ES2636248T3 - Derivados de pirimidina pirido- o pirrolo-fusionados como inhibidores de autotaxina para el tratamiento del dolor - Google Patents
Derivados de pirimidina pirido- o pirrolo-fusionados como inhibidores de autotaxina para el tratamiento del dolor Download PDFInfo
- Publication number
- ES2636248T3 ES2636248T3 ES14702336.0T ES14702336T ES2636248T3 ES 2636248 T3 ES2636248 T3 ES 2636248T3 ES 14702336 T ES14702336 T ES 14702336T ES 2636248 T3 ES2636248 T3 ES 2636248T3
- Authority
- ES
- Spain
- Prior art keywords
- mmol
- dihydro
- equiv
- pyrimidin
- ylamino
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
- 238000011282 treatment Methods 0.000 title claims description 21
- 208000002193 Pain Diseases 0.000 title claims description 18
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 title description 33
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 title description 33
- 239000003112 inhibitor Substances 0.000 title description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 133
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- -1 2,3-dihydro-1H-inden-2-ylamino Chemical group 0.000 claims description 114
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- ILOFWCAZDNILKY-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-2-[2-(2h-triazol-4-yl)ethoxy]ethanone Chemical compound C1C2=CN=C(NC3CC4=CC=CC=C4C3)N=C2CN1C(=O)COCCC1=CNN=N1 ILOFWCAZDNILKY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 309
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 202
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
- 239000000243 solution Substances 0.000 description 117
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 89
- 230000015572 biosynthetic process Effects 0.000 description 87
- 238000003786 synthesis reaction Methods 0.000 description 82
- 239000012141 concentrate Substances 0.000 description 79
- 238000003756 stirring Methods 0.000 description 76
- 239000000284 extract Substances 0.000 description 75
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- 238000002360 preparation method Methods 0.000 description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 239000007787 solid Substances 0.000 description 46
- 239000012043 crude product Substances 0.000 description 41
- 238000004440 column chromatography Methods 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 40
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
- 239000010410 layer Substances 0.000 description 33
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- XGRLSUFHELJJAB-JGSYTFBMSA-M sodium;[(2r)-2-hydroxy-3-[(z)-octadec-9-enoyl]oxypropyl] hydrogen phosphate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)([O-])=O XGRLSUFHELJJAB-JGSYTFBMSA-M 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 238000012360 testing method Methods 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 23
- 235000011152 sodium sulphate Nutrition 0.000 description 23
- 239000012267 brine Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 17
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 12
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 201000008482 osteoarthritis Diseases 0.000 description 11
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000002211 L-ascorbic acid Substances 0.000 description 10
- 235000000069 L-ascorbic acid Nutrition 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 229960005070 ascorbic acid Drugs 0.000 description 10
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 159000000000 sodium salts Chemical class 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- DMTCYHWCFBNXPW-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidine-6-carboxylic acid Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C(CN(C(=O)O)CC2)C2=N1 DMTCYHWCFBNXPW-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 229960001231 choline Drugs 0.000 description 6
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 5
- NDKUBLKSJQPEBQ-UHFFFAOYSA-N N=1C=NCCC1C(=O)N Chemical compound N=1C=NCCC1C(=O)N NDKUBLKSJQPEBQ-UHFFFAOYSA-N 0.000 description 5
- UTIHNMCZTVCQCH-UHFFFAOYSA-N OC1=C(C(=O)O)N=NN1CC1=CC=CC=C1 Chemical compound OC1=C(C(=O)O)N=NN1CC1=CC=CC=C1 UTIHNMCZTVCQCH-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 150000007942 carboxylates Chemical class 0.000 description 5
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- BZXBCSVQKRJOET-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-2-[2-(2h-triazol-4-yl)ethoxy]ethanone Chemical compound C1CC2=NC(NC3CC4=CC=CC=C4C3)=NC=C2CN1C(=O)COCCC1=CNN=N1 BZXBCSVQKRJOET-UHFFFAOYSA-N 0.000 description 4
- DKFVEDKCRIZEEM-UHFFFAOYSA-N 3-(1h-imidazol-5-yl)propan-1-ol Chemical compound OCCCC1=CNC=N1 DKFVEDKCRIZEEM-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- NFCMGQZXBVWWNN-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-6,7-dihydro-5h-pyrrolo[3,4-d]pyrimidin-2-amine;hydrate;dihydrochloride Chemical compound O.Cl.Cl.C1C2=CC=CC=C2CC1NC1=NC=C2CNCC2=N1 NFCMGQZXBVWWNN-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- MCOKBWHXSOXSSP-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-2-[2-(2h-triazol-4-yl)ethylamino]ethanone Chemical compound C1C2=CN=C(NC3CC4=CC=CC=C4C3)N=C2CN1C(=O)CNCCC1=CN=NN1 MCOKBWHXSOXSSP-UHFFFAOYSA-N 0.000 description 3
- QTBDVJRDGXHWHJ-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-5-(2h-tetrazol-5-yl)pentan-1-one Chemical compound C1C2=CN=C(NC3CC4=CC=CC=C4C3)N=C2CN1C(=O)CCCCC1=NN=NN1 QTBDVJRDGXHWHJ-UHFFFAOYSA-N 0.000 description 3
- OKRROXQXGNEUSS-UHFFFAOYSA-N 1h-imidazol-1-ium-1-carboxylate Chemical compound OC(=O)N1C=CN=C1 OKRROXQXGNEUSS-UHFFFAOYSA-N 0.000 description 3
- KVCXTHNEGWAWBR-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylic acid Chemical compound C1C(CC2=CC=CC=C12)NC=1N=CC2=C(N=1)CN(C2)C(=O)O KVCXTHNEGWAWBR-UHFFFAOYSA-N 0.000 description 3
- QGTIZFBNPGUBQP-UHFFFAOYSA-N 2-chloro-1-[2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethanone Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C2CN(C(=O)CCl)CC2=N1 QGTIZFBNPGUBQP-UHFFFAOYSA-N 0.000 description 3
- XDKYMKYVFBRHSC-UHFFFAOYSA-N 3-amino-1-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]propan-1-one Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C(CN(C(=O)CCN)CC2)C2=N1 XDKYMKYVFBRHSC-UHFFFAOYSA-N 0.000 description 3
- WNLVSFGQIATVSL-UHFFFAOYSA-N 3-chloropropyl pyrimidine-4-carboxylate Chemical compound ClCCCOC(=O)C1=CC=NC=N1 WNLVSFGQIATVSL-UHFFFAOYSA-N 0.000 description 3
- IFXGTTGFKFJPRP-UHFFFAOYSA-N 4,5-dihydropyrimidine-6-carboxylic acid Chemical compound OC(=O)C1=NC=NCC1 IFXGTTGFKFJPRP-UHFFFAOYSA-N 0.000 description 3
- SHHMZGODDGYBRU-UHFFFAOYSA-N 5-(1h-1,2,4-triazol-5-yl)pentanoic acid Chemical compound OC(=O)CCCCC1=NN=CN1 SHHMZGODDGYBRU-UHFFFAOYSA-N 0.000 description 3
- YTRRZWTXQVETAL-UHFFFAOYSA-N 5-imidazol-1-ylpentanoic acid Chemical compound OC(=O)CCCCN1C=CN=C1 YTRRZWTXQVETAL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- 108010000659 Choline oxidase Proteins 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 101000966782 Homo sapiens Lysophosphatidic acid receptor 1 Proteins 0.000 description 3
- 102100040607 Lysophosphatidic acid receptor 1 Human genes 0.000 description 3
- VOLGDVHQHHLZNI-UHFFFAOYSA-N OC1=CN=NN1CC1=CC=CC=C1 Chemical compound OC1=CN=NN1CC1=CC=CC=C1 VOLGDVHQHHLZNI-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- UDLLFLQFQMACJB-UHFFFAOYSA-N azidomethylbenzene Chemical compound [N-]=[N+]=NCC1=CC=CC=C1 UDLLFLQFQMACJB-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 3
- MDUPGSVZADYURN-UHFFFAOYSA-N methyl 5-(1h-1,2,4-triazol-5-yl)pentanoate Chemical compound COC(=O)CCCCC1=NN=CN1 MDUPGSVZADYURN-UHFFFAOYSA-N 0.000 description 3
- AOJCPQABHBGKLZ-UHFFFAOYSA-N methyl 5-imidazol-1-ylpentanoate Chemical compound COC(=O)CCCCN1C=CN=C1 AOJCPQABHBGKLZ-UHFFFAOYSA-N 0.000 description 3
- GPWHRNCWEWWREW-UHFFFAOYSA-N methyl 6-imino-6-methoxyhexanoate Chemical compound COC(=N)CCCCC(=O)OC GPWHRNCWEWWREW-UHFFFAOYSA-N 0.000 description 3
- VSUAUEZJDNPFJU-UHFFFAOYSA-N n-[3-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-3-oxopropyl]-2-(2h-triazol-4-yl)acetamide Chemical compound C1CC2=NC(NC3CC4=CC=CC=C4C3)=NC=C2CN1C(=O)CCNC(=O)CC1=CN=NN1 VSUAUEZJDNPFJU-UHFFFAOYSA-N 0.000 description 3
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- 208000021722 neuropathic pain Diseases 0.000 description 3
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- WBLJAFRACIKJPO-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-4-(2h-triazol-4-yloxy)butan-1-one Chemical compound C1C2=CN=C(NC3CC4=CC=CC=C4C3)N=C2CN1C(=O)CCCOC1=CN=NN1 WBLJAFRACIKJPO-UHFFFAOYSA-N 0.000 description 2
- FCVLURNBAXUBNK-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-2-[2-(2h-triazol-4-yl)ethylamino]ethanone Chemical compound C1CC2=NC(NC3CC4=CC=CC=C4C3)=NC=C2CN1C(=O)CNCCC1=CNN=N1 FCVLURNBAXUBNK-UHFFFAOYSA-N 0.000 description 2
- RETKKMHFGPNHKX-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-(1h-1,2,4-triazol-5-yl)pentan-1-one Chemical compound C1CC2=NC(NC3CC4=CC=CC=C4C3)=NC=C2CN1C(=O)CCCCC1=NN=CN1 RETKKMHFGPNHKX-UHFFFAOYSA-N 0.000 description 2
- YPCJETBKQKPMJR-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]prop-2-en-1-one Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C(CN(C(=O)C=C)CC2)C2=N1 YPCJETBKQKPMJR-UHFFFAOYSA-N 0.000 description 2
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- XEHNLVMHWYPNEQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-2-amine;hydron;chloride Chemical compound Cl.C1=CC=C2CC(N)CC2=C1 XEHNLVMHWYPNEQ-UHFFFAOYSA-N 0.000 description 2
- RPWOXDPRCWDGAV-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-2-yl)guanidine;hydrochloride Chemical compound Cl.C1=CC=C2CC(NC(=N)N)CC2=C1 RPWOXDPRCWDGAV-UHFFFAOYSA-N 0.000 description 2
- UVRGQTUGTYVJMY-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-2-ylamino)-n-[3-(2h-triazol-4-yl)propyl]-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxamide Chemical compound C1C2=CN=C(NC3CC4=CC=CC=C4C3)N=C2CN1C(=O)NCCCC1=CNN=N1 UVRGQTUGTYVJMY-UHFFFAOYSA-N 0.000 description 2
- HIEBJAJYYYIJBG-UHFFFAOYSA-N 2-(3-benzyltriazol-4-yl)ethanol Chemical compound OCCC1=CN=NN1CC1=CC=CC=C1 HIEBJAJYYYIJBG-UHFFFAOYSA-N 0.000 description 2
- IJOIRJZTDNTHBH-UHFFFAOYSA-N 2-[2-(2h-triazol-4-yl)ethoxy]acetic acid Chemical compound OC(=O)COCCC1=CN=NN1 IJOIRJZTDNTHBH-UHFFFAOYSA-N 0.000 description 2
- YJLNTPGLVQYOHF-UHFFFAOYSA-N 2-[2-(2h-triazol-4-yl)ethoxy]acetic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)COCCC=1C=NNN=1 YJLNTPGLVQYOHF-UHFFFAOYSA-N 0.000 description 2
- GROBUVWLBAUKRV-UHFFFAOYSA-N 2-[2-(3-benzyltriazol-4-yl)ethoxy]acetic acid Chemical compound OC(=O)COCCC1=CN=NN1CC1=CC=CC=C1 GROBUVWLBAUKRV-UHFFFAOYSA-N 0.000 description 2
- LMHHFZAXSANGGM-UHFFFAOYSA-N 2-aminoindane Chemical compound C1=CC=C2CC(N)CC2=C1 LMHHFZAXSANGGM-UHFFFAOYSA-N 0.000 description 2
- CRFNTPQWQJNNIJ-UHFFFAOYSA-N 2-chloro-1-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]ethanone Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C(CN(C(=O)CCl)CC2)C2=N1 CRFNTPQWQJNNIJ-UHFFFAOYSA-N 0.000 description 2
- MIYYHRKHTATJBK-UHFFFAOYSA-N 3-cyanopropyl 2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C2CN(C(OCCCC#N)=O)CC2=N1 MIYYHRKHTATJBK-UHFFFAOYSA-N 0.000 description 2
- MTZYOLLXSSOINO-UHFFFAOYSA-N 4-(2h-triazol-4-yloxy)butanoic acid Chemical compound OC(=O)CCCOC=1C=NNN=1 MTZYOLLXSSOINO-UHFFFAOYSA-N 0.000 description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 108010022198 alkylglycerophosphoethanolamine phosphodiesterase Proteins 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- YFEPBWKUBQUBKL-UHFFFAOYSA-N methyl 3-(1h-imidazol-5-yl)propanoate Chemical compound COC(=O)CCC1=CN=CN1 YFEPBWKUBQUBKL-UHFFFAOYSA-N 0.000 description 2
- KLYWBEYHBMQROR-UHFFFAOYSA-N methyl 4-(2h-triazol-4-yloxy)butanoate Chemical compound COC(=O)CCCOC=1C=NNN=1 KLYWBEYHBMQROR-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- BZLLXCHQGATQEU-UHFFFAOYSA-N n-[3-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-3-oxopropyl]-2h-triazole-4-carboxamide Chemical compound C1CC2=NC(NC3CC4=CC=CC=C4C3)=NC=C2CN1C(=O)CCNC(=O)C1=CNN=N1 BZLLXCHQGATQEU-UHFFFAOYSA-N 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 description 2
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 2
- GGCHVJMWJMWPKE-UHFFFAOYSA-N tert-butyl pyrimidine-4-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=NC=N1 GGCHVJMWJMWPKE-UHFFFAOYSA-N 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- HEZMIBYFHMDJNE-UHFFFAOYSA-N 1-[2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-6-yl]-5-imidazol-1-ylpentan-1-one Chemical compound C1CC2=NC(NC3CC4=CC=CC=C4C3)=NC=C2CN1C(=O)CCCCN1C=CN=C1 HEZMIBYFHMDJNE-UHFFFAOYSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PFNOXNBSXVMIAI-UHFFFAOYSA-N 2-(2h-triazol-4-yl)acetamide Chemical compound NC(=O)CC1=CNN=N1 PFNOXNBSXVMIAI-UHFFFAOYSA-N 0.000 description 1
- VJPICIAGVDFWEO-UHFFFAOYSA-N 2-chloro-6,7-dihydro-5h-pyrrolo[3,4-d]pyrimidine Chemical compound ClC1=NC=C2CNCC2=N1 VJPICIAGVDFWEO-UHFFFAOYSA-N 0.000 description 1
- AMSDWLOANMAILF-UHFFFAOYSA-N 2-imidazol-1-ylethanol Chemical compound OCCN1C=CN=C1 AMSDWLOANMAILF-UHFFFAOYSA-N 0.000 description 1
- GTODOEDLCNTSLG-UHFFFAOYSA-N 2h-triazole-4-carboxylic acid Chemical compound OC(=O)C1=CNN=N1 GTODOEDLCNTSLG-UHFFFAOYSA-N 0.000 description 1
- WCFJUSRQHZPVKY-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NCCC(O)=O WCFJUSRQHZPVKY-UHFFFAOYSA-N 0.000 description 1
- JJNHCVLGDXAMEW-UHFFFAOYSA-N 3-chloropropyl 2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C2CN(C(=O)OCCCCl)CC2=N1 JJNHCVLGDXAMEW-UHFFFAOYSA-N 0.000 description 1
- UXIGAUJZNRUQSO-UHFFFAOYSA-N 3-chloropropyl 2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidine-6-carboxylate Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C(CN(C(=O)OCCCCl)CC2)C2=N1 UXIGAUJZNRUQSO-UHFFFAOYSA-N 0.000 description 1
- JOMRZAVGSLQILC-UHFFFAOYSA-N 5-[3-[(2-methylpropan-2-yl)oxycarbonyl]imidazol-4-yl]pentanoic acid Chemical compound CC(C)(C)OC(=O)N1C=NC=C1CCCCC(O)=O JOMRZAVGSLQILC-UHFFFAOYSA-N 0.000 description 1
- OQQQSCLHEDSFOH-UHFFFAOYSA-N 5-bromopentanamide Chemical compound NC(=O)CCCCBr OQQQSCLHEDSFOH-UHFFFAOYSA-N 0.000 description 1
- WNXNUPJZWYOKMW-UHFFFAOYSA-N 5-bromopentanoic acid Chemical compound OC(=O)CCCCBr WNXNUPJZWYOKMW-UHFFFAOYSA-N 0.000 description 1
- DMSUMDMNEXNYPC-UHFFFAOYSA-N 6-[2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-6-oxohexanenitrile Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C2CN(C(CCCCC#N)=O)CC2=N1 DMSUMDMNEXNYPC-UHFFFAOYSA-N 0.000 description 1
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- 235000011330 Armoracia rusticana Nutrition 0.000 description 1
- 240000003291 Armoracia rusticana Species 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 229940122849 Autotaxin inhibitor Drugs 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- LVHLLQKVXQGXNU-UHFFFAOYSA-N OC1=C(C(=O)OCC)N=NN1CC1=CC=CC=C1 Chemical compound OC1=C(C(=O)OCC)N=NN1CC1=CC=CC=C1 LVHLLQKVXQGXNU-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000014190 Phosphatidylcholine-sterol O-acyltransferase Human genes 0.000 description 1
- 108010011964 Phosphatidylcholine-sterol O-acyltransferase Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- DFPOZTRSOAQFIK-UHFFFAOYSA-N S,S-dimethyl-beta-propiothetin Chemical compound C[S+](C)CCC([O-])=O DFPOZTRSOAQFIK-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- XSBPYGDBXQXSCU-UHFFFAOYSA-N but-3-yn-1-amine Chemical compound NCCC#C XSBPYGDBXQXSCU-UHFFFAOYSA-N 0.000 description 1
- PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 description 1
- ICXXXLGATNSZAV-UHFFFAOYSA-N butylazanium;chloride Chemical compound [Cl-].CCCC[NH3+] ICXXXLGATNSZAV-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- LJQOTKFLOZZVML-UHFFFAOYSA-N chloryl chlorate Chemical compound O=[Cl](=O)O[Cl](=O)=O LJQOTKFLOZZVML-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- ZCKYOWGFRHAZIQ-UHFFFAOYSA-N dihydrourocanic acid Chemical compound OC(=O)CCC1=CNC=N1 ZCKYOWGFRHAZIQ-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 239000011536 extraction buffer Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- AILKHAQXUAOOFU-UHFFFAOYSA-N hexanenitrile Chemical compound CCCCCC#N AILKHAQXUAOOFU-UHFFFAOYSA-N 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- HNWWAWKDVFVJRG-UHFFFAOYSA-N hydron;6-hydroxy-1h-pyridin-2-one;chloride Chemical compound Cl.OC1=CC=CC(=O)N1 HNWWAWKDVFVJRG-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- QAFBDRSXXHEXGB-UHFFFAOYSA-N imidazol-1-ylacetic acid Chemical compound OC(=O)CN1C=CN=C1 QAFBDRSXXHEXGB-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- IKOMUVKGGBXEKG-UHFFFAOYSA-N methyl 4-(3-benzyltriazol-4-yl)oxybutanoate Chemical compound COC(=O)CCCOC1=CN=NN1CC1=CC=CC=C1 IKOMUVKGGBXEKG-UHFFFAOYSA-N 0.000 description 1
- QAWFLJGZSZIZHO-UHFFFAOYSA-N methyl 4-bromobutanoate Chemical compound COC(=O)CCCBr QAWFLJGZSZIZHO-UHFFFAOYSA-N 0.000 description 1
- RAVVJKCSZXAIQP-UHFFFAOYSA-N methyl 5-bromopentanoate Chemical compound COC(=O)CCCCBr RAVVJKCSZXAIQP-UHFFFAOYSA-N 0.000 description 1
- FLUGZEGZYQCCTQ-UHFFFAOYSA-N methyl 5-cyanopentanoate Chemical compound COC(=O)CCCCC#N FLUGZEGZYQCCTQ-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- RESRVDFIMBPWDM-UHFFFAOYSA-N n-(2,3-dihydro-1h-inden-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine Chemical compound C1NCCC2=NC(NC3CC4=CC=CC=C4C3)=NC=C21 RESRVDFIMBPWDM-UHFFFAOYSA-N 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- DBZSBXFQTNEHIA-UHFFFAOYSA-N tert-butyl 2-(2,3-dihydro-1h-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C2CN(C(=O)OC(C)(C)C)CC2=N1 DBZSBXFQTNEHIA-UHFFFAOYSA-N 0.000 description 1
- VZOQZQKRMKARBR-UHFFFAOYSA-N tert-butyl 2-(2,3-dihydro-1h-inden-2-ylamino)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidine-6-carboxylate Chemical compound C1C2=CC=CC=C2CC1NC1=NC=C(CN(C(=O)OC(C)(C)C)CC2)C2=N1 VZOQZQKRMKARBR-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- MTBKGWHHOBJMHJ-UHFFFAOYSA-N tert-butyl imidazole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CN=C1 MTBKGWHHOBJMHJ-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000005292 vacuum distillation 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Epidemiology (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361751363P | 2013-01-11 | 2013-01-11 | |
| US201361751363P | 2013-01-11 | ||
| US201361777201P | 2013-03-12 | 2013-03-12 | |
| US201361777201P | 2013-03-12 | ||
| PCT/US2014/010400 WO2014110000A1 (en) | 2013-01-11 | 2014-01-07 | Pyrido- or pyrrolo-fused pyrimidine derivatives as autotaxin inhibitors for treating pain |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2636248T3 true ES2636248T3 (es) | 2017-10-05 |
Family
ID=50031555
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES14702336.0T Active ES2636248T3 (es) | 2013-01-11 | 2014-01-07 | Derivados de pirimidina pirido- o pirrolo-fusionados como inhibidores de autotaxina para el tratamiento del dolor |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US8969555B2 (enExample) |
| EP (1) | EP2943494B1 (enExample) |
| JP (1) | JP6285461B2 (enExample) |
| KR (1) | KR101757997B1 (enExample) |
| CN (1) | CN104903327B (enExample) |
| AU (1) | AU2014205642B2 (enExample) |
| BR (1) | BR112015015812A2 (enExample) |
| CA (1) | CA2893253C (enExample) |
| EA (1) | EA025106B1 (enExample) |
| ES (1) | ES2636248T3 (enExample) |
| MX (1) | MX2015008971A (enExample) |
| TW (1) | TWI499591B (enExample) |
| WO (1) | WO2014110000A1 (enExample) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201500356A (zh) * | 2013-04-12 | 2015-01-01 | Lilly Co Eli | 二氫吡啶并嘧啶化合物 |
| EP3878848A1 (en) | 2013-11-22 | 2021-09-15 | Sabre Therapeutics LLC | Autotaxin inhibiting indole compounds |
| US9051320B1 (en) | 2014-08-18 | 2015-06-09 | Pharmakea, Inc. | Methods for the treatment of metabolic disorders by a selective small molecule autotaxin inhibitor |
| GB201501870D0 (en) | 2015-02-04 | 2015-03-18 | Cancer Rec Tech Ltd | Autotaxin inhibitors |
| GB201502020D0 (en) | 2015-02-06 | 2015-03-25 | Cancer Rec Tech Ltd | Autotaxin inhibitory compounds |
| EP4026549A1 (en) | 2015-05-27 | 2022-07-13 | Sabre Therapeutics LLC | Autotaxin inhibitors and uses thereof |
| HK1252425A1 (zh) | 2015-06-05 | 2019-05-24 | Vertex Pharmaceuticals Incorporated | 用於治疗脱髓鞘疾病的三唑类药物 |
| WO2018106643A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Heterocyclic azoles for the treatment of demyelinating diseases |
| WO2018106641A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Pyrazoles for the treatment of demyelinating diseases |
| WO2018106646A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Aminotriazoles for the treatment of demyelinating diseases |
| KR101798840B1 (ko) | 2017-05-17 | 2017-11-17 | 주식회사 레고켐 바이오사이언스 | 신규 오토탁신 저해 화합물 및 이를 함유하는 약제학적 조성물 |
| US10961242B2 (en) | 2017-05-17 | 2021-03-30 | Legochem Biosciences, Inc. | Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same |
| JP7274767B2 (ja) * | 2018-05-24 | 2023-05-17 | ▲広▼州市恒▲諾▼康医▲薬▼科技有限公司 | 芳香族複素環式化合物及びその医薬組成物 |
| AU2019308231B2 (en) * | 2018-07-16 | 2022-12-22 | The Scripps Research Institute | Opioid haptens, conjugates, vaccines, and methods of generating antibodies |
| US12221449B2 (en) * | 2019-02-01 | 2025-02-11 | Wuhan Humanwell Innovative Drug Research and Development Center Limited Company | Pyrrolopyrimidine derivative and use thereof |
| EP4029858A4 (en) | 2019-09-06 | 2023-11-01 | Wuhan Humanwell Innovative Drug Research and Development Center Limited Company | PYRIMIDINE COMPOUND AND PROCESS FOR PRODUCTION THEREOF |
| CN114787135A (zh) * | 2019-09-17 | 2022-07-22 | 比亚尔R&D投资股份公司 | 经取代的咪唑甲酰胺及其在治疗医学病症中的用途 |
| WO2021088957A1 (zh) * | 2019-11-07 | 2021-05-14 | 广州市恒诺康医药科技有限公司 | 芳杂环化合物、其药物组合物及其应用 |
| KR20220113731A (ko) * | 2019-12-11 | 2022-08-16 | 스촨 하이스코 파마수티컬 씨오., 엘티디 | 질소-함유 헤테로사이클릭 오토택신 억제제, 및 이를 함유하는 조성물 및 이의 용도 |
| CN113943296B (zh) * | 2020-07-16 | 2025-07-04 | 武汉人福创新药物研发中心有限公司 | 吡咯并嘧啶衍生物及其应用 |
| CN113943295B (zh) * | 2020-07-16 | 2025-08-12 | 武汉人福创新药物研发中心有限公司 | 吡咯并嘧啶类化合物及其用途 |
| CN113999235B (zh) * | 2020-07-28 | 2025-06-10 | 武汉人福创新药物研发中心有限公司 | 含氮杂环化合物的固体形式及其药物组合物和用途 |
| JP7663685B2 (ja) * | 2020-07-28 | 2025-04-16 | 武漢人福創新薬物研発中心有限公司 | 含窒素複素環化合物の塩及びその塩の固体形態、医薬組成物並びに用途 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SV2002000205A (es) * | 1999-11-01 | 2002-06-07 | Lilly Co Eli | Compuestos farmaceuticos ref. x-01095 |
| AU2003242252A1 (en) | 2002-06-07 | 2003-12-22 | Kyowa Hakko Kogyo Co., Ltd. | Bicyclic pyrimidine derivatives |
| DE102004020908A1 (de) * | 2004-04-28 | 2005-11-17 | Grünenthal GmbH | Substituierte 5,6,7,8,-Tetrahydro-pyrido[4,3-d]pyrimidin-2-yl- und 5,6,7,8,-Tetrahydro-chinazolin-2-yl-Verbindungen |
| CA2606760C (en) * | 2005-05-04 | 2014-12-23 | Renovis, Inc. | Tetrahydronaphthyridine and tetrahydropyrido[4,3-d]pyrimidine compounds and compositions thereof useful in the treatment of conditions associated with neurological and inflammatory disorders and disfunctions |
| AU2009321867B2 (en) * | 2008-12-01 | 2015-12-10 | Merck Patent Gmbh | 2,5-Diamino-substituted pyrido[4,3-d]pyrimidines as autotaxin inhibitors against cancer |
| WO2012009258A2 (en) * | 2010-07-13 | 2012-01-19 | Edward Roberts | Peptidomimetic galanin receptor modulators |
| EP2606031B1 (en) * | 2010-08-20 | 2017-09-27 | Amira Pharmaceuticals, Inc. | Autotaxin inhibitors and uses thereof |
| WO2012085167A1 (en) * | 2010-12-22 | 2012-06-28 | Merz Pharma Gmbh & Co. Kgaa | Metabotropic glutamate receptor modulators |
| WO2013054185A1 (en) * | 2011-10-13 | 2013-04-18 | Pfizer, Inc. | Pyrimidine and pyridine derivatives useful in therapy |
| JP6158817B2 (ja) * | 2011-10-28 | 2017-07-05 | インヒビタクシン リミテッド | 治療に有用なピリダジン誘導体 |
| TW201520219A (zh) * | 2013-03-12 | 2015-06-01 | Lilly Co Eli | 咪唑並吡啶化合物 |
| TW201500356A (zh) * | 2013-04-12 | 2015-01-01 | Lilly Co Eli | 二氫吡啶并嘧啶化合物 |
-
2013
- 2013-12-30 TW TW102149122A patent/TWI499591B/zh active
-
2014
- 2014-01-07 EP EP14702336.0A patent/EP2943494B1/en active Active
- 2014-01-07 US US14/148,775 patent/US8969555B2/en active Active
- 2014-01-07 CN CN201480004482.6A patent/CN104903327B/zh not_active Expired - Fee Related
- 2014-01-07 AU AU2014205642A patent/AU2014205642B2/en not_active Ceased
- 2014-01-07 BR BR112015015812A patent/BR112015015812A2/pt not_active IP Right Cessation
- 2014-01-07 WO PCT/US2014/010400 patent/WO2014110000A1/en not_active Ceased
- 2014-01-07 EA EA201591098A patent/EA025106B1/ru not_active IP Right Cessation
- 2014-01-07 JP JP2015552726A patent/JP6285461B2/ja not_active Expired - Fee Related
- 2014-01-07 KR KR1020157018295A patent/KR101757997B1/ko not_active Expired - Fee Related
- 2014-01-07 CA CA2893253A patent/CA2893253C/en not_active Expired - Fee Related
- 2014-01-07 MX MX2015008971A patent/MX2015008971A/es unknown
- 2014-01-07 ES ES14702336.0T patent/ES2636248T3/es active Active
Also Published As
| Publication number | Publication date |
|---|---|
| US8969555B2 (en) | 2015-03-03 |
| EA025106B1 (ru) | 2016-11-30 |
| TW201437209A (zh) | 2014-10-01 |
| EA201591098A1 (ru) | 2015-11-30 |
| CN104903327B (zh) | 2016-09-07 |
| CA2893253A1 (en) | 2014-07-17 |
| KR20150092761A (ko) | 2015-08-13 |
| KR101757997B1 (ko) | 2017-07-13 |
| BR112015015812A2 (pt) | 2017-07-11 |
| EP2943494A1 (en) | 2015-11-18 |
| CN104903327A (zh) | 2015-09-09 |
| JP6285461B2 (ja) | 2018-02-28 |
| CA2893253C (en) | 2017-11-28 |
| AU2014205642A1 (en) | 2015-07-02 |
| US20140200231A1 (en) | 2014-07-17 |
| EP2943494B1 (en) | 2017-02-22 |
| JP2016505010A (ja) | 2016-02-18 |
| WO2014110000A1 (en) | 2014-07-17 |
| TWI499591B (zh) | 2015-09-11 |
| AU2014205642B2 (en) | 2016-02-25 |
| MX2015008971A (es) | 2015-09-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2636248T3 (es) | Derivados de pirimidina pirido- o pirrolo-fusionados como inhibidores de autotaxina para el tratamiento del dolor | |
| ES2639125T3 (es) | Compuestos de imidazo piridina | |
| JP6133491B2 (ja) | ジヒドロピリドピリミジン化合物 | |
| ES2911428T3 (es) | Inhibidores de STAT3 | |
| AU2020241258A1 (en) | Novel small molecule inhibitors of tead transcription factors | |
| WO1992018504A1 (en) | PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVE AND ANTI-INFLAMMATORY CONTAINING THE SAME | |
| PT1246623E (pt) | Compostos específicos para o receptor de adenosina a1,a2a e a3 e as suas utilizações | |
| JP7138768B2 (ja) | ジメチルホスフィンオキシド化合物 | |
| JPH07502743A (ja) | Ｐａｆ及びアンジオテンシン２の拮抗剤としての複素環スルホンアミド誘導体 | |
| ES2909709T3 (es) | Inhibidores del receptor 2 activado por proteasa | |
| US7622502B2 (en) | Nitric oxide releasing prodrugs of diaryl-2-(5h)-furanones as cyclooxygenase-2 inhibitors |