WO2011149213A2 - Nouveau dérivé ayant une activité inhibitrice contre 11β-hsd1, son procédé de préparation, et composition pharmaceutique le contenant comme principe actif - Google Patents

Nouveau dérivé ayant une activité inhibitrice contre 11β-hsd1, son procédé de préparation, et composition pharmaceutique le contenant comme principe actif Download PDF

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WO2011149213A2
WO2011149213A2 PCT/KR2011/003656 KR2011003656W WO2011149213A2 WO 2011149213 A2 WO2011149213 A2 WO 2011149213A2 KR 2011003656 W KR2011003656 W KR 2011003656W WO 2011149213 A2 WO2011149213 A2 WO 2011149213A2
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methyl
benzenesulfonylamino
adamantane
chloro
adamantan
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PCT/KR2011/003656
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Korean (ko)
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WO2011149213A3 (fr
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한철규
어진
한창균
윤정혁
김남두
김태정
이윤호
정현근
신영준
곽호영
한동오
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주식회사 이큐스앤자루
안국약품 주식회사
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Priority claimed from KR1020110046273A external-priority patent/KR101377419B1/ko
Publication of WO2011149213A2 publication Critical patent/WO2011149213A2/fr
Publication of WO2011149213A3 publication Critical patent/WO2011149213A3/fr

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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/48—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
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    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/42—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/30—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/30—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/14—The ring being saturated
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    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a novel derivative having an inhibitory activity of 11beta-HSD1 enzyme, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient.
  • Glucocorticoids cortisol in humans, corticosterone in mice and mice
  • Glucocorticoids that bind to the glucocorticoid receptor are steroid hormones present in almost all vertebrates (Dallman MF, Strack AM, Akana SF et al. 1993; Front Neuroendocrinol 14, 303-347. It regulates the expression of liver enzymes involved in gluconeogenesis to increase stromal supply by releasing glycerol from fat cells and releasing amino acids from muscle. It has also been reported that glucocorticoids play an important role in the differentiation of adipocyte precursors into mature adipocytes capable of storing triglycerides (Bujalska IJ et al.
  • Induced glucocorticoids themselves play an important role in disease states associated with abdominal obesity, a risk factor for type 2 diabetes, hypertension and coronary artery disease (Bjorntorp P & Rosmond R 2000; Int. J. Obesity 24, S80-S85).
  • the glucocorticoid activity is determined by secretion of cortisol, as well as by active cortisol and inactive cortisol by 11beta-hydroxysteroid dehydrogenase type 1 (11 ⁇ -HSD1) and 11beta-hydroxysteroid dehydrogenase type 2 (11 ⁇ -HSD2). It has been experimentally demonstrated that it is also controlled at the tissue level by intracellular interconversion of (Sandeep TC & Walker BR 2001 Trends in Endocrinol & Metab. 12, 446-453). At this time, the 11 ⁇ -HSD1 converts the inactive glucocorticoid into activity, thereby playing an important role in the regulation of the concentration of the cellular agonist and the activation of the corticosteroid receptor in the target tissue.
  • This mechanism has been shown to play a very beneficial role in the treatment of diabetes and obesity. Specifically, it has been demonstrated using treatment with carbenoxolone, an anti-ulcer drug that inhibits both 11 ⁇ -HSD1 and 11 ⁇ -HSD2, which increases insulin sensitivity, whereby inhibition of 11 ⁇ -HSD1 decreases the cell's cortisol concentration. By controlling the effects of insulin (Walker BR et al. 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159).
  • the present inventors have studied to prepare a substance that selectively inhibits 11 ⁇ -HSD1, and thus synthesize new derivatives, and these derivatives exhibit excellent inhibitory activity against 11 ⁇ -HSD1.
  • the present invention has been completed with the understanding that it is possible to treat diseases and conditions mediated by resistance, obesity, lipid disorders, metabolic syndrome and excessive glucocorticoid action.
  • An object of the present invention is to provide a substance that selectively inhibits 11 ⁇ -HSD1.
  • Another object of the present invention to provide a method for producing a substance that selectively inhibits the 11 ⁇ -HSD1.
  • Another object of the present invention to provide a pharmaceutical composition containing a substance that selectively inhibits the 11 ⁇ -HSD1 as an active ingredient.
  • the present invention provides a derivative represented by the following formula (1).
  • R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined herein.
  • the present invention provides a method for preparing the compound of Formula 1.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease caused by the overactivity of 11 ⁇ -HSD1 containing the compound of Formula 1 as an active ingredient.
  • the compounds according to the invention selectively inhibit 11-beta-hydroxysteroid dehydrogenase type 1 (11 ⁇ -HSD1), thereby causing diseases caused by overactivity of 11 ⁇ -HSD1, for example insulin independent type 2 It can be usefully used as a therapeutic agent for treating diseases and conditions mediated by diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, and excessive glucocorticoid action.
  • 11 ⁇ -HSD1 11-beta-hydroxysteroid dehydrogenase type 1
  • insulin independent type 2 for example insulin independent type 2
  • the present invention provides a compound having a inhibitory activity of the 11 ⁇ -HSD1 enzyme represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • X is carbonyl or sulfonyl
  • R 1 is C 1 to C 4 straight or branched chain alkyl, C 3 to C 8 cycloalkyl, C 5 to C 12 aryl, C 10 to C 12 biaryl, N or O hetero atoms in the ring 1 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl containing one or more N or O heteroatoms in the ring, C 5 -C 12 aryl C 1 -C 3 straight or branched alkyl Or C 3 -C 6 cycloalkyl C 1 -C 3 straight or branched alkyl;
  • the aryl is unsubstituted or substituted by one or more halogens, unsubstituted or straight or branched chain of a C 1 substituted with one or more halogen ⁇ C 4 alkyl, straight or branched chain of a C 1 ⁇ C 4 substituted with an unsubstituted or at least one halogen Alkoxy, nitro, amino, cyano, formamide, unsubstituted or one or more cyano, halogen, C 5 to C 12 aryl substituted with C 1 to C 4 straight or branched alkyl, and C 3 to C 8 cycloalkyl Substituted with a substituent selected from the group consisting of;
  • cycloalkyl, heterocycloalkyl or heteroaryl is unsubstituted or substituted with C 1 to C 4 straight or branched alkyl or C 5 to C 12 aryl;
  • R 2 and R 3 are each independently one hydrogen, C 1 -C 4 straight or branched alkyl, the other is C 1 -C 4 straight or branched alkyl, C 3 -C 8 cycloalkyl, C 5 ⁇ C 12 aryl, N, or O a 5-8 straight-chain or branched-heteroaryl, C 5 ⁇ C 12 aryl C 1 ⁇ C 4 of the members comprising at least one alkyl, C 5 ⁇ C 8 cycloalkyl C 1 ⁇ C 3 is straight or branched alkyl, norbornyl or adamantyl, or together with the nitrogen to which they are attached may form a 5-8 membered heterocycloalkyl,
  • the aryl is unsubstituted or substituted with halogen, C 1 ⁇ C 3 straight or branched alkoxy,
  • heterocycloalkyl is unsubstituted or substituted with C 1 -C 3 straight or branched alkyl
  • the adamantyl is unsubstituted or hydroxy, methylsulfonyl, C 1 to C 4 straight or branched chain alkylsulfanyl, formamide, methylformamide, dimethylformamide, pyrrolidinecarbonyl, ethanethioate and carboxyl. Substituted with a substituent selected from the group consisting of carboxyl;
  • R 4 and R 5 are each independently hydrogen, C 1 -C 4 straight or branched chain alkyl, 5-8 membered heteroaryl C 1 -C 3 including S, straight or branched chain alkyl or a carbon atom to which they are attached Or may form C 3 -C 6 cycloalkyl, dihydroindenyl or indolyl with adjacent nitrogen atoms.
  • X is carbonyl or sulfonyl
  • R 1 is methyl, ethyl, propyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthalenyl, a 5-6 membered heterocycloalkyl containing at least one hetero atom of N or O in the ring, ring 5-6 membered heteroaryl containing at least one hetero atom of N or O, phenylmethyl, phenylethyl, phenylcyclopropyl, phenylcyclobutyl or C 3 -C 5 cycloalkyl C 1 -C 2 alkyl ,
  • phenyl is unsubstituted or one or more of F, Cl, methyl, ethyl, propyl, n-butyl, t-butyl, trifluoromethyl, trichloromethyl, methoxy, alkoxy, trifluoromethoxy, trichloromethoxy, Substituted with a substituent selected from the group consisting of nitro, amino, cyano, formamide, cyanophenyl, fluorophenyl, difluorophenyl, methylphenyl and cyclohexyl,
  • heterocycloalkyl or heteroaryl is unsubstituted or substituted with methyl, ethyl, propyl or phenyl;
  • R 2 and R 3 are each independently one hydrogen, methyl, ethyl, propyl, the other methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, N Or 5- or 6-membered heteroaryl containing 1 or more of O, phenylmethyl, phenylethyl, phenylpropyl, cycloheptyl methyl, cycloheptyl ethyl, norbornyl or adamantyl, or methylpipera together with the nitrogen atom to which they are attached; Form genyl or azocanyl,
  • the adamantyl is composed of unsubstituted or hydroxy, methylsulfonyl, methylsulfanyl, ethylsulfanyl, formamide, methylformamide, dimethylformamide, pyrrolidinecarbonyl, ethylthioate and carboxyl. Substituted with a substituent selected from the group;
  • R 4 and R 5 are each independently hydrogen, methyl, ethyl, propyl or together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, dihydroindenyl, thiophenylethyl, or carbon atoms to which they are attached and adjacent nitrogen Together with the atoms, they form indolyl.
  • X is carbonyl or sulfonyl
  • R 1 is isobutyl, cyclopropyl, phenyl, morpholinyl, pyridinyl, isooxazolyl substituted with isopropyl, phenylmethyl, phenylcyclopropyl, cyclopropyl methyl, naphthalenyl;
  • phenyl is unsubstituted or one or more of F, Cl, methyl, t-butyl, methoxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, formamide, cyanophenyl, fluorophenyl, di Substituted with a substituent selected from the group consisting of fluorophenyl, methylphenyl and cyclohexyl;
  • R 2 and R 3 are each independently one hydrogen, methyl or isopropyl, the other methyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, fluorophenyl, pyridinyl, phenyl ethyl substituted with methoxy, meth Phenyl methyl, cycloheptyl methyl, norbornyl or adamantyl substituted with oxy, or together with the nitrogen atom to which they are attached form methyl piperazinyl or azocanyl,
  • adamantyl is unsubstituted or selected from the group consisting of hydroxy, methylsulfonyl, methylsulfanyl, formamide, methylformamide, dimethylformamide, pyrrolidinecarbonyl, ethylthioate and carboxyl Substituted with a substituent;
  • R 4 and R 5 are each independently hydrogen or methyl, or they form cyclopropyl, dihydroindenyl, thiophenylethyl together with the carbon atoms to which they are attached, or indolyl together with the adjacent carbon atoms and carbon atoms to which they are attached; do.
  • the compound represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • the expression pharmaceutically acceptable salt is a concentration that has a relatively nontoxic and harmless effect on the patient and that any side effects due to the salt do not degrade the beneficial efficacy of the base compound of formula 1, or Means inorganic addition salts.
  • These salts may include inorganic acids and organic acids as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, and the like, and citric acid, acetic acid, lactic acid, maleic acid, and fumarine as organic acids.
  • Acids Gluconic Acid, Methanesulfonic Acid, Glyconic Acid, Succinic Acid, Tartaric Acid, Galluturonic Acid, Embonic Acid, Glutamic Acid, Aspartic Acid, Oxalic Acid, (D) or (L) Malic Acid, Maleic Acid, Methanesulphonic Acid, Ethene Sulfur Phonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid and the like can be used.
  • These salts also include alkali metal salts (sodium salts, potassium salts, and the like), alkaline earth metal salts (calcium salts, magnesium salts, and the like) and the like.
  • acid addition salts include acetates, aspartates, benzates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, disylates, ecylates, formates, fumarates, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / chloride, Hydrobromide / Bromide, Hydroiodide / Iodide, Isetionate, Lactate, Maleate, Maleate , Malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharide , Stearate, succinate, tartrate, tosylate, tri
  • the compound represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates, and solvates that can be prepared by conventional methods.
  • the addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an aqueous acid solution of, followed by precipitation or crystallization. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
  • a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • Some compounds of Formula 1 include chiral centers or geometric isomeric centers (E and Z isomers), and the present invention may be understood to encompass all such optical isomers, diastereomers, and geometric isomers having 11 ⁇ -HSD1 inhibitory activity. have.
  • the present invention relates to any tautomer of a compound of formula 1 having 11 ⁇ -HSD1 inhibitory activity, and it can be understood that certain compounds of formula 1 may exist in solvate and non-solvate forms, such as hydrated forms. . It is to be understood that the present invention encompasses all such solvated forms having 11 ⁇ -HSD1 inhibitory activity.
  • the present invention provides a method for preparing the compound of Formula 1.
  • the compound of Chemical Formula 1 reacts the substituted sulfonyl or acetyl halide of Chemical Formula 3 with the amine derivative of Chemical Formula 2, as represented by Schemes 1 and 2 below, or the carboxylic acid of Chemical Formula 5 and Chemical Formula It can be prepared by reacting an amine derivative of 4.
  • the sulfonyl or acetyl halide compound of Formula 3 may be used by purchasing a commercially available material, and the compounds of Formulas 2, 5 and 6 are commercially available depending on the substituent group Or a person having ordinary skill in the art can easily prepare and use.
  • the compound of Chemical Formula 1 according to the present invention is added to the amine derivative compound of Chemical Formula 2 by adding sulfonyl or acetyl halide of Chemical Formula 3 and an appropriate amount of diisopropylethylamine in a general organic solvent such as dichloromethane. It can be manufactured easily by making it react.
  • the reaction temperature and reaction time is preferably performed for 1 hour to 24 hours in the room temperature range according to the chemical reactivity of the sulfonyl or acetyl halide of the formula (3).
  • the compound of Formula 1 according to the present invention is a cycloalkyl, bicycloalkyl, aryl, heteroaryl or 1-adamantyl of Formula 4 in a carboxylic acid of Formula 5 in a general organic solvent such as dichloromethane, It can be easily prepared by adding 2-adamantyl or benzyl amine, an appropriate amount of diisopropylethylamine, and bis (2-oxo-3-oxazolidinyl) phosphonic chloride to react.
  • the reaction temperature and the reaction time is from 1 hour to room temperature depending on the chemical reactivity of the cycloalkyl, bicycloalkyl, aryl, heteroaryl or 1-adamantyl, 2-adamantyl or benzyl amine of the formula (4) Preference is given to performing for 24 hours.
  • the compound of Chemical Formula 1 is prepared by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement, and elemental analysis calculations and actual measurements of representative compounds. The molecular structure can be confirmed by comparison.
  • the present invention provides a pharmaceutical composition containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of Formula 1 showed an excellent inhibitory effect of 11 ⁇ -HSD1 activity by showing an activity inhibition rate of 1104-HSD1 as 0.0004 to 5.8 ⁇ M in the evaluation of 11 ⁇ -HSD1 enzyme inhibitory activity (see Table 12).
  • the compound of formula 1 according to the present invention is excellent in 11 ⁇ -HSD1 inhibitory activity, and diseases caused by abnormally activated 11 ⁇ -HSD1, for example, insulin independent type 2 diabetes, insulin resistance, obesity, lipid disorders , Metabolic syndrome and diseases mediated by excessive glucocorticoid action can be usefully used.
  • the pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or non-oral dosage forms as described below. It may be formulated and administered, but is not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose). Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • diluents e.g., lactose, dextrose
  • Rose sucrose, mannitol, sorbitol, cellulose and / or glycine
  • lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt.
  • the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1,000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.
  • the 30% fuming sulfuric acid solution was warmed to 60 ° C. and 1 g (6.02 mmol) of 5-hydroxy-2-adamantanone dissolved in 6 ml of 99% formic acid was slowly added over 1 hour. 6 ml of 99% formic acid was slowly added over 1 hour and then stirred at 60 ° C. for 1 hour.
  • the reaction solution was slowly added to 50 ml of methanol cooled to 0 ° C., and the reaction solution was distilled under reduced pressure after stirring at room temperature for 2 hours. 15 g of ice and 50 ml of methylene chloride were added thereto, and the mixture was further extracted twice with methylene chloride. The mixture was washed with brine, dried over Na 2 SO 4, and the solvent was distilled under reduced pressure to obtain 1.09 g (87%) of 4-oxo-adamantane-1-carboxylic acid methyl ester.
  • Example 2 Through the same synthesis method as in Example 2, the compounds of Examples 3 to 16 were prepared, and the results and chemical structures thereof are shown in Table 1 below.
  • Example 35 Through the same synthesis method as in Example 35, the compound of Examples 36 to 40 was prepared and the results are shown in Table 3 below.
  • Example 41 By the same synthesis method as in Example 41, the compounds of Examples 42 to 60 were prepared and the results are shown in Table 4 below.
  • Example 61 Through the same synthesis method as in Example 61, the compound of Examples 62 to 64 was prepared and the results are shown in Table 5 below.
  • Example 65 Through the same synthesis method as in Example 65, to prepare a compound of Examples 66 to 70 and the results are shown in Table 6 below.
  • Example 72 By the same synthesis method as in Example 71, the compound of Example 72 was prepared and the results are shown in Table 7 below.
  • Example 74 By the same synthesis method as in Example 73, to prepare a compound of Example 74 shown in Table 8.
  • Example 76 By the same synthesis method as in Example 76, to prepare a compound of Examples 77 and 78 are shown in Table 9.
  • Example 79 47 mg (0.10 mmol) of 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid prepared in Example 79 was prepared. Dissolved in 3 ml of methylene chloride, 16 mg (0.116 mmol) of HOBt and 22 mg (0.116 mmol) of EDCI were added thereto. After stirring for 1 hour at room temperature, 3 ml of 30% aqueous ammonia was added thereto, followed by stirring at room temperature for 20 hours.
  • Example 10 Through the same synthesis method as in Example 80, the compounds of Examples 81 to 127 were prepared, and the results are shown in Table 10 below.
  • Example 128 4- [3- (3-Chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] -N-methyl-adamantane-1-carboxylic acid amide
  • test compound dissolved in DMSO were diluted with pH 6.0 tris 20 mM EDTA 5 mM buffer, followed by addition of 160 nM of substrate cortisone (C2755, Sigma) and 200 ⁇ M of coenzyme NADPH (N1630, Sigma).
  • a total of 10 ⁇ l volume of reaction mixture was made by adding 11 ⁇ -HSD1 as microsomal fraction (M0317, Sigma) isolated from human liver and 11 ⁇ -HSD1 enzyme assay was performed on 384 well microtiter plates.
  • the compounds according to the present invention can be confirmed that the inhibitory activity of the inhibitory activity against 11 ⁇ -HSD1 is 0.0004 to 5.8 ⁇ M, especially Examples 74, 80, 81, 85, 88, 91 , 98, 99, 100, 101, 115, 122, 123 and 125 showed an inhibitory activity of less than 0.0010 ⁇ M activity against 11 ⁇ -HSD1.
  • diseases caused by abnormally activated 11 ⁇ -HSD1 such as insulin-independent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and diseases mediated by excessive glucocorticoid action This can be useful for.
  • the compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • an injection was prepared by containing the above components in the contents shown.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Emergency Medicine (AREA)
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  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau dérivé ayant une activité inhibitrice contre 11β-hydroxystéroide déhydrogénase de type 1 (11β-HSD1), son procédé de préparation, et une composition pharmaceutique le contenant comme principe actif. Le composé selon l'invention, qui inhibe de manière sélective 11β-HSD1, peut donc servir comme agent thérapeutique pour traiter des maladies causées par une hyperactivité de 11β-HSD1, par exemple, diabètes sucrés non insulinodépendants (diabètes type II), résistance à l'insuline, obésité, troubles lipidiques, syndrome métabolique, et maladies et état médiés par l'action glucocorticoïde excessive.
PCT/KR2011/003656 2010-05-25 2011-05-17 Nouveau dérivé ayant une activité inhibitrice contre 11β-hsd1, son procédé de préparation, et composition pharmaceutique le contenant comme principe actif WO2011149213A2 (fr)

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WO2013191396A1 (fr) * 2012-06-20 2013-12-27 주식회사 셀비온 Nouveau composé ayant la capacité à inhiber l'enzyme 11β-hsd1 ou un sel pharmaceutiquement acceptable de celui-ci, procédé de production associé, et composition pharmaceutique contenant celui-ci en tant que principe actif
KR101456628B1 (ko) * 2014-04-14 2014-11-13 주식회사 셀비온 １１β－ＨＳＤ１ 효소의 억제활성을 갖는 신규한 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 약학적 조성물

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KR20070068432A (ko) * 2004-10-29 2007-06-29 아스트라제네카 아베 염증 질환의 치료를 위한 글루코코르티코이드 수용체조절제로서의 신규 술폰아미드 유도체

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WO2000063165A1 (fr) * 1999-04-19 2000-10-26 Fujisawa Pharmaceutical Co., Ltd. Inhibiteur mmp
US20050245533A1 (en) * 2004-04-29 2005-11-03 Hoff Ethan D Inhibitors of the 11-beta-hydroxysteroid dehydrogenaseType 1 enzyme and their therapeutic application
KR20070068432A (ko) * 2004-10-29 2007-06-29 아스트라제네카 아베 염증 질환의 치료를 위한 글루코코르티코이드 수용체조절제로서의 신규 술폰아미드 유도체

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WO2013191396A1 (fr) * 2012-06-20 2013-12-27 주식회사 셀비온 Nouveau composé ayant la capacité à inhiber l'enzyme 11β-hsd1 ou un sel pharmaceutiquement acceptable de celui-ci, procédé de production associé, et composition pharmaceutique contenant celui-ci en tant que principe actif
AU2013278234B2 (en) * 2012-06-20 2015-05-21 Ahn-Gook Pharmaceutical Co., Ltd. Novel compound having ability to inhibit 11beta-HSD1 enzyme or pharmaceutically acceptable salt thereof, method for producing same, and pharmaceutical composition containing same as active ingredient
CN104903290A (zh) * 2012-06-20 2015-09-09 安国乐品株式会社 具有抑制11β-HSD1酶活性的新型化合物或其药学上可接受的盐及其制备方法,以及包含其作为活性成分的药物组合物
US9464044B2 (en) 2012-06-20 2016-10-11 Ahn-Gook Pharmaceutical Co., Ltd. Compound having ability to inhibit 11Beta-HSD1 enzyme or pharmaceutically acceptable salt thereof, method for producing same, and pharmaceutical composition containing same as active ingredient
EA026005B1 (ru) * 2012-06-20 2017-02-28 Бамикем Ко., Лтд. НОВОЕ СОЕДИНЕНИЕ, ОБЛАДАЮЩЕЕ СПОСОБНОСТЬЮ ИНГИБИРОВАТЬ ФЕРМЕНТ 11β-HSD1, ИЛИ ЕГО ФАРМАЦЕВТИЧЕСКИ ПРИЕМЛЕМАЯ СОЛЬ, СПОСОБ ЕГО ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СОДЕРЖАЩАЯ ТАКОЕ СОЕДИНЕНИЕ В КАЧЕСТВЕ АКТИВНОГО ИНГРЕДИЕНТА
KR101456628B1 (ko) * 2014-04-14 2014-11-13 주식회사 셀비온 １１β－ＨＳＤ１ 효소의 억제활성을 갖는 신규한 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 약학적 조성물

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