ES2895969T3 - Derivados de [1,2,4]triazolo como inhibidores de PDE1 para el tratamiento de diabetes - Google Patents
Derivados de [1,2,4]triazolo como inhibidores de PDE1 para el tratamiento de diabetes Download PDFInfo
- Publication number
- ES2895969T3 ES2895969T3 ES18759465T ES18759465T ES2895969T3 ES 2895969 T3 ES2895969 T3 ES 2895969T3 ES 18759465 T ES18759465 T ES 18759465T ES 18759465 T ES18759465 T ES 18759465T ES 2895969 T3 ES2895969 T3 ES 2895969T3
- Authority
- ES
- Spain
- Prior art keywords
- scheme
- mmol
- reduced pressure
- under reduced
- mixture
- 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
- 206010012601 diabetes mellitus Diseases 0.000 title description 4
- 229940121836 Phosphodiesterase 1 inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 12
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims abstract description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000019256 formaldehyde Nutrition 0.000 claims abstract description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims abstract description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 9
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 208000020832 chronic kidney disease Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 127
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 86
- 230000002829 reductive effect Effects 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 239000000047 product Substances 0.000 description 73
- 239000000284 extract Substances 0.000 description 65
- 239000000203 mixture Substances 0.000 description 63
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 62
- 239000012141 concentrate Substances 0.000 description 62
- 238000002360 preparation method Methods 0.000 description 50
- -1 AcOH Chemical class 0.000 description 45
- 229920006395 saturated elastomer Polymers 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 41
- 238000003756 stirring Methods 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 239000011780 sodium chloride Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- 229910001868 water Inorganic materials 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 238000004587 chromatography analysis Methods 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- 238000000746 purification Methods 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 20
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 0 *CN(C(CCOC1)=C1N=C1NN)C1=O Chemical compound *CN(C(CCOC1)=C1N=C1NN)C1=O 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 239000007832 Na2SO4 Substances 0.000 description 16
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 16
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- 238000007796 conventional method Methods 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 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 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 235000019341 magnesium sulphate Nutrition 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
- 101001117099 Homo sapiens Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B Proteins 0.000 description 9
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- XYVCFEDFMLOASQ-UHFFFAOYSA-N 1-cyclopropylcyclopropane-1-carboxylic acid Chemical compound C1CC1C1(C(=O)O)CC1 XYVCFEDFMLOASQ-UHFFFAOYSA-N 0.000 description 8
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-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
- 102100024318 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B Human genes 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 102100024317 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C Human genes 0.000 description 7
- 101001117089 Drosophila melanogaster Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 Proteins 0.000 description 7
- 101001117044 Homo sapiens Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A Proteins 0.000 description 7
- 101001117094 Homo sapiens Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C Proteins 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000003495 polar organic solvent Substances 0.000 description 7
- 235000019345 sodium thiosulphate Nutrition 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 101000609947 Homo sapiens Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha Proteins 0.000 description 6
- 101000988419 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4D Proteins 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 5
- KUCSFTQJADYIQH-UHFFFAOYSA-N 3-aminooxan-4-ol Chemical compound NC1COCCC1O KUCSFTQJADYIQH-UHFFFAOYSA-N 0.000 description 5
- 101001098818 Homo sapiens cGMP-inhibited 3',5'-cyclic phosphodiesterase A Proteins 0.000 description 5
- RFAXLXKIAKIUDT-UHFFFAOYSA-N IPA-3 Chemical compound C1=CC=C2C(SSC3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 RFAXLXKIAKIUDT-UHFFFAOYSA-N 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
- HCHDWLDDXRUBRA-UHFFFAOYSA-N 1-(1-cyclopropylcyclopropyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-one Chemical compound C1(CC1)C1(CC1)C1=NN=C2N1C=1CCCCC=1NC2=O HCHDWLDDXRUBRA-UHFFFAOYSA-N 0.000 description 4
- ZWOFTVSNNFYPAB-UHFFFAOYSA-N 2-aminocycloheptan-1-ol Chemical compound NC1CCCCCC1O ZWOFTVSNNFYPAB-UHFFFAOYSA-N 0.000 description 4
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 4
- OPSJIGGYLIIFFG-UHFFFAOYSA-N 4-(cyclopropylmethyl)-2-hydrazinyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-3-one Chemical compound C1(CC1)CN1C2=C(N=C(C1=O)NN)CCCCC2 OPSJIGGYLIIFFG-UHFFFAOYSA-N 0.000 description 4
- VSACBGUIUMIXMR-UHFFFAOYSA-N C1(CC1)C1(CC1)C(=O)NNC=1C(N(C2=C(N=1)CCCCC2)CC1CC1)=O Chemical compound C1(CC1)C1(CC1)C(=O)NNC=1C(N(C2=C(N=1)CCCCC2)CC1CC1)=O VSACBGUIUMIXMR-UHFFFAOYSA-N 0.000 description 4
- KZEMGNTWPPEABJ-UHFFFAOYSA-N C1(CC1)CNC(=O)C(=O)NC1C(CCCCC1)=O Chemical compound C1(CC1)CNC(=O)C(=O)NC1C(CCCCC1)=O KZEMGNTWPPEABJ-UHFFFAOYSA-N 0.000 description 4
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 4
- ZROLVJZDMSMQRL-UHFFFAOYSA-N O=C1NC2=C(CCCCC2)N(CC2CC2)C1=O Chemical compound O=C1NC2=C(CCCCC2)N(CC2CC2)C1=O ZROLVJZDMSMQRL-UHFFFAOYSA-N 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 102000055551 human PDE1A Human genes 0.000 description 4
- 102000048009 human PDE6A Human genes 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920000936 Agarose Polymers 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- JNZHDIBQOIISJU-UHFFFAOYSA-N C(CCC)N1C2=C(N=C(C1=O)Cl)CCOC2 Chemical compound C(CCC)N1C2=C(N=C(C1=O)Cl)CCOC2 JNZHDIBQOIISJU-UHFFFAOYSA-N 0.000 description 3
- NSTJBODBDYSZEW-UHFFFAOYSA-N C1(CC1)CNC(=O)C(=O)NC1C(CCCCC1)O Chemical compound C1(CC1)CNC(=O)C(=O)NC1C(CCCCC1)O NSTJBODBDYSZEW-UHFFFAOYSA-N 0.000 description 3
- 102100024316 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A Human genes 0.000 description 3
- WLYAPNZTYZDHRG-UHFFFAOYSA-N Cl.NNC(=O)C1(CC1)C1CC1 Chemical compound Cl.NNC(=O)C1(CC1)C1CC1 WLYAPNZTYZDHRG-UHFFFAOYSA-N 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
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZETGQZGXOHIJEP-UHFFFAOYSA-N N-(cyclopropylmethyl)-N'-(3-hydroxyoxan-4-yl)oxamide Chemical compound C1(CC1)CNC(=O)C(=O)NC1C(COCC1)O ZETGQZGXOHIJEP-UHFFFAOYSA-N 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 102100029170 cAMP-specific 3',5'-cyclic phosphodiesterase 4D Human genes 0.000 description 3
- 102100037093 cGMP-inhibited 3',5'-cyclic phosphodiesterase A Human genes 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- VRXCJMOABLQKQP-UHFFFAOYSA-N ethyl 2-(cyclopropylmethylamino)-2-oxoacetate Chemical compound CCOC(=O)C(=O)NCC1CC1 VRXCJMOABLQKQP-UHFFFAOYSA-N 0.000 description 3
- KGSUEYMMVBJVSO-UHFFFAOYSA-N ethyl 2-oxo-2-(prop-2-enylamino)acetate Chemical compound CCOC(=O)C(=O)NCC=C KGSUEYMMVBJVSO-UHFFFAOYSA-N 0.000 description 3
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 3
- 102000048135 human PDE4D Human genes 0.000 description 3
- 239000003791 organic solvent mixture Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- ZYOYYQRWXITKFF-UHFFFAOYSA-N pyrazine-2,3-dione Chemical compound O=C1N=CC=NC1=O ZYOYYQRWXITKFF-UHFFFAOYSA-N 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000002821 scintillation proximity assay Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- PQMCFTMVQORYJC-UHFFFAOYSA-N 2-aminocyclohexan-1-ol Chemical compound NC1CCCCC1O PQMCFTMVQORYJC-UHFFFAOYSA-N 0.000 description 2
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 2
- PBQHDTRHGNGTLZ-UHFFFAOYSA-N 4-aminooxan-3-ol Chemical compound NC1CCOCC1O PBQHDTRHGNGTLZ-UHFFFAOYSA-N 0.000 description 2
- NHHYCGIUZMMXNN-UHFFFAOYSA-N 5-butyl-1-(1-cyclopropylcyclopropyl)-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-one Chemical compound C1(CC1)(C1CC1)C1=NN=C2N1C=1CCCCC=1N(C2=O)CCCC NHHYCGIUZMMXNN-UHFFFAOYSA-N 0.000 description 2
- MLOZFLXCWGERSM-UHFFFAOYSA-N 8-oxabicyclo[5.1.0]octane Chemical compound C1CCCCC2OC21 MLOZFLXCWGERSM-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HWRSZLAJPKAMEI-UHFFFAOYSA-N C(CCC)N1C2=C(N=C(C1=O)NNC(=O)C1(CC1)C1CC1)CCOC2 Chemical compound C(CCC)N1C2=C(N=C(C1=O)NNC(=O)C1(CC1)C1CC1)CCOC2 HWRSZLAJPKAMEI-UHFFFAOYSA-N 0.000 description 2
- NZAKUYGYWCPXCA-UHFFFAOYSA-N C(CCC)N1C2=C(N=C(C1=O)NNC(=O)C1(CC1)C1CC1)COCC2 Chemical compound C(CCC)N1C2=C(N=C(C1=O)NNC(=O)C1(CC1)C1CC1)COCC2 NZAKUYGYWCPXCA-UHFFFAOYSA-N 0.000 description 2
- PCAGOZHYDAOLQK-UHFFFAOYSA-N C(CCC)NC(=O)C(=O)NC1C(COCC1)O Chemical compound C(CCC)NC(=O)C(=O)NC1C(COCC1)O PCAGOZHYDAOLQK-UHFFFAOYSA-N 0.000 description 2
- RLQPTLNTJDLJIE-UHFFFAOYSA-N C(CCC)NC(=O)C(=O)NC1COCCC1O Chemical compound C(CCC)NC(=O)C(=O)NC1COCCC1O RLQPTLNTJDLJIE-UHFFFAOYSA-N 0.000 description 2
- YYYBSXDCPDHBHG-UHFFFAOYSA-N C1(CC1)CNC(=O)C(=O)NC1C(COCC1)=O Chemical compound C1(CC1)CNC(=O)C(=O)NC1C(COCC1)=O YYYBSXDCPDHBHG-UHFFFAOYSA-N 0.000 description 2
- GSAWJAWWSFIYCZ-UHFFFAOYSA-N C1(CC1)CNC(=O)C(=O)NC1COCCC1=O Chemical compound C1(CC1)CNC(=O)C(=O)NC1COCCC1=O GSAWJAWWSFIYCZ-UHFFFAOYSA-N 0.000 description 2
- DPKRFKYZKXQNSQ-UHFFFAOYSA-N C1(CC1)CNC(=O)C(=O)NC1COCCC1O Chemical compound C1(CC1)CNC(=O)C(=O)NC1COCCC1O DPKRFKYZKXQNSQ-UHFFFAOYSA-N 0.000 description 2
- PWQJHWAYCAOFNB-UHFFFAOYSA-N C1(CCC1)CNC(=O)C(=O)NC1COCCC1O Chemical compound C1(CCC1)CNC(=O)C(=O)NC1COCCC1O PWQJHWAYCAOFNB-UHFFFAOYSA-N 0.000 description 2
- BTOITRLBLOBEIF-UHFFFAOYSA-N CCCCN1C(=O)C(=O)NC2=C1CCOC2 Chemical compound CCCCN1C(=O)C(=O)NC2=C1CCOC2 BTOITRLBLOBEIF-UHFFFAOYSA-N 0.000 description 2
- NYHOHPXPMSKZSP-UHFFFAOYSA-N CCCCN1C(=O)C(=O)NC2=C1COCC2 Chemical compound CCCCN1C(=O)C(=O)NC2=C1COCC2 NYHOHPXPMSKZSP-UHFFFAOYSA-N 0.000 description 2
- SRRWKZNQSJJVNU-UHFFFAOYSA-N CCCCN1C(=O)C(NN)=NC2=C1CCOC2 Chemical compound CCCCN1C(=O)C(NN)=NC2=C1CCOC2 SRRWKZNQSJJVNU-UHFFFAOYSA-N 0.000 description 2
- PPIZHLCUMDEZCN-UHFFFAOYSA-N CCCCn1c2CCOCc2n2c(nnc2c1=O)C1(CC1)C1CC1 Chemical compound CCCCn1c2CCOCc2n2c(nnc2c1=O)C1(CC1)C1CC1 PPIZHLCUMDEZCN-UHFFFAOYSA-N 0.000 description 2
- 102000000584 Calmodulin Human genes 0.000 description 2
- 108010041952 Calmodulin Proteins 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- VXLBYALRBCEQBB-UHFFFAOYSA-N ClC1=NC2=C(N(C1=O)CC1CC1)COCC2 Chemical compound ClC1=NC2=C(N(C1=O)CC1CC1)COCC2 VXLBYALRBCEQBB-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 101000609949 Homo sapiens Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- NYRDVQMHKMEPED-UHFFFAOYSA-N N-butyl-N'-(3-oxooxan-4-yl)oxamide Chemical compound C(CCC)NC(=O)C(=O)NC1C(COCC1)=O NYRDVQMHKMEPED-UHFFFAOYSA-N 0.000 description 2
- UMYVXROKZRPCKY-UHFFFAOYSA-N N-butyl-N'-(4-oxooxan-3-yl)oxamide Chemical compound C(CCC)NC(=O)C(=O)NC1COCCC1=O UMYVXROKZRPCKY-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- QFEOBNGVPGUYSR-UHFFFAOYSA-N NNC1=NC2=C(CCOC2)N(CC2CC2)C1=O Chemical compound NNC1=NC2=C(CCOC2)N(CC2CC2)C1=O QFEOBNGVPGUYSR-UHFFFAOYSA-N 0.000 description 2
- ZVLKVUPKMTYOPG-UHFFFAOYSA-N NNC1=NC2=C(CCOC2)N(CC2CCC2)C1=O Chemical compound NNC1=NC2=C(CCOC2)N(CC2CCC2)C1=O ZVLKVUPKMTYOPG-UHFFFAOYSA-N 0.000 description 2
- PRTMMUURWHETJF-UHFFFAOYSA-N O=C1NC2=C(CCOC2)N(CC2CCC2)C1=O Chemical compound O=C1NC2=C(CCOC2)N(CC2CCC2)C1=O PRTMMUURWHETJF-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102100039177 Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha Human genes 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- MHAAXYQLMRKDKU-UHFFFAOYSA-N ethyl 2-(butylamino)-2-oxoacetate Chemical compound CCCCNC(=O)C(=O)OCC MHAAXYQLMRKDKU-UHFFFAOYSA-N 0.000 description 2
- GIVQQIREZOKSMZ-UHFFFAOYSA-N ethyl 2-(cyclobutylmethylamino)-2-oxoacetate Chemical compound CCOC(=O)C(=O)NCC1CCC1 GIVQQIREZOKSMZ-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 102000055047 human PDE3A Human genes 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000012536 storage buffer Substances 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZOYWVKURDMXZTC-UHFFFAOYSA-N 1-(1-cyclopropylcyclopropyl)-5-propyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-one Chemical compound CCCN1C(=O)C2=NN=C(N2C2=C1CCCC2)C1(CC1)C1CC1 ZOYWVKURDMXZTC-UHFFFAOYSA-N 0.000 description 1
- KPGVJESIOZYYCN-UHFFFAOYSA-N 1-cyclopropyl-N'-[1-(cyclopropylmethyl)-2-oxo-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-3-yl]cyclopropane-1-carbohydrazide Chemical compound O=C(NNC1=NC2=C(CCOC2)N(CC2CC2)C1=O)C1(CC1)C1CC1 KPGVJESIOZYYCN-UHFFFAOYSA-N 0.000 description 1
- CBOOYQXLMKLROJ-UHFFFAOYSA-N 1-cyclopropyl-N'-[4-(cyclopropylmethyl)-3-oxo-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-2-yl]cyclopropane-1-carbohydrazide Chemical compound O=C(NNC1=NC2=C(COCC2)N(CC2CC2)C1=O)C1(CC1)C1CC1 CBOOYQXLMKLROJ-UHFFFAOYSA-N 0.000 description 1
- NSEUGIOBLOALKP-UHFFFAOYSA-N 1-cyclopropylcyclopropane-1-carbohydrazide Chemical compound C1(CC1)C1(CC1)C(=O)NN NSEUGIOBLOALKP-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- 102000001707 3',5'-Cyclic-AMP Phosphodiesterases Human genes 0.000 description 1
- 108010054479 3',5'-Cyclic-AMP Phosphodiesterases Proteins 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- YXBLPELQAKXZRS-UHFFFAOYSA-N C1(CC1)(C1CC1)C1=NN=C2N1C1=C(N(C2=O)CC2CCC2)CCOC1 Chemical compound C1(CC1)(C1CC1)C1=NN=C2N1C1=C(N(C2=O)CC2CCC2)CCOC1 YXBLPELQAKXZRS-UHFFFAOYSA-N 0.000 description 1
- OTQSGQJYNNQNSN-UHFFFAOYSA-N C1(CC1)(C1CC1)C1=NN=C2N1C1=C(N(C2=O)CCCC)COCC1 Chemical compound C1(CC1)(C1CC1)C1=NN=C2N1C1=C(N(C2=O)CCCC)COCC1 OTQSGQJYNNQNSN-UHFFFAOYSA-N 0.000 description 1
- FFFJCGFOVPXVCS-UHFFFAOYSA-N C1(CC1)CN1C2=C(N=C(C1=O)NN)CCOC2 Chemical compound C1(CC1)CN1C2=C(N=C(C1=O)NN)CCOC2 FFFJCGFOVPXVCS-UHFFFAOYSA-N 0.000 description 1
- CQBTWMVUFSSSRF-UHFFFAOYSA-N C1(CCC1)CN1C2=C(N=C(C1=O)N(N)C(=O)C1(CC1)C1CC1)COCC2 Chemical compound C1(CCC1)CN1C2=C(N=C(C1=O)N(N)C(=O)C1(CC1)C1CC1)COCC2 CQBTWMVUFSSSRF-UHFFFAOYSA-N 0.000 description 1
- AMDOWOSSSGNTQL-UHFFFAOYSA-N CCCN1C(=O)C2NN=C(N2C2=C1CCCC2)C1(CC1)C1CC1 Chemical compound CCCN1C(=O)C2NN=C(N2C2=C1CCCC2)C1(CC1)C1CC1 AMDOWOSSSGNTQL-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 101100351286 Dictyostelium discoideum pdeE gene Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NDHZBNFDGLLLOF-UHFFFAOYSA-N N-(cyclobutylmethyl)-N'-(4-oxooxan-3-yl)oxamide Chemical compound C1(CCC1)CNC(=O)C(=O)NC1COCCC1=O NDHZBNFDGLLLOF-UHFFFAOYSA-N 0.000 description 1
- KYNSWNPAGFWHID-UHFFFAOYSA-N N1C2=C(NC(C1=O)=O)COCC2 Chemical class N1C2=C(NC(C1=O)=O)COCC2 KYNSWNPAGFWHID-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- SZXRRCSWGKUWMI-UHFFFAOYSA-N O=C1NC2=C(CCOC2)N(CC2CC2)C1=O Chemical compound O=C1NC2=C(CCOC2)N(CC2CC2)C1=O SZXRRCSWGKUWMI-UHFFFAOYSA-N 0.000 description 1
- BMVDVTZGAITBEQ-UHFFFAOYSA-N O=C1NC2=C(COCC2)N(CC2CC2)C1=O Chemical compound O=C1NC2=C(COCC2)N(CC2CC2)C1=O BMVDVTZGAITBEQ-UHFFFAOYSA-N 0.000 description 1
- FOSHUFIWZBKIJO-UHFFFAOYSA-N O=c1n(CC2CC2)c2CCCCCc2n2c(nnc12)C1(CC1)C1CC1 Chemical compound O=c1n(CC2CC2)c2CCCCCc2n2c(nnc12)C1(CC1)C1CC1 FOSHUFIWZBKIJO-UHFFFAOYSA-N 0.000 description 1
- VGHIZNBWVGBFNE-UHFFFAOYSA-N O=c1n(CC2CC2)c2CCOCc2n2c(nnc12)C1(CC1)C1CC1 Chemical compound O=c1n(CC2CC2)c2CCOCc2n2c(nnc12)C1(CC1)C1CC1 VGHIZNBWVGBFNE-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 102100039174 Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta Human genes 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- LQNHRNOPWKZUSN-UHFFFAOYSA-N cyclobutylmethanamine Chemical compound NCC1CCC1 LQNHRNOPWKZUSN-UHFFFAOYSA-N 0.000 description 1
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- RZMZBHSKPLVQCP-UHFFFAOYSA-N ethyl 2-amino-2-oxoacetate Chemical class CCOC(=O)C(N)=O RZMZBHSKPLVQCP-UHFFFAOYSA-N 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
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 102000055462 human PDE1B Human genes 0.000 description 1
- 102000054507 human PDE6B Human genes 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 101150037969 pde-6 gene Proteins 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762543427P | 2017-08-10 | 2017-08-10 | |
| PCT/US2018/045081 WO2019032383A1 (en) | 2017-08-10 | 2018-08-03 | [1,2,4] TRIAZOLO DERIVATIVES AS PDE1 INHIBITORS FOR THE TREATMENT OF DIABETES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2895969T3 true ES2895969T3 (es) | 2022-02-23 |
Family
ID=63364164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES18759465T Active ES2895969T3 (es) | 2017-08-10 | 2018-08-03 | Derivados de [1,2,4]triazolo como inhibidores de PDE1 para el tratamiento de diabetes |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US11401274B2 (enExample) |
| EP (1) | EP3665174B1 (enExample) |
| JP (1) | JP6834057B2 (enExample) |
| CN (1) | CN110914273B (enExample) |
| AR (1) | AR112346A1 (enExample) |
| ES (1) | ES2895969T3 (enExample) |
| TW (1) | TW201920188A (enExample) |
| WO (1) | WO2019032383A1 (enExample) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113072453A (zh) * | 2021-04-08 | 2021-07-06 | 红宝丽集团股份有限公司 | 一种2-氨基环烷醇的制备方法 |
| WO2025059641A1 (en) | 2023-09-14 | 2025-03-20 | Eli Lilly And Company | Pde1 inhibitors |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4354027A (en) | 1980-05-19 | 1982-10-12 | Usv Pharmaceutical Corporation | Triazoloquinoxalin-4-ones |
| FR2662163A1 (fr) * | 1990-05-16 | 1991-11-22 | Lipha | Nouvelles 8-amino-1,2,4-triazolo(4,3-a) pyrazines, procedes de preparation et medicaments les contenant. |
| CN1285834A (zh) | 1997-11-11 | 2001-02-28 | 小野药品工业株式会社 | 稠合吡嗪化合物 |
| DE602006021044D1 (de) * | 2005-09-29 | 2011-05-12 | Glaxo Group Ltd | Pyrazoloä3,4-büpyridinverbindungen und ihre verwendung als pde4-inhibitoren |
| ES2599054T3 (es) * | 2006-12-13 | 2017-01-31 | Aska Pharmaceutical Co., Ltd. | Derivados de quinoxalina |
| WO2008103357A1 (en) | 2007-02-21 | 2008-08-28 | E. I. Du Pont De Nemours And Company | Fungicidal tricyclic 1,2,4-triazoles |
| WO2012033101A1 (ja) * | 2010-09-07 | 2012-03-15 | アステラス製薬株式会社 | キノキサリン化合物 |
| IN2015DN00334A (enExample) | 2012-06-18 | 2015-06-12 | Dart Neuroscience Cayman Ltd | |
| AR107456A1 (es) | 2016-02-12 | 2018-05-02 | Lilly Co Eli | Inhibidor de pde1 |
| JOP20170164A1 (ar) | 2016-08-25 | 2019-01-30 | Lilly Co Eli | مشتق ترايازولو بيرازينون مفيد كمثبط لـ pde1 بشري |
-
2018
- 2018-07-27 TW TW107126001A patent/TW201920188A/zh unknown
- 2018-07-27 AR ARP180102122 patent/AR112346A1/es unknown
- 2018-08-03 CN CN201880051513.1A patent/CN110914273B/zh active Active
- 2018-08-03 EP EP18759465.0A patent/EP3665174B1/en active Active
- 2018-08-03 WO PCT/US2018/045081 patent/WO2019032383A1/en not_active Ceased
- 2018-08-03 US US16/628,164 patent/US11401274B2/en active Active
- 2018-08-03 JP JP2020506974A patent/JP6834057B2/ja active Active
- 2018-08-03 ES ES18759465T patent/ES2895969T3/es active Active
Also Published As
| Publication number | Publication date |
|---|---|
| EP3665174B1 (en) | 2021-09-15 |
| TW201920188A (zh) | 2019-06-01 |
| JP6834057B2 (ja) | 2021-02-24 |
| JP2020530023A (ja) | 2020-10-15 |
| CN110914273B (zh) | 2023-05-16 |
| WO2019032383A1 (en) | 2019-02-14 |
| CN110914273A (zh) | 2020-03-24 |
| US11401274B2 (en) | 2022-08-02 |
| US20210147437A1 (en) | 2021-05-20 |
| EP3665174A1 (en) | 2020-06-17 |
| AR112346A1 (es) | 2019-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2879645T3 (es) | Inhibidor de PDE1 | |
| EP2582668B1 (en) | Carboline carboxamide compounds useful as kinase inhibitors | |
| KR20250073451A (ko) | 신형 prmt5 억제제 및 그 응용 | |
| JP2009537531A (ja) | 置換されたピラゾロピリミジン | |
| CN105712998B (zh) | 氮杂吲哚类衍生物、其制备方法及其在医药上的应用 | |
| EA027533B1 (ru) | Конденсированные тетра- или пентациклические дигидродиазепинокарбазолоны в качестве ингибиторов parps | |
| JP2014520071A (ja) | Ｎ−［（１ｈ−ピラゾール−１−イル）アリール］−１ｈ−インドール又は１ｈ−インダゾール−３−カルボキサミドの誘導体、それらの製造及びｐ２ｙ１２アンタゴニストとしてのそれらの使用 | |
| CN113999232B (zh) | Mat2a抑制剂 | |
| ES2800433T3 (es) | Derivado de la triazolopirazinona útil como inhibidor de la pde1 humana | |
| ES2895969T3 (es) | Derivados de [1,2,4]triazolo como inhibidores de PDE1 para el tratamiento de diabetes | |
| JP2022137065A (ja) | ［１，２，４］トリアゾロ［４、３－ａ］ピラジン－８－オン誘導体 | |
| JP6850396B2 (ja) | ［１，２，４］トリアゾロ［４，３−ａ］ピラジン−６（５ｈ）−オン誘導体 | |
| WO2025077857A1 (zh) | Prmt5抑制剂在治疗肿瘤或癌症中的用途 | |
| CN115703738A (zh) | 含2-芳杂环取代的脲类化合物、其制备方法和用途 | |
| HK40075934B (zh) | 含氮并环类衍生物抑制剂、其制备方法和应用 | |
| WO2024240256A1 (zh) | 作为激酶抑制剂的多环化合物及其制备方法和用途 | |
| HK40042879B (en) | [1,2,4]triazolo[4,3-a]pyrazin-8-one derivatives | |
| HK40042879A (en) | [1,2,4]triazolo[4,3-a]pyrazin-8-one derivatives | |
| OA18433A (en) | Substituted nucleoside derivatives useful as anticancer agents |