ES2655540T3 - Inhibidores de factor XIa macrocíclicos condensados con heterociclos - Google Patents
Inhibidores de factor XIa macrocíclicos condensados con heterociclos Download PDFInfo
- Publication number
- ES2655540T3 ES2655540T3 ES15705427.1T ES15705427T ES2655540T3 ES 2655540 T3 ES2655540 T3 ES 2655540T3 ES 15705427 T ES15705427 T ES 15705427T ES 2655540 T3 ES2655540 T3 ES 2655540T3
- Authority
- ES
- Spain
- Prior art keywords
- independently selected
- chf2
- pharmaceutically acceptable
- alkyl
- tautomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 125000000623 heterocyclic group Chemical group 0.000 title abstract description 3
- 108010080805 Factor XIa Proteins 0.000 title description 9
- 239000003112 inhibitor Substances 0.000 title description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 77
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 76
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims abstract description 38
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims abstract description 38
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims abstract description 38
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 16
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 13
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 208000035475 disorder Diseases 0.000 claims description 10
- 230000009424 thromboembolic effect Effects 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 206010047249 Venous thrombosis Diseases 0.000 claims description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000002526 effect on cardiovascular system Effects 0.000 claims 2
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims 1
- 206010002388 Angina unstable Diseases 0.000 claims 1
- 200000000007 Arterial disease Diseases 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 206010003658 Atrial Fibrillation Diseases 0.000 claims 1
- 206010008088 Cerebral artery embolism Diseases 0.000 claims 1
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 claims 1
- 206010051055 Deep vein thrombosis Diseases 0.000 claims 1
- 206010014513 Embolism arterial Diseases 0.000 claims 1
- 206010037379 Pulmonary embolism and thrombosis Diseases 0.000 claims 1
- 206010063544 Renal embolism Diseases 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 208000032109 Transient ischaemic attack Diseases 0.000 claims 1
- 208000007814 Unstable Angina Diseases 0.000 claims 1
- 208000002528 coronary thrombosis Diseases 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000007943 implant Substances 0.000 claims 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims 1
- 201000010849 intracranial embolism Diseases 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 230000003836 peripheral circulation Effects 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 claims 1
- 201000005060 thrombophlebitis Diseases 0.000 claims 1
- 201000010875 transient cerebral ischemia Diseases 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 102000003827 Plasma Kallikrein Human genes 0.000 description 12
- 108090000113 Plasma Kallikrein Proteins 0.000 description 12
- 230000008728 vascular permeability Effects 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 4
- 206010019860 Hereditary angioedema Diseases 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 201000011190 diabetic macular edema Diseases 0.000 description 4
- 229940126155 plasma kallikrein inhibitor Drugs 0.000 description 4
- 230000002207 retinal effect Effects 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- 108010054265 Factor VIIa Proteins 0.000 description 3
- 108010074864 Factor XI Proteins 0.000 description 3
- 108010080865 Factor XII Proteins 0.000 description 3
- 102000000429 Factor XII Human genes 0.000 description 3
- 108010074860 Factor Xa Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- 108010011867 ecallantide Proteins 0.000 description 3
- 229940012414 factor viia Drugs 0.000 description 3
- VBGWSQKGUZHFPS-VGMMZINCSA-N kalbitor Chemical compound C([C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]2C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=3C=CC=CC=3)C(=O)N[C@H](C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)NCC(=O)NCC(=O)N[C@H]3CSSC[C@H](NC(=O)[C@@H]4CCCN4C(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CO)NC(=O)[C@H](CC=4NC=NC=4)NC(=O)[C@H](CCSC)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O)CSSC[C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC3=O)CSSC2)C(=O)N[C@@H]([C@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N1)[C@@H](C)CC)[C@H](C)O)=O)[C@@H](C)CC)C1=CC=CC=C1 VBGWSQKGUZHFPS-VGMMZINCSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 3
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 2
- 0 C[C@](CCC[C@@](c1nccc(-c([n](*)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(C(F)(F)F)c1)=C1)C1=O)C2=O Chemical compound C[C@](CCC[C@@](c1nccc(-c([n](*)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(C(F)(F)F)c1)=C1)C1=O)C2=O 0.000 description 2
- 102100022641 Coagulation factor IX Human genes 0.000 description 2
- 102100023804 Coagulation factor VII Human genes 0.000 description 2
- 108010076282 Factor IX Proteins 0.000 description 2
- 108010023321 Factor VII Proteins 0.000 description 2
- 108010014173 Factor X Proteins 0.000 description 2
- 108010071241 Factor XIIa Proteins 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 2
- 102100035792 Kininogen-1 Human genes 0.000 description 2
- 108010094028 Prothrombin Proteins 0.000 description 2
- 102100027378 Prothrombin Human genes 0.000 description 2
- 102100030951 Tissue factor pathway inhibitor Human genes 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
- 229940009550 c1 esterase inhibitor Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 229960001174 ecallantide Drugs 0.000 description 2
- 229960004222 factor ix Drugs 0.000 description 2
- 229940012413 factor vii Drugs 0.000 description 2
- 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 description 2
- 229940127215 low-molecular weight heparin Drugs 0.000 description 2
- 150000002678 macrocyclic compounds Chemical class 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229940039716 prothrombin Drugs 0.000 description 2
- 230000004291 retinal vascular dysfunctions Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- NLTPGIKXKMMXDT-MWTRTKDXSA-N CC[n]1ncc(NC([C@H](C)CCC[C@@H]2N(CCC(c(c(F)c(cc3)Cl)c3F)=C3)C3=O)=O)c1-c1ccnc2c1 Chemical compound CC[n]1ncc(NC([C@H](C)CCC[C@@H]2N(CCC(c(c(F)c(cc3)Cl)c3F)=C3)C3=O)=O)c1-c1ccnc2c1 NLTPGIKXKMMXDT-MWTRTKDXSA-N 0.000 description 1
- FVCOYPOFDPKGBN-VLWQZHSMSA-N C[C@H](C(CC[C@@H](c1cc(F)cc(-c([n](C)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)F)C2=O Chemical compound C[C@H](C(CC[C@@H](c1cc(F)cc(-c([n](C)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)F)C2=O FVCOYPOFDPKGBN-VLWQZHSMSA-N 0.000 description 1
- VMVNLRRSCQKIMO-NSYGIPOTSA-N C[C@H](CCC[C@@H](c1cc(-c([n](C(F)F)nc2)c2N2)ccn1)N(CCC(c1cc(Cl)ccc1-[n]1nncc1)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1cc(-c([n](C(F)F)nc2)c2N2)ccn1)N(CCC(c1cc(Cl)ccc1-[n]1nncc1)=C1)C1=O)C2=O VMVNLRRSCQKIMO-NSYGIPOTSA-N 0.000 description 1
- ZBKLUZXVHBEDBC-MWTRTKDXSA-N C[C@H](CCC[C@@H](c1cc(-c([n](C)nc2)c2N2)ccc1)N(CCC(c(c(C(F)(F)F)ccc1Cl)c1F)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1cc(-c([n](C)nc2)c2N2)ccc1)N(CCC(c(c(C(F)(F)F)ccc1Cl)c1F)=C1)C1=O)C2=O ZBKLUZXVHBEDBC-MWTRTKDXSA-N 0.000 description 1
- QFDNOTYEXPUHBR-QRQCRPRQSA-N C[C@H](CCC[C@@H](c1cc(-c([n](C)nc2)c2N2)ccn1)N(C=CC(c(c(Cl)ccc1Cl)c1F)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1cc(-c([n](C)nc2)c2N2)ccn1)N(C=CC(c(c(Cl)ccc1Cl)c1F)=C1)C1=O)C2=O QFDNOTYEXPUHBR-QRQCRPRQSA-N 0.000 description 1
- RWSFQYYBMJNULH-NSYGIPOTSA-N C[C@H](CCC[C@@H](c1cc(-c([n](C)nc2)c2N2)ccn1)N(CCC(c(c(F)c(cc1)Cl)c1-c1c[n](C(F)F)nc1)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1cc(-c([n](C)nc2)c2N2)ccn1)N(CCC(c(c(F)c(cc1)Cl)c1-c1c[n](C(F)F)nc1)=C1)C1=O)C2=O RWSFQYYBMJNULH-NSYGIPOTSA-N 0.000 description 1
- FCOJVJYCZGABTJ-NSYGIPOTSA-N C[C@H](CCC[C@@H](c1cc(-c([n](CC(F)F)nc2)c2N2)ccn1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1cc(-c([n](CC(F)F)nc2)c2N2)ccn1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O FCOJVJYCZGABTJ-NSYGIPOTSA-N 0.000 description 1
- MXMFSGMZSRWTRG-NSYGIPOTSA-N C[C@H](CCC[C@@H](c1cc(-c(c(N2)c3)n[n]3-c3cncnc3)ccn1)N(CCC(c(c(C(F)(F)F)ccc1Cl)c1F)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1cc(-c(c(N2)c3)n[n]3-c3cncnc3)ccn1)N(CCC(c(c(C(F)(F)F)ccc1Cl)c1F)=C1)C1=O)C2=O MXMFSGMZSRWTRG-NSYGIPOTSA-N 0.000 description 1
- VEDBHRXSFISFNF-CJAUYULYSA-N C[C@H](CCC[C@@H](c1cccc(-c([n](C)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1cccc(-c([n](C)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O VEDBHRXSFISFNF-CJAUYULYSA-N 0.000 description 1
- JWFUMXQPAIKABK-NSYGIPOTSA-N C[C@H](CCC[C@@H](c1nc(-c([n](C)nc2)c2N2)ccc1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1nc(-c([n](C)nc2)c2N2)ccc1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O JWFUMXQPAIKABK-NSYGIPOTSA-N 0.000 description 1
- FPBFACDWOSWVSH-OTNKZJLDSA-N C[C@H](CCC[C@@H](c1nccc(-c([n](C(C2)C2(F)F)nc2)c2N2)c1)N(CCC(c(cc(cc1)Cl)c1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1nccc(-c([n](C(C2)C2(F)F)nc2)c2N2)c1)N(CCC(c(cc(cc1)Cl)c1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O FPBFACDWOSWVSH-OTNKZJLDSA-N 0.000 description 1
- LRGILUKKMWWYGX-GYCJOSAFSA-N C[C@H](CCC[C@@H](c1nccc(-c([n](C(F)F)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1nccc(-c([n](C(F)F)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nnc(Cl)c1)=C1)C1=O)C2=O LRGILUKKMWWYGX-GYCJOSAFSA-N 0.000 description 1
- IGMIJNCZUCBTNY-GYCJOSAFSA-N C[C@H](CCC[C@@H](c1nccc(-c([n](C)nc2)c2N2)c1)N(CCC(c(c(C(C)=O)ccc1Cl)c1F)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1nccc(-c([n](C)nc2)c2N2)c1)N(CCC(c(c(C(C)=O)ccc1Cl)c1F)=C1)C1=O)C2=O IGMIJNCZUCBTNY-GYCJOSAFSA-N 0.000 description 1
- AMDIVJKIFCPDJH-OLILMLBXSA-N C[C@H](CCC[C@@H](c1nccc(-c([n](C2CCC2)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nncc1)=C1)C1=O)C2=O Chemical compound C[C@H](CCC[C@@H](c1nccc(-c([n](C2CCC2)nc2)c2N2)c1)N(CCC(c1cc(Cl)ccc1-[n]1nncc1)=C1)C1=O)C2=O AMDIVJKIFCPDJH-OLILMLBXSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001409 amidines Chemical group 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 238000013132 cardiothoracic surgery Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 229940126051 coagulation factor XIa Drugs 0.000 description 1
- 229940072645 coumadin Drugs 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003870 intestinal permeability Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229940020573 plavix Drugs 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000020964 regulation of blood coagulation Effects 0.000 description 1
- 230000004268 retinal thickening Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- WCYWZMWISLQXQU-FIBGUPNXSA-N trideuteriomethane Chemical compound [2H][C]([2H])[2H] WCYWZMWISLQXQU-FIBGUPNXSA-N 0.000 description 1
- 108010036927 trypsin-like serine protease Proteins 0.000 description 1
Classifications
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461933948P | 2014-01-31 | 2014-01-31 | |
| US201461933948P | 2014-01-31 | ||
| PCT/US2015/013647 WO2015116882A1 (en) | 2014-01-31 | 2015-01-30 | Macrocyclic factor xia inhibitors condensed with heterocycles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2655540T3 true ES2655540T3 (es) | 2018-02-20 |
Family
ID=52484569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES15705427.1T Active ES2655540T3 (es) | 2014-01-31 | 2015-01-30 | Inhibidores de factor XIa macrocíclicos condensados con heterociclos |
Country Status (24)
| Country | Link |
|---|---|
| US (3) | US20170057961A1 (enExample) |
| EP (1) | EP3099688B1 (enExample) |
| JP (1) | JP6419836B2 (enExample) |
| CN (1) | CN106459051B (enExample) |
| AR (1) | AR099228A1 (enExample) |
| BR (1) | BR112016016741B1 (enExample) |
| CA (1) | CA2937738C (enExample) |
| CY (1) | CY1120534T1 (enExample) |
| DK (1) | DK3099688T3 (enExample) |
| EA (1) | EA032650B1 (enExample) |
| ES (1) | ES2655540T3 (enExample) |
| HR (1) | HRP20172002T1 (enExample) |
| HU (1) | HUE038060T2 (enExample) |
| LT (1) | LT3099688T (enExample) |
| MX (1) | MX2016009385A (enExample) |
| NO (1) | NO2760821T3 (enExample) |
| PL (1) | PL3099688T3 (enExample) |
| PT (1) | PT3099688T (enExample) |
| RS (1) | RS56785B1 (enExample) |
| SI (1) | SI3099688T1 (enExample) |
| SM (1) | SMT201800024T1 (enExample) |
| TW (1) | TWI703144B (enExample) |
| UY (1) | UY35972A (enExample) |
| WO (1) | WO2015116882A1 (enExample) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2766346B1 (en) | 2011-10-14 | 2017-03-29 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| JP6479763B2 (ja) | 2013-03-25 | 2019-03-06 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 第ｘｉａ因子阻害剤としての置換アゾール含有のテトラヒドロイソキノリン |
| NO2760821T3 (enExample) | 2014-01-31 | 2018-03-10 | ||
| PE20210470A1 (es) | 2014-01-31 | 2021-03-08 | Bristol Myers Squibb Co | Macrociclos con grupos p2' heterociclicos como inhibidores del factor xia |
| CN107074821B (zh) | 2014-09-04 | 2020-05-22 | 百时美施贵宝公司 | 为fxia抑制剂的二酰胺大环化合物 |
| US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
| NO2721243T3 (enExample) * | 2014-10-01 | 2018-10-20 | ||
| JP6742348B2 (ja) | 2015-06-19 | 2020-08-19 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 第ｘｉａ因子阻害剤としてのジアミド大員環 |
| CN114805365B (zh) | 2015-07-29 | 2024-07-23 | 百时美施贵宝公司 | 携带非芳族p2′基团的因子xia新大环 |
| KR102086934B1 (ko) | 2015-07-29 | 2020-03-09 | 브리스톨-마이어스 스큅 컴퍼니 | 알킬 또는 시클로알킬 P2' 모이어티를 갖는 인자 XIa 마크로시클릭 억제제 |
| EP3371162B1 (en) | 2015-10-29 | 2022-01-26 | Merck Sharp & Dohme Corp. | Macrocyclic spirocarbamate derivatives as factor xia inhibitors, pharmaceutically acceptable compositions and their use |
| CA2998902C (en) * | 2015-10-29 | 2024-03-26 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as factor xia inhibitors |
| WO2017151746A1 (en) | 2016-03-02 | 2017-09-08 | Bristol-Myers Squibb Company | Diamide macrocycles having factor xia inhibiting activity |
| US10143681B2 (en) | 2016-08-22 | 2018-12-04 | Merck Sharp & Dohme Corp. | Factor XIa inhibitors |
| WO2018095953A1 (de) | 2016-11-23 | 2018-05-31 | Bayer Cropscience Aktiengesellschaft | 2-[3-(alkylsulfonyl)-2h-indazol-2-yl]-3h-imidazo[4,5-b]pyridin-derivate und ähnliche verbindungen als schädlingsbekämpfungsmittel |
| KR102515694B1 (ko) | 2017-01-10 | 2023-03-29 | 바이엘 악티엔게젤샤프트 | 해충 방제제로서의 헤테로사이클 유도체 |
| JP7098630B2 (ja) | 2017-01-10 | 2022-07-11 | バイエル・アクチエンゲゼルシヤフト | 有害生物防除剤としてのヘテロサイクレン誘導体 |
| CN110062757B (zh) * | 2017-01-18 | 2022-03-04 | 广东东阳光药业有限公司 | 凝血因子XIa抑制剂及其用途 |
| CN110922412A (zh) * | 2018-09-20 | 2020-03-27 | 复旦大学 | 具有抗精神病作用药物化合物的不对称合成方法 |
| CN113677682B (zh) * | 2019-04-16 | 2023-05-30 | 华润生物医药有限公司 | 作为XIa因子抑制剂的大环衍生物 |
| WO2021007354A1 (en) * | 2019-07-08 | 2021-01-14 | Gary Sharp Innovations, Llc | Compact polarization-based collimators with high contrast |
| JP7286001B2 (ja) * | 2019-07-23 | 2023-06-02 | メッドシャイン ディスカバリー インコーポレイテッド | 第ＸＩａ因子阻害剤としての大環状誘導体 |
| TW202229280A (zh) * | 2020-10-12 | 2022-08-01 | 美商必治妥美雅史谷比公司 | （６ｒ，１０ｓ）－１０－｛４－［５－氯－２－（４－氯－１ｈ－１，２，３－三唑－１－基）苯基］－６－側氧基－１（６ｈ）－嘧啶基｝－１－（二氟甲基）－６－甲基－１，４，７，８，９，１０－六氫－１１，１５－（亞甲橋基）吡唑并［４，３－ｂ］［１，７］二氮雜環十四炔－５（６ｈ）－酮之製備方法 |
| WO2022222960A1 (zh) * | 2021-04-21 | 2022-10-27 | 上海美悦生物科技发展有限公司 | FXIa抑制剂及其药物组合物、制备方法和用途 |
| TW202515882A (zh) * | 2023-06-30 | 2025-04-16 | 大陸商深圳信立泰藥業股份有限公司 | 一種多取代的大環化合物及其製備方法與應用 |
Family Cites Families (107)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1525186A (fr) | 1967-03-29 | 1968-05-17 | Roussel Uclaf | Nouvelles pénicillines et procédé de préparation |
| EP0028489B1 (en) | 1979-11-05 | 1983-10-05 | Beecham Group Plc | Enzyme derivatives, and their preparation |
| DE4034829A1 (de) | 1990-11-02 | 1992-05-07 | Merck Patent Gmbh | Cyclopeptide |
| JP3190431B2 (ja) | 1991-07-01 | 2001-07-23 | 三菱化学株式会社 | ケトン誘導体 |
| GB9206757D0 (en) | 1992-03-27 | 1992-05-13 | Ferring Bv | Novel peptide receptor ligands |
| WO1996034010A2 (en) | 1995-03-29 | 1996-10-31 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US5624936A (en) | 1995-03-29 | 1997-04-29 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US5869682A (en) | 1996-04-03 | 1999-02-09 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| JP2000507597A (ja) | 1996-04-03 | 2000-06-20 | メルク エンド カンパニー インコーポレーテッド | ファルネシルタンパク質トランスフェラーゼ阻害剤 |
| PE121699A1 (es) | 1997-02-18 | 1999-12-08 | Boehringer Ingelheim Pharma | Heterociclos biciclicos disustituidos como inhibidores de la trombina |
| ZA985247B (en) | 1997-06-19 | 1999-12-17 | Du Pont Merck Pharma | Guanidine mimics as factor Xa inhibitors. |
| TW557297B (en) | 1997-09-26 | 2003-10-11 | Abbott Lab | Rapamycin analogs having immunomodulatory activity, and pharmaceutical compositions containing same |
| CN1321129C (zh) | 1998-03-19 | 2007-06-13 | 沃泰克斯药物股份有限公司 | 卡斯帕酶抑制剂 |
| IL139599A0 (en) | 1998-05-26 | 2002-02-10 | Warner Lambert Co | Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation |
| US6307049B1 (en) | 1998-09-30 | 2001-10-23 | The Procter & Gamble Co. | Heterocyclic 2-substituted ketoamides |
| WO2000040571A1 (en) | 1999-01-02 | 2000-07-13 | Aventis Pharma Deutschland Gmbh | Novel malonic acid derivatives, processes for their preparation, their use and pharmaceutical compositions containing them (inhibition of factor xa activity) |
| EP1016663A1 (en) | 1999-01-02 | 2000-07-05 | Aventis Pharma Deutschland GmbH | Novel malonic acid derivatives, processes for their preparation, their use and pharmaceutical compositions containing them (inhibition of factor Xa activity) |
| SK14232001A3 (sk) | 1999-04-09 | 2002-06-04 | Basf Aktiengesellschaft | Nízkomolekulové inhibítory komplementárnych proteáz |
| WO2000076970A2 (en) | 1999-06-14 | 2000-12-21 | Eli Lilly And Company | Serine protease inhibitors |
| DE19962924A1 (de) | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
| EP1125925A1 (en) | 2000-02-15 | 2001-08-22 | Applied Research Systems ARS Holding N.V. | Amine derivatives for the treatment of apoptosis |
| ATE310728T1 (de) | 2000-05-11 | 2005-12-15 | Bristol Myers Squibb Co | Tetrahydroisochinolin-analoga als wachstumshormon-sekretagoga |
| SV2003000617A (es) | 2000-08-31 | 2003-01-13 | Lilly Co Eli | Inhibidores de la proteasa peptidomimetica ref. x-14912m |
| AR035216A1 (es) | 2000-12-01 | 2004-05-05 | Astrazeneca Ab | Derivados de acido mandelico ,derivados farmaceuticamente aceptables, uso de estos derivados para la fabricacion de medicamentos, metodos de tratamiento ,procesos para la preparacion de estos derivados, y compuestos intermediarios |
| AU2002322802A1 (en) | 2001-07-27 | 2003-02-17 | Merck And Co., Inc. | Thrombin inhibitors |
| US6951840B2 (en) | 2001-08-31 | 2005-10-04 | Eli Lilly And Company | Lipoglycopeptide antibiotics |
| KR100909141B1 (ko) | 2001-09-21 | 2009-07-23 | 브리스톨-마이어스스퀴브컴파니 | 인자 Ｘａ 억제제로서의 락탐-함유 화합물 및 그의 유도체 |
| WO2003041641A2 (en) | 2001-11-09 | 2003-05-22 | Bristol-Myers Squibb Company | Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity |
| WO2003106438A1 (en) | 2002-06-18 | 2003-12-24 | The Scripps Research Institute | Synthesis of diazonamide "a" core |
| US20040180855A1 (en) | 2003-02-19 | 2004-09-16 | Schumacher William A. | Methods of treating thrombosis with reduced risk of increased bleeding times |
| US7138412B2 (en) | 2003-03-11 | 2006-11-21 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives useful as serine protease inhibitors |
| US7129264B2 (en) | 2003-04-16 | 2006-10-31 | Bristol-Myers Squibb Company | Biarylmethyl indolines and indoles as antithromboembolic agents |
| JP2007501844A (ja) | 2003-08-08 | 2007-02-01 | トランス テック ファーマ，インコーポレイテッド | アリール及びヘテロアリール化合物、組成物並びに使用方法 |
| US7417063B2 (en) | 2004-04-13 | 2008-08-26 | Bristol-Myers Squibb Company | Bicyclic heterocycles useful as serine protease inhibitors |
| US7429604B2 (en) | 2004-06-15 | 2008-09-30 | Bristol Myers Squibb Company | Six-membered heterocycles useful as serine protease inhibitors |
| US7453002B2 (en) | 2004-06-15 | 2008-11-18 | Bristol-Myers Squibb Company | Five-membered heterocycles useful as serine protease inhibitors |
| WO2006017295A2 (en) | 2004-07-12 | 2006-02-16 | Idun Pharmaceuticals, Inc. | Tetrapeptide analogs |
| US7459564B2 (en) | 2005-01-13 | 2008-12-02 | Bristol-Myers Squibb Company | Substituted biaryl compounds as factor XIa inhibitors |
| US20060183771A1 (en) | 2005-02-17 | 2006-08-17 | Seiffert Dietmar A | Novel combination of selective factor VIIa and/or factor XIa inhibitors and selective plasma kallikrein inhibitors |
| US20070111947A1 (en) | 2005-10-14 | 2007-05-17 | Mcmurry Thomas J | Fibrin targeted therapeutics |
| JP4955009B2 (ja) | 2005-11-11 | 2012-06-20 | エフ．ホフマン−ラ ロシュ アーゲー | 凝固因子Ｘａの阻害剤としての炭素環式縮合環アミン |
| WO2007070816A2 (en) | 2005-12-14 | 2007-06-21 | Bristol-Myers Squibb Company | Thiophene derivatives as factor xia inhibitors |
| AU2006325754B2 (en) | 2005-12-14 | 2012-04-12 | Bristol-Myers Squibb Company | Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIa inhibitors |
| KR20080080173A (ko) | 2005-12-14 | 2008-09-02 | 브리스톨-마이어스 스큅 컴퍼니 | 세린 프로테아제 억제제로서 유용한 6-원 헤테로사이클 |
| PE20071132A1 (es) | 2005-12-23 | 2007-12-14 | Bristol Myers Squibb Co | Compuestos macrociclicos como inhibidores del factor viia |
| ES2546815T3 (es) | 2006-12-15 | 2015-09-28 | Bristol-Myers Squibb Company | Análogos de arilpropilamida, arilacrilamida, arilpropinamida o arilmetilurea como inhibidores del factor XIa |
| PE20081775A1 (es) | 2006-12-20 | 2008-12-18 | Bristol Myers Squibb Co | Compuestos macrociclicos como inhibidores del factor viia |
| CL2008001724A1 (es) | 2007-06-13 | 2008-08-08 | Bristol Myers Squibb Co | Compuestos derivados de analogos dipeptidos, inhibidores del factor de coagulacion; composicion farmaceutica que comprende a dicho compuesto; y uso del compuesto para el tratamiento de un trastorno tromboembolico, infarto de miocardio, trombosis, ate |
| CN102026996B (zh) | 2008-03-13 | 2015-01-07 | 百时美施贵宝公司 | 作为凝血因子xia抑制剂的哒嗪衍生物 |
| US8624040B2 (en) | 2009-06-22 | 2014-01-07 | Millennium Pharmaceuticals, Inc. | Substituted hydroxamic acids and uses thereof |
| WO2011002520A2 (en) | 2009-07-02 | 2011-01-06 | Angion Biomedica Corp. | Small molecule inhibitors of parp activity |
| AR077695A1 (es) | 2009-08-04 | 2011-09-14 | Schering Corp | Derivados de pirimidina como inhibidores del factor ixa |
| TWI520965B (zh) * | 2010-02-11 | 2016-02-11 | 必治妥美雅史谷比公司 | 作為因子ｘｉａ抑制劑之巨環類 |
| US9161924B2 (en) | 2011-07-08 | 2015-10-20 | Merck Sharp & Dohme Corp. | Factor IXa inhibitors |
| TW201311689A (zh) | 2011-08-05 | 2013-03-16 | 必治妥美雅史谷比公司 | 作為因子ｘｉａ抑制劑之新穎巨環化合物 |
| TW201319068A (zh) * | 2011-08-05 | 2013-05-16 | 必治妥美雅史谷比公司 | 作為ｘｉａ因子抑制劑之環狀ｐ１接合劑 |
| EP2766345B1 (en) | 2011-10-14 | 2016-03-16 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| EP2766347B1 (en) | 2011-10-14 | 2016-05-04 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| EP2766346B1 (en) | 2011-10-14 | 2017-03-29 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| GB2497806A (en) | 2011-12-21 | 2013-06-26 | Ono Pharmaceutical Co | Pyridinone and pyrimidinone derivatives as factor XIa inhibitors |
| ES2765891T3 (es) | 2011-12-21 | 2020-06-11 | Ono Pharmaceutical Co | Derivados de piridinona y pirimidinona como inhibidores del factor XIa |
| US20140350034A1 (en) | 2012-01-27 | 2014-11-27 | Novartis Ag | Aminopyridine derivatives as plasma kallikrein inhibitors |
| US20140378474A1 (en) | 2012-01-27 | 2014-12-25 | Novartis Ag | 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors |
| JP2015083542A (ja) | 2012-02-08 | 2015-04-30 | 大日本住友製薬株式会社 | ３位置換プロリン誘導体 |
| LT2847228T (lt) | 2012-05-10 | 2018-11-12 | Bayer Pharma Aktiengesellschaft | Antikūnai, galintys jungtis prie koaguliacijos faktoriaus xi ir (arba) jo aktyvuotos formos faktoriaus xia, ir jų panaudojimas |
| GB201209138D0 (en) | 2012-05-24 | 2012-07-04 | Ono Pharmaceutical Co | Compounds |
| CA2881566A1 (en) | 2012-07-19 | 2014-01-23 | Yohei Ikuma | 1-(cycloalkyl-carbonyl)proline derivative |
| HRP20170506T1 (hr) * | 2012-08-03 | 2017-06-02 | Bristol-Myers Squibb Company | Dihidropiridon p1 kao inhibitori xia faktora |
| JP6082462B2 (ja) * | 2012-08-03 | 2017-02-15 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 第ｘｉａ因子阻害剤としてのジヒドロピリドンｐ１ |
| US9315519B2 (en) | 2012-10-12 | 2016-04-19 | Bristol-Myers Squibb Company | Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors |
| WO2014059214A1 (en) | 2012-10-12 | 2014-04-17 | Bristol-Myers Squibb Company | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| TR201807316T4 (tr) | 2012-10-12 | 2018-06-21 | Bristol Myers Squibb Co | Bir faktör XIa inhibitörünün kristalli formları. |
| EP2934538B1 (en) | 2012-12-19 | 2021-03-31 | Merck Sharp & Dohme Corp. | Factor ixa inhibitors |
| GB201300304D0 (en) | 2013-01-08 | 2013-02-20 | Kalvista Pharmaceuticals Ltd | Benzylamine derivatives |
| GB2510407A (en) | 2013-02-04 | 2014-08-06 | Kalvista Pharmaceuticals Ltd | Aqueous suspensions of kallikrein inhibitors for parenteral administration |
| JP6479763B2 (ja) | 2013-03-25 | 2019-03-06 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 第ｘｉａ因子阻害剤としての置換アゾール含有のテトラヒドロイソキノリン |
| TWI633089B (zh) | 2013-03-28 | 2018-08-21 | 拜耳製藥股份有限公司 | 經取代的酮基吡啶衍生物 |
| WO2015011087A1 (de) | 2013-07-23 | 2015-01-29 | Bayer Pharma Aktiengesellschaft | Substituierte oxopyridin-derivate und ihre verwendung als faktor xia / plasma |
| WO2015044170A1 (de) | 2013-09-26 | 2015-04-02 | Bayer Pharma Aktiengesellschaft | Substituierte phenylalanin-derivate und ihre verwendung zur behandlung von thrombotischen / thromboembolischen erkrankungen |
| EP3049404A1 (de) | 2013-09-26 | 2016-08-03 | Bayer Pharma Aktiengesellschaft | Substituierte phenylalanin-derivate |
| MX2016003588A (es) | 2013-09-26 | 2016-06-02 | Bayer Pharma AG | Derivados de fenilalanina sustituidos. |
| US20160237067A1 (en) | 2013-09-26 | 2016-08-18 | Bayer Pharma Aktiengesellschaft | Substituted phenylalanine derivatives |
| EP3049394A1 (de) | 2013-09-26 | 2016-08-03 | Bayer Pharma Aktiengesellschaft | Substituierte phenylalanin-derivate als faktor xia modulatoren |
| WO2015044172A1 (de) | 2013-09-26 | 2015-04-02 | Bayer Pharma Aktiengesellschaft | Substituierte phenylalanin-derivate |
| EP3049410A1 (de) | 2013-09-26 | 2016-08-03 | Bayer Pharma Aktiengesellschaft | Substituierte phenylalanin-derivate als faktor xia modulatoren |
| UY35747A (es) | 2013-09-26 | 2015-04-30 | Bayer Pharma AG | Derivados sustituidos de fenilalanina |
| WO2015047973A1 (en) | 2013-09-27 | 2015-04-02 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
| US20160257668A1 (en) | 2013-10-07 | 2016-09-08 | Merck Sharp & Dohme Corp. | Factor XIa Inhibitors |
| JP6337750B2 (ja) | 2013-11-22 | 2018-06-06 | 小野薬品工業株式会社 | 化合物 |
| CN106103453A (zh) | 2014-01-14 | 2016-11-09 | 大日本住友制药株式会社 | 缩合5‑噁唑烷酮衍生物 |
| PE20210470A1 (es) | 2014-01-31 | 2021-03-08 | Bristol Myers Squibb Co | Macrociclos con grupos p2' heterociclicos como inhibidores del factor xia |
| NO2760821T3 (enExample) | 2014-01-31 | 2018-03-10 | ||
| BR112016018062B1 (pt) | 2014-02-07 | 2022-11-16 | Exithera Pharmaceuticals Inc | Compostos terapêuticos, composição farmacêutica e usos |
| EP3104702B1 (en) | 2014-02-11 | 2022-08-10 | Merck Sharp & Dohme LLC | Factor xia inhibitors |
| EP3104701B1 (en) | 2014-02-11 | 2019-01-30 | Merck Sharp & Dohme Corp. | Factor xia inhibitors |
| EP3104703B1 (en) | 2014-02-11 | 2020-11-18 | Merck Sharp & Dohme Corp. | Factor xia inhibitors |
| WO2015120777A1 (zh) | 2014-02-14 | 2015-08-20 | 四川海思科制药有限公司 | 一种吡啶酮或嘧啶酮衍生物、及其制备方法和应用 |
| EP4663636A2 (en) | 2014-03-07 | 2025-12-17 | BioCryst Pharmaceuticals, Inc. | Trifluoromethyl substituted pyrazoles as human plasma kallikrein inhibitors |
| EP3131897B8 (en) | 2014-04-16 | 2022-08-03 | Merck Sharp & Dohme LLC | Factor ixa inhibitors |
| WO2015160634A1 (en) | 2014-04-16 | 2015-10-22 | Merck Sharp & Dohme Corp. | Factor ixa inhibitors |
| KR20150136294A (ko) | 2014-05-27 | 2015-12-07 | 주식회사 레고켐 바이오사이언스 | 인자 ＸＩａ 억제 활성을 가지는 신규한 화합물 |
| RU2016150410A (ru) | 2014-05-28 | 2018-06-28 | Мерк Шарп И Доум Корп. | Ингибиторы фактора xia |
| EP3197891B1 (de) | 2014-09-24 | 2018-11-21 | Bayer Pharma Aktiengesellschaft | Faktor xia hemmende pyridobenzazepin- und pyridobenzazocin-derivate |
| NO2721243T3 (enExample) | 2014-10-01 | 2018-10-20 | ||
| US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
| MX385021B (es) | 2014-12-10 | 2025-03-14 | Ono Pharmaceutical Co | Derivado de dihidroindolizinona. |
| JP6742348B2 (ja) | 2015-06-19 | 2020-08-19 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 第ｘｉａ因子阻害剤としてのジアミド大員環 |
-
2012
- 2012-08-31 NO NO12780535A patent/NO2760821T3/no unknown
-
2015
- 2015-01-30 SI SI201530121T patent/SI3099688T1/sl unknown
- 2015-01-30 ES ES15705427.1T patent/ES2655540T3/es active Active
- 2015-01-30 HR HRP20172002TT patent/HRP20172002T1/hr unknown
- 2015-01-30 CN CN201580017759.3A patent/CN106459051B/zh active Active
- 2015-01-30 DK DK15705427.1T patent/DK3099688T3/en active
- 2015-01-30 AR ARP150100295A patent/AR099228A1/es unknown
- 2015-01-30 CA CA2937738A patent/CA2937738C/en active Active
- 2015-01-30 PL PL15705427T patent/PL3099688T3/pl unknown
- 2015-01-30 TW TW104103315A patent/TWI703144B/zh active
- 2015-01-30 HU HUE15705427A patent/HUE038060T2/hu unknown
- 2015-01-30 UY UY0001035972A patent/UY35972A/es active IP Right Grant
- 2015-01-30 RS RS20180033A patent/RS56785B1/sr unknown
- 2015-01-30 LT LTEP15705427.1T patent/LT3099688T/lt unknown
- 2015-01-30 PT PT157054271T patent/PT3099688T/pt unknown
- 2015-01-30 EA EA201691561A patent/EA032650B1/ru not_active IP Right Cessation
- 2015-01-30 SM SM20180024T patent/SMT201800024T1/it unknown
- 2015-01-30 BR BR112016016741-4A patent/BR112016016741B1/pt active IP Right Grant
- 2015-01-30 WO PCT/US2015/013647 patent/WO2015116882A1/en not_active Ceased
- 2015-01-30 EP EP15705427.1A patent/EP3099688B1/en active Active
- 2015-01-30 JP JP2016549270A patent/JP6419836B2/ja active Active
- 2015-01-30 MX MX2016009385A patent/MX2016009385A/es active IP Right Grant
- 2015-01-30 US US15/115,319 patent/US20170057961A1/en not_active Abandoned
-
2017
- 2017-08-18 US US15/680,729 patent/US20170342071A1/en not_active Abandoned
- 2017-12-29 CY CY20171101357T patent/CY1120534T1/el unknown
-
2018
- 2018-04-06 US US15/946,837 patent/US10273236B2/en active Active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2655540T3 (es) | Inhibidores de factor XIa macrocíclicos condensados con heterociclos | |
| ES2687498T3 (es) | Macrociclos con grupos P2¿ heterocíclicos como inhibidores del factor XIa | |
| ES2659045T3 (es) | Derivados de oxopiridina sustituidos | |
| CA2683793C (en) | Combination anticoagulant therapy with a compound that acts as a factor xa inhibitor | |
| US20250051303A1 (en) | Substituted oxopyridine derivatives for the treatment and/or prophylaxis of thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications | |
| ES2713624T3 (es) | Derivados de oxopiridina sustituidos | |
| ES2694189T3 (es) | Derivados de oxopiridina sustituidos | |
| US10077265B2 (en) | Substituted oxopyridine derivatives | |
| KR20210087467A (ko) | 치료 화합물 및 조성물 | |
| ES2716417T3 (es) | Derivados de oxopiridina sustituidos con acción antiinflamatoria y antitrombótica | |
| RU2125450C1 (ru) | Применение 2-фенил-3-ароилбензотиофенов для увеличения экспрессии тромбомодулина | |
| JP2008528527A (ja) | 血栓塞栓性疾患の予防および処置 | |
| ZA200404147B (en) | Pyrrolidine-2-ones as factor Xa inhibitors. | |
| WO2015044173A1 (de) | Substituierte phenylalanin-derivate als faktor xia modulatoren | |
| HK1247615A1 (zh) | 作为治疗血栓形成的因子xia抑制剂的氧代吡啶衍生物 | |
| Furugohri et al. | Paradoxical enhancement of the intrinsic pathway-induced thrombin generation in human plasma by melagatran, a direct thrombin inhibitor, but not edoxaban, a direct factor Xa inhibitor, or heparin | |
| CN104098647A (zh) | 阿加曲班类似物及其制备方法和医药用途 | |
| CN116730980A (zh) | 一种化合物及其立体异构体、或其药学上可接受盐与用途 | |
| KR20230084183A (ko) | 치료 화합물, 조성물, 및 그것의 사용 방법 | |
| CN116782911A (zh) | 治疗性化合物、组合物及其使用方法 | |
| NZ733574B2 (en) | Dihydroindolizinone derivative | |
| HK1227852A1 (en) | Substituted oxopyridine derivatives | |
| TW200845971A (en) | Novel heteroaryl carboxamides | |
| HK1237777A1 (en) | Substituted oxopyridine derivatives |