowing to stand for 1 hour, it was crystallized and washed with water (25 mL) three times with filtration and then filtered. The solid was dissolved in dichloromethane: methanol (97: 3) to obtain 30 mg (21%) of the desired compound as a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.48 (s, 2H), 5.88 (d, J = 7.9Hz, 1H), 5.58 (s, 1H) 5.29 (s, 1H), 4.41 (s, 2H) , 4.14-4.09 (m, 3H), 2.75 (t, J = 7.1 Hz, 2H), 2.12-1.45 (m, 13H).

4- (2- (6- (2- Chloro -4- Nitrophenyl )-4- methyl -1,1- Dioxido -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan -1-car Le Copy My (Formula 8)

(120 mg, 0.52 mmol) was dissolved in DMSO (700 mg) and then DIPEA (338 mg, 2.60 mmol), i-PrOH (25 mL), 2- (6- (204 mg, 0.52 mmol), EDCI (200 mg, 1.04 mmol) and acetic acid ) And HOBt monohydrate (201 mg, 1.04 mmol) were added in this order, followed by stirring at room temperature for 12 hours. After concentrating under reduced pressure at 50 ° C and adding saturated NH ₄ Cl solution (25 mL) and allowing to stand for 1 hour, it was crystallized and washed with water (25 mL) three times with filtration and then filtered. The solid was dissolved in dichloromethane: methanol (97: 3) to obtain 30 mg (11%) of the desired compound as a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.85 (dd, J = 2.1Hz, 1H), 7.63-7.61 (m, 2H), 6.76 (d, J = 7.7Hz, 1H), 5.58 (s, 1H ), 5.26 (s, IH), 4.06-4.02 (m, 2H), 3.90-3.79 (m, IH), 3.69-3.57 (m, 2H), 3.50-3.41 , 2.57 (m, 1H), 2.14-1.52 (m, 13H), 0.97 (d, J = 6.7 Hz, 3H)

4- (2 - ((S) -4- methyl -1,1- Dioxido -6- (2,4,6- Trichlorophenyl ) -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan -One- Carboxamide  (Formula 9)

DIPEA (2.5 g, 19.5 mmol), (S) -dicyclohexylcarbodiimide hydrochloride (900 mg, 3.9 mmol) was dissolved in 40 ml of DMSO and 50 ml of i- 2- (4-methyl-1,1-dioxido-6- (2,4,6-trichlorophenyl) -1,2,6-thiadiazin-2- yl) acetic acid , EDC (894 mg, 4.7 mmol) and HOBT (632 mg, 4.7 mmol) were added, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was extracted with EtOAc, dried (Na ₂ SO ₄ ), filtered, concentrated under reduced pressure and purified by column chromatography (MeOH / DCM 5%) to obtain the title compound (490 mg, y = 32%)

LCMS MH + 563

4- (2- (6- (4- Bromo -2,6- Dichlorophenyl )-4- methyl -1,1- Dioxido -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan -One- Carboxamide (Formula 10)

(58 mg, 0.25 mmol) was dissolved in DMSO (500 mg) and then DIPEA (162 mg, 1.25 mmol), i-PrOH (20 mL), 2- (6- -2,6-dichlorophenyl) -4-methyl-1,1-dioxido-1,2,6-thiadiazin-2-yl) acetic acid (108 mg, 0.25 mmol), EDCI , 0.50 mmol) and HOBt (68 mg, 0.50 mmol) were added in this order, and the mixture was stirred at room temperature for 12 hours. After concentrating under reduced pressure at 50 ° C and adding saturated NH ₄ Cl solution (25 mL), the mixture was allowed to stand for 1 hour, crystallized, washed three times with water (20 mL), and the solid filtered off was washed with dichloromethane: methanol 3) to obtain 68 mg (45%) of the desired compound as a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.57 (d, J = 2.3Hz, 1H), 7.54 (d, J = 2.2Hz, 1H) 6.96 (d, J = 8.2Hz, 1H), 5.56 (s (M, 2H), 2.58 (m, 1H), 5.21 (s, 1H), 4.39-4.32 (m, 1H), 4.09-3.87 , 1H), 2.13-1.55 (m, 13H), 0.94 (d, J = 6.7 Hz, 3H)

4- (2- (6- (2,6- Dichloro -4- Methylphenyl )-4- methyl -1,1- Dioxido -1,2,6- Tiadia Jin -2 days) Acetamido ) Adamantan -One- Carboxamide (Formula 11)

(88 mg, 0.38 mmol) was dissolved in DMSO (800 mg) and then DIPEA (247 mg, 1.90 mol), i-PrOH (30 mL), 2- (6- (140 mg, 0.39 mmol), EDCI (146 mg, 0.76 mmol) and acetic acid mmol) and HOBt (116 mg, 0.76 mmol) were added in this order, followed by stirring at room temperature for 12 hours. After concentrating under reduced pressure at 50 ° C and adding saturated NH ₄ Cl solution (30 mL), the solution was allowed to stand for 1 hour, crystallized, washed three times with water (20 mL), and the solid filtered off was washed with dichloromethane: methanol 3) to obtain 56 mg (27%) of the desired compound as a white solid.

^{1 H NMR (300 MHz, CDCl} 3): δ 7.21 (s, 1H), 7.18 (s, 1H), 7.02 (d, J = 7.9Hz, 1H), 5.60 (s, 1H), 5.43 (s, 1H ), 4.40-4.34 (m, 1H), 4.09-4.00 (m, 2H), 3.95-3.86 (m, 1H), 3.77-3.71 , 1.31 (d, J = 6.7 Hz, 3 H), 2.31 (s, 3 H), 2.11 - 1.56

Experimental Example

Experimental Example  1: 11 [beta] HSD1  Inhibition effect measurement

The following experiments were carried out to determine the effect of the compounds of the present invention on 11? -HSD1 inhibition in the brain. The test material was diluted to 20 mg / kg / 5 ml or 30 mg / kg / 5 ml with 5% DMSO, 45% PEG400, 55% water. The prepared test substance was administered intravenously to the tail of C57BL / 6J mice. One hour after intravenous administration, animals were euthanized by cervical dislocation and brain tissue was obtained. The brain tissue was placed in a mouse brain slicer mold, and the third section from the frontal lobe was washed with physiological saline. The sections were placed in a medium containing 1 μM cortisone and 100 nM NADPH (Dulbeco's Modified Eagle's Medium) and reacted at 37 ° C. for 3 hours. The amount of cortisol produced in the medium after the reaction was measured using a Cortisol ELISA kit (Assay Desighs Inc., Ann Arbor, Mich.). The amount of cortisol measured was corrected by the weight of the tissue. The degree of inhibition of ll [beta] -HSDl in the brain was calculated as follows:

&Quot; (1) "

% Inhibition of 11? -HSD1 in brain = 100 - (cortisol concentration of drug / cortisol concentration of vehicle group X 100)

The measured inhibitory effects are shown in Table 1 below.

The inhibition of 11? -HSD1 in the brain by each compound compound Experimental concentration % Inhibition of 11? -HSD1 in brain (2) 30 mg / kg 71.58 (3) 30 mg / kg 66.05 Formula 4 20 mg / kg 45.80 Formula 5 30 mg / kg 57.53 6 20 mg / kg 82.03 Formula 7 10 mg / kg 31.81 8 20 mg / kg 40.14 Formula 9 20 mg / kg 62.14 10 20 mg / kg 41.14 Formula 11 20 mg / kg 69.05

Experimental Example  2: Local ischemia of mouse - Reperfusion  Brain protection against model

In order to investigate whether the compounds of the present invention have an effect of protecting against cerebral ischemia, the anti-ischemic effect on mice was examined through the following experiment.

The management and use of experimental animals such as animal experimental protocol and experimental protocol was reviewed and managed by the Animal Experiment Committee installed in the Korea Research Institute of Chemical Technology (KITA). Male mice (20-24 g, Orient Bio, Seongnam) zolethyl) 30 mg / kg and Rompoun 10 mg / kg intraperitoneally. After anesthesia, the median line of the neck was dissected and the common carotid artery, external carotid artery, and internal carotid artery were carefully examined to separate the surrounding tissues and nerves. A small hole was made in the external carotid artery, and a silicone-coated 7-0 nylon thread (Doccol, USA) was inserted. The patient was carefully inserted into the internal carotid artery to occlude the origin of the middle cerebral artery. Afterwards, the inserted nylon thread was removed to reperfusion the blood. During the experiment, the body temperature of the mice was kept constant at 37.5 ° C. The vehicle or drug was intraperitoneally injected two times after 1 hour and 5 hours after induction of ischemia, and 4- (2- (6- (2,6-dichloro-4- (trifluoromethyl) phenyl) -1,6-thiadiazin-2-yl) acetamido) adamantane-1-carboxamide (compound of formula 6) 10, and 30 mg / kg, respectively.

Twenty-four hours after induction of ischemia-reperfusion, neurological deficit score due to cerebral ischemia was assessed in each experimental group, and the degree was scored as grade 5. 0 for no apparent obser- vation defects, 1 for incomplete spreading of the forelimb opposite to the cerebral ischemia when the tail was tilted, and 2 for the mouse to move freely and continue to the paralyzed side. And 3 in the case of falling to the opposite side of the cerebral ischemia.

After evaluating the neurological deficit, the animals were sacrificed and the brain was excised. The extracted brain was cut into 2 sections at intervals of 2 mm from the frontal pole using a brain template (ASI Instruments, USA). Five sections were prepared. The sections were incubated with 2% 2,3,5- The cells were incubated with 2,3,5-triphenyltetrazolium chloride (TTC) at room temperature for 20 min and fixed in 10% neutral formalin solution. After the stained tissue sections were taken, the area of the infarcted areas remained white without staining due to cerebral infarction was measured using a computer program for image analysis (Image pro plus). In consideration of the effect of ischemic cerebral edema, the cerebral infarct volume of each segment was obtained by indirect measurement using the following equation (2), and then the sum of the cerebral infarctions was calculated to calculate the total cerebral infarct volumes.

&Quot; (2) "

Infarct volume per brain segment (mm ³ ) =

(Normal tissue area on the left side - normal tissue area on the right side) x 2 (thickness)

On the first day after cerebral ischemia-reperfusion, neurological deficits were observed in the control group, but the neurological behavioral index improved significantly in the group administered with the compound of the present invention. As can be seen in Figure 1, the levels were lower in the 10 mg / kg (1.4 ± 0.2; 33.3%) and 30 mg / kg (1.1 ± 0.1; 47.6%) groups than in the vehicle (2.1 ± 0.2) can confirm.

As shown in FIG. 2, the compounds of the present invention reduce ischemic stroke infarct size to a significant level with respect to the control group. The infarct volume of each of the five brain slices was measured. The volume of cerebral infarction in the control group (29.9 ± 2.3, 31.9 ± 2.5, 18.5 ± 1.9 mm ³ ) increased in the third, fourth, When the compound of the present invention was administered intraperitoneally after 5 hours, it was significantly decreased. Specifically, at 10 mg / kg, the volume of cerebral infarction was significantly reduced to 18.6 ± 2.8 (41.7%) and 8.9 ± 1.1 mm ³ (51.9%) in the fourth and fifth sections, respectively. , 22.3 ± 1.3 (25.4%), 18.8 ± 2.7 (41.1%) and 9.9 ± 1.5 mm ³ (46.5%) in the 4th and 5th sections, respectively. The total cerebral infarct volume derived from the sum of the infarct volume of each slice was also dose-dependent when the compound of the present invention was administered. The volume of the cerebral infarction was 90.3 ± 6.0 mm ³ in the solvent-administered group, indicating that brain tissue damage caused by ischemia was very severe. On the other hand, when the compounds of the present invention were administered intraperitoneally, the volume of ischemia was not changed to 86.6 ± 2.7 mm ³ at 3 mg / kg, but when 10 and 30 mg / kg were administered, the volume of cerebral infarction was 66.2 ± 2.7 mm ³ (26.7%) and 59.0 ± 3.7 mm ³ (34.7%), indicating significant anti-ischemic effects. Thus, it can be seen that the compounds of the present invention can be usefully used as therapeutic agents for ischemic stroke.

Experimental Example  3: Cardioprotective effect on ischemic heart model of mouse

Anti-ischemic effects of the compounds of the present invention were investigated in the following experiments in order to examine whether they act to protect the ischemic heart.

The management and use of experimental animals such as animal experimental protocol and experimental plan were reviewed and managed by the Animal Experiment Committee installed in the Korea Research Institute of Chemical Technology. Mice were anesthetized by intraperitoneal injection of pentobarbital at 75 mg / kg in male rats (380-430 g, Orient Bio, Seongnam). After tracheotomy, respiration was maintained at 60 beats per minute at a volume of 10 ml / kg. A cannula was inserted into the femoral vein and the femoral artery and used for drug administration and blood pressure measurement, respectively. On the other hand, body temperature in the ischemic myocardial injury model has a significant effect on the outcome. Therefore, the body temperature of the mouse is adjusted to 37 ° C using a probe for body temperature measurement inserted in the rectum and a homeothermic blanket control unit Respectively. The mean arterial blood pressure and heart rate (HR) of the mice were then continuously measured during the experimental period. The heart rate was measured using a Stratam P23XL pressure transducer (Statham P23XL pressure transducer, Grass Ins., MA, USA) and the ECG / RATE Coupler (Hugo Sachs Electronic, Germany) . All changes were recorded continuously using the Graphtec Linearcorder WR 3310 (Hugo Sachs Electronic).

The left coronary artery was ligated by the method of Selye H. as follows. In other words, the left thoracotomy (left thoracotomy) to open the chest part of the left hand with the long finger (long finger) anesthetized the right chest pressure of the mouse to push out the heart out of the left hand with the thumb and index finger lightly Lt; / RTI > Afterwards, a suture needle with a 5-0 silk ligature was carefully placed over the area containing the left anterior descending coronary artery (LAD) cavity, and the surgical tip was placed on the outside. Surgical ends were passed through a PE tube (PE100, 2.5 cm) and allowed to stabilize for 20 minutes. The vehicle or drug was then administered via a cannula inserted into the femoral vein and left to stand for 5 minutes to fully demonstrate the effect of the drug. At this time, the test drug was administered at a concentration of 20 mg / kg.

Thereafter, the PE tube inserted into the thread was pushed into the heart, the end tube of the tube was pulled with a hemostatic tweezers, and the PE tube was tightly pressed against the coronary artery and pressure was applied. The coronary artery was ligated occlusion), and the hemostatic tweezers were removed and reperfused for 3 hours.

Coronary arteries were reocclused by the method described above and 2 ml of 1% Evans blue solution was intravenously administered. The mice were then euthanized by intravenous injection of pentobarbital and the heart was removed to remove the right ventricle and both atria. The left ventricle was horizontally cut into 5-6 slices from the heart and the weight of each slice was measured. The surface of each of the cardiac segments was input into a computer using a compact micro vision system, Hi-scope, and a computer program for image analysis (Image pro plus) The area of normal blood flow tissue stained with color and the area of uncolored area were measured. The area ratio of the uncolored area to the total area of each slice was calculated and multiplied by the weight of each slice to calculate the area at risk (AAR) of each slice. The AARs (%) were obtained from the following equation (3) by adding all the AARs to the obtained slices and dividing them by the total weight of the left ventricle.

&Quot; (3) "

AAR (%) = (sum of AAR for each section) / (total left ventricular weight) × 100

After obtaining the AAR, the heart slice was incubated for 15 minutes in a 1% 2,3,5-triphenyltetrazolium chloride (TTC) phosphate buffer (37 ° C, pH 7.4) % Formalin solution for 20-24 hours. In this way, 2,3,5-triphenyltetrazolium chloride is reduced by NADH, a dehydrogenase of the myocardium and a cofactor, to form a formazan dye, so that the normal region of the tissue is reddish brown (brick-red color). On the other hand, 2,3,5-triphenyltetrazolium chloride is not reduced because of the absence of dehydrogenase and cofactors in the infarct region of the tissue, and thus it does not become reddish brown.

As described above, the normal region and the infarct size of each slice were determined in the same manner as in the AAR measurement, depending on whether or not the tissue region was stained with 2,3,5-triphenyltetrazolium chloride . IS (%) was obtained by the following equation (4) by adding up the infarct areas for each of the sections obtained as described above and dividing by the total AAR weight or the total left ventricular weight. In this experimental model, it was determined that the lower the IS (%), the stronger the anti-ischemic effect of the test substance. The results are shown in Table 2 below.

&Quot; (4) "

IS (%) = (total infarct area for each segment) / (total left ventricle or total AAR weight) x 100

As shown in the following Table 2, the compound of the present invention showed a significantly reduced rate of myocardial infarction to the dangerous area in an ischemic myocardial injury model using anesthetized mice. Specifically, in the solvent-administered group, the myocardial infarction rate (IS / AAR,%) to the dangerous area (AAR) was 53.6%, indicating that cardiac muscle damage caused by ischemia was very severe. On the other hand, when the compound of the present invention was administered, the myocardial infarction rate was 37.2%, indicating significant anti-ischemic effect. As described above, the compounds of the present invention are excellent in the protective action against ischemic cardiovascular diseases, and thus can be used as therapeutic agents related to ischemic cardiovascular diseases.

Cardiovascular interaction of the compound of formula (1) Test drug Experimental Example 2 Cardiac ischemia (in vivo experiment with mouse) (20 mg / kg) AAR / LV (%) IS / AAR (%) menstruum 40.46 ± 2.11 53.58 ± 1.54 Example Compound 39.39 ± 1.76 37.17 + 2.97 (p < 0.05)

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (10)

A pharmaceutical composition for preventing or treating cerebral diseases and ischemic heart diseases comprising a sulfamide derivative represented by the following formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient:
Formula 1

Wherein R ₁ and R ₃ are each independently hydrogen or halogen and R ₂ is halogen, nitro or C ₁ -C ₃ alkyl unsubstituted or substituted with halogen;

Represents a single bond or a double bond; When R ₄ or R ₅ form a double bond with the adjacent ring carbon, R ₄ is oxygen and R ₅ is CH ₂ , and when R ₄ or R ₅ forms a single bond with the adjacent ring carbon, R ₄ is hydrogen and R ₅ is hydrogen or C ₁ -C ₃ alkyl, R ₄ and R ₅ do not form a double bond with adjacent ring carbon atoms at the same time, and n is an integer of 1-2.
2. The compound according to claim 1, wherein R ₁ and R ₃ in Formula 1 are each independently hydrogen or chloro; R ₂ is chloro, bromo, nitro, methyl or trifluoromethyl; When R ₄ or R ₅ forms a single bond with adjacent ring carbon, then R ₄ is hydrogen and R ₅ is methyl; and n is 1.
delete The composition according to claim 1, wherein the sulfamide derivative represented by the formula (1) is selected from the group consisting of compounds represented by the following formulas (2) to (11)
(2)

(4)

(6)

(8)

(10)

5. The composition according to claim 4, wherein the sulfamide derivative is selected from the group consisting of compounds represented by formulas (6), (9) and (11).
The composition according to claim 1, wherein the brain disease is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases due to ischemia or reperfusion, and mental illnesses.
7. The composition of claim 6, wherein said neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis.
7. The composition according to claim 6, wherein the disease caused by ischemia or reperfusion is ischemic stroke.
The composition of claim 1, wherein the ischemic heart disease is selected from the group consisting of angina, myocardial infarction, and heart failure.
2. The composition of claim 1, wherein the composition inhibits the activity of ll [beta] -hydroxysteroid dehydrogenase type 1 (llbeta-HSDl).

Images