TWI399203B - 作為TAFIa抑制劑之脲衍生物及磺醯二胺衍生物 - Google Patents
作為TAFIa抑制劑之脲衍生物及磺醯二胺衍生物 Download PDFInfo
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- TWI399203B TWI399203B TW096145997A TW96145997A TWI399203B TW I399203 B TWI399203 B TW I399203B TW 096145997 A TW096145997 A TW 096145997A TW 96145997 A TW96145997 A TW 96145997A TW I399203 B TWI399203 B TW I399203B
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- Prior art keywords
- alkyl
- alkylene
- phenyl
- group
- substituted
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- 239000003112 inhibitor Substances 0.000 title description 16
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 title 1
- 150000003672 ureas Chemical class 0.000 title 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 469
- -1 butyl- Chemical group 0.000 claims description 399
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 236
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 224
- 125000005843 halogen group Chemical group 0.000 claims description 150
- 150000001875 compounds Chemical class 0.000 claims description 131
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 104
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 59
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 125000004076 pyridyl group Chemical group 0.000 claims description 50
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 40
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 39
- 125000002947 alkylene group Chemical group 0.000 claims description 39
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 39
- 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 38
- 125000003943 azolyl group Chemical group 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 37
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 36
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 35
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 32
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 30
- 125000002619 bicyclic group Chemical group 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical class N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- 125000006413 ring segment Chemical group 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 150000001413 amino acids Chemical class 0.000 claims description 24
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 23
- 229920006395 saturated elastomer Polymers 0.000 claims description 23
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 21
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 21
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 18
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 18
- 125000005605 benzo group Chemical group 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 18
- 125000002757 morpholinyl group Chemical group 0.000 claims description 18
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 18
- 125000001544 thienyl group Chemical group 0.000 claims description 18
- 208000007536 Thrombosis Diseases 0.000 claims description 17
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 17
- 125000004122 cyclic group Chemical group 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 12
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 11
- 239000011737 fluorine Chemical group 0.000 claims description 11
- 229910052731 fluorine Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 238000001356 surgical procedure Methods 0.000 claims description 11
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 11
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 10
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 9
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 9
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 9
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 claims description 9
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 9
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims description 9
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000002393 azetidinyl group Chemical group 0.000 claims description 9
- 125000004069 aziridinyl group Chemical group 0.000 claims description 9
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 claims description 9
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 9
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 9
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000002720 diazolyl group Chemical group 0.000 claims description 9
- 125000005509 dibenzothiophenyl group Chemical group 0.000 claims description 9
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 claims description 9
- 125000003838 furazanyl group Chemical group 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 9
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims description 9
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 9
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 9
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 claims description 9
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 9
- 125000002755 pyrazolinyl group Chemical group 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 9
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 9
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
- 150000003463 sulfur Chemical class 0.000 claims description 9
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 9
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 claims description 9
- 229940125670 thienopyridine Drugs 0.000 claims description 9
- 239000002175 thienopyridine Substances 0.000 claims description 9
- 150000003573 thiols Chemical class 0.000 claims description 9
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 9
- 229930192474 thiophene Natural products 0.000 claims description 9
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims description 8
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 claims description 8
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 8
- 102000009123 Fibrin Human genes 0.000 claims description 7
- 108010073385 Fibrin Proteins 0.000 claims description 7
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 239000008280 blood Substances 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 229950003499 fibrin Drugs 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 208000005189 Embolism Diseases 0.000 claims description 6
- 230000005526 G1 to G0 transition Effects 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 5
- 230000008021 deposition Effects 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 4
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 4
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 4
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- 239000008177 pharmaceutical agent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000009863 secondary prevention Effects 0.000 claims description 4
- 239000011593 sulfur Chemical class 0.000 claims description 4
- 229910052717 sulfur Chemical class 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 201000005665 thrombophilia Diseases 0.000 claims description 4
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 3
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 3
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- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- GNTFBMAGLFYMMZ-UHFFFAOYSA-N bicyclo[3.2.2]nonane Chemical compound C1CC2CCC1CCC2 GNTFBMAGLFYMMZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 3
- 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
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- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 claims description 2
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- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 claims description 2
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 7
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- 150000001924 cycloalkanes Chemical class 0.000 claims 2
- 235000019260 propionic acid Nutrition 0.000 claims 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims 2
- ISGJHRGZGUNOGI-XSRYCBBQSA-N (2s)-6-amino-2-[[(2r)-3-cyclohexyl-1-(2-methylpyrrolidin-1-yl)-1-oxopropan-2-yl]carbamoylamino]hexanoic acid Chemical compound CC1CCCN1C(=O)[C@H](NC(=O)N[C@@H](CCCCN)C(O)=O)CC1CCCCC1 ISGJHRGZGUNOGI-XSRYCBBQSA-N 0.000 claims 1
- GJAAVXDJHXJNFO-DLBZAZTESA-N (2s)-6-amino-2-[[(2r)-3-cyclohexyl-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]carbamoylamino]hexanoic acid Chemical compound C([C@@H](NC(=O)N[C@@H](CCCCN)C(O)=O)C(=O)N1CCCC1)C1CCCCC1 GJAAVXDJHXJNFO-DLBZAZTESA-N 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 claims 1
- AXIPBRXJGSXLHF-UHFFFAOYSA-N piperidine;pyrrolidine Chemical compound C1CCNC1.C1CCNCC1 AXIPBRXJGSXLHF-UHFFFAOYSA-N 0.000 claims 1
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- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 claims 1
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- 239000002585 base Substances 0.000 description 72
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Classifications
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006057413 | 2006-12-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW200838498A TW200838498A (en) | 2008-10-01 |
| TWI399203B true TWI399203B (zh) | 2013-06-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW096145997A TWI399203B (zh) | 2006-12-06 | 2007-12-04 | 作為TAFIa抑制劑之脲衍生物及磺醯二胺衍生物 |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US8389764B2 (OSRAM) |
| EP (1) | EP2104497B1 (OSRAM) |
| JP (1) | JP5396279B2 (OSRAM) |
| KR (1) | KR20090087044A (OSRAM) |
| CN (1) | CN101553219B (OSRAM) |
| AR (1) | AR064119A1 (OSRAM) |
| AU (1) | AU2007327959B2 (OSRAM) |
| BR (1) | BRPI0720241A2 (OSRAM) |
| CA (1) | CA2671861C (OSRAM) |
| CL (1) | CL2007003494A1 (OSRAM) |
| CO (1) | CO6180422A2 (OSRAM) |
| CY (1) | CY1116384T1 (OSRAM) |
| DK (1) | DK2104497T3 (OSRAM) |
| ES (1) | ES2537093T3 (OSRAM) |
| HR (1) | HRP20150514T1 (OSRAM) |
| MA (1) | MA30968B1 (OSRAM) |
| MX (1) | MX2009005516A (OSRAM) |
| NO (1) | NO20092246L (OSRAM) |
| NZ (1) | NZ577312A (OSRAM) |
| PE (1) | PE20081349A1 (OSRAM) |
| PL (1) | PL2104497T3 (OSRAM) |
| PT (1) | PT2104497E (OSRAM) |
| RU (1) | RU2459619C2 (OSRAM) |
| SI (1) | SI2104497T1 (OSRAM) |
| TW (1) | TWI399203B (OSRAM) |
| WO (1) | WO2008067909A2 (OSRAM) |
| ZA (1) | ZA200903040B (OSRAM) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA104002C2 (ru) | 2008-06-06 | 2013-12-25 | Санофи-Авентис | МАКРОЦИКЛИЧЕСКИЕ ПРОИЗВОДНЫЕ МОЧЕВИНЫ И СУЛЬФАМИДА КАК ИНГИБИТОРЫ TAFIa |
| KR20110025970A (ko) | 2008-06-23 | 2011-03-14 | 아스트라제네카 아베 | 트롬빈 억제제로서 사용하기 위한 신규 복소환 카복스아미드 |
| US8354444B2 (en) | 2008-09-18 | 2013-01-15 | Hoffmann-La Roche Inc. | Substituted pyrrolidine-2-carboxamides |
| AU2009310841A1 (en) | 2008-10-29 | 2010-05-06 | Taisho Pharmaceutical Co., Ltd. | Compounds having TAFIa inhibitory activity |
| JP6461113B2 (ja) * | 2013-06-10 | 2019-01-30 | サノフイSanofi | TAFIaの阻害剤としての大環状尿素誘導体、それらの製造および医薬としての使用 |
| CN104529859B (zh) * | 2015-01-13 | 2016-08-17 | 佛山市赛维斯医药科技有限公司 | 含苯胺和二烯氟代金刚烷结构的化合物、其制备方法和用途 |
| RU2687254C1 (ru) * | 2018-10-03 | 2019-05-08 | Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) | N-гетероциклические производные борниламина в качестве ингибиторов ортопоксвирусов |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0611776A2 (de) * | 1993-02-15 | 1994-08-24 | Bayer Ag | Neue antiviral wirksame Pseudopeptide |
| EP0641779A1 (de) * | 1993-09-07 | 1995-03-08 | F. Hoffmann-La Roche Ag | Neue 1-Amidinopiperidine und 4-Amidinomorphozine als Aggregationshemmer |
| WO1999011606A2 (en) * | 1997-08-28 | 1999-03-11 | Pharmacia & Upjohn Company | Inhibitors of protein tyrosine phosphatase |
| WO2000044335A2 (en) * | 1999-01-28 | 2000-08-03 | Microcide Pharmaceuticals, Inc. | Uridyl peptide antibiotic (upa) derivatives, their synthesis and use |
| US20060105995A1 (en) * | 2004-10-05 | 2006-05-18 | Schering Aktiengesellschaft | TAFI inhibitors and their use to treat pulmonary fibrosis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2362705A1 (en) * | 1999-03-19 | 2000-09-28 | Joseph B. Santella, Iii | N-adamant-1-yl-n'-¬4-chlorobenzothiazol-2-yl| urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent |
| US6359129B1 (en) * | 2000-08-15 | 2002-03-19 | University Of Kansas | Amino acid-derived, 7-membered cyclic sulfamides and methods of synthesizing the same |
| PL361054A1 (en) * | 2000-08-17 | 2004-09-20 | Pfizer Inc. | Substituted imidazoles as tafia inhibitors |
| DE102004020186A1 (de) * | 2004-04-22 | 2005-11-17 | Aventis Pharma Deutschland Gmbh | Heterocyclylessigsäuren als Inhibitoren von TAFla |
-
2007
- 2007-11-22 KR KR1020097011740A patent/KR20090087044A/ko not_active Abandoned
- 2007-11-22 DK DK07856207.1T patent/DK2104497T3/en active
- 2007-11-22 CA CA2671861A patent/CA2671861C/en not_active Expired - Fee Related
- 2007-11-22 SI SI200731653T patent/SI2104497T1/sl unknown
- 2007-11-22 PL PL07856207T patent/PL2104497T3/pl unknown
- 2007-11-22 EP EP07856207.1A patent/EP2104497B1/de active Active
- 2007-11-22 MX MX2009005516A patent/MX2009005516A/es active IP Right Grant
- 2007-11-22 WO PCT/EP2007/010101 patent/WO2008067909A2/de not_active Ceased
- 2007-11-22 HR HRP20150514TT patent/HRP20150514T1/hr unknown
- 2007-11-22 BR BRPI0720241-5A patent/BRPI0720241A2/pt not_active IP Right Cessation
- 2007-11-22 ES ES07856207.1T patent/ES2537093T3/es active Active
- 2007-11-22 AU AU2007327959A patent/AU2007327959B2/en not_active Ceased
- 2007-11-22 CN CN2007800435586A patent/CN101553219B/zh not_active Expired - Fee Related
- 2007-11-22 RU RU2009125534/15A patent/RU2459619C2/ru not_active IP Right Cessation
- 2007-11-22 NZ NZ577312A patent/NZ577312A/en not_active IP Right Cessation
- 2007-11-22 JP JP2009539631A patent/JP5396279B2/ja not_active Expired - Fee Related
- 2007-11-22 PT PT78562071T patent/PT2104497E/pt unknown
- 2007-12-04 PE PE2007001712A patent/PE20081349A1/es not_active Application Discontinuation
- 2007-12-04 CL CL200703494A patent/CL2007003494A1/es unknown
- 2007-12-04 TW TW096145997A patent/TWI399203B/zh not_active IP Right Cessation
- 2007-12-04 AR ARP070105408A patent/AR064119A1/es unknown
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2009
- 2009-05-04 ZA ZA2009/03040A patent/ZA200903040B/en unknown
- 2009-06-03 CO CO09057335A patent/CO6180422A2/es active IP Right Grant
- 2009-06-03 MA MA31948A patent/MA30968B1/fr unknown
- 2009-06-08 US US12/480,348 patent/US8389764B2/en not_active Expired - Fee Related
- 2009-06-10 NO NO20092246A patent/NO20092246L/no not_active Application Discontinuation
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2015
- 2015-05-15 CY CY20151100436T patent/CY1116384T1/el unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0611776A2 (de) * | 1993-02-15 | 1994-08-24 | Bayer Ag | Neue antiviral wirksame Pseudopeptide |
| EP0641779A1 (de) * | 1993-09-07 | 1995-03-08 | F. Hoffmann-La Roche Ag | Neue 1-Amidinopiperidine und 4-Amidinomorphozine als Aggregationshemmer |
| WO1999011606A2 (en) * | 1997-08-28 | 1999-03-11 | Pharmacia & Upjohn Company | Inhibitors of protein tyrosine phosphatase |
| WO2000044335A2 (en) * | 1999-01-28 | 2000-08-03 | Microcide Pharmaceuticals, Inc. | Uridyl peptide antibiotic (upa) derivatives, their synthesis and use |
| US20060105995A1 (en) * | 2004-10-05 | 2006-05-18 | Schering Aktiengesellschaft | TAFI inhibitors and their use to treat pulmonary fibrosis |
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| Pavel Majer and Pamnarayan S. Randad, A Safe and Efficient Method for Preparation of N,N'-Unsymmetrically Disubstituted Ureas Utilizing Triphosgene, Journal of Organic Chemistry, 59(7), 1937-1938, 1994 * |
| T. Shin-Watanabe et al., The Structure of beta-MAPI, a novel Proteinase Inhibitor, Tetrahedron, 38(12), 1775-1780, 1982. * |
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