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WO2014112798A1 - Nouveau phényléthynyl-benzamide activateur de la glucokinase et son procédé de préparation - Google Patents

Nouveau phényléthynyl-benzamide activateur de la glucokinase et son procédé de préparation Download PDF

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Publication number
WO2014112798A1
WO2014112798A1 PCT/KR2014/000457 KR2014000457W WO2014112798A1 WO 2014112798 A1 WO2014112798 A1 WO 2014112798A1 KR 2014000457 W KR2014000457 W KR 2014000457W WO 2014112798 A1 WO2014112798 A1 WO 2014112798A1
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methyl
methoxy
ethoxy
benzamide
pyrazol
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Korean (ko)
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박갑주
이병문
이동훈
최현호
현관훈
이춘호
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Yuhan Corp
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Yuhan Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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

Definitions

  • the present invention relates to a novel glucokinase activator, and more particularly, to a novel compound that activates glucokinase, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a method for preparing the same, It relates to a pharmaceutical composition, a method of treatment and use thereof.
  • Glucokinase is a member of the hexokinase family that catalyzes the phosphorylation of glucose, the first step in glucose metabolism, and is involved in the production of glucose-6-phosphate (Alexander M. Efanov, David G. Barrett et al., Endocrinology , 146 , 3696-3701, 2007 ), which directly regulates the amount of glucose present in the blood to maintain glucose homeostasis in the body.
  • Glucokinase is expressed mainly in ⁇ -cells and hepatocytes of the pancreas. Glucokinase acts as a rate-regulating enzyme in glucose metabolism in ⁇ -cells of the pancreas, leading to glucose-dependent insulin secretion. Glucokinase in the liver leads to glucose uptake and glycogen synthesis. (D. Zelent, H. Najafi, S. Odili, C. Buettger, H. Weik-Collins, C. Li, N. Doliba, J. Grimsby, FM Matschinsky, Biochemical Society Transactions , 33 , 306-310 , 2005 ).
  • Glucokinase-deficient mice exhibited severe hyperglycemia, and mice transplanted with glucokinase (GK) showed decreased levels of basal blood glucose and resistance to high-fat diet-induced diabetes. Close association with diabetes development has been demonstrated. These results indicate that glucokinase (GK) acts as an excellent glucose sensor for maintaining glucose homeostasis, and shows the possibility of drug development that increases the activity of glucokinase (GK) as a diabetes treatment.
  • Glucokinase exists in three different configurations: 'open', 'super-open', and 'closed', and 'slow' or 'fast' catalytic cycles. Will cycle.
  • the allosteric pocket is in a good condition to bind to a substance that activates glucokinase (ie, a glucokinase activator (GKA)) (Sarabu, R., Taub, R., Grimsby, J., Drug Discovery Today: Therapeutic Strategies , 4 , 111-115, 2007 ).
  • GKA glucokinase activator
  • the glucokinase activator binds to the allosteric pocket of glucokinase and causes a slight change in the glucokinase structure. As a result, it stabilizes the closed form of glucokinase, thereby activating glucokinase and metabolizing glucose as a substrate.
  • glucokinase activators do not activate other hexokinases and only act on glucokinases having these allosteric pockets.
  • glucokinase activators act on the ⁇ -cells and hepatocytes of the pancreas, which affect glucose homeostasis, thereby promoting insulin secretion and glucose metabolism. Therefore, studies on glucokinase activators as agents for treating type 2 diabetes have been actively conducted. .
  • Glucokinase activators known to date are, depending on the chemical backbone, 'carbon'-centered GKAs, aromatic ring-centered GKAs, amino acids It is classified as a reference glucokinase activator (amino-acid-based GKAs) and analogs thereof (Sarabu, R., Berthel, SJ, Kester, RF, Tilley, J., W., Expert Opin.Ther .
  • Patents , 18 , 759-768, 2008 Matschinsky, FM, Magnuson, MA, Eds., In Frontiers in Diabetes , 16 , 145-154, 2004 ; Kamata, K., Mitsuya, M., Nishimura, T., Eiki, J.-i .; Nagata, Y., Structure , 12 , 429, 2004 ; WO03 / 097824; WO08 / 075073).
  • the inventors have found that the phenylalkyne derivative compounds of formula (1) significantly activate glucokinase, whereby the derivatives are useful for the treatment of glucokinase mediated diseases such as hyperglycemia and diabetes.
  • the present invention provides a novel compound for activating the glucokinase, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, a method for preparing the same, and a pharmaceutical composition comprising the same, a method for treating the same, and a use thereof. It aims to provide.
  • glucokinase by activating glucokinase, a novel compound having a hypoglycemic activity, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is provided.
  • novel intermediates useful for preparing the compounds, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof are provided.
  • a pharmaceutical composition comprising the compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
  • a method of preventing or treating a glucokinase mediated disease by administering to a subject said compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • composition comprising the compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient for pharmaceutical preparation for preventing or treating a glucokinase mediated disease. Use is provided.
  • heteroaryl means a 5-6 membered monocyclic heteroaryl including 1 to 3 heteroatoms selected from the group consisting of N, O and S atoms, or fused with a benzene ring or a pyridine ring. It means a bicyclic heteroaryl group which can be.
  • monocyclic heteroaryl may be thiazole, pyrazole, oxazole, imidazole, pyrrole, furan, thiophene, isothiazole, isoxazole, triazole, thiadiazole, tetrazole, oxadiazole , Triazine, pyridine, pyridazine, pyrimidine, pyrazine and the like.
  • bicyclic heteroaryl is benzothiazole, benzoxazole, benzimidazole, benzofuran, benzothiophene, benzisoxazole, indole, indolin, quinoline, isoquinoline, quinazoline, imidazopyridine, oxazolo Pyridine and the like.
  • aryl means at least one ring having a shared pi electron system, and includes a hydrocarbon ring having 6 to 12 carbon atoms such as phenyl, naphthyl, biphenyl, and the like.
  • alkyl' also means aliphatic hydrocarbon radicals and includes both straight and branched chain hydrocarbon radicals.
  • C 1 -C 6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, methyl, ethyl, propyl, n -butyl, n -pentyl, n -hexyl, isopropyl, isobutyl, sec -butyl, tert -Butyl, neopentyl, isopentyl and the like.
  • alkoxy means a radical in which the hydrogen atom of a hydroxy group is substituted with alkyl unless otherwise defined, for example C 1 -C 6 alkoxy refers to methoxy, ethoxy, propoxy, n-butoxy , n-pentyloxy, isopropoxy, sec -butoxy, tert -butoxy, neopentyloxy, isopentyloxy and the like.
  • solvate means a conventional organic solvent used for preparing an organic compound, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- Acetates, acetone, acetic acid, anisole, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethylsulfoxide, pentane, heptane, and the like.
  • the solvates of the invention are not limited.
  • the present invention provides a compound of formula 1, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • a ring is heteroaryl having at least one N atom and having 1 to 3 heteroatoms selected from N and S, wherein the heteroaryl is substituted with a C 1 -C 6 alkoxy-C 1 -C 6 alkoxy group or Unsubstituted straight or branched C 1 -C 6 alkyl; Hydroxycarbonyl; C 1 -C 6 alkoxycarbonyl; 4-morpholin carbonyl; halogen; And may be substituted or unsubstituted with one or more substituents selected from the group consisting of cyano,
  • R 1 is substituted with C 1 -C 6 alkoxy or unsubstituted or C 1 -C 6 straight chain alkyl on the grinding ring,
  • R 2 is hydrogen; Hydroxy, halogen, C 1 -C 6 alkoxy, where alkoxy is C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, hydroxycarbonyl, phenyl unsubstituted or substituted with one or more halogens, and pyridyl Unsubstituted or substituted with one or more substituents selected from the group consisting of: C 1 -C unsubstituted or substituted with a substituent selected from the group consisting of NR 3 R 4 and C 3 -C 7 cycloalkylthio 6 alkyl;
  • Hetero selected from the group consisting of pyridyl, pyrimidyl, pyridazinyl, imidazolyl, thiophenyl, indolyl, benzo [1,3] dioxyl, and 2,3-dihydrobenzo [1,4] dioxylyl
  • Aryl group wherein the heteroaryl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of linear or pulverized C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and cyano unsubstituted or substituted with one or more halogens.
  • R 3 and R 4 independently of each other, are hydrogen; C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkoxy, pyridyl, cyano, phenyl, phenyl substituted with one or more halogen groups, substituted with straight chain or ground C 1 -C 6 alkyl Linear or pulverized C 1 -C 6 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of pyridyl; C 3 -C 7 cycloalkyl; C 1 -C 6 alkylcarbonyl; C 3 -C 7 cycloalkylcarbonyl; Or pyrimidyl,
  • R 5 is 4-morpholinyl; C 1 -C 6 straight or branched dialkylamino; Azepanyl; C 1 -C 6 alkoxy; Piperidyl; Pyrrolidyl; C 3 -C 7 cycloalkyl; C 1 -C 6 alkoxycarbonyl; C 1 -C 6 alkoxy-C 1 -C 6 alkoxy; Tetrahydrofuranyl; [1,3] dioxoranyl; Cyano; Imidazolyl; Imidazolyl substituted with one or more cyano groups; Imidazolyl substituted with one or more straight chain or ground C 1 -C 6 alkyl; Pyrazolyl; Pyrazolyl substituted with one or more straight or milled C 1 -C 6 alkyl; And straight or pulverized C 1 -C 6 alkyl substituted or unsubstituted with one or more substituents selected from the group consisting of pyrazolyl substituted with hydroxycarbony
  • R 6 is C 3 -C 7 cycloalkyl; Straight or branched C 1 -C 6 alkyl unsubstituted or substituted with hydroxycarbonyl or C 1 -C 6 alkoxycarbonyl; Straight or branched C 1 -C 6 alkylamino; Or C 3 -C 7 cycloalkylamino,
  • R 7 is straight or branched C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl
  • R 8 and R 9 are, independently from each other, hydrogen; Dialkylamino a linear or branched C 1 -C 6, pyrrolidin pyridyl and 4-morpholinyl substituted by one or more substituents selected from the group consisting of or a C 1 -C 6 alkyl of the unsubstituted straight or branched chain .
  • the A ring is C 5 -C 6 heteroaryl having 1 or 2 N atoms, and the heteroaryl is C 1 -C 3 Alkoxy-C 1 -C 3 alkoxy group substituted or unsubstituted straight or branched C 1 -C 3 alkyl; Hydroxycarbonyl; 4-morpholin carbonyl; And may be substituted or unsubstituted with one or more substituents selected from the group consisting of cyano,
  • R 1 is straight or pulverized C 1 -C 3 alkyl unsubstituted or substituted with C 1 -C 3 alkoxy
  • R 2 is hydroxy, C 1 -C 3 alkoxy, where alkoxy is C 1 -C 3 alkoxy, C 3 -C 7 cycloalkyl, hydroxycarbonyl, phenyl substituted by one or more halogens and pyridyl from substituted or unsubstituted with one or more substituents selected may be ring), NR 3 R 4, and C 3 -C 7 cyclo alkylthio substituted with a substituent selected from the group consisting of unsubstituted straight chain or C 1 -C 4 alkyl on the grinding ;
  • Hetero selected from the group consisting of pyridyl, pyrimidyl, pyridazinyl, imidazolyl, thiophenyl, indolyl, benzo [1,3] dioxyl, and 2,3-dihydrobenzo [1,4] dioxylyl
  • R 3 and R 4 independently of each other, are hydrogen; C 1 -C 3 alkoxy, C 1 -C 3 alkoxy-C 1 -C 3 alkoxy, pyridyl, cyano, phenyl, phenyl substituted with one or more halogen groups, substituted with straight chain or ground C 1 -C 6 alkyl Linear or pulverized C 1 -C 5 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of pyridyl; C 3 -C 7 cycloalkyl; C 1 -C 6 alkylcarbonyl; C 3 -C 7 cycloalkylcarbonyl; Or pyrimidyl,
  • R 5 is 4-morpholinyl; C 1 -C 3 straight or branched dialkylamino; Azepanyl; C 1 -C 3 alkoxy; Piperidyl; Pyrrolidyl; C 3 -C 7 cycloalkyl; C 1 -C 3 alkoxycarbonyl; C 1 -C 3 alkoxy-C 1 -C 3 alkoxy; Tetrahydrofuranyl; [1,3] dioxoranyl; Cyano; N-imidazolyl; N-imidazolyl substituted with one or more cyano groups; N-imidazolyl substituted with one or more straight or milled C 1 -C 3 alkyl; Pyrazolyl; Pyrazolyl substituted with one or more straight or milled C 1 -C 3 alkyl; And straight or pulverized C 1 -C 5 alkyl substituted or unsubstituted with one or more substituents selected from the group consisting of pyrazolyl
  • R 6 is C 3 -C 7 cycloalkyl; Straight or branched C 1 -C 3 alkyl unsubstituted or substituted with hydroxycarbonyl or C 1 -C 3 alkoxycarbonyl; Straight or branched C 1 -C 4 alkylamino; Or C 3 -C 7 cycloalkylamino,
  • R 7 is straight or branched C 1 -C 3 alkyl or C 3 -C 7 cycloalkyl
  • R 8 and R 9 are, independently from each other, hydrogen; A linear or branched C 1 -C 3 dialkylamino, pyrrolidinyl and 4-pyridyl mol Poly substituted carbonyl from the group consisting of with one or more substituents selected or unsubstituted straight or branched chain C 1 -C 3 alkyl of one Can be.
  • the A ring is preferably heteroaryl selected from the group consisting of pyridyl, pyrazolyl and pyrazinyl, and C 1 -C 3 alkoxy Straight or branched C 1 -C 3 alkyl unsubstituted or substituted with a C 1 -C 3 alkoxy group; Hydroxycarbonyl; 4-morpholin carbonyl; And cyano may be substituted or unsubstituted with one or more substituents selected from the group consisting of.
  • the A ring is more preferably heteroaryl selected from the group consisting of 2-pyridyl, 3-pyrazolyl and 2-pyrazinyl.
  • the heteroaryl is methyl; Methoxyethoxymethyl; Hydroxycarbonyl; 4-morpholin carbonyl; And cyano may be substituted or unsubstituted with one or more substituents selected from the group consisting of.
  • R 1 may be 2-methoxy- (1S) -methyl-ethyl.
  • R 2 is preferably hydroxy, C 1 -C 2 alkoxy, where alkoxy is C 1 -C 2 alkoxy, cyclopropyl It may be unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxycarbonyl, phenyl substituted with one or more fluoro and pyridyl), NR 3 R 4 , and cyclopentylthiomethyl Straight or branched C 1 -C 4 alkyl substituted or unsubstituted with a substituent;
  • Hetero selected from the group consisting of pyridyl, pyrimidyl, pyridazinyl, imidazolyl, thiophenyl, indolyl, benzo [1,3] dioxyl, and 2,3-dihydrobenzo [1,4] dioxylyl
  • R 3 and R 4 independently of each other, are hydrogen; Straight or pulverized C 1 unsubstituted or substituted with one or more substituents selected from the group consisting of methoxy, methoxymethoxy, pyridyl, cyano, phenyl, phenyl substituted with one or more halogen groups, pyridyl substituted with a methyl group -C 5 alkyl; C 3 -C 6 cycloalkyl; C 1 -C 2 alkylcarbonyl; Cyclopropylcarbonyl; Or pyrimidyl,
  • R 5 is 4-morpholinyl; Dialkylamino of C 1 -C 2 ; Azepanyl; C 1 -C 3 alkoxy; Piperidyl; Pyrrolidyl; Cyclopropyl; Ethoxycarbonyl; Methoxymethoxy; Tetrahydrofuranyl; [1,3] dioxoranyl; Cyano; N-imidazolyl; N-imidazolyl substituted with one or more cyano groups; N-imidazolyl substituted with C 1 -C 2 alkyl; Pyrazolyl; Pyrazolyl substituted with a methyl group; And straight or pulverized C 1 -C 5 alkyl substituted or unsubstituted with one or more substituents selected from the group consisting of pyrazolyl substituted with hydroxycarbonyl,
  • R 6 is cyclopropyl; C 1 -C 2 alkyl unsubstituted or substituted with hydroxycarbonyl or methoxycarbonyl; Straight or branched C 1 -C 4 alkylamino; Or cyclopentylamino,
  • R 7 is methyl or cyclopropyl
  • R 8 and R 9 are, independently from each other, hydrogen; Or C 1 -C 2 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of dimethylamino, N-pyrrolidyl and 4-morpholinyl.
  • R 2 is more preferably hydroxy, C 1 -C 2 alkoxy, where alkoxy is C 1 -C 2 alkoxy, cyclo Or unsubstituted with one or more substituents selected from the group consisting of propyl, hydroxycarbonyl, 4-fluorophenyl, and 2-pyridyl), NR 3 R 4 , and cyclopentylthiomethyl Straight or branched C 1 -C 4 alkyl substituted or unsubstituted with a substituent;
  • R 3 and R 4 independently of each other, are hydrogen; One or more substituents selected from the group consisting of methoxy, methoxymethoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, cyano, phenyl, phenyl substituted with one or more halogen groups, 2-methylpyridyl Substituted or unsubstituted Straight chain or ground C 1 -C 5 alkyl; C 3 -C 6 cycloalkyl; C 1 -C 2 alkylcarbonyl; Cyclopropylcarbonyl; Or 2-pyrimidyl,
  • R 5 is 4-morpholinyl; Dialkylamino of C 1 -C 2 ; N-azepanylethyl; C 1 -C 3 alkoxy; N-piperidyl; N-pyrrolidyl; Cyclopropyl; Ethoxycarbonyl; Methoxymethoxy; 2-tetrahydrofuranyl; [1,3] dioxoran-2-yl; Cyano; N-imidazolyl; 4,5-dicyano (N-imidazolyl); 2-ethyl (N-imidazolyl); 2-methyl (N-imidazolyl); 4-methyl (N-imidazolyl); N-pyrazolyl; 4-methyl (N-pyrazolyl); And 4-hydroxycarbonyl (N-pyrazolyl) straight or pulverized C 1 -C 5 alkyl substituted or unsubstituted with one or more substituents selected from the group consisting of
  • R 6 is cyclopropyl; methyl; ethyl; Hydroxycarbonylmethyl; Methoxycarbonylmethyl; Ethylamino; Tert-butylamino; Isopropylamino; Propylamino; Or cyclopentylamino,
  • R 7 is methyl or cyclopropyl
  • R 8 and R 9 are, independently from each other, hydrogen; Or C 1 -C 2 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of dimethylamino, N-pyrrolidyl and 4-morpholinyl.
  • the compound of formula 1 of the present invention may be in the form of a pharmaceutically acceptable salt.
  • the salts are conventional acid addition salts, for example salts derived from inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, Salts derived from organic acids such as malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, p -toluenesulfonic acid, oxalic acid or trifluoroacetic acid.
  • the salts also include salts derived from conventional metal salt forms, such as metals such as lithium, sodium, potassium, magnesium, or calcium.
  • the present invention provides a process for preparing a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof comprising reacting a compound of Formula 2 with a compound of Formula 3:
  • the compound of Formula 1 may be prepared by performing the Sonogashira reaction between the compound of Formula 2 and the alkyne compound of Formula 3.
  • the reaction can be carried out using a palladium catalyst, the palladium catalyst is palladium diacetate (Pd (OAc) 2 ), tris (dibenzylideneacetone) dipalladium (tris (dibenzylideneacetone) dipalladium, Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ) or palladium (II) [1,1′-bis (diphenylphosphino) ferrocene] dichloride (PdCl 2 (dppf) 2 ) And the like.
  • ligands and bases may be added in addition to the palladium catalyst.
  • the ligand is (S) -2,2-bis (diphenylphosphino) -1,1-binafphyl (BINAP), 1,1'-bis (diphenylphosphino) ferrocene (dppf) or (tri- O-tolyl) phosphine (P (O-Tol) 3 ) and the like
  • the base is cesium carbonate (Cs 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), Potassium fluoride (KF), cesium fluoride (CsF), sodium hydroxide (NaOH), potassium phosphonate (K 3 PO 4 ), sodium tert -butoxide ( tert- BuONa) or potassium tert -butoxide ( tert- BuOK) and the like.
  • the reaction is carried out in a polar organic solvent such as non-polar organic solvent such as benzene or toluene or dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, or N, N -dimethylformamide as a reaction solvent. It may be carried out at °C to 150 °C, preferably at 80 °C to 110 °C. Other reaction conditions, including reaction time, can be carried out according to known methods for the Sonogashira reaction (Sonogashira K. and Tohda Y., STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS , 2005 ).
  • Sonogashira reaction Sonogashira K. and Tohda Y., STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS , 2005 ).
  • the compound of Formula 3 may be purchased commercially, and the compound of Formula 2 may be prepared, for example, according to Scheme 1 below:
  • a ring and R 1 are the same as defined above, and Hal is halogen.
  • the compound of Formula 2a may be purchased commercially. By introducing a protecting group into the carboxylic acid by the reaction of the compound of Formula 2a, the compound of Formula 2b may be obtained.
  • a polar solvent such as methanol may be used as the reaction solvent, and may be performed using thionyl chloride, sulfuric acid, or the like.
  • the reaction temperature may be performed at 0 ° C to room temperature, but in some cases, may be performed at room temperature to 100 ° C.
  • the compound of Formula 2d may be prepared by reacting the compound of Formula 2b with the compound of Formula 2c.
  • the compound of Formula 2c may be purchased commercially.
  • the reaction of the compound of Formula 2b with the compound of Formula 2c is, depending on the Mitsunobu reaction, diethylazodicarboxylate (DEAD) or diiso in the presence of triphenylphosphine or tri n -butylphosphine. It can be carried out using propyl azodicarboxylate (DIAD).
  • a polar organic solvent such as dichloromethane, dioxane, or tetrahydrofuran may be used as the reaction solvent.
  • the reaction temperature may be performed at 0 ° C.
  • reaction conditions including reaction time, can be carried out according to known methods for the Mitsunobu reaction (Barbara Czako and Laszlo Kurti, STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS , 2005 ).
  • Deprotection of the carboxyl protecting group may be performed on the compound of Formula 2d to obtain Formula 2e, and then may be obtained as a compound of Formula 2 by coupling with a commercially available amine compound of Formula 9.
  • an inorganic base for example, sodium hydroxide, lithium hydroxide or potassium hydroxide aqueous solution may be used.
  • a reaction solvent a polar solvent such as distilled water or tetrahydrofuran or alcohol, and a mixed solvent with water may be used, and the reaction may be preferably performed at room temperature to 50 ° C.
  • the coupling carried out subsequently i.e., amide coupling, can be carried out using known methods such as acyl halide method, azide method, carboxylic anhydride method, carbodiimide method, active ester method, or carbonyldiimidazole method (e.g. , Miklos Bodanszky, Principles of Peptide Synthesis , 2nd Ed., 1993 ).
  • the carbodiimide method or the acyl halide method can be used.
  • the coupling reaction may be carried out in an inert solvent such as dichloromethane, acetonitrile or N, N-dimethylformamide, and also triethylamine, diisopropylethylamine, N -methylmorpholine, N In an organic base such as , N -dimethylaminopyridine or N -methylpyrrolidine, it may be performed at room temperature to 50 ° C.
  • an inert solvent such as dichloromethane, acetonitrile or N, N-dimethylformamide
  • triethylamine, diisopropylethylamine, N -methylmorpholine N
  • organic base such as , N -dimethylaminopyridine or N -methylpyrrolidine
  • the coupling reaction according to the acyl halide method is performed by converting a carboxylic acid into an acyl halide using a thionyl chloride or an oxalyl chloride in the compound of Formula 8, followed by pyridine, triethylamine, diisopropyl ethylamine, N -methyl In the presence of an organic base such as morpholine, N, N -dimethylaminopyridine or N -methylpyrrolidine, the compound of formula (9) may be reacted.
  • the coupling reaction may be performed at room temperature to 100 ° C. in a reaction solvent such as dichloromethane or pyridine.
  • the present invention provides a process for preparing a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, comprising reacting a compound of Formula 4 with a compound of Formula 5:
  • the compound of Formula 1 may be prepared by performing an amide coupling reaction between the compound of Formula 4 and the compound of Formula 5.
  • the coupling reaction may be performed by the same method as the amide coupling reaction of Scheme 1.
  • a ring and R 1 are the same as defined above.
  • the compound of Formula 2d and the compound of Formula 2f may be subjected to Sonogashira reaction to obtain a compound of Formula 2g.
  • the starting compound of formula 10 can be purchased commercially.
  • the sonogashira reaction may be performed by the same method as the reaction of Chemical Formula 2.
  • the compound of formula 5 may be obtained by performing a deprotection reaction of the carboxyl protecting group of the compound of formula 2g.
  • the deprotection reaction of the carboxyl protecting group can be carried out in substantially the same manner as the reaction carried out on the compound 2d in Scheme 1.
  • the present invention provides a compound of formula (2), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof that can be used as an intermediate for the preparation of the compound of formula (I):
  • the present invention provides a compound of formula (6), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof that can be used as an intermediate for the preparation of the compound of formula (I):
  • R 1 and R 2 are the same as defined above and X is hydroxy or C 1 -C 3 alkoxy.
  • the present invention provides a pharmaceutical composition for the prophylaxis or treatment of glucokinase mediated diseases comprising a therapeutically effective amount of a compound of formula 1, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the glucokinase mediated diseases include hyperglycemia, diabetes, obesity, type 1 diabetes, insulin resistance in type 2 diabetes, obesity, metabolic syndrome, and the like.
  • the glucokinase mediated disease may be one or more diseases selected from the group consisting of hyperglycemia, obesity and diabetes.
  • the pharmaceutical composition may include pharmaceutically acceptable carriers such as excipients, disintegrants, sweeteners, lubricants or flavoring agents commonly used, tablets, capsules, powders, granules and suspensions, according to conventional methods, Oral preparations such as emulsions or syrups; Or in preparations for parenteral administration such as injections.
  • pharmaceutically acceptable carriers such as excipients, disintegrants, sweeteners, lubricants or flavoring agents commonly used, tablets, capsules, powders, granules and suspensions, according to conventional methods, Oral preparations such as emulsions or syrups; Or in preparations for parenteral administration such as injections.
  • the formulations can be formulated in a variety of forms, for example, in single or multiple dosage forms.
  • the pharmaceutical composition of the present invention may be administered intravenously, intramuscularly or orally, preferably orally.
  • the daily dosage of the compound of formula 1 or a pharmaceutically acceptable salt thereof may range from about 10 to about 500 mg / kg, but this may vary depending on the condition, age, weight, sensitivity, symptoms or route of administration of the patient. have.
  • the present invention provides a method for preventing or treating a glucokinase mediated disease by administering a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a subject.
  • the subject may be a mammal including a human.
  • the present invention is the use of a composition comprising a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient for pharmaceutical preparation for preventing or treating a glucokinase mediated disease To provide.
  • the compound according to the present invention ie, the phenylalkyne derivative compound of formula (1), can be usefully applied to the treatment of glucokinase mediated diseases such as hyperglycemia and diabetes by significantly activating glucokinase.
  • methyl is Me
  • ethyl is Et
  • phenyl is Ph
  • tert -butyloxycarbonyl is BOC
  • EDAC N- (3-dimethylaminopropyl) -N'- Ethyl carbodiimide
  • 1-hydroxybenzotriazole is HOBT.
  • the starting material of each Example was synthesize
  • Step 2 3-Bromo-5- (2-methoxy- ( 1S ) -methyl-ethoxy) -benzoic acid methyl ester
  • Step 4 3-Bromo-5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -benzamide
  • Step 4 3- (3-amino-4-methyl-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole -3-yl) -benzamide
  • Step 2 3- (N -BOC- prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- 3-day) -benzamide
  • N- BOC propazyl amine prepared in step 2 was dissolved in 12.0 g of tetrabutylammonium fluoride trihydrate, and 3-bromo-5- (2-methoxy- (1 S )-prepared in Reference Example 1 methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide 3.0 g, palladium (II), [1,1'- bis (diphenylphosphino) ferrocene] dichloride 0.6 g was added thereto, followed by stirring at 85 ° C. for 3 hours.
  • Step 3 3- (3-amino-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- 3-day) -benzamide
  • Step 1 3- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -5- [3- (tetrahydropyran- 2-yloxy) -prop-1-ynyl] -benzamide
  • the reaction mixture was diluted with ethyl acetate, washed with distilled water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow liquid residue.
  • Step 2 3- (3-hydroxy-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole -3-yl) -benzamide
  • Step 3 3- (3-bromo-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole -3-yl) -benzamide
  • Step 1 3- (3-amino-4-methyl-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) -benzoic acid methyl ester
  • Step 2 3- (3-amino-4-methyl-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) -benzoic acid
  • Step 1 3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (2-methoxy-phenylethynyl) -benzoic acid methyl ester
  • Step 2 3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (2-methoxy-phenylethynyl) -benzoic acid
  • Step 1 3- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -5-ethynyl-trimethylsilanyl-benzamide
  • Step 2 5-ethynyl-3- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -benzamide
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 2 was prepared in the same manner as in Example 1, except that 334.0 mg of 3-ethynylaniline was used instead of methylpropazyl.
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 3 was prepared in the same manner as in Example 1, except that 334.0 mg of 4-ethylnylaniline was used instead of methylpropazyl.
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 5 was prepared in the same manner as in Example 1, except that 331.0 mg of 4-ethynyltoluene was used instead of methylpropazyl.
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 6 was prepared in the same manner as in Example 1, except that 157.0 mg of propargylamine was used instead of methylpropazyl.
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 7 was prepared in the same manner as in Example 1, except that 237.0 mg of 3-dimethylamino-1-propyne was used instead of methylpropazyl. Prepared.
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 8 was prepared in the same manner as in Example 1, except that 417.0 mg of 4-ethynylbenzoic acid was used instead of methylpropazyl.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- After dissolving 100.0 mg of 3-yl) -benzamide in 5.0 mL of N, N -dimethylformamide, 50.9 mg of iodineethane and 120.0 mg of potassium carbonate were added and stirred overnight at 85 ° C. The reaction mixture was washed with distilled water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow liquid residue.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- Example 9, except that 3-yl) -benzamide was used and 60.7 mg of 4- (2-chloroethyl) morpholine hydrochloride (4- (2-chloroethyl) morpholineHCl) was used instead of iodineethane. In the same manner, the compound of Example 10 was prepared.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- carried out, except for using dimethyl amine hydrochloride (2-chloro- N, N -dimethylethylamine ⁇ HCl) 47.0 mg - 3- yl) benzamide ahmayideueul use, ethane iodide instead of 2-chloro-N, N
  • the compound of Example 11 was prepared in the same manner as in Example 9.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- Example 9, except that 3-yl) -benzamide was used and 64.7 mg of 1- (2-chloroethyl) azane hydrochloride (1- (2-chloroethyl) azepane.HCl) was used instead of iodineethane. In the same manner, the compound of Example 12 was prepared.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- A compound of Example 13 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 35.4 mg of 2-chloroethyl ethyl ether instead of iodineethane was used. It was.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- The compound of Example 14 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 46.3 mg of iodomethane was used instead of iodineethane.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- Example 9, except using 3-yl) -benzamide and 60.1 mg of 1- (2-chloroethyl) piperidine hydrochloride (1- (2-chloroethyl) piperidineHCl) instead of iodineethane In the same manner as in the compound of Example 15 was prepared.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- Example 9, except using 3-yl) -benzamide and using 55.5 mg of 1- (2-chloroethyl) pyrrolidine hydrochloride (1- (2-chloroethyl) pyrrolidineHCl) instead of iodineethane In the same manner as in the compound of Example 16 was prepared.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- A compound of Example 17 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 29.6 mg of chloromethylcyclopropane was used instead of iodineethane.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- A compound of Example 18 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 30.9 mg of 2-chloroethyl methyl ether was used instead of iodineethane. It was.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- A compound of Example 19 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 40.0 mg of ethyl chloroacetate was used instead of iodineethane.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- Example, except using 3-yl) -benzamide and 40.7 mg of 1-chloro-2- (methoxymethoxy) ethane instead of iodineethane The compound of Example 20 was prepared in the same manner as in Example 9.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- the same manner as in example 9 except for using diethylamine), 44.3 mg 3- yl) benzamide used, ethane iodide instead of N ahmayideueul - - ((2-chloroethyl 2- chloroethyl) diethylamine (N) The compound of Example 21 was prepared.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- The compound of Example 22 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 39.4 mg of tetrahydrofurfuryl chloride was used instead of iodineethane.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- Same as Example 9, except using 3-yl) -benzamide and using 40.0 mg of 2-chloromethyl-1,3-dioxolane instead of iodineethane The compound of Example 23 was prepared by the method.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- In the same manner as in Example 9, except using 3-yl) -benzamide and 40.0 mg of 1- (2-chloroethoxy) propane instead of iodineethane The compound of Example 24 was prepared.
  • Example 26 (- 4-ethynyl-phenyl) -5- embodiment 3-1 prepared in Example 3 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole-
  • the compound of Example 26 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 39.2 mg of bromoacetonitrile was used instead of iodineethane.
  • Example 31 (- 4-ethynyl-phenyl) -5- embodiment 3-1 prepared in Example 3 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- A compound of Example 31 was prepared in the same manner as in Example 9, except for using 3-yl) -benzamide and using 40.0 mg of ethyl chloroacetate instead of iodoethane.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- The compound of Example 34 was prepared in the same manner as in Example 33, except using 3-yl) -benzamide and using 26.6 mg of propionyl chloride instead of cyclopropanecarbonyl chloride.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- The compound of Example 35 was prepared in the same manner as in Example 33, except that 3-yl) -benzamide was used and 39.2 mg of methyl malonyl chloride was used instead of cyclopropanecarbonyl chloride.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- The compound of Example 36 was prepared in the same manner as in Example 33, except for using 3-yl) -benzamide and using 22.5 mg of acetyl chloride instead of cyclopropanecarbonyl chloride.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- The procedure was carried out in the same manner as in Example 33, except that 3-yl) -benzamide was used and 30.6 mg of 1-chloro-3-methylbutane instead of cyclopropanecarbonyl chloride was used. The compound of Example 37 was prepared.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- The compound of Example 38 was prepared in the same manner as in Example 33, except that 3-yl) -benzamide was used and 32.9 mg of methanesulfonyl chloride was used instead of cyclopropanecarbonyl chloride.
  • Example 2 To a solution of 3- prepared in (3-Amino-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- The compound of Example 39 was prepared in the same manner as in Example 33, except that 3-yl) -benzamide was used and 40.3 mg of cyclopropanesulfonyl chloride was used instead of cyclopropanecarbonyl chloride.
  • Example 40 (- 4-ethynyl-phenyl) -5- embodiment 3-1 prepared in Example 3 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole-
  • the compound of Example 40 was prepared in the same manner as in Example 33, except for using 3-yl) -benzamide and using 26.6 mg of propionyl chloride instead of cyclopropanecarbonyl chloride.
  • Example 41 (- 4-ethynyl-phenyl) -5- embodiment 3-1 prepared in Example 3 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole-
  • the compound of Example 41 was prepared in the same manner as in Example 33, except for using 3-yl) -benzamide and using 22.5 mg of acetyl chloride instead of cyclopropanecarbonyl chloride.
  • Example 42 (- 4-ethynyl-phenyl) -5- embodiment 3-1 prepared in Example 3 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole- A compound of Example 42 was prepared in the same manner as in Example 33, except using 3-yl) -benzamide and 30.0 mg of cyclopropanecarbonyl chloride.
  • Example 43 (- 4-ethynyl-phenyl) -5- embodiment 3-1 prepared in Example 3 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole-
  • the compound of Example 43 was prepared in the same manner as in Example 33, except that 3-yl) -benzamide was used and 39.2 mg of methyl malonyl chloride was used instead of cyclopropanecarbonyl chloride.
  • Example 43 N- ⁇ 4- [3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (1-methyl-1 H -pyrazol-3-ylcarbamoyl) prepared in Example 43 The same method as Step 3 of Reference Example 1, except using -phenylethynyl] -phenyl ⁇ -malonamic acid methyl ester, dissolved in 2.0 ml of tetrahydrofuran and 2.0 ml of methanol and using 1.0 mL of 3N sodium hydroxide solution. The compound of Example 44 was prepared.
  • Example 8 4- [3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (1-methyl-1 H -pyrazol-3-yl-carbamoyl) -phenyl prepared in Example 8 Except for using ethynyl] -benzoic acid and 37.3 mg of 4- (2-aminoethyl) morpholine instead of 1-methyl-1 H -pyrazol-3-ylamine. Then, the compound of Example 45 was prepared in the same manner as in Step 4 of Reference Example 1.
  • Example 8 4- [3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (1-methyl-1 H -pyrazol-3-yl-carbamoyl) -phenyl prepared in Example 8 The same procedure as in Step 4 of Reference Example 1 was conducted except that ethynyl] -benzoic acid was used and 21.0 mg of diethylamine was used instead of 1-methyl-1 H -pyrazol-3-ylamine. The compound of Example 46 was prepared.
  • Example 8 4- [3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (1-methyl-1 H -pyrazol-3-yl-carbamoyl) -phenyl prepared in Example 8
  • Example 8 was carried out in the same manner as in Step 4 of Reference Example 1, except that ethynyl] -benzoic acid was used and 9.0 mg of methylamine was used instead of 1-methyl-1 H -pyrazol-3-ylamine. 47 compound was prepared.
  • Example 49 4- [3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (1-methyl-1 H -pyrazol-3-yl-carbamoyl) -phenyl prepared in Example 8 ethynyl] benzoic acid used, and 1-methyl -1 H-pyrazol-3-ylamine instead of N, N-dimethyl-ethylene-diamine (N, N -dimethylethylenediamine) and the reference, except for using 25.3 mg
  • the compound of Example 49 was prepared by the same method as Step 4 of Example 1.
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 51 was prepared in the same manner as in Example 1, except that 37.9 mg of 3-ethynylanisole was used instead of methylpropazyl.
  • Example 55 (- 3-hydroxy-phenylethynyl) -5 embodiment 3-1 prepared in Example 50 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole
  • the compound of Example 55 was prepared in the same manner as in Example 9 except for using 3-yl) -benzamide and using 27.1 mg of 2-chloroethyl methyl ether instead of iodoethane. Prepared.
  • Example 50 (- 3-hydroxy-phenylethynyl) -5 embodiment 3-1 prepared in Example 50 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole Same as Example 9, except using 3-yl) -benzamide and using 42.4 mg of 1- (2-chloroethyl) piperidine instead of iodoethane
  • the compound of Example 56 was prepared by the method.
  • Example 50 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole
  • the compound of Example 57 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 31.7 mg of bromoacetonitrile was used instead of iodoethane.
  • Example 58 (- 3-hydroxy-phenylethynyl) -5 embodiment 3-1 prepared in Example 50 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole
  • the compound of Example 58 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 22.5 mg of 2-chloropropane was used instead of iodoethane.
  • Example 60 (- 3-hydroxy-phenylethynyl) -5 embodiment 3-1 prepared in Example 50 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole
  • the compound of Example 60 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and a compound suitable for 26.0 mg of chlorocyclobutane was used instead of iodoethane.
  • Example 60 (- 3-hydroxy-phenylethynyl) -5 embodiment 3-1 prepared in Example 50 (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazole A compound of Example 60 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and a compound suitable for 34.6 mg of tetrahydrofurfuryl chloride was used instead of iodoethane. It was.
  • Example 61 was prepared in the same manner as in Example 9, except that 3-yl) -benzamide was used and 36.6 mg of 2- (chloromethyl) pyridine instead of iodoethane. The compound was prepared.
  • Example 65 3- (2-methoxy - (1 S) - methyl-ethoxy) -5- (4-methyl-3- propionylamino-ethynyl-phenyl) - N-(1- methyl -1 H -Pyrazol-3-yl) -benzamide
  • Example 66 (- phenylethynyl 3-amino-4-methyl) -5- Reference Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 66 was prepared in the same manner as in Example 65, except that pyrazol-3-yl) -benzamide was used and 23.0 mg of cyclopropanecarbonyl chloride was used instead of propionyl chloride. It was.
  • Example 67 (- phenylethynyl 3-amino-4-methyl) -5- Reference Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 67 was prepared in the same manner as in Example 65, except that pyrazol-3-yl) -benzamide was used and 29.5 mg of methyl malonyl chloride was used instead of propionyl chloride. It was.
  • Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 68 was prepared in the same manner as in Example 65, except for using -pyrazol-3-yl) -benzamide and using 17.0 mg of acetyl chloride instead of propionyl chloride.
  • Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H Same method as Example 65, except using pyrazol-3-yl) -benzamide and 23.0 mg of 1-chloro-3-methylbutane instead of propionyl chloride The compound of Example 69 was prepared.
  • Example 70 3 - [(3-cyclo propyl-amino) -4-methyl-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- Methyl-1 H -pyrazol-3-yl) -benzamide
  • Example 70 (- phenylethynyl 3-amino-4-methyl) -5- Reference Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 70 was prepared in the same manner as in 65, except that -pyrazol-3-yl) -benzamide was used and 20.0 mg of (chloromethyl) cyclopropane was used instead of propionyl chloride. Prepared.
  • Example 71 in the same manner as in Example 65, except that pyrazol-3-yl) -benzamide was used and 20.4 mg of 2-chloroethyl methyl ether instead of propionyl chloride was used.
  • pyrazol-3-yl 2-chloroethyl methyl ether instead of propionyl chloride was used.
  • Example 72 (- phenylethynyl 3-amino-4-methyl) -5- Reference Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 72 was prepared in the same manner as in Example 65, except that -pyrazol-3-yl) -benzamide was used and 33.7 mg of iodoethane instead of propionyl chloride was used.
  • Example 74 (- phenylethynyl 3-amino-4-methyl) -5- Reference Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 74 was prepared in the same manner as in Example 65, except that -pyrazol-3-yl) -benzamide was used and 30.7 mg of iodomethane was used instead of propionyl chloride.
  • Example 75 (- phenylethynyl 3-amino-4-methyl) -5- Reference Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 75 was prepared in the same manner as in Example 65, except that -pyrazol-3-yl) -benzamide was used and 24.8 mg of methanesulfonyl chloride was used instead of propionyl chloride. .
  • Example 76 (- phenylethynyl 3-amino-4-methyl) -5- Reference Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 76 was prepared in the same manner as in Example 65, except that -pyrazol-3-yl) -benzamide was used and 26.5 mg of ethyl chloroacetate instead of propionyl chloride was used.
  • Example 77 (- phenylethynyl 3-amino-4-methyl) -5- Reference Example 2 3-manufactured (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • -pyrazol-3-yl) -benzamide was used and 22.4 mg of 4-chlorobutyronitrile instead of propionyl chloride was prepared.
  • Example 80 3- (3-acetyl-amino-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol Zol-3-yl) -benzamide
  • Example 80 was prepared in the same manner as in Example 78, except that pyrazol-3-yl) -benzamide was used and 17.0 mg of acetyl chloride was used instead of 2-chloropyrimidine.
  • Example 82 was manufactured in the same manner as in Example 78.
  • Example 84 was prepared in the same manner as in Example 78, except that pyrazol-3-yl) -benzamide was used and 17.0 mg of 2-chloropropane was used instead of 2-chloropyrimidine. .
  • Example 85 was prepared in the same manner as in Example 78, except that pyrazol-3-yl) -benzamide was used and 22.6 mg of cyclopropanecarbonyl chloride was used instead of 2-chloropyrimidine. .
  • Example 86 was prepared in the same manner as in Example 78, except that pyrazol-3-yl) -benzamide was used and 20.0 mg of propionyl chloride was used instead of 2-chloropyrimidine.
  • Example 87 was prepared in the same manner as in Example 78, except for using pyrazol-3-yl) -benzamide and using 19.4 mg of 3-chloropropionitrile instead of 2-chloropyrimidine. Prepared.
  • Example 88 was prepared in the same manner as in Example 78, except that pyrazol-3-yl) -benzamide was used and 27.4 mg of benzyl chloride was used instead of 2-chloropyrimidine.
  • Example 90 See 3- (3-amino-prop-1-ynyl) prepared in Reference Example 3 5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H- Same as Example 78, except using pyrazol-3-yl) -benzamide and 35.1 mg of 2,6-difluorobenzyl chloride instead of 2-chloropyrimidine Example 90 was prepared by the method.
  • Example 91 See 3- (3-amino-prop-1-ynyl) prepared in Reference Example 3 5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H- Same as Example 78, except using pyrazol-3-yl) -benzamide and 35.1 mg of 2,4-difluorobenzyl chloride instead of 2-chloropyrimidine
  • Example 91 was prepared by the method.
  • Example 92 was prepared in the same manner as in Example 78.
  • Example 4 To a solution of 3- prepared in (3-bromo-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H The compound of Example 95 was prepared in the same manner as in Example 94, except for using -pyrazol-3-yl) -benzamide and using 14.5 mg of cyclopropylamine instead of cyclopentylamine.
  • Example 4 To a solution of 3- prepared in (3-bromo-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H
  • the compound of Example 96 was prepared in the same manner as in Example 94, except for using -pyrazol-3-yl) -benzamide and using 22.0 mg of 3-aminopentane instead of cyclopentylamine It was.
  • Example 4 To a solution of 3- prepared in (3-bromo-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H The compound of Example 97 was prepared in the same manner as in Example 94, except that pyrazol-3-yl) -benzamide was used and 18.5 mg of sec-butylamine was used instead of cyclopentylamine. It was.
  • Example 4 To a solution of 3- prepared in (3-bromo-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H A compound of Example 98 was prepared in the same manner as in Example 94, except for using -pyrazol-3-yl) -benzamide and using 25.8 mg of cyclopentanethiol instead of cyclopentylamine.
  • Example 4 To a solution of 3- prepared in (3-bromo-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H The compound of Example 99 was prepared in the same manner as in Example 94, except for using -pyrazol-3-yl) -benzamide and using 18.0 mg of cyclobutylamine instead of cyclopentylamine.
  • Example 100 2- ⁇ 3- [3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (1-methyl-1 H -pyrazol-3-ylcarbamoyl) -phenyl ] -Prop-2-ynyloxy ⁇ -propionic acid
  • Example 4 To a solution of 3- prepared in (3-bromo-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H The compound of Example 100 was prepared in the same manner as in Example 94, except that -pyrazol-3-yl) -benzamide was used and 22.7 mg of lactic acid was used instead of cyclopentylamine.
  • Example 4 To a solution of 3- prepared in (3-bromo-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H The compound of Example 102 was prepared in the same manner as in Example 94, except for using -pyrazol-3-yl) -benzamide and using 25.0 mg of cyclohexylamine instead of cyclopentylamine.
  • Example 5 To a solution of 3- bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (5- methyl-pyrazin-2-yl) benzamide used ahmayideueul, and 3
  • the compound of Example 104 was prepared in the same manner as in Example 103, except that 97.5 mg of 1-ethynylcyclohexylamine was used instead of, 3-dimethyl-1-butyne.
  • Example 5 To a solution of 3- bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (5- methyl-pyrazin-2-yl) benzamide used ahmayideueul, and 3 A compound of Example 105 was prepared in the same manner as in Example 103, except that 85.6 mg of 2-ethynylthiophene was used instead of, 3-dimethyl-1-butyne.
  • Example 5 To a solution of 3- bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (5- methyl-pyrazin-2-yl) benzamide used ahmayideueul, and 3 The compound of Example 108 was prepared in the same manner as in Example 103, except that 87.2 mg of 1-ethynylcyclopentanol was used instead of, 3-dimethyl-1-butyne.
  • Example 110 3- (3-diethylamino-prop-1-ynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (5- methyl-pyrazin-2 -Sun) -benzamide
  • Example 5 To a solution of 3- bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (5- methyl-pyrazin-2-yl) benzamide used ahmayideueul, and 3 A compound of Example 111 was prepared in the same manner as in Example 103, except that 81.6 mg of 4-ethynylpyridine was used instead of, 3-dimethyl-1-butyne.
  • Example 121 4- [3- [1- (2-methoxy-ethoxymethyl) -1 H -pyrazol-3-ylcarbamoyl] -5- (2-methoxy- (1 S ) -methyl -Ethoxy) -phenylethynyl] -benzoic acid
  • Step 2 3-benzo [1,3] dioxo-5-ethynyl-5-yl (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H- Pyrazol-3-yl) -benzamide
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • a compound of Example 125 was prepared in the same manner as in Example 123, except that 10.0 g of 5-iodoindole was used instead of 1-iodo-3,4-methylenedioxybenzene. It was.
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 130 was prepared in the same manner as in Example 123, except that 10.0 g of 3-iodobenzonitrile was used instead of 1-iodo-3,4-methylenedioxybenzene. Prepared.
  • Example 1 3-bromo-5 prepared in (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) benzamide ahmayideueul
  • the compound of Example 131 was prepared in the same manner as in Example 123, except that 10.0 g of 2-iodobenzonitrile was used instead of 1-iodo-3,4-methylenedioxybenzene. Prepared.
  • Step 1 3- (2-Methoxy- ( 1S ) -Methyl-ethoxy) -5- [3- (pyridin-2-ylmethoxy) -prop-1-ynyl] -benzoic acid methyl ester
  • Step 2 3- (2-Methoxy- ( 1S ) -methyl-ethoxy) -5- [3- (pyridin-2-ylmethoxy) -prop-1-ynyl] -benzoic acid
  • step 1 G 3- (2-Methoxy- ( 1S ) -methyl-ethoxy) -5- [3- (pyridin-2-ylmethoxy) -prop-1-ynyl] -benzoic acid methyl ester 1.8 prepared in step 1 G was dissolved in 25.0 mL of methanol, 0.8 g of sodium hydroxide was dissolved in 20.0 mL of distilled water, and slowly added thereto, followed by stirring overnight at 40 ° C. The reaction mixture was acidified to pH 6 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown solid residue.
  • Step 3 3- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -5- [3-pyridin-2-ylmethoxy Methoxy) -prop-1-ynyl] -benzamide
  • Example 140 3- (3-amino-4-methyl-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (1- methyl -1 H-pyrazol Zol-3-yl) -benzamide
  • Example 141 3-manufactured (3-amino-4-methyl-phenylethynyl) -5- (2-methoxy - (1 S) - methyl-ethoxy) - N - (5- methyl-pyrazin- 20.1 mg of the compound of Example 142 as a white solid, in the same manner as in Example 65, except for using 2-yl) -benzamide and 4-bromobutyronitrile instead of propionyl chloride (Yield 10.4%) was prepared.
  • Example 9 5-Methylpyrazine-2- using 3- (2-methoxy- ( 1S ) -methyl-ethoxy) -5- (2-methoxy-phenylethynyl) -benzoic acid prepared in Reference Example 9
  • a compound of Example 144 was prepared in the same manner as in Example 143, except that 236.0 mg of 2-amino-5-cyanopyridine was used instead of one amine.
  • Example 150 3- (3-Amino-phenylethynyl) - N - [1- (2-methoxy-ethoxymethyl) -1 H-pyrazol-3-yl] -5- (2-methoxy -( 1S ) -Methyl-ethoxy) -benzamide

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Abstract

La présente invention concerne un nouveau phényléthynyl-benzamide, des sels pharmaceutiquement acceptables de celui-ci, ou des hydrates ou des solvates de celui-ci, un procédé de préparation de ce composé et une composition pharmaceutique le contenant. Le nouveau phényléthynyl-benzamide, les sels pharmaceutiquement acceptables de celui-ci, ou les hydrates ou les solvates de celui-ci, selon la présente invention, permettent d'activer sensiblement la glucokinase et peuvent ainsi être avantageusement utilisés pour le traitement de maladies transmises par l'intermédiaire de la glucokinase, telles que l'hyperglycémie et le diabète.
PCT/KR2014/000457 2013-01-16 2014-01-16 Nouveau phényléthynyl-benzamide activateur de la glucokinase et son procédé de préparation Ceased WO2014112798A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111704558A (zh) * 2020-06-22 2020-09-25 浙江农林大学暨阳学院 一种钯催化制备苯基-2-（2’-氰基苯基）乙炔类化合物的方法

Citations (6)

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JPH11222435A (ja) * 1998-02-05 1999-08-17 Otsuka Pharmaceut Factory Inc 一酸化窒素合成酵素阻害剤
WO2002079145A1 (fr) * 2001-03-30 2002-10-10 Millennium Pharmaceuticals, Inc. Composes de benzamide, inhibiteurs ddu factor xa
KR20040029324A (ko) * 2001-06-26 2004-04-06 아스트라제네카 아베 글루코키나제(ｇｌｋ) 조절제로서 아미노 니코티네이트유도체
WO2005113494A2 (fr) * 2004-05-07 2005-12-01 Amgen Inc. Modulateurs de proteines kinases et procede d'utilisation
WO2007077005A1 (fr) * 2005-12-30 2007-07-12 Novartis Ag Dérivés de pipéridine 3,5-substitués en tant qu'inhibiteurs de rénine
KR20110033057A (ko) * 2009-09-22 2011-03-30 주식회사유한양행 신규의 글루코키나제 활성화제 및 그의 제조방법

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11222435A (ja) * 1998-02-05 1999-08-17 Otsuka Pharmaceut Factory Inc 一酸化窒素合成酵素阻害剤
WO2002079145A1 (fr) * 2001-03-30 2002-10-10 Millennium Pharmaceuticals, Inc. Composes de benzamide, inhibiteurs ddu factor xa
KR20040029324A (ko) * 2001-06-26 2004-04-06 아스트라제네카 아베 글루코키나제(ｇｌｋ) 조절제로서 아미노 니코티네이트유도체
WO2005113494A2 (fr) * 2004-05-07 2005-12-01 Amgen Inc. Modulateurs de proteines kinases et procede d'utilisation
WO2007077005A1 (fr) * 2005-12-30 2007-07-12 Novartis Ag Dérivés de pipéridine 3,5-substitués en tant qu'inhibiteurs de rénine
KR20110033057A (ko) * 2009-09-22 2011-03-30 주식회사유한양행 신규의 글루코키나제 활성화제 및 그의 제조방법

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111704558A (zh) * 2020-06-22 2020-09-25 浙江农林大学暨阳学院 一种钯催化制备苯基-2-（2’-氰基苯基）乙炔类化合物的方法
CN111704558B (zh) * 2020-06-22 2023-05-30 浙江农林大学暨阳学院 一种钯催化制备苯基-2-（2’-氰基苯基）乙炔类化合物的方法

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