KR20190117007A - Ssao 억제제로서 유용한 아미노 피리미딘 화합물 - Google Patents
Ssao 억제제로서 유용한 아미노 피리미딘 화합물 Download PDFInfo
- Publication number
- KR20190117007A KR20190117007A KR1020197026490A KR20197026490A KR20190117007A KR 20190117007 A KR20190117007 A KR 20190117007A KR 1020197026490 A KR1020197026490 A KR 1020197026490A KR 20197026490 A KR20197026490 A KR 20197026490A KR 20190117007 A KR20190117007 A KR 20190117007A
- Authority
- KR
- South Korea
- Prior art keywords
- mmol
- compound
- mixture
- tert
- methyl
- 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.)
- Ceased
Links
- 102100027159 Membrane primary amine oxidase Human genes 0.000 title description 29
- 101710132836 Membrane primary amine oxidase Proteins 0.000 title description 27
- 239000003112 inhibitor Substances 0.000 title description 3
- 150000005005 aminopyrimidines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 28
- 238000011282 treatment Methods 0.000 claims description 20
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 claims description 2
- 150000003018 phosphorus compounds Chemical class 0.000 claims 5
- 208000019423 liver disease Diseases 0.000 abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
- 239000000203 mixture Substances 0.000 description 76
- 238000002360 preparation method Methods 0.000 description 51
- 239000007787 solid Substances 0.000 description 41
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 33
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
- 239000000243 solution Substances 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- -1 3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy Chemical group 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 15
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 15
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- 239000000284 extract Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 11
- 239000005909 Kieselgur Substances 0.000 description 11
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 238000002953 preparative HPLC Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 208000019425 cirrhosis of liver Diseases 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 0 CC*(CC(C)(C)*1)CC1=O Chemical compound CC*(CC(C)(C)*1)CC1=O 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 208000002193 Pain Diseases 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 7
- XOCCSJLRSSDCLM-UHFFFAOYSA-N 2-chloro-5-phenylmethoxypyrimidine Chemical compound C1=NC(Cl)=NC=C1OCC1=CC=CC=C1 XOCCSJLRSSDCLM-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000004761 fibrosis Effects 0.000 description 6
- 208000006454 hepatitis Diseases 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- TZEMIYUAQCVSGK-UHFFFAOYSA-N 8-(5-hydroxypyrimidin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one Chemical compound OC=1C=NC(=NC=1)N1CCC2(CCN(C2=O)C)CC1 TZEMIYUAQCVSGK-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 206010016654 Fibrosis Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 4
- 125000005997 bromomethyl group Chemical group 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 208000010706 fatty liver disease Diseases 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- AMFRKQGBWOZZCA-UHFFFAOYSA-N 1-methyl-3-piperidin-4-yloxypyrrolidin-2-one Chemical compound O=C1N(C)CCC1OC1CCNCC1 AMFRKQGBWOZZCA-UHFFFAOYSA-N 0.000 description 3
- OIPHXMIUUREBMO-UHFFFAOYSA-N 1-methyl-3-pyridin-4-yloxypyrrolidin-2-one Chemical compound N1=CC=C(C=C1)OC1C(N(CC1)C)=O OIPHXMIUUREBMO-UHFFFAOYSA-N 0.000 description 3
- IRTPBYOVXXUWQO-UHFFFAOYSA-N 2-methyl-8-(5-phenylmethoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-1-one Chemical compound C(C1=CC=CC=C1)OC=1C=NC(=NC=1)N1CCC2(CCN(C2=O)C)CC1 IRTPBYOVXXUWQO-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
- 239000007821 HATU Substances 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 102000004316 Oxidoreductases Human genes 0.000 description 3
- 108090000854 Oxidoreductases Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 208000018191 liver inflammation Diseases 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 230000007863 steatosis Effects 0.000 description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VWURDVTYCLUBGR-UHFFFAOYSA-N tert-butyl 2-tert-butyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate Chemical compound C(C)(C)(C)N1C(C2(CC1)CCN(CC2)C(=O)OC(C)(C)C)=O VWURDVTYCLUBGR-UHFFFAOYSA-N 0.000 description 3
- HFYXNCRSUOCOBN-UHFFFAOYSA-N 2-cyclopropyl-8-(5-phenylmethoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-1-one Chemical compound C(C1=CC=CC=C1)OC=1C=NC(=NC=1)N1CCC2(CCN(C2=O)C2CC2)CC1 HFYXNCRSUOCOBN-UHFFFAOYSA-N 0.000 description 2
- AZHHGRZCYPRKKG-UHFFFAOYSA-N 2-methyl-9-(5-phenylmethoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one Chemical compound C(C1=CC=CC=C1)OC=1C=NC(=NC=1)N1CCC2(CCCN(C2=O)C)CC1 AZHHGRZCYPRKKG-UHFFFAOYSA-N 0.000 description 2
- KVYHMNDIXVAOAX-UHFFFAOYSA-N 2-tert-butyl-2,8-diazaspiro[4.5]decan-1-one;hydrochloride Chemical compound Cl.O=C1N(C(C)(C)C)CCC11CCNCC1 KVYHMNDIXVAOAX-UHFFFAOYSA-N 0.000 description 2
- QAOWLBNKIQNGHH-UHFFFAOYSA-N 2-tert-butyl-8-(5-phenylmethoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-1-one Chemical compound C(C1=CC=CC=C1)OC=1C=NC(=NC=1)N1CCC2(CCN(C2=O)C(C)(C)C)CC1 QAOWLBNKIQNGHH-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- VCNFNJZYLQLDJB-UHFFFAOYSA-N 9-(5-phenylmethoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one Chemical compound C(C1=CC=CC=C1)OC=1C=NC(=NC=1)N1CCC2(CCCNC2=O)CC1 VCNFNJZYLQLDJB-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 2
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 2
- 101000694615 Homo sapiens Membrane primary amine oxidase Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000010909 Monoamine Oxidase Human genes 0.000 description 2
- 108010062431 Monoamine oxidase Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000003149 assay kit Methods 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- NXWCXLOJJCLDBX-UHFFFAOYSA-N hydron;2-methyl-2,8-diazaspiro[4.5]decan-1-one;chloride Chemical compound Cl.O=C1N(C)CCC11CCNCC1 NXWCXLOJJCLDBX-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- KXUGZEAPIHEJDX-UHFFFAOYSA-N tert-butyl 2-cyclopropyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate Chemical compound C1(CC1)N1C(C2(CC1)CCN(CC2)C(=O)OC(C)(C)C)=O KXUGZEAPIHEJDX-UHFFFAOYSA-N 0.000 description 2
- VOKYHQSBAJSOMV-UHFFFAOYSA-N tert-butyl 4-(5-bromopyridin-2-yl)-2-oxopiperazine-1-carboxylate Chemical compound C1C(=O)N(C(=O)OC(C)(C)C)CCN1C1=CC=C(Br)C=N1 VOKYHQSBAJSOMV-UHFFFAOYSA-N 0.000 description 2
- DKTDUEDPGACFLJ-UHFFFAOYSA-N tert-butyl 4-(5-hydroxypyridin-2-yl)-2-oxopiperazine-1-carboxylate Chemical compound OC=1C=CC(=NC=1)N1CC(N(CC1)C(=O)OC(C)(C)C)=O DKTDUEDPGACFLJ-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- JRHPOFJADXHYBR-HTQZYQBOSA-N (1r,2r)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@@H]1CCCC[C@H]1NC JRHPOFJADXHYBR-HTQZYQBOSA-N 0.000 description 1
- LJCJRRKKAKAKRV-UHFFFAOYSA-N (2-amino-2-methylpropyl) 3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoate Chemical group CC(C)(N)COC(=O)CCC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 LJCJRRKKAKAKRV-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- NNFXHNCYQVSTPV-UHFFFAOYSA-N 1,2-diazaspiro[4.5]decan-3-one Chemical compound N1NC(=O)CC11CCCCC1 NNFXHNCYQVSTPV-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- JTPZTKBRUCILQD-UHFFFAOYSA-N 1-methylimidazolidin-2-one Chemical compound CN1CCNC1=O JTPZTKBRUCILQD-UHFFFAOYSA-N 0.000 description 1
- UHFYTRKXKDDMME-UHFFFAOYSA-N 2,9-diazaspiro[5.5]undecan-1-one Chemical compound O=C1NCCCC11CCNCC1 UHFYTRKXKDDMME-UHFFFAOYSA-N 0.000 description 1
- WTDRWDUTUWDVBC-UHFFFAOYSA-N 2-(cyclopropylmethyl)-8-(5-hydroxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-1-one Chemical compound C1(CC1)CN1C(C2(CC1)CCN(CC2)C1=NC=C(C=N1)O)=O WTDRWDUTUWDVBC-UHFFFAOYSA-N 0.000 description 1
- BQRUHKOBVUIRPT-UHFFFAOYSA-N 2-(cyclopropylmethyl)-8-(5-phenylmethoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-1-one Chemical compound C(C1=CC=CC=C1)OC=1C=NC(=NC=1)N1CCC2(CCN(C2=O)CC2CC2)CC1 BQRUHKOBVUIRPT-UHFFFAOYSA-N 0.000 description 1
- BOGPIHXNWPTGNH-UHFFFAOYSA-N 2-chloropyrimidin-5-ol Chemical compound OC1=CN=C(Cl)N=C1 BOGPIHXNWPTGNH-UHFFFAOYSA-N 0.000 description 1
- FVUQJYLIXOBULT-UHFFFAOYSA-N 2-cyclopropyl-2,8-diazaspiro[4.5]decan-1-one Chemical compound C1(CC1)N1C(C2(CC1)CCNCC2)=O FVUQJYLIXOBULT-UHFFFAOYSA-N 0.000 description 1
- VTPJUGVPIXOPIC-UHFFFAOYSA-N 2-cyclopropyl-2,8-diazaspiro[4.5]decan-1-one hydrochloride Chemical compound Cl.O=C1N(CCC11CCNCC1)C1CC1 VTPJUGVPIXOPIC-UHFFFAOYSA-N 0.000 description 1
- XGBMQBPLWXTEPM-UHFFFAOYSA-N 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1CC1 XGBMQBPLWXTEPM-UHFFFAOYSA-N 0.000 description 1
- COXYYNSHUGDIRL-UHFFFAOYSA-N 2-cyclopropyl-8-(5-hydroxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-1-one Chemical compound C1(CC1)N1C(C2(CC1)CCN(CC2)C1=NC=C(C=N1)O)=O COXYYNSHUGDIRL-UHFFFAOYSA-N 0.000 description 1
- YLZYSVYZMDJYOT-UHFFFAOYSA-N 2-methoxypyrimidine Chemical group COC1=NC=CC=N1 YLZYSVYZMDJYOT-UHFFFAOYSA-N 0.000 description 1
- BJIVBYSMQCTLMY-UHFFFAOYSA-N 3-[(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]-1-methylpyrrolidin-2-one Chemical compound C(C1=CC=CC=C1)N1CCC(=CC1)OC1C(N(CC1)C)=O BJIVBYSMQCTLMY-UHFFFAOYSA-N 0.000 description 1
- ZHQJIJUMPYNVAZ-UHFFFAOYSA-N 3-hydroxy-1-methylpyrrolidin-2-one Chemical compound CN1CCC(O)C1=O ZHQJIJUMPYNVAZ-UHFFFAOYSA-N 0.000 description 1
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- DGYUSABUTWNBOU-UHFFFAOYSA-N 8-(5-phenylmethoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-1-one Chemical compound C(C1=CC=CC=C1)OC=1C=NC(=NC=1)N1CCC2(CCNC2=O)CC1 DGYUSABUTWNBOU-UHFFFAOYSA-N 0.000 description 1
- VCPPNRNBMQRKGE-UHFFFAOYSA-N 9-(5-hydroxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one Chemical compound OC=1C=NC(=NC=1)N1CCC2(CCCNC2=O)CC1 VCPPNRNBMQRKGE-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- MZKNSTYQEMDKTP-UHFFFAOYSA-N CC(C)C(NC1CC1)=O Chemical compound CC(C)C(NC1CC1)=O MZKNSTYQEMDKTP-UHFFFAOYSA-N 0.000 description 1
- CWDXSDLAJBBUSO-UHFFFAOYSA-N CN(C)C(NC1CC1)=O Chemical compound CN(C)C(NC1CC1)=O CWDXSDLAJBBUSO-UHFFFAOYSA-N 0.000 description 1
- KBZAGSVCUHRYGO-UHFFFAOYSA-N CN(CCC1Oc2cc[n+](Cc3ccccc3)cc2)C1=O Chemical compound CN(CCC1Oc2cc[n+](Cc3ccccc3)cc2)C1=O KBZAGSVCUHRYGO-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 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
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 101150051213 MAOA gene Proteins 0.000 description 1
- 101150115032 MAOB gene Proteins 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 1
- DPWPWRLQFGFJFI-UHFFFAOYSA-N Pargyline Chemical compound C#CCN(C)CC1=CC=CC=C1 DPWPWRLQFGFJFI-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- IRJKSAIGIYODAN-ISLYRVAYSA-N benzyl (ne)-n-phenylmethoxycarbonyliminocarbamate Chemical compound C=1C=CC=CC=1COC(=O)/N=N/C(=O)OCC1=CC=CC=C1 IRJKSAIGIYODAN-ISLYRVAYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- UVJHQYIOXKWHFD-UHFFFAOYSA-N cyclohexa-1,4-diene Chemical compound C1C=CCC=C1 UVJHQYIOXKWHFD-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- WLDBKDYSWDAYMZ-UHFFFAOYSA-N decan-1-one Chemical compound CCCCCCCCC[C]=O WLDBKDYSWDAYMZ-UHFFFAOYSA-N 0.000 description 1
- KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical compound CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 description 1
- BGPYMEASGIVIES-UHFFFAOYSA-N decanal;dihydrochloride Chemical compound Cl.Cl.CCCCCCCCCC=O BGPYMEASGIVIES-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IOXXVNYDGIXMIP-UHFFFAOYSA-N n-methylprop-2-en-1-amine Chemical compound CNCC=C IOXXVNYDGIXMIP-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960001779 pargyline Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- GSSYTYYSDFJBFK-UHFFFAOYSA-N piperidine-4-carboxamide;hydrochloride Chemical compound [Cl-].NC(=O)C1CC[NH2+]CC1 GSSYTYYSDFJBFK-UHFFFAOYSA-N 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-M piperidine-4-carboxylate Chemical compound [O-]C(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-M 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 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 1
- ADPIEGXXCABJCH-UHFFFAOYSA-N tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11C(=O)NCC1 ADPIEGXXCABJCH-UHFFFAOYSA-N 0.000 description 1
- SRXNZBIOGZNYEO-UHFFFAOYSA-N tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11C(=O)NCCC1 SRXNZBIOGZNYEO-UHFFFAOYSA-N 0.000 description 1
- MPLXMQMCYBMEIM-UHFFFAOYSA-N tert-butyl 2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate Chemical compound O=C1N(C)CCC11CCN(C(=O)OC(C)(C)C)CC1 MPLXMQMCYBMEIM-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- KMPQYAYAQWNLME-UHFFFAOYSA-N undecanal Chemical compound CCCCCCCCCCC=O KMPQYAYAQWNLME-UHFFFAOYSA-N 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D471/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2017/000157 WO2018148856A1 (en) | 2017-02-14 | 2017-02-14 | Diazaspirodecanyl-pyrimidine compounds useful as ssao inhibitors |
| CNPCT/CN2017/000157 | 2017-02-14 | ||
| CNPCT/CN2017/117791 | 2017-12-21 | ||
| PCT/CN2017/117791 WO2018149226A1 (en) | 2017-02-14 | 2017-12-21 | Amino pyrimidine compounds useful as ssao inhibitors |
| PCT/US2018/017152 WO2018151985A1 (en) | 2017-02-14 | 2018-02-07 | Amino pyrimidine compounds useful as ssao inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20190117007A true KR20190117007A (ko) | 2019-10-15 |
Family
ID=63169081
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020197026490A Ceased KR20190117007A (ko) | 2017-02-14 | 2018-02-07 | Ssao 억제제로서 유용한 아미노 피리미딘 화합물 |
Country Status (13)
| Country | Link |
|---|---|
| US (2) | US10278970B2 (enExample) |
| EP (1) | EP3582780B1 (enExample) |
| JP (2) | JP7030827B2 (enExample) |
| KR (1) | KR20190117007A (enExample) |
| CN (2) | CN108778278B (enExample) |
| AU (1) | AU2018221322B2 (enExample) |
| CA (1) | CA3052044A1 (enExample) |
| DK (1) | DK3582780T3 (enExample) |
| ES (1) | ES2897666T3 (enExample) |
| IL (1) | IL268625A (enExample) |
| MX (1) | MX2019009501A (enExample) |
| SG (2) | SG10201913492YA (enExample) |
| WO (3) | WO2018148856A1 (enExample) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018027892A1 (en) | 2016-08-12 | 2018-02-15 | Eli Lilly And Company | Amino pyrimidine ssao inhibitors |
| WO2018148856A1 (en) | 2017-02-14 | 2018-08-23 | Eli Lilly And Company | Diazaspirodecanyl-pyrimidine compounds useful as ssao inhibitors |
| CN109251166B (zh) * | 2017-07-13 | 2021-11-05 | 广东东阳光药业有限公司 | 抑制ssao/vap-1的胺类化合物及其在医药上的应用 |
| CN109810041B (zh) | 2017-11-21 | 2023-08-15 | 药捷安康(南京)科技股份有限公司 | 卤代烯丙基胺类ssao/vap-1抑制剂及其应用 |
| CN109988106B (zh) * | 2017-12-29 | 2023-03-31 | 广东东阳光药业有限公司 | 抑制ssao/vap-1的胺类化合物及其在医药上的应用 |
| WO2020006177A1 (en) * | 2018-06-29 | 2020-01-02 | Blade Therapeutics, Inc. | Vascular adhesion protein-1 (vap-1) modulators and therapeutic uses thereof |
| CN110938059A (zh) * | 2018-09-25 | 2020-03-31 | 上海轶诺药业有限公司 | 胺基脲敏感性胺氧化酶抑制剂制备及其应用 |
| WO2020063854A1 (zh) * | 2018-09-27 | 2020-04-02 | 南京明德新药研发有限公司 | 作为vap-1抑制剂的喹啉类衍生物 |
| US12213970B2 (en) | 2018-10-29 | 2025-02-04 | Boehringer Ingelheim International Gmbh | Pyridinyl sulfonamide derivatives, pharmaceutical compositions and uses thereof |
| PH12021550901A1 (en) | 2018-10-29 | 2022-03-21 | Boehringer Ingelheim Int | Pyridinyl sulfonamide derivatives, pharmaceutical compositions and uses thereof |
| EP3892621B1 (en) * | 2019-01-11 | 2024-09-18 | TransThera Sciences (Nanjing), Inc. | Haloallylamine compounds and application thereof |
| CN111471037B (zh) * | 2019-01-23 | 2023-02-10 | 药捷安康(南京)科技股份有限公司 | 烯丙基胺类化合物及其应用 |
| EP4051669A4 (en) | 2019-10-29 | 2023-12-13 | Eccogene (Shanghai) Co., Ltd. | SSAO INHIBITORS AND THEIR USE |
| CN113149957A (zh) * | 2020-01-23 | 2021-07-23 | 轶诺(浙江)药业有限公司 | 胺基脲敏感性胺氧化酶抑制剂制备及其应用 |
| IL300853A (en) | 2020-08-25 | 2023-04-01 | Lilly Co Eli | Polymorphs of an ssao inhibitor |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008123469A1 (ja) | 2007-03-30 | 2008-10-16 | Japan Tobacco Inc. | ６員環アミド化合物およびその用途 |
| AU2008280784A1 (en) | 2007-07-20 | 2009-01-29 | Merck Frosst Canada Ltd | Bicyclic heteroaromatic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
| WO2009066152A2 (en) * | 2007-11-21 | 2009-05-28 | Pharmaxis Ltd. | Haloallylamine inhibitors of ssao/vap-1 and uses therefor |
| EP2479165B1 (en) * | 2009-09-16 | 2017-10-25 | Astellas Pharma Inc. | Glycine compound |
| JP2011136942A (ja) | 2009-12-28 | 2011-07-14 | Kowa Co | 新規な置換ピリミジン誘導体およびこれを含有する医薬 |
| PL2695881T3 (pl) | 2011-03-15 | 2016-11-30 | Związek guanidynowy | |
| DK2844637T5 (en) | 2012-05-02 | 2018-08-13 | Boehringer Ingelheim Int | SUBSTITUTED 3-HALOALLYLAMINE INHIBITORS BY SSAO AND USES THEREOF |
| AU2013344603B2 (en) | 2012-11-16 | 2017-07-06 | Bristol-Myers Squibb Company | Pyrrolidine GPR40 modulators |
| US8962641B2 (en) * | 2013-04-17 | 2015-02-24 | Boehringer Ingelheim International Gmbh | Pyrimidine-substituted pyrrolidine derivatives, pharmaceutical compositions and uses thereof |
| JP6378752B2 (ja) | 2013-05-17 | 2018-08-22 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ピロリジン誘導体、その医薬組成物及び使用 |
| GB201416444D0 (en) * | 2014-09-17 | 2014-10-29 | Proximagen Ltd | New compounds |
| WO2018027892A1 (en) | 2016-08-12 | 2018-02-15 | Eli Lilly And Company | Amino pyrimidine ssao inhibitors |
| WO2018148856A1 (en) | 2017-02-14 | 2018-08-23 | Eli Lilly And Company | Diazaspirodecanyl-pyrimidine compounds useful as ssao inhibitors |
-
2017
- 2017-02-14 WO PCT/CN2017/000157 patent/WO2018148856A1/en not_active Ceased
- 2017-12-21 WO PCT/CN2017/117791 patent/WO2018149226A1/en not_active Ceased
-
2018
- 2018-02-07 CA CA3052044A patent/CA3052044A1/en active Pending
- 2018-02-07 SG SG10201913492YA patent/SG10201913492YA/en unknown
- 2018-02-07 JP JP2019543810A patent/JP7030827B2/ja active Active
- 2018-02-07 DK DK18706109.8T patent/DK3582780T3/da active
- 2018-02-07 CN CN201880000825.XA patent/CN108778278B/zh active Active
- 2018-02-07 KR KR1020197026490A patent/KR20190117007A/ko not_active Ceased
- 2018-02-07 MX MX2019009501A patent/MX2019009501A/es unknown
- 2018-02-07 EP EP18706109.8A patent/EP3582780B1/en active Active
- 2018-02-07 WO PCT/US2018/017152 patent/WO2018151985A1/en not_active Ceased
- 2018-02-07 CN CN202210027271.0A patent/CN114369095B/zh active Active
- 2018-02-07 SG SG11201907032RA patent/SG11201907032RA/en unknown
- 2018-02-07 AU AU2018221322A patent/AU2018221322B2/en active Active
- 2018-02-07 ES ES18706109T patent/ES2897666T3/es active Active
- 2018-06-19 US US16/012,140 patent/US10278970B2/en active Active
-
2019
- 2019-03-18 US US16/356,895 patent/US10471060B2/en active Active
- 2019-08-11 IL IL26862519A patent/IL268625A/en unknown
-
2022
- 2022-02-22 JP JP2022025774A patent/JP7247389B2/ja active Active
Also Published As
| Publication number | Publication date |
|---|---|
| IL268625A (en) | 2019-10-31 |
| US10471060B2 (en) | 2019-11-12 |
| CN114369095A (zh) | 2022-04-19 |
| CA3052044A1 (en) | 2018-08-23 |
| CN108778278A (zh) | 2018-11-09 |
| US20180296560A1 (en) | 2018-10-18 |
| SG11201907032RA (en) | 2019-08-27 |
| US10278970B2 (en) | 2019-05-07 |
| EP3582780A1 (en) | 2019-12-25 |
| JP7247389B2 (ja) | 2023-03-28 |
| AU2018221322B2 (en) | 2022-04-14 |
| WO2018149226A1 (en) | 2018-08-23 |
| MX2019009501A (es) | 2019-11-05 |
| ES2897666T3 (es) | 2022-03-02 |
| CN114369095B (zh) | 2025-03-14 |
| JP2022068325A (ja) | 2022-05-09 |
| JP7030827B2 (ja) | 2022-03-07 |
| US20190275041A1 (en) | 2019-09-12 |
| DK3582780T3 (da) | 2021-11-01 |
| WO2018148856A1 (en) | 2018-08-23 |
| JP2020507589A (ja) | 2020-03-12 |
| WO2018151985A1 (en) | 2018-08-23 |
| SG10201913492YA (en) | 2020-03-30 |
| EP3582780B1 (en) | 2021-10-13 |
| AU2018221322A1 (en) | 2019-08-15 |
| CN108778278B (zh) | 2022-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7247389B2 (ja) | Ｓｓａｏ阻害剤として有用なアミノピリミジン化合物 | |
| KR102662205B1 (ko) | 신규 plk1 분해 유도 화합물 | |
| KR20200006125A (ko) | 키나아제 억제제 및 이의 용도 | |
| JP2018528203A (ja) | Ｉｒａｋ４モジュレーターとしての二環式縮合ヘテロアリールまたはアリール化合物 | |
| KR20220079919A (ko) | 헤테로시클릭 rip1 억제 화합물 | |
| US20210261541A1 (en) | 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof | |
| WO2016039458A1 (ja) | ナトリウム依存性リン酸トランスポーター阻害剤を含有する医薬 | |
| EP3481823B1 (de) | 7-substituierte 1-pyridyl-naphthyridin-3-carbonsäureamide und ihre verwendung | |
| JP2025526433A (ja) | 治療に使用するためのｐａｒｐ１４の標的化タンパク質分解 | |
| EP3296298A1 (de) | 7-substituierte 1-aryl-naphthyridin-3-carbonsäureamide und ihre verwendung | |
| WO2024108009A1 (en) | Dyrk/clk protacs and uses thereof | |
| HK40000285A (en) | Amino pyrimidine compounds useful as ssao inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0105 | International application |
Patent event date: 20190909 Patent event code: PA01051R01D Comment text: International Patent Application |
|
| PG1501 | Laying open of application | ||
| A201 | Request for examination | ||
| PA0201 | Request for examination |
Patent event code: PA02012R01D Patent event date: 20210126 Comment text: Request for Examination of Application |
|
| E902 | Notification of reason for refusal | ||
| PE0902 | Notice of grounds for rejection |
Comment text: Notification of reason for refusal Patent event date: 20230110 Patent event code: PE09021S01D |
|
| E601 | Decision to refuse application | ||
| PE0601 | Decision on rejection of patent |
Patent event date: 20230317 Comment text: Decision to Refuse Application Patent event code: PE06012S01D Patent event date: 20230110 Comment text: Notification of reason for refusal Patent event code: PE06011S01I |