NZ538443A - 2,5-dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12 - Google Patents
2,5-dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12Info
- Publication number
- NZ538443A NZ538443A NZ538443A NZ53844303A NZ538443A NZ 538443 A NZ538443 A NZ 538443A NZ 538443 A NZ538443 A NZ 538443A NZ 53844303 A NZ53844303 A NZ 53844303A NZ 538443 A NZ538443 A NZ 538443A
- Authority
- NZ
- New Zealand
- Prior art keywords
- dioxoimidazolidin
- acetamide
- ethyl
- methyl
- phenyl
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 10
- 101000577881 Homo sapiens Macrophage metalloelastase Proteins 0.000 title claims abstract 4
- CSGWGMMFAMMBSX-UHFFFAOYSA-N n-(2,5-dioxoimidazolidin-4-yl)acetamide Chemical class CC(=O)NC1NC(=O)NC1=O CSGWGMMFAMMBSX-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 12
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 11
- 208000006673 asthma Diseases 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 6
- 208000027771 Obstructive airways disease Diseases 0.000 claims abstract description 5
- -1 cyano, carboxyl Chemical group 0.000 claims description 102
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 86
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 75
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 62
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 125000001424 substituent group Chemical group 0.000 claims description 56
- 125000004122 cyclic group Chemical group 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 150000002367 halogens Chemical class 0.000 claims description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 35
- 125000005842 heteroatom Chemical group 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 33
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 30
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 239000001301 oxygen Substances 0.000 claims description 29
- 239000005864 Sulphur Chemical group 0.000 claims description 28
- 229920006395 saturated elastomer Polymers 0.000 claims description 27
- 239000012453 solvate Substances 0.000 claims description 27
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 16
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 15
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 13
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 10
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 9
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 9
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 6
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- JGSIAOZAXBWRFO-UHFFFAOYSA-N 3-methylsulfanyl-1-phenyl-4,5-dihydrobenzo[g]indazole Chemical compound C1CC2=CC=CC=C2C2=C1C(SC)=NN2C1=CC=CC=C1 JGSIAOZAXBWRFO-UHFFFAOYSA-N 0.000 claims description 5
- 102100027998 Macrophage metalloelastase Human genes 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- XIWREPKZTFSDQK-UHFFFAOYSA-N 2-(2,5-dioxoimidazolidin-4-yl)-n-[2-(4-fluorophenyl)ethyl]acetamide Chemical compound C1=CC(F)=CC=C1CCNC(=O)CC1C(=O)NC(=O)N1 XIWREPKZTFSDQK-UHFFFAOYSA-N 0.000 claims description 2
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- 238000001952 enzyme assay Methods 0.000 claims description 2
- 150000004795 grignard reagents Chemical class 0.000 claims description 2
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 claims description 2
- IAXISOBSDXGUGB-UHFFFAOYSA-N n-[2-[(4-bromophenyl)methoxy]ethyl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound C1=CC(Br)=CC=C1COCCNC(=O)CC1C(=O)NC(=O)N1 IAXISOBSDXGUGB-UHFFFAOYSA-N 0.000 claims description 2
- SCWMECAYLFDSKL-UHFFFAOYSA-N n-[2-[4-(1-benzofuran-2-yl)phenyl]ethyl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound C=1C=C(C=2OC3=CC=CC=C3C=2)C=CC=1CCNC(=O)CC1NC(=O)NC1=O SCWMECAYLFDSKL-UHFFFAOYSA-N 0.000 claims description 2
- NLHUGCVIYWKIEZ-UHFFFAOYSA-N n-[2-[4-(4-chlorophenoxy)phenyl]ethyl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound C1=CC(Cl)=CC=C1OC(C=C1)=CC=C1CCNC(=O)CC1C(=O)NC(=O)N1 NLHUGCVIYWKIEZ-UHFFFAOYSA-N 0.000 claims description 2
- YHUYHOFRMQTNOL-UHFFFAOYSA-N n-[2-[4-(4-cyanophenoxy)phenyl]ethyl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound C=1C=C(OC=2C=CC(=CC=2)C#N)C=CC=1CCNC(=O)CC1NC(=O)NC1=O YHUYHOFRMQTNOL-UHFFFAOYSA-N 0.000 claims description 2
- BDRSXBQCSHDDDQ-UHFFFAOYSA-N n-[5-(1-benzothiophen-2-yl)-2,3-dihydro-1h-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound C1C2=CC=C(C=3SC4=CC=CC=C4C=3)C=C2CC1NC(=O)CC1(C)NC(=O)NC1=O BDRSXBQCSHDDDQ-UHFFFAOYSA-N 0.000 claims description 2
- XYYPDMLHRHZYLN-UHFFFAOYSA-N n-[5-(4-fluoro-3-methylphenyl)-2,3-dihydro-1h-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound C1=C(F)C(C)=CC(C=2C=C3CC(CC3=CC=2)NC(=O)CC2(C)C(NC(=O)N2)=O)=C1 XYYPDMLHRHZYLN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 claims 1
- 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 claims 1
- NPMLDDPWPVRLQN-UHFFFAOYSA-N C=1C=C(C=2C=CC=CC=2)C=CC=1C(=O)COC(=O)CC1NC(=O)NC1=O Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1C(=O)COC(=O)CC1NC(=O)NC1=O NPMLDDPWPVRLQN-UHFFFAOYSA-N 0.000 claims 1
- 239000012131 assay buffer Substances 0.000 claims 1
- 239000003599 detergent Substances 0.000 claims 1
- 125000004125 inden-2-yl group Chemical group [H]C1=C(*)C([H])([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
- YQLXJIZFXGDDJH-UHFFFAOYSA-N n-[2-[4-(3-cyanophenyl)phenyl]propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound C=1C=C(C=2C=C(C=CC=2)C#N)C=CC=1C(C)CNC(=O)CC1(C)NC(=O)NC1=O YQLXJIZFXGDDJH-UHFFFAOYSA-N 0.000 claims 1
- YEIOYBVMYCFROD-UHFFFAOYSA-N n-[5-(3-acetamidophenyl)-2,3-dihydro-1h-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound CC(=O)NC1=CC=CC(C=2C=C3CC(CC3=CC=2)NC(=O)CC2(C)C(NC(=O)N2)=O)=C1 YEIOYBVMYCFROD-UHFFFAOYSA-N 0.000 claims 1
- KYRHXDXGNOEBPC-UHFFFAOYSA-N n-[[1-(4-chlorophenyl)cyclopropyl]methyl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide Chemical compound C1=CC(Cl)=CC=C1C1(CNC(=O)CC2C(NC(=O)N2)=O)CC1 KYRHXDXGNOEBPC-UHFFFAOYSA-N 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 130
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 19
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 19
- 239000000460 chlorine Substances 0.000 description 19
- 229910052801 chlorine Inorganic materials 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 18
- 229910052794 bromium Inorganic materials 0.000 description 18
- 229910052731 fluorine Inorganic materials 0.000 description 18
- 239000011737 fluorine Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 229910001868 water Inorganic materials 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229940093499 ethyl acetate Drugs 0.000 description 12
- 239000011630 iodine Substances 0.000 description 12
- 229910052740 iodine Inorganic materials 0.000 description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 12
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 12
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 11
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 11
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 102000005741 Metalloproteases Human genes 0.000 description 10
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- DQQLZADYSWBCOX-UHFFFAOYSA-N 2-(2,5-dioxoimidazolidin-4-yl)acetic acid Chemical compound OC(=O)CC1NC(=O)NC1=O DQQLZADYSWBCOX-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 125000006606 n-butoxy group Chemical group 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 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 6
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- PVKYEQBKDNMLBJ-UHFFFAOYSA-N 2-imidazolidin-4-ylacetic acid Chemical compound OC(=O)CC1CNCN1 PVKYEQBKDNMLBJ-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102100022087 Granzyme M Human genes 0.000 description 4
- 101000900697 Homo sapiens Granzyme M Proteins 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 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 3
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- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
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- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 description 1
- IVUNKMFXUDPABM-UHFFFAOYSA-N tert-butyl 4-(2-phenylethynyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C#CC1=CC=CC=C1 IVUNKMFXUDPABM-UHFFFAOYSA-N 0.000 description 1
- MQUCODGJTOCTPR-UHFFFAOYSA-N tert-butyl 4-ethynylpiperidine-1-carboxylate;4-(2-phenylethynyl)piperidine Chemical compound C1CNCCC1C#CC1=CC=CC=C1.CC(C)(C)OC(=O)N1CCC(C#C)CC1 MQUCODGJTOCTPR-UHFFFAOYSA-N 0.000 description 1
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 1
- LALFAEKVNOWOKJ-UHFFFAOYSA-N tert-butyl n-[2-[4-(4-fluorophenyl)phenyl]propyl]carbamate Chemical compound C1=CC(C(CNC(=O)OC(C)(C)C)C)=CC=C1C1=CC=C(F)C=C1 LALFAEKVNOWOKJ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| SE0202539A SE0202539D0 (sv) | 2002-08-27 | 2002-08-27 | Compounds |
| PCT/SE2003/001328 WO2004020415A1 (en) | 2002-08-27 | 2003-08-26 | 2,5-dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase mmp12. |
Publications (1)
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| NZ538443A true NZ538443A (en) | 2006-09-29 |
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| NZ538443A NZ538443A (en) | 2002-08-27 | 2003-08-26 | 2,5-dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12 |
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| SE0202539D0 (sv) | 2002-08-27 | 2002-08-27 | Astrazeneca Ab | Compounds |
| GB0221246D0 (en) * | 2002-09-13 | 2002-10-23 | Astrazeneca Ab | Compounds |
| US6979750B1 (en) | 2003-04-18 | 2005-12-27 | The Regents Of The University Of California | Thyronamine derivatives and analogs and methods of use thereof |
| US7321065B2 (en) * | 2003-04-18 | 2008-01-22 | The Regents Of The University Of California | Thyronamine derivatives and analogs and methods of use thereof |
| SE0400850D0 (sv) * | 2004-03-30 | 2004-03-31 | Astrazeneca Ab | Novel Compounds |
| SE0401763D0 (sv) * | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Compounds |
| SE0401762D0 (sv) * | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Novel compounds |
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| SE0403086D0 (sv) * | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Compounds |
| SE0403085D0 (sv) * | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Novel componds |
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| TW200740769A (en) * | 2006-03-16 | 2007-11-01 | Astrazeneca Ab | Novel process |
| WO2008027466A1 (en) * | 2006-08-31 | 2008-03-06 | Schering Corporation | Hydantoin derivatives useful as antibacterial agents |
| TW200831488A (en) * | 2006-11-29 | 2008-08-01 | Astrazeneca Ab | Novel compounds |
| CN101024619B (zh) * | 2007-03-29 | 2010-12-01 | 上海大学 | N-取代邻溴苄酰胺的合成方法 |
| UY31968A (es) | 2008-07-09 | 2010-01-29 | Sanofi Aventis | Nuevos derivados heterocíclicos, sus procesos para su preparación, y sus usos terapéuticos |
| WO2010043721A1 (en) | 2008-10-17 | 2010-04-22 | Oryzon Genomics, S.A. | Oxidase inhibitors and their use |
| US8993808B2 (en) | 2009-01-21 | 2015-03-31 | Oryzon Genomics, S.A. | Phenylcyclopropylamine derivatives and their medical use |
| FR2944525B1 (fr) * | 2009-04-17 | 2011-06-24 | Ipsen Pharma Sas | Derives d'imidazolidine-2,4-dione et leur utilisation comme medicament |
| US8859555B2 (en) | 2009-09-25 | 2014-10-14 | Oryzon Genomics S.A. | Lysine Specific Demethylase-1 inhibitors and their use |
| EP2486002B1 (en) | 2009-10-09 | 2019-03-27 | Oryzon Genomics, S.A. | Substituted heteroaryl- and aryl- cyclopropylamine acetamides and their use |
| WO2011106106A2 (en) | 2010-02-24 | 2011-09-01 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for diseases and disorders associated with hepadnaviridae |
| WO2011106574A2 (en) | 2010-02-24 | 2011-09-01 | Oryzon Genomics, S.A. | Inhibitors for antiviral use |
| CA2796726C (en) | 2010-04-19 | 2021-02-16 | Oryzon Genomics S.A. | Lysine specific demethylase-1 inhibitors and their use |
| BR112013002164B1 (pt) | 2010-07-29 | 2021-11-09 | Oryzon Genomics S.A. | Inibidores de desmetilase à base de arilciclopropilamina de lsd1, seus usos, e composição farmacêutica |
| US9006449B2 (en) | 2010-07-29 | 2015-04-14 | Oryzon Genomics, S.A. | Cyclopropylamine derivatives useful as LSD1 inhibitors |
| US9061966B2 (en) | 2010-10-08 | 2015-06-23 | Oryzon Genomics S.A. | Cyclopropylamine inhibitors of oxidases |
| WO2012072713A2 (en) | 2010-11-30 | 2012-06-07 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for diseases and disorders associated with flaviviridae |
| EP2712315B1 (en) | 2011-02-08 | 2021-11-24 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for myeloproliferative disorders |
| US20140329833A1 (en) * | 2011-05-19 | 2014-11-06 | Oryzon Genomics, S.A | Lysine demethylase inhibitors for inflammatory diseases or conditions |
| US20140296255A1 (en) * | 2011-05-19 | 2014-10-02 | Oryzong Genomics, S.A. | Lysine demethylase inhibitors for thrombosis and cardiovascular diseases |
| JP6046154B2 (ja) | 2011-10-20 | 2016-12-14 | オリソン ヘノミクス エセ． アー． | Ｌｓｄ１阻害剤としての（ヘテロ）アリールシクロプロピルアミン化合物 |
| EP2768805B1 (en) | 2011-10-20 | 2020-03-25 | Oryzon Genomics, S.A. | (hetero)aryl cyclopropylamine compounds as lsd1 inhibitors |
| WO2014051538A1 (en) * | 2012-09-25 | 2014-04-03 | Empire Technology Development Llc | Oxidizing agents on pigments |
| AR092971A1 (es) * | 2012-10-26 | 2015-05-06 | Lilly Co Eli | Inhibidores de agrecanasa |
| CN103588758A (zh) * | 2013-11-04 | 2014-02-19 | 南京大学 | 一类含1,4-苯并二噁烷骨架的硝基咪唑衍生物的合成、制备及其在抗癌药物中的应用 |
| EP2907512A1 (en) | 2014-02-14 | 2015-08-19 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Inhibitors of MMP-12 as antiviral Agents |
| CN104030930B (zh) * | 2014-06-20 | 2016-02-24 | 河北序能生物技术有限公司 | 一种反式-（1r,2s）-2-（3,4-二氟苯基）环丙胺盐酸盐的合成方法 |
| KR102861502B1 (ko) | 2018-05-15 | 2025-09-18 | 포시 파마슈티컬스 유에스에이 인코포레이티드 | 기질 금속단백분해효소 (mmp) 억제제 및 이의 사용 방법 |
| CN112755023B (zh) * | 2021-01-22 | 2023-04-25 | 湖南师范大学 | 一种新型表观遗传因子抑制剂2800z在制备肝癌药物中的应用 |
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| CA2486350A1 (en) | 2002-06-05 | 2003-12-24 | Kaneka Corporation | Process for producing optically active .alpha.-methylcysteine derivative |
| SE0202539D0 (sv) | 2002-08-27 | 2002-08-27 | Astrazeneca Ab | Compounds |
| SE0202692D0 (sv) | 2002-09-11 | 2002-09-11 | Astrazeneca Ab | Compounds |
| SE0202693D0 (sv) | 2002-09-11 | 2002-09-11 | Astrazeneca Ab | Compounds |
| GB0221246D0 (en) | 2002-09-13 | 2002-10-23 | Astrazeneca Ab | Compounds |
| GB0221250D0 (en) | 2002-09-13 | 2002-10-23 | Astrazeneca Ab | Compounds |
| US20040266832A1 (en) | 2003-06-26 | 2004-12-30 | Li Zheng J. | Crystal forms of 2-(3-difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonyl pyridine |
| TWI220073B (en) | 2003-07-24 | 2004-08-01 | Au Optronics Corp | Method for manufacturing polysilicon film |
| SE0401763D0 (sv) | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Compounds |
| US7648992B2 (en) | 2004-07-05 | 2010-01-19 | Astrazeneca Ab | Hydantoin derivatives for the treatment of obstructive airway diseases |
| SE0401762D0 (sv) | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Novel compounds |
| SE0403085D0 (sv) | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Novel componds |
| SE0403086D0 (sv) | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Compounds |
| TW200740769A (en) | 2006-03-16 | 2007-11-01 | Astrazeneca Ab | Novel process |
| TW200831488A (en) | 2006-11-29 | 2008-08-01 | Astrazeneca Ab | Novel compounds |
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| LAPS | Patent lapsed |