CN106866523A - PTP1B inhibitor, preparation method and its usage containing niacin hydroxyacyl amine structure - Google Patents
PTP1B inhibitor, preparation method and its usage containing niacin hydroxyacyl amine structure Download PDFInfo
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- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 title abstract description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title abstract description 5
- 229960003512 nicotinic acid Drugs 0.000 title abstract description 5
- 235000001968 nicotinic acid Nutrition 0.000 title abstract description 5
- 239000011664 nicotinic acid Substances 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 125000003277 amino group Chemical group 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 59
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 claims 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 4
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 150000001412 amines Chemical group 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N C1CCNCC1 Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 0 Cc1cc(CS(c(cc*(O)c2)c2C(N2CCCCC2)=O)(=O)=O)ccc1 Chemical compound Cc1cc(CS(c(cc*(O)c2)c2C(N2CCCCC2)=O)(=O)=O)ccc1 0.000 description 1
- LDYHSNAIHRCZHG-UHFFFAOYSA-N Cc1cc(CSc(ccnc2)c2C(O)=O)ccc1 Chemical compound Cc1cc(CSc(ccnc2)c2C(O)=O)ccc1 LDYHSNAIHRCZHG-UHFFFAOYSA-N 0.000 description 1
- FWLWTILKTABGKQ-UHFFFAOYSA-N Cc1cccc(CBr)c1 Chemical compound Cc1cccc(CBr)c1 FWLWTILKTABGKQ-UHFFFAOYSA-N 0.000 description 1
- LDWGZODGFLAMPD-UHFFFAOYSA-N Cc1cccc(CSc(ccnc2)c2C(N2CCCCC2)=O)c1 Chemical compound Cc1cccc(CSc(ccnc2)c2C(N2CCCCC2)=O)c1 LDWGZODGFLAMPD-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 108010072039 Histidine kinase Proteins 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- QXGWKRJJEODSIZ-UHFFFAOYSA-N OC(c(cncc1)c1S)=O Chemical compound OC(c(cncc1)c1S)=O QXGWKRJJEODSIZ-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004155 insulin signaling pathway Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the drug field related to type ii diabetes.Specifically, the present invention relates to PTP1B inhibitor of the class containing niacin hydroxyacyl amine structure, its preparation method and the application in type ii diabetes medicine is prepared.Wherein, R is selected from H, C1‑C3Alkyl, C3‑C8Cycloalkyl.
Description
Technical field
The present invention relates to the drug field of type ii diabetes treatment.More particularly, it relates to type ii diabetes
Have PTP1B inhibitor, its preparation method of the medicative class containing niacin hydroxyacyl amine structure, and the purposes in pharmacy.
Background technology
Type ii diabetes are a kind of common metabolic disturbance diseases, it is characterized in that periphery produces resistant function to film island element,
Insulin being shown as in molecular level, rear signal transduction missing is combined with insulin receptor.The phosphorylation level of protease propylhomoserin is
The important regulation factor of intracellular signal transduction, it is by protease histidine kinase (protein tyrosine kinase, PTK)
Regulate and control jointly with protease propylhomoserin phosphatase (protein tyrosine phosphatase, PTP).Research in recent years discovery, egg
White enzyme propylhomoserin phosphatase 1 B can play important negative regulation with dephosphorylation protease propylhomoserin in Insulin signaling pathway
Effect.PTPIB genes are knocked out, or suppresses the expression of internal PTP1B albumen and mRNA with antisense core former times acid (ASO), not only may be used
To significantly improve sensitiveness of the test mice to insulin, and can substantially reduce the ill probability of obesity.These research tables
Bright, PTP1B is likely to become the novel targets for the treatment of type ii diabetes.
The invention discloses the novel PTP1B inhibitor containing niacin hydroxyacyl amine structure of a class formation, these compounds can use
In the medicine for preparing treatment type ii diabetes.
The content of the invention
It is an object of the present invention to provide a kind of PTP1B inhibitor of the excellent activity with formula I.
It is a further object to provide method of the preparation with compounds of formula I.
It is also another object of the present invention to provide containing compounds of formula I type ii diabetes are being treated as active ingredient
The application of aspect.
Present invention is specifically described in conjunction with the purpose of the present invention.
The present invention has following structural formula with compounds of formula I：
Wherein, R is selected from H, C1-C3Alkyl, C3-C8Cycloalkyl.
More preferably compounds of formula I has following structure,
Compound of Formula I of the present invention is synthesized by following route：
There is substitution reaction in compound II, obtain compound IV with compound III in the presence of a base；Compound IV is in DCC
Reacted with compound V in the presence of (N, N'- dicyclohexyl carbodiimide), obtain VI；Compound VI is oxidized agent oxidation, obtains
Compound I；Wherein, R is defined as described above.Compound II can prepare (Leon Katz according to literature method；et al,
Journal of Organic Chemistry,1954,19,711)。
Compound of Formula I of the present invention has the inhibitory action of PTP1B, can be used to prepare II types sugar as active ingredient
The sick medicine of urine.The activity of compound of Formula I of the present invention is verified by receptor binding assays.
Compound of Formula I of the invention is effective in comparatively wide dosage range.The dosage for example taken daily is about
In the range of 1mg-1000mg/ people, it is divided into and once or is for several times administered.The dosage for actually taking compound of Formula I of the present invention can be by
Doctor determines according to relevant situation.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should
Within the protection domain required by the application claim.
The synthesis of the compound I-1 of embodiment 1
A. the synthesis of compound IV-1
Compound II (1.55g, 10mmol), compound III-1 (1.71g, 10mmol) and solid K2CO3(5.53g,
40mmol) add in the dry DMF of 30mL, be stirred overnight at room temperature, TLC tracking finds that reaction is completed.Reactant mixture is toppled over
Enter in 200mL frozen water, stirring adjusts pH=4-5 with concentrated hydrochloric acid, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, use salt solution
Washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining uses post
Chromatographic purifying, obtains compound IV-1, white solid.ESI-MS, m/z=244 ([M-H] -).
B. the synthesis of compound VI-1
Compound IV-1 (1.23g, 5mmol), compound V-1 (0.43g, 5mmol), DCC (1.24g, 6mmol) and 4- bis-
Methylamino pyridine (DMAP, 0.3g) is dissolved in dry 20mL THF, is stirred overnight at room temperature, and TLC tracking finds that reaction is completed.
Reactant mixture is poured into 200mL frozen water, stirring, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, dilute with 2% successively
Hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and what is obtained is residual
Excess is purified using column chromatography, obtains compound VI-1, white solid.ESI-MS, m/z=313 ([M+H]+)。
C. the synthesis of compound I-1
Compound VI-1 (0.62g, 2mmol) is dissolved in 10mL CH2Cl2In, stir at room temperature, add metachloroperbenzoic acid
(mCPBA, 1.72g, 10mmol), reactant mixture is stirred at room temperature 1 hour, then temperature rising reflux 3 hours, and TLC detections are anti-
Should complete.Reactant mixture is poured into 200mL frozen water, stirring, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, successively
Use saturation NaHCO3Solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is steamed on a rotary evaporator
Dry, the residue for obtaining is purified using column chromatography, obtains compound I-1, white solid.ESI-MS, m/z=361 ([M+H]+)。
The synthesis of the compound I-2 of embodiment 2
A. the synthesis of compound IV-2
Compound II (1.55g, 10mmol), compound III-2 (1.85g, 10mmol) and solid K2CO3(5.53g,
40mmol) add in the dry DMF of 30mL, be stirred overnight at room temperature, TLC tracking finds that reaction is completed.Reactant mixture is toppled over
Enter in 200mL frozen water, stirring adjusts pH=4-5 with concentrated hydrochloric acid, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, use salt solution
Washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining uses post
Chromatographic purifying, obtains compound IV-2, white solid.ESI-MS, m/z=258 ([M-H]-)。
B. the synthesis of compound VI-2
Compound IV-2 (1.30g, 5mmol), compound V-1 (0.43g, 5mmol), DCC (1.24g, 6mmol) and 4- bis-
Methylamino pyridine (DMAP, 0.3g) is dissolved in dry 20mL THF, is stirred overnight at room temperature, and TLC tracking finds that reaction is completed.
Reactant mixture is poured into 200mL frozen water, stirring, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, dilute with 2% successively
Hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and what is obtained is residual
Excess is purified using column chromatography, obtains compound VI-2, white-yellowish solid.ESI-MS, m/z=327 ([M+H]+)。
C. the synthesis of compound I-2
Compound VI-2 (0.65g, 2mmol) is dissolved in 10mL CH2Cl2In, stir at room temperature, add metachloroperbenzoic acid
(mCPBA, 1.72g, 10mmol), reactant mixture is stirred at room temperature 1 hour, then temperature rising reflux 3 hours, and TLC detections are anti-
Should complete.Reactant mixture is poured into 200mL frozen water, stirring, uses CH2Cl2(60mL × 3) extract, and merge extraction phase, successively
Use saturation NaHCO3Solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is steamed on a rotary evaporator
Dry, the residue for obtaining is purified using column chromatography, obtains compound I-2, white solid.ESI-MS, m/z=375 ([M+H]+)。
Embodiment 3-9
With reference to the operating procedure of embodiment 1, compound listed in Table is synthesized.
Suppression of the Compound ira vitro of embodiment 9 to PTP1B is tested
By original concentration for the compound solution of 50mM carries out 1/2 gradient dilution with 95%DMSO, 11 concentration are diluted altogether
Gradient.Enzyme activity reaction system amounts to 102 μ L, and it is 2 that wherein compound adds volumeμL.First, 50 μ are sequentially added in 96 orifice plates
L PTP1B albumen, the testing compound of 2 μ L various concentrations shakes 1min, 30 DEG C of incubation 30min, is subsequently adding 50 μ L pNPP
(para-nitro-pheneye phosphate), shakes 10s.Absorbance is surveyed once for 6 seconds with the change in reaction time under determining 405nm wavelength, surveys 60
It is individual, parallel determination three times, and course of reaction curve is drawn out, so as to calculate suppression of each compound to enzyme under various concentrations
Activity, non linear fit analysis are carried out using the softwares of software GraphPad Prism 5, with residual activity value as ordinate, chemical combination
Thing log concentration value is that abscissa draws curve, calculates the IC of the compound50Value.
Test result see the table below.
| Compound | Compound | ||
| The compound of embodiment 1 | 18.6 | The compound of embodiment 5 | 9.3 |
| The compound of embodiment 2 | 4.5 | The compound of embodiment 6 | 10.4 |
| The compound of embodiment 3 | 8.7 | The compound of embodiment 7 | 21.5 |
| The compound of embodiment 4 | 7.4 | The compound of embodiment 8 | 24.1 |
Can be seen that compound of the invention from upper table result has very strong inhibitory action to PTP1B, can be as system
The medicine of standby treatment type ii diabetes.
Claims (4)
1. there is the compound of general formula I,
Wherein, R is selected from H, C1-C3Alkyl, C3-C8Cycloalkyl.
2. compound of Formula I defined in claim 1, is selected from：
3. any defined methods for belonging to compounds of formula I of claim 1-2 are synthesized：
There is substitution reaction in compound II, obtain compound IV with compound III in the presence of a base；Compound IV is in N, N'- bis-
Reacted with compound V in the presence of cyclohexylcarbodiimide, obtain VI；Compound VI is oxidized agent oxidation, obtains compound I；
Wherein, the definition of R is as described in claim 1-2 is any.
4. application of the defined compound of Formula I of one of claim 1-2 in terms for the treatment of diabetes B medicine is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710074730.XA CN106866523A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor, preparation method and its usage containing niacin hydroxyacyl amine structure |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510108697.9A CN104725308A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide structure and preparation method and use thereof |
| CN201710074730.XA CN106866523A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor, preparation method and its usage containing niacin hydroxyacyl amine structure |
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| CN201510108697.9A Division CN104725308A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide structure and preparation method and use thereof |
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| Publication Number | Publication Date |
|---|---|
| CN106866523A true CN106866523A (en) | 2017-06-20 |
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| CN201710074730.XA Pending CN106866523A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor, preparation method and its usage containing niacin hydroxyacyl amine structure |
| CN201510108697.9A Pending CN104725308A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide structure and preparation method and use thereof |
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| CN201510108697.9A Pending CN104725308A (en) | 2015-03-12 | 2015-03-12 | PTP1B inhibitor containing nicotinic acid amide structure and preparation method and use thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1300291A (en) * | 1998-03-12 | 2001-06-20 | 诺沃挪第克公司 | Modulators of protein tyrosine phosphatases |
| WO2002018321A2 (en) * | 2000-08-29 | 2002-03-07 | Abbott Laboratories | Amino(oxo)acetic acid protein tyrosine phosphatase inhibitors |
| CN101123964A (en) * | 2004-12-24 | 2008-02-13 | 普罗西迪恩有限公司 | G protein-coupled receptor (GPR116) agonists and their use for the treatment of obesity and diabetes |
| CN101484440A (en) * | 2006-07-06 | 2009-07-15 | 艾尼纳制药公司 | Modulators of metabolism and the treatment of disorders related thereto |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6262044B1 (en) * | 1998-03-12 | 2001-07-17 | Novo Nordisk A/S | Modulators of protein tyrosine phosphatases (PTPASES) |
-
2015
- 2015-03-12 CN CN201710074730.XA patent/CN106866523A/en active Pending
- 2015-03-12 CN CN201510108697.9A patent/CN104725308A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1300291A (en) * | 1998-03-12 | 2001-06-20 | 诺沃挪第克公司 | Modulators of protein tyrosine phosphatases |
| WO2002018321A2 (en) * | 2000-08-29 | 2002-03-07 | Abbott Laboratories | Amino(oxo)acetic acid protein tyrosine phosphatase inhibitors |
| CN101123964A (en) * | 2004-12-24 | 2008-02-13 | 普罗西迪恩有限公司 | G protein-coupled receptor (GPR116) agonists and their use for the treatment of obesity and diabetes |
| CN101484440A (en) * | 2006-07-06 | 2009-07-15 | 艾尼纳制药公司 | Modulators of metabolism and the treatment of disorders related thereto |
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