WO2014077532A1 - Nouveau dérivé de pipérazine, sel pharmaceutiquement acceptable ou isomère optique de celui-ci, procédé pour le préparer et composition pharmaceutique le contenant comme ingrédient actif pour la prévention et le traitement de troubles métaboliques - Google Patents

Nouveau dérivé de pipérazine, sel pharmaceutiquement acceptable ou isomère optique de celui-ci, procédé pour le préparer et composition pharmaceutique le contenant comme ingrédient actif pour la prévention et le traitement de troubles métaboliques Download PDF

Info

Publication number
WO2014077532A1
WO2014077532A1 PCT/KR2013/009857 KR2013009857W WO2014077532A1 WO 2014077532 A1 WO2014077532 A1 WO 2014077532A1 KR 2013009857 W KR2013009857 W KR 2013009857W WO 2014077532 A1 WO2014077532 A1 WO 2014077532A1
Authority
WO
WIPO (PCT)
Prior art keywords
isopropyl
piperazin
piperazine
butan
oxadiazol
Prior art date
Application number
PCT/KR2013/009857
Other languages
English (en)
Korean (ko)
Inventor
양진
김진웅
이한규
김재현
손창모
이규환
최형호
김대훈
최효선
이재걸
Original Assignee
현대약품 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 현대약품 주식회사 filed Critical 현대약품 주식회사
Publication of WO2014077532A1 publication Critical patent/WO2014077532A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating metabolic diseases containing the same as an active ingredient.
  • Type I diabetes also known as insulin dependent diabetes (IDDM)
  • IDDM insulin dependent diabetes
  • Type II diabetes also known as non-insulin dependent diabetes mellitus (NIDDM)
  • NIDDM non-insulin dependent diabetes mellitus
  • Type II diabetes can be characterized by a deficiency in insulin secretion or insulin resistance, ie, people with type II diabetes who have little insulin or are unable to use insulin effectively.
  • diabetes is high levels of glucose accumulate in the blood and urine within the bowl yeojeok, resulting in excessive urination, thirst, baegopum, fat and protein, and i rohyeon: Russia raises issues related ebhls and dysentery metabolism.
  • Such diabetes can cause life-threatening complications such as blindness, kidney failure and heart disease, cause damage to the retina of the back of the eye, and increase the risk of cataracts and glaucoma. It also interferes with the ability to feel pain associated with nerve damage to the legs and feet and can cause serious infections.
  • current treatments for diabetes include insulin, insulin secretagogues, glucose lowering effectors, and activators of peroxysome proliferator-activated receptors (PPARs).
  • PPARs peroxysome proliferator-activated receptors
  • issues related to currently available therapies including hypoglycemia, weight gain, decreased responsiveness to treatment over time, and gastrointestinal edema, are aimed at areas aimed at bringing new, more effective therapies to market
  • GPR119 is a G-protein coupler receptor (GPCR) expressed in the pancreas, small intestine, colon and adipose tissue. Recently, GPR119 Studies have shown that the profile has potential utility for the treatment of obesity and diabetes. GPR119 activation has been demonstrated to stimulate cAMP to induce glucose-dependent GLP-1 and insulin secretion (Non-Patent Document 1). In addition to effects on plasma glucose levels, GPR119 activators have been demonstrated to cause acute food intake in rats after chronic administration and to reduce body weight (Patent Literatures 1 and 2 and Non-Patent Literature 2).
  • GPCR G-protein coupler receptor
  • Patent Documents 4 to 4 it has been reported for a diabetes treatment using aryl, heteroaryl or heterocyclyl derivatives, characterized in that activating IC-GPCR2 or GPR119 as a treatment for type II diabetes associated with insulin resistance (Patent Documents 4 to 4). Patent document 6).
  • Patent Document 1 International Publication No. 2005/007647;
  • Patent Document 2 International Publication No. 2005/007658
  • Patent Document 3 International Publication No. 2004/065380;
  • Patent Document 4 International Publication No. 2008/083238;
  • Patent Document 5 International Publication No. 2008/081206;
  • Patent Document 6 International Publication No. 2008/081208.
  • Non-Patent Document 1 T. Soga et al. , Biochem. B i ophy Res. Commu. 326, (2005), 744-751;
  • Non-Patent Document 2 0 Verton, H.A. et al Cell metabolism 3, (2006), 167-175.
  • An object of the present invention is to provide novel piperazine derivatives, pharmaceutically acceptable salts or optical isomers thereof.
  • the object of the invention is a novel piperazine derivative, To provide a pharmaceutically acceptable salt or a method for preparing the optical isomer thereof.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases, which contains a novel piperazine derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
  • the present invention provides a novel piperazine derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.
  • the present invention provides a novel piperazine derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which comprises a novel piperazine derivative represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
  • novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention have high solubility in water and are excellent in body absorption and low in cytotoxicity compared to the compounds known as GPR119 activators. This is pretty good. Above all, the effect of activating GPR119 to promote cAMP is remarkably excellent, so that the novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention can be treated by activating GPR119 to treat obesity, type I diabetes, It can be usefully used as a pharmaceutical composition for the prevention or treatment of type ⁇ diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.
  • the present invention provides a novel piperazine derivative represented by the following Chemical Formula 1. It provides a pharmaceutically acceptable salt or optical isomer thereof. [Formula 1]
  • A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
  • R is — C00R '; Or unsubstituted or substituted heteroaryl;
  • B is unsubstituted or substituted straight or branched chain alkyl of dC 5 or unsubstituted or substituted d-Cs straight or branched haloalkyl;
  • heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S:
  • R 'or R' ' are each independently hydrogen; Or straight or branched chain alkyl of d-Cs unsubstituted or substituted with one or more hydroxy groups; Or R ′ and R ′ ′ are 1 to together with N to which they are attached
  • n is an integer from 1 to 10.
  • A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
  • heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S;
  • the substituted phenyl is selected from the group consisting of -S (0) 2 R ', -R'S (0) 2 R ", halogen, -R', -C00R ', -CONR'R", and N, 0 and S Phenyl substituted with one or more substituents selected from the group consisting of 5- or 6-membered heteroaryl containing 1 to 4 hetero atoms selected; Wherein R ′ or R ′′ are each independently hydrogen; or straight or branched chain alkyl of dC 5 unsubstituted or substituted with one or more hydroxy groups; or R ′ and R ′′ together with N to which they are attached 1-4 With N, 0 and S A five-member containing heteroatoms selected from the group consisting of
  • the substituted heteroaryl is heteroaryl substituted with —R ′ or —S (0) 2 R ′; Wherein R 'is straight or branched alkyl of dC 5 : more preferably,
  • A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridine;
  • the substituted phenyl is methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl, polouro, chloro, bromo, methyl, ethyl, ethoxycarbonyl, hydroxyisoisopropylaminocarbonyl, dihydroxy Propylaminocarbonyl ,
  • the substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl.
  • substituents selected from the group consisting of methyl, ethyl and methanesulfonyl.
  • R is -C00R '; Or unsubstituted or substituted heteroaryl; Wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S;
  • the substituted heteroaryl is heteroaryl substituted with straight or branched chain alkyl of d-Cs;
  • R is t-butoxycarbonyl; Or unsubstituted or substituted pyrimidine or oxadiazole;
  • the substituted pyrimidine or oxadiazole is heteroaryl substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl isopropyl, butyl and t-butyl.
  • substituents selected from the group consisting of methyl, ethyl, propyl isopropyl, butyl and t-butyl.
  • B is an unsubstituted or substituted d-Cs straight or branched alkyl group; More preferably,
  • B is methyl, ethyl or propyl. Furthermore, in the compound of Formula 1 according to the present invention, A is unsubstituted or substituted phenyl; Or unsubstituted or substituted heteroaryl;
  • heteroaryl is a 5 or 6 membered heteroaryl including 1 to 4 hetero atoms independently selected from the group consisting of N, 0 and S;
  • the substituted phenyl is -S (0) 2 R ', -R'S (0) 2 ", halogen, -R', -C00R '-CONR'R" and 1 selected from the group consisting of ⁇ , 0 and S Phenyl substituted with one or more substituents selected from the group consisting of 5- or 6-membered heteroaryl containing hetero atoms of 4 to 4;
  • the substituted heteroaryl is or heteroaryl substituted with —S (0) 2 R ′; Wherein R 'is straight or branched alkyl of;
  • R is — C00R '; Or unsubstituted or substituted heteroaryl; Wherein said heteroaryl is a 5 or 6 membered heteroaryl comprising 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S;
  • the substituted heteroaryl is heteroaryl substituted with straight or branched chain alkyl of dC 5 ;
  • B is an unsubstituted or substituted d-Cs straight or branched alkyl group; n is an integer of 1 to 5;
  • A is unsubstituted or substituted phenyl; Or unsubstituted or substituted pyridine;
  • the substituted phenyl is methanesulfonyl, methanesulfonylmethyl, 1-methanesulfonylethyl fluoro, chloro, bromo, methyl, ethyl, ecoxycarbonyl, hydroxyisopropylaminocarbonyl, dihydroxypropylamino Carbonyl,
  • the substituted pyridine is pyridine substituted with one or more substituents selected from the group consisting of methyl, ethyl and methanesulfonyl;
  • R is t-subspecific carbonyl; Or unsubstituted or substituted pyrimidine or oxadiazole;
  • the substituted pyrimidine or oxadiazole is heteroaryl substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and t-butyl;
  • B is methyl, ethyl or propyl; And n is an integer of 1-5.
  • n is an integer of 1-5.
  • n is an integer of 1-3.
  • Specific examples of the novel piperazine derivative represented by Chemical Formula 1 are as follows.
  • (21) 1 ′ (4- (6- (methylsulfonyl) pyridin 3-yloxy) butan-2-yl). 4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazine oxalate; (22) l- (4- (3-chloro-4-((methylsulfonyl) methyl) phenoxy) butan-2-yl) -4- (3-isopropyl-1,2,4-oxadiazol -5-yl) piperazine oxalate;
  • (121) (4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -3-fluorophenyl) ( Pyridin-1-yl) methanone;
  • the novel piperazine derivatives represented by Formula 1 according to the present invention can be used in the form of pharmaceutically acceptable salts.
  • acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphoric acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoate alkanedio Obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically toxic salts include sulfated, pyrosulfate 0 bisulfate, sulfite, bisulfite, nitrate phosphate 0 monohydrogen phosphate, dihydrogen phosphate 0 metaphosphate, pyrophosphate chloride, bro ⁇ oiodide, fluoride, acetate, propione ⁇ decanoate, caprylate, acrylate, pome ⁇ isobutyrate, caprate, tempanoate, propionic acid, oxalic acid malonic acid, succinic acid, suverate, Sebacate, fumarate, maleate butene-1,4-dioate, nucleic acid-1,6-dioic acid, benzoic acid, chlorobenzoic acid methylbenzoic acid, dinitrobenzoic acid, hydroxybenzoate, methoxybenzoic acid phthalic acid, terephthalate, Benzenesulfonic acid, toluenesul
  • hydrochloric acid, oxalic acid or trifluoroacetic acid can be preferably used.
  • the acid addition salt according to the present invention is dissolved in a conventional method, for example, an aqueous solution of an excess of acid, and the salt is dissolved in a water miscible organic solvent, such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, inexpensive compound salt filtering, and evaporation and drying of the filtrate.
  • the metal salt it is pharmaceutically suitable to produce lithium, sodium, potassium or calcium salts.
  • Corresponding silver salts are also obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).
  • a suitable silver salt eg silver nitrate
  • Step 2 Preparing a compound represented by Chemical Formula 5 by performing a reaction of reducing the compound of Chemical Formula 4 prepared in Step 1 (Step 2); And coupling the compound represented by Chemical Formula 5 and the compound represented by Chemical Formula 6 prepared in Step 2 to prepare a compound represented by Chemical Formula la (Step 3).
  • Step 3 Provided are methods for preparing the derivatives.
  • step 1 is a step of preparing a compound represented by Chemical Formula 4 by coupling a compound represented by Chemical Formula 2 and a piperidine derivative represented by Chemical Formula 3 with a coupling reaction.
  • the compound of formula (2) and piperazine of formula (3) are dissolved in methane, and then subjected to a reflux stirring to perform a reaction of adding an amine to the alkenyl group of formula (2).
  • the solvent may be used methanol ethane, dichloromethane (DCM) or toluene which does not adversely affect the reaction, methane may be used.
  • step 2 is a step of preparing a compound represented by Formula 5 by performing a reduction reaction of the compound of Formula 4 prepared in Step 1.
  • the solvent may be used tetrahydrofuran (THF), diethyl ether, diphenyl ether or diisopropyl ether (DIPE) that does not adversely affect the reaction, preferably tetrahydrofuran (THF) Can be.
  • THF tetrahydrofuran
  • DIPE diisopropyl ether
  • step 3 is a step of preparing a compound represented by the formula la by coupling the compound represented by the formula (5) and the compound represented by the formula (6) prepared in step 2.
  • a compound of formula la is prepared by performing a Mitsunobu reaction by slowly adding dropwise addition of an azocarboxylate reagent to a solution containing a compound of formula 5, a compound of formula 6, and triphenylphosphine. Step.
  • the azocarboxylate compound that can be used is diethyl azodicarboxylate (DEAD) or
  • Di isopropyl azodi car boxy late may be used, and preferably diisoopropyl azodi car boxy late (DIAD) may be used.
  • the solvent which can be used can use tetrahydrofuran (THF), dichloromethane (DCM), toluene, or acetonitrile which does not adversely affect a reaction,
  • THF tetrahydrofuran
  • DCM dichloromethane
  • acetonitrile which does not adversely affect a reaction
  • tetrahydrofuran THF
  • the method may further include preparing an acid addition salt represented by Chemical Formula 1A by treating the compound with an organic acid or an inorganic acid.
  • the usable organic or inorganic acid may be used oxalic acid hydrochloric acid or trifluoroacetic acid.
  • the solvent which can be used methanol, ethane which does not adversely affect reaction, acetone, acetonitrile or ethyl acetate (EA) can be used, and ethyl acetate (EA) can be used preferably.
  • the present invention is as shown in the following reaction formula 2,
  • Lithium salt of Formula lc prepared in Step 1 and the formula (7) It provides a method for producing a novel piperazine derivative represented by the formula (1) comprising the step of preparing a compound represented by the formula (Id) by performing the compound amidation reaction.
  • Step 1 is a step of preparing a litop salt represented by Chemical Formula lc by reacting a compound represented by Chemical Formula lb and lithium hydroxide.
  • the compound of formula lb is dissolved in a mixed solution of tetrahydrofuran (THF) and distilled water, and then reacted with the addition of lithium hydroxide monohydrate. After the reaction, the undissolved compound is filtered
  • the step 2 is to prepare a compound represented by the formula (Id) by performing an amidation reaction between the lithium salt of the formula (lc) prepared in step 1 and the compound represented by the formula (7) to be.
  • the lithium salt of formula ( 1) prepared in step 1 and the amine compound of formula 7 are dissolved in an organic solvent, an amide reagent is added, and the amidation reaction is performed at room temperature. Step of preparing a compound of Id.
  • the amide reagent is benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium nucleofluorophosphate (Py-
  • BOP 0-benzotriazole- ⁇ , ⁇ , ⁇ , ⁇ -tetramethyl-uronium-nucleus-fluoro-phosphate
  • HBTU 2- (7-aza-in-benzotriazol-1-yl)- 1,1,3,3- Tetramethyluronium nucleus fluorophosphate
  • HOBt 1-hydroxybenzotriazole
  • DCC dicyclonucleosilcarbodiimide
  • EDC 1-ethyl— 3- (3-dimethylaminopropyl) carbodiimide
  • CDI carbonyldiimidazole
  • 1-ethyl-3- (3—dimethylaminopropyl) carbodiimide (EDC) and 1-hydroxybenzotriazole ( HOBt) can be used together.
  • the usable organic solvent may be reacted using methanol, tetrahydrodurofuran (THF), dimethylformamide, dichloromethane or tolueneol, which does not adversely affect the reaction.
  • Dichloromethane (DCM) can be used.
  • the present invention as shown in the following reaction formula 3,
  • Step 1 is a step of preparing a compound represented by Chemical Formula 9- (S) by reacting a compound represented by Chemical Formula 8- (S) with t-butyldimethylsilyl chloride (TBSC1) (Step 1).
  • the step of protecting the hydroxy group of the compound represented by the formula (8) by reacting t-butyldimethylsilyl chloride (TBSC1) with a compound of the formula (8) in the S- form in the presence of a base.
  • the base usable in the reaction may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIPEA), pyridine or imidazole, and preferably imidazole may be used.
  • usable solvents include tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene or benzene. May be used, preferably dichloromethane (DCM).
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • DMS0 dimethylsulfoxide
  • DCM dichloromethane
  • chlorobenzene toluene or benzene. May be used, preferably dichloromethane (DCM).
  • step 2 of the formula 9- (S) prepared in step 1 A compound and methanesulfonyl chloride (MsCl) are reacted to prepare a compound represented by Chemical Formula 10- (S).
  • the base usable in the reaction may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine (DIPEA), pyridine or imidazole, preferably triethylamine (TEA) Can be used.
  • TAA triethylamine
  • DEA diethylamine
  • DIPEA diisopropylethylamine
  • pyridine preferably triethylamine (TEA) Can be used.
  • Step 3 is a step of preparing a compound represented by Chemical Formula 11-0?) By reacting the compound represented by Chemical Formula 10- (S) and Chemical Formula 3 prepared in Step 2.
  • the usable organic solvent may use tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) or dichloromethane (DCM), preferably dimethyl Formamide (DMF) can be used.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • DMSO dimethyl sulfoxide
  • DCM dichloromethane
  • DMF dimethyl Formamide
  • step 4 is a step of preparing a compound represented by the formula (5-) by performing a deprotection reaction of the compound represented by the formula (ll- (R) prepared in step 3.
  • the protected hydroxy group present at the terminal of the compound of formula 11 in which the stereostructure prepared in step 3 is R-form is deprotected using tetrabutylammonium fluoride (TBAF).
  • TBAF tetrabutylammonium fluoride
  • the usable organic solvent may be methanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMS0) or acetonitrile, preferably tetrahydrofuran (THF) can be used.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMS0 dimethyl sulfoxide
  • acetonitrile preferably tetrahydrofuran (THF) can be used.
  • reaction is not particularly limited, but may be used within the range of room temperature to reflux temperature of the solvent. 7
  • step 5 is a step of preparing a compound represented by Formula 1- (R) by performing a coupling reaction of the compound represented by the formula 5-00 and the compound represented by the formula (6) prepared in step 4.
  • the azocarboxylate reagent is slowly added dropwise to the solution of the compound of Formula 5, the compound of Formula 6, and triphenylphosphine having the R-form conformation prepared in Step 4 to react Mitsunobu (Mitsi by performing an obu reaction) to prepare a compound of formula 1 having a R-form conformation.
  • the azocarboxylate compound that can be used is diethyl azodicarboxylate (DEAD) or
  • Diisopropyl azodi 7 carboxylate (di i sopropy 1 azodi carboxy 1 ate, DIAD) may be used, preferably di isoprop azodicarboxylate (di i sopropy 1 azodi car boxy late, DIAD) Can be used.
  • the usable solvent may be tetrahydrofuran (THF), dichloromethane (DCM), toluene or acetonitrile, which does not adversely affect the reaction, preferably tetrahydrofuran (THF) may be used.
  • THF tetrahydrofuran
  • the present invention is prepared by reacting the compound represented by the formula 8- (R) and t- butyl dimethylsilyl chloride (TBSC1) as shown in Scheme 4 to prepare a compound represented by the formula 9-(R) Step (step 1);
  • step 5 To prepare a compound represented by the formula 1- (S) by performing a coupling reaction between the compound represented by the formula (5-) and the compound represented by the formula (6) prepared in step 4 (step 5); Provided is a method for preparing a novel piperazine derivative represented by the formula (1).
  • the method of preparing Banung Formula 4 is a method for preparing S-isomers of the piperazine derivatives according to the present invention, and instead of using the compound of Formula 8 having a S-form conformation in the preparation method of Banung Formula 3. Except for using the compound of formula (8) in which the stereostructure is in the R- form was carried out in the same manner as the reaction conditions described in Scheme 3.
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which comprises a novel piperazine derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.
  • GPR119 is a common G-form found in the pancreas, small intestine, colon and adipose tissue With receptors bound to proteins (GPCR), the GPR119 expression profile has potential utility for the treatment of various metabolic diseases including obesity and diabetes.
  • GPCR receptors bound to proteins
  • novel piperazine derivatives represented by Formula 1 according to the present invention, pharmaceutically acceptable salts thereof, or optical isomers thereof have an excellent effect of activating the GPR119 receptor, thereby stimulating cAMP.
  • Experimental Example 3 the water solubility in water is excellent in the body absorption rate, the cardiac toxicity and cytotoxicity is significantly lower than the conventionally known GPRU9 activator, so there is no side effect, the stability to the human body is quite high (Experimental Examples 4 to 6 ). Therefore, the novel piperazine derivatives, pharmaceutically acceptable salts thereof or optical isomers thereof according to the present invention have excellent absorption in the body, high stability to the human body, and an effect of activating GPR119, a receptor associated with metabolic diseases.
  • the metabolic diseases include, for example, obesity, type I diabetes, type ⁇ diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, X syndrome Can be mentioned.
  • the compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, it is prepared using diluents or excipients such as filler extenders, binders, wetting agents, disintegrants, surfactants, etc., which are commonly used. do.
  • Solid preparations for oral administration include politics, patients, powders, granules, capsules, troches, and the like, which may comprise at least one excipient such as starch, calcium carbonate, water, or the like. Prepared with a mixture of sucrose or lactose (1 actose) or 3 ⁇ 4 latin. In addition to simple excipients, lubricating seeds such as magnesium styrate talc are also used.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions or syrups.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be used. Can be.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl acrylate and the like can be used.
  • a suppository base witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
  • the effective dosage of the compound of the present invention to the human body is generally about 0.001-100 mg / kg / day, preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, typically 0.0 7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals depending on the physician's or pharmacist's observations. It can also be administered in divided doses.
  • a target compound was obtained in the same manner as in Production Example 2, except that 4- (methylthio) -m-cresol was used instead of 3-fluoro-4— (methylthio) phenol.
  • a target compound was obtained in the same manner as in Preparation Example 1, except that 4-bromo-2,6-difluorophenol was used instead of 4-bromo-2-fluorophenol.
  • the target compound was prepared in the same manner as in Preparation Example 2, except that 3,5-difluoro-4— (methylthio) phenol was used instead of 3-fluoro-4- (methylthio) phenol. Got it.
  • a target compound was obtained in the same manner as in Preparation Example 15, except that 4-aminophenol was used instead of 4-amino-2-fluorophenol.
  • a target compound was obtained in the same manner as in Preparation Example 15, except that 4-amino-3-fluorophenol was used instead of 4-amino-2-fluorophenol.
  • a target compound was obtained in the same manner as in Preparation Example 15, except that 4-amino-3,5-difluorophenol was used instead of 4-amino-2-fluorophenol.
  • a target compound was obtained in the same manner as in Preparation Example 19, except that 3-fluoro-4-hydroxybenzoic acid was used instead of 2-fluoro-4-hydroxybenzoic acid.
  • Step 1 Preparation of t-butyl-4- (4-methoxy-4—oxobutan-2-yl) piperazine-1-carboxylate
  • Methyl crotonate (3.3 g) and methane (50 mL) were added and dissolved in a 100 mL flask under nitrogen atmosphere, and then t_butyl-1-piperazine carboxylate (5 g) was added dropwise. More than 24 hours The reflux was stirred. When the reaction was terminated, the solvent was removed by concentration under reduced pressure, and purified by silica column chromatography to obtain a wood compound.
  • Lithium aluminum hydride (LAH, 880 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 mL flask under nitrogen atmosphere, and then the above step was added to tetrahydrofuran (THF, 50 mL).
  • THF tetrahydrofuran
  • the solution of compound (2.7 g) prepared in 1 was slowly added dropwise to the flask for 5 minutes.
  • 1M-sodium hydroxide (50 mL) was slowly added dropwise, extracted with ethyl acetate (40 mL), and washed with brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the target compound.
  • step 2 In a 100 mL flask under a nitrogen atmosphere, the compound (0.4 g), triphenylphosphine (PPh 3 , 0.63 g), 4- (methylsulfonyl) phenol (0.35 g) and tetrahydrofuran (THF) prepared in step 2 were prepared. Was added and stirred to dissolve. The reaction when slowly added dropwise in the reaction ⁇ diisopropylamino 0 1, crude dimethyl ⁇ 1 "Le butyl (di isopropyl azodi carboxyl ate, 0.5 mL) to 0 ° C and stirred at for 12 hours or more at room temperature.
  • triphenylphosphine PPh 3 , 0.63 g
  • 4- (methylsulfonyl) phenol (0.35 g)
  • THF tetrahydrofuran
  • Lithium aluminum hydride (LAH 900 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 ml flask under nitrogen atmosphere, and then, in step 2 above, in tetrahydrofuran (THF, 50 mL).
  • a solution of the prepared compound (2.7 g) was slowly added dropwise to the flask for 5 minutes.
  • 1M-sodium hydroxide (50 mL) was slowly added dropwise, extracted with ethyl acetate (40 mL), and washed with brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the target compound.
  • step 3 the compound (2 g) ol dichloromethane (DCM, 100 mL) prepared in step 3 was stirred and dissolved, triethylamine (TEA, 1.2 mL) was added, Ponyl chloride (0.6 mL) was slowly added dropwise at 0 ° C. After the addition was completed, the mixture was stirred for 30 minutes, extracted with dichloromethane (DCM, 40 mL), and washed with brine (100 mL). The washed compound was dried over anhydrous magnesium sulfate and concentrated to obtain the target compound.
  • DCM dichloromethane
  • the target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 5 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
  • Step 1 Preparation of t-butyl-4-cyanopiperazine-1-carboxylate Piperazine-1-carboxylic acid t-butylester (10 g), acetonitrile (50 mL) and distilled water (50 mL) were injected, then cooled to 0 ° C. and stirred to dissolve. Sodium bicarbonate (6 g ) and cyanogenbromide (6.3 g) were slowly added to the flask. Then isothermally stirred to 50 ° C. and stirred for 3 hours. After the reaction was completed, the pH was neutralized at 1 ° C.
  • Methyl crotonate (3.3 g) and methanol (50 mL) were added and dissolved in a 100 ml flask under nitrogen atmosphere.
  • the compound (5 g) prepared in Step 2 was added dropwise and stirred under reflux for 24 hours. It was. When the reaction was terminated, the solvent was removed by concentration under reduced pressure, and purified by silica column chromatography to obtain the target compound.
  • Lithium aluminum hydride (LAH, 900 mg) was dissolved in tetrahydrofuran (THF, 50 mL) at 0 ° C. in a 100 ml pool flask under nitrogen atmosphere, and then dissolved in tetrahydrofuran (THF, 50 mL).
  • THF tetrahydrofuran
  • the solution of compound (2.7 g) prepared in step 3 was slowly added dropwise to the flask for 5 minutes.
  • 1M-Saturated Hydroxide 50 mL was slowly added dropwise, extracted with ethyl acetate (40 mL), and washed with brine (100 mL). The washed organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the target compound.
  • Example 9 The compound (200 mg) prepared in Example 9 was dissolved in ethyl acetate (10 mL), and then the same equivalent number of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
  • the target compound was obtained in the same manner as in Example 6, except that 4- (methylsulfonyl) phenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.
  • the extracted organic layer was washed with brine (40 mL), dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography.
  • the purified compound was dissolved in ethyl acetate (EA, 10 mL) again and stirred under reflux for 30 minutes by adding the same equivalent number of oxalic acid dropwise. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
  • the target compound was obtained in the same manner as in Example 19, except that 4N-hydrochloric acid (1,4-dioxane solution) was used instead of oxalic acid in Example 19.
  • the target compound was prepared in the same manner as in Example 6, except that 3-chloro-4-methanesulfonylmethylphenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6.
  • H R R 400 Hz, D 2 0
  • 6 7.35 (lH, d), 7.09 (lH, d) 6.90 (lH, dd)
  • Example 6 The above procedure was performed in step 6 of Example 6, except that 3-chloro-4-methanesulfonylmethylphenol was used instead of the compound prepared in Preparation Example 2, and hydrochloric acid was used instead of oxalic acid.
  • the target compound was obtained in the same manner as in Example 6.
  • the target compound was prepared in the same manner as in Example 6, except that 4-methanesulfonylmethyl-2-methylphenol was used instead of the compound prepared in Preparation Example 2 in Step 6 of Example 6. Got it.
  • the target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 2 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
  • the compound (1.4 g) prepared in step 2 and dimethylformamide (DMF, 40 mL) were injected and stirred to dissolve, followed by sequentially preparing the compound prepared in Preparation Example 25 (1.3 g) and potassium carbonate (1 g) were added and isothermalized to 5 C C and stirred for 24 h.
  • the temperature was cooled to room temperature, distilled water (30 mL) was added slowly, and extracted with ethyl acetate (EA, 100 mL). The extracted organic layer was washed three times with distilled water (20 mL), dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the target compound.
  • Step 5 l-((R) -4- (3-fluoro-4- (methylsulfonyl) phenoxy) butan-2-yl) -4- (3-isopropyl—1,2,4-oxa Preparation of Diazol-5-yl) piperazine oxalate
  • the target compound was obtained in the same manner as in Example 27, except that hydrochloric acid was used instead of oxalic acid in Step 5 of Example 27.
  • Example 3 and Example 3 except that using the compound prepared in Preparation Example 2 instead of 4- (methylsulfonyl) phenol in Example 5, and using hydrochloric acid instead of oxalic acid
  • the target compound was obtained by the same method.
  • the target compound was obtained in the same manner as in Example 4, except that 3-chloro-4-methanesulfonylmethyl-phenyl was used instead of the compound prepared in Sezo Example 5 in Example 4.
  • Example 30 The compound prepared in Example 30 was dissolved in ethyl acetate (EA mL), and then the same equivalent number of oxalic acid was added dropwise and stirred under reflux for 30 minutes. After the reaction was completed, the temperature was cooled to room temperature, and the solid was filtered to obtain the target compound.
  • EA mL ethyl acetate
  • Example 6 except for using the compound prepared in Preparation Example 14 instead of using the compound prepared in Preparation Example 2 in Example 6, using trifluoroacetic acid instead of using oxalic acid
  • the target compound was obtained by the same method as the method of 6.
  • Example 6 except that the compound prepared in Preparation Example 14 is used instead of the compound prepared in Preparation Example 2, and hydrochloric acid is used instead of oxalic acid.
  • the target compound was obtained by the method.
  • Example 6 instead of using the compound prepared in Preparation Example 2 in the step 6 of Example 6 except for using trifluoroacetic acid instead of using oxalic acid
  • the target compound was obtained by the same method as the method of 6.
  • Example 6 in the same manner as in Example 6 except for using the compound prepared in Preparation Example 7 instead of using the compound prepared in Preparation Example 2, and instead of using the oxalic acid in step 6 of Example 6
  • the target compound was obtained by the method.
  • Example 6 except that the compound prepared in Preparation Example 10 is used instead of the compound prepared in Preparation Example 2, and hydrochloric acid is used instead of oxalic acid.
  • the target compound was obtained by the method.
  • Example 40 (4- (5-methyl-6- (methylsulfonyl) pyridin-3-yloxy) butan-2-yl) -4- (3-isopropyl-1,2, 4- Preparation of oxadiazole-5-yl) piperazine oxalate
  • the target compound was obtained in the same manner as in Example 3, except that the compound prepared in Preparation Example 19 was used instead of 4- (methylsulfonyl) phenol in Step 5 of Example 3.
  • Example 44 Into a 100 ml flask under nitrogen atmosphere, the compound (310 mg) and dichloromethane (DCM, 50 mL) prepared in Example 44 were injected, stirred, and dissolved, and then 1-ethyl-3— (3-dimethylaminopropyl).
  • Carbodiimide hydrochloride (EDCI, 170 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 120 mg) ol were added and stirred for 30 minutes. Then 2-amino-1,3-propanediol (100 mg) ol was added and stirred at silver for 5 hours.
  • Example 45 In the same manner as in Example 45, except that (R)-(-)-2-amino-1-propanol was used instead of 2-amino-1,3-propanediol in Example 45. This was carried out to obtain the target compound.
  • Example 46 The same method as in Example 46, except that (R)-(-)-2-amino-1-propanol is used instead of 2-amino-1,3-propanediol in Example 46.
  • the title compound was obtained by the following procedure.
  • Example 45 The same procedure as in Example 45 was performed except that (R) -3 amino-1,2-propanedi was used instead of 2-amino-1,3-propanedi in Example 45. The compound was obtained.
  • Example 51 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -2-fluoro-N Preparation of-(l, 3-dihaadoxypropane-2-yl) benzamide oxalate
  • Example 42 Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 42 (600 mg) and dichloromethane (DCM, 50 mL) were added, stirred, and dissolved, and then 1-ethyl-3- (3-dimethylaminopropyl).
  • Example 42 Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 42 (600 mg) and dichloromethane (DCM, 50 mL) were added, stirred, and dissolved, and then 1-ethyl-3- (3-dimethylaminopropyl).
  • Example 51 The same method as in Example 51, except that (R) — ( ⁇ )-2-amino-1-propane is used instead of 2-amino-1,3—propanediol in Example 51.
  • the title compound was obtained by the following procedure.
  • Example 54 4- (3- (4- (3-isopropyl-1,2,4-oxadiazole-5) Preparation of 1) piperazin-1xyl) butoxy) -2-fluoro-N-((R) -1-hydroxypropan-2-yl) benzamide hydrochloride
  • Example 52 was carried out in the same manner as in Example 52, except for using (R)-(-)-2-amino-1-propanolol instead of using 2-amino-1,3-propanedi To obtain the target compound.
  • Example 55 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-yl-yl) particular) -2-fluoro-N Preparation of-((R) -2,3-dihydrotoxapropyl) benzamide oxalate
  • Example 51 was carried out in the same manner as in Example 51, except for using (R) -3 -amino-1,2-propanediol instead of 2-amino-1,3-propanedi The desired compound was obtained.
  • Example 52 The same procedure as in Example 52 was conducted except that 00-3-amino-1,2-propanediol was used instead of 2-amino-1, 3-propanediol in Example 52. The compound was obtained.
  • the target compound was obtained in the same manner as in Example 52, except for using pyrrolidine instead of using 2-amino-1,3-propanedi in Example 52.
  • Example 59 In a 100 mL flask under a nitrogen atmosphere, the compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 59 were charged and dissolved by stirring. Lithium hydroxide monohydrate (170 mg) was then added to the reaction and stirred for 18 hours at phase silver. At the end of the reaction, the solvent was concentrated, dissolved in dichloromethane (DCM, 50 mL) and the insoluble solid was filtered off. The filtrate was concentrated and solidified using diethyl ether and nucleic acid to obtain the target compound.
  • DCM dichloromethane
  • Example 62 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) butoxy) -N-((R) Preparation of -l-hydroxypropan-2-yl) benzamide hydrochloride
  • Example 60 Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Example 60 (600 mg) and dichloromethane (DCM, 50 mL) were dissolved by stirring, and dissolved in 1-ethyl-3- (3-dimethylaminopropyl). Carbodiimide hydrochloride (EDCI, 420 mg) and 1-hydroxybenzotriazole monohydrate (KOBt, 290 mg) were added and stirred for 30 minutes. Then (R)-(-) — 2-amino-1-propanol (200 mg) was added and stirred at room temperature for 5 hours.
  • DCM dichloromethane
  • Example 61 above except for using (R) -3-amino-1,2-propanedi instead of using (R)-(-)-2-amino-1-propanol
  • the target compound was obtained by the same method.
  • Example 64 4- (3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin-1-yl) particular) -3-fluoro-N Preparation of-((S) -2,3-dihydroxypropyl) benzamide trifluoroacetate
  • Example 62 above except for using (R) -3-amino-1,2-propanediol instead of using (R)-(-)-2-amino— 1-propane
  • the target compound was obtained by the same method as the method of 62.
  • Example 61 Except for using (R)-(-)-2-amino-1-propane in Example 61 was carried out in the same manner as in Example 61 to obtain the target compound.
  • Example 62 Except for using (R)-(-)-2-amino-1-propanol in Example 62 was carried out in the same manner as in Example 62, except that pylinol was used to obtain the target compound.
  • Example 61 Except for using 2-amino-1,3-propanedi instead of using (R)-()-2-amino-1-propanol in Example 61, The target compound was obtained in the same manner as in Example 61.
  • H ⁇ R 400 Hz, D 2 0: ⁇ 7.50 (2H, m), 7.10 (1H, t), 4.30 (lH, m), 4.20 (2H, m), 4.10 (2H, m), 3.74 (3H, m), 3.62 (2H, t), 3.43 (2H, t), 2.82 (lH, m), 2.30 (lH, m), 2. ll (lH, m), 1.35 (3H, d), 1.10 (6 H, d).
  • Example 70 4- (3- (4- (3-isopropyl-l, 2,4-oxadiazol-5-yl) piperazin-l-yl) butoxy) -3-pullouro- Preparation of N- (l, 3-dihydroxypropane-2-yl) benzamide hydrochloride
  • Example 62 was carried out in the same manner as in Example 62, except that 2-amino-1,3-propanedi was used instead of (R)-(-)-2-amino-1-propanolol. To obtain the target compound.
  • Example 61 above except for using (S) -3-amino-1,2-propanedi instead of using (R)-(-)-2-amino-1-propane
  • the target compound was obtained by the same method as described above.
  • a target compound was obtained by the same method as described in 6, except that the compound prepared in Preparation Example 10 was used instead of the compound prepared in Preparation Example 2.
  • Step 2 Into a 100 mL flask under nitrogen atmosphere, the compound prepared in Step 2 (1.4 g) and dimethylformamide (DMF, 40 mL) were injected and stirred to dissolve, followed by the compound prepared in Preparation Example 25 (1.3 g) and potassium carbonate (1 g) were added and isothermalized at 50 ° C. and stirred for 24 h.
  • the temperature was cooled to room temperature, distilled water (30 mL) was added slowly, and extracted with ethyl acetate (EA, 100 mL). The extracted organic layer was washed three times with distilled water (20 mL), dried over anhydrous magnesium sulfate, concentrated and purified by silica column chromatography to obtain the target compound.
  • EA ethyl acetate
  • Step 5 ethyl 4- (00—3- (4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperazin— 1-yl) butoxy) -2-fluorobenzo Preparation of ate oxalate
  • the compound (600 mg), potassium carbonate (360 mg) and dimethylformamide (DMF, 30 mL) prepared in step 4 were added thereto, stirred, and dissolved.
  • Compound (350 mg) prepared in 19 was added and silver was isothermally stirred to 70 ° C.
  • Distilled water (20 ml) was added slowly and extracted with ethyl acetate (EA, 60 mL).
  • Example 73 Into a 100 mL flask under a nitrogen atmosphere, the compound (200 mg), tetrahydrofuran (40 mL) and distilled water (20 mL) prepared in Example 73 were injected and stirred to dissolve. Then, lithiumhydride-side monohydrate (170 mg) was added to the reaction product and stirred for 18 hours at phase silver. At the end of reaction, the solvent was concentrated and then dissolved in dichloromethane (DCM, 50 mL) and the insoluble solid was filtered off. The filtrate was concentrated and solidified with diethyl ether and nucleic acid to obtain the target compound.
  • DCM dichloromethane
  • Example 60 Prepared in Example 60 above in a 100 mL flask under nitrogen atmosphere Compound (600 mg) and dichloromethane (DCM, 50 mL) were injected and stirred to dissolve, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 420 mg) and 1 -Hydroxybenzotriazole monohydrate (KOBt, 290 mg) was added and stirred for 30 minutes. Then (R) -3-amino- 1,2-propane was added (200 mg) and stirred for 5 hours at phase silver.
  • DCM dichloromethane
  • Example 73 except that (S)-(+) -l, 3-butanediol was used instead of (R)-(-)-l, 3-butanedi in Example 73.
  • the target compound was obtained by the same method.
  • Example 74 was carried out in the same manner as in Example 74, except that the compound prepared in Example 72 was used instead of the compound prepared in Example 73, to obtain the target compound.
  • the target compound was obtained in the same manner as in Example 75, except that the compound prepared in Example 77 was used instead of the compound prepared in Example 74.
  • HIT-T15 cells Korea Cell Line Bank
  • beta cells derived from hamsters containing GPR-119 were used to accumulate intracellular cAMP activation due to stimulation of GPR119.
  • 60,000 HIT-T15 cells were plated per well in 96-well plates. The day after plating, cells were treated with various concentrations of the compounds according to the invention and incubated at 37 ° C. for 1 hour. At this time, the compound to be treated was treated at a concentration of 6 in the range of 0.0032 to 10 ⁇ .
  • cAMP activity was measured using the cAMP dynamic kit from Cis Bio (Bedford, Mass.) according to the manufacturer's instructions. Cells were lysed and cAMP levels were measured by competitive immunoassay using D2 labeled cAMP and cryptate labeled anti cAMP antibodies. Fluorescence was read by Flex Station (Molecular Devices). D2 and cryptate showed fluorescence resonance energy transfer (FRET) when very close, and were measured at a fluorescence ratio of 665 nm / 620 nm. Unlabeled c P in cell lysate was cryptate labeled The antibody competed with D2 labeled cAMP.
  • FRET fluorescence resonance energy transfer
  • FRET Fluorescence Resonance Energy Transition
  • the activity of the compound was calculated to the extent of fluorescence resonance energy transfer (FRET) signal change through the amount of dimethyl sulfoxide (DMS0).
  • FRET fluorescence resonance energy transfer
  • the compounds according to the invention were shown to activate cAMP.
  • the 74 compounds evaluated for activating cAMP more than half of the compounds of about 55> were found to have EC 50 values of 2 ⁇ M or less, particularly in Examples 1, 4, 6, 8, 12, 15, 17 , 18, 20, 22-24, 27, 28, 31 33-35, 41, 50, 53-55, 57, 58, 73 and 75 compounds have EC 50 values in nanomolar units of 1 ⁇ or less appear.
  • piperazine derivatives according to the present invention as a GPR119 receptor it can be seen that the effect of activating cAMP is excellent.
  • the L- piperazin derivative according to the present invention is excellent in activating cAMP and can be treated by activating J GPR119, obesity, type I diabetes mellitus, inadequate glucose tolerance, It can be usefully used as a pharmaceutical composition for the prevention or treatment of insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.
  • Experimental Example 2 Evaluation of cAMP Activity in CH0-K1 Cells Overexpressing GPR119 Receptor
  • CH0 cells were plated in 96-well plates with RPMI (Wel lgene) medium containing 100 ⁇ L of 10% FBS, 100 ug / ml penicillin (penici 1 ⁇ ), and 100 ⁇ g / ml streptomycin. Plated at 4 cells / well. Then, the plasmid expressing human GPRU9 in pCMV6-XL5 vector (Origene, C216685) and the plasmid expressing GPR119 in mouse (Origene, MR224908) were transferred to the CH0 cells using FuGENE6 reagent (Promega, E2311). Transfection.
  • RPMI Wel lgene
  • HBSS Hanks buffered salt solut ion, welgene, LB containing 5 mM HEPES (Gibco, 15630-106), 0.5 mM IBMX (sigma, 15879) and 0.1% BSA (sigma, A7030). 003-03) was incubated in a C0 2 incubator for 10 minutes.
  • Compounds according to the invention in HBSS medium were diluted to various concentration ranges (10, 2, 0.4, 0.08, 0.16, 0.0032 ⁇ ), treated to cells and incubated in a 37 ° C., CO 2 incubator for 90 minutes.
  • Instant cAMP was measured using two step protoc in HTRF (Homogeneous Time-Resolved Fluorescence, CISBI0, 62AM4PEB) technique.
  • the cAMP-d2 and anti-cAMP cryptate conjugates were mixed in the cells and reacted in the silver for 3 hours, followed by fluorescence (f hiorescence, excitation wavelength: 337 nm) using flexation (Flexstat ion, Molecular Devices). , Emission wavelength: 665 nm, 620 nm).
  • the result was calculated as ⁇ F () value as the control group was not activated, converted to EC 50 (y M) value using the degree of activation (%) by treatment with the compoundol according to the present invention, 3 is shown.
  • the piperazine derivatives according to the present invention are used in both human and mouse GPR119 overexpressed cell lines. It has been shown to have an effect of activating cAMP.
  • the compound of Example 75 (R-form), which is the structural isomer of Example 55 was shown to have an EC 50 value with nanomolar units, whereas the compound (S-form) of Example 78 was from 2 y M to 4 It was found to have an EC 50 value of ⁇ ⁇ . From this, it can be seen that the piperazine derivatives according to the present invention have an excellent effect of promoting GPR119 in humans and mice, and thus the cAMP promoting effect is excellent.
  • Example 55 which is a racemate prepared according to the present invention, and the structural isomers thereof, through the EC 50 value of the compounds of Examples 75 (R-form) and Example 78 (S-form) It can be seen that the R-form structural isomer has a better effect of activating cAMP than the -form structural isomer. Therefore, the novel piperazine derivatives according to the present invention have an excellent effect of activating cAMP by promoting GPR119, and thus, obesity, type I diabetes, type II diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, It can be usefully used as a pharmaceutical composition for the prevention or treatment of hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia or syndrome X.
  • Experimental Example 3 Oral Glucose Tolerance Test Oral Glucose Tolerance Test;
  • glucose (2 g / kg) was orally administered at a dose of 10 mL / kg.
  • Blood glucose was measured using Accusek Active Co., Ltd. (Rosche diagnostic Co.) and measurement time was measured by puncture of the microvenous veins at -30, 0, 20, 40, 60 and 120 minutes based on the time of glucose administration. The results are shown in Table 4 below.
  • the compounds according to the present invention were found to have an AUC (area under curve) drop effect of about 16 to 23%.
  • the compounds of Comparative Examples 1 to 3, which are conventionally known as an activator of GPR119 were found to have an AUC (area under curve) strengthening effect of 16% or less compared to the compound according to the present invention. From this, it can be seen that the piperazine derivatives according to the present invention have considerably superior AUC (area under curve) lowering effects compared to the compounds known as activators of the conventional GPR119. Therefore, the novel piperazine derivatives according to the present invention have an excellent effect of activating cAMP by promoting GPR119.
  • obesity can be usefully used as a pharmaceutical composition for the prevention or treatment of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.
  • Piperazine Derivative Salt of Example 75 was dissolved in distilled water at a concentration of 2 mg / mL, transferred to a vial, decomposed for about 1 hour, and then 300 for about 24 hours. Shake at rpm and mix. Thereafter, the solution is centrifuged at 10000 rpm at 25 ° C for 10 minutes, the supernatant is filtered and transferred to the vial to prepare a test solution.
  • a sample solution was prepared at a concentration of 2.5 mM, diluted in 1/10 times methyl alcohol, and then diluted 1/2 fold sequentially to prepare calibration solutions having five different concentrations.
  • the solubility of the piperazine derivative prepared in Example 75 according to the present invention was 5267 ⁇ , and the pharmaceutically acceptable salt thereof was more than 25000 ⁇ in water.
  • Comparative Examples 1 and 2 which are conventionally known as GPR119 activators, the solubility in water was markedly low. From this, it can be seen that the piperazine derivatives according to the present invention are remarkably superior in solubility in water to at least 3000 times compared to the compounds known in the art as GPR119 activators.
  • the novel piperazine derivatives according to the present invention not only have an excellent effect of activating GPR119 and promoting c P, but also have a superior solubility in water as compared to a compound known as a GPR119 activator.
  • Absorption, type I diabetes, type ⁇ diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, or X which can be treated by activating GPR119 due to its excellent absorption rate. It can be usefully used as a pharmaceutical composition for the prevention or treatment of syndrome.
  • HEK293 human embryonic kidney 293 cells in which the expression of the HERG channel was stably maintained, and the inhibition level of the HERG channel were confirmed by the positive control group, astemizole.
  • the method of measuring the total cell current includes a convexial patch-clamp technique or a port-a-patch (Nanion germany) semi-passive technique, which measures the microcurrent through the cell membrane.
  • the composition of the extracellular perfusion solution and the intracellular perfusion solution used in the experiment is as follows.
  • the extracellular perfusion solution was formulated with 136 mM sodium chloride (NaCl), 5.4 mM potassium chloride (KCl), 1.8 mM calcium chloride (CaCl 2 ), 1 mM magnesium chloride (MgCl 2 ), 10 mM glucose and 10 mM HEPES and then with sodium hydroxide. Titrated to pH 7.4.
  • the intracellular perfusion pipette solution was formulated with 130 mM potassium chloride (KCl), 1 mM magnesium chloride (MgCl 2 ), 10 mM EGTA, 5 mM magnesium-ATP and 10 mM HEPES, and titrated to pH 7.2 with potassium hydroxide.
  • Patch pipettes for conventional patch-clamp techniques were pulled with a PP-83 pipette puller (Nar ishige, Tokyo, Japan) and exhibited a resistance of 2-4 ⁇ to external perfusion solutions.
  • the resulting ion current was described in EPC7 plus am l f iers (HEKA electronic, Germany).
  • the pCl amp computer progr am (Axon Instruments, USA) was used for voltage one-clamp amplification control, data collection, and analysis.
  • the solution was continuously perfused through HEK 293 cells through the chamber.
  • Port-a-Patch (Nanion, Germany)
  • the recording of the semi-automatic patch recording system follows the procedure recommended by Nan ion and the amplifier is EPC10 (HEKA electronic, Germany).
  • the membrane potential was maintained at -80 mV. It moved to +20 mV for 4 seconds and back to -80 mV after moving to -50 mV for 6 seconds. This process was repeated every 25 seconds.
  • the compounds of the comparative example as GPR119 activators have a significant effect of inhibiting the HERG channel, which is important for cardiac toxicity such as arrhythmia, from which the compounds according to the present invention are known.
  • Rae jin can be an example, indicating that cardiac toxicity, such as arrhythmia, is 2-20 times or more lower than GPR119 activator. Therefore, the novel piperazine derivative according to the present invention activates GPR119, and not only has an excellent effect of promoting cAMP, but also significantly lowers cardiac toxicity compared to a compound known as a GPR119 activator.
  • compositions for the prevention or treatment of obesity, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X It can be usefully used as a red composition.
  • the setting is 23 ⁇ 3 ° C, humidity is 55 ⁇ 15%, illuminance is 150-300 Lux, ventilation rash
  • Feed is a laboratory animal feed pellets for sterilization by radiation received (5L79 Lab Diet, Purina Mills, Rich ⁇ mond, IN, USA) the Orient supplied from Bio-free, and to consume water is UV sterilizer, and microfiltration device to be water After sterilization, free sawing was ingested using a water bottle. Water and feed pollutants were inspected in accordance with the relevant SOP of CamOn Co., Ltd.
  • the compound of Example 55 was diluted in excipients (0.5% CMC) at a concentration of 2000 mg / kg, and the test substance was administered intragastricly once a day using a mouse zonde to 5 populations. Twice a day, the general condition, intoxication and death of the animals were observed. The results showed that the LD 50 value of the female ICR mice was more than 2 g / kg. From this, the piperazine derivatives according to the present invention can be seen that the cytotoxicity is very low.
  • the novel piperazine derivatives according to the present invention activate GPR119, and not only have an excellent effect of promoting cAMP, but also have low cytotoxicity and thus have high stability in the human body, obesity treatable by activating GPR119, type I diabetes mellitus. , ⁇ type diabetes mellitus, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, or X-syndrome can be usefully used as a pharmaceutical composition for the prevention or treatment of syndrome.
  • the piperazine derivative of Chemical Formula 1 according to the present invention may be formulated in various forms. The following illustrates a method in which the piperazine derivative represented by 1 according to the present invention is contained as an active phase, and the present invention is not limited thereto.
  • Talc 10 mg The above ingredients are combined and layered in an airtight cloth to prepare a powder.
  • Magnesium stearate 2 nig After mixing the above components and tableting according to the conventional manufacturing method of the tablet to prepare a tablet.
  • Magnesium stearate 2 mg A capsule is prepared by mixing the above ingredients and layering the gelatine capsules according to a conventional capsule preparation method.
  • pH adjuster amount Amount (2) per one ampoule is prepared according to the conventional method for preparing an injection. 1-5. Preparation of liquid
  • Appropriate amount of purified water Dissolve by adding each component to purified water according to the usual method of preparing a liquid solution, add a proper amount of lemon flavor, mix the above components, add purified water and adjust the total to 100 m by adding purified water to a brown bottle Layered and sterilized to prepare a liquid.
  • novel piperazine derivatives, pharmaceutically acceptable salts or isomers thereof according to the present invention have high solubility in water and are excellent in absorption in the body and low in cytotoxicity, as compared to the compounds known as GPR119 activators. This is pretty good. Above all, since the effect of activating GPR119 to promote cAMP is remarkably excellent, the novel piperazine derivatives, pharmaceutically acceptable salts thereof or isomers thereof according to the invention T / KR2013 / 009857

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un nouveau dérivé de pipérazine, un sel pharmaceutiquement acceptable ou un isomère optique de celui-ci, un procédé pour le préparer et une composition pharmaceutique le contenant comme ingrédient actif pour la prévention et le traitement de troubles métaboliques. Le nouveau dérivé de pipérazine et son sel pharmaceutiquement acceptable ou un isomère optique de celui-ci, selon la présente invention, présente une excellente capacité d'absorption in vivo et une innocuité exceptionnelle dans le corps humain, car sa solubilité dans l'eau est plus élevée que celle de composés conventionnellement connus comme activateurs de GPR119 et il présente une faible cytotoxicité. En outre, le composé de la présente invention présentant l'excellent effet de promouvoir cAMP en activant GPR119, en présentant ainsi le remarquable effet de réduire le glucose sanguin en une seule dose, il peut être efficacement utilisé comme composition pharmaceutique pour la prévention ou le traitement de l'obésité, du diabète type I, du diabète type II, d'une tolérance au glucose inadéquate, de la tolérance à l'insuline, de l'hyperglycémie, de l'hyperlipidémie, de l'hypertriglycéridémie, de l'hypercholestérolémie, de la dyslipidémie ou du syndrome X qui peuvent être traités par activation de GPR119.
PCT/KR2013/009857 2012-11-16 2013-11-01 Nouveau dérivé de pipérazine, sel pharmaceutiquement acceptable ou isomère optique de celui-ci, procédé pour le préparer et composition pharmaceutique le contenant comme ingrédient actif pour la prévention et le traitement de troubles métaboliques WO2014077532A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020120130598A KR20140063919A (ko) 2012-11-16 2012-11-16 신규한 피페라진 유도체, 이의 약학적으로 허용가능한 염 또는 이의 광학이성질체, 이의 제조방법 및 이를 유효성분으로 함유하는 대사질환 예방 또는 치료용 약학적 조성물
KR10-2012-0130598 2012-11-16

Publications (1)

Publication Number Publication Date
WO2014077532A1 true WO2014077532A1 (fr) 2014-05-22

Family

ID=50731399

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2013/009857 WO2014077532A1 (fr) 2012-11-16 2013-11-01 Nouveau dérivé de pipérazine, sel pharmaceutiquement acceptable ou isomère optique de celui-ci, procédé pour le préparer et composition pharmaceutique le contenant comme ingrédient actif pour la prévention et le traitement de troubles métaboliques

Country Status (2)

Country Link
KR (1) KR20140063919A (fr)
WO (1) WO2014077532A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015140130A1 (fr) * 2014-03-17 2015-09-24 Remynd Nv Composés d'oxadiazole

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4582833A (en) * 1984-04-16 1986-04-15 American Cyanamid Company 2-(substituted-1-piperazinyl)[1,2,4]triazolo[1,5-a]pyrimidines
US20090281097A1 (en) * 2006-04-14 2009-11-12 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US20100160323A1 (en) * 2008-12-23 2010-06-24 Alexander Bischoff NOVEL PIPERAZINE DERIVATIVES AS INHIBITORS OF STEAROYL-CoA DESATURASE
US20110245267A1 (en) * 2008-12-19 2011-10-06 Schering Plough Corporation Piperidine and piperazine derivatives and methods of use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4582833A (en) * 1984-04-16 1986-04-15 American Cyanamid Company 2-(substituted-1-piperazinyl)[1,2,4]triazolo[1,5-a]pyrimidines
US20090281097A1 (en) * 2006-04-14 2009-11-12 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US20110245267A1 (en) * 2008-12-19 2011-10-06 Schering Plough Corporation Piperidine and piperazine derivatives and methods of use thereof
US20100160323A1 (en) * 2008-12-23 2010-06-24 Alexander Bischoff NOVEL PIPERAZINE DERIVATIVES AS INHIBITORS OF STEAROYL-CoA DESATURASE

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015140130A1 (fr) * 2014-03-17 2015-09-24 Remynd Nv Composés d'oxadiazole
US10562869B2 (en) 2014-03-17 2020-02-18 Remynd Nv Oxadiazole compounds

Also Published As

Publication number Publication date
KR20140063919A (ko) 2014-05-28

Similar Documents

Publication Publication Date Title
JP6449845B2 (ja) 疼痛の処置のためのナトリウムチャネルモジュレーター
JP2021185206A (ja) チエノピリミジンジオンａｃｃ阻害剤の固体形態およびその生成のための方法
JP6445565B2 (ja) とう痛及び糖尿病の治療用ナトリウムチャネル調節物質
JP6375539B2 (ja) シクロヘキセン誘導体、その製造方法及びこれを有効成分として含有する代謝性疾患の予防又は治療用薬学的組成物
WO2011078371A1 (fr) Nouveau dérivé 3-hydroxy-5-arylisothiazole
ES2869910T3 (es) Preparación compuesta, que contiene un nuevo derivado de ácido 3-(4-(benciloxi)fenil)hex-4-inoico y otro principio activo, para prevenir o tratar enfermedades metabólicas
CN101657453B (zh) 作为PKC-θ抑制剂的嘌呤类
CN107007587A (zh) 用于诱导软骨形成的化合物和方法
US9504675B2 (en) Alpha-ketoheterocycles and methods of making and using
TW201904968A (zh) 以三唑并吡啶治療rbp4相關疾病之方法
JP4825266B2 (ja) 置換環状化合物、その調製工程およびその医学的使用
KR20130083592A (ko) 치환된 피페리딘 유도체 및 이의 제조방법
CN105367565A (zh) 哌嗪(啶)环己基衍生物及其治疗精神神经疾病的应用
ES2758981T3 (es) Compuesto que tiene actividad agonista GPR119, método para preparar el mismo, y composición farmacéutica que incluye al mismo como componente eficaz
CN116249695A (zh) 结晶PPAR-δ激动剂
JP2017527573A (ja) 糖尿病の治療用の選択的ＮａＶ１．７阻害剤
WO2014077532A1 (fr) Nouveau dérivé de pipérazine, sel pharmaceutiquement acceptable ou isomère optique de celui-ci, procédé pour le préparer et composition pharmaceutique le contenant comme ingrédient actif pour la prévention et le traitement de troubles métaboliques
Tang et al. Structure–activity relationship and hypoglycemic activity of tricyclic matrines with advantage of treating diabetic nephropathy
ES2390053T3 (es) Derivado de ácido fenilacético, procedimiento para producir el mismo y uso
ES2965684T3 (es) Derivados de 6-hidroxi-8-oxatriciclo[3.2.1.02,4]octano-2-carboxamida para inducir condrogénesis para el tratamiento del daño articular
RU2818783C2 (ru) Тетрагидропиридопиразиновые модуляторы gpr6
ES2629019T3 (es) Derivado de tiazinamida y composición farmacéutica y uso de los mismos
CN107567451A (zh) 作为用于治疗心血管疾病的可溶性鸟苷酸环化酶（sgc）刺激物的n‑取代的8‑[(2,6‑二氟苄基)氧基]‑2,6‑二甲基咪唑并[1,2‑a]吡嗪‑3‑甲酰胺衍生物
TW202339760A (zh) 用於預防或治療心臟衰竭(hf)之組合物
KR20130015727A (ko) 치환된 아제티딘 유도체 및 이를 포함하는 약학적 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13854488

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13854488

Country of ref document: EP

Kind code of ref document: A1