TW200948366A - Chlorothiophene-amides as inhibitors of coagulation factors Xa and thrombin - Google Patents

Info

Publication number

TW200948366A

TW200948366A TW098105198A TW98105198A TW200948366A TW 200948366 A TW200948366 A TW 200948366A TW 098105198 A TW098105198 A TW 098105198A TW 98105198 A TW98105198 A TW 98105198A TW 200948366 A TW200948366 A TW 200948366A

Authority

TW

Taiwan

Prior art keywords

alkyl

group

base

independently

unsubstituted

Prior art date

2008-02-21

Links

• Espacenet
• Global Dossier
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• 108090000190 Thrombin Proteins 0.000 title abstract description 27
• 229960004072 thrombin Drugs 0.000 title abstract description 27
• 239000003112 inhibitor Substances 0.000 title abstract description 6
• PUKKVMZZENXNSR-UHFFFAOYSA-N 3-chlorothiophene-2-carboxamide Chemical class NC(=O)C=1SC=CC=1Cl PUKKVMZZENXNSR-UHFFFAOYSA-N 0.000 title 1
• 108010039209 Blood Coagulation Factors Proteins 0.000 title 1
• 102000015081 Blood Coagulation Factors Human genes 0.000 title 1
• 239000003114 blood coagulation factor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 143
• 238000000034 method Methods 0.000 claims abstract description 91
• 230000002265 prevention Effects 0.000 claims abstract description 10
• 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 4
• 208000001435 Thromboembolism Diseases 0.000 claims abstract description 4
• 238000002560 therapeutic procedure Methods 0.000 claims abstract description 3
• -1 azaspiroalkyl Chemical group 0.000 claims description 232
• 125000000623 heterocyclic group Chemical group 0.000 claims description 128
• 125000000217 alkyl group Chemical group 0.000 claims description 119
• 125000003118 aryl group Chemical group 0.000 claims description 97
• 229910052736 halogen Inorganic materials 0.000 claims description 92
• 239000000203 mixture Substances 0.000 claims description 90
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 83
• 150000002367 halogens Chemical group 0.000 claims description 69
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 67
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 56
• 150000003839 salts Chemical class 0.000 claims description 50
• 239000007789 gas Substances 0.000 claims description 47
• 229910052757 nitrogen Inorganic materials 0.000 claims description 46
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 42
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 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 37
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 36
• 229910052740 iodine Inorganic materials 0.000 claims description 34
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
• 238000003971 tillage Methods 0.000 claims description 34
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 29
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
• 125000005843 halogen group Chemical group 0.000 claims description 28
• 229930192474 thiophene Natural products 0.000 claims description 28
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 26
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
• 229910052760 oxygen Inorganic materials 0.000 claims description 21
• 239000001301 oxygen Substances 0.000 claims description 21
• YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 21
• 125000001544 thienyl group Chemical group 0.000 claims description 21
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 20
• 206010036790 Productive cough Diseases 0.000 claims description 19
• 210000003802 sputum Anatomy 0.000 claims description 19
• 208000024794 sputum Diseases 0.000 claims description 19
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 18
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 18
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 17
• 125000002947 alkylene group Chemical group 0.000 claims description 16
• BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 16
• 229910052717 sulfur Inorganic materials 0.000 claims description 16
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
• 150000002576 ketones Chemical class 0.000 claims description 15
• XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 claims description 15
• RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 15
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 14
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
• 125000006239 protecting group Chemical group 0.000 claims description 14
• 210000003296 saliva Anatomy 0.000 claims description 14
• 239000011593 sulfur Substances 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
• 125000003277 amino group Chemical group 0.000 claims description 12
• 230000015271 coagulation Effects 0.000 claims description 12
• 238000005345 coagulation Methods 0.000 claims description 12
• 125000001624 naphthyl group Chemical group 0.000 claims description 12
• JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 claims description 11
• 239000001257 hydrogen Substances 0.000 claims description 11
• 229910052739 hydrogen Inorganic materials 0.000 claims description 11
• 239000011734 sodium Substances 0.000 claims description 11
• 229910052708 sodium Inorganic materials 0.000 claims description 11
• 239000000126 substance Substances 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 10
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 10
• 210000004369 blood Anatomy 0.000 claims description 10
• 239000008280 blood Substances 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
• 150000004141 diterpene derivatives Chemical class 0.000 claims description 10
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 10
• NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 9
• 208000007536 Thrombosis Diseases 0.000 claims description 9
• 239000003146 anticoagulant agent Substances 0.000 claims description 9
• 239000004305 biphenyl Substances 0.000 claims description 9
• 235000010290 biphenyl Nutrition 0.000 claims description 9
• 125000006612 decyloxy group Chemical group 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 9
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• 208000037803 restenosis Diseases 0.000 claims description 9
• 230000002792 vascular Effects 0.000 claims description 9
• 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 8
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
• DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 claims description 8
• 125000002393 azetidinyl group Chemical group 0.000 claims description 8
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 201000010099 disease Diseases 0.000 claims description 8
• 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims description 8
• 125000002950 monocyclic group Chemical group 0.000 claims description 8
• 229960005181 morphine Drugs 0.000 claims description 8
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
• 125000005888 tetrahydroindolyl group Chemical group 0.000 claims description 8
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
• VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 7
• 229910008338 Si—(CH3) Inorganic materials 0.000 claims description 7
• 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 7
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 7
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 7
• 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 7
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 7
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
• 125000002757 morpholinyl group Chemical group 0.000 claims description 7
• 150000002923 oximes Chemical class 0.000 claims description 7
• 125000003386 piperidinyl group Chemical group 0.000 claims description 7
• 150000004032 porphyrins Chemical class 0.000 claims description 7
• 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 7
• 238000001356 surgical procedure Methods 0.000 claims description 7
• 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 6
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 6
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 6
• WXLCDTBTIVJDCE-UHFFFAOYSA-N 1,4-oxazepine Chemical compound O1C=CC=NC=C1 WXLCDTBTIVJDCE-UHFFFAOYSA-N 0.000 claims description 6
• UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 6
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
• 125000005602 azabenzimidazolyl group Chemical group 0.000 claims description 6
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
• 229930004069 diterpene Natural products 0.000 claims description 6
• 239000011737 fluorine Substances 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
• 229940124530 sulfonamide Drugs 0.000 claims description 6
• 125000000335 thiazolyl group Chemical group 0.000 claims description 6
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 6
• 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 5
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 5
• 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 5
• 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 claims description 5
• LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims description 5
• 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 5
• QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 5
• 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 5
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
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• UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 5
• 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 5
• 125000005605 benzo group Chemical group 0.000 claims description 5
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• 229910052797 bismuth Inorganic materials 0.000 claims description 5
• JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 5
• 239000000460 chlorine Substances 0.000 claims description 5
• 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 5
• 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 5
• 125000000468 ketone group Chemical group 0.000 claims description 5
• OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 5
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• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
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• FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 4
• RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims description 4
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• WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 4
• 240000007594 Oryza sativa Species 0.000 claims description 4
• 235000007164 Oryza sativa Nutrition 0.000 claims description 4
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• 125000003725 azepanyl group Chemical group 0.000 claims description 4
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• 125000004432 carbon atom Chemical group C* 0.000 claims description 4
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• 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 claims description 4
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• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
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• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
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