CN106986874A - (1H-pyrazolo [3,4-d ] pyrimidine) -4-amino derivatives and their use as IDO inhibitors in the manufacture of medicaments - Google Patents
(1H-pyrazolo [3,4-d ] pyrimidine) -4-amino derivatives and their use as IDO inhibitors in the manufacture of medicaments Download PDFInfo
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- CN106986874A CN106986874A CN201610040272.3A CN201610040272A CN106986874A CN 106986874 A CN106986874 A CN 106986874A CN 201610040272 A CN201610040272 A CN 201610040272A CN 106986874 A CN106986874 A CN 106986874A
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- Prior art keywords
- compound
- ido
- amino
- medicine
- pyrimidine
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 title claims description 11
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical compound C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 title abstract 2
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims abstract description 33
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 208000030507 AIDS Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 208000015181 infectious disease Diseases 0.000 claims abstract description 7
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 6
- 208000002177 Cataract Diseases 0.000 claims abstract description 6
- 208000030159 metabolic disease Diseases 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 230000004913 activation Effects 0.000 claims description 7
- 230000007969 cellular immunity Effects 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 229940002612 prodrug Drugs 0.000 claims description 3
- 239000000651 prodrug Substances 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 abstract description 11
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 abstract description 10
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 6
- 230000005934 immune activation Effects 0.000 abstract 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 17
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 11
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 11
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000004060 metabolic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- 0 CC1C=*(*)C(O)=CC1 Chemical compound CC1C=*(*)C(O)=CC1 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 2
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical class CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- -1 indoles amines Chemical class 0.000 description 2
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- TZKBVRDEOITLRB-UHFFFAOYSA-N 4-methyl-n-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1h-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2C=C3C=NNC3=NC=2)=C1 TZKBVRDEOITLRB-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- FBKMWOJEPMPVTQ-UHFFFAOYSA-N N'-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboximidamide Chemical compound NS(=O)(=O)NCCNC1=NON=C1C(=NO)NC1=CC=C(F)C(Br)=C1 FBKMWOJEPMPVTQ-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 1
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- MCPLVIGCWWTHFH-UHFFFAOYSA-L methyl blue Chemical compound [Na+].[Na+].C1=CC(S(=O)(=O)[O-])=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[NH+]C=2C=CC(=CC=2)S([O-])(=O)=O)C=2C=CC(NC=3C=CC(=CC=3)S([O-])(=O)=O)=CC=2)C=C1 MCPLVIGCWWTHFH-UHFFFAOYSA-L 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a (1H-pyrazolo [3,4-d ] pyrimidine) -4-amino derivative, a preparation method of the compound and application of the compound as an IDO inhibitor. The compound of the present invention can be used for preventing and/or treating various diseases, such as Alzheimer disease, cataract, infection related to cell immune activation, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism disorder, etc.
Description
Technical field
The present invention relates to 1H- pyrazoles [3,4-d] pyrimidine) -4- aminoderivatives, further relate to its preparation method and suppress as IDO
The purposes of agent.
Background technology
IDO (Indoleamine 2,3-dioxygenase, IDO) is the indoles amines such as catalysis tryptophan
Indole ring oxicracking in molecule, makes it by the rate-limiting enzyme of kynurenine approach catabolism.
IDO plays an important role in tumour immunity exemption and tumour generating process.Under normal circumstances, IDO is in vivo
Low expression level, and the high expression IDO that most of tumour cells can then be constituted, N- formyls dog urine is converted into by L-Trp
Propylhomoserin, reduces the Tryptophan concentration in cell micro-environment so that the T cell synthesis that tryptophan is relied on was stagnated in the G1 phases,
T cell propagation is suppressed, so as to inhibit body immune system to the lethal effects of tumor tissues.Meanwhile, IDO effects
There is cytotoxicity in the metabolite of lower tryptophan, can produce direct dissolution to T cell.
Therefore, the degraded of near tumor cells tryptophan can effectively be prevented by suppressing IDO activity, promote T cell
Propagation, so as to strengthen attacking ability of the body to tumour cell.Also, IDO inhibitor can also be shared with chemotherapeutics,
The drug resistance of tumour cell is reduced, so as to strengthen the antitumor activity of conventional cytotoxic therapy.Take IDO inhibitor simultaneously
Also the curative effect of the therapeutic vaccine of cancer patient can be improved.
Except being played an important role in terms of tumor cell drug resistance, IDO is also related to a variety of and cellular immunity activation
The pathogenesis of disease is closely related.IDO have been found to be the infection related to cellular immunity activation, malignant tumour, from
The target of the major diseases such as body immunity disease, AIDS.Meanwhile, suppress IDO still for the nervous system disease
Such as depression, the critical treatment strategy of the patient of Alzheimer disease.Therefore, IDO inhibitor has wide clinic should
Use prospect.
The content of the invention
To solve the above problems, invention broadly provides the new IDO inhibitor class medicine of a class, they are (1H-
Pyrazoles [3,4-d] pyrimidine) -4- aminoderivatives are the substitutions on ammonia nitrogen.
The invention provides a kind of compound or its pharmaceutically acceptable salt or its solvate, the compound structure
As shown in formula (I)：
Wherein, R1Selected from H, halogen or C1~C4Alkyl；
R2Selected from substituted or non-substituted aryl, cycloalkyl, heteroaryl or heterocyclic radical, the substituted aryl, cycloalkyl,
Heteroaryl or heterocyclic radical are separately by one or more selected from-(CH2)mCOOH, halogen, hydroxyl, amino, nitro,
The substituent of alkyl is replaced；
N=1,2 or 3；
M=0,1,2 or 3.
Further, the R2Selected from phenyl or substituted phenyl, the substituted phenyl is selected from by one or more
-(CH2)mCOOH, halogen, hydroxyl, amino, nitro, the substituent of alkyl are replaced；M=0 or 1.
Further, the R2Selected from one of following radicals：
Further, R1Selected from H or methyl.
Further, the structure of the compound is as follows：
Present invention also offers the method that one kind prepares the formula (I) compound, comprise the following steps：
It is raw material with compound 9 and compound 10, is dissolved in organic solvent, it is anti-in the presence of inert gas environment and alkali
Should, purifying obtains formula (I) compound.
As a kind of specific embodiment, during reaction, compound 9 is slightly excessive.Compound 9 can be according to of the invention specific real
Applying the synthesis of the method in mode can also synthesize according to method of the prior art.
Further, the alkali is selected from organic base or inorganic base, and the organic base is selected from triethylamine or pyridine, the inorganic base
Select sodium acid carbonate, sodium carbonate or sodium hydroxide.
Further, the organic solvent is selected from dimethylformamide, tetrahydrofuran, ethyl acetate, acetone or dichloromethane.
For example, in specific embodiment of the present invention, above-claimed cpd 1a, 1b, 1c and 1d are prepared by following routes
Obtain：
Present invention also offers the compound or its pharmaceutically acceptable salt or its prodrug or its solvate in system
Purposes on standby IDO inhibitor class medicine.
Further, the medicine is prevention and/or treatment Alzheimer disease, cataract, cellular immunity activation correlation
The abnormal medicine of infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism.
Present invention also offers a kind of pharmaceutical composition, it be described compound or its pharmaceutically acceptable salt for activity into
Point, add the preparation that pharmaceutically acceptable auxiliary material is prepared from.
Wherein, the composition is treatment or prevention and/or treatment Alzheimer disease, cataract, cellular immunity activation phase
The abnormal medicine of the infection of pass, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism
C of the present invention1~C4Alkyl refer to the alkyl of the straight or branched with 1~4 carbon atom, including methyl,
Ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl etc..
The prodrug is the derivative of aforesaid compound, and their own may have weaker activity or even without activity, but
It is upon administration, to be converted to corresponding life (such as by metabolism, solvolysis or other mode) in physiological conditions
Thing activity form.
Described preparation can include injection or oral formulations.
Key intermediate and compound in the present invention are separated and purified, and used mode is commonly used in organic chemistry
Isolation and purification method.
The present invention one or more compounds can be used in conjunction with one another, also may be selected by the present invention compound with it is any its
Its active agent is used in combination, for preparing IDO inhibitor., can be by these if using one group of compound
Compound is administered simultaneously, respectively or in an orderly manner to study subject.
Pharmaceutically acceptable auxiliary material of the present invention, refers to the material being included in addition to the active ingredient (s in formulation.
Tests prove that, pyrido [3, the 4-b] indole derivatives that the 9- positions that the present invention is provided replace has excellent to IDO
Inhibitory action, can be used for preventing and/or treats a variety of diseases, such as Alzheimer disease, cataract, cellular immunity activation
Related infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception etc..
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, this is not being departed from
Invent under the premise of above-mentioned basic fundamental thought, the modification of other diversified forms can also be made, replace or change.
The embodiment of form, is described in further detail again to the above of the invention by the following examples.
But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.It is all real based on the above of the present invention institute
Existing technology belongs to the scope of the present invention.
Embodiment
Raw material and reagent are that analysis is pure：Raw materials used to be purchased from Chengdu Rui Ouke Science and Technology Ltd.s, reagent is purchased from Chengdu section dragon
Reagent Company.
The synthesis of intermediate 6- methyl isophthalic acids H- pyrazoles [3,4-d] pyrimidine -4 (7H) -one (8b) of the present invention of embodiment 1
Synthetic route is as follows：
By compound (7) (CAS:5334-31-6,1.0g, 7.94mmol) add glacial acetic acid (6mL) and poly phosphorus
In the mixed solution of sour (6mL), in reaction 7 hours at 120 DEG C.Reaction solution is cooled to room temperature, pours into 70mL water
In, it is 5 with 50% NaOH aqueous solution regulation pH, has white solid precipitation, filter, filter cake is rinsed with a large amount of water.
Filter cake is suspended in methyl alcohol, stirred 10 minutes, filtering, filter cake is washed with 50mL ethyl acetate.Filter cake reduced vacuum
Dry white solid 887.5mg, yield 76%.
The compounds of this invention 1a of embodiment 2 preparation
Synthetic route is as follows：
8a(CAS:315-30-0) can directly it buy.
1st, compound 9a synthesis
By compound 8a (0.5g, 3.68mmol) in the lower instillation thionyl chloride (15ml) of argon gas protection and DMF (1.5mL),
80 DEG C of back flow reactions are warming up to after completion of dropping 2 hours.Reaction solution is cooled to room temperature, is poured slowly into the 150mL being stirred vigorously
In frozen water, extracted three times with 100mL ethyl acetate, merge organic phase, washed with saturated common salt, anhydrous magnesium sulfate is dried,
It is spin-dried for obtaining yellow powder 9a 367mg, yield 64%.
2nd, compound 1a synthesis
Compound 9a (0.32mmol) and compound 10a (40.6mg, 0.27mmol) are dissolved in DMF (1.5mL), plus
Enter triethylamine (66.8 μ L, 0.484mmol), reacted 4 hours in 80 DEG C under argon gas protection.Decompression rotation solvent to the greatest extent, residual
Thing adds 8mL ethyl acetate, with 4mL water washings three times.Organic phase is dried through anhydrous magnesium sulfate, is spin-dried for post
(DCM:MeOH=10:1) faint yellow solid 31.1mg, yield 43%, are obtained.
3- ((1H- pyrazoles [3,4-d] pyrimidine -4- amino) methyl) benzoic acid (1a)1H-NMR(400MHz,d6-DMSO,ppm):
δ13.44(br,2H,COOH and pyrazole NH),8.81(m,1H,amino),8.23(s,1H,pyrimidine-CH),
8.17 (s, 1H, pyrazole-CH), 7.94 (s, 1H, Ar-H2), 7.83 (d, 1H, J=7.6Hz, Ar-H6), 7.46 (d, 1H, J
=7.6Hz, Ar-H4), 7.46 (t, 1H, J=7.6Hz, Ar-H5), 4.80 (d, 2H, J=6.0Hz, benzyl-CH2).
ESI-MS:270.09[M+H].
The compounds of this invention 1b of embodiment 3 preparation
Compound 1b is synthesized according to method similar in embodiment 2, difference is with compound 9b alternative compounds 9a,
Obtain yellow solid 1b, yield 41%.
4- ((1H- pyrazoles [3,4-d] pyrimidine -4- amino) methyl) benzoic acid (1b)1H-NMR(400MHz,d6-DMSO,ppm):
δ14.50(s,1H,br,COOH),13.41(s,1H,pyrazole NH),8.79(m,1H,amino),8.23(s,1H,
Pyrimidine CH), 8.17 (s, 1H, pyrazole CH), 7.91 (d, 2H, J=7.6Hz, Ar-H2 and Ar-H6), 7.46 (d,
2H, J=7.6Hz, Ar-H3 and Ar-H5), 4.82 (d, 2H, J=5.2Hz, benzyl-CH2).ESI-MS:270.09[M+
H].
The compounds of this invention 1c of embodiment 4 preparation
Compound 1c is synthesized according to method similar in embodiment 2, difference is with compound 9b alternative compounds 9a, with
Compound 10b alternative compounds 10a, obtain yellow solid 1c, yield 36%
3- ((6- methyl 1H- pyrazoles [3,4-d] pyrimidine -4- amino) methyl) benzoic acid (1c)1H-NMR(400MHz,d6-DMSO,
ppm):δ 14.58 (s, 1H, pyrazole-NH), 12.92 (br, 1H, COOH), 11.43 (t, 1H, J=6.0Hz, amino),
8.52 (s, 1H, pyrazole-CH), 8.02 (s, 1H, Ar-H2), 7.98 (d, 1H, J=7.6Hz, Ar-H6), 7.56 (d, 1H, J
=7.6Hz, Ar-H4), 7.50 (t, 1H, J=7.6Hz, Ar-H5), 5.02 (d, 2H, J=6.0Hz, benzyl-CH2),2.33(s,
1H,CH3).ESI-MS:284.11[M+H].
The compounds of this invention 1d-k of embodiment 5 preparation
Compound 1d is synthesized according to method similar in embodiment 2, difference is with compound 9b alternative compounds 9a, with
Compound 10b alternative compounds 10a, obtain yellow solid 1d, yield 39%.
4- ((6- methyl isophthalic acid H- pyrazoles [3,4-d] pyrimidine -4- amino) methyl) benzoic acid (1d)1H-NMR(400MHz,d6-DMSO,
ppm):δ 14.74 (s, 1H, pyrazole-NH), 12.94 (br, 1H, COOH), 11.39 (t, 1H, J=6.0Hz, amino),
8.55 (s, 1H, pyrazole-CH), 7.93 (d, 2H, J=8.3Hz, Ar-H2 and Ar-H6), 7.46 (d, 2H, J=8.3Hz,
Ar-H3 and Ar-H5), 5.08 (d, 2H, J=6.0Hz, benzyl-CH2),2.34(s,1H,CH3).ESI-MS:284.11
[M+H].
Corresponding raw material is selected, compound 1e-k is prepared in a similar way, as a result and is characterized as below：
Yellow solid, yield 41%.1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),
8.64(m,1H,amino),8.17(s,1H,pyrimidine CH),8.11(s,1H,pyrazole CH),7.45-6.67(m,5H,
), Ar-H 4.12 (d, 2H, J=5.2Hz, benzyl-CH2).ESI-MS:226.09[M+H].
Yellow solid, yield 49%.1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),
8.64 (m, 1H, amino), 8.19 (s, 1H, pyrimidine CH), 8.12 (s, 1H, pyrazole CH), 7.45 (d, 2H, J=
7.6Hz, Ar-H2 and Ar-H6), 7.12 (d, 2H, J=7.6Hz, Ar-H3 and Ar-H5), 4.01 (d, 2H, J=5.2Hz,
benzyl-CH2),2.33(s,3H,CH3).ESI-MS:240.12[M+H].
Yellow solid, yield 46%.1H-NMR(400MHz,d6-DMSO,ppm):δ13.44(s,1H,pyrazole NH),
8.80 (m, 1H, amino), 8.25 (s, 1H, pyrimidine CH), 8.19 (s, 1H, pyrazole CH), 7.98 (d, 2H, J=
7.6Hz, Ar-H2 and Ar-H6), 7.42 (d, 2H, J=7.6Hz, Ar-H3 and Ar-H5), 4.85 (d, 2H, J=5.2Hz,
benzyl-CH2).ESI-MS:260.06[M+H].
Yellow solid, yield 52%.1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),
8.45 (m, 1H, amino), 8.07 (s, 1H, pyrimidine CH), 8.01 (s, 1H, pyrazole CH), 7.23 (d, 2H, J=
7.6Hz, Ar-H2 and Ar-H6), 7.07 (d, 2H, J=7.6Hz, Ar-H3 and Ar-H5), 4.03 (d, 2H, J=5.2Hz,
benzyl-CH2).ESI-MS:242.12[M+H].
Yellow solid, yield 55%.1H-NMR(400MHz,d6-DMSO,ppm):δ14.59(s,1H,pyrazole-NH),
12.93 (br, 1H, COOH), 11.41 (t, 1H, J=6.0Hz, amino), 8.51 (s, 1H, pyrazole-CH), 8.00 (s, 1H,
), Ar-H2 7.87 (d, 1H, J=7.6Hz, Ar-H6), 7.34 (d, 1H, J=7.6Hz, Ar-H5), 4,98 (d, 2H, J=6.0
Hz,benzyl-CH2).ESI-MS:286.10[M+H].
Yellow solid, yield 46%.1H-NMR(400MHz,d6-DMSO,ppm):δ14.74(s,1H,pyrazole-NH),
12.94 (br, 1H, COOH), 11.23 (t, 1H, J=6.0Hz, amino), 8.51 (s, 1H, pyrazole-CH), 7.86 (d, 2H,
J=8.3Hz, Ar-H2 and Ar-H6), 7.23 (d, 2H, J=8.3Hz, Ar-H3 and Ar-H5), 4.89 (d, 2H, J=6.0
Hz,CH2NH),3.68(s,2H,CH2COOH),2.34(s,1H,CH3).ESI-MS:298.11[M+H].
Yellow solid, yield 41%.1H-NMR(400MHz,d6-DMSO,ppm):δ14.51(s,1H,pyrazole-NH),
12.93 (br, 1H, COOH), 11.41 (t, 1H, J=6.0Hz, amino), 8.53 (s, 1H, pyrazole-CH), 8.02 (s, 1H,
), Ar-H2 7.95 (d, 1H, J=7.6Hz, Ar-H6), 7.52 (d, 1H, J=7.6Hz, Ar-H4), 7.54 (t, 1H, J=7.6
Hz,Ar-H5),4.23(m,2H,CH2),2.94(m,2H,CH2).ESI-MS:284.11[M+H].
Inhibitory activity of the compounds of this invention of embodiment 6 to IDO albumen
Recombined human IDO albumen is obtained through Bacillus coli expression, nickel affinity chromatographic purifying.Compound is real to IDO inhibitory activity
Test using L-Trp as substrate.Testing compound is dissolved in 10%DMSO solution and is configured to dilution.Take 5uL
Dilution is added in 100 μ L reaction systems.Contain 0.5%DMSO, 40nmol/L IDO in 100 μ L reaction systems,
900 μm of ol/L L-Trps, and other reaction concurrent (kaliumphosphate buffer, ascorbic acid, catalases, Asia
Methyl blue).Reactant mixture adds trichloroacetic acid terminating reaction in being cultivated 180 minutes under 37 degree.Use Tecan
Infinite M1000 ELIASAs determine the concentration of the N- formoxyl kynurenins produced at 321nm, so as to evaluate compound
To IDO inhibitory activity.Negative control thing is to replace IDO with 5 μ L buffer solution.The IDO inhibitor of clinical III phases
INCB024360 verifies whether the IDO Activity determinations system that this experiment is set up is effective as positive control.
Each concentration sets up three wells.Data analysis is carried out using software Graphpad Prism.Without testing compound
Reaction solution in, absorbance (At) it is defined as 100% activity.In the reaction solution without IDO, absorbance (Ab) fixed
Justice is 0% activity.For testing compound, active calculation formula is：%activity=[(A-Ab)/(At-Ab)] × 100,
Wherein A is the absorbance of the reaction solution containing testing compound.The calculation formula of inhibiting rate is：%inhibition=100-%
activity.
By above experimental method, the inhibitory activity that the part of compounds in the present invention is directed to IDO is tested.Specific portion
Inhibitory activity of the compound under 1 μM, 10 μM, 100 μM of concentration is shown in Table 1.
Wherein A represents that inhibiting rate is more than 30%, B and represents that inhibiting rate 20%-30%, C represent that inhibiting rate is 10%-20%；
D represents that inhibiting rate is less than 10%；Inhibiting rate of the positive control when concentration is 0.05 μM is 46%.
Inhibitory activity of the compounds of this invention of table 1 to IDO
As a result show, compound of the invention has certain inhibitory activity to IDO.Wherein R2It is selected fromWhen, effect is preferable.
In summary, (1H- pyrazoles [3,4-d] pyrimidine) -4- aminoderivatives that the present invention is provided, have excellent suppression to IDO
Make and use, can be used for preventing and/or treat a variety of diseases, such as Alzheimer disease, cataract, cellular immunity activation phase
Infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception of pass etc..
Claims (12)
1. a kind of compound or its pharmaceutically acceptable salt or its solvate, the structure such as formula (I) of the compound
It is shown：
Wherein, R1Selected from H, halogen or C1~C4Alkyl；
R2Selected from substituted or non-substituted aryl, cycloalkyl, heteroaryl or heterocyclic radical, the substituted aryl, cycloalkyl,
Heteroaryl or heterocyclic radical are separately by one or more selected from-(CH2)mCOOH, halogen, hydroxyl, amino, nitro,
The substituent of alkyl is replaced；
N=1,2 or 3；
M=0,1,2 or 3.
2. compound according to claim 1, it is characterised in that：The R2Selected from phenyl or substituted phenyl, institute
Substituted phenyl is stated by one or more selected from-(CH2)mCOOH, halogen, hydroxyl, amino, nitro, the substitution of alkyl
Base is replaced；M=0 or 1.
3. compound according to claim 2, it is characterised in that：The R2Selected from one of following radicals：
4. compound according to claim 1, it is characterised in that：R1Selected from H or methyl.
5. compound according to claim 1, it is characterised in that：The structure of the compound is as follows：
6. prepare the method for formula (I) compound described in claim 1, it is characterised in that：Comprise the following steps：
It is raw material with compound 9 and compound 10, is dissolved in organic solvent, it is anti-in the presence of inert gas environment and alkali
Should, purifying obtains formula (I) compound.
7. method according to claim 6, it is characterised in that：The alkali is selected from organic base or inorganic base, described to have
Machine alkali is selected from triethylamine or pyridine, the inorganic base selection sodium acid carbonate, sodium carbonate or sodium hydroxide.
8. the method according to claim 6 or 7, it is characterised in that：The organic solvent be selected from dimethylformamide,
Tetrahydrofuran, ethyl acetate, acetone or dichloromethane.
9. the method according to claim any one of 6-8, it is characterised in that：The temperature of the reaction is 25 DEG C -100 DEG C.
10. any one of the claim 1-5 compounds or its pharmaceutically acceptable salt or its prodrug or its solvent
Purposes of the compound on IDO inhibitor class medicine is prepared.
11. purposes according to claim 10, it is characterised in that：The medicine is prevention and/or treatment alzheimer '
Silent disease, cataract, cellular immunity activation related infection, autoimmune disease, AIDS, cancer, depression or color
The medicine of propylhomoserin metabolic disorder.
12. a kind of pharmaceutical composition, it is characterised in that：It is with the compound or its medicine described in claim any one of 1-5
Acceptable salt is active component on, adds the preparation that pharmaceutically acceptable auxiliary material is prepared from.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5593997A (en) * | 1995-05-23 | 1997-01-14 | Pfizer Inc. | 4-aminopyrazolo(3-,4-D)pyrimidine and 4-aminopyrazolo-(3,4-D)pyridine tyrosine kinase inhibitors |
| CN102746306A (en) * | 2012-07-09 | 2012-10-24 | 四川国康药业有限公司 | Allopurinol derivative and preparation method and application thereof |
| WO2015123365A1 (en) * | 2014-02-11 | 2015-08-20 | Mitokinin Llc | Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease |
| CN107849010A (en) * | 2015-06-01 | 2018-03-27 | 卢郡控股(开曼)有限公司 | 3,3- difluoropiperdin carbamate heterocyclic compounds as NR2B nmda receptor antagonists |
-
2016
- 2016-01-20 CN CN201610040272.3A patent/CN106986874B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5593997A (en) * | 1995-05-23 | 1997-01-14 | Pfizer Inc. | 4-aminopyrazolo(3-,4-D)pyrimidine and 4-aminopyrazolo-(3,4-D)pyridine tyrosine kinase inhibitors |
| CN102746306A (en) * | 2012-07-09 | 2012-10-24 | 四川国康药业有限公司 | Allopurinol derivative and preparation method and application thereof |
| WO2015123365A1 (en) * | 2014-02-11 | 2015-08-20 | Mitokinin Llc | Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease |
| CN107849010A (en) * | 2015-06-01 | 2018-03-27 | 卢郡控股(开曼)有限公司 | 3,3- difluoropiperdin carbamate heterocyclic compounds as NR2B nmda receptor antagonists |
Non-Patent Citations (5)
| Title |
|---|
| C. C. CHENG等，: ""Potential purine antagonists. VII. Synthesis of 6-alkylpyrazolo[3,4-d]pyrimidines"", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| COLUMBUS，OHIO，US REGISTRY[ONLINE]: ""STN检索报告"", 《REGISTRY》 * |
| EDWARD Y. SUTCLIFFE等，: ""Potential purine antagonists. XXXII. The synthesis and antitumor activity of certain compounds related to 4-aminopyrazolo[3,4-d]pyrimidine"", 《JOURNAL OF MEDICINAL & PHARMACEUTICAL CHEMISTRY》 * |
| PRIKAZCHIKOVA, L. P.等，: ""4-(arylalkylamino)-substituted pyrazolo[3,4-d]pyrimidines: inhibition of xanthine oxidase and nucleotide pyrophosphatase/phosphodiesterase 1"", 《ZHURNAL ORGANICHNOI TA FARMATSEVTICHNOI KHIMII》 * |
| ROLAND K. ROBINS等，: ""Potential purine antagonists. IX. Further studies of some 4,6-disubstituted-pyrazolo[3,4-d]pyrimidines"", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110294714A (en) * | 2018-03-22 | 2019-10-01 | 西华大学 | Imidazoles methylamine like derivative and its synthetic method with indoles amine -2,3- dioxygenase (IDO) inhibitor activity |
| CN110294714B (en) * | 2018-03-22 | 2022-08-26 | 西华大学 | Imidazolemethylamine derivatives with indoleamine-2, 3-dioxygenase (IDO) inhibitor activity and synthesis method thereof |
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